Computational Study of Ni-Catalyzed C−H Functionalization: Factors That Control the Competition of Oxidative Addition and Radical Pathways

The carbon-hydrogen (C−H) bond in organic molecules is ubiquitous and strong. The selective substitution of hydrogen atoms by other atoms or functional groups, also known as C−H bond functionalization, opens the door to a wide variety of organic molecules, ranging from drug candidates to synthetic polymers. However, the efficient and selective transformation of C−H bonds into useful scaffolds was a significant challenge. Early examples in this area often require expensive metal catalysts, high temperatures, strongly acidic/basic conditions, or powerful oxidizing agents. Recently, inspiring studies utilizing bidentate directing groups have driven the development of increasingly selective C–H functionalization chemistry.

In C–H functionalization reactions, the C–H bond is cleaved, and the hydrogen atom is replaced by other atoms such as carbon, oxygen, or nitrogen or a functional group. Generally, precious transition-metal catalysts such as palladium, rhodium, or iridium, are required to cleave the C–H bond and form a new metal–carbon bond in a reactive organometallic intermediate and thus "activate" the C−H bond for subsequent functionalization with other reagents.

Development of C−H bond functionalization reactions with more earth-abundant and cost-effective first-row transition-metals is particularly advantageous. One such catalyst is nickel which holds several promises for C−H bond functionalization chemistry: a) various types of functionalization can be achieved with both C(sp2)−H and C(sp3)−H bonds b) nickel provides opportunities for unique mechanisms via the open-shell Ni(I) and Ni(III) oxidation states; and c) Ni-catalyzed reactions would be more cost effective than reactions using precious metal catalysts.

To guide the development of a more diverse set of Ni-catalyzed C−H bond functionalizations, a thorough understanding of the mechanisms, reactivity, and selectivity of these reactions is required. Peng Liu and his student Humair Omer have undertaken a computational study of the functionalization of the C−H bonds in molecules that contain the N,N-bidentate directing group with Ni catalyst and various coupling  partners, e.g. phenyl iodide (Ph−I), which has been published in the July 26, 2017 issue of the Journal of the American Chemical Society.

Figure 1. Ni-Catalyzed C−H Bond Functionalization: replacing the hydrogen atom (H) with a phenyl group (Ph).

They used density functional theory (DFT) calculations to elucidate the reaction mechanism by locating key reaction intermediates, transition states, and calculating the energy barriers. They used a mixed cluster-continuum model to incorporate solvation effects: some solvent molecules were explicitly added in the calculations to model the interactions with the Na atoms and an implicit solvation model was used to treat the longer-range electrostatic interactions with the solvent.

Using this approach, they tested several anionic ligands that could bind to the Ni center and identified the most active Ni(II) catalyst: Ni(NaCO3)2•4DMF. The authors then set to study the functionalization reaction depicted above and computed the entire catalytic cycle (reactants à intermediate species à final product). The mechanism of the reaction is as follows:

1. The Ni catalyst first coordinates to the nitrogen atom of the substrate;
2. This step is immediately followed by fast deprotonation of the N−H bond;
3. The C−H bond is cleaved with the assistance of the carbonate ligand; a new Ni−C bond is formed.
4. The other reactant, Ph−I binds to the Ni catalyst;
5. Then, the Ph−I bond is cleaved;
6. A new C−C bond is formed between two groups attached to the nickel: the phenyl group and the carbon atom on the substrate;
7. Finally, the last protonation step releases the active catalyst and yields the final product.

Figure 2. Catalytic cycle of Ni-catalyzed C(sp3)−H arylation with Ph−I.

The thermodynamics of Ni(II)-mediated C−H metalation process is found to be fundamentally different from the corresponding reaction with Pd(II) catalyst. In fact, the C−H metalated Ni intermediates are less stable than the corresponding Pd complexes, which indicate that the C−H metalation is much less favorable thermodynamically with Ni(II) catalysts than with Pd(II). The Ni-mediated C−H metalation is more likely to be a reversible process, and thus the subsequent functionalization of the nickelacycle intermediate (steps 5 and 6) is rate-determining in many Ni-catalyzed C−H bond functionalization reactions. In this functionalization step with Ph−I, the preferred pathway involves the formation of a Ni(IV) intermediate, which is stabilized by the strongly electron-donating 8-aminoquinoline directing group to which Ni is bound. This oxidative addition step to form the Ni(IV) intermediate is indeed the rate-determining step in the overall catalytic cycle.

To investigate the origins of reactivity of such functionalization reactions, the authors tested several aryl halides (organic cycles bound to a halogen atom) with different electronic and steric properties in addition to phenyl iodide. They showed that their computed reactivities depend on their electronic properties (electron-rich compounds have lower barriers), steric effects (sterically congested compounds are substantially less reactive) and carbon−halogen bond strengths.

Figure 3. Selectivity of primary C(sp3)−H bond arylation.

To investigate the origin of the site-selectivity, they calculated the reaction barriers for the functionalization of the different C−H bonds in 2-ethyl-2-methylbutanamide (Figure 3). The final product of the reaction shows that functionalization occurred exclusively on the primary C(sp3)−H bond. The calculations indicate that the C−H cleavage in both pathways is reversible. The site-selectivity of the product is determined in the subsequent oxidative addition and reductive elimination steps and is controlled by the steric effects upon the formation of the C−C bond.

Although the above calculations indicated that the Ni(II)/Ni(IV) mechanism is strongly favored in the Ni-catalyzed C−H arylation using aryl halides, radical pathways involving Ni(I) or Ni(III) species cannot be ruled out in other types of C−H functionalizations. The authors therefore investigated the mechanism of the Ni-catalyzed C(sp2)−H sulfenylation using diphenyl disulfide (PhS−SPh) and methylation using the sterically-hindered dicumyl peroxide (DCP). In both cases, the homolytic dissociation pathway is favorable due to the low bond dissociation energies of the S−S bond in diphenyl disulfide and the O−O bond in DCP compared to the C−I bond in phenyl iodide.

In summary, this study showed that in Ni-catalyzed functionalization reactions, the reactivity of the oxidative addition pathway is controlled by a combination of steric effects, the strength of the cleaving bond, and substrate−metal orbital interactions. In contrast, the reactivity of the homolytic dissociation pathway is mainly determined by the strength of the cleaving R−X or RX−XR bond. The authors expect that their proposed theoretical insights about the mechanisms, reactivity, chemo-, and site-selectivity will guide the development of a more diverse set of C−H bond functionalization reactions utilizing the unique reactivity of the Ni catalysts.