Hemiacetal Formation with a Phenol Nucleophile: Simple Proton Transfers as Rate-Limiting Steps

Article abstract of DOI:10.1021/ja00305a022

A kinetic study is reported of the reversible cyclization in cacodylic acid buffers (pH 5.3-6.5) of (Z)-2'-hydroxy-4-methoxy-α-methylchalcone (C) to its cyclic hemiacetal isomer 2-hydroxy-2-(4-methoxyphenyl)-3-methylflav-3-ene (B).Rate-buffer plots for experiments at constant pH exhibit a complex curvature.It is proposed that there are three regions of behavior: very dilute buffers, with a step increase in rate with increasing buffer concentration; dilute to moderately concentrated buffers, where the rate continues to rise but not nearly so steeply; and very concentrated buffers, where the rate levels.A mechanism is proposed with both the chalcone anion C(1-) and hemiacetal anion B(1-) as intermediates C<*>C(1-)<*>B(1-)<*>B.A kinetic analysis is conducted using the measured equilibrium constant for cyclization, K=/=4, the measured acidity constant for chalcone ionization, pK_C=9.1, and an estimated acidity constant for hemiacetal ionization, pK_B ca. 12.0.Consistent with the two breaks in the buffer dilution plots, this analysis establishes that at some buffer concentration each step in the reaction is (mainly) rate limiting, the first step C<*>C(1-) in very dilute buffers, the third step B(1-)<*>B in more concentrated buffers, and the second step C(1-)<*>B(1-) in very concentrated buffers.The proton-transfer steps are rate limiting in the dilute buffers because the anion equilibration is extremely rapid.The changes in the rate-limiting step arise because of the acceleration of the proton transfers due to participation of the buffer.A comparison with the formation/breakdown of other hemiacetals is presented.The principal difference of the chalcone system is the uncoupling of both proton transfers from C-O bond making or breaking.The factor responsible for this appears to be the increased stability of the phenoxide nucleophile/leaving group.