A detailed investigation into the oxidation mechanism of Hantzsch 1,4-dihydropyridines by ethyl alpha-cyanocinnamates and benzylidenemalononitriles

The mechanism for the oxidation of Hantzsch 1,4-dihydropyridine (HEH) by su bstituted ethyl alpha-cyanocinnamates (1) and benzylidenemalononitriles (2) has been critically investigated. Replacement of HEH by HEH-4,4-d(2) and H EH-N-d gave the observed kinetic isotope effects (KIE) of 5.3-6.0 and 1.2-1 .3 for the reactions with 1 and 2, respectively, which suggests C-4-H bond dissociation is involved in the rate-limiting step and that the N-H bond di ssociation is a non-rate-limiting step. The positive rho values of 1.78 and 1.67 for the reactions of HEH with 1 and 2, respectively, clearly demonstr ate the electrophilic nature of the substrates in the transition state (TS) and so indicate that the hydrogen lost from HEH must be a hydride-like spe cies. Correlation analyses on the kinetics, KIE's, and activation parameter s showed excellent linear dependence on the electronic properties of remote substituents and added further credence to the proposed one-step hydride t ransfer mechanism. Detailed investigation of the activation parameters not only confirmed the direct H-T(-) mechanism, but also revealed experimentall y, for the first time, an entropy-controlled compact TS for the HEH-modeled NAD(P)H oxidations.