High-level ab initio molecular orbital calculations at the G3(MP2) level of theory were carried out to investigate the effects of substituents on the energetics of the uncatalyzed Mukaiyama aldol reaction between trihydrosilyl enol ether and formaldehyde. The concerted pathway, via a twist-boat six-membered ring transition state, is strongly favored over the stepwise pathway which involves a four-membered ring oxetane intermediate. Six substituents (CH(3), NH(2), OH, F, SH, and CHO) on trihydrosilyl enol ether and eight substituents (CH(3), CF(3), NH(2), F, CHO, COOCH(3), CH=CH(2), and C(6)H(5)) on formaldehyde were considered. We find that the reaction exothermicity is the main factor that dominates reactivity. The calculated barriers vary considerably from 30 to 131 kJ mol(-1). With the exception of halogen substitution, the nucleophilicity of silyl enol ether and the electrophilicity of the aldehyde are important in promoting the reactivity of this class of aldol addition. The roles of frontier molecular orbital interactions and electrostatic interactions are also discussed. In addition, our study has revealed that employing substituents on both reactants can act in a cooperatively manner to reduce the activation barrier further. In particular, we predict that the reactions between NH(2)-substituted enol silane and CHO-, COOCH(3)-, and CF(3)-substituted aldehydes have remarkably low barriers (<12 kJ mol(-1)). Thus, these reactions may proceed readily without a catalyst below room temperature. Several substitutions on the silicon group, namely SiF(3), SiCl(3), SiMe(3), and silacyclobutyl, were considered. In agreement with experiment, the O-(silacyclobutyl) and O-(trichlorosilyl) derivatives are found to promote aldol reactivity.