Resolution of (±)-Bicyclo[2.2.1]hept-5-ene-trans-2,3-dicarboxylic Acid: Crystal Structure of Its Cinchoninium Salt

Article abstract of DOI:10.1007/s10870-016-0640-4

Abstract: Single crystals of (+)-cinchoninium (+)-bicyclo[2.2.1]hept-5-ene-trans-2-carboxyl-3-carboxylate (S,S)-2 were obtained upon resolution of racemic (±)-bicyclo[2.2.1]hept-5-ene-trans-2,3-dicarboxylic acid rac-1 with (+)-cinchonine. An X ray diffraction analysis established the most important secondary interactions between the ions that are deemed responsible for the diastereomeric separation process. From (S,S)-2 enantiomerically pure (+)-bicyclo[2.2.1]hept-5-ene-trans-2,3-dicarboxylic acid (S,S)-1 was isolated in 72 % yield. Graphical Abstract: An X-ray diffraction analysis of (+)-cinchoninium (+)-bicyclo[2.2.1]hept-5-ene-trans-2-carboxyl-3-carboxylate (S,S)-2 established the most important secondary interactions between the ions that are deemed responsible for the diastereomeric separation process.[Figure not available: see fulltext.]

Full text of DOI:10.1007/s10870-016-0640-4

J Chem Crystallogr
DOI 10.1007/s10870-016-0640-4
BRIEF COMMUNICATION
Resolution of (–)-Bicyclo[2.2.1]hept-5-ene-trans-2,3-dicarboxylic
Acid: Crystal Structure of Its Cinchoninium Salt
1
2
•
Lissette Jimenez Teresa Gonzalez Alexander Bricen˜o2 Giuseppe Agrifoglio1
•
•
•
´
´
Romano Dorta3
1
•
´
´
Jesus Pastran
Received: 11 June 2015 / Accepted: 24 February 2016
Ó Springer Science+Business Media New York 2016
Abstract Single crystals of (?)-cinchoninium (?)-bicy-
clo[2.2.1]hept-5-ene-trans-2-carboxyl-3-carboxylate (S,S)-
2 were obtained upon resolution of racemic ( )-bicy-
clo[2.2.1]hept-5-ene-trans-2,3-dicarboxylic acid rac-1 with
(?)-cinchonine. An X ray diffraction analysis established
the most important secondary interactions between the ions
that are deemed responsible for the diastereomeric sepa-
ration process. From (S,S)-2 enantiomerically pure (?)-
bicyclo[2.2.1]hept-5-ene-trans-2,3-dicarboxylic acid (S,S)-
1 was isolated in 72 % yield.
Graphical Abstract An X-ray diffraction analysis of (?)-
(?)-bicyclo[2.2.1]hept-5-ene-trans-2-car-
cinchoninium
boxyl-3-carboxylate (S,S)-2 established the most important
secondary interactions between the ions that are deemed
responsible for the diastereomeric separation process.
Keywords Resolution Á Cinchonine Á Chiral dicarboxylic
acid Á Diastereomeric salt Á X-ray structure
Introduction
´
´
& Jesus Pastran
jpastran@usb.ve
The resolution of ( )-Bicyclo[2.2.1]hept-5-ene-trans-2,3-di-
carboxylic acid (rac-1, Scheme 1) has been reported more than
30 years ago by the use of brucine or cinchonine as resolving
agents, but to the best of our knowledge no structural data are
available on the diastereomeric salts that form in this process [1,
2]. Structural studies of the diasteromeric salts that formed upon
reaction of cinchonine with each enantiomer of mandelic acid
((S)-3, (R)-4; Scheme 1) showed that hydrogen bonding deter-
mines their different physical properties [3]. Also in the salt that
1
´ ´ ´
Departamento de Quımica, Universidad Simon Bolıvar,
Caracas, Venezuela
2
3
´
Centro de Quımica, Instituto Venezolano de Investigaciones
Cientıficas, Miranda, Venezuela
´
Department Chemie und Pharmazie, Anorganische und
¨
Allgemeine Chemie, Friedrich–Alexander–Universitat
Erlangen–Nu¨rnberg, Egerlandstraße 1, 91058 Erlangen,
Germany
123

J Chem Crystallogr
internal standards. Melting points were determined on an
Electrothermal Mel-Tem apparatus in open capillary tubes
and are not corrected. CHN Elemental analyses were per-
formed on a Fisons EA 1108 analyzer and samples were
handled in air (hygroscopic compounds are corrected for
water content). Optical rotations were measured on a
Perkin-Elmer 341 polarimeter. Racemic ( )-bicy-
clo[2.2.1]hept-5-ene-trans-2,3-dicarboxylic acid rac-1 was
obtained according to a known procedure [2].
(2R,4S,8R)-2-((S)-hydroxy(quinolin-4-yl)methyl)-8-
vinyl-1-azoniabicyclo[2.2.2]octane-(2S,3S)-3-
carboxybicyclo[2.2.1]hept-5-ene-2-carboxylate
or (1)-cinchoninium (1)-bicyclo[2.2.1]hept-5-ene-
trans-2-carboxyl-3-carboxylate ((S,S)-2)
rac-1 (20.0 g, 109 mmol) was dissolved in an acetone/water
(400 mL/200 mL) mixture with constant stirring at 70 °C.
(?)-cinchonine (32.0 g, 110 mmol) was then added in por-
tions. Once all solid was dissolved, the solution was heated to
reflux for 2 h. After cooling to room temperature ca. 100 mL
of solvent were removed by rotary evaporation, at which
point precipitation of a white solid started. The solid was
separated by filtration and redissolved in an acetone/water
(200/100 mL) mixture, and again ca. 100 mL of solvent
were removed by rotary evaporation to yield a white solid
that was separated by filtration. The third recrystallization
was done by atmospheric evaporation over 3 days of a
solution of the product in an acetone/water (200/100 mL)
mixture yielding crystals (24.7 g, 47 %) that were suit-
able for X-ray diffraction. 1H NMR (DMSO-d6): 8.87–8.86
(d, 1H, JH–H = 3.3 Hz); 8.29–8.27 (d, 1H, JH–H = 8.4 Hz);
8.05–8.03 (d, 1H, JH-H = 8.4 Hz); 7.75–7.59 (m, 4H); 6.25
(s, 2H); 6.11–6.04 (m, 2H); 5.66 (s, 1H); 5.13–5.11 (m, 2H);
3.40–2.95 (m, 6H); 2.80–2.78 (m, 1H); 2.35 (s, 2H);
2.07–2.02 (m. 1H); 1.77 (s, 1H); 1.57–1.48 (m, 4H);
1.32–1.30 (m, 2H). Anal. Calcd. for C19H23N2OÁC9H9O4-
0.2H2O: C, 70.04; H, 6.80; N, 5.83. Found: C, 70.01; H, 6.80;
Scheme 1 ( )-bicyclo[2.2.1]hept-5-ene-trans-2-carboxyl-3-car-
boxylate ((S,S); (R,R), rac-1), structurally characterized cin-
choninium
(?)-bicyclo[2.2.1]hept-5-ene-trans-2-carboxyl-3-
carboxylate ((S,S)-2), cinchoninium salts of mandelate ((S)-3,
(R)-4) and L-tartrate ((R,R)-5)
forms between cinchonine and L-tartaric acid ((R,R)-5,
Scheme 1) it was found that the molecular arrangement is
governed by intermolecular hydrogen bonding [4]. Here, we
wish to report on the crystal structure of cinchoninium (?)-
bicyclo[2.2.1]hept-5-ene-trans-2-carboxyl-3-carboxylate ((S,S)-
2; Scheme 1), which gives a deeper insight into the role played
by the chiral centers in the resolution process. It should be
mentioned that optically pure diacid (S,S)-1 or (R,R)-1 may also
be obtained in good yields by a Et2AlCl-mediated diastereose-
lective Diels-Alder reaction of cyclopentene with dimenthyl
fumarate, followed by saponification of the diester [5].
20
N, 5.98. mp dec. at 195 °C. [a]D = ? 195 (c 0.29, THF).
20
[a]D = ? 123 (c 0.23, acetone).
(?)-Bicyclo[2.2.1]hept-5-ene-trans-2,3-dicarboxylic Acid
((S,S)-1)
(S,S)-2 (25 g, 52 mmol) was dissolved in aqueous HBr
(10 % w/w, 52 mL). The desired product was extracted with
ether (8 9 20 mL) and the organic phase was dried on
MgSO4, filtered and the solvent removed in vacuo (1 9 10-3
mm Hg) to afford a white solid. The product was recrystal-
lized four times from an acetone/water (200 mL/100 mL)
Experimental
General Remarks
mixture. Yield (6.85 g, 72 %). mp 174–175 °C. [a]D20
=
1H and 13C NMR spectra were recorded on a Jeol 400 MHz
? 151 (c 4.48, acetone). Anal. Calcd. for C9H10O4Á
spectrometer at 25 °C with solvent signals allotted as
0.1H2O: C, 58.76; H, 5.59. Found: C, 58.65; H, 5.66.
123

J Chem Crystallogr
X-ray Structure Determination of (S,S)-2
Table 1 Crystal data and experimental crystallographic details
Formula
C19H23N2OÁC9H9O4
X-ray diffraction data were collected using a Rigaku AFC-
7S Mercury diffractometer with graphite-monochromated
Formula weight
Crystal system
Space group
476.56
˚
Trigonal
P31
Mo-Ka radiation (k = 0.71070 A) at room temperature. A
crystal with dimensions of 0.46 9 0.22 9 0.20 mm3 was
used. Cell refinement, data reduction, structure solving and
refining were performed by using the following programs:
CrystalClear [6], SHELXTL-NT V5 [1, 7]. and DIA-
MOND [8]. ORTEP-3 for windows was used to prepare the
material for publication [9]. The H-atoms on C were placed
˚
a (A)
10.2633 (11)
10.2633 (11)
21.182 (2)
90.00
˚
b (A)
˚
c (A)
a (°)
b (°)
c (°)
90.00
in calculated positions using a riding atom model with
2
fixed C-H distances [0.93 A for C(sp , CH), 0.96 A for
120.00
3
˚
˚
˚
V (A )
1932.3 (4)
3
3
3
˚
C(sp , CH3) and 0.97 A for C (sp , CH2)]. The carboxylic
and ammonium hydrogen atoms were located from dif-
ference Fourier maps. All the H atoms were refined with
isotropic displacement parameters set to 1.2 9 Ueq for
C(sp2) and 1.5 for C(sp3) of the attached atom. Absolute
configurations of compound 2 was referenced by internal
correlation with the known absolute configuration of the
(?)-cinchonine. Crystal data and experimental details are
listed in Table 1.
Z
dx (g cm-3
)
1.229
F (000)
l (mm-1
762
)
0.084
Crystal size (mm)
0.46 9 0.22 9 0.20
2.3–28.1
-13 B h B 13
-13 B k B 13
-24 B l B 27
H range (°)
hkl range
Reflections
Collected
22536
Results and Discussion
Unique
5341
Rint
0.091
Full-matrix least-squares on F2
The racemate ( )-Bicyclo[2.2.1]hept-5-ene-trans-2,3-di-
carboxylic 1 was separated by a slightly modified pub-
lished procedure [2]. Partial evaporation of acetone from a
water/acetone solution of rac-1 and (?)-cinchonine causes
the selective precipitation of the less soluble diastereomeric
salt (2R,4S,8R)-2-((S)-hydroxy(quinolin-4-yl)methyl)-8-
vinyl-1-azonia-bicyclo[2.2.2]octane-(2S,3S)-3-carboxy-
bicyclo[2.2.1]hept-5-ene-2-carboxylate (or cinchoninium
(?)-bicyclo[2.2.1]hept-5-ene-trans-2-carboxyl-3-carboxy-
late) (S,S)-2 in 47% yield after three recrystallizations. The
identity of (S,S)-2 was established by 1H NMR spec-
troscopy, elemental analysis, optical rotation, and the data
were in good agreement with published values.
Refinement method
Data/restraints/parameters
Final R indices [I [ 2r(I)]
R indices (all data)
Goodness-of-fit on F2
5341/1/317
R1 = 0.063, wR2 = 0.1349
R1 = 0.1672, wR2 = 0.1678
1.03
-3
)
˚
Max/min Dq (e A
0.17/-0.18
C1–O2 distances confirm that there is a carboxylic acid
group. Single and double bonds between C2–C8 and C4–
C5, respectively, are also evident. The absolute configu-
rations of the carbon atoms C2 and C8 are (S) in both cases
and are referenced by internal correlation with the known
absolute configuration of the cinchoninium cation. Bond
lengths and angles in the cation are in agreement with
values reported for the cinchoninium salts of mandelic acid
and L-tartaric acid [3, 4].
Crystals suitable for an X-ray crystal structure deter-
mination grew from slow evaporation of an acetone/water
solution of (S,S)-2 over the course of 3 days at room
temperature. The molecular structure is depicted in Fig. 1.
(S,S)-2 crystallizes in the space group P31 with an inde-
pendent pair of molecules in the asymmetric unit. This pair
consists of a cinchoninium cation and a (?)-bicy-
clo[2.2.1]hept-5-ene-trans-2-carboxy-3-carboxylate anion.
The similar bond lengths C9–O3 and C9–O4 suggest the
presence of a typical carboxylate function with negative
charge delocalized between the two C—O bonds via res-
onance. On the other hand, differences in the C1–O1 and
The crystal structure consists of the self-assembly of
cations and anions via O–HÁÁÁO- and N?–HÁÁÁO- charge-
assisted hydrogen bonding interactions. These interactions
lead to the formation of supramolecular helical chains
built-up from (?)-bicyclo[2.2.1]hept-5-ene-trans-2-car-
boxy-3-carboxylate moiety linked by O–HÁÁÁO- interac-
tions between carboxylic and carboxylate groups of
adjacent anions (O1–H1ÁÁÁO4) along the c-axis (Fig. 2).
123

J Chem Crystallogr
Fig. 1 Molecular structure of the diasteromeric salt (S,S)-2. Dis-
placement ellipsoids are drawn at the 30 % probability level. Selected
C17–N2 1.499(7), C15–N2 1.498(6), O1–C1–O2 121.9(5), O3–C9–
O4 122.7(4), C1–C2–C8 115.4(4), C9–C8–C2 113.5(4), C3–C4–C5
108.2(7), C6–C5–C4 109.3(7), C13–C19–O5 112.0(4), C20–C19–O5
110.5(4), C13–N2–C17 112.0(4), C13–N2–C15 107.3(4), C15–N2–
C17 109.5(4)
˚
bond lengths (A) and bond angles (°) are: C1–O1 1.301(6), C1–O2
1.205(9), C9–O3 1.248(5), C9–O4 1.265(5), C2–C8 1.557(6), C4–C5
1.288(9), C19–O5 1.413(5), C10–C11 1.31(2), C13–N2 1.521(6),
Fig. 2 View of the helical
chains along the c-axis, showing
charge-assisted hydrogen bonds
in salt (S,S)-2. The hydrogen
atoms are omitted for clarity,
except those involved in
hydrogen bonding interactions
These helical chains are arranged along the threefold
screw axis (31) (Fig. 3)1. The cations are linked to the
chains through the formation of an additional charge-
assisted heterodimeric interaction forming a ring described
by the graph R22(9) between the following groups of
atoms: The hydroxyl group of the cinchoninium ion and the
oxygen atom of the carboxylate ion (O5–H2ÁÁÁO3);
Between the H atom of the ammonium function of the
cinchoninium cation and the oxygen atom of the car-
boxylate anion (N2–H3ÁÁÁO4). Neighbouring helices are
assembled by multiple secondary hydrogen bonding inter-
actions (C–HÁÁÁO and C–HÁÁÁN) and Van der Waals inter-
actions to afford a three-dimensional hydrogen bonded
assembly. Numerical values of the hydrogen bonding
interactions are listed in Table 2.
Finally, the optically enriched diacid (S,S)-1 was liber-
ated in 72 % yield from salt (S,S)-2 by acid work up. The
specific rotation of ?151° of our material is higher than
1
Similar arrangements have been reported for compound with intra
and inter-molecular hydrogen interactions: [10–12]
123

J Chem Crystallogr
diasteromeric salt composed by the cinchoninium cation
and the (?)-bicyclo[2.2.1]hept-5-ene-trans-2-carboxyl-3-
carboxylate anion (S,S)-2 has been disclosed. The config-
uration of the diacid was confirmed and the extended
hydrogen-bonded network that builds the crystal up is
described. Such charge-assisted hydrogen bonding inter-
actions may well be determining for the highly diastere-
oselective crystallization process achieved with this
system.
Supplementary Material
Supplementary crystallographic data for (S,S)-2 are con-
tained in CCDC 1003504. Copies of this information may
be obtained free of charge from the Director, CCDC, 12
Union Road, Cambridge, CB2 1EZ, UK (fax: 144-1223-
336033; e-mail: deposit@ccdc.cam.ac.uk or http://www.
ccdc.cam.ac.uk) or from the authors.
Acknowledgments We thank T.S.U Eleinne Severino (Centro de
Qu´ımica, Instituto Venezolano de Investigaciones Cient´ıficas) for
carrying out the elemental analyses.
Fig. 3 View of the helical chain along the threefold screw axis (31) in
salt (S,S)-2
˚
References
Table 2 Distances and angles (A, °) of hydrogen bonding
interactions
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93:1669
D–HÁÁÁA
D–H
HÁÁÁA
DÁÁÁA
D–HÁÁÁA
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(2001) Acta Cryst. C C57:1447
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son, WI, (1998)
O5–H2ÁÁÁO3
N2–H33ÁÁÁO4
O1–H1ÁÁÁO4
0.850(3)
0.910(3)
1.020(4)
1.822(3)
1.857(2)
1.553(4)
2.628(4)
2.754(4)
2.563(6)
157.48(2)
168.05(3)
169.93(4)
The H atoms are in calculated positions. D donor, A acceptor, H
hydrogen
Symmetry transformations used to generate equivalent atoms: x, y, z;
-y, x - y, 1/3 ? z; -x ? y, -x, 2/3 ? z
8. Brandenburg K (1998) Diamond. Crystal Impact GbR, Bonn
9. Farrugia LJ (2012) J. Appl. Cryst. 45:849
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E. E65:o1241
other reported values and confirms the assignment of the
absolute configuration [1, 2].
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55b:1020
Conclusions
( )-bicyclo[2.2.1]hept-5-ene-trans-2,3-dicarboxylic acid
rac-1 can be resolved with cinchonine, and in this context
the previously unknown crystal structure of the
123