Coupling of Thiazole-2-Amines with Isocyanide Ligands in bis -(Isocyanide) Platinum Complex: A New Type of Reactivity

: The treatment of cis -[PtCl 2 (XylNC) 2 ] with thiazol-2-amines in a 2:1 ratio leads to a re-gioisomeric mixture of two binuclear complexes. These regioisomers are products of kinetic and thermodynamic control capable of regioisomerization. When the same reaction is carried out with a 5-fold excess of thiazol-2-amine, the nucleophile is able to react with the in situ -formed binuclear platinum(II) complexes, yielding a new type of bis -carbene platinum species. All new isolated compounds were characterized by 1 H, 13 C{ 1 H}, and 195 Pt{ 1 H} NMR spectroscopy, high-resolution ESI-MS


Introduction
Platinum metal complexes with diaminocarbene ligands (ADC-acyclic diaminocarbenes, NHC-N-heterocyclic carbenes) have become the subject of constant attention from modern researchers due to their successful application in catalysis [1][2][3], medicinal chemistry [4,5], and materials design [4]. Therefore, a large number of works have appeared that are devoted to methods for the synthesis of these species.
Previously, we reported [35,36] that the treatment of cis-[PdCl 2 (XylNC) 2 ] with thiazol-2-amine leads to a regioisomeric mixture of two binuclear complexes (Scheme 1), one of which proved to be kinetically controlled, while the generation of the other one is thermodynamically driven. In many instances, platinum(II) complexes exhibit similar reactivity as their palladium(II) congeners, although the former species are typically substantially more kinetically inert. This inertness is often used for the tapping and identification of those reaction intermediates that are elusive or quite unstable when relevant palladium(II) species are employed. To get a deeper insight into the mechanism of the reported coupling, for this work we addressed the platinum(II) complex cis-[PtCl 2 (XylNC) 2 ] and studied its reaction with thiazol-2-amines.

The platinum(II)-Mediated Reaction
The reaction of cis-[PtCl 2 (XylNC) 2 ] 1 with amino-substituted azaheterocycles 2 and 3 (2:1 molar ratio) in the presence of a base (t-BuONa) leads to regioisomeric mixtures of two platinum(II) binuclear diaminocarbene complexes 4a/b and 5a/b (Scheme 2, Route A); this coupling proceeds similarly to that of the corresponding palladium(II) complex cis-[PdCl 2 (XylNC) 2 ]. The composition of the mixture depends on the reaction conditions. Thus, the reaction conducted at room temperature (RT) results almost exclusively in isomer a for complex 4 and in a 1:1 isomer mixture for complex 5, whereas the quantity of isomer b increases upon reflux in 1,2-dichloroethane ( Table 1). The product ratios in the reaction mixtures were monitored by 1 H NMR and determined by the peak integration.

The platinum(II)-Mediated Reaction
The reaction of cis-[PtCl2(XylNC)2] 1 with amino-substituted azaheterocycles 2 and 3 (2:1 molar ratio) in the presence of a base (t-BuONa) leads to regioisomeric mixtures of two platinum(II) binuclear diaminocarbene complexes 4a/b and 5a/b (Scheme 2, Route A); this coupling proceeds similarly to that of the corresponding palladium(II) complex cis-[PdCl2(XylNC)2]. The composition of the mixture depends on the reaction conditions. Thus, the reaction conducted at room temperature (RT) results almost exclusively in isomer a for complex 4 and in a 1:1 isomer mixture for complex 5, whereas the quantity of isomer b increases upon reflux in 1,2-dichloroethane ( Table 1). The product ratios in the reaction mixtures were monitored by 1 H NMR and determined by the peak integration.  Refluxing the reaction mixture with an excess of 2 or 3 (3-10 equiv.) without an added base affords predominantly a new type of product: bis-carbene species 6 and 7 (Scheme 2, Route B). Such bis-carbene complexes of platinum(II) containing aminoazaheterocyclic fragments were not previously known. When the reaction is conducted at RT, it results in the generation of all three types of products, namely the two binuclear complexes (Scheme 2, top panel) and one mononuclear monoprotonated bis-carbene (bottom panel).
As in the case of binuclear palladium complexes [35], for platinum(II), the kinetically controlled regioisomer transforms over time into the thermodynamically controlled one. However, in contrast to the palladium congeners, the isomerization of 4a under similar conditions (CDCl 3 , 45 • C) took much longer: 110 days for the Pt(II) species vs. 14 days for the Pd(II) species ( Figure 1).  Refluxing the reaction mixture with an excess of 2 or 3 (3-10 equiv.) without an added base affords predominantly a new type of product: bis-carbene species 6 and 7 (Scheme 2, Route B). Such bis-carbene complexes of platinum(II) containing aminoazaheterocyclic fragments were not previously known. When the reaction is conducted at RT, it results in the generation of all three types of products, namely the two binuclear complexes (Scheme 2, top panel) and one mononuclear monoprotonated bis-carbene (bottom panel).
As in the case of binuclear palladium complexes [35], for platinum(II), the kinetically controlled regioisomer transforms over time into the thermodynamically controlled one. However, in contrast to the palladium congeners, the isomerization of 4а under similar conditions (CDCl3, 45 °C) took much longer: 110 days for the Pt(II) species vs. 14 days for the Pd(II) species ( Figure 1). For a deeper understanding of plausible reaction routes of the coupling of bis(isocyanide) Pt(II) complex with amino-substituted azaheterocycles, we studied the dependence of products ratio on reagents ratio in the model reaction of 1 and thiazole-2-amine 2 ( Table 2). The experiments were conducted at RT for 12 h and the ratios were obtained by the 1 H NMR peak integration. In all reaction mixtures, irrespective of the concentration of 2, we observed the formation of binuclear species 4a and 4b. Regioisomer 4b is generated in trace amounts when the amount of 2 was less than one equiv. For a deeper understanding of plausible reaction routes of the coupling of bis(isocyanide) Pt(II) complex with amino-substituted azaheterocycles, we studied the dependence of products ratio on reagents ratio in the model reaction of 1 and thiazole-2-amine 2 ( Table 2). The experiments were conducted at RT for 12 h and the ratios were obtained by the 1 H NMR peak integration. In all reaction mixtures, irrespective of the concentration of 2, we observed the formation of binuclear species 4a and 4b. Regioisomer 4b is generated in trace amounts when the amount of 2 was less than one equiv. Starting from a 1:1 ratio between 1 and 2, we observed 1 H NMR resonances of bis-carbene 6. Upon the increase of the starting concentration of 2, the fraction of 6 also increases. While studying the reaction mixture with the 5:1 ratio of 2 and 1, we observed changes in the signals' intensities over time. Thus, the intensity of Me-groups' peaks from bis-carbene 6 increased, while those from binuclear species 4a concurrently decreased. After two weeks at RT, we did not observe any signals from 4a, while the reaction mixture remained homogeneous ( Figure 2). Starting from a 1:1 ratio between 1 and 2, we observed 1 H NMR resonances of bis-carbene 6. Upon the increase of the starting concentration of 2, the fraction of 6 also increases. While studying the reaction mixture with the 5:1 ratio of 2 and 1, we observed changes in the signals' intensities over time. Thus, the intensity of Me-groups' peaks from bis-carbene 6 increased, while those from binuclear species 4a concurrently decreased. After two weeks at RT, we did not observe any signals from 4a, while the reaction mixture remained homogeneous ( Figure 2). We assumed that in an excess of 2, binuclear species 4a could transform into bis-carbene 6. To prove this hypothesis, we performed the isolation of binuclear complex 4a and then carried out its reaction with three equiv. of 2. As expected, this reaction yielded bis-carbene 6. Furthermore, we performed a cross-experiment comprising of the addition of three equiv. of another nucleophile, 5-methylthiazol-2-amine 3, to complex 4a. This experiment verified the generation of two bis-carbene complexes 7 and 8, both identified in the reaction mixture by 1 H NMR and HRESI-MS (Scheme 3). We assumed that in an excess of 2, binuclear species 4a could transform into biscarbene 6. To prove this hypothesis, we performed the isolation of binuclear complex 4a and then carried out its reaction with three equiv. of 2. As expected, this reaction yielded bis-carbene 6. Furthermore, we performed a cross-experiment comprising of the addition of three equiv. of another nucleophile, 5-methylthiazol-2-amine 3, to complex 4a. This experiment verified the generation of two bis-carbene complexes 7 and 8, both identified in the reaction mixture by 1 H NMR and HRESI-MS (Scheme 3).
Considering the results of our experiments, we propose the following mechanism for the formation of 6 (Scheme 4). In the first stage, binuclear complex 4a may proceed dissociation into cationic bis-isocyanide intermediate i1 and anionic monocarbene complex i2, which can recombine into isomeric binuclear complex 4b. However, in the presence of 2 acting as a nucleophile and a proton donor, each of these species can transform into monocarbene intermediate i3. The latter reacts with one more equiv. of thiazol-2-amine to eventually provide bis-carbene 6. Considering the results of our experiments, we propose the following mechanism for the formation of 6 (Scheme 4). In the first stage, binuclear complex 4a may proceed dissociation into cationic bis-isocyanide intermediate i1 and anionic monocarbene complex i2, which can recombine into isomeric binuclear complex 4b. However, in the presence of 2 acting as a nucleophile and a proton donor, each of these species can transform into monocarbene intermediate i3. The latter reacts with one more equiv. of thiazol-2-amine to eventually provide bis-carbene 6. Scheme 4. Postulated mechanism of the reaction.
The 1 H NMR spectra of 4−5a/b in each case display signals for each of the four Xyl fragments as well as proton signals of the thiazole core. In the 13 C{ 1 H} NMR spectra of 4−5a/b, two distinct resonances of two Pt-bound NCN fragments were observed at Considering the results of our experiments, we propose the following mechanism for the formation of 6 (Scheme 4). In the first stage, binuclear complex 4a may proceed dissociation into cationic bis-isocyanide intermediate i1 and anionic monocarbene complex i2, which can recombine into isomeric binuclear complex 4b. However, in the presence of 2 acting as a nucleophile and a proton donor, each of these species can transform into monocarbene intermediate i3. The latter reacts with one more equiv. of thiazol-2-amine to eventually provide bis-carbene 6. Scheme 4. Postulated mechanism of the reaction.
The 1 H NMR spectra of 4−5a/b in each case display signals for each of the four Xyl fragments as well as proton signals of the thiazole core. In the 13 C{ 1 H} NMR spectra of 4−5a/b, two distinct resonances of two Pt-bound NCN fragments were observed at Scheme 4. Postulated mechanism of the reaction.
The 1 H NMR spectra of 4−5a/b in each case display signals for each of the four Xyl fragments as well as proton signals of the thiazole core. In the 13 C{ 1 H} NMR spectra of 4−5a/b, two distinct resonances of two Pt-bound NCN fragments were observed at 154.07-154.86 ppm and 182.20−184.50 ppm for kinetically controlled isomers 4-5a and at 149.98 and 170.83 ppm for thermodynamically controlled isomer 4b. The attribution of these signals was performed by 2D (HMBC, HSQC) NMR, and the position of the signals is similar to the analogous binuclear Pd(II) species [35,36]. Finally, in the 195 Pt{ 1 H} spectra of binuclear complexes 4−5a/b, two signals from two Pt(II) centers were observed in the range from −3750 to −3820 ppm.
At the same time, the 1 H NMR spectra of complexes 6 and 7 exhibit only one set of signals for both two xylyl and two thiazole fragments, indicating the symmetric structure of complexes. Similarly, the 13 C{ 1 H} NMR spectra of the complexes display only one signal corresponding to the carbene carbon atom at ca. 160 ppm, and the 195 Pt{ 1 H} Inorganics 2022, 10, 221 6 of 14 NMR spectra display only one signal around −3850 ppm. One should also mention the presence in the 1 H NMR spectra of a high-field signal (12.5-14.0 ppm), corresponding to the N···H···N hydrogen atom involved in a resonance-assisted hydrogen bond [37] between two carbene ligands.
The solid-state structures of 4-5a,b, 6, and 7 were established by single-crystal X-ray diffraction (XRD). The plot of the XRD structures is shown in Figure 3, while the crystal data, data collection parameters, and structure refinement data are given in Tables S1 and S2. is similar to the analogous binuclear Pd(II) species [35,36]. Finally, in the Pt{ H} spectr of binuclear complexes 4−5a/b, two signals from two Pt(II) centers were observed in th range from −3750 to −3820 ppm.
At the same time, the 1 H NMR spectra of complexes 6 and 7 exhibit only one set o signals for both two xylyl and two thiazole fragments, indicating the symmetric structur of complexes. Similarly, the 13 C{ 1 H} NMR spectra of the complexes display only one sig nal corresponding to the carbene carbon atom at ca. 160 ppm, and the 195 Pt{ 1 H} NM spectra display only one signal around −3850 ppm. One should also mention the presenc in the 1 H NMR spectra of a high-field signal (12.5-14.0 ppm), corresponding to th N•••H•••N hydrogen atom involved in a resonance-assisted hydrogen bond [37] betwee two carbene ligands.
The solid-state structures of 4-5a,b, 6, and 7 were established by single-crystal X-ra diffraction (XRD). The plot of the XRD structures is shown in Figure 3, while the crysta data, data collection parameters, and structure refinement data are given in Tables S1 an S2. The structures of complexes 4-5a/b are similar to those for the relevant Pd(II) binu clear complexes with thiazole fragments [35,36]. In structures of 4-5a/b, both metal cen ters adopt a slightly distorted square planar geometry, and the isocyanide ligands are i The structures of complexes 4-5a/b are similar to those for the relevant Pd(II) binuclear complexes with thiazole fragments [35,36]. In structures of 4-5a/b, both metal centers adopt a slightly distorted square planar geometry, and the isocyanide ligands are in the cis-position to the NCN fragments. The bond lengths of the two coordinated CN groups fall in the interval of 1.139-1.165 Å which is typical for the common range of the CN triple bonds in the related isocyanide Pd(II) and Pt(II) complexes [35,36]. In the case of complexes 6 and 7, both carbene fragments are located in cis-position. Despite the single set of signals in the solution NMR spectra for two chelate carbene ligands, in a solid state, two carbene N-C-N fragments appear to be different for both complexes. The first N-C-N fragment possesses both N atoms protonated, and the lengths of both C−N bonds are intermediate between the typical double and single bonds (1.304-1.379 Å), reflecting the diaminocarbene nature. In the second N-C-N fragment, only one N atom is protonated, whereas the second N atom is involved in the intramolecular hydrogen bonding. The latter results in different C−N bond lengths in the fragment: the bond with the protonated N atom is single (1.271-1.283 Å) while the other one is closer to a double bond (1.409-1.412 Å). The disagreement between XRD and NMR data can be explained by the fast exchange of the N-H proton between two N-C-N fragments in a solution, whereas in a solid state, this proton is attributed only to one nitrogen atom.
All other bond lengths in the complexes are typical, and their values agree with those reported for related Pt(II) and Pd(II) carbene and isocyanide complexes [26,32,[34][35][36]. of 4a, 4b, 5a, 6, and 7 Inspection of the crystallographic data for the obtained complexes suggests the presence of intermolecular and intramolecular noncovalent interactions in their structures (dotted lines in Figure 3). Like previously reported Pd II species [35], the binuclear Pt II complexes display the presence of intermolecular chalcogen bonds [39]: S···Cl interactions in the structures of 4a-b and S···N interactions in the structures of 5a-b. At the same time, both bis-carbene complexes 7 and 8 feature intermolecular bifurcated chalcogen-hydrogen bonds µ (S,N−H) Cl [34] with the chloride anion in outer coordination sphere, as well as intramolecular N-H···N hydrogen bonds between two carbene fragments. To confirm the presence of these noncovalent interactions in the crystal structures and quantify their energies from a theoretical point of view, we carried out DFT calculations along with topological analysis of the electron density distribution (quantum theory of atoms in molecules, QTAIM) [40] for the XRD geometries of complexes. The results of the QTAIM analysis are visualized in Figure 4 and summarized in Table 3.      [41]; b E int = 0.429G(r) [42].

Noncovalent Interactions in the Structures
The QTAIM analysis demonstrates the presence of appropriate bond critical points (3, -1) (BCPs) for all discussed interactions. The observed low magnitude of the electron density, positive values of the Laplacian, and close to zero energy density in the BCPs are typical for noncovalent interactions. We have defined energies for the studied contacts in accordance with the conventional approach by Espinosa et al. [41] and Vener et al. [42]. For the binuclear Pt II complexes 4-5a,b, the energies of the intramolecular S···Cl and S···N chalcogen bonds are in the same range as for Pd II analogs (3-5 kcal/mol). Note also the intramolecular N-H···N hydrogen bonds of medium strength (10-15 kcal/mol) in the structures of bis-carbene complexes 6 and 7. The latter interaction should also contribute to stabilization of these new types of complexes.

General
The complex cis-[PtCl 2 (CNXyl) 2 ] (complex 1) was synthesized using the reported procedure [43]. All reagents and solvents were obtained from commercial sources and used as received, apart from chloroform, which was dried by conventional distillation over calcium chloride. Mass spectra were obtained on a Bruker micrOTOF spectrometer equipped with an electrospray ionization (ESI) source, and a mixture of MeOH and CH 2 Cl 2 was used for sample dissolution. The instrument was operated in a positive ion mode using a m/z range of 50-3000 with the capillary voltage of the ion source set at −4500 V and the capillary exit at 50-150 V. The most intensive peak in the isotopic pattern is reported. The 1D ( 1 H, 13 C, 195 Pt) NMR spectra were acquired on a Bruker Avance 400 spectrometer, whereas the 2D ( 1 H, 1 H-COSY, 1 H, 1 H-NOESY, 1 H, 13 C-HSQC, and 1 H, 13 C-HMBC) NMR correlation experiments were recorded on a Bruker Avance III 500 MHz spectrometer. All NMR spectra were measured in CDCl 3 at ambient temperature.

Synthesis of the Complexes
Complexes 4a and 5a. A solution of complex 1 (0.04 mmol, 20 mg), NaOBu t (0.04 mmol, 5.5 mg), and nucleophile 2 (3) (0.02 mmol) in 5 mL of dichloromethane placed in a 10 mL vial were stirred under ultrasonication for 40 min at room temperature. The resulting mixture was filtered off from some insoluble material and then dried under low pressure.

Synthesis of the Complexes
Complexes 4a and 5a. A solution of complex 1 (0.04 mmol, 20 mg), NaOBu t (0.04 mmol, 5.5 mg), and nucleophile 2 (3) (0.02 mmol) in 5 mL of dichloromethane placed in a 10 mL vial were stirred under ultrasonication for 40 min at room temperature. The resulting mixture was filtered off from some insoluble material and then dried under low pressure. Complex 4b. A solution of complex 1 (0.04 mmol, 20 mg), NaOBu t (0.04 mmol, 5.5 mg) and nucleophile 2 (0.02 mmol, 1.9 mg) in 5 mL of dichloroethane placed in a 10 mL vial was stirred at 70 °C for 2 days. The resulting mixture was filtered off from some insoluble material and then dried under low pressure. The title product was isolated by slow crystallization out of the mixture of dichloromethane and acetone (1:2) under normal pressure and room temperature. The crystals were separated from the solution (0.5-1 mL) and dried under low pressure at room temperature. Complex 4b. A solution of complex 1 (0.04 mmol, 20 mg), NaOBu t (0.04 mmol, 5.5 mg) and nucleophile 2 (0.02 mmol, 1.9 mg) in 5 mL of dichloroethane placed in a 10 mL vial was stirred at 70 • C for 2 days. The resulting mixture was filtered off from some insoluble material and then dried under low pressure. The title product was isolated by slow crystallization out of the mixture of dichloromethane and acetone (1:2) under normal pressure and room temperature. The crystals were separated from the solution (0.5-1 mL) and dried under low pressure at room temperature.

Complex 4b.
A solution of complex 1 (0.04 mmol, 20 mg), NaOBu t (0.04 mmol, 5.5 mg) and nucleophile 2 (0.02 mmol, 1.9 mg) in 5 mL of dichloroethane placed in a 10 mL vial was stirred at 70 °C for 2 days. The resulting mixture was filtered off from some insoluble material and then dried under low pressure. The title product was isolated by slow crystallization out of the mixture of dichloromethane and acetone (1:2) under normal pressure and room temperature. The crystals were separated from the solution (0.5-1 mL) and dried under low pressure at room temperature. Complexes 6 and 7. A solution of complex 1 (0.04 mmol, 20 mg), NaOBu t (0.04 mmol, 5.5 mg), and nucleophile 2 (3) (0.11 mmol) in 5 mL of dichloroethane placed in a 10 mL vial was stirred at 70 • C for 2 days. The resulting mixture was filtered off from some insoluble material and concentrated to 1 mL under low pressure and purified from residual binuclear complexes 4 (5) via column chromatography with dichloromethane (19 mL) as eluent on silica gel as a sorbent. The title product was washed from the silica gel with methanol (2 × 2 mL) and dried under low pressure. insoluble material and concentrated to 1 mL under low pressure and purified from residual binuclear complexes 4 (5) via column chromatography with dichloromethane (19 mL) as eluent on silica gel as a sorbent. The title product was washed from the silica gel with methanol (2 × 2 mL) and dried under low pressure.

Computational Details
For studies of the nature of noncovalent interactions, the single-point calculations based on the experimental X-ray geometries for wavefunction generation were carried out for 4-5a,b, while for the structures of 6 and 7, the positions of the heavy atoms were fixed and only the positions of H atoms were optimized. All calculations were carried out at the DFT level of theory using the M06 [50] functional with the empirical corrections for dispersion in accordance with Grimme's D3 model [51] and def2-SVP basis [52,53] set for all atoms by Gaussian-16 program package [54]. The Hessian matrices were calculated analytically for all optimized model structures to prove the location of correct minima on the potential energy surface (no imaginary frequencies were found). The QTIAM analysis was carried out using Multiwfn 3.8 software [55]. The Cartesian atomic coordinates for model structures are given as XYZ files in Supplementary Files.

Conclusions
In this work, we have shown that the reaction of bis(isocyanide) complexes of platinum(II) with aminoazaheterocyles can lead not only to the mixture of binuclear regioisomeric complexes but also to a new type of bis-carbene species not observed previously for the reaction on Pd II metal center. The formation of the bis-carbene complexes occurs via the reaction of binuclear diaminocarbene Pt II species with aminothiazoles, and this process was studied experimentally by 1 H NMR and HR-ESIMS methods. The isolated compounds were characterized by 1 H, 13 C{ 1 H}, and 195 Pt{ 1 H} NMR spectroscopy and HRESI-MS in a solution, whereas the solid-state structures of all complexes were elucidated by single-crystal XRD. In addition, we observed several types of noncovalent interactions in the crystal structures of obtained complexes (S···Cl/N chalcogen bonds, bifurcated chalcogen-hydrogen bonds µ (S,N−H) Cl, N-H···N hydrogen bonds), and their presence was confirmed by the theoretical studies.

Data Availability Statement:
The data presented in this study are available on request from the corresponding author.