CRYSTAL GROWTH & DESIGN
Dimormorphism and Cocrystal Formation of 3-(Chloroacetamido)pyrazole
2005 VOL. 5, NO. 6 2242-2247
Menahem Kaftory,* Mark Botoshansky, and Yana Sheinin Department of Chemistry, Technion-Israel Institute of Technology, Haifa 32000, Israel Received April 2, 2005;
Revised Manuscript Received June 21, 2005
ABSTRACT: 3-(Chloroacetamido)pyrazole (4) crystallizes in two different forms. Crystallization with chloroacetic acid reveals a cocrystal. In the two polymorphs (4R and 4β), all hydrogen acceptors and hydrogen donors take part in the formation of hydrogen bonds. In both structures, the molecules formed dimers through hydrogen bonds; in 4R the site symmetry of the dimer is the 2-fold axis, and it has a bowl shape. The site symmetry of the dimer in (4β) is inversion center, and it is planar. The 2-fold symmetry (in 4R) imposed on the four molecules that are hydrogen bonded to the dimer a propeller-like arrangement with the molecules up and down alternately with regards to the plane of the dimer. When inversion symmetry is present (in 4β), two molecules are up and two molecules are down with respect to the plane of the dimer. In the cocrystal, a molecular compound is formed between a molecule of 3-(chloroacetamido)pyrazole (4) and chloroacetic acid. 3-(Chloroacetamido)pyrazole is also hydrogen bonded to two other molecules of the same kind to form an infinite layered ribbon. Introduction According to McCrone (1965),1 “a polymorph is a solid crystalline phase of a given compound resulting from the possibility of at least two different arrangements of the molecules of that compound in the solid state”. McCrone (1965) also states his own opinion regarding the occurrence of polymorphism “...every compound has different polymorphic forms and that, in general, the number of forms known for a given compound is proportional to the time and money spent in research on that compound”. The above statement of McCrone raises the following question “can one predict that a given molecule will crystallize in various polymorphic forms based on the atomic constituent of the molecule and of its formulae?”. This paper does not intend to answer this rather difficult fundamental question. It might be expected that in cases where strong dominant interactions are expected no polymorphic forms will always be formed because the strong interaction will direct the molecules to pack in the deepest global minima of the potential energy surface. Such strong interactions are expected when the molecule consists of atoms (or group of atoms) that are strong acceptors for hydrogen and atoms (or group of atoms) that are strong donors for hydrogen. What happens when a molecule has more than one group of acceptors and donors to hydrogen? Should we expect to find more than a single polymorph? The following is an example of such a compound. As a result of the reaction between 3-aminopyrazole (1) and chloroacetyl chloride, a mixture of 3-amino-1and -2-(chloroacetyl)pyrazole (2 and 3 in Scheme 1) are produced.2 Upon standing for few days, the solid mixture of 2 and 3 rearranged to 3-(chloroacetamido)pyrazole (4).2 The course of the reaction was monitored by CP/MAS NMR and by 1H NMR spectroscopy, and the conclusion was that the mechanism involves the rearrangement course to be 3 f 2 f 4.2 Following the * E-mail:
[email protected].
Scheme 1
procedure of the reaction described by the authors, we received three different crystals, which were identified by single-crystal X-ray diffraction methods to be two dimorphs of 4 (4R and 4β) and a cocrystal between 4 and chloroacetic acid (4s). The crystal structures of the three different crystalline materials are described as well as a discussion of the tendency of similar molecules with hydrogen acceptors and donors to form double hydrogen bonding. Experimental Section The starting material for the synthesis of acetamide, 2-chloro-N-1H-pyrazol-3-yl-9CI with R-chloroacetic acid) was commercially available from Aldrich. To a 50-mL three-necked round-bottom flask was added 3-aminopyrazole (1, 2 mmol, 0.1491 g), chloroacetyl chloride (2 mmol, 0.2 mL), triethylamine (2 mmol, 0.25 mL), and dichloromethane (5 mL). The solution was mixed at room temperature for 1.5 h, 15 mL of cold water was added, and the solution was mixed at room temperature for 1 h. The reaction mixture was poured into 50 mL of saturated sodium chloride aqueous solution. The organic layer was diluted with dichloromethane, washed with water, and dried over anhydrous MgSO4 overnight. The product was obtained in 90% yield and found to be a mixture of 1- and 2-(chloroacetyl) compounds 2 and 3. The solid was purified by recrystallization from dichloromethane. When the solid is allowed to stand, the rearrangement takes place, and product 4 is formed. After crystallization, three crystal modifications were found. Two of them in the form of plates and cubes were identified as dimorphs of 3-(chloroacetamido)pyrazole (4), and the third modification was identified as a cocrystal of 3-(chloroacetamido)pyrazole with chloroacetic acid. X-ray diffraction intensities were collected on a Nonius KappaCCD diffractometer using monochromated Mo KR radiation.3,4 The crystal structures were solved and refined by
10.1021/cg0501229 CCC: $30.25 © 2005 American Chemical Society Published on Web 07/16/2005
Dimormorphism and Cocrystal Formation
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Table 1. Crystal Data for 4r, 4β, and 4s formula Mr crystal color, habit crystal system space group a [Å] b [Å] c [Å] β [deg] V [Å3] Z Dcalcd [g cm-3] µ [Mo KR] (cm-1) 2θ max [deg] reflns collected independent reflns obsd reflns largest difference peak [e‚Å-3] largest difference hole [e‚Å-3] no. of params Ra wRa GOF b
4r
4β
4s
C5H6ClN3O 159.58 colorless, prism orthorhombic Fdd2 18.734(2) 19.448(4) 7.724(1) 90.0 2814.2(7) 16 1.507 0.0472 50.14 666 666 544 0.168
C5H6ClN3O 159.58 colorless, needle tetragonal I41/a 23.830(5) 23.830(5) 5.196(1) 90.0 2950.6(10) 16 1.437 0.0450 50.10 9799 1253 546 0.279
C5H6ClN3O‚C2H3ClO2 254.07 colorless, prism monoclinic P21/c 5.157(1) 14.293(2) 15.318(3) 103.24(3) 1099.1(4) 4 1.535 0.0582 50.64 6649 1919 1207 0.189
-0.187
-0.287
-0.250
92 0.0342 0.0859 0.996
92 0.0488 0.1140 0.810
136 0.0441 0.1111 1.037
a R ) ∑||F | - |F ||/∑|F |; wR ) [∑w(|F | - |F |)2/∑w|F |2]1/2. b GOF ) [∑w(|F | - |F |)2/(NO - NV)]1/2, where NO is the number of o c o o c o o c observations and NV is the number of variables.
Table 2. Bond Lengths [Å] and Angles [deg] for 4 4r Cl(1)-C(5) O(1)-C(4) N(1)-C(3) N(1)-N(2) N(2)-C(1) N(3)-C(4) N(3)-C(1) C(1)-C(2) C(2)-C(3) C(4)-C(5)
Figure 1. Structure of 3-(chloroacetamido)pyrazole (4) with chloroacetic acid. SHELX86 software.5 Crystal data is given in Table 1. No attempt has been made to determine the absolute structure of 4R.
Results and Discussion Crystal Structures. The structure of 3-(chloroacetamido)pyrazole (4) in its cocrystal with chloroacetic acid with the atomic numbering is given in Figure 1. Comparison of bond lengths and angles, as well as selected torsion angles, is given in Table 2. Comparison of the hydrogen bond geometry is given in Table 3. The geometrical parameters of the pyrazole ring are in very good agreement with the geometry found in the crystal structure of pure pyrazole.6 Perhaps the most interesting feature is the differences between the bond angles around the trigonal atom C1. The inner-ring bond angle N2-C1-C2 is constrained by the ring size and it is
C(3)-N(1)-N(2) C(1)-N(2)-N(1) C(4)-N(3)-C(1) N(2)-C(1)-C(2) N(2)-C(1)-N(3) C(2)-C(1)-N(3) C(3)-C(2)-C(1) N(1)-C(3)-C(2) O(1)-C(4)-N(3) O(1)-C(4)-C(5) N(3)-C(4)-C(5) C(4)-C(5)-Cl(1)
1.752(4) 1.223(4) 1.340(5) 1.350(4) 1.331(4) 1.331(5) 1.407(4) 1.379(5) 1.376(5) 1.518(5)
4β 1.738(3) 1.209(5) 1.308(5) 1.348(4) 1.322(5) 1.342(4) 1.402(5) 1.386(5) 1.359(6) 1.509(6)
4s 1.740(3) 1.214(3) 1.323(3) 1.353(3) 1.327(3) 1.346(3) 1.398(3) 1.389(4) 1.377(4) 1.512(4)
111.6(3) 104.1(3) 125.3(3) 112.8(3) 117.5(3) 129.7(3) 103.7(3) 107.8(3) 124.4(3) 123.3(3) 112.3(3) 111.9(2)
112.1(4) 104.0(3) 125.5(4) 111.8(4) 117.8(4) 130.4(4) 103.8(4) 108.3(4) 123.5(4) 124.0(4) 112.5(4) 111.9(3)
111.4(2) 104.9(2) 125.7(2) 111.7(2) 117.1(2) 131.1(3) 103.7(3) 108.3(2) 123.4(2) 123.9(3) 112.7(2) 113.2(2)
H(3N)-N(3)-C(1)-N(2) 33.3(5) C(4)-N(3)-C(1)-N(2) -146.6(5) C(1)-N(3)-C(4)-O(1) -2.4(7)
-10.4(4) 169.6(4) 0.2(6)
5.2(2) -174.8(2) 2.9(4)
112.8(3)°, 111.8(4)°, and 111.7(2)° in 4R, 4β, and 4s, respectively. The outer-ring bond angles in each of the compounds are not equal; N2-C1-N3 bond angle is significauntly smaller [117.5(3)°, 117.8(4)°, and 117.1(2)° in the three compounds respectively], than C2-C1-N3 [129.7(3)°, 130.4(4)°, and 1301.3(3)° in the three compounds, respectively]. What seems to be that the opening of the bond angle (C2-C1-N3) is a result of steric effect of the carbonyl (C4dO1) was found to be wrong. The same differences are observed in all pyrazole rings. For example, the N-C-N bond angle in 3-nitropyrazole is 117.5° and C-C-N is 128.2°.7 This is also in accordance with ab initio computational geometry calculations of
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Kaftory et al.
Figure 2. DSC thermograph of 4r.
Figure 4. The hydrogen bond pattern in thymine.
Figure 3. DSC thermograph of 4β. Table 3. Comparison of Hydrogen Bond Geometry D-H
d(D-H) d(H‚‚‚A) ∠DHA d(D‚‚‚A) A
N1-H1N
0.860
1.993
4r 175.42
2.851
N3-H3N
0.860
2.083
171.81
2.937
N1-H1N
0.860
1.978
4β 157.36
2.792
N3-H3N
0.860
2.135
173.17
2.991 2.609
O3-H3O
0.820
1.793
4s 173.48
N1-H1N
0.860
1.978
154.68
2.780
N3-H3N
0.860
2.023
164.28
2.860
symmetry
O1 [-x + 3/4, y + 1/4, z - 1/4] N2 [-x + 1/2, -y + 1/2, z] O1 [y + 1/4, -x + 1/4, z - 3/4] N2 [-x + 1, -y, -z] N2 [-x + 1, y + 1/2, -z + 1/2] O1 [-x + 2, y - 1/2, -z + 1/2] O2 [-x + 1, y - 1/2, -z + 1/2]
pyrazole with the B3LYP/6-31-G** basis set where these two bond angles are 119.5° and 128.3° respectively.8 Calorimetric Measurements. The relation between the two polymorphs was investigated by differential scanning calorimetric (DSC) measurements. The DSC thermographs are shown in Figures 2 and 3. Compound 4R undergoes phase transition at 368.8 K (∆H ) 567.0 J mol-1) to 4β and melt at 387.1 K (∆H ) 3.0 kJ mol-1). Hydrogen Bonding and Packing. Compounds having acceptors and donors for hydrogen will use these atoms to form hydrogen bonds resulting the best packing in terms of energy. The number and relative positions of the hydrogen acceptors and hydrogen donors in the molecule determine the three-dimensional packing of the molecules in space. In cases where the molecules are planar and rigid and have a hydrogen acceptor and hydrogen donor that are able to form
Figure 5. The hydrogen bond pattern in uracil.
dimers, layer structures are anticipated. Perhaps the best representative examples are the structures of thymine (Figure 4),9,10 uracil (Figure 5),11,12 and cyanuric acid (Figure 6).13-15 3-(Chloroacetamido)pyrazole (4) consists of a rigid Nd C-N-H fragment that has the potential to form hydrogen bond dimers and a nonrigid CdO group that may be used to build up the three-dimensional structure. It is interesting to see that the shape of the dimer in space determines the formation of different packing, namely, the formation of two dimorphs. The dimer formed in 4r has a bowl shape, while the dimer formed in 4β is planar. An overlay of the two dimers is given in Figure 7. The 2-fold symmetry (in 4r), running perpendicular to the dimer, imposes on the four molecules that are
Dimormorphism and Cocrystal Formation
Figure 6. The hydrogen bond pattern in cyanuric acid.
Figure 7. Overlay of dimer in 4r (green) and dimer of 4β (brown).
hydrogen bonded to the central dimer (Figure 8, left) a propeller-like arrangement with the molecules up and down alternately with regards to the mean plane of the dimer. When inversion symmetry is present (in 4β), two molecules are up and two molecules are down with respect to the plane of the dimer (Figure 8, right). The
Figure 8. Hydrogen bond pattern in 4r (left) and 4β (right).
Crystal Growth & Design, Vol. 5, No. 6, 2005 2245
hydrogen bond pattern in the latter is very similar to that observed in the crystal structure of N-(5-phenyl1H-pyrazol-3-yl)benzamide.16 It is interesting to note that 3-(acetamido)-5-methylpyrazole, where the hydrogen on C3 and the chlorine atom (in 4) are replaced by methyl groups, has similar size and shape to that of 3-(chloroacetamido)pyrazole (4). An overlay of the two molecular structures is shown in Figure 9.17 The two molecules have the same acceptors and donors to hydrogens, and it is expected that the packing of 3-(acetamido)-5-methylpyrazole will be similar to one of the polymorphs of 4. Indeed, it was found that the former is isomorphous to polymorph 4r. Will it be safe to assume that another polymorph of 3-(acetamido)-5-methylpyrazole isomorphous to 4β should be found if we spend time to search for it? I challenge readers of this paper to prove it. In the cocrystal with chloroacetic acid (4s), a molecule of the chloroacetic acid replaces a second molecule of 3-(chloroacetamido)pyrazole (4) in the formation of the dimer (Figure 10). The hydrogen bonding net is farther expanded so that each molecule of 3-(chloroacetamido)pyrazole (4) is hydrogen bonded to two other molecules thus forming an infinite layered ribbon (Figure 10). Dimers and Heterodimers Made-Up by Hydrogen Bonds and Cocrystals. There is an immense tendency of compounds possessing an atom that is bearing a donor and an acceptor for hydrogen to form dimers or heterodimers in the solid state. A search in the Cambridge Crystallographic Data Center (CCDC)18 shows that out of 8097 compounds bearing a carboxylic group (pure organic) in 1579 of them hydrogen bonding dimers of type 5 (Table 4) are formed. A similar search for amides shows that there are 14 682 compounds of which 2179 have dimers of type 9. Out of 4215 compounds containing an NdC-N-H fragment, 455 form dimers of type 14. When two different fragments are present either on the same molecule or on different molecules heterodimers may be formed. A comparison was done among the geometries of 10 different combi-
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Kaftory et al. Table 4. Comparison of the Hydrogen Bond Geometry in Dimers and Heterodimers 5-14
dimer
Figure 9. Overlay of 3-(acetamido)-5-methylpyrazole and 4.
5a 6 6 7 8 8 9a 10 10 11 11 12 13 14a
geometric params
d(H‚‚‚A), Å
∠DHA, deg
d1 A1 d3 d1 A1 d3 d2 A2 d4
1.710(5) 2.061(12) 1.680(13)
d1 A1 d3 d2 A2 d4 d1 A1 d3 d1 A1 d3 d2 A2 d4 d1 A1 d3 d2 A2 d4 d1 A1 d3 d1 A1 d3
d(A‚‚‚D), Å
no. of params
172.4(2) 163.1(8) 167.1(7)
2.651(1) 2.928(8) 2.586(7)
1.988(50) 1.720(38) 1.994(3) 1.759(17) 1.954(29) 1.989(32) 1.983(32) 1.826(35)
166.2(2.2) 167.9(4.3) 170.3(2) 167.9(2.1) 166.5(1.1) 171.8(1.5) 170.9(2.4) 175.1(8)
2.886(33) 2.655(32) 2.883(2) 2.666(7) 2.848(9) 2.918(25) 2.877(21) 2.717(6)
2.108(9)
168.6(7)
2.981(4)
618 78 78 0 7 7 824 7 7 12 12 9 0 168
a
The average geometric parameters were calculated from the symmetric dimers.
be observed between the most electronegative atom (oxygen) and the hydrogen atom that is bonded to the most electronegative atom (oxygen). Therefore, the shortest A‚‚‚H distance is found in dimers of type 5 and heterodimers of type 6 (1.710, and 1.680 Å, respectively) and the O‚‚‚O distances are 2.651 and 2.587 Å in 5 and 6, respectively. Accordingly the longest distance is expected in hydrogen bonds of the type CdN‚‚‚H-N as in 14 (2.108 Å) and the O‚‚‚O distance is 2.981 Å. The data given here is not very encouraging if one wants to prepare cocrystals. However, compounds of type 6 have been shown to be very promising. There are 69 compounds of this type of which more than a half are cocrystals. The cocrystal between 3-(chloroacetamido)pyrazole and chloroacetic acid (4s) forms heterodimers of type 8. Only six other compounds are known to form the heterodimers of such a type of which five of them are cocrystals. Figure 10. Hydrogen bond pattern in 4s.
nations of dimers and heterodimers (5-14). The geometric data for the dimers and heterodimers made up from OdC-O-H, OdC-N-H, NdC-O-H, and NdCN-H was taken from the Cambridge Crystallographic Data Center (CCDC).18 The data were limited for crystal structures refined to R < 0.05, which are not disordered, have no errors, are not ions, and have structures that are of purely organic compounds. The average distances (d1 and d2) and the average angles (A1 and A2) are summarized in Table 4. The average geometric parameters for chemically symmetric dimers of type 5, 9, and 14 were calculated using distances and angles of those that possess either 2-fold symmetry or inversion centers. It is expected that the shortest acceptor‚‚‚H distance will
Conclusions It was shown that when a molecule posseses hydrogen acceptor and hydrogen donor on the same atom, the molecules prefer to pack in dimers or heterodimers formed by hydrogen bonds between them. The presence of additional acceptors and donors to hydrogen are being used for the expansion and build up of the threedimensional structure. It was also shown which are the potential hydrogen acceptors and donors that may provide cocrystals. Acknowledgment. The research was partially supported by The Center for Absorption in Science, Ministry of Immigrant Absorption, State of Israel.
Dimormorphism and Cocrystal Formation Supporting Information Available: X-ray crystallographic information files (CIF) are available for 4r, 4β, and the cocrystal of 4. The material is available free of charge via the Internet at http://pubs.acs.org.
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Crystal Growth & Design, Vol. 5, No. 6, 2005 2247 (9) Ozeki, K.; Sakabe, N.; Tanaka, J. Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem. 1969, 25, 1038. (10) Portalone, G.; Bencivenni, L.; Colapierto, M.; Pieretti, A.; Ramondo, F. Acta Chem. Scand. 1999, 53, 57. (11) Stewart, R. F.; Jensen, L. H. Acta Crystallogr. 1967, 23, 1102. (12) Stewart, R. F.; Jensen, L. H. Z. Krystallogr., Kristallgeom., Kristallphys., Kristallchem. 1969, 128, 133. (13) Verschoor, G. C.; Keulen, E. Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem. 1971, 27, 134. (14) Kutoglu, A.; Hellner, E. Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem. 1978, 34, 1617. (15) Dietrich, H.; Scheringer, C.; Myyer, H.; Sxhulte, K.-W.; Schweig, A. Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem. 1979, 35, 1191. (16) Beam, C. F.; Davis, S. E.; Cordray, T. L.; Chan, K. W.; Kassis, C. M.; Davis, J. G. F.; Latham, G. M.; Guion, T. S.; Hildebran, K. C.; Church, A. C.; Koller, M. U.; Metz, C. R.; Pennington, W. T.; Schey, K. L. J. Heterocycl. Chem. 1997, 34, 1549. (17) Lu, Y.; Kraatz, H.-B. Inorg. Chim. Acta 2004, 357, 159. (18) Allen, F. H. Acta Crystallogr. 2002, B58, 380.
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