In organic chemistry, the Baylis–Hillman, Morita–Baylis–Hillman, or MBH reaction is a carbon-carbon bond-forming reaction between an activated alkene and a carbon electrophile in the presence of a nucleophilic catalyst, such as a tertiary amine or phosphine. The product is densely functionalized, joining the alkene at the α-position to a reduced form of the electrophile (e.g. in the case of an aldehyde, an allylic alcohol).
The reaction is named for Anthony B. Baylis and Melville E. D. Hillman, two of the chemists who developed the reaction at Celanese; and K. Morita, who published earlier work on the same.
The MBH reaction offers several advantages in organic synthesis: It combines easily-prepared starting materials with high atom economy. It requires only mild conditions and eschews transition-metal catalysis. Asymmetric synthesis is possible from prochiral electrophiles. The product's dense functionalization enables many further transformations.
Its disadvantage is that the reaction is extremely slow.
Common reagents
The most frequently-used catalyst for the reaction is the tertiary amine DABCO (triethylenediamine); other known catalysts include 4-dimethylaminopyridine, DBU (diazabicycloundecene), and various phosphines.
Reaction mechanism
, certain questions about MBH reaction's mechanism remain open.
Hill and Isaacs performed the first kinetic experiments in the 1990s, discovering that the reaction rate between acrylonitrile and acetaldehyde was first-order in each reactant and in the DABCO catalyst. α-Deuterated acrylonitrile exhibited no kinetic isotope effect, but the product appeared to catalyze its own generation.
In a model Hoffmann proposed seven years prior, the reaction begins with 1,4-addition of the catalytic amine to the activated alkene. The resulting zwitterionic aza-enolate undergoes aldol addition to the aldehyde. Intramolecular proton shift then generates the final MBH adduct, which eliminates the catalyst.
If Hoffmann's model were correct, then the aldol addition would be the rate-limiting step, which accords with the absent kinetic isotope effect. However, Hoffman's mechanism rationalizes neither the product's autocatalysis nor (in the reaction of aryl aldehydes with acrylates) the considerable generation of a dioxanone byproduct.
In more recent work, McQuade et al and Aggarwal et al reevaluated the MBH mechanism, focusing on the proton-transfer and autocatalysis. According to McQuade, the reaction between methyl acrylate and p-nitrobenzaldehyde is second-order relative to the aldehyde. Moreover, it showed a significant kinetic isotope effect for the acrylate's α-hydrogen (5.2 in DMSO, but ≥2 in all solvents), which would imply that proton abstraction is the rate-determining step.
To account for this reanalysis, McQuade proposed modifying Hoffman's proposal, such that after the first aldol addition, a second aldol adds to form a hemiacetal alkoxide. Then the rate-determining proton transfer releases the adduct A via a six-membered transition state, which further reacts to produce the MBH product B or a dioxanone byproduct C.
In a further modification, Aggarwal noted that observed that methanol inhibited autocatalysis in the MBH reaction. Thus he proposed that in the reaction's early stages, a mechanism equivalent to McQuade's proposal operates, but after 20% conversion, reaction with an alcoholic solvent can replace the second aldol addition. In support of this contention, Aggarwal and Harvey modeled the two pathways using density functional theory calculations and showed that the computed energy profile matches the experimental kinetic isotope effects and observed rate of reaction. Also they showed that the overall enthalpic barrier of the alcohol-catalyzed pathway is slightly smaller than that of the non-alcohol-catalyzed pathway, rationalizing that as the alcohol (MBH product) concentration increases the alcohol-catalyzed pathway starts to dominate.
While McQuade's and Aggarwal's studies received much attention, unequivocal proof of intermediate A's role remained elusive . Because A could be formed by separate addition of B to an aldehyde, any isolated A and C could be the result of side reactions, rather than the MBH itself. Nor has a convincing explanation yet been presented for Hill and Isaac's original first-order data.