Computational and Experimental Studies of Regioselective S_NAr Halide Exchange (Halex) Reactions of Pentachloropyridine

Abstract

The Halex reaction of pentachloropyridine with fluoride ion was studied experimentally and computationally with a modified ab initio G3MP2B3 method. The G3 procedure was altered, as the anionic transition state optimizations failed due to the lack of diffuse functions in the small 6-31G* basis set. Experimental Halex regioselectivities were consistent with kinetic control at the 4-position. The reverse Halex reaction of fluoropyridines with chloride sources was demonstrated using precipitation of LiF in DMSO as a driving force. Reverse Halex regioselectivity at the 4-position was predicted by computations and was consistent with kinetic control. Scrambling of halide ions between chlorofluoropyridines was catalyzed by n-BuPCl, and the products of these reactions were shown to result from a combination of kinetic and thermodynamic control. Comparison of the C-F and C-Cl homolytic bond dissociation energies suggests that an important thermodynamic factor which controls regioselectivity in this system is the weak C2-Cl bond. The differences between ΔH° values of chlorofluoropyridines can be explained by a combination of three factors: (1) the number of fluorine atoms in the molecule, (2) the number of fluorine atoms at the C2 and C6 positions, and (3) the number of pairs of fluorine atoms which are ortho to one another.

Perfluoropyridine: Discovery, Chemistry, and Applications in Polymers and Material Science

“…The last examples of purposeful manipulation of PFPy involve site selective defluorination and halogen exchange (halex), as illustrated in Scheme 7 [ 48 , 49 ]. Both processes generate a regioselective substitution depending on various reaction conditions.…”

“…This strategy was expanded to include the 'one-pot' preparation of amides and esters utilizing PFPy as a coupling agent. The last examples of purposeful manipulation of PFPy involve site selective defluorination and halogen exchange (halex), as illustrated in Scheme 7 [48,49]. Both processes generate a regioselective substitution depending on various reaction conditions.…”

“…Senaweera et al demonstrated high photocatalytic turnover with low-Ir complex loading for the preparation of deyhdrofluorinated PFPy utilizing a flow reactor design, demonstrating the scalability of such useful intermediates [48]. The halex reverse-substitution was achieved in the 4-para-position of PFPy with LiCl, and additional exchanges on the ring with chlorine were achieved from a combination of kinetic and thermodynamic control [49]. Perfluoropyridine has been employed as a nucleophilic fluorination reagent for both alkyl halides (Scheme 6, right-to-left) [46] as well as deoxyfluorination of carboxylic acids (Scheme 6, left-to-right) [47] for the preparation of a versatile pool of substrates.…”

Mechanism of nucleophilic fluorination promoted by bis‐tert‐alcohol‐functionalized crown‐6‐calix[4]arene

“…Indeed, the calculated free‐energy barrier of 26.1 kcal mol −1 is compatible with the reaction conditions needed to promote the reaction. Theoretical studies of S N Ar reactions have been key for a better understanding of this kind of reaction …”

SNAr catalysis enhanced by an aromatic donor–acceptor interaction; facile access to chlorinated polyfluoroarenes

“…However, if the synthetic strategy is reversed (retro-Halex), and chlorination of a perfluoroarene is performed, it takes place with the same regioselectivity. 4 Consequently, the inaccessible chlorination patterns become accessible. Currently, attempts to perform such transformations use forcing conditions (i.e., refluxing sulfolane, bp = 285 °C).…”