Crystal structures and density functional theory calculations of o - and p -nitroaniline derivatives: combined effect of hydrogen bonding and aromatic interactions on dimerization energy

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Introduction
Nitroaromatic compounds are widely used in industrial production of chemicals, such as explosives, pesticides, dyes and pharmaceuticals. 1 Nowadays, crystal forms of nitroarenes and nitroanilines are studied as potential organic non-linear optical (NLO) materials. 2The environmental and biological effects of nitroarenes are significant.Nitroarenes pose toxic and mutagenic effects for organisms, which are further aggravated by the long life-time of nitroarenes in the environment due to resistance to oxidative attack. 3In addition, biosynthesized nitroarenes bear important biological activities, for example, as antibiotics and in signalling. 4In light of recently published data, these effects may rise from the aromatic interactions of nitroarenes with proteins. 5Therefore, detailed understanding of the chemical nature of nitroarenes and their propensity to form weak interactions are useful in order to elucidate the biological activities and toxicity of nitro compounds and to develope new crystal materials for NLO applications.
In crystal engineering, complete understanding of weak intermolecular interactions in a crystal would be optimal for predicting the exact crystal packing and creating desired properties for crystalline materials.Over the years, the trend has been to look for weaker and weaker bonding forces to increase the understanding of complicated crystal packing and molecular recognition phenom-ena.For example, halogen bonding 6 and weak C-H• • • O hydrogen bonds, where C-H group acts as a hydrogen bond donor and oxygen as an hydrogen bond acceptor, 7,8 have been studied and used in crystal engineering of supramolecular complexes. 9Many of these compounds have nitrobenzene functionality, since the oxygen atoms of the nitro group are good acceptors for weak hydrogen bonds. 10The analysis of crystal structures of nitrobenzene and nitroaniline compounds reveals the abundancy of these bonds, which, in many cases, are important factors in crystal packing. 11In addition, nitro groups form dipole-dipole interactions, which, depending on the geometry, form mainly by electrostatic interaction between negatively charged oxygens and positively charged nitrogens, 12 or may attain significant contribution from dispersion forces. 13omatic interactions have an important role in self-assembly and crystal packing of aromatic compounds.The role of π-stacking, edge-to-face π-stacking and weaker aliphatic C-H• • • π interaction in protein folding and small molecule binding into proteins have recently been illustrated. 5,146][17] Nevertheless, electrostatic component may be used to predict the binding energy. 18Electron density withdrawing substituents, such as nitro group, polarize the π-electron cloud of the benzene ring, 19 and consequently, influence optimal geometry of the π − π -interactions.For example, nitrobenzene dimers prefer slipped-parallel (offset face-to-face) orientation over T-shaped (edge-to-face) geometry (Figure 1), which is most stable for benzene dimers. 17 crystal structures, nitro groups are usually coplanar with the phenyl ring. 20Possible explanation could be resonance coupling between the nitro group and the aromatic ring as indicated in the quinonoid structure (Figure 2).However, the lack of correlation between C-N bond lengths and coplanarity of the nitro group does not support this hypothesis. 21In addition, NMR and computational analysis have shown for para substituted nitrobenzenes, such as 4-nitroaniline, that the nitro group withdraws a constant amount of electron density from the ring regardless of the presence of electron density donating substituents. 22These findings suggest that the resonance of the nitro group and the benzene ring are not strongly coupled, and the planar geometry is mainly caused by rotation barrier around C-N bond or crystal packing. 21On the other hand, the electron deficient nitrophenyl ring accepts more readily the lone pair of the amino substituent, which enhances the input of quinonoid structure in the resonance hybrid of nitroanilines.Also substitution geometry creates differences in the electronic structure and aromaticity between o-, mand p-nitroanilines. 23Nitroaniline forms an intramolecular hydrogen bond between nitro and amino groups, which creates a six-membered chelate ring further extending the electron delocalization in the aromatic ring.During investigation of new supramolecular resorcinarene hosts, 24,25  Crystal packing and intermolecular interactions were analyzed using Hirshfeld surfaces and fingerprint plots.26 Bond lengths and harmonic oscillation measure for aromaticity (HOMA) 27 were compared in order to elucidate differences between aromatic interactions of 2-and 4-nitroaniline derivatives.In addition, density functional theory was applied to the molecules and their dimers in order to understand how the substitution affects conformation, the π-stacking geometries, as well as, interplay of weak interactions in crystal packing.Taken together, these methods provide detailed and quantitative results about molecular conformation, strength of weak hydrogen bonds and π-stacking in nitroaniline crystals.

Single crystal X-ray diffraction
Crystals of 1A and 2A were grown in CHCl 3 solution with hexane diffusion.Crystals of 1B, 2B and 3A were grown in a NMR tube in CDCl 3 solution.Crystals of 4A and 5B were obtained directly from the recrystallization in chloroform-hexane solution.
Single crystal X-ray data were recorded on a Nonius Kappa CCD diffractometer with Apex II detector using graphite monochromatized CuK α (λ = 1.54178Å) radiation at a temperature of 173 K.The data were processed and absorption correction was made to all structures with Denzo-SMN v.0.97.638. 31The structures were solved by direct methods (SHELXS-97) and refined (SHELXL-97) against F 2 by full-matrix least-squares techniques using SHELX-97 software package 32 and Olex2. 33The hydrogen atoms were calculated to their idealized positions with isotropic temperature factors (1.2 or 1.5 times the C temperature factor) and refined as riding atoms, except amine hydrogens, which were located from the Q-peaks and restrained using DFIX 0.91.Crystal structure analysis and figures were prepared using Mercury CSD 3.0, 34 and Olex2.Hirshfeld surfaces (plotted against d norm , curvature and shape index) and 2D fingerprint plots were calculated using CrystalExplorer. 35Crystallographic data (excluding structure factors) for the structures in this paper have been deposited with the Cambridge Structural Data Center as supplementary publication nos.CCDC 930277-930283.

Powder X-ray diffraction
PXRD patterns of the nitroaniline derivatives were measured after recrystallization from chloroformhexane solution using a PANalytical X'Pert Pro system in a reflection mode with monochromatized CuK α radiation (λ = 1.54178Å) at ambient temperature.

Computational
DFT calculations were performed using Turbomole program V6.4. 36,37PBE exchange-correlation functional 38 with Grimme's van der Waals corrections 39 as implemented in Turbomole V6.4 were used.All calculations were performed with aug-cc-pVDZ basis. 40The ground state geometries were fully optimized for 1A, 1B, 2A, 2B and N-ethyl-2-nitroaniline using crystallographic coordinates for isolated monomers and dimers as a starting point.

Crystal structures
The nitroaniline derivatives crystallized readily as yellow or orange crystals from chloroform or chloroform-hexane solution.Crystal structures of 1A-5B were solved by single crystal X-ray diffraction (Tables 1 and 2).Powder X-ray diffraction patterns of the compounds were recorded to ensure that the single crystal structure was a good representative for the sample. 41e conformation of the nitroaniline ring in all derivatives was close to planar.The nitro group tilt angle from the phenyl ring plane was 2.9 • in 1A, 7.8 • in 2A, 4.5 • in 3A and 5.7 • in 4A.In  Visual inspection of the structures revealed that the small inclination of the nitro group is caused in most cases by weak hydrogen bonds to nitro oxygens, such as in 2A, 2B, 3A and 4A.
The amino nitrogen resides coplanary to the phenyl ring (1.5-7.9 • tilt), which denotes a sp 2 hybridization.The torsion of the amino group hydrogen against C=C bond of the aromatic ring (C=C-N-H torsion) varies between 1.4-8.4(7) chain between amino hydrogen and nitro oxygen (Figure 8).Most of the nitroaniline derivatives formed at least one aromatic π-stacking interaction (Table 3).Compound 1B formed a parallel π-interaction between two opposing molecules, and a T-shaped π-interaction to a π-stacked dimer above and below.Compound 2A obtained a step-like conformation and formed continuous displaced parallel π-stacks of tolyl rings, and separate stacks for 2-nitroaniline rings (Figure 11).As in 1B, the nitro and amino groups in the π-stacks are aligned in an antiparallel fashion.Compound 2B adopted a clip-like conformation, in which the  tolyl and 4-nitroaniline rings formed an intramolecular π-stack.The tolyl rings of two molecules further stacked in a displaced parallel geometry, and the 4-nitroaniline rings formed an edge-toface π-interaction, in which a short contact between aryl C-H and nitro O5 has a significant role (Figure 12).Compounds 3A and 4A formed aromatic interaction between two 2-nitroaniline rings, again with an antiparallel orientation of the nitro and amino substituents.1A and 5B did not form aromatic interactions in a conventional geometry.In 1A, the aromatic rings align as sheets, and on the one side the geometry seems favorable to dipole-dipole interaction between two nitro groups (Figure 13).On the other side, however, the Hirshfeld surface indicates flat and shape complementary areas between an aromatic ring of one molecule and an hydrogen  bonded chelate ring of the other (Figure 10).The distance between the phenyl ring centroids, R 1 , is too long for a aromatic interaction, whereas, the distance between the centroid of the chelate ring and centroid of the phenyl ring (R 2 ) is within bonding distance (first entry in Table 3).In 5B the N-H group lies on top of the aromatic ring but the geometry does not remind an aromatic interaction, and overall, the position of the nitroaniline rings is more likely directed by the pairs of dipole-dipole interactions between the nitro groups (Figure 8).

Aromaticity of the nitroaniline rings
The substituent effects on the electron delocalization of the nitroaniline rings were analyzed by comparing C-C and C-N bond lengths.The C−NO 2 bond length was 1.44-1.45Å for all derivatives, close to a typical C-N bond length for nitro substituent in a crystal structure, 1.47 Å. 44 The C-NH bond lengths were 1.35-1.37Å, which correspond to a C-N bond to a planar sp 2 nitrogen showing that the amino nitrogen donates its lone pair to the aromatic π-electron system.
The aromaticity of the nitroaniline rings were compared using C-C bond lengths to calculate harmonic oscillation measure of aromaticity (HOMA) indices. 27HOMA indice is calculated by summing the deviation of the observed bond lengths from ideal bond lengths (R opt ) and scaling the result to give HOMA = 0 for Kekulé type of structure and HOMA = 1 for completely delocalized structure with all bonds equal to R opt = 1.388Å. 45 The 2-nitroaniline derivatives had slight decrease in aromaticity in comparison to the 4-nitroaniline derivatives.The mean of HOMA indices for 2-nitroaniline derivatives was 0.88, and for 4-nitroaniline derivatives 0.93 (Table 4).Similar values have previously been obtained for oand p-nitroaniline, 0.86 and 0.93, respectively, 23 and these values were close to the HOMA1 indices calculated for DFT optimized structures of 1A, 1B, 2A and 2B.In addition, the HOMA indice for the hydrogen bonded chelate ring in o-nitroaniline has previously been reported to be 0.59. 23Similar calculation for group A derivatives gave a mean HOMA indice for chelate ring 0.67.In comparison to o-nitroaniline, the aromaticity of the chelate ring was slightly increased, which probably results from the inductive effect of the N-ethyl substituent.Recently, crystal structures of Schiff base salicylidene ligands suggesting a π-stacking interaction between a pseudo-aromatic ring formed through intramolecular hydrogen bonding and ordinary aromatic ring, have been published. 46,47The chelate ring of 2-nitroaniline derivatives also show aromatic character based on the HOMA indices, even though the hydrogen bonded system is different lacking keto-enol tautomerism.Table 3 indicates that π-stacks of 2-nitroanilines contain shorter interplanar distances (D = 3.33-3.44Å) than 4-nitroanilines (D = 3.50-3.51Å).In addition, shortest interplanar distances, D < 3.40 Å, were connected with longest centroid-centroid distances, R 1 > 4 Å, and shortest phenyl and chelate centroid-centroid distances, R 2 < 3.70 Å, that is, stacking of the phenyl and chelate rings.A search of crystal structures in CSD revealed that the stacking of phenyl and chelate rings is present in many 2-nitroaniline compounds. 48Considering the π-stacking geometries of 2-nitroaniline derivatives, especially in 1A, and the aromatic character of the chelate ring, the interaction between phenyl ring and hydrogen bonded chelate ring was investigated using density functional theory calculations.

DFT calculations
Ground state energies and optimized geometries were calculated for compounds 1A, 1B, 2A and 2B starting from the crystal structure coordinates for isolated monomers and dimers in gas phase.
The optimized geometries of 1A, 2A and 2B monomers were very close to the conformation in the crystal structure, indicating that monomers are in a relaxed conformation.In contrast, optimized geometry of 4-nitroaniline monomer 1B deviates from the crystal structure indicating that intermolecular interactions are required for sustaining the observed conformation.In crystal structure, the conformation of 1B is linear and the monomers are connected into hydrogen bonded R 2 2 (14) dimer.When 1B monomer was relaxed with DFT, it formed an intramolecular N-H• • • O hydrogen bond to the sulfonyl oxygen.However, when 1B dimer was relaxed with DFT, the intermolecular hydrogen bonds were re-established, and dimerization energy of -0.31 eV was obtained.
Thus, intermolecular hydrogen bonds are stronger and likely improve the crystal packing into a regular structure, whereas intramolecular hydrogen bond may be weakened by molecular strain.
Although the 2B monomers are nearly relaxed in the crystal, intermolecular hydrogen bonding and π-stacking stabilize the crystal.Based on DFT geometry optimizations, dimerization energy of R 2 2 (14) hydrogen bonded 2B monomers is -0.87 eV, and dimerization energy of intermolecular tosyl-tosyl π-stacked 2B monomers is -0.55 eV.
In order to calculate interaction energy for phenyl-chelate stacking, a dimer of 1A molecules was relaxed starting from the crystal structure coordinates.The optimized geometry for the 1A dimer is very similar to the original crystal structure geometry (Figure 14) having dimerization energy of -0.81 eV.The dimer is held together by two weak hydrogen bonds from aryl H3 to sulfonyl O5, and the proposed phenyl-chelate stacking interaction.The effect of weak hydrogen bonds on dimerization was eliminated by repeating optimization for a N-ethyl-2-nitroaniline dimer, which lacks the hydrogen bond acceptors.Dimerization energy for the relaxed structure is -0.62 eV.However, the stacking geometry is different than for the 1A dimer.Therefore, we extracted a stacking geometry closely resembling the stacking geometry of the 1A dimer from the geometry optimization path.This structure has dimerization energy of -0.53 eV.The energy difference of 0.09 eV between this partially relaxed structure and the optimal structure can be easily overcome by the hydrogen bonds.Moreover, the crystal structure and DFT optimized geometry of 2A with dimerization energy of -0.65 eV is actually quite close to the fully relaxed structure of the N-ethyl-2-nitroaniline dimer.Thus, it can be concluded, that there is a binding interaction between the phenyl and chelate rings, which contributes significantly to stabilization of the 1A and 2A crystals.

Conclusion
The effect of o/p-substitution on intra-and intermolecular hydrogen bonds, dipole-dipole interactions and aromatic interactions in nitroaniline derivatives was investigated using crystal structure analysis and DFT calculations.Nitro and amino functionalities were approximately coplanar with the phenyl ring.The 2-nitroaniline derivatives formed an intramolecular hydrogen bond between amino and nitro groups creating a six-membered chelate ring, whereas in 4-nitroaniline derivatives, the amino hydrogen is sterically available for intermolecular hydrogen bonding.This material is available free of charge via the Internet at http://pubs.acs.org/.

Figure 1 :
Figure1: Classification of π-stacking geometries.Parameter R 1 is centroid-centroid distance, D is interplanar distance, and S is shift or centoid-centroid distance projected to a phenyl ring plane.Tshaped π-interaction is also known as edge-to-face, and parallel and slipped parallel as face-to-face and offset face-to-face π-interaction.

Figure 2 :
Figure 2: Benzenoid and quinonoid resonance structures for oand p-nitroaniline showing intramolecular hydrogen bond of o-nitroaniline with a dashed bond.

Figure 10 :
Figure 10: Hirshfeld surface of 1A plotted against a) d norm (red color indicates contacts shorter than vdW distance), b) shape index, arrows point to complementary patches.Fingerprint plots of 1A, 1B, 2A and 2B showing O• • • H contacts in color.

Figure 14 :
Figure 14: DFT optimized structures for 1A dimer and N-ethyl-2-nitroaniline dimer.Top view of XRD structure and DFT structures.

4 -
Nitroaniline derivatives 1B and 2B, which contain sulfonyloxy groups, formed N-H• • • O hydrogen bonded dimers.DFT calculations indicated that the hydrogen bonded dimer is more stable than an intramolecular hydrogen bond by -0.31 eV for 1B and -0.87 eV for 2B.In addition to strong hydrogen bonds, C-H• • • O hydrogen bonds into sulfonyl oxygens and nitro oxygens were important in crystal packing for most derivatives, especially in 1A, 1AB, 2A, 2B and 4A.Dipole-dipole interactions between nitro groups were in a minor role, and found only in structures 1A and 5B.Differences in the shape and electron distribution between 2-and 4-nitroaniline rings creates variation in π-stacking geometries.2-nitroaniline derivatives had slightly lower aromaticity than 4-nitroaniline derivatives based on the HOMA indices.In 4-nitroaniline derivatives, parallel and T-shaped π-interactions were observed, whereas in 2-nitroaniline derivatives, parallel displaced π-stacking and phenyl-chelate stacking was abundant.Closer investigation of the 2-nitroaniline derivatives 1A and 2A using DFT, revealed that stacking of a phenyl and a chelate ring formed a weakly bonded dimer, in which, phenyl-chelate stacking contributed significantly to the dimerization energy.Thus, phenyl-chelate stacking may be regarded as a complementary interaction to phenyl-phenyl stacking, which affects crystal packing of 2-nitroaniline derivatives.addition, 40 out of 112 π-stacking interactions may have contribution from phenyl-chelate stacking (R 2 < R 1 ).
•.In 2B, however, a larger torsion angle of -19.5 • was observed, resulting from the intermolecular hydrogen bond to sulfonyl oxygen.