Density Functional Studies on Secondary Amides: Role of Steric Factors in Cis/Trans Isomerization
| Autor: | Balmukund S. Thakkar, John S. Svendsen, Richard A. Engh |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Methyl Ethers
Steric effects tert-butyl additivity principle Pharmaceutical Science VDP::Mathematics and natural scienses: 400::Chemistry: 440::Theoretical chemistry quantum chemistry: 444 010402 general chemistry 01 natural sciences secondary amides Article Analytical Chemistry lcsh:QD241-441 chemistry.chemical_compound lcsh:Organic chemistry Computational chemistry Enzymatic hydrolysis Organisk kjemi / Organic chemistry Drug Discovery Peptide bond dipeptides Physical and Theoretical Chemistry density functional theory Glycylglycine 010405 organic chemistry Hydrolysis Organic Chemistry Stereoisomerism Amides Cis trans isomerization VDP::Matematikk og naturvitenskap: 400::Kjemi: 440::Teoretisk kjemi kvantekjemi: 444 0104 chemical sciences cis/trans isomerization Kinetics chemistry Chemistry (miscellaneous) Thermodynamics Molecular Medicine Density functional theory Peptides Isomerization Cis–trans isomerism steric effects |
| Zdroj: | Molecules Volume 23 Issue 10 Molecules, Vol 23, Iss 10, p 2455 (2018) Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry |
| Popis: | Source at https://doi.org/10.3390/molecules23102455 . 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. |
| Databáze: | OpenAIRE |
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