Synthesis, Spectrometric Characterization, X-Ray Crystallography and Quantum Chemical Calculations of 2-oxo-2H-chromen-7-yl Propionate

The title compound, (I), has been solved by direct methods and refined to a final R value of 0.038 for 1835 independent reflections. In the structure, the planar [r.m.s deviation = 0.014 Å] chromen-2-one ring and the 7-propionate side chain are inclined to one another at an acute angle of 65.34(9)°. The molecules form R4 (30) tetrameric units via C—H···O interactions which extend into layers approximately parallel to the ab plane. Furthermore, the crystal structure is supported by π–π stacking interactions between neighbouring benzene and pyrone or coumarin rings [centroid–centroid distances in the range 3.6097(8)–3.6475(9)Å], as well as C–H···π interactions [H···centroid distances in the range 2.95–3.00Å]. The molecular geometry of (I) was also optimized using density functional theory (DFT/RB3LYP), RMP2 and RHF methods with the 6311G(d, p) basis set in ground state. The theoretical data resulting from these quantum chemical calculations are in good agreement with the observed structure, although the observed C—O—C—C torsion angle between the coumarin ring system and the 7-propionate side chain (121.49 (16)°) is somewhat lower than the DFT/RB3LYP calculated value (132.32°) and larger than the RMP2 (114.65°) and the RHF (69.19°) values. Hirshfeld surface analysis has been used to confirm and quantify the supramolecular interactions.


Introduction
Coumarins and their derivatives constitute one of the major classes of naturally occurring compounds and interest in their chemistry continues unabated because of their usefulness as biologically active agents. They also form the core of several molecules of pharmaceutical importance. Coumarin and its derivatives have been reported to serve as anti-bacterial [1], anti-oxidant [2] and anti-inflammatory agents [3].

Synthesis
To a solution of propionic anhydride (6.17 mmol; 0.85ml) in dried diethyl ether (25 ml), was added dried pyridine (4.7 molar equivalents; 2.35 ml) and 7-hydroxycoumarin (6.17 mmol; 1g) in small portions over 30 min. The mixture was then left under agitation at room temperature for 3 hours and poured into 40 ml of chloroform. The solution was acidified with diluted hydrochloric acid until the pH was 2-3. The organic layer was extracted, washed with water to neutrality, dried over MgSO 4 and the solvent removed. The crude product was washed with petroleum ether and recrystallized from acetone. White crystals of the title compound were obtained (yield 89.5%); M.p: 366-368 K.

Electrospray Ionisation Mass Spectrum
Mass spectrometry is a highly valuable technique in the field of structural biochemistry. Electrospray ionization mass spectrometry (ESI-MS), with an accuracy of about 0.01%, provides an extremely sensitive method for determining the precise molecular mass of small and biological molecules. The spectrum of figure 1 was recorded on a 3200 QTRAP (Applied Biosystems SCIEX) spectrometer equipped with a pneumatically assisted air pressure ionization (API) source for ESI-MS + experiment. 1 H and 13 C NMR spectra figures 2 and 3 were recorded on a Bruker TopSpin spectrometer at 400 and 100 MHz, respectively, using CDCl 3 as internal standard (chemical shifts in δ values, J in Hz).

Crystal Structure Analysis
Diffraction data for the title compound was collected on Rigaku Oxford Diffraction SuperNova, Dual, Cu at zero, AtlasS2 diffractometer [6] using a mirror monochromator and Cu Kα radiation (λ = 1.54184 Å) at 298 K. The structure was solved by direct methods using SIR2014 [7] and implemented in the WinGX [8] program suite. The refinement was carried out by full-matrix least squares method on the positional and anisotropic temperature parameters of the non-hydrogen atoms, or equivalently corresponding to 146 crystallographic parameters, using SHELXL2014 program [9]. All H atoms were placed in calculated positions [C-H = 0.93 (aromatic), 0.96 (methyl) or 0.97 Å (methylene group)] and refined using a riding model approximation with Uiso(H) constrained to 1.2 (aromatic and methylene group) or 1.5 (methyl group) times Ueq of the respective parent atom. Data collection is by CrysAlis PRO [6], cell refinement by CrysAlis PRO [6], and data reduction by CrysAlis PRO [6]. The general-purpose crystallographic tool PLATON [10] was used for the structure analysis and presentation of the results. Details of the data collection conditions and the parameters of the refinement process are given in Table 1. CCDC-1845532 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif; e-mail: deposit@ccdc.cam.ac.uk.

Hirshfeld Surface
Molecular Hirshfeld surfaces of 2-oxo-2H-chromen-7-yl propionate were calculated using a standard (high) surface resolution, and with the three-dimensional d norm surfaces mapped over a fixed colour scale of -0.205 (red) to 1.418 a.u. (blue) with the program CrystalExplorer 3.1 [11].

Computational Procedures
The geometry optimization of compound (I) was performed by using the density functional theory (DFT) with restricted B3LYP exchange correlation functional, restricted Moller-Plesset perturbation theory (RMP2) and restricted Hartree-Fock (RHF) methods with a 6-311 ++ G(d,p) basis set. The crystal structure in the solid state was used as the starting structure for the calculations. All calculations are performed with the GAUSSIAN09 program package [12].

Interpretation of Electrospray Ionisation Mass
Spectrum In the spectrum Figure 1,

1 H Spectrum Analysis
The experimental values (chemical shifts and couplings) taken from the 1 H NMR spectrum Figure 2

13 C Spectrum Analysis
The 13 C NMR spectrum Figure 3 exhibits, as expected, twelve peaks.
Chemical shift (ppm) and the corresponding carbon:

Conclusion
The combination of the above results originating from the spectra analysis confirm the molecule drawn in Figure 4. Other studies such as X-ray and theoretical calculations have been used to confirm this conclusion.

Structural Description
The molecular structure of the title coumarin derivative, (I), is illustrated in Figure 4.

Geometry and Conformation
The positional parameters, interatomic distances, bond angles and torsion angles are presented in Tables 4, 5, 6 and 7. The analysis and interpretation of the geometrical characteristics relating to bond distances compared to standard values [13] indicate that carbon-oxygen bonds:  (3) Å] bond lengths are shorter and longer, respectively, than those expected for a Car-Car bond. This suggests that the electron density is preferentially located in the C2-C3 bond of the pyrone ring, as seen in other coumarin derivatives [16][17].

Hirshfeld Surface Analysis
The analysis of intermolecular interactions through the mapping of three-dimensional d norm involves the contact distances d i and d e from the Hirshfeld surface to the nearest atom inside and outside, respectively. In the studied coumarin, the surface mapped over d norm highlights two brite red and three faint-red spots, reflecting distances shorter than the sum of the van der Waals radii. These dominant interactions correspond to intermolecular C-H…O hydrogen bonds, H…C, C-H…π and π-π stacking interactions between the surface and the neighbouring environment. The mapping also shows white spots, with distances equal to the sum of the van der Waals radii, and blue regions with distances longer than the sum of the van der Waals radii.
Transparent surfaces are displayed in order to visualize the molecule Figure 7a. In the shape-index map (-1.00 to 1.00 a.u., Figure 7b), the adjacent red and blue triangle-like patches show concave regions that indicate π-π stacking interactions [20]. Furthermore, the two-dimensional fingerprint plots (FP) are decomposed to highlight particular close contacts of atom pairs, and the contributions from different contacts are provided in Figure 8. The blue spots in the middle of the surface appearing near d e = d i ≃ 1.8-2.0 Å correspond to close C…C interplanar contacts. These contacts, which comprise 4.8% of the total Hirshfeld surface area, are related to π-π interactions Figure 8a as predicted by the X-ray study. The most significant contribution to the Hirshfeld surface (38.1%) is from H…O/O…H contacts, which appear on the left side as blue spikes with the tip at d e + d i ≃ 2.6 Å, top and bottom Figure 8b

Quantum Chemical Computational Studies
The resulting geometrical parameters are compared with those obtained from the X-ray crystallographic study. An analysis of the computational bond lengths and bond angles and comparison with the crystallographic results shows a good agreement between them, with a root-mean-square deviation of 0.021 Å (DFT/RB3LYP), 0.022 Å (RMP2) and 0.022 Å (RHF) for bond lengths and 1.21° (DFT/RB3LYP), 1.20° (RMP2) and 1.13° (RHF) for bond angles Tables 5 and 6. In addition, an inspection of the calculated torsion angles shows that the coumarin ring system is planar, which is in good agreement with the crystallographic prevision, although the observed C10-O3-C7-C8 torsion angle between this ring system and the 7-propionate side chain (121.49 (16) Table 7.

Molecular Electrostatic Potential (MEP)
The molecular electrostatic potential surface and contour map may lead to better understanding sites for electrophilic attack and nucleophilic reactions as well as hydrogenbonding interactions [21][22][23] of the compound under study. The molecular electrostatic potential, ( ), may be either positive or negative in any given region, depending upon whether the effect of the nuclei or the electrons is dominant there.
For convenience, V(r) is typically written in terms of atomic units, a.u; it then has the following form [24]: where is the charge of nucleus A located at , ( ') is the electronic density function of the molecule, and ' is the dummy integration variable. Being a real physical property, V( ) can be determined experimentally by diffraction or by computational methods [25]. To predict reactive sites for electrophilic and nucleophilic attack for the title molecule, MEP was computed at the DFT/RB3LYP, RMP2 and RHF optimized geometries using the 6-311 ++ G(d,p) basis set. The negative (red) regions of MEP were related to electrophilic reactivity and the positive (blue) regions to nucleophilic reactivity shown in Figure 9. As can be seen from the figure, there are two possible sites on compound (I) for electrophilic attack. These negative regions are localised on the oxygen atoms O2 and O4 with a maximum value of -0.095, -0.078 and -0.079 a.u. for DFT/RB3LYP/6-311 ++ G(d,p), RMP2/6-311 ++ G(d,p) and RHF/6-311 ++ G(d,p) basis sets, respectively. These results provide information concerning the region where the studied compound can interact intermolecularly. Therefore, Figure 9 confirms the existence of the intermolecular C12-H12B…O2 interaction.

HOMO-LUMO Analysis
The distributions and energy levels of the highest occupied molecular orbital (HOMO) and the lowest lying unoccupied molecular orbital (LUMO) calculated at the DFT/RB3LYP/6-311 ++ G(d,p), RMP2/6-311 ++ G(d,p) and RHF/6-311 ++ G(d,p) level for the title compound are shown in Figure 10. The calculations indicate that the title compound has 57 occupied molecular orbitals and the value of the energy separation between the LUMO and HOMO are 0.12137, 0.35689 and 0.36066 a.u for at the same levels, respectively. These frontier orbital gaps in the range 0.12137-0.3606 a.u show that 2-oxo-2H-chromen-7-yl propionate is polarizable and is associated with a high chemical reactivity and low kinetic stability and is also termed as soft molecule [26]. The HOMO and LUMO energies, the energy gap (∆ ), the ionization potential ( ), the electron affinity ( ), the absolute electronegativity (! ), the absolute hardness (" ), and softness (# ) for compound (I) have been computed at the same levels and the results are given in Table 9. By using HOMO and LUMO energy values for a molecule, electronegativity and chemical hardness can be calculated as follows [27]: = -HOMO (5) = -LUMO (6)

The Mulliken Charge Population
The Mulliken atomic charge calculation has an important role in the application of quantum chemical calculation to molecular system because atomic charges effect dipole moment, molecular polarizability, electronic structure, and a lot of properties of molecular systems. The charge distributions calculated by the Mulliken method [28][29][30][31] for the equilibrium geometry of the title compound is given in Table 8. The computed Mulliken charges of C12 and H12B atoms are determined as -0.595 and 0.166 e, -0.651 and 0.165 e, -0.652 and 0.164 e for the DFT/RB3LYP/6-311 ++ G(d,p), RMP2/6-311 ++ G(d,p) and RHF/6-311 ++ G(d,p) methods, respectively. These values confirm intermolecular hydrogen bond C12-H12B…O2[x+1, y, z]. However, the C8-H8…O4[x, y+1, z] obseved in the solid state is not discernable in the gas phase. Also, the calculated Mulliken charges of C3 and H3, C6 and H6 atoms Table 8 may suggest other intermolecular contacts in the gaseous state.

Conclusions
In this present investigation, molecular structure was analyzed by X-ray cristallography and the intermolecular interactions by Hirshfeld surface analysis. Also, molecular electrostatic potential, HOMO-LUMO analysis and the Mulliken charge populations of 2-oxo-2H-chromen-7-yl propionate have been studied using DFT/RB3LYP/6-311 ++ G(d,p), RMP2/6-311 ++ G(d,p) and RHF/6-311 ++ G(d,p) calculations. The calculated geometric parameters (bond lenght, bond angle, and torsion angle) are compared with their experimental data. It is seen that there are no significant differences, when the experimental structure is compared with theoretical structures except the experimental torsion angle, C10-O3-C7-C8, which differs from those of the calculeted values. The MEP maps show that the negative potential sites are on electronegative atoms and the positive potential sites are around the hydrogen atoms. These sites provide information concerning the region from where the compound can undergo intra-and intermolecular interactions. Similarly, the Mulliken charges confirm the intermolecular C12-H12B…O2 hydrogen bond in the solid state.