SYNTHESIS OF THE COMPLEXES OF QUINAZOLINE-4(3H)-ONE WITH VARIOUS METAL SALTS (Ag, Cu, Pb) AND THEIR INFRARED SPECTROSCOPIC ANALYSIS

ABSTRACT

In this study, complexes of xinazolin-4(3H)-one with Ag(I), Cu(II), and Pb(II) metal ions were synthesized, and their infrared (IR) spectroscopic properties were extensively analyzed. Derivatives of quinazoline belong to an important class of heterocyclic structures that exhibit high biological activity in medicine, agriculture, and pharmacology. The interactions between xinazolin-4(3H)-one and metal ions, as well as structural changes during complex formation, were comparatively studied through IR spectra. Spectral analysis confirmed coordination of the ligand via its nitrogen atoms by observing significant shifts in C=N and C–N vibrations, intensification of aromatic ring deformations, and the appearance of new metal–nitrogen (M–N) vibration bands in the 600–450 cm⁻¹ region. The complexation strength was found to follow the order Pb(II) > Cu(II) > Ag(I). The obtained results demonstrate that xinazolin-4(3H)-one can form stable coordination complexes with various metals and highlight its potential as an effective ligand for future synthesis of biologically active compounds.

АННОТАЦИЯ

В данной работе синтезированы комплексы хиназолин-4(3H)-она с ионами металлов Ag(I), Cu(II) и Pb(II), а также проведён подробный анализ их инфракрасных (ИК) спектроскопических характеристик. Хиназолиновые производные относятся к важным гетероциклическим структурам с высокой биологической активностью, широко применяемым в медицине, фармакологии и сельском хозяйстве. В исследовании рассмотрено взаимодействие хиназолин-4(3H)-она с ионами металлов, структурные изменения при образовании комплексов и их сопоставление на основе ИК-спектров. Спектроскопический анализ показал значительные сдвиги полос C=N и C–N, усиление деформации ароматического кольца, а также появление новых полос в области 600–450 см⁻¹, характерных для связей металл–азот (M–N), что подтверждает координацию лиганда через атомы азота. Установлено, что прочность комплексообразования изменяется в ряду Pb(II) > Cu(II) > Ag(I). Полученные результаты демонстрируют высокую способность хиназолин-4(3H)-она образовывать устойчивые координационные комплексы с различными металлами, что подчёркивает его перспективность в синтезе биологически активных соединений.

Keywords: quinazoline‑4(3H)-one, metal complexes, Ag(I), Cu(II), Pb(II), infrared spectroscopy, coordination, ligand, M–N bond, spectral analysis

Ключевые слова: хиназолин-4(3H)-он, металлические комплексы, Ag(I), Cu(II), Pb(II), инфракрасная спектроскопия, координация, лиганд, связь M–N, спектральный анализ

Introduction

In recent years, many derivatives synthesized on the basis of heterocyclic compounds containing the quinazoline nucleus have been widely used in agriculture and medicine. The main reason for this is that quinazoline -based substances are effectively employed against viruses, bacteria, fungi, colds and oncological diseases [1], as well as being useful as plant-growth stimulators [2]. Nowadays, diseases considered especially relevant — cardiovascular diseases of the circulatory system [3], diabetes mellitus [4], various oncological diseases [5] and viral infections [6] — are widespread. As an example, one can cite drugs such as imatinib [7], erlotinib [8], afatinib [9], gefitinib [8,10,11] which belong to the class of quinazoline derivatives and are used against tuberculosis and cancer.

The presence of reactive centers in molecules containing the quinazoline ring — the N-1 and N-3 nitrogen atoms, the C-4 carbonyl group, and the C-5 and C-8 positions of the fused benzene ring — allows them to undergo nucleophilic and electrophilic substitution reactions [16–19]. From this point of view, electrophilic substitution reactions occurring especially at the N-3 position are of particular importance. That is, by synthesizing derivatives with various halogenated compounds and alkyl halides, and changing their functional groups, it becomes possible to discover new fundamental regularities, as well as to identify biologically active substances. In particular, it is considered important to synthesize complex compounds and, on that basis, multifunctional drugs.

Method.

The solvents used — chloroform, hexane, cyclohexane, benzene, ethyl alcohol and methyl alcohol — were dried and purified based on data from the literature [14]. The IR spectra were studied using FT‑IR/NIR Spectrum 3 IR‑Fourier spectrometer (Perkin Elmer), applying the general and total reflection method. The synthesized compounds were checked by thin layer chromatography (TLC), using “Sorbfil” (Russia) and “Whatman® UV‑254” (Germany) plates. As eluents (solvent systems), ethanol:water (3:1) and ethanol:methanol (8:1) mixtures were used. The melting points of the synthesized compounds were determined using “Boetius” (Germany) and “MEL‑TEMP” (USA) instruments.

Result and Discussion.

Quinazolin-4(3H)-one (1). 1.46 g (0.01 mol) of AgNO₃ and 3.4 g (0.02 mol) were placed in a 100 mL round‑bottom flask, connected with a reflux condenser, and heated for 2–3 hours in a water bath at 90–101 °C. At first the mixture boiled, then a clear solution was formed. The resulting clear solution was monitored to remain neutral (pH = 5–6) until the process was completely finished. The obtained clear solution was evaporated under vacuum to dryness to obtain the product for crystallization. The resulting crystals were stored for 1 week in a dark place in ethyl alcohol (C₂H₅OH) for recrystallization, which yielded 1.56 g (98 %) of the compound with a melting point of 245 °C.

IR spectrum (ν, cm⁻¹): 1395.94 (C–N), 2915.26 (C–H), 2990 (CH₂), 1669 (C=O), 1609 (C=N).

The obtained IR spectrum — analysis in the main region 3200–2800 cm⁻¹: C–H stretching (aromatic and CH₃).

The IR spectra of quinazoline and the complex product obtained with AgNO₃ were compared (Fig. 2). The comparison results show that during the process of complex formation, significant changes occurred in the molecule’s electronic structure and vibrational properties.

In general, when the complex formed, a number of major vibrational bands in the IR spectrum were shifted, their intensities increased, or new vibrations appeared. This clearly confirms that coordination between the quinazoline molecule and Ag⁺ ion has occurred.

C–H stretching vibrations (3200–2800 cm⁻¹) In both spectra the vibrations characteristic of aromatic and aliphatic C–H bonds were observed in the 3050–2900 cm⁻¹ range. In the complex spectrum, these bands became somewhat broadened and their intensity decreased, which can be explained by redistribution of electron density in the molecule.

C=N and aromatic ring vibrations (1700–1500 cm⁻¹) In quinazoline the C=N stretching vibration appears around 1668–1650 cm⁻¹. In the spectrum of the complex the said vibration is shifted by about 20–30 cm⁻¹ towards lower wavenumbers. This shift indicates that coordination with Ag⁺ via the ring nitrogen has occurred, because coordination reduces the bond strength of the C=N bond. The shift of the aromatic‑ring vibrations in the 1510–1470 cm⁻¹ region also confirms the presence of interaction with the metal.

C–N and ring vibrations (1300–1000 cm⁻¹) In the 1290–1150 cm⁻¹ range, significant changes were observed in the C–N stretching vibrations: the bands broadened, their intensity increased, and the frequencies shifted by 10–20 cm⁻¹. This indicates that the electron density around the N atom changed as a result of coordination. The increase in intensity of the vibrations in the 1130–1020 cm⁻¹ region also supports the formation of the complex.

Low‑frequency region (900–500 cm⁻¹) In pure quinazoline, the ring deformation vibrations were observed in the 880–650 cm⁻¹ region. In the complex spectrum, new vibrations appeared around 830–760 cm⁻¹ and 720–600 cm⁻¹. The bands observed at 550–450 cm⁻¹ may be related to Ag–N bond vibrations or deformation vibrations of the nitrate ion.

Infrared spectral analysis clearly confirms that the quinazoline molecule forms a coordination complex with the Ag⁺ ion. The shift of the C=N stretching vibration to lower frequencies, the broadening of vibrations in the 1500–1200 cm⁻¹ region, and the appearance of new bands in the 900–500 cm⁻¹ range are spectral evidence of complexation. These results indicate that the metal ion is coordinated primarily through the ring nitrogen, and that electron density in the molecule is redistributed on complex formation.

The infrared spectra of quinazoline and the complex product obtained with AgNO₃ were recorded (Fig. 3).

The infrared spectroscopy results (Fig. 3) clearly show the differences in functional groups between the two samples based on quinazoline. In the high‑frequency region of the spectra (3200–2800 cm⁻¹), the bands observed at 3123–2922 cm⁻¹ correspond to aromatic C–H stretching, and in both samples these appeared in the same way. This confirms that the aromatic framework of the molecule remained intact.

1700–1600 cm⁻¹ region: changes in C=O / C=N groups In the black spectrum, there are clearly expressed strong vibrations in the 1698–1654 cm⁻¹ range — these correspond to the C=O / C=N stretching vibrations characteristic for the quinazoline structure. In the red spectrum, the frequencies of these bands are shifted to the 1694–1603 cm⁻¹ range. This shift indicates a redistribution of electron density and a change in the bonding strengths around these functional centers. The difference between spectra confirms that the chemical environment of the imino / carbonyl center in the molecule has significantly changed.

1500–1200 cm⁻¹ region: C–N and aromatic‑skeletal vibrations In the spectra of both samples, the bands at 1464, 1387, 1318 and 1232 cm⁻¹ are associated with C–N stretching and deformation of the aromatic ring. In the red spectrum (the complex), the shape, intensity and frequencies of these bands changed — they were redistributed in the regions 1388–1323 and 1249–1232 cm⁻¹.

This change clearly confirms that the stable electronic structure of the aromatic ring in quinazoline has been altered. In particular, the increase in intensity of the C–N vibrations indicates a change in electron density at the N‑center.

1100–700 cm⁻¹ region: changes in ring and substituents The vibrations in the 1100–700 cm⁻¹ region correspond to C–H vibrations outside the aromatic ring. Between the black and red spectra there are clear differences at lines 1170, 1124, 1024, 909, 880, 803, 763 and 725 cm⁻¹. The changes in frequencies indicate significant differences in the spatial arrangement of the substituent groups attached to the aromatic ring and in their ability to deform.

Low‑frequency region 600–400 cm⁻¹

In both spectra, vibrations at 543, 500 and 464 cm⁻¹ were noted. In the red spectrum these bands are intensified, which confirms ring‑deformations and changes in bonding angles. The differences in this region show a clear distinction in the stable structure of the molecule and the vibration properties when heavy atoms are involved.

Comparative analysis of the IR spectra shows that the main difference between the two quinazoline‑based samples lies in the shift of the C=O/C=N vibrational frequencies, increase in intensity of C–N vibrations, and redistribution of ring deformations in the 1100–700 cm⁻¹ region. These changes reliably confirm that the electronic structure of the molecule has been reorganized, that the influence of substituents has increased, and that the bonding tensions around the ring have changed (Fig. 4).

Quinazolin-4(3H)-one (1). 1.46 g (0.01 mol) and 6.62 g (0.02 mol) of Pb(NO₃)₂ were placed in a 100 mL round‑bottom flask, connected to a reflux condenser, and heated for 2–3 hours in a water bath at 90–101 °C. At first the mixture boiled, then a clear solution formed. The resulting clear solution was monitored to stay neutral (pH = 5–6) until the process was completely finished. The clear solution obtained was evaporated under vacuum to dryness to isolate the product for crystallization. The resulting crystals were stored for 1 week in ethyl alcohol (C₂H₅OH), in a dark place, for recrystallization. As a result, 1.56 g (98%) of the compound was obtained, with a melting point of 245 °C.

The IR spectra of quinazoline and its complex with Pb(NO₃)₂ were obtained (Fig. 5).

The comparison clearly shows that the complexation process led to structural changes. The main differences between the spectra are observed through shifts in vibrational frequencies, intensity, and shape of the functional groups.

3400–2800 cm⁻¹ region: O–H/N–H and C–H stretching vibrations In the complex spectrum, a broad, high‑intensity band is observed around 3447 cm⁻¹, indicating that the hydrogen bonding system within the molecule has been strengthened under the influence of Pb(II) ions. In quinazoline, the corresponding bands (3123–2920 cm⁻¹) appear in a narrower form. The C–H stretching vibrations in the 2849–2916 cm⁻¹ range are slightly weakened in the complex spectrum, suggesting that the electron density around the ring has been redistributed following coordination with Pb(II).

1700–1600 cm⁻¹ region: changes in C=N and carbonyl centers This region shows the most significant spectral differences confirming complexation. In quinazoline, characteristic C=N stretching vibrations appear in the 1694–1603 cm⁻¹ range. In the Pb(II) complex, these bands are shifted to 1701–1654 cm⁻¹. The shift of the C=N vibrations to higher frequencies confirms the formation of a coordination bond. The Pb²⁺ ion binds to the nitrogen center, increasing the bond strength of C=N, which is reflected in the frequency increase. Consequently, the coordination of the nitrogen atom with Pb(II) is reliably evidenced spectrally.

1580–1400 cm⁻¹ region: In the complex spectrum, the aromatic‐skeletal vibrations show clear differences: peaks at 1576 cm⁻¹ and 1449 cm⁻¹ become distinctly stronger, which indicates that deformation vibrations of the aromatic ring are enhanced. In quinazoline the corresponding bands are more diffuse and of lower intensity. This difference suggests that the electron system of the aromatic ring has changed due to coordination with Pb²⁺.

1350–1200 cm⁻¹ region: C–N and NO₃⁻ group vibrations. In the complex spectrum, the regions around 1388, 1318 and 1228 cm⁻¹ appear clearly and strongly. This supports two effects: strengthening of the C–N bond due to Pb–N coordination, and the addition of vibrations from the nitrate ion (NO₃⁻) present in Pb(NO₃)₂. In quinazoline, these regions are much weaker, further confirming complex formation (Fig. 6).

1100–700 cm⁻¹ region: deformations of ring and substituents In the complex spectrum the bands at 1127, 1043, 890, 809, 766 cm⁻¹ become clearly amplified and change in shape compared with the spectrum of quinazoline. These differences indicate: the C–H vibrations outside the aromatic ring have been redistributed; there has been a spatial reorganization in the molecule. The coordination of the Pb(II) ion likely occurred near the “ring center”.

In the 600–420 cm⁻¹ spectral region (chromophore region): Pb–N vibrations, and the appearance in the complex spectrum of bands at 598 cm⁻¹, 529 cm⁻¹ and in the 461–423 cm⁻¹ region is characteristic for the Pb–N coordination bond. In the case of the ligand (quinazoline), the bands in that region are not arranged in this manner. This firmly confirms that Pb(II) is directly coordinated to the molecule.

IR spectral analysis clearly confirms the complexation process between quinazoline and Pb(NO₃)₂. In the complex spectrum, the shift upward of the C=N stretching vibrations, the strengthening of C–N and aromatic ring vibrations, along with the appearance of vibrations characteristic of Pb–N bond in the 600–420 cm⁻¹ region, indicate that the Pb(II) ion has formed a coordination bond with the nitrogen center in the quinazoline molecule.

These results definitively demonstrate that formation of the complex significantly affected the electronic structure of the molecule.

Conclusion

Infrared spectroscopy results clearly confirmed that the quinazoline‑based compounds form stable complexes with Ag(I), Cu(II) and Pb(II) ions. The upward shift of the C=N stretching vibration, the intensification of the C–N vibrations, and the appearance of lines characteristic for M–N bonds in the 600–450 cm⁻¹ range show that the ligand coordinates mainly through the nitrogen atom. According to the spectral description, the order of coordination strength was determined as: Pb(II) > Cu(II) > Ag(I). The complexation process causes significant changes in the electronic structure of the molecule, confirming that quinazoline can serve as an effective bidentate ligand for metal ions.

References:

1. Wu X., Li M., Tang W., Zheng Y., Lian J., Xu L., Ji M. Design Synthesis and In vitro Antitumor Activity Evaluation of Novel 4-pyrrylamino Quinazoline Derivatives. //Chemical biology & drug design. -2011;78(6):932-940 p.
2. Singh K, Sharma P, Kumar A, Chaudhary A, Roy R. 4-Aminoquinazoline Analogs: A Novel Class of Anticancer Agents. //Mini reviews in medicinal chemistry.-2013;13(8):1177-1194
3. Mikra C., Bairaktari M., petridi M., Detsi A. Issue 10. 2022. 20-21 p. doi.org10.3390
4. Wang S.B., Deng X.Q., Zheng Y., Yuan Y.P., Quan Z.S., Guan L.P. Synthesis and evaluation of an- ticonvulsant and antidepressant activities of 5alkoxytetrazolo[1,5-c]thieno[2,3e]pyrimidine deriva- tives. //European journal of medicinal chemistry. -2012;56:139-144 p.
5. Sordella R., Bell D.W., Haber D.A. and Settleman J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. //Science. -2004. -Vol. 305. - 1163-1167 p.
6. Cohen M.H., Johnson J.R., Chen Y.F., Sridhara R., Pazdur R. FDA drug approval summary: erlotinib (Tarceva) tablets.// Oncologist. -2005. -10:461–466 p.
7. Pawan K., Premnath D., Muhammad T., Mazlee S., Yaman M., Nurul S., Muhammad S. et al. A controlled, efficient and robust process for the synthesis of an epidermal growth factor receptor in- hibitor//Afatinib Dimaleate. -February 4, 2019. -5-105-106 p. DOI:10.25082/CR.2019.01.001
8. Petrov K.G., Zhang Y.M., Carter M., Cockerill G.S., Dickerson S., Gauthier C.A., Guo Y., Mook
9. R.A. Jr, Rusnak D.W., Walker A.L., Wood E.R., Lackey K.E. Optimization and SAR for dual ErbB-1 ⁄ ErbB-2 tyrosine kinase inhibition in the 6-furanylquinazoline series.// Bioorg Med.-2006. - Chem Lett; 16:4686–4691.
10. Li S., Guo C., Sun X., Li Y., Zhao H., Zhan D., Lan M., Tang Y. Synthesis and biological evalua- tion of quinazoline and quinoline bearing 2,2,6,6-tetramethylpiperidine-N-oxyl as potential epider- mal growth factor receptor EGFR) tyrosine kinase inhibitors and EPR bio-probe agents.//European Journal of Medicinal Chemistry. -2012. -271-278 p.
11. Singh K., Sharma P., Kumar A., Chaudhary A., Roy K. 4-Aminoquinazoline Analogs: A Novel Class of Anticancer Agents. //Mini reviews in medicinal chemistry. -2013. -13 p.
12. Haghighijoo Z., Eskandari M., Khabnadideh S. Method optimization for synthesis of trisubstitued quinazoline derivatives //Medical Research Archives. – 2017. – Т. 5. – №. 5.
13. Nguyen Th.N., Tran P.T., Vu H.M., Nguyen H.B., Dao S.H., Trinh N.T. 6-Nitro-7-tosylquinazolin- 4(3H)-one. //Molbank. -21 November 2020. -2-7 p. doi:10.3390/M1168
14. Kumar S., Ganguly S., Veerasamy R., De Clercq E. Synthesis, antiviral activity and cytotoxicity evaluation of Schiff bases of some 2-phenyl quinazoline-4 (3) H-ones. //European journal of medic- inal chemistry. -2010.-45(11).-5474-5479 p.
15. Wu J., Bai S., Yue M., Luo L., Shi Q., Ma J., Du X., Kang S., Hu D., Yang S. Synthesis and insec- ticidal activity of 6, 8-dichloro-quinazoline derivatives containing a sulfide substructure. //Chemical Papers. -2014.-68(7):969-975 p.
16. Harris C.S., Kettle J.G., Williams E.J., Facile F.D. Synthesis of 7-amino anilinoquinazolines via di- rect amination of the quinazoline core. //Tetrahedron letters. -2005. -42,43 p.