The reversible cyclisation of a chalcone, 1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(4-ethoxyphenyl)prop-2-en-1-one: a kinetic and mechanistic study

Abstract

Cyclisation of the title 2′-hydroxychalcone 1 to the flavanone 2 in 30% v/v isopropyl alcohol is a reversible process with a complex rate–pH profile. In alkali, while the forward reaction goes through the anion of 1, its reverse goes via hydroxide ion attack on 2, so that k_f and k_r dominate under different conditions and can be separately studied and dissected. The hitherto unstudied reaction in acid shows a plateau at low pH which results from a change in rate-determining step. With the help of model rates and equilibria it has proved possible to assign values to every microscopic rate and equilibrium constant at both low and high pH. One result has been to assign a plausible value to log K_T for the keto–enol equilibrium present in 2. Another has been the unequivocal assignment of reaction mechanism. In alkali, the reverse (β-elimination) reaction is neither E2 nor (E1 cb)_l but a rare example of the (E1 cb)_R mechanism with PhCO as activating group and PhO^– as nucleofuge; a value can be given to the hitherto unknown ranking order of PhO^– for this case. In acid, the mechanism of rate-limiting β-elimination is (E1 cb)_l but, in addition, loss of PhOH takes place at close to the encounter limit. The transition states for loss both of PhOH and of PhO^– involve minimal C–O bond fission. Some alternative reaction mechanisms are discussed and eliminated. In addition, the position of K_eq is discussed; it is concluded that ring closure probably involves EM ≈ 10³.