Oxidation of the Platinum(II) Anticancer Agent [Pt{(p-BrC6F4)NCH2CH2NEt2}Cl(py)] to Platinum(IV) Complexes by Hydrogen Peroxide

PtIV coordination complexes are of interest as prodrugs of PtII anticancer agents, as they can avoid deactivation pathways owing to their inert nature. Here, we report the oxidation of the antitumor agent [PtII(p-BrC6F4)NCH2CH2NEt2}Cl(py)], 1 (py = pyridine) to dihydroxidoplatinum(IV) solvate complexes [PtIV{(p-BrC6F4)NCH2CH2NEt2}Cl(OH)2(py)].H2O, 2·H2O with hydrogen peroxide (H2O2) at room temperature. To optimize the yield, 1 was oxidized in the presence of added lithium chloride with H2O2 in a 1:2 ratio of Pt: H2O2, in CH2Cl2 producing complex 2·H2O in higher yields in both gold and red forms. Despite the color difference, red and yellow 2·H2O have the same structure as determined by single-crystal and X-ray powder diffraction, namely, an octahedral ligand array with a chelating organoamide, pyridine and chloride ligands in the equatorial plane, and axial hydroxido ligands. When tetrabutylammonium chloride was used as a chloride source, in CH2Cl2, another solvate, [PtIV{(p-BrC6F4)NCH2CH2NEt2}Cl(OH)2(py)].0.5CH2Cl2, 3·0.5CH2Cl2, was obtained. These PtIV compounds show reductive dehydration into PtII [Pt{(p-BrC6F4)NCH=CHNEt2}Cl(py)], 1H over time in the solid state, as determined by X-ray powder diffraction, and in solution, as determined by 1H and 19F NMR spectroscopy and mass spectrometry. 1H contains an oxidized coordinating ligand and was previously obtained by oxidation of 1 under more vigorous conditions. Experimental data suggest that oxidation of the ligand is favored in the presence of excess H2O2 and elevated temperatures. In contrast, a smaller amount (1Pt:2H2O2) of H2O2 at room temperature favors the oxidation of the metal and yields platinum(IV) complexes.


Introduction
The serendipitous discovery of cisplatin as an anticancer drug has served humankind for decades [1,2].Despite its success in treating testicular, ovarian, head and neck, small-cell lung, and bladder cancers, with a 90% cure rate for testicular cancer [3][4][5][6][7][8], cisplatin still has limited applications owing to natural and acquired resistance against tumors [9,10].Additionally, it causes severe side effects, such as nephrotoxicity, neurotoxicity, and myelosuppression [9-16], and it can only be administered intravenously.The need to address these limitations and increase their applications to a broader spectrum of cancers produced cisplatin derivatives and new Pt II compounds.However, only Pt IV compounds showed the potency to shift the paradigm because their relatively inert nature reduces the extent of side reactions-it makes them less toxic and provides the possibility of their oral administration [8,[17][18][19][20] for improved quality of life of cancer patients.Furthermore, they are more water-soluble than Pt II drugs and are more easily absorbed in the gastrointestinal tract; their high lipophilicity causes enhanced diffusion through the cell membrane, and they are not cross-resistant with cisplatin [21][22][23].
Generally, Pt IV compounds (e.g., tetraplatin, iproplatin, and satraplatin) are considered to be Pt II prodrugs [24,25].They are relatively inert to ligand substitution reactions due to their electronic configuration, but liable to two-electron reduction.They are reduced to their active Pt II analogue in vivo by biomolecules, such as glutathione (GSH), by the loss of their axial ligands [8,26,27].The ease with which Pt IV complexes are reduced to Pt II depends on the nature of the axial ligands [28], which affect the reduction potential (E red ) for the Pt IV/II process.For example, the order of the ease of reduction of Pt IV [28] in tetraplatin (axial ligand Cl − ) [29], JM216 (axial ligand CH 3 COO − ) [30], and Iproplatin (axial ligand OH − ) [31] is Cl − > RCO 2 − > OH − .Photoactive Pt IV complexes have also been explored for better efficiency [32,33].Nanoparticle-based drug delivery of Pt IV complexes has been introduced to address the resistance issues and further lower the toxicity [34,35].In most cases, the reduction of the Pt IV prodrug generates the parent Pt II compound by the loss of two axial ligands [27,36].Some reports also mentioned the formation of more than one reduction product, depending on the reducing agents used [37,38].
Molecules 2023, 28, x FOR PEER REVIEW 2 of 18 tract; their high lipophilicity causes enhanced diffusion through the cell membrane, and they are not cross-resistant with cisplatin [21][22][23].Generally, Pt IV compounds (e.g., tetraplatin, iproplatin, and satraplatin) are considered to be Pt II prodrugs [24,25].They are relatively inert to ligand substitution reactions due to their electronic configuration, but liable to two-electron reduction.They are reduced to their active Pt II analogue in vivo by biomolecules, such as glutathione (GSH), by the loss of their axial ligands [8,26,27].The ease with which Pt IV complexes are reduced to Pt II depends on the nature of the axial ligands [28], which affect the reduction potential (E red ) for the Pt IV/II process.For example, the order of the ease of reduction of Pt IV [28] in tetraplatin (axial ligand Cl − ) [29], JM216 (axial ligand CH3COO − ) [30], and Iproplatin (axial ligand OH − ) [31] is Cl − > RCO2 − > OH − .Photoactive Pt IV complexes have also been explored for better efficiency [32,33].Nanoparticle-based drug delivery of Pt IV complexes has been introduced to address the resistance issues and further lower the toxicity [34,35].In most cases, the reduction of the Pt IV prodrug generates the parent Pt II compound by the loss of two axial ligands [27,36].Some reports also mentioned the formation of more than one reduction product, depending on the reducing agents used [37,38].
The need to find better drugs led to "rule breaker" [39] or "non-traditional" drugs [40], which violate structure-activity rules [41].One such example is the polynuclear platinum compound BBR3464 [42][43][44].Other "rule breakers" include two classes of organoamidoplatinum(II) compounds, namely, Class 1, [Pt{N(R)CH2}2(py)2] (R = polyfluoroaryl), with no H atoms on the N-donor atoms, and Class 2, trans-[Pt{N(R) CH2CH2NRʹ2}X (py)] (R = polyfluoroaryl; R′ = Et, Me; and X = Cl, Br, I), with trans amine ligands and trans anionic ligands, and no H atoms on the N-donor atoms (see Figure 1).Both classes show promising anticancer activity in vitro and in vivo [45][46][47].The investigation of DNA binding properties by Resonant X-ray emission spectroscopy (RXES) shows that after hydrolysis of [Pt{N(p-HC6F4)CH2}2(py)2] (Pt-103) (py = pyridine), the [N(p-HC6F4)CH2]2 2− moiety behaves as a leaving group, and hydroxylation of the Pt center generates a hydrolyzed species, which then reacts with DNA and preferentially coordinates to the adenine site, rather than the guanine site [48].This could explain why Pt-103 is biologically active against cisplatin-resistant cell lines.Pt IV compounds are generally six coordinate octahedral complexes and can be synthesized by oxidative addition of four coordinate square planar Pt II compounds.However, Pt IV compounds are generally six coordinate octahedral complexes and can be synthesized by oxidative addition of four coordinate square planar Pt II compounds.However, some five coordinat Pt IV complexes also have been reported to be formed in the oxidation of Pt II to Pt IV [49].The Platinum Group Metals (PGMs) in higher oxidation states (as Pt IV ) have been reported as possible intermediates in some organic synthetic procedures due to their lower stability [50][51][52][53].

Results and Discussion
In the present work, the chemical oxidation of 1 was undertaken with H 2 O 2 at room temperature in a range of solvents to determine if isolable Pt IV complexes could be obtained under mild conditions.The H 2 O 2 oxidation in acetone produced the gold-colored dihydroxidoplatinum(IV) compound 2•H 2 O (gold) as a hydrate, along with 1H, and 1H 0.25 1Br 0.75 organoenamineamidoplatinum(II) compounds as minor products (Scheme 1 (bottom, red)).
The Pt IV complex 2•H 2 O (gold) showed slow reductive dehydration in the solid state to produce the organoenamineamide Pt II complex 1H, which is the product of oxidation of the ligand [47] (see below).Earlier studies showed that some Pt IV complexes also exhibit reductive elimination similar to what is better known for Pd IV complexes [50].
The selectivity for formation of Pt IV compounds was enhanced by optimizing the experimental conditions to produce the outcome shown in Scheme 2. We proposed previously that, in the absence of any other source of Cl − in the reaction mixture, the chloride needed to form 1Cl is generated from the oxidation of the Pt-Cl bond of 1 [47].Thus, H 2 O 2 oxidation reactions of 1 were also performed with deliberately added chloride to examine whether this would enhance the yield of 1Cl or would promote the formation of Pt IV complexes, as the Pt-Cl bond should remain intact due to the presence of excess chloride.Scheme 2 is a schematic representation of the major products obtained from the oxidation of 1 with limited H 2 O 2 under a range of experimental conditions.Two differently colored samples of 2•H 2 O, red and gold (2•H 2 O (red) and 2•H 2 O (gold) ), were isolated.The amounts of the reagents and the yields of the products are shown in Table 1.The results demonstrate that the addition of chloride enhances the formation of dihydroxidoplatinum(IV) complexes.
The H 2 O 2 oxidation reaction of 1 in the presence of LiCl in CH 2 Cl 2 at room temperature produced the Pt IV complex 2•H 2 O in two colors, red and golden crystals (see experimental section).Both were characterized by X-ray crystallography (see below) and microanalyses.Both have one molecule of water of crystallization per molecule of the complex (some previous works have also reported the observation of transient red color upon oxidation of cisplatin with chlorine [63,64]).Related results were obtained with added tetrabutylammonium chloride, in CH 2 Cl 2 (see Table 1 and Experimental section).In this case, a deep-red-colored Pt IV complex containing 0.5 of a CH 2 Cl 2 molecule in the asymmetric unit, 3•0.5CH 2 Cl 2 , with some 2•H 2 O (gold) was obtained.A few crystals of NBu 4 [PtCl 3 (py)] also were obtained and characterized by X-ray crystallography only.All the experimental results suggest that adding chloride simplifies the reaction by preventing the dissociation oxidation of the Pt-Cl bond.
The mechanism for H 2 O 2 oxidation of Pt II to Pt IV has been reported as single-step two-electron oxidation or as two very rapid one-electron processes that exclusively produce trans-hydroxide complexes [65].In this oxidation reaction, the square planar configuration of the original Pt II complex is retained, and the two hydroxido ligands coordinate trans to each other.A 195 Pt NMR study has suggested that one of the trans-coordinated hydroxido ligands originates from H 2 O 2 and the other from the solvent water [66,67].
Notably, all Pt IV solvate complexes show reductive dehydration, i.e., from Pt IV to Pt II species.However, the resulting Pt II species is not the parent compound 1, as is generally the case with Pt IV species.Instead, an organoenamineamidoplatinum(II) compound 1H with an oxidized coordinating ligand is formed (below).

Scheme 2. Oxidation of 1 with H2O2 under mild conditions showing major products.
Table 1.Quantities of reagents and product yields (crystalline) for the oxidation of 1 with 30% H2O2 reactions performed at room temperature.The mechanism for H2O2 oxidation of Pt II to Pt IV has been reported as single-step twoelectron oxidation or as two very rapid one-electron processes that exclusively produce trans-hydroxide complexes [65].In this oxidation reaction, the square planar configuration of the original Pt II complex is retained, and the two hydroxido ligands coordinate trans to each other.A 195 Pt NMR study has suggested that one of the trans-coordinated hydroxido ligands originates from H2O2 and the other from the solvent water [66,67].

Compound Cl
Notably, all Pt IV solvate complexes show reductive dehydration, i.e., from Pt IV to Pt II species.However, the resulting Pt II species is not the parent compound 1, as is generally the case with Pt IV species.Instead, an organoenamineamidoplatinum(II) compound 1H with an oxidized coordinating ligand is formed (below).

X-ray Crystal Structures
The molecular structures of 2•H 2 O (red) and 2•H 2 O (gold) Pt IV complexes are shown in Figure 2, and that of 3 in Figure 3. 2•H 2 O (gold) crystallizes in the space group (C2/c), whereas 2•H 2 O (red) crystallizes in the Cc space group.Despite these space group differences, their unit cells are virtually identical (Table 2), as are their X-ray powder diffractograms generated from their single-crystal data (Figure S1).Accordingly, the structures are the same, despite the optimum solutions being in different space groups.The molecular structure of 2•H 2 O (red) has the same ratio of complex to solvent of crystallization (water) as in 2•H 2 O (gold) .In 2•H 2 O (red) , two dihydroxidoplatinum(IV) molecules bridged with two water molecules by H-bonding are present in the asymmetric unit (Figure 2c), whereas in 2•H 2 O (gold) , a single molecule of 2 is associated with a single water molecule of crystallization (Figure 2a).However, the crystal structure of 2•H 2 O (gold) extended to two asymmetric units (Figure 2b) reveals the same structure as in the asymmetric unit of 2•H 2 O (red) .Red and yellow compounds with essentially the same structure are observed in the case of yellow and red mercuric oxide, ref [68] where the difference is attributed to particle size.Likewise, [RuBr 2 (CO) 2 (tpy)] (tpy = 2,2 :6 ,2 -terpyridine) exists in red and yellow forms with essentially the same structure [69].Although the powder diffractograms of bulk 2•H 2 O (red) and 2•H 2 O (gold) show significant differences (Figure S7), this is attributed to different rates of reductive dehydration in the solid state (see below).3•0.5CH 2 Cl 2 crystallizes in the C2/c space group with one formula unit in the asymmetric unit (Figure 3a), and the crystal packing shows a hydrogen-bonded dimer (Figure 3b).
2•H2O(gold), a single molecule of 2 is associated with a single water molecule of crystallization (Figure 2a).However, the crystal structure of 2•H2O(gold) extended to two asymmetric units (Figure 2b) reveals the same structure as in the asymmetric unit of 2•H2O(red).Red and yellow compounds with essentially the same structure are observed in the case of yellow and red mercuric oxide, ref [68] where the difference is attributed to particle size.Likewise, [RuBr2(CO)2(tpy)] (tpy = 2,2′:6′,2′′-terpyridine) exists in red and yellow forms with essentially the same structure [69].Although the powder diffractograms of bulk 2•H2O(red) and 2•H2O(gold) show significant differences (Figure S7), this is attributed to different rates of reductive dehydration in the solid state (see below).3•0.5CH2Cl2 crystallizes in the C2/c space group with one formula unit in the asymmetric unit (Figure 3a), and the crystal packing shows a hydrogen-bonded dimer (Figure 3b).All Pt IV solvate complexes have an octahedral stereochemistry around the Pt metal atom with trans hydroxido axial ligands.The bond lengths are listed in Table 3, the bond angles are in Tables S1 and S2, and the crystal data are in Table 2.The OPtO angles in  All Pt IV solvate complexes have an octahedral stereochemistry around the Pt metal atom with trans hydroxido axial ligands.The bond lengths are listed in Table 3, the bond angles are in Tables S1 and S2, and the crystal data are in Table 2.The OPtO angles in 2•H 2 O (gold) , 2•H 2 O (red) , and 3•0.5CH 2 Cl 2 are 177.7(3),177.9 (3)/ 177.8(4) (molecules A and B), and 176.57(13), respectively.These angles are comparable to 179.73(9) in [Pt{((p-HC 6 F 4 )NCH 2 ) 2 }(py) 2 (OH) 2 ] ([Pt103(OH 2 )]) [54], as expected for a linear and trans arrangement of axial ligands.Equatorial positions have a square planar arrangement of the donor atoms, as in the parent compound 1.The Pt-O bond lengths shown in Table 3 are similar to those for the dihydroxidoplatinum(IV) complex, [Pt103(OH 2 )] [54], shown in Table 3.The Pt-N bond lengths are expected to lengthen with an increase in the coordination number from 4 to 6.However, an increase in the oxidation state from +2 to +4 is expected to shorten the Pt-N bond lengths.Apparently, these contrary effects cancel each other out, so the Pt-N bond lengths remain close to those of the parent platinum(II) compound (1) at the three-esd level.The angles between OH and other donor atoms in the square planar arrangement are close to 90 • , consistent with octahedral stereochemistry.• ).However, the N atoms have less trigonal character than in the platinum(II) complexes 1 (∑356.9• ) and 1H (∑357 • ).
These Pt IV complexes show a range of inter-and intramolecular H-bonding (Figures 2 and 3), as also observed for related Pt II    S2.In the asymmetric unit, only half of the molecule is present, and the other half is symmetrically generated.Crystallographic data are given in Table S3, and selected bond lengths and angles are listed in Table S4.

Powder X-ray Diffraction (PXRD) Study
Powder diffraction patterns for bulk 2•H 2 O (red) and 2•H 2 O (gold) exhibit differences (Figure S7) and also differ from the identical patterns generated from single-crystal data (Figure S1).These solids, especially red 2•H 2 O, changed in physical appearance with time (over almost 90 days) and turned from deep-red crystals (block) into a mixture of red powder and some yellow solid.
A comparison of the PXRD pattern for a bulk sample of 2•H 2 O (red) with those calculated from the single-crystal data for the platinum(II) complex [Pt(p-BrC 6 F 4 )NCH=CHNEt 2 } Cl(py)], 1H [47]  A yellow crystal of 1H was collected from the bulk sample of 2•H 2 O (red) , and X-ray diffraction data were obtained (see Table S5).The crystal structure showed twinning, but the cell parameters were consistent with 1H [47].Another yellow crystal of co-crystallized ([Pt(p-BrC 6 F 4 )NCH=CHNEt 2 }Cl(py)], 1H and [Pt(p-BrC 6 F 4 )NCH=C(Cl)NEt 2 }Cl(py)], 1Cl, 1H/Cl) also was collected from a bulk sample of 2•H 2 O (gold) , and X-ray diffraction data were obtained (see Table S5).The crystal structure showed twinning, but the cell parameters were consistent with co-crystallized (1H/Cl) [47].The mechanism for formation of 1Cl by reductive dehydration in the solid state is not fully understood, but it is probably via a similar path to that proposed for its formation in the oxidation of 1 by H 2 O 2 under aggressive conditions [47].

Isolation of PtIV from the Solution of an Aged Bulk Sample
To examine if platinum(IV) species can be recovered from solution, an aged sample of 3•0.5CH 2 Cl 2 was returned to the reaction mixture from which  S6) as in Table 2.However, 3 (with 0.5 CH 2 Cl 2 in the crystal lattice) could not be isolated.A yellow crystal of co-crystallized (1H/Cl) again was isolated from the solution, and the unit cell parameters collected (Table S6) are in agreement with those reported in Table S5.Some pale-yellow crystals were also isolated from the solution, and X-ray diffraction data were obtained, establishing the identification as [NBu 4 ][PtCl 3 (py)] (Figure S2), as also isolated from the preparation of 3•0.5CH 2 Cl 2 (above).

NMR Spectroscopy
The rearrangement of the Pt IV complexes into the Pt II species, 1H, was initially detected by NMR spectroscopy.Notably, no Pt IV species was detected in the NMR spectra of The other two resonances show the small separation observed for F2,6 and F3,5 of the p-HC 6 F 4 group in other 2,3,5,6-tetrafluorophenylethane-1,2-diaminatoplainum(IV) complexes [54].The signals are shifted to a higher frequency than for the corresponding resonances of the Pt II precursor due to the higher oxidation state.
In the 1 H NMR spectrum of 2•H 2 O (red) in (CD 3 ) 2 CO, two separate resonance sets were observed for ortho, meta, and even for the para protons of the pyridine ligands.That is only possible when two species are present in the solution.One set of resonances corresponds to those reported for 1H [47].The remaining resonances are attributed to those of the platinum(IV) complex 2 in a 1:1 ratio with 1H.Further to this assignment, in the 1 H NMR spectra, one of the two sets of pyridine 1 H resonances appears at a higher frequency than the other set.This set of resonances is assigned to pyridine of a platinum(IV) species. 1    5.For 2•H 2 O (gold), only 1H was observed, and the Pt IV complex was not observed; therefore, only the data for 1H are shown in Table 5.The complete NMR data and integrations showing relative amounts are provided in the Experimental section.All the above observations indicate that Pt IV complexes show reductive dehydration to Pt II species, mainly 1H, in solution (Equation ( 1)) and in the solid state.In this rearrangement, the metal is reduced, and the ligand is oxidized with water loss.This is a net dehydration reaction, as given in Equation (1).The rate at which Equation (1) occurs is strongly dependent on the environment.After the peroxide reaction, these Pt IV complexes were isolated with the addition of water (see Experimental section), so Equation ( 1) is not favored.In the solid state, slow loss of water or dehydration occurs.In an organic solvent with minimal water content, water loss is facilitated and faster than in the solid state.
Variable-Temperature NMR Spectra To monitor Equation (1) in solution further, the temperature dependence of 1 H and 19 F NMR resonances was examined.The spectra were taken at 20 • intervals, from 25 • C to −60 • C, and are shown in Figures S3-S6.The temperature variation study was performed almost 60 days after the NMR spectra were first recorded for 2•H 2 O (red) (Experimental section), when Pt II and Pt IV were present in an almost 1:1 ratio.The integration ratios of Pt IV to Pt II are 40% and 60%, respectively, at 25 • C. 1 H and 19 F NMR spectra do not show a any significant change in the temperature range of 25 • C to −60 • C. The F 2, 6 and F 3, 5 resonances for Pt II do not show any change with variation in the temperature.However, a slightly increased separation between F 3, 5 resonances of Pt II and Pt IV was observed in the 19 F NMR spectra, with some broadening and reduced definition of F 3, 5 of the Pt IV species.The broadening is attributed to crystallization at lower temperatures.The integration ratio of Pt IV to Pt II decreases upon cooling, consistent with partial crystallization of the former.
When the solution was heated from 25 • C to 50 • C and the spectra were collected, the 1H resonances showed an increase in intensity in the 19 F NMR spectra consistent with the further extent of the reaction in Equation ( 1), as shown in Figure S6.

Electrospray MS Measurements
As described in the supporting information, no Pt IV complexes were detected via electrospray MS measurements.Similar to what was observed for trans-organoenamineamidoplatinum(II) complexes [47], the starting material 1 was observed.

Instrumentation/Analytical Procedure
NMR spectra were recorded in deuterated solvents with Bruker DPX 300, 400, or 600 spectrometers (Billerica, MA, USA) supported by Top Spin NMR 4.3.0software on a Windows NT workstation.CFCl 3 and tetramethylsilane were used for the internal calibration of 19 F NMR and 1 H NMR spectra, respectively.Infrared spectra were recorded on a Perkin-Elmer 1600 FT-IR spectrophotometer as Nujol and hexachlorobutadiene (HCB) mulls between NaCl plates or recorded with an Agilent Cary 630 (Agilent Technologies Ltd., Yarnton, UK) attenuated total reflectance (ATR) spectrometer in the range 4000-600 cm −1 .Low-resolution ESI measurements were recorded on a Waters micromass ZQ QMS connected to an Agilent 1200 series HPLC system.High-resolution accurate mass measurements were performed on a TOF (Agilent) instrument with a multimode source by using the dual methods ESI (electrospray ionization) and APCI (atmospheric pressure chemical ionization).Microanalyses were carried out by the Science Centre, London Metropolitan University Elemental Analysis Service.An electrothermal IA6304 apparatus was used to measure the melting points (uncalibrated) of the compounds.PXRD patterns were measured using a Bruker D8-Focus diffractometer (Billerica, MA, USA) with a 1 • divergence slit, 0.2 • receiving slit, and carbon monochromators (Cu-Kα radiation, λ = 1.5406Å) in the range 2θ = 2-60 • at 0.02 • increments, at room temperature.The Mercury 4.3.0software was used to generate the calculated powder patterns generated from the single-crystal diffraction models.

X-ray Crystallography
X-ray diffraction data obtained from single crystals of 2•H 2 O (gold) , [NBu 4 ][PtCl 3 (py)], and 3 were collected at a wavelength of λ = 0.712 Å using the MX1 beamline at the Australian Synchrotron, Victoria, Australia, with Blue Ice [72], a GUI using the same method as mentioned in the Experimental section of the previous report [62].Data were processed with the XDS [73] version 20230630 software package.The structures were solved using direct methods with SHELXS-97 [74] and refined using conventional alternating leastsquares methods with SHELXL-97 [74].Single crystals of 2•H 2 O (red) were loaded onto a fine glass fiber or cryoloop using hydrocarbon oil and the data collected at 123K using an open-flow N 2 Oxford Cryptosystem.A Bruker Apex II diffractometer was used to collect the data, which was processed using the SAINT [75] program.The program OLEX2 [76] was used as the graphical interface.All non-hydrogen atoms in the structures were refined anisotropically, and hydrogen atoms attached to carbon were placed in calculated positions and allowed to ride on the atom to which they were attached.The positions of the hydrogen atoms attached to the oxygen atoms were experimentally located and refined by using multiple refinement cycles.
Crystallographic data for all the structures reported in this paper have been de In acetone: 1 (0.630 g, 1.0 mmol) was dissolved in 16 mL acetone, and (0.2 mL, 2.0 mmol) of 30% H 2 O 2 solution was added.The reaction mixture was stirred at room temperature for 12 days.The color of the solution changed from initially yellow to deep red and then to reddish-orange; MnO 2 (see the warning below) [77] (2 g) was added at that time.After filtration and evaporation of the solution to 5-6 mL, distilled water (20 mL) was added, producing a cloudy solution with deep-red oil.The cloudy solution was decanted off, filtered, and a red-brown powder was collected.Crystallization of the red-brown powder from acetone/hexane produced crystals of 1H by slow evaporation, characterized by X-ray single-crystal diffraction, 1   [47].
The remaining red-orange filtrate was concentrated using a rotatory evaporator.The entire solution changed color from reddish-orange to gold, and more red-brown oil was obtained.After separation from the oil, the gold-colored filtrate produced shiny golden flakes upon cooling at −10 • C.These golden flakes were recrystallized from acetone/water, and gold-colored crystals of the platinum(IV) complex 2•H 2 O(H 2 O) were obtained.After collecting crystals, slow evaporation of the remaining mother liquor produced [Pt{(p-BrC 6 F 4 )NCH=C(H 0.25 Br 0.75 )NEt 2 }Cl(py)], 1H 0.25 Br 0.75 , as characterized by X-ray crystallog-raphy, yielding the same unit cell as reported earlier [47].The red-brown oil was dissolved in acetone, and many unsuccessful attempts of crystallization were made with various solvents. 1 (0.1 mL, 1 mmol) was added.The reaction mixture was stirred at room temperature for 7 days.The color of the solution changed from initial orange to deep red after 2 days and then to orange-red.MnO 2 (2 g) was added, the solution was stirred for 0.5 h, filtered, and MnO 2 was washed with acetone.After concentrating the filtrate, distilled water (6 mL) was added until it became cloudy.A deepred-colored oil formed with a cloudy solution.The red oil was separated and dissolved in acetone, and crystallization from acetone/hexane at −10 • C produced deep-red-colored blocks of the platinum(IV) species, 2•H 2 O (red) (0.1637 g, yield = 50%).The cloudy solution was evaporated until dryness and then dissolved again in acetone; crystallization from acetone/hexane produced the mononuclear platinum(IV) species golden 2•H 2 O in a 14% yield, identified by X-ray crystallography.
WARNING: Concentrated H 2 O 2 in the acetone in presence of an acid catalyst can form the shock and friction-sensitive explosive triacetone triperoxide (TATP).MnO 2 was used to decompose any residual H 2 O 2 catalytically before workup [77].In a solution of 1 (0.314 g, 0.48 mmol) in 20 mL CH 2 Cl 2 , 0.127 g TBACl (0.48 mmol) in 2 mL of CH 2 Cl 2 and (0.1 mL, 1.0 mmol) of 30% solution of H 2 O 2 were added.The solution was heated at near refluxing temperature for 6 h and then stirred at room temperature for 4 days.The color of the solution changed from yellow to dark orange, but not deep red;

Scheme 1 .
Scheme 1.A comparison of the products obtained from the H2O2 oxidation of 1 in aceto heating (top blue) and at room-temperature (bottom red) conditions.
complexes are shown in Figure 2, and that of 3 in Figure 3. 2•H2O(gold) crystallizes in the space group (C2/c), whereas 2•H2O(red) crystallizes in the Cc space group.Despite these space group differences, their

Scheme 2 .
Scheme 2. Oxidation of 1 with H2O2 under mild conditions showing major products.
compounds [70].The interaction distances are listed in Table 4.In 2•H 2 O (red) and 2•H 2 O (gold), both H atoms of the trans-OH groups are facing toward the o-F atoms of the polyfluoroaryl ring.However, in 3, one of the H atoms of the trans-OH ligands, faces away, as it makes an H-bond with Br(p-BrC 6 F 4 ) of an adjacent molecule with an H• • • Br distance, 3.0993(5), as shown in Figure 3.

2 •H 2 O
(gold) , and only 1H was observed (see Experimental section), showing that the rate of reductive dehydration for 2•H 2 O (gold) is fast in solution.In the 19 F NMR spectrum of 2•H 2 O (red) in deuterated acetone, four resonances in a 1:1:1:1 ratio are present at −138.24, −138.34,−140.64, and −148.16ppm, together with very low-intensity resonances of precursor compound 1.The highest and lowest frequency resonances correspond to those of 1H [47].

Figure S8 :
Normalized powder X-ray diffraction data for bulk sample of 2•H 2 O (red) with normalized powder X-ray diffraction data generated from the single crystal of 1H and 2•H 2 O (red) ; Figure S9: Normalized powder X-ray diffraction data for bulk sample of 2•H 2 O (gold) with normalized powder X-ray diffraction data generated from the single crystals of 1H and 2•H 2 O (gold) [78-81].]S5. Isolation of Pt IV from the solution of an aged bulk sample [

Table 1 .
Quantities of reagents and product yields (crystalline) for the oxidation of 1 with 30% H 2 O 2 reactions performed at room temperature.

Table 2 .
Crystallographic data for the molecular structures of 2

Table 3 .
Selected bond lengths for compounds 2

Table 4 .
Inter-and intramolecular H-bonding interaction distances for 2

•H 2 O (gold) than for 2•H 2 O (red) .
(Scheme 1) and single crystals of 2•H 2 O (red) (see Figure S8) clearly shows that Pt IV 2•H 2 O (red) and 1H both are present in the bulk sample of stored 2•H 2 O (red) .A comparison between the PXRD patterns of the bulk sample of 2•H 2 O (gold) with those calculated from the single-crystal data for 1H and single crystals of 2•H 2 O (gold), (Figure S9), clearly shows 2•H 2 O (gold) and 1H both are present in the bulk sample of 2•H 2 O (gold) .However, 1H is present in larger amounts in this bulk sample than in the bulk sample of 2•H 2 O (red) .All observations and the experimental facts confirm that these Pt IV samples undergo reductive dehydration to produce a Pt II complex with an oxidized ligand, where the rate is faster for 2

3•0.5CH 2 Cl 2 was
isolated in the first place and was completely dissolved in CH 2 Cl 2 to obtain an homogeneous solution.Crystallization from the CH 2 Cl 2 /hexane mixture enabled the isolation of red crystals of [Pt IV {(p-BrC 6 F 4 )NCH 2 CH 2 NEt 2 }Cl(OH) 2 (py)].H 2 O, 2•H 2 O (red) having the same cell parameters (see Table H and 19 F NMR spectra of 2•H 2 O (red) in CD 2 Cl 2 also showed both species, confirming that this observation is not solvent-specific.Similar behavior was shown by 3•0.5CH 2 Cl 2 .In the solution, 3•0.5CH 2 Cl 2 produces a Pt IV species and 1H, as observed for 2•H 2 O (red) .However, this compound also shows the chloro-substituted organoenamineamide species [Pt(p-BrC 6

Table 5 .
1H and19F NMR chemical shifts and assignments for 1H
The data are extracted from complex NMR spectra of the compounds plus their reductive dehydration products.The full NMR data and integrations showing relative amounts are provided in the Experimental section.* For 2•H 2 O (gold), only 1H was observed.Pt IV was not observed.

•H 2 O(H 2 O), with
H and19F NMR revealed the presence of Pt IV species, 2some Pt(py) 2 Cl 2 .Some colorless shiny crystals of trans-Pt(py) 2 Cl 2 were obtained after a long period and were characterized by X-ray diffraction.(

Table
S5 Unit cell parameters for 1H and co-crystallized 1(H/Cl) collected from the bulk sample of 2