Kinetics and mechanism of the cyclisation of 2′,6′-dihydroxy-4,4′-dimethoxy-chalcone; influence of the 6′-hydroxy group on the rate of cyclisation under neutral conditions

Abstract

The Ph–rate profile for the cyclisation of the title compound has been established under aqueous conditions and is accounted for in terms of contributions from uncatalysed cyclisation of neutral, monoanionic, and dianionic chalcone species, together with an acid-catalysed cyclisation. At high pH the reaction does not go to completion and a kinetic term representing hydroxide promotion of the reverse ring-opening reaction of the flavanone anion intervenes. Rate coefficients for all contributing reactions and dissociation constants for the chalcone and its monoanion are established. The chalcone monoanion cyclises about 440 times faster than the neutral chalcone and about 3 times faster than the dianion. The known ease of cyclisation under neutral conditions of 2′,6′-dihydroxychalcones as compared with other 2′-hydroxychalcones is considered to be associated with two contributing factors: (i) a much larger first dissociation constant of the chalcone which results in a higher proportion of the chalcone being present as the reactive monoanion at neutral pH; (ii) specially high reactivity of the chalcone monoanion associated with intramolecular general acid catalysis by the 6′-OH group. The latter is implicated through the observation of a large kinetic isotopeeffect for monoanion cyclisation, which is 5.7 times slower in D₂O than in H₂O. This isotope effect also establishes for the monoanion that the s-cis→ s-trans conformational isomerisation of the monoanion must be a pre-equilibrium rather than the rate-determining stage in the cyclisation.