Organotin(IV) Dithiocarbamate Complexes: Chemistry and Biological Activity

molecules

Review Organotin(IV) Dithiocarbamate Complexes: Chemistry and Biological Activity

Jerry O. Adeyemi 1,2 and Damian C. Onwudiwe 1,2,*

1 Material Science Innovation and Modelling (MaSIM) Research Focus Area, Faculty of Natural and Agricultural Science, North-West University, Maﬁkeng Campus, Private Bag X2046, Mmabatho 2735, South Africa; [email protected] 2 Department of Chemistry, Faculty of Natural and Agricultural Science, North-West University, Maﬁkeng Campus, Private Bag X2046, Mmabatho 2735, South Africa * Corresponding: [email protected]; Tel.: +27-18-389-2545; Fax: +27-18-389-2420

Received: 15 September 2018; Accepted: 4 October 2018; Published: 9 October 2018

Abstract: Significant attention has been given to organotin(IV) dithiocabamate compounds in recent times. This is due to their ability to stabilize specific stereochemistry in their complexes, and their diverse application in agriculture, biology, catalysis and as single source precursors for tin sulfide nanoparticles. These complexes have good coordination chemistry, stability and diverse molecular structures which, thus, prompt their wide range of biological activities. Their unique stereo-electronic properties underline their relevance in the area of medicinal chemistry. Organotin(IV) dithiocabamate compounds owe their functionalities and usefulness to the individual properties of the organotin(IV) and the dithiocarbamate moieties present within the molecule. These individual properties create a synergy of action in the hybrid complex, prompting an enhanced biological activity. In this review, we discuss the chemistry of organotin(IV) dithiocarbamate complexes that accounts for their relevance in biology and medicine.

Keywords: organotin(IV); dithiocarbamate; structure; biological properties; stereochemistry

1. Introduction Metals are relevant for medicinal applications because they play crucial roles in the living systems of organisms. They become soluble in biological systems by losing electrons to form positively charged species. It is in this ionic state that they play their biological roles [1]. Metal ions lack electrons, while biological molecules like DNA and proteins are electron-rich, thus encouraging the propensity for these opposing charges of both metal ions and biological molecules to interact and bind. This tendency is also applicable to the interaction of metal ions with other small molecules and ions that are crucial to life, such as oxygen [1]. Tin, a group V metal, can be found in numerous inorganic/organometallic compounds. It has two 5s and two 5p electrons in its outer shell. It is able to lose the two electrons in the 5p orbital to form Sn2+ ions, or share all four electrons with other atoms by acquiring the stable electronic conﬁguration of xenon. The chemistry of tin, mostly revealed in aqueous media, is more convoluted, because it uses inert electron pairs (a result of poor shielding of the outer electrons compared to those in the inner core) to direct its stereochemistry. Neither Sn4+ nor Sn2+ is found in aqueous solutions. Tin can bond with carbon to form a group of compounds known as organotin compounds [2]. Organotin compounds have contributed immensely to the study and the understanding of organometallic compounds, which began in 1949, and this has led to their usage in diverse application ﬁelds. Detailed studies on the structural properties and changes which occur in solution and solid states of organotin compounds have been reported [3].

Molecules 2018, 23, 2571; doi:10.3390/molecules23102571 www.mdpi.com/journal/molecules Molecules 2018, 23, 2571 2 of 27

Organotin compounds have at least one covalent carbon–tin bond, and are mostly tetravalent in structure [4]. These compounds were first discovered by Edward Frankland in 1894, with the first compound being diethyltindiiodide ((C2H5)2SnI2). Since two oxidation numbers are known for tin (+2 and +4), organotin compounds can exist as organotin(II) (sp2 hybridized) or organotin(IV) (sp3 hybridized) species. However, the +IV oxidation state has been found to be more stable than their +II state which oxidizes easily to their +IV state and often polymerizes. The only known stable organotin(II) compound is bis(cyclopentadienyl)tin(II) [3], but many organotin(IV) compounds are known and they conform to the general formula RxSn(L)4-x, where R = alkyl or aryl substituents; L = organic or inorganic ligand [5]., The presence of one or more covalent C-Sn bonds affects the activity of the whole compound depending on the number and nature of the alkyl (R) substituents attached to the Sn center [6]. Variation of the alkyl or aryl substituent in the organotin(IV) compounds has shown notable effects on the biological activities of these compounds [7]. These compounds contain a Sn centre with an anion, usually oxide, hydroxide, chloride, fluoride, carboxylate or thiolate [7]. They are widely used organometallic compounds and have been used over the last few decades for different applications in industry and agriculture such as pesticides, fungicides and as anti-fouling agents [8]. Organotin(IV) compounds have unique characteristics such as catalytic and redox capacity, structural diversity, the tendency for ligand exchange and a variety of available interactions with biologically useful properties [9]. Derivatives of organotin(IV) compounds have shown great therapeutic potential on diverse tumor cells, although their specific mode of action still remains unclear [10]. They have been reported to show good biological activities as an antimicrobial, schizonticidal, antitumor, antimalarial and as biocides in agriculture [11–14]. Their cations can easily form complexes with ligands possessing S, N, O and P donor atoms with various composition and stability [7]. An example of such ligand is the dithiocarbamate group. Organotin(IV) dithiocabamate complexes have received attention due to their ability to stabilize specific stereochemistry in their complexes, and their diverse application in the field of agriculture, biology, catalysis [15] and their usefulness as single source precursors for tin sulfide nanoparticles are notable reasons for their modern relevance [16]. These complexes possess unique stereo-electronic properties which underline their relevance in the area of medicinal chemistry [17–20]. Organotin(IV) dithiocarbamates, therefore, owe their functionalities and usefulness to the individual attributes of the organotin and the dithiocarbamate moieties present within the molecule. For example, due to the presence of two sulfur atoms in the molecule, dithiocarbamates ligands show strong metal binding capacity, and this has encouraged a growing interest in this field of sulfur donor ligands [21]. This is the reason for their proven capacity to inhibit enzymes and ultimately affect biological environments [22]. This property has encouraged a growing interest in their usage as anticancer, antibacterial, antifungal and several industrial applications such as in rubber vulcanization [23,24]. Thus, the synergy exhibited by the organotin(IV) moiety and dithiocarbamate ligands has resulted in the enhanced biological activity of this hybrid molecule and this has led to the large interests in the chemistry and biological relevance of these complexes. Dithiocarbamate (DTC) ligands are very useful in complex formation [25] due to the possible functionalization of the substituents on the nitrogen atom of the dithiocarbamate backbone, which helps create various analogues of this compound. This has resulted in varieties of structures with refined attributes, which, consequently, enhances physical and chemical properties [26]. In this survey, some of the applications of organotin(IV) dithiocarbamates as biologically useful compounds will be reviewed. This is not intended to be exhaustive, but designed to discuss the chemistry and also highlight recent and exciting advances of this group of organometallic complexes in the area of medicine and biology.

2. Chemistry of Organotin(IV) Dithiocarbamate Dithiocarbamates are the hemi-amides of dithiocabonic acids [27]. They belong to the carbamate family in which the two oxygen atoms have been replaced with sulfur atoms (Figure1). They are Molecules 2018, 23, 2571 3 of 27

Molecules 2018, 23, x FOR PEER REVIEW 3 of 27 Moleculesmono-anionic 2018, 23, chelatingx FOR PEER ligands, REVIEW and are capable of forming stable complexes with a large number3 of 27 of the main group elements, all transition metals and also lanthanides and actinides [28]. This is of the presence of the anionic CS2¯ moiety which has a wide range of binding modes, thus, possessing ofbecause the presence of the presenceof the anionic of the CS anionic2¯ moiety CS which¯ moiety has whicha wide hasrange a wide of binding range modes, of binding thus modes,, possessing thus, good coordination capacity. This interesting2 coordination and stability observed between goodpossessing coordination good coordination capacity. capacity.This interesting This interesting coordination coordination and and stability stability observed observed between between dithiocarbamate ligands and a metal derivative like organotin salts is based on the fact that some dithiocarbamate ligands ligands and and a a metal metal derivative derivative like like organotin organotin salts salts is is based based on on the the fact fact that that some some metals (like tin) act as strong Lewis acids [29,30], thus, they easily complex with the electron rich metals (like tin)tin) actact as as strong strong Lewis Lewis acids acids [29 [29,30],30], thus,, thus, they they easily easily complex complex with with the electron the electron rich sulfur rich sulfur dithiocarbamate ligand based on the Hard Soft [Lewis] Acid Base (HSAB) principle [31]. They sulfurdithiocarbamate dithiocarbamate ligand ligand based based on the on Hard the SoftHard [Lewis] Soft [Lewis] Acid BaseAcid (HSAB) Base (HSAB) principle principle [31]. They [31]. showThey show good solubility in water or organic solvents depending on the nature of the cation. showgood solubilitygood solubility in water in water or organic or organic solvents solvents depending dependin on theg on nature the nature of the of cation. the cation.

(a) (b) (a) (b) R = Aryl, Alkyl, Alkylene and M = K+/Na+ R = Aryl, Alkyl, Alkylene and M = K+/Na+

Figure 1. Structure of carbamate (a) and dithiocarbamate ((b).). Figure 1. Structure of carbamate (a) and dithiocarbamate (b). Various biological biological activities activities can can be prompted be prompted when incorporated when incorporated into other into molecular other structures.molecular Various biological activities can be prompted when incorporated into other molecular Thus,structures. they areThus, good they pharmacophore are good pharmacophore and have been and shown have to been possess shown useful to biological possess useful activities biological such as structures. Thus, they are good pharmacophore and have been shown to possess useful biological theiractivities usage such as antifungalas their usage drugs. as Thiramantifungal (Figure drugs.2a): Thiram for food (Figure dressing 2a): and for control food dressing of turf diseases and control and activities such as their usage as antifungal drugs. Thiram (Figure 2a): for food dressing and control disulﬁramof turf diseases (Figure and2b): disulfiram for the treatment (Figure 2b): of addiction for the treatment to alcoholic of drinksaddiction [ 32 to,33 alcoholic]. However, drinks the original[32,33]. of turf diseases and disulfiram (Figure 2b): for the treatment of addiction to alcoholic drinks [32,33]. andHowever, still the the main original use ofand disulﬁram still the main is as use a catalyst of disulfiram in rubber is as vulcanization a catalyst in [rubber34]. vulcanization [34]. However, the original and still the main use of disulfiram is as a catalyst in rubber vulcanization [34].

(a) (b) (a) (b) Figure 2. Structures of (a) thiram and (b) disulfiram. Figure 2. Structures of (a) thiram and (b) disulfiram. Dithiocarbamate compoundsFigure 2. Structures are capable of (a of) thiram inhibiting and (b the) disulfiram. growth of bacteria by altering the metabolicDithiocarbamate activities which compounds take place are capablein the bacteria. of inhibiting This the ligand growth continues of bacteria to receive by altering increased the Dithiocarbamate compounds are capable of inhibiting the growth of bacteria by altering the attentionmetabolic due activities to the presence which take of the place carbon-sulfur in the bacteria. bond which This isligand useful continues in many products to receive of biologicalincreased metabolic activities which take place in the bacteria. This ligand continues to receive increased andattention medicinal due to relevance the presence [35]. of This the bondcarbon is-sulfur also useful bond in which the formation is useful in of many organic products intermediates of biological with attention due to the presence of the carbon-sulfur bond which is useful in many products of biological interestingand medicinal chemistry relevance [35 ,[35]36].. ReportsThis bond on is their also usage useful in in protein the formation folding, of redox organic signaling intermediates and enzyme with and medicinal relevance [35]. This bond is also useful in the formation of organic intermediates with catalysisinteresting have chemi beenstry attributed [35,36]. Reports to the strong on their nucleophilic usage in protein character folding, and peculiarredox signaling properties andof en sulfurzyme interesting chemistry [35,36]. Reports on their usage in protein folding, redox signaling and enzyme tocatalysis undergo have redox been reaction attributed [33]. to They the strong have found nucleophilic other usage character in agriculture and peculiar as pesticides, properties herbicides, of sulfur catalysis have been attributed to the strong nucleophilic character and peculiar properties of sulfur andto undergo fungicides redox [37 reaction–39]. Some [33] compounds. They have found of these other classes usage have in agriculture been commercialized as pesticides, such herbicides, as zineb, to undergo redox reaction [33]. They have found other usage in agriculture as pesticides, herbicides, maneb,and fungicides nabam, [37 ziram–39] and. Some ferbam compounds [40]. of these classes have been commercialized such as zineb, and fungicides [37–39]. Some compounds of these classes have been commercialized such as zineb, maneb,The nabam, earliest ziram synthetic and ferbam record [40] of dithiocarbamate. synthesis involved the use of thiophosgene, maneb, nabam, ziram and ferbam [40]. chlorothioformateThe earliest synthetic and an isothiocyanate record of dithiocarbamate [40]. This had synthesis many drawbacks involved such the useas long of thiophosgene, reaction time, The earliest synthetic record of dithiocarbamate synthesis involved the use of thiophosgene, usechlorothioformate of expensive and and toxic an isothiocyanate reagents, and harsh [40]. This reaction hadconditions. many drawbacks Several such synthetic as long procedures reaction time, have chlorothioformate and an isothiocyanate [40]. This had many drawbacks such as long reaction time, beenuse of developed expensive involvingand toxic one-potreagents, condensation and harsh reac oftion amines, conditions. carbon disulfideSeveral synthetic and electrophiles procedures such have as use of expensive and toxic reagents, and harsh reaction conditions. Several synthetic procedures have alkylbeen developed halides, epoxides, involving carbonyl one-pot compounds condensation and ofα, βamines,-unsaturated carbon compounds disulfide and [40 electrophiles]. They have beensuch been developed involving one-pot condensation of amines, carbon disulfide and electrophiles such preparedas alkyl halides, from both epoxides, the primary carbonyl and secondarycompounds amine and [ 32α,β,41-unsaturated,42] as shown compounds in Scheme1 .[40] The. They respective have as alkyl halides, epoxides, carbonyl compounds and α,β-unsaturated compounds [40]. They have aminesbeen prepared react with from carbon both the disulfide primary in and the secondary a strong amine base like [32,41,42] potassium/sodium as shown in Scheme hydroxide 1. The or been prepared from both the primary and secondary amine [32,41,42] as shown in Scheme 1. The respective amines react with carbon disulfide in the a strong base like potassium/sodium hydroxide respective amines react with carbon disulfide in the a strong base like potassium/sodium hydroxide or ammonium hydroxide to form the corresponding dithiocarbamate salts of sodium ion (K+/Na+) or or ammonium hydroxide to form the corresponding dithiocarbamate salts of sodium ion (K+/Na+) or ammonium ion (NH4+). In this reaction, the addition of the strong base is to catalyze the reaction, ammonium ion (NH4+). In this reaction, the addition of the strong base is to catalyze the reaction,

Molecules 2018, 23, 2571 4 of 27 Molecules 2018, 23, x FOR PEER REVIEW 4 of 27 hence making an important impact on the dithiocarbamate formation rate [32]. The dithiocarbamates Moleculesammonium 2018, 23 hydroxide, x FOR PEER to REVIEW form the corresponding dithiocarbamate salts of sodium ion (K+/Na4 of 27+) obtained from secondary+ amines are more stable than the products obtained from primary amines or ammonium ion (NH4 ). In this reaction, the addition of the strong base is to catalyze the reaction, hence making an important impact on the dithiocarbamate formation rate+ [32]. The+ dithiocarbamates duehence to making the presence an important of acidic impact hydrogen on the on dithiocarbamate the nitrogen [32] formation. The Na rate or [32 NH]. The4 salts dithiocarbamates of DTCs are obtained from secondary amines are more stable than the products obtained from primary amines reasonablyobtained from stable secondary compared amines to their are more corresponding stable than carbamic the products acids. obtained The sodium from primary salts of amines DTCs dueare + + whitedue to crystalline the presence solids of acidicwhich hydrogenare soluble on in the water. nitrogen These [32] salts+. The are Nausually+ or NH stable4 salts for ofa long DTCs time, are to the presence of acidic hydrogen on the nitrogen [32]. The Na or NH4 salts of DTCs are reasonably neverthelessreasonablystable compared stable whenever to compared their required; corresponding to their the solutionscorresponding carbamic of acids.DTCs carbamic Theare sodiumto be acids. prepared salts The of sodiumfreshly. DTCs are salts white of crystallineDTCs are whitesolids whichcrystalline are soluble solids inwhich water. are These soluble salts in are water. usually These stable salts for are a long usually time, stable nevertheless for a long whenever time, neverthelessrequired; the whenever solutions ofrequired; DTCs are the to solutions be prepared of DTCs freshly. are to be prepared freshly.

Scheme 1. Preparation of dithiocarbamate from primary and secondary amine.

Another reportedSSchemecheme 1. method PreparationPreparation for of the dithiocarbamate synthesis of dithiocarbamatefrom primary and s secondary which are amine amine. soluble. in organic solvents involves the reaction of two equivalents of a secondary amine (in the absence of any base) Another reported method for the synthesis of dithiocarbamates which are soluble in organic with Anothercarbon disulfide. reported Onemethod equivalent for the of synthesis amine acts of asdithiocarbamate the base whiles thewhich other are as soluble a nucl einophile organic for solvents involves the reaction of two equivalents of a secondary amine (in the absence of any base) thesolvents reaction involves to give the the reaction ammonium of two salt equivalents of the compound of a secondary [43]. amine (in the absence of any base) with carbon disulﬁde. One equivalent of amine acts as the base while the other as a nucleophile for the with Severalcarbon disulfide. metal dithiocarbamate One equivalent complexes of amine acts have as been the base synthesized while the simply other as by a thenucl reactioneophile for of reaction to give the ammonium salt of the compound [43]. dithiocarbamatethe reaction to give ligand the ammonium with the corresponding salt of the compound metal salts [43] in. an appropriate solvent [43–49]. The Several metal dithiocarbamate complexes have been synthesized simply by the reaction of metalSeveral dithiocarbamate metal dithiocarbamate complexes formed complexes are often have via beensimple synthesized metathesis simplywith corresponding by the reaction metal of dithiocarbamate ligand with the corresponding metal salts in an appropriate solvent [43–49]. The metal saltdithiocarbamate [15,50]. Some ligand metal with complexes the corresponding of dithiocarbamate metal salts are in colored, an appropriate and this solvent has been [43 useful–49]. The in dithiocarbamate complexes formed are often via simple metathesis with corresponding metal facilitatingmetal dithiocarbamate their spectrophotometric complexes formed studies are especially often via in simple visible metathesis or near UV with region. corresponding Most heavy metal salt [15,50]. Some metal complexes of dithiocarbamate are colored, and this has been useful in dithiocarbamatesalt [15,50]. Some compounds metal complexes are sparingly of dithiocarbamate soluble in solvents are colored, that are and organic this has in nature been useful such as in facilitating their spectrophotometric studies especially in visible or near UV region. Most heavy chloroform,facilitating their alcohols, spectrophotometric dimethyl sulfoxide studies and especially dimethyl in formamide visible or near [51,52] UV. region. Most heavy metal metal dithiocarbamate compounds are sparingly soluble in solvents that are organic in nature such as dithiocarbamateWith an appropri compoundsate choice are of sparingly the substituents soluble inon solventsthe secondary that are amine, organic and in a natureright choice such of as chloroform, alcohols, dimethyl sulfoxide and dimethyl formamide [51,52]. cation,chloroform, a uniquealcohols, modificationdimethyl sulfoxide in the and stereodimethyl-electronic formamide properties [51,52]. of the corresponding With an appropriate choice of the substituents on the secondary amine, and a right choice of dithiocarbamateWith an appropri ligandate can choice be obtained of the substituents[17]. Dithiocarbamates on the secondary are lipophilic amine, and and possess a right the choice ability of cation, a unique modiﬁcation in the stereo-electronic properties of the corresponding dithiocarbamate tocation, bind to a metal unique ions as modification monodentate in ( I) the(using stereo one binding-electronic site of properties S), as bidentate of the (II ) corresponding(using the two ligand can be obtained [17]. Dithiocarbamates are lipophilic and possess the ability to bind to metal Sdithiocarbamate atoms in binding ligand to the can central be obtained metal atom[17]. Dithiocarbamatesor ion) or bidentate are bridging lipophilic ligands and possess (III) (in the which ability it ions as monodentate (I) (using one binding site of S), as bidentate (II) (using the two S atoms in binding bindsto bind to to the metal metal ions ion as withmonodentate one sulfur (I) and(using forms one bindinga bridge site with of adjacentS), as bidentate molecule (II ) with(using the the other two to the central metal atom or ion) or bidentate bridging ligands (III) (in which it binds to the metal ion sulfur)S atoms [53] in .binding This is becauseto the central DTC canmetal exist atom in 3 or different ion) or resonantbidentate forms bridging [54] ligandsas shown (III in) (inFigure which 3. In it with one sulfur and forms a bridge with adjacent molecule with the other sulfur) [53]. This is because thebinds resonance to the metal form ionof the with dithiocarbamate, one sulfur and there forms is aa singlebridge bond with b adjacentetween the molecule nitrogen with atom the and other the DTC can exist in 3 different resonant forms [54] as shown in Figure3. In the resonance form of the Csulfur) bearing [53] the. This two is S becauseatoms as DTC presented can exist in ( Iin) and 3 different (III), and resonant the delocalization forms [54] ofas theshown -1 charge in Figure between 3. In dithiocarbamate, there is a single bond between the nitrogen atom and the C bearing the two S atoms the carbonresonance and form two ofsulfur the dithiocarbamate, atoms. The lone therepair on is athe single nitrogen bond atom between (N) inthe the nitrogen ‘thioureide’ atom andform the is as presented in (I) and (III), and the delocalization of the -1 charge between the carbon and two sulfur delocalizedC bearing the as two sho Swn atoms in the as form presented (II), resulting in (I) and in (III π ),(double and the bond) delocalization character of between the -1 charge the N between and the atoms. The lone pair on the nitrogen atom (N) in the ‘thioureide’ form is delocalized as shown in the Cthe bearing carbon the and two two S sulfurgroups atoms. with negativeThe lone charges. pair on theThe nitrogen nitrogen atom is sp 2(N) hybridized in the ‘thioureide’ in this resonance form is form (II), resulting in π (double bond) character between the N and the C bearing the two S groups form.delocalized The resonance as shown form in the (II form) is described (II), resulting as a hard in π ligand (double because bond) itcharacter can stabilize between hard the metal N andcenters the with negative charges. The nitrogen is sp2 hybridized in this resonance form. The resonance form (II) atC bearinghigher oxidation the two S states groups while with both negative forms charges. (I) and The(III) nitrogencan stabilize is sp soft2 hybridized metals at in lower this resonanceoxidation is described as a hard ligand because it can stabilize hard metal centers at higher oxidation states while statesform. The[43] .resonance form (II) is described as a hard ligand because it can stabilize hard metal centers both forms (I) and (III) can stabilize soft metals at lower oxidation states [43]. at higher oxidation states while both forms (I) and (III) can stabilize soft metals at lower oxidation states [43].

(I) (II) (III)

Figure 3. Resonance structure of dithiocarbamate. (I) Figure 3. Resonance structure(II) of dithiocarbamate. (III)

Figure 3. Resonance structure of dithiocarbamate.

Molecules 2018, 23, 2571 5 of 27

The exceptional stability of dithiocarbamate is often explained by the outstanding contribution of resonance form (II) to the overall electronic structure, which ensures that this anion is an effective ligand for metal complexation. They exhibit various modes of coordination in homo and heteronuclear complexes, depending on the mode of attachment between the ligands and the metal ion [37]. The ease of replacement of hydrogen from -SH group in dithiocarbamate and their complexes in inorganic analysis is the main reason for their numerous applications. This usually occurs when a coordinate bond is formed through S, forming strongly colored complexes with a number of metals. This outstanding metal binding capacity of the dithiocarbamates was noted by Delepine [55]. The interesting chemistry of organotin(IV) dithiocarbamates results from the individual properties of both the organotin and dithiocarbamate moieties. As such, the chemistry and the application of these sets of complexes is believed to be the consequence of the synergistic activity of both the organotin and dithiocarbamate compound. Generally, different methods have been used to prepare organotin(IV) complexes of dithiocarbamate, and there is no specific method of synthesis. However, organotin(IV) dithiocarbamate complexes have been mostly reported to be prepared in situ. The in situ method involves a one pot system in which the organotin(IV) compound is introduced into the flask containing freshly prepared dithiocarbamate, and allowed to react for a few hours [40]. Some organotin(IV) dithiocarbamate complexes prepared via this method have been reported. Bashira et al., synthesized organotin(IV) dithiocarbamate complexes using “in situ” insertion method, involving the reactions of bis-2-methoxyethyl dithiocarbamate with some organotin compounds of the type RxSnClx (where R = Bu, Me, Ph and x = 1, 2 or 3) [56]. Organotin compounds with the molecular formula RmSn[S2CN(CH3)(C6H11)]4-m (where m = 2, R = CH3,C2H5; m = 3, R = C6H5) were reported by Awang et al., [24]. They also prepared organotin(IV) dithiocarbamate complexes derived from methoxyethyldithiocarbamate, with corresponding di- and tri-organotin chloride bearing alkyl group (R3SnL and R2SnL2;L = R = C6H5 or C4H9)[57]. Kamaludin et al., reported some organotin(IV) N-butyl-N-phenyldithiocarbamate compounds using the dithiocarbamate derivatives obtained from N-butylamine and the corresponding organotin chloride in different ratios [58]. The number of anions (e.g., Cl−) present in the organotin(IV) salt often determines the mole ratio of the dithiocabamate ligand to the organotin(IV) salts, because the chloride ion are labile and are easily replaced by the dithiocarbamate ligand. Thus, the molar ratio of the dithiocarbamate ligand to the organotin salt (for a substituted derivative) is 2:1 for di-substituted organotin(IV) salt and 3:1 for a tri-substituted derivatives. Various spectroscopic techniques have been used to characterize organotin compounds and they give insight on the geometry of the compound. In the infrared spectroscopy, specific bands, aid in identifying the dithiocarbamate. Characteristic bands such as the thioureide band υ(C=N), the υ(C-S) and υ(M-S) band are peculiar. The thiouride band is often found in the 1450–1550 cm−1 band region of the spectrum, which is associated with the vibration of C-N bond that displays a partial double bond and a polar character. The υ(C-S) stretching vibrational band often appears in the 950–1000 cm−1 region, while the υ(M-S) stretching vibration band is found in the 350–450 cm−1 [59]. The movement of the C-N vibrational band after complexation with a metal to a higher frequency of about 15 cm−1 often indicates the delocalization of the electron cloud of the –NCSS group towards the metal center [60]. Thus, giving the C-N bond a partial double bond character [61]. The υ(M-S) band usually appears in the far infrared region, and indicates that complexation occurred [62]. In dithiocarbamate ligands, there are often two types of υ(C-S) band, the υ(CS2)asym and υ(CS2)sym; and they appear around 1055 cm−1 and 961 cm−1 respectively [63]. When these are replaced by strong singlet at approximately 1000 cm−1 in complexes, it indicates a symmetrical coordination of the dithiocarbamate moiety to the metal ions. However, the splitting of the same band within a difference of 20 cm−1 in the same region is ascribed to the monodentate binding mode of dithiocarbamate ligand [64]. The electronic spectra of organotin(IV) dithiocarbamate complexes are generally characterized by three principal bands which are attributed to (C=N) bond, the electron pair of sulfur and the metal-ligand (M-L) bond in the UV-visible absorption spectra [65]. From the dithiocarbamate moiety, Molecules 2018, 23, 2571 6 of 27 the absorption band of (C=N) chromophore due to the intramolecular π-π* transition is found around 300 nm [56]. However, the movements of this peak to a lower/shorter wave length often reveals the involvement of the band in complex formation. This, therefore, shows the contribution of the NCS2 group in the complexation of the dithiocarbamate ligand to the organotin(IV) moiety [65]. The existence of a nonbonding electron pair of the S atom in the range 240–261 nm has been attributed to n-π* transition [65]. Furthermore, the presence of a broad shoulder band in the complexes, which is usually found above 300 nm, is attributed to charge transfer transition from the metal to the ligand (M-L). The absorption indicates an extended conjugation system due to the electronic transition between p-orbital of sulfur and 5d-orbital of tin metal [56,65,66]. In the characterization of organotin(IV) complexes, one of the widely and often used techniques useful for the prediction of geometry in organotin(IV) complexes is NMR spectroscopy. Parameters such as the coupling constant (J)[nJ(119Sn,1H), nJ(119Sn,13C)], and the chemical shifts (δ) of 119Sn-NMR are obtained from this technique and these give useful information in solution state about the geometry of the tin center in the organotin(IV) complexes [67]. Studies have shown that the coordination of tri and dimethyl derivatives of tin(IV) compounds having nJ (n = 1, 2) values are: tetra-coordinated in tin(IV) compounds, if the coupling constant (1J) are predicted to be less than 400Hz then 2J values should be less than 59 Hz; penta-coordinated, if the coupling constant (1J) is between 450 and 670 Hz and 2J values is between 65 and 80 Hz; and hexa-coordinated, if the coupling constant (1J) is greater than 670 Hz and 2J values is greater than 83 Hz [67,68]. These observed J values could be utilized in the calculation of the bond angle (θ) of C–Sn–C in solution using Lockhart’s equation, and the equation for the phenyl and the butyltin(IV) compounds were proposed by Howard et al. [69]:

θ = 0.0105 |2J(119Sn–1H)|2 − 0.799 |2J(119Sn–1H)| + 122.4 (1)

|1J(119Sn–13C)| = 11.4 θ − 875 (2)

(for methyl and ethyl derivatives).

|1J(119Sn–13C)| = (9.99 ± 0.73)θ − (746 ± 100) (3)

(for butyl derivatives).

|1J(119Sn–13C)| = (15.56 ± 0.84)θ − (1160 ± 101) (4)

(for phenyl derivatives).

These bond angles (θ) are attributed to tetracoordinated geometry, if θ ≤ 112◦; penta-coordinated, if θ = 115–130◦; and hexa-coordinated, if θ = 129–76◦ [67]. The tin chemical shift (119Sn) values often indicate the coordination number around the tin center and, thus, provide valuable information about the geometry of organotin(IV) complexes [67]. The shifts are, however, found to be dependent on the nature of the group attached to Sn. Caution is important in this analysis because tin resonance is strongly dependent on factors such as temperature, concentration used and electronegativity of the ligands [67,70,71]. With an electron donating group, Sn atom becomes more shielded, thereby leading to an increase in the chemical shift value [67]. The spectra of 119Sn-NMR of an organotin(IV) complex usually show a singlet which is significantly lower in frequency than corresponding organotin(IV) salts [71]. The lower chemical shifts observed in the spectra of organotin(IV) complexes are due to the change in the coordination number and bond angle around the tin center, caused by possible presence of electronegative substituents and dπ–pπ bonding effect. Hence, lower frequency upon coordination is an indication of increased coordination number [72]. The 119Sn-NMR shifts for organotin(IV) complexes are either tetra-(δ = 200 to −60 ppm), penta-( δ = −90 to −190 ppm) or hexa (δ = −210 to −400 ppm)-coordinated [73]. Chemical shifts (δ) in the range of −600 to −700nm suggest either 6- or 7-coordination geometry around the tin center. This has been attributed to a possible chemical Molecules 2018, 23, 2571 7 of 27 equilibrium between octahedral and pentagonal-bypiramidal arrangement due to intramolecular metal ligand bond [74]. X-ray single crystal technique, on the other hand, exploits the fact that X-rays (in the Ångström range, ~10−8 cm) are scattered (diffracted) by electron cloud of an atom with similar sizes to determine the three dimensional structures of molecules [75]. Accurate knowledge of molecular structures are known to aid the development of effective drugs [76] and therapeutic complexes. This is achieved by the growth of crystal, which when diffracted gives useful information such as bond distances, bond angles, and can clearly show the geometry of molecules. This analytical technique gives clearer information compared to spectroscopic techniques which are often limited. However, X-ray single crystal diffraction analysis is limited since the molecule is in the solid state and not much information is obtained about the behavior of the molecule in solution [77]. Generally, the structural geometries of tin(IV) complexes are tetrahedral, trigonal pyramidal, or octahedral. For organotin(IV) compounds, the tri-substituted (R3SnX) and the di-substituted (R2SnX2) derivatives often possess five and six coordinate geometries respectively [2,78]. Thus, the high coordination number often observed in organotin(IV) complexes of the formula RnSnX4–n (n = 1–3, X = halide, carboxylate, dithiocarbamate etc.) with Lewis bases is due to the increase in the Lewis acid strength of the tin metal [3]. These geometries are often influenced by the mole ratio of the ligand to organotin(IV) salt used. These coordination geometries have been found to depend on the mode of bonding in the dithiocarbamate moiety, which is mostly monodentate or bidentate fashion [79]. Four coordinate geometries are mostly common for the tri-substituted organotin(IV) complexes. These complexes are not completely tetrahedral but are distorted due to the distance of the second non-coordinated sulfur atom which often hangs as a “pendant” as shown in Figure4. The structures of triphenyltin(IV) complexes of p-bromo-N-methylbenzylamine dithiocarbamate and p-fluoro-N-methylbenzylaminedithiocarbamate have been reported [80]. Both complexes contain discrete molecular units with the central tin atom bonded to the triphenyltin moeties in a monodentate fashion, forming a supposed tetra-coordinated geometry as presented in Figure4a,b. The bond lengths and angles observed for Sn-S bonds show that in both complexes, the modentate bond was through one of the sulfur atoms with the distance of 2.464(10) Å and 2.4671(4) Å. The bond lengths of the non-coordinating sulfur atoms with the tin metal was found below the van der Waal radii of 4.0 Å, but too weak because of the wide distances between Sn1-S2 bonds (3.022(7) Å and 3.066(8) Å). The bond angles S1-Sn1-C7 and C1-Sn1-C13 in triphenyltin(IV) p-bromo-N-methylbenzylaminedithiocarbamate are 90.54(9)◦ and 114.62(13)◦; and in triphenyltin(IV)N-methylbenzylaminedithiocarbamate, the S1-Sn1-C13 and C1-Sn1-C7 are 92.82(2)◦ and 119.75(14)◦ respectively, which showed a deviation from the expected 109.5◦. The wider angles show deviation from the expected tetrahedral angle, and have been attributed to the influence of the proximity of the non-coordinated sulfur atoms in the complexes [80]. Yandav et al., reported a monodentate coordination for the organotin(IV) complex obtained from 4-hydroxypiperidine dithiocarbamate. The ligand imposes a distorted tetrahedral geometry around the tin center as shown in Figure5[ 81]. The covalent Sn–S bond distances are unequal with Sn1–S1 and Sn1–S2, having distances of 2.4757(7) Å and 3.0336(7) Å respectively. The longer distance (3.0336(7) Å) is significantly high, but less than the sum of the van der Waal radii of two atoms, which suggested a weak interaction for the Sn1–S2 bond. Thus, the geometry of the coordination around the tin atom suggests a deviation away from the regular tetrahedron to a trigonal bipyramidal structure due to the weak bond interaction of Sn1–S2. This complex has subtending angles for the atoms in the axial and equatorial positions smaller than the ideal tetrahedral, which supports the deviation towards trigonal bipyramidal (for equatorial substituents C19–Sn1–C13 = 118.12(10)◦; S1–Sn1–C19 = 112.75(7)◦; S1–Sn1–C13 = 116.54(7)◦). Molecules 2018, 23, x FOR PEER REVIEW 7 of 27

X-ray single crystal technique, on the other hand, exploits the fact that X-rays (in the Ångström range, ~10−8 cm) are scattered (diffracted) by electron cloud of an atom with similar sizes to determine the three dimensional structures of molecules [75]. Accurate knowledge of molecular structures are known to aid the development of effective drugs [76] and therapeutic complexes. This is achieved by the growth of crystal, which when diffracted gives useful information such as bond distances, bond angles, and can clearly show the geometry of molecules. This analytical technique gives clearer information compared to spectroscopic techniques which are often limited. However, X-ray single crystal diffraction analysis is limited since the molecule is in the solid state and not much information is obtained about the behavior of the molecule in solution [77]. Generally, the structural geometries of tin(IV) complexes are tetrahedral, trigonal pyramidal, or octahedral. For organotin(IV) compounds, the tri-substituted (R3SnX) and the di-substituted (R2SnX2) derivatives often possess five and six coordinate geometries respectively [2,78]. Thus, the high coordination number often observed in organotin(IV) complexes of the formula RnSnX4–n (n = 1–3, X = halide, carboxylate, dithiocarbamate etc.) with Lewis bases is due to the increase in the Lewis acid strength of the tin metal [3]. These geometries are often influenced by the mole ratio of the ligand to Moleculesorganotin(IV)2018, 23, 2571 salt used. These coordination geometries have been found to depend on the mod8e ofof 27 bonding in the dithiocarbamate moiety, which is mostly monodentate or bidentate fashion [79].

Molecules 2018, 23, x FOR PEER REVIEW 8 of 27

Four coordinate geometries are mostly common for the tri-substituted organotin(IV) complexes. These complexes are not completely tetrahedral but are distorted due to the distance of the second non-coordinated sulfur atom which often hangs as a “pendant” as shown in Figure 4. The structures of triphenyltin(IV) complexes of p-bromo-N-methylbenzylamine dithiocarbamate and p-fluoro-N- methylbenzylaminedithiocarbamate have been reported [80]. Both complexes contain discrete molecular units with the central tin atom bonded to the triphenyltin moeties in a monodentate fashion, forming a supposed tetra-coordinated geometry as presented in Figures 4a and 4b. The bond (a) lengths and angles observed for Sn-S bonds show that in both complexes, the modentate bond was through one of the sulfur atoms with the distance of 2.464(10) Å and 2.4671(4) Å. The bond lengths of the non-coordinating sulfur atoms with the tin metal was found below the van der Waal radii of 4.0 Å, but too weak because of the wide distances between Sn1-S2 bonds (3.022(7)Å and 3.066(8)Å). The bond angles S1-Sn1-C7 and C1-Sn1-C13 in triphenyltin(IV) p-bromo-N- methylbenzylaminedithiocarbamate are 90.54(9)° and 114.62(13)°; and in triphenyltin(IV)N- methylbenzylaminedithiocarbamate, the S1-Sn1-C13 and C1-Sn1-C7 are 92.82(2)° and 119.75(14)° respectively, which showed a deviation from the expected 109.5˚. The wider angles show deviation from the expected tetrahedral angle, and have been attributed to the influence of the proximity of the non-coordinated sulfur atoms in the complexes [80]. Yandav et al., reported a monodentate coordination for the organotin(IV) complex obtained from 4-hydroxypiperidine dithiocarbamate. The ligand imposes a distorted tetrahedral geometry around the tin center as shown in Figure 5 [81]. The covalent Sn–S bond distances are unequal with Sn1–S1 and Sn1–S2, having distances of 2.4757(7) Å and 3.0336(7) Å respectively. The longer distance (3.0336(7) Å) is significantly high, but less than the sum of the van der Waal radii of two atoms, which suggested a weak interaction for the Sn1–S2 bond. Thus, the geometry of the coordination around the tin atom suggests a deviation away from the regular(b) tetrahedron to a trigonal bipyramidal structure due to the weak bond interaction of Sn1–S2. This complex has subtending angles for the Figure 4. Molecular structures of (a) triphenyltin(IV) p-bromo-N-methylbenzylamine dithiocarbamate atoms in the axial and equatorial positions smaller than the ideal tetrahedral, which supports the andFigure (b) triphenyltin(IV) 4. MolecularN -methylbenzylaminedithiocarbamate structures of (a) triphenyltin(IV) with p ellipsoidal-bromo-N- displacementmethylbenzylamine at 50% deviation towards trigonal bipyramidal (for equatorial substituents C19–Sn1–C13 = 118.12(10)°; S1– probabilitydithiocarbamate level (For and clarity, (b) H triphenyltin(IV) atoms were omitted). N-methylbenzylaminedithiocarbamate Redrawn from [80], with permission with from ellipsoidal Elsevier Sn1–C19 = 112.75(7)°; S1–Sn1–C13 = 116.54(7)°). (Copyright 2018).

Figure 5. The molecular structure of triphenyltin(IV) 4-hydroxypiperidine dithiocarbamate. (For clarity, Figure 5. The molecular structure of triphenyltin(IV) 4-hydroxypiperidine dithiocarbamate. (For H atoms were omitted). Redrawn from [81], with permission from Elsevier (Copyright 2018). clarity, H atoms were omitted). Redrawn from [81], with permission from Elsevier (Copyright 2018).

Similarly, the structures of triphenyltin(IV) N-cyclohexyl-N-ethyl- and N-cyclohexyl-N- methyldithiocarbamate were reported to have anisobidentate coordination with one Sn-S short distance Sn1–S2 = 2.9426(10) Å and another long Sn1–S2 = 3.0134(8) Å, resulting in a distortion in

Molecules 2018, 23, 2571 9 of 27

MoleculesSimilarly, 2018, 23,the x FOR structures PEER REVIEW of triphenyltin(IV) N-cyclohexyl-N-ethyl- and N-cyclohexyl-9 of 27 N- methyldithiocarbamateMolecules 2018, 23, x FOR PEER were REVIEW reported to have anisobidentate coordination with one Sn-S9 of short 27 geometry. Thus, the geometry in both complexes about the Sn center is between tetrahedral and distance Sn1–S2 = 2.9426(10) Å and another long Sn1–S2 = 3.0134(8) Å, resulting in a distortion trigonal bypiramidal [82]. ingeometry. Thus, Thus, the the geometry geometry in in both both complexes complexes about about the the Sn Sn center center is is between between tetrahedral tetrahedral and and trigonalSome bypiramidal di-organotin(IV) [82]. salts have shown, from the crystallographic data obtained, the ability to trigonal bypiramidal [82]. bind Some in a monodentatedi-organotin(IV) fashion salts withhave dithiocarbamateshown, from the ligandcrystallographic [83,84]. This data is obtained, uncommon the ability for most to Some di-organotin(IV) salts have shown, from the crystallographic data obtained, the ability substitutedbind in a monodentate di-organotin(IV) fashion complexes with dithiocarbamate which are often ligand found [83,84] to bond. This in a is bidentate uncommon fashion. for most An to bind in a monodentate fashion with dithiocarbamate ligand [83,84]. This is uncommon for examplesubstituted is the di- diorganotin(IV)-organotin(IV) complexes complexes which of p- bromoare often-N- methylbenzylaminedithiocarbamatefound to bond in a bidentate fashion. and An p- most substituted di-organotin(IV) complexes which are often found to bond in a bidentate fashion. fluoroexample-N -ismethylbenzylaminedithiocarbamate. the di-organotin(IV) complexes of p -bromo The structural-N-methylbenzylaminedithiocarbamate data showed that the ligands and are p- p N Anbondedfluoro example-N -methylbenzylaminedithiocarbamate. in is the a di-organotin(IV) monodentate fashion. complexes In of Thedimethyltin(IV)-bromo- structural-methylbenzylaminedithiocarbamate data bis ( showed-bromo- N that-methylbenzylamine the ligands are and p-fluoro-ditbondedhiocarbamateN -methylbenzylaminedithiocarbamate. in a ) monodentatecomplex (Figure fashion. 6), the bond In Thedistances dimethyltin(IV) structural of Sn1 data -S1 bis showedand(-bromo Sn1 that-S2-N -were themethylbenzylamine ligands 2.530(2) are Å bonded and in2.515(19)dit a monodentatehiocarbamate Å respectively,) fashion.complex (Figure In and dimethyltin(IV) 6), Sn1 the– S1bond and distances bis(-bromo- Sn1– S3of Sn1N for-methylbenzylamine- S1 dimethyltin(IV)and Sn1-S2 were dithiocarbamate)bis(2.530(2)p-fluoro Å and-N- complexmethylbenzylaminedithiocarbamate2.515(19) (Figure Å 6), respectively, the bond distances and of) Sn1 were Sn1-S1–S1 2.5139(7) and Sn1-S2 Sn1Å and–S3 were 2.5181(7) for 2.530(2) dimethyltin(IV) Å, Årespectivel and 2.515(19) y (Figurebis( Åp- respectively,fluoro 7). The-N- anddithiocarbamatemethylbenzylaminedithiocarbamate Sn1–S1 and Sn1–S3 ligands for in dimethyltin(IV) dimethyltin(IV)) were bis(2.5139(7) complexesp-fluoro- Å andhaveN-methylbenzylaminedithiocarbamate) 2.5181(7) similar structuralÅ, respectivel motifsy (Figure and bonds 7). The werein 2.5139(7)similardithiocarbamate Å fashion. and 2.5181(7) ligands The distance Å,in respectivelydimethyltin(IV) of the non (Figure- bondedcomplexes7). The sulfur have dithiocarbamate atoms similar (S2 structural and ligands S4) motifs to in the dimethyltin(IV)and Sn bonds atom in complexesdimethyltin(IV)similar fashion. have similar bis The(p -bromo structural distance-N - ofmethylbenzylamine motifs the non and-bonded bonds in di sulfur similarthiocarbamate atoms fashion. (S2) Theare and = distance S4)2.902(7) to ofthe and the Sn 3.104(9) non-bonded atom inÅ sulfuranddimethyltin(IV) in atoms dimethyltin(IV) (S2 bis and(p- S4)bromo bis( top-fluoro- theN-methylbenzylamine Sn-N- atommethylbenzylamine in dimethyltin(IV) dithiocarbamate dithiocarbamate) bis(p) -bromo-are = are2.902(7)N 2.997(7)-methylbenzylamine and and 3.104(9) 3.023(8) Å dithiocarbamate)Åand respectively. in dimethyltin(IV) They are are bis( = relativelyp 2.902(7)-fluoro-N longer and-methylbenzylamine 3.104(9) than the coordinatedÅ anddithiocarbamate) in Sn dimethyltin(IV)–S distances, are 2.997(7) but bis( significantlyandp -fluoro-3.023(8) N- methylbenzylamineshorterÅ respectively. than the Theysum dithiocarbamate) of are the relatively van der Waal longer are 2.997(7)force. than This the and coordinatedweak 3.023(8) interaction Å Sn respectively.–S which distances, exists They but between significantly are relatively the S2 and S4 atoms with the tin metal forces the opening of the angle between the C-Sn-C, and the closing longershorter than than the t coordinatedhe sum of the Sn–S van distances,der Waal force. but significantly This weak interaction shorter than which the sumexists of between the van derthe WaalS2 up of the angle between the S-Sn-S to a small value, which is less than the expected tetrahedral value force.and ThisS4 atoms weak with interaction the tin metal which forces exists the between opening theof the S2 angle and S4 between atoms the with C- theSn-C, tin and metal the forcesclosing the of 109°. Hence, resulted into a distortion away from the expected tetrahedral geometry around the openingup of the of theangle angle between between the S the-Sn C-Sn-C,-S to a small and thevalue, closing which up is ofless the than angle the between expected the tetrahedral S-Sn-S to value a small Sn center [83]. value,of 109°. which Hence, is less resulted than the into expected a distortion tetrahedral away from value the of expected 109◦. Hence, tetrahedral resulted geometry into a distortion around the away Sn center [83]. from the expected tetrahedral geometry around the Sn center [83].

Figure 6. The molecular structure of dimethyltin(IV) bis(p-bromo-N-methylbenzylamine FiguredithiocarbamateFigure 6. 6. TheThe) . (Formolecular molecular clarity, structure Hstructure atoms were of dimethyltin(IV) omitted).dimethyltin(IV) Redrawn bisbis( from(pp--bromo-bromo [83], -withNN-methylbenzylamine-methylbenzylamine permission from dithiocarbamate).Elsevierdithiocarbamate (Copyright).(For (For 2018). clarity, clarity, H H atoms atoms were were omitted). omitted). Redrawn Redrawn from from [83] [83, ],with with permission permission from from ElsevierElsevier (Copyright (Copyright 2018). 2018).

Figure 7. The molecular structure of dimethyltin(IV) bis(p-ﬂuoro-N-methylbenzylamine dithiocarbamate).Figure 7. The (For molecular clarity, H structure atoms were of omitted)dimethyltin(IV) [83]. Redrawn bis(p-fluoro from-N- [methylbenzylamine83], with permission fromdithiocarbamate).Figure Elsevier 7. (CopyrightThe (For molecular clarity, 2018). H structure atoms were of omitted) dimethyltin(IV) [83]. Redrawn bis( fromp-fluoro [83]-,N with-methylbenzylamine permission from Elsevierdithiocarbamate). (Copyright (For 2018). clarity, H atoms were omitted) [83]. Redrawn from [83], with permission from AElsevier distorted (Copyright tetrahedral 2018). geometry has also been reported for the organotin(IV) complex obtained from ammoniumA distorted pyrrolidinedithiocarbamatetetrahedral geometry has also ([Sn{Sbeen reported2CN(CH for2) 4the}2n-Bu organotin(IV)2]) [84]. The complex dithiocarbamate obtained ligandfrom Awas ammonium distorted bonded tetrahedral topyrrolidinedithiocarbamate the adjacent geometry side has of also the organotin(IV)been ([Sn{S reported2CN(CH for moiety2)4} the2n-Bu organotin(IV) via2]) [84] a single. The sulfurcomplex dithiocarbamate atom obtained at both endligandfrom as shown ammonium was bonded in Figure pyrrolidinedithiocarbamate to 8the. The adjacent bond side distances of the obtainedorganotin(IV) ([Sn{S2CN(CH for the moiety2) Sn-S4}2n-Bu via bond2] )a [84]single are. Sn–S The sulfur dithiocarbamate (1) atom = 2.534 at both Å and Sn–Sendligand (3) as =shownwas 2.532 bonded in Å. Figure to the 8. Theadjacent bond side distances of the obtainedorganotin(IV) for the moiety Sn-S bondvia a singleare Sn –sulfurS (1) = atom 2.534 at Å both and Snend–S as (3) shown = 2.532 in Å. Figure 8. The bond distances obtained for the Sn-S bond are Sn–S (1) = 2.534 Å and Sn–S (3) = 2.532 Å.

MoleculesMolecules2018 2018, ,23 23,, 2571 x FOR PEER REVIEW 10 of10 27 of 27 Molecules 2018, 23, x FOR PEER REVIEW 10 of 27

Figure 8. The molecular structure of dibutyltin(IV) pyrrolidinedithiocarbamate complex

FigureFigure[Sn{S2CN(CH 8. 8. The2The)4} 2n molecular-Bu molecular2] and the structure atom structure numbering of of dibutyltin(IV) dibutyltin(IV) (For clarity, H pyrrolidinedithiocarbamate atoms pyrrolidinedithiocarbamate were omitted). Redrawn complex complexfrom [Sn{S[Sn{S[84],2 with2CN(CHCN(CH permission22))44}2}n2-n-BuBu 2from] 2and] and Elsevier the theatom atom(Copyright numbering numbering 2018). (For clarity, (For clarity, H atoms H were atoms omitted). were omitted). Redrawn Redrawnfrom from[84], [with84], withpermission permission from Elsevier from Elsevier (Copyright (Copyright 2018). 2018). When a dithiocarbamate ligand bonds with its two sulfur atoms in a bidentate fashion, it often resultsWhenWhen in aa an dithiocarbamatedithiocarbamate octahedral geometry ligand ligand bonds bonds around with with theits its two tin two sulfur atom sulfur atoms[85] atoms. in This ina bidentate a class bidentate of fashion, organotin(IV) fashion, it often it often resultsresultsdithiocarbamate in in an octahedralan octahedral complexes geometry geometry is represented around around the tin in the atom Figure tin [85 9a atom].– Thisc. Phenylpiperazine[85] class. of This organotin(IV) class -1 of-dithiocarbamate organotin(IV) dithiocarbamate 1 complexesdithiocarbamate[(nBu)2Sn(L is1) represented2] and complexes N-benzyl in - FigureN is -methyl represented9a–c.-4-pyridyldithiocarbamate Phenylpiperazine-1-dithiocarbamate in Figure 9a–c. Phenylpiperazine [(nBu)2Sn(L2)2], -as1 [(nBu)- dithiocarbamateshown2Sn(L in Figure)2] and 1 2 2 N[(nBu)9a-benzyl-,b, show2Sn(LN -methyl-4-pyridyldithiocarbamate that)2] and the N metal-benzyl occupies-N-methyl a - twofold4-pyridyldithiocarbamate axis [(nBu) such2Sn(L that ) half2], [(nBu) as of shown the2Sn(L molecule in)2], Figure as shown is 9 founda,b, in show Figure in the that the9aasymmetric,b, metal show occupies that unit. the The a metal twofold molecular occupies axis structure such a twofold that and half axis structural of such the that molecule data half obtainedof is the found molecule for in the is asymmetricdibutyltin(IV) found in the unit. Theasymmetriccomplexes molecular of unit. 4 structure- In Thethe dibuty molecular andltin(IV) structural structure complexes, data and obtained the structural two fordithiocarbamate the data dibutyltin(IV) obtained ligands for complexes thebonds dibutyltin(IV) through of 4- the In the dibutyltin(IV)complexestwo available of 4sulfur complexes,- In the (S11 dibuty and theltin(IV) S13) two in dithiocarbamate complexes,an unequal thedistance two ligands dithiocarbamate (2.533(1) bonds–2.554(1) through ligands Å) theto thebonds two tin available throughatom and the sulfurat (S11twoa somewhat andavailable S13) longer insulfur an unequaldistance (S11 and of distance S13) 2.896(1) in an (2.533(1)–2.554(1)– unequal2.971(1) Ådistance respectively. Å)(2.533(1) to the – tin2.554(1) atom Å) and to the at a tin somewhat atom and longer at distancea somewhat of 2.896(1)–2.971(1) longer distance of Å 2.896(1) respectively.–2.971(1) Å respectively.

(a) (a)

(b) (b) Figure 9. Cont.

Molecules 2018, 23, 2571 11 of 27 Molecules 2018, 23, x FOR PEER REVIEW 11 of 27

(c)

Figure 9. Molecular structures of dibutyltin (IV) 4-phenylpiperazine-1-dithiocarbamate (a) Figure 9. 1 Molecular structures of dibutyltin (IV) 4-phenylpiperazine-1-dithiocarbamate2 (a) [(nBu)2Sn(L )2], dibutyltin(IV) N-benzyl-N-methyl-4-pyridyldithiocarbamate (b) [(nBu)2Sn(L )2] and [(nBu)2Sn(L1)2], dibutyltin(IV) N-benzyl-N-methyl-4-pyridyldithiocarbamate (3b) [(nBu)2Sn(L2)2] and diphenyltin(IV) N-benzyl-N-methyl-3-pyridyldithiocarbamate (c) [(Ph)2Sn(L )2], the atom numbering 3 schemediphenyltin(IV) (all hydrogen N-benzyl atoms-N are-methyl omitted-3-pyridyldithiocarbamate for clarity). Redrawn from(c) [(Ph) [262],Sn(L with)2], permission the atom numbering from Elsevier (Copyrightscheme (all 2018). hydrogen atoms are omitted for clarity). Redrawn from [26], with permission from Elsevier (Copyright 2018). The longer distances are well within the sum of the van der Waals radii of tin and sulfur (3.97 Å),The and longer are distances considered are aswell bonds. within The the distancessum of the of van Sn-C der bondsWaals inradii these of tin complexes and sulfur observed (3.97 Å), and are considered as bonds. The distances of Sn-C bonds in these complexes observed in the in the range 2.140(2)–2.145(5) Å are within the range found for di-organotin(IV) dithiocarbamates. range 2.140(2)–2.145(5) Å are within the range found for di-organotin(IV) dithiocarbamates.3 For For diphenyltin(IV) N-benzyl-N-methyl-3-pyridyl dithiocarbamate [(Ph)2Sn(L )2], similar unequal diphenyltin(IV) N-benzyl-N-methyl-3-pyridyl dithiocarbamate [(Ph)2Sn(L3)2], similar unequal distances were observed as for Sn-S bond, 2.593(1) and 2.680(1) Å. The Sn-C41 bond length is 2.139(4) Å. distances were observed as for Sn-S bond, 2.593 (1) and 2.680 (1) Å. The Sn-C41 bond length is 2.139 the geometry around these complexes is best described as distorted octahedral geometry [26]. Similar (4) Å. the geometry around these complexes is best described as distorted octahedral geometry [26]. geometriesSimilar geometries involving involving organotin(IV) organotin(IV) complexes complexes of N-methyl- of N-methylN-phenyldithiocarbamate-N-phenyldithiocarbamate of the of formular the R SnL (R = CH and Bu = C H ) presented in Figures 10 and 11 have been reported by our 2formular2 R2SnL2 3(R = CH3 and Bu4 =9 C4H9) presented in Figures 10 and 11 have been reported by our researchresearch group group [ 86[86]].. The The four four sulfursulfur atomsatoms ofof thethe ligand in in complexes complexes [(CH [(CH3)32)SnL2SnL2] 2and] and (C (C4H49)2SnLH9)2SnL2 2 (L(L = N=N-methyl--methylN-N-phenyldithiocarbamate)-phenyldithiocarbamate) bonded to thethe centralcentral SnSn atomatom inin anan anisobidentate anisobidentate mode mode due ◦ ◦ ◦ todue the to minute the minute opening opening of the of bond the anglebond angle of C-Sn-C of C- towardsSn-C towards 180 ; (142.06180°; (142.06°for [(CH for 3[(CH)2SnL3)2SnL] and2] and (137.7 ◦ for(137.7° [(C4H for9) 2[(CSnL4H29])2 movingSnL2] moving away away from from 109 109°.. The The tin-sulﬁde tin-sulfide bonds bonds inin [(CH [(CH33)2)SnL2SnL2] 2were] were observed observed toto bond bond in in an an unequal unequal distancedistance at bothboth end of of the the complex. complex. The The Sn1 Sn1-S12-S12 [2.9785(6) [2.9785(6) Å] Å]and and Sn1 Sn1-S22-S22 [2.9479(7)[2.9479(7) Å] Å] bonds bonds werewere longerlonger than the the Sn1 Sn1-S11-S11 [2.5199(7) [2.5199(7) Å] Å] and and Sn1 Sn1-S21-S21 [2.5259(5) [2.5259(5) Å]. Å].The The Sn- Sn-SS bondbond distances distances observed observed for for [(C [(C4H4H9)92)2SnLSnL22] similarlysimilarly show unequal distances for Sn1-S11Sn1-S11 [2.5179(8) Å], Sn1-S12Å], Sn1 [3.0275(8)-S12 [3.0275(8) Å], Sn1-S21 Å], Sn1 [2.507(7)-S21 [2.507(7) Å] and Å] Sn1-S22 and Sn1 [3.0465(9)-S22 [3.0465(9) Å]. Thus, Å]. Thus, this consequently this consequently resulted inresulted an asymmetric in an asymmetric molecule molecule [81]. The [81] shorter. The bondshorter distances bond distances have a have stronger a stronger Sn-S bonds Sn-S bonds with anwith acute anglean acute cis toangle each cis other to each at 83.80(2) other at◦ 83.80while(2) the° while weaker the weaker and the and longer the longer Sn-S bond Sn-S hasbond a bondhas a bond angle of angle of◦ 146.16(2)° which is less co-linear with each other for [(CH3)2SnL2] [37]. Similar observation 146.16(2) which is less co-linear with each other for [(CH3)2SnL2][37]. Similar observation was was made in [(C4H9)2SnL2]. In both complexes, the longer bond distances were found well below the made in [(C4H9)2SnL2]. In both complexes, the longer bond distances were found well below expected van der Wall radii (3.97 Å) [81]. Thus, they were reported as Sn‒S bond, although weaker the expected van der Wall radii (3.97 Å) [81]. Thus, they were reported as Sn-S bond, although than a typical Sn-S bonds (2.42 Å). The degree of coordination about the Sn center in this complex weaker than a typical Sn-S bonds (2.42 Å). The degree of coordination about the Sn center in this resulted in a shift from the expected bite angle of the chelating dithiocarbamate ligand and thus gave complex resulted in a shift from the expected bite angle of the chelating dithiocarbamate ligand a different bond length [81]. The six coordination geometry expected were badly distorted around and thus gave a different bond length [81]. The six coordination geometry expected were badly the central metal due to steric and electronic reasons, and the asymmetric nature of the distorteddithiocarbamate around theligands. central Therefore, metal due the to geometry steric and about electronic the tin reasons, center for and both the complexes asymmetric is best nature ofdescribed the dithiocarbamate as a skew trapezoidal ligands. Therefore,-bipyramidal the geometry geometry similar about to the what tin center has been for reported both complexes for di- is bestorganotin(IV) described complexes as a skew [87,88] trapezoidal-bipyramidal. geometry similar to what has been reported for di-organotin(IV) complexes [87,88].

Molecules 2018, 23, x FOR PEER REVIEW 12 of 27 Molecules 2018, 23, 2571 12 of 27 Molecules 2018, 23, x FOR PEER REVIEW 12 of 27

FigureFigureFigure 10. 10.Molecular Molecular10. Molecular structure structure structure of of dimethyltin(IV)of dimethyltin(IV) dimethyltin(IV) complexes complexescomplexes of of of NN -Nmethyl-methyl--methyl-N-N-phenyldithiocarbamateN-phenyldithiocarbamate-phenyldithiocarbamate [(CH3)2SnL2]. (For clarity, H atoms were omitted). Redrawn from [86], with permission from Elsevier [(CH3[)(CH2SnL3)22SnL]. (For2]. (For clarity, clarity, H H atoms atoms were were omitted). omitted). Redrawn from from [86] [86, ],with with permission permission from from Elsevier Elsevier (Copyright(Copyright(Copyright 2018). 2018). 2018).

Figure 11. Molecular structure of dibutyltin(IV) complexes of N-methyl-N-phenyldithiocarbamate [(C4H9)2SnL2]. (For clarity, H atoms were omitted). Redrawn from [86], with permission from Elsevier FigureFigure 11. 11.Molecular Molecular structure structure of of dibutyltin(IV) dibutyltin(IV) complexes complexes of ofN N-methyl--methylN-N-phenyldithiocarbamate-phenyldithiocarbamate [(C H(Copyright) SnL ]. (For2018). clarity, H atoms were omitted). Redrawn from [86], with permission from Elsevier [(C44H99)22SnL2]. (For clarity, H atoms were omitted). Redrawn from [86], with permission from Elsevier (Copyright 2018). (CopyrightContrary 2018). to most known structures of di-organotin(IV) complexes of dithiocarbamate, another Contrarystructural tomotif most exists known in which structures one of the of two di-organotin(IV) dithiocarbamate complexes ligands can of bond dithiocarbamate, to the central metal another atomContrary in a monodentate to most known fashion structures and the other of di in-organotin(IV) a bidentate fashion complexes (with second of dithiocarbamate, sulfur hanging as another a structural motif exists in which one of the two dithiocarbamate ligands can bond to the central metal structuralpendant). motif This exists consequently in which one results of the in five two-coordinate dithiocarbamate geometry ligands around can the bond central to Snthe atom. central An metal atom in a monodentate fashion and the other in a bidentate fashion (with second sulfur hanging atomexample in a monodentate is the dimethyltin(IV) fashion and complex the other of the in N,Na bidentate-dimethyldithiocarbamate fashion (with second ligand sulfur [79], in hanging which as a as a pendant). This consequently results in ﬁve-coordinate geometry around the central Sn atom. pendant).one of Thisthe ligands consequently is bonded results in an anisobidenta in five-coordinatete fashion geometry due to the aroundunequal distances the central of the Sn tin atom. to An An examplesulfur bond is the (Sn dimethyltin(IV)-S1 = 2.795 (1) complex and Sn-S3 of = the 2.489N, N (1)-dimethyldithiocarbamate Å) and a bite angle of 67.56(2)°. ligand [ The79], non in which- example is the dimethyltin(IV) complex of the N,N-dimethyldithiocarbamate ligand [79], in which one ofcoordinating the ligands pendant is bonded sulfur in atom an anisobidentate S4 possesses a distance fashion of due 3.532(1) to the Å. unequalThe geometry distances around of the the tin tin to one of the ligands is bonded in an anisobidentate fashion due to the unequal distances of the tin to sulfurmetal bond o (Sn-S1bserved = has 2.795(1) been anddescribed Sn-S3 as = 2.489(1)a distorted Å) trigonal and a bite bipyramid. angle of 67.56(2)The two◦ bulky. The non-coordinatinggroups of the sulfur bond (Sn-S1 = 2.795 (1) and Sn-S3 = 2.489 (1) Å) and a bite angle of 67.56(2)°. The non- pendanttert- sulfurbutyl ligandatom S4 moiety possesses has been a distance suggested of 3.532(1) to be responsible Å. The geometry for the around five coordinate the tin metal geometry observed coordinating pendant sulfur atom S4 possesses a distance of 3.532(1) Å. The geometry around the tin has beenaround described the Sn center as a distorted[79]. trigonal bipyramid. The two bulky groups of the tert-butyl ligand metal observed has been described as a distorted trigonal bipyramid. The two bulky groups of the moiety hasWe been have suggested reported similar to be responsible geometry involving for the ﬁve dimethyltin(IV) coordinate geometry and dibutyltin(IV) around thecomplexes Sn center of [79]. tert-butylN-ethyl ligand-N-phenyldithiocarbamate moiety has been suggested represented to as be [Me responsible2SnL2] and for [Bu the2SnL five2] respectively coordinate (Me geometry = We have reported similar geometry involving dimethyltin(IV) and dibutyltin(IV) complexes of aroundmethyl, the Sn Bu center = butyl [79] and. L = N-ethyl-N-phenyldithiocarbamate). The structures are presented in N-ethyl-N-phenyldithiocarbamate represented as [Me2SnL2] and [Bu2SnL2] respectively (Me = methyl, FiguresWe have 12 reportedand 13 [89] similar. The bidentate geometry dithiocarbamate involving dimethyltin(IV) ligands in both and complexes dibutyltin(IV) are bonded complexes in an of Bu =anisobidentate butyl and fashion L = Nto-ethyl- the Sn Natom-phenyldithiocarbamate). due to the unequal bond distances The structures of the Sn to are S in presented complex in N-ethyl-N-phenyldithiocarbamate represented as [Me2SnL2] and [Bu2SnL2] respectively (Me = Figures[Me 122SnL and2]: 13 Sn1[-89S11]. [2.5193 The bidentate (5) Å], Sn1 dithiocarbamate-S12 [2.9135 (6) Å]) ligands and a in bite both angle complexes of [65.50 (2)°], are bonded and in in methyl, Bu = butyl and L = N-ethyl-N-phenyldithiocarbamate). The structures are presented in an anisobidentate[Bu2SnL2]: Sn1-S12 fashion [2.5250 to (7)Å], the SnSn1 atom-S11 [2.8619 due to(8)Å] the with unequal a bite angle bond of distances [66.39 (2)°]. of The the adjacent Sn to S in Figures 12 and 13 [89]. The bidentate dithiocarbamate ligands in both complexes are bonded◦ in an complex [Me2SnL2]: Sn1-S11 [2.5193(5) Å], Sn1-S12 [2.9135(6) Å]) and a bite angle of [65.50(2) ], and in anisobidentate fashion to the Sn atom due to the unequal bond distances of the Sn◦ to S in complex [Bu2SnL2]: Sn1-S12 [2.5250(7) Å], Sn1-S11 [2.8619(8) Å] with a bite angle of [66.39(2) ]. The adjacent [Me2SnL2]: Sn1-S11 [2.5193 (5) Å], Sn1-S12 [2.9135 (6) Å]) and a bite angle of [65.50 (2)°], and in dithiocarbamate bonds to the tin atom via a single sulfur atom in a mondentate fashion in both [Bu2SnL2]: Sn1-S12 [2.5250 (7)Å], Sn1-S11 [2.8619 (8)Å] with a bite angle of [66.39 (2)°]. The adjacent complexes with bond distances of 2.5193(5) and 2.5318(8) Å in [Me2SnL2] and [Bu2SnL2] respectively.

Molecules 2018, 23, x FOR PEER REVIEW 13 of 27 Molecules 2018, 23, x FOR PEER REVIEW 13 of 27 dithiocarbamate bonds to the tin atom via a single sulfur atom in a mondentate fashion in both complexesdithiocarbamateMolecules 2018 with, 23, 2571 bond bonds distances to the tinof 2.5193 atom (5) via and a single 2.5318 sulfur (8) Å in atom [Me in2SnL a 2 mondentate] and [Bu2SnL fashion2] respectively. in13 both of 27 Acomplexes non-bonding with distancebond distances of the pendant of 2.5193 sulfur (5) and to 2.5318 the metal (8) Å atom in [Me (S222SnL atom2] and at [Bu3.122 S(6)nL and2] respectively. 3.12 (9) Å) hasA non been-bonding observed distance in each of theof the pendant complexes. sulfur Thisto the was metal ascribed atom (S22to a atomweak atcoordination 3.12 (6) and of3.12 a sulfur(9) Å) A non-bonding distance of the pendant sulfur to the metal atom (S22 atom at 3.12(6) and 3.12(9) Å) has atomhas been due observedto a change in eachin one of ofthe the complexes. short Sn- SThis bonds was in ascribed the dithiocarbamate to a weak coordination moiety, consequently of a sulfur been observed in each of the complexes. This was ascribed to a weak coordination of a sulfur atom leadingatom due to toa positional a change changein one ofwhich the shoris approximatelyt Sn-S bonds orthogonalin the dithiocarbamate to the Sn-S22 moiety, plane [15] consequently. due to a change in one of the short Sn-S bonds in the dithiocarbamate moiety, consequently leading to leadingThe to geometry a positional around change the whichSn center is approximately was best described orthogonal as trigonal to the bipyramidal. Sn-S22 plane This [15] .due to the a positional change which is approximately orthogonal to the Sn-S22 plane [15]. equatorialThe geometry position aroundoccupied the by Sn the center alkyl was groups best ondescribed the organotin(IV) as trigonal moiety bipyramidal. and the This axial due position to the The geometry around the Sn center was best described as trigonal bipyramidal. This due to the occupiedequatorial by position the sulfur occupied atoms by [S12 the -alkylSn1-S21] groups 144.91 on the(2)° organotin(IV) in the dimethyltin(IV), moiety and and the [S11axial- Sn1position-S21] equatorial position occupied by the alkyl groups on the organotin(IV) moiety and the axial position 147.88occupied (3)° by in thethe sulfurdibutyltin(IV) atoms [S12complexes.-Sn1-S21] The 144.91 percentage (2)° in along the dimethyltin(IV), the trigonal bipyramid and [S11 to-Sn1 square-S21] occupied by the sulfur atoms [S12-Sn1-S21] 144.91(2)◦ in the dimethyltin(IV), and [S11-Sn1-S21] pyramid147.88 (3)° berry in the pseudorotation dibutyltin(IV) was complexes. 18.8 and The16.7 percentagefor [Me2SnL along2] and the [Bu trigonal2SnL2] respectively bipyramid. to square 147.88(3)◦ in the dibutyltin(IV) complexes. The percentage along the trigonal bipyramid to square pyramid berry pseudorotation was 18.8 and 16.7 for [Me2SnL2] and [Bu2SnL2] respectively. pyramid berry pseudorotation was 18.8 and 16.7 for [Me2SnL2] and [Bu2SnL2] respectively.

FigureFigure 12. 12.The The molecular molecular structure structure of dimethyltin(IV) of dimethyltin(IV) complexes of complexesN-ethyl-N -phenyl of N- dithiocarbamateethyl-N-phenyl dithiocarbamateFigure 12. The [Me molecular2SnL2]. (For structureclarity, H atoms of dimethyltin(IV) were omitted). Redrawn complexes from of [89] N, with-ethyl permission-N-phenyl [Me2SnL2]. (For clarity, H atoms were omitted). Redrawn from [89], with permission from Elsevier dithiocarbamate [Me2SnL2]. (For clarity, H atoms were omitted). Redrawn from [89], with permission from(Copyright Elsevier 2018). (Copyright 2018). from Elsevier (Copyright 2018).

FigureFigure 13. 13. TheThe molecular molecular structure structure of of dibutyltin(IV) dibutyltin(IV) complexes complexes of N--ethyl-ethyl-N--phenyldithiocarbamatephenyldithiocarbamate [Figure[BuBu22SnLSnL 13.2].2]. The(For (For molecularclarity, clarity, H H structureatoms atoms were were of dibutyltin(IV)omitted). omitted). Redrawn Redrawn complexes from from of[89] [ 89N],,- ethylwith with- Npermission permission-phenyldithiocarbamate from from Elsevier Elsevier (C[(CopyrightBuopyright2SnL2]. (For 2018). 2018). clarity, H atoms were omitted). Redrawn from [89], with permission from Elsevier (Copyright 2018). Thermal Decomposition Studies 2.1. Thermal Decomposition Studies 2.1. ThermalThermogravimetric Decomposition analyses Studies of compounds are usually carried out in order to gain insight into Thermogravimetric analyses of compounds are usually carried out in order to gain insight into the thermal properties and stability of the compounds; and in most dithiocarbamate complexes it helps the thermalThermogravimetric properties and analyses stability of compoundsof the compounds; are usually and carriedin most out dithiocarbamate in order to gain complexes insight into it ascertain the possible use of the complexes as single source precursors for metal sulfides nanoparticles. helpsthe thermal ascertain properties the possible and stability use of theof the complexes compounds; as single and in source most precursorsdithiocarbamate for metal complexes sulfides it In the case of organotin(IV) dithiocarbamate, a possible formation of tin sulfide is envisaged [81]. nanoparticles.helps ascertain In the the possible case of useorganotin(IV) of the complexes dithiocarbamate, as single a source possible precursors formation for of metal tin sulfide sulfides is The thermochemistry of metal dithiocarbamates has shown, from its wide study, that the complexes envisagednanoparticles. [81] . InThe the thermochemistry case of organotin(IV) of metal dithiocarbamate, dithiocarbamates a has possible shown, formation from its wide of tin study, sulfide that is either volatilize to leave a negligible amount of residue or decompose to yield metal sulfide [90]. theenvisaged complexes [81] .either The thermochemistry volatilize to leave of ametal negligible dithiocarbamates amount of residue has shown, or decompose from its wide to yield study, metal that The major techniques employed for the thermal study of a wide variety of metal dithiocarbamate sulfidethe complexes [90]. either volatilize to leave a negligible amount of residue or decompose to yield metal sulfidecomplexes [90].are TGA, STA and DSC [91]. These techniques have made it possible to study the trend within a group of complexes with relevant analytical and structural significance, and also classify them based on their thermal properties. A common intermediate that is associated with the thermal

Molecules 2018, 23, 2571 14 of 27 decomposition of metal dithiocarbamate is metal thiocyanate intermediate [92]. Metal thiocyanate has been reported as an intermediate for a number of transition metal dithiocarbamate complexes which often decomposes to give their corresponding metal sulfides as final residues [93–96]. The decomposition pattern of some organotin(IV) dithiocarbamate complexes can also progress via the tin thiocyanate intermediate to give a tin sulfide residue [86]. Thermal study data relating to the decomposition of tin dithiocarbamates are available [91], but it has been observed (generally) that there is no clear cut trend in the thermal decomposition pattern within this group of organotin(IV) complexes irrespective of structural similarity. Tin dithiocarbamates exhibit complicated thermochemistry and an unpredictable thermal decomposition pattern even for a series of structurally related complexes [91]. Even among structurally related compounds, it is almost impossible to establish a trend because they do not follow similar decomposition pathway [91]. Two types of residues, including tin sulfide or tin oxide, are often obtained from the thermal decomposition of organotin(IV) dithiocarbamate complexes, and they are dependent on the decomposition condition (inert or in air) [97]. Tin sulfides can exist in three possible phases: SnS that 2+ 4+ exhibit layer structures, SnS2 and Sn2S3 which has a mixed valence of Sn /Sn with a ribbon-like structure [16]. Tin sulfide has semiconducting properties; and due to its low toxicity, it is used as a solar energy absorber in holographic recording and for infrared detection [98]. Tin sulfide in its various forms possesses the following band gaps: SnS (1.3 eV), SnS2 (2.18 eV), and Sn2S3 (0.95 eV). The electronic band gap of SnS has attracted much attention because it lies between that of Ga and Si [98]. Tin sulfide nanoparticles of different morphologies such as rods, belts, and spheres have been produced via the thermal decomposition of organotin(IV) dithiocarbamate complexes under specific conditions [99]. Hence, it is imperative to understand the thermal behavior of organotin(IV) dithiocarbamate complexes [91]. New routes for making cheaper and micro scale inorganic material with well-defined sizes and shapes have led to the continuous research in materials science. Dithiocarbamate complexes, on the other hand, have been regarded as a good single source materials for metal sulfides [100]. This is because they possess sulfur as the only heteroatom to the metal center (after their thermal decomposition) while avoiding the formation of undesired impurities like metal oxides to exclusively yield metal sulfide nanoparticles [101]. The product of the thermal decomposition of organotin(IV) dithiocarbamate has various applications. For example, tin oxides are used as light detectors (visible and infrared), solar cells, light emitting diodes and as gas sensors [97]. Tin sulfides have outstanding electronic and optical properties due to their narrow bad gap. They have been used to replace cadmium chalcogenides (due to toxicity) or silicon based sensors in low cost green photovoltaic devices [16]. Thermogravimetric analyses have been carried out (under nitrogen) on some organotin(IV) 4-hydroxypiperidine dithiocarbamate. The decomposition of these complexes proceeded via a single step decomposition regardless of the nature of the alkyl group attached. The final residue obtained for these sets of complexes was found to be SnS [81]. Similarly, the TGA of (diphenyltin(IV) N-benzyl-N-methyl-3-pyridyldithiocarbamate and dibutyltin-4-ethoxycarbonyl piperidine-1- dithiocarbamate) at similar heating rate of 10 ◦C min−1 (to a temperature of 600 ◦C) under nitrogen gave a double decomposition pattern leaving SnS2 and SnS residue respectively [26]. In the report of Menezes et al., [16], the thermal study of two organotin(IV) complexes of ammonium pyrrolidinedithiocarbamate with the formula [Sn{S2CN(CH2)4}2{C6H5}2] and [Sn{S2CN(CH2)4}{C6H5}3 ] were carried out. The decomposition of these complexes were observed to ◦ ◦ proceed in a pseudo-single step which began at 207 and 233 C(±2 C) for [Sn{S2CN(CH2)4}2{C6H5}2] ◦ and [Sn{S2CN(CH2)4}{C6H5}3] respectively, and terminates at about 350 C in both cases as shown in Figure 14. In [Sn{S2CN(CH2)4}{C6H5}3], it was observed that the presence of an extra phenyl group increased temperature of decomposition by approximately 26 ◦C. The final residues of these decompositions were chemically and structurally characterized. The electron probe micro analyzer (EPMA) results, clearly shows the presence of S and Sn as the major elements found in the residues. However, a minute amount of O2 was observed and attributed to the formation of SnO2 as a much lesser Molecules 2018, 23, x FOR PEER REVIEW 15 of 27

(EPMA)Molecules 2018 results,, 23, x clearlyFOR PEER shows REVIEW the presence of S and Sn as the major elements found in the residues.15 of 27 However, a minute amount of O2 was observed and attributed to the formation of SnO2 as a much (EPMA) results, clearly shows the presence of S and Sn as the major elements found in the residues. lesserMolecules product.2018 ,This23, 2571 O2 was suggested to originate from the N2, which was not completely15 free of 27 from However, a minute amount of O2 was observed and attributed to the formation of SnO2 as a much moisture or oxygen. The pattern observed from the diffraction of these residues suggested the lesser product. This O2 was suggested to originate from the N2, which was not completely free from formation of a mixed phase γ-Sn2S3 and SnS for both orthorhombic phases, in view of the diffraction moistureproduct. or This oxygen. O was The suggested pattern to originateobserved from from the the N , which diffraction was not of completely these residues free from suggested moisture the lines. 2 2 formationor oxygen. of a mixed The pattern phase observed γ-Sn2S3 fromand SnS the diffractionfor both orthorhombic of these residues phases, suggested in view the of formation the diffraction of lines.a mixed phase γ-Sn2S3 and SnS for both orthorhombic phases, in view of the diffraction lines.

Figure 14. Thermogravimetric curves of (a) [Sn{S2CN(CH2)4}2{C6H5}2] and (b) [Sn{S 2CN(CH2)4}{C6H5}3] 2 in NFigure [16]. Redrawn 14. Thermogravimetric from [16], with curves permission of (a) [Sn{S2 fromCN(CH Elsevier2)4}2{C6 H(Copyright5}2] and (b) [Sn{S2018).2CN(CH 2)4}{C6H5}3] Figure 14. Thermogravimetric curves of (a) [Sn{S2CN(CH2)4}2{C6H5}2] and (b) [Sn{S2CN(CH2)4}{C6H5}3] in N2 [16]. Redrawn from [16], with permission from Elsevier (Copyright 2018). Ourin N 2 [16] group. Redrawn has also from repor[16], withted permission the thermal from decomposition Elsevier (Copyright study 2018). of some mono and di- organotin(IV)Our group complexes has also of reported some N the-alkyl thermal-N-phenyldithiocarbamate decomposition study of some complexes mono and [86,89] di-organotin(IV). The thermal complexesOur group of some has alsoN-alkyl- reporN-phenyldithiocarbamateted the thermal decomposition complexes [86 study,89]. The of thermal some mono properties and di- properties between 50 to 700 °C of the complexes were studied in an inert environment. Few of the organotin(IV)between 50 complexes to 700 ◦C of of some the complexesN-alkyl-N- werephenyldithiocarbamate studied in an inert complexes environment. [86,89] Few. The of thermal the complexes decomposed via tin thiocyanate intermediate but no noticeable trend was observed in the propertiescomplexes between decomposed 50 to 700 via tin°C thiocyanateof the complexes intermediate were butstudied no noticeable in an inert trend environment. was observed Few in the of the decomposition pattern of these complexes. Although these complexes are structurally related, complexesdecomposition decomposed pattern via of these tin thiocyanate complexes. Althoughintermediate these but complexes no noticeable are structurally trend was related, observed different in the different decomposition patterns/steps and intermediates were observed for each of the complexes decompositiondecomposition pattern patterns/steps of these and complexes. intermediates Although were observed these for complexes each of the are complexes structurally as shown related, as shown in Figures 15 and 16. However, the complexes gave only SnS as the final residue with no differentin Figures decomposition 15 and 16. However, patterns/steps the complexes and intermediates gave only SnS were as the observed ﬁnal residue for each with noof the additional complexes additionalphase/product. phase/product. as shown in Figures 15 and 16. However, the complexes gave only SnS as the final residue with no additional phase/product. 100 40

100 40 80 0 30

80 60 0 30

-2 20

60 40 -2 20

Weight (%) -4 10

Heat Flow (W/g) Heat Flow 40 20 (%/min) Deriv. Weight

Weight (%) -4 10

Heat Flow (W/g) Heat Flow

20 -6 0 (%/min) Deriv. Weight 0

-6 0 0 -20 -10 0 200 400 600 Exo Up Temperature (°C) Universal V4.5A TA Instruments -20 -10 Figure 15. TG/DTG and0 DSC curves of200 diphenyltin(IV)400 N-ethyl-N-phenyl600 dithiocarbamateobtained Figure 15. TG/DTG andExo Up DSC curves of diphenyltin(IV)Temperature (°C) N-ethyl-N-phenylUniversal V4.5A TA Instrumentsdithiocarbamateobtained ◦ in Nin2 (75 N2 (75 mL/min mL/min at heatingat heating rate rate 10 10 °C/min).C/min). copied copied from [[89]89] with with permission permission from from Elsevier Elsevier Figure 15. TG/DTG and DSC curves of diphenyltin(IV) N-ethyl-N-phenyl dithiocarbamateobtained (Copyright(Copyright 2018). 2018). in N2 (75 mL/min at heating rate 10 °C/min). copied from [89] with permission from Elsevier (Copyright 2018).

Molecules 2018, 23, 2571 16 of 27 Molecules 2018, 23, x FOR PEER REVIEW 16 of 27

100 30

80 2.5

60 2.0

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40 Heat Flow (W/g) 1.5

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20 1.0

0 -10 0 100 200 300 400 500 600 Exo Up Temperature (°C) Universal V4.5A TA Instruments Figure 16. TG/DTG and DSC curves of diphenyltin(IV) N-methyl-N-phenyl dithiocarbamate obtained Figure 16. TG/DTG and DSC curves of diphenyltin(IV)◦ N-methyl-N-phenyl dithiocarbamate obtained in N2 (75 mL/min at heating rate 10 C/min. Copied from [86] with permission from Elsevier in N2 (Copyright(75 mL/min 2018). at heating rate 10 °C/min. Copied from [86] with permission from Elsevier (Copyright 2018). 3. Biological Applications of Organotin(IV) Dithiocarbamate

3. Biological3.1. Antimicrobial Applications Properties of Organotin( of Organotin(IV)IV) Dithiocarbamate Dithiocarbamate

3.1. AntimicrobialThe various Properties antimicrobial of Organotin( activitiesIV of) organotin(IV)Dithiocarbamate dithiocarbamate complexes originate from the individual properties associated with organotin(IV) and dithiocarbamates. Generally, the antimicrobial Themechanisms various antimicrobial of action involve activities interference of with organotin(IV) the cell wall synthesisdithiocarbamate (by altering complexes the cell permeability), originate from the individualmetabolic interference properties with associated various cellular with organotin(IV) enzymes, cellular and impairment dithiocarbamates. due to denaturing Generally, of the antimicrobiproteins,al mechanisms and alteration of of action the normal involve cell interference processes due with to thethe hydrogencell wall bondingsynthesis through (by altering the the azomethine group with active cellular constituents [102]. The stereo-electronic properties of sulfur cell permeability), metabolic interference with various cellular enzymes, cellular impairment due to containing ligands have been attributed to their good activity as antimicrobial agents which is enhanced denaturingupon coordination of proteins, to andmetals alteration [17], while of the the antimicrobial normal cellactivities processes of organotin(IV) due to complexesthe hydrogen are often bonding throughgoverned the azomethine by their molecular group with weight active and cellular lipophilicity constituents [39]. Complex [102] formation. The stereo causes-electronic an increased properties of sulfurantimicrobial containing activity ligands [103 have], which, been in attributed turn, alters theto their polar good nature activity of the metal as antimicrobial by the delocalization agent ofs which is enhancedelectron upon and charge coordination sharing with to sulfur metals donor [17] groups., while This the electron antimicrobial delocalization activities enhances of organotin(IV) plasma complexesmembrane are often permeability governed for by the their complexes molecular [14]. Rehmanweight etand al., lipophilicity have suggested [39] the. Complex mechanism formation of causes complexesan increased with antimicrobial organotin(IV) moiety activity within [103] their, which, structure in turn, to proceed alters either the polar by inhibiting nature theof the active metal by site for multiplication or by killing of the microorganism [104]. Gram positive bacteria are known to the delocalization of electron and charge sharing with sulfur donor groups. This electron have a simpler cell wall compared to the more complex wall of the Gram negative bacteria, thus, are delocalizationmore induced enhances by the plasma complexes membrane to give higher permeability activity. The for complexity the complexes observed [14] in the. Rehman Gram negative et al., have suggestedbacteria the hasmech beenanism attributed of complexes to the outer-lipid with organotin(IV) membrane formed moiety from lipopolysaccharide within their structure contributing to proceed either byto the inhibiting antigenic the speciﬁcity active ofsite the for Gram multiplication negative bacteria or by [38 ].killing of the microorganism [104]. Gram positive bacteria are known to have a simpler cell wall compared to the more complex wall of the 3.1.1. Antibacterial Studies Gram negative bacteria, thus, are more induced by the complexes to give higher activity. The complexityOrganotin(IV) observed in dithiocarbamatethe Gram negative complexes, bacteria due has to theirbeen useful attributed biological to the potentials, outer-lipid have beenmembrane formedutilized from as lipopolysaccharide important pharmacophore contributing in the development to the antigenic of metal based specificit drugsy [ of86 ]. the Organotin(IV) Gram negative compounds as well as dithiocarbamate compounds, have been used in their uncombined state to bacteria [38]. develop several antimicrobial agents [32,33,84]. The potential activities of these compounds on individual basis, therefore indicate that both compounds can be combined to give a hybrid molecule 3.1.1. Antibacterialwith enhanced Studies biological properties which could exert some synergistic biological activity [84,105]. Organotin(IV)Some currently dithiocarbamate used antibacterial drugscomple arexes, known due to to contain their metaluseful fragments. biological These potentials, central metal have been ions help in maintaining proper structure and/or enhance their activities as antibiotics. Removal utilized as important pharmacophore in the development of metal based drugs [86]. Organotin(IV) compounds as well as dithiocarbamate compounds, have been used in their uncombined state to develop several antimicrobial agents [32,33,84]. The potential activities of these compounds on individual basis, therefore indicate that both compounds can be combined to give a hybrid molecule with enhanced biological properties which could exert some synergistic biological activity[84,105]. Some currently used antibacterial drugs are known to contain metal fragments. These central metal ions help in maintaining proper structure and/or enhance their activities as antibiotics. Removal of the metal ions from these antibiotics could result into transformation and loss of activity [106]. Among this group of antibiotics with metal centers are bleomycin, streptonigrin, and bacitracin [106]. Drug resistance is a serious global challenge and remains the greatest threat to prevention and

Molecules 2018, 23, 2571 17 of 27 of the metal ions from these antibiotics could result into transformation and loss of activity [106]. Among this group of antibiotics with metal centers are bleomycin, streptonigrin, and bacitracin [106]. Drug resistance is a serious global challenge and remains the greatest threat to prevention and treatment of infectious diseases. According to WHO, antimicrobial resistance is the opposition of a microorganism towards the drug that effectively treats the infection caused by the pathogen. Despite the various research and usage of antibiotics, most of them are often accompanied by the evolution of microbial resistance [107]. Hence, the need for continuous search for alternative drugs that can effectively combat pathogenic organism. Awang et al., synthesized some organotin(IV) dithiocarbamate compounds with the molecular formula RmSn[S2CN(CH3)(C6H11)]4-m bearing different alkyl and phenyl derivatives (where m = 2, R = CH3,C2H5; m = 3, R = C6H5) which were screened against four bacteria: Staphylococcus aureus, Salmonella typhimurium, Pseudomonas aeruginosa and Bacillus subtilis. The studied complexes generally gave moderate to good antibacterial activity. It was noted that the phenyl containing complex showed inhibitory effect on selected bacteria strains. Cytotoxicity assays of the compounds confirm the potential of these complexes for further research [24]. Furthermore, they synthesized some organotin(IV) complexes derived from methyltin(IV), butyltin(IV), phenyltin(IV), methyltin(IV), butyltin(IV), phenyltin(IV) and the ligands methylcyclohexyldithiocarbamate and ethylcyclohexyldithiocarbamate. These complexes were also screened for their antimicrobial properties against the ESKAPE bacteria, i.e., Enterococcus raffinosus, Staphylococcus aureus, Klebsiella sp., Acinetobacter baumanni, Pseudomonas aeruginosa, and Enterobacter aerogenes, using disc diffusion and microdilution methods. It was observed that phenyltin(IV) methylcyclohexyldithiocarbamate derivative showed good activity towards most bacteria tested similar to ampicillin (2.5 mg/mL) in the minimum inhibitory concentration (MIC). Overall, all the complexes showed bacteriostatic effects at the minimum bactericidal concentration (MBC) higher than the MIC values, but phenyltin(IV) complex exhibited the best activity and has potential as an antibacterial agent upon further clinical investigation [108]. Good activities have been reported by Sainorudin et al., [53] for dibutyltin(IV) and triphenyltin(IV) complexes of di-2-ethylhexyldithiocarbamate and N-methylbutyldithiocarbamate ligands. These complexes were screened against some bacterial strains including Escherichia coli, Staphylococcus aureus, Salmonella typhi and Bacillus cereus using penicillin and streptomycin as positive and negative control respectively. These complexes showed good antimicrobial activity and, thus, can be useful as anitibacterial agents [53]. Similarly, Adli et al., screened some organotin(IV) dithiocarbamate complexes of 1-methylpiperazinedithiocarbamate and N-methylcyclohexyl-dithiocarbamate against Staphylococcus aureus, Bacillus cereus, Salmonella typhi and Escherichia coli. The microbial test carried out showed all synthesized complexes possessed great potential as antimicrobial agents [65]. Some aforementioned organotin(IV) complexes of N-methyl-N-phenyldithiocarbamate synthesized by our research group have been screened in vitro against some bacterial organisms (S. Aureus, B. cerues, K. pneumonia, P. aeruginosa and E. coli) for their antimicrobial potentials. It was observed that the phenyl and diphenyltin complexes showed the best antibacterial activity (within the series) with inhibition diameter ranging between 10 to 21 mm. This was attributed to the presence a planar phenyl groups attached to the tin center which increases the lipophilic properties of the complexes through the lipid bilayer of the bacteria organisms. Generally it was observed that the complexes showed good activity against gram negative bacterial activity due to their lack of cell wall. The Gram positive organism on the other hand possess a complex cell wall due to an outer-lipid membrane formed from lipopolysaccharide contributing to the antigenic specificity and, therefore, prevents the permeation of the complexes into these organism. The complexes, when compared to a standard antibacterial drug, showed a moderate activity and thus, could be an alternative antibacterial drug after some clinical trials [86]. Molecules 2018, 23, 2571 18 of 27

3.1.2. Antifungal Studies Although resistance to antibiotics by bacteria has become a widely recognized public health threat, not much is known about the effects of drug-resistance in fungal infections. Just as there has been increase in the discovery and usage of antibacterial drugs with increase in high-risk patients, discoveries of the widespread and increasing rates of serious invasive fungal infections have also been recorded and the available antifungals have become less effective against certain infections due to emergence of drug-resistance [109]. There has been an increase in the number of deaths caused by Aspegillosis (a variety of diseases caused by fungi infection of the genus Aspergillus) which has been attributed to the action of immunosuppressive drugs, diseases, cancer or AIDs. In the treatment of aggressive aspergillosis, liposomal amphotericin B and voriconazole are the first choice drugs which can be dangerous to the kidney and liver. Resistance to antifungal drugs in conventional treatment has been found to be related to target alterations of the drug, ergosterol biosynthesis interference and/or increase in the expression of drug efflux pumps. These reasons have made the need for alternative drugs very important and synthesis of metal-based drugs might provide a novel platform for new alternative antifungal agents, either alone or in combination with already used drugs to 1 1 overcome resistance [110]. Tri-oganotin(IV) complexes [SnPh3{S2CNR(R )}], [SnCy3{S2CNR(R )}], 2 2 2 1 [SnMe3{S2CNR(R )}], [SnPh3{S2CNR(R )}] and [SnCy3{S2CNR(R )}], [R = CH3,R = CH2 CH(OMe)2, and R2 = 2-methyl-1,3-dioxolane] have been isolated, and screened by Ferreira et al., against Aspergillus flavus, Aspergillus niger, Aspergillus parasiticus and Penicillium citrinum. Good antifungal activities were observed which was in correlation with a study on the structural-activity relationship (SAR) 2 carried out. Complex [SnPh3{S2CNR(R )}] showed a noteworthy biocidal activity. Complexes 1 2 [SnPh3{S2CNR(R )}] and [SnPh3{S2CNR(R )}] exhibited a nanomolar inhibition concentration in terms of IC50 [111]. Some tin(IV) complexes of pyrrolidinedithiocarbamate, [Sn{S2CN(CH2)4}2Cl2], [Sn{S2CN(CH2)4}2Ph2], [Sn{S2CN(CH2)4}Ph3], [Sn{S2CN(CH2)4}2n-Bu2], [Sn{S2CN(CH2)4}Cy3] have been screened for antifungal activities using agar disk diffusion against human pathogenic fungi (Candida albican). The complexes were active with inhibition zones ≥ 11 mm, intermediate inhibition zones within the range 11–9 mm and resistant ≤ 9 mm. The inhibition zone for the commercial nystatin was 14 mm and was used to compare the activities of the complexes. The C. albicans exhibited resistance against pyrrolidinedithiocarbamate ligand but showed moderate activities with most of the tin(IV) complexes. Complexes [Sn{S2CN(CH2)4}2Cl2] and [Sn{S2CN(CH2)4}2n-Bu2] showed the highest activities. The penetration of the complexes through the yeast membrane was attributed to the size and structure of the complexes. The two chlorine atoms in complex [Sn{S2CN(CH2)4}2Cl2] were attributed to its ease of penetration across the cell membrane compared to other complexes [84]. Organotin(IV) methyl- and ethylisopropyldithiocarbamate complexes: dimethyltin(IV) methyl-isopropyldithiocarbamate, dibutyltin(IV) methylisopropyldithiocarbamate, triphenyltin(IV) methylisopropyldithiocarbamate, dimethyltin(IV) ethylisopropyldithiocarbamate, dibutyltin(IV) ethylisopropyldithiocarbamate, triphenyltin(IV) ethylisopropyldithiocarbamate have been synthesized and their biological activities were evaluated. The antifungal activities of these complexes were screened against three species of fungi namely Aspergillus niger, Candida albicans, and Saccharomyces cerevisiae using qualitative disc diffusion and quantitative broth microdilution method. Very good antifungal activities were observed for all the fungi tested. Minimum inhibitory concentration (MIC) values obtained for these compounds were better than streptomycin against B. cereus, S. aureus, and S. mutans [18].

3.2. Anticancer/Antitumor Studies Metal complexes have, overtime, proven to be useful in the fight against cancer. Cisplatin, an inorganic complex of platinum discovered by Rosenberge, exhibits antitumor characteristics, and remains one of the world’s bestselling anticancer drugs. This discovery led to changes in the course of therapeutic management of several tumors, such as those of the ovary, testes, head and neck [112]. However, this spectacular clinical activity of cisplatin has been found to be limited by Molecules 2018, 23, 2571 19 of 27 significant side effects such as DNA damage and the emergence of drug resistance [113]. As a result of this usual accompanied side effect of the platinum based antitumor drug, further research for alternative metal based drugs with improved antitumor activities such as the non-platinum based anticancer complex have been initiated. Good activities have been recorded with metals such as copper, gold [114], gallium, germanium, tin, ruthenium, iridium, lanthanum [115], but none has entered the clinical trial stage till date. Among the afore mentioned, gold and tin derivatives have gained increased interest and have appeared very promising as potential anticancer drugs [116]. Hence, the continual search for novel chemotherapeutic agents with decreased toxic side-effects and improved specificity. In vitro screening of new coordination complexes, followed by careful selection of best active anticancer compounds, remains the best way of identifying potential antitumor agents. The underlying mechanism of the organotin(IV) compounds involve the inhibition of F1F0 ATP synthase [117,118]. F1F0 ATP synthase have been found to be harmful to all life forms [118]. In their uncombined form as ordinary salts, organotin(IV) compounds such as tributyltin(IV) chloride have been reported to inhibit ATP synthases by targeting the Na+ channel. Likewise, oxidative phosphorylation and ATP synthesis in the mitochondria has been suggested to be suppressed by the dibutyltin(IV) dichloride [119]. Other reports have suggested their mechanism of action to involve binding to both DNA base and phosphate contrary to the cisplatin which could bind to DNA with a cross link. This can induce DNA damage by inhibiting DNA and protein synthesis while increasing RNA synthesis, thereby affecting structural selectively [120]. These observed modes of actions have been suggested to hinder the usage of organotin(IV) compounds as improved antitumor agents due to the cellular targets of these compounds in their mechanism regardless of the mitochondrial oxidative phosphorylation [6]. Nevertheless, there is a need to further understand how to modulate these toxic effects. Various studies with interesting results have been conducted by Amir et al., on the in vitro antitumor properties of organotin(IV) complexes of dithiocarbamate against a wide panel of tumor cell lines of human origin [121]. Series of phenyltin(IV) dithiocarbamates of the formula Ph4-nSn(S2CNEt2)n, where n = 1–3, were evaluated for their cytotoxicity against L1210 mouse leukaemia cell line. About 50% growth inhibition rating of 0.3 µM was found compared with 0.6 and 1.2 µM for the drugs cisplatin and carboplatin respectively. It was also discovered that when chloride was introduced, as in PhSn(S2CNEt2)2Cl and Ph2Sn(S2CNEt2)Cl, it resulted in low toxicity. Nevertheless, it was found to still exert more cytotoxic effect than drugs containing Pt metal [15]. In another study, organotin(IV) dithiocarbamates with general formula (ArCH2)2Sn(S2CNR’2)Cl and (ArCH2)2Sn(S2CNR’2)2 were evaluated against various panels of human cancer cell lines. It was reported that the group with chloride were more cytotoxic than their counterparts without chloride substituents, i.e., (ArCH2)2Sn(S2CNR’2)2. From this study it was suggested that the ease of hydrolysis of the former might be the reason for such behavior. The complex, (4-NC-C6H4CH2)2Sn[S2CN(CH2CH2)2NCH3]Cl, was found to be the most cytotoxic compound in the series, and more cytotoxic than cisplatin [63]. Kadu et al., synthesized some binuclear diphenyltin(IV) dithiocabamate macrocyclic complexes through a self-assembly process involving 0 novel diamino precursors 4,4 -bis(2-(alkylamino)acetamido)diphenyl ethers, CS2 and Ph2SnCl2. Using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cytotoxic activity was carried out against HEP 3B (hepatoma) and IMR 32 (neuroblastoma). The complexes were extremely active against both cell lines and cytotoxicity data having better 16-fold potency compared to cisplatin. The flow cytometric analysis of annexin V–propidium iodide-stained cells of L5, 4 and 6 was found to possess the ability to induce apoptosis in HEP 3B and IMR 32 cells, which is a requirement for major cancer therapy. The binuclear complex shows an extraordinary potency which can be correlated to result from the higher LUMO energy together with the great charge value on the Sn(IV) center [17]. Organotin(IV) compounds of the type R3SnCl and R2SnCl2 (R = C6H5 or C4H9) with methoxyethyldithiocarbamate dithiocarbamate ligands have been evaluated for their in vitro anti-proliferative activities against HL-60 cell lines. The results showed that both complexes exhibited Molecules 2018, 23, 2571 20 of 27

high cytotoxicities toward HL-60 cell lines with the IC50 values below 1 mM. These complexes were found to possess high anti-proliferative effects; thus, in correlation with an earlier ﬁnding of Awang et al., (2010). The potency against the HL-60 cells and the IC50 of triphenyltin(IV) complex was much less than the dibutyltin(IV) complex which displayed a higher potential. It was concluded that both complexes have the potential of becoming a good antitumor agents due to their potent cytotoxic effect at micromolar concentrations [57].

3.3. Other Biological Studies The biological applications of organotin(IV) dithiocarbamate are not only limited to the highlighted areas, other biological activities of organotin(IV) dithiocarbamates have also been reported. Organotin(IV) dithiocarbamate have shown good activities as antileishmainial agent. Series of complexes of di- and triorganotin(IV) dithiocarbamates with 4,4-trimethylenedipiperidine- 1-carbodithioate have shown better antileishmanial activity above the currently used standard drug. Their high activities have been attributed to low binding energy with enzyme trypanothione synthetase. It was concluded that, with further clinical investigations the synthesized complexes have a promising potential for the treatment of leishmaniasis [122]. Promising insecticidal activities have been obtained in a study involving complexes of 0 tri-organotin(IV) dithiocarbamates of the formula R3SnS2CNR2 by Eng et al., (where R = Cy, Ph; 0 NR2 = NEt2,N(n-Bu)2,N(i-Bu)2, N(n-Pr)2,N(CH2)5, NH(n-Pr), NH(n-Bu), NH(i-Bu)). This was achieved against the second larval instar of the Anopheles stephensi and Aedes aegypti mosquitoes. These studies showed no signiﬁcant activities with triphenyltin and tricyclohexyltin derivatives but showed moderate action against the larvae of both species [123]. The scavenging potential for radicals of some organotin(IV) dithiocarbamate complexes of Cyclohexylcarbamodithioic acid have been studied. This was achieved using 2,2-diphenyl- 1-picrylhydrazyl (DPPH) radical assay. The IC50 values and the percentage inhibition of both the ligand and complexes were obtained and compared with a known antioxidant agent (butylated hydroxytoluene). The ligand itself showed a good radical scavenging potential which was enhanced upon coordination to the respective organotin(IV) salts [38].

3.4. Limitation Associated with Toxicity of Organotin(IV) Compound Several reports have been made about the diverse use of organotin(IV) compounds as biological agents with better activity. Nevertheless, most of these compounds have not been cleared for clinical practice because most derivatives are generally very toxic [6]. They often leave undesirable effects on the nervous, reproductive, endocrine and other systems of animals. Some of which includes cognitive impairment in learning and memory [120]. One factor that increases the toxicity of organotin(IV) compounds is the number of alkyl groups present within the moiety [6]. The bulkiness and the number of these alkyl groups affect the toxicity of the molecule which in turn affects their hydrophilicity at large [124]. Trimethyltin(IV) have been used as stabilizers in PVC, as disinfectants and as insecticides but has a strong neurostatic effect and has been reported to impair spatial memory in rats and mice [120]. Dibutyltin(IV) compounds have also shown neurostatic effect by aggregating on the brain cell cultures. In platinum chemotherapy, sulfur-containing molecules have been used as chemo-protectants due to their anticancer potential and the ability to modulate cisplatin nephrotoxicity [17]. The mechanism of this modulation is still unknown, but there are reports that propose the DNA to be the probable target of the cytotoxic activity [6,125]. Therefore, regardless of the associated toxicity, organotin(IV) compounds and their derivatives can have their toxicities modulated by a judicious choice of the ligand (like dithiocarbamate) coordinated to the organotin(IV) moiety to minimize this drawbacks [6]. Molecules 2018, 23, 2571 21 of 27

4. Conclusions The chemistry and the synergy created by the individual moieties of organotin(IV) and dithiocarbamate compounds has led to the enhanced biological activity of organotin(IV) dithiocarbamate complexes. The large volume of research data available for these sets of compounds has made it possible to predict the geometry and also consider them for other conceivable applications. A major attribute of these complexes is their ability to have the coordination number around the tin center increased and thus influence the geometry in the complexes. Their geometries are not exactly perfect, but are distorted due to the asymmetric nature of the dithiocarbamate ligand which consequently leads to unequal distances of the tin-sulfur bond. The possibilities for several resonance structures of the dithiocarbamate moiety explain their outstanding stability. Numerous applications + + + of dithiocarbamate compounds stems from the ease of replacing the cations (K /Na /NH4 ) in a coordinate bond through the sulfur atom to form a complex with a metals. Thermal studies of these complexes have shown that they could be useful single source precursors for tin-sulfide nanoparticle which can exist as SnS, SnS2, or Sn2S3 with good semiconducting properties. Hence, these compounds also found relevance in Materials chemistry. The various biocidal activities of organotin(IV) dithiocarbamate complexes are worthy of development and utilization. Their usage should not only be limited to their application in the industries, agriculture and material science but can be further explored for the treatment of diseases as described and enumerated here. The use of these complexes in drug design could make a significant contribution to human lives, and also provide alternative medication which might be cheaper and better than the currently available drugs. The World Health Organization [126] recently gave a report about the availability of antibiotics and the an alarming encroachment of resistance to the modified existing class of the currently used antibiotics. Hence, the need for new therapeutic agents to combat this menace is imperative. Organtin(IV) dithiocarbamate complexes, therefore, can prove useful in the fight against antimicrobial resistance and against other infectious diseases due to the diverse biological potentials. However, considerable effort must be made to understand their specific mechanism of action and side effects which is still a drawback in their usage. Regardless of the side effects, these complexes can offer a platform for the design of novel therapeutic agents, thus new approaches/ideas and detail studies are needed to outwit these drawbacks.

Funding: This research was funded by Material Science Innovation and Modelling (MaSIM) Research Focus Area of North-West University, South Africa. Acknowledgments: The authors wish to acknowledge North-West University, South Africa for the facilities used to carry out this studies. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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