A Combined Experimental and Computational Investigation on the Unusual Molecular Mechanism of the Lossen Rearrangement Reaction Activated by Carcinogenic Halogenated Quinones

[Image: see text] The classic Lossen rearrangement is a well-known reaction describing the transformation of an O-activated hydroxamic acid into the corresponding isocyanate. In this study, we found that chlorinated benzoquinones (C(n)BQ) serve as a new class of agents for the activation of benzohydroxamic acid (BHA), leading to Lossen rearrangement. Compared to the classic one, this new kind of C(n)BQ-activated Lossen rearrangement has the following unique characteristics: (1) The stability of C(n)BQ-activated BHA intermediates was found to depend not only on the degree but also on the position of Cl-substitution on C(n)BQs, which can be divided into two subgroups. (2) It is the relative energy of the anionic C(n)BQ–BHA intermediates that determine the rate of this C(n)BQ-activated rearrangement, which is the rate-limiting step, and the Cl or H ortho to the reaction site at C(n)BQ is crucial for the stability of the anionic intermediates. (3) A pK(a)–activation energy correlation was observed, which can explain why the correlation exists between the rate of the rearrangement and the acidity of the conjugate acid of the anionic leaving group, the hydroxlated quinones. These findings may have broad implications for future research on halogenated quinoid carcinogens and hydroxamate biomedical agents.