Physico‐chemical properties important to drug discovery (pKa, LogP, and aqueous solubility), as well as metabolic stability, were studied for a series of functionalized gem‐difluorinated cycloalkanes and compared to those of non‐fluorinated and acyclic counterparts to evaluate the impact of the fluorination. It was found that the influence of the CF2 moiety on the acidity/basicity of the corresponding carboxylic acids and amines was defined by inductive the effect of the fluorine atoms and was nearly the same for acyclic and cyclic aliphatic compounds. Lipophilicity and aqueous solubility followed more complex trends and were affected by the position of the fluorine atoms, ring size, and even the nature of the functional group present; also, significant differences were found for the acyclic and cyclic series. Also, gem‐difluorination either did not affect or slightly improved the metabolic stability of the corresponding model derivatives. The presented results can be used as a guide for rational drug design employing fluorine and establish the first chapter in a catalog of the key in vitro properties of fluorinated cycloalkanes.

The physicochemical properties (pKa(H), log P, and aqueous solubility) of fluoroalkyl‐substituted heterocyclic amines were profiled to facilitate the amines’ rational application in medicinal chemistry research. The features of fluorine‐containing compounds were compared to those of the corresponding parent non‐fluorinated heterocycles and the corresponding fluorinated n‐alkylamines. Amine basicity was observed to change in a monotonic fashion depending on the fluorination pattern. Although the introduction of fluoroalkyl groups had complex effects on the lipophilicity and aqueous solubility of the compounds, possible contributions of the fluorination pattern, ring size, and conformation of the substituent in the ring were addressed for a series of derivatives. The summarized data provide a useful guideline for the application of fluorinated motifs for fine‐tuning a compound's properties related to drug discovery.

Synthesis of previously unavailable 1,2‐disubstituted cyclobutane building blocks bearing mono‐, di‐ and trifluoromethyl groups are disclosed. The key steps included deoxofluorination or TMAF‐mediated nucleophilic substitution in the appropriate bifunctional cyclobutanes; for the CF3‐substituted derivatives, alternative methods based on cyano‐ or azidotrifluoromethylation of cyclobutene using the Togni reagent II were also proposed. All methods provided trans diastereomers of the target primary amines and carboxylic acids (6 representatives) and were suitable for their multigram preparation. Furthermore, dissociation constants (pKa) and lipophilicity (logP) values were measured to evaluate the effect of the fluoroalkyl substituents on acidity/basicity and lipophilicity of the building blocks obtained.

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The CF2 dragon reborn! The difluoromethylene dragon has evolved from difluorocyclopropanations (presented in a series of previous covers, see Adv. Synth. Catal., DOI: 201801304 and Eur. J. Org. Chem. 201900911) to the full strength of all other gem‐difluorocycloalkanes. In the Research Article by O. O. Grygorenko and co‐authors (DOI: 10.1002/chem.202200331), the key in vitro properties of functionalized gem‐difluorinated cycloalkanes (pKa, log P, aqueous solubility, and intrinsic clearance) are discussed thoroughly.