Absolute Helical Arrangement of Sulfonamide in the Crystal

Article abstract of DOI:10.1021/ol035509o

(Matrix presented) 1,2-Bis(N-benzenesulfonyl-N-methylamino)benzene (2), which has no fixed asymmetric element, was crystallized from ethyl acetate as chiral crystals belonging to space group P4₁2₁2 (No. 92) or P4₃2₁

Full text of DOI:10.1021/ol035509o

ORGANIC
LETTERS
2003
Vol. 5, No. 21
3939-3942
Absolute Helical Arrangement of
Sulfonamide in the Crystal
,†
Isao Azumaya,* Takako Kato,† Iwao Okamoto,‡ Ryu Yamasaki,§ Aya Tanatani,§
Kentaro Yamaguchi,| Hiroyuki Kagechika,§ and Hiroaki Takayanagi†
School of Pharmaceutical Sciences, Kitasato UniVersity, 5-9-1 Minato-ku,
Shirokane, Tokyo 108-8641, Japan, Showa Pharmaceutical UniVersity,
3-3165 Higashi-tamagawagakuen, Machida, Tokyo 194-1543, Japan,
Graduate School of Pharmaceutical Sciences, UniVersity of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan, and Chemical Analysis Center,
Chiba UniVersity, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522
azumayai@pharm.kitasato-u.ac.jp
Received August 11, 2003
ABSTRACT
1,2-Bis(N-benzenesulfonyl-N-methylamino)benzene (2), which has no fixed asymmetric element, was crystallized from ethyl acetate as chiral
crystals belonging to space group P41212 (No. 92) or P43212 (No. 96). The array of molecules built by the CH−π interaction along the c-axis
forms an enantiomeric helical superstructure in each individual crystal. The absolute configurations of the chiral crystals of 2 were determined
by X-ray crystal structure analysis using the Flack parameter method. The solid-state CD spectra of the chiral crystals in KBr were mirror
images. The equilibrium between the two enantiomers in solution is fast during crystallization at ambient temperature, and the energy barrier
q
(∆G ) is estimated to be 11.7 ± 0.3 kcal/mol (233 K).
The spontaneous resolution of an achiral compound on
crystallization in the absence of any chiral source is of great
interest, for example, in the field of absolute asymmetric
synthesis in the solid state1 and especially in connection with
the origin of homochirality of life.2 Formation of chiral
crystals of a compound without any stereogenic element
(chiral center, axis, or face) is rare. However, some com-
pounds having various functional groups or analogous
bimolecular combinations do crystallize as chiral crystals in
high ratio.3 In the course of our investigation of such
spontaneous resolution of various amides, we found that
o-phenylenediamine derivatives such as 1,2-bis(N-benzoyl-
N-methylamino)benzene (1)4 afford chiral crystals in an
unusual ratio. In this paper, we report that 1,2-bis(N-
benzenesulfonyl-N-methylamino)benzene (2) afforded chiral
crystals which consisted of a single enantiomer arranged in
(1) (a) Moradpour, A.; Nicoud, J. F.; Balovoine, G.; Kagan, H. J. Am.
Chem. Soc. 1971, 93, 2353-2354. (b) Toda, F.; Yagi, M.; Soda, S. J. Chem.
Soc., Chem. Commun. 1987, 1413-1414. (c) Sakamoto, M. Chem. Eur. J.
1997, 3, 684-689. (d) Takahashi, M.; Sekine, N.; Fujita, T.; Watanabe, S.;
Yamaguchi, K.; Sakamoto, M. J. Am. Chem. Soc. 1998, 120, 12770-12776.
(e) Kohmoto, S.; Masu, H.; Tatsuno, C.; Kishikawa, K.; Yamamoto, M.;
Yamaguchi, K. J. Chem. Soc., Perkin Trans. 1 2000, 4464-4468. (f)
Sakamoto, M.; Iwamoto, T.; Nono, N.; Ando, M.; Arai, W.; Mino, T.; Fujita,
T. J. Org. Chem. 2003, 68, 942-946.
† Kitasato University.
‡ Showa Pharmaceutical University.
§ The University of Tokyo.
| Chiba University.
10.1021/ol035509o CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/20/2003

Table 1. Crystal Data for M-2, P-2, and 3
crystal
M-2
P-2
3
formula
mol wt
crystal system
space group
a (Å)
b (Å)
c (Å)
V (Å3)
Dø (Mg m-3
C
20H20O4N2S2
C
20H20O4N2S2
C
22H24O4N2S2
416.51
tetragonal
P41212
8.478(1)
8.478(1)
27.182(2)
1953.6(5)
1.416
416.51
444.56
orthorhombic
Pbcn
11.994(3)
11.904(3)
15.388(3)
2197.2(9)
1.344
tetragonal
P43212
8.475(1)
8.475(1)
27.185(1)
1952.7(4)
1.417
)
Z
4
4
4
no. reflns used
1144
1217
2178
R[I > 0.00σ(I)]
0.050
0.051
0.073
Rw[I > 0.00σ(I)] 0.072
0.062
0.084
Flack param
for P41212
Flack param
for P43212
CCDC No.
0.000698
1.063694
(0.042455)
-0.063699
(0.042455)
217005
-
(0.041448)
0.999296
(0.041448)
217006
-
217007
a helical manner, in contrast to the racemic crystal of 1,2-
bis(N-4-toluenesulfonyl-N-methylamino)benzene (3).
Figure 1. ORTEP stereoviews of the crystal structure of (a)
compound 2 (P-2: P43212, chiral) and (b) compound 3 (Pbcn,
racemic). The thermal ellipsoids are drawn at the 50% probability
level.
The sulfonamides 2 and 3 were prepared by condensation
of o-phenylenediamine and the corresponding sulfonyl
chloride, followed by N-methylation using CH3I/NaH. Re-
crystallization of 2 from ethyl acetate afforded colorless
prisms with space group P41212 or P43212 (orthorhombic),
which are enantiomeric, in X-ray crystallographical analysis
(Table 1). The absolute configuration in each crystal could
be determined from the Flack parameter.5 An ORTEP
drawing of the sulfonamide 2 with a P41212 unit cell is shown
in Figure 1a. The chirality of the crystals of 2 was derived
from the assembly of a single enantiomer of the molecule
into the unit cell, and the conformational chirality was based
on atropisomerism around two Ar-N bonds. The P41212 or
P43212 crystals contain a folded C2-symmetrical (R,R)- or
(S,S)-conformer, respectively (Figure 2a). Compared to the
planar cis (E) conformations of most aromatic N-methylated
amide bonds, as observed in the crystal structure of 1 with
(R,R)- or (S,S)-conformation, the sulfonamide bonds were
chiral synclinal (Figure 2b), and the torsion angles of the
sulfonamide moiety [C(Ar)-S-N-C(Ar)] are -78.0(3)
(P41212) and +78.1(2) (P43212). Interestingly, the sulfona-
mide 3, a tosyl analogue of 2, was crystallized from ethyl
acetate to give racemic crystals with space group Pbcn (Table
1, Figure 1b). The conformation of 3 in the racemic crystals
is similar to that of 2, and the two enantiomers (torsion angle
(2) (a) Cohen, M. D.; Schmidt, G. M. J. J. Chem. Soc. 1964, 1996-
2000. (b) Schmidt, G. M. J. Pure Appl. Chem. 1971, 27, 647-678 (c) Elias,
W. E. J. Chem. Educ. 1972, 49, 448-454. (d) Pincock, R. E.; Wilson, K.
R. J. Chem. Educ. 1973, 50, 455-457. (e) Green, B. S.; Lahav, M.;
Rabinovich, D. Acc. Chem. Res. 1979, 12, 191-197. (f) Addadi, L.; Lahav,
M. In Origin of Optical ActiVity in Nature; Walker, D. C., Ed.; Elsevier:
Amsterdam, 1979; Chapter 14. (g) Mason, S. F. Nature (London) 1984,
311, 19-23. (h) Kaupp, G.; Haak, M. Angew. Chem., Int. Ed. Engl. 1993,
32, 694-695.
(3) (a) Havinga, E. Biochim. Biophys. Acta 1954, 13, 171-173. (b)
Pincock, E. R.; Wilson, K. R. J. Am. Chem. Soc. 1971, 93, 1291-1292. (c)
Koshima, H.; Nakagawa, T.; Matsuura, T.; Miyamoto, H.; Toda, F. J. Org.
Chem. 1997, 62, 6322-6325. (d) Gong, B.; Zheng, C.; Zeng, H.; Zhu, J. J.
Am. Chem. Soc. 1999, 121, 9766-9767. (e) Tanaka, K.; Fuijimoto, D.;
Oeser, T.; Irngartinger, H.; Toda, F. Chem. Commun. 2000, 413-414. (f)
Kuroda, R.; Imai, Y.; Sato, T. Chirality 2001, 13, 588-594. (g) Asakura,
K.; Soga, T.; Uchida, T.; Osanai, S.; Kondepudi, D. K. Chirality 2002, 14,
85-89.
(4) (a) Azumaya, I.; Yamaguchi, K.; Okamoto, I.; Kagechika, H.; Shudo,
K. J. Am. Chem. Soc. 1995, 117, 9083-9084. (b) Azumaya, I.; Okamoto,
I.; Nakayama, S.; Tanatani, A.; Yamaguchi, K.; Shudo, K.; Kagechika, H.
Tetrahedron 1999, 55, 11237-11246. 1,2-Bis(formylamino)benzene also
gave chiral crystals: (c) Azumaya, I.; Okamoto, I.; Takayanagi, H. Anal.
Sci., X-page 2003, 19, 3-4.
(5) Flack, H. D. Acta Crystallogr. 1983, A39, 876-881.
3940
Org. Lett., Vol. 5, No. 21, 2003

Figure 4. CD spectra of two enantiomeric crystals of 2 (M-2, red
line; P-2, blue line) and 3 (green line) in KBr. A mixture of 8 µg
of each crystal and 100 mg of KBr was ground well and formed
into a transparent disk with a radius of 5 mm.
Figure 2. (a) Conformations of the two enantiomers of the
sulfonamides and (b) (synclinal conformations around the sul-
fonamide bond.
crystals. Since the distance between the terminal phenyl ring
(Ar-SO2) and the carbon atom of the N-methyl group in the
adjacent molecule was 3.3 Å both for the chiral crystal of 2
and the racemic crystal of 3, CH-π interaction between
adjacent molecules may exist in both the helical and straight
molecular arrangements.
Solid-state CD spectra6 were measured in a KBr matrix
for P-2 and M-2 and 3 (Figure 4), as well as for compounds
that crystallize as chiral crystals.3,4 Mirror-image CD spectra
were obtained for the two chiral crystals, and no CD peak
was obtained for a racemic crystal of 3. Characteristic
vibration structures were observed at 275 and 268 nm and a
broadened peak at around 245 nm in the CD spectra of P-2
and M-2. A linear relation between the concentration and
the intensity of ellipticity was seen at concentrations below
80 µg/100 mg KBr in the tablet.
of C(Ar)-S-N-C(Ar) (89.5(2)°) exist in a 1:1 ratio in the
unit cell.
In the packing structures of 2, one enantiomer was piled
along the c-axis with successive rotations by one-fourth in
the unit cell, and the molecular arrangement showed a
beautiful left-handed (M-2) or right-handed (P-2) helix in
the chiral crystal of P41212 or P43212, respectively (Figure
3). On the other hand, the two enantiomers of the sulfona-
mide 3 alternated linearly along the c-axis in the racemic
The sign of the Cotton effect of the chiral sulfonamide 2
corresponded to the absolute configuration determined from
the Flack parameter in X-ray analysis. The absolute config-
uration of the crystals with positive sign in the CD spectrum
was (R,R), i.e., space group P41212, and that of the crystals
with negative sign was (S,S), which is P43212. The sulfona-
mide was crystallized from various solvents (CH2Cl2, CHCl3,
ethyl acetate, ethanol, methanol, toluene) to give chiral
crystals. Whereas the amide 1 afforded chiral and racemic
crystals on recrystallization from dry and wet solvents,
respectively,4 the crystallization of 2 from water-saturated
ethyl acetate or aqueous ethanol also gave chiral crystals.
The equilibrium between the two enantiomeric conformers
is fast in solution, since no CD peak was observed when a
chiral crystal of 2 was dissolved in various solvents. The 1H
NMR spectrum of 2 afforded a single set of peaks even at
low temperature, and no separation of peaks corresponding
to each enantiomeric conformation of 2 was observed when
chiral 1,1-bi-2-naphthol was added as a chiral shift reagent.4
To estimate the energy barrier to racemization of the
sulfonamide 2 in solution, 2,3-bis(N-benzenesulfonyl-N-
methylamino)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphtha-
lene (4) was synthesized and dynamic 1H NMR measurement
of 4 was performed. Compound 4 has two kinds of benzylic
Figure 3. Space-filling plots of the molecular arrays along the
c-axis in the crystal of M-2 (left), P-2 (right), and 3 (middle). The
molecules at the bottom show the conformations of which each
molecular array consists.
(6) Kuroda, R.; Honma, T. Chirality 2000, 12, 269-277.
Org. Lett., Vol. 5, No. 21, 2003
3941

methyl groups that should be observed as different peaks if
racemization between the two enantiomeric conformers is
slow enough. Actually, coalescence of the peaks was
observed at 233 ( 5 K and the energy barrier (∆Gq)
calculated from the temperature and the chemical shift
difference (∆ν ) 20 Hz) of the peaks of methyl groups
observed at lower temperature than Tc was 11.7 ( 0.3 kcal/
mol (at Tc).7 The energy barrier was lower than that of the
chiral amide 1 (∆Gq ) 16.3 kcal/mol at 233 K).4 This means
the racemization is fast at ambient temperature and the
chirality is fixed into the crystal only at the stage of
crystallization.
in the initial stage of a chiral arrangement, that is, generation
of optical activity by spontaneous resolution in crystals.
We present an example of chiral transformation of a
sulfonamide during crystallization. The molecules are ar-
ranged in a chiral helix with a single chirality in the crystal
through CH-π interaction, though the molecule exists in fast
equilibrium between the two enantiomers in solution. This
phenomenon should shed light on the mechanisms involved
Acknowledgment. I.A. thanks The Asahi Glass Founda-
tion for financial support of this research.
Supporting Information Available: Spectral data for
sulfonamides 2-4 and the synthetic procedure and dynamic
1H NMR spectra of compound 4. This material is available
free of charge via the Internet at http://pubs.acs.org.
(7) Oki, M. Applications of Dynamic NMR Spectroscopy to Organic
Chemistry; VCH Publishers: Florida, 1985.
OL035509O
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Org. Lett., Vol. 5, No. 21, 2003