The Influence of Methoxy and Ethoxy Groups on Supramolecular Arrangement of Two Methoxy-chalcones

The structures of two methoxylated chalcones, namely (E)-1-(4-methoxyphenyl)3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one and (E)-3-(4-ethoxyphenyl)-1-(4-methoxyphenyl) prop-2-en-1-one, reveal the effect of the inclusion of the methoxyl and ethoxyl substituents of the conformation on methoxy-chalcone. Structural comparative study between two chalcones was done in this work and some effects on geometric parameters, such as planarity and dihedral angles, were described. In addition, intermolecular interactions responsible for crystalline packaging were investigated by Hirshfeld surfaces and the values of those interactions were analysed by comparing experimental and theoretical models. The molecular stability was expressed in terms of softness and hardness, both obtained from frontier molecular orbitals. Finally, there is a good agreement between calculated and experimental infrared spectrum, which allowed the assignment of the normal vibrational modes.


Introduction
][12][13] Chalcones and chalcone derivatives are often obtained from natural or synthetic sources. 8,14][21] A study with methoxychalcone 19 investigated the optical properties of 3,4-dimethoxy-4'-methoxychalcone and it has shown promise for nonlinear optical applications.On the basis of these features, the investigation on structural and synthetic perspective assumes noteworthy importance for the extending and understanding of the applicability of molecule.(2).Vol. 28, No. 11, 2017   In the course of our studies of chalcone derivatives, we have reported a detailed single crystal analysis for chalcone 2 ((E)-3-(4-ethoxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one), and a structural comparison with the chalcone 1 ((E)-1-(4-methoxyphenyl)-3- (3,4,5-trimethoxyphenyl)  prop-2-en-1-one) analogue.The supramolecular and crystal packing features of both structures have been characterized by Hirshfeld surfaces.In addition, electronic structure calculation was performed in order to explain differences due to solid and gas phases, to confirm site of interactions and to evaluate their chemical stability.

Synthesis and crystallization
It was used 0.3 g (2 mmol) of 4-methoxyacetophenone with 0.39 g (2 mmol) of 3,4,5-trimethoxybenzaldehyde to obtain chalcone 1 and 0.3 g (2 mmol) of 4-methoxyacetophenone with 0.30 g (2 mmol) of 4-ethoxybenzaldehyde benzaldehydes to obtain chalcone 2. The substituted acetophenones was dissolved in 3 mL of methanol under stirring on ice bath.Then, 9 mL of a NaOH solution (50% m/v) was added after the substituted benzaldehydes.The resulting solution was stirred at room temperature for 24 h and then poured into ice water and neutralized with HCl solution 50%.The resulting precipitate was filtered, washed with water and purified by recrystallization.Chalcone 2 crystallized through slow evaporation of solvent, in which ethyl acetate (CH 3 COOCH 2 CH 3 ) was used.The process occurred at 10 th day at a temperature of 25 °C with bottle semi-open.A yellow prismatic single crystal with dimension of 0.34 × 0.32 × 0.26 mm was selected.Chalcone 1 was also obtained by slow evaporation of solvent, however using methanol (CH 3 OH) as solvent.The crystallization occurred at 5 th day at a temperature of about 2 °C, with open bottle.For compound 2, a pale yellow prismatic single crystal measuring 0.59 × 0.515 × 0.445 mm was selected.

Single crystal X-ray analysis
The diffraction data from chalcone 2 were obtained by the diffractometer KappaCCD model with monochromatic radiation Mo Kα at room temperature.Then, the software Saint 22 was used for cell refinement and data reduction.The structure was solved by direct methods and anisotropically refined with full-matrix least-squares on F 2 by the refinement program Shelxl-2014. 23All the hydrogen atoms were placed in calculated positions and refined with fixed individual displacement parameters [U iso (H) = 1.2U eq or 1.5U eq ] according to the riding model (C-H bond lengths of 0.97 and 0.96 Å, for aromatic and methyl groups, respectively).The Ortep maps from asymmetric unit and the molecular representations were obtained through the programs Ortep, 24 Mercury 25 and Crystal Explorer. 26The possible H-bond were checked by the Parst 27 and Platon 28 softwares.The crystallographic information files of compound 2 were deposited in the Cambridge Structural Data Base (CCDC) 29,30 under the code CCDC 1529799.Copies of the data can be obtained, free of charge, via www.ccdc.cam.ac.uk.The compound 1 was previously synthesized and published, under the code CCDC 841293, by our own researcher group 31 and, in order to get a better comparison, those information are also present in Table 1 and Figure 2. Additionally, Table 2 shows the atomic coordinates and equivalent isotropic displacement parameters of compounds 1 and 2.

Hirshfeld surface analysis
Hirshfeld surface was used to visualize and interpret the potential intermolecular interactions of the compounds in study.The Hirshfeld surface can be understood as an attempt to define the occupied space by a molecule in a crystal where the electronic density is partitioned into molecular fragments and a weight function w a (r) is defined for each atom in a molecule as: (1) where ρ i at (r) are spherically averaged electron densities of the various atoms.Thus, the electron density of an atomic fragment can be defined as (2)   where ρ mol (r) indicates the molecular electron density.This graphical tool represents all molecular interactions of a given compound and is important for studying molecular crystal structures because it describes the standards of molecular interactivity and it is possible to estimate the intermolecular contacts that can provide important information of molecular functions.[34]

GC-MS analysis
Gas chromatography coupled with mass spectrometry (GC-MS) was carried out on a Shimadzu QP2010-Plus mass spectrometer, in a non-polar columns (RTX-5 Restek, 30 m × 0.25 mm × 0.25 μm film thickness).The column oven was programmed to start at 80 °C for 5 min and subsequently increased to 250 °C at a rate of 20 °C min -1 with a final hold of 10 min.The chromatogram of 1 (Figure S1) and 2 (Figure S2) are available in the Supplementary Information (SI).

Spectroscopic characterization
Infrared spectroscopy (IR), mass spectroscopy and nuclear magnetic resonance of hydrogen ( 1 H NMR) (Figures S3 and S4, SI) and carbon ( 13 C NMR) (Figures S5 and S6, SI) were carried out.Infrared spectra were recorded on a PerkinElmer Frontier in the range 4000-400 cm -1 using the KBr pellet technique. 1H and 13 C NMR spectra were obtained on a Bruker 500 MHz spectrometer using CDCl 3 and MeOD (Aldrich).Chemical shifts assignments were expressed as ppm using tetramethylsilane (TMS) as internal standard.Spectra visualization was performed through the Program ACD LABS 12.0.

Computational procedures
For the theoretical calculations it was carried out the molecular geometries of chalcones 1 and 2 from the crystallographic information file (CIF) resulting from the data collection from crystalline samples by means of X-ray diffraction.Then this geometry was fully optimized using the density functional theory (DFT) implemented in the Gaussian 09 package, 35 with the Handy and co-workers' 36 long range corrected version of B3LYP using the Coulomb-attenuating method, CAM-B3LYP as functional and, as basis set, we use the 6-311+g(d) of Pople and co-workers. 37The wavefunction generated using CAM-B3LYP/6-311+g(d) was used for molecular electrostatic potential map (MEP) and frontier molecular orbitals calculations. 38,39
Since the aromatic substituents have a significant influence on the structure and packing of chalcones, the crystal structure of compounds 1 and 2 have been investigated.Chalcone 1 is a methoxyl-chalcone with three methoxy groups attached to C3, C4 and C5 atoms from ring B. Meanwhile, chalcone 2 presents a similar structure with only one ethoxyl substituent on the ring B (Figures 1 and 2).The compound 1 has crystallized in a monoclinic and space group P2 1 /c, with Z' = 1, while 2, 31 unlike 1, crystallized in a orthorhombic crystal system 40 and space group Pna2 1 , also with four molecules per unit cell measuring a = 6.32500 (10)  From the values obtained by X-ray analysis, it appears that the substituents do not change the bonding distances considerably, since the sum of the differences between all bonds present in both structures is slightly greater than 0.1 Å.About the angles of connection, the greatest difference is found for the angle O1−C3−C4 (8.45°), moreover, there is also a difference of 2.33° in the angle C1−C6−C7.Both mentioned angles are formed by atoms of ring A. Furthermore, a difference of 1.88° appears for the angle formed by the C10−C15−C14 atoms of ring B, which is the aromatic ring that presents different substituents.Structurally, the difference that attracts the most attention is the difference in the dihedral C19-O1-C3−C4, which causes the methoxy group methyl to be disposed in opposite directions.The experimental and theoretical parameters of chalcones 1 and 2, obtained by X-ray diffractometry and DFT analysis are present in Table 3.
An overlap (ring A was used as fragment) of chalcones 1 and 2 showed the angle δ (δ1 for 1 and δ2 for 2) formed between the aromatic rings of the two molecules (Figure 3).This angle is 36.39°for 1 and 51.18° for 2, occurring in opposite directions in each compound, resulting in a difference of about 90° in relation to plans formed by aromatic A.
When the chalcone 2 is analyzed taking as reference the red plane, it is observed that the molecular planarity deviation arises as expressive form at C8 atom resulting in a value of 36.39° in the aromatic ring.The chalcone 1 on the other hand, although having a deviation of molecular planarity in an opposite direction, also starts the rotation at C8 carbon.Chalcones 1 and 2 also differ by dihedral angles C19−O1−C3−C4 (ω 1 ), C8−C9−C10−C15 (ω 2 ) and C14-C13−O4−C17 (ω 3 ).The values of ω 1 (174.65°for 1 and −5.26° for 2) and ω 3 (−120.16°for 1 and −179.54° for 2) show that the methyl from methoxy groups and  By analyzing the Figure 5a, it is possible to see that for the packaging of the first chalcone the angles formed between the molecules and the c axis are bigger (39.19°) than the existing angles in the second molecule that has a most planar layer on packing (4.07°).This difference on packing corroborates the nonplanarity of compound 1 and hence, the greatest number of intermolecular interactions.It can be explained by the presence of more electronegative group, such as the three methoxy on aromatic ring B.Moreover, the increase on electronegative groups also explains the difference noted     The Influence of Methoxy and Ethoxy Groups on Supramolecular Arrangement of Two Methoxy-chalcones in dihedral angle ω 2 , present near to carbonyl group and olefinic portion.The intermolecular interactions of 1 and 2 were visualized and interpreted using Hirshfeld surface (HS) analysis.Hirshfeld surfaces are a valuable tool for the recognition of intermolecular interactions and were used in this study to promote analysis of the intermolecular interactions present in 1 and 2. First, it involves distances between the nucleus of an internal atom to HS indicating a donor regions of intermolecular contacts (d i ), and the distance between an extern nucleus to HS indicating an acceptor regions of intermolecular contacts (d e ).Then, this surface is denominated d norm due to its normalization as a function of van der Waals radius. 34ntermolecular interactions of compound 1 are represented in Figures 6(1a) and 6(1b), followed by intermolecular interactions of compound 2, in Figures 6(2a 41 The distances d i and d e were combined on a twodimensional graph, representing a fingerprint of these functions.This combination of distances functions provides a mapping of all contacts present in the molecule, making the fingerprints unique for each compound. 42The fingerprints with respective percentage of each contact were established for chalcone 1 and 2 (Figure 8). In

Theoretical calculations
The root of the mean squared deviation (RMSD) values for internuclear distances and bond angles were calculated for both molecules.It is noted that 1 has a higher difference between theoretical and experimental models (RMSD 1 = 0.3569) than 2 (RMSD 2 = 0.3045), as can be seen in Figure 9.
Like the deviation of planarity, this higher value for RMSD 1 is due to stronger intermolecular interactions in 1.The most variance value for chalcone 1 was observed for the C7−C8−C9 angle, while C1−C6−C7 is the most variance angle in chalcone 2. In general, large deviations between these measurements exist because the X-ray results are in the solid phase, while the geometry was optimized for free molecule in vacuum.
MEP is useful for characterizing properties of chemical and biological systems, emphasizing the charge distribution of molecules three-dimensionally. 43 The MEP surface of 2 and 1 are shown in Figure 10.The MEP presents the negative red regions and they are concentrated at the oxygen atoms showing the electrophilic sites of both molecules.
Blue regions show positive charge concentration areas, which are concentrated over the hydrogen atoms and methyl groups explaining the nucleophile sites of both molecules.The green region represents the zero potential regions.Therefore, when examining the Figure 10 it can be confirmed the existence of intra and intermolecular interactions of these molecules in solid state.The dipole moment is another parameter that predicts the polarized nature of the molecule. 44The theoretical calculations show that compound 2 (6.2954D) has more than double of the value of dipole moment of compound 1 (3.0503D), being the most polarized between the title compounds.We can see that the electron density on the O4 atom is different in the compounds, for chalcone 1 the charge in O4 atom is more negative than the same atom in chalcone 2.
The difference in energy of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) orbitals is an important index for the chemical stability of molecules, these energies are directly related to the ability to donate and accept electrons.The energy difference between HOMO and LUMO is an important chemical stability index.A small HOMO-LUMO gap automatically means small excitation energies to the manifold of excited states and a large HOMO-LUMO gap implies high stability with respect to chemical reaction.They are also used to describe chemical softness and hardness. 6,45The distribution and levels of energy for HOMO and LUMO orbitals for chalcones 1 and 2 were calculated at the theory level CAM-B3LYP/6-311+G(d) (Figure 11).For chalcone 1 the HOMO orbital   The Influence of Methoxy and Ethoxy Groups on Supramolecular Arrangement of Two Methoxy-chalcones J. Braz.Chem.Soc.2188 is localized entirely on the ring with the trimethoxy group and in the vinyl group, while the LUMO orbital is spread out throughout the molecule, except for two methoxy groups.
For 2 the HOMO and LUMO orbitals are spread out throughout the molecule, except for methyl groups.The high gap energy for chalcone 2 (6.4007 against 6.2611 eV for chalcone 1) indicates that this compound has a slightly high kinetic stability and low chemical reactivity.The following formulas 46 were used to calculate softness (σ) and hardness (η), respectively: The softness and hardness were calculated for 2 (σ = 0.3124 eV and η = 3.2003 eV) and for 1 (σ = 0.3194 eV and η = 3.1305 eV).Thus we conclude the 1 has a higher capacity to receive electrons while 2 has a higher capacity to resist charge transference (i.e, resistance to change its electronic configuration).

Assignments
The infrared absorption spectra of chalcones 1 and 2 were obtained in KBr, ca.1% solution, on FTIR/IR Affinity-1 Shimadzu spectrophotometer, and the principal absorptions bands (4000 to 400 cm -1 ) are represented in Table 5.
Figure 12 shows the theoretical and the experimental infrared spectra of 1 and 2. As can be seen in Table 5, these values are in line with each other and between the expected experimental values, according to the literature. 47Table 5. Vibrational assignments, experimental and calculated wavenumbers in cm -1 of 1 and 2 at CAM-B3LYP/6-311+g(d)

IR assignments
Unscaled IR frequency a / cm -1 Scaled IR frequency a / cm -1 I / (K mmol -1 ) FTIR / (K mmol -1 ) In order to make a better comparison between theoretical and experimental results, we apply in the theoretical values a scaling factor of 0.958 48 for the results obtained at CAM-B3LYP/6-311+g(d) level of theory.This procedure corrects the systematic overestimation of the vibrational frequencies that is characteristic of the DFT methods and, besides, makes easier the assignments of the vibrational modes.In this study the IR spectra were obtained for 1 and 2 dissolved in KBr and theoretical measurements were made supposing they were in gas phase, which may explain the difference between results.
Experimentally the carbonyl group strongly absorbs in the range from 1850 to 1650 cm -1 .In chalcones we must consider the conjugations effects that increase the single bond character of the C=O and C=C bonds in the resonance hybrid and hence lower their force constants, resulting in a lowering of the frequencies absorptions.Generally, this effect results in a 25 to 45 cm -1 lowering of the carbonyl frequency. 49These calculated frequencies are 1691.06cm -1 for chalcone 2 and 1692.65 cm -1 for chalcone 1, in experimental IR spectra these values are 1612 and 1656 cm -1 , respectively.For chalcones with methoxy group, just like in both molecules, the C=O stretching occurs, in average, around 1663 cm -1 .The stretching modes of vinyl group occur at 1660-1600 cm -1 though C=C stretch appears at lower frequencies, with increased intensity, when conjugated with carbonyl group. 49The calculated wavenumbers for this mode are 1629.22and 1624.62 cm -1 for chalcone 2 and chalcone 1, respectively, and in the IR spectra these modes appear in 1589 and 1607 cm -1 , respectively.The O−C stretching vibration of the O-CH 3 group appears in the wide region of 975 ± 125 cm -1 with an intensity varying from weak to strong. 47,50The O-CH 3 stretching was calculated at 1049-1051 cm -1 for chalcone 2, while experimental bands appears in 974-1019 cm -1 .In the range of 1026.89-1061.70cm -1 for chalcone 1, it can be observed as weak bands in IR at 996-1029 cm -1 .A methoxy group attached to an aromatic ring gives the asymmetric stretching in the range 1310-1210 cm -1 . 50he ab initio calculations give 1338.89and 1304.81cm -1 as methoxy stretching vibrations for chalcone 2, while chalcone 1 presents these vibrations in 1244.34,1259.67 and 1349.01 cm -1 .IR spectra values for this vibrational mode appear in 1360 and 1305 cm -1 for chalcone 2 and 1254, 1269 and 1332 cm -1 for chalcone 1. Electronic effects such as back-donation and induction, mainly caused by the presence of oxygen atom adjacent to methyl group, can shift the position of CH stretching mode.In aromatic methoxy compounds the asymmetric mode are expected in the regions 2985 ± 20 and 2955 ± 20 cm -1 and the symmetric mode in the region 2845 ± 15 cm -1 . 50For chalcone 2 the computed wavenumbers of asymmetric stretching of CH 3 group are 2978.16and 3008.22 cm -1 , while the bands in 2916.33 and 2941.57cm -1 are assigned as symmetric stretching mode.In IR spectra these values are 2967 cm -1 for asymmetric stretching and 2914 and 2948 cm -1 as symmetric stretching mode.For chalcone 1 the computed wavenumbers of asymmetric stretching of CH 3 group are in the range of 2975.00-2985.01cm -1 , while the bands in the range of 2913.64-2919.96cm -1 are assigned as symmetric stretching mode.In the IR spectra, these values are 2944-3000 cm -1 and 2840-2927 cm -1 for asymmetric and symmetric stretching modes, respectively.

Conclusions
Different substitution patterns of aromatic B caused significant variations in the crystal structure of the chalcones studied.Chalcone 1, due to its greater number of methoxy groups, has an increase in its electronegativity and, hence, has more intermolecular interactions than chalcone 2. These interactions can be the planarity deviation cause, observed by overlapping of both structure.In contrast, the crystalline state of chalcone 2 is stabilized by only C−H•••C and C−H•••π interactions, as can be seen by the shape index Hirshfeld surfaces.
T h e t h e o r e t i c a l c a l c u l a t i o n s u s i n g CAM-B3LYP/6-311+g(d) systematically over-estimated the IR vibrational spectra and to avoid this we used a scale factor 48 of 0.958 with the objective of better convergence with the experimental results.The spectroscopic data are consistent with the crystal structure.Moreover, the CAM-B3LYP functional showed to be a good option to obtain the vibrational spectra.The correlation between the experimental and theoretical structural values is very good, the higher variance value in 1 was observed for the C7-C8-C9 angle while in 2 the C1−C6−C7 angle was the higher variance.With respect to the dipole moment, compound 2 has more than the double of the value of compound 1 which makes it the most polarized molecule between the title compounds.Of the analysis of the frontier molecular orbitals we have that the compound 2 has slightly higher kinetic stability and lower chemical reactivity compared to compound 1, furthermore, the softness and chemical hardness energy, the results shown compound 1 has a higher capacity to receive electrons while compound 2 has a higher capacity to resist a charge transference.

( 3 )
is symmetric in d e and d i , with r i vdw and r e vdw being the van der Waals radii of the atoms.In a graphical representation of d norm , close intermolecular distances are characterized by two identically colored regions and this function

Figure 3 .
Figure 3. Overlapping of 1 and 2, showing the angles formed by aromatic A (red) and B (blue) rings.
the fingerprints, the C−H•••π interactions are represented by C•••H contacts, while the π•••π interactions are recognized by C•••C contacts.Due to the substitution pattern, 2 has more C−H•••π interactions than 1.This

Figure 8 .
Figure 8.Quantification of different types of contacts (a) and the fingerprints established for chalcones 1 and 2 (b and c).

Figure 10 .
Figure 10.Electrostatic potential maps for 1 and 2. Red color indicates regions more negative.

Table 1 .
Crystal data and structure refinement for chalcone 1 and chalcone 2

Table 3 .
The experimental (X-ray) and theoretical (DFT) geometric parameters of chalcones 1 and 2

Table 4 .
Main observed intermolecular interactions for chalcones 1 and 2