Abstract
Cis/trans isomerization of amide bonds is a key step in a wide range of biological and synthetic processes. Occurring through C-N amide bond rotation, it also coincides with the activation of amides in enzymatic hydrolysis. In recently described QM studies of cis/trans isomerization in secondary amides using density functional methods, we highlighted that a peptidic prototype, such as glycylglycine methyl ester, can suitably represent the isomerization and complexities arising out of a larger molecular backbone, and can serve as the primary scaffold for model structures with different substitution patterns in order to assess and compare the steric effect of the substitution patterns. Here, we describe our theoretical assessment of such steric effects using tert-butyl as a representative bulky substitution. We analyze the geometries and relative stabilities of both trans and cis isomers, and effects on the cis/trans isomerization barrier. We also use the additivity principle to calculate absolute steric effects with a gradual increase in bulk. The study establishes that bulky substitutions significantly destabilize cis isomers and also increases the isomerization barrier, thereby synergistically hindering the cis/trans isomerization of secondary amides. These results provide a basis for the rationalization of kinetic and thermodynamic properties of peptides with potential applications in synthetic and medicinal chemistry.
Highlights
The chemistry of the amide bond has attracted the interest of chemists with diverse specializations.Its unique characteristics arise from the delocalization of electrons from nitrogen to the carbonyl group, which confers a partial double-bond character to the C-N bond and stabilizes a planar geometry with a relatively high energy rotational barrier that hinders the free rotation, giving rise to cis and trans isomers [1,2,3]
The resonance effect protects the amide moiety against nucleophilic attacks at the carbonyl carbon; it is a common practice to activate amides using Lewis acids for chemical transformation
Studies on enzymatic hydrolysis of amides have revealed that distortion in the amide bond planarity via C-N bond rotation results in amide bond activation, increasing susceptibility to nucleophilic attack [4,5,6]
Summary
Its unique characteristics arise from the delocalization of electrons from nitrogen to the carbonyl group, which confers a partial double-bond character to the C-N bond and stabilizes a planar geometry with a relatively high energy rotational barrier that hinders the free rotation, giving rise to cis and trans isomers [1,2,3]. The resonance effect protects the amide moiety against nucleophilic attacks at the carbonyl carbon (e.g., it is virtually immune to hydrolysis at ambient temperature and pH in non-enzymatic conditions); it is a common practice to activate amides using Lewis acids for chemical transformation. Cis/trans isomerization is one phenomenon whereby the amide moiety loses its planarity, as significant geometric and hybridizational changes occur throughout C-N bond rotation [7]. Information regarding the stabilities of cis and trans forms of amides, C-N bond rotation in terms of cis/trans isomerization, and relevant energy barriers can be useful for understanding the activation by deformation for a variety of amides, especially peptides
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