Carbon–hydrogen bond activation

In organic chemistry and organometallic chemistry, carbon–hydrogen bond activation (C−H activation) is a type of organic reaction in which a carbon–hydrogen bond is cleaved and replaced with a C−X bond (X ≠ H is typically a main group element, like carbon, oxygen, or nitrogen). Some authors further restrict the term C–H activation to reactions in which a C–H bond, one that is typically considered to be "unreactive", interacts with a transition metal center M, resulting in its cleavage and the generation of an organometallic species with an M–C bond. The organometallic intermediate resulting from this step (sometimes known as the C−H activation step) could then undergo subsequent reactions with other reagents, either in situ (often allowing the transition metal to be used in a catalytic amount) or in a separate step, to produce the functionalized product.

The alternative term C−H functionalization is used to describe any reaction that converts a relatively inert C−H bond into a C−X bond, irrespective of the reaction mechanism (or with an agnostic attitude towards it). In particular, this definition does not require the cleaved C–H bond to initially interact with the transition metal or for an organometallic intermediate to exist in the reaction mechanism. In contrast to the organometallic variety, this broadened type of C-H activation is widely employed industrially and in nature. This broader definition encompasses all reactions that would fall under the restricted definition of C–H activation given above. However, it also includes iron-catalyzed alkane C–H hydroxylation reactions that proceed through the oxygen rebound mechanism (e.g. cytochrome P450 enzymes and their synthetic analogues), in which an organometallic species is not believed to be involved in the mechanism. In other cases, organometallic species are indirectly involved. This occurs, for example, with Rh(II)-catalyzed C–H insertion processes in which an electrophilic metal carbene species is generated and the hydrocarbon C–H bond inserts into the carbene carbon without direct interaction of the hydrocarbon with the metal. Other mechanistic possibilities not involving direct C–H bond cleavage by the metal include (i) generation of arylmetal species by electrophilic aromatic substitution mechanism (common for electrophilic Pd, Pt, Au, Hg species), (ii) cleavage of the C–H bond via hydrogen atom abstraction by an O- or N-centered radical, which may then go on to further react and undergo functionalization with or without forming an organometallic intermediate (e.g., Kharasch–Sosnovsky reaction), and (iii) C–H deprotonation at the α-position of a π-system assisted by initial formation of a π-complex with an electrophilic metal to generate a nucleophilic organometallic species (e.g., by cyclopentadienyliron complexes).

Often, when authors make the distinction between C–H functionalization and C−H activation, they will restrict the latter to the narrow sense. However, it may be challenging to definitively demonstrate the involvement or non-involvement of an interaction between the C–H bond and the metal prior to cleavage of the bond. This article discusses C–H functionalization reactions in general but with a focus on C–H activation sensu stricto.