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

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 CC(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, pKC=9.1, and an estimated acidity constant for hemiacetal ionization, pKB 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 CC(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.

Hydration of the Flavylium Ion. 3. The Effect of 3-Alkyl Substitution

An investigation is reported of the transformations undergone by four flavylium salts-two 3-methyl-substituted cations, the 3-methylflavylium ion, and the 4'-methoxy-3-methylflavylium ion-and two cations where an ethylene unit bridges the 3-position and the 2'-position of the phenyl ring, the 5,6-dihydrobenzoxanthylium ion, and the 3-methoxy-5,6-dihydrobenzoxanthylium ion.Three transformations have been identified and studied-a rapid and reversible hydration of the cations to produce a pseudobase, the rapid reversible ring opening of this pseudobase to a (Z)-chalcone, and the slow irreversible cis-trans isomerization of this species to an (E)-chalcone.Rate and equilibrium constants have been obtained for these processes and compared with values previously obtained for 3-H-substituted flavylium ions, the parent flavylium ion itself, and the 4'-methoxyflavylium ion.There is little effect of the alkyl substitution on the pseudobase: (Z)-chalcone equilibration.The ethylene-bridged systems undergo cis-trans isomerization at a similar rate to the 3-H systems, while the 3-methyl systems undergo this reaction about 30 times more slowly.The most significant effect, however, is seen on the flavylium ion hydration equilibrium, the bridged cations being about 2 orders of magnitude more stable than their 3-H-substituted counterparts with these in turn 2 orders of magnitude more stable than the 3-methyl analogues.To explain this, it is proposed that there is a steric interaction involving the 3-hydrogen or 3-methyl substituent and an ortho hydrogen on the nearby phenyl ring, resulting in a twisting of this ring so that it is not coplanar with the benzopyrylium portion of the cation.