Figure 1. Examples of stable nitroxyl radicals widely used in synthetic chemistry and biology.
General Information:2,2,6,6-Tetramethylpiperidinyloxyl (TEMPO) is a stable nitroxyl radical used in organic synthesis for the oxidation of several functional groups including phosphines, amines, phenols, and most importantly alcohols. Nitroxyl radical oxidations benefit of a certain popularity, mainly due to the generally mild reaction conditions required and the low toxicity of the reagents employed. (1)
A part from being bench stable oxidants, nitroxyl radicals find also applications in polymer chemistry (to control the length of the polymers) as well as in biology and medicine to study processes involving radical species (2,3). Interestingly, TEMPO derivatives are also utilized in electron spin resonance spectroscopy as spin labels (3).
The exceptional stability of nitroxyl radicals can be explained by the lack of hydrogen atoms in alpha to the N-O radical or by the impossibility to form a nitrone C=N double bond (like for example in compounds having a bridged system that would violate the Bredt’s rule like ABNO). These molecular settings can prevent the nitroxyl radical to undergo a disproportionation reaction and consequent decomposition.
Reaction Mechanism: Many variants of TEMPO oxidations are known in the literature, especially regarding the choice of the secondary oxidants and of the reaction conditions, therefore in certain cases the reaction mechanisms can be more complex than the one described below (Figure 2) (4). However, it is generally accepted a mechanism in which the nitroxyl radical (TEMPO) is converted by a secondary oxidant into an oxoammonium salt, which is the actual oxidant species (5). This latter reacts with a molecule of alcohol converting it into the corresponding aldehyde. As a consequence a molecule of hydroxylamine is released, which is in turn re-oxidized to regenerate the TEMPO radical, and thereby closing the catalytic cycle.
Figure 2. General mechanism of TEMPO oxidations.
In light of the mechanism described, TEMPO oxidations can be run using both stoichiometric and catalytic conditions. In the early days oxoammonium salts like compound 1 (Scheme 1) were used to oxidize alcohols to aldehydes (6). Examples of oxidations using hydroxylamine 2 in the presence of mCPBA have been also reported in the literature during the 60’s. Nitroxyl radicals were also effective oxidants when used in catalytic amounts and in the presence of a secondary oxidant (mCPBA) (6).
Scheme 1. Stoichometric and catalytic oxidation examples.
It was in the 80’s however (7) that Anelli described the first examples of TEMPO catalyzed oxidations using catalytic nitroxyl radical 3 under phase transfer catalysis and NaClO (bleach) as the secondary oxidant (Scheme 1). These seminal discoveries made the reaction widely employed and it was also used in a few industrial applications (8).
The variants of these early reaction conditions are really infinite nowadays, and a number of quite sophisticated end refined examples are available on the literature for specific purposes.
Nitroxyl Radicals and Reaction Systems With Improved Reactivity. Improved TEMPO derivatives have been obtained by substitutions in the 4-position in order to influence the redox potential of the molecule and consequently its oxidant power. It is also worth mentioning the fact that a number of different combinations of nitroxyl radicals and external oxidant are possible. Among the more popular co-oxidants used are, just to name a few: PhI(OAc)2, Ruthenium, Cobalt and Manganese complexes, and even environmentally friendly Iron and Copper complexes.
Figure 3. Examples of more reactive nitroxyl radicals species, analogues of TEMPO.
In order to obtain nitroxyl radicals with higher reactivity, stable radicals possessing less steric hindrance near the radical center have been prepared and are available now on the market. They can be useful for particularly reluctant alcohols (Figure 2) or slow reactions (9) with traditional TEMPO.
Carbon-carbon Bond Formation Using TEMPO. TEMPO oxidations can be used also to form C-C bonds. Below are reported a few examples of in situ generated imines that can undergo several reaction types, including a remarkable one-pot hetero Diels-Alder initiated by a nitroxyl radical amine oxidation triggered by ABNO.
Scheme 5. Examples of TEMPO catalyzed C-C bond formation.
Nitroxyl Radicals in Biology and Medicinal Chemistry. Nitroxyl radicals are widely used in diagnostics and in biomedical research where they find applications mainly as contrast agents in nuclear magnetic resonance (10) and electron paramagnetic resonance (3). Nitroxyl radicals can also be conjugated with other molecules and delivered into a specific cellular or tissue compartment. For example nitroxyl radicals conjugated with phospholipids can be used to study cellular membranes trafficking. More recently the use of nitroxyl radicals as therapeutic agents is emerging as a novel field of investigation. When conjugated with biologically relevant molecules,stabilized radicals may be used as drug delivery systems to access specific areas of a body for the treatment of a disease (11).
1) Bobbitt J.M., Bruckner C., and Merbouh N., Org. React., 2009, 74, 106.
2) a) Pattison D.I. , Lam M., Shinde S.S., Anderson R.F.,Davies M.J. Free Radical Biology and Medicine, 53, 9, 2012, 1664. b) Ikeda M., Nakagawa H, Ban S., Tsumoto H., Suzuki T., Miyata N. Free Radical Biology and Medicine, 49,11,2010, 1792.
3) Kocherginsky N.,Swartz H.M.,Sentjure M., Nitroxide spin labels: reactions in biology and chemistry ISBN 0-8493-4204-X.
4) a) Hoover J.M., Ryland B.L., Stahl S. J. Am. Chem. Soc., 135, 2013, 2357−2367. b) Szpilman A. M., Iron M.A., Chemistry a European Journal :DOI: 10.1002/chem.201604402.
5) Angelin M., Hermansson M., Dong H., Ramström O., Eur. J. Org. Chem., 2006, 4323.
6) Tojo, G., Fernandez, M.I. Oxidation of Primary Alcohols to Carboxylic Acids A Guide to Current Common Practice. ISBN: 978-0-387-35431-6 and references therein.
7) Anelli L., Biffi C, Montanari F. and Quici S., J. Org. Chem., 1987, 52, 2559.
8) Ciriminna R., Pagliaro M., Org. Process Res. Dev., 2010, 14, 245.
9) Cao Q, Dornan L.M., Rogan L., Hughes N. L.,and Muldoon M.J., Chem. Commun., 50, 2014, 4524.
10) Zhelev Z., Bakalova R., Aoki I., Matsumoto K., Gadjeva V., Anzai K., Kanno I. Chem. Commun. 2009, 1, 53.
11) Grigor'ev I.A., Tkacheva N.I., Morozov S.V. Curr Med Chem. 21(24), 2014, 2839.
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