Specific Optical Rotation and Absolute Configuration of Flexible Molecules Containing a 2‐Methylbutyl Residue

Abstract

Establishing the absolute configuration of flexible molecules is difficult, and specific optical rotation (SOR) might be an optional strategy. However, complex conformation distributions inevitably generate ambiguous results. Herein, the relationship between SORs and the absolute configuration of flexible molecules containing a 2‐methylbutyl residue was studied using quantum chemical calculations. The existence of a nitrogen atom might increase the uncertainty of the predicted SOR. Compared with the optical rotation calculation step, the geometry optimization step is more influential. Computational parameters including hybrid functionals, basis sets, and solvation models could exert a great effect on the Boltzmann distribution, leading to substantial variation in the SORs. To achieve unambiguous SOR prediction results for flexible molecules, the calculation needs to be performed using at least two combinations of different levels.

Stereochemistry of Chiral 2-Substituted Chromanes: Twist of the Dihydropyran Ring and Specific Optical Rotation

“…Although DFT and TDDFT calculations of chiroptical spectroscopy have been regarded as powerful tools for AC assignment of chiral molecules [ 18 ], ambiguous results are often encountered. As shown in our previous work and other reports [ 33 , 86 ], the uncertainty mainly arose from the conformational distribution, which might affect the overall SOR values, as well as the ECD and VCD spectra. The correlation of SORs and C2 stereochemistry described in this study has the advantages of being much more facile, less time-consuming, and less dependent on accurate conformational analysis.…”

“…As shown for compounds 33-47 (Figure 5), esterification or amidation of 2-carboxylic acid (37)(38)(39)(40)(41)(42), halogen (33,35,36,(38)(39)(40)47), methoxy (34,41) and amine (45) groups at C6 exerted little effect on the correlation (Figure 5). Nevertheless, 2-hydroxamic acid (43) or the 8-amine group (46) would invert the correlation.…”

“…Both quantum-chemical calculations using density functional theory (DFT) and mechanistic analyses were conducted to verify the association between the helicity of the dihydropyran ring and the sign of the SORs of chiral 2-substituted chromanes. Since different computational approaches might yield misleading results [ 33 ], several combinations of computational parameters, B3LYP [ 34 ]/Aug-cc-pVDZ [ 34 ]//B3LYP/6-311G(d,p) (the BL approach) and M06-2X [ 35 ]/Aug-cc-pVDZ//M06-2X/TZVP (the M6 approach), together with the polarized continuum model (PCM) [ 36 ] or solvation model based on density (SMD) [ 37 ] were tested to compare their uniformity.…”

“…This hypothesis was confirmed by comparison with the [α] D value of compound 32 (R configuration, [α] D −6.3) because of the minor effect of the 6-methyl group. Since the BH approach was shown to be favorable for 2-carboxylic acid chromanes (32)(33)(34)(35)(36), the SOR value of compound 78 calculated using this approach was regarded as more reliable and had the same sign as the predicted SOR value, according to the correlation. The assignment according to the correlation is very convenient and could be performed in minutes by a nonexpert.…”

Computational methods and points for attention in absolute configuration determination

“…Finally, an important phenomenon should be noted. Many linear chiral compounds have only very small OR values (Lu et al, 2020). In these cases, it is common to use quantum methods to compute OR values to assign AC unless there is a so-called known analogue's OR (theoretical and experimental OR values used as reference).…”