Theoretical and Experimental Spectroscopic Study on 2-Chloro-3-(substituted-phenylamino)-1,4-naphthoquinone Derivatives

Abstract

The 1,4-naphthoquinones are an important group of compounds intensively studied because of their wide range of biological activities. Four 2-chloro-3-(substituted-phenylamino)-1,4 naphthoquinone derivatives were synthesized, and the vibrational modes of these molecules were assigned using Raman and Fourier transform infrared spectroscopy (FTIR) techniques. In addition, X-ray studies were performed for one of these derivatives. Density functional theory (DFT) calculations were also developed for these compounds and presented. In summary, the results obtained from these studies can assess chemical changes in the structures of functionalized quinones and the discovery of candidate biologically active compounds.

Keywords: 1,4-naphthoquinones; Raman spectroscopy; FTIR; DFT

Introduction

Quinones represent a privileged class of biologically active¹-⁶ that play an important role in biological electron transfer processes (e.g., photosynthesis and respiration)⁷,⁸ and a variety of industrial applications in color chemistry such as hair dyeing, photosensitizers, and anion sensors.⁹-¹²

In the field of chemotherapy, several quinone derivatives, such as anthracyclines, are clinically important drugs used in cancer treatment.¹³ In particular, aminoquinone frameworks show different activities, acting as antitumoral, antimicrobial, antimalarial, antifungal and molluscicidal.¹⁴-¹⁸

Quinones exert their biological effects via quinone-hydroquinone redox cycling, leading to reactive oxygen species (ROS) generation, such as superoxide anion radical (O₂^•-) and hydroxyl radical (•OH).¹⁹ ROS production leads to an oxidant-antioxidant imbalance or oxidative stress and can lead to irreversible biomolecules damage such as lipids, proteins, ribonucleic acid (RNA), and deoxyribonucleic acid (DNA), followed by cell death.²⁰,²¹ Other DNA damage mechanisms associated with quinone derivatives include DNA alkylating reaction and intercalation in the DNA double helix.²²

The quinone redox cycle may be influenced by adding electron-attracting or donating substituents to the quinoid system. In this context, quinone compounds containing a substituted amino group in their structures have been identified by our research group as having biological activities against different targets.³-⁵ Aminoquinone derivatives have also been used as a potential building block for the synthesis of bioactive modified quinones.¹⁴,¹⁵,¹⁹

Several computational and structural X-ray diffraction studies,¹⁸,²³-²⁵ in search for quantitative three-dimensional correlation structure-property (3D-QSAR)²⁶ have aided in the comprehension of these biological applications. The evaluation of the importance of intramolecular electronic properties, such as parameters highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energies, hardness, atomic charges, dipole moment, polarizability, molecular volume and Gibbs free energy, can provide indications of potential target molecules. Moreover, the crystalline package containing intermolecular interactions of the classic and non-classical hydrogen bond type can justify the importance of the biophoric sites of these substances.²⁷ However, theoretical-experimental studies of vibrational and electronic spectroscopy containing a quinonoidic ring have placed great emphasis on p-benzoquinone and its derivatives,²⁸,²⁹ with a reduced approach to studies of complete aminoquinone assignment. Such techniques are routinely used in the quality control of pharmaceutics and may allow the identification and distinction of crystal forms.³⁰,³¹

In this work, we described the synthesis, evaluated a new crystal structure, and investigated how electron-donating substituents by inductive effect and by resonance effect affect the electronic structure, molecular topology and vibrational properties of 2-chloro-3-(substituted-phenylamino)-1,4-naphthoquinone derivatives (Figure 1).

Figure 1
Structure of 2-chloro-3-phenylamino-1,4-napthoquinone (1a), 2-chloro-3-((4-methylphenyl)amino) (1b), 2-chloro-3-((4-methoxyphenyl)amino)-1,4-napthoquinone (1c), and 2-chloro-3-((3,4-dimethoxyphenyl)amino)-1,4-napthoquinone (1d).

Experimental

All reagents and solvents used in the preparation of substances 1a-1d were used without purification. The progress of the reactions was routinely monitored by thin layer chromatography (TLC) on silica gel plates (60F-F254) aluminum sheets 20 × 20 cm (Merck KGaA, Darmstadt, Germany) and visualized using ultraviolet light (UV-254 and 366 nm). The eluent mixture used was prepared volume by volume (v/v). Compounds 1a-1d had their respective melting points (mp) determined with a Fisher Johns instrument (Niterói, Brazil), which are uncorrected. Purification of compounds was carried out by silica gel flash column chromatography from Merck (Darmstadt, Germany). Hydrogen nuclear magnetic resonance spectra (¹H NMR) were performed using CDCl₃ as solvent (Sigma-Aldrich, São Paulo, Brazil) using a Varian Unity Plus 500 MHz spectrometer and tetramethylsilane (TMS) as an internal standard. The respective chemical shifts (δ) were expressed in parts per million (ppm) and the coupling constant (J) in hertz.

Synthesis of 2-chloro-3-(phenylamino)-1,4-naphthoquinone derivatives 1a-1d

The synthesis of 2-chloro-3-(substituted-phenylamino)-1,4-naphthoquinone derivatives 1a-1d (Figure 2) was achieved by nucleophilic substitution between anilines 3a 3d and 2,3-dichloro-1,4-naphthoquinone (2) with high yield when anilines substituted with electron donating groups are used. Thus, following these principles, the preparation and characterization of the compounds 1a 1d are described below.

Figure 2
Reaction scheme of 2-chloro-3-(phenylamino)-1,4-naphthoquinone derivatives.

In a 50 mL flask bottom, 0.5 mmol of 2,3-dichloro­naphthoquinone (2) in 10 mL of water and 0.5 mmol of aniline 3a or the analogues substituted 3b-3d were added. The mixture was kept under stirring at room temperature for 20 h. Upon completion of the reaction, they were filtered through a vacuum, and the precipitate was washed with water. Then, the substituted 2-amino-1,4-naphthoquinones 1a-1d were purified by chromatography column on a silica gel using a blend of hexane/ethyl acetate (7:3) as eluent. The solid obtained had a yield ranging from 84 to 90%.²¹

2-Chloro-3-(phenylamino)-1,4-naphthoquinone (1a)

The substance 1a was obtained as a burgundy solid; mp 214-216 °C, in 85% yield; IR (film) n_max / cm^-1 3232, 1674, 1634, 1561; ¹H NMR (500.00 MHz, CDCl₃) δ 7.08 (d, 2H, J 7.5 Hz, H-2’/H-6’), 7.22 (t, 1H, J 7.5 Hz, H-4’), 7.35 (dd, 2H, J 7.5, 2.5 Hz, H-3’/H-5’), 7.68 (s, 1H, N-H), 7.70 (td, 1H, J 7.5, 1.5 Hz, H-6), 7.77 (td, 1H, J 9.0, 1.0 Hz, H-7), 8.12 (dd, 1H, J 7.5, 1.0 Hz, H-5), 8.19 (dd, 1H, J 8.0, 1.0 Hz, H-8).

2-Chloro-3-(4-methylphenylamino)-1,4-naphthoquinone (1b)

The substance 1b was obtained as a burgundy solid; mp 184-186 °C, in 88% yield; IR (film) n_max / cm^-1 3220, 1674, 1636, 1563; ¹H NMR (500.00 MHz, CDCl₃) δ 2.37 (s, 3H, CH₃), 7.01 (d, 2H, J 8.0 Hz, H-2’/H-6’), 7.15 (d, 2H, J 8.5 Hz, H-3’/H-5’), 7.68 (td, 1H, J 7.5, 1.0 Hz, H-6), 7.76 (td, 1H, J 7.5, 1.5 Hz, H-7), 8.11 (dd, 1H, J 7.5, 1.0 Hz, H-5), 8.19 (dd, 1H, J 7.5, 1.0 Hz, H-8).

2-Chloro-3-(4-methoxyphenylamino)-1,4-naphthoquinone (1c)

The substance 1c was obtained as a burgundy solid; mp 221-223 °C, with 90% yield; IR (film) n_max / cm^-1 3247, 1674, 1636, 1565; ¹H NMR (500.00 MHz, CDCl₃) δ 3.83 (s, 3H, OCH₃), 6.88 (dd, 2H, J 6.5, 2.0 Hz, H-2’/H-6’), 7.05 (dd, 2H, J 7.0, 2.0 Hz, H-3’/H-5’), 7.63 (s, 1H, N-H), 7.67 (td, 1H, J 7.5, 1.0 Hz, H-6), 7.76 (td, 1H, J 7.5, 1.0 Hz, H-7), 8.11 (dd, 1H, J 8.0, 1.0 Hz, H-5), 8.18 (dd, 1H, J 8.5, 1.0 Hz, H-8).

2-Chloro-3-(3,4-dimethoxyphenylamino)-1,4-naphtho­quinone (1d)

The substance 1d was obtained as a burgundy solid, with 86% yield; mp < 300 °C; IR (film) n_max / cm^-1 3222, 1670, 1636, 1563; ¹H NMR (500.00 MHz, CDCl₃) δ 3.87 (s, 3H, OCH₃), 3.90 (s, 3H, OCH₃), 6.66 (d, 1H, J 2.5 Hz, H-2’), 6.69 (dd, 1H, J 8.5, 2.5 Hz, H-6’), 6.82 (d, 2H, J 2.5 Hz, H-5’), 7.66 (s, 1H, N-H), 7.69 (td, 1H, J 7.5, 1.0 Hz, H-6), 7.77 (td, 1H, J 7.5, 1.0 Hz, H-7), 8.11 (dd, 1H, J 7.5, 1.0 Hz, H-5), 8.19 (dd, 1H, J 8.0, 1.0 Hz, H-8).

Single crystal X-ray

Single crystal X-ray data for 1d were collected on a Bruker D8 Venture diffractometer (Niterói, Brazil) using graphite-monochromated Mo Ka radiation (l = 0.71073 Å) at 298 K. Data collection, cell refinement and data reduction were performed with Bruker Instrument Service v4.2.2, APEX3 and SAINT,³²,³³ respectively. The absorption correction using equivalent reflections was performed with the SADABS program.³⁴ The structure solutions and full-matrix least-squares refinements based on F² were performed with the SHELX package.³⁵,³⁶ All H atoms were refined with fixed individual displacement parameters [Uiso\(H) = 1.2 Ueq (Csp² and C_ar) or 1.5 U_eq (Csp³)] using a riding model. All non-hydrogen atoms were refined anisotropically. Structure illustrations were generated using ORTEP-3 for Mercury and the crystallographic tables were constructed using Olex2.³⁷,³⁸

The equipment is located at the Multiuser X-Ray Diffraction Laboratory, LDRX-UFF of the Instituto de Física of the Universidade Federal Fluminense, Brazil.

Vibrational and electronic spectroscopy

The Fourier transform infrared (FTIR) spectra were measured on Nicolet^TM iS50 (Niterói, Brazil) spectrometer equipment with an attenuated total reflectance accessory and LaTGS detector for the ranges of 4000-400 cm^-1 and 600-50 cm^-1 with an average of 128 scans at room temperature with 4 cm^-1 resolution. Data analysis was performed on the Omnic software.

The FT-Raman spectra were obtained using a Bruker MultiRAM spectrometer (Niterói, Brazil) in the region between 3500-70 cm^-1 with 2 cm^-1 resolution. The exciting laser wavelength radiation (Nd:YAG laser line as the excitation source) presented a wavelength of 1064 nm, and the spectra were recorded at room temperature with a germanium detector kept in liquid nitrogen. The samples were measured in the hemispheric opening of an aluminum sample holder. Data analysis was performed using the OPUS software.

The UV-visible measurements were done in the solid state diluted in MgO and in an acetonitrile solution using a Cary 5000, UV-Vis NIR spectrometer (Niterói, Brazil) and a Cary 50, UV-Vis spectrometer (Niterói, Brazil), respectively. Both measurements were performed from 190 to 800 nm with 0.1 s nm^-1 resolution. Data analysis was performed using the Cary WinUV software.

The equipment are located at the Multiuser Spectroscopy Laboratory (LAME-UFF) of the Instituto de Química of the Universidade Federal Fluminense, Brazil.

Calculations

The molecular properties were evaluated using the program Gaussian 09 for Linux,³⁹ with the CAM B3LYP functional for the development of the density functional theory (DFT) calculation. This functional was selected because it describes the high accuracy systems, including corrections for a better description of long-range interactions.⁴⁰,⁴¹ A theoretical polar environment was simulated by means of the integral equation formalism in the implicit solvation method of the polarizable continuous model (IEFPCM) implicit solvation method,⁴² using acetonitrile, dichloromethane and dimethyl sulfoxide (DMSO) as solvents to emulate possible intermolecular interactions around the analyzed molecules. The basis set used for developing of all the calculations was the double zeta 6-311G(d,p) for all atoms.⁴³ The partial atomic charges and the electrostatic potential surfaces (ESP) were calculated according to the Merz-Singh-Kollman scheme.⁴⁴,⁴⁵ The evaluation of the molecular orbitals was carried out using a Mulliken population analysis, and the percentage of atomic orbitals and the graphical population analysis software GaussSum were employed.⁴⁶ Every visualization and check of the calculated data were done through the ChemCraft 1.8 program.⁴⁷

Using as a starting point different conformations for the molecular units containing different dihedral angles between the quinone and the phenyl group, interconnected by the amino group, the most stable structural variations of the molecular units of the compounds were analyzed together with their vibrational spectra for acetonitrile data without the presence of imaginary harmonic vibrational modes, indicating that the analysis of isolated units alone, such as neglecting the intermolecular interactions, still allowed good agreement between the calculated and experimental data (crystallographic). The vibrational wavenumber, Raman scattering, and infrared adsorption intensities were visualized through the potential energy distribution (PED) analysis using the VEDA 4 software.⁴⁸ The natural bond orbital (NBO) analysis was performed to calculate the natural charge, and analyze a donor-acceptor energy and the natural resonance theory (NRT) provides the analysis of the molecular electron density in terms of resonance structures and weights.⁴⁹-⁵³

Transition energies and oscillator strengths in the UV-Vis spectra of the optimized structures were obtained from time-dependent density functional theory (TD-DFT) calculations. The evaluation of the theoretical methods was accomplished using the first 50 lowest energy states in the solution. The analysis of the TD-CAM-B3LYP states and the spectra simulation were carried out with the GaussSum software, using Gaussian functions with half-widths of 3000 cm^-1.⁴⁶

The cluster computers and programs used are located at the Multiuser Computational Chemistry Laboratory, LMQC-UFF, of the Instituto de Química of the Universidade Federal Fluminense, Brazil.

Results and Discussion

Structures

Structural analysis of compounds listed in this study, such as 1a and 1b, are reported in the literature.⁵⁴,⁵⁵ The main characteristic confirmed is that the phenyl and naphthoquinone rings are not in the same plane. The compounds 1a and 1b present crystalline packing with P21/c and Pna21 group spaces, respectively. This class of compounds present intermolecular interaction, with detached for hydrogen bonds connected by systems with N…O in the range from 2.70 to 3.05 Å, which can be treated as resonance assisted hydrogen bonding. Thus, NH…O(2) interaction in 1a and 1b is observed between adjacent units involving the amine and carbonyl group of naphthoquinone which is vicinal to the halogen group.

We also studied the 2-chloro-3-((4-methoxyphenyl)amino)-1,4-naphthoquinone (1c) by X-ray diffraction. Red single crystals were successfully grown from ethanol by the slow solvent evaporation method at room temperature. The unit cell parameters of the 2-chloro-3-((4-methoxyphenyl)amino)-1,4-naphthoquinone (1c) crystal were obtained from the single crystal X-ray diffraction analysis using a Bruker D8 Venture diffractometer with graphite-monochromated Mo Ka radiation (l = 0.71073 Å) at 298 K. The calculated lattice parameters were a = 12.12 Å, b = 24.16 Å, c = 4.76 Å, a = 90°, b = 90°, g = 90°, and volume (V) = 1397.3 ų. The grown crystal belonged to an orthorhombic crystal system with space group Pna2₁. Figure 3 shows the Oak Ridge thermal ellipsoid plot (ORTEP) diagram of the compound. Table S1 of the Supplementary Information (SI) section provides the crystal data and refinements. The resonance assisted hydrogen bonding effect was not as relevant, with an N…O distance of 3.075 Å and NH…O of 131.9º, unlike for other structures.

Figure 3
Asymmetric unit representation of 2-chloro-3-((4-methoxy­phenyl)amino)-1,4-naphthoquinone (1c) (ellipsoids at 50% probability).

Finally, even though we did not perform an X-ray diffraction structural analysis for the 1d compound, we evaluated the skeleton centered on the secondary amine between the naphthoquinone and phenyl groups for the 2-chloro-3-((3,5-dimethoxyphenyl)amino)-1,4 naphthoquinone.⁵⁶ This compound presents a P-1 space group with the smallest resonance assisted hydrogen bonding effect, presenting an N…O distance of 3.227(3) Å, as observed for the 1c structure.

The structural properties observed from the optimized geometries obtained from the theoretical study agree with those obtained from the crystallographic study, regardless of considering solvent effects with the integral equation formalism variation of the polarizable continuum model (IEFPCM). As shown in Figure 4, the optimized structural skeleton is centered on the secondary amide group. Theoretical values, such as the C₁₁N₁C₂ angle, were close to 130º, and the C₁₁N₁C₂C₃ presented dihedral angles ranging from 25 to 30º. The first showed a variation of 2º and the second, with values ranging from 3 to 7º compared to the experimental values.

Figure 4
Optimized geometries of the compounds 1a-1d.

The observed variations may be related to the crystalline packing, highlighting the identified intermolecular forces, especially for the short distance bonds N-H…O and N-H…Cl.⁵⁴-⁵⁶ The other studied parameters from the theoretical calculations agree with the experimental results, as observed in Table 1 and Tables S2 and S3 found in SI section.

Table 1
Comparison of calculated (CAM-B3LYP/IEFPCM in MeCN) and experimental (X-ray) geometrical parameters, in compounds 1a-1d

Geometric parameter / Å	1a	X-raya	1b	X-rayb
C=C(Benz. and Naphtq.)	1.361-1.517	1.367-1.508	1.362-1.517	1.374-1.500
C=O(Naphtq.)	1.212-1.216	1.210-1.227	1.212-1.216	1.218-1.229
N-C(Benz. and Naphtq.)	1.349-1.417	1.335-1.410	1.347-1.419	1.345-1.412
C-C(-CH3)			1.505	1.507
C-Cl(Naphtq.)	1.738	1.732	1.739	1.727
C-C-C(Benz. and CH3) C-N-C(Benz. and Naphtq.)	130.14	128.82	121.02 130.07	121.30 128.95
C-N-C-C(Benz. and Naphtq.)	29.63	21.34	28.31	25.16
	1c	X-rayc	1d	X-rayd
C=C(Benz. and Naphtq.)	1.363-1.518	1.370-1.441	1.361-1.517	1.364-1.502
C=O(Naphtq.)	1.212-1.217	1.207-1.230	1.212-1.216	1.218-1.223
N-C(Benz. and Naphtq.)	1.345-1.421	1.345-1.415	1.348-1.419	1.347-1.419
C-O(-OCH3)	1.355-1.420	1.372-1.422	1.353-1.429	1.356-1.412
C-Cl(Naphtq.)	1.741	1.735	1.739	1.717
C-O-C(Benz. and CH3) C-N-C(Benz. and Naphtq.)	118.42 130.11	117.15 127.69	115.10-118.37 130.10	117.32-118.92 128.43
C-N-C-C(Benz. and Naphtq.) C-O-C-C(Benz. and CH3)	25.18 0.24	29.39 1.84	28.64 0.87-73.34	34.79 3.06-6.52

• ^a
  Reference 54;
• ^b
  reference 55;
• ^c
  this work;
• ^d
  reference 56. Benz.: benzene ring; Naphtq.: naphthoquinone ring.

The analysis by root-mean-square deviation (RMSD) was performed to facilitate the comparison of crystallographic data with theoretical data and the results are shown in Figure S1 of the SI section. Note that, in this analysis, only the compounds 1a, 1b, and 1c were evaluated because their molecular structures present higher similarity. The observed results indicate a reasonable approximation between the IEFPCM-optimized data and the crystallographic data, with RMSD < 0.5. The theoretical data resulted in divergence only in the methoxy group in 1c, with RMSD = 0.40. Therefore, these results indicate that bond length and bending in the 2-chloro-3-phenylamino-1,4-napthoquinones skeleton are close to those determined experimentally, demonstrating that the theoretical approach can describe the system with great accuracy and contribute to understanding additional topics, such as vibrational and electronic spectra. Even though 1d has not been analyzed in isolation without considering the crystalline structure, it is clear that it follows the same trend as the other compounds in this study.

Finally, by evaluating the partial atomic charges calculated through the Merz-Singh-Kollman (MSK) and natural charge scheme, as available in Tables S4 and S5 in the SI section, it was possible to identify the influence of the more electronegative atoms that result in the stronger intermolecular interactions. For example, in all molecules 1a-1d, oxygen (O₁ and O₂) and nitrogen (N₁) atoms have the more negative charge values. These atoms are then involved in the main interactions detected in the crystal packing. The amino group has a hydrogen atom with a strong positive charge. It indicates an electron deficiency that justifies the formation of hydrogen bonds. The other oxygen atoms of the methoxy groups through MSK charge for the compounds 1c and 1d also have a negative charge, but due to the position of the amino group in the benzene ring, an inductive effect that removes electron density is perceived. This observation was not corroborated by the natural charge obtained by the NBO calculation, since the partial atomic charges of the oxygen atoms show similar values, as observed in Table S5.

Interestingly, even though 1c has a methoxy group that is an electron density donor by resonance effect in the para position, the charge concentration on the nitrogen atom of the amino group is higher than the previous cases in 1d; however, it is still lower than the compound without a substituent (Figure 5). The evaluation of the charges of the naphthoquinone groups showed certain regularity regardless of the compounds evaluated. The oxygen (O₂) that is adjacent to the chlorine group linked to carbon (C₃) has a charge concentration higher than the oxygen (O₁) adjacent to the amino group.

Figure 5
Resonance structures of the compound 1c.

A recent study by Rajalakshmi et al.⁵⁴ using several substituents in the phenyl group indicated the effect on the amino group when the nature of the inductive and resonance effects could affect NH group’s acidity and the action itself in the hydrogen bonds between adjacent units. For example, the compound 3-chloro-2-(4-chlorophenylamino)-1,4 naphthoquinone presents in its crystalline packaging with an N…O distance of 2.966 Å and NH…O of 131.4º with N-C_phenyl of 1.407 Å. In this case, the chloro substituent on the phenyl group has a weak deactivating action. This implies an action of removing the electron density of the amine group, which makes it more acidic. In addition, the quinone ring has an O=C-C=C-NHR p-conjugated system that allows evaluating this effect on the C=O bond distance (1.233 Å), which is longer than the reference molecule 1a unsubstituted (1.227 Å). Specifically for molecule 1c of our work, containing a methoxy substituent on the phenyl group, which is a strong activating substituent (Figure 5), an increase in the N(1)-C(11) bond distance to 1.415 Å is observed, according to the X-ray diffraction. This distance was greater than the N-C_phenyl distance for compounds 1a (1.410 Å) and 1b (1.412 Å) in X-ray diffraction,⁵⁴,⁵⁵ where the first is unsubstituted and the second has a methyl substituent which is a weak activator group. Associated with the C=O bond distance vicinal to the chloro group of quinone, with values of 1.229 and 1.230 Å, respectively for compounds 1b and 1c, the effect of resonance assisted hydrogen bonding confirms the influence of the substituents in the phenyl group (R). The crystalline packaging for 1a, 1b and 1c present N…O distance from 3.049 to 2.983 Å.⁵⁴

These crystallographic observations were corroborated by the theoretical data since the RMSD analysis indicated great similarity between the experimental and theoretical structures. But to support this observation, we performed an analysis by natural resonance theory (NRT) that indicates the percentage contribution of different resonance structures in relation to a reference and prediction of NBO delocalization, available in Tables S6-S9 in the SI section. The highest weight of structures with a concentration of partial positive atomic charge on the nitrogen atom of the amine was found for the structure of compound 1a (26.15%), followed by structures of compound 1b (18.69%) and finally for compounds 1c and 1d (6.87 and 6.48%). This indicates the effect of the methoxy substituent with an activating action on the phenyl group, increasing the charge density on the amino group, which makes it more basic.

Figure 6 shows the electrostatic potential surfaces (ESP) of the molecules. These surfaces permit interpreting the overall charge distribution of the molecules. The red color describes the higher concentration of negative charges, while the blue color describes the most positive sites. The hydrogen atom of the amino group is the most positively charged. Contrarily, the oxygen (O) in the carbonyl group of naphthoquinones is the most negatively charged atom, corroborating information described in the literature for these functional groups in naphthoquinone systems.²⁰ In terms of the electrostatic aspect, the benzenoid ring has a neutral characteristic even in the presence of more electronegative atoms while the naphthoquinone group is positively charged.

Figure 6
Electrostatic potential surfaces (range: -0.002 to 0.05) of the compounds 1a-1d in MeCN.

Vibrational analyses

Theoretical-experimental vibrational studies involving compounds containing the 1,4-naphtoquinone group have been reported in recent years using density functional theory assistance through the B3LYP hybrid method with different double or triple zeta basis functions with or without pseudopotential, in addition to the use of an implicit solvent method for the study of solvation effects.⁵⁷,⁵⁸ The use of techniques such as potential energy distribution (PED) analysis of theoretical vibrational spectra is also reported. However, as they are the simplest target molecules and have non-functionalized amino groups or only the functionalized 1,4-naphtoquinone molecule, the observed spectra are simpler and have fewer bands and fewer couplings than the molecules in this study.⁵⁹,⁶⁰

Thus, solid-state experimental spectra for compounds show characteristic bands of the most important chemical groups in each compound between 4000 and 600 cm^-1 in Figure 7 and from 600 to 150 cm^-1 in Figure S2 (SI section). The broad band of the amino group in the infrared and Raman spectra and multiple bands between 1675 and 1500 cm^-1 due to C=C and C=O stretching modes are the most evident bands. The complete assignment of all spectra is given below, with five regions considered: 3500-2800, 1800-1300, 1300-1200, 1000-600 and 600-150 cm^-1, where the first four regions belong to the mid-infrared spectrum and the latter to the far-infrared spectrum. This division was also accompanied by the Raman spectrum.

Figure 7
Experimental Raman (blue) and infrared (ATR, red) spectra of the compounds 1a-1d between 4000-600 cm^-1.

All vibrational modes of the four compounds 1a-1d were classified as part of either the benzene ring or the naphthoquinone ring. The substituents were identified as methoxy or methyl groups according to the components of each derivative, as illustrated in Figure 7.

The molecules presented between 84 and 96 normal vibrational modes in the theoretical spectra. Tables 2-5 describe the experimental Raman and infrared wavenumbers and the unscaled theoretical values obtained at CAM B3LYP/6-311G(d,p) level up to 600 cm^-1. The complete tables with all the theoretical vibrations are available in the SI section (Tables S10-S13).

Table 2
Experimental and theoretical vibrational wavenumbers of 1a

Experimental wavenumber / cm-1		Calculated wavenumber / cm-1	IR intensity / cm-1	Raman intensity / cm-1	PED / %
Infrared	Raman
3234		3539	234.03	1312	xυNH Naphtq. (100)
	3066	3222	7.32	1534	υCH Benz. Sym. (90)
3062		3216	20.97	245	υCH Benz. Asym. (90)
3039	3040	3208	20.85	437	υCH Benz. Asym. (86)
1674	1675	1781	338.78	7980	υC=O Naphtq. (85)
1635	1635	1754	318.10	11942	υC=O Naphtq. (81)
1603	1604	1683	101.46	13764	υCC Naphtq. + υCC Benz. (63)
1591		1670	224.70	515	υCC Naphtq. + υCC Benz. (48)
	1577	1666	105.70	204	υCC Benz. (57)
1558	1561	1644	928.64	11886	υCC Naphtq. (51)
1506	1515	1576	837.28	2959	υCC Naphtq. (21); δHNC Naphtq. (54)
1489	1488	1545	39.82	631	rHCCH Benz. (50)
	1480	1536	55.73	173	rHCCH Naphtq. (49); δCCC Naphtq. (23)
1460	1459	1508	6.47	97	υCC Naphtq. (26); rHCCH Naphtq. (51)
1442	1446	1499	72.85	292	υCC Benz. (23); rHCCH Benz. (40)
1329	1329	1371	188.34	1994	υCC Naphtq. (57)
	1316	1364	31.14	264	rHCCH Benz. (77)
	1305	1348	5.51	5563	υCC Naphtq. Asym + υCC Benz.Asym. (46)
1286		1318	624.32	1993	υCC Naphtq. Asym. (13); υCC Benz. Asym. (40)
	1255	1290	295.91	4458	υCC Naphtq. + υNC Naphtq. + υCN Benz. (26)
1240		1270	215.12	2296	υCC Naphtq. Asym. (15); δHCC Naphtq. (24)
1190	1193	1226	25.46	704	υCC Naphtq. Asym. + υNC Naphtq. Sym. + υCN Benz. Sym. (41)
1173	1174	1202	3.23	937	υCC Naphtq. Asym. + υCC Benz. Asym. (12); δHCC Benz. (71)
1161	1164	1186	39.14	1385	δHCC Naphtq. (74)
	1153	1180	3.25	236	δHCC Benz. (71)
1140	1140	1169	144.27	3593	υCC Naphtq. Asym. (27); δHCC Naphtq. (13)
1089	1091	1124	1.18	194	rHCCH Naphtq. (30); δCCC Naphtq. (17)
1076		1115	34.39	346	υCCBenz. Asym. (35); rHCCH Benz. (37)
1047	1048	1062	24.12	262	υCC Benz. (43); δCCC Benz. (13); rHCCH Benz. (21)
1016	1017	1049	72.87	4998	υCC Naphtq. (39)
997	1002	1028	5.41	4739	υCC Benz. (24); δCCC Benz. (66)
982	977	1011	0.13	91	τHCCH Benz. (68); τCCCC Benz. (20)
921	925	956	26.66	503	ωHCC Benz. (54)
899	898	930	8.32	729	δCNC Benz. + δCCN Naphtq. (14); τHCCH Benz. (23)
	850	868	38.03	1306	ωHCCH Benz. (46)
848		866	54.80	327	υCCl Naphtq. (13); ωHCCH Benz. (44)
	810	823	0.35	248	τHCCH Naphtq. (10); ωCC=O Naphtq. + τCCCC Naphtq. (59)
800	801	821	34.13	258	ωCCC Benz. (10)
789	792	789	69.38	268	ωHCCH Benz. (58)
756		752	70.09	252	ωHCCH Naphtq. (33); ωCC=O Naphtq. (35)
717	722	720	62.40	71	ωHCCH Benz. (40); τCCCC Benz. (50)
692	690	712	27.48	146	τCCC Naphtq. (11); τCCN Naphtq. + τCC=O Naphtq. (37)
665	665	683	8.98	1174	δCCC Naphtq. (32)
640	643	650	10.37	2122	δCCC Naphtq. (11); δCC=O Naphtq. + ωCCN Benz. (12); ωCCC Benz. (10)
624	627	636	8.68	3895	δCCC Benz. (58)
610	616	613	71.57	4150	δCCC Naphtq.+δCCC Benz. (12); τHNC Naphtq. (32)

δτσ:

Table 3
Experimental and theoretical vibrational wavenumbers of 1b

Experimental wavenumber / cm-1		Calculated wavenumber / cm-1	IR intensity / cm-1	Raman intensity / cm-1	PED / %
Infrared	Raman
3221	3228	3539	238.56	1401	υNH Naphtq. (100)
3062	3062	3206	13.16	811	υCH Benz. Asym. (91)
3030		3189	24.00	293	υCH Benz. Asym. (89)
2958		3136	23.91	458	υCH Subst. Asym. (100)
2921	2921	3111	25.67	541	υCH Subst. Asym. (99)
2852		3052	37.99	1553	υCH Subst. Sym. (99)
1674	1675	1781	329.78	8251	υC=O Naphtq. (85)
1633	1636	1752	285.53	13427	υC=O Naphtq. (81)
	1613	1693	21.50	15414	υCC Benz. Asym. (63); δHCC Benz. (16)
1593	1596	1672	245.42	2083	υCC Naphtq. Sym. (48)
1558	1563	1644	978.55	13802	υCC Naphtq. Asym. (53)
1515	1523	1578	836.90	4310	υCN (24); δHNC Naphtq. (33); δHCC Benz. (12)
1494		1562	133.29	313	δHNC Naphtq. (27); δHCC Benz. (32)
1459	1459	1536	59.98	169	δCCC Naphtq. (12); δHCC Naphtq. (53)
1410	1409	1494	44.90	367	δH3CC Subs. (23); τHCH Subst. (48)
1375	1378	1456	12.77	205	υCC Benz. Asym. (28); δHCC Benz. (26); τHCC Subst. (20)
1329	1326	1371	224.18	2698	υCC Naphtq. Asym. (40)
1311	1314	1344	8.23	5104	υCCNaphtq. Asym. (10); ρHCCH Benz. (23)
1298	1303	1334	130.14	946	υCC Naphtq. (26); ρHCCH Benz. + ρHCCH Naphtq. (12)
1284	1289	1315	632.59	2286	υCC Naphtq. Asym. + υCC Benz. Asym. (47)
1240		1291	227.72	5013	υCCNaphtq. Asym. + υCC Benz. Asym. (16); υNC Benz. (13)
	1212	1270	201.24	2201	υCC Naphtq. Asym. (12); δHCC Naphtq. (26)
1190	1191	1250	14.62	1046	υCC Benz.Asym. + υCH3-C Subst. (53); δHCC Benz. (20)
1174	1176	1229	22.77	740	υCC Benz. Sym. (10); υNC Naphtq. (16); υNC Benz. (12)
1157	1160	1206	6.27	1726	δHCCH Benz. (72)
1140	1141	1170	140.70	3564	υCC Naphtq. (30)
1109		1144	29.81	108	υCC Benz. Asym. (22); δHCCH Benz. (63)
1047		1079	11.40	69	υCC Naphtq. (25); ρHCC Naphtq. (21)
1018		1050	103.10	6412	υCC Naphtq. Asym. (50)
984		1027	1.32	4	τHCCH Naphtq. (78); ωCCCC Naphtq. (11)
964	962	1016	1.35	138	τHCH Subs. (60); ωHCC Subst. (11)
943	944	986	8.23	232	τHCCH Benz. (74)
914	915	940	27.23	1522	δCCCl Naphtq. + δCCN Naphtq. + δCNC Naphtq. (30)
848	852	872	65.57	1664	υCC Benz. Sym. + υCCl Naphtq. (21); δCCC Naphtq. (16)
818	817	842	70.86	1245	υCCl Naphtq. + υCC Benz. Sym + υCC Naphtq. Sym (40)
804		829	15.42	131	ωHCCH Naphtq. (45); ωCC=O Naphtq. (28)
787		776	18.83	264	ωCCC Benz. + ωCCC Naphtq. (14)
758	757	752	69.96	457	ωHCCH Naphtq. (29); ωCC=O Naphtq. (30)
	744	744	24.12	350	ωCNC Benz. + ωCCC Benz. (20)
716	720	711	26.62	140	τHCCH Naphtq. (11); ωCCC Naphtq. (18); τCCC Naphtq. (19)
679	674	682	11.17	1077	τCCC Naphtq. + δCCN Naphtq. + τCNC Naphtq. + ωCCC Benz. + τCCN Benz. (23)
660	659	660	11.53	850	δCCC Naphtq. + δCCN Benz. (61)
640	641	643	27.06	8255	δCCC Naphtq. (21); ωHNC Naphtq. (21)
613	614	610	109.14	16578	ωHNC Naphtq. (63)

δτσ:

Table 4
Experimental and theoretical vibrational wavenumbers of 1c

Experimental wavenumber / cm-1		Calculated wavenumber / cm-1	IR intensity / cm-1	Raman intensity / cm-1	PED / %
Infrared	Raman
3247		3538	244.68	1409	υNH Naphtq. (100)
	3069	3233	11.05	1245	υCH Naphtq. Sym. (100)
	3048	3219	6.26	965	υCH Benz. Asym. (94)
3040		3217	7.93	791	υCH Naphtq. Asym. (90)
	3017	3205	3.42	448	υCH Naphtq. Asym. (92)
2960		3169	26.41	565	υCH Subst. Asym. (100)
2920		3107	44.54	316	υCH Subst. Asym. (100)
2852		3041	59.37	729	υCH Subst. Sym. (100)
1674	1675	1781	331.62	8358	υC=O Naphtq. (86)
1633	1636	1750	264.12	14394	υC=O Naphtq. (81)
	1610	1691	79.28	16254	υCC Benz. (58); δCCH Benz. (12)
1593	1592	1672	230.06	2445	υCC Naphtq. (61)
1564	1565	1643	968.97	14544	υCC Naphtq. + υCN Naphtq. (56)
1514	1517	1578	1053.81	4028	δHNC Benz. (40); δHCC Benz. (10)
1493	1500	1560	181.45	406	δHNC Benz. (20); δHCC Benz. (37)
1454	1455	1536	57.24	148	δHCC Naphtq. (53); δCCC Naphtq. (14)
1439	1442	1505	58.98	356	δHCH Subst. (69); τH3CO Subst. (23)
1417	1419	1492	14.14	449	δHCH Subst. (71); τH3CO Subst. (22)
1328		1373	305.91	5685	υCC Naphtq. Asym. (52)
1311		1358	42.23	5984	υCN Naphtq. Asym. + υCC Benz. Asym. + υCC Naphtq. Asym. + υC-O Benz. Asym. (49)
	1303	1340	31.50	2826	ρHCCH Naphtq.+ρHCCH Benz. (41); υCC Naphtq. Asym. (12)
1284		1291	915.32	1107	υCO Benz. + υCC Benz. Asym. (50); ρHCCH Benz. (11)
	1268	1290	62.71	3507	υCN Benz. + υCC Benz. Asym. (33); ρHCCH Naphtq.
1234	1241	1271	183.13	2275	υCC Naphtq. Sym.(17); δHCC Naphtq. (32)
1194	1193	1197	35.89	1920	υCC Benz. Sym. (12); δHCC Benz. (70)
1180	1172	1186	51.49	2237	δHCC Naphtq. (67)
1167		1171	127.01	3980	υCC Naphtq. Sym. (11); ρHCC Naphtq. (14)
1140	1142	1138	52.46	252	υCC Benz. Asym. (14); ρHCC Benz. (64)
1047		1082	90.73	73	υCO Subst. (51); ρHCCH Naphtq. (10)
1028	1021	1050	97.77	6726	υCC Naphtq. Sym. (51)
970		979	5.17	323	tHCCH Benz. (68)
933	934	940	30.88	1653	υCC Benz. Sym. (12); δCNC + δCCN Naphtq. (20)
	873	873	66.58	1271	υCC Benz. Sym. (13); δCCC Naphtq. (17); δHCCC Benz. (14)
848	855	842	118.47	1469	υCC Benz. Sym. (14); υCl-C Sym. (15); δCCC Benz. + δCC=O Naphtq. (13); δCCC Naphtq. (10)
829		829	14.15	171	τHCC Naphtq. (47); ωCCC=O (27); ωCCCC Naphtq. (10)
818	818	822	1.15	264	ωCC=O+ ωCCC Naphtq. + τHCC Naphtq. (63)
789	788	782	4.43	134	τCC=O+ ωCCC Naphtq. + ωCCC Benz. (18)
758	759	752	81.09	378	τHCC Naphtq. (28); ωO=CC (33)
717	720	711	28.21	153	τHCC Naphtq. (10); τCCN Naphtq. + ωCCC Naphtq. (22); ωCCC Naphtq. (11)
683		683	4.03	1332	δCC=O Naphtq.+ δCCC Benz. + δCCC Naphtq. (28)
652	653	657	14.00	1219	δCCC Benz. + δCCC Naphtq. (49); δCC=O Naphtq. (13)
	641	644	43.67	14535	δCCC Naphtq.+ ωCCC Benz. (15); ωHNCC Benz. (31)
609		617	85.27	13870	ωHNC Benz. (49)

δτσ:

Table 5
Experimental and theoretical vibrational wavenumbers of 1d

Experimental wavenumber / cm-1		Calculated wavenumber / cm-1	IR intensity / cm-1	Raman intensity / cm-1	PED / %
Infrared	Raman
3222	3228	3542	246.97	1363	υNH Naphtq. (100)
3085	3087	3233	13.00	1433	υCH Naphtq. Sym. (93)
3064	3067	3221	5.20	958	υCH Benz. Sym. (97)
	3054	3218	6.59	747	υCH Naphtq. Asym. (93)
3041	3043	3208	8.77	419	υCH Benz. Asym. (99)
2999	3002	3172	23.26	510	υCH Subst. Asym. (90)
2970	2969	3160	34.25	613	υCH Subst. Asym. (98)
2939	2936	3121	41.80	296	υCH Subst. Asym. (97)
2922		3112	40.11	282	υCH Subst. Asym. (99)
2848	2850	3045	49.55	1205	υCH Subst. Sym. (95)
2835	2836	3044	77.03	168	υCH Subst. Asym. (91)
1670	1671	1781	325.97	8125	υC=O Naphtq. (84)
1635	1636	1754	286.63	13334	υC=O Naphtq. (82)
	1609	1683	132.12	15910	υCC Benz. (56)
1593		1672	185.83	2134	υCC Benz. (11); υCC Naphtq. (43)
1564	1563	1644	955.73	11152	υCC Naphtq.+ υCN Naphtq. (36)
1520	1525	1573	877.30	1790	υCN Benz. (11); δHNC Benz.(38)
1500	1501	1561	268.95	1212	υC-O Benz. (10); δHNC Benz. (25); δHCC Benz. (27)
1467		1508	14.42	270	υCC Naphtq. (15); δHCC Naphtq. (30); ωHCH Subt. (16)
	1455	1507	78.72	531	δHCC Naphtq. (12); ωHCH Subt. (38)
1446		1503	51.10	1159	δHCH Subt. (60); τH3CO Subt. (14)
1421	1422	1493	16.24	402	δHCH Subt. (16); τH3CO Subt. (76)
1331		1370	286.70	3345	υCC Naphtq. Asym. (50)
1294	1293	1336	205.46	1446	υCC Naphtq. Asym.+ υCC Benz. Asym. (43)
1284		1317	413.50	1545	υCC Naphtq. Asym. + υCC Benz. Asym. (62)
1236	1235	1274	541.47	664	υOC Benz. (18); υCC Benz. (10); δHCC Benz. (13)
1221	1220	1262	81.30	1673	υOCBenz (22); δHCC Naphtq. (13)
1188		1222	27.56	292	δHCO Subt. (10); ωHCH Subt. (50)
1157		1212	56.98	325	δHCC Benz. (10); ωHCH Subt. (51)
1130	1133	1185	58.45	1863	δHCC Naphtq. (68)
1043	1041	1077	64.94	358	υCO Subst. (60); ρHCCH Benz. (19)
1026		1053	142.41	2085	υCO Subst. (64)
	1019	1049	71.11	4928	υCC Naphtq. Sym. (30); υCO Subst. (11); δCC=O Naphtq. (14)
973	975	1003	55.02	726	υCC Benz. (24)
881		891	40.77	183	δCCC Naphtq. + δCCO Naphtq. + δCCN Naphtq. (10); ωHCC Benz. (65)
854		854	95.73	519	υCl-C Sym. + υCC Naphtq. (46); δCCC Naphtq. + δCCC Benz. (15)
831		829	14.28	202	ωHCCC Naphtq. (49); τCCCC Naphtq. (36)
802		802	3.52	1082	υO-C Benz. (17); τCCC Benz. (22)
769		773	29.44	2948	υCC Benz. (12); ωCCC Benz. + ωCCC Naphtq. (13)
748	749	749	53.18	178	τHCC Naphtq. (23); ωCC=O Naphtq.(25)
719	719	711	25.43	166	ωCCC Naphtq. (16); ωCC=O Naphtq. (38)
685	685	688	12.12	1067	δCCC Naphtq. + ωCC=O Naphtq. + τCCC Benz. (14)
654	651	660	25.71	911	δCCC Naphtq. (34); ωCCC Benz. (12)
634	634	626	22.86	1823	ωCCC Benz. (24)

δτσ:

Assignment of the normal modes was done using Veda 4.1 software,⁴⁸ which performs potential energy distribution analyses to identify the most significant components in each vibrational mode and describes them using internal coordinates. The percentage contributions of each coupled mode at the same frequency were indicated in parentheses. The sum of all possible representations for a given vibrational mode was indicated by the sum of multiple assignments.

The theoretical and experimental wavenumbers showed high correlation for the regions between 3100 and 150 cm ¹. The coefficient of determination (R²) for the correlation between experimental and theoretical wavenumbers was between 0.998 and 0.999. These results are available in the SI section (Figure S3). Thus, by simulating the theoretical spectra according to the values of the calculated scale factors between 0.953 and 0.960, there was a good theoretical and experimental correlation, wherein the intensities of the spectra were comparable and allowed adequate assignment. Scaling factors were applied to the calculated wavenumbers in the SI section (Tables S10-S13).

Discussion of the spectra: region between 4000-2800 cm^-1

The region observed at 3350-3150 cm^-1 in all spectra in Figure 7 was classified as the region associated with the N-H stretching mode. The Raman spectrum showed a single band of low intensity between 3250 and 3220 cm^-1. The infrared spectra of the solid phase have a medium intensity broadband indicating the influence of intermolecular interactions, particularly hydrogen bonding. This profile confirms the presence of the secondary aromatic amino group. Due to the presence of the hydrogen bonds in the crystal packing, this band was not included in the calculation of the scale factor mentioned in the previous item.

Aromatic C-H stretching modes were observed for all compounds in the region between 3040 and 3100 cm ¹. The asymmetric and symmetric aromatic ν_CH modes (benzenoid and naphthoquinone groups) were assigned. The methoxylated compounds 1c and 1d showed the lower definition of these bands in the infrared spectra. Stretching modes of the aliphatic C-H bonds were observed in the region between 2850 and 3000 cm^-1. The theoretical information and the differences between the vibrational modes were essential in the assignment of these bands, due to the spectra complexity in this region. Bands in 2958, 2921 and 2852 cm^-1 were identified in 1b and 1c as asymmetric and symmetric ν_CH modes. In the spectrum of derivative 1d, a larger number of bands is noticed, reflecting the increase in the number of methoxy groups.

Region between 1800-1300 cm^-1

Bands of high intensity due to ν_C=C, ν_C=O and ν_CN modes and coupled stretching modes were observed in the experimental spectra between 1670 and 1450 cm^-1, as shown in Figure 7. In infrared spectra, ν_C=O modes in the naphthoquinone group were identified in two bands at 1675/1670 and 1635/1633 cm^-1. The ν_C=C modes of the aromatic groups were observed in the 1593 cm^-1 as a high intensity band. The band at 1564/1558 cm^-1 was assigned as a coupled mode of ν_C=C and ν_CN, followed by bands at 1520 and 1500 cm^-1 that have been associated with HCC and HNC angle strain coupling modes. In the Raman spectra, these bands are observed, but especially on the band at 1636/1635 cm^-1 as ν_C=O modes. These data reinforce the similarity of the four compounds with their benzenoid and naphthoquinone groups.

Region between 1300-1000 cm^-1

The region between 1285 and 1130 cm^-1 shows greater complexity for the spectrum in Figure 7 containing the two methoxy groups compared to the other systems studied. The compound 1d presents an envelope of bands where the most intense band is found at 1236 cm^-1 associated with the coupling ν_C-O-CH3, ν_CC and ν_{HCC Benz}. This compound still presents intense bands at 1284 and 1130 cm^-1 that are associated with ν_CC and ν_{CCH Naphtq.} modes. These two bands are the most prominent among the other compounds. Even though the 1c substance contains the methoxy group, it has been identified as participating in the coupled mode at 1284 cm^-1. In the Raman spectra, the band at 1255 cm^-1 was highlighted for the compounds 1a and 1b, assigned as ν_CC + ν_CN mode and presents in both aromatic groups. For the compounds 1c and 1d, this intense band is observed at 1268 and 1293 cm^-1.

Region between 1000-600 cm^-1

The infrared spectrum in Figure 7 for the compound 1d reinforces the distinction between the compounds according to the highest number of substituents present. The characteristic region of aromatic rings respiration and deformation outside the plane was observed with bands at 854, 831 802, 748, 719, 685 and 654 cm^-1. Furthermore, the first highlighted band is assigned by coupling the breathing mode of the aromatic rings with the ν_CCl. For the other compounds 1a-1c, this mode stands out as a band of medium intensity found in the other compounds at 848/818 cm^-1, in addition to the out-of-plane deformation of the aromatic rings at 717/715 cm^-1. In the Raman spectrum, this region stands out for a band of weak intensity between 686 and 653 cm^-1 related to the δ_CCC angular deformation of the aromatic rings.

Region between 600-150 cm^-1

As previously discussed, this region presents a great complexity, as it presents several active bands for all compounds in Figure S2 in the SI section. However, this region allows for greater differentiation between the compounds through the profile and intensity of the bands, also featuring a fingerprint region to distinguish these compounds. However, the intense band between 390 and 382 cm^-1 stands out in all compounds for describing the out-of-plane deformation of aromatic rings with low intensity bands between 360 and 331 cm^-1 which is assigned by the coupling of ν_CC + ν_CCl + δ_CC=O. In the Raman spectrum, the band between 296 and 283 cm^-1 is an indication for all compounds as τ_{CCC Naphtq.} + τ_{CCN Naphtq.} + τ_{CCCl Naphtq.}

Electronic spectra

The compounds 1a-1d listed in this study show a color that ranges from purple to black in solid state, which in solution with the indicated solvents shows a red-orange color, typical of dyes containing anthraquinone groups.⁶¹ The experimental UV-Vis spectra for different compounds and in different solvents show high similarity, as observed in other studies containing aminoquinones.²³ All the spectra in the solution presented a lower intensity band in the visible region between 470 and 500 nm, which was responsible for a bluish-green to blue-green absorption that justifies the colors observed in solution⁶²,⁶³ presented in Figure 8. This spectral region is similar to the study observed by Rajalakshmi et al.⁵⁴ with an aqueous N-(2-hydroxyethyl)piperazine-N’-(2-ethanesulfonic acid (HEPES) buffer:N,N-dimethylformamide (DMF) (2:8 v/v) solution. In the spectra in the ultraviolet region, two bands are observed: the first, a low-intensity band between 320 and 335 nm, and the second, a high-absorptivity band ranging from 275 to 283 nm. Using acetonitrile as a solvent, the highlighted spectrum obtained presents a medium intensity band ranging from 228 to 240 nm, which is not defined for the other solvents due to their transparency regions. When evaluating the solid-state spectra in Figure S4 in the SI section, a very broad and intense band is noticeable between 400 and 700 nm in the visible region and a more defined band in the ultraviolet region between 277 and 292 nm. The characteristics of the first band may explain the reason for the color variation observed in the solid state, since there is an overlap of multiple absorption bands in this region influenced by crystal packing with multiple intermolecular interactions.

Figure 8
UV-Vis spectra (200 to 600 nm) in (a) acetonitrile, (b) dichloromethane, and (c) DMSO for the compounds 1a-1d.

The deconvolution spectra were obtained using different Gaussian numbers; five for acetonitrile, four for dichloromethane, and three for DMSO. Some bands were estimated at below 200 nm to aid in the deconvolution process. The overall-fit parameters and the molar absorptivities are presented in Table S14 of the SI section. Notably, all compounds 1a-1d have molar absorptivity values at around 10⁴ in the UV region and 10³ in the visible. When assessing the visible band with the different solvents, a bathochromic effect accompanied by a hypochromic effect is observed when comparing these bands in acetonitrile/CH₂Cl₂ to DMSO. This can be explained by the difference in polarity between these solvents and the aromatic groups. Another relevant effect related to this band was the solvent-independent bathochrome shift used in ascending order for the compounds 1a < 1b < 1c < 1d. This demonstrates an effect of the different substituents as highlighted in the charge analysis, as it should also be observed in the HOMO-LUMO boundary orbitals that will be evaluated in the next section. When evaluating the values of molar absorptivity, we can infer a strong participation of p ®p* transitions to the intense band in the ultraviolet region and n®p* in the visible region with the effect of a donor substituent such as methoxy containing isolated electron pairs that generate a known bathochromatic effect on the transitions. There is also the participation of auxochromic groups present in naphthoquinone that has a profile resembling p-benzoquinone²⁸,⁶⁴ but is difficult to predict without an analysis of orbitals and electronic excitations as reported by Pereira-da-Silva et al.²⁸

Molecular orbitals analysis

The ground state for all compounds 1a-1d consists of the frontier region of occupied molecular orbitals distributed between 7 and 12 eV for CAM-B3LYP. Table 6 briefly presents these orbitals in an IEFPCM (solvent MeCN) with the associated Koopmans’ energy and Mulliken analysis of the virtual and occupied orbitals. Five occupied orbitals and five virtual ones with lower energy were analyzed for 1c and 1d, while for the other compounds five occupied orbitals and eleven virtual ones with lower energy are highlighted. HOMO, LUMO, and other molecular orbitals of compounds are shown in Figure 9. The same analysis performed for the data obtained with the IEFPCM model with CH₂Cl₂ and DMSO is found in the SI section in Tables S15 and S16.

Table 6
Koopmans’ energy, Mulliken population analysis and assignment for the frontier orbitals of 1a-1d of the CAM-B3LYP method

Orbital	Energy / eV	Mulliken population		Energy / eV	Mulliken population
	1a			1b
L+4	1.16	p*C=CBenz. + p*C=CNaphtq. (6% of NH; 58% of Benz.; 36% of Naphtq.)		1.19	p*C=CBenz. + p*C=CNaphtq. (6% of NH; 57% of Benz.; 33% of Naphtq.)
L+3	0.77	p*C=CBenz. (99% of Benz.)		0.78	p*C=CBenz. (97% of Benz.)
L+2	0.41	p*C=CNaphtq. + p*C=CBenz. (32% of Benz.; 66% of Naphtq.)		0.45	p*C=CNaphtq. + p*C=CBenz. (29% of Benz.; 68% of Naphtq.)
L+1	-0.15	p*C=C Naphtq. (97% of Naphtq.)		-0.13	p*C=C Naphtq. (97% of Naphtq.)
LUMO*	-2.10	πC=C Naphtq. + nO (94% of Naphtq.)		-2.08	πC=C Naphtq. + nO (94% of Naphtq.)
HOMO*	-7.58	πC=CBenz. + πC=C Naphtq. + nO + nCl + nN (24% of NH; 34% of Benz.; 43% of Naphtq.)		-7.47	πC=CBenz. + πC=C Naphtq. + nO + nCl + nN (22% of NH; 39% of Benz.; 37% of Naphtq.)
H-1	-8.69	pC=CBenz. + nCl (87% of Benz.; 13% of Naphtq.)		-8.59	pC=CBenz. + nCl + pC=C Naphtq. (64% of Benz.; 31% of Naphtq.)
H-2	-8.90	pC=CBenz. + pC=C Naphtq. + nCl (59% of Benz.; 39% of Naphtq.)		-8.76	pC=CBenz. + pC=C Naphtq. (79% of Benz.; 18% of Naphtq.)
H-3	-9.08	pC=C Naphtq. (99% of Naphtq.)		-9.07	pC=C Naphtq. (100% of Naphtq.)
H-4	-9.30	pC=C Naphtq. + nO (95% of Naphtq.)		-9.28	pC=C Naphtq. + nO (97% of Naphtq.)
H-5	-9.38	nO + sC-CNaphtq. (5% of Benz.; 94% of Naphtq.)		-9.34	nO + sC-CNaphtq. (97% of Naphtq.)
H-6	-10.00	nO + sC-CNaphtq. (98% of Naphtq.)		-9.99	nO + sC-CNaphtq. (98% of Naphtq.)
H-7	-10.63	nCl + sC-CNaphtq. (5% of Benz.; 92% of Naphtq.)		-10.58	nCl + sC-CNaphtq. (8% of Benz.; 90% of Naphtq.)
H-8	-10.99	nCl + pC=CBenz. (13% of NH; 41% of Benz.; 46% of Naphtq.)		-10.84	nCl + pC=CBenz. (14% of NH; 37% of Benz.; 44% of Naphtq.)
H-9	-11.53	nCl + sC-CBenz. (77% of Benz.; 21% of Naphtq.)		-11.31	sC-CNaphtq. + nCl + sC-H (74% of Benz.; 11% of Naphtq.; 12% of CH3)
H-10	-11.76	nCl + pC=CNaphtq+ pC=O + sC-CBenz. (8% of NH; 32% of Benz.; 59% of Naphtq.)		-11.59	sC-CBenz. + sC-H (62% of Benz.; 9% of Naphtq.; 26% of CH3)
		1c			1d
L+4	1.33	p*C=CBenz. + p*C=CNaphtq. (5% of NH; 66% of Benz.; 25% of Naphtq.)		1.24	p*C=CBenz. + p*C=CNaphtq. (6% of NH; 60% of Benz.; 28% of Naphtq.)
L+3	0.69	p*C=CBenz. (98% of Benz.)		0.95	p*C=CBenz. (90% of Benz.; 6% of Naphtq.)
L+2	0.55	p*C=CNaphtq. + p*C=CBenz. (20% of Benz.; 76% of Naphtq.)		0.44	p*C=CNaphtq. + p*C=CBenz. (28% of Benz.; 69% of Naphtq.)
L+1	-0.11	p*C=CNaphtq. (98% of Naphtq.)		-0.14	p*C=CNaphtq. (97% of Naphtq.)
LUMO*	-2.06	πC=CNaphtq. + nO + nN (94% of Naphtq.)		-2.10	πC=C Naphtq. + nO (94% of Naphtq.)
HOMO*	-7.29	πC=CBenz. + πC=CNaphtq. + nO + nCl + nN (16% of NH; 45% of Benz.; 12% of OCH3; 27% of Naphtq.)		-7.33	πC=CBenz. + πC=C Naphtq. + nO + nCl + nN (15% of NH; 48% of Benz.; 25% of Naphtq.; 5% of OCH3; 7% of OCH3)
H-1	-8.31	pC=CBenz. + nO + nCl + nN (10% of NH; 30% of Benz.; 11% of OCH3; 49% of Naphtq.)		-8.14	pC=CBenz. + nO + nCl + pC=C Naphtq. (8% of NH; 52% of Benz.; 22% of Naphtq.; 18% of OCH3)
H-2	-8.85	pC=CBenz. (95% of Benz.)		-8.61	pC=CBenz. + nO + nCl (53% of Benz.; 35% of Naphtq.; 9% of OCH3)
H-3	-9.06	pC=CNaphtq. (100% of Naphtq.)		-9.07	pC=C Naphtq. (100% of Naphtq.)
H-4	-9.26	pC=CNaphtq. + nO (97% of Naphtq.)		-9.28	pC=C Naphtq. (95% of Naphtq.)

Benz.: benzene ring; Naphtq.: naphthoquinone ring; n: isolated pair.

Figure 9
Orbital representation at the CAM-B3LYP level of compounds 1a-1d. The contour values of the orbitals are all 0.03 a.u.

According to Borges et al.,⁶⁵ through DFT calculations it is feasible to predict the cytotoxic or cytoprotective effect of quinones by redox mechanism. For this, it is possible to use as a parameter the energy of the molecular orbitals HOMO and LUMO of compounds 1a-1d, whose values are shown in Table 6. It is generally observed that quinones that exhibit higher eHOMO have the ability to donate electrons more easily, being carriers of cytoprotective properties. On the other hand, substances with high eLUMO imply electron acceptor molecules, which have cytotoxic properties. Thus, it can be noted that the quinones 1a-1d studied in this work, especially the compounds 1b and 1c-1d, which contain electron-donating substituents by the electron-donating inductive effect and by the resonance effect, respectively, have high values of eHOMO and low values of eLUMO. These results indicate a greater capacity to donate electrons and, therefore, having probable cytoprotective effects.⁶⁶

Based on Koopman’s theorem, it is worth mentioning that the HOMO-LUMO energy difference for the compounds fluctuates from 5.48 to 5.23 eV in solvent acetonitrile and is very close to the other results obtained for the other two-solvent systems. A relevant observation is that the highest barriers are found for compounds 1a, without a para substituent on the benzene ring, 1b with a methyl substituent (5.39 eV) and the lowest for compounds 1c and 1d with methoxy substituents. Such values are compatible with the inverse order of the activation strength of the substituents on phenyl group, where more activating groups tend to make the species more reactive to the detriment of less activating groups.

Orbitals close to the HOMO-LUMO border of H-3, H-2 through L+1 are characterized by the participation of orbitals associated with pC=C_Benz. and pC=C_Naphtq and isolated pairs of oxygen (carbonyl), nitrogen (amino) and chlorine (halogen) atoms. Specifically, for methoxy groups, orbitals where the most relevant participation exists for these groups are found in regions farther away from the HOMO-LUMO boundary orbitals. The electronic density of states (DOS) revealed that variations in the presence of substituent groups are found in the upper and lower energy ranges, different from those observed for the orbitals near the HOMO-LUMO border (Figure 10). This analysis confirms the similarity of the boundary orbitals, indicating the dominance of the benzenoid group orbital in HOMO and the naphthoquinonic group in LUMO. These trends are also reproduced in data with IEFPCM in CH₂Cl₂ and DMSO, with the results shown in Figures S5 and S6 of the SI section. This analysis confirms the observation highlighted by Rajalakshmi et al.⁵⁴ that intramolecular charge transfer (ICT) occurs from the benzenoid group to the quinone ring.

Figure 10
Energy level diagrams of compounds (a) 1a, (b) 1b, (c) 1c, and (d) 1d with SCF molecular orbitals within the CAM-B3LYP method and density orbital states (DOS) analysis.

Electronic transitions

The first 50 singlet electronic excited states were calculated through the TD-CAM-B3LYP method. The observation of spin-allowed p ®p* transitions was the major concern in this work; therefore, the calculations were restricted to singlet states. All calculations were carried out without symmetry and with ground-state orbitals, to obtain the oscillator strength between the ground state and all excited states. The results of the energy and oscillator strength of the main calculated transitions are listed in Table 7, using the IEFPCM, with MeCN solvent. Tables S17 and S18 show the calculated excited states for IEFPCM with CH₂Cl₂ and DMSO (SI section). All calculations presented the first transition with a monoreferential nature and a dominant configuration coefficient involving the HOMO-LUMO orbitals. The states obtained in the ultraviolet region presented a multiconfigurational nature according to the values of the configuration interaction coefficients. By comparing the experimental results with the calculated excitations with proportional oscillator strengths, it can be seen that variations of less than 0.5 eV were observed in the calculations for the first bands in the UV-Vis spectra for the CAM-B3LYP orbitals regardless of the solvent used.

Table 7
Main singlet transition energies and oscillator strength from the ground state for compounds 1a-1d, for TD-CAM-B3LYP/IEFPCM (solvent MeCN)

Band	Dominant configurationa	Energy / eV	fb		Dominant configurationa	Energy / eV	fb
	1a				1b
1	73®74 (0.90)	2.95	0.1088		77®78 (0.88)	2.92	0.1174
2	70®74 (0.89) 69®74 (0.16); 71®74 (0.38); 72®74 (0.31)	4.27 4.33	0.0918 0.1565		73®78 (0.15); 75®78 (0.12); 76®78 (0.52) 74®78 (0.90)	4.23 4.28	0.1136 0.1132
3	69®74 (0.18); 71®74 (0.15); 72®74 (0.53) 68®74 (0.18); 69®74 (0.37); 71®74 (0.24) 73®75 (0.64); 73®76 (0.17)	4.74 4.96 5.14	0.0688 0.1216 0.6736		73®78 (0.20); 75®78 (0.39); 76®78 (0.27) 72®78 (0.11); 73®78 (0.44); 75®78 (0.29) 77®79 (0.63); 77®80 (0.17)	4.72 4.89 5.11	0.0618 0.1299 0.7351
4	69®75 (0.40); 70®76 (0.10); 71®75 (0.13) 70®75 (0.15); 72®77 (0.15); 73®78 (0.30); 73®79 (0.12) 65®74 (0.14); 72®76 (0.15); 73®77 (0.22)	5.98 6.30 6.44	0.0751 0.1614 0.1247		70®78 (0.86) 73®79 (0.44); 74®80 (0.10) 74®79 (0.26); 77®82 (0.20)	5.79 5.97 6.25	0.0425 0.0822 0.1940
5	63®74 (0.17); 70®76 (0.17) 71®75 (0.16); 71®77 (0.22); 72®77 (0.13)	7.00 7.18	0.3575 0.2862		66®78 (0.22); 76®80 (0.12) 66®78 (0.18); 73®79 (0.13); 74®80 (0.24)	6.97 6.97	0.3459 0.3737
	1c				1d
1	80®82 (0.16); 81®82 (0.81)	2.89	0.1194		88®90 (0.14); 89®90 (0.77)	2.90	0.1140
2	75®82 (0.46); 76®82 (0.14); 80®82 (0.22) 75®82 (0.32); 80®82 (0.41) 78®82 (0.89)	3.86 4.07 4.28	0.0222 0.0623 0.1012		82®90 (0.20); 88®90 (0.47); 89®90 (0.14) 86®90 (0.90) 85®90 (0.10); 87®90 (0.58); 88®90 (0.24)	4.04 4.27 4.36	0.0328 0.1000 0.0705
3	77®82 (0.61); 79®82 (0.12) 77®82 (0.13); 79®82 (0.34); 81®85 (0.36) 79®82 (0.19); 81®83 (0.40); 81®85 (0.16)	4.76 4.89 5.08	0.1479 0.0695 0.4993		85®90 (0.70); 87®90 (0.11) 89®91 (0.33); 89®92 (0.28); 89®93 (0.19) 89®L+1 (0.24); 89®93 (0.37)	4.82 5.03 5.17	0.1818 0.5669 0.1955
4	77®83 (0.41); 80®83 (0.12) 73®82 (0.31); 74®82 (0.18); 78®83 (0.23) 73®82 (0.12); 78®83 (0.33); 81®86 (0.12)	5.94 6.18 6.25	0.1025 0.1264 0.1689		85®91 (0.16); 89®94 (0.21) 85®91 (0.34); 89®94 (0.12) 86®91 (0.45) 88®91 (0.11); 88®92 (0.13); 88®93 (0.16); 89®93 (0.20)	5.90 5.98 6.19 6.29	0.0859 0.0999 0.1154 0.1615
5	76®84 (0.17); 79®85 (0.29); 80®84 (0.14)	6.83	0.3770		85®91 (0.17); 86®92 (0.34)	7.05	0.3516

• ^a
  CI weights to the orbital list, shown in Table 6;
• ^b
  oscillator strength.

Concerning the experimental observations and theoretical results, the final assignments of the UV-Vis spectra electronic transitions are summarized in Table 8. The first transitions of each case are associated with the following assignments pC=C_Benz. + pC=C _Naphtq. + nO + nCl + nN®pC=C _Naphtq. + nO. In other words, the influence of chromophore groups is confirmed in this band, without the participation of orbitals that indicate the presence of methyl or methoxy groups. However, single paired substituents are noted here. The other bands follow this trend, highlighting the nature of the transition p®p* with a multiconfigurational nature in some transitions.

Table 8
Assignment of the electronic transitions at the CAM-B3LYP level for the compounds 1a-1d

Peak	Wavelength / nm			Assignment
	MeCN	CH2Cl2	DMSO
1a
1	470	473	484	pC=CBenz. + pC=C Naphtq. + nO + nCl + nN ® pC=C Naphtq. + nO
2	319	327	332	pC=C Naphtq. ® pC=C Naphtq. + nO	pC=CBenz. + pC=C Naphtq. + nCl ® pC=C Naphtq. + nO
3	275	278	279	pC=C Naphtq. + nO ® pC=C Naphtq. + nO	pC=CBenz. + pC=C Naphtq. + nO + nCl + nN ® p*C=C Naphtq.
4	228	225a		pC=CBenz. + pC=C Naphtq. + nO + nCl + nN ® pC=C Naphtq. + nO	pC=CBenz. + pC=C Naphtq. + nO + nCl + nN ® p*C=CBenz.
5	167a			pC=C Naphtq. ®pC=CBenz. + pC=C Naphtq. + nCl	pC=CBenz. + pC=C Naphtq. + nCl ® p*C=CBenz.
1b
1	478	482	494	pC=CBenz. + pC=C Naphtq. + nO + nCl + nN ® pC=C Naphtq. + nO
2	328	328	332	pC=CBenz. + nCl + pC=C Naphtq. ® pC=C Naphtq. + nO	pC=C Naphtq. ® pC=C Naphtq. + nO
3	276	280	280	pC=CBenz. + pC=C Naphtq. + nO + nCl + nN ® p*C=C Naphtq.	pC=C Naphtq. + nO ® pC=C Naphtq. + nO
4	237	231		pC=C Naphtq. ® p*C=C Naphtq.	pC=C Naphtq. + nO ® p*C=C Naphtq.
5	139a			pC=C Naphtq. ® p*C=CBenz.	nCl + pC=CNaphtq+ pC=O ® pC=C Naphtq. + nO
1c
1	487	490	504	pC=CBenz. + pC=CNaphtq.+nO + nCl + nN ® pC=CNaphtq. + nO + nN
2	331	335	337	pC=CNaphtq. ® pC=CNaphtq. + nO + nN	pC=CBenz. + nO + nCl + nN ® pC=CNaphtq. + nO + nN
3	277	279	281	pC=CBenz. + pC=CNaphtq. + nO + nCl + nN ® p*C=CNaphtq.	C=CNaphtq. + nO ® pC=CNaphtq. + nO + nN
4	233	232		pC=CNaphtq. ® p*C=CNaphtq.	nCl + pC-NNaphtq. + sC-CBenz. + sC-OBenz. ® pC=CNaphtq. + nO + nN
5	169a			pC=CBenz. ® p*C=CBenz.
1d
1	493	496	496	pC=CBenz. + pC=C Naphtq. + nO + nCl + nN ® pC=C Naphtq. + nO
2	332	335	335	pC=C Naphtq. ® pC=C Naphtq. + nO	pC=CBenz. + nO + nCl ® pC=C Naphtq. + nO
3	280	283	283	pC=CBenz. + pC=C Naphtq. + nO + nCl + nN ® p*C=CNaphtq.	pC=C Naphtq. ® pC=C Naphtq. + nO
4	240	230		pC=CBenz. + nO + nCl ® p*C=CNaphtq.	pC=CBenz. + pC=C Naphtq. + nO + nCl + nN ® p*C=CBenz.
5	197a			pC=C Naphtq. ® p*C=CNaphtq. + p*C=CBenz.

• ^a
  Estimated spectrum devolution value. n: isolated pair.

These results are compatible with several studies already carried out with different methods, such as semi-empirical, ab initio and DFT, for structures containing quinone groups with benzoquinone and its functionalized derivatives.²³,²⁸

Conclusions

The synthesis and theoretical-experimental characterization of the four 2-chloro-3-(phenylamino)-1,4-naphthoquinone derivatives presented in this work allowed corroborating and extending the observations highlighted in other studies for this compound class reported in the literature. Specifically, in this work, the combination of structural analysis by X-ray diffraction with the presentation of a new structure and associated with a broad theoretical discussion about the factors influencing the molecular characteristics enabled us to confirm the relevance of the intermolecular forces present in these derivatives. The analysis of the solid-phase vibrational and electronic spectra described in this article corroborated the analysis of the charge distribution, the presence of electronegative functional groups, and the study of the potential energy surface. Furthermore, the success in the spectroscopic assignment based on the isolated molecular units with the application of the implicit solvation model confirmed that such structures can show the maintenance of these conformations. Such information is relevant, since it can provide subsidies for the planning of new 1,4-naphthoquinone derivatives that can be explored for the development of compounds with potentiated biological activities.

Supplementary Information

Crystallographic data (excluding structure factors) for the structures in this work were deposited in the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 2169169. Copies of the data can be obtained, free of charge, via https://www.ccdc.cam.ac.uk/structures/.

Supplementary data are available free of charge at http://jbcs.sbq.org.br as PDF file.

Acknowledgments

The authors acknowledge the financial support received from the Fundação Carlos Chagas de Amparo à Pesquisa do Estado do Rio de Janeiro-FAPERJ (project numbers E-26/210.302/2019 and E-26/211.091/2019), Proppi-UFF (FOPESQ-2020), Conselho Nacional de Desenvolvimento Científico e Tecnológico - Brasil (CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) for the master and doctorate fellowship granted to R. S. M. Moraes. We thank the PhD Henrique de Castro Silva Junior for the discussion on NBO calculations. We would also like to thank in special the LDRX-UFF, LAME-UFF and LMQC laboratory at Universidade Federal Fluminense.

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Edited by

• Editor handled this article: Brenno A. D. Neto (Associate)

Publication Dates

• Publication in this collection
  10 Feb 2023
• Date of issue
  2023

History

• Received
  30 Apr 2022
• Accepted
  28 July 2022