The Ritter reaction produces an amide through the SN1 substitution of an alkene or alcohol with nitrile in the presence of an acid. Advances in the reaction have enabled its application in the synthesis of various molecules, such as polymers and bioactive compounds. The harsh acidic conditions and lack of asymmetric methods limit the applications of the reaction. Ritter reactions have been catalyzed in milder conditions, but no catalytic, enantioselective methods exist in the literature. A computational investigation of chiral BINOL-derived Brønsted acids as potential catalysts for the Ritter reaction was done, as these acids can achieve the acidity needed for the reaction to proceed while also providing a scaffold for enantioinduction. In this work, DFT studies (B3LYP/6-31+G*) on Ritter reactions in the presence of an N-triflyl phosphoramide (NTP) acid were completed, as NTP acid was determined to successfully catalyze the reaction. Two benzylic alcohols, one with an additional <i>ortho</i>-hydroxy group, were used as the substrates in the example system, reacting with either acetonitrile or benzonitrile as the solvent electrophile. In the stereodetermining step, the transition states exhibited moderate enantioselectivity for the amide product with up to 3.2 kcal/mol difference in transition state energies. This predicts up to 99% ee for a given reaction of substrate with a nitrile. The enantioselectivity of the reaction is hypothesized to be controlled by a suite of non-covalent interactions between the substrate complex and the catalyst. Interactions between the nitrile and the aryl substituents at the 3,3'-positions of the BINOL backbone were identified to be particularly influential via NCI analysis. These substituents can be further modified to optimize enantioselectivity of the Ritter reaction.

Theoretical design of a Brønsted acid catalyst for asymmetric Ritter reactions

ACS Spring 2022

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