Design of a Series of Isostructural Co-Crystals with Aminopyrimidines

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

bS Supporting Information ABSTRACT: A series of 17 co-crystals involving 2-amino-4chloro-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 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.

’ INTRODUCTION 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 molecular 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.5 10 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 pharmaceutical 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 developing strategies in preparing co-crystals. The recent literature has revealed several strategies and analysis in this regard.13 19 In fact, a special issue has been solely devoted to pharmaceutical cocrystals 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 r 2011 American Chemical Society

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.22 35 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.21,36 38 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 substantiated by a CSD study.39 Thus, this strategy (chloro/methyl interchange) is concerned with the design of isostructural cocrystals. The idea behind this study is to present the exciting prospect of designing materials of different composition with the same structural building block. Received: April 28, 2011 Revised: June 6, 2011 Published: June 08, 2011 3579

dx.doi.org/10.1021/cg200539a | Cryst. Growth Des. 2011, 11, 3579–3592

Crystal Growth & Design Scheme 1. Structures of Different Co-Crystal Formers and the Aminopyrimidine Bases

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.42 49 In the present study, 17 co-crystals using aminopyrimidine 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.

’ 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 13 16 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-nitrobenzoic acid (4NBA)/phthalic acid (PA)/cinnamic acid (CA)/3-nitrobenzoic 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. 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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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 1 17 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 refinement 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 (SHELXL86/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 1 17 are presented in Table 1, while the hydrogen bond distances are listed in Table 2. ’ RESULTS Crystal Structures of MP 3 2MBA (1), MP 3 3MBA (2), CP 3 4 CBA (3), and MP 3 4CBA (4). Compounds 1 4 crystallize in the

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-complementary secondary N(2) H(2X) 3 3 3 N(3) (X indicates different values which vary for different structures) hydrogen bonds to form a four-component supermolecule. Thus, the primary and secondary hydrogen bonds, O(1) H(1) 3 3 3 N(1), N(2) H(2X) 3 3 3 O(2), and N(2) H(2X) 3 3 3 N(3) combine to form a linear heterotetramer motif. Two of these inversion related heterotetramers are linked through a couple of weak C(X) H(X) 3 3 3 O(2) bonds to form a cyclic R86(28) ring motif (Figure 1A). The free C(X) H(X) 3 3 3 O(2) bonds on either 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 5.77 for 1, 3.7505(7) Å and 24.43 for 2, 3.7465(11) Å and 24.96 for 3, and 3.8037(11) Å and 24.92 for 4 respectively. 3580

dx.doi.org/10.1021/cg200539a |Cryst. Growth Des. 2011, 11, 3579–3592

Crystal Growth & Design

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Table 1. Crystallographic Data and Refinement Details for Co-Crystals 1 17 MP 3 2MBA (1)

MP 3 3MBA (2)

CP 3 4CBA (3)

MP 3 4CBA (4)

CP 3 BA (5)

CP 3 3MBA (6) C8H8O2, C5H6ClN3

empirical formula

C8H8O2, C6H9N3

C8H8O2, C6H9N3

C5 H6ClN3, C7H5ClO2

C6H9N3, C7H5ClO2

C5H6ClN3, C7H6O2

formula weight

259.31

259.31

300.14

279.72

265.70

279.72

crystal system

monoclinic

monoclinic

monoclinic

monoclinic

monoclinic

monoclinic P21/c

space group

C2/c

C2/c

C2/c

C2/c

P21/c

a [Å]

24.7397(2)

26.9424(12)

26.6684(4)

26.5020(4)

7.5335(13)

7.526(5)

b [Å]

7.5123(1)

7.3192(3)

7.3762(1)

7.4361(1)

8.1173(12)

8.809(5)

c [Å]

14.9760(2)

14.3603(6)

14.2490(2)

14.3922(2)

21.321(2)

21.362(5)

R [] β []

90 90.949(1)

90 92.473(4)

90 99.869(2)

90 98.915(1)

90 103.213(6)

90 102.732(15)

γ []

90

90

90

90

90

90

V [Å3]

2782.94(6)

2829.2(2)

2761.46(7)

2802.03(7)

1269.3(3)

1381.4(13)

Z

8

8

8

8

4

4

D (calc) [g/cm3]

1.238

1.218

1.444

1.326

1.390

1.345

μ (MoKR) [ /mm ]

0.085

0.084

0.471

0.274

0.299

0.278

tot., uniq. data,

31 878, 5007,

33 227, 5405

29 403, 3947

24 129, 2791

9807, 4090

16 745, 4807

observed data [I > 2.0σ (I)]

2500

3106

2316

2101

2953

2603

R

0.0560

0.0598

0.0484

0.0471

0.0482

0.0613

wR2

0.1779

0.2134

0.1522

0.1473

0.1668

0.1741

S

1.03

1.05

1.03

1.05

1.09

1.02

min, max peak [e/Å3] CCDC no.

0.18, 0.21

0.22, 0.24

762803

0.34, 0.29

762804

MP 3 2CBA (7)

0.35, 0.27

762800

CP 3 2CBA (8)

0.32, 0.32

762806

CP 3 2MBA (9)

721433

MP 3 4NBA (10)

0.26, 0.29 762798

CP 3 4NBA (11)

MP 3 3NBA (12)

empirical formula formula weight

C6H9N3, C7H5ClO2 C5H6ClN3, C7H5ClO2 C8H8O2, C5H6ClN3 C6H9N3, C7H5NO4 C7H5NO4, C5H6ClN3 C6H9N3, C7H5NO4 279.72 300.14 300.14 290.28 310.70 290.28

crystal system

monoclinic

monoclinic

monoclinic

triclinic

triclinic

triclinic

space group

P21/c

P21/c

P21/c

P1

P1

P1

a [Å]

7.8510(1)

7.7594(3)

7.9118(1)

6.8705(12)

6.9797(4)

6.9651(1)

b [Å]

24.1910(4)

24.3335(7)

24.0539(4)

7.4812(14)

7.3469(4)

7.5279(2)

c [Å]

8.3116(1)

8.2817(3)

8.2112(1)

13.717(2)

13.7131(7)

13.2985(3)

R []

90

90

90

81.763(9)

80.291(3)

94.254(1)

β [] γ []

120.591(1) 90

120.610(3) 90

119.926(1) 90

80.563(9) 84.009(9)

78.448(3) 85.491(3)

92.751(1) 98.482(1)

V [Å3]

1358.87(4)

1345.80(9)

1354.32(4)

686.0(2)

678.35(6)

686.52(3)

Z

4

4

4

2

2

2

D (calc) [g/cm3]

1.367

1.481

1.372

1.405

1.521

1.404

μ (MoKR) [ /mm ]

0.283

0.483

0.284

0.107

0.304

0.107

tot., uniq. data,

16820, 4464

12788, 2639

14915, 3296

12693, 3002

19134, 4899

16350, 4323

[I > 2.0σ (I)] R

2942 0.0481

1744 0.0508

2360 0.0486

2166 0.0470

3632 0.0514

3255 0.0500

wR2

0.1467

0.1478

0.1560

0.1385

0.1600

0.1666

S

1.05

1.03

1.05

1.06

1.07

1.07

observed data


0.20, 0.30

0.42, 0.41

762802

0.40, 0.37

762796

0.18, 0.24

762797

0.35, 0.41

762807

721434

0.23, 0.32 762805

CP 3 PA (13)

CP 3 CA (14)

CP 3 3NBA (15)

CP 3 4MOBA (16)

MP 3 CA (17)

empirical formula

C5H6ClN3, C8H6O4

C9H8O2, C5H6ClN3

C7H5NO4, C5H6ClN3

C8H8O3, C5H6ClN3

2(C9H8O2), C6H9N3

formula weight crystal system

309.71 monoclinic

291.73 monoclinic

310.70 monoclinic

295.72 triclinic

419.47 triclinic

space group

P21/c

P21/c

P21/c

P1

P1

a [Å]

11.1623(5)

6.0521(12)

9.8924(3)

7.5499(1)

8.6811(1)

b [Å]

7.4613(3)

7.9650(16)

15.0036(4)

8.9221(1)

11.5513(2)

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Table 1. Continued CP 3 PA (13)

CP 3 CA (14)

CP 3 3NBA (15)

CP 3 4MOBA (16)

MP 3 CA (17)

c [Å] R []

17.0269(8) 90

30.415(5) 90

β []

93.404(3)

97.137(11)

121.196(2)

99.632(1)

77.166(1)

γ []

90

90

90

94.909(1)

81.834(1)

V [Å3]

1415.59(11)

1454.8(5)

1439.78(8)

712.204(18)

1121.49(3)

Z

4

4

4

2

2

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 [I > 2.0σ (I)]

21234, 4358 3140

19771, 4108 2475

10187,1942 1495

17239, 5036 2924

24521,5974 3139

11.3404(4) 90

11.1715(2) 104.400(1)

11.5896(2) 87.227(1)

R

0.0547

0.0517

0.0406

0.0486

0.0492

wR2

0.1648

0.1991

0.1360

0.1737

0.1525

S

1.04

1.06

1.05

1.03

1.03


0.61, 0.47 723878

0.35, 0.31

0.27, 0.25

721432

Crystal Structures of CP 3 BA (5), CP 3 3MBA (6), MP 3 2CBA (7), CP 3 2CBA (8), and CP 3 2MBA (9). All the five co-crystals

(5 9) 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) H(1) 3 3 3 N(1), N(2) H(2X) 3 3 3 O(2), and N(2) H(2X) 3 3 3 N(3)) involving the amino and hydroxyl protons 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 7 9 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 7 9. In the former case, two of the heterotetramers stack partially one over the other, having π π stacking between the inversely related acid base dimers (Figure 2C). The Cg—Cg distance and the slip angles are 3.6650(12) Å and 13.36 for MP 3 BA and 3.701(3) Å and 18.55 for MP 3 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 22.90, 22.82, and 18.76 for 7, 8, and 9 respectively. Crystal Structures of MP 3 4NBA (10), CP 3 4NBA (11), and MP 3 3NBA (12). In each of the compounds 10 12, crystallizing 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 moieties engaging in O(1) H(1) 3 3 3 N(1) and N(2) H(2A) 3 3 3 O(2) and N(2) H(2A) 3 3 3 N(3) hydrogen bonds 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 C H 3 3 3 O

762799

0.22, 0.35 762801

0.19, 0.22 762808

hydrogen bonds to form a large ring motif with graph set notation R66(30) for 10 and 11 and R66(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 23.98 for 10, 3.8568(8) Å and 28.37 for 11, and 3.6431(7) Å and 20.90 for 12. In CP 3 4NBA, besides the stacking interaction, the free oxygen in the 4-nitro group and the chlorine in CP connects the neighboring ribbons through Cl(1) 3 3 3 O(4) interaction (Figure 3B) with a Cl(1) 3 3 3 O(4) distance of 3.0904(18) Å and C(4) Cl(1) 3 3 3 O(4) angle of 175.54(6). Crystal Structure of CP 3 PA (13). In 13, the asymmetric unit 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 3 PA is different from the rest of them as there is no formation of the heterotetrameric motif. The presence of another strong functionality (carboxyl group) in the aromatic ring has disrupted the formation 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 interactions involving pyrimidine moieties are O(1) H(1) 3 3 3 N(1), N(2) H(2A) O(2), and O(3) H(3) 3 3 3 N(3), N(2) H(2B) 3 3 3 O(4)) which prevents the formation of a base pair unlike 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 N(2) H(2A). The C(5) H(5) 3 3 3 O(2) bonds involving O(2) of one of the helical chains, form hydrogen bonds with the C(5) H(5) of a centrosymmetrically related chain thus holding both chains in close proximity. The closeness of the helices is partly due to the π π stacking interactions between the pyrimidines of the interpenetrated helices (Cg Cg distance and slip angle of 3.7606(10) Å and 24.79 respectively) and the weak C(5) H(5) 3 3 3 O(2) hydrogen bonds. 3582



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Table 2. Hydrogen Bond Metrics for Compounds 1 17 H 3 3 3 A (Å)

D 3 3 3 A (Å)

—D H 3 3 3 A

O(1)--H(1) 3 3 3 N(1) N(2)--H(2A) 3 3 3 O(2)

1.81

2.6158(16)

166

2.12

2.9644(18)

168

N(2)--H(2B) 3 3 3 N(3) C(12)--H(12) 3 3 3 O(2)

2.27

3.1277(17)

173

2.45

3.378(2)

173

D---H 3 3 3 A

Table 2. Continued

MP 3 2MBA (1)

1.80

2.6052(14)

167

2.16 2.04

3.0203(14) 2.8927(16)

177 171

C(12)--H(12) 3 3 3 O(2) CP 3 4CBA (3)

2.67

3.5170(12)

151

O(1)--H(1) 3 3 3 N(1) N(2)--H(2A) 3 3 3 O(2)

1.87

2.687(2)

171

2.04

2.892(3)

170

N(2)--H(2B) 3 3 3 N(3) C(13)--H(13) 3 3 3 O(2) MP 3 4CBA (4) O(1)--H(1) 3 3 3 N(1)

2.19

3.043(2)

174

2.56

3.426(3)

154

D 3 3 3 A (Å) 3.3845(19) 3.6501(2)

—D H 3 3 3 A 162 148

O(1)—H(1) 3 3 3 N(1) N(2)—H(2A) 3 3 3 O(2)

1.95

2.7700(19)

173

2.00

2.855(2)

171

N(2)—H(2B) 3 3 3 O(4) O(3)—H(3) 3 3 3 N(3) C(5)—H(5) 3 3 3 O(2)

2.01

2.854(2)

169

1.90

2.715(2)

171

2.50

3.261(2)

139

1.89

2.695(2)

170

2.10

2.945(2)

166

N(2)--H(2B) 3 3 3 N(3) CP 3 3NBA (15)

2.21

3.074(3)

177

O(1)--H(1) 3 3 3 N(1) N(2)--H(2A) 3 3 3 N(3) N(2)--H(2B) 3 3 3 O(2)

1.86

2.671(3)

170

2.20

3.054(3)

172

2.02

2.878(3)

171

C(5)--H(5) 3 3 3 O(3) C(14)--H(14) 3 3 3 O(4)

2.39 2.48

3.295(4) 3.236(3)

165 139

CP 3 PA (13)

MP 3 3MBA (2) O(1)--H(1) 3 3 3 N(1) N(2)--H(2A) 3 3 3 N(3) N(2)--H(2B) 3 3 3 O(2)

H 3 3 3 A (Å) 2.46 2.80

D---H 3 3 3 A C(8)--H(8B) 3 3 3 O(3) C(5)--H(5) 3 3 3 O(4)

CP 3 CA (14) O(1)--H(1) 3 3 3 N(1) N(2)--H(2A) 3 3 3 O(2)

1.79

2.595(2)

167

3 N(3) 3 O(2)

2.18

3.036(2)

175

2.03

2.877(3)

171

C(12)--H(12) 3 3 3 O(2) CP 3 BA (5)

2.51

3.386(3)

158

O(1)--H(1) 3 3 3 N(1) N(2)--H(2A) 3 3 3 N(3)

1.91

2.7190(17)

170

2.23

3.0493(19)

159

O(1)--H(1) 3 3 3 N(1) N(2)--H(2A) 3 3 3 O(2) N(2)--H(2B) 3 3 3 N(3) CP 3 3MBA (6)

1.86

2.6683(18)

166

2.01

2.8590(19)

168

2.11

2.963(2)

170

N(2)--H(2B) 3 3 3 O(2) MP 3 CA (17)

2.21

3.059(2)

168

O(1)--H(1) 3 3 3 N(1) N(2)--H(2A) 3 3 3 N(3) N(2)--H(2B) 3 3 3 O(2)

1.91 2.26

2.699(3) 3.113(3)

162 171

2.12

2.972(3)

169

N(2)--H(2A) 3 3 N(2)--H(2B) 3 3

MP 3 2CBA (7) O(1)--H(1) 3 3 3 N(1)

1.79

2.5999(16)

167

3 N(3)

2.18

3.0303(17)

171

3 O(2)

2.01

2.8579(18)

167

O(1)--H(1) 3 3 3 N(1) N(2)--H(2A) 3 3 3 N(3)

1.88

2.689(3)

170

2.19

3.044(4)

170

N(2)--H(2B) 3 3 3 O(2) CP 3 2MBA (9)

2.07

2.897(4)

162

O(1)--H(1) 3 3 3 N(1) N(2)--H(2A) 3 3 3 N(3) N(2)--H(2B) 3 3 3 O(2) MP 3 4NBA (10)

1.90

2.713(2)

171

2.23

3.073(2)

167

2.13

2.939(2)

157

O(1)--H(1) 3 3 3 N(1) N(2)--H(2A) 3 3 3 N(3)

1.75

2.552(2)

163

2.21

3.052(2)

167

N(2)--H(2B) 3 3 3 O(2) C(5)--H(5) 3 3 3 O(3)

2.17

3.003(2)

163

2.60

3.403(2)

145

O(1)--H(1) 3 3 3 N(1) N(2)--H(2A) 3 3 3 N(3) N(2)--H(2B) 3 3 3 O(2)

1.83

2.6312(17)

164

2.28 2.21

3.1139(19) 3.0406(19)

163 163

C(5)--H(5) 3 3 3 O(3) MP 3 3NBA (12)

2.43

3.257(2)

148

O(1)--H(1) 3 3 3 N(1) N(2)--H(2A) 3 3 3 N(3)

1.76

2.5676(15)

166

2.20

3.0481(15)

168

N(2)--H(2B) 3 3 3 O(2)

2.05

2.8894(16)

166

N(2)--H(2A) 3 3 N(2)--H(2B) 3 3 CP 3 2CBA (8)

CP 3 4NBA (11)

CP 3 4MOBA (16)

O(1A)--H(1A) 3 3 3 N(1) O(1B)--H(1B) 3 3 3 N(3) N(2)--H(2A) 3 3 3 O(2B) N(2)--H(2B) 3 3 3 O(2A) C(16B)--H(16B) 3 3 3 O(2A)

1.88

2.6919(17)

170

1.87 2.14

2.6757(18) 2.9813(18)

167 167

2.08

2.9094(19)

163

2.53

3.381(3)

153

Crystal Structure of CP 3 CA (14). In the co-crystal 14, crystallizing in the space group P21/c, the asymmetric unit contains a molecule of CP and CA. These molecules are interconnected through O(1) H(1) 3 3 3 N(1) and N(2) H(2A) 3 3 3 O(2) hydrogen bonds to form a dimeric unit. These dimers self-assemble with one another and pair up to form a four-component supermolecule as expected through secondary hydrogen bonds (N(2) H(2B) 3 3 3 N(3)) (Figure 5). Crystal Structure of CP 3 3NBA (15). The asymmetric unit in 15 (crystallized in the space group P21/c) contains a molecule of CP and 3NBA. The crystal structure of CP 3 3NBA consists of O(1) H(1) 3 3 3 N(1) and N(2) H(2B) 3 3 3 O(2) interactions forming a dimer (primary motif). Two dimers connect through selfcomplementary N(2) H(2A) 3 3 3 N(3) hydrogen bonds to generate a linear heterotetrameric supermolecule. These supermolecules combine together through a couple of C(5) H(5) 3 3 3 O(3) bonds to produce a large ring motif with graph set notation R55(22). In addition to this three of the supermolecules are connected to one another through a couple of C(14) H(14) 3 3 3 O(4) and a C(5) H(5) 3 3 3 O(3) hydrogen bonds to form another ring motif, R44(24). These motifs recur continuously in two-dimensional planes linking all the heterotetramer. On the whole, the structure may be expressed as a supramolecular sheet lying on the (302) plane as shown in Figure 6. Crystal Structure of CP 3 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 3583



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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 1 4 along the z-axis.

through the primary hydrogen bonds, the unused amino proton forms N(2) H(2A) 3 3 3 N(3) hydrogen bonds with the pyrimidine

nitrogen extending the architecture into a four-component supermolecule. Albeit there are no other hydrogen bonds present 3584



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Figure 2. (A) Crystal structures of 5 and 6 showing similar packing arrangements. (B) Exhibition of similar packing arrangements in structures 7 9. (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 3585



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Figure 3. (A) Supramolecular ribbons formed in crystal structures 10 12 through interlinking of C H 3 3 3 O bonds. (B) View of supramolecular ribbon formed through Cl 3 3 3 O interaction in 11.

plane with Cg Cg distances of 3.8159(9) Å, 3.7375(9) Å and slip angles of 26.17, 23.36, respectively. Crystal Structure of MP 3 CA (17). Unlike other compounds, 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 3 CA also possessed the same number of molecules but crystallized in orthorhombic Pbcn space group (crystallized using ethanol).42 In an attempt to prepare an isostructural compound CP 3 CA, we tried the same reaction in methanol solvent and ended up with a polymorphic form. In 17, two molecules of cinnamic acid form complementary hydrogen bonds (O(1A) H(1A) 3 3 3 N(1) and N(2) H(2B) 3 3 3 O(2A) and O(1B) H(1B) 3 3 3 N(3) and N(2) H(2A) 3 3 3 O(2B)) with AMPY leading to a heterotrimer distinctive from the rest similar to the earlier polymorph. Inversely related heterotrimers are connected to each other through weak C(16B) H(16B) 3 3 3 O(2A) to form a large ring motif R64(24). However, it is only at this step where both structures

differ from each other. The hexameric supermolecules selfassemble 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 12.55).

’ DISCUSSION 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 both have similar volumes). In all the compounds a R22(8) ring motif is formed when the carboxylic acid group interacts with the corresponding 2-aminopyrimidine moiety. This ring 3586


Crystal Growth & Design motif, which is formed through a pair of N H 3 3 3 O and O H 3 3 3 N hydrogen bonds, is one of the top five ring motifs among the 24 most frequently observed hydrogen-bonded cyclic bimolecular motifs (supramolecular synthons). 54,55

Figure 4. Side view of helical chains along the b-axis in 13.

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The synthon further interacts through supramolecular interactions (base-pairing through a couple of N H 3 3 3 N hydrogen bonds involving R22(8)) in all the compounds except CP 3 PA and MP 3 CA to form a stable linear heterotetramer (Scheme 3a). In CP 3 PA the supermolecule interacts through the N H 3 3 3 O interactions in preference to the N H 3 3 3 N hydrogen bonds (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 3 CA the supermolecule interacts with another molecule of cinnamic acid to form an acid base-acid linear heterotrimer (Scheme 3c). Thus, the architectures of all the compounds are mainly governed by the presence of the two types of R2 2 (8) motifs. The present study clearly concludes this style of formation: acid base-acid base linear heterotetramer in majority of the cases with the exception of two co-crystals, MP 3 PA and MP 3 CA. In addition to this almost all compounds are stabilized by stacking interactions with the exception of CP 3 CA and CP 3 3NBA. Most compounds show predominant π π stacking between the pyrimidine pyrimidine 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. 3587



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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

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

compounds, we have categorized them into different sets as shown in Table 3. The preliminary examination of the lattice parameters suggests that there are four sets of isostructural compounds. The identical space groups and lattice parameters of 1 4, 5 and 6, 7 9, and 10 12, suggest some degree of isostructurality among themselves. 13 also shows good isostructurality with its corresponding analogue (AMPYPA, reported in a thesis56). The unit cell similarity index (Π) for the orthogonalized lattice parameters 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, namely, MP-2,5-dimethyl benzoic acid (MP 3 25DMBA), 3588


Crystal Growth & Design Scheme 3. (a) Linear Heterotetramer Synthons of Aminopyrimidine Carboxylic 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

MP-2,4,6-trimethyl benzoic acid (MP 3 246TMBA), MP-2,3-difluoro benzoic acid (MP 3 23DFBA), and MP-4-methoxybenzoic acid (MP 3 4MOBA).19The first three of them showed a relationship with those of 1 4, and the fourth appears to be in close association with those of 10 12. 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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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 3 4CBA and CP 3 4CBA pair with each other they express a high degree 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 3 2MBA and MP 3 3MBA), the three-dimensional arrangements in the lattice are different which accounts for the differing IV values (Figure 9). In the case of MP 3 3MBAMP 3 246TMBA, MP 3 2MBA-MP 3 246TMBA, MP 3 25DMBAMP 3 246TMBA, and MP 3 246TMBA-MP 3 3DFBA pairs of compounds, all show IV around 50%. It is clear that MP 3 246 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 3 246TMBA, none of the cases showed any definite trend in the 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 discussed earlier (Figure 2B). From the earlier discussion of 10 12, we understood that MP 3 3NBA demonstrates a similar type of ribbon formation like 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 3 3NBA not to be isostructural 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 3 PA and CP 3 PA is evident from the high value of IV (IV = 90) and is 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. 3589



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Table 3. Calculated Values of Π and IV for All Related Structures

a

crystal structures

setsa

co-crystals

unit cell similarity index (Π)

volumetric isostructurality index (IV (%))

MP 3 2MBA (1) MP 3 3MBA (2) CP 3 4CBA (3) MP 3 4CBA (4) MP 3 25DMBA (reported) MP 3 246TMBA (reported) MP 3 23DFBA (reported)

(I)

CP 3 BA (5) CP 3 3MBA (6) MP 3 2CBA (7) CP 3 2CBA (8) CP 3 2MBA (9) MP 3 4NBA (10) CP 3 4NBA (11) MP 3 3NBA (12) MP 3 4MOBA (reported)

(II)

MP 3 2MBA P 3 3MBA MP 3 2MBA CP 3 4CBA MP 3 2MBA MP 3 4CBA MP 3 2MBA MP 3 25DMBA MP 3 2MBA MP 3 246TMBA MP 3 2MBA MP 3 23DFBA MP 3 3MBA CP 3 4CBA MP 3 3MBA MP 3 4CBA MP 3 3MBA MP 3 25DMBA MP 3 3MBA MP 3 246TMBA MP 3 3MBA MP 3 23DFBA CP 3 4CBA MP.4CBA CP 3 4CBA MP 3 25DMBA CP 3 4CBA MP 3 246TMBA CP 3 4CBA MP 3 23DFBA MP 3 4CBA MP 3 25DMBA MP 3 4CBA MP 3 246TMBA MP 3 4CBA MP 3 23DFBA MP 3 25DMBA MP 3 246TMBA MP 3 25DMBA MP 3 23DFBA MP 3 246TMBA MP 3 23DFBA CP 3 BA CP 3 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

MP 3 2CBA CP 3 2CBA MP 3 2CBA CP 3 2MBA CP 3 2CBA CP 3 2MBA MP 3 4NBA CP 3 4NBA MP 3 4NBA MP 3 3NBA MP 3 4NBA MP 3 4MOBA CP 3 4NBA MP 3 3NBA CP 3 4NBA MP 3 4MOBA MP 3 3NBA MP 3 4MOBA CP 3 PA MP 3 PA

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

CP 3 PA (13) MP 3 PA (reported)

(III)

(IV)

(V)

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 10 12. 3590



’ CONCLUSION It is clear from all the structures that the weak forces play a major role once the stronger hydrogen bonds have been utilized and consumed. With the exception of 14 and 15, all the compounds possess stacking interactions. The majority of the compounds showed π π stacking between the pyrimidine pyrimidine moieties and acid pyrimidine rather than acid acid moieties. In fact no stacking has been observed between acid acid molecules in any of the cases as they lie far beyond the limits. Among the C H 3 3 3 O interactions in all the compounds, C5 H5 3 3 3 O(X) was found to be present in majority of the cases. This suggests that the C H bond is acidic in nature which readily contributes as a donor once the strong hydrogen bonds are quenched. The present results show good success in the harvest of isostructural compounds. There have been several cases in which isostructurality is exhibited despite the absence of chloro/methyl exchange, and these are accounted for on the basis of the formation of the reliable heterotetrameric synthon. As established by Fabian and Kalman,37 Iv > 70% seems to have good structural similarities and 50% > Iv < 70% indicates pronounced resemblance, and Iv < 30% has no great significance in the structural similarity. It is concluded from the present study that supramolecular synthons can be used as a strategy for systematic construction of isostructural solids with appreciable knowledge of the hierarchy of the hydrogen bonds. Since the present work also demonstrates the same, with the understanding of this phenomenon, one will be able to exploit them by engineering materials of the desired property from preselected molecular precursors both in the field of medicinal chemistry and material science. ’ ASSOCIATED CONTENT

bS

Supporting Information. Crystallographic information files (CIF) of structures 1 17 and other information are available free of charge via the Internet at http://pubs.acs.org

’ AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Phone: ++91-431-2407053. Fax: ++91-431-2407045, 2407030.

’ 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 1 4, 6 10, 12, and 15 17), 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. ’ REFERENCES (1) Thakur, T. S.; Desiraju, G. R. Cryst. Growth Des. 2008, 8, 4031–4044. (2) Desiraju, G. R. Crystal Engineering: the Design of Organic Solids; Elsevier: Amsterdam, 1989. (3) Steiner, T. Angew. Chem., Int. Ed. 2002, 41, 48–76. (4) Pollino, J. M.; Weck, M. Chem. Soc. Rev. 2005, 34, 193–207. (5) Fyfe, M. C. T.; Stoddart, J. F. Acc. Chem. Res. 1997, 30, 393–401. (6) Seidel, S. R.; Stang, P. J. Acc. Chem. Res. 2002, 35, 972–983. (7) Desiraju, G. R. Angew. Chem., Int. Ed. 2007, 46, 8342–8356. (8) Sarma, J. A. R. P.; Desiraju, G. R. Acc. Chem. Res. 1986, 19, 222–228.

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Design of a Series of Isostructural Co-Crystals with Aminopyrimidines

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