Complex conformational surfaces in fluorine substituted molecules and biomolecules

Fluorine substitution in molecules is a common practice in bio-organic chemistry in order to modulate physicochemical properties and biological activity of molecules and an increasing number of drugs on the market contain fluorine, the presence of which is often of major importance to modify pharmacokinetics properties and molecular activity. The rationale for such a strategy is that fluorine is generally a stronger electron acceptor than the other halogen atoms and its size is intermediate between that of hydrogen and oxygen. Moreover its electronic properties (high electronegativity and low polarisability) can produce an effect on the solubility and lipophilicity of fluorinated drugs but it can also increase the stability of an active conformation or change the electronic properties. We present the results obtained on two fluorinated analogs of phenylethylamine (PEA), the prototype molecule for adrenergic neurotransmitters, namely: 4-Fluoro (4FPEA) and 2-Fluoro-2-phenylethylamine (2FPEA) studied by Molecular Beam Fourier Transform Microwave Spectroscopy in the frequency range 6-18 GHz and ab initio calculations. These results show how non-bonding interactions compete to shape the complex conformational space of these molecules and how these interactions can change drastically through substitution of even a single atom.