Halogen bond in high-performance liquid chromatography enantioseparations: Description, features and modelling

Area of Science:

• Analytical Chemistry
• Organic Chemistry
• Computational Chemistry

Background:

• Halogen bonding (XB) utilizes electrophilic σ-holes on halogens for molecular recognition.
• XB-driven enantioseparation is an emerging field, with limited understanding of underlying mechanisms.
• Previous work demonstrated the role of electrophilic halogens (Cl, Br, I) in enantioseparation.

Purpose of the Study:

• Investigate unexplored aspects of XB-driven chiral recognition mechanisms.
• Develop a theoretical model for predicting enantiomer elution orders (EEOs).
• Analyze the interplay of halogen bonding and hydrogen bonding in competitive chiral recognition systems.

Main Methods:

• 32 molecular dynamic (MD) simulations using polyhalogenated 4,4'-bipyridines and polysaccharide-based polymers.
• Calculation of enantiomer elution orders (EEOs) from simulation data.
• Theoretical re-examination of Pirkle's enantioseparations and computation of electrostatic potentials (EPs).
• Experimental enantioseparation of halogenated 2-nitro-1-arylethanols on cellulose tris(3,5-dimethylphenylcarbamate) (CDMPC).

Main Results:

• A theoretical model was developed that accounts for experimental EEO inversions.
• The study compared the strength of σ-holes and hydrogen bond centers in competitive recognition.
• Correlation between theoretical predictions and experimental data for halogenated 2-nitro-1-arylethanols was established.
• The influence of halogen substituents on chromatographic results was evaluated.

Conclusions:

• Halogen bonding is a key driver in enantioseparation, offering predictable chiral recognition.
• Computational methods, including MD simulations, are valuable tools for understanding and predicting enantioseparation behavior.
• The findings provide a deeper mechanistic insight into XB-driven enantioseparation, aiding in the design of chiral stationary phases and separation strategies.