Synthesis, crystal structure, and DFT study of (E)-N2,N2-dimethyl-6-styryl-1,3,5-triazine-2,4-diamine and (E)-N-(4-(dimethylamino)-6-styryl-1,3,5-triazin-2-yl) acetamide

Abstract (E)-N2,N2-dimethyl-6-styryl-1,3,5-triazine-2,4-diamine and (E)-N-(4-(dimethylamino)-6-styryl-1,3,5-triazin-2-yl) acetamide are important intermediates for the synthesis of triazine compounds. The structure of the target compounds were confirmed using 1H NMR, 13C NMR, HRMS and FT-IR spectroscopy. The precise structure of (E)-N2,N2-dimethyl-6-styryl-1,3,5-triazine-2,4-diamine and (E)-N-(4-(dimethylamino)-6-styryl-1,3,5-triazin-2-yl) acetamide were analyzed using single-crystal X-ray diffraction. The molecular structures were further calculated using density functional theory (DFT), which were compared with the X-ray diffraction value. The results of the conformational analysis indicate that the molecular structures optimized by DFT were consistent with the crystal structures determined by single crystal X-ray diffraction. In addition, the molecular electrostatic potential and frontier molecular orbitals of the title compounds were further investigated by DFT, and some physicochemical properties of the compounds are revealed.


Introduction
Triazine compounds are a very important class of nitrogen heterocyclic compounds.In organic synthesis, it is widely used in many fields such as chemistry, pharmacy and industry [1].Triazine derivatives are found as core structural components in a range of drug classes, such as anticancer, anticonvulsant, analgesic, antidepressant, anti-inflammatory [2][3][4][5][6][7], antitrypanosoma [8], antifungal [9], antianemia [10], muscle relaxants, anti-ulcers, and antioxidants.R. J. Melander found that triazine derivatives are drugs that destroy bacteria or prevent bacterial reproduction, and they are classified according to their target specificity, that is, "narrow spectrum" antimicrobials, which only target certain types of bacteria, such as gram-positive or Gram-negative bacteria, and are essentially called bactericidal, while "broad spectrum" antimicrobials have a wide range of effects, It is called bacteriostasis [11].In addition, A. Gz found that triazine compounds could also be used as heat-resistant explosive materials [12].
Then the title compounds were subjected to the conformational analysis, and the structures from the XRD measurement were compared with the structures optimized by DFT.The results showed that the molecular structures optimized by DFT were consistent with the crystal structures determined by single crystal XRD.In addition, the molecular electrostatic potential and frontier molecular orbitals of the title compound were further investigated using DFT, revealing that the compound had certain reactivity and good chemical stability.

General remarks
High resolution mass spectra were recorded in ESI mode on an Triple TOF5600þ LC-MS instrument (AB SCIEX, USA). 1 H NMR and 13 C NMR spectra were recorded on a Bruker AVANCE III HD 600, 600 MHz spectrometer (Bruker Bioscience, Billerica, MA, USA) using TMS as the internal standard.The IR spectrum of the title compound was recorded on a VERTEX-70V FT-IR spectrometer (Bruker, Germany), in the range of 4000-400 cm À1 using the KBr pellet technique with a 1.0 cm À1 resolution.X-ray diffraction data for A crystal and B crystal were recorded using a Gemini X-ray single crystal diffractometer.For the title compounds: data collection on APEX2; cell refinement with SAINT; the program used to solve the structures SHELXT-2014/7; the program used to refine the structures and draw molecular figures SHELXTL-2014/7; the program used to the measure centroid-centroid distance Mercury 3.3.All the materials were obtained from commercial suppliers and used without further purification.

Synthesis of metformin (1)
61.11 g (0.387 mol) of metformin hydrochloride, 17.03 g (0.426 mol) of sodium hydroxide and a suitable amount of water were added into a 1000 mL round flask, stir to dissolve, room temperature stir for 2 h.After the reaction, solvent was evaporated, 30 mL of ethanol was added, solvent were evaporated to dryness, 20 mL of absolute ethanol was added again, filter with Buchner funnel, and spin the filtrate dry.In order to completely remove the generated salt, recrystallize the free alkali with appropriate amount of toluene, and finally metformin compound one was obtained as white solid (44.31g, 88.62%).

X-ray crystal structure determination
Title compound A was dissolved in petroleum ether/acetone, and add a small amount of 10% diluted hydrochloric acid to the solution.Then the solvent was slowly evaporated in the air at room temperature.A few days later, a single crystal the title compound, suitable for the X-ray crystallographic analysis, was obtained.X-ray diffraction data for the crystal of the title compound was recorded on a Gemini X-ray single crystal diffractometer with graphite-monochromated MoK a radiation (k ¼ 0.71073 Å) at 293 K.The structures were solved by direct methods using OLEX2 [15] and SHELXS-2014/7 [16] and refined by the full-matrix least-squares procedure on F 2 for all data using SHELXL-2014/7.Hydrogen atoms were determined by theoretical calculations.In order to further investigate the structural characteristics of the synthesized compound, title compound A was subjected to the X-ray diffraction crystal structure analysis.The ORTEP diagram of the crystal structure of A is shown in Fig. 1.The crystallographic and refinement data are gathered in Table S1, Supplementary Material.
The results of the single crystal X-ray diffraction analysis of compound A have been deposited with the Cambridge Crystallographic Data Center (DC 2241326), and can be freely obtained by request via the Web-site: www.ccdc.cam.ac.uk/data_request/cif.
Title compound B was dissolved in petroleum ether/acetone.Then the solvent was slowly evaporated in the air at room temperature.A few days later, a single crystal the title compound, suitable for the X-ray crystallographic analysis, was obtained.X-ray diffraction data for the crystal of the title compound was recorded on a Gemini X-ray single crystal diffractometer with graphite-monochromated MoK a radiation (k ¼ 0.71073 Å) at 293 K.The structures were solved by direct methods using OLEX2 [15] and SHELXS-2014/7 [16] and refined by the full-matrix least-squares procedure on F 2 for all data using SHELXL-2014/7.Hydrogen atoms were determined by theoretical calculations.In order to further investigate the structural characteristics of the synthesized compound, title compound B was subjected to the X-ray diffraction crystal structure analysis.The ORTEP diagram of the crystal structure of B is shown in Fig. 2. The crystallographic and refinement data are gathered in Table S1, Supplementary Material.
The results of the single crystal X-ray diffraction analysis of compound B have been deposited with the Cambridge Crystallographic Data Center (DC 2246213), and can be freely obtained by request via the Web-site: www.ccdc.cam.ac.uk/data_request/cif.

Quantum chemistry/DFT calculation
In this study, all theoretical calculations of the title compounds were performed with the Gaussian 09 software package in the ground state (vacuum), exerting the B3LYP

Synthesis and characterization
Title compounds A and B were obtained by three steps substitution reaction and their structures were confirmed by FTIR, 1 H and 13 C NMR spectroscopy, and MS (Figs.S1-S8 of Supplementary Materials).

Crystallographic analysis
As shown in Tables S2 and S3 (Supplementary Materials), all bond lengths, bond and torsion angles obtained by the crystallographic analysis of the title compounds match well with the calculation results with the DFT-optimized structure, and they are all within the normal range.

Conformational determination
The conformation of a molecule seriously influences its physical and chemical properties.Therefore, a reliable conformational analysis plays a key role in the understanding of the structure.The initial conformational search for title compound A and B were performed by the Spartan 08 program [20] with molecular mechanics force field (MMFF) [21,22].Then, geometry optimizations and frequency calculation of all the possible conformers were performed by DFT/B3LYP/6-311G ÃÃ in the Gaussian 09 package.Based on the relative free energies, the percentage of each conformer in the equilibrium mixture at room temperature can be predicted.The Gibbs free energy (G), the relative Gibbs free energy (DG ¼ exp(-G i/RT), the gas constant R ¼ 8.314 J/molÁK), and the Boltzmann distribution (Boltzmann weight factor Pi ¼ expðÀGi=RTÞ P j exp ðÀGi=RTÞ 100% for different conformers of compounds A and B are given in Table 3. The conformers of compounds A and B are shown in Fig. 5. Compound A was detected to have two relatively stable conformers: A1 (27.39%) and A2 (72.61%).Compound B was detected to have four relatively stable conformers: B1 (35.46%),B2 (30.17%),B3 (19.91%),B4 (14.46%).The difference between conformation A1 and A2 is due to the difference in torsion angles of C6-C16-C20-C18 and the potential energy surface of the molecule was scanned.The difference between conformation B1$B4 is due to the difference in torsion angles of C7-C8-C9-C10 and C1-C2-C1-C3 and the potential energy surface of the molecule was scanned.
The main crystallographic data are summarized in Table S1, Supplementary Materials.Some geometric parameters of the experimental values of the crystal and the calculated values of their conformation are listed in Tables S2 and S3, Supplementary Materials.The results show that the calculated geometric parameters of conformer A1 and B3 are basically close to the X-ray diffraction data.

Molecular electrostatic potential (MEP)
To gain information on the region where the conformer (the major conformer) undergoes intermolecular interactions, MEP was calculated by the B3LYP/6311G(2d, p) method.In the MEP map, different electrostatic potentials on the surface are     denotes the electron rich area and the blue region indicates the electron deficient region.The neutral potential regions are indicated by white and yellow, and most parts of the molecule are neutral with a white-yellow gradient.As shown in Fig. 6, O1 ion in the conformer B3 are surrounded by negative charges, indicating some possible sites for the nucleophilic attack.In addition, the positive charge regions are located on the H atom attached to N3 atom.

Frontier molecular orbitals (FMOs)
To study the chemical stability of the conformational isomers of the two title compounds, the HOMO and LUMO energies along with their orbital energy gap were calculated by the B3LYP/6-311G(2d,p) method.The pictorial illustration of FMOs and their respective positive and negative regions represented by red and green colors are shown in Fig. 7.The LUMO and HOMO values of A1 were À2.6186 eV and À6.4420 eV, respectively, B3 were À2.0327 eV and À6.3381 eV.The energy separation between the HOMO and the LUMO was À3.8234 eV for conformers A1, for conformers B3 was 4.3054 eV.The large HOMO-LUMO gap automatically implied high excitation energies of the excited states and good stability.Furthermore, the ionization energy and the electron affinity can be expressed as: I ¼ -E HOMO ¼ 6.4420 eV, A ¼ -E LUMO ¼ 2.6186 eV for conformers A1, I ¼ -E HOMO ¼ 6.3381 eV, A ¼ -E LUMO ¼ 2.0327 eV for conformers B3.The hardness, which can be denoted as g ¼ (I -A)/2, indicates the resistance toward the deformation of the electron cloud of chemical systems under small perturbation encountered during the chemical process [23][24][25].The hardness of compound A is 1.9117 eV, The hardness of compound B is 2.1527 eV.The chemical potential m ¼ -(I -A)/2.m ¼ -1.8093 eV of conformation A1, and m ¼ -1.51635 eV of conformation B3 are all negative, indicating that the two crystals are stable and do not spontaneously decompose into elements.

Scheme 1 .
Scheme 1. Synthesis route of the title compound A and B.

Figure 1 .
Figure 1.Experimental and DFT-optimized crystal structures of A.

Figure 2 .
Figure 2. Experimental and DFT-optimized crystal structures of B.

Figure 3 .
Figure 3. Crystal structure stacking (a) and hydrogen bonding interactions (b) diagrams of A.

Figure 4 .
Figure 4. Crystal structure stacking (a) and hydrogen bonding interactions (b) diagrams of B.
MOLECULAR CRYSTALS AND LIQUID CRYSTALSrepresented by different colors, and the potential increases in the order of red < orange ( yellow < green < blue (see the electronic version).The color code of the maps in the range of À6.796 e À2 (deepest red) to 6.796 e À2 (deepest blue) on the surface of the title molecule compound A, where the red color denotes the electron rich area and the blue region indicates the electron deficient region.The neutral potential regions are indicated by white and yellow, and most parts of the molecule are neutral with a white-yellow gradient.As shown in Fig.6, O22B atom and Cl2 ion in the conformer A1 are surrounded by negative charges, indicating some possible sites for the nucleophilic attack.In addition, the positive charge regions are located on the H atom attached to N20 atom.The color code of the maps in the range of À5.458 e À2 (deepest red) to 5.458 e À2 (deepest blue) on the surface of the title molecule compound B, where the red color

Table 1 .
Hydrogen bond geometry of A.

Table 2 .
Hydrogen bond geometry of B.

Table 3 .
Gibbs free energy (G), relative Gibbs free energy (DG), a and Boltzmann weighting factor (Pi,%) b of the conformers of compounds A and B.
a Related to the most stable conformer.b Boltzmann weighting factor (Pi,%) based on DG.