Molecular Structure , Spectroscopic and DFT Computational Studies of Arylidene-1 , 3-dimethylpyrimidine-2 , 4 , 6 ( 1 H , 3 H , 5 H )-trione

Assem Barakat 1,3,*, Saied M. Soliman 2,3,*, Hazem A. Ghabbour 4,5, M. Ali 1, Abdullah Mohammed Al-Majid 1, Mohammad Shahidul Islam 1 and Ayman A. Ghfar 1 1 Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia; maly.c@ksu.edu.sa (M.A.); amajid@ksu.edu.sa (A.M.A.-M.); shahid.10amui@gmail.com (M.S.I.); aymanghfar@gmail.com (A.A.G.) 2 Department of Chemistry, Rabigh College of Science and Art, P.O. Box 344, Rabigh 21911, Saudi Arabia 3 Department of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, Alexandria 21321, Egypt 4 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; ghabbourh@yahoo.com 5 Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt * Correspondences: ambarakat@ksu.edu.sa (A.B.); saied1soliman@yahoo.com (S.M.S.); Tel.: +966-11467-5884 (A.B.); +966-56545-0752 (S.M.S.); Fax: +966-11467-5992 (A.B.)


Introduction
The barbituric acid scaffold and particularly the substituted derivatives at the C5-position are found as a core structure in many potential pharmaceutical drugs.Several examples of the arylidene derivatives of barbituric acid possessing significant implementation in the pharmaceutical field such as antitumor [1], immunomodulating, matrix metalloproteinase (MMP) inhibitor [2], antioxidant [3], antibacterial agent [4], anticonvulsant potentials [5], and mutant SOD1-dependent protein aggregation [6] were investigated.Additionally, these compounds were shown to haveseveral targets in dye manufacturing [7], supramolecular chemistry [8], and in nonlinear optical study [9].
In green chemistry, water is the ideal solvent: it is non-toxic, benign, sustainable, non-flammable, has a high specific heat capacity to absorb energy from reactions, has a very low odor, and is available at a low cost [10].Due to these advantages, a wide variety of chemical reactions can be performed in water.One of these reactions is the Aldol condensation that proceeds smoothly in water.

Chemistry
The arylidene-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione derivatives 1 and 2 were synthesized as shown in Scheme 1. Barbituric acid derivatives, and 3-hydroxy-4-methoxybenzaldehyde (for the synthesis of 1) or 4-hydroxy-3-methoxybenzaldehyde (for the synthesis of 2) are commercially available.The reaction proceeds smoothly with the mixingof equimolar amounts of the substituted aldehyde and barbituric acid derivative in water at room temperature providing the arylidene compounds in excellent yield.The molecular structures of the later products were investigated by using different spectroscopic techniques such as 1 H, 13 C-NMR, IR, GCMS, and the X-ray single crystal technique.

X-Ray Crystal Structure of 1 and 2
A crystalline material was grown in a mixture of DCM/EtOH/Et2O at room temperature (r.t.) for 24h.The molecular structure was solved by SHELXS-97 [18,19] software.Crystal data and Ortep (Oak Ridge Thermal-Ellipsoid Plot Program)diagrams of the compounds are shown in Table 1 and Figures 1 and 2, respectively.Selected geometric parameters of compounds 1 and 2 are listed in Tables 2-5.

X-Ray Crystal Structure of 1 and 2
A crystalline material was grown in a mixture of DCM/EtOH/Et 2 O at room temperature (r.t.) for 24h.The molecular structure was solved by SHELXS-97 [18,19] software.Crystal data and Ortep (Oak Ridge Thermal-Ellipsoid Plot Program)diagrams of the compounds are shown in Table 1 and Figures 1  and 2, respectively.Selected geometric parameters of compounds 1 and 2 are listed in Tables 2-5.

Chemistry
The arylidene-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione derivatives 1 and 2 were synthesized as shown in Scheme 1. Barbituric acid derivatives, and 3-hydroxy-4-methoxybenzaldehyde (for the synthesis of 1) or 4-hydroxy-3-methoxybenzaldehyde (for the synthesis of 2) are commercially available.The reaction proceeds smoothly with the mixingof equimolar amounts of the substituted aldehyde and barbituric acid derivative in water at room temperature providing the arylidene compounds in excellent yield.The molecular structures of the later products were investigated by using different spectroscopic techniques such as 1 H, 13 C-NMR, IR, GCMS, and the X-ray single crystal technique.

X-Ray Crystal Structure of 1 and 2
A crystalline material was grown in a mixture of DCM/EtOH/Et2O at room temperature (r.t.) for 24h.The molecular structure was solved by SHELXS-97 [18,19] software.Crystal data and Ortep (Oak Ridge Thermal-Ellipsoid Plot Program)diagrams of the compounds are shown in Table 1 and Figures 1 and 2, respectively.Selected geometric parameters of compounds 1 and 2 are listed in Tables 2-5.
Both 1 and 2 crystallized in space group P-1 and the lattice constants are roughly the same in each case.However, there are both similarities and significant differences in the packing modes between the two closely related molecules.The crystal structure of 1 projected along the c axisis shown in Figure 2.  5).

Optimized Structure of 1 and 2
The optimized structures of the two isomers 1 and 2 are given in Figure 3. Overlay between the optimized and experimental structures are also shown in the same Figure .Tables S1 and S2 (Supplementary Materials) showed the complete list of bond distances and bond angles obtained from the Density functional theory (DFT) calculations and compared with the X-ray results.The results indicated good agreement between the calculated and experimental structures.The correlation coefficients between the calculated and experimental geometrical parameters are 0.988-0.993and 0.985-0.987for bond distances and angles, respectively.The maximum bond distance deviations are 0.027 Å (1.95%) and 0.024 Å (1.76%) for compounds 1 and 2, respectively.Similarly, the bond angles are predicted very well, the maximum percentage errors are 1.86% (2.194 • ) for 1 and 1.97% (2.312 • ) for 2. The small differences between the calculated and experimental geometries are mainly attributed to the known fact that the experimental solid state structure includes intermolecular forces that significantly affect the geometric parameters while the calculated one is a single molecule in the gas phase.It is worth noting that1is characterized by an intramolecular O-H-O(CH 3 ) interaction between the OH group and the neighboring oxygen of the methoxy group where the H-O distance is calculated to be 2.097 Å while the donor-acceptor (O-O) distance is predicted to be 2.650 Å (exp.2.690Å).Such H-O interaction was not observed in 2.

Energy Analysis of the Two Isomers
The total energies (Etot), zero point energy correction (ZPVE) and the corrected total energy (Ecorr) of the two isomers are given in Table 6.According to these results, isomer 1 is more stable than isomer 2 by 2.56194 Kcal/mol.Also, the thermodynamic parameters such as enthalpy and Gibbs free energy are given in the same table.Based on the Gibbs free energy difference between the two isomers, 1 is thermodynamically more stable than 2. The extrastability of compound 1 could be attributed to the presence of the intramolecular H-O interaction.

Frontier Orbital Energy Analysis
The frontier molecular orbitals, HOMO and LUMO are related to the bioactivity of molecules as they give information about theirability to gain or lose electrons.Thus, study on frontier orbital energy can provide useful information about the biological mechanism.The energies of the HOMO and LUMO levels as well as the HOMO-LUMO were obtained from the DFT/B3LYP calculations and the results are listed in Table 7. Compound 1 has lower energy HOMO level than 2. In contrast, compound 2 has a more stable LUMO level of the lower energy level than that for 1. Hence 2 is a better electron donor and also a slightly better electron acceptor than1.The energy gaps between HOMO and LUMO are 3.57751 and 3.51955 eV for 1and 2, respectively.As a result, 1 has a higher energy gap and is

Energy Analysis of the Two Isomers
The total energies (E tot ), zero point energy correction (ZPVE) and the corrected total energy (E corr ) of the two isomers are given in Table 6.According to these results, isomer 1 is more stable than isomer 2 by 2.56194 Kcal/mol.Also, the thermodynamic parameters such as enthalpy and Gibbs free energy are given in the same table.Based on the Gibbs free energy difference between the two isomers, 1 is thermodynamically more stable than 2. The extrastability of compound 1 could be attributed to the presence of the intramolecular H-O interaction.

Frontier Orbital Energy Analysis
The frontier molecular orbitals, HOMO and LUMO are related to the bioactivity of molecules as they give information about theirability to gain or lose electrons.Thus, study on frontier orbital energy can provide useful information about the biological mechanism.The energies of the HOMO and LUMO levels as well as the HOMO-LUMO were obtained from the DFT/B3LYP calculations and the results are listed in Table 7. Compound 1 has lower energy HOMO level than 2. In contrast, compound 2 has a more stable LUMO level of the lower energy level than that for 1. Hence 2 is a better electron donor and also a slightly better electron acceptor than 1.The energy gaps between HOMO and LUMO are 3.57751 and 3.51955 eV for 1 and 2, respectively.As a result, 1 has a higher energy gap and is predicted to be more stable towards the electron transport process than 2. Figure 4 shows the HOMO and LUMO levels of both isomers.The HOMO and LUMO levels are mainly distributed over the π-system of the studied compounds and hence the HOMO-LUMO electron transfer is considered mainly as a π-π* transition.predicted to be more stable towards the electron transport process than 2. Figure 4 shows the HOMO and LUMO levels of both isomers.The HOMO and LUMO levels are mainly distributed over the π-system of the studied compounds and hence the HOMO-LUMO electron transfer is considered mainly as a π-π* transition.

Natural Atomic Charges (QN) and Electrostatic Potential (ESP)
Figure 5 exhibits the calculated natural atomic charges (QN) for all atomic sites.The O and N-atoms have the highest electronegativity and so are expected to have the highest natural charge values.Hence these sites are the most favored to interact with the positively charged receptor active site.In contrast, the OH proton is the most electropositive and is the most favored site to be attached by the negative part of the receptor active sites.The aliphatic carbon atoms are predicted to be more electronegative than the aromatic ones.The ring C-atoms attached to either O or N atoms showed high electropositive character.The most electropositive carbon is the one lying between two N atoms and one O atom.The formation of H-bonding interaction usually affects the charges at the hydrogen, donor and acceptor atoms.It is of note that the charge at the OH proton of 1 is higher than that in 2. In contrast, its oxygen atom (H-donor) is more electronegative in the former compared to the latter.The acceptor O-atom (OCH3) in 1 has more negative charge in 1 than 2.The electrostatic potential (ESP) map shown in Figure 6 indicates that the most reactive electrophilic (blue) and nucleophilic (red) sites are the OH proton and O-atoms in both compounds.Figure 5 exhibits the calculated natural atomic charges (Q N ) for all atomic sites.The O and N-atoms have the highest electronegativity and so are expected to have the highest natural charge values.Hence these sites are the most favored to interact with the positively charged receptor active site.In contrast, the OH proton is the most electropositive and is the most favored site to be attached by the negative part of the receptor active sites.The aliphatic carbon atoms are predicted to be more electronegative than the aromatic ones.The ring C-atoms attached to either O or N atoms showed high electropositive character.The most electropositive carbon is the one lying between two N atoms and one O atom.The formation of H-bonding interaction usually affects the charges at the hydrogen, donor and acceptor atoms.It is of note that the charge at the OH proton of 1 is higher than that in 2. In contrast, its oxygen atom (H-donor) is more electronegative in the former compared to the latter.The acceptor O-atom (OCH 3 ) in 1 has more negative charge in 1 than 2.The electrostatic potential (ESP) map shown in Figure 6 indicates that the most reactive electrophilic (blue) and nucleophilic (red) sites are the OH proton and O-atoms in both compounds.

General Remarks
X-ray crystal structure analysis was collected on a Bruker APEX-II D8 Venture area diffractometer (Bruker, Billerica, MA, USA).The NMR spectra were run in deuterated chloroform (DMSO-d6) using a Jeol-400 NMR spectrometer (Tokyo, Japan).

General Remarks
X-ray crystal structure analysis was collected on a Bruker APEX-II D8 Venture area diffractometer (Bruker, Billerica, MA, USA).The NMR spectra were run in deuterated chloroform (DMSO-d6) using a Jeol-400 NMR spectrometer (Tokyo, Japan).

General Remarks
X-ray crystal structure analysis was collected on a Bruker APEX-II D8 Venture area diffractometer (Bruker, Billerica, MA, USA).The NMR spectra were run in deuterated chloroform (DMSO-d 6 ) using a Jeol-400 NMR spectrometer (Tokyo, Japan).

Procedure for the Synthesis of 1 and 2
A mixture was made of (1 mmol) barbituric acid and (1mmol)3-hydroxy-4-methoxybenzaldehyde (for the synthesis of 1) or 4-hydroxy-3-methoxybenzaldehyde (for the synthesis of 2) in 3 mL of H 2 O, and thereaction mixture stirred for 1h.Thereaction was monitored by thin layer chromatography (TLC).After the reaction was complete, the precipitated product was collected by filtration, washed with 2 mL of water, and dried to give the desired compounds 1 and 2. Further crystallization by slow diffusion of a solution in DCM/EtOH in Et 2 O was carried out to provide a single crystal suitable for X-ray diffraction analysis.

Theoretical Calculations
The DFT-B3LYP method and the 6-31 G(d, p) basis set in the Gaussian 03 package [20] were used to optimize the structures obtained from the X-ray single crystal structure analysis.Frequency calculations of the optimized structures revealed that the optimized structures are the energy minimum on the potential energy surfaces as no negative frequencies were obtained.

Conclusions
This section is not mandatory, but can be added to the manuscript if the discussion is unusually long or complex.

Supplementary Materials:
The following are available online at http://www.mdpi.com/2073-4352/6/9/110/s1. Table S1.The calculated bond distances and bond angles compared to the experimental data of 1; Table S2.The calculated bond distances and bond angles compared to the experimental data of 2.

Figure 1 .
Figure 1.ORTEP (Oak Ridge Thermal-Ellipsoid Plot Program) of the synthesized compound 1 (left) and 2 (right).Displacement ellipsoids are plotted at the 40% probability level for non-H atoms.

1 2 Figure 2 .
Figure 2. View of the molecular packing in compounds 1 and 2 The O-H … O and C-H … O hydrogen bonds are shown as dashed lines.

Figure 2 .
Figure 2. View of the molecular packing in compounds 1 and 2 The O-H . . .O and C-H . . .O hydrogen bonds are shown as dashed lines.

1 .
The molecules are connected by two classical O-H•••O and two non-classical C-H•••O hydrogen bonds (Table 3) forming flat sheets.Comparison of the crystal structures reveals that 2 is more loosely packed than The effective volume of the molecule in 2 estimated by V/Z is larger by ca 1% than that for 1. Molecules in compound 2 are packed with one O-H•••O and three C-H•••O hydrogen bonds along the b, c axes (Table

1 2Figure 3 .
Figure 3.The optimized structures (left) and comparative overlay of the calculated and experimental structure (right).Bond distance values are given in Å.

Figure 3 .
Figure 3.The optimized structures (left) and comparative overlay of the calculated and experimental structure (right).Bond distance values are given in Å.

Figure 4 .
Figure 4.The frontier molecular orbitals of the studied isomers.

Figure 4 .
Figure 4.The frontier molecular orbitals of the studied isomers.

1 2Figure 5 . 2 Figure 6 .
Figure 5.The natural charges at the different atomic sites of compounds 1 and 2.

Figure 5 .Figure 5 . 2 Figure 6 .
Figure 5.The natural charges at the different atomic sites of compounds 1 and 2.

Table 1 .
The crystal and experimental data of 1 and 2.

Table 1 .
The crystal and experimental data of 1 and 2.

Table 6 .
The total energy (E tot ), zero point energy correction (ZPVE), corrected total energy (E corr ) and energy difference (∆E) between the two isomers 1 and 2.

Table 7 .
The frontier orbital energy (eV) of the studied isomers.

Table 7 .
The frontier orbital energy (eV) of the studied isomers.