Science of Synthesis

DOI: 10.1055/sos-SD-226-00001

de Vries, J. G., Science of Synthesis: Catalytic Reduction in Organic Synthesis, (2017) 1, 1.

I have been somehow engaged with reduction reactions my entire working life. My doctoral thesis was on chiral NADH models that were used for asymmetric reduction of activated ketones, and, in passing, I also invented the reduction of aldehydes and ketones using sodium dithionite. None of this was catalytic, of course. From my six years as a medicinal chemist in the pharma industry, I particularly remember the hydrogenolysis of para-nitrobenzyl esters as the last step in a lengthy total synthesis of carbapenems, and later the hydrogenolysis of the benzyloxycarbonyl protecting groups of peptides that were going to be the ultimate painkillers. When I moved to DSM I was encouraged to work on asymmetric hydrogenation. Initially, we developed a water-soluble rhodium–bisphosphine catalyst for asymmetric imine hydrogenation that was highly enantioselective, but too expensive. Thus, after I became part-time professor in Groningen, together with Adri Minnaard and Ben Feringa, we focused on the development of cheap and simple ligands, an endeavor that culminated in the invention of the monodentate phosphoramidite ligands for the rhodium-, iridium-, and ruthenium-catalyzed homogeneous hydrogenation of a range of different substrates. At DSM, together with Laurent Lefort, we managed to robotize the ligand synthesis, allowing us to make and screen 96 ligands in two days. This eventually also led to a large-scale asymmetric hydrogenation process. In my current research, here at the Leibniz-Institut für Katalyse in Rostock, I also use hydrogenation and hydrogenolysis extensively for the deoxygenation of biomass and biomass-derived platform chemicals.

In 2007, I edited the three-volume Handbook of Homogeneous Hydrogenation together with Kees Elsevier (University of Amsterdam), so when Thieme approached me with a proposal for a new addition to the Science of Synthesis Reference Library on catalytic reduction, I thought it would be a great opportunity to check where homogeneous hydrogenation stands now, 10 years later, and at the same time make a comparison with heterogeneous hydrogenation. It is clear that heterogeneous hydrogenation is used frequently and on large scale in the bulk and fine chemical industries. However, when it comes to published work, I, and most of the authors who have participated in this work, discovered that there is a very noticeable difference between homogeneous and heterogeneous catalysis: Whereas in the former the products are always isolated and are extensively characterized, the focus in the latter is generally on the preparation and characterization of the heterogeneous catalyst, and the catalysis itself is usually a minor part. Worse still, in none of these publications are the products actually isolated; all conversions and yields reported are based on the use of GC. Thus, the reader must be forewarned that, in practice, the actual yields may be lower than the values given in the tables.

In comparison to 10 years ago, a number of trends in catalytic reduction can be seen: First and foremost, there has, of course, been a renaissance in the use of inexpensive metals (iron, cobalt, and recently also manganese) in homogeneous hydrogenation. The ligands that are used are still a bit too expensive, but this situation may change very soon. In connection with this theme, there has also been a resurgence in the use of pincer ligands.

A second trend is the use of metal nanoparticles. In heterogeneous catalysis, the synthesis of well-defined nanoparticles on a solid support can now be achieved in a highly controlled manner. There is also more information available that allows us to predict whether smaller or larger nanoparticles are required to optimize the selectivity of a particular reaction. In addition, the homogeneous catalysis community has also embraced the use of metal nanoparticles that are not on a support, but are instead suspended in solution. Here, the art is in the use of stabilizers as well as ligands, and the first asymmetric conversions using nanoparticles have even been reported.

A third major trend is the application of catalytic reduction in the conversion of biomass and biomass-derived platform chemicals. In contrast to the conversions of fossil-derived raw materials, here the game is to remove oxygen in a highly selective manner. This topic surfaces in many of the chapters, and was at the basis of many new developments in the field of ether and alcohol hydrogenolysis.

Finally, the return of photocatalysis in full force has been rather overwhelming. Only weak echoes of this movement can be found in these volumes, as hydrogenation reactions are exothermic and usually can proceed very fast catalytically without any light. Nevertheless, a few examples can be found in some chapters.

Luckily, I have been able to find excellent authors for all of the chapters. We decided to drop the chapter on epoxide hydrogenation, as not much progress has been made in the past 15 years. By the way, most authors have adhered nicely to the planned restriction of only covering the period from 2000 to 2017.

Homogeneous hydrogenation of alkenes is, of course, 99% enantioselective hydrogenation. This can be seen in Section 1.1.1 on homogeneous alkene reduction, which was produced by Xuefeng Tan, Hui Lv, and Xumu Zhang. This is a large chapter, reflecting the enormous amount of work that has been performed in this area in the past 17 years, with many new ligands being developed. Interestingly, the metals used are still the old favorites: rhodium, ruthenium, and iridium. Thus, there is an obvious gap in this area of research that one hopes will be filled soon, namely asymmetric hydrogenation using catalysts based on inexpensive metals. Not accidentally, the authors are Chinese; a tremendous number of publications on this topic have come from China, particularly in the past 10 years.

Not much progress has been made in the heterogeneous reduction of alkenes during this period, except in the area of nanoparticle catalysis. Audrey Moores and Reuben Hudson have nicely summarized the latest developments in this lively field in Section 1.1.2. Although palladium is obviously still everyoneʼs friend, there are some nice examples using nickel and iron nanoparticles as well.

Section 1.2 on the partial reduction of polyenes has been expertly put together by Nicoletta Ravasio and Federica Zaccheria, who have worked in this area for a long time. Interestingly, the driver in this field has been, and continues to be, the conversion of polyene natural products such as terpenes and polyunsaturated fatty acids. Indeed, the number of publications in this area is rising as a result of the interest in renewable chemicals. Selectivity remains an issue.

Section 1.3 is on the reduction of arenes to cycloalkenes and cycloalkanes, a field of enormous importance in the production of bulk chemicals. The reduction reactions of benzene to cyclohexane or cyclohexene are important steps in the large scale production of nylon intermediates such as caprolactam and adipic acid. The progress in this field is nicely summarized by Feng Shi and Xingchao Dai. Although in the past many homogeneous ruthenium species were reported to be active catalysts, it is now generally accepted that these compounds form ruthenium nanoparticles that are the true catalysts. Thus, this area largely belongs to the heterogeneous catalysis domain.

Section 1.4, the reduction of hetarenes, is of particular importance for the pharma industry and hence, unsurprisingly, there is also a strong emphasis on enantioselective reduction in this area. The recent work in this field has been expertly reviewed by Yong-Gui Zhou and Zhang-Pei Chen. The Zhou group has indeed made many contributions to this field.

In the reduction of alkynes and allenes (Section 1.5), or more specifically the semireduction of these substrates to the monoalkenes, selectivity is the major issue. This is, of course, a field that has emanated from the vitamins industry, where this type of conversion is frequently required. Indeed, the Lindlar catalyst originates from one of the companies that produce vitamins. I am happy to say that I managed to persuade veteran vitamin chemists Werner Bonrath, Jonathan Medlock, and Marc-André Müller to write this chapter, and their experience shows in the composition of this interesting chapter, which also contains a wealth of information from an industrial viewpoint.

Section 1.6, the catalytic reduction of alcohols, phenols, and diols, is on a topic that was a bit of an oddity in the past, but has now assumed an entirely new meaning in the context of the conversion of renewables to chemicals and fuels. There is a lot of glycerol around since the production of biodiesel has begun on large scale. And, of course, the removal of hydroxy groups from sugars and phenols to transform them into useful chemicals is also desired. However, this is not an easy task and this field is only at the beginning of a long period of development. Because there are not many people working in this field, we had a hard time finding an author and therefore this chapter is authored by my colleague Sergey Tin and myself. We both think these are amazing reactions and we plan to investigate this topic ourselves in the future.

Section 1.7, on the hydrogenolysis of ethers, is very similar in this respect. Who would want to destroy an ether, if the ether was not obtained from a sugar [as in furfural and 5-(hydroxymethyl)furfural]? The expert in the field Keiichi Tomishige, aided by his colleagues Yoshinao Nakagawa and Masazumi Tamura, has performed an excellent piece of work in summarizing this emerging area.

Something that was also not on the horizon 10 years ago was the reduction of carbonates. In Section 1.8, Kuiling Ding and Yuehui Li describe this interesting new area that is closely connected to the use of carbon dioxide as a renewable building block. Not only is the reduction of organic carbonates described, but also the reduction of carbonate salts.

As mentioned above, the hydrogenation of carbon dioxide has taken on enormous importance in recent times. This is mainly related to the fact that the conversion of carbon dioxide into methanol (or methane) using hydrogen that is obtained by water electrolysis using renewable energy (windmills, photovoltaic cells) is seen as a feasible way to store surplus renewable energy. There already exists a genuine problem in the use of wind turbines in countries such as Germany and Denmark; if the wind blows hard, these countries produce so much electricity that they need to sell it at a negative price. Thus, storage would represent a much better option. Catherine Cazin and Fady Nahra have done an excellent job of summarizing the recent work in this area in Section 1.9. Not only that, they have also summarized the work on using carbon dioxide/hydrogen as methylation reagents.

We are all used to the existence of sluggish substrates that need special catalysts, and high temperatures and pressure, to be reduced. One could almost forget that there are also classes of chemicals that are too easily reduced as they are strong oxidants. Here, safety becomes the most important issue. In Section 1.10, Peter Poechlauer and Axel Zimmermann describe the reduction of peroxo compounds, ozonides, and molozonides, based for a large part on their own industrial experience in this field. This is very interesting chemistry, but please heed the safety warnings if you want to try these reactions yourself.

Section 1.11, on the reduction of sulfur compounds, is relatively small in view of the limited substrate scope. Nevertheless, Kiyotomi Kaneda and Takato Mitsudome have done an excellent job in summarizing the catalytic reduction of sulfoxides, sulfones, and disulfides. Yes, there are catalysts that keep working in the presence of sulfur compounds!

In Section 1.12, Banibrata Ghosh and Robert Maleczka, Jr. expertly describe catalytic dehalogenation reactions using metal catalysts. This field is of course strongly associated with remediation of polluting organic halides, but the chemistry occasionally also comes in handy for a total synthesis. Not surprisingly, this is an area where photocatalysis can bring some interesting results.

Volume 2 opens with Section 2.1 on the reduction of aldehydes, another area that has gained recent importance because of the renewables angle. Think, for instance, of the reduction of furfural to 2-(hydroxymethyl)furan, an important and large-scale industrial process, or the reduction of 5-(hydroxymethyl)furfural to 2,5-bis(hydroxymethyl)furan. My colleagues from Rostock, Kathrin Junge and Norbert Steinfeldt, have done an excellent job in summarizing the methodologies based on homogeneous catalysis as well as nanoparticle catalysis for these transformations, with a particular emphasis on the selective reduction of an aldehyde in the presence of other functional groups.

Who could be better suited to write Section 2.2, on transfer hydrogenation of ketones to alcohols, than Takao Ikariya, one of the pioneers of asymmetric transfer hydrogenation, together with his colleagues Yoshito Kayaki and Asuka Matsunami? Unfortunately, during the preparation of this book we learned of the passing of Professor Ikariya. He was an excellent scientist and a good friend and colleague, and he will be sorely missed by the chemistry community. Nevertheless, we are very grateful to his colleagues for finishing this excellent chapter.

Virginie Ratovelomanana-Vidal and her colleagues Quentin Llopis, Phannarath Phansavath, and Tahar Ayad had the daunting task of reviewing the catalytic hydrogenation of ketones (Section 2.3). Although initially the plan was to cover both enantioselective and non-chiral reductions, this was simply too much and hence it was decided to concentrate solely on the enantioselective hydrogenations. Even then, it was still an immense task that has been expertly performed. Ruthenium, iridium, and iron seem to be the metals of choice in this area. The diversity of ligands used is enormous.

Section 2.4, the hydrogenolysis of aryl ketones and aldehydes, benzylic alcohols and amines, and their derivatives, describes technology that is used quite frequently in synthesis. Think, for example, of the benzyloxycarbonyl (Z- or Cbz-group) deprotection via hydrogenolysis. Here, Ivana Fleischer and Benjamin Ciszek have done an excellent job of summarizing the recent developments in this field. Most reactions are catalyzed by heterogeneous catalysts, but the reduction of aromatic aldehydes and ketones can, of course, also be performed with homogeneous catalysts.

The hydrogenation of carboxylic acids and derivatives is an area where there has been an explosion of interest recently, and hence it was decided that this should be divided into separate parts covering heterogeneous catalysis and homogeneous catalysis. Section 2.5.1, on the homogeneous catalytic hydrogenation of carboxylic acids, anhydrides, esters, amides, and acid chlorides has been written by Yiping Shi, David Cole-Hamilton, and Paul Kamer. They have put together a splendid piece of work, even though David could not resist the temptation to narrate the entire history of homogeneous ester hydrogenation, which goes back to well before 2000; it is indeed interesting to be able to put everything in the correct context. An enormous amount of work was involved, but this has led to a fascinating chapter. In particular, the earlier work in the field of ester hydrogenation and also acid hydrogenation was performed at rather high temperatures. This is probably the main reason that the more stable metal pincer complexes seem to dominate this field.

To date, all industrial hydrogenations of carboxylic acid derivatives are performed at high temperatures using heterogeneous catalysts. Michèle Besson and Catherine Pinel have done an excellent job in Section 2.5.2, where they give an overview of the recent developments in the heterogeneous catalytic hydrogenation of carboxylic acids and derivatives. In this chapter, one can find discussion of the classical fatty acid hydrogenations, but also little gems such as the gas-phase hydrogenation of carboxylic acids to aldehydes. That is a great reaction!

Section 2.6 covers the reduction of imines and the reductive amination of aldehydes and ketones, an area where again much work has been done in the past two decades. This chapter is a very nice contribution from a French/Spanish consortium consisting of Carmen Claver, Philippe Kalck, Martine Urrutigoïty, and Itziar Peñafiel. Although the emphasis is on enantioselective reductions of imines and direct reductive amination, the heterogeneous methods are also summarized, making this a pretty complete overview.

And then there are all these other nitrogen-containing compounds that can also be reduced. Sandra Hinze, Pim Puylaert, and Arianna Savini, co-workers of mine in Rostock, have done a splendid job in Section 2.7, on the reduction of nitro compounds to amines, azo compounds, hydroxylamines, and oximes, and also of N-oxides to amines. Again, the emphasis here is very much on the selective reduction of these functional groups in the presence of other reducible entities. Heterogeneous catalysis is of course very important for these transformations, but some homogeneous catalysis, particularly based on iron catalysts is also included.

Section 2.8, on the reduction of azides, was written by Hironao Sajiki and Yasunari Monguchi. This transformation is, of course, very important to the synthetic chemist, as it is often used to transform an alcohol into an amine. The authors have done an excellent job in charting the relative selectivities of often-used catalysts and reaction conditions to effect only the reduction of azides in the presence of other functional groups. As a bonus, they also describe the selective reduction of alkynes in the presence of azides that remain untouched. Many synthetic examples are given in this chapter.

Section 2.9, the catalytic reduction of nitriles, was written by Bhalchandra Bhanage and Dattatraya Bagal. This excellent chapter is an interesting mix that includes coverage of old, well-established chemistry based on heterogeneous catalysis, but is mostly concerned with the new developments using metal nanoparticles and homogeneous catalysts, including systems based on iron, cobalt, and manganese. Of course, selectivity remains a very important issue in this chemistry, as the formation of secondary or even tertiary amines needs to be suppressed.

After having read all the chapters, I am happy to say that much has happened in the last 17 years. There have been many interesting new developments, some of which are only at an early stage. I think someone may need to do a new book on this subject 10 years from now.

Many thanks to all of the authors, who have dedicated so much of their precious time to writing the excellent contributions.