Suzuki reaction

The Suzuki reaction is an organic reaction, classified as a cross-coupling reaction, where the coupling partners are a boronic acid and an organohalide catalyzed by a palladium(0) complex. It was first published in 1979 by Akira Suzuki and he shared the 2010 Nobel Prize in Chemistry with Richard F. Heck and Ei-ichi Negishi for their effort for discovery and development of palladium-catalyzed cross couplings in organic synthesis. In many publications this reaction also goes by the name Suzuki–Miyaura reaction and is also referred to as the Suzuki coupling. It is widely used to synthesize poly-olefins, styrenes, and substituted biphenyls. Several reviews have been published describing advancements and the development of the Suzuki Reaction. The general scheme for the Suzuki reaction is shown below where a carbon-carbon single bond is formed by coupling an organoboron species (R1-BY2) with a halide (R2-X) using a palladium catalyst and a base. R 1 − BY 2 organoboron species + R 2 − X halide → Base Pd catalyst R 1 − R 2 {displaystyle {ce {{overset {organoboron species}{R1-BY2}}+{overset {halide}{R2-X}}->R1-R2}}} (Eq.1) The Suzuki reaction is an organic reaction, classified as a cross-coupling reaction, where the coupling partners are a boronic acid and an organohalide catalyzed by a palladium(0) complex. It was first published in 1979 by Akira Suzuki and he shared the 2010 Nobel Prize in Chemistry with Richard F. Heck and Ei-ichi Negishi for their effort for discovery and development of palladium-catalyzed cross couplings in organic synthesis. In many publications this reaction also goes by the name Suzuki–Miyaura reaction and is also referred to as the Suzuki coupling. It is widely used to synthesize poly-olefins, styrenes, and substituted biphenyls. Several reviews have been published describing advancements and the development of the Suzuki Reaction. The general scheme for the Suzuki reaction is shown below where a carbon-carbon single bond is formed by coupling an organoboron species (R1-BY2) with a halide (R2-X) using a palladium catalyst and a base. The mechanism of the Suzuki reaction is best viewed from the perspective of the palladium catalyst 1. The first step is the oxidative addition of palladium to the halide 2 to form the organopalladium species 3. Reaction with base gives intermediate 4, which via transmetalation with the boron-ate complex 6 (produced by reaction of the boronic acid 5 with base) forms the organopalladium species 8. Reductive elimination of the desired product 9 restores the original palladium catalyst 1 which completes the catalytic cycle. The Suzuki coupling takes place in the presence of a base and for a long time the role of the base was not fully understood. The base was first believed to form a trialkyl borate (R3B-OR), in the case of a reaction of an trialkylborane (BR3) and alkoxide (−OR); this species could be considered as being more nucleophilic and then more reactive towards the palladium complex present in the transmetalation step. Duc and coworkers investigated the role of the base in the reaction mechanism for the Suzuki coupling and they found that the base has three roles: Formation of the palladium complex , formation of the trialkyl borate and the acceleration of the reductive elimination step by reaction of the alkoxide with the palladium complex. In most cases the oxidative Addition is the rate determining step of the catalytic cycle. During this step, the palladium catalyst is oxidized from palladium(0) to palladium(II). The palladium catalyst 1 is coupled with the alkyl halide 2 to yield an organopalladium complex 3. As seen in the diagram below, the oxidative addition step breaks the carbon-halogen bond where the palladium is now bound to both the halogen and the R group. Oxidative addition proceeds with retention of stereochemistry with vinyl halides, while giving inversion of stereochemistry with allylic and benzylic halides. The oxidative addition initially forms the cis–palladium complex, which rapidly isomerizes to the trans-complex. The Suzuki Coupling occurs with retention of configuration on the double bonds for both the organoboron reagent or the halide. However, the configuration of that double bond, cis or trans is determined by the cis-to-trans isomerization of the palladium complex in the oxidative addition step where the trans palladium complex is the predominant form. When the organoboron is attached to a double bond and it is coupled to an alkenyl halide the product is a diene as shown below. Transmetalation is an organometallic reaction where ligands are transferred from one species to another. In the case of the Suzuki coupling the ligands are transferred from the organoboron species 6 to the palladium(II) complex 4 where the base that was added in the prior step is exchanged with the R1 substituent on the organoboron species to give the new palladium(II) complex 8. The exact mechanism of transmetalation for the Suzuki coupling remains to be discovered. The organoboron compounds do not undergo transmetalation in the absence of base and it is therefore widely believed that the role of the base is to activate the organoboron compound as well as facilitate the formation of R2-Pdll-OtBu from R2-Pdll-X. The final step is the reductive elimination step where the palladium(II) complex (8) eliminates the product (9) and regenerates the palladium(0) catalyst(1). Using deuterium labelling, Ridgway et al. have shown the reductive elimination proceeds with retention of stereochemistry. The advantages of Suzuki coupling over other similar reactions include availability of common boronic acids, mild reaction conditions, and its less toxic nature. Boronic acids are less toxic and safer for the environment than organotin and organozinc compounds. It is easy to remove the inorganic by-products from the reaction mixture. Further, this reaction is preferable because it uses relatively cheap and easily prepared reagents. Being able to use water as a solvent makes this reaction more economical, eco-friendly, and practical to use with a variety of water-soluble reagents. A wide variety of reagents can be used for the Suzuki coupling, e.g., aryl- or vinyl-boronic acids and aryl- or vinyl-halides. Work has also extended the scope of the reaction to incorporate alkyl bromides. In addition to many different type of halides being possible for the Suzuki coupling reaction, the reaction also works with pseudohalides such as triflates (OTf), as replacements for halides. The relative reactivity for the coupling partner with the halide or pseudohalide is: R2–I > R2–OTf > R2–Br >> R2–Cl. Boronic esters and organotrifluoroborate salts may be used instead of boronic acids. The catalyst can also be a palladium nanomaterial-based catalyst. With a novel organophosphine ligand (SPhos), a catalyst loading of down to 0.001 mol% has been reported:. These advances and the overall flexibility of the process have made the Suzuki coupling widely accepted for chemical synthesis.