The 2010 Nobel prize for chemistry has been awarded to three pioneers of synthetic organic chemistry whose eponymous reactions have become ubiquitous and indispensible.
Richard Heck of the University of Delaware in Newark, US, Ei-ichi Negishi of Purdue University, US, and Akira Suzuki of Hokkaido University in Japan, independently developed palladium-catalysed cross-coupling reactions as a way to forge new carbon-carbon bonds with precision and under mild reaction conditions. Heck, Negishi and Suzuki reactions are now used universally in every organic synthesis laboratory across the world, as well as in major industrial processes.
The three chemists have been working in the field for decades, and if there is one surprise about their being awarded the prize, it is perhaps that it didn't come sooner.
Richard Heck, Ei-ichi Negishi and Akira Suzuki share the Nobel Prize in Chemistry 2010
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Heck published a series of papers in 1968 reporting the addition of methyl and phenylpalladium halides to olefins at room temperature. A further step allowed the unprecedented alkylation of an olefin. In 1976 Negishi investigated the palladium-catalysed cross-coupling of organometallic species with organohalides, eventually demonstrating that organozinc compounds could permit highly selective reactions under mild conditions and in the presence of a range of functional groups. Suzuki focused on organoboron compounds, demonstrating in 1979 that such species in the presence of a base could be cross coupled with vinyl and aryl halides in the presence of a palladium catalyst.
In subsequent years these reactions were improved and modified to become indispensible tools for the organic chemist and have been used to synthesise a range of complex natural products which would otherwise remain extremely difficult if not impossible to make.
Speaking from his home in the US at 6am, having been awoken an hour earlier with news of the prize, Negishi pronounced himself 'extremely happy - this means a lot.' He conceded that he knew the award of the Nobel Prize was a possibility, and indeed had been a long-held ambition. 'There had been some mumblings and I did begin to think of this and that,' he laughed. 'I have been dreaming about this prize for half a century, since I came to America and encountered several Nobel laureates, when I realised it was not a story - it was a reality which in principle could happen to anyone, including myself.'
Negishi added, 'I have accomplished half my goal. I would like to keep working for at least several more years.'
Guy Lloyd-Jones, a synthetic organic chemist at the University of Bristol in the UK, says that the trio are 'extremely worthy' winners. 'It is hard now to pick up an issue of any mainstream chemistry journal that features organic synthesis which does not contain a number of papers in which these reactions have been used. These reactions have revolutionised our ability to make selective carbon-carbon bonds. The prize is absolutely deserved and the only question that some people have asked is why it has taken so long.'
SUZUKI CROSS-COUPLING
In 1979, A. Suzuki and N. Miyaura reported the stereoselective synthesis of arylated (E)-alkenes by the reaction of 1- alkenylboranes with aryl halides in the presence of a palladium catalyst. The palladium-catalyzed cross-coupling reaction between organoboron compounds and organic halides or triflates provides a powerful and general method for the formation of carbon-carbon bonds known as the Suzuki cross-coupling. There are several advantages to this method: 1) mild reaction conditions; 2) commercial availability of many boronic acids; 3) the inorganic by-products are easily removed from the reaction mixture, making the reaction suitable for industrial processes; 4) boronic acids are environmentally safer and much less toxic than organostannanes (see Stille coupling); 5) starting materials tolerate a wide variety of functional groups, and they are unaffected by water; 6) the coupling is generally stereo- and regioselective; and 7) sp3-hybridized alkyl boranes can also be coupled by the B-alkyl Suzuki-Miyaura cross-coupling. Some disadvantages are: 1) generally aryl halides react sluggishly; 2) by-products such as self-coupling products are formed because of solvent-dissolved oxygen; 3) coupling products of phosphine-bound aryls are often formed; and 4) since the reaction does not proceed in the absence of a base, side reactions such as racemization of optically active compounds or aldol condensations occur. Improvements of the Suzuki cross-coupling include the development of catalysts facilitating coupling of unreactive aryl halides, the ability to react sp3-hybridized alkyl halides, and the use of alkyl, alkenyl, aryl, and alkynyl trifluoroborates in place of boronic acids.
Mechanism:
The mechanism of the Suzuki cross-coupling is analogous to the catalytic cycle for the other cross-coupling reactions and has four distinct steps: 1) oxidative addition of an organic halide to the Pd(0)-species to form Pd(II); 2) exchange of the anion attached to the palladium for the anion of the base (metathesis); 3) transmetallation between Pd(II) and the alkylborate complex; and 4) reductive elimination to form the C-C sigma bond and regeneration of Pd(0). Although organoboronic acids do not transmetallate to the Pd(II)-complexes, the corresponding ate-complexes readily undergo transmetallation. The quaternization of the Aboron atom with an anion increases the nucleophilicity of the alkyl group and it accelerates its transfer to the palladium in the transmetallation step. Very bulky and electron-rich ligands (e.g., P(t-Bu)3) increase the reactivity of otherwise unreactive aryl chlorides by accelerating the rate of the oxidative addition step.
NEGISHI CROSS-COUPLING
In 1972, after the discovery of Ni-catalyzed coupling of alkenyl and aryl halides with Grignard reagents (Kumada cross-coupling), it became apparent that in order to improve the functional group tolerance of the process, theorganometallic coupling partners should contain less electropositive metals than lithium and magnesium. In 1976, E. Negishi and co-workers reported the first stereospecific Ni-catalyzed alkenyl-alkenyl and alkenyl-aryl cross-coupling of alkenylalanes (organoaluminums) with alkenyl- or aryl halides. Extensive research by Negishi showed that the best results (reaction rate, yield, and stereoselectivity) are obtained when organozincs are coupled in the presence of Pd(0)-catalysts. The Pd- or Ni-catalyzed stereoselective cross-coupling of organozincs and aryl-, alkenyl-, or alkynyl halides is known as the Negishi cross-coupling. The general features of the reaction are: 1) both Ni- and Pdphosphine complexes work well as catalysts. However, the Pd-catalysts tend to give somewhat higher yields and better stereoselectivity, and their functional group tolerance is better; 2) the active catalysts are relatively unstable Ni(0)- and Pd(0)-complexes but these can be generated in situ from more stable Ni(II)- and Pd(II)-complexes with a reducing agent (e.g., 2 equivalents of DIBAL-H or n-BuLi); 3) in the absence of the transition metal catalyst, the organozinc reagents do not react with the alkenyl halides to any appreciable extent; 4) the most widely used ligand is PPh3, but other achiral and chiral phosphine ligands have been successfully used; 5) the various organozinc reagents can be prepared by either direct reaction of the organic halide with zinc metal or activated zinc metal or by transmetallation of the corresponding organolithium or Grignard reagent with a zinc halide (ZnX2); 6) the use of organozinc reagents allows for a much greater functional group tolerance in both coupling partners than in the Kumada cross-coupling where organolithiums and Grignard reagents are utilized as coupling partners; 7) other advantages of the use of organozincs include: high reactivity, high regio-, and stereoselectivity, wide scope and applicability, few side reactions and almost no toxicity; 8) the reaction is mostly used for the coupling of two C(sp2) carbons but C(sp2)-C(sp) as well as C(sp2)-C(sp3) couplings are well-known; 9) besides organozincs, compounds of Al and Zr can also be utilized; 10) if the organoaluminum and organozirconium derivatives are not sufficiently reactive, they can be transmetallated by the addition of zinc salts, and this protocol is referred to as the double metal catalysis; and 11) of all the various organometals (Al, Zr, B, Sn, Cu, Zn), organozincs are usually the most reactive in Pd-catalyzed cross-coupling reactions and do not require the use of additives (e.g., bases as in Suzuki crosscouplings) to boost the reactivity; Some of the limitations of the Negishi cross-coupling are: 1) propargylzincs do not couple well but homopropargylzincs do; 2) secondary and tertiary alkylzincs may undergo isomerization, but crosscouplings of primary alkyl- and benzylzincs give satisfactory results; and 3) due to the high reactivity or organozincs, CO insertion usually does not happen unlike in the case of less reactive organotins (see carbonylative Stille crosscoupling).
Mechanism:
HECK REACTION
In the early 1970s, T. Mizoroki and R.F. Heck independently discovered that aryl, benzyl and styryl halides react with olefinic compounds at elevated temperatures in the presence of a hindered amine base and catalytic amount of Pd(0) to form aryl-, benzyl-, and styryl-substituted olefins.1-3 Today, the palladium-catalyzed arylation or alkenylation of olefins is referred to as the Heck reaction. Since its discovery, the Heck reaction has become one of the most widely used catalytic carbon-carbon bond forming tools in organic synthesis. The general features of the reaction are: 1) it is best applied for the preparation of disubstituted olefins from monosubstituted ones; 2) the electronic nature of the substituents on the olefin only has limited influence on the outcome of the reaction; it can be either electron-donating or electron-withdrawing but usually the electron poor olefins give higher yields; 3) the reaction conditions tolerate a wide range of functional groups on the olefin component: esters, ethers, carboxylic acids, nitriles, phenols, dienes, etc., are all well-suited for the coupling, but allylic alcohols tend to rearrange; 4) the reaction rate is strongly influenced by the degree of substitution of the olefin and usually the more substituted olefin undergoes a slower Heck reaction; 5) unsymmetrical olefins (e.g., terminal alkenes) predominantly undergo substitution at the least substituted olefinic carbon; 6) the nature of the X group on the aryl or vinyl component is very important and the reaction rates change in the following order: I > Br ~ OTf >> Cl; 7) the R1 group in most cases is aryl, heteroaryl, alkenyl, benzyl, and rarely alkyl (provided that the alkyl group possesses no hydrogen atoms in the b-position), and these groups can be either electron-donating or electron-withdrawing; 8) the active palladium catalyst is generated in situ from suitable precatalysts (e.g., Pd(OAc)2, Pd(PPh3)4) and the reaction is usually conducted in the presence of monodentate or bidentate phosphine ligands and a base; 9) the reaction is not sensitive to water, and the solvents need not be thoroughly deoxygenated; and 10) the Heck reaction is stereospecific as the migratory insertion of the palladium complex into the olefin and the b-hydride elimination both proceed with syn stereochemistry. There are a couple of drawbacks of the Heck reaction: 1) the substrates cannot have hydrogen atoms on their b-carbons, because their corresponding organopalladium derivatives tend to undergo rapid-b-hydride elimination to give olefins; and 2) aryl chlorides are not always good substrates because they react very slowly. Several modifications were introduced during the past decade: 1) asymmetric versions; 2) generation of quaternary stereocenters in the intramolecular Heck reaction; 3) using water as the solvent with water-soluble catalysts;56,57,47 and 4) heterogeneous palladium on carbon catalysis.
Mechanism:
The mechanism of the Heck reaction is not fully understood and the exact mechanistic pathway appears to vary subtly with changing reaction conditions. The scheme shows a simplified sequence of events beginning with the generation of the active Pd(0) catalyst. The rate-determining step is the oxidative addition of Pd(0) into the C-X bond. To account for various experimental observations, refined and more detailed catalytic cycles passing through anionic, cationic or neutral active species have been proposed.
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