Copper-Catalyzed Aromatic Fluorination of 2-(2-bromophenyl)pyridine via Cu(I)/Cu(III) Mechanism in Acetonitrile Solvent: Cluster-Continuum Free Energy Profile and Microkinetic Analysis

Abstract

Nucleophilic fluorination via copper catalysis has been a challenging transformation and only special substrates can react. One example is the 2-(2-bromophenyl)pyridine, which was fluorinated with AgF using CuPF6 catalyst in acetonitrile solvent. In this work, a detailed analysis of this catalyzed reaction was done using theoretical methods. The free Cu+ ion and the CuF ion pair in acetonitrile solvent were modeled using a quasi-chemical cluster-continuum approach and electronic energies calculated at DLPNO-CCSD(T) level with a quadruple-zeta basis set. The catalytic cycle involves the Cu(I)/Cu(III) mechanism via cationic (Cu+ ion) or neutral (CuF ion pair) pathways. The solubility of AgF and CuF was included in the analysis, as well as the transmetalation step. The calculated free energy profile was used to perform a microkinetic analysis of the reaction system. The results point out that the reaction proceeds via the cationic mechanism, with the formation of the catalyst-substrate complex followed by the oxidative addition step with ΔG‡ = 30.8 kcal mol−1. The formed intermediate is high in free energy and the reductive elimination step is the rate-determining one, with an overall ΔG‡ = 32.6 kcal mol−1. Analysis of the free energy profile and the microkinetic modeling point out almost zero-order kinetics in substrate concentration when the catalyst is used in substoichiometric quantity. Approximated experimental ΔG‡ is estimated as being 30.7 kcal mol−1, in very good agreement with the theoretical value. The neutral mechanism with the soluble CuF ion pair has ΔG‡ = 33.4 kcal mol−1, which is competitive with the cationic mechanism. However, due to the low solubility and concentration of this ion pair, the reaction does not take place by this pathway.