UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Synthesis of large container molecules Mungaroo, Rajesh 2003

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

Item Metadata

Download

Media
831-ubc_2003-859789.pdf [ 7.61MB ]
Metadata
JSON: 831-1.0061191.json
JSON-LD: 831-1.0061191-ld.json
RDF/XML (Pretty): 831-1.0061191-rdf.xml
RDF/JSON: 831-1.0061191-rdf.json
Turtle: 831-1.0061191-turtle.txt
N-Triples: 831-1.0061191-rdf-ntriples.txt
Original Record: 831-1.0061191-source.json
Full Text
831-1.0061191-fulltext.txt
Citation
831-1.0061191.ris

Full Text

Synthesis of Large Container Molecules by Rajesh Mungaroo B.Sc, University of Bergen, 1995 M.Sc., University of Bergen, 1996 A THESIS SUBMITTED IN PARTIAL F U L F I L L M E N T OF THE REQUIREMENT FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE F A C U L T Y OF G R A D U A T E STUDIES (Department of Chemistry) We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH C O L U M B I A June, 2003 © Rajesh Mungaroo, 2003 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 The University of British Columbia Vancouver, Canada D a t e 2G.Juw , ^ o o i DE-6 (2/88) Abstract This thesis presents the synthesis and guest binding abilities o f a multitude o f hosts derived from cavitand 37. In chapter 2, the mechanism o f formation o f hemicarceplex 60 • guest using transition state models is discussed. This chapter includes reactions and complexation experiments with 61 (R = R = H) and its derivatives in N-formylpiperidine (NFP) and nitrobenzene. 60«guest 61,67-69«guest The formation o f tris-carceplex 75«(methyl acetate^ and tris-capsule 76«(methyl acetate)3 from hexamer 74 is discussed in chapter 3. In chapter 4, we present the formation and guest binding abilities o f hosts 78 and 81. The guest decomplexation rate o f 78«(l,3,5-triethynylbenzene)2 is also discussed. In chapter 5, we discuss the entrapment and the reaction o f PI1COCHN2 to produce PhCHC=C=0 within the cavity o f 45. In situ generation o f l,3,5-tris(iodomethyl)benzene, and its entrapment within the cavity 152 are described. The stability o f bound l,3,5-tris(iodomethyl)benzene is also discussed. i i 78* (1 ,3 ,5 - t r i e thyny lbenzene) 2 4 5 « P h C O C H N 2 . N F P 6~ 76» ( m e t h y l a c e t a t e ) 3 75» ( m e t h y l a c e t a t e ) 3 152* 1 ,3 ,5 - t r i s ( i odomethy l )benzene iii Table of Contents Abstract 1 1 Table of Contents 1 V List of Figures x l List of Schemes x v l List of Tables • x i x List of Abbreviations X X 1 Acknowledgements x x m Dedications X X 1 v 1.0 Introduction 1 1.1 Supramolecular Chemisty 1 1.1.1 Crown Ethers 2 1.1.2 Cryptands 3 1.1.3 Spherands 3 1.1.4 Catenanes 4 1.1.5 Rotaxanes • • 6 1.1.6 Cyclodextrins 8 1.1.7 Cucurbit[n]urils 8 1.1.8 Cryptophanes 9 1.1.9 Calix[n]arenes 10 1.1.10 Cavitands H 1.1.11 Carceplexes .' 13 iv 1.1.12 Hemicarceplexes 18 1.1.13 Capsules 19 1.1.14 Solid State "Supermolecules" : 22 1.1.14.1 Clathrates 22 1.1.14.2 Zeolites 23 1.2 Goals and Summary o f Thesis 23 1.3 References 25 2.0 Mechanism of Formation of a Hemicarceplex Using Transition State Models 31 2.1 Template Ratios and Guest Determining Step (GDS) 31 2.2 Goal o f this Study 34 2.3 Results and Discussions 36 2.3.1 Template Studies with Diol 61 in NFP 36 2.3.2 Binding Studies with 61 and its Derivatives 37 2.3.3 Template Ratios with 61 in Nitrobenzene 45 2.4 Summary and Conclusions 45 2.5 Experimental Section 46 2.5.1 Determination o f Template Ratios in NFP or Nitrobenzene 48 2.5.2 Determination o f K a and K r e i . for Complexes 61»guest 48 2.5.3 Synthesis and Characterization o f Mesylate 66 52 2.5.4 Synthesis and Characterization o f Bromobutyl 67 53 2.5.4.1 Determination o f K a and K r e i . for Complexes 67»guest 53 2.5.5 Synthesis and Characterization o f Benzyl 68 55 2.5.5.1 Determination o f K a and K r e i . for Complexes 68«guest 55 2.5.6 Synthesis and Characterization o f Dimethyl 69 58 2.5.6.1 Determination o f K a and K r e i . for Complexes 69«guest 59 2.6 References 61 3.0 Formation of a Tris-Capsule and a Tris-Carceplex from a Cyclic Six-Bowl Assembly 62 3.1 Introduction 62 3.2 Goal o f this Study 63 3.3 Results and Discussions 64 3.3.1 Synthesis and Characterization o f 73 64 3.3.2 Synthesis and Characterization o f 74 64 3.3.3 Synthesis and Characterization o f Tris-Carceplex 75«(methyl acetate)3 66 3.3.4 Efficiency o f the Assembly o f Tris-Carceplex 75*(methyl acetate)3 70 3.3.5. Synthesis and Characterization o f Tris-Capsule 76*(methyl acetate)3 72 3.4 Summary and Conclusions 74 3.5 Experimental 75 3.5.1 Synthesis and Characterization o f Hexamer 73 76 3.5.2 Synthesis and Characterization o f Hexamer 74 76 3.5.3 Synthesis and Characterization o f Tris-Carceplex 75»(methyl acetate)3 77 3.5.4 Synthesis and Characterization o f Tris-capsule 76*(methyl acetate)3 80 3.6 References 81 v i 4.0 Synthesis and Uses of Novel Large Hosts 82 4.1 Background and Goals 82 4.2 Results and Discussions 88 4.2.1 Synthesis o f trimer cavitand 11 88 4.2.2 Synthesis and Characterization o f Hemicarcerand 78 88 4.2.2.1 Binding Studies with Hemicarcerand 78, and Formation and Characterization o f Bis-Hemicarceplex 78»(1,3,5-triethynylbenzene)2 • 90 4.2.2.2 Dimensions o f 78 and Guest Orientations in 78»(1,3,5-triethynylbenzene)2 94 4.2.2.3 Kinetics o f Decomplexation o f 78»(l,3,5-triethynylbenzene) 2 96 4.2.3 Synthesis and Characterization o f 81 99 4.2.3.1 Binding Studies with 81 103 4.2.3.2 Formation o f Bis-Complex 81»(p-xylene) 2 103 4.2.3.3 Drug Binding Studies with 81 107 4.2.4 Comparison o f 78 and 81 with Other Large Covalently-Linked Hosts 108 4.3 Summary and Conclusions I l l 4.4 Experimental 112 4.4.1 Synthesis o f Trimer Cavitand 77 112 4.4.2 Synthesis and Characterization o f Bis-Hemicarcerand 78 113 4.4.2.1 Formation and Characterization o f Bis-Hemicarceplex 78«(1,3,5-triethynylbenzene)2 114 4.4.2.2 Decomplexation Studies with Bis-Hemicarceplex 78»(1,3,5-triethynylbenzene)2 115 4.4.3 Synthesis o f Triol 87 117 4.4.4 Synthesis and Chracterization o f Tris-Bromobutyl 88 118 4.4.5 Synthesis o f Monobenzyl 68 118 4.4.6 Synthesis and Chracterization o f Dibenzyl 79 119 4.4.7 Synthesis and Characterization o f Diol 80 120 4.4.8 Synthesis and Characterization o f Host 81 120 4.4.8.1 Formation and Characterization o f 81«(p-xylene)2 121 4.4.8.2 Determination o f K a for 81»(p-xylene) 2 122 4.5 References 122 5.0 Generation, Entrapment, Stabilization and Reactions of Reactive Intermediates within the Cavities of Trimer Carceplexes 45 and 152 124 5.1 Introduction 124 5.2 Background 124 5.2.1 Work Done by the Cram Group ; ' 124 5.2.2 Work Done by the Warmuth Group 127 5.2.3 Work Done in Our Labs 130 5.2.4 Formation o f PhCH=C=0 131 5.2.5 Formation o f Ac id Enols 132 5.3 Goals o f this Study 133 v i i i 5.4 Results and Discussions 135 5.4.1 Synthesis and Characterization o f Trimer Carceplex 45«PhCOCHN 2»NFP... 135 5.4.2 Photolysis o f 45»PhCOCHN 2«NFP and Formation o f 45«PhCH=C=0»NFP 144 5.4.3 Hydrolysis o f 45»PhCH=C=0»NFP and Formation o f 45«PhCH 2 COOH»NFP«(H 2 0) n 149 5.4.4 Synthesis o f Trimer Carceplex 152«l,3,5-tris(iodomethyl)benzene 154 5.4.4.1 Stability o f Trimer Carceplex 152«l,3,5tris(iodomethyl)-benzene 156 5.5 Summary and Conclusions 156 5.6 Experimental Section 157 5.6.1 Synthesis and Characterization o f Trimer Carceplex 45«PhCOCHN 2«NFP...158 5.6.2 Formation and Characterization o f Trimer Carceplex 45«PhCH=C=0«NFP..159 5.6.3 Formation and Characterization o f Trimer Carceplex 45»PhCH 2COOH« N F P » ( H 2 0 ) n 160 5.6.4 Synthesis and Characterization o f Trimer Carceplex 152«1,3,5-tris(iodomethyl)benzene 161 5.6.5 Synthesis and Characterization o f Trimer Carceplex 152* 1,3,5-tris(bromomethyl)benzene 161 5.6.6 Synthesis and Characterization o f Trimer Carceplex 152«NFP 162 5.7 References 163 ix 6.0 Overall Conclusion and Future Work 165 6.1 Overall Conclusion 165 6.2 Overall Conclusion 167 6.3 Future Work 168 6.3.1 Full Characterization o f Products Obtained from the Hydrolysis o f 45«PhCH=C=0»NFP 168 6.3.2 Stabilization o f Oxirenes within the Shell o f 45 169 6.4 References 172 A.O Appendix 173 A. 1 Calculation o f Assembly Numbers 173 A. 1.1 Assembly Number for 38»pyrazine 173 A. 1.2 Assembly Number for 44»(pyrazine)2 174 A. 1.3 Assembly Number for 75«(methyl acetate^ 175 A.2 Kinetics o f Decomplexation o f 78«(l,3,5-triethynyl-benzene)2 184 A.2.1 Determination o f Rate Constant ". 184 A.2.2 Calculation o f Gibbs Energy o f Activation (AG 1 ) 187 A.2.3 Calculation o f Activation Energy (E a) 188 A.2.4 Relation between E a and A G1 188 A.2.4 Estimation o f Error 189 A.3 Calculation o f Binding Constants for 81»p-xylene and 81»(p-xylene) 2 189 A.4 References 191 x List of Figures Figure 1.1. A few examples o f crown ethers : 2 Figure 1.2. Cryptand 4 3 Figure 1.3. Schematic representation o f arotaxane 6 Figure 1.4. Schematic representation o f cyclodextrins, and cyclodextrin 18 8 Figure 1.5. Cryptophane 23 10 Figure 1.6. Self-assembly o f bifunctional metallo-porphyrin receptor 24«25 11 Figure 1.7. Structures o f cavitands 26-28, and guests 29-33 12 Figure 1.8. C-isobutylpyrogallol[4]arenes 55 and 56, and 566«(guest)n 21 Figure 1.9. Structure o f zeolite 23 Figure 1.10. Structure o f diol 61 24 Figure 2.1. ' H N M R spectra (400 MHz, nitrobenzene-^ at 27 °C) o f (a) 2.73 m M diol 61, (b) 2.48 m M diol 61 and 24.8 m M 3-pentanol 38 Figure 2.2 Proposed structure o f intermediate formed between 61 and D B U 40 Figure 2.3. *H N M R spectra (400 MHz, nitrobenzene-^ at 27 °C) o f (a) 2.73 m M diol 61, (b) 2.65 m M diol 61 and 7.95 m M D B U (c) 2.41 m M diol 61, 7.25 m M D B U and 24.1 m M 3-pentanol 41 Figure 2.4. 70«guest, the most likely structure o f the GDS in the formation 60«guest...44 Figure 2.5. Guest structures with labeling 47 Figure 2.6. Structures o f hosts 61 and 66-69 wi th labeling 47 Figure 3.1 ' H N M R spectra (400 MHz, DMSO -c i 6 ) o f hexamer 74 (a) at 27 °C, (b) at 87 °C 65 Figure 3.2. Partial ' H N M R spectrum (400 MHz, C 6 D 6 ) o f tris-carceplex 75«(methyl x i acetate) 3at57°C .":.68 Figure 3.3. M A L D I mass spectrum o f 75*(methyl acetate)3»Na+ 70 Figure 3.4 ' H N M R spectra (400 MHz, C 6 D 5 N 0 2 ) o f (a) 2.52 m M 74 and 17.7 m M D B U at 27 °C, (b) tris-capsule 76*(methyl acetate)3 (2.52 m M 74, 17.7 m M D B U and 27.9 m M methyl acetate) at 27 °C (c) tris-capsule 76»(methyl acetate)3 (2.52 m M 74, 17.7 m M D B U and 27.9 m M methyl acetate) at 127 °C 73 Figure 3.4. Proton labeling for 75»(methyl acetate)3 78 Table 3.2. NOESY/EXSY and COSY correlations o f selected protons in tris-capsule 76«(methyl acetate)3 80 Figure 4.1. Structures o f bis-hemicarceplexes 82»(guesf)2 and 83«(guest)2 86 Figure 4.2. Energy diagram for a complexation-decomplexation process 87 Figure 4.3. Structures o f hemicarceplexes 60 and 84-86 87 Figure 4.4. ' H N M R spectra (400 MHz, CDC1 3 , 27 °C) o f (a) trimer cavitand 77 (b) trimer carceplex 45«(DMA) 2 , (c) bis-hemicarcerand 78 89 Figure 4.5. M A L D I - M S signals corresponding to (a) 78«Na+, (b) 78«H 2 0«Na + and 78«K + (c) 78«H 2 0»K + 90 Figure 4.6. [ H N M R spectrum (500 MHz, nitrobenzene-t^) o f 78»(l,3,5-triethynylbenzene)2 at 27 °C 92 Figure 4.7. M A L D I mass spectrum of 78»(l,3,5-triethynylbenzene)2 92 Figure 4.8. [ H N M R spectra (500 MHz, nitrobenzene-^, 27 °C) o f (a) 78»(1,3,5-triethynylbenzene)2 wi th free 1,3,5-triethynylbenzene (b) 78»(1,3,5-triethynylbenzene)2, (c) 78«(l,3,5-triethynylbenzene)2 after heating for 3 hours at 120 °C in nitrobenzene-^ 93 x i i Figure 4.9. Dimensions o f hemicarcerand 78 94 Figure 4.10. Guest orientation in 78«(l,3,5-triethynylbenzene)2 96 Figure 4.11. Graphs o f ln(conc, o f bound guest) vs time for decomplexation experiments performed at (a) 120 °C, (b) 100 °C 98 Figure 4.12. Structures o f hemicarceplexes 52»ethyl acetate and 64«DMF 99 Figure 4.13. *H N M R spectra (400 MHz, CDC1 3 , 27 °C) o f (a) diol 80 (b) host 81 102 Figure 4.14. M A L D I mass spectrum o f 81 (mass corresponds to 81«Na+) 103 Figure 4.15. lH N M R spectra (500 MHz, nitrobenzene-e?j, 27 °C) o f (a) 81, (b) mixture o f 81»(/?-xylene)i and 81»(p-xylene)2, (c) 81«(p-xylene)2 105 Figure 4.16. Structures o f 60, 82 and 83 106 Figure 4.17. Structures o f hosts 89-92 108 Figure 4.18. Structures o f hosts 93, 94 and guest 97 109 Figure 4.19. Structure o f 95 and 96 110 Figure 4.20. Structure o f 98 I l l Figure 5.1. Guest orientations in 60»guest 127 Figure 5.2. ! H N M R spectra (CDC1 3 , 27 °C) o f (a) 45»PhCOCHN 2»NFP (400 MHz) , (b) sieve-dried 45«PhCH=C=0»NFP (400 MHz) , (c) sieve-dried product obtained from hydrolysis o f 45«PhCH=C=0«NFP (500 MHz) 138 Figure 5.3. 2-D COSY (400 MHz, CDC1 3 , 27 °C) spectrum o f 45«PhCOCHN 2 •NFP 139 Figure 5.4. 2-D NOESY (400 MHz, CDC1 3 , 27 °C) spectrum o f 45«PhCOCHN 2 •NFP 140 Figure 5.5. FT-IR spectra (KBr pellet) o f (a) 45»PhCOCHN 2»NFP, x m (b) 45»PhCH=C=0»NFP, (c) product obtained from hydrolysis o f 45»PhCH=C=0»NFP !• 142 Figure 5.6. UV-Vis spectra (CHC1 3 ) o f (a) 45«PhCOCHN 2»NFP, (b) 45«PhCH=C=0«NFP, (c) product obtained from hydrolysis o f 45«PhCH=C=0»NFP 143 Figure 5.7. 2-D COSY (500 MHz, CDCI3, 27 °C) spectrum of 45«PhCH=C=0»NFP . 146 Figure 5.8. 2-D NOESY (400 MHz, CDC1 3 , 27 °C) spectrum of 45«PhCH=C=0«NFP 147 Figure 5.9. Structure o f oxirene 153 148 Figure 5.10. 2-D COSY (400 MHz, CDCI3, 27 °C) spectrum o f product obtained from hydrolysis o f 45»PhCH=C=0»NFP 150 Figure 5.11. 2-D NOESY (500 MHz, CDCI3, 27 °C) spectrum o f product obtained from hydrolysis o f 45»PhCH=C=0»NFP 151 Figure 5.12. [ H N M R (500 MHz, CDC13) spectrum o f trimer carceplex 152« l,3,5-tris(iodomethyl)benzene 155 Figure 5.13. M A L D I mass spectrum o f 152»l,3,5-tris(iodomethyl)benzene 155 Figure 6.1. Structures o f hosts 60, 61, 67-69 and 81 165 Figure 6.2. Structures o f 74-76 and 78 166 Figure 6.3. Structures o f trimer carceplexes 45 and 152 167 Figure A . l . Probability o f obtaining 38»pyrazine 173 Figure A.2. Probability o f obtaining 44»(pyrazine)2, A - H = OH 174 Figure A.3. Formation o f 75*(methyl acetate)3, A - L = OH 175 xiv Figure A.4. Formation o f the first bridge towards the formation o f 75»(methyl acetate)3 176 Figure A.5. Formation o f second bridge (the first bridge was formed between A and C) towards the formation o f 75»(methylacetate)3.. 177 Figure A.6. Formation o f third and subsequent bridges (the first and second bridges were formed between A and C, and B and D, respectively) towards the formation o f 75«(methyl acetate)3 178 Figure A.7. Formation o f third and subsequent bridges (the first and second bridges were formed between A and C, and E and G, respectively) towards the formation o f 75«(methyl acetate)3 179 Figure A.8. Formation o f third and subsequent bridges (the first and second bridges were formed between A and C, and F and H, respectively) towards the formation o f 75»(methyl acetate)3 180 Figure A.9. Formation o f third and subsequent bridges (the first and second bridges formed between A and C, and I and K, respectively) towards the formation o f 75«(methyl acetate)3 181 Figure A.10. Formation o f third and subsequent bridges (the first and second bridges were formed between A and C, and J and L, respectively) towards the formation o f 75*(methyl acetate)3 182 Figure A . l l . Formation o f second and subsequent bridges (the first bridge was formed between A and K) towards the formation o f 75»(methyl acetate)3 183 xv List of Schemes Scheme 1.1. Synthesis o f spherand 6 4 Scheme 1.2. Assembly o f catenane 10b 5 Figure 1.3. Schematic representation o f a rotaxane 6 Scheme 1.3. Sythesis o f rotaxane 17 7 Scheme 1.4. Synthesis o f Cucurbit[n]urils 9 Scheme 1.5. Synthesis o f benzylthia-bridged carceplex 36»guest 13 Scheme 1.6. Synthesis o f carceplex 38»guest 14 Scheme 1.7. Synthesis o f cyclic oligomers 15 Scheme 1.8. Synthesis o f bis-carceplex 44«(pyrazine)2 16 Scheme 1.9. Synthesis o f trimer carceplex 45«(DMF)3 16 Scheme 1.10. Synthesis o f supercarceplex 48«(DMSO)7 17 Scheme 1.11. Synthesis o f disulfide-bridged carceplex 50»(DMF)2 and carceplex 50»(DMA) 2 18 Scheme 1.12. Synthesis o f hemicarceplex 52«DMA 19 Scheme 1.13. Synthesis o f capsule 54»pyrazine 20 Scheme 1.14. Assembly o f 58 22 Scheme 1.15. Synthesis o f hemicarceplex 60»guest 24 Scheme 2.1. Formation o f carceplex 38»guest, hemicarceplex 64»guest and capsules 62«guest and 65«guest 32 Scheme 2.2. Formation o f hemicarceplex 60«guest from tetrol 37 34 Scheme 2.3. Formation o f hemicarcplex 60«guest from diol 61, and complexes 61, 67-69 • guest from 61 and 67-69 35 xv i Scheme 3.1. Synthesis o f cyclic oligomers from 39 62 Scheme 3.2. Formation o f bis-capsule 71«(pyrazine)2 and bis-carceplex 44»(pyrazine)2 from tetramer 43 63 Scheme 3.3. Formation o f tris-carceplex 75»(methyl acetate)3 from cyclic hexamer 74..67 Scheme 3.4. Formation o f tris-capsule 76*(methyl acetate)3 from hexamer 74 74 Scheme 4.1. Formation o f cyclic oligomers from diol 39. 83 Scheme 4.2. Formation o f trimer carcerplex 45«(DMF) 3 and trimer cavitand 77 83 Scheme 4.3. Formation o f host 78 from trimer cavitand 77 84 Scheme 4.4. Formation o f 81 85 Scheme 4.5. Formation o f monobenzyl 68 100 Scheme 4.6. Synthesis o f compounds 79-81 101 Scheme 5.1. Formation o f cyclobutadiene from 99 within the shell o f hemicarceplex 64, and its reactions 125 Scheme 5.2. Reduction and oxidation reactions within the cavity o f hemicarceplex 60. 126 Scheme 5.3. Formation o f hemicarceplexes 60»116-118, and 119 starting from 60*115 128 Scheme 5.4. Formation o f hemicarceplexes 120*123-125 and 121 • 123-125, and insertion products 126 and 127 starting from hemicarceplexes 120*122 and 121*122 129 Scheme 5.5. Formation o f trimer carceplexes 45*129, 45*130*CH2=CH2 and 45*131*CH2=CH2 starting from trimer carceplex 45*128 130 Scheme 5.6. Formation o f 134 from 132, and its reactions 132 xv i i Scheme 5.7. Photolysis o f 142 and 146, and their subsequent products 133 Scheme 5.8. Formation o f 45*134, 45*135 and 45»141 starting from 45*132 134 Scheme 5.9. Formation o f 60«150 and 60»151 starting from 60»115 134 Scheme 5.10. Formation o f 152»l,3,5-tris(iodomethyl)benzene 135 Scheme 5.11. Synthesis o f 45«PhCOCHN 2«NFP 136 Scheme 5.12. Formation o f 45»PhCH=C=0«NFP from photolysis o f 45«PhCOCHN 2«NFP 144 Scheme 5.13. Formation o f cycloaaduct 154 148 Scheme 5.14. Formation o f 45«PhCH 2 COOH«NFP»(H 2 0) n from hydrolysis o f 45»PhCH=C=0«NFP 153 Scheme 6.1. Formation o f cycloadduct 154 169 Scheme 6.2. Formation o f ketocarbenes, oxirenes and ketenes from diazo ketones 170 List o f Tables Table 2.1. Template ratios for the formation o f carceplex 38»guest and hemicarceplex 64«guest, starting from 37 and 63, respectively 33 Table 2.2. Template ratios for the formation o f 60«guests starting from 37 and 61 36 Table 2.3. K a and K r e K for 61»guests (OH, OH) 39 Table 2.4. K a and K r e i . for 67*guests (OH, OCH2CH2CH2CH2Br) 43 Table 2.5. K a and K r e ). for 68»guests (OH, OBn) 43 Table 2.6. K a and K r e i . for 69»guests (OMe, OMe) 44 Table 2.7. Template ratios for the formation o f 60»guests from 37 and 61 in either NFP or nitrobenzene 45 Table 2.8. Template ratios for the formation o f 61»guests starting from 61 48 Table 3.1. NOESY and COSY correlations o f selected protons in tris-carceplex 75«(methyl acetate)3 69 Table 3.2. NOESY/EXSY and COSY correlations o f selected protons in tris-capsule 76«(methyl acetate)3 80 Table 4.1. Data obtained from the decomplexation o f bis-hemicarceplex 78«(1,3,5-triethynylbenzene)2 at 100 °C 116 Table 4.2. Data obtained from the decomplexation o f bis-hemicarceplex 78«(1,3,5-triethynylbenzene)2 at 120 °C 117 Table 5.1. COSY and NOESY correlations o f selected protons in 45«PhCOCHN2«NFP 141 Table 5.2. COSY correlations o f selected protons o f bound guests in 45«PhCH=C=0»NFP 148 xix Table 5.3. COSY and NOESY correlations o f selected protons o f bound guests in 45»guest(s) List of Abbreviations 1 -D one-dimensional 2-D two-dimensional A C 1,3 substituted or linked Bn benzyl calcd calculated COSY correlated spectroscopy CPK Corey-Pauling-Koltun 8 chemical shift (ppm) A8 change in chemical shift AG* free Gibbs energy o f activation D B U l,8-diazabicyclo[5.4.0]undec-7-ene D M A AfJV-dimethylacetamide D M F AfN-dimethylformamide D M P U 1,3-dimethyl-3,4,5,6-tetrahydro-2(li/)-pyrimidinone DMSO dimethylsulfoxide d doublet E a activation energy equiv. equivalent EXSY Exchange SpectroscopY GDS guest determining step IR infrared J coupling constant xx i K a association or binding constant Krei. Relative association constant m multiplet M A L D I - M S matrix asssisted laser desorption ionization mass spectroscopy m/z mass to charge ratio NFP Af-formylpiperidine N M P Af-methylpyrrolidinone N M R nuclear magnetic resonance NOESY nuclear overhauser effect via correlation spectroscopy ppm part per mi l l ion RT room temperature s singlet ( 'H NMR) t triplet ti/2 half-life TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography U V ultraviolet v/v volume per volume Acknowledgements First o f all, I would like to thank my research supervisor, Professor John Sherman, for his guidance, constructive criticism and high standards. I am indebted to the past and present members o f the Sherman group (Ashley Causton, Richard Cheng, Alfredo Franco, Susan Gui, Heidi Huttunen, Ayub Jasat, Vishnu Kodumuru, James Lan, Darren Makeiff, Christoph Naumann, Mehran, Nikan, Samuel Place, Emily Seo, Jianyu Sun and Diana Wallhorn) for their help and numerous discussions regarding my projects, presentations, proof-reading o f materials, etc... I am grateful to the Staffs o f the N M R and Mass Spectrometry Labs for their assistance in acquiring N M R and MS data for my research. I would like to express my gratitude to the research groups o f Professor Dolphin, Professor Piers and Professor Scheffer, and Dr. Subramanian Iyer for letting me use their equipment. I would also like to thank Professor Thomas Tidwell from the University o f Toronto for sending me a sample o f PhCOCHN2 for the work described in o f Chapter 5. I am indebted to Professor Ralf Warmuth for deriving the rate law for the decomplexation experiments described in Chapter 4. I would also like to thank Dr. Nick Burlinson for his valuable discussions in this matter. I would like to thank my friends, in particular, Cristian Harrison, Ayub Jasat , An i l Jugessur and Diana Wallhorn for their moral support and making life outside the lab more enjoyable. I would also like to extend my gratitude to my cousin Roy Mungaroo and his family who made my stay in Vancouver more pleasant. Finally, I would like to thank my family, my soul mate Olga Steriopolo and her family for their unconditional love, support and encouragement, and for believing in me. xx i i i I dedicate this thesis to my family and my soul mate Olga Steriopolo xxiv 1.0 Introduction 1.1 Supramolecular Chemistry Supramolecular chemistry is the study o f the formation o f reversible or irreversible assembly o f large "supermolecules" from smaller molecular subunits.1 The assembly process (reversible and irreversible) is usually facilitated by hydrogen bonding, aromatic K-K stacking, CH-7C, polar and van der Waals interactions. The structural features and chemical properties o f the assembled macro-molecules are different from those o f the building blocks. The formation o f a "supermolecule" involves two important processes: molecular recognition and self-assembly. The process by which molecules bind other molecules in a selective way and a structurally well-defined pattern o f intermolecular forces is called molecular recognition. 2 The highly specific substrate recognition by enzymes is a good example o f such a process. The efficient and spontaneous assembly o f molecules into structured and stable noncovalently joined aggregates is called self-assembly.3 Since the self-assembled aggregate represents the thermodynamically most stable structure, its structure is retained after the assembly process. The pairing o f complementary nucleoside bases to form the double helix tertiary structure o f D N A is a perfect example o f a self-assembly process. Templation plays a key role in supramolecular chemistry as it usually helps in the assembly o f complex molecular structures. A chemical template organizes an assembly o f atoms or molecules in order to accomplish a particular l inking o f the atoms or molecules. 4 The formation o f crown ethers is a good example o f a templated process. In the last three decades, researchers have made considerable effort in synthesizing "supermolecules". Such molecules may exhibit molecular recognition, and may function as molecular switches or drug delivery systems. Crown ethers, cryptands, spherands, catenanes, rotaxanes, cyclodextrins, cucurbit[n]urils, cryptophanes, calix[n]arenes, cavitands, carceplexes, hemicarceplexes, hemicarcerands, capsules, clathrates and zeolites are all examples o f "supermolecules". The fol lowing sections give a br ief summary o f the above compounds. 1.1.1 Crown Ethers Crown ethers are large cyclic polyethers. Their structures are symmetric, and they usually bind cations. The binding process is quite specific. For example, 12-crown-4 (1) forms a complex wi th singly charged cation such as L i + but not K + (Figure 1.1).5 On the other hand, dicyclohexano-18-crown-6 (2) forms a complex with doubly charged cations such as H g 2 + but not C d 2 + or Z n 2 + , while 15-crown-5 (3) forms a complex wi th Sr 2 + but not C a 2 + . 5 Such a specificity has allowed separations o f cations.6 Crown ethers can also be used as catalysts in nucleophilic substitution reactions, especially when the nucleophiles (their salts) are insoluble in nonpolar solvents. The solubility is due to the formation o f crown ether-cation complexes.7 1 2 3 Figure 1.1. A few examples o f crown ethers 2 1.1.2 Cryptands Bicyclic and polycyclic ethers are called cryptands. They form more stable complexes in water than monocyclic ethers do. For example, 4 « K + and 4 « B a 2 + have stability constants o f 10 5 and 10 1 0 M" 1 , respectively, compared to typical values o f ~10 2 M" 1 for crown ether complexes (Figure 1.2).8 The larger the stability constant, the more l ikely that the cation is in a bound state (assuming there is one mole o f cation per mole o f host). 4 Figure 1.2. Cryptand 4 1.1.3 Spherands Spherands are rigid cyclic aromatic compounds wi th spherical cavities that are capable o f binding ions. A spherand-metal ion complex is termed a spheraplex, for example, 6«L iC l . Spheraplex 6»L iC l was synthesized in 28% yield starting from 5 (Scheme 1.1).9 Spherand 6 selectively binds L i + and N a + . Other ions, such as, L i + , M g 2 + and Ca are not bound. 3 Me Br Me Br Me 3. E D T A 4. HCI 1. BuLi 2. Fe(acac) 3 Me Me Me 5 (28%) 6 Scheme 1.1. Synthesis o f spherand 6. 1.1.4 Catenanes Catenanes are molecular "chains", the threads are interlocked, and their cavities are fi l led by the adjacent threads. For example, when 7a and 8 are mixed in water, [2]catenane 10a is formed, which is in equilibrium with the monomeric ring 9a (Scheme 1.2).1 0 The monomeric ring is the major species when the concentrations o f 7a and 8 are lower than 2 m M , whereas catenane 10a is the predominant species when the concentrations o f 7a and 8 are higher than 50 m M . When Pt(II) complex 7b is used instead, 9b does not interconvert to 10b under ordinary conditions, and vice versa. However, when 9b is heated at 100 °C in highly polar media in the presence o f NaNCb, the Pt(II)-pyridine coordinate bond becomes breakable, and two rings o f 9b rearrange to give 10b.11 Upon cooling and salt removal, pure 10b can be isolated. 4 7a, M = Pd(ll) 8 7b, M = Pt(ll) H 20 Scheme 1.2. Assembly o f catenane 10b. 5 1.1.5 Rotaxanes Rotaxanes are macrocyclic molecules that consist o f a "thread", two "stoppers" and one or two "beads", refer to Figure 1.3. 1 2 The stoppers and thread are covalently linked, whereas the bead is wrapped around the thread. The cavity o f the bead is fi l led by the thread component, hence a rotaxane is an inclusion compound. Stoddart and co-workers made rotaxane 17 in 70% yield using 11, 12 and 14 as building blocks (Scheme 1.3). 1 2 a The X-ray crystal structure o f 17 showed that its conformation was stabilized by N — H - -O and N — H — N hydrogen bonds between (a) the central amino group o f the "thread" and one o f the P-ether oxygen atoms o f the "bead" and (b) one o f the N H groups o f the "bead" and the nitrogen atom of the thread, n-% Stacking between one of the 3,5-dimethoxyphenyl rings o f the "stoppers" and one o f the aminophenol rings o f the "bead" was also involved in the stabilization o f the structure o f 17. Figure 1.3. Schematic representation o f a rotaxane. 6 11 17 Scheme 1.3. Synthesis o f rotaxane 17. 7 1.1.6 Cyc lodext r ins Cyclodextrins are bucket-shaped cyclic oligosaccharides consisting o f at least six 1-4-linked glucose units (Figure 1.4). They have a cylindrical cavity wi th diameters larger than 5 A and depth o f 7-8 A. The internal walls o f cyclodextrin cavities consist o f many methylene and methine groups, and hence the cavities are hydrophobic. Cyclodextrins bind neutral, anionic and cationic guest molecules. 1 3 Since cyclodextrins are optically active, they show some enantioselectivity in binding optically active molecules. For example, 6-amino-6-deoxy-P-cyclodextrin 18 forms a more stable complex wi th the R isomer o f hexahydromandelic acid, the complex stability constants in water at pH 6.9 at 25 °C are 2290 and 1490 M" 1 for the R and S isomers, respectively. 1 3 3 Figure 1.4. Schematic representation o f cyclodextrins, and cyclodextrin 18 1.1.7 C u c u r b i t [ n ] u r i l s Cucurbit[n]urils (CB[n]) are macrocyclic cage molecules obtained from the condensation o f glycoluril (19) and formaldehyde (Scheme 1.4). They have hydrophopic cavities, and bind small organic molecules through hydrophobic interactions. In addition, the carbonyl groups on the upper and lower rims o f cucurbiturils allow them to bind ions 18 8 and molecules through charge-dipole as well as hydrogen bonding interactions. CB[6] (21) is the most common cucurbituril, and it binds small molecules such as T H F , 1 4 toluene, 1 5/?-xylenedaiammonium ion . 1 6 Recently Dance and co-workers reported the first synthesis o f 22 wi th the inclusion o f 20.17 Compound 22«20 is crystalline and stable in solution. Its structure was elucidated by *H and 1 3 C N M R , electrospray and X-ray crystallography. O HN "NH H H + / H 2 0 H + HCHO NH O 19 Scheme 1.4. Synthesis o f Cucurbit[n]urils. n = 5-10 20, n = 5 21, n = 6 22, n = 10 1.1.8 Cryptophanes Cryptophanes are bridged aromatic compounds. Their structures are similar to those o f hemicarcerands (see section 1.1.12), and they bind small guest molecules readily in solution. For example, 23 (Figure 1.5) binds methane, chloroform and xenon in CDC1 2CDC1 2 wi th affinity constants o f 130 M"'(27 °C), 230 M_ 1 (27 °C, 860 M" 1 at 5 °C) and 3 x 10 3 M" 1 (5 °C), respectively. 1 8 9 23 Figure 1.5. Cryptophane 23 1.1.9 Calix[n]arenes Calix[n]arenes are [ In ] metacyclophanes. This term was introduced by Gutsche. 1 9 They are obtained from the base-catalyzed condensation o f phenols and formaldehyde. Calix[4]arenes are the most studied compounds among the calix[n]arenes because they 20 are versatile and quite easy to make (they are the major products at high temperatures). Calixarenes have been used to bind neutral molecules, metal ions and anions. They have also been used as phase transfer catalysts2 1 as well as catalytic receptors. 2 2 Calixarenes have also been used in self-assembly processes. For example, 24*25 is formed when calixarene 24 and metallo-porphyrin 25 are mixed together. 24«25 is a bifunctional receptor. The calixarene moiety binds N a + , whereas the metallo-porphyrin binds SCN" (Figure 1.6).2 3 Several units o f calix[4]arenes have also been used to make large assemblies.2 4 10 Figure 1.6. Self-assembly o f bifunctional metallo-porphyrin receptor 24»25. 1.1.10 Cavitands Cavitands are compounds with enforced cavities, which are capable o f forming complexes (caviplexes) with neutral organic molecules or ions. 2 5 Binding studies have been done in organic as wel l as aqueous media. For example, cavitand 26 forms 26«1-fluoroadamantane (26«29) and 26»l-iodoadamantane (26»30) wi th stability constants o f <5 and 4393 M" 1 , respectively, in toluene-d s at 25 °C (Figure 1.7).2 6 Cavitand 27 binds small neutral guest molecules such as (CH 3 ) 2 CO and C H 3 C 0 2 C H 3 in D 2 0 wi th association constants o f 19 and 270 M" 1 , respectively, at a pD o f 9.4 and temperature o f 11 25 °C. 2 7 On the other hand, 28 binds fairly large ammonium salts, such as aminomethyladamantane and aminomethylcyclohexane hydrochlorides (31 and 32), and 28 Af-methylquinuclidinium trifluoroacetate (33) in D 2 0 . R R R R 26 R= CH 2 CH 2CgH5 R R R R 28 FT = NHC(0 )OCH 2 CH 3 R.= (CH 2 ) 4 OC(0)NHCH 2 C(0)NHC(CH 2 OSi(CH 3 ) ) 3 27 R = ( C H 2 ) 3 O P 0 3 H N H 4 X NH 3+CI" 32 NH 3+CI" 29, X = F 31 30, X = I CH 0 CFoCOO" 33 Figure 1.7. Structures o f cavitands 26-28, and guests 29-33. 12 1.1.11 Carceplexes A carceplex is a closed-surface macromolecule within which a guest molecule is permanently entrapped. The entrapped guest molecule can be only released by breakage o f covalent bonds o f the carcerand (an empty carceplex). Donald J. Cram proposed the idea o f a carceplex in 1983 2 9 and reported the synthesis o f benzylthia-bridged carceplex 36a«guest (the very first carceplex) in 1985 (Scheme 1.5). 3 0 ' 3 1 Since the solubility o f carceplex 36a»guest was poor, its ful l characterization was not possible. 35 36»Guest 36a, R = C H 3 36b,R = ( C r ^ ) 4 C H 3 36c,R = CH2CH2Ph 36d,R = ( C r ^ ) 1 0 C H 3 Scheme 1.5. Synthesis o f benzylthia-bridged carceplex 36 ©guest. Carceplex 38 • guest, the first ful ly characterizable/soluble carceplex, was made by Cram and Sherman in 1989 by linking two units o f tetrol 37 using bromochloromethane as linker (Scheme 1.6).3 2 The reactions to form carceplex 38»guest were run in D M A , D M F , and DMSO as solvents and gave carceplexes 38»DMA, 38«DMF and 38«DMSO in 54, 49 and 6 1 % yields, respectively. The soluble benzylthia-bridged carceplex 36b-13 d»guests were eventually made and ful ly characterized. Guests such as methanol, ethanol, acetonitrile, D M A , butanone and pentan-3-one were trapped. R = CH2CH2Ph 38'Guest Scheme 1.6. Synthesis o f carceplex 38«guest. Dalcanale et al have successfully used square-planar palladium(II) and platinum(II) complexes to make positively charged metal-bridged carceplexes wi th the inclusion o f CF3SO3". 3 3 In our labs, we are currently investigating the linkage o f more than two units o f tetrol 37 in order to create larger and higher order assemblies to trap large/multiple guest molecule(s) to make bigger carceplexes, hemicarceplexes and complexes. Dio l 39 has been successfully used by Chopra to make cyclic oligomers as novel hosts. 3 4 When compound 39 was treated with CH 2 BrCl and K2CO3 in DMSO or DMF, products such as trimer 40 and tetramer 41 were formed (Scheme 1.7). 14 B n O O B n BnO OH ? H Q B n 39 R = C H 2 C H 2 P h 1) CH2t3rCI K0CO3 DMF or DMSO »• 2) H 2 / cat 40, R ! = Bn 42, R ! = OH o X o O i R O R o 7 OR1 R'O W—OR Z - 0 O R I o-A 4 1 , R ! = Bn 43, R' = OH Scheme 1.7. Synthesis o f cyclic oligomers. + Oligomers When a mixture o f tetramer 43, K2CO3, CH 2 ClBr, pyrazine and NMP was heated at 60 °C, bis-carceplex 44«(pyrazine)2 was obtained in 74% yield (Scheme 1.8).3 4 Similarly, when a mixture o f 42, 2,4,6-tris(bromomethylmesitylene), K I , K2CO3 and D M F was stirred for several hours, trimer carceplex 45«(DMF)3 was obtained in 36% yie ld. 3 5 When the reaction was run in D M A , trimer carceplex 45«(DMA) 2 was isolated 15 in 82% yield. 3 5 Later on, trimer 42 was also used to trap larger molecules such as benzophenone, butyrophenone, 1,3,5-triethynylbenzene and trimethyl 1,3,5-benzenetricarboxylate.3 6 The inner phase o f 45 has also been used to carry out reactions. This w i l l be discussed further in chapter 5. 3 6 Scheme 1.8. Synthesis o f bis-carceplex 44«(pyrazine)2. Scheme 1.9. Synthesis o f trimer carceplex 45»(DMF)3. 16 In our labs, Makei f f also synthesized and used A,B-linker trimer 47 to make supercarceplex 48«(DMSO)7 in 35% yield using the conditions shown in Scheme 1.10. 3 6 b Supercarceplex 48«(DMSO)7 is the largest carceplex ever made. Even though 48 has seven bound DMSO molecules, its cavity is not ful ly fi l led, it can reversibly bind additional guest molecules such as water. Scheme 1.10. Synthesis o f supercarceplex 48»(DMSO )7 . A l l the above-mentioned carceplexes are built from [4]cavitands. However Naumann was the first person to make a carceplex from [5]cavitands (a larger building block). When a mixture o f pentathiol 49, CS2CO3 and either DMF or D M A was stirred in the presence o f oxygen, disulfide-bridged carceplex 50«(DMF)2 and carceplex 50«(DMA)2 were obtained in 25 and 16% yields, respectively (Scheme 1.11). The entrapment o f two D M F or D M A guest molecules by 50 obviously suggests that its 17 cavity is considerably bigger than those o f 36 and 38 which entrap only one D M F or one D M A guest molecule. Incidentally, these are the first examples o f a disulfide-bridged carceplex. 2 Scheme 1.11. Synthesis o f disulfide-bridged carceplex 50»(DMF)2 and carceplex 50» (DMA) 2 . 1.1.12 Hemicarceplexes Hemicarceplexes are like carceplexes, but differ in that the shell's portals are large enough for guest egress to occur upon sufficient heating without covalent bond breakage. 3 1 ' 3 8 Hemicarcerands are the corresponding host molecules without entrapped guests. The inner phase o f hemicarcerands has been used to generate and stabilize 31 38 reactive intermediates. This w i l l be discussed in chapter 5. ' Tetrol 37 and its anologues have been extensively used to ' make a series o f hemicarceplexes, 3 9 for example when a mixture o f 37, 1,2-(BrCH2)2CgH4 (51), D M A and CS2CO3 were stirred for several hours, hemicarceplex 5 2 « D M A was isolated in 23% yield, refer to Scheme 1.12. 3 9 h 52»DMA is stable at room temperature, guest egress starts occuring at elevated temperatures. D M A was successfully released when 5 2 « D M A was heated in 1,4-(CH3)2CHC6H 4CH(CH 3) 2 (a solvent too large to enter the cavity o f 52) 18 at 160 °C for 24 hours. Hemicarcerand 52 easily binds small molecules such as H 2 0 , N 2 and 0 2 at ambient temperature. Cram and co-workers have also made bis-hemicarceplexes. Please refer to chapter 4 for more details. 4 0 2 5 2 . D M A (23%) Scheme 1.12. Synthesis o f hemicarceplex 52»DMA. 1.1.13 Capsules Capsules are formed by the non-covalent self-assembly o f smaller sub-units. 4 1 ' 4 2 The assembly o f capsules is reversible, and their thermodynamic stability is dependent on solvent and temperature. Hydrogen bonding plays a major role in the assembly o f capsules. A variety o f capsules have been made in our labs, for example when 2 mole equivalents o f cavitand 53 were treated with 4 mole equivalents o f D B U in the presence o f excess pyrazine in CDCI3, capsule 54«pyrazine was quantitatively formed (Scheme 1.13).4 3 The two cavitands were held together by charged hydrogen bonds, as shown in Scheme 1.13. The identity o f 54«pyrazine was confirmed by electrospray ionization mass spectrometry and X-ray crystallography. Capsule 54 binds other guest molecules as 19 well , but pyrazine was found to be the best guest, for example, 54»pyrazine is 1000-fold more stable than 54«benzene in nitrobenzene-ds at 60 °C. However, these capsules fall apart by adding 10% o f a polar solvent such as CD3OD. Rebek and others have successfully used calixarene and resorcinarene modules to make a series o f dimeric capsules. 4 1 ' 4 2 Bis-capsules have also been made in our laboratories, this w i l l be discussed in chapter 3. Me Me Me Me 54«Guest Scheme 1.13. Synthesis o f capsule 54«pyrazine. Atwood and MacGil l ivray used six molecules o f 55 (Figure 1.8) to make 556»(H20)g in wet apolar aromatic solvents. Hexameric capsule 556»(H20)8 is stable in solution as. well as in the solid state.4 5 The structure o f 55 6«(H 20)8 was determined by *H N M R spectroscopy, mass spectrometry, and X-ray crystallography. Atwood described 556«(H20)g as a snub cube, one o f the 13 Archimedean solids, and he estimated the internal volume o f 55 6«(H 20)8 to be -1,375A 3 . Capsule 55 6 »(H 2 0) 8 has been reported by Rebek and Cohen to encapsulate other guest molecules such as tetraalkylammonium 4 6 ' 4 7 or phosphonium 4 6 salts, and tetrabutylantimony (V) and tetraphenylantimony(V) bromides. 4 8 20 The above-mentioned hexameric capsules were all assembled in fairly non-polar solvents. Mattay and co-workers found that C-isobutylpyro-gallol[4]arenes 56a formed hexameric capsule (56a) 6»(CH 3CN)io in acetonitrile.4 9 This giant capsule was held together by 72 intermolecular O—H- -0 hydrogen bonds between the hydroxyl groups o f adjacent C-isobutylpyro-gallol[4]arene molecules. However, crystals o f (56a) 6«(CH 3CN)io were obtained only once, all attempts to make it for second time was unsuccessful. 4 9 Also, no evidence o f a hexameric structure was obtained in solution. Atwood and co-workers eventually managed to grow crystals o f hexameric capsules (56a-d)6»(CH3OH)i8 in methanol wi th either nitrobenzene or o-dichlorobenzene as co-solvent in a reproducible way (Figure 1.8).50 These capsules are stable in apolar media (acetone-^ and toluene-^) as well as in polar media (DMSO-Jg and D 20/acetone-J6 (1 :1 , v/v)). (56a-d) 6«(CH 3OH)i8 is also stable up to at least 150 °C in acetone-^ (pressurized N M R sample). WW, l - V — i 1 I V J L I (jf ! ; l \ " V - / 3 1 , I "V — I I 56a, R = isobutyl, R1 = R 2 = OH 56b, R = n-propyl, R1 = R 2 = OH 56c, R = n-butyl, R1 = R 2 = O H 56d, R = n-pentyl, R1 = R 2 = OH Figure 1.8. C-isobutylpyrogallol[4]arenes 55 and 56, and 566»(guest)n. 21 Metal containing capsules have also been reported. For example, Fujita and co-workers found that two molecules o f 58 (58 is itself formed from four and six molecules o f 7a and 57, respectively) and four molecules o f m-terphenyl 59 self-assemble into dimeric capsule 58 2«59 4 in water (Scheme 1.14).5 1 Capsule 58 2»59 4 is stable in solution as well as in the solid state. 1.1.14 Solid State "Supermolecules" 1.1.14.1 Clathrates Clathrates are crystalline solids that consist o f interstitial guest molecules. For example, urea crystallizes in a hexagonal lattice in the presence o f guest molecules such 22 as dibutyl maleate and dibutyl fumarate. 5 2 In the absence o f an appropriate guest, urea crystallizes in a tetragonal lattice instead. Thiourea, water, cyclodextrins, cyclophospagene and deoxycholic acid are all capable o f forming clathrates.5 3 1.1.14.2 Zeolites Zeolites are insoluble polymeric inorganic solids consisting o f pores o f molecular dimensions o f 3-13 A that allow inclusion o f small molecules such as water and benzene. 5 4 The pores o f zeolites can be emptied at high temperatures without any structural changes. Figure 1.9 shows a representive zeolite structure (it has an aluminosilicate framework). It should be noted that there are other types o f structures as we l l . 5 4 Zeolites have been frequently used to remove water from solvents and gases. 5 4 In certain cases, zeolites have also been used as enzyme mimics for oxidation processes.55 Figure 1.9. Structure o f zeolite. 1.2 Goals and Summary of Thesis The goals o f this thesis were: 1. To study the mechanism o f formation o f hemicarceplex 60 • guest using transition state models (Scheme 1.15). The findings are discussed in Chapter 2. This chapter 23 includes reactions and complexation experiments wi th 61 (Figure 1.10) and its derivatives in A^-formylpiperidine (NFP) and nitrobenzene. C s 2 C 0 3 KI Guest NFP Br(CH2)4Br CH 2 Guest ' ; H ? QH 2 CH 2 CH2 C H 2 CH 2 \ , X C H 2 , CH^ CH 2 37 R— Ch^CH^CgHs Scheme 1.15. Synthesis o f hemicarceplex 60«guest. 60»guest Figure 1.10. Structure o f diol 61. 2. To use the cyclic hexamer o f cavitands obtained from the cyclization reaction o f A,C-diol 39 using CH 2 BrCl and K 2 C 0 3 (Scheme 1.7), and extend the work o f Chopra 34 24 That is, the goal was to make a tris-capsule and a tris-carceplex. The preparation and characterization o f these compounds are described in Chapter 3. 3. To use trimer 42 (Scheme 1.7) and diol 61 (Figure 1.10) to make bigger hosts for encapsulation o f multiple or large guest molecules. The synthesis, characterization and guest binding properties o f two new hosts obtained from the linkages o f 42 and 61 are discussed in Chapter 4. 4. To use trimer 42 (see Scheme 1.9 for structure) to incarcerate reactive compounds in the form o f trimer carceplexes 45»guest and study their reactivity in closed shells. The entrapment, and the reaction o f PI1COCHN2 to produce PhCHC=C=0 within the cavity o f 45 is discussed in chapter 5. The stability and reaction o f bound PhCHC=C=0 is also presented. In situ generation o f l,3,5-tris(iodomethyl)benzene, and its entrapment within the cavity o f an analogue o f 45 are described. The stability o f bound l,3,5-tris(iodomethyl)benzene is also discussed in chapter 5. 1.3 References 1. Steed, J. W.; Atwood, J. L. Supramolecular Chemistry, John Wiley & Sons, Chichester, 2000. • , . 2. Lehn, J.-M. Angew. Chem. Int. Ed. Engl. 1988, 27, 89. 3. Whitesides, G. M. ; Mathias, J. P.; Seto, C. T. Science 1991, 254, 1312. 4. Busch, D. H. J. Inclusion Phenom. Mol. Recognit. Chem. 1992,12, 389. 5. March, J. Advanced Organic Chemistry : Reactions, Mechanisms, and Structure, 4 t h ed.; Wiley: New York, 1992, p. 82 and references therein. 6. Heumann, K. G. Topic Curr. Chem. 1985,127, 77. 25 7. Dehmlow, E. V. ; Dehmlow, S. S. Phase Transfer Catalysis, 2 n d ed.; V C H Publishers, New York, 1983. 8. Echegoyen, L. E.; Mil ler, S. R.; Gokel, G. W.;Echegoyen, L. Inclusion Phenomena and Molecular Recognition, ed. Atwood, J. L.; Plenum Press: New York, 1990, p. 152. 9. (a) Trueblood, K.N.; Maverick, E. F., Knobler, C. B. Acta Crystallogr.1991, B47, 389. (b) Cram, D. J.; Kaneda, T.; Helgeson, R. C ; Brown, S. B., Knobler, C. B.; Maverick, E. F.; Trueblood, K.N. J. Am. Chem. Soc. 1985,107, 3645. 10. Fujita, M. ; Ibukuro, F.; Hahihara, H.; Ogura, K. Nature 1994, 367, 720. 11. Fujita, M. ; Ibukuro, F.; Yamaguchi, K.; Ogura, K. J. Am. Chem. Soc. 1995,117, 4175. 12. (a) Glink, P. T.; Olivia, A. I.; Stoddart, J.F.; White, A. J. P.; Wil l iams, D. J. Angew. Chem. Int. Ed. 2001, 40, 1870. (b) Schalley, C. A.; Beizei, K.; Vogtle, F. Acc. Chem. Res. 2001, 34, 465. (c) Kawaguchi, Y.; Harada, A. J. Am. Chem. Soc. 2000,122, 3797. (d) Clegg, W.; Gimenez-Saiz, C ; Leigh, D. A.; Murphy, A. ; Slawin, A. M. Z.; Teat, S. J. J. Am. Chem. Soc. 1999,121, 4124. (e) Schmieder, R.; Hubner, G.; Seel, C ; Vogtle, F. Angew. Chem. Int. Ed. 1999, 38, 3528. 13. (a) Rekharsky, M. ; Inoue, Y. J. Am. Chem. Soc. 2002,124, 813. (b) Hishiya, T.; Asanuma, H.; Komiyama, M. / . Am. Chem. Soc. 2002,124, 570. (c) L iu , Y. ; Han, B. -H . ; Sun, S.-X,; Wada, T.; Inoue, Y. J. Org. Chem. 1999, 64, 1487. 14. Jeon, Y . - M . ; K im , J.; Whang, D.; K im , K. J. Am. Chem. Soc. 1996,118, 9790. 15. Dantz, D. A. ; Meshcke, C ; Buschmann, H.-J.; Schollmeyer, E. Supramol. Chem. 26 1998, 9, 79. 16. Tuncel, D.; Steinke, J. H. J. Chem. Commun. 2001, 253. 17. Day, A. I.; Blanch, R. J.; Arnold, A. P.; Lorenzo, S.; Lewis, G. R.; Dance, I. Angew. Chem. Int. Ed. 2002, 41, 275. 18. (a) Canceil, J.; Lacombe, L; Collet, A . J. Chem. Soc., Chem. Commun. 1987, 219. (b) Garel, L.; Dutasta, J.-P.; Collet, A. Angew. Chem., Int. Ed. Engl. 1993, 32, 1169. (c) Bartik, K.; Luhmer, M.; Dutasta, J.-P.; Collet, A.; Reisse, J. J. Am. Chem. Soc. 1998, 120, 784. 19. Gutsche, C. D. Calixarenes; The Royal Society o f Chemistry; Cambridge, 1989. 20. Ungaro, R., Calixarenes in Action, ed. Mandolini, L.; Ungaro, R.; Imperial College Press: Singapore, 2000, p. 1. 2 1 . (a) Nomura, E.; Taniguchi, H.; Kawaguchi, K.; Otsuji, Y . J. Org. Chem. 1993, 58, 4709. (b) Taniguchi, H.; Nomura, E. Chem. Lett. 1988, 1773. 22. Pirrincioglu, N.; Zaman, F.; Will iams, A. / . Chem. Soc, Perkin Trans. 2,1996, 2561. 23. Rudkevich, D. M.; Shivanyuk A. N., Brzozka Z., Verboom W.; Reinhoudt, D. N. Angew. Chem., Int. Ed. Engl. 1995, 34, 2124. 24. (a) Castellano, R. K.; Rebek, J. Jr. J. Am. Chem. Soc. 1998,120, 3657. (b) Prins L. J.; Timmerman P.; Reinhoudt D. N. Pure &Appl. Chem. 1998, 70, 1459. 25. (a) Moran, J. R; Karbach, S.; Cram, D. J. / . Am. Chem. Soc. 1982,104, 5826. (b) for recent reviews on cavitands see; ( i )S i lwa, W.; Matusiak, G; Deska, M. Heterocycles 2002, 57, 2179. (i i) Rudkevich, D. M. Bull. Chem. Soc. Jpn. 2002, 75, 393. 26. Gibb, C. L. D.; Stevens, E. D.; Gibb, B.C. J. Am. Chem. Soc. 2001,123, 5849. 27. Gui, X.; Sherman, J. C. Chem. Commun. 2001, 2680. 27 28. Haino, T.; Rudkevich, D. M. ; Rebek, J. Jr. Am. Chem. Soc. 1999,121, 11253. 29. Cram, D. J. Science 1983, 219, 1177. 30. Cram, D. J.; Karbach, S.; K im , Y. H.; Baczynskyj, L.; Mart i , K.; Sampson, R. M. ; Kalleymeyn, G. W. Am. Chem. Soc. 1988,110, 2554. (b) Cram, D. J.; Karbach, S.; K i m , Y. H..; Baczynskyj L.; Kalleymeyn, G. W. J. Am. Chem. Soc. 1985, 707, 2575. 31 . For a recent review on carceplexes and hemicarceplexes, see: Jasat, A.; Sherman, J. C. Chem. Rev. 1999, 99, 931. 32. Sherman, J. C ; Cram, D. J. J. Am. Chem. Soc. 1989, 111, 4527. 33. Jacopozzi, P.; Dalcanale, E. Angew. Chem. Int. Ed. Engl. 1997, 36, 613. 34. Chopra, N.; Sherman, J. C ; Angew. Chem. Int. Ed. Engl. 1997, 36, 1727. 35. Chopra, N.; Sherman, J. C ; Angew. Chem. Int. Ed. 1999, 38, 1955. 36. (a) Kodumuru, V. unpublished results, (b) Makeiff, D. Ph.D. thesis, University o f British Columbia, 2003. 37. Naumann, C ; Place, S.; Sherman, J. C. J. Am. Chem. Soc. 2002,124, 16. 38. For recent reviews on hemicarcerands and hemicraceplexes see: (a) Warmuth, R. Eur. J. Org. Chem. 2001, 423. (b) Warmuth, R.; Yoon, J. Acc. Chem. Res. 2001, 34, 95. 39. (a) Piatnitski, E. L.; Deshayes, K. D. Angew. Chem. Int. Ed. 1998, 37, 970. (b) Yoon, J.; Cram, D. J. J. Am. Chem. Soc. 1997,119, 11796. (c) Helgeson, R. C ; Knobler, C. B.; Cram, D. J. J. Am. Chem. Soc. 1997, 119, 3229. (d) Yoon, J.; Sheu, C ; Houk, K. N.; Knobler, C. B.; Cram, D. J. J. Org. Chem. Soc. 1996, 61, 9323. (e) Helgeson, R. C ; Paek, K.; Knobler, C. B.; Maverick, E. F.; Cram, D. J. J. Am. Chem. Soc. 1996, 118, 5590. (f) Robbins, T. A.; Knobler, C. B.; Bellew, D. R.; Cram, D. J. J. Am. 28 Chem. Soc. 1994, 116, 111. (g) Nuwasir, L. M.; Castoro, J. A.; Yang, C. L . -C ; Wilkins, C. L. J. Am. Chem. Soc. 1992, 114, 5748. (h) Cram, D. J.; Blanda, M . T.; Paek, K.; Knobler, C. B. J. Am. Chem. Soc. 1992,114, 7765. (i) Cram, D. J.; Tanner, M . E. ; Knobler, C. B. J. Am. Chem. Soc. 1991, 113, 7717. (j) Cram, D. J.; Tanner, M. E.; Thomas, R.; Angew. Chem. Int. Ed. Engl. 1991, 30, 1024. 40. Yoon, J.; Cram, D. J. Chem. Commun. 1997, 2065. 41 . For recent reviews on calixarene and self-assembling capsules, see: (a) Rebek, J., Jr. Chem. Commun. 2000, 637. (b) Conn, M.; Rebek, J., Jr. Chem. Rev. 1997, 97, 1647. 42. For few examples o f dimeric resorcinarene capsules, see : (a) Craig, S. L.; L in , S.; Chen, J.; Rebek, J., Jr. J. Am. Chem. Soc. 2002,124, 8780. (b) Cave, G. W. V. ; Hardie, M . J.; Roberts, B. A.; Raston, C. L. Eur. J Org. Chem. 2001, 3227 (c) Park, S. J.; Hong, J.-I. Chem. Commun. 2001, 1554. (c) Shivanyuk, A.; Rebek, J., Jr. Chem. Commun. 2001, 2374. (d) MacGill ivray, R. L.; Diamente, P. R; Reid, J. L.; Ripmeester, J. A. Chem. Commun. 2000, 359. (e) Ma, S.; Rudkevich, D. M. ; Rebek, J. Jr. J. Am. Chem. Soc. 1998,120, 4977. 43. (a) Chapman, R. G.; Olovsson, G.; Trotter, J.; Sherman, J. C. J. Am. Chem. Soc. 1998,120, 6252. (b) Chapman, R. G.; J.; Sherman, J. C. J. Am. Chem. Soc. 1998, 720,9818. ' 44. Chopra, N.; Naumann, C ; Sherman, J. C ; Angew. Chem. Int. Ed. 2000, 39, 194. 45. MacGill ivray, L. R.; Atwood, J. L. Nature 1997, 389, 469. 46. Shivanyuk, A.; Rebek, J., Jr. Proc. Natl. Acad. Sci. U.S.A, 2001, 98, 7662. 47. Avram, L.; Cohen, Y. Am. Chem. Soc. 2002,124, 15148. 48. Shivanyuk, A.; Rebek, J., Jr. Chem. Commun. 2001, 2424. 29 49. Gerkensmeier, T.; W. Iwanek, W.; Agena, C.; Frohlich, R.; Koti la, S.; Nather, C.; Mattay, J. Eur. J. Org. Chem. 1999, 2257. 50. Atwood, J. L.; Barbour, L. J.; Jerga, A. Chem. Commun. 2001, 2376. 51. (a) Hiraoka, S.; Fujita, M. J. Am. Chem. Soc. 1999,121, 10239. (b) Yu , S.-Y.; Kasukawa, T.; Biradha, K.; Fujita, M. J. Am. Chem. Soc. 2000,122, 2665. (c) Ikeda, A. ; Udzu, H.; Zhong, Z.; Shinkai, S.; Sakamoto, S.; Yamaguchi, K. J. Am. Chem. Soc. 2001,123, 3872. 52. Radell, J.; Connolly, J. W.; Cosgrove, W. R. Jr. J. Org. Chem. 1961, 26, 2960. 53. Ripmeester, J. A. ; Ratcliffe C. I. Inclusion Compounds, Volume 5, Inorganic and Physical Aspects of Inclusion, ed. Atwood, J. L.; Davies, J. E. D.; MacNicol, D. D.: Oxford University Press: New York, 1991, p 37. 54. Herron, N. Inclusion Compounds, Volume 5, Inorganic and Physical Aspects of Inclusion, ed. Atwood, J. L.; Davies, J. E. D.; MacNicol D. D.: Oxford University Press: New York, 1991, p 90. 55. (a) Herron, N.; Tolman, C. A.; Stucky, G. D. J. Chem. Soc, Chem. Commun., 1986, 1521. (b) Herron, N. J. Coord. Chem., 1998,19, 25. 30 2.0 Mechanism of Formation of a Hemicarceplex Using Transition State Models. 2.1 Template Ratios and Guest-Determining Step (GDS) The formation o f carceplexes and hemicarceplexes require proper templates (guests). In their absence, the precursors give polymerized products and hemicarcerands, respectively, in low yields. Detailed studies have been done in our labs to understand the mechanisms o f carceplex and hemicarceplex formation. For example, pyrazine was found to be 10 6 better as template as ./V-methylpyrrolidinone (NMP) in the formation o f 38«guest starting from tetrol 37 (Scheme 2.1). 1 When a series o f two-guest reactions are run, like guests A and B in one reaction, guests B and C in a second reaction, guests C and D in a third reaction, and so on, the relative guest strength o f A can be indirectly compared with that o f C and D, and vice versa. The relative guest strength is also known as the template ratio. A good guest gives a large template ratio, whereas a poor guest gives a small value. Table 2.1 shows the template ratios for the formation o f 38»guest (Scheme 2.1). 1 Under a standard set o f reaction conditions, the template ratio is constant. That is, once the guest-determining step (GDS) is reached, guest exchange stops occurring. It can only change i f conditions are altered. Charged capsule 62 • guest served as a good transition state model for the GDS in the formation o f 38»guest, and it was deduced that the formation o f the second 2 3 acetal bridge was the GDS. ' Similar results (Table 2.1) were obtained when such studies were done on o f the formation o f hemicarceplex 64»guest from 63 (Scheme 2.1). 4 31 Scheme 2.1 . Formation o f carceplex 38«guest, hemicarceplex 64»guest and capsules 62 • guest and 65 • guest. 32 Table 2.1. Template ratios for the formation o f carceplex 38»guest and hemicarceplex 64«guest, starting from 37 and 63, respectively. Guest Template Ratio for 38»guest Template Ratio for 64 • guest Pyrazine 1000000 170000 1,4-Dioxane 290000 52000 DMSO 70000 6200 THF 12000 1100 Acetone 6700 620 Pyrrole 1000 360 1,3,5-Trioxane 100 10 D M A 20 2 N M P 1 1 In our labs, template studies have also been performed on the formation o f benzylthia-bridged carceplex 36«guest (Scheme 1.5 in Chapter 1) and of slightly larger hemicarceplex 60«guest (Scheme 2.2). In the formation o f carceplex 36«guest, a guest selectivity range o f two mil l ion was observed.5 In the formation o f hemicarceplex 60* guest, p-xylene and NFP were found to be the best and worst guest, respectively (p-xylene is 3600 times as good as NFP). 6 It was thought that capsule 62»guest could serve as a good transition state model for the GDS in the formation o f 60«guest. However, results obtained from templation studies in the formation o f 60 • guest suggest that capsule 62• guest is not a good transition state model for the GDS. 6 Larger guests served as good templates in the formation 60»guest, which otherwise were not suitable for 38 33 and 62. It has been postulated that either the formation of the third or fourth bridge is the GDS, i.e., once the second or third bridge is formed, the appropriate guest stays permanently within the shells of the intermediate under the reaction conditions.6 R = CH 2CH 2C 6H 5 60*guest Scheme 2.2. Formation of hemicarceplex 60»guest from tetrol 37. » 2.2 Goal of this Study Since diol 61 can be fairly easily made,7 it was the chosen precursor to make hemicarceplex 60«guest (Scheme 2.3) and determine the template ratios of the guests used in the previous study.6 Host 61 is most probably a late intermediate on the reaction pathway in the formation of 60 • guest. A good correlation between the two sets of template ratios (values obtained under the conditions shown in Schemes 2.2 and 2.3) would confirm that it is the formation of the fourth bridge that is the GDS in the synthesis of 60«guest. A bad correlation would suggest that the GDS is prior to the formation of the fourth bridge. 34 As the cavity size and shape (revealed by C P K models) of 61 are complementary to those of the guests employed in the hemicarceplex reactions, another goal was to perform binding studies with hosts 61 and its derivatives. Results obtained from such studies would give information about the structure of the transition state for the GDS. 61 C s 2 C 0 3 KI Guest NFP Br(CH 2) 4Br 2H, .Cfi, • CH 2 CH, QH, CH 2 . -CM, ph R R R 60»guest R R R R H. I I ,H H | I ,H R R R -H H i I .H Nitrobenzene Guest 61, R 1 = R 2 = H 66, R 1 = H, R 2 = C H 2 C H 2 C H p H 2 O S ( 0 ) 2 C H 3 67, R1 = H, R 2 = C H 2 C H 2 C H 2 C H 2 B r 68, R1 = Bn, R 2 = H 69, R1 = R 2 = Me 61, 67-69»guest R — CH 2CH 2CgH5 Scheme 2.3. Formation of hemicarceplex 60»guest from diol 61, and complexes 61, 67-69«guest from 61 and 67-69. 35 2.3 Results and Discussions 2.3.1 Template Studies with Diol 61 in N F P Diol 61 was made using Cram's procedure,7 and it was used as a precursor to make 60«guest. The reactions were run, and the template ratios were calculated in the same way as reported previously, 6 but only seven guests were used, namely: p-xylene, p-dichlorobenzene, 3-pentanol, 2-butanol, cyclohexane, isopropyl acetate and NFP. The results obtained in these studies together wi th those obtained when the reactions were done wi th 37, are summarized in Table 2.2. These two sets o f values compare very wel l . This suggests that the guest-determining step is indeed formation o f the fourth bridge. Had the GDS been the formation o f either the second or third bridge, then the two sets o f template ratios would have been completely different. Table 2.2. Template ratios for the formation o f 60«guests starting from 37 and 61. Guests Template ratio Template ratio (starting from 61, (starting from 37) using NFP as solvent) p-xylene 3700 3600 p-dichlorobenzene 870 840 3-pentanol 390 490 2-butanol 140 200 cyclohexane 28 58 isopropyl acetate 9 10 NFP 1 1 3 6 2.3.2 Binding Studies with 61 and its Derivatives A 2.73 m M solution o f diol 61 was prepared in nitrobenzene-^, 500 juL portions were added to N M R tubes and excess amounts o f the appropriate guests were added to record the *H N M R spectra o f the pure complexes. Complexes between 61 and guests from Table 2.2 did form (Figure 2.1), and equilibrium was reached within minutes (no changes were observed when the N M R data were collected right after mixing and several hours later). Known amounts o f two or more guests were then added to solutions o f 61, and the bound guest signals were carefully integrated to find their relative association constants ( K r e i ) . The results are summarized in Table 2.3 (the K r e i . o f 61«p-xylene is normalized to 3700). The relative association constants o f 61»/>-xylene, p-dichlorobenzene, cyclohexane and isopropyl acetate are comparable with the template ratios o f the hemicarceplexes. However, 2-butanol and 3-pentanol show large discre-pancies, they are better guests in the complexation experiments than in the formation o f hemicarceplex 60«guest. Complexation at 80 °C (the temperature at which the hemicarceplex reactions were carried out) did not give any better values. Excess D B U was then added to a solution o f 61 in nitrobenzene-Jj to form a charged species; such a species likely forms during the course o f the hemicarceplex formation. The chemical shifts o f 61 in the presence o f D B U are different from those o f 61 without D B U , refer to the 4.5-6.5 ppm region in Figure 2.3. M A L D I - M S o f 61 in the presence o f D B U gave signals corresponding to a singly charged (negative) species, most l ikely only one proton was pulled off, and capsule-like intermediate 61a was formed (Figure 2.2). Upon the addition o f guests to a mixture o f 61 and D B U in nitrobenzene-^, 37 (a) 9.5 8.5 7.5 6.5 5.5 4.5 3.5 2.5 1.5 0.5 -0.5 -1.5 -2.5 (ppm) Figure 2.1. ! H N M R spectra (400 MHz, nitrobenzene-^ at 27 °C) o f (a) 2.73 m M diol 61, (b) 2.48 m M diol 61 and 24.8 m M 3-pentanol. 38 complexes were formed. The chemical shifts o f 61«guest in the presence o f D B U are different from those o f 61, 61 in the presence o f D B U without guest, and 61»guest in the absence o f D B U , refer to Figures 2.2 and 2.3 (in particular 4.0-6.5 and 0.0-2.5 ppm regions) and to the experimental section to see the exact chemical shifts o f these complexes. The K r e i . values o f 61*guest in the presence o f D B U correlate even worse than in the absence o f base, as the binding constant o f />xylene dropped by more than tenfold, while those o f 2-butanol and 3-pentanol did not change by much. These results clearly indicate that 61 does not serve as a good transition state model for the guest-determining step in the hemicarceplex reaction. Table 2.3. K a and K r e i . for 61*guests (OH, OH) Guests K a ( a t 2 7 °C)/MA K r e l (at 27 °C) K r e i . (at 80 °C) K a ( w i t h D B U at 27 °C)/M{ Krel. (with D B U at 27 °C) K r e l . (with D B U at 80 °C) p-xylene 1300 3700 3700 110 3700 3700 p-dichlorobenzene 220 630 - - - - -3-pentanol 690 2000 2300 450 15000 16000 2-butanol 1400 3900 6000 1700 56000 63000 cyclohexane 14 40 - - - -isopropyl acetate 3 8 - - - -NFP Not measurable Not measurable - - - -39 61a Figure 2.2 Proposed structure o f intermediate formed between 61 and D B U . Bromobutyl 67 (refer to Scheme 2.3 for structure), an intermediate further up on the reaction pathway in the formation o f 60»guest, was then synthesized to carry out the complexation studies. jP-Xylene, 3-pentanol and 2-butanol (the guest showing the biggest discrepancy) were employed in the complexation studies. The values obtained wi th these two alcohols again do not correlate with the template ratios, even at 80 °C (Table 2.4). Experiments wi th D B U were not performed because it reacts with 67 in the presence o f a guest to give 60»guest. Instead, the monobenzyl derivative 68 (Scheme 2.3) was used for this purpose, but the K r e i . values o f the complexes with D B U still did not correlate wi th the template ratios. The sets o f K r e i . values o f the complexes o f 67 and 68 without D B U were comparable. 4 0 (c) (b) (a) ' ' 0 . 5 S . 5 1 . 5 6 . 5 5 . 5 4 . 5 3 . 5 2 . 5 J . 5 0 . 5 - U . 5 - Y . S Figure 2.3. ' H N M R spectra (400 MHz, nitrobenzene-^ at 27 °C) o f (a) 2.73 m M diol 61, (b) 2.65 m M diol 61 and 7.95 m M D B U (c) 2.41 m M diol 61, 7.25 m M D B U and 24.1 m M 3-pentanol. 41 61, 67 and 68 all have a common hydroxyl group. It is very l ikely that there is an intramolecular hydrogen bond network operating between the phenolic groups o f hosts 61, 67 and 68, and the guests which can be either hydrogen bond donors (2-butanol and 3-pentanol) or hydrogen bond acceptors (2-butanol, 3-pentanol and isopropyl acetate). This interaction might not be present on the transition state o f the GDS. That is, the intermediate involved in the GDS probably does contain a free hydroxyl group. Thus, dimethyl 69 (see Scheme 2.3 for its structure) was synthesized to test this theory. Compound 69 does not contain a hydrogen atom that is suitable to form hydrogen bonds wi th guests such as 2-butanol and 3-pentanol. Hence, the complexes would be expected to have similar non-covalent interactions as the hemicarceplexes have, i.e., it could serve as an acceptable transition state model for the guest-determining step in the hemicarceplex reaction. Indeed, when complexation experiments wi th dimethyl 69 were performed, the fol lowing order in guest affinity was obtained: /(-xylene > p-dichlorobenzene > 3-pentanol > 2-butanol > cyclohexane > isopropyl acetate (Table 2.6). This order is the same as the one obtained from the hemicarceplex reactions, however the K r e i . values are slightly different from the template ratios. This could be due to one, or the combination o f all the fol lowing reasons: (i) Some residual hydrogen bonding between the host and guests, especially wi th 2-butanol. (i i) The reactions were run in NFP, but the complexation experiments were done in nitrobenzene-dj, there might be solvent effects. When the complexes and hemicarceplexes are formed, the interactions between guests and solvents should be overcome. For example, due to aromatic Ji-7i stacking between /7-xylene and 42 nitrobenzene-^, the desolvation energy o f p-xy\ene might be higher in nitro-benzene-^ than in NFP. On the other hand, the desolvation energy o f 2-butanol might be similar in nitrobenzene-d$ and NFP. As a net result, the binding energy o f host»/?-xylene might be slightly lower in nitrobenzene-G/5, while that o f host»2-butanol might be the same in nitrobenzene-rfj and NFP. This phenomenon would in turn affect the K r e i . values and template ratios, ( i i i ) The shape and portal size o f 60 are slightly different from those o f 69. For example, 2-butanol might have a better f i t (more favorable interaction) in 69»2-butanol than in 60»2-butanol, while ^-xylene might have similar f it in 60«p-xylene and in 69«p-xylene. Table 2.4. K a and K r e l . for 67»guests (OH, OCH 2 CH 2 CH 2 CH 2 Br ) Guests K a (at 27 °C)/M" 1 K r e l . (at 27 °C) K r e i . (at 80 °C) p-xylene 910 3700 3700 3-pentanol 410 1700 2400 2-butanol 2100 8700 5600 Table 2.5. K a and K r d . for 68»guests (OH, OBn) Guests K a ( a t 2 7 0C)/MA K r e l . (at 27 °C) K r e i . (at 80 °C) K (with D B U at 27 °C)M'1 K r e l . (with D B U at 27 °C) Krel. (with D B U at 80 °C) p-xylene 1300 3700 3700 570 3700 3700 3-pentanol 770 2200 2300 210 1300 2100 2-butanol 3700 11000 10000 530 3500 7400 43 Table 2.6. K a and K r e i . for 69»guests (OMe, OMe) Guests K a f a t 2 7 0 C)/M" ' K r e l . (at 27 °C) K r e l . (at 80 °C) p-xylene 7700 3700 3700 p-dichlorobenzene 1200 600 -3-pentanol 1100 520 -2-butanol 820 400 750 cyclohexane 22 11 -isopropyl acetate 2 0.9 -NFP Not measurable Not measurable -These findings reveal that out o f all the partially bridged hosts, 69 serves as the best transition state model for the guest-determining step for the hemicarceplex reaction, suggesting that there in no hydrogen bond donation from the host to the guest. Taking all the results into account, 70 (Figure 2.4) would be predicted to be the actual transition state for the GDS. We were unable to test 70 because o f its poor solubility in nitrobenzene-Jj. It is a bit surprising that 68 in the presence o f D B U did not serve as a good model for the GDS. It might be possible that D B U does not fu l ly deprotonate 68, and 2-butanol and 3-pentanol can still form hydrogen bonds wi th the host. R R R R R R R R 70®guest Figure 2.4. 70»guest, the most likely structure o f the GDS in the formation 60«guest. 44 2.3.3 Template Ratios with 61 in Nitrobenzene To verify the solvent effects, the hemicarceplex reactions were run in nitrobenzene instead o f NFP to see whether there was any change on the template ratios. Table 2.7 shows the results obtained in nitrobenzene along with those obtained in NFP. The order o f guest strength is not quite the same as in nitrobenzene as it is in NFP, implying that there is indeed a solvent effect. The set o f K r e i . values for 69 correlate a bit better wi th the set o f template ratios from nitrobenzene than with the set from NFP, however, the difference is not that significant. Table 2.7. Template ratios for the formation o f 60«guests from 37 and 61 in either NFP or nitrobenzene. Guests Template ratio Template ratio Template ratio (starting from 61, (starting from 61, (starting from 37) using NFP as using nitrobenzene solvent) as solvent) p-xylene 3700 3700 3600 /?-dichlorobenzene 870 1600 840 3-pentanol 390 2100 490 2-butanol 140 560 200 cyclohexane 28 14 58 isopropyl acetate 9 2.8 10 NFP 1 0.27 1 2.4 Summary and Conclusions The guest-determining step in the formation o f hemicarceplex 60»guest was successfully determined. Results obtained from reactions run with 61 and complexation experiments with 61, 67, 68 and 69 (see Scheme 2.3 for structures) suggest that it is the formation o f the fourth bridge, more l ikely the formation o f the last bond. The transition state most probably does not contain a neutral hydroxyl group, and host 69 is an acceptable transition state model. 61, 67, 68 and 69 and its derivatives all have different binding abilities; 61, 67, 68 prefer 2-butanol, whereas 69 prefers /(-xylene as guests. 69 could serve as a good transition state model for the guest-determining step even though the K r e i . values o f the guests are slightly different from the template ratios. The actual transition state for the guest-determining step is most probably 70 (Figure 2.4). 2.5 Experimental Section General. A l l reagents were purchased from Aldrich Co. Inc., and were used without purification unless stated otherwise. NFP and nitrobenzene were distilled, and stored over 4 A sieves under a nitrogen atmosphere. 1-D and 2-D *H N M R spectra were recorded on either an Avance-400 or a Bruker A M X 500 MHz spectrometer in either CDCI3 or n i t robenzene-us ing their residual [ H signals as references. 2-D NOESY spectra were run with mixing time o f 400 milliseconds. H; n and H o ut refer to the diastereotopic O C H 2 0 intra-bowl bridges, para -H refer to the protons on the bridged aromatic rings. The structures and proton labeling o f the guest molecules and hosts 61 and 66-69 are shown in Figures 2.5 and 2.6, respectively. Mass spectra were recorded on a Bruker Reflex M A L D I - T O F instrument in the reflectron mode. Column chromatography was performed using silica gel (BDH, 230-400). Errors in the template ratio values are estimated to be ± 20% (error generated by integration). A l l complexes took minutes or less to reach equilibrium as determined by recording ' H N M R spectra right after mixing and again hours later. A l l complexes showed slow exchange on the [ H 46 N M R timescale. Complexation experiments were performed 1-3 times; the K r e i . values o f 61, 67-69«/7-xylene are normalized to 3700 and errors are estimated to be < 20%. Dio l 61 was synthesized as described in literature.7 Since complexes 61«isopropyl acetate and 69*isopropyl acetate have weak stability and the complexed ' H N M R signals overlap wi th free host signals, only complexed guest signals are reported. a CH. C H 3 a HoC, OH r i Cl Cl C H 3 H 3 C . O CHo H,C CH, Figure 2.5. Guest structures with labeling. R R \ H 2 9H2 C H 2 R — C^ChljCgHg 61, R1 = R2= H 66, R1 = H, R2= CH2CH2CHpH2OS{0)2CH3 67, R! = H, R2= CH2CH2CH2CH2Br 68, R1 = Bn, R2= H 69, R1 = R2 = Me Figure 2.6. Structures o f hosts 61 and 66-69 wi th labeling. 47 2.5.1 Determination of Template Ratios in N F P or Nitrobenzene Diol 61 (10.0 mg, 4.56pmol), K I (2.8 mg, 16.8 jumol, 3.7 equiv.), C s 2 C 0 3 (13.9 mg, 42.7 ^ m o l , 9.4 equiv.), guest 1 (1 mol % o f the solvent), guest 2 (2-5 mol % o f the solvent) were mixed in 3.71 mL o f either N-formylpiperidine or nitrobenzene, stirred at 80 °C for 10 minutes, and then 1,4-dibromobutane (2.8 /uL, 23.0 jumol, 5.0 equiv.) was added. The rest o f the procedure was the same as described in the literature. 6 Table 2.8 summarizes the results obtained. Table 2.8. Template ratios for the formation o f 61«guests starting from 61 Guests Template ratio Template ratio (starting from 61, (starting from 61, using NFP as using nitrobenzene solvent) as solvent) p-xylene 3700 3700 p-dichlorobenzene 870 1600 3-pentanol 390 2100 2-butanol 140 560 cyclohexane 28 14 isoproyl acetate 9 2.8 NFP 1 0.27 2.5.2 Determination of K a and K r e ) . for Complexes 61«gues t A 2.73 m M solution o f diol 61 was prepared in nitrobenzene-dj, 500 fiL portions were poured in N M R tubes and excess amounts o f the appropriate guests were added to record the ' H N M R spectra o f the pure complexes. To find the K r e i . values, known amounts o f two or more guests were then added to solutions o f 61, and the bound guest signals were carefully integrated. The association constant o f only 61»3-pentanol was determined, the values o f the other complexes were obtained by mult iplying the association constant o f 61«3-pentanol with the K r e i . values o f the respective guests and then dividing them with the K r e i . value o f 61»3-pentanol (690 x K r e i . o f the appropriate guest -5- 2014). For the D B U complexation experiments, 4 mol equivalents per host o f D B U was added to 500 juL portions o f 2.73 m M o f host 61 in nitrobenzene-^ solution and the mixture was left standing for several hours. The rest o f the procedure is the same as described above. 61«/?-xylene: ' H N M R (500 MHz, nitrobenzene-^) 5 6.81-7.66 (m, C&H5 + paraH + C 6 D 4 # N 0 2 ) , 6.41 (s, 4H, H b ) , 6.17 (d, 4H, J= 6.0 Hz, H o u t ) , 6.06 (d, 4H, J = 6.0 Hz, H o u t ) , 5.19 (m, 4H, Hmethine), 5.13 (m, 4H, H m e t h i n e ) , 4.60 (m, 8H, H i n ) , 4.33 (brs, 4H, O C # 2 C H 2 C H 2 G r Y 2 0 ) , 4.18 (brs, 4H, O C # 2 C H 2 C H 2 G r 7 2 0 ) , 3.76 (brs, 4H, O C / / 2 C H 2 C H 2 C # 2 0 ) , 2.79 (m, 32H, CH2CH2?h), 2.23-2.42 (m, O C H 2 C / / 2 C 7 7 2 C H 2 0 + water + free /^-xylene), 1.95 (brs, 4H, O C H 2 G r 7 2 C / / 2 C H 2 0 ) , -1.47 (s, 6H, H a ) . 61«p-dichlorobenzene: ' H N M R (500 MHz, nitrobenzene-J5) 5 6.97-7.66 (m, CeH5 + paraH + freep-dichlorobenzene + C 6 D 4 # N 0 2 ) , 6.74 (s, 4H, H a ) , 6.19 (d, 4H, J= 6.3 Hz, H o u t ) , 5.99 (d, 4H, J= 6.5 Hz, H o u t ) , 5.12-5.17 (m, 8H, Hm e thine), 4.53 (d, 4H, J= 6.3 Hz, H i n ) , 4.48 (d, 4H, J= 6.5 Hz, H i n ) , 4.25-4.30 (m, 8H, O C # 2 C H 2 C H 2 C 7 7 2 0 ) , 3.98 (brs, 4H, O C r Y 2 C H 2 C H 2 C / / 2 0 ) , 2.78 (m, 32H, CH2CH2?h), 2.28 (brs, O C H 2 G r 7 2 C r 7 2 C H 2 0 + water), 2.02 (brs, 4H, O C H 2 G r 7 2 G r 7 2 C H 2 0 ) . 61«3-pentanol: *H N M R (400 MHz, nitrobenzene-Jj) 5 7.07-7.67 (m, C 6 H 5 + paraH + C6M ) 4 N0 2 ) , 6.31 (d, 4H, J= 6.6 Hz, H o u t ) , 5.98 (d, 4H, J= 6.7 Hz, H o u t ) , 5.13 (m, 8H, 49 H m e t hine) , 4.66 (m, 8H, H i n ) , 4.22 (m, 12H, OC/ / 2 CH 2 CH 2 C/7 2 0) , 2.78 (m, 32H, CH2CH2?h), 2.23 (m, O C H 2 C i / 2 C # 2 C H 2 0 + water), 1.97 (m, 1H, H c ) , -0.20 (m, 2H, H b ) , -0.37 (m, 2H, H b ) , -2.35 (t, 6H, J = 7.0 Hz, H a ) . 61«2-butanol: ! H N M R (400 MHz, nitrobenzene-^) 8 7.07-7.67 (m, CeH5 + paraH + C 6 # D 4 N 0 2 ) , 6.37 (m, 4H, H o u t ) , 6.01 (d, 4H, / = 6.3 Hz, H o u t ) , 5.13 (brs, 8H, Hm ethine), 4.49-4.63 (m, 8H, H i n ) , 4.08-4.17 (m, 12H, O C i / 2 C H 2 C H 2 C i / 2 0 ) , 2.77 (m, C 7 / 2 G r 7 2 C 6 H 5 ) , 2.26 (m, O C H 2 C 7 / 2 C / / 2 C H 2 0 + water), 2.0 l (m, 1H, H c ) , -0.20 (m, 1H, H b ) , -0.29 (m, 1H, H b ) , -2.17 (d, 3H, J= 6.0 Hz, H e ) , -2.42 (t, 3H, J= 6.7 Hz, H a ) . 61«cyclohexane. ] H N M R (500 MHz, nitrobenzene-Jj) 8 7.06-7.65 (m, CeH5 + paraH + QD^rTNCh), 6.27 (d, 4H, J= 6.8 Hz, H o u t ) , 5.99 (d, 4H, J= 6.3 Hz, H o u t ) , 5.11 (m, 8H, H m e t h i n e ) , 4.61 (d, 4H, J= 6.3 Hz, H i n ) , 4.52 (d, 4H, J= 6.8 Hz, H i n ) , 4.17 (m, 8H, OGrY iCH^HsC/^O) , 4.09 (m, 4H, OC/ / 2 CH 2 CH 2 C/7 2 0) , 2.76 (m, 32H, C/7 2 C// 2 Ph), 2.21 (m, O C ^ C i ^ C T ^ C ^ O + water), -0.2l(s, 12H, H a ) . 61»isopropyl acetate. ' H N M R (400 MHz, nitrobenzene-d5, partially characterized) 8 -0.05 (brs, 6H, H a ) , -1.81 (brs, 3H, H b ) . 61«p-xylene in the presence o f D B U : ' H N M R (500 MHz, nitrobenzene-^) 8 6.81-7.74 (m, C(J15 + paraR + free ^ -xylene + C 6 D 4 # N 0 2 ) , 6.41 (s, 4H, H b ) , 6.37 (d, 4H, J = 6.7 Hz, Hou,), 6.16 (d, 4H, J= 6.5 Hz, H o u t ) , 5.29 (t, J= 7.5 Hz, 4H, Hmethine), 5.24 (t, J = 7.6 Hz, 4H, H m e t b i n e ) , 4.77 (d, 4H, J= 6.3 Hz, H i n ) , 4.67 (d, 4H, / = 7.0 Hz, H i n ) , 4.48 (m, 50 6H, O C # 2 C H 2 C H 2 G r 7 2 0 ) , 4.19 (m, 6H, O C # 2 C H 2 C H 2 C / / 2 0 ) , 2.82 (m, 32H, CH2CH2?h), 2.49-2.54 (m, 8H, O C H 2 G r 7 2 G r Y 2 C H 2 0 ), 2.35 (m, OCH 2 Gfi r 2 Gr7 2 CH 2 0 + DBU),-1.43 (s, 6H, H a ) . 61»3-pentanol in the presence o f D B U : ' H N M R (500 MHz, nitrobenzene-^) 5 7.06-7.67 (m, C 6 H 5 + paraW + C 6 D 4 ^ N 0 2 ) , 6.64 (d, 4H, J= 6.1 Hz, H o u t ) , 6.12 (d, 4H, / = 6.1 Hz, H o u t ) , 5.30 (m, 4H, H m e t h i n e ) , 5.19 (m, 4H, Hm e thine), 4.89 (m, 4H, H i n ) , 4.69 (m, 4H, H i n ) , 4.26-4.30 (m, 12H, O C # 2 C H 2 C H 2 G r 7 2 0 ) , 2.76 (m, CH2CH2?h + DBU) , 2.31 (m, 12H, O C H 2 C / / 2 C # 2 C H 2 0 ) , 2.10 (m, I H , H c ) , -0.14 (m, 2H, H b ) , -0.24 (m, 2H, H b ) , -2.32 (t, 6H, J = 7 . 0 H z , H a ) . 61»2-butanol in the presence o f D B U : *H N M R (400 MHz, nitrobenzene-c/5) 5 7.06-7.67 (m, Cffls + paraW + C 6 # D 4 N 0 2 ) , 6.68 (d, 2H, J= 6.6 Hz, H o u t ) , 6.63 (d, 2H, J = 4.8 Hz, H o u t ) , 6.06 (d, 4H, J = 5.7 Hz, H o u t ) , 5.37 (m, 4H, Hm e thine), 5.29 (m, 4H, Hmethine), 4.77 (d, 2H, J = 6.4 Hz, Hin), 4.74 (d, 2H,J= 6.1 Hz, H i n ) , 4.63 (m, 4H, H i n ) , 4.10-4.25 (m, 12H, O C / / 2 C H 2 C H 2 C / ^ 0 ) , 2.79 (m, CH2CH2C^Ws + DBU) , 2.25-2.38 (m, O C H 2 C # 2 C / / 2 C H 2 0 + DBU) , 2.10 (m, I H , H c ) , -0.06 (m, I H , H b ) , -0.23 (m, I H , H b ) , -2.10 (d, 3H, J= 4.0 Hz, H e ) , -2.36 (t, 3H, J= 6.8 Hz, H a ) . 51 Table 2.3. K a and K r e ] . for 61»guests (OH, OH) Guests K a ( a t 2 7 °C)/Ml K r e l . (at 27 °C) K r e l . (at 80 °C) K a (with D B U at 27 0 C) /M- ' Krel. (with D B U at 27 °C) Krel. (with D B U at 80 °C) p-xylene 1300 3700 3700 110 3700 3700 p-dichlorobenzene 220 630 - - - -3-pentanol 690 . 2000 ' 2300. • 450 15000 16000 2-butanol 1400 3900 6000 1700 56000 63000 cyclohexane 14 40 - - - -isopropyl acetate 3 8 - - - • -NFP Not measurable Not measurable - - - -2.5.3 Synthesis and Characterization of Mesylate 66 Mesylate 66: Mesylate 66 was obtained as a byproduct in the synthesis o f 61. The purification was done as follows: the crude mixture from the synthesis o f 61 was first eluted from a silica gel column with chloroform to get rid o f the unpolar compounds, then followed by ethyl acetate/hexanes (1:3); the second fraction was collected, and dried in vacuo. The residue was recrystalized in CH 2Cl 2/hexanes to give 66 (~5% yield). *H N M R (400 MHz, CDC13) 5 7.15-7.24 (m, C(fl5, + CHCh), 6.77-6.86 (m, 8H, paraR), 6.56 (s , lH , OH), 6.02 (d, 2H, J= 7.3 Hz, H o u t ) , 5.91 (d, 2H, J= 7.1 Hz, H o u t ) , 5.82-5.85 (m, 4H, H o u t ) , 4.75-4.84 (m, 8H, H m e t h i n e ) , 4.15-4.28 (m, 12H, H i n + OGr7 2 CH 2 CH 2 C/7 2 0) , 3.80-3.94 (m, 12H, OC J r7 2 CH 2 CH 2 C// 2 0) , 2.94 (s, 3H, OS(0 2 )C#»), 2.67 (m, 16H, C H 2 C / / 2 C 6 H 5 ) , 2.46 (m, 16H, C i / 2 C H 2 C 6 H 5 ) , 1.70-2.15 (m, 16H, O C H 2 C / / 2 C # 2 C H 2 0 ) : MS: m/z = 2346.2 (100 %) [ M « H + ] , calcd for 1 2 Ci 44 1 3 CiH 1 4 o0 2 7Si - H + = 2346.9. 52 2.5.4 Synthesis and Characterization of Bromobutyl 67 Bromobutyl 67: 66 (20 mg, 8.5 / /mol) , NaBr (4.4 mg, 43 /umol, 5 equiv.) were placed in a round bottom flask, and 5 m L distilled D M F was added to it. The mixture was stirred for 24 hours, filtered through a pad o f Celite, and the solvent was removed in vacuo. The residue was redissolved in CH2CI2, silica gel (50 mg) was added to it, and the solvent was removed in vacuo. The mixture was dry loaded on a silica gel (1 g) column, and eluted wi th ethyl acetate/hexanes. The first fraction was collected, and dried in vacuo. The residue was recrystallized in CH 2Cl 2/hexanes to give 67 as a white solid (15 mg, 75%). ' H N M R (500 MHz, CDCI3) 5 7.12-7.24 (m, C(Ji5 + C//CI3), 6.78-6.86 (m, 8H, pardK), 6.56 (s, 1H, OH), 6.02 (d, 2H, J= 7.5 Hz, H o u t ) , 5.91 (d, 2H, / = 6.9 Hz, Hout), 5.83 (m, 4 H , H o u t ) , 4.73-4.83 (m, 8 H , H m e t h i n e ) , 4.14-4.26 (m, 8 H , H i n ) , 3.81-3.93 (m, 14H, OGt f 2 CH 2 CH 2 C7 / 2 0 ) , 3.45 (t, 2H, J= 6.6 Hz, O C H 2 C H 2 C H 2 G t f 2 B r ) , 2.66 (m, 16H, C H 2 C / J 2 P h ) , ) , 2.46 (m, 16H, C # 2 C H 2 P h ) , 1.83-2.06 (m, OCH 2 C/ / 2 C77 2 C H 2 ) : MS: m/z = 2330.8 (100 %) [M»H + ] , calcd for , 2 C i 4 , 3 C i H i 3 7 0 2 4 7 9 B r i » H + = 2330.9. 2.5.4.1 Determination of K a and K r e | . for Complexes 67»gues t The complexation experiments with 67 were done the same way as it was done wi th 61. 67«p-xylene: f H N M R (500 MHz, nitrobenzene-^) 5 6.81-7.66 (m, CsH5 + paraR + C 6 D 4 # N 0 2 ) , 6.36 (s, 4 H , H b ) , 5.94-6.11 (m, 8 H , H o u t ) , 5.18 (m, 8 H , H m e t hine) , 4.48-4.56 (m, 8 H , H i n ) , 4.13-4.30 (m, 10H, OC7/ 2 CH 2 CH 2 C/7 2 ) , 3.89 (m, 2H, O C / / 2 C H 2 C H 2 C / / 2 ) , 3.67 (m, 4 H , OCi / 2 CH 2 CH 2 C77 2 ) , 2.81 (m, 32H, C# 2 C77 2 Ph), 2.23-2.41 (m, 53 OCU2CH2CH2Crl2 + water + free ^-xylene), 1.94-1.99 (m, 6H, O C H 2 O T C / f c C H 2 ) , -1.51 (s, 6H, H a ) . 67«3-pentanol: ' H N M R (500 MHz, nitrobenzene-Jj) 8 6.89-7.66 (m, CsHs + paraH + C 6 / / D 4 N 0 2 ) , 6.24 (d, 2H, J= 6.7 Hz, H o u t ) , 6.17 (d, 2H, J= 6.1 Hz, H o u t ) , 6.01 (d, 2H, J = 6.0 Hz, H o u t ) , 5.96 (d, 2H, J= 5.5 Hz, H o u t ) , 5.14 (m, 8H, Hm e thine), 4.45-4.71 (m, 8H, H i n ) , 4.19 (m, 14H, O C i / 2 C H 2 C H 2 G r 7 2 ) , 3.73 (t, 2H, J= 6.5Hz, O C H 2 C H 2 C H 2 G r Y 2 B r ) , 2.79 (m, 32H, G r 7 2 G r 7 2 P h ) , 2.23 (m, 16H, OCH 2 Ci£Ci fcCH 2 ) , 1.85 (brs, I H , H c ) , -0.31 (m, 2H, H b ) , -0.45 (m, 2H, H b ) , -2.48 (t, 6H, J= 7.2 Hz, H a ) . 67«2-butanol: lH N M R ((500 MHz, nitrobenzene-^) 8 7.08-7.67 (m, C 6 H 5 + paraW + C 6 / / D 4 N 0 2 ) , 6.30 (d, I H , J= 6.1Hz, H o u t ) , 6.26 (d, IH,J= 7.2 Hz, H o u t ) , 6.19 (m, 2H, H o u t ) , 5.96-6.01 (m, 4H, H o u t ) , 5.13 (m, 8H, H ^ n e ) , 4.48-4.51 (m, 10H, H i n + O C / ^ C H ^ H z G f i k O ) , 4.06-4.13 (m, 12H, OC J rY 2 CH 2 CH 2 C/ f 2 0) , 3.56 (t, 2H, J= 6.1 Hz, OCH2CH2CH2C/72Br), 2.78 (m, 32H, CH2CH2?h), 2.25 (m, O C H 2 C / i 2 C / / 2 C H 2 + water), 1.92 (m, I H , H c ) , -0.31 (m, I H , H b ) , -0.42 (m, I H , H b ) , -2.28 (d, 3H, J= 4.9 Hz, H a ) , 2.53 (t, 3H, 7 = 7 . 0 Hz, H e ) . Table 2.4. K a and K r e i . for 67«guests (OH, OCH 2 CH 2 CH 2 CH 2 Br ) Guests K a (at 27 °C)/M"1 K r e l . (at 27 °C) K r e l . (at 80 °C) p-xylene 910 3700 3700 3-pentanol 410 1700 2400 2-butanol 2100 8700 5600 5 4 2.5.5 Synthesis and Characterization of Monobenzyl 68 Monobenzyl 68: Diol 61 (20 mg, 9.1 / /mol) , D B U (1.5 fiL, 10/zmol, 1.1 equiv.) were placed in a round bottom flask, and 5 m L acetone was added to it. The mixture was stirred for one hour, and BnBr (1.5 JUL, 10 / /mol , 1.1 equiv.) was added to it. The resulting mixture was stirred for five hours. The solvent was removed in vacuo, 1 M HC1 (25 mL) was added to the residue, and it was extracted with CH3CI ( 3 x 1 0 mL) . The organic extract was dried over anhydrous MgS04, and the solvent was removed in vacuo. The residue was redissolved in CH2CI2 (0.5 mL) , and loaded on a silica gel (1 g) column. The column was eluted with CH2CI2; the first fraction was collected, and dried in vacuo. The residue was recrystallized in CH 2Cl 2/hexanes to give 6 as a white solid (17.7 mg, 85%). *H N M R (400 MHz, CDCI3) 5 7.46 (m, 2H, OOfcCef l i ) , 7.34 (m, 2H, OCrfcCV/j) , 7.11-7.24 (m, C(Ji5 + OCH 2 C6#5 + CHCI3), 6.84 (m, 2H, paraR), 6.81 (s, IR, paraR), 6.79 (s, 2H, paraR), 6.73 (s, 2H, paraR), 6.52 (s, 1H, paraR), 6.44 (s, H, OH, exchanges with D 2 0 ) , 6.02 (d, 2H, / = 7.3 Hz, H o u t ) , 5.82 (m, 6H, H o u t ) , 5.11 (s, 2H, OCZ/iPh), 4.72-4.83 (m, 8H, H m e t h ine ) , 4.24 (m, 4H, H i n ) , 4.12-4.17 (m, 4H, H i n ) , 3.82-3.92 (m, 12H, O C i / 2 C H 2 C H 2 C / / 2 0 ) , 2.56-2.66 (m, 16H, CH 2 C// 2 Ph) , 2.41-2.48 (m, 16H, Gf / 2 CH 2 Ph), 1.96-2.03 (m, 12H, O C H 2 C / f 2 C / / 2 C H 2 0 ) : MS: m/z = 2286.4 (100 %) [M*R+], calcd for 1 2 C i 4 6 1 3 C i H i 3 6 0 2 4 « H + = 2286.9. 2.5.5.1 Determination of K a and K r e i . for Complexes 68«gues t The complexation experiments with 68 were done the same way as it was done wi th 61. 55 68«p-xylene: *H N M R (500 MHz, nitrobenzene-^) 5 7.66-6.82 (m, CeH5 + paraR + OCU2CeH5 + C6M ) 4 N0 2 + free /^-xylene), 6.35 (s, 4H, H b ) , 6.10 (d, 2H, J= 6.1 Hz, H o u t ) , 6.06 (d, 2H, J= 6.0 Hz, H o u t ) , 6.02 (d, 2H,J= 6.1 Hz, H o u t ) , 5.98 (d, 2H, J= 6.0 Hz, H 0ut), 5.29 (s, 2H, OC/ftPh), 5.12-5.19 (m, 8H, H m e t h l ne) , 4.58 (m, 4H, H i n ) , 4.51 (d, 2H, J = 6.5 Hz, H i n ) , 4.47 (d, 2H, J = 6.4 Hz, H i n ) , 4.27-4.30 (m, 4H, O C / / 2 C H 2 C H 2 C i / 2 0 ) , 4.13 (m, 4H, O C # 2 C H 2 C H 2 C / / 2 0 ) , 3.81 (m, 2H, O C / 7 2 C H 2 C H 2 C / 7 2 0 ) , 3.61 (m, 2H, O C / / 2 C H 2 C H 2 C / 7 2 0 ) , 2.79 (m, 32 H, CH2CH2Ph), 2.23 (m, O C H 2 G t f 2 C i / 2 C H 2 0 + free ^ -xylene), 1.95 (m, 4H, O C H 2 G t f 2 G t f 2 C H 2 0 ) , -1.53 (s, 6H, H a ) . 68»3-pentanol: ' H N M R (400 MHz, nitrobenzene-^) 5 7.08-7.83 (m, CeH5 + paraR + OCH 2 C6ffj+ C6flD 4 N0 2 ) , 6.66 (s, lU,pardH), 6.26 (d, 2H, / = 7.1 Hz, H o u t ) , 6.13 (d, 2H, J= 6.6 Hz, H 0ut), 6.00 (d, 2H, J= 6.7 Hz, H o u t ) , 5.95 (d, 2H,J= 6.7 Hz, H o u t ) , 5.50 (s, 2H, CH2C6H5), 5.08-5.14 (m, 8H, Umethine), 4.69 (m, 4H, H i n ) , 4.51 (m, 4H, H i n ) , 4.18 (m, 12H, O C 7 / 2 C H 2 C H 2 C / / 2 0 ) , 2.75 (m, 32 H, CH2CH2?h), 2.24 (m, OCH 2C/ftC/7;?CH 20 + water ) , 1.83 (m, 1H, H c ) , -0.33 (m, 2H, H b ) , -0.47 (m, 2H, H b ) , -2.49 (t, 6H, J = 7 . 0 Hz, H a ) . 68«2-butanol: *H N M R (400 MHz, nitrobenzene-^) 8 7.08-7.83 (m, CeH5 + paraR + O C H 2 C 6 / f t + C6ffl>4N0 2 ), 6.31 (m, 2H, H o u t ) , 6.19 (d, 2H, J= 6.7 Hz, H o u t ) , 6.00-5.95 (m, 4H, Hout), 5.53 (s, 2H, OC# 2 Ph), 5.08-5.13 (m, 4H, H m e t h m e ) , 4.59 (d, 2H, J= 6.6 Hz, H i n ) , 4.44-4.60 (m, 6H, H i n ) , 4.10-4.16 (m, 12H, OCi / 2 CH 2 CH 2 C77 2 0) , 2.75 (m, 32H, 56 CH2CH2?h ), 2.25 (m, O C H 2 C / / 2 C / / 2 C H 2 0 + water), 1.91 (m, I H , H c ) , -0.33 (m, I H , H b ) , -0.40 (m, I H , H b ) , -2.20 (d, 3H, J= 7.2 Hz, H a ) , -2.54 (t, 3H, J= 6.3 Hz, H e ) . 68«p-xylene in the presence o f D B U : *H N M R (500 MHz, nitrobenzene-^) 5 6.81-7.82 (m, C(J-[5 + paraH + OCrl2CeH5 + C 6 / / D 4 N 0 2 + free /^-xylene), 6.38 (s, 4H, H b ) , 6.10 (d, 2H, J = 6.7 Hz, H o u t ) , 6.00-6.04 (m, 6H, Hz, H o u t ) , 5.33 (s, 2H, OCH2?h), 5.14-5.19 (m, 8H, Hm e thine), 4.50-4.59 (m, 8H, H i n ) , 4.21 (m, 4H, O G r 7 2 C H 2 C H 2 C t f 2 0 ) , 4.09 (m, 4H, O C / / 2 C H 2 C H 2 C / / 2 0 ) , 3.90 (m, 2H, O C / / 2 C H 2 C H 2 C / / 2 0 ) , 3.75 (m, 2H, O C / 7 2 C H 2 C H 2 C / / 2 0 ) , 2.80 (m, 32 H, CH2CH2?h), 2.23 (m, O C H 2 C / 7 2 C / 7 2 C H 2 0 + free ^-xylene), 2.01 (m, O C H 2 G r 7 2 G f Y 2 C H 2 0 + DBU) , -1.47 (s, 6H, H a ) . 68«3-pentanol in the presence o f D B U : *H N M R (400 MHz, nitrobenzene-^) 8 7.08-7.83 (m, CsH5 + paraW + OCR2CeH5+ C^HD^HOi), 6.66 (s, j raraH), 6.26 (d, 2H, J = 7.4 Hz, H o u t ) , 6.13 (d, 2H, J= 6.4 Hz, H o u t ) , 5.99 (d, 2H, J= 6.3 Hz, H o u t ) , 5.95 (d, 2H, J= 7.0 Hz, H o u t ) , 5.49 (s, 2H, O C / / 2 C 6 H 5 ) , 5.08-5.13 (m, 8H, Hm e t hine), 4.69 (m, 4H, H i n ) , 4.51 (m, 4H, H i n ) , 4.18 (m, 12H, O G r Y 2 C H 2 C H 2 G f 7 2 0 ) , 2.23-2.76 (m, CH2CH2?h + O C H 2 C / / 2 C i / 2 C H 2 0 + D B U ), 1.84 (m, H c + D B U ), -0.32 (m, 2H, H b ) , -0.46 (m, 2H, H b ) , -2.48 (t, 6H, J= 6.9 Hz, H a ) . 68«2-butanol in the presence o f D B U : *H N M R (400 MHz, nitrobenzene-^) 8 7.07-7.83 (m, CeH5 + paraW + OCH2CeH5 + CeHD^NO^, 6.28-6.33 (m, 2H, H o u t ) , 6.19 (d, 2H, J= 5.9 Hz, H0ut), 5.96-6.00 (m, 4H, H o u t ) , 5.53 (s, 2H, O C i ^ C e H s ) , 5.08-5.12 (m, 8H, Hmethine), 4.59 (d, 2H, J = 5.6 Hz, H i n ) , 4.46-4.51 (m, 6H, H i n ) , 4.09-4.16 (m, 12H, 57 OC/^CH2CH2Gr720), 2.75 (m, CH2CH2C6rl5 + DBU) , 2.25 (m, OCrl2CH2CH2CH20 + DBU) , 1.84 (m, H c + DBU),-0.33 (m, I H , H b ) , -0.42 (m, I H , H b ) , -2.29 (d, 3H, / = 4.1 Hz, H e ) , 2.56 (t, 3H, J = 6.3 Hz, H a ) . Table 2.5. K a and K r e i . for 68»guests (OH, OBn) Guests K a ( a t 2 7 K r e i . (at K r e i . (at K (with K r e l . Krel. °C)/M" 1 27 °C) 80 °C) D B U at (with (with 27 D B U at D B U at °C)/M-' 27 °C) 80 °C) p-xylene 1300 3700 3700 570 3700 3700 3-pentanol 770 2200 2300 210 1300 2100 2-butanol 3700 11000 • 10000 530 3500 7400 2.5.6 Synthesis and Characterization of Dimethyl 69 Dimethy l 69: 61 (20 mg, 9.1 / /mol) , C H 3 I (2.3 juL, 36 ^ m o l , 4 equiv.) and K 2 C 0 3 (248 mg, 1.8 mmol, 20 equiv.) were placed in a round bottom flask, and 5 m L distilled D M F was added to it. The mixture was stirred for 24 hours, and the solvent was removed in vacuo. 1 M HC1 (25 mL) was added to the residue, and it was extracted wi th CHC1 3 (3 x 10 mL) . The organic extract was dried over anhydrous MgS04, and the solvent was removed in vacuo. The residue was redissolved in CH 2 C1 2 (0.5 mL) , and loaded on a silica gel (1 g) column. The column was eluted wi th CH 2 C1 2 ; the first fraction was collected, and dried in vacuo. The residue was recrystallized in CH 2Cl 2/hexanes to give 7 as a white solid (18.2 mg, 90%). ! H N M R (400 MHz, CDC13) 5 7.13-7.25 (m, CeHs + CHCh ) , 6.81 (m, 8R,paraK), 5.87 (d, 4H, 7.2 Hz, H o u t ) , 5.83 (d, 4H, J= 7.1 Hz, H o u t ) , 4.80 (m, 8H, H m e t h i n e ) , 4.23 (d, 4H, J= 7.1 Hz, H i n ) , 4.16 (d, 4H, J= 7.2 Hz, H i n ) , 3.87 (m, 18H, O C / / 2 C H 2 C H 2 C # 2 0 + OCH3), 2.67 (m, 16H, CR2CH2?h), 2.47 (m, 16H, 58 C// 2 CH 2 Ph), 1.99 (brs, 12H, O C H 2 C # 2 G r Y 2 C H 2 0 ) ; MS: m/z = 2224.8 (100 %) [ M » H + ] , calcd for 1 2 C i 4 i 1 3 C i H i 3 4 0 2 4 » H + = 2224.9. 2.5.6.1 Determination of K a and K r e i . for Complexes 69«gues t The complexation experiments with 69 were done the same way as it was done wi th 61. 69»p-xylene: ! H N M R (500 MHz, nitrobenzene-^) 5 6.81-7.67 (m, Cffls + paraU + C6D4# N 0 2 ) , 6.37 (s, 4 H , H b ) , 6.05 (d, 4 H , J = 6.4 Hz, H o u t ) , 5.89 (d, 4 H , J = 7.0 Hz, H o n t ) , 5.10 (m, 8 H , H m e t h i n e ) , 4.52 (d, 4 H , J= 6.1 Hz, H i n ) , 4.47 (d, 4 H , J = 6.0 Hz, H i n ) , 4.32 (brs, 8 H , O C # 2 C H 2 C H 2 G r Y 2 0 ) , 3.94 Cbrs, 4 H , O C # 2 C H 2 C H 2 G r 7 2 0 ) , 3.48 (s, 6 H , OCH3), 2.81 (m, 3 2 H , GrY 2 Cr7 2 Ph) , 2.41 (brs, OCK2CH2CH2CH20 + water), 2.01 (brs, 4 H , OCH 2 Ci7 2 Ci7 2 CH 2 0) , -1.58 (s, 6 H , H a ) 69^-dichlorobenzene: * H N M R (400 MHz, nitrobenzene-Jj) 5 6.94-7.67 (m, Crfs + parall + C 6 D 4 ^ N 0 2 ) , 6.71 (s, 4 H , H a ) , 6.06 (d, 4 H , J= 6.3 Hz, H o u t ) , 5.90 (d, 4 H , J = 6.6 Hz, Hout), 5.16 (brt, 8 H , H m e t h i n e ) , 4.46 (d, 4 H , / = 5.9 Hz, H i n ) , 4.39 (d, 4 H , / = 6.3 Hz, H i n ) , 4.30-4.34 (m, 12H, O C / 7 2 C H 2 C H 2 C / / 2 0 ) , 4.02 (brs, 4 H , O C / / 2 C H 2 C H 2 C / f 2 0 ) , 3.61 (s, 6 H , OCH3), 2.80 (m, 3 2 H , CH2CH2Ph), 2.33 (brs, O C H 2 C / / 2 C / / 2 C H 2 0 + water), 2.03 (brs, 4 H , O C H 2 C f Y 2 C # 2 C H 2 0 ) . 69»3-pentanol: ' H N M R (400 MHz, nitrobenzene-Ji) 5 7.07-7.67 (m, CeH5 + parall + C 6 D 4 ^ N 0 2 ) , 6.05 (d, 4 H , J= 6.5 Hz, H o u t ) , 5.95 (d, 2 H , J - 6.6 Hz, H o u t ) , 5. 14 (brs, 59 8H, H m e t h i n e ) , 4.67 (d, 4H, J= 6.4 Hz, H i n ) , 4.51 (d, 4H, J= 6.4 Hz, H i n ) , 4.11-28 (m, 18H, O C # 2 C H 2 C H 2 C # 2 0 + OCH3), 2.78 (m, 32H, CH2CH2?h), 2.28 (brs, 12H, O C H 2 C # 2 C / / 2 C H 2 0 ) , 1.90 (brs, 1H, H c ) , -0.26 (m, 2H, H b ) , -0.43 (m, 2H, H b ) , -2.36 (t, 6H, J = 7.1 Hz, H a ) . 69«2-butanol: *H N M R (400 MHz, nitrobenzene-Jj) 8 7.07-7.70 (m, C(Ji5 + paraR + O C H 2 C 6 # 5 + C 6 / / D 4 N O 2 ) , 6.07 (m, 4H, H o u t ) , 5.98 (d, 4H, J= 6.7 Hz, H o u t ) , 5.14 (m, 8H, H m e t h i n e ) , 4.57 (m, 4H, H i n ) , 4.44 (d, 4H, J = 6.8 Hz, H i n ) , 4.08-4.14 (m, 18H, O C # 2 C H 2 C H 2 C / J 2 0 + OCH3), 2.78 (m, 32H, C/7 2C77 2C 6H 5), 2.25 (m, 12H, O C H 2 C / / 2 C 7 / 2 C H 2 0 ) , 1.89 (m, 1H, H c ) , -0.24 (m, 1H, H b ) , -0.34 (m, 1H, H b ) , -2.15 (d, 3H, J = 5.9 Hz, H e ) , -2.43 (t, 3H, J= 7.2 Hz, H a ) . 69«cyclohexane: ' H N M R (500 MHz, nitrobenzene-^) 8 7.07-7.67 (m, + paraR + C 6 D 4 # N 0 2 ) , 6.05 (d, 4H, / = 6.4 Hz, H o u t ) , 5.99 (d, 4H, J = 7.0 Hz, H o u t ) , 5.13 (m, 8H, H m e t h i n e ) , 4.51 (m, 8H, H i n ) , 4.12-4.16 (m, 18H, O C / / 2 C H 2 C H 2 C / 7 2 0 + OCH3), 2.78 (m, 32H, CH2CH2?h), 2.23 (brs, 12H, O C H 2 C / / 2 C / / 2 C H 2 0 ) , -0.27 (s, 12H, H a ) . 69«isopropyl acetate: ' H N M R (500 MHz, nitrobenzene-^, partially characterized) 8 -0.03 (brs, 6H, H a ) , -1.81 (brs, 3H, H b ) . 60 Table 2.6. K a and K r e i . for 69»guests (OMe, OMe) Guests K a ( a t 2 7 °C)/Ml K r e l . (at 27 °C) K r e l (at 80 °C) /^-xylene 7700 3700 3700 p-dichlorobenzene 1200 600 -3-pentanol 1100 520 -2-butanol 820 400 750 cyclohexane 22 11 -isopropyl acetate 2 0.9 -NFP Not measurable Not measurable -2.6 References 1. Chapman, R. G.; C. Sherman, J. C. J. Org. Chem. 1998, 63, 4103. 2. Chapman, R. G.; Sherman, J. C. J. Am. Chem. Soc. 1998,120, 9818. 3. Chapman, R. G.; Olovson, G.; Trotter, Sherman, J C. J. Am. Chem. Soc. 1998, 120, 6252. 4. Chopra, N.; Sherman, J. C. Supramol. Chem. 1995, 5, 31. 5. Jasat, A. Unpublished data. 6. Makeiff, D. A.; Pope, D. J.; Sherman, J. C. J. Am. Chem. Soc. 2000,122, 1337. 7. Yoon, J.; Sheu, C ; Houk, J. N.; Knobler, C. B.; Cram, D. J. J. Org. Chem. 1996, 61 , 9323. 61 3.0 Formation of a Tris-Capsule and a Tris-Carceplex from a Cyclic Six-Bowl Assembly 3.1 Introduction As discussed in chapter 1 and 2, extensive work have been done in our labs to show that cavitand 37 forms carceplex 38 and capsule 62 in high yields by an efficient assembly process (Scheme 2 .1 ) . 1 - 3 The driving force for the assembly process to form these "supermolecules" is due to hydrogen bonding, aromatic JI-JI stacking, and C H - J I , polar and van der Waals interactions between the hosts and guests. Similarly, cyclic tetramer 43 forms both bis-capsule 71 and bis-carceplex 44 (Scheme 3 .2 ) . 4 ' 5 When D B U was added to a solution o f tetramer 43 in CDCI3 containing either pyrazine, or methyl acetate, bis-capsules 71 •(pyrazine^, and 71 "(methyl acetate^ were formed, respectively.4 These two capsules were characterized by ' H N M R spectroscopy. Bis-carceplex 44»(pyrazine) 2 formed in a 74% yield when 43 was treated with C H 2 B r C l and K2CO3 in NMP using pyrazine as guest.5 Considering the complexity o f this reaction (the formation o f 8 new bonds and assembly o f seven molecules), a yield o f 74% is remarkable. BnO OBn 0 1)CH2BrCI K2CO3 2) H 2 / cat DMF or DMSO BnOOHTbBn R = Cr ipHgPh 39 40, n = 3, R = OBn 72, n = 5, R = OBn 41, n = 4, R1 = OBn 73, n = 6, R1 = OBn 42, n = 3, R1 = OH 74, n = 6, R 1= OH 43, n = 4, R1 = OH Scheme 3.1. Synthesis o f cyclic oligomers from 39. 62 44«(pyrazine) 2 = Pyrazine (74%) Scheme 3.2. Formation o f bis-capsule 71«(pyrazine)2 and bis-carceplex 44«(pyrazine) 2 from tetramer 43. 3.2 Goal of this Study As mentioned in chapter one, the linkage o f diol 39 with CH 2 BrCl gives a number o f cyclic oligomers (Scheme 3.1). The cyclic trimer 40 and tetramer 41 have been isolated and ful ly characterized. Cyclic pentamer 72 and hexamer 73 have also been detected, but not ful ly characterized.5'6 The goal o f this study was to use 74 (it is obtained by the debenzylation o f 73) to make a tris-carceplex and a tris-capsule. Can six bridging molecules, three guest molecules, and a conformationally mobile host be brought together to create 12 new bonds efficiently to form a tris-carceplex? Or is the cost o f entropy too high? These questions are addressed in this chapter. 63 3.3 Results and Discussions 3.3.1 Synthesis and Characterization of 73 Since pentamer 72 and hexamer 73 have similar R f values, they could not be separated by just column chromatography. Hexamer 73 was separated from pentamer 72 by radial chromatography (the bands become thinner as the chromatogram develops, i.e., the resolution is better). Its yield was < 1 % from diol 39 cyclization. The *H N M R spectrum o f 73 looks similar to those o f trimer 40 and tetramer 41, which is not surprising. M A L D I - M S o f 73 showed a strong peak at 7281 m/z which corresponds to 73«Na + (calcd for 73« N a + = 7279). 3.3.2 Synthesis and Characterization of 74 Hydrogenolysis o f 73 yielded 74 in 90% yield. The signals o f the ! H N M R spectrum o f 74 recorded in CDCI3 are broad and overlapped at 27 °C, as well as at higher temperatures. When the spectrum was recorded in DMSO-ck at 27 °C, the signals were resolved, but still broad. However, the signals did become sharper and more resolved at higher temperatures (Figure 3.1). In CDCI3, it is l ikely that 74 either forms aggregates or forms intramolecular hydrogen bonds to give a number o f conformers that interconvert rapidly on the N M R time scale. Since DMSO-cfc is a polar solvent, i t most probably breaks the intramolecular bonds in 74. The M A L D I mass spectrum o f 74 gave a signal at 6200 m/z which corresponds to 74»Na+ (calcd for 74« N a + = 6197). 64 V (b) Figure 3.1 ' H N M R spectra (400 MHz, DMSO - ^ j ) o f hexamer 74 (a) at 27 °C, (b) at 87 °C. 65 3.3.3 Synthesis and Characterization of Tris-Carceplex 75»(methyl acetate)3 When a mixture o f hexamer 74, CH 2 BrCl , K 2 C 0 3 , methyl acetate (guest) and N M P was heated at 55 °C, a relatively unpolar product was isolated in 37% yield (Scheme 3.3). We used methyl acetate as guest instead o f pyrazine because the chemical shifts o f bound methyl acetate protons yield signals in an open window, < 0 ppm, whereas signals from bound pyrazine are in the crowded 4.3 ppm region. 5 The *H N M R spectrum o f this compound recorded in C^D^ at 57 °C (the signals are very broad at room temperature) contains signals at -0.09, -0.33, -1.70 and -1.91 ppm (Figure 3.2). These signals integrate in a 1:2:1:2 ratio, and account for 18 protons when integrated against the host signals. This suggests that three methyl acetate molecules are bound and the product formed is 75*(methyl acetate)3. Based on the integration, the signals at -0.09 and -1.70 ppm are assigned to the protons o f the guest trapped in the inner cavity, and the signals at -0.33 and -1.91 ppm are assigned to the guests trapped in the outer cavities. However, the signals o f the host's protons are quite broad and overlapped in the 4.5-7.5 ppm region. The broadness o f these signals is due to the low symmetry o f the compound. Intra- and inter-chamber conformational twisting might have also contributed towards such a complex spectrum. Wi th the help o f NOESY and COSY experiments, it was possible to assign the host's proton signals. Table 3.1 gives the NOESY and COSY correlations o f selected proton signals o f 75»(methyl acetate)3. M A L D I - M S o f this compound gave a strong signal at 6494 m/z that corresponds to the mass o f 75«(methyl acetate)3«Na+ (Figure 3.3). 66 When a sample o f 75*(methyl acetate)3 was heated in nitrobenzene-^ at 150 °C for five days, no loss o f guest was observed, which confirms that 75*(methyl acetate)3 is a true carceplex. 7 4 ( 3 7 % ) Scheme 3.3. Formation o f tris-carceplex 75»(methyl acetate)3 from cyclic hexamer 74. 67 Figure 3.2. Partial *H N M R spectrum (400 MHz, C 6 D 6 ) o f tris-carceplex 75«(methyl acetate)3 at 57 °C. 68 Table 3.1. NOESY and COSY correlations o f selected protons in tris-carceplex 75*(methyl acetate)3 Protons and their chemical NOESY correlations COSY couplings shifts (ppm) H C ; 6 ( 6 . 3 8 ) H a , b, d, f, g, h H d , f Hi(6.38) Hk, m, n H m H g ; h (6.38, 5.97) H c , d, e, f Hg,h Hj (6.29) none none H n (6 .24) H i , m none H j (6.01) H c , d none H k (5 .21) Hi , m , paraR, Gf / 2 CH 2 Ph C/7 2CH 2Ph H a , b (5-05) H c , d, e,f,paraH, CH2CH2?h C//2CH 2 Ph H d ; f (4.61, 4.53) H a , b, c, e, g, h> CH3COOCH3 bound in the outer cavities H c , e H m ( 4 . 5 9 ) Hk, in,CH3COOCH3 bound in the inner cavity H, C//3COOCH3 guest bound in the outer cavities (-1.91) H c , d, e, f,paraU, none C//5COOCH3 guest bound in the inner cavity (-1.70) H m , l none C//3COOCH3 guest bound in the outer cavities (-0.33) H c , d, e,f, paraR, none CH3COOC//3 guest bound in the inner cavity (-0.09) H m , l none 69 0 . 0 0 7 0 ~i 6 4 9 4 . 0 Figure 3.3. M A L D I - M S o f 75«(methyl acetate)3»Na+. 3.3.4 Efficiency of the Assembly of 75«(methyl acetate)3 38«pyrazine and 44«(pyrazine)2 were formed in 87 and 74% yields, respectively. Is the formation o f 75«(methyl acetate)3 less efficient? An 87% yield o f 38»pyrazine corresponds to an average yield per new bond formed (eight) o f 98%. Similarly, a 74% yield o f 44«(pyrazine)2 corresponds to an average yield per new bond formed (eight) o f 96%. In the case o f 75*(methyl acetate)3, 12 new bonds are formed, hence a yield o f 37% corresponds to an average yield per bond o f 92%. Considering the conformational f lexibi l i ty o f 74, the formation o f 12 new bonds and high loss in entropy in bringing 10 molecules together to form 75«(methyl acetate)3, an average yield per bond o f 92% seems to be reasonable. Hence, one would conclude that the formation o f 75«(methyl acetate)3 is efficient. According to Gibb and Gibb, the efficiency o f an assembly process 70 can be quantified by a parameter called assembly number (AN) . 7 A N is the number obtained when the observed yield is divided by the theoretical yield (statistical yield). The theoretical yield is obtained in a rather complex way, please refer to the Appendix for details. The higher the A N , the more efficient the assembly process is considered to be. Gibb and Gibb calculated a theoretical yield o f 33.3% for the formation o f 38»pyrazine.7 Wi th an observed yield o f 87% for 38«pyrazine, the A N was hence calculated to be 2.6. 7 Using Gibb's approach, we obtained a theoretical yield o f 14.3% for 44»(pyrazine)2, refer to the Appendix. Wi th an observed yield o f 74% for 44»(pyrazine)2, an assembly number o f 5.2 is obtained for the synthesis o f bis-carceplex 44«(pyrazine)2. Similarly, a theoretical yield o f 0.84% and an assembly number o f 44 are obtained for the formation o f tris-carceplex 75»(methyl acetate)3. Both the calculations based on the average yield per bond, and A N suggest that the formation o f tris-carceplex 75»(methyl acetate)3 is efficient. However, we can not say whether the formation o f the mono-, bis- or tris-carceplex is the most efficient assembly process. The calculation based on observed yield per bond formation gives the same number for the efficiency o f a particular assembly whether there are many or few paths that may lead to undesired products. On the other hand, different assembly numbers can be obtained for the same observed yield because the theoretical yields are subjective. That is, one person might include highly strained bonds leading to undesired products, and a second person might consider the formation o f the same bonds unlikely. Thus, prudence must be exercised when the efficiencies o f assemblies are compared. Overall, the formation o f tris-carceplex 75»(methyl acetate^ appears to be efficient. 7 1 3.3.5 Synthesis and Characterization of Tris-Capsule 7 6 « ( m e t h y l acetate)3 The *H N M R spectrum o f hexamer 74 wi th 7 mole equiv. o f D B U in nitrobenzene-^ contains broad and overlapped signals. In the presence o f methyl acetate, the host signals stay broad, but two new signals o f equal intensity are clearly seen at 0.0 and -1.5 ppm. These signals are assigned to the protons o f bound methyl acetate. Upon heating, these two signals each resolved into two signals that integrated in 2:1 ratios (Figure 3.4) and accounted for 18 protons in total wi th respect to the host. NOESY/EXSY experiments indicated that there was exchange between the free and bound guests, suggesting that the methyl acetate molecules were bound irreversibly. These results indicate that tris-capsule 76*(methyl acetate)3 formed in a similar way as bis-capsule 71»(methyl acetate^ did (Scheme 3.4). The host signals o f tris-capsule 76«(methyl acetate)3 are broader and less resolved than that o f 71»(methyl acetate)2.4 This is most l ikely because o f the lower symmetry and the higher fluctional nature o f 76. When the complexation experiments were performed with smaller amounts (< 3 mol equiv.) o f methyl acetate, the same number o f bound guest signals and chemical shifts were observed as when the experiment was done with an excess amount o f the guest. I t can be concluded that guest binding in tris-capsule 76 is cooperative, that is, 76«(methyl acetate)n, where n = 1 or 2, were most l ikely not formed in measurable amounts. Bis-capsules 71»(guest)2 were reported to show similar cooperativity. 4 Tris-capsule 76«(methyl acetate)3 fell apart either by heating the solution to temperatures higher than 150 °C, or by the addition o f 10% methanol-^ (v/v). That is, 76»(methyl acetate)3 was thermodynamically unstable under these conditions. 72 ( c ) (b) (a) S> 5 A. 5 7.5 fi.5 5.5 -/.5 $.5 ' 2 . 5 1.5 O. 5 -CIS -1.5 (jppm} Figure 3.4 *H N M R spectra (400 MHz, C 6 D 5 N 0 2 ) o f (a) 2.52 m M 74 and 17.7 m M D B U at 27 °C, (b) tris-capsule 76«(methyl acetate)3 (2.52 m M 74, 17.7 m M D B U and 27.9 m M methyl acetate) at 27 °C (c) tris-capsule 76«(methyl acetate)3 (2.52 m M 74, 17.7 m M D B U and 27.9 m M methyl acetate) at 127 °C. 73 74 76 •(methyl acetate) 3 Scheme 3.4. Formation o f tris-capsule 76»(methyl acetate^ from hexamer 74. 3.4 S u m m a r y and Conclusions Cyclic hexamer 74 can be used to make a tris-carceplex as well as a tris-capsule even the cost o f entropy is high. Tris-carceplex 75»(methyl acetate^ contains its guests via covalent acetal bridges, whereas tris-capsule 76»(methyl acetate^ is held together by charged hydrogen bonds (Schemes 3.3 and 3.4). As guest selectivity has been studied thoroughly wi th mono-carceplex 38 and mono-capsule 62 (Scheme 2.1), it was not considered necessary to repeat these studies on 75 and 76. Tris- carceplex 75 and tris-capsule 76 would be expected to show similar guest selectivity as monocarceplex 38 and mono-capsule 62 do. 74 The guests in the outer versus the central chambers o f 75 and 76 can be distinguished by their chemical shifts and integration. Such information may permit one to investigate the guest-guest communication as well as the dynamics within each chamber. Even though the yield o f 75«(methyl acetate^ is low, as compared to those o f 38»pyrazine and 44»(pyrazine)2 (Scheme 3.2), the efficiency o f this assembly seems to be high. A better method to estimate the efficiency o f an assembly process is certainly needed. 3 . 5 Experimental HPLC grade acetone (Fisher), benzene (Fisher), methanol (Fisher), DMSO (Fisher) and methyl acetate (Aldrich) were used without further purification. NMP (Advanced Chem Tech) was distilled over BaO and stored over 4 A molecular sieves. 1 -D and 2-D ' i f N M R spectra were recorded on an Avance-400 MHz instrument in C D C I 3 , DMSO-ak, C6D6 or nitrobenzene-^ using the residual solvent signals as references. 2-D NOESY spectra were run with mixing time o f 400 milliseconds. "Acetal" in the N M R assignments refers to the O C H 2 O linkages between the bowls; H j n and H o u t refer to the diastereotopic O C H 2 O intra-bowl bridges; "para"-H refers to the protons on the bridged aromatic rings. Mass spectra were recorded on a Bruker Reflex MALDI -TOF instrument in the reflectron mode and are accurate to one part per thousand. The calculated molecular weights are based on the average mass o f the various isotopes. Column chromatography was performed using silica gel (BDH, 230-400). Radial chromatography was performed on a chromatotron (Model 7924, Harrison Research) wi th plates prepared using silica gel (60 PF254, E M Reagents). 75 3.5.1 Synthesis and Characterization of Hexamer 73 Hexamer 73: Dio l 39 (1.00 g, 0.835 mmol) and CH 2 BrCl (271 pCL, 4.18 mmol , 5 equiv.) were each dissolved in DMSO (50 mL) , placed in two separate syringes, and added over a period o f 24 hours to a three-necked flask kept at 60 °C containing DMSO (500 mL) and K2CO3 (2.3 l g , 16.7 mmol, 20 equiv.). The mixture was stirred constantly under an N2 atmosphere for 48 hours. The solvent was removed in vacuo, and 1 M HC1 (300 mL) was added to the residue. The aqueous layer was extracted with CHCI3 (3 x 100 mL) , and the combined organic extracts were dried over M g S 0 4 and filtered. The solvent was removed in vacuo and the crude mixture was dissolved in a minimum amount o f ethyl acetate and kept at 4 °C for 24 hours. The mixture was filtered and the filtrate was concentrated, redissolved in chloroform and loaded on a silica gel (50 g) column. The column was then eluted wi th CHCb/hexanes (4:1) followed by neat chloroform. The relevant fractions were collected and the solvent was removed in vacuo to give a yellow residue. The residue was dissolved in CH2CI2, loaded onto a chromatotron, and eluted with CH2CI2. The second fraction was collected, dried, and the solid was recrystallized in CHCl3/hexanes to give hexamer 73 (10 mg, - 1 % yield). ' H N M R (CDCI3) 5 7.05-7.29 (m, C H 2 C H 2 C 6 ^ j + CHC1 3), 6.86 (s, 12 U,para-K), 6.80 (s, 12 H,para-H), 5.70 (d, 7.1 Hz, 24H, H o u t ) , 5.36 (s, 12H, H a c e t a i ) , 4.89 (s, 24H, OCftPh), 4.79 (t, 7.7 Hz, 24H, H m e t h i n e ) , 4.42 (d, 7.1 Hz, 24H, H i n ) , 2.61 (m, 48H, C H 2 C i / 2 C 6 H 5 ) , 2.42 (m, 48H, C7/ 2 CH 2 C 6 H 5 ) ; MS: m/z = 7281 (100%) [M«Na + ] , calcd for C474H408O72«Na+ = 7279. 3.5.2 Synthesis and Characterization of Hexamer 74 Hexamer 74: Hexamer 73 (15.0 mg, 2.07 ^ mo l ) was dissolved in benzene (5 mL) , methanol (250 /uL), and acetone (250 JUL). 10% Pd/C (15.0 mg) was added to the 76 mixture. The flask was evacuated before applying a hydrogen pressure o f four atmospheres. The flask was opened to the air after shaking for 48 hours. The mixture was poured onto a pad o f celite, and eluted with chloroform/methanol (97/3). The solvent was removed in vacuo to give a white residue, which was recrystallized in chloroform to give hexamer 74 (11.5 mg, 1.86 fimol, 90%). ' H N M R (DMSO-d 6 , 87 °C) 5 8.57 (s, 12H, OH, disappears upon addition o f D 2 0 ) , 7.49 (s, 12 H,para-H), 7.10-7.29 (m, 120H, CH2CH2CV75), 7.01 (s, 12 H, para-U), 5.74 (d, 7.2 Hz, 24H, H o u t ) , 5.42 (s, 12H, H a c e t a l ) , 4.64 (m, 24H, H m e t hine), 4.32 (d, 7.2 Hz, 24H, H i n ) , 2.56 (m, 96H, CH2CH2C6K5); MS: m/z = 6200 (100%) [M«Na + ] , calcd for C39oH336 0 72«Na + = 6197. 3.5.3 Synthesis and Characterization of Tris-Carceplex 75«(methyl acetate)3 Tris-carceplex 75«(methyl acetate^: Hexamer 74 (10.2 mg, 1.65 ^ m o l ) , K2CO3 (9.1 mg, 65.6 ^ m o l , 40 equiv.), CH 2 BrCl (11.6 JUL o f 1 mmol/mL CH 2 BrCl solution prepared in NMP, 7 equiv.) and 5 mol % methyl acetate (410 JUL, 3126 equiv.) were added to A^-methylpyrrolidinone (10 mL) . The mixture was stirred under an N2 atmosphere for 24 hours at ambient temperature. On the second day, an additional amount o f CH 2 BrCl (7 equiv.) was added to the flask, the temperature was raised to 55 °C, and and the resulting mixture was stirred for 24 hours. The solvent was removed in vacuo, and 1 M HC1 (10 mL) was added to the residue. The aqueous layer was extracted wi th chloroform ( 3 x 1 0 mL) , dried over MgS04, filtered, and concentrated in vacuo. The crude mixture was redissolved in a minimum amount o f CHCI3, loaded on a silica gel (1 g) column, and eluted with CHCb/hexanes (3:1). The least polar fraction was concentrated under vacuum, redissolved in CHCI3 (0.5 mL) , and methanol (0.2 mL) 7 7 was added. The resulting mixture was kept at 4 °C overnight, and the precipitate was filtered to give tris-carceplex 75»(methyl acetate^ (4.0 mg, 0.618 / /mol , 37 % ) . ! H N M R ; ' H - ' H COSY and NOE correlations are summarized in Table 3.1, see Figure 3.4 for labels: ( C 6 D 6 , 330 K ) 8 7.34-6.80 (m, paraH + C H 2 C H 2 C 6 H 5 + C 6 D 5 H) , 6.38 (m, 28H, H c , e , g o r h , i ) , 6.29(s, 8H, Hj), 6.24(m, 4H, H n ) , 6.01 (brs, 4H, H,), 5.97 (m, 4H, H g o r h ) , 5.2l(m, 8H, H k ) , 5.05 (m, 16H, H a , b ) , 4.61 (m, 8H, H d o r f ) , 4.59 (m, 8H, H m ) , 4.53 (m, 8H, H d or f ) , 2.65 (m, 48H, CH 2C77 2Ph), 2.41 (m, 48H, C# 2 CH 2 Ph) , -0.09 (s, 3H, CH3COOC#3 bound within the inner cavity), -0.33 (s, 6H, C H 3 C O O C # j bound within the outer cavities), -1.70 (s, 3H, C//5COOCH3 bound within the inner cavity), -1.91 (s, 6H, C//3COOCH3 bound within the outer cavities); MS: m/z = 6494 (100 %) [A/»Na + ] , calcd for C 3 9oH3360 7 2 »Na + = 6492. Figure 3 .4. Proton labeling for 75«(methyl acetate^ 78 Table 3.1. NOESY and COSY correlations o f selected protons in tris-carceplex 75«(methyl acetate)3 Protons and their chemical NOE correlations COSY couplings shifts (ppm) H c , e (6-38) H a , b, d, f, g, h H d , f H i (6.38) Hk, m, n H m H g ; h (6.38, 5.97) H c , d, e, f H g , h H j (6 .29 ) none none H n ( 6 . 2 4 ) H l , m none H j (6.01) H c , d none H k ( 5 . 2 1 ) Hi, m , parall, Gr72CH2Ph C/ / 2 CH 2 Ph H a > b (5.05) H c , d, Q,f,pararl, CH2CH2?h C/f2CH 2 Ph H d ; f (4.61, 4.53) H a , b, c, e, g, h? CH3COOCH3 bound in the outer cavities H c , e H m ( 4 . 5 9 ) H k , \,n,CH3COOCH3 bound in the inner cavity Hi C//3COOCH3 guest bound in the outer cavities (-1.91) H c , d, e,f,paraH, none C//3COOCH3 guest bound ' in the inner cavity (-1.70) H m , i none C//3COOCH3 guest bound in the outer cavities (-0.33) H c , d, e,hpararl, none CH3COOC//3 guest bound in the inner cavity (-0.09) H m , i none 7 9 3.5.4 Synthesis and Characterization of Tris-Capsule 7 6 » ( m e t h y l acetate)3 Tris-capsule 76»(methyl acetate) 3: Hexamer 74 (7.0 mg, 1.13 /umo\), D B U (1.2 /uL, 8.02 ,umol, 7 equiv.), methyl acetate (1 pCL, 12.6 fimol, 11 equiv.) were placed in an N M R tube and nitrobenzene-d5 (450 JUV) was added. *H N M R : ' H - ' H COSY and NOE/EXSY correlations are summarized in Table 3.2; (nitrobenzene-^, 127 °C) 5 7.05-7.50 (m, C H 2 C H 2 C 6 ^ + paraU + C 6 D 4 H N 0 2 ) , 6.91 (m, 8H, H o u t ) , 6.72 (m, 8H, H o u t ) , 6.41 (m, 8H, H o u t ) , 5.1-5.3 (m, 36H, H m e t hine + H a c e t a l ) , 4.6-4.8 (m, 24H, H i n ) , 2.78 (m, CH2CH2?h + DBU) , 0.10 (s, 6H, C H 3 C O O C # 5 bound within the outer cavities), 0.05 (s, 3H, CH3COOC//5 bound within the inner cavity), -1.47 (s, 6H, C7/3COOCH3 bound within the outer cavities), -1.51 (s, 3H, C # 3 C O O C H 3 bound within the inner cavity). Table 3.2. NOESY/EXSY and COSY correlations o f selected protons in tris-capsule 76*(methyl acetate)3 Protons and their chemical shifts (ppm) NOESY/EXSY correlations COSY couplings H o u t (6.91, 6.72, 6.41) Hin Hin Hmethine (5.1-5.3) CH2CU2?h,para}i C # 2 C H 2 P h H i n (4.6-4.8) H o u t ^ « r a H H0ut Hacetal (5.1-5.3) none none CH3COOC7/3 bound within the outer cavities (0.10) unbound C H 3 C O O C ^ none CH3COOC//3 bound within the inner cavity (0.05) unbound CH3COOC//3 none C//3COOCH3 bound within the outer cavities (-1.47) unbound CH3COOCR2 none C / / 3 C O O C H 3 bound within the inner cavity (-1.51) unbound C / / 3 C O O C H 3 none 80 3.6 References 1. Chapman, R. G.; Sherman, J. C. J. Org. Chem. 1998, 63, 4103. 2. Chapman, R. G; Sherman, J. CJ. Am. Chem. Soc. 1998,120, 9818. .. 3. Chapman, R. G; Olovsson, G.; Trotter, J.; Sherman, J. C. J. Am. Chem. Soc. 1998, 120, 6252. 4. Chopra, N.; Naumann, C ; Sherman, J. C. Angew. Chem., Int. Ed., 2000, 39, 194. 5. Chopra, N.; Sherman, J. C. Angew. Chem., Int. Ed. Engl, 1997, 36, 1727. 6. Naumann, C. Unpublished results. 7. Gibb, C. L. D.; Gibb, B. C. J. Supramol. Chem., 2001,1, 39. 4.0 Synthesis and Uses of Novel Large Hosts 4.1 Background and Goals As discussed in chapter one, one o f our group's main interest is to create large host molecules that can bind either multiple guest molecules, or single large molecules. The derivatives o f tetrol 37 (refer to Scheme 1.6 for its structure) have been successfully used as a building block to make large molecules. For example, the linkage o f diol 39 wi th methylene bridges provides host molecules such as cyclic trimer 40, tetramer 4 1 , pentamer 72 and hexamer 73 (Scheme 4.1). 1 - 3 Tetramer 43 forms bis-carceplex 44«(pyrazine)2 as well as bis-capsule 71«(pyrazine)2 (Scheme 3.2). 1 , 4 The guests in 44 are permanently trapped, whereas those in 71 are bound reversibly. As discussed in chapter 3, hexamer 74 forms tris-carceplex 75 • (methyl acetate)3 and tris-capsule 76«(methyl acetate)3 (Schemes 3.3 and 3.4)..3 Trimer 42 forms 45«(guest) n, where n = 1, 2 and 3 for 1,3,5-triethynylbenzene, D M A and D M F respectively (Scheme 4.2). . 5 - 7 Compound 45 has a single cavity, while 44 and 71 each have two cavities o f identical size comparable to those o f 38. Similarly, 75 and 76 each have three cavities o f almost identical size. The single cavity o f 45 is bigger than those o f 38, 44, 71 , 75 and 76. Hence 45 can encapsulate bigger guests (for example, 1,3,5-triethynylbenzene) than the latter hosts.6 Interestingly, trimer cavitand 77 was obtained as a side product in the synthesis o f trimer carceplex 45»(DMF) 3 (Scheme 4.2).6 The goal o f the present study was to l ink two molecules o f 77 with three acetal bridges to make compound 78 (Scheme 4.3). A CPK model o f 78 revealed that the inter-trimer region can be adjusted to give either a single large cavity at least double the size o f 45 or two identical cavities roughly the same 82 size o f 45. Would this host bind twice the number o f guest molecules as 45 does? In addition to the bowl region o f 78, can the inter-trimer region o f 78 be used to bind guests as well? Would the guests bound within the shell o f 78 be permanently entrapped as in the case o f 45? Permanent entrapment o f guests by 78 would suggest that 78»(guest) n is a carceplex. Or, are the portals in the inter-trimer region big enough to allow guest egress to occur? Guest egress from 78«(guest) n by heating would imply that 78«(guest) n is a BnO 0 ) H \ / o H \ / \ O B n 1)CH2BrCI rfa A .o^o . ^ x K2CO3 DMF or DMSO R R R BnO OH fHQBn 39 hemicarceplex. 2) H 2 / cat R = CHjpCri^Ph 40, n = 3, R1 = OBn 4 1 , n = 4, R1 = OBn 42, n = 3, R1 = OH 43, n = 4, R1 = OH 72, n = 5, R1 = OBn 73, n = 6, R1 = OBn 74, n = 6, R1= OH Scheme 4 .1 . Formation o f cyclic oligomers from diol 39. 42 K2CO3 DMF KI Br. 2 T O Br Br DMF = HO. (5-18%) 77 (36%) 4 5 - ( D M F ) 3 Scheme 4.2. Formation o f trimer carcerplex 45»(DMF)3 and trimer cavitand 77 83 Scheme 4.3. Formation o f host 78 from trimer cavitand 77. A second goal was to l ink two molecules o f diol 61 to make host 81 (Scheme 4.4). Compound 81 cannot be made in one step. CH^BrCl reacts with one molecule o f 61 to give hemicarceplex 60a. The structure o f 60a is similar to that o f 60 (Scheme 2.2), but the fourth bridge is a methylene instead o f tetramethylene.8 CPK model examinations revealed that the conformations o f the tetramethylene bridges in 81 can be adjusted to give a single large cavity (-14 x -19 A) as well as two separate cavities with identical size (-14 x -7 A ) and shape as in Cram's bis-hemicarceplexes 82 and 83 (Figure 4.1). 9 It was discussed earlier in chapter 2 that 60 forms stable hemicarceplexes. Whereas, 61 and its derivatives form complexes, i.e., guest molecules move freely in and o f the host cavities. Bis-hemicaceplexes 82 and 83 have moderate stabilities. The bound guests o f 82 and 83 could be easily exchanged under chromatographic conditions.9 Would the guest binding property and guest stability o f 81 be similar to those of hemicarceplex 60, diol 61 84 or Cram's bis-hemicarceplexes 82 and 83. Can 81 bind a single large molecule that occupies most o f the cavity space? R R= CH2CH2C6H5 68 1. KfiOZ C H 2 B r C I D M A 2. H 2 / P d Benzene/ M e O H K 2 C 0 3 C H 2 B r C I D M A 79, R 1 = O B n 80, R 1 = O H 81 Scheme 4.4. Formation o f 81. 85 Figure 4 .1 . Structures o f bis-hemicarceplexes 82«(guesf)2 and 83«(guesf)2. For a guest to enter or escape from the cavity o f a hemicarceplex, heating is normally required. That is, the intrinsic and constrictive bindings should be overcome. 1 0 Intrinsic binding is same as the free energy o f complexation, whereas constrictive binding refers the activation energy needed for a guest to enter or leave the cavity o f a hemicarcerand (Figure 4.2). The smaller the portal size o f the host, the higher the constrictive binding energy. Cram and co-workers found that the constrictive binding energy is dependent on the portal size o f a host. The constrictive binding energy o f 60«l,4-dimethoxybenzene > 84»l,4-dimethoxybenzene > 85»l,4-dimethoxybenzene > 86«l,4-dimethoxybenzene (Figure 4.3) . 8 ' 1 1 86 Energy Constrictive Binding Energy s — Hemicarceplex «guest • ^Kj^F Guest \ Hemicarcerand ntrinsic Binding Energy Figure 4.2. Energy diagram for a complexation-decomplexation process. R = CH 2CH 2Ph 60, A = (CH 2) 4 84, A=(CH2)5 85, A = Jp> 86, A = (CH 2 ) 6 Figure 4.3. Structures o f hemicarceplexes 60 and 84-86. 87 4.2 Results and Discussions 4.2.1 Synthesis of Trimer Cavitand 77 Since the route employed in Scheme 4.2 gives a poor yield o f trimer cavitand 77, an alternative synthetic procedure was developed. One o f the mesitylene caps o f trimer carceplex 45«(DMA) 2 was selectively removed by TFA to yield 77 in 50% yield when a 1.1 m M 45«(DMA) 2 solution (TFA/CH 2 C1 2 , 1:1, v/v) was stirred for 2 hours. 1 2 Both caps were removed when the solution o f 45»(DMA) 2 was stirred for 24 hours to regenerate 42 in an almost quantitative yield. The caps could not be removed by hydrogenolysis. Compound 45 survived a pressure as high as 60 atmospheres. 4.2.2 Synthesis and Characterization of Hemicarcerand 78 When a mixture o f compound 77, CH 2 BrCl , K 2 C 0 3 and distilled D M A was heated at 60 °C, compound 78 was obtained in 10 - 20% yield. No bound guest was detected by either *H N M R or M A L D I - M S . The *H N M R spectrum o f compound 78 is fairly simple, and it has the same symmetry as 77 (Figure 4.4). M A L D I - M S gave a peak at 6566 m/z, corresponding to 78«K + (Figure 4.5). Since 78 has big portals, it might be possible that the bound guests escaped during the work-up and purification processes. Similar results were obtained when the reaction was run in DMF. In an attempt to improve the yield o f 78, diiodomethane was used as linker ( D M A as solvent). Unfortunately the products obtained could not be isolated due to difficult separation and insufficient amount o f material (lower yield). The reactions were also run in bulkier solvents/guests such as D M P U and N M P in the hope o f entrapping them, but unfortunately only partially bridged and polymerized products were obtained. 88 (0 o -!= co -L- E I I X O I a a. Q. a. CO I I I II o o o o JUJL_Jcr±JUlA_l. (b) i if 1 1 1 5 8 o cu 1 1 I E O I i J L _ _ i j L £ x ^ x T o o o CM i t o 0 = 0 CO CO ~r~ o o —A— 1 -*1 I o z o=o X ? o (a) i to I I I o o o .2. .5 Figure 4.4. J H N M R spectra (400 MHz, CDC1 3 , 27 °C) o f (a) trimer cavitand 77 (b) trimer carceplex 45«(DMA)2, (c) bis-hemicarcerand 78. 89 co r-- r- <— t*~> <— co LD o <3- t.o c o ^ ^ * bT LO i n i n L O uo irt C O C O C O C O C O - - J - L O C O O Q C O C O C O C O C O in c n UO c n c n C O C O C O C O C O co o <— N C O C O O D L O L O L O L O C O C O C O C O (b) 6550 6570 6590 m/z Figure 4.5. M A L D I - M S signals corresponding to (a) 78«Na + , (b) 78»K + (c) 7 8 » H 2 0 » K+ . 4.2.2.1 Binding Studies with Hemicarcerand 78, and Formation and Characterization of Bis-Hemicarceplex 7 8 « ( l , 3 , 5 - t r i e t h y n y l b e n z e n e ) 2 Since 1,3,5-triethynylbenzene was found to be an excellent guest for 45 and 77, i t was the chosen guest for binding studies wi th 78.6 Makei f f found that when 1,3,5-triethynylbenzene was added to a solution o f 77 in nitrobenzene-^, trimer caviplex 90 11 • 1,3,5-triethynylbenzene was formed. The stability constant o f trimer caviplex 77•1,3,5-triethynylbenzene was measured to be 200 M" 1 at 27 °C. 6 When we recorded the [ H N M R spectrum o f a solution o f excess 1,3,5-triethynylbenzene and 78 in nitrobenzene-^, we did see any evidence o f binding. We eventually saw guest binding when we heated the sample (the solution in the N M R tube) at 100 °C for 24 hours in an oil bath. The formation o f 77* 1,3,5-triethynylbenzene did not require such heating. The ' H N M R spectrum o f the resulting mixture looked completely different from that o f the starting material (Figure 4.6). Moreover a new signal appeared at -0.56 ppm. By comparing the chemical shifts o f the protons o f 77•1,3,5-triethynylbenzene, the signal at -0.56 ppm was assigned to the acetylenic protons o f the bound guests. (the chemical shifts o f the acetylenic protons, o f the bound guest in trimer carceplex 45« 1,3,5-triethynylbenzene and trimer caviplex 77» 1,3,5-triethynylbenzene are at -1.18 and -0.54 ppm, respectively).6 The ' H N M R signals were assigned by running COSY and NOESY experiments. Integration o f the peaks yielded a host to guest ratio o f 1:2. Upon the removal o f excess guest (the sample was precipitated out by adding hexanes, and dried in vacuo), no significant change was observed in the *H N M R o f the sample, other than the disappearance o f the free guest signals. M A L D I - M S showed a peak at 6860 m/z that corresponds to 78» (l,3,5-triethynylbenzene) 2»K + (Figure 4.7). When the ! H N M R spectra o f a solution o f 78» (l,3,5-triethynylbenzene)2 in nitrobenzene-^ were recorded after 1 ,2 ,3 and 7 days, there was still no change on the spectra. This suggests that the complex was kinetically stable at room temperature. However, when 78«(l,3,5-triethynylbenzene)2 was heated in nitrobenzene-^ at 120 °C for three hours, around 28 % o f the guest was freed from the cavities o f 78 (Figure 4.8c). 91 Interestingly, 78»l,3,5-triethynylbenzene was also observed by *H N M R (Figure 4.8c) and M A L D I - M S . These results suggest that 78 has two chambers o f equal size, and fairly large portals that allow the movement o f guest molecules in and out o f the cavities o f 78 at high temperatures. Hence, i t can be concluded 78»(l,3,5-triethynylbenzene)2 is a bis-hemicarceplex. !" g.S " ' ' ? . S 6 . 5 ' J . 5 4 . 5 3 ' . 5 " '2.3'f.S r"~"o.5 *~ ' ' ""-&.S "" ' "*-i:3 Figure 4.6. *H N M R spectrum (500 MHz, nitrobenzene-Jj) o f 78«(1,3,5-triethynylbenzene)2 at 27 °C. 78«(1,3,5-triethynylbenzene)i.Na+ 78«(1,3,5-triethynylbenzene)2«K + Figure 4.7. M A L D I mass spectrum o f 78«(l,3,5-triethynylbenzene)2. 92 (c) ( b ) w (a) AJ v Free Guest Free Guest 78e(guest)2 / 78®(guest)1 Bound Guest Bound Guest Bound Guest " 3 3 2 . 5 (ppm) "ay - 0 . . 5 - 7 . 5 Figure 4.8. ! H N M R spectra (500 MHz, nitrobenzene-^, 27 °C) o f (a) 78«(1,3,5-triethynylbenzene)2 wi th free 1,3,5-triethynylbenzene (b) 78»(l,3,5-triethynylbenzene) 2, (c) 78»(l,3,5-triethynylbenzene) 2 after heating for 3 hours at 120 °C in nitrobenzene-*^. 93 4.2.2.2 Dimensions of 78 and Guest Orientations in 78 • (1,3,5-triethynylbenzene)2 Host 78 has two cavities o f equal size with a hexagonal shape (Figure 4.9). Its CPK o model gave the fol lowing dimensions (1.25 c m = 1 A , this value was supplied by the manufacturer): o (i) ~21 +/- 2 A for the total cavity length (surface to surface) (i i) ~12 +/- 1 A for the cavity width (surface to surface) Figure 4.9. Dimensions o f hemicarcerand 78. 94 With a diameter o f - 1 2 A , it is not surprising that 1,3,5-triethynylbenzene is an excellent guest for 78. The cavities o f 78 seem indistinguishable from that o f 77. C P K models also revealed that the plane o f the guests is perpendicular to the C3 axis o f 78. The ethynyl groups o f the guests point towards the center o f the bowls wi th the acetylenic protons lying deep into the cavities (Figure 4.10). Analogous to 45 and 77, this alignment gives an optimum CH-rc interaction between 78 and the guests. Also, the aromatic protons are situated near the H ; n and H o u t o f the bowls. This simply means that the acetylenic protons are more shielded than the aromatic ones. The difference between the resonances o f free and bound guest strongly supports C P K modeling (A8 = -1.60 and -3.97 ppm for the aromatic and acetylenic protons, respectively). When a NOESY spectrum o f 78«(l,3,5-triethynylbenzene)2 was recorded, the fol lowing observations were made: (i) NOESY correlation between the acetylenic protons o f the bound guests and mainly H ; n (i i) NOESY correlations between the aromatic protons o f the bound guests, and H j n and Hout These observations confirm that the ethynyl groups o f the guests point towards the center o f the bowls with the acetylenic protons lying deep into the cavities, and the aromatic protons are situated near the H j n and H o u t o f the bowls. 95 Figure 4.10. Guest orientation in 78»(l,3,5-triethynylbenzene)2. 4.2.2.3 Kinetics of Decomplexation of 7 8 « ( l , 3 » 5 - t r i e t h y n y l b e n z e n e ) 2 We were not surprised that 78 bound 1,3,5-triethynylbenzene in a similar way to 45 and 77, as the cavities are very similar. We thought that in addition to the bowl region o f 77, the inter-trimer region o f 78 could also bind one or two molecules o f 1,3,5-triethynylbenzene. However, 78 bound only two molecules o f 1,3,5-triethynylbenzene in the bowl regions. We thus sought to determine the rates o f decomplexation o f 78»(1,3,5-triethynylbenzene)2 to compare wi th 77* 1,3,5-triethynylbenzene. 96 Solutions of 78«(l,3,5-triethynylbenzene)2 in nitrobenzene-dj were heated at 100 and 120 °C in N M R tubes, and ' H N M R data were collected every 1-3 hour(s). The decomplexation of 78«(l,3,5-triethynylbenzene)2 obeys the following rate law: where k = dissociation rate constant, K = equilibrium constant, [78]e = final equilibrium concentration of free host, [G] e = final equilibrium concentration of free guest and x = [C] t - [C] e. [C] t and [C] e are the concentrations of bound guest at time t and at the final equilibrium stage, respectively. Integration of equation 4.1 yields: A graph of ln(x/(l + ([78]e + [G] e)/K - x/K)) versus time yields a straight line. The value of k can be calculated from the slope of the graph. The rate law was derived by Professor Ralf Warmuth, please refer to the Appendix for more details. The data obtained from the decomplexation experiments at 100 and 120 °C fitted on straight lines (Figure 4.11). The first-order rate constants (k) were found to be 0.030 +/-0.001 b/1 (ti/2 = 23 +/- 1 h) and 0.108 +/- 0.004 h"1 (ti / 2= 6.4 +/- 0.2 h) at 100 and 120 °C, respectively. At 100 °C, a value of 31 +/- 1 kcal/mol was obtained for AG* (AG* = -RTln(kA/kt>T, where R = gas constant, T = temperature, h = Planck constant, k b = Boltzmann constant). Using the Arrhenius equation (k = A ' e " E a / R T , refer to the Appendix for more details), the activation energy (E a) and the pre-exponential factor (A) for the guest expulsion were calculated to be 18 +/- 1 kcal/mol, and (3.9 +/- 0.5) x 10s s"1, respectively. Extrapolation gave a half-life of approximately one year at 25 °C in nitrobenzene-^. When compared to other systems, for example, 52•ethyl acetate and dx/dt = k(x 2 /K- x(l + [78]e + [G]e)/K)) (Eq. 4.1) ln(x/(l + ([78]e + [G] e)/K - x/K)) = const. - (1 + ([78]e + [G]e)/K)kt (Eq.4.2) 97 64«DMF (Figure 4.12), it can be said that 78«(l,3,5-triethynylbenzene)2 is kinetically less stable than 64»DMF ( t i / 2 = 14 hours at 140 °C in 1,2,4-C13C6H3), but more stable than 52«ethyl acetate ( t i / 2 = 6.8 hours at 100 °C in CDC1 2 CDC1 2 ) . 1 0 , 1 3 (b) 1 ' 1 ' 1 r slope = (1 + ([78]e + [G]e)/K)k (a) 2" -St ST L ineai" Regression Simple we^titing Conetaiiou CoaiTidBnt (t) » -0.9876 Variable value Std. Er. Intercept -7.3199 0.0062 Slope -0.0644 0.0034 Linest Regression Simple weighting Correlation Coefficient (r) = -0,9957 Intercept -6.SS84 0.0324 Slope -0.2051 0.007$ Figure 4.11. Graphs o f ln(x/( l + ([78]e + [G] e ) /K - x/K))vs time for decomplexation experiments performed at (a) 120 °C, (b) 100 °C. 98 52.ethyl acetate 64 .DMF Figure 4.12. Structures o f hemicarceplexes 52«ethyl acetate and 64«DMF Hosts 45, 77 and 78 have similar guest selectivity, but they form host-guest complexes wi th different kinetic stabilities. Bis-hemicarceplex 78»(1,3,5-triethynylbenzene)2 has a guest stability that lies between that o f trimer carceplex 45« 1,3,5-triethynylbenzene5 (the guest is permanently trapped, it does not escape even upon heating) and trimer caviplex 77« 1,3,5-triethynylbenzene (its stability constant was calculated to be 200 M" 1 , and the guest decomplexation rate to be roughly 2 s" 1). 6 4.2.3 Synthesis and Characterization of 81 Monobenzyl 68 was synthesized by either the method described in chapter 2 or by the route shown in Scheme 4.5. The second alternative is slightly better than the first one because all the products can be easily purified. The synthesis o f 79 was accomplished by treating monobenzyl 68 wi th CH2BrCl and K2CO3 in D M A (Scheme 4.6). Compound 79 was easily purified by column chromatography, and obtained in 80% yield. It has similar symmetry as 68 has, as evidenced by *H N M R . The inter-bowl acetal proton was located 99 at 5.89 ppm. M A L D I - M S o f 79 gave a strong signal at 4625 m/z that corresponds to 79«K + . 37 R R R R 68 (30 %) DBU BrCrfePh Acetone 37 K p 0 3 DMA R R R R 87 (50 %) K.,CO, BrCH 2CH 2CH 2CH 2Br DMA 88 (80 %) Scheme 4.5. Synthesis o f monobenzyl 68. The debenzylation o f 79 gave 80 in 85% yield. As expected, the ' H N M R spectrum (Figure 4.13a) did not show any signal around 5.0 ppm (OCfi^Ph resonance). A singlet at 6.28 ppm that disappeared upon the addition D 2 0 was assigned to the OH groups. M A L D I - M S o f 80 gave a peak at 4443 m/z that corresponds to 80»K + . However, it is a bit surprising that diol 80 is less polar than dibenzyl 79. This is most probably due to intramolecular hydrogen bonds between the two OH groups. 100 Treatment o f 80 wi th K 2 C 0 3 and CH 2 BrCl in D M A gave 81 in 50 % yield. ' H N M R indicated that 81 has similar symmetry as 61 has, which is as expected. There was no signal in the upfield region o f the *H N M R spectrum (Figure 4.13b). This suggests that there was no bound D M A within the shells o f 81. A peak at 4440 mlz (81«K + ) on the M A L D I spectrum (Figure 4.14) confirmed the identity o f 81. 68 1. KsCOg CH^rCI DMA 2. Hb/Pd Benzene/ MeOH/ 79, R' = OBn (80%) 80, R' = OH (85%) K 2 C0 3 ChfeBrCI DMA |; 1:; 81 (50%) Scheme 4.6. Synthesis o f compounds 79-81. 101 CeHg+H (a) + ^para 1 1 1 1 1 1 1 1 1 1 ' ' ' 1 1 i 1 1 i ' • • ' i • • • • 1 • • • ' 1 ' ' 7.0 6.0 5.0 4.0 3.0 2.0 • 1 1 1 • • 1 1.0 (ppm) 0.0 Figure 4.13. ' H N M R spectra (400 MHz, CDC1 3,27 °C) o f (a) diol 80 (b) host 81 . 102 Figure 4.14. M A L D I mass spectrum o f 81 (mass corresponds to 81»Na+). 4.2.3.1 Binding Studies with 81 4.2.3.2 Formation of Bis-Complex 81»( /? -xy lene) 2 Since p-xylcne is the best guest for 60, it was the first guest used to perform binding studies with 81. Indeed, when an excess amount o f p-xy\ene was added to a solution o f 81 in nitrobenzene-^, a complex was formed (Figure 4.15). The chemical shifts o f the host's signals were different in the presence o f j^-xylene as compared to those in the absence o f /^-xylene. Moreover, one new singlet appeared at -1.53 ppm which was assigned to the methyl protons o f bound p-xylene. When this signal was integrated wi th respect to the host's signals, a host to guest ratio o f 1:2 was obtained. This suggests that 81«(p-xylene)2 was formed. NOESY/EXY experiments showed that there was exchange 103 between bound and free guest molecules. This observation indicates that the guests were moving in and out o f the host cavities. When smaller amounts o f p-xylene was added to a solution o f 81 in nitrobenzene-c?j, and the *H N M R spectrum was recorded, one extra signal at -1.49 ppm in addition to the one at -1.53 was observed in the upfield region (Figure 4.15b). The signal at -1.49 ppm was due to 81»/?-xylene. This implies that guest binding with 81 is not cooperative (same as 78). The equilibria were reached within minutes and the binding constants o f 81«p-xylene and 81»(/?-xylene)2 were calculated to be ~ 500 M " 1 (K a , ) and ~ 2 x 10 s M " 2 (K a ), respectively, at 27 °C in nitrobenzene-^ (refer to the Appendix for more details). The value o f K a2 (~ 400 M" 1 ) is roughly the same as the one for. K a i (each cavity binds guest wi th same strength in a non-cooperative way). However, the value o f either K a i or K a 2 seems to be quite low as compared to the K a (7700 M " 1 at 27 °C in nitrobenzene-^j) value for 69»p-xylene (Figure 4.16, 69 is electronically similar to 81). The superior binding stability o f 69 •/ '-xylene might be due to extra CH-;t interaction between the methyl groups o f 69 and /^-xylene. K a 1 H + G • H»G H «G + G - K a 2 ' H»G 2 (K a) K a i K a 2 H + 2G • H«G 2 When hexane was added to the 81«(p-xylene)2 solution to get r id o f excess p-xy\ene, and the precipitate was redissolved in nitrobenzene-^, a large amount o f 81«(p-xylene)2 was destroyed. This implies that 81»(p-xylene)2 is a bis-complex, and not a bis-hemicarceplex. Compound 81 adopts a conformation that has two cavities o f equal size 104 that can accommodate two molecules o f p-xylene in nitrobenzene. In structure, 81 is similar to 82 and 83, but its guest retention ability is comparable to that o f 69 (Figure 4.16). •&S- 'tis <o *:* ~4is x:s i:s dis -b.s -y.a (ppm) Figure 4.15. ' H N M R spectra (500 MHz, nitrobenzene-Jj, 27 °C) o f (a) 81, (b) mixture o f 81 • (p-xylene)i and 81»(/?-xylene)2, (c) 81 • (p-xylene). 105 R — Ch^ChljCgh^ 6 1 , R 1 = H 69, R 1 = Me Figure 4.16. Structures o f 60, 82 and 83. 106 4.2.3.3 Drug Binding Studies with 81 Single large molecules such as allopurinol (89, used to cure gout), 2-ethylhexyl p-methoxycinnamate (90, an active ingredient used in sunscreens), sulfadiazine (91, an antibacterial drug), and griseofulvin (92, an antibiotic) were also attempted to be trapped within the cages o f 81 (see Figure 4.17 for the guest structures).1 4 Compounds 89-92 were chosen because o f the following reasons: (i) Both 89 and 90 are easily oxidized before they reach their targets, that is, they become less effective. When bound within the cavity o f 81 , 89 and 90 might be rendered more resistant to oxidation, and hence they could become more effective. (i i) Compounds 91 and 92 have very poor solubility in water, they could be made more soluble when bound to water-miscible hosts. Despite the hydrophobicity o f 81 , it was used to screen 91 and 92 in organic solvents. Positive results obtained from such an experiment would have allowed the design o f water-soluble hosts (it is easier to make water insoluble hosts than water soluble ones). When these drugs were added to solutions o f 81 in CDCI3, acetone-J<$ or nitrobenzene-Jj, unfortunately no binding was observed by ' H N M R spectroscopy at room temperature as wel l when the host-guest mixtures were heated up to 150 °C. 107 OH O N N H MeO' 89 90 NH 2 MeO Me' O Cl 91 92 Figure 4.17. Structures o f 89-92. 4.2.4 Comparison of 78 and 81 with Other Large Covalently-Linked Hosts The cavity sizes o f 78 and 81 are comparable to those o f 93-96 (Figures 4.18 and 4.19). Hosts 93 and 94 were made by Rebek and co-workers. 1 5 ' 1 6 They estimated that these two hosts have cavity dimensions o f about 23 x 10 A and internal volumes o f approximately 800 A 3 . A t room temperature 93 and 94 adopt a vase conformation in solution. Host 93 exists in an S-shaped conformation. Its two cavities bind two guest molecules such as 97 in a non-cooperative manner; only the adamantyl moiety o f 97 is complexed. On the other hand, 94 exists in a C-shaped conformation. It binds one molecule o f 97 in a cooperative way with a binding constant o f 500 M" 1 and a guest exchange rate o f ~ 0.5 s"1 in toluene-^ at 22 °C. The mass (346 daltons) o f 97 compares wel l wi th the combined masses (300 daltons) o f two molecules o f 1,3,5-triethynylbenzene (two o f these were bound within the cavities o f 78). 108 Figure 4.18. Structures o f hosts 93, 94 and guest 97. Calix[4]arene-cavitand hybrid host 95 was made by Reinhoudt and co-workers. 1 7 ' 1 8 Host 95 has a rigid structure. This is mainly due to the hydrogen bonds between the amide hydrogens, and the oxygens in the acetal bridges. Because o f its large holes, 95 got the nickname holand. Holand 95 has cavity dimensions o f about 15 x 20 A and an approximate volume o f 1000 A 3 . Guest binding studies were performed wi th Fe n -phthalocyanine (98, a guest whose size and shape are complementary to those o f the cavity o f 95, refer to Figure 4.20 for its structure) in CDCI3, but no binding was observed even after the sample was heated at 50 °C for several hours in the presence o f K C N or 1 n pyridine-ds (KCN and pyridine-ds rupture the polymeric phthalocyanine structures). 109 Host 96 was synthesized by Gibb and co-workers. 1 9 The cavity and portals size o f 96 are estimated to be ~ 19 x 15 A and 9.5 x 11.5 A , respectively. However, the guest binding ability o f 96 has not been documented. Figure 4.19. Structures o f hosts 95 and 96. 110 98 Figure 4.20. Structure o f 98. 4.3 Summary and Conclusions Two molecules o f trimer cavitand 77 can be linked with three methylene bridges to give hemicarcerand 78 (Scheme 4.3). Hemicarcerand 78 has a total cavity dimensions o f ~ 12 x ~ 21 A. Guests such as D M A and D M F are too small to be retained within the cavities o f 78. D M A and DMF most probably escaped through the large portals o f 78 during work-up. Host 78 binds two molecules o f 1,3,5-triethynylbenzene in nitrobenzene to give 78«(l,3,5-triethynylbenzene)2 upon heating. Compound 78«(1,3,5-triethynylbenzene)2 is a bis-hemicarceplex, and its guests can be emptied wi th half-lives o f 23 +/- 1 and 6.4 +/- 0.2 hours at 100 and 120 °C, respectively. The Gibb's free energy o f activation (AG*) was calculated to be 31 +/- 1 kcal/mol at 100 °C. The stability o f bis-hemicarceplex 78»(l,3,5-triethynylbenzene)2 lie between those o f trimer caviplex 7 7 * 1,3,5-triethynylbenzene and trimer carceplex 45» 1,3,5-triethynylbenzene. Dio l 61 can also be linked wi th two methylene bridges via monobenzyl 68 to give host 81 (Scheme 4.4). ' H N M R spectroscopy and mass spectrometry o f 81 indicate that it did not contain any bound guest. In its synthesis, the cavities o f 81 might have been solvated by D M A molecules, which most probably escaped through the large portals o f 81 during work-up. However, 81 binds jo-xylene in a non-cooperative way to give complexes 81«p-xylene and 81«(p-xylene)2 in nitrobenzene. Due to its larger portals, 111 81 has different guest retention abilities as compared to bis-hemicarceplexes 82 and 83 (Figure 4.1). Hence, we proudly add container molecules 78 and 81 to the class o f large molecules such as 82, 83, and 93-96; 4.4 Experimental General. A l l reagents were purchased from Aldrich Co. Inc., and were used without purification unless stated otherwise. D M A , DMF, D M P U , NMP and nitrobenzene were distilled, and stored over 4 A sieves under a nitrogen atmosphere. 1-D and 2-D ! H N M R spectra were recorded on either an Avance-400 or a Bruker A M X 500 M H z spectrometer in either CDCI3 or nitrobenzene-Jj using their residual ' H signals as references. H j n and Hout refer to the diastereotopic OCH2O intra-bowl bridges, para -H refers to the protons on the bridged aromatic rings. Mass spectra were recorded on a Bruker Reflex M A L D I -TOF instrument in the reflectron mode. Column chromatography was performed using silica gel (BDH, 230-400). Radial chromatography was performed on a chromatotron (Model 7924, Harrison Research) with plates prepared using silica gel (60 PF254, E M Reagents). 4.4.1 Synthesis of Trimer Cavitand 77 Trimer cavitand 77: 45»(DMA) 2 (100 mg, 28.0 umol) was dissolved in a mixture o f TFA/CH2CI2 (50 ml , 1:1, v/v), and stirred for 2 hours. The solvent was removed in vacuo, redissolved in chloroform and loaded on a silica gel (5 g) column. The column was eluted with chloroform and then followed by CHCb/MeOH (97:3). The CHCb/MeOH fraction was concentrated, redissolved in CH2CI2 and loaded onto a 112 chromatotron. The plate was then eluted with C ^ C V M e O H (98:2, v/v). The relevant fraction was collected, dried, and the solid was recrystallized in CHCl3/MeOH (2:1, v/v) to give trimer cavitand 77 (50.0 mg, 55% yield). The spectral data were in accordance wi th the literature values.7 4.4.2 Synthesis and Characterization of Bis-Hemicarcerand 78 Bis-Hemicarcerand 78: Trimer cavitand 77 (50.0 mg, 15.4 ummol) and CHiBrCl (5.0 uL, 77.1 umol, 5 equiv.) were each dissolved in 10 m L of distilled D M A and added over a period o f 24 hours to a mixture o f 30 m L of distilled D M A and K 2 C O 3 (42.6 mg, 308 ummol, 20 equiv.) kept at 40 °C with constant stirring under N 2 . A n excess amount o f C tbBrC l (5.0 uL, 77.1 umol, 5 equiv.) was then added, the temperature was increased to 60 °C, and the mixture was stirred for an additional 24 hours. The solvent was removed in vacuo, and 50 m L o f 0.5 M HC1 was added to the crude mixture. The organic components were extracted with CHCI3 (3 x 50 mL). The chloroform solution was dried over M g S C v , filtered, and concentrated. The crude mixture was dissolved in CH2CI2 (0.5 mL) and then eluted wi th CH2Cl2/hexanes (3:1, v/v) through a silica gel (5 g) column. The least polar fraction was redissolved in CH2CI2 /hexanes (1:1, v/v) and kept at 4 °C for 24 hours. The mixture was filtered, and the precipitate was collected and dried under high vacuum to give 78 (7.5 mg, 15% yield). ' H N M R (400 MHz, CDC1 3) 5 6.93-7.21 (m, 120H, CH2CH2C6/7.5), 6.88 (s, 6H, parall), 6.74 (m, 18H, parall), 6.03 (m, 24H, H0ut), 5.98 (d, J= 4.2 Hz, 6H, intra-trimer acetal), 5.88 (s, 6H, inter-trimer acetal), 5.63 (d, J= 4.2 Hz, 6H, intra-trimer acetal), 5.18 (s,12H, ( O C / ^ C ^ C i ^ s ) , 4.92 (t, J= 7.8 Hz, 12H, H m e t h i n e ) , 4.78 (t, J= 7.8 Hz, 12H, H m e thi„e), 4.43 (m, 24H, H i n ) , 2.87 (s, 18H, 113 (OCH2)3C6(C//3)3), 2.68 (m, 24H, -CU2CH2?h), 2.47 (m, 48H, CH2CH2?h), 2.30 (m, 24H, C/fcCHfePh); MS (MALDI ) m/z = 6566 (100 [ M » K + ] , calcd for C 4 i 7 H 3 6o0 7 2 » K + = 6563. 4.4.2.1 Formation and Characterization of Bis-Hemicarceplex 7 8 « ( l , 3 , 5 - t r i e t h y n y l b e n z e n e )2 Bis-hemicarceplex 78«(l,3»5-triethynylbenzene)2: Bis-hemicarcerand 78 (7.0 mg, 1.07 umol) and 1,3,5-triethynylbenzene (3.2 mg, 21.4 umol, 20 equiv.) were weighed in an N M R tube and 500 m L o f nitrobenzene-^ was then added to it. The tube was sealed and heated for 24 hours in an oil-bath kept at 100 °C. The mixture was cooled to room temperature, and hexanes was added to it to precipitate 78«(l,3,5-triethynylbenzene)2. After filtration and drying, a pale yellow powder was obtained (6.6 mg, 90%). *H N M R (500 MHz, nitrobenzene-^) 5 7.07-7.58 ( C ^ / j + parall + C 6 D 4 # N 0 2 ) , 6.88 (s, 6H, parall), 6.37 (m, 12H, H o u t ) , 6.21-6.29 (30H, H o u t + Ha Cetai), 5.68 (m, 6H, bound C6#3(CCH) 3 ) , 5.29 (m, 12H, Hm ethine), 5.08-5.15 (m, 24H, H m e t h i n e + (OC / /2 ) 3 C 6 (CH 3 ) 3 ) , 4.72 (brs, 24H, H i n ) , 2.62-2.89 (m, 114H, m, CH2CH2?h + (OCH 2 ) 3 C 6 (C / / 5 ) 3 ) , -0.56 (s, 6H, bound C 6 H 3 (CC/ / ) 3 : MS: m/z = 6860 (100 %) [ M « K + ] , calcd for C 4 4 i H 3 7 2 0 7 2 « K + = 6860. 114 4.4.2.2 Decomplexation Studies with Bis-Hemicarceplex 78•(1,3,5-triethynylbenzene)2 78«(l,3,5-triethynylbenzene)2 (2.7 mg, 0.90 mmol) was placed in an N M R tube and 450 m L o f nitrobenzene-^ was added to it. The sample was dissolved and the tube was completely sealed before it was placed in an oil-bath kept at 100 °C. The tube was removed from the oil-bath after three hours, cooled down to ambient temperature, and a ' H N M R spectrum was recorded. Heating, cooling and recording o f ' H N M R spectra were repeated unti l the ratio o f free to bound guest was constant. The data obtained are summarized in Table 4.1. The initial concentration o f bound guest is twice that o f 78«(l,3,5-triethynylbenzene)2 because there are two moles o f 1,3,5-triethynylbenzene per mole o f 78. The decomplexation experiment was repeated at 120 °C, but the initial concentration o f 78»(l,3,5-triethynylbenzene)2 was 0.98 m M and the data were recorded every hour to begin with (Table 4.2). 115 Table 4.1. Data obtained from the decomplexation o f bis-hemicarceplex 78«(1,3,5-triethynylbenzene)2 at 100 °C. Time/hr Total concentration o f bound guest/mM 0.00 1:79 3.00 1.55 6.00 1.40 9.00 1.35 12.0 1.17 15.0 1.13 18.5 1.03 21.0 0.975 24.0 0.929 27.0 0.917 30.0 0.872 34.0 0.788 40.2 0.788 50.0 0.656 56.0 0.665 116 Table 4.2. Data obtained from the decomplexation o f bis-hemicarceplex 78»(1,3,5-triethynylbenzene)2 at 120 °C. Time/hr Total concentration o f bound guest/mM 0.00 1.95 1.00 1.72 2.00 1.54 3.00 1.41 4.00 1.32 5.00 1.16 6.00 1.10 7.00 0.967 14.0 0.791 30.0 0.606 46.0 0.600 64.0 0.613 4.4.3 Synthesis of Triol 87 T r i o l 87: Tetrol 37 (1.00 g, 0.983 mmol) and D B U (167 mg, 1.08 mmol, 1.1 equiv.) were placed in a round bottom flask, and acetone (100 mL) was added to it. The mixture was stirred for one hour, and BnBr (131 /uL, 1.08 mmol, 1.1 equiv.) was added to it. The resulting mixture was stirred for five extra hours. The solvent was then removed in vacuo, 1 M HC1 (50 mL) was added to the residue, and it was extracted wi th CH3CI (3 x 50 mL) . The organic extract was dried over anhydrous M g S 0 4 , and the solvent was removed in vacuo. The residue was redissolved in ethyl acetate (1.0 mL) , and loaded on 117 a silica gel (50 g) column. The column was successively eluted wi th hexanes/ethyl acetate (1:1 and 1:2) mixtures. The relevant fraction was collected, and dried in vacuo. The residue was recrystallized in CH 2Cl 2/hexanes (1:1) to give 68 as a white solid (542 mg, 50%). The spectral data were in accordance with the literature values.7 4.4.4 Synthesis and Characterization of Tris-Bromobutyl 88 Tr is-bromobuty l 88: Triol 87 (500 mg, 0.451 mmol), K 2 C 0 3 (1.25 g, 9.04 mmol, 20 equiv.) and D M A (10 mL) were placed in a round bottom flask, and stirred at room temperature for one hour under an N 2 atmosphere. 1,4-dibromobutane (5.40 ml , 45.2 mmol , 100 equiv.) was then added to the mixture, and the mixture was stirred for a further 24 hours. The solvent was removed in vacuo, and the residue was redissolved in CH 2 C1 2 . The sample was loaded on a silica gel column (50 g) and eluted wi th CH 2 C1 2 . The first fraction was collected, the solvent was removed in vacuo and recrystallized in a CH 2Cl 2/hexanes (1:1, v/v) mixture to give 88 as a white solid (545 mg, 0.36 mmol, 80%). ' H N M R (400 MHz, CDC1 3) 5 7.12-7.41 (m, C ^ C r f e C ^ j + OCU2CeH5 + CHCh), 6.84 (s, m,para-U), 6.82(s, 3H, para-rl), 5.79 (d, 7.1 Hz, 4 H , H o u t ) , 4.97 (s, 2H, O C / / 2 C 6 H 5 ), 4.79-4.82 (m, 4 H , H m e t h i n e ) , 4.37-4.42 (m, 4 H , H i n ) , 3.92-3.95 (m, 6 H , OC/72CH 2 CH 2 CH 2 Br), 3.47-3.50 (m, 6 H , O C H 2 C H 2 C H 2 C / / 2 B r ) , 2.66 (m, 8 H , CH 2 C/f 2 C6H 5 ) , 2.46 (m, 8H, C / / 2 C H 2 C 6 H 5 ) ; 2.02-2.06 (m, 6 H , OCH 2 C77 2 CH 2 CH 2 Br) , 1.79-1.81 (m, 6H, OCH 2 CH 2 C77 2 CH 2 Br): MS: m/z = 1535 (100%) [M»Na + ] , calcd for C 8 3 H 8 3 O i 2 B r 3 » N a + = 1535. 4.4.5 Synthesis of Monobenzyl 68 Monobenzyl 68: Tetrol 37 (250 mg, 0.245 mmol), K 2 C 0 3 (678 mg, 4.91 mmol , 20 equiv.) and D M A (75 mL) were put in a round bottom flask, and stirred at room temperature for one hour under an N 2 atmosphere. 88 (376 mg, 0.245 mmol, 1 equiv.) was then added and the mixture was stirred for a further 24 hours. The temperature was 118 increased to 60 °C, and the mixture was stirred for an additional 24 hours. The solvent was removed in vacuo, and 1 M HC1 (25 mL) was added to the residue. The aqueous layer was extracted wi th CHCI3 (3 x 25 mL) , and the combined organic extracts were dried over MgSC>4 and filtered. The solvent was removed in vacuo, the crude mixture was dissolved in CH2CI2 and loaded on a silica gel (25 g) column. The column was eluted wi th CH2CI2, the first fraction was collected and the solvent was removed in vacuo. The residue was recrystalized in a CfbCh/methanol (1:1, v/v) mixture to give 68 as a white solid (168 mg, 30%). monobenzyl 68 can be also synthesized by the method described in chapter 2. 4.4.6 Synthesis and Chracterization of Dibenzyl 79 Dibenzyl 79: Monobenzyl 68 (100 mg, 43.7 jummol), K 2 C 0 3 (121 mg, 875 ,ummol, 20 equiv.), CFbBrCl (14.2 juh, 218 / /mol , 5 equiv.) and D M A (15 mL) were put in a round bottom flask, and stirred at room temperature for 24 hours under an N2 atmosphere. A n excess amount o f CELTJrCl was then added (14.2 / / L , 218 / /mol , 5 equiv.), the temperature was raised to 60 °C and the mixture was stirred for an additional 24 hours. The solvent was removed in vacuo, and 1 M HC1 (25 mL) was added to the residue. The aqueous layer was extracted with CHCI3 (3 x 25 mL) , and the combined organic extracts were dried over MgSC>4 and filtered. The solvent was removed in vacuo, the crude mixture was dissolved in CH 2 Cl2 and loaded on a silica gel (5 g) column. The column was then eluted with CH2CI2. The first fraction was collected and the solvent was removed in vacuo. The residue was recrystalized in a CEbCVmethanol (1 :1 , v/v) mixture to give 79 as a white solid (80.2 mg, 80% yield). ' H N M R (400 MHz, CDC1 3) 5 7.32 -7.41 (m, 8 H , O C H z Q ^ ) , 7.03-7.24 (m, C H s C H j C ^ + OCHaQ/Zj + Gt fC l 3 ) , 6.75-6.83 (m, \4K, para-K), 6.66 (s, 2H, para-R), 5.89 (s, 2H, OCH20), 5.81 (m, 8 H , 119 H o u t ) , 5.63 (m, 8H, H o u t ) , 5.01 (s, 2H, OCH2C6U5), 4.76-4.84 (m, 12H, H m e f t i „ e ) , 4.66 (t, 4H, J = 7.6 Hz, Hm e thine), 4.20 (m, 8H, H i n ) , 4.05 (m, 8H, H i n ) , 3.72-3.3.89 (m, 24H, OC/72CH2CH2C/72O), 2.31-2.67 (m, 64H, CH2CH2C6K5), 1.87-1.96 (m, 24H, OCH2C/ 6 C//2CH2O): MS: m/z = 4625 (100%) [M*K+], calcd for C 295H 272048»K + = 4625. 4.4.7 Synthesis and Characterization of Diol 80 Dio l 80: Dibenzyl 79 (50.0 mg, 10.9 / /mol) and 10% Pd/C (50.0 mg) were added to a high pressure flask containing a mixture o f benzene (8 mL) , methanol (2 mL) and triethylamine (a few drops). The flask was evacuated before applying a hydrogen pressure o f four atmospheres. The flask was opened to the air after shaking for 48 hours. The mixture was poured onto a pad o f celite, and eluted wi th chloroform/methanol (97/3). The solvent was removed in vacuo, and the residue was redissolved in CH2CI2. The sample was loaded on a silica gel column (5g) and eluted wi th CH2CI2. The first fraction was collected, the solvent was removed in vacuo and recrystallized in a CH2CI2/CH3OH (1 :1 , v/v) mixture to give 80 (40.8 mg, 85%). *H N M R (400 MHz, CDC1 3) 5 6.70-7.24 (m, para-H + C H 2 C H 2 C 6 / / 5 + C i /C l 3 ) , 6.40 (s, 2R,para-U), 6.28 (s, 2H, OH, exchanges wi th D 2 0 ) , 6.12 (d, 4H, 7.2 Hz, H o u t ) , 5.97 (m, 6H, H o u t + H a c e t a i ) , 5.82 (d, 8H, 6.9 Hz, H0ut), 4.76-4.84 (m, 12H, H m e t h i n e ) , 4.65-4.70 (m, 4H, H m e t hi„e ) , 4.16-4.24 (m, 16H, H i n ) , 3.86 (m, 24H, O C i ^ C ^ C ^ C T ^ O ) , 2.22-2.65 (m, 64H, CH2CH2C6K5); 2.00 (m, 24H, OCH2C//2C//2CH2O): MS: m/z = 4443 (100%) [M»K+], calcd for C283H 2 6o0 4 8»K + = 4443. 4.4.8 Synthesis and Characterization of Host 81 Host 8 1 : Dio l 80 (50.0 mg, 11.4 umol), K 2 C 0 3 (31.5 mg, 228 umol, 20 equiv.) and D M A (50 mL) were put in a round bottom flask, and stirred at room temperature for one hour under an N2 atmosphere before the addition o f C H 2 B r C l (3.7 juL, 56.9 umol, 5 120 equiv.) The mixture was stirred for 24 hours, and an additional amount o f CI-bBrCl (3.7 juL, 56.9 umol, 5 equiv.) was added to it. The temperature was then increased to 60 °C, and the mixture was stirred for an additional 24 hours. The solvent was removed in vacuo, and 1 M HC1 (25 mL) was added to the residue. The aqueous layer was extracted wi th C H C I 3 (3 x 25 mL) , and the combined organic extracts were dried over MgS04 and filtered. The solvent was removed in vacuo, the crude mixture was dissolved in CH2CI2 and loaded on a silica gel (3 g) column. The column was eluted with CH2CI2, the fraction was collected and the solvent was removed in vacuo. The residue was recrystalized in a CH 2Cl 2 /methanol to give 81 as a white solid (25.2 mg, 50% yield). ' H N M R (400 MHz, CDCI3) 5 7.04-7.24 (m, C ^ C H s C ^ + G r Y C l 3 ) , 6.91-6.93 (m, 14H, C H 2 C H 2 C 6 ^ ) , 6.76-6.78 (m, \6H,para-rl), 6.05 (d, 8H, J= 6.8 Hz, H o u t ) , 5.86 (s, 4H, OCH20), 5.81 (d, 8H, J= 6.8 Hz, H o u t ) , 4.79 (t, 8H, J= 7.8 Hz H m e t h i n e ) , 4.70 (t, 8H, J= 7.8 Hz, H m e t h i n e ) , 4.18-4.23 (m, 16H, H i n ) , 3.89-3.93 (m, 24H, O G r Y i C ^ C ^ G ^ O ) , 2.26-2.66 (m, 64H, CH2CH2C(,rl5), 1.98 (m, 24H, OCH2Ci72C//2CH20): MS: m/z = 4440 (100%) [M«Na + ] , calcd for C282H26oC>48»Na+ = 4440. 4.4.8.1 Formation and Characterization of 8 1 » ( r > x y l e n e ) 2 H 3 C ^ ^ - C H 3 H b A 0.165 m M solution o f host 81 was prepared in nitrobenzene-^ and 500 JUL portions were poured in N M R tubes. Excess amounts o f j?-xylene were then added to the solution o f 81 to record the l H N M R spectra. *H N M R (500 MHz, nitrobenzene-^) 5 6.81-7.66 (m, CeH5 + para-H. + free p-xylene + C 6 D 4 / / N 0 2 ) , 6.39 (m, 12H, bound p-xylene (H b ) + OCH20), 6.30 (m, 8H, H o u t ) , 5.98 (m, 8H, H o u t ) , 5.12-5.17 (m, 16H, H m e t h i n e ) , 4.56 (m, 16H, H i n ) , 4.18 (m, 16H, OC// 2CH2CH 2C//20), 3.94 (m, 8H, 121 OC//2CH2CH2C//2O), 2.61-2.78 (m, 64H, CH2CH2C6K5), 2.22 (m, OCH 2 C7/2C / / 2 CH 2 0 -+ free p-xy\ene), -1.53 (s, 12H, bound /^-xylene (H a )) . 4.4.8.2 Determination of K a for 81»0p-xylene)2 To f ind the K a value o f 81»(p-xylene)2, known amounts o f p-xylene were added to 0. 165 m M solutions o f 81 in nitrobenzene-ck, and *H N M R spectra were immediately recorded after mixing, and then again minutes and hours later. The bound guest signal (the methyl protons) was carefully integrated with respect to that o f the free guest signal. A value o f ~2 x 105 M" 2 was obtained for the association constant (refer to the Appendix for details). A n exact K a value for 81«(p-xylene)2 could not be calculated because the signal o f 81«(p-xylene)2 overlapped with that o f 81«(p-xylene)i. 4.5 References 1. Chopra, N.; Sherman, J. C. Angew. Chem. Int. Ed. Engl. 1997, 36, 1727. 2. Naumann, C. unpublished results. 3. Mungaroo, R.; Sherman, J. C. Chem. Commun. 2002, 1672. 4. Chopra, N.; Naumann, C ; Sherman, J. C. Angew. Chem. Int. Ed. 2000, 39, 194. 5. Chopra, N.; Sherman, J. C. Angew. Chem. Int. Ed. 1999, 38, 1955. 6. Makeiff, D. Ph.D. thesis, University o f British Columbia, 2003. 7. Chopra, N. Ph.D. thesis, University o f British Columbia, 1997. 8. Yoon, J.; Sheu, C ; Houk, K. N.; Knobler, C. B.; Cram, D. J. J. Org. Chem. 1996, 6 1 , 9323. 9. Yoon, J.; Cram, D. J. Chem. Commun. 1997, 2065. 10. Cram, D. J.; Tanner, M.E.; Knobler, C. B. J. Am. Chem. Soc. 1991,113, 7717. 11. Yoon, J.; Cram, D. J. Chem. Commun. 1997, 1505. 122 12. (a)Trimer carceplex 45«(DMA)2 was itself synthesized in 50% yield by stirring a mixture o f 42, 2,4,6-tris(bromomethyl)mesitylene, K I and K2CO3 for 24 hours, (b) I would like to thank Ayub Jasat for suggesting me to use TFA as a cleaving reagent. 13. Cram, D. J.; Choi, H. J.; Bryant, J. A. ; Knobler, B. C. J. Am. Chem. Soc. 1992, 114, 7748. 14. 1996 Physicians GenRx, The Complete Drug Reference; Mosby: St Louis, 1996. 15. Lucking, U ; Tucci, F. C; Rudkevich, D. M.; Rebek, J. Jr. J. Am. Chem. Soc. 2000, 122, 8880. 16. Tucci, F. C; Renslo, A. R.; Rudkevich, D. M.; Rebek, J. Jr. Angew. Chem. Int. Ed. 2000, 39, 1076. 17. Timmerman, P. W.; Nierop, K. G. A.; Brinks, E. A.; Verboom, W.; Van Veggel, F. C. J. M. ; Van Hoorn, W. P.; Reinhoudt, D. N. Chem. Eur. J. 1995, / , 132. 18. Timmerman, P. W.; Verboom, W.; Van Veggel, F. C. J. M. ; Van Hoorn, W. P.; Reinhoudt, D. N. Angew. Chem. Int. Ed. Engl. 1994, 33, 1292. 19. Gibb, C. L. D.; Stevens, E. D.; Gibb, B. C. Chem. Commun. 2000, 363. 123 5.0 Generation, Entrapment, Stabilization and Reactions of Reactive Intermediates within the Cavities of Trimer Carceplexes 45 and 152 5.1 Introduction Cram described the inner phases o f carceplexes and hemicarceplexes as a new phase o f matter.1 Guests bound within the cavities o f carceplexes and hemicarceplexes are protected from molecules that are too large to enter the hosts' cavities. For example, when a solution o f hemicarceplex 64*CH2Br2 (refer to Scheme 5.1 for the structure o f 64) in THF was subjected to a large excess o f «-butyllithium for one minute, CH 2Br2 remained unreacted.2 5.2 Background 5.2.1 Work Done by. the Cram Group Cram and co-workers were the first to report the generation, stabilization and reactions o f a reactive intermediate within the cavity o f a hemicarceplex. Hemicarceplex 64*cyclobutadiene (64*101) was obtained by the photolysis o f hemicarceplex 6 4 * a -pyrone (64*99), refer to Scheme 5 . I . 1 Compound 101 normally dimerizes to cyclooctatetra-l,3,5,7-ene (104), but it is stable within the cavity o f 64 at room temperature. However, upon heating, 101 was freed from the cavity o f 64, and it was converted to 104. When a solution o f 64*101 in CDCI3 was saturated with oxygen, 6 4 * (Z)-CHOCH=CHCHO (64*103) was obtained. When 64*99 was irradiated for a shorter time, 64*photopyrone (64*100) was the major product. On the other hand, when 64*99 was irradiated for a longer time, free acetylene was observed (acetylene is small compared to the host's cavity, hence it came out once it was formed). Bound 100 could be converted to 102 by heating a solid sample o f 64*100 at 90 °C. Hemicarceplex 64*100 could also be converted back to 64*99 by heating a solid sample o f 64*102. 124 o2 Scheme 5.1. Formation o f cyclobutadiene from 99 within the shell o f hemicarceplex 64, and its reactions. 60*105 60*106 60*107 60*108 60*113 Red Ox. Red. Ox. Red. Ox. Red. Ox. Red 60*109 60*110 60*111 60*112 60*114 Red. = THF, CH 3 OH, Sml 2 ) Reflux Ox. = C e ( N H 4 ) 2 ( N 0 2 ) 6 , Silica gel, CCI 4, 25 °C or TI(0 2 CCF 3 ) 3 , CCI 4, Reflux Scheme 5.2. Reduction and oxidation reactions within the cavity o f hemicarceplex 60. Cram and Robbins have also demonstrated that guests such as hydroquinones 105-108 can be oxidized to quinones 109-112, respectively (Scheme 5.2), within the cavity o f 60 (represented by the oval drawing, refer to Scheme 2.2 for its structure).3 Quinones 109-112 could not be directly encapsulated within the cavity o f 60 otherwise. This is because these quinones decomposed upon heating (heating is normally required for guest incarceration within the cavity o f 60). Quinones 109-112 can be converted back to 105-108, respectively, by reduction with S11112/CH3OH in THF. Similarly, bound nitrobenzene (114) could be reduced to 113. Note that it is most probably water molecules, electrons and protons that penetrate into the cavity o f 60 to carry out the 126 chemical transformations, and not the oxidizing and reducing agents themselves (these reagents are too bulky to enter the host cavity). S N 2 reactions have also been performed on certain guests bound within the cavity o f 60. o-Methylphenol and /w-methylphenol were both methylated within the shell o f 60 when 60*o-methylphenol and 60•w-methylphenol were subjected to THF-NaH-CH3l (Figure 5.1). 4 p-Methylphenol could not be methylated when 60*/?-methylphenol was subjected to the same conditions. This is because the hydroxyl group o f bound p-methylphenol is too hindered to undergo an S N 2 reaction under normal conditions. In a similar way, methyllithium and borane reacted selectively with one carbonyl group o f benzocyclobutenedione (115). 5 (a) (b) Figure 5.1. Guest orientations in 60 • guest 5.2.2 Work Done by the Warmuth Group Warmuth reported the generation, stabilization and first innermolecular reaction o f o-benzyne (117) within the cavity o f 6 0 . 6 7 When 60*115 was photolyzed (k > 4 0 0 nm) at - 1 9 6 ° C , benzocyclobutenedione (115) was converted to benzocyclopropenone (116) (Scheme 5.3). Subsequent photolysis o f 60*116 (k = 2 8 0 nm) at - 1 9 6 ° C provided 60*117. Upon heating to room temperature, 117 formed Diels-Alder adduct 119 wi th the host (Scheme 5.3). Hemicarceplex 60*116 was stable in water-free solution at room temperature. However, in water-saturated CHCI3, bound 116 was converted to 60*benzoic acid (60*118). 127 Scheme 5.3. Formation o f hemicarceplexes 60*116-118, and 119 starting from 60*115. The Warmuth research group has reported the generation and stabilization o f 1,2,4,6-cycloheptatetraene (123, as free guest, it readily dimerizes in solution) within the shells o f hemicarcerands 120, 121 and their anologues.8"1 1 When 120*phenyldiazirine (120*122) and 121*phenyldiazirine (121*122) were photolyzed (X >320 mn) at -196 °C, 120*123 and 121*123 together with insertion products 126 and 127 were obtained (Scheme 5.4). Under these conditions 126 and 127 were the major products formed. However, in the presence o f sensitizer acetophenone, 120*123 and 121*123 were the major products. Hemicarceplexes 120*123 and 121*123 reacted wi th oxygen to give 120*benzene and 121*benzene. Carbon dioxide was also liberated in this process. When solutions o f 120*123 and 121*123 were saturated wi th HC1 gas, 120*124 and 128 121*124 were obtained, respectively. Addit ion o f methanol to solutions o f 120*124 and 121*124 afforded 120*125 and 121*125. Tol-oV CDCI 3 / Acetophenone-c/s -196°C 120*122 121*122 h\>,X> 320 nm Tol-oV CDCb -196°C 120*123 121*123 HCI 120*124 121*124 120, A = C H 2 121, A = CD, R — ( C H ^ ^ C H j O, -196 °C 120-benzene 121*benzene 120*125 121*125 126, A = C H 2 , R '=H 127, A = C D 2 , R'= D Scheme 5.4. Formation o f hemicarceplexes 120*123-125 and 121*123-125, and insertion products 126 and 127 starting from hemicarceplexes 120*122 and 121*122. 129 The mechanism o f thermal decompositions o f 122 and other diazirines have also 12 been studied by the Warmuth group. 5.2.3 Work Done in Our Labs In our labs, Kodumuru and Makeif f generated and stabilized enol 129 within the enclosed shell o f 45 (Scheme 5.5).1 3'1 4 When trimer carceplex 45*128 was photolyzed (k > 300 nm) in benzene, butyrophenone (128) was converted to enol 129 and ethene through Norrish type I I photocleavage mechanism. Trimer carceplex 45*130 was also obtained as a side product. Bound enol 129 was indefinitely stable in dry CDCI3. No change was observed when a solid sample o f 45*129 was heated for several days at HO-BO °C. However, when a solution o f 45*129 in CDCI3 was saturated with water, enol 129 was slowly converted to acetophenone (131). The rate o f ketonization (kobs) was determined to be 1.5 x 10"4 s"1 at 100 °C (U/2 = 78 min.) in nitrobenzene.1 4 Extrapolation gave a value o f 7.4 x 10"9 s"1 at 25 °C ( t 1 / 2 = 1.6 x 106 min.) for kob s. 45»131»CH 2 =CH 2 Scheme 5.5. Formation o f trimer carceplexes 45*129, 4 5 * 1 3 0 * C H 2 = C H 2 and 4 5 * 1 3 1 * C H 2 = C H 2 starting from trimer carceplex 45*128. 130 5.2.4 Formation of P h C H O O In general, ketenes are very reactive. 1 5 ' 1 6 For example, PhCH=C=0 (134) either rapidly reacts with nucleophilic solvents such as water, methanol and diethylamine to give phenylacetic acid (135),17 methyl phenylacetate (136)1 8 and N,N-diethylphenylacetamide (137),19 respectively, or it dimerizes to 138 and 139 (enolizes to 140) by [2 + 2] cycloaddition reaction (Scheme 5.6). 2 0 ' 2 1 Ketene 134 was originally obtained by zinc dechlorination o f PhCHClCOCl by Staudinger.2 2 However, these researchers were unable to isolate 134, but its presence as a transient species was confirmed by trapping experiments. Subsequently, 134 was prepared by photolysis o f PhCOCHN2 (132). When heated or photolyzed, 132 was converted to 134 via transient keto carbene 133 by W o l f f rearrangement (Scheme 5.6). 2 3 Lusztyk and coworkers were able to measure the stretching frequency o f the C=C=0 group o f 134 by laser flash photolysis wi th time-resolved infrared detection in acetonitrile. 1 9 When 132 was photolyzed in acetonitrile, a strong band at 2118 cm" 1 was observed. This signal had a lifetime o f > 500 us, but this was shortened in the presence o f diethylamine. Tidwell and coworkers measured a similar value (2117 cm" 1) for the stretching frequency o f the C = C = 0 group o f 134 when they photolyzed a 8.5 x 10"4 M solution o f 132 in isooctane purged wi th argon. 2 4 UV-Vis spectroscopy gave two ?^ax values (248.5 and 378.0 nm) 131 141 137 136 P h x _ / O H H OH Ph" Et N-Et o O C 2 H 5 PK H hv or A N + II N" 132 Ph V + N^N 133 Ph. .OH ,H = O Ph 140 C 2 H 5 O H H O 134 135 [2 + 2] H O H [2 + 2] H Ph-Ph O P h f 0 \ 139 Ph 138 S c h e m e 5.6. Formation o f 134 from 132, and its reactions. 5.2.5 Formation of Acid Enols Tidwell believes that the formation o f 135 from 134 proceeds via transient PhCHC(OH) 2 (141, an acid enol, refer Scheme 5.6 to see its structure) when an aqueous solution o f 132 is photolyzed (laser flash photolysis). 2 5 Two transient species are observed by U V spectroscopy, one is believed to be 133 and the other 141. However, there is not sufficient evidence to confirm this hypothesis. Ac id enols have been definitely observed in other systems. 2 6 ' 2 7 For example, when 10"4 M a-cyano-a-diazoacetophenone (142) aqueous solution (neutral or acidic) was photolyzed, the acid 132 enol (144) o f a-cyano-a-phenylacetic acid (145) was observed as a transient species by U V spectroscopy (Scheme 5.7). 2 6 Acid enol 148 has also been observed as a transient 27 species when an aqueous solution o f 146 was photolyzed (Scheme 5.7). O 0 N 2 / n q = 300 nm i N C > = C = Q H 2 Q ^ NC OH H 2 Q ^ P h ^ 0 H Ph OH CN PK r P h -CN 142 143 144 145 N 2 Mv,A. = 248nm H 0 H 2 0 HOJI M M P h OH PH 146 147 148 149 Scheme 5.7. Photolysis o f 142 and 146, and their subsequent products. 5 . 3 Goals of this Study Tidwell suggested that acid enol 141 might be stabilized within the cavity o f 45. We thought that might well be the case. Thus, we set the fol lowing goals for this study: (i) To encapsulate PhCOCHN 2 (132) in the form o f trimer carceplex 45*132. (i i) To photolyze 132 to generate and stabilize 134 within the confines o f 45 (Scheme 5.8). This would be the first example o f ketene stabilization within the shell o f a carceplex/hemicarceplex. On a related note, it is necessary to point out that in a review, Warmuth mentioned that (bis)ketene 150 formed as a transient species within the shell o f hemicarceplex 60 when 60*115 was photolyzed (A, > 400 nm), refer to Scheme 5.9. 2 8 Bound 150 immediately reacted wi th trace amount o f water to give 60*151. (i i i) To hydrolyze 134 to 135 within the cavity o f 45. (iv) To see whether acid enol 141 is formed and stabilized within the confines o f 45 when 134 is hydrolyzed. 133 Another goal was to generate a reactive compound such as l,3,5-tris(iodo-methyl)benzene in situ, and then trap it within the cavity o f 152 (Scheme 5.10). The size and shape o f 152 are similar to those o f 45, the only difference is that the caps o f 152 do not have methyl groups. This would be the first example o f in situ generation o f a guest and its entrapment. hv, X > 300 nm 45*132 45*134 45*135 45*141 Scheme 5.8. Formation o f 45*134, 45*135 and 45*141 starting from 45*132. 134 152* 1 !3154ris(iod!omethyl)benzene Scheme 5.10. Formation o f 152«l,3,5-tris(iodomethyl)benzene. 5.4 Results and Discussions 5.4.1 Synthesis and Characterization of Trimer Carceplex 4 5 « P h C O C H N 2 » N F P When a mixture o f trimer 42, K2CO3, 2,4,6-tris(bromomethyl)mesitylene, KI, P I 1 C O C H N 2 and NFP (we chose NFP because it is a poor template, but good solvent for the formation o f 45 ) 1 4 was stirred for 48 hours, trimer carceplex 45» P h C O C H N 2»NFP, trimer carceplex 45«NFP and trimer carceplex 45»(NFP) 2 were obtained (Scheme 5.11). Trimer carceplex 45«PhCOCHN 2 «NFP was isolated in 25% yield from the NFP carceplexes by either preparative TLC or radial chromatography. 135 RT (25%) Scheme 5.11. Synthesis o f 45»PhCOCHN 2»NFP. The ' H N M R signals o f the host are somewhat broad and complex (Figure 5.2a), as compared to other trimer carceplexes. 1 4 ' 2 9 This was most probably due to restricted guest rotations within the cavity. We recorded the COSY (Figure 5.3) and NOESY (Figure 5.4) spectra o f 45»PhCOCHN 2«NFP to make the necessary assignments. The COSY and NOESY correlations are summarized in Table 5.1. The doublet at 6.51 and triplet at 4.65 ppm show COSY correlations with a signal buried in the 5.15 ppm region. The singlet at 4.52 ppm shows NOESY correlation with the doublet at 6.51 ppm, and moreover its integration is half to that o f the signal at 6.51. These observations are consistent wi th the structure o f PhCOCHN 2 . We hence assign the signals at 6.51, 5.15, 4.64 and 4.52 ppm to H,, H 2 , H 3 and CHN2, respectively, o f bound PhCOCHN 2 . The signals at 5.21, 1.51, 1.16, -0.33, -0.89 and -1.19 ppm show COSY and NOESY correlations that are consistent wi th the structure o f NFP. Hence these signals are assigned to H f , H e , H d , H b , H c and H a , respectively, o f bound NFP. NOESY correlations between H i , and H b and H c indicated that PhCOCHN 2 and NFP are trapped together within the same host molecule. Moreover, the integration o f H i is the same as the one o f H b or H c . By comparing the chemical shifts o f other carceplexes o f 45, we assign the signals in the 5.81-6.11 ppm region to H o u t and Hacetai o f 45. The signals that give COSY 136 correlations wi th H o u t are assigned to H j n . The signals in the 4.90-5.02 ppm region are assigned to Hmethine (they show COSY correlations with the C / ^ C f ^ P h signals that are in the 2.4-2.5 ppm region). The other host signals are assigned by their integrations, and by comparing the chemical shifts o f other carceplexes o f 45.14'29 The overall integration suggests that there is one molecule o f bound PhCOCHN 2 and one molecule o f bound NFP per molecule o f host. When the M A L D I mass spectrum o f 45«PhCOCHN 2«NFP was recorded (nitroaniline was used as matrix, silver trifluoromethane sulphonate was also added), signals at 3740 and 3765 m/z were obtained. These two signals correspond to 45«PhCOCHN 2 «NFP«Ag + -N 2 and 45«PhCOCHN 2 «NFP«Ag + , respectively. A band at 2105 cm" 1 ( l i t . 1 8 2107 cm" 1 in acetonitrile for unbound PhCOCHN 2 ) and a peak at 310 nm (an authentic sample o f unbound PhCOCHN 2 gave a peak at 300 nm) on the IR and U V spectra, respectively (Figures 5.5a and 5.6a), confirmed that the carceplex is indeed trimer carceplex 45«PhCOCHN 2»NFP. 137 8 . 5 7 . 3 6 . 5 5 . 5 4 . 5 3 . 5 2 . 3 1 . 5 6 . 3 - 6 i s (ppm) Figure 5.2. XW N M R spectra (CDCI3,27 °C) o f (a) 45«PhCOCHN 2 »NFP (400 MHz) , (b) sieve-dried 45»PhCH=C=0«NFP (400 MHz) , (c) sieve-dried product obtained from hydrolysis o f 45«PhCH=C=0«NFP (500 MHz) . 138 •a CD cn i i nj . o ro 3 ' Figure 5.3 2-D COSY (400 MHz, CDC1 3 , 27 °C) spectrum of 45»PhCOCHN 2 «NFP. 139 Table 5 .1 . COSY and NOESY correlations o f selected protons in 45»PhCOCHN 2« NFP Protons and their chemical shifts (ppm) COSY correlations NOESY correlations H i (6.51) H 2 H 2 , H j n , Hout, CiZN 2 , H c H o u t (5.81-6.11) H i n H i n , Hacetal, C /7 3 (cap), O C / 7 2 ( c a p ) , H d Hacetal (5.81-6.11) none H ; n , H 0 u t H f ( 5 . 2 6 ) none H i n , H d O C / / 2 ( c a p ) (5.09-5.20) none C7/3(cap) H 2 (5.13) Hi,3 Hl,3, H ; n H i n (5.02) H 0 u t unclear H m e th ine (4.90-5.02) G t f 2 C H 2 P h Hpara, H j n , H o u t , C / / 2 C / 7 2 P h H i n (4.70) Hout Hout, C7/ 5(cap), H e H 3 (4.64) H 2 H 2 , H i n C O G t f N 2 (4.52) none H i , H i n H i n (4.13-4.26) H 0 u t H , . 3 , C O C # N 2 , H 0 u t , Hacetal, C /7 3 (cap), O C / / 2 ( c a p ) , H a . e H e (1.51) H b • H a , b ,d , H m H d (1 .16 ) H c Ha,c,e,f H b (-0.32) H a , e H ; n , H a > e H c (-0.89) H a , d H j n , H a , d H a (-1.19) H b , c H ; n , Hb , c , d 141 :ie 13.16 3: oeDAti to. ; ,fi\ I \l A ! / 1/ v v ^ » ^ r W * * V W j j H 1 6 6 0 1 4 1 1 5 1 $ 1 6 4 9 - 5 " i l^O ASS ItM 1 1 6 9 . K i 131-1.1 3 3) l/'i J • 1 ! ^ (a) fl si 1: A I I i 1 If i MU1 u Ml J •Wo.* 1 1 I Figure 5.5. FT-IR spectra (KBr pellet) o f (a) 45»PhCOCHN 2«NFP, (b) 45»PhCH=C=0«NFP, (c) product obtained from hydrolysis o f 45«PhCH=C=0«NFP. 142 (c) 2.6273-2.10184 \ ^ 1.0509-0.00004. 200 500 URVELENGTH (b) 2.4000 1.60004-0.80000-t "I" 1 400 UflUELENGTH — ^ 500 (a) 2.3837-1.89854 1.4133-0.92806. 0.44287 -0.0423 3-200 300 500 U f l V E L E N G T H — r — r BOO 800 Figure 5.6. UV-V is spectra (CHC13) o f (a) 45«PhCOCHN 2»NFP, (b) 45»PhCH=C=0»NFP, (c) product obtained from hydrolysis o f 45«PhCH=C=ONFP. 5.4.2 Photolysis of 4 5 « P h C O C H N 2 » N F P and Formation of 4 5 » P h C H = C = 0 » N F P When trimer carceplex 45«PhCOCHN 2 «NFP was photolyzed (k > 300 nm) in dry benzene for three hours, and the 'H N M R spectrum (Figure 5.2b) o f the resulting compound was recorded, the chemical shifts were different f rom those o f the starting material (Figure 5.2a). COSY and NOESY spectra were recorded, and the signals were assigned in a similar way as it was done with 45»PhCOCHN 2 »NFP. The COSY and NOESY correlations are shown in Figures 5.7 and 5.8, and are summarized in Table 5.2. T L C of this product showed only one spot, and it had the same Rf value as the starting material, suggesting that the host was chemically unchanged. The IR spectrum (Figure 5.5b) o f the compound shows a band at 2117 c m 1 which is assigned to a C = C = 0 group. This value is accordance with the literature values of unbound PhCH=C=0, 2117 and 2118 cm"1 in isooctane and acetonitrile, respectively. 1 9 , 2 4 The band at 2106 cm"' disappeared at the expense of the one at 2117 c m 1 . Also, the U V spectrum of the photolyzed product does not have a peak at 310 nm (Figure 5.6b). Hence, it is concluded that PhCOCHN 2 was converted to P h C H O O (Scheme 5.12). M A L D I - M S gave a peak at 3655 m/z that corresponds to trimer carceplex 45»PhCH=C=0«NFP«Na + . N=N 45»PhCOCHN2»NFP 45»PhCH=C=0«NFP Scheme 5.12. Formation o f 45«PhCH=C=0«NFP from photolysis o f 45«PhCOCHN 2 «NFP. 144 The ' H N M R spectrum o f sieve-dried 45»PhCH=C=0»NFP is broad and complex (Figure 5.2b). COSY indicated that there are three sets o f signals for H i . Unfortunately the relative populations o f the species could not be estimated because the signals are overlapped. These sets o f signals are l ikely due to three different guest orientations within the cavity o f 45. Or, it might be possible that there are just two orientations; in one orientation the two H i are in different environments, and in the other orientation they are under identical environment. A third possibility is that there might be a mixture o f hydrates, that is, 45«PhCH=C=0«NFP»(H 2 0) n . Even though we did our best to perform the photolysis experiment and record the *H N M R spectra o f 45«PhCH=C=0«NFP under dry conditions, we do not exclude the possibility o f hydrates. Even though carbene 133 can in principle give insertion products and cylopropanes, results f rom hydrolysis experiments (see section 5.4.3) suggest that these products are most l ikely not formed in our system. That is, ! H N M R spectroscopy indicated that the product(s) obtained from the photolysis experiment was/were quantitatively transformed to other products during the hydrolysis process. We would not expect the insertion products and cyclopropanes (ketones) to react wi th water to give new products. Furthermore, the IR spectrum o f the photolyzed sample shows only one carbonyl stretch which is most l ikely the stretching frequency o f N C = 0 o f NFP. Photolysis o f PhCOCHN 2 could also furnish oxirene 153 (Figure 5.9). However, we do not believe that 153 would be stable under the conditions we employed (the photolysis and data acquiring were done at room temperature) because oxirenes are very reactive. Oxirenes have only been detected at very low temperatures in argon matrices. 3 0 ' 3 1 Could bound PhCH=C=0 have reacted with bound NFP to give a cycloadduct 154 (Scheme 5.13)? The presence o f a band at 1676 cm" 1 (N-C=0 frequency), and absence o f a band in the 1750-1800 cm" 1 region (lactone frequency) on the IR spectrum o f the photolyzed sample suggest that NFP did not react wi th PhCH=C=0 to give 154. 145 U s * * * Figure 5.7. 2-D COSY (500 MHz, CDC1 3 , 27 °C) spectrum o f 4 5 » P h C H = C O « N F P . •a co ai J*. PJ o 3 Figure 5.8. 2-D NOESY (400 MHz, CDC1 3 , 27 °C) spectrum o f 45»PhCH=C=0«NFP. 147 Table 5.2. COSY correlations o f selected protons o f bound guests in 45«PhCH=C=0»NFP Protons and their chemical shifts (ppm) COSY correlations H i (5.83-6.10) H 2 (three cross-peaks) H 2 (4.73-5.32) H i , 3 H 3 (4.73-5.32) H 2 Bound NFP signals:1 0.39 -0.15 -0.15 0.39 -0.28 -0.79 -0.79 -0.28,-1.44 -1.44 -0.79 J The connections could not be deconvoluted to yield the assignments. 153 Figure 5.9. Structure o f oxirene 153. 45»PhCHC=C=0«NFP 45«154 Scheme 5.13. Formation o f cycloadduct 154. In a control experiment, a sample o f trimer carceplex 45 • (NFP) 1,2 was photolyzed using the same conditions employed for 45«PhCOCHN2»NFP. There was no difference between the lU N M R and IR spectra o f the sample before and after the photolysis experiment. These results suggest that trimer 45 • (NFP) 1,2 remained unchanged after photolysis. Hence, it can be concluded that when 45«PhCOCHN2«NFP was photolyzed, bound NFP did not undergo any reaction wi th the host or with itself. 5.4.3 Hydrolysis of 4 5 « P h C H = C = 0 « N F P and Formation of 4 5 » P h C H 2 C O O H « N F P » ( H 2 0 ) n When a 0.275 m M solution o f trimer carceplex 45»PhCH=C=0«NFP in water-D M S O (1.99, v/v) was heated at 90 °C for 48 hours, the solvents were removed in vacuo, the *H N M R spectrum (Figure 5.2c) o f the sample in sieve-dried CDCI3 looked different from the starting material (Figure 5.2b). The signals o f the products are more resolved than those o f the starting material. Results from COSY and NOESY (Figures 5.10 and 5.11, and Table 5.3) experiments suggested that there was no starting material left, and three new species were formed. That is, three sets o f values were obtained for Hi (5.83, 5.81 and 5.72 ppm), H 2 (5.32, 5.20 and 4.62 ppm) and H 3 (4.20, 3.48 and 2.98). The signals at 7.98 and 8.22 ppm are most l ikely due to the protons o f hydroxyl groups o f carboxylic acids. The intensity o f the signal at 7.98 ppm is around half the intensity o f the signal at 1.79 ppm. A long range COSY correlation was also observed between these two signals. These results suggest that bound PhCH=C=0 most probably reacted wi th water to give bound PI1CH2COOH (unbound PhCH=C=0 reacts wi th water to give PI1CH2COOH). Hence the signal at 1.79 ppm is assigned to the methylene protons o f PI1CH2COOH. The doublets at 3.60 and 3.97 ppm are roughly o f the same intensity, and gave COSY correlation to each other. These signals did not seem to diminish in intensity when a solution o f trimer carceplex 45»PhCH=C=0»NFP in water-DMSO was heated at 90 °C for five days. So, the doublets could not be due to PhCH=C(OH)2, i.e., any acid 149 Figure 5.10. 2-D COSY (400 MHz, CDCI3, 27 °C) spectram o f product obtained from hydrolysis o f 45«PhCH=C=0»NFP. Figure 5.11. 2-D NOESY (500 MHz, CDC1 3 , 27 °C) spectrum o f product obtained from hydrolysis o f 45«PhCH=C=0«NFP. 151 Table 5.3. C O S Y and N O E S Y correlations o f selected protons o f bound guests in 45«guest(s) Protons and their C O S Y correlations N O E S Y correlations chemical shifts (ppm) H i (5 .83 ) H 2 ( 4 . 8 3 ) H 2 ( 4 . 8 3 ) , H i n , C / / 2 C O O H H i (5 .81) H 2 ( 4 . 6 2 ) H 2 ( 4 . 6 2 ) , H i n H i (5 .72) H 2 ( 5 . 3 2 ) H 2 ( 5 . 3 2 ) , H i n H 2 ( 5 . 3 2 ) H i (5 .72 ) , H 3 ( 4 . 2 0 ) H i ( 5 .72 ) , H 3 ( 4 . 2 0 ) , H i n H 2 ( 4 . 8 3 ) H i (5 .83 ) , H 3 (3 .48) H i ( 5 .83 ) , H 3 ( 3 . 4 8 ) , H i n H 2 ( 4 . 6 2 ) Hi (5.81), H 3 (2 .98) H i (5 .81 ) , H 3 ( 2 . 9 8 ) , H i n H 3 (4 .20) H 2 ( 5 . 3 2 ) H 2 ( 5 . 3 2 ) , H i n 3 . 9 7 3 . 6 0 3 . 6 0 , 1.12, H i n 3 . 6 0 3 . 9 7 3 . 9 7 , Hm H 3 (3 .48) H 2 (4 .83) H 2 ( 4 . 8 3 ) , H i n H 3 ( 2 . 9 8 ) H 2 (4 .62) H 2 ( 4 .62 ) , H i n G r 7 2 C 0 0 H ( 1 . 7 9 ) none - 0 . 8 8 , H , Bound guest signals in the upfield region: 1.12 - 0 . 7 4 3 . 9 7 , - 0 . 6 1 , - 0 . 7 4 , -0 .88 , H i n , C H 3 ( c a p ) -0 .03 - 0 . 8 8 , - 1 . 3 3 - 0 . 6 1 , - 0 . 8 8 , - 1 . 3 3 , H i n , C H 3 ( c a p ) -0 .61 -0 .03 1 . 1 2 , - 0 . 0 3 , - 0 . 7 4 , -1.33, Hjn - 0 . 7 4 1 . 1 2 , - 0 . 8 8 1 . 1 2 , - 0 . 6 1 , - 0 . 8 8 , H o U t , H i n , C H 3 ( c a p ) - 0 . 8 8 - 0 . 0 3 , - 0 . 7 4 1 . 1 2 , - 0 . 0 3 , - 0 . 6 1 , - 7 4 , H i n , G r 7 2 C O O H -1 .33 - 0 . 0 3 , -0 .61 - 0 . 0 3 , - 0 . 6 1 , H i n 152 enol formed would have been most probably converted to PhCH 2 COOH, and the doublets should have disappeared or diminished in intensity. Bound PhCH=C=0 might have reacted wi th bound NFP to give 154 during heating (Scheme 5.13). H x and H y o f 154 would be expected to give doublets. Hence, the doublets at 3.60 and 3.97 ppm might have stemmed from 154. The signals at 1.12, -0.03, -0.61, -0.74, -0.88, -1.17 and -1.33 are from the protons o f bound NFP, H 2 0 (-0.74 ppm), and may be 154 (refer to Figure 5.10 and Table 5.3 for COSY correlations). 45«PhCH=C=0«NFP 45«PhCH 2COOH«NFP Scheme 5.14. Formation o f 45»PhCH 2 COOH«NFP»(H 2 0) n f rom hydrolysis o f 45«PhCH=C=0»NFP. The IR spectrum o f the hydrolyzed sample (KBr pellet) shows bands at 1693, 1712, 1719 and 3442 (broad) cm" 1 (Figure 5.5c). Also there was no band at 2117 cm" 1 (ketene signal). These data suggest that bound PhCH=C=0 was indeed converted to PhCH 2 COOH, and maybe to some other product(s). The IR spectrum o f an authentic sample o f unbound PhCH 2 COOH shows a broad band in the 2500-3500 cm"1 region and a sharp band at 1702 cm" 1 ( l i t . 2 4 ' 3 3 1716 and 1695 cm" 1 in isooctane and nujol, respectively). The UV-Vis spectrum of the photolyzed sample in CHCI3 shows a peak at 250 nm and a shoulder at 310 nm (Figure 5.6c). A n authentic sample o f unbound PhCH 2 COOH shows a broad peak around 250 nm. Since we do not know to what extent the host changes the absorptivity o f PhCH 2 COOH, we can not say for sure whether the peak at 310 nm is due 153 to PhCH 2 COOH, or an another species. M A L D I mass spectroscopy gave a major peak at 3708 m/z that corresponds to 4 5 » P h C H 2 C 0 0 H « N F P » H 2 0 » K + . Similar results were obtained when the hydrolysis experiment was done in either water-saturated nitrobenzene or water-saturated chloroform. A l l these results lead us to believe that when a solution o f 45»PhCH= :C=0»NFP in water-DMSO was heated at 90 °C, 45»PhCH 2 COOH»NFP»(H 2 0) n , where n > 0, and maybe 45*154 are formed. We performed the hydrolysis experiment for shorter time intervals, and over a range o f temperature (27-90 °C) to determine whether the formation o f PhCH 2 COOH from PhCH=C=0 proceeds via PhCH=C(OH) 2 or not. Unfortunately, we were unable to get a definite answer. 5.4.4 Synthesis o f T r i m e r Carceplex 152»l ,3 ,5- t r is ( iodomethyl )benzene When a mixture o f trimer 42, K4CO3, K I , l,3,5-tris(bromomethyl)benzene and NFP was stirred for 48 hours, trimer carceplex 152«l,3,5-tris(iodomethyl)benzene was obtained in 28% yield (Scheme 5.10). The XW N M R spectrum o f 152*1,3,5-tris(iodomethyl)benzene is easy to interpret (Figure 5.12). The chemical shifts o f bound l,3,5-tris(iodomethyl)benzene are located at 2.65 (benzyl protons) and 5.38 (aryl protons) ppm, respectively. The M A L D I mass spectrum shows a peak at 3850 m/z that corresponds to trimer carceplex 152»l,3,5-tris(iodomethyl)benzene»K + (Figure 5.13). When the above reaction was repeated in the absence o f trimer 42, 1,3,5-tris(iodomethyl)benzene was obtained. Only trimer carceplex 152» 1,3,5-tris(bromomethyl)benzene was obtained when a mixture o f trimer 42, K 2 C03 and 1,3,5-tris(bromomethyl)benzene was stirred. When the above reaction was run under dilute condition (1 mg 42 per m L NFP) and in the absence o f K I , only trimer carceplex 154 152«NFP was isolated. These results confirm that l,3,5-tris(iodomethyl)benzene was indeed formed in situ and then trapped within the cavity o f 152. Figure 5.12. *H N M R (500 MHz, CDC13) spectrum o f trimer carceplex 152»l,3,5tris(iodomethyl)benzene. Figure 5.13. M A L D I mass spectrum o f 152*1,3,5-tris(iodomethyl)benzene. 155 5.4.4.1 Stability of Trimer Carceplex 1 5 2 » l , 3 , 5 - t r i s ( i o d o m e t h y l ) b e n z e n e When a solution o f 152«l,3,5-tris(iodomethyl)benzene in water-saturated chloroform or water-saturated nitrobenzene was heated at 60 °C for several days, bound l,3,5-tris(iodomethyl)benzene did not undergo decomposition. On the other hand, when a solution o f l,3,5-tris(iodomethyl)benzene in CDCI3 was saturated wi th water, 1,3,5-tris(iodomethyl)benzene suffered decomposition within hours even at room temperature. Addit ion o f tetrabutylammonium hydroxide, potassium hydroxide, «-butyllit ium or methyl-l ithium to a solution o f 152»l,3,5-tris(iodomethyl)benzene in THF did not have any effect. A l l these results suggest that when bound, l,3,5-tris(iodomethyl)benzene is indefinitely stable. 5.5 Summary and Conclusions PI1COCHN2 was successfully trapped within the confines o f 45 (Scheme 5.11). Upon photolysis, bound PhCOCHN 2 was converted to PhCH=C=0 (Scheme 5.12). Trimer carceplex 45«PhCH=C=0 »NFP was stable at room temperature. When a solution o f 45»PhCH=C=0»NFP in water-DMSO, water-saturated chloroform or water-saturated nitrobenzene was heated, 45«PhCH2C00H«NFP«(H20)n seemed to be formed (Scheme 5.14). Trimer carceplex 45*154 (Scheme 5.13) might have been formed as wel l , but presently we do not have sufficient evidence to support it. We could not determine whether the formation o f PhCH2COOH from PhCH=C=0 proceeds via PhCH=C(OH) 2 or not. In situ generated l,3,5-tris(iodomethyl)benzene was trapped and stabilized within the cavity o f 152 (Scheme 5.10). Bound l,3,5-tris(iodomethyl)benzene did not decompose 156 when a solution o f 152«l,3,5-tris(iodomethyl)benzene in THF was refluxed in the presence o f water, potassium hydroxide or tetrabutylammonium hydroxide. Even n-butyll i thium or methyll ithium did not have any effect on 152«l,3,5-tris(iodomethyl)-benzene. In a similar way, other compounds that are more reactive than 1,3,5-tris(iodomethyl)benzene could in principle be generated in situ and then trapped within the shell o f 45 and 152. It might even be possible to trap transiently formed reactive intermediates and study their structures. 5.6 Experimental Section General. A l l reagents were purchased from Aldrich Co. Inc., and were used without purification unless stated otherwise. NFP and benzene were distilled, and stored over 4 A sieves under a nitrogen atmosphere. PI1COCHN2 was kindly provided by Professor Thomas Tidwell from the University o f Toronto. Deionized distilled water was used for the hydrolysis experiments. 1-D and 2-D ! H N M R spectra were recorded at 27 °C on either an Avance-400 or a Bruker A M X 500 MHz spectrometer in CDCI3 using its residual ' H signal as reference. 2-D NOESY spectra were run wi th mixing time o f 400 milliseconds. H j n and H o u t refer to the diastereotopic OCH2O intra-bowl bridges, para -H refer to the protons on the bridged aromatic rings and cap refer to the (OCH 2 )3C6(CH3)3 moeities. Mass spectra were recorded on a Bruker Bif lex IV M A L D I -TOF instrument in the reflectron mode and are accurate to one part per thousand. The calculated molecular weights are based on the average mass o f the various isotopes. FT-IR spectra were recorded on a Perkin-Elmer 1710 Fourier transform spectrophotometer. 157 UV-Vis spectra were recorded on a Hewlett Packard 8452A diode array spectrophotometer. Photolysis experiments were done at wavelength > 300 nm (a Hanovia 450 W medium pressure Hg-arc lamp fitted with a pyrex filter). Column chromatography was performed using silica gel (BDH, 230-400). Radial chromato-graphy was performed on a chromatotron (Model 7924, Harrison Research) with plates prepared using silica gel (60 PF254, E M Reagents). Preparative thin layer chromatography were run on 1 mm plates (60 PF254, E M Reagents). 5.6.1 Synthesis and Characterization of Trimer Carceplex 4 5 » P h C O C H N 2 « N F P Trimer carceplex 45«PhCOCHN 2«NFP: Trimer 42 (100 mg, 32.4 jxmmol) was first dissolved in a flask containing NFP (1.0 mL). KI (27.0 mg, 163 ummol, 5 equiv.), PhCOCHN 2 (300mg, 2.05 mmol, 63 equiv.) and K 2 C 0 3 (90.0 mg, 651 ummol, 20 equiv.) were then added to the solution. The mixture was stirred under an N 2 atmosphere for 1 hour at room temperature. l,3,5-tris(bromomethyl)mesitylene (64.5 mg, 162 ummol, 5 equiv.) was then added, and the mixture was stirred for 24 hours. A n extra amount of NFP (1.0 mL) was added to the sample, and the resulting mixture was stirred for 24 hours. The products were precipitated out by adding an excess amount of methanol. The precipitate was dissolved in CHC1 3 and eluted with CHC1 3 through a silica gel (10 g) 158 column. The eluent was concentrated, redissolved in CH2CI2 and loaded onto a chromatotron. The plate was then eluted with CH2Cl2/hexanes (3 :1 , v/v). The relevant fraction was collected, dried, and the solid was recrystallized in CHC^/MeOH (2:1, v/v) to give trimer carceplex 45«PhCOCHN 2»NFP as a white solid (29.6 mg, 25% yield). ! H N M R (400 MHz, CDCI3, refer to Table 5.1 for COSY and NOESY correlations) 8 7.19-7.24 (m, CH 2 CH2C6#5 + C//C1 3), 6.77-7.08 (m, UU, parall), 6.51 (d, 2H, 7.3 Hz, H i ) , 5.81-6.11 (m, 18H, H o u t + H a c e tai), 5.26 (s, I H , H f ) , 4.90-5.24 (m, 28H, OCH2 (cap) + Hme,hine + H 2 + H i n ) , 4.70 (m, 2H, H i n ) , 4.64 (t, I H , J = 7.1 Hz, H 3 ) , 4.52 (s, I H , COCHN 2 ) , 4.13-4.26 (m, 8H, H i n ) , 2.41-2.93 (m, 66H, (CH3 (cap) + CH2CH2Ph), 1.51 (m, 2H, H e ) , 1.16 (m, 2H, H d ) , -0.32 (m, 2H, H b ) , -0.89 (m, 2H, H c ) , -1.19 (m, 2H, H a ) ; MS ( M A L D I ) m/z = 3740 (100%) [ M » A g + - N 2 ] , calcd for C233H209N3O 38«Ag+-N2= 3739; IR (KBr pellet) cm" 1 2105 (VC=N=N), 1733 (v P h C =o) ; UV-Vis (^ax )nm 250,310. 5.6.2 Formation and Characterization of Trimer Carceplex 4 5 » P h C H = C = 0 » N F P H 45»PhCH=C=0»NFP: 45»PhC0CHN 2»NFP (10 mg, 2.73 ummol) was dissolved o in a flask containing dry distilled benzene (10 mL) , crushed sieves (4 A ) and a stir bar. The flask was stoppered wi th a rubber septum and flushed with argon for hal f an hour. The flask was made airtight wi th parafilm. The solution was then irradiated wi th U V light, A, > 300 nm, for three hours. The sample was filtered, and the solvent was removed in vacuo to give 45«PhCH=C=0«NFP as a white solid (9.4 mg, 95%). ' H N M R (400 MHz, sieve-dried CDC1 3 , refer to Table 5.2 for COSY correlations) 8 6.79-7.34 (m, C H 2 C H 2 C 6 ^ 5 + parall + C M 3 ) , ) , 5.70-6.10 (m, 20H, H i + H o u t + H a c e tai), 4.73-5.32 (m, 159 2 7 H , H 2 + H 3 + OCH2 (cap) + H m e t h i n e ) , 3.93-4.38 (m, 12H, H i n ) , 2.52-2.91 (CH3 (cap) + CH2CH2?h), 0.39, -0.15, -0.28, -0.79, -1.44 (m, 5 H , H a . e ) , H 4 and H f could not be located due to the complexity o f the spectrum; MS ( M A L D I ) m/z = 3655 (100%) [ M « N a + ] , calcd for C 233H 2o 9Ni038*Na + = 3654; IR (KBr pellet) cm" 1 2117 (vc=c=o); UV-Vis (^ax) nm 250. 5.6.3 Formation and Characterization of Trimer Carceplex 4 5 » P h C H 2 C O O H « N F P » ( H 2 0 ) „ 4 5 « P h C H 2 C O O H « N F P » ( H 2 0 ) „ , (may contain other products): 45«PhCH=C=0 •NFP (5.0 mg, 1.38 ummol) was dissolved in a flask (fitted with a condenser) containing 5 m L o f water-DMSO (1:99, v/v), and the resulting solution was heated for 48 hours at 90 °C. The solvents were removed, and the sample was reprecipitated out in a chloroform/hexanes (1:2, v/v) mixture. ! H N M R (400 MHz, sieve-dried CDCI3, refer to Table 5.3 for COSY and NOESY correlations) 5 8.22 (m, COO//) , 7.98 (m, COO#) , 6.73-7.44 (m, C H ^ H ^ ^ j + paraR + C//CI3), 5.69-6.02 (m, H i + H o u t + H a c e tai), 5.32 (t, J= 7.8 Hz, H 2 ) /4.82-5.20 (m, H 2 + OCH2 (cap) + Hmethine), 4.62 (t, J = 7.7 Hz, H 2 ) , 4.04-4.47 (m, H 3 + H i n ) , 3.97 (d, J= 8.7 Hz), 3.60 (d, J= 8.7 Hz), 3.54 (d, J= 9.2 Hz), 3.49 (t, J= 7.0 Hz, H 3 ) , 2.98 (t, J= 7.1 Hz, H 3 ) , 2.47-2.86 (CH3 (cap) + CH2CH2?h), 1.79 (m, C7/ 2 COOH), 1.12, -0.03, -0.61, -0.74, -0.88, -1.17, -1.33 (m, bound guests, bound water seems to be at -0.74 ppm); MS ( M A L D I ) m/z = 3708 (100%) [ M « H 2 0 » K + ] , calcd for C 2 3 3 H 2 i i N , 0 3 9 » H 2 0 « K + = 3706; IR (KBr pellet) cm" 1 3442 ( v 0 H ) , 1719, 1712, 1693 (VCOOH); UV-Vis ( ^ nm 250, 310. 160 5.6.4 Synthesis and Characterization of Trimer Carceplex 152«1,3,5-tris(iodomethyl)benzene Trimer. carceplex 152»l,3?5-tris(iodometliyl)benzene: Trimer 42 (20.0 mg, 6.48 ummol) was first dissolved in a flask containing NFP (250 uL). K I (5.4 mg, 32.5 ummol, 5 equiv.) and K2CO3 (18.0 mg, 130 ummol, 20 equiv.) were then added to the solution. The mixture was stirred under an N2 atmosphere for 1 hour at room temperature. l,3,5-tris(bromomethyl)benzene (11.6 mg, 32.5 ummol, 5 equiv.) was then added, and the mixture was stirred for an additional 48 hours. The products were precipitated out by adding an excess amount o f methanol. The precipitate was dissolved in CH2CI2 (0.5 mL) and then eluted with CH2CI2 through a silica gel (3 g) column. The least polar compound was redissolved in a 1:1 (v/v) mixture o f CH2CI2 and hexanes, and kept at 4 °C for 24 hours. The mixture was filtered, and the precipitate was collected and dried under high vacuum to give 152«l,3,5-tris(iodomethyl)benzene as a white solid (7.0 mg, 28% yield). ' H N M R (500 MHz, CDC1 3) 5 7.37 (s, 6H, ((OCR2)3C6H3)), 7.16-7.24 (m, CH2CH2C6 / /5 + CHC\3), 6.88 (s, 6R, paraR), 6.71 (s, 6R, paraR), 5.94 (d, 12H, J = 6.4 Hz, H o u t ) , 5.91 (s, 6H, H a c e t ai), 5.38 (s, 3H, bound (ICIfcfcCotfj), 4.98 (s, 12H, (OC//2) 3C 6H 3), 4.90 (t, 12H, J= 7.8 Hz, Hmethine), 4.54 (d, 12H, / = 6.5 Hz, H i n ) , 2.70 (m, 24H, CR2CH2Ph), 2.65 (s, 6H, bound ( I C H z ^ C s ^ ) , 2.50 (m, 24H, CH2CH2?h); MS ( M A L D I ) m/z = 3850 (100%) [ M « K + ] , calcd for C 2 22Hi89l30 3 6«K + = 3853. 5.6.5 Synthesis and Characterization of Trimer Carceplex 152»1,3>5-tris(bromomethyl)benzene Trimer carceplex 152«l,3,5-tris(bromomethyl)benzene: Same as above, but no K I was used. Trimer carceplex 152«l,3,5-tris(bromomomethyl)benzene was obtained a white solid in 18% yield. ' H N M R (500 MHz, CDC13) 8 7.34 (s, 6H, ( ( O C ^ ^ C ^ ) ) , 7.16-7.24 (m, CH2CH2C6 / /5 + C/7C13), 6.92 (s, 6H,^araH) , 6.75 (s, 6H, paraR), 5.97 (d, 12H, J = 6.2 Hz, H o u t ) , 5.89 (s, 6H, H a c e t a i ) , 5.52 (s, 3H, bound ( B r C H 2 ) 3 C 6 ^ ) , 4.93 161 (s,12H, ( O C / / 2 ) 3 C 6 H 3 ) , 4.89 (t, 12H, / = 7.9 Hz, H m e t h m e ) , 4.35 (d, 12H, J= 6.2 Hz, H i n ) , 2.66-2.71 (m, 30H, C H 2 C 7 / 2 P h + bound (BrCH 2 ) 3 C6#3) , 2.50 (m, 24H, C 7 / 2 C H 2 P h ) ; MS ( M A L D I ) m/z = 3710 (100%) [ M « K + ] , calcd for C 2 2 2 H i 8 9 B r 3 0 3 6 » K + = 3712. 5.6.6 Synthesis and Characterization of Trimer Carceplex 1 5 2 « N F P Trimer carceplex 152»NFP: Same procedure as done for 152»l,3,5-tris-(iodomethyl)benzene, but 20 m L o f NFP was used instead o f 250 uL, and also no K I was used. Trimer carceplex 152»NFP was obtained as a white solid in 23% yield. ' H N M R (500 MHz, CDC1 3) 5 7.45 (s, 6H, ( (OCH 2 ) 3 C6#j ) ) , 7.17-7.24 (m, C H 2 C H 2 C y 7 5 + C # C 1 3 ) , 6.95 (s, 6U,paraH), 6.75 (s, 6H,paraU), 6.03 (d, 12H, J= 6.7 Hz, H o u t ) , 5.92 (s, 6H, Hacetai), 4.99 (s, I H , H f ) , 4.87-4.91 (m, 24H, (OC77 2)3C 6H 3) + H m e t h i n e ) , 4.08 (d, 12H, J= 6.7 Hz, H i n ) , 2.70 (m, 24H, CH 2C7/ 2Ph), 2.50 (m, 24H, C / ^ C H ^ h ) , 1.61 (m, 2H, H e ) , 1.40 (m, 2H, H d ) , -0.81 (m, 2H, H b ) , -0.28 (m, 2H, H c ) , -0.39 (m, 2H, H a ) ; MS-( M A L D I ) m/z = 3467 (100%) [ M » K + ] , calcd for C 2 i 9 H , 9 i N i 0 3 7 « K + = 3468. 162 5.7 References 1. Cram, D. J.; Tanner, M. E.; Thomas, R. Angew. Chem. Int. Ed. Engl. 1991, 30, 1024. 2. Cram, D. J.; Tanner, M. E.; Knobler, C. B. Am. Chem. Soc. 1991,113, 7717. 3. Robbins, T. A.; Cram, D. J. J. Am. Chem. Soc. 1993,115, 12199. 4. Kurdistani, S. K; Helgeson. R. C ; Cram, D. J. J. Am. Chem. Soc. 1995,117, 1659. 5. Warmuth, R.; Maverick, E. F.; Knobler, C. B.; Cram, D. J. J. Org. Chem. 2003, 68, 2077. 6. Warmuth, R. Chem. Commun. 1998, 59. 7. Warmuth, R. Angew. Chem. Int. Ed. Engl. 1997, 36, 1347. 8. Kerdelhue, J.-L.; Langenwalter, K. J.; Warmuth, R. J. Am. Chem. Soc. 2003,125, 973 9. Warmuth, R.; Marvel M. A. Chem. Eur. J. 2001, 7, 1209. 10. Warmuth, R. J. Am. Chem. Soc. 2001,123, 6955. 11. Warmuth, R.; Marvel M. A. Angew. Chem. Int. Ed. 2000, 39, 1117. 12. Warmuth, R.; Kerdelhue, J.-L.; Carrera, S. S.; Langenwalter, K. J.; Brown, N. Angew. Chem. Int. Ed. 2002, 41, 96. 13. Kodumuru, V. unpublished results. 14. Makeiff, D. Ph.D. thesis, University o f British Columbia, 2003. 15. Tidwel l , T. T. Ketenes; John Wiley and Sons: New York, 1995. 16. Patai, S., Ed. The Chemistry of Ketenes, Allenes, and Related Compounds; John Wi ley and Sons: New York, 1980. 17. Al len, A. D.; Kresge, J.; Schepp, N. P.; Tidwel l , T. T. Can. J. Chem. 1987, 65, 1719. 18. Kowalski, C. J.; Reddy, R. E. J. Org. Chem. 1992, 57, 7194. 163 19. Wagner, B. D.; Arnold, B. R.; Brown, G. S.; Lusztyk, J. J. Am. Chem. Soc. 1998, 120, 1827. 20. Farnum, D. G.; Johnson, J. R.; Hess, R. E.; Marshall, T. B.; Webster, B. J. Am. Chem. Soc. 1965,57,5191. 21 . Baldwin, J. E.; Roberts, J. D. J. Am. Chem. Soc. 1963, 85, 2444. 22. Staudinger, H. Chem. Ber. 1911, 44, 533. 23. Bothe, E.; Meier, H.; Schulte-Frohlinde, D.; von Sonntag, C. Angew. Chem. Int. Ed. Engl. 1976,75,380. 24. Al len, A. D.; Cheng, B.; Fenwick, M. H.; Givenchi, B.; Henry-Riyad, H.; Nikolaev, V. A. ; Shikhova, E. A. ; Tahmassebi, D.; Tidwell, T. T.; Wang, S. J. Org. Chem. 2001,55,2611. 25. Tidwel l , T. unpublished results. 26. Andraos, J.; Chiang, Y. ; Kresge, A. J.; Pojarlieff, I. G.; Schepp, N. P.; Wirz, J. J. Am. Chem. Soc. 1994,116, 73. 27. Chiang, Y.; Kresge, A. J.; Popik, V . V.; Schepp, N. P. J. Am. Chem. Soc. 1997, 119, 10203. 28. Warmuth, R. Eur. J. Org. Chem. 2001, 423. 29. Chopra, N.; Sherman, J. C. Angew. Chem. Int. Ed. 1999, 38, 1955. 30. Lewars, E.- G. Chem. Rev. 1983, 83, 519. 31. Torres, M.; Bourdelande, J. L.; Clement, A.; Strausz, O. P. J. Am. Chem. Soc. 1983, 105, 1698. 32. For [2 + 2] cycloadditions involving ketenes, see references 15 and 16. 33. Aldrich Library of Infrared Spectra, Part 2. 164 6.0 Overall Conclusion and Future Work 6.1 Overall Summary Tetrol 37 (refer to Scheme 1.6 for its structure) has been successfully used as a starting material to make a multitude o f hosts that are able to form complexes, hemicarceplexes and carceplexes. The cavity size and shape, and guest binding abilities o f these hosts vary. A t room temperature, the guests o f hemicarceplex 60 (Figure 6.1) do not leave the cavity. On the other hand, the guests o f 61 and 67-69 (Figure 6.1) move freely in and out o f their cavities. The guest recognition ability o f 81 (Figure 6.1) is comparable to those o f 61 and 67-69. However, 81 binds two guest molecules. R = Ch^CH^CgHjj 61, R 1 = R 2 = H 67, R1 = H, R 2 = (CH 2 ) 4 Br 68, R1 = Bn, R z = H 69, R1 = R 2 = Me Figure 6.1. Structures o f hosts 60, 61, 67-69 and 81. 165 Hexamer 74 can be used to make tris-carceplex 75 as well as tris-capsule 76 (Figure 6.2). Tris-carceplex 75»(methyl acetate^ is kinetically more stable than 76»(methyl acetate)3. Even though 75»(methyl acetate^ and bis-hemicarceplex 78«( 1,3,5-triethynylbenzene)2 (Figure 6.2) each contain six bowls, their size and shape and guest binding abilities are totally different. Tris-carceplex 75 traps three small molecules (one in each cavity) such as methyl acetate. Whereas, 78 traps two fairly large molecules such as 1,3,5-triethynylbenzene (one in each cavity). The guests o f 78«( 1,3,5-triethynylbenzene)2 can be emptied by heating, whereas those o f 75 cannot be. ' ? 0 H 0 HO O J " 74 78*(1,3,5-tr iethynylbenzene) 2 75« (methyl acetate) 3 76» (methyl acetate) 3 Figure 6.2. Structures o f 74-76 and 78. 166 PhCOCHN 2 can be trapped within the shell o f 45 under mi ld condition (no heating is required). When a sample o f 45»PhCOCHN2»NFP (Figure 6.3) is photolyzed, bound PhCOCHN 2 can be converted to PhCH=C=0 that can itself react with water to give PhCH 2 COOH. l,3,5-tris(iodomethybenzene) can be synthesized in situ and trapped within the cavity o f 152 (Figure 6.3). When bound, l,3,5-tris(iodomethybenzene) is indefinitely stable. 45»PhCOCHN 2«NFP 152* 1,3.5-tris(iodomethyi)benzene Figure 6.3. Structures o f trimer carceplexes 45 and 152. 6.2 Overall Conclusion Cram's idea o f coining the inner phase o f a hemicarceplex or a carceplex as a new phase o f matter is not far-fetched.1 As discussed in this thesis, the magnetic environment o f guests within the cavities o f hemicarceplexes and carceplexes is largely affected. The mobil i ty o f bound guest is restricted. Reactive intermediates can also be stabilized within the shells o f these host molecules. In this thesis, I consider the work presented on the generation and stabilization o f PhCH=C=0 within the shell o f 45 to be my most significant contribution to the scientific community. Drugs that decompose before they reach their targets might be trapped and stabilized within the confines o f carceplexes or hemicarceplexes, and then administered to patients 167 in the future. However, before hemicarceplexes and carceplexes are used as drug delivery devices, they must ful f i l l the following criteria: (i) Their metabolites and they themselves should be non-toxic (i i) They should be soluble or at least sparingly soluble under physiological conditions. ( i i i ) They should be easily made in high yields. (iv) They should neither decompose before the drugs reach their targets, nor be too stable that the drugs can not be delivered at all. 6.3 Future Work 6.3.1 Ful l Characterization of Products Obtained from the Hydrolysis of 4 5 » P h C H = C = 0 « N F P Further studies need to be done to ful ly characterize the products obtained from the hydrolysis o f 45«PhCH=C=0«NFP. Hydrolysis o f 45»PhCH=C=0»NFP in other solvents such as THF, CH2CI2 or benzene might give data that are more interpretable. A solid sample or a dry solution o f 45»PhCH=C=0»NFP can be heated to see whether 45»154 is formed or not (Scheme 6.1). Such an experiment would confirm or reject the hypothesis that a cycloaddition process competes wi th the hydrolysis process at elevated temperatures. Labelled PhCOCHN 2 (PhCOCDN 2) could be also trapped and photolyzed to give 45«PhCD=C=0»NFP. The signal o f bound P h C D = O 0 could be then located by running 2 D N M R experiments. In case PhCD=C(OH) 2 is formed in the hydrolysis o f 168 P h C D = O 0 , i t might be easily differentiated from PhCHDCOOH by 2 D N M R spectroscopy. 45»PhCH=C=ONFP 45»154 Scheme 6.1. Formation o f cycloadduct 154. 6.3.2 Stabilization of Oxirenes within the Shell of 45 Another interesting thing that could be done, is the stabilization o f oxirenes within the cavity o f 45. Oxirenes are antiaromatic species, and they are very unstable. Various studies have been performed in rare gas matrices at low temperatures to show the involvement o f oxirene intermediates in the photolysis o f a-diazo ketones.2"5 Wi th the help o f infrared spectroscopy, Strausz and coworkers were able to detect oxocarbene 156 and oxirene 157 as transient species in addition to ketene 158 when hexafiuoro-3-diazo-2-butanone (155) was photolyzed at low temperatures (Scheme 6.2). 4 Oxirene 157 decomposed rapidly even at a temperature as low as -238 °C. On the other hand, ketocarbene 156 was stable up to -123 °C. Considering the cavity size and binding properties o f 45, diazo ketone 159 is a good candidate for such a study (Scheme 6.2). Compound 159 might be more useful than 132 169 157 FoC N 2 C F 3 155 hv F 3 C ^ C F 3 4 Q F a C C F 3 156 F 3 C F 3 C > = C = 0 158 H hv H Ph H a a Ph' C=0 132 133 134 Scheme 6.2. Formation o f ketocarbenes, oxirenes and ketenes from diazo ketones. 1 7 0 because the intermediates from 159 can be more easily characterized. For example, ] H N M R spectroscopy would most probably give only singlets for the H a o f 133, 134 and 153 (Scheme 6.2). On the other hand, the H a o f 160 or 161 would most probably give a singlet, and that o f 162 would give a triplet. That is, it would be easy to differentiate 160 or 161 from 162. A subtle steric effect within the confines o f 45 might favor oxirene 161 over carbene 160 or ketene 162 over a longer range o f temperature. The photolysis and data acquiring should be most probably done at low temperatures. The photochemistry o f 159 is well-known. When a sample o f 159 was photolyzed in methanol, ester 163 was obtained (Scheme 6.2). 6 Compound 163 was formed by the reaction o f methanol wi th ketene 163 which was itself generated by W o l f f rearragement o f carbene 160. 171 6.4 References 1. Cram, D. J.; Tanner, M. E.; Thomas, R. Angew. Chem. Int. Ed. Engl. 1991, 30, 1024. 2. Bachmann, C ; N'Guessan, T. Y.; Debu, F.; Monnier, M. ; Pourcin, J.; Aycard, J.-P.; Bodot, H. J. Am. Chem. Soc. 1990,112, 7488. 3. Mahaffy, P. G.; Visser, D.; Torres, M.; Bourdelande, J. L.; Strausz, O. P. J. Org. Chem. 1987, 52, 2680. 4. Torres, M. ; Bourdelande, J. L.; Clement, A.; Strausz, O. P. J. Am. Chem. Soc. 1983, 105, 1698. 5. Lewars, E. G. Chem. Rev. 1983, 83, 519. 6. Tomioka, H.; Okuno, H; Clement, A.; Izawa, Y. J. Org. Chem. 1980, 45, 5278. 172 A .O Appendix A . l Calculation of Assembly Numbers A . 1.1 Assembly Number for 38»pyraz ine Assembly Number (AN) is the number obtained when the observed yield is divided by the theoretical (statistical) yield. 1 In the calculation o f the theoretical yield, judgement has to be made on which bonds are make-able, and which are not. That is, this analysis is subjective. Moreover, each pathway leading to a product or non-product is given the same likelihood o f occurring. For the formation o f 38»pyrazine, there is only one possibility o f forming the first bridge (Figure A . l ) . However, there are nine ways o f forming the second bridge, and only three o f them can lead to the desired product. Once the second bridge is formed between A and A ' , B and B ' or C and C, the formation o f the subsequent bridges are assumed to lead exclusively to the product (it is assumed that polymers are not formed from these intermediates). This analysis gives a statistical yield o f 33.3% for 38«pyrazine. Wi th an observed o f 87% yield for 38*pyrazine, an assembly number o f 2.6 is obtained. Figure A . l . Probability o f obtaining 38«pyrazine. 173 A.1.2 Assembly Number for 44»(pyrazine )2 Towards the formation o f 44»(pyrazine)2, there are six ways o f forming the first bridge (Figure A.2). Only two o f these bridges can lead to the required product. For example, when the first bridge is formed between A and C, 44»(pyrazine)2 can be only formed i f the second bridge is formed between B and D. Once the linkages between A and C, and B and D are formed, the subsequent bond formation can lead to the desired product. A l l the other possibilities are shown in Figure A.2. A statistical yield o f 14.3% is obtained for 44«(pyrazine)2- Wi th an observed yield o f 74% for 44«(pyrazine)2, the assembly number works out to be 5.3. 44 •(pyrazine) 2 (74%) Figure A.2. Probability o f obtaining 44»(pyrazine)2, A - H = OH. 174 A . 1.3 Assembly Number for 75•(methyl acetate)3 When hexamer 74 is treated with K 2 C 0 3 and CH 2 ClBr, there are ten ways o f forming the first bridge. Out o f the 10 possibilities, only the bridges formed between A and C, E and K can lead to 75»(methyl acetate)3. The probability o f getting the product from A C and A E is the same. There are 39 ways o f forming the second bridge once the first bridge between A and C is made. But, only five o f them can lead to the product. Figures A.4-11 show various possibilities o f getting the right product. The total probability o f getting 75»(methyl acetate)3 is 2 x (0.91 + 1.90 + 5.55 + 1.67 + 1.74 + 1.90 + 5.55) x 10"4 + 1/220, i.e., 0.84%. Wi th an observed yield o f 37%, an assembly number o f 44 is obtained for the formation o f 75«(methyl acetate)3. Figure A .3 . Formation o f 75«(methyl acetate)3, A - L = OH. 175 Figure A.4. Formation o f the first bridge towards the formation o f 75»(methyl acetate)3. r Same Probability 176 Figure A .5 . Formation o f second bridge (the first bridge was formed between A and C) towards the formation o f 75»(methyl acetate)3. 177 Figure A.6. Formation o f third and subsequent bridges (the first and second bridges were formed between A and C, and B and D, respectively) towards the formation o f 75«(methyl acetate^. 178 Figure A.l. Formation o f third and subsequent bridges (the first and second bridges were formed between A and C, and E and G, respectively) towards the formation o f 75«(methyl acetate)3. 1/117260 1/469040 1/469040 1/117260 1/10660 1/298480 1/298480 1/74620 1/298480 1/298480 1/53300 1/53300 1/213200 1/213200 179 Figure A.8. Formation o f third and subsequent bridges (the first and second bridges were formed between A and C, and F and H, respectively) towards the formation o f 75»(methyl acetate)3. 180 Figure A . 9 . Formation o f third and subsequent bridges (the first and second bridges were formed between A and C, and I and K, respectively) towards the formation o f 75«(methyl acetate)3. 181 F i g u r e A . 1 0 . Formation o f third and subsequent bridges (the first and second bridges were formed between A and C, and J and L, respectively) towards the formation o f 75«(methyl acetate^. 182 Figure A.11. Formation o f second and subsequent bridges (the first bridge was formed between A and K ) towards the formation o f 75»(methyl acetate)3. Bridges formed between E and I, and F and J would also lead to the right product. The probability of getting product from El would be the same as the one from CG. In a similar way, the probability of getting product from FJ would be the same as the one from DH. Hence the probability of getting product from AK is 1 /220 + (2 x 1.90 x 10"4) + (2 x 5.54 x 10"4). 183 A.2 Kinetics of Decomplexation of 7 8 » ( l , 3 > 5 - t r i e t h y n y l b e n z e n e ) 2 A.2.1 Determination of Rate Constant When a solution o f 78«(Guest)2 is heated in nitrobenzene, the bound guest molecules escape from the cavities o f 78. As a result, a mixture o f 78, 78»Guest, 78»(Guesf)2 and free guest is obtained. After a certain period o f time, an equilibrium is reached. The dissociation/association scheme for an equilibrium between 78, 78»Guest and 78«(Guest) 2 (shown as 78()(), 78(Guest)() and 78(Guest)2, respectively) can be represented as the fol lowing equations: k, 78(Guest) 2 5 = = - 78(Guest)() + Guest k-i k 2 78(Guest)() 7800 + G u e s t k-2 I f k i = k2 and k_i = k_2 and i f a cavity can be fil led or emptied independent o f the second cavity this sequential scheme can be simplified to: k C « 78 + G with k = k i = k2 = dissociation rate constant k' and k' = k_i = k_2 = association rate constant C is defined as fi l led cavity or complex, G as guest and 78 as empty cavity or host. Their concentration at time t are [C] t , [G] t and [78] t , respectively. It is important to note that [C ] t is the total concentration o f fi l led cavities (2x[78(Guest) 2] t + [78(Guest)()]) and [78] t the total concentration o f empty cavities (2x[78()()] + [78(Guest)()]). A t the final equilibrium, the concentrations o f C, 78 and G are [C] e , [78] e and [G] e , respectively. 184 The equilibrium constant K for this system at the experimental temperature is defined as: [78 ] e [G] e K = k / k ' = (1) [C ] e The rate o f the reaction in this case is defined as: Rate = d[C] t/dt = - k [ C ] t + k ' [78] t [G] t (2) Forward reaction Reverse reaction decreases C increases C A t this stage it is helpful to define x as a measure o f how far the system at time t is away from the final equilibrium: x = [ C ] t - [ C ] e or [C], = x + [C ] e (3) [78] t and [G] t can be written as: [78], = [78] e - x (4) [G ] t = [ G ] e - x (5) substitution o f equations (3) - (5) into (2) gives: d[C] t/dt = - k(x + [ C ] e ) + k ' ( [78] e - x ) ( [G] e - x ) or d[C] t/dt = - kx - k [ C ] e + k ' ( [78] e [G] e - x ( [G ] e + [78] e) + k ' x2 (6) From the definition o f the equilibrium (equation 1), one derives that k [ C ] e = k ' [78 ] e [G] e . Thus, the second and third term on the right o f equation (6) cancel each other: d[C] t/dt = - kx - k ' x ( [G] e + [78] e) + k 'x2 (7) By replacing k' = k/K in equation (7), equation (8) is obtained: 185 d[C] t/dt = - kx - x k/K ( [G ] e + [78] e) + k/K x2 d[C] t/dt = - kx ((1 + ( [G ] e + [78] e )/K) - x/K) d[C] t/dt = - kx (a + bx) wi th a = 1 + ( [G ] e + [78] e ) /K and b = -1/K since d[C] t/dt = dx/dt, (10) becomes: dx/dt = - kx (a + bx) or dx = - k d t x (a + bx) integration over the limits x 0 -> x; and t 0 = 0 -> t gives 1 (a+bx) I x — In a x 1 x — In a (a+bx) X 0 X 0 = - k t or w i t h - l n ( a ) = l n ( l / a ) - k t or X 0 In (a+bx) In (a+bxo) = - a k t (8) (9) (10) define D as D = In (a+bx 0) gives: In (a+bx) D - a k t When a and b are replaced as defined above, the fol lowing rate law is obtained: In (1 + ( [ G ] e + [ 7 8 ] e ) / K -x/K) D - ( l + ( [ G ] e + [ 7 8 ] e ) / K ) k t 186 A plot o f the left side against t should be linear. From the slope, k can be calculated. Sample Calculat ion: [78»(l,3,5-triethynylbenzene)2]0 = 0.9769 mM - . [C]0 = [bound l,3,5-triethynylbenzene]o = 2 x 0.9769 mM = 1.954 mM At t = 1 hour, Integration o f bound 1,3,5-triethynylbenzene = 1.66 Integration o f free 1,3,5-triethynylbenzene = 0.22 [C] = [Bound 1,3,5-triethynylbenzene] = 1.66 - (1.66 + 0.22) * 1.954 m M = 1.725 m M x = [C] - [78]e = ( 1.725- 0.606) 10"3 = 1.11 mM The values o f [C]e, [78]e and [G ] e were calculated to be 0.606, 1.344 and 1.344 mM, respectively. Hence, K = 1.344 * 10"3 * 1.344 x 10"3 - (0.606 * 10"3) = 2.98 * 10"3 M x 1 .11* 10"3 In - = -7.63 (1 + ( [ G ] e + [78]e)/K -x/K) 1 + (1.344 +3.344)10"3/2.98 * IO"3 A.2.2 Calculation of Gibbs Energy of Activation (AG*) The Gibbs energy o f activation (AG*) o f a process can be calculated from the equation below: 3 AG* = -RTln (k/ j /k B T) where R = gas constant (8.31 J K " 1 mol" 1)) (11) 187 T = temperature k = rate constant h = Planck constant (6.626 x 10" 3 4 J s) k b = Boltzmann constant (1.38 x 10"2 3 J K"1) A t a temperature o f 120 °C and a rate constant o f 2.9 x 10"5 s"1, the value o f AG* for the guest decomplexation o f 78»(l,3,5-triethynylbenzene)2 was calculated to be 31 +/- 1 kcalmoi" 1. A.2.3 Calculation of Activation Energy (E a) The activation energy (E a) can also be calculated by using the Arrhenius equation: k = A e - E a / R T ( 1 2 ) where A = frequency, or pre-exponential factor. (12) can be rearranged to (13). E a = RTlnA - RTlnk (13) By measuring the values o f k at two different temperatures, the values o f E a and A can thus be calculated. 18 +/- 1 kcalmoi" 1 and (3.4 +/- 0.5) x 105 s"1 were obtained for E a and A , respectively. A.2.4 Relation between E a and A G * Since AG* = -RTln(kA/k bT) (11) and k = A e "E a / R T (12), k can be substituted by A e " E a / R T in (11) to give: AG* - -RTln(A/k bT) - RTln A e "E a / R T (14) Equation (14) can be rearranged to give: 188 A G * = E a - R T l n ( A M : b T ) (15) Hence, the value o f AG* can be calculated at any temperature i f E a and A are known.. A.2.4 Estimation of Error For an equation, x = f ( p , q , r , . . . ) , (16) the error in x can be written as:5 A x = | 3x/3p»Ap | + | 5x/3q»Aq | + | dx/dr»Ar | + ... (17) Thus, the error in Ea (AE a) can be written as (A ' and R are assumed to be constant), AE a = | R l n A ' ' A T | + | Rink-AT | + | RT/k«Ak | (18) Sample Calculation: T = 373 +/- 2 K k= (8 .3+/- 0.4)IO - 6 s"1 A = 3.9 x 105 s"1 R = 8.31 JK- 'mol " 1 A E a = | 8.31 x l n ( 3 . 9 x 1 05 ) x 2 | + | 8.31 x ln(8.3 x IO - 6) x 2 | + | 8.31 x 373 - 8.3 x 10" 6x 0.4 x IO"6 | = 604 J/mol = 144 cal/mol A.3 Calculation of Binding Constants for 81«/>-xylene and Sl*(p-xylene)2 For a solution containing p-xy\ene (G), host 81 (H), 81 •/ '-xylene (H«G) and 81«(p-xylene) 2 (H«G2), the fol lowing equilibria are observed:3 K a i H + G — H»G K a 2 _ H«G + G H»G 2 Thus, K a l = [ H . G ] / [ H f ] [ G f ] (19) K a 2 = [ H « G 2 ] / [ H » G ] [ G f ] (20) where [H«G] = concentration o f 81«/>xylene [H«G 2 ] = concentration o f 81»(p-xylene) 2 [Hf] = concentration o f free host [Gf ] = concentration o f free guest The overall equation can be written as: H + 2G — — H«Gc K a l K a 2 = K a = [ H . G 2 ] / [ H f ] [ G f ]2 , (21) These values were determined by starting with known concentrations o f host and guest, and by integrating the ' H N M R signals o f the bound and free guest. [Gf] = integration o f free guest (integration o f free guest + integration o f bound guest) x total concentration o f guest [H«G] = integration o f guest bound as H » G ^ (integration o f free guest + integration o f bound guest)) x total concentration o f guest 190 [ H » G 2 ] = ^(integration o f guest bound as H « G 2 + (integration o f free guest + integration o f bound guest)) x total concentration o f guest [H f ] = total concentration o f host - [H«G 2 ] - [H«G] A.4 References 1. Gibb, C. L. D.; Gibb, B. C. J. Supramol. Chem., 2001,1, 39. 2. Alberty, R. A . Physical Chemistry, 4 t h ed.; John Wiley and Sons: New York, 1987, pp. 681-685. 3. Sandstrom, J. Dynamic NMR Spectroscopy; Academic Press: London, 1982. 4. Connors, K. A. Binding Constants: The Measurement of Molecular Complex Stability; John Wi ley and Sons: New York, 1987. 5. Skoog, D. A ; Holler, F. J; Nieman, T. A. Principles of Instrumental Analysis, 5 t h ed; Saunders College Publishing: USA, 1998. 191 

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.831.1-0061191/manifest

Comment

Related Items