The kinetics and primary isotope effect for reduction of acridinium ions by a NAD(P)H “model”; facts and fallacy

A kinetic study of the reduction of the 10-methyl-9-phenylacridinium ions (AcPh⊕) by 1-benzyl-1,4-dihydronicotinamide (PyH2) is presented. The primary kinetic isotope effect (kH/kD = 4.5) of this reaction equals the product isotope partitioning observed upon reduction with mono C-4 deuterated 1-benzyl-1,4-dihydronicotinamide (PyHD). Furthermore, the rate constant for the reduction decreases upon increasing the solvent polarity. This behaviour contrasts with that reported for the reduction of the 10-methylacridinium ion (AcH⊕) where acceleration due to increased solvent polarity and significant discrepancies between the kinetic isotope effect and the product isotope partitioning have been observed. Reinvestigation of the latter process by means of kinetic measurements and via a competition experiment, involving reduction with equal amounts of PyH2 and the dideuterated species (PyD2), shows that the kinetic data and especially the kinetic isotope effect data are easily subject to experimental error. Thus it is shown that an intolerable inaccuracy is introduced if the value of kH/kD is determined by comparing the rate of reduction with PyH2 with that of PyHD rather than by comparing those of PyH2 and PyD2. Furthermore, the kinetic data in protic solvents for AcH⊕, but not for AcPh⊕, are found to be disturbed by a reversible side reaction. This reaction is thought to involve formation of a covalent adduct by attack of PyH2 at the electrophilic C-9 position of AcH⊕. The less electrophilic nature of this position in AcPh⊕ prevents such adduct formation and leads to uncomplicated kinetic behaviour in all the solvent systems investigated.