Determination of the absolute configuration of conformationally flexible molecules by simulation of chiro-optical spectra: a case study

The assignment of the absolute configuration (AC) of two conformational flexible organic molecules by means of TD-DFT simulation of the electronic circular dichroism (ECD) spectra is presented. The factors leading to a reliable assignment were evaluated in the various steps of the process. The effects of different functionals and basis sets in the geometry optimization step is very limited in terms of the resulting optimized geometries, whereas the inclusion of the solvent in the calculations has a much larger effect on the correct evaluation of the conformational ratio. B3LYP and M06-2x were found to be the most accurate functionals for geometry optimization. CAM-B3LYP and ωB97X-D provided the best results in the TD-DFT simulations.

Boltzmann weighted calcd. 3 J values 3.9 13.0 5.4 11.7 5.4 11.6 3.8 13.0 Experimental values 3.9 11.9 3.9 11.9 3.9 11.9 3.9 11.9 _____________ a These values are the contributions to the weighted J value of each conformation, i.e. the calculated J value multiplied for the population.

Table S2
Relative energies of the best thirteen conformations of 1a calculated with B3LYP using two different basis sets, with or without the solvent (IEF-PCM). Relative energies in kcal/mol. The columns reporting the enthalpies (H°) are those of    Table 2 of the main text. Figure S7. Example of ECD simulations of the thirteen conformations of 1a, obtained at the TD-CAM-B3LYP/6-311++G(2d,p)//PCM-B3LYP/6-311++G(2d,p) level. Figure S8. TD-DFT simulations obtained at the CAM-B3LYP/6-311++G(2d,p) level using the four geometries optimized by B3LYP, using the 6-31G(d) and 6-311++G(2d,p) basis sets, in both the gas phase and including the solvent acetonitrile. Figure S9. ECD simulation for the conformations of 1a. The number in each quadrant is the conformation label; the four colored lines are the ECD spectra obtained by TD-DFT at the CAM-B3LYP level of theory using four basis sets (top-left quadrant). Optimized geometries at the PCM-B3LYP/6-311++G(2d,p) level.                 . UV simulations for 1a using the geometries obtained by the reported functional and the 6-311++G(2d,p) basis set. The simulated spectrum was obtained by using the conformational ratio derived from the energies of Table 4. Figure S27. UV simulations for 1a using the geometries obtained by the reported functional and the 6-311++G(2d,p) basis set. The simulated spectrum was obtained by using the conformational ratio derived from the energies of Table 4. Figure S28. UV simulations for 1b using the geometries obtained by the reported functional and the 6-311++G(2d,p) basis set. The simulated spectrum was obtained by using the conformational ratio derived from the energies of Table 4. Figure S29. UV simulations for 1b using the geometries obtained by the reported functional and the 6-311++G(2d,p) basis set. The simulated spectrum was obtained by using the conformational ratio derived from the energies of Table 4. Figure S30. TD-DFT simulations (colored traces) of the experimental ECD spectrum (black trace) of 1a. Simulated spectra were red-shifted and scaled to have the best match with the experimental spectrum, as from the table. Similarity factor were obtained with SpecDis software.  Figure S31. TD-DFT simulations (colored traces) of the experimental ECD spectrum (black trace) of 1b. Simulated spectra were red-shifted and scaled to have the best match with the experimental spectrum, as from the table. Similarity factor were obtained with SpecDis software.

Crystal data for compound 1a
A specimen of C 17 H 20 ClNO 3 , approximate dimensions 0.250 mm x 0.400 mm x 0.400 mm, was used for the X-ray crystallographic analysis. The X-ray intensity data were measured. The total exposure time was 16.55 hours. The frames were integrated with the Bruker SAINT software package using a narrow-frame algorithm. The integration of the data using an orthorhombic unit cell yielded a total of 5581 reflections to a maximum θ angle of 26.00° (0.81 Å resolution), of which 3184 were independent (average redundancy 1.753, completeness = 97.9%, R int = 1.70%, R sig = 2.79%) and 2977 (93.50%) were greater than 2σ(F 2 ). The final cell constants of a = 10.0517(8) Å, b = 11.1214(9) Å, c = 15.3258(14) Å, volume = 1713.3(2) Å 3 , are based upon the refinement of the XYZ-centroids of 9921 reflections above 20 σ(I) with 4.530° < 2θ < 70.17°. Data were corrected for absorption effects using the Multi-Scan method (SADABS). The ratio of minimum to maximum apparent transmission was 0.903. The calculated minimum and maximum transmission coefficients (based on crystal size) are 0.9120 and 0.9440. The structure was solved and refined using the Bruker SHELXTL Software Package, using the space group P 21 21 21, with Z = 4 for the formula unit, C 17 H 20 ClNO 3 . The final anisotropic full-matrix least-squares refinement on F 2 with 208 variables converged at R1 = 3.32%, for the observed data and wR2 = 8.39% for all data. The goodness-of-fit was 1.036. The largest peak in the final difference electron density synthesis was 0.167 e -/Å 3 and the largest hole was -0.191 e -/Å 3 with an RMS deviation of 0.027 e -/Å 3 . On the basis of the final model, the calculated density was 1.248 g/cm 3 and F(000), 680 e -. Flack parameter for the 9R,10R absolute configuration: 0.03(2). CCDC 1897062 contains the full data. Absorption coefficient 0.234 mm -1 F(000) 680 Table 2. Data collection and structure refinement for mazza1802.
Theta range for data collection 2.26 to 26.00° Table 3. Atomic coordinates and equivalent isotropic atomic displacement parameters (Å 2 ) for mazza1802.
U(eq) is defined as one third of the trace of the orthogonalized U ij tensor.
x/a y/b z/c U(eq) Cl01 0.82987 (7) 0.65765 (7) 0.54100 (5)     Crystal data for compound 2b A specimen of C 17 H 20 ClNO 3 , approximate dimensions 0.100 mm x 0.100 mm x 0.300 mm, was used for the X-ray crystallographic analysis. The X-ray intensity data were measured. The total exposure time was 13.33 hours. The frames were integrated with the Bruker SAINT software package using a narrow-frame algorithm. The integration of the data using an orthorhombic unit cell yielded a total of 24496 reflections to a maximum θ angle of 27.25° (0.78 Å resolution), of which 3897 were independent (average redundancy 6.286, completeness = 99.5%, R int = 3.31%, R sig = 2.23%) and 3445 (88.40%) were greater than 2σ(F 2 ). The final cell constants of a = 9.9020(12) Å, b = 19.022(2) Å, c = 9.2904(11) Å, volume = 1749.9(4) Å 3 , are based upon the refinement of the XYZ-centroids of 9886 reflections above 20 σ(I) with 4.384° < 2θ < 53.59°. Data were corrected for absorption effects using the Multi-Scan method (SADABS). The ratio of minimum to maximum apparent transmission was 0.866. The calculated minimum and maximum transmission coefficients (based on crystal size) are 0.9340 and 0.9770. The structure was solved and refined using the Bruker SHELXTL Software Package, using the space group P 21 21 21, with Z = 4 for the formula unit, C 17 H 20 ClNO 3 . The final anisotropic full-matrix least-squares refinement on F 2 with 207 variables converged at R1 = 4.31%, for the observed data and wR2 = 11.45% for all data. The goodness-of-fit was 1.063. The largest peak in the final difference electron density synthesis was 0.162 e -/Å 3 and the largest hole was -0.223 e -/Å 3 with an RMS deviation of 0.035 e -/Å 3 . On the basis of the final model, the calculated density was 1.221 g/cm 3 and F(000), 680 e -. Flack parameter for the C006S,C00BR absolute configuration: 0.04(2). CCDC 1897063 contains the full data.  Table 3. Atomic coordinates and equivalent isotropic atomic displacement parameters (Å 2 ) for mazza1801.
U(eq) is defined as one third of the trace of the orthogonalized U ij tensor.