AN INVESTIGATION OF THE REACTIVITY OF [PT2(Μ-S)2(PPH3)4] TOWARD ACTIVATED ALIPHATIC BROMOACYL ELECTROPHILES, BRCH2C(O)C(CH3)3 AND BRCH2C(O)CH2CH3- FORMATION OF MONO- AND HOMODI- ALKYLATED

CHAPTER ONE

• Introduction

The chemistry of platinum and sulfur has received tremendous attention since they were discovered owing to their interesting chemical activities. Platinum earned its name only in the 18th century, although it was known since ancient times. The first known reference to platinum is contained in the writings of the Italian physician, scholar, and poet Julius Caesar Scaliger (1484-1558). Scaliger apparently saw platinum while visiting Central America in 1557. Platinum was later found in large quantities as an impurity in 1750 by Spaniards mining for silver in Rio Pinto, Colombia. It was then named “little silver” (sometimes called “white gold”). Its first complete description was given by the Spanish military leader Don Antonio de Ulloa (1716-95). While serving in South America from 1735 to 1746, de Ulloa collected samples of platinum and later wrote a report describing the metal. De Ulloa is often given credit for discovering platinum (in 1735) on the basis of the report. The name ʺplatinumʺ was derived from the Spanish platina, meaning “little silver”. Since its discovery, platinum and many of its compounds have been used in catalysis, synthetic precursors and therapeutic medicine. They have continued to gain important prominence in many areas.These include synthetic chemistry where they are employed in synthesizing novel molecular systems, for which examples include (2,2^‘–bipyridine)dichloroplatinum(II) and cis–Bis-(acetonitrile)dichloroplatinum(II) used in Proton Enhanced Membrane (PEM) fuel cells.They are also used in self-assembly of supramolecular structures (Roxanne et al.,2008)e.g., {Pt(en)(4,4^‘–dipyridyl)}₄, as synthetic precursors e.g. cis-PtCl₂(PPh₃)₂ (Chatt and Mingos, 1970; Ugo et al.,1971). In therapeutic medicine they are used as antitumor drugs (Ovejero et al., 2007)e.g., cis-platin, PtCl₂(NH₃)₂ {cis-diaminedichloridoplatinum(II), used for treatment of testicular and ovarian cancers (Cotton et al.,1972)}.The glass industry uses platinum for optical fibers and liquid crystal display (or LCD) glasses, especially for laptops (B. V. Lenntech, personal writing on platinum).

Platinum has six isotopes, with 194, 195 and 196 as the most abundant ones. It exists in variable oxidation states ranging from 0 to VI, although several barium palatinates have been synthesized in which the platinum exhibits negative oxidation states ranging from –1 to –2, e.g., BaPt, Ba₃Pt₂ and Ba₂Pt (Karpov, Konuma and Jansen, 2006). Jansen (2005) had previously shown that cesium platinate contains Pt^2– anions.Complexes of certain carbonyl anions with the general formula [Pt₃(CO)₃(µ-CO)₃]_n^2- possess formal negative oxidation states. Jansen (2005) reiterated that the negative oxidation states exhibited by platinum are however unusual for metallic elements, although they are attributed to the relativistic stabilization of the 6s orbitals.Oxidation states of II and IV are however most common. As expected, tetracoordinated Pt(II) complexes tend to adopt 16-electron square planar geometries. The I and III oxidation states are less common and are often stabilized by metal bonding in bimetallic (or polymetallic) species. Zerovalent platinum complexes usually possess a tetrahedral structure and are stabilized by phosphine ligands e.g.,{Pt(PPh₃)₃} and {Pt[P(OR)₃]₄}. The tetracarbonyl complex, {Pt(CO)₄} does not exist unlike the nickel analog although {Pt(PF₃)₄} and {Pt[PF(CF₃)₂]₄} have been synthesized and characterized (Cotton et al.,1972). Complexes of Pt⁰ have been employed in catalysis, especially in C–C coupling reactions because of the ease with which they undergo oxidative addition reactions. Low-valence platinum forms numerous clusters, usually based on the Pt₃ triangle, as in the carbonyl phosphine complexes (Figure 1.0). The cluster, [Pt₁₅(CO)₃₀]^2– catalyzes the hydrogenation of MeCN, PhCHO and other organic substances. The higher states V and VI are seen only in a few fluoro compounds (Cotton et al., 1972).

Figure 1.0: Low-valence platinum cluster with general formula Pt_n(CO)_x(PR₃)_y(n=x=y=3)

Platinum salts can cause health issues (such as DNA alterations, cancer, allergic skin reactions, organ impairment and hearing damage), but the metal element has not been linked to adverse health effects (World health Organization, 2000).  The health effects of Platinum salts are strongly dependent upon the kind of bonds formed with body proteins. Platinum -protein bonds are often the reason Pt moieties are applied as medicine to cure cancer.

Sulfur is known to catenate, forming interlinked polysulfido ligands (S_n²) where n is up to 8 (cyclic octatomic molecules). It is a strong coordinating ligand with the tendency to extend its coordination sphere. This can be seen in compounds ranging from terminal groups e.g.( [Mo₂S₁₀]^2-) (Clegg, Christou, Garner and Sheldrick, 1981) to μ-sulfido groups e.g. [Pt₂(μ-S)₂(PPh₃)₄] (Ovejero et al., 2007) and to cluster complexes such as [Rh₁₇(S)₂(CO)₃₂]^3- which consists of a S-Rh-S moiety lying in the cavity of a rhodium-carbonyl cluster (Vidal, Fiato, Cosby and Pruett, 1978). The coordination ability of sulfur ligands manifests in the unique variety of structures they form with most of the transition metals in different oxidation states (Bayo´n, Claver and Masdeu-Bulto´, 1999). Sulfur is an essential element in biological systems, but almost always in the form of organosulfur compounds or metal sulfides. Three amino acids (cysteine, cystine, and methionine) and two vitamins (biotin and thiamine) are organosulfur compounds. Many cofactors also contain sulfur including glutathione and thioredoxin and iron-sulfur proteins such as feredoxins. Disulfides containing the S–S bonds confer mechanical strength and insolubility of the protein keratin, found in outer skin, hair, and feathers. Sulfur has 25 known isotopes, four of which are stable: ³²S (95.02%), ³³S (0.75%), ³⁴S (4.21%), and ³⁶S (0.02%).

The outstanding ability of sulfur to bind to heavy metals has also generated a lot of interest in metal sulfides with diverse structures and applications. Typical examples can be found in the occurrence of platinum (including the other group 10 members, palladium and nickel) and sulfur in alluvial deposits e.g., Cooperite (Pt_0.6Pd_0.3Ni_0.1S) (Wells, 1984; Carbri, Laflamme, Stewart, Tunner and Skinner, 1978), Braggite (Pt_0.38Pd_0.50 Ni₀.₁₀S_1.02) (Carbri, Laflamme, Stewart, Tunner and Skinner, 1978) and the sulfide (Pt, Pd)S. As a soft acid, platinum has shown a strong affinity for sulfur donors such as DMSO where numerous complexes have been reported (Han, Huynh and Tan, 2000). Both SO₂ and SO₃^2-are coordinated to platinum via S rather than O. There are also polysulfide dianions S_n^2- which form complexes with puckered MS_n rings, e.g., K₂PtCl₄ and K₂S₄ yield [Pt₄S₂₂]^4- which consists of a [Pt₄S₄]⁴⁺cubane core surrounded by six bridging ligands (Kim and Kanatzidis, 1993).Anionic thiolato complexes such as [Pt(SR)₄]^2- and [Pt₂(µ-SR)₂(SR)₄]^2- are also well known (Cotton et al.,1972). The use of platinum compounds like cis-platin, oxaliplatin, thioplatin and carboplatin as anti-cancer drugs is also a major factor that has greatly influenced rising interest in platinum-sulfur complexes. Soon after B. Rosenberg’s discovery in 1968 that the cis-isomer of PtCl₂(NH₃)₂ has antitumor activity, well over 2000 different types of complexes with different amines and anionic ligands were synthesized and screened (Cotton et al.,1972).The side effects of cis-platin include nausea and vomiting, hair loss, tinnitus, hearing loss, and nephrotoxicity (Carinder, 2014).The nephrotoxicity in particular and other therapeutic drawbacks generally associated with platinum-based anti-cancer drugs have been attributed to the high reactivity between sulfur and organo-thiolate compounds (such as glutathione) with platinum (Taguchi, Nazneen, Abid and Razzaque, 2005). Investigations for solution to the problem also provided additional drive for further studies into platinum-sulfur complexes.

1.1 Statement of Problem

            The binding ability of Pt-S compounds toward a wide variety of electrophiles has generated a lot of interest because of its potential as a synthetic template for oganosulfur compounds (Wei, Wang and Guo, 2005). However, available literature on the alkylation chemistry of [Pt₂(µ-S)₂(PPh₃)₄] 1 is limited to simple alkyls, aryls and very few functionalized organic electrophiles (Devoy, Henderson, Nicholson and Hor, 2010). There are still many functionalized organic electrophiles whose reactivity toward 1 is not known.

In addition, reactions of 1 with electrophiles are not always straightforward as undesired side products could be formed. Real time visualization and characterization of products and other species in the alkylation chemistry of 1 by Pressurized Sample Infusion Electrospray Ionization Mass Spectrometry (PSI-ESI-MS) could help in eliminating this problem, improve isolation of target products, determine the reaction mechanism and allow for the acquisition of reaction kinetic information. At present, this approach has not been explored in solving the synthetic complexities surrounding the double alkylation of 1.

1.2 Objectives of the Present Research