The Michaelis–Arbuzov reaction (also known simply as the Arbuzov reaction) refers to the transformation where trivalent phosphite esters react with alkyl halides to produce pentavalent alkyl phosphonates. The reaction was first discovered by August Michaelis in 1898 and later thoroughly investigated by Aleksandr Arbuzov.

The Michaelis–Arbuzov reaction is one of the most fundamental transformations in organic chemistry and has been widely used for over a century to synthesize organophosphorus compounds.

• Reagents: Solvent

• Reactants: Alkyl halides, phosphite esters, phosphonites (phosphinic acid esters), hypophosphites (hypophosphorous acid esters)

• Products: Alkyl phosphonates

Experimental Tips:

• Primary alkyl halides react readily, while most secondary and tertiary alkyl halides do not participate effectively in the reaction.

• The reactivity order of alkyl halides is: R′–I > R′–Br > R′–Cl.

• In addition to simple alkyl halides, benzyl halides, acyl halides, haloesters, and chloroformates can also participate in the reaction.

• Aryl and alkenyl halides generally do not undergo substitution in this reaction.

• Hypophosphorous acid esters (hypophosphites) are the most reactive, followed by phosphinates and then phosphites, which are the least reactive.

• For trialkyl phosphites (R₁R₂P–OR₃), electron-withdrawing groups slow the reaction rate, while electron-donating groups accelerate it. If R₁, R₂, and R₃ are all aryl groups, a stable phosphonium salt is formed, and the reaction may not proceed further under standard conditions.

Reaction Mechanism:

The reaction begins with a nucleophilic SN2 attack by the phosphorus reagent on the electrophilic carbon of the alkyl halide, forming a phosphonium salt intermediate. This intermediate is typically unstable under heat or in the presence of alcohols/bases. The halide ion, displaced in the first SN2 reaction, may carry out a second SN2 reaction at one of the R₁ carbons of the phosphonium salt, displacing the oxygen atom to yield the final phosphonate product along with another alkyl halide.

Original Literature:

Michaelis, A.; Kaehne, R. Berichte der deutschen chemischen Gesellschaft, 1898, 31 (1), 1048–1055.

Key References:

• Lewis Acid-Mediated Michaelis–Arbuzov Reaction at Room Temperature: A Facile Preparation of Arylmethyl/Heteroarylmethyl Phosphonates. Org. Lett., 2011, 13 (6), 1270–1273.

• Visible-Light Photo-Arbuzov Reaction of Aryl Bromides and Trialkyl Phosphites Yielding Aryl Phosphonates. ACS Catal., 2016, 6 (12), 8410–8414.