Science Watch consulted Steve Ley, the 1702 Professor of Organic Chemistry at Cambridge (England). "This is strategically one of the most important reactions currently in use in the pharmaceutical and agrochemical industries," he replied, "and it has revolutionized the way organic molecules are assembled." Clearly papers #3 and #4 merit a closer look—and they do indeed deserve to be highly cited because they make an important group of organic compounds easy to synthesize. The Suzuki reaction is the linking of two benzene rings.

Paper #3 comes from a team headed by Greg Fu, and it reports how a mixture of palladium dibenzylidene acetone and tri-butyl-phosphine will catalyze the reaction to give excellent yields, sometimes even at room temperature. Paper #4 comes from Stephen Buchwald’s group and reports similar benefits from palladium acetate, again giving good yields at room temperatures using only tiny amounts of catalyst (parts per million).

The direct linking of benzene rings is not easily achieved by direct chemical reaction, hence the importance of the Suzuki reaction. It is carried out by the elimination of substituents attached to each ring, one of which must be a boronic acid group. As the substituents are eliminated, the two rings join carbon-to-carbon to produce so-called biaryl products. These have a wide range of applications, for example as drugs for treating high blood pressure. Other commercial applications of the Suzuki reaction have been for the synthesis of liquid crystals, polymers, and herbicides.

Another bonus of the Suzuki reaction, other than the high yields of products and mild conditions under which it operates, is that the boronic acid starting materials are air stable, water stable and non-toxic and, when the reaction is complete, it is usually fairly straightforward to separate the boron by-products from the desired product, particularly important in its industrial applications. Moreover, the Suzuki reaction does not disturb other functional groups that are attached to the benzene rings, so it can be performed on highly complex molecules.

According to Fu, a major limitation of the Suzuki reaction has been the poor reactivity of aryl chlorides, which are cheap and plentiful, compared to that of aryl bromides, iodides, and triflates, which are the ones previously needed to get the reaction to work. The trick of making the Suzuki reaction work with aryl chlorides has been to find the right catalysts, and this is what papers #3 and #4 are all about. The result of this work at MIT has been to transform this reaction into one that now has wide commercial appeal.

Buchwald’s paper describes 35 Suzuki couplings in which palladium acetate is boosted by two ligands, themselves diaryl compounds, and both available commercially. They work better than traditional phosphine type catalysts and they work with aryl chlorides as reagents. A more recent paper from Buchwald’s group, on making chiral compounds using the Suzuki reaction, was published in the Journal of the American Chemical Society (see J.J Yin, et al., 122[48]:12051-2, 2000). Carbon-nitrogen ring couplings have also been reported in the Journal of Organic Chemistry, (see J.P. Wolfe et al., 65[4]:1158-74, 2000).

Fu’s paper describes 58 Suzuki couplings, also showing it works with aryl chlorides, and he has also been investigating the wider use of palladium catalysts in other carbon-carbon bond-forming reactions: the Heck reaction (see A.F. Littke, et al., J. Org. Chem., 64[1]:10-1,1999); the Stille reaction (see A.F. Littke, et al., Angew. Chem. Int. Ed., 38[16]:2411-3,1999); the Negishi reaction (see C.Y. Dai, et al., J. Am. Chem. Soc., 123[12]-2719-26, 2001); and, in work done jointly with Buchwald's group, the Sonogashira reaction (see T. Hundertmark, et al., Org. Lett., 2(12):1729-31, 2000).