Synthesis and Characterization of Amine-Functionalized Thiosemicarbazone Cyclopalladated Compounds †
Department of Inorganic Chemistry, University of Santiago de Compostela, 15705 Santiago de Compostela, Spain
*
Author to whom correspondence should be addressed.
†
Presented at the 25th International Electronic Conference on Synthetic Organic Chemistry, 15–30 November 2021; Available online: https://ecsoc-25.sciforum.net/ .
Chem. Proc. 2022, 8(1), 73; https://doi.org/10.3390/ecsoc-25-11762
Published: 14 November 2021
(This article belongs to the Proceedings of The 25th International Electronic Conference on Synthetic Organic Chemistry)
Abstract
:Differences in the functional groups of the ligands can change the properties of the cyclometallated compounds and modify their suitability for various applications, such as catalysis and biomedicine. Herein, we report the synthesis and characterization of a new series of cyclometallated palladium compounds bearing an amine-functionalized thiosemicarbazone. The synthesis of the ligands was achieved by condensation of the thiosemicarbazide and aminoacetophenone. The reaction of the ligands with an appropriate metallating agent gave rise to the tetranuclear cyclometallated compounds. The compounds were characterized by EA, 1H-NMR and IR spectroscopy.
1. Introduction
Palladacycles have shown a wide variety of applications in recent years. The ubiquity of these compounds in practical approaches is proof of the versatility and effectiveness of the cyclometallated moiety. The challenges are the low solubility of the compounds in aqueous media and their dependence on the use of organic solvents, which are main contributors of waste in industry, e.g., the pharmaceutical industry, where solvent use has an environmental impact because of the energy needed for the evaporation, cooling, heating, and extraction of organic solvents [1]. This has motivated a change in the use of metal catalysts to a more sustainable chemistry [2] that can be achieved by the exploration of different organometallic compounds.
Functional groups can be included in palladacycles, modifying their properties and their suitability for these and other applications [3]. In a recently published work, we explored the effect of different substituents in the chemotherapeutic effect of thiosemicarbazone palladacycles [4].
Thiosemicarbazones show intrinsic properties in a wide variety of biological applications, including antiplasmodial [5] and antinocinoceptive [6] applications. Their cyclometallated derivatives have been studied in the past, but their potential as drugs keeps expanding in antiplasmodic [7], antiprotozoic [8], and anticancer [9,10] research.
Herein, we report the synthesis and characterization of a new series of cyclometallated palladium compounds bearing an amine-functionalized thiosemicarbazone. The synthesis of the ligands was achieved by condensation of the thiosemicarbazide and aminoacetophenone. Reaction of the ligands with an appropriate metallating agent gave rise to the tetranuclear cyclometallated compounds.
The compounds were characterized by EA, 1H-NMR, and IR spectroscopy.
2. Materials and Methods
Reagents and solvents were used as received.
The synthesis of the ligands is achieved by the condensation reaction of p-aminoacetophenone and the corresponding 4-substituted thiosemicarbazide.
First, the thiosemicarbazide (3.7 mmol, 1 equiv.) was dissolved in acidified water. Then, the p-aminoacetophenone (500 mg, 3.7 mmol.) was added with stirring, at which point it was possible to observe the precipitation of a white solid. The reaction mixture was stirred overnight, and the precipitate was filtered off and washed with cold water, dried under vacuum, and stored.
The metalating agent of choice is potassium tetrachloropalladate.
Potassium tetrachloropalladate (75 mg, 0.23 mmol) was dissolved in a small amount of water (ca. 2 cm3). The solution was added dropwise to stirred ethanol, forming a suspension. Then, the thiosemicarbazone ligand (0.23 mmol, 1 equiv.) was added to the suspension. The reaction mixture was stirred for 24 h, at which point water was added and a solid is formed. The solid was separated by centrifugation and then washed with cold water.
Ligands a–d and compounds 1a–d were characterized by EA, IR, and 1H-NMR. NMR spectra were recorded in deuterated DMSO.
3. Discussion
3.1. NMR
The NMR spectra of the ligands show signals characteristic for the thiosemicarbazone moiety (e.g., Figure 1). The hydrazinic proton is assigned to the down field signal ca. 10 ppm, which is a singlet. The AA′XX′ system appears as a pair of apparent doublets in the aromatic region of the spectra, as expected. The NHR proton resonance can change its shift depending on the substituent. For the phenyl group, the signal appears deshielded ca. 10 ppm, in close proximity to the hydrazinic proton, whereas the alkyl substituents change field and the multiplet appears ca. 8 ppm. In the case of the amide, there are two signals for the non-equivalent protons.
The signals for the remaining thiosemicarbazone ligands are assigned in Table 1.
Cyclometallation is evidenced in the NMR spectra of the products 1a–d by the changes in the signals in the aromatic region (e.g., Figure 2). The aromatic AA′XX′ system of the ligands disappears due to the metallation in the 6 position, changing the multiplicity and shift of the remaining protons. The H5 signal appears as a singlet or as a small J doublet while those for H2 and H3 change to a pair of coupled doublets, as can be seen in Table 2.
3.2. IR Spectroscopy
The IR spectroscopic data for the ligands and their corresponding cyclometallated compounds show a shift in the position of the ν(C=N) band corresponding to the iminic group (Table 3). The magnitude of this shift confirms coordination through the nitrogen lone pair. Moreover, the ν(C=S) band is missing in the palladacycles due to coordination in thiol form. Bands assignable to the N-H stretch can also be observed around 3300–3000 cm−1.
4. Results
The main results of the study are summarized in Table 4.
5. Conclusions
A new family of thiosemicarbazone cyclometallated compounds bearing the amine functional group has been satisfactorily synthesized and characterized.
The amine group is not affected by metallation and does not hinder the synthesis of the cyclometallated compounds.
The IR analysis confirms the thione form in solid state of the thiosemicarbazone ligand and the coordination to the palladium center in thiolic form, while the NMR analysis confirms the ortho-metalation of the phenyl ring, confirming the proposed structure of the compounds.
Author Contributions
Methodology, F.R.; investigation, F.R.; writing—original draft preparation, F.R.; writing—review and editing, F.R. and J.M.V.; supervision, J.M.V. and M.T.P. All authors have read and agreed to the published version of the manuscript.
Funding
This work was also made possible thanks to financial support received from the Xunta de Galicia (Galicia, Spain) under the Grupos de Referencia Competitiva Programme (Project GRC2019/14).
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
Not applicable.
Acknowledgments
F.R. thanks the Spanish Ministry of Education (Grant FPU15/07145).
Conflicts of Interest
The authors declare no conflict of interest.
References
- Clarke, C.J.; Tu, W.C.; Levers, O.; Bröhl, A.; Hallett, J.P. Green and Sustainable Solvents in Chemical Processes. Chem. Rev. 2018, 118, 747–800. [Google Scholar] [CrossRef]
- Hayler, J.D.; Leahy, D.K.; Simmons, E.M. A Pharmaceutical Industry Perspective on Sustainable Metal Catalysis. Organometallics 2019, 38, 36–46. [Google Scholar] [CrossRef]
- Vila, J.M.; Pereira, M.T.; Lucio-Martínez, F.; Reigosa, F. Palladacycles as Efficient Precatalysts for Suzuki-Miyaura Cross-Coupling Reactions. In Palladacycles; Elsevier: Amsterdam, The Netherlands, 2019; pp. 1–20. [Google Scholar] [CrossRef]
- Reigosa-Chamorro, F.; Raposo, L.R.; Munín-Cruz, P.; Pereira, M.T.; Roma-Rodrigues, C.; Baptista, P.V.; Fernandes, A.R.; Vila, J.M. In Vitro and in Vivo Effect of Palladacycles: Targeting A2780 Ovarian Carcinoma Cells and Modulation of Angiogenesis. Inorg. Chem. 2021, 60, 3939–3951. [Google Scholar] [CrossRef] [PubMed]
- Khanye, S.D.; Gut, J.; Rosenthal, P.J.; Chibale, K.; Smith, G.S. Ferrocenylthiosemicarbazones conjugated to a poly(propyleneimine) dendrimer scaffold: Synthesis and in vitro antimalarial activity. J. Organomet. Chem. 2011, 696, 3296–3300. [Google Scholar] [CrossRef]
- Moreira, D.R.M.; Santos, D.S.; do Espírito Santo, R.F.; dos Santos, F.E.; de Oliveira Filho, G.B.; Leite, A.C.L.; Soares, M.B.P.; Villarreal, C.F. Structural improvement of new thiazolidinones compounds with antinociceptive activity in experimental chemotherapy-induced painful neuropathy. Chem. Biol. Drug Des. 2017, 90, 297–307. [Google Scholar] [CrossRef]
- Adams, M.; Barnard, L.; de Kock, C.; Smith, P.J.; Wiesner, L.; Chibale, K.; Smith, G.S. Cyclopalladated organosilane-tethered thiosemicarbazones: Novel strategies for improving antiplasmodial activity. Dalt. Trans. 2016, 45, 5514–5520. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cipriani, M.; Toloza, J.; Bradford, L.; Putzu, E.; Vieites, M.; Curbelo, E.; Tomaz, A.I.; Garat, B.; Guerrero, J.; Gancheff, J.S.; et al. Effect of the metal ion on the anti T. cruzi activity and mechanism of action of 5-nitrofuryl-containing thiosemicarbazone metal complexes. Eur. J. Inorg. Chem. 2014, 2014, 4677–4689. [Google Scholar] [CrossRef]
- Kovala-Demertzi, D.; Galani, A.; Miller, J.R.; Frampton, C.S.; Demertzis, M.A. Synthesis, structure, spectroscopic studies and cytotoxic effect of novel palladium(II) complexes with 2-formylpyridine-4-Nethyl-thiosemicarbazone: Potential antitumour agents. Polyhedron 2013, 52, 1096–1102. [Google Scholar] [CrossRef]
- Matesanz, A.I.; Hernández, C.; Rodríguez, A.; Souza, P. 3,5-Diacetyl-1,2,4-triazol bis(4N-substituted thiosemicarbazone) palladium(II) complexes: Synthesis, structure, antiproliferative activity and low toxicity on normal kidney cells. J. Inorg. Biochem. 2011, 105, 1613–1622. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Figure 1.
1H-NMR spectrum of compound d in DMSO.
Figure 2.
1H-NMR spectrum of compound 1d in DMSO.
Table 1.
Assignation of the NMR signals of compounds a–d.
| a | b | c | d | |
|---|---|---|---|---|
| NNH | 10.06 (s, 1H) | 9.99 (s, 1H) | 9.89 (s, 1H) | 9.87 (s, 1H) |
| NHR | 8.16 (s, 1H) | 8.30 (s, 1H) | 8.32 (t, J = 6.0 Hz, 1H) | 10.37 (s, 1H) |
| NH2 | 5.52 (s, 2H) | 5.50(s, 2H) | 5.48 (s, 2H) | 5.53 (s, 2H) |
| H2/H6 | 7.72 (d, J = 8.3 Hz, 2H) | 7.68 (d, J = 8.4 Hz, 2H) | 7.63 (d, J = 8.3 Hz, 2H) | 7.71 (d, J = 8.3 Hz, 2H) |
| H3/H5 | 6.70 (d, J = 8.2 Hz, 2H) | 6.63 (d, J = 8.4 Hz, 2H) | 6.54 (d, J = 8.4 Hz, 2H) | 6.55 (d, J = 8.4 Hz, 2H) |
| R | 7.79 (s, 1H) | 3.01 (s, 3H) | 3.59 (p, J = 6.9 Hz, 2H) 1.13 (t, J = 7.0 Hz, 3H) | 7.58 (d, J = 7.8 Hz, 2H) 7.35 (t, J = 7.6 Hz, 2H) 7.18 (t, J = 7.3 Hz, 1H) |
| Me | 2.20 (s, 3H) | 2.18 (s, 3H) | 2.18 (s, 3H) | 2.27 (s, 3H). |
Table 2.
Assignation of the NMR signals of compounds 1a–d.
| 1a | 1b | 1c | 1d | |
|---|---|---|---|---|
| NHR | 6.37 (s, 2H) | 6.64 (s, 1H) | 6.66 (s, 1H) | 9.04 (s, 1H) |
| NH2 | 5.43 (s, 2H) | 5.44 (s, 2H) | 5.41 (s, 2H) | 5.62 (s, 2H) |
| H2 | 6.82 (d, J = 8.1 Hz, 1H) | 6.84 (d, J = 8.2 Hz, 1H) | 6.84 (d, J = 8.1 Hz, 1H) | 6.95 (d, J = 8.2 Hz, 1H) |
| H3 | 6.14 (d, J = 8.1 Hz, 1H) | 6.15 (d, J = 8.2 Hz, 1H) | 6.16 (dd, J = 8.2, 2.1 Hz 1H) | 6.18 (dd, J = 8.2, 2.1 Hz 1H) |
| H5 | 6.76 (s, 1H) | 6.78 (s, 1H) | 6.79 (d, J = 2.0 Hz, 1H) | 6.81 (d, J = 2.1 Hz, 1H) |
| R | - | 2.74 (s, 3H) | 3.19 (p, J = 6.9 Hz, 2H) 1.07 (t, J = 7.1 Hz, 3H) | 7.65 (d, J = 8.1 Hz, 2H) 7.23 (t, J = 7.7 Hz, 2H) 6.88 (t, J = 7.3 Hz, 1H) |
| Me | 2.12 (s, 3H) | 2.17 (s, 3H) | 2.17 (s, 3H) | 2.30 (s, 3H) |
Table 3.
Summary of the main bands that experience changes due to the metalation.
| ν(C=N) | Δ(ν(C=N)) | ν(C=S) | |
|---|---|---|---|
| a | 1596 | - | 829 |
| b | 1594 | - | 830 |
| c | 1597 | - | 831 |
| d | 1591 | - | 830 |
| 1a | 1572 | 24 | - |
| 1b | 1571 | 23 | - |
| 1c | 1576 | 21 | - |
| 1d | 1567 | 24 | - |
Table 4.
Summary of the experimental data.
| Compound | Yield% | IR/cm−1 | EA Found (Calcd) | RMN |
|---|---|---|---|---|
| a | 93 | 3304, 3210, 2971, 2950, 2932 ν(N-H) 1596 ν(C=N) 829 ν(C=S) | C, 52.0; H, 5.7; N, 26.8; S, 15.2 (C, 51.9; H, 5.8; N, 26.9; S, 15.4) | 1H NMR (250 MHz, DMSO-d6) δ 10.06 (s, 1H, NNH), 8.16 (s, 1H, NH2), 7.79 (s, 1H, NH2), 7.72 (d, J = 8.3 Hz, 2H, H2/H6), 6.70 (d, J = 8.2 Hz, 2H, H3/H5), 2.20 (s, 3H, Me) |
| b | 95 | 3302, 3207, 2945 ν(N-H) 1594 ν(C=N) 830 ν(C=S) | C, 53.8; H, 6.6; N, 25.1; S, 14.3 (C, 54.0; H, 6.4; N, 25.2; S, 14.4) | 1H NMR (250 MHz, DMSO-d6) δ 9.99 (s, 1H, NNH), 8.30 (s, 1H, NHMe), 7.68 (d, J = 8.4 Hz, 2H, H2/H6), 6.63 (d, J = 8.4 Hz, 2H, H3/H5), 3.01 (s, 3H, NHMe), 2.18 (s, 3H, Me) |
| c | 94 | 3300, 3205, 2969, 2944, 2928 ν(N-H) 1597 ν(C=N) 831 ν(C=S) | C, 55.6; H, 6.9; N, 23.5; S, 13.4 (C, 55.9; H, 6.8; N, 23.7; S, 13.6) | 1H NMR (250 MHz, DMSO-d6) δ 9.89 (s, 1H, NNH), 8.32 (t, J = 6.0 Hz, 1H, NHEt), 7.63 (d, J = 8.3 Hz, 2H, H2/H6), 6.54 (d, J = 8.4 Hz, 2H, H3/H5), 5.48 (s, 2H, NH2), 3.59 (p, J = 6.9 Hz, 2H, CH2), 2.18 (s, 3H, Me), 1.13 (t, J = 7.0 Hz, 3H, CH3). |
| d | 98 | 3355, 3279, 3182 ν(N-H) 1591 ν(C=N) 830 ν(C=S) | C, 63.1; H, 5.6; N, 19.6; S, 11.2 (C, 63.4; H, 5.7; N, 19.7; S, 11.3) | 1H NMR (250 MHz, DMSO-d6) δ 10.37 (s, 1H, NHPh), 9.87 (s, 1H, NNH), 7.71 (d, J = 8.3 Hz, 2H/H6, H2), 7.58 (d, J = 7.8 Hz, 2H, o-Ar), 7.35 (t, J = 7.6 Hz, 2H, m-Ar), 7.18 (t, J = 7.3 Hz, 1H, p-Ar), 6.55 (d, J = 8.4 Hz, 2H, H3/H5), 5.53 (s, 2H, NH2), 2.27 (s, 3H, Me). |
| 1a | 89 | 3324, 3162, 2912 ν(N-H) 1572 ν(C=N) | C, 34.8; H, 3.3; N, 18.0; S, 10.4 (C, 34.6; H, 3.2; N, 17.9; S, 10.3) | 1H NMR (400 MHz, DMSO-d6) δ 6.82 (d, J = 8.1 Hz, 1H, H2), 6.76 (s, 1H, H5), 6.37 (s, 2H, NH2), 6.14 (d, J = 8.1 Hz, 1H, H3), 5.43 (s, 2H, NH2), 2.12 (s, 3H, Me). |
| 1b | 91 | 3334, 3176, 2912 ν(N-H) 1571 ν(C=N) | C, 36.5; H, 3.5; N, 17.1; S, 9.6 (C, 36.8; H, 3.7; N, 17.2; S, 9.8) | 1H NMR (400 MHz, DMSO-d6) δ 6.84 (d, J = 8.2 Hz, 1H, H2), 6.78 (s, 1H, H5), 6.64 (s, 1H, NHR), 6.15 (d, J = 8.2 Hz, 1H, H3), 5.44 (s, 2H, NH2), 2.74 (s, 3H, CH3), 2.17 (s, 3H, Me) |
| 1c | 86 | 3307, 3150, 2914 ν(N-H) 1576 ν(C=N) | C, 38.7; H, 4.0; N, 16.2; S, 9.2 (C, 38.8; H, 4.1; N, 16.4; S, 9.4) | 1H NMR (400 MHz, DMSO-d6) δ 6.84 (d, J = 8.1 Hz, 1H, H2), 6.79 (d, J = 2.0 Hz, 1H, H5), 6.66 (s, 1H, NHEt), 6.16 (dd, J = 8.2, 2.1 Hz 1H, H3), 5.41 (s, 2H, NH2), 3.19 (p, J = 6.9 Hz, 2H, CH2), 2.17 (s, 3H, Me), 1.07 (t, J = 7.1 Hz, 3H, CH3). |
| 1d | 94 | 3360, 3200, 3022, 2914 ν(N-H) 1567 ν(C=N) | C, 46.5; H, 3.5; N, 14.3; S, 8.1 (C, 46.3; H, 3.6; N, 14.4; S, 8.3) | 1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H, NHPh), 7.65 (d, J = 8.1 Hz, 2H, o-Ar), 7.23 (t, J = 7.7 Hz, 2H, m-Ar), 6.95 (d, J = 8.2 Hz, 1H, H2), 6.88 (t, J = 7.3 Hz, 1H, p-Ar), 6.81 (d, J = 2.1 Hz, 1H, H5), 6.18 (dd, J = 8.2, 2.1 Hz 1H, H3), 5.62 (s, 2H, NH2), 2.30 (s, 3H, Me). |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
MDPI and ACS Style
Reigosa, F.; Pereira, M.T.; Vila, J.M. Synthesis and Characterization of Amine-Functionalized Thiosemicarbazone Cyclopalladated Compounds. Chem. Proc. 2022, 8, 73. https://doi.org/10.3390/ecsoc-25-11762
AMA Style
Reigosa F, Pereira MT, Vila JM. Synthesis and Characterization of Amine-Functionalized Thiosemicarbazone Cyclopalladated Compounds. Chemistry Proceedings. 2022; 8(1):73. https://doi.org/10.3390/ecsoc-25-11762
Chicago/Turabian StyleReigosa, Francisco, María Teresa Pereira, and José Manuel Vila. 2022. "Synthesis and Characterization of Amine-Functionalized Thiosemicarbazone Cyclopalladated Compounds" Chemistry Proceedings 8, no. 1: 73. https://doi.org/10.3390/ecsoc-25-11762
