Predicting and Tuning Physicochemical Properties in Lead Optimization: Amine Basicities

Abstract

This review describes simple and useful concepts for predicting and tuning the pK(a) values of basic amine centers, a crucial step in the optimization of physical and ADME properties of many lead structures in drug-discovery research. The article starts with a case study of tricyclic thrombin inhibitors featuring a tertiary amine center with pK(a) values that can be tuned over a wide range, from the usual value of around 10 to below 2 by (remote) neighboring functionalities commonly encountered in medicinal chemistry. Next, the changes in pK(a) of acyclic and cyclic amines upon substitution by fluorine, oxygen, nitrogen, and sulfur functionalities, as well as carbonyl and carboxyl derivatives are systematically analyzed, leading to the derivation of simple rules for pK(a) prediction. Electronic and stereoelectronic effects in cyclic amines are discussed, and the emerging computational methods for pK(a) predictions are briefly surveyed. The rules for tuning amine basicities should not only be of interest in drug-discovery research, but also to the development of new crop-protection agents, new amine ligands for organometallic complexes, and in particular, to the growing field of amine-based organocatalysis.

An Unexpected and Significantly Lower Hydrogen‐Bond‐Donating Capacity of Fluorohydrins Compared to Nonfluorinated Alcohols

“…[34] Another important conclusion is that the electronegativity of a gauche fluorine substituent is only partially translated to the hydroxy group: for compounds 2-4 (all containing F···HO), the increase in H-bond acidity resulting from introduction of an anti fluorine substituent is about twice the increase in H-bond acidity resulting from introduction of a gauche fluorine substituent (Figure 1: compare 2!7 with 3,4!8). These observations are corroborated by Bols et al, in the context of amine basicity and glycoside hydrolysis, who concluded that the electronegativity of a polar substituent (e.g., OH, F) is greater in an antiperiplanar arrangement, compared to a gauche, [8,35] which may originate from a stereochemical dependence of hyperconjugation donor/acceptor abilities of s bonds involved. [36] Given the weak nature of an F···HO interaction, its ability to overturn the influence of the fluorine electronegativity is most surprising, even if the incomplete translation of electronegativity due to a gauche dihedral angle is taken into account.…”

“…In this context, it is interesting to observe that the F···HN + interaction is not overriding the effect of fluorine electronegativity on the pK a of ammonium ions, but only attenuates the decrease in pK a . [8] In summary, we reported alcohol H-bond acidity measurements of a range of conformationally restricted fluorohydrins. The results force the conclusion that contrary to current assumptions, fluorination can lead to a significant attenuation of alcohol H-bond acidity compared to the corresponding nonfluorinated alcohols.…”

“…Furthermore, this decrease in pK a can be attenuated if intramolecular NH + ···F electrostatic interactions can occur. [8] Hence, a comprehensive understanding of the effects of fluorination is a prerequisite for successful planning and rationalization of fluorine introduction, and research that increases our knowledge in that respect is highly relevant.…”

“…[7,8] Interestingly, NBO (natural bond orbital) and AIM (atoms in molecules) analyses reveal, for fluorohydrin 5, a significant charge transfer (17.1 kJ mol À1 ) from the fluorine lone pair to the antibonding s* OH orbital and a bond critical point (BCP) between the F and H atoms (1 = 0.0192 e), a weak value typical of an H-bond interaction. [28] Much weaker charge transfer (between 2.2 and 4.2 kJ mol À1 , Table 2) and no BCP are found for the vicinal fluorohydrins, suggesting that in these cases, this intramolecular OH···F interaction probably represents more a weak electrostatic stabilization than a typical H-bond.…”

Influence of Alcohol β‐Fluorination on Hydrogen‐Bond Acidity of Conformationally Flexible Substrates

“…[1,4] The impact of fluorination on Brønsted acid/base properties is well-understood: in general, fluorine introduction increases Brønsted acidity, and decreases Brønsted basicity, even if subtle effects may occur. [5] On the other hand, the fluorine influence on H-bond properties of adjacent functional groups has been shown to be less chemically intuitive. While the strong increase in H-bond donating capacity (H-bond acidity) of polyfluorinated alcohols such as hexafluoroisopropanol (HFIP) and trifluoroethanol (TFE) has been well-documented, [6] our work involving stereochemically defined, conformationally rigid fluorohydrins [7] ( Figure 1) shows that monofluorination can lead to a decreased OH H-bond acidity on the pKAHY scale, [6c] and that β,β-difluorination only leads to a modest increase.…”