Cis Conformational Preference Research Articles

Conformational Properties of Aromatic Amides Bearing Imidazole Ring and Acid-Induced Trans–Cis Amide Switching

Aromatic amides bearing secondary amide bond exist in trans conformation both in the crystal and in solution, whereas the conformation of the N-methylated derivatives is cis in the crystal and predominantly cis in various solvents. The cis conformational preference of N-alkylated benzanilide provides access to aromatic foldamers such as oligo(N-alkyl-p-benzamide)s, which adopt dynamic helical structures. Here, the conformational properties of imidazole-substituted amide in the crystal and in solution were examined. Imidazole-substituted amides 2a and 4a existed mainly in the cis conformation in solution. The ratio of the cis conformer of N-methyl-N-(1-methyl-1H-imidazol-4-yl)benzamide (4a) was smaller than that of N,1-dimethyl-N-phenyl-1H-imidazole-2-carboxamide (2a) or N-methylbenzanilide, but the introduction of a substituent strongly affected the conformer ratio. Compounds 6a and 7a bearing an electron-withdrawing group on the imidazole ring existed predominantly in trans form. On the other hand, the introduction of an electron-withdrawing group on the phenyl ring or a bulky substituent on the amide nitrogen of 4a increased the ratio of cis conformer. Further, the major conformer of N-alkylated N-imidazolylamides was switched from cis to trans by the addition of acid. These results suggest that imidazole-substituted amides might be applicable as conformational switches in aromatic foldamers to enable environment-dependent structural change.

Preference of cis-Thioamide Structure in N-Thioacyl-N-methylanilines.

The thioamide group represents a highly attractive isostere of the amide bond. We report a combined structural and computational study on cis-thioamide conformation of N-thioacyl-N-methylanilines. Amide to thioamide replacement in a class of anilides that are highly valuable as conformational locks results in a higher preference for cis conformation in a unique compacted template intrinsic to the thioamide structure. The study strongly supports the use of N-methylthioanilides as cis-conformational locks in various facets of chemistry.

N-Ethynylation of Anilides Decreases the Double-Bond Character of Amide Bond while Retaining trans-Conformation and Planarity.

Activated amide bonds have been attracting intense attention; however, most of the studied moieties have twisted amide character. To add a new strategy to activate amide bonds while maintaining its planarity, we envisioned the introduction of an alkynyl group on the amide nitrogen to disrupt amide resonance by nN→Csp conjugation. In this context, the conformations and properties of N-ethynyl-substituted aromatic amides were investigated by DFT calculations, crystallography, and NMR spectroscopic analysis. In contrast to the cis conformational preference of N-ethyl- and vinyl-substituted acetanilides, N-ethynyl-substituted acetanilide favors the trans conformation in the crystal and in solution. It also has a decreased double bond character of the C(O)-N bond, without twisting of the amide. N-Ethynyl-substituted acetanilides undergo selective C(O)-N bond or N-C(sp) bond cleavage reactions and have potential applications as activated amides for coupling reactions or easily cleavable tethers.

Novel Helical Foldamers Based on the Conformational Properties of Aromatic Amides

In this review, we focus on our recent work on the development of novel helical foldamers based on the cis conformational properties of aromatic amide bonds. First, we describe the conformational properties of N-alkylated pyrroleamides and their oligomers. The conformation of the amide bond on the pyrrole ring is altered by N-alkylation, and the ratio of the cis conformer is lower in N-methylated amides with an N-pyrrole ring compared with that in N-methylbenzanilide. Pyrrole-containing oligomers, in which benzene and pyrrole rings are linked alternately by amide bonds with chiral N-substituents, show significant CD signals that depend on the chain length, temperature, and solvent properties, indicating that the oligoamides take folded conformations in solvents. Second, we describe the design and synthesis of alternately N-alkylated aromatic oligoamides as novel helical oligoamides with larger cavities compared with those of poly(N-alkylated p-benzamides). Spectroscopic studies and calculated optimized structures indicate that these oligoamides adopt helical structures with a cavity of about 9 Å in diameter. Finally, we describe the synthesis of a series of strained aromatic oligoamide macrocycles based on the cis conformational preference of the aromatic N-alkylated amide bond, building on the work of Huc et al. on the construction of large macrocycles by cyclization of helical quinoline oligoamides. The crystal structures are also presented. Our findings demonstrate that N-alkylated amides with the cis conformation are useful building blocks for unique aromatic foldamers.

Conformational Properties of Aromatic Oligoamides Bearing Pyrrole Rings.

N-Alkylbenzanilides generally exist in cis conformation both in the crystalline state and in various solvents, and this cis conformational preference can be utilized to construct dynamic helical oligoamides. Here, we synthesized the pyrrole-containing amides 2-5 and their oligomers 6-8 and examined their conformations in the crystalline state and in solution. All the N-methylated amides showed cis conformational preference in solution, but the ratio of the cis isomer was decreased when the amide bond was attached at the 4-position of the pyrrole ring, probably because the destabilization of the trans conformer due to electronic repulsion between the pyrrole π electrons and the amide carbonyl lone-pair electrons is reduced due to the small torsion angle between the 5-membered N-pyrrole and the amide bond. In the crystalline state, N-methylated amides showed cis structure, except for compound 5, and cis conformational preference was observed for the pyrrole amides. The CD spectra of oligoamides 15-18 bearing chiral N-substituents were consistent with the presence of dynamic and well-defined chiral foldamers, which were structurally distinct from N-alkylated poly( p-benzamide)s 1.

The Building Blocks of Cellulose: The Intrinsic Conformational Structures of Cellobiose, Its Epimer, Lactose, and Their Singly Hydrated Complexes

A combination of vibrational spectroscopy conducted under molecular beam conditions and quantum chemical calculation has established the intrinsic three-dimensional structures of the cellulose disaccharide and, focusing on the critical beta1,4-linkage at the nonreducing end of the growing cellulose polymer, its C-4' epimer. Left to their own devices they both adopt a cis (anti-phi/syn-psi) glycosidic configuration, supported in the epimer by strong, cooperative inter-ring hydrogen bonding. In the cellulose disaccharide, however, where the OH-4'(Glc) group is equatorial, the cooperativity is reduced and the corresponding inter-ring hydrogen bonding is relatively weak. The cis conformational preference is still retained in their singly hydrated complexes. In the cellulose disaccharide insertion of the water molecule at the favored binding site between OH-4' and the neighboring hydroxyl group OH-6' promotes a structural reorganization to create a configuration that parallels that of its unhydrated epimer and greatly strengthens the inter-ring hydrogen bonding. In the C-4' epimer, the axial orientation of OH-4' blocks this binding site and the bound water molecule simply adds on at the end of the (OH-O)(n) chain, which has a negligible effect on the (already strong) inter-ring bonding. The implications of these results are discussed with respect to the structure and insolubility of native cellulose polymers.

環境応答型芳香族アミド化合物の構造変換と動的制御

The three–dimensional structure and the dynamic behavior of a molecule is important issue for regulating the molecular function or biological activity. Recently the development of functional molecular devices that undergo reversible conformational interconversion between two or more stable states when exposed to an external stimulus, such as light, electricity or a chemical reaction, has received much attention. In our investigations on the cis conformational preference of aromatic N–methylated amides, we found several aromatic amides altered the stable conformations depending on the external stimulus. Namely, 3,5–bis (dimethylamino) –N–methylacetanilide (6) existed in cis form in CD2Cl2, while the addition of TFA–d caused the conformational alteration into trans form. Similarly, N– (2,5–dihydroxyphenyl) –N–phenylacetanilide (8) and N–phenylbenzohydroxamic acid (12) changed the amide conformation by redox reaction or solvent properties, respectively. N–Methylated pyridylamide also showed unique conformational properties. The stable conformation of the diamide 16 is solvent–dependent, and the acceptor number of the solvent seems to be significant. These pyridylamides and the oligomers changed the conformation by addition of acid. Further, we demonstrated the conformational change of the amide molecules could be detected by fluorescence spectra. These properties of the aromatic amides would be applied to the molecular switch or fluorescent sensors towards some external stimulus.

ChemInform Abstract: Aromatic Architecture Based on cis Conformational Preference of N-Methylated Amides

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A layered artificial dinucleotide complex

An X-ray diffraction analysis of the 1:1 complex of N, N′-dimethyl- N, N′-bis[2-(3-methylureido)pyrid-5-yl]urea ( 1) and a 1, 3-bis(cytosyl)propane derivative ( 2a) revealed layered triply-hydrogen-bonded pairings. The conformation of 1 in the complex is similar to that in the crystal structure of 1 alone, with anti conformation of the two aromatic rings. A unique heterodimer formation with aromatic layered structure is formed between artificial nucleotide analogs 1 and 2a, based on the cis conformational preference of 1. [Display omitted]

Facile formation of aromatic cyclic N-methylamides based on cis conformational preference

Treatment of meta-(methylamino)benzoic acid ( 2) with tetrachlorosilane afforded several cyclic oligomers ( 3 – 6). All the amide bonds of the four oligomers are cis in the crystal. 1H-NMR spectra of the trimer 3 showed the existence of an equilibrium between chiral truncated cone ( syn) and anti conformations.