Cutting-edge research for a greener sustainable futureszolcsanyi/education/files/Organicka... · 2015-02-12 · Transition metal based catalysts in the aerobic oxidation of alcohols

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Cutting-edge research for a greener sustainable future

COVER ARTICLECardona and ParmeggianiTransition metal based catalysts in the aerobic oxidation of alcohols

www.rsc.org/greenchem Volume 14 | Number 3 | March 2012 | Pages 531–856

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www.rsc.org/greenchem TUTORIAL REVIEW

Transition metal based catalysts in the aerobic oxidation of alcohols

Camilla Parmeggiani*a,b and Francesca Cardona*a

Received 27th October 2011, Accepted 19th December 2011DOI: 10.1039/c2gc16344f

The oxidation of alcohols to the corresponding carbonyl compounds is a pivotal reaction in organicsynthesis. However, traditional oxidants are often toxic and release considerable amounts of by-products.As an alternative, oxygen (or even better air) is among the cheaper and less polluting stoichiometricoxidants, since it produces no waste or water as the sole by-product. The implementation of a transitionmetal-based catalyst in combination with oxygen represents an emerging alternative to the traditionalprocedures. This review aims to give an overview on the most important advances made by the scientificcommunity in the last 15 years in the field of aerobic oxidations of alcohols catalyzed by transition metalsin the form of homogeneous catalysts, heterogeneous catalysts and, more recently, nanoparticles.

Introduction

Oxidation reactions are among the most useful and used reac-tions in industrial processes. However, at the same time, they areamong the most polluting and hazardous processes, often occur-ring with a high E-factor (mass of waste per mass unit ofproduct)1 and delivering considerable amounts of toxic waste,for instance metal salts in oxidations employing stoichiometric

Cr(VI) or Mn(VII) derivatives or nitrogen oxides in oxidationscarried out with HNO3. In particular, the oxidation of primaryand secondary alcohols to the corresponding carbonyl com-pounds is of fundamental importance in organic synthesis, dueto the wide ranging utility of these products as important precur-sors and intermediates for many drugs, vitamins and fragrances.A recent publication by Pfizer’s medicinal chemists2 showed thatthe three most popular oxidants used in Pfizer for the oxidationof primary alcohols to the corresponding aldehydes are theDess–Martin periodinane3 or its precursor IBX, the Swernreagent4 and the TPAP/NMO5 system. All of these methods stillhave poor atom efficiencies6 and significant scale-up issues. As aresult, the oxidation of an alcohol to a carbonyl compound, inspite of being a fundamentally important reaction, yet is actuallyavoided by the pharmaceutical industry.7 From an environmental

Dr Camilla Parmeggiani

Dr Camilla Parmeggiani wasborn in Fiesole, Italy, in 1981.She obtained her Ph.D. inChemistry in 2010 under thesupervision of Prof. A. Goti,University of Florence. Sheinvestigated the synthesis ofpolyhydroxylated iminosugarswith Prof. A. Goti at the Uni-versity of Florence, organome-tallic addition to nitrones toobtain pyridine-based imino-sugars with Prof. P. Merinoduring her degree work at the

University of Zaragoza and allenes addition to nitrones withProf. H.-U. Reiβig at Freie Universität in Berlin during herPh.D. course. She is currently doing a post-doctoral fellowshipat CNR-INO working on liquid crystal elastomers syntheses withProf. D. Wiersma.

Dr Francesca Cardona

Dr Francesca Cardona wasborn in Florence, Italy, in 1971.After her Ph. D. in Chemistryunder the supervision ofProf. A. Brandi (1998) she wasa post-doctoral fellow at theUniversity of Lausanne, Swit-zerland, with Prof. P. Vogel(1999–2000). From 2002 she isa researcher at the Universityof Florence. In 2006 shereceived the “G. Ciamician”silver medal of the ItalianChemical Society, as the best

organic chemist of the year under 35 years old. She has morethan 50 publications and 5 chapters in scientific books. Researchinterests: stereoselective syntheses of iminosugars, new greenoxidation methods, parallel kinetic resolutions by cycloadditionreactions.

aDepartment of Chemistry, ‘Ugo Schiff’ University of Florence, viadella Lastruccia 3–13, Sesto Fiorentino (FI), Italy. E-mail: [email protected]; Fax: +39 0554573531; Tel: +39 0554573504bCNR-INO and European Laboratory for Non-Linear Spectroscopy(LENS), University of Florence, via N. Carrara 1, Sesto Fiorentino (FI),Italy. E-mail: [email protected]; Fax: +39 0554572451;Tel: +39 0554573536

This journal is © The Royal Society of Chemistry 2012 Green Chem., 2012, 14, 547–564 | 547

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www.rsc.org/greenchem


point of view, it is of particular importance to develop methodswhich use cleaner oxidants and minimize the amount and tox-icity of the released waste. Moreover, the use of catalysis, thatallows processes to occur under mild conditions in order to savethe overall implied energy, is strongly encouraged.8 In thisrespect, the recovery and reuse of the catalyst is a further impor-tant goal.

In this review, we will present an overview of the recentadvances made by the international scientific community in thisfield. Oxygen (or even better air) is among the cheaper and lesspolluting stoichiometric oxidants, since it produces no waste orwater as the sole by-product.9 The implementation of a catalystin combination with molecular oxygen represents an emergingalternative to the traditional procedures.

In the development of transition metal-catalyzed aerobicalcohol oxidations, several challenges exist, as the need of lowpressures of O2 especially in flammable organic solvents, mildreaction conditions, low catalyst loadings, and avoidance ofcostly or toxic additives. Another main issue is the functionalgroup tolerance and the chemoselectivity of the alcohol trans-formation when other groups susceptible to oxidation arepresent. A further goal is the development of methods able tooxidize one class of alcohols in the presence of another. Finally,an ultimate goal is the development of diastereo- and/or enantio-selective alcohol oxidations. Both homogeneous and hetero-geneous catalytic systems have been developed,10 and morerecently, metals in the form of nanoparticles.11 Indeed, especiallyin industrial chemistry, heterogeneous catalytic systems are pre-ferred over homogeneous ones due to easier recyclability.However, they usually suffer from low catalytic activity relativeto their homogeneous counterparts. Much effort has been madeto overcome the difficulties encountered with heterogeneous cat-alysis, because reduction of environmental loading due to easyseparation and reuse of the catalyst could result. Also in view ofa possible recycling and reuse of the catalyst, alternative solventssuch as ionic liquids, fluorinated solvents and supercritical CO2

have been taken in consideration.This review, that does not pretend to be exhaustive, aims to

give an overview on the most significant procedures developedin this extremely investigated field of the research. Due to thehuge amount of literature available on this topic, a choice of themetals was made, trying to analyze and discuss the most versa-tile and studied metal catalysts (copper-, ruthenium-, palladium-,gold-, iron-, vanadium-, iridium-, osmium-, and cobalt-basedcatalysts), highlighting their synthetic potential and alwaystaking into account the previously mentioned synthetic chal-lenges. Some selected examples of catalysis by bimetallicsystems will also be briefly presented while discussing thevarious metals.

Homogeneous, heterogeneous and nanocatalysis

An homogeneous catalyst (typically a soluble metal complex) isin the same phase as the reactants, with the advantage of havingall catalytic sites accessible to all reagents. Proper modificationof the ligands allows to tune the chemo-, regio- and enantioselec-tivity of homogeneous catalysts, that have several other advan-tages such as high efficiency, high selectivities, and yields. They

are used both in academia and in industry. However, their use inindustrial applications (where metal contamination is highlyregulated) is limited by the difficulties encountered in catalystseparation from the final products. Removal of trace amounts ofcatalyst from the target product is of crucial importance and stillremains a key challenge that homogeneous catalysis has to face.

To overcome the separation problems encountered in homo-geneous catalysis, chemists have introduced heterogeneous cata-lysts. Even if the first attempts of heterogenization were madewith polymeric materials as solid supports, the greatest part ofthe novel heterogenized catalysts are based on silica supports,since silica has an excellent chemical and thermal stability, goodaccessibility, and porosity. Moreover, organic moieties can berobustly anchored to the surface to provide catalytic centers (orligands) for metal-based catalysis. These hybrid organic inor-ganic catalysts can anchor the catalytic metal through covalentbinding or through simple adsorption. However, some issues stillremain, as the accessibility of all active sites to reagents whichrenders heterogeneous catalysts often less efficient than homo-geneous ones, and the leaching of metals from solid supports,which again needs separation of traces of metal from the finalproduct.

Nanoparticles are emerging as excellent sustainable alterna-tives to conventional solid supports, since they increase theexposed surface area of the active component of the catalyst,thus enhancing the contact between the reagents and the catalyticcenter, as it happens in homogeneous catalysis. However, ifnanoparticles are immobilized on a solid, insoluble support, theycan be easily separated from the reaction mixture, which is themain advantage of heterogeneous catalysis. Thus, nanocatalysisis generally considered as the “frontier”, or the “bridge” betweenhomogeneous and heterogeneous catalysis, since it offers a novelsustainable alternative to conventional materials.11

Copper-based catalysts

Homogeneous catalysts

Copper seems an appropriate metal for the catalytic oxidation ofalcohols with O2 since it is present in Nature as the catalyticcentre in a variety of enzymes (e.g. galactose oxidase) that cata-lyze this conversion. Some catalytically active biomimeticmodels for these enzymes have been designed and constituteseminal examples in this area.12 In 1984, Semmelhack reportedthe first practical Cu-catalyzed aerobic oxidation of alcohols,using Cu in combination with the stable nitroxyl radical TEMPO(2,2,6,6-tetramethyl-1-piperidine-N-oxyl) in DMF as solvent;however, this system was efficient only for activated primaryalcohols.13 Markό and co-workers pioneered much of the cata-lyst development. In their initial report, a combination of CuCl(5 mol%), phenantroline (5 mol%) and di-tert-butylazodicarbox-ylate, DBAD (5 mol%) allowed oxidation of alcohols with greattolerance of other functional groups.14 However, this systemrequired the presence of 2 equivalents of a base (K2CO3) andwas not consistent for the oxidation of primary aliphatic alco-hols. In these basic conditions, alcohols bearing α-stereogeniccenters could be oxidized with no racemisation. In these firstreports, the active catalyst was postulated to be heterogeneous,and absorbed on the insoluble K2CO3, that seems to also serve

548 | Green Chem., 2012, 14, 547–564 This journal is © The Royal Society of Chemistry 2012

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as a solid support, since filtration of the mixture gave a solutiondevoid of any oxidizing ability. A change of the solvent fromtoluene to fluorobenzene allowed use of a catalytic base,15 andfurther investigations led to the discovery that addition of cataly-tic N-methylimidazole dramatically enhanced the activity of thesystem allowing efficient conversion of primary aliphatic alco-hols (Scheme 1).16 In these optimized conditions all reagentsand catalysts are in the same reaction phase and thus the catalysisis undoubtedly homogeneous.

The use of such a system in combination with a diazo reagentand triphenyl phosphine recently allowed a domino one-pot oxi-dation–olefination process that could be applied to a wide varietyof alcohols including aliphatic secondary ones. α-Chiral alcoholscould be converted into olefins without any detectable racemiza-tion (Scheme 2).17

In addition to the work of Markό and co-workers, othergroups reported chemoselective oxidations of primary alcoholswith Cu in combination with TEMPO.18 Sheldon and co-workers showed that CuBr2 and TEMPO in the presence of 2,2′-bipyridine (bpy) as a ligand for Cu led to the oxidation ofseveral primary alcohols with no overoxidation to carboxylicacids. The advantage of this very mild procedure was that excel-lent conversions were obtained with air (instead of pure oxygen)at room temperature (Scheme 3).19,20

The author postulated a copper mediated dehydrogenationmechanism, in which TEMPO acts as a hydrogen acceptor and isable to regenerate the active Cu(II) species (Scheme 4).21

This mechanism, analogous to that observed for galactoseoxidase, was in contrast with the previously proposed one.13

When mixtures of primary and secondary alcohols were reactedin these conditions, only the first were converted. The lack ofreactivity of secondary alcohols was explained by the authors byassuming a steric hindrance of an additional R′ group of a sec-ondary alcohol preventing the formation of species A(Scheme 5), and the stabilization of the radical species B by thesecond β-hydrogen of a primary alcohol, which is obviously notpossible with a secondary alcohol.

Careful analysis of a series of catalysts/ligands/bases/solventsfor the copper-catalyzed aerobic oxidation of alcohols ledrecently to the discovery of a new (bpy)CuI/TEMPO systemwhich showed, in the presence of NMI as the base and inCH3CN as solvent, a broad scope, excellent functional group tol-erance and exquisite selectivities for 1° over 2° alcohols, allow-ing selective oxidation of diols without the need of protectinggroups.22

In the presence of an enantiopure bidentate ligand, Sekar andco-worker achieved an efficient kinetic resolution of several sec-ondary benzylic amino alcohols (Scheme 6).23

Scheme 1 The Cu-catalytic system developed by Markό and co-workers.

Scheme 2 Copper-catalyzed tandem oxidation-olefination process.

Scheme 3 The Cu(II)–TEMPO catalyzed aerobic oxidation of primaryalcohols by Sheldon and co-workers.

Scheme 4 Proposed role of TEMPO.

Scheme 5 Explanation for the lack of reactivity of secondary alcohols.

Scheme 6 Oxidative kinetic resolution of secondary benzylic aminoalcohols.


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Several other groups reported the use of alternative solventswith the aim of allowing catalyst recycling and simple productpurification. In 2002 Ansari and Gree developed a CuCl–TEMPO catalyzed aerobic oxidation of several primary and sec-ondary benzylic and allylic alcohols in the 1-butyl-3-methylimi-dazolium hexafluorophosphate ([bmim]PF6) ionic liquid. Inthese conditions, the authors could recycle the ionic liquidbut not the catalyst.24 Jiang and Ragauskas reported the useof a pyridyl based ionic liquid, 1-butyl-4-methylpyridiniumhexafluorophosphate ([bmpy]PF6) in a room-temperature aerobicoxidation of primary alcohols catalyzed by a three-componentsystem acetamido-TEMPO/Cu-(ClO4)2/DMAP, that allowed therecovery and reuse of catalyst up to five runs without loss ofactivity (Scheme 7).25

More recently, they reported a similar three component systemunder solvent-free conditions, and simply recovered the threecatalyst components by addition of a non polar solvent (hexane)that selectively dissolved the product aldehydes.26 In case ofsolid alcohols, PEG-200 (not oxidized in these reaction con-ditions) was used as solvent.

To enhance catalyst recyclability, Knochel and co-workersalso used a biphasic solvent system, (chlorobenzene/perfluoroc-tyl bromide), and a pyridine ligand containing fluorinated pony-tails for a CuBr–Me2S–TEMPO catalytic system, and they couldrecover and reuse the fluorous layer containing the catalyst up toeight times with little loss of activity.27 Furthermore, the selec-tive aerobic oxidation of benzyl alcohols to the correspondingbenzaldehydes could be achieved using the sole water as solventwithout the need of any organic or alternative solvent, employinga multinuclear copper(II) compound in combination withTEMPO at 25–80 °C.28

Heterogeneous catalysts

In contrast to the great development of homogeneous copper-based catalysts, heterogeneous systems are still largely unex-plored. One of the few examples is a recyclable Cu–Mn mixedoxide supported on active carbon that was employed in combi-nation with TEMPO as co-catalyst for the aerobic oxidation ofseveral benzylic primary alcohols.29 Moreover, a pioneeringstudy on the use of silica-supported complexes in supercriticalCO2 was recently reported.30

Ruthenium-based catalysts


Ruthenium compounds have been extensively studied as cata-lysts for the aerobic oxidation of alcohols.31 This metal gives thewidest range of oxidation states from +2 to +8, therefore a largevariety of oxidative transformations has been developed. The

activity of common low valent ruthenium precursors such asRuCl2(PPh3)3 can be increased by the use of ionic liquids as sol-vents.32 Ruthenium-based compounds have been extensivelyinvestigated as catalysts for hydrogen transfer reactions. Thesesystems, in combination with a hydrogen acceptor as co-catalystand dioxygen as oxidant, can be readily adapted in a multicataly-tic process. For example Bäckvall and co-workers, employing abenzoquinone and a cobalt–Schiff’s base complex, developedone of the fastest catalytic systems reported for the oxidation ofsecondary alcohols (Scheme 8).33 The sole weakness of this pro-cedure was the requirement of high loading of 2,6-dimethoxy-1,4-benzoquinone (20 mol%), which served as electron transfermediator (ETM). Recently Bäckvall and co-workers reported, incombination with Ru Shvo’s catalyst,34 a second generation Cohybrid catalyst that comprises cobalt salens and pendant hydro-quinone groups, thus avoiding the use of benzoquinone andaffording excellent conversions of alcohols.35

On the other hand, Ishii and co-workers demonstrated that theregeneration of benzoquinone can also be achieved in theabsence of the cobalt co-catalyst in PhCF3 as solvent.

36 In theseconditions, primary alcohols could be chemoselectively oxidizedin the presence of secondary ones.

Sheldon and co-workers developed one of the most efficientsystems for the aerobic oxidation of non activated primary andsecondary alcohols using RuCl2(PPh3)3 in combination withTEMPO in PhCl at 100 °C (Scheme 9).37

Overoxidation of primary alcohols to carboxylic acids wascompletely suppressed by catalytic TEMPO, which avoided theautooxidation of aldehydes by efficiently scavenging free radicalintermediates. Unfortunately, this system required 10 barpressure and a number of alcohols containing heteroatoms (O,N, S) still remained unreactive, probably due to their coordi-nation to the ruthenium metal centre and subsequent catalystinactivation. An oxidative hydrogenation mechanism, analogousto that proposed by Bäckvall and co-workers for the Ru/quinonesystem, can be envisaged for the Ru/TEMPO system.

Scheme 7 Cu(II)–TEMPO-catalyzed oxidation in ionic liquid.

Scheme 8 Bäckvall’s multicatalytic system for the aerobic oxidation ofalcohols.

Scheme 9 Ruthenium/TEMPO catalyzed oxidation of alcohols.


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High valent perruthenate catalysts, i.e. tetra-n-propylammo-nium perruthenate (TPAP), are excellent air-stable Ru-catalysts,non volatile and soluble in a wide range of organic solvents. In1997 Markό et al.38 and Ley et al.39 simultaneously showed thatTPAP is able to perform the aerobic oxidation of alcohols;however, both systems had some drawbacks such as the need ofhigh catalyst loading in a chlorinated solvent39 or the need ofhigh temperature (70–80 °C) (Scheme 10)38 and were not effec-tive for the oxidation of primary aliphatic alcohols in contrast tousing NMO as the stoichiometric oxidant.5

More recently, Katsuki and co-workers have published severalpapers on Ru-salen based catalysts. They designed an efficientcatalyst for the photo-induced chemoselective oxidation ofprimary alcohols in the presence of secondary ones,40 and uponfurther derivatization of chiral ligands they could accomplishefficient kinetic resolutions of secondary alcohols41 and desym-metrization of meso-diols (Scheme 11).42 Moreover, recently,they developed a Ru-salen catalyst that did not need furtherirradiation conditions.43

In conclusion, ruthenium has proved to be effective for thisreaction, but some further work remains to develop catalysts thatemploy low catalyst loading and perform under mild conditions.


A pioneering work by Ley and co-workers dates back to 1997and reports the use of polymer-supported perruthenate (PSP) inthe aerobic oxidation of alcohols; however, this catalyst sufferedfrom oxidative degradation of the polymer support.44 Soon laterthe same authors found a mesoporous silicate (MCM-41) asan efficient alternative support for TPAP and showed the

recyclability of this catalyst up to 12 times (Scheme 12);45 thismaterial was used in a ten-step linear synthesis of the powerfulanalgesic natural product epibatidine, which employed only solidsupported reagents.46

The grafting of an organic moiety onto solid surfaces allowsthe building of organic-inorganic hybrid materials, which arepromising supports for catalyst design.47 For example, organi-cally modified silicates (ORMOSIL) were studied by Pagliaroand Ciriminna for the encapsulation of the TPAP via a sol–gelprocess (SG-TPAP).48 However, the first reports did not show awide substrate scope; in order to broaden the application of theSG-TPAP catalyst, alternative conditions were investigated suchas supercritical carbon dioxide (scCO2)

49 and the introduction ofionic moieties50 or of fluoroalkyl chains51 into the silica matrixof SG-TPAP (Scheme 13). They reported the use of hybridfluorinated silica glass doped with TPAP (denoted FluoRuGel)as a versatile catalyst for the conversion of different alcohols indense CO2.

51–53

The perruthenate ion was also immobilized on a polymer sup-ported 1-vinyl-3-butylimidazolium chloride, and the oxidation ofbenzyl alcohol to benzaldehyde was conducted in scCO2 at80 °C. After extraction of the products with scCO2, this catalystcould be reused.54

Low valent ruthenium species have been also supported onsolid matrices. Zeolites impregnated with RuO2 nanoclusters(RuO2-FAU) were found to be effective and selective catalystsfor a wide variety of both activated and unactivated substrates.These materials display a strong shape selectivity due to uniformpore size, and in a competitive experiment benzyl alcohol wasreacted in the presence of unreacted 9-hydroxyfluorene.55

Kaneda and co-workers developed a monomeric ruthenium

Scheme 10 TPAP-catalyzed aerobic oxidation of alcohols.

Scheme 11 Ru-salen catalyzed oxidative desymmetrization of meso-diols.

Scheme 12 Ley’s modified mesoporous silicate materials MCM-41.

Scheme 13 TPAP-heterogeneous catalysts developed by Pagliaro andco-workers.


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cation on the surface of hydroxyapatite (Ru/HAP), which gaveefficient conversions of primary, secondary and functionalizedalcohols (Scheme 14). The main disadvantage of this processwas the need for a high catalyst loading (17 mol%).56,57

Ruthenium supported on alumina (Ru(OH)x/Al2O3) wasdeveloped by Yamaguchi and Mizuno and demonstrated theability to oxidize both primary, secondary and non-activatedalcohols in PhCF3 as solvent or even in solvent-free con-ditions.58 Moreover, the use of superparamagnetic nanoparticlesas a supporting material for immobilized metal catalysts wasreported. For example, Mizuno and co-workers showed that aruthenium hydroxide species on magnetite (Ru(OH)x/Fe3O4) per-formed very well, and catalyst/product(s) separation was extre-mely simple. Indeed, after completion of the oxidation reaction,a permanent magnet was attached to the outside wall of the glassreactor to magnetically “hold” the catalyst, and the reaction sol-ution including the product(s) was separated by simpledecantation.59

In contrast to the many reports of inorganic supports ororganic–inorganic hybrid materials, after the pioneering PSP byLey and co-workers44 only a few polymer-supported catalystswere reported. Kobayashi developed a polymer incarceratedruthenium (PI Ru), based on the technique of microencapsula-tion and cross-linking from a polystyrene-based copolymer andruthenium chloride hydrate as the metal source (Scheme 15).60

However, this catalyst needed the presence of 15 mol% ofTEMPO to show wide applicability, and leaching of Ru metalwas observed in some cases (never exceeding 0.72%), which istypical of polymer supported catalysts, that suffer from lowchemical and/or mechanical resistance. The authors later showedthat introduction of inorganic species to organic moieties, thusgoing back to the creation of organic–inorganic hybrid catalystsgenerated by the sol–gel approaches, allowed the synthesis of aneffective heterogeneous catalyst which worked well without theneed of any additive, avoiding the leaching of Ru.61

The main problem with all these heterogeneous catalysts isthat they can be accessed with some difficulties since they arehandmade and/or expensive. Much effort has been devoted todevelop efficient methods using the readily available carbon-sup-ported metal catalysts.10

Ruthenium is less expensive than Au, Pd or Pt; however, oneof the few reports of Ru/C-catalyzed procedures was presentedrecently by Sajiki and co-workers, who showed that 10% Ru/Cas a catalyst in toluene (at 50 °C) under an oxygen atmospherewas able to convert various secondary and primary benzylicalcohols to the corresponding carbonyl compounds and primary

aliphatic alcohols to carboxylic acids when water was added as aco-solvent (Scheme 16).62

Palladium-based catalysts


Overall, Pd(II) catalysis represents one of the most mature fieldsin the aerobic oxidation of alcohols. Much effort has beendevoted to finding synthetically useful methods, and some excel-lent reviews on this topic have appeared.63 Many mechanisticstudies have been undertaken and a generally accepted mechan-ism involves initial coordination of the alcohol to the PdII cata-lyst A to give intermediate B (Scheme 17). An exogenous basehelps deprotonation of the alcohol to yield the PdII-alkoxideintermediate C. Then, β-hydride elimination furnishes the PdII-hydride intermediate D, that undergoes reductive elimination togive E.63b,64,65 The transient Pd(0) species E is metastable andprone to aggregation to bulk palladium metal (Pd black) withconcomitant loss of catalytic activity. One approach to avoid thisis to add coordinating ligands, which stabilize the transient Pd(0)species.

The first synthetically useful system was reported in 1998 byPeterson and Larock, who showed that simple Pd(OAc)2 in com-bination with NaHCO3 as a base in DMSO as solvent catalyzedthe aerobic oxidation of primary and secondary allylic andbenzylic alcohols to the corresponding aldehydes and ketones,respectively.66 The replacement of the non-green DMSO by animidazole-type ionic liquid resulted recently in a higher activityof the Pd-catalyst.67 However, this method suffered from narrowsubstrate scope. Uemura and co-workers reported an improvedprocedure using Pd(OAc)2 (5 mol%) in combination with pyri-dine and 3 Å molecular sieves in toluene at 80 °C,68 that

Scheme 14 Heterogeneous Ru/HAP catalyst developed by Kanedaand co-workers.

Scheme 15 Polymer incarcerated (PI) ruthenium catalyst.

Scheme 16 Ru/C-catalyzed aerobic oxidation of alcohols.


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allowed oxidation of primary and secondary aliphatic alcohols inaddition to benzylic and allylic ones. When applied to tert-cyclo-butanols, this reaction proceeded with cleavage of the C–C bond(Scheme 18).69 This approach could also be employed underfluorous biphasic conditions.70

A much more active catalyst is represented by a water-solublepalladium(II) complex of sulfonated bathophenantroline intro-duced by Sheldon and co-workers.71 This stable, recyclable cata-lyst allowed oxidation in a two-phase aqueous–organic mediumin 5 h at 100 °C/30 bar air with 0.25 mol% catalyst. No organicsolvent was required (except for solid alcohols) and the carbonylproduct was recovered easily by phase separation. Primary alco-hols afforded the corresponding carboxylic acids via further oxi-dation of the aldehyde intermediate; otherwise, in the presenceof 1 mol% of TEMPO, the aldehyde was obtained in high yield(Scheme 19).71 Pd-neocuproine (in the presence of ethylene car-bonate as co-solvent) was found to be even more active andexceptionally tolerant to many functional groups such as CvCbonds, triple bonds, halides, ethers, amines etc., thus showing abroad synthetic utility.72 However, a more detailed recent investi-gation of this latter ligand proved that in this case formation ofPd nanoparticles, which are presumably the active catalyticspecies, occurs (see later for a more detailed discussion).73

One of the main problems associated with homogeneousPd(II)-catalysts is often represented by Pd black formation. Tsujiand co-workers used substituted pyridines as ligands to preventformation of Pd black, allowing oxidations to be performedunder air and using low catalyst loading.74 Sigman and co-workers also developed three novel Pd(II)-catalysts,75 and in a

comparison study they evaluated the substrate scope and thereaction conditions of each of them, concluding that thePd(OAc)2/TEA system represents the most convenient amongthe three developed.76 For example, this catalyst was employedfor the direct conversion of α-hydroxy ketones into quinoxalines(Scheme 20).77

Another nice example of Pd oxidation catalysis in tandemreactions was shown by Lebel and Paquet, who applied the cata-lyst developed by Sigman75b to the one-pot synthesis of alkenesthrough a tandem oxidation/olefination process (Scheme 21).78

In the presence of a chiral diamine, the scope of these oxi-dations can be expanded to asymmetric catalysis, as for examplethe oxidative kinetic resolution (OKR) of racemic secondaryalcohols79 or the oxidative desymmetrization of meso-diols.Sigman et al. and Stoltz et al. independently discovered80 that inthe presence of the chiral diamine (−)-sparteine, which plays adual role of chiral ligand for Pd and exogenous chiral base,81 thePd(II)-catalyzed aerobic oxidation of alcohols afforded efficient

Scheme 17 The generally accepted mechanism of the aerobic PdII-catalyzed oxidation of alcohols.

Scheme 18 Pd(II)-catalyzed oxidative ring cleavage of tert-cyclobuta-nols under O2 atmosphere.

Scheme 19 Sheldon’s Pd-catalyzed aerobic oxidation of alcohols.

Scheme 20 Quinoxaline synthesis via a tandem oxidation process.

Scheme 21 One-pot Pd-catalyzed oxidation and Rh-catalyzed methy-lenation reaction.


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OKRs of secondary alcohols, with enantiomeric excesses up to99.8% (Scheme 22).82 This methodology was recently applied tothe enantioselective total synthesis of various alkaloids,83 and tothe kinetic resolution of key pharmaceutical building blocks, rel-evant to the enantioselective preparation of Prozac®, Singulair®

and the promising hNK-1 receptor antagonist from Merck.84

This is an excellent method, leading to remarkably high eevalues under optimized conditions; the main limitation of spar-teine as a chiral ligand is that only the (−)-enantiomer is avail-able in large quantities, and this will remain a problem until aneffective method is found for the preparation of quantities of itsenantiomer or a surrogate thereof.85 However, all the Pd(II)-cata-lysts reported to date are not widely used on a larger industrialscale. Catalysts with improved stability and activity need to bedeveloped and the research is still very active in this field. Arecent study investigated the use of N,O-ligated Pd(II) com-plexes, which compared well with the previously reported N,N-ligands in the aerobic oxidation of 2-octanol on the gram scale.86


Besides the aerobic oxidation of alcohols, palladium catalyzesmany oxidative transformations including epoxidation ofalkenes, oxidation of terminal alkenes to ketones and otherWacker-type reactions, oxidation of alkanes, hydroxylation ofbenzenes, and oxidative coupling reactions.87 Among the tran-sition metals, palladium shows very promising catalytic proper-ties in the form of heterogeneous metal catalysts ornanoparticles. As an example, Uemura and co-workers heteroge-nized Pd(OAc)2 on a naturally produced basic clay mineral,hydrotalcite, and applied it to the oxidation of allylic alcoholssuch as geraniol and nerol.88

The general routes to nanoclusters/nanoparticles synthesis arebased on the chemical reduction of transition metal salts with theappropriate reducing agent in the presence of a stabilizer for themetal. The resulting stabilized metal nanoclusters dispersed insolution can be used as catalysts as such or subsequently hetero-genized on solid supports by different means (e.g. surfaceadsorption, covalent anchoring, embedding by sol–geltechniques).

Kaneda and co-workers reported hydroxyapatite-supportedpalladium nanoclusters (Pd/HAP-0) prepared from stoichiometricHAP with [PdCl2(PhCN)2] as a metal source.89 Fresh Pd/HAP-0 had an induction period of about 10 min, in which Pd(II)species were converted into Pd(0) nanoparticles. A wide varietyof alcohols, also bearing heteroatoms, were oxidized with thisheterogeneous catalyst in trifluorotoluene at 90 °C, in water at110 °C or in solvent-free conditions. 1-Phenyl ethanol was oxi-dized on a quite large scale (30 g) without any solvent at160 °C.

An amphiphilic resin dispersion of palladium nanoparticles(ARP-Pd) was reported by Uozumi and Nakao, readily preparedby reduction of a PS-PEG resin-supported Pd(II) complex withbenzyl alcohol (Scheme 23). This catalyst was applied to theaerobic oxidation of benzylic, allylic and secondary aliphaticalcohols in refluxing water.90 In the case of primary aliphaticalcohols, the corresponding carboxylic acids were obtained inexcellent yields in the presence of K2CO3.

However, organic polymers used as support for Pd nanoclus-ters are potentially susceptible to oxidative degradation underaerobic oxidative conditions. Besides the already mentionedhydrotalcite and hydroxyapatite minerals, an inorganic alterna-tive for forming a scaffold in which three-dimensional disper-sions of nanoparticles can be supported is represented byordered mesoporous structures (such as MCM-41 and SBA-15)with regular channel and pore diameters in the range of 2 to30 nm. These supports were used by Karimi and co-workers todevelop a new type of palladium catalyst immobilized on func-tionalized SBA-15, that was applied to the oxidation of variousalcohols in toluene at 80 °C in the presence of K2CO3 (1 equiv-alent), which was found to be essential to avoid formation of Pdblack.91 Primary alcohols were converted to the correspondingesters, presumably by previous selective oxidation to carboxylicacids. This example showed that the combination of an organicligand and ordered mesoporous channels (Scheme 24) resultedin an interesting synergistic effect that led to enhanced reactivity,prevention of the agglomeration of the Pd nanoparticles and gen-eration of a durable catalyst.

Scheme 22 Pd(II)-catalyzed oxidation kinetic resolutions of alcohols.

Scheme 23 Preparation of amphiphilic resin-dispersion of nanoparti-cles of palladium (ARP-Pd).

Scheme 24 Nanoparticles stabilized on mesoporous channels ofSBA-15.


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Park and co-workers reported aluminium hydroxide sup-ported-palladium nanoparticles (Pd/AlO(OH)) prepared from[Pd(Ph3)4], tetra(ethylene glycol), 1-butanol, and aluminum tri-sec-butoxide.92 This catalyst displayed dual catalytic activity forboth alkene hydrogenation and aerobic oxidation of alcohols.Successful hydrogenation of cholesterol followed by aerobic oxi-dation to give cholestan-3-one was demonstrated in a one-potmanner (Scheme 25).

Some other examples of palladium-based heterogeneous cata-lysts obtained by dispersion of the metal on an inorganic supporthave been recently reported, such as Pd/MgO93 or Pd/Al2O3.

94 Itshould be stressed that the preparation method of such catalystsis important for the catalytic performance.95 A peculiar mechan-istic study in the aerobic oxidation of benzyl alcohol by PdOx/Al2O3 in scCO2 as solvent was undertaken by Grunwaldt andco-workers, that helped to elucidate the structure–activityrelationships at the solid/fluid interphase.96

Supercritical carbon dioxide was also investigated by Leitnerand co-workers, who developed a quite different approach. Theyfound that the giant palladium cluster, [Pd561phen60(OAc)180],dispersed in poly(ethylene glycol) (PEG), efficiently catalyzesthe aerobic oxidation of alcohols in scCO2 (Scheme 26).97

In this biphasic system, the PEG matrix contains the catalyst(helping in preventing aggregation and deactivation of the cataly-tically active nanoparticles) while the supercritical carbondioxide phase dissolves the substrate and the product (thus pro-viding a safe environment for the use of molecular oxygen underessential solvent-free conditions and allowing continuous oper-ation, even with substrates of low volatility). The authors postu-late that the high activity and long term stability of the newcatalytic system is due to the high dispersion of Pd-nanoparticles

in the PEG phase during the reaction. A variety of alcohols wereoxidized in these conditions. Both the catalyst matrix and themobile phase used in this approach are toxicologically innocuousand environmentally benign materials, thus making thisapproach particularly appealing for “green” nanoparticlecatalysis.

Interestingly, as previously mentioned, Sheldon and co-workers recently demonstrated that, contrarily to the catalyticsystem based on the bathophenanthroline disulfonate ligand(Scheme 19),71 their previously described homogeneous cataly-tic system based on Pd(II) acetate in combination with the morehindered neocuproine ligand72 actually involves palladium nano-particles. The substrate alcohol acts indeed as the reducing agentand in situ forms Pd-nanoparticles which are the effective cata-lysts. The catalytic system based on neocuproine-stabilized palla-dium nanoparticles was applied to the oxidation of nandrolone(Scheme 27).73

In conclusion, much work has to be done yet in order to inves-tigate in detail the mechanisms involved when nanoparticles areformed in the reaction. Indeed, it is difficult to attribute theactual catalytic activity solely to the ligand bound Pd or to thePd nanoparticles.

Gold-based catalysts


The homogeneous alcohol oxidation catalyzed by gold hasrarely been reported. Shi and co-workers,98 in early evaluations,optimized the reaction using AuCl (5 mol%) and ligand (6.3 mol%) in toluene at 90 °C under oxygen atmosphere (Scheme 28).

With activated benzyl and allylic substrates, both conversionsand yields were very high, only aldehydes were produced with

Scheme 25 Cholesterol hydrogenation followed by aerobic oxidation.

Scheme 26 Aerobic oxidation of alcohols catalyzed by PEG-stabilizedPd-nanoparticles in scCO2.

Scheme 27 Aerobic oxidation of nandrolone with Pd nanoparticles inaqueous media.

Scheme 28 Oxidation of alcohols with gold(I) complexes.


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no overoxidation to carboxylic acids; however, primary aliphaticalcohols were slowly oxidized and formed aldol byproducts.This system was then improved, in terms of sustainability ofthe process, by using water as solvent.99 Different oxidants,bases and ligands were studied and a final optimized systemusing a 1 : 1 ratio of gold(I)-neocuproine as the catalyst inaqueous basic solution under O2 atmosphere was found. Thelimitation of this procedure is the same as the previous: thenarrow substrate scope, being limited to secondary benzylic orallylic alcohols. Moreover, given Sheldon’s results with Pd-neo-cuproine, we cannot exclude that the effective catalysts here aregold nanoparticles formed in situ by gold reduction by thealcohol substrate.


Although bulk gold has for a long time being regarded as apoorly active metal, the surprisingly high activity of gold nano-particles has initiated intensive research into their use for aerobicoxidation reactions. Moreover, the recent findings related to thesynergic activity of bimetallic nanocluster catalysis has furtherexpanded the possibilities for the design of new efficient gold-based heterogeneous catalysts.

The general procedure for the synthesis of gold nanoparticlesis based on the reduction of Au salts by a reducing agent or bythe support itself in some cases. The first to clearly demonstratethat supported gold nanoparticles could be very effective cata-lysts for the oxidation of alcohols were Rossi, Prati and co-workers. They employed Au/carbon catalysts, which were effec-tive for a wide range of substrates like diols, glucose and ami-noalcohols, and found that the presence of a base was essentialfor catalysis.100 Similar Au/SiO2 catalysts were found to beeffective with gas-phase reactants and, in this case, no baseaddition was required.101 These pioneering studies using Au/carbon catalysts were extended by Hutchings and co-workers102

who showed that Au supported on graphite could oxidize gly-cerol to glycerate with 100% selectivity using dioxygen as theoxidant in water with yields approaching to 60%. It wasobserved that the selectivity to glyceric acid and the glycerolconversion were strongly dependent upon the glycerol/NaOHratio (Scheme 29).

One of the most significant advances in the field of alcoholoxidations has been the observations by Corma and co-workerswho showed that Au/CeO2 catalyst was active for the selectiveoxidation of alcohols to aldehydes and ketones.103 In thesestudies, the catalysts were active in solvent-free conditions, usingO2 as oxidant without the requirement for the addition of NaOHto achieve high activity. Subsequently they showed that for therelevant oxidation of allylic alcohols, gold presented uniqueselectivity when compared with Pd (Scheme 30).104

In many catalytic studies, the support-catalyst interaction is acrucial factor for controlling reactivity. Interestingly, Rossi andco-workers showed that water-dispersed “naked” gold colloidalparticles could be very effective catalysts for the oxidation ofglucose to gluconic acid.105 These particles were produced as acolloidal sol by reducing HAuCl4 in the presence of a largeexcess of glucose acting either as reagent and protector. Christen-sen, Riisager and co-workers made a number of significantadvances in the direct oxidation of primary alcohols using sup-ported gold nanocrystals and they focused their efforts ondecreasing the amount of base required in these oxidations. Theyshowed that Au-MgAl2O4 could catalyze the oxidation ofaqueous solutions of ethanol to give acetic acid in high yields.106

This provides a potential new route to a key commodity chemi-cal that is based on a bio-renewable feedstock using a substan-tially green technology approach. Recently, they presented theone-pot conversion of alcohols to imines (Scheme 31) byaerobic oxidation with Au/TiO2 followed by condensation withprimary amines in methanol.107

Although a small particle size is essential for catalysis bygold, no generalized reaction mechanism at a molecular level hasbeen established, because of the difficulties in controlling thesize of gold clusters and the structures of their interfaces withsolid supports. Colloidal gold, in which the gold clusters are dis-persed quasi-homogeneously in a medium, allows to control thecluster size more finely than heterogeneous gold. Colloidal goldcan be obtained, for instance, by stabilization of gold nanoclus-ters by suitable polymeric compounds such as poly(N-vinyl-2-pyrrolidone) (Au:PVP). The main role of the polymer is to termi-nate the aggregation of gold(0) atoms at a very early stage,thereby giving nanometre-sized gold clusters.108 The polymer onthe gold cluster acts as a protecting layer against aggregation.The gold clusters can be treated as normal chemical compounds,being collected and stored in powder form and then dispersed inliquid media. All the catalysts required the presence of a base,such as KOH or K2CO3, in contrast to palladium or platinum-based catalysts. The oxidation of primary alcohols typicallyafforded the corresponding carboxylic acids; however, in somecases the aldehyde was obtained as the major product. Water oraqueous mixtures were used as solvents and the reactions withAu:PVP did not proceeded in organic solvent, suggesting thatwater also plays an essential role in the catalysis.109 The maindrawbacks of colloidal nanogold are the difficulties in recovering

Scheme 29 Oxidation of glycerol using Au/graphite catalysts.

Scheme 30 Aerobic oxidation of allylic alcohols under solvent-freeconditions.

Scheme 31 Au-catalyzed one-pot formation of imines.


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from homogeneous dispersion for its reuse and the degradationof the catalyst during the reaction. One method to solve theseproblems is to use insoluble cross-linked polymers as stabilizers.As an example, Kobayashi and co-workers developed a highlystable and reusable catalyst based on a polystyrene-based cross-linked polymer (polymer-incarcerated gold catalyst, PI Au) thatcould be reused at least seven times with negligible loss ofactivity.110 They also included carbon black (CB) to the compo-sition of the PI Au to enhance the stability of gold nanoclustersprobably via synergistic π–π interactions between the three com-ponents, which enabled to increase the metal loading amount upto 0.60 mmol g−1.111

Recently, the synergic activity of bimetallic nanoclusters waspresented. Hutchings and co-workers showed that alloying Pdwith Au in supported Au/TiO2 catalysts, that was found to be thebest support in previously studies, the activity for alcohol oxi-dation was enhanced under solvent-free conditions by a factor ofover 25.112 The use of bimetallic Au–Pt nanoparticles supportedon the zeolite H-mordenite allowed to selectively oxidize gly-cerol directly to glyceric acid without the use of basic con-ditions.113 Also Kobayashi and co-workers studied the aerobicoxidation of alcohols under ambient condition with gold-plati-num bimetallic clusters114 and in a recent publication they com-pared the different selectivities using different metal combinationcatalysts.115 An intriguing extension of this chemistry was theincarceration of two different metal catalysts able to perform twodistinct organic transformations in order to build an hetero-geneous catalyst for tandem reactions. Kobayashi and co-workers recently succeeded in the development of a polymerincarcerated bimetallic Au–Pd nanocluster and boron on carbonblack (CB) for the sequential oxidation–addition reaction of 1,3-dicarbonyl compounds with allylic alcohols (Scheme 32).116

Hirao and co-workers reported the first example of catalystdesign using a redox-active polymer as the catalyst support(Scheme 33).117 They demonstrated that the redox-active PMAS(poly(2-methoxyaniline-5-sulfonic acid)) can work in a multi-catalytic process as both a stabilizer of Au NPs and a redoxmediator for aerobic alcohol oxidation in water. This designconcept provides a new type of redox catalyst system for trans-ferring protons and electrons.

Iron-based catalysts


Iron is an extremely abundant metal in the earth’s crust and oneof its important function in living systems is the oxygen transportand electron transport connected with the oxidation of substrates

and the reduction of O2. Based on the understanding of the roleof iron in living systems, some examples of aerobic oxidation ofalcohols using this metal as catalyst were recently presented.

In 2002, Martin and Suárez reported the first Fe-catalyzedsystem that used a combination of Fe(NO3)3 and FeBr3 andworked well under an ambient air atmosphere at room tempera-ture (Scheme 34).118 Both secondary and benzylic alcohols wereoxidized in good yields and no over oxidation or formation ofother products were detected in the reaction mixture. A second-ary alcohol was selectively oxidized in the presence of a primaryone.

More recently, a Fe-catalyzed aerobic alcohol oxidation wasdisclosed by Liang and co-workers that employed NaNO2/TEMPO as co-catalysts.119 The optimized conditions for thissystem used 5 mol% FeCl3, 5 mol% NaNO2 and 2 mol%TEMPO in trifluorotoluene at room temperature under ambientair pressure. This system worked well on primary and secondarybenzylic alcohols and cinnamyl alcohol but, unfortunately, oxi-dation of primary aliphatic alcohols resulted in modest selectivityfor aldehyde formation with both acid and ester byproductsobserved. The use of 4-substituted TEMPOs instead of TEMPOallowed to develop an improved system that oxidized efficientlyalso a variety of primary alcohols to the correspondingaldeydes.120

In order to avoid the use of environmentally unfriendly halo-genated solvents (PhCF3 or CH2Cl2), the authors recently devel-oped a catalytic system, based on the cheap, readily availableand non-toxic Fe(NO3)3·9H2O as catalyst in combination with 4-OH-TEMPO as co-catalyst for the aerobic oxidation of a widerange of primary and secondary alcohols in acetonitrile at roomtemperature under ambient atmosphere (Scheme 35).121 This cat-alytic system showed excellent substrate tolerance and was notdeactivated by sulphur-containing compounds.

Scheme 32 Tandem reactions with polymer incarcerated multimetalnanoclusters.

Scheme 33 Proposed multi-catalytic cycles for the oxidation with AuNPs and PMAS.

Scheme 34 Fe-catalyzed aerobic alcohol oxidation.

Scheme 35 Fe(NO3)3/4-OH-TEMPO catalyzed alcohol oxidation.


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More recently, Ma and co-workers disclosed an iron nitrate/TEMPO-catalyzed aerobic oxidation by applying an unusualinorganic ligand (NaCl) approach, which was very efficient atroom temperature, and converted within a couple of hours essen-tially all types of alcohols bearing different unsaturated carbon–carbon bonds with high efficiency (Scheme 36).122 However, theexact role of NaCl is not clear.

A nice example of iron-based catalysis was recently reportedby Zhang, He and co-workers.123 A task-specific bimagneticimidazolium salt [Imim-TEMPO][FeCl4] containing cooperativefunctionalities (Scheme 37) was easily synthesized and appliedto the selective aerobic oxidation of aromatic alcohols. Afterrough optimization of the reaction conditions, quantitative yieldswith excellent selectivity could be achieved at mild conditionswithout the use of any organic solvent. It is worth to be men-tioned that the reaction also performed well even when using airas an oxidant instead of pure oxygen, and was totally immune tomoisture.

In each run, [Imim-TEMPO][FeCl4] could be readily recov-ered by ether extraction, then subjected to a subsequent run bycharging with fresh substrate and NaNO2. The catalyst could bereused for at least five times with retention of high activity andselectivity. At least in principle, the use of a magnet to recoverthis magnetic IL is also possible and is currently underinvestigation.

Vanadium-based catalysts


In the first studies, the aerobic homogeneous vanadium-catalyzedoxidations were limited to α-hydroxycarbonyl compounds andof propargylic alcohols as substrates (Schemes 38 and 39). Asimple procedure using 1 mol% VOCl3 in acetonitrile at roomtemperature resulted in the oxidation of several α-hydroxycarbo-nyl compounds (Scheme 38).124 On the other hand, the use of1 mol% VO(acac)2 in acetonitrile at 80 °C oxidized a variety of

propargyl alcohols including aryl, vinyl, alkynyl and aliphaticsubstrates (Scheme 39).125 Besides propargylic alcohols, variousother alcohols (simple benzylic, aliphatic, and allylic alcohols)were exposed to the same reaction conditions, but only moderateyields of the corresponding carbonyl compounds were achieved.

A detailed investigation of the reaction mechanism providedevidences that V(V) is the catalytically active species in the oxi-dation.125b The authors proposed a mechanism involving initialoxidation of V(IV) to V(V) by O2 followed by the attack ofalcohol to a form a V-alkoxide species B (Scheme 40). Elimin-ation of the alcoxide then results in formation of the product anda V(III) species C, that can be reoxidized by O2 to reform theactive V(V) catalyst A.126

Velusamy and Punniyamurphy used V2O5 (5 mol%) as thecatalyst to broaden the scope of oxidation to benzylic, allylic,and aliphatic alcohols.127 This reaction required 0.5 equiv. ofK2CO3 in toluene as solvent at 100 °C, and proceeded well withsecondary aliphatic alcohols, while primary aliphatic alcoholsprovided only moderate yields. This prompted the authors to trya competition experiment in which cyclohexanol and 1-heptanolwere exposed to the same oxidative conditions, and indeed theyisolated 87% of cyclohexanone and one trace amount of hepta-nal. Therefore, this system can be employed for the chemoselec-tive oxidation of secondary aliphatic alcohols.

The use of chiral O,N,O-chelating tridentate ligands forvanadium recently allowed the oxidative kinetic resolution

Scheme 37 Oxidation of alcohols by [Imim-TEMPO][FeCl4].

Scheme 36 Fe(NO3)3·9H2O/TEMPO/NaCl-catalyzed aerobic oxi-dation of alcohols.

Scheme 38 V-catalyzed aerobic oxidation of α-hydroxycarbonyls.

Scheme 39 VO(acac)2-catalyzed oxidation of propargylic alcohols.

Scheme 40 Proposed mechanism for V-catalyzed aerobic oxidation ofpropargylic alcohols.


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(OKR) of α-hydroxy esters, amides and phosphonates.128 Avariety of racemic aryl, vinyl, and alkyl substituted α-hydroxyesters were efficiently resolved with selectivity factors rangingfrom 12 to >50 (Scheme 41).128a Unfortunately, the applicationof this system to the OKR of a propargyl hydroxyl esters resultedin a poor resolution.

In the search for more environmentally friendly vanadium cat-alyzed oxidation procedures, Jiang and Ragauskas found that acombination of VO(acac)2 and DABCO (1,4-diazabicyclo[2.2.2]octane) catalyzed the oxidation of benzylic and allylic alcoholsin ionic liquids at 80–100 °C.129 The catalyst could be recycledand reused for three runs without significant loss of activity.Using air instead of pure oxygen was also advantageous, redu-cing the safety hazard associated with heating organic solventsunder elevated O2 pressure. Actually, all the methods reportedfor the vanadium-catalyzed alcohol oxidation use an atmosphereof pure oxygen, apart from the recent findings of Hanson andco-workers, who showed that the complex (HQ)2VO(OiPr) (HQ= 8-quinolinate), easily prepared by the reaction of 8-hydroxy-quinoline with VO(acac)2 under air in 2-propanol, efficiently cat-alyzed the oxidation of benzylic, allylic, and propargylicalcohols with air in the presence of NEt3 (Scheme 42).130

In conclusion, vanadium has proven to be the most effectivemetal for the aerobic oxidation of propargyl alcohols and for theOKR of α-hydroxy esters. However, recently the scope of theoxidation has been expanded to other types of alcohols.


The complex VO(acac)2 was easily heterogenized by using poly-aniline as solid support.131 This catalyst, which oxidized several

aromatic and aliphatic alcohols in toluene at 100 °C, did notrequire the presence of a base and the catalyst could be recycledwithout loss of activity. More recently, OKRs of α-hydroxy(thio)esters and amides were achieved with good enantioselectivities(up to 99% ee) by employing chiral vanadyl(V) tert-leucinatesimmobilized onto a polystyrene support through the ClickChemistry approach.132 Conversely, the non green solventCHCl3 was found to perform best in those reactions.

As an example of inorganic support for vanadium, a calciumphosphate-vanadite apatite (CPVAP), formed by partial substi-tution of PO4

3− ions by VO43− ions in hydroxyapatite, was also

reported to oxidize several propargylic alcohols.133

Iridium-based catalysts


The first example proving that iridium-based catalysts couldpromote the aerobic oxidation of alcohols to aldehydes was pre-sented by Gabrielsson and co-workers.134,135 They showed thatwhen compounds [Cp*Ir(Cl)(bpy)]OTf and [Cp*Ir(Cl)(bpym)]OTf (Scheme 43), usually used as transfer hydrogenation cata-lysts, were heated in refluxing methanol, ethanol or benzylalcohol in the presence of air and a base (NaOH or Na2CO3), thecorresponding aldehydes were formed.

The authors, on the basis of the iridium catalyzed transferhydrogenation mechanism136,137 and after some NMR and massspectroscopy studies, proposed a cyclic mechanism (Scheme 44)in which substitution of the halide by the alcohol gives analcohol complex (step 1), deprotonation results in an alkoxidecomplex (step 2) which rapidly undergoes β-hydride eliminationto give a hydride (step 3). Deprotonation of the hydride gener-ates Cp*Ir(bpy) or Cp*Ir(bpym) (step 4). Oxidation followed bysolvation (step 5) returns the alcohol complex. The reoxidationof Ir(I) complexes presumably forms a peroxide species.

Scheme 41 V-catalyzed aerobic OKR of α-hydroxy esters.

Scheme 42 Mild vanadium catalyzed oxidation with air.

Scheme 43 Iridium catalysts.

Scheme 44 Proposed mechanism for the iridium catalyzed aerobicoxidation of alcohols.


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After this first example, Ison and co-workers reported that asimple and commercially available Ir(III) complex, [Cp*IrCl2]2,catalyzed the oxidation of primary and secondary alcohols at 1atm O2 in the presence of catalytically amount of Et3N.

138 Thesystem was found to work well with both primary and secondarybenzylic and aliphatic alcohols. They also presented a newmechanism that suggests that the transition metal maintains its(+3) oxidation state throughout the entire catalytic cycle(Scheme 45), in contrast with Gabrielsson mechanism.

Evidence in support of the presented mechanism includes (1)demonstration that O2 is needed for catalytic turnover, (2) kineticdata from oxygen uptake experiments consistent with the pro-posed mechanism, (3) kinetic isotope and isotopic labelling datathat implicate that Ir hydrides are the key intermediates in thecatalytic reaction, (4) identification of the Ir hydride A(Scheme 45) as a key and kinetically competent intermediate inthe catalytic cycle, and (5) identification of the reaction of A(Scheme 45) with O2 as the turnover limiting step of the catalyticsystem.

Interestingly, Ishii and co-workers found that primary alcoholsundergo oxidative dimerization in the presence of a catalyticamount of [IrCl(coe)2]2 under air without any additive andsolvent to give the corresponding esters in good yields.139

Based on the finding that O2 is a promising hydrogen accep-tor, Ikariya and co-workers demonstrated the first example ofaerobic oxidative kinetic resolution (OKR) of racemic secondaryalcohols with Ir bifunctional catalysts, that provided chiral alco-hols with up to 99% ee and with a process that proceeded undermild conditions with high efficiency and minimal organic waste(Scheme 46).140

However, the system worked efficiently only with benzylicsubstrates.


The sole example of heterogeneous catalysis based on iridiumwas recently presented by Naito and co-workers and used highlydispersed Ir metal particles on TiO2 surface as catalyst, readilyprepared by a conventional impregnation method.141 The reac-tion worked well on benzylic and allylic alcohols without baseaddition and the catalyst could be recycled at least three times.Several other oxides were tried as solid supports, but TiO2 gavethe best results. Compared to an homogeneous Ir complex, thecatalytic activity of Ir/TiO2 was ten times higher. The authorsproposed that the reaction proceeds through the formation of Ir-hydride species.

Osmium-based catalysts


Osmium has long been used as catalyst for the dihydroxylationof olefins142 and, recently, also in the aerobic oxidation ofalcohols.

Beller and co-workers disclosed the first and sole osmium-cat-alyzed homogeneous procedure.143 The system operated with acommercially available osmium catalyst, using low catalyst load-ings (≤0.5 mol %), even at 1 bar of molecular oxygen, alongwith catalytic DABCO under mild conditions, and was appliedto the oxidation of different (primary and secondary) benzylic(aromatic and heteroaromatic) alcohols in good yields(Scheme 47).

Under optimized reaction conditions a remarkable catalystproductivity was observed (0.005 mol% of catalyst loading andTON up to 16 600) for the oxidation of sec-phenethyl alcohol toacetophenone.

Several bimetallic systems using osmium in combination withanother metal were reported, such as Os–Cu144 or Os–Cr145

bifunctional catalysts. In those systems osmium is likely to beresponsible for the oxidation of alcohol, while the other metal isresponsible for the activation of oxygen and therefore preventscatalyst decomposition. Further addition of quinuclidine as aligand for osmium resulted in a 10-fold increase in activity.144b

However, all these systems were limited to benzylic and allylicsubstrates, while aliphatic alcohols were not oxidized at all.


Also only one example of osmium-based heterogeneous catalysisfor aerobic alcohol oxidation is reported in literature. Os(0)nanoclusters stabilized by the framework of zeolite-Y (Os(0)-Y)were prepared by introduction of Os(III) cations into the zeolite-Y by ion-exchange in aqueous solution and then reduction byNaBH4 at room temperature. The resulting well-dispersed Os (0)

Scheme 45 Alternative mechanism proposed for Ir-catalyzedoxidations.

Scheme 46 Aerobic oxidative kinetic resolution of secondary alcohols.

Scheme 47 Os-catalyzed aerobic alcohol oxidation.


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nanoclusters within the zeolite matrix were applied to theaerobic oxidation of various alcohols at 80 °C under 1 atm O2

pressure or air.146 All benzylic and allylic substrates were con-verted to the corresponding carbonyl compounds in >99% selec-tivity. Unactivated alcohols, such as 2-heptanol, were alsosmoothly oxidized in high conversion and selectivity usinglonger reaction time. Moreover, Os(0)-Y showed exceptional cat-alytic activity in the oxidation of heteroatom containing alcohols.The catalyst could be isolated after completion of the reaction asa dark brown powder by suction filtration and, after washingwith acetone and drying under vacuum at room temperature,reused at least three times.

Cobalt-based catalysts


After the first Co-catalyzed aerobic oxidation of alcohols usingCo-nitro complexes published by Tovrog and co-workers in1981,147 several systems have emerged. Unfortunately all ofthem have some drawbacks like the need for high temperature,sacrificial reagents or some additive addition (like bases orMCBA). Ishii and co-workers presented a N-hydroxyphtalimide(NHPI)/Co(III) complexes system able to successfully oxidized avariety of alcohols under aerobic conditions.148 The optimizedprocedure, presented in their most recent report, employed0.5 mol% Co(OAc)2, 10 mol % NHPI and 5 mol% m-chloroben-zoic acid (MCBA) under an oxygen atmosphere at room temp-erature and probably involves a free radical mechanism. Thismethod was successful for the oxidation of secondary aliphatic,allylic and benzylic substrates; primary alcohols were selectivelyoxidized to the corresponding carboxylic acids. Internal vicinaldiols were converted to the corresponding diketones, otherwiseoxidation of terminal vicinal diols resulted in C–C bond clea-vage and formation of the corresponding carboxylic acid.

Systems involving Co(II)-Schiff base catalysts were presentedby both Iqbal et al. and Sain et al. (Scheme 48 method A andmethod B, respectively).149,150

These systems converted both secondary aliphatic andbenzylic alcohols and the main difference between them was theaddition of iso-butanal in method A. Sain and co-workersshowed that α-hydroxyketones were oxidized using ligandL2.150

Sain and co-workers also presented a Co-phtalocyaninecomplex able to oxidize secondary benzylic, aliphatic and

propargylic alcohols and a variety of α-hydroxyketones using5 mol % catalyst and 1 equiv. KOH in xylenes at reflux under anO2 atmosphere.151

For the efficient conversion of propargylic alcohols to α,β-ace-tylenic carbonyl compounds (ynones), Blay and co-workers pre-sented a system using pivaldehyde and an o-phenylelebis(N′-methyloxamidate) cobalt(III) complex.152

Recently, Jing and co-workers presented a three-componentcatalytic system, based on Co(NO3)2/dimethylglyoxime (DH2)/TEMPO (molar ratio 1 : 4 : 1), working on primary and second-ary aliphatic and benzylic alcohols.153 However, this procedureused quite harsh conditions (0.4 MPa O2 at 70 °C in CH2Cl2).

Cobalt complexes were also recently used in oxidative kineticresolutions (OKRs) of secondary benzylic alcohols154 and enan-tioselective aerobic oxidation of α-hydroxy esters155 or in theoxidation of lignin in ionic liquids to increase the oxygen func-tionality.156 Lignocellulose biomass is a renewable resource thathas the potential to serve as a feedstock for the production offuels, chemicals, and energy. Novel oxidation procedures oflignin are particularly important for a future biorefinery in whichoxygen functionality is increased prior to depolymerization oradditional functionalization of already depolymerized lignin isachieved.


Only two examples of heterogeneous catalyst are reported in theliterature, both involving Co(II) Shiff base complexes. In the firstcase, Reiser and co-workers used the copper catalyzed [3 + 2]azide-alkyne cycloaddition (CuAAC) and the metal-free Staudin-ger ligation for grafting cobalt Schiff base complexes onto poly-styrene supports.157 A variety of primary and secondary alcoholwere oxidized and the catalyst could be recovered and reused forfive cycles without further activation.

Jain, Sinha and co-workers used the same copper catalyzed[3 + 2] azide-alkyne cycloaddition (CuAAC) for grafting Co(II)Schiff base complexes to mesoporous silica supports and usedthis catalytic system (2 mol % of the catalyst) with 1.5 equiv. of2-methylpropanal in acetonitrile under dioxygen atmosphere at50 °C to oxidize a variety of primary benzylic alcohols.158 Alsoin this case recover and reuse of catalyst was achievedsuccessfully.

Conclusions

During the last 15 years there has been a considerable increaseof interest in the area of metal-catalyzed aerobic alcohol oxi-dations. In the field of homogeneous alcohol oxidations, theMarko’s Cu-(phen), the Sheldon’s Pd-(sulfonated bathophenan-troline) and the Sigman’s Pd(OAc2)/TEA systems are the mostmature. Ruthenium-based catalysts often suffer from the need ofhigh catalyst loading. A considerable effort has been also madeto replace common organic solvents with alternative solventssuch as ionic liquids, fluorinated solvents or supercritical CO2 orto perform the oxidation reactions in water or without theemploy of any solvent at all. Regarding the chemoselectivity ofthe reaction, it is interesting to note the complementaritybetween Cu-based catalysts, who better work with primary

Scheme 48 Co-Schiff base catalyzed aerobic alcohol oxidations.


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alcohols, and gold-based or iron-based catalysts, who betterperform the oxidation of secondary alcohols. Selective methodsto obtain aldeydes or carboxylic acids from primary alcoholswere also developed. Moreover, elegant examples of efficientkinetic resolutions (OKRs) of racemic secondary alcohols anddesymmetrization of meso-diols were achieved with Pd-basedcatalysts in the presence of (−)-sparteine as the chiral ligand.Some other examples of OKRs were reported with iridium- andcobalt-based catalysts. Vanadium is the metal of choice for theaerobic oxidation of propargyl alcohols and for the OKR ofα-hydroxy esters. The discovery that Pd and Au nanoparticlesare effective catalysts for the oxidation of alcohol moieties hasfurther expanded this research field in the search for new hetero-geneous systems, that can allow recovery and reuse of the metalcatalyst and the obtainment of pure products. Mechanistically,not much work has been done to elucidate the fine details formany of the metal-catalyzed aerobic alcohol oxidations, exceptfor Pd-catalyzed aerobic alcohol oxidations. Especially for thenew heterogeneous procedures involving nanoparticles, the exactnature of the active catalyst has still to be understood. Whilethere has been a tremendous amount of effort applied to thedevelopment and improvement of metal-catalyzed aerobicalcohol oxidations, many improvements can be still envisioned.For instance, in order to use these methods in target synthesis,the scope of the individual catalytic systems must be broadenedto include more complex alcohols that are synthetically relevant.Moreover, each method should be tested on a larger scale toexplore its potential utility in the industrial processes.

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