Determination of absolute configurations of chiral molecules using ab initio time-dependent Density Functional Theory calculations of optical rotation: how reliable are absolute configurations obtained for molecules with small rotations?

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.

Determination of the absolute configuration of [3(2)](1,4)barrelenophanedicarbonitrile using concerted time-dependent density functional theory calculations of optical rotation and electronic circular dichroism.

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.

Determination of absolute configuration using concerted ab Initio DFT calculations of electronic circular dichroism and optical rotation: bicyclo[3.3.1]nonane diones.

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.

Determination of absolute configuration using ab initio calculation of optical rotation.

Ab initio Density Functional Theory (DFT) calculations of transparent spectral region, discrete frequency specific rotations were used to assign the absolute configurations (ACs) of: 1, 2H-naphtho[1,8-bc]thiophene 1-oxide; 2, m-F-phenyl glycidic acid methyl ester; 3, o-Br-phenyl glycidic acid methyl ester; 4, p-CH(3)-phenyl glycidic acid methyl ester; 5, 2-(1-hydroxyethyl)-chromen-4-one; and 6, 6-Br-2-(1-hydroxyethyl)-chromen-4-one. The ACs of 5 and 6 were previously determined via X-ray crystallography to be: 5, R(-)/S(+); 6, R(+)/S(-). The ACs obtained using [alpha](D) are the same for both 5 and 6: R(+)/S(-). We conclude that the previously reported AC of 5 is incorrect.

Determination of absolute configuration using optical rotation calculated using density functional theory.

[structure: see text] We report the first determinations of the absolute configurations (ACs) of chiral molecules using discrete frequency, transparent spectral region optical rotations calculated using density functional theory (DFT). The ACs of 2H-naphtho[1,8-bc]thiophene 1-oxide (3), naphtho[1,8-cd]-1,2-dithiole 1-oxide (4), and 9-phenanthryl methyl sulfoxide (5) are determined by comparison of their specific rotations to values calculated via the time-dependent DFT/gauge-invariant atomic orbital (TDDFT/GIAO) methodology using the B3LYP functional and the aug-cc-pVDZ basis set.

Configurational and conformational analysis of chiral molecules using IR and VCD spectroscopies: spiropentylcarboxylic acid methyl ester and spiropentyl acetate.

The chiral monosubstituted derivatives of spiropentane, spiropentylcarboxylic acid methyl ester, 1, and spiropentyl acetate, 2, have been synthesized in optically active form. Configurational and conformational analysis of 1 and 2 has been carried out using infrared (IR) and vibrational circular dichroism (VCD) spectroscopies. Analysis of the experimental IR and VCD spectra has been carried out using ab initio density functional theory (DFT). For both 1 and 2, DFT predicts two populated conformations. Comparison to experiment of the conformationally averaged IR and VCD spectra of 1 and 2, predicted using DFT, provides unequivocal evidence of the predicted conformations and yields the absolute configurations R(-)/S(+) for 1 and R(+)/S(-) for 2. These absolute configurations are consistent with the R(-)/S(+) absolute configuration of spiropentylcarboxylic acid, assigned previously via X-ray crystallography of its alpha-phenylethylammonium salt.

Ab initio prediction of optical rotation: comparison of density functional theory and Hartree-Fock methods for three 2,7,8-trioxabicyclo[3.2.1]octanes.

We report ab initio calculations of the frequency-dependent electric dipole-magnetic dipole polarizabilities, beta(nu), at the sodium D line frequency and, thence, of the specific rotations, [alpha](D), of 2,7,8-trioxabicyclo[3.2.1]octane, 1, and its 1-methyl derivative, 2, using the Density Functional Theory (DFT) and Hartree-Fock/Self-Consistent Field (HF/SCF) methodologies. Gauge-invariant (including) atomic orbitals (GIAOs) are used to ensure origin-independent [alpha](D) values. Using large basis sets which include diffuse functions DFT [alpha](D) values are in good agreement with experimental values (175.8 degrees and 139.2 degrees for (1S,5R)-1 and -2, respectively); errors are in the range 25-35 degrees. HF/SCF [alpha](D) values, in contrast, are much less accurate; errors are in the range 75-95 degrees. The use of small basis sets which do not include diffuse functions substantially lowers the accuracy of predicted [alpha](D) values, as does the use of the static limit approximation: beta(nu) approximately beta(o). The use of magnetic-field-independent atomic orbitals, FIAOs, instead of GIAOs, leads to origin-dependent, and therefore nonphysical, [alpha](D) values. We also report DFT calculations of [alpha](D) for the 1-phenyl derivative of 1, 3. DFT calculations find two stable conformations, differing in the orientation of the phenyl group, of very similar energy, and separated by low barriers. Values of [alpha](D) predicted using two different algorithms for averaging over phenyl group orientations are in good agreement with experiment. In principle, the absolute configuration (AC) of a chiral molecule can be assigned by comparison of the optical rotation predicted ab initio to the experimental value. Our results demonstrate the critical importance of the choice of ab initio methodology in obtaining reliable optical rotations and, hence, ACs, and show that, at the present time, DFT constitutes the method of choice.

Is N-protonated hydrogen isocyanide, H2NC+, an observable interstellar species?

Ab initio molecular orbital theory is used to examine the singlet and triplet potential energy surfaces for the CH2N+ system. The results confirm those of earlier studies which suggested that the singlet H2NC+ isomer could be formed via the corresponding triplet isomer. Also, it is shown that the reaction HCN+ + H2 might lead to this metastable isomer without invoking the triplet species. The best test of the hypothesis that this molecule can be formed by gas phase, ion molecule reactions and may be an important precursor in the interstellar synthesis of HCN and HNC is to search for it in space. To this end, theoretical predictions are made of its rotational frequencies and its vibrational frequencies and intensities to serve as a guide to laboratory spectroscopists and radioastronomers.

Dilatation and evacuation procedures and second-trimester abortions. The role of physician skill and hospital setting.

Some clinicians have hesitated to perform dilatation and evacuation (D & E) procedures at 13 weeks' gestation or later because D & Es are more difficult to perform safely than suction-curettage procedures. Moreover, many clinicians still believe all second-trimester abortion procedures should be performed in a hospital. To evaluate these concerns, we analyzed 24,664 abortion performed between 1973 and 1978 by four physicians associated with a large outpatient abortion facility; 3,711 (15%) of the abortions were second-trimester procedures. Dilatation and evacuation was associated with a lower rate of serious complications per 100 procedures (0.23) than instillation of either dinoprost (prostaglandin F2 alpha) (1.28) or hypertonic saline (2.26). In addition, D & E had lower rates for most other specific complications. We conclude that D & E, while requiring more operator skill than earlier suction-curettage procedures, can be learned by gynecologists familiar with suction-curettage, can be performed more safely than the alternative instillation procedures, and can be safely practiced in selected ambulatory settings.

PIP: Continuing controversies have surrounded the emergence of dilatation and evacuation procedures as a method of performing 2nd trimester abortions. To evaluate concerns relating to 2nd trimester abortions, the 6 year experience between 1973-1978 of a labor abortion facility in the midwest, staffed by 4 physicians, was analyzed. Due to the fact that focus was on 1 specific practice, the situation of comparing different case series results among different institutions was avoided. Additionally, the facility served women from the same locality and socioeconomic stratum throughout the study interval. By restricting analysis to 1 group of physicians, variations in operator technique were controlled for, thus reducing the potential biases resulting from clinicians with different levels of training, experience, and innate skill. Excluding abortions performed concurrnetly with sterilization, the Meadowbrook Women's Clinic (MWC) in Minneapolis performed 24,664 abortion procedures during the 6-year study interval. At 12 week's gestation or earlier, 20,953 (84% of the total) were performed by suction curettage. At 13 weeks' gestation or later, 2204 (9%) were by dilatation and evacuation, 884 (4%) by saline instillation, and 623 (3%) by dinoprost instillation accounted for almost all abortions at 13 week's gestation or later. The overall serious complication rate for procedures at MWC was low. Approximately 1 in 400 dilatation and evacuation procedures, 1 in 80 dinoprost instillation procedures, and 1 in 40 saline instillation procedures led to temperature greater than 38 degrees Centigrade for more than 3 days, hemorrhage requiring transfusion, or unintended abdominal surgery. Fewer than 1 in 1000 women undergoing a suction curettage procedure suffered serious complications. Of those procedures available at 13 weeks' gestation or later, dilatation and evacuation was the safest. Compared with dinoprost instillation, dilatation and evacuation was associated with significantly lower rates of serious complications, hemorrhage, retained products of conception, re-evacuation, endometritis, and febrile morbidity. Even when performed at 17 weeks' gestation or later, dilatation and evacuation had a lower rate of serious complications than either dinoprost or saline instillation, although only significantly so for the latter. Dilatation and evacuation had a slightly higher rate of cervical injury, although this was not statistically significant. At MWC, neither gestational age, the physician, nor the type of facility had a great effect on the relatively low risks of dilatation and evacuation.

Endometrial abnormalities occurring in young women on long-term sequential oral contraception.

Recently the occurrence of adenocarcinoma of the endometrium has been reported in young women exposed to sequential oral contraceptive agents for long periods of time. Twelve young women who had been using Oracon for periods of from 13 to 93 months were subjected to office endometrial aspirations. Tissue specimens showed endometrium which varied in diagnosis from proliferative endometrium to severe atypical adenomatous endometrial hyperplasia bordering on endometrial carcinoma in situ. Adenomatous endometrial hyperplasia is though by many investigators to be a precancerous condition. The progression of endometrial changes from benign proliferation to cystic hyperplasia and adenomatous hyperplasia accompanied by varying degrees of anaplasia in young women exposed to Oracon for long periods of time is significant. It is not surprising, therefore, that adenocarcinoma of the endometrium has been reported in these women at an age where this condition had been relatively uncommon prior to the use of sequential oral contraceptives.