Michaelis–Arbuzov reaction

The Michaelis–Arbuzov reaction (also called the Arbuzov reaction) is the chemical reaction of a trivalent phosphorus ester with an alkyl halide to form a pentavalent phosphorus species and another alkyl halide. The picture below shows the most common types of substrates undergoing the Arbuzov reaction; phosphite esters (1) react to form phosphonates (2), phosphonites (3) react to form phosphinates (4) and phosphinites (5) react to form phosphine oxides (6). The Michaelis–Arbuzov reaction (also called the Arbuzov reaction) is the chemical reaction of a trivalent phosphorus ester with an alkyl halide to form a pentavalent phosphorus species and another alkyl halide. The picture below shows the most common types of substrates undergoing the Arbuzov reaction; phosphite esters (1) react to form phosphonates (2), phosphonites (3) react to form phosphinates (4) and phosphinites (5) react to form phosphine oxides (6). The reaction was discovered by August Michaelis in 1898, and greatly explored by Aleksandr Arbuzov soon thereafter. This reaction is widely used for the synthesis of various phosphonates, phosphinates, and phosphine oxides. Several reviews have been published. The reaction also occurs for coordinated phosphite ligands, as illustrated by the demethylation of {(C5H5)Co3}2+ to give {(C5H5)Co3}−, which is called the Klaui ligand. The Michaelis–Arbuzov reaction is initiated with the SN2 attack of the nucleophilic phosphorus species (1 - A phosphite) with the electrophilic alkyl halide (2) to give a phosphonium salt as an intermediate (3). These intermediates are occasionally stable enough to be isolated, such as for triaryl phosphites which do not react to form the phosphonate without thermal cleavage of the intermediate (200°C), or cleavage by alcohols or bases. The displaced halide anion then usually reacts via another SN2 reaction on one of the R1 carbons, displacing the oxygen atom to give the desired phosphonate (4) and another alkyl halide (5). This has been supported by the observation that chiral R1 groups experience inversion of configuration at the carbon center attacked by the halide anion. This is what is expected of an SN2 reaction. Evidence also exists for a carbocation based mechanism of dealkylation similar to an SN1 reaction, where the R1 group initially dissociates from the phosphonium salt followed by attack of the anion. Phosphite esters with tertiary alkyl halide groups can undergo the reaction, which would be unexpected if only an SN2 mechanism was operating. Further support for this SN1 type mechanism comes from the use of the Arbuzov reaction in the synthesis of neopentyl halides, a class of compounds that are notoriously unreactive towards SN2 reactions. Based on the principle of microscopic reversibility, the inert nature of the neopentyl halides towards the SN2 reaction indicates that an SN2 reaction is unlikely to be the mechanism for the synthesis of the neopentyl halides in this reaction. Substrates that cannot react through an SN2 pathway or an SN1 pathway generally do not react, which include vinyl and aryl groups. For example, the triaryl phosphites mentioned above generally do not react because they form stable phosphonium salts. Since aryl groups do not undergo SN1 and SN2 type mechanisms, triaryl phosphites lack a low energy pathway for decomposition of the phosphonium salt. An allylic rearrangement mechanism (SN2`) has also been implicated in allylic and propargylic halides. Stereochemical experiments on cyclic phosphites have revealed the presence of both pentavalent phosphoranes and tetravalent phosphonium intermediates in chemical equilibrium being involved in the dealkylation step of the reaction using 31P NMR. The decomposition of these intermediates is driven primarily by the nucleophilicity of the anion. There exists many instances of the intermediate phosphonium salts being sufficiently stable that they can be isolated when the anion is weakly nucleophilic, such as with tetrafluoroborate or triflate anions.