Theoretical Explanation of Reaction Site Selectivity in the Addition of a Phenoxy Group to Perfluoropyridine

Abstract

Pentafluoropyridine, a potentially useful precursor in organofluorine methodology, undergoes selective substitution of a fluorine with a phenoxide at the site para to the nitrogen. Subsequent aryloxide substitutions can be accomplished at the ortho-positions with aryloxide groups containing various functional groups para to the phenoxide oxygen. During this phase of the reaction, “reverse reactions” involving substitutions of the original para substituent with a free fluoride or with another aryloxide moiety are observed with a frequency that depends on the functional group para to the oxygen on the aryloxide. Herein, we provide a theoretical explanation of these observations through use of density functional theory.

Theoretical Prediction and Explanation of Reaction Site Selectivity in the Addition of a Phenoxy Group to Perfluoropyrimidine, Perfluoropyridazine, and Perfluoropyrazine

“…This is significantly larger than that of the reactions at carbon four for perfluoropyrimidine (1.699 kcal/mol) and perfluoropyridazine (2.572 kcal/mol). For the sake of comparison, the previously reported computed activation energy associated with a substitution at carbon four on perfluoropyridine is 4.16 kcal/mol [23]. It is thus expected that both perfluoropyrimidine and perfluoropyridazine will react faster with phenoxide ion than perfluoropyridine, while perfluoropyrazine will react more slowly.…”

“…For the sake of comparison, the previously reported computed activation energy associated with a substitution at carbon four on perfluoropyridine is 4.16 kcal/mol. [23] It is thus expected that both perfluoropyrimidine and perfluoropyridazine will react faster with phenoxide ion than perfluoropyridine, while perfluoropyrazine will react more slowly. The question is, why is there such a stark difference between the transition state energies, and thus the activation energies (Table 1) for these reactions when they happen at different carbon atoms?…”

“…Our goal was to examine reactants and possible products, intermediates, and transition states to determine which products were most likely to form. We assumed, as we did in our perfluoropyridine work [23], the reactions proceed without formation of a Meisenheimer intermediate. Some reports debate whether these reactions should be considered as two-step processes with a Meisenheimer intermediate, or as a concerted reaction with a short-lived transition state [24,25].…”

Synthesis of complex unnatural fluorine-containing amino acids

“…Highly fluorinated aromatic species have unique properties. Due to their highly electron deficient nature, perfluoroaromatics can have significant effects on the electronics of molecular systems [ 60 ]. Perfluoroaromatic moieties have therefore seen use in materials [ 61 ], catalysis [ 62 , 63 ] and organic synthesis [ 64 , 65 ], and have been exploited in peptide [ 66 , 67 ] and peptoid chemistry [ 68 ].…”

Carboxylic Acid Deoxyfluorination and One-Pot Amide Bond Formation Using Pentafluoropyridine (PFP)

“… 17 Both PFP ( 2 ) and cyanuric fluoride possess aromatic fluorines that are highly susceptible to displacement via S N Ar reactions. Previously, the ability to undergo S N Ar reactions has led to applications for PFP ( 2 ) in protecting group chemistry, 18 peptide modification, 19 unsymmetrical biaryl synthesis, 20 polymer chemistry, 21 and macrocycle synthesis. 22 We speculated that PFP ( 2 ) could be reactive enough to generate acyl fluorides directly from carboxylic acids through an S N Ar, deoxyfluorination sequence.…”