Kinetics and mechanism of tetrazole-catalyzed phosphoramidite alcoholysis

Kinetics of the tetrazole-catalyzed reaction of diisopropyl N,N-diisopropylphosphoramidite (1b) with tert-butyl alcohol has been studied by 31P NMR spectroscopy in THF, and the results obtained have been compared to those observed for the possible partial reactions involved, viz. the formation of diisopropyl tetrazolylphosphite (2b) and its subsequent alcoholysis. The stoichiometry of the processes was first examined with dimethyl N,N-diisopropylphosphoramidite (1a) in MeCN. The tetrazole-promoted disappearance of 1b is as fast in the absence and in the presence of the alcohol: the alcoholysis of 1b is zero-order in the concentration of alcohol and second-order in the concentration of tetrazole. The reaction of 1b with tetrazole is independent of the concentration of the tetrazolide anion and second-order in that of tetrazole, while the reverse reaction, aminolysis of 2b is first-order in the concentration of the amine. The alcoholysis of 2b is, in turn, first-order in the concentration of alcohol and second-order in that of tetrazole, but it also proceeds, although slowly, in the absence of tetrazole. The time-dependent product distribution of the alcoholysis of 1b shows intermediary accumulation of 2b, but at a lower level than could be predicted by applying the rate constants determined independently for the assumed partial reactions. Accordingly, tetrazole-catalyzed alcoholysis of 1b is shown to proceed at least mainly via 2b, but an additional pathway not involving 2b as an intermediate is proposed. Mechanisms of the partial reactions are discussed on the basis of the formal kinetics observed.