AbstractThe relationship between S‐ and N‐alkylating reactivity and herbicidal activity within a series of chloroacetamides, including several commercial herbicides and newly synthesised analogues was studied. The S‐alkylating reactivity of selected chloroacetamides, as well as those of atrazine and chlorfenprop‐methyl, was determined by in vitro GSH conjugation at a ratio of GSH to alkylating agent of 25 : 1. A spectrophotometric reaction using 4‐(4‐nitrobenzyl)pyridine was used to characterise the N‐alkylating reactivity of the chemicals. Our results indicate that a reduced level of N‐alkylating reactivity correlates with an improved herbicidal efficacy at a practical rate. However, the phytoxicity of the molecules is not simply dependent on chemical reactivities, but strictly related to the molecular structure, indicating that lipophilicity, uptake, mobility and induction of detoxifying enzymes may also be decisive factors in the mode of action.© 2002 Society of Chemical Industry