Conformational consequences of the dynamic processes in the stereolabile atropisomers of acyl-substituted m-terphenyl derivatives

By means of low-temperature NMR spectroscopy, conformers (stereolabile atropisomers) due to the restricted rotation about the Ar-Ar and Ar-C(O)R bonds were detected in a number of acylphenyl derivatives, substituted in positions 2 and 6 by the 3-isopropylphenyl moiety (compounds 1-3, R=H, Me, and t-Bu, respectively). The conformational assignment was accomplished on the basis of the symmetry of the low-temperature 13C NMR spectra with the added support of ab initio calculations. The interconversion barriers were also determined by complete line shape simulation of the NMR spectra, and the experimental values were satisfactorily reproduced by ab initio calculations. In the case of the asymmetric derivative 4, two enantiomers, generated by the restricted t-BuC(O)-Ar rotation, were found sufficiently stable to allow their separation by means of the enantioselective HPLC technique at ambient temperature and to obtain the corresponding CD spectra.     

Conformational studies by dynamic NMR. 86. Structure, stereodynamics, and cryogenic enantioseparation of the stereolabile isomers of o-dinaphthylphenyl derivatives

Static and dynamic stereochemistry of the hydrocarbon comprising a phenyl ring bearing two alpha-naphthyl substituents in the ortho positions, i.e., 1,2-di-(4-methyl-naphth-1-yl)-benzene 1, has been studied by a combination of variable temperature NMR, cryogenic HPLC, and MM calculations. Whereas in solution both syn (meso) and anti (chiral) forms were observed and the corresponding interconversion barrier was determined (Delta G(++) = 19.5 kcal mol(-1)), only the diastereoisomer anti was found to be present in the crystalline state (X-ray diffraction). When the molecule is rendered asymmetric by introduction of a nitro group in the phenyl ring as in 1,2-di-(4-methyl-naphth-1-yl)-4-nitrobenzene 2, the chiral syn and anti diastereoisomers are simultaneously present both in solution and in the solid state, albeit in different proportions. Cryogenic chromatography on a HPLC chiral stationary phase at 20 degrees C allowed the stereolabile diastereoisomers and the corresponding enantiomers to be separated.     

Conformational studies by dynamic NMR. 80.(1) cog-wheel effect in the stereolabile helical enantiomers of dimesityl sulfoxide and sulfone

The (1)H NMR solution spectra of the title compounds display anisochronous lines for the o-methyl substituents below -170 degrees C, due to the existence of two propeller-like M and P conformational enantiomers. The free energies of activation for the interconversion were determined to be 4.5 and 5.0 kcal mol(-)(1), respectively, for dimesityl sulfoxide and dimesityl sulfone. Molecular mechanics calculations indicate that the enantiomerization process occurs via a correlated rotation (cog-wheel effect) entailing a one-ring flip (gear-meshing) pathway. (13)C NMR (CP-MAS) spectra and X-ray diffraction show that these helical enantiomers are stable in the crystalline state.     

Conformational studies by dynamic NMR. 83. Correlated enantiomerization pathways for the stereolabile propeller antipodes of dimesityl substituted ethanol and ethers

Below -100 degrees C, the NMR spectra of dimesityl derivatives of ethanol and of various ethers reveal how these molecules exist as M and P propeller-like stereolabile enantiomers, owing to the restricted rotation about the Ar-C bond. Single-crystal X-ray diffraction of one such derivative confirmed the existence of a two-blade propeller structure. Computer analysis of the NMR line shape allowed the barriers for the enantiomerization process to be determined. Theoretical modeling (Molecular Mechanics) of the interconversion circuit produced good agreement between the computed and experimental barrier for a correlated dynamic process where a disrotatory one-ring flip pathway reverses the helicity of the conformational enantiomers. Introduction of a configurationally stable chiral center allowed two distinct NMR spectra to be detected at appropriate low temperature for two stereolabile diastereoisomers.     

Conformational studies by dynamic NMR spectroscopy. Part 96: Stereomutations of highly hindered naphthylphenyl atropisomers in solution and in the solids

When a benzene ring bears two 2-methyl-1-naphthyl moieties in the para, meta or ortho positions as in 1,4-bis(2-methyl-1-naphthyl)benzene, 1, 1,3-bis(2-methyl-1-naphthyl)benzene, 2 and 1,2-bis(2-methyl-1-naphthyl)benzene 3, two rotational isomers (atropisomers) are generated, with the two naphthyl substituents in a syn or anti relationship. In the case of the para and meta derivatives (1 and 2, respectively) these atropisomers could not be separated but were detected by NMR spectroscopy, that also allowed the determination of their syn-anti interconversion barriers in solution (19.5 and 20.4 kcal mol⁻¹, respectively) and, in the case of 2, also in the solid state (26.7 kcal mol⁻¹). In the more hindered ortho derivative 3, the syn (meso) and anti (racemic) atropisomers interconvert in solution with a barrier (31.2 kcal mol⁻¹) sufficiently high to allow their physical separation. The racemic form could also be separated (by enantioselective HPLC) into the PP and MM enantiomers. Analysis of the corresponding CD spectra allowed the assignment of the absolute configuration. When three such naphthyl substituents are bonded to the phenyl in a meta relationship, two atropisomers in statistical proportions were observed: the anti (C_s symmetry) and the syn (C_3v symmetry) display a 3:1 ratio at the equilibrium in solution. This ratio is different in the solid state, as is the interconversion barrier (22.1 and 32.1 kcal mol⁻¹ in solution and in the solid, respectively).     

Conformational studies by dynamic NMR. 84.(1) structure, conformation, and stereodynamics of the atropisomers of N-aryl-tetrahydropyrimidines

The existence of stereolabile atropisomers for a number of N-aryl-tetrahydropyrimidines in solution has been deduced from the observation of the anisochronous NMR signals of prochiral methylene groups. The interconversion barriers for these atropisomers have been measured by line shape analysis of dynamic NMR spectra at various temperatures: a Molecular Mechanics modeling resulted in good agreement with these values. In an appropriate case, distinct NMR signals for the two enantiomeric forms could be observed at ambient temperature in a chiral environment. Evidence was also obtained for an exchange process occurring between two conformers experiencing a very biased equilibrium. Single-crystal X-ray diffraction of one such compound yielded a molecular structure in good agreement with the results obtained by ab initio calculations.     

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.     

Conformational studies by dynamic NMR. 90. Structure and stereodynamics of the rotamers of di- and tri-alpha-naphthylphenyl derivatives

The crystal structure of 1,3,5-tris(4-methylnaphth-1-yl)benzene, 1, shows one naphthyl substituent in an anti relationship to the other two. On the other hand, low temperature (-70 degrees C) (1)H NMR spectra in solution show the presence of a second rotational conformer (rotamer) having all the three naphthyl substituents in a syn relationship. The interconversion barrier between the anti (77%) and syn (23%) rotamers of 1 was determined by line shape simulation of the temperature-dependent NMR spectra (Delta G(++) = 12.1 kcal mol(-1)). In the analogous disubstituted meta and paraderivatives, that is, 1,3- and 1,4-bis(4-methylnaphth-1-yl)benzene (2 and 3, respectively), the presence of both the anti and syn rotamers was also detected by low-temperature NMR spectroscopy. In the latter compounds, the proportions of the anti and syn forms are nearly equal, and the corresponding anti to syn interconversion barriers were found to be lower (11.4 and 11.1(5) kcal mol(-1), respectively) than those of the trisubstituted derivative 1.     

Conformational studies by dynamic NMR. 98. Stereodynamics of bond rotation in beta-hydroxyesters

The dynamic processes due to restricted intramolecular motions have been observed in a number of variously substituted beta-hydroxyesters by variable-temperature NMR spectroscopy. The barriers for three such processes (i.e. Ph-C, t-Bu-C, and C(alpha)-C(beta) bond rotation) have been measured.     

Conformational studies by dynamic NMR. 94.1 cogwheel pathway for the stereomutations of durene derivatives containing the mesityl ring

The low-temperature NMR spectra of 1,4-bis(mesitoyl)durene, 1, and of 1,4-bis(mesitylethenyl)durene, 2, reveal the presence of syn and anti rotamers at the equilibrium, their relative proportions depending on the dielectric constant of the solvent. In solution the more stable rotamer of 1 is the anti whereas, in the case of 2, the more stable is the syn. Depending on the crystallization solvent employed the more (anti) and the less stable (syn) rotamers were both observed (X-ray diffraction) in the solid state of 1. On the other hand, only the less stable rotamer (anti) was found to be present in the solid state of 2. As shown by MM calculations, the syn-to-anti interconversion occurs via a correlated process (cogwheel pathway) involving the mesityl-C and durene-C bond rotations: the dynamic NMR technique yields an experimental barrier of 8.2 kcal mol(-)(1) for 1 and 13.1 kcal mol(-)(1) for 2. In the case of derivative 2 a second barrier, due to a second type of correlated rotation process (torsion), was also determined (8.6 kcal mol(-)(1)). As a consequence of the restriction of this second torsional motion the anti rotamer of 2 displays two distinguishable NMR spectra at -133 degrees C, corresponding to a pair of conformers with different symmetry (anti C(i)() and anti C(2)).     

Structure, conformation, and dynamic processes of the stereolabile atropisomers of hindered terphenyl hydrocarbons

[reaction: see text] Ortho-substituted p-terphenyl hydrocarbons exist as trans and cis atropisomers that were identified by low-temperature NMR spectroscopy. The interconversion barriers increase with the dimensions of the ortho substituents, the experimental values being matched by ab initio calculations. X-ray diffraction shows that only the trans atropisomer is present in the solids. Spectra of a tert-butyl derivative in nonequilibrium conditions indicate that the cis is more populated than the trans atropisomer in solution, favored by attractive interactions.     

Conformational studies by dynamic NMR. Part XV. The rotational barrier of N-methyl aniline

Low temperatures C-13 NMR spectra allowed the determination of the rotational barrier of N-methyl aniline in solution. The shifts of the anisochronous ortho and meta carbons were assigned by $\text{ab initio}$ calculations.     

13C NMR spectra of adamantane derivatives

The carbon-13 chemical shifts of mono- and 1,3-disubstituted adamantanes are reported. The effects caused by the substituents are compared with those met in aliphatic and alicyclic compounds. It is shown that the 1,4-interactions have only minor importance in l-substituted adamantanes. The influence of polar groups on the chemical shifts of γ- and δ-carbon atoms is a typical ‘through-the-bonds’ interaction and correlates with inductive parameters of the substituents.     

Conformational studies by dynamic NMR. 91. Conformational stereodynamics of tetraethylmethane and analogous C(CH2X)4 compounds

Variable-temperature NMR studies of tetraethylmethane (1a), tetrapropylmethane (1b), tetrachloromethylmethane (1c), tetrabromomethylmethane (1d), tetracyclopropylmethylmethane (1e), and tetrabenzylmethane (1f) show a range of dynamic behavior. Separate signals for two types of conformation are observed for 1a, 1c, and 1d at low temperatures, with more than 95% of the molecules in a time-averaged D2d conformation, and the S4 conformation as the minor populated alternative. Compound 1e populates only S4-type conformations but equilibrates slowly between degenerate versions of these at low temperatures. Compounds 1b and 1f show a temperature-dependent spectrum but the low-temperature limit spectrum could not be observed. Ab initio calculations agree well with experiment on the conformational equilibria and suggest in particular that compounds 1b and 1f behave similarly to compounds 1a and 1e, respectively. A crystal structure of compound 1f is reported.     

Analysis of intramolecular dynamic processes in enantiomeric diaryl atropisomers and related derivatives by 2H NMR spectroscopy in polypeptide liquid crystals

We demonstrate the analytical potential of 2H-{1H} NMR spectroscopy in weakly ordering, chiral lyotropic liquid crystals made of poly(gamma-benzyl-L-glutamate) (PBLG) dissolved in chloroform or dichloromethane for investigating the intramolecular dynamic processes of four deuterated diaryls (derivatives of 1-(4'-methylphenyl)naphthalene). When the rotation of the aryl groups about the sp(2)--sp(2) bond is sufficiently slow relative to the NMR timescale, the method allows the spectral discrimination of enantiomeric atropisomers or enantiotopic directions in the prochiral derivatives. The effect of the position of substituents on the phenyl group on the conformational dynamics of these compounds has been examined as well as the nature of the organic co-solvent. When coalescence phenomena are observed, simulation of the experimental 2H-{1H} lineshapes using a formalism tailored for two deuterons undergoing mutual exchange allows the rate constants and the activation parameters for the internal rotation processes to be calculated. Experimental values of DeltaH(not equal) have been compared with data evaluated by molecular modelling calculations and the activation parameters are discussed for the various compounds. It is shown that these polypeptide mesophases have no significant impact on the interconversion dynamics of these compounds. In contrast with the nematic thermotropic phases, Haller's equation cannot be used to predict the evolution of the quadrupolar splittings (Deltanu(Q) values), and hence the order parameters, versus T in the PBLG mesophases. For these particular lyotropic systems, it is shown that an exponential function of the form Deltanu(Q)[Hz]=C x exp (-E/RT[K]) provides excellent agreement between the experimental and expected Deltanu(Q) values. Analysis of the results reported in this work suggests that orientation and chiral discrimination phenomena in these lyotropic solvents could be treated separately because they would involve different interaction mechanisms.