A series of ketoimines bearing pendant quinolyl substituents were prepared by Schiff base condensation of 1,3-diketones with two different substituents: trifluoromethyl and an alkyl/aryl group (e.g., Me, Et, iPr, tBu, Ph). Synthetic reactions of ketoimines with varying alkyl/aryl substituents altered the distribution of regioisomers as measured in isolated yields and detected by 1H and 19F NMR spectroscopy of crude reaction mixtures. Reactions with the least sterically encumbered diketones (CF3 with Me) resulted in mixture of ketoimines with quantitative formation of the ketoimine resulting from quinolyl addition to the carbonyl adjacent to the alkyl substituent. As the steric bulk of the hydrocarbon substituent increased (CF3 with Et, iPr, or Ph), the distribution of regioisomers flipped to a ratio which favored quinolyl addition adjacent to the trifluoromethyl substituent. Only a single ketoimine was isolated or observed with CF3 and tBu substituents with quinolyl addition adjacent to CF3. In order to investigate the role of steric and electronic influence of differing alkyl/aryl substitution, Density Functional Theory (DFT) calculations were employed to determine probable transition state structures as well as quantify differences in activation energy between the two regioisomer products. Transition state structures were calculated using QST3 calculations and verified with IRC calculations at the B3LYP level of theory. Comparisons between ΔΔG‡ determined by DFT agreed well with those calculated experimentally and supported steric driven regioselectivity for the series of ketoimines.

Experimental and theoretical investigation of regioselectivity for a series of ketoimines with nuclear magnetic resonance spectroscopy and density functional theory

ACS Spring Meeting 2021

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