Nucleophilic Aromatic Substitution of Halobenzenes and Phenols with Catalysis by Arenophilic π Acids

ConspectusLewis π acids, particularly high-valent transition metals with vacant orbitals, can coordinate with unsaturated compounds such as alkynes and alkenes by means of π-bonding. The coordination enhances the electrophilicity of the bound compounds, thereby facilitating reactions─such as nucleophilic addition─that take place at the ligated carbon-carbon multiple bonds. This activation phenomenon occurs at the ligand rather than at the metal atom, and it has been extensively utilized in the development of catalytic methods. In addition to alkynes and alkenes, aromatic compounds featuring a phenyl ring can be activated by an electrophilic transition-metal unit (e.g., Cr(CO)₃, [Mn(CO)₃]⁺, [CpFe]⁺, or [CpRu]⁺, where Cp = cyclopentadienyl) through π coordination. Over the past several decades, remarkable advances have been achieved in the development of reactions occurring on bound arenes, capitalizing on the highly electron-withdrawing nature of these transition-metal units and on the thermodynamic stability of η⁶-arene complexes. A prime example is the extension of nucleophilic aromatic substitution (S_NAr) reactions to electron-neutral and -rich halobenzenes. Such arenes, which are normally inert to classical S_NAr, can undergo sequences involving complex formation, substitution, and complex decomposition. Despite the successes achieved through the utilization of preformed complexes, the application of reversible arene coordination to catalytic systems has seen only limited progress. Consequently, in π-coordination activation, transition-metal units are commonly considered to be components of bound arene complexes rather than π-acid catalysts.In this Account, we summarize our recent research on catalytic S_NAr reactions of halobenzenes and phenols enabled by reversible π-coordination of the arenes with electrophilic Ru or Rh catalysts, which we refer to as arenophilic π-acids. First, we developed a method for S_NAr amination of fluorobenzenes with catalysis by a Ru(II) complex with a hemilabile P,O-bidentate ligand. The use of the hemilabile ligand significantly enhanced catalytic efficiency, allowing electron-rich and -neutral arenes to undergo amination without the need of excess fluorobenzenes. In a subsequent study of hydroxylation and alkoxylation reactions, we found that Rh(III) catalysts bearing a Cp-type ligand had a substantial activating effect. In addition, by isolating an η⁵ complex as the reaction intermediate, we obtained evidence in support of the long-standing hypothesis that S_NAr of η⁶-arene complexes proceeds via a stepwise mechanism. Next, we extended the Rh-catalyzed S_NAr to chloro- and bromobenzenes, which are abundant and readily available but are less reactive than corresponding fluorides toward S_NAr. When the weakly nucleophilic alcohol hexafluoroisopropanol was used as a reaction partner, we were able to synthesize hexafluoroisopropyl aryl ethers, which are challenging to obtain by means of conventional approaches. Beyond halobenzenes, we successfully applied π-coordination strategy to achieve umpolung substitution reactions of phenols, which are typically nucleophilic. We found that an arenophilic Rh or Ru catalyst activated the phenol ring by π coordination instead of κ-O coordination, generating transient η⁵-phenoxo complexes that subsequently underwent carbonyl-amine condensation to produce anilines without the need for an exogenous oxidant or reductant. We anticipate that our research on catalyst development and reactions involving π-coordination activation will facilitate further advances in the application of arenophilic π acids.