Crystalline structure of N-(S)-2-heptyl (1R,2R)-2-(2,3- anthracenedicarboximido)cyclohexanecarboxamide that differs from its preferred conformation in the solvent used for crystallization

Article abstract of DOI:10.1271/bbb.69.2002

The crystalline structure of N-(S)-2-heptyl (1R,2R)-2-(2,3- anthracenedicarboximido)cyclohexamide (1), which was crystallized from methanol, was determined by an X-ray analysis and had a different conformation from its preferred one in CD₃OD by

Full text of DOI:10.1271/bbb.69.2002

Biosci. Biotechnol. Biochem., 69 (10), 2002–2004, 2005
Note
Crystalline Structure of N-(S)-2-Heptyl (1R,2R)-2-(2,3-Anthracenedicarbox-
imido)cyclohexanecarboxamide That Differs from Its Preferred Conformation
in the Solvent Used for Crystallization
y
1
Kazuaki AKASAKA,1; Takashi OHTAKI,1 Chizuko KABUTO,2 Takeshi KITAHARA,3 and Hiroshi OHRUI
1Graduate School of Life Sciences, Tohoku University, 1-1 Tsutsumidori-Amamiya, Aobaku, Sendai 981-8555, Japan
2Faculty of Sciences, Tohoku University, Aramaki, Sendai 980-8578, Japan
3Kitasato Institute, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan
Received May 6, 2005; Accepted July 11, 2005
The crystalline structure of N-(S)-2-heptyl (1R,2R)-2-
(2,3-anthracenedicarboximido)cyclohexamide (1), which
was crystallized from methanol, was determined by an
X-ray analysis and had a different conformation from
its preferred one in CD3OD by a 1H-NMR analysis.
Inter- and intra-molecular CH-ꢀ interaction in a crystal
plays a very important role in crystal packing. The
preferred conformation of the amide derivative in a
solution allows us to exploit (1R,2R)-2-(2,3-anthracene-
dicarboximido)cyclohexanecarbonyl chloride as a con-
version reagent to determine the absolute configuration
1H-NMR.5) The acid chloride of the reagent also seemed
to be useful as a conversion reagent for amines. Since
the conformation of the derivative is a very important
factor for chiral discrimination, a conformational analy-
sis of its 2-heptyl amide derivatives was performed.
(S)-2-Heptylamine was converted with (1R,2R)-
2-(2,3-anthracenedicarboximido)cyclohexanecarbonyl
chloride, which had been prepared by the reaction with
an excess amount of oxalyl chloride in toluene at 50 ꢀC
for 1 h with subsequent evaporation of the solvent and
excess oxalyl chloride in vacuo, in toluene in the
presence of 4-dimethylaminopyridine at 50 ꢀC for 5 h to
give N-(S)-2-heptyl (1R,2R)-2-(2,3-anthracenedicarbox-
imido)cyclohexanecarboxamide (1, Fig. 1). After puri-
fication by silica gel column chromatography [toluene/
EtOAc (5:2, v/v), Rf ¼ 0:49], 1 was crystallized from
methanol to give crystals suitable for an X-ray analysis.
The X-ray intensity data were measured with a Rigaku
mercury detector equipped with Rigaku AFC8 Goni-
ometer by using graphic monochromated MoKꢀ (ꢁ ¼
1
of chiral amines by H-NMR.
Key words: crystalline structure; N-(S)-2-heptyl (1R,
2R)-2-(2,3-anthracenedicarboximido)cyclo-
hexanecarboxamide; chiral reagent; fluo-
rescent reagent
The molecular structure determined in the crystalline
state is often used to explain the properties of that
molecule in the solution state. However, in some cases,
the crystal structure is influenced by effects such as
crystal packing. It is necessary to determine the structure
independently in both the crystalline and solution states
to make clear the relationship between the molecular
structures in these two states. However, there are few
reports about a combined study on the molecular
structures in the two states.1,2) We describe in this paper
an example showing the crystalline structure of a
compound differs from its preferred conformation in
the solvent used for crystallization.
ꢀ
0:71070 A). The crystal and experimental data for the
crystals are listed in Table 1.
All the hydrogen atoms, except for NH, were
calculated from the standard bond lengths and angles.
The X-ray crystalline structures of 1 are shown in Fig. 1.
The noteworthy points for the crystalline structure in
Fig. 1A are as follows: (1) the C3–C7 alkykl chain is
located over the anthracenedicarboximide group, (2) the
conformation of H10–C10–C=O is s-cis, (3) the con-
formation of O=C–NH–C2–H2 is 1,3-syn, and (4) the
conformation of H20–C20–N–C=O is 1,3-syn.
We have developed both (1R,2R)- and (1S,2S)-2-(2,3-
anthracenedicarboximido)cyclohexanecarboxylic acid
as chiral conversion reagents.3) These reagents have
proved very useful to separate by HPLC both chiral
primary and secondary alcohols having a chiral methyl
branch at a remote position from the hydroxyl group.3,4)
The reagents have also been useful to discriminate the
chirality of the secondary alcohol itself by HPLC and
The conformations in points 3 and 4 are the preferred
ones. Since the preferred conformation of H–C–C=O of
cyclohexanecarboxamide in solution is s-trans, the s-cis
conformation of crystal 1 is not the preferred one. These
results prompted us to study the preferred conformation
of 1 in methanol, because the conformation in solution is
very important for chiral discrimination by this reagent.
Conformational analyses of both 1 and its diaster-
y
To whom correspondence should be addressed. Tel: +81-22-717-8804; Fax: +81-22-717-8806; E-mail: akasaka@biochem.tohoku.ac.jp

Crystalline Structure of a 2-Heptyl Cyclohexanecarboxamide
2003
Fig. 1. X-ray Structures of 1 Showing the Conformation (A) and Intermolecular Interaction (B).
Table 1. Crystal and Experimental Data
Formula: C30H34N2O3
Formula weight ¼ 470:61
Crystal system: triclinic
Space group: P1(#1)
Lattice Parameters
a ¼ 5:140ð1Þ A
ꢀ ¼ 88:091ð9Þꢀ
ꢀ
b ¼ 9:448ð2Þ A
ꢂ ¼ 82:725ð8Þꢀ
ꢃ ¼ 87:283ð9Þꢀ
ꢀ
c ¼ 12:771ð3Þ
ꢀ 3
V ¼ 614:3ð2Þ A
Dcalc ¼ 1:272 g/cm3
Z value ¼ 1
No. of reflections measured ¼ 13222
Detector: Rigaku mercury
Gonimeter: Rigaku AFC8
Structure solution: direct method (SIR92)
Refinement: full-matrix least-squares on F2
eomer, N-2-(R)-heptyl (1R,2R)-2-(2,3-anthracenedicar-
boximido)cyclohexanecarboxamide (2), which was pre-
pared in the similar manner to that for 1, in CD3OD
1
were performed by H-NMR. In this case, 2 didn’t give
1
crystals suitable for an X-ray analysis. H-NMR spectra
were recorded with a Varian Unity Inova 500 spec-
trometer at 20 ꢀC in CD3OD, using Me4Si as an internal
1
standard. The H-NMR spectra of 1 and 2, and their
preferred conformations in CD3OD deduced from the
1H-NMR study are shown in Fig. 2.
The protons of the C3–C7 alkyl chain of 2 are
significantly shielded due to anisotropy by the anthra-
cenedicarboximide group, and those of the C1-methyl
appeared at the normal position. These results indicate
that the C3–C7 alkyl chain exists in the deshielded
region of anisotropy by the anthracenedicarboximide
Fig. 2. 1H-NMR Spectra of 1 (A) and 2 (B) in CD3OD, and Their
Preferred Conformations Deduced by the 1H-NMR Study.
group and that the C1-methyl group is not in the
preferred conformation of 2 in CD3OD (Fig. 2B).
On the other hand, the protons of the C1-methyl group

2004
K. AKASAKA et al.
of 1 are significantly shielded, while those of the C3–C7
alkyl chain are not (Fig. 2A). These results indicate that
the C1-methyl group exists in the deshielded region of
anisotropy by the anthracenedicarboximide group and
that the C3–C7 alkyl chain is not in the preferred
conformation of 1 in CD3OD. The preferred conforma-
tions of 1 and 2 can be attained by the conformation of
H10–C10–C=O as s-trans and of O=C–NH–C2–H2 as
1,3-syn, the most stable conformation of N-secondary-
alkylcyclohexanecaroxamide, as shown in Fig. 2.
C30H35N2O3 [ðM þ HÞþ], 471.2647; found, 471.2656.
N-(R)-2-Heptyl (1R,2R)-2-(2,3-anthracenedicarbox-
imido)cyclohexanecarboxamide (2). Yellow crystals
22
(40% from methanol), mp 223–224 ꢀC, ½ꢀꢁ ꢂ75:33ꢀ
1
(c 0.15, CHCl3); H-NMR ꢅ: 0.075 (d, J ¼ 6:8 Hz, 3H),
0.44 (m, 4H), 0.70 (m, 2H), 0.931 (d, J ¼ 6:3 Hz, 3H),
0.98 (m, 2H), 1.36–1.54 (m, 2H), 1.55–1.65 (m, 1H),
1.78–1.96 (m, 4H), 2.16–2.25 (m, 1H), 3.33 (dt, J ¼
3:4 Hz, 11.7 Hz, 3H), 3.60 (m, 1H), 4.47 (dt, J ¼ 3:9 Hz,
12.2 Hz, 1H), 7.62 (m, 2H), 8.11 (m, 2H), 8.50 (s, 2H),
8.75 (s, 2H); HRMS (FAB) m=z: calcd. for C30H35N2O3
[ðM þ HÞþ], 471.2647; found, 471.2651.
CH-ꢄ interaction is one of the important factors to
stabilize a conformation.6–8) If 1 had the same crystal
structure as the preferred conformation in the solution,
the C1 methyl group should be located over the aromatic
ring. However, the crystalline structure of 1 differed
from its preferred conformation in methanol. In this
crystal structure, the C3–C7 alkyl chain was laid
between two aromatic rings to stabilize the structure
by both intra- and inter-molecular CH-ꢄ interactions
(Fig. 1B). Although the three single bonds, C10–CO,
CO–NH and NH–C2, of the amide part of 1 could rotate
to provide the conformation for CH-ꢄ interaction, only
the C10–CO bond rotated in the crystalline structure.
These results suggest that the 1,3-syn conformation at
O=C–NH–C2(R,R0)–H2 was more stable than the s-
trans conformation at H10–C10–C=O. In the solution,
inter-molecular CH-ꢄ interaction between the C3–C7
alkyl chain and the anthracene ring of another molecule
may be too weak to form. This might be due to the
difference of molecular structure in the solid state and in
the solution for this system. The foregoing results
suggest that CH-ꢄ interaction is one of the important
factors causing structural differences in the two states.
In the solution, the stereochemistry of the amino
group on a chiral secondary carbon atom determines
which alkyl group on the chiral carbon atom is laid on
the aromatic ring, because they form s-trans at H10–
C10–C=O, 1,3-syn at O=C–NH–C2–H2, and 1,3-syn at
H20–C20–N–C=O conformations as most preferred
ones. This allows us to exploit 2-(2,3-anthracenedicar-
boximido)cyclohexanecarbonyl chloride as a chiral
conversion reagent to determine the absolute configu-
Acknowledgments
The authors express their thanks to Prof. Dr. Lindner
of Vienna University for useful discussions.
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22
(76.1% from methanol), mp 207–208 ꢀC, ½ꢀꢁ
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