Kinetic investigation of reactions of a 3-arylidene-2-thiohydantoin derivative with palladium(II) salts ACCEPTED MANUSCRIPT This is an early electronic version of an as-received manuscript that has been accepted for publication in the Journal of the Serbian Chemical Society but has not yet been subjected to the editing process and publishing procedure applied by the JSCS Editorial Office. Please cite this article as P. B. Stanić, D. P. Ašanin, T. V. Soldatović and M. D. Živković, J. Serb. Chem. Soc. (2023) https://doi.org/10.2298/JSC230626052S This “raw” version of the manuscript is being provided to the authors and readers for their technical service. It must be stressed that the manuscript still has to be subjected to copyediting, typesetting, English grammar and syntax correc- tions, professional editing and authors’ review of the galley proof before it is published in its final form. Please note that during these publishing processes, many errors may emerge which could affect the final content of the manuscript and all legal disclaimers applied according to the policies of the Journal. https://doi.org/10.2298/JSC230626052S J. Serb. Chem. Soc.00(0)1-14 (2023) Original scientific paper JSCS–12456 Published DD MM, 2023 1 Kinetic investigation of reactions of a 3-arylidene-2-thiohydantoin derivative with palladium(II) salts PETAR B. STANIĆ*, DARKO P. AŠANIN, TANJA V. SOLDATOVIĆ1 AND MARIJA D. ŽIVKOVIĆ2,3* University of Kragujevac, Institute for Information Technologies, Department of Science, Jovana Cvijića bb, 34000 Kragujevac, Serbia, 1State University of Novi Pazar, Department of Natural-Mathematical Sciences, Vuka Karadžića 9, 36300 Novi Pazar, Serbia, 2University of Kragujevac, Faculty of Medical Sciences, Department of Pharmacy, Svetozara Markovića 69, 34000 Kragujevac, Serbia and 3Center for Harm Reduction of Biological and Chemical Hazards, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovića 69, 34000 Kragujevac, Serbia (Received 26 June; Revised 23 July; Accepted 14 August 2023) Abstract: 1H NMR spectroscopy was used to monitor the reactions of an arylidene 2-thiohydantoin derivative, 3-((phenylmethylene)amino)-2-thioxo-4- imidazolidinone (3), with PdCl2, cis-[PdCl2(dmso-S)2] and K2[PdCl4] in DMSO- d6 in order to elucidate the reaction kinetics and mechanism. The 2-thiohydantoin derivative 3 formed cis-[Pd(3-N,S)(dmso-S)2] + complex (5) in reactions with PdCl2 and cis-[PdCl2(dmso-S)2], while no reaction with K2[PdCl4] was observed. A two-step mechanism for the reactions of 3 with PdCl2 and cis-[PdCl2(dmso- S)2] is proposed, in which fast coordination to the side chain nitrogen occurs in the first step, while chelation and coordination to the sulfur atom in the 2- thiohydantoin ring is the second, slower, rate-determining step. The reaction rate constants were calculated and reactivities of the 2-thiohydantoin derivative 3 towards the palladium(II) salts were compared and discussed. Reaction of 3 with cis-[PdCl2(dmso-S)2] was faster than with PdCl2. The investigated palladium(II) salts also react with the solvent, DMSO-d6, and the influence of these side reactions on the outcome and kinetics of the 2-thiohydantoin derivative complexation reaction is discussed in detail. The obtained results of this study can have an impact in explanation of the coordination behavior of antitumor active palladium(II) and platinum(II) complexes. Keywords: 1H NMR spectroscopy; reaction mechanism; 2-thioxo-4- imidazolidinone; coordination; Pd(II) complexes. *Corresponding authors. E-mail: mzikvovic@kg.ac.rs; petar.stanic@uni.kg.ac.rs. https://doi.org/10.2298/JSC230626052S A cc ep te d m an us cr ip t https://doi.org/10.2298/JSC230626052S 2 STANIĆ et al. INTRODUCTION Thiohydantoins are sulphur derivatives of hydantoin, in which one or both of the carbonyl groups in the cyclic ureide structure are replaced with a thiocarbonyl group.1 Out of this class of compounds, 2-thiohydantoins are certainly the most prominent and extensively researched. 2-Thiohydantoins represent a valuable molecular scaffold, exhibiting various biological and pharmacological activities and they have found applications in both medicine and industry.2,3 They display a wide range of biological activities, such as antibacterial and antifungal,4 anti-HIV,5 anticarcinogenic,6,7 anti-ulcer and anti-inflammatory,8 anticonvulsive,9 antimutagenic10 and antimelanogenic.11 2-Thiohydantoins found various applications in industry, such as C-terminal protein sequencing standards,12 textile printing reagents13 and polymerization and complexation catalysts.14 Coordination of active compounds with biologically relevant transition metal ions can, at times, increase their activities, especially in regards to anticarcinogenic activity.15 A newer, hybrid approach, in discovering new potential antitumor agents is coordination of active compounds with metal ions in order to improve their activity and selectivity.16,17 2-Thiohydantoins have a great affinity for coordination with transition metal ions.18,19 Even though it is a small molecule, 2- thiohydantoin has four derivatization points, making its derivatives very versatile ligands. In addition to the heteroatoms in the ring, 2-thiohydantoin derivatives most often contain heteroatoms in the side chains of its substituents. Many kinds of various 2-thiohydantoin complexes have been synthesized and reported so far.20–26 In particular, transition metal complexes of arylidene 2-thiohydantoin derivatives have been researched extensively, largely due to the biological activities they exhibit, primarily antimicrobial and anticancer.21,27,28 The aim of this study was to investigate the kinetics and mechanism of the coordination reactions of 3-((phenylmethylene)amino)-2-thioxo-4- imidazolidinone, an arylidene 2-thiohydantoin derivative, with some palladium(II) salts. As arylidene 2-thiohydantoin metal complexes, palladium(II) in particular,28 show some promise as prospective antitumor agents, a better understanding of the mechanisms of their formation, coordination modes and kinetics might prove beneficial for the design and conceptualization of novel, more potent compounds. EXPERIMENTAL Materials and methods All chemicals and reagents used in this investigation were commercially obtained (from either Sigma-Aldrich or Acros) and were high in purity. They were used as received, without additional purification. NMR spectra were recorded on a Varian Gemini-2000 spectrometer at 50 MHz and 200 MHz. DMSO-d6 was used as the solvent and all chemical shifts were referenced accordingly. Downfield shifts were recorded as positive numbers. Tetramethylsilane was used as the internal reference and all chemical shits were rounded to the nearest 0.01 ppm. A cc ep te d m an us cr ip t REACTIONS OF ARYLIDENE 2-THIOHYDANTOIN WITH PALLADIUM(II) SALTS 3 Synthesis and characterization of 3-((phenylmethylene)amino)-2-thioxo-4-imidazolidinone (3) 3-((Phenylmethylene)amino)-2-thioxo-4-imidazolidinone (3) was synthesized using a slight modification of a formerly published procedure.28 Benzaldehyde (0.01 mol) and thiosemicarbazide (0.01 mol) in methanol (30 mL) were heated for 3 h under reflux and cooled thereafter. Ethyl chloroacetate (0.01 mol) and anhydrous sodium acetate (0.03 mol) were added in situ and the mixture was heated for another 6 h under reflux. Upon the completion of the reaction, the mixture was cooled at room temperature and then added to cold water, for the resulting product to precipitate. The product was filtered off, rinsed with hot water, dried and re-crystallized from hot methanol. Structure and purity of the compound was confirmed by NMR (1H and 13C) and IR spectroscopy. The corresponding IR and NMR (1H and 13C) spectra are provided in the ESI (Fig. S-1 – S-3). 1H NMR kinetic experiments 1H NMR kinetic measurements of the reactions of 3-((phenylmethylene)amino)-2-thioxo- 4-imidazolidinone (3) (0.021 mmol) with PdCl2, cis-[PdCl2(dmso-S)2] and K2[PdCl4] (0.021 mmol) in DMSO-d6 (0.6 mL) were performed in standard 5 mm NMR tubes at room temperature in an overnight experiment. DMSO-d6 solutions of the reactants (0.3 mL each) were freshly prepared right before the start of the experiment. After the mixing of the reactants, 29 spectra in total were recorded overnight for each one of the experiments. The first six spectra were recorded with no delay, then the next three with a 5 min delay, then sets of three every 10, 15 and 30 min, and finally the last 11 spectra were recorded with an hour delay between them. The concentrations of the products at given experiment intervals were determined by integrating suitable proton signals in the 1H NMR spectra. The first-order rate constants were determined according to Equation 1. ln(c) = -kt + ln(c0) (1) where c is concentration, c0 is starting concentration, k is the first-order rate constant and t is experiment time. RESULTS AND DISCUSSION 3-((Phenylmethylene)amino)-2-thioxo-4-imidazolidinone (3) was synthesized from benzaldehyde in a reaction with thiosemicarbazide (Scheme 1). Nucleophilic addition of thiosemicarbazide to benzaldehyde (1) yield thiosemicarbazone (2). Thiosemicarbazone (2) then undergoes a cyclocondenzation reaction with ethyl chloroacetate in the presence of anhydrous sodium acetate, forming the arylidene 2-thiohydantoin derivative, 3- ((phenylmethylene)amino)-2-thioxo-4-imidazolidinone (3). Scheme 1. Synthesis of 3-((phenylmethylene)amino)-2-thioxo-4-imidazolidinone (3). A cc ep te d m an us cr ip t 4 STANIĆ et al. For the purpose of investigating the kinetics and mechanism of 3-arylidene-2- thiohydantoin coordination with Pd(II), a kinetic time-dependent experiment, monitoring the reactions of 3-((phenylmethylene)amino)-2-thioxo-4- imidazolidinone (3) with PdCl2, cis-[PdCl2(dmso-S)2] and K2[PdCl4] in DMSO-d6, was performed. DMSO-d6 was used because it is suitable for dissolving both the 2-thiohydantoin derivative and the metal salts. Coordination of 3 to Pd(II) was tracked through the changes in specific signals in the spectra. 1H NMR spectra of the reaction of 3-((phenylmethylene)amino)-2-thioxo-4- imidazolidinone (3) with cis-[PdCl2(dmso-S)2] in DMSO-d6 are shown in Figure 1. Signals of the coordinated 3-((phenylmethylene)amino)-2-thioxo-4- imidazolidinone (3) can be observed, even from the first spectrum. Fig. 1. Time-dependent 1H NMR spectra of the reaction of 3-((phenylmethylene)amino)-2- thioxo-4-imidazolidinone (3) and cis-[PdCl2(dmso-S)2] in DMSO-d6. As can be seen from Fig. 1, the singlet of the 2-thiohydantoin ring CH2 group (a) is shifted downfield from 3.90 to 4.15 ppm. Multiplets of the aromatic benzene ring protons (b) moved downfield from 7.25-7.95 to 9.57-9.84 ppm, while the singlet of the double bond CH proton (c) is shifted downfield from 8.41 to 9.37 A cc ep te d m an us cr ip t REACTIONS OF ARYLIDENE 2-THIOHYDANTOIN WITH PALLADIUM(II) SALTS 5 ppm. Signals of the coordinated 2-thiohydantoin derivative (a, b and c) can be observed from the first spectrum and their intensities do not change throughout the experiment. This, in fact, indicates fast initial coordination, too fast for the NMR time-scale. One more thing that implies coordination is the absence of the broad singlet of the 2-thiohydantoion ring NH proton. 2-Thiohydantoins are known to exist in two tautomeric forms in equilibrium (Scheme 2).29 It is proposed that the thio-enol tautomeric form (4) is responsible for coordination and furthermore, that this ‘keto- enol’ equilibrium shifts to the thio-enol form during the reaction.27 The SH protons of the thio-enol tautomer can be seen in the spectra as a singlet at 1.85 ppm (Fig. 1). Furthermore, a newly formed singlet at 10.15 ppm (d) can be observed increasing in intensity throughout the experiment. The new singlet at 10.15 ppm belongs to hydrochloric acid that forms from the deprotonation of the 2- thiohydantoin ring and the chloride anions that are substituted from cis- [PdCl2(dmso-S)2]. Scheme 2. Reactions of 3-((phenylmethylene)amino)-2-thioxo-4-imidazolidinone (3) with PdCl2, cis-[PdCl2(dmso-S)2] and K2[PdCl4]. No reaction of 3 was observed with K2[PdCl4] during the course of the experiment (see Fig. S-4). A cc ep te d m an us cr ip t 6 STANIĆ et al. The reaction as a whole is proposed to proceed in two steps. In the first step (Equation 2), initial coordination takes place through the nitrogen in the side chain. This is the faster reaction step, which is supported by the presence of the signals of the complex (a, b and c) in the first spectrum of the experiment, that then do not change in intensity during the experiment. The second, slower reaction step is deprotonation of the 2-thiohydantoin ring and coordination through the sulfur atom in the ring (Equation 3). The resulting complex (5) is a five-membered chelate with palladium(II) coordinated to the 2-thiohydantoin ring sulfur and the double bond nitrogen in the side chain. cis-[PdCl2(dmso-S)2] + 3 → cis-[PdCl(3-N)(dmso-S)2]+ + Cl- (2) cis-[PdCl(3-N)(dmso-S)2]+ + H2O → cis-[Pd(3-N,S)(dmso-S)2]+ (5) + H3O+ + Cl- (3) Even though the spectral data clearly shows a reaction between the 2- thiohydantoin derivative 3 and cis-[PdCl2(dmso-S)2], it does not necessarily give a clear insight in the chemistry of reaction beyond modes of coordination. Concentrations of the formed complex 5 were calculated by integration of the suitable proton signal at 10.15 ppm (Fig. 2). As hydrochloric acid forms equimolarly with the complex 5, according to Equation 3, concentrations determined from that signal can be regarded as concentrations of complex 5. The singlet at 10.15 ppm was integrated against the singlet of the uncoordinated 2- thiohydantoin derivative 3 at 8.40 ppm. The relative changes of the intensity of the singlet at 10.15 ppm is directly proportional to the change in concentration of complex 5, and the concentrations were calculated from the relative integral values. A cc ep te d m an us cr ip t REACTIONS OF ARYLIDENE 2-THIOHYDANTOIN WITH PALLADIUM(II) SALTS 7 Fig. 2. Changes in product concentration, cis-[Pd(3-N,S)(dmso-S)2] +, during the substitution reaction of cis-[PdCl2(dmso-S)2] with 2-thiohydantoin derivative 3 in DMSO-d6. It can be seen in the plot that after about an hour into the experiment, complex formation slows down drastically. If we take into consideration the stoichiometry of the system, at the end of the experiment, more than half of the initial amount of the 2-thiohydantoin derivative 3 has not undergone any sort of reaction, implying that the reaction system is a bit more complex and that cis-[PdCl2(dmso-S)2] undergoes multiple competing reactions. In order to gain a deeper insight into the details of the mechanism of the reaction, a plot of the logarithm of the product concentration vs experiment time was analyzed (Fig. 3). In the plot, it is clearly visible that this is not a linear first- order reaction, but instead, two linear slopes can be observed. This goes along with the conclusion that multiple processes are occurring, not just the reaction of cis- [PdCl2(dmso-S)2] with 2-thiohydantoin derivative 3. For the first hour, the reaction direction can be described with the equation y = (1.63±0.17)∙10-4x – 5.01. After about an hour, the reaction kinetics change course and the new direction can be described with the equation y = (3.36±0.20)∙10-6x - 4.46. The first phase of the reaction is significantly faster, with the slope coefficient k1 = 1.63∙10-4 s-1, than the second phase with the coefficient k2 = 3.36∙10-6 s-1. A change in the system occurred and a chemical species emerged, the concentration of which has only become significant after an hour into the experiment. A cc ep te d m an us cr ip t 8 STANIĆ et al. Fig. 3. First-order plot for the substitution reaction of cis-[PdCl2(dmso-S)2] with 2-thiohydantoin derivative 3 in DMSO-d6. cis-[PdCl2(dmso-S)2] most likely engages in a parallel reaction with the solvent, as it is known that cis-[PdCl2(dmso-S)2] can react with DMSO, yielding cis-[Pd(dmso-O)2(dmso-S)2]2+.30,31 cis-[PdCl2(dmso-S)2] has two molecules of DMSO in cis-configuration bonded through sulfur atoms. DMSO molecules coordinated through the sulfur atoms exhibit a very strong trans effect on the neighbouring chlorido ligands, which in turn weakens their bonds with palladium(II). With this in mind, cis-[PdCl2(dmso-S)2], apart from reaction with the 2-thiohydantoin derivative 3, reacts with DMSO, forming tetrakis(dimethyl sulphoxide)palladium(II), cis-[Pd(dmso-O)2(dmso-S)2]2+, with the other two DMSO molecules bonded through the oxygen. There is a slight deviation from the ideal square-planar structure in cis-[Pd(dmso-O)2(dmso-S)2]2+, the biggest of which being the angle between the two sulfur bonded DMSO molecules, due to steric repulsions between the methyl groups of one DMSO and the sulfoxy group of the other. These steric repulsions prohibit the S-bonding of the other DMSO molecules, which is believed to be the main reason for coordination through oxygen.30 Two parallel reactions of cis-[PdCl2(dmso-S)2] take place during the experiment. The first is with the 2-thiohydantoin derivative 3 (Equation 4) and the other is with the solvent, DMSO, (Equation 5). cis-[PdCl2(dmso-S)2] + 3 + H2O → cis-[Pd(3-N,S)(dmso-S)2]+ + H3O+ + 2Cl- (4) A cc ep te d m an us cr ip t REACTIONS OF ARYLIDENE 2-THIOHYDANTOIN WITH PALLADIUM(II) SALTS 9 cis-[PdCl2(dmso-S)2] + 2DMSO → cis-[Pd(dmso-O)2(dmso-S)2]2+ + 2Cl- (5) The reaction is faster in the first phase, during the first hour of the experiment (k1 = 1.63∙10-4 s-1), up until a dynamic equilibrium is achieved and a significant amount of cis-[Pd(dmso-O)2(dmso-S)2]2+ is formed, then the complex formation reaction (Equation 4) slows down in the second phase (k2 = 3.36∙10-6 s-1), because there is a significantly smaller amount of the reactant, cis-[PdCl2(dmso-S)2], in the system. Coordination of 3-((phenylmethylene)amino)-2-thioxo-4-imidazolidinone (3) in the reaction with PdCl2 takes place in the same manner as with cis-[PdCl2(dmso- S)2]. All the same signals with identical chemical shifts can be observed in the spectra of the reaction (Fig. 4). Pairs of signals of the coordinated and uncoordinated 3, among which are singlets of the 2-thiohydantoin ring CH2 group protons (a), multiplets of the aromatic benzene ring protons (b) and singlets of the double bond CH proton (c), can be seen at the same chemical shift in the spectra. Thio-enol tautomer -SH proton is at 1.85 ppm, the broad singlet of the 2- thiohydantoin ring -NH proton is missing and the HCl singlet at 10.15 ppm increases throughout the experiment. Fig. 4. Time-dependent 1H NMR spectra of the reaction of 3-((phenylmethylene)amino)-2-thioxo-4-imidazolidinone (3) and PdCl2 in DMSO-d6. A cc ep te d m an us cr ip t 10 STANIĆ et al. Upon calculating the concentrations of the formed cis-[Pd(3-N,S)(dmso-S)2]+ complex (5) (Equation 3) from the spectral data, an obvious difference in reaction rates was observed and it was noticed that the reaction with PdCl2 is slower than with cis-[PdCl2(dmso-S)2]. Changes in complex 5 concentrations over the course of the experiment are shown in Fig. 5. The difference in the kinetics of the systems are somewhat perplexing, as spectral data confirms that the same reaction product is formed in both cases. Fig. 5. Changes in cis-[Pd(3-N,S)(dmso-S)2] + complex (5) concentration during the substitution reaction of PdCl2 with 2-thiohydantoin derivative 3 in DMSO-d6. In order to get to the bottom of this, a plot of the logarithm of the product concentration vs experiment time was analyzed (Figure 6). As with cis- [PdCl2(dmso-S)2], in this case there are also two phases, with two linear slopes that intercept after little over an hour. The first phase can be described with the equation y = (1.80±0.22)∙10-4x - 6.59, while the second phase can be described with the equation y = (1.25±0.09)∙10-5x – 5.77. The first phase, where most of the complex is formed, has a coefficient k1 = 1.80∙10-4 s-1, which is very close to the slope coefficient of the first phase of the reaction of cis-[PdCl2(dmso-S)2] (k1 = 1.63∙10- 4 s-1). It is known that PdCl2 has great affinity towards DMSO and reacts with it to form cis-[PdCl2(dmso-S)2],32 according to Equation 6. PdCl2 + 2DMSO → cis-[PdCl2(dmso-S)2] (6) It can be concluded that in both cases, basically the same reaction occurs (Equation 4), which is supported by the very close values of the reaction coefficients k1. The reaction is slower with PdCl2 because the salt itself does not react with the 2-thiohydantoin derivative 3. Only when a sufficient amount of cis- A cc ep te d m an us cr ip t REACTIONS OF ARYLIDENE 2-THIOHYDANTOIN WITH PALLADIUM(II) SALTS 11 [PdCl2(dmso-S)2] forms does the reaction take place. The lower rate of the reaction with PdCl2 can be explained with the lower reactant concentration. Fig. 6. First-order plot for the substitution reaction of PdCl2 with 2-thiohydantoin derivative 3 in DMSO-d6. In the case of the third examined palladium(II) salt, K2[PdCl4], there was no reaction with 3-((phenylmethylene)amino)-2-thioxo-4-imidazolidinone (3) during the course of the experiment. No signals of a newly formed 2-thiohydantoin complex species of any kind could be observed (Figure S-4). The four chlorido ligands in K2[PdCl4] are kinetically equivalent and a strong possibility is that all of them were substituted with DMSO, as tetrachloroplatinate(II) and also tetrachrloropalladate(II) can react with DMSO in this manner.33 This would prohibit the reaction with the 2-thiohydantoin derivative 3. CONCLUSION Reactions of an arylidene 2-thiohydantoin derivative, 3- ((phenylmethylene)amino)-2-thioxo-4-imidazolidinone (3) with PdCl2, cis- [PdCl2(dmso-S)2] and K2[PdCl4] in DMSO-d6 were monitored in a time dependent kinetic 1H NMR experiment. In the cases of PdCl2 and cis-[PdCl2(dmso-S)2], the complex cis-[Pd(3-N,S)(dmso-S)2]+ (5) was formed, with palladium(II) coordinated through the nitrogen in the side chain and the 2-thiohydantoin ring sulfur atom. The mechanism of complex 5 formation consists of two steps. The first step is fast monodentate coordination of 3 via its nitrogen atom in the side chain. This step is too fast for the NMR time-scale, but it is confirmed with the corresponding signals of the complex 5 that are unchanged during the course of the experiment. The second, rate determining step of the reaction is chelation of A cc ep te d m an us cr ip t 12 STANIĆ et al. the intermediate cis-[PdCl(3-N)(dmso-S)2]+ complex through deprotonation of the 2-thiohydantoin ring of 3 and its coordination with the sulfur atom, finally yielding to the formation of complex 5. Most of the complex 5 is formed during the first hour of the experiment. It is concluded that simultaneously, a competing reaction with the solvent occurs during which cis-[Pd(dmso-O)2(dmso-S)2]2+ is formed, which ultimately halts the reaction. No reaction with K2[PdCl4] was observed during the course of the experiment. Ž Acknowledgements: The authors are grateful for financial support from the Ministry of Education, Science and Technological Development of the Republic of Serbia (Agreements Noumbers 451-03-68/2022-14/200378, 451-03-68/2022-14/200252 and 451-03-47/2023- 01/200111) and the Faculty of Medical Sciences, University of Kragujevac (JP02/20). SUPPLEMENTARY MATERIAL Supplementary Materials are available electronically from https://www.shd- pub.org.rs/index.php/JSCS/article/view/12456, or from the corresponding authors on request. И З В О Д КИНЕТИЧКО ИСПИТИВАЊЕ РЕАКЦИЈА 3-АРИЛИДЕНСКОГ ДЕРИВАТА 2- ТИОХИДАНТОИНА СА СОЛИМА ПАЛАДИЈУМА(II) ПЕТАР Б. СТАНИЋ, ДАРКО П. АШАНИН, ТАЊА В. СОЛДАТОВИЋ1 И МАРИЈА Д. ЖИВКОВИЋ2,3 Универзитет у Крагујевцу, Институт за информационе технологије, Сектор за природно- математичке науке, Јована Цвијића бб, 34000 Крагујевац, Србија, 1Државни универзитет у Новом Пазару, Департман за природно-математичке науке, Вука Караџића 9, 36300 Нови Пазар, Србија, 2Универзитет у Крагујевцу, Факултет медицинских наука, Департман за фармацију, Светозара Марковића 69, 34000 Крагујевац, Србија и 3Центар за смањење штетности биолошких и хемијских хазарда, Факултет медицинских наука, Универзитет у Крагујевцу, Светозара Марковића 69, 34000 Крагујевац, Србија Протонска НМР спектроскопија је употребљена за праћење реакције арилиденског деривата 2-тиохидантоина, 3-((фенилметилен)амино)-2-тиоксо-4-имидазолидинона (3), са PdCl2, cis-[PdCl2(dmso-S)2] и K2[PdCl4] у DMSO-d6, да би се испитали кинетика и механизам реакције. Испитивани дериват 2-тиохидантоина 3 је наградио комплекс cis-[Pd(3- N,S)(dmso-S)2]+ (5) у реакцији са PdCl2 и cis-[PdCl2(dmso-S)2], док са K2[PdCl4] није уочена реакција. Претпостављен је двостепени механизам за реакције 3 са PdCl2 и cis-[PdCl2(dmso- S)2], у коме се у првом кораку одиграва брза координација за азот из бочног низа, а хелатизација и координовање за тиохидантоински сумпор је други, спорији корак, који одређује брзину реакције. Израчунате су константе брзине реакције и реактивности деривата 2-тиохидантоина 3 према солима паладијума(II) су упоређене и дискутоване. Реакција 3 са cis-[PdCl2(dmso-S)2] је била бржа од реакције са PdCl2. Испитиване соли паладијума(II) су такође реаговале са растварачем (DMSO-d6) и утицај ових реакција на исход и кинетику реакције комплексирања деривата 2-тиохидантоина је детаљно дискутован. Резултати добијени у оквиру овог истраживања могу имати утицај на појашњење координационог понашања антитуморски активних комплекса паладијума(II) и платине(II). (Примљено 26. јуна, ревидирано 23. јула, прихваћено 14. августа 2023.) A cc ep te d m an us cr ip t https://www.shd-pub.org.rs/index.php/JSCS/article/view/12456 https://www.shd-pub.org.rs/index.php/JSCS/article/view/12456 REACTIONS OF ARYLIDENE 2-THIOHYDANTOIN WITH PALLADIUM(II) SALTS 13 REFERENCES 1. M. A. Metwally, E. Abdel-Latif, J. Sulfur Chem. 33 (2012) 229. (https://www.doi.org/10.1080/17415993.2011.643550) 2. S. H. Cho, S. H. Kim, D. Shin, Eur. J. Med. Chem. 164 (2019) 517. (https://doi.org/10.1016/j.ejmech.2018.12.066) 3. P. P. Gawas, B. Ramakrishna, N. Veeraiah, V. Nutalapati, J. Mater. Chem. C 9 (2021) 16341. (https://www.doi.org/10.1039/D1TC04090A) 4. J. Marton, J. Enisz, S. Hosztafi, T. Timar, J. Agr. Food Chem. 41 (1993) 148. (https://www.doi.org/10.1021/jf00025a031) 5. A. I. Khodair, H. I. el-Subbagh, A. 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