Zinc Chloride - Applications - in Organic Synthesis

In Organic Synthesis

In the laboratory, zinc chloride finds wide use, principally as a moderate-strength Lewis acid. It can catalyze (A) the Fischer indole synthesis, and also (B) Friedel-Crafts acylation reactions involving activated aromatic rings

Related to the latter is the classical preparation of the dye fluorescein from phthalic anhydride and resorcinol, which involves a Friedel-Crafts acylation. This transformation has in fact been accomplished using even the hydrated ZnCl₂ sample shown in the picture above.

Hydrochloric acid alone reacts poorly with primary alcohols and secondary alcohols, but a combination of HCl with ZnCl₂ (known together as the "Lucas reagent") is effective for the preparation of alkyl chlorides. Typical reactions are conducted at 130 °C. This reaction probably proceeds via an S_N2 mechanism with primary alcohols but S_N1 pathway with secondary alcohols.

Zinc chloride also activates benzylic and allylic halides towards substitution by weak nucleophiles such as alkenes:

In similar fashion, ZnCl₂ promotes selective NaBH₃CN reduction of tertiary, allylic or benzylic halides to the corresponding hydrocarbons.

Zinc chloride is also a useful starting reagent for the synthesis of many organozinc reagents, such as those used in the palladium catalyzed Negishi coupling with aryl halides or vinyl halides. In such cases the organozinc compound is usually prepared by transmetallation from an organolithium or a Grignard reagent, for example:

Zinc enolates, prepared from alkali metal enolates and ZnCl₂, provide control of stereochemistry in aldol condensation reactions due to chelation on to the zinc. In the example shown below, the threo product was favored over the erythro by a factor of 5:1 when ZnCl₂ in DME/ether was used. The chelate is more stable when the bulky phenyl group is pseudo-equatorial rather than pseudo-axial, i.e., threo rather than erythro.