Probing the structural and electronic effects to stabilize nonplanar forms of thioamide derivatives: A computational study

Abstract

Density functional calculations have been performed to examine the stability of nonplanar conformations of thioamide derivatives. Electrostatic, orbital, and ring strain effects were invoked to stabilize the nonplanar conformations of thioamide systems 2-7. Electrostatic interactions helped to achieve the twisted forms of thioamide derivatives; however, pyramidal forms predicted to be the global minimum. Negative hyperconjugative type interactions enhanced the stability of the twisted form 4b when compared with the planar form 4a. The influence of ring strain effect to achieve the twisted form of thioamide was observed with azirine ring. The predictions made with B3LYP/cc-pVDZ+ level of theory was found to be in good agreement with more accurate CBS-QB3 method. The solvent calculations performed with polarized continuum solvation model suggest that the relative stabilities of the nonplanar forms of thioamide derivatives are in general similar to the gas phase results. The importance of hydrogen bonding interactions between the solvent molecules and thioamide derivatives was observed toward the enhanced stability of twisted forms using a combination of explicit solvent molecules and continuum model. The natural bond orbital analysis confirmed the participation of n(N) → π*(C=S) delocalizations in the planar forms and corroborated the earlier reports on larger delocalizations in thioamide systems. Furthermore, the influence of electrostatic and ring strain effects on the amide, natural amides, and selenoamide has also been studied.

Chemistry of Bridged Lactams and Related Heterocycles

“…These include enhanced reactivity toward amide bond hydrolysis 61–66 and toward nucleophilic attack at the carbonyl atom, 67–69 different regiochemistry of amide protonation and alkylation reactions, 70–74 different spectroscopic 16–18,75 and physical properties. 76–83 Besides the insight that such compounds provide into the nature of the amide bond, twisted amides are analogous to the transition state encountered by peptides as they undergo cis-trans isomerisation, 84–87 a critical feature of protein folding.…”

“…Owing to the fact that the lone pair of electrons of the nitrogen atom is no longer in conjugation with the adjacent π orbitals of the carbonyl group, , bridged amides have properties that differ from those of planar amides. These include enhanced reactivity toward amide bond hydrolysis − and toward nucleophilic attack at the carbonyl atom, − different regiochemistry of amide protonation and alkylation reactions, − and different spectroscopic − , and physical properties. − Besides the insight that such compounds provide into the nature of the amide bond, twisted amides are analogous to the transition state encountered by peptides, as they undergo cis–trans isomerization, − a critical feature of protein folding.…”

Endothioxopeptides: A conformational overview

“…The data obtained suggest that the n N → π * CSe electron delocalization is governed by the π ‐donor character of the substituents at the C sp2 atom rather than by their electron‐withdrawing nature. In another study, it was found that the propensity to adopt the twist conformation is higher in the case of the CONH amides if compared to those of the sulfur‐ or selenium‐based amides …”

Does hydrohalic acid HX (X = F, Cl) form true N-protonated twisted amide salts? Effects of anions on the ion-pair interactions and on the amide moiety in N-protonated tricyclic twisted amide salts

“…In contrast to planar amides, the synthesis, structure, bonding and reactivity of bridged twisted amides have been less investigated. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] In bridged twisted amides a non-planar (or twisted) amide bond is achieved by incorporating nitrogen at the bridgehead position. Twisted amides have been invoked in a variety of enzymatic transformations, including peptide hydrolysis, [18][19][20][21] protein splicing, [22][23][24][25] and the cis-trans isomerization of peptidyl-proline bonds.…”