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Mitsunobu reaction

The Mitsunobu reaction is an organic reaction that converts an alcohol into a variety of functional groups, such as an ester, using triphenylphosphine and diethyl azodicarboxylate (DEAD).^[1] Of importance to note is that the alcohol undergoes an inversion of stereochemistry.

Several reviews have been published.^[2]^[3]^[4]^[5]

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1 Reaction mechanism
- 1.1 Order of addition of reagents
2 Variations
3 Uses
4 References
5 See also

Reaction mechanism

The reaction mechanism of the Mitsunobu reaction is fairly complex. The identity of intermediates and the roles they play has been the subject of debate.

Initially, the triphenyl phosphine (2) makes a nucleophilic attack upon diethyl azodicarboxylate (1) producing a betaine intermediate 3, which deprotonates the carboxylic acid (4) to form the ion pair 5. The carboxylate ion deprotonates the alcohol (6) forming an alkoxide that can form the key oxyphosphonium ion 8. The ratio and interconversion of intermediates 8 - 11 depend on the carboxylic acid pKa and the solvent polarity.^[6]^[7]^[8] Although several phosphorus intermediates are present, the attack of the carboxylate anion upon intermediate 8 is the only productive pathway forming the desired product 12 and triphenylphosphine oxide (13).

Hughes et al. has found that the formation of the ion pair 5 is very fast. The formation of the oxyphosphonium intermediate 8 is slow and facilitated by the alkoxide. Therefore, the overall rate of reaction is controlled by carboxylate basicity and solvation.^[9]

Order of addition of reagents

The order of addition of the reagents of the Mitsunobu reaction can be important. Typically, one dissolves the alcohol, the carboxylic acid, and triphenylphosphine in tetrahydrofuran, cool to 0 °C using an ice-bath, slowly add the DEAD dissolved in THF, then stir at room temperature for several hours. If this is unsuccessful, then preforming the betaine may give better results. To preform the betaine, add DEAD to triphenylphosphine in tetrahydrofuran at 0 °C, followed by the addition of the alcohol and finally the acid.^[10]

Variations

Other nucleophilic functional groups

Many other functional groups can serve as nucleophiles besides carboxylic acids. For the reaction to be successful, the nucleophile must have a pKa less than 15.

Nucleophile	Product
hydrazoic acid	alkyl azide
imide	substituted imide^[11]
phenol	alkyl aryl ether
sulfonamide	substituted sulfonamide^[12]

Modifications

A useful variation of the Mitsunobu Reaction uses resin-bound triphenylphoshine and di-t-butylazodicarboxylate instead of DEAD. The oxidized triphenylphosphine can be removed by filtration, and the di-t-butylazodicarboxylate is removed by treatment with trifluoroacetic acid.^[13]

Phosphorane reagents

Tsunoda et al. have shown that one can combine the triphenylphosphine and the diethyl azodicarboxylate into one reagent: a phosphorane ylid. Both (cyanomethylene)trimethylphosphorane (CMMP, R = Me) and (cyanomethylene)tributylphosphorane (CMBP, R = Bu) have proven particularly effective.^[14]

The ylid acts as both the reducing agent and the base. The byproducts are acetonitrile (6) and the trialkylphosphine oxide (8).

Uses

The Mitsunobu reaction has been applied in the synthesis of aryl ethers ^[15]:

With these particular reactants the conversion with DEAD fails because the phenol is only weakly acidic. Instead the related 1,1'-(azodicarbonyl)dipiperidine or ADDP is used of which the betain intermediate is a stronger base. The phosphine is a polymer-supported triphenylphosphine (PS PPh₃).

References

^ Mitsunobu, O.; Yamada, Y. Bull. Chem. Soc. Japan 1967, 40, 2380-2382.
^ Mitsunobu, O. Synthesis 1981, 1-28. (Review)
^ Castro, B. R. Org. React. 1983, 29, 1. (Review)
^ Hughes, D. L. Org. React. 1992, 42, 335-656. (Review)
^ Hughes, D. L. Org. Prep. 1996, 28, 127-164. (Review)
^ Grochowski, E. H., B. D.; Kupper, R. J.; Michejda, C. J. J. Am. Chem. Soc. 1982, 104, 6876-6877. (doi:10.1021/ja00388a110)
^ Camp, D. J., I. D. J. Org. Chem. 1989, 54, 3045-3049. (doi:10.1021/jo00274a016)
^ Camp, D. J., I. D. J. Org. Chem. 1989, 54, 3049-3054. (doi:10.1021/jo00274a017)
^ Hughes, D. L. R., R. A.; Bergan, J. J.; Grabowski, E. J. J. J. Am. Chem. Soc. 1988, 110, 6487-6491. (doi:10.1021/ja00227a032)
^ Volante, R. Tetrahedron Lett. 1981, 22, 3119.
^ Hegedus, L. S.; Holden, M. S.; McKearin, J. M. Organic Syntheses, Coll. Vol. 7, p.501 (1990); Vol. 62, p.48 (1984). (Article)
^ Kurosawa, W.; Kan, T.; Fukuyama, T. Organic Syntheses, Coll. Vol. 10, p.482 (2004); Vol. 79, p.186 (2002). (Article)
^ Tetrahedron Lett. 2000, 41, 797-800.
^ Tsunoda, T.; Nagino, C.; Oguri, M.; Itô, S. Tetrahedron Lett. 1996, 37, 2459.
^ ADDP and PS-PPh3: An efficient Mitsunobu protocol for the preparation of pyridine ether PPAR agonists Humphries P, Do Q, Wilhite D Beilstein Journal of Organic Chemistry, 2006, 2, 21 ( 31 October 2006 ) (doi:10.1186/1860-5397-2-21)