[2564-83-2]  · C9H18NO  · 2,2,6,6-Tetramethylpiperidin-1-oxyl  · (MW 156.28)

(oxidizing agent for the conversion of primary alcohols to aldehydes2,3 or carboxylic acids,2 of secondary alcohols to ketones,2 and of diols to lactones or hydroxy aldehydes4)

Alternate Name: TEMPO.

Physical Data: mp 40.0 °C; fp 67 °C.

Solubility: sol all organic solvents and 0.03 mol L-1 in H2O at 25 °C.

Form Supplied in: red orange solid; commercially available.

Analysis of Reagent Purity: IR (Nujol) 1330, 1180, 1060, 975, 950 cm-1;5 UV-Vis, l (ε) = heptane, 470 nm (10.5), dioxane, 465 nm (10.4), 240-242 nm (2030).5

Purification: sublimation.6

Handling, Storage, and Precautions: TEMPO is a toxic substance, and a severe irritant which is readily absorbed through the skin.7 Its toxicity is probably related to the formation of hydroxylamine metabolites.8

Oxammonium Salts.

Oxammonium salts (2) can be prepared in situ by oxidation of the nitroxide (1).1e There is evidence that the oxoammonium ion (2) is actually the product of an acid-catalyzed disproportionation between two nitroxide molecules (1), which produces one oxoammonium ion (2) and one hydroxylamine molecule (3).1e Peracids, for instance, do not oxidize nitroxides to oxoammonium ions, yet do act as the secondary oxidant. The chemical stability of (2) depends on the counterion, and this can be easily exchanged; the chloride salt is not very stable. The oxammonium salt is the active species in the oxidation of primary and secondary alcohols to carbonyl derivatives and can be used in stoichiometric or catalytic fashion.1e Catalytic procedures require a co-oxidant such as Copper(II) Chloride-O2,9 peroxy acids,10 electrooxidation,11 or Sodium Hypochlorite.2-4 Oxammonium salts can be titrated iodometrically.1e

It has been proposed that (2) reacts with alcohols, forming carbonyl derivatives and hydroxylamine (3).

Oxidation of Alcohols.2,3,7

Primary alcohols are converted into aldehydes by the following catalytic system: 0.01-0.002 equiv of TEMPO (or its 4-methoxy derivative), 0.05 equiv of KBr as co-catalyst, and aqueous NaOCl buffered at pH 8.5-9.5 in a CH2Cl2/H2O two-phase system. At this pH, HOCl is the co-oxidant and in the presence of KBr it is likely transformed into HOBr which is more efficient in the oxidation of (1) to (2). The reaction is exothermic. For reactions carried out on a 1-10 mmol scale the temperature can be easily maintained at 0 °C and conversion is complete in few minutes. On a larger scale, a very efficient cooling system is required. A compromise is to maintain the temperature in the range 10-15 °C with an ice bath; note that higher temperatures lead to fast decomposition of the catalyst. The pH is buffered by adding the appropriate amount of NaHCO3 to the aqueous NaOCl. NaH2PO4.2H2O and Na2HPO4.2H2O have been used as alternatives.12

Oxidation of secondary alcohols similarly affords ketones. The oxidation can be applied to saturated alkyl and aryl-alkyl substrates; relatively unstable protecting groups such as acetonide derivatives of diols are not affected. Side reactions occur with substrates with isolated and conjugated double bonds, leading to lower yields. The reaction rates are markedly decreased by the presence of electron-donor groups in the aromatic ring of benzyl alcohol, but they can be speeded up by addition of catalytic amounts of quaternary ammonium salts (Q+X-). At the pH of commercial bleach (12.7), reactions are very slow. At lower pH, HOCl is distributed between the aqueous and the organic phase, thus making the phase transfer catalyst unnecessary. Optically active alcohols afford the corresponding aldehydes in good yields and high enantiomeric purity (eq 1).3,13

Oxidation of Diols.

Diols are easily oxidized with this reagent; the nature of the products depends on the amount of oxidant used, the difference in oxidation rates of primary vs. secondary alcohols, the presence of Q+X-, and on the relative distance between the OH groups in the aliphatic chain. Under the reaction conditions reported above, primary-secondary diols afford hydroxy or keto aldehydes. In the presence of a catalytic amount of Q+X-, primary-secondary diols lead to ketocarboxylic acids. Selectivity in these oxidations also depends on the substituents on the 2,2,6,6-tetramethylpiperidine ring.14

Lactones are obtained from 1,4- and 1,5-diols, whereas a,o-diols give unresolvable mixtures of polymeric products.4 Oxidation of hydrophilic 1,4- and 1,5-diols to g- and d-lactones and of hydrophilic alcohols to aldehydes is best conducted using CH2Cl2/solid LiOCl in the presence of solid NaHCO3. Commercial LiOCl contains 7% of H2O so that reaction conditions are those of a pseudo solid-liquid system.4

Oxidation of Primary Alcohols and Aldehydes to Carboxylic Acids.2

The addition of catalytic amounts of quaternary salt to the oxidizing system leads to the fast and direct formation of carboxylic acids. This oxidation requires the presence, in the organic phase, of ClO- and/or BrO- anions which behave as strong bases. Again, electron-donor groups in benzyl alcohol or aromatic aldehydes strongly lower the reaction rates.

1. (a) Rozantsev, E. G.; Sholle, V. D. S 1971, 190. (b) S 1971, 401. (c) Keana, J. F. W. CRV 1978, 78, 37. (d) Yamaguchi, M.; Miyazawa, T.; Takata, T.; Endo, T. PAC 1990, 62, 217. (e) Bobbitt, J. M.; Flores, M. C. L. H 1988, 27, 509. (f) Ma, Z.; Bobbitt, J. M. JOC 1991, 56, 6110.
2. Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. JOC 1987, 52, 2559.
3. Anelli, P. L.; Montanari, F.; Quici, S. OS 1990, 69, 212.
4. Anelli, P. L.; Banfi, S.; Montanari, F.; Quici, S. JOC 1989, 54, 2970.
5. Brière, R.; Lemaire, H.; Rassat, A. BSF 1965, 3273.
6. Mahoney, L. R.; Mendenhall, G. D.; Ingold, K. U. JACS 1973, 95, 8610.
7. Straub, T. S. J. Chem. Educ. 1991, 68, 1048.
8. Luzhkov, V. B. DOK 1983, 268, 126 (CA 1983, 98, 155 990v).
9. Semmelhack, M. F.; Schmid, C. R.; Cortés, D. A.; Chou, C. S. JACS 1984, 106, 3374.
10. (a) Cella, J. A.; Kelley, J. A.; Kenehan, E. F. JOC 1975, 40, 1860. (b) Cella, J. A.; McGrath, J. P.; Kelley, J. A.; El Soukkary, O.; Hilpert, L. JOC 1977, 42, 2077.
11. (a) Semmelhack, M. F.; Chou, C. S.; Cortés, D. A. JACS 1983, 105, 4492. (b) Inokuchi, T.; Matsumoto, S.; Torii, S. JOC 1991, 56, 2416.
12. BASF A.-G. Ger. Offen. 4 007 923, 1990 (CA 1991, 114, 163 728e).
13. Leanna, M. R.; Sowin, T. J.; Morton, H. E. TL 1992, 33, 5029.
14. Siedlecka, R.; Skarzewski, J.; Mlochowski, J. TL 1990, 31, 2177.

Fernando Montanari & Silvio Quici

Università di Milano, Italy

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