Bonding magic

The Nobel Prize in Chemistry goes to three scientists for the development of palladium-catalysed cross-coupling in organic synthesis'.

CARBON-BASED chemistry, or organic chemistry, is the basis of life and is also the underlying mechanism for many natural biological phenomena. Carbon atoms can form long chains and rings, bind to other elements such as hydrogen, oxygen and nitrogen, form double bonds, and so on. These carbon atoms, variously arranged, constitute the backbone of most of the molecules that form and regulate living systems. But humankind has also learnt from nature's chemistry and uses organic chemistry, which is basically carbon's ability to provide a stable skeleton for functional molecules, not only to mimic or reproduce artificially in laboratory nature's chemistry but also produce new medicines and revolutionary materials such as polymers and plastics or novel materials for the electronics industry.

In doing so, the greatest challenge for chemists, when they attempt to replicate or improve upon nature's complex molecules, has been to find ways of making and breaking the bonds between carbon atoms. But the carbon found in nature is stable and carbon atoms do not readily react with one another. This year's Nobel Prize in Chemistry has been awarded to Richard F. Heck, Ei-ichi-Negishi and Akira Suzuki for the development of palladium-catalysed cross-coupling in organic synthesis', a technique that achieves carbon-carbon, or C-C bonds, highly selectively and under relatively gentle conditions.

While 79-year-old Heck, who until recently was a Willis F. Harrington Professor Emeritus at the University of Delaware, United States, now leads a retired life in the Philippines, 75-year-old Negishi is Herbert C. Brown Distinguished Professor of Chemistry at Purdue University, U.S., and 80-year-old Suzuki is Distinguished Professor Emeritus at Hokkaido University.

The formation of new C-C bonds is of such central importance to organic chemistry that a total of five Nobel Prizes have been awarded so far to scientists who have successfully tackled this problem. The previous awards given for the subject were for the Grignard reaction (1912), the Diels-Alder reaction (1950), the Wittig reaction (1979) and olefin metathesis (to Y. Chauvin, R.H. Grubbs and R.R. Shrock in 2005).

To understand the difficulty in creating C-C bonds, one needs to understand the structure of an atom as quantum theory tells us. The electron in an atom is actually a negatively charged cloud that envelopes the positively charged nucleus, and around the nucleus there are several different layers of these clouds. The larger the atom, the greater the number of layers. Chemistry is basically about the number of electrons found in the outermost layer, and chemical reactions are all about atoms trying to make this layer complete for stability. The atoms seek to acquire eight electrons in the outermost layer, akin to noble gases such as argon and neon which have little tendency to react chemically because their outer layers are already full with eight electrons.

Carbon has only four electrons in its outermost layer and, therefore, it strives to attach to other atoms so that electrons can be shared between atoms in a molecule through chemical bonds. Methane, the simplest organic molecule, has a carbon atom sharing electrons with four hydrogen atoms, thus making the outer layer (orbital) full. To build complex organic molecules, chemists start with pre-existing smaller molecules; this is where the problem arises because in such molecules the carbon atoms are in stable configuration and, therefore, have little reactivity with other molecules. The question is how to make carbon atoms more reactive so that they combine with other carbon atoms.

The early methods to kick-start the binding of carbon atoms together used reactive substances that rendered carbon more reactive. In 1912, the chemist Victor Grignard found that coupling a reactive element such as magnesium, which has a greater tendency to get rid of the two electrons in its incomplete layer, achieved the objective of making carbon reactive because magnesium's two electrons got pushed on to the outermost layer of carbon contained in the reagent called the Grignard Reagent (an organohalide), rendering it unstable and reactive. Such methods proved good enough for building simple molecules. But when more complex molecules were to be produced, chemists found that too many unwanted byproducts formed, which used up the carbon atoms and left very little amounts for the desired product which either did not form at all or whose yields were very low.

During the latter half of the last century, a group of elements with similar chemical properties, called transition metals, began to play an important role in organic chemistry. These elements themselves or their compounds acted as catalysts. This resulted in the development of many transition-metal-catalysed reactions for creating organic molecules. Transition metals have a unique ability to activate various organic compounds; this activation is the basis for their ability to catalyse the formation of new bonds. One transition metal that was investigated by chemists in the 1950s for catalysing organic transformations was palladium.

Interest in palladium had been inspired by the industrial discovery in 1956 that ethylene is oxidised by air in the presence of palladium to acetaldehyde, an important raw material used in paint binding agents and plastic softeners and in the manufacture of acetic acid. It was discovered by the German chemical company Wacker Chemie AG and hence this industrially important catalytic reaction came to be called the Wacker process.

Heck reaction

As the chemical industry began to get curious about the success of the palladium-based Wacker process, an American chemical company in Delaware, where Richard Heck was working, too got into the act. It put Heck on the job of investigating palladium-based catalysis. In 1968, Heck published a series of scientific articles describing his work. One of his important findings was that a ring of carbon atoms could be linked to a shorter fragment of carbon resulting in styrene (Fig. 1), the key component of the plastic polystyrene.

The palladium-catalysed cross-coupling reaction is unique since the process occurs under mild conditions and with very high precision. Palladium acts as a point of rendezvous for the carbon atoms. The underlying principle is that two organic molecules that combine with palladium via the formation of metal-carbon bonds which occurs given the intrinsic chemical property of transition metals are assembled together. The carbon atoms bound to palladium are thus brought very close to one another. Palladium functions as a catalyst and enables the coupling of the two molecules by the formation of a new C-C single bond. Palladium itself does not get consumed in the process.

Precision is achieved because there is no need to activate the carbon atom. This results in fewer byproducts and more efficient reaction. Heck had used olefins to do what the Grignard reagent did with magnesium. In an olefin, carbon is naturally slightly activated and when it binds to the palladium atom, it combines with another carbon atom more readily than with any other. Through this reaction Heck had designed an unprecedented reaction arylation of an olefin.

Heck also gave a correct mechanism for arylation of olefins, and, after more detailed research, in 1969 he provided an explanation for the stereochemical course (the relative spatial arrangement of atoms in molecules) of the reaction. Heck further improved his process in 1972 that increased the yield of synthesis. Today the reaction, called Heck reaction, is one of the most important methods for creating C-C single bonds.

Negishi's finding

In 1976, Negishi initiated a series of studies on variants of the Grignard reagent in order to improve upon the selectivity of palladium-catalysed couplings with organohalides. After positive results from zirconium and aluminium compounds as coupling partners, Negishi achieved a breakthrough in 1977 when he used zinc instead. Carbon actually becomes less reactive when zinc is used but the zinc atom transfers the carbon atom to the palladium atom. When subsequently the carbon atom meets another carbon atom it is prone to establish a C-C bond. The zinc compound gave higher yields as compared to other organometallic compounds and, moreover, they were very mild and highly selective.

One of our findings is that metals, especially transition metals, are truly reactive, useful elements at least for synthesis, Negishi remarked in his post-Nobel award interview. He also believes that in asymmetric synthesis where the 2001 Nobel awardees (Ryoji Noyori, Barry Sharpless and William Knowles) had made a significant contribution by using transition metal catalysts and which is still a field that is growing since precision control of such synthesis is still a difficult proposition transition metal will continue to play a significant role.

Things go back to [Roald] Hoffman (Nobel 1981), [Robert] Woodward (Nobel 1965) [Kenichi] Fukui (Nobel 1981 with Hoffman)they told us, Negishi added. But few people really understood the true meaning of the magical thing that the transition metals offer. But, of course, many of us eventually understood. I am in awe of the power of transition metals. It's based on a very simple principle, which we, the chemists, should all know. But, my guess is that, at the moment, it is even to most chemists black magic'. I call this the magic of combination of empty orbital and filled non-bonding orbital. With transition metals we can have highly reactive, yet stable, even commercially available, compounds with this fundamental property.

Suzuki reaction

Two years after Negishi's finding, Suzuki used the element boron. He and his co-workers found that organoboron compounds in the presence of a base are useful coupling partners in palladium-catalysed reactions. It is the mildest activator and is even less toxic than zinc, which is an advantage when it comes to large-scale applications like in the pharmaceutical industry. The reaction using this organoboron reagent is called the Suzuki reaction.

The palladium-catalysed C-C bond forming reactions of Heck, Negishi and Suzuki have had a large impact in synthetic organic chemistry and have found many applications in target-oriented synthesis. A spectacular example of the use of palladium-catalysed cross-coupling reaction is in the test-tube creation of palytoxin a gigantic molecule in the chemical world. It is a naturally occurring poison that was first isolated from a coral in Hawaii in 1971 (Fig. 2). Palytoxin consists of 129 carbon, 223 hydrogen, three nitrogen and 54 oxygen atoms. Chemists recreated this in 1994 with the help of the Suzuki reaction.

The mild conditions associated with these three reactions and their tolerance for a wide range of organic functional groups have resulted in the widespread use of these reactions both in research and in industry. These cross-coupling reactions have been applied in the synthesis of a large number of natural products and biologically active compounds with complex structures. They have also found applications in fine chemical and pharmaceutical industries.

The Heck reaction has been used in the synthesis of more than 100 different natural products and bio-active compounds. For example, the manufacture of Taxol, a widely used cancer drug, makes use of this reaction. The reaction has also been used as an important C-C bonding step in the synthesis of other complex organic molecules such as steroids, strychnine and diterpenoid. The anti-inflammatory drug naproxen and the asthma drug montelukast (Singulair) are other examples of the use of Heck reaction in the pharmaceutical industry.

Similarly, the Negishi and Suzuki reactions have been used for the synthesis of natural products. The Negishi reaction, for example, is used in recreating in the lab discodermolide, a molecule discovered from Discoderma dissoluta, a sponge living in the Caribbean Sea in the late 1980s. Found at a depth of about 33 metres, its ability to escape enemies attracted the attention of marine scientists. It was found that the sponge could produce large and complex chemical molecules that were poisonous, which prevented other organisms from attacking it.

Subsequently, it was found that discodermolide could attack cancer cells in the same manner as Taxol. Besides discodermolide, palladium-catalysed reaction has also helped in the synthesis of diazonamide, a substance originating in an ascidian, a sac-like marine creature found in the Philippines. There are many such marine chemicals that have been discovered over the years with antibiotic, antiviral or anti-inflammatory characteristics. The challenge is to be able to synthesise them in the laboratory. Palladium catalysis appears to be a powerful tool for chemists to achieve this.

Pumiliotoxin A is a similar toxic alkaloid found in frog skin, which the frog uses for its defence. The total synthesis of this molecule was achieved by the use of Negishi's coupling in one of the key steps. The Negishi reaction was also used to produce the natural marine antiviral hennoxazole A. The Suzuki reaction was used in the production of the antiviral bromoindole alkaloid dragmacidin F, which was isolated from a sponge living off the coast of Italy. The drug is found to be useful against both the herpes virus and the human immunodeficiency virus (HIV).

The Suzuki reaction has also been used in one of the key C-C bond forming steps in the efficient synthesis of the potent natural anti-tumour agent (+)-dynemecin A.

These reactions have also been used to modify naturally occurring medicinal substances to increase their efficacy. Vancomycin, an antibiotic that was first isolated in the 1950s from a soil sample from the jungles of Borneo, Indonesia, is today used against methicillin-resistant Staphylococcus aureus (MRSA) and enterococci, bacteria that have become resistant to commonly used antibiotics. Variants of vancomycin, which have an effect on the resistant bacteria, have been produced using palladium-catalysed cross-coupling reaction.

The palladium-catalysed cross-coupling reactions are suitable for large-scale production thousands of tonnes a year of substances. The sulfonyl urea herbicide prosulfuron is produced on a large scale with a process that uses the Heck reaction. Similarly, Suzuki's reaction is used in the commercial synthesis of a substance that protects agricultural crops from fungi.

The electronics industry is also making use of these reactions. For example, organic light emitting diodes (OLEDs), which consist of organic molecules that emit light, are known to be better sources of light. They are used in the electronics industry for producing extremely thin, just a few millimetres thick, monitor screens. Palladium-catalysed cross-coupling reactions have been used to optimise the blue light in the OLEDs. Early this year, scientists attached palladium to graphene, the substance of this year's Nobel Prize in Physics, and the resulting solid material was used to carry out the Suzuki reaction in water.

Few reactions have contributed to enhancing the efficiency of organic synthesis as much as the palladium-catalysed coupling reactions, says the Nobel background dossier on the award.

It is important to emphasise the great significance the discoveries have for both academic and industrial research. These reactions have changed the practice of the science of synthesis, it adds. These reactions continue to be developed even today and, as Negishi remarked, they will continue to play an important role in organic synthesis.