Mechanism of Metal Chloride-Promoted Mukaiyama Aldol Reactions

Ab initio calculations (MP2/6-311+G**//B3LYP/6-31G*) were employed to investigate the mechanism of metal chloride-promoted Mukaiyama aldol reaction between trihydrosilyl enol ether and formaldehyde. The metal chlorides considered include TiCl₄, BCl₃, AlCl₃, and GaCl₃. In contrast to the concerted pathway of the uncatalyzed aldol reaction, the Lewis acid-promoted reactions favor a stepwise mechanism. Three possible stepwise pathways were located. The lowest energy pathway corresponds to a simultaneous C−C bond formation and a chlorine atom shift in the first (rate-determining) step. This process is calculated to have a low activation barrier of 12 kJ mol^-1 for the TiCl₄-promoted reaction. The alternative [2+2] cycloaddition and direct carbon−carbon bond formation pathways are energetically competitive. BCl₃, AlCl₃, and GaCl₃ are predicted to be efficient catalysts for the silicon-directed aldol reaction as they strongly activate the formaldehyde electrophile. Formation of a stable pretransition state intermolecular π−π complex between enol silane and the activated formaldehyde (CH₂O···MCl_n) is a key driving force for the facile metal chloride-promoted reactions.