Why is fluorine so attractive to medicinal chemists?

In medicinal chemistry, fluorine substitution of alkyl or aryl hydrogen is an increasingly popular strategy to optimize lead compounds. Fluorine offers unique properties. It is almost as small as a hydrogen but very electronegative. The C-F bond is highly polarized.

Conformation effect of fluorine

The polarity of the C-F bond influences the conformation of aliphatic systems.

conformation_fluorine

It is generally accepted that fluorine can interact with hydroxyl, amine and amide functions through hydrogen bond interaction and induce specific conformation.

hydrogen_bond_fluorine

Influence on pKa, permeability and pharmacokinetic properties of fluorine

The electron-withdrawing properties of fluorine can reduce pKa of amines and make them less basic. The similar effect is observed on carboxylic acids and make them more acidic. The change in pKa will influence conformation, potency, permeability, and pharmacokinetic properties.

pKa of fluorinated acids, alcohols or amines

CH3CO2H      4.8       CH2FCO2H    2.6

(CH3)2CHOH 17.1     (CF3)2CHOH  9.3

CH3CH2NH2  10.7      CF3CH2NH2   5.7

Improve metabolic stability

Because of the strength C-F bond, fluorine substitution of a hydrogen is a common way to improve stability. It can be done in both aliphatic and aromatic systems. Fluorine will also increase metabolic stability of electron-rich aromatic ring.

 

Learn how to add fluorine in your lead compounds here.

 

Read more
Eric P. Gillis, Kyle J. Eastman, Matthew D. Hill, David J. Donnelly, and Nicholas A. Meanwell, Applications of Fluorine in Medicinal Chemistry, J. Med. Chem., 2015
http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b00258

 

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