Next Article in Journal
Comparative Study of Volatile Compounds in the Fruit of Two Banana Cultivars at Different Ripening Stages
Next Article in Special Issue
Synthesis of Gemcitabine-Threonine Amide Prodrug Effective on Pancreatic Cancer Cells with Improved Pharmacokinetic Properties
Previous Article in Journal
Measuring Artificial Sweeteners Toxicity Using a Bioluminescent Bacterial Panel
Previous Article in Special Issue
Ruthenium-Based Catalytic Systems Incorporating a Labile Cyclooctadiene Ligand with N-Heterocyclic Carbene Precursors for the Atom-Economic Alcohol Amidation Using Amines
Open AccessArticle

Density Functional Studies on Secondary Amides: Role of Steric Factors in Cis/Trans Isomerization

Department of Chemistry, UiT The Arctic University of Norway, N-9037 Tromsø, Norway
*
Authors to whom correspondence should be addressed.
Molecules 2018, 23(10), 2455; https://doi.org/10.3390/molecules23102455
Received: 1 September 2018 / Revised: 21 September 2018 / Accepted: 21 September 2018 / Published: 25 September 2018
(This article belongs to the Special Issue Amide Bond Activation)
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. View Full-Text
Keywords: density functional theory; cis/trans isomerization; secondary amides; dipeptides; steric effects; tert-butyl; additivity principle density functional theory; cis/trans isomerization; secondary amides; dipeptides; steric effects; tert-butyl; additivity principle
Show Figures

Graphical abstract

MDPI and ACS Style

Thakkar, B.S.; Svendsen, J.S.M.; Engh, R.A. Density Functional Studies on Secondary Amides: Role of Steric Factors in Cis/Trans Isomerization. Molecules 2018, 23, 2455.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop