Why Do N-Alkylated Anilides Bend Over? The Factors Dictating the Divergent Conformational Preferences of 2° and 3° N-Aryl Amides

Abstract

The conformational preferences of 28 sterically and electronically diverse N-aryl amides were determined using density functional theory (DFT), using the B3LYP functional and 6-31G­(d) basis set. For each compound, both the cis and trans conformers were optimized, and the difference in ground state energy calculated. For six of the compounds, the potential energy surface was determined as a function of rotation about the N-aryl bond (by 5° increments) for both cis and trans conformers. A natural bond orbital (NBO) deletion strategy was also employed to determine the extent of the contribution of conjugation to the energies of each of the conformers. By comparing these computational results with previously reported experimental data, an explanation for the divergent conformational preferences of 2° N-aryl amides and 3° N-alkyl-N-aryl amides was formulated. This explanation accounts for the observed relationships of both steric and electronic factors determining the geometry of the optimum conformation, and the magnitude of the energetic difference between cis and trans conformers: except under the most extreme scenarios, 2° amides maintain a trans conformation, and the N-bound arene lies in the same plane as the amide unless it has ortho substituents; for 3° N-alkyl-N-aryl amides in which the alkyl and aryl substituents are connected in a small ring, trans conformations are also favored, for most cases other than formamides, and the arene and amide remain in conjugation; and for 3° N-alkyl-N-aryl amides in which the alkyl and aryl substituents are not connected in a small ring, allylic strain between the two N-bound substituents forces the aryl substituent to rotate out of the plane of the amide, and the trans conformation is destabilized with respect to the cis conformation due to repulsion between the π system of the arene and the lone pairs on the oxygen atom of the carbonyl. The cis conformation is increasingly more stable than the trans conformation as electron density is increased on the arene because the more electron-rich arenes adopt a more orthogonal arrangement, increasing the interaction with the carbonyl oxygen, while simultaneously increasing the magnitude of the repulsion due to the increased electron density in the π system. The trans conformation is favored for 2° amides even when the arene is orthogonal to the amide, in nearly all cases, because the C–N–C bond angle can expend at the expense of the C–N–H bond angles, while this is not favorable for 3° amides.

Interrogation of the Structure–Activity Relationship of a Lipophilic Nitroaromatic Prodrug Series Designed for Cancer Gene Therapy Applications

“…Analytical HPLC and 1 H NMR analyses of compounds 2-4 demonstrated that they exist as a mixture of atropisomers [24] at ambient temperature. A well-described phenomena for tertiary aromatic amides bearing an ortho substituent wherein the aromatic ring and the amide plane are near perpendicular [25,26]. Hindered rotation about the amide bond results in two conformations that can interconvert slowly on an NMR timescale at ambient temperature and are hence detectable by NMR and characterized by chemical exchange effects in NMR experiments [27][28][29].…”

“…tert-Butyl 4-(ethylsulfonyl)-5-fluoro-2-nitrobenzoate (26). Reaction of compound 18 (24.4 g, 87.8 mmol) with tert-butyl acetate (150 mL) and perchloric acid (70%, 3.70 mL, 61.4 mmol), using the same procedure as described for 25, afforded the title compound 26 as pale-yellow crystals (20.5 g, 70%), M.p.…”

Synthesis of Indolo[2,3-c]quinolin-6(7H)-ones and Antimalarial Isoneocryptolepine. Computational Study on the Pd-Catalyzed Intramolecular C–H Arylation

“…For all intermediates, a conformational analysis was carried out considering the possibility of a rotation around the amide bond. Following the oxidative addition, the cis structure (shown in Figure ) is more stable than the trans conformer in the case of 5d-II , which agrees with the previous findings for tertiary N -aryl amides . After the coordination of the carbonate ( 5d-III ), the cis structure (shown in Figure ) is destabilized because of increased repulsion between the phenyl ring and the carbonate ion.…”

Analysis of Conformational Preferences in Caffeine

“… Specific hyperconjugative contributions from the methyl groups to the eight conformers in Figure 2 were obtained by deletion of all donor→acceptor interactions involving the methyl groups. Hyperconjugation effects on molecular geometries: following a strategy suggested elsewhere [ 29 , 78 , 79 , 80 , 81 , 82 ], geometry optimizations for the rotations of the methyl groups within the lowest energy structure were carried out by deleting all hyperconjugative interactions involving each methyl group separately and then involving all methyl groups simultaneously. …”

“…Hyperconjugation effects on molecular geometries: following a strategy suggested elsewhere [ 29 , 78 , 79 , 80 , 81 , 82 ], geometry optimizations for the rotations of the methyl groups within the lowest energy structure were carried out by deleting all hyperconjugative interactions involving each methyl group separately and then involving all methyl groups simultaneously.…”