2014 Volume 62 Issue 8 Pages 836-838
We previously reported the atropisomeric properties of 2′-t-butyl-6′-iodo-substituted N-benzoyl-3-bromocarbazole, i.e., the steric or electronic effects of the substituents restricted the rotation about the N–C7′ and C7′–C1′ bonds to separate four stereoisomers (cis/trans for the N–C7′ axis, aR/aS for the C7′–C1′ axis). Furthermore, the 2′-t-butyl-6′-iodo-substituted N-benzoyl 3-bromocarbazole was confirmed to be a gear molecule, in which the rotation about the C7′–C1′ bond was in perfect concert with that about the N–C7′ bond. Herein, we report a unique crystallization-induced diastereomeric transformation found in this molecule. In the isolation process, where the product is recrystallized from the diastereoisomeric mixture, in situ isomerization and selective crystallization could lead to a diastereomeric transformation, and a mixture of diastereomers (trans/cis=54 : 46) was converted to trans-isomer-enriched crystals (trans/cis>96 : 4) in 95% yield. Conformational analysis clarified the preference for the trans versus cis isomer.
Recently, we have reported on the atropisomeric properties of the 2′-t-butyl-6′-iodo-substituted N-benzoyl 3-bromocarbazole (1).1) Because the rotations about the N–C7′ and C7′–C1′ axes are fully restricted, four stereoisomers (cis/trans for the N–C7′ axis, aR/aS for the C7′–C1′ axis) of 1 were resolved on a chiral column (CHIRALPAK IB) (Fig. 1). Using the enantiomerically pure stereoisomer, the stereochemical stability was examined at 37°C. It was found that (cis, aS)-1 was converted to (trans, aR)-1 with a ΔG‡ value of 102 kJ/mol, and no interconversion between any other pair [i.e., (cis, aS)-1/(cis, aR)-1, (cis, aS)-1/(trans, aS)-1] was observed. Similarly, (trans, aS)-1 was converted to (cis, aR)-1 with a ΔG‡ value of 103 kJ/mol, and no interconversion between any other pair [i.e., (trans, aS)-1/(trans, aR)-1, (trans, aS)-1/(cis, aS)-1] was observed. It is clear that the rotation about the C7′–C1′ axis must be in perfect concert with the rotation about the N–C7′ axis at 37°C.1)
With our interest in this gear molecule,2,3) we studied its physicochemical properties in detail to discover a crystallization-induced diastereomeric transformation (CIDT).4–8) Crystallization, where the pure isomer is crystallized from diastereomeric mixtures, could be cost-effective compared with conventional column chromatography. In particular, diastereomeric transformation allowing an isomer to be converted to the desired one through in situ isomerization and selective crystallization might be very practical. Such in situ isomerization and crystallization (CIDT) has been researched recently by many groups.4–8)
In the course of the crystallization experiments on 1, we discovered that the diastereoisomeric mixture 1 was crystallized through isomerization to give trans-isomer-enriched crystals in nearly quantitative yield (Fig. 2).
Following the established method,1) 2′-t-butyl-6′-iodo-substituted N-benzoyl-3-bromocarbazole 1 was prepared as a crude solid. HPLC analysis using a nonchiral column showed two peaks corresponding to trans-1 and cis-1 (54 : 46).9) In order to purify 1, we examined recrystallization using various solvents and found that 1 was isomerized in a mixed solvent of AcOEt–hexane to produce crystals of trans-1 preferentially. The crude solid of 1 (1.019 g: trans/cis=54 : 46) was dissolved in AcOEt–hexane (1 : 2) and slowly recrystallized at 2°C for 12 h. The crystals obtained (703.5 mg) were analyzed using nonchiral HPLC, and we found that the trans-isomer was selectively crystallized (trans-1/cis-1=97 : 3).9) From its mother liquor, a second recrystallization was performed at 2°C for 15 h and yielded 195.5 mg of trans-1-enriched crystals (trans-1/cis-1=96 : 4).9) Furthermore, a third recrystallization from the second mother liquor (at 2°C for 14 h) yielded 68.8 mg of trans-1-enriched crystals (trans-1/cis-1=98 : 2).9) These recrystallization procedures produced a total of 967.8 mg of trans-1-enriched crystals (trans-1/cis-1>96 : 4) in 95% yield.
Although the first crystals of the trans-1-enriched (trans-1/cis-1=97 : 3) mixture retained the ratio for weeks in the crystal state, the mixture reached an equilibrium state (trans-1/cis-1=54 : 46) in CDCl3 solution within 126 h (5.25 d) at 25°C (Fig. 3). When analyzed using a chiral column (CHIRALPAK IB), the trans-1-enriched crystals10) were shown to exist as a racemate.
We found it surprising that the 3-bromo-substituted carbazole derivative 1 showed a preference for the trans-isomer in the crystal state, which resulted in efficient CIDT. Therefore, we carried out in silico conformational analysis of 1 to confirm the advantage of the trans- over the cis-isomer. Using the density functional theory method, minimum energy conformations among the stereoisomers [(trans, aR)-1, (trans, aS)-1, (cis, aR)-1, and (cis, aS)-1] were explored at the B3LYP/LanL2DZ level. It was estimated that the energy difference between the trans- and cis-isomer was 1.01 kJ/mol (ΔE value, 25°C, gas phase) (Fig. 4).
Thus, a preference for the trans-isomer was theoretically predicted. As mentioned above, HPLC and 1H-NMR provided the information that 1 is in equilibrium (trans-1/cis-1=54 : 46) in solution at 23°C, which means that the ΔG‡ value should be 0.39 kJ/mol. Both the theoretical and experimental investigations suggested that the energy difference between trans- and cis-isomers is very small, which is insufficient to explain the unusual preference for the trans-isomer in the crystal state. We therefore conclude that CIDT, which provides trans-isomer-enriched crystals, should be attributed to the crystallization characteristics of 1. Although we have only limited information on CIDT, we hope that this study will contribute to elucidating the physicochemical property of the N-acylated carbazoles.
NMR Spectra were recorded on a JEOL JNM-ECS 400 spectrometer at 400 MHz for 1H-NMR. Melting points were taken on a Yanaco micro melting point apparatus and are uncorrected. High-pressure liquid chromatography (HPLC) was performed with a Shimadzu Prominence system. All solvents used were of analytical grade.
Procedure of RecrystallyzationThe crude solid of 1 (trans/cis=54 : 46) weighing 1.019 g was dissolved in mixed solvents (AcOEt/hexane=1 : 2) and slowly recrystallized at 2°C for 12 h. The crystals obtained (703.5 mg) were analyzed using nonchiral HPLC. Its mother liquor was immediately analyzed to find the diastereomeric mixtures with a ratio of trans-1/cis-1=42 : 58. The second and the third recrystalyzations followed the way mentioned above. Each mother liquor was analyzed in the same way to find the diastereomeric mixtures (trans-1/cis-1=40 : 60).
Determination of Diastereomer Ratio of 1 Using Nonchiral HPLCDiastereomers of 1 were analyzed using nonchiral HPLC (YMC SIL-06 (0.6 cm×25 cm), flow rate 0.5 mL/min; temperature 23°C; detection 254 nm) with eluent hexane/ethyl acetate (20 : 1) to separate each diastereomer (tR 18.7 min for cis-isomer, tR 20.2 min for trans-isomer).
Analysis of trans-1-Enriched Crystals Using Chiral HPLCtrans-1-enriched crystals (trans-1/cis-1=97 : 3) were analyzed using CHIRALPAK IB ((0.46 cm×25 cm), flow rate 0.5 mL/min; temperature 23°C; detection 254 nm) with eluent hexane/ethyl acetate (20 : 1) to separate each stereoisomer (tR 14.6 min, 16.7 min, 19.7 min, 23.4 min).
Physical Property of trans-1-Enriched Crystalstrans-1-enriched crystals (50 mg: trans-1/cis-1=97 : 3) were dissolved in 0.5 mL of CH2Cl2, in 1.5 mL of AcOEt, in 3.8 mL of Et2O, respectively. mp: 166–167°C.
This work was supported in part by a Grant-in-Aid for Scientific Research (C) (24590020) from the Japan Society for the Promotion of Sciences and by a Research Grant from Astellas Foundation for Research on Metabolic Disorders.
