Controlled Formation of the AcidâPyridine Heterosynthon over the

DOI: 10.1021/cg900786b

Controlled Formation of the Acid-Pyridine Heterosynthon over the Acid-Acid Homosynthon in 2-Anilinonicotinic Acids

2009, Vol. 9 4993–4997

Sihui Long and Tonglei Li* Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky Received July 9, 2009; Revised Manuscript Received October 16, 2009

ABSTRACT: Four substituted 2-anilinonicotinic acids were synthesized, and their crystal structures were analyzed. It was found that by chemically introducing bulky functional groups to the aniline ring of the molecules, it is possible to dislodge the planar conformation due to steric repulsion. As a result, acid-pyridine heterosynthons, not acid-acid homosynthons, are formed in the crystals. The study is believed to offer a refreshing case of how a molecule’s conformation can affect intermolecular interactions and consequent crystal packing. Tessellation of organic molecules forming periodic structures in the solid state is often a compromising result of the energy balance between molecular conformation and intermolecular interaction. On the one hand, a molecule likes to keep its most energy-favorable conformation while, on the other hand, the molecule may have to adjust its spatial arrangement in order to interact more strongly with its neighboring molecules. The fact that the energy of a conformational change is often on par with that of intermolecular interaction leads to one of the most intriguing features of an organic crystal, polymorphism,1-3 which is also attributed to the rich diversity of available organic functional groups that interact through van der Waals forces and, in many cases, stronger hydrogen bonding.4 Crystallization conditions undoubtedly play a key role in controlling the delicate energy balance and have been actively studied.5 For those organic molecules that have hydrogen-bonding moieties, the intermolecular hydrogen bonds are critical in determining how molecules pack themselves and form distinctive crystal structures.4,6 This is not only because hydrogen bonding is much stronger than the omnipresent van der Waals force, but also due to its directionality. It is well-known that the strongest direction should follow that of a covalent bond between a partially positive hydrogen atom and its host, typically called a hydrogen-bond donor and most often being carbon, oxygen, or nitrogen.7 Because the covalent bond is a σ molecular orbital, acceptance of partial sharing of electrons from a hydrogen-bond acceptor can be maximized when the hydrogen-bond angle is straight. Thus, it is very likely that a molecule may take a different conformation from its most energy-favorable one to best position itself for fully taking advantage of intermolecular hydrogen bonding. The interplay becomes even more interesting when a molecule has more than one functional group that can attract adjacent molecules by hydrogen bonding, epitomized by various synthons.8-10 It should not be surprising that many such examples have been studied and reported in the literature.3,11,12 We have recently reported a polymorphism study of 2-(phenylamino)nicotinic acid (2-PNA), a simple diarylamine with both carboxylic acid and pyridine functional groups (Scheme 1 where R1 = R2 = R3 = H).13 Four polymorphs were found, and two of the crystals, R and β, form hydrogen-bonding dimers between neighboring carboxyl groups while γ and δ form one-dimensional chains that are sustained by acid and pyridine hydrogen-bonding interactions. Whether the same molecule forms the acid-acid homosynthon or the acid-pyridine heterosynthon seems to be associated with the conformations that the molecule adapts. One

Scheme 1

*Corresponding author. Address: 514 College of Pharmacy, University of Kentucky, 725 Rose Street, Lexington, Kentucky 40536-0082. Phone: (859) 257-1472. Fax: (859) 257-7585. E-mail:[email protected].

major difference in the molecular conformation in the four forms stems from the torsion angle, τ2 (Scheme 1). Because of the expected conjugation or delocalization of the lone pair of electrons on the secondary amino group’s nitrogen bridging the two aromatic rings, the molecule is inclined to adopt a planar conformation, as suggested by the two torsion angles being both near zero degree, demonstrated by the conformer in the R form; the most stable form;of 2-PNA.13 Quantum mechanical calculations of the single molecule in the gas phase further indicated that the phenyl ring can be relatively easy to rotate around τ2 with a small energy barrier of 25 kJ/mol at about 90°, a position that completely “breaks” the conjugation between the amino group and the phenyl ring. Due to the small energy barrier, the molecule inherits a large conformational flexibility as defined by τ2 and may freely take a different conformation in the solid state. In fact, the values of τ2 in the four polymorphs are considerably different and can be grouped into two categories. In the R and β forms, τ2 tends to be flat while, in the γ and δ forms, the angle becomes more vertical. Considering that there are two different hydrogenbonding motifs or synthons formed in the four crystal structures, the conformational change appears to be commensurate with the intermolecular interactions. A close examination of the molecular structure indeed suggests that it is difficult to form a meaningful hydrogen bond between the pyridinyl nitrogen and carboxyl at the planar or the most stable conformation, in which the phenyl ring “blocks” the site for a hydrogen-bond donor to lock in the nitrogen atom. It is thereby reasonable to argue that, in order to form the hydrogen-bonding chain based on the acid-pyridine heterosynthon, the molecule has to adjust itself to a less energyfavorable conformation and empty the vicinity next to the pyridinyl nitrogen. It is also likely that, in terms of hydrogenbonding strength, the acid-acid homosynthon is less favored energetically than the acid-pyridine heterosynthon;a fact echoed by others in the literature.14-17 Therefore, in the crystals of 2-PNA, the molecule can either remain at its most stable conformation but form the weaker acid-acid homosynthon or take a small energy penalty for rotating around τ2 and form the stronger acid-pyridine heterosynthon. The underlying cause for these possibilities lies in the energy barrier of τ2 being akin to that of a moderate hydrogen bond.

r 2009 American Chemical Society

Published on Web 11/04/2009

pubs.acs.org/crystal

4994

Crystal Growth & Design, Vol. 9, No. 12, 2009

Long and Li

Table 1. Crystallographic Data of Crystal Structures Obtained of Compounds 1-4 formula formula weight crystal size/mm3 crystal system space group a/A˚ b/A˚ c/A˚ R/deg β/deg γ/deg Z, Z0 V/A˚3 Dcal/g 3 cm-3 T/K Abs coeff (mm-1) F(000) θ range (deg) limiting indices completeness to 2θ unique reflections R1 [I > 2σ(I)] wR2 (all data)

1a

1b

2a

2b

2c

3

4

C14H14N2O2 242.27 0.30 0.25 0.15 monoclinic P21/n 11.334(1) 16.927(2) 13.730(1) 90 111.26(1) 90 8, 2 2454.8(4) 1.311 90.0(2) 0.089 1024.0 1.00-27.48 -14 e h e 14 -21 e k e 21 -17 e l e 17 99.9% 5637 0.056 0.1617

C14H14N2O2 242.27 0.20 0.15 0.05 triclinic P1 13.8393(3) 15.1320(3) 18.7080(4) 86.603(1) 82.027(1) 89.849(1) 12, 6 38.73.01(14) 1.246 90.0(2) 0.688 1536.0 3.22-68.20 -16 e h e 16 -17 e k e 18 -22 e l e 22 98.9% 13941 0.058 0.1661


C15H16N2O2 256.30 0.50 0.10 0.10 hexagonal P32 7.5301(2) 7.5301(2) 20.6215(10) 90 90 120 3, 1 1012.63(6) 1.261 90.0(2) 0.085 408.0 1.00-27.48 -9 e h e 9 -7 e k e 7 -26 e l e 26 100.0% 2213 0.0554 0.1484


C15H16N2O2 256.30 0.40 0.20 0.15 monoclinic P21/c 22.242(3) 8.921(1) 14.367(2) 90 104.07(1) 90 8, 2 2765.2(6) 1.231 90.0(2) 0.083 1088.0 1.00-27.48 -28 e h e 28 -11 e k e 11 -18 e l e 18 99.9% 6330 0.0513 0.1415

C13H12N2O2 228.25 0.45 0.10 0.10 monoclinic P21/c 4.933(1) 21.146(4) 10.378(2) 90 97.10(1) 90 4, 1 1074.3(4) 1.411 90.0(2) 0.097 480.0 1.00-27.48 -6 e h e 6 -27 e k e 27 -13 e l e 13 99.8% 2559 0.0467 0.1414

To further explore the connection between a molecule’s conformation and the intermolecular hydrogen-bonding motif in an organic crystal, crystal formation of a few 2-PNA analogues is discussed in this report. The chemical derivation of the compounds, as compared with 2-PNA, was aimed to limit the conformational flexibility of a 2-anilinonicotinic acid molecule by forcing the phenyl ring dislodged from the conjugation so as to make the pyridinyl nitrogen accessible for hydrogen bonding. It was expected that, with both of the hydrogen-bonding acceptors available, it would be just the acid-pyridine heterosynthon, not the acid-acid homosynthon, that can be formed. This was accomplished by introducing some bulky functional groups, such as methyl, to the phenyl ring so that the molecule cannot retain its most stable, planar conformation due to strong steric repulsion between the bulky groups and pyridinyl and/or amino. Shown in Scheme 1 are the molecules that were synthesized and tested in this study, including 2-[(2,6-dimethylphenyl)amino]-3-pyridinecarboxylic acid (1), 2-(mesitylamino)nicotinic acid (2), 2-[[2-(1methylethyl)phenyl]amino]-3-pyridinecarboxylic acid (3), and 2-[(2-methylphenyl)amino]-3-pyridinecarboxylic acid (4). For compound 3, an isopropyl group was linked to the phenyl ring of 2-PNA; for the other three compounds, one or more methyl groups were introduced. Crystallization experiments were conducted, and structures of obtained crystals were solved by single X-ray diffraction. (For details, see the Supporting Information.) Table 1 lists crystallographic data of crystals that were identified. For compound 1, two polymorphs were discovered (1a and 1b), with both exhibiting so-called conformational polymorphism as well as conformational isomorphism.18 1a has a space group P21/n, and 1b, P1; for compound 2, three conformational polymorphs (2a, 2b, and 2c) with one (2a) displaying also conformational isomorphism were obtained. All but one belong to the monoclinic, P21/n space group and bear centrosymmetry; 2b has a chiral space group (P32) and is polar. For compounds 3 and 4, each showed just one polymorph of space group P21/c. As expected, molecules in compounds 1-3 form the acid-pyridine heterosynthon and show one-dimensional hydrogen-bonding chains in their respective crystal structures, while 4 illustrates the acid-acid homosynthon. Their structures are highlighted in Figure 1. 1a has two molecules with similar conformations in the asymmetric unit (Z0 = 2); interestingly, each conformer forms its

own hydrogen-bonding chain, denoted as C(6) by graph set notation,19-21 between carboxyl and pyridinyl nitrogen. The chains extend perpendicularly to the (101) plane with their directions alternating, pointing to the opposite directions;the direction of a hydrogen bond is as that from the donor to acceptor.22 The two distinct hydrogen bonds have the same lengths (2.67 A˚) and different angles (175.4° and 135.1°, respectively). In addition to the intermolecular hydrogen bonding, an intramolecular hydrogen bond, denoted as S(6) by the graph set concept, can be found in both conformers. 1b has six molecules in the asymmetric unit (Z0 = 6). Interestingly, all of these six conformers participate in the same one-dimensional chain sustained by the acid-pyridine heterosynthon (Figure 1b). These hydrogen bonds have similar lengths (from 2.63 A˚ to 2.69 A˚) and angles (from 166° to 176°). An intramolecular S(6) hydrogen bonding motif exists in each conformer. In contrast, as further discussed below, the conformational difference among the molecules is substantially larger than that of the two conformers in 1a. Compound 2 has three polymorphs, and they all demonstrate the acid-pyridine heterosynthon based chain motif. The chains propagate along the a, c, and b axes in forms 2a, 2b, and 2c, respectively (Figures 1c-e). In forms 2a and 2c, the directions of the adjacent chains alternate; in form 2b, due to the lack of centrosymmetry, all of the chains point to the same direction. The four molecules in all of the asymmetric units of the three polymorphs (Z0 = 2 in form 2a) show a significant conformational difference. Due to the conformational variation, the hydrogen bonds differ in lengths (from 2.61 to 2.72 A˚) and angles (from 131.6 to 171.6°). In 2a, the chains are formed between the same conformers. The chain motif is also found in the crystal of compound 3, which shows two different conformers. The hydrogen-bonding chains extend along the c axis, formed only between the same conformers; the chains alternate, pointing to the opposite directions due to the centrosymmetry. The two hydrogen bonds display similar lengths (2.66 and 2.67 A˚) and angles (169.1 and 172.6°). In addition, intramolecular hydrogen bonding, S(6), is present in both conformers. Different from these structures, compound 4 forms acid-acid dimers in its crystal. No chain motif is found in the crystal structure. The length and angle of the intermolecular hydrogen bond are 2.64 A˚ and 177.7°, respectively. An intramolecular bond exists as well.

Communication


4995

Table 2. Values of the Torsion Angle, τ2 (deg), of the Molecules in Crystal Structures of Compounds 1-4 1a

1b

2a

2b

2c

3

4

-120.1 115.9

-86.4 82.8 -101.4 -111.4 -90.3 -112.9

-89.7 -68.8

-104.3

-61.1

-98.0 127.3

-175.8

Figure 2. Potential energy of a single molecule of 1 as a function of its torsion angle, τ2. The slight unsymmetry of the curve with respect to zero degrees is an artifact of the calculation during which all lengths and angles were fixed except for τ2.

Figure 1. Hydrogen-bonding motifs of 1a (a), 1b (b), 2a (c), 2b (d), 2c (e), 3 (f), and 4 (g). For 1a, 2a, and 3, where Z0 = 2, each chain motif is formed by the same conformers. Because of the similarity, only one chain is illustrated. Also, for clarity, only intermolecular hydrogen bonds are shown (dash lines).

Molecules of compounds 1-3 demonstrate twisted conformations because of the steric repulsion effected by the introduced functional groups, while the molecule of 4 remains flat. The torsion angles of the identified crystal structures, τ2, are listed in Table 2. Apparently, the two aromatic rings of the molecules in the crystals of compounds 1-3 are dislodged from the planar conjugation of π electrons because the two rings are twisted toward each other. Compound 4, however, demonstrates an almost planar conformation (τ2 = -175.8°). The yellow color

of 4 also suggests the conjugation of the whole molecule, while crystals of 1-3 are colorless. Thus, it seems likely that a lone methyl group at the ortho position of the phenyl ring is not bulky enough to force the dislodgement of conjugation. Two or three methyl groups, nonetheless, can introduce adequate steric repulsions so that the molecule has to give up the conjugation and adopt twisted conformations. In compound 3, the isopropyl at the ortho position is much bulkier than the methyl in 4 and can exert steric repulsion not just on the pyridinyl but also on the amino group. In fact, in another recent polymorphic study of 2-[methyl(phenyl)amino]nicotinic acid, a methyl was linked to the amino of 2-PNA, causing the molecule to take various twisted conformations in four distinct polymorphs in which only the hydrogen-bonding chains exist.22 To further illustrate the steric effect on a molecule’s conformation, a potential energy scan of compound 1 was conducted with respect to τ2. As shown in Figure 2, the lowest energy is located at twisted positions when τ2 is around (90°; when the molecule is planar, the energy reaches a maximum as high as 1000 kJ/mol (not shown in Figure 2). On the contrary, 2-PNA has a small barrier of 25 kJ/mol of rotating τ2 and it is at the vertical position.13 The two conformers in the crystal of 1a are within the energy minimum and, from Figure 2, the energy cost of taking these conformations is smaller than 4 kJ/ mol with regard to the most favorable τ2. A similar energy distribution can be found by the six conformers 1b with respect to τ2. Given the large conformational distribution, as illustrated by the high Z0 number of crystals (2 and 6 of 1a and 1b, respectively), it seems that the conformational energy window for the molecule to take is within a few kilojoules per mole and covers about 25° (Figure 2). This is further illustrated by Figure 3a, in which the eight conformers are superimposed, giving a fairly uniform distribution of the 25° window. More

4996


Long and Li the rotation about τ2 may be halted entirely and the conformational polymorphism could be quenched, despite reaction difficulties to covalently attach a large substitution group to the ortho position. Still, compounds 1-3 demonstrate large conformation flexibilities with the conformational polymorphism and isomorphism. From the viewpoint of the molecular structure-crystal packing relationship, this study illustrates a unique case of the mutual influence between a molecule’s conformation and intermolecular hydrogen-bonding motifs. For 2-PNA, it can remain at its most energy-favorable conformation by fully conjugating its aromatic electrons to form intermolecular hydrogenbonding dimers in the crystal. It can also take a slight energy penalty, less than 25 kJ/mol, but most likely gain a stronger intermolecular hydrogen bonding due to the conformational change. The possibility to retain the planar conformation is eliminated by the additional functional groups in compounds 1-3, and thereby, the acid-pyridine heterosynthon, not the acid-acid homosynthon, becomes the preferred choice. Studies are now underway to further understand the impact of the conformational flexibility of a molecule on modulating its intermolecular interactions and packing in the crystal. One focus is to chemically increase the energy barrier of τ2 of 2-PNA analogues so that it is difficult for a molecule to adopt other conformations than the conjugated, planar one. As a result, perhaps only the acid-acid homosynthon can be formed in solid state. Another focus is to use quantum mechanical calculations, in particular, conceptual density functional theory,23-26 for understanding whether the acid-pyridine heterosynthon is stronger than the acid-acid homosynthon. Results will be disseminated shortly. Acknowledgment. The authors are grateful to the NSF for the financial support of this study (DMR-0449633).

Figure 3. Overlay of eight conformers found in the asymmetric units of 1a and 1b (a) and four of the three polymorphs of compound 2 (b). For clarity, hydrogen atoms are omitted.

conformational polymorphs are possible;the absence of a Z0 = 1 structure is intriguing;as we just carried out a preliminary polymorph screening with a few solvents (see Supporting Information). Moreover, if the same energy scan (Figure 2) can be applied to 2 (assuming that the para-methyl group has little effect on the rotation of τ2), the four conformers of 2a-c exhibit a larger energy distribution than that by 1 with a window of more than 10 kJ/mol and 40° (Table 2 and Figure 2). The superimposed conformations, shown in Figure 3b, distribute fairly well. Still, it is tempting to believe that more conformational polymorphs of 2 are possible with different Z0 and τ2 within the 40° window. It is also likely that 1 can expand its energy window from a few to more than 10 kJ/mol, raising the possibilities of more polymorphic structures. In summary, four analogues of 2-PNA were synthesized and their crystal structures were solved. Compounds 1-3 display onedimensional hydrogen-bonding chains based on the acid-pyridine heterosynthon while 4 shows acid-acid homodimers between carboxyl groups. The molecular conformations in 1-3 are twisted because of steric repulsions by the functional groups that were attached to the phenyl ring. The molecules in 4 remain planar, as a lone methyl group is not bulky enough to force the disruption of the planar conjugation. The polymorphic structures suggest that having functional groups at the two ortho positions or a bulky one at one ortho position is able to disrupt the planar conjugation and force the molecules to leave the pyridinyl nitrogen available for accepting a hydrogen bond. When the substitution group is big enough, it is possible and interesting to see that

Supporting Information Available: Experimental details of synthesis and characterization of the 2-PNA analogues, crystal growth, crystal structure determination, and conformational search; crystal structures in the form of crystallographic information files (CIF). This material is available free of charge via the Internet at http:// pubs.acs.org.

References (1) McCrone, W. C. In Physics and Chemistry of the Organic Solid State; Fox, D., Labes, M. M., Weissberger, A., Eds.; Interscience Publishers: New York, 1965; Vol. 2, pp 725-767. (2) Nangia, A. J. Indian Inst. Sci. 2007, 87, 133–147. (3) Nangia, A. Acc. Chem. Res. 2008, 41, 595–604. (4) Almarss€ on, O.; Zaworotko, M. J. Chem. Commun. 2004, 1889– 1896. (5) Llinas, A.; Goodman, J. M. Drug Discovery Today 2008, 13, 198– 210. (6) Desiraju, G. R. Angew. Chem., Int. Ed. 2007, 46, 8342–8356. (7) Steiner, T. Angew. Chem., Int. Ed. 2002, 41, 49–76. (8) Desiraju, G. R. Crystal Engineering. The Design of Organic Solids; Elsevier: Amsterdam, 1989. (9) Desiraju, G. R. Angew. Chem., Int. Ed. 1995, 34, 2311–2327. (10) Desiraju, G. R. Crystal Design. Structure and Function. Perspectives in Supramolecular Chemistry; Wiley: Chichester, 2003. (11) Brittain, H. G., Ed. Polymorphism in Pharmaceutical Solids; Marcel Dekker: New York, 1999. (12) Bernstein, J. Polymorphism in Molecular Crystals; Oxford University Press: New York, 2002. (13) Long, S.; Parkin, S.; Siegler, M. A.; Cammers, A.; Li, T. Cryst. Growth Des. 2008, 8, 4006–4013. (14) Steiner, T. Acta Crystallogr., B 2001, 57, 103–106. (15) Aaker€ oy, C. B.; Beatty, A. M.; Helfrich, B. A. Angew. Chem., Int. Ed. 2001, 40, 3240–3242. (16) Vishweshwar, P.; Nangia, A.; Lynch, V. M. Cryst. Growth Des. 2003, 3, 783–790. (17) Shattock, T. R.; Arora, K. K.; Vishweshwar, P.; Zaworotko, M. J. Cryst. Growth Des. 2008, 8, 4533–4545.

Communication (18) Corradini, P. Chim. Ind. (Milan) 1973, 55, 122–129. (19) Etter, M. C. Acc. Chem. Res. 1990, 23, 120–126. (20) Etter, M. C.; Macdonald, J. C.; Bernstein, J. Acta Crystallogr., B 1990, 46, 256–262. (21) Berstein, J.; Davis, R. E.; Shimoni, L.; Chang, N. L. Angew. Chem., Int. Ed. 1995, 34, 1555–1573. (22) Long, S.; Parkin, S.; Siegler, M.; Brock, C. P.; Cammers, A.; Li, T. Cryst. Growth Des. 2008, 8, 3137–3140.


4997

(23) Parr, R. G.; Yang, W. Density-Functional Theory of Atoms and Molecules; Oxford University Press: New York, 1989. (24) Geerlings, P.; De Proft, F.; Langenaeker, W. Chem. Rev. 2003, 103, 1793–1873. (25) Ayers, P. W.; Parr, R. G.; Pearson, R. G. J. Chem. Phys. 2006, 124, 194107. (26) Li, T.; Ayers, P. W.; Liu, S.; Swadley, M. J.; Aubrey-Medendorp, C. Chem.;Eur. J. 2009, 15, 361–371.

Controlled Formation of the AcidâPyridine Heterosynthon over the

Recommend Documents

Controlled Formation of the AcidâPyridine Heterosynthon over the