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The absolute configuration (AC) of a chiral molecule can be determined via calculation of its specific rotation. Currently, the latter is most accurately carried out using the TDDFT/GIAO methodology. Here we examine the reliability of this methodology in determining ACs of molecules with small specific rotations. We report TDDFT/GIAO B3LYP/aug-cc-pVDZ//B3LYP/6-31G* calculations of the sodium D line specific rotations, [alpha]D, of 65 conformationally rigid chiral molecules whose experimental [alpha]D values are small (<100). The RMS deviations, sigma, of calculated and experimental [alpha]D values is 28.9. The distribution of deviations is approximately Gaussian, i.e., random. For eight molecules, more than 10% of the set, the sign of the predicted [alpha]D is incorrect. In determining an AC of a rigid molecule from [alpha]D with 95% confidence, the calculated [alpha]D value must lie within +/-2sigma of the experimental [alpha]D for one, but not both, of the possible ACs. For the 65 molecules of this study +/-2sigma is 57.8. For conformationally flexible molecules, the error bar is +/- >57.8.

Unraveling the reaction mechanism of extremely complex catalytic processes can be a challenging task from a purely experimental viewpoint. For an industrially important process like the conversion of methanol into olefins (MTO), [1] this is especially the case, as secondary reactions often consume and mask the primary products. Methanol is easily and economically converted into olefins over solid acid zeolite catalysts, yet the ease of MTO conversion is in stark contrast to the difficulty of elucidating the underlying mechanism.[1] Instead of plainly following direct routes, [2][3][4][5] the MTO process has been found to proceed through a hydrocarbon pool mechanism, in which organic reaction centers act as co-catalysts inside the zeolite pores, adding a whole new level of complexity to this issue. [6][7][8][9] Therefore, a detailed understanding of the elementary reaction steps can best be obtained with the complementary assistance of theoretical modeling. Several experimental observables add to the theoreticians challenge: any full catalytic cycle should not only provide low-energy pathways towards olefin formation, but it should also explain the zeolite-specific product distribution. Furthermore, it should contain the cationic intermediates as observed by in situ NMR spectroscopic methods, [7,10,11] as well as an explanation for the scrambling of labeled carbon atoms into both the hydrocarbon pool species and the olefin products. [7, 9,12] Herein, we report a working catalytic cycle for the conversion of methanol into olefins, in full consistency with both experimental and theoretical observations. For each step, rate constants are presented which were obtained by quantum chemical simulations on a supramolecular model of both the HZSM-5 zeolite and the co-catalytic hydrocarbon pool species (see Methods section). This work not only represents the most robust computational analysis of a successful MTO route to date, but it also succeeds in tying together the many experimental clues.

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The determination of the absolute configurations (ACs) of chiral molecules using the chiroptical techniques of optical rotation (OR), electronic circular dichroism (ECD), and vibrational circular dichroism (VCD) has been revolutionized by the development of density functional theory (DFT) methods for the prediction of these properties. Here, we demonstrate the significance of these advances for the stereochemical characterization of natural products. Time-dependent DFT (TDDFT) calculations of the specific rotations, [alpha](D), of four cytotoxic natural products, quadrone (1), suberosenone (2), suberosanone (3), and suberosenol A acetate (4), are used to assign their ACs. TDDFT calculations of the ECD of 1 are used to assign its AC. The VCD spectrum of 1 is reported and also used, together with DFT calculations, to assign its AC. The ACs of 1 derived from its [alpha](D), ECD, and VCD are identical and in agreement with the AC previously determined via total synthesis. The previously undetermined ACs of 2-4, derived from their [alpha](D) values, have absolute configurations of their tricyclic cores identical to that of 1. Further studies of the ACs of these molecules using ECD and, especially, VCD are recommended to establish more definitively this finding. Our studies of the OR, ECD, and VCD of quadrone are the first to utilize DFT calculations of all three properties for the determination of the AC of a chiral natural product molecule.

The concerted use of ab initio time-dependent density functional theory (TDDFT) calculations of transparent spectral region optical rotation and of circular dichroism has recently become practicable, permitting the concerted use of transparent spectral region optical rotation and circular dichroism in determining the absolute configurations of chiral molecules. Here, we report concerted TDDFT calculations of the transparent spectral region specific rotations and of the circular dichroism spectra originating in n --> pi C=O group excitations of four bicyclo[3.3.1]nonane diones, 1-4. Comparison to experiment yields absolute configurations for 1-4. For each dione, specific rotations and circular dichroism spectra give identical absolute configurations. Our results are consistent with previous work, with the exception of the Octant Rule-derived absolute configuration of the 2,9-dione.

The technique of time-dependent density functional theory (TDDFT) has very recently been applied to the calculation of both transparent spectral region optical rotations and electronic circular dichroism (CD). Here, we report the concerted application of the new methodologies to the determination of the absolute configuration (AC) of [3(2)](1,4)barrelenophanedicarbonitrile, 1, the first optically active barrelenophane. 1 is conformationally flexible: the two three-carbon bridges of 1 can each exhibit two conformations, leading to three inequivalent conformations of 1: a, b, and c. Conformational structures and energies are predicted using DFT at the B3LYP/6-31G level. Comparison of the calculated structures to structures obtained via X-ray crystallography of (+)-1 shows that (remarkably) all three conformations a-c are simultaneously present in crystalline (+)-1. The sodium D line specific rotations, [alpha](D), and CD spectra of a-c are calculated using TDDFT at the B3LYP/aug-cc-pVDZ level. Comparison of the conformationally averaged specific rotation and CD spectrum to the experimental data of Matsuda-Sentou and Shinmyozu leads to the AC 9S,12S(+)/9R,12R(-). The same AC is obtained both from [alpha](D) and from the CD, strongly supporting its reliability.

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