Book Reviews

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Nomenclature of Organic Compounds, Principles and Practice (Second Edition)

Robert B. Fox and Warren H. Powell, American Chemical Society/Oxford University Press, xvii + 437 pp., price £150, ISBN 0-8412-3648-8 Search PubMedIt is a rare event to see a new book on chemical nomenclature. This is perhaps slightly unexpected, as chemical nomenclature underpins all analysis. If you do not know what you are looking for, how do you analyse it? This volume is a very much expanded and revised version of the first edition published in 1973. The Chemical Abstracts Service (CAS) of the American Chemical Society and The International Union of Pure and Applied Chemistry (IUPAC) have both produced lengthy recommendations for naming chemicals. Although there are many similarities between the two systems, there are differences, and regulatory bodies frequently ask for both CAS and IUPAC names. Messrs Fox and Powell have an immense amount of experience in nomenclature and are very well-placed to share their expertise. The authors recommend a hybrid approach, trying to include the best aspects of each system. Rather surprisingly, this includes the CAS nesting order for enclosures, which is [[[[[( )]]]]], rather than the IUPAC {[({[( )]})]} etc. They stress the importance of using unambiguous and understandable names, and also of defining abbreviations the first time they appear in any document. There is a very interesting history of organic names.

The authors include a useful comparison of IUPAC and CAS methods, highlighting inconsistencies. IUPAC tends to have a lengthy review procedure before publishing recommendations for types of nomenclature. However, CAS have to register new chemicals, so may need to make fairly rapid decisions about procedures for naming new classes of chemicals. The authors recommend the IUPAC positioning of locants, for example, IUPAC would say “pentan-2-ol”, whilst CAS would say “2-pentanol”. They briefly forget this convention later on when they say the systematic name for methyl ethyl ketone is “2-butanone”, rather than “butan-2-one”. It is questionable whether you need a locant at all in this particular case. American spellings are used, so we have “eicosane” rather than the IUPAC “icosane”. This must be one of the few occasions where Americans retain a Greek spelling, when the rest of the world has abandoned it.

The book gains from the presence of many illustrative examples. The official text books tend to avoid giving examples, which can lead to ambiguity. Users have to make their own choices about which paths to follow. This can lead to many equally valid systematic names for the same compound. Fox and Powell nail their colours to the mast and make specific recommendations. The majority of these follow the CAS procedure, but IUPAC methods are certainly not forgotten. There is a very handy chapter on common errors, which should be read by anybody who uses chemical names. Explanations are provided on why you should not say isopropanol, for example. (Isopropane does not exist.)

The chapter on aromatic hydrocarbons sticks to CAS policy on fused hydrocarbons, e.g. mentioning dibenz[a,h]anthracene, with no mention of IUPAC's current policy of retaining the “o”, hence, dibenzo[a,h]anthracene. Having said that, several examples are given of the different numbering by CAS and IUPAC of internal atoms in fused aromatic systems. This would be particularly useful for people used to one system of numbering when confronted with what appear to be totally illogical locants in such a structure. This chapter brings us right up to date, as there are sections on cyclophanes and fullerenes, which have only recently had rules published. IUPAC are still considering fullerenes, as the numbering causes a few problems.

Although the book title refers to organic nomenclature, the authors do venture into inorganic territory. In the section on replacement nomenclature, examples are given of structures where all the carbon atoms have been replaced by other atoms. This is a logical extension of the system. The opportunity is also taken to deal with sulfur analogues of anhydrides etc. There is also an entire chapter on boron compounds, which would normally be considered inorganic, but the naming techniques make use of organic and inorganic forms, so this is justified, and should really be regarded as a bonus, rather than a digression.

There is lengthy coverage of stereoisomerism, dealing with CAS, IUPAC and Beilstein systems. This offers a useful comparison, especially as the CAS system has just been improved, and it now has some similarities with the IUPAC system. The authors also include chapters on natural products and polymers, which are clearly organic, but have their own naming systems. Useful appendices covering prefixes, group names and a glossary follow.

This is a very wide-ranging book, and it benefits from a large number of illustrative examples. Anyone who has tried to name chemicals will be aware that both IUPAC and CAS systems have good points and bad points, so it is tempting to use a hybrid system, as espoused by the authors. Indeed, there are almost as many forms as nomenclature as there are nomenclators! Unfortunately, creating hybrid systems can cause more confusion, but nomenclature is evolving and recommended procedures do change. The proposed hybrid system may be adopted one day. This book offers a very good guide to the provision of organic names, and it would be very useful for anyone interested in the subject.

Kevin Thurlow
LGC Ltd

The Nitro Group in Organic Synthesis

Noboru Ono, Wiley-VCH, 2001, xvi + 372 pp., price £92.95, ISBN 0-471-31611-3 Search PubMedOno's book is the latest addition to the Organic Nitro Chemistry series. The purpose of the series is to review the nitro chemistry encountered by organic chemists of nitro compounds and structurally related molecules (such as nitrones or nitrile oxides). The Nitro Group in Organic Synthesis focuses on modern advances in the field rather than giving a comprehensive overview of earlier work.

The first impression a reader has when opening this book is that it is well presented with numerous detailed schemes. Each chapter covers its topic in a comprehensive and well-written fashion. The research covered is referenced at the end of each chapter. Further inspection reveals that the real emphasis of this text is on the synthetic transformations that have been achieved in the last 20 years, the references being largely dated through the 1980s and the 1990s.

The book is clearly intended for those who already have some familiarity with nitro chemistry. Mechanistic considerations are sometimes mentioned but, largely, the reader is assumed to be familiar with the basics while the author concentrates on describing the results of chemical reactions. The overall style of the book is that of a series of reviews covering the more important recent advances over the more classical methods. This approach can be a weakness if the text appears fragmented, however, the author's presentation is consistent for each topic and so the book retains a sense of cohesiveness throughout.

The introduction is extremely brief, less than two pages, and explains in broad terms the importance of nitro chemistry and goes on to explain the emphasis on the new developing areas detailed in the book.

Chapter 2 gives a comprehensive account of modern methods for the preparation of nitro compounds. This begins, logically enough, with the nitration of different molecular types (arenes, alkanes, alkanes etc. . . .) and then examines the formation of nitro compounds via the oxidation of amines and oximes. Nitration is often associated with heavy industrial processes emitting large volumes of noxious nitrogen oxides and generating considerable amounts of acid waste. Ono makes no attempt to duck this issue, admitting that this is a still a problem in parts of the industry, but he goes on to outline some avenues of research which have been investigated in an attempt to alleviate these problems.

Chapter 3 is dedicated to the Henry reaction (nitro-aldol reaction). The first part of this chapter discusses modern methods for the preparation of β-nitro alcohols, giving a large array of substrates and conditions. The second section covers derivatives from β-nitro alcohols, particularly nitro-alkenes. The third part of this chapter gives examples of stereoselective Henry reactions and their application in organic synthesis. Given that classical Henry reactions are prone to give mixtures of syn and anti isomers this is a particularly welcome section.

Chapter 4 gives a detailed account of the Michael addition showing nitroalkenes as Michael acceptors (section 1) and the anions of nitroalkanes as Michael donors (section 3). The addition–elimination reactions of β-heterosubstituted nitroalkenes are also covered (section 2) as is the use of nitro compounds in asymmetric Michael additions (section 4).

Chapter 5 is concerned with C–C bond forming reactions of nitro compounds and covers alkylation, arylation, acylation and retro-acylation. Separate sections are devoted to alkylation via alkyl radicals and for using transition metal catalysis.

Chapter 6 is entitled ‘conversion of nitro compounds into other compounds’ and while it is true that this is the basis of the chapter, almost half of this is concerned with modern variants of the Nef reaction. A brief section considers the formation of nitrile oxides and nitriles from nitro compounds and another section considers the reduction of the nitro group to the amine. Oximes, hydroxylamines and other nitrogen derivatives are singled out but this section is short and is not as comprehensive as other parts of book.

The displacement of a nitro group from α-nitro ketones, α-nitro nitriles, α-nitro esters or α,α-dinitro compounds by nitroalkane salts or other stabilised carbanions is a relatively new reaction (discovered in 1970). The reaction proceeds by a radical chain mechanism and is briefly described in Chapter 7. This chapter also includes other reactions involving the substitution or elimination of NO₂ from various nitroalkanes. Particular attention is drawn to the area of radical denitrohydrogenation and this is well described in some depth. The elimination of the NO₂ group from aliphatic nitro compounds to give olefins is also described in this chapter.

Cycloaddition of nitro compounds is now seen as a well-established and particularly effective method for the construction of various cyclic ring systems. Diels–Alder reactions with nitroalkenes or the [3 + 2] cycloaddition methodologies of nitrones or nitrile oxides have been demonstrated to be especially effective in ring construction. Chapter 8 amply covers these topics and particular emphasis is rightly placed on the work of Denmark and his seminal work on the tandem [4 + 2]–[3 + 2] cycloaddition of nitroalkenes.

Chapter 9 is involved with a description of nucleophilic aromatic displacement of aromatic nitro compounds and describes the recent developments in this area of research and especially into vicarious nucleophilic substitutions of hydrogen.

The last chapter covers the synthesis of heterocyclic compounds. Most of this chapter is devoted to the construction of pyrroles and indoles although a variety of other ring systems are also briefly mentioned.

Overall, this book is thoughtfully laid out, well referenced and easy to read. Perhaps the only area in which the book does not fully achieve one of its cited aims is in the area of ‘green chemistry’. This starts out well in the second chapter but then the coverage becomes very scattered. There are a few typographical errors (missing words or letters from words) but they do not detract from what is a highly competent rendering of the use of the nitro group in modern organic synthesis.

Joseph P. Adams
GlaxoSmithKline

Medicinal Chemistry – Into the Millennium

M. M. Campbell and I. S. Blagbrough, The Royal Society of Chemistry, UK, x + 398 pp., price £69.50, ISBN 0-85404-769-7 Search PubMedDespite enormous developments over the past decade or so, design and discovery of new biologically active molecules for use as pharmaceutical agents is an ongoing challenge. Advances in genomics have identified new molecular targets for investigation, while on the synthetic side, production of large chemical libraries has increased efficiency in lead generation and optimisation. Converting these technological developments into new efficient pharmaceutical agents poses a significant challenge to scientists in the pharmaceutical sector.

In this book, the Proceedings of the European Federation of Medicinal Chemistry Symposium held in September 1998, contributions from scientists in the pharmaceutical sector and academic researchers offer an interesting blend of insights into recent (in 1998) developments in Medicinal Chemistry. Organisation of the material into a number of themes each consisting of between two and five individual contributions is particularly useful.

The first section covering New Technologies in Drug Discovery reflects recent activity in the areas of library construction and design, and informatics. The first contribution by Paul Bartlett’s group discusses design of macrocyclic peptidase inhibitors, while the second by Daniel Rich’s group focuses on protease inhibitors. Both articles highlight the interplay between rational design and combinatorial approaches. This section is completed by a contribution from Ken Siddle and Tom Blundell’s groups showing the use of structural genomics and protein superfamilies in drug discovery.

The next section on Ion Channels features two contributions, the first from Paul Leeson at AstraZeneca focusing on ligand-gated ion channels as targets, in particular the NMDA receptor as a target for CNS disorders, while the chapter by Frank Slok and co-workers discusses the design of selective ligands for Excitatory Amino Acid (EAA) receptors. This is followed by two contributions on Glycine Antagonists, with the first by David Jane exploring the therapeutic potential of these antagonists acting at the NMDA receptor complex, while the second by G. Gaviraghi and co-workers at GlaxoWellcome describes the discovery and development of novel indole-2-carboxylates as potent and selective glycine antagonists for use as neuroprotective agents in brain ischaemia.

The section on 7TM receptors commences with a contribution from David Horwell and co-workers from Parke-Davis describing the use of ligand based design to modify neuropeptides to give therapeutically useful peptoids as antagonists, focusing on bombesin and tachykinins. Interestingly this article also explores the use of dendroids as a non-peptide motif as mimetics of protein–protein interactions. Following this, a contribution from Steven Bromidge of SmithKline Beecham describes the discovery by high throughput screening of a lead bis-aryl sulfonamide as a ligand for the 5-HT₆ receptor and subsequent optimisation of the bioactivity through structural modification. Autoradiography studies using a highly specific radioligand demonstrated for the first time that 5-HT₆ receptors are present in the human brain. F. Ince from Astra Charnwood then describes the discovery of a family of dual D₂-receptor and β₂-adrenoceptor agonists for application in the treatment of airway disorders such as asthma and COPD.

Two contributions on Growth Factors commence with an article by J. I. Luengo and co-workers at SmithKline Beecham and Ligand Pharmaceuticals on the discovery of a small, non-peptidyl mimic of granulocyte-colony stimulating factor showing for the first time that a small non-peptidyl molecule can trigger the selective activation of a cytokine receptor. The second chapter by Andrew Barker, Zeneca, describes the use of 4-anilinoquinazolines as inhibitors of epidermal growth factor receptor tyrosine kinase for application in cancer therapy.

The section on Intracellular Signalling consists of five articles, the first by A. J. Bridges and co-workers at Parke-Davis describes the development of highly selective, irreversible epidermal growth factor receptor tyrosine kinase inhibitors, again based on the anilinoquinazoline pharmacophore, for cancer therapy. Jerry Adams and co-workers at SmithKline Beecham then describe the development of pyrimidinylimidazoles as p38 MAP kinase inhibitors for anti-inflammatory application. Peter Davis and co-workers from Celltech Chiroscience discuss the development and optimisation of inhibitors of T-cell specific tyrosine kinases. Alan Lewis and Anthony Manning of Signal Pharmaceuticals discussed the role of gene regulating kinases in inflammatory diseases and strategies for designing inhibitors. The final contribution in this section from David Gani’s group describes the mechanism of catalytic hydrolysis of inositol-1-phosphate by inositol monophosphatase; design and solid phase synthesis of inhibitors based on the catalytic mechanism is discussed. Novel aspects of the solid phase synthesis include new protocols for quantifying resin loading using ¹⁹F gel-phase NMR spectroscopy.

The next topic in the book is Protease Inhibitors: Michael Venuti and co-workers from Axys Pharmaceuticals describe the discovery of small molecules for zinc-dependent serine protease inhibition, including use of X-ray crystallography to explore the zinc binding. P. S. Dragovich, Agouron Pharmaceuticals, describes the structure based design of irreversible inhibitors of human rhinovirus 3C protease based on ketomethylene dipeptide isosteres. Furthermore optimisation of tripeptide derived inhibitors of the same target using solid phase synthesis and high-throughput assay is reported. Daniel Veber and co-workers describe the design of 1,3-bis(acylamino)propan-2-ones as new potent, reversible inhibitors of the cysteine protease cathepsin K, with a view to developing treatment for osteoporosis.

Five varied contributions in the area of Glycochemistry and Glycobiology form an interesting section of the book, starting with an article by Horst Kunz and co-workers describing the synthesis and use of glycoconjugates as tumour-associated antigens and ligands in regulatory processes. The next contribution by Elizabeth Hounsell and David V. Renouf outlines new potential drug targets based in glycochemistry focusing in particular on protein glycosylation in immuno- and neuro-pathology. The next contribution by Per-Erik Jansson incorporating a multiinternational group of co-workers, describes investigation of the chemistry of lipopolysaccharides—biologically active surface polymers—from Helicobacter pylori and Vibrio cholerae. Structure–activity relationships in synthetic heparin-like oligosaccharides are described by C. M. Dreef-Tromp and co-workers from Organon, leading to well defined synthetic antithrombotics with tailor made profiles with respect to anti-factor Xa and anti-thrombin activities. The final contribution from P. M. St Hilaire and co-workers describes the use of automated techniques for the synthesis of glycopeptides and use of these structures for investigation of protein–carbohydrate interactions.

Richard Silverman’s group describes the design of selective inhibitors of three isozymes of Nitric Oxide Synthase, demonstrating that relatively minor structural modifications can produce very different results, implying that subtle differences exist in the active sites of the three isozymes.

Converting lead compounds based on molecular targets into commercial drugs is one of the major challenges in the pharmaceutical sector. In particular the areas of drug metabolism and pharmacokinetics (DMPK), which are often investigated late in the discovery process, lack predictivity, and can be a major stumbling block. Accordingly there are currently significant efforts invested in attempting to develop predictive methods for DMPK, and earlier use of these in the cycle of drug discovery. The final section of the book involves four contributions in the area of Predicting DMPK highlighting some of the problems and solutions in this regard. Dennis Smith, Pfizer, describes absorption and distribution as factors in drug design, and demonstrates how structural features which provide good dissolution properties, such as inclusion of an ionised group, can markedly improve the duration of the compound in vivo. Bernard Testa then highlights the importance of detailed understanding of drug metabolism. Marc Bertrand and co-workers from Technologie Servier describe techniques for rapid screening and assessment of drug metabolism long before clinical trials, allowing understanding of the fate of a potential drug in vivo. The final contribution from Nico Vermeulen and co-workers describes the investigation of the active sites of cytochrome P450s using modelling techniques.

In a collection of this nature inevitably the selection of molecular targets included can never be comprehensive. However, those included cover many therapeutically significant areas. Inclusion of the opening section on New Technologies for Drug Discovery and the closing section on Predicting DMPK ensure that the book provides a useful overview of the process of drug discovery. This book will be of interest to all involved in medicinal chemistry, especially to those in the pharmaceutical sector.

Anita R. Maguire
University College Cork, , Ireland

Molecular Switches

Ed. Ben L. Feringa, Wiley-VCH, Germany, xxii + 454 pp., price £85, ISBN 3-527-29965-3 Search PubMedInformation storage at the molecular level, using switchable molecular devices, may revolutionise information processing and communication systems. This book illustrates many of the types of switchable molecular systems which have been created through a combination of rational design and serendipity. Photochromic dyes (compounds which change colour when exposed to light due to photochemical reaction) feature as prominent components of these systems. Such dyes occur in nature, for example in the rod and cone cells of the retina, and synthetic photochromic dyes have been known for well over 100 years, but it is only recently that highly fatigue-resistant systems have been developed.

The book consists of 13 articles each written by different experts in the field. The first chapter, by Lukas and Wasielewski, provides a very readable account of multi-chromophore arrays which might be used to store and process information by photoinduced electron and energy transfer. The emphasis then changes from photophysics to photochemistry and Chapters 2–4 review three classes of photochromic dyes: bis(thiophen-3-yl)perfluorocyclopentenes (by Irie), dihydroazulenes (by Mrozek, Daub and Ajayaghosh) and fulgides (by Yokoyama). Dihydroazulenes undergo photochemical electrocyclic ring opening to vinylheptafulvenes, followed by thermal reversion, whereas in general bis(thiophen-3-yl)perfluorocyclopentenes and fulgides are photochemically reversible and thermally irreversible. Irie's bis(thiophen-3-yl)perfluorocyclopentenes offer phenomenal fatigue-resistance. It is not just the colours of these dyes which change when they switch; changes in redox activity, cation-binding, refractive index, fluorescence and biological activity point to diverse applications and facilitate nondestructive read-out. In Chapter 5, Feringa, van Delden and ter Wiel explain how photochromic molecules can be used as chiropical switches. The idea is to achieve nondestructive read-out by monitoring the optical rotation at much longer wavelengths than those used for switching. This section includes both the switching of enantiomers, with circularly polarised light, and the switching of diastereomeric photochromic dyes. Feringa's creation of a unidirectional rotary motor is an inspirational tour de force. Enzymes are notoriously shape-selective, so it is no surprise that the two isomers of a photochromic dye tend to have different biological activity, leading to the possibility of photoswitchable biomaterials and optobioelectronics. This theme is developed by Willner and Willner in Chapter 6. Switchable catenanes and rotaxanes are reviewed in Chapter 7, by Raymo and Stoddart, and in Chapter 8, by Collin, Kern, Raehm and Sauvage. Here the emphasis changes from photo-switches to electrochemically-induced switching. Each of these chapters tells an amazing story of synthetic accomplishment, from the template-directed synthesis of simple catenanes and rotaxanes to the creation of electromechanical molecular machines and random access memory devices. In Chapter 10, Shinkai summarises his work on switchable molecular receptors, including allosteric systems, where one binding process (to protons, metal cations or sugars) switches the affinity for a second guest. This theme of protonation-controlled switching continues in the next two chapters. Chapter 10, by Maesri, Pina and Balzani, discusses photochromic flavyliums, which exhibit a series of pH-dependent equilibria; protonation and deprotonation can be used to lock and unlock the photochemically switched forms. In Chapter 11, de Silva, McClenaghan and McCoy show how cation binding can be used to regulate fluorescence, leading to molecular logic systems. Photoresponsive liquid crystals are covered in Chapter 12, by Ikeda and Kanazawa, and photoswitchable polypeptides are discussed in Chapter 13, by Ciardelli and Pieroni.

Several other types of switchable molecular systems could have been included. For example saturable absorbers, which switch from a strongly absorbing ground state to a weakly absorbing excited state, are used for Q-switching lasers, whereas reverse saturable absorbers, which switch from a weakly absorbing ground state to a strongly absorbing excited state, are used to protect sensors from laser damage. These systems differ from photochromic dyes in that the response does not involve chemical reaction, so is much faster. Nuclear magnetic excitation in molecules with several coupled spins can be used to achieve quantum computing; this is another type of molecular switching. Although the book gives many examples, it does not provide a precise definition of a “molecular switch”. In fact the authors appear to have conflicting definitions. Thus in Chapter 1, Lukas and Wasielewski discuss switches with lifetimes on picosecond to nanosecond timescales, and say that longer lived states “are no longer switches, but are considered as memory devices”, whereas in Chapter 2, Irie says that a structure with a half life of less that half an hour cannot be applied in photoswitchable molecular systems. Clearly the definition of a “molecular switch” depends on its intended application, but there is a danger that the term might become so all-inclusive as to become virtually meaningless, like “nano-chemistry”. Is phenolphthalein a proton-sensing molecular switch? Can any molecule which changes to another structure, or excited state, when treated with light, heat or chemical reagents be regarded as a switch! In practice one cannot impose strict definitions, so one must judge each molecular system on its scientific merits, without worrying about its name-tag.

The study of molecular switches is an interdisciplinary field, generating as much interest among materials scientists and physicists as among chemists. This book will appeal most to organic chemists, because of the way new structures are introduced through their synthesis, but it will also provide a useful introduction for other scientists, provided they are conversant with molecular structures. Some of the chapters closely resemble recently published reviews by the same authors, whereas others are completely fresh, and it is valuable to have all 13 reviews collected together in one monograph. The book will be provide an interesting read for any graduate students and research workers who wish to gain an up to date overview of molecular switches.

Harry Anderson
University of Oxford, , UK

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