Three researchers share this year's Nobel Prize in Chemistry, Professor Richard F. Heck, who has been working at University of Delaware, Newark, Delaware, U.S., Professor Ei-ichi Negishi, Purdue University, West Lafayette, Indiana, U.S., and Professor (emeritus) Akira Suzuki, Hokkaido University, Sapporo, Japan. The Royal Swedish Academy of Sciences is rewarding the three chemists for: “palladium-catalyzed cross couplings in organic synthesis”.
The discoveries by the three organic chemists have had a great impact on academic research, the development of new drugs and materials, and are used in many industrial chemical processes for the synthesis of pharmaceuticals and other biologically active compounds. This year's Nobel Prize in Chemistry concerns the development of methods for palladium-catalyzed formation of carbon-carbon bonds via so-called cross-coupling reactions. The formation of new carbon-carbon bonds is of central importance in organic chemistry and a prerequisite for all life on earth. Through the assembly of carbon atoms into chains, complex molecules, e.g. molecules of life, can be created.
Transition metals
During the second half of the 20th century, transition metals have come to play an important role in organic chemistry and this has led to the development of a large number of transition metal-catalysed reactions for creating organic molecules.
Transition metals have a unique ability to activate various organic compounds and through this activation they can catalyse the formation of new bonds. One metal that was used early on for catalytic organic transformations was palladium. One event that stimulated research into the use of palladium in organic chemistry was the discovery that ethylene is oxidized to acetaldehyde by air in a palladium-catalysed reaction and this became the industrially important Wacker process.
Subsequent research on palladium-catalysed carbonylation led to new reactions for the formation of carbon-carbon bonds. In general, transition metals, and in particular palladium, have been of importance for the development of reactions for the formation of carbon-carbon bonds.
In 2005 the Nobel Prize in chemistry was awarded to metal-catalyzed reactions for the formation of carbon-carbon double bonds. This year the Nobel Prize in chemistry is awarded to the formation of carbon-carbon single bonds through palladium-catalyzed cross-coupling reactions.
Cross coupling
The principle of palladium-catalyzed cross couplings is that two molecules are assembled on the metal via the formation of metal-carbon bonds. In this way the carbon atoms bound to palladium are brought very close to one another. In the next step they couple to one another and this leads to the formation of a new carbon-carbon single bond. There are two types of cross-coupling reactions that have become important in organic synthesis according to this principle.
A common feature of the two types of cross couplings is that the organic groups from the reagents are assembled on palladium. Furthermore, both reactions begin by generating an organopalladium complex — RPdX. The organopalladium species RPdX will subsequently react with the nucleophilic coupling partner.
Pioneering work
In 1968 Heck reported in a series of papers that in situ-generated methyl- and phenylpalladium halides are added to olefins at room temperature. The addition of phenylpalladium chloride to ethylene followed by elimination of palladium gave styrene.
Through this discovery Heck had designed an unprecedented reaction — an arylation (or alkylation) of an olefin. This reaction was to become one of the most important reactions for making carbon-carbon single bonds.
Since palladium(0) is formed at the end of the reaction, the overall reaction is not catalytic if it is run without any additives.
In these early examples the organopalladium compound, RPdX (R = aryl or alkyl), was generated from an organomercury compound, RHgX, and a palladium(II) salt. Heck then demonstrated in 1968 that the reaction can be made catalytic with respect to palladium by the use of CuCl2 as a reoxidant for Pd(0).
In 1972, Heck made an important modification of his reaction that increased its synthetic utility. In this new version, which became the standard protocol for carrying out the Heck reaction, the organopalladium complex is generated from an organohalide, and Pd(0) in a so-called oxidative addition. Such oxidative additions to Pd(0) had been previously reported by Fitton.
Heck was aware of Fitton's work and used it for generating the organopalladium complex for the coupling reaction. Thus, with this new modification, arylation of an olefin was achieved from the reaction of an aryl halide and an olefin in the presence of a palladium catalyst.
The reaction begins when the active Pd(0) catalyst reacts with the organohalide RX in a so-called oxidative addition. In this reaction the oxidation state of palladium formally changes from Pd(0) to Pd(II) with the formation of an organopalladium compound RPdX. In this process a new palladium-carbon bond is formed.
In the next step the olefin co-ordinates to palladium, and the olefin and the R group are now assembled on the metal and can react with one another. In the next step the R group on palladium migrates to one of the carbons of the co-ordinated olefin and palladium will shift to the other carbon of the olefin. This process is called a migratory insertion and generates the carbon-carbon bond.
Finally, the release of the organic group occurs via a beta-hydride elimination which forms the new olefin in which the R group from the organohalide RX has replaced a hydrogen atom on the substrate olefin. In this step a short-lived HPdX species is formed, which loses HX to give Pd(0). The Pd(0) species formed is now ready to enter another catalytic cycle.
Other researchers have also contributed to the development of this reaction.
Negishi's development
In the meanwhile, other scientists had used other reagents in cross-coupling reactions, but these were not optimal for synthetic applications.
In 1976, Negishi initiated a series of studies to explore more chemoselective organometallic species in the palladium-catalyzed couplings with organohalides.
In the first studies Negishi employed organozirconium or organoaluminium compounds as coupling partners. The positive results obtained from these studies stimulated him to try even less reactive organometallic species. The breakthrough came in 1977 when Negishi introduced organozinc compounds as the nucleophilic coupling partners in palladium-catalysed cross coupling.
The organozinc compounds gave superior yields compared to other organometallic compounds, and furthermore, they were very mild and highly selective. The use of organozinc compounds in the palladium-catalysed cross-coupling reaction allowed for the presence of a wide range of functional groups. The new coupling reaction became a very important method for making carbon-carbon single bonds and it is called the Negishi reaction.
Suzuki's discovery
In 1979 Suzuki and co-workers reported in two papers that organoboron compounds in the presence of a base can be used as coupling partners in palladium-catalyzed cross coupling with vinyl and aryl halides. Thus, base activation of organoboron reagents as boronate intermediates facilitated the transfer of the organic group from boron to palladium (transmetallation). The reaction has later been extended to also include couplings with alkyl groups.
A further significant development came from the observation that arylboronic acids are able to participate as coupling partners in the palladium-catalyzed cross-coupling reaction. In the latter case the reaction was even more efficient and weaker bases could be employed. The stability and weak nucleophilic nature of organoboron compounds has made this reaction very practical. Furthermore, boron compounds are generally non-toxic and the reaction can be run under very mild conditions. This has made the reaction popular in the pharmaceutical industry. The reaction is called the Suzuki reaction.
in the presence of a catalytic amount of a palladium(0) complex. The reaction leads to the formation of a new carbon-carbon single bond.
The first step in the Negishi and Suzuki cross-coupling reactions is identical to that of the Heck reaction. This step is an oxidative addition of R'X to Pd(0) to give an organopalladium compound. In the second step the organic group, R on zinc or boron, is transferred to palladium in a process called transmetallation. In this way the two organic groups are assembled on the same palladium atom via palladium-carbon bonds. In the final step the R' and R groups couple with one another to give a new carbon-carbon single bond and R-R' is released from palladium. In this process Pd(II) is reduced to Pd(0) and therefore the final step is called a reductive elimination.
Applications
The palladium-catalyzed carbon-carbon bond forming reactions developed by Heck, Negishi and Suzuki have had a large impact on synthetic organic chemistry and have found many applications in target oriented synthesis. Their widespread use in organic synthetic applications is due to the mild conditions associated with the reactions together with their tolerance of a wide range of functional groups.
These three cross-coupling reactions have been applied to the synthesis of a large number of natural products and biologically active compounds of complex molecular structures.
They have also found applications in the fine chemical and pharmaceutical industries. Some examples of the use of the Heck, Negishi, and Suzuki reactions in natural product synthesis and industrial applications are given below.
The Heck reaction has been used in more than 100 different syntheses of natural products and biologically active compounds. The first example is for the synthesis of Taxol, where the Heck reaction was employed for creating the eight-membered ring. The ring closure to complete the rigid tricyclic system is not trivial. In the other example an intramolecular Heck-type coupling provides the morphine skeleton and the product is transformed to morphine in a few steps.
The Heck reaction has also been used as an important carbon-carbon bond-forming step in the synthesis of other complex organic molecules such as steroids, strychnine, and the diterpenoid scopadulcic acid B31 with cytotoxic and antitumor activity.
The Negishi and Suzuki reactions have also been frequently employed in natural product synthesis. Pumiliotoxin A is a toxic alkaloid found in the skin of frogs from the Dendrobatidae family that the frog uses for its defence. The total synthesis of pumiliotoxin A was performed via the use of a Negishi coupling in one of the key steps. It is interesting to note that an alkylzinc compound with beta-hydrogens is used in this reaction.
An efficient synthesis of the potent natural antitumor agent (+)-dynemicin A involved a Suzuki coupling in one of the key carbon-carbon bond forming steps.
The Negishi coupling was employed in the synthesis of the natural marine antiviral product hennoxazole A and the Suzuki reaction was used for preparing the antiviral bromoindole alkaloid dragmacidin F.
The palladium-catalyzed cross-coupling reactions are suitable for carrying out on a large scale and the Heck reaction has been used for a number of large scale industrial applications.
The sulfonyl urea herbicide Prosulforon is produced on a large scale with a process developed by Ciba-Geigy.The anti-inflammatory drug Naproxen and the asthma drug Singulair are other examples of industrial manufacturing of pharmaceuticals via the Heck reaction.
Their discoveries have great significance for both academic and industrial research and in the production of fine chemicals – including pharmaceuticals, agricultural chemicals, and high tech materials – that benefit society. (Excerpts from ‘2010 Nobel Prize Chemistry - Advanced Information' at www. nobelprize.org ).
