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New [3+3] Schiff-base macrocycles and their complexes Gallant, Amanda Jane 2006

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N E W [3+3] SCHIFF-BASE M A C R O C Y C L E S A N D THEIR C O M P L E X E S  by A M A N D A JANE G A L L A N T B.Sc, Hon, University of Prince Edward Island, 2001  A THESIS SUBMITTED IN P A R T I A L F U L F I L L M E N T OF T H E REQUIREMENTS FOR THE D E G R E E OF DOCTOR OF PHILOSOPHY in THE F A C U L T Y OF G R A D U A T E STUDIES (Chemistry)  THE UNIVERSITY OF BRITISH C O L U M B I A April 2006  © Amanda Jane Gallant, 2006  Abstract  A series of conjugated [3+3] Schiff-base macrocycles containing both a central crown ether-like pocket and three tetradentate N2O2 binding sites were prepared and investigated. The formation mechanism was investigated through the synthesis and study of macrocycle fragments. Further understanding of the macrocycle conformations and dynamics was obtained through computational studies. A monoreduced macrocycle where one of the six imines has been reduced was obtained as a by-product of macrocycle formation. Reactivity studies and deuterium labeling investigations revealed that the  selective reducing agent is likely a  benzimidazoline. This intermediate is generated in situ during the formation of the nonreduced  macrocycle and with macrocycle reduction is converted to a  stable  benzimidazole unit. Upon addition of small cations, the conjugated Schiff-base macrocycles assemble into tubular structures. Spectroscopic and mass spectrometric studies have shown that the cations bind to the crown ether-like centre of the macrocycle and induce aggregation to form structures composed of alternating cations and macrocycles. With the addition of seven equivalents of Z n  2 +  or C d  2 +  to these fully conjugated  macrocycles surprising heptametallic complexes were obtained. Here, the trimetallated macrocycle is first formed (with metal ions bound to the three N2O2 pockets) and then this templates the formation of a [IvLtO] * cluster that caps the cone-shaped macrocycle. 6  N M R studies indicated that these zinc complexes dimerize under certain solvent  ii  conditions forming capsule-like structures resembling cavitands used in host-guest chemistry. Variations of these [3+3] Schiff-base macrocycles were prepared by modifying the substituents of the diformyl diol unit. In this way naphthalene-based macrocycles were prepared. Studies on a series of related model compounds revealed that the ketoenamine isomer is stabilized in these macrocycles rather than the enol-imine isomer as observed in the analogous phenyl-based macrocycles.  iii  Table of Contents  Abstract  ii  Table of Contents  iv  List of Tables  vii  List of Figures  viii  List of Symbols and Abbreviations  xv  List of Schemes  xxii  Acknowledgements  xxiv  Co-Authorship Statement  xxv  CHAPTER 1  Introduction  1  1.1 Supramolecular Chemistry  1.2 1.3 1.4  1.5 1.6  1  1.1.1 Historical Perspective 1.1.2 Highlights of Supramolecular Chemistry Calixarenes and Related Macrocycles Shape-Persistent Macrocycles Schiff-Base Macrocycles 1.4.1 Schiff-Base Chemistry 1.4.2 Robson-Type Macrocycles 1.4.3 Schiff-Base Expanded Porphyrins 1.4.4 [3+3] Schiff-Base Macrocycles Goals and Scope References  CHAPTER 2  [3+3] Schiff-Base Macrocycles  2.1 Introduction 2.2 Results and Discussion 2.2.1 Synthesis and Characterization 2.2.2 Self-Assembly 2.2.3 Reactivity 2.2.4 Calculations 2.3 Conclusions 2.4 Experimental 2.4.1 General  iv  1 3 8 15 21 21 25 28 30 32 35 40 40 42 42 47 52 66 73 74 74  2.4.2 Procedures 2.4.3 X-Ray Diffraction Studies 2.5 References CHAPTER 3  Keto-Enol Tautomerism in Naphthalene-Based Macrocycles  3.1 Introduction 3.2 Results and Discussion 3.2.1 Synthesis and Characterization 3.2.2 Model Compounds <3.2.3 Investigations of Keto-Enol Tautomerization 3.3 Conclusions 3.4 Experimental 3.4.1 General 3.4.2 Procedures 3.4.3 X-Ray Diffraction Studies 3.4.4 Computational Studies 3.5 References CHAPTER 4  Ion-Induced Tubular Assemblies  4.1 Introduction 4.2 Results 4.2.1 Mass Spectrometry 4.2.2 Colourimetric Investigations 4.2.3 N M R Spectroscopy , 4.2.4 Electrochemistry 4.3 Discussion 4.3.1 Cation Size Dependence 4.3.2 Control Studies 4.3.3 Crown Ether Comparisons 4.3.4 Postulated Structures 4.4 Conclusions 4.5 Experimental 4.5.1 General 4.5.2 Procedures 4.6 References CHAPTER 5  New Heptanucleax Metal Cluster Complexes  5.1 Introduction 5.2 Results and Discussion 5.2.1 Synthesis of Zinc Metallocycles 5.2.2 Mechanism of Formation 5.2.3 Capsule Formation 5.2.4 Heptanuclear Cadmium Complexes  v  75 88 92 96 96 98 98 101 104 110 110 110 111 116 120 122 124 124 126 126 128 132 136 139 139 140. 142 147 151 152 152 153 154 15 7 157 158 158 168 172 178  5.3 Conclusions 5.4 Experimental 5.4.1 General 5.4.2 Procedures 5.4.3 Semi-Empirical Calculations 5.4.4 N M R Simulation 5.4.5 X-Ray Diffraction Studies 5.4.6 Dynamic Light Scattering 5.5 References CHAPTER 6  Conclusions and Future Direction  6.1 6.2 6.3 6.4 6.5 6.6  Overview [3+3] Schiff-Base Macrocycles In Situ Monoreduction Ion-Induced Aggregation Metal Incorporation Experimental 6.6.1 General 6.6.2 Procedures 6.7 References  181 182 182 183 188 189 189 193 195 199 199 199 206 208 209 210 210 211 217  vi  List of Tables  Table 2.1 Comparison of Selected Bond Lengths and Angles for the Macrocycles.  71  Table 2.2 X-ray diffraction data for compounds 26b and 37b.  89  Table 3.1 Calculated and Measured Lengths of Selected Bonds (A).  105  Table 3.2 X-ray diffraction data for compounds 48, 50 and 51.  117  Table 4.1 Peak potentials for the irreversible oxidation wave of macrocycle 26f with different alkali metals.  138  Table 5.1 Zn - O and Zn - Zn bond lengths within the crystal structure of 56b and the averages of related bond lengths.  166  Table 5.2 O—Zn-0 and Z n - O - Z n bond angles within the crystal structure of 56b and the averages of related bond angles.  167  Table 5.3 Z n - 0 and Zn - Zn bond lengths within the crystal structure of 57b and the averages of related bond lengths.  171  Table 5.4 O - Z n - 0 and Z n - O - Z n bond angles within the crystal structure of 57b and the averages of related bond angles.  172  Table 5.5 X-ray diffraction data for compounds 56b, 56e and 57b.  191  Table 6.1 X-ray diffraction data for compounds 60b.  214  vii  List of Figures  Figure 1.1 Macrocycles capable of complexing alkali metals (1 : Pedersen's dibenzo-18-crown-6, 2 : Lehn's [2.2.2]cryptand, 3 : Cram's spherand where R = CH ). 3  Figure 1.2 Octapeptide cyclo[-(L-Gln-D-Ala-L-Glu-D-Ala) -] self-assembles through hydrogen-bonding to form tubular structures (R groups are removed from assembled structure for clarity). 2  Figure 1.3 A tennis ball-like structure obtained from the assembly of two molecules of 4 with bridgehead phenyl groups omitted for clarity in the crystal structure. (Taken from reference 11). Figure 1.4 Assembly of 18 P d units and six l,3,5-tris(3,5-pyrimidyl)benzene units to form a supramolecular hexahedron; en = ethylenediamine. u  Figure 1.5 Six gable porphyrin units (highlighted in blue) assemble into a large cyclic structure. Figure 1.6 /?-ter/-Butylcalix[4]arene. Figure 1.7 The four different conformers of calix[4]arenes. Figure 1.8 Purification of C6o from impurities such as C70 by complexation with />te>t-butylcalix[8]arene. Figure 1.9 Resorcinarenes linked head-to-head to form a carcerand with encapsulated guest (R = CH CH Ph). 2  2  Figure 1.10 Large, snub-cube structure of six self-assembled resorcinarenes shown as (a) a cross-sectional view (green = C, red = O, white = H - involved in hydrogen-bonds) and (b) a space filling model. (Taken from reference 31). Figure 1.11 Early shape-persistent macrocycles (5 : Staab's hexa-m-phenylene, 6 : Fujioka's o,/?,o,^,o,/?-hexaphenylene and 7 : Newkome's sexipyridine). Figure 1.12 A few examples of shape-persistent macrocycles 8a : R = R = 0 ( C H C H 0 ) 3 C H 3 , 9 : R = R = O C 3 H 7 , R = C H R = O C i H , 10 : R = f  2  2  3  4  3  2  8  3 7  C H , , 1 1 : R = C H i 3 1 2 : R = mesityl, 14 : R = B u . l  6  3  6  Figure 1.13 Salen-like compounds for asymmetric epoxidation (15) and electroluminescence (16).  viii  Figure 1.14 Early Schiff-base macrocycles (17 : Curtis 1962, 18 : Busch 1964, 19 : Jager 1968).  23  Figure 1.15 Schematic representation of the reversible Schiff-base condensation reaction to from a thermodynamically stable macrocyclic product.  24  Figure 1.16 Conformational isomerism of an imine-containing w-phenyleneethynylene macrocycle.  25  Figure 1.17 Robson-type macrocycle 20 for studies on antiferromagnetic exchange interactions.  26  Figure 1.18 Schiff-base macrocycles containing pyrrole units.  29  Figure 1.19 (a) Dipalladium complex of macrocycle 21 and (b) dipalladium PacMan bisporphyrin.  29  Figure 1.20 [3+3] Schiff-base macrocycles.  31  Figure 1.21 Envisioned assembly through coordination chemistry of a trimetallated macrocycle with small linker molecules to form a tubular structure.  32  Figure 1.22 The [3+3] Schiff-base macrocycle 26 possesses (a) three salphenlike N2O2 pockets and (b) one central crown ether-like cavity.  33  Figure 2.1 Phenyleneethynylene and Schiff-base macrocycles.  41  Figure 2.2 *H N M R spectrum (300 M H z , CDC1 ) of 26f (* = CHCI3).  45  Figure 2.3 Molecular structure of macrocycle 26b as determined by single crystal X-ray diffraction with thermal ellipsoids at 50% probability. Solvent molecules are removed for clarity. Red = oxygen, blue = nitrogen, (a) View from the top of the macrocycle showing strong intramolecular hydrogen-bonding, (b) View of macrocycle 26b from the side showing the non-planarity of the macrocycle (efhyloxy groups and hydrogen atoms are removed for clarity), (c) View of the packing diagram for macrocycle 26b normal to the (100) axis, revealing the stacking pattern for the pores.  47  Figure 2.4 Macrocycle intermediates (1:1 condensation product 34, condensation product 35, and 2:1 condensation product 36).  1:2  49  Figure 2.5 Bottom: *H N M R spectrum (300 M H z , CDC1 ) of monoreduced macrocycle 37f. Top: ESI mass spectra for the [M+H] ion in (a) macrocycle 26f and (b) monoreduced macrocycle 37f.  53  3  3  +  ix  Figure 2.6 (a) Molecular structure (from single crystal X-ray diffraction) of monoreduced macrocycle 37f with H2O coordinated in the centre (thermal ellipsoids shown at 33% probability), (b) Monoreduced macrocycle 37 with one reduced imine group.  54  Figure 2.7 Compounds for deuterium labelling experiments.  60  Figure 2.8 Possible transition state for the reduction of macrocycle 26 (fragment shown on top) by benzimidazoline 40 (below).  61  Figure 2.9 Benzimidazoles formed from 35 and 36 producing 1:2 bis(benzimidazole) 42 and 2:1 benzimidazole 43 respectively.  63  Figure 2.10 ESI-MS of the crude reaction mixture of monoreduced macrocycle 37f.  63  Figure 2.11 Proposed structure of fragment 44 formed by homolytic cleavage in the ESI mass spectrum. This is not to imply a precise structure for the fragment [44+H] , which may be different in the gas phase, but only to indicate the chemical composition.  64  Figure 2.12 Computed low energy conformations A - D for macrocycle 26a. Views of the structures are shown from the top and side of the macrocycle, with hydrogen atoms omitted for clarity.  67  Figure 2.13 Three easy rotation axes for macrocycle 25.  68  Figure 2.14 Relaxed scan of rotation computed for macrocycle 26a. The angle of rotation corresponds to the dihedral angle of the C - C - N = C bond. A dihedral angle of 0° indicates that the catechol undergoing rotation in 10° intervals is oriented toward the centre of the macrocycle; for a dihedral angle of 180°, the catechol is oriented away from the centre of the macrocycle.  70  Figure 3.1 Structures of macrocycles 26 and 45.  97  Figure 3.2 (a) Solid-state structure of 48 as determined by S C X R D . (b) 1-D nstacked assembly of 48 showing the 1/3 pitch. Thermal ellipsoids are shown at 50% probability.  99  Figure 3.3 (a) IR and (b) UV-visible spectra of macrocycle 26e (red) and macrocycle 45e (blue).  101  Figure 3.4 Structure of compound 50 as determined by S C X R D . (a) View perpendicular to naphthalene ring, (b) View parallel to the naphthalene ring reveals 0 = C - C - C H torsions (dihedral angles of 0.7° and 4.8°). Thermal ellipsoids are shown at 50% probability.  103  +  x  Figure 3.5 Structure of compound 51 as determined by S C X R D . (a) View perpendicular to naphthalene ring, (b) View parallel to the naphthalene ring reveals O C - C - C H torsions (dihedral angles of 5.9° and 7.3°). Thermal ellipsoids are shown at 50% probability.  104  Figure 3.6 resonance).  C N M R spectra of 50 at varying temperatures (carbonyl/enol  106  Figure 3.7 Plot of -RlnK vs. 1/T as determined by the V T C N M R experiment for 50 in CDC1 (R = 0.99 for best-fit line).  108  Figure 3.8 Calculated structure of, 52 (enol) as viewed from (a) the top and (b) the side.  121  Figure 3.9 Calculated structure of 52 (keto) as viewed from (a) the top and (b) the side.  121  Figure 4.1 Conjugated macrocycles 8 and 26f.  125  1 3  3  Figure 4.2 The ESI-MS of macrocycle 26f + NaBPlu in C H C l / M e O H .  126  Figure 4.3 The relative peak intensities of macrocycle-Na complexes, [26f +Na ] , in the ESI-MS as the cone voltage is varied. Points taken every 10 V (Added salt = NaOAc).  127  Figure 4.4 The colour change observed upon addition of various salts to a 1 x 10" M solution of macrocycle 26f in CH2CI2: (A) macrocycle 26f; (B) 26f + NaBPlu; (C) 26f + K B P l u ; (D) 26f + RbBPru; (E) 26f + CsBPlu; and (F) 26f +  129  3  +  m+  n  m  4  NFLLBPIU.  Figure 4.5 U V - V i s spectra of 26f (ca. 4.8 x 10" M in 95:5 CHCl :MeCN) upon addition of CsBPlu (in MeCN). Each line represents an increase of ca. 0.1 equiv. C s to 261 The spectra show up to a [Cs ]:[26f] - 1 . 5 : 1 . Inset: low concentration experiments (0 to 0.5 equiv. of Cs ).  130  Figure 4.6 U V - V i s spectra of 26f (ca. 4.2 * 10' M in 95:5 CHCl :MeCN) upon addition of NaBPlu (in MeCN). Each line represents an increase of ca. 0.1 equiv. N a to 26f. The spectra show up to a [Na ]:[26f] ~ 1.5:1. Inset: low concentration experiments (0 to 0.5 equiv. of Na ).  131  Figure 4.7 Stacked *H N M R spectra of macrocycle 26f with increasing amounts of NaBPlu. The ratio of [Na ]:[26fJ for each sample is shown (* = CHC1 ; + = BPlu").  133  6  3  +  +  +  6  3  +  +  +  +  3  xi  Figure 4.8 Stacked H N M R spectra of macrocycle 26f with increasing amounts of CsBPlu. The ratio of [Cs ]:[26f] for each sample is shown (* = CHC1 ; + = !  134  +  3  BPI14").  Figure 4.9 Chemical shift of the imine proton (N=C#) as different small cations are added to macrocycle 26f in CDCI3.  136  Figure 4.10 The voltammogram (top) and differential pulse voltammogram (bottom) of macrocycle 26f (dashed line) along with that for macrocycle 26f upon addition of KBPI14 (solid line).  137  Figure 4.11 The voltammogram (top) and differential pulse voltammogram (bottom) of macrocycle 26f after addition of different alkali metals (red = C s , green = K , brown = N a , blue = Rb ).  138  Figure 4.12 ' H N M R spectrum of macrocycle 26f after addition of NaBF4 in CDCl /MeCN- d .  141  Figure 4.13 Salphen 54 designed for a control experiment to ensure that the small cations are binding to the central phenolic oxygen atoms and not the salphen N2O2 pockets.  142  Figure 4.14 N M R studies on the affinity of macrocycle 26f and 18-crown-6 for N a in CDC1 . (a) 18-Crown-6, (b) 18-crown-6 after the addition of NaBPlu, (c) 18-crown-6 first mixed with NaBPlu followed by addition of macrocycle 26f, and (d) macrocycle 26f first mixed with NaBPlu followed by addition of 18crown-6.  143  Figure 4.15 ' H N M R studies on the affinity of macrocycle 26f and 18-crown-6 for K in CDCI3. (a) 18-Crown-6, (b) 18-crown-6 after the addition of KBPI14, (c) 18-crown-6 first mixed with K B P l u followed by addition of macrocycle 26f, and (d) macrocycle 26f first mixed with KBPI14 followed by addition of 18-crown-6.  144  Figure 4.16 ' H N M R spectrum of an excess of NaBPlu added to a mixture of macrocycle 26f and 18-crown-6 in CDC1 (* - CHC1 , + = BPlu", = impurity in NaBPlu). The crown ether resonance is shifted from 3.66 ppm (uncomplexed) to 3.46 ppm (complexed).  145  Figure 4.17 N a N M R spectra (CDC1 , 400MHz) of macrocycle 26f with NaBPlu (top) and 18-crown-6 with NaBPlu (bottom). .  146  +  +  +  3  +  3  1  +  3  +  A  3  3  2 3  3  xii  Figure 4.18 Postulated structures of (a) a sodium dimer (minimized with molecular mechanics force field), (b) an ion-induced tubular assembly of macrocycle 26f with N a (minimized with molecular mechanics force field), (c) space-filling model of an ion-induced tubular assembly of macrocycle 26f with N a (minimized with molecular mechanics force field) and (d) space-filling model of an ion-induced tubular assembly of macrocycle 26f with N a (elongated for visualization purposes).  150  Figure 5.1 Schiff-base macrocycle 26 and trimetallated macrocycle 55.  158  Figure 5.2 *H N M R spectra (300 M H z , CDC1 ) of (a) the reaction mixture after addition of 1 equiv. of Zn(OAc)2 to macrocycle 26f and (b) the dimetallated macrocycle along with the structure of the macrocycle showing the three different imine environments (* = CHCI3 and = phenolic, imine and aromatic peaks from unreacted macrocyle 26f).  160  Figure 5.3 ' H N M R spectra (300MHz, CDCI3) of metallomacrocycle 56f (bottom) and macrocycle 26f (top). Inset: (a) Experimental data and (b) simulation of the OCH2 resonance for compound 56f. (* = CHCI3)  161  Figure 5.4 Molecular structure of 56b as determined by S C X R D . Thermal ellipsoids are shown at 50% probability, (a) Top view with protons removed for clarity and (b) side view with alkoxy chains and protons removed for clarity. Black = C, red = O, blue = N and green = Zn.  162 -  Figure 5.5 (a) View of 56b from the side showing the truncated metallocone (black), the [ZiLfO] * tetrahedron (red), //-1,2 acetates (green) and ju-1,1,2 acetates (blue), (b) Cartoon representation of the zinc tetrahedron capping the truncated metallocone in 56b.  164  Figure 5.6 Schematic representation of the macrocycle and its capping cluster. The macrocycle is represented by the large triangle with Z n , Z n and Z n at the apices. The bottom of the cluster is represented by the smaller triangle with Z n , Z n and Z n at its apices. The Z n represents the top of the [Zri40] cluster and is situated directly above the tetrahedreal oxygen atom (tM-O) that is bound to Z n , Zn , Zn and Zn but which is not seen from the angle of this diagram.  165  Figure 5.7 Molecular structure of complex 57b as obtained by S C X R D (H atoms omitted for clarity). Thermal ellipsoids are shown at 50% probability (Black - C, blue = N , red = O, green = Zn, yellow - S). (a) View of 57b from the side (ethoxy groups removed), (b) View of 57b from the top. A D M S O solvent molecule is coordinated to the third Zn in the macrocycle.  171  +  +  +  3  0  6  1  2  3  4  5  6  7  6+  4  xiii  Figure 5.8 (a) Dimer of 56e viewed from the top (SCXRD); (b) dimer of 56e viewed from the side (SCXRD); (c) calculated structure of 56a viewed from the top (PM3); (d) calculated structure of 56a viewed from the side (PM3). Hydrogen atoms have been removed for clarity (Black = C, green = N , red = O, dark green = Zn).  173  Figure 5.9 H N M R spectra (300 MHz) of 56e in (a) CDCI3, (b) C D , (c) toluene-dg, and (d) p-xylenes-dw- *H resonances are broadened in the case of (c) and (d).  174  Figure 5.10 (a) H V T - N M R spectra of 56h in p-xylenes-d . (b) Plot of fullwidth at half-maximum (FWHM) for the imine resonance (~8 ppm) of 56f vs. T in C6D6 (•), toluene-afo (•), and/?-xylenes-fi?/o (V).  175  Figure 5.11 Plot of normalized F W H M of the imine resonance vs. vol. % of added solvent to a solution of 56h in toluene-^s (ca. 5.2 * 10" M ) ; from left to right: D M S O (•), PrOH (•), M e C N (o), acetone ( • ) , and CHC1 (V).  177  Figure 5.12 *H N M R spectrum (CDC1 , 300 MHz) of cadmium complex 58f (* = CHCI3) which resembles closely that for complex 56f (Figure 5.3 top).  179  Figure 5.13 C d N M R spectrum (CDCI3, 400 MHz) of cadmium complex 58f with inset showing coupling.  180  Figure 6.1 (a) Triphenylene, (b) phenyleneethynylene macrocycle, (c) macrocycle 26, and (d) proposed macrocycle with additional solubilizing groups.  202  Figure 6.2 (a) Macrocycle 60b,e and (b) molecular structure (SCXRD) of macrocycle 60b (C = black, N = blue, O =• red). Thermal ellipsoids are shown at 50% probability.  204  Figure 6.3 Examples of diformyl linker units that have been prepared in the MacLachlan group, to be used in the formation of [3+3] Schiff-base macrocycles with increased cavity sizes.  206  !  6  6  ]  w  3  j  3  3  1 1 3  xiv  List of Symbols and Abbreviations  Abbreviation  Description  @  at  -  covalent bond  °  degrees  29  max  highest angle at which data is collected  MoKa  Molybdenum Ka radiation  fi(MoKa)  absorption coefficient  1-D  one dimensional  3-D  three dimensional  A  Angstrom  a.m.u.  atomic mass units  APT  attached proton test  B3LYP  Becke 3-parameter, Lee, Yang and Parr  boc  terft'ary-butyloxycarbonyl  Bu  butyl  "Bu  norma/-butyl  Bu  tertiary-butyl  °C  degrees Celsius  ca.  circa (approximately)  Calc'd  calculated  l  l  xv  cat.  catalyst  CCD  charge coupled detector  cf.  confer (to compare)  (CH20) cm cm"  n  paraformaldehyde centimeter  1  wavenumber  CPK  Corey, Pauling, Koltun  A  reflux, change  8  chemical shift (in ppm)  d  days, doublet  dba  dibenzylideneacetone  dd  doublet of doublets  Dcalc  calculated density  DCM  dichloromethane  dec.  decomposed  deg  degrees  DFT  density functional theory  DLS  dynamic light scattering  DMF  dimethylformamide  DMSO  dimethylsulfoxide  DN  donor number  E  molar absorptivity/molar extinction coefficient (M" cm" )  E  energy  1  xvi  1  e"  electron  Eb  binding energy  Et  total energy  ee  enantiomeric excess  e.g.  exempli gratia (for example)  en  ethylenediamine  equiv.  equivalents  esd  estimated standard deviation  ESI  electrospray ionization  Fooo  number of electrons in the unit cell  F  0  observed structure factor  F  c  calculated structure factor  FWHM  full-width at half-maximum  g  gram  h  hours  HFS  Hartree-Fock-Slater  HMBC  heteronuclear multiple-bond correlation  HMQC  heteronuclear multiple-quantum correlation  HRMS  high resolution mass spectrometry  Hz  Hertz  I  intensity  i  current  i.e.  id est (that is to say; in other words)  xvii  IR  infrared  J  coupling constant (NMR)  K  Kelvin, equilibrium constant  kcal  kilocalories  L  ligand, litre  X  wavelength  Xmax  wavelength at band maximum (nm)  \i  bridging  U4  tetradentate  uA  microampere  uL  microliter  uM  micromolar  um  micrometer  umol  micromoles  m  multiplet  m  meta  M  molarity (molL" ), metal ion  MALDI  matrix-assisted laser desorption ionization  Me  methyl  mg  milligram  mol  moles  MHz  megahertz  mins  minutes  1  xviii  mL  milliliter  MMFF  molecular mechanics force field  mmol  millimoles  Mp.  melting point  MS  mass spectrometry  mV  millivolts  mW  milliwatt  m/z  mass-to-charge ratio  v  frequency  nm  nanometer  NMR  nuclear magnetic resonance  o  ortho  OAc  acetate  OMet  methacrylate  %  percent  p  para  PC  personal computer  PCC  pyridiniumchlorochromate  Pd/C  palladium on carbon (catalyst)  Ph  phenyl  PM3  Parameterized Model number 3  ppm  parts per million  'Pr  wo-propyl  xix  q  quartet  R  alkyl groups  Rl  least square residual based on F  RT  room temperature •  s  singlet  salen  2,2 '-N,N'-bis(salicylidene)ethylenediamine  salpen  2,2'-N,N'-bis(salicylidene)propylenediamine  salphen  2,2 '-N,N'-bis(salicylidene)phenylenediamine  SCXRD  single crystal X-ray diffraction  SEM  scanning electron microscopy  STO  Slater-type orbitals  t  triplet  T  temperature  TEM  transmission electron miscroscopy  THP  tetrahydropyranyl  tmeda  tetramethylethylene diamine  TOF  time of flight  UBC  University of British Columbia  UV  ultraviolet  V  volt  vis  visible  vol.  volume  VT  variable temperature  xx  ,  v/v  volume ratio  w  weighting factor  wR2  weighted residual based on F  X  halogen  Z  number of molecules or formula units in the unit cell  xxi  List of Schemes  Scheme 1.1 One-pot synthesis of calixarenes.  9  Scheme 1.2 Step-wise synthesis of calix[4]arenes.  9  Scheme 1.3 [3+1] synthesis of calix[4]arenes.  10  Scheme 1.4 Synthesis of classical resorcinarenes.  12  Scheme 1.5 Synthesis of resorcinarenes with reduced conformational mobility.  13  Scheme 1.6 Commonly used cyclization reactions (a) Sonogashira coupling to form 8b where R = B u and R = H ; and (b) Glaser coupling to form 9 b where R = R = O C H , R = Me and R = OTHP; THP = tetrahydropyranyl.  18  Scheme 1.7 Synthesis of 8 by Stephens-Castro coupling in 4.6% yield (a), Sonogashira coupling in 75% yield (b) and alkyne metathesis in 68% yield (c).  19  Scheme 1.8 General Schiff-base condensation reaction between an aldehyde and a primary amine.  21  Scheme 1.9 Formation of Schiff-base salen and salphen compounds.  22  Scheme 1.10 The first synthesis of a dinuclear Schiff-base complex.  26  Scheme 1.11 Molecular ladders formed through coordination chemistry of Robson-type metallomacrocycles.  27  Scheme 1.12 A Robson-type metallomacrocycle as a catalyst for asymmetric cyclopropanation.  28  Scheme 2.1 Synthesis of precursor 29.  43  Scheme 2.2 Synthesis of precursor 33a-i.  43  Scheme 2.3 Synthesis of conjugated [3+3] Schiff-base macrocycles 26a-h with reaction yields shown in parentheses.  44  Scheme 2.4 Reaction of intermediates to form macrocycle 26.  50  Scheme 2.5 Synthesis of Robson-type macrocycle 38.  56  Scheme 2.6 Reactions of 29 and 33f with macrocycle 26f.  57  37  1  1  l  2  2  3  3  3r  4  7  xxii  Scheme 2.7 Proposed mechanism for the formation of 37 by in situ reduction of macrocycle 26.  59  Scheme 3.1 Synthesis of the diformyl precursor 48.  98  Scheme 3.2 Synthesis of macrocycle 45.  100  Scheme 3.3 Synthesis of model compounds 49-51 and the tautomers of compound 52 used for calculations.  102  Scheme 3.4 Keto-enol isomers of compound 50 (A = enol isomer, B = keto isomer).  106  Scheme 3.5 Tautomerization of macrocycle 45 between the enol-imine and ketoenamine tautomers. The latter is more stable in the case of this naphthalene-based macrocycle.  109  Scheme 5.1 Two possible mechanisms for the formation of heptazinc complexes 56. (a) Trimetallated macrocycle complexes preformed cluster or (b) trimetallated macrocycle templates the cluster formation. Acetate ligands and central U4-O are not shown for clarity.  169  Scheme 6.1 Proposed synthesis of 2,3-dimefhoxyanthracene which could lead to the formation of an anthracene-based diformyl species.  201  Scheme 6.2 Synthesis of diformyl species 59.  203  Scheme 6.3 Synthesis of diformyl species 61.  205  xxm  Acknowledgements  I would like to thank my supervisor Mark MacLachlan for all his help over the years. He has been an "excellent" inspiration and constantly reminds me why I love chemistry. Thanks also to the MacLachlan group members who have helped me throughout this work, in and out of the lab. It has been a wonderful learning experience and a good lot of fun. A special thanks to Inhee Cho, Charles Yeung and Michael Yun who I was given the opportunity to supervise and who provided results for this thesis. I am grateful for the many helpful talks and discussions with Nick Burlinson (NMR) and Yun Ling (ESI-MS) from whom I've learned so much. Thanks to Brian Patrick and Jonathan Chong for all the X-ray diffraction help. I would also like to thank the U B C Chemistry Department staff and personnel who have helped make my time at U B C productive and enjoyable. Lastly, I would like to thank my family and friends who have all helped this work in their own ways. In particular, I would like to thank my postdoc for everything he has taught me about chemistry, love and life.  xxiv  Co-Authorship Statement  Chapter 1:1 wrote this chapter myself.  Chapter 2: I undertook all of the synthesis and characterization. Calculations were performed in collaboration with Federico E. Zahariev and Y . Alexander Wang (University of British Columbia). The crystal structures were solved by Brian O. Patrick (University of British Columbia). I wrote this chapter, with input from my supervisor, Mark J. MacLachlan.  Chapter 3: This chapter was written by me with input from Mark J. MacLachlan. Crystallography was performed by Jonathan H . Chong (University of British Columbia). Calculations were performed by Mark J. MacLachlan. I performed most of the synthesis and characterization  including N M R studies,  but  some  of the  synthesis  and  characterization were performed by Michael Yun, Marc Sauer, and Charles S. Yeung (University of British Columbia).  Chapter 4: Most experiments were undertaken by me with the exception of a few. Mass spectrometry experiments were performed by Yun Ling (University of British Columbia) and the electrochemistry was performed in collaboration with Bernie Kraatz (University of Saskatchewan).  xxv  Chapter 5:1 performed all the synthesis and characterization of the complexes discussed. The dynamic light scattering experiments were performed in collaboration with Yunyong Guo and Matthew G. Moffitt (University of Victoria). The calculations of the dimer complex were performed  in collaboration with Lei L i u and Y . Alexander Wang  (University of British Columbia). The crystal structures were solved by Jonathan H . Chong (University of British Columbia). I wrote this chapter, with input from Mark J. MacLachlan.  Chapter 6: A l l synthesis and characterizations were performed by me with the crystal structure solved by Jonathan H . Chong (University of British Columbia).  xxvi  CHAPTER 1 Introduction 1.1  1.1.1  Supramolecular Chemistry  Historical Perspective  Pedersen serendipitously synthesized macrocyclic polyethers in the 1960s and his discovery would later be considered the birth of a new field of chemistry  -  supramolecular chemistry. Macrocyclic polyethers were actually first synthesized in the 1  late 1930s but little study followed as their ability to complex small cations was not recognized. Pedersen, employed by DuPont, was working on the synthesis of a new ligand to study its effects on the catalytic properties of vanadyl. As a by-product he obtained 0.4% white crystals with a silky fibrous structure. He observed that this puzzling by-product was not soluble in common polar solvents unless a sodium salt was added. Through UV-visible spectroscopy and molecular weight studies, Pedersen determined the structure of this unusual compound, 1, recognizing that he had synthesized a macrocyclic polyether. The solubility of this new compound was affected by its ability to complex with small cations revealing the first neutral compound capable of binding alkali metal cations. Following this discovery, Pedersen synthesized many related compounds and named this new class of compounds crown ethers for their crown-like resemblance in the solid state.  3  1  References on page 35.  R  R 3 Figure 1.1  Macrocycles capable of complexing alkali metals (1 : Pedersen's dibenzo-  18-crown-6, 2 : Lehn's [2.2.2]cryptand, 3 : Cram's spherand where R = C H 3 ) .  Shortly after Pedersen's work had been reported, three-dimensional analogues of crown ethers were designed by Lehn, a researcher at the Universite Louis Pasteur in Strasbourg. Lehn surmised that three-dimensional, spheroidal compounds that could entirely surround a bound ion should form stronger complexes than Pedersen's related flat macrocycles. From this idea he designed and synthesized macrobicyclic ligands (e.g., 2) that exhibit a higher affinity for cations than do Pedersen's crown ethers. The enhanced metal binding ability of these macrobicyclic ligands is due to the threedimensional nature of their cavity enabling spherical recognition of metal cations. Lehn 4  termed this new class of compounds cryptands from their ability to entirely surround or entomb metal cations, as in a crypt which comes from the Greek work kruptos meaning hidden. Cryptate is the name given to a cryptand that is complexed to a metal cation.  5  Crystal structures of the originally synthesized crown ethers and cryptands show that in their uncomplexed state they do not contain cavities or pre-formed binding sites. Cram designed a ligand with its oxygen atoms arranged in such a way that they have no 2  References on page 35.  choice but to be octahedrally arranged around an enforced spherical cavity. He termed these compounds spherands (e.g., 3). This was the first system to be arranged for alkali metal complexation before the complexation process itself. From his work, Cram 6  concluded that preorganization is a central determinant of binding power. After the initial reports by these three researchers many scientists became interested in this new field of "chemistry beyond the molecule". Charles Pedersen, JeanMarie Lehn, and Donald Cram were jointly awarded the Nobel Prize in Chemistry in 1987 "for their development and use of molecules with structure-specific interactions of high selectivity". From their early works the field of supramolecular chemistry emerged. 7  In 1978 Lehn defined this growing field of supramolecular chemistry as the chemistry of (  8  molecular assemblies and of the intermolecular bond. Molecular chemistry deals with covalent bond formation whereas supramolecular chemistry deals with the formations of non-covalent, intermolecular bonds. In its infancy supramolecular chemistry mostly involved a host (receptor) and a guest (substrate) but this field of chemistry has evolved to encompass many different systems involving the assembly of molecules through intermolecular interactions. 1.1.2  Highlights of Supramolecular Chemistry  With such enormous diversity found within the field of supramolecular chemistry, a comprehensive description cannot be presented, but instead a few systems are highlighted to display some of the variety in this field. Over the past fifteen years many studies in this broad field have been strongly influenced by nature. The desire to create  3  References on page 35.  controllable supramolecules that mimic complex biological systems has created a field with nearly limitless boundaries.  •  Figure 1.2  Octapeptide cyclo[-(L-Gln-D-Ala-L-Glu-D-Ala)2-] self-assembles through  hydrogen-bonding to form tubular structures (R groups are removed from assembled structure for clarity).  As the interest in biological mimicry increased the desire to synthesize organic nanotubes analogous to ion channels found within cell membranes also increased. There are several motifs available to construct organic nanotubes; one design is through the 9  assembly of stacked macrocycles. Macrocycles such as octa- (n = 2) and dodeca- (n = 3) peptides cyclo[-(L-Gln-D-Ala-L-Glu-D-Ala) -] have been synthesized and shown to n  assemble into hollow tubular structures through anti-parallel P-sheet hydrogen-bonding (Figure  1.2).  10  These  structures contain van der Waals internal diameters  of  approximately 7 and 13 A , respectively, which are entirely controlled by the pore size of  4  References on page 35.  the macrocycles used. In this way tunable, uniform organic nanotubes have been synthesized. Many different hydrogen-bonded structures can be obtained by choosing the appropriate shape and functionality of precursor units. A tennis ball-like structure has been assembled through self-complementary hydrogen-bonding when two molecules of compound 4 assemble through reversible dimerization to form a closed-shell cavity, Figure 1.3." The observed dimerization arises from the self-complementary hydrogenbond donors and acceptors of the lactam function in compound 4 and its molecular curvature, a consequence of the two 7-membered rings present. This tennis ball-like dimer contains eight hydrogen bonds and has an internal cavity of 60 A . 3  Figure 1.3  A tennis ball-like structure obtained from the assembly of two molecules  of 4 with bridgehead phenyl groups omitted for clarity in the crystal structure. (Taken from reference 11).  Coordination chemistry has also been employed to form supramolecular structures. Many researchers have used small organic components linked together by transition metals to obtain different shapes (e.g., molecular squares, rhomboids, triangles).  Through transition-metal-based coordination chemistry, Fujita assembled 24  5  References on page 35.  small components (18 metal ions and six triangular ligands) to form a hexahedron with an internal space of 900 A . 3  1 3  This was achieved by the reaction of an exo-hexadentate  ligand l,3,5-tris(3,5-pyrimidyl)benzene with c/'s-protected palladium(Il), Pd(N03)2(en)2, Figure 1.4.  form a supramolecular hexahedron; en = ethylenediamine.  Supramolecular assemblies of porphyrins have been synthesized as model systems for energy-transport investigations that may lead to artificial light harvesting systems.  14  One example of how porphyrins can be assembled through coordination  chemistry is the formation of large cyclic structures of m-phenylene linked porphyrin units, a gable porphyrin. Complementary coordination of zinc containing gable porphyrins with peripheral imidazolyl groups has led to large cyclic structures such as the hexamer shown in Figure 1.5.  15  6  References on page 35.  Figure 1.5  Six gable porphyrin units (highlighted in blue) assemble into a large cyclic  structure.  This section has highlighted a few representative examples from the remarkable field of supramolecular chemistry. One of the larger areas of this vast field is that involving macrocyclic chemistry, with particular interest in host-guest interactions. Building on the early supramolecular investigations of Pederson, Lehn and Cram many barrel- or vase-shaped macrocyclic systems have been investigated, including the sugarbased cyclodextrins, the glucoluril-based cucurbiturils, the phenol-based calixarenes and the resorcinol-based resorcinarenes.  16  7  References on page 35.  1.2  Calixarenes and Related Macrocycles  The term calixarene was coined by Gutsche to describe the cyclic array of four phenol moieties linked by methylene groups whose C P K model resembles a Greek vase known as a Calix crater.  17  The term now generally describes cyclic arrays of n phenol  moieties linked by methylene groups even though the larger systems do not form Calix crater-like vase shapes. This terminology denotes the number of phenolic residues present by a number in square brackets (e.g., calix[4]arene) and has found widespread use as it greatly simplifies the awkward Chemical Abstracts nomenclature for these systems. Calixarenes are depicted with their phenolic groups down (lower rim) and their parasubstituents pointing upward (upper rim), Figure 1.6, to reveal their vase-like structures.  upper rim  OH  OH OH HO  lower rim Figure 1.6  ;?-fert-Butylcalix[4]arene.  Calixarenes were first synthesized by a base catalyzed condensation of p-tertbutylphenol with formaldehyde (Scheme 1.1).  This reaction, however, resulted in a  mixture of calixarenes, mostly calix[4]arene, calix[6]arene and calix[8]arene. A step-wise synthesis was later designed by Hayes and Hunter where a linear tetramer was first  8  References on page 35.  obtained which could be cyclized to obtain calix[4]arenes (Scheme 1.2).  Differentpara-  arylsubstituents could be incorporated within calixarenes when Bohmer reported the [3+1] synthesis shown in Scheme 1.3.  Scheme 1.1  One-pot synthesis of calixarenes. 'Bu  Scheme 1.2  Step-wise synthesis of calix[4]arenes.  9  References on page 35.  Scheme 1.3  [3+1] synthesis of calix[4]arenes.  Calixarenes are conformationally flexible and are found as a mixture of conformers in solution. For example, calix[4]arenes have four conformers: the cone, the partial cone, the 1,2-alternate and the 1,3-alternate (Figure 1.7).  The cone conformation  often dominates this equilibrium due to strong intramolecular hydrogen-bonding. The interconversion between conformers in solution has been studied by ' H N M R spectroscopy revealing that interconversion is likely achieved by rotation of the OR groups at the lower rim of the macrocycle through the central cavity in what is termed a "lower rim through annulus" pathway.  22  Interconversion is slowed by the addition of  larger groups to the lower rim and an "upper rim through annulus" pathway seems to be unfavoured due to sterics even if the /rara-substituents are hydrogen atoms.  10  References on page 35.  R  R  R  R  R  R  R  R  R  R  cone Figure 1.7  partial cone  R  R  R  R  R  R  1,2-alternate  1,3-alternate  The four different conformers of calix[4]arenes.  Both the upper and lower rims of calixarenes can be functionalized affecting the properties of these vase-like systems. When ester groups are added to its lower rim calix[4]arene selectively binds N a ions similar to crown ethers.  In this case, however,  the oxygen atoms are appended to the periphery of the macrocycle rather than embedded within the macrocyclic backbone. Cesium cations can bind to the cavity of calix[8]arenes through 7t-cation interactions. In strongly basic solutions these calix[8]arenes can transport bound cesium ions from one aqueous phase to another through a non-aqueous phase such as chloroform. Calix[4]arenes can be linked through ethylene bridges where 24  the resulting dimer selectively binds potassium cations.  25  The binding ability of  calixarenes is not confined to metal cations as they possess a hydrophobic cavity with aromatic walls where neutral guests such as toluene can bind through CH-7t interactions.  Atwood and Shinkai independently determined that calixarenes can be  used in the purification of fullerene C6o-  In toluene, calix[8]arene forms an insoluble  complex with C6o that when added to chloroform dissociates with the calixarene dissolving leaving purified C6o, Figure 1.8.  11  References on page 35.  +  toluene  ©  p-terf-butylcalix[8]arene  soluble in toluene  calixarene is recycled  Q  chloroform  insoluble in toluene  soluble in chloroform  insoluble in chloroform Purification of C6o from impurities such as C70 by complexation with p-  Figure 1.8  te/t-butylcalix[8]arene.  The condensation of resorcinol (3-hydroxyphenol) with aldehydes does not result in a mixture but rather in a calix[4]arene-like system with a wider, shallower bowl (Scheme  1.4).  These  systems  have been  termed  resorcinarenes  and possess  intramolecularly hydrogen-bonded hydroxyl groups appended to their upper rim.  Scheme 1.4  Synthesis of classical resorcinarenes.  12  References on page 35.  By linking the hydroxyl residues of classical resorcinarenes through methylene bridges, the conformational mobility of these systems is reduced thereby producing a more rigid class of resorcinarenes.  The synthesis of these new resorcinarenes is shown  in Scheme 1.5 where a classical resorcinarene is treated with excess CfbClBr and base.  Scheme 1.5  Synthesis of resorcinarenes with reduced conformational mobility.  Many studies have been undertaken to probe the host-guest properties of these systems. For example, by linking these systems head-to-head a molecular cage or a carcerand is formed where guest molecules become incarcerated by the host and cannot be freed, Figure 1.9.  In 1997 it was reported that the reaction of six [4]resorcinarenes  with eight water molecules produces a self-assembled snub-cube structure (Figure 1.10). This remarkable chiral, spherical hexamer contains 60 hydrogen-bonds with a 31  cavity diameter of 17.7 A and an internal volume of 1375 A . 3  13  References on page 35.  Figure 1.9  Resorcinarenes linked head-to-head to form a carcerand with encapsulated  guest (R = CH CH Ph). 2  Figure 1.10  2  Large, snub-cube structure of six self-assembled resorcinarenes shown as  (a) a cross-sectional view (green = C, red = O, white = H - involved in hydrogen-bonds) and (b) a space filling model. (Taken from reference 31).  14  References on page 35.  1.3  Shape-Persistent Macrocycles  Shape-persistent macrocycles have emerged within the field of supramolecular chemistry as useful building blocks for the organization of molecular entities into structures with a high level of complexity. These fully conjugated macrocycles are obtained when rigid building blocks are connected to form a cyclic structure with a nanometer sized interior and a final non-collapsible, conformationally rigid, structure (unlike crown ethers and cycloalkanes).  Much of the pioneering work in this area was  done in the 1960s on polyphenylenes '  (e.g., 5 and 6) and was extended in the early  33 34  1980s to include heteronuclear macrocycles  5 Figure 1.11  such as sexipyridine, 7 (Figure 1.11).  6  7  Early shape-persistent macrocycles (5 : Staab's hexa-w-phenylene, 6 :  Fujioka's o,/?,o,/?,0,/?-hexaphenylene and 7 : Newkome's sexipyridine).  With the development of repetitive growth schemes, high-dilution techniques and robust coupling conditions much larger macrocycles have since been designed and synthesized. Within the past decade many chemists have become interested in rigid  15  References on page 35.  macrocycles as the ability to tune the interior and exterior of these macrocycles may influence their properties and applications. In a recent review , 108 fully conjugated shape-persistent macrocycles were 36  presented, containing only sp- and sp -hybridized carbon atoms in the macrocyclic 2  backbone, with many shapes, sizes and functionalities. A few representative examples of these macrocycles are shown in Figure 1.12. O f all the macrocycles presented in this review only two do not possess flexible chains attached for solubility. These side chains have become very important in the study of shape-persistent macrocycles as solubility is of crucial importance for characterization. Also, the position of such side-chain groups can influence the supramolecular properties or functions of the macrocycles.  16  References on page 35.  r  R  9  1  Figure 1.12  A few examples of shape-persistent macrocycles 8a : R  = R  =  0(CH CH 0)3CH3, 9 : R = R = O C H , R = C H R = O C H , 1 0 : R = C Hi ,11 : R 1  2  2  3  2  3  7  4  3  18  37  6  3  = C Hi312 : R = mesityl, 14 : R = Bu. l  6  17  References on page 3 5 .  The majority of shape-persistent macrocycles are synthesized with a cyclization step involving transition metal-induced homo- or cross-coupling reactions. The most commonly used cyclization reactions are aryl/alkynyl (Sonogashira) and alkynyl/alkynyl (Glaser) coupling (Scheme 1.6). These coupling reactions are used because of their 36  tolerance toward functional groups, their generally high yields and their well documented precursor methods. The best yields for macrocycle formation are often reported when the cyclization requires the formation of only one bond. In this case the precursor is an openchain version of the macrocycle and needs only to be joined end to end. To avoid formation of larger oligomers or polymers, this final bond forming step often requires high-dilution techniques.  Scheme 1.6  Commonly used cyclization reactions (a) Sonogashira coupling to form  8b where R = B u and R = H ; and (b) Glaser coupling to form 9b where R = R = 37  1  l  2  38  1  2  O C H , R = Me and R = OTHP; THP = tetrahydropyranyl. 3  3  4  7  Pd(dba) , PPh , Cul, Et N 2  3  3  80°C, 12h, 75%  .OTHP  2 THPO.  OTHP  18  References on page 35.  Scheme 1.7  Synthesis of 8 by Stephens-Castro coupling in 4.6% yield (a), Sonogashira  coupling in 75% yield (b) and alkyne metathesis in 68% yield (c).  8a R = 0(CH CH 0)3CH3 2  2  8b R = H 8c R = 'Bu  a  pyridine, reflux, 24h Pd(dba) , PPh , Cul, 70 °C, 12 h EtC=MorNAr(tBu)] ,/>-nitrophenol, 30 °C, 22h b  c  2  3  3  Macrocycles consisting of phenylene and ethynylene units are widely studied shape-persistent  macrocycles  with  investigations  supramolecular properties and functions.  undertaken  The synthesis of  to  explore  their  phenyleneethynylene  macrocycle 8 was first reported in 1974. Macrocycle 8b was formed in a 4.6% yield by 40  an intermolecular, six fold Stephens-Castro  coupling of the copper salt of m-  iodophenylacetylene. With the low yield of this synthesis few found need to investigate this system, until 1992 when a new route was reported forming macrocycle 8c in a 75% yield , Scheme 1.7. However, the synthesis of the open-chain precursor needed for such 41  a cyclization reaction is cumbersome. This difficulty was recently surpassed with the  19  References on page 35.  development of a new, one-pot synthesis of phenyleneethynylene macrocycles through reversible alkyne metathesis  42  (Scheme 1.7).  These rigid macrocycles are able to self-assemble in solution through face-to-face 7i-7t stacking  interactions of their aromatic rings  4 3  For such self-association the rigidity of  the macrocycle is important as related less rigid macrocycles or open-chain precursors show little to no association, respectively. The electronic character and orientation of substituents also strongly influence the aggregation behaviour of the macrocycles, with exo-annular, non-bulky, electron withdrawing substituents favoured, as in macrocycle 8d where R = C O O C H . n  4  9  Macrocycle 8e with R = O C7Hi5 is a toroidal-shaped mesogen, that selfn  organizes into discotic nematic liquid crystalline phases. The relative rigidity and large 44  internal diameter of this macrocycle is ideal to produce tubular liquid crystalline phases. These macrocycles may find interesting applications as functionalization of their e«Jopositions may be used to modify the internal channel environments. These phenyleneethynylene macrocycles have also been employed as building blocks for porous materials. Macrocycle 8f (R = OH) forms hexagonally closest-packed 45  two-dimensional hydrogen-bonded networks and in the solid state the macrocycles stack to form open channels (containing solvent molecules). Unlike other non-macrocyclic networks this system does not interpenetrate to minimize void in the structure. Here the channel walls are formed by the interior of the macrocyclic building blocks. This may allow for synthetic tuning of these extended channel structures.  20  References on page 35.  1.4  Schiff-Base Macrocycles  1.4.1  Schiff-Base Chemistry  The condensation reaction of an aldehyde with an amine to form an imine (a Schiff-base  46  condensation) has long been a useful reaction (Scheme 1.8). With its  reversible nature and undemanding synthetic conditions this reaction has found its way into many different areas of chemistry.  Scheme 1.8  47  General Schiff-base condensation reaction between an aldehyde and a  primary amine. _P  R  +  H N-R' 2  -  .  R - ^  N  _  R  '  +  H  2  °  One important application of the Schiff-base condensation reaction is in the preparation of N,N'-bis(salicylidene)ethylenediamines, a class of compounds known as salens. These ligands are prepared by the Schiff-base condensation of salicylaldehyde (sal) with ethylenediamine (en), Scheme 1.9. Related compounds can be synthesized by varying  the  choice  of  propylenediamine = salpn)  diamine  linker  (e.g.,  phenylenediamine  =  salphen,  48  21  References on page 35.  Scheme 1.9  Formation of Schiff-base salen and salphen compounds. N  N=\  OH H O - / HN 2  NH  \  +  2 H 0  +  2 H,0  2  2  Salen  ( ^ O H  HO  Salphen  With a tetradentate N2O2 pocket, these Schiff-base compounds can bind many metals in the periodic table to form coordination complexes, '  some with useful  47 49  properties. For example, commercially available Jacobsen's  catalyst (15),  which  incorporates M n " , Figure 1.13, can mediate asymmetric epoxidation of achiral olefinic substrates. The bulky tert-buty\ substituents on the salicylaldehyde units direct the 50  substrate toward the chiral cyclohexanediimine group, which imparts the asymmetric selectivity in the oxygen transfer. ^(CH ) 2  15 Figure 1.13  6  16  Salen-like compounds for asymmetric epoxidation (15) and electro-  luminescence (16). 22  References on page 35.  In 2000 the synthesis of a Zn coordination complex (16) was reported, Figure 1.13. This salen-like complex shows electroluminescence in the blue region of the spectrum when incorporated into a layered device.  51  Such complexes are promising  candidates for developing metal-organic light emitting diodes. Schiff-base condensation reactions have enabled researchers to synthesize a variety of macrocycles. Some of the earliest small macrocycles, developed for binding 52  transition metals, were prepared by Schiff-base condensation, Figure 1.14.  C0 R 2  17 Figure 1.14  18  19  Early Schiff-base macrocycles (17 : Curtis 1962, 18 : Busch 1964, 19 :  Jager 1968).  The reversibility of the Schiff-base condensation reaction makes it ideal for a ring closing step. Oligomers and polymers may form but under the appropriate reaction conditions the thermodynamically stable macrocyclic product can be obtained (Figure 1.15).  23  References on page 35.  NH  2  N  2  0  N  j -H 0  —  2  NH \  N  2  0  Schematic representation  /  /  o  -H 0 w H 0 2  Polymer  2  2  Figure 1.15  $  +  +H 0  Thermodynamic Product  2  i  ^  2  H N  H 0 2  v /  v  r  I  /  of the reversible Schiff-base  condensation  reaction to from a thermodynamically stable macrocyclic product.  In this way, Moore prepared phenyleneethynylene macrocycles containing two imine bonds. Rather than using a Sonogashira coupling reaction, Moore used a Schiffbase condensation reaction as the ring closing step for macrocycle formation and studies were undertaken on the conformational isomerization of this new macrocycle (Figure 1.16).  53  24  References on page 35.  R  R  R  R  R  R  H . N  H ^ N  R  N^.H  N^H  R  R  R  R  R  R = C0 (CH2CH 0)3CH3 2  Figure 1.16  2  Conformational isomerism of an imine-containing w-phenyleneethynylene  macrocycle.  1.4.2  Robson-Type Macrocycles  One of the  most  studied  Schiff-base  macrocycles  is the  Robson-type  metallomacrocycle. This macrocycle belongs to a class of [2+2] Schiff-base macrocycles where 2 diformyl units plus 2 diamine units combine to form a macrocycle. The first Robson-type macrocycle was prepared in 1970 by the reaction of 2,6-diformyl-4methylphenol with 1,3-diaminopropane in the presence of a metal salt (Scheme 1.10).  54  Metal-free analogues of these macrocycles are virtually unknown as their synthesis without the use of a metal template has proven difficult.  25  References on page 35.  Scheme 1.10  The first synthesis of a dinuclear Schiff-base complex.  CH  3  Many different groups have investigated cooperative metal-metal interactions, redox activities, and bimetallic reactivities in this class of metallomacrocycles. The dicopper  Robson-type  macrocycle 20  (Figure  1.17)  has  been  reported  with  antiferromagnetic exchange interactions not only mediated through the phenoxide oxygen bridges but also through the conjugated macrocyclic ligand itself.  55  2+  CH  3  20 Figure 1.17  Robson-type macrocycle 20 for studies on antiferromagnetic exchange  interactions.  26  References on page 35.  Robson-type metallomacrocycles have been used in supramolecular chemistry as building blocks for the assembly of molecular ladders (Scheme 1.11). Here, the two 56  zinc atoms of the [2+2] macrocycle have a distorted octahedral coordination environment with two apical positions occupied by bridging 4,4'-bipyridine ligands to form a ladderlike structure.  Scheme 1.11  Molecular ladders formed through coordination chemistry of Robson-type  metallomacrocycles. s  Recently, the preparation of dinuclear Co and Co" Robson-type macrocyclic 11  1  complexes have been reported. These complexes show efficiency toward catalytic asymmetric cyclopropanation of styrene with diazoacetate (Scheme 1.12). dinuclear Co  111  57  For the  complex a product yield of 92% was obtained with a trahs-to-cis ratio of  74:26 and enantiomeric excesses (ee) of 88.4 and 94.2 for the trans and cis cyclopropane 27  References on page 35.  1  isomers, respectively. Little difference is observed when compared with the analogous Co" complex, suggesting that the mechanism is related in both cases.  Scheme 1.12  A Robson-type  metallomacrocycle  as  a  catalyst  for  asymmetric  cyclopropanation.  trans  1.4.3  Schiff-Base Expanded Porphyrins  Polypyrrolic macrocycles exhibit rich and diverse chemistry. Calix[4]pyrrole is a neutral macrocycle that binds fluoride ions strongly, but with such a small cavity binding CO  of larger anions is not possible.  Texaphyrin, however, with its large cavity is able to  form stable complexes with lanfhanide ions. A hybrid of these two macrocycles has 59  been designed in hopes of creating new systems with unique properties. From the condensation of diformyldipyrromethane units with phenylene diamine a new [2+2] Schiff-base expanded porphyrin 21 (Figure 1.18) was prepared that is able to selectively bind chloride ions.  60  28  References on page 35.  XX  OMe  MeO  22  21 Figure 1.18  Schiff-base macrocycles containing pyrrole units.  Schiff-base polypyrrolic macrocycle 21 contains two N4 pockets able to bind transition metals. Upon the addition of Pd to this macrocycle a dipalladium complex is 11  obtained with a structure analogous to that of the Pac-Man bisporphyrins (Figure 1.19).  61  (a)  Figure 1.19  (a) Dipalladium complex of macrocycle 21 and (b) dipalladium Pac-Man  bisporphyrin.  29  References on page 35.  Using bipyrrole rather than pyrromethane units, macrocycle 22 can be prepared possessing a large 7i-conjugated system.  62  This fully conjugated macrocycle is able to  bind two molecules of methanol, one within each of its N4 pockets. The crystal structure shows that the methanol molecules are bound through N - H — O bonding with the bipyrrole units. Solution phase binding information was obtained through N M R spectroscopic studies, where shifts in the H resonances are observed upon the step-wise !  addition of methanol to a solution of macrocycle 22. Macrocycle 22 also shows affinity for other alcohols, such as ethanol, trifluoroethanol and phenol, but in all cases other than methanol only 1:1 species are observed.  1.4.4  [3+3] Schiff-Base Macrocycles  [3+3] Schiff-base macrocycles are formed by the reaction of 3 difromyl units plus 3 diamine units to yield a macrocycle. Before the work of this thesis began very few [3+3] Schiff-base macrocycles had been reported. The synthesis of macrocycles 23 was reported in 1995 by the Schiff-base condensation of a diformylnaphthalene unit and various diamines (Figure 1.20).  The synthesis of these macrocycles requires a barium  template which cannot later be removed and further work on these macrocycles was never published.  30  References on page 35.  24  23  25  R — CH2CH2 CH2CH2CH2 1,2-phenyl trans-1,2-cyclohexyl  Figure 1.20  [3+3] Schiff-base macrocycles.  In 2000, [3+3] chiral macrocycle 24 was synthesized from the Schiff-base condensation  of (li?,2i?)-l,2-diaminocyclohexane and  1,2-diformylbenzene.  64  By  following this reaction by ' H N M R spectroscopy it was determined that after two hours less than 5% of the starting materials were left. The ' H N M R spectra of these new [3+3] macrocycles show an overall D3 symmetry. These macrocycles seem to be the highly favoured products of the condensation reaction and even when ratios other than one-toone were used the [3+3] macrocycle was the only product isolated. The pore size of macrocycle 24 can be varied by using different sized, but similarly shaped, diformyl precursors (e.g., terphenyl and tetraphenyl).  65  The built-in chirality of these macrocycles  may be useful as potential receptors for chiral recognition. The synthesis of a new fully conjugated [3+3] Schiff-base macrocycle 25 was reported in 2001 while our work on these macrocycles was underway.  66  The reported  macrocycle, which requires a two week cyclocondensation step, is not soluble in organic  31  References on page 35.  solvents and no further work has been published. However, extended analogues of macrocycle 25 have recently been reported where biphenyl units are incorporated.  1.5  Goals and Scope  This chapter has introduced the topic of shape-persistent macrocycles and placed them in the context of supramolecular chemistry. The long-term goal of my research was to develop macrocycles with multiple metal centres and to explore their assembly into molecule-based nanotubes, as shown in Figure 1.21.  uniform  Trimetallated macrocycle Figure 1.21  Ring stacking  Envisioned assembly through coordination chemistry of a trimetallated  macrocycle with small linker molecules to form a tubular structure.  32  References on page 35.  This posed several challenges as rigid macrocycles containing metals have low solubility and there are no simple routes to prepare them. Therefore, my first goal was to develop a new class of conjugated shape-persistent macrocycles employing the Schiffbase condensation reaction as the ring-closing step. It was proposed that the targeted macrocycle 26 might be prepared by the condensation of a l,2-dihydroxy-3,6diformylbenzene with a l,2-dialkoxy-4,5-diaminobenzene. Solubility and other properties could be modified by choosing different substituents on the phenylenediamine precursor unit. These macrocycles were designed to chelate to three metals in N2O2 pockets, and could potentially be used as precursors for coordination nanotubes (Figure 1.21). They would also possess a central cavity with six oxygen atoms arranged in a way to resemble the interior of a crown ether (18-crown-6), Figure 1.22. Although the long-term objective of this work was not achieved, and may be out of reach altogether, this thesis describes significant strides toward that goal.  Figure 1.22  The [3+3] Schiff-base macrocycle 26 possesses (a) three salphen-like  N2O2 pockets and (b) one central crown ether-like cavity.  33  References on page 35.  In chapter 2 the synthesis and characterization of conjugated [3+3] Schiff-base macrocycles (26a-h) are described. The mechanism of their assembly has been probed by isolation of oligomeric and partially reduced species that form during the condensation reaction. In addition, ab initio calculations were employed to rationalize the symmetry of the macrocycles observed in solution and in the solid-state. Chapter 3 describes the preparation of related naphthalene macrocycles (45c,e) along with that of some model compounds.  Investigations  were undertaken  to explore the  observed keto-enol  tautomerism of these macrocycles. Chapter 4 discusses the cation-induced tubular assembly of macrocycles 26 using ' H and  23  N a N M R spectroscopy, UV-visible  spectroscopy, mass spectrometry, and electrochemistry. Chapter 5 describes the incorporation of metal atoms into macrocycles 26. These macrocycles are shown to template the formation of a zinc-oxide cluster resulting in a new heptanuclear zinc complex. The self-association of these interesting new coordination complexes was investigated by N M R spectroscopy, light-scattering techniques and ab initio calculations. Finally, Chapter 6 presents a brief thesis summary with a look at future directions in this field.  34  References on page 35.  1.6  References  (1) Steed, J. W.; Atwood, J. L. Supramolecular Chemistry John Wiley & Sons: Toronto, 2000. (2) Luttringhaus, A . ; Ziegler, K . Liebigs Ann. Chem. 1937, 528, 155. (3) Pedersen, C. J. Angew. Chem. Int. Ed. Engl. 1988, 27, 1021. (4) Lehn, J.-M. Angew. Chem. Int. Ed, Engl. 1988, 27, 89. (5) (a) Dietrich, B.; Lehn, J. M . ; Sauvage, J. P. Tetrahedron Lett. 1969, 2885. (b) Dietrich, B.; Lehn, J. M . ; Sauvage, J. P. Tetrahedron Lett. 1969, 2889. (6) Cram, D. J. Angew. Chem. Int. Ed. Engl. 1988, 27, 1009. (7) Nobel Lectures in Chemistry 1981-1990; Malmstrom, B. G., Ed.; World Scientific Publishing Company: Singapore, 1993 (8) Lehn, J.-M. Acc. Chem. Res. 1978,11, 49. (9) Bong, D. T.; Clark, T. D.; Granja, J. R.; Ghadiri, M . R. Angew. Chem. Int. Ed. 2001, 40, 988. (10) (a) Ghadiri, M . R.; Granja, J. R.; Milligan, R. A . ; McRee, D. E.; Khazanovich, N . Nature 1993, 366, 324. (b) Khazanovich, N . ; Granja, J. R.; McRee, D. E.; Milligan, R. A.; Ghadiri, M . R. J. Am. Chem. Soc. 1994,116, 6011. (11) Wyler, R.; de Mendoza, J.; Rebek, J., Jr. Angew. Chem. Int. Ed. Engl. 1993, 32, 1699. (12) (a) Leininger, S.; Olenyuk, B.; Stang, P. J. Chem. Rev. 2000,100, 853. (b) Fujita, M . Chem. Soc. Rev. 1998, 27, 417. (13) Takeda, N . ; Umemoto, K.; Yamaguchi, K.; Fujita, M . Nature 1999, 398, 794.  35  (14) Sessler, J. L.; Wang, B.; Harriman, A . J. Am. Chem. Soc. 1995,117, 704. (15) Ikeda, C ; Satake, A . ; Kobuke, Y . Org. Lett. 2003, 5, 4935. (16) Large Ring Molecules; Semlyen, J. A., Ed.; John Wiley & Sons: Toronto, 1996. (17) Gutsche, C. D.Acc. Chem. Res. 1983,16, 161. (18) (a) Zinke, A.; Ziegler, E. Chem. Ber. 1944, 77, 264. (b) Patrick, T. B.; Egan, P. A . J. Org. Chem. 1977, 42, 382. (c) Gutsche, C. D.; Muzaffer, I.; Stewart, D. J. Org. Chem. 1986, 51, 742. (19) (a) Hayes, B . T.; Hunter, R. F. Chem. Ind. 1956, 193. (b) Hayes, B. T.; Hunter, R. F. J. Appl. Chem. 1958, 8, 743. (20) Bohmer, V . ; Chhim, P.; Kammerer, H . Makromol. Chem. 1979,180, 2503. (21) Gutsche, C. D.; Dhawan, B.; Levine, J. A.; Kwang, H. N . ; Bauer, L . J. Tetrahedron 1983,39.409. (22) Gutsche, C D . Calixarenes Revisited Royal Society of Chemistry: Cambridge, 1998. (23) Arnaud-Neu, F.; Collins, E. M . ; Deasy, M . ; Ferguson, G.; Harris, S. J.; Kaitner, B . ; Lough, A . J.; McKervey, M . A.; Marques, E.; Ruhl, B . L.; Schwing-Weill, M . J.; Seward, E. M.J. Am. Chem. Soc. 1989, 111, 8681. (24) (a) Izatt, R. M . ; Lamb, J. D.; Hawkins, R. T.; Brown, P. R.; Izatt, S. R.; Christensen, J. J. J. Am. Chem. Soc. 1983,105, 1782. (b) Izatt, S. R.; Hawkins, R. T.; Christensen, J. J.; Izatt, R. M . J. Am. Chem. Soc. 1985, 707, 63. (25) Schmitt, P.; Beer, P. D.; Drew, M . G. B.; Sheen, P. D. Angew. Chem. Int. Ed. Engl. 1997,36,1840. (26) Andreetti, G. D. J. Chem. Soc, Chem. Commun. 1979, 1005.  36  (27) (a) Atwood, J. L.; Koutsantonis, G. A . ; Raston, C. L. Nature 1994, 368, 229. (b) Suzuki, T.; Nakashima, K.; Shinkai, S. Chem. Lett. 1994, 699. (28) (a) Niederl, J. B.; Vogel, H . J. J. Am. Chem. Soc. 1940, 62, 2512. (b) Hogberg, A . G. S. J. Am. Chem. Soc. 1980,102, 6046. (c) Hogberg, A . G. S. J. Org. Chem. 1980, 45, 4498. (29) Cram, D. J.; Karbach, S.; Kim, H:-E.; Knobler, C. B.; Maverick, E. F.; Ericson, J. L.; Helgeson, R. C. J. Am. Chem. Soc. 1988,110, 2229. (30) (a) Sherman, J. C ; Knobler, C. B.; Cram, D. J. J. Am. Chem. Soc. 1991,113, 2194. (b) Chapman, R. G.; Chopra, N . ; Cochien, E. D.; Sherman, J. C. J. Am. Chem. Soc. 1994, 116, 369. (31) MacGillivray, L. R.; Atwood, J. L. Nature 1997, 389, 469. (32) Hoger, S. Chem. Eur. J. 2004,10, 1320. (33) Staab, H . A . ; Binnig, F. Tetrahedron Lett. 1964, 319. (34) Fujioka, Y. Bull. Chem. Soc. Jpn. 1984, 57, 3494. (35) Newkome, G. R.; Lee, H.-W. J. Am. Chem. Soc. 1983,105, 5956. (36) Grave, C ; Schluter, A. D. Eur. J. Org. Chem. 2002, 3075. (37) Zhang, J.; Pesak, D. J; Ludwick, J. L.; Moore, J. S. J. Am. Chem. Soc. 1994,116, 4227. (38) Hoger, S.; Bonrad, K.; Mourran, A.; Beginn, U . ; Moller, M . J. Am. Chem. Soc. 2001,123, 5651. (39) Zhao, D.; Moore, J. S. Chem. Commun. 2003, 807. (40) Staab, H . A . ; Neunhoeffer, K. Synthesis 1974, 424. (41) Moore, J. S.; Zhang, J. Angew. Chem. Int. Ed. Engl. 1992, 31, 922.  37  (42) Zhang, W.; Moore, J. S.J. Am. Chem. Soc. 2004,126, 12796. (43) Shetty, A . S.; Zhang, J.; Moore, J. S. J. Am. Chem. Soc. 1996,118, 1019. (44) Zhang, J.; Moore, J. S. J. Am. Chem. Soc. 1994,116, 2655. (45) Venkataraman, D.; Lee, S.; Zhang, J.; Moore, J. S. Nature 1994, 371, 591. (46) First reported synthesis: Schiff, H . Ann. Suppl. 1864, 3, 343. (47) Calligaris, M . ; Randaccio, L . Comprehensive Coordination Chemistry Pergamon Press: London, 1987; Vol. 2, Chapter 20. (48) Dubsky, J. V . ; Sokol, A . Collect. Czech. Chem. Commun. 1931, 3, 548. (49) Yamada S. Coord. Chem. Rev. 1966,1, 415. (50) Tokunaga, M . ; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N . Science 1997, 277, 936. (51) Sano, T.; Nishio, Y . ; Hamada, Y . ; Takahashi, H.; Usuki, T.; Shibata, K. J. Mater. Chem. 2000,10, 157. (52) (a) Blight, M . M . ; Curtis, N . F. J. Chem. Soc. 1962, 3016. (b) Curry, J. C ; Busch, D. H . J. Am. Chem. Soc. 1964, 86, 592. (c) Jager, E. G. Z. Chem. 1968, 8. 30. (53) Zhao, D.; Moore, J. S. J. Org. Chem. 2002, 67, 3548. (54) Pilkington, N . H.; Robson, R. Aust. J. Chem. 1970, 23, 2225. (55) Dziembowska, T.; Guskos, N . ; Tupek, J.; Szymczak, R.; Likodimos, V . ; Glenis, S.; Lin, C. L.; Wabia, M . ; Jagodzinska, E.; Fabrycy, E. Mater. Res. Bull. 1999, 34, 943. (56) Huang, W.; Gou, S.; Hu, D.; Chantrapromma, S.; Fun, H.-K.; Meng, Q. Inorg. Chem. 2001, 40, 1712. (57) Gao, J.; Woolley, F. R.; Zingaro, R. A . Org. Biomol. Chem. 2005, 3, 2126. (58) Gale, P. A . ; Sessler, J. L.; Krai, V . ; Lynch, V . J. Am. Chem. Soc. 1996,118, 5140. (59) Sessler, J. L.; Mody, T. D.; Hemmi, G. W.; Lynch, V . Inorg. Chem. 1993, 32, 3175.  38  (60) Sessler, J. L.; Cho, W.-S.; Dudek, S. P.; Hicks, L.; Lynch, V . M . ; Huggins, M . T. J. Porphyrins Phthalocyanines 2003, 7, 97. (61) Givaja, G.; Blake, A . J.; Wilson, C.; Schroder, M . ; Love, J. B . Chem. Commun. 2003, 2508. (62) Sessler, J. L.; Mody, T. D.; Lynch, V . J. Am. Chem. Soc. 1993,115, 3346. (63) Huck, W. T. S.; van Veggel, F. C. J. M . ; Reinhoudt, D. N . Reel. Trav. Chim. PaysBas, 1995,114, 273. (64) Gawronski, J.; Kolbon, H . ; Kwit, M . ; Katrusiak, A . J. Org. Chem. 2000, 65, 5768. (65) Kuhnert, N . ; Burzlaff, N . ; Patel, C ; Lopez-Periago, A . Org. Biomol. Chem. 2005, 3, 1911. (66) Akine, S.; Taniguchi, T.; Nabeshima, T. Tetrahedron Lett. 2001, 42, 8861. (67) Akine, S.; Hashimoto, D.; Saiki, T.; Nabeshima, T. Tetrahedron Lett. 2004, 45, 4225.  39  CHAPTER 2 [3+3] Schiff-Base Macrocycles* 2.1  Introduction  The primary goal of this work was to develop rigid, conjugated macrocycles that could bind multiple transition metals within their macrocyclic backbone. While a great deal of work has been directed at phenyleneethynylene-based macrocycles (e.g. 8) the 1  investigation of conjugated metallomacrocycles is less known. Macrocycle 26 (Figure 2.1) was targeted as such a macrocycle with its three tetradentate N2O2 binding sites organized in an equilateral triangle, as well as a pocket in the centre that is surrounded by six phenolic oxygen atoms resembling 18-crown-6. Such macrocycles may function as ligands for the development of new size- and shape-selective catalysts, or for developing new coordination materials. These triangular macrocycles should be accessible by Schiffbase condensation since the [3+3] Schiff-base macrocycle is expected to be the thermodynamically stable product. The incorporation of peripheral substituents is necessary to render the macrocycles soluble.  f A version of this chapter has been published: (a) Gallant, A . J.; Hui, J. K . - H . ; Zahariev, F. E.; Wang, Y . A.; MacLachlan, M . J. "Synthesis, Structure, and Computational Studies of Soluble Conjugated Multidentate Macrocycles" J. Org. Chem. 2005, 70, 7936. (b) Gallant, A . J.; Patrick, B . O.; MacLachlan, M . J. "Mild and Selective Reduction of Imines: Formation of an Unsymmetrical Macrocycle" J. Org. Chem. 2004, 69, 8739. Calculations were performed in collaboration with F. E . Zahariev and Y . A . Wang (University of British Columbia). 40  References on page 92.  R  25 Figure 2.1  26  Phenyleneethynylene and Schiff-base macrocycles.  Prior to the work presented here preliminary studies of a related macrocycle (23) prepared using a Ba  template were reported by Reinhoudt. These were plagued by  insolubility and the template could not later be removed. Six months into this project, investigating new [3+3] Schiff-base macrocycles, Akine et. al. reported the structure of macrocycle 25. Their synthesis required a two week reaction time and, as we expected, the macrocycle is nearly insoluble in organic solvents (e.g., CHCI3, MeOH, MeCN). 41  References on page 92.  This chapter focuses on the synthesis, characterization and computational studies of soluble conjugated Schiff-base macrocycles. By isolating intermediates and byproducts of the condensation, insight into the mechanism of macrocycle formation is provided. One surprising by-product, a monoreduced macrocycle, is reported and a plausible in situ mechanism for its reduction is proposed.  2.2  2.2.1  Results and Discussion  Synthesis and Characterization  The Schiff-base condensation of aldehydes with amines is a route to imines, functional groups with carbon-nitrogen double bonds. By preparing a molecule with two aldehyde functionalities and one with two amine functionalities this Schiff-base condensation could yield polymers, oligomers, or macrocycles. For the synthesis of new soluble [3+3] conjugated Schiff-base macrocycles the appropriate precursors must first be synthesized. The diformyl species 29 will provide the correct geometry for cyclization and dialkoxyphenylenediamine precursors 33a-i, with alkyl chains of varying length, will be employed to modify the solubility of these macrocycles. Compound 29 can be synthesized in multigram quantities in an overall yield of cci. 50% beginning with veratrole (27). Ortho-lithiation followed by quenching with D M F of compound 27 yields the diformyl species 28. The desired diformyl dihydroxy benzene (29) can then be obtained by reaction with BBr3 as shown in Scheme 2.1.  42  3  References on page 92.  Scheme 2.1  Synthesis of precursor 29.  Diamines 33a-i can be synthesized as shown in Scheme 2.2 with an overall yield of  ca. 50%.  Reaction of catechol (30)  4  with the desired alkylbromide gives  dialkoxybenzene 31, which can then be selectively bisnitrated to yield 32. Reduction with hydrazine and a Pd/C catalyst gives diamine 33.  Scheme 2.2  „  <^Y  Synthesis of precursor 33a-i.  K C0  u  2  3  {  ^ ^ O H  DMF  30  ifY  _  _ ..  n  0 h  ^ \ ) R  n  q  2  N  3  0  31a-i  2  y v  _  D  N " ^ ^ O R  32a-i  H NNH -H 0 2  2  10% Pd/c  2  t  EtOH  u  M  2 y^y  h  n  H  2  ~  0  N - ^ ^ O R  33a-i  a R = CH f R = "C6Hi3 b R = C H gR = C H cR = C H h R = C H d R = C4Hg i R = C H29 eR = C H-|-| 3  n  2  5  n  7  1 5  8  1 7  n  3  7  n  n  14  n  5  The reported macrocycle 25 is insoluble in most solvents and takes two weeks to synthesize,  therefore  a general and convenient route to macrocycles possessing  peripheral alkoxy chains was developed to increase solubility. The reaction of diformyl dihydroxy benzene 29 with diamine 33 afforded red, fibrous or microcrystalline product 43  References on page 92.  26 in moderate to high yield, 60-90% (Scheme 2.3). Unlike 25, macrocycles 26b-h with 5  peripheral alkoxy chains, are soluble in a wide-range of organic solvents such as chloroform, toluene and dimethylformamide. The significance of the peripheral alkoxy substituents to aid in solubility could be demonstrated by using dimethoxy diamine 33a, with very short alkoxy groups, as a macrocylic precursor. The resulting product, likely macrocycle 26a, was insoluble in common organic solvents and difficult to characterize.  Scheme 2.3  Synthesis of conjugated  [3+3] Schiff-base macrocycles 26a-h with  reaction yields shown in parentheses. RO  aR = CH b R=C H c R= C H d R= C H 3  2  5  n  3  7  n  4  9  (N/A) (77%) (68%) (78%)  eR = f R= gR= hR =  n  n  n  C C C C  5  n  7  8  H H H H  6  1 1 1 3  1 5  1 7  OR  (63%) (75%) (70%) (87%)  The electrospray ionization mass spectrometry (ESI-MS) data of macrocycles 26b-h all show the expected protonated products and N a complexes. Their IR spectra +  confirm a single imine environment with a C - N stretch (1610 cm" ) and show no 1  aldehyde C=0 absorption from starting material 29 (1660 cm" ). The *H N M R spectra of 1  44  References on page 92.  26b-h (26f shown in Figure 2.2) are indicative of high symmetry with one imine (8 = 8.5 ppm) and two singlet aromatic resonances (8 = 6.6, 6.9 ppm) consistent with an average T>SH  symmetry of the macrocycle. Based on 2D N M R experiments (HMQC, H M B C ) the  aromatic resonances are assigned to protons situated on the catechol portion of the macrocycle (6.9 ppm) and on the phenylenediamine portion (6.6 ppm). These are each shifted from the resonances observed for starting materials 29 and 33 found at 7.2 and 6.4 ppm, respectively. The phenolic O H resonance is observed at 13.3 ppm, where the significant downfield shift, as compared to catechol (5.18 ppm), arises from strong hydrogen-bonding to the nearby imine. The C N M R spectra of 26b-h are also consistent , 3  for a macrocyclic structure with a single imine resonance found between 161 and 163 ppm.  i—i—i—i—i—i—i—i—i—.—i—i—i—i—i—i—.—.—i—i—.—.—i—i—i—.—i—•—,—,—i—,—i  14  Figure 2.2  12  10  8  6  4  2  0  ppm  ' H N M R spectrum (300 M H z , CDC1 ) of 26f (* = CHC1 ). 3  45  3  References on page 92.  ' H N M R spectra of the macrocycles show water resonances between 1.9 and 2.5 ppm in CDCI3. The significant downfield shift from 1.5 ppm, the usual chemical shift of water in CDCI3, is indicative of hydrogen-bonding suggesting that macrocycles 26 may form supramolecular complexes with small, polar molecules. These  compounds  are  intensely  coloured, analogous  to porphyrins  and  phthalocyanines, but are not luminescent. In the solid-state, they appear deep red to 6  brown in colour and they absorb very strongly in the UV-visible region of the spectrum with peaks centred at ca. 400 nm (s ~ 8 x 10 mol L" cm" ). This intense transition is 4  1  1  primarily attributed to the n-n* transition of the conjugated ring. Crystals of macrocycle 26b were obtained from D M F and the single-crystal X-ray diffraction (SCXRD) confirms that the structure is a macrocycle (Figure 2.3). Moreover, the macrocycle is non-planar, as in the case of the related structure of macrocycle 25. The molecule is triangular  in shape, with the  apices  defined  by the three  diethyloxyphenylenediimine moieties. There are six hydroxyl groups within the molecule that are strongly hydrogen-bonded to the adjacent imines, with average intramolecular O—N distances of 2.60(4) A . Two sides of the macrocycle are twisted, with C - C - N = C  7  dihedral angles of ca. 39°, such that the catechol groups are twisted out of the plane of the macrocycle in opposite directions. The third side is nearly planar, with the catechol group only twisted slightly out of the plane. Intermolecular rc-stacking is apparent between the flat sides of the macrocycles in the solid-state, with nearest intermolecular separations of 3.59 A along the stacking axis. The macrocycles are arranged in layers, and stacked in a way that reveals a porous structure when viewed normal to the (100) axis, as shown in Figure 2.3c (the pores contain D M F solvent molecules removed for  46  References on page 92.  clarity). This result is in good agreement with other previously reported examples of Q porous crystalline structures based on shape-persistent macrocycles.  Figure 2.3  Molecular structure of macrocycle 26b as determined by single crystal X -  ray diffraction with thermal ellipsoids at 50% probability. Solvent molecules are removed for clarity. Red = oxygen, blue = nitrogen, (a) View from the top of the macrocycle showing strong intramolecular hydrogen-bonding, (b) View of macrocycle 26b from the side showing the non-planarity of the macrocycle (ethyloxy groups and hydrogen atoms are removed for clarity), (c) View of the packing diagram for macrocycle 26b normal to the (100) axis, revealing the stacking pattern for the pores.  47  References on page 92.  2.2.2  Self-Assembly  The macrocycle synthesis is remarkably efficient, and the [3+3] macrocycle is the major product obtained. As the preparation of macrocycle 26 depends on the assembly of six different components (three of the diformyl species, 29, and three phenylenediamine species, 33), it likely occurs stepwise through several intermediates. The previously published report of macrocycle 25 indicated observations of a 2:2 condensation product, formed from the reaction of two diformyl moieties and two phenylenediamine molecules, as well as a postulated oligomeric compound composed of three molecules of each of the starting materials, but where ring closing condensation has not occurred. Although these are sensible intermediates of the condensation process, such intermediates have not been isolated during the studies of related macrocycles 26 possessing alkoxy substituents. Other small fragments of these macrocycles, however, were isolated through variation of the reaction conditions. The difficulty encountered trying to isolate these fragments was that they tended to decompose or condense affording macrocycles during attempts to purify them by recrystallization or column chromatography. Thus, it was necessary to find conditions where the fragments were obtained in the highest possible purity directly from the reaction. When using longer alkoxy chains (10 or more linear carbon atoms) and keeping the reaction temperature between 0-25 °C, the major product observed is the 1:1 condensation product 34 consisting of one diformyl species and one diamine. The ' H N M R spectrum of 34i (R = "CuTfe, prepared using 33i) shows both a formyl and an imine peak (9.9 and 8.5 ppm, respectively) with the two phenolic proton resonances shifted downfield due to hydrogen-bonding with the imine nitrogen and with the formyl group (13.7 and 10.9 ppm, respectively). Most distinctive is the aromatic 48  References on page 92.  region of the spectrum with two doublets for the phenolic ring and two singlets for the diaminobenzene ring. The IR spectrum for compound 34i is similar to that of macrocycles 26b-h with the addition of an aldehyde C=0 stretch at 1686 cm" and amine 1  N - H stretches at 3390 and 3315 cm" . The UV-visible spectrum of this compound 1  contains three major peaks (304, 338, and 413 nm) and a broad shoulder (~460 nm) with an overall shape quite different from that of macrocycle 26. RO  34 (34i R = C H )  35 (35f R = C H )  n  14  Figure 2.4  36 (36i R = C H )  n  29  6  OR  n  13  14  Macrocycle intermediates (1:1 condensation product 34, 1:2 condensation  product 35, and 2:1 condensation product 36).  By performing the condensation reaction at room temperature and adjusting the stoichiometry appropriately a 1:2 condensation product (35) was obtained. The ESI-MS indicates that when diamine 33f is employed, pure product 35f is obtained, and the H !  N M R spectrum shows three singlets in the aromatic region rather than the two observed for the macrocycle. The IR spectrum shows both a C - N (1611 cm" ) stretch and N - H 1  stretches (3376, 3303, 3169 cm" ), with no evidence of any aldehyde C=0 stretches. The 1  UV-visible spectrum of 35f is similar to that of 33i at lower wavelengths (306 and 346  49  References on page 92.  29  nm) but is red shifted at higher wavelengths (468 nm) and different from that of macrocycle 26.  Scheme 2.4  Reaction of intermediates to form macrocycle 26.  26 To prove that compounds 34 and 35 are intermediate species in macrocycle formation, both were shown independently to form macrocycle 26 (Scheme 2.4). Compound 34i was heated in  CHCI3  forming macrocycle 26i as the major product (ca.  70% by 'Ft N M R ) , with a mixture of by-products including compound 37i (refer to Figure 2.6b for the structure of 37). When compound 35f was heated in  CHCI3 with  one  equivalent of 29, macrocycle 26f was produced (ca. 90% by H N M R ) as shown in l  50  References on page 92.  Scheme 2.4. The fact that 35 reacts in the presence of 29 to give macrocycle 26 indicates i that the reaction conditions allow for the hydrolysis of an imine bond in 35. Compound 36, formed by the reaction of diamine 33 with two equivalents of compound 29, is an intermediate that might be expected to form during the condensation. This species, however, has proven difficult to isolate. Only through reaction of excess diformyl dihydroxy benzene 29 (4-5 equivalents) with diamine 33i could this product be obtained (with an impurity of 29), as verified by ESI-MS. The *H N M R spectrum shows resonances attributed to an aldehyde, an imine, and three aromatic protons (two doublets and a singlet). In addition, the alkoxy OCH2 resonance, at ca. 4 ppm, appears as a welldefined triplet, indicative of a symmetrical environment for the phenylenediamine moiety. The isolation of compounds 34-36 in reactions of 29 with 33 suggests that the macrocycles are assembled stepwise. Either small oligomers form which eventually reach the correct length to cyclize into the [3+3] macrocycles or longer oligomers are first formed which hydrolyze until the correct length is achieved for cyclization. The isolated oligomeric compounds unsymmetrically  34-36 are also of interest  substituted  macrocycles  that  as precursors incorporate  to preparing two  different  phenylenediamine molecules. Such macrocycles may be assembled i f the rates of condensation and hydrolysis of the imines are significantly different, or i f the hydrolysis of the fragments is prevented by chelation to a metal. It is noteworthy that the [3+3] condensation product is the only species isolated without any observation of larger macrocycles or oligomers. Macrocycle 26 could be prepared in CHCI3, CHCls/MeCN, or in toluene, indicating that the solvent is likely not  51  References on page 92.  templating the, macrocycle formation. It has been proposed that the driving force for the formation of 25 is the insolubility of the macrocycle. To prove that this is not the case for macrocycle 26 with its alkoxy substituents, compounds 29 and 33f were reacted in CHCI3 under dilute enough conditions that the product did not precipitate. Upon rapid solvent removal, ' H N M R spectroscopy of the mixture indicated that the macrocycle 26f was the major species in solution. In the case of macrocycle 25, crystallization may indeed be a driving force since the product is much less soluble than macrocycles 26 and crystallizes more easily. In theory, the condensation of compounds 29 and 33 in a 1:1 ratio could form a [3+3] macrocycle, larger macrocycles, or linear (helical) oligomers and polymers. Macrocycle formation is favoured entropically over oligomers or helices but the formation of the [3+3] macrocycle is also enthalpically favoured as it minimizes strain and maximizes intramolecular hydrogen-bonding. Experimentally, the [3+3] macrocycle is a strongly favoured product and remains the major product even when trying to hinder macrocycle formation by the addition of a full equivalent of salicylaldehyde as a capping species to the preparation. Also, no evidence for tautomerism has been observed in any of the macrocycles 26b-h or the fragments 34-36.  2.2.3  Reactivity  Intermediates and by-products of the Schiff-base condensation reaction to form macrocycle 26 can provide insight into its reactivity. In the formation of macrocycle 26, the reaction generally proceeds smoothly to the final product. This is quite surprising since a wide variety of side reactions are possible. Phenylenediamines are known to 52  References on page 92.  undergo  various  reactions  with  benzimidazolines and benzimidazoles.  benzaldehyde,  including reactions  to  form  9  100 a)  1310  m/z  1325  1320  1315  J U UK 14 Figure 2.5  12  10  ppm  8  Bottom: ' H N M R spectrum (300 M H z , CDC1 ) of monoreduced 3  macrocycle 37f. Top: ESI mass spectra for the [M+H] ion in (a) macrocycle 26f and (b) +  monoreduced macrocycle 37f.  A deep red crystalline by-product (-10-20% by mass) was isolated by fractional crystallization from the crude reaction mixture of macrocycle 26f.  10  The ' H N M R  spectrum of this compound shows five imine (8-8.5 ppm) and six hydrogen-bonded phenol (11-15 ppm) resonances, as well as numerous aromatic protons (6.2-7.2 ppm),  53  References on page 92.  Figure 2.5. This is in contrast to macrocycle 26f, which shows only one imine resonance (8.5 ppm), one phenol O H (13.3 ppm), and two aromatic protons due to its average Dj/, symmetry. The *H and  1 3  C N M R spectra of this by-product show new peaks at 4.4 and  48.5 ppm, respectively, consistent with a C//2NH group.  Figure 2.6  (a) Molecular structure (from single crystal X-ray diffraction) of  monoreduced macrocycle 37f with H 0 coordinated in the centre (thermal ellipsoids 2  shown at 33% probability), (b) Monoreduced macrocycle 37 with one reduced imine group.  The IR spectrum of this by-product is very similar to that of 26f, showing an intense C=N stretch (1609 cm" ) and no carbonyl group. In addition, a new peak at 3605 1  cm" was observed and is characteristic of the N - H stretch for a secondary amine. ESI1  M S revealed the mass of this by-product to be greater than that of macrocycle 26f by 54  References on page 92.  exactly 2 a.m.u. Single crystal X-ray diffraction confirmed that the by-product was indeed a macrocycle and not an oligomeric compound, Figure 2.6. Together, the structural and spectroscopic data indicate the by-product to be monoreduced macrocycle 37f.  10  The crystal structure of 37f confirms that this by-product is cyclic, and shows that the compound is non-planar with a single molecule of water hydrogen-bonded to the centre of the macrocycle. It was impossible to identify exactly which imine was reduced due to disorder. The macrocycle appears to pack equally well with the imine or amine in any position as there is a plane of symmetry that runs through the molecule, reflecting one half of the macrocycle onto the other (i.e., the macrocycle appears more symmetrical due to disorder). The six hydroxyl groups of the macrocycle are tilted out of planarity with two of the dihydroxy components oriented upward, and the third downward relative to the centre of the macrocycle. Within the unit cell, the macrocycles are organized into planes, but the pores of the macrocycles are not aligned into channels It is not surprising that this macrocycle is non-planar. Even the fully conjugated macrocycle (with or without alkoxy groups) is non-planar as deduced by single crystal X •  35  ~~  ray diffraction. ' These macrocycles likely twist to relieve interatomic interactions within the macrocycle, but there may also be an electronic or solvent effect (i.e., due to the water molecule hydrogen-bonded in the centre). As imines are usually reduced using considerable pressures of hydrogen, or in the presence of a metal catalyst,  11  it was surprising to isolate the  unsymmetrical  monoreduced macrocycle 37f without the addition of any formal reducing agent or catalyst. Similar results, however, have been reported for Robson-type macrocycles such 55  References on page 92.  as 38. '  12 13  The condensation of a 2,6-diformylphenol with a diamine to form the fully-  conjugated organic macrocycle 38 is usually complicated by in situ reduction and yields mostly the partially reduced macrocycle 39, Scheme 2.5.  A few research groups have  studied these reduced products, but the reducing agent in these reactions is still disputed. '  Experiments have therefore been conducted on the larger macrocychc  system 26 to identify the in situ reducing agent involved and to investigate the reduction process itself.  12  Scheme 2.5  Synthesis of Robson-type macrocycle 38.  (minor)  (major)  Initially, it was postulated that either starting material 29 or 33 could serve as a reducing agent, forming a quinone or diimine, respectively. It has been postulated that the amine may be responsible for the in situ reduction observed in the synthesis of related 12b  macrocycle 38 forming direduced macrocycle 39.  The combination of equimolar  concentrations of compound 29 and macrocycle 26f in acid-free CHCI3 (dried with K2CO3)  produced no reaction. However, when using commercial 56  CHCI3,  which contains  References on page 92.  residual acid, results varied but most often a mixture of products was obtained (Scheme 2.6). 'PI N M R spectroscopy of such mixtures show the monoreduced macrocycle 37f and the 1:1 condensation product 34f. The reaction of diamine 33f with macrocycle 26f shows only a 1:2 condensation product 35f (and unreacted 33f) as shown in Scheme 2.6. There is no evidence by ' H N M R spectroscopy of monoreduced macrocycle 37f in both commercial and acid-free CHCI3 (even after reflux for 24 h). This suggests that neither 29 nor 33 is independently responsible for the reduction of 26. Compounds 34 and 35, which have been shown to be intermediates in the macrocycle formation but which may also form via hydrolytic fission of the macrocycle, could be independently prepared by the controlled reaction of 29 and 33 in the appropriate stoichiometry. 14  Scheme 2.6  Reactions of 29 and 33f with macrocycle 26f. acid-free C H C I  3  No Reaction  + 26f other commercial C H C I  QH  3  34f(R = C H ) n  6  RO  Nr^V ^ 1  RO  2  acid-free  CHCI3 or  commercial C H C I  RO  /=\  ^  3  13  HO  NH  OR /==< OH H N  2  2  35f(R = C H )  33f  n  6  13  Reaction of equimolar quantities of diformyl dihydroxy benzene 29 and diamine 33f in commercial CHCI3 at 50 °C afforded mostly monoreduced macrocycle 37f. In the 57  References on page 92.  presence of added macrocycle 26f, the major product was still monoreduced species 37f. As these reactions may involve formation of the 1:1 condensation product, compound 34i was combined with 26f at 50 °C and, after 7 h, the ' H N M R spectrum showed that 15  26f was consumed (>80%) with monoreduced macrocycle 37f as the major product. When the same three experiments were performed using acid-free CHCI3, no monoreduced product was observed. These results indicate that residual acid must be present in the reaction solvent for macrocycle reduction. Moreover, an intermediate condensation product (e.g., 34) needs to be present to permit the reduction. The formation of 37 proceeds slowly (days) in commercial CHCI3 from diformyl dihydroxy benzene 29 and diamine 33, but noticeably faster (hours) when acid is added. As macrocycle 26 forms quickly in solution, the acid may catalyze the hydrolysis of 26 to yield significant amounts of 34 that would not otherwise be present to allow for reduction. Unsyrnmetrical macrocycle 37f could be prepared in 53% yield by the addition of less than 5% j9-toIuenesulfonic acid to 29 and 33f in CHC1 , keeping the reaction 3  mixture at approximately 50 °C. Monoreduced macrocycles with different alkoxy substituents (e.g., 37d,e) could also be prepared by the same procedure, demonstrating the generality of this reaction. Alternatively, monoreduced macrocycle 37f could be obtained by the addition of less than 5% /Moluenesulfonic acid to macrocycle 26f in CHCI3; in this case, however, the reaction leads to a mixture of products and a lower yield of 37f. It has been postulated that a benzimidazoline may be involved in the formation of 39 12a, 13a j j  o w e v e r j  ft  w  a  s  n o  t believed that macrocycle 38 was being reduced, but rather  that 39 formed through recombination of reduced intermediates. It was reported that in  58  References on page 92.  the first step, the diformylphenol and o-phenylenediamine condense to form a. 1:1 condensation product. This species then undergoes disproportionation in the second step to yield a benzimidazole and a reduced 1:1 condensation product. In the final step, two reduced 1:1 condensation products combine to form direduced macrocycle 39. Although this does rationalize the formation of 39, it is not clear why a monoreduced macrocycle is not also obtained as a product. For the [3+3] macrocyclic system it is also likely that a benzimidazoline is responsible for the in situ reduction of macrocycle 26, but that the preformed macrocycle is being reduced directly. That is, macrocycle 37 is not assembled from reduced components but rather a benzimidazoline, 40, formed from the 1:1 condensation product 34, is responsible for the in situ reduction of macrocycle 26 affording monoreduced macrocycle 37. Benzimidazolines, generated in situ by the reaction of a diamine with an aldehyde, are known to be selective, mild reagents for reducing C=C bonds.  16  In the  reaction to form monoreduced macrocycle 37, benzimidazoline 40 is likely generated from 34, and reacts with macrocycle 26 to afford 37, yielding benzimidazole 41 as a byproduct, Scheme 2.7.  59  References on page 92.  Scheme 2.7  Proposed mechanism for the formation of 37 by in situ reduction of  macrocycle 26.  A deuterium labeling experiment was conducted to provide insight into the reaction mechanism. Diformyl dihydroxy benzene 29-rf^ with deuterium-labeled formyl groups and macrocycle 26f-</<s with deuterium-labeled imines were synthesized (Figure 2.7). When diformyl dihydroxy benzene 29-rf^ and phenylenediamine 33f were combined  60  References on page 92.  with a catalytic amount of acid and macrocycle 26f-</<{ in CDCI3, compound yH-d.7 was observed to be the major product by *H N M R spectroscopy within a few hours. The absence of a peak at 4.4 ppm in the ' H N M R spectrum, where the characteristic C//2NH resonance is observed in 37f, indicated that only deuterium atoms were on the methylene carbon of the reduced imine in Yl-dy. This suggests that the reduction does not involve H D formation.  RO  OR  RO  26f-£/  37f-d  6  Figure 2.7  OR  7  Compounds for deuterium labelling experiments.  A n experiment in which the O H and NH2 groups in 29 and 33f, respectively, were deuterated (by exchange with D2O) was also conducted. When treated with catalytic acid to generate 37f, the product showed no significant deuterium incorporation into the methylene adjacent to the amine as determined by *H N M R spectroscopy. This further confirms that regioselective H D transfer occurs during the reaction. Analogous to the reduction of C=C bonds,  16b  reduction may take place by either a  stepwise mechanism with hydride (H") transfer from the C - H of 40 followed by proton (H*) transfer from the N - H of 40, or by the concerted addition of H" and H 61  +  from  References on page 92.  benzimidazoline 40. Also, the acid catalyst may protonate the imine of 26 thereby y  promoting FT abstraction by the carbon adjacent to the iminium cation of 26.  17  A general  mechanism is shown in Figure 2.8 depicting the transfers necessary for this reduction to take place between macrocycle 26 and benzimidazoline 40. OR  HO  Figure 2.8  OH  Possible transition state for the reduction of macrocycle 26 (fragment  shown on top) by benzimidazoline 40 (below).  Supporting the proposed mechanism, benzimidazole 41 has been isolated from the /?-toluenesulfonic acid-catalyzed reaction of 29 with 33f. Its identity was verified by ESIM S and N M R experiments. Presumably, this fluorescent product is formed as a byproduct in the reduction of macrocycle 26f to afford 37f. While the isolation of benzimidazole 41 lends support to 40 being the reducing agent, it is possible that other condensation products are also responsible for the reduction. For example, a bis(benzimidazoline) formed from 35 may be involved, which after reduction of the macrocycle would yield compound 42 (Figure 2.9). There may also be oligomeric species that are involved but could not be isolated. The presence of these  62  References on page 92.  oligomeric species in reactions to form 37 is difficult to discern by H N M R spectroscopy due to the complexity of the spectrum of 37. However, ESI-MS analysis of a reaction mixture showed major peaks assigned to both benzimidazoles 41 and 42, providing evidence for the involvement of oligomeric species in the reaction (Figure 2.10). The same species (but with butyl substituents in the place of hexyl groups) were observed in the ESI mass spectrum of the crude reaction mixture to form 37d. The peak assigned to 42 in the mass spectrum is also observed as a fragment of both macrocycles 26f and 37f, but compound 41 is not.  18  The ESI-MS experiments indicate that 41 is present in the  crude reaction mixture and does not form during the isolation procedure. Efforts to isolate benzimidazoline 40 or benzimidazole 42 from the reaction mixtures have been unsuccessful. It has also not been possible to prepare 41 or 42 separately by oxidation (including the use of catalytic F e C ^ ) .  19  RO  OR  43 (43fR = C H ) n  6  Figure 2.9  13  Benzimidazoles formed from 35 and 36 producing 1:2 bis(benzimidazole)  42 and 2:1 benzimidazole 43 respectively.  63  References on page 92.  455.1  100  [41+H]  +  287.0  [37f+H]  +  1317.7  [26f+Na]  +  1337.6  |1338.6  [44+H]-  1339.6  [42+H]  +  743.3  1353.6  259.0 11354.6  [26f+K]  +  258.0  299.0 371.0  257.0 203.0 100  300  Figure 2.10  469.1  313.0[  JU*-  |1355.6  M4.3  460  1471.1 £ 500  [746.3 877.4893.4 ^ 3 589.1 659.2 589.1 600 760' 800 ' 900  1 0 4 3  .  3  1100  1181-5,205.5 12'00  1356.5 .  1300  - 1482.5 1400 1500 1 3 5 7  5  mlz '1600  ESI-MS of the crude reaction mixture of monoreduced macrocycle 37f.  The ESI mass spectrum of the crude reaction mixture in the preparation of monoreduced macrocycle 37f shows monoreduced macrocycle ([37f+H] ), conjugated +  macrocycle ([26f+Na] , [26f+K] ), benzimidazole ([41+H] ), and bis(benzimidazole) +  +  +  ([42+H] ) as the major species present in solution. The species [44+H] is observed in the +  +  ESI-MS spectra of macrocycles 26f and 37f, and appears to be formed by homolytic cleavage of C=N bonds which is a common fragmentation pathway for this macrocycle. A proposed structure of the fragment is shown in Figure 2.11. The peak at m/z = 455.1 a.m.u. corresponding to [41+H] is not a fragment observed for either macrocycles 26f or +  37f. 18  64  References on page 92.  13  44 Figure 2.11  Proposed structure of fragment 44 formed by homolytic cleavage in the  ESI mass spectrum. This is not to imply a precise structure for the fragment [44+H] , +  which may be different in the gas phase, but only to indicate the chemical composition.  Benzimidazole 41 is presumably formed from benzimidazoline 40, which is in equilibrium with 34, during the in situ reduction of macrocycle 26. Recent calculations indicate that the reaction to form a benzimidazoline from a 1:1 condensation compound (i.e., 34) should be endothermic.  12a  High temperature N M R experiments of 34 in C2D2CI4  and C2D2CL;/EtOH show no evidence for a benzimidazoline species. Similar experiments with the 1:2 condensation compound 35 failed to show any evidence for equilibrium with a bis(benzimidazoline). Either the equilibrium concentration of benzimidazoline is too low to detect by *H N M R spectroscopy, or the equilibrium is acid catalyzed (acid was not added to the reaction as this was shown previously to afford macrocycle 37). Remarkably, the reaction is selective and stops after monoreduction of the macrocycle. No polyreduced macrocycles were observed (*H N M R ) even after several days or under a variety of conditions. ESI-MS of the reaction mixture after nearly complete monoreduction seen by *H N M R spectroscopy shows only macrocycles 26f and 37f (plus benzimidazoles 41 and 42), with no further reduced products present (Figure 2.10). It was anticipated that the imines would be reduced non-selectively, especially those that are separated across the macrocycle, but this is not the case. After  65  References on page 92.  monoreduction, the macrocycle may be stabilized by additional hydrogen-bonding from the amine, or there may be stabilization from hydrogen-bonding solvent molecules (e.g., H2O) in the interior of the macrocycle. Interestingly, attempts to synthesize macrocycle 38 usually afford the direduced macrocycle 39, with no evidence of mono, tri, or fully reduced macrocycles (or other direduced isomers). This selectivity in the reduction of macrocyclic imines suggests that benzimidazolines may be mild and selective reducing agents for other imines. The driving force for the reduction of macrocycle 26 to monoreduced macrocycle 37 is likely the formation of a stable, aromatic benzimidazole. A related benzimidazole has been suggested as the driving force for the formation of 39. Macrocycle 26 with 48 71 electrons is not aromatic, so the reduction does not break aromaticity. The reduction may also afford a relief of strain from interatomic repulsion or torsions within the macrocycle to lead to a stable monoreduced product. It is very likely that" hydrogen-bonding to solvent or water trapped within the macrocycle plays a role in stabilizing the monoreduced macrocycle relative to the fully conjugated precursor. During attempts to prepare 2:1 condensation product 36 with hexyloxy substituents (i.e., 36f), a by-product was isolated in low yield. The M S of the new product shows the expected mass for 36f, but the ' H N M R spectrum shows two aldehyde groups, two OCH2 groups, no imine, and several aromatic peaks. The characterization data are consistent with benzimidazole 43. Compound 43 may be derived from the 2:1 condensation product 36 similar to the formation of 41 from 1:1 condensation product 34. It is noteworthy that the reaction of benzaldehyde with phenylenediamine leads to the formation of benzimidazoles without isolation of the imine. In the case of  66  References on page 92.  macrocycles 26 and 37, the hydroxyl groups likely stabilize the imine diminishing its tendency to cyclize.  2.2.4  Calculations  The experimental N M R spectra of macrocycle 26 show an average symmetry that corresponds to a planar macrocycle (D#, symmetry) in solution. A low-temperature ' H N M R experiment indicates that this symmetry is retained to below -85 °C. In the solidstate, however, the macrocycles appear to have a distortion in which the catechol moieties are all oriented out of the plane. To obtain a better understanding of their conformations and dynamics, computational studies of the macrocycles were undertaken. As a model, ab initio computations were performed on macrocycle 26a with peripheral methoxy substituents.  Geometry optimizations and frequency  performed in B3LYP/6-31G(d,p), after HFS/STO-3G and B3LYP/4-31G. ' 20  calculations were  a preliminary geometry  optimization in  No symmetry constraints were applied unless  21  indicated. Preliminary calculations starting with a near-planar conformation indicate that the macrocycle has two stable conformations, neither of which is flat (Figure 2.12). In the first conformation (A), the molecule has approximately C  s  symmetry, with the  phenylenediimine groups co-planar and all of the catechol moieties oriented out of the 99  plane, but with two up and one down.  The other conformation (B) has C3 symmetry V  and lies only 1.6 kcal/mol above the C isomer. Again, the O H groups of the catechol s  moieties are oriented out of the plane, but are all on the same side of the macrocycle. The  67  References on page 92.  planar configuration (Dj^ symmetry) of the macrocycle (forced with constraints) has an energy that is ca. 14.4 kcal/mol above the C isomer A . s  >  B * *  * *  * * •  * •* %  • * ** «  %.» * <  D Figure 2.12  Computed low energy conformations A - D for macrocycle 26a. Views of  the structures are shown from the top and side of the macrocycle, with hydrogen atoms omitted for clarity.  The absence of planarity in the macrocycle for conformations A and B is consistent with the solid-state structure obtained for 26b. It is not surprising that this  68  References on page 92.  macrocycle would be non-planar, since it is anti-aromatic, possessing 48 electrons in the closed rc-system of the large macrocycle. As a result of this anti-aromaticity, the macrocycle adopts a non-planar conformation that retains the planarity and aromaticity of the substituted benzene components that make up the macrocycle.  Figure 2.13  Three easy rotation axes for macrocycle 25.  In solution, the macrocycles appear to have Dj/, symmetry, indicating that the calculated structures must interconvert on the N M R timescale. The macrocycle has three easy rotation axes passing through the catechol units between imine carbon atoms, Figure 2.13. One possibility for interconversion between isomers A and B is via the rotation of one catechol group while the others remain stationary. To evaluate the energy profile for such a rotation, a relaxed rotation calculation using DFT was performed. Starting with the C3v isomer B, a catechol moiety was rotated about one of the easy axes of rotation shown in Figure 2.13. The dihedral angles of the two P h - N bonds (i.e., C-C-N=C) along the same side of the triangle were fixed in 10° intervals, and the structure was permitted to  69  References on page 92.  relax to the nearest local minimum energy for each position with this constraint. Figure 2.14 shows the relative calculated energy for the minimized structures as a function of dihedral angle. Most notably, there are four local minima, including two that had not been encountered before. The rotation scan revealed two local minima in which one catechol is directed away from the centre of the macrocycle. Figure 2.12 shows the macrocycle in each of these two new conformations (C and D).  o E "oi o o3 c  UJ  o >  •4—'  JJ o 01  40  80  120  160  200  240  280  320  360  Angle of Rotation (deg) Figure 2.14  Relaxed scan of rotation computed for macrocycle 26a. The angle of  rotation corresponds to the dihedral angle of the C - C - N = C bond. A dihedral angle of 0° indicates that the catechol undergoing rotation in 10° intervals is oriented toward the centre of the macrocycle; for a dihedral angle of 180°, the catechol is oriented away from the centre of the macrocycle.  70  References on page 92.  Overall, the calculated values of the bond lengths and angles for the conformations agree well with those deduced from the X-ray diffraction study of macrocycle 26b. Table 2.1 provides a comparison of the bond lengths measured and computed for the macrocycles. Typically, the bond lengths are within 0.1 A .  Table 2.1 Bond  Comparison of Selected Bond Lengths and Angles for the Macrocycles. Measured for 26b (SCXRD)  Computed for 26a (A)  Computed for 26a (C)  Computed for 26a (D )  C-N  1.415(6)A  1.403 A  1.400 A  1.408 A  C=N  1.284(6)A  1.294 A  1.295 A  1.300 A  C-OH  1.354(4) A  1.334 A  1.336 A  1.327 A  HOC=COH  1.402(4) A  1.424 A  1.422 A  1.424 A  C-CN  1.454(8) A  1.448 A  1.449 A  1.446 A  HO-C-COH  117.7(4)°  117.4°  117.4°  117.4°  C=N-C  121(1)°  121.6°  122.3 °  122.7°  N-C-CCOH  122(1)°  122°  122.3  123°  0  3h  For the macrocycles to interconvert between the local energy minima, they must surmount a barrier of only ca. 5 kcal/mol. At room temperature, the conformations may readily interconvert without actually passing through a flat conformation. Any catechol moiety may move to the other side of the macrocycle either by allowing the hydroxyl groups to pass through the centre of the ring, or alternatively to rotate outside of the ring (i.e., the aromatic protons moving through the centre). The latter motion, where the hydroxyl groups rotate outside of the centre of the macrocycle, has a lower energy 71  References on page 92.  barrier. These calculations are consistent with the experimental observation that the conformations cannot be resolved at -85 °C. Although the macrocycles appear in solution to have D h symmetry, they are in fact rapidly interconverting between the local energy 3  minima, and never have D H symmetry. 3  The computed structure C is not necessarily the global minimum structure. A l l possible conformations of the macrocycle have not been searched, however, enough possibilities have been investigated to suggest that this is likely close in energy and geometry to the global minimum. In the crystalline state, the conformation of macrocycle 26b most closely resembles the calculated structure A with approximately C symmetry. s  This agrees with calculations that this conformation should be stable. The influences of crystal packing, intermolecular interactions (e.g., rc-stacking), and solvent, likely affect the relative stability of this conformation over the calculated minimum of conformation C.  2.3  Conclusions  This chapter has described the convenient synthesis and characterization of discshaped, soluble macrocycles possessing peripheral alkoxy chains. The macrocycles are formed from the [3+3] Schiff-base condensation of a substituted phenylenediamine with 3,6-diformyl-l,2-dihydroxybenzene. Several oligomeric intermediates in the reaction, including 1:1, 1:2, and 2:1 condensation products have been isolated, providing evidence that the macrocycles are formed in a stepwise manner. Moreover, a single crystal X-ray diffraction study of the macrocycle with short peripheral alkoxy chains indicates that the  72  References on page 92.  macrocycle is nonplanar and organizes into a tubular structure in the solid-state. Density functional theory has been employed to understand the interconversion of the various conformations available to the macrocycle. A monoreduced macrocycle, isolated as a by-product, has also been investigated. Based on isolation of a benzimidazole species and deuterium labeling experiments, it has been determined that this compound is obtained by the reduction of the fully conjugated macrocycle with a benzimidazoline intermediate. This intermediate is generated in situ from the diformyl dihydroxy benzene and diamine starting materials. This discovery may shed light on the reduction of other Schiff-base macrocycles and may lead to improved synthetic  routes to  these compounds.  More  generally, in situ generation  of  benzimidazolines may offer a convenient, purely organic reducing agent for mild and selective reduction of imines.  2.4  2.4.1  Experimental  General  Diethyl ether, toluene, and dichloromethane were dried by passing over an activated alumina column. Chloroform and acetonitrile were dried over 3 A molecular sieves and degassed by sparging with N2 for 20 min. Acid-free, anhydrous chloroform was obtained by drying over anhydrous  K2CO3, followed  by vacuum transfer. 3,6-  Diformyl-l,2-dihydroxybenzene (29) and l,2-dialkoxy-4,5-diaminobenzene (33) were prepared by literature methods. '  3 4  and  1 3  C N M R spectra were recorded on either a  73  References on page 92.  Bruker AV-300 or AV-400 spectrometer. ' H and C N M R spectra were calibrated to the 1 3  residual protonated solvent at 8 7.24 and 8 77.00 ppm, respectively, in CDCI3.  C NMR  spectra were recorded using a proton decoupled pulse sequence. H M Q C and H M B C experiments were performed on a Bruker AV-400 spectrometer. UV-vis spectra were obtained on a Varian Cary 5000 UV-vis-near-IR spectrophotometer using a 1 cm quartz cuvette. IR spectra were obtained as K B r discs with a Bomems MB-series spectrometer. Electrospray ionization (ESI) mass spectra were obtained on a Micromass L C T time-offlight (TOF) mass spectrometer equipped with an electrospray ion source. The samples were analyzed in MeOHrCHCf? (1:1) at 100 u M . Flow rate: 20 p.L min" ; sample cone: 1  90 V ; source temperature: 120 °C; desolvation temperature: 120 °C. Elemental analyses (C,H,N) were performed at the U B C Microanalytical Services Laboratory. Melting points were obtained on a Fisher-John's melting point apparatus. Density-functional calculations 20 * were carried out on a Linux cluster of I B M machines with Intel Xeon processors Gaussian'03  21  package. Further details of the calculations, performed in collaboration  with Professor Alex Wang, have been published. 2.4.2  using  5  Procedures  Macrocycles 26b-i; General procedures. Under a nitrogen atmosphere, 6.0 mmol of the appropriate diaminobenzene 33 was dissolved in 60 mL of 1:1 degassed C H C l 3 : M e C N . 3,6-Diformyl-l,2-dihydroxybenzene 29 (1.0 g, 6.0 mmol) was added turning the solution from colourless to deep red. After heating at reflux (90 °C) for 2 h, the solution was cooled to room temperature, yielding red needles of 26. Macrocycle 26 was isolated on a  74  References on page 92.  Buchner funnel, washed with cold M e C N , and dried under vacuum. Macrocycles 26b and 26c were too insoluble to obtain a good  C N M R spectrum.  Data for Macrocycle 26b (R = C H ) . Yield: 77%. H N M R (300 M H z , CDC1 ) 6 n  !  2  5  3  13.27 (s, 6H, OH), 8.56 (s, 6H, CH=N), 6.98 (s, 6H, aromatic CH), 6.79 (s, 6H, aromatic CH), 4.14 (q, 12H, OCH ), 1.47 (t, 18H, CH Gtf ) ppm. UV-vis (CH C1 ) X 2  2  3  2  2  max  (e) =  402.5 (6.1 x 10 ) nm (L mol" cm" ). ESI-MS: m/z = 1017.7 [26b+K] . IR (KBr): v = 4  1  1  +  3442, 2979, 2932, 2885, 1605, 1515, 1492, 1468, 1416, 1374, 1298, 1260, 1218, 1189, 1104, 1039, 939, 821 cm" . Mp. > 270 °C. H R M S for 26b+H (C 4H 5N Oi ): 979.3878. 1  +  5  Found: 979.3889. Anal. Calc'd for 26b  (C54H54N6O12):  5  6  2  C, 66.25; H , 5.56; N , 8.58.  Found: C, 65.86; H , 5.64; N , 8.90.  Data for Macrocycle 26c (R = C H ) . Yield: 68%. H N M R (300 M H z , CDC1 ) 6 n  ]  3  7  3  13.35 (s, 6H, OH), 8.49 (s, 6H, CH=N), 7.01 (s, 6H, aromatic CH), 6.68 (s, 6H, aromatic CH), 3.95 (t, 12H, OCH ), 1.84 (m, 12H, CH ), 1.05 (t, 18H, CH CH ) 2  (CH C1 ) X 2  2  2  2  ppm. UV-vis  (s) = 403.5 (8.32 x 10 ) nm (L mol" cm" ). ESI-MS: m/z = 1063.6 4  max  3  1  1  [26c+H] , 1085.6 [26c+Na] . IR (KBr): v = 3442, 2961, 2932, 2876, 1610, 1515, 1492, +  +  1473, 1411, 1378, 1298, 1255, 1217, 1185, 1109, 1062, 1005, 967, 835, 788, 741 cm" . 1  Mp. > 270 °C. H R M S for 26c+H (C oH67N 0, ): 1063.4817. Found: 1063.4810. Anal. +  6  6  2  Calc'd for 26c2H 0 (C oH7oN 0,4): C, 65.56; H , 6.42; N , 7.65. Found: C, 65.61; H , 2  6  6  6.36; N , 8.06.  75  References on page 92.  Data for Macrocycle 26d (R = C H ) . Yield: 78%. n  4  1 3  9  C N M R (75.5 M H z , CDC1 ) 5 3  161.1, 150.7, 149.1, 135.1, 121.0, 120.7, 104.3, 69.4 (OCH ), 31.4 (CH ), 19.3 (CH ), 2  2  2  13.9 (CH ) ppm; ' H N M R (300 M H z , CDC1 ) 5 13.32 (s, 6H, OH), 8.49 (s, 6H, CrY=N), 3  3  6.98 (s, 6H, aromatic CH), 6.69 (s, 6H, aromatic CH), 4.00 (t, 12H, OCH ), 2  12H, CH ), 1.53 (m, 12H, CH ), 1.00 (t, 2  2  (CH C1 ) X 2  2  3  JHH  = 7.3 Hz, 18H, C H C # ) ppm. UV-vis 2  3  (e) = 403 (8.06 x 10 ) nm (L mol" cm" ). ESI-MS: m/z = 1147.8 [26d+H] , 4  max  1.83 (m,  1  1  +  1169.8 [26d+Na] . IR(KBr): v - 3442, 2956, 2932, 2871, 1610, 1515, 1487, 1472, 1383, +  1303, 1260, 1218, 1189, 1114, 1062, 1019, 1005, 972, 925, 879 cm" . Mp. > 270 °C. 1  H R M S for 26d+H ( Q ^ N e O ^ ) : +  1147.5756. Found: 1147.5740. Anal. Calc'd for  26dH 0 (C 6H8oN 0 ): C, 68.02; H , 6.92; N , 7.21. Found: C, 67.58; H , 6.90; N , 7.36. 2  6  6  13  Data for Macrocycle 26e (R = C H „ ) . Yield: 63%. C N M R (75.5 M H z , n  1 3  5  CDCI3)  5  160.5, 150.7, 149.1, 134.8, 121.2, 120.6, 103.5, 69.5 (OCH ), 29.0 (CH ), 28.2 (CH ), 2  22.6 (CH ), 14.1 (CH ) ppm; *H N M R (300 M H z , 2  3  CDC1 ) 3  2  5 13.20 (s, 6H, OH), 8.55 (s,  6H, CH=N), 6.98 (s, 6H, aromatic CH), 6.75 (s, 6H, aromatic CH), 4.02 (t, 12H, OCH ), 2  1.85 (m, 12H, CH ), 1.44 (m, 24H, CH ) 0.94 (t, 2  C H C i / ) ppm. UV-vis (CH C1 ) X  2  2  3  2  2  3  J  H H  3  J  H H  = 6.2 Hz,  = 7.1 Hz, 18H,  (s) = 404 (6.43 x 10 ) nm (L mol" cm" ). ESI-MS: 4  mm  2  1  1  m/z = 1232.0 [26e+H] ; 1254.0 [26e+Na] . IR (KBr): v = 3442, 2956, 2932, 2871, 1610, +  +  1515, 1496, 1468, 1421, 1378, 1303, 1260, 1218, 1189, 1109, 1005, 934, 840 cm" . Mp. 1  -270 °C (dec). H R M S for 26C+H+ ( C H 9 i N 0 , ) : 1231.6695. Found: 1231.6732. Anal. 72  6  2  Calc'd for 26e ( C H N O ) : C, 70.22; H , 7.37; N , 6.82. Found: C, 69.98; H , 7.32; N , 72  90  6  12  6.72.  76  References on page 92.  Data for Macrocycle 26f (R = C H i ) . Yield: 75%. C N M R (75.5 M H z , CDC1 ) 5 n  1 3  6  3  3  160.9, 150.7, 149.0, 135.0, 121.2, 120.7, 103.9, 69.6 (OCH ), 31.7 (CH ), 29.3 (CH ), 2  2  2  25.8 (CH ), 22.7 (CH ), 14.1 (CH ) ppm; *H N M R (300 M H z , CDC1 ) 5 13.23 (s, 6H, 2  2  3  3  OH), 8.54 (s, 6H, CH=N), 6.99 (s, 6H, aromatic CH), 6.73 (s, 6H, aromatic CH), 4.01 (t, 3  JHH  = 6.5 Hz, 12H, OCH ), 2  CH ), 0.91 (t,  3  2  J  H H  1.83 (m, 12H, CH ), 1.48 (m, 12H, CH ), 1.37 (m, 24H, 2  = 7.0 Hz, 18H, CH CH ) 2  3  2  ppm. UV-vis (CH C1 ) X 2  2  m a x  (s) - 404 (8.51 x  10 ) nm (L mol" cm" ). ESI-MS: m/z = 1315.9 [26f+H] ; 1337.9 [26f+Na] . IR (KBr): v 4  1  1  +  +  = 2953,2928, 2858, 1610, 1515, 1496, 1468, 1411, 1379, 1300, 1262, 1218, 1193, 1114, 1015, 836, 788, 699 cm" . Mp. -270 °C (dec). Anal. Calc'd for 26f ( C ^ H ^ N e O ^ ) : C, 1  71.21; H , 7.81; N , 6.39. Found: C, 70.98; H , 7.93; N , 6.59.  Data for Macrocycle 26g (R = C H , ) . Yield: 70%. C N M R (75.5 M H z , CDC1 ) 8 n  1 3  7  5  3  161.4, 150.6, 149.0, 135.0, 121.2, 120.7, 104.3, 69.6 (OCH ), 31.9 (CH ), 29.4 (CH ), 2  2  2  29.2 (CH ), 26.0 (CH ), 22.7 (CH ), 14.1 (CH ) ppm; H N M R (300 M H z , CDC1 ) 8 5  2  2  2  3  3  13.22 (s, 6H, OH), 8.55 (s, 6H, CH=N), 6.99 (s, 6H, aromatic CH), 6.73 (s, 6H, aromatic CH), 4.01 (t,  3  JRH  = 6.4 Hz, 12H, OCH ), 1.84 (m, 12H, CH ), 1.45 (m, 12H, CH ), 1.33 2  (m, 36H, CH ) 0.89 (t, 2  3  J  H H  2  2  = 6.6 Hz, 18H, C H C / / ) ppm. UV-vis (CH C1 ) X 2  3  2  2  max  (s) =  403.5 (8.19 x 10 ) nm (L mol" cm" ). ESI-MS: m/z = 1400.0 [26g+H] ; 1421.9 4  1  1  +  [26g+Na] . IR (KBr): v = 3541, 2951, 2926, 2869, 2855, 1610, 1518, 1494, 1469, 1415, +  1377, 1302, 1261, 1218, 1191, 1113, 1007, 925, 843, 792, 719 cm" . Mp. -270 °C (dec). 1  H R M S for 26g+H ( C ^ H ^ N e O ^ ) : 1399.8573. Found: 1399.8583. Anal. Calc'd for 26g +  ( C 4 H i N 0 , ) : C, 72.07; H , 8.21; N , 6.00. Found: C, 71.70; H , 8.20; N , 5.98. 8  14  6  2  77  References on page 92.  Data for Macrocycle 26h (R = C H i ) . Yield: 87%. n  8  7  1 3  C N M R (75.5 M H z , CDC1 ) 3  5 160.8, 150.7, 149.1, 135.0, 121.1, 120.7, 103.9, 69.6 (OCH ), 31.9 (CH ), 29.5 (CH ), 2  2  2  29.4 (CH ), 26.1 (CH ), 22.7 (CH ), 14.1 (CH ) ppm; "H N M R (300 M H z , CDC1 ) 8 2  2  2  3  3  13.28 (s, 6H, OH), 8.51 (s, 6H, Cft=N), 7.00 (s, 6H, aromatic CH), 6.70 (s, 6H, aromatic CH), 3.99 (t, J  = 6.3 Hz, 12H, OCH ), 1.83 (m, 12H, CH ), 1.48 (m, 12H, CH ), 1.29  3  H H  2  (m, 48H, CH ) 0.88 (t, J  = 6.8 Hz, 18H, CU CH )  3  2  2  H H  2  2  ppm. UV-vis (CH C1 ) X  3  2  2  max  (s) =  402.5 (8.44 x 10 ) nm (L mol" cm" ). ESI-MS: m/z = 1485.3 [26h+H] ; 1507.3 4  1  1  +  [26h+Na] . IR (KBr): v = 2955, 2952, 2855, 1611, 1517, 1497, 1468, 1426, 1377, 1299, +  1262, 1218, 1193, 1114, 1020, 801, 724, 663 cm" . Mp. -250 °C (dec). H R M S for 1  26h+Na ( C 9 C H +  12  13  8  126  N 0, 6  23 2  N a ) : 1506.9365. Found: 1506.9353. Anal. Calc'd for  2 6 h H 0 (C oH, N Oi3): C, 71.97; H , 8.59; N , 5.60. Found: C, 71.83; H , 8.56; N , 5.75. 2  9  28  6  Macrocycle 26f-</<$ (R = "CeHo). The deuterated macrocycle was synthesized in the same manner as macrocycle 26 with the use of diformyl dihydroxy benzene 29-d . A 2  deep red solid (25 mg, 0.01 mmol) was obtained in 47% yield.  Data for Macrocycle 26f-rf (R = C H ) . H N M R (300 M H z , CDC1 ) 8 13.4 (s, 6H, H n  !  6  6  13  3  bonded OH), 7.01 (s, 6H, aromatic CH), 6.63 (s, 6H, aromatic CH), 3.93 (t, 12H, OCH ), 2  1.80 (m, 12H, CH ), 1.46 (m, 12H, CH ), 1.35 (m, 24H, CH ), 0.91 (m, 18H, C H C / f ) 2  2  2  2  3  ppm. ESI-MS: m/z= 1321.2 [26f-d +H] . +  6  3,6-Diformyl-l,2-dimethoxybenzene (28). Under a nitrogen atmosphere, 10 mL of veratrole (27) (78.4 mmol) and 28 mL of tmeda (188 mmol) were added to 600 mL of dry  78  References on page 92.  ether. "BuLi (200 mL, 1.6 M in hexanes) was added dropwise turning the reaction mixture a cloudy off-white colour. After stirring for 20 h, the reaction mixture was placed in an ice/water bath and anhydrous D M F (27 mL, 353 mmol) was added dropwise turning the mixture to a milky white colour. The ice/water bath was removed and the mixture was stirred at room temperature for 1 h. Hydrochloric acid (400 mL, 6 M ) was added to the reaction and the product extracted with D C M . The combined organic fractions were dried over \MgSO4 and the solvent removed under vacuum to leave a transparent yellow oil. Pale yellow crystals were obtained from ether. Yield: 6.453 g (33 mmol, 43% yield).  Data for 3,6-Diformyl-l,2-dimethoxybenzene (28).  !  H N M R (300 M H z , CDC1 ) 5 3  10.44 (s, 2H, CH=0), 7.63 (s, 2H, aromatic CH), 4.06 (s, 6H, OCH ) ppm. EI-MS: m/z = 3  194 [28] . +  l,2-Dihydroxy-3,6-formylbenzene (29). Under a nitrogen atmosphere, 8.0 g (41 mmol) of 28 was dissolved in -200 mL of dry D C M cooled in an ice/water bath. BBr3 (17.5 mL, 185 mmol) was added turning the reaction red in colour. After stirring for 12 h at room temperature, the reaction was quenched with water and the product extracted from D C M . The combined organic fractions were dried over MgSOvj, filtered, and dried under vacuum to leave a yellow solid. Recrystallization from minimal D C M yielded yellow needles. Yield: 4.936 g (30 mmol, 73% yield).  79  References on page 92.  Data for 3,6-Diformyl-l,2-dihydroxybenzene (29). ' H N M R (300 M H z , CDC1 ) 5 3  10.87 (s, 2H, OH), 10.01 (s, 2H, CH=0), 7.26 (s, 2H, aromatic CH) ppm. EI-MS: m/z = 166 [29] . +  Diformyl dihydroxy benzene 29-d2. The diformyl dihydroxy benzene was prepared following literature procedures that involve a sequence of (a) lithiation of veratrole, (b) 3  quenching with D M F , (c) acid work-up, and (d) demethylation with BBr3, substituting DMF-tfV for D M F in the reaction. The ' H N M R spectrum and M S of the yellow crystals confirmed near 100% incorporation of D in the formyl groups.  Data for diformyl dihydroxy benzene 29-d . H N M R (300 M H z , CDC1 ) 5 10.9 (s, 2H, l  2  3  H-bonded OH), 7.24 (s, 2H, aromatic CH) ppm. EI-MS: m/z= 168 [29-d ] . +  2  1:1 Condensation Product 34. Compound 34 could only be isolated with long alkoxy chains as substituents; attempts to purify samples of 34 with shorter chains (e.g., 34f) were complicated by further condensation. Compound 34 with tetradecyloxy (O Ci4H29) n  chains was prepared as follows: At a temperature of 10 °C and under a nitrogen atmosphere, 3,6-diformyl-l,2-dihydroxybenzene 29 (60 mg, 0.36mmol) was dissolved in degassed acetonitrile and added dropwise to a degassed chloroform solution of 1,2bis(tetradecyloxy)-4,5-diaminobenzene 33i (160 mg, 0.3 mmol) immediately forming an orange precipitate. After the mixture was stirred for 1 h, the product was isolated by vacuum filtration under nitrogen to obtain 178 mg (0.2 mmol, 87% crude yield) of a deep red solid. This was stored under nitrogen and contained a small amount (-10 %) of the  80  References on page 92.  1:2 condensation product 35 as indicated by spectrometry.  H N M R spectroscopy and mass  Attempts to purify the product by recrystallization led to  further  condensation.  Data for Condensation Product 34i (R = C H ) . n  14  29  1 3  C N M R (75.5 M H z , CDC1 ) 5 3  196.0, 155.4, 151.9, 150.6, 149.4, 142.4, 137.6, 124.9, 123.8, 121.8, 121.3, 120.9, 105.4, 101.8, 71.1, 69.0, 31.9, 29.6, 29.3, 26.0, 22.6, 14.1 ppm; H N M R (300 M H z , CDC1 ) 5 ]  3  13.7 (s, 1H, 0//H-bonded to N), 10.9 (s, 1H, Of/H-bonded to O), 9.93 (s, 1H, CH=0), 8.54 (s, 1H, Gtf=N), 7.13 (d, 1H, aromatic CH), 7.04 (d, 1H, aromatic CH), 6.81 (s, 1H, aromatic CH), 6.32 (s, 1H, aromatic CH), 3.93 (m, 6H, OCH + N77 ), 1.77 (m, 4H, CH ), 2  2  2  1.45 (m, 4H, CH ), 1.24 (m, 40H, CH ), 0.86 (t, 6H, C H C / / ) ppm. UV-vis (CH C1 ) 2  2  2  3  2  2  ^max (e) = 413 (1.3 x 10 ), 3 3 8 (1.1 x 10 ), 303.5 (1.6 x 10 ) nm (L mol" cm" ). ESI-MS: 4  4  4  1  1  m/z = 681.5 [34i+H] . IR (KBr): v = 3390, 3315, 2918, 2852, 1686 (v =o), 1610 (v = ), +  c  c  N  1525, 1464, 1431, 1379, 1303, 1212, 1256, 1199, 1148, 10.01, 831, 779 cm" . Mp. -160 1  °C. H R M S for 34i+H (C 2H 9N 0 ): 681.5214. Found: 681.5206. +  4  6  2  5  1:2 Condensation Product 35f (R = "CgHu). Under an inert atmosphere of nitrogen, l,2-dihexyloxy-4,5-diaminobenzene 33f (186 mg, 0.6 mmol) was dissolved in a 1:1 mixture of C H C l / M e C N giving a clear solution. 3,6-Diformyl-l,2-dihydroxybenzene 29 3  (50 mg, 0.3 mmol) was added, turning the solution red. The solution was stirred at reflux (90°C) for 30 mins followed by solvent removal under reduced pressure. The product was recrystallized from a D C M / M e C N mixture to obtain 35f as an orange powder. Yield: 169 mg (0.23 mmol, 75% yield).  81  References on page 92.  Data for 1:2 Condensation Product 35f (R = C H , ) . n  6  3  1 3  C N M R (75.5 M H z , CDC1 ) 5 3  157.0, 151.2, 149.3, 142.3, 136.9, 126.0, 121.0, 120.9, 105.9, 102.0, 71.2, 69.1, 31.6, 31.5, 29.5, 29.1, 25.7, 22.6, 14.0 ppm; ' H N M R (300 M H z , CDC1 ) 5 13.5 (s, 2H, H 3  bonded OH), 8.53 (s, 2H, C//=N), 6.97 (s, 2H, aromatic CH), 6.80 (s, 2H, aromatic CH), 6.34 (s, 2H, aromatic CH), 3.94 (m, 12H, OCH + N# ),1-78 (m, 8H, CH ), 1.64 (m, 8H, 2  2  2  CH ), 1.33 (m, 16H, CH ), 0.89 (t, 12H, C H C / / ) ppm. UV-vis (CH C1 ) X 2  2  2  3  2  2  m a x  (s) =  467.5 (2.4 x 10 ), 346 (1.5 x 10 ), 306 (1.8 x 10 ) nm (L mol" cm" ). ESI-MS: m/z = 4  4  4  1  1  747.6 [35f+H] . IR (KBr): v = 3376, 3303, 3169, 2956, 2930, 2856, 1611 (v = ), 1501, +  c  N  1467, 1432, 1313, 1256, 1204, 1139, 1003, 940, 838, 813, 724 cm" . Mp. 173-176 °C. 1  Anal. Calc'd for 35f ( C 4 H N 0 ) : C, 70.74; N , 7.50; H , 8.91. Found: C, 70.59; N , 7.65; 4  66  6  6  H , 8.83. H R M S for 35f+tf (C 4H67N 0 ): 747.5074. Found: 747.5061. 4  4  6  2:1 Condensation Product 36i (R = Ci4H29). Under an atmosphere of nitrogen 160 mg n  (0.3 mmol) of diamine 33i and 100 mg (0.6 mmol) of diformyl dihydroxy benzene 29 were each dissolved in 5 mL of degassed CHCI3. The diamine solution was added dropwise to the diformyl dihydroxy benzene solution turning the solution first orange, then deep red. This was then stirred for 2h at room temperature. The solvent was removed in vacuo and the crude N M R showed >75% of the desired product by *H N M R . Attempts to obtain this species pure have not been successful. A similar reaction using 56 equiv. of diformyl dihydroxy benzene 29 has afforded 36i in -90% ( H N M R ) but as a l  mixture with the excess diformyl dihydroxy benzene.  82  References on page 92.  Data for 2:1 Condensation Product 36i (R = "C14H29). *H N M R (300 M H z , CDC1 ) 5 3  13.38 (s, 2H, OH), 10.52 (s, 2H, OH), 9.99 (s, 2H, CH=0), 8.60 (s, 2H, CH=N), 7.13 (d, 3  J  H  H  = 6.0 Hz, 2H, aromatic CH), 7.03 (d,  3  JHH  = 5.7 Hz, 2H, aromatic CH), 6.79 (s, 2H,  aromatic CH), 4.05 (t, 4H, OCH ), 1.84 (broad, 4H, CH ), 1.48 (broad, 4H, CH ), 1.24 2  (broad, 40H, CH ), 0.856 (t,  3  2  J  2  H  H  2  = 4.9 Hz, 6H, CH ) ppm; ESI-MS: m/z = 829.8 3  [36i+H] , 851.8 [36i+Na] . +  +  Monoreduced Macrocycle 37f (R = "CgHo). Under an atmosphere of nitrogen, compound 33f (186 mg, 0.6 mmol) and ca. 2-5 mol% /?-toluenesulfonic acid were dissolved in 20 mL of degassed CHCI3 to give a colourless solution. Compound 29 (100 mg, 0.6 mmol) was added, turning the solution deep red in colour. The mixture was stirred at 50 °C for 24 h, after which the solvent was removed by rotary evaporation. .'H N M R spectroscopy of the crude reaction mixture indicated that 37f was the major component, with a very small quantity of 26f present (less than 10%). ESI-MS of the crude reaction mixture confirmed that both 26f and 37f were present (as well as benzimidazoles 41 and 42), with no further reduction products (Figure 2.9). The product was recrystallized from C H C l / M e C N (ca. 1:5), yielding macrocycle 37f as a red/black 3  microcrystalline solid (141 mg, 53%).  Data for Monoreduced Macrocycle 37f (R = C H ) . n  6  13  1 3  C N M R (75.5 M H z , CDCI3) 5  161.1, 160.4, 159.8, 157.5, 156.8, 151.3, 150.6, 150.1, 149.8, 149.4, 149.3, 149.2, 149.1, 149.0, 148.9, 146.4, 140.6, 139.8, 135.8, 134.7, 134.1, 132.9, 127.2, 126.8, 121.9, 121.3, 121.1, 120.6, 120.4, 120.3, 119.6, 118.2, 106.3, 103.4, 102.8, 102.2, 101.2, 98.6, 71.3,  83  References on page 92.  69.5, 69.0, 48.5, 31.7, 31.6, 29.7, 29.5, 29.4, 29.3, 29.2, 25.8, 25.7, 25.6, 22.7, 14.0 ppm; ' H N M R (300 M H z , CDC1 ) 8 14.76 (s, 1H, H-bonded OH), 14.08 (s, 1H, H-bonded 3  OH), 13.48 (s, 1H, H-bonded OH), 13.26 (s, 1H, H-bonded OH), 13.25 (s, 1H, H-bonded OH), 11.35 (s, 1H, H-bonded OH), 8.45 (s, 1H, imine), 8.38 (s, 1H, imine), 8.31 (s, 1H, imine), 8.23 (s, 1H, imine), 8.09 (s, 1H, imine), 7.2 - 6.2 (m, 12H, aromatic protons), 4.40 (s, 2H, C# N), 4.1 - 3.7 (m, 12H, OCH ), 2.0 - 1.6 (m, 12H, CH ), 1,6 - 1.1 (m, 36H, 2  2  2  CH ), 1.0-0.85 (m, 18H, CH ) ppm. UV-vis (CH C1 ) X 2  3  2  2  (s) = 389 (5.0 x 10 ), 345 (4.6 4  max  x 10 ) nm (L mol" cm" ). ESI-MS: m/z = 1317.7 [37f+H] . IR (KBr): v = 3606, 3523, 4  1  1  +  3351, 2954, 2931, 2855, 1609 (v = ), 1519, 1499, 1471, 1420, 1379, 1364, 1259, 1215, c  N  1192, 1114, 1085, 1059, 1007, 946, 913, 842, 805, 725 cm" . Mp. -220 °C (dec). Anal. 1  Calc'd for 3 7 f H 0 (CygHioeNeOn): C, 70.14; N , 6.29; H , 8.00. Found: C, 70.07; N , 6.54; 2  H , 8.02. H R M S for 37f+H (C 8Hio N Oi ): 1317.7760. Found: 1317.7790. +  7  5  6  2  Compounds 37d,e were synthesized in an analogous manner using 33d,e in place of 33f.  Data for Monoreduced Macrocycle 37d (R = C H ) . Red crystals. Yield: 47%. H n  l  4  9  N M R (300 M H z , CDC1 ) 5 14.73 (s, 1H, H-bonded OH), 14.06 (s, 1H, H-bonded OH), 3  13.50 (s, 1H, H-bonded OH), 13.27 (s, 2H, H-bonded OH), 11.29 (s, 1H, H-bonded OH), 8.46 (s, 1H, imine), 8.38 (s, 1H, imine), 8.31 (s, 1H, imine), 8.22 (s, 1H, imine), 8.09 (s, 1H, imine), 7.1 - 6.3 (m, 12H, aromatic protons), 4.40 (s, 2H, C# N), 4.1 - 3.8 (m, 12H, 2  OCH ), 2.0-1.7 (m, 12H, CH ), 1.7-1.4 (m, 12H, CH ), 1.0 (m, 18H, CH ) ppm. UV-vis 2  2  (CH C1 ) X 2  2  2  (s) = 389 (4.3 x io ) nm (L mol" cm" ). ESI-MS: m/z = 1149.7 [37d+H] . 4  max  3  1  1  +  IR (KBr): v = 3433, 2956, 2933, 2871, 1610 (V =N), 1516, 1497, 1473, 1426, 1379, 1294, C  84  References on page 92.  1256, 1190, 1110, 1063, 1006, 954, 920 cm . Mp. -280 °C (dec). H R M S for 37d+H -1  +  ( C H i N 0 i 2 ) : 1149.5892. Found: 1149.5912. 66  8  6  Data for Monoreduced Macrocycle 37e (R = C H ) . Red crystals. Yield: -50%. H n  ]  5  n  N M R (300 MHz, CDC1 ) 5 14.75 (s, 1H, H-bonded OH), 14.09 (s, 1H, H-bonded OH), 3  13.49 (s, 1H, H-bonded OH), 13.28 (s, 1H, H-bonded OH), 13.27 (s, 1H, H-bonded OH), 11.25 (s, 1H, H-bonded OH), 8.47 (s, 1H, imine), 8.41 (s, 1H, imine), 8.31 (s, 1H, imine), 8.26 (s, 1H, imine), 8.13 (s, 1H, imine), 7.2 - 6.4 (m, 12H, aromatic protons), 4.40 (s, 2H, C / / N ) , 4.0 - 3.7 (m, 12H, OCH ), 2.0 - 1.6 (m, 12H, CH ), 1.6-1.3 (m, 24H, CH ), 1.0 2  2  2  (m, 18H, CH ) ppm. UV-vis (CH C1 ) X 3  2  2  2  (e) = 394 (5.2 x 10 ), 349 (4.6 x 10 ), -310 4  max  4  (shoulder) nm (L mol" cm" ). ESI-MS: m/z = 1233.7 [37e+H] . IR (KBr): v = 3601, 1  1  +  3524, 3390, 2953, 2934, 2859, 1609 (v = ), 1573, 1518, 1498, 1470, 1425, 1415, 1378, c  N  r-  1300, 1260, 1216, 1192, 1114, 1074, 1050, 1006, 988, 935, 889, 838, 780, 748, 716 cm" . 1  Mp. -220 °C (dec). Axial. Calc'd for 37e 1.5H 0 2  (C72H95N6O13.5):  C, 68.60; N , 6.67; H ,  7.60. Found: C, 68.58; N , 7.10; H , 7.47. H R M S for 37C+FT ( C H 9 3 N O i ) : 1233.6833. 72  6  2  Found: 1233.6851.  Benzimidazole 41e (R = "CsHn). This by-product of macrocycle reduction was obtained from the acid-catalyzed (-5% p-toluenesulfonic acid) reaction of equimplar amounts of 29 and 33e under a nitrogen atmosphere in  CHCI3  at 50°C. After stirring overnight the  monoreduced product was filtered and the filtrate was concentrated under vacuum to obtain an orange film. This was triturated with D C M to leave an orange film of pure benzimidazole 41e.  85  References on page 92.  Data for Benzimidazole 41e (R = C H ) . N  5  1 3  n  C N M R (75.5 MHz, DMSO-tf ) 8 191.2, 6  150.4, 149.0, 147.4, 146.9, 122.4, 117.8, 117.0, 115.2, 99.4 (broad), 68.9, 28.5, 27.8, 21.9,  13.9 ppm; ' H N M R (300 M H z , DMSO-d ) 5 13.5 (very broad peak, s, 2H, H 6  bonded OH), 10.30 (s, 1H, CH=0), 7.55 (dd, 2H, J = 0.28 Hz and J = 0.03 Hz, aromatic CH), 7.18 (s, 2H, aromatic CH), 4.01 (t, 4H, J = 0.02 OCH ), 1.75 (m, 4H, CH ), 1.40 (m, 2  2  8H, CH ), 0.90 (t, 6H, J = 0.02 C H C / / ) ppm. UV-vis (CH C1 ) X 2  2  3  2  2  = 375, 268 nm.  max  ESI-MS: m/z = 427.3 [41e+H] . H R M S for 41e+H ( C H 3 i N 0 ) : 427.2239. Found: +  +  24  2  5  427.2233.  Benzimidazole 43f (R = "C^Kis). During a reaction to synthesize the 2:1 condensation product 36f a very small amount of compound 43f was isolated as a by-product. Diformyl dihydroxy benzene 29 (5 equiv.) was added to a solution of diamine 33f and stirred at 50 °C overnight. The first fraction obtained was a crude mixture with the major product the anticipated 2:1 condensation product 36f (*H N M R ) . However, the second fraction, recrystallized from a mixture of DCM/EtOH (1:2), shows both benzimidazole 41f along with benzimidazole 43f as determined by *H N M R and ESI-MS.  Data for Benzimidazole 43f (R = C H ) . ' H N M R (300 MHz, CDC1 ) 5 9.89 (s, 1H, N  6  1 3  3  CH=0), 9.84 (s, 1H, CH=0), 7.30 (s, 1H, aromatic CH), 7.05 (d,  3  aromatic CH), 7.01 (d,  3  3  J  H  H  = 8.7 Hz, 1H, aromatic CH), 6.92 (d,  aromatic CH), 6.68 (s, 1H, aromatic CH), 6.39 (d, (s, 2H, C / / N H ) , 4.07 (t, 2  3  JHH  3  J  H  H  86  = 8.1 Hz, 1H,  J  = 8.4 Hz, 1H,  H  H  = 8.1 Hz, 1H, aromatic CH), 5.62  = 6.6 Hz, 2H, OCH ), 3.94 (t, 2  JHH  3  J  H  H  = 6.6 Hz, 2H, OCH ), 2  References on page 92.  1.83 (m, 4H, CH ), 1.47 (m, 4H, CH ), 1.33 (m, 8H, CH ), 0.884 (m, 6H, CH ) ppm. ESI2  2  2  3  M S : m/z = 605.3 [43f+H] . +  Test Reaction in  Competitive Macrocycle Formation in  the  Presence  of  Salicylaldehyde. Salicylaldehyde (65 uL, 0.6 mmol) was added to a solution of diamine 33f (186 mg, 0.6 mmol) in 10 mL of degassed 1:1 C H C l : M e C N . Diformyl dihydroxy 3  benzene 29 (100 mg, 0.6 mmol) was added, and the resulting deep red solution was heated to reflux at ca. 80 °C under N for 2 h. Upon cooling, a red precipitate formed. 2  This product was isolated on a Buchner funnel and was confirmed to be macrocycle 26f by ' H N M R spectroscopy. Yield: 140 mg (53%). The ' H N M R spectrum of the supernatant solution showed it to contain primarily salicylaldehyde, diamine 33f, and macrocycle 26f.  Test Reaction to Prove Crystallization is not Driving Force for Macrocycle Formation. Diformyl dihydroxy benzene 29 (100 mg, 0.6 mmol) and diamine 33f (186 mg, 0.6 mmol) were combined in a 250 mL Schlenk flask under N . The solids were 2  dissolved in 20 mL of degassed CHCI3, giving a red solution. After heating to reflux (~ 80 °C) for 2 h under N , the solution was cooled to room temperature. No solid 2  precipitated, so the solution was quickly reduced to dryness by rotary evaporation. The 'IT N M R spectrum of the residual solid indicated that it was mostly macrocycle 26f.  87  References on page 92.  NMR Experiments for Monoreduced Macrocycle Studies. A l l experiments were performed with -10 mg (0.008 mmol) of macrocycle or ~10 mg (0.06 mmol) of starting materials in 0.5 mL of CDCI3.  2.4.3  X-Ray Diffraction Studies  Measurements were made using a C C D area detector coupled with either a Bruker X 8 or a Pvigaku A F C 7 diffractometer with graphite monochromated MoKa radiation (X = 0.7107 A). The data were collected at a temperature of -100.0 + 0.1 °C Data were collected and integrated using either the Bruker S A I N T , d * T R E K 23  24  or TwinSolve  25  software package. The data was corrected for absorption effects using a multiscan method either S A D A B S  2 6  or CrystalClear . The data were corrected for Lorentz and 25  97  polarization effects. The structures were solved by direct methods using either SIR92 or SIR2002 and refined as full-matrix least-squares against | F | using SHELX -. A l l non28  2  29  30  hydrogen atoms were refined anisotropically. A l l hydrogen atoms involved in hydrogenbonding were located in difference maps, while all other hydrogen atoms were included in calculated positions but not refined. For solvent molecules that are disordered in multiple orientations, that could not be modeled adequately, the SQUEEZE  function in  ^9  PLATON  was used to adjust the data to account for residual electron density found  within lattice void spaces. X-ray Diffraction Study of 26b. Crystals of 26b suitable for X-ray diffraction were grown by vapor diffusion of ether into a solution of 26b in D M F . The material crystallizes with six molecules of D M F in the asymmetric unit. Four of these solvent 88  References on page 92.  molecules were found in difference maps and refined with little difficulty. Two of these molecules appear to be disordered in multiple orientations. As it was impossible to model these two molecules adequately, the SQUEEZE function in P L A T O N was used to adjust the data to account for residual electron density found within lattice void spaces. X-ray diffraction data shown in Table 2.2. Further crystallographic data has been published.  5  X-ray Diffraction Study of 37f. Crystals of 37f suitable for X-ray diffraction were grown by slow evaporation of a; CHCb/EtOH solution containing 37f. A l l of the nonhydrogen atoms of the central ring (including the coordinated water) were found and have sensible bonding distances and thermal parameters, but there is considerable disorder present in the peripheral alkoxy chains that was modeled. Due to disorder in the packing of the macrocycle, the reduced imine could not be identified (the only difference in the refinement being two attached H atoms). X-ray diffraction data shown in Table 2.2. Further crystallographic data has been published.  Table 2.2  10  X-ray diffraction data for compounds 26b and 37b. 26b  37bH 0 2  A. Crystal Data Empirical Formula  C72H96N12O18  C78H104N6O13  Formula Weight  1417.61  1333.67  Crystal Color, Habit  red, plate  red, block  89  References on page 92.  Crystal Dimensions (mm)  0.35x0.10x0.10  0.50x0.50x0.20  Crystal System  primitive  C-centred  Lattice Type  triclinic  monoclinic  Lattice Parameters  a= 10.3139(9) A b = 16.569(2) A c = 22.171(3) A a = 83.097(4)° p = 79.186(4)° y = 77.884(4)° V = 3625.7(7) A  a = 18.170(3) A b = 28.681(3) A c = 14.745(3) A a = 90° P= 104.00(1)° Y = 90° V = 7456(2) A  Space Group  P-l (#2)  C2/c (#15)  Z value  2  4  Dcalc  1.299 g/cm  Fooo  1512  p.(MoKa)  0.94 cm"  3  3  3  1.406 g/cm  3  2872 0.81 cm"  1  1  B. Intensity Measurements Diffractometer  Bruker X8 A P E X  Rigaku/AFC7 C  Radiation  MoKa (X = 0.71073 A)  MoKa $, = 71073 A)  Data Images  1794 exposures @30s  460 exposures @ 63 s  Detector Position  37.50 mm  38.82 mm  20max  50.3  49.96 °  No. of Reflections Measured  Total: 63763 Unique: 12828 (R = 0.040)  0  int  90  Total: 6270 Unique: 6270 (Rim = 0.0000)  References on page 92.  Corrections  Absorption T = 0.825 T = 0.991  Absorption T = 1.0000 T = 0.8268  m i n  m i n  m a x  m a x  C. Structure Solution and Refinement Structure Solution  Direct Methods (SIR92)  Direct Methods (SIR92)  Refinement  Full-matrix leastsquares on F  Full-matrix leastsquares on F  Function Minimized  Sw(Fo -Fc )  Ew(Fo -Fc )  Least Squares Weights w = l/(a (Fo )+(jtP) +yP)  x = 0.1405 y = 1.6429  x = 0.0558 y = 0.0000  Anomalous Dispersion  A l l non-hydrogen atoms  A l l non-hydrogen atoms  No. Observations (I>0.00a(I))  12828  6270  No. Variables  839  464  Reflection/Parameter Ratio  15.29  13.51  2  2  2  2  2  2  2  2  2  2  2  Residuals (refined on F , all 0.103; 0.243 data):Rl;wR2  0.2002; 0.3548  Goodness of Fit Indicator  1.09  1.019  No. Observations (I>2.00CT(I))  8654  6270  Residuals (refined on F): Rl;wR2  0.075; 0.227  Max shift/error in final cycle  0.000  Max. peak in final diff. map  1.68 e7 A  2  0.1115; 0.3079  0.000 3  0.622 e7 A Min. peak in final diff. map  -0.66 e7 A  3  3  -0.432 e7 A  91  3  References on page 92.  2.5  References  (1) Zhao, D.; Moore, J. S. Chem. Commun. 2003, 807. (2) Huck, W. T. S.; van Veggel, F. C. J. M . ; Reinhoudt, D. N . Reel. Trav. Chim. PaysBas, 1995,114, 273. (3) Akine, S.; Taniguchi, T.; Nabeshima, T. Tetrahedron Lett. 2001, 42, 8861. (4) Kim, D.-H.; Choi, M . J.; Chang, S.-K. Bull. Korean Chem. Soc. 2000, 21, 145. (5) Gallant, A . J.; Hui, J. K . - H . ; Zahariev, F. E.; Wang, Y. A . ; MacLachlan, M . J. J. Org. Chem. 2005, 70, 7936. (6)  Porphyrin Handbook; Kadish, K . M . ; Smith, K . M . ; Guilard, R., Eds.; Elsevier  Science: San Diego, 2003; Vol. 16. (7) Refer to Figure 2.12 to clarify the axes of rotation about which the catechol groups are twisted out of the plane of the macrocycle. (8) (a) Miiller, P.; Uson, I.; Hensel, V . ; Schluter, A . D.; Sheldrick, G. M. Helv. Chim. Acta. 2001, 84, 778. (b) Henze, O.; Lentz, D.; Schluter, A . D . Chem. Eur. J. 2000, 6, 2362. (c) Campbell, K . ; Kuehl, C. J.; Ferguson, M . J.; Stang, P. J.; Tykwinski, R. R. J. Am. Chem. Soc. 2002,124, 7266. (9) Smith, J. G.; Ho, I. Tetrahedron Lett. 1971, 3541. (10) Gallant, A . J.; Patrick, B. O.; MacLachlan, M . J. J. Org. Chem. 2004, 69, 8739. (11) Adams, J. P. J. Chem. Soc, Perkin Trans. 1 2000, 125. (12) (a) Borisova, N . E.; Reshetova, M . D.; Ustynyuk, Y . A . Russ. Chem. Bull., Int. Ed. 2004, 53, 181. (b) Tian, Y . ; Tong, J.; Frenzen, G.; Sun, J.-Y. J. Org. Chem. 1999, 64, 1442.  92  (13)  (a) Ustynyuk, Y . A . ; Borisova, N . E.; Nosova, V . M . ; Reshetova, M . D.;  Talismanov, S. S.; Nefedov, S. E.; Aleksandrov, G. A . ; Eremenko, I. L . ; Moiseev, I. I. Russ. Chem. Bull, Int. Ed. 2002, 51, 488. (b) Aguiari, A . ; Bullita, E.; Casellato, U . ; Guerriero, P.; Tamburini, S.; Vigato, P. A . Inorg. Chim. Acta 1992, 202, 157. (c) Brychcy, K.; Drager, K.; Jens, K.-J.; Tilset, M . ; Behrens, U . Chem. Ber. 1994,127, 1817. (d) Kumar, D. S.; Alexander, V . Inorg. Chim. Acta 1995, 238, 63. (e) Bowden, F. L . ; Ferguson, D. J. Chem. Soc, Dalton Trans. 1974, 460. (14) The 1:1 condensation product 34 containing both an amine and an aldehyde is quite reactive, readily undergoing condensation. Attempts to purify this compound with short alkoxy chains failed; 34 with short alkoxy chains (4, 5 and 6 carbon atoms) could be observed by ' H N M R spectroscopy but could only be isolated with long alkoxy chains (-12 or 14 carbon atoms). A s well, it always contained an impurity of -10% of compound 35 (confirmed by ' H N M R spectroscopy and MS). (15)  Due to the difficulty of purifying 34 with short alkoxy chains, 34i with  tetradecyloxy chains was used for these experiments. (16) (a) Chikashita, H . ; Nishida, S.; Miyazaki, M . ; Itoh, K . Synth. Commun. 1983, 13, 1033. (b) Chikashita, PL; Nishida, S.; Miyazaki, M . ; Morita, Y.; Itoh, K. Bull. Chem. Soc. Jpn. 1987, 60, 737. (c) Risitano, F.; Grassi, G.; Foti, F, Bilardo, C. Heterocycles 2001, 55, 1311. (d) Chikashita, PL; Morita, Y . ; Itoh, K . Synth. Commun. 1985,15, 527. (e) Itoh, K.; Ishida, FL; Chikashita, H . Chem. Lett. 1982, 1117; (17)  Lewis acids, such as [CpFe(CO)2(THF)]  +  coordinate to imines to generate  electrophilic iminium ions that react with nucleophiles. For example, see: Mayer, M . F.; Hossain, M . M . J. Org. Chem. 1998, 63, 6839.  93  (18)  Tandem mass spectrometry was used to verify the fragmentation pattern of  macrocycles 26f and 37f by M S . By analyzing the mass spectra of macrocycles 26 with various chain lengths the peaks are easily assigned. One fragment of [26f+H] and +  [37f+H] is a species with the same chemical composition as bis(benzimidazole) 42. +  Compound 41 is never observed as a fragment of [26f+X] or [37f+X] (X = H , Na, K , +  +  Rb,Cs). (19) (a) Coville, N . J.; Neuse, E. W. J. Org. Chem. 1977, 42, 3485. (b) Mackman, R. L . ; Hui, H . C ; Breitenbucher, J. G.; Katz, B . A . ; Luong, C ; Martelli, A . ; McGee, D.; Radika, K.; Sendzik, M . ; Spencer, J. R.; Sprengeler, P. A . ; Tario, J.; Verner, E.; Wang, J. Bioorg. Med. Chem. Lett. 2002,12, 2019. (20) Westgrid (UBC). (21) Frisch, M . J.; etal. Gaussian 03, Revision A.l. Gaussian, Inc., Pittsburgh PA, 2003 (22) In every stable conformation of the macrocycle, the phenylenediimine rings are coplanar, and these are referred to as the "plane of the macrocycle", although it is recognized that the macrocycle is not truly planar. (23) SAINT. Version 6.02. Bruker A X S Inc., Madison, Wisconsin, U S A (1999). (24) d*TREK. Area Detector Software. Version 7.11. Molecular Structure Corporation (2001). (25) CrvstalClear 1.3.5 SP2. Molecular Structure Corporation (2003). (26) S A D A B S . Bruker Nonius area detector scaling and absorption correction - V2.05, Bruker A X S Inc., Madison, Wisconsin, USA, (27) SIR92: Altomare, A.; Cascarano, M . ; Giacovazzo, C ; Guagliardi, A . J. Appl. Cryst. 1994, 26, 343.  94  (28) SIR2002: Burla, M . C ; Camalli, M . ; Carrozzini, B.; Cascarano, G. L.; Giacovazzo, C ; Polidori, G.; Spagna, R. J. Appl. Cryst. 2003, 36, 1103. (29) Least Squares function minimized: Ew(F ^-F 2)2 0  c  (30) S H E L X : Sheldrick, G. M . Programs for Crystal Structure Analysis (Release 97-2). University of Gottingen, Germany (1997). (31) SQUEEZE: Van der. Sluis, P.; Spek, A . L. Acta Crystallogr., Sect A 1990, 46,194. (32) P L A T O N , A Multipurpose Crystallographic Tool, Utrecht University, Utrecht, The Netherlands, A . L . Spek, (1998).  95  CHAPTER 3 Keto-Enol Tautomerism in Naphthalene-Based Macrocyclesf 3.1  Introduction  Conjugated macrocycles, such as porphyrins and phthalocyanines have been extended by replacing benzene rings with polyaromatic components in order to modify their electronic and optical properties. '  1 2  Macrocycles with free volume, such as  cyclodextrins, calixarenes, and resorcinarenes, have long been investigated as hosts for 3  4  5  supramolecular chemistry. The size, shape and chemical properties of the cavity within these molecules influences the guests to which they bind. Extending the cavity of the macrocycle and creating a deeper bowl, may enhance the binding affinity or selectivity of the macrocycle. For example, attaching a second row of linked aromatic moieties to the upper rim of the resorcinarene scaffold produces compounds with even deeper cavities.  6  These macrocycles can be used as templates for the formation of large crown ethers, as well as enzyme mimics and have been shown to self-assemble into molecular capsules.  7  f A version of this chapter has been published: Gallant, A . J.; Yun, M . ; Sauer, M . ; Yeung, C. S.; MacLachlan, M . J. "Tautomerization in Naphthalenediimines: A KetoEnamine Schiff Base Macrocycle" Org. Lett. 2005, 7, 4827. 96  References on page 122.  Figure 3.1  Structures of macrocycles 26 and 45.  Fully conjugated Schiff-base macrocycle 26 (Figure 3.1) with three N2O2 pockets and a crown ether-like interior has been synthesized, as discussed in Chapter 2. The crystal structure and calculations of this rigid macrocycle reveal that it is non-planar, with the macrocycle adopting an open-cavity structure similar to classical calixarenes. In an effort to expand these macrocycles and to modify their properties, the dihydroxybenzene rings in 26 were replaced with dihydroxynaphthalene rings to generate macrocycle 45 with increased aromatic exposure, retaining the hydroxy-imine functionality in the centre. The incorporation of naphthalene into Schiff-base macrocycles related to 26 has previously been investigated. However, it was necessary to utilize B a 9  2 +  as a template,  which could not later be removed. Moreover, the structural aspects of the macrocycle were not investigated.  97  References on page 122.  3.2  3.2.1  Results and Discussion  Synthesis and Characterization  The previously reported route to l,4-diformyl-2,3-dihydroxynaphthalene 48 was problematic  and  resulted  in  low  yields.  bis(hydroxymethyl)-2,3-dimethoxynaphthalene  10  9  With (46),  the  recent  report  of  1,4-  a simple route to 48  was  developed that could be scaled to multigram quantities (Scheme 3.1). Oxidation of 46 with pyridinium chlorochromate (PCC) yielded the diformyl species 47 (85%), which afforded compound 48 in 80%) yield after deprotection with BBr3. The structure of 48 was verified by single-crystal X-ray diffraction (SCXRD). Notably, the molecules assemble into a 1-D 7t-stacked assembly with a pitch of 1/3 and an average separation between the molecules of 3.356 A (Figure 3.2).  Scheme 3.1  Synthesis of the diformyl precursor 48.  98  References on page 122.  Figure 3.2  (a) Solid-state structure of 48 as determined by S C X R D . (b) 1 -D 7t-stacked  assembly of 48 showing the 1/3 pitch. Thermal ellipsoids are shown at 50% probability.  Reaction of compound 48 with phenylenediamine  33c  or 33e  afforded  macrocycles 45c and 45e as shown in Scheme 3.2. The product was remarkably soluble as compared to macrocycle 26, particularly when long alkoxy chains were employed. It was anticipated that the additional aromatic rings of 45 would render the macrocycle less soluble than 26, as polyaromatic hydrocarbons are known to be insoluble. The ' H N M R spectrum of this extended macrocycle shows the expected resonances for the macrocycle. However, the resonances assigned to the hydroxyl (15.5 ppm) and imine (9.5 ppm) groups are considerably shifted downfield relative to where they are observed in the spectrum for 26 (13.3 and 8.5 ppm, respectively). The naphthalene CO and imine C resonances are observed at  162.1 and 155.6 ppm, respectively, by  1 3  spectroscopy. For comparison, the imine C is observed at ca. 161 ppm in the  C NMR  1 3  C NMR  spectra of macrocycles 26d-h.  99  References on page 122.  Scheme 3.2  Synthesis of macrocycle 45.  CHCVMeCN, 12h, 80 °C, 30-50% yield  The mass spectra of macrocycles 45c,e show the expected mass for the [3+3] Schiff-base macrocycle. However, the IR and UV-vis spectra are substantially different for this new extended macrocycle as compared to macrocycle 26 (Figure 3.3) suggesting a fundamental difference between these two systems. A difference in the UV-visible spectrum is expected as macrocycle 45 has an extended conjugated system compared to that of macrocycle 26 which would result in a red shift, as is observed. The IR spectra are expected to be very similar as there should not be any fundamentally different stretching  100  References on page 122.  or bending modes. However, the overall shape of the fingerprint region is different with new peaks at 1551 and 1322 cm" . 1  a)  b) 70 -i  40 J  0.4 -,  , 1600  , 1400  , 1200  , 1 000  , 800  0.0 J  Wave number (cm" )  . 4 00  •— 500  Wavelength (nm)  1  Figure 3.3  , 300  (a) IR and (b) UV-visible spectra of macrocycle 26e (red) and macrocycle  45e (blue).  3.2.2  Model Compounds  To investigate further the differences between this new macrocycle 45 and the previously synthesized macrocycle 26, model compounds 49-51  were synthesized  (Scheme 3.3). The imine and hydroxyl resonances in the ' H N M R spectrum of 49 are comparable to those of macrocycle 26. Both the macrocycle and the model compound are unequivocally present as the enol-imine tautomer. The C O H resonance is observed at 150.7 and 150.3 ppm in the  C N M R spectra of 26 and 49, respectively.  The imine and hydroxyl resonances of compounds 50 and 51 are similar to those of macrocycle 45 rather than those of macrocycle 26, suggesting that it is the naphthalene unit responsible for the observed differences. It is possible that these differences arise from a keto-enol tautomerization. The  1 3  C N M R spectrum of the model compounds 50  101  References on page 122.  and 51 reveal the naphthalene CO resonance at 168.7 and 158.6 ppm, respectively. Although these resonances are shifted downfield relative to the typical position of a phenol (e.g., 154.9 ppm in 48), the assignment of enol-imine versus keto-enamine tautomer is ambiguous.  Scheme 3.3  Synthesis of model compounds 49-51 and the tautomers of compound 52  used for calculations.  52 (enol) a  52 (keto)  EtOH, 12h, 80 °C, 60-80% yield  102  References on page 122.  To obtain more accurate structural information, S C X R D was performed on both 50 and 51. The single crystal structure of 50 (Figure 3.4) reveals that the model compound is in the keto-enamine form in the solid-state at -100 °C. The naphthalene C - O bond lengths observed in the structure are characteristic of ketones rather than phenols and the C - N bond is elongated relative to that of a typical imine. Moreover, the hydrogen atoms involved in hydrogen-bonding are located on the nitrogen atoms rather than on the oxygen atoms. The structure of 51 (Figure 3.5) is also in agreement with the ketoenamine form.  02  Figure 3.4  01  Structure of compound 50 as determined by S C X R D .  (a) View  perpendicular to naphthalene ring, (b) View parallel to the naphthalene ring reveals 0 = C - C - C H torsions (dihedral angles of 0.7° and 4.8°). Thermal ellipsoids are shown at 50% probability.  103  References on page 122.  Figure 3.5  Structure of compound 51 as determined by S C X R D .  (a) View  perpendicular to naphthalene ring, (b) View parallel to the naphthalene ring reveals 0 = C - C - C H torsions (dihedral angles of 5.9° and 7.3°). Thermal ellipsoids are shown at 50% probability.  3.2.3  Investigations of Keto-Enol Tautomerization  To confirm that 50 and 51 were present as keto-enamine tautomers in the solidstate, ab initio DFT calculations were performed using compound 52 as an analogue of 50 and 51. Energy-minimized structures were determined using B 3 L Y P with a 631G(d,p) basis set. DFT calculations of compound 52 (keto) predict the bond lengths 11  and overall structure of the model compounds very well. Table 3.1 compares key bond lengths obtained from the crystal structures and calculations. Most bonds affected by the tautomerization agree with the calculated bond lengths for the keto isomer within error. These data show that the model compounds 50 and 51, which are structurally analogous to one side of the [3+3] Schiff-base macrocycle 45, are present mostly in the keto-  104  References on page 122.  enamine tautomer at -100 °C. Moreover, the DFT calculations predict that the keto tautomer 52 ( keto) is ca. 0.7 kcal/mol more stable than the enol tautomer 52 (enol) (0 K , vacuum);  Table 3.1 Bond  a b  Calculated and Measured Lengths of Selected Bonds (A). 50"  3  51"  52 (keto)  52 (enol)  c  c  C2-01  1.275(3)  1.261(7)  1.247  1.328  Cll-Nl  1.324(4)  1.33(1)  1.341  1.298  C4-C11  1.399(3)  1.39(1)  1.392  1.449  C1-C2  1.494(3)  1.510(6)  1.519  1.438  C2-C4  1.427(3)  1.428(9)  1.401  1.450  Labelling as in Figure 3.4 and Figure 3.5; averaged assuming mirror symmetry through naphthalene ring; S C X R D (-100 ° C ) ; Calculated B3LYP/6-31 G(d,p) c  To temperature  determine the extent of tautomerization in these systems a variable C N M R experiment was performed using model compound 50. The keto-  enol equilibrium for 50 is shown in Scheme 3.4, where the enol-imine isomer is depicted as A and the keto-enamine isomer as B . C N M R spectra were obtained at various , J  temperatures in CDCI3 and it was noted that the resonance assigned to the carbonyl/enol C (ca. 168 ppm) was temperature sensitive (Figure 3.6).  105  References on page 122.  Scheme 3.4  H CO-Hf 3  Keto-enol isomers of compound 50 (A = enol isomer, B = keto isomer).  y—N  7  y—\ N—<f HO OH  V-OCH3  N  H3CO—<f  V - NH  HN—<f O  A  B  50°C  I  40°C  I  30°C  J  20°C  I  10°C  I  o°c  I I  -10°C  -30°C  .  I  -40°C  1  -50°C  -,  p—,  180  V-OCH  O.  1  ,  ,  ,  1  175  .  .  ,  .  ,  170  ,_—,  ,  ,  ,  165  , _ ,  ,  ,  ,  ppm  1  Figure 3.6  C N M R spectra of 50 at varying temperatures (carbonyl/enol resonance).  106  References on page 122.  3  The theoretical chemical shift ( 1TC) of the C=0 resonance for 52 (keto) was determined to be 174 ppm (related to isomer B), and the shift of the C - O H resonance for 52 (enol) to be 153 ppm (related to isomer A). At a given temperature the equilibrium constant (K) can be determined by: K = —x  (3.1)  where x is the mole fraction of isomer A and l-x  the mole fraction of isomer B .  Assuming rapid equilibrium the observed chemical shift ( C b ) will be the weighted 13  0  S  average of the shifts for each isomer as follows: C =xA  + (l-x)B  u  obs  (3.2)  Equation (3.2) can be rearranged to give: C -B x=—— A-B 1 3  (3.3)  allowing for the determination of the equilibrium constant at different temperatures. -RlnK  = AH  f V  1 \  AS  (3.4)  J  Since at equilibrium equation (3.4) holds, a plot of -RlnK  versus 1/T at varying  temperatures should be linear with a slope of AH and an intercept of - AS. Such a linear plot was obtained for model compound 50 (Figure 3.7). From this linear plot the following thermodynamic parameters for the equilibrium of A and B in CDCI3 can be determined: AH= -11.8(6) kJ mol" AS= -30(2) J mol" K" 1  1  1  107  References on page 122.  -4  T  -6 -  -26 -I  .  1  ,  •  1  ,  ,  1  0.0030 0.0032 0.0034 0.0036 0.0038 0.0040 0.0042 0.0044 0.0046  1/T(K" ) 1  Figure 3.7  Plot of -RlnK vs. 1/T as determined by the V T C N M R experiment for 1 3  50 in CDC1 (R = 0.99 for best-fit line). 3  Based on these numbers, there is 22% of the enol isomer (isomer A ) present at room temperature and only 1% at -100 °C. This is, however, only an estimate and is based on two important assumptions: (1) the  1 3  C shift of the C = 0 / C - O H would be the  same in 52 and 50; and (2) the calculated values of the  C shifts are accurate. It is well-  known that the equilibrium constants for tautomerization are strongly solvent dependent. But, here the crystal structures are also able to depict almost exclusively the keto form of 50 and 51.  108  References on page 122.  Scheme 3.5  Tautomerization of macrocycle 45 between the enol-imine and keto-  enamine tautomers. The latter is more stable in the case of this naphthalene-based macrocycle. RO  OR  RQ  OR  These results suggest that the [3+3] Schiff-base macrocycle 45 is a mixture of tautomers, but predominantly the keto-enamine isomer at room temperature, Scheme 3.5.  Such tautomerization would break the conjugation in the macrocycle rendering it  more flexible and, thus, more soluble. This tautomerization breaks the conjugation in the macrocycle and renders it more flexible and, thus, more soluble. The formation of stable keto-enamines is a sufficient driving force to overcome the aromatic stabilization of the *  second ring in naphthalene.  13  It is therefore expected that any multiring system with two  enol/imine moieties on the same ring will undergo tautomerization to the keto-enamine form.  109  References on page 122.  3.3  Conclusions  New  naphthalenediimine  model  compounds  that  undergo  keto-enol  tautomerization have been studied. These compounds are the first naphthalene-based 1,4diimines to be structurally characterized in the keto-enamine form. A reversible Schiffbase condensation has been used to prepare a new [3+3] Schiff-base macrocycle incorporating naphthalene groups and it has been established that it is present mostly as the keto-enamine tautomer (ca. 88% at room temperature), exposing a hexaketo interior.  3.4  3.4.1  Experimental  General  Dichloromethane was dried by passing over an activated alumina column. Chloroform and acetonitrile were dried over 3 A molecular sieves and degassed by sparging with N for 20 min. l,4-Bis(hydroxymethyl)-2,3-dimethoxynapthalene (46),  10  2  l,2-alkoxy-4,5-diaminobenzenes (33c,e),  14  l,2-dihydroxy-3,6-diformylbenzene, ' and 8 15  A^-(fer/-butyloxycarbonyl)-l,2-diaminobenzene  16  were prepared by literature methods.  Other reagents were obtained from standard suppliers. ' H and C N M R spectra were 1 3  recorded on either a Bruker AV-300 or AV-400 spectrometer. recorded using a proton decoupled pulse sequence. ' H and  1 3  1 3  C N M R spectra were  C N M R spectra were  calibrated to the N M R solvent at 8 7.24 (residual CHC1 ) and 8 77.00 (CDC1 ), 3  3  respectively, in CDC1 and 8 2.50 (DMSO-d ) and 8 29.84 (DMSO-d ), respectively, in 3  5  6  DMSO-fifc- Carbonyl and vinyl peaks of all compounds were assigned through the use of  110  References on page 122.  13  C A P T and H M B C pulse sequences. UV-vis spectra were obtained on a Varian Cary  5000 UV-vis/near-IR spectrophotometer using a 1 cm quartz cuvette. IR spectra were obtained as K B r discs with a Bomems MB-series spectrometer. EI spectra were obtained using a double focusing mass spectrometer (Kratos MS-50) coupled with a M A S P E C data system with EI operating conditions of: source temperature 200 °C and ionization energy 70 eV. M A L D I - T O F mass spectra were obtained in a dithranol matrix (cast from THF) on a Bruker Biflex IV instrument where spectra were acquired in the positive reflection mode with delay extraction. Elemental analyses (C,H,N) were performed at the U B C Microanalytical Services Laboratory. Melting points were obtained on a FisherJohn's melting point apparatus.  3.4.2  Procedures  Macrocycle 45. Under a nitrogen atmosphere, l,4-diformyl-2,3-dihydroxynaphthalene (48) (150 mg, 0.69 mmol) and one equivalent of the appropriate l,2-dialkoxy-4,5diaminobenzene (33c or 33e) (0.69 mmol) were dissolved in 30 mL of degassed CHCI3 and stirred at reflux for 12 h. The solvent was then reduced to 5 mL and the product precipitated from 25 mL of M e C N to yield a deep red solid.  Data for macrocycle 45c. Yield: 46%. C N M R (75.5 M H z , DMSO-tfc) 5 162.0 ( C O ) , 1 3  155.6 (CH-NH), 148.8, 130.6, 126.1, 124.6, 121.0, 111.5, 104.6> 70.5, 22.2, 10.5 ppm; ' H N M R (300 M H z , DMSO-<4) 6 15.57 (b, 6H, N#), 9.58 (b, 6H C / / - N H ) , 8.38 (b, 6H, aromatic CH), 7.48 (b, 6H, aromatic CH), 7.39 (b, 6H, aromatic CH), 4.13 (b, 12H, OGH ), L79 (b, 12H, C//2CH3), 1.04 (b, 18H, C H C # ) ppm. U V - V i s (CH C1 ) A™* (e) 2  2  111  3  2  2  References on page 122.  = 441 (4.97 x 10 ), 319 (2.93 x 10 ), 233 (7.04 x 10 ) nm (L mol" cm" ). M A L D I - T O F 4  4  4  1  1  M S : m/z = 1213.8 [45c+H] , 1236.0 [45c+Na] ; 1251.9 [45c+K] . IR (KBr): v = 3431, +  +  +  2964, 2936, 2872, 1616, 1548, 1370, 1318, 1258, 1177, 1012, 807, 743, 694 cm" . Mp. > 1  270 °C. Anal. Calc'd for 45c4H 0 (C 2H oN Oi ): C, 67.27; N , 6.54; H , 6.27. Found: C, 2  7  8  6  6  67.37; N , 6.88; H , 6.08.  Data for macrocycle 45e. Yield: 31%. *H N M R (400 M H z , D M S O - ^ ) 5 15.61 (b, 6H, Nfl), 9.61 (b, 6H C / / - N H ) , 8.39 (b, 6H, aromatic CH), 7.52 (b, 6H, aromatic CH), 7.39 (b, 6H, aromatic CH), 4.16 (b, 12H, OCH ), 1.77 (b, 12H, CH ), 1.47 (b, 12H, CH ), 1.41 2  2  2  (b, 12H, C//2CH3), 1.04 (b, 18H, CU CH ) ppm. U V - V i s (CH C1 ) W 2  3  2  2  (e) = 446 (6.67 x  10 ), 3 1 6 (3.98 x 10 ) nm (L mol" cm" ). M A L D I - T O F - M S : m/z = 1382.6 [45c+H] , 4  4  1  1  +  1403.2 [45c+Na] ; 1419.2 [45c+K] . IR (KBr): v = 3435, 2956, 2936, 2867, 1615, 1551, +  +  1523, 1467,. 1422, 1382, 1322, 1261, 1217, 1181, 1088, 1020, 947, 806, 742, 585 cm" . 1  Mp. > 270 °C.  l,4-diformyl-2,3-dimethoxynaphthalene (47).  1,4-Bis(hydroxymethyl)-2,3-dimethoxy-  napthalene (46) (2.22 g, 9.1 mmol) was dissolved in 600 mL of dry dichloromethane and pyridinium chlorochromate (7.84 g, 36.4 mmol) was added slowly with stirring, resulting in a dark brown solution. Stirring was continued for 2h at room temperature. The solution was filtered through a plug of silica washing with dichloromethane to give a yellow solution. Rotary evaporation of the solid afforded 1.86 g (7.6 mmol, 84% yield) of yellow solid. Compound 47 could be purified further by vacuum sublimation.  112  References on page 122.  Data for 47.  1 3  C N M R (100.6 M H z , CDC1 ) 5 192.0, 158.2, 128.7, 128.5, 127.8, 124.8, 3  63.0 ppm; ' H N M R (400 M H z , CDC1 ) 8 10.83 (s, 2H, CH=0), 9.01 (dd, J 3  3  4  J  = 3.6 Hz, 2H, aromatic CH), 7.59 (dd, J 3  H H  = 6.6 Hz, J 4  H H  CH), 4.09 (s, 6H, O C / / 3 ) ppm. UV-vis (CH C1 ) X 2  2  H H  H H  = 6.4 Hz,  = 3.4 Hz, 2H, aromatic  (s) = 356 (8.7 x. 10 ), 264 (1.4 x 3  max  10 ), 227 (2.5 x 10 ) nm (L mol" cm" ). EI-MS: m/z = 244 [47] . IR (KBr): v = 3351, 4  4  1  1  +  3101, 2944, 2874, 2767, 1688, 1612, 1572, 1503, 1455, 1431, 1399, 1370, 1346, 1326, 1241, 1205, 1181, 1161, 1109, 1073, 1036, 1020, 883, 803, 771, 574, 513, 461 cm" . M p . 1  101-102 °C. Anal. Calc'd for 47 ( C H , 0 ) : C, 68.85; H , 4.95. Found: C, 68.45; H , 5.02. 14  2  4  l,4-Diformyl-2,3-dihydroxynaphthaIene (48). Under an atmosphere of nitrogen 1.77 g (7.25 mmol) of compound 47 was dissolved in 120 mL of dry dichloromethane and cooled in an ice/water bath. While stirring, BBr3 (3.1 mL, 32.6 mmol) was added, with the solution turning orange in colour. This solution was stirred for 12 h while slowly warming to room temperature. The reaction was quenched with water (50 mL) and the product was extracted with dichloromethane (3 x 50 mL). The combined organic fractions were dried over MgSC<4 then filtered. The solvent was removed by rotary evaporation to yield 1.25 g (5.75 mmol, 80% yield) of yellow solid. Compound 48 could be further purified by vacuum sublimation.  Data for 48.  I 3  C N M R (100.6 M H z , CDC1 ) 8 194.3, 154.9, 126.7, 126.1, 119.9, 115.3 3  ppm; ' H N M R (300 M H z , CDC1 ) 8 12.95 (s, 2H, H-bonded OH), 10.88 (s, 2H, CH=0), 3  8.37 (dd, J 3  = 6.4 Hz, J 4  H H  = 3.4 Hz, 2H, aromatic CH), 7.57 (dd, J 3  H H  = 6.4 Hz, J 4  H H  H H  =  3.3 Hz, 2H, aromatic CH) ppm. UV-vis (CH C1 ) ? w (s) = 388 (8.78 x 10 ), 227 (5.06 x 3  2  113  2  References on page 122.  10 ) nm (L mol" cm" ). EI-MS: m/z = 216 [48] . IR (KBr): v = 3302, 2360, 2348, 1680, 4  1  1  +  1640, 1603, 1555, 1515, 1446, 1410, 1374, 1305, 1225, 1016, 923, 855, 746, 661, 601, 512, 456 cm" . Mp. decomposition > 180 °C.  '  1  Synthesis  of model compounds  (49-51).  100 mg of either 3,6-diformyl-l,2-  dihydroxybenzene (29) or l,4-diformyl-2,3-dihydroxynaphthalene (48) was dissolved in 50 mL of EtOH to give a yellow solution. Two molar equivalents of the appropriate amine (either 4-methoxyaniline or iV-(fer?-butyloxycarbonyl)-l,2-diaminobenzene) was added, turning the solution deep red in colour. The mixture was stirred at reflux for 12h and, after cooling, an orange precipitate formed. The product was isolated by filtration and was dried under vacuum.  Data for 49. Yield: 82%.  1 3  C N M R (75.5 M H z , CDC1 ) 5 159.7 (CH=N), 159.2 3  (COCH3), 150.3 (C-OH), 141.0, 122.5, 120.9, 120.5, 114.7, 55.6 (CH ) ppm; ' H N M R 3  (300 M H z , D M S O - J ) 5 13.42 (s, 2H, OH), 8.97 (s, 2H, Ci/=N), 7.45 (d, 6  4H, aromatic CH), 7.20 (s, 2H, aromatic CH), 7.04 (d,  3  J  H  H  3  J  H  H  = 8.7 Hz,  = 8.7 Hz, 4H, aromatic CH),  3.80 (s, 6H, OCr7 ) ppm; • h N M R (400 M H z , CDCI3) 5 8.65 (s, 2H, CH=N), 7.38 (d, 3  3  JHH  = 8.4 Hz, 4H, aromatic CH), 7.12 (s, 2H, aromatic CH), 6.95 (d,  3  J  H  H  = 8.8 Hz, 4H,  aromatic CH), 3.83 (s, 6H, OCH ) ppm. UV-vis (CH C1 ) Vax (s) = 390 (4.37 x 10 ), 300 4  3  2  2  (1.08 x 10 ), 236 (2.76 x 10 ) nm (L mol" cm" ). EI-MS: m/z = 376 [49] . IR (KBr): v = 4  4  1  1  +  3447, 3033, 2924, 2843, 1733, 1612, 1580, 1548, 1435, 1362, 1322, 1306, 1246, 1205, 1165, 1105, 1024, 855, 835, 815, 791, 758, 694, 618, 570 cm" . M p . slow decomposition 1  114  References on page 122.  > 120 °C. Anal. Calc'd for 49  C, 70.20; N , 7.44; H , 5.36. Found: C, 70.24;  (C22H20N2O4):  N , 7.84; PL 5.42.  Data for 50. Yield: 63%.  1 3  C N M R (100.6 M H z , CDC1 ) 6 168.7 (C=0), 158.4 3  (COCH3), 150.8 (C=C-N), 135.5, 126.4, 124.3, 120.7, 119.2, 114.9, 109.8, 55.5 (CH ) 3  ppm; ' H N M R (400 M H z , CDC1 ) 5 15.68 (d,  3  3  Hz, 2H, C / / - N ) , 7.84 (dd,  3  J  H  = 6.2 Hz,  H  Hz, 4H, aromatic CH), 7.27 (dd, 3  J  H  H  3  J  H  H  4  J  H  J  H  = 7.2 Hz, 2H, Ntf), 9.02 (d,  H  3  J  H  H  = 7.6  = 3.4 Hz, 2H, aromatic CH), 7.33 (d, 8.8  H  = 6.0 Hz,  4  J  H  H  = 3.2 Hz, 2H, aromatic CH), 6.97 (d,  = 8.8 Hz, 4H, aromatic CH), 3.82 (s, 6H, O C / / 3 ) ppm. UV-vis (CH C1 ) K*x (e) = 2  2  459 (2.92 x 10 ), 303 (1.80 x 10 ), 243 (3.90 x 10 ) nm (L mof cm ). EI-MS: m/z = 426 4  4  4  1  4  [50] . IR (KBr): v = 3439, 3061, 3040, 2995, 2843, 1737, 1624, 1551, 1511, 1467, 1435, +  1403, 1322, 1298, 1254, 1189, 1125, 1028, 968, 823, 755, 694, 557 cm" . Mp. 243-257 °C 1  (dec). Anal. Calc'd for 50  (C26H22N2O4):  C, 73.23; N , 6.57; H , 5.20. Found: C, 73.20; N ,  6.88; H , 5.20:  Data for 51. Yield: 74%. C N M R (75.5 M H z , CDC1 ) 5 158.5 ( O O ) , 158.1 (C=C-N), 1 3  3  152.7 (C=0 - from boc), 136.7, 132.3, 128.2, 126.4, 125.3, 123.7, 120.5, 120.2, 119.1, l  112.6, 81.1(C-CH ), 28.3 (CH ) ppm; ' H N M R (400 M H z , CDC1 ) 8 14.65 (s, 2H, N#), 3  3  9.30 (s, 2H, C#-N), 8.15 (d, 4  JHH  3  J  3  H  H  = 8.0 Hz, 2H, aromatic CH), 8.10 (dd,  = 3.2 Hz, 2H, aromatic CH), 7.43 (dd,  CH), 7.32 (m, 2H, aromatic CH), 7.20 (d,  3  J  H  J H  3  H  H  = 6.4 Hz,  3  J  H  = 6.4 Hz,  H  = 3.2 Hz, 2H, aromatic  ' JHH 4  = 8.0 Hz, 2H, aromatic CH), 7.14 (m, 2H,  aromatic CH), 7.06 (s, 2H, N # - from W ) , 1.51 (s, 18H, CC# ) PPm. UV-vis (CH C1 ) 3  2  2  ^max (e) = 439.5 (2.77 x 10 ), 271 (2.40 x 10 ), 237.5 (6.25 x 10 ) nm (L mol" cm" ). EI4  4  115  4  1  1  References on page 122.  M S : m/z = 596 [51] . IR (KBr): v = 3451, 3033, 2984, 2928, 2856, 1729, 1620, 1600, +  1548, 1515, 1491, 1451, 1370, 1326, 1250, 1157, 1052, 1028, 747, 698 cm" . Mp. 2001  230 °C (dec). Anal. Calc'd for 51  (C34H36N2O6):  C, 68.44; N , 9.39; H , 6.08. Found: C,  68.05; N , 9.56; H , 6.18.  3.4.3  X-Ray Diffraction Studies  Measurements were made using a C C D area detector coupled with either a Bruker X 8 or a Rigaku AFC7 diffractometer with graphite monochromated MoKa radiation (k = 0.7107 A ) . The data were collected at a temperature of -100.0 + 0.1 °C Data were 17  1R  collected and integrated using either the Bruker SAINT , d*TREK  1Q  or TwinSolve  software package. The data was corrected for absorption effects using a multiscan method either S A D A B S or CrystalClear . The data were corrected for Lorentz and 2 0  19  91  polarization effects. The structures were solved by direct methods using either SIR92 or 99  SIR2002  9 91  94  and refined as full-matrix least-squares against |F | using S H E L X . A l l non-  hydrogen atoms were refined anisotropically. A l l hydrogen atoms involved in hydrogenbonding were located in difference maps, while all other hydrogen atoms were included in calculated positions but not refined. For solvent molecules that are disordered in •  9S  multiple orientations, that could not be modeled adequately, the SQUEEZE  function in  9f*  PLATON  was used to adjust the data to account for residual electron density found  within lattice void spaces.  116  References on page 122.  X-ray Diffraction Study of 48. Crystals of 48 suitable for X-ray diffraction were grown from C H 2 C I 2 . X-ray diffraction data shown in Table 3.2. Further crystallographic data has *  been published.  12  X-ray Diffraction Study of 50. Crystals of 50 suitable for X-ray diffraction were grown by slow evaporation of a concentrated solution of 50 in EtOH. X-ray diffraction data shown in Table 3.2. Further crystallographic data has been published.  X-ray Diffraction Study of 51. Crystals of 51 suitable for X-ray diffraction were grown by slow evaporation of a concentrated solution of 51 in EtOH. X-ray diffraction data shown in Table 3.2. Further crystallographic data has been published.  Table 3.2  X-ray diffraction data for compounds 48, 50 and 51. 48  50  51  A. Crystal Data Empirical Formula  C12H8O4  C26H22N2O4  C 8H48N 0  Formula Weight  216.18  426.46  688.80  Crystal Color, Habit  yellow, prism  orange, prism  red, needle  Crystal Dimensions (mm)  0.50x0.25x0.17  0.50x0.30x0.25  0.35x0.07x0.03  Crystal System  primitive  primitive  primitive  Lattice Type  orthorhombic  monoclinic  triclinic  117  3  4  8  References on page 122.  Lattice Parameters  a = 10.126(5) A b = 14.618(5) A c = 18.704(5) A a = 90° P = 90° y = 90° V = 2768.6(18) A  3  a= 11.649(5) A b = 7.4767(16) A c =-23.829(8) A a = 90° P= 103.823(13)° Y = 90° V = 2015.2(12) A  3  a= 11.0671(13) A b = 11.9912(12) A c = 14.8146(15) A a = 101.064(5)° P = 93.762(4)° Y = 95.581(4)° V = 1913.16(53) J  Space Group  Pccn (#56)  P21M (#14)  P-l (#2)  Z value  12  4  2  Dcalc  1.556 g/cm  Fooo  1344  |i(MoKa)  1.18 cm"  3  1.406 g/cm  3  896 0.96 cm"  1  1.196 g/cm  3  736 0.84 cm"  1  1  B. Intensity Measurements Diffractometer  Bruker X8 A P E X  Bruker X8 A P E X  Bruker X8 A P E X  Radiation  MoK« fX = 0.71073 A)  MoKa (k = 0.71073 A)  MoKa (k = 0.71073 A)  Data Images  879 exposures @ 12 s .  1125 exposures @45 s  1400 exposures @60s  Detector Position  37.83 mm  37.97 mm  37.91 mm  20max  52.98 °  50.10°  43.02 °  No. of Reflections Measured  Total: 8268 Unique: 5263 (R , = 0.0542)  Total: 21437 Unique: 3569 (R = 0.0456)  Total: 23286 Unique: 4922 (R = 0.1550)  Absorption T = 0.613 T x = 0.980  Absorption T = 0.861 T = 0.976  Absorption T „ = 0.751 T = 0.997  in  Corrections  m i n  m a  118  int  m i n  m a x  int  m)  m a x  References on page 122.  C. Structure Solution and Refinement Structure Solution  Direct Methods (SIR92)  Direct Methods (SIR2002)  Direct Methods (SIR2002)  Refinement  Full-matrix leastsquares on F  Full-matrix leastsquares on F  Full-matrix leastsquares on F  Function Minimized  2w(Fo -Fc )  Ew(Fo -Fc )  Zw(Fo -Fc )  Least Squares Weights w = l/(a (Fo )+(xP) +^P)  x = 0.0474 ^ = 0.0000  x = 0.0558 y = 0.0000  x = 0.0489 y = 0.0000  Anomalous Dispersion  A l l non-hydrogen atoms  A l l non-hydrogen atoms  A l l non-hydrogen atoms  No. Observations (J>0.00a(I))  8268  21437  23286  No. Variables  266  377  611  Reflection/Parameter Ratio  31.08  56.86  38.11  Residuals (refined on F , all data): R l ; wR2  0.1243; 0.1075  0.0765; 0.0995  0.2010; 0.1372  Goodness of Fit Indicator  0.683  0.990  0.957  No. Observations (I>2.00ct(I))  5263  3569  4922  Residuals (refined on F): R l ; wR2  0.0435; 0.0981  0.0385; 0.0857  0.0596; 0.0996  Max shift/error in final cycle  0.000  -0.000  -0.024  Max. peak in final diff. map  0.151 e 7 A  Min. peak in final diff. map  -0.275 e7 A  2  2  2  2  2  2  2  2  2  2  '  2  0.161 e"/A  3  3  119  2  0.187 e7 A  3  -0.204 e7 A  2  2  3  2  2  3  -0.188 e"/A  3  References on page 122.  3.4.4  Computational Studies  A n ab initio study was performed to establish whether structures of compounds 50 and 51 determined from single crystal X-ray diffraction studies were consistent with the enol-imine or keto-enamine tautomer. In addition, it was hoped that the calculations would help establish which isomer is likely to be most stable. Ab initio DFT calculations were performed on a PC with a dual Xeon 2.80 GHz (1 GB R A M ) using Spartan '04 for Windows.  11  Both the keto and enol isomers of 52 were geometry minimized using  B 3 L Y P with a 6-31G(d,p) basis set. For each molecule, the calculation was started with different possible orientations of the peripheral benzene rings until the minimum energies were determined. Although it is not known for certain that the geometries are the absolute minima, they are likely very close. Bond lengths and bond angles of both 50 and 51 agree closely with the calculated structure of 52 (keto), which is the more stable tautomer (0 K , vacuum).  Energies of B3LYP/6-31G(d,p) minimized structures: 52 (enol)  E = -1185.3867337 Hartree  52 (keto)  E =-1185.3878286 Hartree  120  References on page 122.  Figure 3.8  Calculated structure of 52 (enol) as viewed from (a) the top and (b) the  side.  Figure 3.9  Calculated structure of 52 (keto) as viewed from (a) the top and (b) the  side.  121  References on page 122.  3.5  References  (1) Manley, J. M . ; Roper, T. J.; Lash, T. D. J. Org. Chem. 2005, 70, 874. (2)  (a) Vagin, S.; Hanack, M . Eur. J. Org. Chem. 2003, 2661. (b) Kobayashi, N . ;  Nakajima, S.-L; Ogata, H.; Fukuda, T. Chem. Eur. J. 2004,10, 6294. (3) Harada, A . Acc. Chem. Res. 2001, 34, 456. (4) (a) Ikeda, A.; Shinkai, S. Chem. Rev. 1997, 97, 1713. (b) Gutsche, C. D. Acc. Chem. Res. 1983,16, 161. (5) (a) Moran, J. R.; Karbach, S.; Cram, D. J. J. Am. Chem. Soc. 1982, 104, 5826. (b) Rudkevich, D. M . ; Rebek, J., Jr. Eur. J. Org. Chem. 1999, .1991. (c) MacGillivray, L . R.; Atwood, J. L. Nature 1997, 389, 469. (6) Gibb, C. L . D.; Stevens, E. D.; Gibb, B. C. J. Am. Chem. Soc. 2001,123, 5849. (7) (a) L i , X . ; Upton, T. G.; Gibb, C. L . D.; Gibb, B . C. J. Am. Chem. Soc. 2003, 125, 650. (b) Laughrey, Z. R.; Gibb, C. L. D.; Senechal, T.; Gibb, B . C. Chem. Eur. J. 2003, 9, 130. (c) Gibb, C. L. D.; Gibb, B. C. J. Am. Chem. Soc. 2004,126, 11408. (8) Gallant, A . J.; Hui, J. K . - H . ; Zahariev, F. E.; Wang, Y . A.; MacLachlan, M . J. J. Org. Chem. 2005, 70, 7936. (9) Huck, W. T. S.; van Veggel, F. C. J. M . ; Reinhoudt, D. N . Reel. Trav. Chim. PaysBas, 1995,114, 273. (10) Tran, A . H.; Miller, D. O.; Georghiou, P. E. J. Org. Chem. 2005, 70, 1115. (11) Spartan '04 (Wavefunction: Irvine, CA). (12) Gallant, A . J.; Yun, M . ; Sauer, M . ; Yeung, C. S.; MacLachlan, M . J. Org. Lett. 2005, 7, 4827.  122  (13) (a) Fabian, W. M . F.; Antonov, L.; Nedeltcheva, D.; Kamounah, F. S.; Taylor, P. J. J. Phys. Chem. A 2004, 108, 7603. (b) Ohshima, A . ; Momotake, A . ; Arai, T. J. Photochem. Photobiol, A 2004,162, 473. (14) Kim, D.-H.; Choi, M . J.; Chang, S.-K. Bull. Korean Chem. Soc. 2000, 21,145. (15) Akine, S.; Taniguchi, T.; Nabeshima, T. Tetrahedron Lett. 2001, 42, 8861. (16) Seto, C. T.; Mathias, J. P.; Whitesides, G. M . J. Am. Chem. Soc. 1993,115, 1321. (17) SAINT. Version 6.02. Bruker A X S Inc., Madison, Wisconsin, U S A (1999). (18) d*TREK. Area Detector Software. Version 7.11. Molecular Structure Corporation (2001). (19) CrvstalClear 1.3.5 SP2. Molecular Structure Corporation (2003). (20) S A D A B S . Bruker Nonius area detector scaling and absorption correction - V2.05, Bruker A X S Inc., Madison, Wisconsin, U S A . (21) SIR92: Altomare, A.; Cascarano, M . ; Giacovazzo, C ; Guagliardi, A . J. Appl. Cryst. 1994, 26, 343. (22) SIR2002: Burla, M . C ; Camalli, M . ; Carrozzini, B.; Cascarano, G. L.; Giacovazzo, C ; Polidori, G.; Spagna, R. J. Appl. Cryst. 2003, 36, 1103. (23) Least Squares function minimized: £ w ( F - F 2 ) 2 2  0  c  (24) S H E L X : Sheldrick, G. M . Programs for Crystal Structure Analysis (Release 97-2). University of Gottingen, Germany (1997). (25) SQUEEZE: Van der. Sluis, P.; Spek, A . L. Acta Crystallogr., Sect A 1990, 46, 194. (26) P L A T O N , A Multipurpose Crystallographic Tool, Utrecht University, Utrecht, The Netherlands, A . L . Spek, (1998).  123  CHAPTER 4 Ion-Induced Tubular Assembliesf  4.1  Introduction  The supramolecular assembly of molecular precursors  into well-defined  architectures is a promising way to develop new materials and devices. Supramolecular 1  polymers are linear chains of molecules held together by non-covalent interactions, and they may have unusual properties in solution and in the solid-state. Molecular precursors 2  (e.g., cyclic peptides and hydrogen-bonded rosettes) can be assembled into nanotubes through hydrogen-bonding ' or coordination chemistry. Conjugated macrocycles, such 3 4  5  as porphyrins and phthalocyanines, can also be assembled into polymers. Generally, the 6  coordination of metals to flexible macrocycles, such as crown ethers, does not lead to polymeric structures, though dimer formation is common. However, in the case of 7  calix[4]arene-guanosine conjugates small cations such as sodium have been shown to template the formation of self-assembled nanotubes.  8  The assembly of rigid, shape-persistent  macrocycles can lead to novel  supramolecular architectures that are of interest for porous nanomaterials. For example, 9  in polar solvent, phenyleneethynylene macrocycles (e.g., 8), Figure 4.1, self-associate through face-to-face n-n interactions to form tubular structures. These assemblies can 10  | A version of this chapter has been published: Gallant, A . J.; MacLachlan, M . J. "IonInduced Tubular Assembly of Conjugated Schiff-Base Macrocycles" Angew. Chem. Int. Ed. 2003, 42, 5307. Electrochemical experiments were performed in collaboration with B. Kraatz (University of Saskatchewan).  124  References on page 154.  be useful models for the rational design of columnar liquid crystals and organic nanotubes. The work presented here involves the investigation of new conjugated, shapepersistent macrocycles that may be used to build supramolecular architectures. In particular, macrocycles that are capable of both binding transition metals and assembling into supramolecular tubular architectures may form the basis of catalytic nanomaterials or ion-conducting channels. This chapter reports the ion-induced assembly of well-defined conjugated macrocycles to form supramolecular structures.  '13  8 (8d  Figure 4.1  26f  R = COOC4H9)  Conjugated macrocycles 8 and 26f.  Conjugated [3+3]  Schiff-base macrocycle 26f (Figure 4.1) contains three  tetradentate N2O2 binding sites organized in an equilateral triangle, as well as a pocket in the centre that is surrounded by six phenolic oxygen atoms resembling 18-crown-6. The u  binding of ions to these types of macrocycles has not yet been explored.  125  References on page 154.  4.2  4.2.1  Results  Mass Spectrometry  During the investigations of macrocycle 26f it was observed that the electrospray mass spectrum (ESI-MS) of this macrocycle, without any added salt, showed not only [26f+H] , but also [26f+Na] and [26f +Na] species. Here, the N a is presumably +  +  +  +  2  obtained from background solvent contaminants or ionic contaminations leached from the glassware. This was the first indication that these macrocycles may complex small cations in a similar manner to crown ethers. Upon addition of NaBPh* to macrocycle 26f the mass spectrum shows various sodium complexes up to [26f3+Na2] (Figure 4.2). 2+  [26f+Na]  +  1337.9  100  1338.9  [26f+H]  +  1315.9  ,1339.9  o  •"'i  ,200  i  400  '  i  600  '  800  h  ' "  [26f +Na ] 3  I  i' 11»I  i«'i«  [26f +Na]  2+  2  11'i  +  2  I  11111 1  V11! i w\rn 11  1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 m/z  Figure 4.2  The ESI-MS of macrocycle 26f + NaBPlu in C H C l / M e O H . 3  126  References on page 154.  To further these investigations, ESI-MS experiments with addition of NaOAc were conducted while the voltage applied to the sampling cone was varied. At low cone voltages large aggregates are observed, up to [26fs+Na4] , but as the cone voltage is +  increased the extra energy applied to the sample ions can lead to fragmentation, in this case leaving mainly the [26f+Na] macrocycle-cation complex. A plot of the relative +  peak intensity versus cone voltage is shown in Figure 4.3 and reveals the relative number of species present as the cone voltage is varied. At a low cone voltage of 20 V [26f5+Na4] , [26f4+Na3] 4+  and [26f3+Na2]  3+  2+  macrocycle-cation species are observed  along with the smaller [26f +Na2] and [26f+Na] . By increasing the cone voltage to 120 2+  +  2  V , the larger aggregates are not observed but only the smaller [26f2+Na] and [26f+Na] +  +  are seen.  100  20  40  60  80  100  120  Cone Voltage (V) Figure 4.3  The relative peak intensities of macrocycle-Na complexes, [26f +Nam] , +  m+  n  in the ESI-MS as the cone voltage is varied. Points taken every 10 V (Added salt = NaOAc). 127  References on page 154.  These results were also observed during the investigation of other small cations (K , R b and Cs ). The relative number of species present at a specific cone voltage +  +  +  varies slightly with different cations but in all cases upon increasing the cone voltage only smaller aggregates are observed. As a mild ionization technique, ESI-MS is known to give meaningful data from species in solution. ' Therefore, these macrocycle-salt 12 13  mixtures likely consist of large aggregates in solution which fragment upon ionization in ESI-MS. The lower cone voltage experiments are quite soft and allow larger aggregates to be observed, but as the cone voltage is increased, greater fragmentation is observed. Thus, it is most likely that complex species made up of at least five macrocycles and four cations, [26f +Na4] , are present in the solution before ionization. 4+  5  4.2.2  Colourimetric Investigations  When alkali metal and ammonium salts (MBPI14, M = N a , K , R b , Cs , NFL; ) +  +  +  +  +  are added to a solution of 26f in CH2CI2 or CHCI3 a colour change from orange to redbrown is observed (Figure 4.4). The counter-ion shows no apparent effect on these colour changes. Tetraphenylborate (BPI14") was the counterion of choice for these experiments as studies with other anions were problematic due to lack of solubility of the macrocyclecation complexes. Similarly, the addition of divalent metals (e.g., M g ) to a solution of 2+  macrocycle 26f caused precipitation of the resulting complexes prohibiting further study. Difficulties were also observed when using L i salts as these systems are also plagued by +  insolubility.  128  References on page 154.  i i i i i i  A B C D E F  Figure 4.4  The colour change observed upon addition of various salts to a 1 * 10 M  solution of macrocycle 26f in CH C1 : (A) macrocycle 26f; (B) 26f + NaBPh^ (C) 26f + 2  2  KBPhu (D) 26f + RbBPlu; (E) 26f + CsBPlu; and (F) 26f + NH4BPI14.  The UV-visible spectrum of 26f in CHCI3 shows three large peaks centred near 302, 342, and 404 nm, as well as a weaker absorbance at 560 nm. Titration studies were undertaken to investigate the effect of small cations on the spectrum of 26f. Initially a solution of 26f in CHCI3 was prepared and the salt in MeOH was added in aliquots, showing shifts in the electronic spectrum of 26f. However, a control experiment where only MeOH was added to macrocycle 26f in CHCI3 led to similar changes in the spectrum. The colour change upon the addition of MeOH may be a consequence of hydrogen-bonding or stacking of the macrocycles as the solvent polarity increases. The addition of M e C N alone to a solution of 26f in CHCI3 caused small changes to the spectrum, stopping when the concentration reached ca. 1-2% M e C N . The M e C N may be acting as a guest in the macrocycles as the *H N M R chemical shift of M e C N in samples of macrocycle 26f is observed at 1.99 ppm in CDCI3 (cf. 2.10 ppm in neat CDCI3). As well, the crystalline compound contains M e C N that is difficult to remove under vacuum.  129  References on page 154.  Titration experiments were therefore carried out by preparing a solution of 26f in ca. 95:5 C H C l : M e C N , and adding aliquots of the salt in M e C N . 3  0.4  T  1  300  400  500  600  700  Wavelength (nm) Figure 4.5  U V - V i s spectra of 26f (ca. 4.8 * 10" M in 95:5 CHCl :MeCN) upon 6  3  addition of CsBPlu (in MeCN). Each line represents an increase of ca. 0.1 equiv. C s to +  26f. The spectra show up to a [Cs ]:[26f] -1.5:1. Inset: low concentration experiments (0 +  to 0.5 equiv. of Cs ). +  A l l MBPI14 salts ( M = N a , K , R b , Cs , NFL; ) investigated produced similar +  +  +  +  +  changes to the visible spectrum of 26f. As the M in solution was increased by ca. 0.1 +  equivalents, the peak at ca. 404 nm increased and slightly red shifted, the peak at ca. 342 nm red shifted, the peak at ca. 302 nm decreased and the shoulder at ca. 560 nm increased. Figure 4.5 shows the effect of adding CsBPlu to a solution of macrocycle 26f. An isosbestic point was seen at low salt concentrations (see inset in Figure 4.5) and can  130  References on page 154.  be rationalized as the conversion of macrocycle to a cationic sandwich complex, [26f2+Cs] . A s the ratio of salt to macrocycle was increased, the isosbestic point +  disappeared, consistent with the formation of higher aggregates. Similar results were observed upon addition of R b and NFL} salts. However, upon the addition of N a or K +  +  +  +  salts these low concentration isosbestic points are not well defined. In these cases the macrocycle does not convert cleanly to a single product, even at low concentrations and is likely a mixture of varying sized aggregates (Figure 4.6 shows the titration of macrocycle 26f with NaBPlu).  300  400  500  600  700  Wavelength (nm) Figure 4.6  U V - V i s spectra of 26f (ca. 4.2 * 10" M in 95:5 C H C l : M e C N ) upon 6  3  addition of NaBPlu (in MeCN). Each line represents an increase of ca. 0.1 equiv. N a t o +  26f. The spectra show up to a [Na ]:[26f] - 1 . 5 : 1 . Inset: low concentration experiments (0 +  to 0.5 equiv. of Na ). +  131  References on page 154.  The changes that occur in the electronic absorption spectrum of macrocycle 26f upon addition of small cations may be partly due to electrostatic effects of coordinating the ions to the phenolic oxygen atoms, or alternatively, to an interaction between the n orbitals of the macrocycles as they are stacked. The lack of a clear isosbestic point during the formation of the aggregates supports the latter conclusion, as the different sized aggregates appear to have different electronic spectra.  4.2.3  N M R Spectroscopy  The interaction of macrocycle 26f with monovalent cations was also investigated by H N M R spectroscopy. Samples for the N M R experiments were prepared by mixing a !  solution of macrocycle 26f (ca. 7.6 x 1 0 M ) in CDCI3 with a large excess of the 3  tetraphenylborate  salt  (MBPI14).  The solution was  filtered and  aliquots  were  quantitatively transferred into N M R tubes. The salt solutions were then diluted with a standard solution of 26f in CDCI3 so that the final volume and concentration of the macrocycle was approximately the same in each case. The original [M ]:[26fJ ratio was +  determined by integration of the H N M R spectrum of the most concentrated solution, 5  and was near 1:1 in each case ( M = N a , K , Rb , C s , N H / ) . Even with the addition of +  +  +  +  an excess of tetraphenylborate salt no ratios of [M ]:[26fJ larger than 1:1 are observed in +  solution. Figure 4.7 shows the *H N M R spectrum of 26f with varying concentrations of NaBPh4. As the ratio of sodium to macrocycle increases, there is a broadening and a gradual upfield shift in the position of the peaks. Notably, the imine and aromatic peaks shift by as much as -1.5 ppm at a [Na ]:[26fJ ratio of ca. 1:1. This dramatic upfield shift +  132  References on page 154.  is characteristic of n-n stacking whereby the proton resonances are affected by the ring currents of adjacent rings.  10  As two rings approach in proximity, the electron density  surrounding an attached proton is increased resulting in an upfield chemical shift related to the distance between the two rings.  14  [Na ] +  1 0.8 1 0.6 1 0.4 1 0.2 1 0 1  yv •A ^ A A 13  14 Figure 4.7  [26f]  12  11  10  ppm  Stacked H N M R spectra of macrocycle 26f with increasing amounts of  NaBPlu. The ratio of [Na ]:[26fJ for each sample is shown (* = CHC1 ; + = BPhf). +  3  The presence of a single product by H N M R spectroscopy, and the lack of any starting material after NaBPlu is added, indicates that the system is dynamic and that the macrocycles are freely interchanging between aggregates. Even at low concentrations of N a ([Na ]:[26fJ - 0.1:1), there is a single set of broad resonances that are consistent with +  +  this dynamic system. It appears that the coordination of small cations to the central phenolic oxygen atoms of macrocycle 26f does not cause deprotonation of the phenols.  133  References on page 154.  The H N M R spectra clearly show O H resonances that are broadened and shifted upfield due to either stacking of the macrocycles or binding to N a . +  14  13  Figure 4.8  12  11  5  10  4  ppm  Stacked H N M R spectra of macrocycle 26f with increasing amounts of  CsBPh4. The ratio of [Cs ]:[26fJ for each sample is shown (* - CHC1 ; + = BPI14"). +  3  The addition of KBPh4 to 26f gave results similar to NaBPh^ but addition of NH BPh4, RbBPh4, and CSBPI14 produced different results. Figure 4.8 shows the *H 4  N M R spectral changes that occur for the addition of CsBPh4 to 26f. Above ca. 0.3:1 [Cs ]:[26fJ, there is only a single set of peaks that is significantly shifted upfield from the +  pristine macrocycle 26f, but broadened due to dynamic exchange and/or a distribution of aggregate sizes similar to the case for NaBPrt^. At lower concentrations, however, other  134  References on page 154.  species are observed. At a ratio of [Cs ]:[26f] = 0.05:1, the macrocycle and a small +  amount of another species, 53, are present. The intermediate 53 has an O H resonance at 13.6 ppm, an imine resonance at 8.0 ppm, and two aromatic resonances at 6.2 and 6.5 ppm. From integration of the *H N M R spectrum, the new species formed at low concentrations of C s has a formula of [26f2+Cs] characteristic of a sandwich complex. +  +  Moreover, the imine resonance at 8.0 ppm is intermediate to that in the macrocycle (8.5 ppm) and that in the 1:1 [Cs ]:[26f] product (7.5 ppm). If the observed chemical shift of +  this 1:1 product corresponds to the macrocycle in a tubular assembly, the intermediate species 53 is most likely a sandwich complex. In this complex, the aromatic protons would only experience the influence of the ring currents from a single neighbouring macrocycle, leading to half of the change in chemical shift seen for a macrocycle in a tubular assembly. In addition, the OCHj resonances of 53 are split into two multiplets. In a sandwich-type complex, these two protons are diastereotopic due to breaking of the mirror symmetry in the macrocycle. Up to concentrations of [Cs ]:[26f] = 0.3:1, the free macrocycle is gradually +  replaced by species with broad peaks characteristic of the aggregates. The two resonances of the OCH2 groups merge into a single broad resonance when the symmetry of the macrocycle is restored in a tubular structure. It appears that the sandwich complex is most stable, but that macrocycle exchange can occur once the aggregates have grown beyond this stage. When the chemical shift is plotted against the ratio of metal to macrocycle, different curves are observed depending on the choice of metal ion as shown in Figure 4.9. N a gives a nearly linear result and it is likely that the chemical shift difference +  135  References on page 154.  between different sized aggregates is similar in each case. However, all other species show an initially large chemical shift difference that then decreases. This can be explained by the initial chemical shift change for the sandwich complex being higher than that for the larger aggregates. This suggests that slightly different binding mechanisms may be involved.  8.6  i  8.4 • 8.2 • 8.0 • E Q- 7.8 Q. '-C  7.6 7.4 7.2 7.0 0.0  0.2  0.4  0.6  0.8  1.0  [M ]:[26f] +  Figure 4.9  Chemical shift of the imine proton (N=Cr7) as different small cations are  added to macrocycle 26f in CDCI3.  4.2.4  Electrochemistry  To further substantiate complexation in these aggregates electrochemistry was performed. The voltammogram of macrocycle 26f shows an irreversible trace (dashed line in Figure 4.10) with a peak potential of 586 mV. The irreversibility likely arises from the oxidation of the macrocycle to a quinone-type structure with loss of H2. Upon  136  References on page 154.  addition of alkali metal salts (1:1 ratio of [M ]:[26fJ), the irreversible peak shifts to more +  positive potentials. This positive shift in potential is illustrated in Figure 4.10 (solid line) for the addition of KBPI14 to macrocycle 26f and is an indication that the K is complexed +  to the hydroxyl oxygen atoms within the centre of the macrocycles consistent with the [K ]:[26f] system being more difficult to oxidize. A much smaller shift in potential would +  be expected i f the K cations were binding to the periphery of the macrocycle. The +  oxidation potential shows strong cation dependence upon the addition of different metal salts as well, Figure 4.11. The oxidation wave is irreversible for all macrocycle-cation complexes but there is no clear trend directly correlating to the cation size (Table 4.1).  0.2  0.4  0.6  0.8 E/mV  1.0  1.2  1.4  E/mV Figure 4.10  The voltammogram (top) and differential pulse voltammogram (bottom)  of macrocycle 26f (dashed line) along with that for macrocycle 26f upon addition of KBPI14 (solid line).  137  References on page 154.  0.2  0.4  0.6  0.8 E/mV  1.0  1.2  E/mV Figure 4.11  The voltammogram (top) and differential pulse voltammogram (bottom)  of macrocycle 26f after addition of different alkali metals (red = C s , green = K , brown +  +  = N a , blue = Rb ). +  Table 4.1  +  Peak potentials for the irreversible oxidation wave of macrocycle 26f with  different alkali metals. Peak potential (mV) Na K  966  +  786  +  Rb  +  863  Cs  +  934  No metal  586  138  References on page 154.  4.3  Discussion  4.3.1  Cation Size Dependence  The 'IT N M R spectra of these aggregates show a change in chemical shift of the proton resonances of macrocycle 26f upon addition of small cations. These shifts appear to be dependent on cation size, with the imine (N=CH) peak shifted most dramatically for the smaller N a cation (AS = 1.48 ppm) and least for the larger C s cation (A8 = 0.98 +  +  ppm). Figure 4.9 shows the differences in these chemical shifts at a [M ]:[26f] ratio of +  ca. .1:1. The imine resonances of 26f with the intermediate sized cations (NFL; , K , and +  +  Rb ) are found between those of N a and Cs , but are not distinguished by cation size. +  +  +  These results may be obscured by peaks assigned to CHCI3 and BPI14" in the spectra. In a tubular structure where macrocycles are bridged by cations, the size of the cation should affect the chemical shifts since this affects the proximity of the neighbouring macrocycles and their relative shielding.  14  The changes observed in the UV-visible spectra upon titration with different salts also seem to be affected by the cation size. The greatest electronic changes are observed for addition of the small cation N a and the smallest changes for the large cation Cs . As +  +  well, formation of sandwich 53 at low salt concentrations seems more pronounced in the case of larger cations (e.g., Rb , Cs , N H / ) indicated by a clear isosbestic point. This is +  +  not observed for smaller cations (e.g., N a , K ) which do not cleanly convert to a single +  +  product, even at low salt concentrations. Visually, a colour variation is seen upon the addition of M * to macrocycle 26f in CH2CI2 (Figure 4.4) that seems dependent on cation size with the most pronounced colour change observed when a N a salt is added. +  139  References on page 154.  4.3.2  Control Studies  Upon addition of the tetraphenylborate salts to macrocycle 26f, large upfield shifts are observed in the ' H N M R spectra. CH-7t interactions have been observed in imidazolium tetraphenylborate systems where the tetraphenylborate anion can shield the protons of the cation and cause upfield shifts of up to 4.5 ppm.  15  To confirm that the  tetraphenylborate anion was not the source of shielding in the H N M R studies of 26f !  with MBPI14, an experiment was carried out using BF4" in the place of BPlu". This counterion does not possess any aromatic groups that could influence such chemical shifts. Upon the addition of an excess of NaBF4 to a solution of macrocycle 26f in CDCI3 the mixture became viscous, and its ' H N M R spectrum could not be obtained. However, when this salt was dissolved in MeCN-dj and added to a solution of macrocycle 26f in CDCI3 the solution did not become viscous and the H N M R spectrum shown in Figure !  4.12 was obtained. The spectrum of this mixture resembles that observed when NaBPlu is added to a solution of macrocycle 26f confirming that the aromatic groups of the counterion are not responsible for the observed chemical shifts.  140  References on page 154.  1 4 - 1 2  Figure 4.12  10  8  6  4  2  0  ppm  ' H N M R spectrum of macrocycle 26f after addition of N a B F  4  in  CDCl /MeCN- d . 3  3  Macrocycle 26f possesses three N2O2 binding sites, as well as a crown ether-like centre. Upon the addition of M B P l u salts the small cations are likely coordinating to the central phenolic oxygen atoms of the macrocycle rather than to the tetradentate N2O2 pockets, as the oxygen atoms are harder than the imine nitrogen atoms. A control experiment in which salphen 54 (Figure 4.13) was mixed with an excess of NaBPlu in  CDCI3  showed no change in colour or in its ' H N M R spectrum, indicating that 54 does  not incorporate NaBPlu. In addition, the final [M ]:[26f] ratio for each of the varying M+ +  samples was close to 1:1; a larger ratio than this would be expected i f the cations were coordinating to the N2O2 pockets of each macrocycle.  141  References on page 154.  54 Figure 4.13  Salphen 54 designed for a control experiment to ensure that the small t  cations are binding to the central phenolic oxygen atoms and not the salphen N2O2 pockets.  4.3.3  Crown Ether Comparisons  From the many studies done on these systems it seems that macrocycle 26f is complexing small cations in a similar manner to crown ethers; however in this case the complexation induces aggregation. It would be interesting to qualitatively investigate the affinity of macrocycle 26f for small cations as compared to the related crown ether, 18crown-6. Crown ether 18-crown-6 shows a single peak in its ' H N M R spectrum at 3.66 ppm which is shifted upfield to 3.46 ppm upon the addition of NaBPhi (Figure 4.14 a,b). To investigate the affinity of 18-crown-6 and macrocycle 26f for small cations two experiments were performed. In the first experiment, excess NaBPlu was added to a solution of 18-crown-6 in  CDCI3, then  the sample was shaken and filtered before the  addition of macrocycle 26f. For the second experiment, excess NaBPI^ was first added to a solution of macrocycle 26f in  CDCI3,  then after shaking and filtering the sample, 18-  crown-6 was added. In both cases the ' H N M R spectra show shifted and broadened macrocycle peaks and a crown ether peak at 3.66 ppm (Figure 4.14 c,d). This reveals that  142  References on page 154.  the crown ether remains uncomplexed but that macrocycle 26f is able to complex the Na forming aggregates, as observed in the absence of crown ether.  >.  10  1  1  9  8  Figure 4.14  7  '  i  i  i  i  6  5  4  3  2  i  1  i  i  0  ppm  ' H N M R studies on the affinity of macrocycle 26f and 18-crown-6 for N a  +  in CDC1 . (a) 18-Crown-6, (b) 18-crown-6 after the addition of NaBPlu, (c) 18-crown-6 3  first mixed with NaBPlu followed by addition of macrocycle 26f, and (d) macrocycle 26f first mixed with NaBPlu followed by addition of 18-crown-6.  Since 18-crown-6 is known to show highest affinity for K cations, a second set +  of experiments was performed using K B P l u . In this case the chemical shift of 18-crown-6 when complexed to K is observed at. 3.52 ppm, however, upon addition of macrocycle +  the uncomplexed crown ether peak at 3.66 ppm is observed (Figure 4.15). Again, the macrocycle resonances are broadened and shifted as expected when complexing K . +  143  References on page 154.  (d) (c)  .-A  (b)  _ 1  (a)  10  ppm  Figure 4.15 in  CDCI3.  ' H N M R studies on the affinity of macrocycle 26f and 18-crown-6 for K (a) 18-Crown-6, (b) 18-crown-6 after the addition of  KBPI14,  +  (c) 18-crown-6  first mixed with KBPI14 followed by addition of macrocycle 26f, and (d) macrocycle 26f first mixed with KBPli4 followed by addition of 18-crown-6.  The integration ratio of [Na ]:[26fJ and [K ]:[26fJ varies between 0.5:1 and 0.6:1 +  +  in all cases. When an excess of N a salt was added to a solution containing both +  macrocycle 26f and 18-crown-6, the macrocycle resonances were shifted and broadened as expected and the crown ether peak was also shifted to 3.46 ppm indicating a complexed species (Figure 4.16). This suggests that 18-crown-6 can complex N a cations +  in the presence of macrocycle 26f but that this will occur only after macrocycle 26f has been fully complexed.  144  References on page 154.  14  12  Figure 4.16  10  8  6  4  2  0  ppm  ' H N M R spectrum of an excess of NaBPlu added to a mixture of  macrocycle 26f and 18-crown-6 in CDC1 (* = CHC1 , + = 3  3  BPI14",  A  = impurity in  NaBPlu). The crown ether resonance is shifted from 3.66 ppm (uncomplexed) to 3.46 ppm (complexed).  These results show that macrocycle 26f competes with 18-crown-6 in CHC1 for 3  N a and K . Therefore, macrocycle 26f has a stronger affinity for these cations than 18+  +  crown-6 which is known to complex N a and K with logK of 4.4 and 6.1, respectively. +  Since  +  16  N a is an N M R active nucleus with a nuclear spin of 3/2, a natural  abundance of 100% and a sensitivity of 0.0925 (as compared to ' H with 99.98% natural abundance and a sensitivity of 1), the [Na ]:[26f] system could be further investigated +  through  23  N a N M R spectroscopy.  17  The N a chemical shift of NaBPlu in different 23  solvents varies between 16.1 and -2.6 ppm, depending on the solvating abilities of the solvent.  In M e O H a peak at 5.4 ppm is observed. The N a N M R spectrum of a solution 145  References on page 154.  of macrocycle 26f and NaBPlu (ca. 1:1 ratio) shows a peak at 7.21 ppm (Figure 4.17, top). A related experiment was performed using a solution of crown ether with added NaBPlu and shows a peak at -12.8 ppm, which is shifted upfield from the macrocyclic system (Figure 4.17, bottom). The different chemical shifts observed between these systems is expected as the oxygen atoms of 18-crown-6 are better at shielding the bound N a nucleus than that of the phenolic oxygen atoms of macrocycle 26f. Related studies in +  MeOrJ/E^O on cryptand-Na complexes show that as the number of oxygen atoms in the +  cryptand is increased from four to five to six, upfield shifts are observed in the  Na  N M R spectra due to the increased shielding experienced by the N a within the complex. +  I . . . .  15  Figure 4.17  / j  I . . . .  10  ,  5  . | . . .. | . .. 0  -5  . , , , , -10  19  , , , , , , , , , .  -15  -20  ppm  N a N M R spectra (CDC1 , 106MHz) of macrocycle 26f with NaBPlu 3  (top) and 18-crown-6 with NaBPlu (bottom).  146  References on page 154.  4.3.4  Postulated Structures  Many techniques have been used to study these interesting new systems that arise upon the addition of small cations to macrocycle 26f. Each experimental method has 20  provided useful information regarding these assemblies but no single technique has allowed for a complete description of these systems. However, when considered together, the collected data from the various techniques used to study these systems presents an interesting picture of the likely structures of these assemblies in solution. The ESI mass spectral data show evidence that upon addition of metal salts to macrocycle 26f, aggregates form with a formula of [26f +M -i] " n  n  n  1+  (where n > 2 and M =  N a , K , Rb , Cs ). By varying the cone voltage (the energy used to ionize the sample) +  +  +  +  different spectra are obtained. At low cone voltages aggregates as large as [26fs+M4]  4+  were observed but with increased cone voltages these fragment and only smaller aggregates are seen. Even at low cone voltages, it is possible that the observed aggregates may only be fragments of the true species present in solution. This data reveals the presence of aggregates in solution but does not provide insight into the binding and structure of these aggregates. A colour change from orange to red-brown is observed upon addition of  MBPI14  salts to macrocycle 26f accompanied by a red shift in the UV-visible spectra. The source of this red shift is likely due to 71-71 interactions between the macrocycles when stacked. The difference in electronic states of the macrocycles decreases causing an increase in the wavelength of the observed absorption peak. With increasing salt concentrations isosbestic points are not well defined suggesting that different sized aggregates have different electronic spectra. This data also  147  References on page 154.  reveals that the change in electronic spectra is due to the n orbital overlap of the conjugated macrocycles upon stacking. If such changes in these spectra were caused by the electronic effects of binding a small cation to the phenolic oxygen atoms of the macrocycle clean isosbestic points would be expected, which is not the case. Peak broadening and upfield proton shifts were observed in the H N M R spectra ]  of macrocycle 26f upon addition of MBPI14 salts ( M = N a , K , R b , C s , N H / ) . These +  +  +  +  upfield shifts are characteristic of a n stacked assembly in which neighbouring aromatic rings shield the nearby protons. Similar effects have been observed in stacked cyclic phenyleneethynylene molecules. With the addition of small cations to macrocycle 26f 10  the H N M R spectra show that the resonances of the alkoxy groups are shifted very little, l  unlike those of the protons within the macrocyclic backbone. This is consistent with a stacking motif where the alkoxy groups remain unaffected on the periphery of these newly formed aggregates. Control experiments have shown that these shifts are not due to the influence of the tetraphenylborate anion. ' H N M R spectroscopy has also confirmed that the small cations do not bind to the N2O2 pockets within macrocycle 26f, supporting the proposal that the cations bind instead to the central crown ether-like region of the macrocycle. Also, macrocycle 26f shows a higher affinity for N a and K than does the +  +  related crown ether, 18-crown-6, in CDCI3. This is surprising as crown ethers are known to form stable complexes with small cations. In this case the %-n stacking of the assembled system may add additional stability favouring the macrocycle-cation interaction. Related ESI-MS studies have revealed that aromatic 71-71 interactions can influence the formation of crown ether-cation dimers.  148  22  References on page 154.  The electrochemical studies do not directly support aggregation but show that the small cations are binding to the central crown ether-like pore of macrocycle 26f. The large shift in peak potential when small cations are added to the macrocyle suggests that the cations are binding close to where oxidation occurs, which is believed to be the central phenolic pore. The combined results of these techniques suggest that small cations induce aggregation of macrocycles such as 26f to form tubular assemblies. At low [M ]:[26f] +  ratios, intermediate species (e.g., sandwich-type complexes) are observed while at higher concentrations dynamic stacked structures are formed. The macrocycles within these aggregates are not likely planar as the crystal structure and calculations of the unbound macrocycle 26f shows twisted motifs. The small cations within these aggregates likely adopt an octahedral coordination as they do in 18-crown-6. This could occur i f the catechol units of the macrocycles were oriented so that two have their hydroxy groups pointing up out of the plane of the macrocycle and one has them pointing down below the plane of the macrocycle. In such an arrangement each small cation would be bound to two catechol units from one macrocycle and one from the neighbouring macrocycle. In this fashion small cations would be able to assemble crown ether-like macrocycles, such as 26f, into tubular structures. Postulated structures of a cationic dimer and an ioninduced tubular assembly with sodium are shown in Figure 4.18.  149  References on page 154.  Figure 4.18  Postulated structures of (a) a sodium dimer (minimized with molecular  mechanics force field), (b) an ion-induced tubular assembly of macrocycle 26f with N a  +  (minimized with molecular mechanics force field), (c) space-filling model of an ioninduced tubular assembly of macrocycle 26f with N a (minimized with molecular +  mechanics force field) and (d) space-filling model of an ion-induced tubular assembly of macrocycle 26f with N a (elongated for visualization purposes). +  These structures have been energy minimized using molecular mechanics force field (MMFF) and the macrocycles do indeed adopt a "two catechol up and one down" motif. In Figure 4.18d the assembled structure has been elongated to aid in the visualization of these aggregates. Here it can be seen that the sodium ions do not form a  150  References on page 154.  straight line within these assemblies but rather vary in their exact binding position throughout this supramolecular structure. It is likely that in solution these cations are mobile and freely exchanging between macrocycles. The chemical shift differences observed in the ' H N M R spectra of these aggregated systems as compared to the free macrocycles can be as large at 1.5 ppm. Such shifts of the proton resonances are due to the ring current effects from neighbouring macrocycles and can be correlated to a CH-71 distance of ca. 3-3.5 A . similar  4.4  CH-7C  1 4  This is consistent with the M M F F calculations that show  distances between macrocycles within the cation-induced assemblies.  Conclusions  In summary, this chapter reports the ion-induced tubular assembly of macrocycle 26f upon addition of small cations (Na , K , Rb , Cs , NFL;*). Macrocycle 26f behaves +  +  +  +  like a crown ether, where the phenolic oxygen atoms inside the macrocycle coordinate to small cations. Investigations reveal that macrocycle 26f shows a stronger affinity for small cations than does 18-crown-6. These results provide a new avenue for selfassembled materials and small cation sensors.  151  References on page 154.  4.5  4.5.1  Experimental  General  Tetraphenylborate salts of sodium, potassium, rubidium, cesium, and ammonium were obtained from Aldrich. ' H N M R spectra were recorded on either a Bruker AV-300 or AV-400 spectrometer and were calibrated to the N M R solvent at 7.24 ppm (residual  CHCI3). For  N a experiments the Bruker AV-400 spectrometer was externally calibrated  to NaCl in D2O (0 ppm). UV-vis spectra were obtained on a Varian Cary 5000 U V vis/near-IR spectrophotometer using a 1 cm quartz cuvette. Electrospray ionization (ESI) mass spectra were obtained on a Micromass L C T time-of-flight (TOF) mass spectrometer equipped with an electrospray ion source. The samples were analyzed in MeOH:CHCl3 (1:1) at 100 p.M. The concentrations of both M " (MBPI14 or M O Ac salts) and 26f were 1  about the same. Flow rate: 20 p.L min" ; sample cone: 90 V (for cone voltage experiments 1  this was varied between 10 and 130 V ) ; source temperature: 120 °C; desolvation temperature: 120 °C. C V experiments were conducted on a B A S gold electrode (2mm diameter). The glassy carbon electrode was discarded due to very strong adsorption of the compounds onto the surface. Scan rate in each case was 100 mV/s. A l l potentials are given versus the Ag/AgCl reference electrode. Voltammograms were obtained in dry CH2CI2 using a scan rate of 100 mV/s. Molecular modeling was performed with Spartan '02  152  References on page 154.  4.5.2  Procedures  NMR Titrations Two standard solutions were first prepared of macrocycle 26f in  CDCI3  both with a concentration of 0.01 M . Excess salt (MBPI14) was added to one of these solutions and after vigorous shaking the mixture was filtered. This solution had a ratio of ca. 1:1 [M ]:[26f]. The two solutions were then combined in varying ratios to produce +  mixtures of equal macrocycle concentration but with varying salt concentration. The amount of salt in solution was determined more accurately by the integration of the BPI14" counterion in the'if N M R spectrum.  UV-vis Titrations A solution of macrocycle 26f was prepared in 95:5 CHCls/MeCN with a concentration of 4-5 x 10" M . A solution of salt (MBPI14) in M e C N was prepared so 6  that 50 uL would contain 1 equivalent of salt. The salt solution was then added to the macrocycle solution in 5 uL aliquots (0.1 equiv.) up to ca. 1.5 equivalents of salt.  153  References on page 154.  4.6  References  (1) Alivisatos, A . P.; Barbara, P. F.; Casfleman, A . W.; Chang, J.; Dixon, D. A . ; Klein, M . L.; McLendon, G . L . ; Miller, J. S.; Ratner, M . A . ; Rossky, P. J.; Stupp, S. I.; Thompson, M . E. Adv. Mater. 1998,10, 1297. (2) Brunsveld, L.; Folmer, B . J. B.; Meyer, E. W.; Sijbesma, R. P. Chem. Rev. 2001, 707,4071. (3) (a) Ghadiri, M . R.; Granja, J. R.; Milligan, R. A . ; McRee, D. E.; Khazanovich, N . Nature, 1993, 366, 324. (b) Khazanovich, N . ; Granja, J. R.; McRee, D. E.; Milligan, R. A . ; Ghadiri, M . R. J. Am. Chem. Soc. 1994, 776", 6011. (4) (a) Fenniri, H.; Mathivanan, P.; Vidale, K . L . ; Sherman, D. M . ; Hallenga, K.; Wood, K. V.; Stowell, J. G. J. Am. Chem. Soc. 2001,123, 3854. (b) Moralez, J. G.; Raez, J.; Yamazaki, T.; Motkuri, R. K.; Kovalenko, A.; Fenniri, H . J. Am. Chem. Soc. 2005, 727, 8307. (5) (a) Yamaguchi, T.; Tashiro, S.; Tominaga, M . ; Kawano, M . ; Ozeki, T.; Fujita, M . J. Am. Chem. Soc. 2004,126, 10818. (b) Aoyagi, M . ; Biradha, K . ; Fujita, M . J. Am. Chem. Soc. 1999, 727, 7457. (6) (a) Kadish, K . M . ; Smith, K . M . ; Guilard, R. The Porphyrin Handbook Academic Press: San Diego, 2000; Vol. 6. (b) Michelsen, U . ; Hunter, C. A . Angew. Chem. Int. Ed. 2000, 39, 764. (c) K i m , Y . ; Mayer, M . F.; Zimmerman, S. C. Angew. Chem. Int. Ed. 2003, 42, 1121. (d) Engelkamp, H.; Nolte, R. J. M . J. Porphyrins Phthalocyanines 2000, 4,454. (7) Steed, J. W. Coord. Chem. Rev. 2001, 275, 171.  154  (8) Sidorov, V . ; Kotch, F. W.; El-Kouedi, M . ; Davis, J. T. Chem. Commun. 2000, 2369. (9) (a) Zhao, D.; Moore, J. S. Chem. Commun. 2003, 807. (b) Hoger, S.; Bonrad, K . ; Mourran, A . ; Beginn, U . ; Moller, M . J. Am. Chem. Soc. 2001,123, 5651. (10) (a) Lahiri, S.; Thompson, J. L . ; Moore, J. S. J. Am. Chem. Soc. 2000, 122, 11315. (b) Zhao, D.; Moore, J. S. J. Org. Chem. 2002, 67, 3548. (c) Shetty, A . S.; Zhang, J.; Moore, J. S. J. Am. Chem. Soc. 1996,118, 1019. (d) Zhang, J.; Moore, J. S. J. Am. Chem. Soc. 1992,114,9701. (11) (a) Gallant, A . J.; Hui, J. K . - H . ; Zahariev, F. E.; Wang, Y . A . ; MacLachlan, M . J. J. Org. Chem. 2005, 70, 7936. (b) Akine, S.; Taniguchi, T.; Nabeshima, T. Tetrahedron Lett. 2001, 42, 8861. (12) (a) Schalley, C. A . Mass Spectrom. Rev. 2001, 20, 253. (13)  The mass spectra were not obtained under conditions from which reliable  quantification of the species could be made. See: Leize, E.; Jaffrezic, A . ; Van Dorsselaer, A . J. Mass Spectrom. 1996, 31, 537. (14) (a) Rapp, A . ; Schnell, I.; Sebastiani, D.; Brown, S. P.; Percec, V . ; Spiess, H . W. J. Am. Chem. Soc. 2003,125, 13284. (b) Sozzani, P.; Comotti, A . ; Bracco, S.; Simonutti, R. Chem. Commun. 2004, 768. (15)  Dupont, J.; Suarez, P. A . Z.; De Souza, R. F.; Burrow, R. A . ; Kintzinger, J.-P.  Chem. Eur. J. 2000, 6, 2377. (16) Lamb, J. D.; Izatt, R. M . ; Swain, C. S.; Christensen, J. J. J. Am. Chem. Soc. 1980, 102, 475. (17) Laszlo, F.Angew. Chem. Int. Ed. Engl. 1978,17, 254. (18) Erlich, R. H.; Roach, E.; Popov, A . I. J. Am. Chem. Soc. 1970, 92, 4989.  155  (19) Kintzinger, J. P.; Lehn, J.-M. J. Am. Chem. Soc. 1974, 96, 3313. (20) Gallant, A . J.; MacLachlan, M . J. Angew. Chem. Int. Ed. 2003, 42, 5307. (21) Wu, J.; Frechtenkotter, A.; Gauss, J.; Watson, M . D.; Kastler, M . ; Frechtenkotter, C ; Wagner, M . ; Mullen, K. J. Am. Chem. Soc. 126, 2004, 11311. (22)  Sherman, C. L . ; Brodbelt, J. S.; Marchand, A . P.; Poola, B . J. Am. Soc. Mass  Spectrom. 2005,16,1162.  156  CHAPTER 5 New Heptanuclear Metal Cluster Complexes! 5.1  Introduction  Supramolecular coordination chemistry is a gateway to new materials such as chemical sensors, molecular devices, and porous substances. " Grids and frameworks 1  4  represent beautiful examples of harnessing coordination chemistry to direct selfassembly. Organic macrocycles (e.g., crown ethers) and molecules with bowl, cone, or 5  barrel structures (e.g., carceplexes, calixarenes, cucurbiturils) have a rich history of hostguest chemistry. Inorganic analogues that may be self-assembled using coordination 6  chemistry promise to marry the selectivity and recognition of organic supramolecular chemistry with the useful catalytic, magnetic, and optical properties of the metal centres, Q  producing functional materials. One of the long sought after goals of this field is to develop self-assembled capsules with accessible metal coordination sites.  9  Work on shape-persistent macrocycles has led to new substances capable of aggregating, forming liquid crystalline phases, and yielding porous 3-D networks.  10  Although metal coordination to ligands inside and outside of macrocycles has been demonstrated,  11  the use of shape-persistent macrocycles as a template for creating  molecular clusters has received very little attention.  f A version of this chapter has been submitted for publication: Gallant, A . J.; Chong, J. H.; MacLachlan, M . J. "Novel Heptametallic Bowl-Shaped Complexes Derived From Conjugated Schiff-Base Macrocycles: Synthesis, Characterization and X-Ray Crystal Structures" Inorg. Chem. 2006. Dynamic light scattering experiments were performed in collaboration with Y. Guo and M . G. Moffitt (University of Victoria). 157  References on page 195.  This chapter describes the first shape-persistent metallomacrocycles capped by a [M40]  6+  cluster (where M = Zn, Cd). These bowl-shaped heptanuclear metal complexes  are interesting new coordination compounds and in the case of zinc are shown to exhibit solvent-dependent  aggregation in solution. Here the structural characterization and  calculations of these new supramolecular complexes as well as evidence of capsule formation in solution is presented.  5.2  5.2.1  Results and Discussion  Synthesis of Zinc Metallocycles  RO  OR  RO  26b (R = C H )  55b (R = C H )  26e(R = C H )  55e (R =  26f (R = C H  )  55f (R = C H  26h (R = C H )  55h (R = C H  2  5  2  n  5  1 1  n  6  1 3  8  5  CH)  n  s  u  1 3  )  1 7  )  n  6  n  Figure 5.1  OR  n  1 7  8  Schiff-base macrocycle 26 and trimetallated macrocycle 55.  Macrocycle 26 (Figure 5.1), formed by the Schiff-base condensation of 3,6diformyl-l,2-dihydroxybenzene (29) and 4,5-dialkoxy-l,2-phenylenediamine (33), has  158  References on page 195.  the potential to coordinate three transition metals in tetradentate N2O2 salen-type pockets. ' Reaction of 26f with three equivalents of Zn(OAc)2 produces a product with 12 13  a very broad ' H N M R spectrum. The ESI mass spectrum of the product indicates that compound 55f forms (Figure 5.1), but also shows many species that correspond to aggregates (e.g., [55f2J , [55f 2+  2  + Zn] , [55f ] ). These results suggest that the 2+  2+  3  trimetallated macrocycle can be prepared, but that it aggregates strongly in solution. To study the metal incorporation into macrocyle 26f, a stepwise addition was investigated. Upon addition of one equivalent of Zn(OAc)2 to macrocycle 26f, H N M R J  spectroscopy showed a 1:1 mixture of the unmetallated macrocycle and what seems to be the dimetallated macrocycle (Figure 5.2a). The ESI mass spectrum of this mixture shows three major peaks corresponding to the protonated macrocycle, its sodium adduct and the protonated dimetallated macrocycle. The monometallated macrocyle may be present but is not observed in any considerable amounts. It seems that the dimetallated macrocycle is favoured over the monometallated species. This may be due to geometry constraints or due to increased acidity of the phenols upon coordination of one metal. When two equivalents of Zn(OAc)2 are mixed with macrocycle 26f a single product is observed in the ' H N M R spectrum as evidenced by the presence of one OH resonance, three imine (C7/=N) resonances, a complex aromatic region and two OC//2 resonances. This spectrum corresponds well to a dimetallated macrocycle as shown in Figure 5.2b.  159  References on page 195.  3N=CH  OH  b)_i_  A. •••I  14  Figure 5.2  i  12  i  i  10  i  i  8  i'  "i  4  6  r  "r-  r  2  0  ppm  *H N M R spectra (300 M H z , CDC1 ) of (a) the reaction mixture after 3  addition of 1 equiv. of Zn(OAc)2 to macrocycle 26f and (b) the dimetallated macrocycle along with the structure of the macrocycle showing the three different environments (* =  CHCI3  and  0  imine  = phenolic, imine and aromatic peaks from unreacted  macrocyle 26f).  Continuing with the investigation of zinc incorporation into macrocycle 26f, the macrocycle was reacted with an excess of Zn(OAc)2 and a single orange microcrystalline product 56f precipitated from solution. The *H N M R spectrum of 56f (Figure 5.3) indicates that the macrocyclic ligand retains its C3 axis since the number of aromatic and imine (N=CH) resonances is unchanged from that for 26f. Notably, the phenolic proton  160  References on page 195.  resonance of 26f (13.23 ppm) is absent in the spectrum for 56f, as expected i f the ligand is bound to three metals. Two new resonances at 1.93 and 1.84 ppm, characteristic of acetate groups, are also present in the spectrum of 56f and integrate to six acetates per macrocycle in a 3:3 ratio.  i  I  i  i  i  i  i  i  i  i  r.  i  i  i  14  13  12  11  10  9  8  7  6  5  4  3  2  Figure 5.3  1  i  1 ppm  H N M R spectra (300MHz, CDC1 ) of metallomacrocycle 56f (bottom) 3  and macrocycle 26f (top). Inset: (a) Experimental data and (b) simulation of the OC//2 resonance for compound 56f. (* =  CHCI3)  Examination of the H N M R spectrum of 56f reveals that the resonance assigned !  to the OCHj (triplet in 26f) of the peripheral alkoxy groups shows a complex coupling pattern (Figure 5.3, inset). The experimental data can be simulated as an ABX2 spin system. In particular, the protons on the OCH2 for 56f are inequivalent and display both  161  References on page 195.  geminal and vicinal coupling. Since the macrocycle in 56f clearly exhibits C j rotational symmetry and there is only a single OC//2 carbon environment ( C N M R spectroscopy) 13  in the molecule, the plane of symmetry perpendicular to the C3 axis in the molecule must be absent, leading to diastereotopic H atoms in the OCH2 group. The ESI mass spectrum  of 56f  shows a single ion corresponding to  [55f]Zn2(OAc)4Na (m/z = 1894), a species with five Z n +  2 +  ions, but elemental analysis  indicates clearly that compound 56f contains seven Zn atoms per macrocycle. Unable to obtain crystals of 56f that would diffract X-rays, analogous complexes 56b, 56e, and 56h were prepared from macrocycles 26b, 26e, and 26h, respectively. Crystals of 56b were obtained from DMSO/ether, and a single-crystal X-ray diffraction (SCXRD) experiment was undertaken. Figure 5.4 shows the surprising solid-state molecular structure of complex 56b.  Figure 5.4  Molecular structure of 56b as determined by S C X R D . Thermal ellipsoids  are shown at 50% probability, (a) Top view with protons removed for clarity and (b) side view with alkoxy chains and protons removed for clarity. Black = C, red = O, blue = N and green = Zn. 162  References on page 195.  From the S C X R D structure it can be seen that the molecule has a bowl shape with overall C i symmetry, consistent with the observed *H N M R spectrum. The side of the v  9+  bowl is formed by a trimetallated macrocycle with three Zn  ions in square pyramidal  9+  geometry, (in the solid state one of these Zn  ions is coordinated by a D M S O solvent  molecule, giving it an octahedral geometry). These molecules might be termed "nanobowls"  8d  as the metallomacrocycle adopts a cone shape due to the constrained  geometry inside the macrocycle upon coordination to Z n  2 +  ions. The C - C - N = C dihedral  angles within the macrocyclic backbone are ca. 31° leading to the overall cone shape. Oxygen atoms in the interior of the shape-persistent macrocycle are further coordinated to a near-tetrahedral [Zri40] cluster (Figure 5.5a, red) that closes the bowl. The basic 6+  14  zinc acetate cluster is bridged by three //-1,2 bidentate acetate ligands (Figure 5.5a, green). Three tridentate acetate ligands (Figure 5.5a, blue) bridge the Zn atoms in the macrocyclic N2O2 pockets with those at the base of the [Zri40]  6+  cluster. These ligands  bridge in the rare //-1,1,2 fashion with monodentate and syn-anti bidentate bridges. The 15  structure may be viewed as a cluster-capped trimetallated macrocycle, Figure 5.5b. Overall, the molecule contains Zn  truncated-cone-shaped  ions in tetrahedral, square  pyramidal, and octahedral coordination geometries. A few salen-type zinc cluster complexes are known with Z n - N and Z n - 0 distances within the N2O2 pockets of ca. 16  2.09 and ca. 2.03, respectively, as compared to ca. 2.12 and ca. 2.04, respectively, of complex 56f.  163  References on page 195.  a)  b)  Figure 5.5  (a) View of 56b from the side showing the truncated metallocone (black),  the [ZruO]^ tetrahedron (red), ju-1,2 acetates (green) and//-1,1,2 acetates (blue), (b) Cartoon representation of the zinc tetrahedron capping the truncated metallocone in 56b.  The near-tetrahedral [Zi^O] * cluster within this structure was surprising but these 6  clusters are not uncommon in zinc carboxylate chemistry. Some researchers have even 14  used similar clusters as molecular building blocks for the formation of molecular organic frameworks.  17  To compare bond lengths (Table 5.1) and bond angles (Table 5.2yof the  capping cluster within 56b, the Z n  2+  ions will be referred to as Z n - Z n and the acetate 1  7  bridging ligands as O A c - O A c as shown in Figure 5.6. The three Z n 1  6  2 +  •  ions within the 1 2  N2O2 pockets of the macrocycle (square pyramidal) will be referred to as Zn , Zn and Z n (Zn is actually octahedral as it is bound to a D M S O solvent molecule), those at the 3  3  bottom of the capping cluster (octahedral) will be called Zn , Z n and Zn , while the lone 4  Zn  5  6  ion (tetrahedral) at the top of the capping cluster will be Z n . The acetate ligands  2+  7  that link the macrocycle to the capping cluster (blue in Figure 5.5a) will be referred to as O A c , O A c and O A c while those joining the bottom of the [ZruO] " " tetrahedron to the 1  2  3  6  1  top as O A c , O A c and O A c (green in Figure 5.5a). 4  5  6  164  References on page 195.  Figure 5.6  Schematic representation of the macrocycle and its capping cluster. The  macrocycle is represented by the large triangle with Zn , Zn and Zn at the apices. The bottom of the cluster is represented by the smaller triangle with Z n , Z n and Z n at its 4  apices. The Z n represents the top of the [ Z n 0 ] 7  4  6+  5  6  cluster and is situated directly above  the tetrahedral oxygen atom (U4-O) that is bound to Z n , Z n , Z n and Z n but which is 4  5  6  7  not seen from the angle of this diagram.  165  References on page 195.  Table 5.1  Z n - 0 and Zn - Zn bond lengths within the crystal structure of 56b and  the averages of related bond lengths. Bond Zn" - O A c Zn - O A c Zn - O A c  Length (A) 1  2  2  3  3  Zn  3  Zn Zn Zn Zn Zn Zn  4 4 5 5 6 6  -  ODMSO  -OAc -OAc -OAc -OAc -OAc -OAc  Zn - O A c Zn - O A c Zn - O A c  1 2  2 3 3  1  4  4  5  5  6  6  Zn - O A c Zn - O A c Zn - O A c 7  4  7  5  7  6  Average (A)  1.987(4) 1.995(4) 2.056(4)  Bond Zn - U4-O Zn -1X4-0 Zn - U 4 - O 4  2.01(4)  5  6  2.280(4)  Zn  7  2.507(4) 2.572(4) 2.592(4) 2.462(4) 2.400(4) 2.667(4)  Zn Zn Zn Zn Zn Zn  1  2.53(9)  1.978(4) 1.977(4) 1.979(4) 1.981(4) 1.979(4) 1.976(4)  1.979(3)  Average (A)  1.916(4) 1.926(4) 1.932(4)  1.925(8)  -  U4-0  1.981(3)  -  Zn Zn Zn Zn Zn Zn  4  3.512(5) 3.602(5) 3.553(5) 3.568(5) 3.559(5) 3.523(5)  Zn - Zn Zn - Z n Zn - Z n  5  Zn - Zn Zn - Z n Zn - Zn 4  7  5  7  6  7  1 2 2 3 3  6  4  5 5  6  4  1.978(1)  a  Length (A)  5  6  6  4  3.55(3)  3.305(5) 3.233(5) 3.315(5)  3.28(4)  2.969(5) 3.004(5) 2.987(5)  2.99(2)  H -0 is the central oxygen of the [Zn OJ tetrahedron +  4  4  166  References on page 195.  Table 5.2  O - Z n - 0 and Z n - O - Z n bond angles within the crystal structure of 56b  and the averages of related bond angles. Atoms  Angle (°)  3  O-Zn-OAc O'-Zn-OAc  1  0-Zn -OAc 0'-Zn -OAc 2  1  2  2  0-Zn -OAc 0'-Zn -OAc 3  2  108.31(16) 109.18(17)  108.7(6)  108.29(16) 107.68(16)  107.9(4)  95.75(16) 93.53(16)  3  3  3  Average (°)  Atoms  Angle (°)  0-Zn -OAc 0'-Zn -OAc 6  103.83(16) 109.07(16)  6  6  6  OAc -Zn -OAc OAc -Zn -OAc OAc -Zn -OAc 4  7  5  5  7  6  6  7  4  4  106.95(15) 109.08(16)  4  4  4  Zn -jo.4-0-Zn 4  7  Z n - (0.4-O-Zn  7  108(2)  Z n - U4-0-Zn  7  Z n - H4-0-Zn  5  Z n - U4-0-Zn  6  Z n - m-O-Zn  4  6  4  0-Zn -OAc 0'-Zn -OAc 5  107.33(16) 105.98(16)  5  5  5  106(4)  100.41(17) 101.20(17) 102.55(17)  101(1)  99.23(15) 100.48(16) 99.53(15)  99.8(7)  118.71(17) 113.89(17) 118.98(19)  117(3)  95(2) 5  0-Zn -OAc 0'-Zn -OAc  Average (°)  106(1)  5  6  O and O' are the two oxygen atoms of the N 0 pockets 2  2  Related zinc clusters of the form ZruOLe, where L is pivalate or benzoate rather than acetate, are known.  143  In the solid-state molecular structure of these clusters the Z n -  O bond lengths to the bridging ligands are slightly shorter than the ca. 1.98 A observed in the structure of 56b, being between 1.93 and 1.96 A . The Z n - 0 distances to the central U4-0 of these related clusters are similar to those of Zn , Z n and Z n being ca. 1.93 A but 4  5  6  the capping Z n has a longer distance to the central oxygen with a distance of 1.98 A . 7  This produces a distorted tetrahedral environment for the central U4-O atom within the structure of 56b. Crystals suitable for S C X R D were also obtained for the complex 56e. The obtained crystal structure is very similar to that of 56b with nearly identical bond distances and angles. The solid-state structures of both 56b and 56e are consistent with  167  References on page 195.  the solution data ('H, C N M R spectroscopy) for complexes 56b,e,f,h. Although ESIl 3  M S of 56f shows only [56f-Zn 0(OAc) +Na] (= [55f+Zn (OAc) Na] ) as the largest +  2  +  2  2  4  ion, [56b-OAc] and [56e-OAc] have also been observed by ESI-MS or M A L D I - T O F +  +  M S , as well as, other sensible fragments of the Zn7 complex. These heptazinc complexes are stable for several months in solution. A high temperature N M R experiment of 56f in (CDC1 ) showed no decomposition or dynamic 2  2  motion in the complex at temperatures up to ca. 120 °C. Moreover, these molecules are insensitive to small quantities of water.  5.2.2  Mechanism of Formation  Formation of 56 from 26 begins with trimetallation of the macrocycle (i.e, formation of 55). The most likely avenues for formation of the cluster complex are that the macrocycle coordinates to a preformed cluster in solution, or that the cluster is templated inside the metallomacrocycle (Scheme 5.1). To investigate the possibility of a templated mechanism such as that depicted in Scheme 5.1b ' H N M R spectroscopy studies were undertaken. In this mechanism the trimetallated macrocycle is first formed followed by a sequential addition of zinc to the catechol units of the macrocycle and concluding with capping by a final zinc atom. When four equivalents of Zn(OAc) were added to macrocycle 26f, the ' H N M R spectrum was 2  ambiguous. In this broad spectrum the Zn7 species was not observed and the spectrum does not resemble the spectra previously obtained for the dimetallated or trimetallated macrocycles either. This may be some other intermediate in the formation of complex 56 but it is difficult to discern what this new species might be.  168  References on page 195.  Scheme 5.1  Two possible mechanisms for the formation of heptazinc complexes 56.  (a) Trimetallated macrocycle complexes preformed  cluster or (b)  trimetallated  macrocycle templates the cluster formation. Acetate ligands and central U4-O are not shown for clarity.  With the addition of five or six equivalents of Zn(OAc)2 to macrocycle 26f the H N M R spectra show the resonances expected for the heptametallated cluster complex but also show a second set of peaks shifted only slightly from those of the Zn7 species. The mixture is difficult to separate but this second set of resonances may correspond to either  169  References on page 195.  the penta- or hexametallated complex. Crystals suitable for S C X R D could not be obtained from these mixtures and mass spectrometry provided little concrete evidence as the heptametallic species is known to fragment to Zns and Zri6 species upon ionization. When the mixtures obtained from either the addition of four, five or six equivalents of Zn(OAc)2 were treated with further amounts of Zn(OAc)2 the heptanuclear zinc complex 56f was obtained ( ' H N M R spectroscopy). This suggests a supramolecular templating mechanism for the formation of cluster compounds 56 whereby the metallated macrocycle guides the formation of the cluster in its interior. To expand the investigation of these systems zinc methacrylate was substituted for zinc acetate in hopes that the reactivity of the resulting complexes would be altered to allow for the study and isolation of possible intermediates. When zinc methacrylate was reacted with macrocycle 26b rather than zinc acetate a tetrazinc species 57b was formed. Single crystals suitable for X-ray diffraction were obtained and the S C X R D reveals a complex with four zinc centres in square pyramidal geometry (Figure 5.7). Three Z n  2 +  ions occupy the N2O2 binding sites, imparting a cone shape to the macrocycle similar to complex 56b, with Z n - N and Zn-O distances of ca. 2.11 and ca. 1.99, respectively and C - C - N = C dihedral angles of ca. 24°. In this case, however, only one Z n  2 +  ion is  coordinated in the interior of the metallomacrocycle to the oxygen atoms of one catechol unit. Two bridging methacrylate ligands and a water molecule complete the coordination sphere of the capping Z n  2 +  ion. Table 5.3 and 5.4 show selected bond lengths and bond  angles, respectively, of complex 57b with the same notation as that presented for complex 56b (Figure 5.6) but with the methacrylate ligands denoted as OMet and 1  OMet . 2  170  References on page 195.  Figure 5.7  Solid-state molecular structure of complex 57b as obtained by S C X R D (H  atoms omitted for clarity). Thermal ellipsoids are shown at 50% probability (Black = C, blue = N , red = O, green = Zn, yellow = S). (a) View of 57b from the side (ethoxy groups removed), (b) View of 57b from the top. A D M S O solvent molecule is coordinated to the third Zn in the macrocycle.  Table 5.3  Zn - O and Zn - Zn bond lengths within the crystal structure of 57b and  the averages of related bond lengths. Bond Z n - OMet Zn - O M e t 1  1  2  2  Z n - OMet Z n - OMet 4  1  4  2  Zn - Zn Zn - Zn 1  4  2  4  Zn  3  Zn  4  -  —  Length (A)  Average (A)  2.031(3) 2.038(4)  2.035(5)  2.069(3) 2.031(3)  2.05(3)  3.444(5) 3.456(5)  3.450(8)  ODMSO  2.051(4)  0 20  1.967(3)  H  171  References on page 195.  Table 5.4  O - Z n - 0 and Z n - O - Z n bond angles within the crystal structure of 57b  and the averages of related bond angles. Atoms O-Zn'-OMet O'-Zn'-OMet  1  0-Zn -OMet 0'-Zn -OMet 2  1  2  2  2  OMet-Zn -OMet 4  97.93(13) 101.10(15)  99(2)  95.30(13) 101.36(15)  98(4)  102.52(14) 99.06(14)  4  H  a  Average (°)  87.07(14)  2  OMet'-Zn -0 20 OMet -Zn -OH20 2  Angle (°)  4  100(2)  O and O' are the two oxygen atoms of the N 0 pockets 2  2  Complex 57b represents an intermediate trapped during the growth of the heptanuclear metallic cluster. The H2O molecule coordinated to the capping Zn poised to form the centre of a [Zri40]  6+  ion is  tetrahedron. Again, this supports a templated  formation of the [Zri40] cluster. This coordinated H2O molecule is observed in the ' H 6+  N M R spectrum of complex 57b as a broad singlet at 10.0 ppm. As well, three imine resonances are observed (8.91, 8.83 and 8.77 ppm), each of which integrate to two protons as would be expected i f a fourth zinc atom were bound to one catechol unit in solution.  5.2.3  Capsule Formation  These multimetallic cluster complexes possess a concave surface of aromatic rings, creating a large void space. Interestingly, there is a D M S O molecule coordinated (via O) to one of the Zn  ions inside the bowl in the single-crystal structure of complex  172  References on page 195.  56b, but it must be rapidly exchanging in solution since the H N M R spectrum of 56b in ]  D M S O shows Cjv symmetry. A crystal structure of complex 56e obtained from benzene shows the same overall structure as for 56b, but there is no solvent coordinated inside the bowl.  Figure 5.8  (a) Dimer of 56e viewed from the top (SCXRD); (b) dimer of 56e viewed  from the side (SCXRD); (c) calculated structure of 56a viewed from the top (PM3); (d) calculated structure of 56a viewed from the side (PM3). Hydrogen atoms have been removed for clarity (Black = C, green = N , red = O, dark green = Zn).  173  References on page 195.  In the solid state, 56e is organized into dimers (Figure 5:8a,b) with the molecules arranged such that they nearly form a capsule, where two of the molecules are oriented face-to-face, with ca. 60° rotation. The molecules are not interlocked, but are separated by 6-7 A with disordered solvent in the space between them. !  H N M R studies of complexes 56b,e,f,h show that these systems form dimeric  capsules in some solvents. For example, the H N M R spectrum of 56e in CDCI3, CD2CI2, l  and CeD6 reveals sharp peaks, whereas broad peaks are observed in toluene-afc and pxylenes-dyo, Figure 5.9.  1  Figure 5.9  1  1  8  -~—r~  • 1  1  4  1  1  —T  1  2  1  ppm  ' H N M R spectra (300 MHz) of 56e in (a) CDC1 , (b) C D , (c) toluene-<4 3  6  6  and (d) p-xylenes-djo. H resonances are broadened in the case of (c) and (d). !  174  References on page 195.  Upon heating the deuterated toluene and ^-xylenes solutions to 80 °C and 100 °C, respectively, the peaks for the zinc complex sharpen to similar linewidths as those observed in benzene, Figure 5.10. At high temperature, the full-width at half-maximum (FWHM) of the imine (N=CH) resonances converge to the same value in all solvents (ca. 0.01 ppm).  b)  a)  0.16 0.14  1  i 1  120°C  1  1 i  100 "C  1  n  fc  80°C  ^  60°C  ^  40 °C  ^  0.12  y  M  0.10  \'\J \ji v, \  n  0.08  U J [AM.  0.06 0.04 0.02  25 °C T  1  8  1  1  7  r—  Figure 5.10  —i  4  1  1  3  r—i  2  0.00 1  1  1  1  1  ppm  20  60  40  80 T/°C  100  120  •  (a) ' H V T - N M R spectra of 56h in />xylenes-e? . (b) Plot of full-width at /0  half-maximum (FWHM) for the imine resonance (~8 ppm) of 56f vs. T in C^D^ (•), toluene-cfe (•), and p-xylenes-dio (V).  These observations, which are reversible, can be attributed to dimerization of the complex in solution. As the linewidths of the aromatic and imine resonances are most dramatically affected by the solvent change (the linewidths for the acetate resonances are virtually unchanged), the dimerization is likely occurring between two bowl-shaped faces of the structure, analogous to the solid-state molecular structure of 56e, Figure 5.8a,b. In solvents composed of smaller molecules (CDCI3, CD2CI2, C^De), the interior of the bowl  175  References on page 195.  is effectively solvated. Solvents composed of larger molecules (toluene, xylenes), are unable to adequately solvate the interior of the bowl, leading to dimerization. At low temperature, exchange between monomer and dimer is slow and leads to broad peaks in the H N M R spectrum. At high temperature, the dimers dissociate into monomers in all }  of the solvents. Dynamic light scattering experiments of 56h in CHCI3 and /^-xylenes (RT and 80 °C) indicate that no large aggregates are present. From the autocorrelation function for the sample in CHCI3, a diameter of 2-4 nm for the molecule was extracted, consistent with a monomeric or dimeric structure. In /^-xylenes, background scattering from the solvent was too great compared to scattering from the sample to enable an estimate of the particle diameters, but no large particles were detected. It is likely that the absence of significant light scattering is due to the small size of the aggregates (e.g., monomeric or dimeric) rather than due to refractive index matching between the complex and the solvent. A large scattering signal and correspondingly large particles from the autocorrelation function (-400 nm from Contin) were observed from a sample of 56h as it dissolved in />-xylenes before warming; these aggregates disappeared on warming the solution and did not return when the sample was cooled. To further substantiate this possible dimer formation, the effect of adding solvent to solutions of 56h in toluene-a^ was examined. Coordinating solvents with large donor 18  numbers (DNs),  such as D M S O , cause disruption of the aggregates at low  concentrations (< 1% v/v) while larger concentrations are required for solvents with small DNs (e.g. CHCI3). Figure 5.11 shows a plot of the normalized linewidths of the imine resonance vs. vol. % of added solvent to a solution of 56h in toluene-ofo. As the  176  References on page 195.  introduction of coordinating solvents does not affect any of the acetate group resonances, it is likely that the solvent is coordinating reversibly with the vacant coordination sites of the metals on the interior of the macrocyclic bowl, similar to the D M S O observed in the crystal structure of 56b, leading to dissociation of the dimer.  0  2  4  6  8  10  12  14  16  18  Vol. % of Added Solvent  Figure 5.11  Plot of normalized F W H M of the imine resonance vs. vol. % of added  solvent to a solution of 56h in toluene-d§ (ca. 5.2 x 10" M ) ; from left to right: D M S O 3  (•), 'PrOH (•), M e C N (o), acetone (T), and CHC1 (V). 3  The open faces of the aromatic rings are complementary and can fit together to maximize van der Waals interactions. To study this further, semi-empirical (PM3) calculations were performed on the monomeric complex 56a (with peripheral methoxy groups) as well as on a model dimer. Energy minimizations were performed starting 19  with the atomic coordinates for 56e, with only three Z n - 0 bond lengths fixed in the model. Semi-empirical calculations were able to accurately mimic the shape of the complexes. Calculations indicate that a stable dimer will form between two molecules of  177  References on page 195.  56 where they are rotated by ca. 60° relative to one another and accompanied by a horizontal translation. Figures 5.8c and 5.8d show the energy minimized structure of the dimer held together by van der Waals interactions between the molecules. The calculations estimate that the binding energy is only 9 kcal/mol in the gas phase, which is consistent with the weak, solvent-dependent interaction that is observed. The driving force of most dimer formations depends on the influence of intermolecular forces such as hydrogen-bonding or  7t-7t  interactions. In the case of  heptametallic complexes 56b,e,f,h only van der Waals interactions are available to influence the dimerization. Substituted resorcinarenes have also been shown to form dimers in solution where the only driving force is van der Waals interactions between the 90  molecules.  These molecules, known as "velcraplexes", show a large solvent  dependence for dimerization. Moreover, the interaction between these macrocycles is ca. 1-9 kcal/mol, which is on the same order as the calculations obtained for heptametallic complexes 56b,e,f,h. 5.2.3  Heptanuclear Cadmium Complexes  9+  Upon addition of Zn(OAc)2 to macrocycle 26, three Zn  ions bind within the  N2O2 pockets of the macrocycle forming a truncated cone which is then able to template the formation of a [Zri40] cluster that caps the cone to form a bowl-like structure. With 6+  addition of different sized metal atoms it may be possible to form bowls of different curvatures, tuneable by the choice of metal ion. With this in mind studies involving the 9+  larger Cd ion were undertaken.  178  References on page 195.  When seven equivalents of Cd(0Ac)2 were added to a solution of macrocycle 26f a red solid was obtained (58f) whose *H N M R spectrum resembles very closely that of the zinc species 56f (Figure 5.12). Again, no hydrogen bonded hydroxyl resonances are observed and the overall  symmetry of the system remains. Like the related Zn  system (56f) there is a loss of mirror plane in the system as seen by a complex splitting pattern of the OCH2 resonance and here, as well, two different acetate resonances are observed.  1  1  1  1  1  10  8  Figure 5.12  n  —1  '  1  1  1  1  6  1  4  1  '  1  1  <  '  1  2  r—  1  ppm  0  ' H N M R spectrum (CDC1 , 300 M H z ) of cadmium complex 58f (* = 3  CHCI3) which resembles closely that for complex 56f (Figure 5.3 top). m  Cdand  1 1 3  C d are N M R active nuclei, both with a nuclear spin of 1/2, and have  a natural abundance of 12.75% and 12.26% with a sensitivity of 0.00954 and 0.0109, respectively (as compared to *H with 99.98% natural abundance and a sensitivity of 1). Cadmium satellites are observed in the imine (N=CH) resonance (8.26 ppm,  JHC<I  =  34.6  Hz) as these protons are only three bonds removed from the Cd atoms within the N2O2  179  References on page 195.  pockets of the macrocycle.  1 1 3  C d N M R spectra could be obtained for 58f and three  cadmium environments are observed (Figure 5.13) which is expected i f the cadmium system is analogous to the heptanuclear zinc system 56f. The resonance at 140 ppm shows splitting due to coupling with the imine (N=CH) protons ( JcdH - 34.1 Hz) 3  suggesting that the Cd atoms within the macrocycle backbone are deshielded more than those of the capping cluster. Few salen-type cadmium complexes are known and those that have been prepared '  160 21  are often part of a more complex structure where coupling  constants cannot be identified due to overlapping resonances. Therefore, the C d - H coupling constant obtained from N M R spectroscopy of the heptacadmium complex 58f could not be compared to other related systems.  —  i  •  160  Figure 5.13  1  140  113  •  1  120  •  1  100  •  r~  60  80  —i—  —i—  40  20  -20  ppm  C d N M R spectrum (CDC1 , 88.7 MHz) of cadmium complex 58f with 3  inset showing coupling.  180  References on page 195.  There are a few differences between the  C N M R spectra of cadmium complex  58f and zinc complex 56f. The first is a single broad peak at 181 ppm in the spectrum of 58f in place of the two singlets in spectrum 56f corresponding to the two O2CCH3 environments. Second, only one  O2CCH3  resonance is observed in the spectrum of 58f  with the second resonance likely having a chemical shift that is coincident with one of the alkoxy group carbon atoms. The *H N M R spectrum of 58f confirms that there are indeed two different acetate environments in this cadmium complex as two acetate resonances at 2.15 and 2.00 ppm are observed. These peaks are slightly shifted from that of the O2CC//3 resonances of the zinc complex suggesting some small differences between these two systems. These differences may arise from a varied cone size of the bowl structure in complex 58f resulting from the complexation of the larger cadmium ions. However, crystals suitable for X-ray diffraction could not be obtained and the actual cone size of this heptanuclear complex remains unknown. If the cone size of this complex is different than that for the zinc analogue then the size of this bowl-like system is tuneable by the choice of the incorporated metal ions. No other bowl-shaped systems have been reported that can be tuned in such a way. This heptametallic system could then provide a powerful new tool to dictate bowl size without the need of further synthetic design.  5.3  Conclusions  In summary, this chapter communicates the surprising discovery of new bowlshaped metal cluster complexes obtained during the metallation of shape-persistent conjugated macrocycles. Moreover, significant evidence reveals that these unusual  181  References on page 195.  structures arise from a supramolecular templating mechanism within the shape-persistent macrocycle. These stable, soluble bowl-shaped molecules form capsules in solution, opening the possibility for their use in molecular recognition and host-guest chemistry. The presence of accessible coordination sites in the bottom of the bowl has been verified by solid-state (SCXRD with and without D M S O coordinated) and solution (donor number dependence) measurements.  5.4  5.4.1  Experimental  General  Zinc(II) acetate dihydrate, zinc(II) methacrylate, cadmium(II) acetate dihydrate and (CDCl2)2 were obtained from Aldrich. Ethanol was distilled from magnesium under 191  N2. Macrocycle 26 was prepared by the literature procedure.  11  111  H , C and  spectra were recorded on either a Bruker AV-300 or AV-400 spectrometer.  Cd N M R 1 3  C NMR  spectra were recorded using either a proton decoupled or APT pulse sequence. ' H N M R spectra were calibrated to the residual protonated solvent at 7.24 (CDCI3) and 8.03 (DMF-tfV) ppm. C N M R spectra were calibrated to the residual protonated solvent at 1 3  77.00 (CDCI3) and 163.2 (DMF-J ) ppm. For C d N M R experiments the Bruker A V u 3  7  400 spectrometer was externally calibrated to Cd(C104)2 in D2O (0 ppm). UV-vis spectra were obtained in CHC1 (ca. 6 x 10" M ) on a Varian Cary 5000 UV-vis-near-IR 6  3  spectrophotometer using a 1 cm quartz cuvette. IR spectra were obtained as K B r discs with a Bomems MB-series spectrometer. Electrospray (ESI) mass spectra were obtained on a Micromass L C T time-of-flight (TOF) mass spectrometer equipped with an 182  References on page 195.  electrospray ion source. M A L D I - T O F mass spectra were obtained in a dithranol matrix (cast from THF) on a Bruker Biflex IV instrument where spectra were acquired in the positive reflection mode with delay extraction. The samples were analyzed in MeOH:CHCl  3  (1:1) at 100 u M . Elemental analyses (C,H,N,Zn) were performed at  Canadian Microanalytical Services (Delta, B C ) and the U B C Microanalytical Services Laboratory. Melting points were obtained on a Fisher-John's melting point apparatus. ' H N M R data of the OCH2 group in 56 were simulated on a PC as an ABX2 spin system with MestRe-C v2.3a  22  This work has shown that in general, mass spectrometry of these complexes rarely gives the molecular ion. Most of the major peaks observed by M A L D I or ESI techniques can  be assigned  to  sensible  fragments.  In the  ESI of the  complexes, [ M -  Zn20(OAc)2+Na] is usually the major fragment observed. +  5.4.2  Procedures  Heptazinc Complex 56e (R = "CsHn). Zinc acetate dihydrate (374 mg, 1.70 mmol) was added to a solution of 26e (250 mg, 0.202 mmol) in 50 mL of dry ethanol under N2. The deep red solution turned bright orange within a few minutes at room temperature. After stirring at reflux (~90 °C) for 2 h, the orange mixture was cooled to room temperature and the precipitate isolated by filtration. The crude solid was recrystallized from ethanol to afford an orange microcrystalline solid 56e. Yield: 307 mg (0.15 mmol, 74%).  Data for 56e (R = C H ) . n  s  n  1 3  C N M R (100.7 M H z , CDCI3) 5 180.0 ( 0 C C H ) , 178.8 2  3  (O2CCH3), 161.9, 158.6, 150.2, 134.1, 120.8, 119.3, 102.0, 69.7 (OCH ), 28.9 (CH ), 2  183  2  References on page 195.  28.2 (CH ), 23.4 ( 0 C C H ) , 22.4 (CH ), 21.7 ( 0 C C H ) , 14.0 (CH CH ) ppm; *H N M R 2  2  3  2  2  3  2  3  (300 M H z , CDC1 ) 5 8.33 (s, 6H, imine), 6.99 (s, 6H, Ar), 6.72 (s, 6H, Ar), 4.08 (m, 12H, 3  OCH ), 1.95 (s, 9H, 0 C C # ) , 1.89 (m, 12H, CH ), 1.86 (s, 9H, 0 C C / / ) , 1.62 (s, H 0 ) , 2  2  3  2  1.47 (m, 24H, CH ), 0.97 (t, J 3  2  H H  2  3  2  = 7.1 Hz, 18H, CH C77 ) ppm. UV-vis (CH C1 ) 2  3  2  W  2  (s) = 415 (1.2 x 10 ), 347.5 (6.4 x 10 ), 240 (7.4 x 10 ) nm (L mol" cm" ). ESI-MS: m/z = 5  4  4  1  1  1810 [56e-Zn 0(OAc) +Na] , 1870 [56e-Zn(OAc) +H] , 1994 [56e-OAc]". IR (KBr): v = +  2  +  2  2  3451, 2960, 2932, 2860, 1612, 1572, 1503, 1455, 1448, 1399, 1318, 1262, 1215, 1185, 1104, 1036, 927, 751, 690 cm" . Mp. >280 °C. Anal. Calc'd for 56e ( C H i N O Z n ) : 1  84  02  6  25  7  C, 49.13; H , 5.01; N , 4.09. Found: C, 49.23; H , 5.08; N , 4.40. Single crystals suitable for X-ray diffraction were obtained from benzene.  Heptazinc Complex 56b (R = C H ). Heptazinc complex 56b was prepared by a 2  5  procedure analogous to that for 56e. The product was recrystallized from D M F . Yield was ca. 80%.  Data for 56b (R = C H ). C N M R (75.5 M H z , DMF-d ) 5 178.8 ( 0 C C H ) , 173.5 1 3  2  5  7  2  3  ( 0 C C H ) , 163.7, 158.4, 150.3, 134.7, 121.7, 120.5, 102.9, 65.2 (OCH ), 15.0 ( C H C H ) 2  3  2  2  3  ppm; H N M R (300 M H z , DMF-d ) 5 8.80 (s, 6H, imine), 7.53 (s, 6H, Ar), 6.90 (s, 6H, !  7  Ar), 4.30 (m, 12H, OCH ), 1.88 (s, 9H, 0 C C # ) , 1.71 (s, 9H, 0 C C # ) , 1.46 (t, J 3  2  2  3  6.9 Hz, 18H, C H C # ) ppm. UV-vis (CH C1 ) ^ 2  3  2  2  2  3  H H  =  (e) = 413 (1.2 x 10 ), 347 (6.6 x 10 ), 5  4  242 (7.4 x 10 ) nm (L mol" cm" ). ESI-MS: m/z = 1557.2 [56b-Zn 0(OAc) +Na] . 4  1  1  +  2  MALDI-TOF-MS:  m/z = 1557 [56b-Zn 0(OAc) +Na] , +  2  2  1741  2  [56b-OAc]",  1820  [56b+H 0+H] , 1899 [56b+(H 0) +(Na) -H] . IR (KBr): v = 2979, 2923, 2894, 1609, +  2  3+  2  3  2  184  References on page 195.  1562, 1505, 1458, 1444, 1392, 1316, 1264, 1217, 1179, 1108, 1037, 938, 754 cm- . Mp. 1  -250 °C (dec). Anal. Calc'd for 56b-2H 0 (C 6H7oN 025Zn ): C, 43.15; H , 3.84; N , 4.57. 2  6  6  7  Found: C, 42.93; H , 4.05; N , 5.0. Single crystals suitable for X-ray diffraction were obtained from D M S O .  Heptazinc Complex 56f (R = "CeHn). Heptazinc complex 56f was prepared by a procedure analogous to that for 56e. The product was recrystallized from ethanol. Yield was ca. 45%.  Data for 56f (R = C H i ) . C N M R (75.5 M H z , CDC1 ) 5 180.1 ( 0 C C H ) , 178.8 n  1 3  6  3  3  2  3  ( 0 C C H ) , 161.9, 158.7, 150.3, 134.2, 120.8, 119.3, 102.0, 69.7 (OCH ), 31.5 (CH ), 2  3  2  2  29.2 (CH ), 25.7 (CH ), 23.4 ( 0 C C H ) , 22.6 (CH ), 21.6 ( 0 C C H ) , 14.0 ( C H C H ) 2  2  2  3  2  2  3  2  3  ppm; ' H N M R (300 M H z , CDC1 ) 5 8.31 (s, 6H, imine), 6.97 (s, 6H, aromatic CH), 6.69 3  (s, 6H, aromatic CH), 4.07 (m, 12H, OCH ), 1.93 (s, 9H, 0 C C / / ) , 1.86 (m, 12H, CH ), 2  2  3  2  1.84 (s, 9H, 0 C C / / ) , 1.53 (m, 24H, CH ), 1.36 (m, 12H, CH ), 0.91 (t, J •= 6.7 Hz, 3  2  3  2  C H C i / ) ppm. UV-vis (CH C1 ) ^ 2  3  2  2  2  HH  (e) = 415 (1.3 x 10 ), 346 (6.9 x 10 ), 241 (7.8 x 5  4  10 ) nm (L mol" cm" ). ESI-MS: m/z = 1893.8 [56f-Zn 0(OAc) +Na] . IR (KBr): v = 4  1  1  +  2  2  3425, 2953, 2929, 2860, 1617, 1563, 1507, 1462, 1447, 1396, 1319, 1268, 1222, 1183, 1166, 1111, 1017, 722 cm" . Mp. -250 °C (dec). Anal. Calc'd for 56f (C oHii4N 0 5Zn7): 1  9  6  2  C, 50.57; H , 5.38; N , 3.93; Zn, 21.4. Found: C, 50.41; H , 5.41; N , 3.89; Zn, 20.30.  185  References on page 195.  Synthesis of Heptazinc Complex 56h (R = "CgHn). Heptazinc complex 56h was prepared by a procedure analogous to that for 56e. The product was recrystallized from D M F . Yield was ca. 50%.  Data for 56h (R = C H i ) . n  8  7  1 3  C N M R (75.5 M H z , CDC1 ) 5 180.1 ( 0 C C H ) , 178.9 3  2  3  (O2CCH3), 161.9, 158.7, 150.2, 134.2, 120.8, 119.3, 102.0, 69.7 (OCH ), 31.8 (CH ), 2  2  29.4 (CH ), 29.3 (CH ), 29.2 (CH ), 26.0 (CH ), 23.4 ( 0 C C H ) , 22.7 (CH ), 21.7 2  2  2  2  2  3  2  ( 0 C C H ) , 14.1 ( C H C H ) ppm; ' H N M R (300 M H z , CDC1 ) 5 8.31 (s, 6H, imine), 6.96 2  3  2  3  3  (s, 6H, Ar), 6.69 (s, 6H, Ar), 4.06 (m, 12H, OCH ), 1.93 (s, 9H, 0 C C # ) , 1.85 (m, 12H, 2  2  3  CH ), 1.84 (s, 9H, 0 CGr7 ), 1.71 (s, H 0 ) , 1.50 (m, 24H, CH ), 1.30 (m, 36H, CH ), 2  2  0.88 (t, J  3  2  2  = 6.4 Hz, 18H, C H C # ) ppm. UV-vis (CH C1 ) W  3  H H  2  3  2  2  2  (s) = 414 (1.2 x 10 ), 5  347 (6.2 x 10 ), 242 (6.6 x 10 ) nm (L mol" cm" ). ESI-MS: m/z = 2062 [56h4  4  1  1  Zn 0(OAc) +Na] , 2244 [56h-ZnO+H 0+H] . IR (KBr): v = 2959, 2927, 2856, 1617, +  2  +  2  2  1506, 1459, 1447, 1391, 1324, 1264, 1216, 1185, 1105, 1022, 756, 669, 616 cm" . Mp. 1  -270 °C (dec). Anal. Calc'd for 56h (Ci H,38N O Zn ): C, 53.13; H , 6.03; N , 3.64. 02  6  25  7  Found: C, 53.42; H , 6.30; N , 3.94.  Tetrazinc Complex 57b (R = C2H5). The crystals for the X-ray structure were initially obtained from a crude reaction mixture while attempting to make a heptanuclear complex with methacrylate ligands (i.e., analogous to 56b). Although the N M R spectrum indicated that the major product was a Z n complex, the species that crystallized from DMSO-Og 7  was the Z114 complex 57b. Single crystals of 57b were grown from D M S O . M A L D I - T O F of the  crystals  (identical to that obtained  186  from the  synthesis  below):  1459  References on page 195.  [57b+(H 0) +H] , 2810 [57b-(H 0) +H ] . The compound was then synthesized in high +  2  2+  2  2  2  2  yield by the following procedure:  Tetrazinc Complex 57b (R =  C2H5). A  round bottom flask was charged with 51 mg  (0.05 mmol) of macrocycle 26b and 49 mg (0.21 mmol) of zinc methacrylate. The mixture was cooled to 0 °C in an icebath, and 20 mL of cold ethanol was added. After stirring at 0 °C overnight, the precipitate from the cloudy dark red-orange solution was isolated by centrifugation. The powder was purified by a second centrifugation with fresh ethanol. Compound 57b was dried under vacuum and obtained as a deep red powder (62 mg, yield = 80%).  Data for 57b (R = C H ). *H N M R (300 M H z , DMF-d ) 5 10.0 (broad s, 2H, 2  5  7  coordinated H 0 ) , 8.91 (s, 2H, HC=N), 8.83 (s, 2H, //C=N), 8.77 (s, 2H, HC=N), 7.60 (s, 2  2H, Ar), 7.57 (s, 2H, Ar), 7.51 (s, 2H, Ar), 6.67 (s, 2H, Ar), 6^52 (s, 4H, Ar), 5.91 (s, 2 H , . C=CH ), 5.29 (s, 2H, C=CH ), 4.31 (br s, 12H, OCH ), 1.81 (s, 6H, CH (methacrylate)), 2  2  1.47 (t, J 3  H H  2  3  = 7.8 Hz 18H, CH Ctf ) ppm. UV-vis (CH C1 ) X 2  3  2  2  (e) = 421 (1.3xl0 ), 5  maK  3 50 (5.2 x 10 ) nm (L mol" cm" ). M A L D I - T O F : m/z = 1459.1 [57b+(H 0) +H] . IR 4  1  1  +  2  2  (KBr): v= 3433, 2978, 2929, 2899, 1607, 1553, 1505, 1450, 1419, 1390, 1365, 1326, 1264, 1211, 1183, 1106, 1040, 942, 903, 887, 847, 832, 753, 734 cm" . Anal. Calc'd for 1  5 7 b 3 H 0 (C H N 0 oZn4): C, 50.42; H , 4.50; N , 5.69. Found: C, 50.43; H , 4.58; N , 2  62  66  6  2  5.74.  187  References on page 195.  Heptacadmium complex 58f (R = "CeHo). Heptacadmium complex 58f was prepared by a procedure analogous to that for 56f substituting zinc methacrylate for zinc acetate. Yield was ca. 21%.  Data for 58f (R = C H , ) . n  6  113  3  C d N M R (88.7 M H z , CDC1 ) 5 140.0 (t, J  = 34.1 Hz),  3  3  10.14, 1.12 ppm; C N M R (75.5 M H z , l 3  CDCI3) 5 181.0 (broad, 0  2  C d H  C C H ) , 164.4, 161.3, 3  149.8, 134.6, 120.4, 119.2, 103.5, 69.9 (OCH ), 31.5 (CH ), 29.2 (CH ), 25.6 (CH ), 22.6 2  2  2  2  (CH ), 21.3 ( 0 C C H ) , 14.0 ( C H C H ) ppm; ' H N M R (300 M H z , CDC1 ) 8 8.26 (s, 6H, 2  2  3  2  3  3  imine), 8.26 (d, J cd = 34.6 Hz, 6H, imine) 6.87 (s, 6H, aromatic CH), 6.56 (s, 6H, 3  H  aromatic CH), 4.05 (m, 12H, OCH ), 2.15 (s, 9H, 0 C C i / ) , 2.00 (s, 9H, 0 C C / / ) , 1-84 2  2  3  2  (m, 12H, CH ), 1.50 (m, 24H, CH ), 1.37 (m, 12H, CH ), 0.91 (t, J 3  2  2  C H C # ) ppm. UV-vis (CH C1 ) ^ 2  3  2  2  2  H H  3  = 6.9 Hz, 18H  (s) = 410 (1.1 x 10 ), 348 (6.0 x 10 ), 247 (6.6 x 5  4  10 ) nm (L mol" cm" ). M A L D I - T O F - M S : m/z = 2130.9 [58f-Cd 0(OAc) +Na] , 2465.7 4  1  1  +  2  2  [58f] . IR (KBr): v = 3443, 2956, 2932, 2860, 1608, 1572, 1499, 1451, 1415, 1399, 1334, +  1266,1181,1156,1100,1012, 932, 903, 751, 698 cm" . Mp. -250 °C (dec). 1  5.4.3  Semi-Empirical Calculations.  The geometries of the monomer and dimer of 56a (R = CH3) were optimized by applying the semi-empirical PM3 method in Gaussian 03 package. During the optimization, the 19  Z n - 0 bond lengths for the zinc atom at the top of the cluster were fixed to be the experimental value, 2.03 A , for 56b (three bonds fixed in monomer, six bonds in fixed in dimer).  188  References on page 195.  The binding energy of the dimer, Eb(dimer), was calculated using the following equation:  Eb(dimer) = E (dimer) - 2*Et(monomer) t  where E (dimer) and E (monomer) are the total energies of the dimer and the isolated t  t  monomer, respectively. The final result for Eb(dimer) is -8.67 kcal/mol.  5.4.4  NMR Simulation.  'if N M R data of the OC//2 group in 56f were simulated on a PC as an ABX2 spin system with MestRe-C v2.3a. ' H N M R data were simulated as an ABX2 spin system using 8 22  4.044 (H ), 4.102 (H ), 1.80 ( H ) ppm; A  B  x  2  J  = 8.70 Hz; J A X = 6.60 Hz; 3  A  B  3  J  B  X  = 6.40 Hz.  Peaks Calc'd (Found): 1242.45 (1242.71), 1236.06 (1236.29), 1233.81 (1233.60), 1227.35 (1227.25), 1223.23 (1223.18), 1220.97 (1220.97), 1216.65 (1216.66), 1210.02 (1210.03), 1207.94 (1207.72), 1201.27 (1200.78) Hz.  5.4.5  X-Ray Diffraction Studies.  Measurements were made using a C C D area detector coupled with either a Bruker X8 or a Rigaku A F C 7 diffractometer with graphite monochromated MoKa radiation (k = 0.7107 A ) . The data were collected at a temperature of -100.0 + 0.1 °C Data were collected and integrated using either the Bruker S A I N T , d * T R E K 23  24  or TwinSolve  25  software package. The data was corrected for absorption effects using a multiscan method either S A D A B S  or CrystalClear . The data were corrected for Lorentz and  189  References on page 195.  polarization effects. The structures were solved by direct methods using either SIR92 or SIR2002 and refined as full-matrix least-squares against | F | using S H E L X . A l l non28  2  29  30  hydrogen atoms were refined anisotropically. A l l hydrogen atoms involved in hydrogenbonding were located in difference maps, while all other hydrogen atoms were included in calculated positions but not refined. For solvent molecules that are disordered in multiple orientations, that could not be modeled adequately, the S Q U E E Z E PLATON  3 2  31  function in  was used to adjust the data to account for residual electron density found  within lattice void spaces.  X-Ray Diffraction Study of 56b. Crystals of 56b suitable for X-ray diffraction were grown from D M S O by ether diffusion. The S Q U E E Z E  31  function in P L A T O N  3 2  was  used to remove approximately three disordered D M S O molecules per asymmetric unit. X-ray diffraction data shown in Table 5.5.  X-Ray Diffraction Study of 56e. Crystals of 56e suitable for X-ray diffraction were grown from benzene. The S Q U E E Z E  31  function in P L A T O N  3 2  was used to remove  approximately two disordered benzene molecules per asymmetric unit. The carbons on some of the alkoxy groups were disordered and modeled in two orientations. Largest parameter shift was 4.243 times its esd (one of the free variables for refining the disorder alkyl chains - all other parameters were near 0 x esd). X-ray diffraction data shown in Table 5.5.  190  References on page 195.  X-Ray Diffraction Study of 57b. Crystals of 57b suitable for X-ray diffraction were grown from D M S O . The S Q U E E Z E  function in P L A T O N  31  3 2  was used to remove  approximately four disordered D M S O molecules per asymmetric unit. The carbons on one of the ethoxy groups was disordered and modeled in two orientations. X-ray diffraction data shown in Table 5.5.  Table 5.5  X-ray diffraction data for compounds 56b, 56e and 57b. 56b  56e  57b  A . Crystal Data Empirical Formula  C72H N 028S Zn7  C84H102N6O25 Zn7  C74H96N6O23S6Z114  Formula Weight  2239.87  2053.46  1891.53  Crystal Color, Habit  red, prism  red, needle  orange, prism  Crystal Dimensions (mm)  0.50x0.30x0.20  0.30x0.10x0.05  0.225x0.125x0.075  Crystal System  primitive  C-centred  primitive  Lattice Type  triclinic ,  monoclinic  triclinic  Lattice Parameters  a= 12.0360(11) A b = 26.181(3) A c = 26.547(3) A a = 118.824(3)° p = 93.440(3)° 7 = 90.154(3)° V = 7310.9(14) A  a = 27.342(5) A b = 38.204(5) A c = 20.526(5) A a = 90° P = 113.343(5)° 7 = 90° V = 19686(7) A  a= 13.0855(21)A b = 17.6039(33) A c = 21.7220(40) A a = 70.3680(80)° p = 81.4740(70)° 7 = 70.9570(80)° V = 4450.8(21) A  Space Group  P-l (#2)  C2/c (#15)  P-l (#2)  Z value  4  4  2  D )  1.031 g/cm  96  9  6  3  ca  c  3  191  1.4382 g/cm  3  3  3  1.165 g/cm  3  References on page 195.  8424  000  2332  ^(MoKa)  12.67 cm"  r  1608  17.46 cm"  1  11.69 cm"  1  1  B. Intensity Measurements Diffractometer  Rigaku/AFC7 C C D  Bruker X8 A P E X  Bruker X8 A P E X  Radiation  MoKa (A, = 0.71073 A)  MoK„ (k = 0.71073 A)  MoK« (A, = 0.71073 A)  Data Images  460 exposures @59s  1017 exposures @20s  1813 exposures @25 s  Detector Position  38.28 mm  38.39 mm  37.06 mm  2 ©max  52.04 °  47.60 °  56.60 °  Total: 60844 Unique: 27033 (R = 0.0756)  Total: 90372 Unique: 15013 (R = 0.0749)  Total: 81131 Unique: 20789 (R , = 0.0981)  Absorption T = 0.7855 T,„ax = 1.0000  Absorption T = 0.720 T = 0.916  Absorption T = 0.779 T = 0.916  No. of Reflections Measured  int  Corrections  m i n  irt  in  m i n  m i n  m a x  m a x  C. Structure Solution and Refinement Structure Solution  Direct Methods (SIR92)  Direct Methods (SIR92)  Direct Methods (SIR92)  Refinement  Full-matrix leastsquares on F  Full-matrix leastsquares on F  Full-matrix leastsquares on F  Function Minimized  Ew(Fo -Fc )  Iw(Fo -Fc )  Sw(Fo -Fc )  Least Squares Weights w = l/(a (Fo )+(xP) +yP)  x = 0.1089 y = 0.0000  x = 0.0824 y = 0.0000  x = 0.0797 y = 0.0000  Anomalous Dispersion  A l l non-hydrogen atoms  A l l non-hydrogen atoms  A l l non-hydrogen atoms  2  2  2  2  2  2  2  192  2  2  2  2  2  2  2  2  References on page 195.  No. Observations (I>0.00a(I))  27033  15013  20789  No. Variables  1202  1031  878  Reflection/Parameter Ratio  22.49  14.56  23.68  Residuals (refined on F2, all 0.1035; 0.2056 data): R l ; wR2  0.1013; 0.1489  0.1649; 0.1748  Goodness of Fit Indicator  0.962  1.015  0.885  No. Observations (I>2.00o(I))  17491  9145  8512  Residuals (refined on F): R l ; wR2  0.0731; 0.18321  0.0551; 0.1355  0.0642; 0.1549  Max shift/error in final cycle  0.001  4.243  0.197  Max. peak in final diff. map  0.891 eV A  Min. peak in final diff. map  -0.737 e7 A  5.4.6  0.970 e7 A  3  3  0.901 e7 A  3  -0.624 e7 A  3  3  -0.843 e7 A  3  Dynamic Light Scattering.  Dynamic light scattering (DLS) experiments were carried out on a Brookhaven Instruments photon correlation spectrometer equipped with a BI-200SM goniometer, a BI-9000AT digital autocorrelator, and a Melles Griot He-Ne Laser (632.8 nm) with maximum power output of 75 mW. To ensure the accuracy of DLS measurements, great care was taken to eliminate dust from the samples.  Experiments with 56h  ( R = "CSHIT).  Spectroscopic grade chloroform and reagent grade  /^-xylene were used to gravimetrically prepare ~5 mg/mL stock solutions in each solvent by adding the solvent to 56h and stirring at room temperature for at least 1 h. The stock  193  References on page 195.  solution of 56h in /^-xylene was heated at 83 °C for 1 h and then cooled to room temperature. Scintillation vials for light scattering measurements were thoroughly cleaned with filtered chloroform and p-xylene, then measured quantities of stock solution were filtered into the dust-free scintillation vials through two 0.45 um nominal pore size filters connected in series. To maximize scattering signal for these experiments, the solutions were not diluted by adding pure solvent, so that the concentration of measured solutions  were  5.13  mg/mL  (chloroform) and  5.01  mg/mL  (p-xylene). D L S  measurements for both solutions and the respective pure solvents were carried out at a 90 ° detection angle with three repeat measurements of the autocorrelation function obtained under each set of conditions. For chloroform and chloroform solutions, D L S measurements were conducted at 23 °C. For p-xylene and p-xylene solutions, measurements were conducted first at 23 °C, and then at 83 °C, with 30 min. equilibration time after the temperature change.  194  References on page 195.  5.5  References  (1) (a) Gianneschi, N . C ; Masar, M . S., III. ; Mirkin, C. A . Acc. Chem. Res. 2005, 38, 825. (b) Holliday, B. J.; Mirkin, C. A . Angew. Chem. Int. Ed. 2001, 40, 2022. (2) (a) de Silva, A . P.; McCaughan, B.; McKinney, B. O. F.; Querol, M . Dalton Trans. 2003, 1902. (b) Mines, G. A . ; Tzeng, B.-C.; Stevenson, K . J.; L i , J.; Hupp, J. T. Angew. Chem. Int. Ed. 2002, 41, 154. (3) (a) Balzani, V . ; Credi, A . ; Raymo, F. M . ; Stoddart, J. F. Angew. Chem. Int. Ed. 2000, 39, 3348. (b) Jimenez-Molero, M . C ; Dietrich-Buchecker, C ; Sauvage, J.-P. Chem. Commun. 2003, 1613. (c) Crowley, J. D.; Goshe, A . J.; Steele, I. M . ; Bosnich, B . Chem. Eur. J. 2004,10, 1944. (4) (a) Chae, H . K.; Siberio-Perez, D. Y.; Kim, J.; Go, Y.; Eddaoudi, M . ; Matzger, A . J.; O'Keeffe, M . ; Yaghi, O. M . Nature, 2004 427, 523. (b) Zaworotko, M . J. Angew. Chem. Int. Ed. 2000, 39, 3052. (5)  (a) Ruben, M . ; Rojo, J.; Romero-Salguero, F. J.; Uppadine, L . H . ; Lehn, J.-M.  Angew. Chem. Int. Ed. 2004, 43, 3644. (b) James, S. L . Chem. Soc. Rev. 2003, 32, 276. (6) Large Ring Molecules; Semlyen, J. A., Ed.; John Wiley & Sons, Toronto, 1996. (7) (a) Leininger, S.; Olenyuk, B . ; Stang, P. J. Chem. Rev. 2000,100, 853. (b) Fujita, M . Chem. Soc. Rev. 1998, 2 7, 417. (8) (a) Dinolfo, P. H.; Hupp, J. T. Chem. Mater. 2001,13, 3113. (b) Lee, S. J.; Lin, W. J. Am. Chem. Soc. 2002,124, 4554. (c) Y u , S.-Y.; Kusukawa, T.; Biradha, K.; Fujita, M . J. Am. Chem. Soc. 2000, 122, 2665. (d) Y u , S.-Y.; Huang, H . ; L i u , H.-B.; Chen, Z.-N.; Zhang, R.; Fujita, M . Angew. Chem. Int. Ed. 2003, 42, 686. (e) Pinalli, R.; Cristini, V . ;  195  Sottili, V . ; Geremia, S.; Campagnolo, M . ; Caneschi, A.; Dalcanale, E. J. Am. Chem. Soc. 2004,72(5,6516. (9) Richeter, S.; Rebek, J., Jr. J. Am. Chem. Soc. 2004, 726", 16280. (10) (a) Hoger, S. Chem. Eur. J. 2004, 10, 1320. (b) Tobe, Y . ; Utsumi, N . ; Kawabata, K.; Nagano, A . ; Adachi, K . ; Araki, S.; Sonoda, M . ; Hirose, K . ; Naemura, K . J. Am. Chem. Soc. 2002, 124, 5350. (c) Zhang, J.; Moore, J. S. J. Am. Chem. Soc. 1994, 776, 2655. (11) (a) Campbell, K . ; Kuehl, C. J.; Ferguson, M . J.; Stang, P. J.; Tykwinski, R. R. J. Am. Chem. Soc. 2002, 124, 7266 (b) Opris, D. M . ; Franke, P.; Schluter, A . D. Eur. J. Org. Chem. 2005, 822. (12) (a) Gallant, A . J.; Hui, J. K . - H . ; Zahariev, F. E.; Wang, Y . A . ; MacLachlan, M . J. J. Org. Chem. 2005, 70, 7936. (b) Gallant, A . J.; MacLachlan, M . J. Angew. Chem. Int. Ed. 2003, 42, '5307. (c) Akine, S.; Taniguchi, T.; Nabeshima, T. Tetrahedron Lett. 2001, 42, 8861. (13)  Related macrocycles that bind Zn  in N2O2 pockets: (a) M a , C ; L o , A . ;  Abdolmaleki, A . ; MacLachlan, M . J. Org. Lett. 2004, 6, 3841. (b) M a , C. T. L . ; MacLachlan, M . J. Angew. Chem. Int. Ed. 2005, 44,4178. (14) (a) Clegg, W.; Harbron, D. R.; Homan, C. D.; Hunt, P. A . ; Little, I. R.; Staughan, B . P. Inorg. Chim. Acta 1991, 186, 51. (b) McCowan, C. S.; Groy, T. L . ; Caudle, M . T. Inorg. Chem. 2002, 41, 1120. (c) Gordon, R. M . ; Silver, H . B . Can. J. Chem. 1983, 61, y  1218.  196  (15) (a) Ye, B.-H.; L i , X . - Y . ; Williams, I. D.; Chen, X . - M . Inorg. Chem. 2002, 41, 6426. (b) Adams, FL; Clunas, S.; Fenton, D. E.; Gregson, T. J.; McHugh, P. E.; Spey, S. E . Inorg. Chem. Commun. 2002, 5, 211. (16)  (a) Akine, S.; Taniguchi, T.; Nabeshima, T. Inorg. Chem. 2004, 43, 6142. (b)  Sanmartin, J.; Bermejo, M . R.; Garcia-Deibe, A . M . ; Llamas-Saiz, A . L . Chem. Commun. 2000, 795. (c) Sanmartin, J.; Bermejo, M . R.; Garcia-Deibe, A . M . ; Rivas, I. M . ; Fernandez, A . R. J. Chem. Soc., Dalton Trans. 2000, 4174. (17) L i , FL; Eddaoudi, M . ; O'Keeffe, M . ; Yaghi, O. M . Nature, 1999, 402, 276. (18) (a) Gutmann, V . Coord. Chem. Rev. 1967, 2, 239. (b) Jin, T. Phys. Chem. Chem. Phys. 2000, 2, 1401. (c) Marcus, Y . J. Solution Chem. 1984,13, 599. (19) (a) Gaussian 03, Revision B.05, M . J. Frisch et al, Gaussian, Inc., Pittsburgh P A , 2003. (b) Stewart, J. J. P. J. Comp. Chem. 1989,10, 209. (20) (a) Bryant, J. A . ; Knobler, C. B . ; Cram, D. J. J. Am. Chem. Soc. 1990, 112, 1254. (b) Cram, D. J.; Choi, H.-J.; Bryant, J. A . ; Knobler, C. B . J. Am. Chem. Soc. 1992, 114, 7748. (21) Lo, W.-K.; Wong, W.-K.; Wong, W. Y . ; Guo, J. Eur. J. Inorg. Chem. 2005, 3950. (22) MestRe-C v2.3a, C. Cobas, J. Cruces, and F.J. Sardina, Universidad de Santiago de Compostela, Spain. (23) SAINT. Version 6.02. Bruker A X S Inc., Madison, Wisconsin, U S A (1999). (24) d*TREK. Area Detector Software. Version 7.11. Molecular Structure Corporation (2001). (25) CrvstalClear 1.3.5 SP2. Molecular Structure Corporation (2003).  197  (26) S A D A B S . Bruker Nonius area detector scaling and absorption correction - V2.05, Bruker A X S Inc., Madison, Wisconsin, USA. (27) SIR92: Altomare, A.; Cascarano, M . ; Giacovazzo, C ; Guagliardi, A . J. Appl. Cryst. 1994, 26, 343. (28) SIR2002: Burla, M . C ; Camalli, M . ; Carrozzini, B.; Cascarano, G. L . ; Giacovazzo, C ; Polidori, G.; Spagna, R. J. Appl. Cryst. 2003, 36, 1103. (29) Least Squares function minimized: EH>(F 2-F 2)2 0  c  (30) S H E L X : Sheldrick, G. M . Programs for Crystal Structure Analysis (Release 97-2). University of Gottingen, Germany (1997). (31) SQUEEZE: Van der. Sluis, P.; Spek, A . L. Acta Crystallogr., Sect A 1990, 46, 194. (32) P L A T O N , A Multipurpose Crystallographic Tool, Utrecht University, Utrecht, The Netherlands, A . L . Spek, (1998).  198  CHAPTER 6 Conclusions and Future Direction 6.1  Overview  This thesis has described the synthesis and characterization of new [3+3] Schiffbase macrocycles. These macrocycles are fully conjugated, possessing a crown ether-like central cavity as well as three N2O2 binding sites. The ability of these macrocycles to assemble into supramolecular structures upon the addition of small cations has been discovered. Furthermore, these new macrocycles have been shown to complex transition metal ions to produce a surprising heptanuclear complex. To generate this interesting complex the trimetallated macrocycle acts as a template to form a [IVLtO] * cluster (where 6  M = Zn  and Cd ) that caps the macrocycle resulting in a bowl-like structure. [3+3]  Schiff-base macrocycles are a new class of shape-persistent macrocycles and the work presented in this thesis has only begun to explore this new area of chemistry.  6.2  [3+3] Schiff-Base Macrocycles  Through the reaction of the diformyl species 29 with diamines 33b-i, [3+3] Schiff-base macrocycles 26b-i were synthesized in moderate to high yields (60-90%).' This is surprising as there are many products possible from the addition of 29 to 33b-i. Different sized macrocycles (e.g., [2+2] or [4+4]), oligomers and even helical polymers are all possible products of such a reaction. Due to the reversibility of the Schiff-base condensation reaction the thermodynamic product is obtained, which in this case is the 199  References on page 217.  [3+3] macrocycle. This macrocycle is likely stabilized due to minimized ring strain and strong intramolecular hydrogen bonding within the cavity of the macrocycle. By varying the synthetic conditions or by varying the ratios of starting materials different macrocycle fragments have been isolated (34-36). Upon further reaction, these fragments have been shown to form macrocycle 26 proving that they are intermediates to macrocycle formation and that the macrocycle forms in a stepwise manner. A new [3+3] Schiff-base macrocycle 45 was obtained by substituting a naphthylbased diformyl unit (48) for the phenyl-based unit (29). The central pore size of these 2  new macrocycles remains the same as that of the phenyl-based macrocycles but the macrocyclic backbone has been extended. These naphthyl-based macrocycles do not behave as do their phenyl analogues. In solution at room temperature these macrocycles exist mainly as the keto-enamine isomer, rather than the enol-imine isomer that is common to most salen-based compounds. The extended system generated by the use of naphthyl- rather than phenyl-based units is able to provide added stabilization for the keto-enamine form. It may be possible to further extend this [3+3] macrocycle through the use of an anthracene-based diformyl unit. A synthesis for 2,3-dimethoxyanthracene is shown in Scheme 6.1. With this species in hand, investigations could be undertaken to explore 3  possible ort/zo-formylation reactions. Then, after deprotection of the phenols the desired l,4-diformyl-2,3-dihydroxyanthracene would be obtained. The reaction of this diformyl anthracene unit with diamines 33b-i would be expected to result in anthracene-based [3+3] Schiff-base macrocycles that would likely be present in the keto-enamine form similar to that of the naphthyl-based analogues. The properties and reactivities of these  200  References on page 217.  three analogous macrocycles, phenyl-, naphthyl- and anthracene-based, could be investigated and compared.  Scheme 6.1  Proposed synthesis of 2,3-dimethoxyanthracene which could lead to the  formation of an anthracene-based diformyl species. O  O  OMe  .  ^OMe  MeO  ^  P  OMe 0  ^  0  .OH  .0  'OH ^0  3  HC(OMe) , M e O H , A i) toluene, A ii) K O H / H 0 , bubbling 0 b  3  2  c 2  i) N a B H , 'PrOH, A ii) HC1/H 0 iii) 4  2  N a B H , PrOH, A iv) HC1/H 0 or^o-formylation followed by deprotection j  d  4  2  Initially, it was thought that the [3+3] Schiff-base macrocycles (26) would show liquid crystalline properties. These macrocycles are made up of a rigid centre (the conjugated macrocycle) surrounded by six long alkoxy groups similar to substituted triphenylenes (Figure 6.1a), and phenyleneethynylene macrocycles (Figure 6.1b) which are both known to have liquid crystalline phases. Unfortunately, these macrocycles do 4  not show liquid crystalline properties. By adding substituents to the diformyl units and increasing the number of peripheral substituents on these macrocycles from six to twelve (Figure 6.1c,d), it may be possible to achieve liquid crystalline phases from [3+3] Schiffbase macrocycles.  201  References on page 217.  - » » — ~ v w w v  Figure 6.1  = solubilizing groups (e.g., OCyH^.Ch^COCX^Hs)  (a) Triphenylene, (b) phenyleneethynylene macrocycle, (c) macrocycle 26,  and (d) proposed macrocycle with additional solubilizing groups.  With the interest of forming [3+3] Schiff-base macrocycles with liquid crystalline phases, preliminary work began on the synthesis of the dimethyl analogue of diformyl species 29. It is unlikely that the resulting macrocycles would show liquid crystalline properties but these investigations would elucidate a feasible synthetic strategy to these  202  References on page 217.  macrocycles. The synthesis of 3,6-diformyl-l,2-dihydroxy-4,5-dimethylbenzene 59 was achieved in seven steps as shown in Scheme 6.2 where many of the steps are quantitative.  Scheme 6.2  v  Synthesis of diformyl species 59.  Br  \ ^ ^ r ) M e  Br  XX,  OMe  OAc OMe  -OH  OMe / N ^ O M e  OMe  OAc  ^0  59 a  i) B r , 0-25 °C ii) K O H / H 0 2  2  b  CuBr, NaOMe/MeOH  c  i) ( C H 0 ) , HBr/HOAc, H O O C C F ii) H 0 2  n  3  2  d  i)  NaOAc, A c 0 , HO Ac ii) H 0 i) U A I H 4 ii) H 0 PCC, D C M i) B B r ii) H 0 e  2  2  f  8  2  3  2  The [3+3] Schiff-base macrocycle 60 (Figure 6.2a) was obtained upon reaction of diformyl species 59 with diamines 33b and 33e. The ' H N M R spectrum differs from that of macrocycle 26 only in that the aromatic resonance corresponding to the diformyl unit has been replaced by a single methyl resonance at 2.36 ppm. A single crystal X-ray diffraction study of 60b reveals that this new macrocycle is mostly planar with one catechol unit rotated out of the plane, having a dihedral C - C - N = C angle of 46° (Figure 6.2b).  203  References on page 217.  60e: R = Figure 6.2  C5H11  a) Macrocycle 60b,e and b) molecular structure (SCXRD) of macrocycle  60b (C = black, N = blue, O = red). Thermal ellipsoids are shown at 50% probability.  With a clean route for orf/zo-formylation of l,2-dimethoxy-4,5-dimethylbenzene, work began on the synthesis of a dihexyl analogue. 1,2-Dihexylbenzene was prepared through a Kumada coupling reaction and this was brominated followed by substitution with methoxide to obtain the 4,5-dihexyl-l,2-dimethoxybenzene (Scheme 6.3). However, the following step, to initiate formylation, was difficult, resulting in mixtures of starting material and the mono-substituted species. Many other formylation reactions remain to be explored and the desired product will likely be obtained. After successfully preparing this new diformyl species macrocycle preparation will begin followed by investigations on whether such a compound shows liquid crystalline phases.  204  References on page 217.  Scheme 6.3 CI  Synthesis of diformyl species 61. Br  b  a  .OMe  c  Br  CI  "OMe d Br  .0 .OH  OMe  OH  OMe  'O  a  C H B r , Mg(s), N i 6  2 +  13  (cat.), E t 0 2  b  Br  i) B r , 0-25 °C ii) K O H / H 0 2  c  2  CuBr, NaOMe/MeOH  d  i) ( C H 0 ) , 2  n  HBr/HOAc, H O O C C F ii) H 0 3  2  With the basic chemistry of these new Schiff-base macrocycles worked out, other researchers within the MacLachlan group have begun investigating the possibility of increasing the pore size of these macrocycles by increasing the size oftthe diformyl linker units. Figure 6.3 shows different diformyl units that are being investigated. Some of the resulting macrocycles are insoluble and diamine units with ethylhexyl substituents have been used to aid in solubility. Many of these largely conjugated macrocycles are luminescent with interesting optical properties. Another area yet to be explored is the 5  synthesis of water soluble analogues and their properties.  205  References on page 217.  Figure 6.3  Examples of diformyl linker units that have been prepared in the  MacLachlan group, to be used in the formation of [3+3] Schiff-base macrocycles with increased cavity sizes.  6.3  In Situ Monoreduction  In situ reduction of macrocycle 26 has been shown to take place, where exactly one of the imine groups was reduced to an amine leaving monoreduced macrocycle 39.  6  To further investigate the reaction mechanism, a deuterium labelling experiment was conducted. This work suggested that the reduction does not involve H D formation but that the reduction is selective. The initial step in the formation of [3+3] Schiff-base macrocycles (26) is to form a 1:1 adduct (34) composed of one diformyl unit (29) and one diamine unit (33). This species can undergo further condensations to finally produce  206  References on page 217.  the expected [3+3] macrocycle but transformation to a benzimidazoline species is also possible. This benzimidazoline species (40) is reactive and able to reduce one of the imine bonds within the macrocycle to produce the monoreduced macrocycle 39 and a benzimidazole species (41). This pathway appears to be acid-catalyzed. The Schiff-base 1:1 adducts 34 are not stable and often react to form the thermodynamically favourable [3+3] macrocycle. However, i f a stable version of these species could be designed, by varying the electron withdrawing/donating character of the substituents, it may be possible to use these small molecules as mild reducing agents for other systems. Within the macrocycle only one of the imine groups was reduced and no polyreduced products were observed suggesting that these benzimidazoline species generated in situ during the formation of macrocycle 26 may prove selective in other systems as well. The full reduction of these macrocycles has also been investigated. Other related systems, those that are not fully conjugated, are often fully reduced for additional studies.  7  The addition of U A I H 4 to macrocycle 26 causes decomposition of the  macrocycle itself. With the use of a softer reducing agent such as NaBHt an initial colour change is observed from deep red to white, suggesting loss of conjugation. However, after continued stirring, or during workup, the colour returned and H N M R spectroscopy !  revealed a large mixture of products including the unreduced macrocycle. Other conditions may be needed for the full reduction of these macrocycles or perhaps other Q  reducing agents such as NaBH(OAc)3 may prove useful.  207  References on page 217.  6.4  Ion-Induced Aggregation  Upon the addition of small cations (Na , K , Rb , Cs , N H / ) to a solution of +  +  +  +  macrocycle 26 a colour change is observed that corresponds to the stacking of the macrocycles into tubular structures. Further investigations suggest that these structures 9  are made Up of alternating cations and macrocycles where the small cations bind to the crown ether-like cavities of the macrocycles inducing the tubular assembly. It would be interesting to investigate these structures by transmission electron microscopy (TEM) and scanning electron microscopy (SEM). T E M should reveal the tubular structure of these aggregates i f they are single entities and S E M may clarify whether these tubular assemblies are further assembled to form tubule or thread-like structures. The solid-state crystal structure of macrocycle 60 is different from that of macrocycle 26 and the ability of macrocycle 60 to bind small cations may also differ. With the increase in steric bulk around the periphery of macrocycle 60 it may be unfavourable for these macrocycles to stack into tubular structures like those of macrocycle 26. Other supramolecular structures may be discovered, but i f not these macrocycles may bind small cations in a manner more closely related to that of crown ethers. Macrocycle 26 has shown an affinity for small cations,over that of the crown ether 18-crown-6 which is known to bind small cations strongly. These macrocycles may also find use as sensors for other small molecules. Preliminary investigations performed in the gas phase show selectivity of these macrocycles toward lysine and argenine over other amino acids. Solution investigations of this phenomenon have been plagued by 10  208  References on page 217.  solubility as the macrocycles and the amino acids are not soluble in common solvents. Solution studies may be possible i f an appropriate solvent combination can be established or alternatively if water soluble analogues of these macrocycles are obtained.  6.5  Metal Incorporation  The [3+3] Schiff-base macrocycle 26 possesses three N2O2 pockets capable of binding metal atoms. The stepwise incorporation of metals into these pockets was investigated. No monometallated macrocycle was obtained when one equivalent of Zn(OAc)2 was added to macrocycle 26. It seems that the dimetallated product is favoured instead. It is possible that after the addition of one metal ion to one of the N2O2 pockets the geometry of the macrocycle is constrained to readily accommodate the binding of a second metal ion. When three equivalents of Zn(OAc)2 were added to macrocycle 26 a broad *H N M R spectrum was obtained and ESI-MS indicated that the trimetallated macrocycle was formed but that these were aggregating. With the addition of an excess of Zn(OAc)2 to macrocycle 26 a new heptanuclear structure was obtained. Here the trimetallated macrocycle is first formed but then templates the synthesis of a [ Z n 4 0 ]  6+  cluster that is bound to the top of the macrocycle  through bridging acetate ligands yielding a bowl-like structure.  11  These heptanuclear  complexes have been shown to dimerize forming capsule-like structures in certain solvents. The extended naphthalene-based macrocycle 45 may form related complexes but these would possess deeper cavities, which may be used to investigate the host-guest  209  References on page 217.  properties of these new systems. With the proposed anthracene-based macrocycles even deeper cavities may be possible. A heptacadmium complex has also been synthesized analogous to the zinc complexes. A crystal structure of this cadmium complex would provide further insight into the shape of this system. With the use of the larger cadmium ions rather than zinc ions, this complex likely possesses a different cone size to its bowl-like structure. It may be possible that this complex, like its zinc analogue, forms dimers in solution but with a possible difference in cone size it may exhibit different properties. Further studies on metal incorporation into [3+3] Schiff-base macrocycles could be explored with the addition of different metals such as nickel or cobalt. Also, other zinc species may be obtained when choosing zinc salts with different counterions. If r  unaggregated trimetallated macrocycles can be synthesized, studies on the coordination chemistry of these complexes could prove interesting. With the appropriate linker molecules coordination nanotubes or networks may be possible leading to new supramolecular architectures.  6.6  6.6.1  Experimental  General  Dichloromethane was dried by passing over an activated alumina column. Chloroform and acetonitrile were dried over 3 A molecular sieves and degassed by sparging with N2 for 20 min. Acid-free, anhydrous chloroform was obtained by drying over  anhydrous  K2CO3,  followed  by  210  vacuum  transfer.  3,6-Diformyl-l,2-  References on page 217.  dihydroxybenzene (29) and l,2-dialkoxy-4,5-diaminobenzene (33) were prepared by literature methods. '  1 12  ' H N M R spectra (400 MHz) were calibrated to the residual  protonated solvent at 7.24 ppm, in CDCI3. Electrospray ionization (ESI) mass spectra were obtained on a Micromass L C T time-of-flight (TOF) mass spectrometer equipped with an electrospray ion source. The samples were analyzed in MeOH:CHCl3 (1:1) at 100 u M . Flow rate: 20 uL min" ; sample cone: 90 V ; source temperature: 120 °C; desolvation 1  temperature: 120 °C. EI spectra were obtained using a double focusing mass spectrometer (Kratos MS-50) coupled with a M A S P E C data system with EI operating conditions of: source temperature 200 °C and ionization energy 70 eV. Elemental analyses (C,H,N) were performed at the U B C Microanalytical Services Laboratory.  6.6.2  Procedures  3,6-Diformyl-l,2-dihydroxy-4,5-dimethylbenzene (59). Under a nitrogen atmosphere, 267 mg (1.2 mmol) of 3,6-diformyl-l,2-dimethoxy-4,5-dimethylbenzene was dissolved in -40 mL of dry D C M cooled in an ice/water bath. BBr3 (0.5 mL, 5.4 mmol) was added turning the reaction red in colour. After stirring for 12 h at room temperature, the reaction was quenched with water and the product extracted from D C M . The combined organic fractions were dried over MgS04, filtered, and dried under vacuum to leave an orange solid. Recrystallization from a mixture of DCM/hexanes yielded deep orange needles. Yield: 65 mg (0.33 mmol, 28% yield).  211  References on page 217.  Data for 3,6-Diformyl-l,2-dihydroxy-4,5-dimethylbenzene (59). H N M R (400 M H z , ]  CDCI3)  5 11.89 (s, 2H, OH), 10.45 (s, 2H, CH=0), 2.48 (s, 6H, CH ) ppm. EI-MS: m/z = 3  194 [59] . Anal. Calc'd for 59 (C0H10O4): C, 61.85; H , 5.19. Found: C, 62.00; H , 5.55. +  Macrocycles 60b,e; General procedures. Under a nitrogen atmosphere, 0.26 mmol of the appropriate diaminobenzene  33 was dissolved in 10 mL of 1:1  degassed  C H C h M e C N . Diformyl species 59 (50 mg, 0.26 mmol) was added turning the solution from colourless to deep red. After heating at reflux (90 °C) for 4 h, the solution was cooled to room temperature, yielding a red microcrystalline solid of 60. Macrocycle 60 was isolated on a Biichner funnel, washed with cold M e C N , and dried under vacuum.  Data for Macrocycle 60b (R = C H ) . Yield: 87%. *H N M R (400 MHz, CDC1 ) 5 13.93 2  5  3  (s, 6H, OH), 8.98 (s, 6H, CH=N), 6.80 (s, 6H, aromatic CH), 4.15 (q, 12H, OCH ), 2.36 2  (s, 18H, CH ), 1.60 (broad s, H 0 ) , 1.48 (t, J  = 6.8 Hz, 18H, C H C / / ) ppm. ESI-MS:  3  3  2  H H  2  3  m/z = 1064 [60b+H] , 1102 [60b+K] . Anal. Calc'd for 60b-2H O (CeoHyoNeOw): C, +  +  2  65.56; H , 6.42; N , 6.42. Found: C, 65.31; H , 6.23; N , 7.63.  Data for Macrocycle 60e (R = C H ) . Yield: 77%. *H N M R (400 M H z , CDC1 ) 5 n  s  n  3  13.83 (broad s, 6H, OH), 8.97 (s, 6H, CH=N), 6.81 (s, 6H, aromatic CH), 4.03 (broad s, 12H, OCH ), 2.35 (s, 18H, CH ), 1.98 (s, H 0 ) , 1.84 (m, 12H, CH ), 1,42 (m, 24H, CH ), 2  0.95 (t, J 3  3  2  2  2  = 7.0 Hz, 18H, CH CH ) ppm. ESI-MS: m/z = 1315.7 [60e+H] , 1337.6 +  H H  2  3  [60e+Na] . Anal. Calc'd for 60eH O (C Hio N Oi3): C, 70.24; H , 7.86; N , 6.30. Found: +  2  78  2  6  C, 70.45; H , 7.60; N , 6.70.  212  References on page 217.  6.6.3  X-Ray Diffraction Studies  Measurements were made using a C C D area detector coupled with either a Bruker X8 or a Rigaku A F C 7 diffractometer with graphite monochromated MoKa radiation (k = 0.7107 A). The data were collected at a temperature of -100.0 + 0.1 °C Data were collected and integrated using either the Bruker S A I N T , d * T R E K 13  14  or TwinSolve  15  software package. The data was corrected for absorption effects using a multiscan method either S A D A B S  1 6  or CrystalClear . The data were corrected for Lorentz and 15  polarization effects. The structures were solved by direct methods using either SIR92 or 17  SIR2002 and refined as full-matrix least-squares against | F | using S H E L X . A l l non18  2  19  20  hydrogen atoms were refined anisotropically. A l l hydrogen atoms involved in hydrogenbonding were located in difference maps, while all other hydrogen atoms were included in calculated positions but not refined. For solvent molecules that are disordered in 21  multiple orientations, that could not be modeled adequately, the SQUEEZE PLATON  2 2  function in  was used to adjust the data to account for residual electron density found  within lattice void spaces. X-ray Diffraction Study of 60b. Crystals of 60b suitable for X-ray diffraction were grown from D M F . X-ray diffraction data shown in Table 6.1.  213  References on page 217.  1  Table 6.1  X-ray diffraction data for compounds 60b. 60b  A. Crystal Data Empirical Formula  C75H101N11O18  Formula Weight  1444.67  Crystal Color, Habit  red, prism  Crystal Dimensions (mm)  0.70x0.15x0.10  Crystal System  primitive  Lattice Type  triclinic  Lattice Parameters  a= 12.3999(14) A b= 17.709.(3) A c = .19.450(3) A a = 64.827(5)° p = 84.172(6)° y =. 80.874(6)° V = 3798.3(9) A 3  Space Group  P-l  (#2)  Z value Dcalc  1.263 g/cm  000  1544  u.(MoKa)  0.91 cm  r  3  -1  B. Intensity Measurements Diffractometer  Bruker X 8 A P E X  214  References on page 217.  Radiation  MoKa  (A, = 0.71073 A) Data Images  1465 exposures @30s  Detector Position  38.09 mm  2 ©max  45.44  No. of Reflections Measured  0  Total: 45369 Unique: 9757 (R = 0.1080) int  Absorption T = 0.775 T = 0.991  Corrections  m i n  m a x  C. Structure Solution and Refinement Structure Solution  Direct Methods (SIR2002)  Refinement  Full-matrix leastsquares on F 2  Function Minimized  Sw(Fo -Fc )  Least Squares Weights w = l/(a (Fo )+(jcP) +yP) Anomalous Dispersion  x = 0.1001 y = 2.2759 A l l non-hydrogen atoms  No. Observations (I>0.00a(I))  45369  No. Variables  956  Reflection/Parameter Ratio  47.46  2  2  2  2  2  2  Residuals (refined on F , all 0.170; 0.217 data):Rl;wR2 2  Goodness of Fit Indicator  1.02  215  References on page 217.  No. Observations (I>2.00a(I))  4641  Residuals (refined on F): R l ; wR2  0.0692; 0.1686  Max shift/error in final cycle  -0.002  Max. peak in final diff. map  0.418 e7 A  Min. peak in final diff. map  -0.358 e7 A  216  3  3  References on page 217.  6.7  References  (1) Gallant, A . J.; Hui, J. K . - H . ; Zahariev, F. E.; Wang, Y . A . ; MacLachlan, M . J. J. Org. Chem. 2005, 70,7936. (2) Gallant, A . J.; Yun, M . ; Sauer, M . ; Yeung, C. S.; MacLachlan, M . J. Org. Lett. 2005, 7, 4827. (3) Pozzo, J.-L.; Clavier, G. M . ; Colonies, M . ; Bouas-Laurent, H . Tetrahedron 1997, 53, 6377. (4) (a) Beattie, D . R.; Hindmarsh, P.; Goodby, J. W.; Haslam, S. D.; Richardson, R. M . J. Mater. Chem. 1992, 2, 1261. (b) Zhang, J.; Moore, J. S. J. Am. Chem. Soc. 1994, 116, 2655. (5) Ma, C ; Lo, A . ; Abdolmaleki, A . ; MacLachlan, M . J. Org. Lett. 2004, 6, 3841. (6) Gallant, A . J.; Patrick, B . O.; MacLachlan, M . J. J. Org. Chem. 2004, 69, 8739. (7) Kuhnert, N . ; Rossignolo, G . M . ; Lopez-Periago, A . Org. Biomol. Chem. 2003, 1, 1157. (8) Abdel-Magid, A . F.; Carson, K . G.; Harris, B . D.; Maryanoff, C. A . ; Shah, R. D. J. Org. Chem. 1996, 61, 3849. (9) Gallant, A . J.; MacLachlan, M . J. Angew. Chem. Int. Ed. 2003, 42, 5307. (10) Gallant, A . J.; Ling, Y.; MacLachlan, M . J. manuscript in preparation (11) Gallant, A . J.; Chong, J. H . ; Guo, Y . ; Moffitt, M . G.; MacLachlan, M . J. Angew. Chem. Int. Ed. 2006 manuscript submitted. (12) Kim, D.-H.; Choi, M . J.; Chang, S.-K. Bull. Korean Chem. Soc. 2000, 21, 145. (13) SAINT. Version 6.02. Bruker A X S Inc., Madison, Wisconsin, U S A (1999).  217  (14) d*TREK. Area Detector Software. Version 7.11. Molecular Structure Corporation (2001). (15) CrvstalClear 1.3.5 SP2. Molecular Structure Corporation (2003). (16) S A D A B S . Bruker Nonius area detector scaling and absorption correction - V2.05, Bruker A X S Inc., Madison, Wisconsin, U S A . (17) SIR92: Altomare, A . ; Cascarano, M . ; Giacovazzo, C ; Guagliardi, A . J. Appl. Cryst. 1994, 26, 343. (18) SIR2002: Burla, M . C ; Camalli, M . ; Carrozzini, B.; Cascarano, G. L . ; Giacovazzo, C ; Polidori, G.; Spagna, R. J. Appl. Cryst. 2003, 36, 1103. (19) Least Squares function minimized: Sw(F ^-F 2)2 0  c  (20) S H E L X : Sheldrick, G. M . Programs for Crystal Structure Analysis (Release 97-2). University of Gottingen, Germany (1997). (21) SQUEEZE: Van der. Sluis, P.; Spek, A . L. Acta Crystallogr., Sect A 1990, 46, 194. (22) P L A T O N , A Multipurpose Crystallographic Tool, Utrecht University, Utrecht, The Netherlands, A . L . Spek, (1998).  218  

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