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Towards liquid crystalline [3 + 3] Schiff-base macrocycles Edwards, David Ryan 2007

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TOWARDS LIQUID CRYSTALLINE [3+3] SCHIFF-BASE MACROCYCLES by David Ryan Edwards B.Sc. (Hons.), University of Victoria, 2004 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES (Chemistry) THE UNIVERSITY OF BRITISH COLUMBIA September 2007 © David Ryan Edwards, 2007 Abstract Conjugated Schiff-base macrocycles are interesting compounds of interest as platforms for catalysis, the preparation of novel synthetic ion channels and potentially as porous or tubular discotic liquid crystals. The preparation of organic macrocycles is typically low yielding, with polymerization competing with cyclization; the use of imines derived from the condensation of an aldehyde and an amine provides a means by which to conduct cyclizations under thermodynamic control and thereby improve yields. The use of difunctional aldehydes and amines allows for the formation of macrocycles in high yields without the need for high-dilution conditions. Two highly substituted dialdehydes also bearing phenolic and aikyl functionalities were prepared by several routes in an effort to obtain macrocycle precursors. These precursors were characterized and subsequently employed to prepare [3+3] Schiff-base macrocycles with a large number of appended aikyl and alkoxy substituents in hopes that they would display discotic liquid crystallinity. A series of highly substituted [3+3] Schiff-base macrocycles was prepared and characterized by 'H NMR, 1 3C NMR, UV-Vis, and IR spectroscopies in addition to MALDI- ~ TOF mass spectrometry. The thermal properties of these macrocycles were also examined, and they were not found to display liquid crystalline mesophases either by differential scanning calorimetry or polarizing optical microscopy. A crystal structure of one of the macrocycles was obtained and was found to display structural features not previously observed in related macrocycles. Table of Contents Abstract i i Table of Contents....: i i i List of Tables v List of Figures v i List of Schemes v i i i List of Symbols and Abbreviations ix Acknowledgements x i Chapter 1: Introduction 1 1.1 Schiff Bases 1 1.2 Schiff Base Macrocycles 2 1.3 Liquid Crystals 8 1.3.1 A Historical Perspective 8 1.3.2 A Brief Primer on Liquid Crystallinity 9 1.3.3 Discotic Liquid Crystals 12 1.4 Objectives 16 Chapter 2: Hexasubstituted Benzenes as Macrocycle Precursors 17 2.1 Background 17 2.2 In Pursuit of dialkyldihydroxybenzenedialdehydes 19 2.3 A Brief Discussion of Synthetic Methodologies 32 2.4 Properties of the dialkyldihydroxybenzenedialdehydes 33 2.5 Conclusions and Recommendations 39 2.6 Experimental 40 i i i Chapter 3: [3+3] Macrocycles 53 3.1 Background 53 3.2 Discussion : 56 3.2.1 Synthetic Aspects 56 3.2.2 Characterization 58 3.2.3 Thermal Properties of the Macrocycles 66 3.2.4 Crystallography of Macrocycle 19a... 68 3.3 Conclusions and Recommendations 71 3.4 Experimental • 72 Chapter 4: Conclusions and Future Work 81 4.1 Conclusions 81 4.2 Future Work 82 References 84 Appendix 1: Crystallographic Data for Compounds 31a and 19a 90 iv List of Tables Table 2.1: Optimization of Lithiation/Formylation Conditions 25 Table A l . 1: Crystallographic Data for Compound 31a 90 Table A1.2: Crystallographic Data for Macrocycle 19a 92 V , List of Figures Figure 1.1: Early Polyheterodentate Schiff Base Macrocycles 4 Figure 1.2: Porphine and Some Related Expanded Porphyrin Schiff Base Macrocycles 5 Figure 1.3: A [6+6] Schiff Base Macrocycle 6 Figure 1.4: Schematic Representations of a) Nematic Calamitic, b) Smectic-A, 11 and c) Smectic-C Mesophases Figure 1.5: Schematic Representation of a Chiral Nematic Mesophase 11 Figure 1.6: Prototypical Calamitic and Cholesteric Mesogens 11 Figure 1.7: Widely Investigated Planar Discotic Molecules That Exhibit Liquid 13 Crystallinity; a) hexa-n-alkanoates of benzene; b) hexa-n-alkyl, hexa-n-alkoxy, and hexa-n-alkanoate derivatives of triphenylene; c) octasubstituted phthalocyanines; d) hexasubstituted hexa-pen-hexabenzocoronenes (HBCs) Figure 1.8: Schematic Representation of Nematic and Columnar Discotic Mesophases 13 Figure 1.9: Pyramidal or Bowl ic Mesogens 15 Figure 1.10: Target [3+3] Schiff Base Macrocycles 16 Figure 2.1: [3+3] Schiff Base Macrocycles Bearing Six A lkoxy Substituents 17 Figure 2.2: 400 M H z *H N M R of the Crude Product of the Lithiation and 26 Formylation of 25b Figure 2.3: Determination of Product Distribution by N M R Integration , 26 Figure 2.4: 400 M H z ' H N M R Spectrum of Compound 31a 33 Figure 2.5: 100 M H z 1 3 C N M R Spectrum of Compound 31a 34 Figure 2.6: IR Spectrum of Compound 31a 34 Figure 2.7: O R T E P Diagram of the Assymetric Unit Cel l of a Single Crystal of 36 Compound 31a Figure 2.8: V i e w Along the a A x i s for a Single Crystal of 31a 37 Figure 2.9: V i e w Along the b A x i s for a Single Crystal of 31a 37 Figure 2.10: V i e w Along the c Ax i s for a Single Crystal of 31a 38 vi Figure 2.11: Possible Quinoidal Tautomers for 2,3-dialkyl-5,6-dihydroxybenzene- 38 1,4-dialdehydes Figure 3.1: Structures of the [3+3] Macrocycles Prepared in this Work 55 Figure 3.2: Structures o f Some of the [1+2] Fragments Obtained 55 Figure 3.3: 400 M H z *H N M R Spectrum of Macrocycle 19a 59 Figure 3.4: 100 M H z 1 3 C N M R Spectrum of Macrocycle 19a 60 Figure 3.5: 400 M H z *H N M R Spectrum of Macrocycle 20e 60 Figure 3.6: IR Spectrum of Macrocycle 19a 61 Figure 3.7: IR Spectrum of Macrocycle 20e 61 Figure 3.8: M A L D I - T O F Mass Spectrum of 19a 62 Figure 3.9: M A L D I - T O F Mass Spectrum of 20e 63 Figure 3.10: Normalized Absorption Spectra of Macrocycles 19a, 19b and 19f 64 Figure 3.11: 400 M H z ] H N M R Spectrum of the [1+2] Compound 32a 65 Figure 3.12:IR Spectrum of the [1+2] Compound 32b 65 Figure 3.13: D S C Trace for Macrocycle 19b ". 67 Figure 3.14: D S C Trace for Macrocycle 19f... 67 Figure 3.15: Top V i e w of Macrocycle 19a as Determined by S C X R D 68 Figure 3.16: Side V i e w of Macrocycle 19a as Determined by S C X R D . . 69 Figure 3.17: Packing V i e w of Macrocycle 19a Along the a-Axis 70 Figure 3.18: Packing V i e w of Macrocycle 19a Along the c-Axis 70 v i i List of Schemes Scheme 1.1: General Schiff Base Condensation 2 Scheme 1.2: Structual Diversity from the Condensation of Diftinctional 3 Amines and Carbonyls Scheme 1.3: Formation of [3+3] Schiff Base Macrocycles 7 Scheme 2.1: Some Routes Employed to Prepare the Target Compounds 18 Scheme 2.2: Kumada Coupling 19 Scheme 2.3: Bromination of 1,2-dialkylbenzenes 21 Scheme 2.4: Methoxylation of l,2-dibromo-4,5-dialkylbenzenes 21 Scheme 2.5: Direct Formylation of 1,2-dimethoxybenzene 23 Scheme 2.6: Bromination of l,2-dimethoxy-4,5-dialkylbenzenes 24 Scheme 2.7: Lithiation/Formylation of l,4-dibromo-2,3-dialkyl-5,6- 25 dimethoxybenzenes Scheme 2.8: Lithiation/Acylation of l,4-dibromo-2,3-dialkyl-5,6-dimethoxybenzenes 27 Scheme 2.9: Reduction of Crowded Benzoate Esters with L1AIH4 28 Scheme 2.10: Reduction with D I B A L - H .29 Scheme 2.11: Cyanation of A r y l Bromides 29 Scheme 2.12: Proposed General Mechanism for Formylation with H M T A 31 Scheme 2.13: Possible Route to Longer Chain Analogues of 30a and 30b 39 Scheme 3.1: Possible Mechanism for Piperidine-Catalyzed Imine Formation 58 via an Iminium Intermediate List of Symbols and Abbreviations A a.m.u. br ca. , 3 C N M R d d 5 dec. D C M D I B A L - H dppp D S C 8 equiv. ESI h H M T A ' H N M R H R - E I - M S H z /'. e. angstroms (1 A = 10"8 m) atomic mass units broad ( N M R , IR) circa (about) carbon-13 nuclear magnetic resonance deuterium ( N M R ) doublet ( N M R ) chemical shift decomposes dichloromethane diisobutylaluminum hydride l,3-bis(diphenylphosphino)propane differential scanning calorimetry molar extinction coefficient exempli gratia (for example) equivalents electrospray ionization hours hexamethylenetetramine proton nuclear magnetic resonance high resolution electron impact mass spectrometry Hertz id est (that is) IR J M M A L D I - T O F - M S m.p. m Me M e O M e O H min mol m/z N M R O R T E P P C C ppm q R s S C X R D t T M E D A T H F U V - V i s infrared coupling constant ( N M R ) moles/L matrix-assisted laser desorption/ionization time-of-flight mass spectrometry melting point multiplet ( N M R ) methyl group methoxy group methanol minutes moles mass to charge ratio nuclear magnetic resonance Oak Ridge thermal ellipsoid plot pyridinium chlorochromate parts per mi l l ion ( N M R ) quartet ( N M R ) alkyl group singlet ( N M R ) single crystal x-ray diffraction triplet ( N M R ) tetramethyleneethylenediamine tetrahydrofuran ultraviolet-visible Acknowledgements I would like to take the opportunity to thank Dr. Mark MacLachlan for his support and patience when times were trying. I know I can be difficult and for your tolerance I have the utmost gratitude. I would also like to thank Jon Chong for his assistance with the crystallography, Joseph Hui for his assistance with the MALDI and Alfred Leung for useful discussions on the fine art of chromatography. I am grateful to the MacLachlan group as a whole for their good humour and acceptance; you are a solid bunch and I wish you luck in life, love, and lit. preps. May all your reactions be high yielding and all your crystals be single. I would also like to thank the various support staff associated with the Department of Chemistry; your tirelessness and dedication keep the pursuit of knowledge on track. My sincere thanks go out to the staff of the NMR facilities, the Mass Spec, and Microanalysis lab, and the Crystallography labs. My apologies to anyone I may have forgotten. Finally, I would like to thank my family; your love and support are worth more to me than I can ever hope to express. xi Chapter 1: Introduction 1.1-Schiff Bases Ever since the discovery of the condensation between primary amines and carbonyl compounds (see Scheme 1.1) by Hugo Schiff in 1864, chemists have used this reaction to generate a staggering array of compounds. Examples of these so-called Schiff bases (also known as imines or azomethines) are legion in the literature owing to their ease of synthesis as well as their versatility in binding metals. The ease with which these compounds can be prepared has much to do with the reversibility of all the steps in the condensation reaction as well as the extrusion of water; these features allow the reactions to be conducted under thermodynamic conditions in which water can be removed by a variety of means, thereby allowing them be driven effectively to completion. Schiff bases have been demonstrated to play a role in biochemical processes,1 adding to their appeal as targets of investigation for mechanistic elucidation of enzymatic processes and as structural models for metalloenzymes as well as for the design of new catalysts.2'3 The imines derived from the condensation of mono-functional carbonyl compounds and amines (and their metal complexes) are of interest not only as models for biochemical processes and metalloproteins but also for use as liquid crystals4 (vide infra). Another interesting application of Schiff base chemistry, at least from the standpoint of materials chemistry, is the condensation of polyfunctional amines and carbonyl compounds to generate linear polymers and cyclic oligomers. The preparation and characterization of some of these cyclic oligomers, in the form of macrocycles, forms the basis of this thesis. 1 -OH -OH R"' " H R" H R + H + R R' R R' +H 2 0 R R' H N = < ® > N = < = N + P ® R" H R" -H 2 0 H R" H Scheme 1.1: General Schiff Base Condensation 1.2 - Schiff Base Macrocycles Schiff base macrocycles have the distinction of being some of the earliest known and most thoroughly investigated (non-naturally occurring) cyclic, polydentate ligands. Although the earliest work in the field involved the condensation of bifunctional monomers (i.e. those in which amine and aldehyde functionalities are present on the same molecule),5 a huge array of possible macrocyclic structures can be imagined arising from the condensation of a difunctional carbonyl unit and a diamine unit. Based on the number and structural diversity of these building blocks, a massive library of macrocyclic ligands can be envisioned. The choice of possible constituent diamine and dicarbonyl moieties is huge; a range of aliphatic and aromatic compounds have been employed to generate a wealth of novel macrocyclic species.6 In general, the condensation of a difunctional amine and a difunctional carbonyl unit will result in the formation of a number of compounds (see Scheme 1.2),6,7 in effect generating a dynamic combinatorial library ranging from discrete mono-condensation products to oligomers and polymers. Through judicious choice of structural features in the building blocks, such as the geometry of the functional groups, macrocycles can be constructed preferentially in relatively high yields. 2 N- H A X A H + N- H 2 N " Y " N H 2 H 2 N . Y , N ^ X ^ N . Y , N H 2 H H [1+2] O 0 H A X ^ N ^ N ^ X A H [2+1] H 2 N 0 Y - N y—H H [1+1] >tN N =< ) = N N:=< H Y J n H [2+2], [3+3] [N+N] H H n linear oligomers and polymers X, Y = aliphatic, aromatic or some combination thereof Scheme 1.2: Structual Diversity from the Condensation of Difunctional Amines and Carbonyls (in this case, aldehydes) Extensive research in the field has produced a diverse collection of macrocycles, ranging from relatively small [2+2] species to very large [6+6] cycles incorporating a huge array of different spacers.6 The smallest macrocycles possible arising from the condensation of difunctional building blocks are of the [2+2] variety; some of the most widely examined compounds of this class are the so-called Robson 8 and M c K e e 9 macrocycles, the prototypes of which are illustrated in Figure 1.1 as structures 1 and 2, respectively. These were some of the first Schiff base macrocycles to incorporate heterodentate binding sites; the early Robson macrocycles were shown to coordinate up to two metal atoms in the two N 2 O 2 compartments or pockets while M c K e e macrocycles can coordinate as many as four. 1 0 A number of homo and heterometallic complexes have been prepared and investigated and several of the homometallic tetrametallated, mixed-valence compounds display cooperative redox behaviour attributable to their geometrically-constrained coordination environments. 1 1 Structural diversification of these types of macrocycles is an active area of research, with a number of different modifications reported in the literature including the use of thiophenolate donors' 2 and the expansion of the diamine 1 3 or dialdehyde 1 4 linkers to name just a few. Figure 1.1: Early Polyheterodentate Schiff Base Macrocycles Another interesting class of Schiff base macrocycles is that consisting of dicarbonyl units which include one or more pyrrole units ("expanded porphyrins"). 1 5 Porphyrins and other structurally related polypyrrolic compounds are naturally occurring macrocyclic ligands that are present in a number of important biological systems; these extremely versatile and varied molecules are central to biochemical processes such as photosynthesis (as chlorophylls) and in oxygen fixation and aerobic respiration (as hemes). Elaboration of these types of macrocycles has been the topic of significant investigation in efforts to design artificial mimics of these natural systems as well as to probe their properties. Expanded porphyrins incorporating Schiff bases are often obtained by polycondensation of dicarbonyl units on pyrroles or oligopyrroles, the diamine moieties consisting of phenylene diamine derivatives 1 6 ' 1 7 or even small molecules 18 like hydrazine. A n example of the prototypical porphyrin, 3 ( also known as porphine), along with an expanded porphyrin (4) are illustrated in Figure I.2.- Intriguingly, some of these planar, rigid core, expanded porphyrins (5, with n = 6, 10 and 14) have been shown to display discotic liquid crystalline properties (vide infra)}* 4 Needless to say, there is a huge array of Schiff base macrocycles represented in the chemical literature, the diversity of which is limited only by the imaginations of chemists and the synthetic accessibility of the building blocks. Much work in the MacLachlan group has focused on the construction of new dialdehyde units for incorporation into novel cycles. A significant body of work has been established in particular in the construction of [3+3] species, along with larger [6+6] cycles (e.g. 6; see Figure 1.3).19 Further elaboration of these types of macrocycles through thoughtful variation of the constituent synthons and the investigation of their properties as ligands, small-molecule and ion sensors, and components in supramolecular assemblies are active areas of ongoing research. 5 O C 6 H i 3 0CgHi3 6 Figure 1.3: A [6+6] Schiff Base Macrocycle The specific work undertaken in this project is related to the structural elaboration of a class of [3+3] macrocycles (9a), originally reported in the literature by Akine and coworkers,20 which are derived from the polycondensation of three equivalents of 3,6-diformylcatechol (7) and three equivalents of 1,2-phenylenediamine (8a; see Scheme 1.3); subsequent work in the MacLachlan group expanded on this macrocyclic core by the incorporation of alkoxy substituents on the diamine moiety, significantly improving the solubility of these species (9b-m) and reducing the required reaction time from weeks at room temperature to hours at reflux in a mixture of chloroform and acetonitrile. The resulting soluble macrocycles were shown to display a high affinity for small alkali metal cations resulting in their aggregation into dimeric and trimeric assemblies as evidenced by mass spectrometry and through the use of UV-Vis and N M R spectroscopies.19d 6 e R = O C 4 H 9 | R = O C , 6 H 3 3 f R = O C 5 H n m R = O C 1 8 H 3 7 Scheme 1.3: Formation of [3+3] Schiff Base Macrocycles Fully conjugated macrocycles based on this type of structure have several distinct features that make them desirable synthetic targets for materials chemistry applications. One is their remarkable ease of synthesis; the combination of stoichiometric amounts of an aromatic diamine and an aromatic dialdehyde with the appropriate patterns of substitution, in particular those bearing phenolic groups adjacent to the aldehydes, almost invariably results in the formation of at least some [3+3] macrocycle. This propensity to form macrocyclic products has been attributed to the presence of strong hydrogen-bonding in both the intermediate condensation products and in the final cycles themselves.6'19'20'21 In a sense, these types of structures can be regarded as self-templating, whereas a number of other classes of Schiff base macrocycles (such as those of the Robson or McKee variety) typically require the presence of metal ions to guide the cyclization process to the desired products in preference to linear oligomers and polymers. Indeed, the versatility of this type of core has also been demonstrated through the use of aliphatic diamine linkers (specifically l,2-bis(aminooxy)ethane) with 3,6-diformyl catechol to produce an analogous [3+3] hexaoxime macrocycle in the absence of a metal template, albeit in low yields.22 Another feature that makes these types-of structures attractive from a materials standpoint is the aforementioned affinity for small metal cations and the possible tubular assemblies which can be produced;19d these assemblies may constitute a new class of synthetic ion channels. 7 1.3 — Liquid Crystals 1.3.1 A Historical Perspective23 It was long believed that matter existed in only three states: solid, liquid and vapour; In the mid to late 1800s, scientists working with biologically derived molecules such as stearic acid (octadecanoic acid) and its salts observed strange optical behaviour as these materials neared their melting points. Stearic acid, for example, was observed to undergo several visibly distinct transitions when heated from the solid state, namely from a waxy solid to a cloudy liquid, then to an opaque liquid and finally to an isotropic liquid (i.e. one in which the properties are independent of direction). In 1888, the Austrian botanist Friedrich Reinitzer observed that the benzoate ester of cholesterol melted initially to a cloudy liquid at 146 °C and to an isotropic liquid at 179 °C. On cooling back to the solid state, the sample briefly displayed a blue colour at the isotropic transition temperature (the clearing point) and a violet colour just prior to crystallization. At the time these observations were inexplicable, however the scientific community rose to the challenge and proposed the existence of intermediate states between liquid and solid. Recognition of these intermediate, liquid crystalline states (dubbed mesophases from the Greek meso, or middle) sparked a great deal of interest in the topic at the time. Despite early interest in the field, work on liquid crystals seemed to flounder for several decades in the mid 20th century. In spite of pioneering early work by scientists like Walter Nernst (who proposed and later retracted the idea that the observed optical phenomena occurred as a result of emulsions or tautomerization rather than mesomorphism) and F.C. Frank (who developed the continuum theory of liquid crystallinity), the field grew largely quiescent between about 1925 and 1960. In 1957, an excellent comprehensive review on the topic was published24 helping to prompt a resurgence of research interest in the field. As new characterization 8 techniques became available, the understanding of the mesomorphic state grew and in the ensuing years the field of liquid crystals flourished in both academic and industrial circles culminating in the pioneering use of liquid crystals in optical sensors, optoelectronic devices and display technologies. In more recent history, the discovery by Chandrasekhar in 1977 that hexaesters of benzene exhibited mesophase behaviour25 introduced to the world to a new class of mesogens: discotic liquid crystals. At present, liquid crystals represent some of the most commercially successful advanced materials and dominate the electronic display industry with sales on the order of tens to hundreds of billions of dollars per year. In addition, these materials furnish a rich field of study; the sheer number and structural diversity of compounds which display liquid crystallinity presents an opportunity for chemists to investigate fundamental structure-property relationships for materials with significant commercial applications. 1.3.2 A Brief Primer on Liquid Crystallinity Although lacking the positional order of solids, liquid crystalline phases display some degree of orientational order intermediate between that of crystalline solids and isotropic liquids, the degree of which can vary with temperature and concentration. Several broad classes of liquid crystals are known, and their mesophase behaviour can largely be correlated with their molecular structure. For these types of materials (i.e. mesogens), structural anisotropy on the molecular scale can be paralleled in an emergent fashion by anisotropy on significantly larger length scales. Amphiphilic molecules, most commonly encountered in everyday life as surfactants and soaps, will often form concentration-dependant mesophases when solvated. The micellar, lamellar, and hexagonal columnar arrangements typical of these lyotropic mesogens can be regarded as occurring as a result of the phase segregation of incompatible components on a molecular scale resulting in assemblies which can cooperatively associate into structures possessing micro or even macroscopic dimensions. While lyotropic liquid crystals comprise one 9 broad class of mesogens, another class is the thermotropic mesogens in which temperature most strongly affects mesophase formation and structure. In these types of compounds (like cholesteryl benzoate) within a certain temperature range there is sufficient thermal energy to disrupt crystal packing but insufficient energy to overcome certain non-covalent interactions between nearby molecules. This results in the formation of assemblies or ensembles of molecules that, while lacking long-range positional periodicity, do maintain a degree of orientational order with respect to one another. A s mentioned, molecular structure often correlates well with the mesophase behaviours observed in liquid crystals. Rod-like (or calamitic) molecules typically display so called nematic mesophases, in which the molecules lose all long-range positional order but maintain a certain degree of orientational order. For these types of molecules, the long axis of the molecule generally defines the director, n, along which they align. The nematic calamitic is the least ordered mesophase observed (see Figure 1.4a). Other arrangements are possible for calamitic mesogens, including a number of smectic phases. In these types of phases, the molecules maintain orientational order (once again with respect to the director, n, usually the long molecular axis), but also gain some positional order relative to a nematic calamitic arrangement. Two examples of smectic calamitic mesophases are illustrated in Figure 1.4b and c; in the Smectic-A phase, the director is perpendicular to the planes of the layers, while in the Smectic-C phase, the molecules are tilted with respect to the plane. When chirality is present in the molecules it can be reflected in the mesophases they display. The so-called chiral nematic (or cholesteric) phase, first observed for the esters of cholesterol, is illustrated in Figure 1.5. In this type of mesophase the molecules are still aligned into layers, however successive layers are twisted with respect to one another. Prototypical examples of calamitic and cholesteric mesogens are illustrated in Figure 1.6 as structures 11 and 12, respectively. A number of other 10 types of mesophase structures have been observed and are generally classified according to variations in the structure of their interlayer arrangements. Figure 1.5: Schematic Representation of a Chiral Nematic Mesophase 11 calamitic 12 cholesteric Figure 1.6: Prototypical Calamitic and Cholesteric Mesogens 11 1.3.3 Discotic Liquid Crystals As mentioned, a relatively recent discovery in the field of liquid crystals was that not only can rod-shaped molecules display mesomorphism, but those with disc-like cores can do so as well. This discovery has prompted researchers to investigate a wide variety of disc-like molecules as potential mesogens; some of the most thoroughly examined discotic mesogenic cores are illustrated in Figure 1.7. While these molecules display the same general sort of mesophase behaviours as their thermotropic rod-like cousins (such as birefringence of the mesophase), they differ in several obvious respects. One difference is the dimensionality of the systems; rod-like mesogens can be effectively considered one-dimensional, while discotic mesogens can be considered to extend into two dimensions. This increased dimensionality has an effect on the structures of the mesophases that these materials tend to display. In particular, discotic mesogens, in addition to displaying nematic phases analogous to those of calamitic mesogens (albeit with the director, n, perpendicular to the plane of the cores), most commonly arrange themselves into columnar arrays (see Figure 1.8).26'27 These columnar discotic mesophases display a number of interesting properties including highly anisotropic charge transport. Hexa-peri-hexabenzocoronene (HBC) derivatives (16, Figure 1.7d), for example, show remarkably high charge carrier mobilities parallel to the columns, comparable to those found for graphite or single crystal organic semiconductors,27'28 raising the intriguing possibility of using these types of materials as molecular wires or interconnects. Early studies on these types of mesogens typically focused on the smallest possible aromatic core demonstrated to display mesomorphism, namely benzene, however researchers rapidly realized that larger cores might prove advantageous in maximizing the intermolecular, cofacial n-n interactions that have been shown to play a role not only in the charge transport 12 c) R R R 16 Figure 1.7: Widely Investigated Planar Discotic Molecules That Exhibit Liquid Crystallinity; a) hexa-n-alkanoates of benzene; b) hexa-n-alkyl, hexa-n-alkoxy, and hexa-n-alkanoate derivatives of triphenylene; c) octasubstituted phthalocyanines; d) hexasubstituted hexa-peri-hexabenzocoronenes (HBCs) Figure 1.8: Schematic Representation of Nematic and Columnar Discotic Mesophases • < • 28 * properties but also in stabilizing the mesophase. A number of other interesting structure-property relationships have been established for the rigid, aromatic core discotics in which strong correlations have been observed between the nature of the substituents and the connecting 77 groups and the temperature of the mesophase and melting transitions. In general, it has been observed that for a series o f rigid discotics with a common core, increasing the length of the 13 substituents decreases the temperature at which the phase transitions occur. Similarly, the use of alkoxy linkers to the core reduces the phase transition temperatures relative to aikyl substituents 29 of the same length. The opposite effect is observed when esters or amides are used as linkers; typically this type of substitution results in an increase in the phase transition temperatures, typically attributed to the increased dipole-dipole interactions between the molecules. Although these sorts of general trends have been observed, there are significant variations between systems based on different cores and in many cases the formation of a mesophase has been shown to be extremely sensitive to small changes in the structure of the pendant groups. For example, for a series of ester substituted triphenylene derivatives it was observed that inclusion of a single bromine atom on the substituent groups was sufficient to completely inhibit mesophase formation. 3 0 Although rigid core discotic molecules are by far the most commonly reported discotic mesogens represented in the literature, examples exist where molecules with flexible cores can display columnar discotic mesophases. Two examples of such rare, flexible core mesogens (referred to as pyramidic or bowlic) are illustrated in Figure 1.9. Certain calix[4]arenes (17, Figure 1.9a) with pendant alkoxy or ester groups have been shown to form columnar arrays in the mesophase; these molecules also have a sizeable net dipole moment, giving rise to potentially ferri- or antiferrielectric mesophases whose orientation can readily be changed by application of an external field. In these species, although inversion of the cone is rapid for isolated molecules in isotropic solutions at the temperatures at which mesophase ordering is observed, cooperativity is believed to slow this process in columnar aggregates. Another example of a bowlic mesogen is that based on hexaacylated azacrown[18]-N6 (Figure 1.9b). In this type of compound, the columnar stacks produced in the mesophase have been described as tubular discotic, with evidence suggesting that the columns retain a hollow space in the middle. 3 2 14 Variation of the substituents appended to the nitrogen atoms indicated that these tubular mesophases were somewhat difficult to induce; only those possessing the long chain alkyl benzamide moieties exhibited mesomorphism (18a and 18b). In analogous compounds with straight chain amides or amides in which aromatic groups were separated from the core by one or more methylene groups, all mesophase behaviour was absent.3 3 Nonetheless, despite the relative rarity of this type of mesogen and the sensitivity of the observed mesophase behaviour to the substitution, these materials offer the intriguing possibility of creating persistent hollow columns that are not only interesting from a fundamental standpoint but also as potential for ion transport media or for the preparation of novel inclusion complexes. a) R R b) R R R O R = alkoxy, alkanoate 18a R = C6H4OC12H. 18b R = CehUOC-nH; 17 Figure 1.9: Pyramidal or Bowl ic Mesogens 15 1.4 - Objectives The goal of the work undertaken in this project was to develop new, highly soluble macrocycles in the [3+3] Schiff base family incorporating a large number of appended aikyl and porous or tubular discotic liquid crystalline mesophases. Although previous attempts to impart liquid crystallinity to these types of macrocycles through the incorporation of six peripheral alkoxy substituents were unsuccessful, it was thought that the inclusion of a larger number of appended groups (in this case aikyl as in 19c-f and 20c-e) might induce liquid crystallinity. This thesis w i l l describe the synthesis of highly substituted dialdehyde units required to for these cycles in Chapter 2 and their subsequent use in the preparation of [3+3] macrocycles and related compounds in Chapter 3. Characterization and the thermal behaviour of these macrocycles w i l l also be discussed along as the crystal structure of 19a. alkoxy groups (see Figure 1.10) in the hopes that these species might be induced to display R R R R 19a R = H 19b R = OMe 20b R = OMe 20c R = OC 6H 1 3 20d R = OC 1 6H 3 20e R = OC 1 8H 3 20a R = H 19c R = OC 6H 1 3 19d R = OC 1 4 H 2 9 19e R = OC 1 6 H 3 3 19f R = OC 1 8 H 3 7 Figure 1.10: Target [3+3] Schiff Base Macrocycles 16 Chapter 2: Hexasubstituted Benzenes as Macrocycle Precursors 2.1 - Background C o n s t r u c t i o n o f the target [3+3] S c h i f f base macrocyc les requires both a di funct ional amine and a d i funct ional aldehyde. S o m e o f the previous w o r k i n the M a c L a c h l a n group focused o n v a r i a t i o n o f the d i a m i n e components, i n particular the use o f 4 ,5 -d ia lkoxy phenylenediamine derivatives (8b-I), and their condensation w i t h 3 ,6-di formylcatechol (7) to produce a l ibrary o f macrocyc les bearing s ix s o l u b i l i z i n g a l k o x y groups (9b-l, see Figure 2.1). A l t h o u g h these m a c r o c y c l e s have been investigated w i t h regards to possible mesogenic i ty , 1 none were observed to be l i q u i d crystal l ine either as metal free or as metal lated species. 2 ' 3 It was thought that incorporat ion o f more pendant groups, i n this case o n the dialdehyde, might lead to mesogenic [3+3] macrocyc les . W i t h such goals i n m i n d , and g i v e n the relative fac i l i ty i n construct ing the [3+3] core w i t h the appropriate starting materials and w i t h the synthesis o f the d i a m i n e moieties already being w e l l establ ished, 4 the crux o f this project can essentially be v i e w e d as the synthesis and pur i f i ca t ion o f the diol/dialdehyde species (31) required for the preparat ion o f the macrocycles , R R 9a-l F i g u r e 2.1: [3+3] S c h i f f Base M a c r o c y c l e s B e a r i n g S i x A l k o x y Substituents 17 A s such, attempts were made to find a general method to produce these deceptively simple looking molecules. A variety of methods were employed in attempts to find a general route to these compounds, the majority of which are summarized in Scheme 2.1. Scheme 2.1: Some Routes Employed to Prepare the Target Compounds a) Ni(dppp)Cl 2; b) Br 2 ; c) NaOMe/MeOH, CuBr, EtOAc; d) BBr 3 ; e) Br 2 , FeCl 3 ; f). Vilsmeyer-Haack (and modifications); g) SnCl 4 , C 1 C H 2 0 C H 3 ; h) T i C l 4 , C l 2 C H O C H 3 ; i) H -BuLi , D M F ; j) CuCN, DMF; k) «-BuLi, C lC0 2 Et ; 1) D I B A L - H ; m) H M T A , TFA; n) M n 0 2 ; o) PCC. 2.2 - In Pursuit of dialkyldihydroxybenzenedialdehydes The first step in the syntheses employed a Kumada coupling in which the appropriate Grignard reagent was reacted with 1,2-dichlorobenzene (21) in the presence of a nickel (II) 5 7 * * catalyst (see Scheme 2.2). " This reaction is known to be fairly broad in scope, however certain complications arose for alkyl chains longer than hexyl. The rate of the reaction appeared to be directly related to the length of the alkyl chains employed in preparing the Grignard reagent; the longer the chain, the greater the viscosity of the solution and the slower the reaction. It is a known drawback of the Grignard that long reaction times promote the formation of the homocoupling product, with the presence of the nickel catalyst presumably exacerbating this tendency. Indeed, related catalyst systems have been employed to cross-couple aliphatic Grignards and halides, often resulting in complex product mixtures. 6 This homocoupling reaction was observed to be particularly evident for reactions with R=octyl, decyl and dodecyl, with a large proportion of the isolated products on workup appearing to being hexadecane, dodecane and tetracosane, respectively, based on ' H N M R integration. The reactions employing octyl- and decyl- magnesium bromide were particularly problematic inasmuch as the homocoupled product distilled in the same temperature range as the desired product, namely the 1,2-dialkylbenzene. Although easier to purify by distillation, further complications arose with the subsequent functionalization of the didodecyl derivative (vide infra). C l Ni(dppp)CI2 •<2 + 2.5BrMgR Cl Et 2 0, N 2, A 21 22a-c Scheme 2.2: Kumada Coupling The next step was the fairly straightforward dibromination of the 1,2-dialkylbenzenes (see Scheme 2.3). 8 ( R = b u t y l ) ' 9 ( R = h e x y l ) Typically, the distilled dialkylbenzene was treated with a 19 slight excess of elemental bromine in the presence of h and in the dark. This was followed by quenching with an aqueous solution of sodium sulfite and sodium hydroxide. Although the literature reports suggest that the dibromo derivative of 1,2-dibutylbenzene can be obtained as a solid directly from the bromination, 8 it was found in practice that the crude materials obtained were viscous oils from which the l,2-dibromo-4,5-dibutylbenzene would very slowly crystallize on storage at -11 °C. The dibromodibutylbenzene was by far the most easily isolated being a solid (mp = 33-35 °C, lit. 34-35 °C); 8 the dihexyl analogue, when pure, was a low.melting solid (mp ~18 °C; reported in the literature as an oi l at room temperature)9 which was prone to melt during filtration. Fortunately, the somewhat more pure solids/oils, which were obtained by filtration, could be recrystallized from 2-propanol affording materials of high purity in synthetically useful yields for R=butyl and hexyl (-15-20% yield over two steps). Unfortunately, for the dioctyl and didecyl species the distillation of the dialkylbenzenes proved particularly problematic given the co-distillation of the homocoupled alkanes. For these derivatives the bromination of the crude mixture of dialkylbenzene and alkane was undertaken, but the products appeared to be themselves viscous oils which made product isolation problematic. Purification of these oils by distillation required high temperatures (typically >250 °C at <0.1. mm Hg) that resulted in significant decomposition. It was possible to purify the 1,2-didodecylbenzene prepared from the Kumada coupling by distillation, however bromination of this material by the method employed for the shorter chain analogues was not effective. Once again, the longer the chain, the longer the reaction times required and the more likely it was to observe products arising from the competitive bromination of benzyllic positions rather than direct bromination of the ring. In fact, the bromination of 1,2-didodecylbenzene with either L or FeCl3 as catalyst seemed to only afford the mono-brominated product, and even that only after long reaction times and in very low yields (<10%) after chromatographic separation. Other authors have reported the preparation of the target compound by bromination in CCI4; given the 20 relative scarcity of this solvent and the somewhat unsatisfactory characterization presented, this method was not attempted. R 1) X S Br 2 , cat. I2, 0°C->RT B r \ r ^ 5 ^ R ~ R 2) aq. 5% N a 2 S 2 0 3 , 5% NaOH B r ^ ^ ^ R 22a, b 23a, b Scheme 2.3: Bromination of 1,2-dialkylbenzenes Reaction of an aryl bromide with sodium methoxide in methanol in the presence of a catalytic amount of copper (I) bromide and ethyl acetate affords arylmethoxy ethers in high yields. 1 1 This reaction was employed on the dibromodialkyl substrates affording the desired products in good yields for the dibromodibutyl- and dibromodihexylbenzenes (see Scheme 2.4). The products were typically obtained as viscous, water-white oils. Attempts were made to use this reaction to prepare the (mono)methoxy ether of the chromatographically purified 1-bromo-3,4-bisdodecylbenzene in the hopes that the product could be further brominated and resubjected to the methoxylation conditions to afford the desired l,2-dimethoxy-4,5-didodecylbenzene, but the substrate appeared to be incompatible with the conditions and none of the desired methoxylated product was observed spectroscopically. This is likely attributable to the immiscibility of the long-chain dialkyls with the extremely polar solvent conditions and their consequent reduced reactive cross section. 25 wt.% NaOMe in M e O H „ rt B r V V R cat. EtOAc, CuBr M e O ^ ^ R B r - ^ ^ R N 2 , A M e O ^ ^ R 2 3 a ' b 24a, b Scheme 2.4: Methoxylation of l,2-dibromo-4,5-dialkylbenzenes With the dimethoxydibutyl- and dimethoxydihexyl-benzenes in hand, a general method for introducing formyl groups to the aromatic core was sought. Initial attempts involved use of ' 12 13 Vilsmeyer-Haack conditions ' in hopes that the system would be sufficiently activated towards 21 formylation by the presence of four electron donating groups on the ring. Attempts were made using the standard conditions, namely the formation of the complex of D M F and P O C I 3 followed by addition of the substrate at 0 °C followed by heating, 1 4 ' 1 5 however no formylated product was observed on workup. Complexes of D M F and other Lewis acids were also employed (namely anhydrides of acetic-, trifluoroacetic-, methanesulfonic-, and trifluoromethanesulfonic acids) with no success. It is interesting to note that authors have reported the monoformylation of 1,3,5-trimethylbenzene in 60% yield and of anisole in 80% yield (-1:4 o/p) using trifluoromethanesulfonic a c i d / D M F . 1 6 Attempts were also made to formylate or chloromethylate these substrates (compounds 24a and 24b) through use of tin tetrachloride/chloromethyl methyl ether and titanium tetrachloride/ dichloromethyl methyl ether, respectively. The substrates were completely unreactive to the former, while the latter only afforded only mono-formylated product after acidic hydrolysis, and that only in low yield (-20-80%) and after long reaction times (~3 days at reflux in D C M ) . Presumably the failure of these methods is attributable to the hindered nature of the substrates; the hexasubstitution of benzene is known to be somewhat difficult. The second general method attempted to diformylate these substrates consisted broadly of attempts to lithiate the remaining positions on the ring followed by quenching with an electrophile. Direct lithiation of the ring was possible through the use of «-BuLi (ortho-lithiation), however quenching with D M F afforded predominantly the mono-formylated species. The use of T M E D A and a sizeable excess of «-BuLi was no more effective. This is in contrast to the preparation unhindered analogues (see Scheme 2.5), in which direct lithiation and formylation with D M F (followed by deprotection) affords the desired pyrocatechol derivatives in 1 7 low to moderate yields. 22 C H O \ ^ ^ O M e 2) DMF then H 2 0 ^ \ ) M e 32 C H O 33, - 3 0 % yield Scheme 2.5: Direct Formylation of 1,2-dimethoxybenzene O M e 1) nBuLi, T M E D A , E t 2 0 O M e Although direct or/Zzo-lithiation of aryl ethers is a well known method for further functionalization of aromatic compounds, 1 8 it was clearly not adequate to prepare the desired diformyl compounds required for the synthesis of the target macrocycles. One method which has been employed successfully to increase the reactivity of aromatics towards lithiation and subsequent structural elaboration is through the use of bromine-lithium exchange, 1 8 particularly generally somewhat less hindered) substrates, in which bromine-lithium exchange followed by quenching with D M F or N-methylformanilide has been used to formylate aromatics. 2 0 As such, the l,2-dimethoxy-3,4-dialkylbenzenes (24a, b) were subjected to bromination conditions in an effort to obtain more reactive substrates. It was found that several different methods could be employed to introduce bromine onto the remaining unsubstituted ring positions of these compounds. The use of N B S in D C M was adequate to introduce a single bromine atom-in good yields, however dibromination with this reagent was not feasible even using a large excess of N B S . This was observed using both the longer chain compounds (R=butyl, hexyl) as well as with dimethylveratrole. Presumably the introduction of a single bromine atom onto the ring (in addition to the inherent steric congestion of these compounds) is sufficient to deactivate it towards further bromination. That being said, the use of elemental bromine in the presence of a Lewis acid catalyst (FeCU) in dichloromethane remarkably afforded the dibromo derivatives in reasonable yields and purities (see Scheme 2.6). at low temperatures.1 9 Indeed, the use of this methodology has been applied to similar (albeit 23 Care had to be taken however to not "overbrominate" the compounds, the benzyllic positions being activated towards radical bromination. MeO Br 3 " Y ^ Y ' R XS NBS, CH 3CN M e O ^ / L , R 1.2 Br2, cat. FeCI3, CH2CI M e O ^ ^ ^ R 0°C->RT 24a, b MeO ^ R XS Br2, cat. FeCI3, CH 2CI 2 0°C->RT Br MeO MeO' ^R Br A 25a, b 0°CH>RT Scheme 2.6: Bromination of l,2-dimethoxy-4,5-dialkylbenzenes With l,4-dibromo-2,3-dibutyl-5,6-dimethoxybenzene and l,4-dibromo-2,3-dihexyl-5,6-dimethoxybenzene in hand, attempts were made to apply the bromine-lithium exchange protocol followed by quenching with formylating agents. A number of different conditions were employed in attempts to optimize this method; typically the concentrations were held constant while conditions like temperature and the electrophile were varied. Initial attempts focused on the use of conditions analogous to those applied to the dihydro- analogues, namely lithiation followed by quenching with anhydrous D M F . Although a distribution of products was always observed, some of the diformylated species was obtained on workup along with monoformylated and regenerated dihydro- compounds (see Scheme 2.7). N o brominated starting material was generally observed spectroscopically after application of this protocol. A typical ' H N M R spectrum of the crude material obtained from this method is illustrated in Figure 2.2. Different conditions and formylating agents were employed in an attempt to maximize the yield of the desired product (see Table 2.1); however, regardless of the conditions employed, the proportion of the diformylated compounds never exceeded - 5 0 % as determined by N M R integration, the methoxy signals being diagnostic (see Figure 2.3). Chromatography on the crude material also 24 proved problematic; despite numerous attempts it was extremely difficult to find conditions that would separate all three components. Typically, it was found that conditions that would separate the formylated products from the dihydro species were inadequate to resolve mono- and di-formylated species. After many attempts at method optimization and given the somewhat capricious chromatography and relative lack of scalability, it was concluded that this method was not suitable for the preparation of the target compounds in the quantities required for the ultimate synthesis of the target macrocycles. 25a, b 26a, b 24a, b a, R = butyl b, R = hexyl Scheme 2.7: Lithiation/Formylation of l,4-dibromo-2,3-dialkyl-5,6-dimethoxybenzenes Table 2.1 - Optimization of Lithiation/Formylation Conditions Substrate Conditions Approximate Product Distribution (diformylated (26a,b):monoformylated:dihydro (24a,b)) 24b 4 equiv. rc-BuLi, 2.5 equiv. T M E D A , room temp., 10 equiv. D M F 10%: 6 5 % : 25% 24b 4 equiv. «-BuLi, 2.5 equiv. T M E D A , reflux prior to quench, 10 equiv. D M F 15% : 60% : 25% 25b 4 equiv. rc-BuLi, room temp, 10 equiv. D M F 20% : 50% : 30% 25b 4 equiv. rc-BuLi, 0 °C, 10 equiv. D M F 35% : 45% : 20% 25b 4 equiv. «-BuLi, -78 °C, 10 equiv. D M F 50% : 45% : 5% 25b 6 eq. w-BuLi, -78 °C, 10 eq. D M F 4 5 % : 4 5 % : 10% 25b 4 equiv. «-BuLi, 2.5 equiv. T M E D A -78 °C, 10 equiv. D M F 30% : 50% : 20% 25a 4 equiv. n B u L i , room temp., 10 equiv. trimethyl orthoformate 0% : 0% : 100% 25a 4 equiv. «-BuLi, -78 °C, 10 equiv. methyl formate 40% : 50% : 10% 25 Chloroform-d 11.5 11.0 10.5 10,0 9.5 9.0 8.5 8.0 7.5 7.0 6,5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm Figure 2.2: 400 M H z ' H N M R of the Crude Product of the Lithiation and Formylation of 25b 3.93 ppm 3.88, 3.87 ppm 3.84 ppm 4.15 4.10 4.05 4,00 3 90 3 85 ppm 3,75 3.70 Figure 2.3: Determination of Product Distribution by N M R Integration (indicated chemical shifts are for the methoxy protons) 26 Thus, with substrates active towards lithiation but not particularly suited for direct formylation in high yields, other routes to the target 2,3-dialkyl-5,6-dihydroxybenzene-l,4-dialdehydes were sought. It was found that quenching of the dilithiated species with the more reactive ethyl chloroformate afforded the 1,4-diesters 27a and 27b in reasonable yields (-80%) and with a higher proportion of disubstituted relative to monosubstituted product (usually > 2:1; see Scheme 2.8). Chromatographic separation of these compounds was also easier given the almost complete absence of regenerated dihydro- species. That being said, the functionality of these materials was in the wrong oxidation state, necessitating their net reduction to aldehydes for subsequent macrocyclization. Scheme 2.8: Lithiation/Acylation of l,4-dibromo-2,3-dialkyl-5,6-dimethoxybenzenes Interestingly, it was found that these esters were completely inert to reduction with lithium aluminum hydride even after treatment with a large molar excess (> 1 Ox) and at reflux in dry T H F or 1,4-dioxane under nitrogen for three days. This is in contrast to the reduction of similar compounds reported in the literature in which LiAlH4 reductions of crowded benzoate esters have been reported to afford the benzyl alcohols 2 1 ' 2 2 under the appropriate conditions in >75% yields (-4 and < 1 equivalents LiAlH4 respectively and < 3 hours at reflux in dry diethyl ether or T H F ; see Scheme 2.9). Given the relatively mild conditions reported for these reductions of related compounds, one must conclude that the steric congestion present in the compounds prepared in this work can once again be implicated in their lack of reactivity. Br Br C0 2 Et 27a, b 25a, b 27 C 0 2 E t HO. MeO. THF, A, N 2 MeO. + UAIH4 M e O O M e 45 minutes MeO' O M e 0.16 mmol 34 0.04 mmol 35, 87% yield C 0 2 M e HO + -0.7 UAIH4 E t 2 0 , A, N 2 2hrs 36 37, 75% yield Scheme 2.9: Reduction of Crowded Benzoate Esters with L iAlFL; (see references 21 and 22) Despite the failure of L i A I H 4 to reduce the diesters, other reducing agents were sought in hopes of ultimately obtaining a synthetically useful route to the target compounds. It is known that stoichiometric amounts of neutral aluminum hydrides (e.g. diisobutyl aluminum hydride, or D I B A L - H ) can be used to selectively reduce esters to aldehydes at low temperature.2 3 In spite of the relative bulk of the isobutyl groups present and the previous issues of steric crowding in the substrates, it was found that the reaction of stoichiometric amounts of D I B A L - H with the esters did, in fact, reduce the compounds however the results were not exactly as anticipated. Use of two equivalents of D I B A L - H at -78 °C instead seemed to reduce some of the material entirely to benzyl alcohol while leaving some unchanged. Unfortunately, the selectivity of D I B A L - H decreases with increasing temperature; 2 3 ' 2 4 use of stoichiometric amounts of this reagent at ambient temperature also did not appear to yield any aldehyde but instead only partial conversion directly to the benzyl alcohol. Use of an excess of this reagent at reduced or at ambient temperature afforded the bis-benzylalcohol (28) in low yields (<20%) after purification (see Scheme 2.10). Subsequent attempts to oxidize these compounds back to aldehydes were unsuccessful; they were found to be completely unreactive towards MnC»2 oxidation while 28 oxidation with P C C in dichloromethane gave a distribution of products, only a very small proportion of which was the desired dialdehyde. Scheme 2.10: Reduction with D I B A L - H A r y l bromides are versatile substrates for carbon-carbon bond forming reactions. A number of modern reactions employing these compounds as substrates have been developed including palladium catalyzed reactions like the Heck and Sonogashira couplings. A classical reaction employing these types of reagents is the Rosenmund-von Braun reaction in which an aryl bromide is converted into an aromatic nitrile by the action of a stoichiometric amount of copper (I) cyanide. Although the original conditions call for the reaction do be done in the absence of solvent, it has been found that the use of high boiling, coordinating solvents (such as pyridine, A^-methylpyrrolidone or D M F ) greatly simplify the workup and do not adversely affect the yields. 2 6 3 " 0 Applying this reaction to compounds 25a and 25b remarkably afforded the dinitrile species 29a and 29b in high yields (>85%; see Scheme 2.11). Subsequent reduction of 29a with a stoichiometric amount of D I B A L - H 2 4 ' 2 7 followed by acidic hydrolysis afforded the corresponding dialdehyde (26a) in - 5 0 % yield after chromatography. 25a, b 2 9 a - b Scheme 2.11: Cyanation of A r y l Bromides 29 Considering the large number of steps and resulting less than satisfactory yields and difficult chromatography associated with the lithiation/formylation and cyanation methods, yet another different route to the target 2,3-dialkyl-5,6-dihydroxybenzene-l,4-dialdehydes was sought. Phenols are generally quite reactive substrates for electrophilic.aromatic substitution and, as such, reactions were sought in which the 1,2-dihydroxy-4,5-dialkylbenzenes might be formylated directly, hopefully minimizing the number of steps and improving the yields. One such reaction that has been used to formylate activated aromatics is the Duff reaction, in which a phenol is reacted with hexamethylenetetramine ( H M T A ) in an acidic medium usually affording formylated products in low to moderate yields (see Scheme 2.12). 2 8 More recent examples of this reaction in the literature using trifluoroacetic acid as the solvent indicate improvements in yields and also, fairly remarkably, the triformylation of a hindered aromatic system (albeit in low yields). 3 0 Along those lines, this reaction was applied to l,2-dihydroxy-4,5-dialkylbenzenes (30a and 30b) prepared by deprotection of compounds 24a and 24b with boron tribromide. The initial results of this method were promising, with spectra indicating the presence of the desired products in the crude reaction mixture after hydrolysis and extraction. Although the chromatography seemed initially intractable given the marked tendency of the products to tail on the column (presumably owing to their high polarity), suitable conditions were eventually discovered allowing the isolation of the target compounds in synthetically useful yields and high purities. 30 N l -N C F 3 C 0 2 H - N Scheme 2.12: Proposed General Mechanism for Formylation with HMTA (adapted from reference 31) 2.3 - A Brief Discussion of Synthetic Methodologies In synthesis, unless some new, specific methodology is being devised and explored, it seems evident that a key factor in the choice of synthetic routes is economy of effort; it is often advantageous to minimize the number of steps required to obtain any given target compound in order to maximize yields. A number of different avenues were explored in an effort to devise a general method to obtain 2,3-dialkyl-5,6-dihydroxybenzene-l,4-dialdehydes (31a,b) for use in the preparation of novel Schiff base macrocycles. Although three different general routes were successful in producing the target compounds for relatively short butyl and hexyl chains (namely the lithiation/formylation approach, the cyanation/reduction approach and the direct formylation approach), the efficiency of these methods differ markedly in terms of the number of steps required as well as the ease of purification of the intermediates and products. From a yield standpoint, the Duff route is certainly the preferred method; overall yields for this route were on the order of 25-30% from the known compounds 23a and 23b over three steps. B y contrast, the lithiation/formylation and cyanation/reduction routes had yields on the order of 10-15% over four steps and 20-25% over five steps, respectively. In addition, although chromatography is required at (at least) the final stage for all three routes, that for the Duff formylation is by far the most forgiving and most easily executed. It seems unfortunate in hindsight that in terms of ease and yields the routes were explored chronologically from hardest to easiest; however this would seem to be the nature of devising routes to new compounds. Everything is easy once you know what w i l l and wi l l not work, figuring out which is which is the challenge of synthesis. 32 2.4 - Properties of the dialkyldihydroxybenzenedialdehydes Although seemingly simple compounds, the 2,3-dialkyl-5,6-dihydroxybenzene-l,4-dialdehydes (31a,b) present some interesting spectral and structural features which seem worthy of mention. While the ' ff N M R and 1 3 C N M R spectra of the dibutyl compound (31a, see Figures 2.4 and 2.5, respectively) are in accord with what one might expect for, this sort of symmetrically substituted aromatic core, the IR spectrum presents some interesting features (see Figure 2.6). In particular, the C = 0 stretching mode is observed at ca. 1650 cm" 1, which is quite low for an aromatic aldehyde, but not entirely unexpected given the presumed strong hydrogen bonding present owing to the adjacent phenol. Similarly, the band at 1294 cm" 1, which can tentatively be assigned to the phenolic C - 0 stretching mode, is somewhat higher that that typically observed for unsubstituted phenols. This may indicate some strengthening/shortening of the C - 0 bond possibly signifying some quinoidal character to the bonding (vide infra). Chlorolorm-d water T 1.89 2.03 4 00 ' 6.05 y a • y y 1 3 1 2 1 1 ' " • 1 0 9 8 7 6 ' 5 4 3 2 1 0 ppm Figure 2.4: 400 M H z [ H N M R Spectrum of Compound 31a 33 •uinininn4ii««»tmi»iii iiwinin 5 ^ <N I Figure 2.5: 100 M H z 1 3 C N M R Spectrum of Compound 31a It was possible to grow single crystals of compound 31a by slow evaporation of a concentrated hexanes solution. Two distinct conformers are present within the asymmetric unit 34 cell of 31a (see Figure 2.7), one in which the aldehyde groups point towards the phenolic groups and are apparently engaged in strong intramolecular hydrogen bonding. In the other conformer, one aldehyde points towards the phenols, the other towards the (disordered) aikyl chains; in both conformers the aldehydes lie in approximately the same plane as the ring. Packing views along the a, b, and c crystallographic axes are illustrated in Figures 2.8, 2.9, and 2.10, respectively. The view along the a axis suggests that the molecules pack "head to head," forming an interdigitated, lamellar type arrangement in which the polar head groups are, at least to some extent, segregated from the aikyl chains. For a table of the crystallographic parameters as well as selected bond lengths and angles see Appendix 1, Table 1. Closer examination of the bond lengths in the higher symmetry conformer reveals, in general, a slight expansion of the bonds in the aromatic core from those typically observed (ca. 1.38-1.43 A observed vs. 1.37-1.40 A for typical aromatic C - C bonds). 3 2 Although some degree of bond alternation seems evident, it is not particularly pronounced and by no means dramatic. The aldehyde C = 0 bonds also seem to be slightly elongated relative to related compounds (ca. 1.21-1.22 A observed vs. 1.19-1.20 A for typical aromatic aldehydes). The phenolic C - 0 bonds are somewhat shortened relative to that of a typical phenol, for example (ca. 1.35 A observed vs. 1.36 A for phenols), however this difference is admittedly quite small. Taken together, these trends in bond lengths would seem to suggest possible contributions from a quinoidal tautomer (see Figure 2.11), however the contribution is likely minimal considering the only slight observed bond alternation. The expansion of the aromatic C - C bonds could readily be attributed to the high degree of substitution of the system and the consequent strain induced. The thermal behaviour of these compounds was also investigated, both by differential scanning calorimetry (DSC) and by polarizing optical microscopy (POM). Although both 31a 35 and b both exhibited well defined melting transitions by D S C (at 54 °C and 41 °C, respectively), the dibutyl analogue (31a) was also observed on occasion to display an endothermic transition at -50 °C. The possibility that this transition corresponded to the formation of a mesophase was investigated through the use of P O M , however no textures that might be attributed to liquid crystallinity were observed. Although conceivably an artifact, it is also possible that this transition represents a transformation from one crystalline polymorph to another prior to melting. No analogous transition was observed for the hexyl analogue 31b. Figure 2.7: O R T E P Diagram of the Assymetric Unit Cel l of a Single Crystal of Compound 31a 36 37 Figure 2.10: V i e w Along the c A x i s for a Single Crystal of 31a R R R R R R Figure 2.11: Possible Quinoidal Tautomers for 2,3-dialkyl-5,6-dihydroxybenzene-l,4-dialdehydes 38 2.5 - Conclusions and Recommendations Three different routes to the highly substituted, target 2,3-dialkyl-5,6-dihydroxybenzene-1,4-dialdehydes (31a and 31b) were explored. These routes can broadly be classified as the lithiation/formylation route, the cyanation/reduction route and the direct formylation route. Yields for these different routes were on the order of 10-15%, 20-25%) and 25-30% from known compounds, respectively. In terms of ease of synthesis, yield, and minimization of the steps required, the direct formylation route was found to be preferable. Although all three methods were successful for relatively short alkyl chains (butyl and hexyl), the preparation of longer chain analogues was hampered at an early stage by difficulties in purification and functionalization by the methods employed (namely Kumada coupling followed by electrophilic bromination). A recently reported synthesis of the di dodecyl analogue of compounds 30a and 30b using sequential Friedel-Crafts acylations and reductions of 1,2-dimethoxybenzene followed by deprotection (see Scheme 2.13) 3 3 may provide a viable alternative route to the longer chain analogues of compounds 31a and 31b, as well as to possible asymmetric dialdehydes, however compatability with'the direct formylation conditions remains to be seen. O Scheme 2.13: Possible Route to Longer Chain Analogues of 30a and 30b 39 2.6 - Experimental Materials. o-Dichlorobenzene, 1-bromoalkanes, nickel (II) chloride hexahydrate, bromine, iodine, N-bromosuccinimide, iron (III) chloride, copper (I) bromide, copper (I) cyanide, 25 wt.% N a O M e in M e O H , anhydrous N,N-dimethylformamide, M-butyllithium (1.6M in hexanes), methyl formate, tetramethyleneethylenediamine ( T M E D A ) , ethyl chloroformate, lithium aluminum hydride, calcium hydride, diisobutyl aluminum hydride ( D I B A L - H , 1 .OM in hexanes), boron tribromide, trifluoroacetic acid, and hexamethylene tetraamine ( H M T A ) were obtained from Aldr ich or Fisher Scientific. Diethyl ether and T H F were distilled from sodium/benzophenone ketyl under nitrogen. Methyl formate and D M F were distilled from calcium hydride under nitrogen. Hexanes was dried by passage through a column of activated alumina. Deuterated solvents were obtained from Cambridge Isotope Laboratories, Inc. Dichloro[l,3-bis(diphenylphosphino)propane] nickel (II) was prepared according to the literature method 6 using l,3-bis(diphenylphosphino)propane obtained from Strem Chemical Company. Equipment. A l l reactions were carried out under nitrogen unless otherwise noted. 300 M H z *H N M R spectra and 75.5 M H z 1 3 C N M R spectra and 400 M H z *H N M R spectra and 100 M H z 1 3 C N M R spectra were recorded on Bruker A V - 3 0 0 and A V - 4 0 0 spectrometers respectively. ' H N M R spectra were calibrated to residual protonated solvent while 1 3 C N M R spectra were calibrated to deuterated solvent. U V - V i s spectra were obtained on a Varian Cary 5000 U V -vis/near-IR spectrophotometer using a 1 cm quartz cuvette. IR spectra were obtained from K B r pellets or as neat or drop cast films on N a C l plates using a Bomem MB-series spectrometer. Electron impact (EI) and electrospray ionization (ESI) mass spectra as well as elemental analyses were performed at the U B C Microanalytical Services Laboratory. Differential scanning calorimetry (DSC) thermograms were obtained using a Perkin Elmer Diamond D S C . A n 40 Olympus B X 4 1 polarizing optical microscope (POM) equipped with a variable temperature hot stage was employed to look for liquid crystalline textures. Melt ing points were determined by D S C , P O M , or on a Fisher-Johns melting point apparatus. S C X R D data was collected on a Bruker X 8 A P E X diffractometer with graphite monochromated M o - K a radiation. Synthesis of l,2-dibromo-4,5-dibutylbenzene (23a):5"9 To a I L 3-neck round bottom flask under nitrogen was added 22.10g (0.853 moles) magnesium turnings and ca. 300 m L dry diethyl ether. 1-Bromobutane (100 m L , 0.853 moles) was added by addition funnel over 2 h at a rate sufficient to maintain the solution at reflux. After the addition was complete, the solution was heated to reflux for one hour then chilled to 0 °C on ice. The chilled solution was transferred by syringe to 0 °C solution of 30 m L 1,2-dichlorobenzene (0.284 moles) in 100 m L dry diethyl ether containing 231 mg Ni(dppp)Cl2 (0.428 mmol, 1.5 mol% with respect to dichlorobenzene). The resulting green/black suspension was heated to reflux for 48 h after which it was cooled on ice and an additional 230 mg Ni(dppp)Cl2 added. Over the course of another 16h at reflux, large amounts of grey/green salt precipitated; N M R at this time indicated only traces of starting materials. The reaction was quenched by careful addition to 300 m L ice-cold 0 .5M HCI then extracted with diethyl ether (3x80 mL) . The organic fractions were dried over MgS04, filtered and the solvent removed by rotary evaporation to afford 44.35g of a thin yellow oi l . Distillation at reduced pressure (b.p.=58-64 °C at -0.1 mm Hg) afforded 18.68g (98.2 mmol, 35% yield) of 1,2-dibutylbenzene as a thin, colourless liquid. To 15.03g (79.0 mmol) of the distilled 1,2-dibutylbenzene was added ca. 20 mg iodine followed by 8.3 m L Br2 (-160 mmol) in the dark at 0 °C vented through a concentrated aqueous N a O H solution until the cessation of H B r evolution (typically -48 h). When no residual starting material was observed by N M R , the solution was diluted with 100 m L dichloromethane and 41 quenched by careful addition of an aqueous 5% K O H / 5 % Na2S03 solution. The organic fraction was dried over MgS04, filtered, and the solvent removed by rotary evaporation. Storage at -11 °C over a week afforded large, pale yellow crystals. The crude solid was filtered and recrystallized from 2-propanol yielding 11.63g l,2-dibromo-4,5-dibutylbenzene as water-white crystals over two crops (33.4 mmol, 42% yield from 1,2-dibutylbenzene). The characterization of this compound conformed to that reported in reference 6. *H N M R (300 M H z , CDC1 3 ) : 8 7.36 (s, 2H, Ar-H), 2.51 (t, 4 H , A r - C / / 2 ) , 1.3-1.6 (m, 8H), 0.93 (t, 6H, terminal CH3). Synthesis of l,2-dibromo-4,5-dihexylbenzene (23b): Conditions analogous to those for the preparation of l,2-dibromo-4,5-dibutylbenzene were employed. 1,2-Dihexylbenzene was obtained as a thin, colourless oi l (b.p. ~ 135-145 °C at -0.1 mm Hg, 50% yield). Bromination afforded l,2-dibromo-4,5-dihexylbenzene as a low melting solid (m.p. = 18-22 °C) after four rounds of recrystallization from 2-propanol (30% yield from 1,2-dihexylbenzene). The characterization of this compound conformed to that reported in reference 7. ! H N M R (300 M H z , CDC1 3 ) : 8 7.35 (s, 2H, Ax-H), 2.50 (t, 4 H , Ar-C#2), 1.3-1.6 (m, 16H), 0.89 (t, 6H, terminal CHj). Synthesis of l,2-dimethoxy-4,5-dibutylbenzene (24a): To 3.042g (8.74 mmols) 1,2-dibromo-4,5-dibutylbenzene was added 100 m L of 25 wt. % N a O M e in M e O H , 3 drops of ethyl acetate and 27 mg CuBr (0.19 mmols, 2 mol %). This produced a dark blue suspension which was kept at reflux overnight under nitrogen. The reaction was cooled, checked by N M R to ensure completion, and then poured quickly into 100 m L ice-cold water. The resulting pale blue suspension was extracted with 3x60 m L diethyl 42 ether. The organic layer was rinsed with 50 m L dilute (-0.1 M ) N H 4 O H ( a q ) then 2x50 m L water, dried over MgS04 and filtered. The solvent was removed in vacuo affording 1.948g (7.78 mmol, 89% yield) l,2-dimethoxy-4,5-dibutylbenzene as a thin, colourless o i l . ' H N M R (400 M H z , CDC1 3): 5 6.62 (s, 2H, Ai-H), 3.84 (s, 6H , OCH3), 2.53 (t, J=7.6Hz, 4H , Ax-CH2), 1.53 (m, 4 H , A r - C H 2 C / / 2 ) , 1.39 (m, 4H), 0.94 (t, J -7 .2 Hz , 6H , terminal CH3); 1 3 C N M R (100 M H z , CDCI3): 5 146.8 (Ar-OCK3), 132.6, 112.6, 55.9 ( A r - O C H 3 ) , 33.9, 32.1, 22.8, 14.0; U V - V i s (CH2CI2): km,* (e) 284 nm (430 L-mof'-cm" 1); IR (neat): v = 2957, 2930, 2860, 1609, 1598, 1578, 1495, 1460, 1394, 1260, 1200, 1051, 875, 750 cm" 1; Anal . Calc 'd for C,6H2602: C , 76.75; H , 10.47; O, 12.78. Found: C, 76.59; H , 10.44. Synthesis of l,2-dimethoxy-4,5-dihexylbenzene (24b): Conditions analogous to those for the preparation of l,2-dimethoxy-4,5-dibutylbenzene were employed. l,2-Dimethoxy-4,5-dihexylbenzene was obtained as a thin, colourless oil (91% yield). ' H N M R (400 M H z , CDC1 3 ) : 5 6.64 (s, 2H , Ar-H), 3.84 (s, 6H , OCH3), 2.52 (t, J=7.6Hz, 4H, A1-CH2), 1.3-1.6 (m, 16H), 0.89 (t, J=7.2 Hz , 6H, terminal CfY 3 ); 1 3 C N M R (100 M H z , CDC1 3 ) : 8 146.8 04r-OCH 3 ) , 132.5, 112.6,55.9 ( A r - O C H 3 ) , 33.9, 32.1,31.6, 29.8,22.8, 14.0 U V - V i s (CH2CI2): lmax (e) 282 nm (380 L-mof'-cm" 1); IR (neat): u = 2956, 2928, 2856, 1610, 1519, 1465, 1266, 1224, 1115, 1036, 1006, 859, 742cm"1; Anal . Ca lc 'd for C20H34O2: C , 78.38; H , 11.18; O, 10.44. Found: C, 78.03; H , 11.00. Synthesis of l,4-dibromo-2,3-dibutyl-5,6-dimethoxybenzene (25a): To 1.948g (7.78 mmol) l,2-dimethoxy-4,5-dibutylbenzene was added 50 m L dichloromethane and -10 mg F e C ^ and the resulting solution chilled to 0 °C on ice. To this solution -1 m L Br2 (-19 mmol) was added slowly by pipette and the mixture left to warm to room temperature with stirring overnight. The resulting orange solution was quenched by addition of 40 m L of an aqueous 5% N a O H / 5 % Na2S03 solution followed by extraction with 3x40 m L dichloromethane. The organic fraction was dried over MgS04, filtered, and the solvent removed in vacuo. The resulting crude, pale yellow oi l was separated chromatographically on silica using 3:1 hexanes:DCM as the eluent affording 2.361g (5.78 mmol, 74% yield) l,4-dibromo-2,3-dibutyl-5,6-dimethoxybenzene as a viscous, pale yellow oi l (>95% pure by N M R integration). *H N M R (400 M H z , CDC1 3 ) : 5 3.86 (s, 6H, OCH3), 2.78 (t, J=7.9Hz, 4 H , Ar-CH2), 1.3-1.6 (m, 8H), 0.97 (t, .7=7.0 Hz , 6H , terminal CH3); 1 3 C N M R (100 M H z , CDC1 3 ) : 5 149.0, 137.5, 120.1, 60.6, 33.6, 31.8, 23.1, 13.8; H R - E I - M S : m/z = 408.01226 (calc), 408.01208 (found); U V - V i s (CH2CI2): W (e) 290 nm (540 L - m o l ' W 1 ) ; IR (neat): v = 2956, 2928, 2872, 2860, 1596, 1556,,1527, 1458, 1405, 1384, 1298, 1265, 1166, 1087, 1029, 976, 764, 740 cm" 1. Synthesis of l,4-dibromo-2,3-dibutyl-5,6-dimethoxybenzene (25b): Conditions analogous to those for the preparation of l,4-dibromo-2,3-dimethoxy-5,6-dibutylbenzene were employed. l,4-dibromo-2,3-dimethoxy-5,6-dihexylbenzene was obtained as a viscous, pale yellow oil (73% yield and >95% pure by N M R integration after chromatography). ' H N M R (400 M H z , CDCI3): 5 3.86 (s, 6H, OCH3), 2.77 (t, J=7.8Hz, 4 H , Ar-CfY 2 ) , 1.3-1.6 (m, 16H), 0.90 (t, J=7.2 Hz , 6H, terminal C / / 3 ) ; 1 3 C N M R (100 M H z , CDC1 3 ): 5 149.0, 137.5, 120.1, 60.6, 33.9, 31.5, 29.7, 29.6, 22.6, 14.1; H R - E I - M S : m/z = 464.07486 (calc), 464.07501 (found); U V - V i s (CH2CI2): lmax (e) 291 nm (480 L-mof'-cm" 1); IR (neat): u = 2957, 2928, 2857, 1528, 1458, 1405, 1384, 1301, 1214, 1164, 1091, 1033, 974, 766 cm" 1. 44 Synthesis of 2,3-dibutyl-5,6-dimethoxybenzene-l,4-dialdehyde (26a) via dibromo 25a: Although several sets of conditions were employed, an optimized reaction was as follows: to an oven-dried 100 m L Schlenk was added 0.707rg (1.73 mmol) l,4-dibromo-2,3-dimethoxy-5,6-dibutylbenzene which was dried under vacuum for ~1 h. To this was added -30 m L dry, freshly distilled diethyl ether and the solution cooled to -78 °C with an acetone/dry ice bath under nitrogen. /7-BuLi in hexanes (4.3mL, 1.6M, -6.9 mmols, - 2 equiv.) was slowly added resulting in a bright yellow/orange solution. The solution was stirred at -78 °C for 5 min and quenched by addition of 1.3 m L dry, distilled D M F (-17 mmol, - 5 equiv.). The resulting solution was allowed to warm to room temperature under nitrogen over 1-2 h and the resulting cloudy, yellow solution treated with 80 m L distilled water followed by extraction with 3x30 m L diethyl ether. The organic fraction was dried over MgSCM, filtered, and the solvent removed in vacuo affording a yellow/orange oi l consisting of regenerated l,2-dimethoxy-4,5-dibutylbenzene, mono- and di-formylated compounds. Chromatography on silica first with toluene as eluent then again with 1:3 hexanes:DCM afforded the dialdehyde as a thin yellow oi l (0.176g, 0.57 mmol, 33% yield, >95% pure by N M R integration). ' H N M R (400 M H z , CDC1 3 ) : 5 10:52 (s, 2H , aldehyde CH), 3.93 (s, 6H , OMe) , 2.80 (t, J=7.6 Hz, 4H , Ax-CH2), 1.3-1.6 (m, 8H), 0.89 (t, J=7.3 Hz , 6H, terminal CH3); 1 3 C N M R (100 M H z , CDC1 3 ) : 8 192.8, 153.8, 139.1, 132.9, 62.0,31.7, 29.7,22.6, 14.0; IR (neat): u = 2956, 2934, 2872,2866, 2752, 1708 (vs, aldehyde C=0), 1596, 1565, 1442, 1411, 1373, 1262, 1158, 1128, 1042, 862, 794, 744, 667 cm" 1; U V - V i s (CH 2 C1 2 ) : lmax (s)'298 nm (5.6 x 10 3 L - m o l " W ) . Synthesis of 2,3-dihexyl-5,6-dimethoxybenzene-l,4-dialdehyde (26b) via dibromo 25b: Conditions analogous to those for the preparation of 2,3-dibutyl-5,6-dimethoxybenzene-l,4-dialdehyde were employed. 2,3-Dihexyl-5,6-dimethoxybenzene-l,4-dialdehyde was obtained as a thin yellow oi l (31% yield and >95% pure by N M R integration after chromatography). 45 ' H N M R (400 M H z , CDCI3): 5 10.52 (s, 2H, aldehyde CH), 3.93 (s, 6H , OMe) , 2.81 (t, J=7.6 Hz, 4H , Ar-Cr7 2 ) , 1.3-1.6 (m, 16H), 0.90 (t, J=7.3 Hz , 6H , terminal CH3); 1 3 C N M R (100 M H z , CDCI3): 5 192.9, 153.9, 139.2, 133.1,62.0,31.7,31.5,29.8,27.9, 22.6, 14.0; IR (neat): v = 2956, 2933, 2872, 2861, 2754, 1706 (vs, aldehyde C=0), 1598, 1566, 1443, 1412, 1375, 1260, 1156, 1128, 1042, 895, 862, 794, 738, 668 cm' 1 ; U V - V i s (CH 2 C1 2 ) : lmax 00 302 nm (5.4 x 10 3 L-mol" '•cm" 1). Synthesis of 2,3-dihexyl-5,6-dihydroxybenzene-l,4-dialdehyde (31b) via dibromo 25b: To 0.186g (0.556 mmol) 2,3-dihexyl-5,6-dimethoxybenzene-l,4-dialdehyde was added 30 m L dicholoromethane and the resulting solution cooled to 0 °C under nitrogen. To this solution was added 0.5 m L (~5.3 mmol, ~5 equiv.) boron tribromide by syringe. The solution was stirred under nitrogen overnight warming to room temperature then quenched by addition of 50 m L distilled water followed by three drops of concentrated HCI . The aqueous layer was extracted with 2x30 m L D C M and the organic fractions dried over MgS04 , filtered, and the solvent removed in vacuo ultimately affording 2,3-dihexyl-5,6-dihydroxybenzene-l,4-dialdehyde as a waxy orange solid (0.139g, 0.416 mmol, 75% yield; see 31b via 30b for complete characterization). ' H N M R (400 M H z , CDCI3): 5 11.96 (s, 2H, Ar-OH), 10.34 (s, 2H , Ar-CrYO), 2.85 (t, 4H, A r -CH2), 1.50 (m, 4H), 1.30-1.35 (m, 12H), 0.98 (t, 6H, terminal CH3). Synthesis of diethyl 2,3-dibutyl-5,6-dimethoxybenzene-l,4-dioate (27a): To an oven dried 250 m L Schlenk was added 1.958g (4.80 mmol) l,4-dibromo-2,3-dimethoxy-5,6-dibutylbenzene which was dried under vacuum on for ~1 h. To this was added -50 m L dry, freshly distilled diethyl ether (~50 mL) was added and the solution cooled to -78 °C with an acetone/dry ice bath while flushing the reaction with nitrogen. To this solution was slowly 46 added 12 mL of 1.6 M rc-BuLi in hexanes (-19.2 mmols, -2 equiv.) resulting in a bright yellow solution. The.solution was stirred at -78 °C for 5 minutes and quenched by addition of 4.6 mL ethyl chloroformate (-48 mmol, -5 equiv.). The resulting solution was warmed to room temperature under nitrogen over the course of 1 h and the resulting cloudy, yellow solution treated with 100 mL distilled water followed by extraction with 3x50 mL diethyl ether. The organic fraction was dried over MgSCv, filtered, and the solvent removed in vacuo affording a yellow/orange oil consisting of a mixture of mono- and diester. Chromatography on silica with 3:1 hexanes:DCM afforded the diester as a thin, pale yellow oil (1.195g, 3.02 mmol, 63% yield, >95% pure by NMR integration). 'H NMR (400 MHz, CDC13): 8 4.39 (q, 4H, OC/72CH3), 3.85 (s, 6H, Ar-OC/73), 2.47 (t, 4H, Ar-CH2), 1.74-1.82 (m, 4H), 1.38 (t, 6H, OCH2C//3), 1.24-1.30 (m, 4H), 0.89 (t, 6H, terminal CH3); EI-MS: m/z = 394 (M+, 35%), 348 (M+-EtOH, 100%). Synthesis of diethyl 2,3-dihexyl-5,6-dimethoxybenzene-l,4-dioate (27b): Conditions analogous to those for the preparation of diethyl 2,3-dibutyl-5,6-dimethoxybenzene-1,4-dioate were employed. Diethyl 2,3-dihexyl-5,6-dimethoxybenzene-l,4-dioate was obtained as a thin, pale yellow oil (55% yield and >95% pure by NMR integration after chromatography). 'H NMR (300 MHz, CDC13): 8 4.39 (q, 4H, OC//2CH3), 3.84 (s, 6H, Ar-OC//3), 2.47 (t, 4H, Ar-CH2), 1.74-1.82 (m, 4H), 1.38 (t, 6H, OCH2C/73), 1.25-1.35 (m, 12H), 0.89 (t, 6H, terminal CH3); 13CNMR(100 MHz, CDC13): 8 167.7, 153.1, 134.1, 122.2, 62.8,61.2,39.0, 34.8,31.4, 25.4, 23.0, 14.2, 14.0; EI-MS: m/z = 450 (M+, 20%), 404 (M+-EtOH, 100%); IR (neat): v = 2958, 2932,2872, 2861, 1759 (sh), 1736 (vs, ester C=0), 1596, 1560, 1459, 1413, 1368, 1265, 1154, 1099, 1044, 895, 864, 794, 738 cm"1. 47 Synthesis of l,2-dibutyl-3,6-bis(hydroxymethyl)-4,5-dimethoxybenzene (28): To an oven dried 100 m L Schlenk was added 0.686g (1.52 mmol) diethyl 2,3-dihexyl-5,6-dimethoxybenzene-l,4-dioate which was dried under vacuum for -30 min. To this was added -50 m L dry hexanes and the solution cooled to -78 °C with an acetone/dry ice bath under nitrogen. A 1.0 M D I B A L - H solution in hexanes (10 mL, -19.2 mmols, - 6 equiv.) was slowly added by syringe resulting in a clear, pale yellow solution. The solution was stirred at -78 °C for 5 min then warmed to room temperature. The resulting clear and colourless solution was quenched by slow addition of 30 m L 10% KOH( a q ) , then extracted with 3x30 m L diethyl ether. The organic fraction was dried over MgS04, filtered, and the solvent removed in vacuo affording a waxy ivory-coloured solid. Recrystallization from acetone afforded a white solid (0.094g, 0.26 mmol, 17% yield, >95% pure by N M R integration). ' H N M R (400 M H z , CDC1 3 ) : 5 4.69 (d, J=6.3 Hz , 4H , A r C / / 2 O H ) , 3.89 (s, 6H , Ar -OCt f 3 ) , 2.63 (t, 4H , Ar -C7/ 2 ) , 2.23 (t, J=6.3 Hz , 2H , OH), 1.42-1.48 (m, 4H),T.26-1.30 (m, 4H), 0.96 (t, 6H, terminal CH3); 1 3 C N M R (100 M H z , CDC1 3 ) : 8 149.6, 136.1, 133.0, 60.8, 58.0, 34.4, 28.9, 23.3, 13.9; E I - M S : m/z = 310 ( M + , 20%), 292 ( M + - H 2 0 , 100%); IR (thin film): u = 3381 (br, OH), 3310 (sh), 2296, 2931, 2871, 2859, 1458, 1418, 1338, 1310, 1263, 1095, 999, 745 cm" 1; mp = 78-80 °C (dec). Synthesis of 2,3-dibutyl-5,6-dimethoxybenzene-l,4-dinitrile (29a): Into a 50 m L round bottom flask was weighed 1.013g (2.48 mmol) l,4-dibromo-2,3-dimethoxy-5,6-dibutylbenzene. This was dissolved in 20 m L dry D M F followed by addition of 0.672g C u C N (7.50 mmol, -3 equiv.). The resulting orange, turbid solution was heated to reflux for 3 h then poured hot into a solution of 2.15g F e C l 3 in 75 m L water and 20 m L cone. HCI . After stirring for 30 min, this solution was then extracted with toluene (3x40 mL); the organic extracts were rinsed with 2x20 m L water then dried over MgS04, filtered, and the solvent removed in 48 vacuo. The resulting viscous green oil was flushed through silica with D C M ultimately affording 0.715g of 2,3-dibutyl-5,6-dimethoxybenzene-l,4-dinitrile as a viscous, pungent orange oi l (2.38 mmol, 96% yield, >90% pure by N M R integration). ' H N M R (400 M H z , CDC1 3 ) : 5 4.01 (s, 6H, OMe), 2.77 (t, 4 H , A r - C i / 2 ) , 1.46-1.50 (m, 8H), 0.97 (t, 6H, terminal CH3); 1 3 C N M R ( 1 0 0 M H z , CDC1 3 ) : 5 152.8, 141.1, 128.9, 114.2,61.8,32.9, 29.4, 22.4, 13.9; H R - E I - M S : m/z = 300.18378 (calc), 300.18426 (found); IR (neat): u = 2957, 2932,2875,2859, 2228, 1575, 1555, 1467, 1416, 1378, 1321, 1257, 1189, 1108, 1092, 1069, 1032, 1012, 967, 863, 794, 746, 593 cm' 1 . Synthesis of 2,3-dihexyl-5,6-dimethoxybenzene-l,4-dinitrile (29b): Conditions analogous to those for the preparation of 2,3-dibutyl-5,6-dimethoxybenzene-l,4-dinitrile were employed. 2,3-Dihexyl-5,6-dimethoxybenzene-l,4-dinitrile was obtained as a viscous, pungent orange oi l (89% yield, >90% pure by N M R integration). ' H N M R (400 M H z , CDCI3): 5 4.02 (s, 6H, OMe) , 2.77 (t, 4H , A r - C i / 2 ) , 1.42-1.48 (m, 16H), 0.97 (t, 6H, terminal CH3); 1 3 C N M R ( 1 0 0 M H z , CDC1 3 ): 5 152.8, 141.3, 128.9, 114.2,61.8, 33.0, 31.3, 30.9, 29.4, 22.4, 13.9; H R - E I - M S : m/z = 356.24638 (calc), 356.24710 (found); IR (neat): u = 2986, 2928,2860, 2228, 1608, 1576, 1556, 1467, 1416, 1323, 1266, 1101, 1070, 1040,971,798,730,669 cm" 1. Synthesis of 2,3-dibutyl-5,6-dimethoxybenzene-l,4-dialdehyde (26a) via nitrile 29a: To an oven-dried 100 m L Schlenk flask was added 0.409g (1.36 mmol) 2,3-dibutyl-5,6-dimethoxybenzene-l,4-dinitrile. To this was added -20 m L dry, distilled diethyl ether by syringe under N 2 . The resulting yellow solution was cooled to -78 °C in an acetone/dry ice bath; once cooled, 3.4 m L 1.0 M D I B A L - H in hexanes (3.4 mmol, -1.2 equiv.) was added slowly. The solution was then warmed to room temperature with stirring. After stirring at room 49 temperature for -30 min, 40 m L 10% H 2S04( a q) was carefully added and the solution stirred at ambient temperature for another 30 min. This solution was diluted with 20 m L water and extracted with diethyl ether (3x25 mL) . The organic layer was dried over M g S 0 4 , filtered and the solvent removed in vacuo. The resulting yellow/orange oi l was chromatographed on silica with toluene as the eluent affording 0.2lOg (0.69 mmol, 50% yield) 2,3-dibutyl-5,6-dimethoxybenzene-l,4-dialdehyde as a thin, pale yellow oi l (>95% pure by N M R integration). ' H N M R (400 M H z , CDC1 3 ) : 5 10.52 (s, 2H, CHO), 3.93 (s, 6H , O C / / 3 ) , 2.81 (t, 4H , A r - C / / 2 ) , 1.45 (m, 8H), 0.97 (t, 6H , terminal CH2). Synthesis of 2,3-dibutyl-5,6-dihydroxybenzene-l,4-dialdehyde (31a) via catechol 30a: To 2.332g (9.31 mmol) l,2-dimethoxy-4,5-dibutylbenzene was added 100 m L dicholoromethane and the resulting solution chilled to 0 °C under nitrogen. To this solution was added 3.8 m L (-40 mmol, - 2 equiv.) boron tribromide by syringe. The solution was stirred under nitrogen overnight warming to room temperature then quenched by addition of 150 m L distilled water followed by three drops of concentrated HCI . The aqueous layer was extracted with 3x50 m L D C M and the organic fractions dried over Na2S04, filtered, and the solvent removed in vacuo affording l,2-dihydroxy-4,5-dibutylbenzene as a tan solid; this material was found to slowly degrade on standing in air and was not isolated ( ! H N M R (400 M H z , CDC1 3 ) : 5 6.65 (s, 2H, A r -H), 5.27 (br s, 2 H , ArOH), 2.46 (t, 4 H , A r - C / / 2 ) , 1.48-1.52 (m, 4H), 1.25-1.35 (m, 4H), 0.88 (t, 6H, terminal CH3)). The solid was dissolved in 75 m L trifluoroacetic acid under nitrogen. To the resulting pink solution was added 5.430g H M T A (38.7 mmol, - 2 equiv. relative to 1,2-dimethoxy-4,5-dibutylbenzene), and the solution heated to reflux for 3 h under nitrogen. On heating, the solution changed from pink to orange to dark red. After 3 h at reflux the solution was cooled to room temperature and 100 m L - 4 M HCl( a q ) was added. This solution was then held at reflux overnight under nitrogen. The resulting orange/red solution was cooled to room 50 temperature, transferred to a separatory funnel and diluted with 100 m L distilled water. A suspension formed and was extracted with D C M (4x60 mL) . The pooled organic extracts were rinsed with 60 m L distilled water, 80 m L 1% NaHC03( a q ) , and another 60 m L distilled water then dried over Na 2 S04, filtered, and the solvent removed by rotary evaporation. The crude material was obtained as a viscous orange/red tar and was purified by chromatography on silica using 0.5% acetone in D C M as the eluent. The desired product eluted first, with subsequent fractions containing a sizeable proportion of the product along with impurities. Later fractions were retained and resubjected to the column conditions. The product 2,3-dibutyl-5,6-dihydroxybenzene-l,4-dialdehyde was obtained as a waxy, bright orange solid (0.899g, 3.23 mmol, 35% yield after three column passes). Crystals suitable for x-ray diffraction were grown by slow evaporation of a hexanes solution. ' H N M R (400 M H z , CDC1 3 ): 5 11.95 (s, 2H, Ai-OH), 10.35 (s, 2H , A r - C / / 0 ) , 2.86 (t, 4H , A r -CH2), 1.44-1.56 (m, 8H, A r - C H 2 C / / 2 C i / 2 ) , 0.98 (t, 6H, terminal CH3); 1 3 C N M R (100 M H z , CDCI3): 5 196.60 (Ar -CHO) , 151.17 (Ar-OU), 132.4, 120.9, 35.5, 26.2, 22.9, 13.8; U V - V i s (CH 2 C1 2 ) : lmax (s) 304 nm (1.5 x 10 4 L-mof'-cm" 1), 441 nm (3.5 x 10 3 L-mof'-cm" 1); IR (thin film): i) = 3388 (br, OH) , 3085 (br, OH) , 2959, 2929, 1646 (vs, C=0), 1554, 1439, 1397, 1294, 1247, 1195, 929, 758 cmT; Anal . Calc 'd for C i 6 H 2 2 0 4 : C , 69.04; H , 7.97; O, 22.99. Found: C, 69.07; H , 7.99. M.p . = 54 °C. 51 Synthesis of 2,3-dihexyl-5,6-dihydroxybenzene-l,4-dialdehyde (31b) via catechol 30b: Conditions analogous to those for the preparation of 2,3-dibutyl-5,6-dihydroxybenzene-l,4-dialdehyde were employed. 2,3-dihexyl-5,6-dihydroxybenzene-l,4-dialdehyde was obtained as a waxy, bright orange solid (31% yield after 3 column passes). ' H N M R (400 M H z , CDCI3): 5 5 11.96 (s, 2H , Ar-O/f ) , 10.34 (s, 2 H , A r - C M ) ) , 2.85 (t, 4 H , A r -CH2), 1.50 (m, 4 H ) , 1.30 (m, 12H), 0.98 (t, 6 H , terminal CH3); 1 3 C N M R (100 M H z , CDC1 3 ): 8 196.6 (Ar -CHO) , 151.2 (Ar-Orl), 132.4, 120.9, 35 .5, 32.6, 29.6, 26.2, 22.9, 13.8; U V - V i s (CH2CI2): ^ m a x (e) 299 nm (1.4 x 104 L-mor'-cm-'), 436 nm (3.1 x 10 3 L-mor ' -cm - 1 ) ; IR (neat): v = 3387 (br, OH) , 3085 (br, OH), 2956, 2856, 1645 (vs, C=0), 1555, 1440, 1397, 1296, 1236, 1117, 1094, 936, 764 cm" 1; Anal . Calc 'd for C 2 o H 3 o 0 4 : C , 71.82; H , 9.04; O, 19.14. Found: C, 72.02; H , 9.11. M.p . = 41 °C. 52 Chapter 3: [3+3] Macrocycles 3.1 - Background The formation of Schiff bases is the relatively straightforward condensation of an aldehyde and a primary or secondary amine (vide supra). Preparation of macrocyclic Schiff base compounds requires difunctional amines and aldehydes; condensation of these types of precursors have yielded a diverse array of macrocyclic products ranging from those of the Robson and M c K e e families, expanded porphyrins, as well as much larger cycles. Although so-called [2+2] macrocycles are fairly common in the literature (e.g. the aforementioned Robson and McKee cycles), those derived from the condensation of three equivalents of dialdehyde and diamine, namely [3+3] macrocycles are rarer. While reports exist in which condensation of aliphatic but structurally constrained stereogenic diamines such as trans-\,2-diaminocyclohexane or l,2-diamino-l,2-diphenylethane derivatives with aromatic dialdehydes yields [3+3] species (dubbed trianglimines), 4 ' 5 the stability of these species appears to be highly dependant not only on the geometry of the functional groups but also on the presence of functionality that enables strong intramolecular hydrogen bonding within the core. 6 Even less well represented in the literature are [3+3] Schiff base macrocycles in which conjugation exists around the periphery of the core. The earliest reported compounds of this type, derived from the condensation of 3,6-diformylcatechol (7) and 1,2-phenylenediamine (8a; see Scheme 1.3), were found to be quite insoluble in common organic solvents. 7 Subsequent work in which 4,5-diamino-l,2-dialkoxybenzenes were used in the cyclocondensation afforded soluble [3+3] macrocycles with a number of interesting properties including small cation induced aggregation as well as the templation of heptametallic zinc-oxo clusters. These macrocycles have also been found to be versatile ligands for polymetallation; the formation of 53 heptanuclear manganese complexes as well as trimetallated nickel, copper, and cobalt species have recently been reported. 1 0 In addition to improving the solubility of these shape-persistent, conjugated [3+3] macrocycles, the appending of six alkoxy substituents was undertaken in an effort to explore the possibility that these materials might display liquid crystallinity. Although none was observed for any of the resulting macrocycles nor for the metallated analogues, 1 1 the intriguing possibility that the sort of tubular arrangement proposed for the cation-induced aggregates believed to exist in solution might be displayed in the bulk materials by the formation of tubular, columnar discotic mesophases prompted further investigation. Indeed, the possibility that by appending a larger number of substituents to the periphery of these relatively small macrocyclic cores that these materials would display discotic liquid crystalline behaviour was the principal rationale for the work undertaken in this project. This chapter w i l l describe the synthesis and characterization of a series of highly substituted [3+3] Schiff base macrocycles (see Figure 3.1) as well as certain smaller [1+2] condensation products that were isolable and are presumed intermediates in the cyclocondensation (see Figure 3.2). The crystal structure obtained for macrocycle 19a wi l l also be discussed. 54 H9C4 C4H9 R H i 3 C 6 C s H 1 3 R J M ! R -i > - N > = < N — * HO OH 1 N V O H HO >^ Hi3°6 \U/ 0 H H o ^fV" C 6 H i 3 H i 3 C 6 \ = N N = / C 6 H 1 3 19a R = H 19b R = OMe 19c R = O C 6 H 1 3 19d R = O C 1 4 H 2 9 1 9 e R = O C 1 6 H 3 3 19f R = O C 1 8 H 3 7 20a R = H 20b R = OMe 20c R = O C 6 H 1 3 20d R = O C 1 6 H 3 3 20e R = O C 1 8 H 3 7 Figure 3.1: Structures of the [3+3] Macrocycles Prepared in this Work HgC 4 P4H9 R " N ^ / R O H O H J—? N H 2 N H 2 3 2 a R = O C 6 H 1 3 32b R = O C 1 2 H 2 5 Figure 3.2: Structures of Some of the [1+2] Fragments Obtained 55 3.2 - Discussion 3.2.1: Synthetic Aspects With the appropriate "starting materials, namely aromatic diamines and aromatic dialdehydes, the construction of [3+3] macrocycles 19a-f and 20a-e proved to be quite facile. Combination of stoichiometric amounts of reagents in a suitable solvent system was sufficient to generate the target macrocycles in yields ranging from 25% to 65% however certain details of these systems deserve mention. Macrocycles derived from phenylenediamine (19a and 20a) would readily precipitate from solution on cooling after several hours at reflux, whereas those bearing six relatively short alkoxy chains (19b-c and 20b-c) were found to be extremely soluble in the reaction medium (namely a 2:1 mixture of acetonitrile and choloroform) even after cooling or reduction of the solvent volume. This enhanced solubility was much more pronounced for macrocycles bearing longer alkoxy chains; these compounds were found not only to be soluble in very small volumes of chlorinated solvents but also, quite remarkably, in alkanes such as petroleum ether and hexanes as well as aromatic solvents such as toluene. This made purification of these species by precipitation virtually impossible; despite being insoluble in acetonitrile, addition of concentrated solutions of macrocycle in chloroform or D C M to acetonitrile (or conversely, addition of acetonitrile to concentrated solutions of macrocycle) would not induce precipitation. Attempts at varying the solvent conditions of the reaction were attempted, namely increasing the proportion of acetonitrile relative to chloroform, however use of 5:1 and 10:1 ratios seemed simply to induce precipitation of oligomers and fragments during the course of the reaction. This is in marked contrast to the related macrocycles without aikyl substitution on the dialdehyde moieties (9a-m), which could all be isolated and purified by precipitation. Indeed, it would seem that incorporation of aikyl substituents on the dialdehydes in addition to alkoxy substituents on the diamines produces macrocycles that are the most 56 soluble species present in the reaction medium, the smaller fragments being somewhat less soluble. This poses a challenge for the purification of these macrocycles, the strategy employed being to remove the insoluble materials (typically fragments and oligomers as determined by N M R and M A L D I ) by filtration followed by removal of the solvent. Although this was adequate to obtain the macrocycles in acceptable purities (ca. 85-95% pure by N M R integration), analytically pure samples of these materials are likely unattainable by this method. Further attempts at purification by conventional chromatography were unsuccessful given the apparent lability of the imine bonds, the end result being decomposition on the column yielding only fragments on elution. This tendency to decompose on silica has been observed by other researchers for similar [3+3] Schiff base macrocycles necessitating reduction of the imines to amines with sodium borohydride for successful chromatographic resolution. 4 Another interesting feature in the preparation of these compounds was the apparent need to include a catalytic amount of piperidine in the reaction mixture to generate macrocycles in a practical length of time. In the absence of piperidine, refluxing for up to three days would afford predominantly [1+2] condensation products (e.g. 32a-b), with only traces of macrocycle evident by N M R . Previous work on the related macrocycles produced similar [1+2] condensation products by careful control of the stoichiometry. 1 2 It is known that the nucleophilicity of the second amine in aromatic diamines (such as 1,2-phenylenediamine) dramatically drops after the formation of a first imine . 1 3 ' 1 4 This is supported by the observation that the isolable [1+2] condensation products prepared in the absence of piperidine consist of diamine-capped dialdehydes. Although the exact mechanism of the catalysis is unknown, it seems reasonable to assume that the intermediacy of a relatively more reactive intermediate derived from the dialdehyde and piperidine is significant. In particular, it seems likely that an iminium from the 57 condensation these two species would be quite labile 1 5 and consequently more reactive to subsequent displacement by an aromatic amine (see Scheme 3.1). Scheme 3.1: Possible Mechanism for Piperidine-Catalyzed Imine Formation via an Iminium Intermediate 3.2.2: Characterization Standard techniques were employed for the characterization of the [3+3] macrocycles and [1+2] fragments prepared in this work including N M R , IR and U V - V i s spectroscopies as well as M A L D I - T O F mass spectrometry. On the whole, proton and carbon N M R for the various species conformed to what was anticipated. The ' H and 1 3 C N M R spectra for macrocycle 19a are presented in Figures 3.3 and 3.4, respectively, along with the ' H N M R spectrum of macrocycle 20e in Figure 3.5. The appearance of the spectra suggest an overall Dih symmetry for these species in solution due to fluxionality and signal averaging on the N M R timescale; this symmetry does not exist in the solid state, however, with crystallographic evidence indicating much lower symmetry (vide infra). This apparent high symmetry in solution is consistent with previously reported related macrocycles. 1 2 The (averaged) phenolic resonance for these macrocycles tends to appear far downfield (ca. 14.0-14.7 ppm), consistent with the associated protons being strongly hydrogen-bonded within the macrocyclic core. The sharpness of these resonances suggests that the protons are not undergoing significant exchange with any water 58 present in the deuterated solvent. The chemical shifts for these phenolic protons seem to vary not only between different macrocycles but also from sample to sample of the same compound, presumably owing to different degrees of hydration (i.e. how wet the N M R solvent is). The 1 3 C N M R spectra present the number of signals expected for systems of this (apparent) symmetry, with the imine carbon resonances appearing in the range of ca. 160-165 ppm. N o resonances around 195 ppm attributable to residual aldehyde were observed (see Figure 2.5 for example). For the macrocycles with long alkoxy chains (19d-f and 20d-e), not all of the carbon signals between about 20 and 35 ppm could be resolved, however they all displayed the requisite number of signals in the aromatic and imine regions. 6.03 U 6.49 12.19 24.56 18.00 1=1 t = J U 15 14 13 12 11 10 Figure 3.3: 400 M H z ' H N M R Spectrum of Macrocycle 19a 59 Chloroform-d • I " ' I i' i " P i 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm Figure 3.4: 100 MHz 13C NMR Spectrum of Macrocycle 19a 6.00 U 5.60 U 12.25 12.41 16 15 14 13 12 11 Figure 3.5: 400 MHz 'H NMR Spectrum of Macrocycle 20e 60 Infrared spectra for the macrocycles (see Figures 3.6 and 3.7) were also consistent with the absence of residual aldehyde. The carbonyl bands observed for the 2,3-dialkyl-5,6-dihydroxybenzene-l,4-dialdehydes at -1650 cm"1 were noticeably absent, being replaced with C=N stretching bands of low to medium intensity ranging between 1605 and 1620 cm" 1. Although seemingly quite low, these bands fall within the range of those previously reported for aromatic Schiff bases. 1 6 N o bands attributable to residual diamine were observed. Wavenumber (cm-1) Figure 3.6: IR Spectrum of Macrocycle 19a s Wavenumber (cm-1) Figure 3.7: IR Spectrum of Macrocycle 20e 61 The macrocycles were also characterized by mass spectrometry, specifically by matrix assisted laser desorption/ionization time-of-flight ( M A L D I - T O F ) mass spectrometry. Although somewhat limited in terms of resolution, M A L D I is ideal for the characterization of these relatively fragile macrocycles for which other methods of ionization result in extensive fragmentation.1 1 The correct molecular weights (M+l ) were observed for all the synthesized macrocycles (see Figures 3.8 and 3.9); the mass spectra typically also displayed peaks corresponding to the macrocycles plus a sodium ion (M+23 a.m.u.) as well as macrocycle plus a sodium ion plus water (M+41 a.m.u.). Occasionally, multiply hydrated species were also observed. The affinity of these macrocycles for sodium ions has been previously reported,8 but the appearance of multiple hydrates is of some interest. Although often shown to crystallize with at least one water molecule present,7 the observation of water in the mass spectra of these types of macrocycles would seem to suggest that the cores remain hydrated even under the high vacuum conditions of a M A L D I experiment (ca.-10"7 torr). 1 0 6 0 1 1 1 0 1 1 6 0 m / z Figure 3.8: M A L D I - T O F Mass Spectrum of I9a 62 SM SM U L Figure 3.9: M A L D I - T O F Mass Spectrum of 20e The macrocycles were also characterized by U V - V i s spectroscopy (see Figure 3.10). Macrocycles 19a and 20a both exhibited a single broad absorption feature centered at about 370 nm with extinction coefficients of 1.58xl0 5 M"'-cm' 1 and 1.56xl0 5 M " 1 •cm" respectively. The hexaalkoxy substituted macrocycles (19b-f and 20b-e) were remarkable only in the similarity of their absorption spectra; all were virtually superimposable and exhibited peak maxima (Xmax) in the range of 414-420 nm along with a smaller shouldering peak centered in the range of 350-355 nm. The slight red shift observed seemed to correlate with the length of the alkoxy groups, possibly indicating some degree of aggregation even in very dilute solution (ca. 10"5 M ) , however this is by no means definitive. N o significant differences in the absorption of macrocycles derived from dibutyl- and dihexyl- substituted dialdehydes (31a and 31b) were observed. 63 1.2 Macrocycle 19a Macrocycle 19b Macrocycle 19f 300 400 500 600 700 800 Wavelength /nm Figure 3.10: Normalized Absorption Spectra of Macrocycles 19a, 19b and 19f Characterization of the [1+2] fragments was also conducted using NMR, IR and UV-Vis spectroscopies. The 'H NMR spectrum of the [1+2] compound 32a is presented in Figure 3.11. The spectrum is consistent with a C2V symmetric species and displays a single sharp phenolic resonance at 14.43 ppm, a single imine peak at 8.87 ppm and two aromatic peaks corresponding to the two chemically distinct protons present on the flanking diamines. Signals attributable to the amines are not immediately apparent, however two broad resonances on either side of the multiplet at 3.95 ppm (OCH2) can likely be assigned to them. The IR spectrum of the [1+2] compound 32b is presented in Figure 3.12. Noticeably absent is the carbonyl band of the starting dialdehyde while the relatively sharp band at 3373 cm"1 which can be assigned to an N-H stretching mode. MALDI-TOF mass spectra of these compounds were also consistent, often 64 displaying strong peaks corresponding to (M+2H20+Na +) in addition to the parent ion peaks corresponding to (M+l) . 3.2.3: Thermal Properties of the Macrocycles The primary motivation for the work undertaken was to generate a series of highly substituted [3+3] Schiff base macrocycles in hopes that they would display thermotropic liquid crystallinity. As such, the thermal properties of these materials were of significant interest. The target macrocycles were examined by differential scanning calorimetry (DSC) as well as by polarizing optical microscopy (POM) to ascertain whether or not they would, in fact, from mesophases. A typical temperature program consisted of holding the sample at -20 °C for 10 min followed by heating at 5 °C/min to 190 °C. The sample was held at 190 °C for 10 minutes then cooled back to -20 °C at 5 °C/min. The maximum temperature of 190 °C was chosen based on the observation that macrocycles 19b and 20b displayed broad, shallow exotherms above this temperature likely indicating decomposition (see Figure 3.13). Examination of these macrocycles by POM above -190 °C confirmed this, with samples changing from dark orange/red to brown and then black. Although sharp endotherms were observed for two of the macrocycles with long alkoxy chains (e.g. 19e at 111 °C and 19f at 123 °C, see Figure 3.14), for the remainder of the macrocycles no transitions were observed in the temperature range employed. In addition, for those compounds where endotherms were observed, no exotherms were observed on cooling, nor were endotherms observed when reheating the same samples. This suggests that the melting transitions are monotropic, which is to say that they are only observable in one direction, and that the amorphous/melted state is metastable even on holding at -20 °C for prolonged periods. Polarizing optical microscopy confirmed the observations made by DSC. Compounds 19e and 19f melted from seemingly amorphous solids to isotropic liquids at approximately the same temperatures as the transitions observed by DSC. It is conceivable that the observed 66 endotherms for these two compounds occurred as a result of water loss but the absence of sharp transitions in the DSC traces and the P O M observations of the other macrocycles would seem to suggest otherwise. A l l the other macrocycles seemed to smoothly transition from amorphous red/black solids to dark red/orange isotropic liquids at temperatures between 60-80 °C. On heating above -200 °C, all the samples examined changed from dark red/orange to brown then to black. This irreversible decomposition has been observed previously for the related macrocycles 8 j and81 n Peak = 203.77 °C Area = 0.624 mJ Delta H = 0.223 J/g 160 165 170 175 180 185 1 90 1 95 20  205 210 215 20 Temperature C') Figure 3.13: DSC Trace for Macrocycle 19b Peak = 122.58 °C Area = 6.945 mJ Delta H = 5.B90 J/g 90 100 10 120 Temperature ("CO 140 150 Figure 3.14: DSC Trace for Macrocycle 19f 67 3.2.4: Crystallography of Macrocycle 19a Although the long-chain hexaalkoxy substituted macrocycles were isolated as amorphous solids, it was possible to grow single crystals of macrocycle 19a suitable for x-ray diffraction. ORTEP diagrams for the structure obtained are illustrated in Figure 3.15 and 3.16. Although quite similar to crystal structures reported for the parent macrocycle 9a7 and the related macrocycle 9c,12 the structure presents some unique features. In particular, although the phenyl rings associated with the diamine moieties are approximately coplanar, the catechol moieties are all twisted in one direction relative to the plane derived from the phenylenediamine rings and are pointed towards a water molecule nestled in the center of the cycle. This is in contrast to the previously reported related structures in which two of the catechol moieties point to one side of the plane, with the third approximately in the plane. This produces a bowl shape in the solid state, which has previously been reported for macrocycles of this type only after polymetallation with zinc acetate.9 <y-c. ... 0 I J. 9 X Jk \> o o'"'7'b\ Figure 3.15: Top View of Macrocycle 19a as Determined by SCXRD 68 Figure 3.16: Side View of Macrocycle 19a as Determined by SCXRD (butyl groups omitted for clarity) The packing of this macrocycle shows that the macrocycles orient themselves with adjacent "bowls" adopting an up-down (or concave-convex) arrangement. This is most clearly seen when viewed along the a crystallographic axis (see Figure 3.17). There also appear to be channels or pores when the structure is viewed along the c-axis (see Figure 3.18);however the separation of the macrocycles is quite large (ca. 17 A ) , corresponding to the length of the unit cell along c. The convex faces of the bowls are capped by a water molecule while interstitial spaces are filled with several molecules of acetonitrile. For a table of the crystallographic parameters as well as selected bond lengths and angles, see Appendix 1, Table 2. 69 Figure 3.17: Packing View of Macrocycle 19a Along the a-Axis (acetonitrile molecules omitted for clarity) Figure 3.18: Packing View of Macrocycle 19a Along the c-Axis 3.3 - Conclusions and Recommendations A series of [3+3] Schiff base macrocycles bearing six alkoxy and six aikyl groups appended to their peripheries was synthesized. These compounds were characterized by ' H and 1 3 C N M R , IR, and UV-Vis spectroscopies as well as by MALDI-TOF mass spectrometry. As previously reported, the synthesis of these macrocycles is extremely facile; combination of stoichiometric amounts of dialdehyde and diamine in an appropriate solvent system and in the presence of a catalytic amount of piperidine afforded the desired [3+3] cycles in good yields and purities with only a very small proportion of oligomers or fragments observed. The thermal properties of these macrocycles were investigated by differential scanning calorimetry and by polarizing optical microscopy. Although sharp melting transitions were observed for some of the target long-chain alkoxy macrocycles they were, for the most part, amorphous and the melting transitions, when observed, were irreversible. No indication of liquid crystallinity in any these macrocycles was observed. Although it is conceivable that further structural modification of this type of macrocycle might lead to novel discotic liquid crystals, certain features of these systems differentiate them from typical discotic mesogens. In particular, they lack the planarity and structural rigidity of conventional compounds which display discotic liquid crystallinity; they are neither planar in the solid state (as evidenced by the crystal structure of 19a), nor are they particularly rigid. Although appearing to have high symmetry in solution by N M R , this occurs as a result of fluxionality within the macrocyclic core. This does not preclude the possibility that macrocycles based on this core could be liquid crystalline, however examples of bowlic or pyramidal discotic liquid crystals are quite rare in the literature. Perhaps a telling example of the fragility of the 71 mesophase for atypical discotics is the story of those based on hexaacylated azacrown[18]-N6; tubular discotic liquid crystallinity was observed for two of these compounds by Lehn and coworkers. Subsequent systematic variation of the substitution on azacrown[l 8]-N6 core by Idziak and coworkers failed to generate any other related compounds that displayed liquid 18 crystallinity. It may be that examples of this class of liquid crystals (i.e. bowlic mesogens) does not lend themselves to rational design but instead require serendipity for their discovery. 3.4 — Experimental Materials. Solvents were degassed by sparging with nitrogen for ~1 h prior to use. Deuterated solvents were obtained from Cambridge Isotope Laboratories, Inc. 4,5-diamino-l,2-dialkoxybenzenes (8b-m) were prepared by methods previously reported in the literature.19 Equipment. A l l reactions were carried out under nitrogen unless otherwise noted. 300 MHz *H N M R spectra and 75.5 M H z 1 3 C N M R spectra and 400 M H z ! H N M R spectra and 100 MHz 1 3 C N M R spectra were recorded on Bruker AV-300 and AV-400 spectrometers respectively and were calibrated to residual protonated solvent. 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 from neat or drop cast films on NaCl plates using a Bomem MB-series spectrometer. Matrix assisted laser desorption and ionization - time-of-flight (MALDI-TOF) mass spectra as well as elemental analyses were performed at the UBC Microanalytical Services Laboratory. M A L D I mass spectra were obtained from a dithranol matrix on a Micromass LCT time-of-flight mass spectrometer. Differential scanning calorimetry (DSC) thermograms were obtained using a Perkin Elmer Diamond DSC. An Olympus BX41 polarizing optical microscope (POM) equipped with a variable temperature hot stage was employed to look for liquid crystalline 72 textures. Melting points were obtained by DSC and/or by P O M . S C X R D data was collected on a Bruker X8 A P E X diffractometer with graphite monochromated Mo-Ka radiation. Synthesis of Macrocycle 19a: Into a 100 mL round bottom flask 2,3-dibutyl-5,6-dihydroxybenzene-l,4-dialdehyde (31a; 0.359 g, 1.29 mmol) was dissolved in 50 mL acetonitrile and 10 mL chloroform. Phenylenediamine (8a; 0.142 g, 1.35 mmol) was added and the resulting yellow solution stirred briefly under nitrogen for 5 minutes. A drop of piperidine was added immediately turning the solution dark pink/red. This solution heated at reflux overnight under nitrogen, then cooled to room temperature at which point a fine precipitate formed. The solid was filtered on a Buchner funnel rinsing with a small volume of ice-cold acetonitrile. After air drying, the product 19a was obtained as an orange/brown powder (0.108 g, 0.103 mmol, 24% yield, >95% pure by N M R integration). Slow diffusion of acetontrile into a concentrated dichloromethane solution afforded single crystals suitable for x-ray diffraction. ' H N M R (400 MHz, CDC1 3): 5 14.00 (s, 6H, OH), 8.92 (s, 6H, C=NH), 7.36 (br d, 6H, Ar-H), 7.16 (br d, 6H, Ar-H), 2.79 (m, 12H, Ar-CH2), 1.49 (br m, 24H), 0.97 (m, 18H, terminal CH3); 1 3 C N M R ( 1 0 0 MHz, CDC1 3): 5 162.02 (C=N), 151.9, 143.6, 129.4, 127.6, 119.6, 118.5,35.0, 27.6, 23.0, 13.9; MALDI-TOF: m/z =1051.3 ((M+H)+, 100%); IR (thin film): v = 3339, 3198, 2955,2924, 2856, 1618, 1556, 1493, 1465, 1383, 1327, 1215, 1140, 1101, 827, 748 cm"1. U V -Vis (CH 2C1 2): ^max (e) 370 nm (1.58 x 105 L-mof'-cm"1); Anal. Calc'd for CeeHygNeOe: C, 75.40; H, 7.48; N , 7.99; O, 9.13. Found: C, 75.09; H, 8.19; N , 7.17; m.p. = 202 °C. 73 Synthesis of Macrocycle 20a: Conditions analogous to those used for the preparation of macrocycle 19a were employed. Compound 20a was obtained as an orange/brown powder (28% yield, >95% pure by N M R integration). *H N M R (400 MHz, CDC1 3): 8 14.00 (s, 6H, OH), 8.91 (s, 6H, C=NH), 7.36 (br d, 6H, Ar-H), 7.16 (br d, 6H, Ar-H), 2.78 (m, 12H, Ar-Cr72), 1.49 (br m, 24H), 0.97 (m, 18H, terminal Cf73); 1 3 C N M R (100 MHz, CDC1 3): 8 163.19 (C=N), 152.64, 144.58, 130.40, 128.75, 120.39, 119.41, 34.58, 29.64, 27.57, 26.18, 22.98, 13.86; MALDI-TOF: m/z = 1219.9 ((M+H)+, 100%); IR(thin film): n = 3340, 3194, 2956, 2922,2855, 1619, 1556, 1494, 1466, 1382, 1324, 1216, 1149, 1096, 828, 743 cm"1. UV-Vis (CH 2C1 2): X m a x (e) 371 nm (1.56 x 105 L-mor '-cm" 1); m.p. = 205 °C. Synthesis of Macrocycle 19b: Under nitrogen, 2,3-dibutyl-5,6-dihydroxybenzene-l,4-dialdehyde (31a; 86 mg, 0.31 mmol) and 4,5-diamino-l,2-dimethoxybenzene (8b; 52 mg, 0.31 mmol) were weighed into a 100 mL Shlenk flask. Still under nitrogen, 5 mL of degassed chloroform and 10 mL degassed acetonitrile were added by syringe. A drop of piperidine was added and the solution heated to reflux for approximately 24 hours. On cooling, a fine sediment appeared to form. The solution was filtered and the filtrate concentrated in vacuo affording 19b as a red/black solid (88 mg, 0.071 mmol, 69%) yield, ca. 90%) pure.by N M R integration). ' H N M R (400 MHz, CDCI3): 8 14.64 (br s, 6H, OH), 8.96 (s, 6H, C=NH), 6.84 (s, 6H, Ar-H), 3.99 (s, 18H, Ar-OC/fc), 2.83 (m, 12H, Ar-CH2), 1.50 (br m, 24H), 1.00 (m, 18H, terminal CH3); 1 3 C N M R ( 1 0 0 MHz, CDC1 3): 8 163.0 ( O N ) , 152.4, 148.6, 137.4, 122.8, 120.4, 114.4, 70.2 (OCH3), 34.4, 29.6, 27.6, 26.2, 23.1, 13.9; MALDI-TOF: m/z = 1232.2 ((M+H)+, 10%), 1253.9 ((M+Na+), 100%), 1270.0 ((M+H 20+Na+), 30%); IR (thin film): u = 3419 (br), 2955, 2929, 2856, 1605, 1513, 1463, 1385, 1322, 1261, 1219, 1194, 1008, 842, 669 cm"'. UV-Vis (CH 2C1 2): 74 Imz* (s): 352 nm (7.64 x IO5 L-mol"'-cm"'), 414 nm (8.53 x 105 L-mof'-cm"'); m.p. ~ 195 °C (dec). Synthesis of Macrocycle 20b: Conditions analogous to those used for the preparation of macrocycle 19b were employed. Compound 20b was obtained as a red/black solid (65% yield, ca. 90% pure by N M R integration). ' H N M R (400 MHz, CDC1 3): 5 14.56 (br s, 6H, OH), 8.94 (s, 6H, C=NH), 6.82 (s, 6H, Ar-H), 3.99 (s, 18H, Ar-OC// 3 ) , 2.81 (m, 12H, Ar-CH2), 1.46 (br m, 48H), 1.00 (m, 18H, terminal CH3); 1 3 C N M R ( 1 0 0 MHz, CDC1 3): 8 164.1 (C=N), 152.0, 146.5, 139.0, 121.8, 120.3, 115.3,71.0 (OCH3), 34.3, 28.0, 27.7, 26.3, 23.0, 13.9; MALDI-TOF: m/z = 1399.5 ((M+H)+, 100%), 1422.6 ((M+Na+), 100%), 1438.7 ((M+H 20+Na+), 25%); IR (thin film): v = 3422 (br), 2955, 2926, 2855, 1605, 1513, 1464, 1386, 1322, 1261, 1220, 1195, 1008, 841,669 cm - 1; UV-Vis (CH 2C1 2): W (£): 350 nm (7.81 x 105 L-mof'-cm"1), 415 nm (8.64 x 105 L-mof'-cm"'); m.p. ~ 195 °C (dec). Synthesis of Macrocycle 19c: Conditions analogous to those used for the preparation of macrocycle 19b were employed but using 4,5-diamino-l,2-dihexyloxybenzene (8g). Compound 20b was obtained as red/black solid (50% yield, ca. 85% pure by N M R integration). ' H N M R (400 MHz, CDC1 3): 5 14.71 (br s, 6H, OH), 8.91 (s, 6H, C=N#), 6.82 (s, 6H, Ar-H), 4.10 (m, 12H, Ar-OC// 2 ) , 2.81 (m, 12H, Ax-CH2), 1.88 (br m, 12H), 1.44 (br m, 48H), 0.90 (m, 36H, terminal CH3); I 3 C N M R (100 MHz, CDC13): 5 162.38 ( O N ) , 152.5, 146.6, 137.9, 121.9, 120.3, 115.4, 70.8 (OCH 3), 34.3, 31.4, 31.1, 31.0, 28.0, 27.7, 26.3, 23.0, 15.5, 13.9; MALDI-TOF: m/z= 1653.4 ((M+H)+, 100%), 1675.2 ((M+Na+), 50%), 1693.3 ((M+H 20+Na+), 50%); IR 75 (thin film): u = -3200 (v br), 2956, 2926, 2857, 1604, 1509, 1466, 1385, 1322, 1264, 1193, 1093, 1017, 740 cm"1; UV-Vis (CH 2C1 2): ^ m a x (e): 353 nm (6.44 x 105 L-mof'-cm-'), 415 nm (7.99 x 105 L-mof'-cm"'); m.p. ~ 195 °C (dec). Synthesis of Macrocycle 20c: Conditions analogous to those used for the preparation of macrocycle 19b were employed but using 4,5-diamino-l,2-dihexyloxybenzene (8g) and 2,3-dihexyl-5,6-dihydroxybenzene-l,4-dialdehyde (31b). Compound 20b was obtained as a red/black solid (50% yield, ca. 85% pure by N M R integration). ' H N M R (400 MHz, CDC1 3): 5 14.71 (s, 6H, OH), 8.92 (s, 6H, C=NH), 6.83 (s, 6H, Ax-H), 4.10 (m, 12H, Ar-OC# 2), 2.82 (m, 12H, Ax-CH2), 1.87 (br m, 12H), 1.48 (br m, 72H), 0.92 (m, 36H, terminal CH3); 1 3 C N M R ( 1 0 0 MHz, CDC13): 5 163.1 (C=N), 152.0, 146.6, 137.9, 121.8, 120.2, 115.4,71.0 (OCH 3), 34.3, 31.4, 31.1, 31.0, 28.0, 27.7, 26.3, 23.3, 23.0, 15.5, 13.9; MALDI-TOF: m/z= 1821.5 ((M+H)+, 100%), 1843.5 ((M+Na+), 50%), 1859.6 ((M+H 20+Na+), 40%),1877.6 ((M+2H20+Na+), 10%); IR (thin film): n = -3200 (v br), 2956, 2927, 2856, 1606, 1510, 1466, 1386, 1322, 1265, 1193, 1092, 1017, 739 cm"'. UV-Vis (CH 2C1 2): Xmax (s): 354 nm (6.48 x 105 L-mof'-cm"'), 413 nm (8.03 x 105 L-mof'-cm"'); m.p. - 195 °C (dec). Synthesis of [1+2] Fragment 32a: Conditions analogous to those used for the preparation of macrocycle 19b were employed using 4,5-diamino-l,2-dihexyloxybenzene (8g) and 2,3-dibutyl-5,6-dihydroxybenzene-l,4-dialdehyde (31a), however no piperidine was added as catalyst. Compound 32a was obtained as a pink/orange solid (28% yield, > 90% pure by N M R integration). ' H N M R (400 MHz, CDC1 3): 8 14.43 (s, 2H, OH), 8.37 (s, 2H, C=N//), 6.75 (s, 2H, Ar-H), 6.36 (s, 2H, Ar-H), 3.95 (m, 8H, Ar-OC// 2 ) , 3.90 (s, v br, - 4H , N / / 2 ) , 2.80 (t, 8H, Ax-CH2), 1.80 (m, 76 8H, OCH 2 C/ / 2 ) , 1-40 (br m, 32H), 0.92 (m, 18H, terminal CH3); I 3 C N M R (100 MHz, CDC13): 8 156.6, 151.1, 149.4, 142.2, 136.8, 130.1, 126.8, 118.6, .106.2, 102.3, 71.3, 69.3, 32.7, 31.7, 31.6, 29.7, 29.5, 29.2, 27.9, 25. 8, 25.7, 22.7, 22.6, 14.0; IR (thin film): u = 3373 (NH stretch), 3152 (br), 2955, 2925, 2852, 1609, 1586, 1522, 1465, 1432, 1385, 1263, 1207, 1158, 839 cm"1; U V -Vis (CH 2C1 2): X m a x (s): 315 nm (2.82 x 105 L-mof'-cm"1), 473 nm (4.70 x 105 L-mof'-cm"1); Anal. Calc'd for C 5 2 H 8 2 N 4 0 6 : C, 72.69; H , 9.62; N , 6.52; O, 11.17. Found: C, 72.46; H , 9.69; N, ' 5.92; m.p. = 228-232 °C. Synthesis of Macrocycle 19d: Conditions analogous to those used for the preparation of macrocycle 19b were employed but using 4,5-diamino-l,2-bis(tetradecyloxy)benzene (8k). Compound 19d was obtained as a waxy, amorphous orange/black solid (30% yield, ca. 85% pure by N M R integration). ' H N M R (400 MHz, CDCI3): 8 14.10 (br s, 6H, OH), 8.89 (s, 6H, C=N//), 6.78 (s, 6H, Ar-//), 4.07 (m, 12H, Ar-OC// 2 ) , 2.76 (m, 12H, Ar-C/Z 2), 1.88 (br m, 12H), 1.40 (br m, 156H), 0.87 (m, 36H, terminal C/ / 3 ) ; l 3 C N M R (100 MHz, CDC1 3 ): 8 164.2 ( O N ) , 152.6, 146.4, 137.8, 122.6, 121.4, 116.9, 70.7 (OCH3), 34.3,31.2,31.1,30.9, 28.0, 27.7, 26.3,23.0, 16.8, 15.5, 13.9; MALDI-TOF: m/z = 2326.2 ((M+H)+, 10%), 2348.2 ((M+Na+), 100%), 2364.3 ((M+H20+Na+), 60%); IR (thin film): u = 2955, 2922, 2852, 1604, 1511, 1466, 1385, 1322, 1260, 1214, 1015, 838, 721, 668 cm"1; UV-Vis (CH 2C1 2): Xmax (e): 355 nm (3.94 x 105 L-mof'-cm"1), 417 nm (4.92 x 105 L-mof'-cm"1); m.p. ~ 195 °C (dec). 77 Synthesis of [1+2] Fragment 32b: Conditions analogous to those used for the preparation of macrocycle 19b were employed using 4,5-diamino-l,2-bis(tetradecyloxy)benzene (8k) and 2,3-dibutyl-5,6-dihydroxybenzene-l,4-dialdehyde (31a), however no piperidine was added as catalyst. Compound 32a was obtained as a waxy orange solid (35% yield, > 90% pure by N M R integration). ' H N M R (400 MHz, CDC1 3): 6 14.43 (s, 2H, OH), 8.86 (s, 2H, C=NH), 6.75 (s, 2H, Ar-H), 6.36 (s, 2H, Ai-H), 3.95 (m, 8H, Ar-OC// 2 ) , 2.78 (brt, 8H, Ar-C/7 2), 1.55 (br m, 56H), 0.92 (m, 18H, terminal CH3); 1 3 C N M R (100 MHz, CDC13): 8 157.1, 151.1, 149.5, 144.2, 136.7, 129.8, 126.5, 118.5, 106.3, 103.1, 71.3, 69.6, 32.0, 31.7, 31.5, 29.7, 29.6, 29.2, 27.9, 25.8, 25.7, 22.7, 22.6, 14.02, 13.98; MALDI-TOF: m/z = 1308.5 ((M+H)+, 5%), ((M+2H 20+Na+), 100%); IR (thin film): u = 3375 (NH stretch), 3145 (br), 2956, 2917, 2849, 1611, 1585, 1522, 1466, 1432, 1386, 1262, 1207, 839 cm"1; UV-Vis (CH 2C1 2): lmax (e): 315 nm (1.40 x 105 L-mof'-cm"1), 469 nm (2.27 x 105 L-mof'-cm"1); m.p. = 206-209 °C. Synthesis of Macrocycle 19e: Conditions analogous to those used for the preparation of macrocycle 19b were employed but using 4,5-diamino-l,2-bis(hexadecyloxy)benzene (81). Compound 19e was obtained as a waxy, amorphous orange/black solid (45% yield, ca. 85% pure by N M R integration). ' H N M R (400 MHz, CDCI3): 8 14.03 (s, 6H, OH), 8.89 (s, 6H, C=N/f), 6.77 (s, 6H, Ar-H), 4.06 (m, 12H, Ar-OC// 2 ) , 2.76 (m, 12H, Ar-C# 2), 1.86 (br m, 12H), 1.40 (br m, 180H), 0.87 (m, 36H, terminal CH3); 1 3 C N M R ( 1 0 0 MHz, CDCI3): 8 163.1 (C=N), 153.8, 147.0, 138.1, 122.7, 121.3, 117.0, 70.6 (OCH3), 34.2, 31.4, 31.1, 30.7, 28.1, 27.7, 26.4, 23.0, 16.7, 15.5, 13.9; MALDI-TOF: m/z = 2326.2 ((M+H)+, 10%), 2348.2 ((M+Na+), 100%), 2364.3 ((M+H 20+Na+), 60%); IR (thin film): u = 2955, 2922, 2852, 1604, 1511, 1466, 1385, 1322, 1260, 1214, 1015,838, 721,668 78 cm - 1. UV-Vis (CH 2C1 2): Xmax (s): 354 nm (3.88 x IO5 L-mor '-cm" 1), 419 nm (4.83 x 105L-mol"'-cm - 1 ); m.p. ~ 195 °C (dec). Synthesis of Macrocycle 20d: Conditions analogous to those used for the preparation of macrocycle 19b were employed but using 4,5-diamino-l,2-bis(hexadecyloxy)benzene (81) and 2,3-dihexyl-5,6-dihydroxybenzene-1,4-dialdehyde (31b). Compound 19e was obtained as an amorphous orange/black solid (40% yield, ca. 85% pure by N M R integration). ' H N M R (400 MHz, CDCI3): 8 14.73 (s, 6H, OH), 8.91 (s, 6H, C=N#), 6.82 (s, 6H, Ar-H), 4.09 (m, 12H, Ar-OC# 2), 2.81 (m, 12H, Ar-CH2), 1.87 (br m, 12H), 1.40 (br m, 204H), 0.86 (m, 36H, terminal CH3); 1 3 C N M R ( 1 0 0 MHz, CDC1 3 ): 8 162.14 (C=N), 153.0, 146.8, 138.4, 122.0, 121.4, 116.9, 70.6 (OCH3), 34.2,31.5,31.2,30.9, 28.2, 27.6, 26.4, 23.0, 16.8, 15.5, 13.9; MALDI-TOF: m/z = 2662.7 ((M+H)+, 50%), 2684.9 ((M+Na+), 100%), 2701.3 ((M+H 20+Na+), 80%); IR (thin film): n = 2955, 2922, 2852, 1604, 1511, 1466, 1385, 1322, 1260, 1214, 1092, 1015, 838, 721, 668-cm"'1. UV-Vis (CH 2C1 2): W (e): 352 nm (3.81 x 105 L-mor '-cm"'), 414 nm (4.88 x 105 L-mor '-cm" 1); m.p. I l l °C. Synthesis of Macrocycle 19f: Conditions analogous to those used for the preparation of macrocycle 19b were employed but using 4,5-diamino-l,2-bis(octadecyloxy)benzene (8m). Compound 19f was obtained as an amorphous orange/black solid (30% yield, ca. 90% pure by N M R integration). ' H N M R (400 MHz, CDC1 3): 8 14.73 (s, 6H, OH), 8.91 (s, 6H, C=NH), 6.82 (s, 6H, Ar-H), 4.09 (m, 12H, Ar-OC// 2 ) , 2.81 (m, 12H, Ar-CH2), 1.88 (br m, 12H), 1.40 (br m, 204H), 0.87 (m, 36H, terminal CH3); 1 3 C N M R (100 MHz, CDC13): 8 163.2 (C=N), 153.1, 146.8, 138.4, 121.9, 121.5, 116.8, 70.6 (OCH3), 34.2, 31.5, 31,2, 30.9, 28.2, 27.6, 26.4, 23.0, 16.8, 15.5, 13.9; MALDI-TOF: 79 m/z = 2662.4 ((M+H)+, 100%), 2684.8 ((M+Na+), 90%), 2702.3 ((M+H 20+Na+), 70%); IR (thin film): u = 2954, 2921, 2851, 1604, 1510, 1465, 1385, 1321, 1260, 1208, 1093, 1014, 838, 721, 669 cm - 1; UV-Vis (CH 2C1 2): W (s): 356 nm (3.92 x 105 L-mof'-cm"1), 417 nm (4.89 x 105 L-mol"'-cm"'); m.p. 123 °C. Synthesis of Macrocycle 20e: Conditions analogous to those used for the preparation of macrocycle 19b were employed but using 4,5-diamino-l,2-bis(octadecyloxy)benzene (8m) and 2,3-dihexyl-5,6-dihydroxybenzene-1,4-dialdehyde (31b). Compound 20e was obtained as an amorphous orange/black solid (35% yield, ca. 85% pure by N M R integration). ' H N M R (400 MHz, CDC1 3): 5 14.54 (br s, 6H, OH), 8.91 (s, 6H, C=HH), 6.81 (s, 6H, Ax-H), 4.08 (m, 12H, Ar-OCfY 2), 2.80 (m, 12H, Ax-CH2), 1.87 (br m, 12H), 1.40 (br m, 228H), 0.87 (m, 36H, terminal CrY3); 1 3 C N M R (100 MHz, CDC13): 5 163.2 (C=N), 153.0, 146. 8, 138.4, 121.9, 121.5, 116.8, 70.6 (OCH 3), 34.2, 31.4, 31.3, 30.9, 28.2, 27.5, 26.4, 23.1, 16.8, 15.6, 13.9; MALDI-TOF: m/z = 2830.9 ((M+H)+, 100%), 2852.7 ((M+Na+), 80%), 2868.8 ((M+H20+Na+), 60%); IR (thin film): u = 2954, 2921, 2851, 1604, 1510, 1465, 1385, 1321, 1260, 1208, 1093, 1014, 838, 721, 669 cm' 1; UV-Vis (CH 2C1 2): lmax (e): 351 nm (3.15 x 105 L-mof'-cm'1), 416 nm (4.24 x 105 L-mol' 1 •cm'1); m.p. ~ 195 °C (dec). 80 Chapter 4: Conclusions and Future Work 4.1 - Conclusions A number of synthetic routes were investigated in an effort to obtain the highly substituted aromatic dialdehydes 31a and 31b. These compounds were successfully obtained by three different methods that can be categorized as the lithiation/formylation route, the cyanation/reduction route and the direct formylation route. Of the three, the latter was found to be preferable in terms of minimization of the steps required and yields obtained. Although successful for relatively short aikyl chains (i.e. butyl and hexyl), the methods employed were unsuitable for the preparation of longer-chain analogues. An alternative method for the preparation of the related longer-chain compounds was suggested. Compounds 31a and 31b were characterized by ' H N M R , 1 3 C N M R , IR and UV-Vis spectroscopies, as well as by high resolution mass spectrometry. Satisfactory elemental analyses were obtained. In addition, a crystal structure for compound 31a was obtained by single-crystal x-ray diffraction (SCXRD) and was discussed. Compounds 31a and 31b were subsequently used to prepare a series [3+3] Schiff base macrocycles incorporating six alkoxy substituents and six aikyl substituents around their peripheries (19c-f and 20c-e) in hopes that they might form discotic liquid crystalline mesophases. Characterization of these macrocycles by *H N M R , 1 3 C N M R , IR and UV-Vis spectroscopies, as well as by MALDI-TOF mass spectrometry was undertaken. The characterization was consistent with the successful preparation of these compounds, however their extreme solubility in common organic solvents and relative hydrolytic sensitivity made their purification problematic. In addition, the thermal properties of these macrocycles were 81 investigated by differential scanning calorimetry (DSC) and by polarizing optical microscopy (POM). Although sharp endotherms were observed by DSC for two of the macrocycles prepared as were well-defined melting transitions by POM they were, for the most part, amorphous solids which melted directly to isotropic liquids with no indications of mesophase formation. A crystal structure of the related macrocycle 19a was obtained by SCXRD and was discussed. 4.2 - Future Work A number of possible options for further exploration of these types of macrocycles exist. One avenue for future work would be to attempt to further purify the macrocycles; as prepared the purities were typically only on the order of 80-90% by N M R integration. The presence of impurities such as fragments and oligomers may inhibit the formation of mesophases, but the sharp melting transitions observed for some of the prepared macrocycles would seem to suggest (at least circumstantially) a reasonable degree of purity. Unfortunately, the hydrolytic sensitivity of the imine bonds makes purification of these compounds by conventional chromatography quite difficult; attempts to chromatograph these macrocycles on silica afforded only fragments on elution. Gel permeation chromatography may provide a feasible means of purification, or at least provide a better gauge of their purities, assuming the macrocycles are sufficiently robust. For the macrocycles bearing long alkoxy chains (i.e. hexyloxy and longer), purification by precipitation did not seem to be a viable option. The extreme solubility of these compounds in virtually every organic solvent employed (with the exception of acetonitrile) makes this method impractical. In addition, and once again as a result of the hydrolytic sensitivity of the imine bonds, the purity of the compounds seemed to decrease on attempts at purification by precipitation. Nonetheless, it seems likely that some method for obtaining these macrocycles in 82 higher purities, whether through judicious choice of reaction conditions or through some means of post-reaction purification, is possible given further investigation. Another obvious possibility for future investigation is to complex these macrocycles to metals. Although preliminary attempts to incorporate metals in the macrocycles prepared in this work with nickel and zinc were undertaken, they did not seem to appreciably modify their bulk physical properties. On treatment with metal salts, the macrocycles retained their extreme solubility in common organic solvents. That being said, metallation may improve the structural rigidity of the macrocycles making them more likely to form discotic mesophases. In addition, the incorporation of metals may lead to stronger interactions in the solid state, possibly promoting the formation of a tubular mesophase. One of the crowning virtues of these types of [3+3] macrocycles is the variety and structural diversity of the diamine and dialdehyde components from which they can be prepared. The possibilities for structural variation seem almost limitless and, as such, the avenues for the construction of novel macrocycles that might display interesting structural features and physical properties is limited only by one's imagination and synthetic acumen. 83 References Chapter 1 1 - Choi, K . H . ; Lai, V . ; Foster, C.E.; Morris, A.J. ; Tolan, D.R.; Allen, K . N . Biochemistry 2006, 45,8546. 2 - O'Donnell, M.J. Ace. Chem. Res. 2004, 57, 506. 3 - For some examples of the use of Schiff base complexes as catalysts, see: DiMauro, E.F.; Kozlowski, M.C. J. Am. Chem. Soc. 2002,124, 12668. Jacobsen, E.N. Acc. Chem. Res. 2000, 55,421. 4 - For examples of some Schiff base derived liquid crystals, see: Warm, M . A . ; Harbison, G.S. J. Am. Chem. Soc. 1989, 111, 7273. Marcos, M . ; Romero, P.; Serrano, J.L. 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Crystal Data Empirical Formula Formula Weight Crystal Color, Habit Crystal Dimensions Crystal System Lattice Type Lattice Parameters Space Group Z value Dcalc FOOO u(MoKa) C 1 6 H 2 2 O 4 278.34 orange, blade 0.05 X 1.20 X 1.40 mm primitive Monoclinic a = 18.1497(16) A b = 7.2908(7) A c = 24.030(2) A a = 9 0 ° p = 109.146(5)° y = 9 0 ° V = 3003.8(5) A 3 P2,/a(#14) 8 1.231 g/cm 3 1200 0.87 cm" 1 B. Intensity Measurements Diffractometer Radiation Data Images Detector Position 29max No. of Reflections Measured Corrections C. Structure Solution and Refinement Structure Solution Refinement Function Minimized Least Squares Weights Anomalous Dispersion Bruker X8 A P E X MoKoc (k = 0.71073 A ) graphite monochromated 2349 exposures @ 10.0 seconds 35.99 mm 54.46° Total: 56005 Unique: 6689 (Ri n t = 0.0528) Absorption (T m i n = 0.778, T m a x = 0.996) Lorentz-polarization Direct Methods (SIR92) Full-matrix least-squares on F 2 I w (Fo 2 - F c 2 ) 2 w=l/(a2(Fo2)+(0.0805P) 2+4.3362P) A l l non-hydrogen atoms 90 C. Structure Solution and Refinement (continued) No. Observations (I>0.00a(I)) 6689 No. Variables 414 Reflection/Parameter Ratio 16.16 Residuals (refined on F 2 , all data): R l ; wR2 0.1052; 0.2001 Goodness of Fit Indicator 0.991 No. Observations (I>2.00a(I)) 4348 Residuals (refined on F): R l ; w R 2 0.0632; 0.1605 Max Shift/Error in Final Cycle -0.001 Maximum peak in Final Diff. Map 0.948 e'/A^ Minimum peak in Final Diff. Map -0.416 e"/A^ D. Selected Bond Lengths and Angles 0 ( 7 ) - C (20) 1 342(3) 0 ( 8 ) - C(24) 1 217 (3) 0 ( 3 ) - C(4) 1 337(3) 0(6) - C(19) 1 344(3) 0 ( 2 ) - C(3) 1 356(3) 0 ( 4 ) - C(8) 1 218(3) 0 ( 1 ) - C(7) 1 222(3) C(18) -C(19) 1' 388 (4) C(18) - C ( 1 7 ) 1 415 (4) C(18) -C(23 ) 1 488 (4 ) C ( 5 ) - C(4) 1 401(3) C ( 5 ) - C(6) 1 416 (3) C ( 5 ) - C(8) 1 466(3) C ( 4 ) - C(3) 1 403(3) C ( 2 ) - C(3) 1 387(3) C ( 2 ) - C ( l ) 1 418(3) C ( 2 ) - C(7) 1 466(3) C (20) -C(19) 1 403(3) C (20) -C(21) 1 396(3) C(21) - C (22) 1 416(4) C(21) - C ( 2 4 ) 1 461 (4) C(15) -C(16) 1 512 (4) C(15) -C(14) 1 514(3) C (22) - C ( 1 7 ) 1 397 (4)' C (22) - C (29) 1 519 (4) C ( 6 ) - C ( l ) 1 391(3) C ( 6 ) - C(13) 1 512(3) C ( D - C(9) 1 509(3) C(10) - C ( l l ) 1 511 (4) C(10) - C ( 9 ) 1 529 (4) C(14) -C(13 ) 1 529(3) C (23) -0 (5) 1 191(4) C (25) - C ( 2 6 B ) 1 456(8) C (25) -C(17 ) 1 494 (4) C (25) -C(26) 1 623 (7) C ( l l ) -C(12 ) 1 493 (5) C (29) -C(30) 1 533(6) C (30) -C(31) 1 510 (5) C(31) - C ( 3 2 ) 1 521 (10) C (26) -C(27) 1 488 (7) C(27) -C(28) 1 531(9) C ( 2 7 B ) - C ( 2 8 B ) 1. 537(9) C (27B) -C(26B) 1. 546(9) C ( 1 9 ) - C ( 1 8 ) - C (17) C ( 1 7 ) - C ( 1 8 ) - C ( 2 3 ) C ( 4 ) - C ( 5 ) - C ( 8 ) 120 .9 (2) 125 .1 (2) 117 .4 (2) C ( 1 9 ) - C ( 1 8 ) - C ( 2 3 ) 114 .1 (2 ) C ( 4 ) - C ( 5 ) - C ( 6 ) 120 .9 (2) C ( 6 ) - C ( 5 ) - C ( 8 ) 121 .6 (2) D. Selected Bond Lengths and Angles (continued) 0 ( 3 ) - C ( 4 ) - C ( 3 ) . 1 1 6 . 8 2 ) 0 ( 3 ) - C ( 4 ) - C ( 5 ) 1 2 4 1 ( 2 ) C ( 3 ) - C ( 4 ) - C ( 5 ) 1 1 9 . 2 2 ) C ( 3 ) - G ( 2 ) - C ( l ) . 1 2 1 2 ( 2 ) C ( 3 ) - C ( 2 ) - C ( 7 ) 1 1 7 . 7 2 ) C ( l ) - C ( 2 ) - C ( 7 ) 1 2 1 0 ( 2 ) 0 ( 7 ) - C ( 2 0 ) - C ( 1 9 ) 1 1 5 . 9 2 ) 0 ( 7 ) - C ( 2 0 ) - C ( 2 1 ) 1 2 4 7 ( 2 ) C ( 1 9 ) - C ( 2 0 ) - C ( 2 1 ) 1 1 9 . 4 2 ) 0 ( 6 ) - C ( 1 9 ) - C ( 1 8 ) 1 1 9 1 ( 2 ) 0 ( 6 ) - C ( 1 9 ) - C ( 2 0 ) 1 2 0 . 6 2 ) C ( 1 8 ) - C ( 1 9 ) - C ( 2 0 ) 1 2 0 3 ( 2 ) C ( 2 0 ) - C ( 2 1 ) - C ( 2 2 ) 1 2 0 . 5 2 ) C ( 2 0 ) - C ( 2 1 ) - C ( 2 4 ) 1 1 7 6 ( 2 ) C ( 2 2 ) - C ( 2 1 ) - C ( 2 4 ) 1 2 1 . 9 2 ) 0 ( 2 ) - C ( 3 ) - C ( 2 ) 1 2 3 6 ( 2 ) 0 ( 2 ) - C ( 3 ) - C ' ( 4 ) 1 1 6 . 5 2 ) C ( 2 ) - C ( 3 ) - C ( 4 ) 1 1 9 9 ( 2 ) C ( 1 6 ) - C ( 1 5 ) - C ( 1 4 ) 1 1 4 . 2 2 ) C ( 1 7 ) - C ( 2 2 ) - C ( 2 1 ) 1 1 9 9 ( 2 ) C ( 1 7 ) - C ( 2 2 ) - C ( 2 9 ) 1 2 0 . 9 3 ) C ( 2 1 ) - C ( 2 2 ) - C ( 2 9 ) 1 1 9 1 ( 2 ) e d i - C ( 6 ) - C ( 5 ) 1 1 9 . 5 2 ) C ( D - C ( 6 ) - C ( 1 3 ) 1 2 0 4 ( 2 ) c t s ) - C ( 6 ) - C ( 1 3 ) 1 2 0 . 1 2 ) C ( 6 ) - C ( l ) - C ( 2 ) 1 1 9 1 ( 2 ) C ( 6 ) - C ( l ) - C ( 9 ) 1 2 1 . 1 2 ) C ( 2 ) - C ( l ) - C ( 9 ) 1 1 9 8 ( 2 ) 0 ( 4 ) - C ( 8 ) - C ( 5 ) 1 2 4 . 4 2 ) C - ( l l ) - C ( 1 0 ) - C ( 9 ) 1 1 3 6 ( 2 ) C ( 1 5 ) - C ( 1 4 ) - C ( 1 3 ) 1 1 3 . 8 2 ) 0 ( 8 ) - C ( 2 4 ) - C ( 2 1 ) 1 2 4 3 ( 2 ) 0 ( 1 ) - C ( 7 ) - C ( 2 ) 1 2 3 . 9 3 ) C ( D - C ( 9 ) - C ( 1 0 ) 1 1 3 6 ( 2 ) C ( 6 ) - C ( 1 3 ) - C ( 1 4 ) 1 1 3 . 2 2 ) 0 ( 5 ) - C ( 2 3 ) - C ( 1 8 ) 1 2 8 3 ( 3 ) . C ( 2 6 B ) - C ( 2 5 ) - C ( 1 7 ) 1 2 3 . 6 6 ) C ( 1 2 ) - C ( 1 1 ) - C ( 1 0 ) 1 1 3 3 ( 3 ) C ( 2 2 ) - C ( 1 7 ) - C ( 1 8 ) 1 1 9 . 0 2 ) C ( 2 2 ) - C ( 1 7 ) - C ( 2 5 ) 1 2 1 0 ( 3 ) C ( 1 8 ) - C ( 1 7 ) - C ( 2 5 ) 1 1 9 . 9 3 ) C ( 2 2 ) - C ( 2 9 ) - C ( 3 0 ) 1 1 2 0 ( 3 ) C ( 3 1 ) - C ( 3 0 ) - C ( 2 9 ) 1 1 3 . 0 5 ) C ( 3 0 ) - C ( 3 1 ) - C ( 3 2 ) 1 1 2 5 ( 6 ) C ( 2 7 ) - C ( 2 6 ) - C ( 2 5 ) 1 1 4 . 0 6 ) C ( 2 6 ) - C ( 2 7 ) - C ( 2 8 ) 1 1 2 8 8 ) C ( 2 8 B ) - C ( 2 7 B ) - C ( 2 6 B ) L 1 0 . 2 ( 8 ) C ( 2 5 ) - C ( 2 6 B ) - C ( 2 7 B ) 1 0 8 1 ( 7 ) Table A l .2: X-Ray Diffraction Data for Compound 19a A. Crystal Data • Empirical Formula Formula Weight Crystal Color, Habit Crystal Dimensions Crystal System Lattice Type Lattice Parameters Space Group . Z value Dcalc F000 u(MoKoc) C 6 8 H 8 3 N 7 O 7 1110.41 red, blade 0.50X0.10X0.05 mm primitive triclinic a = 13.284(6) A b = 16.492(7) A c= 16.775(7) A a = 61.51(2)° (3 = 68.97(2) ° y = 80.20(3) ° V = 3014.7(3) A 3 P-l (#2) 2 1.223 g/cm 3 2224 0.80 cm" 1 B. Intensity Measurements Diffractometer Radiation Data Images Detector Position 29max No. of Reflections Measured Corrections C. Structure Solution and Refinement Structure Solution Refinement Function Minimized Least Squares Weights Anomalous Dispersion No. Observations (I>0.00a(I)) No. Variables Reflection/Parameter Ratio Residuals (refined on F 2 , all data): R l ; wR2 Goodness of Fit Indicator No. Observations (I>2.00cj(I)) Residuals (refined on F): R l ; wR2 Max Shift/Error in Final Cycle Maximum peak in Final Diff. Map Minimum peak in Final Diff. Map Bruker X8 A P E X M o K a (A, = 0.71073 A ) graphite monochromated 1901 exposures @ 25.0 seconds 36.01 mm 45.10° Total: 34824 Unique: 7883 (Rim = 0.0305) Absorption (T m i n = 0.089, T m a x = 0.961) Lorentz-polarization Direct Methods (SIR2002) Full-matrix least-squares on F 2 E w (Fo 2 - F c 2 ) 2 w=l/(a2(Fo2)+(0.1165P) 2+6.1219P) A l l non-hydrogen atoms 7883 771 10.22 0.1088; 0.2419 1.027 5757 0.0810; 0.2140 0.003 1.089 e" /A 3 -0.690 e- /A 3 93 D. Selected Bond Lengths and Angles C(l ) -C(6) 1 391 (7) C (1) -C(2) 1 401 (7) C (1) -N(l) 1 411 (6) C(2) -C(3) 1 370 (7) C (3)- C(4) 1 365 (7) C (4) -C(5.) 1 371 (7) C(5) - C ( 6 ) 1 391 (6) C (6)- N(2) 1 415 (6) C (7) -N(2) 1 290 (6) c m -G(8) 1 453 (7) c 8)- C(9) 1 388 (6) C (8) -C(10)- 1 409 (7) C(9) -0(1) 1 352 (6) c 9)- C(l-l) 1 408 (7) C (10 )-C(12) 1 380 (7) C (10 )-C(43) 1 527 (6) c 11) -0(2) 1 348 5) C (11 )-C(13) 1 387 (6) . C(12 )-C(13) 1 430 (6) c 12) -C(47) 1 520 (7) C (13 )-C(14) 1 449 (6) C (14 )-N(3) 1 296 (5) c 15) -C(20) 1 395 (6) C 15 )-C(16) 1 396 (6) C (15 )-N(3) 1 418 (6) c 16) -C(17) 1 375 (6) C (17 )-C(18) 1 371 (7) C (18' )-C(19) 1 374 (6) c 19) -C(20) 1 397 6) C 20 )-N(4) 1 418 (5) C (21 )-N(4) 1 283 5) c 21) -C(22) 1 455 6) C (22 )-C(23) 1 397 (6) C(22 )-C (24) 1 422 (6) c 23) -0(3) 1 346 5) C 23 )-C(25) 1 389 (6) C (24 )-C(26) 1 385 6) c 24) -C(51) 1 510 6) c 25 )-0(4) 1 359 (5) C (25 )-C(27) 1 394 6) c 26) -C(27) 1 426 6) c 26 )-C(55) 1 519 6) C (27 )-C(28) 1 449 6) c 28) -N(5) 1 292 5) c 29 )-C(30) 1 386 6) C (29 )-C(34) 1 406 6) c 29) -N(5) 1 418 5) c 30 )-C(31) 1 372 6) C (31 )-C(32) 1 380 (7) c 32) -C(33) 1 378 6) c 33 )-C(34) 1 388 6) C (34 ) -N(6) 1 419 (5) c 35) - N ( 6 ) 1 281 5) C- 35 )-C(36) 1 461 6) C (36 )-C(37) 1 399 (6) c 36) -C(38) 1 420 6) c 37 )-0(5) 1 350 5) C (37 )-C(39) 1 390 6) c 38) -C(40) 1 389 6) . c 38 )-C(59) 1 517 6) C (39 ) - 0 ( 6 ) 1 359 6) c 39) -C(41) 1 388 6) c 40 )-C(41) 1 409 7) C (40 )-C(63) 1 523 7) c 41) -C(42) 1 481 7) c 42 )-N(l) 1 221 6) C (43 )-C(44) 1 529 7) c 44) -C(45) 1 517 7) c 45 )-C(46) 1 499 9) C (47 )-C(48) 1 414 10) c 48) -C(4 9) 1 395 8) c 49 )-C(50) 1 445 11) C (51 )-C(52) 1 544 8) . c 52) -C(53) 1 483 9) c 53 )-C(54) 1 545 14) D. Selected Bond Lengths and Angles (contined) c ( 5 5 ) - C ( 5 6 ) 1 . 5 1 9 ( 7 ) C 5 6 ) - C ( 5 7 ) 1 . 6 0 1 ( 7 ) c ( 5 9 ) - C ( 6 0 ) 1 . 5 2 9 ( 7 ) c 6 0 ) - C ( 6 1 ) 1 . 5 1 0 ( 8 ) c ( 6 3 ) - C ( 6 4 ) 1 . 5 1 1 ( 7 ) c 6 4 ) - C ( 6 5 ) 1 . 5 3 0 ( 8 ) c ( 6 ) - C ( l ) - C ( 2 ) 1 1 8 8 (4 ) C ( 6 ) - C ( D - N ( l ) c ( 2 ) - C ( l ) - N ( l ) 1 2 2 7 ( 4 ) C ( 3 ) - C ( 2 ) - C ( l ) c ( 4 ) - C ( 3 ) - C ( 2 ) 1 2 0 1 ( 5 ) C ( 3 ) - C ( 4 ) - C ( 5 ) c ( 4 ) - C ( 5 ) - C ( 6 ) 1 2 0 8 ( 5 ) C ( 1 ) - C ( 6 ) - C ( 5 ) c ( 1 ) - C ( 6 ) - N ( 2 ) 1 1 7 8 ( 4 ) C ( 5 ) - C ( 6 ) - N ( 2 ) N ( 2 ) - C ( 7 ) - C ( 8 ) 1 2 3 7 ( 4 ) C ( 9 ) - C ( 8 ) - C ( 1 0 ) C ( 9 ) - C ( 8 ) - C ( 7 ) 1 1 8 7 ( 4 ) C ( 1 0 ) - C ( 8 ) - C ( 7 ) 0 ( 1 ) - C ( 9 ) - C ( 8 ) 1 2 3 9 ( 4 ) 0 ( 1 ) - C ( 9 ) - C ( l l ) c ( 8 ) - C ( 9 ) - C ( l l ) 1 1 9 7 ( 4 ) C ( 1 2 ) - C ( 1 0 ) - C ( 8 ) c ( 1 2 ) - C ( 1 0 ) - C ( 4 3 ) 1 2 2 6 ( 4 ) C ( 8 ) - C ( 1 0 ) - C ( 4 3 ) 0 ( 2 ) - C ( 1 1 ) - C ( 1 3 ) 1 2 3 5 (4 ) 0 ( 2 ) - C ( l l ) - C ( 9 ) c ( 1 3 ) - C ( 1 1 ) - C ( 9 ) 1 2 0 0 ( 4 ) c ( 1 0 ) - C ( 1 2 ) - C ( 1 3 c ( 1 0 ) - C ( 1 2 ) - C ( 4 7 ) 1 2 1 1 (4 ) c ( 1 3 ) - C ( 1 2 ) - C ( 4 7 c ( 1 1 ) - C ( 1 3 ) - C ( 1 2 ) 1 2 0 1 ( 4 ) c ( 1 1 ) - C ( 1 3 ) - C ( 1 4 c ( 1 2 ) - C ( 1 3 ) - C ( 1 4 ). 1 2 0 9 ( 4 ) N ( 3 ) - C ( 1 4 ) - C ( 1 3 ) c ( 2 0 ) - C ( 1 5 ) - C ( 1 6 ) 1 1 9 1 (4 ) C ( 2 0 ) - C ( 1 5 ) - N ( 3 ) c ( 1 6 ) - C ( 1 5 ) - N ( 3 ) ' 1 2 2 1 ( 4 ) c ( 1 7 ) - C ( 1 6 ) - C ( 1 5 c ( 1 8 ) - C ( 1 7 ) - C ( 1 6 ) 1 1 9 7 ( 4 ) c ( 1 7 ) - C ( 1 8 ) - C ( 1 9 c ( 1 8 ) - C ( 1 9 ) - C ( 2 0 ) 1 2 0 7 ( 4 ) c ( 1 5 ) - C ( 2 0 ) - C ( 1 9 c ( 1 5 ) - C ( 2 0 ) - N ( 4 ) 1 1 8 4 ( 4 ) c ( 1 9 ) - C ( 2 0 ) - N ( 4 ) N ( 4 ) - C ( 2 1 ) - C ( 2 2 ) 1 2 2 4 (4 ) c ( 2 3 ) - C ( 2 2 ) - C ( 2 4 c ( 2 3 ) - C ( 2 2 ) - C ( 2 1 ) 1 1 9 0 (4 ) c ( 2 4 ) - C ( 2 2 ) - C ( 2 1 0 ( 3 ) - C ( 2 3 ) - C ( 2 5 ) 1 1 6 8 (4 ) c ( 3 ) - C ( 2 3 ) - C ( 2 2 ) c ( 2 5 ) - C ( 2 3 ) - C ( 2 2 ) 1 2 0 0 ( 4 ) c ( 2 6 ) - C ( 2 4 ) - C ( 2 2 c 2 6 ) - C ( 2 4 ) - C ( 5 1 ) 1 2 0 6 ( 4 ) c ( 2 2 ) - C ( 2 4 ) - C ( 5 1 0 4 ) - C ( 2 5 ) - C ( 2 3 ) 1 1 6 7 ( 4 ) 0 ( 4 ) - C ( 2 5 ) - C ( 2 7 ) c 2 3 ) - C ( 2 5 ) - C ( 2 7 ) 1 2 0 8 ( 4 ) c 2 4 ) - C ( 2 6 ) - C ( 2 7 c 2 4 ) - C ( 2 6 ) - C ( 5 5 ) 1 2 0 8 ( 4 ) c 2 7 ) - C ( 2 6 ) - C ( 5 5 c 2 5 ) - C ( 2 7 ) - C ( 2 6 ) 1 1 9 3 ( 4 ) c 2 5 ) - C ( 2 7 ) - C ( 2 8 c 2 6 ) - C ( 2 7 ) - C ( 2 8 ) 1 2 1 1 ( 4 ) N 5 ) - C ( 2 8 ) - C ( 2 7 ) c 3 0 ) - C ( 2 9 ) - C ( 3 4 ) 1 1 8 4 (4 ) c 3 0 ) - C ( 2 9 ) - N ( 5 ) c 3 4 ) - C ( 2 9 ) - N ( 5 ) 1 1 7 8 3 ) c 3 1 ) - C ( 3 0 ) - C ( 2 9 c 3 0 ) - C ( 3 1 ) - C ( 3 2 ) 1 1 9 8 4 ) c 3 3 ) - C ('32 ) - C ( 3 1 c 3 2 ) - C ( 3 3 ) - C ( 3 4 ) 1 2 0 4 4 ) c 3 3 ) - C ( 3 4 ) - C ( 2 9 c 3 3 ) - C ( 3 4 ) - N ( 6 ) 1 2 2 3 4 ) c 2 9 ) - C ( 3 4 ) - N ( 6 ) N 6 ) - C ( 3 5 ) - C ( 3 6 ) 1 2 1 9 4 ) c 3 7 ) - C ( 3 6 ) - C ( 3 8 c 3 7 ) - C ( 3 6 ) - C ( 3 5 ) 1 1 9 2 4 ) c 3 8 ) - C ( 3 6 ) - C ( 3 5 0 5 ) - C ( 3 7 ) - C ( 3 9 ) 1 1 7 1 4 ) 0 5 ) - C ( 3 7 ) - C ( 3 6 ) c 3 9 ) - C ( 3 7 ) - C ( 3 6 ) 1 2 0 7 4 ) c 4 0 ) - C ( 3 8 ) - C ( 3 6 c 4 0 ) - C ( 3 8 ) - C ( 5 9 ) 1 2 0 4 4 ) c 3 6 ) - C ( 3 8 ) - C ( 5 9 0 6 ) - C ( 3 9 ) - C ( 4 1 ) 1 2 0 5 4 ) 0 6 ) - C ( 3 9 ) - C ( 3 7 ) c 4 1 ) - C ( 3 9 ) - C ( 3 7 ) 1 1 9 9 4 ) c 3 8 ) - C ( 4 0 ) - C ( 4 1 c 3 8 ) - C ( 4 0 ) - C ( 6 3 ) 1 2 0 4 4 ) c 4 1 ) - C ( 4 0 ) - C ( 6 3 c 3 9 ) - C ( 4 1 ) - C ( 4 0 ) 1 2 0 1 4 ) c 3 9 ) - C ( 4 1 ) - C ( 4 2 c 4 0 ) - C ( 4 1 ) - C ( 4 2 ) 1 2 1 7 5 ) N 1 ) - C ( 4 2 ) - C ( 4 1 ) c 1 0 ) - C ( 4 3 ) - C ( 4 4 ) 1 1 2 7 4 ) c 4 5 ) - C ( 4 4 ) - C ( 4 3 c 4 6 ) - C ( 4 5 ) - C ( 4 4 ) 1 1 4 . 0 5 ) c 4 8 ) - C ( 4 7 ) - C ( 1 2 c 4 9 ) - C ( 4 8 ) - C ( 4 7 ) 1 3 0 . 1 7 ) c 4 8 ) - C ( 4 9 ) - C ( 5 0 c 2 4 ) - C ( 5 1 ) - C ( 5 2 ) 1 1 2 . 3 4 ) c 5 3 ) - C ( 5 2 ) - C ( 5 1 c 5 2 ) - C ( 5 3 ) - C ( 5 4 ) 1 1 0 . 5 9 ) c 5 6 ) - C ( 5 5 ) - C ( 2 6 c 5 5 ) - C ( 5 6 ) - C ( 5 7 ) 1 1 0 . 1 4 ) c 5 8 ) - C ( 5 7 ) - C ( 5 6 c 3 8 ) - C ( 5 9 ) - C ( 6 0 ) 1 1 3 . 1 4 ) c 6 1 ) - C ( 6 0 ) - C ( 5 9 c 6 2 ) - C ( 6 1 ) - C ( 6 0 ) 1 1 2 . 9 6 ) c 6 4 ) - C ( 6 3 ) - C ( 4 0 C ( 5 7 ) - C ( 5 8 ) 1 . 4 8 3 ( 9 ) C ( 6 1 ) - C ( 6 2 ) 1 . 5 0 2 ( 1 1 ) C ( 6 5 ) - C ( 6 6 ) 1 . 4 8 3 ( 8 ) 1 1 8 5 ( 4 1 2 0 8 ( 5 1 2 0 3 ( 5 1 1 9 2 ( 4 1 2 3 0 ( 4 1 2 0 5 ( 4 1 2 0 6 ( 4 1 1 6 4 (4 1 2 0 1 (4 1 1 7 3 (4 1 1 6 5 (4 1 1 9 3 (4 1 1 9 6 ( 4 1 1 9 0 ( 4 1 2 2 4 (4 1 1 8 7 ( 4 1 2 1 0 ( 4 1 2 0 5 ( 4 1 1 8 9 (4 1 2 2 6 (4 1 2 0 1 (4 1 2 0 9 (4 1 2 3 2 (4 1 1 9 5 (4 1 1 9 8 (4 1 2 2 5 (4 1 2 0 2 (4 1 1 8 9 (4 1 1 9 6 4 1 2 2 8 (4 1 2 3 7 4 1 2 1 5 4 1 2 0 1 4 1 1 9 7 4 1 1 7 9 4 1 1 9 5 4 1 2 1 2 4 1 2 2 2 4 1 1 9 2 4 1 2 0 4 4 1 1 9 5 4 1 2 0 4 4 1 1 9 1 4 1 1 8 2 5 1 2 5 5 5 1 1 2 9 4 1 1 6 8 7 1 3 1 . 5 9 1 1 5 . 1 7 1 1 3 . 3 4 1 0 9 . 6 8 1 1 4 . 6 5 1 1 3 . 4 4 D. Selected Bond Lengths and Angles (contined) C ( 6 3 ) - C ( 6 4 ) - C ( 6 5 ) 1 1 1 . 8 ( 5 ) C ( 4 2 ) - N ( 1 ) - C ( 1 ) 1 2 1 . 5 ( 5 ) C ( 1 4 ) - N ( 3 ) - C ( 1 5 ) 1 1 9 . 7 ( 4 ) C ( 2 8 ) - N ( 5 ) - C ( 2 9 ) 1 2 0 . 0 ( 3 ) C ( 6 6 ) - C ( 6 5 ) - C ( 6 4 ) 1 1 4 . 3 ( 5 ) C ( 7 ) - N ( 2 ) - C ( 6 ) 1 1 9 . 9 ( 4 ) C ( 2 1 ) - N ( 4 ) - C ( 2 0 ) 1 2 0 . 8 ( 4 ) C ( 3 5 ) - N ( 6 ) - C ( 3 4 ) 1 2 1 . 4 ( 4 ) 

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