Synthesis, crystal structure elucidation, Hirshfeld surface analysis, 3D energy frameworks and DFT studies of 2-(4-fluorophenoxy) acetic acid European Journal of Chemistry 12 (3) (2021) 304-313 European Journal of Chemistry ISSN 2153-2249 (Print) / ISSN 2153-2257 (Online) – Copyright © 2021 The Authors – Atlanta Publishing House LLC – Printed in the USA. This work is published and licensed by Atlanta Publishing House LLC – CC BY NC – Some Rights Reserved. https://dx.doi.org/10.5155/eurjchem.12.3.304-313.2099 European Journal of Chemistry View Journal Online View Article Online Synthesis, crystal structure elucidation, Hirshfeld surface analysis, 3D energy frameworks and DFT studies of 2-(4-fluorophenoxy) acetic acid Akhileshwari Prabhuswamy 1, Yasser Hussein Eissa Mohammed 2, Fares Hezam Al-Ostoot 2,3, Geetha Doddanahalli Venkatesh 1, Sridhar Mandayam Anandalwar 1,*, Shaukath Ara Khanum 2 and Lokanath Neratur Krishnappagowda 1 1 Department of Studies in Physics, Manasagangotri, University of Mysore, Mysuru 570 006, India akhila@uomphysics.net (A.P.), geetha@uomphysics.net (G.D.V.), mas@physics.uni-mysore.ac.in (S.M.A.), lokanath@physics.uni-mysore.ac.in (L.N.K.) 2 Department of Chemistry, Yuvaraja’s College, University of Mysore, Mysuru 570 006, India issayasser16@gmail.com (Y.H.E.M.), faresalostoot@gmail.com (F.H.A.), shaukathara@yahoo.co.in (S.A.K.) 3 Department of Biochemistry, Faculty of Education and Science, Al-Baydha University, Yemen * Corresponding author at: Department of Studies in Physics, Manasagangotri, University of Mysore, Mysuru 570 006, India. e-mail: mas@physics.uni-mysore.ac.in (S.M. Anandalwar). 10.5155/eurjchem.12.3.304-313.2099 Received: 30 January 2021 Received in revised form: 26 July 2021 Accepted: 07 August 2021 Published online: 30 September 2021 Printed: 30 September 2021 The compound 2-(4-fluorophenoxy) acetic acid was synthesized by refluxing, 4-fluoro- phenol as a starting material with ethyl chloroacetate in acetone as solvent. The compound crystallizes in the monoclinic crystal system with the space group P21/c. Crystal data for C8H7FO3, a = 13.3087(17) Å, b = 4.9912(6) Å, c = 11.6018(15) Å, β = 104.171(4)°, V = 747.21(16) Å3, Z = 4, T = 293(2) K, μ(CuKα) = 1.142 mm-1, Dcalc = 1.512 g/cm3, 8759 reflections measured (13.72° ≤ 2Θ ≤ 130.62°), 1246 unique (Rint = 0.0528) which were used in all calculations. The final R1 was 0.0458 (>2sigma(I)) and wR2 was 0.1313 (all data). The structure was stabilized by C-H···O and C-H···Cg interactions. The intermolecular interactions in the crystal were studied using Hirshfeld surface analysis. 3D energy frameworks were computed to visualize the packing modes. DFT calculations were performed. The FMOs were studied to estimate the kinetic stability and reactivity of the molecule. The MEP surface was generated to investigate the charge distribution and chemical reactive sites in the molecule. DFT MEP HOMO-LUMO Crystal structure Phenoxyacetic acid Hirshfeld surface analysis Cite this: Eur. J. Chem. 2021, 12(3), 304-313 Journal website: www.eurjchem.com 1. Introduction Organic synthesis is one of the most important sources of new compounds that have the ability to bind and shape new items with new chemical and physical properties that affect our daily life in medicine, agriculture, and life in general [1-3]. Phenoxy acids are unquestionably among the most significant functional groups in organic chemistry. They are present, among several other structures, in certain naturally occurring particles, synthesized polymers, peptides, and pharmaceutical agents [4-7]. The formation of phenoxy acid bonds was one of the most significant pharmaceutical synthesis transformations [8,9], taking into account a high percentage of all preliminary evaluation responses in industrial and medical applications laboratories as recently reported [10]. The true usefulness of phenoxy systems for medicinal chemists is the ability to synthesize one library based on a particular core scaffold and screen it against a wide range of different receptors, gaining several active compounds. Phenoxy acid analogs are considered really significant substances in medicinal chemistry. The molecules have also been found to provide a great antifungal event against microorganisms. They also have moderate activity against Gram-negative bacteria compared to regular standard ciprofloxacin [11]. Compounds with a phenoxy acetamide core structure have attracted considerable interest as these derivatives have established a wonderful range of pharmacological potentials such as anti-inflammatory, anti- bacterial, anti-parasitic, anti-cancer, anti-viral and anti- hypoglycemic effects [12-20]. The effects of aryloxyaliphatic acid on blood vessel permeability and the antimicrobial action of phenoxyacetic acid against human pathogens have been recorded. Azomethine and its phenoxy acetic acid-derived complexes have reported biological importance including pyridoxal phosphate anti-metabolites, bacteriostatic activity, and antitumor activity [21-26]. In view of their broad spectrum of medicinal properties and as a part of our ongoing work on the synthesis and characterization of novel compounds [27-29], the title compound was synthesized. ABSTRACT RESEARCH ARTICLE KEYWORDS https://dx.doi.org/10.5155/eurjchem.12.3.304-313.2099 https://www.eurjchem.com/ https://dx.doi.org/10.5155/eurjchem.12.3.304-313.2099 mailto:akhila@uomphysics.net mailto:geetha@uomphysics.net mailto:mas@physics.uni-mysore.ac.in mailto:lokanath@physics.uni-mysore.ac.in mailto:issayasser16@gmail.com mailto:faresalostoot@gmail.com mailto:shaukathara@yahoo.co.in mailto:mas@physics.uni-mysore.ac.in http://www.eurjchem.com/ https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.12.3.304-313.2099&domain=pdf&date_stamp=2021-09-30 Prabhuswamy et al. / European Journal of Chemistry 12 (3) (2021) 304-313 305 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.3.304-313.2099 O OCl (1) (2) (3) (4) Acetone NaOH(i) (ii) Ethanol OH F O F O O O F O OH (i) (ii) K2CO3 Figure 1. Schematic representation of the synthesis of the title compound. Figure 2. ORTEP diagram of the molecule drawn at 50% probability. The compound obtained was characterized spectros- copically, and the structure was confirmed by X-ray diffraction studies. The crystal structure characterization of the title compound was previously reported by Smith et al. [30]. Hirshfeld surface analysis and DFT study of the title compound were presented in this article. 2. Experimental 2.1. Instrumentation The chemicals required for the synthesis of the title compound were procured from M/S Sigma-Aldrich Chemical Co. The reaction progress was checked by thin layer chromatography (TLC) which was performed on aluminum- backed silica plates and the spots were detected by exposure to UV-light at λ = 254 nm. The melting point and the boiling point were measured in a Chemiline Microcontroller-Based Melting Point/Boiling Point-CL725 apparatus with a digital thermo- meter. The IR spectrum was recorded on the Agilent Techno- logies Cary 630 FTIR spectrometer, 1H and 13C NMR spectra were recorded on a VNMRS-400 Agilent-NMR spectrophoto- meter. The mass spectrum was obtained with a VG70-70H spectrometer and elemental analysis (C, H, and N) was performed on an elemental analyzer Elementar Vario EL III. The results of the elemental analysis are within ±0.5% of the theoretical values. 2.2. Synthetic procedure for 2-(4-fluorophenoxy) acetic acid The compound 2-(4-fluorophenoxy) acetic acid was synthesized by refluxing 4-fluorophenol as a starting material with ethyl chloroacetate in acetone as solvent to achieve the corresponding ester as 4-fluorophenoxy ethyl acetate (3). This was followed by hydrolysis with sodium hydroxide in the presence of ethanol. A mixture of 4-fluorophenol (0.04 mol), ethyl chloroacetate (0.040 mol) and anhydrous potassium carbonate (0.04 mol) in dry acetone (50 mL) was refluxed for 10 hours. Then the reaction mixture was cooled and the solvent was removed by distillation. The residual mass was triturated with cold water to remove potassium carbonate and extracted with ether (3×30 mL). The organic layer was then washed with 10% sodium hydroxide solution (3×30 mL) followed by water (3×30 mL) and dried over anhydrous sodium sulphate and evaporated to give the corresponding 4-fluoro phenoxy ethyl acetate ester (3). The compound 3 (0.015 mol) was then dissolved in ethanol (15 mL) with sodium hydroxide as solvent (0.030 mol), then water (5 mL) was added to the reaction mixture. The reaction was monitored by TLC using a hexane: ethyl acetate: methanol (5:2:1) system. The mixture was refluxed for 8 hours and the reaction mixture was cooled and acidified with 2 N hydrochloric acid [31,32]. The precipitate was filtered off and washed with water, and finally recrystallized from ethanol to yield a colorless needle-like crystal. The schematic representation of the synthesis of the title compound is shown in Figure 1. 2-(4-Fluorophenoxy) acetic acid: Yield: 75%. M.p.: 105- 107 °C. FT-IR (KBr, ν, cm-1): 1730-1760 (C=O), 1245-1255 (Ar- O-C), 3350-3375 (OH). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 4.67 (s, 2H, OCH2), 6.55-7.55 (d, 4H, Ar-H), 13.03 (bs, 1H, OH). LC-MS (m/z): 171 [M+1]. Anal. calcd. for C8H7FO3: C, 56.46; H, 4.14. Found: C, 56.38; H, 4.08%. 2.3. X-ray diffraction analysis Single crystal X-ray diffraction study was carried out to determine the unit cell parameters. A colorless single crystal of the title compound with appropriate dimension 0.22×0.21× 0.20 mm was used to study the X-ray diffraction. XRD analysis reveals that the title compound C6H7O3F crystallizes in the monoclinic crystal system with the space group P21/c. The reflections were collected on a Rigaku XtaLAB mini diffracto- meter equipped with CuKα radiation with the wavelength 1.54178 AÅ . The data reductions of all measured reflections were carried out using the CrystalClear software [33]. Crystal structure was solved by direct method using SHELXS-97 and refined by full-matrix least squares on F2 using SHELXL-97 [34]. The positions of the hydrogen atoms attached to the carbon atoms were generated geometrically. Hydrogen atoms are allowed to ride on their parent atoms. All non-H atoms were refined anisotropically. A total of 110 parameters were refined with 1246 unique reflections. The residual factor R converged to 0.0458 and the wR2 was 0.1313 for all data. Geometrical calculations were performed using PLATON [35]. The ORTEP of the molecule with thermal ellipsoids drawn at 50% probability is shown in Figure 2. The molecular and packing diagrams were generated using MERCURY [36]. The crystal data was deposited at the Cambridge Crystallographic Data Center (CCDC) as deposition number 1949545. 3. Results and discussions 3.1. Crystal structure description The title compound crystallizes in the monoclinic crystal system with the space group P21/c. 306 Prabhuswamy et al. / European Journal of Chemistry 12 (3) (2021) 304-313 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.3.304-313.2099 Table 1. Crystal data and structure refinement details. CCDC Number 1949545 Empirical formula C8H7FO3 Formula weight 170.14 Temperature (K) 293(2) Crystal system Monoclinic Space group P21/c a (Å) 13.3087(17) b (Å) 4.9912(6) c (Å) 11.6018(15) β (°) 104.171(4) Volume (Å3) 747.21(16) Z 4 ρcalc (g/cm3) 1.512 μ (mm-1) 1.142 F(000) 352.0 Crystal size (mm3) 0.22 × 0.21 × 0.20 Radiation CuKα (λ = 1.54178) 2Θ range for data collection (°) 13.72 to 130.62 Index ranges -15 ≤ h ≤ 15, -5 ≤ k ≤ 5, -13 ≤ l ≤ 13 Reflections collected 8759 Independent reflections 1246 [Rint = 0.0528] Data/restraints/parameters 1246/0/110 Goodness-of-fit on F2 1.108 Final R indexes [I≥2σ (I)] R1 = 0.0458, wR2 = 0.1295 Final R indexes [all data] R1 = 0.0472, wR2 = 0.1313 Largest diff. peak/hole (e Å-3) 0.30/-0.27 Table 2. Geometry of hydrogen bond interactions. D-H…A D-H (Å) H···A (Å) D···A (Å) D-H···A (°) C12-H12···O11i 0.82 1.82 2.636(1) 172 C9-H9B···O11ii 0.97 2.42 3.249(2) 144 Symmetry codes: i = 2-x, -1-y, -z; ii =2-x, 1/2+y, 1/2-z. Figure 3. Packing of molecules viewed along the b axis. The unit cell parameters are a = 13.3087(17) AÅ , b = 4.9912(6) AÅ , c =11.6018(15) AÅ , and β = 104.171(4)°. Crystal data and structure refinement details are listed in Table 1. The values of bond length, bond angle, and torsion angles obtained by the X-ray diffraction studies are given in the CIF file. The structure consists of a hexagonal ring (C2-C3-C4-C5- C6-C7) that is planar with a maximum deviation of 0.007(2) AÅ for C3 atom from the mean plane. The six-membered ring (C2- C3-C4-C5-C6-C7) is sp2 hybridized. The crystal structure exhibits intermolecular hydrogen bonds of the type O-H···O and C-H···O whose symmetry codes are 2-x, -1-y, -z and 2-x, 1/2+y, 1/2-z, respectively. In the structure, the C5-O8 bond length is 1.379(2) Å, which signifies a typical single bond, whereas the C10-O11 bond length is 1.261(2) Å indicates the double bond. The torsion angles for C9-O8-C5-C4 (-176.1(1)°) and C9-O8-C5-C6 (4.8(2)°) indicate the anti-periplanar and syn-clinal conformations, respectively. The molecular structure exhibits a short ring Cg···Cg interaction. cg is the centroid of the ring C2-C3-C4-C5-C6-C7 with Cg···Cg distance of 4.7992(1) Å, and perpendicular distance of cg on itself is -3.1529(1) Å with a slippage value of 3.623 Å. The symmetry code for the Cg···Cg interaction is 1-x, 1- y, -z. The structure further involves C-F…cg interaction; C2-F1 atoms and the centroid of the ring (C2-C3-C4-C5-C6-C7). The F1-cg distance is 3.7787(2), and γ is 21.47°, C2-cg distance is 4.214(2) Å, and C2-F···Cg angle is 99.05(1)° with the symmetry code x, 1+y, z. The structure is stabilized by C-H…cg interactions. The distance between H-Cg (H9A···Cg) is 2.67 Å, γ = 8.68°, and C9- Cg distance is 3.4245(2) Å. The angle of deviation of C9-H9A from the π plane is 134°. The molecules are further connected by C-H···O and O-H···O intermolecular interactions. Hydrogen bond interactions are listed in Table 2. The packing of the molecules when viewed along the b axis is shown in Figure 3. 3.2. Hirshfeld surface analysis The Hirshfeld surface analysis is the visualization of intermolecular interactions between the molecules in a crystal. It helps to anatomize the interplanar distance, angles, and packing modes in the crystal. Prabhuswamy et al. / European Journal of Chemistry 12 (3) (2021) 304-313 307 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.3.304-313.2099 Figure 4. Hirshfeld surface of the molecule mapped over dnorm. Figure 5. 2D fingerprint plot of all intermolecular contacts. The Hirshfeld surface of a molecule divides the electron density of a crystal into molecular fragments. It divides the crystal into regions where the electron distribution of a sum of spherical atoms for the molecule (the promolecule) dominates the corresponding sum over the crystal (the procrystal) [37]. The Hirshfeld surface is generated for the molecule and the proximity of its nearest neighbor’s. Thus, it contains the details of the intermolecular interactions. The Hirshfeld surface of the molecule mapped over the dnorm is shown in Figure 4. Hirshfeld surfaces and two-dimensional fingerprint plots are generated using CrystalExplorer17.5 software [38]. The dnorm value is positive for shorter contacts (blue region), negative for longer contacts (red regions) compared to van der Waals (vdW) separation. It is zero (white) for the contacts around the vdW separation. The computed molecular Hirshfeld surface area is 193.86 Å2, which encloses the volume of 182.08 Å3. Other calculated shape descriptors are globularity (G = 0.801) and a sphericity (Ω = 0.235). The bright red regions on the Hirshfeld surface are due to O-H···O (a) and C-H···O (b) intermolecular interactions. The 2D fingerprint plot provides a precise two-dimensional graphical representation of the intermolecular interactions in a crystal. The contributions from different contacts to the total Hirshfeld surface area are O···H (31.5%), H···H (23.4%), C···H (15.8%), and F···H (15.4%). The major contributors are O···H and F···H contacts, which are the short intermolecular interactions. The general contributions of the different contacts to the total Hirshfeld surface area are shown in Figure 5. The short intermolecular O-H contacts are represented by sharp spikes with di+de = 2 Å. The wings (see Figure 6c) are due to C-H contacts with di+de values of 3.2 Å. Here di and de are the distance from the Hirshfeld surface to the nucleus internal to the surface and the distance from the Hirshfeld surface to the nucleus external to the surface, respectively. The central green color region indicates the C-H···π interactions. The contributions of different contacts such as O-H, H-H, C-H, and F- H to the total surface area and the corresponding dnorm surface are shown in Figure 6. 3.3. Shape index, curvedness, and electrostatic potential The shape index and curvedness are the two properties of the Hirshfeld surface. The shape index and curvedness are properties to scale the morphology of the crystal. The shape index is a measure of ‘which shape’ [39]. The shape index map can be used to identify the complementary pairs (red colored hollows and blue-colored bumps) where two surfaces touch each other. These triangular patterns of hollows and bumps on the shape index surface shed light on close interplanar contacts. Proper triangular patterns are not observed on the shape index map. Curvedness is a measure of ‘how much shape’. The flat regions correspond to low values of curvedness and explicate the characteristic arrangement of planar stacking of the molecules in the crystal [40]. Sharp regions on the plot show the high values of curvedness. The molecule shows flat regions on the curvedness map indicating the planar arrangement. Electrostatic potential map on the Hirshfeld surface indicates the complementarity between the adjacent molecules. The red and blue colored regions on the electrostatic potential map show the hydrogen bond acceptors and hydrogen bond donors respectively. The red colored regions are present around the oxygen atom showing the hydrogen bond acceptor. Fragment patches on the Hirshfeld surface show the molecular interactions corresponding to their coordination number. Hirshfeld surfaces mapped with shape index, curvedness, electrostatic potential, and fragment patches are shown in Figure 7. 3.4. 3D energy frameworks The energy frame works gives insight about the supra- molecular association of the molecules in the crystal. The energy framework calculations were performed using Crystal Explorer17.5 software [38] by employing symmetry operations using the B3LYP/6-31G(d,p) functional basis set. A cluster of molecules within a radius of 3.8 Å was generated around a molecule. The molecules involved in the calculation of interaction energies along the c axis is shown in Figure 8. The electrostatic polarization, dispersion, and repul- sion energies between the molecular pairs were calculated and listed in Table 3. The R is the distance between the mean atomic positions (molecular centroids). The scaling factors used for benchmarked energies for B3LYP/6-31G(d,p) are kele = 1.015, kpol = 0.740, kdisp = 0.871, and krep = 0.618 [41]. 308 Prabhuswamy et al. / European Journal of Chemistry 12 (3) (2021) 304-313 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.3.304-313.2099 (a) (a1) (b) (b1) (c) (c1) (d) (d1) Figure 6. The 2D fingerprint plot of the molecule from various contributions. (a), (b), (c), and (d) indicate the interactions from O-H, H-H, C-H, and F-H, respectively. (a1), (b1), (c1), and (d1) represent the corresponding dnorm surfaces, respectively. Shape index Curvedness Electrostatic potential Fragment patches Figure 7. Hirshfeld surface mapped with shape index, curvedness, electrostatic potential, and fragment patches. Prabhuswamy et al. / European Journal of Chemistry 12 (3) (2021) 304-313 309 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.3.304-313.2099 Table 3. Different interaction energies of molecular pairs in kJ/mol. Color N Symop R Electron Density E_ele E_pol E_dis E_rep E_tot 1 x, y, z 4.99 B3LYP/6-31G(d,p) -11.2 -1.9 -35.4 22.5 -30.3 2 x, -y+1/2, z+1/2 5.8 B3LYP/6-31G(d,p) -4.2 -0.9 -13.1 6 -12.8 2 x, -y+1/2, z+1/2 7.61 B3LYP/6-31G(d,p) -2.1 -0.4 -8.6 4.4 -7.3 1 -x, y+1/2, -z+1/2 9.01 B3LYP/6-31G(d,p) 0.6 -0.2 -3.4 0.3 -2.3 1 -x, -y, -z 10.04 B3LYP/6-31G(d,p) -5.3 -0.6 -7 5.2 -8.8 1 -x, -y, -z 7.59 B3LYP/6-31G(d,p) 6.6 -1.9 -16.8 7.4 -4.5 1 x, y+1/2, -z+1/2 6.98 B3LYP/6-31G(d,p) -8.3 -3.1 -8 11.4 -11 Table 4. Comparison of bond lengths. Atoms XRD (Å) DFT (Å) 6-31G(d,p) 6-31+G(d,p) C2-F1 1.363(2) 1.352 1.363 C2-C7 1.367(3) 1.386 1.385 C3-C2 1.373(3) 1.393 1.392 C3-C4 1.385(2) 1.390 1.392 C4-C5 1.385(2) 1.403 1.403 C5-C6 1.386(2) 1.399 1.399 C6-C7 1.388(3) 1.399 1.401 O8-C5 1.379(2) 1.372 1.374 O8-C9 1.411(2) 1.410 1.409 C9-C10 1.496(2) 1.519 1.518 C10-O11 1.261(2) 1.211 1.213 C10-O12 1.256(2) 1.344 1.344 Table 5. Comparison of bond angles. Atoms XRD (°) DFT (°) 6-31G(d,p) 6-31+G(d,p) C5-O8-C9 115.7(1) 118.3 118.1 F1-C2-C7 118.7(2) 119.0 118.8 C3-C2-C7 122.6(2) 121.5 121.9 F1-C2-C3 118.7(2) 119.1 118.8 C2-C3-C4 118.3(2) 119.0 118.8 C3-C4-C5 120.3(2) 120.2 120.2 O8-C5-C4 115.5(1) 115.3 115.4 O8-C5-C6 124.4(1) 124.7 124.5 C4-C5-C6 120.1(2) 119.9 119.9 C5-C6-C7 119.8(2) 119.7 119.8 C2-C7-C6 118.9(2) 119.3 119.1 O8-C9-C10 111.5(1) 111.4 111.5 O11-C10-C9 114.8(1) 121.7 121.6 O12-C10-C9 120.7(1) 114.2 114.4 O11-C10-O12 124.5(1) 124.0 123.8 Figure 8. Molecules involved in the calculation of the interaction energies along the c-axis. The pictorial representation of Coulomb energy, dispersion energy, and the total interaction energy of the molecule viewed along a, b, and c axis is shown in green, red, and blue colors respectively and are displayed in Figure 9. The different interaction energies viz., electrostatic, dispersion, polarization, and repulsion energies are -163.2, -134.2, -43.5, and 220.3 kJ/mol, respectively. The total energy is -186.1 kJ/mol. The electrostatic energy dominates over the dispersion energy. The lattice energy of the molecule is -69.85 kJ/mol. The cylinders in the energy framework depict the relative strengths of the molecular packing and the associated energies between the molecular pairs in different directions [42]. The absence of cylinders along a particular direction is due to weak interactions below a threshold energy and they are omitted for the less crowded appearance. 3.5. Density functional theory The computational quantum mechanical method was employed to study the electronic structure and chemical properties of the molecule. The quantum computational method, density functional theory (DFT) calculations were carried out using Gamess software [43]. Geometric calculations were performed using B3LYP hybrid functionals with 6- 31G(d,p) and 6-31+G(d,p) as basis sets. The geometry optimization and vibrational analysis also were also carried out. The frontier molecular orbitals; Highest Occupied Molecular Orbitals (HOMO) and Lowest Unoccupied Molecular Orbitals (LUMO) were studied to ascertain the chemical stability of the molecule. The theoretically predicted values of bond length, bond angles, and torsion angles are in good agreement with the experimental values. Comparison of theoretical and experi- mental values is listed in Tables 4-6. It is inferred that the optimized molecule is not a stationary point on the molecular potential energy surface. Frequency calculations were performed and are tabulated (Table 7). Imaginary frequencies were not observed. The optimized structure of the molecule is shown in Figure 10. 310 Prabhuswamy et al. / European Journal of Chemistry 12 (3) (2021) 304-313 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.3.304-313.2099 Table 6. Comparison of torsion angles in degree. Atoms XRD (°) DFT (°) 6-31G(d,p) 6-31+G(d,p) C9-O8-C5-C4 −176.1(1) -178.8 -178.8 C9-O8-C5-C6 4.8(2) 1.1 1.1 C5-O8-C9-C10 174.7(1) 178.5 178.5 C3-C2-C7-C6 −0.4(3) -0.0 -0.0 F1-C2-C3-C4 −179.3(2) -179.9 -179.9 F1-C2-C7-C6 −179.9(2) -179.9 -180.0 C7-C2-C3-C4 1.2(3) 0.0 0.0 C2-C3-C4-C5 −0.9(3) -0.0 0.0 C3-C4-C5-C6 −0.1(2) -0.0 -0.0 C3-C4-C5-O8 −179.3(2) 179.9 179.8 C4-C5-C6-C7 0.9(3) 0.1 0.1 O8-C5-C6-C7 180.0(2) -179.9 -179.9 C5-C6-C7-C2 −0.6(3) -0.0 -0.0 O8-C9-C10-O11 180.0(1) 179.9 -179.6 O8-C9-C10-O12 −0.2(2) -0.1 0.3 Table 7. Interaction energies. Parameters E (kJ/mol) H (kJ/mol) G (kJ/mol) CV (J/mol.K) CP (J/mol.K) S (J/mol.K) Electronic 0.000 0.000 0.000 0.000 0.000 0.000 Translational 3.718 6.197 -45.323 12.472 20.786 172.800 Rotational 3.718 3.718 -34.873 12.472 12.472 129.436 Vibrational 424.957 424.957 313.706 172.888 172.888 373.137 Total 432.394 434.873 233.511 197.831 206.145 675.373 Figure 9. Representation of the Coulomb interaction energy, dispersion energy, and total energy in red, green, and blue colors along the a, b, and c axes, respectively. Prabhuswamy et al. / European Journal of Chemistry 12 (3) (2021) 304-313 311 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.3.304-313.2099 Table 8. Global reactivity descriptors and their estimated energy values. Descriptor Energy HOMO -6.41 eV LUMO -0.89 eV Energy difference (ΔE) 5.51 eV Ionization potential (I) 6.41 eV Electron affinity (A) 0.89 eV Chemical potential (μ) -3.81 eV Electronegativity (χ) 3.81 eV Global hardness (η) 2.76 eV Global softness (σ) 0.36 eV-1 Electrophilicity (ω) 2.63 eV Figure 10. The optimized structure of the molecule. Figure 11. HOMO-LUMO energy level of the molecule. 3.6. Frontier molecular orbitals The frontier molecular orbitals viz., HOMO and LUMO and the energy difference between them is computed with the exchange correlation functional B3LYP/6-31+G(d,p) basis set. HOMO acts as an electron donor, and LUMO acts as an electron acceptor. The energy gap between HOMO and LUMO is 5.51 eV. The molecule is highly stable and less reactive compared to other molecules [44]. The energy gap of the molecule predicts the stability and reactivity [45]. HOMO is localized in the phenoxy ring. The energy level of the molecular orbitals HOMO and LUMO of the molecule is shown in Figure 11. To understand the chemical reactivity of the molecule, molecular descriptors have been studied. The molecular descriptors, viz. ionization potential (I), electron affinity (A), chemical potential (μ), electronegativity (χ), global softness (σ), global hardness (η), and electrophilicity (ω) are listed in Table 8. The global parameters were calculated using the formulae, I = -EHOMO, A = ELUMO, χ = 1/2(I + A), μ = -χ, η = ΔE/2, σ = 1/η, and ω = μ2/2 η. 3.7. Molecular electrostatic potential The molecular electrostatic potential (MEP) map illustrates the charge distribution of molecules in three dimensions. The values of electrostatic potential determine the electrophilic or nucleophilic reactive sites. The molecular electrostatic poten- tial map is generated by covering all atoms of a molecule at van der Waals radius of the atoms. It is calculated for the regions distributed evenly on the van der Waals surface. The regions obtained are color coded [46]. The red colored regions on the MEP map indicate the negative electrostatic potential (regions of attraction for positive charge). The blue colored regions indicate the positive electrostatic potential (regions of attraction for negative charge). The intermediate potential values are indicated by yellow, green, and light blue colored regions. The distribution of electrostatic potential on the molecular surface is shown in Figure 12. It shows that the negative electrostatic potential is spread over the oxygen atom and the positive electrostatic potential is concentrated around the hydrogen atom attached to the phenoxy ring. Figure 12. Molecular electrostatic potential map of the molecule. 312 Prabhuswamy et al. / European Journal of Chemistry 12 (3) (2021) 304-313 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.3.304-313.2099 4. Conclusions The molecule, 2-(4-fluorophenoxy) acetic acid, crystallizes in the monoclinic crystal system with the space group P21/c. Hirshfeld surface analysis revealed the C-H···O intermolecular interactions in the crystal. The three-dimensional energy frameworks indicate that the electrostatic energy is dominant over the dispersion energy. DFT calculations were carried over B3LYP/6-31+G(d,p) basis set infers that the theoretically predicted structural values are in good agreement between the experimental values. The energy gap between HOMO and LUMO is 5.51 eV, which implies the stability of the molecule. The analysis of the molecular electrostatic potential surface revealed the electronegative and electropositive sites are around the oxygen and hydrogen atoms, respectively. Acknowledgement Akhileshwari Prabhuswamy was thankful to the Karnataka Science and Technology Promotion Society (KSTePS), DST, Government of Karnataka for providing the fellowship. Yasser Hussein Eissa Mohammed is thankful to the University of Hajjah, Yemen. Fares Hezam Al-Ostoot thanks the Government of Yemen and Al-Baydha University, Yemen, for providing financial assistance under the teacher's fellowship and Mysore University, Mysuru, India. Shaukath Ara Khanum thanks the financial support provided by VGST, Bengaluru, under the CISEE Program [Project sanction order: No. VGST/CISEE/282]. Supporting information CCDC-1949545 contains the supplementary crystallo- graphic data for this paper. These data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/ or by e- mailing data_request@ccdc.cam.ac.uk or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(0)1223-336033. Disclosure statement Conflict of interests: The authors declare that they have no conflict of interest. Author contributions: All authors contributed equally to this work. 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Bendjeddou, A.; Abbaz, T.; Ayari, A.; Benahmed, M.; Gouasmia, A.; Villemin, D. Orient. J. Chem. 2016, 32 (2), 799–806. [46]. Gasteiger, J.; Li, X.; Rudolph, C.; Sadowski, J.; Zupan, J. J. Am. Chem. Soc. 1994, 116 (11), 4608–4620. Copyright © 2021 by Authors. This work is published and licensed by Atlanta Publishing House LLC, Atlanta, GA, USA. The full terms of this license are available at http://www.eurjchem.com/index.php/eurjchem/pages/view/terms and incorporate the Creative Commons Attribution-Non Commercial (CC BY NC) (International, v4.0) License (http://creativecommons.org/licenses/by-nc/4.0). By accessing the work, you hereby accept the Terms. This is an open access article distributed under the terms and conditions of the CC BY NC License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited without any further permission from Atlanta Publishing House LLC (European Journal of Chemistry). No use, distribution or reproduction is permitted which does not comply with these terms. Permissions for commercial use of this work beyond the scope of the License (http://www.eurjchem.com/index.php/eurjchem/pages/view/terms) are administered by Atlanta Publishing House LLC (European Journal of Chemistry). http://www.eurjchem.com/index.php/eurjchem/pages/view/terms http://creativecommons.org/licenses/by-nc/4.0 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms 1. Introduction 2. Experimental 2.1. Instrumentation 2.2. Synthetic procedure for 2-(4-fluorophenoxy) acetic acid 2.3. X-ray diffraction analysis 3. Results and discussions 3.1. Crystal structure description 3.2. Hirshfeld surface analysis 3.3. Shape index, curvedness, and electrostatic potential 3.4. 3D energy frameworks 3.5. Density functional theory 3.6. Frontier molecular orbitals 3.7. Molecular electrostatic potential 4. Conclusions Acknowledgement Supporting information Disclosure statement ORCID References PrintField10: PrintField11: PrintField12: PrintField13: PrintField14: PrintField15: PrintField16: PrintField17: PrintField18: PrintField19: PrintField20: PrintField21: PrintField22: PrintField23: PrintField24: PrintField25: PrintField26: PrintField27: PrintField28: PrintField29: