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Chiral Catalyst Immobilisation and Recycling

D. E. De VosI. F. J. Vankelcom and P. A. Jacobs, VCH-Wiley, VCH-Wiley, 2000, pp. 320, price £80, ISBN 3-527-29952-1 Search PubMedSome thirty years ago heterogeneous catalysts were limited primarily to inorganic oxides and mixed oxides exploited mainly in large scale chemical production. At the time these were regarded as selective and a great deal of compositional variation had been explored to identify catalysts with optimum activity and selectivity. A few processes were also employing sulfonic acid ion exchange resins as heterogeneous catalysts. By the demands of the modern speciality and fine chemicals businesses these early heterogeneous catalysts were and remain relatively non-selective, and the emergence of organometallic chemistry, and the spin-off in terms of structurally well-defined highly selective soluble metal complex catalysts, has transformed the level of selectivity in catalysis now available to organic synthetic chemists.

The evolution of zeolitic metal oxide catalysts was the first advance in the selectivity achievable with heterogeneous catalysts. While this development was in progress a few chemical entrepreneurs were experimenting with the concept of using insoluble crosslinked polymer resin beads upon which to construct ligands structurally analogous to the low molecular weight ligands comprising the newly emerging highly selective soluble metal complex catalysts. The driving force was and remains the generation of heterogeneous catalysts of comparable or improved selectivity, knowing that such species are experimentally more convenient and cost effective to use both on a small and a large scale, and offer the prospect of being able to recover and reuse the often hard won metal complexes, and indeed to exploit them in continuous processes. Despite a set-back in research in this area in the late 1980’s caused primarily as a reaction to academics paying little or no attention to metal leaching and catalyst recycling issues, the area has exploded as we have moved into the new millennium. The emphasis in terms of both inorganic and organic polymer supports is on the immobilisation of increasingly sophisticated and structurally well-defined metal complex catalyst species, with chiral catalysts being a very important sub-set.

Two key review texts covering immobilised catalysts appeared in the 1980’s: one written by F. R. Hartley in 1985 focussing mainly on polymer supports, and one edited by P. Laszlo in 1987 dealing with inorganic systems. These contain a wealth of earlier information, but relatively few references however deal with chiral catalysts. The latter have been reviewed in small articles from time to time, but the editors of the present textbook have made the judgement that the time is ripe for a more comprehensive review of immobilised chiral catalysts, and even a brief examination of their text is evidence that their judgement is correct. Their objective has been to produce a book that will stand the test of time, and become a benchmark for many years to come. In selecting 28 authors from leading world groups to contribute in their specialised areas, and in going to VCH-Wiley as the publisher, they have indeed gone as far as it is possible to achieve these objectives (see later).

The coverage is comprehensive with an introductory chapter setting the scene in terms of the academic and industrial environments and the challenges posed for immobilised catalysts, and the challenges arising in delivering effective immobilised catalysts. More focussed contributions follow. Chapter 2 deals with catalyst immobilisation on inorganic supports and Chapter 3 a complementary review of polymer-supported asymmetric catalysts. These two chapters also differ from the remainder in that they deal with some of the general issues associated with inorganic and polymer supports respectively, and also cover a substantial variety of catalyst systems. Chapter 3 for example refers to the use of linear soluble polymers, polymer resin beads, dendrimers and polymer encapsulated species. It covers the asymmetric catalysis of alkene hydrogenation, carbonyl and imine reduction, carbon–carbon bond formation, carbonyl alkylation, Diels–Alder reactions, enolate chemistry, Strecker chemistry, alkene dihydroxylation, alkene epoxidation and epoxide ring-opening, and acylation catalysts.

Chapter 4 describes liquid biphasic enantioselective catalysis. A few industrial processes now operate under this type of technology although only time will show how robust this approach is, as equally or more effective solid supported catalysts compete. Reactions covered include alkene hydrogenation and hydroformylation, asymmetric Wacker oxidation, Lewis acid-catalysed reactions, and enzymatic reactions. The latter lead logically to Chapter 5, immobilised enzymes in enantioselective synthesis. This area has been around for some time and the topic means different things to different practitioners. Early immobilised systems used relatively crude immobilisation techniques, and yet commercialisation was achieved (is there an important lesson here?). The chapter covers immobilisation methodologies (previously also well written up by other authors) but goes on to give a contemporary view and to describe some operational systems. Clearly this still remains an area with considerable potential and it would be nice to see a broader range of enzyme systems working effectively in an immobilised state.

Chapters 6 and 7 deal with enantioselective hydrogenation of unsaturated esters and ketones catalysed by immobilised Pt in the presence of chiral modifiers. The latter of these two focuses more on theoretical issues. The area is an industrially important one, and yet nevertheless it is surprising how many groups are involved and how much effort continues in this narrow area. Cynics might say that the extensive research activity exists because the methodology involved is relatively simple and requires only the correct chiral modifier to be (physically) added to already well-developed supported Pt catalysts i.e. no complex ligand design, synthesis and immobilisation are required. In reality, however, the key researchers at least are trying hard to introduce scientific design and understanding into their systems. A number of quality reviews of this area already exist, and hence these two chapters focus on attempts to understand the processes involved.

Chapter 8 complements the preceding two in dealing with Ni catalysts for enantio-differentiating hydrogenations. The most important substrates are β-ketoesters, and early SiO₂ supported Ni species modified with tartaric acid have been improved enormously over 35 years, and now offer ee% above 98. The chapter deals comprehensively with catalyst formulation, preparation and application, but also summarises in some detail the mechanistic rationalisation that has emerged over the years.

Chapter 9 deals with catalytic asymmetric hydrogenation, hydroformylation and hydrosilylation of alkenes, unsaturated esters and ketones employing immobilised chiral P- and N-containing ligands. Rh is the key metal but Ru complexes are also covered. The area is one where both inorganic and polymer supports have been widely exploited, and considerable design input is apparent in terms of many of the complex tailored ligands involved. The chapter nicely updates this area. Chapter 10 describes catalytic heterogeneous enantioselective alkene dihydroxylation and epoxidation. Very important advances have been made with soluble chiral complexes in this area, and not surprisingly vigorous efforts have been made by a number of groups in the world in trying to produce equally effective heterogeneous analogues. Some very promising inorganic oxide and polymer-supported species have now been developed and this chapter summarises the position to late 1999.

Arguably enantioselective C–C bond formation is perhaps the most important area in terms of constructing complex organic molecules and Chapter 11 reviews the progress in immobilising chiral catalysts which are effective in this respect. Systems which have been studied using both inorganic and organic supports are the alkylation of aldehydes using organozinc reagents in the presence of chiral aminoalcohols, and TADDOL and binaphthol-based Ti species. Zeolites and mesoporous silicas are also described in this context. The other important area is asymmetric Diels–Alder reactions and again the use of polymer and inorganic oxide immobilised chiral Lewis acids are reviewed in this chapter.

The final chapter, 12, deals with heterogeneous diastereoselective catalysis which perhaps has not been as widely investigated as it might have been. The advantage here is that the immobilised species need not be a complex asymmetric entity since diastereomeric control is exercised by an existing stereogenic centre in the substrate. Important reactions that are reviewed are hydrogenations of C=C, C=N and C=O bonds, and also of aromatic and heterocyclic compounds. Standard heterogeneous catalysts such as supported Rh, Pd, Ni and Pt are described mostly supported on SiO₂, Al₂O₃ or carbon. Other miscellaneous reactions are hydrogenolyses, cyclisations, Diels–Alder cycloadditions, enolate protonations, Claisen rearrangements, epoxidations and epoxide rearrangements. Obviously in these systems the enantiomerically pure substrates are more important than the immobilised catalysts, although the situation involving a chiral substrate and a chiral catalyst offers intriguingly novel possibilities.

Of particular relevance is that the title of the text makes specific reference to the recycling of immobilised catalysts and hence also by implication to catalyst (metal) leaching, catalyst stability and deactivation and to support stability. These aspects of immobilised catalysts have been ignored by many researchers, and even today numerous papers are appearing in print with either no reference to these issues, and even more often no data offered in this respect. All of the authors in the present book have tried to make reference to these factors (presumably on the guidance of the editors) when the original papers make this information available, and this is a big step forward. The situation in the primary literature could be much improved if the referees of original manuscripts were encouraged to reject submissions which make no reference to recovery, recycling, stability etc., and to request the provision of data when only casual and unsubstantiated comments about recycling issues are made.

So will this book become a benchmark text for the area? This reviewer believes ‘yes’, not the least because of its sheer coverage (types of support, catalysts and reactions), and the detailed critical discussions offered within each chapter. Some of the authors emphasise that their treatment is not exhaustive, but in practice all chapters are comprehensive with valuable listings of primary references to late 1999. Some areas however are developing very rapidly, and inevitably some chapters will age more quickly than others. Indeed key papers have emerged or are in-the-pipeline since the submission date for the chapters, and to some extent this has to be regarded as a good indication of the vibrance of this whole research area. The text will also stand the test of time because of the excellent planning of the editing team. Despite the numerous authors involved the text looks and reads coherently as if written in a single style by a small group of native English-speaking authors, or indeed a single such author. There is some overlap between particular chapters, but this is not serious, and indeed has some value. In at least one instance data incorrectly quoted by authors in one chapter is correctly cited by authors in another. There are however few obvious errors overall.

The production quality of the text is immaculate, and while this in part is no doubt due to the best of modern technology, the latter has to be applied carefully. This high quality is what we have come to expect from this VCH-Wiley publication series, and so presumably the desk-editing team also are to be congratulated. The very high consistency in structural representations and in figures adds to the attraction of the text, and the professionally put together index offers an alternative way into chapters rather than via the contents list.

Overall the book is one that must be acquired by all serious libraries wishing to maintain their chemistry collection at the cutting edge of knowledge. In addition the text will be an invaluable one for personal acquisition by all scientists involved in supported chemical synthesis, and indeed by many mainstream synthetic chemists who will find this an invaluable work of reference to have to hand in their own office or study.

This reviewer complements the editors and the authors on an excellent piece of scholarly work, and regrets only that his name is not amongst the list of authors as a result of an earlier commitment to write a review for publication elsewhere.

David C. Sherrington
University of Strathclyde, Scotland, UK

Compendium of Organic Synthetic Methods Volume 9

M. B. Smith, Wiley-Interscience, USA, 2000, pp. 439, price £71.50, ISBN 0-471-14579-3 Search PubMedAs the name suggests, this is the 9th volume in a series of texts which have been produced every few years for over 20 years now. The latest volume consists of 439 pages comprising a series of chapters and a 49 page author index. The first fifteen chapters deal with the preparation of a different functional group, with all the expected functional groups being present along with a chapter on hydrides (conversion of functional groups into C–H bonds) and oxides (sulfoxides, phosphine oxides etc.). Each chapter is subdivided into sections based on the functional group that the product was prepared from (preparation of alkynes from alkenes etc.). The final chapter which occupies over 150 pages is on the synthesis of difunctional compounds and is again subdivided into sections based on the two functional groups present. Two useful tables are provided at the front of the book to allow the relevant sections to be found rapidly. Although this subdivision is mostly logical, there are a number of sections on the protection of functional groups which are included within the chapters on the synthesis of that functional group. Thus, the protection of alcohols is covered in the chapter on the synthesis of alcohols, rather than in the chapters on preparation of ethers, esters etc. Each chapter consists of a series of chemical reactions to illustrate the transformation occurring and the reagents being used, accompanied by a literature reference and occasionally a brief note on the scope or limitations of the transformation. For each reaction, the percentage yield of the product is also included.

The main problem with this book is that only literature published between 1993 and 1995 is included, so it is already six years out of date! One has to admire the effort which has been put into the searching of the original literature to produce a compilation of this type, but also question whether if it takes six years it is really worth doing. Nowadays (at least in the UK) electronic databases (e.g. Beilstein online) are readily available which contain exactly the same information as this text, but are far more up to date. If I wanted to know how to prepare an alkyne from an alkene for example, I would not dream of consulting this text and its eight precursors, in far less time I would obtain the information directly from an electronic database.

I was also concerned at the number of errors in the text, whilst typographical errors will always be present, especially in a text which essentially consists of a series of chemical structures, I was uneasy about the quality of production when I noticed that in just the third line of the preface, ‘literature’ was spelt incorrectly. Sure enough, I only had to check as far as the top of page 6 to find the first error in the chemical structures, an alcohol apparently being oxidized to give unreacted starting material. Unfortunately, this is not a one off error, throughout the text I found numerous examples of wrongly drawn chemical structures, ranging from the obvious—half an aromatic ring missing—to the frustrating—heteroatoms or double bonds missing. On more than one occasion, I found myself thinking ‘that’s an interesting reaction’ only to check the original literature and find that in fact it was a very routine reaction with the product misdrawn. The text would also have benefited from a more logical ordering of reactions in each section. For example, section 45A is concerned with the protection of alcohols, and contains a number of methods for the introduction of THP protecting groups. However, these are dotted at random amongst ways of introducing or cleaving all the other alcohol protecting groups. It would have been far more helpful to group them all together. Another example of this is section 209 which is concerned with the preparation of alkenes from alkenes and contains references to a number of papers on olefin metathesis, but these are mixed amongst references to Diels–Alder reactions, ene-reactions, and other ways of converting one alkene into another.

This book is also in direct competition with Larock’s excellent Comprehensive Organic Transformations, which, for about the same price covers all of the literature, not just three years worth, and is now available on CD-Rom. In summary, I am left with the feeling that this series of books was an excellent idea when it started, but has been overtaken by modern technology. Given the current pressure on library (and individual budgets), I cannot see this text being a high priority purchase.

M. North
Department of Chemistry, King’s College, London, UK

Specialist Periodical Report: Organometallic Chemistry, Volume 28

M. Green, Royal Society of Chemistry, 2000, pp. 544, price £219.50, ISBN 0-85404-323-3 Search PubMedThe 28th volume of this specialist periodical report reviews the organometallic literature published during 1998. As can be appreciated by anyone with even a casual interest in organometallics, this is a vast area of research with over a thousand publications arising in any year. A review of such a body of literature needs to set some limits. Fortunately, the majority of the contributors to this volume elect to review, what they consider to be, the most interesting or important aspects to have arisen in the discipline over the year. Like previous volumes, volume 28 is divided into a number of chapters. This volume, however, also sees the introduction of a new chapter on theoretical organometallic chemistry and also provides a number of World Wide Web URLs (chapter 9) which might be of interest to the ‘organometallic chemist’.

It is the nature of this ‘organometallic chemist’ which the book seems uncertain about. With the exception of the chapter on the lanthanides, the first seven chapters are not for the faint hearted. The tone each chapter takes and the literature it reviews is most definitely biased towards a structural and inorganic perspective. The result is that it makes it a dry read for those from a more synthetic background. The chapter on group 13 metals is notable for its absence of any mention of the work of H. C. Brown. In addition, it fails to mention some of the new organo-aluminium and organo-indium reagents being reported for use in synthesis. The chapter on group 14 elements also contains very little of interest for the organic or synthetic chemist, despite having the rich chemistry of phosphorus to draw upon. These early chapters also lack sufficient diagrams detailing chemical structure, preferring instead to use condensed molecular formulae.

Chapter 8 is a welcome oasis of synthetic organic chemistry, dealing as it does with ‘organic aspects of organometallic chemistry’. This chapter is chemical structure rich and highlights progress made during the year in a number of areas (cross coupling reactions, carbon–heteroatom bond formation, carbonylation, oxidations, etc.), each one worthy of a review in its own right. Again, only that which the authors have judged to be outstanding has been included. The chapters on metal carbonyls and metal clusters revert back to the format of the first few chapters. These chapters concentrate mainly on the synthesis and structural elucidation of these compounds, rather than their chemistry. As such these contributions will be of little interest to the synthetic organic chemist.

The remaining four chapters deal with the chemistry of σ- and η-bonded organo-transition metal complexes. These chapters strike a good balance between the structural slant adopted by the earlier chapters and the synthetic view embraced by chapter 8. Of particular interest to the organic chemist will be the mature and exciting applications of organo-titanium and organo-zirconium reagents in organic synthesis and the intriguing possibilities that organo-niobium and organo-tantalum complexes may provide. Of course, the remainder of the middle to late transition series is also covered. Included are the structure, synthesis and chemistry of a number of ‘important’ η⁵ cyclopentadienyl complexes, η² complexes and carbenoids of various transition metals. These entries provide a springboard for interested parties to dive into the significant literature of these areas.

In general, volume 28, highlights the key references in the literature published during 1998. If a comprehensive review is desired then this book will disappoint. While this book will be at home on the shelf of a structural chemist or an organometallic chemist with leanings towards inorganic chemistry, it will probably not find much use on the shelf of an organic colleague. For those of us with a synthetic upbringing, browse through this one in the library.

Paul A. Clarke
University of Nottingham, UK

Medicinal Chemistry: An Introduction

Gareth Thomas, Wiley, Chichester, 2000, pp. 539, price £24.95, ISBN 0-471-48935-2 Search PubMedLearning medicinal chemistry requires an understanding of the chemical principles of drug design and drug action, but also requires knowledge of biological drug targets, and the pharmacology of drug delivery, administration and breakdown.

This book covers quite comprehensively the principles of medicinal chemistry, primarily from a chemistry viewpoint, but introducing necessary material from pharmacology and biochemistry. The chapters are organised logically, introducing the principles of drug action and drug design, then the importance of drug solubility and interaction with biological membranes, and its delivery to the target in the body. Enzymes as drug targets are then discussed, followed by the therapeutic applications of metal complexes. Receptors are then discussed, and examples of receptor agonists and antagonists given. Drug metabolism is then illustrated, followed by a discussion of nucleic acids as drug targets, and a chapter on nitric oxide and its emergence as a drug target. Finally there is a chapter on asymmetric methods of organic synthesis for drug synthesis. Each chapter is supplemented with a useful summary and questions on the text. There are a good number of chemical structures, and the book is on the whole well illustrated. In several places model calculations are included, which are helpful.

Overall, the book is well suited for an introductory text for chemistry students learning about medicinal chemistry. By comparison with other texts in this area, it has the advantage that it is fairly comprehensive in its coverage, and that there is a good deal of chemistry illustrated. There are places where more in-depth coverage might be needed by students, for example case studies of receptor agonists/antagonists and enzyme inhibitors. Some groups of drugs, for example antimicrobial agents, are split between several chapters according to their mode of action, rather than drug class. The final chapter on asymmetric synthesis is of a quite different flavour to the rest of the book, and would be covered elsewhere on most chemistry courses, but would be valuable to students on pharmacology courses.

I would say that this book is certainly competitive with other medicinal chemistry texts, and is clear and balanced in its coverage. Although in certain areas it has less detail than other texts, as a general introduction it will prove very useful to students.

T. D. H. Bugg
University of Warwick, UK

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