# Conformational analysis of difluoromethylornithine: factors influencing its gas-phase and bioactive conformations

## TL;DR

This paper studies how fluorine affects the shape of DFMO, a drug used to treat African trypanosomiasis, and explains why certain molecular conformations are more stable.

## Contribution

The study reveals that the fluorine gauche effect in DFMO is driven by hyperconjugative stabilization and is modulated by steric and electrostatic effects.

## Key findings

- Type-I conformers dominate due to the fluorine gauche effect and hyperconjugative stabilization.
- Steric effects influence the relative stability of low-energy conformers.
- The bioconformation of DFMO in crystallographic data is a type-II structure due to hydrogen bonding.

## Abstract

Difluoromethylornithine (DFMO, eflornithine) is a fluorinated analogue of ornithine that serves both as an inhibitor of ornithine decarboxylase and as a therapeutic agent against African trypanosomiasis. Beyond its pharmacological importance, DFMO provides a valuable model for examining how fluorine substitution governs molecular conformation. A comprehensive quantum-chemical study was performed to elucidate the origins of DFMO’s conformational stability. High-level DLPNO-CCSD(T)/CBS calculations revealed that type-I conformers – those maximizing gauche interactions between C–F and C–N bonds – dominate the equilibrium population, confirming the presence of the fluorine gauche effect. natural bond orbital (NBO) analysis showed that this preference arises primarily from hyperconjugative stabilization, particularly the σCH → σ*CN interaction, while steric effects modulate the relative stability among low-energy conformers. The gauche effect is intensified in the zwitterionic form due to electrostatic interactions. In contrast, the bioconformation observed in crystallographic data corresponds to a type-II structure, imposed by strong hydrogen bonding of the amino and carboxyl groups with surrounding residues. Thus, DFMO’s intrinsic conformational preferences are dictated by stereoelectronic effects, but these can be overridden by specific intermolecular interactions in biological environments. This study clarifies the electronic origin of DFMO’s gauche effect and provides insight into how local electronic factors determine the structure of fluorinated amino acid derivatives.