Spectroscopic properties (FT-IR, NMR and UV) and DFT studies of amodiaquine

Abstract

Amodiaquine (AQ) was synthesized by a condensation reaction and characterized by experimental FT-IR, ¹H and ¹³C nuclear magnetic resonance (NMR) and UV spectroscopies. In the present work, Density Functional Theory (DFT) calculations.

The structural and spectroscopic (FT-IR, ¹H and ¹³C NMR and UV) data of amodiaquine molecule in ground state have been investigated by using Density Functional Theory (DFT). The calculations have been performed at the using B3LYP method with 6–311++G(d,p) and 6–311++G(2d, p) basis sets theory level were performed, first, to confirm its structure, then to explain its reactive nature through its molecular properties such as natural charges, local and global reactivity descriptors or natural bond orbital (NBO). Afterwards, the calculated properties were compared with experimental results. The ¹H and ¹³C NMR chemical shifts were calculated by using the gauge-independent atomic orbital (GIAO) method, while the electronic UV–Vis spectrum is predicted using the time-dependent density functional theory (TD-DFT). Globally, the computerized results showed good agreement close similarity with the experimental values. The molecular properties such as natural charges, local and global reactivity descriptors, molecular electrostatic potential (MEP), natural bond orbital (NBO) of title molecule were calculated insights into the stability, reactivity and reactive sites on the molecule.

The calculated energy band gap (E_LUMO-E_HOMO) value of AQ was found to be 4.09 eV suggesting that it could be considered as a hard molecule with high stability, supported by global reactivity descriptors. Molecular electrostatic potential (MEP) analysis revealed heteroatoms (oxygen and nitrogen) as the most putative nucleophilic sites when hydrogen atoms to which they are linked appear as electrophilic sites. The potential use of amodiaquine as non-linear optical (NLO) material and its thermodynamic indicators have also been assessed.

1. Introduction

Quinolines are considered as one of the most attractive and versatile class of organic compounds because of their fascinating pharmacological activities such as antibacterial [1], anticancer [2], antitubercularosis [3], antiviral [4], antileishmanial [5,6], anti-inflammatory [7], antimalarial [8] among others. Amodiaquine (AQ), 4-[(7-chloro-4-quinolinyl)amino]-2-[(diethylamino)methyl] phenol (see Fig. 1 with atom numbering), a Mannich base quinoline is synthesized for the first first time in 1940(s) by Burkhalter and co-workers [9]. It is a 4-aminoquinoline similar to chloroquine® in structure and activity, and it has been widely used in the past to treat and prevent malaria. Because of serious toxicity associated with use as prophylaxis, it was withdrawn by the World Health Organisation (WHO) from the list of drugs involved in the treatment of malaria [10,11], and then re-introduced in 21st century as combination with other antimalarial drugs like artesunate® [[12], [13], [14]] and pyrimethamine-sulfadoxine® [[15], [16], [17]], especially in Africa. Many experimental and theoretical studies, have been carried out to characterize this organic compound, including X-Ray powder diffraction (XRD) [18,19] nuclear magnetic resonance (NMR) [20], Fourier transformed infrared spectroscopy (FT-IR) and UV spectrophotometry for analytical techniques [[21], [22], [23]]. Because of their reasonable accuracy, computational efficiency and broad applicability to different molecular systems, DFT calculations provide a better description of molecular properties [24,25].Literature review reveals that very few studies using DFT calculations have been performed. The molecular geometry and natural charge distribution of AQ have been reported at the B3LYP/6-31G(d,p) level of theory by A. Semeniuk et al. [18].M. Hagar exposed DFT calculations and molecular docking of AQ as with regard to COVID 19 [26].Arguelho et al. worked on electrochemical and theoretical evaluation of the interaction between DNA and AQ [27].Theoretical study of the adsorption process of AQ into acrylamide-base hydrogel model using DFT methods was presented by Cortes et al. [28].To the best of our knowledge, spectroscopic, optical and thermodynamic properties of AQ have not been previously studied. To highlightening the characteristics responsible for the biological activity it is crucial to give a more complete description of molecular motion, vibrational, electronic and thermodynamic properties at the quantum scale because these properties are very useful in pharmacology and drug design [29,30]. The main purpose of this research work is to study IR, UV and NMR of AQ molecule using DFT calculations at B3LYP/6–311++G(d,p) and sometimes at B3LYP/6–311++G(2d,p) levels of theory. Furthermore, the natural bond orbital (NBO) analysis, natural charges analysis, molecular electrostatic potential (MEP), local and global reactivity descriptors, Non-Linear optical (NLO), and thermodynamic properties were also provided.

Fig. 1.

Optimized geometry of AQ at the B3LYP/6–311++G(d,p) level of the theory.

2. Materials and methods

2.1. Experimental details

The pure sample of AQ was obtained from International Chemical Reference Substance (ICRS) Company (in Sweden). The infrared spectrum of title compound were was recorded in the region 4000-400 cm⁻¹ using the spectrophotometer with KBr pellet technique (solid phase). Absorption spectra were determined on PerkinElmer UV–Vis spectrometer.The sample was dissolved in the water deuteride (D₂O) solvent. The¹H and ¹³C NMR spectra were recorded on a Bruker Advance (600 MHz for ¹H and 125 MHz ¹³C) NMR spectrometer using tetramethylsilane (TMS) as the internal standard.

2.2. Computational details

The GaussView program 5.0 [31] was utilized used to build the initial structure of AQ molecule. There After which molecular geometry optimizations were carried out in gas phase with the DFT method using the Gaussian 16 program [32]. Results were analyzed with GaussView program 5.0 [31] and GaussSum program [33]. To perform the assignments, potential energy distribution (PED) is calculated using VEDA program [34]. The optimal geometries were verified on minima conditions of frequencies amongst which no imaginary values was were observed. All our calculations were performed using the DFT functional, B3LYP (Becke's three parameter Lee-Yang-Parr) and the 6–311++G(d,p)basis set [29,30].The DFT method tends to overestimate the fundamental modes; therefore scalling factor (0.967 [35,36]) has to be used for to obtaining a considerably better agreement with experimental data. The ultraviolet visible spectrum was predicted in gas phase and in aqueous solution by using time-dependant DFT (TD-DFT) calculations. NMR chemical shifts were calculated with Gauge including atomic orbital (GIAO) method [37,38], using B3LYP/6–311++G(2d,p) level of theory. These spectrumsa were compared with the experimental ones. Furthermore several properties like frontier molecular orbitals (FMOs), energy gap, reactivity descriptors, NBO, natural charges, MEP, NLO and thermodynamic properties were also theoretically investigated.

3. Results and discussion

3.1. Molecular geometry

The molecular structure of AQ was fully optimized in gas phase at B3LYP/6–311++G(d, p) level of the theory, as illustrated in Fig. 1. The results of the selected optimized structure parameters (bond lengths and bond angles) were compared with their corresponding experimental values [18] in Table 1. The C–N bond lengths were calculated from 1.317 Å to 1.467 Å in the same basis set. The three bond lengths C29–N17, C41–N17 and C26–N18 disclose higher values, at 1.466, 1.467 and 1.421 Å, respectively. The bonds with N17 are the highest Here, C41–N17 is the highest among the values of all C–N bonds, due to sp3 hybridation of the atoms. The experimental bond angle In bond angles values, the angle C2–N18–C26 is 125.9°, the highest value slightly higher than the ∼120° value corresponding to angles with an sp² central atom; the free rotation around the N18–C26 bond, hence σ-properties, could justify that 125.9°value. The correlation coefficients (R²) between experimental and theoretical values were 0.956 for bond lengths and 0.930 for bond angles. There are only minor deviations between the theoretical and experimental geometrical parameters. Such deviations can be ascribed to the differences in the molecular environment [39]. The experimental X-ray diffraction analysis were carried out in the crystalline phase whereas the theoretical calculation was carried out in the gas phase.

Table 1.

Selected theoretical values of geometrical parameters of AQ.

Geometric parameters	Experimental valuesa	B3LYP/6–311++G (d, p)
Bond length (Å)
C2–N18	1.369(3)	1.381
C4–N16	1.369(3)	1.363
C5–N16	1.320(3)	1.317
C9–C11	1.359 (4)	1.371
C11–C12	1.397(4)	1.410
C29–N17	1.473(4)	1.466
C41–N17	1.485(4)	1.467
C26–N18	1.418(3)	1.421
C20–C22	1.377(4)	1.393
C22–C23	1.395(4)	1.406
Rb	/	0.956
Bond angles (°)
C9–C11–C12	121.7(2)	121.6
C4–N16–C5	116.0 (2)	116.5
C29–N17–C41	112.1(3)	114.1
C2–N18–C26	125.9(2)	126.1
C2–N18–H19	118(2)	116.1
C26–N18–H19	116(2)	115.2
C20–C22–C23	120.2(2)	120.3
R2	/	0.930

For numbering of atoms refer to Fig. 1.

^aSee reference [18].

^bR² represents the correlation coefficient between experimental and theoretical data.

3.2. Vibrational assignments

Molecular structure of AQ, consisting of 47 atoms showing 135 vibrational modes, belongs to C₁ symmetry point group. The goal of the vibrational analysis is to find vibrational modes connected with specific molecular structure of calculated compound. The experimental and calculated vibrational frequencies of the title molecule with their tentative assignments are presented in Table 2. The experimental FT-IR spectrum was recorded in a solid state using reflectance mode. A comparison of experimental spectrums of AQ in solid phase with the corresponding prediction in gas phase by using B3LYP/6–311++G(d,p) method can be seen in Fig. 2. From results we observed that the calculated wavenumbers are higher than the corresponding experimental values due to: 1-difference in physical states; 2-discard of anharmonicity present in real system.

Table 2.

Experimental FT-IR and calculated vibrational frequencies in cm⁻¹ for AQ.

Exp. FT-IR (cm−1)	B3LYP/6–311++G(d.p)			Vibrational assignments
	Unscaled	Scaled	aIIR
3406 m	3838	3711	87,14	(O–H)
3348 m	3633	3513	22,80	(N–H)
3170 m	3213	3107	0,57	ν(C–H) R1
	3209	3103	5,57	ν(C–H) R1
	3206	3100	2,74	ν(C–H) R1
	3176	3071	5,90	ν(C–H) R2
	3175	3070	5,99	ν(C–H) R2
	3171	3066	8,92	ν(C–H) R1
	3150	3046	21,07	ν(C–H) R2
3000	3135	3032	26,15	ν(C–H) R1
	3100	2998	50,19	νasCH3 (C35)
	3097	2995	34,81	νasCH3 (C44)
	3092	2990	56,35	νasCH3 (C35)
	3087	2985	29,21	νsCH3 (C44)
	3071	2970	12,53	(C29–H30)
	3067	2966	7,53	νasCH2 (C41)
	3047	2946	7,64	ν(C–H) D
	3042	2942	29,47	νsCH2 (C41)
2937w	3030	2930	23,86	νsCH3 (C35)
	3028	2928	23,91	νsCH3 (C44)
	2936	2839	72,23	ν(C–H) D
	2905	2809	85,92	ν(C–H) D
1586s	1652	1597	14,67	ν(CC) R2
	1643	1589	102,03	ν(CC) R1
	1635	1581	5,23	ν(CC) R2
	1621	1568	51,93	ν(CC) R1
	1600	1547	327,49	ν(CC) R1
1508w	1555	1504	265,59	β(HNC) (N18)
	1536	1485	134,36	β(HCC) R2
	1520	1470	0,95	βCH2 (C32)
	1509	1459	17,88	βCH2 (C32)
	1507	1457	2,56	βCH2 (C32)
	1504	1454	2,95	δasCH3 (C44)
	1502	1452	2,54	βCH3 (C44)
	1498	1449	4,73	βCH3 (C35)
	1487	1438	1,76	βCH2 (C41)
	1484	1435	3,21	βCH2 (C29)
	1474	1425	19,30	β(HCN) R1
1445s	1463	1415	253,13	ν(CC) R2
1364w	1429	1382	9,39	τ(HCNC) D
	1405	1359	7,72	wCH3 (C35)
	1404	1358	27,44	wCH3 (C44)
	1400	1354	100,23	(N–C) R1
	1389	1343	43,04	twCH2 (C41)
	1380	1334	6,86	wCH2 (C41)
	1371	1326	38,39	ν(CC) R1
	1356	1311	16,90	β(HOC)
	1353	1308	138,80	τ(HCCC) (C29)
	1349	1304	38,99	twCH2 (C41)
	1337	1293	31,47	twCH2 (C32)
	1317	1274	33,34	twCH2 (C32)
1209 m	1289	1246	14,78	ν(OC)
	1281	1239	50,44	τ(HCCC) (C29)
	1266	1224	34,17	β(HCC) R1
	1261	1219	2,46	β(HCC) R1
	1225	1185	13,82	τ(HCCN) D
	1221	1181	15,02	ν(NC) R1
1163w	1202	1162	87,33	β(HOC)
	1194	1155	20,33	twCH2 (C29)
	1187	1148	17,64	β(HCC) R1
	1177	1138	8,30	β(HCC) R2
	1142	1104	9,78	τ(HCNC) D
	1130	1093	1,21	β(HCC) R1
1055w	1122	1085	107,20	β(HCC) R2
	1092	1056	6,85	τ(HCCN) D
	1089	1053	37,05	ν(CC) R1
1047w	1070	1035	33,35	ν(NC) D
	1066	1031	28,71	ν(CC) R1
	1053	1018	17,44	ν(CC) D
	1016	982	5,85	ν(CC) D, β(HCC) (C29)
	983	951	2,02	τ(HCNC) R2
	971	939	15,40	ν(CC) D
	964	932	4,34	ν(CC) R2
	955	923	0,32	τ(HCCC) R1
	935	904	4,88	τ(HCCN) R2
	928	897	11,98	τ(HCCN) R1
	911	881	35,81	β(CCC) R1
	907	877	22,49	ν(CC) D
	906	876	12,26	τ(HCCC) R1
839w	864	835	79,39	β(NCC) R1
	844	816	18,54	τ(HCCC) R1
	836	808	23,91	τ(HCCC) R1
	823	796	7,78	τ(HCCC) R1
	819	792	8,82	τ(HCCN) D
755w	797	771	6,69	β(CCC) R2
	788	762	11,26	τ(HCCC) R1
	781	755	20,00	τ(HCCN) D
	778	752	13,54	β(CCC) R1
	771	746	7,53	τ(CCNC) R2
	765	740	1,49	β(CCC) R2
	738	714	1,11	τ(CCCC) R2
650w	677	655	6,82	ν(CC) R2, β(CCC) R2
	653	631	7,92	τ(CCCC) R1
	632	611	2,82	τ(CCCN) (N18)
	605	585	5,62	β(CNC) R2
	589	570	5,90	τo(NCCC) (N18)
542vw	564	545	11,60	β(CCC) R2
	530	513	16,83	β(CCC) R1, β(NCC) (N18)
	514	497	4,99	τo(CCCC) R2
	512	495	7,14	τo(OCCC) R1
	487	471	7,13	β(OCC)
	482	466	1,46	β(CCN) D
	461	446	7,57	β(CCC) R1
	449	434	2,57	β(CNC) D
	437	423	18,07	τ(CCCC) R1
	388	375	10,16	τ(CCCC) R2
	378	366	6,95	ν(ClC) R2
	366	354	11,16	β(CCN) D
	355	343	22,42	τ(CCCC) R2
	338	327	110,35	τ(HNCC) (N18)
	320	309	54,41	τ(HOCC)
	316	306	24,15	β(CCC) (C29)
	288	278	0,54	τ(HCCN) D
	268	259	1,41	τo(ClCCC) R2
	247	239	2,56	β(ClCC) R2
	238	230	0,41	β(ClCC) R2
	233	225	0,30	τ(CCCN) (N18)
	226	219	2,36	β(CNC) D
	202	195	0,82	τo(CCCN) D
	162	157	0,21	τ(CCCC) R1
	137	132	0,51	β(CCN) (N18)
	128	124	0,35	τ(CCNC) D
	120	116	2,01	τ(CNCC) R1
	95	92	0,97	τ(CCNC) D
	81	78	0,48	τ(CCCC) R1
	70	68	0,37	τ(CCNC) D
	50	48	0,16	β(CNC) (N18)
	40	39	0,24	τ(CNCC) D
	31	30	0,19	τ(CNCC) D
	19	18	0,59	τ(CNCC) (N18)
	14	14	0,17	τ(CCNC) (N18)

vs, very strong; s, strong; m, medium; w, weak; vw, very weak; ^aI_IR: IR intensities (Km/Mol), ν: stretching; β: deformation in the plane; δ: deformation; w: wagging; tw: twisting; τ: torsion; R₁: quinolone ring; R₂: phenyl ring; D: diethylamino)methyl.

Fig. 2.

Experimental and simulated FT-IR spectra of AQ.

3.2.1. O–H vibration

O–H vibrations of phenols generally appear at roughly 3500 cm⁻¹ [40] with broad band. In the present study the stretching vibration of hydroxyl group of AQ was observed in IR spectrum at 3406 cm⁻¹and predicted scaled value is 3711 cm⁻¹.The in-plane bending vibration of O–H is observed at 1163 cm⁻¹and the calculated value is 1162 1185 cm⁻¹. They are well coincided perfectly well with the PED values.

3.2.2. N–H vibration

N–H vibrations are expected in the range 3500-3300 cm⁻¹ [41,42]. In the present case DFT calculations provided value at 3513 cm⁻¹ while the IR peak is experimentally observed at 3348 cm⁻¹. The N–H in-plane bending vibrations usually occur in the region 1650-1580 cm⁻¹ [43]. The N–H in-plane bending vibration is observed at 1508 1445 cm⁻¹ and the calculated value is 1504 1470 cm⁻¹.

3.2.3. C–H vibrations

The aromatic structure shows the presence of = C–H stretching vibrations around 3100-3000 cm⁻¹ [41,44]. In this work, the = C–H stretching vibrations of the AQ ring appear in the IR spectrum at 3000 cm⁻¹ while simulated ones at 3107, 3103, 3100, 3071, 3066, 3046 and 3032 cm⁻¹. Because of the confusion (sometimes strongly) with various C C ring vibrations, many bands in the 1600-1000 cm⁻¹ are involved in-plane C-Η bending vibrations [45,46]. The C–H in plane bending vibrations of phenyl rings were observed at ∼1055 cm⁻¹ (FTIR spectrum), while the calculated values appeared at 1485, 1224, 1219, 1148, 1138 and 1085 cm⁻¹.

3.2.4. CH₂ and CH₃ vibrations

The asymmetric methylene stretching vibrations are typically observed in the range of 3000-2900 cm–1 while the symmetric ones are observed at the interval 2900-2800 cm–1 [47,48]. There were five fundamental vibrations belonging to CH₂ modes in this molecule (asymmetric stretching, symmetric stretching, in-plane bending, twisting and wagging vibrations). These vibrations were predicted at 2966 cm–1 (asym.), 2942 cm–1 (sym.), 1470, 1459, 1457, 1438 and 1435 cm–1 (in plane bending), 1304, 1293, 1274 and 1155 (twist.) and 1380 cm–1 (wag.).

The vibrations of the CH₃ group, are expected in the range of 2900 3050-2900 cm⁻¹ [49,50]. The calculated asymmetric stretching modes of the methyl group were found to be: 2998, 2995, and 2990 cm⁻¹ while, the symmetric modes were at 2985, 2930 and 2928 cm⁻¹. Experimental bands were observed at 2937 cm⁻¹ in the IR spectrum. The CH₃ symmetric stretching vibrations were found after calculations at 2930 cm⁻¹at a value very closed to experimental one (2930 cm⁻¹). The predicted wavenumbers at 1454, 1452 and 1449 cm^⎯1 were assigned as CH₃ bending vibrations while wagging wCH₃ of AQ were identified at 1359 and 1358 cm^⎯1.

3.2.5. C C and C N vibrations

Generally C C stretching vibrations in aromatic compounds display bands between 1430 and 1650 and 1430 cm⁻¹ [51,52]. In this work, experimental C C stretching bands were observed at 1615, 1588, 1543, 1550 and 1445 1395 cm⁻¹ and they were computerized to be 1597, 1589, 1581, 1568, 1547 and 1415 cm⁻¹, respectively.

Because of the mixing of several bands, the identification of C N vibrations is a very difficult task. Silverstein assigned C N and C–N absorption in the region 1382–1266 cm⁻¹ and 1250-1020 cm⁻¹, respectively [53]. The bands observed at 1364 cm⁻¹ in FT-IR spectrum have been assigned to C N. The theoretically calculated latter value of C N is observed at 1354 1382 cm⁻¹ while C–N stretching were observed at 1047 cm⁻¹ in FT-IR and predicted at 1035 cm⁻¹ by B3LYP/6–311++G(d,p) method. The CCN (quinoline ring) in plane bending is observed at 839 cm⁻¹ in FT-IR and theoretically computed scaled wave number at 835 cm⁻¹.

3.2.6. C–O vibrations

The C–O stretching vibrations of phenols were observed between 1300 and 1200 cm⁻¹ in the literature [54,55]. The experimental C₂₂–O₃₉ stretching vibration was observed at 1209 cm⁻¹ in IR spectra of AQ. Here, the C₂₂–O₃₉ (H) stretching mode given at 1209 cm⁻¹ and the computed mode was found at 1246 cm⁻¹.

3.3. ¹H and ¹³C NMR data

The NMR is particularly useful in determining the structure of organic and inorganic compound in solution by revealing hydrogen and carbon skeleton. In order to provide a definite assignment and analysis of ¹H and ¹³C NMR spectra, the Gauge Including Atomic Orbital (GIAO) ¹H and ¹³C chemical shifts calculations of AQ were performed. The IEFPCM and universal solvation methods were employed in the optimization of AQ in solution because the solvent effects are considered [56,57]. The obtained data have been compared with experimental ones (see Table 3 and Table 4). Fig. 3, Fig. 4 depicts the experimental ¹H and ¹³C NMR spectra of AQ, respectively. The correlation graph between the experimental and calculated chemical shifts for ¹H and ¹³C NMR are shown in Fig. 5.

Table 3.

The experimental and theoretical ¹H NMR chemical shifts for AQ.

Atoms	Experimental	B3LYP/6–311++(2d,p)
H10	8.5	8.76
H13	/	8.28
H6	/	8.18
H14	7.9	7.79
H25	7.6	7.48
H28	7.5	7.23
H7	7.2	7.02
H21	/	7.00
H19	6.8	6.65
H40	4.7	4.59
H30	/	3.77
H31	3.4	3.71
H34	/	3.13
H43	/	2.79
H33	/	2.68
H42	/	2.62
H37	1.5	1.32
H47	/	1.11
H38	/	1.07
H45	/	0.91
H36	/	0.90
H46	/	0.18

Table 4.

The experimental and theoretical¹³C NMR chemical shifts for AQ.

Atoms	Experimental	B3LYP/6–311++(2d,p)
C22	/	160.3
C5	/	158.0
C4	/	156.7
C2	/	155.0
C11	148.0	148.4
C26	136.0	136.4
C9	134.0	134.2
C23	132.0	133.0
C24	132.0	132.9
C12	/	129.9
C27	/	128.8
C8	/	126.6
C3	123.0	123.5
C20	119.0	119.7
C1	105	103.6
C29	/	55.3
C32	45.0	50.3
C41	40.0	40.4
C35	/	14.3
C44	/	1.1

Fig. 3.

¹H NMR spectra of AQ.

Fig. 4.

¹³C NMR spectra of AQ.

Fig. 5.

Correlation graph between experimental and calculated ¹H NMR (a) and ¹³C NMR (b) chemical shift using B3LYP/6–311++(2d,p) level.

Chemical shifts of O–H (H19) and N–H (H40) group was observed at 6.8 ppm and 4.7 ppm, respectively, while they were predicted at 6.65 ppm and 4.59 ppm using B3LYP/6–311++ (2d, p). As seen at Fig. 4, there are correlations between experimental and calculated ¹H NMR results and the corresponding R² values were found as 0.992.

The ¹³C NMR spectra of AQ showed the chemical shifts of C–OH (C22) are predicted at 160.3 ppm at B3LYP/6–311++ (2d, p). The correlation values (R² = 0.992) for ¹H NMR and (R² = 0.999) for ¹³C NMR show that there is a perfect agreement similarity between the experimental and theoretical chemical shifts.

3.4. Frontier molecular orbitals (FMO) (HOMO-LUMO) and UV–Vis analysis

The energies of HOMO (E_H) and LUMO (E_L) characterize the ability of a molecule to donate and accept electrons, respectively [[58], [59], [60]]. These orbitals are named as frontier molecular orbitals (FMOs).The difference between E_H and E_L is called energy gap (Δ_EG). The energy gap of HOMO–LUMO explains the eventual charge transfer interaction [61] within the molecule and the stability of a molecule, influencing its the biological activity of the molecule. From FMOs calculations, the kinetic stability, UV spectra and chemical reactivity and chemical hardness-softness were predicted. According to the HSAB (hard and soft acids and bases) principle, a molecule with a high HOMO-LUMO energy gap is less reactive and can be considered as a hard molecule [[62], [63], [64]]. The HOMO, LUMO, HOMO-1 and LUMO+1 orbitals of AQ were calculated with Gaussian 16 program using B3LYP/6–311++G(d, p).These energies are illustrated in Fig. 5 and their values were summarized in Table 4. The value of the energy separation between the HOMO and LUMO is 4.09 eV. This result probably suggested that it is a hard molecule.

In addition to the frontier orbitals, other orbitals are involved in the development of the UV–Vis spectrum. This is the case for the orbital preceding the HOMO, whose energy will be noted as E_H-1, and the orbital following the LUMO, noted as E_L+1, whose values have been obtained in Table 4.

3.5. UV–Vis spectra analysis

Electronic transitions are usually classified according to the orbitals engaged or to specific parts of the molecule involved. Common types of electronic transitions in organic compounds are n→σ*, n→π* and especially (donor)→π*(acceptor) [63]. In order to understand the electronic transitions of AQ, theoretical calculations ofn electronic absorption spectrum were performed in the ground state and in solution (water) using TD-DFT calculations [48,65] with the B3LYP/6–311++G(d, p) level of theory. The computed properties such as absorption wavelengths (λ), excitation energies (E) and oscillator strengths (f) are shown in Table 5. The theoretical electronic absorption wavelengths values for title molecule are 341.3, 333.9 and 302.0 nm in gas phase and 354.7, 341.4 and 304.1 in water. The experimental value is found to be 342.9 nm. The predicted wavelengths are in good agreement with experiment. This electronic absorption corresponds to the transition from HOMO (H) to LUMO (L) in water and HOMO-1 to LUMO in gas phase; (see transitions in Table 5). It seems most likely that solvation (possibly referring to hydrogen bonds formation) tends to decrease energy gap within the H-1 → L transition, hence the bathochromic effect noticeable from gas phase to water medium. The observed UV–Vis and calculated spectra of AQ molecule are shown in Fig. 6.

Table 5.

HOMO-LUMO and dipole moment of AQ by B3LYP/6–311++G(d, p) method.

Property	Symbol and formular	B3LYP/6–311++G (d, p)
Electronic energy (a.u)	/	−1475.35
HOMO energy (eV)	EH	−5.81
LUMO energy (eV)	EL	−1.72
ΔEHOMO-LUMOgap (eV)	EG = EL-EH	4.09
HOMO-1 energy (eV)	EH-1	−5.86
LUMO+1 energy (eV)	EL+1	−1.01
ΔEHOMO-1-LUMO+1gap (eV)	EG = EL+1-EH-1	4.86
Dipole moment (Debye)	D	5.96

Fig. 6.

Atomic orbital compositions of AQ.

3.6. Reactivity descriptors

3.6.1. Global reactivity descriptors

Global reactivity descriptors such as ionization potential (IP), electron affinity (EA), chemical hardness (ƞ), softness (S), chemical potential (μ), electrophilicity index (ω) and electronegativity (χ) were calculated using HOMO and LUMO results. All these properties which are defined in Table 6 provide additional informations on the chemical stability of the molecule.

Table 6.

Experimental and calculated electronic bands of AQ.

Experimental		TD-B3LYP/6–311++G(d,p)
Water		GAS				Water
ʎ (nm)	Abs.	ʎ (nm)	E (eV)	f (a.u)	Major/Minor contribs	ʎ (nm)	E (eV)	f (a.u)	Major/Minor contribs
341.9	0.50	341.3	3,63	0.227	H-1- > LUMO (61 %), HOMO- > LUMO (36 %)	354.7	3,50	0.279	H-1- > LUMO (46 %), HOMO- > LUMO (53 %)
		333.9	3,71	0.012	H-1- > LUMO (36 %), HOMO- > LUMO (63 %)	341.4	3,63	0.006	H-1- > LUMO (53 %), HOMO- > LUMO (47 %)
		302.0	4,11	0.012	HOMO- > L+1 (76 %), HOMO- > L+2 (16 %) H-1- > L+2 (5 %)	304.1	4,08	0.008	H-3- > LUMO (11 %), H-1- > L+1 (47 %), HOMO- > L+1 (34 %) H-2- > LUMO (5 %)

Absorption wavelength λ (nm), Excitation energies E (eV), Oscillator strengths (f), HOMO (H) and LUMO (L)

For the title compound, the calculated values of ionization potential, electron affinity, hardness, softness, chemical potential, electrophilicity and electronegativity were 5.81, 1.72, 2.04, 362.46, −3.77, 3.47 and 3.77 eV respectively. Note that the high ionization energy and negative chemical potential (μ) indicate stability of molecule. The electrophilicity (ω) of the AQ molecule is greater than 1.5 eV [66], indicating that it could be classified as strong electrophiles, probably consequent to acidic properties of hydrogen atoms linked to heteroatoms (nitrogen and oxygen) whose free doublets take part to delocalization (like someone of chlorine) with π-electrons of aromatic rings.

3.6.2. Local reactivity descriptors

Some important indicators of reactivity are the Fukui functions (FFs) which provide information on the local site reactivity within the molecule and system, aiming to understand the nature of chemical reactions (nucleophilic and electrophilic behaviours of the molecule). These values correspond to the qualitative descriptors of reactivity of different atoms in the molecule. A study by Ayers and Parr [67] has shown that a larger FF suggests an attack by soft reagents and a smaller FF means an attack by hard reagents. From Mulliken atomic charges of cationic and anionic states, local Fukui functions (f⁺, f⁻), and local softness values (s⁺, s⁻) were calculated using the following equations:

$$f^{+}=\left[q\left(N+1\right)-q\left(N\right)\right]\text{for}\text{nucleophilic}\text{attack}$$

$$f^{-}=\left[q\left(N\right)-q\left(N-1\right)\right]\text{for}\text{electrophilic}\text{attack}$$

$$f^0=1/2\left[q\left(N+1\right)+q\left(N-1\right)\right]\text{for}\text{radical}\text{attack}\text{.}$$

Local softness values are calculated using.

$S^{+}=s{f}^{+}$, $S^{-}=s{f}^{-}$ where + and − signs show nucleophilic and electrophilic attack, respectively with S = 13.32 a.u.

According to DFT/B3LYP/6–311++G(d, p) calculations, Fukui functions and local softness values for selected atomic sites in AQ are listed in Table 7. The relative high values of local reactivity descriptors (f⁺, s⁺) in Table 7 at Cl15, N16 and N18 indicate nucleophilic sites that these sites are prone to nucleophilic attacks whereas the relative high value of local reactivity descriptors (f⁻, s⁻) at H21, H40 and H19 indicate electrophilic sites that those sites are more prone to electrophilic attacks. In order to clarify reactivity, dual descriptor (Δf) introduced by Morell et al. [68] was also calculated by:

$$\Delta f\left(k\right)=f_k^{+}-f_k^{-}$$

Table 7.

The calculated HOMO–LUMO energy and Global reactivity descriptor values of AQ using B3LYP/6–311++G (d, p).

Property	Symbol and Formular	B3LYP/6–311++G (d, p)
Ionization potential (eV)	I = -EH	5.81
Electron affinity (eV)	EA = -EL	1.72
Chemical hardness (eV)	ɳ = (EL-EH)/2	2.04
Global Softness or Chemical reactivity (eV-1)	S = 1/ɳ	362.46
Chemical potential (eV)	μ= (EL + EH)/2	−3.77
Electrophilicity index (eV)	ω = μ2/2ɳ	3.47
Electronegativity (eV)	χ = -μ	3.77

The atomic sites with a higher nucleophilic tendency are those having positive dual descriptor value while those having negative dual descriptor value are the most electrophilic sites [69]. The nitrogen (N16, N18) and oxygen (O39) atoms have the positive dual descriptor indicating possible nucleophilic sites in the drug while hydrogen (H19, H21 and H40) and chlorine (Cl15) atoms have negative dual descriptor indicating possible electrophilic site.

3.7. Molecular electrostatic potential (MEP) analysis

In order to validate the evidence about the reactivity of title compound, MEP was calculated at the B3LYP/6–311++G(d, p) optimized geometry and is shown in Fig. 7. This figure provides a visual representation of the chemically active sites and comparative reactivity of atoms. The potential values increase from red to blue color [70]. Blue colour indicates the strongest attraction and the red colour indicates the strongest repulsion [44]. Regions of negative potential are usually associated with the lone pair of electronegative atoms. The negative electrostatic potential corresponds to an attraction of the proton by the aggregate electron density in the molecule (shades of red), while the positive electrostatic potential corresponds to the repulsion of the proton by the atomic nuclei (shades of blue) [71]. The colour code of MEP map is in the range between −0.06179e (deepest red) to 0.06179e (deepest blue) in our molecule. As can be seen from Fig. 7 the negative electrostatic potential regions (red) were localized on the oxygen (O39) and nitrogen (N16) atoms indicating possible nucleophilic sites for electrophilic attacks. However, positive potential regions (blue) were localized on hydrogen atoms (H40 and H19) around O–H, N–H groups (O39, N18), and indicating possible electrophilic sites for nucleophilic attacks as previously hypothesised. The docking study by M. Hagar et al. [26] reveals that AQ could be a better inhibitor of SARS-CoV-2 M^pro with binding affinity −7.77 kcal/mol compared to hydroxychloroquine (−6.06 kcal/mol) and remdesivir (−4.96 kcal/mol). AQ interacted with the receptor by different hydrophobic interactions besides three hydrogen bonds with amino acids Leu141, Cys145, and Gln189.

Fig. 7.

Experimental and theoretical UV-spectra of AQ.

The effective interactions of proteins with the AQ were found on the atoms (N16, N18, and O39) and this could be attributed to the presence of lone pair electrons on these atoms.

3.8. Natural charges analysis

Atomic charges determine many properties of molecular systems. The natural atomic charges of title molecule obtained by natural bond orbital (NBO) analysis are tabulated in Table 8 (atom numbering according to Fig. 1). All carbon atoms are negative, except C2, C4, C5, C22 and C26 that are bonded to electron-withdrawing nitrogen and oxygen atoms, with C2 and C26 bound to N18, C4 and C5 bound to N16 and C22 bound to O39 being the most-positively charged carbon atoms in the molecule, whereas C44 and C35 are the most-negatively charged carbon atoms. All electronegative oxygen and nitrogen atoms have a negative charge, perform as donor atoms, they should endure electrophilic reaction. The oxygen O39 atom is found to exhibit the most negative charge in the molecule due to its electron withdrawing nature. The dominance of red colour in the MEP map around this oxygen atom also confirms this hypothesis. All hydrogen atoms are positive however the most positive charges are localized on hydrogen atoms (H40 and H19) connected to heteroatoms (oxygen O39 and nitrogen N18) because they can be involved in hydrogen bonding.

Table 8.

Fukui functions (f⁺, f⁻) and local softness (s⁺, s⁻) for selected atomic sites of AQ, using Mulliken population analysis at B3LYP/6–311 G (d, p) level.

N° Atom	N	N+1	N-1	f+	f−	Δf	f0	s−	s+
Cl15	0.465654	0.549051	0.357426	0.083397	0.108228	−0.024831	0.0958125	1.44159696	1.11084804
N16	0.021326	0.100847	−0.035008	0.079521	0.056334	0.023187	0.0679275	0.75036888	1.05921972
N18	0.195469	0.254541	0.169666	0.059072	0.025803	0.033269	0.0424375	0.34369596	0.78683904
H19	0.21189	0.241657	0.081163	0.029767	0.130727	−0.10096	0.080247	1.74128364	0.39649644
H21	0.145912	0.189003	−0.288558	0.043091	0.43447	−0.391379	0.2387805	5.7871404	0.57397212
O39	−0.202845	−0.170546	−0.23336	0.032299	0.030515	0.001784	0.031407	0.4064598	0.43022268
H40	0.268432	0.288778	0.013485	0.020346	0.254947	−0.234601	0.1376465	3.39589404	0.27100872

3.9. Natural bond orbital (NBO) analysis

The natural bond orbital (NBO) calculations were performed using NBO program [72] as implemented in Gaussian 16 package at the DFT/B3LYP level under 6–311++G(d, p) basis set in order to understand second order interactions between filled Lewis-type (bond or lone pair) and vacant (anti-bond Rydberg) orbital spaces, which provide an evidence for the charge transfer interactions arising within the molecular systems. This interaction was deduced from the second-order Fock matrix [73,74], as follows:

$$E\left(2\right)=\Delta E_{ij}=q\frac{{\left(F_{ij}\right)}^2}{\left(E_j-E_i\right)}$$

Where E(2) is stabilization energy with the delocalization for each donor (i) and acceptor (j), q is the donor orbital occupancy, E_i and E_j are diagonal elements and F_ij is the off diagonal NBO Fock matrix element [75]. The larger E(2) value the more intensive is the interaction between electron donors and acceptor i.e. the more donation tendency from electron donors to electron acceptors and the greater the extent of conjugation of the whole system [40]. Delocalization of electron density between occupied Lewis type (bond or lone pair) NBO orbitals and formally unoccupied (antibond or Rydgberg) non-Lewis NBO orbital's corresponding to a stabilizing donor-acceptor interaction. Table 9 shows the most important interactions between donor and acceptor elements of title molecule in supporting information (SI). The results of the natural bond orbital analysis show that the strong stabilization energy occurs at 92845.91 kcal.mol⁻¹due to BD(1) O39–H40 to RY*(1) C24 interaction. This highest activity around the phenyl ring can induce the large biological properties of AQ. The energy contribution of BD(1) C24–H25 -˃ RY*(7) C26, BD(1) O39–H40 -˃ RY*(7) C41 and BD(1) C22–O39 -˃RY*(1) C31 are 65072.77, 59862.22 and 52218.60 kcal mol⁻¹, respectively.

Table 9.

NBO charges of AQ.

Atom	Charge	Atom	Charge	Atom	Charge	Atom	Charge	Atom	Charge
C1	−0.31742	C11	−0.04358	H21	0.2021	H31	0.16994	C41	−0.17653
C2	0.23772	C12	−0.20917	C22	0.32513	C32	−0.16437	H42	0.19451
C3	−0.10991	H13	0.23314	C23	−0.06542	H33	0.18977	H43	0.18977
C4	0.18213	H14	0.22383	C24	−0.19474	H34	0.15699	C44	−0.60113
C5	0.09398	Cl 15	0.00167	H25	0.21561	C35	−0.5822	H45	0.19497
H6	0.19659	N16	−0.48485	C26	0.12217	H36	0.20374	H46	0.20355
H7	0.22158	N17	−0.55906	C27	−0.2021	H37	0.19173	H47	0.19247
C8	−0.18579	N18	−0.6008	H28	0.20834	H38	0.20226
C9	−0.19446	H19	0.38667	C29	−0.1821	O39	−0.66802
H10	0.18292	C20	−0.26409	H30	0.21513	H40	0.46741

3.10. NLO properties

The NLO properties were performed to study the influence of the molecular structure on the polarizations and hyperpolarizations of title molecule due to their suitability for optoelectronic and photonic applications [76]. NLO analysis deals with the interaction of electromagnetic fields in various materials to produce new fields, altered in wavenumber phase or other physical properties [77,78]. The first hyperpolarizability (β), dipole moment (μ), polarizability (α) and anisotropy of polarizability (Δα) of AQ were calculated using B3LYP/6–311++G(d, p) level using Gaussian 16 program package. The x,y,z components of μ, α, and β were used to extract the values of interest using the following equations [79].

$${\beta }_x={\beta }_{xxx}+{\beta }_{xyy}+{\beta }_{xzz}{\beta }_y={\beta }_{yyy}+{\beta }_{xxy}+{\beta }_{yzz}{\beta }_z={\beta }_{zzz}+{\beta }_{xxz}+{\beta }_{yyz}$$

$$\beta =\sqrt{{\beta }_x^2+{\beta }_y^2+{\beta }_z^2}\mu =\sqrt{{\mu }_x^2+{\mu }_y^2+{\mu }_z^2}\alpha =\frac{{\alpha }_{xx}+{\alpha }_{yy}+{\alpha }_{zz}}{3}$$

$$\Delta \alpha =\frac{1}{\sqrt{2}}\sqrt{{\left({\alpha }_{xx}-{\alpha }_{yy}\right)}^2+{\left({\alpha }_{yy}-{\alpha }_{zz}\right)}^2+{\left({\alpha }_{zz}-{\alpha }_{xx}\right)}^2+6\left({\alpha }_{xy}^2+{\alpha }_{yz}^2+{\alpha }_{xz}^2\right)}$$

The NLO results are given in Table 10. The calculated values were converted into electrostatic units (esu) from atomic units (a.u.) (for α, 1a.u = 0.1482 × 10⁻²⁴ esu; for β, 1a.u = 8.6393 × 10⁻³³ esu) [79]. The calculated values of μ, α and β are 6.0 D, −23,7 × 10⁻²⁴ esu and 2577,1 × 10⁻³³ esu, respectively. The μ and β values obtained are very large (4.3 times for dipole moment, 7.5 times for hyperpolarizability) compared to that of urea (μ = 1.3732D, β = 343.272 × 10⁻³³ esu) found in the literature [49]). Urea is the reference molecule which is used in the study of the NLO properties of molecular systems. Hence our results indicate that AQ is an effective candidate for NLO application.

Table 10.

Second order perturbation theory analysis of Fock matrix in NBO basis for AQ.

Donor NBO (i)	Acceptor NBO (j)	E(2)a kcal.mol-1	E(j)-E(i)b a.u.	F(i,j)c a.u.
BD (1) C8 – C12	RY*(5) C44	10633.52	0.08	0.809
BD (1) N17 – C41	RY*(1) H30	9940.26	0.03	0.526
BD (1) C20 – C22	BD*(1) C4–N16	50613.15	0.06	1.503
	RY*(9) C24	41897.58	0.10	1.854
	RY*(4) H46	9895.59	0.29	1.531
BD (1) C22–O39	RY*(1) H31	52218.60	0.01	0.745
BD (1) C24–H25	RY*(7) C26	65072.77	0.03	1.336
	BD*(1) C4–C9	11211.72	0.10	0.957
BD (1) O39 – H40	RY*(1) C24	92845.91	0.06	2.042
	RY*(7) C41	59862.22	0.10	2.139
	RY*(4) H25	17618.20	0.34	2.193
	BD*(1) C11–C12	15939.07	0.24	1.749
	RY*(5) C41	15537.24	0.32	2.003
	BD*(1) C26–C27	14904.98	0.26	1.757
	RY*(9) C24	13286.74	0.41	2.093
	BD*(1) C4–N16	9843.83	0.37	1.696
CR (1) C41	RY*(17) C44	9604.83	0.47	1.896
CR (1) C44	RY*(17) C44	28780.08	0.43	3.142

3.11. Thermodynamic properties

Thermodynamic properties, including heat capacity (C_v), entropy (S) and enthalpy changes (ΔH) for title compound were also performed in the gas phase. The calculated properties are given in Table 11. From Tables 11 and it can be observed that these thermodynamic functions are increasing with temperature in the range 100–700K probably owing to the intensities of the molecular vibrations increasing with temperature [80,81]. The correlations between heat capacity, entropy, enthalpy changes and temperatures were fitted by quadratic formulars and the corresponding fitting factors (R²) for these thermodynamic properties are 0.9992, 1.0000 and 0.9998 respectively. The corresponding fitting equations are defined as follows and the correlation graphics are shown in Fig. 8 (see Table 12).

$$C_v=2.09229+0.34179T-1.33345\text{.}{10}^{-4}{T}^2\left(R^2=0.9992\right)$$

$$S=66.96+0.36384T-7.95821\text{.}{10}^{-5}{T}^2\left(R^2=1.0000\right)$$

$$\Delta H=-1.12985+0.02069T+1.1955\text{.}{10}^{-4}{T}^2\left(R^2=0.9998\right)$$

Table 11.

The electric dipole moment, polarizability and first order hyperpolarizability of AQ.

	a.u	esu (10−24)		a.u	esu (10−33)
αxx	−176.8	−26.2	βxxx	−197.4	−1705,6
αxy	−2.1	−0.3	βxxy	33.9	293,0
αyy	−147.8	−21.9	βxyy	−64.7	−558,8
αxz	−8.5	−1.3	βyyy	49.8	430,7
αyz	−4.9	−0.7	βxxz	−21.9	−189,3
αzz	−155.4	−23.0	βxyz	8.7	74,9
α	−160.0	−23.7	βyyz	−25.6	−220,9
Δα	31.3	4.6	βxzz	−13.1	−112,8
μx	−4.8		βyzz	7.9	67,9
μy	2.3		βzzz	−22.4	−193,3
μz	−2.7		βx	−275.2	−2377,1
μ	6.0		βy	91.6	791,6
			βz	−69.8	−603,4
			β	298.3	2577,1

Fig. 8.

Molecular electrostatic potential map of AQ.

Table 12.

Thermodynamic functions of AQ at the B3LYP/6–311++G(d,p) level.

Temperature (K)	Heat capacities Cv(cal.mol−1.k−1)	Entropies S (cal.mol−1.k−1)	ΔH (Kcal/mol)
100	36.259	102.201	2388
200	63.607	137.137	7585
300	91.375	168.968	15,529
400	117.977	199.536	26,218
500	140.914	228.847	39,397
600	159.740	256.624	54,660
700	175.094	282.747	71,626

These thermodynamic data supply helpful information for the further study of AQ (see Fig. 9). They can be used to compute other thermodynamic energies based on the relationships between thermodynamic functions and estimate directions of chemical reactions according to the second law of thermodynamics [82].

Fig. 9.

Correlation graph of thermodynamic functions for AQ.

4. Conclusion

In this study, when clarifying the characterization of AQ, structural parameters, vibrational frequencies, chemical shift values and UV spectra were calculated experimental and theoretical approaches were used to analyse structural and vibrational (FT-IR, ¹H and ¹³C NMR and UV–visible) features of the AQ molecule. The calculations were performed using DFT method at the B3LYP/6–311++(d, p) level of theory then compared with corresponding experimental values. The geometrical parameters of the title compound agree with the XRD results given in literature. On basis of calculated potential energy distribution results assignments of the fundamental vibrational frequencies have been made unambiguously using VEDA program. A very good correlation between the observed and calculated vibrational spectra reveals the advantages of higher basis sets for quantum chemical calculations. ¹H and ¹³C NMR calculations were done using GIAO methods and the results were found to be in good agreement with experimental data. The electronic properties were also simulated and compared with experimental UV–visible spectrum which exhibits mainly π→π* and n→π* absorption peaks. The calculated HOMO and LUMO energies reflected the charge transfer within the molecule. The mapped MEP surface support the electrophilic sites on positive charges of hydrogen atom of hydroxyl and amino groups while the nucleophilic sites are observed on the oxygen and nitrogen (N16) atoms. Stability of the molecule arising from hyper-conjugative interactions should lead to its bioactive's properties. Charge delocalization has been analyzed using NBO analysis. A computation of the first order hyperpolarizability indicates that the title compound might be a good candidate as a NLO material.

5. Data availability

- No data associated with this study has been deposited into a publicly available repository.

- No data was used for the research described in the article.

CRediT authorship contribution statement

Pélagie Manwal A Mekoung: Writing – review & editing, Writing – original draft, Investigation, Formal analysis, Conceptualization. Alhadji Malloum: Methodology, Data curation. Munusamy Govindarajan: Visualization, Resources. Rose Ngono Mballa: Resources, Project administration. Issofa Patouossa: Visualization, Software, Formal analysis. Auguste Abouem A Zintchem: Formal analysis. Charles P.N. Nanseu: Investigation, Formal analysis. Ibrahim N. Mbouombouo: Writing – review & editing, Supervision, Project administration, Formal analysis, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.