Research Projects
:: Formation and Stability of Simple Quinone Methides
The parent p-quinone methide 1 and its relatives that contain the
quinone methide functionality have long attracted the interest of
discerning chemists. 1 can be thought of as a formally neutral benzylic
carbocation at which there is limiting resonance stabilization by electron
donation from a p-oxygen anion substituent to the cationic benzylic carbon.
This strong interaction results in a high kinetic stability of, and large
nucleophile selectivities towards, quinone methides, and is responsible in
part for the interesting biological activity observed for more complex
quinone methides.
We have used two simple quinone methides as platforms to address several
general questions about the effect of this very strong delocalization of
charge on electrophilic reactivity.
(1) We have shown by several criteria of their chemical reactivity that
quinone methides behave as a member of the larger class of strongly
resonance-stabilized carbocations, where resonance stabilization is
provided by electron-donation from the 4-alkoxy substituent. See
Journal of the American Chemical Society, 122, 1664-1774 (2000).
(2) There have been few measurements of rate and equilibrium constants
for addition of halide ions to weakly reactive electrophiles, because these
anions do not form stable adducts to such electrophiles. The adducts of
halide ions to 2 (2-Nu, Scheme 1) are likewise unstable; however, rate and
equilibrium data for their formation can be obtained by coupling
nucleophile addition to protonation of the phenoxide oxygen of 2-Nu- to
give H-2-Nu (Scheme 2). We have reported report rate and equilibrium data
for the addition of halide and acetate ions to 1, which allows for
extension to these nucleophiles of the well-known Ritchie N+ relationship
for carbocation-nucleophile addition reactions. See
Journal of the American Chemical Society, 122, 1664-1774 (2000).
(3) We are interested in understanding how the transition state for
nucleophile addition changes with extreme changes in electrophile
reactivity. We have reported that the Broensted parameter
βnuc = 0.11 for
addition of strongly nucleophilic thiol anions to the weak electrophile 2,
with rate constants kNu = 3 x 106 M-1 s-1, is significantly smaller than
βnuc = 0.32 for addition of weakly nucleophilic alcohols to the
1-(4-methoxyphenyl)ethyl carbocation, with rate constants kNu = 1 x 107 M-1
s-1. This striking observation of similar rate constants, but very
different values of βnuc, for two related carbocation-nucleophile addition
reactions provides interesting insight into the nature of the reaction
coordinate profiles for nucleophile addition. See
Journal of the American Chemical Society, 122, 11073-11084 (2000).
(4) We have used 2 in the first direct comparison of the reactivities of
thiol anions (RS-), thiols (RSH) and sulfides (RSR) towards carbocations.
Such a comparison is difficult because thiol anions are strongly
nucleophilic and undergo activation-limited addition only to relatively
stable carbocations, and these carbocations do not form stable adducts with
the much more weakly nucleophilic sulfides. Our data show that the effect
of substitution of Me for H at RSH on nucleophilic reactivity in water is a
significant fraction of that expected for reaction in the gas phase, where
the greater polarizability of the methyl group provides strong
stabilization of positive charge at sulfur. See
Journal of the American Chemical Society, 122, 11073-11084 (2000).
(5) We have compared rate and equilibrium date for 1,6 addition of water
to the simple quinone methide 1 with the corresponding data for the
1,2-addition of water to the simple carbonyl group at formaldehyde. This
comparison provides much insight into the effect of formation of the
aromatic ring in the product of 1,6-addition on the thermodynamic driving
force for addition of water to p-quinone methide 1. See
Journal of the American Chemical Society, 125, 8814-8819 (2003).
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