Kinetics of Solvolyses of Various N-Alkyl-N-nitrosoureas in Neutral and Alkaline Solutions

Abstract

The N- alkyl- N -nitrosoureas possess antitumor activity but readily decompose at the pH of biological fluids with half-lives about 20 minutes at pH 7 and 37.5°. The effect of substituents, R, on the kinetics of solvolysis of synthesized R─N─(NO)─CO─NH 2 was determined in the phosphate buffer region, pH 6–7.8, as a basis for the proper design of biologically effective compounds. Spectrophotometric techniques were used over a range of several temperatures. The solvolytic rates were first order in substrate and hydroxyl ions and the log k -pH profile was linear with a slope of + 1.0. No solvent or general acid-base catalysis was observed, and salt effects were negligible. No significant differences in reactivities, entropies, or heats of activation were observed for R = methyl, ethyl, and butyl. The 2-methylpropyl was slightly more reactive. When R = allyl, phenethyl, and benzyl, a significant increase in reactivities was observed. The unsaturated substituents favored hydroxyl ion attack as expected. However, the cyclohexyl compound also had high reactivity to hydroxyl ion attack.