Determination of absolute configuration remains a difficult undertaking, one usually solved by x-ray crystallography. In my book (Chapter 1.6.3) and blog (see these posts) I have noted the use of computations in conjunction with optical rotation or electronic circular dichroism as an alternative: possible configurations are optimized and their optical properties are computed and then matched against experimental spectra.

Neri and coworkers have utilized this approach to determine the absolute configuration of the chiral calix[4]arene 1.1

Computed optical rotations (TDDFT/B3LYP/6-31G* at 5 frequencies) are compared with experimental values in Table 1. While the magnitude is off (as is typical) the sign of the activity along with the trend matches up very well for the cS configuration shown in Figure 1. It should be noted that a second conformation makes up about 10% of the Boltzmann population, and the contribution of this second configuration is included in the computed values shown in Table 1. In addition, computations at higher levels give very similar results. Lastly, the computed ECD spectrum of the cS isomer also matches up well with experiment.

Table 1. Optical rotation of the cS isomer of 1 compared with experiment

Wavelength (nm)

Experiment

Computed

589.3

108

58.8

577

120

61.7

546

140

70.2

435

264

122.6

405

367

147.6

Figure 1. B3LYP/6-31G* optimized structure of the major conformation of 1.

Given the relatively low level of theory employed here, further use of this combined experimental/computational approach to obtaining absolute configurations of large molecules is encouraged.

References

(1) Talotta, C.; Gaeta, C.; Troisi, F.; Monaco, G.; Zanasi, R.; Mazzeo, G.; Rosini, C.; Neri, P., "Absolute Configuration Assignment of Inherently Chiral Calix[4]arenes using DFT Calculations of Chiroptical Properties," Org. Lett., 2010, 12, 2912-2915, DOI: 10.1021/ol101098x

InChIs

1: InChI=1/C59H78O7/c1-16-19-64-53-36-22-35-32-47(59(13,14)15)50(51-48(61)33-45(60)34-49(51)62)46(52(35)63)31-41-30-44(58(10,11)12)29-40(55(41)66-21-18-3)24-39-28-43(57(7,8)9)27-38(54(39)65-20-17-2)23-37(53)26-42(25-36)56(4,5)6/h25-30,32-34,60-63H,16-24,31H2,1-15H3
InChIKey=VGWOVZXMYMCPQO-UHFFFAOYAS