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Home , Negishi coupling

Nobel prize Carbon couplers take the prize Three giants of organic chemistry, who pioneered the now ubiquitous - catalysed cross , have at last been recognised by sharing this year’s Nobel prize. Simon Hadlington catches up with them

When the 2010 Nobel prize for at the University of Stockholm that had been previously synthesised chemistry was announced on In short in Sweden and a member of but whose chemistry had 6 October there were few, if any,  The 2010 Nobel prize the prize committee, says, ‘It is received relatively little attention. raised eyebrows. For it was never went to Richard Heck, important to emphasise the great ‘There had been some reports of a case of ‘if’ Richard Heck, Ei-ichi Ei-ichi Negishi and Akira significance their discoveries have organopalladium compounds being Negishi and would Suzuki for developing for both academic and industrial made in the literature, but no one win the prize, but ‘when’. The three palladium-catalysed research and in the production had much looked at their chemistry,’ recipients were given science’s cross coupling reactions of fine chemicals – including Heck told Chemistry World from his most prestigious award for creating,  The Heck, Negishi pharmaceuticals, agricultural home in the Philippines. ‘It occurred in the judges words, ‘great art in and Suzuki couplings chemicals, and high tech materials to me that they might be able to do a test tube’. In the process, they have revolutionised C–C – that benefit society. Few reactions something useful.’ revolutionised the chemistry of bond formation, both in have contributed to enhancing the Heck demonstrated that methyl- forging bonds between carbon atoms academic and industrial efficiency of organic synthesis as and phenylpalladium halides – the essence of synthetic organic synthesis much as the palladium-catalysed generated in situ could be added to chemistry and the gateway to myriad  The organic chemistry cross-coupling reactions. These olefins at room temperature. For compounds of value to medicine, community has welcomed reactions have changed the practice example phenylpalladium chloride agriculture and electronics. the award, which has of the science of synthesis and could be added to ethylene, yielding The three prize winners been anticipated for they are used for making complex styrene once the palladium had independently developed many years molecules producing both natural been eliminated. This discovery led palladium-catalysed cross coupling products and biologically active to the design of an unprecedented reactions. Such a way of linking compounds.’ reaction, the arylation or alkylation organic molecules had previously The development of the of an olefin. In the early reactions been impossible, especially under technique is a beautiful example the organopalladium compound the mild reaction conditions and of how an enquiring and intuitive was generated in stoichiometric with the high degrees of selectivity intellect can draw upon the existing quantities from an organomercury and stereochemical control body of scientific knowledge and species and a palladium salt. A afforded by palladium. These apply it to a new problem to produce key advance was to render the coupling reactions are now carried stunning results. reaction catalytic in palladium out routinely across the world, in by using cuprous chloride to research laboratories and industrial An enquiring mind reoxidise the palladium, making processes to assemble the building In 1968 Heck, working for the it available for subsequent cycles. blocks of complex molecules. chemical company Hercules in Four years later Heck, by then As Jan-Erling Bäckvall, Delaware, US, set out to investigate at the University of Delaware in professor of organic chemistry the utility of palladium compounds Newark, modified the system to 40 | Chemistry World | November 2010 www.chemistryworld.org www.chemistryworld.org Chemistry World | November 2010 | 41 Nobel prize AP PHOTOS x 3 x PHOTOS AP generate the organopalladium then coordinates to the palladium, Negishi (left), Heck zero valent state, in preparation for complex from an organohalide and bringing the two carbons to be (centre) and Suzuki another cycle of the reaction. palladium in its zero valent state. In coupled – one each from the halide (right) waited a long time ‘The results came very quickly,’ this way arylation of olefins became and the olefin – into close proximity. for their Nobel prize Heck recalls. ‘This was a reaction possible by reacting an aryl halide The carbon-bearing moiety of the that was possible with other metals, with an in the presence of a halide partner migrates from the but it did not work very well. With palladium catalyst, which became Pd centre to one of the carbons palladium it worked much better.’ the standard protocol for carrying of the olefin, with the palladium Heck understood the significance of out the reaction that was to bear shifting to the other of the olefin’s the work immediately. ‘At the time Heck’s name. carbons – a migratory insertion that I realised that this was something During the the results in the new carbon–carbon that would be useful because you Pd(0) catalyst undergoes oxidative bond. The palladium then grabs a could not do these things easily addition of the organohalide – hydrogen atom from a neighbouring in any other way.’ Palladium is, essentially inserting Pd into the carbon atom to reform the C=C of course, expensive and he was carbon–halogen bond and forming double bond, and the newly formed concerned that the reactions might an organopalladium species. In the molecule is released. Reductive struggle to be competitive with process the palladium is oxidised elimination of hydrogen halide conventional organic chemistry. ‘But from Pd(0) to Pd(ii).The olefin leaves the palladium in its original it turned out that you didn’t need much palladium, so that solved the problem and made it practical.’ A prize thoroughly deserved Heck, who remained at the University of Delaware until his Chemists involved in the for making carbon bonds with The Nobel prize is fully retirement in 1989, is now 79. Of synthesis of organic compounds reactions that were simply not deserved, says Craig. ‘This winning the Nobel prize he says, ‘It are pleased that three giants of known. It has become a very reaction has made a huge makes it all seem worthwhile.’ the field have at last received the reliable, easy and convenient difference to people’s lives. And ultimate accolade in the form of way of joining building blocks looking back over the history Fishing in the periodic table the Nobel prize for chemistry. of larger molecules and is now of this field, these three are the In the early 1960s, Negishi arrived ‘One of the main features of the absolutely part of the lexicon of guys responsible.’ at the University of Pennsylvania in reactions which has contributed the organic chemist that will be Guy Lloyd-Jones of the Philadelphia, US, on a scholarship to the prize being awarded to used thousands of times a day University of Bristol, UK, and immediately discovered the Heck, Negishi and Suzuki is that worldwide.’ agrees. ‘They all made major, frustrations of organic synthesis. they are catalytic processes More recent work has fundamental contributions to the ‘Why is synthesis so difficult, even that allow synthetic chemists to extended the utility of development of transition metal when you follow the cookbook do things which they could not palladium catalysed cross catalysed chemistry, particularly recipe?’ he remembers asking. previously do – to join carbon coupling to create carbon– palladium, which transformed ‘Some syntheses start off with a atoms together in a new way,’ nitrogen and carbon– the use of palladium catalysts complicated compound, only to blast says Donald Craig of Imperial bonds. ‘This has significantly from a curiosity into something off most of it – why do we go about it College London, UK. ‘They increased the scope of the with wide practical applications in such a round about way? This led developed a new paradigm reaction,’ Craig adds. in synthetic chemistry.’ me to start thinking about new ways of cross coupling.’

42 | Chemistry World | November 2010 www.chemistryworld.org Negishi moved to the laboratory of Herbert Brown at Purdue University in West Lafayette, US, and began investigating cross coupling using organometallics and transition metal catalysts. ‘I thought we should go fishing, using the periodic table as our guide,’ he told Chemistry World. There was already a body of literature dating back more than 30 years on the use of transition metals for a range of coupling reactions. Cobalt, nickel and iron could catalyse the C–C bond forming reactions of Grignard reagents – or aryl magnesium halides – with organohalides. However, these reactions were intolerant of certain delicate functional groups, and showed relatively low selectivity, giving synthetic organic chemists something of a headache. Eventually, Negishi hit upon a combination of organoaluminium and nickel, which, he says, was the eureka moment. ‘I realised quickly that this reaction would have wide then brings Simplified catalytic University. ‘Sadly, we will never know applicability,’ he says. Having the two partners together, forging a cycles for the three what could have been.’ moved to Syracuse University, US, new C–C bond and regenerating the prize-winning reactions To illustrate the diversity and between 1976 and 1978 Negishi Pd(0) catalyst. importance of the palladium- published several papers describing A fourth pioneer of palladium catalysed cross coupling reactions, Pd- or Ni-catalysed cross coupling catalysed cross coupling was John the Nobel prize committee cited of various organometals. He found Stille, an American chemist who a number of examples, from both a number of combinations that many believe would also have shared academic and industrial scale provided high selectivity and yield. the prize had he not been killed synthesis. These include the total Today, those reactions involving zinc, in an airline crash in Iowa in 1989. synthesis of the anticancer drug Taxol aluminium and zirconium are called Twelve years earlier at Colorado (paclitaxel) where the Heck reaction Negishi coupling. State University in Fort Collins, US, is used to create the complex, tricyclic At 75, Negishi remains active as the Stille discovered that palladium could eight-membered ring at the heart of HC Brown distinguished professor catalyse cross coupling reactions the compound.1 The Heck reaction is of chemistry at Purdue, and says of organohalides with organotin Molecules whose also used to make a strategic bond in a that the award of the Nobel prize compounds. ‘The three scientists synthesis relied on Pd. synthesis of morphine.2 will not prompt him to retire. ‘I have who ultimately shared the prize were Bonds formed by cross Negishi coupling was key to the accomplished maybe half my goal,’ he strongly deserving of the honour, coupling are shown in red laboratory synthesis of the natural says. ‘I would like to keep working for but I cannot help but think that the product hennoxazole A, a marine at least several more years.’ committee’s decision was made easier antiviral compound.3 While Suzuki in many ways by the untimely death coupling is used to prepare the Milder and milder of John Stille,’ says Tomislav Rovis, antiviral bromoindole In 1979 Suzuki, working at Hokkaido the current holder of the John K Stille dragmacidin F.4 These latter two University in Japan, made his key chair in chemistry at Colorado State are particularly nice examples of discovery. In the presence of a base, where sensitive functional groups are organoboron compounds can cross present and therefore mild reaction couple with vinyl and aryl halides conditions are paramount. These with palladium as catalyst. The innate are merely a handful of examples of stability of organoboron compounds, palladium-catalysed cross coupling, mild reaction conditions and broad which has been used – and continues tolerance mean to be used – in the synthesis of that this reaction has become highly thousands of important compounds, practical, both in academic and from the most complex natural industrial settings. Suzuki, who is products to tonne-scale industrial now 80, retired in 1994 but remains an intermediates. emeritus professor at Hokkaido. References Suzuki and Negishi couplings begin 1 S J Danishefsky et al, J. Am. Chem. Soc., 1996, the same way as the Heck reaction, 118, 2843 with of Pd(0) to an 2 C Y Hong, N Kado and L E Overman, J. Am. organohalide. The second coupling Chem. Soc., 1993, 115, 11028 3 P Wipf and S Lim, J. Am. Chem. Soc., 1995, partner is delivered to palladium by 117, 558 a process from the 4 N K Garg, D D Caspi and B M Stoltz, J. Am. relevant organometallic reagent. Chem. Soc., 2004, 126, 9552 www.chemistryworld.org Chemistry World | November 2010 | 43