Steric effect in alkylation reactions by N‐alkyl‐N‐nitrosoureas: a kinetic approach

Abstract

The alkylation reactions of 4-( p-nitrobenzyl)pyridine (NBP), a trap for alkylating agents with nucleophilic characteristics similar to DNA bases, by five N-alkyl-N-nitrosoureas (methyl-, ethyl-, propyl-, butyl-, and allylnitrosourea) were investigated in 7:3 (v/v) water/dioxane medium in the 5.0-6.5 pH range. Decomposition of alkylnitrosoureas (ANU) gives rise to alkyldiazonium ions that yield NBP-R adducts directly or through carbocations in certain instances. The NBP alkylation rate constants by these species were determined. The following sequence of alkylating potential was found: methyl-> ethyl-> allyl-> propyl-> butyl group. Application of Ingold-Taft correlation analysis to the kinetic results revealed that the NBP alkylation reactions occur mainly through steric control. The values of the molar absorption coefficients of the NBP-R adducts also reveal the determinant influence of a steric effect in the formation of alkylation adducts. The kinetic results are consistent with the biological activity of ANU.

Alkylating potential of N‐phenyl‐N‐nitrosourea

“…The value of the rate constants for NBP alkylation by phenylnitrosourea is consistent with its biological activity in comparison with other nitrosoureas. [9] The NBP alkylation rate constant by the methyldiazonium ion (previously calculated with data from [5] and [20] ) is about 20,000-fold greater than that of the phenyldiazonium ion. This result is consistent with their relative biological activities, can be observed in Table 2.…”

“…In the 5.0-6.0 pH range, no dependence on the acidity of the medium was observed, unlike other nitrosoureas. [5] Therefore, the mechanism of the NBP alkylation by PhNU, through the formation of the benzenediazonium ion, which is more stable than aliphatic alkyldiazonium ions, must be different from that of other nitrosoureas. Since the intercept of the k 1 /[NBP] plot is not significantly different from 0 ( Fig.…”

“…Integration of Eqn (1) gives Figure 3 shows the fitting of the experimental data to Eqn (5). In order to calculate the alkylation rate constant, k alk (Scheme 1), experiments at different [NBP] were carried out (Fig.…”

“…We found that these alkylation reactions occur mainly through steric control. [5] Due to its instability, N-phenyl-N-nitrosourea [6] (PhNU) is easily hydrolyzed to a benzenediazonium ion (PhN þ 2 ) [7] and induces local tumors in rats. [8] However, painting PhNU on mouse skin failed or induced few skin tumors.…”

The reactivity of vinyl compounds as alkylating agents

“…In previous work we studied the in vitro reactivity of several alkylating compounds capable of forming DNA adducts: sorbic acid [4] and sorbates [5], nitrosoureas [6,7], p-nitrostyrene oxide [8], and lactones [9][10][11][12]. The results revealed a correlation between the carcinogenicity of the substances and their reactivity with 4-(p-nitrobenzyl)pyridine (NBP), a trap for alkylating agents with nucleophilicity similar to that of DNA [13,14].…”