Quinone methides and related electrophiles represent a common class of intermediates that form during metabolism of drugs and xenobiotics and may lead to DNA alkylation. The intrinsic reactivity of these species has now been characterized using a stable model compound, O-(tert-butyldimethylsilyl)-2-bromomethylphenol, designed to generate an o-quinone methide in the presence of fluoride. The resulting deoxynucleoside adducts were assigned unambiguously through use of two-dimensional NMR and,in particular, heteronuclear multiple-bond connectivity (HMBC); Both purines, dG and dA, reacted at their exo-amino groups. In contrast, dC had previously been shown to react at its cyclic N3 position [Rokita, S. E.; Yang, J.; Pande, P.; Greenberg, W. A. J. Org. Chem. 1997, 62, 3010-3012], and the relatively nonnucleophilic T remained inert under all conditions examined. Surprisingly, the efficiency of cytosine modification exceeded that of adenine and guanine by more than 10-fold in competition studies with the deoxymononucleosides. Reaction of all residues was suppressed in duplex DNA, but none was affected more than cytosine (>3600-fold). Guanine consequently emerged as the predominant target in duplex DNA in accord with the selectivity of most natural products forming quinone methide-like species. These general observations may then in part reflect the ability of the exo-amino group of guanine to maintain its reactivity most effectively from nucleoside to helical DNA.