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Spontaneous transfer of chirality in an atropisomerically enriched two-axis system.

Barrett KT, Metrano AJ, Rablen PR, Miller SJ - Nature (2014)

Bottom Line: In a compensatory manner, the enantiomeric ratio of the other diastereomeric pair decreases.These observations are made for a class of unsymmetrical amides that exhibits two asymmetric axes--one axis is defined through a benzamide substructure, and the other axis is associated with differentially N,N-disubstituted amides.The stereodynamics of these substrates provides an opportunity to observe a curious interplay of kinetics and thermodynamics intrinsic to a system of stereoisomers that is constrained to a situation of partial equilibrium.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Yale University, PO Box 208107, New Haven, Connecticut 06520-8107, USA.

ABSTRACT
One of the most well-recognized stereogenic elements in a chiral molecule is an sp(3)-hybridized carbon atom that is connected to four different substituents. Axes of chirality can also exist about bonds with hindered barriers of rotation; molecules containing such axes are known as atropisomers. Understanding the dynamics of these systems can be useful, for example, in the design of single-atropisomer drugs or molecular switches and motors. For molecules that exhibit a single axis of chirality, rotation about that axis leads to racemization as the system reaches equilibrium. Here we report a two-axis system for which an enantioselective reaction produces four stereoisomers (two enantiomeric pairs): following a catalytic asymmetric transformation, we observe a kinetically controlled product distribution that is perturbed from the system's equilibrium position. As the system undergoes isomerization, one of the diastereomeric pairs drifts spontaneously to a higher enantiomeric ratio. In a compensatory manner, the enantiomeric ratio of the other diastereomeric pair decreases. These observations are made for a class of unsymmetrical amides that exhibits two asymmetric axes--one axis is defined through a benzamide substructure, and the other axis is associated with differentially N,N-disubstituted amides. The stereodynamics of these substrates provides an opportunity to observe a curious interplay of kinetics and thermodynamics intrinsic to a system of stereoisomers that is constrained to a situation of partial equilibrium.

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Energetic considerations and analysis of racemization dynamics. a, Computed geometries and modes of isomerization of 5-(Me) with a concerted C-N/Ar-CO rotation and independent C-N rotation leading to racemization at high temperatures. b, Experimentally and theoretically calculated barriers to racemization of atropisomeric benzamides.
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Figure 6: Energetic considerations and analysis of racemization dynamics. a, Computed geometries and modes of isomerization of 5-(Me) with a concerted C-N/Ar-CO rotation and independent C-N rotation leading to racemization at high temperatures. b, Experimentally and theoretically calculated barriers to racemization of atropisomeric benzamides.

Mentions: Of interest to the present system are previous reports by Clayden, which showed that rotations about the Ar-CO bond axis of sterically hindered tertiary amides follow a mechanistic course involving concerted rotations of the Ar-CO axis and the amide C-N bond axis, in a gearing fashion, when sufficient energy is available to the system.21,23 Our calculations for the present system reassert these conclusions. However, the system we present here is distinct in that (a) the action of a chiral catalyst delivers diastereomeric amides of different er that allows for the observation of fluctuating enantiomeric ratios, and (b) distinct steric demands of the substrate that separate the energetic barriers of geared Ar-CO/C-N isomerization from independent C-N bond rotation substantially. Computations employing a relaxed potential energy scan of the Ar-CO dihedral angle led to a simultaneous rotation about the amide C-N bond. The optimized transition states along this torsional energy profile were marked by non-coplanar N- and aryl-substituents and imaginary frequencies that showed coupled rotation about both axes. Compared to independent Ar-CO rotation, which suffers from an implausibly high computed barrier, this concerted Ar-CO/C-N rotation represents the lowest energy pathway to inversion of the atropisomeric axis (TS-5b, Figure 6a). However, below these energetic thresholds, our results with compound 5 are consistent with independent C-N rotation, as noted above.


Spontaneous transfer of chirality in an atropisomerically enriched two-axis system.

Barrett KT, Metrano AJ, Rablen PR, Miller SJ - Nature (2014)

Energetic considerations and analysis of racemization dynamics. a, Computed geometries and modes of isomerization of 5-(Me) with a concerted C-N/Ar-CO rotation and independent C-N rotation leading to racemization at high temperatures. b, Experimentally and theoretically calculated barriers to racemization of atropisomeric benzamides.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4008667&req=5

Figure 6: Energetic considerations and analysis of racemization dynamics. a, Computed geometries and modes of isomerization of 5-(Me) with a concerted C-N/Ar-CO rotation and independent C-N rotation leading to racemization at high temperatures. b, Experimentally and theoretically calculated barriers to racemization of atropisomeric benzamides.
Mentions: Of interest to the present system are previous reports by Clayden, which showed that rotations about the Ar-CO bond axis of sterically hindered tertiary amides follow a mechanistic course involving concerted rotations of the Ar-CO axis and the amide C-N bond axis, in a gearing fashion, when sufficient energy is available to the system.21,23 Our calculations for the present system reassert these conclusions. However, the system we present here is distinct in that (a) the action of a chiral catalyst delivers diastereomeric amides of different er that allows for the observation of fluctuating enantiomeric ratios, and (b) distinct steric demands of the substrate that separate the energetic barriers of geared Ar-CO/C-N isomerization from independent C-N bond rotation substantially. Computations employing a relaxed potential energy scan of the Ar-CO dihedral angle led to a simultaneous rotation about the amide C-N bond. The optimized transition states along this torsional energy profile were marked by non-coplanar N- and aryl-substituents and imaginary frequencies that showed coupled rotation about both axes. Compared to independent Ar-CO rotation, which suffers from an implausibly high computed barrier, this concerted Ar-CO/C-N rotation represents the lowest energy pathway to inversion of the atropisomeric axis (TS-5b, Figure 6a). However, below these energetic thresholds, our results with compound 5 are consistent with independent C-N rotation, as noted above.

Bottom Line: In a compensatory manner, the enantiomeric ratio of the other diastereomeric pair decreases.These observations are made for a class of unsymmetrical amides that exhibits two asymmetric axes--one axis is defined through a benzamide substructure, and the other axis is associated with differentially N,N-disubstituted amides.The stereodynamics of these substrates provides an opportunity to observe a curious interplay of kinetics and thermodynamics intrinsic to a system of stereoisomers that is constrained to a situation of partial equilibrium.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Yale University, PO Box 208107, New Haven, Connecticut 06520-8107, USA.

ABSTRACT
One of the most well-recognized stereogenic elements in a chiral molecule is an sp(3)-hybridized carbon atom that is connected to four different substituents. Axes of chirality can also exist about bonds with hindered barriers of rotation; molecules containing such axes are known as atropisomers. Understanding the dynamics of these systems can be useful, for example, in the design of single-atropisomer drugs or molecular switches and motors. For molecules that exhibit a single axis of chirality, rotation about that axis leads to racemization as the system reaches equilibrium. Here we report a two-axis system for which an enantioselective reaction produces four stereoisomers (two enantiomeric pairs): following a catalytic asymmetric transformation, we observe a kinetically controlled product distribution that is perturbed from the system's equilibrium position. As the system undergoes isomerization, one of the diastereomeric pairs drifts spontaneously to a higher enantiomeric ratio. In a compensatory manner, the enantiomeric ratio of the other diastereomeric pair decreases. These observations are made for a class of unsymmetrical amides that exhibits two asymmetric axes--one axis is defined through a benzamide substructure, and the other axis is associated with differentially N,N-disubstituted amides. The stereodynamics of these substrates provides an opportunity to observe a curious interplay of kinetics and thermodynamics intrinsic to a system of stereoisomers that is constrained to a situation of partial equilibrium.

Show MeSH
Related in: MedlinePlus