Analysis of Interconversion between Atropisomers of Chiral Substituted 9,9’-Bicarbazole

Article abstract of DOI:10.1002/ejoc.202001385

Interconversion of atropisomers of chiral 3,3’-di-tert-butyl-9,9’-bicarbazole linked by a single N?N bond was analyzed by DFT calculations and experiments. The calculations revealed that the trans transition state has a lower energy for the interconversion than the cis transition state. The lowest transition state of interconversion between natural dixiamycins A and B containing a 9,9’-bicarbazole structure was found to be the trans transition state. The calculations also indicated that degradation through N?N bond cleavage was faster than racemization. Atropisomeric enantiomers of 3,3’-di-tert-butyl-9,9’-bicarbazole were resolved by chiral HPLC for the first time, and then racemization and N?N bond cleavage were investigated by heating experiments, showing that racemization did not take place below the degradation temperature.

Full text of DOI:10.1002/ejoc.202001385

Communications
doi.org/10.1002/ejoc.202001385
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Analysis of Interconversion between Atropisomers of Chiral
Substituted 9,9’-Bicarbazole
[a]
[b]
[b]
[a]
Toshifumi Kobayashi, Fumitaka Ishiwari, Takanori Fukushima, Kengo Hanaya,
[a]
[a]
Takeshi Sugai, and Shuhei Higashibayashi*
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Interconversion of atropisomers of chiral 3,3’-di-tert-butyl-9,9’-
bicarbazole linked by a single NÀ N bond was analyzed by DFT
calculations and experiments. The calculations revealed that the
trans transition state has a lower energy for the interconversion
than the cis transition state. The lowest transition state of
interconversion between natural dixiamycins A and B contain-
ing a 9,9’-bicarbazole structure was found to be the trans
transition state. The calculations also indicated that degradation
through NÀ N bond cleavage was faster than racemization.
Atropisomeric enantiomers of 3,3’-di-tert-butyl-9,9’-bicarbazole
were resolved by chiral HPLC for the first time, and then
racemization and NÀ N bond cleavage were investigated by
heating experiments, showing that racemization did not take
place below the degradation temperature.
In recent years, nitrogen-containing heteroaromatic dimers with
NÀ N bond linkages have emerged as fascinating molecules in
many fields such as organic chemistry, materials chemistry, and
[1,2]
medicinal chemistry. Among such heterocyclic dimers, dimers
of unsymmetrical heterocycles linked by a single NÀ N bond can
possess axis chirality depending on the rotational energy barrier
(Figure 1A). To date, only two examples of resolution of such
atropisomers, 2,2’,5,5’-tetramethyl-1,1’-bipyrrole-3,3’-dicarbox-
[3]
ylic acid (1) and natural antibiotic dixiamycins A (2) and B
[4]
(
3), have been reported (Figure 1B). The resolution of racemic
bipyrrole 1 by crystallization as diastereomeric salts of brucine
was achieved in 1931. However, the enantiomeric purity of 1
and the thermal stability of its chirality were not clear, since the
enantiomeric purity was studied only by optical rotation. More
recently, reported natural dixiamycins A (2) and B (3) are
diastereomers but not enantiomers owing to the additional
stereogenic centers. The reported calculated transition state for
the interconversion between 2 and 3 is not consistent with that
Figure 1. (A) Atropisomeric enantiomers of heterocyclic dimers linked by a
NÀ N bond. (B) Reported atropisomers, 2,2’,5,5’-tetramethyl-1,1’-bipyrrole-
[3]
[4]
3
,3’-dicarboxylic acid (1) and dixiamycins A (2) and B (3). (C) Atropiso-
meric enantiomers of 3,3’-di-tert-butyl-9,9’-bicarbazole (4).
[5]
of 9,9’-bicarbazole. Given this background, in order to develop
novel chiral heteroaromatic dimers with a NÀ N bond, it is
necessary to clarify the molecular dynamic properties of
atropisomeric enantiomers of a simple heteroaromatic dimer. In
this paper, we report a theoretical analysis on the interconver-
sion between atropisomeric enantiomers of chiral 3,3’-di-tert-
butyl-9,9’-bicarbazole 4 (Figure 1C), the first resolution of
enantiomers by chiral HPLC, and an experimental analysis of
the racemization and degradation.
[a] T. Kobayashi, Prof. Dr. K. Hanaya, Prof. Dr. T. Sugai,
Prof. Dr. S. Higashibayashi
Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio
University
1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
E-mail: higashibayashi-sh@pha.keio.ac.jp
[
b] Prof. Dr. F. Ishiwari, Prof. Dr. T. Fukushima
Laboratory for Chemistry and Life Science, Institute of Innovative Research,
Tokyo Institute of Technology
Based on a reported theoretical study of the conformation
[5]
of 9,9’-bicarbazole, the stable conformation of 4 and the
transition states for the interconversion between the atropisom-
ers were calculated at the B3LYP/6-31G(d) level of theory
4259 Nagatsuta, Midori-ku, Yokohama 226-8503, Japan
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202001385
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449
© 2020 Wiley-VCH GmbH

Communications
doi.org/10.1002/ejoc.202001385
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Figure 2. Calculated transition states for interconversion between atropisomeric enantiomers and homolytic cleavage of the NÀ N bond of 4.
(
Figure 2). Depending on the direction of the lone pairs on the
nitrogen atoms, cis and trans forms exist for the transition states
Figure 3). Due to the tert-butyl substituents, the cis and trans
forms possess three [(R)-cis-TS1 , (S)-cis-TS1 , cis-TS2 ] and three
reinvestigated (Figure 4, Figure S1). Although cis transition
states were previously reported to have the lowest transition
states (196.0–197.7 kJ/mol), the lowest transition states were
revised to be the trans transition states (163.2–165.2 kJ/mol).
(
4
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4
*
(
trans-TS1 , (R)-trans-TS2 , (S)-trans-TS2 ) transition states, re-
The energies of two molecules of the carbazolyl radical 5
4
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spectively. The energies of the trans transition states (166.9–
67.0 kJ/mol) were lower than those of the cis transition states
200.2–200.3 kJ/mol). Therefore, the interconversion between
the atropisomers of 4 takes place through the trans transition
state in our calculations. Similarly, the transition states of
interconversion between dixiamycins A (2) and B (3) were also
were also calculated [roB3LYP/6-31G(d)] (Figure 2), since 9,9’-
[
6]
1
(
bicarbazole is known to undergo thermal NÀ N bond cleavage.
The energy was calculated to be 135.3 kJ/mol, which is lower
than the energies of the trans transition states of interconver-
sion. Thus, the thermal degradation of the enantiomer of 4
through NÀ N bond cleavage is predicted to be faster than the
racemization.
In order to confirm the calculation results for 4, we
succeeded in resolving the enantiomers of 4 by chiral HPLC for
the first time using a DAICEL CHIRALPAK IB column (hexane)
(Figure 5A). The circular dichroism (CD) spectra of the enan-
tiomers of 4 and UV-vis absorption spectrum of (�)-4 were
recorded as shown in Figure 5B and Figure 55C. Since a single
crystal to determine the absolute configuration for X-ray
analysis was not obtained, the absolute configuration was
assigned by TD-DFT calculations [cam-B3LYP/6-31G(d)] (Fig-
ure 5D and Figure 5E). The simulated CD and UV-vis absorption
spectra showed good correlation with the experimental
Figure 3. Cis and trans transition states of 9,9’-bicarbazole.
[7]
spectra. Judging from the sign of the simulated and
experimental CD spectra, the absolute configurations of the
resolved enantiomers of 4 were assigned as shown in Figure 5A
and Figure 5B. To determine the degradation temperature,
thermolysis of (�)-4 was performed. The solution of (�)-4 in o-
dichlorobenzene-d was heated at 120 or 140°C and the
4
1
degradation was followed by H NMR spectroscopy using
anisole as an internal standard. While the degradation was not
observed at 120°C, it did take place at 140°C, and the amount
of (�)-4 was reduced to 87% after 20 h. Based on this result,
the resolved enantiomer of 4 was heated in o-dichlorobenzene
at 120 or 140°C and the racemization was monitored by chiral
HPLC analysis. Racemization was not observed after 20 h at
either temperature. This result is consistent with the calcu-
Figure 4. Cis and trans transition states of dixiamycins.
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take place below the degradation temperature. We believe that
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these fundamental results obtained by a combination of
theoretical and experimental methods will be useful for the
creation of novel chiral heteroaromatic compounds with a NÀ N
bond and the elucidation of their chiral properties.
Acknowledgements
This work was supported by the Japan Society for the Promotion
of Science (JSPS) KAKENHI Grant No. 20K05499 (S.H.). Part of the
calculations was performed using Research Center for Computa-
tional Science, Okazaki, Japan.
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Conflict of Interest
The authors declare no conflict of interest.
Keywords: Atropisomer · Axis chirality · Bicarbazole · Optical
resolution · Racemization
[
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In conclusion, DFT calculations of 3,3’-di-tert-butyl-9,9’-
bicarbazole 4 indicated that the trans transition states were the
lowest transition states for the interconversion between the
atropisomers. The calculated lowest transition state of inter-
conversion between dixiamycins A and B was also revised to be
the trans transition state. Furthermore, the calculations pre-
dicted that degradation was faster than racemization. Indeed,
enantiomers of 4 were resolved by chiral HPLC for the first time,
and heating experiments showed that racemization did not
[
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Manuscript received: October 19, 2020
Revised manuscript received: November 5, 2020
Accepted manuscript online: November 9, 2020
Eur. J. Org. Chem. 2021, 449–451
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