Negishi coupling

The Negishi coupling is a widely employed transition metal catalyzed cross-coupling reaction. The reaction couples organic halides or triflates with organozinc compounds, forming carbon-carbon bonds (c-c) in the process. A palladium (0) species is generally utilized as the metal catalyst, though nickel is sometimes used: The Negishi coupling is a widely employed transition metal catalyzed cross-coupling reaction. The reaction couples organic halides or triflates with organozinc compounds, forming carbon-carbon bonds (c-c) in the process. A palladium (0) species is generally utilized as the metal catalyst, though nickel is sometimes used: Palladium catalysts in general have higher chemical yields and higher functional group tolerance. The Negishi coupling finds common use in the field of total synthesis as a method for selectively forming c-c bonds between complex synthetic intermediates. The reaction allows for the coupling of sp3, sp2, and sp carbons, (see orbital hybridization) which make it somewhat unusual among the Palladium-catalyzed coupling reactions. Organozincs are moisture and air sensitive, so the Negishi coupling must be performed in an oxygen and water free environment, a fact that has hindered its use relative to other cross-coupling reactions that require less robust conditions (i.e. Suzuki reaction). However, organozincs are more reactive than both organostannanes and organoborates which correlates to faster reaction times. The reaction is named after Ei-ichi Negishi who was a co-recipient of the 2010 Nobel Prize in Chemistry for the discovery and development of this reaction. Negishi and coworkers originally investigated the cross-coupling of organoaluminum reagents in 1976 initially employing Ni and Pd as the transition metal catalysts, but noted that Ni resulted in the decay of stereospecifity whereas Pd did not. Transitioning from organoaluminum species to organozinc compounds Negishi and coworkers reported the use of Pd complexes in organozinc coupling reactions and carried out methods studies, eventually developing the reaction conditions into those commonly utilized today. Alongside Richard F. Heck and Akira Suzuki, El-ichi Negishi was a co-recipient of the Nobel Prize in Chemistry in 2010, for his work on 'palladium-catalyzed cross couplings in organic synthesis'. The reaction mechanism is thought to proceed via a standard Pd catalyzed cross-coupling pathway, starting with a Pd(0) species, which is oxidized to Pd(II) in an oxidative addition step involving the organohalide species. This step proceeds with aryl, vinyl, alkynyl, and acyl halides, acetates, or triflates, with substrates following standard oxidative addition relative rates (I>OTf>Br>>Cl). The actual mechanism of oxidative addition is unresolved, though there are two likely pathways. One pathway is thought to proceed via an SN2 like mechanism resulting in inverted stereochemistry. The other pathway proceeds via concerted addition and retains stereochemistry. Though the additions are cis- the Pd(II) complex rapidly isomerizes to the trans- complex. Next, the transmetalation step occurs where the organozinc reagent exchanges its organic substituent with the halide in the Pd(II) complex, generating the trans- Pd(II) complex and a zinc halide salt. The organozinc substrate can be aryl, vinyl, allyl, benzyl, homoallyl, or homopropargyl. Transmetalation is usually rate limiting and a complete mechanistic understanding of this step has not yet been reached though several studies have shed light on this process. It was recently determined that alkylzinc species must go on to form a higher-order zincate species prior to transmetalation whereas arylzinc species do not. ZnXR and ZnR2 can both be used as reactive reagents, and Zn is known to prefer four coordinate complexes, which means solvent coordinated Zn complexes, such as ZnXR(solvent)2 cannot be ruled out a priori. Studies indicate competing equilibriums exist between cis- and trans- bis alkyl organopalladium complexes, but that the only productive intermediate is the cis complex.