The Mitsunobu reaction is a reaction in organic chemistry in which, under the influence of triphenylphosphine and diethyl ether of azodicarboxylic acid (C 2 H 5 O 2 CN = NCO 2 C 2 H 5 , DEAD ), the hydroxyl group of alcohols is converted into various functional groups. Essentially is intermolecular dehydration. The reaction was discovered in the 60s of the XX century. [1] During the reaction, the alcohol undergoes a reversal of configuration.
The Mitsunobu reaction plays an important role in modern organic synthesis. She was devoted to several review publications. [2] [3] [4] [5]
Reaction mechanism
The reaction mechanism is a bit complicated, the identification of intermediates playing a key role in the reaction is a matter of debate.
Initially, triphenylphosphine ( 2 ) nucleophilically attacks diethyl azodicarboxylate ( 1 ), forming betaine ( 3 ), which deprotonates carboxylic acid ( 4 ) and forms an ion pair with it ( 5 ). DEAD also deprotonates alcohol ( 6 ), and the resulting alkoxide forms the key oxophosphonium ion ( 8 ). The ratio of intermediates 8 to 11 depends on the strength of the carboxylic acid and the polarity of the solvent. [6] [7] [8] Although several intermediates 9–11 are formed , only the interaction of the carboxylate anion with the oxophosphonium ion leads to the desired reaction product 12 and triphenylphosphine oxide.
Hughes et al. Found that the formation of ion pair 5 occurs very quickly. The formation of oxophosphonium intermediate 8, on the contrary, is slow and depends on the concentration of alkoxide. Thus, the reaction rate is controlled by the basicity of the carboxylate. [9]
Notes
- ↑ Mitsunobu, O .; Yamada, Y. Bull. Chem. Soc. Japan 1967 , 40 , 2380-2382.
- ↑ The Use of Diethyl Azodicarboxylate and Triphenylphosphine in Synthesis and Transformation of Natural Products Mitsunobu, O. Synthesis 1981 , 1-28.
- ↑ Castro, BR Org. React 1983 , 29 , 1.
- ↑ Hughes, DL Org. React 1992 , 42 , 335–656.
- ↑ Hughes, DL Org. Prep. 1996 , 28 , 127-164.
- ↑ Edward Grochowski, Bruce D. Hilton, Robert J. Kupper, Christopher J. Michejda. Mechanism of the triphenylphosphine and diethyl azodicarboxylate induced dehydration reactions (Mitsunobu reaction). The central role of pentavalent phosphorus intermediates // Journal of the American Chemical Society. - 1982-12-01. - T. 104 , no. 24 . - S. 6876–6877 . - ISSN 0002-7863 . - DOI : 10.1021 / ja00388a110 .
- ↑ David Camp, Ian D. Jenkins. The mechanism of the Mitsunobu esterification reaction. Part I. The involvement of phosphoranes and oxyphosphonium salts // The Journal of Organic Chemistry. - 1989-06-01. - T. 54 , no. 13 . - S. 3045-3049 . - ISSN 0022-3263 . - DOI : 10.1021 / jo00274a016 .
- ↑ David Camp, Ian D. Jenkins. The mechanism of the Mitsunobu esterification reaction. Part II. The involvement of (acyloxy) alkoxyphosphoranes // The Journal of Organic Chemistry. - 1989-06-01. - T. 54 , no. 13 . - S. 3049-3054 . - ISSN 0022-3263 . - DOI : 10.1021 / jo00274a017 .
- ↑ DL Hughes, RA Reamer, JJ Bergan, EJJ Grabowski. A mechanistic study of the Mitsunobu esterification reaction // Journal of the American Chemical Society. - 1988-09-01. - T. 110 , no. 19 - S. 6487–6491 . - ISSN 0002-7863 . - DOI : 10.1021 / ja00227a032 .