DFT computational studies of hydrogen bonding-based diastereomeric complexes - Limitations and applications to enantiodifferentiation

Molecular modeling calculations using DFT at the B3LYP/6-31G(d,p) level of theory have been performed on diastereomeric complexes formed between chiral carboxylate anions and chiral urea receptors, a combination previously demonstrated to enable enantiodifferentiation by electrochemical sensing. The calculations correctly predicted the stability order of the enantiomers in acetonitrile solution when the distinction between the enantiomers was above the declared threshold reliability value of 1 kcal mol−1 for computations at this level of theory. Thus, the calculations can not only be applied to predict the likely success of undertakings using the analytical method, it can also, provided ΔE is sufficient, potentially be used to determine the absolute configuration of chiral analytes with at least the racemate in hand. The previously successful enantiodifferentiations of various amino acids and alcohols using chiral ion mobility spectroscopy (CIMS) with (S)-2-butanol as the chiral selector were also evaluated by DFT calculations. The calculations again correctly predicted the stability order of the enantiomers when the calculated ΔE was above the threshold value though cases not providing a value for ΔE above the threshold value was problematic for this system. Attempts to address this shortcoming included an expanded conformational evaluation, a broader analytical approach, and an extended basis set.