UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Asymmetric synthesis in solid state photochemistry Leibovitch, Mordechai 1997

Your browser doesn't seem to have a PDF viewer, please download the PDF to view this item.

Item Metadata

Download

Media
831-ubc_1997-250903.pdf [ 12.71MB ]
Metadata
JSON: 831-1.0059541.json
JSON-LD: 831-1.0059541-ld.json
RDF/XML (Pretty): 831-1.0059541-rdf.xml
RDF/JSON: 831-1.0059541-rdf.json
Turtle: 831-1.0059541-turtle.txt
N-Triples: 831-1.0059541-rdf-ntriples.txt
Original Record: 831-1.0059541-source.json
Full Text
831-1.0059541-fulltext.txt
Citation
831-1.0059541.ris

Full Text

A S Y M M E T R I C SYNTHESIS IN SOLID S T A T E P H O T O C H E M I S T R Y by M O R D E C H A I L E B B O V I T C H B.Sc, University of Toronto, Canada, 1989 M.Sc, University of Toronto, Canada, 1991 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (DEPARTMENT OF CHEMISTRY) We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA JUNE 1997 © Mordechai Leibovitch, 1997 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of The University of British Columbia Vancouver, Canada 7 DE-6 (2/88) ABSTRACT The Norrish/Yang type II photochemistry of sixteen ketones has been studied in the crystalline state as well as in solution. In both media, the ketones, for the most part, undergo stereoselective cyclobutanol formation in which the c/s-stereochernistry is produced exclusively. The reactive y-hydrogen atoms are identified and the distance and angular parameters associated with their abstractions are derived from crystallographic data. Four of the sixteen ketones were found to be photochemically inert as a result of their 1,4-biradical intermediates being poorly aligned for cleavage and also as a result of an excessive distance between the radical centres. The chiral ionic auxiliary concept was shown to be useful for inducing asymmetric induction in solid state photochemistry. Chiral crystals from prochiral carboxyJic acids and optically pure amines were made (seventeen in total), and solid state photolyses of these salts afforded cyclobutanol photoproducts in optically active form (10% to 100% ee). Solid state stmcture-reactivity relationships are discussed based on X-ray crystal structures of the starting chiral salts. Due to the ionic character of the salts described above, they tend to have strong lattice forces and relatively high melting points. These "natural" two-component crystalline materials proved to be more robust than purely molecular crystals and survived photolysis to higher conversions without loss of topochemical control. In this thesis, we ii report the first example of a topotactic, enantioselective solid state photorearrangement that involves an ionic chiral auxiliary of known absolute configuration, so that X-ray diffraction studies allowed mapping of the absolute steric course of the photochemical reaction. This was accomplished by obtaining an X-ray crystal structure of the same single crystal at the beginning, midpoint and final stages of reaction. The results of asymmetric induction studies of the Norrish type II photoreaction conducted within zeolites are also presented in this thesis. The results show that zeolites, when modified with chiral inductors, yield photoproducts with low to moderate enantiomeric excess. iii TABLE OF CONTENTS Abstract ii Table of Contents • • • iv List of Figures viii List of Tables xv Acknowledgements xx Dedication xxi INTRODUCTION Chapter 1 Introduction 1 1.1. General Considerations 2 1.2. Crystal Lattice Effects in Solid State Chemistry 4 1.3. Electronic Aspects of Organic Photochemistry 12 1.4. Photochemistry of Ketones 18 1.5. Geometric Concerns for Intramolecular Hydrogen Atom Abstraction 22 1.6. Asymmetric Induction in the Solid State 25 1.7. The Chiral Handle Concept in Asymmetric Synthesis 31 1.8. Use of Hosts in Photochemical Asymmetric Synthesis 34 1.9. Research Objectives 38 1.10. References for Introduction 41 RESULTS AND DISCUSSION Chapter 2 Preparation of Substrates 48 2.1. Synthesis of fer/-Butyl Cyclohexyl Aryl Ketones 49 2.2. Synthesis of Adamantyl Aryl Ketones 53 iv 2.3 The Preparation of Optically Active Salts from Carboxylic Acids 70 and 83 56 Chapter 3 The Preparation and Identification of Photoproducts 60 3.1. The Photochemical Reactions of Cycloalkyl Aryl Ketones 60 3.2. Identification of Cleavage Photoproducts 102 and 103 64 3.3. Identification of Cyclization Photoproducts: Gs-Cyclobutanol 104-110 • • •• 68 3.4. Identification of Cyclization Photoproduct: rrara-Cyclobutanol 116 92 3.5 Photochemistry of Adamantyl Aryl Ketones: Formation of Os-Cyclobutanol 111-115 101 3.6. Photolysis of Salts: Enantiomeric Excess Determination 113 Chapter 4 Structure-Reactivity Correlation Studies 118 4.1. General Considerations 118 4.2. Photochemical Studies in Solution 4.3. Photochemical Studies in the Solid State 122 4.4. Cleavage vs Cyclization: Solution State • 126 4.5. Cleavage vs Cychzation: Solid State 136 4.6. Why are Cis-Cyclobutanols Formered Preferentially in Both the Solution and Solid State? 141 4.7. The Photolysis of Chiral Salts 85-95 and 96-101 1 4 3 4.8. Asymmetric Induction in Salts 85-95 150 4.9. Asymmetric Induction in Salts 96-101 1 5 4 4.10. Continuing the Discussion of the Single Crystal-to-Single Crystal Photoreaction of Salts 99 162 4.11. Reinvestigating ct-Adamantyl Acetophenones 166 v Chapter 5 Chemical Reactions in Other Organized Media 171 5.1. General Considerations 171 5.2. Inclusion of Ketones in ZeoUtes 172 5.3. Asymmetric Induction in Polymer Films 182 Chapter 6 Photophysical Properties of the Ketones 185 6.1. Quantum Yield Studies 185 6.2. Laser Flash Photolysis Studies 193 6.3. References for Results/Discussion Section 201 EXPERIMENTAL Chapter 7 Experimental 208 7.1 General Considerations 209 7.2 Synthesis of fer^Butylcyclohexyl Aryl Ketones 212 7.3. Synthesis of Salts with Acid 70 231 7.4. Synthesis of 2-Adamantyl Aryl Ketones 247 7.5. Synthesis of Salts with Acid 83 262 Chapter 8 Photochemical Studies: Isolation and Characterization of Photoproducts 271 8.1 General Considerations 271 8.2 Photolysis of Compound 56 273 8.3. Photolysis of Compound 57 274 8.4. Photolysis of Compound 58 276 8.5. Photolysis of Compound 66 280 8.6 Photolysis of Compound 67 291 8.7. Photolysis of Compound 68 296 vi 8.8. Photolysis of Compound 69 301 8.9. Photolysis of Compound 70 306 8.10. Photolysis of Compound 71 307 8.11. Photolysis of Compound 78 313 8.12. Photolysis of Compound 81 316 8.13. Photolysis of Compound 82 320 8.14. Photolysis of Compound 83 323 8.15. Photolysis of Compound 84 324 8.16. Photolysis of Salts 85-95 328 8.17. Photolysis of Salts 96-101 329 8.18. Photolysis of a Single Crystal of Salt 99 330 8.19. Partial Photolysis of a Single Crystal of Salt 99 332 8.20. Quantum Yields 334 8.21. References for Experimental Section 343 Appendix A 345 vii LIST OF FIGURES Figure Caption Page 1.1 Photochemistry of/ra^-cinnamic acid in solution and crystalline states 6 1.2 Pictorial representation of Cohen's "reaction cavity" concept. Reaction cavity before reaction (solid line) and at the transition state (broken line) 7 1.3 Photochemistry of a diacyl peroxide 9 1.4 Steric compression control in solid state photochemistry of compound 6 10 1-5 Cobaloxime complexes investigated by Ohashi and co-workers. 22 11 1.6 Topotactic photodimerization of 2-benzyl-5-benzylidenecyclo-pentanone (8) 12 1.7 HOMO and LUMO of C=C and C=0 double bond-containing molecules 13 1.8 Electronic configurations of a ketone, showing the occupancy of carbonyl bond orbitals in: (a) the singlet ground state, (b) the n -» n* singlet excited state, and (c) the n —» 7t* triplet excited state 15 1.9 Jablonski diagram for general molecular photophysical processes 16 110 Carbonyl non-bonding n-orbital.33 19 111 7t and TC* orbitals of a carbonyl group.3 3 19 1-12 The Norrish Type I reaction 3 ^ 20 viii 1.13 The Norrish Type TJ photochemical reaction. R and R' can be alkyl or aromatic moieties 21 1.14 Parameters denning spatial relationship for the abstraction of a hydrogen atom by the carbonyl oxygen atom, d = distance between hydrogen and oxygen, O H ; 0 = O H-C angle; A = C=0 H angle and co = dihedral angle formed between the O-H vector and its projection on the nodal plane of the C=0 group 22 1.15 Solid state asymmetric bromination of 10 27 1.16 Absolute asymmetric solid state [2+2] photodimerization of 12 28 1.17 Asymmetric single crystal-to-single crystal [2 + 2] photoaddition 29 1.18 [2 + 2] cycloaddition of achiral acyclic imides 29 1.19 Unimolecular absolute asymmetric photoreactions in chiral crystals 30 1.20 Asymmetric induction using P-chiraUty 32 1.21 Asymmetric induction of various salts via the di-7i-methane photorearrangement 33 1.22 Asymmetric induction of salt 35 via the Norrish Type JJ reaction 33 1.23 Asymmetric reactions in inclusion complexes 35 1.24 Typical resolved host molecules 35 1.25 Illustration of the sodalite type zeolites 37 1.26 Photobehavior of cis- and frans-stilbene 38 2.1 Synthesis of ketones 56, 57 and 58 49 2.2 Synthesis of ketones 66, 67 and 68 50 2.3 Synthesis of ketones 69, 70 and 71 51 2 4 Typical lH NMR spectra of ketones 57, 66, 68 and 71 5 2 2.5 Synthesis of ketones 77 and 78 53 2.6 Synthesis of ketones 80, 81, 82, 83 and 84 54 2 7 Typical lU NMR spectra of ketones 78, 80, 82 and 84 5 5 3.1 Photolyses of ketones 56 and 58 64 ix 3.2 Photolysis of ketone 57 65 3 3 (a) The lH NMR spectrum (400 MHz, CDC13) and (b) the X H NMR COSY spectrum (400 MHz, CDCI3) of photoproduct 103 3.4 Photolysis of ketone 120 to bicyclic alcohol 121 69 3.5 Structure and assignment of bicyclo[3.1.1]heptan-6-ols studied by Wiberg and co-workers 69 3 6 (a) The A H NMR spectrum (500 MHz, C 6 D 6 ) and (b) full HMQC 70 71 spectrum (500 MHz, CgDg) of photoproduct 104 ' 3.7 Photolysis of ketone 68 72 3 8 Hi NMR spectrum (500 MHz, CgDg) of photoproduct 107 7 3 3.9 The ORTEP stereodiagram of photoproduct 107 74 3.10 The crystal packing stereodiagram of photoproduct 107 74 3 1 1 i H NMR spectra (500 MHz, C 6 D 6 ) of photoproducts (a) 105, (b) 106, 75 78 (c) 108, and (d) 110 3 - 1 2 (a) Close-up of the 8 = 0.90 - 2.20 ppm region of the lH NMR (500 MHz, C 6 D 6 ) and (b) partial HMQC spectrum (500 MHz, C 6 D 6 ) 82, 83 of photoproduct 110 3 1 3 Partial COSY lll NMR spectrum (400 MHz, C 6 D 6 ) of 84 photoproduct 110 3.14 NOE experiments on photoproduct 110 (a) irradiation at 5 = 7.31 ppm (H12), (b) irradiation at 6 = 2.02 (H6'), (c) irradiation at 5 = 1.80 ppm (H6), (d) irradiation at 8 = 1.35 ppm (H5 and H5'), and (e) off-oz: on resonance spectrum °° ' 3.15 The photolysis of ketone 123 89 3.16 A structure correlation between salt 124s and photoproduct 124 89 x 3.17 General picture of photoproducts 104-110 92 3.18 1 H NMR spectrum (500 MHz, CgD 6) of photoproduct 116. Exact 93 assignments for the hydrogens at C5 and C6 could not be determined .... 3 1 9 Partial COSY ! H NMR spectra (400 MHz, C 6 D 6 ) of photoproduct 116. 9 4 3.20 Partial HMQC spectrum (500 MHz, C 6 D 6 ) of photoproduct 116 95 3.21 NOE experiment on photoproduct 116 (a) irradiation at 5 = 7.14 ppm (H12), (b) irradiation at 5 = 0.17 ppm (H7), and (c) off-resonance spectrum 9 8 3.22 Irradiation of ketone 127 99 3 2 3 lU NMR spectra (500 MHz, C^D6) of photoproducts (a) 112 and (b) 115 1 0 5 3.24 Partial HMQC spectra (500 MHz, CgDg) of photoproducts (a) 112 and (b) 115 1 0 6 3 2 5 lU COSY spectrum (500 MHz, C 6 D 6 ) for photoproduct 115 1 0 7 3.26 The ORTEP stereodiagram of photoproduct 112 108 3.27 The crystal packing stereodiagram diagram of photoproducts 112 109 3 2 8 The down-field portion of the 75.6 MHz 1 3 C spectrum (DMSO, dg) of photoproduct 112 at the indicated temperatures ^ 3.29 X-ray analysis derived structure for photoproducts (a) 107 and (b) 112 .. 112 3.30 Packing composition of the CHIRALCEL OD column 114 xi 3.31 Chromatogram of a racemic sample of photoproduct 110 with starting material (ketone 71) present 116 3.32 Chromatogram of a racemic sample of photoproduct 115 with starting material (ketone 84) present 117 4.1 Photoreactivity of ketones 77 and 80 in solution and in the solid state .... 119 4.2 Possible reaction mechanism for the photolysis of ketones 77 and 80 in the presence of a deuterated mercaptan 120 4.3 Reaction mechanism for the photolysis of ketones 56 and 57 in the solution state 121 4.4 Conformations of 1,4-biradicals 128 4.5 Coirformation of the 1,4-biradical from a type II photoreaction 128 4.6 Conformation of the ketones of this thesis. Ketones 56, 57, 58, 67, 68 and 70 have the fer/-butylcyclohexyl ring system, while 77, 78, 81 and 84 have the adamantyl ring system 134 4.7 The hypothetical photolysis of ketones 77 and 80 to form cleavage products 131 and 132 respectively 135 4.8 A diagrammatic representation of the biradical intermediate reaction centre, showing (pi, (p4 and cp torsion angles 136 4.9 Biradical intermediate reaction centre. The structures are general for both ter/-butyl cyclohexyl and 2-admantyl aryl ketones 141 4.10 Systematic numbering of the salts, biradicals and photoproducts 148 4.11 Structure correlation between the salts and photoproducts HOP and 115P 149 4.12 (a) The ORTEP drawing and (b) the crystal packing diagram of salt 93 .. 151 4.13 Reaction pathway for the photolysis of salt 93 in the solid state 152 4.14 Absolute structure of (+)-11 OP. Exact stereochemistry is (IR, 2R, 3R, 4S) 153 4.15 (a) The ORTEP drawing and (b) the crystal packing diagram of salt 98 ... 155 xii 4.16 (a) The ORTEP drawing and (b) the crystal packing diagram of salt 99 .. 156 4.17 (a) The ORTEP drawing and (b) the crystal packing diagram of salt 101. 157 4.18 (a) The ORTEP drawing and (b) the crystal packing diagram of photoproduct 99P 159 4.19 Reaction pathway for the photolysis of salts 96-101 in the solid state. H x abstraction occurs in those salts where the a-b-c-d dihedral angle is positive ^1 4.20 Absolute structure of (-)-115P. Exact stereochemistry is (IS, 2S, 3R, 4S, 6R, 8R, 9S) 162 4.21 Stereodiagram showing the superposition of reactant 99 (open bonds) and photoproduct 99P (shaded bonds) in a single crystal of the former photolyzed to 60% conversion. To improve clarity, the hydrogen atoms present in the adamantane portion of the structure have been omitted 164 4.22 Crystal packing diagram of 99/99P pair 164 5.1 The mode of photoreaction of ketones 69 and 71 in zeohtes 172 5.2 The photochemical behaviour of ketones 71 and 138 when included within zeolites 177 5.3 Molecular model diagram of ephedrine and ketone 71 vvithin the supercage of X or Y zeolite. Guest structures have been minimized, but the guest-host assembly has not. The figure shows that both the ephedrine and ketone can fit within zeolite cages 177 5.4 Results of photolysis of ketone 71 in Na Y and Na X zeolites 179 5.5 Photolysis of ketone 138 within Na Y- ephedrine 181 5.6 (a) Structure of PHBA/co-PFfVA polymer, (b) the guest substrate, ketone 71 and (c) the photoproduct (110) isolated from the photolyses of the polymer/71 mixture 182' xiii 6.1 Rate processes in the Norrish type II reaction of aryl ketones 185 6.2 Stern-Vohner plots for quenching by 2,5-dimethyl-2,4-hexadiene of cleavage product formation from the fer/-butylcyclohexyl aryl ketones 56 and 57 188 6.3 Stern-Volmer plots for quenching by 2,5-dimethyl-2,4-hexadiene of cyclobutanol formation from the fert-butylcyclohexyl aryl ketones 58, 67 and 68 188 6.4 Stern-Volmer plots for quenching by 2,5-dimethyl-2,4-hexadiene of cyclobutanol formation from the tert-butylcyclohexyl aryl ketones 66, 69 and 71 189 6.5 Stern-Volmer plots for quenching by 2,5-dimethyl-2,4-hexadiene of cyclobutanol formation from the adamantyl aryl ketones 78, 81, 82 and 84 189 6.6 Photorearrangement observed via laser flash photolysis 194 6.7 Triplet-Triplet spectrum of ketone 68 in methanol 195 6.8 Decay traces monitored at X = 398 nm ascribed to the triplet of 68 in benzene quenched by 1,3-cyclohexadiene 196 6.9 Stern-Volmer analysis of the quenching of ketone 68 by 1,3-cyclohexadiene in benzene 197 xiv LIST OF TABLES Table Caption Page 1.1 Theoretical ideal values of the geometrical parameters for hydrogen atom abstraction by an excited carbonyl oxygen 24 2.1 The preparation of optically active salts from carboxylic acid 70 58 2.2 The preparation of optically active salts from carboxylic acid 83 59 3.1 Photoproduct ratios for fer^butylcyclohexyl aryl ketones 61 3.2 Photoproduct ratios for adamantyl aryl ketones 62 3.3 Numbering of isolated photoproducts as compiled from Tables 3.1 and 3.2 63 3 4 ! H nmr data (400 and 500 MHz, C^D^) for photoproducts of the 79 general structure below 3 5 1 3 C nmr (50.3 and 125.8 MHz, CgDg) data for photoproducts of the general structure below ^ 3.6 The enantiomeric excesses of photoproducts 124 and 125 from the photolyses of chiral salts 123n and 123p 88 3-7 lH nmr data (400 and 500 MHz, CgDg) for photoproducts of the general structure below 3 8 1 3 C nmr (125.8 MHz, CgDg) data for photoproducts of the 103 general structure below 3.9 Interatomic distances in photoproducts 107 and 112 113 3.10 Chromatographic data for photoproducts 110 and 115 on the CHIRALPAK OD Column (25 cm * 0.46 cm ID.) at room temperature 115 xv 4.1 Crystallographically derived C=0-"Hy abstraction geometries 124 4.2 Average values for d, co, A, and 9 for reactive and unreactive ketones 125 4.3 Comparison of the crystallographically and molecular mechanics (MM3) derived geometries of ketones 56, 58, 77 and 78 130 4.4 Comparison of the molecular mechanics (MM3) derived 01ClC2Ra dihedral angles of ketones 56, 58, 77 and 78 and the energies associated with each conformation 131 4.5 Crystallographically derived biradical parameters of ketones 138 4.6 Asymmetric Induction in the Solid State Photochemistry of Salts of Keto Acid 70 144 4.7 Asymmetric Induction in the Solid State Photochemistry of Salts of Keto Acid 83 146 4.8 Crystallographically derived biradical geometries and predicted behavior 160 4.9 Details of X-ray structural analyses 165 4.10 Structure of the a-Adamantyl Acetophenones 167 4.11 Crystallographically derived C=0"Hy abstraction geometries 168 5.1 Asymmetric induction in the photochemistry of zeolite Na-Y/chiral inductor/ketone complexes 174 5.2 The composition of the polymer/substrate solutions used 184 6.1 Triplet state kinetic parameters for various aryl alkyl ketones 187 6.2 Rate constants for triplet Y-hydrogen abstraction in benzene by ring substituted valerophenones 191 6.3 Rate constants for triplet y-hydrogen abstraction in benzene by ring substituted fer/-butyl cyclohexyl aryl ketones 192 xvi 6.4 Rate constants for triplet y-hydrogen abstraction in benzene by ring substituted adamantyl aryl ketones 192 6.5 Intrinsic lifetimes, rate constants and quenching rate constants derived from quenching of the triplet excited state of ketone 68 in methanol, benzene and acetonitrile solutions 198 7.1 Optically active amines used in this thesis to form salts 232 8 1 ! H nmr Data (400 MHz, CDC13) for Photoproduct 103 2 7 5 8 2 lH nmr Data (400 and 500 MHz, CgDg) for Photoproduct 104 2 7 8 8 3 X H nmr (500 MHz) and 1 3 C nmr (125.8 MHz) Data for Photoproduct 104 2 7 9 8 4 iH nmr Data (400 and 500 MHz, CgDg) for the Major 282 Photoproduct 105 8 5 ! H nmr (500 MHz) and 1 3 C nmr (125.8 MHz) Data for the Major Photoproduct 105 2 8 3 8 6 a X H nmr Data (400 and 500 MHz, C 6 D 6 ) for the Minor Photoproduct 116. Protons on C5 and C6 assigned according to Table 8.7a 2 8 6 8 6 b ^ nmr Data (400 and 500 MHz, C 6 D 6 ) for the Minor Photoproduct 116. Protons on C5 and C6 assigned according 787 to Table 8.7b 8 7 a i H nmr (500 MHz) and 1 3 C nmr (125.8 MHz) Data for the Minor Photoproduct 116. C5 assigned as 8 = 35.04 ppm 2 8 8 8 - 7 ° i H nmr (500 MHz) and 1 3 C nmr (125.8 MHz) Data for the Minor Photoproduct 116. C5 assigned as 8 = 35.04 ppm 2 9 0 xvii 8 - 8 1 H nmr Data ( 4 0 0 and 5 0 0 MHz, C^D6) for Photoproduct 106 2 9 3 8 9 I H nmr ( 5 0 0 MHz) and 1 3 C nmr ( 1 2 5 . 8 MHz) Data for 2 9 4 Photoproduct 106 8 . 1 0 I H nmr Data ( 4 0 0 and 5 0 0 MHz, C 6 D 6 ) for the Major 2 9 8 Photoproduct 107 8 . 1 1 I H nmr ( 5 0 0 MHz) and 1 3 C nmr ( 1 2 5 . 8 MHz) Data for the Major 2 9 9 Photoproduct 107 8 - 1 2 I R nmr Data ( 4 0 0 and 5 0 0 MHz, C 6 D 6 ) for Photoproduct 108 3 0 2 8 . 1 3 l H nmr ( 5 0 0 MHz) and 1 3 C nmr ( 1 2 5 . 8 MHz) Data for 3 0 4 Photoproduct 108 8 - 1 4 I H nmr Data ( 4 0 0 and 5 0 0 MHz, C 6 D 6 ) for the Major 3 1 0 Photoproduct 110 8 . 1 5 1 H nmr ( 5 0 0 MHz) and 1 3 C nmr ( 1 2 5 . 8 MHz) Data for the Major 3 1 1 Photoproduct 110 8 - 1 6 I H nmr Data ( 5 0 0 MHz, C 6 D 6 ) for Photoproduct 111 3 1 4 8 . 1 7 l H nmr ( 5 0 0 MHz) and 1 3 C nmr ( 1 2 5 . 8 MHz) Data for 3 1 5 Photoproduct 111 8 - 1 8 I H nmr Data ( 5 0 0 MHz, C 6 D 6 ) for Photoproduct 112 3 1 7 8 1 9 I H nmr ( 5 0 0 MHz) and 1 3 C nmr ( 1 2 5 . 8 MHz) Data for 3 1 8 Photoproduct 112 8 2 0 I H nmr ( 4 0 0 MHz) and 1 3 C nmr ( 5 0 . 3 MHz) Data for 3 2 0 Photoproduct 113 8 2 1 I H nmr Data ( 5 0 0 MHz, C 6 D 6 ) for Photoproduct 115 3 2 6 8 2 2 I H nmr ( 5 0 0 MHz) and I 3 C nmr ( 1 2 5 . 8 MHz) Data for 3 2 7 Photoproduct 115 xviii 8.23 Crystallographic data for photoproduct 99P 331 8.24 Crystallographic data for mixed crystal 99/99P 333 8.25 Quantum yield data for ter/-butylcyclohexyl aryl ketones:the change in quantum yield vs. reaction conversion 338 8.26 Steady state Stern-Vohner data for ter^butylcyclohexyl aryl ketones in benzene with 2,5-dimethyl-2,4 hexadiene as quencher 340 8.27 Quantum yield data for the adamantyl aryl ketones:the change in quantum yield vs. reaction conversion 342 8.28 Steady state Stern-Vohner data for the adamantyl aryl ketones in benzene with 2,5-dimethyl-2,4 hexadiene as quencher 343 xix ACKNOWLEDGEMENTS I would like to express my deepest gratitude to my research supervisor, Professor John R. Scheffer, for his valuable guidance and encouragement throughout the years. His patience and understanding helped bring this thesis to a much anticipated conclusion. I would like to thank past and present members of the JRS group; they were the ones who had to put up with me on a daily basis. Special thanks to Eugene Cheung and Kristin Janz for proof-reading my thesis. I couldn't do it without you. I am grateful to Professor James Trotter and members of his research group for the X-ray crystallographic analysis, which is a valuable part of this thesis. I will forever be in debt to Dr. Gunnar Olovsson, who is responsible for the majority of the X-ray structures in this thesis. Special thanks go out to: Cornelia Bohne and Mark Kleinman (University of Victoria) for their laser flash photolysis work; Professor V. Ramamurthy (Tulane University) for the zeolite work; Dr. Fiona Geiser (Chiral Technologies) for her HPLC expertise. I appreciate the support of my close friends Naveen Chopra, Angelo Ariganello, Bob Chapman, and Dean Clyne throughout my education at UBC. Finally, I would like to express my appreciation for all the help from the NMR laboratory, Mass Spectrometry faculties, Mr. Peter Borda (Elemental Analysis laboratories), and also from the Chemistry departmental staff. xx In memory of my Grandparents Chana & Hersz Szuster, and Leah & Meier Leibovitch Dedicated to my parents Ester & Peretz, to Mike, Alex & Epi, and to my loving wife Jaci with love xxi I n t r o d u c t i o n i Introduction/Chapter 1 CHAPTER 1 1.1. General Considerations Chemical reactions induced by light have undergone systematic investigation in laboratories only during the last two centuries^ ; however, their significance far predates those investigations.2 Photochemical reactions have played an important role in the evolution of life on our planet.3a Bacteria and plant life have been utilizing the energy from the sun to produce oxygen gas, O 2 , through a process called photosynthesis. This oxygen gas has itself been photolyzed to produce stratospheric ozone.3?4'5,6 xhj s ozone has been the vital ultra-violet radiation protective layer for life on earth. The earliest studies of photochemical reactions used sunlight as the irradiation source. 1 However, these photolyses usually took days or weeks to perform, and were also quite dependent on the weather. In the early twentieth century, an artificial light source, the mercury broad band arc lamp, was invented, which revolutionized the study of photochemical reactions. It was then possible to obtain intense, localized exposure of substrates with light energy, which resulted in drastically reduced photolysis times. For the better part of the last two centuries, studies of chemical reactions were mainly focused on the liquid and gaseous states. These two states were thought to allow the reacting molecules to possess the necessary molecular freedom required for a chemical reaction to take place. The molecules in crystals were considered to have only very small translational and vibrational motions associated with them. However, the atomic and molecular motions in the solid state are not as restricted as originally thought.7 2 Introduction/Chapter 1 There has been a growing trend over the last 30 years in the study of organic photochemistry taking place in organized media.8 This is the study of photon-induced chemical reactions in an anisotropic environment. Examples of organized media include crystals, polymer matrices, zeolites, cyclodextrins, micelles, and monolayers. These can dramatically alter the selectivity of photoproduct formation, as compared to the solution state. Of the various types of organized media, the most extensive work has been done with the crystalline phase. Molecules in a crystal are usually organized so that they are arranged in a periodic pattern in three dimensions; thus the crystal environment is rigid in nature. As long as the crystal lattice remains intact, the systematic repetition of each unit cell allows each reacting molecule in the lattice to exist in the same environment. Friedrich Wohler, in 1828, discovered the first solid state chemical reaction-the thermal transformation of crystalline ammonium cyanate into urea.9 A few years later, the first solid state photochemical reaction was discovered; in 1834, H. Trommsdorff observed the yellowing and cleavage of crystals of santonin exposed to sunlight. 10 Over the next 100 years, although dramatic advances were made in the field of photochemistry, the study of solid state photochemistry was lirnited because of the lack of knowledge about molecular and crystal structures.I'll Since the development of single crystal X-ray diffraction techniques, spectacular progress has been made in the field of solid state chemistry. In the past 40 years, X-ray crystallography has made it possible to correlate solid state reactivity with structural information, the so-called crystal structure-reactivity correlation method. This involves 3 Introduction/Chapter 1 the determination of chemical reactivity of a series of closely related compounds in the crystalline state, and the correlation of this information with X-ray crystallographic structural data for the same molecules. The crystal structure-reactivity correlation method has become the most important approach to solid state photochemistry, but it is still in the "discover-and-explain" stage, and not a fully predictive synthetic tool. This is primarily because crystal packing is unique to each molecule and cannot be predicted beforehand. 1.2. Crystal Lattice Effects in Solid State Chemistry In 1918, Kohlschutter proposed the topochemical postulate, the first theory which attempted to explain the results observed in solid state chemical reactions. ^ 2 He suggested that the nature and properties of the products of solid state reactions are governed by the fact that they take place within or on the surface of the solid. It was not until the advent of X-ray crystallographic techniques, about forty years later, that the important set of topochemical rules finally emerged connecting the configuration of the product and the crystal structure of the reactant. 13 This was accomplished by Schmidt and co-workers during the 1960's with their work on the solid state [2 + 2] photocycloaddition reactions of /rara-cinnamic acid derivatives (1, Figure 1.1). 13 As early as 1889, the photodimerization of both forms of cinnamic acid in crystals was known. 14 This work was reinvestigated in 1943 by Bernstein and Quimby, who interpreted the formation of a-traxillic and P-truxinic acids crystals from crystals of cinnamic acid as a crystal lattice-controlled reaction.^ This was followed by the pioneering work by Schmidt, who proposed that the course of the [2 + 2] 4 Introduction/Chapter 1 photocycloaddition reaction in the crystalline state is governed by the molecular packing in the crystal lattice, which determines the orientation and distance between the two reacting double bonds. I 3 Since solid state reactions occur in a constrained environment, they will proceed with a nrinimum amount of atomic and molecular movement. Hence only those topochemically controlled reactions that can satisfy the minimum motion criterion will be allowed in the solid state. Both substituted and unsubstituted fra«s-cinnamic acids have three packing modes in the solid state: a, P and y. When these compounds are photolyzed in solution, cisltrans isomerization is the only result. However, in the crystalline state, photolysis of the cc-form gives [2 + 2] cycloaddition product 3, the P-form reacts to give [2 + 2] product 4 and the y-form is unreactive. The photo stability of the y-form was interpreted as being due to lattice constraints which do not permit the potentially reactive centers to move sufficiently close together to form a photodimer. After studying the [2 + 2] photocycloaddition reactions of rram-cinnamic acid and its derivatives, it was proposed that, in order for photocycloaddition to occur in the solid state, the center-to-center distance between two neighbouring double bonds should be less than a critical distance of 4.2 A. 5 Introduction/Chapter 1 1 \ ; o o H Solution 2 P h P h H O O c ' W , ^ h v »• H O O C \ 7v W t O O H A F O R M V L ^ Y O O H P h P h 3 (a -truxillic acid) P h hv P h P h ' S = \ " * " P h \ T V V ^ t o O H P f 0 ™ V - ( \ o O H P h C O O H C O O H 4 ( P -truxinic acid) H O O C c: o o H hv y form No Reaction Figure 1.1. Photochemistry of /rawj-cinnamic acid in solution and crystalline states. However, the distance between the reacting double bonds is not the only factor to be considered in detemnhing whether the solid state [2 + 2] photocycloaddition reaction will take place. There must be also a parallel alignment of the reacting double bonds. There are examples where the distance between the centers of adjacent double bonds lies within the proposed reaction limit but the double bonds are not parallel to each other, and no solid state photodimerization reaction is observed in these cases. ^ a However, a few cases have also been reported where the reacting double bonds were not exactly parallel, but the photodimerization reaction was observed. For example, in crystals of 7-methoxycoumarin, the reactive double bonds are rotated by about 65° with respect to each other, and the centre-to-centre distance between them is 3.83 A. Nonetheless, photodimerization does occur with such an unfavourable arrangement.^0 6 Introduction/Chapter 1 Another concept, the reaction cavity theory, was introduced by Cohen as an aid in interpreting the course of solid state reactions.17 Cohen suggested that, due to the requirements of crystal packing, the reacting molecule exists in a cavity formed by its neighbouring molecules. As the molecule reacts, proceeding from reactant to transition state to product, its physical geometry changes (Figure 1.2). Reactions which involve minimal changes in geometry proceed without much interference from the reaction cavity walls; reactions with transition state geometries incompatible with the cavity will be disfavored. Recently, Ramamurthy et al. expanded the reaction cavity concept to include other organized media, where it had previously been applied only to the crystalline state.18 Figure 1.2. Pictorial representation of Cohen's "reaction cavity" concept. Reaction cavity before reaction (solid line) and at the transition state (broken line). An extension to Cohen's reaction cavity concept comes from Gavezzotti, who suggested that free volume or space in crystals determines reactivity in the solid state.7' i 9 a Packing density diagrams, calculated from a computer program, allowed him 7 Introduction/Chapter 1 to determine the location and volumes of the empty and filled spaces in crystal lattices. A variety of solid state reactions were analyzed, and it was concluded that a prerequisite for crystal reactivity is the availabihty of free space around the reaction site. Zimmerman and co-workers have performed extensive research into obtaining a general quantitative theoretical basis for predicting crystal reactivity. 19b,c They developed a computer program to generate a mini crystal lattice having the appropriate space group symmetry, X-ray atomic coordinates and with a central molecule surrounded by reactant molecules. 19d,e Replacement of the central molecule with a transition state molecule provided a new mini-lattice. Overlap of the central, partially reacted species with the surrounding molecules provided one criterion. Molecular motion of the reactant excited state in forming the partially reacted species provided a test of least motion as a second criterion. Utilizing MM3 geometry optimization of the reacting species imbedded in the rigid mini-lattice provided a measure of the increase in intra- and intermolecular energy of this molecule. A final approach determined the points of nearest molecule-lattice approach and mapped these in the form of a "lock and key"; this indicated which interactions result in inhibition or lack thereof of a particular reaction route. Zimmerman used this method to predict successfully the observed reaction stereochemistry in the aryl-group migration of a variety of 4,4-charylcyclohexenones.l9d,e In attempting to explain the mechanism by which diacyl peroxides (5) decompose in the solid state (Figure 1.3), McBride et al. introduced the concept of local stress?-® As a C O 2 molecule is liberated in this reaction, an anisotropic local stress is suggested to develop inside the crystal lattice. This is postulated to be the controlling factor in the 8 Introduction/Chapter 1 migration of the phenyl group. This stress is transmitted to one side of the migration terminus, thus inclining the radical carbon in the opposite direction, more towards the migrating phenyl group. By studying a variety of diacyl peroxides, it was concluded that local stress is so important in these reactions that it overrides the topochemical postulate when the two are in opposition. O O h v Ph Figure 1.3. Photochemistry of a diacyl peroxide. Another approach in trying to determine the effect of the crystalline environment on solid state reactivity comes from Scheffer and Trotter and is referred to as steric compression control?-^ As an example, compound 6 (Figure 1.4) was found to be unreactive towards [2 + 2] photocycloaddition in the solid state, even though the double bonds are arranged in a topochemically favorable orientation. This lack of reactivity was suggested to be a consequence of the arrangement of the neighbouring molecules in the crystal lattice. If the [2 + 2] reaction were to proceed, the steric compression of the two methyl groups of the reacting molecules with those of the surrounding molecules would increase. This effect would be so unfavourable that the photocycloaddition does not occur. Introduction/Chapter 1 neighbouring steric compressio upon dimerizatio molecule Figure 1.4. Steric compression control in solid state photochemistry of compound 6. Ohashi and co-workers22 were able to develop a quantitative relationship between a solid state reaction rate and a crystal lattice parameter. The reaction studied was the X-ray-initiated racemization at the cyanoethyl chiral centre of several optically active cobaloxime complexes (7, Figure 1.5). These reactions were found to be single crystal-to-single crystal in nature (topotactic, discussed below), and thus the reaction cavity volumes could be calculated from the X-ray crystal structure data. When the reaction rates were correlated with the reaction cavity volumes, the data suggested that the reaction rates were greatest for those molecules with the largest reaction cavities. 10 Introduction/Chapter 1 OH—-O X = (S) - NH2CH(CH3)C6H5[(R)-l-cyanoethy = (S) - NH2CH(CH3)C6H5[(S)-l-cyanoethy = C6H5N[(S)-l-cyanoethyl] X 7 Figure 1.5. Cobaloxime complexes investigated by Ohashi and co-workers. Another important consideration in solid state photochemistry is the possibility that phase changes may occur during the course of a reaction. If the conversion of a reactant crystal to a product crystal occurs without any phase separation during the reaction, the process is referred to as a topotactic (single-crystal-to-single-crystal) reaction.23 Topotactic reactions are homogeneous, i.e., the product molecules form a continuous solid solution with the reactant molecules in all proportions, and thus crystalhnity is preserved throughout the reaction. Few topotactic reactions are known; hence they are extremely sought after.24 One example of a topotactic reaction is the photodimerization of 2-benzyl-5-benzvlidenecyclopentanone (8, Figure 1.6).23 Crystallographic studies of this reaction indicate that the cell parameters change continuously with conversion and that the packing arrangement of the starting material and the product are such that the reaction requires very little atomic motion. 11 Introduction/Chapter 1 1.3. Electronic Aspects of Organic Photochemistry A full understanding of photochemical reactions requires an appreciation of the nature and properties of electronically excited states. The fonowing is a brief overview of the theory behind some of the more relevant aspects of the excited states of molecules. Detailed reviews on this topic can be found in publications by Turro2^ and de Mayo.2** The total spin angular momentum possessed by a many-electron atom or molecule is represented by the total spin quantum number S, which is calculated as the vector sum of all the individual contributions from each electron. In any given atomic orbital, two electrons, each possessing spin quantum number s = V2, may be present. Pauli's exclusion principle requires the two electrons in the same orbital to have opposite spins. With the spins opposed, the total spin quantum number S is zero. The spin multiplicity gives the number of states expected in the presence of an applied magnetic field and is given by 2S + 1. For most organic molecules, the ground electronic states have all electrons spin-12 Introduction/Chapter 1 paired. Such an electronic state is referred to as the singlet ground state, abbreviated by the symbol S 0. An electronically excited state is produced when a molecule absorbs a photon of light. There are five molecular orbitals of interest in describing an excited state: the sigma bonding (a) and anti-bonding (a*) orbitals, the pi bonding (n) and anti-bonding (71*) orbitals, and the non-bonding (n) orbital. When the electrons in a molecule are arranged in these, there will be a highest occupied molecular orbital (HOMO) and a lowest unoccupied molecular orbital (LTJMO) (Figure 1.7).27 c=c 7c* L U M O 71 H O M O C=0 a* 7 1 * L U M O n H O M O 7t rj Figure 1.7. HOMO and LUMO of C=C and C=0 double bond-containing molecules. When a molecule is excited, an electron from the HOMO is transferred to the LUMO, and the old LUMO then becomes the new HOMO. Four types of excitations are of particular interest to organic photochemists: 13 Introduction/Chapter 1 1. r j - » G * 2. n->a* 3. 7t —> 7C* 4. n - » 7 t * These are listed above in order of decreasing energy, the n—»7C* process being the lowest energy photochemical transition. Since all organic molecules possess a-bonding electrons, they all have the possibility of undergoing electronic transitions of the first type. Of course, n-electrons are necessary for (n—»o~*) transitions, 7t-electrons are necessary for ( T I — » T C * ) transitions and both are required for (n->TC*) transitions.28 When a molecule is excited from its singlet ground state, S 0 (Figure 1.8a), it enters the singlet excited state, Si (Figure 1.8b). The two original electrons from the ground state are now in different orbitals, but they still have opposite spins since the excited electron residing in the new HOMO retains its original spin.29 Because the electrons are no longer in the same orbital, Pauli's exclusion principle does not apply, and the electrons do not have to retain opposite spins. Therefore, the excited electron can spin invert to attain the same spin as the unexcited electron, giving a triplet excited state, T\ (Figure 1.8c). This spin inversion is known as intersystem crossing (ISC). It is a forbidden process, but occurs to some extent through spin-orbit coupling. The triplet excited state is of lower energy than the singlet excited state; however, the spin-inverted electron cannot return to the old HOMO without undergoing a second spin inversion, so that it can again obey Pauli's exclusion principle. 14 Introduction/Chapter 1 (a) Figure 1.8. n TZ hv TZ" n TZ (b) 7C" n Electronic configurations of a ketone, showing the occupancy of carbonyl bond orbitals in: (a) the singlet ground state, (b) the n -» 7t* singlet excited state, and (c) the n -»7r* triplet excited state. A less simplistic model of the electronic levels for an organic molecule is shown in the Jablonski Diagram (Figure 1.9)?® Molecules possess second, third and higher electronically excited states, which may involve higher energy TZ* or a* molecular orbitals. Normally broad band high energy photons are used, which would excite the ground state molecule to the other higher energy electronically excited states (S2, S3, ...) thus causing a cascade of decomposition modes. Fortunately, it is easier to excite selectively (n,7C*) vs. (71,7c*) since the former transition has a much lower HOMO/LUMO energy gap. Once the molecule has been excited by the absorption of a photon, it can return to its ground state by various routes. Two types of decay are possible: radiative (luminescent) and non-radiative (radiationless). Radiative decay involves the emission of light, and can occur through either fluorescence or phosphorescence. In fluorescence, the molecule returns to the ground state electronic configuration from the singlet excited state by emitting a photon of light. The process is spin allowed and usually occurs at a rate of 10 -101L sec" . In phosphorescence, a molecule in the triplet excited state returns to its 15 Introduction/Chapter 1 ground state by emitting a photon of light and having the excited electron undergo a spin inversion. This is a spin disallowed process, but it does occur through spin-orbit coupling at a rate of lO^-lO6 sec1. Non-radiative decay occurs when an excited molecule returns to its ground state without the emission of light. There are also two types of radiationless decay, and again the difference lies in whether or not there is a spin inversion, hi internal conversion (IC), the excited molecule is in the singlet state and returns to the ground state without any change in spin.31 Intersystem crossing (ISC) involves a molecule in the triplet excited state that returns to the ground state via a spin inversion. In the solution phase this excess energy is rapidly removed by collisions with solvent molecules, a process sometimes referred to as vibrational relaxation. Most photochemical reactions occur from either the Si or T i excited state. Energy / Singlet Reaction T2 Tl LEGEND abs = absorption isc - intersystem crossing fluor = fluorescence phos = phosphorescenc ic = internal conversion S = singlet level T = triplet level Triplet Reaction Figure 1.9. Jablonski diagram for general molecular photophysical processes. 16 Introduction/Chapter 1 A useful term to mention here is Quantum Yield (<X>), which is a measure of the efficiency of a photo-induced reaction to yield a given product. For a general photochemical conversion (Equation 1): A + hv ->B Eq. 1 we may define the quantum yield for the production of B as shown in Equation 2: No. of molecules B formed per unit time per unit volume ^B = Eq 2 No. of quanta absorbed B per unit time per unit volume '^ Therefore, if A rearranges to B each time it absorbs a photon, <Pg will equal unity, and the conversion is 100% efficient. If, however, the excited state of A has de-excitation pathways available to it that do not lead to the production of B, then the quantum yield will be lower than unity, and the efficiency of the conversion will be less than 100%. An extension of the measurement of quantum yields is the determination of the Stern-Volmer coefficient. Explanation of this first requires an introduction to the phenomenon of quenching, which is the transfer of excited triplet energy from one molecule to another, and which can be represented by the following equation (Equation 3): 3 D + lA -> !D + 3 A Eq. 3 Triplet-triplet energy transfer requires that the acceptor or quencher, A, does not absorb at the wavelength(s) used for exciting the donor or sensitizer, D. h° such a mixture is irradiated, only the donor should become directly excited electronically. Hence, there is a partitioning between the two competing processes of product formation from triplet donor molecule and destruction of the triplet donor molecule. Several criteria must be satisfied 17 Introduction/Chapter 1 for successful energy transfer. First, the energy of the excited donor triplet must be higher than that of the acceptor triplet. Second, the donor and acceptor must collide with one another in order for energy to be transferred. The efficiency of the second factor is ultimately dependent on the rate of diffusion between donor and acceptor and on the lifetime of the excited triplet donor molecule. For reactions occurring from triplet excited states, the quantum yield for product formation will be reduced by the presence of a triplet quencher, and the extent of this reduction will depend on the quencher concentration. We can define (J)0 as the quantum yield in the absence of a quencher ([Q] = 0) and (j) as the quantum yield at a specific quencher concentration. If we then plot (|)0/(j) against quencher concentration according to the following equation (Equation 4): (b0/4) = 1 + k q x [Q] Eq.4 the result will be a linear graph with an intercept of unity and a slope of kq x. This term is called the Stern-Vohner coefficient, and it provides us with an indirect method for determining triplet lifetime, T , if the quenching rate constant, kq , is known. 1.4. Photochemistry of Ketones For ketones, the orbitals of interest are those of the carbonyl group. The n-orbital (Figure 1.10) donates very little electron density to the area between the carbon and oxygen nuclei, and consequently does not contribute to the carbon-oxygen double bond. Since the ionization potential required to remove an electron from the n-orbital is low, this orbital will be involved in the lowest energy electronic transition.32 18 Introduction/Chapter 1 z Figure 1.10. Carbonyl non-bonding n-orbital.-" The p-orbital electrons are delocalized over the carbon and oxygen atoms. From the linear combination of the atomic orbitals, bonding and anti-bonding molecular orbitals are obtained (Figure 1.11), with the anti-bonding orbital having a higher energy. In the case of a carbonyl-containing compound, these bonding and anti-bonding orbitals are of the TC and %* type. The charge density of the bonding molecular orbital is skewed so that more negative charge is located over the electronegative atom; that is, oxygen. In contrast, the anti-bonding molecular orbital has electronic displacement towards the carbon atom.33 Figure 1.11. n and n* orbitals of a carbonyl group. i i Ketones have perhaps undergone more photochemical investigations than any other compounds.32 The interest in ketones stems in part from their ability to absorb 19 Introduction/Chapter 1 light of ultraviolet (UV) wavelengths. Since the ground state HOMO of a ketone is the n-orbital, the lowest energy transition that ketones can undergo is of the n-»7i* type. The energy difference between the singlet and triplet excited states is small and, therefore, S\ will often undergo intersystem crossing to T\.34,35 After excitation, three main types of reactions can occur: Norrish Type I, Norrish Type JJ and photoreduction.36 The Norrish type I reaction, also known as a-fission, involves cleavage of the bond between the carbonyl carbon and the cc-carbon, resulting in an acyl radical and an alkyl radical (Figure 1.12). The radicals themselves can then undergo various reactions to achieve stability. ^ S R! R4 'p| R i V. / i 1,,. . II _ _/ J C^r—R2 hv R 3 ^ 5 ' 1 5 I v / R H 3 Figure 1.12. The Norrish type I reaction.-^ A Norrish type II reaction involves an intramolecular y-hydrogen abstraction, which results in the formation of a 1,4-biradical (Figure 1.13). This biradical can return to a stable state by various reactions such as cleavage, cychzation, and reverse hydrogen transfer (disproportionation). This thesis will be concerned mainly with the Norrish type II reaction. The third reaction mentioned above, photoreduction, involves an intermolecular hydrogen atom abstraction, and is the main intermolecular photoreaction of ketones. 20 Introduction/Chapter 1 In the Norrish type U reaction, it is generally the y-hydrogen atom that is abstracted, but there is some competition from the (3- and 5-hydrogens. A linear transition state is favoured in hydrogen transfer between two atoms, but this is clearly impossible in a six-centre transition state process.38,39 Wagner suggested that a chairlike, six-membered transition state geometry is less strained than a five or seven-membered transition state.4^ However, Houk et al. employed force-field models and ab initio calculations to show that the preference for regioselective hydrogen abstraction through a six-membered rather than a seven-membered ring transition state arises from a favourable entropy of activation rather than an unstrained chair-like transition state geometry.41 Abstractions of (3- and 5-hydrogens are usually observed only when there are no y-hydrogens available for abstraction.42 Once the 1,4-biradical has formed, it can react by three possible routes: (1) cleavage to form an enol and an alkene, (2) cyclization to form a cyclobutanol, and (3) reverse hydrogen abstraction to reform the original ketone (Figure 1.13). In the cleavage or ehrnination reaction, the enol later tautomerizes to the keto form.4 3 H H H r\ , R' Yang HO . H HO R' C l s trans cyclization cleavage j? ketonization 9^  ^ ^ R-^ CH,-" R""S:H2 CH2 Figure 1.13. The Norrish type II photochemical reaction. R and R' can be alkyl or aromatic moieties 21 Introduction/Chapter 1 When dealing with solid state photochemical reactions, it is often assumed that the transition states for abstraction are limited to conformations that closely resemble the ground state reactants. As a result, valuable information about the transition state geometry can be found by obtaining the X-ray crystal structure of the reactant prior to reaction. The probable conformation of the 1,4-biradical intermediate of the reaction can also be predicted, and it is thus possible to understand more about the partitioning behavior of the biradical intermediate between cyclization, cleavage and disprop ortionation. 1.5 Geometric Concerns for Intramolecular Hydrogen Atom Abstraction The geometry of hydrogen abstraction by the triplet n,7t* excited state is crucial in determining if such a reaction will take place. Four geometric parameters have been defined and these are used to describe the spatial relationship of the "n" orbital on oxygen to the hydrogen being abstracted (Figure 1.14).44,45 Figure 1.14. Parameters defining spatial relationship for the abstraction of a hydrogen atom by the carbonyl oxygen atom. d=distance between hydrogen and oxygen, O H ; 8 = O H - C angle; A = C=0 H angle and co=dihedral angle formed between the O - H vector and its projection on the nodal plane of the C=0 group. 22 Introduction/Chapter 1 Early theoretical work proposed that an interatomic distance of 1.8 A was the upper limit for y-hydrogen abstraction (type H).4(> From their measurements obtained from molecular models on the McLafferty rearrangement of steroidal ketones, Djerassi and co-workers also proposed a d = 1.8 A upper limit for this process.47 Modeling of conformationally rigid steroid systems suggested a distance of 2.1 A . 4 8 However, when Scheffer et al. studied a series of ene-dione compounds, they found that the previous theoretical upper limits were not entirely true experimentally.49 Scheffer et al. found that successful intramolecular hydrogen abstraction by oxygen occurred with O H contact distances less than or equal to 2.7 A. These results suggested that hydrogen atom abstraction could take place over distances less than or equal to the sum of the van der Waals radii of the atoms involved^ (van der Waals radius of oxygen = 1.52 A ; hydrogen = 1.20 A). 51 However, further research on a-cycloalkyl-/> substituted acetophenones^2 and a-adamantyl-p-substituted acetophenones^ 3 led to the discovery that even the 2.72 A van der Waals radii sum for hydrogen atom abstraction is not an absolute upper limit. Of the seventeen compounds studied, five had abstraction distances greater than 2.72 A. For hydrogen atom abstraction to take place, there must be substantial overlap between the non-bonding n-orbital of the oxygen atom and the hydrogen atom being abstracted. Since the non-bonding orbital involved in the abstraction lies in the nodal plane of the % bond, it was suggested that the hydrogen atom should he in this plane so that co = 0°.54 It is expected that abstraction will be most facile when co = 0° and slowest 23 Introduction/Chapter 1 when co = 90°. However, there have been numerous examples in the literature reporting intramolecular hydrogen transfer for compounds with large co-angles.40 Intermolecular hydrogen abstraction has been observed in solid complexes of acetophenone and deoxycholic acid even when co = 90°.55 Wagner has proposed that there may be a cos2co dependency of the abstraction rate. 56 Theoretical studies have deemed a linear arrangement for C-H O ( 6 = 180°) to be the preferred orientation.57 Ab initio calculations by Houk and co-workers on triplet butanal revealed that large deviations from 0 = 180° and co = 0° increase the AH J (enthalpy) dramatically. 5 7 However, several examples show that 0 can vary significantly from 180°. 4 0>50,56,58 The best value for the C=0 H angle A is believed to be between 90° and 120°, depending on the orbital hybridization model selected, since the oxygen uses its in-plane n-orbital for abstraction. 59 The ideal values of the geometrical parameters for an efficient hydrogen atom abstraction by the carbonyl oxygen are summarized in Table 1.1.59a Table 1.1. Theoretical ideal values of the geometrical parameters for hydrogen atom abstraction by an excited carbonyl oxygen. d(A) co (deg) A (deg) 0(deg) <2.7 0 90-120 180 24 Introduction/Chapter 1 1.6. Asymmetric Induction in the Solid State In the last few decades, the demand for optically active materials has grown enormously. Industries in the biological and physical sciences- especially the pharmaceutical industry- have invested significant funds in the search for more efficient syntheses of optically pure compounds.^ Oa There are a number of ways to produce single enantiomers. Resolution is often used to separate racemic mixtures, but it is a labor-intensive method and limited in its apphcability, even though modern chromatographic techniques can give good resolution for many compounds.60b,c Nature provides an abundance of chiral compounds, in many instances 100% of one enantiomer, and these can be either isolated from natural sources or manufactured by enzymatic processes. Another method by which enantiopure compounds may be obtained is asymmetric synthesis.61 Asymmetric synthesis is defined as a process which converts a prochiral or racemic unit in a substrate molecule into a chiral unit, in such a way that the product enantiomers are produced in unequal amounts. 62 Enantiomeric excess (e.e.) is used in evaluating the efficiency of an asymmetric synthesis. Moreover, diastereomeric excess (d.e.) is used when diastereomers are produced. Both are defined below: e e % = x 1°° = %R - %S = r [ a , ] n U X x 100 Eq. 5 lAi + [pj [a]pure where R and S are the two enantiomers. d-e.% = \A} ' ^ j , x 100 = %A - %B Eq. 6 [A] + [B] where A and B are the two diastereomers. 25 Introduction/Chapter 1 Asymmetric synthesis in a photochemical reaction can be achieved by conducting the reaction in an optically active environment. This may result from the use of resolved chiral reactants, solvents, sensitizers, auxiliaries or circularly polarized light. 63 a This asymmetric influence on a prochiral or racemic reactant will lead to diastereomeric transition states of different energies; as a result, enantiomerically (or diastereomerically) enriched products will be generated. Unfortunately, in solution these photochemical asymmetric syntheses usually give photoproducts with low optical purities. Molecules are often too loosely coordinated in solution for one to exert a definitive asymmetric influence on the reactivity of another. 63 a In the solid state, there are 230 possible ways to pack molecules into a crystal lattice, and these are called space groups. Of the 230 space groups, 65 are chiral. Chiral crystals possess a dissymmetric spatial arrangement of the molecules in the crystal lattice; consequently, all resolved chiral molecules must crystallize in chiral space group s.63b,c,d An achiral molecule does not necessarily have to crystallize in one of the achiral space groups. It can crystallize in one of the 65 chiral space groups in a process called spontaneous resolution. Spontaneous resolutions are uncommon and at the present time can not be predicted beforehand. 64 Also, if one such resolution does occur there is an equal probability of obtaining both enantiomorphous crystals upon recrystallization, as has been demonstrated by Pincock et a/. 65. However, intentional seeding, stirring or accidental seeding from the environment of the recrystallization solution can result in the formation of enantiomorphously pure crystals. 66 26 Introduction/Chapter 1 These enantiomorphously pure crystals can provide optically active environments for solid-state photochemical reactions, aUowing asymmetric syntheses to be achieved. This was first demonstrated by Schmidt et al. in 1969.67 TJiey showed that achiral 4,4'-dimethyl-chalcone (10) crystallizes spontaneously in the chiral space group P2]2i2i. When single crystals of this material were treated with gaseous bromine, the chiral dibromide (11) was produced in 6% e.e. (Figure 1.15). Schmidt termed this process, which proceeds from a prochiral starting material to a chiral product without using any chiral reagent, an absolute asymmetric synthesis. The first photochemical absolute asymmetric synthesis was also reported by Schmidt and co-workers in 1973.68 j^Qy conducted [2 + 2] photodimerizations of dilute solid solutions of 12b in 12a, which also crystallize in the space group Fl\l\l\, to afford up to 70% enantiomeric excess of heterodimers 13c (Figure 1.16).69 Br Br O 10 11 Figure 1.15. Solid state asymmetric bromination of 10. 27 Introduction/Chapter 1 Til Ph Ph V 12a Th Ph Th V H - \ ^ Ar hv 13a Ar 13b Ar Ar Ar 12b Th Ph Ar Ph Th Ar Ar 13c Ar Ar Th / Cl Ar = Cl Figure 1.16. Absolute asymmetric solid state [2+2] photodimerization of 12. Solid state [2 + 2] dimerization was one of the first photoreactions applied to the problem of asymmetric induction,69,70 m ( \ j t n a s D e e n studied intensively.71.72 More recently, an absolute asymmetric synthesis by solid state [2 + 2] photocycloaddition of a charge-transfer complex was followed by X-ray powder diffraction and found to be a single crystal-to-single crystal transformation (14a, Figure 1.17). 73 The enantiomeric excesses for the photoproduct ranged from moderate to a high of 95%. Another recent example, which involves an intramolecular [2 + 2] photocycloaddition in the crystalline state, was also shown to give high enantioselectivity. Sakamoto reported that the achiral acyclic imide 15 underwent [2 + 2] cycloaddition to give a chiral oxetane 16 in >95% e.e. (determined by polarimetry) (Figure 1.18).74 28 Introduction/Chapter 1 Methyl group syn Methyl group anti at 0°C at -78°C syn 16/anti 16 ratio = 3.7 syn 16lanti 16 ratio = 6.5 major product syn, 35% e.e. major product syn, >95% e.e. Figure 1.18. [2 + 2] cycloaddition of achiral acyclic imides. Other unimolecular photoreactions have also been investigated for the purpose of solid state absolute asymmetric induction. Two examples of Norrish type II reactions in chiral crystals have been reported, and are shown in Figure 1.19. Scheffer et al. discovered that the achiral adamantyl ketone 18 crystallizes in the chiral space group Fl\2\2\, and solid state photolysis of these crystals yielded cyclobutanol 19 in 80% enantiomeric excess (Eq.l, Figure 1.19).75 The second example comes from Toda et al; 29 Introduction/Chapter 1 compound 20, which crystallizes in space group P2]2i2i, was photoisomerized to afford p-lactam 21 in 93% optical yield (Eq 2, Figure 1.19).76 The di-7r-methane rearrangement of dibenzobarrelenes has been thoroughly investigated in our laboratory, with several dibenzobarrelenes having been shown to undergo absolute asymmetric photochemical rearrangements in the solid state.7 7'7 8 p o r example, dibenzobarrelene 22 crystallizes in the space group P2i2i2i, and the solid state di-7t-methane rearrangement of the crystal gives photoproduct 23 in >95% optical yield (Eq 3, Figure 1.19).75'79 However, for this and other examples, enantioselectivity is high only when the photolysis is carried out to low conversion. Figure 1.19. Unimolecular absolute asymmetric photoreactions in chiral crystals. 30 Introduction/Chapter 1 1.7. The Chiral Handle Concept in Asymmetric Synthesis As shown in the previous section, it is possible to perform an "absolute asymmetric synthesis" using only achiral molecules. However, this approach has a significant drawback: the spontaneous crystallization of achiral reactant molecules in chiral space groups is rare and cannot be predicted. A more practical approach to obtaining enantioenriched products in solid state reactions involves the use of an external resolved chiral handle. The idea is to co-crystallize a prochiral photoreactive molecule with a photostable but optically active counterpart. Since an optically active component is present, a chiral space group is guaranteed. Moreover, with these two components being in close contact with each other in the crystalline state, the effect of asymmetric induction may be expected to be greater than for the corresponding reaction in solution phase. A recent example of the use of chiral handles in asymmetric induction involves the use of a (hphosphine oxide molecule with P-chirahty (Figure 1.20).%® Four optically active a^phosphine oxides with different aromatic (Ar) groups were prepared, and all were found to form 1:2 crystalline complexes with dibenzobarrelene 26. Solid state photolyses of these crystals gave compounds 27 and 28 in low to moderate enantiomeric excess. 31 Introduction/Chapter 1 O O II , •P Ph 25 COOH COOH COOEt 26 27 28 Figure 1.20. Asymmetric induction using P-chirality. An extension of the chiral handle concept employs acid/base chemistry. Prochiral acids and amines can be forced into chiral space groups by formation of salts with resolved amines and acids, respectively. This approach is referred to as the Ionic Chiral Auxiliary Concept. Upon photoreaction, asymmetric induction can occur in the prochiral compounds. Three examples in which moderately high enantioselectivities were obtained using ionic chiral auxiliaries are given in Figures 1.21 and 1.22. The solid state di-7t-methane rearrangement of dibenzobarrelenes 29 and 34 gave high optical yields; in addition, information was obtained on the absolute stereochemical pathway of this type of rearrangement (Figure 1.21).81,82 Enantiomeric excesses as high as 97% were achieved for the Norrish type II reaction of a-adamantyl derivative 35 when a salt of this compound with prolinol was photolyzed (Figure 1.22). 83 in both cases, the absolute stereochemical reaction pathways in the solid state were rationalized according to topochemical 32 Introduction/Chapter 1 principles.82'83 As expected, solution photolyses of all of the above salts gave racemic products. Figure 1.21. Asymmetric induction of various salts via the di-7i-methane photorearrangement. Figure 1.22. Asymmetric induction of salt 35 via the Norrish type II reaction. 33 Introduction/Chapter 1 1.8. Use of Hosts in Photochemical Asymmetric Synthesis Toda's group has succeeded in controlling the stereochemical courses of photoreactions of guest molecules in crystalline inclusion complexes of resolved host molecules.84 As shown in Figure 1.23, Toda et al. carried out different reactions including inter- and intramolecular [2 + 2] photocycloadditions (Eq 3 and 4), electrocyclic ring closure (Eq 1) and Norrish type II photocyclization (Eq 2). Different resolved host molecules were used, and two typical examples, 46 and 47, are shown in Figure 1.24. Most of the products obtained witlhn the inclusion complexes were formed in good to quantitative enantiomeric excesses.85,86 34 Introduction/Chapter 1 O (1) o OR hv Electrocyclic reaction R = Me,Et 38 39 Host e.e.% 46 100 (2) » M OH hv Ph-Ph N N Norrish type II , M e ^ X M e O ~ M e 40 4 1 Host e.e.% Chemical yield v. 46 100 82% o (3) MeO Me02 hv O P + 21 MeO MeCh 42 43 (4) Host e.e.% Chemical yield 47a 100 57% Host e.e.% Chemical yield 46 78 55% Figure 1.23. Asymmetric reactions in inclusion complexes. Cl' Ph 2 C— OH -O Cl Ph>' C - C = C - C = C - C ^ P h OH OH Ph2C - O H O (CH2)n (R,R)-(-)-46 47a n = 2 47b n = 3 Figure 1.24. Typical resolved host molecules. 35 Introduction/Chapter 1 Other groups have used inclusion complexes for solution phase asymmetric induction reactions. For example, Weber et al. carried out photocatalytic enantiodiscriminating oxygenations of a-pinene using cyclodextrin-linked porphyrins and molecular oxygen.8? These cyclodextrin molecules have been found to include preferentially one of the enantiomers of a-pinene over the other; enantioenriched products were thereby formed from the inclusion complexes. Depending on the solvents used, the enantiomeric excesses ranged from near zero to 40%. Another family of host molecules that has recently received considerable attention is that of the zeolites. Zeolites are ciystalline aluminosilicates with open framework structures having as primary building blocks either [SiO^ 4 - or [ A l O ^ - tetrahedra.88 When these building blocks are arranged in the sodalite configuration, they form the zeolite structure known as faujasite. The overall total framework charge of the zeolite is negative and hence must be balanced by a cation (M), typically an alkali or alkaline earth metal cation. These cations are readily exchangeable by conventional methods. The two most common unit cell compositions of faujasite zeolites are as follows: XType: M 8 6 (AlO 2 ) 8 6 (SiO 2 ) 1 0 6 -264 H 2 0 YType: M 5 6(A10 2) 5 6(Si0 2) 1 3 6-253 H 2 0 , where M is a monovalent cation. The tetrahedra in the zeolite framework are linked at all their corners to form channels and cages or cavities of discrete size. Access to the interior of the zeolites is provided by pores or windows, which can be of the same size or smaller than the channels, cages and cavities. The dimension of the pores determines the size of molecules 36 Introduction/Chapter 1 that can be adsorbed into these structures. X- and Y-type zeolites have spherical cavities of 13 A diameter with each of these connected through 8 A windows.89 The difference between X- and Y-type zeolites lies in the location that the charge compensating cations are situated, which ultimately determines the free volume available vvithm the supercage. Figure 1.25 shows the general structure of sodahte type zeolites. (a) (b) C A T I O N L O C A T I O N I N S I D E F A U J A S T T E C A G E S Figure 1.25. (a) Illustration of the sodalite type zeolites and (b) cation locations (1, H, III) within the faujasite cages with an illustration of the reduction in available space (relative) within the supercage as the cation size increases. This tinee-dimensional network causes zeolites to be viewed as supramolecular microreactors, in which the cages can exert their own special effects on the included molecules. A good example of this comes from the work of Ramamurthy et al. on polyenes (stilbene, 1,4-diphenylbutadiene and 1,6-diphenyIhexatriene) incorporated into either faujasite zeolites or pentasil zeolites (ZSM-5, -8, and -11) (Figure 1.26.).9^ Both 37 Introduction/Chapter 1 cis- and r^a^ s-stilbene (48 and 49 respectively) can be included into faujasites; only the latter was accommodated by pentasils. Ramamurthy concluded that the supercages have a profound effect on the molecular motion of the included guest and hence cause a drastic change in its photophysical properties. 4 9 hv 4 8 Medium Initial Photo stationary state mixture trans cis Benzene trans 28 72 cis 26 74 Li-X trans 56 44 cis 12 88 ZSM-5 trans 100 0 ZSM-8 trans 100 0 ZSM-11 trans 100 0 Figure 1.26. Photobehavior of cis- and frww-stilbene. 1.9. Research Obj ectives The present study is an extension of previous work from our laboratory on Norrish type II photoreactions in the solid state, with the aim of improving our knowledge of the empirical guidelines on hydrogen abstractability by the carbonyl oxygen. The first major objective of the present research is to develop structure-reactivity correlations in solid 38 Introduction/Chapter 1 state photochemistry. This is achieved by conducting photochemical reactions in the solid state and deterrnining structures of the reactant (and product) crystals by single crystal X-ray crystallography. We first chose to investigate the fer^butylcycloalkyl aryl ketones (structure 50) since it has been known for some time that these compounds are converted into a racemic mixture of photoproducts in high chemical and quantum yield with virtually no type II cleavage observed when irradiated in the solution state.9! Therefore it seemed likely that all the derivatives would have solid state conformations with abstractable y-hydrogen atoms. With the promising results obtained with the fer^butylcycloalkyl aryl ketones, the adamantyl aryl ketones (structure 51) also seemed like excellent candidates for undergoing the Norrish type II photoreaction. From the X-ray data, it is possible to determine the hydrogen atom abstraction geometry for these ketones and, when combined with previous knowledge, this information can help us to understand better the preferred spatial requirements for a successful type II reaction. 50 51 R = H or CH3 X = FL CH3, OCH3, F, CN, COOH or COOCH3 39 Introduction/Chapter 1 Our second goal was to study the partitioning of the biradical intermediates into photoproducts. We were interested in studying the effect of the crystal lattice on product selectivity (cleavage/cyclization and cis/trans product ratios), which would be influenced by the rigid conformations of the 1,4-biradical intermediates enforced by the solid state. Therefore, observation of the formation of topochemically controlled products in the solid state was the ultimate ambition. For comparison, detailed studies of the product ratios in isotropic media (solution state) were also explored. The third goal was to extend and explore further the field of asymmetric induction with the use of ionic chiral handles. Prochiral acids (52 and 53) were made to form salts with different optically active amines. Seventeen chiral salts were prepared, photolyzed, and their asymmetric induction ability examined. Again, X-ray crystallography was an invaluable tool by which to probe the possible topotacticity, i.e. single-crystal to single-crystal rearrangement, of these reactions. + X = optically active amine An extension of our third goal in asymmetric induction was an investigation of the photochemistry of some of the ketones in zeolites. This was a collaborative project with 40 Introduction/Chapter 1 Professor V. Ramamurthy at Tulane University. The work was initiated in order to see if asymmetric induction in these reactions could be carried out in other organized media. Our fourth and final goal was to perform MM3 calculations (energy minimization and steric calculations) of several ketones in order to determine the low energy conformations. A correlation between the experimental results and those calculated by MM3 was used as the basis by which to predict photoproduct formation. 1.10. References for Introduction 1. Roth, H. D. Angew. Chem. Ed. Engl. 1989, 28, 1193 and references cited therein. 2. Canuto, V. M.; Levine, J. S.; Auguston, T. R.; Imhoff, C. L.; Giampapa, M. S. Nature (London). 1983, 305, 281. 3. (a) Raven, P. H.; Johnson, G. B. Biology: Second Edition; Times Mirror/Mosby College Pubhshing: St. Louis, 1989; Chapter 9. (b) Cloud, P. Am. J. Sci. 1972, 272, 537. 4. Margulis, L.; Walker, J. C. G ; Rambler, M. Nature (London). 1976, 264, 620. 5. Blake, A. J.; Carver, J. H. J. Atoms Sci. 1977, 34, 720. 6. Levine, J. S.; Hays, P. B.; Walker, J. C. G. Icarus. 1979, 39, 295. 7. Gavezzotti, A.; Simonetta, M. Chem. Rev. 1982, 82, 1. 8. Photochemistry in Organized and Constrained Media; Ramamurthy, V., Ed.; VCH Publishers: New York, 1991. 9. Wohler, F. Pogg. Ann. 1828, 72, 253. 10. Trommsdorff H. Ann. Chem. Phar. 1834,11, 180. 41 Introduction/Chapter 1 11. (a) Markwald, W. Z. Phys. Chem. 1899, 30, 140. (b) Ciamician, G.; Silber, P. Chem. Ber. 1901, 34, 2040. (c) Ciamician, G.; Silber, P. Ber. Dtsch. Chem. Ges. 1907, 34, 2040. (d) Stobbe, H.; Steinberger, F. K Chem. Ber. 1922, 55, 2225. (e) De Jong, A. W. K. Chem. Ber. 1923, 56, 818. (f) Senier, A ; Shepheard, F. G. J. Chem. Soc. 1909, 95, 1943. 12. Kohlshutter, H. W. Z. Anorg. Allg. Chem. 1918, 105, 121. 13. (a) Cohen, M. D.; Schmidt, G. M. J. J. Chem. Soc. 1964, 1996. (b) Cohen, M. D.; Schmidt, G. M. J.; Sonntag, F. I. J. Chem. Soc. 1964, 2000. (c) Schmidt, G. M. J. J. Chem. Soc. 1964, 2014. (d) Schmidt, G. M. J. Pure Appl. Chem. 1971, 27, 647. 14. Libermann, C. Chem. Ber. 1889, 22, 124 and 782. 15. Bernstein, H. I.; Quimby, W. C. J. Am. Chem. Soc. 1943, 65, 1845. 16. (a) Ramamurthy, V.; Venkatesan, K. Chem. Rev. 1987, 87, 433. (b) Ramasubbu, N.; Guru Row, T. N.; Venkatesan, K.; Ramamurthy, V.; Rao, C. N. R. J. Chem. Soc, Chem. Comm. 1982, 178. 17. Cohen, M. D. Angew. Chem., Int. Ed. Engl. 1975, 14, 386. 18. Weiss, R. G.; Ramamurthy, V.; Hammond, G. S. Acc. Chem. Res. 1993, 26, 530. 19. (a) Gavezzotti, A.; Simonetta, M. In Organic Solid State Photochemistry; Desiraju, G. R , Ed.; Elsevier: Amsterdam, 1987; pp. 391. (b) Zimmerman, H. E.; Kutateladze, A. G.; Maekawa, Y.; Mangette, J. E. J. Am. Chem. Soc. 1994, 116, 9795. (c) Zimmerman, H. E.; Wilson, D. W. J. Org. Chem. 1994, 59, 1809. (d) Zimmerman, H. E.; Zhu, Z. J. Am. Chem. Soc. 1994, 116, 9151. (e) Zimmerman, H. E.; Zhu, Z. J. Am. Chem. Soc. 1995, 117, 5245. 20. (a) McBride, J. M. Acc. Chem. Res. 1983,16, 304. (b) McBride, J. M.; Segmuller, B. E.; Hollingsworth, M. D.; Mills, D. E.; Weber, B. A. Science 1986, 234, 830. 21. Ariel, S.; Askari, S.; Evans, S. V.; Hwang, C ; Jay, J.; Scheffer, J. R; Trotter, J.; Walsh, L.; Wong, Y. Tetrahedron 1987, 43, 1253. 22. (a) Kurihara, T.; Uchida, A ; Ohashi, Y.; Sasada, Y.; Ohgo, Y. J. Am. Chem. Soc. 1984,106, 5718. (b) Ohashi, Y.; Yanagi, T.; Kurihara, T.; Sasada, Y.; Ohgo, Y. J. Am. Chem. Soc. 1982,104, 6353. (c) Ohashi, Y.; Uchida, A ; Sasada, Y.; Ohgo, Y. Acta. Crystallogr. 1988, B44, 538. 23. Theocharis, C. R; Jones, W. In Organic Solid State Photochemistry; Desiraju, G. R, Ed.; Elsevier: Amsterdam, 1987; Chapter 2, pp. 47-68. 42 Introduction/Chapter 1 24. Baughman, R. H. J. Chem. Phys. 1978, 68, 3110. 25. Turro, N. J. Modern Molecular Photochemistry; BenjanriWCunmiings: Menlo Park, 1978. 26. De Mayo, P. In Rearrangements in Ground and Excited States, Volume 3; De Mayo, P., Ed.; Academic Press: New York, 1980. 27. Kagan, J. Organic Photochemistry: Principles and Applications; Academic Press: San Diego, 1993; pp. 5. 28. March, J. Advanced Organic Chemistry: Reactions, Mechanisms and Structure, Third Edition; John Wiley and Sons, Inc.: New York, 1985; pp. 205. 29. Shriver, D. F.; Atkins, P.; Langford, C. H. Inorganic Chemistry, Second Edition; Oxford University Press: London, 1994; pp. 70-73. 30. (a) Barltrop, J. A.; Coyle, J. D. Excited States in Organic Chemistry; John Wiley and Sons, Inc.: Toronto, 1975; pp. 55. (b) Shriver, D. F.; Atkins, P.; Langford, C. H. Inorganic Chemistry, Second Edition; Oxford University Press: London, 1994; pp. 28. (c) Michl, J.; Bonacic-Koutecky, V. Electronic Aspects of Organic Chemistry; John Wiley and Sons, Inc.: Toronto, 1990; pp. 26. 31. Falk, K. J.; Steer, R. P. J. Am. Chem. Soc. 1989, 111, 6518. 32. Wagner, P.; Park, B. In Organic Photochemistry, Volume. 11; Padwa, A., Ed.; Marcel Dekker Inc.: New York, 1991; Chapter 4. 33. Horspool, W. M. Aspects of Organic Photochemistry; Academic Press: New York, 1976; pp. 6. 34. (a) Coxon, J. M.; Halton, B. Organic Photochemistry; Cambridge University Press: London, 1987, pp. 3. (b) Michl, J.; Bonacic-Koutecky, V. Electronic Aspects of Organic Chemistry; John Wiley and Sons, Inc.: Toronto, 1990; pp. 44. 35. Baum, E. J.; Wan, J. K. S.; Pitts, J. N. J. Am. Chem. Soc. 1966, 88, 2652. 36. (a) Coyle, J. D. Introduction to Organic Photochemistry; John Wiley and Sons, Inc.: Toronto, 1986; pp. 119-125. (b) Kagan, J. Organic Photochemistry: Principles and Applications; Academic Press: San Diego, 1993; pp. 58-59. (c) Horspool, W. M. Aspects of Organic Photochemistry; Academic Press: New York, 1976; pp. 172-174. 37. Coxon, J. M.; Halton, B. Organic Photochemistry; Cambridge University Press: London, 1987; pp. 72. 43 Introduction/Chapter 1 38. O'Neil, H. E.; Miller, R. G.; Gunderson, E. J. Am. Chem. Soc. 1974, 96, 3351. 39. Scheffer, J. R. In Organic Solid State Photochemistry; Desiraju, G. R , Ed.; Elsevier Science Publishers: New York, 1987; Chapter 1. 40. Wagner, P. J.; Kelso, P. A.; Kemppainen, A E.; Zepp, R. G. J. Am. Chem. Soc. 1972, 94, 7500. 41. (a) Dorigo, A E. Houk, K. N. J. Org. Chem. 1988, 53, 1650. (b) Dorigo, A E.; McCarrick, M. A.; Loncharich, R. J.; Houk, K N. J. Am. Chem. Soc. 1990, 772, 7508. 42. Coxon, J. M.; Halton, B. Organic Photochemistry; Cambridge University Press: London, 1987; pp. 85. 43. Stephenson, L. M.; Brauman, J. I. J. Am. Chem. Soc. 1971, 93, 1988. 44. (a) Ariel, S.; Ramamurthy, V.; Scheffer, J. R; Trotter, J. J. Am. Chem. Soc. 1983, 105, 6959. (b) Ramamurthy, V.; Venkatesan, K. J. Am. Chem. Soc. 1987, 87, 433. 45. (a) Scheffer, J. R. Org. Photochem. 1987, 8, 249. (b) Scheffer, J. R. In Organic Solid State Chemistry; Desiraju, G. R, Ed.; Elsevier: New York, 1987; pp. 1. 46. (a) Pople, J. A ; Gordon, J. J. Am. Chem. Soc. 1967, 89, 4253. (b) Winnik, M. A. Acc. Chem. Res. 1977, 10, 173. (c) Dewar, M. J. S.; Doubleday, C. . J. Am. Chem. Soc. 1978, 100, 493 5. (d) Morrison, H.; Miller, A.; Pandey, B.; Severance, D.; Strommen, R; Bigot, B. Pure Appl. Chem. 1982, 54, 1723. 47. (a) Djerassi, R. Pure Appl. Chem. 1964, 9, 159. (b) Djerassi, C ; Williams, D. H.; von Muntzenbecher, G.; Budzikiewicz, H. J. Am. Chem. Soc. 1965, 87, 817. 48. Hewster, K ; Kalvoda, J. J. Angew. Chem., Int. Ed. Engl. 1964, 3, 525. 49. (a) Scheffer, J. R; Bhandari, K. S.; Gayler, R. E.; Wostradowski, R. A. J. Am. Chem. Soc. 1975, 97, 2178. (b) Scheffer, J. R; Jerrnings, B. M.; Louwerens, J. P. J. Am. Chem. Soc. 1976, 98, 7040. (c) Scheffer, J. R; Dzakpasu, A. A. J. Am. Chem. Soc. 1978, 100, 2163. (d) Ariel, S.; Evans, S.; Hwang, C ; Jay, J.; Scheffer, J. R; Trotter, J.; Wong, Y. F. Tetrahedron Lett. 1985, 26, 965. (e) Ariel, S.; Askari, S.; Scheffer, J. R; Trotter, J. Tetrahedron Lett. 1986, 27, 783. (f) Ariel, S.; Askari, S.; Scheffer, J. R; Trotter, J.; Wireko, F. J. Am. Chem. Soc. 1987, 109, 4623. (g) Ariel, S.; Askari, S.; Scheffer, J. R; Trotter, J.; Wireko, F. Acta Crystallogr. 1987, B43, 532. 50. Scheffer, J. R; Garcia-Garibay, M.; Omkaram, N. Org. Photochem. 1987, 8, 249. 44 Introduction/Chapter 1 51. (a) Bondi, A. J. Phys. Chem. 1964, 68, 441. (b) Edward, J. T. J. Chem. Educ. 1970, 47, 261. 52. Ariel, S.; Evans, S. V.; Omkaram, N.; Scheffer, J. R; Trotter, J. Mol. Crys. Liq. Cryst. 1986, 134, 169. 53. (a) Ariel, S.; Evans, S.; Garcia-Garibay, M.; Harkness, B. R; Omkaram, N.; Scheffer, J. R; Trotter, J. J. Am. Chem. Soc. 1988,110, 5591. (b) Scheffer, J. R; Trotter, J. Chem. Rev. Int.. 1988, 9, 271. (c) Ariel, S.; Garcia-Garibay, M.; Scheffer, J. R; Trotter, J. Acta. Crystallogr. 1989, B45, 153. (d) Evans, S.; Omkaram, N.; Scheffer, J. R; Trotter, J. Tetrahedron Lett. 1986, 27, 1419. (e) Evans, S.; Garcia-Garibay, M.; Omkaram, N.; Scheffer, J. R; Trotter, J. J. Am. Chem. Soc. 1986, 108, 5648. 54. Turro, N. J.; Weiss, D. S. J. Am. Chem. Soc. 1968, 90, 2185. 55. (a) Popovitz-Biro, R; Chang, H. C ; Tang, C. P.; Shochet, N. R; Lahav, M. Leiserowitz, L. Pure andAppl. Chem. 1980, 52, 2693. (b) Vaida, M; Popovitz-Biro, R.; Leiserowitz, L.; Lahav, M. In Photochemistry in Organized and Constrained Media; Ramamurthy, V., Ed.; VCH Publishers: New York, 1991; Chapter 6. 56. Wagner, P. J. Top. Curr. Chem. 1976, 66, 1. 57. Dorigo, A. E.; McCarrick, M. A.; Loncharich, R. J.; Houk, K. N. J. Am. Chem. Soc. 1990, 772, 7508 and references cited therein. 58. Lewis, E.S. In Isotopes in Organic Chemistry; Volume 2; Buncel, E.; Lee, C. C , Eds.; Elsevier: Amsterdam, 1976; pp. 134. 59. (a) Scheffer, J. R In Organic Solid State Photochemistry; Desiraju, G. R., Ed.; Elsevier: Amsterdam, 1987; Chapter 1, pp. 1-45. (b) Turro, N. J. Modern Molecular Photochemistry; Benjamin/Cummings: Menlo Park, 1978; Chapter 10. 60. (a) Federsel, H.J. CHEMTECH 1993, 24. (b) Mosbach, K.; Robinson, D. K. Chem. Comm. 1989, 969. (c) Mosbach, K.; Kempe, M. J. Chromatogr. A. 1995, 3, 694. 61. Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New York, 1983; Volumes 1-5. 62. Morrison, J. D.; Mosher, H. S. Asymmeric Organic Reaction; Prentice-Hall: New York, 1971. 63. (a) Inoue, Y. Chem. Rev. 1992, 92, 741. (b) Jacques, I; Collet, A.; Wilen, S. H. Enantiomers, Racemates and Resolution; Wiley Interscience: New York, 1983. (c) Bueger, M. J. Elementary Crystallography;WA<zy\ New York, 1963; pp. 199. 45 Introduction/Chapter 1 (d) Hahn, T.; Klapper, H. ^ International Tables for Crystallography; Hahn, T., Ed.; Reidel, Dordrecht: Holland, 1983; Volume A, Chapter 10. 64. Addadi, L.; Lahav, M. In Origins of Optical Activity in Nature; Walker, D. C , Ed.; Elsevier: New York, 1979; Chapter 14. 65. (a) Pincock, R. E.; Wilson, K. R. J. Am. Chem. Soc. 1971, 93, 1291. (b) Pincock, R. E.; Perkins, R. R; Ma, A. S. Science 1971, 774, 1018. 66. (a) Kondepudi, D.; Kaufinan, R.; Singh, N. Science 1990, 250, 975. (b) Kondepudi, D.; Bullock, K. M.; Digits, J. A.; Hall, J. K; Miller, J. M. J. Am. Chem. Soc. 1993, 775, 10211. (c) McBride, J. M.; Carter, R. L. Angew Chem. Int. Ed. Engl. 1991, 30, 293. (d) Fu, T.; Liu, Z.; Scheffer, J. R; Trotter, J. J. Am. Chem. Soc. 1993, 775, 12202. 67. Penzien, K.; Schmidt, G. M. J. Angew. Chem., Int. Ed. Engl. 1969, 8, 608. 68. Elgavi, A.; Green, B. S.; Schmidt, G. M. J. J. Am. Chem. Soc. 1973, 95, 2058. 69. (a) Green, B. S.; Lahav, M.; Schmidt, G. M. J. Mol. Cryst. Liq. Cryst. 1975, 29, 187. (b) Elgavi, A.; Green, B. S.; Schmidt, G. M. J. J. Am. Chem. Soc. 1973, 95, 2058. 70. Scheffer, J. R; Garcia-Garibay, M.; Nalamasu, O. In Photochemistry on Solid Surfaces, Anpo, M.; Matsuura, T., Eds.; Elsevier: Amsterdam, 1989. 71. Addadi, L.; Lahav, M. Pure Appl. Chem. 1979, 51, 1269. 72. Hasegawa, M.; Chung, C. -M.; Muro, N.; Maekawa, Y. J. Am. Chem. Soc. 1990, 112, 5676. 73. Suzuki, T.; Fukishima, T.; Yamashita, Y.; Miyashi, T. J. Am. Chem. Soc. 1994,116, 2793. 74. Sakamoto, M.; Takahashi, M.; Fujita, T.; Watanabe, S.; Ida, I; Nishio, T.; Aoyama, H. J. Org. Chem. 1993, 58, 3476. 75. Evans, S. V.; Garcia-Garibay, M.; Omkaram, N.; Scheffer, J. R; Trotter, J. J. Am. Chem. Soc. 1986, 108, 5648. 76. (a) Toda, F.; Yagi, M.; Soda, S. J. Chem. Soc, Chem. Commun. 1987, 1413. (b) Sekin, A.; Hori, K.; Ohashi, Y.; Yagi, M.; Toda, F. J. Am. Chem. Soc. 1989, 111, 697. 77. (a) Organic Chemistry in Anisotropic Media; Scheffer, J. R., Turro, N. J., Ramamurthy, V., Eds.; Tetrahedron Symposia-in-Print: Amsterdam, 1987; Number 4 6 Introduction/Chapter 1 29. (b) Scheffer, J. R.; Garcia-Garibay, M.; Nalamasu, O. In Organic Photochemistry; Padwa, A., Ed.; Marcel Dekker: New York, 1987; Volume 2, Part 2, Chapter 20. (c) Chen, J.; Scheffer, J. R; Trotter, J. Tetrahedron 1992, 48, 3251. 78. Scheffer, J. R; Trotter, J; Yang, J In Handbook of Organic Photochemistry and Photobiology; HorspooL W. M , Ed.; CRC Press: Boca Raton, 1994; Chapter 16, pp.204-221. 79. Caswell, L.; Garcia-Garibay, M.; Scheffer, J. R; Trotter, J. J. Chem. Educ 1993, 70, 785. 80. Borecka, B.; Fu, T. Y.; Jones, R; Liu, Z.; Scheffer, J. R; Trotter, J. Chem. Mater. 1994, 6, 1094. 81. (a) Gudmundsdottir, A.; Scheffer, J. R. Tetrahedron Lett. 1990, 31, 6807. (b) Gudmundsdottir, A.; Scheffer, J. R. Photochem. Photophys. 1990, 54, 535. 82. Gudmundsdottir, A.; Scheffer, J. R; Trotter, J. Tetrahedron Lett. 1994, 35, 1397. 83. Jones, R; Scheffer, J. R; Trotter, J.; Yang, J. Tetrahedron Lett. 1992, 38, 5481. 84. Toda, F. Synlett 1993, 303. 85. Toda, F.; Miyamoto, H.; Takeda, K ; Matsugawa, R; Maruyama, N. J. Org. Chem. 1993, 58, 6208. 86. Toda, F. Mol. Cryst. Liq. Inc. Nonlin. Opt. 1988, 161, 355. 87. Weber, L.; Imiolxzyk, I.; Haufe, G.; Rehorek, D.; Hennig H. J. Chem. Soc, Chem. Commun. 1992, 301. 88. Ramamurthy, V. In Photochemistry in Organized and Constrained Media; Ramamurthy, V., Ed.; VCH Publishers: New York, 1991; Chapter 10. 89. Ramamurthy, V.; Eaton, D. F.; Caspar, J. V. Acc. Chem. Res. 1992, 25, 299. 90. Ramamurthy, V.; Caspar, J. V.; Corbin, D. R; Eaton, D. F.; Kauffman, J. S.; Dybowski, C. J. Photochem. Photobiol. A, Chem.. 1990, 51, 259. 91. Lewis, F. D.; Johnson, R. W.; Johnson, D. E. J. Am. Chem. Soc. 1974, 96, 6090. 47 RESULTS AND DISCUSSION 4 8 Results/Discussion/Chapter 2 CHAPTER 2 Preparation of Substrates 2 . 1 . Synthesis of tert-Butyl Cyclohexyl Aryl Ketones The following three schemes (Figures 2.1-2.3) detail the synthetic routes that were taken in the preparation of the ter t-butyl cyclohexyl phenyl ketones. cis- and trans-54 COOH l) H 2 NCSNH 2 (separation of isomers') ^ 2)H 2 0 cis-54 O H X = H: 56 X = F: 57 ,X AlCk. X = H or F Cl for X = H 1) NaH 2) Mel o CH, 58 Figure 2.1. Synthesis of ketones 56, 57 and 58. 49 Results/Discussion/Chapter 2 COOH H+ CH3OH 54 CH,OH CH 3 LiAlH 4 cis- and trans- 61 silica gel column chromatography CFf>OH CH 3 PCC CH 2C1 2 cis- 61 CO2CH3 X = F 66 CH 3 67 OCH3 68 59 1) LDA 2) Mel C 0 2 C H 3 CH 3 cis- and trans- 60 O CH 3 62 X—(^)—MgBr X = F , C H 3 , O C H 3 X = F 63 CH 3 64 OCH 3 65 Figure 2.2. Synthesis of ketones 66, 67 and 68. 5 0 Results/Discussion/Chapter 2 1) O H , H 2 0 2) H + , H 2 0 T COOH Figure 2.3. Synthesis of ketones 69, 70 and 71. These fer^-butyl cyclohexyl aryl ketones are all new compounds, except for 56 and 58, which were prepared previously by others. 1 The spectra of ketones 56 and 58 were identical to those reported in the literature. All of the new compounds were fully characterized by spectroscopic and analytical methods and X-ray structure analyses in some cases. The syntheses and characterizations are described in greater detail in the Experimental Section (Chapter 7 ) . Typical iH-NMR spectra of the ketones are shown in Figure 2 . 4 . In the Results and Discussion section, trivial names for these ferNbutylcyclohexyl-substituted aryl ketones are used for simplicity and clarity; their IUPAC nomenclatures are given in the Experimental section. 51 Results/Discussion/Chapter 2 57 A < i i 1 r i i i i r i i i i i i i— i i i | i r B 7 4 T " I | I I 3 66 A—JL__ M « 4 . Jw B / 4 3 2 1 b 68 • • . • l i . • , i , • 1 M M . 4 3 2 1 b 71 ' ' 1 1 1 ' r ' ' I' i v i i i i i i i i | ' 4 Figure 2.4. Typical iH -NMR spectra of ketones 57,66,68 and 71. 52 Results/Discussion/Chapter 2 2.2. Synthesis of Adamantyl Aryl Ketones A similar synthetic route was employed in the preparation of the adamantyl phenyl ketones as was used with the fe^butylcyclohexyl phenyl ketones. The synthetic pathways are outlined in Figures 2.5 and 2.6. 1) NaH 2) Mel 1' 78 Figure 2.5. Synthesis of ketones 77 and 78 53 Results/Discussion/Chapter 2 80 KCN/ DMSO 84 Figure 2.6. Synthesis of ketones 80, 81, 82, 83 and 84. 54 Results/Discussion/Chapter 2 These adamantyl phenyl ketones are all new compounds and were fully characterized by spectroscopic and analytical methods and X-ray structure analyses in some cases. The syntheses and characterizations are described in greater detail in the Experimental Section (Chapter 7). Typical ^H-NMR spectra of the ketones are shown in Figure 2.7. 78 80 1 1 1 1 i * ' S 1 J , 1 -i—r-j—i—i—i—i—III ! i 1 j1" T"i—i i i r i—i—i—\—i—i—i—i—r 4 3 ? -i—r—l—i—i—r-(ppm) Figure 2.7. Typical %-NMR spectra of ketone 78, 80, 82 and 84. 55 Results/Discussion/Chapter 2 In the Results and Discussion section, trivial names for these adamantyl-substituted ketones are used for simplicity and clarity; their IUPAC nomenclatures are given in the Experimental section. 2.3. The Preparation of Optically Active Salts from Carboxylic Acids 70 and 83 One of the main aims for this thesis was to find salts of acids 70 and 83 in which the Norrish Type II photoreaction is very enantioselective. Therefore, it was never considered to use non-optically active bases (amines). It remained to find optically active bases which form salts with acids 70 and 83. These salts must be crystalline so that the chirahty of the crystals can be transferred via the Norrish type II reaction into the photoproducts. The degree of asymmetric induction will then depend on the molecular arrangement in the crystals. A decision was made to utilize natural chiral amines and their simple derivatives as a chiral resource. No special preferences were made in selecting amines for these studies other than they had to be readily available. It did turn out that all of the bases used in this thesis were either primary or secondary amines. Crystalline salts were prepared by reaction of carboxylic acids 70 and 83 with several optically active amines (Tables 2.1 and 2.2). All of the salts were shown to be simple 1:1 complexes. The characterization of the newly formed salts was performed by first measuring their melting points. The melting points of all the salts are different from those of their precursors, i.e. the carboxylic acid and the corresponding amine. Secondly, the solid state TR spectra (KBr pellet) were analyzed. Salt formation resulted in a characteristic change in the carboxylic acid OH stretching band at ca. 3500-2400 cm'l, which was replaced with multiple combination bands for ammonium N H + in the 3200-2200 cm"l region. Also, the strong carboxylic acid carbonyl stretch at ca. 1690 cm"l was 56 Results/Discussion/Chapter 2 replaced by two bands for the carboxylate anion; a strong absorption in the 1650-1550 crn"1 region and a weaker one near 1400 cm~l. Informative data also came from the FAB mass spectra of these salts, which gave the (M + 1)+ peak in each case. In addition, the NMR, i 3 C NMR, APT experiment and elemental analyses were all in agreement with the proposed structures. X-ray diffraction analysis of salts 93, 98, 99 and 101 were also carried out to reveal more structural features which will be discussed later in this thesis. 57 Results/Discussion/Chapter 2 Table 2.1. The Preparation of Optically Active Salts from Carboxylic Acid 70 70 70-Salt Entry Salt# Optically Active Amine Solvent Crystal Morphology Melting Point (°C) 1 85 S-(+)-prolinol acetonitrile powder 167-169 2 86 (lS,2S)-(+)-v|/-ephedrine acetonitrile or sublimation long thin plates 151-154 3 87 S-(+)-arginine ethanol powder 222-224 4 88 (S)-(-)-a-methyl-benzyl amine acetonitrile long thin flat needles 224-225 5 89 (R)-(+)-a-methyl-benzyl amine acetonitrile long thin flat needles 224-225 6 90 (lR,2S)-(-)-ephedrine acetonitrile long thin plates 179-181 7 91 (S)-(-)-proline -^butyl ester acetonitrile powder 227-229 8 92 (lR,2S)-(-) norephedrine acetonitrile/ ethanol long flat plates 171-174 9 93 S-(-)-prolinamide acetonitrile plates* 147-148 10 94 (lS)-(-)-2,10-camphorsultam methanol/ acetonitrile plates (flakes) 219-225 11 95 (S)-(+)-lysine ethanol slightly yellow plates 204-206 Crystals were suitable for X-ray diffraction analysis. 58 Results/Discussion/Chapter 2 Table 2.2. The Preparation of Optically Active Salts from Carboxylic Acid 83 COOH HNRR COO" NH 2RR 83 83-Salt Entry Salt# Optically Active Amine Solvent Crystal Morphology Melting Point (°C) 1 96 S-(+)-prolinol acetonitrile powder 133-135 2 97 (lS,2S)-(+)-M7-ephedrine acetonitrile acetonitrile or ethanol 158-161 3 98 (S)-(-)-a-methyl-benzyl amine ethanol/ acetonitrile long thin flat needles* 210-212 4 99 (R)-(+)-a-methyl-benzyl amine ethanol/ acetonitrile long thin flat needles* 210-212 5 100 (lR,2S)-(-)-ephedrine acetonitrile long thin plates 186-188 6 101 (lR,2S)-(-)-norephedrine acetonitrile/ ethanol long flat plates* 147-149 Crystals were suitable for X-ray diffraction analysis. 59 Results/Discussion/Chapter 3 CHAPTER 3 Preparation and Identification of Photoproducts 3.1. The Photochemical Reactions of Cycloalkyl Aryl Ketones Hydrogen atom abstraction by photoexcited carbonyl compounds has played a central role in the development of a general picture of how photochemical reactions occur. The reactions of biradicals- in particular, the mechanisms for intersystem crossing and product formation- have become topics of major interest. New biradical rearrangements are regularly reported, and have even been applied by synthetic organic chemists in natural products synthesis. ^  By 1972, the Norrish type II reaction of ketones was known to involve both singlet and triplet state 1,4-biradical intermediates.^  Because the singlet state reaction usually involves short biradical lifetimes, it is less well understood than the triplet reaction and thus the triplet reactions of aryl ketones have been the most widely studied. 4 Tables 3.1 and 3.2 list the ketones which we have studied. Photolysis, with light of X >290 nm, in dilute solution (benzene, acetonitrile or acetone) or in the solid state yielded Norrish type II photoproducts exclusively, through either the cleavage or the cyclization route. Product ratios for the two different mechanisms are also given in these tables; product ratios were unaffected by changes in solvent (for solution photolyses) or conversion levels. The numbering assigned to the photoproducts is given in Table 3.3. 60 Results/Discussion/Chapter 3 Table 3.1. Photoproduct ratios for tert-butyl cyclohexyl aryl ketones. Ketone R = X = Irradiation % Photoproduct Distribution (%): Medium f Conversion cleavage vs cyclization cleavage cis- trans-56 H H benzene solution 37 100 0 0 sohd state nil nil nil 57 H F benzene solution 24 100 0 0 sohd state nil nil nil 58 C H 3 H benzene solution 98 0 100 0 sohd state 83 0 100 0 66 C H 3 F benzene solution 100 0 94 6 sohd state 100 0 100 0 67 C H 3 C H 3 acetone solution 85 0 100 0 sohd state 100 0 100 0 68 C H 3 OCH 3 acetone solution 89 0 92 8* sohd state 58 0 100 0 69 C H 3 CN acetone solution 94 0 100 0 sohd state 100 0 100 0 70 C H 3 COOH acetone solution 100 0 93$ 7*$ sohd state 100 0 100$ 0 71 C H 3 C 0 2 C H 3 acetone solution 88 0 93 7 * sohd state 79 0 100 0 f The solution phase photolysis of substrates 56 and 58 were previously reported in the literature (ref. Ic). $ These photoproducts were only isolated as their corresponding methyl ester. * These photoproducts were only characterized spectroscopically as part of a mixture. NOTE; In this thesis (Chapters 3, 4, and 8), the carbon atom numbering of the cyclobutanol photoproducts do not follow IUPAC nomenclature rules. For the correct IUPAC numbering, see Appendix A (page 345). In Chapter 8, the cyclobutanol names follow the carbon atom numbering given in Appendix A, and thus are the correct names. 61 Results/Discussion/Chapter 3 Table 3.2. Photoproduct ratios for adamantyl aryl ketones. cyclization product cw-cyclobutanol Ketone R = X = Irradiation % Photoproduct Distribution (%): Medium Conversion cleavage vs cyclization cleavage cis- trans-11 H H benzene solution nil nil nil solid state nil nil nil 78 C H 3 H benzene solution 97 0 100 0 solid state 100 0 100 0 80 H F benzene solution nil nil nil solid state nil nil nil 81 C H 3 F benzene solution 93 0 100 0 solid state 100 0 100 0 82 C H 3 CN benzene solution 97 0 100 0 solid state 100 0 100 0 83 C H 3 COOH benzene solution 100 0 100* 0 solid state 100 0 100* 0 84 C H 3 C Q 2 C H 3 benzene solution 91 0 100 0 solid state 100 0 100 0 This photoproduct was only isolated as its corresponding methyl ester. NOTE: In this thesis (Chapters 3, 4, and 8), the carbon atom numbering of the cyclobutanol photoproducts do not follow IUPAC nomenclature rules. For the correct IUPAC numbering, see Appendix A (page 345). In Chapter 8, the cyclobutanol names follow the carbon atom numbering given in Appendix A, and thus are the correct names. 62 Results/Discussion/Chapter 3 Table 3.3. Numbering of isolated photoproducts as compiled from Tables 3.1 and 3.2. Ketone R = X = Photoproduct cleavage cis- trans-56 H H 102 57 H F 103 58 C H 3 H 104 66 C H 3 F 105 116 67 C H 3 C H 3 106 68 C H 3 OCH 3 107 117* 69 C H 3 CN 108 70 C H 3 COOH 109f 118*f 71 C H 3 C 0 2 C H 3 110 119* 78 C H 3 H 111 81 C H 3 F 112 82 C H 3 CN 113 83 C H 3 COOH 114f 84 C H 3 C Q 2 C H 3 115 * These photoproducts were only characterized spectroscopically as part of a mixture. | These photoproducts were never isolated and only determined as their corresponding methyl esters. The solution state photochemistry of ketones 56 and 58 had been investigated in some detail as far back as the 1960's,ia>D but a full paper was not published until 1974.1° Early papers used these ketones as probes in attempts to understand the effects of molecular conformation on photochemical behaviour.1 Lewis et al. reported that photolyses of ketones 56 and 58 led to the formation of photoproducts 102 and 104 respectively (Figure 3.1). Irradiation of ketone 56 in either benzene or 1-propanol solution resulted in formation of the elimination product 102 as the only primary photoproduct observed by gas chromatography or NMR analysis of the reaction mixture. ^ c Prolonged irradiation converted 56 to acetophenone. Infrared 63 Results/Discussion/Chapter 3 analysis of the product mixture corifirmed the absence of alcoholic products; i.e., no cyclization product was formed. Unlike 56, ketone 58 gave bicyclic alcohol 104 as the only photoproduct upon irradiation in benzene. These results were corifirmed in the present study. Figure 3.1. Photolyses of ketones 56 and 58. 3.2. Identification of Cleavage Photoproducts 102 and 103 The structure of 102 can be easily deduced from the following selected spectral data mentioned in the paper published by Lewis and co-workers^0: a) IR spectrum (film) 1680 cm'l. b) i H NMR (CC14, 90 MHz): 8 7.9 (2 H, m, Ax-H), 7.4 (3H, m, Ar-H), 5.9-4.8 (3H, m), 2.82 (2H, t), 2.1 (IH, m), 1.4 (4H, m), 0.85 (9H, s, fert-butyl). c) LRMS: (EI) m/e (relative intensity), 244 (M +), 188, 133, 120, 105 (base peak), 77. 64 Results/Discussion/Chapter 3 The IR spectrum reveals the presence of a carbonyl group, while the mass spectrum indicates that the photoproduct has the same molecular mass as the starting ketone 56. The most important piece of data is the three-hydrogen multiplet at 8 = 5.9-4.8 ppm in the Ifl NMR, which indicates the presence of vinylic protons. An analogue of ketone 56 (ketone 57) was prepared for this thesis, and its photolysis led to formation of a similar elimination product (103, Figure 3.2). Selected spectral features of photoproduct 103 are shown in Figure 3.3. Figure 3.2. Photolysis of ketone 57. 65 Results/Discussion/Chapter 3 F 9H 66 Results/Discussion/Chapter 3 Figure 33. (a) The *H NMR spectrum (400 MHz, CDC13) and (b) the ! H NMR COSY spectrum (400 MHz, CDCI3) of photoproduct 103. 67 Results/Discussion/Chapter 3 Photolysis of ketone 57 in benzene solution yielded photoproduct 103; however, conversion had to be kept to < 20%, since compound 103 can itself undergo the Norrish type II reaction to yield 4-fluoroacetophenone. Interestingly, when 56 and 57 were irradiated in the solid state, they were both found to be photostable. As a result, no further fer/-butyl cyclohexyl aryl ketones possessing a-hydrogens were synthesized. A discussion of the lack of photoreactivity of ketones 56 and 57 will be presented later in this thesis. 3.3. Identification of Cyclization Photoproducts: Cis-Cyclobutanols 104 - 1 1 0 . In contrast to compound 102, determination of the structure of cyclobutanol 104 is difficult. Lewis et al. showed only the following spectral data:Ac a) IR spectrum (CCI4) 3610 cm"1. b) A H NMR (CCI4, 90 MHz): 8 7.2 (5 H, m), 2.6 (IH, m), 1.15 (3H, s), 0.65 (9H, s). c) LRMS: (EI) m/e (relative intensity), 258 (M+), 256, 242, 145, 143, 129, 91 (base peak), 81, 77. Lewis and co-workers also photolyzed ketone 120 in benzene solution, and obtained the bicyclic alcohol 121 and benzaldehyde as the only primary products (Figure 3.4). The following spectroscopic data were reported for alcohol 121:1° a) IR spectrum (CCI4) 3610 cm"1. b) Hi NMR (CCI4, 90 MHz): 8 7.2 (5 H, m), 2.48 (IH, m, H 5), 2.28 (IH, t, J AB = 8.0 Hz), 2.1-1.6 (6H, m), 1.64 (IH, s, OH), 1.22 (3H, s, CH 3), 1.20 (IH, d, H a). 68 Results/Discussion/Chapter 3 The structure of 121 was assigned on the basis of spectroscopic data consistent with previous reports for bicyclo[3.1.1]heptan-6-ols (122, Figure 3.5). 5 Hence the stereochemical assignment of 104 was assigned according to photoproduct 121. Ph + PhCH 120 121 Ha Figure 3.4. Photolysis of ketone 120 to bicyclic alcohol 121. endo-12 OH Figure 3.5. Structure and assignment of bicyclo[3.1. l]heptan-6-ols studied by Wiberg and co-workers. We were puzzled by the fact that the apparently less stable c/s-isomer of 104 would be favoured. This isomer, which has the phenyl ring located over the bulk of the cyclohexyl ring, is sterically more hindered than the trans-isomer. Therefore, we undertook further investigations in order to determine if the assignment of photoproduct 104 as the czs-isomer is in fact correct. Figure 3.6 shows selected spectral features for compound 104. Extensive NMR spectroscopic techniques were performed, including HETCOR and NOE. Since 104 is an oil, X-ray crystallographic techniques could not be employed in order to determine positively the stereochemistry of the cyclobutanol. 69 Results/Discussion/Chapter 3 However, we were able to determine the X-ray structure of a derivative of 104. The structure of this derivative (107) showed conchisfvery that the stereochemical assignment of a c/s-cyclobutanol to 104 was indeed correct. As will be shown later, compounds 104 and 107 had similar spectroscopic properties. 13 (a) I | l I I 1—(—1 1 1 i | r—I r 8.0 7.<5 7.71 H3,H7' 70 Results/Discussion/Chapter 3 (b) Ji •4» + i i i i i i i | i i i i i i i i i i i i i i i i i i i | i i i i i i i i i i i i i i i i i M | i i i i i i i m i i i i i i i i i | i i i i i i i i i i i i i i i i i i i | i r 8 6 4 2 0 PP" Figure 3.6. (a) The lH NMR spectrum (500 MHz, CgDg) and (b) full HMQC spectrum (500 MHz, C$D6) of photoproduct 104. 71 Results/Discussion/Chapter 3 major j^or Figure 3.7. Photolysis of ketone 68. Cyclobutanol 107 was prepared by photolysis of ketone 68 in either the solution or solid state (Figure 3.7). The Iff NMR spectrum, ORTEP drawing and packing diagram of this photoproduct are shown in Figures 3.8, 3.9 and 3.10, respectively. X-ray diffraction analysis was conducted on crystals derived from the solid state photolysis. According to the X-ray crystallographic analysis, product 107 crystallizes from diethyl ether/hexanes solution as colourless prisms in the achiral space group (P2i/c), with 4 molecules in the unit cell. 72 Results/Discussion/Chapter 3 107 H12 H13 I 1 1 1 1 ppa H15 H3,H7' H8 H7 H6' OH i l l I I I I I 1 H9 i ' 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 6 5 4 3 2 H5tH5' • 1 1 1 1 1 1 1 Figure 3.8. lH NMR spectrum (500 MHz, CgDg) of photoprochict 107. 73 Results/Discussion/Chapter 3 Figure 3.9. The ORTEP stereodiagram of photoproduct 107. Figure 3.10. The crystal packing stereodiagram of photoproduct 107. 74 Results/Discussion/Chapter 3 All these photoproducts, which were derived from the photofyses of ferf-butyl cyclohexyl ketones, were shown to have similar spectral features. Figure 3.11 shows X H NMR spectra for compounds 105, 106, 108 and 110, and tables 3.4 and 3.5 compare the A H and A ^C spectra for all major photoproducts of the fe/7-butyl cyclohexyl aryl ketones. (a) 105 J I OH I—I—I—i—|—i—i—i—i—j—,—i T — i — | — i — i — i — i — | — i — i — i — i — | — i — i — i — i — | — i — i — i — I — | — i — i — i — i — l — i — i — i — i — | — i — I — i — i — | — r 0 6.5 «.0 3.5 3.0 2.5 2.0 1.5 1.0 .5 PPM 75 Results/Discussion/Chapter 3 76 Results/Discussion/Chapter 3 77 Results/Discussion/Chapter 3 t i Figure 3.11. J H NMR spectra (500 MHz, C 6 D 6 ) of photoproducts (a) 105, (b) 106, (c) 108, and (d) 110. 78 Results/Discussion/Chapter 3 Table 3.4: A H nmr data (400 and 500 MHz, C^J)^) for photoproducts of the general structure below. A H nmr spectrum (400 and 500 MHz, CgD 6), 5 ppm a Assignment H-x X = H 104 X = F 105 X = C H 3 106 X = O C H 3 107 X = C N 108 X = C 0 2 C H 3 110 H-3 part of the multiplet (2H) at: 2.91-2.88 | 2.85-2.79 | 2.93-2.88 2.95-2.89 2.76-2.69 2.86-2.80 H-4 multiplet (IH) at: 1.71-1.66 | 1.67-1.61 1.73-1.67 1.74-1.68 1.60-1.54 1.67-1.60 H-5 and H-5' multiplet (2H) at: 1.49-1.35 | 1.39-1.23 1.55-1.38 1.56-1.39 1.37-1.00 1.41-1.22 H-6 multiplet (IH) at: 1.90-1.82 | 1.85-1.78 1.92-1.84 1.93-1.86 1.78-1.69 1.84-1.76 H-6' multiplet (IH) at: 2.16-2.11 | 2.02-1.95 2.20-2.13 2.19-2.12 1.89-1.82 2.06-2.00 H-7 doublet (IH) at:b 1.03-1.01 | 1.00-0.97 1.06-1.01 1.05-1.02 0.93-0.91 1.00-0.96 H-7' part of the multiplet (2H) at: 2.91-2.88 | 2.85-2.79 | 2.93-2.88 2.95-2.89 2.76-2.69 2.86-2.80 H-8 singlet (3H) at: 1.11 | 1.03 1.14 1.15 0.93 1.05 H-10 singlet (9H) at: 0.66 | 0.63 0.68 0.69 0.53 0.61 H-12 multiplet (2H) at: 7.35-7.32 | 7.16-7.11 7.30-7.26 7.32-7.28 7.01-6.96 7.34-7.30 H-13 multiplet (2H) at: 7.11-7.01 | 6.76-6.71 6.95-6.91 6.73-7.28 7.01-6.96 8.07-8.03 H-14 multiplet (IH) at: 7.11-7.01 I I I | | H-15 singlet (3H) at: 1 2.10 3.32 H-16 singlet (3H) at: 3.52 O H singlet (IH) at: 1.30 | 1.22 1.36 1.31 1.16 1.40 X H nmr spectrum of photoproduct 108 acquired at 400 MHz, all others at 500 MHz. H7 for photoproduct 110 is actually a multiplet (see Figure 3.12a) and not a doublet. 79 Results/Discussion/Chapter 3 Table 3.5: 1 3 C nmr (50.3 and 125.8 MHz, CgD 6) data for photoproducts of the general structure below. 1 3 C nmr spectrum (50.3 and 125.8 MHz, CgDg), 5 ppm a C-x X = H 104 X = F b 105 X = C H 3 106 X = OCH 3 107 X = CN 108 X = C 0 2 C H 3 110 1 47.25 47.13 47.29 47.34 46.88 47.11 2 80.98 80.39 80.92 80.76 80.33 80.67 3 47.63 47.49 47.62 47.53 47.86 47.94 4 54.65 54.48 54.71 54.68 54.30 54.54 5 20.57 20.41 20.61 20.55 20.49 20.62 6 37.27 37.09 37.34 37.39 36.78 37.04 7 46.74 46.66 46.78 46.79 46.44 46.63 8 19.91 19.73 19.94 19.91 19.59 19.79 9 32.74 32.70 32.77 32.78 32.62 32.69 10 28.80 28.72 28.86 28.85 28.59 28.71 11 146.30 142.09 & 142.06 143.45 138.53 150.47 129.48 12 127.32 129.63 & 129.57 127.90 129.04 128.36 127.94 13 127.86 114.58 & 114.41 128.46 113.19 131.33 129.27 14 128.34 163.17 & 161.21 136.68 159.17 118.82 151.02 15 21.07 54.67 111.40 166.54 16 51.55 1 J C nmr spectrum of photoproduct 108 acquired at 50.3 MHz, all others at 125.8 MHz. For compound 105, carbons C l l to C14 are doublets due to C-F coupling. 80 Results/Discussion/Chapter 3 Analysis of the spectral data for photoproduct 110 is shown below, and similar analyses for each of photoproducts 104 to 109 can be performed. Elemental analysis and high resolution mass spectroscopic analysis revealed that 110 has the same formula and parent mass as the starting ketone 71. The IR spectrum possesses a sharp OH stretching band at 3492 cm"1, indicating that photoproduct 110 might be one of two possible Norrish type II cyclobutanol cyclization products. The ^H NMR spectrum for photoproduct 110 was well resolved, and NMR and APT spectra were used to differentiate the methyl and methine carbons from the other carbons in the molecule. The HETCOR experiment (Figure 3.12) revealed that the single overlapping signal in the A H NMR at 5 = 2.86-2.80 ppm is comprised of a methine hydrogen and one hydrogen of a methylene group. Although there are three methylene carbons in the photoproduct- C5, C6 and C7- only the hydrogens of C5 should couple to both a methine hydrogen (H4) and to methylene hydrogens (H6 and H6'). From the COSY spectrum (Figure 3.13), it can be deduced that the signal between 8 = 1.41-1.22 ppm arises from the hydrogens attached to C5. Following this assignment, the signals corresponding to the remaining hydrogens can be assigned easily from the COSY spectrum. 81 Results/Discussion/Chapter 3 82 Results/Discussion/Chapter 3 (b) H16 H3,H7' C10 C8 C5~ C9 -C6 — C7 C1 ^ C3 C4 h30 HO (-50 Figure 3.12. (a) Close-up of the 8 = 0.90 - 2.20 ppm region of the lH NMR (500 MHz, CgDg) and (b) partial HMQC spectrum (500 MHz, CgD6) of photoproduct 110. 83 Results/Discussion/Chapter 3 Figure 3 .13 . Partial COSY j H NMR spectrum (400 MHz, CgDg) of photoproduct 110. 84 Results/Discussion/Chapter 3 For all of the photoproducts, H5 and H5' were not sufficiently resolved in order to allow accurate deterrnination of which hydrogen is axial (up) and which is equatorial (down). For H6 and H6', it can be deduced from the NOE experiment that the more downfield signal (H6' by convention) from 8 = 2.06-2.00 ppm is in fact the equatorial (up) hydrogen (vide infra) (Figure 3.14). H7' was determined to be the equatorial hydrogen on the basis of three pieces of evidence. First, from the COSY spectrum (Figure 3.13), we see a small coupling between H6' (the equatorial hydrogen) to a hydrogen forming part of the signal at 8 = 2.86-2.80 ppm. This downfield signal is a combination of the protons H3 and H7', and the small coupling is assumed to be due to w-coupling, for which only the equatorial proton attached to C7 is properly aligned. The NOE experiment yields the second piece of evidence. When the signal at 8 = 1.84-1.76 ppm (H6) is irradiated, a weak enhancement is observed for the upfield H7 hydrogen peak at 8 = 1.00-1.96 ppm (Figure 3.14c). This lends credence to the conclusion that H7 is closer to the axial H6 hydrogen than H7' is. The third piece of evidence comes from analysis of other compounds from our laboratory, 6 and will be discussed on pages 88-90. After this, we will return to a full discussion of the NOE experiment performed on photoproduct 110 in order to complete the analysis of its structure assignment. 85 Results/Discussion/Chapter 3 (d) H12 Figure 3.14. NOE experiments on photoproduct 110 (a) irradiation at 5 = 7.31 ppm (H12), (b) irradiation at 8 = 2.02 (H6'), (c) irradiation at 6 = 1.80 ppm (H6), (d) irradiation at 8 = 1.35 ppm (H5 and H5'), and (e) off-resonance spectrum., 87 Results/Discussion/Chapter 3 The optically active salt 123 was made by acid-base reaction between the corresponding achiral a-adamantylacetophenone-p-carboxyhc acid with S-(+)-prolinol.^  Crystals of salt 123 exist in two forms: the needle shaped dimorph 123n, and the plate dimorph 123p. The results of the solid state irradiation of the two dimorphs are given in Table 3.6 and shown in Figures 3.15 and 3.16. Irradiation of 123n (space group P2\2j2\) in the solid state led to cyclobutanol derivative 124 as the major product in 97% ee, following acidic workup and esterification with diazomethane. Irradiation of the salt formed with R-(-)-prolinol led to (-)-124 in similar ee. Table 3.6: The enantiomeric excesses of photoproducts 124 and 125 from the photolyses of chiral salts 123n and 123p. Salt Conversion Reaction 124/125 124 125 % Medium ee%* ee% 123n 87 Crystal 5.5:1 97 (+) 37(-) 123p 79 Crystal 5.5:1 12(-) 17(-) 123n 40 Chloroform 1.6:1 0 0 Estimated error ± 3 % . Sign of optical rotation of predominant enantiomer shown in parentheses. Following the solid state photolysis of salt 123n, recrystallization of the crude reaction mixture from acetone deposited plate-like crystals (space group P2i2j2i) containing not only unreacted starting material, but also the (S)-(+)-prolinol salt of the cyclobutanol photoproduct (124s). X-ray diffraction analysis of this complex was conducted, and it was determined that (+)-124 is the trans cyclobutanol and has the absolute configuration (R) at the hydroxyl-bearing carbon atom. 88 Results/Discussion/Chapter 3 CH2OH Figure 3.15. The photolysis of ketone 123. 124s 124 Figure 3.16. A structure correlation between salt 124s and photoproduct 124. The A H NMR spectrum of product 124 contained a broad doublet at 8 = 2.91 ppm, which ^C, APT and HETCOR experiments revealed to be a one hydrogen signal from a methylene group. Using the crystal structure data on salt 124s, calculations were conducted on the distances between the hydroxyl oxygen and its neighboring hydrogens. It was found that the shortest distance was OT-H10a at 2.35 A. This is less than the 89 Results/Discussion/Chapter 3 sum of the van der Waals radii, 2.72 A. Based on this information, it was suggested^ that the aforementioned broad doublet in the proton NMR spectrum of 124 is the signal from hydrogen HlOa. Because hydrogen HlOa is very close to the electronegative oxygen atom 01, its NMR signal is shifted significantly downfield from the other methylene hydrogens in the molecule. A similar analysis can be performed for photoproduct 107, for which a crystal structure has been determined. The distance between the OH oxygen and the equatorial hydrogen H7' (8 = 2.86-2.80 ppm) is 2.45 A, which is also less than the sum of the van der Waals radii. Since photoproduct 107 has similar spectral characteristics as 110 (see Tables 3.4 and 3.5), a similar distance between the OH oxygen and H7' is likely Therefore, the assignment of H7' making up part of the two hydrogen downfield A H NMR signals (8= 2.86-2.80 ppm) is complete. Returning to the structure assignment of cyclobutanol 110, the cis and trans isomers can be differentiated by NOE experiments (Figure 3.14). For instance, NOE irradiation of protons HI 2 should lead to enhancement of the protons of C5 and/or C6 in the cis cyclobutanol, but to enhancement of the C7 protons in the trans cyclobutanol. 9 0 Results/Discussion/Chapter 3 NOE Experiment, irradiation of H12 (Figure 3.14a) H6' (Figure 3.14b) H5 and H5' (Figure 3.14d) H6 (Figure 3.14c) H7 (Figure 3.14e) Result strong enhancement of H6' signal H7 and H7' signals not enhanced strong enhancement of H12 signal Conclusion cis- cyclobutanol H6' equatorial (up) hydrogen not /ram-cyclobutanol cis- cyclobutanol H6' equatorial (up) hydrogen moderate enhancement of H12 signal - cis-cyclobutanol -strong enhancement of H6' signal - negative enhancement of H12 signal - weak enhancement of H7 signal - H12 signals not enhanced - geminal partners H6 and H6' -relay NOE from F£6' - H7 axial (down) hydrogen - not /ra/is-cyclobutanol All of these data lead to the conclusion that compound 110 is the c/s-cyclobutanol and that H6' is the equatorial (up) proton. Unambiguous assignment of the C5 protons as axial or equatorial can not be made. The general view of photoproducts 104-110 is shown as structure 126 in Figure 3.17. 91 Results/Discussion/Chapter 3 Equatorial Protons H3, H6' and H7' Axial Protons H4, H6 and H7 H H 126 Figure 3.17. General picture of photoproducts 104-110. 3.4. Identification of Cyclization Photoproduct: Trans-Cyclobutanol 116. Of the seven tert-butyl cyclohexyl aryl ketones, four yielded some other type of compound from solution state photolyses; that is, the cis-cyclobutanol was not the sole product. Unfortunately, due to difficulties encountered in the separation process, only one of these could be isolated in pure form by column chromatography on silica gel. The characterization of the isolated product was carried out in a similar fashion as those of the c/5-photoproducts. The following spectral analysis of product 116, which was produced from the solution state photolysis of ketone 66, showed it to be the frvms-cyclobutanol. 92 Results/Discussion/Chapter 3 The A H NMR spectrum was not as well-resoh/ed as that of the cis isomer; however, almost complete identification of the signals was achieved. Some of the more Figure 3.18. The ! H NMR spectrum (500 MHz, CgDg) of photoproduct 116. Exact assignments for the hydrogens at CS and C6 could not be determined. 93 Results/Discussion/Chapter 3 94 Results/Discussion/Chapter 3 Figure 3.20. Partial HMQC spectrum (500 MHz, CgDg) of photoproduct 116. 95 Results/Discussion/Chapter 3 Again, a full spectral analysis was performed. Elemental analysis and high resolution mass spectrometry showed that the photoproduct had the same composition and molecular mass as the starting ketone. Infrared analysis showed the presence of a hydroxylband at 3467 cm" 1 and the absence of a ketone stretch at 1670 cm" 1. The i H N M R spectrum had overlapping proton signals at 5 = 1.28-1.20, 1.10-0.99 and 0.89-0.80 ppm (Figure 3.18). The first and second multiplets were each made up of a methine proton and one hydrogen of a methylene group. The third multiplet was due to overlapping peaks from one hydrogen of a methylene group and one O H proton. These hydrogens were all attached to different carbons, as shown in the HETCOR experiment (Figure 3.20). Therefore, we have the location of both methine protons (H3 and H4) and one hydrogen of each of the three methylene groups (C5, C6 and C7). The remaining hydrogens from the three methylene groups were separated from the other signals and appeared at 8 = 1.76-1.65 (multiplet), 1.59-1.52 (multiplet) and 0.19-0.15 (triplet, J = 7 Hz) ppm. Since each signal corresponded to a single proton from each of the three methylene groups present, a COSY experiment seemed likely to reveal which hydrogen was attached to C7, since this hydrogen should not be coupled to either of the other two signals (Figure 3.19). In the COSY, the peak at 8 = 0.19-0.15 ppm does not show any coupling to the two downfield signals at 8 - 1.76-1.65 and 1.59-1.52 ppm, whereas, these two signals show strong coupling to each other and to many other protons. Therefore, the signal at 8 = 0.19-0.15 ppm is determined to be from H7. Also from the COSY spectrum, the gerninal partner for H7 is situated at 8 = 0.89-0.80 ppm (H7'). Since H7 was also shown to have a strong coupling to the two hydrogen signal at 8 = 1.10-0.99 96 Results/Discussion/Chapter 3 ppm, this signal must include the methine hydrogen H3. As a result, the other methine proton (H4) must be situated in the two hydrogen multiplet at 8 = 1.28-1.20 ppm, along with a single proton from either C5 or C6. Deterarination of the trans- stereo chemistry by NOE experiments can be accomplished without knowing the exact assignments for the hydrogens at C5 and C6. Figure 3.21 shows the relevant NOE results obtained for photoproduct 116. Since the OH signal is very close to the H7' signal, irradiation of the 8 = 0.89-0.80 ppm peaks would not be helpful. However, if H12 is irradiated, an enhancement of the C7 proton(s) should occur. This was found to be the case, irradiation of H12 caused weak/medium enhancement of H7' (Figure 3.21a), the low intensity of this enhanced peak indicating that there is probably a large distance between the two protons. When H7 is irradiated, a significant enhancement in signal is seen only for its geminal partner at 8 = 0.89-0.80 ppm (Figure 3.21b). These results indicate that H7' is the equatorial (up) proton and that compound 116 is the trans isomer. 97 Results/Discussion/Chapter 3 H13 H7' H13 H7' H7' H7 L B.'5 «,'. s.'s 5 . . ,.'s 3.'s ».'. ,.'5 2.'. \\\- "V.1.' ' " . ' 5 Figure 3 .21 . NOE experiment on photoproduct 116 (a) irradiation at 5 = 7.14 ppm (H12), (b) irradiation at 5 = 0.17 ppm (H7), and (c) off-resonance spectrum. 98 Results/Discussion/Chapter 3 The interesting feature of this trans cyclobutanol is the chemical shift observed for the two C7 hydrogens. One peak, identified by NOE experiments as the equatorial (up) proton, occurs at 8 = 0.89-0.80 ppm. The other, a triplet at 8 = 0.19-0.17 ppm (J = 7 Hz), corresponds to the axial (down) proton. It is intriguing to find this proton at such a high field, as compared to its geminal partner. However, some insight into this H7 upfield shift comes from results obtained in our lab during a study of the photoproducts cis- and trans-(4-cyanophenyl)-bicyclo [6.2.0] decan-9-ol derived from the photolysis of 2-cyclooctyl-l-(4-cyanophenyl)-ethanone, 127 (Figure 3.22).^  He Hd Ha 128 129 130 Solvent Temp. °C (128+129):130 128:129 Acetonitrile -32 82:18 51:49 Acetonitrile 22 72:28 56:44 Benzene 22 72:28 75:25 Solid State -32 87:13 83:17 Figure 3.22. Irradiation of ketone 127. 99 Results/Discussion/Chapter 3 Figure 3.22 gives results for the irradiation of compound 127. The IjT N M R spectrum of the trans-cyclobutanol 128 is very complicated, making it difficult to draw structural correlations. Only the four aromatic protons resonating at 8.0 and 8.1 ppm are distinguishable. The N M R spectrum of the cw-isomer 129, on the other hand, is more revealing, showing a multiplet signal at 0.38 ppm. The fact that this signal, which integrates for one proton, is located at such a high field, suggests that it must be located in the shielding region of % electron density above and below the plane of the aryl group. Decoupling experiments positively concluded that this high field signal must be due to one of the hydrogen atoms H c or FLj. It was speculated that proton FLj was responsible. Even though NOE experiments performed on photoproduct 116 suggest that the aryl group is a long distance from the C7 protons, it does have a significant effect on the environment that these protons reside in. Proton H7 must be in the shielding region of % electron density of the aryl group to a greater extent than its geminal partner H7' . As was mentioned, the minor photoproducts 117 and 119 could not be separated in pure form from the major photoproducts 107 and 110, respectively. They were characterized spectroscopically by N M R as part of a mixture. The mixtures did show upfield signals at 8 < 0.2 ppm, indicative of the H7' proton on C-7, but this is the only evidence that the minor photoproducts observed in the photolyses of ketones 67, 69 and 70 are /ra/is-cyclobutanols. 100 Results/Discussion/Chapter 3 3.5. Photochemistry of Adamantyl Ary l Ketones: Formation of Cw-Cyclobutanols 1 1 1 - 1 1 5 . As shown in Table 3.2, the five adamantyl aryl ketones (78, 81-84) each yielded a single photoproduct from both solution and sohd state photolyses. In contrast, ketones 77 and 80 were photochemically inert in both the solution and sohd state. Like cis-cyclobutanols 104-110, the products observed for photoreaction of the adamantyl aryl ketones all showed similar spectral characteristics. The and NMR spectral features for these photoproducts are given in Tables 3.7 and 3.8. 101 Results/Discussion/Chapter 3 Table 3.7: A H nmr Data (400 and 500 MHz, C6D 6) for photoproducts of the general structure below. 6 *H nmr spectrum (500 MHz, CgD 6), 8 ppm (mult., J (Hz))a Assignment H-x X = H 111 X = F 112 X = CN 113 X = C 0 2 C H 3 115 doublet (IH) at: 0.80-0.75 (J= 11 Hz) 0.78-0.73 (J= 11 Hz) 0.76-0.65 (J = 12 Hz) 0.79-0.72 (J = 12 Hz) H-12 singlet (3H) at: 1.32 1.23 1.14 | 1.22 multiplet (8H) at: 1.80-1.49 1.70-1.45 1.65-1.28 | 1.70-1.45 multiplet (IH) at: 1.85-1.80 1.78-1.73 | 1.85-1.65 1.76-1.70 multiplet (IH) at: 2.02-1.97 | 1.93-1.88 | 1.85-1.65 1.94-1.88 triplet (IH) at: 2.65-2.61 (1 = 6 Hz) 2.54-2.50 (J = 6 Hz) 2.45-2.37 (J = 6 Hz) 2.55-2.50 (J = 6 Hz) multiplet (IH) at: 2.94-2.90 | 2.87-2.82 2.82-2.71 2.87-2.82 aromatic multiple 7.04-7.01 (IH) 7.09-7.05 (1H) 7.18-7.11 (2H) 7.18-7.11 (IH) ;t(s) at: 6.84-6.76 (IH) 6.95-6.90 (IH) 6.84-6.76 (2H) 6.69-6.59 (IH) 6.84-6.75 (IH) 7.10-7.00 (2H) 7.00-6.93 (IH) 7.13-7.06 (IH) 8.15-8.07 (2H) H-18 singlet (3H) at 1 1 3.53 OH singlet (IH) at: 1.04 1.09 0.95 1.06 a Not all the signals recorded in this table are assigned. H-18 for photoproduct 115 corresponds to the methoxy protons of the ester group. 102 Results/Discussion/ Chapter Table 3.8: 1 3 C nmr (125.8 M H z , CgDg) data for photoproducts of the general structure below. 6 1 3 C nmr spectrum (125.8 M H z , CgDfi), 5 p p m a C-x X = H 111 X = F 112 X = C N 113 X = C 0 2 C H 3 115 12 18.96(-ve) 18.79 (-ve) 18.66 (-ve) 18.79 (-ve) 25.88 (-ve) 25.81 (-ve) 25.61 (-ve) 25.77 (-ve) 29.40 (-ve) 29.29 (-ve) 28.95 (-ve) 29.17 (-ve) 31.16 (+ve) 31.11 (+ve) 30.85 (+ve) 31.02 (+ve) 34.22 (+ve) 34.19 (+ve) 33.91 (+ve) 34.07 (+ve) 35.15 (+ve) 35.03 (+ve) 35.27 (+ve) 35.31 (+ve) 35.95 (+ve) 35.91 (+ve) 35.61 (+ve) 35.79 (+ve) 37.25 (-ve) 37.14 (-ve) 36.80 (-ve) 37.01 (-ve) 37.54 (-ve) 37.58 (-ve) 37.40 (-ve) 37.50 (-ve) 46.54 (-ve) 46.56 (-ve) 46.26 (-ve) 46.49 (-ve) 1 49.99 (+ve) 49.92 (+ve) 49.69 (+ve) 50.02 (+ve) 2 83.20 (+ve) 82.55 (+ve) 82.49 (+ve) 82.80 (+ve) 124.52 (-ve) 115.83 and 116.00 (-ve) ( 2 J C . F = 21 Hz) 116.69 (+ve) 124.47 (-ve) 125.11 (-ve) 116.16 and 116.33 (-ve) ( 2 J C . F = 21 Hz) 124.90 (-ve) 125.11 (-ve) 126.88 (-ve) 125.99 and 126.05 (-ve) ( 3 J C . F = 8 Hz) 125.51 (-ve) 129.17 (+ve) 129.21 (-ve) 126.81 and 126.87 (-ve) ( 3 J c . F = 8Hz) 132.87 (-ve) 130.86 (-ve) 129.43 (-ve) 143.19 and 143.22 (+ve) ( 4 J c _ F = 4Hz) 133.00 (-ve) 130.96 (-ve) 147.36 (+ve) 161.60 and 163.01 (+ve) ( 1 J C _ F = 245 Hz) 151.36 (+ve) 151.95 (+ve) 17 111.02(+ve) 166.59 (+ve) 18 51.58 (-ve) a Not all the signals recorded in this table are assigned.. The peaks are listed in ascending chemical shift. C-17 is the carbon of the nitrile group in 113 and the carbonyl of methyl ester in 115. C-18 is the methoxy carbon of the ester group in 115. 103 Results/Discussion/Chapter 3 Unlike the spectra obtained for photoproducts of the tert-butyl cyclohexyl aryl ketones (104-110), the A H NMR spectra of these photoproducts showed many overlapping peaks; therefore, exact identification of the peaks was not possible. Figures 3.23-3.25 show some representative spectra. Figures 3.23 and 3.24 show the ^H NMR spectra and the partial HMQC correlations for photoproducts 112 and 115. Figure 3.25 shows a A H COSY spectrum for photoproduct 115. 104 Results/Discussion/Chapter 3 105 Results/Discussion/Chapter 3 (a) (b) J J L J J L . 3.0 2.8 8.0 l.S l io L_JUA1 1 Figure 3.24. Partial H M Q C spectra (500 MHz, CgDg) of photoproducts (a) 112 and (b) 115. 106 1 A fA JL_ o 0 c i • o 0 C 0 c p o PM 2.5 20 1.5 1.0 «UL o «4 1 0 D M M B O Figure 3.25. ] H COSY spectrum (500 MHz, CfcDg) for photoproduct 115. 107 Results/Discussion/Chapter 3 We were able to determine the X-ray crystal structure of cyclobutanol 112, which was prepared by photolysis of ketone 81 in either the solution or sohd state. The ORTEP drawing and packing diagram are shown in Figures 3.26 and 3.27, respectively. X-ray diffraction analysis was conducted on crystals derived from the solid state photochemical reaction of ketone 81. According to the x-ray crystallographic analysis, product 112 crystallizes from petroleum ether solution as colourless prisms in the achiral space group (Pca2 )^, with 8 molecules in the asymmetric unit cell. Figure 3.26. The ORTEP stereodiagram of photoproduct 112. 108 Results/Discussion/Chapter 3 Figure 3.27. The crystal packing stereodiagram diagram of photoproducts 112. An interesting feature unique to these photoproducts and not observed for the photoproducts of terf-butyl cyclohexyl aryl ketones was that each of the six carbons of the aromatic ring showed a different signal in the l 3 C N M R spectra. This indicates that there is hindered rotation about the C2-C13 bond for these photoproducts. A variable temperature l 3 C N M R experiment was performed with cyclobutanol 112. A sample of the photoproduct was dissolved in the Mgh-boiling solvent dunethyl sulfoxide-d6. The coalescence of the l 3 C N M R peaks arising from C14 & C14' and C15 109 Results/Discussion/Chapter 3 & C15' was recorded as the temperature was raised from room temperature to 140 °C (Figure 3.28), and the presence of a rate process was confirmed. All the signals are sharp at room temperature, and the separation of the aromatic C-H signals is 0.235 ppm (17.69 Hz) and 0.722 ppm (54.55 Hz). Upon increasing the temperature, the aromatic peaks broadened, but the other l^C peaks remain sharp. Unfortunately, even at 140 °C, the peaks were never observed to completely coalesce. With the use of the foUowing equation:** A G ? / RT C = loge [ (2)1/2 R / 7iNh] + loge (T c / Sv) 22.96 + loge (Tc / 5 v ) where T c represents the coalescence temperature and 8v is the chemical shift difference at room temperature, the calculated free energy of activation (AG?) for the rotation of the aryl ring was determined to be > 21.4 kcal mol"1. This estimation of AGt uses T c = 140 °C (the highest temperature attained in the experiment). 110 (a) 40 °C i t V ' ' I 1 1 1 1 I I' I' | I I I I |. I I I I I I | l | | [ | | | . | | | | . | | | | . | | | | . | | , | . WOO » 4 0 0 t 2 0 0 8000 ~ L : - '-• 8800 eeoo (b) 110°C Si Si i s I i ' i i i i i ' i i ' ' II i i ' ' ' i ' ' • ' i i i i i i i i i i i i (8O0 »»00 » « 0 0 9200 »000 i l l | i i i i I i ' I ' | 1 1 1 8800 8600 MOO HZ s i I Figure 3.28. The down-field portion of the 75.6 MHz 1 3 C spectrum (DMSO, dg) of photoproduct 112 at the indicated temperatures. 111 Results/Discussion/Chapter 3 This hindered rotation about the C2-C13 bond is consistent with the crystal structures determined for photoproducts 107 and 112. Figure 3.29 shows these two photoproducts. In 107, the torsion angle between the aryl ring and the alcohol oxygen atom is 53.2 °, whereas in photoproduct 112, the torsion angle is 93.9° (89.2° in the second molecule in the unit cell). Moreover, Table 3.9 reports some relevant intermolecular distances for photoproducts 107 and 112. In 107, C13 is 2.70 A from the axial proton on C5 (H6), but in 112, the corresponding distance (C13-H10 or H10A) is 2.24 A. The aryl ring is definitely in a congested environment in both 107 and 112, but there are more steric interactions present in photoproduct 112. 1 1 2 Results/Discussion/Chapter 3 Table 3.9: Interatomic distances in photoproducts 107 and 112. photoproduct 107 photoproduct 112a atom-atom distance atom-atom distance (A) (A) C13 H6 (ax) 2.70 C13 H10 (ax) 2.24 C13A H10A (ax) 2.23 C13 H5 (eq) 4.13 C13 H9 (eq) 3.79 C13A H9A' (eq) 3.78 C13 H8 (eq) 3.23 C13 H2 (eq) 3.39 C13A H2A (eq) 3.42 a Photoproduct 112 has two independent molecules in its unit cell while there is only one for photoproduct 107. 3.6. Photolysis of Salts: Enantiomeric Excess Determination The past ten years have seen an increasing demand, particularly from the pharmaceutical industry, for accurate, reliable and convenient methods of measuring enantiomeric or optical purity.^  Optical purity is denned as: Q Q % = ^mixture of enantiomers x ] 00% [a] L Jpure enantiomer or e.e.% = j^j " ^j, x 100% [R] + [S] Optical purity can be determined by a number of analytical procedures.10 Polarimetry is usually used for comparisons with literature data, but is not sufficiently reliable if any optically active impurities are likely to be present. Modern methods for the separation and/or determination of enantiomers include: (1) derealization using chiral reagents, followed by analysis by HPLC, GLC, TLC, NMR, etc;10 (2) the use of chiral stationary 113 Results/Discussion/Chapter 3 phases for HPLC, GLC, T L C ; 1 1 (3) NMR spectroscopy with chiral shift reagents;9'12 and (4) enantiomer-specific immunoassays. In order to monitor asymmetric syntheses in the experimental work described in this thesis, we used HPLC with chiral stationary phases. Various methods were attempted in order to determine the enantiomeric excesses in photoproducts 110 and 115. Neither chiral GC (column Cyclodex-B, J & W Scientific), nor the NMR chiral shift reagent method (Eu(hfc)3 and Yb(hfc)3) gave sufficient separation of the enantiomers. However, chiral HPLC did give baseline separation. A CHTJRALCEL OD column packed with cellulose tri-(3,5-dimethylphenyl carbamate) on a 10 pm silica gel substrate was used. The packing composition is shown in Figure 3.30. Figure 3.30. Packing composition of the C H T R A L C E L O D column. The CFITRALCEL OD column is known to resolve compounds with aromatic, carbonyl, nitro, cyano or hydroxy! groups. The chromatographic results obtained for separation of the photoproducts are shown in Table 3.10, along with the chromatographic resolution, R s. This was calculated based on the equation: 13 114 Results/Discussion/Chapter 3 2(t2-ti) R s - twl + tw2 where t\ and t2 are the retention times of the two components and tw\ and tw2 are the band widths of the two components. Table 3.10: Chromatographic Data for Photoproducts 110 and 115 on the CHTRALPAK OD Column (25 cm * 0.46 cm ID.) at Room Temperature HPLC conditions retention cmpda solvents flow rate detector time (min)b R s comments (ml /min) UV (nm) 110 92:8 1.00 230, 250 (-): 5.7 3.6 well hexane/ (+): 8.7 separated 2-propanol 115 95:5 1.00 230, 250 (+): 12.2 1.5 well hexane/ (-): 14.8 separated 2-propanol (a) The structures of these compounds are shown in Table 3.1(110) and Table 3.2 (115). (b) The determination of the sign of rotation was performed at the sodium D line using an H P L C D3Z-CHIRALYSER optical detector. Owing to the small amounts of sample used, the magnitude of the optical rotation for photoproducts 110 and 115 could not be determined. We thank Dr. Fiona Geiser, Chiral Technologies Inc., for measuring the optical rotation signs. Figures 3.31 and 3.32 show the chromatographic results for racemic samples of photoproducts 110 and 115 on the CFflRALCEL OD column. In Figure 3.31a, the starting material (71, t = 4.03 min), as well as the two enantiomers of photoproduct 110 (t - 5.66 and 8.70 nain) are all separated. Figure 3.31b shows the results for analysis of the same sample, using a IBZ-CF1IRALYSER optical detector instead of a UV detector. As shown, the first enantiomer to elute has a negative sign of rotation. Figure 3.32a shows the separation of the enantiomers of photoproduct 115; in this case, the first enantiomer has a positive sign of rotation (Figure 3.32b). 115 Results/Discussion/Chapter 3 (a) 1.20 l.OO Q.80 Q.GO 0 .40 e -> . , 1 r O.OO 0.20 1 1 , , , I . . . I r 0.40 0.60 a .BO x 10 1 n l n u t i t 1 .OO 1.20 Figure 3.31. Chromatogram of a racemic sample of photoproduct 110 with starting material (ketone 71) present, (a) Column, CHIRALCEL OD; eluent, 92:8 hexane/2-propanol; flow rate, 1.0 mL/min; detector, UV at 230 nm; room temperature. Compound 71, t = 4.03. (-)-photoproduct 110, t = 5.66. (+>photoproduct 110, t = 8.70. (b) Same conditions as in (a), but using an IBZ-CHIRALYSER optical detector. 116 Results/Discussion/Chapter 3 Chromatogram of a racemic sample of photoproduct 115 with starting material (ketone 84) present, (a) Column, CHTRALCEL OD; eluent, 95:5 hexane/2-propanol; flow rate, 1.0 mL/min; detector, UV at 230 nm; room temperature. Compound 84, t = 5 78 (+>photoproduct 115, t = 12.18. (->photoproduct 115, t = 14.77. (b) Same conditions as in (a), but using an ffiZ-CHIRALYSER optical detector. 117 Results/Discussion/Chapter 4 CHAPTER 4 Structure-Reactivity Correlation Studies 4.1. General Considerations It is difficult to obtain accurate pictures of the prereaction shapes and orientations of confoimationally mobile organic molecules in solution or the gas phase. However, for sohd state chemistry, such elucidations have been facilitated by X-ray crystallography. In the crystal structure-sohd state reactivity correlation method, a given reaction is performed on several closely related compounds, and the reactivity patterns are then correlated to the X-ray crystal structures. 14 X-ray crystallography essentially "photographs" the reacting molecule and its surroundings, and can provide detailed mechanistic information about the atomic distances and angular requirements for reaction. Crystals provide ideal environments in which to study the effects of molecular structure on chemical reactivity. 1 ^  Because the crystalline medium is highly viscous and because the crystal lattice imposes considerable restraints on diffusion and rotation, transition states and intermediates tend to resemble then ground state progenitors in size and shape. Accordingly, reactions in the solid state generally occur with a minimum of atomic and molecular motion. This is, of course, the well-known topochemical principle first proposed by Kohlshutter in 1918 (see Chapter 1)16 m& popularized by Cohen and Schmidt. 1 7 118 Results/Discussion/Chapter 4 4.2. Photochemical Studies in Solution To provide a basis of comparison for the solid state studies, the sixteen ketones prepared in the present thesis were first irradiated in solution and their photoproducts separated and identified. In every case except two, direct photolysis in solution led to smooth y-hydrogen abstraction and formation of either the Yang cyclization1^ product(s) or the type II efarrniation product. The two exceptions were ketones 77 and 80, which proved to be inert under all photolysis conditions employed (Figure 4.1), both direct and sensitized. No Reaction X = H, 77 F, 80 Figure 4.1. Photoreactivity of ketones 77 and 80 in solution and in the solid state. In order to deterniine whether this apparent lack of reactivity might be the result of rapid and reversible hydrogen atom transfer, ketones 77 and 80 were photolyzed in tert-butyl alcohoL which is a good hydrogen bonding solvent. Wagner has shown that, through hydrogen bonding to the hydroxyl proton of the 1,4-hydroxy biradical intermediate, such solvents (Lewis bases) retard the reverse hydrogen transfer step leading back to the starting ketone.3' 19,20 j]j e hydrogen-bond is broken during the disproportionation step, but not during cleavage or cyclization, and hence the quantum 119 Results/Discussion/Chapter 4 yield of photoproduct formation is increased. The increased lifetime of the biradical intermediate in polar solvents has been attributed to this effect.21 However, when ketones 77 and 80 were photolyzed in fer/-butyl alcohol, both remained inert. It had been shown in 1972, through mercaptan trapping of the 1,4-biradicals, that one form of "radiationless decay" for these ketones involved reversion of the biradical intermediates to starting material, with racemization at the y-carbon.22 Therefore, ketones 77 and 80 were photolyzed in benzene which contained a high concentration of deuterated rc-heptyl thiol, C7H15SD (ca. 3 M). irreversible hydrogen transfer were responsible for the observed lack of product formation, deuterium-enriched substrates 77D and 80D, should have been isolated (Figure 4.2). It should be noted that although structures 77D and 80D show incorporation of only one deuterium, these molecules can react further to incorporate additional deuterium atoms into the structure. O H V - A r solution + RSH R = M-heptyl X = H, 77 F, 80 77BR 80BR 77D 80D Figure 4.2. Possible reaction mechanism for the photolysis of ketones 77 and 80 in the presence of a deuterated mercaptan. 120 Results/Discussion/Chapter 4 The ketones were irradiated for 24 h with light of X > 290 nm. To the crude photolysate solution was added concentrated KMnC«4 solution, to destroy the excess n-heptyl thiol solvent. Following purification by silica gel chromatography, analysis by mass and Ifi NMR spectrometry showed that there had been no detectable deuterium incorporation. Lack of deuterium incorporation in these ketones could be a result of a biradical being too short-lived to allow for mercaptan trapping. Therefore, it cannot be concluded for certain whether 77BR and 80BR are actually being formed in solution state photolyses. Of the remaining fourteen ketones studied, all but two yielded cyclization products from solution state photolysis. Ketones 56 and 57 produced the cleavage products 102 and 103 exclusively (Figure 4.3). Possible reasons for this interesting reactivity difference will be discussed later in this chapter. 121 Results/Discussion/Chapter 4 Once the photoproducts had been fully characterized and identified (see Chapters 3 and 8), attention was directed to deterrnining the solution phase (benzene) photoproduct distributions. For ketones 56 and 57, conversions were kept low in order to minimize possible secondary photoreactions of the products, which still contain potentially reactive carbonyl groups. It was observed that for all ketones studied, the photoproduct distributions were constant with respect to conversion and choice of solvent (benzene, acetone, acetonitrile or methanol). 4.3. Photochemical Studies in the Solid State The sohd state irradiation samples were prepared by crashing the crystals between two Pyrex microscope slides and sealing the "sandwiches" under nitrogen in polyethylene bags. These sandwiches were photolyzed at room temperature with the output from a 450-W Hanovia medium pressure mercury lamp. As was shown in Chapter 3 (Tables 3.1 and 3.2), the tert-butyl cyclohexyl and adamantyl aryl ketones reacted much more selectively in the crystalline state than in solution, forming exclusively the cis- cyclization photoproduct in all cases. As in solution, ketones 77 and 80 were completely unreactive. Ketones 56 and 57 were also unreactive, although they had yielded cleavage products under solution state photolysis conditions. Four of the ketones (66, 68, 70 and 71) produced a small amount of trans-cyclization product from the solution state photolyses, in addition to the major cis-cyclization product. When these same ketones were irradiated in the sohd state, only the 122 Results/Discussion/Chapter 4 cis-cyclization product was formed. This observation will be discussed later in this chapter (Section 4.6). As was discussed in the Introduction (Section 1.5), four parameters serve to define the geometry of hydrogen atom abstraction.23,24 J J O W ^0 t n e v a i u e s 0 f these parameters (as determined by X-ray crystallography) for the ketones compare with the ideal values? The values of d, co, A, and 0 for the ketones are compiled in Table 4.1 along with a new parameter, D, the interatomic distance between the two radical carbon centres in the 1,4-biradical. Also included in Table 4.1 are the parameters from the salts, since they too underwent the Norrish type II photoreaction smoothly and cleanly in the solid state to yield exclusively c/s-cyclobutanols. Asymmetric induction of the salts will be discussed in the Sections 4.7 to 4.10 of this chapter. 123 Results/Discussion/Chapter 4 Table 4.1. Crystallographically derived C=0"Hy abstraction geometries. ketone R= X= Paramet d(A) ers for Ne A O sarest H - / e f ) t^om co(°) C C D(A) ideal values <2.72 90-120 180 0 < 3.4 tert-butyl cyclohexyl aryl ketone 56 H H 2.61 3.17 95.3 62.6 115.9 113.2 32.4 56.7 3.23 3.15 57 H F 2.59 3.17 95.9 63.2 115.7 113.2 31.8 56.9 3.23 3.15 58 C H 3 H 2.70 80.9 113.5 56.9 3.09 67 C H 3 C H 3 2.69 82.8 112.3 57.0 3.11 68 C H 3 OCH 3 2.63 3.49 85.2 45.7 113.4 107.8 55.7 45.2 3.10 3.11 70 C H 3 COOH (2 independent molecules in unit cell) 2.65 3.50 2.61 3.44 84.7 45.5 87.5 48.8 113.4 107.6 113.7 108.4 55.0 45.2 52.2 48.2 3.11 3.11 3.12 3.12 93 C H 3 COO'-(S)-prolinamide salt 2.75 3.61 77.3 38.9 111.9 107.6 59.7 39.1 3.06 3.11 adamantyl aryl ketones 77 H H 2.47 3.13 98.3 63.5 116.8 113.2 28.5 56.9 3.17 3.12 78 C H 3 H 2.50 3.41 83.5 43.8 116.5 110.0 57.3 44.4 • 3.02 3.05 81 C H 3 F 2.54 3.47 79.8 40.5 116.4 109.1 60.7 40.8 2.99 3.04 84 C H 3 C 0 2 C H 3 2.58 79.1 114.6 60.6 3.00 98 C H 3 COO"-(S)-a-methyl benzyl amine salt 2.62 3.59 74.8 35.9 114.3 106.6 62.0 36.8 2.96 3.05 99 C H 3 COO"-(R)-a-methyl benzyl amine salt 2.60 3.59 75.0 35.9 114.1 106.3 62.1 36.7 2.95 3.05 101 C H 3 COO"-(lR,2S)-norephedrine salt 2.55 3.47 80.0 41.4 116.3 109.3 60.1 41.7 3.00 3.05 a Except in the case of the salts, y-Hydrogen atoms for which d > 3.50 A are not included in this table. 124 Results/Discussion/Chapter 4 One remarkable observation is that the ketones which did not react in the sohd state all have acceptable parameters for d, co, A, and 0 (only three have had their X-ray structures deduced). Based on the data recorded in Table 4.1, we can divide the ketones into two categories: reactive (eleven in total) and unreactive (three in total). The averages of the geometric data for each category of ketone are shown in Table 4.2. Table 4.2. Average values for d, co, A, and 8 for reactive and unreactive ketones.a ketone d(A) A(deg) 9 (deg) co (deg) D(A) ideal <2.72 90-120 180 0 <3.4 reactive0 2.62 ±0.07 8 1 ± 4 114 ± 2 58 ± 3 3.04 ±0.06 unreactive0 2.56 ±0.08 97 ± 2 116.1 ±0.6 3 1 ± 2 3.21 ±0.03 a The implicit assumption will be made that the nearer y-hydrogen is abstracted (see page 132). D Average value with standard deviation for all y-hydrogens with d < 2.75 A, for ketones that showed reactivity in the solid state (12 total). c Average value with standard deviation for all y-hydrogens with d < 2.75 A, for ketones that showed no reactivity in the solid state (3 total). These ground-state data are only roughly applicable to the excited state. There are three main problems with such parameters: (i) carbonyl carbon atoms may become pyramidalized in their 11,71* excited states, although this effect is more pronounced for aliphatic ketones and is usually not important for aromatic ketones;253 moreover, the crystalline environment may to some extent also limit this geometrical change, (ii) it is accepted that excitation lengthens carbonyl bonds by about 0.1 A 2 5 d and (hi) crystallographically determined C-H bond lengths are consistently underestimated by approximately 0.1 A because the X-rays are diffracted primarily by the electrons in the C-H bonds and not by the atoms themselves. 1 2 5 Results/Discussion/Chapter 4 Despite these problems, we continue to use uncorrected C-H bond lengths for the following reasons: (i) all our previous structure-reactivity correlations have been based on hydrogen sites, as determined by X-ray crystallography, and a change now would make comparisons with previous discussions confusing; (ii) since C-H--0 angles (G-value) are all near 115 °, a correction of +0.1 A to the C-H distances would do no more than decrease all O H distances by about 0.05 A and (iii) the O—H distances detenrrined by X-ray crystallography; i.e., from oxygen to the centres of the H electron clouds, may in fact be more relevant than distances to the hydrogen nuclei. Despite these uncertainties, it can be seen from Table 4.2. that all four of the parameters are most favourable in the ketones that did not react in the solid state. What is the reason for their apparent photo stability in the solid state? Before we can answer that question, we must look more closely at the difference between the type II cleavage and cyclization pathways. 4.4. Cleavage vs Cyclization: Solution State Unlike all the other ketones studied, substrates 5 6 , 5 7 , 7 7 and 8 0 each have a hydrogen atom in the a-position. The other ketones each have an a-methyl group. The predominance of cyclization products for substrates where R Q . = C H 3 has been observed, and is referred to as the "oc-alkyl group effect. "3326-28 Both Wagner and Lewis found that a-substituents greatly alter the cyclization: elimination ratios of acyclic ketones. For example, a-methyl and a,a-dimethyl substitution of valerophenone increases the percentage of cyclization from 10 to 29 and 126 Results/Discussion/Chapter 4 89%, respectively.27 The increase in cyclization product has been attributed to nonbonded interactions present in the 1,4-biradical. Because of their short lifetimes, the biradicals can undergo only a few rotations before reacting. Consequently, if a substituent introduces a substantial barrier to some rotation which is necessary in order to bring the biradical into a conformation required for reaction, that rotation may become rate-determining. It is generally accepted that the cleavage of a 1,4-biradical can occur efficiently only in a conformation in which the two radical-containing p-orbitals are parallel to the C-C a bond (a,(3-bond) being broken.2^"29 Evidence for this emerges from Hoffinan's calculations, in which extensive overlap between the p-orbitals and the central sigma bond of a 1,4-biradical intermediate optimizes the mixing of 71 and a levels.-^ 0 In agreement with this notion, type II cleavage is inefficient for cyclic ketones in which the 1,4-biradical cannot assume such a conformation. ^ 1 Figure 4.4 shows various conformations, ranging from transoid through gauche to cisoid. The cisoid suffers eclipsing interactions about the middle C-C bond. In the transoid and cisoid conformations, all four carbon atoms are coplanar; in gauche, the y-carbon is rotated out of the plane of the other three carbons by 60 0 so as to relieve echpsing about the middle C-C bond. Due to overlap considerations, the gauche and cisoid arrangements of the 1,4-biradical intermediates can undergo both cyclization and cleavage, while the transoid arrangement undergoes cleavage exclusively. 127 Results/Discussion/Chapter 4 transoid gauche cisoid Figure 4.4. Conformations of 1,4-biradicals. In the solid state, where the crystal lattice would impose considerable restraints towards bond rotations, the conformation of the biradical intermediate would resemble that of the starting material (Figure 4.5). With the help of X-ray crystallography, we can get a picture of this probable biradical intermediate. In solution, however, rapid bond rotations ensure that X-ray data do not, for the most part, reflect what is really happening. Therefore, with the help of MM3 calculations, we can reveal the conformational preferences of these ketones in solution. 32 starting ketone biradical intermediate Figure 4.5. Conformation of the 1,4-biradical from a type II photoreaction. 128 Results/Discussion/Chapter 4 Ketones 56, 58, 77 and 78 were subjected to molecular mechanics analysis (MM3) and the results are shown in Table 4.3. MM3 calculations give gas phase conformations, which can be indicative of the corresponding solution phase conformation. The results indicate that in solution these ketones adopt a similar conformation as that found in the sohd state. All of the parameters listed in Table 4.3 show remarkable consistency between the MM3 and sohd state values. For all of the four ketones, the higher energy conformations found are associated with rotation about the C1-C2 bond. The dihedral angle 01ClC2Ra is a measure of this rotation. Table 4.4 gives the 01ClC2Rcx dihedral angles associated with the conformations found within the 11 kJ mol"1 energy window set. 129 Results/Discussion/Chapter 4 Table 4.3. Comparison of the crystallographically and molecular mechanics (MM3) derived geometries of ketones 56, 58, 77 and 78.a>° Ra= H 56 77 C H 3 58 78 Conformation determined Rot group d ( A ) A(°) e ( ° ) cpl (°) <p4 O <P(°) 0 1 C 1 C 2 R a (°) D ( A ) ketone 56 H solid state 2.61 95.3 115.9 85.1 36.2 74.9 122.0 3.23 3.17 62.6 113.2 29.6 31.0 73.8 3.15 MM3 2.50 98.8 113.2 89.1 34.8 70.0 118.7 3.20 3.21 61.0 108.2 31.7 30.8 69.6 3.15 ketone 58 C H 3 sohd state 2.70 80.9 113.5 63.6 32.8 68.8 92.5 3.09 MM3 2.75 77.3 110.1 55.1 30.8 66.3 83.1 3.09 ketone 77 H solid state 2.47 98.3 116.8 82.4 31.1 69.9 125.6 3.17 3.13 63.5 113.2 27.2 29.5 70.7 3.12 MM3 2.45 96.4 114.1 87.6 31.1 68.3 115.0 3.1.5 3.22 58.5 108.6 35.9 29.4 68.1 3.12 ketone 78 C H 3 solid state 2.50 83.5 116.5 65.5 29.4 63.4 93.7 3.02 3.41 43.8 110.0 53.2 28.1 60.6 3.05 MM3 2.60 78.8 111.7 56.2 28.5 62.0 84.4 3.01 a y-Hydrogen atoms for which d > 3.50 A are not included in this table. D A description of the parameters cpl, (p4 and (p can be found in the next section of this chapter (Section 4.5). 130 Results/Discussion/Chapter 4 Table 4.4. Comparison of the molecular mechanics (MM3) derived 01ClC2Ra dihedral angles of ketones 56, 58, 77 and 78 and the energies associated with each conformation.a? conformation relative energy kJmol-1 01ClC2R a conformation relative energy kJmol"1 01C1C2RO-ketone 56 ketone 58 1 0 118.7 1 0 83.1 2 0.20 113.6 2 5.87 115.5 3 0.32 125.7 3 6.48 130.1 4 0.35 111.9 4 7.38 141.0 5 0.42 126.3 5 7.68 151.9 6 0.51 127.4 6 9.44 179.7 7 0.84 123.2 8 1.78 103.8 9 4.12 94.6 10 9.86 75.7 ketone 77 ketone 78 1 0 115.0 1 0 84.4 2 0.72 120.1 2 8.08 119.6 3 0.79 123.6 3 8.68 112.7 4 1.75 131.5 4 10.48 133.0 5 9.66 163.5 As shown in Table 4.3, the conformational values obtained in the X-ray study can be, to some degree, transferred into a discussion about the solution state reactivity of these ketones. Although there is good agreement between the MM3 and solid state values, solution state discussions using the four parameters d, co, A, and 0 are hampered by the fact that they all depend on the position of the carbonyl group, which can rotate relatively freely about the C1-C2 bond. The interatomic distance, D, however is less variable and therefore more useful. The value of D gives the distance between the carbonyl carbon and the y-carbon(s). Since the value of D relies on the position of two 131 Results/Discussion/Chapter 4 atoms in the backbone of the ketone structure, the data in Table 4.3 shows that this parameter does not change with rotation about the C1-C2 bond. To a considerable extent, successful hydrogen abstraction depends on the C=0—-H contact distance, and, in these ketones, only one of the y-hydrogens will usually he within a reasonable distance for abstraction. Successful intramolecular y-hydrogen abstractions in the solid state have been carried out over contact distances of up to 3.1 A. 3 3 Therefore, the abstraction of y-hydrogen atoms with distances close to 3 A may be possible; however, the reported abstractions of the y-hydrogen atoms with contact distances close to 3 A have better angular parameter values of co and A for abstraction, which are also important in determining hydrogen abstractability Therefore, for the remainder of this chapter, the implicit assumption will be made that the nearer y-hydrogen is abstracted. This is not unreasonable if one considers the following fact: the tert-butyl cyclohexyl and adamantyl aryl ketones have in reality four and eight y-hydrogens, respectively. However, X-ray structure and MM3 analyses has shown that only one y-hydrogen in the molecule is at a reasonable distance from the carbonyl oxygen (< 2.8 A). The remaining hydrogens have distances greater than 3.4 A away from the carbonyl oxygen atom and are certainly too far away to be abstracted. The original arguments put forth by Lewis and Wagner in their explanation of the ct-alkyl effect34,35 ^ acyclic aryl ketones will now be applied to the cyclic aryl ketones of this thesis. The initial conformation of the biradical is as shown in Figure 4.5. The y-p-orbital radical centre is almost parallel to the a,(3-bond broken in the cleavage reaction, while the benzylic p-orbital radical centre is almost perpendicular to it. hi order for the 132 Results/Discussion/Chapter 4 biradical to attain the gauche conformation for which cleavage occurs, a 90 0 rotation about the ClC2-bond is required. Any a-methyl groups would undergo severe non-bonded interactions with the ortho hydrogens of the benzene ring impeding the crucial rotation enough to lower the rate of the cleavage process. Thus, the cyclization reaction would become favored. As shown in Table 4.1, the D-values for ketones having = H are longer than those for ketones with R Q . = CH3. This is caused primarily by the difference in the (3-angle when the cx-hydrogen is replaced by an a-methyl group (Figure 4.6). Thus the unreactive ketones ( R Q . = H) have D > 3.17 A , but all the reactive ketones ( R Q . = CH3) have D < 3.12 A . This is not much of a difference when one considers that the sum of the van der Waals radii for two carbon atoms is 3.40 A,24d and it might seem reasonable to assume that these distances provide reasonable overlap between the two carbon centres that would be joined in a cyclization photoproduct. However, Griesbeck and co-workers have shown in their investigation of a series of [2 + 2] photocycloaddition reactions that an interatomic distance of 3.4 A is not a realistic limit for radical combination.36 Then-results suggest that if the radical centres in a triplet 1,4-biradical are separated in space by more than about 3 A , and an additional rotation around the central single bond is required in order to enable bonding interaction, the cleavage pathway will be preferred.36 This was also observed by Zimmerman and Carpenter in their studies of the aryl version of the cyclopropyl-Tt-methane rearrangement,37 and is reflected in our results as well. From X-ray crystallography, ketones 56 and 57 have their 1,4-biradical centres separated 133 Results/Discussion/Chapter 4 by > 3.2 A; hence the cyclization pathway is not accessible. The significance of the interatomic distance between the radical centres will be discussed later in this thesis in more detail, along with a reinterpretation of some previous work from our laboratory. Figure 4.6. ketone R = p-substituent a(deg) P (deg) 56 H H 105 114 57 H F 107 114 58 Me H 108 110 67 Me Me 107 109 68 Me OMe 108 109 70 Me C O O H 107 109 77 H H 105 115 78 Me H 104 109 81 Me F 104 109 84 Me COOMe 103 108 of this thesis. Ketones 56, 57, 58, 67, 68 and 70 have the tert-butylcyclohexyl ring system, while 77, 78, 81 and 84 have the adamantyl ring system. The lack of photoreactivity observed for ketones 77 and 80 in the solution state is more puzzling. There is no reason to expect that these ketones cannot attain a conformation with significant p-orbital overlap so as to promote an efficient cleavage reaction. Therefore, the failure of ketones 77 and 80 to form cleavage products might be associated with instabihty and strain that is present in the photoproduct that would be produced from the cleavage reaction (Figure 4.7). Another plausible explanation is in the structure of the 1,4-biradical precursors for 131 and 132. If the reactions from 77BR and 80BR to 131 and 132, respectively, were to occur, as bond "c-e" is being broken the creation of the "b-c" double bond must take place. Since the a-b-c-d dihedral angle is about 60 °, this may make it difficult for the molecule to attain a planar double bond at the transition state. Therefore, the second step in Figure 4.7 may be slow relative to reverse 134 Results/Discussion/Chapter 4 hydrogen transfer. In contrast, cleavage products were observed in the fe/7-butyl cyclohexyl compounds because of the less rigid nature of the cyclohexyl ring system relative to the adamantyl ring system. X = H 77 77BR 131 F 80 80BR 132 Figure 4.7. The hypothetical photolysis of ketones 77 and 80 to form cleavage products 131 and 132 respectively. If the cleavage pathway is slow, it seems likely that a cyclization product could be formed instead. However, this is not the case. It cannot be due to the steric strain of forming a four-membered cyclobutanol ring to the adamantane backbone, since we observed efficient cyclization for the ketones with R Q . = CH3. Therefore, the two radical centres that combine to form the cyclobutanol are too far apart at D = 3.17 A (for ketone 77, Table 4.1) to allow the cyclization reaction to occur. The net effect is that neither cleavage nor cyclization will occur in ketones 77 and 80. 135 Results/Discussion/Chapter 4 4.5. Cleavage vs Cyclization: Solid State The general preference for cyclization products in the sohd state photochemistry of alkyl aryl ketones can be related to the 1,4-biradical geometry. It is assumed that hydrogen abstraction in the crystalline phase occurs with minimal conformational change, and produces biradicals having the same basic conformation as their ketonic precursors. The conformation of the biradical intermediate can be denned by three torsional angles, cpi, (p4 and (p. cp j - Angle of the p-orbital on CI with respect to the C2-C3 bond. (P4 - Angle of the p-orbital on C4 with respect to the C2-C3 bond, cp - Dihedral angle C1-C2-C3-C4. The torsional angles q>i and cp4 (Figure 4.8), are calculated from the X-ray crystal structure data based on two assumptions: (i) the hybridization of the ring carbon C4 bearing the unabstracted y-hydrogen atom changes from sp^  to sp2, and (ii) the p-orbitals at CI and C4 lie perpendicular to the planes denned by 01-C1-C2 and C3-C4-C5, respectively. C2- C3 Figure 4.8. A diagrammatic representation of the biradical intermediate reaction centre, showing cpi, (P4 and cp torsion angles. 136 Results/Discussion/Chapter 4 The (pi and 94 values and the torsional angles around the central sigma bond ((p) are given in Table 4.5. From Table 4.5, it is apparent that all biradical intermediate C1-C2-C3-C4 conformations are gauche rather than cisoid or and, with dihedral angles around the central sigma bond on the order of 70 °. The singly occupied p-orbitals at CI and C4 in the biradical intermediate are in close proximity to one another, but (pi is much more out of alignment with the central sigma bond C2-C3 than (p4 is. In each case, the angle (p4 is on the order of 30 °, and (pi varies from 60 0 to 80 °. 137 Results/Discussion/Chapter 4 Table 4.5. Crystallographically derived biradical parameters of ketones.3 ketone R= X= d ( A ) cpl (°) <p4 O D(A) ideal values <2.72 0 0 <3.40 tert-butyl cyclohexyl aryl ketone 56 H H 2.61 85.1 36.2 74.9 3.23 3.17 29.6 31.0 73.8 3.15 57 H F 2.59 84.4 36.0 75.2 3.23 3.17 28.9 31.0 74.5 3.15 58 C H 3 H 2.70 63.6 32.8 68.8 3.09 67 C H 3 C H 3 2.69 56.5 34.5 70.9 3.11 68 C H 3 OCH 3 2.63 68.4 34.7 69.1 3.10 3.49 51.3 31.2 65.5 3.11 70 C H 3 COOH 2.65 68.2 34.9 69.4 3.11 3.50 51.6 31.3 65.5 3.11 2.61 72.0 35.3 70.0 3.12 3.44 47.3 31.4 58.6 3.12 93 C H 3 COO~-(S)-prolinamide salt 2.75 3.61 -59.2 60.5 -33.4 30.2 69.2 -64.2 3.06 3.11 2-adamantyl aryl ketones 77 H H 2.47 82.4 31.1 69.9 3.17 3.13 27.2 29.5 70.7 3.12 78 C H 3 H 2.50 65.5 29.4 63.4 3.02 3.41 53.2 28.1 60.6 3.05 81 C H 3 F 2.54 60.5 28.8 62.8 2.99 3.47 58.0 28.6 60.1 3.04 84 C H 3 C 0 2 C H 3 2.58 60.5 29.9 64.9 3.00 98 C H 3 COO"-(S)-a-methyl benzyl amine salt 2.62 3.59 -55.0 64.2 -38.0 29.6 63.7 -60.2 2.96 3.05 99 C H 3 COO"-(R)-cx-methyl benzyl amine salt 2.60 3.59 55.3 -64.0 26.8 -29.3 -63.0 60.0 2.95 3.05 101 C H 3 COO"-(lR,2S)-norephedrine salt 2.55 3.47 61.3 -56.6 28.7 -28.4 -63.5 60.2 3.00 3.05 a Except in the case of the salts, y-Hydrogen atoms for which d > 3.50 A are not included in this table. 138 Results/Discussion/Chapter 4 Due to overlap considerations, the gauche and cisoid arrangements of the 1,4-biradical intermediates can undergo both cyclization and cleavage, but the and arrangement undergoes cleavage exclusively. Furthermore, it is generally accepted that the cleavage of a 1,4-biradical requires a nearly co-planar ahgnment of the central carbon-carbon bond (the sigma bond being broken) with the participating p-orbitals.29 As a result, extensive atomic and molecular motions around the C1-C2 and C3-C4 bonds are required in order to align the p-orbitals on C l and C4 with the C2-C3 bond and achieve an ideal arrangement for cleavage because cpl and (p4 both need to approach 0 °. Since the y-carbon atom is part of a ring, cp4 is much more fixed (about 30 °) than cpl. When the biradical is formed in solution, the p-orbital on the hydroxyl bearing carbon can freely rotate and become aligned with the C2-C3 bond. However, in the solid state, the molecule is unable to rotate bonds to a significant degree in order to produce a better alignment, due to the rigid nature of the lattice. Thus, the cleavage pathway is not available for these ketones unless good overlap exists between the p-orbital at the hydroxyl-bearing carbon atom and the central C2-C3 bond, as reflected by cpl values that approach 0 °. Values of cp 1 for the ketones under investigation were > 60 °. Since significant through-space overlap of the singly occupied orbitals is considered necessary for successful cyclkation2>3,20,38; j t j s n o t surprising that the preferred least motions in the solid state would lead to a predominant cyclization. Thus, since the orbitals involved are well oriented for ring closure, and the carbon atoms involved in bond formation are separated by less than 3.1 A (significantly less than 3.40 A, 139 Results/Discussion/Chapter 4 the sum of the van der Waals radii for two carbon atoms), it is not surprising that cyclization predominates in the crystalline state. In solution, as opposed to the solid state, bond rotations in the 1,4-biradical intermediates can allow for better overlap of the singly occupied orbitals with the C2-C3 bond, which can in turn increase the probability of obtaining cleavage products. This is reflected in our results, where none of the ketones studied gave type II cleavage products in the solid state, but ketones 56 and 57 did yield type n cleavage products in solution state photolyses. Most of the ketones studied produced exclusively the type II cyclization product in the solution state even though the p-orbital on the y-carbon is better situated for cleavage, but is still slightly misaligned ((P4). In summary, the lack of reactivity observed for compounds 56, 57, 77 and 80 in the solid state appears to be the result of several factors. First, in the crystalline state, the cpi angle is completely misaligned for orbital overlap, making the cleavage process unfavourable. As well, cleavage product formation (as opposed to formation of the cyclization product) would require more extensive reorganization of the atoms in the lattice. Both of these factors should favour the formation of cyclization products. However, as discussed, the distance D between the two radical centres is too large for cyclization to the cyclobutanol to occur. The net result of these factors is that ketones 56, 57, 77 and 80 are unreactive in the solid state. 140 Results/Discussion/Chapter 4 4.6. Why are Cw-Cyclobutanols Formed Preferentially in Both The Solution and Solid State? As shown in Figure 4.9, the biradical intermediate has four modes of closure by which the cyclobutanol may be obtained. However, because of the rigid nature of the cyclohexyl ring, these pathways are not all accessible. Biradical closure through paths "c" or "d" are extremely high energy processes which lead to highly strained products. Only the pathways labeled "a" and "b" provide possible reaction routes, with the least motion route path "a" leading to the m-cyclobutanol derivative, whereas "path b" would provide a trans- cyclobutanol. Figure 4.9. Biradical intermediate reaction centre. The structures are general for both /err-butyl cyclohexyl and 2-admantyl aryl ketones. Since closure of the biradical to products is probably topochemically controlled in the sohd state, the least motion closure through "path a" should be favoured. This pathway leads to the cis-cyclobutanol derivative. As shown in Tables 3.1-3.2, cis-cyclobutanol derivatives were indeed obtained exclusively in the sohd state. A large 141 Results/Discussion/Chapter 4 preference for cis- over /rara-cyclobutanol formation is also observed in solution. Stereoselectivity is expected to decrease in solution, since free rotation can usually occur. As is well established for the type II reactions of aromatic carbonyl compounds, photochemical reactions were found to occur primarily through the triplet n,7i* excited state. ^  9 Chapter 6 has the quantum yield and quenching studies on these ketones. The Stern-Volmer plots showed that these ketones do indeed react through the triplet manifold. In aromatic ketones, the rapid intersystem crossing (ISC) from singlet to triplet excited states causes the type II reaction to occur through a triplet biradical intermediate. The triplet biradical cannot directly produce the ground state products due to the spin forbidden nature of this process, hence the lifetime of the 1,4-biradical is simply a measure of how fast it interconverts irreversibly to the singlet biradical that then yields products in a fast process.40 Jn other words, product formation involves separate, consecutive steps, namely, a rate determining triplet to singlet intersystem crossing and chemical reaction of the l,4-biradical.41 Scaiano has also proposed that in addition to controlling the biradical lifetimes, intersystem crossing in triplet-derived biradicals plays a critical role in determining the behaviour and products which result from singlet biradical reactions. 42 With the lifetime of the singlet biradical being much shorter than that required for rotational equilibration, the nature and yields of products can be controlled by interactions at the triplet manifold level. Since C-C bond rotation rates are usually faster than the decay processes of the triplet l,4-bkadicals,43 the biradical may be able to reach conformational equihbrium, from which it can then produce some of the trans-M i Results/Discussion/Chapter 4 cyclobutanol.44,45 As m e r e s u i t s show, some trans-cyclobutanol is indeed formed through photoreaction of four of the ketones (66, 68, 70 and 71), but the required 180 ° rotation about the C1-C2 bond is evidently slow relative to direct closure to the cis-cyclobutanol. 4.7. The Photolysis of Chiral Salts 85 -95 and 96-101 Our goal was to bring about asymmetric induction in the sohd state Norrish type II photochemical reaction, and the achiral carboxylic acids 70 and 83 seemed ideal. Both are converted into chiral photoproducts in high chemical and quantum yield with no observed type II cleavage; as well, the reaction is stereo specific, with exclusive formation of the cis-cyclobutanol. By treatment of a keto-acid with an optically active amine and subsequent photolysis of the resulting salt, two diastereomeric photoproduct salts can be formed. If one is formed in greater amounts than the other, an asymmetric induction has been achieved, and the optically active ammonium ion has acted as an ionic chiral auxiliary.46 Irradiation of crystalline chiral salts was conducted at room temperature and at - 40 °C. No colour change or melting of the crystals was observed during the reaction. Following irradiation, the photolysis mixture was dissolved in a mixture of ethyl acetate and water and treated with excess ethereal diazomethane to form the methyl ester of the acid. The ester was freed of the chiral auxiliary by short path silica gel chromatography and then analyzed (as described in Section 3.6) by chiral HPLC.47 The results are summarized in Tables 4.6 and 4.7. Irradiation of the salts in either acetonitrile or methanol solution gave racemic photoproducts after workup. 143 Results/Discussion/Chapter Table 4.6. Asymmetric Induction in the Solid State Photochemistry of Salts of Keto Acid 70.a salt # optically active morphology irradiation irradiation conversion e e % c amine of salt medium and time (min) (%) temperature1 85 L-(+)-prolinol powder slides 7 1 (-)-12.2 R.T. 11 5 10.3 40 31 8.5 54 70 5.5 84 94 4.9 120 100 4.3 powder tube 15 4 O H 1-7 R.T. 120 47 8.3 powder slides 12 2 0-14.9 -40°C 54 12 12.3 86 (lS,2S)-(+)-v|/- long thin slides 5 2 (-)-100.0 ephedrine plates R.T. 20 18 97.3 173 82 63.5 long thin tube 7.5 3 (-)-lOO.O plates R.T. 73 40 79.2 90 61 72.7 120 59 71 480 87 63.5 powder slides 5 4 (+)- 21.2* R.T. 10 21 20.4* 15 34 18.3* 15 37 21.1* 20 48 13.7* 25 61 11.0* 42 88 8.8* powder tube 22 17 (+)-19.5* R.T. 52 75 8.1* 87 L-(+)-arginine powder slides 5 12 (+)-90.5* R.T. 15 29 84.6* 42 74 83.0* 88 (S)-(-)-ot-methyl- long thin slides 2 0.7 (+)-97.3* benzyl amine flat needles R.T. 6 24 95.8* 14 44 90.4* 52 92 84.8* 144 Results/Discussion/Chapter 4 Table 4.6. Continued salt # optically active morphology irradiation irradiation conversion ee % c amine of salt medium and time (min) (%) temperature1 89 (R)-(+)-a- long thin slides 5 7 (-)-96.9 methyl-benzyl flat needles R.T. 15 24 96.5 amine 25 66 94.3 45 85 92.1 90 (lR,2S)-(-)- long thin slides 9 0.4 (+)-78.5* ephedrine plates R.T. 21 1.0 77.2* 103 26 67.3* 200 65 58.7* long thin slides 69 3 (+)-81.7* plates -40°C 160 8 78.6* 91 (S)-(-)-proline powder slides 0.5 0.6 (-)-52.0 t-butyl ester R.T. 2 7 51.0 5 19 46.6 15 53 25.5 42 93 2.8 powder slides 21 11 (0-55.2 -40°C 69 32 50.4 92 (lR,2S)-(-)- long flat slides 5 8 (+)-96.5* norephedrine plates R.T. 15 34 95.8* 42 58 86.4* 90 97 81.1* 93 L-(-)-prolinamide plates slides 6 7 (+)-86.5* R.T. 30 51 68.2* 52 83 28.7* plates tube 2 0.5 (+)-85.2* R.T. 6 12 82.4* 52 78 33.4* 94 (lS)-(-)-2,10- plates slides 9 18 (0-5.3 camphorsultam (flakes) R.T. 21 31 4.0 57 59 3.8 plates slides 21 3 (0-7.1 (flakes) -40°C 69 11 6.9 95 L-(+)-lysine slightly slides 10 4 (0-3.8 yellow R.T. 20 11 1.4 plates 45 72 1.2 a Photolysis of salts in acetonitrile or methanol solution led to racemic mixtures of photoproduct 71. D For irradiation medium: slides means that the salt was crushed between two glass slides and irradiated, tube means that the salt was irradiated in a degassed N M R tube, so that crystal morphology remained intact. For temperature: R.T. means room temperature. c An asterisk indicates that the second (dextrorotatory) enantiomer of keto ester 71 eluted from H P L C was in excess. Optical rotation studies showed that this enantiomer had a positive (+ve) rotation at the sodium D line. 145 Results/Discussion/Chapter Table 4.7. Asymmetric Induction in the Solid State Photochemistry of Salts of Keto Acid 83. a salt # optically active morphology irradiation irradiation conversion e e o/ o c amine of salt medium and time (min) (%) temperature1 96 L-(+)-prolinol powder slides 2 0.8 (-)-27.3* R.T. 4 3.0 26.0* 15 7.2 25.9* 30 14.4 25.8* tube 50 21.3 (-)-26.2* R.T. 96 33.6 23.0* 210 93.2 19.5* slides 30 1.5 (-)-27.5* -40°C 90 6.9 26.3* 9 7 (lS,2S)-(+)-v|/- long thin slides 2 3.1 (+)-27.4 ephedrine plates R.T. 4 12.6 25.5 15 43.6 22.0 35 75.7 20.4 tube 7 25.9 (+)-27.2 R.T. 96 100 25.0 slides 30 2.7 (+)-29.0 -40°C 90 8.8 27.9 98 (S)-(-)-a- long thin slides 2 1.8 (+)-87.5 methylbenzyl flat plates R.T. 5 13.5 87.5 amine 10 39.5 86.9 20 64.0 86.0 47 89.4 81.0 tube 10 42.6 (+)-88.5 R.T. 96 100 79.9 slides 30 8.4 (+)-89.4 -40°C 90 19.9 88.2 99 (R)-(+)-a- long thin slides 2 3.5 (-)-88.0* methylbenzyl- flat plates R.T. 4 17.9 86.9* amine salt 8 37.8 86.4* 19 60.5 86.2* 43 82.3 82.4* tube 10 33.9 (-)-87.8* R.T. 96 100 78.9* slides 30 10.5 (-)-87.9* -40°C 90 22.6 87.3* 146 Results/Discusion/Chapter 4 Table 4.7. Continued salt # opticaly active morpholgy iradiation iradiation conversion ee o/o c amine of salt medium and time (min) (%) temperature^  100 (lR,2S)-(-> long thin slides 3 4.5 (+)-18.0 ephedrine plates R.T. 6 13.3 16.3 11 26.6 15.6 23 46.7 13.7 65 91.4 4.6 tube 1 2.1 (+)-19.0 R.T. 45 72.7 10.2 90 100 4.9 slides 30 3.9 (+)-18.9 -40°C 90 26.7 16.3 101 (lR,2S)-(-> long flat slides 2 1.8 (-)-88.0* norephedrine- plates R.T. 4 2.9 87.8* 15 11.6 81.9* 41 26.8 74.8* tube 7 4.7 (-)-87.8* R.T. 96 43.3 73.7* 210 92.4 69.8* slides 30 1.9 (-)-88.2* -40°C 90 7.8 87.9* a Photolysis of salts in acetonitrile or methanol solution led to racemic mixtures of photoproduct 84. D For iradiation medium: slides means that the salt was crushed betwen two glass slides and iradiated, tube means that the salt was iradiated in a degased NMR tube, so that crystal morpholgy remained intact. For temperature: R.T. means room temperature. c An asterisk indicates that the second (levorotatory) enantiomer of keto ester 84 eluted from HPLC was in excess. Optical rotation studies showed that this enantiomer had a negative (-ve) rotation at the sodium D line. In all cases, two compounds were observed by both GC and HPLC after treatment of the photolyzed sohd with ethereal diazomethane. These are the methyl esters of the cw-cyclobutanol and of the unreacted keto acid starting material. The labeling scheme for the intermediates and photoproducts, which will be followed for the remainder of this chapter, is shown in Figures 4.10 and 4.11. As an example, for compounds 85-95, which used acid 70 as the carboxylic acid part of the salt, the biradicals formed will be labeled 85BR-95BR. Thus, the photoproduct formed before diazomethane workup will be designated 85P-95P (Figure 4.10). After diazomethane addition, all the photoproducts 147 will be designated HOP (Figure 4.11). (Figures 4.10 and 4.11). Results/Discussion/Chapter 4 Similar numbering is shown for salts 96-101 Hy hydrogen abstracted 85-95 85BR-95BR 85P-95P Hy hydrogen abstracted 96-101 96BR-101BR 96P-101P Figure 4.10. Systematic numbering of the salts, biradicals and photoproducts. 148 Results/Discussion/Chapter 4 HO Ar diazomethane^ workup C 0 2 C H 3 Ar OH CH3O2C 8 5 P - 9 5 P H O P HQ Ar 9 6 P - 1 0 1 P diazomethane^ workup C 0 2 C H 3 C H 3 0 2 C Ar = o COO" + NHRR' 1 1 5 P Figure 4.11. Structure correlation between the salts and photoproducts H O P and 115P. For salts 85-95 and 96-101, the two axial y-hydrogen atoms H x and H y are enantiotopic, and two enantiomeric forms of photoproducts 8 5 P - 9 5 P and 9 6 P - 1 0 1 P are 149 Results/Discussion/Chapter 4 therefore possible. Since we know the absolute configuration of the amine, X-ray crystallographic results can establish the absolute configurations of the salt and corresponding photoproduct; thus, a direct correlation between the two can be made. 4.8. Asymmetric Induction in Salts 85-95 As shown in Table 4.6, a few of the optically active amines tested (prolinol, 2,10-camphorsultam and lysine) gave poor results. However, most worked fairly well (ephedrine, proline t-butyl ester and prolinamide), and some were outstanding (pseudoephedrine, arginine, a-methylbenzyl amine, and norephedrine). Photolysis of the (S)-(-)- and (R)-(+)-a-methylbenzyl amine salts afforded the optical antipodes of cyclobutanol HOP, indicating that the system is well behaved.48 As part of this project, we wanted to determine the absolute configuration of each of the enantiomers of photoproduct HOP so that we could carry out an absolute-to-absolute configuration correlation study. However, we were unable to produce X-ray quality crystals of any of the salt photoproducts, 85P-95P. We were able to determine the X-ray structure of one of the eleven starting salts listed in Table 4.6. The salt between keto acid 70 and L-(-)-prolinamide gave upon recrystallization from acetonitrile (containing a few drops of ethanol) plates of salt 93. The packing diagram and ORTEP drawings of salt 93 are shown in Figure 4.12. According to the X-ray crystallographic analysis, salt 93 crystallizes in the chiral space group (P2i), with two salt molecules and two molecules of acetonitrile solvent in the unit cell. 150 Results/Discussion/Chapter 4 Results/Discussion/Chapter 4 Upon closer examination of the crystal structure of salt 93, it is apparent that the ketone component of this molecule adopts a chiral conformation in which the ketonic oxygen is much closer to one enantiotopic y-hydrogen atom than the other (Figure 4.13). This is caused by twisting about the carbonyl carbon-to-cc-carbon bond (labeled as bond b-c in Figure 4.13). The hydrogen atom abstraction geometric parameters are listed in Tables 4.1 and 4.5. It was found that only Hy is within the proposed hydrogen abstraction distance of 3.0 A. The absolute value of the dihedral angle a-b-c-d is -86.7 °, and this situates the carbonyl oxygen 2.75 A from Hy, but 3.61 A from H x . This indicates that Hy should be abstracted preferentially. Figure 4.13. Reaction pathway for the photolysis of salt 93 in the solid state. According to the proposed Norrish type II reaction mechanism in the photolysis of salt 93, the abstraction of Hy by the carbonyl oxygen leads to the formation of 1,4-biradical intermediate 93BR. The intramolecular radical coupling of 93BR can give cis-and ?ra«5-cyclobutanols. It can be postulated that, in the sohd state, biradical 93BR 152 Results/Discussion/Chapter 4 retains the same basic conformation as the starting material 93; thus direct closure of the biradical should lead to the observed c/s-cyclobutanol 93P, isolated after diazomethane workup as compound HOP. Salt 93 yielded after workup an excess of the (+)-enantiomer of HOP. This enantiomer was the second one eluted from HPLC. Since hydrogen Hy should be abstracted preferentially, the final structure of the positive optical antipode of product HOP is expected to be as shown in Figure 4.14. Figure 4.14. Absolute structure of (+)-110P. Exact stereochemistry is (IR, 2R, 3R, 4S). The photoproduct from salt 93 lost optical purity very drastically as conversion increased (Table 4.6). At less than 5% conversion, we saw a very respectable ee for HOP of about 80%, but at greater than 80% conversion, the ee fell to about 30%. As shown in Table 4.6, the other salts studied also form small amounts of the topochemically disfavored enantiomer of photoproduct HOP. Such nontopochemical solid state behaviour has usually been attributed to reaction at the surface, at preexisting defect sites, or at defect sites generated by the reaction. 46 in all three sites, the high degree of order characteristic of the perfect crystal lattice is absent, allowing the occurrence of reactions 4 CH 3 153 Results/Discussion/Chapter 4 which would normally be topochemically forbidden. With all eleven salts, as the conversion is increased, the extent of nontopochemical behavior also increases; that is, the enantiomeric excesses decrease with increasing conversion. This indicates that defects generated by reaction contribute significantly to nontopochemical behavior (for example, with salts 86, 90 and 93). The ee of the photoproducts was found to be insensitive to surface phenomena or defects brought about by crashing, as parallel photochemical studies on large, carefully grown single crystals (irradiated in degassed NMR tubes) gave almost identical results to those obtained by irradiation of the "sandwich" samples (Table 4.6). Therefore, defect sites generated by reaction seem to be the most important factor for these salts. A similar conclusion can be drawn about the behaviour of salts 96-101 (Table 4.7). 4.9. Asymmetric Induction in Salts 96-101 As shown in Table 4.7, the salts produced by reacting keto acid 83 with the six optically active amines gave photochemical results ranging from poor (prolinol, ephedrine and pseudoephedrine) to excellent (a-methylbenzyl amine and norephedrine). As before, photolysis of the (S)-(-)- and (R)-(+)-a-methylbenzylamine salts afforded the optical antipodes of cyclobutanol 115P, indicating that the system is well behaved. We were able to grow X-ray quality crystals for both (S)- and (R)- oc-methylbenzylamine salts (98 and 99). Figures 4.15 and 4.16 show the packing diagrams and ORTEP drawings of salts 98 and 99, respectively. An X-ray crystal structure was also 1 5 4 Results/Discussion/Chapter 4 obtained for the (lR,2S)-norephedrine salt (101), and Figure 4.17 shows its packing diagram and ORTEP drawings. Figure 4.15. (a) The ORTEP drawing and Q>) the crystal packing diagram of salt 98. 155 Results/Discussion/Chapter (b) Figure 4.16. (a) The ORTEP drawing and (b) the crystal packing diagram of salt 99. 156 Results/Discussion/Chapter 4 (a) (b) Figure 4.17. (a) The ORTEP drawing and (b) the crystal packing diagram of salt 101. 157 Results/Discussion/Chapter 4 As for the photoproducts from salts 85 to 95, repeated attempts to grow suitable photoproduct crystals from salts 96P to 101P were unsuccessful. During our attempt to determine the absolute configuration of photoproduct 115P, we noticed that crystals of salt 99 did not change in appearance upon photolysis, even at conversions as high as 90%. This suggested the occurrence of a single crystal-to-single crystal (topotactic) process. As shown in Table 4.7 there is a slight diminution in the ee as percent conversion is increased from 3.5% (88% ee) to 100% (78.9% ee). The single crystal of the (R)-(+)-a-methylbenzylamine salt 99 which had been previously subjected to X-ray diffraction analysis was photolyzed for a time sufficient to insure complete conversion to photoproduct 99P, whereupon a second crystallographic data set was collected. Both data sets refined successfully in space group P 2 ] 2 i 2 ] to final R values of 4.6 and 4.9%, thus indicating that this sohd state photorearrangement is indeed a single crystal-to-single crystal process. Figure 4.18 shows the packing diagram and ORTEP drawing of salt 99 after a 2 h photolysis to produce compound 99P. 158 Results/Discussion/Chapter 4 Results/Discussion/Chapter 4 Figure 4.18. (a) The ORTEP drawing and (b) the crystal packing diagram of photoproduct 99P. As was observed for salt 93, the ketone groups of salts 98, 99 and 101 adopt chiral conformations in which the ketonic oxygen atom is much closer to one enantiotopic y-hydrogen atom than to the other. Table 4.8 shows the relevant parameters for salts 98, 99 and 101, along with the designation of the hydrogen which is probably being abstracted. Table 4.8. Crystallographically derived biradical geometries and predicted behavior.3'0 salt hydrogen d(A) A(°) 0(°) O D(A) q>l (°) cp2 (°) cp(°) 98 H x 3.59 35.9 106.6 36.8 3.05 64.2 29.6 -60.2 Hy 2.62 74.8 114.3 62.0 2.96 -55.0 -38.0 63.7 99 H x 2.60 75.0 114.1 62.1 2.95 55.3 26.8 -63.0 Hy 3.59 35.9 106.3 36.7 3.05 -64.0 -29.3 60.0 101 H x 2.55 80.0 116.3 60.1 3.00 61.3 28.7 -63.5 H v 3.47 41.4 109.3 41.7 3.05 -56.6 -28.4 60.2 salt predicted H- a-b-c-d (°) enantiomer abstracted of ketone formed 98 Hy -83.9 (+) 99 H x 85.7 (-) 101 H x 90.2 (-) a The dihedral angle a-b-c-d is defined in Figure 4.19. 0 The enantiomer formed represents the sign of the optical rotation observed at the sodium D line. The values in Table 4.8 show a remarkable degree of internal consistency. For example, salts 99 and 101 adopt similar conformations in the crystalline state, with the absolute value of the a-b-c-d dihedral angle approximately 90 ° and positive (Figure 4.19). Thus, the H x hydrogen should be abstracted preferentially, and in agreement with this, 160 Results/Discussion/Chapter 4 both salts were shown to form an excess of the same enantiomer of 115P. The enantiomer obtained gives negative rotation at the sodium D line. Closer examination of the crystal structure of 99P (Figure 4.18) shows that the carbon atom to which H x was attached is in fact part of the newly formed four-membered ring. Therefore, the negative enantiomer of 115P must have the (S)-absolute configuration at the hydroxyl carbon. Figure 4.20 shows the structure of (-)-115P. hv H x abstraction biradical closure Ar 0 H C H , hydroxyl carbon (S) Ar = O %b_Ar c d hv -COO" NH,RR' Hy abstraction biradical closure OH C H , hydroxyl carbon (R) Figure 4.19. Reaction pathway for the photolysis of salts 96-101 in the solid state. H x abstraction occurs in those salts where the a-b-c-d dihedral angle is positive. 161 Results/Discussion/Chapter 4 CH 3 Q 2 . P H CH 3 Figure 4.20. Absolute structure of (-)-115P. Exact stereochemistry is (IS, 2S, 3R, 4S, 6R, 8R, 9S). 4.10. Continuing the Discussion of the Single Crystal-to-Single Crystal Photoreaction of Salt 99. As was shown in the previous section, the photochemical reaction of salt 99 is the first example of a crystalline phase photorearrangement that is not only topotactic, but which also (i) occurs with a high degree of asymmetric induction (ca. 90% enantiomeric excess) and (ii) involves an ionic chiral auxiliary of known absolute configuration, so that X-ray diffraction studies can be performed. In fact, we were able to map the absolute steric course of the photochemical reaction undergone by salt 99 because X-ray diffraction studies were successfully determined of the same crystal not only at the beginning (salt 99) and final stages (product 99P), but also at the midpoint of the reaction.49 The first and only other example of a topotactic, enantioselective sohd state process whose absolute course has been elucidated by X-ray crystallography is that which 162 Results/Discussion/Chapter 4 occurs between deoxycholic acid and various ketones in crystalline host-guest complexes formed between the two.^ O Suzuki and co-workers have provided an example of a solid state bimolecular photoreaction that is both enantioselective and topotactic, but for which absolute configuration correlations between reactant and as-prepared photoproduct were not possible owing to unresolved disorder in crystals of the latter. 51 As well, there have been numerous enantio selective, nontopotactic reactions for which absolute configuration correlations have been carried out. 52 A single crystal of salt 99 was subjected to 15 minutes of irradiation from the output of a 450W-medium pressure mercury lamp. X-ray structure analysis was then performed where it proved possible to resolve the structures of 99 and 99P in the same crystal. The crystal of 99 was detenrrined to have undergone approximately 60% conversion into 99P. This conclusion was based on GC analysis, and on refinement of atom occupancy factors in the X-ray study. Figure 4.21 shows a stereodiagram of the superposition of the 99/99P pair present in this crystal. As shown, there is a nearly perfect atom-for-atom correspondence between reactant and photoproduct. The major difference between the two structures is a movement of the adamantane ring and a slight shift in orientation of the carbon-oxygen bond-changes which are represented for photoproduct 99P by the shaded bonds of Figure 4.21. Slightly larger values of the anisotropic displacement parameters, especially for the atoms of the adamantane group, indicate an inexact match in location of reactant and product molecules; separate atom sites could not be resolved in this (room temperature) 163 Results/Discussion/Chapter 4 Figure 4.21. Stereodiagram showing the superposition of reactant 99 (open bonds) and photoproduct 99P (shaded bonds) in a single crystal of the former photolyzed to 60% conversion. To improve clarity, the hydrogen atoms present in the adamantane portion of the structure have been omitted. Figure 4.22. Crystal packing diagram of 99/99P pair. 164 Results/Discussion/Chapter 4 Figure 4.22. Crystal packing diagram of 99/99P pair. As shown in the structure diagram of the 99/99P pair (Figure 4.21), a direct correlation can be made between the starting material and photoproduct. As described earlier, the F£x hydrogen is abstracted, and 99P possesses the (S)-absolute configuration at the hydroxyl carbon. A gradual and smooth conversion of ketone into cyclobutanol product occurs, as shown in Table 4.9. The space group remains P2i2]2i, and the number of molecules in the unit cell is constant at Z = 4. The cell dimensions (a, b, and c) show a progressive increase (a) or decrease (b and c) in going from 99 to 99P, whereas the cell volume shows an initial increase in going from 99 to 99/99P and then a decrease as the crystal is converted entirely into 99P. This observation is not unique and has been observed previously with other single-crystal-to-single-crystal reactions.50c>53 The volume and density of the crystal were found to vary by less than 1% as the topotactic photoreaction occurred. Table 4,9. Details of X-ray structural analyses. 99 99/99P a 99P % change0 space group P2i2i2i P2i2i2i P2i2i2i a (A) 11.791 (2) 12.113 (3) 12.475 (2) +5.8 b(A) 29.795 (3) 29.419(3) 28.796 (2) -3.4 c(A) 6.550(2) 6.507 (4) 6.430 (3) -1.8 V(A3) 2301.1 (7) 2319(1) 2310(1) +0.4 z 4 4 4 Dcalcd (§ c m ~ 3) 1.211 1.202 1.206 -0.4 165 Results/Discussion/Chapter 4 R (%) 0.046 0.068 0.049 a 99/99P represents a crystal of 99 photolyzed to 60% conversion, i.e., 99:99P = 40:60. ^ values shown are only for the percentage change in the parameters between 99 and 99P. With the study presented in this thesis, the use of chiral crystalline environments to carry out asymmetric inductions in high optical yields is established beyond question as a viable technique in organic photochemistry. The discovery of the single crystal-to-single crystal (topotactic) reaction of salt 99 shows that this may be the beginning of a new way of trying to discover topotactically inclined molecules. Because of their high-melting, ionic, two-component character, chiral salts may be the future answer in the search for substrates for absolute asymmetric syntheses. 4.11. Reinvestigating a-Adamantyl Acetophenones The photochemical behavior of a-adamantyl acetophenones has been well documented. 54-59 r e c e n i years, the photochemistry of a-adamantyl acetophenone and its derivatives has been studied by Scheffer, Trotter and co-workers,54,58,59 D o m ^ solution and in the solid state. As before, no cleavage products were found. Recent work in our laboratory on the a-adamantyl acetophenones showed some interesting results.60 The acetophenones studied are shown in Table 4.10. The values of d, co, A, 0 and D for the a-adamantyl acetophenones for which X-ray structure analyses were done are shown in Table 4.11. 166 Results/Discussion/ Chapter 4.10. Structure of the a-Adamantyl Acetophenones1 Compound # R X 131* H F 132* H CN 133 H COOH 134 H COOMe 123n* H COO" L-prolinol salt 123p* H COO" L-prolinol salt 135 C H 3 F 136* C H 3 CN 137* C H 3 COOH 138 C H 3 COOMe * crystals were suitable for x-ray analysis 123n (needles) and 123p (plates) are dimorphs 167 Results/Discussion/Chapter 4 Table 4.11. Crystallographically derived C=0-"Hy abstraction geometries.a>D'c ketone hydrogen d(A) A(°) co(°) e n D(A) Comment <2.72 90-120 0 180 <3.2 ideal values 123n H2B 2.70 87.0 45.9 118.5 3.19 reactive H9A 3.14 53.5 53.0 114.3 2.92 H2A 3.47 81.0 20.7 69.9 3.19 123p H2b 2.70 84.5 53.5 114.6 3.15 reactive (R) H2a 3.31 84.7 26.2 78.8 3.15 H9a 3.43 47.5 47.8 108.9 3.06 123p H32b 2.67 82.6 53.9 115.0 3.09 reactive (S) H32a 3.24 83.1 25.9 78.3 3.09 H39a 3.50 46.0 44.7 109.4 3.11 136 H6a 2.73 74.4 62.6 110.0 3.18 reactive H6b 3.13 81.8 37.7 84.2 3.18 131 H16 2.64 80.0 59.6 112.0 3.03 unreactive H20 2.79 72.4 62.9 106.5 2.99 H19 3.07 82.5 39.6 88.4 2.99 H15 3.12 85.0 31.4 81.3 3.03 132 H10 2.57 93.9 33.3 120.5 3.20 unreactive H7 3.02 61.3 58.9 115.5 2.98 H9 3.40 84.3 9.8 67.1 3.20 137 H2 2.50 99.2 14.3 121.2 3.21 unreactive H10 2.57 89.6 44.4 120.2 3.12 a y-hydrogen numbering as taken from reference 60. 0 For ketone 123p, there were two independent molecules in the unit cell, having the opposite configurations. c The labeling under the comment section refers to solid state reactivity only. All the ketones yielded cyclization products in solution state photolyses, since the cleavage product, adamantene, is a high energy, unstable olefin whose formation would have to proceed via a high energy reaction pathway. In the solid state, three of the 168 Results/Discussion/Chapter 4 ketones were photostable. As shown in Table 4.11, most of the y-hydrogen abstraction parameters are within the proposed ideal values. It seemed unclear why these ketones should be photostable in the sohd state and no explanation was ever proposed. Examination of ketone 132 shows that only one hydrogen lies within the d < 2.72 A abstraction distance. The interatomic distance between the carbonyl carbon and y-carbon (D) is also quite high, at 3.20 A. This may be the possible reason for its photo stability. This distance may make the cyclization pathway slow relative to reverse hydrogen transfer, thus no cyclization product is produced. For ketone 137, two y-hydrogens are quite nicely situated for abstraction. If the closest hydrogen is abstracted, the two radical centres produced are at D = 3.21 A apart. This is too far apart to lead to cyclization; hence reversion of the biradical to starting material occurs. Abstraction of the second available hydrogen at d = 2.57 A would yield a biradical with D = 3.12 A. A possible reason why this does not occur is that the abstraction of the closer hydrogen is so much more favourable, all four of the parameters being better suited for abstraction. Therefore, the compound would preferentially revert back and forth between starting material and biradical with abstraction and replacement of H2, rather than have H10 abstracted. Scheffer et al. has found that medium-sized ring and macrocyclic diketones display this type of behaviour.23 When two hydrogens are situated at d < 2.8 A, the closer one is preferentially abstracted. Ketone 131 has similar abstraction parameters to those observed for ketone 123, which did react. With D equal to only 3.03 A, this ketone should undergo cyclization to the cyclobutanol photoproduct. If we again assume that the abstraction of the closest 169 Results/Discussion/Chapter 4 hydrogen did occur in ketone 131, as in ketone 137, then the corresponding biradical intermediate could be reverting to starting material for some reason. This might be due to an unfavourable crystal packing that disallows motion of the atoms in the crystal to form the single bond in the cyclobutanol between the two radical-bearing carbons. However, the true cause of the sohd state photostability of ketone 131 is still unclear and deserves further investigation. As for the reactive ketones found in Table 4.11, all were found to have D < 3.19 A. It may be hard to propose an absolute upper distance limit for radical coupling, since there are obvious exceptions (for example, ketone 131). However, it is conceivable that the D-parameter could be more important in some cases than in others, depending on which additional constraints may be present in the various substrates. It might be advantageous to study further the importance of the D-parameter in the coupling of the two radical centres produced in the Norrish type II photoreaction. 170 Results/Discussion/Chapter 5 CHAPTER 5 Chemical Reactions In Other Organized Media 5.1. General Considerations There are many examples in the literature of organic molecules whose solution phase and sohd state chemical behavior are very different, because of the anisotropic steric environment of the crystal lattice. 61 The environment around a given molecule in the bulk of the crystal may sterically impede certain reaction pathways of that molecule while allowing others in a manner that is completely dependent on the packing arrangement. However, most of the work thus far has focused on the solution and crystalline states. 62 In isotropic media, the transformation of achiral reactants into chiral products, via photochemical reactions, leads to racemic mixtures. When such reactions are conducted in optically active media, the previously enantiomeric transition states become diastereotopic due to differing interactions with the media. These transition states will, in general, have unequal energies, thus resulting in the formation of one photoproduct enantiomer being favored kineticalfy over the other. For example, irradiation of any of the chiral salts (85-101) dissolved in solution led to no measurable optical activity in the photoproduct. In the crystalline state, however, where the intermolecular forces are stronger and much more highly organized, the extent of the asymmetric induction can be quite high, as shown in the previous chapter.50a,63 This chapter will deal with two attempts at promoting asymmetric induction with the use of a chiral environment other than the pure crystalline state. The first deals with 171 Results/Discussion/Chapter 5 the use of zeolites which have been previously made chiral by preabsorption of optically active host molecules.48,64 ^s will be shown, this method leads to low to modest asymmetric induction. The second method involves the use of thin films of optically active organic polymers containing dissolved guest molecules. This method did not lead to appreciable asymmetric induction. 5.2. Inclusion of Ketones in Zeolites As was shown previously in this thesis, the use of optically active ammonium ions as ionic chiral auxiliaries for photochemistry in the crystalline state yields photoproducts with very high enantiomeric excesses. This section deals with our complementary work using modified zeolites as microreactors^ in which a certain proportion of the cages have been rendered chiral through preadsorption of an optically active inductor molecule. This "zeolite method" was applied to ketones prepared in our laboratory in a collaborative study with V. Ramamurthy (Tulane University, New Orleans Louisiana, USA). All photoreactions in zeolites were performed by Ramamurthy et al. The compounds studied for the present work are shown in Figure 5.1. t-Bu Ar Me hv t-Bu HQ Ar •Me Ar = /?-Ph-CN, 69 Ar = p-Ph-COOMe, 71 108 110 Figure 5.1. The mode of photoreaction of ketones 69 and 71 in zeolites. 172 Results/Discussion/Chapter 5 Incorporation of various optically active inductor molecules (amines or alcohols) within the supercages was accomplished in the following manner.66 Zeolite (X or Y) , having been dried at about 500 °C for at least 6 h, was quickly transferred to a solution of anhydrous inductor in hexanes (10 mL) and stirred vigorously at room temperature. After stirring overnight (« 15 h) the slurry was filtered and rinsed with hexanes (2 X 10 mL). After it had been determined that the hexane washings contained no residual inductor material, the zeohte/inductor complex was dried under vacuum (IO" 4 Torr) for about 6 h. The dried zeohte/inductor complex was quickly transferred to a solution of ketone in hexanes (10 mL) and stirred overnight (« 15 h). The zeolite/inductor/ketone complex was then filtered, rinsed with hexanes (2 X 10 mL), are stirred with hexanes (10 mL) for 10 min, after which the supernatant was removed; as before, the washings were clean, indicating complete incorporation of the substrate within the zeolite cages. Typical loadings were 5-50 mg of chiral inductor and 5 mg of ketone in 200 mg of zeolite. This corresponds to an occupancy number (S) (denned as the average number of guest molecules per zeolite supercage) of 0.3-2.6 for the chiral inductors and about 0.14 for the ketones. The zeohte/inductor/ketone complexes were photolyzed both as dry powders and as hexane slurries (suspension in 10 mL of degassed hexanes). Approximately 20% conversions could be realized in 10 min in hexane slurries, but irradiations of approximately 1 h were required to achieve the same conversion in the sohd state. Following photolysis, the organic materials were extracted from the zeolites with diethyl ether (mass balances were excellent) and analyzed by chiral HPLC. The photoproducts 173 Results/Discussion/Chapter 5 were found to be separable with baseline resolution on Chrralcel OD and OJ HPLC columns.47 The results of the photolyses are compiled in Table 5.1.67 Table 5.1. Asymmetric induction in the photochemistry of zeolite Na-Y/chiral inductor/ketone complexes3^ ketone chiral inductor quantity0 occupancy T ee (mg) number (S)^ (°C) (%)e 69 (-)-ephedrine 5 0.3 20 10* 10 0.5 20 16* 15 0.8 20 22* 20 1.0 20 22* 25 1.3 20 25* 25 1.3 0 19* 30 1.6 20 23* 35 1.8 20 25-30* 35 1.8 0 18* 40 2.0 20 5-10* 50 2.6 20 <5* 71 (-)-ephedrine 10 0.5 20 <5* 15 0.8 20 10.2* 20 1.0 20 18.9* 25 1.3 20 28-30* 25 1.3 0 28.2* 25 1.3 -40 27* 30 1.5 20 5-10* 35 1.8 20 5-10* 35 1.8 0 10* 35 1.8 -40 5* 40 2.0 20 10* 50 2.6 20 <5* 174 Results/Discussion/Chapter 5 Table 5.1 Continued ketone chiral inductor quantity0 occupancy T ee (mg) number <S>d (°C) (%) e 71 (+)-ephedrine 25 1.3 20 30 (-)-menthol 20 1.1 20 5.2 30 1.6 20 8.1 (-)-borneol 10 0.6 20 9.8 20 1.2 20 4 30 1.7 20 9.2 40 2.4 20 9 (+)-b omylarnine 10 0.6 20 3.1 20 1.2 20 5.2 30 1.7 20 6.3 L-proline tert-butyl ester 10 0.5 20 <1* 20 1.0 20 <1* 30 1.5 20 <1* 40 2.0 20 <1* a Photolyzed to « 2 0 % conversion in hexane slurries by using the Pyrex-filtered output of a 450 W Hanovia medium-pressure mercury lamp. Chemical yields estimated to be 90-95% by G C analysis using an internal standard. Recovery of the chiral inductor could not be quantitated owing to poor G C and H P L C characteristics. D In each case, 5 mg of ketone was complexed with 200 mg of Na-Y (<S> « 0.14). c Amount of chiral inductor per 200 mg of zeolite of Na-Y. d The occupancy number, represented by <S>, is defined as the average number of guest molecules per supercage. e An asterisk indicates that the second enantiomer of the photoproduct eluted from H P L C was in excess. In the case of 71 , this is the dextrorotatory enantiomer; the hydroxyl bearing carbon has the (R) absolute configuration, as determined from Section 4.8 of this thesis. Ephedrine proved to be the best of the chiral inductors tested, giving enantiomeric excesses in the range of 25-30%. The use of (+)- or (-)-ephedrine afforded the optical antipodes of the photoproduct, indicating that the system is well behaved. Changes in the photolysis temperature had little effect on the enantiomeric excess, and the use of chiral inductor loadings different from (S) « 1.5 lowered the enantiomeric excesses. Control runs showed that irradiation of the ketones in hexanes in the presence of ephedrine, as well as photolyses in Na-Y in the absence of ephedrine, led to racemic photoproducts. Also, there was no selective inclusion of either photoproduct enantiomer vvdthin the modified 175 Results/Discussion/Chapter 5 zeolite. This was demonstrated by including a racemic mixture of cyclobutanol photoproduct in the ephedrine-contahring Na-Y zeolite, and showing that the cyclobutanol obtained after extraction with ether remained racemic. These results establish that zeolites, when modified with chiral inductors such as ephedrine, can yield photoproducts with low to moderate enantiomeric excess. Therefore, we wished to find out what the important parameters are that determine enantio selectivity during photoproduct formation within zeolites. Figure 5.2 shows the ketones chosen for this study. Since ephedrine is the best chiral inductor, and is most effective when the occupancy number is one, photoreaction of the two ketones within the supercages of faujasites was investigated. These supercages are large enough to accommodate simultaneously both one molecule of ephedrine and either one of the ketones 71 and 138 (Figure 5.3.). 176 Results/Discussion/Chapter 5 Figure 5.2. The photochemical behaviour of ketones 71 and 138 when included within zeolites. Figure 5.3. Molecular model diagram of ephedrine and ketone 71 within the supercage of X or Y zeolite. Guest structures have been minimized, but the guest-host assembly has not. The figure shows that both the ephedrine and ketone can fit within zeolite cages. 177 Results/Discussion/Chapter 5 Since ketone 71 has been shown to give only one cyclobutanol diastereomer within zeolites, it was used to determine the effect that the supercage free volume has on enantio selectivity. Unlike 71, ketone 138 gives both cyclobutanol diastereomers upon irradiation. As these two cyclobutanol products have different molecular sizes and shapes, ketone 138 was used to establish the effect that the product volume has on the enantio selectivity and diastereoselectivity within zeolites. The results obtained with ketone 71 are presented in Figure 5.4. The most notable observations relate to the nature of the enantiomer that is enhanced in the two zeolites Na-X and Na-Y. When (-)-ephedrine is employed as the chiral inductor within zeolite Na-Y, modest enantio selectivity (ca. 30%) for the (+)-isomer is observed. When Na-X is used, the same chiral inductor leads to favouring of the (-)-isomer, but with much lower enantioselctivity (ca. 5%). A similar reversal is seen when (+)-ephedrine is used as the chiral inductor, with similar enantioselectivities. This observation may be attributed to the differences in supercage free volume between Na-X (852 A 3 ) and Na-Y (827 A 3 ) . This difference in supercage dimension results in the orientation between the reactant and the chiral inductor within zeolite Na-X to be different to that in Na-Y. The orientation is favoured in zeolite Na-X because of the comparatively larger dimension of the supercages in this zeolite. Supporting this interpretation are the results obtained with K-X (800 A 3 ) , Rb-X (770 A 3 ) and Cs-X (732 A 3 ).66 when the supercage free volume is reduced until it is the same as or smaller than that of Na-Y by exchanging Na-X with different cations, the enantio selectivity is found to be the same as that obtained in Na-Y. 178 Results/Discussion/Chapter 5 (-)-isomer Figure 5.4. Results of photolysis of ketone 71 in Na Y and Na X zeolites. Ketone 138 has been shown to give both cyclobutanol diastereomers upon irradiation, in ratios depending greatly on the medium in which the irradiation is conducted. In hexane solution, the ratio of trans to cis cyclobutanol is 2.8, whereas within Na-Y zeohte, the ratio is 1.^ 8 Such variations have been attributed to the differences in size and shape of the two isomers, and to the influence of the supercage free volume on the partitioning of the 1,4-diradical intermediates that result from the y-hydrogen abstraction. The c/s-cyclobutanol is expected to be more spherical in shape than the frvms-isomer, which is predicted to be elliptical in shape. The shapes and sizes of 179 Results/Discussion/Chapter 5 the 1,4-diradical precursors are expected to be similar to those of the photoproducts. Therefore, it was proposed that the trans-isomer and its precursor biradical cannot fit within the same cage due to their elongated, elliptical shape, and thus require two cages. The c/5-isomer, however, and its biradical precursor can fit nicely within a single cage because of their spherical shape. Therefore, the cis-cyclobutanol and its precursor should be subjected to a greater influence by the chiral inductor ephedrine than trans-cyclobutanol and its precursor, which are accommodated within two cages. Subsequently, a difference in enantio selectivity between the two diastereomeric cyclobutanols within the chirally modified zeolites is expected. Photolysis of ketone 138 with Na-Y containing one (-)-ephedrine molecule per supercage gave the trans- and c/s-cyclobutanols in the ratio of 1.4. The slight increase in the trans isomer is consistent with a decrease in free volume of the cage due to the presence of ephedrine.69 The results are summarized in Figure 5.5. The cis-cyclobutanol is formed with higher enantio selectivity (35%) than the trans-isomsr (5%). This is consistent with the prediction of a difference in enantio selectivity between the diastereomers and indicates that the extent of enantio selectivity (valid for at least the Norrish-Yang reaction) within zeolites depends on how well the reactant, the 1,4-diradical and the products fit within a supercage. A tight fit between the reactant and the chiral inductor may be a prerequisite to achieve significant enantioselectivity.^ O 180 Results/Discussion/Chapter 5 Figure 5.5. Photolysis of ketone 138 within Na Y-ephedrine. These results show that asymmetric induction can be achieved using zeolites, which have been preloaded with an optically active and non-light absorbing guest molecule, so that when a second, photochemically reactive molecule is introduced into the same (or nearby) cage, it senses the asymmetric field due to the first and reacts enantioselectively. The zeolite method is potentially more versatile than the ionic crystal method, since the latter method requires the photoreactants to be acidic (or basic, in which case one would use an optically active acid as the chiral auxiliary). At the moment though, the zeolite method affords lower optical yields than the ionic crystal method. Both techniques complement the work of Toda and others on the use of optically active host compounds for photochemical asymmetric synthesis.71 181 Results/Discussion/Chapter 5 5.3. Asymmetric Induction in Polymer Films Organic molecules dissolved in polymer films find themselves in environments that, while still restricting diffusion and major conformational change to a considerable degree, are less uniform and probably less resistant to deformation than those existing in the crystal.62 jn other words, polymer matrices have properties intermediate between those of liquids and solids.72 it occurred to us that asymmetric syntheses could be induced if we carried out a photochemical reaction in a film of optically active polymer. The chiral organic polymer used in this investigation was poly(3-hydroxybutyric acid)/poly(3-hydroxyvaleric acid) copolymer (PHBAco-PHVA, PHVA content 8 wt.%), supplied by the Aldrich Chemical Company. Figure 5.6 shows the structures of the polymer and of ketone 71 used in this experiment, as well as the photoproduct isolated from the photolyses. (a) O C H 3 II I - C - C H 2 - C — O I H J x O C H 2 C H 3 II I - C - C H 2 - C — O I H (b) (c) o C H 3 C 0 2 C H 3 C H 3 0 2 C Figure 5.6. (a) Structure of PHBA/co-PHVA polymer, (b) the guest substrate, ketone 71 and (c) the photoproduct (110) isolated from the photolyses of the polymer/71 mixture. 182 Results/Discussion/Chapter 5 Before use the polymer was freed of stabilizers and other low molecular weight impurities by dissolution in chloroform, reprecipitation by addition of methanol, suction filtration and vacuum drying. This process was repeated three times. Table 5.2 shows the composition of the polymer/substrate solutions used in this study. The films were prepared by applying ca 0.5 mL of a solution containing polymer and photoactive guest to the top of a microscope slide and distributing it evenly over the surface using a second slide as a straightedge. After coating, the films were air dried for 24 h and then dried in vacuo for 48 h at room temperature. The films (five for each solution prepared) were placed in polyethylene bags and thoroughly degassed with nitrogen; the bags were then sealed under a positive pressure of nitrogen with a heat-sealing device. The bags and thin films were irradiated with the full output from a 450 W Hanovia mercury lamp for times ranging from 30 s to 10 min. After irradiation, the polymer films were redissofved in chloroform, and diethyl ether was added. The polymer precipitated out, and the mother liquor was decanted and concentrated in vacuo. It was subjected to short path silica gel chromatography using 3% diethyl ether in petroleum ether (v/v) as eluent. GC analyses showed conversions ranging from ca. 5% to 100% and only one photoproduct being formed, corresponding to cyclobutanol 110. The isolated photoproduct was analyzed by HPLC, as described previously in this thesis. 183 Results/Discussion/Chapter 5 Table 5.2. The composition of the polymer/substrate solutions used.3 Trial mass of mass of Volume of polymer/ cone, of ketone polymer (mg) ketone (mg) solution (mL) ketone mass (IO"2, M) ratio 1 63.4 4.6 5.0 13.8 0.291 2 204.3 14.8 5.0 13.8 0.936 3 403.8 28.1 5.0 14.4 1.78 4 210.6 27.4 5.0 7.7 1.73 a The polymer used was poly(3-hydroxybutyric acid)/poly(3-hydroxyvaleric acid) copolymer, and the substrate used was ketone 71. Four different polymer solutions were prepared so that the relationship of both polymer and guest concentration with respect to photoproduct e.e. could be determined. It was observed that the isolated photoproduct from each of the runs showed no enantiomeric enrichment. Nonetheless, it can be construed that the viscous polymer matrix did in fact exert a restrictive influence in the Norrish type II reaction since the polymer/71 mixture yielded only the CM-cyclobutanol whereas in solution ketone 71 was found to yield a small amount of trans-cyclobutanol along with the major photoproduct cis-cyclobutanol. After obtaining these results, no further work for this thesis was performed with the use of polymer films 184 Results/Discussion/Chapter 6 CHAPTER 6 Photophysical Properties of the Ketones 6.1. Quantum Yield Studies The Norrish type II reaction involves formation of two consecutive intermediates; first an excited state (that can be singlet and/or triplet) and then a biradical. The rapid ( > 1010 s _ i) intersystem crossing in aryl ketones usually produces exclusive triplet reactivity. 73 The photochemical process is shown by Figure 6.1, where GS, T and BR denote the ground and triplet states of a ketone and its biradical, respectively, while [Q] is the concentration of triplet state quencher and kjj, kp, k^ and kq are the respective rate constants. Ar O hv tf kq [Q] Ar A Ar k H 1^  ^OH J^-^ P r o t m c t s k d ^ GS GS BR Figure 6.1. Rate processes in the Norrish type II reaction of aryl ketones. The quantum yield for the appearance of a photoproduct (in the Norrish type II reaction, either cleavage or cyclization products) is based on the product of two separate probabilities, ie., the probability that the triplet excited state will react to give the biradical 185 Results/Discussion/Chapter 6 (^BR) m & m e probability that the biradical will proceed on to product ((pp). As it turns out, quantum yields for aryl ketones are determined solely by the behavior of the 1,4-biradical intermediate. ^  This means that (pgR is equal to unity and thus the quantum inefficiency of the type n reaction is due solely to reverse hydrogen transfer (k )^ in the biradical. 26 The quantum yields for product formation from the ketones studied in this thesis are given in Table 6.1. Quantum yields for type II cleavage or cyclization increased with added fert-butanol and are also shown in Table 6.1 as <pmax- Triplet lifetimes (x) for the ketones were determined by standard steady state Stern-Vohner quenching techniques as described in the Experimental chapter (Section 8.20). 74 Hie quencher used was 2,5-dimethyl-2,4-hexadiene with benzene as the solvent. Plots of (p0/(p for product formation vs. quencher concentration were linear. From the slopes of the Stern-Vohner plots (kq x) and the assumption that kq = 5 X 10^  M " 1 sec'l for exothermic quenching in benzene,75 the triplet lifetimes, x, were obtained. Figures 6.2 and 6.5 show the Stern-Vohner plots obtained for the fer^butylcyclohexyl and adamantyl aryl ketones. 186 Results/Discussion/Chapter 6 Table 6.1. Triplet state kinetic parameters for various aryl alkyl ketones.a>D,c ketone aryl group ketone T para-sab stituent cone. (M) d ^max k q xg 10-9 sh tert-butvl c >vlohexvl arvl ketones 56 H 0.040 0.0095 0.36 0.42 0.084 0.024* 0.098* 0.74* 0.15* 57 F 0.032 0.0022 0.21 0.20 0.040 58 H 0.043 0.074 0.29 8.1 1.6 0.019* 0.06* 7.3* 1.5* 66 F 0.030 0.049 0.24 6.1 1.2 67 Me 0.030 0.067 0.18 28 5.6 68 OMe 0.030 0.083 0.31 292 58 69 CN 0.030 0.020 0.17 13 2.6 70 COOH 0.030 0.22 71 COOMe 0.030 0.047 0.22 9.6 1.9 adamantyl arvl ketones 78 H 0.031 0.15 0.26 1.6 0.31 81 F 0.036 0.10 0.16 1.8 0.36 82 CN 0.023 0.41 0.69 4.5 0.90 83 COOH 0.015 0.24 84 COOMe 0.014 0.073 0.17 2.1 0.41 a Valerophenone (0.10 M) in benzene was used as actinometer in a parallel irradiation at 3130 A. D <|> and <t>max extrapolated to zero conversion. c Asterisk indicates data taken from reference lc with <)> determined in benzene and <)>max determined in 8.9M 1-propanol in benzene. d Ketone solution was opaque at 3130 A. e Determined in purified benzene. ^ Determined in 67% tert-butanol/benzene (w/w). § Stern-Volmer slopes in benzene. n k q ~ 5X10^M"^s"^ 187 Results/Discussion/Chapter 6 Figure 6.2. Stern-Volmer plots for quenching by 2,5-dimethyl-2,4-hexadiene of cleavage product formation from the fer/-butylcyclohexyl aryl ketones 56 and 57. ketone 68 Q],M Figure 6.3. Stern-Volmer plots for quenching by 2,5-dimethyl-2,4-hexadiene of cyclobutanol formation from the fert-butylcyclohexyl aryl ketones 58, 67 and 68. 188 Results/Discussion/Chapter 6 <l>o/<l> 15 13 11 9 7 5 3 1 ketone 69 •"ketone 71, x ketone 66 0.5 1 Q ] , M 1.5 Figure 6.4. Stern-Volmer plots for quenching by 2,5-dimethyl-2,4-hexadiene of cyclobutanol formation from the terf-butylcyclohexyl aryl ketones 66, 69 and 71. Figure 6.5. Stern-Volmer plots for quenching by 2,5-dimethyl-2,4-hexadiene of cyclobutanol formation from the adamantyl aryl ketones 78, 81, 82 and 84. 189 Results/Discussion/Chapter 6 Aryl ketones can have either n,7t* or 71,71* lowest triplets.73 Distinct spin localization in an n,7C* triplet causes it to resemble a 1,2-biradical and thus display similar chemical reactivity as an alkoxy radical.3,74,75 On the other hand, 7C,TC* triplets have delocalized spin and thus have little spin density on oxygen. 76 These characteristics make n,7C* triplets far more reactive towards hydrogen atom abstraction than n,K* triplets.3>73-75 Unsubstituted phenyl ketones have n,7i* lowest triplets with a K,TI* triplet a few kilocalories per mole higher in energy.77 When ring substitution leads to a situation where the TZ,K* triplet is lower in energy than the n,7t* triplet, most of the measured reactivity arises from low concentrations of the n,7i* triplet in thermal equihbrium with the lower 7r,,7t* triplet.3>78,79 Table 6.2 shows the kj-j values for some ring substituted valerophenones. Also included in Table 6.2 is the percent population of the n,7c* triplet in valerophenones as calculated from Equation 6.1. Values of AE are used in Equation 6.2 to calculate % n n . Equations 6.1 and 6.2 are applicable only for ketones where the n,7i* triplet provides most or all of the reactivity in the observed rate constants for hydrogen abstraction, i.e., AE ( E ^ -Enn) < 5 kcalmol"1 (21 kJmol"1):7 3 = Xn,7i kn,7r + XTC,7I ^71,71 Eq. 6.1. Xn,7t = ( 1" %n,K ) = [ e" A E / R T ] / [ 1 + e_^E/RT ] E q 6 2 190 Results/Discussion/Chapter 6 Table 6.2. Rate constants for triplet y-hydrogen abstraction in benzene by ring substituted valerophenones.a'°' c entry Substituent a k H , 107 s"1 % n,7r* -1 p-F 0.06 15 99 15 2 H 0 13 99 13 3 p-CN 0.66 6.8 21 32 4 p-alkyl -0.17 1.8 18 10 5 />-C0 2 CH 3 0.45 12 40 30 6 P - O C H 3 -0.27 0.06 1 6 a kjj values were all determined from maximum type II quantum yields and triplet lifetimes (kjj = <)>max IT). D All data taken from reference 73. c The intrinsic k n n values reflect independently measured substituent effects on rate constants for bimolecular hydrogen abstraction (p = 0.5, reference 80) and derived values for the percentage of n,7t* triplets in equilibrium with n,n* triplets. Tables 6.3 and 6.4 contain rate constants for hydrogen abstraction of all the ketones studied. These are all derived from the reciprocal triplet lifetimes contained in the kq T values, with kq equaling 5 X 10^  M _ 1 s"l in benzene. 81 Rate constants kjj for y-hydrogen abstraction equal <t)max/t For all of the aryl ketones <t>max 1S l e s s m an unity, which means that there are other triplet decays occurring. For the para-substituted aryl ketones with %,%* triplets lower than the reactive n,7i* triplets, the reactivity can be sufficiently reduced so that some quenching by solvent or impurities occurs, such that 1/T > kpj. Therefore, all decay other than y-hydrogen abstraction can be combined into k(j by equating it to 1/T - kjj.83 191 Results/Discussion/Chapter 6 Table 6.3. Rate constants for triplet y-hydrogen abstraction in benzene by ring substituted fert-butyl cyclohexyl aryl ketones.a entry ketone Substituent 109 s"1 kd> 1/T <t>max X 1/T 109 s-1 1 57 p-F 25 0.53 24.5 2 56 H 12 0.43 11.6 6.7* 0.66* 6.0* 3 66 p-F 0.82 0.20 0.62 4 58 H 0.62 0.18 0.44 0.68* 0.041* 0.64* 5 69 /7-CN 0.38 0.065 0.31 6 67 P-CTL3 0.18 0.032 0.15 7 71 / > - C 0 2 C H 3 0.52 0.11 0.41 8 68 P - O C H 3 0.017 0.0053 0.012 a Asterisk indicates data was taken from reference lc with § determined in benzene and § m a x determined in 8.9M 1-propanol in benzene. Table 6.4. Rate constants for triplet y-hydrogen abstraction in benzene by ring substituted adamantyl aryl ketones. entry ketone Substituent k H , 109 s-1 kd> 1/T V a x x 1 / t 109 s-l 1 81 p-F 2.8 0.45 2.3 2 78 H 3.2 0.83 2.4 3 82 p-CS 1.1 0.75 0.35 4 84 p-C02CTL3 2.4 0.41 2.0 We are not the first group to measure the triplet lifetimes of ketones 56 and 58 by steady state Stern-Volmer quenchhig.l0 Our results are somewhat different from those previously determined. There are numerous differences in the way that the two sets of data were obtained; namely, in the type of actinometer and quencher used. For the actinometer, we used the formation of acetophenone from valerophenone, whereas the previous data used the photoreduction of benzophenone to benzhydrol. For the type of 192 Results/Discussion/Chapter 6 quencher, the previous studies used naphthalene and ^ ra«5-l,3-pentadiene for ketones 58 and 56 respectively, whereas we used 2,5-dimethyl-2,4-hexadiene for both ketones. In this study, the maximum quantum yields, (pniax •> were determined in 67% tert-butanol-benzene (w/w) as the solvent, whereas Lewis et al?c used 8.9M 1-propanol-benzene. As was pointed out in the Lewis et al. paper, the quantum yields did not attain a maximum value in the 1-propanol solvent, so that these quantum yields provide only a lower limit value instead of a true maximum.1C We used 67% fe/7-butanol-benzene (w/w) solution to determine the maximum quantum yields, which is proven to be more reliable. 84 6.2. Laser Flash Photolysis Studies This section of the thesis describes our study of the Norrish type II reaction with the use of the nanosecond laser flash photolysis technique. This work was a collaborative study with Professor C. Bohne (University of Victoria, British Columbia, Canada), with all work performed by Mark Kleinman and C. Bohne. The laser flash photolysis technique has been in use for over twenty years*^  and the setup of their equipment is described elsewhere. 86 With the use of a laser, a sample of ketone can be excited in order for it to undergo the Norrish type II reaction. Using a laser pulse of duration < 10 ns and energies-per-pulse on the order of several rnilhjoules, transient concentrations in the 10-50 uM range in 193 Results/Discussion/Chapter 6 the volume probed by the monitoring beam can be generated. 7 9 Three ketones were studied (Figure 6.6). n3 Ketone X = 67 C H 3 68 O C H 3 71 COOCH3 Figure 6.6. Photorearrangement observed via laser flash photolysis. The transient absorption between 300-700 nm caused by the excitation of ketone 68 in both polar and non polar solvents was measured. As an example, the time-resolved absorption spectrum for the methanol solution is given in Figure 6.7. It was observed that the decay curve for the methanol solution, as well as in the other solvents, consisted of only one component. All the decay traces fit a single exponential function exactly as shown in Figure 6.8. Clenching plot analyses were carried out in order to determine the intrinsic lifetimes T 0 and the quencMag rate constant kq. A typical plot is shown in Figure 1 9 4 Results/Discussion/Chapter 6 6.9. The analysis for oxygen quenching was carried out in a similar manner. The concentration of oxygen in the solvent being used was taken from the literature.**7 The data for the quenching studies in different solvents are shown in Table 6.5. excitation wavelength = 266 nm 0.020 + 100 ns after laser flash • 280 ns after laser flash o 510 ns after laser flash • 660 ns after laser flash 0.015 400nm < 0.010 0.005 6 « 0 Oo 0.000 T • % + + % + • _ + + 5" • Of ° f °m 300 350 400 450 500 550 600 650 700 Wavelength /nm Figure 6.7. Triplet-Triplet spectrum of ketone 68 in methanol. 195 Results/Discussion/Chapter 6 ] . 0 ' ' ' ' 1 1 1 I 1 I.— I 1 I Ir l 1 J 1 J . L _ 0.0 0.5 1.0 l . S Time / us Figure 6.8. Decay traces monitored at X = 398 nm ascribed to the triplet of 68 in benzene quenched by 1,3-cyclohexadiene. 196 Results/Discussion/Chapter 6 Figure 6.9. Stern-Volmer analysis of the quenching of ketone68 by 1,3-cyclohexadiene in benzene. 197 Results/Discussion/Chapter 6 Table 6.5. Intrinsic lifetimes, rate constants and quencliing rate constants derived from quenching of the triplet excited state of ketone 68 in methanol, benzene and acetonitrile solutions.a>D,c Rate Data Quencher 1,3- cyclohexadiene 1,4-cyclohexadiene oxygen (0 2) In Methanol k 0 ( ± 10%) s"1 2.7 X 106 2.5 X 106 2.6 X 106 T 0 (± 10%) ns 370 400 385 k q (± 10%) M"1 s"1 6.7 X 109 2.1 X 106 3.2 X 109 K S V (± 10%) M"1 2480 0.84 1230 In Benzene k 0 (± 10%) s-1 1.3 X 107 1.3 X 107 1.3 X 107 T 0 (± 10%) ns 77 77 77 k q (± 10%) M"1 s"1 4.8 X 109 2.3 X 106 4.3 X 109 K S V ( ± 10%) M " 1 370 0.18 330 In Acetonitrile k 0 (± 10%) s"1 9.1 X 106 8.7 X 106 x 0 (± 10%) ns 110 115 kq (± 10%) M'1 s"1 6.0 X 109 7.3 X 109 K S V (± 10%) M"1 660 840 For Methanol: (1) the values represent the averages of 2 experiments. (2) in oxygen quenching experiments, only 3 points were used (O2 saturated =10.3 mM, atmospheric O2 = 2.2 m M and 0 m M O2). For Benzene: (1) the values represent the averages of 2 experiments. (2) in oxygen quenching experiments, only 3 points were used (O2 saturated = 9.02 mM, atmospheric O2 = 1.9 m M and 0 m M O2). For Acetonitrile: (1) the values represent determination from 1 experiment. (2) in oxygen quenching experiments, only 3 points were used (O2 saturated = 9.1 mM, atmospheric 02= 1.9 m M and 0 mM O2). Quenching studies were carried out by irradiating at 308 nm because the olefins used to quench the triplet ketone absorb at 266 nm. k 0 is the intercept from the plot of kQ^s vs [Quencher] and represents the observed rate constant in the absence of quencher. T 0 is the lifetime of the triplet and is the reciprocal of k 0 . kq is the slope from the plot of k 0 ^ s vs [Quencher] and represents the quenching rate constant. K g y is the Stern-Volmer constant and is the product of kq and T 0 . 198 Results/Discussion/Chapter 6 Strict adherence to first-order kinetics was observed for all the decay traces, indicating that there is only one species being observed. Therefore, the decay trace shown in Figure 6.6 can be assigned to either the triplet excited state of ketone 68 or the triplet 1,4-hydroxy biradical derived from it. The spectrum has been assigned to the triplet excited state of ketone 68 and is based on a few characteristics observed: (i) the spectra of the biradicals produced in the Norrish type II reaction from aromatic ketones typically show a weak but characteristic band at X « 415 nm and a stronger band in the UV region at X « 320 nm,7^ which is not the case seen in Figure 6.7, where a strong absorption at X « 400 nm and a weaker one at X « 475 nm is observed, (ii) the lifetime of the biradical produced from ketone 68 would be expected to be shorter lived than its triplet excited state just like that observed for /?-methoxyvalerophenone,88 and (hi) the decay is readily quenched by both olefins and oxygen, for which the lifetimes of biradicals only show a dependence with the latter and not the former.79,89 Only the methoxy derivative, 68, was studied due to the others having triplet lifetimes too short to be observed with the system used. A signal was observed for the ester derivative 71, but due to the time resolution of the equipment, the lifetime could not be resolved. Therefore, it can be said that the triplet lifetime for this compound is < 10 ns in both benzene and methanol. The spectrum was similar to that seen for ketone 68 as shown in Figure 6.6. No signal was observed for the methyl derivative, 67, even at very short times. This was attempted in both benzene and methanol. The region from 320 inn to 550 nm was scanned. 199 Results/Discussion/Chapter 6 Quenching by 1,3-cyclohexadiene occurs by energy transfer, which is similar to 2,5-dimethyl-2,4-hexadiene (the quencher used in the steady state Stern-Vohner quenching studies discussed in Section 6.1 of this thesis), while quenching by 1,4-cyclohexadiene occurs through hydrogen abstraction and thus is expected to occur at a slower rate.**7 This can be observed by comparing the rate constants for the quenching by the olefins in Table 6.5. The Stern-Vohner constant determined in benzene in the presence of 1,3-cyclohexadiene was about 370 M" 1 , in reasonable agreement with the value obtained in the steady state method of 290 M ' l using 2,5-dimethyl-2,4-hexadiene as the triplet quencher. This result gives us confidence in our quantum yield and kjj values determined (shown in Tables 6.1, 6.3 and 6.4). Studies were done in acetonitrile to investigate the effect of hydrogen bonding on the lifetime of the triplet. The intrinsic lifetime in acetonitrile (dielectric constant = 37.5) was much more similar to that in benzene (dielectric constant = 2.3) than methanol (dielectric constant = 32.7).90 Acetonitrile is the most polar of the three solvents, but is a poor hydrogen bonding solvent like benzene and unlike methanol. Therefore, the results indicate that the predominant factor that determines the triplet lifetime of an excited state in solution is not polarity, but is the hydrogen bonding ability of the solvent. This is the normal trend observed for triplet excited states.7** 200 Results/Discussion/Chapter 6 6.3. References for Results/Discussion Section 1. (a) Padwa, A.; Eastman, D. J. Am. Chem. Soc. 1969, 91, 462. (b) Mcintosh, C. L. Can. J. Chem. 1967, 45, 2267. (c) Lewis, F. D.; Johnson, R. W.; Johnson, D. E. J. Am. Chem. Soc. 1974, 96, 6090. 2. Wagner, P.; Park, B. In Organic Photochemistry, Volume H Padwa, A , Ed.; Marcel Dekker Inc.: New York, 1991; Chapter 4. 3. Wagner, P. l.Acc. Chem. Res. 1971, 4, 168. 4. (a) Wagner, P. J. hi Molecular Rearrangements, Volume 3; de Mayo, P., Ed.; Academic Press: New York, 1980; p. 381. (b) Coulson, D. R; Yang, N. C. J. Am. Chem. Soc. 1966, 88, 4511. 5. (a) Wiberg, K. B.; Hess, B. A. J. Org. Chem. 1966, 31, 2250. b) Wiberg, K. B.; Chen, W. J. Org. Chem. 1972, 37, 3235. 6. (a) Jones, R; Scheffer, J. R; Trotter, J.; Yang, J. Tetrahedron Lett 1992, 33, 5481. (b) Jones, R; Scheffer, J. R; Trotter, J.; Yang, J. Acta Crystallogr. 1994, B50, 601. 7. Harkness, B. R. M. Sc. Thesis, University of British Columbia, 1984, pp. 58-61. 8. Abraham, R. J.; Loffus, P. Proton and Carbon-13 NMR Spectroscopy, An Integrated Approach; John Wiley and Sons: Great Britain, 1985; Chapter 7. 9. Parker, D. Chem. Rev. 1991, 91, 1441. 10. (a) Asymmetric Synthesis, Morrison, J. D., Ed; Academic Press: New York, 1983; Vol. 1. (b) Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates and Resolutions; John Wiley: New York, 1981. 11. (a) ACS Symposium Series 471, Chiral Separation by Liquid Chromatography, Ahuja, S., Ed.; American Chemical Society, Washington DC 1991. (b) Stevenson, D; Wilson, I. D. Chiral Separations; Plenum: New York, 1988. 12. Wenzel, T. J. NMR Shift Reagents; CRC Press: Baca Raton, FL, 1987. 13. Snyder, L. R.; Kirkland, J. J. Introduction to Modern Liquid Chromatography, John Wiley and Sons: New York, 1974; Chapter 2. 14. (a) Scheffer, J. R; Dzakpasu, A. A. J. Am. Chem. Soc. 1978, 100, 2163. (b) Paquette, L. A.; Temansky, R. J.; Balogh, D. W.; Kentgen, G. J. Am. Chem. Soc. 1983, 105, 5446. 201 Results/Discussion/Chapter 6 15. For general review, see Photochemistry in Organized and Constrained Media; Ramamurthy, V.; Ed.; VCHPublisher: New York, 1991. 16. Kohlshutter, H. W. Z.Allg. Chem. 1918, 105, 121. 17. a) Cohen, M. D.; Schmidt, G. M. J. J. Chem. Soc. 1964, 1996. b) Cohen M. D. Angew. Chem., Int. Ed. Engl. 1975, 14, 386. 18. Cyclobutanol products in type II photochemistry were first reported by: Yang, D. H. J. Am. Chem. Soc. 1958, 80, 2913. 19. Wagner, P. J.; Kochevar, I. E.; Kemppainen, A. E.J. Am. Chem. Soc. 1972, 94, 7489. 20. Wagner, P. J.Acc. Chem. Res. 1983, 16, 461. 21. Small, R. D. Jr.; Scaiano, J. C. Chem. Phys. Lett. 1978, 59, 246. 22. Wagner, P. J.; Kelso, P. A.; Zepp, R. G.J. Am. Chem. Soc. 1972, 94, 7480. 23. Gudmundsdottir, A. D.; Lewis, T. J.; Randall, L. H.; Scheffer, J. R; Rettig, S. I; Trotter, J.; Wu, C-H. J. Am. Chem. Soc. 1996, 118, 6167. 24. (a) Turro, N. J. Modern Molecular Photochemistry; Benjarnin-Cummings: Menlo Park, CA, 1978; Chapter 10. (b) Kasha, M. Radiat. Res. 1960, Suppl. 2, 243. (c) Zimmerman, H. E.; Schuster, D. I. J. Am. Chem. Soc. 1962, 84, 4527. (d) Bondi, A. J. J. Phys. Chem. 1964, 68, 441. (e) Edward, J. T.J. Chem. Educ. 1970, 47, 261. (f) Dorigo, A. E.; Houk, K. N. J. Am. Chem. Soc. 1987, 109, 2195. and references cited therein. 25. (a) Scheffer, J. R; Trotter, J.; Omkaram, N.; Evans, S. V.; Ariel, S.Mol. Cryst. Liq. Cryst. 1986, 134, 169. (b) Chandler, W.; Goodman, L.J. Molec. Spectrosc. 1970, 35, 232. 26. Wagner, P. I; Kelso, P. A.; Kemppainen, A. E.; McGrath, J. M.; Schott, H. N.; Zepp, R. G. J. Am. Chem. Soc. 1972, 94, 7506. 27. Lewis, F. D.; Hilhard, T. A.J. Am. Chem. Soc. 1970, 92, 6672. 28. Lewis, F. D.; Ruden, R. A. Tetrahedron Lett. 1971, 715. 29. Wagner, P. L; Kelso, P. A.; Kemppainen, A. E.J. Am. Chem. Soc. 1968, 90, 5896. 30. Hoffman, T.; Swaminathan, S.; O'Dell, B. G ; Gleiter, K.J. Am. Chem. Soc. 1970, 92, 7091. 202 Results/Discussion/Chapter 6 31. (a) Padwa, A.; Eastman, D. J. Am. Chem. Soc. 1969, 91, 462. (b) Gagosian, R. B.; Dalton, J. C ; Turro, N. J. J. Am. Chem. Soc. 1970, 92, 4752. 32. Molecular Mechanics calculations were performed using the Monte Carlo Multiple Minimum Search Method (MCMM) of Macromodel V3.5 & V4.5 with MM2* or MM3* force field parameters: (a) Still, W. C. Macromodel V3.5 & V4.5, Department of Chemistry, Columbia University, New York, (b) Buckert, U ; Allinger, N. L. Molecular Mechanics, ACS Monograph 177: Washington, 1982. (c) Allinger, N. L.; Yuh, Y. H.; Lii, J-H. J. Am. Chem. Soc. 1989, 111, 8551. 33. Scheffer, J. R. In Organic Solid State Chemistry; Desiraju, G. R , Ed.; Elsevier: Amsterdam, 1987; Chapter 1. 34. Wagner, P. I; Kelso, P. A.; Kemppainen, A. E.; Zepp, R. G.J. Am. Chem. Soc. 1972, 94, 7500. 35. Lewis, F. D.; Hilhard, T. A.J. Am. Chem. Soc. 1970, 92, 6672 36. Griesbeck, A. G.; Mauder, H.; Stadtmiiller. Acc. Chem. Res. 1994, 27, 70. 37. Zimmerman, H. E.; Carpenter, C. W. J. Am. Chem. Soc. 1988, 110, 3298. 38. Wagner, P. J. hi Molecular Rearrangements, Volume 3; de Mayo, P., Ed.; Academic Press: New York, 1980; Chapter 20. 39. Wagner, P. J.; Hammond, G. S. J. Am. Chem. Soc. 1966, 55, 1245. 40. (a) Small, R. D. Jr.; Scaiano, J. C. J. Phys. Chem. 1977, 57, 2126. (b) Small, R. D. Jr.; Scaiano, J. C. J. Am. Chem. Soc. 1978, 100, 4512. (c) Closs, G. L. Adv. Magn. Res. 1974, 7, 157. (d) Caldwell, R. A ; Creed, D. J. Phys. Chem. 1978, 82, 2644. (e) Encinas, M. V.; Scaiano, J. C. J. Photochem. 1979, 11, 241. (f) Casey, C. P.; Boggs, R. A. J. Am. Chem. Soc. 1912, 94, 6457. (g) Doubleday, C. Jr. Chem. Phys. Lett. 1981, 77, 131. 41. (a) Scaiano, J. C. Acct. Chem. Res. 1982, 15, 252. (b) Caldwell, R. A. Pure Appl. Chem. 1984, 56, 1167. (c) Closs, G. L. Redwine, O. D. J. Am. Chem. Soc. 1985, 707, 4543. (d) Zimmt, M. B.; Doubleday, C. Jr.; Gould, I. R; Turro, N. J. J. Am. Chem. Soc. 1985, 707, 6724. (e) Zimmt, M. B.; Doubleday, C. Jr.; Turro, N. J. J. Am. Chem. Soc. 1986, 705, 3618. 42. Scaiano, J. C. Tetrahedronl9S2, 38, 819 203 Results/Discussion/Chapter 6 43. (a) Golden, D. M.; Furuyama, S.; Benson, S. VI. Int. J. Chem. Kinet. 1969, 1, 57. (b) Pitzer, K. S. Discuss. Faraday Soc. 1951, 10, 66. (c) Lide, D. R , Jr.; Mann, D. E. J. Chem. Phys. 1958, 29, 914. (d) Lide, D. R, Jr. J. Chem. Phys. 1958, 29, 1426. 44. O'Neal, H. E.; Miller, R. G.; Gunderson, E. J. Am. Chem. Soc. 1974, 96, 3351. 45. Encinas, M. V.; Scaiano, J. C. J. Am. Chem. Soc. 1978, 100, 7101. 46. Gamlin, J. N.; Jones, R; Leibovitch, M.; Patrick, B.; Scheffer, J. R; Trotter, J.Acc. Chem. Res. 1996, 29, 203 and references cited therein. 47. The possibility that we took to be the minor enantiomer of the photoproduct on HPLC was an unidentified impurity was ruled out by (1) showing that this peak had exactly the same retention time as in the case of the racemic mixture, (2) checking the UV absorption spectrum of each peak (diode array detector), and (3) checking the enatiomer excesses on two different HPLC column (Chiralcel OD and OJ). Attempted determination of the enantiomeric excesses by chiral shift reagent NMR techniques was unsuccessful. 48. Portions of this work have appeared in preliminary communication form: Leibovitch, M.; Olovsson, G.; Sundarababu, G.; Ramamurthy, V.; Scheffer, J. R; Trotter, JJ. Am. Chem. Soc. 1996, 118, 1219. 49. Portions of this work have appeared in preliminary communication form: Leibovitch, M.; Olovsson, G.; Scheffer, J. R.; Trotter, J.J. Am. Chem. Soc. 1997, 119, 1462. 50. (a) For a review, see Vaida, M.; Popovitz-Biro, R; Leiserowitz, L.; Lahav, M. In Photochemistry in Organized and Constrained Media; Ramamurthy, V., Ed.; VCH Publishers: New York, 1991; Chapter 6. (b) Popovitz-Biro, R; Chang, H. C ; Tang, C. P.; Shochet, N. R.; Lahav, M.; Leiserowitz, L.Pure and Appl. Chem. 1980, 52, 2693. Topotactic solid state reactions are rare. The following references plus those given in footnote 43 represent the majority of known examples, (c) Enkelmann, V.; Wegner, G.; Novak, K ; Wagener, K. B.J. Am. Chem. Soc. 1993,115, 10,390. (d) Novak, K ; Enkelmann, V.; Wegner, G.; Wagener, K. BAngew. Chem., Int. Ed. Engl. 1993, 32, (e) Ohashi, Y. Acc. Chem. Res. 1988, 21, 268. (f) Wang, W-N.; Jones, W. Tetrahedron 1987, 43, 1273. (g) Tieke, B. J. Polym. Sci., Polym. Chem. Ed. 1984, 22, 2895. (h) Miller, E.; Brill, T. B.; Rheingold, A. L.; Fultz, W. C.J. Am. Chem. Soc. 1983, 105, 7580. (i) Hasegawa, M. Chem. Rev. 1983, 83, 507. (j) Thomas, J. M. Nature 1981, 289, 633. (k) Cheng, K ; Foxman, B. J. Am. Chem. Soc. 1977, 99, (1) Wegner, G.Pure Appl. Chem. 1977, 49, 443. (m) Osaki, K.; Schmidt, G. M. J. Isr. J. Chem. 1972, 10, 189. 51. Sukuki, T.; Fukushima, T.; Yamashita, Y.; Miyashi, TJ. Am. Chem. Soc. 1994, 77<5, 2793. 204 Results/Discussion/Chapter 6 52. (a) Garcia-Garibay, M.; Scheffer, J. R; Trotter, J.; Wireko, F. J. Am. Chem. Soc. 1989, 111, 4985. (b) Fu, T. Y.; Liu, Z.; Scheffer, J. R.; Trotter, J. J. Am. Chem. Soc. 1993, 115, 12,202. (c) Gudrnunsdottir, A. D.; Scheffer, J. R; Trotter, J. Tetrahedron Lett. 1994, 35, 1397. (d) Jones, R.; Scheffer, J. R; Yang, J.; Acta Cryst. 1994, B50, 601. (e) Hashizume, D.; Kogo, H.; Sekine, A.; Ohashi, Y.; Miyamoto, H.; Toda, F. J. Chem. Soc, Perkin Trans. 2. 1996, 61. 53. (a) Thomas, J. M.; Morsi, S. E. Desvergne, J. P. Adv. Phys. Org. Chem 1977, 15, 63. (b) Hine, J. Adv. Phys. Org Chem 1977, 15, 1. 54. Evans, S. V.; Garcia-Garibay, M.; Nalamasu, O.; Scheffer, J. R; Trotter, J.; Wireko, F. J. Am. Chem. Soc. 1986, 108, 5648. 55. Gagosian, R. B.; Dalton, J. C ; Turro, N. J. J. Am. Chem. Soc. 1970, 92, 4725. 56. Gagosian, R. B.; Dalton, J. C ; Turro, N. J. J. Am. Chem. Soc. 1975, 97, 5189. 57. Lewis, F. D.; Johnson, R. W.; Kory, D. RJ. Am. Chem. Soc. 1974, 96, 6100. 58. Evans, S. V.; Omkaram, N.; Scheffer, J. R.; Trotter, J.Tetrahedron Lett. 1986, 27, 1419. 59. Scheffer, J. R; Trotter, J.; Omkaram, N.; Evans, S. V.; Ariel, S.Mo/. Cryst. Liq. Cryst. 1986, 134, 169. 60. Yang, J. Ph.D. Thesis, University of British Columbia, 1993, Chapter 3. 61. (a) Scheffer, J. R.; Garcia-Garibay, M.; Nalamasu, O. laOrganic Photochemistry, Volume 8, Padwa, A., Ed.; Marcel Dekker Inc.: New York, 1991; pp. 249-347. (b) Ramamurthy, V.; Venkatesan, K.Chem. Rev. 1987, 87, 433. 62. Guillet, J. Polymer Photophysics and Photochemistry; Cambridge University Press: Cambridge, England, 1985; Chapter 5. 63. Scheffer, J. R.; Garcia-Garibay, M. ^ Photochemistry on Solid Surfaces; Anpo, M. and Matsuura, T., Eds.; Elsevier: New York, 1989; Chapter 9.3. 64. Sundarababu, G ; Leibovitch, M.; Corbin, D. R.; Scheffer J. R; Ramamurthy, V. Chem. Comm. 1996, 2159. 65. For reviews on photochemistry in zeolites, see: (a) Ramamurthy, V. In Photochemistry in Organized and Constrained Media; Ramamurthy, V., Ed.; VCH: New York, 1991; Chapter 10. (b) Ramamurthy, V.; Eaton, D. F.; Caspar, J. VAcc Chem. Res. 1992, 25, 299. 205 Results/Discusion/Chapter 6 66. Breck, D. W. Zeolite Molecular Sieve: Structure, Chemistry, and Use; Wiley, New York, 1974. (b) van Bekkum, H . ; Flanigen, E. M . ; Jansen, J. C. Introduction to Zeolite Science and Practice; Elsevier: Amsterdam, 1991. (c) Dyer, A. An Introduction to Zeolite Molecular Sieves; Wiley: New York, 1988. 67. Photolyses were also carried out on samples in which the order of inclusion was reversed, i.e., inclusion of the ketone followed by inclusion of chiral inductor, as well as on samples prepared simultaneous adsorption of ketone and chiral inductor form hexane solution. In both instances, the enantiomeric excesses obtained were considerably lower than those reported in Table 5.1. 68. Such a dependence is not unprecedented, see (a) Wagner, P. J.; Park, B. S.Org. Photochem. 1991, 11, 227. (b) Yang, N . C ; Yang, D. H.J. Am. Chem. Soc. 1958, 80, 2913. (c) Wagner, P. J.Acc. Chem. Res. 1989, 22, 83. (d) Scaiano, J. C. Acc. Chem. Res. 1982, 15, 252. (e) Ramamurthy, V . ; Corbin, D. R ; Johnston, L. J. J. Am. Chem. Soc. 1992, 114, 3870. (f) Ramamurthy, V . ; Sanderson, D. R. Tetrahedron Lett. 1992, 33, 2757. 69. An increase in trans- to c/s-cyclobutanol ratio has been observed when the supercage free volume is decreased by exchanging Na+ by Cs+ (see reference 68e and 68f). 70. As would be expected, with the change in ephedrine from the (-) to the (+) isomer, the opposite enantiomer is enhanced. Neither of the optical isomers of the two cyclobutanols were selectively included/retained within zeolites. This was checked by including and re-extracting racemic-cyclobutanols from Na Y . 71. Toda, F. Topics Curr. Chem 1988, 149, 211. (b) Toda, Y.Mol. Cryst. Liq. Cryst. 1990, 41, 187. (c) Ramamurthy, V. ^ Photochemistry in Organized and Constrained Media; Ramamurthy, V. , Ed.; V C H : New York, 1991; Chapter 7. 72. Gudmunsdottir, A. D.; Scheffer, J. R. Tetrahedron Lett. 1989, 30, 419. 73. Wagner, P. J. InOrganic Photochemistry and Photobiology;Yioxspoo\, W. M . and Song, P-S, Eds.; CRC Press, Inc.: Boca Raton, 1995; Chapter 38. 74. Wagner, P. J. JnCreation and Detection of the Excited State; Lamola, A. A. , Ed.; Marcel Dekker: New York, 1971; pp. 174-212. 75. Wagner, P. J.; McGrath, J. M . ; Zepp, R. G. J. Am. Chem. Soc. 1972, 94, 6883. 76. Hammond, G. S.; Leermakers, P. A. J. Am. Chem. Soc. 1962, 84, 207. 77. (a) Lamola, A. A. J. Chem. Phys. 1967, 47, 4810. (b) Hochstrasser, R. M . ; Marzzacco, C. J. Chem. Phys. 1968, 49, 971. (c) Rauh, R. D.; Leermakers, P. A. 206 Results/Discussion/Chapter 6 J. Am. Chem. Soc. 1968, 90, 2246. (d) Li, Y. H.; Lirn, E. C. Chem. Phys. Lett. 1970, 7, 15. 78. Wagner, P. J.; Kelso, P. A.; Kemppainen, A. E.; Schott, H. N .J. Am. Chem. Soc. 1973, 95, 5604. 79. Johnston, L. J.; Scaiano, J. C. Chem. Rev. 1989, 89, 521. 80. Wagner, P. J.; Truman, R. J.; Scaiano, J. C. J. Am. Chem. Soc. 1985, 707, 7093. 81. (a) Scaiano, J. C ; Leigh, W.; Meador, M. A ; Wagner, P. JJ. Am. Chem. Soc. 1985, 707, 5806. (b) Wagner, P. J.; Zhou, B. J. Am. Chem. Soc. 1988, 770, 611. 82. Wagner, P. J.; Kemppainen, A. E. J. Am. Chem. Soc. 1972, 94, 7495. 83. Wagner, P. J.; Frenking, Jr, H. W. Can. J. Chem. Soc. 1995, 73, 2047. 84. Wagner, P. J.; Meador, M. A.; Zhou, B.; Park, B-S. J. Am. Chem. Soc. 1991, 113, 9630. 85. (a) Scaiano, J. C. Acc. Chem. Res. 1983,16, 234. (b) Scaiano, J. C. Acc. Chem. Res. 1982, 15, 252. (c) Porter, G.; Topp, M. KProc. R. Soc. London, Ser. A 1970, 315, 163. (d) Porter, G. Nobel Symp. 1967, 5, 141. 86. Liao, Y.; Bonne, C.J. Phys. Chem. 1996, 700, 734. 87. Murov, S. L.; Carmichael, I.; Hug, G. L. Handbook of Photochemistry; Marcel Dekker Inc.: New York, 1993. 88. The lifetime for triplet />methoxyvalerophenone in hydrocarbons at room temperature is 750 ns, while the biradical has a lifetime of 30-100 ns, depending on the conditions, particularly the solvent (Encinas, M. V.; Lissi, E. A.; Lemp, E.; Zanocco, A.; Scaiano, J. C. J. Am. Chem. Soc. 1983, 105, 1856). See also reference 79. 89. (a) Wagner, P. J.; Siebert, E. J.J. Am. Chem. Soc. 1981, 103, 7329. (b) Zimmerman, H. E. Adv. Photochem. 1963,1, 183. (c) Wagner, P. J.; Hammond, G. S.Adv. Photochem. 1968, 5, 21. (d) Walling, C ; Gibian, M. J. J Am. Chem. Soc. 1965, 87, 3361. (e) Beckett, A ; Porter, G. Trans. Faraday Soc. 1963, 59, 2051. (f) Porter, G.; Suppan, P. Trans. Faraday Soc. 1965, 61, 1664. (g) Yang, N. C. In Reactivity of the Photoexcited Organic Molecule; Interscience: London, 1967; pp. 150. 90. (a) Hayashi, H.; Nagakura, S. Bull. Chem. Soc. Jpn. 1980, 53, 1519. (b) CRC Handbook of Chemistry and Physics-63rd Edition; Weast, R. C ; Astle, M. J., Eds.; CRC Press, Inc.: Florida, 1983; pp. E50-53. 2 0 7 EXPERIMENTAL 208 Experimental/Chapter 7 CHAPTER 7 7 .1. General Considerations Infrared Spectra (IR)- Infrared spectra were recorded on a Perkin Elmer 1710 Fourier transform spectrometer. The positions of the absorption maxima (v^x) are reported in cm - 1. Sohd samples were ground in KBr (1-5%) and pelleted in an evacuated die (Perkin Elmer 186-0002) with a laboratory press (Carver, model B) at 17,000 psi. Liquid samples were run neat as thin films between two sodium chloride plates. Melting Points (mp)- Melting points were determined on a Fisher-Johns hot stage apparatus and are uncorrected. Nuclear Magnetic Resonance Spectra (NMR)- Proton nuclear magnetic resonance spectra ( A H NMR) were recorded in deuterated solvents as noted. The spectrometers used were a Bruker AC-200 (200 MHz) arid a Briiker WP-400 (400 MHz). Signal positions (8) are given in parts per million (ppm) with the solvent signal as the internal reference. The number of protons, signal multiplicities, coupling constants in Hertz (Hz) and assignments are given in parentheses following the signal position. The multiphcities of the signals have been abbreviated as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet and br = broad. Carbon nuclear magnetic resonance (l^C NMR) spectra were recorded at 50.3 MHz on a Bruker AC-200, at 75.4 MHz on a Varian XL-300 and at 125 MHz on a 209 Experimental/Chapter 7 Bruker AMX-500 spectrometers using deuterated solvents as indicated; the middle peak of the solvent signal was used as internal reference. All spectra were run under broad band ^C-l 1!!} decoupling. Chemical shifts (8) are reported in ppm Assignments, where given, were supported by APT (attached proton test) l 3 C NMR spectra. For APT, positive (+) signifies C or CH_2 while negative (-) signifies CH or C H 3 . Mass Spectra (MS)- Low and high resolution mass spectra were obtained from a Kratos MS 50 instrument operating at 70 eV. Fast atom bombardment (FAB) mass spectra were recorded on an AEI MS-9 mass spectrometer with xenon bombardment of an alcohol matrix (as noted) of the sample. Mass to charge ratios (m/e) are reported with relative intensities in parentheses (only for EI). Molecular ions are designated as M + (for EI) and M++1 (for FAB). Ultraviolet and Visible Spectra (UV-Vis)- Ultraviolet and visible spectra were recorded on a Perkin Elmer Lambda-4B UVWis spectrometer in the solvents indicated. Wavelengths (X) in nanometers (nm) are reported, and molar extinction coefficients (s) are given in parentheses. Spectral grade solvents available from BDH or Fisher were used without further purification. Microanalyses (EA)- Elemental analyses were performed by the departmental microanalyst, Mr. Peter Borda. 210 Experimental/Chapter 7 Gas Liquid Chromatography (GLC)- Gas chromatographic analyses were run on a Hewlett-Packard 5890 A gas chromatograph, using the following 15 m * 0.25 mm fused silica capillary columns: DB-1, DB-5, DB-17, HP-5 (J & W Scientific Inc.) or 20 m x 0.21 mm Carhowax 20 M (Hewlett Packard) and with a column head pressure (carrier gas: hehum) of 15 psi unless otherwise specified. The signal from a flame ionization detector was integrated by a Hewlett-Packard 3392 A integrator. Silica Gel Chromatography- Analytical thin layer chromatography was performed on commercial pre-coated silica gel plates (E. Merck, type 5554) and the plates were developed in the indicated solvent system The developed plates were observed with UV light. Column chromatography was carried out by using 230-400 mesh size silica gel (Merck 9385) slurry packed with the eluting solvent. Column size was determined according to the amount of crude material to be purified. High Pressure Liquid Chromatography (HPLC)- High pressure liquid chromato-graphy was performed on a Waters 600E system controller connected to a tunable absorbance UV detector (Waters 486) or programmable photodiode array detector (Waters 994). The chiral column Chiralcel OD, 250 mm x 4.6 tnrn; Chiral Technologies Inc., was used to determine enantiomeric excesses (optical purities). X-ray Analyses- All X-ray crystal structures were determined on a Rigaku AFC6S 4-circle diffractometer using single crystal X-ray analysis by Dr. Tai Y. Fu, Dr. Steve 211 Experimental/Chapter 7 Rettig, and Dr. Gunnar Olovsson in Professor James Trotter's laboratory in the UBC Chemistry Department. Stereoscopic diagrams were drawn with a locally modified version of the ORTEP program at a 50% probability level. Optical Rotations- Optical rotations were measured on a Jasco-J710/ORD-M instrument at room temperature using the sodium D line, 589 nm, as the monitoring wavelength. As well, optical rotations were performed by Dr. F. Geiser, Chiral Technologies Inc., using an mZ-CHJJRALYSER Optical Detector on a HPLC instrument (Chiralcel OD column). Solvents and Reagents- Spectral grade solvents were used for spectroscopic and photochemical studies. Further purification was not carried out unless otherwise noted. Reagents for the syntheses of starting materials were purified according to methods reported in the literature as indicated. 7.2. Synthesis of ter^Butylcyclohexyl Ary l Ketones cis-A-(\ J-dimethylethyl)cvclohexvl phenyl methanone The procedure of Padwa and Eastman was followed. 212 Experimental/Chapter 7 The method of Van Bekkum et al was employed to separate the isomers o£4-(tert-butyl)cyclohexane carboxylic acid 54.2 A 25.0 g (135.7 mmol) mixture of cis- and trans-4-(ter/-butyl)cyclohexane carboxylic acid (54, Aldrich, used without purification) was dissolved in 100 mL of methanol. The solution was heated under reflux and saturated with thiourea (Fisher, certified reagent grade, used without purification). After cooling to 5 °C, crystals of the trans-54 acid/thiourea adduct plus excess thiourea were collected. This treatment was repeated twice with the filtrate. The methanolic mother liquor was then poured into water. The crude cw-54 acid was collected by vacuum filtration, dried, and recrystallized from petroleum ether to yield plate-like flakes. There was obtained 10.0 g of cis-54 acid, mp 114-116 °C (lit.2 mp 116-118 °C, lit.3 mp 117-118 °C). In a flame-dried 50 mL round bottomed flask equipped with a condenser was placed 5.0 g (27 mmol) of cis-54 acid and 10.0 g (84 mmol) of thionyl chloride. After stirring at room temperature for 30 min, the mixture was refluxed for 2 h. The excess thionyl chloride was removed by distillation. The residue was treated with 10 mL of dry benzene and the benzene was distilled. The liquid residue was stored under vacuum at room temperature overnight. Acid chloride 55 was used without further purification.33 A 250 mL three neck round bottomed flask equipped with an addition funnel was flame dried under a nitrogen atmosphere. Then 3.0 g (14.8 mmol) of the acid chloride 55 in 25 mL of dry benzene was added over a 30 min period to 7.0 g (52.5 mmol) of aluniinum chloride (Aldrich, used without purification), which was suspended in 150 mL of dry benzene. The slightly yellow-green aluminum chloride suspension turned brown-black within 5 min after the first addition of the acid chloride. After an additional 5 h of 213 Experimental/Chapter 7 stirring at room temperature, 100 mL of water was very caremlly added to the flask. The mixture was extracted twice with ether (2 X 75 mL). The combined ethereal layers were washed with water, dried over magnesium sulphate, and evaporated to dryness in vacuo. The residue crystallized overnight under vacuum at room temperature. Recrystallization of the substrate with 98:2 hexanes: diethyl ether yielded colourless plates of ketone 56 (1.2 g, 4.9 mmoL 33.1% yield). M.P. 107-108 °C (lit.1*4 108-109 °C). * H NMR (CDC13, 200 MHz): 8 7.90-7.80 (2H, m, Ai-H), 7.60-7.40 (3H, Ar-H), 3.60-3.40 (IH, m, a-C-H), 2.25-2.10 (2H, m, ring H), 1.80-1.50 (4H, m, ring H), 1.40-0.90 (3H, m, ring H), 0.82 (9H, s, tert-butylH). 1 3 C NMR (CDCI3, 50 MHz): 8 23.40 (+), 27.48 (-), 28.25 (+), 32.53 (+), 40.46 (-), 48.11 (-), 128.17 (-), 128.45 (-), 132.24 (-), 136.93 (+), 204.37 (+). LRMS: (EI) m/e (relative intensity), 245 (5.9), 244 (32.1, M + ) , 238 (14.7), 223 (52.5), 187 (14.3), 161 (8.9), 146 (8.7), 133 (35.3), 120 (16.6), 105 (100.0), 77 (79.0), 57 (34.8), 55 (14.1), 51 (12.2), 41 (11.2), 40 (27.8). HRMS: Calculated mass for C 1 7 H 2 4 O : 244.1827. Found: 244.1824. IR, cm"1: (KBr pellet) 2950, 2862, 1681, 1597, 1579, 1446, 1363, 1221, 973, 766, 698; lit.4 1688 (C=0) (CCI4); lit.1 1684 ( C O ) (neat). UV: hexane, 238 (12,200), 278 (768), 329 (79); lit.1 95% ethanol, 240 (12,023), 275 (204), 319 (91) nm. The structure was confirmed by X-ray crystallographic analysis. C i 7 H 2 4 O crystallized in space group P2i/c (#14), a = 6.142 (1) A, b = 10.7665 (9) A, 214 Experimental/Chapter 7 c = 22.2470 (9) A, p = 93.821 (9)°, V = 1467.8 (5) A 3 , Z = 4, D c a l c = 1.106 g/cm 3, R = 0.038, R w = 0.041. cis-4-(l J-dimethvlethvlVl-methylcvclohexvl phenyl methanone The procedure of Lewis et al. was followed. ^  Ketone 56 (2.0 g, 8.2 mmol) and sodium hydride (1.0 g, 41.7 mmol) in 50 mL of dry 1,2-dimethoxyethane were refluxed for 4 h under a nitrogen atmosphere. The mixture was cooled to 0 °C in an ice bath, methyl iodide (1 mL, 2.3 g, 16.2 mmol) was syringed into the mixture, and stirring was continued for an additional 30 min. Additional sodium hydride (0.5 g, 20.8 mmol) was added to the flask and the mixture refluxed for 90 min. The solution was cooled to 0 °C and 1 mL (16.2 mmol) of methyl iodide was added to the mixture. Usually a third reflux time with additional sodium hydride was required to insure that all of the starting ketone was consumed. After careful addition of 30 mL of water, the reaction mixture was extracted with pentane, dried over magnesium sulphate, and the solvent removed in vacuo. The residue sohdified after a few min at room temperature. Repeated recrystallizations using hexanes yielded colourless plates of ketone 58 (1.1 g, 4.3 mmol, 51.9% yield). 215 Experimental/Chapter 7 M.P. 60-62 °C (lit.5 58-62 °C). * H NMR (CDC13, 200 MHz): 8 7.75-7.65 (2H, m, Ai-H), 7.15-7.00 (3H, Ar-H), 2.60-2.50 (2H, m, ring#), 1.55-1.43 (2H, m, ring//), 1.11 (3H, s, -CH3), 1.20-0.90 (5H, m, ring H), 0.78 (9H, s, tert-butyl H). 1 3 C NMR (CDCI3, 50 MHz): 8 24.54 (+), 27.42 (-), 28.52 (-), 32.32 (+), 37.34 (+), 47.60 (-), 48.57 (+), 127.37 (-), 128.01 (-), 130.62 (-), 139.73 (+), 209.80 (+). LRMS: (EI) m/e (relative intensity), 259 (6.4), 258 (26.9, M + ) , 243 (7.5), 201 (3.7), 183 (1.5), 153 (20.2), 152 (67.1), 121 (7.2), 105 (100.0), 97 (83.7), 83 (39.9), 77 (44.8), 69 (23.5), 57 (89.3), 41 (10.4). HRMS: Calculated mass for C i 8 H 2 60: 258.1984. Found: 258.1980. IR, cm"1: (KBr pellet) 2960, 2865, 1668, 1449, 1365, 1293, 1273, 1226, 1197, 962, 728, 699; lit.5 1686 (C=0) (neat). UV: hexane, 235 (11,500), 273 (703), 322 (154) nm The structure was confirmed by X-ray crystallographic analysis. C 1 8 H 2 6 ° crystallized in space group Pna2i (#33), a = 20.120 (4) A, b = 13.075 (4) A , c = 6.149(4)A, V = 1618(2)A 3,Z = 4 , D c a i c = 1.061 g/cm3, R = 0.037, R w = 0.045. 216 Experimental/Chapter 7 cis-4-(l J-dirnethvlethvDcvclohexyl l-(4-fluorophenvl) methanone A 100 mL round bottomed flask equipped with a condenser which itself had an addition funnel was flame dried under a nitrogen atmosphere. The addition funnel was charged with 3.0 g (14.8 mmol) of acid chloride 55 and 10 mL of fluorobenzene (Aldrich, used without further purification), while 7.0 g (52.5 mmol) of aluminum chloride (Aldrich, used without purification) and 50 mL of fluorobenzene was placed in the round bottomed flask. The contents of the addition funnel were added over a 30 min period to the aluminum chloride suspension. The mixture was then refluxed for 7 h. The slightly yellow-green aluminum chloride suspension turned brown-black within 30 min after refluxing was first observed. After cooling to room temperature, 100 mL of water was very carefully added to the flask. The mixture was extracted twice with ether (2 X 75 mL). The combined ethereal layers were washed with water, dried over magnesium sulphate, and evaporated to dryness in vacuo. The residue crystallized overnight under vacuum at room temperature. Recrystallization of the substrate from methanol yielded colourless plates of ketone 57 (2.2 g, 8.4 mmoL 56.7% yield). M.P. 82-84 °C. Anal. Calcd. for C 1 7 H 2 3 0 F : C, 77.82; H , 8.84; O, 6.10; F, 7.24. 217 Experimental/Chapter 7 Found: C, 78.05; H , 9.10. * H N M R (CDCI3, 200 MHz): 5 7.99-7.82 (2H, m, Ax-H), 7.18-7.02 (2H, Ar-H), 3.52-3.41 (1H, m, a-CH), 2.22-2.09 (2H, m, ring H), 1.72-1.50 (4H, m, ring H), 1.36-1.11 (3H, m, ring if), 0.80 (9H, s, fer/-butylH). 1 3 C N M R (CDCI3, 50 MHz): 5 23.34 (+), 27.46 (-), 28.27 (+), 32.52 (+), 40.32 (-), 48.06 (-), 115.28 and 115.70 ( 2 Jc -F = 2 1 H z , -ve), 130.66 and 130.84 (3Jc-F = 9 Hz, -ve), 133.11 and 133.17 (4Jc-F = 3 Hz, +ve), 162.71 and 167.74 ( A Jc-F = 2 5 3 H z , +ve), 202.60 (+). L R M S : (EI) m/e (relative intensity), 263 (9.4), 262 ( M + 45.1), 247 (7.0), 205 (17.0), 165 (6.6), 151 (42.4), 138 (18.2), 124 (15.8), 123 (100.0), 112 (6.2), 109 (8.8), 95 (17.0), 83 (5.3), 75 (4.0), 69 (5.3), 57 (35.1), 55 (10.9), 41 (18.1), 32 (4.4). H R M S : Calculated mass for C17H23OF: 262.1733. Found: 262.1734. IR, cm" 1: (KBr pellet) 2923, 2856, 1675, 1599, 1508, 1467, 1453, 1407, 1393, 1365, 1345, 1302, 1217, 1171, 1158, 1142, 974, 908, 856, 828, 791, 661, 607, 559, 522, 484. U V : hexane, 242 (15,500), 269 (3320), 325 (110) hm The structure was confirmed by X-ray crystallographic analysis. C17H23OF crystallized in space group P2i/c (#14), a = 6.186 (1) A , b = 10.7873 (9) A , c = 22.769 (1) A, 3 = 96.618 (8)°, V = 1509.2 (2) A 3 , Z = 4, D c a l c = 1.155 g/cm 3, R = 0.049, R w = 0.048. cis-4-( 1.1 -dimethvlethvl V1 -methvlc vclohexyl 1 -(4-fluorophenvr) methanone 218 Experimental/Chapter 7 Acid 54 (used without purification or separation of the isomers) was esterified by either reaction with diazomethane or refluxing with methanol with a catalytic amount of /rara-toluenesulfonic acid to yield the corresponding esters, 59, in quantitative yield. As described in the literature the cyclohexyl ring can be alkylated selectively to yield preferentially the cis isomer in a >85/15 cisltrans ratio.°" A 250 mL three neck round bottomed flask was flame dried under a nitrogen atmosphere. To this flask, n-butylhthium (28 mL of 1.6 M in hexane, Aldrich, 44.8 mmol) was added to a solution of 4.05 g of dhsopropylamine (5.6 mL, 40.0 mmol) in 100 mL of anhydrous tetrahydrofuran (THF) at -78 °C under a N 2 atmosphere. The mixture was allowed to stir for 30 min. Esters 59 (8.0 g, 39.9 mmol) were dissolved in 20 mL of anhydrous THF and added via a syringe slowly over 5 min. The resulting yellow solution was allowed to stir at -78 °C for 1 h. Then 5 mL (11.4 g, 80.3 mmol) of methyl iodide was quickly syringed into the flask. The solution turned milky white within 30 s after the addition of the methyl iodide. The solution was stirred for an additional 3 h at -78 °C, whereupon it was allowed to warm to room temperature. The reaction mixture was then poured into ice/water containing 75 mL of pentane. The layers were separated and the aqueous layer was extracted three more times with 40 mL portions of pentane. The combined pentane layers were then washed two times with 50 mL of cold water, one time with 50 mL of 10% sodium thiosulphate solution, and one time with 50 mL of saturated sodium chloride solution. The organic 219 Experimental/Chapter 7 layer was then dried over sodium sulphate, and the solvent removed in vacuo to yield 7.4 g of an epimeric mixture of ester 60 (34.5 mmol, 86.5% yield). Ester 60 (7.4 g, 34.5 mmol) was dissolved in a suspension of 4.0 g (105 mmol) of hthium aluminum hydride (LiAlFLj) in 100 mL of THF. The mixture was refluxed for 1 h. After cooling to room temperature, 100 mL of IN sulphuric acid was used to quench the reaction. The mixture was extracted twice with diethyl ether (2 X 75 mL), followed by subsequent washings of the organic layer with water (75 mL), dilute sodium carbonate solution (75 mL) and then with water again (75 mL). The organic layer was dried over magnesium sulphate and the solvent was removed in vacuo. The white solid alcohol mixture 61 was prepared in a quantitative yield (6.3 g). The isomers of alcohol 61 were easily separated via silica gel 60 (mesh 230-400) column chromatography with 7% ethyl acetate in hexanes as the eluent. The fractions corresponding to >97/3 cis to trans ratio were collected. Repeated separations were needed to obtain most of the corresponding cw-alcohol 61. According to the literature on similar alcohols, the alcohol can be oxidized to the aldehyde very efficiently using pyridinium chlorochromate (PCC) in methylene chloride solution.7 Alcohol 61 (5.3 g, 28.8 mmol) was placed in a 250 mL three neck round bottomed flask equipped with a 50 mL addition funnel which was previously flame dried under a nitrogen atmosphere. The alcohol was dissolved in 20 mL of dry methylene chloride and placed in the addition funnel. In the flask, 7.0 g (32.5 mmol) of PCC was suspended in 100 mL of methylene chloride. The alcohol was added to the flask over 5 min. The orange suspension of PCC quickly turned brown-black upon niixing with the 220 Experimental/Chapter 7 alcohol. After all of the alcohol was added, the mixture was allowed to stir at room temperature for 2 h. Diethyl ether was then added to the reaction mixture and the supernatant hquid was decanted from the black solid. The insoluble residue was repeatedly washed with diethyl ether and the combined ethereal layers were passed through a short plug of Florisil until the solution was virtually clear and colourless. This process usually required at least 3 repeated filtrations. The solvent was then removed in vacuo. The slightly yellow liquid aldehyde 62 (5.1 g, 28.0 mmol 97% yield) was used without further purification. In a flame dried 250 mL flask under a nitrogen atmosphere, 3.0 g (16.5 mmol) of aldehyde 62 was dissolved in 75 mL of THF and cooled in an ice bath. The 4-fluoro phenyl magnesium bromide (Aldrich, 1.6 M in hexane solution in THF, 50.0 mL, 80.0 mmol) Grignard reagent was added via a syringe over 5 min to the ice bath-cooled solution of the aldehyde 62. The mixture was stirred at room temperature for 5 h, after which saturated ammonium chloride was added carefully. The mixture was extracted twice with diethyl ether (2 X 75 mL). The combined organic layers were washed once with water (75 mL) and dried over sodium sulphate. The solvent was removed in vacuo to yield a slightly yellow Hquid (4.1 g, 14.7 mmoL 89.3% yield) of the alcohol 63 (used later without further purification). Jones reagent (10.0 g Cr03, 5.0 mL of water and 2.0 mL of concentrated sulphuric acid) in 50 mL of acetone was used to oxidize 4.1 g (14.7 mmol) of alcohol 63 to ketone 66. After removal of the acetone in vacuo, cold water (100 mL) was added and the niixture was extracted twice with diethyl ether (2 X 75 mL). After washing the 221 Experimental/Chapter 7 organic layer with water (75 mL), then with 10% sodium bicarbonate solution (75 mL) and again with water (75 mL), it was dried over sodium sulphate. Removal of the solvent in vacuo left a shghtly yellow sohd, which was recrystallized from methanol to yield colourless flakes of ketone 66 (3.9 g, 14.1 mmol, 96.1% yield, overall yield from aldehyde 85.6%). M.P. 76-78 °C. Anal . Calcd. for CigFf^OF: C, 78.22; H, 9.12; O, 5.79; F, 6.87. Found: C, 78.45; H, 9.18. ! H N M R (CDC13, 200 MHz): 8 7.60-7.50 (2 H, m, Ax-H), 6.80-6.60 (2H, Ar-//), 2.48-2.42 (2H, m, ring//), 1.48-1.42 (2 H, m, ring//), 1.16 (3H, s, -C//3), 1.11-0.90 (5H, m, ring H), 0.78 (9H, s, tert-butylH). 1 3 C N M R (CDCI3, 50 MHz): 8 24.48 (+), 27.39 (-), 28.45 (-), 32.28 (+), 37.49 (+), 47.57 (-), 48.45 (+), 114.83 and 115.27 ( 2 J C . F = 22 Hz, -ve), 130.01 and 130.18 (3JC-F = 8 Hz, -ve), 135.39 and 135.45 ( 4 J C . F = 3 Hz, +ve), 161.60 and 166.63 ( l j C-F = 2 5 2 H z> +ve), 207.69 (+). LRMS: (EI) m/e (relative intensity), 277 (1.8), 276 (7.6, M+), 262 (21.5), 247 (3.7) , 219 (4.3), 205 (10.6), 187 (1.7), 165 (8.9), 152 (25.3), 138 (13.7), 123 (100), 109 (9.8) , 97 (54.6), 83 (29.4), 81 (12.4), 71 (11.1), 69 (21.5), 57 (98.3), 55 (34.6), 43 (11), 41(33.1). HRMS: Calculated mass for C 1 8 H 2 50F: 276.1889. Found: 276.1897. IR, cm"1: (KBr pellet) 2952, 2864, 1667, 1599, 1504, 1451, 1364, 1293, 1230, 1195, 1157, 1101, 965, 846, 767. 222 Experimental/Chapter 7 UV: hexane, 241 (8500), 311 (sh. 200) nm. cis-4-( 1.1 -dimethvlethyP)- 1 -methvlcvclohexvl 1 -(4-methvlphenvP) methanone Under a nitrogen atmosphere, to a 25 mL flame dried round bottomed flask equipped with a condenser, 1.23 g (50.6 mmol) of magnesium turnings (Fisher) was added to a solution of 20 mL of dry tetrahydrofuran (THF) and 5.56g (32.5 mmol) of 4-bromotoluene. After addition of a small crystal of iodine, the solution was vigorously stirred until the solution began to reflux spontaneously. It was allowed to reflux and cool to room temperature over a period of 1 h. In a second flame dried 100 mL round bottomed flask was placed 1.1 g (6.0 mmol) of aldehyde 62 in 20 mL of dry THF. The flask was cooled in an ice bath and the p-toluene magnesium bromide was quickly syringed into the flask. The mixture turned brown within 10 min and it was allowed to stir at room temperature for 2 h. The reaction was quenched by cautiously adding 40 mL of saturated ammonium chloride solution. The mixture was extracted with two portions of 50 mL of diethyl ether. The combined ethereal layers were washed once with water (50 mL), dried over magnesium sulphate and the solvent removed in vacuo. Product 64 was a shghtly yellow liquid which was used without further purification. 223 Experimental/Chapter 7 The residual liquid 64 was dissolved in a 250 mL round bottomed flask using 70 mL of acetone and the solution was cooled to 5 °C. A solution consisting of 5.0 g of Cr03, 20 mL of water, and 8 mL of sulphuric acid was added dropwise to the cooled solution until the Jones reagent was visibly in excess. After removal of the acetone in vacuo, cold water (75 mL) was added and the mixture was extracted twice with diethyl ether (2 X 75 mL). After washing the organic layer with water (50 mL), then with 10% sodium bicarbonate solution (50 mL) and again with water (50 mL), it was dried over sodium sulphate. Removal of the solvent in vacuo left a white solid, which was recrystallized from petroleum ether to yield colourless plates of ketone 67 (1.2 g, 4.4 mmoL 73.1% yield). M.P. 96-98 °C. Anal. Calcd. for Ci 9 H 2 8 O : C, 83.77; H, 10.36; O, 5.87. Found: C, 83.53; H, 10.22. * H NMR (CDC13, 200 MHz): 5 7.64-7.58 (2H, d, J - 8 Hz, Ar-//), 7.20-7.10 (2 H, d, J = 8 Hz, Ar-//), 2.60-2.42 (2H, m, ring H), 2.38 (3H, s, Ai-CH3), 1.60-1.48 (2H, m, ring//), 1.38 (3H, s, -C//3), 1.30-1.10 (2H, m, ring//), 1.08-0.82 (3H, m, ring/0, ° - 7 8 (9B, s, fert-butylH). 1 3 C NMR (CDCI3, 50 MHz): 5 21.42 (-), 24.53 (+), 27.42 (-), 28.54 (-), 32.32 (+), 37.54 (+), 47.65 (-), 48.43 (+), 127.76 (-), 128.65 (-), 136.67 (+), 141.14 (+), 209.00 (+). LRMS: (EI) m/e (relative intensity), 273 (2.4), 272 (11.8, M + ) , 257 (6.4), 239 (0.5), 215 (1.1), 161 (2.6), 152 (9.4), 135 (2.7), 121 (23.1), 120 (9.6), 119 (100.0), 97 224 Experimental/Chapter 7 (18.3), 95 (11.8), 91 (24.6), 83 (9.6), 67 (5.2), 65 (9.7), 57 (50.9), 55 (14.4), 41 (16.2), 32 (20.8). HRMS: Calculated mass for Ci 9 H 2 80: 272.2140. Found: 272.2138. IR, cm"1: (KBr pellet) 2965, 2938, 2860, 2837, 1666, 1608, 1450, 1433, 1364, 1293, 1273, 1228, 1184, 965, 829, 760, 747. UV: methanol, 245 (10,800), 270 (sh. 860), 324 (120) nm The structure was confirmed by X-ray crystallographic analysis. C 1 9 H 2 8 ° crystallized in space group Pbca, a = 21.015 (4) A , b = 25.974 (4) A , c = 6.176 (2) A , V = 3371 (1) A 3 , Z = 8, D c a i c = 1.073 g/cm3, R = 0.040, R w = 0.031. cis-A-(\, 1 -dimethylethyl)-1 -methyl cyclohexyl 1 -(4-methoxyphenyl) methanone The same procedure was employed as that used for ketone 67. The amounts of reagents used for this synthesis were as follows: i) 0.97 g (40 mmol) of magnesium turnings (Fisher), and 5.17 g (27.6 mmol) of 4-bromoanisole in 20 mL of dry THF, ii) 1.0 g (5.5 mmol) of aldehyde 62 in 20 mL of dry THF, and ih) Jones reagent (5.0 g CrC>3, 20 mL water, and 8 mL sulphuric acid). Crude ketone 68 was recrystalhzed from 95:5 (v/v) petroleum ether:ethanol to yield white needles (1.1 g, 3.8 mmol, 69.6 % yield). M.P. 106-107 °C. 225 Experimental/Chapter 7 Anal. Calcd. for C i 9 H 2 8 0 2 : C, 79.12; H, 9.78; O, 11.09. Found: C, 79.24; H, 9.78. A H NMR (CDCI3, 200 MHz): 8 7.80-7.70 (2H, m, Ax-H), 6.93-6.82 (2H, Ax-H), 3.83 (3H, s, Ar-OCZ/j), 2.60-2.42 (2H, m, ring H), 1.60-1.50 (2H, m, ring H), 1.38 (3H, s, -CH3), 1.30-1.10 (2H, m, ring//), 1 05-0.80 (3H, m, ring//), 0.75 (9H, s, tert-butylH). 1 3 C NMR (CDCI3, 50 MHz): 8 24.52 (+), 27.42 (-), 28.59 (-), 32.31 (+), 37.85 (+), 47.71 (-), 48.24 (+), 55.32 (-), 113.18 (-), 130.19 (-), 131.50 (+), 161.73 (+), 208.84 (+). LRMS: (EI) m/e (relative intensity), 289 (1.0), 288 (4.5, M + ) , 273 (1.3), 257 (0.4), 231 (0.4), 206 (0.5), 163 (0.6), 150 (3.2), 137 (11.4), 135 (100), 107 (4.7), 97 (3.2), 92 (3.6), 77 (7.2), 64 (2.5), 57 (14.3), 41 (6.4), 32 (7.7). HRMS: Calculated mass for C 1 9 H 2 8 0 2 : 288.2089. Found: 288.2089. IR, cm"1: (KBr pellet) 2962, 2937, 2867, 2841, 1661, 1604, 1575, 1507, 1455, 1444, 1413, 1366, 1309, 1253, 1230, 1176, 1143, 1033, 964, 836, 767, 648. U V : methanol, 268 (18,700), 319 (sh. 700) nm The structure was confirmed by X-ray crystallographic analysis. Ci Q H 2 8 0 2 crystallized in space group Pbca (#61), a = 26.010 (2) A, b = 21.414 (2) A , c = 6.191 (1) A , V = 3448 (1) A 3 , Z = 8, D c a j c =1.111 g/cm3, R = 0.038, R w = 0.034. 226 Experimental/Chapter 7 cis-4-( 1.1 -dirnethvlethvlV1 -methvlcvclohexvl 1 -(4-cvanophenvP) methanone To a flame dried 100 mL flask equipped with a stirrer and condenser, 2.90 g (10.5 mmol) of ketone 66 and 1.4 g (21.6 mmol) of potassium cyanide were dissolved in 70 mL of dry dimethyl sulfoxide (DMSO). The mixture was refluxed until all of the starting material was consumed (thin layer chromatography: 2% diethyl ether in hexanes, Rf 66 = 0.75, Rf 69 = 0.15). The solution was observed to change from yellow to dark yellow (a little cloudy) to red-brown-orange at the end of the necessary reflux time (usually overnight). Upon cooling to room temperature the mixture was red-orange with small white particles floating in the solution. The solution was poured into 100 mL of water and cautiously extracted with diethyl ether (3 x 50 mL). The combined organic layers were washed with 75 mL water, 75 mL of 5% sodium bicarbonate and dried over magnesium sulphate. The solvent was remove in vacuo to yield a yellow powder. The solid was recrystallized using 95:5 (v/v) petroleum ether:diethyl ether to yield a very slightly yellow powder of ketone 69 (2.9 g, 10.2 mmoL 97.5% yield). All other solvents yielded only powdery compound. •CN {69} M .P . 115-117 °C. Anal. Calcd. for C 1 9 H 2 5NO: C, 80.52; H, 8.89; N, 4.94; O, 5.65. Found: C, 80.67; H, 8.85; N, 4.84. 227 Experimental/Chapter 7 *H NMR (CDCI3, 200 MHz): 5 7.78-7.65 (4H, m, Ar-//), 2.52-2.30 (2H, m, ring//), 1.63-1.50 (2H, m, ring//), 1.34 (3H, s, -C//3), 1.25-1.10 (2H, m, ring H), 1.05-0.80 (3H, m, ring H), 0.76 (9H, s, tert-butyl H). 1 3 C NMR (CDCI3, 50 MHz): 5 25.54 (+), 27.38 (-), 28.29 (-), 32.31 (+), 36.91 (+), 47.44 (-), 48.85 (+), 114.16 (+), 118.07 (+), 127.73 (-), 131.97 (-), 143.58 (+), 208.74 (+). LRMS: (EI) m/e (relative intensity), 284 (2.0), 283 (7.4, M + ) , 268 (4.4), 255 (0.5), 226 (2.8), 172 (5.0), 153 (27.0), 131 (26.8), 130 (20.5), 102 (13.9), 97 (52.9), 95 (10.8), 83 (25.1), 69 (15.2), 57 (100.0), 55 (23.3), 41 (24.0). HRMS: Calculated mass for Ci9H 2 80 2 : 283.1936. Found: 283.1942. IR, cm"1: (KBr pellet) 2963, 2942, 2857, 2232, 1674, 1602, 1453, 1393, 1364, 1291, 1274, 1242, 1219, 1196, 1167, 1142, 983, 958, 931, 861, 844, 771, 563. UV: methanol, 241 (17,100), 280 (1500), 328 (sh. 240) nm. eis-4-(l, 1 -dimethylethyiy 1 -methylcy clohexyl 1 -(4-carboxyphenyl) methanone To a 100 mL round bottomed flask equipped with a condenser was added 2.0 g (7.1 mmol) ketone 69, 50 g of potassium hydroxide, 75 mL of water and 15 mL of ethanol. The mixture was refluxed for 72 h. The mixture was cooled to room temperature and washed with diethyl ether (50 mL) once. The aqueous layer was acidified 228 Experimental/Chapter 7 by careful addition of concentrated hydrochloric acid. The white sohd was collected by vacuum filtration and recrystalhzed from water: ethanol solution. Ketone 70 was collected as long, white thin needles (2.1 g, 6.9 mmoL 98.4% yield). M.P. 232-233 °C. Anal. Calcd. for C 1 9 H 2 6 0 3 : C, 75.46; H, 8.67; O, 15.87. Found: C, 75.20; H, 8.84. A H NMR (CDC13, 200 MHz): 8 8.26-8.00 (2 H, d, J = 8 Hz, Ar-//), 7.81-7.53 (2H, d, J = 8 Hz, Ax-H), 2.56-2.31 (2H, m, ring H), 1.75-1.45 (2H, m, ring H), 1.38 (3H, s, -CH3), 1.42-1.12 (2H, m, ring//), 1.12-0.83 (3H, m, ring/0, 0-78 (9H, s, tert-butylH), no COO// signal observed. 1 3 C NMR (CDCI3, 50 MHz):' 8 24.55 (+), 27.40 (-), 28.37 (-), 32.32 (+), 36.97 (+), 47.49 (-), 48.83 (+), 127.17 (-), 130.01 (-), 130.68 (+), 144.74 (+), 170.10 (+), 209.88 (+). LRMS: (EI) m/e (relative intensity), 303 (1.4), 302 (6.0, M + ) , 287 (4.1), 278 (1.2), 269 (0.6), 257 (12.3), 245 (1.9), 227 (1.8), 191 (2.0), 206 (0.5), 165 (2.3), 153 (12.5), 152 (21.2), 150 (48.7), 149 (29.3), 136 (2.7), 121 (9.8), 109 (4.5), 97 (57.4), 95 (15.3), 94 (17.2), 83 (27.1), 81 (13.8), 71 (10.6), 69 (19.0), 65 (11.6), 57 (100.0), 55 (28.7), 41 (24.1), 32 (6.1). HRMS: Calculated mass for C 1 9 H 2 6 0 3 : 302.1882. Found: 302.1887. IR, cm"1 : (KBr pellet) 3433, 2952, 2905, 2869, 2667, 2544, 2349, 2303, 1956, 1690, 1672, 1568, 1504, 1452, 1423, 1405, 1364, 1317, 1287, 1220, 1194, 1126, 961, 948, 931, 867, 735,556, 534. 229 Experimental/Chapter 7 UV: methanol, 244 (12,700), 284 (sh. 1,800 ), 322 (200) nm The structure was confirmed by X-ray crystallographic analysis. Ci 9H26O3 crystallized in space group P2i/c (#14), a = 6.117 (1) A, b = 24.331 (4) A, c = 23.152 (2) A, p = 93.66 (1)°, V = 3438.8 (8) A 3 , Z = 8, D c a i c = 1.168 g/cm3, R= 0.041, R w = 0.039. cis-4-( 1.1 -dimethvlethvO-1 -methvlcvclohexyl 1 -(4-carbomethoxyphenvn methanone Acid 70 (0.7 g, 2.3 mmol) was taken up in 35 mL of methanol, 0.5 g of p-toluenesulphonic acid was added as the catalyst, and the mixture was heated at reflux for 24 h. The reaction mixture was cooled to room temperature, poured into 30 mL of ice/water and extracted five times with 30 mL portions of hexane. The hexane extracts were then washed two times with 40 mL portions of cold water, two times with 40 mL portions of dilute sodium bicarbonate solution, and one time with 40 mL of saturated sodium chloride solution. The hexane extracts were then dried over sodium sulphate, and the solvent removed in vacuo. The residue was a slightly yellow sohd. Recrystallization from petroleum ether gave 0.7 g (2.2 mmoL 95.6% yield) of ketone 71 as a white powder. M .P . 140-141 °C. 230 Experimental/Chapter 7 Anal. Calcd. for C20H28O3: C, 75.91; H, 8.92; O, 15.17. Found: C, 75.84; H, 8.91. 1-H NMR (CDCI3, 200 MHz): 5 8.12-7.99 (2 FL d, J = 8 Hz, Ar-H), 7.71-7.55 (2FL d, J = 5 Hz, Ar-//), 3.94 (3H, s, COOC//3), 2.54-2.33 (2H, m, ring H), 1.66-1.48 (2H, m, ring //), 1.37 (3H, s, -CH3), 1.36-1.12 (2H, m, ring H), 1.09-0.81 (3H, m, ring //), 0.67 (9H, s, tert-butyl H). 1 3 C NMR (CDCI3, 50 MHz): 8 24.53 (+), 27.40 (-), 28.38 (-), 32.31 (+), 37.02 (+), 47.49 (-), 48.77 (+), 52.33 (-) 127.07 (-), 129.32 (-), 131.68 (+), 143.85 (+), 166.37 (+), 209.85 (+). LRMS: (EI) m/e (relative intensity), 317 (5.0), 316 (18.0, M + ) , 301 (11.4), 285 (11.0), 257 (30.4), 245 (1.0), 218 (1.8), 192 (3.9), 179 (3.6), 165 (11.6), 164 (100.0), 163 (57.4), 153 (14.7), 152 (30.6), 136 (25.6), 135 (11.7), 120 (4.6), 104 (10.3), 97 (39.0), 95 (14.3), 94 (16.7), 83 (17.0), 81 (13.9), 69 (12.7), 57 (67.7), 55 (21.3), 41 (22.3). HRMS: Calculated mass for C20H28O3: 316.2039. Found: 316.2036. IR, cm"1: (KBr pellet) 2963, 2948, 2865, 1722, 1670, 1471, 1463, 1449, 1404, 1365, 1311, 1282, 1223, 1195, 1110, 1019, 961, 865, 754, 737, 716. UV: methanol, 244 (17,000), 281 (1,200), 327 (180) nm. 7.3. Synthesis of S alts with Ac id 70 All salts were prepared by dissolving equimolar amounts of ketone 70 and an organic amine in the solvents indicated. Crystalline salts were usually first obtained by spontaneous deposition from solution at room temperature. Crystals were collected by 231 Experimental/Chapter 7 suction filtration. Recrystallization of the salts in an appropriate solvent was accomplished by slow evaporation of the solvent from a fully dissolved solution of the salt. The composition of all salts was shown to be 1:1 by NMR spectroscopy (CDCI3, 200 MHz). Also, Infrared spectra were taken of the salts as well. Table 7.1 shows the structures of the various optically pure amines used in the synthesis of these salts. Table 7.1. Optically active amines used in this thesis to form salts. (lS,2S)-(+) pseudoephedrine H 1 y O H C 6 H 5 — V N>,A—NHCH3 H 3 C L (^+)-prolinol or (S)-(+)-2-pyrroUdinemethanol ^ N ^ C H 2 O H 1 H (S)-(-)-a-methylbenzylamine H C 6 H 5 ^ „ , C H 3 N H 2 (1 S)-(-)-2,10-camphorsultam C H 3 v ^ / C H 3 i JL l ^ n h ^ ^ S = 0 s (lR,2S)-(-)-ephedrine O H ? ,.H H „ ^ — N H C H 3 H 3 C L-(S)-(+)-arginine H2NC(=NH)NH(CH2)2CH2 H „ ^ — C 0 2 H H 2 N 232 Experimental/Chapter 7 Table 7.1. Continued I^ (-)-(S)-prolmamide L-(S)-(-)-proline t-butyl ester H 0 k N J < c - ° - C ( C H 3 > 3 H ^ L-(S)-(+)-lysine H 2 N(CH 2 )3CH 2 H „ ^ — C 0 2 H H 2 N (R)-(+)-a-memylbenzylamine N H 2 C 6 H 5 — f " H CH 3 (lR,2S)-(-)-norephedrine OH L-(+Vprolinol or (SVr+V2-pwolidinemethanol salt (85) Acid 70 (245.7 mg, 0.813 mmol) and S-(+)-2-pyrrolidine methanol (82.1 mg, 0.812 mmol) were mixed in 30 mL of acetone. The solution was heated until the solid material dissolved. The solution was allowed to stand at room temperature for 1 hour. A white powder (252.5 mg, 77.0% yield) was collected by filtration. Recrystallization from various solvents afforded salt 85 as a white powder. M.P. 167-169 °C. Anal. Calcd. for C24H37O4N: C, 71.42; H, 9.25; N, 3.47; O, 15.86. Found: C, 71.27; H, 9.26, N, 3.43. X H NMR (CDCI3, 200 MHz): 5 8.60 (2H, br. s, -NH2+), 8.05-7.90 (2 H, d, 233 Experimental/Chapter 7 J = 9 Hz, Ai-H), 7.65-7.50 (2H, d, J = 9 Hz, Ar-//), 4.00-3.85 (IH, m, -C//-CH 2OH), 3.85-3.65 (2H, m, -CH2OH), 3.38-3.20 (2H, t, J = 7 Hz, -CH2-NH2+-), 2.46-2.37 (2H, m, ring H), 2.20-1.68 (5H, m, -CH2-CH2-CH2-CU- and OH), 1.60-1.40 (2H, m, ring H), 1.37 (3H, s, -CH3), 1.36-1.08 (2H, m, ring H), 1.07-0.77 (3H, m, ring //), 0.76 (9H, s, tert-huty\H). 1 3 C NMR (CDC13, 50 MHz): 8 24.51,24.74,26.47,27.40,28.46,32.31,37.18, 45.29, 47.51, 48.66, 61.53, 61.62, 112.56, 126.89, 128.92, 141.89, 173.39, 210.57. LRMS: (FAB, +LSJJV1S) m/e, 404 (M+ +1), 391, 333, 305, 304, 303, 301, 286, 285, 229, 149 (base peak), 133, 102 [Matrix: Thioglycerol + MeOH]. HRMS: Calculated mass for C 2 4H 3 8 04N (M+l): 404.2801. Found: 404.2808. IR, cm"1: (KBr pellet) 3430, 3227, 2943, 2869, 2837, 2801, 2551, 2502, 2416, 1668, 1642, 1582, 1537, 1498, 1446, 1394, 1364, 1292, 1273, 1222, 1194, 1115, 1093, 961, 839, 800, 756, 740. UV: methanol, 247 (18,000), 282 (sh, 2,100), 323 (256) nm (lS-2SV(+V\|/-ephedrine salt (TO Acid 70 (202.2 mg, 0.669 mmol) and (lS-2S)-(+)-vj/-ephedrine (110.6 mg, 0.669 mmol) were placed in 30 mL of ethanol. The solution was allowed to stand for several hours. No sohd was observed to form; therefore most of the solvent was removed in vacuo. Diethyl ether was then added until white sohd was observed to come out of solution. The white powder (292.8 mg, 93.6% yield) was collected by filtration. Recrystallization from acetonitrile or ethanol yielded long thin plates of salt 86. Various other solvents yielded only a white powdery substance. Sublimation at atmospheric (oil 234 Experimental/Chapter 7 bath: 140°C) or reduced pressure (water aspirator, oil bath: <100°C) yielded very small plates. M.P. 158-160 °C. Anal. Calcd. for C29H4104N-2H20: C, 69.15; H, 9.01; N, 2.78; O, 19.06. Found: C, 69.16; H, 8.86; N, 2.76. *H NMR (CDC13, 200 MHz): 8 8.04-7.90 (2 H, d, J = 9 Hz, Ax-H), 7.60-7.50 (2H, d, J = 9 Hz, Ax-H), 7.40-7.20 (5H, m, Ax-H of amine), 6.38 (4H, br. s, H20), 4.70-4.60 (IH, d, J = 10 Hz, PhC#-), 3.34-3.18 (1H, m, PhCH(OH)C#-), 2.63 (3H, s, -NCi/j), 2.50-2.38 (2H, m, ring H), 1.60-1.40 (2H, m, ring H), 1.37 (3FL s, -CH3), 1.36-1.10 (2H, m, ring H), 1.06-1.02 (3H, d, J = 6 Hz, PhCH(OH)CH(C//3)-), 0.97-0.80 (3H, m, ring H), 0.76 (9H, s, ter/-butyl H), no N-/7 nor O-H signals were detectable. 1 3 C NMR (CDCI3, 50 MHz): 8 12.65, 24.51, 27.41, 28.45, 30.29, 32.30, 37.18, 47.52, 48.64, 60.76, 75.27, 126.83, 127.11, 128.39, 128.69, 129.04, 138.33, 140.48, 141.74, 173.31,210.22. LRMS: (FAB, +LSIMS) m/e, 468 ( M + +1), 393, 380, 347, 304, 303, 285, 229, 167, 166 (base peak), 165, 149, 148, 133 [Matrix: Thioglycerol + MeOFTJ. HRMS: Calculated mass for C29H42O4N (M+l): 468.3114. Found: 468.3118. IR, cm'1: (KBr pellet) 3398, 3162, 3034, 3005, 2953, 2869, 2742, 1670, 1589, 1546, 1496, 1455, 1391, 1365, 1293, 1272, 1222, 1194, 1065, 1051, 961, 756, 743, 698, 542. UV: methanol 249 (30,200), 281 (sh, 3,200), 320 (400) nm. 235 Experimental/Chapter 7 L-r+Vargjriine salt (87) Salt 87 was prepared by combining a solution of 112.8 mg (0.647 mmol) of L-(+)-arginine (free base) in 2 mL water and a solution of 196.8 mg (0.651 mmol) of acid 70 in 25 mL of ethanol. The mixture was allowed to stand for several hours. No sohd was observed to form; therefore the solvent was removed in vacuo. The white sohd was washed repeatedly with diethyl ether leaving 301.7 mg (97.4% yield) of the desired salt. Recrystallization from ethanol or ethanol/water yielded only fine white powder of salt 87 (279.7 mg, 92.7% yield). M.P. 222-224 °C. Anal. Calcd. for C 2 5 H 4 0 O 5 N 4 : C, 63.00; H, 8.46; N, 11.76; O, 16.78. Found: C, 62.92; H, 8.52; N, 11.63. A H NMR ( C D 3 O D , 200 MHz): 6 7.94-7.80 (2 H, d, J = 9 Hz, Ai-H), 7.54-7.40 ( 2 H , d, J = 9 Hz, Ax-H), 3.43-3.30 (IH, m, C H 2 - G r 7 ( N H 2 ) C 0 2 H ) , 3.10-2.87 ( 2 H , m, NH3C(=NH)NHC#2CH2-), 2.40-2.20 ( 2 H , m, ring H), 1.80-1.30 ( 6 H , m, 4 ring H and N H 3 C ( = N H ) N H C H 2 C#2CH2- ) , 1.23 ( 3 H , s, -CH3), 1.23-0.93 ( 4 H , m, 2 ring H and -C / /2 -CH(NH 2 )C0 2 H), 0.90-0.68 ( 3 H , m, ring H), 0.66 ( 9 H , s, tert-butyl H), no COOH nor N- / / signals could be detected. 1 3 C NMR ( C D C 1 3 , 50 MHz): 5 23.82, 23.99, 26.63, 27.71, 27.93, 31.64, 36.61, 40.06, 46.98, 48.23, 53.55, 126.31, 128.27, 130.62, 140.91, 156.98, 172.84, 173.06, 210.91. LRMS (FAB, -LSJJVIS): m/e, 475 (M" -1), 445, 409, 407, 383, 317, 302, 301 (base peak), 285, 257, 229, 209, 173, 121, 120 [Matrix: Thioglycerol]. 236 Experimental/Chapter 7 HRMS: Calculated mass for C 2 5 H 3 9 O 5 N 4 (M-l): 475.2920. Found: 475.2903. IR, cnr 1: (KBr pellet) 3398, 3162, 3034, 3005, 2953, 2869, 2742, 1670, 1589, 1546, 1496, 1455, 1391, 1365, 1293, 1272, 1222, 1194, 1065, 1051, 961, 756, 743, 698, 542. UV: methanol, 245 (11,800), 320 (245) nm (SV(-)-g-methvlbeiigvlarrjine salt (88) Salt 88 was prepared by adding a solution of 13.2 mg (0.109 mmol) of (S)-(-)-a-methylbenzylamine (free base) in 10 mL of diethyl ether to a solution of 32.6 mg (0.108 mmol) of acid 70 in 20 mL of diethyl ether. The white solid that precipitated from solution was filtered and washed repeatedly with diethyl ether to yield 32.7 mg (71.4%) of the desired salt. Recrystalhzation from acetonitrile yielded long tlhn flat needles of salt 88 (29.8 mg, 91.1% yield). M.P. 224-225 °C. Anal. Calcd. for C 2 7 H 3 7 O 3 N : C, 76.55; FL 8.81; N, 3.31; O, 11.34. Found: C, 76.69; FL 8.84; N, 3.44. *H NMR ( C D C I 3 , 200 MHz): 8 8.45 ( 3 H , br. s, -N//3+), 7.70-7.60 (2 H, d, J = 8 Hz, AT-H), 7.50-7.40 ( 2 H , d, J = 8 Hz, Ar-//), 7.36-7.20 ( 2 H , m, amine Ar-//), 7.20-7.1 (3H , m, amine Ar-//), 4.30-4.18 (IH, m, Ph-C//(Me)NH3+), 2.38-2.20 ( 2 H , m, ring //), 1.60-1.45 ( 5 H , m, 2 ring H and Ph-CH(C//3)NH3 +), 1.39 ( 3 H , s, -CH3), 1.30-1.05 ( 2 H , m, ring H), 1.05-0.80 ( 3 H , m, ring //), 0.78 ( 9H , s, tert-butylH). 237 Experimental/Chapter 7 1 3 C NMR ( C D C I 3 , 50 MHz): 8 21.81, 24.54, 27.42, 28.47, 32.32, 37.19, 47.51, 48.65, 51.15, 126.33, 126.71, 128.15, 128.32, 128.83, 129.01, 141.77, 153.78, 172.46, 210.10. LRMS: (FAB, +LSJJVIS) m/e, 424 ( M + +1), 395, 377, 333, 304, 303, 285, 277, 241, 229, 214, 165 149, 122 (base peak), 105 [Matrix: Glycerol + MeOHJ. HRMS: Calculated mass for C 2 7 H 3 8 0 3 N (M+l): 424.2852. Found: 424.2845. IR, cm"1: (KBr pellet) 2943, 2865, 2632, 2541, 2204, 1665, 1633, 1580, 1521, 1456, 1387, 1292, 1271, 1223, 1195, 1136, 1095, 961, 872, 836, 756, 740, 700, 540. UV: methanol, 248 (30,900), 278 (sh, 3,000), 320 (350) nm (RV(+Va-methvlbenzvlamine salt (89) To a solution of 28.7 mg (0.237 mmol) of (R)-(+)-a-memylbenzylamine (free base) in 10 mL of diethyl ether was added a solution of 71.6 mg (0.237 mmol) of acid 70 in 20 mL of diethyl ether. The solution turned cloudy within 5 min. The solution was allowed to stand for an additional 1 h. The white sohd was collected by filtration and washed repeatedly with diethyl ether to yield 77.7 mg (77.5%) of the desired salt. Recrystallization from acetonitrile yielded long thin flat needles of salt 89 (74.9 mg, 96.4% yield). M.P. 224-225 °C Anal. Calcd. for C 2 7 H 3 7 0 3 N : C, 76.55; H, 8.81; N, 3.31; O, 11.34. Found: C, 76.68; H, 8.86; N, 3.15. 238 Experimental/Chapter 7 *H NMR ( C D C I 3 , 200 MHz): 5 7.92 (3H, br. s, -NH3+), 7.70-7.60 (2 H, d, J = 8 Hz, Ax-H), 7.50-7.40 (2H, d, J = 8 Hz, Ax-H), 7.36-7.20 (2H, m, amine Ax-H), 7.20-7.10 (3H, m, amine Ax-H), 4.30-4.18 (1H, m, Ph-C#(Me)NH3+), 2.38-2.20 (2H, m, ring H), 1.60-1.45 (5H, m, 2 ring H and Ph-CH(C//3)NH3+), 1.39 (3H, s, -CH3), 1.30-1.05 (2H, m, ring H), 1.05-0.80 (3H, m, ring H), 0.78 (9H, s, tert-butylH). 1 3 C NMR ( C D C I 3 , 50 MHz): 8 21.81, 24.54, 27.42, 28.47, 32.32, 37.19, 47.51, 48.65, 51.15, 126.33, 126.71, 128.15, 128.32, 128.83, 129.01, 141.77, 153.78, 172.46, 210.10. LRMS: (FAB, +LSIMS) rn/e, 424 ( M + +1), 395, 377, 341, 304, 303, 285, 241, 229, 215, 214, 201, 165 149, 122 (base peak), 105 [Matrix: Glycerol + MeOH]. HRMS: Calculated mass for C27H 3 8 0 3 N (M+l): 424.2852. Found: 424.2846. IR, cm"1: (KBr pellet) 2942, 2866, 2539, 2204, 1666, 1634, 1580, 1520, 1456, 1387, 1292, 1271, 1222, 1195, 961, 872, 836, 755, 740, 700, 540. UV: methanol, 248 (30,900), 278 (sh, 3,000), 320 (350) nm (1R.2SV(-Vephedrine salt (9(n To a solution of 14.4 mg (0.087 mmol) of (lR,2S)-(-)-2-(methylamino)-l-phenylpropan-l-ol (or (-)-ephedrine) in 10 mL of diethyl ether was added a solution of 26.4 mg (0.087 mmol) of acid 70 in 20 mL of diethyl ether. Within 1 min the solution turned cloudy white. The solution was allowed to stand for an additional 1 h. White powdered solid (32.8 mg, 80.4%) was obtained upon filtration after being washed 239 Experimental/Chapter 7 repeatedly with diethyl ether. Recrystallization from acetonitrile yielded long, thin plates of salt 90 (31.1 mg, 94.8% yield). M.P. 179-181 °C. Anal. Calcd. for C29H41O4N: C, 74.48; H, 8.84; N, 3.00; O, 13.68. Found: C , 74.12;H, 8.79; N, 2.97. A H NMR (CDCI3, 200 MHz): 8 8.05-7.95 (2 H, d, J = 8 Hz, Ax-H), 7.63-7.50 (2H, d, J = 8 Hz, Ai-H), 7.47 (2H, br. s, -N// 2 + ) , 7.32-7.20 (5H, m, amine Ar-//), 5.42-5.38 (IH, d, J = 2 Hz, Ar-C//(OH)-), 3.22-3.12 (IH, m, -C//(CH 3)-NH 2 +), 2.77 (3H, s, -NH 2 +-C//3), 2.53-2.40 (2H, m, ring//), 1.60-1.41 (2H, m, ring//), 1.37 (3H, s, -C//3), 1.30-1.17 (3H, m, 2 ring H and Ar-CH(0/ /» , 1.11-1.02 (3H, d, J = 7 Hz, -CH(CH3y N H 2 + ) , 1.00-0.80 (3H, m, ring//), 0.73 (9H, s, tert-buty\H). 1 3 C NMR (CDCI3, 50 MHz): 8 9.35, 24.53, 27.41, 28.47, 31.56, 32.31, 37.18, 47,52, 48.67, 61.78, 71.19, 125.75, 126.91, 127.45, 128.33, 129.05, 139.96, 142.07, 144.11, 173.41,210.17. LRMS: (FAB:+LSIMS) m/e, 468 ( M + +1), 452, 433, 395, 361, 331, 304, 303, 285, 258, 229, 167, 166 (base peak), 149, 148, 133 [Matrix: Glycerol + MeOHJ. HRMS: Calculated mass for C 2 9 H4 2 04N (M+l): 468.3114. Found: 468.3106. IR, cm"1: (KBr pellet) 3459, 3112, 2953, 2867, 2834, 2481, 1668, 1633, 1581, 1544, 1509, 1455, 1397, 1381, 1292, 1272, 1221, 1194, 1120, 961, 872, 838, 803, 754, 739, 706, 686, 672, 548, 520, 493, 467. UV: methanol, 247 (16,500), 283 (sh 1,500), 318 (164) nm 240 Experimental/Chapter 7 L-(SVr-Vproline-fe^-butvl ester salt (91) To a solution of 70.7 mg (0.413 mmol) of L-(-)-2-proline-fert-butyl ester in 15 mL of diethyl ether was added a solution of 124.9 mg (0.413 mmol) of acid 70 in 20 mL of diethyl ether. Within 10 min the solution turned cloudy white. The solution was allowed to stand for an additional 1 h. White powdered solid (169.9 mg, 86.9%) was obtained upon filtration after being washed repeatedly with diethyl ether. Recrystallization from various solvents only yielded a powdery white solid of salt 91 (161.1 mg, 94.8% yield). M.P. 227-229 °C. Anal. Calcd. for C28H43O5N: C, 71.00; H, 9.15; N, 2.96; O, 16.89. Found: C, 70.98; H, 8.91; N, 2.80. ! H NMR (CDCI3, 200 MHz): 8 9.63 (2H, br. s, -N// 2 + -) , 8.10-8.00 (2 H, d, J = 8 Hz, Ar-//), 7.62-7.53 (2H, d, J = 8 Hz, Ax-H), 4.32-4.18 (IH, m, - N H 2 + - C / / -C0 2C(CH 3) 3), 3.40-3.20 (2H, m, -CU2-CH2-NH2+-), 2.54-2.40 (2H, m, ring //), 2.40-1.70 (4H, m, - C ^ - C ^ - C / ^ - C H - ) , 1.60-1.50 (2H, m, ring H), 1.49 (9H, s, -CH-C02C(CH3)3), 1.38 (3H, s, -CH3), 1.34-1.04 (2H, m, ring//), 1.02-0.80 (3FL m, ring//), 0.76 (9H,s, tert-butylff). 1 3 C NMR (CDCI3, 50 MHz): 8 24.50, 24.68, 27.39, 27.92, 28.43, 30.00, 32.29, 37.14, 45.83, 47.51, 48.65, 58.94, 83.15, 126.83, 129.22, 136.01, 142.36, 170.95, 171.54,210.15. LRMS: (FAB:+LSIMS) m/e, 474 ( M + +1), 441, 409, 379, 371, 343, 304, 303, 301, 285, 229, 173, 172, 149, 133, 116 (base peak), 83, 70 [Matrix: Thioglycerol]. HRMS: Calculated mass for C28H44O5N (M+l): 474.3220. Found: 474.3223. 241 Experimental/Chapter 7 IR, cm"1: (KBr pellet) 2943, 2866, 1741, 1671, 1584, 1541, 1457, 1381, 1289, 1254, 1225, 1160, 958, 871, 843, 833, 796, 756, 743, 716, 517, 460. UV: methanol, 248 (19,800), 284 (sh, 1,850), 327 (152) nm riR.2SV(-Vnorephedrine salt (92) To a solution of 24.5 mg (0.16 mmol) of (lR,2S)-(-)-norephedrine in 10 mL of diethyl ether was added a solution of 49.0 mg (0.16 mmol) of acid 70 in 10 mL of diethyl ether. Within 5 min, long flat needles (plate-like) were observed to form at the bottom of the vial. The solution was allowed to stand until almost all of the solvent evaporated. The remaining solvent was decanted and the sohd material was washed repeatedly with diethyl ether. The white crystalline and powdery sohd (71.5 mg, 97.3%) was recrystalhzed from acetonitrile/ethanol to yield long flat plates of salt 92 (69.0 mg, 96.5% yield). M.P. 171-174 °C. Anal. Calcd. for C28H39O4N: C, 74.14; H, 8.67; N, 3.09; O, 14.11. Found: C, 74.24; H, 8.54; N, 3.08. ! H NMR (CDCI3, 200 MHz): 5 8.04-7.96 (2 H, d, J = 10 Hz, Ar-H), 7.60-7.50 (2H, d, J = 10 Hz, Ar-//), 7.21-7.03 (5H, m, amine Ax-H), 5.90 (3H, br. s, -N/ / 3 + ) , 5.06-5.00 (IH, d, J = 4 Hz, Ar-C#(OH)-CH(CH3)-NH3+), 3.54-3.40 (IH, m, Ar-CH(OH)-C//(CH 3)-NH 3 +), 2.50-2.30 (2H, m, ring H), 1.60-1.44 (2H, m, ring H), 1.37 (3H, s, -CH3), 1.35-1.11 (3H, m, 2 ring H and Ar-CH(OZ/>), 1.00-0.91 (3H, d, J = 7 Hz, Ar-CH(OH)-CH(C//3)-NH3+), 0.90-0.78 (3H, m, ring//), 0.76 (9H, s, tert-butylH). 242 Experimental/Chapter 7 1 3 C NMR (CDCI3, 50 MHz): 8 12.35, 24.25, 27.01, 28.09, 31.97, 36.86, 47.22, 48.50, 52.12, 72.58, 125.69, 126.58, 127.45, 128.13, 128.70, 137.58, 139.86, 141.58, 171.60, 210.66. LRMS: (FAB:+LSJJVIS) m/e, 454 ( M + +1), 433, 395, 336, 304, 303, 285, 258, 244, 229, 166, 152 (base peak), 134, 118 [Matrix: Glycerol + MeOH]. HRMS (FAB): Calcmated mass for C28H40O4N: 454.2957. Found: 454.2965. IR, cm"1: (KBr pellet) 3400-2400, 2942, 1669, 1582, 1541, 1508, 1455, 1396, 1364, 1223, 1195, 1054, 960, 835, 800, 742, 702, 548. UV: methanol, 247 (18,500), 281 (sh, 1,723), 319 (227) nm (L)-(-)-prolinamide salt (93^ ) To a solution of 7.6 mg (0.067 mmol) of (L)-(-)-prolinamide in 2 mL of ethanol was added a solution of 20.2 mg (0.067 mmol) of acid 70 in 5 mL of acetonitrile. The solution was allowed to stand until almost all of the solvent evaporated. The solvent was decanted and the solid material was washed repeatedly with diethyl ether (yield, 26.8 mg, 96.4%). The solid was recrystallized from acetonitrile to yield small colourless plates of salt 93 (24.8 mg, 92.5% yield). M.P. 147-148 °C. Anal. Calcd. for C24H3 60 4N 2: C, 69.20; H, 8.71; N, 6.72; O, 15.36. Found: C, 68.91; H, 8.80; N, 6.66. X H NMR (CD 3OD, 200 MHz): 8 8.10-8.00 (2 H, d, J = 8 Hz, Ar-//), 7.70-7.55 (2H, d, J = 8 Hz, Ar-//), 4.45-4.30 (IH, m, amine -NC//-), 3.33-3.10 (2H, m, amine ring 243 Experimental/Chapter 7 H), 2.54-2.38 ( 2 H , m, ring H), 2.38-2.15 (IH, m, amine ring H), 2.13-1.80 ( 3 H , m, amine ring H), 1.68-1.48 ( 2 H , m, ring H), 1.36 ( 3 H , s, -CH3), 1.40-1.10 ( 2 H , m, ring H), 1.10-0.70 ( 3 H , m, ringiT), 0.76 ( 9 H , s, tert-butylH). 1 3 C NMR (CD 3OD, 50 MHz): 8 24.52, 25.03, 27.40, 28.42, 30.60, 32.29, 37.11, 47.50, 48.36, 48.67, 59.88, 126.94, 129.16, 142.36, 146.64, 168.58, 176.13, 208.73. LRMS: (FAB) m/e, 417 (M+ +1), 395, 317, 304, 303, 285, 258, 244, 229, 215, 207, 166, 152, 134, 115 (base peak) [Matrix: Glycerol + MeOH]. HRMS: Calculated mass for C 2 4 H 3 7 O 4 N 2 : 417.2753. Found: 417.2755. IR (KBr pellet), cm"1: 3385, 3180, 2942, 2865, 1699, 1669, 1594, 1542, 1457, 1387, 1222, 1194, 961, 834, 757, 742, 459. UV: methanol, 247 (13,540), 281 (sh, 1,200), 320 (115) nm The structure was confirmed by X-ray crystallographic analysis. C 2 4 H 3 6 O 4 N 2 crystallized with 1 mole of C H 3 C N in space group P 2 i , a = 7.116 (1) A, b = 9.324 (2) A, c = 20.502 (1) A, J3 = 94.555 ( 9 ) ° , V = 1356.0 (2) A 3 , Z = 2, Dcalc= 1 1 2 1 g/cm3, R = 0.051, R w = 0.045. (lSVC-V2,10-camphorsultam salt (94) Salt 94 was prepared by adding a solution of 20.9 mg (0.097 mmol) of (lS)-(-)-2,10-camphorsultam in 5 mL of diethyl ether to a solution of 29.7 mg (0.098 mmol) of acid 70 in 10 mL of diethyl ether. The solution was observed to become cloudy within 20 min, whereupon it was allowed to stand for an additional 1 h. White powdery sohd (42.4 244 Experimental/Chapter 7 mg, 83.8%) was obtained upon filtration after being washed repeatedly with diethyl ether. Recrystallization from 10% methanol in acetonitrile yielded small flake-like plates of salt 94 (39.7 mg, 93.6% yield). M.P. 219-225 °C X H NMR (CD 3OD, 200 MHz): 8 8.20-8.07 (2 H, d, J = 8 Hz, Ar-//), 7.73-7.60 (2H, d, J = 8 Hz, Ax-H), 4.00-3.90 (1H, m, amine H), 3.47-3.30 (1H, m, amine H), 3.05 (2H, s, amine CH2-S02-), 2.50-2.30 (2H, m, ring H), 1.95-1.60 (4H, m, amine H), 1.40-1.23 (2H, m, ring H), 1.18 (3H, s, -CH3), 1.17-0.88 (4H, m, 2 ring H and 2 amine H), 0.85 (3H, s, amine -CH3), 0.80-0.55 (3H, m, ring H), 0.76 (3H, s, amine -CH3), 0.59 (9H, s, tert-buxyl H), no N-H signals detected. 1 3 C NMR ( C D 3 O D , 50 MHz): 8 19.77, 19.99, 24.22, 26.48, 26.94, 28.17, 31.92, 32.31, 35.57, 36.66, 44.50, 47.03, 48.54, 49.99, 50.88, 54.23, 62.39, 126.66, 129.27, 143.33, 145.59, 179.96, 210.71. IR (KBr pellet), cm"1: 3525, 3447, 2943, 2866, 2669, 2543, 1686, 1609, 1568, 1560, 1507, 1473, 1421, 1363, 1317, 1289, 1221, 1195, 1127, 959, 865, 737. UV: methanol, 244 (19,000), 319 (930) nm 245 Experimental/Chapter 7 ayivsine salt (95) Salt 95 was prepared by combining a solution of 10.8 mg (0.074 mmol) of L-lysine (free base) in 0.5 mL of water and a solution of 22.3 mg (0.074 mmol) of acid 70 in 6 mL of ethanol. No sohd was observed to form after several hours of standing; therefore the solvent was removed in vacuo. The sohd material was washed repeatedly with diethyl ether leaving 33.1 mg (100.0% yield) of a slightly yellow sohd. Recrystallization from ethanol yielded small slightly yellow plates of salt 95 (27.5 mg, 83.1% yield). M.P. 204-206 °C. Anal. Calcd. for C25H40O5N2: C, 66.94; H, 8.99; N, 6.24; O, 17.83. Found: C, 66.74; H, 9.08; N, 6.16. A H NMR ( C D 3 O D , 200 MHz): 5 7.80-7.65 (2 H, d, J = 9 Hz, te-H), 7.45-7.30 (2H, d, J = 9 Hz, Ai-H), 3.35-3.27 (IH, m, amine -CJrY(C02H)NH2), 2.73-2.60 (2H, t, J = 7 Hz, amine H 3 N + -C//2-CH 2 -) , 2.30-2.10 (2H, m, ring H), 1.80-1.40 (8H, m, 2 ring H and H 3 N + - C H 2 - C F 2 - C / / 2 - c ^ 2 - C H ( C 0 2 H ) N H 2 ) 5 1 3 7 (3H> s> ~CH3% 1.10-0.90 (2H, m, ring H), 0.90-0.55 (3H, m, ring H), 0.50 (9H, s, tart-butyl H), no COOH nor N-H signals could be detected. 1 3 C NMR (CDC13, 50 MHz): 5 23.05, 25.62, 27.84, 28.07, 28.83, 31.53, 33.07, 38.21, 40.22, 48.77, 49.72, 55.79, 127.90, 129.88, 140.87, 142.55, 174.01, 174.17, 212.05. LRMS (FAB, +LSIMS): m/e, 449 ( M + +1), 433, 417, 383, 347, 341, 331, 315, 303, 293, 285, 261, 229, 215, 201, 169, 147 (base peak), 130, 91 [Matrix: Thioglycerol]. HRMS (FAB): Calculated mass for C25H41O5N2 (M+l): 449.3015. 246 Experimental/Chapter 7 Found: 449.3010. IR (KBr pellet), cm"1: 3447, 2943, 2866, 2126, 1671, 1586, 1541, 1473, 1456, 1447, 1392, 1362, 1293, 1275, 1225, 1194, 1135, 962, 838, 802, 757, 741, 717, 549 UV: methanol, 249 (19660), 280 (sh, 2920), 320 (460) nm 7.4. Synthesis of 2-Adamantyl Aryl Ketones phenyl tricvcloD .3.1.1 ^ ^]dec-2-\\ methanone The method of Alberts et al. was used to prepare 2-adamantane carboxylic acid 75.9 A 3-neck 250 mL round bottomed flask equipped with an addition funnel was flame dried under a nitrogen atmosphere. The round bottomed flask was charged with 19.3 g (56.3 mmol) of methoxymemyltriphenylphosphinechloride, CH30CH2P(C6H5)CL and 130 mL of dry diethyl ether, while to the addition funnel was added 7.4 g of adamantanone 72 (49.2 mmol) in 75 mL of dry diethyl ether. The flask was cooled to 10 °C. To this mixture, 42 mL of n-butylhthium (1.6 M solution, 67.2 mmol) was slowly syringe injected over 5 min. The mixture was observed to change from yellow to red in colour. The scarlet red suspension was stirred for 1 h under a nitrogen atmosphere. The adamantanone was slowly added over 1 h and the mixture was allowed to stir at room 2 4 7 Experimental/Chapter 7 temperature overnight. Under vigorous stirring, 10 g of anhydrous zinc chloride (73.4 mmol) was added to complex with the suspended triphenylphosphine oxide. The almost colourless ethereal layer was decanted and evaporated to yield the enol ether 73 (used without further purification). The vinyl ether 73 was hydrolyzed in 90 mL of diethyl ethyl which contained 9 mL of 70% perchloric acid and 5 mL of water. The mixture was refluxed for 1 h after which the mixture was poured into 100 mL of water. The organic layer was separated, washed with water and dried over sodium sulphate. The solvent was removed in vacuo to yield 6.3 g (78.0% yield) of the aldehyde 74 (used with further purification). Aldehyde 74 was dissolved in a 250 mL round bottomed flask using 70 mL of acetone and the solution was cooled to 5 °C. A solution consisting of 5.0 g of CrC>3, 20 mL of water, and 8 mL of sulphuric acid was added dropwise to the cooled solution until the Jones reagent was in excess. The mixture was allowed to stir at room temperature for 2.5 h, after which the acetone was removed in vacuo. Cold water (100 mL) was added and the mixture was extracted with diethyl ether (3 X 75 mL). The combined ethereal layers were extracted with IN sodium hydroxide (5 X 50 mL). After washing with ether, the aqueous layer was acidified with concentrated hydrochloric acid. The white precipitate was extracted with ether. After washing with water, drying over sodium sulphate and removal of solvent in vacuo, acid 75 was left as a white sohd (5.9 g, 85.3% yield from aldehyde, 66.5% yield from adamantanone). It was recrystallized from methanol-water, mp 139-141 °C. (lit.9 mp 141-143 °C). 248 Experimental/Chapter 7 In a flame dried 50 mL round bottomed flask equipped with a condenser and under a nitrogen atmosphere was placed 5.0 g (27 mmol) of acid 75 and 10.0 g (84 mmol) of thionyl chloride. After stirring at room temperature for 30 min, the rnixture was refluxed for 2 h. Most of the excess thionyl chloride was removed by direct distillation. When nearly all of the thionyl chloride was removed, 10 mL of dry benzene was added and the distillation was further continued until no more Uquid was coming off. The sample was then stored in vacuo at room temperature overnight. The acid chloride, 76, was used without further purification. A 250 mL three neck round bottomed flask equipped with an addition funnel was flame dried under a nitrogen atmosphere. Then 3.0 g (14.8 mmol) of acid chloride 76 in 25 mL of dry benzene was added over 30 min to 7.0 g (52.5 mmol) of aluminum chloride (Aldrich, used without purification) which was suspended in 150 mL dry benzene. The shghtly yellow-green aluminum chloride suspension turned brown-black within 5 min after the first addition of the acid chloride. After an additional 5 h of stirring at room temperature, 100 mL of water was very carefully added to the flask. The mixture was extracted twice with ether (2 X 75 mL). The combined ethereal layers were washed with water, dried over magnesium sulphate, and evaporated to dryness in vacuo. The residue crystallized overnight under vacuum at room temperature. Recrystallization of the substrate from methanol yielded colourless plates of ketone 77 (1.2 g, 4.9 mmoL 33.1% yield). M.P. 91-93 °C. Anal. Calcd. for C 1 7 H 2 oO: C, 84.96; H, 8.39; O, 6.66. 249 Experimental/Chapter 7 Found: C, 85.12; FL 8.43. *H NMR (CDCI3, 200 MHz): 5 7.90-7.80 (2 H, m, Ax-H), 7.60-7.40 (3H, Ar-H), 3.50-3.40 (1H, m, a-C-H), 2.30 (2H, m, ring//), 2.10-1.40 (12H, m, ring//). 1 3 C NMR (CDCI3, 50 MHz): 5 27.52 (-), 27.96 (-), 30.31 (-), 32.77 (+), 37.44 (+), 38.82 (+), 52.14 (-), 128.04 (-), 128.41 (-), 132.12 (-), 137.23 (+), 204.08 (+). LRMS: (EI) m/e (relative intensity), 241 (3.5), 240 (M+, 20.1), 239 (13.4), 222 (0.9), 197 (1.9), 179 (2.7), 145 (1.8), 135 (12.0), 120 (2.4), 105 (34.1), 93 (7.3), 91 (6.0), 79 (10.3), 77 (17.7), 67 (7.4), 51 (5.2), 41 (6.5). HRMS: Calculated mass for C 1 7 H 2 o O : 240.1514. Found: 240.1509. IR, cm"1: (KBr pellet) 2950, 1676, 1447, 1364, 1221, 973, 766, 698. UV: methanol, 238 (17,800), 278 (sh. 1500), 339 (80) nm. The structure was confirmed by X-ray crystallographic analysis. C 1 7 H 2 0 ° crystallized in space group PI bar (#2), a = 10.2520 (9) A , b = 10.6436 (8) A , c = 6.4898 (3) A , a = 97.515 (5)°, 0 = 100.783 (5)°, y = 68.523 (6)°. V = 645.84 (9) A 3 , Z = 2, D c a i c = 1.236 g/cm3, R = 0.037, R w = 0.040. 250 Experimental/Chapter 7 phenyl 2-methyltricyclo[3.3.1.13,7]dec-2-yl methanone A 100 mL round bottomed flask equipped with a condenser was flame dried under a nitrogen atmosphere. Ketone 77 (2.0 g, 8.2 mmol) and 1.0 g (41.7 mmol) of powdered sodium hydride were placed in the flask and suspended in 50 mL of dry 1,2-dimethoxyethane. The mixture was refluxed for 4 h after which time it was allowed to cool to 0 °C in an ice bath. Methyl iodide (1 mL, 2.3 g, 16.2 mmol) was syringed into the mixture. Stirring was continued for an additional 30 min. Additional sodium hydride (0.5 g, 20.8 mmol) was added to the flask and the mixture refluxed for 90 min. Again the solution was cooled to 0 °C and 1 mL (16.2 mmol) of methyl iodide was syringed into the flask. After careful addition of 30 mL of water, the reaction mixture was extracted with pentane, dried over magnesium sulphate, and the solvent removed in vacuo. The residue sohdified after a few minutes at room temperature. The residue was silica gel chromatographed using 5% diethyl ether in hexanes (v/v) as the eluent. The second compound to elute from column was collected. Repeated recrystallizations using hexanes yielded colourless plates of ketone 78 (1.1 g, 4.3 mmoL 51.9% yield). M .P . 56-57 °C. Anal. Calcd. for CigH^O: C, 84.99; H, 8.72; O, 6.29. Found: C, 84.78; H, 8.75. 251 Experimental/Chapter 7 ! H N M R (CDCI3, 200 MHz): 8 7.78-7.64 (2 H, m, Ax-H), 7.50-7.30 (3H, Ar-H), 2.38 (2H, m, ring/?), 2.18-2.07 (2H, m, ring if), 1.90-1.62 (10H, m, ring H), 1.60 (3H, s, -CH3). 1 3 C N M R (CDCI3, 50 MHz): 8 23.80 (-), 27.04 (-), 27.24 (-), 32.54 (+), 34.11 (-), 35.04 (+), 38.10 (+), 53.10 (+), 127.85 (-), 127.92 (-), 130.79 (-), 139.20 (+), 210.80 (+). LRMS: (EI) m/e (relative intensity), 254 (M + , 3.6), 150 (12.1), 149 (100.0), 148 (9.5), 121 (4.0), 107 (9.4), 105 (8.8), 93 (16.1), 91 (5.5), 81 (11.3), 79 (8.8), 77 (11.6), 67 (8.9), 55 (3.2), 41 (4.2), 32 (4.6). HRMS: Calculated mass for C 1 8 H 2 2 0 : 254.1671. Found: 254.1668. IR, cm"1: (KBr pellet) 2950, 2913, 2862, 1666, 1596, 1462, 1446, 1256, 1214, 1163, 1138, 1104, 1081, 1002, 968, 953, 942, 928, 888, 795, 726, 697. UV: methanol, 239 (9500), 270 (sh, 795), 322 (143) nm. The structure was confirmed by X-ray crystallographic analysis. C 1 8 H 2 2 ° crystallized in space group Pbca (#61), a = 18.258 (2) A, b = 13.672 (1) A, c = 11.127 (2) A, V = 2777.5 (9) A 3 , Z = 8, D c a l c = 1.217 g/cm3, R = 0.037, R w = 0.045. 252 Experimental/Chapter 7 1 -r4-fluorophenvn-tricvclo[3.3.1.13,7]dec-2-yl methanone £ 8 0 } In a flame dried 250 mL flask under a nitrogen atmosphere, 3.0 g (16.5 mmol) of aldehyde 74 was dissolved in 75 mL of THF and cooled in an ice bath. The 4-fluoro phenyl magnesium bromide (Aldrich, 1.6 M in hexane solution, 50.0 mL, 80.0 mmol) Grignard reagent was added via a syringe over 5 min to the ice-cooled solution of aldehyde 62. The mixture was stirred at room temperature for 5 h after which saturated ammonium chloride was added carefully. The mixture was extracted twice with diethyl ether (2 X 75 mL). The combined organic layers were washed once with water and dried over sodium sulphate. The solvent was removed in vacuo to yield a shghtly yellow liquid ( 4 . 1 g, 14.7 mmol, 89.3% yield) of the alcohol 79 (used later without further purification). Jones reagent (10.0 g CrC>3, 5 mL of water and 2.0 mL of concentrated sulphuric acid) in 50 mL of acetone was used to oxidize the alcohol 79 to the ketone 80. After removal of the acetone in vacuo, cold water (75 mL) was added and the mixture was extracted twice with diethyl ether (2 X 75 mL). After washing the organic layer with water (50 mL), then with 10% sodium bicarbonate solution (50 mL) and again with water (50 mL), it was dried over sodium sulphate. Removal of the solvent in vacuo left a 253 Experimental/Chapter 7 slightly yellow solid, which was recrystallized from methanol to yield colourless plates of ketone 80 (3.9 g, 14.1 mmol, 96.1% yield, overall yield from aldehyde 85.6%). M.P. 93-94 °C. Anal. Calcd. for C 1 7 H 1 9 O F : C, 79.04; H, 7.41; O, 6.19; F, 7.35. Found: C, 79.09; H, 7.57. ! H N M R (CDC13, 200 MHz): 5 7.92-7.80 (2 H, m, Ar-//), 7.18-7.02 (2FL m, Ar-//), 3.40 (1FL m, a-C-H), 2.25 (2H, m, ring H), 2.16-1.46 (12FL m, ring //). 1 3 C N M R (CDCI3, 50 MHz): 5 27.47 (-), 27.92 (-), 30.40 (-), 32.70 (+), 37.38 (+), 38.80 (+), 52.05 (-), 115.24 and 115.67 (2Jc-F = 2 2 Hz, -ve), 130.52 and 130.70 ( 3 j C-F = 9 H z > -ve), 133.36 and 133.42 (4Jc-F = 3 Hz, +ve), 162.61 and 167.64 (^C-F = 253 Hz, +ve), 202.32 (+). LRMS: (EI) m/e (relative intensity), 259 (11.8), 258 (M + , 64.7), 257 (24.9), 240 (1.4), 215 (3.3), 197 (5.9), 177 (3.1), 163 (5.5), 151 (1.9), 138 (7.9), 136 (8.5), 135 (76.5), 124 (7.8), 123 (100.0), 107 (5.5), 95 (25.1), 93 (15.6), 91 (7.0), 81 (8.2), 79 (17.4), 67 (10.7), 55 (1.5), 41 (1.6). HRMS: Calculated mass for C 1 7 H 1 9 O F : 258.1420. Found: 258.1413. IR, cm"1: (KBr pellet) 2902, 2851, 1678, 1593, 1504, 1451, 1407, 1344, 1336, 1297, 1268, 1237, 1206, 1157, 1101, 1010, 948, 861, 846, 829, 813, 795, 619, 505. UV: methanol, 241 (10,700), 274 (sh. 300), 342 (60) nm 254 Experimental/Chapter 7 l-r4-fluorophenvlV2-methyltricvclo[3.3.1. l3,7]dec-2-yl methanone A 100 mL round bottomed flask equipped with a condenser was flame dried under a nitrogen atmosphere. Ketone 80 (2.0 g, 8.2 mmol) and 1.0 g (41.7 mmol) of powdered sodium hydride were placed in the flask and suspended in 50 mL of dry 1,2-dhnethoxyethane. The mixture was refluxed for 4 h after which time it was allowed to cool to 0 °C in an ice bath. Methyl iodide (1 mL, 2.3 g, 16.2 mmol) was syringed into the mixture. Stirring was continued for an additional 30 min. Additional sodium hydride (0.5 g, 20.8 mmol) was added to the flask and the mixture refluxed for 90 min. Again the solution was cooled to 0 °C and 1 mL (16.2 mmol) of methyl iodide was syringed into the flask. After careful addition of 30 mL of water, the reaction mixture was extracted with pentane, dried over magnesium sulphate, and the solvent removed in vacuo. The residue sohdified after a few minutes at room temperature. Repeated recrystallizations using hexanes yielded colourless plates of ketone 81 (1.1 g, 4.3 mmol, 51.9% yield). M .P. 86-87 °C. Anal. Calcd. for Ci 8 H 2 i O F : C, 79.38 ; H, 7.77; O, 5.87; F, 6.98. Found: C, 79.31; H, 7.86. 255 Experimental/Chapter 7 *H NMR (CDCI3, 200 MHz): 8 7.84-7.70 (2 H, m, Ax-H), 7.14-6.99 (2H, m, Ax-H), 2.34 (2H, m, ring H), 2.19-2.05 (2H, m, ring H), 1.90-1.72 (3H, m, ring H), 1.72-1.55 (7H, m, ring//), 1.50 (3H, s, -CH3). 1 3 C NMR (CDCI3, 50 MHz): 8 23.67 (-), 26.97 (-), 27.19 (-), 32.50 (+), 34.21 (-), 34.96 (+), 38.01 (+), 53.00 (+), 114.74 and 115.17 (2Jc-F = 2 1 Hz, -ve), 130.30 and 130.47 ( 3 Jc -F = 8 Hz, -ve), 135.01 and 135.08 (4Jc-F = 3 Hz, +ve), 161.64 and 166.65 ( l j C-F = 2 3 2 H z , +ve), 208.47 (+). LRMS: (EI) m/e (relative intensity), 273 (0.3), 272 (M + , 1.5), 189 (0.2), 181 (0.3), 169 (0.3), 150 (14.2), 149 (100.0), 148 (4.6), 133 (0.6), 123 (7.3), 121 (1.2), 107 (4.0), 95 (5.0), 93 (4.9), 81 (2.4), 79 (2.1), 67 (1.1), 55 (0.3), 41 (0.2). HRMS: Calculated mass for C 1 8 H 2 1 O F : 272.1577. Found: 272.1571. IR, cm"1: (KBr pellet) 2921, 2858, 1668, 1598, 1504, 1454, 1354, 1259, 1226, 1160, 1142, 1103, 1084, 970, 954, 940, 851, 821, 769, 759, 608, 543, 492. UV: methanol, 241 (8900), 333 (70) nm The structure was confirmed by X-ray crystallographic analysis. C 1 8 H 2 i O F crystallized in space group Pbca (#61), a = 13.5633 (8) A, b = 17.406 (1) A, c= 12.168(1) A, V = 2872.7 (4) A 3 , Z = 8, D c a i c = 1.259 g/cm3,R = 0.051, R w = 0.060. 256 Experimental/Chapter 7 1 -r4-cvanophenvlV2-methvltricvclo[3.3.1.13,7] dec-2-vl methanone To a flame dried 100 mL flask equipped with a magnetic stirrer and condenser, 2.90 g (10.5 mmol) of ketone 81 and 1.4 g (21.6 mmol) of potassium cyanide were dissolved in 70 mL of dry dimethyl sulfoxide (DMSO). The mixture was refluxed until the starting material was totally consumed (monitored by gas chromatography). The solution was observed to go from yellow to dark yellow (a little cloudy) to red-brown-orange at the end of the necessary reflux time (usually overnight). Upon cooling to room temperature the mixture was red-orange with small white particles floating in the solution. The solution was poured into 100 mL of water and extracted with diethyl ether (3 x 50 mL). The combined organic layers were washed with 75 mL of water, 75 mL of 5% sodium bicarbonate and dried over magnesium sulphate. The solvent was removed in vacuo to yield a solid yellow powder. The solid was recrystallized using 95:5 (v/v) petroleum ether:diethyl ether to yield very slightly yellow plates of ketone 82 (2.9 g, 10.2 mmoL 97.5% yield). M .P . 134-135 °C. Anal. Calcd. for C i 9 H 2 i N O : C, 81.68; FL 7.58; N, 5.01; O, 5.73. Found: C, 81.66; H, 7.67; N, 4.97. 257 Experimental/Chapter 7 A H NMR (CDCI3, 200 MHz): 8 7.81-7.65 (4H, m, Ar-//), 2.28 (2H, m, ring H), 2.18-2.05 (2H, m, ring//), 1.90-1.72 (2H, m, ring//), 1.72-1.55 (8H, m, ring//), 1.50 (3H,s,-C// 3). 1 3 C NMR (CDCI3, 50 MHz): 8 23.75(-), 26.87 (-), 27.11 (-), 32.34 (+), 33.92 (-), 35.03 (+), 37.89 (+), 53.42 (+), 114.31 (+), 118.10 (+), 128.33 (-), 131.85 (-), 142.86 (+), 209.09 (+). LRMS: (EI) m/e (relative intensity), 280 (0.3), 279 (M+, 1.4), 181 (0.4), 169 (0.4), 150 (12.2), 149 (100.0), 131 (1.0), 130 (4.3), 121 (1.1), 107 (3.6), 102 (3.2), 95 (1.3), 93 (4.9), 91 (1.6), 81 (2.4), 79 (2.0), 77 (1.1), 69 (0.4), 67 (1.1), 55 (0.4), 41 (0.3). HRMS: Calculated mass for C 1 9 H 2 i O N : 279.1623. Found: 279.1621. IR, cm"1: (KBr pellet) 2904, 2855, 2230, 1669, 1460, 1450, 1401, 1354, 1286, 1251, 1221, 1140, 1105, 1083, 973, 954, 941, 845, 768, 707, 594, 545, 528, 512. UV: methanol, 243 (15600), 323 (200) nm 258 Experimental/Chapter 7 l-C4-carboxyphenvlV2-methvltricvclo[3.3.1. l3,7id ec-2-yl methanone To a 100 mL round bottomed flask equipped with a condenser was added 2.0 g (7.1 mmol) of ketone 82, 50 g of potassium hydroxide, 75 mL of water and 15 mL of ethanol. The nrixture was refluxed for 72 h. The mixture was cooled to room temperature and washed with diethyl ether (50 mL) once. The aqueous layer was acidified by careful addition of concentrated hydrochloric acid. The white solid was collected by vacuum filtration and recrystallized from water: ethanol solution. Ketone 83 was collected as long, white thin needles (2.1 g, 6.9 mmol, 98.4% yield). M.P. 216-218 °C. Anal. Calcd. for C19H22O3: C, 76.47; H, 7.44; O, 16.09. Found: C , 76.35; H , 7.39. *H NMR (CDCI3, 200 MHz): 5 8.20-8.10 (2H, d, J = 8Hz, Ar-//), 7.85-7.75 (2H, d, J = 8Hz, Ar-//), 2.32 (2H, m, ring H), 2.20-2.08 (2H, m, ring H), 1.92-1.7'4 (2H, m, ring H), 1.73-1.59 (8H, m, ring H), 1.53 (3H, s, -CZ/3), no COOH signal was detectable. 1 3 C NMR (CDC13, 50 MHz): 8 23.79 (-), 26.96 (-), 27.17 (-), 32.43 (+), 33.94 (-), 35.07 (+), 37.99 (+), 53.40 (+), 127.81 (-), 129.89 (-), 130.92 (+), 143.97 (+), 170.99 (+), 210.17 (+). 259 Experimental/Chapter 7 LRMS: (EI) m/e (relative intensity), 299 (0.3), 298 (M + , 1.1), 281 (0.5), 253 (3.0), 178 (0.4), 159 (0.4), 150 (16.4), 149 (100.0), 148 (1.9), 131 (1.1), 121 (2.5), 107 (3.3), 93 (4.4), 81 (2.1), 79 (1.9), 65 (1.1), 55 (0.4), 41 (0.3). HRMS: Calculated mass for C 1 9 H220 3 : 298.1569. Found: 298.1562. IR, cm"1: (KBr pellet) 3420, 2910, 2882, 2855, 1694, 1681, 1506, 1456, 1435, 1404, 1322, 1298, 1255, 1214, 1127, 1104, 974, 955, 940, 866, 789, 766, 735, 703, 547, 531, 459. UV: methanol, 247 (16000), 275 (sh, 1300), 322 (200) nm. l-(4-carbomethoxyphenyl)-2-methyltricyclo[3.3.1. l3,7]d ec-2-yl methanone Ketone 83 (0.7 g, 2.3 mmol) was taken up in 35 mL of methanol, 0.5 g of p-toluenesulphonic acid was added as the catalyst, and the triixture was heated at reflux for 24 h. The reaction mixture was cooled to room temperature, poured into 30 mL of ice/water and extracted five times with 30 mL portions of hexane. The hexane extracts were then washed two times with 40 lriL portions of cold water, two times with 40 mL portions of dilute sodium bicarbonate solution, and one time with 40 mL of saturated sodium chloride solution. The hexane extracts were then dried over sodium sulphate, and 2 6 0 Experimental/Chapter 7 the solvent removed in vacuo. The residue was a shghtly yellow sohd. Recrystallization from petroleum ether gave 0.7 g (2.2 mmol, 95.6% yield) of ketone 84 as white plates. M.P. 90-92 °C. Anal. Calcd. for C20H24O3: C, 76.88; H, 7.75; O, 15.37. Found: C, 76.91; H, 7.84. *H NMR (CDCI3, 200 MHz): 5 8.10-8.00 (2H, d, J = 8Hz, Ar-//), 7.80-7.70 (2H, d, J = 8Hz, Ar-//), 3.94 (3H, s, COOC//3), 2.32 (2H, m, ring H), 2.21-2.07 (2H, m, ring//), 1.93-1.73 (2H, m, ring/0, 1.73-1.50 (8H, m, ring/0, 1-52 (3H, s, -C / /3). 1 3 C NMR (CDCI3, 50 MHz): 8 23.78 (-), 26.95 (-), 27.16 (-), 32.44 (+), 33.95 (-), 35.04 (+), 37.99 (+), 52.33 (-), 53.33 (+), 127.71 (-), 129.23 (-), 131.85 (+), 143.10 (+), 166.37 (+), 210.10 (+). LRMS: (EI) m/e (relative intensity), 312 (M + , 0.8), 297 (1.4), 281 (3.6), 253 (11.9), 164 (13.2), 163 (9.2), 150 (12.9), 149 (100.0), 135 (2.2), 121 (1.2), 107 (3.4), 93 (4.3), 79 (2.0). HRMS: Calculated mass for C 1 8 H 2 i O F : 312.1725. Found: 312.1720. IR, cm"1: (KBr pellet) 2911, 2859, 1727, 1696, 1673, 1457, 1438, 1402, 1285, 1255, 1218, 1107, 1017, 972, 954, 860, 791, 743, 709. UV: methanol, 247 (15800), 275 (sk., 1360), 323 (200) nm. The structure was confirmed by X-ray crystallographic analysis. C 2 0 H 2 4 ° 3 crystallized in space group P2i/n (#14), a = 11.3399 (8) A, b = 6.5515 (8) A, c = 22.473 (1) A, 0 =97.789 (6)°, V = 1654.2 (2) A 3 , Z = 4, D c a l c = 1.254 g/cm3, R = 0.041, R w = 0.041. 261 Experimental/Chapter 7 7.5. Synthesis of Salts with Ac id 83 All these salts were prepared by dissolving equimolar amounts of ketone 83 and an organic amine in the solvents indicated. Ciystalline salts were usually first obtained by spontaneous deposition at room temperature. Crystals were collected by suction filtration. Recrystallization of the salts in an appropriate solvent was accomplished by slow evaporation of the solvent from a fully dissolved solution of the salt. The conroosition of all salts was confirmed by Iff NMR spectroscopy (CDCI3, 200 MHz), which simply consisted of a 1:1 ratio of acid to amine. Also, Infrared spectra were taken of the salts as well. L-C+Vprolinol or (Syf+V2-pyrrolidmemethanol salt (96) Salt 96 was prepared by placing 245.7 mg (0.813 mmol) of acid 83 and 82.1 mg (0.812 mmol) of S-(+)-2-pyrrolidine methanol in 30 mL of acetone. The solution was heated until the solid dissolved. The solution was allowed to stand at room temperature for 1 h. A white powder (252.5 mg, 77.0% yield) was collected by filtration. Recrystallization from various solvents only yielded a white powdery substance of salt 96. M.P. 133-135 °C. Anal. Calcd. for C24H33O4N: C, 72.15; H, 8.33; N, 3.51; O, 16.02. Found: C, 72.32; H, 8.36; N, 3.55. J H NMR (CDCI3, 200 MHz): 5 8.67 (2H, br. s, N// 2 + X 8.02-7.90 (2H, d, J = 8Hz, Ar-//), 7.75-7.62 (2H, d, J = 8Hz, Ar-//), 4.02-3.86 (1H, m, -C//-CH 2OH), 3.86-262 Experimental/Chapter 7 3.69 (2H, m, -CH2OH), 3.37-3.20 (2H, t, J = 6.5 Hz, -C#2-NH2 +-), 2.33 (2H, m), 2.20-1.90 (5H, m), 1.90-1.48 (12H, m), 1.51 (3H, s, - C H 3 ) . 1 3 C NMR (CDC13, 50 MHz): 8 23.78 (-), 24.69 (+), 26.44 (+), 26.98 (-), 27.16 (-), 32.48 (+), 34.00 (-), 35.03 (+), 38.03 (+), 45.27 (+), 53.17 (+), 61.49 (+), 61.60 (-), 127.46 (-), 128.80 (-), 138.50 (+), 141.15 (+), 173.42 (+), 210.51 (+). LRMS: (FAB: +LSJJVIS) m/e, 400 (M+ +1), 371, 358, 343, 316, 300, 299, 297, 281, 237, 203, 181, 149, 133, 131, 124, 103, 102 (base peak) [Matrix: Tbioglycerol]. HRMS: Calculated mass for C24H34O4N (M+l): 400.2488. Found: 400.2499. IR (KBr pellet), cm"1: 3400-2000 (OH), 3305, 2910, 2858, 2364, 2344, 1677, 1630, 1589, 1551, 1457, 1396, 1353, 1258, 1217, 1067, 970, 952, 942, 870, 840, 801, 790, 759, 750, 715, 698, 669, 657. UV: methanol, 248 (18,800), 325 (330) nm. qS-2Sy(+>w-ephedrine salt (97) Acid 83 (202.2 mg, 0.669 mmol) and 110.6 mg (0.669 mmol) of (lS-2S)-(+)-M>-ephedrine were dissolved in 30 mL of ethanol. The solution was allowed to stand for several hours. No solid was observed to form; therefore most of the solvent was removed in vacuo. Diethyl ether was added until a white solid was observed to precipitate out of solution. The white powder (292.8 mg, 93.6% yield) was collected by filtration. Recrystallization from acetonitrile or ethanol yielded long thin plates of salt 97. M.P. 158-161 °C. Anal. Calcd. for C29H 3 7 0 4 N: C, 75.13; H, 8.04; N, 3.02; O, 13.80. 263 Experimental/Chapter 7 Found: C, 74.80; H, 8.02; N, 2.96. A H NMR (CDC13, 200 MHz): 5 9.07 (2H, br. s, NH2+), 8.08-7.95 (2H, d, J = 8Hz, Ar-H), 7.74-7.62 (2H, d, J = 8Hz, Ai-H), 7.47-7.25 (5H, m, Ax-H of amine), 4.78-4.65 (IH, d, J = 10 Hz, PhC//-), 3.39-3.20 (IH, m, PhCH(OH)C#-), 2.67 (3H, s, -NC//3), 2.33 (2H, m), 2.20-2.05 (2H, m), 1.91-1.49 (11H, m), 1.51 (3H, s, -CH3), 1.15-1.03 (3H, d, J = 7 Hz, PhCH(OH)CH(Cr73)-). 1 3 C NMR (CDCI3, 50 MHz): 5 12.63 (-), 23.78 (-), 27.00 (-), 27.20 (-), 30.16 (-), 32.50 (+), 34.00 (-), 35.03 (+), 38.05 (+), 53.17 (+), 60.72 (-), 75.26 (-), 127.14 (-), 127.42 (-), 128.37 (-), 128.66 (-), 128.98 (-), 138.23 (+), 140.50 (+), 141.18 (+), 173.15 (+), 210.51 (+). LRMS: (FAB: +LSJJVIS) m/e, 464 ( M + +1), 448, 413, 388, 348, 331, 314, 299, 297, 281, 258, 225, 201, 167, 166 (base peak), 148, 133 [Matrix: Glycerol]. HRMS: Calculated mass for C 2 9 H 3 8 0 4 N (M+l): 464.2801. Found: 464.2810. IR (KBr pellet), cm"1: 3400-2000 (OH), 3261, 3064, 3033, 2904, 2849, 2687, 2446, 2364, 1674, 1594, 1552, 1494, 1456, 1360, 1319, 1256, 1217, 1129, 1105, 1042, 1011, 973, 955, 943, 923, 915, 875, 832, 801, 792, 767, 747, 704, 669, 546. UV: methanol, 247 (16,900), 325 (320) nm 264 Experimental/Chapter 7 (S)-(-)-g-methylbenzylamine salt (98) To a solution of 13.2 mg (0.109 mmol) of (S)-(-)-a-methylbenzylamine (free base) in 10 mL of diethyl ether was added a solution of 32.6 mg (0.108 mmol) of acid 83 in 20 mL of diethyl ether. Within 5 min the solution was observed to become cloudy white. The solution was allowed to stand for an additional 1 h. White powdered sohd (32.7 mg, 71.4%) was obtained upon filtration after being washed repeatedly with diethyl ether. Recrystallization from acetonitrile containing a few drops of ethanol yielded long thin flat needles of salt 98 (29.8 mg, 91.1% yield). M.P. 210-212 °C Anal. Calcd. for C27H33O3N: C, 77.29; H, 7.93; N, 3.34; O, 11.44. Found: C, 77.35; H, 7.89; N, 3.23. A H NMR (CDCI3 with ldrop CD3OD, 200 MHz): 8 7.96-7.87 (2H, d, J = 8Hz, Ar-//), 7.69-7.59 (2H, d, J = 8Hz, Ar-//), 7.40-7.20 (5H, in, amine Ax-H), 4.35-4.21 (1H, q, J = 7 Hz, Ph-C//(Me)NH3+), 2.27 (2H, m), 2.16-2.00 (2H, m), 1.84-1.40 (13H, m), 1.46 (3H, s, -CH3), no N-H peaks detected. 1 3 C NMR (CDCI3, 50 MHz): 8 21.15 (-), 23.64 (-), 26.64 (-), 27.05 (-), 32.32 (+), 34.13 (-), 34.89 (+), 37.87 (+), 50.77 (-), 53.16 (+), 126.11 (-), 127.28 (-), 128.38 (-), 128.75 (-), 128.88 (-), 137.88 (+), 140.04 (+), 141.01 (+), 172.22 (+), 211.21 (+). LRMS: (FAB: +LSIMS) m/e, 421, 420 ( M + +1), 391, 327, 300, 299, 297, 282, 281, 253, 214, 201, 165, 152, 149, 122 (base peak), 105 [Matrix: Glycerol + MeOH]. HRMS: Calculated mass for C 2 7 H 3 4 0 3 N (M+l): 420.2539. Found: 420.2541. 265 Experimental/Chapter 7 IR (KBr pellet), cm"1: 2920, 2775, 2643, 2556, 2365, 2346, 2222, 1664, 1636, 1578, 1527, 1498, 1458, 1381, 1259, 1220, 1090, 973, 945, 864, 839, 797, 766, 747, 697. UV: methanol, 244 (15,800), 329 (sh. 400) nm. The structure was confirmed by X-ray crystallographic analysis. C27H33O3N crystallized in space group P 2 i 2 i 2 i (#19), a = 11.799 (2) A, b = 29.816 (2) A, c = 6.557 (2) A, V = 2306.5 (6) A 3 , Z = 4, D C £ U C = 1.208 g/cm3, R = 0.040, R w = 0.039. (RV(+)-a-methvlbenzylamine salt (99) To a solution of 28.7 mg (0.237 mmol) of (R)-(+)-a-memylbenzylamine (free base) in 10 mL of diethyl ether was added a solution of 71.6 mg (0.237 mmol) of acid 83 in 20 mL of diethyl ether. Within 5 min the solution was observed to become cloudy white. After allowing the solution to stand for an additional 1 h, the white powdered solid was collected by filtration. The solid was washed repeatedly with diethyl ether to yield 77.7 mg (77.5%) of the desired salt. Recrystallization from acetonitrile containing a few drops of ethanol yielded long thin flat needles of salt 99 (74.9 mg, 96.4% yield). M.P. 210-212 °C. Anal. Calcd. for C27H33O3N: C , 77.29; H, 7.93; N, 3.34; O, 11.44. Found: C, 77.07; FL 7.87; N, 3.20. * H N M R (CDCI3 with 1 drop of C D 3 O D , 200 MHz): 5 7.96-7.87 (2H, d, J = 8Hz, Ax-H), 7.69-7.59 (2H, d, J = 8Hz, Ax-H), 7.40-7.20 (5H, m, amine Ax-H), 4.35-4.21 266 Experimental/Chapter 7 (1H, q, J = 7 Hz, Ph-CrY(Me)NH3+), 2.27 (2H, m), 2.16-2.00 (2H, m), 1.84-1.40 (13H, m), 1.46 (3H, s, -CH3), no N-H peaks detected. 1 3 C NMR (CDCI3, 50 MHz): 5 21.15 (-), 23.64 (-), 26.64 (-), 27.05 (-), 32.32 (+), 34.13 (-), 34.89 (+), 37.87 (+), 50.77 (-), 53.16 (+), 126.11 (-), 127.28 (-), 128.38 (-), 128.75 (-), 128.88 (-), 137.88 (+), 140.04 (+), 141.01 (+), 172.22 (+), 211.21 (+). LRMS: (FAB) m/e, 421, 420 ( M + +1), 391, 357, 327, 300, 299, 297, 282, 281, 253, 215, 214, 201, 165, 152, 149, 134, 122 (base peak), 105 [Matrix: Glycerol + MeOHJ. HRMS: Calculated mass for C27H34O3N (M+l): 420.2539. Found: 420.2537. IR (KBr pellet), cm"1: 2907, 2775, 2644, 2557, 2364, 2344, 2221, 1668, 1636, 1579, 1527, 1498, 1458, 1382, 1260, 1219, 1090, 993, 974, 946, 863, 839, 797, 767, 748, 725, 698, 578, 540, 489. UV: methanol, 244 (16,000), 329 (sh. 400) nm. The structure was confirmed by X-ray crystallographic analysis. C27H33O3N crystallized in space group P2 12 12 1 (#19), a = 11.791 (2) A , b = 29.795 (3) A , c = 6.550 (2) A , V = 2301.1 (7) A 3 , Z = 4, D c a i c = 1.211 g/cm3, R = 0.046, R w = 0.042. qR ,2SH-Vephedririe salt ( 1 0 0 ) Salt 100 was prepared by adding a solution of 14.4 mg (0.087 mmol) of (1R,2S)-(-)-2-(memylamino)-l-phenylpropan-l-ol (or (-)-ephedrine) in 10 mL of diethyl ether to a solution of 26.4 mg (0.087 mmol) of acid 83 in 20 mL of diethyl ether. Within 1 min the 267 Experimental/Chapter 7 solution was observed to become cloudy white. The solution was allowed to stand for an additional 1 h. White powdered solid (32.8 mg, 80.4%) was obtained upon filtration after being washed repeatedly with diethyl ether. Recrystallization from acetonitrile yielded long, thin plates of salt 100 (31.1 mg, 94.8% yield). M.P. 186-188 °C. Anal. Calcd. for C29H37O4N: C, 75.13; H, 8.04; N, 3.02; O, 13.80. Found: C, 75.17; H, 8.07; N, 3.19. * H N M R (CDCI3, 200 MHz): 8 8.58 (2H, br. s, N/ / 2 + ) , 8.08-7.95 (2H, d, J = 8Hz, Ar-//), 7.74-7.65 (2H, d, J= 8Hz, Ar-//), 7.49-7.21 (5H, m, amine Ar-//), 5.48-5.39 (IH, d, J = 2 Hz, Ar-C//(OH)-), 3.38-3.11 (IH, m, -C//(CH 3)-NH 2 +), 2.77 (3H, s, -NH 2 +-C//3), 2.33 (2H, m), 2.20-2.05 (2H, m), 1.91-1.49 (11H, m), 1.51 (3H, s, -CH3), 1.18-1.05 (3H, d, J = 7 Hz, -CH(C//3)-NH2+). 1 3 C N M R (CDCI3, 50 MHz): 8 9.03 (-), 23.79 (-), 27.00 (-), 27.20 (-), 31.44 (-), 32.50 (+), 34.01 (-), 35.04 (+), 36.05 (+), 53.22 (+), 61.62 (-), 71.05 (-), 125.74 (-), 127.50 (-), 128.33 (-), 128.76 (-), 128.97 (-), 137.90 (+), 139.91 (+), 141.43 (+), 173.26 (+), 210.49 (+). LRMS: (FAB: +LSEVIS) m/e, 465, 464 ( M + +1), 429, 391, 350, 331, 314, 300, 299, 297, 282, 281, 258, 225, 167, 166 (base peak), 149, 148, 133, 105 [Matrix: Glycerol + MeOH]. HRMS: Calculated mass for C 2 9 H 3 8 0 4 N : 464.2801 (M+l). Found: 464.2802. 268 Experimental/Chapter 7 IR (KBr pellet), cm"1: 3600-2000 (OH), 3339, 3059, 2999, 2912, 2862, 2483, 2366, 2346, 1676, 1627, 1588, 1546, 1458, 1376, 1253, 1212, 1126, 1063, 991, 970, 844, 798, 764, 744, 700, 573, 540, 520. UV: methanol, 246 (15,400), 318 (400) nm. (lR,2SV(-)-norephedrine salt (101) To a solution of 4.9 mg (0.032 mmol) of (lR^2S)-(-)-norephedrine in 10 mL of diethyl ether was added a solution of 9.8 mg (0.032 mmol) of acid 83 in 10 mL of diethyl ether. Long flat needles (plate-like) were observed to form at the bottom of the vial within 5 min. The solution was allowed to stand until almost all of the solvent evaporated. The remaining solvent was decanted and the sohd material was washed repeatedly with diethyl ether. The white crystalline sohd (14.3 mg, 97.3%) was recrystalhzed from acetonitrile/ethanol to yield long flat plates of salt 101 (13.8 mg, 96.5% yield). M.P. 147-149 °C. Anal. Calcd. for C28H35O4N: C, 74.80; H, 7.85; N, 3.12; O, 14.23. Found: C, 74.76; H, 7.89; N, 3.21. A H NMR (CDCI3, 200 MHz): 5 8.20-7.70 (5H, d with br. base, J = 8 Hz, Ax-H and N#3+), 7.65-7.50 (2H, d, J = 8Hz, Ax-H), 7.30-7.10 (5H, m, amine Ax-H), 5.22-5.10 (IH, d, J = 2Hz, Ar-C#(OH)-CH(CH3)-NH3 +), 3.58-3.40 (IH, m, Ar-CH(OH)-C#(CH3)-NH3+), 2.26 (2H, m), 2.22-2.03 (2H, m), 1.82 (IH, m), 1.78-1.40 (10H, m), 1.44 (3H, s, -CH3), 1.10-0.98 (3H, d, J = 7 Hz, Ar-CH(OH)-CH(C#3)-NH3 +). 269 Experimental/Chapter 7 1 3 C NMR (CDCI3, 50 MHz): 5 11.92 (-), 23.72 (-), 26.96 (-), 27.15 (-), 32.44 (+), 33.94 (-), 35.00 (+), 38.00 (+), 53.01 (-), 53.18 (+), 72.66 (-), 125.72 (-), 127.53 (-), 127.61 (-), 128.32 (-), 128.93 (-), 137.91 (+), 139.76 (+), 141.41 (+), 173.37 (+), 210.44 (+). LRMS: (FAB: +LSDVIS) m/e, 451, 450 ( M + +1), 429, 391, 334, 304, 303, 300, 299, 297, 281, 244, 225, 153, 152 (base peak), 149, 134, 118 [Matrix: Glycerol]. HRMS: Calculated mass for C 2 8 H 3 6 0 4 N (M+l): 450.2644. Found: 450.2637. IR (KBr pellet), cm"1: 3484 (OH), 2918, 2860, 2365, 2144, 1664, 1622, 1527, 1455, 1385, 1263, 1216, 1150, 1132, 1104, 1043, 1027, 970, 946, 868, 837, 798, 766, 752, 701. UV: methanol, 248 (15,800), 319 (370) nm. The structure was confirmed by X-ray crystallographic analysis. C28H35O4N crystallized with one molecule of CH 3 CN in space group V2\ (#4), a = 15.099 (2) A, b = 6.766 (3) A, c = 15.528 (1) A, (3 = 118.901 (8)°, V = 1388.8 (5) A 3 , Z = 2, D c a l c = 1.173 g/cm3, R = 0.042, R w = 0.039. 270 Experimental/Chapter 8 CHAPTER 8 Photochemical Studies 8.1. General Considerations IRRADIATION SOURCE All analytical and preparative photolyses were performed by using a Hanovia 450 Watt medium pressure mercury lamp placed in either (i) a water-cooled Pyrex immersion well (thickness = 4 mm, transmits X > 290 nm) or (ii) a water-cooled Quartz immersion well (thickness = 4 m m transmits X > 200 nm). SOLUTION STATE PHOTOLYSES For analytical solution phase photolyses, the sample in a Pyrex tube or an NMR tube was degassed by several freeze-thaw-pump cycles and sealed under nitrogen prior to photolysis. The solvent used was spectral grade (Fisher) quality. A minimum of 3 samples was irradiated, and for each photolysis at least 3 gas chromatographic (GC) runs were performed. GC detector response was calibrated with appropriate internal standards and compounds to be detected. Average results are reported. The overall precision of the reported results obtained was ± 7%. For preparative photolyses, in general, the compound under investigation was dissolved or suspended in the solvent indicated and purged with nitrogen at least half an hour prior to the photolysis. The solution was photolyzed until all the starting material had disappeared as shown by GC. After irradiation, the solvent was removed in vacuo and the residue chromatographed to isolate the photoproducts. 271 Experimental/Chapter 8 SOLID STATE PHOTOLYSES Analytical runs were carried out by irradiating single crystals or polycrystalline samples (powders) in 3 mm sealed Pyrex or quartz tubes under a nitrogen atmosphere. The degassing procedure was conducted on the vacuum line to pump off the ah and then fill the tube with the nitrogen gas. A minimum of 3 samples was irradiated, and for each photolysis at least 3 gas chromatographic (GC) runs were performed. GC detector response was calibrated with appropriate internal standards and compounds to be detected. Average results are reported. The overall precision of the reported results obtained was ± 7%. For preparative sohd state photolyses, the sample was placed between two Pyrex microscope plates, and by shding the top and bottom plates back and forth, the sample was distributed over the surface in a thin, even layer. The sample plates were then Scotch-taped together at the top and bottom ends, placed in a polyethylene bag and thoroughly degassed with nitrogen; this bag was then sealed under a positive pressure of nitrogen with a heat-sealing device. After irradiation, the sohd material was chromatographed. Low temperature photolyses were carried out by placing the sample in a solvent reservoir of ethanol/water cooled by a Cryocool immersion cooler, CC-100 TJ, and the temperature was controlled by a Cryotrol from NESLAB Instruments Inc. The temperature was kept within ±2 °C of the designated temperature. The sealed polyethylene bag containing the sohd sample sandwiched between two glass plates was placed within the ethanol/water reservoir as close to the Hanovia mercury lamp as possible. 272 Experimental/Chapter 8 Isolation and Characterization of Photoproducts 8.2. Photolysis of Compound 56 According to the literature^8, irradiation of ketone 56 in benzene (specially purified to remove thiophene and water) or acetonitrile resulted in the formation of the ehtnination product 102 as the only primary photoproduct observed by G C or I H NMR analysis of the reaction mixture. Prolonged irradiation results in a complex mixture of products with acetophenone being identified by G C (comparison to an authentic sample of this compound). The photoproduct l-phenyl-5-fert-butyl-6-hepten-l-one (102) was a colourless hquid. For this thesis, the general procedure for solution phase photolysis at > 290 nm was followed with compound 56 (25 mg, 0.10 mmol) in 4 mL of benzene. After 2 hours of irradiation, the solvent was removed in vacuo and analysis of the crude reaction mixture by infrared spectrometry confirmed the absence of alcoholic products. The general procedure for solid phase photolysis at > 290 nm and > 200 nm was followed with compound 56 (10 mg, 0.04 mmol). Ketone 56 was found to be photochemically unreactive in the solid state. No further work was done on this ketone. The following are the spectral data taken from reference 5. 273 Experimental/Chapter 8 l-phenyl-5-(l,l-dimethylethyl)-6-hepten-l-one (102) A H NMR (CCI4, 90 MHz): lit.5 8 7.9 (2 H, m, Ar-//), 7.4 (3H, m, Ar-H), 5.9-4.8 (3H, m), 2.82 (2H, t), 2.1 (IH, m), 1.4 (4H, m), 0.85 (9H, s, tart-butyl). LRMS: (EI) m/e (relative intensity): Ut.5, 242 (M +), 188, 133, 120, 105 (base peak), 77. IR,cm- 1 : 1680 (C=0). lit.5 8.3. Photolysis of Compound 57 The general procedure for solution phase photolysis at > 290 nm was followed with compound 57 (108 mg, 0.41 mmol) in 10 mL of benzene. During the 2 hours of photolysis, the solution was observed to change from colourless to yellow and then finally to yellow-orange. After the photolysis time period (24.2% conversion), the solvent was removed in vacuo, and the photoproduct mixture was subjected to silica gel chromatography using 5% diethyl ether in hexanes (v/v) as eluent. Photoproduct 103, l-(4-fluorophenyl)-5-tart-butyl-6-hepten-l-one, was isolated as a low-melting sohd (23 mg, 88.0% yield). Prolonged irradiation of a solution of ketone 57 in benzene resulted in a complex mixture of products and the decrease of the primary photoproduct 103. The compound 4-fluoroacetophenone was an observed photoproduct in this case. This determination was 274 Experimental/Chapter 8 accomplished by comparison of the retention times in GC (DB 17) to that of an authentic sample of 4-fluoroacetophenone (Aldrich). The general procedure for solid phase photolysis at > 290 nm was followed with compound 57 (10 mg, 0.04 mmol). Ketone 57 was found to be photochemically unreactive. Moreover, when photolysis at > 200 nm was performed, ketone 57 was still found to be unreactive (as determined by GC and TLC). l-(4-fluorophenyl)-5-(l ,l-dimethylethyl)-6-hepten-l-one (103) M.P.: 31-34°C. Anal. Calcd. for C17H23OF: C, 77.82; H, 8.84; O, 6.10; F, 7.24. Found: C, 77.91; H, 9.00. Table 8.1: *H nmr Data (400 MHz, CDCI3) for Photoproduct 103. 9 / 8 Assignment *H nmr (400 MHz) COSY Correlations13 H-x a 8 ppm (mult., J (Hz)) (400 MHz) H-2 2.97-2.80 (2H, m) H-3' H-3 part of the m (2H) at 1.60-1.45 (IH) H-3' 1.83-1.70 (lH,m) H-4 H-4 1.25-1.10 (lH,m) H-3', H-5 H-41 part of the m (2H) at 1.60-1.45 (IH) H-5 1.70-1.60 (IH, m) H-4, H-6 H-6 5.60-5.49 (IH, m) H-5, H-7 H-7 5.08-4.88 (2H, m) H-6 H-9 0.88 (9H, s) H - l l 7.98-7.92 (2H, m) H-12 H-12 7.15-7.06 (2H,m) H - l l a- H indicates the hydrogen of a pair which is more downfield (H-3' is more downfield than H-3). b- Only those COSY correlations that could be unambiguously assigned are recorded. 275 Experimental/Chapter 8 1 3 C NMR (C 6 D 6 , 50 MHz): 5 23.20 (C4, +ve), 27.82 (C9, -ve), 28.60 (C3, +ve), 32.60 (C8, +ve), 38.36 (C2, +ve), 55.40 (C5, -ve), 115.25 and 115.69 (C12, 2JC-F = 22 Hz, -ve), 116.42 (C7, +ve), 130.66 and 130.84 (Cl l , 3Jc_F = 9 Hz), 134.07 and 134.00 (CIO, 4 J C . F = 4 Hz, +ve), 140.25 (C6, -ve), 168.50 and 163.50 (C13, ijc.p = 252 Hz, +ve), 198.88 (CI, +ve). LRMS: (EI) m/e (relative intensity), 263 (0.4), 262 (1.8, M+), 247 (2.1), 229 (1.5), 207 (7.6), 206 (49.3), 205 (7.2), 191 (3.1), 177 (8.9), 165 (4.9), 152 (6.2), 151 (54.4), 139 (10.7), 138 (100.0), 123 (85.7), 109 (8.9), 95 (28.1), 75 (6.1), 67 (11.5), 58 (15.7), 57 (64.5), 56 (2.4), 41 (30.6), 32 (7.1). HRMS: Calculated mass for C 1 7 H 2 30F: 262.1733. Found: 262.1726. IR, cm"1: 3080, 2970, 2912, 2870, 1682, 1597, 1504, 1477, 1459, 1407, 1364, 1345, 1318, 1291, 1269, 1233, 1197, 1155, 1095, 1008, 998, 985, 917, 851, 819, 745, 601, 568. UV: hexane, 241 (15,600), 268 (1,285), 273 (1,040). 8.4. Photolysis of Compound 58 The general procedure for solution phase photolysis at > 290 nm was followed with compound 58 (145 mg, 0.41 mmol) in 10 mL of benzene. After 3 hours of irradiation (98.4% conversion), the photoproduct mixture was subjected to silica gel chromatography using 5% diethyl ether in hexanes (v/v) as eluent. A single photoproduct (138 mg, 96.7% yield) was isolated, which was identified as the same c/s-cyclobutanol product, 104 (colourless hquid), found by Lewis et al.5 276 Experimental/Chapter 8 The general procedure for sohd phase photolysis at > 290 nm was followed with compound 58 (65 mg, 0.25 mmol). After 2 hours of irradiation (83.4% conversion) the sample was a colourless liquid. Compound 104 (52 mg, 95.9% yield) was isolated as the sole photoproduct from the mixture. Very limited spectroscopic details were reported in the literature for photoproduct 104, and thus we set out to identify unambiguously the stereochemistry of this compound in depth. The following are the reported spectroscopic details of the structure from reference 5. (IS*, 4R*, 5S*, 6S*)-4-(l,l-dimethylethyI)-l-methyl-6-phenylbicyclo[3.1.1]-heptan-6-oI(104) * H NMR (CCI4, 90 MHz): 8 7.2 (5 H, m, Ai-H), 2.6 (IH, m), 1.15 (3H, s), 0.65 (9H, s, tart-butyl). LRMS: (EI) m/e, 258 (M +), 256, 242, 145, 143, 129, 91 (base peak), 81, 77 IR, cm"1: 3610. The foUowing are the additional spectroscopic values for photoproduct 104 determined for this thesis. 277 Experimental/Chapter Table 8.2: *H nmr Data (400 and 500 MHz, C 6 D 6 ) for Photoproduct 104. 13 Assignment H-x a lH nmr (500 MHz) 8 ppm (mult., J (Hz)) COSY Correlations15 (400 MHz) NOE Correlations0 (400 MHz) H-3 part of the m (2H) at 2.91-2.88 (IH) H-7 H-4 1.71-1.66 (m, IH) H-5, H-5' str. H-7, H-10 med. H-3 and/or H-7', H-6 (neg), H-12 w. H-13 H-5 and H-51 1.49-1.35 (m, 2H) H-4, H-6, H-6' H-6 1.90-1.82 (m, IH) H-5, H-5', H-6' str. H-12, H-13, H-6 H-6' 2.16-2.11 (m, IH) H-5, H-5', H-6 str. H-12, H-6 H-7 1.03-1.01 (d,J = 6.8Hz, IH) H-7'and/or H-3 H-7' part of the m (2H) at 2.91-2.88 (IH) H-7 H-8 1.11 (s, 3H) str. H-12, H-7' w. H-6, H-6' H-10 0.66 (9H) str. H-12, H-3, H-4, H-5, H-51 H-12 7.35-7.32 (m, 2H) H-13 str. H-13, H-6' H-13 part of the m (3H) at 7.11-7.01 (2H) H-12, H-14 H-14 part of the m (3H) at 7.11-7.01 (IH) H-13 OH 1.30 (br. s, IH) a- H indicates the hydrogen of a pair which is more downfield (H-G is more downfield than H-6). b- Only those COSY correlations that could be unambiguously assigned are recorded, c- Only those NOE data that could be unambiguously assigned are recorded (str. = strong, med. = medium, and w. = weak)(neg. = negative). 278 Experimental/Chapter 8 Table 8.3: *H nmr (500 MHz) and 1 3 C nmr (125.8 MHz) Data for Photoproduct 104. E N T R Y C-x 1 3 C nmr spectrum (125.8 MHz) 8 ppm, A P T 8 H M Q C b ' c ' d X H nmr correlations (500 MHz) 8 ppm (assignment) i H - ^ C H M B C b ' c ' d Long-range Correlations H-x a 1 47.25 (+ve) H-8 (2 bonds) b 2 80.98 (+ve) H-12 (3 bonds) H-4 (3 bond) H-6 (3 bond) H-8 (3 bonds) c 3 47.63 (-ve) part of the m (2H) at 2.91-2.88 (H-3) H-5 & 5' (3 bonds) H-8 (4 bonds) d 4 54.65 (-ve) 1.71-1.66 (H-4, IH) H-10 (3 bonds) e 5 20.57 (+ve) 1.49-1.35 (H-5 and H-5', 2H) H-4 (2 bond) H-10 (4 bonds) f 6 37.27 (+ve) 1.90-1.82 (H-6, IH) and 2.16-2.11 (H-61, IH) H-8 (3 bonds) g 7 46.74 (+ve) 1.03-1.01 (H-7, IH) and part of the m (2H) at 2.91-2.88 (H-7') H-4 (3 bonds) H-8 (3 bonds) h 8 19.91 (-ve) 1.11 (H-8, 3H) i 9 32.74 (+ve) H-10 (2 bonds) j 10 28.80 (-ve) 0.66 (H-10, 9H) H-4 (3 bonds) k 11 146.30 (+ve) H-13 (3 bonds) 1 12 127.32 (-ve) 7.35-7.32 (H-12, 2H) m 13 127.86 (-ve) part of the m (3H) at 7.11-7.01 (H-13, 2H) n 14 128.34 (-ve) part of the m (3H) at 7.11-7.01 (H-14, IH) a- The results of the APT experiment are given in parentheses (-ve for CH and CH3 carbon signals). b- The table reads from left to right. The assignment and the chemical shifts of the ^ C nmr spectrum are listed in the first and second columns, respectively. The third column shows the *H nmr signal(s) which correlate(s) with the carbon of the first two columns, as obtained from the HMQC experiment (1 bond correlation). The last column lists the hydrogen(s) which correlate(s) with the ^ C nmr signal of the first two columns as obtained from HMBC experiments(2,3 and 4 bond correlation(s)) c- Only those HMQC and HMBC data that could be unambiguously assigned are recorded d- H indicates the hydrogen of a pair which is more downfield (H-6 is more downfield than H-6) 279 Experimental/Chapter 8 8.5. Photolysis of Compound 66 major minor The general procedure for solution phase photolysis at > 290 nm was followed with compound 66 (208 mg, 0.75 mmol) in 20 mL of benzene. During the 3 hours of photolysis, the solution was observed to change from colourless to light red. GC analysis on the crude photolysis solution showed the complete consumption of ketone 66 and the presence of two photoproducts in a 94:6 ratio. After removal of the solvent in vacuo, the photoproduct mixture was subjected to radial chromatography using 3% diethyl ether in hexanes (v/v) as eluent. Unfortunately, only very small amounts of the minor photoproduct 116 could be isolated in a pure form from the major photoproduct 105. After 3 CHROMATOTRON separations, 152 mg (73.1%) of pure major photoproduct 105, 46 mg (22.1%) of a mixture of 105/116 and 7 mg (3.4%) of pure minor photoproduct 116 were obtained. Both photoproducts 105 and 116 were clear, colourless oils. The photoproduct distribution (ratio) was found to be unaffected by changes in solvent. 280 Experimental/Chapter 8 The general procedure for sohd phase photolysis at > 290 nm was followed with compound 66 (72 mg, 0.26 mmol). Sohd state photolysis for 3 h (100 % conversion) of ketone 66 was found to lead to the formation of a single photoproduct, which was determined by gas chromatography and A H NMR to be cyclobutanol 105. Exclusive formation of cyclobutanol 105 was observed at all photolysis conversions in the sohd state. Separation of ketone 66 from cyclobutanol 105 was accomplished with silica gel chromatography using 5% diethyl ether in hexanes (v/v) as eluent. Major Photoproduct (IS*, 4R*, 5S*, 6S*)-4-(l,l-dimethylethyl)-l-methyl-6-(4-fluorophenyl)bicyclo [3.1.1]-heptan-6-ol (105) Anal. Calcd. for Ci 8 H 2 50F: C, 78.22; H, 9.12; O, 5.79; F, 6.87. Found: C, 78.48; H, 9.18. LRMS: (EI) m/e, 277 (1.4), 276 (6.6, M + ) , 275 (2.4), 274 (2.2), 258 (4.3) , 243 (1.8), 219 (47.1), 201 (9.8), 187 (6.4), 178 (12.1), 177 (10.8), 165 (46.3), 163 (20.1), 161 (36.4), 153 (15.8), 152 (38.6), 151 (13.7), 147 (21.3), 138 (12.9), 137 (13.6), 123 (100.0), 109 (31.3), 97 (41.3), 95 (43.1), 84 (55.1), 83 (21.4), 82 (10.5), 81 (35.0), 69 (14.7), 57 (91.0), 55 (16.3), 43 (22.1), 41 (32.2). HRMS: Calculated mass for C 1 8 H 2 5 O F : 276.1889. Found. 276.1893. IR, cm"1: (neat film NaCl plates) 3424 (OH), 2951, 2866, 1605, 1510, 1472, 1365, 1229, 1157, 1052, 1012, 909, 839, 814. 281 Experimental/Chapter 8 Table 8.4: A H nmr Data (400 and 500 MHz, CgDg) for the Major Photoproduct 105. Assignment A H nmr (500 MHz) COSY Correlations0 NOE Correlations0 H-x a 8 ppm (mult., J (Hz)) (400 MHz) (400 MHz) H-3 part of the broad m (2H) at 2.85-2.79 (IH) H-4 1.67-1.61 (m, IH) H-5, H-5' H-5 and H-5' 1.39-1.23 (m, 2H) H-4, H-6, H-6" str.H-12 med. H-6' w. H-6, H-13 H-6 1.85-1.78 (m, IH) H-5, H-5', H-6' H-6' 2.02-1.95 (m, IH) H-5, H-5', H-6 H-7 1.00-0.97 (d, J = 7.8Hz, IH) H-3 and/or H-71 H-7' part of the broad m (2H) at 2.85-2.79 (IH) H-8 1.03 (s, 3H) H-10 0.63 (s, 9H) H-12 7.16-7.11 (m,2H) H-13 str. H-13, H-6' w. H-3 and/or H-7', H-6 (neg), H-5, H-5' H-13 6.76-6.71 (m, 2H) H-12 OH 0.88 or 1.22 (s, IH) | a- H indicates the hydrogen of a pair which is more downfield (H-6' is more downfield than H-6). b- Only those COSY correlations that could be unambiguously assigned are recorded, c- Only those NOE data that could be unambiguously assigned are recorded (str. = strong, med. = medium, and w. = weak)(neg. = negative). 282 Experimental/Chapter 8 Table 8.5: *H nmr (500 MHz) and 1 3 C nmr (125.8 MHz) Data for the Major Photoproduct 105. 13 F ^ ^ - 1 2 E N T R Y C-x 1 3 C nmr spectrum (125.8 MHz) 8 ppm, A P T 3 H M Q C b ' c ' d *H nmr correlations (500 MHz) 8 ppm (assignment) 1 H - 1 3 C H M B C b ' c ' d Long-range Correlations H-x a 1 47.13 (+ve) H-3 (3 bonds) and/or H-7' (2 bonds) H-5 and/or H-5' (3 bonds) H-6 (2 bonds) H-6' (2 bonds) H-8 (2 bonds) b 2 80.39 (+ve) H-3 (2 bonds) and/or H-7' (3 bonds) H-4 (3 bonds) H-6 (3 bonds) H-7 (3 bonds) H-8 (3 bonds) H-12 (3 bonds) c 3 47.49 (-ve) part of the m (2H) at 2.85-2.79 (H-3) H-4 (2 bonds) H-5 &/or H-51 (3 bonds) H-8 (4 bonds) d 4 54.48 (-ve) 1.67-1.61 0^ -4, IH) H-3 (2 bonds) and/or H-7' (3 bonds) H-5 and/or H-5' (2 bonds) H-6' (3 bonds) H-10 (3 bonds) e 5 20.41 (+ve) 1.39-1.23 (H-5 and H-5', 2H) H-3 (3 bonds) and/or H-7' (4 bonds) H-4 (2 bond) H-10 (4 bonds) f 6 37.09 (+ve) 1.85-1.78 (H-6, lH)and 2.02-1.95 (H-6', IH) H-3 (3 bonds) and/or H-7'(4 bonds) H-5 and/or H-5' (2 bonds) H-8 (3 bonds) 283 Experimental/Chapter 8 Table 8.5. Continued E N T R Y C-x 1 3 C nmr spectrum (125.8 MHz) 8 ppm, A P T 3 H M Q C b ' c ' d I H nmr correlations (500 MHz) 8 ppm (assignment) A H - 1 3 C H M B C b ' c ' d Long-range Correlations H-x g 7 46.66 (+ve) 1.00-0.97 (H-7, IH) and part of the m (2H) at 2.85-2.79 (H-71) H-4 (3 bonds) H-8 (3 bonds) h 8 19.73 (-ve) 1.03 (H-8, 3H) i 9 32.70 (+ve) H-3 (3 bonds) and/or H-7' (4 bonds) H-4 (2 bonds) H-10 (2 bonds) j 10 28.72 (-ve) 0.63 (H-10, 9H) H-4 (3 bonds) k 11 142.09 & 142.06 ( 4 J c _ F = 3.8Hz)(+ve) H-13 (3 bonds) ! 12 129.63 & 129.57 ( 3 J c . F = 7.6Hz) (-ve) 7.16-7.11 (H-12, 2H) m 13 114.58 & 114.41 ( 2 J C -F = 21.4Hz)(-ve) 6.76-6.71 (H-13,2H) n 14 163.17-161.21 ( l j C - F = 2 4 6 5 Hz) (+ve) H-12 (3 bonds) H-13 (2 bonds) a- The results of the APT experiment are given in parentheses (-ve for CH and CH3 carbon signals). b- The table reads from left to right. The assignment and the chemical shifts of the l 3 C nmr spectrum are listed in the first and second columns, respectively. The third column shows the X H nmr signal(s) which correlate(s) with the carbon of the first two columns, as obtained from the HMQC experiment (1 bond correlation). The last column lists the hydrogen(s) which correlate(s) with the l 3 C nmr signal of the first two columns as obtained from HMBC experiments(2,3 and 4 bond correlation(s)) c- Only those HMQC and HMBC data that could be unambiguously assigned are recorded d- H' indicates the hydrogen of a pair which is more downfield (H-6' is more downfield than H-6). 284 Experimental/Chapter 8 Minor Photoproduct (IS*, 4R*, 5S*, 6R*)-4-(14-dimethylethyl)-l-methyl-6-(4-fluorophenyl)bicyclo [3.1.1]-heptan-6-ol (116) Anal. Calcd. for C 1 8 H 2 50F: C, 78.22; H, 9.12; O, 5.79; F, 6.87. Found: C, 78.33; FL 8.99. LRMS: (EI) m/e, 277 (1.6), 276 (7.9, M+), 261 (4.4), 259 (1.3), 258 (6.1), 243 (2.9), 233 (0.7), 221 (1.3), 220 (6.3), 219 (36.8), 205 (7.9), 202 (4.9), 201 (14.5), 191 (6.3), 187 (12.7), 178 (7.8), 177 (7.3), 166 (19.3), 165 (41.0), 163 (13.0), 161 (34.4), 154 (9.5), 153 (11.0), 152 (25.0), 151 (9.1), 148 (10.3), 147 (19.2), 139 (13.4), 138 (9.9), 137 (14.8), 133 (6.8), 124 (7.3), 123 (77.0), 122 (12.1), 109 (39.3), 97 (32.2), 96 (10.6), 95 (27.1), 94 (13.2), 83 (22.5), 81 (27.8), 71 (14.7), 69 (17.3), 57 (100.0), 55 (22.6), 43 (60.6), 41 (30.8). HRMS: Calculated mass for C 1 8 H 2 50F: 276.1889. Found: 276.1892. IR, cm"1: (KBr pellet) 3467 (OH), 2955, 2866, 1636, 1510, 1472, 1457, 1397, 1364, 1229, 1157, 1052, 1012, 987, 949, 909, 840, 816, 733, 602, 546, 474. 285 Experimental/Chapter 8 Table 8.6a: *H nmr Data (400 and 500 MHz, CgDg) for the Minor Photoproduct 116. Protons on C5 and C6 assigned as according to Table 8.7a. Assignment H-x a ! H nmr (500 MHz) 5 ppm (mult., J (Hz)) COSY Correlations13 (400 MHz) NOE Correlations0 (400 MHz) H-3 partofthem(2H)at 1.10-0.99 (IH) H-7, H-7' H-4 partofthem(2H)at 1.28-1.20 (m, IH) H-5' H-5 partofthem(2H)at 1.10-0.99 (IH) H-5', H-6' H-5' 1.59-1.52 (m, IH) H-4 and/or H-6, H-5, H-6' str. H-3 and/or H-5, H-4 and/or H-6, H-8, H-10 H-6 part of the m (2H) at 1.28-1.20 (m, IH) H-6' H-6" 1.76-1.65 (m, IH) H-5, H-5', H-6 str. H-4 and/or H-6 H-7 0.15-0.19 (t, J= 7 Hz, IH) H-3, H-7' str. OH and/or H-7' w. H-4 and/or H-6 H-7' partofthem(2H)at 0.89-0.80 (IH) H-3, H-7 str. H-7' w. H-4 and/or H-6 H-8 1.08 (s, 3H) H-10 0.95 (s, 9H) H-12 7.17-7.12 (m, 2H) H-13 str. H-13 med. H-7' and/or OH H-13 6.80-6.74 (m, 2H) H-12 str. H-12 OH partofthem(2H)at 0.89-0.80 (IH) a- H indicates the hydrogen of a pair which is more downfield (H-6' is more downfield than H-6). For completeness, C5 and C6 hydrogens are assigned, b- Only those COSY correlations that could be unambiguously assigned are recorded, c- Only those NOE data that could be unambiguously assigned are recorded (str. = strong, med. = medium, and w. = weak)(neg. = negative). 286 Experimental/Chapter 8 Table 8.6b: *H nmr Data (400 and 500 MHz, C6D 6) for the Minor Photoproduct 116. Protons on C5 and C6 assigned as according to Table 8.7b. Assignment H-x a *H nmr (500 MHz) 8 ppm (mult., J (Hz)) COSY Correlations0 (400 MHz) NOE Correlations0 (400 MHz) H-3 partofthem(2H)at 1.10-0.99 (IH) H-7, H-7' H-4 partofthem(2H)at 1.28-1.20 (m, IH) H-6' H-5 partofthem(2H)at 1.28-1.20 (m, IH) H-5' H-5' 1.76-1.65 (m, IH) H-6, H-61, H-5 str. H-4 and/or H-5 H-6 part of the m (2H) at 1.10-0.99 (IH) H-6', H-5' H-6' 1.59-1.52 (m, IH) H-4 and/or H-5, H-6, H-5' str. H-3 and/or H-6, H-4 and/or H-5, H-8, H-10 H-7 0.15-0.19 (t, J = 7 Hz, IH) H-3, H-7' str. OH and/or H-7' w. H-4 and/or H-5 H-7' partofthem(2H)at 0.89-0.80 (IH) H-3, H-7 str. H-7' w. H-4 and/or H-5 H-8 1.08 (s, 3H) H-10 0.95 (s, 9H) H-12 7.17-7.12 (m,2H) H-13 str. H-13 med. H-7' and/or OH H-13 6.80-6.74 (m, 2H) H-12 str. H-12 OH partofthem(2H)at 0.89-0.80 (IH) a- H" indicates the hydrogen of a pair which is more downfield (H-6' is more downfield than H-6). For completeness, C5 and C6 hydrogens are assigned, b- Only those COSY correlations that could be unambiguously assigned are recorded, c- Only those NOE data that could be unambiguously assigned are recorded (str. = strong, med. = medium, and w. = weak)(neg. = negative). 287 Experimental/Chapter 8 Table 8.7a: X H nmr (500 MHz) and 1 3 C nmr (125.8 MHz) Data for the Minor Photoproduct 116. C5 assigned as 8 = 35.04 ppm. 13 -F E N T R Y C-x 1 3 C nmr spectrum (125.8 MHz) 8 ppm, A P T 3 H M Q C b ' c ' d 3 H nmr correlations (500 MHz) 8 ppm (assignment) 1 H - 1 3 C H M B C b ' c > d Long-range Correlations H-x a 1 35.20 (+ve) H-4 (4 bonds) and/or H-6 (2 bonds) H-6' (2 bonds) H-8 ( 2 bonds) b 2 68.65 (+ve) H-5' (4 bonds) H-6' (3 bonds) H-7 (3 bonds) c 3 23.52 (-ve) part of the m (2H) at 1.10-0.99 03-3) H-4 (2 bonds) and/or H-6 (4 bonds) H-7 (2 bonds) d 4 46.20 (-ve) part of the m (2H) at 1.28-1.20 (H-4, IH) H-5' (2 bonds) H-6' (3 bonds) H-7 (3 bonds) H-10 (3 bonds) e 5 35.04 (+ve) part of the m (2H) at 1.10-0.99 (H-5, IH) and 1.59-1.52 (H-5', IH) H-4 (2 bonds) and/or H-6 (2 bonds) H-6' (2 bonds) H-8 (4 bonds) f 6 19.88 (+ve) part of the m (2H) at 1.28-1.20 (H-6, IH) and 1.76-1.65 (H-6', IH) H-3 (4 bonds) and/or H-5 (2 bonds) g 7 18.86 (+ve) 0.19-0.15 (H-7, IH) and part ofthem(2H) at 0.89-0.80 (H-71, IH) H-4 (3 bonds) and/or H-6 (3 bonds) h 8 28.68 (-ve) 1.08 (H-8, 3H) i 9 33.85 (+ve) H-4 (2 bonds) and/or H-6 (4 bonds) H-10 (2 bonds) j 10 27.37 (-ve) 0.95 (H-10, 9H) 288 Experimental/Chapter 8 Table 8.7a. Continued « N T R Y C-x l 3 C nmr spectrum (125.8 MHz) 5 ppm, A P T 3 H M Q C b ' c ' d A H nmr correlations (500 MHz) 8 ppm (assignment) 1 H - 1 3 C H M B C D ' c ' d Long-range Correlations H-x k 11 140.18 & 140.16 ( 4 j C-F = 2 5 Hz) ( + v e ) H-13 (3 bonds) 1 12 133.73 & 133.66 ( 3 j C-F = 8 8 H 2) (-ve) 7.17-7.12 (H-12, 2H) m 13 114.88 & 114.71 ( 2 J c _ F = 21.4Hz)(-ve) 6.80-6.74 (H-13, 2H) n 14 163.08-161.14 ( l j C - F = 244.0Hz) (+ve) H-12 (3 bonds) H-13 (2 bonds) a- The results of the APT experiment are given in parentheses (-ve for CH and CH3 carbon signals). For completeness, C5 and C6 carbons are assigned 35.04 and 19.88 ppm respectively; however these assignments can be reversed which would lead to a reversal of C5 and C6 hydrogen assignments. b- The table reads from left to right. The assignment and the chemical shifts of the l 3 C nmr spectrum are listed in the first and second columns, respectively. The third column shows the *H nmr signal(s) which correlate(s) with the carbon of the first two columns, as obtained from the HMQC experiment (1 bond correlation). The last column lists the hydrogen(s) which correlate(s) with the l 3 C nmr signal of the first two columns as obtained from HMBC experiments(2,3 and 4 bond correlation(s)) c- Only those HMQC and HMBC data that could be unambiguously assigned are recorded d- H indicates the hydrogen of a pair which is more downfield (H-6' is more downfield than H-6). 2 8 9 Experimental/Chapter 8 Table 8.7b: 3 H nmr (500 MHz) and 1 3 C nmr (125.8 MHz) Data for the Minor Photoproduct 116. C5 assigned as S = 19.88 ppm. 13 -F ;2 £ N T R Y C-x 1 3 C nmr spectrum (125.8 MHz) 8 ppm, A P T 3 H M Q C b » M *H nmr correlations (500 MHz) 8 ppm (assignment) ! H - 1 3 C H M B C b ' c ' d Long-range Correlations H-x a 1 35.20 (+ve) H-4 (4 bonds) and/or H-5 (2 bonds) H-5' (2 bonds) H-8 ( 2 bonds) b 2 68.65 (+ve) H-6' (4 bonds) H-5' (3 bonds) H-7 (3 bonds) c 3 23.52 (-ve) part of the m (2H) at 1.10-0.99 (H-3) H-4 (2 bonds) and/or H-5 (4 bonds) H-7 (2 bonds) d 4 46.20 (-ve) part of the m (2H) at 1.28-1.20 (H-4, IH) H-6' (2 bonds) H-5' (3 bonds) H-7 (3 bonds) H-10 (3 bonds) e 5 19.88 (+ve) part of the m (2H) at 1.28-1.20 (H-5, IH) and 1.76-1.65 (H-51, IH) H-3 (4 bonds) and/or H-6 (2 bonds) f 6 35.04 (+ve) part of the m (2H) at 1.10-0.99 (H-6, IH) and 1.59-1.52 (H-6\ IH) H-4 (2 bonds) and/or H-5 (2 bonds) H-5' (2 bonds) H-8 ( 4 bonds) g 7 18.86 (+ve) 0.19-0.15 (H-7, IH) and part ofthem(2H) at 0.89-0.80 (H-7', IH) H-4 (3 bonds) and/or H-5 (3 bonds) h 8 28.68 (-ve) 1.08 (H-8, 3H) i 9 33.85 (+ve) H-4 (2 bonds) and/or H-5 (4 bonds) H-10 (2 bonds) j 10 27.37 (-ve) 0.95 (H-10, 9H) 290 Experimental/Chapter 8 Table 8.7b. Continued E N T R Y C-x 1 3 C nmr spectrum (125.8 MHz) 8 ppm, A P T 3 H M Q C b ' c » d X H nmr correlations (500 MHz) 8 ppm (assignment) 1 H - 1 3 C H M B C b ' c ' d Long-range Correlations H-x k 11 140.18 & 140.16 ( 4 j C-F = 2 5 Hz) (+ve) H-13 (3 bonds) 1 12 133.73 & 133.66 ( 3 J c _ F = 8.8Hz)(-ve) 7.17-7.12 (H-12, 2H) m 13 114.88 & 114.71 ( 2 J c . F = 21.4Hz)(-ve) 6.80-6.74 (H-13, 2H) n 14 163.08-161.14 ( l j C - F = 244.0Hz) (+ve) H-12 (3 bonds) H-13 (2 bonds) a- The results of the APT experiment are given in parentheses (-ve for CH and CH3 carbon signals). For completeness, C5 and C6 carbons are assigned 35.04 and 19.88 ppm respectively; however these assignments can be reversed which would lead to a reversal of C5 and C6 hydrogen assignments. b- The table reads from left to right. The assignment and the chemical shifts of the 1 3 C nmr spectrum are listed in the first and second columns, respectively. The third column shows the *H nmr signal(s) which correlate(s) with the carbon of the first two columns, as obtained from the HMQC experiment (1 bond correlation). The last column lists the hydrogen(s) which correlate(s) with the 1 3 C nmr signal of the first two columns as obtained from HMBC experiments(2,3 and 4 bond correlation(s)) c- Only those HMQC and HMBC data that could be unambiguously assigned are recorded d- H indicates the hydrogen of a pair which is more downfield (H-6' is more downfield than H-6). 8.6. Photolysis of Compound 67 The general procedure for solution phase photolysis at > 290 nm was followed with compound 67 (69 mg, 0.25 mmol) in 10 mL of benzene. After 2 hours of irradiation (85.2% conversion), the solvent was removed in vacuo, and the crude mixture was subjected to silica gel chromatography using 5% diethyl ether in hexanes (v/v) as eluent. 291 Experimental/Chapter 8 White powdered photoproduct 106 (54.1 mg, 92.0% yield) was isolated. Recrystallization from various solvents gave only a powdered solid. The general procedure for solid phase photolysis at > 290 nm was followed with compound 67 (58 mg, 0.21 mmol). Solid state photolysis for 4 h (100 % conversion) of ketone 67 was found to lead to the formation of a single photoproduct, which was determined by GC and A H NMR to be cyclobutanol 106. (IS*, 4R*, 5S*, 6S*)-4-(l,l-dimethylethyl)-l-methyl-6-(4-methylphenyl)bicyclo [3.1.1]-heptan-6-ol (106) M.P.: 59-61°C. Anal. Calcd. for Ci 9 H 2 80: C, 83.77; FL 10.36; O, 5.87. Found: C, 83.84; H, 10.25. LRMS: (EI) m/e, 273 (0.4), 272 (M+ 2.4), 254 (30.1), 239 (7.2), 226 (1.4), 215 (6.5), 198 (12.9), 197 (58.4), 184 (18.1), 183 (67.3), 182 (12.1), 181 (8.8), 171 (13.6), 170 (42.5), 169 (29.5), 167 (10.9), 165 (11.7), 161 (12.3), 157 (25.0), 156 (18.1), 155 (37.1), 153 (11.1), 152 (11.0), 143 (24.5), 142 (12.5), 141 (18.8), 129 (15.1), 128 (18.5), 121 (11.9), 119 (79.1), 117 (9.3), 115 (17.2), 106 (10.3), 105 (100.0), 91 (33.9), 83 (10.3), 81 (19.5), 79 (13.4), 77 (13.5), 69 (12.3), 67 (11.5), 57 (43.7), 55 (15.0). HRMS: Calculated mass for C 1 9 H 2 8 0 : 272.2140. Found: 272.2141. IR, cm"1: (KBr pellet) 3432, 3600-3200, 2948, 2864, 1514, 1470, 1396, 1365, 1327, 1304, 1217, 1052, 1011, 984, 948, 908, 820, 760. 292 Experimental/Chapter 8 Table 8.8: *H nmr Data (400 and 500 MHz, CgD 6) for Photoproduct 106. 10- . Assignment H-xa lH nmr (500 MHz) 8 ppm (mult., J (Hz)) COSY Correlations0 (400 MHz) NOE Correlations0 (400 MHz) H-3 partofthem(2H)at 2.93-2.88 (IH) H-7 H-4 1.73-1.67 (m, IH) H-5, H-5' str. H-10, H-7 med. H-3 and/or H-7', H-6', H-6 (neg), H-12, H-13 H-5 1.46-1.38 (m, IH) H-4, H-6, H-6' med. H-6', H-12, OH (neg) w. H-3 and/or H-7', H-6, H-13, H-5' 1.55-1.46 (m, IH) H-4, H-6, H-6' med. H-6', H-12 w. H-3 and/or H-7', H-6, H-13, H-6 1.92-1.84 (m, IH) H-5, H-5', H-6' str. H-6' med. H-7 w. H-5, H-5', H-12, H-13 H-6' 2.20-2.13 (m, IH) H-5, H-5', H-6 w-coupling to H-7' str. H-6, H-12 w. H-5, H-5', H-13 H-7 1.06-1.01 (m, IH) H-7'and/or H-3 str. H-3 and/or H-7', H-4, med. H-6, OH (neg) w. H-8, H-12, H-13 H-7' part of the m (2H) at 2.93-2.88 H-7 H-8 1.14 (s, 3H) H-10 0.68 (s, 9H) H-12 7.30-7.26 (m, 2H) H-13 str. H-13, H-6 med. H-8, H-10 w. H-4 (neg), H-5, H-5', OH H-13 6.95-6.91 (d,J= 8 Hz, 2H) H-12 H-15 2.10 (s, 3H) OH 1.36 (br. s, IH) a- H indicates the hydrogen of a pair which is more downfield (H-& is more downfield than H-6). b- Only those COSY correlations that could be unambiguously assigned are recorded, c- Only those NOE data that could be unambiguously assigned are recorded (str. = strong, med. = medium, and w. = weak)(neg. = negative). 293 Experimental/Chapter 8 Table 8.9: *H nmr (400 and 500 MHz) and 1 3 C nmr (125.8 MHz) Data for Photoproduct 106. E N T R Y C-x 1 3 C nmr spectrum (125.8 MHz) 8 ppm, A P T 3 H M Q C b > c ' d X H nmr correlations (500 MHz) 8 ppm (assignment) 1 H - 1 3 C H M B C b ' c ' d Long-range Correlations H-x a 1 47.29 (+) H-3 (3 bonds) and/or H-7' (2 bonds) H-5 (3 bonds) H-5' (3 bonds) H-8 (2 bonds) b 2 80.92 (+) H-4 ( 3 bonds) H-6 (3 bonds) H-8 (3 bonds) H-12 (3 bonds) 1 c 3 47.62 (-) part of m (2H) at 2.93-2.88 (H-3, IH) H-5 & 5' (3 bonds) H-7 (2 bonds) H-8 (4 bonds) H-10 (4 bonds) d 4 54.71 (-) 1.73-1.67 (H-4, IH) H-3 (2 bonds) and/or H-7' (3 bonds) H-6' (3 bonds) H-10 (3 bonds) e 5 20.61 (+) 1.55-1.38 (H-5 & H-5', 2H) H-3 (3 bonds) and/or H-7' (4 bonds) H-4 (2 bonds) H-6 (2 bonds) H-6' (2 bonds) H-7 (4 bonds) H-8 (4 bonds) f 6 37.34 (+) 2.20-2.13 (H-6', IH) and 1.92-1.84 (H-6, IH) H-3 (4 bonds) and/or H-7' (3 bonds) H-8 (3 bonds) g 7 46.78 (+) part of m (2H) at 2.93-2.88 (H-7, lH)and 1.06-1.01 (H-7, IH) H-4 (3 bonds) H-6 (3 bonds) H-6' (3 bonds) H-8 (3 bonds) 294 Experimental/Chapter 8 Table 8.9. Continued E N T R Y C-x 1 3 C nmr spectrum (125.8 MHz) 8 ppm, A P T a H M Q C b , c , d A H nmr correlations (500 MHz) 8 ppm (assignment) 1 H - 1 3 C H M B C b ' c » d Long-range Correlations H-x h 8 19.94 (-) 1.14 (H-8, 3H) i 9 32.77 (+) H-4 (2 bonds) H-10 (2 bonds) j 10 28.86 (-) 0.68 (H-10, 9H) H-4 (3 bonds) k 11 143.45 (+) H-13 (3 bonds) 1 12 127.90 (-) 7.30-7.26 (H-12, 2H) H-15 (4 bonds) m 13 128.46 (-) 6.95-6.91 (H-13, 2H) H-15 (3 bonds) n 14 136.68 (+) H-12 (3 bonds) H-15 (2 bonds) 0 15 21.07 (-) 2.10 (H-15, 3H) H-13 (3 bonds) a- The results of the APT experiment are given in parentheses (-ve for CH and CH3 carbon signals). b- The table reads from left to right. The assignment and the chemical shifts of the l 3 C nmr spectrum are listed in the first and second columns, respectively. The third column shows the *H nmr signal(s) which correlate(s) with the carbon of the first two columns, as obtained from the HMQC experiment (1 bond correlation). The last column lists the hydrogen(s) which correlate(s) with the nmr signal of the first two columns as obtained from HMBC experiments(2,3 and 4 bond correlation(s)) c- Only those HMQC and HMBC data that could be unambiguously assigned are recorded d- H indicates the hydrogen of a pair which is more downfield (H-6' is more downfield than H-6). 295 Experimental/Chapter 8 8.7. Photolysis of Compound 68 major minor Photolysis of 89.7 mg (0.31 mmol) of ketone 68 in either 10 mL of acetone or benzene for 4 h led to the formation of two photoproducts in a 94:6 ratio (as determined by GC). The photoproducts were separated from unreacted ketone 68 by silica gel column chromatography using 5% diethyl ether in hexanes as the eluent to yield 10.3 mg (11.5%) of ketone 68. The mixture of photoproducts was subjected to column and radial chromatography (3% diethyl ether in hexanes as eluent), but the minor photoproduct could never be separated from the major photoproduct. Photoproduct 107 was recovered as a white powder (60.4 mg, 67.3%), while 18.5 mg (20.6%) was inseparable. Photoproduct 107 was recrystallized from diethyl ether/hexanes (5% v/v) to afford colourless prisms. The general procedure for solid phase photolysis at > 290 nm was followed with compound 68 (74 mg, 0.26 mmol). Solid state photolysis for 4 h (58 % conversion) of ketone 68 was found to lead to the formation of a single photoproduct, which was detennined by GC and A H NMR to be the same as the major photoproduct formed from the solution state photolysis (107). 296 Experimental/Chapter 8 Major Photoproduct (107) (IS*, 4R*, 5S*, 6S*)-4-(l,l-dimethylethyl)-l-methyl-6-(4-methoxyphenyl)bicyclo [3.1.1]-heptan-6-ol (107) M.P.: 73-76°C. Anal. Calcd. for C i 9 H 2 8 0 2 : C, 79.12; H, 9.78; O, 11.09. Found: C , 79.33; H , 9.85. LRMS: (EI) m/e, 289 (2.2), 288 (M + , 16.9), 287 (2.8), 271 (13.4), 270 (16.4), 257 (9.2), 232 (8.1), 231 (46.2), 213 (29.5), 199 (14.7), 186 (28.6), 177 (52.6), 175 (15.8), 173 (31.1), 171 (10.9), 164 (20.8), 150 (61.6), 137 (52.3), 136 (33.6), 135 (100.0), 121 (47.7), 115 (12.3), 109 (10.8), 107 (14.8), 105 (10.2), 95 (14.5), 92 (13.5), 91 (17.1), 81 (26.8), 79 (11.5), 77 (26.8), 69 (16.3), 57 (34.8), 55 (15.8), 43 (11.8), 41 (17.0). HRMS: Calculated mass for C 1 9 H 2 8 0 2 : 288.2089. Found: 288.2091. IR, cm"1: (KBr pellet) 3516 (OH), 2942, 2863, 1608, 1511, 1473, 1456, 1362, 1242, 1177, 1033, 1013, 985, 908, 834, 817, 792, 605, 555. 297 Experimental/Chapter 8 Table 8.10: *H nmr Data (200, 400 and 500 MHz, CgDg) for the Major Photoproduct 107. 15 Assignment H-x a *H nmr (500 MHz) 8 ppm (mult., J (Hz)) COSY Correlations15 (200 MHz) NOE Correlations0 (400 MHz) H-3 partofthem(2H)at 2.95-2.89 (IH) H-7 H-4 1.74-1.68 (m, IH) H-5, H-5' str. H-7, H-10, H-6 (neg) med. H-5, H-5' (neg) w. H-6', H-3 and/or H-7' H-5 1.47-1.39 (m, IH) H-4, H-6, H-6' med. H-6', H-10, H-12 H-5' 1.56-1.47 (m, IH) H-4, H-6, H-6' med. H-6', H-10, H-12 H-6 1.93-1.86 (m, IH) H-5, H-5', H-6' str. H-6' med. H-7, H-12 (neg) w. H-5, H-5' H-6' 2.19-2.12 (m, IH) H-5, H-5', H-6 w-coupling to H-7' str. H-6, H-12 w. H-5, H-5', H-13 (neg) H-7 1.05-1.02 (d, J= 7 Hz, IH) H-7' and/or H-3 str. H-3 and/or H-7' med. H-4, OH (neg) w.H-6 H-7' part of the m (2H) at 2.95-2.89 (IH) H-7 H-8 1.15 (s, 3H) H-10 0.69 (s, 9H) H-12 7.32-7.28 (d, J=8Hz, 2H) . H-13 str. H-13, H-6 med. H-8, H-10 w. H-4 (neg), H-5, H-5' (neg), OH H-13 6.73-6.69 (d, J=8Hz, 2H) H-12 H-15 3.32 (s, 3H) OH 1.31 (s, IH) a- H indicates the hydrogen of a pair which is more downfield (H-G is more downfield than H-6). b- Only those COSY correlations that could be unambiguously assigned are recorded, c- Only those NOE data that could be unambiguously assigned are recorded (str. = strong, med. = medium, and w. = weak)(neg. = negative). 298 Experimental/Chapter 8 Table 8.11: ! H nmr (400 and 500 MHz) and 1 3 C nmr (125.8 MHz) Data for the Major Photoproduct 107. E N T R Y C-x 1 3 C nmr spectrum (125.8 MHz) 8 ppm, APT a H M Q C b ' c ' d A H nmr correlations (500 MHz) 8 ppm (assignment) A H - 1 3 C H M B C b ' c ' d Long-range Correlations H-x a 1 47.34 (+) H-3 (3 bonds) and/or H-7' (2 bonds) H-5 and H-5' (3 bonds) H-8 (2 bonds) b 2 80.76 (+) H-8 (3 bonds) H-12 (3 bonds) c 3 47.53 (-) part of m (2H) at 2.95-2.89 (H-3, IH) H-7' (2 bonds) H-5 and H-5' (3 bonds) H-8 (4 bonds) d 4 54.68 (-) 1.74-1.68 (H-4, IH) e 5 20.55 (+) 1.56-1.39 (H-5 & H-5', 2H) H-10 (4 bonds) H-4 (2 bonds) H-6 and H-6'(2 bonds) f 6 37.39 (+) 2.19-2.12 (H-6', lH)and 1.93-1.86 (H-6, IH) H-5 and H-5'(2 bonds) H-8 (3 bonds) g 7 46.79 (+) part of m (2H) at 2.95-2.89 (H-T, IH) and 1.05-1.02 (H-7, IH) H-4 (3 bonds) H-6 and H-6' (3 bonds) H-8 (3 bonds) h 8 19.91 (-) 1.15 (H-8, 3H) i 9 32.78 (+) H-10 (2 bonds) H-4 (2 bonds) j 10 28.85 (-) 0.69 (H-10, 9H) H-4 (3 bonds) 299 Experimental/Chapter 8 E N T R Y C-x ^ 3 C nmr spectrum (125.8 MHz) 8 ppm, APT 3 H M Q C b ' c ' d *H nmr correlations (500 MHz) 8 ppm (assignment) 1 H - 1 3 C H M B C b ' c ' d Long-range Correlations H-x k 11 138.53 (+) H-13 (2 bonds) 1 12 129.04 (-) 7.32-7.28 (H-12, 2H) m 13 113.19 (-) 6.73-6.69 (H-13, 2H) n 14 159.17 (+) H-12 (3 bonds) H-15 (3 bonds) 0 15 54.67 (-) 3.32 (H-15, 3H) a- The results of the APT experiment are given in parentheses (-ve for CH and CH3 carbon signals). b- The table reads from left to right. The assignment and the chemical shifts of the liC nmr spectrum are listed in the first and second columns, respectively. The third column shows the *H nmr signal(s) which correlate(s) with the carbon of the first two columns, as obtained from the HMQC experiment (1 bond correlation). The last column lists the hydrogen(s) which correlate(s) with the * 3 C nmr signal of the first two columns as obtained from HMBC experiments(2,3 and 4 bond correlation(s)) c- Only those HMQC and HMBC data that could be unambiguously assigned are recorded d- H indicates the hydrogen of a pair which is more downfield (H-61 is more downfield than H-6). The structure was confirmed by X-ray crystallographic analysis C19H28O2 crystallized in space group P2i/c (#14), a = 11.9961 (9) A, b = 6.4196 (5) A, c = 22.163 (2) A, P = 98.130 (7)°, V = 1689.6 (2) A 3 , Z = 4, D c a l c = 1.134 g/cm3, R = 0.046, R w = 0.049. 300 Experimental/Chapter 8 8.8. Photolysis of Compound 69 C N solution or solid state hv NC • C H 3 The general procedure for solution phase photolysis at > 290 nm was followed with compound 69 (79 mg, 0.28 mmol) in 10 mL of benzene. After 4 hours of irradiation, the solvent was removed in vacuo, and the crude mixture was subjected to silica gel chromatography using 5% diethyl ether in hexanes (v/v) as eluent. White powdered photoproduct 108 (74.3 mg, 94.1%) and 4.7 mg (5.9%) of ketone 68 were isolated. Photoproduct 108 was recrystallized from acetonitrile to yield colourless prisms. The general procedure for sohd phase photolysis at > 290 nm was followed with compound 69 (63 mg, 0.22 mmol). Sohd state photolysis for 5 h (100 % conversion) of ketone 69 was found to lead to the formation of a single photoproduct, which was determined by gas chromatography and A H NMR to be the same as that from the solution state photolysis. (IS*, 4R*, 5S*, 6S*)-4-(l,l-dimethylethyl)-l-methyl-6-(4-cyanophenyl)bicyclo [3.1.1]-heptan-6-ol (1081 M.P.: 181-183°C. Anal. Calcd. for C19H25ON: C, 80.52; H, 8.89; N, 4.94; O, 5.65. Found: C, 80.46; H, 8.89; N, 4.86. LRMS: (EI) m/e, 284 (2.7), 283 (M + , 7.1), 282 (0.9), 268 (1.3), 266 (1.7), 265 (2.9), 250 (2.8), 228 (6.0), 227 (35.6), 226 (33.5), 222 (1.3), 214 (1.7), 213 (1.3), 212 (7.0), 210 (2.3), 209 (4.3), 208 (5.9), 204 (2.0), 199 (1.7), 198 (2.2), 196 (2.2), 195 (2.8), 194 95.1), 193 (1.5), 186 (5.0), 185 (24.1), 184 914.1), 173 (27.9), 172 (63.0), 171 (13.7), 170 (25.2), 169 (7.4), 168 (40.8), 154 (22.3), 153 (28.1), 145 (6.1), 144 (7.3), 131 301 Experimental/Chapter 8 (36.6), 130 (100.0), 116 (24.0), 109 (11.1), 103 (12.5), 102 (41.5), 97 (33.1), 95 (23.2), 83 (13.3), 81 (25.1), 69 (10.8), 57 (66.3), 55 (13.5), 41 (17.2). HRMS: Calculated mass for C19H25ON: 283.1936. Found:283.1936. IR, cm"1: (KBr pellet) 3482, 2968, 2950, 2906, 2863, 2227, 1605, 1475, 1456, 1393, 1361, 1057, 1016, 986, 977, 950, 910, 853, 835, 576, 551, 521, 502. Table 8.12: *H nmr Data (400 and 500 MHz, CgDg) for Photoproduct 108. Assignment H-xa A H nmr (500 MHz) 8 ppm (mult, J (Hz)) COSY Correlations0 (400 MHz) NOE Correlations0 (400 MHz) H-3 part of m(2H) at 2.76-2.69 (IH) H-7 H-4 1.60-1.54 (m, IH) H-5, H-5' str. H-7 med. H-5', H-5 (neg) w. H-3 and/or H-7', H-6' H-5 1.10-1.00 (m, IH) H-4, H-5', H-6, H-6' str. H-5' med. H-3 and/or H-7', H-12 and/or H-13 w. H-4, H-6' H-5' 1.37-1.25 (m, IH) H-4, H-5, H-6 str. H-5 med. H-4, H-6 w. H-12 and/or H-13 H-6 1.78-1.69 (m, IH) H-5, H-5', H-6' str. H-12 and/or H-13 med. H-6' H-6' 1.89-1.82 (m, IH) H-5, H-6 w-coupling to H-7' str. H-6, H-12 and/or H-13 w. H-5 302 Experimental/Chapter 8 Table 8.12. Continued Assignment H-x a lH nmr (500 MHz) 5 ppm (mult., J (Hz)) COSY Correlations0 (400 MHz) NOE Correlations0 (400 MHz) H-7 0.93-0.91 (d, J=8Hz, IH) H-7' and/or H-3 H-7' part ofm(2H) at 2.76-2.69 (IH) H-7, w-coupling to H-6' H-8 0.93 (s, 3H) H-10 0.53 (s, 9H) str. H-4, H-3 and/or H-7', H-12 and/or H-13, OH and/or H-5 (neg) w. H-5' H-12 part of m(4H) at 7.01-6.96 (2H) str. H-6 med. H-8, H-10 H-13 part of m(4H) at 7.01-6.96 (2H) str. H-6 med. H-8, H-10 OH 1.16 (br. s, IH) a- H indicates the hydrogen of a pair which is more downfield (H-61 is more downfield than H-6). b- Only those COSY correlations that could be unambiguously assigned are recorded, c- Only those NOE data that could be unambiguously assigned are recorded (str. = strong, med. = medium, and w. = weak)(neg. = negative). 303 Experimental/Chapter 8 Table 8.13: A H nmr (500 MHz) and 1 3 C nmr (125.8 MHz) Data for Photoproduct 108. E N T R Y C-x 1 3 C nmr spectrum (125.8 MHz) 8 ppm, A P T 3 H M Q C b ' c ' d A H nmr correlations (500 MHz) 8 ppm (assignment) 1 H - 1 3 C H M B C b » c » d Long-range Correlations H-x a 1 46.88 (+ve) H-3 (3 bonds) and/or H-7' (2 bonds) H-6 and H-6'(2 bonds) H-5' (3 bonds) H-8 (2 bonds) b 2 80.33 (+ve) H-3 (2 bonds) and/or H-7' (3 bonds) H-6 and H-6' (3 bonds) H-8 (3 bonds) H-12 (3 bonds) and/or H-13 (4 bonds) c 3 47.86 (-ve) part of m (2H) at 2.76-2.69 (H-3, IH) H-7' (2 bonds) H-4 (2 bonds) H-5' (3 bonds) H-10 (4 bonds) d 4 54.30 (-ve) 1.60-1.54 (H-4, IH) H-5 and H-5'(2 bonds) H-6' (3 bonds) H-7 (3 bonds) H-10 (3 bonds) e 5 20.49 (+ve) 1.37-1.25 (H-5', IH) and 1.10-1.00 (H-5, IH) H-3 (3 bonds) and/or H-7' (4 bonds) H-4 (2 bonds) H-6 and H-6' (2 bonds) H-10 (4 bonds) f 6 36.78 (+ve) 1.89-1.82 (H-6', lH)and 1.78-1.69 (H-6, IH) H-5 and H-5' (2 bonds) H-8 (3 bonds) 304 Experimental/Chapter 8 Table 8.13 Continued £ N T R Y C-x * 3 C nmr spectrum (125.8 MHz) 8 ppm, A P T a H M Q C b ' c ' d * H nmr correlations (500 MHz) 8 ppm (assignment) ! H - 1 3 C H M B C b ' c ' d 1 Long-range Correlations H-x g 7 46.44 (+ve) part of m (2H) at 2.76-2.69 (H-7, IH) and 0.93-0.91 (H-7, IH) H-3 (2 bonds) H-4 (3 bonds) H-6 and H-6' (3 bonds) H-8 (3 bonds) h 8 19.59 (-ve) 0.93 (H-8, 3H) H-6' (3 bonds) i 9 32.62 (+ve) H-4 (2 bonds) H-5 (3 bonds) H-10 (2 bonds) j 10 28.59 (-ve) 0.53 (H-10, 9H) H-4 (3 bonds) k 11 150.47 (+ve) H-12 (2 bonds) and/or H-13 (3 bonds) 1 12 128.36 (-ve) part of m (4H) at 7.01-6.96 (H-12, 2H) H-13 (2 bonds) m 13 131.33 (-ve) part of m (4H) at 7.01-6.96 (H-13, 2H) H-12 (2 bonds) n 14 118.82 (+ve) H-12 (4 bonds) and/or H-13 (2 bonds) 1 ° 15 111.40(+ve) H-12 (4 bonds) and/or H-13 (3 bonds) a- The results of the APT experiment are given in parentheses (-ve for CH and CH3 carbon signals). b- The table reads from left to right. The assignment and the chemical shifts of the 1 3 C nmr spectrum are listed in the first and second columns, respectively. The third column shows the *H nmr signal(s) which correlate(s) with the carbon of the first two columns, as obtained from the HMQC experiment (1 bond correlation). The last column lists the hydrogen(s) which correlate(s) with the ^ C nmr signal of the first two columns as obtained from HMBC experiments(2,3 and 4 bond correlation^)) c- Only those HMQC and HMBC data that could be unambiguously assigned are recorded d- H indicates the hydrogen of a pair which is more downfield (H-6' is more downfield than H-6). 305 Experimental/Chapter 8 8.9. Photolysis of Compound 70 o. 70 hv, solution HOOC COOH CH 3 0 2 C CH 3 l)hv, solid state 2) C H 2 N 2 + 110 COOH CH 3 C H 3 0 2 C C H 2 N 2 HO C O 2 C H 3 CH 3 + Analytical solution phase photolysis of ketone 70 (4.5 mg, 0.015 mmol) was carried out in 3 mL of acetone or chloroform The solution was irradiated through a Pyrex filter for 2 h. The solvent was removed in vacuo and the residue was dissolved in diethyl ether and treated with excess diazomethane. GC (DB-5) analysis showed that ketone 70 was completely consumed and that two photoproducts (94:6 ratio) had formed. These two photoproducts were determined by GC to be the same as those formed when 306 Experimental/Chapter 8 ketone 71 was photolyzed. Analysis of the photoproducts can be found in Section 8.10 (below). The general procedure for solid phase photolysis at > 290 nm was followed with compound 70 (46 mg, 0.15 mmol). Photolysis for 4 h was followed by dissolving the residue in diethyl ether and treatment with excess diazomethane. GC (DB-5) analysis showed complete consumption of ketone 70 and the presence of a single photoproduct, which was determined by both GC and A H NMR to be the same as the major photoproduct from the solution state photolysis. Analysis of the photoproduct can be found in Section 8.10 (below). 8.10. Photolysis of Compound 71 major Photolysis of 125.3 mg (0.40 mmol) of ketone 71 in either 20 mL of acetone or benzene for 2 h led to the formation of two photoproducts in a 94:6 ratio (as determined by GC). The photoproducts were separated from unreacted ketone 71 by silica gel column chromatography using 5% diethyl ether in hexanes as the eluent to yield 15.3 mg 307 Experimental/Chapter 8 (12.2%) of ketone 71. The mixture of photoproducts was subjected to column and radial chromatography (3% diethyl ether in hexanes as eluent); however, the minor photoproduct 119 could never be separated from the major photoproduct 110. Photoproduct 110 was recovered as a white powder (81.2 mg, 64.8%), while 28.8 mg (23.0%) was inseparable. Recrystallization from various solvents gave only powdered photoproduct 110. The general procedure for sohd phase photolysis at > 290 nm was followed with compound 71 (51 mg, 0.16 mmol). Sohd state photolysis for 6 h (79.0 % conversion) led to the formation of a single photoproduct, which was determined by gas chromatography and A H NMR to be the same as the major photoproduct from the solution state photolysis. Major Photoproduct 110 (IS*, 4R*, 5S*, 6S*)-4-(l,l-dimethylethyl)-l-methyI-6-(4-carbomethoxyphenyl) bicyclo |3.1.1 l-heptan-6-ol (110) M.P.: 114-115°C. Anal. Calcd. for C 2oH2 80 3: C, 75.91; H, 8.92; O, 15.17. Found: C, 75.72; H, 8.88. LRMS: (EI) m/e, 317 (0.9), 316 (M+, 2.5), 301 (5.0), 285 (9.3), 260 (8.4), 259 (35.2), 258 (13.8), 257 (55.8), 241 (7.9), 227 (14.6), 205 (29.4), 203 (12.9), 201 (42.1), 192 (22.2), 173 924.0), 169 (12.9), 165 (14.3), 164 (60.4), 163 (100.0), 159 (35.4), 153 (13.6), 152(17.5), 149(13.9), 146(18.1), 145 928.5), 143 (12.9), 141 (12.1), 136 (14.0), 135 (16.4), 131 (18.8), 129 (10.5), 128 (11.2), 115 (15.4), 105 (17.6), 104 (12.3), 103 (14.6), 97 (33.3), 95 (23.1), 94 (15.4), 91 (14.1), 83 (16.6), 81 (35.5), 77 (16.2), 69 (13.5), 59 (11.7), 57 (36.8), 55 (10.5). HRMS: Calculated mass for C 2 0 H 2 8 O 3 : 316.2038. Found: 316.2039. 308 Experimental/Chapter 8 IR, cm"1: (KBr pellet) 3492, 2983, 2946, 2866, 1703, 1608, 1568, 1472, 1456, 1440, 1407, 1363, 1332, 1282, 1225, 1197, 1182, 1111, 1052, 1015, 986, 964, 946, 911, 860, 830, 778, 720, 530, 509. 309 Experimental/Chapter 8 Table 8.14: * H nmr Data (400 and 500 MHz, CgDg) for the Major Photoproduct 110. 16 O Assignment *H nmr (500 MHz) C O S Y Correlations'5 N O E Correlations0 H - x a 8 ppm (mult., J (Hz)) (400 MHz) (400 MHz) H-3 part ofm(2H) at 2.86-2.80 (IH) H-7 H-4 1.67-1.60 (m, IH) H-5 and H-5' str. H-6 (neg), H-7, w. H-5 and H-5', H-6' H-5 and H-5' 1.41-1.22 (m,2H) H-4, H-6, H-6' med. H-4, H-6 w. H-12 H-6 1.84-1.76 (m, IH) H-5 and H-5', H-6' str. H-6' med. H-12 (neg) w. H-7 H-6' 2.06-2.00 (m, IH) H-5 and H-5', H-6, w-coupling to H-7' str. H-6, H-12 H-7 1.00-0.96 (m, IH) H-3 and/or H-7' str. H-3 and/or H-7' med. H-4 w. H-6, O H (neg) H-7' part of m(2H)at2.86-2.80 (IH) H-3, w-coupling to H-6' H-8 1.05 (s, 3H) H-10 0.61 (s, 9H) H-12 7.34-7.30 (m, 2H) H-13 str. H-6', H-8, H-10, H-13 med. H-3 and/or H-7', H-6 (neg) w. H-5 and H-5' H-13 8.07-8.03 (m, 2H) H-12 str. H-12 H-16 3.52 (s, 3H) O H 1.40 (br. s, IH) a- H indicates the hydrogen of a pair which is more downfield (R-6' is more downfield than H-6). b- Only those C O S Y correlations that could be unambiguously assigned are recorded, c- Only those N O E data that could be unambiguously assigned are recorded (str. = strong, med. = medium, and w. = weak)(neg. = negative). 310 Experimental/Chapter 8 Table 8.15: A H nmr (500 MHz) and 1 3 C nmr (125.8 MHz) Data for the Major Photoproduct 110. £ N T R Y C-x l 3 C nmr spectrum (125.8 MHz) 8 ppm, A P T 2 H M Q C b ' c ' d J H nmr correlations (500 MHz) 8 ppm (assignment) i H - ^ C H M B C b ' c ' d Long-range Correlations H-s 47.11 (+ve) H-3 (3 bonds) and/or H-7' (2 bonds) H-4 (4 bonds) H-5 and H-5' (3 bonds) H-6 (2 bonds) H-6' (2 bonds) H-8 (2 bonds) 80.67 (+ve) H-4 (3 bonds) H-6 (3 bonds) H-8 (3 bonds) H-12 (3 bonds) 47.94 (-ve) part of m (2H) at 2.86-2.80 (H-3, IH) H-4 (2 bonds) H-6 (4 bonds) H-6' (4 bonds) H-5 and H-5' (3 bonds) H-7' (2 bonds) H-8 (4 bonds) OH (3 bonds) L 54.54 (-ve) 1.67-1.60 (H-4, IH) H-3 (2 bonds) and/or H-7' (3 bonds) H-5 and H-5'(2 bonds) H-6' (3 bonds) H-10 (3 bonds) OH (4 bonds) 311 Experimental/Chapter 8 Ta )le 8.15 Continued E N T R Y C-x 1 3 C nmr spectrum (125.8 MHz) 8 ppm, A P T 3 H M Q C b ' c ' d * H nmr correlations (500 MHz) 8 ppm (assignment) X H - 1 3 C H M B C b ' c ' d Long-range Correlations H-x e 5 20.62 (+ve) 1.41-1.22 (H-5 & H-5', 2H) H-3 (3 bonds) and/or H-7' (4 bonds) H-4 (2 bonds) H-6 (2 bonds) H-6' (2 bonds) H-5 and H-5' (3 bonds) H-10 (4 bonds) f 6 37.04 (+ve) 2.06-2.00 (H-61, IH) and 1.84-1.76 (H-6, IH) H-3 (4 bonds) and/or H-7' (3 bonds) H-5 and H-5' (2 bonds) H-8 (3 bonds) g 7 46.63 (+ve) part of m (2H) at 2.86-2.80 (H-7', IH) and 1.00-0.96 (H-7, IH) H-3 (2 bonds) H-4 (3 bonds) H-5 and H-5' (4 bonds) H-6 (3 bonds) H-6' (3 bonds) h 8 19.79 (-ve) 1.05 (H-8, 3H) H-3 (4 bonds) and/or H-7' (3 bonds) H-6 (3 bonds) H-6' (3 bonds) H-7 (3 bonds) i 9 32.69 (+ve) H-3 (3 bonds) and/or H-7' (4 bonds) H-4 (2 bonds) H-10 (2 bonds) j 10 28.71 (-ve) 0.61 (H-10, 9H) H-4 (3 bonds) k 11 129.48 (+ve) H-12 (2 bonds) H-13 (3 bonds) 1 12 127.94 (-ve) 7.34-7.30 (H-12, 2H) H-13 (2 bonds) m 13 129.27 (-ve) 8.07-8.03 (H-13, 2H) H-12 (2 bonds) n 14 151.02 (+ve) H-13 (2 bonds) 0 15 166.54 (+ve) H-13 (3 bonds) P 16 51.55 (-ve) 3.52 (H-16, 3H) a- The results of the APT experiment are given in parentheses (-ve for C H and CH3 carbon signals). b- The table reads from left to right. The assignment and the chemical shifts of the nmr spectrum are listed in the first and second columns, respectively. The third column shows the I H nmr signal(s) which correlate(s) with the carbon of the first two columns, as obtained from the H M Q C experiment (1 bond correlation). The last column lists the hydrogen(s) which correlate(s) with the nmr signal of the first two columns as obtained from H M B C experiments(2,3 and 4 bond correlation(s)) c- Only those H M Q C and H M B C data that could be unambiguously assigned are recorded d- H ' indicates the hydrogen of a pair which is more downfield (H-6' is more downfield than H-6). 312 Experimental/Chapter 8 8.11. Photolysis of Compound 78 The general procedure for solution phase photolysis at > 290 nm was followed with compound 78 (88 mg, 0.35 mmol) in 10 mL of benzene. After 1.5 hours of irradiation, the solvent was removed in vacuo, and the crude mixture was subjected to silica gel chromatography using 5% diethyl ether in hexanes (v/v) as eluent. A colourless oily photoproduct 111 (85.7 mg, 97.4%) and 2.3 mg (2.6%) of starting ketone 78 were isolated. The general procedure for solid phase photolysis at > 290 nm was followed with compound 78 (57 mg, 0.23 mmol). Solid state photolysis for 3 h (100 % conversion) of ketone 78 was found to lead to the formation of a single photoproduct, which was determined by gas chromatography and A H NMR to be the same as that from the solution state photolysis (111). (lS*,2S*,3R*,4S*,6R*,8R*,9S*)-l-methyl-2-phenyltetracyclo[4.2.2.1 4' 8.0 3» 9]-undecan-2-ol (111) Anal. Calcd. for C 1 8 H 2 2 0 : C, 84.99; H, 8.72; O, 6.29. Found: C, 84.79; H, 8.72. LRMS: (EI) m/e, 255 (19.7), 254 (M+, 100.0), 253 (33.1), 236 (18.9), 221 (1.4), 211 (2.7), 197 (3.7), 193 (4.0), 179 (6.0), 167 (5.5), 159 (10.5), 150 (12.2), 149 (95.7), 313 Experimental/Chapter 8 145 (10.8), 134 (11.6), 120 (6.1), 115 (5.6), 105 (39.7), 93 (10.2), 91 (8.8), 77 (9.7), 67 (1.2), 55 (0.7), 41 (0.6). HRMS: Calculated mass for C 1 8 H 2 2 0 : 254.1671. Found: 254.1670. IR, car 1: (KBr pellet) 3413, 2911, 2850, 1617, 1485, 1448, 1369, 1335, 1056, 1015, 976, 950, 904, 787, 772, 701, 580. The foUowing are the additional spectroscopic values for the photoproduct formed from both the sohd state and solution state photolysis. Table 8.16: *H nmr Data (500 MHz, C 6 D 6 ) for Photoproduct 111. E N T Assignment H-xa ! H nmr (500 MHz) 8 ppm (mult., J (Hz)) R Y a 7.18-7.11 (m,3H) b 7.09-7.05 (m, IH) c 7.04-7.01 (m, IH) d 2.94-2.90 (m, IH) e 2.65-2.61 (t, J = 6 Hz, IH) f 2.02-1.97 (m, IH) g 1.85-1.80 (m, IH) h 1.80-1.72 (m,2H) i 1.70-1.60 (m,2H) j 1.60-1.53 (m, 3H) k 1.53-1.49 (m, IH) 1 H-12 1.32 (s, 3H) m OH 1.04 (s, IH) n 0.80-0.75 (d, J = l l H z , IH) a- Only those proton assignments that could be unambiguously assigned are recorded. 314 Experimental/Chapter 8 Table 8.17: A H nmr (500 MHz) and 1 3 C nmr (125.8 MHz) Data for Photoproduct 111. 15 1 6 ^ X 1 4 E N T R Y C-x l 3 C nmr spectrum (125.8 MHz) 8 ppm, A P T 3 HMQC D » C A H nmr correlations (500 M Hz) 8 ppm (assignment) a 12 18.96 (-ve) 1.32 (H-12, 3H) b 25.88 (-ve) 1.80-1.72 (IH) c 29.40 (-ve) 2.02-1.97 (IH) d 31.16 (+ve) 1.70-1.55 (2H) e 34.22 (+ve) 1.70-1.60 (IH) and 1.54-1.50 (IH) f 35.15 (+ve) 1.85-1.80 (IH) and 0.80-0.75 (IH) g 35.95 (+ve) 1.60-1.53 (2H) h 37.25 (-ve) 1.80-1.72 (IH) i 37.54 (-ve) 2.94-2.90 (IH) j 46.54 (-ve) 2.65-2.61 (IH) k 1 49.99 (+ve) 1 2 83.20 (+ve) m 124.52 (-ve) part of the m (3H) at 7.18-7.11 (IH) n 125.11 (-ve) 7.04-7.01 (IH) 0 126.88 (-ve) 7.09-7.05 (IH) P 129.21 (-ve) part of the m (3H) at 7.18-7.11 (IH) q 129.43 (-ve) part of the m (3H) at 7.18-7.11 (IH) r 13 147.36 (+ve) a- The results of the APT experiment are given in parentheses (-ve for C H and C H 3 carbon signals). b- The table reads from left to right. The assignment and the chemical shifts of the l 3 C nmr spectrum are listed in the first and second columns, respectively. The third column shows the *H nmr signal(s) which correlates) with the carbon of the first two columns, as obtained from the HMQC experiment (1 bond correlation), c- Only those HMQC data that could be unambiguously assigned are recorded 315 Experimental/Chapter 8 8.12. Photolysis of Compound 81 The general procedure for solution phase photolysis at > 290 nm was followed with compound 81 (127.2 mg, 0.47 mmol) in 10 mL of benzene. After 2.0 h of irradiation, the solvent was removed in vacuo, and the crude mixture was subjected to silica gel chromatography using 5% diethyl ether in hexanes (v/v) as eluent. White powder of photoproduct 112 (118.4 mg, 93.1%) and 8.8 mg (6.9%) of ketone 81 were isolated. Photoproduct 112 was recrystallized from petroleum ether to yield colourless prisms. The general procedure for solid phase photolysis at > 290 nm was followed with compound 81 (83 mg, 0.31 mmol). Solid state photolysis for 5 h (100 % conversion) of ketone 81 was found to lead to the formation of a single photoproduct, which was determined by gas chromatography and A H NMR to be the same as that from the solution state photolysis (112). (lS*,2S*,3R*,4S*,6R*,8R*,9S*)-l-methyl-2-(4-fluorophenyl)tetracyclo [4.2.2.14>8.03>9]-undecan-2-ol (1121 M . P.: 96-98°C Anal. Calcd. for C i 8 H 2 i O F : C, 79.38; H, 7.77; O, 5.87; F, 6.98. Found: C, 79.55; H, 7.77. 316 Experimental/Chapter 8 LRMS: (EI) m/e, 273 (7.8), 272 (M+ 41.9), 271 (18.9), 254 (16.0), 239 (0.7), 229 (1.5), 215 (2.3), 211 (3.0), 197 (4.2), 185 (3.8), 177 (7.6), 163 (8.9), 150 (12.7), 149 (100.0), 138 (7.1), 134 (8.5), 123 (51.9), 107 (6.6), 105 (4.4), 95 (10.6), 93 (13.7), 79 (6.7), 67 (1.7), 55 (0.8), 41 (0.6). HRMS: Calculated mass for C 1 8 H 2 i O F : 272.1577. Found: 272.1571. IR, cm"1: (KBr pellet) 3596, 2906, 2868, 2847, 1600, 1504, 1483, 1445, 1392, 1368, 1354, 1338, 1210, 1149, 1095, 1056, 1014, 998, 975, 953, 911, 839, 810, 582. The following are the additional spectroscopic values for the photoproduct formed from both the solid state and solution state photolyses. Table 8.18: *H nmr Data (500 MHz, C6D 6) for Photoproduct 112. 15 ' entry Assignment % nmr (500 MHz) H-xa 8 ppm (mult., J (Hz)) a 6.95-6.90 (m, IH) b 6.84-6.76 (m, 3H) c 2.87-2.82 (m, IH) d 2.54-2.50 (t, J = 6 Hz, IH) e 1.93-1.88 (m, IH) f 1.78-1.73 (m, IH) g 1.70-1.45 (m, 8H) h H-12 1.23 (s, 3H) i OH 1.09 (br. s, IH) 0.78-0.73 (d, J= 11 Hz, IH) a- Only those proton assignments that could be unambiguously assigned are recorded. 317 Experimental/Chapter 8 Table 8.19: *H nmr (500 MHz) and 1 3 C nmr (125.8 MHz) Data for Photoproduct 112. 10 E N T R Y C-x 1 3 C nmr spectrum (125.8 MHz) 8 ppm, A P T 3 HMQC D » C A H nmr correlations (500 MHz) 8 ppm (assignment) a C-12 18.79 (-ve) 1.23 (H-12, 3H) b 25.81 (-ve) 1.78-1.73 (IH) c 29.29 (-ve) 1.93-1.88 (IH) d 31.11 (+ve) part of the m (8H) at 1.70-1.45 (2H) e 34.19 (+ve) part of the m (8H) at 1.70-1.45 (2H) f 35.03 (+ve) part of the m (8H) at 1.70-1.45 (IH) and 0.78-0.73 (IH) g 35.91 (+ve) part of the m (8H) at 1.70-1.45 (2H) h 37.14 (-ve) part of the m (8H) at 1.70-1.45 (IH) i 37.58 (-ve) 2.87-2.82 (IH) j 46.56 (-ve) 2.54-2.50 (IH) k C-l 49.92 (+ve) 1 C-2 82.55 (+ve) m C-14 and C-14' 115.83 and 116.00 ( 2 J C . F = 21Hz,-ve) 116.16 and 116.33 ( 2 J C -F = 21Hz,-ve) part of the m (3H) at 6.84-6.76 (2H) 318 Experimental/Chapter 8 Table 8.19 Continued E N T R Y C-x l 3 C nmr spectrum (125.8 MHz) 8 ppm, A P T 3 H M Q C D ' C A H nmr correlations (500 MHz) 8 ppm (assignment) n C-15 and C-15' 125.99 and 126.05 (3 j c . F = 8Hz,-ve) 126.81 and 126.87 (3JC-F = 8 Hz, -ve) part of the m (3H) at 6.84-6.76 (IH) 6.95-6.90 (IH) o C-16 143.19 and 143.22 ( 4 j C-F = 4 Hz, +ve) P C-13 161.60 and 163.01 ( 1 J C -F = 245Hz,+ve) a- The results of the APT experiment are given in parentheses (-ve for C H and CH3 carbon signals). b- The table reads from left to right. The assignment and the chemical shifts of the l 3 C nmr spectrum are listed in the first and second columns, respectively. The third column shows the A H nmr signal(s) which correlate(s) with the carbon of the first two columns, as obtained from the H M Q C experiment (1 bond correlation). c- Only those H M Q C data that could be unambiguously assigned are recorded The structure was confirmed by X-ray crystaUograpbic analysis c 18 H 2lOF crystallized in space group Pca2i (#29), a = 13.068 (1) A, b = 6.294 (2) A, c = 34.112 (1) A, V = 2805.6 (6) A 3 , Z = 8, D c a l c = 1.290 g/cm3, R = 0.043, R W - 0.048. 319 Experimental/Chapter 8 8.13. Photolysis of Compound 82 The general procedure for solution phase photolysis at > 290 nm was followed with compound 82 (59.5 mg, 0.21 mmol) in 10 mL of benzene. After 3.0 h of irradiation, the solvent was removed in vacuo, and the crude mixture was subjected to silica gel chromatography using 5% diethyl ether in hexanes (v/v) as eluent. White powder of photoproduct 113 (57.9 mg, 97.3%) and 1.6 mg (2.7%) of ketone 82 were isolated. Recrystallization from various solvents gave only powdered solid of photoproduct 113. The general procedure for solid phase photolysis at > 290 nm was followed with compound 82 (52 mg, 0.18 mmol). Solid state photolysis for 6 h (100 % conversion) of ketone 82 was found to lead to the formation of a single photoproduct, which was detennined by gas chromatography and NMR to be the same as that from the solution state photolysis (113). (lS*,2S*,3R*,4S*,6R*,8R*,9S*)-l-methyl-2-(4-cyanophenyl)tetracyclo [4.2.2.14Ao3>9]-undecan-2-ol (113) M.P.: 168-170°C. Anal. Calcd. for C 1 9 H 2 i O N : C, 81.67; FL 7.58; N, 5.02; O, 5.73. Found: C, 81.55; H, 7.59; N, 4.99. LRMS: (EI) m/e, 280 (6.0), 279 (28.3), 278 (5.7), 261 (7.9), 251 (1.0), 236 (1.6), 218 (2.2), 206 (1.7), 204 (3.1), 181 (5.6), 170 (5.3), 159 (4.2), 150 (12.2), 149 (100.0), 320 Experimental/Chapter 8 134 (6.7), 130 (25.1), 107 (7.2), 102 (10.4), 93 (16.8), 79 (9.8), 67 (2.7), 55 (1.1), 41 (0.7). HRMS: Calculated mass for Ci9H21 ON: 279.1623. Found 279.1617. IR, cm"1: (KBr pellet) 3495, 2911, 2855, 2232, 1683, 1638, 1456, 1407, 1375, 1345, 1281, 1250, 1211, 1191, 1171, 984, 868, 547. The fohowing are the additional spectroscopic values for the photoproduct formed from both the sohd state and solution state photolysis. 321 Experimental/Chapter Table 8.20: *H nmr (400 MHz) and 1 3 C nmr (50.3 MHz) Data for Photoproduct 113. E N T R Y C-X a 1 3 C N M R spectrum (50.3 MHz) 8 ppm, APT D H-X c LH NMR spectrum (400 MHz) 8 ppm (mult., H(Hz)) a C-12 18.66 (-ve) 7.10-7.00 (m,2H) b 25.61 (-ve) 6.84-6.75 (m, IH) c 28.95 (-ve) 6.69-6.59 (m, IH) d 30.85 (+ve) 2.82-2.71 (m, IH) e 33.91 (+ve) 2.45-2.37 (t, J= 6 Hz, IH) f 35.27 (+ve) 1.85-1.65 (m, 2H) g 35.61 (+ve) 1.65-1.27 (m, 8H) h 36.80 (-ve) H-12 1.14 (s, 3H) i 37.40 (-ve) OH 0.95 (br. s, IH) j 46.26 (-ve) 1 0.76-0.65 (d, J= 13 Hz, IH) k C-l 49.69 (+ve) 1 C-2 82.49 (+ve) m C-17 111.02 (+ve) n 116.69 (+ve) 0 124.90 (-ve) P 125.51 (-ve) q 132.87 (-ve) r 133.00 (-ve) s 151.36 (+ve) a- Only those carbon assignments that could be unambiguously assigned are recorded. b- The results of the APT experiment are given in parentheses (-ve for CH and CH3 carbon signals). c- Only those proton assignments that could be unambiguously assigned are recorded. 322 Experimental/Chapter 8 8.14. Photolysis of Compound 83 C O O H HOOC CH 30 2 C O •CH3 hv, solid or solution CHj CH2N2 workup1 CH3 83 114 115 Analytical solution phase photolysis of ketone 83 (7.8 mg, 0.026 mmol) was carried out in 3 mL of benzene. The solution was irradiated through a Pyrex filter for 2 h. The solvent was removed in vacuo, the residue was dissolved in diethyl ether and treated with excess diazomethane. GC (DB-5) analysis showed that ketone 83 was completely consumed and that a single photoproduct had formed. This photoproduct was determined by GC to be the same as those formed for ketone 84. Analysis of the photoproduct can be found in Section 8.15 (below). The general procedure for sohd phase photolysis at > 290 nm was followed with compound 83 (42 mg, 0.14 mmol). Photolysis for 4 h was followed by dissolving the residue in diethyl ether and treatment with excess diazomethane. GC (DB-5) analysis showed complete consumption of ketone 83 and the presence of a single photoproduct, which was determined by both GC and A H NMR to be the same as the major photoproduct from the solution state photolysis. Analysis of the photoproduct can be found in Section 8.15 (below). 323 Experimental/Chapter 8 8.15. Photolysis of Compound 84 o C H 3 C O 2 C H 3 solid or solution hv C H 3 115 The general procedure for solution phase photolysis at > 290 nm was followed with compound 84 (95.5 mg, 0.31 mmol) in 10 mL of benzene. After 3.0 h of irradiation, the solvent was removed in vacuo, and the crude mixture was subjected to silica gel chromatography using 5% diethyl ether in hexanes (v/v) as eluent. White powder of photoproduct 115 (86.8 mg, 90.9%) and 8.7 mg (9.1%) of ketone 84 were isolated. Photoproduct 115 was recrystallized from petroleum ether to yield colourless prisms. The general procedure for solid phase photolysis at > 290 nm was followed with compound 84 (39 mg, 0.13 mmol). Solid state photolysis for 6 h (100 % conversion) of ketone 84 was found to lead to the formation of a single photoproduct, which was determined by gas chromatography and 1 H N M R to be the same as that from the solution state photolysis (115). (lS*,2S*,3R*,4S*,6R*,8R*,9S*)-l-methyl-2-(4-carbomethoxyphenyl)tetracyclo [4.2.2.14>8.03>9]-undecan-2-ol (1151 M.P.: 141-143°C. Anal. Calcd. for C20H24O3: C, 76.88; H, 7.75; O, 15.37. Found: C, 76.72; H, 7.74. 324 Experimental/Chapter 8 LRMS: (EI) m/e, 313 (1.1), 312 (M + , 4.9), 297 (10.6), 294 (15.3), 281 (5.0), 269 (1.0), 255 (3.1), 254 (19.1), 253 (99.8), 235 (7.3), 228 (2.5), 214 (6.3), 192 (5.8), 178 (6.8), 164 (9.3), 163 (45.3), 150 (12.8), 149 (100.0), 135 (7.0), 119 (4.8), 107 (6.7), 105 (8.5), 93 (14.9), 91 (8.7), 79 (7.7), 67 (2.4), 55 (0.9), 41 (0.6). HRMS: Calculated mass for C20H24O3: 312.1725. Found: 312.1718. IR, cm"1: (KBr pellet) 3458, 2912, 2849, 1693, 1609, 1439, 1310, 1294, 1248, 1174, 1112, 1058, 1015, 1004, 951, 860, 791, 721. The foUowing are the additional spectroscopic values for the photoproduct formed from both the sohd state and solution state photolyses. 325 Experimental/Chapter 8 Table 8.21: A H nmr Data (500 MHz, CfiDg) for Photoproduct 115, O 6 e n t r y Assignment H-xa A H nmr (500 MHz) 5 ppm (mult., J (Hz)) a 8.15-8.07 (q. of d, J = 2 Hz, 2H) b I 7.13-7.06 (d. of d, J = 9 Hz, J = 2 Hz, IH) c 7.00-6.93 (d. of d, J = 8 Hz, J = 2 Hz, IH) d H-18 3.53 (s, 3H) e 2.87-2.82 (m, IH) f 2.55-2.50 (t, J = 6 Hz, IH) 8 1.94-1.88 (m, IH) h I 1.76-1.70 (IH) 1 1 1.70-1.45 (m, 8H) j |H-12 1.22 (s, 3H) k O H 1.06 (s, IH) 1 0.79-0.72 (d, J= 12 Hz, IH) a- Only those proton assignment that could be unambiguously assigned are recorded. 326 Experimental/Chapter 8 Table 8.22: *H nmr (500 MHz) and 1 3 C nmr (125.8 MHz) Data for Photoproduct 115. 44 < 6 E N T R Y C-x a * 3 C nmr spectrum (125.8 MHz) 8 ppm,APT b H M Q C c ' d *H nmr correlations (500 MHz) 8 ppm (assignment) a 12 18.79 (-ve) 1.22 (H-12, 3H) b 25.77 (-ve) 1.76-1.70 (IH) c 29.17 (-ve) 1.94-1.88 (IH) d 31.02 (+ve) part of the m (7H) at 1.70-1.45 (2H) e 34.07 (+ve) part of the m (7H) at 1.70-1.45 (2H) f 35.31 (+ve) part of the m (7H) at 1.70-1.45 (IH) and 0.79-0.72 (IH) g 35.79 (+ve) part of the m(7H) at 1.70-1.45 (2H) h 37.01 (-ve) part of the m(7H) at 1.70-1.45 (IH) i 37.50 (-ve) 2.87-2.82 (IH) j 46.49 (-ve) 2.55-2.50 (IH) k 1 50.02 (+ve) 1 18 51.58(-ve) 3.53 (3H) m 2 82.80 (+ve) n 124.47 (-ve) 7.13-7.06 (IH) 0 125.11 (-ve) 7.00-6.93 (IH) P 129.17 (+ve) q 130.86 (-ve) part of the m (2H) at 8.15-8.07 (IH) r 130.96 (-ve) part of the m(2H) at 8.15-8.07 (IH) s 151.95 (+ve) t 17 166.59 (+ve) a- Only those carbon assignments that could be unambiguously assigned are recorded. b- The results of the APT experiment are given in parentheses (-ve for C H and CH3 carbon signals). c- The table reads from left to right. The assignment and the chemical shifts of the nmr spectrum are listed in the first and second columns, respectively. The third column shows the * H nmr signal(s) which correlate(s) with the carbon of the first two columns, as obtained from the H M Q C experiment (1 bond correlation). d- Only those H M Q C data that could be unambiguously assigned are recorded 327 Experimental/Chapter 8 8.16. Photolysis of Salts 85-93 + X = optically active amine Crystals of salts 85-93 (1-2 mg) were placed between two Pyrex microscope plates, and by sliding the top and bottom plates back and forth, the sample was distributed over the surface in a thin, even layer. The sample plates were then Scotch-taped together at the top and bottom ends, placed in polyethylene bags and thoroughly degassed with nitrogen; the bags were then sealed under a positive pressure of nitrogen with a heat-sealing device. For room temperature photolyses, the bags were placed within 10 cm of the irradiation source. For low temperature photolyses, the sample bags were immersed in a cooling bath maintained at -40 °C by means of a cryomat (Cryocool CC-100 IT). After photolysis for the specified time, the sohd nrixture was removed from the slides by chssorving with ethyl acetate. This ethyl acetate solution was subsequently treated with an excess of etheral diazomethane to convert the acids to methyl esters. The organic solution was then washed with water and column chromatographed on silica gel with 3% diethyl ether in petroleum ether (v/v). The eluent was collected and the solvent was removed by ahowing it to evaporate overnight at room temperature. The subsequent sohd 328 Experimental/Chapter 8 materials were analyzed via GC and chiral HPLC to determine conversions and enantiomeric excesses of the only photoproduct observed, photoproduct HOP. 8.17. Photolysis of Salts 94-99 A similar procedure (as described in Section 8.16) was employed for the photolysis of the salts 94-99. After diazomethane workup, compound 115P was the only observed photoproduct. 329 Experimental/Chapter 8 8.18. Photolysis of a Single Crystal of 2-Methyl 2-Adamantyl 4'-Carboxyphenyl Ketone (R)-Methylbenzylamine Salt (99) The X-ray crystal structure was deduced for salt 99. The crystal decay under the X-ray source was only 1.04% for that crystal of salt 99; hence, the same crystal (still mounted to the glass fibre) was irradiated at > 290 nm through a Pyrex filter. No special attempts were made to exclude moisture or air. After 2 h of irradiation, the crystal was subjected to another X-ray structure determination. Crystallographic data appear in Table 8.23 for photoproduct 99P. After the structure was determined, the single crystal was dissolved in a few drops of ethyl acetate and excess diazomethane (in diethyl ether) was added. The solvent was removed in vacuo and the residue subjected to GC (DB-5) analysis. The results indicated that there was only photoproduct 115P present with no trace of ketone 84. Chiral HPLC analysis of the photoproduct indicated similar results to those seen previously. At virtually 100% conversion, the e.e. of the photoproduct was determined to be 80% for the second HPLC eluted enantiomer. This photoproduct was determined to have the (S) absolute 330 Experimental/Chapter 8 configuration at the hydroxyl-bearing carbon atom and to have a negative rotation at the sodium D line. Table 8.23. Crystallographic data for photoproduct 99P. Formula C 2 7 H 3 3 ° 3 N fw 419.56 Crystal System primitive, orthorhombic Space group P212121(#19) a, A 12.475 (2) b,A 28.796 (2) c,A 6.430 (3) V 2310(1) z 4 Dcalc, g/cm3 1.206 F(000) 904.00 Radiation CuKcc (1=1.54178 A) p, cm"l 6.13 Crystal color, habit colourless, needle Crystal size, mm 0.43X0.10X0.08 Temperature 21.0°C Transmission factors 0.9325 - 0.9977 Scan type co-29 Scan range, deg in co 0.89 + 0.20 tanG Scan speed, deg/min 16.0 (9 rescans) Data collected +h, +k, +1 20max> d e S 155.1 Crystal decay 0.60% decline Total reflections 2817 Total unique reflections 2817 Rint N/A No. of reflections 1517 with I>3CT(I) No. of variables 293 p-factor 0.00 R 0.049 R w 0.044 Goodness of fit (gof) 2.33 Max Ala (final cycle) 0.02 Residual density (e/A3) -0.14 to +0.26 331 Experimental/Chapter 8 8.19. Partial Photolysis of a Single Crystal of 2-Methyl 2-Adamantyl-4'-Carboxyphenyl Ketone (R)-Methylbenzylamine Salt (99) Several single crystals of salt 99 were placed in a Pyrex vial. No special attempts were made to exclude moisture or air. The crystals were irradiated at > 290 nm through a Pyrex filter. After photolysis, a single crystal was dissolved in a few drops of ethyl acetate and excess diazomethane (in diethyl ether) was added. The solvent was removed in vacuo and subjected to GC (DB-5) analysis. The results indicated that there was a mixture of photoproduct 116 and ketone 84 in a 54:46 ratio. Refinement of atom occupancy factors in the X-ray study found the 115P:84 ratio to be 60:40. Crystallographic data appear in Table 8.24. Chiral HPLC analysis of the mixture indicated similar results to those seen previously. At approximately 54-60% conversion, the e.e. of the photoproduct was determined to be 86% for the second HPLC eluted enantiomer (negative rotation at the sodium D line). 332 Experimental/Chapter Table 8.24. Crystallographic data for mixed crystal 99/99P. Formula C27H33O3N fw 419.56 Crystal System primitive, orthorhombic Space group P21212!(#19) a, A 12.113 (3) b,A 29.419 (3) c,A 6.507 (4) V 2319(1) z 4 Dcalc, g/cm3 1.202 F(000) 904.00 Radiation CuKa (X=l.54178 A) |i, cm"l 6.11 Crystal color, habit colourless, needle Crystal size, mm 0.10X0.15 X0.33 Temperature 21.0°C Transmission factors 0.6988 - 0.9834 Scan type co-20 Scan range, deg in co 0.89 + 0.20 tanG Scan speed, deg/min 16.0 (up to 9 rescans) Data collected +h, +k, +1 20max> d e g 155.2 Crystal decay 0.05% decline Total reflections 2769 Total unique reflections 2739 Rint N/A No. of reflections 2739 with I>3a(I) No. of variables 311 p-factor 0.02 R 0.068 R w Goodness of fit (got) 1.00 Max A/a (final cycle) 0.05 Residual density (e/A3) -0.20 to +0.19 333 Experimental/Chapter 8 8.20. Quantum Yields The stock solutions of the ketone with standard were prepared by weighing out the required amount of ketone and internal standard into a volumetric flask and filling to volume with solvent. Individual flasks for quenching runs were made up by pipetting an equivalent amount of stock ketone-standard solution into numbered 5 mL volumetric flasks containing the required amount of quencher (weighed into each volumetric flask) and filling to volume with solvent. The solutions were then injected into separate constricted 100X13 mm Pyrex Culture Tubes (Corning, rimless, 9820-13) using 5 mL hypodermic syringes with 6 inch needles, filling each tube uniformly with 2.8 mL. The culture tubes were previously cleaned by boiling in soapy (Alconox cleanser) distilled water overnight followed by four rinse cycles in boiling distilled water. They were heated with an oxygen torch right below the label taken out of the flame and then stretched out 7 cm The ketone solutions were degassed by attaching the tubes to a vacuum line over No. 00 one-hole stoppers on mdividual stopcocks. The solutions were slowly frozen in liquid nitrogen, then vacuum was apphed for several minutes. The samples were allowed to thaw and the cycle was repeated. After the fourth freezing and evacuation, the tubes were sealed off with a gas-oxygen torch. AU volumetric pipettes and flasks used were class-A volumetric ware. They were cleaned in the same manner as the photolysis culture tubes. Irradiations were conducted in a merry-go-round apparatus1^ with a 450 W Hanovia medium pressure mercury lamp housed in a quartz immersion well. The 313 nm 334 Experimental/Chapter 8 mercury line was isolated by a filter combination of 7-54 Corning glass plates and an aqueous solution of 0.002 M K2Cr04 containing 5% K 2 C O 3 (wt/wt) circulated through a Pyrex cooling jacket.A^ The whole merry-go-round apparatus was immersed in a water bath whose temperature was maintained at 20 ± 3°C by passing cold water through a large copper coil inside the water bath. The temperature of the filter solution was also maintained at 20 ± 3°C by another copper coil with cold water running through it. Quantitative Analysis: All quantitative measurements of products and starting ketones concentrations were done by standard gas chromatography techniques. The standards used were all straight chain alkanes ranging from 10 carbons to 30 carbons in length. All were purchased from Aldrich Chemical Company and were purified by appropriate methods. 11 Thiophene-free benzene was used as the solvent and was prepared by successive washes with concentrated sulfuric acid, drying and distillation over sodium metal. H Acetophenone (Aldrich) was distilled under reduced pressure before use. Valerophenone, tricosane and tetradecane (all from Aldrich) were used without further purification. Response factors were calculated from three injections of accurately prepared solutions containing the starting material, photoproduct and the internal standard. They were determined by measuring the relative peak area of the standard and the compounds studied. The internal standards were chosen so that their peaks would not overlap with any other peaks expected and yet have a retention time close to that of the photoproducts to be studied. 335 Experimental/Chapter 8 [Compound] / [standard] = RF (area of compound) / (area of standard) or RF = [Compound] / [Standard] X (area of standard) / (area of compound) The concentration of any compound can be determined by gas chromatography: [Compound] = RF [Standard] X (area of compound) / (area of standard) All quantum yields were determined for photoproduct formation relative to acetophenone formation from valerophenone (VP) in benzene on parallel irradiations of samples of equivalent volumes at 313 nm. The quantum yield of acetophenone (AP) formation has been determined to be 0.33 for an opaque concentration (0.1 M) of valerophenone in benzene.l2 Even though it has been shown that the quantum yield for AP formation from VP is valid even up to 75% disappearance of VP, conversions of VP in this experiment were always limited to under 10%. Thus two 2.8 mL benzene solutions of 0.1 M valerophenone and 1.000 g/mL of tetradecane were degassed in Pyrex phototubes and were photolysed along with the test samples. The formation of acetophenone was also monitored by GC (carbowax, DB-5 or FfP-5). [Compound] = RF X [Standard] X (area of AP)/(area of standard) Tetradecane was used as the internal standard for the valeropheneone actinomer runs. 336 Experimental/Chapter 8 From the concentration of AP, the amount of light absorbed, I a (in Eisteins per hter), can be determined: I a = [AP] /0.33 The quantum yield of product formation, Op, equals the concentration of the product, [P], formed, divided by the light absorbed, Ia: Op =[P]/I a According to the foUowing equation O = Moles of photoproduct formed / Moles of photons absorbed The quantum yield of each photoproduct was calculated at different conversions, and the quantum yields were plotted against the conversions. The reported quantum yield values were determined by a zero conversion extrapolation. According to the foUowing equation: Oo / O = 1 + k Q T [ Q ] the values of each quenching run are plotted as a function of [Q] to give a linear Stern-Volmer plot with a slope equal to kqi. The value of T is detennined by dividing out the known values of kq for the appropriate solvent employed. Chapter 6 has the discussion of the quantum yield and Stern-Vohner quenching experiments. Tables 8.25 to 8.28 have the data of aU of the quantum yield and Stern-Vohner quenching experiments. 337 Experimental/Chapter Table 8.25. Quantum yield data for the fer/-butylcyclohexyl aryl ketones: the change in quantum yield vs. reaction conversion. ketone R= X= [ketone] [standard] conversion • •b 1(T2 M 10" 3 M % 56 H H 3.98 docosane 0.381 0.00948 0.0095 + 3.61 0.900 0.00945 0.0003 1.22 0.00947 3.99 3.28 maximum 0.362 + 1.38 0.355 0.002 2.54 0.347 3.93 0.341 57 H F 3.14 eicosane 0.205 0.00220 0.00220 + 3.079 0.514 0.00219 0.00001 1.28 0.00219 3.14 3.93 maximum 0.211 + 1.35 0.198 0.002 3.61 0.179 5.42 0.161 58 C H 3 H 4.30 docosane 2.45 0.0733 0.0737 ± 3.90 6.84 0.0724 0.0001 9.88 0.0719 4.23 3.80 maximum 0.287 + 0.966 0.286 0.004 3.56 0.273 7.89 0.265 66 C H 3 F 3.017 eicosane 2.53 0.0487 0.0489 + 3.54 5.88 0.0480 0.0003 9.67 0.0478 3.072 3.82 maximum 0.236 ± 1.79 0.232 0.002 4.88 0.228 7.33 0.222 67 C H 3 C H 3 3.028 heneicosane 1.13 0.0667 0.0669 + 3.34 2.74 0.0660 0.0002 5.83 0.0653 3.047 3.203 maximum 0.181 ± 2.43 0.171 0.001 5.78 0.157 8.67 0.145 338 Experimental/Chapter 8 Table 8.25 Continued ketone R= X= [ketone] [standard] conversion • 4>o 10"2 M 1 0 - 3 M % 68 C H 3 O C H 3 3.020 eicosane 1.43 0.0823 0.0833 ± 3.36 2.45 0.0809 0.0006 4.15 0.0799 3.058 4.070 maximum 0.309 ± 2.41 0.301 0.004 3.80 0.291 7.39 0.279 69 C H 3 C N 3.010 heneicosane 1.18 0.0198 0.0199 ± 3.54 2.35 0.0197 0.0001 4.072 0.0196 3.017 3.878 maximum 0.169 ± 4.23 0.159 0.002 6.97 0.154 9.77 0.146 70 C H 3 C O O H 3.00 docosane maximum 0.223 ± 3.73 2.18 0.209 0.001 4.33 0.196 6.95 0.179 71 C H 3 C O O C H 3 2.96 docosane 1.85 0.0468 0.0469 ± 3.99 4.11 0.0464 0.0002 6.68 0.0463 2.95 3.86 maximum 0.22 + 3.97 0.193 0.02 6.22 0.162 9.55 0.149 339 Experimental/Chapter 8 Table 8.26. Steady state Stern-Volmer data for the ferMnitylcyclohexyl aryl ketones in benzene with 2,5 dimethyl-2,4 hexadiene as quencher. ketone R= X= [ketone] [standard] [quencher] V * kqx 1 0 " 2 M 1 0 " 4 M M 56 H H 3.55 eicosane 0.000 1.00 0.42 ± 0.03 3.82 0.0428 1.048 0.185 1.066 0.559 1.22 0.929 1.41 57 H F 3.011 eicosane 0.000 1.00 0.20 ±0 .01 5.98 0.0399 1.0028 0.196 1.066 0.387 1.075 0.778 1.19 1.75 1.41 2.90 1.57 58 C H 3 H 4.52 eicosane 0.000 1.00 8.1 ± 0 . 3 2.57 0.0231 1.28 0.1046 1.98 0.246 2.97 0.690 6.04 1.24 11.3 66 C H 3 F 3.062 eicosane 0.000 1.00 6.10 ± 0 . 0 9 13.8 0.0152 1.11 0.0630 1.29 0.122 1.79 0.298 2.83 0.615 5.046 1.016 7.20 1.46 9.87 67 C H 3 C H 3 3.063 nonadecane 0.000 1.00 nonadecane 13.5 1.00 27.4 ± 0.3 0.0174 1.39 heneicosane 1.39 heneicosane 11.3 0.0615 2.60 27.9 ± 0 . 3 2.60 0.166 4.93 5.0068 0.360 10.80 10.96 0.595 17.0 17.3 0.962 27.2 27.7 340 Experimental/Chapter Table 8.26. Continued 1 ketone R= X= [ketone] [standard] [quencher] V * k q x 1 0 " 2 M 1 0 " 4 M M 68 C H 3 O C H 3 3.011 eicosane 0.000 1.00 292 ± 7 13.5 0.0187 6.38 0.0826 26.6 0.185 54.7 69 C H 3 C N 3.013 heneicosane 0.000 1.00 13.2 ± 0.2 10.61 0.01071 1.12 0.0525 1.53 0.125 2.31 0.313 4.66 0.627 9.14 0.944 13.4 71 C H 3 C O O C H 3 3.012 docosane 0.000 1.00 9.6 ± 0 . 6 15.7 0.0191 1.33 0.0944 2.32 0.217 3.43 0.448 5.36 341 Experimental/Chapter Table 8.27. Quantum yield data for the adamantyl aryl ketones: the change in quantum yield vs. reaction conversion. ketone X = [ketone] [standard] conversion • *o I O " 2 M 1 0 - 3 M % 78 H 3.10 tetracosane 1.53 0.139 0.148 ± 1.80 3.12 0.135 0.003 6.44 0.116 3.10 1.80 maximum 0.260 ± 2.81 0.248 0.002 5.26 0.235 8.90 0.221 81 F 3.64 docosane 0.943 0.1018 0.103 ± 1.42 4.78 0.0864 0.002 7.66 0.0798 10.33 0.0729 maximum 0.160 ± 1.33 0.155 0.001 3.67 0.143 7.89 0.125 82 C N 2.33 tetracosane 4.13 0.274 0.41 ± 1.79 5.06 0.220 0.03 8.45 0.115 maximum 0.69 ± 3.66 0.533 0.04 5.76 0.396 7.44 0.332 8.18 0.322 83 C O O H 1.44 docosane maximum 0.24 ± 1.32 2.34 0.216 0.01 4.66 0.179 7.01 0.157 84 C O O C H 3 1.41 docosane 1.33 0.068 0.073 ± 1.35 3.05 0.059 0.002 5.45 0.051 maximum 0.173 ± 2.03 0.160 0.005 3.98 0.152 5.45 0.139 342 Experimental/Chapter 8 Table 8.28. Steady state Stern- Volmer data for the adamantyl aryl ketones in benzene with 2,5-dimethyl-2,4-hexadiene as quencher. ketone X= [ketone] [standard] [quencher] k q x 10"2M 10- 3 M M 78 H 3.10 tetracosane 0.000 1.00 1.56 ± 0 . 0 7 1.80 0.0256 1.11 0.0853 1.30 0.235 1.43 0.563 2.039 1.18 2.89 81 F 3.64 docosane 0.000 1.00 1.78 ± 0 . 0 6 1.42 0.0196 1.058 0.114 1.304 0.460 1.86 0.892 2.62 82 C N 2.33 tetracosane 0.000 1.00 4.5 ± 0 . 1 1.79 0.0300 1.10 0.0938 1.56 0.291 2.58 0.628 3.88 1.23 6.58 84 C 0 2 C H 3 1.41 docosane 0.000 1.00 2.07 ± 0.05 1.35 0.0223 1.011 0.1094 1.30 0.516 2.11 1.14 3.37 8.21. References for Experimental 1. Padwa, A.; Eastman, D. J. Am. Chem. Soc. 1969, 91, 462. 2. Van Belcbim, H.; Van De Graaf, B.; Van Minnen-Pathuis, G.; Peters, J. A. ; Wepster, B. M. Recueil 1970, 89, 521. 3. (a) Lau, H. H.; Hart, H. J. Am. Chem. Soc. 1959, 81, 4897. (b) Stolow, R. D. J. Am. Chem. Soc. 1959, 81, 5806. 4. Mcintosh, C. L. Can. J. Chem. 1967, 45, 2267. 5. Lewis, F. D.; Johnson, R. W.; Johnson, D. E.J. Am. Chem. Soc. 1974, 96, 6090. 343 Experimental/Chapter 8 6. Krapcho, A. P.; Dundulis, E. A.J. Org. Chem. 1980, 45, 3236. 7. Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 2647. 8. (a) Lewis, F. D.; Hilliard, T. A.J. Am. Chem. Soc. 1972, 94, 3852. (b) Lewis, F. D.; Johnson, R. W.; Ruden, K A.J. Am. Chem. Soc. 1972, 94, 4292. 9. Alberts, A. H.; Wynberg, H.; Strating, J. Synth. Comm. 1972, 2, 79. 10. Murov, S. L. Handbook of Photochemistry; Marcel Dekker: New York, 1973. 11. Perrin, D. D.; Armarego, W. L. F.; Perrin, D. IL Purification of Laboratory Chemicals; 2nd Edition, Permagon Press: Oxford, 1980. 12. Wagner, P. J.; Kochevar, I. E.; Kemppainen, A. E.J. Am. Chem. Soc. 1972, 94, 7489. 344 A P P E N D I X A In Chapters 3, 4 and 8, the carbon atom numbering of the cyclobutanol photoproducts do not follow IUPAC nomenclature rules. The correct IUPAC carbon atom numbering is shown below for the two types of cyclobutanols found in this thesis. The names given in Chapter 8 are based on this numbering scheme. 6 345 

Cite

Citation Scheme:

        

Citations by CSL (citeproc-js)

Usage Statistics

Share

Embed

Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                        
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            src="{[{embed.src}]}"
                            data-item="{[{embed.item}]}"
                            data-collection="{[{embed.collection}]}"
                            data-metadata="{[{embed.showMetadata}]}"
                            data-width="{[{embed.width}]}"
                            async >
                            </script>
                            </div>
                        
                    
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:
http://iiif.library.ubc.ca/presentation/dsp.831.1-0059541/manifest

Comment

Related Items