An Investigation of the Multifunctional Alkylation Chemistry of [Pt₂(μ-S)₂(PPh₃)₄]

This thesis presents the studies on the multifunctional alkylation of the metalloligand [Pt₂ (μ-S)₂(PPh₃)₄] 1.1. Multifunctional organic groups which include semicarbazone and thiosemicarbazone, urea, isocyanate, guanidine, ketones and amides react with 1.1 to generate the corresponding functionalised derivatives containing thiolate ligands produced by alkylation of one or both sulfide centres. Polymers with suitable electrophilic branches also react to immobilise 1.1. By using Electrospray Ionisation Mass Spectrometry (ESI-MS) as the monitoring technique, [Pt₂ (μ-S)₂(PPh₃)₄] was employed as a productive template for structurally and chemically diverse thiolate-platinum complexes. Before this study, 1.1 was known to be one of the best building blocks for multimetallic molecules through the exceptional ligating ability of the two sulfide centres to virtually any transition and main group metal fragment. However, extension of the synthetic versatility of 1.1 to multifunctional non-metallic positive centres has only been explored to a lesser extent and thus far less developed. This thesis is organised into five chapters. Chapter one is the review of literature on [Pt₂ (μ-S)₂(PPh₃)₄] and the development of its chemistry from an efficacious metalloligand for multimetallic assembly to a powerful nucleophile for organic electrophiles. The main geometry and electronic features of 1.1 and analogous complexes were highlighted especially as it affects the dihedral angle (θ) between the two Pt₂S₂ planes in [Pt₂ (μ-S)₂(PPh₃)₄]. The variable reaction modes of 1.1 with different electrophiles were discussed especially as it may affect the less studied multifunctional alkylation. The effectiveness of the ESI-MS as a monitoring tool in the study of 1.1 chemistry is also discussed. Chapter two details the study of the multifunctional monoalkylation reactions of the aforementioned array of multifunctional organic groups with [Pt₂ (μ-S)₂(PPh₃)₄]. Alkylation reaction of 1.1 with organo-halide of the type R–CH₂-X and R–CH₂CH₂-X (R= organic group and X = Cl or Br) formed thiolate-bridged platinum complexes. The main discovery in this study is that any suitable organic functionality can be incorporated into an electrophile for 1.1. By using the ESI-MS monitoring technique, they successfully reacted with 1.1 to give novel monoalkylated platinum complexes with μ-thiolate ligands of the type [Pt₂(μ-S){μ-SR}(PPh₃)₄](PF₆) which included [Pt₂(μ-S){μ-SCH₂C(=NNHC(O)NH₂)R} (PPh₃)₄](PF₆) in 2.1b•PF₆ (R = Ph) and 2.2b•PF₆ (R = CH₃) and [Pt₂(μ-S){μ-SR}(PPh₃)₄](PF₆) (R = -CH₂C(=NOH)Ph 2.3b•PF₆, -CH₂C(=NNHC(NH₂)NH₂) Ph 2.4b•(PF₆)₂, -CH₂C(=NNHC(S)NH₂)CH₂ 2.5b•PF₆, -CH₂CH₂NHC(O)NHPy 2.6b•PF₆ (Py = o-C₅H₄N), -CH₂CH₂NHC(O)N(CH₂CH₂)₂S 2.7b•PF₆ and -CH₂ C(O)NHC(O)NHCH₂CH₃ 2.8b•PF₆. -CH₂C(═NNHTs)Ph 2.9b•PF₆, -CH₂C(═N NHTs)CH₃ 2.10b•PF₆ (Ts = -SO₂C₆H₄CH₃), -CH₂C(=NHNC(O) Py)Ph (Py = o-C₅H₄N) 2.11b•PF₆ and -CH₂C(=NNHC(O)NH₂)C₆H₄C₆H₅ 2.12b•PF₆. Geome- trical isomers formed with BrCH₂C(NNHAr)C₆H₄Ph 2.13a (Ar = 2,4-dinitrophenyl) was studied and characterised with 2D NMR techniques. The X-ray crystal structures of 2.1b•PF₆, 2.4b•(PF₆)₂, 2.7b•PF₆ and 2.8b•PF₆ are also reported. Chapter three reports an investigation of conditions that encourage the formation of homo- and heterodialkylated thiolate complexes of the type [Pt₂(μ-SR)₂(PPh₃)4]² + and [Pt₂(μ-SR){μ-SR'}(PPh₃)₄]²+ since these are currently not well understood. The factors were employed in the selective choice of alkylating agents used in the sequential syntheses of homodialkylated derivatives [Pt₂(μ-SCH₂COPh)₂(PPh₃)₄](PF₆)2 3.1b•(PF₆)₂, [Pt₂(μ-SCH₂C(O)pyr)₂(PPh₃)₄](PF₆)₂ (pyr = pyrene) 3.2b•(PF₆)₂ and [Pt₂(μ-SCH₂C(O)cyl)₂(PPh₃)₄](PF₆)₂ (cyl = coumaryl) (3.4b•(PF₆)₂. A major outcome of this study is the successful syntheses of the heterodialkylated derivatives [Pt₂(μ-SCH₂C(O)Ph)(μ-SBu)(PPh₃)₄](PF₆)₂ 3.5b•(PF₆)₂ and {Pt₂(μ-SCH₂COPh)(μ-SCH₂CH₃)(PPh₃)₄}(PF₆)₂ 3.6b•(PF₆)₂ through a sequential alkylation with organo-halide electrophiles. The X-ray crystal structures of 3.1b•(PF₆)₂ and 3.5b•(BPh₄)₂ are reported. The secondary products resulting from the displacement of a PPh₃ by Br- in the synthesis of the heterodialkylated derivatives 3.5b•(PF₆)₂ and 3.6b•(PF₆)₂, [Pt₂(μ-SCH₂C(O)Ph) (μ-SBu)(PPh₃)₃Br](PF₆) 3.5c•PF₆ and [Pt₂(μ-SCH₂COPh)(μ-SCH₂CH₃)(PPh₃)₃ Br](PF₆) 3.6c•PF₆ were also isolated and characterised by ESI-MS and X-ray crystallography. Chapter four describes the multifunctional intra- and intermolecular bridging dialkylation of 1.1. The variable alkylation mode of α,ω-dialkylating electrophiles, which is dependent on the nature and the number of spacer atoms, was investigated with functionalised electrophiles, ClCH₂C(O)CH₂Cl 4.1a, ClCH₂C(NNHC(O)NH₂) CH₂Cl 4.2a and ClCH₂C(O)NHNHC(O)CH₂Cl 4.3a. A very important novel result is the stabilisation and isolation of an intramolecular bridged five-membered ring derivative 4.1b•PF₆ [Pt₂{μ-SCH₂C(O)CHS}(PPh₃)₄] (PF₆). The reaction of 4.1a with 1.1 in the presence of dilute aqueous NaOH aided the isolation of 4.1b•PF₆ resulting from intramolecular rearrangement of the four membered ring. The semicarbazone derivative 4.2a and diamide 4.3a dialkylated 1.1 by bridging the two sulfide centres to form stable [Pt₂{μ-SCH₂C(NNHC (O)NH₂)CH₂S-μ}(PPh₃)₄](BPh₄)₂ 4.2b•(BPh₄)₂ and Pt₂{μ-SCH₂C(O)NHNH(O) CH₂S}(PPh₃)₄(PF₆)₂ 4.3b•(PF₆)₂. Both 4.1b•PF₆ and 4.2b•(BPh₄)₂ were characterised by X-ray crystallography. The syntheses and X-ray crystal structure analysis of Pt₄ aggregates formed with amide α,ω-dialkylating agents with longer spacer atoms, o- and p-ClCH₂C(O)NHC₆H₄NHC(O)CH₂Cl through the intermolecular linking of two [Pt₂(μ-S)₂(PPh₃)₄] complexes is also reported. Chapter five is the investigation of the immobilisation of [Pt₂(μ-S)₂ (PPh₃)₄] on electrophilic polymer supports. Following the reactivity of [Pt₂(μ-S)₂(PPh₃)₃] with electrophiles established in chapter two a monomeric electrophilic unit 3-chloropropyltetraethoxysilane 5.1a reacted 1.1 to give 5.1b.BPh₄. Further investigations to immobilised 1.1 on solid polymer supports through the alkylation of one of the sulfide centres with electrophilic polymers, Merrifield’s resin 5.2a, 3-bromopropylpolysiloxane 5.3a 3-chloropropyl silica 5.4a and 3-chloropropyl controlled pore glass 5.5a were done. This gave the corresponding immobilised products which is generally represented as [Pt₂(μ-S)(μ-SCH₂R--P )(PPh₃)₄] (where R = phenyl or -CH₂CH₂- groups). The immobilisation of 1.1 was also achieved through phosphine exchange reactions on polymers, a polyethertriamine phosphine derivative 5.6a and diphenylphosphine polystyrene 5.8a. The products were characterised by Scanning Electron Microscopy, solid state ³¹P{H} (CP MAS) NMR, Inductively Coupled Plasma Mass Spectrometry (ICP-MS) and X-ray Photoelectron Spectroscopy (XPS)

The reactivity of [Pt₂(μ-S)₂(PPh₃)₄] towards difunctional chloroacetamide alkylating agents: Formation of cyclized or bridged products

The reactions of [Pt₂(μ-S)₂(PPh₃)₄] towards some bis(chloroacetamide) alkylating agents have been investigated. Reaction with one mole equivalent of the hydrazine-derived compound ClCH₂C(O)NHNHC(O)CH₂Cl led to the cyclized product [Pt₂{SCH₂C(O)NHNHC(O)CH₂S}(PPh₃)₄]²⁺ which showed two different PPh₃ environments in the ³¹P{1H} NMR spectrum, as a result of non-fluxional behavior of the dithiolate ligand in solution. Reactions of [Pt₂(μ-S)₂(PPh₃)₄] with the ortho and para isomers of the phenylenediamine-derived bis(chloroacetamides) ClCH2C(O)NHC6H4NHC(O)CH2Cl gave tetrametallic complexes containing two {Pt₂S₂} moieties spanned by the CH₂C(O)NHC₆H₄NHC(O)CH₂ group. Both the ortho and para isomers were crystallographically characterized; in the ortho isomer there is intramolecular CO=H–N and S•••H–N hydrogen bonding involving the two amide groups

Kinetics and mechanism of the reduction of N, N'-salicylideneiminationiron(III) complex ion by L-ascorbic acid in aqueous acid medium

The kinetics and mechanism of the reduction of the iron(III) complex ion, [FeSalen(H2O)2]+, by L-ascorbic acid has been investigated in aqueous perchloric acid medium at 28.5 ± 0.3 oC. The kinetic data was obtained by monitoring the rate of decay of the complex at 515 nm. Under pseudo-first order conditions of concentration of L-ascorbic acid at about 20-fold excess of concentration of complex, the rate of reaction increased with the concentration of ascorbic acid. Least square fits of observed rate against concentration of ascorbic acid were linear showing first order dependence of rate on concentration of the complex. Also, a plot of logkobs against concentration of ascorbic acid gave a slope of 1.05 implying first order dependence on concentration of ascorbic acid. Second order rate constants were within (31.58 ± 0.50) × 10-2 dm3 mol-1 s-1. More information can be found in the full text

A zwitterionic monoalkylated derivative of [Pt₂(μ-S)₂(PPh₃)₄] from 1,3-propanesultone

Reaction of dinuclear platinum(II) sulfido complex [Pt₂(μ-S)₂(PPh₃)₄] with 1,3-propanesultone gives the novel zwitterionic monoalkylated thiolate complex [Pt₂(μ-S){μ-S(CH₂)₃SO₃}•(PPh₃)₄], which was characterized by NMR spectroscopy, electrospray ionisation mass spectrometry, and a single crystal X-ray structure determination. Crystals are monoclinic, space group P2(1)/c with unit cell dimensions a = 16.8957(3) Å, b = 15.5031(3) Å, c = 28.0121(5) Å, β = 99.780(1)°, for Z = 4

Further investigations on the methylation chemistry of [Pt₂(μ-S)₂(PPh₃)₄]

The methylation product of the reaction between [Pt₂(µ-S)₂(PPh₃)₄] and MeI in diethyl ether has been reinvestigated using positive-ion electrospray mass spectrometry and found to be contaminated with the dimethylated iodide-containing complex [Pt₂(µ-SMe)₂(PPh₃)₃I]⁺, which is believed to be formed early in the reaction. New, facile routes to the monomethylated complex [Pt₂(µ-S)(µ-SMe)(PPh₃)₄]⁺ have been developed using mild methylating agents. Heating [Pt₂(µ-S)₂(PPh₃)₄] in neat dimethyl methylphosphonate results in rapid and selective conversion to [Pt₂(µ-S)(µ-SMe)(PPh₃)₄]⁺; methylation with Me₃S⁺OH⁻ in refluxing methanol also affords pure [Pt₂(µ-S)(µ-SMe)(PPh₃)₄]⁺, isolated as its hexafluorophosphate salt. The X-ray structure of the previously reported complex [Pt₂(µ-SMe)₂(PPh₃)₂I₂] has also been undertaken

E/Z isomerism in monoalkylated derivatives of [Pt₂(μ-S)₂(PPh₃)₄] containing 2,4-dinitrophenylhydrazone substituents

Alkylation of [Pt₂(m-S)₂(PPh₃)₄] with 2,4-dinitrophenylhydrazone-functionalized alkylating agents XC6H4C{¼NNHC₆H₃(NO₂)₂}CH2Br (X¼H, Ph) gives monoalkylated cations [Pt₂(m-S){m-SCH₂C{¼NNHC₆H₃(NO₂)₂}C₆H₄X}(PPh₃)₄]⁺. An X-ray diffraction study on [Pt₂(m-S){m-SCH₂C{¼NNHC₆H₃(NO₂)₂}Ph}(PPh₃)₄]BPh₄ shows the crystal to be the Z isomer, with the phenyl ring and NHC₆H₃(NO₂)₂ groups mutually trans. ¹H- and ³¹P{¹H} NMR spectroscopic methods indicate a mixture of Z (major) and E (minor) isomers in solution, which slowly convert mainly to the E isomer. Reaction of [Pt₂(m-S)₂ (PPh₃)₄] with the dinitrophenylhydrazone of chloroacetone [ClCH₂C{¼NNH(C₆H₃(NO₂)₂}Me] and NaBPh₄ gives [Pt₂ (m-S){m-SCH₂C{¼NNHC₆H₃(NO₂)₂}Me}(PPh₃)₄]BPh₄, which exists as a single (E) isomer

Platinum(II) complexes containing the 3,3-dimethylglutarimidate ligand

Reaction of cis-[PtCl ₂(PPh ₃) ₂] with excess 3,3-dimethylglutarimide (dmgH) and sodium chloride in refluxing methanol gives the mono-imidate complex cis-[PtCl(dmg)(PPh ₃) ₂], which was structurally characterized. The plane of the imidate ligand is approximately perpendicular to the platinum coordination plane which, coupled with restricted rotation about the Pt-N bond, results in inequivalent methyl groups and CH2 protons of the dmg ligand in the room temperature ¹H NMR spectrum. These observations were corroborated by a theoretical study using density functional theory methods. The analogous bromide complex cis-[PtBr(dmg)(PPh ₃) ₂] can be prepared by replacing NaCl with NaBr in the reaction mixture

N'-(Pyridin-3-ylmethylene)benzenesulfonohydrazide: Crystal structure, DFT, Hirshfeld surface and in silico anticancer studies

A new Schiff base, N'-(pyridin-3-ylmethylene)benzenesulfonohydrazide, was synthesized and characterized by elemental analysis, IR, Mass, 1H NMR and 13C NMR spectroscopy, and single-crystal X-ray determination. The asymmetric molecule crystallized in the monoclinic crystal system and P2(1)/c space group. Crystal data for C12H11N3O2S: a = 9.7547(4) Å, b = 9.8108(4) Å, c = 13.1130(5) Å, β = 109.038(2)°, V = 1186.29(8) Å3, Z = 4, μ(MoKα) = 0.270 mm-1, Dcalc = 1.463 g/cm3, 13338 reflections measured (5.296° ≤ 2Θ ≤ 55.484°), 2790 unique (Rint = 0.0494, Rsigma = 0.0400) which were used in all calculations. The final R1 was 0.0345 (I > 2σ(I)) and wR2 was 0.0914 (all data). In the crystal structure of the compound C12H11N3O2S, molecules are linked in a continuous chain by intermolecular of N∙∙∙HN=N hydrogen bonds. The pyridine moiety is planar, while the benzenesulfonohydrazide group adopts a gauche conformation about C-S-N angle (105.54°). The Hirshfeld surface analysis and fingerprint plots were used to establish the presence, nature, and percentage contribution of the different intermolecular interactions, including N-H∙∙∙N, C-H∙∙∙O, C-H∙∙∙C, and π∙∙∙π interactions, with the C-H contacts having the most significant contribution. The pairwise interaction energies were calculated at the B3LYP/6-31G(d,p) level of theory, and interaction energy profiles showed that the electrostatic forces had the most significant contribution to the total interaction energies of the different molecular pairs in the crystal. In-silico technique was used to examine the compound as a possible anticancer agent. The molecule demonstrated zero violation of the criteria of Lipinski’s rule of five with a polar surface area of 116.03 Å2. The molecule displayed favorable binding interactions with ten selected validated anticancer protein targets ranging from -9.58 to -11.95 kcal/mol and -2.73 to -5.73 kcal/mol on scoring and rescoring, respectively, with London dG and Affinity dG scoring functions. Two proteins; farnesyl transferase and signaling protein, preferred interactions with the Schiff-base over their co-crystallized inhibitors according to London dG scoring. Analysis of binding poses indicated that the Schiff-base made contact with amino acid residues of the two proteins through the N-H, sulphonyl oxygen, and phenyl groups, and this could be exploited in chemical and structural modification towards activity optimization