Cyclic imide and open-chain amide carboxylic acid derivatives from the facile reaction of cis-cyclohexane-1,2-dicarboxylic anhydride with three substituted anilines

Article abstract of DOI:10.1007/s10870-012-0353-2

The structures of the compounds from the reaction of cis-cyclohexane-1,2- dicarboxylic anhydride with 4-chloroaniline [rac-2-[(4-chlorophenyl)carbamoyl]- ciscyclohexane- 1-carboxylic acid] (1), 4-bromoaniline [2-(4- bromophenyl)-3a,4,5,6,7,7a-hexahydroisoindole-1,3-dione] (2) and 3-carboxy-4-hydoxyaniline (5-aminosalicylic acid) [2-(3-carboxy-4-hydroxyphenyl) - 3a,4,5,6,7,7a-hexahydroisoindole- 1,3-dione] (3) have been determined at 200 K. Crystals of the open-chain amide carboxylic acid 1 are orthorhombic, space group Pbcn, with unit cell dimensions a = 20.1753(10), b = 8.6267(4), c = 15.9940(9) A , and Z = 8. Compounds 2 and 3 are cyclic imides, with 2 monoclinic having space group P21 and Z = 4, with cell dimensions a = 11.5321(3), b = 6.7095(2), c = 17.2040(5) A , β = 102.527(3)°. Compound 3 is orthorhombic, space group P2₁2₁2₁ with Z = 4 and cell dimensions a = 6.4642(3), b = 12.8196(5), c = 16.4197(7) A . Molecules of 1 form hydrogen-bonded cyclic carboxylic acid dimers [graph set R₂² (8)] which are extended into a two-dimensional layered structure through amide-group associations: 3 forms into one-dimensional zigzag chains through carboxylic acid- ··imide O-atom hydrogen bonds, while compound 2 is essentially unassociated. With both cyclic imides 2 and 3, disorder is found which involves the presence of partial enantiomeric replacement of the cis-1,2-substituted cyclohexane ring systems. Springer Science+Business Media, LLC 2012.

Full text of DOI:10.1007/s10870-012-0353-2

J Chem Crystallogr (2012) 42:1029–1035
DOI 10.1007/s10870-012-0353-2
ORIGINAL PAPER
Cyclic Imide and Open-Chain Amide Carboxylic Acid Derivatives
from the Facile Reaction of cis-Cyclohexane-1,2-Dicarboxylic
Anhydride with Three Substituted Anilines
•
Graham Smith Urs D. Wermuth
Received: 13 February 2012 / Accepted: 4 August 2012 / Published online: 21 August 2012
Ó Springer Science+Business Media, LLC 2012
Abstract The structures of the compounds from the reac-
tion of cis-cyclohexane-1,2-dicarboxylic anhydride with
4-chloroaniline [rac-2-[(4-chlorophenyl)carbamoyl]-cis-
cyclohexane-1-carboxylic acid] (1), 4-bromoaniline [2-(4-
bromophenyl)-3a,4,5,6,7,7a-hexahydroisoindole-1,3-dione]
(2) and 3-carboxy-4-hydoxyaniline (5-aminosalicylic acid)
[2-(3-carboxy-4-hydroxyphenyl)- 3a,4,5,6,7,7a-hexahyd-
roisoindole-1,3-dione] (3) have been determined at 200 K.
Crystals of the open-chain amide carboxylic acid 1 are
orthorhombic, space group Pbcn, with unit cell dimensions
Keywords cis-cyclohexane-1,2-dicarboxylic acid Á
Cyclic imides Á Open-chain amide carboxylic acids
Introduction
Cyclohexane-1,2-dicarboxylic anhydride is of interest as a
reagent because in its reactions it confers the cis configura-
tion [(1R,2S) or (1S,2R)] upon the reaction products. With
the cis-isomer of cyclohexane-1,2-dicarboxylic acid
(CHDC), because of the low interconversion potential
between these components, unlike the trans-isomer [(1R,2R)
or (1S,2S)], the dl enantiomeric pairs are inseparable,
forming racemic pairs [1]. The structures of both the racemic
and chiral trans forms have been determined [2, 3], together
with that of the racemic cis form [4]. The 1:1 stoichiometric
reaction of cyclohexane-1,2-dicarboxylic anhydride with
Lewis bases usually gives the racemic hydrogen cis-CHDC
proton-transfer salts and the structures of a limited number of
these have now been determined: the ammonium salt
(a dihydrate) [5], the 2-aminopyridinium salt [6], the 4-am-
inopyridinium salt [7] and the 4-carbamoylpiperidinium salt
[8] (all three anhydrous). However, the chiral brucinium salt
is also known [9] in which the (1R)-carboxylate-(2S)-car-
boxy-cis-CHDC species has been captured.
˚
a = 20.1753(10), b = 8.6267(4), c = 15.9940(9) A, and
Z = 8. Compounds 2 and 3 are cyclic imides, with 2 mono-
clinic having space group P21 and Z = 4, with cell dimensions
˚
a = 11.5321(3), b = 6.7095(2), c = 17.2040(5) A, b =
102.527(3)°. Compound 3 is orthorhombic, space group
P212121 with Z = 4 and cell dimensions a = 6.4642(3),
˚
b = 12.8196(5), c = 16.4197(7) A. Molecules of 1 form
hydrogen-bonded cyclic carboxylic acid dimers [graph set
R22(8)] which are extended into a two-dimensional layered
structure through amide-group associations: 3 forms into
one-dimensional zigzag chains through carboxylic acid-
ÁÁimide O-atom hydrogen bonds, while compound 2 is
essentially unassociated. With both cyclic imides 2 and 3,
disorder is found which involves the presence of partial
enantiomeric replacement of the cis-1,2-substituted cyclo-
hexane ring systems.
With the substituted anilines, formation of cyclic imides
or open-chain amide carboxylic acids may occur, analogous
to those formed with phthalic anhydride, (the phthalimides
and the phthalanilic acids), often under mild reaction con-
ditions [10]. The structures of the cyclic CHDC imides
formed with 5-benzyloxy-2,4-dichloroaniline [11] and with
urea [12] were the only ones reported until our recent work
[13, 14] provided a number of examples of both cyclic imides
and open-chain amide carboxylic acids from the reaction of
CHDC anhydride with X-monosubstituted anilines (imides:
Electronic supplementary material The online version of this
article (doi:10.1007/s10870-012-0353-2) contains supplementary
material, which is available to authorized users.
G. Smith (&) Á U. D. Wermuth
Science and Engineering Faculty, Queensland University
of Technology, G.P.O. Box 2434, Brisbane, QLD 4001,
Australia
e-mail: g.smith@qut.edu.au
123

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J Chem Crystallogr (2012) 42:1029–1035
X = o-F, p-F, p-OCH3, m-CO2H, p-CO2H; amide acids:
R = m-F, o-OCH3). All products were obtained under mild
1:1 stoichiometric reaction conditions in aqueous ethanolic
solutions.
colourless plates of 1 and 2 or pale brown needles of 3 from
which specimens were cleaved for the X-ray analyses.
Crystallography
Herein we report the structures of the crystalline products
obtained under similar mild reaction conditions from the 1:1
reaction of cis-cyclohexane-1,2-dicarboxylic anhydride
with 4-chloroaniline, the open-chain amide carboxylic acid
[2-[(4-chlorophenyl)carbamoyl]-cis-cyclohexane-1-carboxylic
acid] (1); with 4-bromoaniline [2-(4-bromophenyl)-
3a,4,5,6,7,7a-hexahydroisoindole-1,3-dione] (2) and with
3-carboxy-4-hydroxyaniline (5-aminosalicylic acid) [2-(3-
X-ray diffraction data for 1–3 were acquired at 200(2) K on
an Oxford Diffraction Gemini Ultra CCD-detector diffrac-
tometer employing graphite crystal monochromatized Mo
˚
Ka radiation (k = 0.71073 A). Data collection and reduction
and absorption correction (multi-scan) were completed
using CrysAlis PRO [15]. The structures were solved using
direct methods (SIR92 [16]) and refined with SHELXL97
[17] operating within WinGX [18]. Hydrogen atoms poten-
tially involved in hydrogen-bonding interactions for com-
pounds 1 and 3 were located by difference methods but their
positional parameters were constrained in the final refine-
ment cycles with thermal parameters riding [Uiso(H) = 1.2
Ueq(O)]. Other H atoms in all compounds were included in
the refinements at calculated positions and treated as riding
carboxy-4-hydroxyphenyl)-
3a,4,5,6,7,7a-hexahydroisoin-
dole-1,3-dione] (3) (both cyclic imides) (Scheme 1).
Experimental
Preparation
˚
with C–H = 0.93–0.98 A and Uiso(H) = 1.2 Ueq(C). Dis-
Compounds 1-3 were synthesized by heating together
under reflux for 10 min, 1 mmol quantities of cis-cyclo-
hexane-1,2-dicarboxylic anhydride and the appropriate
aniline (4-chloroaniline for 1, 4-bromoaniline for 2 and
5-aminosalicylic acid for 3), in 50 mL of 50 % ethanol–
water. After concentration to ca. 30 mL, partial room
temperature evaporation of the hot-filtered solutions gave
order was identified within the cyclohexane ringin only the B
molecule in 2, resulting from a partial presence of the
[C8(R),C9(S)] cis-enantiomer (C) [site occupancy fac-
tor = 0.27(1)] with the larger occupancy [C8(S),C9(R)]
(B) cis-enantiomer (S.O.F. = 0.73). The disordered atoms
C4C and C7C were subsequently refined isotropically. With
3 the disorder was more extensive, affecting most of the
perhydroisoindoline-1,2-dione system, also from partial
replacement of the major [C8(R),C9(S)] component
[S.O.F. = 0.85(1)] by the minor component [C8(S),C9(R)]
(A) [S.O.F. = 0.15(1)], which was also refined isotropically.
Absolute configuration of the cis-CHDC species in com-
pounds 2 and 3 could not be confirmed from the analyses and
with 3, in the absence of a suitable heavy atom in the struc-
ture, Friedel pairs (2868) were merged in the final cycles of
refinement. General crystallographic details are given in
Table 1. The atom numbering schemes employed for all
species are shown in Figs. 1, 2 and 3 [19].
CO2H
O
(1)
N
Cl
H
O
N
Br
(2)
Results and Discussion
In the structure of the racemic open-chain amide carboxylic
acid 1 (Fig. 1) the p-chlorophenyl ring is rotated slightly out of
the plane of the interlinking carboxamide side-chain giving a
slight twisting [intra-ring torsion angles C2–C1–C12–N11,
C1–C12–N11–C11 and C12–N11–C11–C61: -179.7(2),
173.0(3) and 152.1(3)°, respectively]. Present also is an
intramolecular aromatic ring C21–HÁÁÁO12(ketone) interac-
O
O
CO2H
(3)
N
OH
˚
tion [2.902(3) A]. The carboxylic acid group is rotated out of
the C1–C2–C3 molecular plane of the cyclohexane ring
[torsion angle C1–C2–C21–O22, 148.9(2)°]. The 1,2-disub-
stituted cyclohexanering as expectedhasthe cis-configuration.
O
Scheme 1 The compounds 1, 2 and 3
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J Chem Crystallogr (2012) 42:1029–1035
1031
Table 1 Crystal data for compounds 1–3
Compound
1
2
3
CCDC reference
Molecular formula
Mr
862425
862424
862423
C15H15NO5
289.28
C
14H16ClNO3
C14H14BrNO2
308.16
281.73
Crystal system
Space group
Orthorhombic
Pbcn
Monoclinic
P21
Orthorhombic
P212121
6.4642(3)
12.8196(5)
16.4197(7)
90
˚
a (A)
20.1753(10)
8.6267(4)
15.9940(9)
90
11.5321(3)
6.7095(2)
17.2040(5)
102.527(3)
1299.46(7)
4
˚
b (A)
˚
c (A)
b (°)
3
˚
V (A )
2783.7(2)
8
1360.68(10)
4
Z
Dc (g cm-3
)
1.344
1.568
1.412
l (mm-1
)
0.278
3.156
0.107
F(000)
1,184
1,288
608
Reflections total, hmax (°)
Crystal size (mm)
9279, 26.0
0.38 9 0.22 9 0.10
9056, 26.0
0.40 9 0.30 9 0.05
5237, 28.9
0.35 9 0.10 9 0.08
Collection range
h
-15 to 24
-10 to 6
-12 to 19
2735
-11 to 14
-8 to 8
-21 to 21
5041
-5 to 8
-16 to 16
-20 to 17
1818
k
l
Reflections (independent)
Reflections [F2 [ 2 r(F2)]
Rint
1616
3774
1624
0.0527
0.0236
0.0264
R1a [F2 [ 2r(F2)]
wR2a (all data)
0.0609
0.0299
0.0433
0.1412
0.0513
0.1011
Sa
0.94
0.83
1.10
np
172
333
222
-3
˚
Residuals (max/min) (eA
)
0.299/-0.222
0.880/0.980
0.400/-0.370
0.714/0.980
0.175/-0.173
0.969/0.990
Transmission factors (max/min)
a
‘
‘
R1 = (R |Fo| - |Fc|)/R |Fo|); wR2 = {R [w(F2o - Fc2)2]/R [w(Fo2)2]} ; S = {R [w(Fo2 - F2c)2]/(n - p)}
In the crystal packing the carboxylic acid group forms
classic centrosymmetric head-to-head cyclic intermolecu-
lar hydrogen-bonding associations [graph set R22(8)] [20]
the cyclohexane ring system as indicated by the relatively
higher thermal activities observed in the constituent carbon
atoms, resulting in disorder which is more extreme in 3.
This activity has also been present in other examples of
cyclic imides of this series [13, 14] but not to the extent
observed in 2 and 3.
˚
[O21–HÁÁÁO22, 2.662(3) A: symmetry code (ii) -x ? 1,
-y ? 1, -z ? 1], the dimers formed being extended into a
two-dimensional sheet structure through amide N11–
ii
˚
HÁÁÁO12 (ketone) hydrogen bonds [2.862(3) A: symmetry
With compound 2, there are two independent cyclic imide
molecules (A and B) in the asymmetric unit (Figs. 3, 4). In
both of these, the cis-configuration is present as expected,
with ordered A having a [C8A(R),C9A(S)] assignment and
the major component of the B molecule, [C8B(S),C9B(R)],
with the minor (C) component [C8C(R),C9C(S)], A and B
representing a partial racemic pair. With the molecule B,
there is significant disorder in most of the atoms of the
cyclohexane ring, with atoms C4B and C7B [site occupancy
factor = 0.73(1)] having alternative ‘flipped’ chair confor-
mational sites [C4C and C7C: S.O.F. = 0.27(1)], C having
the [C8(R),C9(S)] configuration. The two ring systems are
code (i) -x ? 1, y - ‘, z] (Fig. 2). This structure is
similar to that of the analogous compound N-(4-chloro-
phenyl)phthalanilic acid [21].
The two cis-cyclic imides 2 and 3 show many structural
similarities.
Both compounds are conformationally similar with
variations resulting from ring rotations about the imine
N–C(phenyl) bond, as indicated by the minimum C–N2–
C–C torsion angles of 49.8(4)° and -61.1(4)° for the two
independent molecules in 2 and -65.7(3)° in 3. A common
feature of both 1 and 2 is the conformational stress within
123

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J Chem Crystallogr (2012) 42:1029–1035
Fig. 1 Atom numbering
scheme for 1, with non-
hydrogen atoms shown as 40 %
probability ellipsoids [15]
Fig. 2 The hydrogen-bonded
chain structures in 1 showing
the head-to-head cyclic dimeric
carboxylic acid hydrogen-
bonding associations and the
extension through N–HÁÁÁO
hydrogen bonds. Non-
associative H-atoms are omitted
also different with respect to the rotation about the
N–C(phenyl) bond as indicated previously and both this and the
disorder are therefore responsible for the presence of the two
independent pseudo-racemic molecules in the P21 asymmetric
unit rather than forming the common centrosymmetrically
related racemic pairs found in most examples [13, 14].
There are only minor intermolecular aromatic C–HÁÁÁO
interactions in the crystal structure [C21B–HÁÁÁO1Bi,
ii
˚
˚
3.153(4) A, and C61A–HÁÁÁO3A , 3.058(3) A; symmetry
codes: (i) x, y - 1, z; (ii) x, y ? 1, z].
The cyclic imide 3 also has disorder in the cyclohexane
moiety of the molecule which is more extensive than in 2,
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J Chem Crystallogr (2012) 42:1029–1035
1033
Fig. 3 The ordered
(A) molecule in the asymmetric
unit of 2, showing 40 %
probability ellipsoids
Fig. 4 The partially disordered
(B) molecule in the asymmetric
unit of 2, showing 30 %
probability ellipsoids
involving most of the perhydroisoindole-1,3-dione atoms
(Fig. 5). Both components have the cis-configuration with
the major component [site occupancy factor = 0.85(1)
having a slightly distorted chair conformation while the
minor component adopts a more distorted chair confor-
mation. The minimum torsion angle between the benzene
ring and the isoindoline ring (C21–C11–N1–C1) is
-65.7(3)°, while the carboxylic acid group is essentially
coplanar with the benzene ring [torsion angle C21–C31–
C311–O32, 175.2(2)°]. This conformation is maintained by
an intramolecular hydrogen bond between the hydroxyl
and carboxyl groups [O41–HÁÁÁO32, 2.603(3)°; O–HÁÁÁO
angle 138°], which is similar to that found in the parent
salicylic acid [22].
In the crystal packing (Fig. 6), the molecules form one-
dimensionalzigzag chainsthrough intermolecular carboxylic
Fig. 5 The molecular
conformation and atom
numbering scheme for the
disordered molecule of 3,
showing 30 % probability
ellipsoids
123

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J Chem Crystallogr (2012) 42:1029–1035
Fig. 6 A perspective view of 3 in the unit cell viewed down the a axial direction. The minor disordered component (A) of the
hexahydroisoindole ring system and non-associative H-atoms are omitted
acid O–HÁÁÁO(isoindoline) hydrogen bonds [O31–HÁÁÁO1i,
free of charge from The Cambridge Crystallographic Data
Centre via http://www.ccdc.cam.ac.uk/data_request/cif or
by e-mailing data_request@ccdc.cam.ac.uk, or by contact-
ing The Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK.
˚
2.707(3) A: O–HÁÁÁO angle 179°: symmetry code (i) -x,
y - ‘, -z ? ‘]. These chains extend across the b cell
direction in the unit cell.
Acknowledgments The author acknowledges financial support
from the Australian Research Council and the Science and Engi-
neering Faculty, Queensland University of Technology.
Conclusion
This work provides further examples of the structures of
cyclic imides and open-chain amide carboxylic acids from
the facile reaction of cis-cyclohexane-1,2-dicarboxylic
anhydride with substituted anilines. Within this relatively
small set of known structures (currently 11 examples,
including 1–3), there is a much higher incidence of cyclic
imides (8) compared to amide acids (3). However, func-
tional group influence upon which form is preferred is not
apparent from the examples structurally characterized in
this and previous work with this series of compounds.
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Supplementary material
CCDC entries 862423, 862424 and 862425 contain the
supplementary crystallographic data for compounds 3, 2 and
1, respectively, from this paper. These data can be obtained
123

J Chem Crystallogr (2012) 42:1029–1035
1035
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