Effects of Replacing Oxygenated Functionality with Fluorine on Lipophilicity

Abstract

The replacement of oxygenated functionality (hydroxy and alkoxy) with a fluorine atom is a commonly used bioisosteric replacement in medicinal chemistry. In this paper, we use molecular matched-pair analysis to better understand the effects of this replacement on lipophilicity. It seems that the reduced log P of the oxygenated compound is normally dominant in determining the size of this difference. We observe that the presence of additional electron-donating groups on an aromatic ring generally increases the difference in lipophilicity between an oxygenated compound and its fluorinated analogue, while electron-withdrawing groups lead to smaller differences. Ortho-substituted compounds generally display a reduced difference in log P compared to para- and meta-substituted compounds, particularly if an ortho-substituent can form an intramolecular hydrogen bond. Hydrogen-bond acceptors remote to an aromatic ring containing fluorine/oxygen can also reduce the difference in log P between oxygen- and fluorine-substituted compounds.

A General and Efficient Solution to Monofluoroalkylation: Divergent Synthesis of Aliphatic Monofluorides with Modular Synthetic Scaffolds

“…Next, to have a deeper understanding on the functional group tolerance, a series of substituted aryl ethers were synthesized and tested. Excitingly, moderate to good yields were obtained with olefins substituted with electron-withdrawing or electrondonating groups, including methyl (8), ether (9), halide (10,11), cyano (12), aldehyde (13) and ester ( 14) on the phenyl rings. Moreover, the unactivated alkenes installed with heteroarenes such as furan (17) and N-phthalimide (21) reacted efficiently in this reaction, affording the desired products in 52 %-78 % yields.…”

Recent advances in transition-metal catalyzed directed C–H functionalization with fluorinated building blocks

“…5-fluorouracil 2 (5-FU), possessing remarkable antitumor activity in 1957 led to a surge in the introduction of fluorine atoms into organic scaffolds. Since the incorporation of fluorine atoms has the ability to alter several important properties like changes in pK a , lipophilicity, metabolic stability, bioavailability and electrostatic interactions, organofluorine compounds are widely used in many areas, such as pharmaceuticals, [3][4][5][6][7][8][9][10][11][12][13] agrochemicals, [14][15][16] and materials science. 17 It is estimated that around 25% of marketed pharmaceuticals and 30% of all agrochemicals contain at least one fluorine atom within their structures.…”

A General and Efficient Solution to Monofluoroalkylation: Divergent Synthesis of Aliphatic Monofluorides with Modular Synthetic Scaffolds

“…In particular, the fluorine replacement could tremendously improve the metabolic stability, lipophilicity, and bioavailability of the original compounds, thus offering highly appealing solutions to design and development of pharmaceuticals, agriculture chemicals, and special materials (Figure 1a). [1][2][3][4][5][6][7][8][9][10][11][12] Significant advances have been made in developing novel methods for accessing various organofluorine compounds, [13][14][15][16][17][18] especially monofluorinated arenes and alkanes which have seen increasing presence in fluorine-containing drugs, etc. over the past few decades.…”

“…The strategic incorporation of the fluorine atom into organic molecules to replace a hydrogen atom represents a vital tactic to improve the chemical, physical and biological properties of parent molecules. In particular, the fluorine replacement could tremendously improve the metabolic stability, lipophilicity, and bioavailability of the original compounds, thus offering highly appealing solutions to design and development of pharmaceuticals, agriculture chemicals, and special materials (Figure 1a) [1–12] . Significant advances have been made in developing novel methods for accessing various organofluorine compounds, [13–18] especially monofluorinated arenes and alkanes which have seen increasing presence in fluorine‐containing drugs, etc.…”