Transition Metal Catalysis in Aerobic Alcohol Oxidation
Oxidation reactions are excellent tools for converting a functionality in a lower oxidation state to the desired one. They have been, in the past, among the most useful and commonly used reactions in the industrial processes that employ petroleum-based feedstocks as starting materials. However, in addition to often lacking selectivity, traditional oxidation procedures are among the most polluting and hazardous methods, often occurring with a high E-factor (mass of waste per unit mass of product)1 and delivering considerable amounts of toxic waste, for instance, metal salts in oxidations with stoichiometric Cr(vi) or Mn(vii) derivatives or nitrogen oxides when carried out with HNO3. For instance, it was estimated that ∼5–8% of the worldwide anthropogenic emissions of N2O, an inevitable stoichiometric waste in oxidations with HNO3, was produced during cyclohexanol/cyclohexanone conversion to adipic acid, an important key intermediate in the manufacture of nylon-6,6.2 The pharmaceutical industry, which deals with complex and sensitive molecules, has begun to restrict the use of oxidation reactions on a preparative scale for reasons related to process sustainability. Indeed, many are the “non-green” aspects of oxidation reactions. The more selective reagents produce undesired waste by-products, which are often highly reactive and thermally unstable. However, the greatest factor that limits the employment of oxidation reactions on a large scale is the safety of the process, since many common procedures are carried out in flammable organic solvents. The inherent safety concerns associated with oxidative processes combined with the disposal of hazardous by-products limit the use of these reactions to no more than 3–4% of the total reactions on a preparative scale in the pharmaceutical industry.3 Despite the existing challenges, oxidation reactions are routinely run to produce many of the commercial pharmaceuticals available today.4
Nowadays, the principles of green and sustainable chemistry5 have to be carefully considered when designing a new oxidation procedure. For all the reasons stated above, the traditional oxidation methods are no longer acceptable and great efforts have recently been devoted by the synthetic chemistry community in both academia and industry to the search for new, more sustainable oxidants.6
In particular, the oxidation of alcohols to the corresponding aldehydes and ketones7 or carboxylic acids8 is of fundamental importance in organic synthesis, due to occurrence of these moieties in many drugs, vitamins and fragrances (Figure 1).
This pivotal reaction remains one of the most active research areas for the identification of more effective and practical methods. This is partially due to the availability of a plethora of orthogonal protecting groups for alcohols,9 which often allow chemoselective deprotection prior to oxidation.
A publication by Pfizer's medicinal chemists10 showed that the three most popular oxidants used at Pfizer for the oxidation of primary alcohols to the corresponding aldehydes are hypervalent iodine reagents11 such as Dess–Martin periodinane12 or its precursor IBX, the Swern reagent13 and the tetrapropylammonium (TPAP)–N-methylmorpholine N-oxide (NMO)14 protocol (Figure 2).
All of these methods still have poor atom economies15 and significant scale-up issues. The Swern reagent produces the evil-smelling dimethyl sulfide as by-product and the Dess–Martin periodinane is shock sensitive and prohibitively expensive for use on a large scale. Stoichiometric TPAP again has very poor atom economy and is too expensive, and since 1980 only one large-scale use of TPAP to catalyze an oxidation in combination with NMO as co-oxidant was reported, namely the oxidation of a secondary alcohol of a very sensitive macrolide (Scheme 1).16
As a result, the oxidation of an alcohol to a carbonyl compound, in spite of being a fundamentally important reaction, is actually avoided by the pharmaceutical industry. Therefore, there is still an increasing need in the fine chemical and pharmaceutical industries for systems that are green, scalable and have broad synthetic utilities.
An ideal oxidizing reagent should: (i) oxidize in good yield a broad variety of alcohols bearing different functionalities, (ii) have the ability to be used for scale-up procedures and (iii) be as green as possible, considering worker safety, ecotoxicity and atom economy.10
The use of NaOCl as a stoichiometric oxidant certainly represents a dramatic improvement compared with carcinogenic chromium(vi) salts and other reagents referred to above, since it produces one equivalent of acceptable NaCl (environmental quotient EQ=1)5 as by-product. However, the possibility of forming chlorinated impurities cannot be completely excluded in oxidations carried out with NaOCl.
Therefore, there is definitely a pressing need for more catalysis in alcohol oxidation processes. Catalysis allows reactions to occur under mild conditions in order to save the overall implied energy, and for this reason is strongly encouraged.17 Catalytic methodologies employing greener oxidants such as molecular oxygen and hydrogen peroxide would seem to represent a further improvement in this respect. Oxygen in particular (or even better air) is among the cheapest and less polluting stoichiometric oxidants, since it has the highest active oxygen content (100 or 50 wt%) among all reagents and produces no waste or water as the sole by-product.6 The implementation of a metal catalyst in combination with molecular oxygen therefore represents an emerging alternative process to the traditional procedures.
However, also in alcohol oxidation by stoichiometric oxygen there are many shades of green. As Dunn and co-workers pointed out,10 the use of molecular oxygen presents significant safety issues related to the flammability of mixtures of oxygen with volatile organic solvents. These concerns, however, can be reduced by using air or even oxygen diluted to 10% with nitrogen. Moreover, an improved safety profile and more acceptable scalability can be achieved by performing the oxidation in non-flammable solvents such as water.5 Selective metal-catalyzed aerobic oxidation of alcohols has been widely studied not only in conventional liquid solvents but also in alternative fluids such as fluorinated solvents, ionic liquids and supercritical carbon dioxide (scCO2)18 using both batch and continuous-flow reactors. One of the main challenges in the oxidation of primary alcohols with metal catalysts is the selectivity towards aldehyde formation. Aldehydes are prone to hydration and the hydrated aldehyde is considered to be oxidized faster than the non-hydrate compound to carboxylic acids. Therefore, the key to achieving high selectivity in aldehyde formation is to suppress the formation of a carboxylic acid, which can further react with the starting alcohol to yield the ester, which contributes to lowering the aldehyde selectivity.
In this sense, scCO2 seems more suitable for the oxidation of primary alcohols than an aqueous medium, in which aldehyde hydration cannot be avoided (see Chapter 1, Scheme 1.20). However, the addition of catalytic TEMPO (2,2,6,6-tetramethyl-1-piperidine-N-oxyl) in the palladium-catalyzed aerobic oxidation of alcohols in water proved to be effective in the complete suppression of carboxylic acid formation (Scheme 2).19 For details on Pd catalysis see Chapter 4.
Selectivity in aldehyde or acid formation from primary alcohols is only one of the many and different challenges of this transformation. A good procedure should need low pressures of O2, especially in flammable organic solvents, mild reaction conditions, low catalyst loadings and avoidance of expensive or toxic additives. Moreover, it should be able to convert the alcohol moiety selectively in the presence of other groups prone to oxidation (chemoselectivity) and other sensitive functionalities. A further goal is the development of methods able to oxidize one class of alcohols in the presence of another. Finally, an ultimate goal is the development of diastereo- and/or enantioselective alcohol oxidations. In this regard, the groups of Sigman and Stoltz independently discovered20 that in the presence of the chiral diamine (-)-sparteine the scope of the palladium-catalyzed aerobic oxidations can be extended to asymmetric catalysis, as for example the oxidative kinetic resolution (OKR) of racemic secondary alcohols (Scheme 3)21 or the oxidative desymmetrization of meso-diols (Scheme 4).22 Whereas the former method (also in cases of perfect selectivity) produces an undesired ketone as by-product, which can eventually be reduced and recycled, the selective oxidation of one of two alcohols in a meso substrate can in principle give a product with 100% conversion and enantiomeric excess (ee).23
This excellent procedure, which leads to remarkably high ee values under optimized conditions, was recently applied to the enantioselective total synthesis of various alkaloids such as (-)-aurantioclavine, (+)-amurensinine, (-)-lobeline and (-)- and (+)-sedamine,24 and to the kinetic resolution of key pharmaceutical building blocks relevant to the enantioselective preparation of Prozac, Singulair and the promising hNK-1 receptor antagonist from Merck (Figure 3).25
Further details on the Pd-catalyzed oxidative kinetic resolutions of alcohols can be found in Chapter 4. Moreover, Chapter 9 deals with asymmetric oxidations of alcohols with other transition metals, namely ruthenium, iridium and iron complexes.
Both homogeneous and heterogeneous catalytic systems have been developed26 and, more recently, metals in the form of nanoparticles.27 A homogeneous catalyst (typically a soluble metal complex) is in the same phase as the reactants, with the advantage of having all catalytic sites accessible to all reagents. Proper modification of the ligands allows the chemo-, regio- and enantioselectivity of homogeneous catalysts to be tuned. All these properties together allow high efficiency in reactions catalyzed by homogenous catalysts, high selectivities and high yields. They are used both in academia and in industry. However, their use in industrial applications (where metal contamination is highly regulated) is limited by the difficulties encountered in separating the catalyst from the final products. Removal of trace amounts of catalyst from the target product is of crucial importance and still remains a key challenge in homogeneous catalysis. To overcome the separation problems encountered in homogeneous catalysis, heterogeneous catalysts have been introduced. Whereas the first attempts at heterogenization were made with polymeric materials as solid supports, most novel heterogenized catalysts are now based on silica supports, since silica has excellent chemical and thermal stability and good accessibility and porosity, which make it well suited to commercialization. Oxidative degradation of the support is a major problem in particular in oxidation reactions. As an alternative, hybrid systems made of a silica scaffold modified with an organic linker have been proposed. The organic moieties can be strongly anchored to the surface to provide catalytic centers (or ligands) for metal-based catalysis. These hybrid organic inorganic catalysts can anchor the catalytic metal through covalent binding or through simple absorption. However, some issues still remain, such as the accessibility of all active sites to the reagents, which renders heterogeneous catalysts often less efficient than homogeneous catalysts, and the leaching of metals from solid supports, which again needs the separation of traces of metals from the final product. For an interesting overview on emerging in situ techniques developed to address the mechanistic understanding of heterogeneous Pd catalysts, see Chapter 4.
Nanoparticles are emerging as excellent sustainable alternatives to conventional solid supports, since they increase the exposed surface area of the active component of the catalyst, thus enhancing the contact between the reagents and the catalytic center, as occurs in homogeneous catalysis. However, their insolubility in the reaction solvent allows easy separation from the reaction mixture, which is the main advantage of heterogeneous catalysis. Thus, nanoparticle systems can be considered an interesting compromise between heterogeneous and homogeneous catalytic systems.27 Particle size is an important parameter influencing both activity and selectivity; for details on this topic, see Chapters 1 and 4. Chapter 5 addresses the preparation and characterization of gold-based catalysts. This metal, which for a long time was regarded as poorly active, has demonstrated surprisingly high activity when in the form of nanoparticles, which has initiated intense research efforts into its use for aerobic oxidations. However, we must always take into account that there is often an overlap between homogeneous and heterogeneous systems, as pointed out by Sheldon and co-workers, who demonstrated that stabilized nanoparticles are the active catalysts in the Pd–neocuproine system (see Chapter 4 for further details).28
Various metals have been discovered that can be activated by oxygen to form catalytically active species for alcohol oxidation. Berzelius reported the stoichiometric oxidation of ethanol with K2PdCl4 as early as 1828.29 However, the first synthetically useful procedure dates back to 1984, when Semmelhack et al. reported the first practical Cu-catalyzed aerobic oxidation of primary alcohols in the presence of the stable nitroxyl radical TEMPO.30
The coupling of more than one catalysts has also been investigated. In the heterogeneous phase, the synergistic activity of bimetallic nanoclusters is thoroughly discussed in Chapter 4 and 5. Concerning the homogeneous phase, some efficient biomimetic catalytic oxidations of alcohols were reported by Piera and Bäckvall in which transition metal catalysts were coupled with electron-transfer mediators (ETMs). ETMs facilitate the reaction by transporting the electrons from the catalyst to the oxidant along a low-energy pathway, thus mimicking what happens in Nature.31 This topic is reviewed in Chapter 7, together with the possibility of performing multistep reactions by coupling an oxidative reaction to a different reaction. These tandem reactions allow the creation of several new chemical bonds in a one-pot manner without the isolation of sensitive intermediates, thus also simplifying the work-up procedures.
In addition, the gas-phase oxidation of alcohols is a process of industrial relevance. The basic principles of and recent developments in this topic are reviewed in Chapter 8, which also describes the most innovative materials and methods of operation.
Several oxidations of particular industrial relevance are described in this book, such as the oxidation of methanol to produce formaldehyde or dimethoxymethane and the oxidation of ethanol to produce acetaldehyde, acetic acid, ethylene oxide, acetonitrile or 1,2-dichloroethane (an intermediate for the synthesis of vinyl chloride monomer) (Chapter 8). Moreover, the oxidation of allyl alcohol to produce industrially relevant building blocks such as glyceric acid, acrylic acid and 3-hydroxypropionic acid is discussed in Chapter 5.
Finally, the growing production of biodiesel has led to the availability of large volumes of glycerol, the main by-product of the transesterification reaction of triglycerides. Therefore, methods to convert glycerol into different chemicals are highly desirable. Some aspects related to these industrially relevant transformations (in both the liquid and gas phase) are described in Chapters 1, 5 and 8.
This book aims to give an overview of the most significant metal catalysts (homogeneous, heterogeneous or in the form of nanoparticles) that have been developed in this well investigated field of the research. Owing to the huge amount of literature available on this topic, a choice of the metals was made, trying to analyze and discuss the most versatile and best studied ones (copper in Chapter 2, ruthenium in Chapter 3, palladium in Chapter 4, gold in Chapter 5, iron and vanadium in Chapter 6), highlighting their synthetic potential and always taking into account the previously mentioned synthetic challenges. The use of alternative solvents to conventional fluids is also analyzed.