Science of Synthesis

Wessjohann, L. A.; Schreckenbach, H. F.; Kaluđerović, G. N., Science of Synthesis: Biocatalysis in Organic Synthesis, (2015) 2, 177.

General Introduction

The formation of most bonds in natural systems requires either (partially) charged partners (nucleophilic and electrophilic) or radicals; these are reactive intermediates that are stabilized by enzymes. The formation of C—C bonds usually has a higher activation energy than that of carbon–heteroatom bonds. While heteroatoms (O, S, Se, N, P) possess free electron pairs or d-orbitals, or are easily polarized or ionized, ionization or radical formation at a carbon atom is energetically less favored, especially if neighboring-group effects cannot support the process. If one of the reaction partners is a benzenoid system, even more energy must be provided to dearomatize the system during the reaction. Thus, in nature, most substituents found on benzene rings are introduced into nonaromatic precursors prior to aromatization, e.g. resulting in the typical meta-hydroxylation patterns of all aromatic polyketides including, for example, flavonoids. However, nature has also found ways to react benzenes and other aromatics, especially phenolic and benzoylic compounds. The most common reactions at benzenoids are redox reactions, including hydroxylations, but radical phenolic couplings are also known.

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References