Last month we asked for your help to understand the role of the phase-transfer catalyst for this Grignard reaction. We appreciate the input of Peter Wuts of Wuts Chemical Consulting and Joe Schwab of Hybrid Plastics who provided the following references: Zong, H.; Huang, H.; Liu, J.; Bian, G.; Song, L.; J. Org. Chem. 2012, 77, 4645−4652 and J. Org. Chem. 1990, 55, 3281-3286
According to the 2012 JOC article, “By using tetrabutylammonium chloride (NBu4Cl) as a catalyst and diglyme (DGDE) as an additive, this system strongly enhances the efficiency of addition at the expense of enolization and reduction.” They also explained that the tetrabutylammonium chloride “should help to shift the Schlenk equilibrium of Grignard reagents to the side of dimeric Grignard reagents to favor the additions of Grignard reagents to ketones via a favored six-membered transition state to form the desired tertiary alcohols.” As a reminder, the Schlenk Equilibrium is 2 RMgX ⇌ MgX2 + MgR2.
Indeed, challenges to be overcome in Grignard additions to ketones are competing beta-hydride reduction and enolization of ketones, otherwise significant byproducts are often produced along with low yields of desired alcohols. Many methods have been developed to suppress these side reactions, Historically, these included using metal complexes with lithium, cerium and zinc, changing solvent, adding organic bases and more.
This patent and the articles cited use a combination of tetrabutylammonium and glymes to affect selectivity. RMgX favors reduction and enolization. R2Mg favors addition to the ketone.
The order of selectivity toward the addition reaction with different tetrabutylammonium salts is: TBA Cl > TBA Br > > TBA I > TBA ClO4. It is suggested that a complex between the Grignard salt and the Q+X- forms a bridge that favors the dimer.
Thanks again to Dr. Wuts and Dr. Schwab for providing references to help understand the surprising role of phase-transfer catalysis in Grignard.
