A predictive journey towards trans-thioamides/amides

The cis-trans isomerization of (thio)amides was studied by DFT calculations to get the model for the higher preference for the cis conformation by guided predictive chemistry, suggesting how to select the alkyl/aryl substituents on the C/N atoms that lead to the trans isomer. Multilinear analysis, together with cross-validation analysis, helped to select the best fitting parameters to achieve the energy barriers of the cis to trans interconversion, as well as the relative stability between both isomers. Double experimental check led to the synthesis of the best trans candidate with sterically demanding t-butyl substituents, confirming the utility of predictive chemistry, bridging organic and computational chemistry.

Automated summary

The cis-trans isomerization of (thio)amides was investigated using DFT calculations to develop a model that explains the higher preference for the cis conformation. The study suggests a method for selecting alkyl/aryl substituents on the C/N atoms that favor the trans isomer. Multilinear analysis, combined with cross-validation analysis, was used to identify the best fitting parameters for the energy barriers of the cis to trans interconversion and the relative stability between the two isomers. Experimental verification confirmed the synthesis of the best trans candidate with sterically demanding t-butyl substituents, demonstrating the utility of predictive chemistry in bridging organic and computational chemistry.