TEMPO

2,2,6,6-Tetramethylpiperidine-1-oxyl or TEMPO is the chemical compound with the formula (CH₂)₃(CMe₂)₂NO. This heterocycle is a red-orange, sublimable solid. As a stable radical, it has applications throughout chemistry and biochemistry.^[1] TEMPO was discovered by Lebelev and Kazarnowskii in 1960.^[2] It is prepared by oxidation of 2,2,6,6-tetramethylpiperidine. TEMPO is widely used as a radical trap, as a structural probe for biological systems in conjunction with electron spin resonance spectroscopy, as a reagent in organic synthesis, and as an initiator in polymer chemistry.^[3] The stability of this radical is attributed to the steric protection provided by the four methyl groups adjacent to the nitroxyl group.^[4]

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Application in organic synthesis

TEMPO is employed in organic synthesis as a catalyst for the oxidation of primary alcohols to aldehydes. The actual oxidant is the N-oxoammonium salt. In a catalytic cycle with sodium hypochlorite as the stoichiometric oxidant, hypochlorous acid generates the N-oxoammonium salt from the TEMPO.

One typical reaction example is the oxidation of (S)-(-)-2-methyl-1-butanol to (S)-(+)-2-methylbutanal.^[5] 4-Methoxyphenethyl alcohol is oxidized to the corresponding carboxylic acid in a system of catalytic TEMPO and sodium hypochlorite and a stoichiometric amount of sodium chlorite.^[6] TEMPO oxidations also exhibit chemoselectivity, being inert towards a secondary alcohols, but the reagent will convert aldehydes to carboxylic acids.

In cases where secondary oxidizing agents cause side reactions, it is possible to stoichiometrically convert TEMPO to the oxoammonium salt in a separate step. For example in the oxidation of geraniol to geranial 4-acetamido-TEMPO is first oxidized to the oxoammonium tetrafluoroborate.^[7]

References

1. ^ Barriga, S (2001). "2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO)". Synlett (4): 563. doi:10.1055/s-2001-12332.
2. ^ Lebelev, O. L.; Kazarnovskii, S. N. Zhur. Obshch. Khim. 1960, volume 30, page 1631ff.
3. ^ Montanari, F.; Quici, S.; Henry-Riyad, H.; Tidwell, T. T. “2,2,6,6-Tetramethylpiperidin-1-oxyl” Encyclopedia of Reagents for Organic Synthesis; John Wiley & Sons, 2005. DOI: 10.1002/047084289X.rt069.pub2
4. ^ Zanocco, A. L.; Canetem., A. Y.; Melendez, M. X. (2000). "A Kinetic Study of the Reaction between 2-p-methoxyphenyl-4-phenyl-2-oxazolin-5-one and 2,2,6,6-Tetramethyl-1-piperidinyl-n-oxide". Bol. Soc. Chil. Quím. 45: 123-129.
5. ^ P. L. Anelli, F. Montanari, S. Quici. "A General Synthetic Method for the Oxidation of Primary Alcohols to Aldehydes: (S)-(+)-2-Methylbutanal". Org. Synth.; Coll. Vol. 8: 367. 
6. ^ Zhao, M. M.; Li, J.;Mano, E.; Song, Z. J.; Tschaen, D. M.. "Oxidation of Primary Alcohols to Carboxylic Acids with Sodium Chlorite catalyzed by TEMPO and Bleach: 4-Methoxyphenylacetic Acid". Org. Synth. 81: 195. 
7. ^ Bobbitt, J. M.; Merbouh, N.. "2,6-Octadienal, 3,7-dimethyl-, (2E)-". Org. Synth. 82: 80.