A theoretical study of the Duff reaction: insights into its selectivity

Abstract

The Duff reaction is one of the most employed methods for the ortho-formylation of phenols; however, not much is truly known about its mechanism. Using DFT calculations, we disclose the first theoretical study regarding the selectivity-determining step of the reaction. We have found that this stage is governed by a hydrogen bond, that gives rise to a cyclohexa-2,4-dienone intermediate and establishes the position where the formylation will take place. These findings were evaluated by analysis of the reaction outcome of several non-symmetrically substituted phenols.

Emerging computational approaches for the study of regio- and stereoselectivity in organic synthesis

“…In 2016, Grimblat and coworkers reported the first theoretical study of the selectivity of the Duff reaction. 60 It was proposed that the new C-C bond formation proceeded through the reaction between phenols and iminium HMTA + ( protonated HMTA) that provided a β-aminoketone type Mannich base as an intermediate. This intermediate formation is the key regioselective step of reaction followed by hydrolysis to form the final product.…”

“…Calculated activation, formation energies, and product ratios of the Duff reaction (adapted with permission from ref 60). …”

Twice as Nice: The Duff Formylation of Umbelliferone Revised

“…With that, the data on the production of the 6-formylumbelliferones during the Duff reaction was nearly absent in literature [16,18]. This was found to be rather surprising, since according to the theoretical DFT study on the Duff reaction regioselectivity for non-symmetrically substituted phenols [20] we might suggest the simultaneous formation of 6-formyl and 8-formyl substituted umbelliferones as a result of the Duff ortho-formylation, albeit the latter being the predominant product.…”

Metal-free selective aryl C–H formylation co-controlled by 1,2,3-triazole and hydroxyl using DMSO as formyl source

“…1,2 Due to the remarkable application value in chemistry, formylation of arene has attracted much interest of organic chemists. Traditionally, the most classical methods include Vilsmeier-Haack, [3][4][5] Duff reaction, [6][7][8] Reimer Tiemann, 9,10 Rieche 11 and Friedel-Crafts acylations. 12,13 Nevertheless, these reactions generally require excess strong bases or acids in workup processes and are unfriendly to the environment.…”