Intramolecular Hydrogen Bonding and Intermolecular Dimerization in

Intramolecular Hydrogen Bonding and Intermolecular Dimerization in the Crystal Structures of Imidazole-4,5-dicarboxylic Acid Derivatives Paul W. Baures,*,† Jeremy R. Rush, Alexander V. Wiznycia, John Desper, Brian A. Helfrich, and Alicia M. Beatty

CRYSTAL GROWTH & DESIGN 2002 VOL. 2, NO. 6 653-664

Department of Chemistry, Kansas State University, 111 Willard Hall, Manhattan, Kansas 66506 Received July 1, 2002;

Revised Manuscript Received September 7, 2002

ABSTRACT: Diamide and amide-ester derivatives of imidazole-4,5-dicarboxylic acid form reliable hydrogen-bonding motifs in the solid state. The crystal structures of symmetrically substituted and dissymmetrically substituted diamides as well as amide-ester combinations were analyzed in order to identify the intermolecular hydrogen-bonding patterns. An intramolecular seven-membered hydrogen-bonded conformation forms in all derivatives where the possibility existed due to the functionality present. The motifs observed for the diamides include intermolecular NH‚‚‚O and NH‚‚‚N hydrogen-bonded dimers, with the exceptions to these motifs occurring in compounds having benzylamine substituents. The amines with a higher classification (i.e., 3° > 2° > 1°) in the dissymmetrically substituted diamides are the intramolecular hydrogen bond donors in the solid state, consistent with the capacity of the alkyl group to stabilize developing carbocation character resulting from bond polarization. The amide-ester derivatives also form an intramolecular hydrogen bond and an intermolecular motif based on NH‚‚‚N and two different C2-H‚‚‚O hydrogen bonds. A pyrrole amide-ester derivative forms an intramolecular NH‚‚‚O hydrogen bond in the solid state and an intermolecular NH‚‚‚O hydrogen-bonded chain. With the exception of the benzylamine-substituted diamides, the intermolecular hydrogen-bonded motifs appear reliable for these imidazole-4,5-dicarboxylic acid derivatives and will be useful in the design of analogues for specific applications. Introduction The design and development of new materials with optical, magnetic, electrical, or other properties suitable for high technology products are of great interest with organic, inorganic, and organic-inorganic hybrids where small to large molecular mass is important.1,2 As illustrated by recent work, a popular method for the design of supramolecular assemblies is to use noncovalent interactions such as hydrogen bonds to guide the construction of smaller molecules into larger organizations.3-43 Similarly, the field of crystal engineering has long employed the hydrogen bond as a design element in the directed self-assembly of small organic molecules both in the presence and in the absence of other intermolecular attractive forces.44-50 The Etter rules51,52 describe the anticipated hydrogenbonding patterns for several well-studied functional groups and have found use as a working model for the hierarchal application of these rules to the noncovalent synthesis of supramolecular structures. A dominant hydrogen-bonding force described in these rules is the presence of an intramolecular hydrogen bond.52 These rules state that six-membered intramolecular hydrogen bonds are generally unperturbed by the presence of other functional groups and the formation of intermolecular interactions; therefore, these associations can be as dependable as a covalently bonded structure. Indeed, quasi-rings formed through intramolecular hydrogenbonded interactions have been components of drug * To whom correspondence should be addressed. E-mail: pbaures@ signaturebio.com. † Current address: Signature BioScience, Inc., 1240 South 47th Street, Richmond, CA 94804.

design projects where such interactions are used to replace rings or bias conformations.53 Heterocyclic compounds are important in both materials and in biological systems and often interact in the system in a manner dependent upon their hydrogenbonding properties. Imidazole-4,5-dicarboxylic acid derivatives have been studied in terms of their physical properties as well as for their diverse biological activities,54-61 including the use of imidazole-4,5-dicarboxamides (I45DCs) in the development of human immunodeficiency virus (HIV-1) protease inhibitors.62 Oligomeric I45DCs have been shown to form metal complexes63 and have also been included in polyamides.64 The properties and biological activities of I45DCs and analogues are expectedly dependent upon the structure of the molecule including any intra- and intermolecular hydrogen-bonding patterns. Both I45DCs and amideester analogues are known to form strong intramolecular hydrogen bonds in solution.64-66 However, there is little detailed structural information known about these compounds in the solid state with only crystal structures of ring-alkylated derivatives having been reported.67,68 Imidazole-4,5-dicarboxylic acid itself has been used as a cocrystallization agent with amino acids.69 Our interests were in obtaining solid state structural information for derivatives of this scaffold (diamide and amide-ester analogues) in support for the continued development of their biological and material applications. It was anticipated that common hydrogen-bonded motifs would be realized in the crystal structures of these molecules that could then be expected to be relied upon for either molecular recognition in the biological applications or for organizing the solid state of deriva-

10.1021/cg025549j CCC: $22.00 © 2002 American Chemical Society Published on Web 10/12/2002

654

Crystal Growth & Design, Vol. 2, No. 6, 2002

tives bearing useful chemical functionality for material applications. This work reports our initial efforts in identifying the intramolecular and intermolecular hydrogen-bonded associations formed by the symmetricallyN,N′-disubstituted and dissymmetrically-N,N′-disubstituted I45DCs as well as ester-amide analogues. The influence of the I45DC functionality on the observed solid state structures was shown by comparison to both a pyrrole ester-amide analogue that forms an intramolecular hydrogen bond but not the same intermolecular associations and two I45DCs containing only tertiary amides incapable of forming an intramolecular hydrogen bond. The solid state crystal structure of these compounds, with the exception of the I45DCs containing only tertiary amides, all contained a seven-membered intramolecular hydrogen bond. A majority of the N,N′disubstituted I45DCs also formed the same intermolecular hydrogen-bonded dimeric motif based on two NH‚‚‚O hydrogen bonds. In some cases, a second intermolecular hydrogen-bonded dimer based on two NH‚‚‚N hydrogen bonds was also present in the solid state. There were exceptions to these two principle intermolecular hydrogen-bonded motifs although the most notable contained either a version of these motifs with the imidazole rings twisted with respect to one another or a hydrogen-bonded chain between the same donor and the acceptor atoms. Surprisingly, the esteramide analogues repeatedly formed an alternative intermolecular hydrogen-bonded motif that seemingly violates the Etter “strongest donor to the strongest acceptor” paradigm.50,51 In the amide-ester derivatives, a NH‚‚‚N hydrogen bond along with two CH‚‚‚O interactions forms instead of the two NH‚‚‚O hydrogen bonds found in most of the dicarboxamide analogues. Two I45DC structures with tertiary amides were included in order to determine the consequence of no intramolecular hydrogen bond formation on the crystal packing of these compounds. Each of the structures form a different packing motif with respect to one another, although both motifs were observed in the dicarboxamide and amide-ester analogues. In the N-methylbenzylamine derivative, the crystal packing is similar to the amide-ester analogues with intermolecular NH‚‚‚N and two CH‚‚‚O hydrogen bonds. The N,N-dibenzylamine I45DC forms an intermolecular dimer with two NH‚‚‚O hydrogen bonds, although the imidazole rings are twisted with respect to one another. The significance of aromatic ring interactions on the ultimate solid state motif formed by the I45DCs bearing benzylamine substituents is not yet clear from the few examples in this study. Experimental Section General Methods. All apparatuses were oven-dried and cooled in a desiccator. Reagent grade tetrahydrofuran (THF) and dichloromethane were distilled from sodium benzophenone ketyl and CaH2, respectively, before use. All other reagents were purchased from commercial suppliers and used without purification. Thin-layer chromatography was done on 250 µm silica gel plates and was visualized by using UV and I2 as well as ninhydrin spray for amines. Melting points are uncorrected. 1H and 13C NMR spectra were measured at 400 and 50.3 MHz, respectively, in either CDCl3 with CHCl3 as the internal reference for 1H (δ 7.26) and CDCl3 as the internal reference

Baures et al. for 13C (δ 77.06) or in dimethyl sulfoxide (DMSO)-d6 with DMSO as the internal reference for 1H (δ 2.50) and DMSO-d6 as the internal reference for 13C (δ 39.50). General Method for the Synthesis of Symmetrically Substituted I45DCs. To a dry round-bottom flask were added 5,10-dioxo-5H,10H-diimidazo[1,5-a:1′-5′-d]pyrazine-1,6-dicarbonyl dichloride and THF to yield a 10% w/v suspension. The amine (6-24 equiv) was added dropwise as a concentrated solution in THF at 0 °C under an inert gas. The resulting solution was stirred for 6 h before adding 4 volume equiv of a 1 M HCl solution. The product generally precipitated, although an oil formed from this acidic solution in the synthesis of 6. The solids were collected by vacuum filtration, washed with water, and dried overnight. In the case of 6, the solution was decanted to provide the oil that was similarly washed with water. Dissolving the oil in methanol followed by partial concentration yielded 6 as a powder. The size of the alkyl group affected water solubility and additional material was obtained for 1-3 by back-extracting the acid solution with dichloromethane. All of the products were further purified by either crystallization or column chromatography or both. 4,5-Bis[(methylamino)carbonyl]-1H-imidazole (1). Compound 1 was synthesized from 5H,10H-diimidazo[1,5-a: 1′-5′d]pyrazine-1,6-dicarbonyl dichloride (3.0 g, 9.58 mmol) and a solution containing an excess of methylamine in THF that was created by the addition of sodium hydroxide (3.07 g, 76.7 mmol) to suspended methylamine hydrochloride (5.18 g, 76.7 mmol). Workup followed by crystallization from methanol provided 0.260 g (7.4%) of 1; mp 215-218 °C [Lit mp 220-221 °C (ref 70)]; Rf ) 0.07 (EtOAc/hexanes, 7:3). 1H NMR (DMSO-d6): δ 13.19 (bs, 1 H), 11.09 (bs, 1 H), 8.59 (bs, 1 H), 7.79 (s, 1 H), 2.09 (s, 6 H). The carbonyl and an imidazole ring carbon signal were broad in the 13C NMR spectrum with the center of the observed signals reported to the nearest ppm. 13C NMR (CDCl3): δ 162, 160, 135.1, 133, 26.3. 4,5-Bis[(n-propylamino)carbonyl]-1H-imidazole (2). Compound 2 was synthesized from 5H,10H-diimidazo[1,5-a: 1′-5′-d]pyrazine-1,6-dicarbonyl dichloride (0.942 g, 3.01 mmol) and n-propylamine (1.48 mL, 18.0 mmol) in dichloromethane to yield 1.208 g (84%) of 2 following crystallization; mp 138141 °C [Lit mp 141-142 °C (ref 70)]; Rf ) 0.24 (EtOAc/hexanes, 7:3). 1H NMR (DMSO-d6): δ 13.18 (bs, 1 H), 11.18 (bs, 1 H), 8.61 (bs, 1 H), 7.79 (s, 1 H), 3.21-3.27 (m, 4 H), 1.48-1.57 (m, 4 H), 0.87-0.91 (m, 6 H). The carbonyl resonances and the 4(5)-carbons of the imidazole ring were broad in the 13C NMR spectra. The center of these observed signals was estimated to the nearest ppm value. 13C NMR (DMSO-d6): δ 163, 159, 135.8, 132, 129, 40.8, 40.3, 22.4, 11.4. ES+ MS m/z ) 239 [M + H]+. Anal. calcd for C11H18N4O2: C, 55.44; H, 7.61; N, 23.52. Found: C, 55.75; H, 7.34; N, 23.56. 4,5-Bis[(isopropylamino)carbonyl]-1H-imidazole (3). Compound 3 was synthesized from 5H,10H-diimidazo[1,5-a: 1′-5′-d]pyrazine-1,6-dicarbonyl dichloride (0.940 g, 3.01 mmol) and isopropylamine (1.48 mL, 17.4 mmol) in dichloromethane to yield 1.109 g (78%) of 3 following crystallization from methanol; mp 156-158 °C [Lit mp 159-160 °C (ref 70)]; Rf ) 0.24 (EtOAc/hexanes, 7:3). 1H NMR (DMSO-d6): δ 13.17 (bs, 1 H), 11.10 (bs, 1 H), 8.23 (bs, 1 H), 7.78 (s, 1 H), 4.08-4.17 (m, 1 H), 3.96-4.03 (m, 1 H), 1.16-1.18 (m, 12 H). 13C NMR (DMSO-d6): δ 162.4, 157.2, 135.8, 132.6, 128.5, 40.8, 40.4, 22.5, 22.2. ES+ MS m/z ) 239 [M + H]+. Anal. calcd for C11H18N4O2: C, 55.44; H, 7.61; N, 23.52. Found: C, 55.33; H, 7.43; N, 23.60. 4,5-Bis[(n-butylamino)carbonyl]-1H-imidazole (4). Compound 4 was synthesized from 5H,10H-diimidazo[1,5-a:1′-5′d]pyrazine-1,6-dicarbonyl dichloride (0.982 g, 3.14 mmol) and n-butylamine (7.40 mL, 74.9 mmol) in THF to yield 1.255 g (75%) of 4 following crystallization from methanol; mp 133134 °C [Lit mp 132-133 °C (ref 70)]; Rf ) 0.29 (EtOAc/hexanes, 7:3). 1H NMR (DMSO-d6): δ 13.18 (bs, 1 H), 11.16 (bs, 1 H), 8.56 (bs, 1 H), 7.79 (s, 1 H), 3.25-3.32 (m, 4 H), 1.46-1.54 (m, 4 H), 1.28-1.37 (m, 4 H), 0.88-0.91 (m, 6 H). 13C NMR (DMSO-d6): δ 163.3, 158.0, 135.9, 132.8, 128.2, 40.4, 31.2, 19.6, 13.7. ES+ MS m/z ) 267 [M + H]+. Anal. calcd for

Imidazole-4,5-dicarboxylic Acid Derivatives C13H22N4O2: C, 58.62; H, 8.33; N, 21.04. Found: C, 58.79; H, 8.25; N, 20.97. 4,5-Bis[(t-butylamino)carbonyl]-1H-imidazole (5). Compound 5 was synthesized from 5H,10H-diimidazo[1,5-a:1′-5′d]pyrazine-1,6-dicarbonyl dichloride (0.972 g, 3.10 mmol) and tert-butylamine (7.80 mL, 74.2 mmol) in THF to yield 0.986 g (60%) of 5 following crystallization from methanol; mp 155157 °C; Rf ) 0.38 (EtOAc/hexanes, 7:3). 1H NMR (DMSO-d6): δ 13.07 (bs, 1 H), 10.91 (bs, 1 H), 7.75 (s, 1 H), 7.74 (bs, 1 H), 1.39-1.40 (m, 18 H). 13C NMR (CDCl3): δ 163.0, 158.5, 134.0, 129.5, 51.7, 28.8. ES+ MS m/z ) 267 [M + H]+. Anal. calcd for C13H22N4O2: C, 58.62; H, 8.33; N, 21.04. Found: C, 58.60; H, 8.42; N, 21.04. 4,5-Bis[(benzylamino)carbonyl]-1H-imidazole (6). Compound 6 was synthesized from 5H,10H-diimidazo[1,5-a:1′-5′d]pyrazine-1,6-dicarbonyl dichloride (1.044 g, 3.33 mmol) and benzylamine (8.80 mL, 80.6 mmol) in THF to yield 1.438 g (65%) of 6 following crystallization from methanol; mp 155157 °C; [Lit mp 153-154 °C (ref 70)]; Rf ) 0.30 (EtOAc/ hexanes, 7:3). 1H NMR (DMSO-d6): δ 13.33 (bs, 1 H), 11.54 (bs, 1 H), 9.21 (bs, 1 H), 7.88 (bs, 1 H), 7.24-7.88 (m, 10 H), 4.41-4.58 (m, 4 H). 13C NMR (DMSO-d6): δ 163.6, 158.2, 139.0, 132.8, 128.4, 127.2, 126.9, 42.2. ES+ MS m/z ) 335 [M + H]+. Anal. calcd for C19H18N4O2: C, 68.24; H, 5.43; N, 16.76. Found: C, 68.35; H, 5.28; N, 16.86. 4,5-Bis[(R-r-methylbenzylamino)carbonyl]-1H-imidazole (7). Compound 7 was synthesized from 5H,10H-diimidazo[1,5-a:1′-5′-d]pyrazine-1,6-dicarbonyl dichloride (0.941 g, 3.01 mmol) and R-R-methylbenzylamine (2.33 mL, 18.1 mmol) in dichloromethane to yield 1.856 g (85%) of 7 following crystallization from methanol; mp 144-146 °C; Rf ) 0.30 (EtOAc/hexanes, 7:3). 1H NMR (DMSO-d6): δ 13.26 (bs, 1 H), 11.52 (bs, 1 H), 8.88 (bs, 1 H), 7.85 (bs, 1 H), 7.23-7.43 (m, 10 H), 5.21-5.30 (m, 1 H), 5.04-5.18 (m, 1 H), 1.45-1.54 (m, 6 H). 13C NMR (DMSO-d6): δ 162.7, 157.1, 144.0, 136.2, 132.7, 128.4, 126.8, 126.2, 125.8, 48.1, 23.1, 21.9. 13C NMR (CDCl3): δ 162.3, 158.6, 144.6, 142.9, 135.0, 133.2, 128.8, 128.4, 127.5, 127.2, 126.4, 126.1, 50.5, 48.8, 23.1, 22.2. ES+ MS m/z ) 363 [M + H]+. Anal. calcd for C21H22N4O2: C, 69.59; H, 6.12; N, 15.46. Found: C, 69.67; H, 5.87; N, 15.40. 4,5-Bis[(ethoxyglycyl)carbonyl]-1H-imidazole (8). Compound 8 was synthesized from 0.575 g of 5H,10H-diimidazo[1,5-a:1′-5′-d]pyrazine-1,6-dicarbonyl dichloride to yield 0.403 g (33%) of 8 as a crystalline solid following silica gel chromatography and crystallization from CH2Cl2/hexanes; mp 159160 °C; Rf ) 0.34 (EtOAc/hexanes, 7:3). 1H NMR (DMSO-d6): δ 13.40 (bs, 1 H), 11.20 (bs, 1 H), 9.00 (bs, 1 H), 7.91 (s, 1 H), 4.07-4.18 (m, 2 H), 1.15-1.24 (m, 6 H). 13C NMR (DMSO-d6): δ 169.5, 136.7, 60.59, 40.95, 14.08. ES+ MS m/z ) 239 [M + H]+. Anal. calcd for C13H18N4O6: C, 47.85; H, 5.56; N, 17.17. Found: C, 48.04; H, 5.35; N, 17.03. 4,5-Bis[(N-methylbenzylamino)carbonyl]-1H-imidazole (17). Compound 17 was synthesized from 5H,10Hdiimidazo[1,5-a:1′-5′-d]pyrazine-1,6-dicarbonyl dichloride (0.516 g, 1.65 mmol) and N-methylbenzylamine (1.28 mL, 9.89 mmol) in dichloromethane to yield 340 mg (29%) of 17 following chromatography; mp 112-114 °C; Rf ) 0.24 (EtOAc/hexanes, 7:3). 1H NMR (DMSO-d6): 13.10 (bs, 1 H), 7.78 (s, 1H), 7.217.43 (m, 10 H), 4.64 (s, 4 H), 2.86 (s, 6 H). 13C NMR (CDCl3): δ 163.8, 137.4, 135.8, 135.2, 128.5, 127.4, 60.2, 54.1, 51.2, 36.1, 33.8, 20.9, 14.0. ES+ MS m/z ) 363 [M + H]+. Anal. calcd for C21H22N4O2: C, 69.59; H, 6.12; N, 15.46. Found: C, 69.67; H, 5.87; N, 15.40. 4,5-Bis[(N,N-dibenzylamino)carbonyl]-1H-imidazole (18). Compound 18 was synthesized from 5H,10H-diimidazo[1,5-a:1′-5′-d]pyrazine-1,6-dicarbonyl dichloride (0.499 g, 1.59 mmol) and N,N-dibenzylamine (1.84 mL, 9.56 mmol) in dichloromethane to yield 1.048 g (64%) of 18 following crystallization from methanol; mp 243-246 °C; Rf ) 0.17 (EtOAc/hexanes, 7:3). 1H NMR (CDCl3): δ 10.10 (bs, 1 H), 8.31 (s, 1 H), 7.00 7.31 (m, 20 H), 4.50 (s, 2 H), 4.17 (s, 2 H), 3.66 (s, 4 H). 13C NMR (CDCl3): δ 162.4, 148.0, 147.8, 138.0, 135.7, 135.2, 130.4, 130.0, 129.4, 129.1, 128.8, 128.4, 127.8, 127.5, 118.5, 51.0, 48.7, 47.2. ES+ MS m/z ) 516 [M + H]+.

Crystal Growth & Design, Vol. 2, No. 6, 2002 655 5,10-Dioxo-5H,10H-diimidazo{1,5-a:1′,5′-d}pyrazine1,6-dicarbonyl Di-L-valinyl Dibenzyl Ester (19). To a dry round-bottom flask under argon was suspended 2.039 g (6.51 mmol) of 5H,10H-diimidazo[1,5-a:1′-5′-d]pyrazine-1,6-dicarbonyl dichloride in 25 mL of dry dichloromethane. To this stirred solution at -78 °C was added 2 mol equiv of L-valine benzyl ester hydrochloride all at once followed by 4 mol equiv of pyridine over 15 min. The solution was held at -78 °C for 30 min and then stirred for 1 h at room temperature. Solids were removed by filtration through Celite, and the filtrate was extracted against water (three times). The organic fraction was dried over MgSO4, filtered, and concentrated. The residue was suspended in boiling ethyl acetate, stirred for 10 min, and cooled to 0 °C, and the product solid was collected by vacuum filtration to yield 3.118 g (73%) of 19. 1H NMR (CDCl3): δ 8.78 (d, J ) 8.8 Hz, 2 H), 8.65 (s, 2 H), 7.33-7.38 (m, 10 H), 5.165.25 (m, 4 H), 4.86-4.89 (m, 2 H), 2.34-2.38 (m, 2 H), 0.981.02 (m, 12 H. 13C NMR (CDCl3): δ 171.5, 158.1, 149.8, 147.1, 138.9, 135.5, 128.9, 128.8, 119.2, 67.6, 58.1, 31.6, 19.4, 17.9. 5-[(Benzyloxy-L-valyl)carbonyl]-4-methoxycarbonyl1H-imidazole (12). To a dry round-bottom flask was added 19 (0.300 g, 0.458 mmol) in 5 mL of methanol. The solution was gently heated for 15 min, dissolving all of the solids and yielding a clear, colorless solution. Crystals of 12 were obtained upon cooling in quantitative yield; mp 200-202 °C; Rf ) 0.14 (EtOAc/hexanes, 7:3). 1H NMR (CDCl3): δ 12.66 (s, 1 H), 10.74 (s, 1 H), 7.66 (s, 1 H), 7.28-7.32 (m, 5 H), 5.15-5.23 (m, 2 H), 4.66-4.69 (m, 1 H), 3.99 (s, 3 H), 2.34-2.39 (m, 1 H), 0.951.03 (m, 6 H). 13C NMR (CDCl3): δ 171.0, 165.4, 158.7, 136.5, 135.3, 130.8, 130.7, 128.5, 128.3, 128.2, 66.9, 58.5, 53.0, 30.7, 19.2, 17.7. 5,10-Dioxo-5H,10H-diimidazo{1,5-a:1′,5′-d}pyrazine1,6-dicarbonyl Diethyl Ester (20). To a dry round-bottom flask under argon was suspended 1.622 g (5.18 mmol) of 5H,10H-diimidazo[1,5-a:1′-5′-d]pyrazine-1,6-dicarbonyl dichloride in 40 mL of dry ethanol. The suspension was stirred for 7 days at room temperature under Ar before the solid was collected by vacuum filtration to yield 1.542 g (90%) of 20. 1H NMR (CDCl3): δ 8.62 (s, 2 H), 4.53 (q, J ) 7.4 Hz, 2 H), 1.47 (t, J ) 7.4 Hz, 3 H). 13C NMR (CDCl3): δ 160.6, 148.2, 140.4, 138.6, 122.2, 61.7, 13.9. 4-Ethoxycarbonyl-5-[(methoxy-L-phenylalanyl)carbonyl]-1H-imidazole (13). To a dry round-bottom flask were added 0.200 g of 20 (0.602 mmol) and 0.260 g of L-phenylalanine methyl ester hydrochloride (1.20 mmol) in 20 mL of dichloromethane under Ar at -78 °C. To this suspension was added 0.21 mL of diisopropylethylamine dropwise, and the solution was stirred for 20 min at -78 °C and then for 16 h at room temperature. The final solution was washed with 10% citric acid, 1 M NaHCO3, and brine. The organic fraction was dried over MgSO4, filtered, and concentrated under vacuum. The residue was crystallized from dichloromethane/hexanes to yield 251 mg (60%) of 13; mp 185-186 °C; Rf ) 0.04 (EtOAc/ hexanes, 7:3). 1H NMR (CDCl3): δ 10.58 (bs, 1 H), 7.69 (s, 1 H), 7.21-7.35 (m, 5 H), 4.93 - 4.99 (m, 1 H), 4.46 (q, J ) 7.4 Hz, 2 H), 3.75 (s, 3 H), 3.23-3.35 (m, 1 H), 3.12-3.19 (m, 1 H), 1.46 (t, J ) 7.4 Hz, 3 H). 13C NMR (CDCl3): δ 171.7, 164.9, 158.6, 136.8, 136.3, 129.4, 128.8, 127.3, 62.6, 55.0, 52.7, 38.2, 14.4. 4-Ethoxycarbonyl-5-[(methoxyglycyl)carbonyl]-1H-imidazole (14). To a dry round-bottom flask were added 0.644 g of 20 (1.96 mmol) and 0.492 g of glycine methyl ester hydrochloride (3.92 mmol) in 25 mL of dichloromethane under Ar at -78 °C. To this suspension was added 0.69 mL of diisopropylethylamine dropwise, and the solution was stirred for 20 min at -78 °C and then for 16 h at room temperature. The final solution was washed with 10% citric acid, 1 M NaHCO3, and brine. The organic fraction was dried over MgSO4, filtered, and concentrated under vacuum. The residue was crystallized from dichloromethane to yield 255 mg (26%) of 14; mp 178-180 °C; Rf ) 0.11 (EtOAc/hexanes, 7:3). 1H NMR (CDCl3): δ 10.76 (bs, 1 H), 7.86 (s, 1 H), 4.48 (q, J ) 7.4 Hz, 2 H), 4.27 (d, J ) 5.2 Hz, 2 H), 3.79 (s, 3 H), 1.44 (t, J ) 7.4 Hz, 3 H). 13C NMR (CDCl3): δ 169.6, 164.5, 158.7, 136.6, 130.6, 130.3, 62.4, 52.4, 41.7, 14.1.

656

Crystal Growth & Design, Vol. 2, No. 6, 2002

Baures et al.

Table 1. Selected Crystal Data Collection and Refinement Data for 1-7 crystal

1

formula C7H10N4O2 weight (g mol-1) 182.19 crystal size (mm) 0.20 × 0.20 × 0.06 crystal system triclinic space group P1 a (Å) 4.890(1) b (Å) 9.109(2) c (Å) 9.506(2) R (deg) 94.85(1) β (deg) 94.49(1) γ (deg) 96.86(1) Z 2 temp (K) 203(2) 2 R/Rw (obs data) 0.0369/ 0.0834 S 0.876

2

3

4

5

6a

6b

7

C11H18N4O2 238.29 0.30 × 0.20 × 0.10 triclinic P1 13.407(2) 14.641(3) 14.813(2) 94.42(1) 101.66(1) 116.36(1) 8 293(2) 0.0522/ 0.1111 0.823

C26H46N8O5 550.71 0.45 × 0.45 × 0.35 monoclinic P21/c 23.220(3) 8.770(1) 15.362(2) 90.0 96.14(3) 90.0 4 203(2) 0.0436/ 0. 1113 0.992

C13H22N4O2 266.35 0.35 × 0.15 × 0.15 triclinic P1 9.712(6) 13.383(8) 14.026(9) 116.75(1) 90.44(1) 109.83(1) 4 293(2) 0.0967 /0.2375 1.096

C13H22N4O2 266.35 0.35 × 0.20 × 0.20 monoclinic C2/c 24.853(6) 9.431(3) 17.448(4) 90.0 133.11(1) 90.0 8 293(2) 0.0381/ 0.0947 0.927

C19H18N4O2 334.37 0.60 × 0.60 × 0.30 monoclinic P21/c 9.475(2) 9.490(2) 36.087(7) 90.0 95.63(3) 90.0 8 173(2) 0.0695/ 0.1786 1.13

C19H18N4O2 334.37 0.60 × 0.60 × 0.30 monoclinic P21/n 28.386(6) 9.579(2) 38.379(8) 90.0 109.41(1) 90.0 24 233(2) 0.0956/ 0.2580 1.105

C21H22N4O2 362.43 0.35 × 0.20 × 0.10 monoclinic P21 10.140(2) 5.813(1) 16.709(3) 90.0 94.24(1) 90.0 2 293(2) 0.0429/ 0.0821 0.875

Table 2. Selected Crystal Data Collection and Refinement Data for 8-15 crystal data

8

formula C13H18N4O6 weight (g mol-1) 326.31 crystal size (mm) 0.30 × 0.25 × 0.15 crystal system triclinic space group P1 a (Å) 11.029(2) b (Å) 12.203(2) c (Å) 13.128(2) R (deg) 90.28(1) β (deg) 107.85(1) γ (deg) 111.66(1) Z 4 temp (K) 293(2) R/Rw2 (obs data) 0.0500/ 0.1270 S 0.956

9

10

11

12

13

14

15

C12H20N4O2 252.32 0.35 × 0.25 × 0.15 triclinic P1 8.806(3) 12.868(4) 14.701(6) 67.09(2) 72.54(4) 69.90(3) 4 293(2) 0.0471/ 0.1005 0.825



C18H21N3O5 359.38 0.35 × 0.25 × 0.10 orthorhombic P212121 9.793(1) 13.528(2) 13.711(2) 90.0 90.0 90.0 4 293(2) 0.0381/ 0.0757 0.811

C17H19N3O5 345.35 0.40 ¥ 0.40 × 0.30 orthorhombic P212121 9.386(2) 12.653(3) 14.729(3) 90.0 90.0 90.0 4 203(2) 0.0364/ 0.0964 1.022

C10H13N3O5 255.23 0.50 ¥ 0.50 × 0.15 monoclinic P21/c 14.028(2) 9.891(2) 8.676(1) 90.0 101.82(1) 90.0 4 203(2) 0.0536/ 0.1504 1.082

C14H15N3O3 273.29 0.50 × 0.40 × 0.15 orthorhombic P212121 8.773(5) 9.813(5) 30.814(18) 90.0 90.0 90.0 8 203(2) 0.1013/ 0.2242 0.879

4-Methoxycarbonyl-5-[(p-methylbenzylamino)carbonyl]-1H-imidazole (15). To a dry round-bottom flask under argon was suspended 0.300 g (0.958 mmol) of 5H,10Hdiimidazo[1,5-a:1′-5′-d]pyrazine-1,6-dicarbonyl dichloride in 5 mL of dry methanol. The suspension was stirred for 10 min at gentle reflux under Ar before the solid was collected by vacuum filtration. The solid was added to 5 mL of dichloromethane and cooled to 0 °C, and a solution of p-methylbenzylamine (0.24 mL, 1.92 mmol) in dichloromethane was added dropwise. The solution was stirred at room temperature for 2 h before extracting consecutively with 10% citric acid, 1 M NaHCO3, water, and brine. The organic fraction was dried over MgSO4, filtered, and concentrated under vacuum. Crystallization from methanol provided 0.065 g (12%) of 15; mp 198201 °C; Rf ) 0.39 (EtOAc/hexanes, 7:3). 1H NMR (CDCl3): δ 10.40 (bs, 1 H), 7.39 (s, 1 H), 6.86-7.18 (m, 4 H), 4.39-4.47 (m, 2 H), 3.79 (s, 3 H), 2.18 (s, 2H). 13C NMR (CDCl3): δ 165.6, 158.7, 137.4, 136.7, 131.6, 130.3, 129.6, 127.7, 53.2, 43.8, 21.3. 3-[(Benzylamino)carbonyl]-4-ethoxycarbonyl-1H-pyrrole (16). mp 140-142 °C; Rf ) 0.21 (EtOAc/hexanes, 7:3). 1 H NMR (CDCl3): δ 10.96 (bs, 1 H), 10.53 (s, 1 H), 7.52 (s, 1 H), 7.24-7.36 (m, 7 H), 4.64 (s, 2 H), 4.27 (q, J ) 7.4 Hz, 2 H), 1.34 (t, J ) 7.4 Hz, 2H). 13C NMR (CDCl3) δ 166.7, 164.5, 138.9, 128.5, 128.1, 127.4, 126.9, 119.6, 111.8, 60.7, 43.3, 14.3. X-ray Crystallography. Samples for X-ray diffraction were obtained from the slow evaporation of methanolic solutions of the respective compounds with the exception of 3, which was grown from diethyl ether. Data were collected on a Siemens P4 four-circle diffractometer with a Bruker SMART 1000 CCD and integrated with SAINT in order to provide the observable reflections [Fo > 4sig(Fo)]. Crystal stabilities were monitored by measuring three standard reflections after every 97 reflections with no significant decay in observed intensities. A θ 2θ scanning technique was used for peak collection with Lorenz and polarization corrections applied. Hydrogen atom

Table 3. Selected Crystal Data Collection and Refinement Data for 16-18 crystal data

16

formula C15H16N2O3 weight (g mol-1) 272.30 crystal size (mm) 0.35 × 0.20 × 0.20 crystal system triclinic space group P-1 a (Å) 7.892(1) b (Å) 12.386(2) c (Å) 16.108(3) R (deg) 105.08(1) β (deg) 98.67(1) γ (deg) 107.96(1) Z 4 temp (K) 293(2) R/Rw2 (obs data) 0.0398/ 0.0764 S 0.820

17

18



positions were located from difference Fourier maps, and a riding model with fixed thermal parameters [uij ) 1.2Uij(eq) for the atom to which they are bonded] was used for subsequent refinements. In all structures, the SHELXTL PC and SHELXL-93 packages71 were used for data reduction, structure solution, and refinement. Crystal data for compounds 1-7, 8-15, and 16-18 are provided in Tables 1-3, respectively.

Results and Discussion Synthesis. The synthesis of the symmetric I45DCs 1-8, 17, and 18 was done from the pyrazine diacid dichloride through modification of known procedures (Scheme 1).58,65,72 The I45DCs with smaller alkyl chains

Imidazole-4,5-dicarboxylic Acid Derivatives

Crystal Growth & Design, Vol. 2, No. 6, 2002 657

Scheme 1

Figure 1. Representations of an extended conformation and intramolecular hydrogen-bonded folded conformation.

Scheme 2

(methyl and propyl) retain significant water solubility that reduces the isolated yields as compared with the I45DCs substituted with the more hydrophobic amines. An improved method for the synthesis of the dissymmetric I45DCs 9-11 was recently reported.73 The imidazoles substituted with both an amino acid and an ester were prepared by two different routes from the pyrazine diacid dichloride. Compound 12 was prepared by first adding L-valine benzyl ester hydrochloride to create an amino acid-substituted pyrazine, 19, which was ring-opened by gentle reflux in methanol. In contrast, pyrazine diester 20 was prepared from the diacid dichloride by stirring at room temperature with ethanol and to this intermediate was added either

L-phenylalanine methyl ester hydrochloride or glycine methyl ester hydrochloride in the presence of diisopropylethylamine in order to open the pyrazine and yield 13 and 14, respectively. Compound 15 was synthesized from the diacid dichloride by briefly heating with methanol, cooling, isolating the solids, resuspending in solvent, and adding p-methylbenzylamine followed by a workup. The pyrrole benzylamide ethyl ester 16 was isolated as a byproduct from an attempted synthesis of the pyrrole dibenzyl diamide from the pyrrole diethyl diester with 3 equiv of benzylamine in THF at room temperature (Scheme 2). Solution Intra- and Intermolecular Hydrogen Bonding for I45DCs. The formation of an intramolecular hydrogen bond in solution for the I45DCs is supported by the presence of two amide chemical shifts separated generally by 2-3 ppm in the 1H NMR spectrum of these compounds (e.g., 11.5 and 8.5 ppm).64-66,74 This chemical shift difference is observed whether in a hydrogen bond-promoting solvent such as chloroform or a hydrogen bond-disrupting solvent such as DMSO, is consistent throughout a wide concentration range (0.1 mM to 0.5 M), and is unexpected given that the imidazole ring tautomerization is expected to be fast on the NMR time scale. In these experiments, the imidazole NH chemical shift is quite concentrationdependentsmoving approximately 3 ppm over the concentration range noted aboveswhereas both amide NH’s are relatively unaffected (

Intramolecular Hydrogen Bonding and Intermolecular Dimerization in

Recommend Documents