TEMPO Catalyzed Oxidations

The Reaction

TEMPO (2,2,6,6-Tetramethylpiperidinyloxy or 2,2,6,6-Tetramethylpiperidine 1-oxyl) and its derivatives are stable nitroxy radicals used as catalysts in organic oxidation reactions. TEMPO was discovered by Lebedev and Kazarnovskii in 1960. The stable free radical nature of TEMPO is due to the presence of bulky substituent groups, which hinder the reaction of the free radical with other molecules.¹

TEMPO and its derivatives are used mainly for the oxidation of primary and secondary alcohols. TEMPO has excellent solubility properties in both organic solvents and aqueous media,¹ and is used with various reoxidants, such as hypochlorite (for oxidations in aqueous media) and Cu/O₂ (for oxidations in organic media).² In aqueous media, TEMPO is oxidized by the stoichiometric oxidant (sodium hypochlorite) to generate a nitrosonium cation, which is the actual oxidant of the alcohol. During the oxidation of the alcohol, the cation is reduced to a hydroxylamine. The hydroxylamine is then reoxidized back to a nitrosonium ion by a suitable oxidant, completing the catalytic cycle. Hypochlorite is employed as primary oxidant along with bromide as co-catalyst.²

TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl radical) and its derivatives are also catalysts for other oxidation reactions. They are economical substitutes for heavy metal reagents as highly selective oxidation catalysts. They catalyze synthetic reactions involved in the formation of C-C, C-O, C=O, C-N, and C=N bonds.³

Applications

TEMPO-mediated oxidation reaction has found applications in the following areas:

• 4-Amino-2,2,6,6-tetramethylpiperidine-1-oxy radical (4-amino-TEMPO)-mediated oxidation has been employed for the preparation of cellouronic acid, which was analyzed by size-exclusion chromatography attached with a multi-angle laser light scattering detector (SEC-MALS).⁴
• 2-Azaadamantane N-oxyl (AZADO) and 1-Me-AZADO exhibit superior catalytic proficiency as compared to TEMPO for the conversion of various sterically hindered alcohols to the corresponding carbonyl compounds.⁵

• TEMPO participates in the oxidation of regenerated cellulose (viscose rayon). The C6 primary hydroxyl groups in rayon were oxidized to carboxyl groups, thus affording water-soluble products.⁶
• TEMPO derivatives have been recently employed in post-polymerization modification processes for the grafting of polar species such as −OH or ester groups onto the polymers. 4-Hydroxy-TEMPO (HO-TEMPO) and 4-Benzoyloxy-TEMPO (BzO-TEMPO) have been used for the effective functionalization of poly[ethylene-co-(1-octene)]. Nitroxyl free radicals rapidly couple with carbon-centred radical species, such as the macroradicals. Thus can be used as functionalizing agents to graft the polar functionalities.⁷

• Coupling reaction between nitroxide derivatives and macroradical²
• Catalytic systems composed of TEMPO, Ce(IV), and NaNO₂ have been developed for the selective oxidation of different alcohols. Moderate to high yields (45.5–98.0%) of corresponding aldehydes and ketones are obtained in this reaction.⁸

• Synthesis of xanthouronic acid sodium salt (xanthouronan), via TEMPO-catalyzed regioselective oxidation of xanthan has been proposed. The antioxidant activity of xanthouronan was evaluated by using the 2,2′-diphenyl-1-picrylhydrazyle (DPPH) and hydroxyl radical procedures.⁹
• Preparation of pure (1→3)-β-polyglucuronic acid sodium salt, via 4-acetamido-TEMPO/NaClO/NaClO₂ catalyzed oxidation of curdlan, has been reported.¹⁰
• Optimization of the preparation of nanofibrillated cellulose (NFC) from the date palm tree has been achieved by monitoring the TEMPO-mediated oxidation time (degree of oxidation) of the pristine cellulose.¹¹

Recent Research and Trends

• Stable nitroxide radical bearing organic polymer materials have been developed. They have important applications as next generation energy storage materials.¹²
• Cu/nitroxyl catalysts are highly efficient and selective for the aerobic oxidative lactonization reaction of diols. The chemo- and regioselectivity of the reaction can be adjusted by changing the nitroxyl cocatalyst. Cu/ABNO catalyst system (ABNO = 9-azabicyclo[3.3.1]nonan-N-oxyl) has excellent reactivity with symmetrical diols and hindered unsymmetrical diols, while Cu/TEMPO catalyst system has excellent chemo- and regioselectivity for the oxidation of less hindered unsymmetrical diols.¹³
• Chemo-enzymatic modification of cellulose nanofibers (CNFs) in the presence of laccase (biocatalyst) and TEMPO or 4-amino-TEMPO (mediators) results in the introduction of surface active aldehyde groups.¹⁴
• The solid-solid 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO)-mediated electrolytic conversion of diphenylcarbinol to benzophenone has been investigated.¹⁵
• A novel method was developed for the eco-friendly electrochemical oxidation of alcohols without using expensive transition metal catalysts. A thin layer of ordered mesoporous silica (MCM-41) with well-oriented channels is constructed on an electrode surface, which was functionalized by using TEMPO as an electroactive organocatalyst. This electrocatalytic system has been employed for the fast, simple, selective and waste-free protocol for the oxidation of a wide variety of alcohols.¹⁶
• Magnetically separable organocatalyst (Fe₃O₄@SiO₂–TEMPO) has been reported as highly selective for the aerobic oxidation of 5-hydroxymethylfurfural (5-HMF) to 2,5-diformylfuran (DFF) under metal- and halogen-free conditions.¹⁷
• A light-responsive delivery system composed of gelly microspheres, which are made up of TEMPO-oxidized Konjac glucomannan (OKGM) polymers, has been fabricated. These polymers contain carboxyl (COO–) groups, which are crosslinked via ferric ions (Fe³⁺). Functional ingredients can be incorporated into these microspheres. Upon irradiation with sunlight, the microspheres degrade, thereby releasing the encapsulated component(s).¹⁸
• (bpy)CuI/TEMPO/NMI catalyst system (bpy = 2,2′-bipyridine, TEMPO = 2,2,6,6-tetrame-thylpiperidine-N-oxyl, NMI = N-methylimidazole) is useful for the rapid and highly selective oxidation of benzylic and aliphatic alcohols. The “(bpy)CuI/TEMPO” catalyst system employed in the reaction consisted of 5 mol % [Cu(MeCN)₄](OTf), 5 mol % bpy, 5 mol % TEMPO, and 10 mol % NMI in MeCN. Oxidation of benzyl alcohol was rapid while for the aliphatic alcohol (cyclohexylmethanol) it was slower.¹⁹
  
  Scheme for the above mentioned oxidation is shown below (Figure 6):