Design of a series of isostructural Co-crystals with aminopyrimidines: Isostructurality through chloro/methyl exchange and studies on supramolecular architectures

Article abstract of DOI:10.1021/cg200539a

A series of 17 co-crystals involving 2-amino-4-chloro-6-methyl pyrimidine/2-amino-4,6-dimethyl pyrimidine with various carboxylic acids, C ₇H₅O₂-R (where R = H, Cl, CH₃, NO₂, OCH₃, COOH) and C₉H₈O ₂, have been prepared in which the analogues differ only with respect to chlorine and methyl groups. The basis of this work is the formation of isostructural co-crystals based on the chloro/methyl interchange. The results show good success in the harvest of isostructural compounds. Isostructurality calculations have been carried out in order to substantiate these results. Apart from this some of the compounds have been identified to show good resemblance in their structure, yet do not have any relation based on chloro/methyl interchange. This is explained by the fact that all the co-crystals in the present study tend to form one common supermolecule: a linear heterotetramer. This supermolecule is known to be the most stable and reliable heterotetramer formed between an aminopyrimidine and benzoic acid, according to a recent report,(1)which is believed to be responsible for the isostructurality other than chloro/methyl exchange.

Full text of DOI:10.1021/cg200539a

ARTICLE
pubs.acs.org/crystal
Design of a Series of Isostructural Co-Crystals with Aminopyrimidines:
Isostructurality through Chloro/Methyl Exchange and Studies on
Supramolecular Architectures
Samuel Ebenezer,† P. Thomas Muthiah,*,† and Ray J. Butcher‡
†School of Chemistry, Bharathidasan University, Tiruchirappalli-620 024, India
‡Department of Chemistry, Howard University, Washington, D.C. 20059, United States
S Supporting Information
b
ABSTRACT: A series of 17 co-crystals involving 2-amino-4-
chloro-6-methyl pyrimidine/2-amino-4,6-dimethyl pyrimidine
with various carboxylic acids, C7H5O2-R (where R = H, Cl,
CH3, NO2, OCH3, COOH) and C9H8O2, have been prepared
in which the analogues differ only with respect to chlorine and
methyl groups. The basis of this work is the formation of
isostructural co-crystals based on the chloro/methyl inter-
change. The results show good success in the harvest of
isostructural compounds. Isostructurality calculations have
been carried out in order to substantiate these results. Apart
from this some of the compounds have been identified to show
good resemblance in their structure, yet do not have any relation
based on chloro/methyl interchange. This is explained by the fact that all the co-crystals in the present study tend to form one
common supermolecule: a linear heterotetramer. This supermolecule is known to be the most stable and reliable heterotetramer
formed between an aminopyrimidine and benzoic acid, according to a recent report,1 which is believed to be responsible for the
isostructurality other than chloro/methyl exchange.
’ INTRODUCTION
motifs with similar related molecules.21 These are in a way just
the opposite of polymorphs. Polymorphic structures are species
of the same molecules with different arrangements, whereas
isostructural compounds are different species having a similar
structural arrangement. In principle, crystal structures with
similar structures are likely to have similar properties. However,
in the past decade the focus has been shifted to this which is
evident from the vast number of isostructures that have been
published.22À35 A number of articles on isostructurality and
methods to calculate the structural similarity (through several
descriptors) between molecules possessing similar packing
arrangements have been introduced.21,36À38 Some of the most
frequently occurring isostructural pairs are formed when the
methyl group is replaced by chlorine. Around 30% of the pairs of
molecules are found to be isostructural, with chlorine/methyl
exchange because of its comparable volume which is substan-
tiated by a CSD study.39 Thus, this strategy (chloro/methyl
interchange) is concerned with the design of isostructural co-
crystals. The idea behind this study is to present the exciting
prospect of designing materials of different composition with the
same structural building block.
Controlling the mutual organization of molecules in space
using noncovalent interactions for a desired property is the art of
crystal engineering.2 To understand the phenomenon of molec-
ular recognition, one must understand all the noncovalent
interactions, among which hydrogen bonding plays a key role.3,4
It is important to understand the hierarchy of hydrogen bonds in
order to rationally design molecular crystals. The current interest
has been engineering molecules with tailor-made properties by
controlling the solid-state assembly of molecules, especially for
design and synthesis of functional solids.5À10 Recently, much
consideration has been given to synthesis of co-crystals due to
their potential applications in the pharmaceutical industry. The
prime reason for this has been the fact that the active pharma-
ceutical ingredients (APIs) possessing no basic or acidic groups
could be co-crystallized without altering their chemical
properties.11,12 More time and work have been spent on devel-
oping strategies in preparing co-crystals. The recent literature has
revealed several strategies and analysis in this regard.13À19 In fact,
a special issue has been solely devoted to pharmaceutical co-
crystals by the journal Crystal Growth and Design.20
Isostructurality is another phenomenon which has not been
paid much attention to, nor has it been brought into the limelight
unlike polymorphism and co-crystallization. Isostructural solids
are referred to as those compounds forming identical packing
Received: April 28, 2011
Revised:
June 6, 2011
Published: June 08, 2011
r
2011 American Chemical Society
3579
dx.doi.org/10.1021/cg200539a Cryst. Growth Des. 2011, 11, 3579–3592
|

Crystal Growth & Design
ARTICLE
Scheme 1. Structures of Different Co-Crystal Formers and
the Aminopyrimidine Bases
days, colorless platelike crystals of compound 17 separated out of the
mother liquor.
MP and CP were purchased from Sigma-Aldrich, Inc. All acids
except cinnamic acid were purchased from Loba chemie Pvt. Ltd.,
India. Cinnamic acid was purchased from S.d. Fine chemicals Pvt.
Ltd., India.
’ X-RAY CRYSTALLOGRAPHY
Single crystals having suitable dimensions for 1À17 were used
for data collection using a Bruker SMART APEX-II diffractometer50
at room temperature equipped with graphite-monochromatic
Mo-KR radiation (λ = 0.71073 Å). Integration and cell refine-
ment were carried out using Bruker SAINT.50 The absorption
corrections were performed by multiscan method using SADABS.50
Corrections were made for Lorentz and polarization effects. The
molecular structures were solved by direct methods (SHELXL-
86/SHELXL-97) and refinement by full-matrix least-squares on
F2 (SHELXS-97).51 The non-hydrogen atoms were refined
anisotropically, while the hydrogen atoms were placed in their
geometrically idealized positions and constrained to ride on their
parent atoms. The program PLATON52 was used to generate
hydrogen bond table, while MERCURY53 was used for all
graphical representation of the results. The crystallographic data
and all the experimental details for structures 1À17 are presented
in Table 1, while the hydrogen bond distances are listed in
Table 2.
Pyrimidine and aminopyrimidine derivatives are biologically
important for they occur in nature as components of nucleic acid
and drugs.40,41 Several co-crystals of aminopyrimidine and
pyridine derivatives have been reported earlier from our
group.42À49 In the present study, 17 co-crystals using aminopyr-
imidine bases, 2-amino-4, 6-dimethylpyrimidine (MP) and
2-amino-4-chloro-6-methylpyrimidine (CP), with various acids
(Scheme 1) are prepared in which the two bases differ only by a
chlorine/methyl group at C4 of the pyrimidine ring. Thus, the
availability of a series of isostructural co-crystals offers an
opportunity to determine the structural packing arrangement
and their similarities.
’ RESULTS
Crystal Structures of MP 2MBA (1), MP 3MBA (2), CP 4
3
3
3
CBA (3), and MP 4CBA (4). Compounds 1À4 crystallize in the
3
monoclinic space group C2/c. In each of the co-crystals, the
asymmetric unit contains a molecule of pyrimidine base and a
molecule of aromatic acid. The main motif of 1, 2, and 4
comprises one molecule of MP with one molecule of 2MBA,
one molecule of MP with one molecule of 3MBA, and one
molecule of MP with one molecule of 4CBA respectively,
assembled via a complementary hydrogen-bond interaction
between the carboxylic acid and the amino-pyrimidine moiety
to form a dimeric unit. Similarly in 3, the dimer is formed
through a molecule of CP and a molecule of 4CBA. Adjacent
dimeric units are further connected through self-complemen-
’ EXPERIMENTAL SECTION
Compounds 1, 2, 4, 7, 10, and 12 were prepared by mixing hot
ethanolic solution of MP with hot ethanolic solution of 2-methylbenzoic
acid (2MBA)/3-methylbenzoic acid (3MBA)/4-chlorobenzoic acid
(4CBA)/2-chlorobenzoic acid (2CBA)/4-nitrobenzoic acid (4NBA)/
3-nitrobenzoic acid (3NBA) respectively in a 1:1 molar ratio. Each of the
mixtures was warmed over a water bath for half an hour, cooled slowly,
and kept at room temperature. After a few days, colorless platelike
crystals (for compounds 1 and 7) and colorless prismatic crystals
(of compounds 2, 4, 10, and 12) separated out of the corresponding
mixture.
Compounds 3, 5, 6, 8, 9, 11, and 13À16 were prepared by mixing hot
ethanolic solution of CP with hot ethanolic solution of 4-chlorobenzoic
acid (4CBA)/benzoic acid (BA)/3-methylbenzoic acid (3MBA)/
2-chlorobenzoic acid (2CBA)/2-methylbenzoic acid (2MBA)/4-nitro-
benzoic acid (4NBA)/phthalic acid (PA)/cinnamic acid (CA)/3-nitro-
benzoic acid (3NBA)/4-methoxybenzoic acid (4MOBA) respectively in
a 1:1 molar ratio and warmed in a water bath for a few minutes. The
mixtures were then allowed to cool slowly at room temperature. After a
few days, colorless platelike crystals (of compounds 3, 5, 8, 11, 13, 14,
and 16) and colorless prismatic crystals (for compounds 6, 9, and 15)
separated out of the mother liquor.
tary secondary N(2)ÀH(2X)
N(3) (X indicates different
values which vary for different structures) hydrogen bonds to
3 3 3
form a four-component supermolecule. Thus, the primary and
secondary hydrogen bonds, O(1)ÀH(1)
N(1), N(2)À
3 3 3
H(2X)
O(2), and N(2)ÀH(2X)
3 3 3
N(3) combine to form
3 3 3
a linear heterotetramer motif. Two of these inversion related
heterotetramers are linked through a couple of weak C-
6
(X)ÀH(X)
O(2) bonds to form a cyclic R8 (28) ring motif
3 3 3
(Figure 1A). The free C(X)ÀH(X)
O(2) bonds on either
3 3 3
ends connect with similar heterotetramers to form a long
hollow channel as shown in Figure 1B. A similarity is observed
in all the four structures as several such channels lie parallel to
one another along the c-axis (Figure 1C). The pyrimidine rings
between two adjacent cyclic motifs stack one over the other with
a centroid-to-centroid (Cg—Cg) distance and a slip angle
(the angle between the centroid vector and the normal to the
plane) of 3.8686(8) Å and 5.77ꢀ for 1, 3.7505(7) Å and 24.43ꢀ for
2, 3.7465(11) Å and 24.96ꢀ for 3, and 3.8037(11) Å and 24.92ꢀ
for 4 respectively.
Compound 17 was prepared by mixing hot methanolic solution of
MP with hot methanolic solution of cinnamic acid in a 1:1 molar ratio
and warming the mixture over a water bath for a few minutes. The
mixture was then allowed to cool slowly at room temperature. After a few
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Crystal Growth & Design
ARTICLE
Table 1. Crystallographic Data and Refinement Details for Co-Crystals 1À17
MP 2MBA (1)
MP 3MBA (2)
CP 4CBA (3)
MP 4CBA (4)
CP BA (5)
CP 3MBA (6)
3
3
3
3
3
3
empirical formula
formula weight
crystal system
space group
a [Å]
C8H8O2, C6H9N3 C8H8O2, C6H9N3 C5 H6ClN3, C7H5ClO2 C6H9N3, C7H5ClO2 C5H6ClN3, C7H6O2 C8H8O2, C5H6ClN3
259.31
259.31
300.14
279.72
265.70
279.72
monoclinic
C2/c
monoclinic
C2/c
monoclinic
C2/c
monoclinic
C2/c
monoclinic
P21/c
monoclinic
P21/c
24.7397(2)
7.5123(1)
14.9760(2)
90
26.9424(12)
7.3192(3)
14.3603(6)
90
26.6684(4)
7.3762(1)
14.2490(2)
90
26.5020(4)
7.4361(1)
14.3922(2)
90
7.5335(13)
8.1173(12)
21.321(2)
90
7.526(5)
8.809(5)
21.362(5)
90
b [Å]
c [Å]
R [ꢀ]
β [ꢀ]
γ [ꢀ]
V [Å3]
90.949(1)
90
92.473(4)
90
99.869(2)
90
98.915(1)
90
103.213(6)
90
102.732(15)
90
2782.94(6)
8
2829.2(2)
8
2761.46(7)
8
2802.03(7)
8
1269.3(3)
4
1381.4(13)
4
Z
D (calc) [g/cm3]
μ (MoKR) [ /mm ]
tot., uniq. data,
observed data
[I > 2.0σ (I)]
R
1.238
1.218
1.444
1.326
1.390
1.345
0.085
0.084
0.471
0.274
0.299
0.278
31 878, 5007,
33 227, 5405
29 403, 3947
24 129, 2791
9807, 4090
16 745, 4807
2500
3106
2316
2101
2953
2603
0.0560
0.1779
1.03
0.0598
0.2134
1.05
0.0484
0.1522
1.03
0.0471
0.1473
1.05
0.0482
0.1668
1.09
0.0613
0.1741
1.02
wR2
S
min, max peak [e/Å3] À0.18, 0.21
À0.22, 0.24
762804
À0.34, 0.29
762800
À0.35, 0.27
762806
À0.32, 0.32
721433
À0.26, 0.29
762798
CCDC no.
762803
MP 2CBA (7)
CP 2CBA (8)
CP 2MBA (9)
MP 4NBA (10)
CP 4NBA (11)
MP 3NBA (12)
3
3
3
3
3
3
empirical formula
formula weight
crystal system
space group
a [Å]
C6H9N3, C7H5ClO2 C5H6ClN3, C7H5ClO2 C8H8O2, C5H6ClN3 C6H9N3, C7H5NO4 C7H5NO4, C5H6ClN3 C6H9N3, C7H5NO4
279.72
300.14
300.14
290.28
310.70
290.28
monoclinic
P21/c
monoclinic
P21/c
monoclinic
P21/c
triclinic
P1
triclinic
P1
triclinic
P1
7.8510(1)
24.1910(4)
8.3116(1)
90
7.7594(3)
24.3335(7)
8.2817(3)
90
7.9118(1)
24.0539(4)
8.2112(1)
90
6.8705(12)
7.4812(14)
13.717(2)
81.763(9)
80.563(9)
84.009(9)
686.0(2)
2
6.9797(4)
7.3469(4)
13.7131(7)
80.291(3)
78.448(3)
85.491(3)
678.35(6)
2
6.9651(1)
7.5279(2)
13.2985(3)
94.254(1)
92.751(1)
98.482(1)
686.52(3)
2
b [Å]
c [Å]
R [ꢀ]
β [ꢀ]
γ [ꢀ]
V [Å3]
120.591(1)
90
120.610(3)
90
119.926(1)
90
1358.87(4)
4
1345.80(9)
4
1354.32(4)
4
Z
D (calc) [g/cm3]
μ (MoKR) [ /mm ]
tot., uniq. data,
observed data
[I > 2.0σ (I)]
R
1.367
1.481
1.372
1.405
1.521
1.404
0.283
0.483
0.284
0.107
0.304
0.107
16820, 4464
12788, 2639
14915, 3296
12693, 3002
19134, 4899
16350, 4323
2942
1744
2360
2166
3632
3255
0.0481
0.1467
1.05
0.0508
0.1478
1.03
0.0486
0.1560
1.05
0.0470
0.1385
1.06
0.0514
0.1600
1.07
0.0500
0.1666
1.07
wR2
S
min, max peak [e/Å3] À0.20, 0.30
À0.42, 0.41
762796
À0.40, 0.37
762797
À0.18, 0.24
762807
À0.35, 0.41
721434
À0.23, 0.32
762805
CCDC no.
762802
CP PA (13)
CP CA (14)
CP 3NBA (15)
CP 4MOBA (16)
MP CA (17)
3
3
3
3
3
empirical formula
formula weight
crystal system
space group
a [Å]
C5H6ClN3, C8H6O4
309.71
C9H8O2, C5H6ClN3
291.73
C7H5NO4, C5H6ClN3
310.70
C8H8O3, C5H6ClN3
295.72
2(C9H8O2), C6H9N3
419.47
monoclinic
P21/c
monoclinic
P21/c
monoclinic
P21/c
triclinic
triclinic
P1
P1
11.1623(5)
7.4613(3)
6.0521(12)
7.9650(16)
9.8924(3)
7.5499(1)
8.9221(1)
8.6811(1)
11.5513(2)
b [Å]
15.0036(4)
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Crystal Growth & Design
ARTICLE
Table 1. Continued
CP PA (13)
CP CA (14)
CP 3NBA (15)
CP 4MOBA (16)
MP CA (17)
3
3
3
3
3
11.5896(2)
87.227(1)
77.166(1)
81.834(1)
1121.49(3)
2
c [Å]
17.0269(8)
30.415(5)
11.3404(4)
11.1715(2)
104.400(1)
99.632(1)
94.909(1)
712.204(18)
2
R [ꢀ]
β [ꢀ]
γ [ꢀ]
V [Å3]
90
90
90
93.404(3)
90
97.137(11)
90
121.196(2)
90
1415.59(11)
4
1454.8(5)
4
1439.78(8)
4
Z
D (calc) [g/cm3]
1.453
1.332
1.433
1.379
1.242
μ (MoKR) [ /mm ]
0.289
0.267
0.287
0.279
0.086
tot., uniq. data, observed data
21234, 4358
3140
19771, 4108
2475
10187,1942
1495
17239, 5036
2924
24521,5974
3139
[I > 2.0σ (I)]
R
0.0547
0.1648
1.04
0.0517
0.1991
1.06
0.0406
0.1360
1.05
0.0486
0.0492
wR2
0.1737
0.1525
S
1.03
1.03
min, max peak [e/Å3]
À0.61, 0.47
723878
À0.35, 0.31
721432
À0.27, 0.25
762799
À0.22, 0.35
762801
À0.19, 0.22
762808
CCDC no.
Crystal Structures of CP BA (5), CP 3MBA (6), MP 2CBA
(7), CP 2CBA (8), and CP 2MBA (9). All the five co-crystals
hydrogen bonds to form a large ring motif with graph set notation
6 6
3
3
3
R6 (30) for 10 and 11 and R6 (28) for 12 (Figure 3A), respectively.
In all three cases, infinite linear ribbons are formed by the fusion
of these small rings. Such type of ribbons stack with the neighboring
ones through stacking interaction between the inversely related
pyrimidine moieties with a Cg—Cg distance and slip angle of
3.7625(11) Å and 23.98ꢀ for 10, 3.8568(8) Å and 28.37ꢀ for 11,
3
3
(5À9) crystallize in the monoclinic P21/c space group. Each of
them has a molecule of pyrimidine base and a molecule of an acid
in the asymmetric unit. The primary motifs in 5, 6, 8, and 9 are
made up of CP with BA, 3MBA, 2CBA, and 2MBA, respectively,
which are interconnected through acid and amino-pyrimidine
moiety to form a dimeric unit identical to the previous case. The
same is observed in 7, where the dimeric unit is made up of MP
and 2CBA. A similar four-component supermolecule is formed as
in the earlier case, through primary and secondary hydrogen
bonds (O(1)ÀH(1) N(1), N(2)ÀH(2X) O(2), and N-
and 3.6431(7) Å and 20.90ꢀ for 12. In CP 4NBA, besides the
3
stacking interaction, the free oxygen in the 4-nitro group and the
chlorine in CP connects the neighboring ribbons through Cl-
(1) O(4) interaction (Figure 3B) with a Cl(1) O(4)
3 3 3
3 3 3
distance of 3.0904(18) Å and C(4)ÀCl(1) O(4) angle of
3 3 3
3 3 3
3 3 3
(2)ÀH(2X) N(3)) involving the amino and hydroxyl pro-
175.54(6)ꢀ.
3 3 3
tons of carboxylic acid as donors and the two pyrimidine nitrogen
including the oxygen of the carboxyl group as acceptors. The
identical cell parameters between 5 and 6 and those among 7À9
are reflected in their packing arrangement. This is clearly
demonstrated in Figure 2A,B. Common patterns of stacking
interactions are observed between 5 and 6 and those among
7À9. In the former case, two of the heterotetramers stack
partially one over the other, having πÀπ stacking between the
inversely related acidÀbase dimers (Figure 2C). The Cg—Cg
distance and the slip angles are 3.6650(12) Å and 13.36ꢀ for
MP BA and 3.701(3) Å and 18.55ꢀ for MP 3MBA respectively.
In the latter case, there is stacking between inversely related
pyrimidine moieties of adjacent heterotetramers (Figure 2D)
with a Cg—Cg distance of 3.9606(9) Å, 3.955(2) Å, and
3.8448(13) Å and slip angles of 22.90ꢀ, 22.82ꢀ, and 18.76ꢀ for
7, 8, and 9 respectively.
Crystal Structure of CP PA (13). In 13, the asymmetric unit
3
of monoclinic space group P21/c contains a molecule of CP and
PA. The pyrimidine molecule shows substitutional disorder with
the chlorine and methyl groups having partial occupancies at the
fourth and sixth position of the ring. This disorder could be
accounted for on the basis of chlorine/methyl interchange since
both groups are very similar in their volume. CP PA is different
3
from the rest of them as there is no formation of the hetero-
tetrameric motif. The presence of another strong functionality
(carboxyl group) in the aromatic ring has disrupted the forma-
tion of the expected heterotetramer. Phthalic acid possesses two
carboxylic acid groups that lie in different planes thereby forming
a double cyclic hydrogen bonded ring with the pyrimidine
molecules (two sets of complementary hydrogen-bond interac-
3
3
tions involving pyrimidine moieties are O(1)ÀH(1) N(1),
3 3 3
N(2)ÀH(2A)ÀO(2), and O(3)ÀH(3) N(3), N(2)ÀH-
3 3 3
(2B) O(4)) which prevents the formation of a base pair unlike
Crystal Structures of MP 4NBA (10), CP 4NBA (11), and
3 3 3
3
3
MP 3NBA (12). In each of the compounds 10À12, crystallizing
the other compounds. Instead, a helical chain is formed through a
21 screw along the b axis (Figure 4). O(2) acts as a bifurcated
acceptor apart from the intermolecular hydrogen bond with
3
in the triclinic space group P1, the asymmetric unit contains one
molecule of MP with one molecule of 4NBA, one molecule of CP
with one molecule of 4NBA, and one molecule of MP with one
molecule of 3NBA, respectively. In all three cases, the two
molecules are connected through the acid and amino-pyrimidine
N(2)ÀH(2A). The C(5)ÀH(5) O(2) bonds involving O(2)
3 3 3
of one of the helical chains, form hydrogen bonds with the
C(5)ÀH(5) of a centrosymmetrically related chain thus holding
both chains in close proximity. The closeness of the helices is
partly due to the πÀπ stacking interactions between the
pyrimidines of the interpenetrated helices (CgÀCg distance
and slip angle of 3.7606(10) Å and 24.79ꢀ respectively) and
moieties engaging in O(1)ÀH(1) N(1) and N(2)ÀH-
3 3 3
(2A) O(2) and N(2)ÀH(2A) N(3) hydrogen bonds
3 3 3
3 3 3
leading to the formation of the linear heterotetramer. Apart from
the formation of the four-component supermolecule, these
motifs fuse with the neighboring ones through soft CÀH
O
the weak C(5)ÀH(5) O(2) hydrogen bonds.
3 3 3
3 3 3
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Crystal Growth & Design
ARTICLE
Table 2. Continued
Table 2. Hydrogen Bond Metrics for Compounds 1À17
D---H
A
H
A (Å)
D
A (Å) —DÀH
3 3 3
A
3 3 3
3 3 3
2.46
3 3 3
D---H
A
H
A (Å)
D
A (Å) —DÀH
A
3 3 3
MP 2MBA (1)
3 3 3
3 3 3
3 3 3
C(8)--H(8B) O(3)
3.3845(19)
162
3 3 3
3
C(5)--H(5) O(4)
2.80
3.6501(2)
148
3 3 3
O(1)--H(1) N(1)
1.81
2.6158(16)
2.9644(18)
3.1277(17)
3.378(2)
166
168
173
173
3 3 3
CP PA (13)
3
N(2)--H(2A) O(2)
2.12
2.27
2.45
3 3 3
O(1)—H(1) N(1)
1.95
2.00
2.01
1.90
2.50
2.7700(19)
2.855(2)
2.854(2)
2.715(2)
3.261(2)
173
171
169
171
139
3 3 3
N(2)--H(2B) N(3)
3 3 3
N(2)—H(2A) O(2)
3 3 3
C(12)--H(12) O(2)
3 3 3
N(2)—H(2B) O(4)
3 3 3
MP 3MBA (2)
3
O(3)—H(3) N(3)
3 3 3
O(1)--H(1) N(1)
1.80
2.16
2.04
2.67
2.6052(14)
3.0203(14)
2.8927(16)
3.5170(12)
167
177
171
151
3 3 3
C(5)—H(5) O(2)
3 3 3
N(2)--H(2A) N(3)
3 3 3
CP CA (14)
3
N(2)--H(2B) O(2)
3 3 3
O(1)--H(1) N(1)
1.89
2.10
2.21
2.695(2)
2.945(2)
3.074(3)
170
166
177
3 3 3
C(12)--H(12) O(2)
3 3 3
N(2)--H(2A) O(2)
3 3 3
CP 4CBA (3)
3
N(2)--H(2B) N(3)
3 3 3
O(1)--H(1) N(1)
1.87
2.04
2.19
2.56
2.687(2)
2.892(3)
3.043(2)
3.426(3)
171
170
174
154
3 3 3
CP 3NBA (15)
3
N(2)--H(2A) O(2)
3 3 3
O(1)--H(1) N(1)
1.86
2.20
2.02
2.39
2.48
2.671(3)
3.054(3)
2.878(3)
3.295(4)
3.236(3)
170
172
171
165
139
3 3 3
N(2)--H(2B) N(3)
3 3 3
N(2)--H(2A) N(3)
3 3 3
C(13)--H(13) O(2)
3 3 3
N(2)--H(2B) O(2)
3 3 3
MP 4CBA (4)
3
C(5)--H(5) O(3)
3 3 3
O(1)--H(1) N(1)
1.79
2.18
2.03
2.51
2.595(2)
3.036(2)
2.877(3)
3.386(3)
167
175
171
158
3 3 3
C(14)--H(14) O(4)
3 3 3
N(2)--H(2A) N(3)
3 3 3
CP 4MOBA (16)
3
N(2)--H(2B) O(2)
3 3 3
O(1)--H(1) N(1)
1.91
2.23
2.01
2.7190(17)
3.0493(19)
2.8590(19)
170
159
168
3 3 3
C(12)--H(12) O(2)
3 3 3
N(2)--H(2A) N(3)
3 3 3
CP BA (5)
3
N(2)--H(2B) O(2)
3 3 3
O(1)--H(1) N(1)
1.86
2.11
2.21
2.6683(18)
2.963(2)
3.059(2)
166
170
168
3 3 3
MP CA (17)
3
N(2)--H(2A) O(2)
3 3 3
O(1A)--H(1A) N(1)
1.88
1.87
2.14
2.08
2.53
2.6919(17)
2.6757(18)
2.9813(18)
2.9094(19)
3.381(3)
170
167
167
163
153
3 3 3
N(2)--H(2B) N(3)
3 3 3
O(1B)--H(1B) N(3)
3 3 3
CP 3MBA (6)
3
N(2)--H(2A) O(2B)
3 3 3
O(1)--H(1) N(1)
1.91
2.26
2.12
2.699(3)
3.113(3)
2.972(3)
162
171
169
3 3 3
N(2)--H(2B) O(2A)
3 3 3
N(2)--H(2A) N(3)
3 3 3
C(16B)--H(16B) O(2A)
3 3 3
N(2)--H(2B) O(2)
3 3 3
MP 2CBA (7)
3
O(1)--H(1) N(1)
1.79
2.18
2.01
2.5999(16)
3.0303(17)
2.8579(18)
167
171
167
Crystal Structure of CP CA (14). In the co-crystal 14, crystal-
3 3 3
3
N(2)--H(2A) N(3)
lizing in the space group P21/c, the asymmetric unit contains a
molecule of CP and CA. These molecules are interconnected
through O(1)ÀH(1) N(1) and N(2)ÀH(2A) O(2) hy-
3 3 3
N(2)--H(2B) O(2)
3 3 3
CP 2CBA (8)
3 3 3
3 3 3
3
drogen bonds to form a dimeric unit. These dimers self-assemble
with one another and pair up to form a four-component super-
molecule as expected through secondary hydrogen bonds
O(1)--H(1) N(1)
1.88
2.19
2.07
2.689(3)
3.044(4)
2.897(4)
170
170
162
3 3 3
N(2)--H(2A) N(3)
3 3 3
N(2)--H(2B) O(2)
3 3 3
(N(2)ÀH(2B) N(3)) (Figure 5).
3 3 3
CP 2MBA (9)
3
Crystal Structure of CP 3NBA (15). The asymmetric unit in
3
O(1)--H(1) N(1)
1.90
2.23
2.13
2.713(2)
3.073(2)
2.939(2)
171
167
157
3 3 3
15 (crystallized in the space group P21/c) contains a molecule of
CP and 3NBA. The crystal structure of CP 3NBA consists of
N(2)--H(2A) N(3)
3 3 3
3
N(2)--H(2B) O(2)
3 3 3
O(1)ÀH(1) N(1) and N(2)ÀH(2B) O(2) interactions
3 3 3
3 3 3
MP 4NBA (10)
forming a dimer (primary motif). Two dimers connect through self-
3
O(1)--H(1) N(1)
1.75
2.21
2.17
2.60
2.552(2)
3.052(2)
3.003(2)
3.403(2)
163
167
163
145
complementary N(2)ÀH(2A) N(3) hydrogen bonds to generate
3 3 3
3 3 3
N(2)--H(2A) N(3)
a linear heterotetrameric supermolecule. These supermolecules
3 3 3
combine together through a couple of C(5)ÀH(5) O(3)
N(2)--H(2B) O(2)
3 3 3
3 3 3
bonds to produce a large ring motif with graph set notation
C(5)--H(5) O(3)
3 3 3
5
R5 (22). In addition to this three of the supermolecules are
CP 4NBA (11)
3
connected to one another through a couple of C(14)ÀH-
O(1)--H(1) N(1)
1.83
2.28
2.21
2.43
2.6312(17)
3.1139(19)
3.0406(19)
3.257(2)
164
163
163
148
3 3 3
(14) O(4) and a C(5)ÀH(5) O(3) hydrogen bonds to
3 3 3
3 3 3
N(2)--H(2A) N(3)
4
3 3 3
form another ring motif, R4 (24). These motifs recur continu-
ously in two-dimensional planes linking all the heterotetramer.
On the whole, the structure may be expressed as a supramole-
cular sheet lying on the (302) plane as shown in Figure 6.
N(2)--H(2B) O(2)
3 3 3
C(5)--H(5) O(3)
3 3 3
MP 3NBA (12)
3
O(1)--H(1) N(1)
1.76
2.20
2.05
2.5676(15)
3.0481(15)
2.8894(16)
166
168
166
3 3 3
Crystal Structure of CP 4MOBA (16). In 16 (crystallizing in
the space group P1), the asymmetric unit contains a molecule of
CP and a molecule of 4MOBA. After the formation of dimer
3
N(2)--H(2A) N(3)
3 3 3
N(2)--H(2B) O(2)
3 3 3
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Crystal Growth & Design
ARTICLE
Figure 1. (A) View of a cyclic ring motif formed in 2 between two inversely related heterotetramers. (B) Formation of channel through interconnected
ring motifs along the c-axis in 2. (C) Packing view of 1À4 along the z-axis.
through the primary hydrogen bonds, the unused amino proton
nitrogen extending the architecture into a four-component
supermolecule. Albeit there are no other hydrogen bonds present
forms N(2)ÀH(2A) N(3) hydrogen bonds with the pyrimidine
3 3 3
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Crystal Growth & Design
ARTICLE
Figure 2. (A) Crystal structures of 5 and 6 showing similar packing arrangements. (B) Exhibition of similar packing arrangements in structures 7À9.
(C) View of stacking interactions illustrated in crystal structure 5. Hydrogen atoms are omitted for clarity. (D) View of stacking interactions in crystal
structure 7. Hydrogen atoms are omitted for clarity.
for the further aggregation of the heterotetramers, they arrange
themselves adjacent to one another along the (210) plane
(Figure 7). Several such planes lay one over the other through
stacking of the pyrimidine and the acid molecules. There are two
types of stacking involved in the pyrimidine moiety, one with the
acid ring of the upper plane and the other with that of the lower
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Crystal Growth & Design
ARTICLE
Figure 3. (A) Supramolecular ribbons formed in crystal structures 10À12 through interlinking of CÀH O bonds. (B) View of supramolecular
3 3 3
ribbon formed through Cl O interaction in 11.
3 3 3
plane with CgÀCg distances of 3.8159(9) Å, 3.7375(9) Å and
slip angles of 26.17ꢀ, 23.36ꢀ, respectively.
differ from each other. The hexameric supermolecules self-
assemble alongside each other in the (212) plane (Figure 8).
Such a type of planar assembly stacks with one other only through
the pyrimidine rings (Cg—Cg distance of 3.7415(9) Å, and slip
angles of 12.55ꢀ).
Crystal Structure of MP CA (17). Unlike other compounds,
3
17 crystallizes in triclinic P1 space group with two molecules of
CA and one molecule of MP in the asymmetric unit. The
previously reported structure of MP CA also possessed the
3
same number of molecules but crystallized in orthorhombic Pbcn
space group (crystallized using ethanol).42 In an attempt to
’ DISCUSSION
prepare an isostructural compound CP CA, we tried the same
reaction in methanol solvent and ended up with a poly-
morphic form. In 17, two molecules of cinnamic acid form
It is conceivable that both acceptor sites (i.e., N1 and N3) in
MP are accessible for an approaching carboxylic acid equally,
since both have the same groups on adjacent sides, whereas in the
case of CP, the nitrogen near the methyl group is preferentially
bound to carboxylic acid in all cases (Scheme 2). It is perceived
that the electronic effect plays a major role since both chlorine
and methyl groups do not hinder sterically (as a matter of fact
3
complementary hydrogen bonds (O(1A)ÀH(1A)
N(1)
N(3)
3 3 3
3 3 3
and N(2)ÀH(2B)
and N(2)ÀH(2A)
O(2A) and O(1B)ÀH(1B)
3 3 3
O(2B)) with AMPY leading to a hetero-
3 3 3
trimer distinctive from the rest similar to the earlier polymorph.
Inversely related heterotrimers are connected to each other
2
both have similar volumes). In all the compounds a R2 (8)
through weak C(16B)ÀH(16B) O(2A) to form a large ring
ring motif is formed when the carboxylic acid group interacts
with the corresponding 2-aminopyrimidine moiety. This ring
3 3 3
4
motif R6 (24). However, it is only at this step where both structures
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Crystal Growth & Design
ARTICLE
motif, which is formed through a pair of NÀH
O and
The synthon further interacts through supramolecular interac-
3 3 3
OÀH
N hydrogen bonds, is one of the top five ring motifs
tions (base-pairing through a couple of NÀH N hydrogen
3 3 3
3 3 3
2
among the 24 most frequently observed hydrogen-bonded
bonds involving R2 (8)) in all the compounds except CP PA
3
cyclic bimolecular motifs (supramolecular synthons).54,55
and MP CA to form a stable linear heterotetramer (Scheme 3a).
3
In CP PA the supermolecule interacts through the NÀH
O
3
3 3 3
interactions in preference to the NÀH
N hydrogen bonds
3 3 3
(base-pairing) due to the presence of an additional carboxylic
acid in the aromatic ring to form the same motif at the other
end (Scheme 3b) thereby forming a helical chain instead
of heterotetramer and similarly in the case of MP CA
3
the supermolecule interacts with another molecule of cin-
namic acid to form an acidÀbase-acid linear heterotrimer
(Scheme 3c).
Thus, the architectures of all the compounds are mainly
2
governed by the presence of the two types of R2 (8) motifs.
The present study clearly concludes this style of formation:
acidÀbase-acidÀbase linear heterotetramer in majority of
the cases with the exception of two co-crystals, MP PA and
3
MP CA. In addition to this almost all compounds are
3
stabilized by stacking interactions with the exception of
CP CA and CP 3NBA. Most compounds show predomi-
nant πÀπ stacking between the pyrimidineÀpyrimidine
3
3
Figure 4. Side view of helical chains along the b-axis in 13.
moieties.
Figure 5. Heterotetramers formed in crystal structure 14 without any strong forces of attraction within them.
Figure 6. View of supramolecular sheet in crystal structure 15.
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Crystal Growth & Design
ARTICLE
Figure 7. Arrangement of heterotetramers of 16 along the (210) plane.
Figure 8. Illustration of cyclic hexamers observed along the (212) plane in 17.
Scheme 2. MP and CP Showing Two Identical and Two
Dissimilar Acceptor Sites Respectively
compounds, we have categorized them into different sets as
shown in Table 3.
The preliminary examination of the lattice parameters sug-
gests that there are four sets of isostructural compounds. The
identical space groups and lattice parameters of 1À4, 5 and 6,
7À9, and 10À12, suggest some degree of isostructurality among
themselves. 13 also shows good isostructurality with its corre-
sponding analogue (AMPYPA, reported in a thesis56). The unit
cell similarity index (Π) for the orthogonalized lattice para-
meters of all the above related crystals was calculated.21 In
addition to this, the volumetric isostructurality index (IV) for
all of them were calculated which showed some differences in
certain cases.37 Overall, the results were in good agreement
except for a few surprises. Not many of the compounds were
found to be isostructural based on the chloro/methyl exchange
phenomenon, but most others showed isostructurality in spite of
having other substitutions. This prompted us to search for other
structures of MP and CP in the literature and to compare their
cell parameters with ours. We did manage to pick four co-crystals,
CP differs from MP only at the fourth position where
methyl group is replaced by chlorine. It is expected that the
co-crystals of these pyrimidine bases with the same acid tend
to form isostructural compounds since both chlorine and
methyl groups have a similar volume.39 As anticipated, a
series of isostructural co-crystals were obtained. By looking
into the closeness of the lattice cell parameters of the
namely, MP-2,5-dimethyl benzoic acid (MP 25DMBA),
3
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Crystal Growth & Design
ARTICLE
Scheme 3. (a) Linear Heterotetramer Synthons of Amino-
pyrimidineÀCarboxylic Acid System, (b) Trimeric Synthon
Consisting of Two Pyrimidine Bases and an Acid Molecule,
(c) Trimeric Synthon Consisting of Two Acid Molecules and a
Pyrimidine Base
those above 70% (considered to have good structural similarities),
those around 50% (indicate pronounced resemblance), and
those around 30% (generally do not have any structural
similarity). In the first set of compounds (I), when MP 4CBA
3
and CP 4CBA pair with each other they express a high degree
3
of isostructurality (IV = 94.5%), whereas when it pairs up with
the other members of its group it shows IV around 30% inspite
of having Π close to unity. A close scrutiny at these structural
arrangements indicates that even though they form a similar
type of primary motifs like the other related structures
(MP 2MBA and MP 3MBA), the three-dimensional arrange-
3
3
ments in the lattice are different which accounts for the
differing IV values (Figure 9). In the case of MP 3MBA-
3
MP 246TMBA, MP 2MBA-MP 246TMBA, MP 25DMBA-
3
3
3
3
MP 246TMBA, and MP 246TMBA-MP 3DFBA pairs of
compounds, all show IV around 50%. It is clear that MP 246
3
3
3
3
TMBA is the common co-crystal which involves all four cases
and it is understood from the values that it has very little
resemblance with the other four analogues. An inspection into
the structural patterns showed no difference in the packing
arrangements. It is known from the literature that substitution
in more than one atomic site could lead to a decrease in IV
values. From the table, we understand that except for MP
246TMBA, none of the cases showed any definite trend in the
3
IV values with respect to the substitution.
From the high IV values of set II, it clearly indicates that the
methyl group has replaced the hydrogen atom in order to achieve
isostructurality without altering the existing packing similarities.
A close examination of both structures confirms the results. Both
have a similar type of hydrogen bond and stacking interactions as
discussed earlier (Figure 2A).
It is evident by a high value for the volumetric isostructurality
index (IV = 90.8; 91.7; 95.2) for the third set of structures (III)
that they show good isostructurality. The closeness of the volume
of chlorine and methyl group is the basis for the high degree
of isostructurality. All three compounds have a similar type of
hydrogen bonding pattern and stacking arragenments as dis-
cussed earlier (Figure 2B).
From the earlier discussion of 10À12, we understood that
MP 3NBA demonstrates a similar type of ribbon formation like
3
the other members of its family thus showing good resemblance
with the rest of the co-crystals. On evaluating the IV values for
these compounds (IV), we found MP 3NBA not to be iso-
3
structural with the rest of the group. A thorough inspection of the
compounds once again showed that they differ from one another
merely in the direction of the extended ribbons (Figure 10).
In the case of (V), the isostructurality between MP PA and
3
CP PA is evident from the high value of IV (IV = 90) and is
3
MP-2,4,6-trimethyl benzoic acid (MP 246TMBA), MP-2,3-di-
concluded that isostructural compounds have a high degree of
similarity and are formed through chloro/methyl interchange.
It is understandable that isostructurality is common when a
chloro group is replaced by a methyl group; however, the surprise
element comes only when isostructurality is observed for the
other group of compounds. In an attempt to understand the
reason behind this trend, a clue to this was found from a recent
study carried out by Desiraju et al.19 A blind test performed on
the crystal structure prediction of the 1:1 binary crystal of
2-methylbenzoic acid and 2-amino-4-methylpyrimidine has
shown that the formation of a linear heterotetramer is a more
energetically and statistically preferable synthon in comparison
to the other types. Out of the 17 co-crystals from the present
study, 15 of them are consistent with the aforementioned fact.
3
fluoro benzoic acid (MP 23DFBA), and MP-4-methoxybenzoic
3
acid (MP 4MOBA).19The first three of them showed a relation-
3
ship with those of 1À4, and the fourth appears to be in close
association with those of 10À12. Both unit cell similarity index
and volumetric isostructurality indices were calculated for all
these structures and were found to be in good agreement. All
calculations of Π and IV, carried out for different sets (indicated
by roman letters) of structures are highlighted in Table 3.
Though the Π values are close to unity in all cases, indicating
high degree of isostructurality, it is only IV that gives a definite
conclusion (since the calculation takes into account the volumes
occupied in the unit cell of the closely related isostructural
pairs).37 All the pairs with IV are classified into three categories,
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Crystal Growth & Design
ARTICLE
Table 3. Calculated Values of Π and IV for All Related Structures
crystal structures
setsa
co-crystals
unit cell similarity index (Π)
volumetric isostructurality index (IV (%))
MP 2MBA (1)
(I)
MP 2MBAÀP 3MBA
0.029
0.020
0.021
0.056
0.072
0.005
0.009
0.008
0.026
0.041
0.034
0.001
0.036
0.051
0.024
0.035
0.050
0.026
0.014
0.061
0.077
0.020
73.1
37.4
37.0
72.6
53.1
87.6
37.3
37.0
82.3
52.7
80.1
94.5
36.8
37.0
37.5
36.6
36.7
37.1
55.7
76.0
53.5
85.8
3
3
3
MP 3MBA (2)
MP 2MBAÀ CP 4CBA
3 3
3
CP 4CBA (3)
MP 2MBAÀMP 4CBA
3 3
3
MP 4CBA (4)
MP 2MBAÀMP 25DMBA
3 3
3
MP 25DMBA (reported)
MP 2MBAÀMP 246TMBA
3 3
3
MP 246TMBA (reported)
MP 2MBAÀMP 23DFBA
3 3
3
MP 23DFBA (reported)
MP 3MBA ÀCP 4CBA
3
3 3
MP 3MBAÀMP 4CBA
3
3
MP 3MBAÀMP 25DMBA
3
3
MP 3MBAÀMP 246TMBA
3
3
MP 3MBAÀMP 23DFBA
3
3
CP 4CBAÀMP.4CBA
3
CP 4CBAÀMP 25DMBA
3
3
CP 4CBAÀMP 246TMBA
3
3
CP 4CBAÀMP 23DFBA
3
3
MP 4CBAÀMP 25DMBA
3
3
3
3
MP 4CBAÀMP 246TMBA
3
MP 4CBAÀMP 23DFBA
3
MP 25DMBAÀ MP 246TMBA
3
3
MP 25DMBAÀMP 23DFBA
3
3
MP 246TMBAÀMP 23DFBA
3
3
CP BA (5)
(II)
CP BAÀCP 3MBA
3
3
3
CP 3MBA (6)
3
MP 2CBA (7)
(III)
MP 2CBAÀCP 2CBA
0.020
0.004
0.004
0.003
0.006
0.020
0.005
0.023
0.028
0.005
95.2
91.7
90.8
88.1
30.2
76.6
27.3
81.8
22.8
93.5
3
3
3
CP 2CBA (8)
MP 2CBAÀ CP 2MBA
3 3
3
CP 2MBA (9)
CP 2CBA ÀCP 2MBA
3 3
3
MP 4NBA (10)
(IV)
MP 4NBA ÀCP 4NBA
3 3
3
CP 4NBA (11)
MP 4NBAÀMP 3NBA
3 3
3
MP 3NBA (12)
MP 4NBAÀMP 4MOBA
3 3
3
MP 4MOBA (reported)
CP 4NBAÀMP 3NBA
3
3 3
CP 4NBAÀMP 4MOBA
3
3
MP 3NBAÀMP 4MOBA
3
3
CP PA (13)
(V)
CP PAÀMP PA
3 3
3
MP PA (reported)
3
a The different sets are classified based on the structures having similar unit cell parameters.
Figure 9. Comparative view of the channel-like structure propogating
along the c-axis for 2 and 3 respectively.
The close results convince us that the reliable and stable linear
heterotetrameric synthon could perhaps be the driving force in
the formation of isostructural compounds in the other cases
(barring chloro/methyl exchange).
Figure 10. View of the infinite ribbons extending on either sides in
crystal structures 10À12.
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’ CONCLUSION
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possess stacking interactions. The majority of the compounds
showed πÀπ stacking between the pyrimidineÀpyrimidine
moieties and acidÀpyrimidine rather than acidÀacid moieties.
In fact no stacking has been observed between acidÀacid molecules
in any of the cases as they lie far beyond the limits. Among the
CÀH O interactions in all the compounds, C5ÀH5 O(X)
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3 3 3
3 3 3
was found to be present in majority of the cases. This suggests
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S
Supporting Information. Crystallographic information
b
files (CIF) of structures 1À17 and other information are
available free of charge via the Internet at http://pubs.acs.org
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: tommtrichy@yahoo.co.in. Phone: ++91-431-2407053.
Fax: ++91-431-2407045, 2407030.
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’ ACKNOWLEDGMENT
The authors thank the DST - India (FIST programme) for the
use of the Bruker diffractometer at the School of Chemistry,
Bharathidasan University (for crystals 1À4, 6À10, 12, and15À17),
and also the Department of Chemistry, Howard University, for data
collection of crystals 5, 11, 13, and 14. Dr. L. Fabian (Pfizer Institute
for Pharmaceutical Materials Science, Cambridge, U.K.) is thanked
for his assistance in the isostructurality calculation.
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