Stereodynamics and absolute configuration of stereolabile atropisomers in 2,2-dimethyl-1-aryl-1-indanols.

We describe herein the investigation of the stereodynamic processes occurring in a series of 1-aryl-2,2-dimethylindanols, by dynamic NMR. When the aryl moiety is a mesityl or a 2-methyl-1-naphthyl, the rotational barrier exceeds the 25 kcal/mol, so that stable atropisomers are observed. In two cases, all the chiral-atropisomeric species have been separated by enantioselective HPLC, and the comparison between theoretical and experimental electronic circular dichroism spectra allowed the absolute configuration assignment of all the isolated species to be obtained.

Steric effects which determine the conformational preferences and stereodynamic processes of aryl fluorenyl ketones.

The stereodynamic processes and conformational preferences of two classes of aryl fluorenyl ketones have been investigated by means of dynamic NMR spectroscopy, DFT calculations and X-ray diffraction. When the aryl substituent has two hydrogens in the ortho positions, its rotation is independent of that of the fluorene ring. In contrast, if the two ortho hydrogens are replaced by the bulkier methyl groups (e.g. mesityl fluorenyl ketones), the motion of the aryl ring interacts with the fluorene, and the two rings rotate in a correlated manner.

Conformation and absolute configuration of 2-naphthylalkylsulfoxides by combined use of dynamic NMR, ECD spectroscopy, DFT computations, and X-ray diffraction.

The E/Z conformer ratios of five 2-naphtylalkylsulfoxides were determined by means of dynamic NMR spectroscopy at very low temperatures and this information was used to predict, by means of DFT calculations, the ECD spectra of the R and S enantiomers. The latter were separated by enantioselective HPLC technique and the comparison of theoretical and experimental ECD spectra allowed the absolute configurations to be determined. In the case of 2-naphtyl tert-butylsulfoxide (1), the assignment was independently confirmed by anomalous dispersion using single crystal X-ray crystallography.

Stereomutation of conformational enantiomers of 9-isopropyl-9-formylfluorene and related acyl derivatives.

Low-temperature NMR spectra show that the title compound exists as a pair of conformational enantiomers, generated by the restricted rotation about the C9-Pr (i) bond, the corresponding interconversion barrier being 6.9 kcal mol (-1). This interpretation is supported by theoretical (MM and DFT) calculations and by the experimental determination of the analogous barriers occurring in the related MeC=O and Bu(t)C=O derivatives.

Correlated rotations in benzylfluorene derivatives: structure, conformation, and stereodynamics.

Fluorene derivatives, having substituted benzyl groups bonded to position 9, have been investigated by variable temperature NMR spectroscopy. Stereodynamic processes involving restricted rotation about the fluorenyl-CH2 and aryl-CH2 bonds have been observed, leading to conformers and enantiomeric forms, and the corresponding barriers were determined by line shape simulation. These dynamic processes are interpreted as being due to correlated rotation pathways, on the basis of DFT computations that satisfactorily reproduce the experimental barriers. The structures of two such compounds were also determined by single-crystal X-ray diffraction.

Structure, conformation, stereodynamics, dimer formation, and absolute configuration of axially chiral atropisomers of hindered biphenyl carbinols.

NMR spectra of biphenyl derivatives bearing a single CR2OH substituent in the ortho position indicate that they exist as sp (more stable) and ap (less stable) conformers, due to the restricted rotation about the Ar-CR2OH bond. When R = Et (compound 2) the corresponding rotation barrier was determined (7.5 kcal mol-1) by line shape simulation of the low-temperature NMR spectra. Introduction of the prochiral i-Pr group in the position 3' of a biphenyl with the CMe2OH substituent in the position 2 (4) allowed the determination of the enantiomerization barrier (due to the Ar-Ar bond rotation) for the stereolabile axially chiral atropisomers (13.95 kcal mol(-1)). DFT computations of these barriers were all in agreement with the experiments. Biphenyls bearing two CR2OH groups in the 2,2' positions were found to exist as configurationally stable atropisomers: when R = Me (7) they were separated by enantioselective HPLC and the absolute configuration assigned on the basis of the corresponding CD spectra. In solution, compounds 6 (R = H) and 7 (R = Me) were found to originate a dimer, due to H-bond interactions between two enantiomers. In the case of 7, the free energy of activation (9.5 kcal mol-1) for the exchange of the monomer with the dimer could be measured, for the first time, by dynamic NMR. The conformational preferences, predicted by computations for the biphenyls with two CR2OH substituents in the 2,2' positions, were confirmed by X-ray diffraction in the case of R = H (6), R = Me (7), and R = i-Pr (9).

Conformation and stereodynamics of symmetrically ortho-disubstituted aryl carbinols and aryl ethers.

By making use of low-temperature dynamic NMR spectroscopy, the rotation barriers about the sp3-sp2 bond have been determined in a number of hindered benzyl alcohols symmetrically substituted in the ortho positions, the substituents being F, Cl, Br, and Me. The free energies of activation covered the range 4.6-10.1 kcal mol-1. Ab initio computations matched satisfactorily the trend of these values and predicted the conformation adopted by these compounds. In one case, this result could be also confirmed by the X-ray diffraction structure. In the case of the corresponding methyl ethers two barriers could be measured, corresponding to the passage across two distinguishable transition states: the higher barriers covered the range 5.0-8.1 kcal mol-1 and the lower ones the range 4.7-6.2 kcal mol-1.

Ring inversion dynamics of derivatives of thianthrene di- and tetraoxide.

The ring inversion barrier for thianthrene tetraoxide was determined by making use of the variable temperature 13C NMR spectra of the 2,7-diisopropyl derivative (DeltaG(double dagger) = 6.5 kcal mol(-1)). The barrier is lower than that measured for a trans thianthrene dioxide derivative (DeltaG(double dagger) = 9.35 kcal mol(-1)). These results agree well with ab initio theoretical predictions.

Structure, conformation, and stereodynamics of the atropisomers of highly hindered benzyl ethers.

Low-temperature and NOE NMR spectra of four of the title compounds indicate that they adopt a synclinal (sc) conformation, in agreement with the prediction of ab initio computations. In the case of the most-hindered derivative (compound 4), the conformation is syn-periplanar (sp), as is also shown by X-ray diffraction. Such stereolabile sp- or sc-atropisomers exist as two conformational enantiomers: the corresponding enantiomerization barriers, covering the range 6.6 to 9.7 kcal mol(-1), could be measured for all the examined compounds. In two cases (compounds 3 and 5), the minor antiperiplanar (ap) atropisomer has been also observed, and the sc to ap interconversion barrier measured (11.7 and 11.9 kcal mol(-1), respectively). In addition, restricted rotation of the isopropyl and tert-butyl substituents has been detected, and the corresponding barriers have been determined.

Flexible biphenyl chromophore as a circular dichroism probe for assignment of the absolute configuration of carboxylic acids.

A general and nonempirical approach to determine the absolute configuration (AC) of 2-substituted chiral carboxylic acids by circular dichroism (CD) spectroscopy has been developed. In this protocol, the chiral acids are converted to the corresponding biphenyl amides, in which a flexible biphenyl probe gives rise to a Cotton effect at 250 nm (A band) in the CD spectrum, the sign of which is related to the acid AC. Two different mechanisms of transfer of chirality from the acid stereogenic center to the biphenyl moiety are operative in amides derived from 2-alkyl- and 2-aryl-substituted acids, respectively. For both classes of compounds, a model has been defined which allows one to predict, for a given acid AC, the preferred twist of the biphenyl moiety and thus the sign of the A band in the CD spectrum, related to the biphenyl torsion. Interestingly, while in alkyl-substituted substrates the preferred biphenyl twist is determined only by steric interactions, in the aryl-substituted ones the structure of the prevalent conformer and thus the biphenyl twist are dictated by arene-arene edge-to-face stabilizing interactions. Following this protocol, the AC of a 2-substituted chiral acid can be established simply by preparing its biphenyl amides, recording the CD spectrum, and looking at the sign of the A band. From the sign of such a band, the torsion of the biphenyl can be deduced and then the acid AC. Substrates having different structures and functionalities have been investigated, always obtaining reliable AC assignments by this simple protocol.

Stereolabile and configurationally stable atropisomers of hindered aryl carbinols.

Carbinols of the Ar-C(OH)R(2) type, Ar being o-isopropylphenyl, exist as stereolabile syn-clinal (sc) and anti-periplanar (ap) atropisomers when R = Me, Et, i-Pr. In the latter compound, the major atropisomer also comprises two enantiomeric forms that interchange with a barrier of 6.4 kcal mol(-1). X-ray diffraction, NOE experiments, and ab initio calculations indicate that the sc-atropisomer is the more stable form when R = Me, i-Pr, t-Bu but is the less stable one when R = Et. NMR spectra at variable temperature allowed the determination of the barriers for the interconversion of the sc- into the ap-atropisomers (DeltaG++ = 7.6, 8.8, and 13.5 kcal mol(-1) for Me, Et, i-Pr, respectively). When R is a tert-butyl group, the two atropisomers are configurationally stable: the ap-atropisomer is obtained as the kinetic controlled compound, which can be transformed into the thermodynamically more stable sc-atropisomer with a free energy of activation of 29.3 kcal mol(-1). Both atropisomers exhibit restricted rotation of the tert-butyl moiety, the corresponding DeltaG++ values being 9.4 and 8.8 kcal mol(-1) for the sc- and ap-atropisomer, respectively.

Conformational studies by dynamic NMR. 100. Enantiomerization process of stereolabile atropisomers in pyridine-substituted adamantane derivatives.

The barriers for interconverting the conformational enantiomers (stereolabile atropisomers) of pyridine-substituted adamantane derivatives have been determined by dynamic 13C NMR spectroscopy. The trend of these values parallels that anticipated by MM calculations. In at least one case, the computed structure was found to agree with that obtained by single-crystal X-ray diffraction. In addition, it has been possible to achieve a physical separation of a pair of these stereolabile atropisomers at -60 degrees C by means of the enantioselective cryogenic HPLC technique.

Conformational studies by dynamic NMR. 99. Experimental and computed determination of rotation barriers in the crystalline state: the case of naphthylphenylsulfoxide.

The (13)C NMR CP-MAS spectrum of 2-naphthylphenylsulfoxide in the solid state displays line broadening effects due to the restricted rotation about the Ph-S bond. Line shape simulation of the temperature-dependent traces allowed the corresponding barrier to be determined in the solids (14.7 kcal mol(-1)). By making use of the information obtained from single-crystal X-ray diffraction, this barrier could be satisfactorily reproduced by theoretical calculations (14.5 kcal mol(-1)) that take into account the correlated phenyl motion involving a large set of molecules in the crystalline state

A general and nonempirical approach to the determination of the absolute configuration of 1-aryl-1,2-diols.

We describe herein a simple, general, and reliable nonempirical approach, based on the exciton coupling method, to assign the absolute configuration of the benzylic stereogenic center of 1-aryl-1,2-diols. According to this method, it is only necessary to prepare the 4-biphenylboronic esters of the diols and to record their CD spectra in the 230-300 nm range, i.e., in the range corresponding to the long-axis (1)L(a) transition of the biphenyl chromophore. From the sign of the CD couplet or Cotton effect at 260 nm it is possible to know the chirality defined by the aryl and biphenyl chromophore transitions and then to determine the absolute configuration of the benzylic carbon. By this approach, simple rules have been formulated which allow us to establish the absolute configuration of many classes of 1-aryl-1,2-diols.

Conformational studies by dynamic NMR. 97. Structure, conformation, stereodynamics and enantioseparation of aryl substituted norbornanes.

The structure of a 1,7,7-triaryl norbornane (compound 3) has been determined by X-ray diffraction and was found essentially equal to that predicted by molecular mechanics calculations. Restricted rotation of the aryl groups also has been observed by dynamic NMR spectroscopy in this compound and in a number of analogously substituted norbornanes. The aryl-norbornane bond rotation barriers were measured by line shape analysis of the (13)C NMR spectra obtained at temperatures lower than -100 degrees C and were found to cover the range 6.0 to 7.9 kcal mol(-1). An exception was the rotation involving the o-anisyl group in compound 5, which occurs near ambient temperature since the corresponding barrier is much higher (14.4 kcal mol(-1)). In one case (compound 4) configurational enantiomers could be separated by chiral HPLC and the corresponding CD spectra recorded.

Conformational studies by dynamic NMR. 93.(1) Stereomutation, enantioseparation, and absolute configuration of the atropisomers of diarylbicyclononanes.

The structure of 9-(4-methoxyphenyl)-9-(3-methylphenyl) bicyclo[3.3.1]nonane (1) has been determined by single-crystal X-ray diffraction, and the rotation barriers about the two aryl-C9 bonds have been measured by variable temperature NMR spectroscopy in solution. In the case of 9-(4-methoxyphenyl)-9-(1-naphthyl)bicyclo[3.3.1]nonane (3), the barrier involving the naphthyl-C9 rotation was found to be so high as to allow the physical separation of the two atropisomers by enantioselective HPLC at ambient temperature: the absolute configuration could be established on the basis of the corresponding CD spectra. It was also observed that the Ar-C9 rotation barriers of monoaryl-substituted nonanes are much lower than those of the corresponding diaryl-substituted nonanes.

Stable enols of amides ArNHC(OH)=C(CN)CO(2)R. E/Z enols, equilibria with the amides, solvent effects, and hydrogen bonding.

The structures of anilido cyano(fluoroalkoxycarbonyl)methanes ArNHCOCH(CN)CO(2)R, where R = CH(2)CF(3) or CH(CF(3))(2), Ar = p-XC(6)H(4), and X = MeO, Me, H, or Br, were investigated. In the solid state, all exist as the enols ArNHC(OH)=C(CN)CO(2)R 7 (R = CH(2)CF(3)) and 9 (R = CH(CF(3))(2)) with cis arrangement of the hydrogen-bonded ROC=O.HO moiety and a long C1=C2 bond. The product composition in solution is solvent dependent. In CDCl(3) solution, only a single enol is observed, whereas in THF-d(8) and CD(3)CN, two enols (E and Z) are the major products, and the amide is the minor product or not observed at all (K(Enol) 1.04-9 (CD(3)CN, 298 K) and 3 to >/=100 (THF, 300 K)). The percentage of the amide and the Z-enol increase upon an increase in temperature. In all solvents, the percent enol is higher for 9 than for 7. In CD(3)CN, more enol is observed when the aryl group is more electron-donating. The spectra in DMSO-d(6) and DMF-d(7) indicate the presence of mostly a single species, whose spectra do not change on addition of a base and is ascribed to the anion of the ionized carbon acid. Comparison with systems where the CN is replaced by a CO(2)R group (R = CH(2)CF(3), CH(CF(3))(2)) shows a higher percentage of enol for the CN-substituted system. Intramolecular (to CO(2)R) and intermolecular hydrogen bonds determine, to a significant extent, the stability of the enols, their Z/E ratios (e.g., Z/E (THF, 240 K) = 3.2-4.0 (7) and 0.9-1.3 (9)), and their delta(OH) in the (1)H spectra. The interconversion of Z- and E-enol by rotation around the C=C bond was studied by DNMR, and DeltaG() values of >/=15.3 and 14.1 +/- 0.4 kcal/mol for Z-7 and Z-9 were determined. Features of the NMR spectra of the enols and their anions are discussed.

Unprecedented Detection of Distinct Barriers Involving Formally Enantiotopic Substituents: Phenyl Rotation in Solid Diphenyl Sulfoxide.

The formally enantiotopic phenyl rings of Ph2 SO (Cs symmetry) display different rotation rates about the Ph-S bonds in the crystalline state. For example, at 0°C one phenyl ring rotates (see picture; cylinder represents rotating phenyl ring), whereas the other does not. Two distinct barriers (13.0 and 14.0 kcal mol-1 ) were determined by solid-state NMR spectroscopy.