Intramolecular hydrogen bonding involving fluorine atom

Abstract

The present proposal intents to study the strength of intramolecular hydrogen bonds involving fluorine atom and its effect in the conformational preference of fluorinated amino alcohols. The BEPE project was motivated by the results obtained in the project (FAPESP 2018/02634-0) involving compound trans-2-((2-fluorophenyl)amino)-cyclohexanol. A long range JHF coupling between the fluorine atom and the hydrogen of amino group was experimentally measured in this compound. In order to evaluate the contributions through space (intramolecular hydrogen bonding) and through chemical bond to the JHF coupling constant, some non-symmetric derivatives will be synthesized during the BEPE internship, such as trans-2-((2,6-difluoro-3-X-phenyl)amino)cyclohexanol (where X can be F, Cl, Br, or CH3). The confirmation of the existence of intramolecular hydrogen bonding involving fluorine atom can be ascertained whether JFH coupling constants will be different for fluorine atoms at position 2 and 6 on aromatic ring. In addition, other non-symmetric compounds, such as trans-2-((2-fluoro-6-X-phenyl)amino)cyclohexanol (X= Cl or Br), will be synthesized to study the competition (strength) between N-H---F, N-H---Cl and N-H---Br intramolecular hydrogen bonding. For this purpose, Nuclear Magnetic Resonance Spectroscopy will be used to characterize the compounds through their 1H, 13C, 19F and 1H{19F} spectra and from 2D experiments such as COSY, 1H-13C HSQC, 1H-15N HSQC, 1H-13C HMBC, 1H-19F HETCOR and 1H-19F HOESY, and a pseudo 3D experiment called PSYCHEDELIC. After conclusion of the BEPE project, calculations of the electronic structure and NBO (Natural Bond Orbital) and NCI (Non-Covalent Interaction) analyzes will be carried out to verify the strength of possible intramolecular hydrogen bonds as well as other stereoelectronic interactions involved on conformational preference. (AU)