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).

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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 {(C<sub>5</sub>H<sub>5</sub>)Co[(CH<sub>3</sub>O)<sub>3</sub>P]<sub>3</sub>}<sup>2+</sup> to give {(C<sub>5</sub>H<sub>5</sub>)Co[(CH<sub>3</sub>O)<sub>2</sub>PO]<sub>3</sub>}<sup>−</sup>, which is called the Klaui ligand.

Reaction mechanism

center|600px|The mechanism of the Michaelis–Arbuzov reaction

The Michaelis–Arbuzov reaction is initiated with the S<sub>N</sub>2 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&nbsp;°C), or cleavage by alcohols or bases. The displaced halide anion then usually reacts via another S<sub>N</sub>2 reaction on one of the R<sub>1</sub> 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 R<sub>1</sub> groups experience inversion of configuration at the carbon center attacked by the halide anion. This is what is expected of an S<sub>N</sub>2 reaction. Evidence also exists for a carbocation based mechanism of dealkylation similar to an S<sub>N</sub>1 reaction, where the R<sub>1</sub> group initially dissociates from the phosphonium salt followed by attack of the anion.

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 <sup>31</sup>P 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.

Scope

Alkyl halide

Source: Other methods of producing β-ketophosphonates have been developed.

The reaction of trivalent phosphorus compounds with alkyl fluorides is abnormal. One example of this reactivity is shown below.

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Phosphorus reactant

The general form of the trivalent phosphorus reagent can be considered as follows: <chem>ABP-OR</chem> with A and B generally being alkyl, alkoxy or aryloxy groups. Electron-withdrawing groups are known to slow down the rate of the reaction, with electron donating groups increasing the rate of the reaction. This is consistent with initial attack of the phosphorus reagent on the alkyl halide as the rate-determining step of the reaction. The reaction proceeds smoothly when the R group is aliphatic. When all of A, B and R are aryl groups, a stable phosphonium salt is formed and the reaction proceeds no further under normal conditions. Heating to higher temperatures in the presence of alcohols has been known to give the isomerization product. Cyclic phosphites generally react to eject the non-cyclic OR group, though for some 5-member rings additional heating is required to afford the final cyclic product.

Other variants

Traditionally, the Arbuzov reaction is performed with an alkyl halide. However, tricoordinate phosphorus compounds can also attack unsaturated carbon atoms, either directly or in conjugate. In such circumstances, the electrofugal group attached to the phosphorus ester is key; the reaction has maximum reliability with trimethylsilyl phosphites or similar.

See also

  • Abramov reaction
  • Perkow reaction
  • Michaelis–Becker reaction
  • Hirao coupling

References

  • Ford-Moore, A. H.; Perry, B. J. Organic Syntheses, Coll. Vol. 4, p.&nbsp;325 (1963); Vol. 31, p.&nbsp;33 (1951). (Article)
  • Davidsen, S. K.; Phllips, G. W.; Martin, S. F. Organic Syntheses, Coll. Vol. 8, p.&nbsp;451 (1993); Vol. 65, p.&nbsp;119 (1987). (Article)
  • Enders, D.; von Berg, S.; Jandeleit, B. Organic Syntheses, Coll. Vol. 10, p.&nbsp;289 (2004); Vol. 78, p.&nbsp;169 (2002). (Article)