Synthesis, characterization, structural exploration and quantum chemical calculations of (E)-8-(1-((4-aminobenzyl)imino)ethyl)-7-hydroxy-4-methyl-coumarin

Introduction

Coumarin derivatives have been used extensively in several pharmaceuticals due to their diverse biological properties. They have been observed to possess antitumor, antituberculosis, antioxidant, anti-inflammatory, antiviral, and antimicrobial activities ^1-6. Several coumarin derivatives have displayed activities such as inhibition of HIV-1 replication with anti-HIV activity and anti-cancer and anti-tumor activities ^7-14. Coumarin derivatives are used in agricultural sector as potential seed protectants as well as pesticides and rodenticides ^15-17. Coumarin derivatives have shown high fluorescent properties that make them suitable candidates for bioimaging and in-cell fluorescent applications ^18-19. Studies have also shown that several coumarin derivatives act as enzymatic inhibitory agents in neurodegenerative diseases such as Alzheimer disease and hence are being employed in its treatment modalities ^20-22

These various physical and biological properties inspired us to synthesize a novel coumarin derivative: (E)-8-(1-((4-aminobenzyl)imino)ethyl)-7-hydroxy-4-methyl-coumarin. Characterization was carried out using various spectroscopic technique. The optical properties were studied using UV-visible spectroscopy. The final three-dimensional structure of the compound was obtained using XRD method. Intermolecular interactions and their contribution to crystal structure were studied. Energy frameworks analysis and lattice energy computation were also performed. DFT calculations were employed in optimization of the structure. Further, HOMO-LUMO that control most of the global and local, physical and chemical properties were also studied.

Materials and Methods

Instrumentation

All the reagents used in the synthesis of the novel coumarin derivative were obtained from Sigma-Aldrich co.,that were of very high purity and hence used directly. The completion of the reaction was surveilled by means of TLC usingsilica-60 coated plates and fluorescent indicatorof 256 nmultra-violet light. Proton and ¹³C NMR spectral data were collected with“Agilent-NMR” spectrometer and the chemical shifts have been reported in terms of ppm. The FTIR spectrum data were collectedusing“Perkin Elmer 100”and wave numbers have been reported in per centimeters. The recording of UV-visiblespectroscopic investigation was done with the help of“Perkin Elmer λ-35”with acetonitrile as the solvent.

Synthesis of (E)-8-(1-((4-aminobenzyl)imino)ethyl)-7-hydroxy-4-methyl-coumarin.

A novelcoumarin derivative was obtained fromthe reaction between7-hydroxy-4-methylcoumarin and 4-aminobenzylamine in absolute ethanol. 5 mmol solution of 4-aminobenzoylamine in 10 ml of absolute ethyl alcohol was added slowly to the boiling solution of 5 mmol of 7-hydroxy-4-methylcoumarin in absolute ethyl alcohol (25 ml) and was refluxed at 78^oCfor five hours and was cooled overnight. The precipitated product was filtered and dried under reduced pressure. The reaction pathway is representedin the scheme shown in Figure 1.

Figure 1: Schematic representation of reaction pathway. Click here to View figure

Spectroscopic analysis

The compound was characterized using NMR spectroscopy. Both ¹H and ¹³C NMR spectroscopic investigations were undertaken using deuterated DMSO as solvent with the frequency of 400 MHz and 100 MHz respectively.  The NMR spectra is given in Figure 2. The chemical shifts corresponding to the peaks of Proton NMR were observed at: δ 7.36 (d, 1H), δ 7.06 (d, 2H), δ 6.67 (d, 2H), δ 6.43 (d, 1H), δ 5.81 (s, 1H), δ 4.51 (s, 2H), δ 2.38 (s, 3H), δ 2.35 (s, 3H) ppmand the chemical shifts corresponding to the peaks of Carbon-13 NMR were observed at 166.4, 159.8, 159.5, 154.5, 150.0, 140.3, 132.1, 130.5, 129.3, 115.9, 114.5, 112.2, 52.3, 20.8 ppm.

Figure 2: 1H and 13C NMR of the compound. Click here to View figure

The peaks of FTIR spectrum correspond to different molecular vibrations. An absorption peak at 3570 cm^-1 corresponds to N-H stretching and several peaks in the range of 3000 cm^-1 to 3020 cm^-1 correspond to various C-H stretching. Notable absorption peaks at 2510 cm^-1 and 1840 cm^-1 are associated with O-H and C=O stretching vibrations. The finger print region contains several absorption peaks under 1500 cm^-1 corresponding to vibrations involving several bonds. The experimentally measured FTIR spectrum is given in Figure 3.

Figure 3: Experimental and theoretical FTIR spectra of the compound. Click here to View figure

Single crystal XRD studies

XRD studies were carried out using a crystal of size 0.2 × 0.25 × 0.35mm³. Intensity data were recorded on a “RigakuXtaLAB mini” at a temperature of 293 K with MoKα target that produces X-rays of wavelength 0.71073 Å. The φ angular settings were kept (0^o to 90^o) with 0.5^o scan width and three seconds of exposure time. The data were collected with a distance of 50 mm between the sample and the detector. The data integration was carried out using Crystal Clear ²³ software. The initial cell measurement revealed that the title molecule belongs to P 21/c pace group under mono clinic crystal system. Direct methods were employed to solve the crystal and molecular structure. The structure solution and refinement were done using SHELXS and SHELXL software respectively ^24-25. The first difference Fourier map revealed peaks corresponding to all carbon, oxygen and nitrogen atoms that were anisotropically refined before fixing hydrogen atoms at acceptable geometrical position with appropriate riding model. With the progress of refinement as the residual factor converged to 0.0704 andthe difference Fourier map peaks did not retain any chemical significance. The crystal structure parameters, refinement data and results are enlisted in Table 1. PLATON ²⁶ program was used for calculating all the geometrical parameters and MERCURY ²⁷ software was used to obtain the crystallographic diagrams.

Hirshfeld surface analysis

The visual interface provided by the Hirshfeld surface analysis helps in the effective study of molecular shapes in crystalline environment andvarious intermolecular interactions that contribute to the crystal stability. The d_norm mappedHirshfeld surface was generated to explore and quantify the diverse intermolecular interactions present in the title compound. Morphology of Hirshfeld surface was visualized by color coding interior (d_i) or exterior (d_e) distances of the surface to the nearest atoms. TheHirshfeld surface mapped with normalized distance were generated with a color codingof blue for negative values (-0.144 au) and red for positive values (1.38 au)respectively. The fingerprint plots with exterior and interior distances that rangefrom 0.4 Å to 2.6 Å were also generated. Further, the calculations of intermolecular interaction energies, lattice energy and energy frameworks were also carried out. All the calculations were performed using Crystal Explorer v-3.0 ^28-30.

Table 1: Crystal structure and refinement details.

Parameter	Value
CCDC deposit No.	2068030
Formula	C19H18N2O3
Molecularmass	322.35
Radiation	MoKα
Wavelength	0.71073
Crystal family	Monoclinic
S – group
a (Å)	10.8724(1)
b (Å)	5.6298(8)
c (Å)	26.0210(4)
β (°)	97.989(2)
Size (Å3)	1580.3(4)
Z	4
Absorption coeff. (mm‑1)	0.093
F000	680
Crystal dimension (mm3)	0.2 × 0.25 × 0.35
Data collection range: 2θ (°)	2.289 to 32.333
Index ranges	-14 ≤ h ≤ 15; -7 ≤ k ≤ 4; -12 ≤ l ≤ 36
Spots collected/unique/parameters	4942/2431/219
Absorption corr. method	Multi scan
Goof on F2	1.021
R1, wR2 indexes [I>=2σ (I)]	0.0704, 0.1518
R1, wR2 indexes [all]	0.1515, 0.1994
Extreme diff. peak and hole (eÅ-3)	0.364 and -0.249

 

DFT calculations

The electron wave functions generated using the density function of any molecule can be used to compute the physical and chemical properties of the molecule. Such calculations play a very significant role in theoretical investigation of the molecular properties. Gas phase optimization of the structure of the title compoundwas performed with density functional theory.The calculations were performed using B3LYP at 6-311G+(d,p) ^31-33 basis functions. Transitions among various molecular orbitals control the optical properties of the compound. Optical absorption spectrum was generated by studying electronic transitions with the help of time dependent DFT calculations ³⁴. The calculations were done using same set of functionals and basis set for lowest 15 singlet-singlet transitions. HOMO-LUMO,corresponding energy gap, and the associated local and global parameters were estimated ³⁵. The electrostatic potential map of the molecule (MEP) is an effective tool to visualize the possible reactive sites of the molecule. The MEP can be plotted by computing the effective electrostatic potential around the molecule using quantum chemical calculations. All the quantum chemical computations were performed using “Gaussian 09” ³⁶. Results of the calculations were analyzed and visualized using GaussView ³⁷.

Results and Discussions

Optical absorption studies

Transitions among various σ and π states of the molecule results in the absorption in the visible to ultraviolet region of the electromagnetic spectrum. This optical absorbance of the title molecule was studied using UV-visible spectroscopy. The experiment was carried out using solution of the title compound in acetonitrile with 25µg/ml concentration. The absorbance was investigated in the wavelength range from 200 nm to 700 nm.The compound showed no absorbance for wavelength more than 400 nm;however, it displayed a slightly broad absorbance peak from 300 nm to 280 nm. Below 275 nm, the absorbance decreased rapidly and approached zero by 240 nm. The broad peak can be attributed to be due to contribution from several transitions with a nearly equal energy difference. The experimentally measured UV-visible absorbance spectrum is shown in Figure 4 using green colored curve.

Figure 4: Experimental (green) and calculated (red) UV-visible spectrum. Click here to View figure

X-ray diffraction studies

X-ray diffraction is the ultimate tool in three-dimensional structure determination that gives the final confirmation of the molecular structure. The structure of the title compound was determined using single crystal X-ray diffraction studies. The title molecule contains an eleven atom coumarin moiety substituted with a methyl group at position 7 and a benzene ring with substituted amino group at position 4 connected through an imine bond linkage. The coumarin moiety is highly planar with a highest deviation of 0.017 Å from the mean plane for C4 atom.The terminal benzene ring is twisted with respect to the plane of coumarin moiety with a dihedral angle of 69.41(8)°. The title compound is in E-conformation about imine bond as indicated by the C14-N16-C17-C18 torsion angle of 179.4(2)°. The ORTEP diagram not only provides the molecular structure, but also provides the details of thermal vibrations of every atom in the molecule and is given in Figure 5. Structural parameters such as bond length, bond angle and torsion angles were found to be in excellent agreement with the similar structures as well as with those values obtained from theoretical calculations. Table 2 provides a list of selected geometrical parameters of the novel coumarin derivative.

Figure 5: ORTEP of the title compound. Click here to View figure

Table 2: Selected geometrical parameters of the molecule.

XRD				DFT
Selected bond lengths (Å)
		C9	O10		1.211(3)	1.2095
		C9	O11		1.387(3)	1.4058
		O11	C12		1.371(3)	1.3601
		C14	N16		1.303(3)	1.2963
		N16	C17		1.467(3)	1.4636
		C21	N24		1.370(3)	1.3965
		C2	C13		1.443(2)	1.4341
		C17	C18		1.502(3)	1.5139
		Correlation coefficient:				0.9795
Selected bond angles (°)
	C8	C9	O10		127.76	128.2(2)
	C8	C9	O11		115.45	116.2(2)
	O10	C9	O11		116.8	115.6(2)
	C13	C14	N16		115.92	116.82(19)
	C15	C14	N16		122.31	119.0(2)
	C14	N16	C17		123.4	126.2(2)
	N16	C17	C18		111.44	110.7(2)
	C20	C21	C22		118.25	118.01(19)
	C20	C21	N24		120.73	121.2(2)
	C17	C18	C19		121.09	121.7(2)
Correlation coefficient:						0.9412
Selected torsion angles (°)
C14	N16	C17	C18		177.13	150.2(2)
N16	C17	C18	C19		-53.28	-55.8(3)
N16	C17	C18	C23		128.16	128.7(2)
C17	C18	C19	C20		-178.72	-174.9(2)
C8	C9	O11	C12		0.24	0.4(3)
O10	C9	O11	C12		-179.83	-179.8(2)
C9	O11	C12	C5		-0.72	-0.4(3)
C9	O11	C12	C13		179.9	179.9(2)
O1	C2	C13	C12		-177.96	-178.8(2)
O1	C2	C13	C14		2.31	0.0(3)
Correlation coefficient:						0.9998

 

The compound exhibits two intermolecular hydrogen bonds of N24—H24B…O1 and C17—H17A…O10 and one O1—H1…N16 intra molecular hydrogen bond. The C17—H17A…O10 hydrogen bond with donor to accepter distance of 3.355(4) Å results in the formation of  type supramolecular synthon. Further, an array of molecules is formed along b-axis through the N24—H24B…O1 hydrogen bonds as shown in Figure 4.These intermolecular hydrogen bonds enrich the molecular interactions that contribute highly to the stability of crystal structure. Details of the hydrogen bond geometry are given in Table 3. The novel coumarin derivative also exhibits a C—H…Cg interaction with the center of gravity of terminal benzene ring as shown in Figure 6. Further, the terminal benzene rings have shown a weak Cg—Cg interaction witha meandistance of 4.7994 Å between the centers of gravity of the two rings along -x,1/2+y,1/2-z symmetry direction.

Table 3: Various interactions observed in the title compound.

Hydrogen bonds (Distance in Å and angles in degree)
No.	Type	Donor	H		Accepter	Donor—H		H…Accepter		Donor…Accepter	Donor—H…Accepter
1	Intra	O1	H1		N16	0.82		1.75		2.490(3)	149
2	Interi	N24	H24B		O1	0.86		2.10		2.934(3)	163
3	Interj	C17	H17A		O10	0.97		2.57		3.355(4)	138
i: 1-x,-y,1-z;         j: –x,1/2+y,1/2-z
Interaction Geometry
X-H⋯Cg				H⋯Cg			X⋯Cg		X-H⋯Cg
C7—H7B…Cg(3)				2.69			3.453(3)		137
1+x, 1+y, z

 

Figure 6: (a) hydrogen bonds and supramolecular architecture (b) C—H…Cg interaction geometry (c) packing as viewed along b-axis and (d) 1D chain formation down b-axis in the title molecule. Click here to View figure

Hirshfeld surface analysis

The Hirshfeld surface analysis helps in understanding the molecular shape in the crystalline environment and also in quantifying various intermolecular interactions observed in the crystal structure. Hirshfeld surface analysis was carried out and the finger print plots, that are a graphical representation of intermolecular interactions were also plotted. Figure 7 (a) shows the d_norm mapped Hirshfeld surface where the red colored patches represent the high interaction regions that are associated with intermolecular hydrogen bonds. It was observed that the H…H contacts arethe major contributors to the Hirshfeld surface with a contribution of 42.9% of the total intermolecular interactions. C…H followed by O…H interactions were observed to contribute 32.7% and 20.1% of the total intermolecular interactions indicating their significant role in crystal structure stability. Figure-7 shows the fingerprint plots generated for different intermolecular interactions along with their contributions.

Figure 7: dnorm mapped Hirshfeld surface and Finger print plots. Click here to View figure

Along with the quantification of percentage of contribution from various intermolecular interactions to the crystal structure, interaction energies between different molecular pairs were also calculated. The Figure 8 shows selected, highly contributing molecular pairswith very high interaction energies.The strongest intermolecular interactionwas observed to be with themolecule present at symmetry position (x, y, z) with a mean distance of 5.63 Å and has a total interaction energy -37.5 kJ/mol. The next highest interaction energy was observed with the molecular pairat symmetry position (-x, -y, -z) with distance of 6.17 Å and total interaction energy of -37.0 kJ/mol. These two molecules are described in red and blue colors respectively in Figure 8. The two molecules described in yellow and purple colors with a distance of 10.73 Å and 7.92 Å have total interaction energies of -25.7 kJ/moland -24.7 kJ/mol respectively. The total interaction energyhas contributions from various energy factors such as electronic, polarization, dispersive and repulsive energies.Individual energy component and the total interaction energy are listed in Table 4. The energy frameworks consist of tubular representation along with the crystal packing with diameter of the tubes being proportional to the intermolecular interaction energy along that direction. Hence the energy frameworks enable us to understand the strength of the crystalline material along specific directions. Energy frameworks of the molecular packing are displayed in Figure 9.

Figure 8: Major molecular pairs of high strength intermolecular interactions of the title compound. Click here to View figure

Table 4: Interaction energy and lattice energy of the crystal packing.

Color code	Symmetry position	All energies are in kJ/mol
		Coulomb	Polarization	Dispersion	Repulsive	Total
1	x, y, z	-7.0	0.0	-54.4	28.1	-37.5
2	-x, -y, -z	-7.9	0.0	-48.6	22.1	-37.0
3	-x, y+1/2, -z+1/2	-25.5	0.0	-30.2	44.6	-25.7
4	-x, -y, -z	-20.3	0.0	-25.1	30.1	-24.7
Total*		-92.1	-32.6	-251.1	179.3	-229.3

* The total energy corresponds to the total interaction energy of all molecular pairs within the sphere of radius 20 Å and hence it does not match with the actual sum of the above four rows.

Figure 9: Energy frameworks describing major interactions in the molecular structure: Red-Coulomb energy; Green-dispersive energy; Blue-total energy. Click here to View figure

DFT calculations

Density functional theory makes use of electron density function to realize the wave functions of electrons and hence to quantum mechanically evaluate various physical and chemical properties of the molecule. Hence it is one of highly trusted method to theoretically investigate the structure, and allied properties of organic molecules. Gas phase optimization of coordinates was performed using DFT calculations by employing B3LYP functionals combined with 6-311+G(d,p) basis set. The optimized structure corresponding to the lowest energy configuration and shows high correlation with the structure obtained using X-ray diffraction studies as confirmed by high correlation coefficients. Selected structural parameters from DFT calculations are compared with XRD studies in Table 2. The molecular orbitals represent the molecular electronic wave functions that can be used to obtain several important properties like chemical reactivity, electronegativity and many more.The frontier molecular orbitals are the ones which dominantly control these properties.The energy gap between such frontier molecular orbitals was determined to be 3.9026 eV using DFT calculations. The global and local reactive parameters obtained from these molecular orbitals are enlisted in Table 5. Molecular electrostatic potential map was plotted to recognize the possible reactive locations of the title compound that indicates high electronegative regions near the =O and -OH moieties and high electropositive region around the -NH₂ moiety as described by the red and blue colors respectively. The HOMO-LUMO and the molecular electrostatic potential map are provided in Figure 10. Further, the electronic transitions among various molecular orbitals were evaluated with TDDFT calculations. Simulated optical absorption spectrum is provided along with the experimental spectrum in Figure-4. Transition between the frontier molecular orbitals was observed to be weak as indicated by low oscillator strength. However, the highest absorption was observed from HOMO-1 orbital to LUMO+1 at 305.58 nm with an oscillator strength of 0.2217.

Figure 10: HOMO-LUMO and MEP of the title molecule. Click here to View figure

Table 5: HOMO-LUMO energy values and associated properties obtained from DFT calculations

HOMO energy	-5.4694 eV
LUMO energy	-1.5668 eV
ΔE	3.9026 eV
Electronegativity	3.5181 eV
Chemical Potential	-3.5181 eV
Global hardness	1.9513 eV
Global softness	0.2562 eV-1
Electrophilicity	3.1710 eV

 

Conclusion

A novel coumarin derivative was synthesized through the reaction between substituted acetyl coumarin and 4-aminobenzylamine. The compound was characterized using NMR and FTIR spectroscopic techniques. The UV-visible spectroscopy revealed that the compound exhibits no absorption in visible range buta broad absorbance peak that ranging from 280 nm to 300 nm of UV region. The absorption was found to be associated with electronic transitions from HOMO-1 to LUMO+1.Through XRD studies, the compound was found to crystallize in monoclinic crystal system. Diverse intermolecular interactions including N24—H24B…O1and C17—H17A…O10 hydrogen bonds; C7—H7B…Cg(3) and Cg…Cg interactions were observed to enhance the crystal structure stability. These intermolecular hydrogen bonds have resulted in the formation of  type of supramolecula r architecture and an infinite chain down the b-axis. The studies on Hirshfeld surface showed that the H…H (42.9%), C…H (32.7%) and O…H (20.1%) interactions contribute for more than 95% of total interaction.The interaction energy and lattice energy calculations showed that the compound is highly stable. Further,the quantum chemical computations carried out using density functional theory confirmed that the molecular structure determined corresponds to the minimum energy configuration. Geometrical parameters calculated using DFT calculations displayed highcorrelation with the experimental values indicating that the XRD structure. Highly reactive regions were predicted to be present near -OH and -NH₂ groups from molecular electrostatic potential map.  The energy framework analysis showed that strongest intermolecular interaction was observed down the b-axis of the crystal.

Conflicts of Interest

All the authors mention that there no conflict of interest of any kind

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