CF₂H, a Hydrogen Bond Donor

Abstract

The CFH group, a potential surrogate for the OH group, can act as an unusual hydrogen bond donor, as confirmed by crystallographic, spectroscopic, and computational methods. Here, we demonstrate the bioisosterism of the OH and CFH groups and the important roles of CF-H···O hydrogen bonds in influencing intermolecular interactions and conformational preferences. Experimental evidence, corroborated by theory, reveals the distinctive nature of CFH hydrogen bonding interactions relative to their normal OH hydrogen bonding counterparts.

Methods for the Synthesis of α,α‐Difluoroketones

“…[13] Finally, Lippard has shown that compounds such as o-nitro-α,α-difluorotoluene can form hydrogen-bonded dimers in solution and the solid-state, similar in shape to o-nitrophenol. [14] The inductive electronwithdrawing effect of the CF 2 H group is similar to that of an OH group [as measured by their σ I values of 0.29 (CF 2 H) and 0. 33 (OH)].…”

“…In compound 4 a short C–H–O contact between a CF 2 H and an amide is used to stabilise a short peptide mimic into a β‐turn like conformation, overcoming the natural conformational preference to place a fluorine and an adjacent carbonyl group trans ‐coplanar to each other to minimize dipole repulsions . Finally, Lippard has shown that compounds such as o ‐nitro‐α,α‐difluorotoluene can form hydrogen‐bonded dimers in solution and the solid‐state, similar in shape to o ‐nitrophenol . The inductive electron‐withdrawing effect of the CF 2 H group is similar to that of an OH group [as measured by their σ I values of 0.29 (CF 2 H) and 0.33 (OH)].…”

Bulky Diamine Ligand Promotes Cross‐Coupling of Difluoroalkyl Bromides by Iron Catalysis

“…[18] To date,n os uccessful example of difluoromethylation of Grignard reagents with BrCF 2 Hh as been described. In view of the important applications of difluoromethyalted arenes in medicinal chemistry, [19] this method would have potential applications in drug discovery and development. In view of the important applications of difluoromethyalted arenes in medicinal chemistry, [19] this method would have potential applications in drug discovery and development.…”

“…[b] Determined by 19 FNMR spectroscopy using fluorobenzene as an internals tandard. [b] Determined by 19 FNMR spectroscopy using fluorobenzene as an internals tandard.…”

Catalytic Enantioselective Synthesis of Highly Functionalized Difluoromethylated Cyclopropanes

“…Organofluorine chemistry has become av ery important field of research over the last decade.I ndeed, the properties of the fluorine atom [1] have at remendous impact on the physicochemical properties of molecules and thus on their bioactivity.T he presence of either af luorine atom or af luorinated group on am olecule can affect the metabolic profile,the lipophilicity,aswell as the binding affinity toward biological receptors.H ence,t he systematic introduction of either the fluorine atom or fluorinated groups to amolecule is avery popular strategy in drug discovery, [2] and the quest for the development of versatile fluorinated bioisosteres is an attractive research area for organic chemists. [3] As part of this field, the CF 2 Hr esidue is considered to be an excellent bioisostere of alcohol and thiol, for instance.Q uite recently, the groups of Saphier [4] and Lippard [5] independently demonstrated the ability of this motif to act as alipophilic hydrogenbond donor.…”