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

Conspectus: Lewis pi acids, particularly high-valent transition metals with vacant orbitals, can coordinate with unsaturated compounds such as alkynes and alkenes by means of pi-bonding. The coordination enhances the electrophilicity of the bound compounds, thereby facilitating reactions & horbar;such as nucleophilic addition & horbar;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 pi 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 eta(6)-arene complexes. A prime example is the extension of nucleophilic aromatic substitution (SNAr) reactions to electron-neutral and -rich halobenzenes. Such arenes, which are normally inert to classical SNAr, 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 pi-coordination activation, transition-metal units are commonly considered to be components of bound arene complexes rather than pi-acid catalysts. In this Account, we summarize our recent research on catalytic SNAr reactions of halobenzenes and phenols enabled by reversible pi-coordination of the arenes with electrophilic Ru or Rh catalysts, which we refer to as arenophilic pi-acids. First, we developed a method for SNAr 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 eta(5) complex as the reaction intermediate, we obtained evidence in support of the long-standing hypothesis that SNAr of eta(6)-arene complexes proceeds via a stepwise mechanism. Next, we extended the Rh-catalyzed SNAr to chloro- and bromobenzenes, which are abundant and readily available but are less reactive than corresponding fluorides toward SNAr. 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 pi-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 pi coordination instead of kappa-O coordination, generating transient eta(5)-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 pi-coordination activation will facilitate further advances in the application of arenophilic pi acids.