The first cross‐coupling of organozinc nucleophiles with aryl halides was reported in 1977 by Negishi. Unknown to all at the time was the importance of salt additives that were often present as a byproduct from the organozinc preparation. For decades, these salt additives were overlooked until 2006 when it was discovered that two different, yet effective methods for preparing organozinc solutions (i.e. one with salt and one without) provided drastically different results. Since this finding, the exact role of salt additives in cross‐coupling has been debated in the catalysis community. In this Review we highlight all the major discoveries regarding the influence of salt additives on the formation of organozinc reagents and their use in the Negishi reaction. These effects include solubilizing key intermediates, the formation of higher‐order zincates, product inhibition, catalyst protection, and solvent effects.
The impact of LiBr and ZnBr2 salts on the Negishi coupling of alkylZnBr and dialkylzinc nucleophiles with both electron‐rich and ‐poor aryl electrophiles has been examined. Focusing only on the more difficult coupling of deactivated (electron‐rich) oxidative addition partners, LiBr promotes coupling with BuZnBr, but does not have such an effect with Bu2Zn. The presence of exogenous ZnBr2 shuts down the coupling of both BuZnBr and Bu2Zn, which has been shown before with alkyl electrophiles. Strikingly, the addition of LiBr to Bu2Zn reactions containing exogenous ZnBr2 now fully restores coupling to levels seen without any salt present. This suggests that there is a very important interaction between LiBr and ZnBr2. It is proposed that Lewis acid adducts are forming between ZnBr2 and the electron‐rich Pd0 centre and the bromide from LiBr forms inorganic zincates that prevent the catalyst from binding to ZnBr2. This idea has been supported by catalyst design as chlorinating the backbone of the NHC ring of Pd‐PEPPSI‐IPent to produce Pd‐PEPPSI‐IPentCl catalyst now gives quantitative conversion, up from a ceiling of only 50 % with the former catalyst.
The role that LiBr plays in the lifetime of Pd‐NHC complexes has been investigated. A bromide ion is proposed to coordinate to Pd thereby preventing beta hydride elimination (BHE) (to form NHC‐H+) of the reductive elimination (RE) intermediate that normally completes with the desired cross‐coupling catalytic cycle. Coordinating groups, such as anilines, are able to bind suitably well to Pd to prevent this pathway from occurring, thus reducing the need for the added salt. The metal hydride formed from BHE is very unstable and RE of the hydride to the NHC ligand occurs very rapidly giving rise to the corresponding hydrido‐NHC (i.e., NHC‐H+). The use of the per deuterated dibutylzinc shows a significant deuterium isotope effect, shutting down catalyst death almost completely. The use of bis‐neopentylzinc, now possessing no hydrides, eliminates catalyst death all together leading to a very long‐lived catalytic cycle and confirming the untoward role of BHE.
The first cross‐coupling of organozinc nucleophiles with aryl halides was reported in 1977 by Negishi. Unknown to all at the time was the importance of salt additives that were often present as a byproduct from the organozinc preparation. For decades, these salt additives were overlooked until 2006 when it was discovered that two different, yet effective methods for preparing organozinc solutions (i.e. one with salt and one without) provided drastically different results. Since this finding, the exact role of salt additives in cross‐coupling has been debated in the catalysis community. In this Review we highlight all the major discoveries regarding the influence of salt additives on the formation of organozinc reagents and their use in the Negishi reaction. These effects include solubilizing key intermediates, the formation of higher‐order zincates, product inhibition, catalyst protection, and solvent effects.
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