CRYSTAL GROWTH & DESIGN 2006 VOL. 6, NO. 9 2007-2010
Articles Solvent-Dependent Conformational Switching of N-Phenylhydroxamic Acid and Its Application in Crystal Engineering Ryu Yamasaki,† Aya Tanatani,*,‡ Isao Azumaya,§ Hyuma Masu,§ Kentaro Yamaguchi,§ and Hiroyuki Kagechika*,| Graduate School of Pharmaceutical Sciences, and Institute of Molecular & Cellular Biosciences, The UniVersity of Tokyo, Tokyo, Japan, Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri UniVersity, Kagawa, Japan, and School of Biomedical Science, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental UniVersity, Tokyo, Japan ReceiVed March 17, 2006; ReVised Manuscript ReceiVed July 9, 2006
ABSTRACT: N-Phenylbenzohydroxamic acid (3) showed solvent-dependent conformational alteration. Thus, compound 3 exists predominantly in cis form (> 98%) in CD2Cl2, whereas the percentage of the cis isomer decreased to 49% in methanol-d4, and the trans conformer was major (77%) in acetone-d6. Solvent-dependent alteration of the amide conformation was observed only in the hydroxamic acids, and the ratio of the cis conformer (98% in CD2Cl2) of N-phenylbenzhydrazide (6) was little affected by the solvent. Two unique crystal structures were obtained depending on the recrystallization solvent, and each crystal corresponded in structure to the major conformer in the solvent. These two crystals of 3 were distinguished by IR spectroscopy and DSC analysis. Although the origin of the solvent-dependent conformational switching of 3 is unclear, the results could be applied to design and development of solvent- or external-stimuli-responsive molecular machines. Introduction Regulation of molecular conformations and dynamic behaviors is of great interest because of its potential utility in the construction of structurally well-ordered macromolecules or application to molecular recognition events and molecular switches.1 The amide linkage is one of the important building blocks, because conformations with restricted rotation are often influenced by the steric properties of the substituents and by hydrogen-bonding interactions.2 Artificial peptides with Nmethyl, N-hydroxyl, or N-amino groups have been theoretically and empirically investigated with the aim of understanding these effects.3 Previously, we reported that benzanilide (1) exists in trans form, whereas N-methylbenzanilide (2) exists in cis form, in the crystal and in various solvents (Figure 1).4,5 The cis conformational preference caused by N-methylation is a general property of aromatic amides, ureas, and guanidines. Hydroxamic acid is the amide derivative with an N-hydroxyl group and is important as a key functional group in bioactive substances or * Corresponding authors. Tel: 81-3-5841-7848 (A.T.); 81-3-5280-8032 (H.K.). Fax: 81-3-5841-8495 (A.T.); 81-3-5280-8127 (H.K.). E-mail:
[email protected] (A.T);
[email protected]. (H.K.). † Graduate School of Pharmaceutical Sciences, The University of Tokyo. ‡ Institute of Molecular & Cellular Biosciences, The University of Tokyo. § Tokushinma Bunri University. | Tokyo Medical and Dental University.
Figure 1. Cis conformational preference of N-methylbenzanilide (2).
Chart 1
chelating reagents,6 but its chemical characteristics are less well understood. Here, we describe the unique conformational behavior of N-phenylhydroxamic acids 3-5, which show different stable solution and crystal structures depending on the solvent.
10.1021/cg060151z CCC: $33.50 © 2006 American Chemical Society Published on Web 08/09/2006
2008 Crystal Growth & Design, Vol. 6, No. 9, 2006
Kagechika et al.
Experimental Section General. Melting points were determined using a Yanagimoto hotstage melting-point apparatus and are uncorrected. Elemental analyses were carried out in the Microanalytical Laboratory, Faculty of Pharmaceutical Sciences, The University of Tokyo, and were within (0.3% of the theoretical values. 1H NMR spectra were recorded on a JEOL JNM-GX400 (400 MHz) or a JEOL JNM-A500 (500 MHz) spectrometer for dynamic NMR experiments. Chemical shifts are expressed in parts per million relative to tetramethylsilane. X-ray data were collected on a Bruker Smart1000 CCD detector. The crystal structure was solved by direct methods using SHELXS-97 (Sheldrick, 1997) and refined by full-matrix least-squares SHELXL-97 (Sheldrick, 1997). IR spectra were recorded on a JASCO FT/IR460plus. Differential scanneing calorimetry (DSC) was performed on a Seiko Instruments Inc. DSC 6200 at a heating rate of 5 °C/min. N-Phenylbenzohydroxamic acid (3) was pursued from Tokyo Kasei Co. Ltd. and recrystalized before use. Synthesis of N-(4-Toluyl)benzohydroxamic Acid (4). The mixture of 4-nitrotoluene (2.60 g, 14.6 mmol), zinc powder (2.86 g, 20.9 mmol), and ammonium chloride (1.17 g, 17.9 mmol) in ethanol (10 mL) and water (20 mL) was warmed in a water bath for 30 min. The mixture was filtered on Celite, and the filtrate was extracted with AcOEt. After evaporation, the crude was purified by silica gel column chromatography (1:3 AcOEt:n-hexane) to afford N-(4-toluyl)hydroxylamine (838 mg; 47%). N-(4-Toluyl)hydroxylamine: Yellow powder; 1H NMR (400 MHz, CDCl3) δ 7.08 (d, 2 H, J ) 8.5 Hz), 6.90 (d, 2 H, J ) 8.4 Hz), 5.51 (br s, 2 H), 2.30 (s, 3 H). Benzoyl chloride (500 mg, 3.43 mmol) and pyridine (2 mL) were added to a solution of N-(4-toluyl)hydroxylamine (423 mg, 3.43 mmol) in CH2Cl2 (5 mL) at 0 °C. After 4 h, the mixture was poured into ice-water and extracted with AcOEt. The organic layer was washed with 2 M HCl and brine and dried over Na2SO4. After evaporation, the crude was purified by silica gel column chromatography (1:4 AcOEt: n-hexane) to afford 4 (537 mg, 67%). Compound 4: Colorless powder; 1 H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1 H), 7.39 (d, 2 H, J ) 8.4 Hz), 7.16 (d, 2 H, J ) 8.1 Hz), 2.28 (s, 3 H). Synthesis of (E)-N-(4-Bromophenyl)-3-(3-nitorophenyl)propenohydroxamic Acid (5). NaSH was added to a solution of 4-bromonitrobezene (5.00 g, 24.8 mmol) in benzene (30 mL), and the mixture was stirred for 2.5 h. Ammonium chloride (5.23 g) was added to the mixture. The organic layer was separated, and n-hexane was added carefully to give N-(4-bromophenyl)hydroxamine as yellow crystals (553 mg, 12%). N-(4-Bromophenyl)hydroxamine: 1H NMR (400 MHz, CDCl3) δ 7.37 (d, 2 H, J ) 6.8 Hz), 6.88 (d, 2 H, J ) 6.8 Hz), 6.75 (s, 1 H), 5.25 (s, 1 H). Thionyl chloride (20 mL) was added to a solution of 3-nitrocinnamic acid (10.3 g, 54.8 mmol) in dry benzene (40 mL), and the mixture was heated at reflux for 3 h. Removal of the solvent and excess thionyl chloride under a vacuum afforded 3-nitrocinnamoyl chloride as a white solid (11.2 g, 99%). The crude 3-nitrocinnamoyl chloride (782 mg, 3.69 mmol) and dry pyridine (1.5 mL) were added to a solution of N-(4-bromophenyl)hydroxamine (683 mg, 3.63 mmol) in dry CH2Cl2 (20 mL). The reaction mixture was poured into water and extracted with CH2Cl2. The organic layer was washed with 2 M HCl and brine and dried over Na2SO4. After evaporation, the residue was purified by silica gel column chromatography (1:3 AcOEt:n-hexane) to afford 5 (170 mg, 13%). Compound 5: Yellow prisms; 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1 H), 7.70 (s, 1 H), 7.39 (m, 2 H), 6.92 (m, 4 H), 6.74 (m, 3 H). Anal. Calcd for C15H11N2O4Br: C, 49.61, H, 3.05, N, 7.71, Found: C, 49.69, H, 3.26, N, 7.67. Synthesis of N-Phenylbenzhydrazide (6). Potassium carbonate (285 mg) was added to a solution of phenylhydrazine (1.193 g, 11.03 mmol) in CH2Cl2 (8 mL). (Boc)2O (2.532 g, 11.60 mmol) was added dropwise to the mixture at -20 °C. The mixture was stirred for 6 h at -20 °C and then filtered. After evaporation, the crude was recrystallized from AcOEt-n-hexane to give N′-Boc-phenylhydrazine (1.254 g, 55%). N′Boc-phenylhydrazine: Yellow platelet; 1H NMR (400 MHz, CDCl3) δ 7.23 (dd, 2 H, J ) 7.3, 7.7 Hz), 6.88 (t, 1 H, J ) 7.3 Hz), 6.82 (d, 2 H, J ) 7.7 Hz), 6.36 (s, 1 H), 5.72 (s, 1 H), 1.47 (s, 9 H). Benzoyl chloride (819 mg, 5.83 mmol) and pyridine (2 mL) was added to a solution of N′-Boc-phenylhydrazine (1.207 g, 5.80 mmol) in CH2Cl2 (8 mL) at -10 °C, and the mixture was stirred for 3 h at -10 °C. After removal of the solvent under a vacuum, the crude was purified by silica gel column chromatography 1:7 AcOEt:n-hexane) to
Table 1. Cis-Trans Ratio of N-Substituted Amides 1-7 compd 1 2 3 4 5 6 7
ratio of cis conformer at 183 K (%)a N-substituent in CD2Cl2 in CD3OD H CH3 OH OH OH NH2 OCH3
99b >99b 98 (-1.50) 50 (0)
99b 49 (0.018) 59 (-0.14) 3c 95 (-1.00) 63 (-0.19)
in (CD3)2CO 99b 23 (0.40) 33 (0.26) 98%) in CD2Cl2 at 183 K, and the
signals due to the minor trans conformer (2%) were observed at lower field (7.4-7.7 ppm; coalescence point: 228 K). The percentage of the cis isomer decreased to 49% in methanol-d4, and the trans conformer was major (77%) in acetone-d6 (183 K), as reported. Similar solvent-dependent conformational alteration was observed with 4. Further, the conformation of the hydroxamic acid 5, whose crystal structure (crystallized from methanol) was reported to be trans,7 is highly solvent-dependent, and the cis conformer in CD2Cl2 (>99%) and the trans conformer in methanol-d4 (97%) or acetone-d6 (99%) are predominant, respectively. At present, it is difficult to interpret the conformational behaviors in solution, but it is very interesting that a subtle change in solvent properties can cause significant amide conformational switching.14 Solvent-dependent alteration of the amide conformation was observed only in the N-hydroxyl derivatives among the amides listed in Table 1. Benzanilide (1) and N-methylbenzanilide (2) are predominantly in trans and cis form, respectively, in various solvents. An N-amino derivative, i.e., N-phenylbenzhydrazide (6), exists in the cis conformer (98%) in CD2Cl2, and the ratio of conformers is little affected by the solvent. In the case of
2010 Crystal Growth & Design, Vol. 6, No. 9, 2006
compound 7, the O-methylated analogue of 3, the energy difference between trans and cis conformers and the solvent dependency are small. The crystal structure of 3 was also affected by the solvent, and 3 afforded two different crystals depending on the solvent employed for recrystallization (Table 2). The crystals of 3 obtained from CH2Cl2 (crystal A, space group, Fdd2) contained the cis conformer, whereas the crystal from acetone contained the trans isomer (crystal B, space group, P21, Figure 2). The crystal structure of cis-3 is similar to that of 2, and the two benzene rings are located in the face-to-face position with a dihedral angle of 70.7° (67.4° in 2). The trans conformation of 3 has larger dihedral angles between the C-phenyl and amide planes (45.1 and 48.3°) and smaller dihedral angles between the N-phenyl and amide planes (20.4 and 17.9°)15 compared to the crystal structure of 1 (31.4 and 31.5°, respectively). Intermolecular hydrogen-bonding interactions between the carbonyl oxygen atom and hydroxyl group exist in both crystals. In crystal A, double hydrogen bonds between 2-folded cis molecules form a dimeric structure, whereas hydrogen-bonding chains are observed among trans conformers in crystal B. These two crystals of 3 were distinguished by IR spectroscopy, and further by DSC analysis. A single phase-transition point of crystal A appeared at 124.0 °C, whereas crystal B has two phasetransition points at 115.0 and 124.6 °C. These results indicate that crystal B containing the trans conformer transforms to the more stable crystal A containing the cis conformer, which melts at 124.0 °C. From the viewpoint of crystal engineering, both crystals are acentric, and crystal B is chiral, although 3 itself has no fixed asymmetric element. Further study of the phase/ conformation transition in the crystal states of 3 is in progress. A number of compounds afford several different crystals, known as polymorphism.15 Polymorphs arise form the molecular packing and/or conformation, often caused by multi-hydrogen bonding properties and conformational flexibility. The phenomenon observed here is classified as conformational polymorphism, in which each crystal contains different conformer.16,17 In contrast to the most conformational polymorphs, in which the energy barriers between the conformers are small, two conformers of compound 3 exist in rather slow interconversion in solution, and can be distinguished by 1H NMR. In conclusion, the N-phenylhydroxamic acid exhibited solventdependent conformational change. Several small molecules that change conformation depending on the solvent have been reported,2,18 and the phenomenon has a possible application in developing a molecular switch. At present, our observation is a simple example, and only the conformational ratio in equilibrium was detected as the output caused by external stimulus (the solvent property). However, there is no need to have systems with full conversion in the relevant signals for a molecular switch, as well-discussed in the field of logic gates.19 Further, N-phenylhydroxamic acid is unique because we can acquire crystals bearing the desired amide conformation, simply by choosing the appropriate recrystallization solvent. Although the origin of the solvent-dependent conformational switching is unclear and detailed empirical and theoretical studies are needed, the results obtained here could be applied to the design and development of solvent- or external-stimuli-responsive molecular machines and should be helpful in constructing functional amide molecules in the field of medicinal chemistry and materials science. Acknowledgment. This work was supported in part by Grants-in-Aid for Scientific Research from The Ministry of Education, Culture, Sports, Science and Technology, Japan.
Kagechika et al. Supporting Information Available: 1H NMR and IR spectra of 1-3, and the crystal structures of 3. This material is available free of charge via the Internet at http://pubs.acs.org.
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