2,2,6,6-Tetramethylpiperidine 1-Oxyl, Free Radical

2,2,6,6-Tetramethylpiperidine 1-oxyl, free radical

Additional Information

2,2,6,6-Tetramethylpiperidine 1-oxyl is a remarkably stable nitroxyl radical, commonly also known as TEMPO. This red-orange solid was first reported in 1960 by Lebedev and Kazarnovskii,1 and is typically synthesized by the oxidation of 2,2,6,6-tetramethylpiperidine. The stability of the radical has been proposed to be due to the steric influence of the methyl groups which flank the nitroxyl group.2

TEMPO finds frequent use in organic synthesis as a catalytic oxidant, with the N-oxoammonium salt, derived from TEMPO under the reaction conditions, being the actual oxidant. This is illustrated in Scheme 1, where sodium hypochlorite (NaOCl) in stoichiometric quantities forms the N-oxoammonium salt via generation of hypochlorous acid (HOCl).

HOCl

ClO- TEMPO N-oxoammonium salt Scheme 1

These reaction conditions forms the basis of a fast, cheap and highly selective catalytic process for the synthesis of aldehydes from primary alcohols.3 Further oxidation of aldehydes to carboxylic acids is slow, though the rate can be increased by the addition of a catalytic quantity of a phase transfer catalyst. The reaction takes place in a two-phase system of dichloromethane-water, with the aqueous sodium hypochlorite solution pH adjusted to ensure the formation of HOCl. Under these conditions, a variety of saturated primary alkyl and aryl alkyl (benzyl) alcohols are efficiently converted to the corresponding aldehydes, as illustrated in Scheme 2 for (S)-2-methyl-1- butanol, which is the subject of a robust Organic Synthesis preparation.4 Under these conditions, secondary alcohols can also be oxidised to ketones. Substrates containing double bonds, whether isolated or conjugated, are reported to be prone to side reactions, lowering selectivites and yields.3 The use of TEMPO and related stable nitroxyl radicals in alcohol oxidations has been reviewed.5

TEMPO , KBr (cat) (cat) CH Cl , NaOCl 2 2 (aq)

0 - 15ºC Scheme 2

stoichiometric sodium chlorite (NaClO2) to oxidise primary alcohols to carboxylic acids, as shown in Scheme 3 for the preparation of of 4-methoxyphenylacetic acid.6 Substrates with sensitive chiral centres are well tolerated under the conditions, although in common with the oxidation of alcohols to aldehydes or ketones, alkenic alcohols and those containing significantly electron-rich aromatic rings are not tolerated. The procedure is an adaptation of the biphasic (dichloromethane–water) process using sodium hypochlorite alone as the stoichiometric oxidant,3 and has the advantage of improved yields and purities, as well as the environmental benefit of dispensing with the requirement for a chlorinated solvent.

TEMPO (7 mol%), NaOCl (2 (aq) mol%)

35ºC

As well as alcohol oxidation, TEMPO also finds use in the oxidation of other functional groups, including amines, phosphines, phenols, anilines, sulfides and organometallic compounds.7,8

TEMPO also participates in numerous synthetically and analytically useful radical reactions. For example TEMPO can act as a radical scavenger to facilitate the identification of peptide- and protein-based radicals by mass spectrometry,9 and as a carbon-radical trapping reagent in cascade and cyclisation reactions.7

An example of the latter case is shown in Scheme 4, where pyrrolidinones 1 and 2 are formed in good yields from the acyclic trichloroethanamide or iodide precursors respectively under dimanganese decacarbonyl promoted conditions.10 Trapping sequences of this sort are useful as they introduce oxygen functionality at the product radical centre as a hydroxylamine group. The hydroxylamine can subsequently be cleaved to a hydroxyl group under reductive conditions using zinc and acetic acid, or oxidised to aldehydes. 10,11

Mn (CO) , TEMPO Mn (CO) , TEMPO 2 10 2 10

CH2Cl2, UV CH2Cl2, UV irradation irradation 78%, (X = I) 72%, (X = CCl ) 3 2 Scheme 4 1

Ollivier has reported the TEMPO-induced generation of alkyl radicals from alkylcatecholboranes, which in the presence of excess TEMPO can be trapped to yield alkoxyamine derivatives, Scheme 5.12

i) TEMPO, Catecholborane DMA, CH Cl 2 2 ii) DMPU, EtOH, CH Cl , rt 2 2

www.carbosynth.com © 2019 Carbosynth. All rights reserved. ‘Living’ free radical polymerisation techniques are of considerable interest to material scientists as a way of controlling macromolecular structure and yielding narrow polydispersity polymers with controlled molecular weights and chain architectures. TEMPO mediated polymerisation procedures have attracted considerable attention,13 and the initial limiting requirements of high temperatures and extended reaction times for these TEMPO mediated ‘living’ polymerisations have been addressed by the identification of rate enhancing additives.

References

1. Lebedev O et al (1960). Zhur Obshch Khim 30:1631. 2. Zanocco AL et al (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. 3. Anelli PL et al (1987). Fast and selective oxidation of primary alcohols to aldehydes or to carboxylic acids and of secondary alcohols to ketones mediated by oxoammonium salts under two-phase conditions. J Org Chem 52(12): 2559–2562. 4. Anelli PL et al (1990). A general synthetic method for the oxidation of primary alcohols to aldehydes: (S)-(+)-2-Methylbutanal [Butanal, 2-methyl-, (S)-]. Org Synth 69:212. 5. De Nooy AEJ et al (1996). On the use of stable organic nitroxyl radicals for the oxidation of primary and secondary alcohols. Synthesis 10: 1153-1174. 6. Zhao MM et al (2005). Oxidation of primary alcohols to carboxylic acids with sodium chlorite catalyzed by tempo and bleach: 4-methoxyphenylacetic acid [(Benzeneacetic acid, 4-methoxy-)]. Org Synth 81: 195. 7. Vogler T and Armido S (2008). Applications of TEMPO in Synthesis. Synthesis 2008(13): 1979-1993. 8. Barriga S (2001). 2,2,6,6-Tetramethylpiperidin-1-oxyl (TEMPO). Synlett 2001(4): 0563. 9. Wright PJ and English AM (2003). Scavenging with TEMPO* to identify peptide- and protein-based radicals by mass spectrometry: advantages of spin scavenging over spin trapping. J Am Chem Soc 125(28):8655-65. 10. Gilbert BC et al (1999). Radical cyclisations promoted by dimanganese decacarbonyl: A new and flexible approach to 5-membered N-heterocycles. Tetrahedron Letters 40(33), 6095-6098. 11. Studer A (2000). Tin-Free Radical Cyclization Reactions Using the Persistent Radical Effect. Angew Chem Int Ed Engl 39(6):1108-1111. 12. Ollivier C et al (1999). TEMPO-Induced Generation of Alkyl Radicals from B- Alkylcatecholboranes. Synlett 1999(6): 807-809. 13. Hawker CJ (1996). Advances in Living Free-radical Polymerization: Architectural and Structural Control. Trends Polym Sci 4(6): 183. z