Gattermann and Gattermann-Koch Formylation

In 1897, L Gattermann and J.A. Koch successfully introduced an aldehyde group onto toluene by using formyl chloride (HCOCl) as an acylating agent under Friedel-Crafts acylation conditions. Subsequently, the addition of a formyl group into electron-rich aromatic rings by application of CO/HCl/Lewis acid catalysts (AlX₃, FeX₃, where X = Cl, Br, I) to prepare aromatic aldehydes became known as the Gattermann-Koch formylation.

The scope of the Gattermann-Koch reaction is limited due to the lack of suitable substrates, as it is mostly restricted to alkylbenzenes; so Gattermann introduced a modification which allowed the formylation of phenols, phenolic ethers, and heteroaromatic compounds such as pyrroles and indoles.

The main drawback of the Gattermann formylation was that it called for the use of anhydrous hydrogen cyanide (HCN). To avoid handling HCN, R. Adams generated it in situ from zinc cyanide and hydrochloric acid, and this became known as the Adams modification. This method has become more widely used in organic synthesis.

The benzofuran-derived natural product, caleprunin A, was synthesized by R. Stevenson, et al. using the Gattermann formylation as the key step.

Compounds with applications as diverse as fluorescent probes of peptide structures in dynamic environments and potent anti-tumor agents have been synthesized using the Gattermann formylation.