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Helping to address the problems of society ranging from electronics to medicine is a major goal of science. What differentiates a chemist from other scientists is the ability to design a structure that one feels is desirable regardless of whether such structures exist since the chemist can go into the lab and synthesize the structure. A major obstacle is doing so in a time-efficient manner. Thus, there is a need to have a synthetic toolbox that will address such a problem. Herein is the need to improve our synthetic reactions to permit the timely synthesis of any structure regardless of its molecular complexity.

This monograph relates to the explicit role that a subset of Pd-catalyzed reactions, notably with homogeneous catalysts, is having on meeting the above goal. It is instructive to examine how we got here. To begin, let's examine a brief overview of the early days in the discovery of precious metals. At the start, individuals involved with isolation of precious metals frequently spanned a broad range of aspects of the science, from the initial discovery all the way to creating a market. Let me make this point with respect to palladium, the topic of this work. Historically, around the year 1700, miners in Brazil were aware of a metal which they referred to as “ouro podre” or worthless gold, a native alloy of Pd and Au, today known as one of the forms of white gold. It was, however, through the mining of Pt that ultimately led to the actual refining of Pd. By the eighteenth century Pt had found numerous uses, and Percival Norton Johnson, son of assayer John Johnson, played a major role through his company which he co-founded in 1817. In 1838, George Matthey, a banker, joined and led to what is known today as Johnson Matthey. It was the purification of Pt by William Wollaston that led him to find a way to remove a pesky impurity. He ultimately isolated the “impurity” which he believed was a new metal. He called this new material “palladium” after a new asteroid named “Pallas”, named so after the Goddess of Wisdom. Incidentally, he also discovered rhodium. Believing there was commercial value in palladium as a metal, he anonymously announced the properties of this new metal and made it available for sale but refused to reveal the process for making it until shortly before his death in 1826. Since Pd was obtained as a by-product of Pt production, its quantities increased but, unfortunately with no market for the growing supplies. It wasn’t until the 1930's that a German company developed and patented alloys of palladium and gold or silver for use in dentistry.

In 1959, the use of the “noble” metals in catalysis was virtually only taught with respect to heterogeneous hydrogenation. The first industrial process other than hydrogenation involving Pd was the Wacker process which came about in 1956 with the conversion of ethylene to acetaldehyde. Such discoveries stimulated studies into how ligands bind to metals and effect their chemical behavior, thus creating a steep growth spurt. With respect to Pd, the Wacker oxidation allowed the conversion of cheap, readily available hydrocarbons to higher value added “oxidation” products wherein useful oxygen functionality in the form of simple reagents like water and acetic acid was installed via olefinic bonds. This type of Pd process constitutes one of the important fundamental transformations in catalysis which has morphed into a host of synthetic reactions that elaborate olefins into many types of higher value products. Indeed, it was the study of the mechanism of this process that led Richard Heck, then at Hercules Chemical Co. in Wilmington, DE to invent by design what we now call the Heck reaction. In a tour-de-force, Heck disclosed these studies in a series of seven papers of which he was the sole author published back to back in the Journal of the American Chemical Society in 1968. Heck's reports revealed a type of chemical reactivity that heretofore did not exist, the direct addition of a carbon–metal bond to a non-activated carbon–carbon π bond. The only synthetic problem for its use was that the reaction required stoichiometric amounts of palladium. In 1968, Fitton discovered that tetrakis(triphenylphosphine)palladium underwent a stoichiometric reaction with iodobenzene to form a stable phenylpalladium iodide complex. Armed with this information, Heck published a catalytic version of his reaction about 4 years later in 1972 and the rest is history – his sharing of the Nobel Prize in 2010.

During this time, another type of reactivity of Pd(+2) species was reported by Professor Arthur Cope at MIT, best known for reactions like the Cope elimination and Cope rearrangement, who also played with the organic chemistry of Pd. In 1965, he demonstrated what I believe is the first example of an unactivated C–H insertion by a Pd(+2) salt upon reaction with azobenzene to give an isolable organometallic. This process revealed that appropriate coordination to an organic molecule can direct the resultant complex to facilitate the insertion of the Pd into a proximal C–H bond, a type of reactivity that has proven invaluable on the types of Pd catalyzed reactions described in this monograph.

In 1976, Ishikawa noted that the palladium complex of Fitton catalyzed the cross-coupling of aryl Grignard reagents with aryl iodides. A major drawback of this method and related nickel catalyzed reactions was the lack of chemoselectivity associated with the use of Grignard reagents. That same year, Negishi began examining the prospect of using more chemoselective nucleophilic partners such as organoalanes and organozirconium complexes in palladium (as well as nickel) catalyzed vinyl-vinyl cross-coupling processes. Shortly thereafter Negishi noted that in situ generated organozinc compounds participated in chemoselective cross coupling and gave higher yields than Grignard reagents or organoalanes. It is interesting to note that Negishi reports the failure of organoboranes in such processes. In 1979, the landscape changed when Suzuki reported conditions that allowed organoboranes to be used. The grandfather of metal-promoted coupling, the Ullman reaction, morphed from a very limited process stoichiometric in metal into a widely divergent carbon–carbon bond forming process that had the characteristics of nearly perfect selectivity. Correspondingly, palladium has moved from being an esoteric metal of no known use to one of being among the most versatile type of transition metal homogeneous catalyst of any metal known to date. Thus, Negishi and Suzuki joined Heck in the recognition of these pioneers by their receipt of the Noble Prize in 2010.

In a period of slightly more than 30 years, palladium catalysts literally changed the way complex molecules could be made. This monograph vividly illustrates the enormity of the invention. The book opens with an account of the key parameters and mechanistic characteristics of metal-catalyzed reactions in Chapter 1. Chapters 2 to 5 note the remarkable influence of ligands on the chemistry of palladium complexes. Indeed, the ability to tune any specific reaction at one's will by appropriate choice of ligand environment is both a power of this synthetic tool as well as a complication that must be realized. Key to extending the cross-coupling reaction beyond Grignard reagents is understanding how the transmetalation process works, a topic dealt with in Chapter 8. Chapters 5 and 6 demonstrate the breadth of the concept beyond C–C bond forming events to carbon-heteroatom bond forming events, with nitrogen being the most notable. The status of the Heck reaction today is dealt with in Chapter 9. An important component of selectivity in complex molecule synthesis, stereochemical control both relative and absolute, is the topic of Chapter 11. Carbon–carbon bond forming reactions extrapolating from the core Heck–Negishi–Suzuki type are illustrated in a so-called carboiodination pathway as an alternative to the Heck process in Chapter 7 and the ability to intercept an organopalladium intermediate by carbon monoxide to generate the extremely important carbonyl containing products is covered in Chapter 10. Making the reaction more atom economic by effecting such reactions by direct C–H activation is examined in Chapter 12 whereas Chapter 14 deals more broadly with making these palladium catalyzed processes “greener”. A new dimension in homogeneous catalytic processes is performing them under flow conditions. The benefits of these techniques are examined in Chapter 13. In developing new synthetic tools, a critical question is the ability to scale up the processes. Chapter 15 examines this component.

This monograph vividly illustrates that these methods have rapidly gained immense impact on making truly complicated structures. But we must be careful in coming to any conclusion about what is left to be discovered. The trite saying “you don’t know what you don’t know” is especially true in synthetic chemistry. Indeed many of these chapters show that many unimaginable processes have become real. Given the enormity of the variables, it is impossible to guess how much more can be done. It is perhaps why palladium has been referred to as the metal of the twenty-first century. This monograph is only one small step on the path toward being able to make everything imaginable. This book is invaluable to anyone involved in synthesis of organic compounds for any purpose.

Barry M. Trost

About Barry M. Trost

Born in Philadelphia, Pennsylvania, he obtained a BA degree from the University of Pennsylvania in 1962 and PhD degree just three years later at the Massachusetts Institute of Technology (1965). He directly moved to the University of Wisconsin where he was promoted to Professor of Chemistry in 1969 and subsequently became the Vilas Research Professor in 1982. He joined the faculty at Stanford as Professor of Chemistry in 1987 and became Tamaki Professor of Humanities and Sciences in 1990. In addition, he has been Visiting Professor in Germany (Universities of Marburg, Hamburg, Munich and Heidelberg), Denmark (University of Copenhagen), France (Universities of Paris VI and Paris-Sud), Italy (University of Pisa) and Spain (University of Barcelona). He received honorary degrees from the Université Claude-Bernard (Lyon I), France (1994), and the Technion, Haifa, Israel (1997). In recognition of his many contributions, Professor Trost has received a large number of awards, a few among which are the ACS Award in Pure Chemistry (1977), the Dr Paul Janssen Prize (1990), the ASSU Graduate Teaching Award (1991), Bing Teaching Award (1993), the ACS Roger Adams Award (1995), the Presidential Green Chemistry Challenge Award (1998), the Belgian Organic Synthesis Symposium Elsevier Award (2000), the ACS Nobel Laureate Signature Award for Graduate Education in Chemistry (2002), the ACS Cope Award (2004), the Nagoya Medal (2008), the Ryoji Noyori Prize (2013), the International Precious Metals Institute's Tanaka Distinguished Achievement Award (2014), and the German Chemical Society's August-Wilhelm-von-Hofmann Denkmuenze (2014). Professor Trost has been elected a fellow of the American Academy of Sciences (1992) and a member of the U.S. National Academy of Sciences (1990).

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