Micellar Catalysis of Organic Reactions. XXX. A Study of the Mechanism of Hydrolysis of Oxazepam and 2'-Methyldiazepam in the Presence of Micelles and in Water

Abstract

Acidic hydrolysis of oxazepam in water involved initial azomethine cleavage at low acid concentrations (0.1-0.2 M) with initial amide hydrolysis occurring concurrently at higher acid concentrations (0.3-0.6 M). In the presence of micelles of sodium dodecyl sufate the percentage of initial amide cleavage increased.

For the basic hydrolysis of oxazepam in water the rate was dependent on [ NaOH ] indicating at least some initial amide hydrolysis. At higher base concentrations the rate became independent of [ NaOH ], because of the ionization of the NH group of oxazepam, producing an unreactive nitranion. In the presence of cetyltrimethylammonium bromide, the rate of basic hydrolysis was slower than in water, due to the increased amount of ionization in the presence of micelles.

Acidic hydrolysis of 2′-methyldiazepam in water was independent of [ HCl ] in the range 0.1-0.3 M, indicating initial azomethine hydrolysis. The rate was slower than for diazepam itself, indicating the existence of steric hindrance by the 2′-methyl group to water attack at C5.

In basic solution, a biphasic reation was observed. The rate of the first phase was dependent on [ NaOH ], indicating the presence of initial amide hydrolysis for 2′-methyldiazepam, cf. initial azomethine hydrolysis for diazepam. At high base concentrations, a greater than first-order dependence on base concentration was observed. This was attributed to the formation of dianionic intermediates, as previously reported for the hydrolysis of similar anilides at high base concentrations.