Lipophilicity trends upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl groups

Abstract

A systematic comparison of lipophilicity modulations upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl substituents, at a single carbon atom, is provided using directly comparable, and easily accessible model compounds. In addition, comparison with relevant linear chain derivatives is provided, as well as lipophilicity changes occurring upon chain extension of acyclic precursors to give cyclopropyl containing compounds. For the compounds investigated, fluorination of the isopropyl substituent led to larger lipophilicity modulation compared to fluorination of the cyclopropyl substituent.

Hydrogen Bond Acceptor Propensity of Different Fluorine Atom Types: An Analysis of Experimentally and Computationally Derived Parameters

“…For example, they are now included in fluorinated fragment libraries for 19 F NMR screening. [43,[55][56][57] These molecules have a higher degree of three-dimensionality, often improved solubility in water [4,18,40] and the alkyl fluorine atom can participate in polar intramolecular and intermolecular interactions which have important implications for the chemical-physical and structural properties of the molecules, [58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73] chemical reactions [13,38,[74][75][76][77][78][79] and protein-ligand recognition. [39,80] An example of this last point is the shielded alkyl mono-fluorinated tertiary motif contained in the prodrug sofosbuvir which is used for the treatment of chronic hepatitis C virus (HCV) infection.…”

Synthesis and Physicochemical Properties of 2-SF5-(Aza)Indoles, a New Family of SF5 Heterocycles

“…Fine modulation of lipophilicity is central to drug development, − and fluorine-containing substituents play an important role in this regard, whether in the aromatic or aliphatic series. − As a consequence, assessing the impact of the pentafluorosulfanyl motif at the C2-position of indoles on log P was of interest. The lipophilicities of the five indole derivatives were obtained by combining experimental and computational data .…”

Skipped Fluorination Motifs: Synthesis of Building Blocks and Comparison of Lipophilicity Trends with Vicinal and Isolated Fluorination Motifs

“…R f 0.32 (hexane/EtOAc 70:30); IR 3657 (w), 2980 (s), 2889 (m), 1722 (s), 1382 (m), 1092 (s) cm −1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 9.81 (1H, q, J = 1.0 Hz, H 1 ), 7.39−7. 29 5-((tert-Butyldiphenylsilyl)oxy)-4,4-difluoropentanal (33). To a solution of ester 50 (4.80 g, 11.4 mmol) in CH 2 Cl 2 (91 mL) at −78 °C was added DIBAL (1 M in CH 2 Cl 2 , 13.7 mL, 13.7 mmol) slowly over 15 min, keeping the internal temperature below −60 °C.…”

“…Such studies also have importance for data input in computational log P calculation efforts. , While every structural modification of a compound will affect its log P value, fluorine introduction has proven to be particularly useful in this regard, mainly due to a combination of its very strong electronegativity and its small size . Initiated by the seminal work of Müller and colleagues, − the influence of aliphatic chain fluorination on lipophilicities has been investigated by a number of groups, for example, by investigating new motifs − and introduction of fluorine on aliphatic systems − or in amino acid side chains. − …”