Archive for the 'Stereochemistry' Category

Atropisomerization within a cyclic compound

Atropisomers are stereoisomer that differ by axial symmetry, such as in substituted biphenyls or allenes. These acyclic systems have received a fair amount of attention, but now Buevich has looked at atropisomerization that occurs in a ring system.1 1 has a biphenyl as part of the eight-member ring, and the biphenyl can exist in either an M or P orientation. Since C3 is chiral (S), the two isomers are (M,S)-1 and (P,S)-1. Variable temperature NMR analysis concludes that (P,S)-1 is 1.19 kcal mol-1 more stable than (M,S)-1, and the barrier for the interchange (P,S)-1 → (M,S)-1 is 26.77 kcal mol-1.

To identify the process for this atropisomerization process, he utilized B3LYP/6-31G(d) computations of the model system 2. A variety of different techniques were used to identify the local energy minimum conformations of both (M,S)-2 and (P,S)-2, and the lowest energy conformers (M1 for (P,S)-2 and M4 for (M,S)-2) are shown in Figure 1. He then produced a series of 2-D potential energy surfaces varying two of the dihedral angles defining the eight-member ring to help identify potential initial geometries for searching for transition states. (As an aside, this procedure ended up identifying a few additional local energy minima not identified in the initial conformational search – and these all have trans amide groups instead of the cis relationship found initially. These trans isomer are considerably higher in energy than the conformers.) With this model and this computational level, (P,S)-2 is 0.76 kcal mol-1 lower in energy than (M,S)-2.







Table 1. B3LYP/6-31G(d) optimized geometries and relative free energies of some critical points along the lowest energy pathway taking (P,S)-2 → (M,S)-2.

A number of transition states were identified, and the lowest energy pathway that takes M1 into M4 first crosses TS1 to make the minimum M2, which than passes a high barrier (25.8 kcal mol-1) to go to M4. This barrier is in reasonable agreement with the experimental barrier for 1. These TSs are also shown in Figure 1.

Buevich analyzes the conformational process by examination of the changes in the ring dihedral angles following this reaction path. As expected, crossing the highest barrier requires a combination of torsional rotations, but essentially one at a time moving clockwise about the ring.


(1) Buevich, A. V. "Atropisomerization of 8-Membered Dibenzolactam: Experimental NMR and Theoretical DFT Study," J. Org. Chem. 2016, 81, 485–501 DOI: 10.1021/acs.joc.5b02321.


1: InChI=1S/C27H26N2O/c1-3-12-26-27(30)29(20-21-13-6-5-7-14-21)25-18-11-9-16-23(25)22-15-8-10-17-24(22)28(26)19-4-2/h3-11,13-18,26H,1-2,12,19-20H2/t26-/m0/s1

2: InChI=1S/C17H18N2O/c1-12-17(20)19(3)16-11-7-5-9-14(16)13-8-4-6-10-15(13)18(12)2/h4-12H,1-3H3/t12-/m0/s1

Stereochemistry Steven Bachrach 10 Feb 2016 1 Comment

[6]Saddlequat – the ruber glove inversion

In 1955 Mislow1 discussed the possibility of enatiomers interchanging via a path that was entirely chiral, never passing through an achiral structure. His analogy is the inversion of a rubber glove, taking a right hand rubber glove and pulling it inside out creates a left hand glove (its mirror image) but never passing through an achiral glove. Well, now a helicene with this type of stereochemistry has been developed, with a stable chiral intermediate.2

Helicenes typically interchange (PMP) through an achiral saddle-like structure. But larger helicenes can have high-lying intermediates along this pathway. Helquat P-1 interchanges to M-1 through the intermediate 2, which is an achiral structure and can be isolated.

Computations at B3LYP/def2-TZVP//PBE/def2-SV(P) with dispersion corrections (and PCM simulating DMSO) of the inversion process identified a number of intermediates and transition states along the stereoinversion pathway. The intermediate 2 lies 18.4 kJ mol-1 above 1. These structures are shown in Figure 1. The highest lying TS between 2 and P-1 (labeled TSP in Figure 1) is 119 kJ mol-1 above 2. The highest lying TS on the path from 2 to M-1 (labeled TSM in Figure 1) is 138 kJ mol-1 above 2. Note that going from 2 to P-1 is not the mirror image path of going from 2 to M-1.






Figure 1. Optimized structures of 1, 2, and the highest transition states interconverting them.

Heating racemic 2 and following the conversion to 1 with NMR gives the activation barrier of 119 kJ mol-1, in excellent agreement with the computation.

Racemic 2 was resolved through differential crystallization and its x-ray structure indicates it is (+)-[Sa,Ra]. Heating it does give just P-1, as predicted by the computations. Then heating P-1 to 180 °C does racemize it, with an experimental barrier of 157.7 kJ mol-1. The computations predict a barrier of 156.6 kJ mol-1, again in fine agreement with experiment. Overall, a nice piece showing experiment and computation working together to provide an understanding of an interesting chemical system!


(1) Mislow, K.; Bolstad, R., "Molecular Dissymmetry and Optical Inactivity," J. Am. Chem. Soc., 1955, 77, 6712-6713, DOI: 10.1021/ja01629a131

(2) Adriaenssens, L.; Severa, L.; Koval, D.; Cisarova, I.; Belmonte, M. M.; Escudero-Adan, E. C.; Novotna, P.; Sazelova, P.; Vavra, J.; Pohl, R.; Saman, D.; Urbanova, M.; Kasicka, V.; Teply, F., "[6]Saddlequat: a [6]helquat captured on its racemization pathway," Chem. Sci. 2011, ASAP, DOI: 10.1039/C1SC00468A


1: InChI=1/C27H26N2/c1-2-11-23-20(8-1)15-19-29-18-7-10-22-14-13-21-9-3-5-16-28-17-6-4-12-24(28)25(21)26(22)27(23)29/h1-2,4,6,8,11-15,17,19H,3,5,7,9-10,16,18H2/q+2

Stereochemistry Steven Bachrach 18 Oct 2011 2 Comments