Mixed-Ligand Copper(II) Complex with Ethyl (2-(Methylcarbamoyl)phenyl)carbamate and 3-Methylquinazoline-2,4(1H,3H)-dione

Abstract

(This paper presents the synthesis of a novel copper(II) metal complex with ethyl (2-(methylcarbamoyl)phenyl)carbamate and 3-methylquinazoline-2,4(1H,3H)-dione. The characterization of the compound was conducted through various techniques, including melting point determination, microwave plasma atomic emission spectrometry (MP-AES) for Cu, attenuated total reflection (ATR), IR, ¹H NMR, and ¹³C NMR spectroscopy. The coordination compound was obtained after mixing water solutions of the metal salt and the ligand dissolved in DMSO and water solutions of NaOH, in a metal-to-ligand-to-base ratio of 1:2:2. The ligand and the metal chloride were brought into the reaction at room temperature in DMSO and H₂O as solvents, respectively. The results indicate the successful formation of a stable mixed-ligand Cu(II) coordination compound involving N,O-donor ligands. Based on the obtained data, we assumed that the ligands are coordinated through N- and O-donor atoms. Spectroscopic data suggested that the ligand (3-methylquinazoline-2,4(1H,3H)-dione), by using (NaOH), coordinated to a metal ion as a monodentate ligand through the nitrogen atom of the NH group and ethyl (2-(methylcarbamoyl)phenyl)carbamate coordinated in a bidentate fashion through the N- and O-donor atoms of ester group. Additionally, two hydroxyl groups were bridged for two metal ions into the formed dimer structure.

1. Introduction

Copper (Cu²⁺) is an essential trace element involved in key biological processes, including mitochondrial respiration, antioxidant defense, connective tissue formation, and neurotransmitter synthesis. Its redox activity enables function in enzymes such as cytochrome c oxidase, lysyl oxidase, and superoxide dismutase (SOD) [1,2]. Proper Cu²⁺ homeostasis is crucial, as deficiency leads to impaired neurodevelopment and immunity, while excess induces oxidative stress and tissue damage [3]. Disorders such as Wilson’s and Menkes diseases underscore the importance of copper regulation [4,5,6,7,8]. Ongoing clinical trials are assessing the anticancer potential of copper complexes, and significant advances have been achieved in clarifying their pharmacological properties [9,10].

Anthranilic acid (2-aminobenzoic acid), on the other hand, is a valuable component of polymer systems, improving solubility, stability in neutral/alkaline media, and enabling easy modification via its carboxyl group. Its use has shown benefits in corrosion resistance, electronics, solar cells, and biosensors [11]. Recently, Rio et al. presented a series of 16 anthranilic acid derivatives with different substituents [12]. Prasher and Sharma cover the therapeutic potential of anthranilic acid derivatives, surveying their biological profiles and analyzing key drug candidates [13]. The role of anthranilic acid derivatives as pharmacophoric elements in drug discovery should be noted. Figure 1 presents the structures of biologically important compounds used as rational therapeutic agents. Ganeshpurkar et al. described nucleoside and non-nucleoside RdRP inhibitors, based on scaffolds such as anthranilic acid, benzimidazole, indole, and others [14]. Recently, various anthranilic acid analogs with potential anticancer, antimicrobial, insecticidal, antiviral, and anti-inflammatory activities have been reported [15].

A series of metal complexes were obtained by reaction of anthranilic acid and various metal salts, including Ag(I), Cu(II), Ni(II), Co(II), Zn(II), Fe(II), Mn(II), VO(II), Al(III), Bi(III), and Cr(III) [16,17,18,19,20]. Recently, Marinova and Hristov presented the synthesis and biological application of new complexes with anthranilic acid and its analogs [21]. Additionally, Tsoneva et al. discussed the structure and antibacterial and cytotoxic activities of Ni(II) and Co(II) complexes with ethyl (2-(Methylcarbamoyl)phenyl)carbamate [22].

Therefore, the objective of the current study is to synthesize and characterize the structure of a novel copper(II) complex of ethyl (2-(methylcarbamoyl)phenyl)carbamate.

2. Results and Discussion

2.1. Synthesis of the Metal Complex

Copper coordination compounds continue to be an active area of research, due to their structural diversity, accessible redox states, and functional properties [23,24,25,26]. Among other metals, Cu is an excellent option for the synthesis of complexes with biological and therapeutic uses since it is an essential trace metal [27].

N-donor ligands are among the many potential ligands that are essential for the construction of copper coordination compounds. This allows for the formation of stable complexes with a variety of geometries, which facilitates applications in materials science, catalysis, and medicine [28].

Copper(II) complexes with bidentate ligands represent an important and extensively researched family of coordination compounds from a structural standpoint, with carboxylates being among the most common [29].

Therefore, the current study aims to synthesize and characterize a novel copper(II) complex of ethyl (2-(methylcarbamoyl)phenyl)carbamate.

The metal complex was prepared by combining aqueous solutions of the metal salt and NaOH with the ligand dissolved in DMSO, using a metal-to-ligand-to-base ratio of 1:2:2. The only ligand added in the reaction mixture was L1.

We found that the copper complex is stable in air and moisture, and its solubility is limited. The reaction of L1 with the transition metal ion afforded a 35% yield of a stable solid compound. The obtained complex has a bright blue color and limited solubility in DMSO and was insoluble in water, acetone (CH₃COCH₃), tetrahydrofuran (THF), ethanol (C₂H₅OH), ethyl acetate (EtOAc), and cyclohexane. The analytical data, including the yield percentage of the complex, are presented in

Table 1. Analytical and physical characteristics of copper(II) complex ethyl (2-(methylcarbamoyl)phenyl)carbamate (L1) and 3-methylquinazoline-2,4(1H,3H)-dione (L2).

Compound	Solubility	Melting Point (°C)	Yield (%)	Color
L1	soluble in DMSO and CHCl3	136–137	80	colorless
Cu complex	Limited solubility in DMSO, insoluble in H2O, THF, CH3COCH3, EtOH, EtOAc and cyclohexane	243–245 °C	35	bright blue

.

It should be noted that a mixed ligand copper(II) complex of ethyl (2-(methylcarbamoyl)phenyl)carbamate and 3-methylquinazoline-2,4(1H,3H)-dione was obtained for the first time.

2.2. Spectral Data of the Cu(II) Complex

IR- and ATR-Spectra

The structure of the metal complex was readily confirmed by comparing the IR spectra of the free ligands with those of the corresponding metal complex. Selected experimental IR data (cm⁻¹) for the complex and its free ligands are presented in

Table 2. Selected experimental IR data (in KBr, wavenumber in cm⁻¹) for free ligands and their copper(II) complex.

Assignment	L1	L2 [23]	Cu(II)
ν(OH)	-	-	3435
ν(NH, -C(=O)-NH-CH3)	3345		3345
ν(NH, -NH-C(=O)OCH2CH3)	3258		-
ν(NH)		3165	3188
ν(Csp2-H, -Ph)	3072	n/a	3058
ν(C=O)	1739	1715	1717
δ(NH) + ν(C=O), -C(=O)-NH-CH3)	1664		1665
ν(C=O)		1662
δ(NH) + ν(C=O), -NH-C(=O)OCH2CH3)	1633		1645
ν(M-N)	=		563
ν(M-O)	=		467

.

As previously reported [22], the IR spectra revealed additional bands of 3-methylquinazoline-2,4(1H,3H)-dione (L2) in addition to the bands of the ligand L1. As previously described, we assumed that the ligand L2 was formed as a more stable product in the reaction conditions [22].

The structures of the free ligands are given in Figure 2.

The IR spectrum of the free ligand (in blue) and its metal complex with Cu(II) (in red) are given in Figure 3. In the IR spectrum of L1, bands at 3345 cm⁻¹ and 3258 cm⁻¹ correspond to N-H stretching vibrations. For L2, the N-H stretching band appeared at 3165 cm⁻¹ [30]. This band was shifted to higher frequencies by 23 cm⁻¹ in the copper(II) complex, indicating that the N-H group of L2 participates in coordination. The band at 3258 cm⁻¹ in the IR spectrum of the complex was absent. This fact showed that the N-donor atom of L1 participates in coordination with copper(II). In the spectra of L1 and L2, bands at 1739 cm⁻¹ and 1715 cm⁻¹ were assigned to C=O stretching vibrations. The band of the L1 at 1739 cm⁻¹ was shifted to lower frequencies by 22 cm⁻¹, suggesting that the C=O group of L1 does coordinate with the metal ion, but not the C=O of L2. The appearance of new bands in copper complex at 563 cm^−1, assigned to Cu-N vibration, and at 467 cm⁻¹ assigned to Cu-O, respectively. This is similar to the appearance of new bands at 588, 531, and 529 cm⁻¹ assigned to Co-N, Ni-N, and Mn-N and 487 cm⁻¹ for M-O vibration in complexes which Ajibulu obtained [31]. Additionally, a broad band at 3435 cm⁻¹ appears in the complex spectrum, confirming the presence of coordinated water molecules or hydroxyl groups. These findings are consistent with previously reported mixed-ligand complexes of anthranilic acid [31,32]. IR spectra of the Schiff base complexes exhibited bands at 3344–3573 cm⁻¹, which is attributed to the stretching frequencies of a hydrated water molecule [24]. The band at 854 cm⁻¹ can be attributed to the stretching vibration of water-coordinated molecule (δ(H₂O)) [31], similar to our copper complex, where the same band appears at 837 cm⁻¹.

All vibrational frequencies observed in the ATR spectra of the copper complex and the free ligand L1 are given in the Experimental section and in the Supplementary Material Figures S11–S13. In the ATR spectrum of the Cu(II) complex, in the 3548–3433 cm⁻¹ region was observed band that can be attributed to the stretching vibration of ν(OH). In the ATR spectrum of L1, bands at 3342 cm⁻¹ and 3251 cm⁻¹ correspond to N-H stretching vibrations. It should be noted that the same bands in the ATR spectrum of Cu(II) complex were missing. The band of free ligand L1 at 1727 cm⁻¹ can be attributed to the stretching vibration of C=O group of ethyl (2-(methylcarbamoyl)phenyl)carbamate. The same band in the ATR spectrum of the Cu(II) complex appeared at 1714 cm⁻¹ and shifts to a lower frequency by 13 cm⁻¹ as compared to the corresponding free ligand band. This fact shows that the carbonyl and NH from NH-C(=O)OCH₂CH₃ groups of the L1 participate in the coordination with Cu metal ion. Based on the experimental data, the most probable structure for the Cu(II) complex was suggested with two ligand molecules, one coordinated bidentate with O-,N-donor atoms of L1 and other of L2 coordinated monodentate through N-atom nonodentate. The ATR data presented were in agreement with the IR spectrum data and elemental analyses of copper determined by MP-AES.

2.3. NMR-Spectral Data

The experimental ¹H-NMR data for the copper complex and its free ligands are presented in

Table 3. ¹H-NMR data for L1, L2, and its complex with Cu(II).

Atom	δ (1H) ppm L1	δ (1H) ppm L2 [33]	δ (1H) ppm Cu(II)
NH(COO)	10.96 (s)		10.95 *
NH		11.43 (s)	11.42 **
NHCH3	8.72 (q)		8.71 *
CH	8.19 (dd)	7.93 (d)	8.18 * 7.92 **
CH	7.70 (dd)	7.64–7.66 (m)	7.70 * 7.64 **
CH	7.48 (ddd)	7.17–7.21 (m)	7.48 * 7.18 **
CH	7.08 (ddd)	7.17–7.21 (m)	7.08 * 7.18 **
NHCH3	2.78 (d)	3.26 (s)	2.78 * 3.25 **
CH2	4.12 (q)		4.12 *
CH3	1.23 (t)		1.23 *

*—signals of L1 protons in the complex; **—signals of L2 protons in the complex. All signals in the complexes are broad singlets unless otherwise noted.

. It should be noted that in all NMR spectra we used DMSO-d₆ as a solvent. In the ¹H-NMR spectrum of the copper(II) complex, the signal for the proton from the NHCH₃ group is shifted to a lower frequency by 0.01 ppm (see Table 3). The use of DMSO-d₆ would justify the absence of significant differences in NMRs of the free ligands and the complex. It is in fact possible that DMSO-d₆ displaces the ligands from Cu coordination, which also explains the broad signals of the complex. The presented data are in agreement with the IR spectrum data.

The ¹³C-NMR data for the mixed ligand complex of ethyl (2-(methylcarbamoyl)phenyl)carbamate (L1), 3-methylquinazoline-2,4(1H,3H)-dione (L2), and their metal complex are given in

Table 4. ¹³C-NMR data for L1, L2 and its Cu(II) complex.

Atom	δ (13C) ppm L1	δ (13C) ppm L2 [33]	δ (13C) ppm Cu(II)
NH(C=O)	169.16	162.6	169.16 * 162.64 **
NH(COO)	153.37	150.8	153.43 * 150.82 **
C	139.67	139.8	139.62 * 139.76 **
CH	132.53	135.3	132.52 * 135.32 **
CH	128.40	127.7	128.40 * 127.72 **
CH	122.16	122.9	122.16 * 122.89 **
C	120.03	114.1	120.03 * 114.14 **
CH	119.05	115.5	119.06 * 115.52 **
CH2CH3	61.04	-	61.04 *
NHCH3	26.68	27.5	26.69 * 27.46 **
CH2CH3	14.85	-	14.86 *

*—signals of L1 in the complex; **—signals of L2 in the complex. All signals in the complex are broad singlets unless otherwise noted.

.

In the ¹³C-NMR spectrum of the copper(II) complex, the signal for the carbon from the NH(C=O) group was not shifted (see Table 3). In the same spectrum, the signal for the carbon from NH(COO) group was not changed. This is an indication that the two carbonyl groups do not coordinate with the metal ion. The presented NMR data were in agreement with the IR spectrum data.

We assumed that the ligand L1 in the complex coordinates bidentately through the N-atom and O-atom (see Figure 4). We observed that two hydroxyl groups were bridged with the two metal centers. The L2 coordinates monodentately through the N-atom. The structure of the newly obtained copper complex is similar to that reported by Singh et al. in two bis-μ-hydroxo-bridged copper dimers [34] and with the dinuclear copper(II) complexes contain a five-coordinated metallic center in a square pyramidal environment [35]. The structure of the obtained complex is analogous to the Pd(II) complex of N-(2-benzoyl-4,5-dimethoxyphenethyl)-2-phenylacetamide [36]. More recently, Akeredolu et al. synthesized Mn(II), Co(II), Ni(II), and Cu(II) complexes of ethanolamine and 3-nitrobenzaldehyde obtained under alkaline conditions using KOH [37]. In these mixed-ligand complexes, the coordination involved nitrogen and oxygen donor atoms and a chelate structure was formed. Ajibulu et al. presented new Ni(II), Co(II), and Mn(II) complexes where the Schiff base coordinated with nitrogen atoms in a bidentate fashion [31]. Jiemuratova et al. obtained new coordination compounds produced from the interaction between anthranilic acid ligand and transition metal salts (Fe(III), Cu(II), Ni(II), and Co(II)) [38]. The metal–ligand binding takes place through the carboxyl and amino functional groups of the ligand, leading to the generation of stable chelated complexes [38]. The literature surveys reveal that anthranilic acid-based Schiff bases typically coordinate metal ions through azomethine nitrogen (-N=CH-) and the deprotonated hydroxyl oxygen of the carboxyl group, rather than the carbonyl oxygen (C=O) [39]. Some studies, however, report coordination via imine nitrogen and carbonyl oxygen. Although numerous complexes of first-row transition metals exhibit diverse geometries and varying ligand denticities—ranging from N,O-bidentate to O,N,O-tridentate and N₂O₂-tetradentate—have been extensively described, only a limited number of analogous complexes involving heavier transition metals have been documented [39].

Based on the obtained results, the possible structure of the mixed ligand complex of ethyl (2-(methylcarbamoyl)phenyl)carbamate (L1) and 3-methylquinazoline-2,4(1H,3H)-dione (L2) with Cu(II) is proposed (Figure 4).

3. Materials and Methods

3.1. Spectral Data of the Free Ligand

Ethyl (2-(methylcarbamoyl)phenyl)carbamate (L1): white crystals, 80% yield, mp = 136–137 °C [22].

IR (KBr, cm⁻¹): 3345 (ν(N-H)), 3258 (ν(N-H, -NC(=O)O)), 3116 (ν (Csp²-H, Ph-)), 3072 (ν (Csp²-H, Ph-)), 2985 (ν_as(Csp³-H, CH₃-)), 2951 (ν_as (Csp³-H, CH₃-)), 2913 (ν_as (Csp³-H, >CH₂)), 2880 (ν_s (Csp³-H, CH₃-)), 1739 (ν(C=O)), 1664 (δ(-NH) + ν(C=O)), 1633 (δ(-NH) + ν(C=O)), 1605 (ν(C=C-C), Ph-), 1593 (ν(C=C-C), Ph-), 1554 (δ(-NH)), 1530 (ν (C=C-C), Ph-), 1454 (ν(C=C-C), Ph-), 1409, 1390 (δ_s(-CH₃)), 1364 (δ_s(-CH₃)), 1333, 1248, 1218 (ν_as(N-CO-O-)), 1167, 1149, 1122, 1114, 1063, 1049, 951 (ν_s(N-CO-O-)), 870, 849, 820, 768, 753 (γ (Csp²-H, Ph-), 721, 669, 651, 536, and 510.

Raman (cm⁻¹) of L1: 2939, 1730 (C=O), 1641, 1604, 1592, 1555, 1463, 1454, 1392, 1366, 1334, 1305, 1288, 1249, 1219, 1169, 1151, 1123, 1052, 1012, 915, 849, 822, 613, 395, and 364 [22].

¹H-NMR: 1.24 (t, J = 7.1, 3H, CH₂CH₃), 2.79 (d, J = 4.4, 3H, NHCH₃), 4.13 (d, J = 6.8, 2H, CH₂CH₃), 7.07–7.11 (m, 1H, Ar), 7.49 (t, J = 7.8, 1H, Ar), 8.2 (d, J = 8.3, 1H, Ar), 8.72 (broad s, 1H, CONHCH₃), and 10.96 (s, 1H, NHCOO).

¹³C-NMR: 169.17, 153.38, 139.7, 132.5, 128.4, 122.17, 120.04, 119.06, 61.05, 26.69, and 14.86.

ATR (cm⁻¹) of L1: 3342 (ν(N-H)), 3251 (ν(N-H, -NC(=O)O)), 3116 (ν (Csp²-H, Ph-)), 3073 (ν (Csp²-H, Ph-)), 2985 (ν_as(Csp³-H, CH₃-)), 2951 (ν_as (Csp³-H, CH₃-)), 2912 (ν_as (Csp³-H, >CH₂)), 1966, 1930, 1820, 1727 (ν(C=O)), 1664 δ(-NH) + ν(C=O)), 1631 (δ(-NH) + ν(C=O)), 1590 (ν(C=C-C), Ph-), 1527 (ν (C=C-C), Ph-), 1481, 1447, 1408, 1365 (δ_s(-CH₃)), 1332, 1285, 1245, 1215 (ν_as(N-CO-O-)), 1166, 1150, 1122, 1114, 1062, 1048, 1026, 951(ν_s(N-CO-O-)), 914, 870, 848, 819, 751 (γ (Csp²-H, Ph-), 712, 693, 683, 668, 649, and 612.

3.2. Spectral Characteristics for the Cu(II) Complex

IR (KBr, cm⁻¹): 3435 (ν(OH)), 3345 (ν(NH, -C(=O)-NH-CH₃)), 3188 (ν(NH, -NH-C(=O)OCH₂CH₃)), 3058 (ν(C_sp2-H, -Ph)), 3005, 2956, 2921, 1717 (ν(C=O)), 1665 (δ(NH) + ν(C=O),-C(=O)-NH-CH₃)), 1645 (δ(NH) + ν(C=O), -NH-C(=O)OCH₂CH₃)), 1624, 1598, 1556, 1530, 1514, 1493, 1453, 1430, 1386, 1341, 1302, 1295, 1219, 1174, 1155, 1040, 1025, 873, 837, 762, 751, 713, 693, 683, 667, 563, 534, 467, and 432.

¹H-NMR: 1.23 *(t, 3H,) CH₂CH₃), 2.78 *, 3.25 **, 4.12 *, 7.08 *, 7.18 **, 7.48 *, 7.18 **, 7.70 *, 7.64 **, 8.71 *, 8.18 *, 7.92 **, 10.95 *, and 11.42 **. (*—signals of L1 protons in the complex; **—signals of L2 protons in the complex)

¹³C-NMR: 169.16 *, 162.64 **, 153.43 *, 150.82 **, 139.62 *, 139.76 **, 132.52 *, 135.32 **, 128.40 *, 127.72 **, 122.16 *, 122.89 **, 120.03 *, 114.14 **, 119.06 *, 115.52 **, 61.04 *, 26.69 *, 27.46 **, and 14.86 * (*—signals of L1 carbons in the complex; **—signals of L2 carbons in the complex).

ATR (cm⁻¹): 3548, 3511, 3433 (ν(OH)), 3051 (ν (Csp²-H, Ph-)), 2913 (ν_as (Csp³-H, >CH₂)), 1714 (ν (C=O)), 1663 δ(-NH) + ν(C=O)), 1643 δ(-NH) + ν(C=O)), 1623 (δ(-NH) + ν(C=O)), 1598 (ν(C=C-C), Ph-), 1514 (ν (C=C-C), 1492, 1451, 1429, 1385 (δ_s(-CH₃)), 1341, 1302, 1294, 1269, 1221, 1174, 1155, 1106, 1039, 1025, 961, 927 (ν_s(N-CO-O-)), 873, 833, 760, 750 (γ (Csp²-H, Ph-), 713, 693, 683, and 667.

A mass of 0.01 g of the complex was digested in 50% v/v HNO₃. After dilution, the concentration of Cu was determined by inductively coupled plasma mass spectrometry (ICP-MS) Agilent 7700. Isotopes ⁶³Cu and ⁶⁵Cu were measured in He-collision mode using external calibration and ¹⁰³Rh as an internal standard. Results: W(Cu)% = 28.9 ± 3.4

3.3. Synthesis of Cu(II) Complex of Ethyl (2-(Methylcarbamoyl)phenyl)carbamate (L1) and 3-Methylquinazoline-2,4(1H,3H)-dione (L2)–General Procedure

The metal complex was prepared by combining aqueous solutions of the metal salt and NaOH with the ligand dissolved in DMSO, using a metal-to-ligand-to-base ratio of 1:2:2 (the only ligand added was L1). A neutral bright blue precipitate formed, which was subsequently filtered, washed repeatedly with water, and dried over CaCl₂ for two weeks. The synthesis was performed according to a previously reported procedure [22].

3.4. Spectra Measurements

The free ligands ethyl (2-(methylcarbamoyl)phenyl)carbamate and 3-methylquinazoline-2,4(1H,3H)-dione were published previously [22]. The metal salts CuCl₂ (Aldrich Chem) and solvents used for the synthesis of the complexes were of high purity, generally equal to A.C.S. grade and suitable for use in many laboratory and analytical applications. Melting points were measured on a Kruss M5000 melting point meter (A.Krüss Optronic GmbH, Hamburg, Germany). The IR spectra of L1 and its complex were registered in KBr pellet on a Bruker FT-IR VERTEX 70 Spectrometer (Bruker Optics, Ettlingen, Germany) from 4000 cm⁻¹ to 400 cm⁻¹ at a resolution of 2 cm⁻¹ with 25 scans. The NMR spectra of the ligand were registered on a Bruker Avance II NMR spectrometer (Guelph, Ontario, Canada) operating at 600.130 and 150.903 MHz for ¹H and ¹³C, respectively, using the standard Bruker (version 3.6.3) software. The NMR spectra of the metal complex were measured on a Bruker Avance III HD spectrometer (Bruker, Billerica, MA, USA) operating at 500.130 and 125.76 MHz for ¹H and ¹³C, respectively, using the standard Bruker (version 3.6.5) software.

4. Conclusions

This work presents the synthesis of a new mixed ligand complex of ethyl (2-(methylcarbamoyl)phenyl)carbamate (L1) and 3-methylquinazoline-2,4(1H,3H)-dione (L2) with Cu(II). The structure of the new complex is discussed based on melting point analysis, IR, ¹H-, and ¹³C-NMR spectroscopy. Based on the spectral data, we suggested a coordination binding site for the ligands. We assumed that in the mixed-ligand complex, the coordination for L1 involved nitrogen and oxygen donor atoms, and a chelate structure was formed. L2 was coordinated by a monodentate N-atom. Two hydroxyl groups were bridged for two copper ions to form a dimer structure.