DOI: 10.1021/cg100227s
Enforcing Molecule’s π-Conjugation and Consequent Formation of the Acid-Acid Homosynthon over the Acid-Pyridine Heterosynthon in 2-Anilinonicotinic Acids
2010, Vol. 10 2465–2469
Sihui Long and Tonglei Li* Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky Received February 15, 2010; Revised Manuscript Received May 6, 2010
ABSTRACT: Two different synthons, acid-acid and acid-pyridine, are present in the crystal structures of 2-(phenylamino)nicotinic acid. The intermolecular hydrogen-bonding motifs are determined by molecular conformation and conformational energy. By covalently linking electron-withdrawing groups to the phenyl ring, it is possible to strengthen the molecule’s global π-conjugation and thereby lead to only the acid-acid homosynthon in crystal packing and prohibit the competing acid-pyridine heterosynthon. One of the fascinating aspects of crystal packing of organic molecules is conformational polymorphism.1-6 The energy difference among polymorphs of such systems is typically small; often less than 1 kJ/mol;thus making it even more intriguing to study the intricate interaction between a molecular conformation and intermolecular interactions in crystal structures. A simple diarylamine, 2-(phenylamino)nicotinic acid (2-PNA), shown in Scheme 1, has thus far produced four different polymorphs.7 Two distinct supramolecular synthons have been identified. One is the acid-acid homosynthon between adjacent carboxylic acid groups found in the R and β forms, and the other is the acid-pyridine heterosynthon between neighboring pyridine nitrogen and carboxyl in the γ and δ forms. The R form was the most stable and could be transformed from other polymorphs by heating or mechanical manipulation. The major difference in the molecular conformation in the four crystal structures stems from the torsion angle τ2 (Scheme 1). In the R and β forms, the angle (1.8° in form R and -163.4° and 156.8° in two conformers in the form β)7 indicates that the molecules remain relatively flat and thereby form a π-conjugated electronic system between the two aromatic rings bridged by the aniline N lone pair of electrons. Conversely, in the γ and δ forms, τ2 (-147.9°, 132.6°, -125.2°, and -139.4° in the conformers in form γ and -140.0° and -110.6° in the conformers in form δ)7 suggests that the molecules have twisted conformations between the two rings and consequently disrupt the π-conjugation. Moreover, the potential energy scan of τ2 of a single 2-PNA molecule in the gas phase shows an energy barrier of 25 kJ/mol at about 90° (Figure 1), a position in which the conjugation between the aniline N lone pair and phenyl ring is completely disrupted. Because of the small energy barrier to rotate around τ2, the molecule is capable of exhibiting a large degree of conformational flexibility and the π-conjugation is likely to play a subtle role in balancing the conformation and intermolecular interactions. In fact, when the molecule stays in the planar conformation, the pyridine N is spatially blocked by a hydrogen atom of the phenyl ring. Only when the molecule twists the two aryl rings, the vicinity around the nitrogen atom is opened up for accepting hydrogen bonding. As such, the intermolecular hydrogen-bonding patterns in 2-PNA’s polymorphic structures can compensate for unfavorable changes in molecular conformation. The interplay is apparently regulated by the energy barrier of adjusting the molecular conformation around τ2 that is similar in magnitude to the intermolecular hydrogen bonding. Losing the π-conjugation due to a conformational change is compensated by
Scheme 1
*Corresponding author: Tonglei Li, Ph.D., 514 College of Pharmacy, University of Kentucky, 725 Rose Street, Lexington, Kentucky 40536-0082. Telephone: (859) 257-1472. Fax: (859) 257-7585. E-mail:
[email protected].
a similar energy gain from the change of the acid-acid homosynthon to the acid-pyridine heterosynthon;it is reported that the acid-pyridine heterosynthon is more energy-favorable than the acid-acid homosynthon.8-11 It seems, then, reasonable to argue that the conformational polymorphism of 2-PNA lies in a delicate energy balance between the π-conjugation defined by τ2 and the strength of two intermolecular hydrogen-bonding formations. It should be noted that the π-conjugation defined by τ1 between the pyridine and the aniline N lone pair is much stronger, as further discussed below, and is unlikely to be disrupted during crystal packing. To further explore the hypothesis that the molecular conformation and intermolecular interaction of 2-PNA are dependent on the τ2 energy barrier, we sought to raise the bar for the molecule to take twisted conformations by increasing the conjugation between aryl moieties. This should prohibit the acid-pyridine heterosynthon in the crystalline state. To test the theory, fluorine derivatives of 2-PNA were synthesized and crystallized in different solvents. Because fluorine is a strong electron-withdrawing atom, when it is chemically linked to the phenyl ring, the aniline N lone pair may be “pulled” more toward the aromatic ring, strengthening the polarization or delocalization of π electrons. Electronic calculations of single molecules of the synthesized compounds (Scheme 2) and NBO (natural bond orbital) analyses support the likelihood. Listed in Table 1 are the donor-acceptor NBO stabilization energies, evaluated based on the second-order
r 2010 American Chemical Society
Published on Web 05/12/2010
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Long and Li
Figure 1. Potential energy scan of τ2 of 2-PNA. The black line indicates calculated values, while the gray line corrects the calculation by mirroring the values between 0 and (90°. The artifact was caused by way of how the calculation was conducted in which only τ2 was allowed to change.
Scheme 2
Table 1. Donor-Acceptor Stabilization Energies (kJ/mol) of the Lone Pair of Electrons on the Aniline N to the Pyridine Ring, EN-Py, and to the Phenyl Ring, EN-Ph, of Fully Optimized Single Molecules of 2-PNA and Fluorine Derivatives. a ΔEN-Py ΔEN-Ph τ2
2-PNA
1
2
3
4
5
0.00 0.00 179.94
-10.42 5.10 179.96
-6.86 7.99 179.95
-2.76 -2.13 179.95
-16.48 8.95 179.99
-29.20 -56.02 122.99
a Listed are the energy difference using those of 2-PNA as the reference (279.49 and 158.66 kJ/mol of EN-Py and EN-Ph, respectively); a positive value suggests more contribution to the bonding stability.
perturbation theory,12 between the aniline N lone pair and the pyridine ring, EN-Py, or the phenyl, EN-Ph. It is shown that values of EN-Py are significantly larger than those of EN-Ph, indicating that the conjugation with pyridine is much stronger than that with phenyl by the aniline N. τ1 is thus more inclined to remain planar in the crystal. NBO calculations also show that the nature of the covalent bond between the aniline N and pyridine is nearly a double bond while the one between the N and phenyl is more toward a single bond (data listed in the Supporting Information). Furthermore, the effect by the fluorine derivation on EN-Ph is apparent. The first four derivatives (1-4) crystallize in the planar conformations, the same as that of 2-PNA. Of these four compounds, three have higher values of EN-Ph than that of 2-PNA; the largest increase, 8.95 kJ/mol, is of 4, in which two fluorine atoms
are linked to the ortho- and meta-positions, respectively. Interestingly, compound 5 has a much smaller EN-Ph, largely due to its twisted conformation (τ2 = 123° as compared with 180° of 1-4), which is caused by the steric hindrance between the pyridine N and one of the fluorine atoms at the ortho-positions. The NBO results suggest that 1-4 have higher chances of remaining planar and form the acid-acid homosynthon while 5 may form the acid-pyridine heterosynthon. The crystal structures of 1-5 are summarized in Table 2. Each of 1-3 produced one polymorph while 4 generated three (4a, 4b, and 4c) and 5 yielded two (5a and 5b). All structures except for 5b show centrosymmetry. τ2 of crystal 1 is 159.6°, close to the full planar conformation. As shown in Figure 2, the acid-acid homodimer (R22(8) hydrogen bonding motif in the graph set concept)13-15 is formed. Similar results can be found in 2 as well. The molecular conformation is 20° short of being flat (τ2 = -161.1°), and the homodimer motif is formed by adjacent carboxyl groups. In addition, the molecule is disordered, with the fluorinated aromatic ring residing in two positions that roughly show C2 symmetry with each other. As marked in the figure, one conformation has much higher occupancy (70.4%) than the other (29.6%), an interesting feature that may be due to their slightly different conformational energies. For compound 3, the crystal structure is particularly interesting. The asymmetric unit of the crystal contains 1.5 molecules, a whole molecule as a zwitterion with the proton transferred from the carboxyl to the pyridine N and half of the neutral molecule. More importantly, the neutral form is disordered and the two configurations (50:50 ratio) are symmetry related by inversion. As a result, no dimer motif is observed and a chain motif (C(6)) of intermolecular hydrogen bonds is formed by carboxylate O and pyridinium H. These chains are further connected by the disordered neutral molecule through hydrogen bonding between carboxylic OH and caboxylate O (D(2)). It is unclear at this point whether there is a connection between the zwitterion formation and the smaller EN-Ph value of 3 (Table 1), which suggests that the conjugation by the lone pair of electrons from the amino to the phenyl ring is weakened as compared with the 2-PNA molecule. A similar observation can also be made in 5b. Shown in Table 1, compound 4 has the largest energy contribution from conjugation between the aniline N lone pair and the phenyl, so the molecule should tend to be planar. One of the τ2 values of the three polymorphs is in fact almost planar, -176.2°; the other two values are 160.6° and 158.7°, similar to those in 1 and 2. Not surprisingly, 4 forms the homodimer motif (R22(8)) in all three polymorphs, differing mainly in τ2. Other than three polymorphs, two solvates were harvested from acetic acid (S4a) and dimethylformamide (S4b), respectively. In both solvates, the molecule remains nearly perfectly flat, with τ2 being 179.2° in S4a and 173.3° in S4b. Clearly, when the two fluorine atoms steer away from the pyridine N in polymorphs of 4, a planar conformation is maintained. But in 5, such a conformation is unlikely. As predicted, 5a forms one-dimensional hydrogen-bonding chains along the b axis sustained by the acid-pyridine heterosynthon (C(6)) and τ2 is 120.5°, almost identical to the calculated value (Table 1). The packing for 5b is relatively complicated due to the presence of five molecules (labeled as A, B, C, D, and E) in the asymmetric unit (Z0 = 5) and the intermolecular proton transfer between two hydrogen bonded molecules B and C. The proton from the carboxylic acid oxygen O16C is transferred to the pyridine nitrogen N1B. Similar to 5a, the main supramolecular synthon is the acid-pyridine heterosynthon although the carboxylatepyridinium interaction and other hydrogen-bonding patterns also exist. τ2 is steered away from 180° for all five conformers: 118.1°, 106.5°, 119.2°, 90.2°, and 122.4° for A, B, C, D, and E, respectively. Clearly, the planar conformation is not possible due to steric repulsion between the pyridine N and fluorine. Moreover, the N-C bond length between the aniline N and phenyl in the crystal structures further attests the impact by linking the
completeness to 2θ unique reflections R1 [I > 2σ(I )] wR2 (all data)
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 coef (mm-1) F(000) θ range (deg) limiting indices
232.21 0.40 0.20 0.05 monoclinic P21/c 3.7501(1) 20.1157(3) 13.7421(2) 90 95.8489(8) 90 4, 1 1031.25(3) 1.496 90(2) 0.116 480.0 1.80-27.48 -4 e h e 4 -26 e k e 26 -17 e l e 17 99.9% 2348 0.0462 0.1303
formula weight crystal size (mm3)
232.21 0.30 0.20 0.10 triclinic P1 3.7408(1) 10.3642(2) 14.0516(3) 109.4485(9) 97.4322(9) 96.3926(9) 2, 1 502.39(2) 1.535 90(2) 0.119 240.0 1.56-27.45 -4 e h e 4 -13 e k e 13 -18 e l e 18 99.3% 2281 0.0358 0.1013
2
C12H9FN2O2
1
C12H9FN2O2
formula 232.21 0.20 0.10 0.05 monoclinic P21/c 3.7737(8) 32.818(7) 12.844(3) 90 92.24(3) 90 6, 1.5 1589.5(6) 1.456 90(2) 0.113 720.0 1.24-27.50 -4 e h e 4 -42 e k e 41 -16 e l e 16 98.7% 3581 0.0562 0.1670
C12H9FN2O2
3
250.20 0.40 0.10 0.10 monoclinic P21/c 3.6888(1) 21.3264(8) 13.7054(6) 90 95.0034(15) 90 4, 1 1074.08(7) 1.547 90(2) 0.130 512.0 1.77-27.45 -4 e h e 4 -26 e k e 27 -17 e l e 17 100.0% 2455 0.0648 0.1881
C12H8F2N2O2
4a
250.20 0.50 0.10 0.05 triclinic P1 4.2521(2) 9.4407(5) 13.6969(8) 106.3670(23) 90.3310(23) 96.5160(22) 2, 1 523.73(5) 1.587 90(2) 0.134 256 1.55-27.38 -5 e h e 5 -12 e k e 12 -17 e l e 17 100% 2376 0.0738 0.2489
C12H8F2N2O2
4b
250.20 0.30 0.10 0.05 triclinic P1 6.8233(2) 7.6420(3) 10.9371(4) 104.6379(15) 105.2924(15) 94.5914(16) 2, 1 525.64(3) 1.581 90(2) 0.133 256 2.01-27.44 -8 e h e 8 -9 e k e 9 -14 e l e 14 100% 2392 0.0738 0.2489
C12H8F2N2O2
4c C12H8F2N2O2 3 C2H4O2 310.26 0.60 0.20 0.10 monoclinic P21/c 17.9911(4) 3.7728(1) 19.6820(5) 90 99.4392(11) 90 4, 1 1317.86(6) 1.564 90(2) 0.134 640 1.15-27.44 -22 e h e 23 -4 e k e 4 -24 e l e 24 100% 2994 0.0441 0.1299
S4a
Table 2. Crystallographic Data of Crystal Structures Obtained for Compounds 1-5 S4b C12H8F2N2O2 3 C3H7NO 323.30 0.40 0.10 0.10 orthorhombic Pcab 6.1189(2) 13.6856(5) 36.8482(15) 90 90 90 8, 1 3085.7(2) 1.392 90(2) 0.114 1344.0 3.81-25.00 -6 e h e 6 -15 e k e 15 -43 e l e 43 96% 2610 0.060 0.1977
250.20 0.30 0.30 0.10 monoclinic P21/c 7.2500(1) 7.6420(3) 10.6890(2) 90 90.843(11) 90 4, 1 1104.34(3) 1.505 90(2) 0.127 512 2.38-27.47 -9 e h e 9 -18 e k e 18 -13 e l e 13 100% 2523 0.0427 0.1170
250.20 0.30 0.20 0.10 monoclinic Cc 25.7321(3) 14.3518(2) 15.2832(2) 90 104.4479(5) 90 20, 5 5464.88(12) 1.521 90(2) 0.128 2560 1.63-27.49 -33 e h e 33 -18 e k e 18 -19 e l e 19 97% 12140 0.0488 0.1261
5b C12H8F2N2O2
5a C12H8F2N2O2
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Figure 2. Crystal packing of the fluorine derivatives. Disorders are shown in 2 and 3. Intermolecular hydrogen bonding is marked by a dashed line (except for 5b, due to high Z0 , in which just the asymmetric unit is shown).
2468 Long and Li
Communication electron-withdrawing fluorine on the π conjugation. Shorter distances are seen in the fully conjugated systems (1, 2, 3, and 4), with the shortest being1.39 A˚ (4b), while larger values are observed in twisted conformations (5a and 5b), with the largest being 1.42 A˚ (5b). Crystal packing is determined by intermolecular interactions. Accurate and comprehensive evaluation of intermolecular interactions and lattice potentials is critical for understanding and predicting crystal structures as well as for crystal engineering of organic molecules. Given the prevailing challenges in crystal structure prediction,16-19 our studies reported here aim to explore the underlying linkage between the chemistry of diarylamines and their intermolecular interactions and hopefully shed light on developing new ways of calculating crystal packing. Compounds 1, 2, and 4 have the weaker part (EN-Ph) of the π-conjugation reinforced (Table 1), and their crystal structures all bear the acidacid homosynthon. Conversely, 3 and 5 are further weakened, and not only is the acid-pyridine heterosynthon found in the crystal structures but there are also very interesting packing features (inter-/intramolecular proton transfer; high Z0 ) that deserve further investigation. The zwitterion formation is particularly intriguing, and the deterministic linkage with the chemistry of 2-PNA derivatives is currently being sought. Acknowledgment. The authors are grateful to the NSF for financial support of this study (DMR-0449633). The authors also thank Drs. Sean Parkin and Arthur Cammers for helpful discussions. 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 (CIF) files.
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This material is available free of charge via the Internet at http:// pubs.acs.org.
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