Copper Dithiocarbamates: Coordination Chemistry and Applications in Materials Science, Biosciences and Beyond

Abstract

Copper dithiocarbamate complexes have been known for ca. 120 years and find relevance in biology and medicine, especially as anticancer agents and applications in materials science as a single-source precursor (SSPs) to nanoscale copper sulfides. Dithiocarbamates support Cu(I), Cu(II) and Cu(III) and show a rich and diverse coordination chemistry. Homoleptic [Cu(S₂CNR₂)₂] are most common, being known for hundreds of substituents. All contain a Cu(II) centre, being either monomeric (distorted square planar) or dimeric (distorted trigonal bipyramidal) in the solid state, the latter being held together by intermolecular C···S interactions. Their d⁹ electronic configuration renders them paramagnetic and thus readily detected by electron paramagnetic resonance (EPR) spectroscopy. Reaction with a range of oxidants affords d⁸ Cu(III) complexes, [Cu(S₂CNR₂)₂][X], in which copper remains in a square-planar geometry, but Cu–S bonds shorten by ca. 0.1 Å. These show a wide range of different structural motifs in the solid-state, varying with changes in anion and dithiocarbamate substituents. Cu(I) complexes, [Cu(S₂CNR₂)₂]⁻, are (briefly) accessible in an electrochemical cell, and the only stable example is recently reported [Cu(S₂CNH₂)₂][NH₄]·H₂O. Others readily lose a dithiocarbamate and the d¹⁰ centres can either be trapped with other coordinating ligands, especially phosphines, or form clusters with tetrahedral [Cu(μ₃-S₂CNR₂)]₄ being most common. Over the past decade, a wide range of Cu(I) dithiocarbamate clusters have been prepared and structurally characterised with nuclearities of 3–28, especially exciting being those with interstitial hydride and/or acetylide co-ligands. A range of mixed-valence Cu(I)–Cu(II) and Cu(II)–Cu(III) complexes are known, many of which show novel physical properties, and one Cu(I)–Cu(II)–Cu(III) species has been reported. Copper dithiocarbamates have been widely used as SSPs to nanoscale copper sulfides, allowing control over the phase, particle size and morphology of nanomaterials, and thus giving access to materials with tuneable physical properties. The identification of copper in a range of neurological diseases and the use of disulfiram as a drug for over 50 years makes understanding of the biological formation and action of [Cu(S₂CNEt₂)₂] especially important. Furthermore, the finding that it and related Cu(II) dithiocarbamates are active anticancer agents has pushed them to the fore in studies of metal-based biomedicines.

1. Introduction

Copper is an intriguing element with interesting and useful properties and has been widely used by mankind for ca. 6000 years. It is relatively abundant in the earth’s crust (50–60 ppm), being found in both its elemental form and in a range of minerals. Especially pertinent to this review, it is found in a range of copper sulfides including chalcopyrite, digenite, covellite and chalcocite [1]. Copper is an essential element for all living organisms, being a key constituent of the active site of respiratory enzymes cytochrome c oxidases, and a human contains 1.4–2.1 mg of copper per kg of body mass. Balancing copper levels in the body is extremely important, and recently major changes in copper concentrations and its localisation have been identified with Alzheimer’s disease [2]. Copper has an extensive and rich coordination chemistry, forming complexes in oxidation states from 0 to +4, with the +2 (cupric) state being by far the most prevalent, although +1 (cuprous) complexes are also abundant. Its complexes find extensive applications, for example as catalysts, fungicides and pesticides, pigments and solid-state materials with novel physical properties such as high-temperature superconductors.

Dithiocarbamates are an important class of monoanionic dithiolate ligands. Easily prepared from a wide range on secondary and primary amines, they coordinate to most of the elements in the periodic table, including all the transition elements [3,4]. Copper forms dithiocarbamate complexes in three oxidation states, +1, +2 and +3, the most common being four-coordinate Cu(II) bis(dithiocarbamates), [Cu(S₂CNR₂)₂], first documented by Delépine at the beginning of the 20th century [5,6]. Over the past 100+ years, interest in copper dithiocarbamate complexes has developed enormously, for example a SciFinder© search for [Cu(S₂CNEt₂)₂] alone gives ca. 900 hits with applications in areas as diverse as medicine, materials science, agriculture, biochemistry, catalysis and water purification. In this review, we give an overview of the coordination chemistry of copper dithiocarbamates, together with recent developments of their applications, especially towards the synthesis of nanoscale metal sulfides and in biological systems, for example as anti-cancer agents.

2. Copper(II) Bis(dithiocarbamate) Complexes

When Delépine first combined aqueous solutions of NaS₂CNⁱBu₂ and various Cu(II) salts around 1907–8, he would have observed the immediate and high yielding formation of a dark brown precipitate of the bis(dithiocarbamate) complex, [Cu(S₂CNⁱBu₂)₂] [5,6]. This simple reaction works for an astounding variety of secondary amine-derived dithiocarbamate salts. Work up is normally straightforward, involving simple separation by filtration and drying in a standard lab oven [7,8]. Binding constants are of the order 10⁷–10⁸ for simple dialkylamines (in ethanol with CuCl₂) [8] and this has led dithiocarbamates to be developed as reagents capable of removing copper to very low levels in water [9,10], and from pharmaceutical processes where copper has been used as a catalyst [11]. Oxidative addition of thiuram disulfides to copper metal is an alternative synthetic route, giving good yields [12,13].

A wide range of Cu(II) bis(dithiocarbamate) complexes have been reported (Figure 1). They fall into three main types. Most common are dialkyl complexes, which can be symmetrically or unsymmetrically substituted or encompassed into a cyclic system, and a large number of these have been prepared [7,8,14,15,16,17,18,19,20,21]. Over the past decade, an increasing number of alkyl–aryl complexes (Figure 1d) have been documented, also being prepared by the same simple method as described above [22,23,24]. Until recently, diaryl-substituted [Cu(S₂CNAr₂)₂] (Figure 1e) were not well-documented, but they can be made in a similar way starting from the lithium dithiocarbamate salts [25]. Complexes from primary amines, [Cu(S₂CNHR)₂], appear not to be stable, and as far as we are aware, none have been fully characterised [26,27,28,29].

Many variants have been prepared, examples of which are shown in Figure 2. The addition of substituents to the end of alkyl chains (Figure 2a) allows tuning of the water solubility (e.g., X = OH) [16,30,31] and acid-base properties (e.g., X = CO₂H or NEt₂) [30,31]. Beer and co-workers have synthesised a series of macrocyclic complexes containing two (Figure 2b) or three Cu(II) bis(dithiocarbamate) centres [32,33,34], some of which serve as selective anion receptors [32,33]. Due to the lability of the dithiocarbamate ligands (see later), complexes with two different dithiocarbamates will be in equilibrium with the homoleptic species. However, by binding a piperazine onto a gold surface through a thiol linkage, Cao and co-workers have anchored the unsymmetrical copper centre (Figure 2c) to a gold surface [35]. Recently, Omondi and co-workers have extended the number of aryl–alkyl complexes, preparing a small library (Figure 2d) in which the alkyl group has an imine linkage, which can potentially be further derivatised. The complex shown in Figure 2e is representative of those prepared by Fregona and co-workers to probe their anti-cancer activity, with water (ideally or DMSO) solubility being a pre-requisite [36,37]. Appending a crown ether ring onto the backbone (Figure 2f) allows the redox-active Cu(II) centre to act as a sensor for cation binding [26]. Blower and co-workers have prepared bis(phosphonate) derivatives (Figure 2f), incorporating ⁶⁴Cu for imaging applications [38] and Wilton-Ely has linked together ruthenium (Figure 2h) and other metal centres through a Cu(II) dithiocarbamate motif [39].

There are reports of Cu(II) complexes containing two different dithiocarbamates [40,41], but no well-characterised examples, and due to the lability of the dithiocarbamate at the Cu(II) centre, it seems likely these are mixtures with the homoleptic dithiocarbamate complexes (see later). Thus a literature report of [Cu(S₂CNMe₂)(S₂CNEt₂)], formed upon the addition of tetramethyl thiuram disulfide to the Cu(I) cluster, [Cu(μ₃-S₂CNEt₂)]₄ [40], is likely a mixture with [Cu(S₂CNMe₂)₂] and [Cu(S₂CNEt₂)₂]. In contrast, isomeric [Cu(S₂CNMeEt)₂] is well-characterised [42].

Almost a century passed between the initial synthesis of [Cu(S₂CNⁱBu₂)₂] and the elucidation of its structure by single-crystal X-ray diffraction (Figure 3a) [7]. As in all Cu(II) dithiocarbamate complexes, a square-planar structure is adopted and many, like [Cu(S₂CNⁱBu₂)₂], are centrosymmetric in the solid-state, with Cu–S bond lengths [2.268(1) and 2.302(1) Å] and a S–Cu–S bond angle [77.6(1)°] being typical. In the gas phase, the monomeric structure is maintained as shown by an electron diffraction study of [Cu(S₂CNMe₂)₂] [43]. In the solid state, the latter adopts an unusual polymeric structure in which four-coordinate subunits are linked via long-range intermolecular Cu···S interactions, with each copper centre being pseudo-octahedral [44]. This arrangement appears to be unique to the dimethyl-derivative, and all other solid-state structures (broadly) fall into two types, isolated monomers and weakly bound dimers [3,7,8,14,16,21,30,45,46,47]. In the latter, the secondary intermolecular Cu···S interactions are of the order ca. 2.7–2.9 Å and this brings the two copper centres within ca. 3.4–3.8 Å, as highlighted by the solid-state structure of [Cu(S₂CNBu₂)₂] (Figure 3b) [7]. In dimers, the copper centre is five-coordinate and the CuS₄ moiety is significantly deviated from planarity, suggesting that it contains quite soft Cu–S interactions as supported by theoretical calculations [48]. As recently discussed and illustrated by Tiekink [49], secondary C–H···π(chelate ring) interactions are common in the solid-state structures of copper (and structurally similar nickel) dithiocarbamate complexes. Thus, 28 of 59 crystal structures of [Cu(S₂CNR₂)₂] in the Cambridge Crystallographic Data Base have C–H···π (chelate) interactions with individual units tending to self-associate into one- or two-dimensional architectures.

Some structurally interesting solid-state structures have been generated that contain fullerenes and Cu(II) bis(dithiocarbamates). In the first approach, Konarev and co-workers have shown that co-crystallisation of [Cu(S₂CNEt₂)₂] and C₆₀ from benzene gives a layered structure (Figure 4) that shows some interesting physical properties [50]. Thus, while in the dark this solid has a conductivity of only 10−11 S cm⁻¹, illumination by white light increases this by ca. 20–50 times. Further, the photoconductivity spectrum shows a maximum at 470 nm, suggesting that both intermolecular charge transfer between neighbouring C60 molecules and photoexcitation of the Cu(II) centre contributes to the photogeneration of free charge carriers. Related clathrate structures are formed from C60 and C70 with a range of [Cu(S₂CNR₂)₂] and the copper centres can be monomeric, dimeric or tetrameric [50,51].

In a different approach, Beer and co-workers have prepared a range of nanosized polymetallic resorcinarene complexes, containing eight Cu(II) centres (Figure 5), the central cage of which is in the order of 0.4–0.7 nm in diameter [52]. While this cavity is large enough to include C₆₀, access is blocked as the portals are too small to allow entry. Nevertheless, in organic solvents and the presence of NOBF₄, slow incorporation of the fullerene into the cavity was shown by mass spectrometry. This is consistent with the reversible binding of the dithiocarbamate to the copper centre.

As d⁹-centres, all Cu(II) bis(dithiocarbamate) complexes are paramagnetic, exhibiting magnetic susceptibilities of 1.6–1.9 BM, consistent with a single unpaired electron. The latter makes them amenable to study by EPR spectroscopy [53,54], with the spectrum of [Cu(S₂CNEt₂)₂] recorded in heptane being shown (Figure 6) [55]. Spectra are somewhat solvent dependent but vary a little in non-coordinating solvents. However, in coordinating solvents such as DMSO, large variation is observed suggesting the formation of an adduct [56]. The spectra are consistent with the delocalisation of the odd electron over the CuS₄ moiety, which is supported by theoretical calculations [57]. The EPR signal is useful for probing the nature of dithiocarbamates in biological systems [58], especially the fate of the widely used alcohol-abuse drug disulfiram, (Et₂NCS₂)₂, as [Cu(S₂CNEt₂)₂] is readily formed following its reduction [59,60,61,62]. Given their paramagnetism, NMR spectra are not very informative. In some cases, resonances distant from the Cu(II) centre can be observed [36], but frustratingly the distinctive high-field resonance of the backbone carbon in the ¹³C NMR spectrum cannot be observed. A second key feature of Cu(II) bis(dithiocarbamate) complexes is their brown coloration. This results from an intense absorption at ca. 435 nm (ε = 13,000 dm³ mol⁻¹ cm⁻¹) for [Cu(S₂CNEt₂)₂] in CCl₄, being attributed to a solvent-independent equatorial ligand-metal charge transfer, proving extremely useful for characterisation and also for following subsequent chemical transformations.

Their thermal stability has been extensively explored. Melting points are substituent dependent, [Cu(S₂CNEt₂)₂] melting at ca. 200 °C and (modest) increases in volatility are seen for longer alkyl-chain derivatives [7,63,64]. Most of them degrade at 230–300 °C to generate a range of copper sulfides, and this makes them excellent single-source precursors (SSPs) (as will be discussed later). Another key feature is their redox behaviour [65]. They undergo a fully reversible one-electron oxidation to give analogous Cu(III) complexes, [Cu(S₂CNR₂)₂]⁺, while reduction is a quasi-reversible one-electron process (Figure 7). Reduction generates Cu(I) species, [Cu(S₂CNR₂)₂]⁻, which as d¹⁰ complexes should undergo a structural rearrangement from square planar to tetrahedral, accounting for the quasi-reversibility. Attempts to isolate the reduced products lead to loss of a dithiocarbamate with the formation of Cu(I) clusters [Cu(S₂CNR₂)]_n. Redox potentials vary significantly with the nature of the substituents. Thus, [Cu(S₂CNCy₂)₂] oxidises at 0.57 V, while oxidation of [Cu(S₂CNPh₂)₂] occurs at 0.71 V [65]. Likewise, the latter reduces at −0.26 V, as compared to −0.49 V for the dicyclohexyl complex. Interestingly, the resorcinarene complexes (Figure 5) prepared by Beer and co-workers show a single reversible oxidation process suggesting that all eight Cu(II) centres are oxidised in one step, a process that is unaffected by the inclusion of C₆₀ [52].

The reactivity of [Cu(S₂CNR₂)₂] has been widely explored, although only in a few instances have the products been unambiguously characterised (Figure 8). Ligand exchange can occur, but no complex in which one dithiocarbamate has been exchanged for another anionic bidentate ligand has been crystallographically characterised. Mixtures of [Cu(S₂CNEt₂)₂] and [Cu(Se₂CNEt₂)₂] are believed to rapidly equilibrate upon mixing to form [Cu(S₂CNEt₂)(Se₂CNEt₂)] as shown by EPR spectroscopy [55].

The addition of CuCl₂ to [Cu(S₂CNR₂)₂] leads to ligand redistribution and the formation of dimeric [Cu(S₂CNR₂)(μ-Cl)]₂ [65,66,67], a crystal structure of [Cu(S₂CNEt₂)(μ-Cl)]₂ confirming its identity. It consists of weakly associated dimers being held together by intermolecular Cu–C1 (2.874 Å) and Cu–S (2.882 Å) interactions [65]. Most complexes of this type are difficult to crystallise, possibly due to their equilibrium with monomers in solution [66]. A minor product of CuCl₂ addition to [Cu(S₂CNEt₂)₂] is [Cu₃(S₂CNEt₂)Cl₃], a mixed-valence coordination polymer containing square planar Cu(II) and tetrahedral Cu(I) centres. The addition of CuX₂ (X = Cl, Br) to [Cu(S₂CNC₅H₁₀)₂] in CHCl₃/EtOH is also reported to afford mixed-valence Cu(I)–Cu(II) coordination polymers in which the halide-substituted centre has been reduced [68]. Related mixed-valence coordination polymers are also generated upon addition of Cu(I) halides and it may be that there is an error in this paper. If not, then there is clearly a fine balance between ligand-exchange and a one-electron reduction-oxidation upon addition of metal salts to [Cu(S₂CNR₂)₂]. Photochemical reactions of [Cu(S₂CNR₂)₂] have been studied in a range of solvents. They utilise the strongly allowed ligand-metal charge transfer (LMCT) in the visible region, which leads to a reduction of the copper centre [69]. For example, laser pulse photolysis of [Cu(S₂CNEt₂)₂] in CCl₄ induces a series of transformations resulting in the formation of binuclear [Cu₂(Et₂dtc)₃Cl] and tetraethyl-thiuram disulfide [70]. The addition of nitrogen bases such as pyridine to [Cu(S₂CNR₂)₂] results in loss of the EPR signal, being suggested to result from the formation of adducts such as [Cu(S₂CNR₂)₂·py], although no such complexes have been isolated and fully characterised [71]. Water-soluble complexes such as [Cu{S₂CN(CH₂CH₂OH)₂}₂] and [Cu{S₂CN(CH₂CO₂H)₂}₂] trap one and two equivalents of NO in water as shown by spectrophotometric studies [30,72,73]. Stability constants for each binding process are highly dependent upon the nature of the substituents ranging from 10³–10¹⁰ for binding of the first NO and 10²–10⁴ for the second. A very unusual transformation occurs upon stirring [Cu(S₂CNR₂)₂] with the nitrene-source, [PhI=NTs]_n, which leads to sequential insertion of two and four nitrenes into the Cu–S bonds (Figure 8) [74,75]. This reaction is not unique to copper and may initially result from nitrene addition to sulfur, which then rearranges to afford the ring-expanded product.

3. Copper(III) Dithiocarbamate Complexes

Cu(III) complexes are fairly common [76], although there has been a recent challenge to the simple view that copper is in the +3 state in these species [77]. Cu(III) dithiocarbamate complexes are accessible and relatively stable in the solid state. Most common are the bis(dithiocarbamate) cations, [Cu(S₂CNR₂)₂]⁺, which adopt a square planar coordination geometry. As discussed in the preceding section, [Cu(S₂CNR₂)₂] have a relatively low oxidation potential [78]; hence, the addition of a range of oxidising agents results in the formation of the analogous Cu(III) complexes. Common oxidants used are I₂ [79,80,81], (NO)BF₄ [82], InI₃ [83], [Cu(BF₄)₂] [84], polyoxometalates [85,86], [Cu(ClO₄)₂] [87,88,89,90,91] and FeCl₃ [91]. Upon oxidation, brown solutions of [Cu(S₂CNR₂)₂] become green and the Cu(III) complexes often crystallise from the reaction medium. In the solid state, they retain their green colour upon standing in air, but in solution, attempts to run NMR spectra (for those with diamagnetic anions) lead to broad resonances. This is probably due (at least in part) to back reduction to [Cu(S₂CNR₂)₂], but EPR spectra also show other Cu(II) complexes that have not to date been fully characterised [79].

Shtyrlin and co-workers studied the oxidation of [Cu(S₂CNEt₂)₂] by I₂ in CH₂Cl₂ in detail [92]. The initial formation of [Cu(S₂CNEt₂)₂][I₃] is reversible (log K = 5.8), as is further addition of I₂ to give [Cu(S₂CNEt₂)₂][I₅] (log K = 2.02). Electron transfer between both of these Cu(III) species and [Cu(S₂CNEt₂)₂] is very fast (k_e = 3 × 10⁸ M⁻¹·sec⁻¹ at 298 K). This has prompted a mechanism to be put forward that invokes the formation of an iodide-bridged intermediate, in which electron-density is delocalised across both copper centres and the bridging iodine(s). Bond and co-workers generated Cu(III) complexes upon the addition of (NO)BF₄ to [Cu(S₂CNR₂)₂], using these to acquire electrospray mass spectra, molecular ions being readily observed, while in some instances, sulfur-rich species were also seen [82]. Importantly, they found that mixing different Cu(III) dithiocarbamate cations led to global ligand exchange, showing that dithiocarbamates are also labile at the Cu(III) centre.

As mentioned above, all contain a square planar centre with Cu–S bond lengths of ca. 2.2 Å, some 0.1 Å shorter than related Cu(II) complexes, as would be expected upon oxidation of the copper centre. Indeed, this small but reliable shortening is an easy way to determine the difference between Cu(II) and Cu(III) centres in mixed-valence complexes. As has been discussed previously [3,83], several structural motifs are found in the solid-state, the form adopted being sensitive to the nature of the dithiocarbamate substituents and the anion. All show intermolecular interactions, either between cations through secondary Cu···S interactions as discussed for the related Cu(II) complexes, or between anions and cations. A common structural motif is a coordination polymer (Figure 9a), in which cations stack to give a distorted octahedral CuS₆ coordination geometry and anions are separate as found in [Cu(S₂CNEt₂)₂][FeCl₄] [91]. The anions can also coordinate, giving rise to different structures. For example, [Cu(S₂CNEt₂)₂][I₃] is a coordination polymer with anions linking Cu(III) centres via CuS₄I₂ coordination geometry [79] (Figure 9b), while [Cu(S₂CNMe₂)₂][ClO₄] has a pair of Cu(III) centres capped by the anion [91] (Figure 9c).

Copper(III) dihalide complexes, [CuX₂(S₂CNR₂)], are also known and can also be accessed from the addition of thionyl chloride to [Cu(S₂CNR₂)₂] [93] or the oxidative addition of thiuram disulfides to CuX₂ [13,78,94] (Figure 10). These complexes are diamagnetic, consistent with a square-planar d⁸ configuration and have been confirmed in a crystal structure of [CuBr₂(S₂CNBu₂)] [95]. The average Cu–S distance of 2193(6) Å is consistent with binding to a Cu(III) centre. The addition of Cd(CF₃)₂ to [CuX₂(S₂CNR₂)] gives the dialkyl derivative, [Cu(CF₃)₂(S₂CNEt₂)], which has also been crystallographically characterised [96], as has [Cu(C₂F₅)₂(S₂CNEt₂)] prepared upon the addition of tetraethyl thiuram disulfide to Cd(C₂F₅)₂ [97], and contain a square planar Cu(III) centre.

4. Copper(I) Dithiocarbamate Complexes

Copper(I) dithiocarbamate complexes come in two main forms: As clusters in which the dithiocarbamates bind in a capping manner and as mononuclear species with phosphine or phosphite co-ligands. Tetranuclear clusters, [Cu(μ₃-S₂CNR₂)]₄, have been known since the 1960s [98], and can be prepared via three general methods: (i) The reduction of Cu(II) salts by NH₂OH·HCl in the presence of dithiocarbamate salts [99], (ii) from the comproportionation of [Cu(S₂CNR₂)₂] and activated copper powder [100,101] and (iii) the addition of thiuram disulfides to copper powder in organic media [102]. Quite recently, a further route was shown, namely the insertion of CS₂ into a copper-amide bond [103]. All are yellow, and diamagnetic and crystal structures show they consist of a tetrahedral array of copper centres, with each face of the tetrahedron being capped by a dithiocarbamate ligand (Figure 11a). The disproportionation of [Cu(S₂CNR₂)₂] and [Cu(ClO₄)₂] has been a well-developed route to Cu(III) dithiocarbamate complexes [79,84,90], but the nature of the Cu(I) complex remained unknown until Hogarth and co-workers isolated and crystallographically characterised [{Cu(μ₄-S₂CNPr₂)}₈][ClO₄]₂ from the reaction with [Cu(S₂CNPr₂)₂] [100]. This cluster dication (Figure 11b) consists of a cubic array of copper atoms with each square face of the cube capped by a dithiocarbamate. The average Cu–Cu distance of 2.80 Å is slightly longer than that of 2.70 Å found in tetrahedral clusters [100], while in both, the Cu–S distances are ca. 2.24–2.28 Å.

The addition of thiuram disulfide (TDS) to Cu(I) clusters leads to oxidation and the formation of [Cu(S₂CNR₂)₂], and the kinetics and mechanism have been studied [104]. Reactions are proposed to proceed via a rapid equilibrium with adducts [Cu(S₂CNR₂)(TDS)], which undergo intramolecular electron transfer in a rate-determining step to afford the final Cu(II) complexes.

Over the past decade, through the work of Liu and co-workers, the range of copper-dithiocarbamate clusters has expanded greatly including examples containing hydrides [105,106,107,108] and acetylides [109,110,111,112,113] with up to 25 copper atoms. More widely studied are the interconvertible hydride clusters [Cu₇H(μ_3/4-S₂CNR₂)₆] and [Cu₈H(μ₄-S₂CNR₂)₆]⁺ [108] (Figure 12). They are accessible via a number of routes, all involving the addition of [BH₄]⁻ to Cu(I) or Cu(II) salts. Thus, octanuclear [Cu₈H(μ-S₂CNR₂)₆]⁺ results upon the addition of [BH₄]⁻ to [Cu(S₂CNR₂)₂], a process that can be reversed with the loss of H₂ upon oxidation by Ce(IV). The removal of one copper and the formation of heptanuclear [Cu₇H(μ₃-S₂CNR₂)₆] occurs upon further addition of [BH₄]⁻, a transformation reversed upon the addition of Cu(I) sources. Octanuclear clusters have a tetracapped-tetahedral cluster core, the dithiocarbamates forming a distorted icosahedron around this, with each adopting a m₄-coordination mode. Heptanuclear clusters result from the removal of one outer copper centre and contain a tri-capped tetrahedral core, the dithiocarbamates again forming an icosahedron around this, but now some are μ₃ binding and others μ₄. In both types, the hydride lies within the central tetrahedron (interstitial) and can be observed in the ¹H NMR spectrum. The change from a cube to a tetra-capped tetrahedral metal array upon the introduction of the hydride is unexpected, but density functional theory (DFT) calculations of S₂CNH₂ model clusters support this structural change [108].

In 2014, this chemistry was extended in a quite unexpected way, with the addition of excess [BH₄]⁻ to Cu₈ clusters affording molecular nanoscale clusters [Cu₂₈(H)₁₅(μ₄-S₂CNR₂)₁₂][PF₆] [106] (Figure 13a). The core consists of an irregular Cu₄ tetrahedron, encapsulated by a rhombicuboctahedral framework containing 24 Cu atoms (Figure 13b), the 12 square faces of which are capped by a dithiocarbamate. The ¹H NMR spectrum shows three hydride signals in a 1:8:6 ratio, and a neutron diffraction study allows these to be associated with (i) an interstitial hydride within the Cu₄ tetrahedron, (ii) eight hydrides capping triangular faces of the rhombicuboctahedron and (iii) two sets of μ₅ (four) and μ₆ (two) of square-face truncating hydrides. The chemical equivalence in solution of this latter set as well as all dithiocarbamate ligands is associated with a rapid reorientation of the central Cu₄ unit on the NMR timescale. Upon heating to 70–80 °C (alone or in the presence of acids) or upon solar irradiation, these nanoclusters decompose to furnish H₂ and generate both Cu₇ and Cu₈ clusters, along with Cu₂S. This then links these three cluster types while also showing how other copper-dithiocarbamate complexes may decompose to copper-sulfides (see later).

The hydrides in these Cu₂₈ clusters are sufficiently acidic deprotonate alkynes, and this has been exploited to afford acetylide-containing clusters [109,110,111]. Thus, [Cu₂₈(H)₁₅(μ₄-S₂CNR₂)₁₂]⁺ reacts with terminal alkynes with H₂ evolution to give Cu₁₃ clusters [Cu₁₃(μ₄-S₂CNR₂)₆(μ₃-C≡CR)₄]⁺ (Figure 1a), which contain a centred cuboctahedral [Cu₁₃]¹¹⁺ core, being identical to that found in face-centred cubic bulk copper [110]. There are two cluster core electrons and thus, unlike other copper-dithiocarbamate clusters discussed to date, they are mixed-valence complexes containing both Cu(I) and Cu(0) centres. The Cu₁₃ core is capped by acetylides on four of the triangular faces, while each square face is capped with a dithiocarbamate. It is also possible to prepare clusters containing both hydride and acetylide ligands. Thus, when a ten-fold excess of PhC₂H is reacted with [Cu₂₈(H)₁₅(μ₄-S₂CNR₂)₁₂]⁺ at 30 °C, mixtures of [Cu₈H(μ-S₂CNR₂)₆]⁺ and the new clusters [Cu₁₅(H)₂(S₂CNR₂)₆(C≡CPh)₆]⁺ result (Figure 14b). The latter was shown to be intermediates en-route to [Cu₁₃(μ₄-S₂CNR₂)₆(μ₃-C≡CPh)₄]⁺ [109]. The Cu₁₅ clusters are also accessible in higher yields from the simple addition of mixtures of dithiocarbamate salts and phenylacetylene to [Cu(MeCN)₄]⁺/NaBH₄ mixtures in the presence of base. They contain an icosahedral Cu₁₂ core, two faces of which are capped, while the final copper atom is encapsulated as a linear [CuH₂]⁻ moiety (Figure 14b).

The Cu₁₃ clusters are reactive, easily losing a single metal atom to generate a number of related Cu₁₂ clusters including [Cu₁₂(μ₁₂-S)(μ₄-S₂CNR₂)₆(μ₃-C≡CR)₄] and [Cu₁₂(μ₁₂-Cl)(μ₃-Cl)(μ₄-S₂CNR₂)₆(μ₄-C≡CR)₄] formed upon the addition of KS₂CNR₂ and simple dissolution in CH₂Cl₂, respectively [111]. All contain a Cu₁₂ cuboctahedron with the new heteroatom encapsulated within the structure. Incorporation of other metals is also possible [105,109]. The reaction of [Cu₁₅(H)₂(S₂CNBuⁱ₂)₆(C≡CPh)₆]⁺ with [AuCl(PPh₃)] affords [Au@Cu₁₂(S₂CNBu_i2)₆(C≡CPh)]⁺, a highly luminescent cluster suggested to contain an Au@Cu₁₂ alloy core [109], while the central copper centre can also be replaced by silver. Central doping with Ag or Au significantly affects the physiochemical properties as manifested in the dramatic quantum yield enhancement of [Au@Cu₁₂(S₂CNBu₂)₆(C≡CPh)₄]⁺ measured at 0.59 at 77 K. Palladium-containing [PdCu₁₄H₂(S₂CNBuⁱ₂)₆(C≡CPh)₆] results from the addition of PhC₂H to [Cu₂₈(H)₁₅(μ₄-S₂CNBuⁱ₂)₁₂]⁺ in the presence of [PdCl₂(PPh₃)₂] [105]. A neutron diffraction study shows that it contains a [PdH₂]⁻ unit encapsulated with the bicapped-icosahedral Cu₁₄ core. These studies are ongoing and, undoubtedly, further novel Cu(I) dithiocarbamate clusters will be reported in the near future.

As detailed earlier (Figure 7), [Cu(S₂CNR₂)₂] can be quasi-reversibly reduced to Cu(I) anions, [Cu(S₂CNR₂)₂]⁻, but until recently, no examples of these anionic Cu(I) complexes had ever been isolated, with all attempts leading to loss of a dithiocarbamate ligand with concomitant formation of Cu(I) clusters [Cu(S₂CNR₂)]_n. In 2013, Teske reported the preparation and crystal structure of [NH₄][Cu(S₂CNH₂)₂]·H₂O, formed upon the addition of [NH₄][S₂CNH₂] to CuSO₄ in the presence of KCN [114]. Somewhat unexpectedly, however, the structure does not show the expected [Cu(S₂CNH₂)₂]⁻ anion, but rather is a coordination polymer in which each dithiocarbamate ligand spans two copper centres (Figure 15a). This affords a stacked 2D framework, which includes a staggered chain of [NH₄]⁺ and water molecules (Figure 15b). When a similar reaction is carried out at ca. 80–95 °C, a second coordination polymer [Cu(S₂CNH₂)]_n results. While each copper remains bound to four dithiocarbamates, the CuS₄ tetrahedral are now linked in a 3D array reminiscent of a filled β-cristobalite structure [114].

A second well-developed class of Cu(I) dithiocarbamate complexes are those containing phosphine (and to a lesser extent phosphite) co-ligands, first reported in the late 1960s [115,116] and now relatively common [101,117,118,119]. Two general types are accessible, mononuclear four-coordinate complexes [Cu(S₂CNR₂)(PR₃)₂] ((Figure 16a) or [Cu(S₂CNR₂)(κ₂-R₂PXPR₂)] with a Cu:P ratio of 1:2 [116,118,120,121,122,123,124,125,126] and binuclear [Cu(μ-S₂CNR₂)(PR₃)]₂, in which the dithiocarbamates bridge the Cu₂ centre (Figure 16b) [119] [119,127]. They result upon the addition of phosphines to Cu(I) dithiocarbamate clusters [101,115], while the bis(adducts) are also accessible from reactions of [CuX(PR₃)₂] with dithiocarbamate salts [122,124,126]. Mononuclear adducts appear to be quite robust in both solution and the solid state. They contain a tetrahedral Cu(I) centre that is somewhat distorted due to the small bite angle of the dithiocarbamate. Loss of phosphine affords the binuclear complexes, which are less stable, especially in solution, being stable in benzene but not toluene [119]. In the solid state, the central Cu₂S₂ ring is planar and Cu···Cu distances vary at 2.6–2.9 Å. Huang and co-workers prepared a binuclear complex (Figure 16c) in which the two Cu(I) centres are linked via a piperazine-bis(dithiocarbamate) ligand [128], while from reactions of borohydride adducts [Cu(κ₂-BH₄)(PR₃)₂] with PhNCS, Orlandini and co-workers prepared a number of mononuclear bis(phosphine) complexes containing an aniline-derived dithiocarbamate ligand, such as [Cu(S₂CNHPh)(PR₃)₂] (R = Ph, Cy), one of which (R = Ph) (Figure 16d) has been crystallographically characterised [129]. The structure is as expected, but the stability of the primary dithiocarbamate is unexpected given the lack of substantive evidence for analogous Cu(II) complexes. Likely, this results from the soft nature of the Cu(I) vs. Cu(II) centre, which makes deprotonation, with concomitant formation of a dithiocarbamate, less favourable.

Trinuclear phosphine-containing Cu(I) clusters, [Cu₃(μ₃-S₂CNR₂)₂(diphosphine)₂]⁺, have also recently been prepared from the addition of dithiocarbamate salts to [Cu(MeCN)₄][PF₆] in the presence of the diphosphine [107]. The Cu₃ triangle is capped by two dithiocarbamates, and one copper is chelated by a diphosphine while the second bridges a Cu–Cu vector (Figure 17a). There is one report of an unusual phosphine-chloride-containing cluster, namely [Cu₃(PEt₃)₃(μ-Cl)(μ₃-Cl)(μ₃-S₂CNC₄H₈)] (Figure 17b), formed from the 1:2:1 reaction between CuCl, Et₃P and NH₄[S₂CNC₄H₈] [130]. It contains an incomplete cubane core and can be envisaged as the monomer [Cu(PEt₃)(S₂CNC₄H₈)] being “trapped” by [CuCl(PEt₃)]₂ en-route to binuclear [Cu(PR₃)(μ-S₂CNR₂)]₂ [119].

There are a small number of further Cu(I) phosphine-dithiocarbamate complexes, which have been characterised primarily on the basis of only a crystallographic study. These include [Cu₂(μ-dppm)₂(μ-S₂CNEt₂)][ClO₄] (dppm = Ph₂PCH₂PPh₂) with mutually trans diphosphines and a short Cu··Cu vector (2.711(1) Å) [131], [Cu₃(μ-dppm)₃(μ₃-S₂CNR₂)(μ₃-I)]I, which contains a Cu₃ triangle in which each edge is bridged by a diphosphine and the faces by iodide and dithiocarbamate, respectively [122] and octanuclear [Cu₈(SAr)₄(SAr)₂(S₂CNMe₂)₂][PPh₄]₂ (Ar = 4-SC₆H₄Br) [132]. The centrosymmetric cluster core contains eight copper and ten sulfur atoms with all copper atoms bound to three sulfurs of either thiolate or triply bridging dithiocarbamate ligands. Four of the copper atoms are also coordinated to a PPh₃ ligand and have a distorted tetrahedral geometry while the others have a distorted trigonal-planar coordination.

5. Mixed-Valence Copper Dithiocarbamate Complexes

As one might imagine given the rich nature of the chemistry of Cu(I), Cu(II) and Cu(III) dithiocarbamates described above, and the relatively low potentials that link these three oxidation states, there is a rich and diverse mixed-valence copper-dithiocarbamate chemistry. This is primarily focused on Cu(I)–Cu(II) complexes, many of which are coordination polymers, but there are also a reasonable number of Cu(II)–Cu(III) examples. For this reason, this section is subdivided into two separate subsections, with some slight overlap from a single complex which contains copper in all three oxidation states.

Mixed valence Cu(I)–Cu(II) complexes were first detailed in 1974, with Golding and co-workers reporting the formation of coordination polymers from the addition of CuX₂ (X = Cl, Br) to the piperidine dithiocarbamate complex, [Cu(S₂CNC₅H₁₀)₂], in EtOH/CHCl₃ [68]. Isolated complexes had the formulae [Cu(S₂CNC₅H₁₀)₂(CuX)_n] (n = 4, 6) and were found to be insoluble in common organic solvents, and decomposed to give the starting Cu(II) dithiocarbamate in polar coordinating solvents such as DMSO, DMF and pyridine. It is not clear what reduces CuX₂ but it likely results from dithiocarbamate oxidation. Two of these were crystallographically characterised (X = Br) but disorder makes them quite difficult to fully interpret on a molecular scale.

There was little further activity in this area until 2005 when Okubo and co-workers reported the structure of [Cu₅(S₂CNEt₂)₂Cl₃][FeCl₄] (Figure 18a) formed upon the addition of CuCl₂ to [Fe(S₂CNEt₂)₃] in an acetone/CHCl₃ mix [133]. It contains a single Cu(II) centre, as supported by magnetic measurements, and the Cu₅ sub-units are linked through the Cu(II) centres to afford a 2D lattice with the [FeCl₄]⁻ counter ions located between the sheets. The material shows interesting physical properties, for example temperature dependence of the dielectric constants shows 2-D ferroelectric order.

Following this initial report, over the past 15 years, Okubo and co-workers have prepared a range of Cu(I)–Cu(II) coordination polymers [134,135,136,137,138,139,140,141,142,143]. Their synthetic strategy is to react [Cu(S₂CNR₂)₂] with [CuBr(SMe₂)] in mixed organic solvents, with crystals forming upon concentration of the filtrate. The precise nature of the coordination polymer generated depends upon the dithiocarbamate substituents, with those derived from cyclic amines as the favoured species. In all the Cu(II), centres are bound by two dithiocarbamates in a square planar arrangement, and thus these polymers differ primarily in the nature of the Cu(I) halide sub-units and also how they arrange themselves with respect to the Cu(II) centres. Aspects of this work have been reviewed by Batten [144] and the only key examples will be given here. Thus, with [Cu{S₂CN(CH₂)_n}₂] (n = 5, 6) [136,139], 1D chains result (Figure 18b) in which Cu₂Br₄ sub-units link together the Cu(II) bis(dithiocarbamate) centres in the same way as previously reported by Golding and co-workers (n = 4) [68]. With the pyrrolidine dithiocarbamate complex (n = 4), Cu₆ sub-units result, formed via the linking of two crystallographically inequivalent Cu(II) bis(dithiocarbamate) centres linked via two CuBr groups to give a 3D network (Figure 18c) [134]. Methyl-substitution of the rings can have a significant effect on the nature of the polymer produced. For example, with 3,5-dimethylpiperidine dithiocarbamate, a 2D structure results via linking together Cu(II) centres with Cu₃Br₃ sub-units (Figure 18d) [138]. Related iodide-containing coordination polymers can also be prepared [139,141] and they show similar structures to the bromides.

Mixed-valence Cu(I)–Cu(II) dithiocarbamate coordination polymers have interesting physical properties, primarily stemming from their relatively small band gap, which results from the HOMOs of their various components. For example, while the band gap in [Cu(S₂CN-2,6-Me₂C₅H₈)₂] is 1.30 eV, the coordination polymer generated upon the addition of [CuBr(SMe₂)] has a band gap of only 1.04 eV [143] and exhibits semi-conducting behaviour. The estimated bulk conductivity at 300 K of 1.4 × 10⁻⁸ S cm⁻¹ is similar to those with other dithiocarbamate ligands, which can be as high as 5.2 × 10⁻⁷ S cm⁻¹ [134].

A number of mixed-valence Cu(II)–Cu(III) dithiocarbamate complexes are known, falling into a number of different types. They were first reported in the 1970s upon oxidation of Cu(II) bis(dithiocarbamate) complexes with halides or metal salts [145,146,147]. For example, Cras and Willemse prepared mixed-valence complexes [Cu₃(S₂CNBu₂)₆][X] (X = M₂Br₆; M = Zn, Cd, Hg) upon the addition of MBr₂ to [Cu(S₂CNBu₂)₂] [145], a complex disproportionation and dithiocarbamate redistribution reaction, which also afforded [Zn(S₂CNBu₂)₂], [Cu(S₂CNBu₂)₂][ZnCl₃] and a (purported) nonanuclear Cu(I) cluster, most likely being [{Cu(μ₄-S₂CNBu₂)}₈]²⁺ [100]. They are coordination polymers consisting of [Cu₃(S₂CNR₂)₆][X]₂ sub-units, precise structures that are dependent upon the nature of both R and X [145,146]. For example, [Cu₃(S₂CNEt₂)₆][Br]₂, contains stacked Cu(S₂CNEt₂)₂ and Cu(S₂CNEt₂)Br₂ units with both copper centres adopting a distorted octahedral coordination. An analysis of Cu–S distances suggests that it is best considered as being composed of [Cu(S₂CNEt₂)₂]⁺ and [Cu(S₂CNEt₂)Br₂]⁻ ions containing Cu(III) and Cu(II) centres, respectively [146]. Crystal structures of [Cu₃(S₂CNBu₂)₆][X]₂ (X = CdBr₃, HgBr₃) [145,148] show a centrosymmetric Cu₃ unit in which [Cu(S₂CNBu₂)₂] is sandwiched between two Cu(III) [Cu(S₂CNBu₂)₂]⁺ sub-units and the [M₂Br₆]²⁻ counter ions are non-coordinating. Stacking of Cu(II) and Cu(III) units can be extended, with the addition of [Cu(ClO₄)₂] to [Cu(S₂CNPr₂)₂]₂ in CHCl₃ resulting in the formation of the dark green coordination polymer [Cu(S₂CNPr₂)₂]₂[ClO₄]. This polymeric complex consists of a chain of alternating Cu(II) and Cu(III) centres held together by intermolecular Cu–S interactions (Figure 19a), while the perchlorate anions are not metal coordinated [149]. The formation of this mixed-valence polymer presumably results from the initial generation of [Cu(S₂CNPr₂)₂][ClO₄], which co-crystallises with unreacted [Cu(S₂CNPr₂)₂]₂.

A quite different type of mixed-valence Cu(II)–Cu(III) dithiocarbamates are the catenane complexes reported by Beer, which consist of interlocking Cu(II) and Cu(III) rings (Figure 19b) [150]. While there is disorder between the Cu(II) and Cu(III) centres in the solid-state, magnetic susceptibility and electrochemical measurements suggest that the tetranuclear catenane dications consist of alternating Cu(II)Cu(III)Cu(II)Cu(III) centres.

There is one example of a coordination dithiocarbamate complex containing Cu(I), Cu(II) and Cu(III) centres [151]. Octanuclear [Cu₈Br₇(S₂CNC₆H₁₂)₄] (Figure 20) results from the addition of CuBr₂ and Br₂ to [Cu(S₂CNC₆H₁₂)₂] in CHCl₃ and consists of two Cu bis(dithiocarbamate) subunits linked via a Cu₆Br₆ moiety, with a further bromide ion encapsulated within this sub-cluster. Inspection of the Cu–S distances shows that one is a Cu(II) [Cu–S(av) 2.3106 Å] and the second a Cu(III) [Cu–S(av) 2.2186 Å] centre. It is supported by a magnetic susceptibility of 1.49 μ_B at 300 K, consistent with one unpaired electron. Individual octanuclear clusters align head-to-tail via weak intermolecular interactions to generate a 1D coordination polymer. In the UV-visible spectrum, a broad absorption band at 1400 nm is attributed to inter-valence charge transfer from the Cu(II) to Cu(III) centre through the weak Cu-S bonds.

6. Other Copper Dithiocarbamate Complexes

There are a small number of complexes that contain the copper dithiocarbamate group that have not been covered above. While at first sight it might seem surprising that simple mixed-ligand complexes of the type [Cu(S₂CNR₂)(anionic-chelate)] are not known, this likely relates to the lability of the dithiocarbamate at the Cu(II) centre. For example, an obvious candidate would be [Cu(S₂CNEt₂)(acac)], which, while being briefly mentioned in the literature, full characterisation data are always missing. Indeed, while it is suggested to result, along with [Cu(acac)₂(S₂CNEt₂)], from the addition of [Cu(acac)₂] to R-S₂CNEt₂ in reversible-reactivation radical polymerisation reactions [152], the authors could find no evidence for such species in the reactions of [Cu(acac)₂] with tetramethyl thiuram disulfide. The mixed-ligand Cu(I) complex [Cu(κ₁-S₂CNC₄H₈)(κ₂-SeS₂CNC₄H₈)][PPh₄] is an unexpected products of the reaction of [Cu(S₂CNC₄H₈)₂] with [WSe₄][PPh₄]₂ [153]. It formally results from the insertion of selenium into one of the Cu-S bonds, but this is coupled with electron-transfer and the dithiocarbamate is monodentate. This is surprising as insertion of the isoelectronic NTos group affords Cu(II) complexes [74,75].

As far as we are aware, the only well-characterised examples of mixed-ligand Cu(II) dithiocarbamate complexes are 5-coordinate species containing the unsaturated dinitrogen ligands, 2,2′-bipy or 1,10-phen [154,155,156,157], an example being [CuI(S₂CNMe₂)(2,2′-bipy)] (Figure 21a) [154]. Synthetic methods are not always clear as much of this work has appeared in crystallography journals, but [CuI(S₂CNMe₂)(2,2′-bipy)] is prepared by the co-addition of NaS₂CNMe₂ and 2,2′-bipy to [Cu(OAc)₂] in the presence of NaI. All contain a distorted square pyramidal centre with the halide (normally iodide) in the apical position. An unusual variation of this structural motif is PbI₄[Cu(S₂CNMe)(bipy)]₂ formed in low yields upon the addition of PbI₂, NaS₂CNMe₂ and 2,2′-bipy to Cu(OAc)₂ in DMF [158]. Here, two [CuI(S₂CNMe₂)(2,2′-bipy)] sub-units are formally linked via a linear PbI₂ moiety (Figure 21b).

A second group of complexes are sulfide- or selenide-bridged clusters of either vanadium [159,160] or molybdenum-tungsten [161,162,163,164,165], which incorporate between one and four Cu(II) dithiocarbamate moieties. The group 6 clusters result upon the addition of [ME₄]²⁻ (E = S, Se; M = Mo, W) to CuX in the presence of dithiocarbamate salts, with the precise cluster generated being dependent upon the ratio of metal ions. For example, with [MoS₄]²⁻ and CuCl in a ca.1:2 ratio and a slight excess of NaS₂CNMe₂, trinuclear [MoCu₂(μ-S)₄(S₂CNMe₂)₂]²⁻ results (Figure 22a) [165]. These reactions have been shown to proceed via the initial formation of copper halide clusters, with later substitution of the halide for the chelating dithiocarbamate as shown in the synthesis of pentanuclear [WCu₄(μ₃-Se)₄(S₂CNEt₄)₄]²⁻ (Figure 22b) [163]. In the solid state, the geometry around the copper centre is a highly distorted tetrahedron, consistent with Cu(I) centres. Electrochemical measurements also support this assignment with tetranuclear [MoCu₃(μ-S)₄(S₂CNMe₂)₃]²⁻ showing two quasi-reversible oxidations in MeCN [165]. There is one example of a higher nuclearity cluster being generated from these reactions, namely [Mo₂Cu₅S₂(μ₃-S)₆(S₂CNMe₂)₃]²⁻ [166]. It has a fused defective cubane skeleton and can be envisaged as consisting of two MoCu₂S(μ₃-S)₃ linked by a shared copper atom. Two of the dithiocarbamates bridge the copper centres while the third is chelating.

Similar reactions with [VS₄]³⁻ lead to theformation of [Cu(S₂CNR₂)₂] resulting from oxidation of the Cu(I) centre, attributed to the higher oxidative ability of [VS₄]³⁻ as compared to [MS₄]²⁻ (M = Mo, W). The addition of NaSPh to the mixture allows for the isolation of a range of mixed dithiocarbamate-thiophenolate such as [VCu₄(μ-S)₄(SPh)₂(S₂CNR₂)₂]³⁻ (Figure 22c), proposed to result from the concurrent addition of Cu(SPh) and Cu(S₂CNR₂) fragments to [VS₄]³⁻ [160]. The solid-state structures closely resemble those of the group 6 clusters, but in solution, there is evidence of the disproportionation of [VCu₄(μ-S)₄(SPh)_4−n(S₂CNR₂)_n]³⁻ (n = 1, 2), and electrochemistry shows only irreversible redox behaviour.

7. Applications as Single-Source Precursors (SSPs) to Semi-Conducting Nanomaterials

Many methods have been explored for the preparation of nanoscale copper sulfides, and the thermal decomposition of copper-dithiocarbamate single-source precursors (SSPs) via cleavage of relatively weak C–S bonds provides a simple and tuneable route to pure phase materials of different stoichiometries and morphologies [167]. In addition, dithiocarbamates themselves can act as capping agents, thus providing a physical barrier between interparticle interactions, thereby preventing agglomeration, which are particularly important as the nanoscopic properties of materials are optimised [168]. The thermal behaviour of copper dithiocarbamates is dependent on the reaction environment. Under nitrogen, it proceeds via dithiocarbamate loss to give copper sulfide residues, while in air, nonstoichiometric oxygen uptake leads to the formation of copper oxide(s). Oxidation of sulfur-containing species has also been identified at higher temperatures, resulting in the formation of sulfide, with subsequent oxidation to sulfate being followed by decomposition of the sulfate to oxide [169]. Copper dithiocarbamates have, therefore, been extensively utilised in the synthesis of both binary and ternary copper sulfides under inert atmosphere.

7.1. Binary Copper Sulfides

Copper sulfides are widely studied as a result of their application in areas such as optical filters, solar cells, photovoltaics, optical imaging and super-ionic materials [170]. They exist in a variety of stoichiometric phases ranging from copper-rich (Cu₂S) to sulfur-rich (CuS) phases, with a phase-dependent direct/indirect bandgap in the range of 1.1–2.0 eV. Some stoichiometric-dependent properties of Cu_2−xS include plasmonic absorption, observed in the non-stoichiometric phases around the IR region, and electrical conductivity, which decreases from copper-poor to copper-rich stoichiometries [171]. These wide variations in optical and electrical properties also account for the versatility of Cu_2−xS in different applications. The use of copper dithiocarbamates as SSPs for the synthesis of Cu_2−xS offers a simple and tuneable route to the synthesis of various stoichiometries through the choice of metal complex and reaction system.

There are a number of deposition strategies, the simplest being the heating of the SSP in the solid state. [Cu(S₂CNEt₂)₂] melts at ca. 200 °C and decomposes at 230–300 °C [63], and upon increasing the length of the alkyl chain, some small changes in volatility result [7]. Introduction of fluorine, as in [Cu(S₂CN(CH₂CF₃)₂)], significantly reduces the decomposition temperature to 130 °C and this SSP has been used to deposit high-quality, phase-pure, chalcocite films [172]. For thermal decomposition of the solids, the sulfide product has been reported to depend upon the nature of substituents, but most likely it is the temperature that is the key differentiator. For example, decomposition of [Cu(S₂CNOct₂)₂] at 130 °C affords CuS, but at 220 °C pure Cu_1.8S results, highlighting the reduction of Cu(II) at temperatures above 200 °C [173]. Interestingly, when the SSP is damp, microspheres of CuS result at 180 °C, being rationalised by the co-evaporation of water, which creates the central cavities around which the CuS nucleates. The SSP can also be pre-dissolved in a coordinating solvent and then deposited from this solution. Using this approach, trioctylphosphine (TOP) solutions of [Cu(S₂CNEt₂)₂], when heated TO 240–250 °C, deposited hexagonal nano-barrels of Cu₂S (chalcocite) onto Si(100) substrates [174]. Interestingly, they found that the morphology of the nanomaterials could be changed to nanowires, upon first sequentially depositing layers of chromium (2 nm) and bismuth (12 nm) onto the Si(100) substrate, and then decomposing the TOP solution of [Cu(S₂CNEt₂)₂] at 250 °C.

Copper sulfide materials with small dimensions show quantum dot (QD) behaviour, which makes them attractive materials for a range of imaging techniques. Burda and co-workers have reported that decomposition of [Cu(S₂CNEt₂)₂] (in the presence of added sulfur) in a trioctylphosphine (TOP)/TOPO mixture at 250 °C gives Cu_1.8S QDs with a band gap of 2.35 eV, being significantly blue-shifted with respect to the bulk material [175]. The size and shape of these nanomaterials were not given, but Qian and co-workers later reported that a similar decomposition of [Cu(μ³-S₂CNEt₂)]₄, at 110 °C for 12 h in a mixture of oleylamine (OLA) and dodecanethiol (DDT), gave ultra-thin nanowires of chalcocite [176]. By controlling the decomposition conditions (temperature and solvent ratios) they were able to generate nanowires with diameters ranging from 1.7 nm to tens of micro-meters, being aligned in bundles. Alivisatos and co-workers also developed this method forming [Cu(μ³-S₂CNEt₂)]₄ in situ in OLA/DDT at 180 °C to generate hexagonal nanocrystals of chalcocite of 5.4 (±0.4) nm [177]. Further, by varying the copper to ligand ratio they were able to produce mono-disperse Cu_1.93S QDs with sizes ranging 2.5–6 nm [178].

In order to improve the biocompatibility of copper sulfide materials, water-soluble dithiocarbamate complexes with moieties capable of acting as capping agents for the prepared nanoparticles have been explored. These complexes could be thermolysed hydrothermally at relatively low temperature and without employing any organic passivating agent. In this way, thermolysis of [Cu{S₂CN(CH₂OH)₂}₂] in water at 90 °C produces CuS nanospheres with a diameter of 8 ± 1 nm, showing a surface plasmon resonance at ca. 990 nm [31], and to demonstrate their potential therapeutic utility, their photothermal effect was measured using a 785 nm laser. An increase of 15.1 °C over 3 min was found, but this led only to a 2% loss of cervical cancer (HeLa) cells being observed after 24 h exposure in water. Decomposition of [Cu(S₂CNEt₂)₂] in 6-amino caproic acid also gives water-soluble nanoparticles, but now of digenite phase (Cu₉S₅) [179], and irradiation with a 980 nm laser led to a temperature increase of 15.1 °C in 7 min. These nanomaterials have potential applications in photodynamic therapy, although for Cu₉S₅ the photothermal conversion efficiency is likely too low.

High boiling primary amines, especially oleylamine (OLA, bp 364 °C), have been widely used as media in the decomposition of copper dithiocarbamates. This was first reported by Hu and co-workers who decomposed [Cu(S₂CNEt₂)₂] in OLA at 300 °C, to generate OLA-capped Cu₉S₅ nanocrystals with a diameter of ca. 70 nm and athickness of ca. 13 nm [179]. The phase is highly sensitive to the experimental conditions used and, thus, decomposition of the same SSP in OLA/oleic acid (OA) mixtures at 280 °C gives Cu_7.2S₄ with a mean diameter of ca. 20 nm from the decomposition of [Cu(S₂CNEt₂)₂] [180]. More recently, Botha and Ajibade [181] used the hot-injection method to decompose [Cu(S₂CNC₅H₁₀)₂] in OLA and isolated pure phases of CuS and Cu₉S₅ at 180 to 220 °C, respectively. CuS can also be obtained upon decomposing [Cu(S₂CNC₄H₈X)₂] in OLA (X = NPh) [182] or octadecylamine (X = S) [183], and Motaung et al. [184] reported the synthesis of Cu₇S₄ upon thermolysis of [Cu(S₂CNBuPh)₂] in OLA. Wang and co-workers studied the decomposition of the longer-chain SSP, [Cu(S₂CNBu₂)₂], injecting it into a mixture of OLA and OD (2:3) with added DDT (0.8 equiv.) at 190 °C to afford Cu₇S₄ nanocrystals with an average diameter of 9 ± 1 nm [185].

Trindade and co-workers have decomposed both [Cu(S₂CNEt₂)₂] and [Cu(S₂CNBu₂)₂] at 240 °C in ionic liquids, obtaining digenite (Cu₉S₅) nanocrystals, as opposed to covellite, which was formed at the same temperature in OLA [186]. Solvothermal process was recently utilised to decompose [Cu(S₂CNMePh)₂] in OLA. At temperatures below 240 °C, a mixture of CuS and Cu₉S₅ resulted, but above 240 °C pure Cu₉S₅ was formed (Figure 23). Oleylamine was used as the capping agent and the phase selectivity for the Cu₉S₅ phase was attributed to its increased tendency, at high temperature, to drive the reaction towards the copper rich phase [187].

Copper(II) bis(dithiocarbamates) have also been exploited for the introduction of copper as a dopant in metal sulfides [188], resulting in improved charge carrier concentration and current conductivity. Two examples are the preparation of Cu-doped FeS₂ [189] and Cu-doped SnS [188]; bandgap modulation was achieved by varying the percentage of copper. In an attempting to form doped metal sulfides using the SSP route, it is important that all precursors decompose within a similar temperature range, as this allows for their simultaneous decomposition ensuring that dopant levels can be controlled by varying SSP stoichiometries.

The decomposition mechanism of copper dithiocarbamates has not been extensively studied and, thus, we look to related systems for direction. The decomposition of [Ni(S₂CNR₂)₂] in primary amines has been shown to proceed by the initial coordination of the amine to form five or six coordinate adducts [190]. Following this, and at higher temperatures, amide exchange occurs with [Ni(S₂CNR₂)₂] converting to [Ni(S₂CNHR₂)₂], and it is these primary amine derivatives that decompose via deprotonation and loss of isothiocyanate [191]. While this decomposition pathway has not been proved for analogous Cu(II) bis(dithiocarbamates), the structural similarly between d⁸ [Ni(S₂CNR₂)₂] and d⁹ [Cu(S₂CNR₂)₂] make it tempting to suggest a similar mechanism operates for copper. Likewise, for [Fe(S₂CNR₂)₃], the initial amine coordination is followed by an intramolecular electron transfer to generate [Fe(S₂CNR₂)₂] and half an equivalent of the oxidised form of the dithiocarbamate, namely thiuram disulfide (R₂NCS₂)₂ [192]. Thus, while reduction of Ni(II) to Ni(I) is unfavourable, reduction of [Cu(S₂CNR₂)₂] occurs at low potentials and thus Cu(I) species may also be prevalent. Indeed, a number of authors report an initial conversion of brown solutions to yellow, with this colour change being associated with the formation of Cu(I). These two potential decomposition pathways are summarised in Figure 24. Importantly, in the amide-exchange process at nickel, the zwitterionic adducts are shown to be transition states, and not adducts as has been erroneously suggested by some authors [182].

7.2. Ternary Metal Sulfides

Copper dithiocarbamates have been used as SSPs to prepare a range of ternary metal sulfides, the most important of which is copper indium sulfide, CuInS₂. This is a semiconductor with a bandgap (bulk) of ca. 1.45 eV, and its high absorption coefficient in the visible region, exceptional radiation hardness and a pronounced defect tolerance, make it suitable for a range of applications. Further, the metals can be adjusted to fine-tune the properties of the material; when the Cu:In ratio is <1, they display n-type semiconductor properties, while when >1 they are p-type semiconductors. The Bohr exciton radius of CuInS₂ is 4.1 nm, and quantum confinement effects can be observed in nanocrystals of up to ca. 8 nm. At room temperature, CuInS₂ adopts the chalcopyrite structure, but at elevated temperatures, a random distribution of cations is thermodynamically favoured, leading to the zinc blende structure at >980 °C, and wurtzite at >1045 °C. A range of copper and indium dithiocarbamates have been used in the synthesis of CuInS₂. A synthetic challenge arises from the different Lewis acidities of hard In(III) and soft Cu(I). For this reason, the dithiocarbamate SSP approach is extremely useful since both [In(S₂CNR₂)₃] and [Cu(S₂CNR₂)₂]/[Cu(S₂CNR₂)]₄ are easily prepared and handled, and they show similar solubility and decomposition profiles in a range of coordinating solvents.

The SSP approach to CuInS₂ was first reported by Cui et al. who decomposed mixtures of [In(S₂CNEt₂)₃]/[Cu(S₂CNEt₂)₂] in ethylenediamine (en) at 195 °C [193], and soon after, O’Brien prepared thin films of CuInS₂ on a range of substrates by aerosol-assisted chemical vapor deposition (AACVD) at 250–500 °C of [Cu(S₂CNMeHex)₂]/[In(S₂CNMeHex)₃] [194]. While pure chalcopyrite films can be produced, the ratio of the two SSPs must be carefully controlled, with indium-rich mixtures affording β-In₂S₃ as the major product, while copper-rich precursors give mixtures of Cu_1.75−2S and CuInS₂. In 2008, Yang, Lu and co-workers developed a simple method to produce CuInS₂ nanomaterials with both the zinc blende and wurtzite structures [195]. This involves injection of [In(S₂CNEt₂)₃]/[Cu(S₂CNEt₂)₂] into OLA at 200 °C and affords CuInS₂ within minutes. The phase can be adjusted by adding different capping agents to the decomposition mixtures; with oleic acid, the zinc blende phase results, while with DDT, the kinetically metastable wurtzite phase is generated. Further, by simply varying the ratio of the two SSPs the stoichiometry of the zinc blende particles can be controlled in the range Cu₃InS_3.1 to CuIn_2.2S_3.8, and the size of the nanocrystals can also be adjusted by varying the temperature and the amount of OLA. Other copper dithiocarbamates can also be used as SSPs. For example, wurtzite CuInS₂ nanocrystals have been prepared in OLA at 200 °C using [Cu(S₂CNBu₂)₂] [196], while the indium source can also be varied to afford mixtures of wurtzite and chalcopyrite phases, which show dual emission in the visible (600–700 nm) and near-IR (700–800 nm) [197]. The decomposition of mixtures of [Cu{S₂CMe(CH₂CH₂OH)}₂] and [In{S₂CMe(CH₂CH₂OH)}₃] affords ternary nanoparticles (CuInS₂) of the wurtzite phase. A study of their electrochemical properties using cyclic voltametric, square-wave voltammograms and electronic impedance spectroscopy showed that the nanoparticles exhibited good electrocatalytic activities and could be useful in areas such as photovoltaics [198]. The use of copper dithiocarbamates as SSPs to CuGaS₂ has been less widely studied, but methods used broadly follow those described above for indium, using [Ga(S₂CNR₂)₃] as a precursor [194].

While the formation of these materials is clearly a multi-step process, some mechanistic insight has been elucidated. Upon heating [Cu(S₂CNEt₂)₂] and [In(S₂CNEt₂)₃] in OLA/DDT mixtures at 180 °C, after a few minutes the solution changes from yellow to brown, with this being associated with the formation of Cu_1.75S [199]. This acts as a catalyst for the growth of CuInS₂ nanoribbons, which have tips of Cu_1.75S. The tip size is ca. 10–15 nm in the initial stages of nanoribbon growth but increased to ca. 20–40 nm in the final stages. The produced CuInS₂ nanoribbons are 2–3 μm by 20–50 nm and have a ripple-like structure resulting from bending strain. Wurtzite CuInS₂ nanowires can also be prepared using other catalytic centres, for example Ag₂S, which is rapidly generated upon adding [Ag(S₂CNEt₂)]₆ to the reaction mixture [200]. It has been suggested that the high mobility of the group 11 cations promotes the formation of Cu⁺/Ag⁺ vacancies in the first-formed M₂S nanoparticles, which facilitates diffusion of molecular copper and indium species into M₂S to reach supersaturated states. Nanospheres and nanopencils of CuInS₂ can also be prepared. For example, heating [Cu(S₂CNEt₂)₂]/[In(S₂CNEt₂)₃] in OLA/DDT at 200 °C gives wurtzite nanopencils with diameters of 10 nm and lengths of 55 nm, one end of which is narrowed to a point [201]. Adding the chelate 1,10-phenathroline changes the morphology, so-called tadpole-like structures resulting with lengths of 140 nm and diameters of 25 nm. High resolution transmission electron microscopy (HRTEM) shows that growth of the nanopencils is along the (001) direction, and it is suggested that 1,10-phen may disrupt this growth process.

An alternative strategy is to incorporate copper and indium into the same SSP as championed by Nomura and co-workers, who prepared heterobimetallic complexes, such as [ⁱBu₂In(μ-SPr)Cu(S₂CNBu₂)] from the reaction of [ⁱBu₂InSPr] and [Cu(S₂CNBu₂)₂], and used them to prepare thin films of CuInS₂ [201,202]. The heterobimetallic complexes were not fully characterised and this approach has not been widely developed until recently when Nowotny, Schneider and co-workers prepared and crystallographically characterised [(Ph₃P)₂Cu(μ-S₂C₂O₂)In(S₂CNEt₂)₂]. They showed that hot-injection of this SSP into OLA at 240 °C gave nanospheres of CuInS₂ with extremely small diameters (ca. 2 nm) [203].

Semiconductors CuInS₂ and ZnS can be combined to make novel functional materials, and the SSP approach is an effective route. For example, in 2009, Xu and co-workers reported that the simple decomposition of mixtures of [Zn(S₂CNEt₂)₂], [Cu(S₂CNEt₂)₂] and [In(S₂CNEt₂)₃] in octadecane (OD)/OLA in the presence of capping agents could be used to access almost monodispersed nanocrystals of (CuInS₂)_x(ZnS)_1−x alloys over the entire composition range [204]. As with CuInS₂ alone, both zinc blende and wurtzite phases can be formed, being easily controlled by the judicious choice of a capping agent, as shown for pure CuInS₂ [205]. More complex materials can also easily be made, and by simply adding [Cd(S₂CNEt₂)₂] to the decomposition mixture, solid-solution nanocrystals of (CuInS₂)_x(ZnS)_y(CdS)_z can be accessed [206]. The morphology of these materials can also be tuned. The decomposition of mixtures of diethyl dithiocarbamate complexes in OA/DDT affords nanobelts of (CuInS₂)_x(ZnS)_1−x with lengths of ca. 3–5 μm and widths of 50–100 nm [207]. A study of the growth process of the nanobelts showed the initial formation of Cu_1.75S nanoparticles, presumably from the rapid decomposition of [Cu(S₂CNEt₂)₂]. These developed into nanowires by a solution–liquid–solid growth process, with matchstick-like structures observed in the early stages. Simply changing the reaction medium leads to the formation of alloys with very different morphologies, for example spherical (CuInS₂)_x(ZnS)_1−x nanocrystals of ca. 7.1 nm diameter with the zinc blende structure have been prepared through the in situ ethanolamine-derived SSPs in dimethyl formamide (DMF) at 180 °C [208].

Copper dithiocarbamates have also been used in conjunction with other metal dithiocarbamates including bismuth, tin, iron and antimony as dual SSPs for the synthesis of a range of ternary metal sulfides, including copper antimony sulfides (CuSbS₂, Cu₃SbS₄, Cu₁₂Sb₄S₁₃ and Cu₃SbS₃) [209], copper bismuth sulfides (Cu₃BiS₃, and Cu₄BiS₉) [210], copper tin sulfides (Cu₂SnS₃, and Cu₄SnS₄) [211] and copper iron sulfides (CuFe₂S₃ and Cu₅FeS₄) [18]. The unique chemical, physical and structural properties of these ternary copper sulfides makes them potential materials for optoelectronic devices such as solar cells [212], superconductors and sensors. These unique properties arise from the increased stoichiometric variation and possible synergy originating from the introduction of a third element into the structure of the metal sulfide [213,214].

Most researchers use [Cu(S₂CNEt₂)₂] as the copper source as detailed in the syntheses of Cu₃BiS₃, Cu₄Bi₄S₉ and Cu₃SnS₄, with different stoichiometries resulting upon variation of the precursor concentrations, temperature and solvent, and in some instances, the morphology can also be tuned [210]. Xu et al. reported the synthesis of CuSbS₂ and Cu₁₂Sb₄S₁₃ nanomaterials by varying the OLA/DDT solvent ratio, while maintaining a constant precursor ratio and reaction temperature [209]. The addition of 1,10-phenanthroline (phen) resulted in isolation of Cu₃SbS₃ stoichiometry, purportedly via the in situ formation of adduct [Cu(S₂CNEt₂)₂(1,10-phen)], although we note that this complex is not known and this more likely results from some selective metal chelation, which changes the metal–substrate ratio. Since these compounds exhibit stoichiometric and morphology-dependent optical and electrical properties, dithiocarbamate complexes of copper provides a facile route to their controlled syntheses. Co-thermolysis of [SnClBu(S₂CNMePh)] and [Cu(S₂CNEtPh)₂] in different molar ratios provides a simple route to a range of copper tin sulfides. Thus, with an equimolar ratio of the two SSPs, pure Cu₂SnS₃ results, but as the amount of [Cu(S₂CNEtPh)₂] is increased, secondary peaks are seen in the PXRD attributed to tetragonal Cu₂S and orthorhombic Cu₄SnS₄ [215].

A number of iron copper sulfides have been prepared from dithiocarbamate SSPs. Gupta and co-workers used the hot-injection of [Cu(S₂CNEt₂)₂]/[Fe(S₂CNEt₂)₃] into a solution of sulfur in OLA/TOP at 180 °C, to prepare nanocrystals of CuFeS₂ with an average diameter of ca. 12 nm [216], the morphology of which could be tuned from spherical to pyramidal, the latter resulting upon the addition of [Cu(acac)₂] (Figure 25a,b). Hogarth and co-workers reported that heating [Cu(S₂CNⁱBu₂)₂]/[Fe(S₂CNⁱBu₂)₃] in OLA at 230 °C gave spherical nanocrystals of ca. 11 nm in diameter, being slightly reduced upon the addition of ⁱBu₄-TDS to the decomposition mixture [217].

7.3. Quaternary Metal Sulfides

Copper-containing Cu₂ZnSnS₄ (CZTS) and Cu₂ZnSnSe₄ (CZTSe) are amongst the most widely studied quaternary semiconductors as they show potential for applications in thin film solar cells, having power conversion efficiencies of ca. 10%. Over the past decade, there has been many reports of the use of dithiocarbamate SSPs for the synthesis of CZTS thin films and QDs. The formation of quaternary (and multinary) sulfides via the SSP approach adds a further level of complexity with the reactivity of three or more components having to be considered, which can lead to issues of stoichiometric control, while there is also a tendency to generate a plurality of compositional phases in the early stages. Further, for thin film synthesis, the three precursors must have similar volatility and decomposition temperatures/profiles. For the diethyldithiocarbamate derivatives of copper, zinc and tin, their decomposition occurs at 220, 240 and 174 °C, respectively, and the low value of the latter may lead to the initial formation of SnS. O’Brien and co-workers thus utilised the higher decomposition temperature of [Sn(S₂CNBu₂)₄] (300 °C) to form a suitable SSP mixture [218] for the first AACVD synthesis of CZTS thin films. They deposited these at 360 °C to obtain films of kesterite ca. 690 nm thick, which could be increased to 1.15 μm at 400 °C, with optical bandgaps varying at 1.3–1.5 eV. CZTS thin films can also be prepared from dithiocarbamate SSPs nanoparticles via the initial formation of nanoparticles upon initial decomposition in OLA followed by drop-casting toluene suspensions of these onto substrates, with films of up to 10 μm being accessible [219]. Another approach is to aerosol spray toluene solutions of the diethyl-dithiocarbamate complexes onto a hot substrate at ca. 400 °C, which gives thin films comprised of nanoplatelets of CZTS. Further studies have shown the initial formation of a copper-rich phase and this promotes later anisotropic growth [220]. In solvothermal syntheses from OLA/DDT, the initial formation of Cu₂S nanoparticles has also been observed, and these in turn catalyse the growth of CZTS [221]. Thus, a consistent picture emerges whereby the copper dithiocarbamate SSP decomposes first, and the generated copper sulfide catalyses later decomposition processes.

As shown in Figure 24, it is postulated that primary amine complexes [Cu(S₂CNHR)₂] are key intermediates in the formation of copper sulfides. These appear to be unstable, and to date, no well-characterised examples have been reported. They may be generated in situ and it has been reported that the addition of CS₂ to the primary amine solution containing copper, zinc and tin salts and spin-coating the mixture onto substrates, then heating at 320 °C for a few minutes affords thin films of CZTS [222,223]. This suggests that [M(S₂CNHR)_n], including [Cu(S₂CNHR)₂], are generated but rapidly decompose. The quality of the films is dependent upon the nature of the amine dependent upon the amine; with ethanolamine giving the best-quality films. These results suggest that both the rates of formation and decomposition of [Cu(S₂CNHR)₂] (and tin and zinc) complexes are likely substituent dependent. Further studies into this exciting discovery are eagerly awaited.

8. Biological Applications

Copper is an essential element for most aerobic organisms, being present in metalloproteins and metal-labile pools [224], and consequently, copper homeostasis is critically important to normal human physiology. This is exemplified by the life-threatening impact of copper deficiency and overload associated with Menkes and Wilson’s disease, respectively [225,226]. The biological effects of dithiocarbamates centre on their ability to exert both pro-oxidant and antioxidant effects [227], while their high metal-chelating ability allows them to modulate the active sites of many metal-containing proteins [228]. In addition, the free thiol groups may also interact with other molecules such as the sulfhydryl groups. Thus, dithiocarbamates are able to inhibit enzymes and also oxidise glutathione by covalently interacting with free protein thiols [229] and glutathione peroxidase-like activity [230]. They can also affect cellular detoxification mechanisms due to their ability to subdue hepatic microsomal process of drug metabolism [231] and also suppress glutathione S-transferases [232].

Given the biological importance of copper and the use of tetraethyl thiuram disulfide (Disulfiram) since the 1950s as a drug used in alcohol aversion therapy [233,234,235], then it is not surprising that copper dithiocarbamates, especially [Cu(S₂CNEt₂)₂], have been widely studied in a biological context. Thus, it has been shown that free Cu(II) interacts with disulfiram to afford [Cu(S₂CNEt₂)₂] in high yields, a transformation accompanied by the oxidative decomposition of small amounts of disulfiram [236,237]. While disulfiram itself has little effect on cancer cells, in the presence of Cu(II) IC₅₀, values in the nanomolar range have been found against a number of cancer cell lines, and consequently copper-dithiocarbamates have been widely studied in a biological domain, particularly as anticancer agents. Copper dithiocarbamates are able to alter cancer cell metabolism and, in addition, their ability to selectively respond to normal and tumour cells differently forms the basis of their development as complexes with antineoplastic properties [238]. Using complexes derived from biologically active amines suggests potential for both metal and ligand interference with a pathogen’s life cycle [239]. In accordance with Tweedy’s theory, metal complexes would exhibit greater biological activity than the corresponding ligand, with this being attributed to increased π-electron delocalisation in the chelate ring. Chelation results in a reduction in the polarity of metal ions, which enhances the lipophilic nature of chelates and ultimately improves penetration of the lipid layer of the microbial cell membrane and blocking of enzyme metal binding sites [240].

8.1. Anticancer Agents

Cancer cells have a high copper demand for their maintenance, proliferation and metastasis. While platinum complexes are the most widely developed metal-based anticancer agent [241], platinum resistance has led to the consideration of other metals, especially copper [242], complexes of which have been found to induce cancer cell death through the generation of reactive oxygen species (ROS), and by proteosome inhibition. Especially in respect of the latter, copper dithiocarbamates have shown promise in preclinical studies [243]. Detailed molecular mechanisms underlying their anticancer activity remain largely unknown, but mechanistic studies have shown that they can act as DNA intercalators [244], proteasome inhibitors [245], inhibitors of nuclear factor kappa B (NF-κB) [246] and are also able to inactivate numerous metal-containing enzymes [247].

As stated above, disulfiram alone has poor anticancer activity but does have the ability to transverse biological membranes, including the blood–brain barrier. It is also easily reduced to the dithiocarbamate by glucose reductase. Disulfiram is, nevertheless, an extremely active anticancer agent in the presence of copper ions. It does not form a stable complex with Cu(II), but the two react rapidly to afford [Cu(S₂CNEt₂)₂], a process that requires a small stoichiometric excess of disulfiram, and [Cu(S₂CNEt₂)₂] has been identified in the brains of mice fed with disulfiram [62]. O’Brien has proposed a mechanism for this, which involves the initial reduction of Cu(II) to Cu(I) with concomitant formation of bitt-4²⁺, the oxidised form of disulfiram [237] (Figure 26). The bitt-4²⁺ is unstable and undergoes a catastrophic decomposition, which leads to the formation of 30 electrons per molecule and leads to oxidative stress on cells [236]. This likely accounts for the massive cell death observed when exposed to disulfiram-copper mixtures [248,249]. Biological detection of [Cu(S₂CNEt₂)₂] is usually made by EPR [62] but, recently, mass spectrometry has also been used to detect this complex in A549 cell [250].

[Cu(S₂CNEt₂)₂] is also an effective anticancer [236,248,251,252,253,254,255,256] especially in vitro as are many derivatives [36,37,257,258,259,260,261,262]. This was first established for pyrrolidine dithiocarbamate, which exhibits high potency to inhibit a cancer-specific proteasome, showing a cytotoxic effect on different human tumour cells after complexation with copper. Generated [Cu(S₂CNC₄H₈)₂] has also been reported to induce cellular apoptosis in both prostate and human breast cancer cells [257,263] and is a potential treatment for refractory neuroblastoma in children. Zhang et al. [264] have reported suppression of the proliferation of BE(2)C cells (a human neuroblastoma cell line) using this complex, having a higher potency than cisplatin based on IC₅₀ values. The treatment of cancer cells resulted in an arrest of cell cycle progression and cellular apoptosis. Investigation of a series of substituted pyrrolidine complexes has allowed a structure–activity association [265,266]. Thus, both the ligand polarity and ring size affect the activity, with the proteasome-inhibitory ability being significantly decreased upon ring substitution by large and polar groups [266]. Furthermore, Wang et al. have reported that some pyrrolidine derivatives exhibited less inhibition activity of aldehyde dehydrogenase (ALDH) in human breast cancer cells [265].

The activity of [Cu(S₂CNEt₂)₂] against osteosarcoma cancer lines has been measured, showing IC₅₀ values of 2.37 ± 0.12 μM after 24 h, while analogous Fe(III) and Cr(III) complexes were inactive and Mn(III) had higher IC₅₀ values of 13.3 ± 1.43 μM [262]. Higher levels of ubiquitin-bound proteins were observed by cells treated with [Cu(S₂CNEt₂)₂] and the accumulation of proteasome substrate IĸBα. Apoptosis of the cancer cell was observed to proceed by the activation of caspases 3 and 7, which resulted in cleavage of PARP-1 into smaller fragments. The anticancer activity of copper dithiocarbamate complexes can be tuned by varying substituents tuning both structural and electronic properties. This was observed in the study on the antiproliferative activity of two copper complexes of dithiocarbamate glycoconjugates (glucose and galactose) on human cancer cell lines [267]. A four-fold increase in activity was observed as compared to the free ligands. Their activity was also influenced by the nature of the glycoconjugates, with the galactose-based complex showing higher antiproliferation activity as compared to glucose. Further, they exhibit higher activity than related zinc complexes, and the activity of the glycoconjugates is correlated with their hydrophilicity, which determines their ability to move across cell membranes.

A major barrier towards the development of [Cu(S₂CNEt₂)₂] and related complexes derived from non-polar secondary amines is their extremely poor water solubility (<1 mg mL⁻¹). There are a number of possible ways around this, one being to co-deliver disulfiram and Cu(II) such that they react and generate [Cu(S₂CNEt₂)₂] within the tumour microenvironment [268,269,270]. This can be done in a number of ways, the most common being the incorporation of disulfiram and Cu(II) into a polymeric nanoparticle, for example as reported by Pu and co-workers who used a poly(ethylene glycol) (PEG)-b-poly(ester carbonate) (PEC) composite [270]. They established in vitro anticancer activity, although interestingly, loading the nanoparticles with pre-formed [Cu(S₂CNEt₂)₂] gave higher antitumor efficacy. A related approach is the in situ generation of [Cu(S₂CNEt₂)₂] from a prodrug, for example from an enzyme-activatable dithiocarbamate [271,272]. The prodrug was obtained by conjugating the dithiocarbamate through a leucine spacer and a p-aminobenzyl (pAB) linker to the C-terminus of peptides, cleavage of the prodrug obtained from the peptide sequences Arg-Ser-Ser-Tyr-Tyr-Ser-Leu-pAB-DTC and His-Ser-Ser-Lys-Leu-Gln-Leu-pAb-DTC, respectively (point of cleavage indicated by wavy lines) resulting in the generation of [Cu(S₂CNEt₂)₂] (Figure 27).

As hinted above [270], another potential route to circumvent the low water solubility is the so-called Trojan horse approach, whereby the pre-formed copper complex is encapsulated into a vestibule. Approaches here include encapsulation in a polymer matrix [270], the aqueous core of liposomes [273], within hyaluronic acid nanoparticles [274,275] or apoferritin [276]. Related to this approach is an interesting report of stabilised metal ion ligand complex (SMILE) technology, whereby [Cu(S₂CNEt₂)₂] is embedded into nanoparticles comprised of various stabilising agents that are already approved as safe excipients by the UD Food and Drug Administration [277]. For example, PEG−PLA/[Cu(S₂CNEt₂)₂] nanoparticles show excellent stability with only a minor loss of copper concentration after 30 days but have good activity (nanomolar) against drug-resistant DU145-TXR cells. Light-triggered [Cu(S₂CNEt₂)₂] release has also been developed using the Trojan horse approach [278,279], for example Liu and co-workers prepared vestibules from biocompatible phase-change materials incorporating a near-infrared (NIR) dye, thus allowing [Cu(S₂CNEt₂)₂] release upon irradiation with an NIR laser [278].

Another approach is to modify the dithiocarbamate substituents to give enhanced water solubility, although changing these inevitably affects anticancer activity. Fregona and co-workers have utilised proline-derived complexes (Figure 2e) with some water (and DMSO) solubility [40,41]. Their activity is improved by supporting them on a non-ionic block copolymer, with the encapsulated copper complex showing enhanced stability, bioavailability and water solubility. Some of these complexes have shown comparable activity to standard drugs, with few showing higher activity when compared to standard anticancer drugs [259]. Carbohydrate-functionalised complexes have also been prepared and studied by Fregona and co-workers, and an example (CuGlu) is shown (Figure 28) [37]. They have enhanced water solubility, and CuGlu shows an interesting IC₅₀ value toward the HCT116 human colorectal carcinoma cell line, although related complexes bearing two diastereomers of D-glucose did not show any cytotoxic properties.

The mode of action of [Cu(S₂CNEt₂)₂] has been widely studied and reviewed [61]. It functions as a proteasome inhibitor, inducing apoptosis by specifically targeting the ubiquitin-proteasome pathway (UPP) [280,281,282]. Due to the role of UPP in the control of the expression, activities and location of various proteins, a potential strategy in the development of anticancer agents has been found in the selective suppression of proteasome and apoptotic induction in cancer cells. Recently, the p-97-NPL4-UFDI protein has been identified as a target for [Cu(S₂CNEt₂)₂], being proposed that this leads to accumulation of ubiquitinated proteins leading to a heat shock response [62]. Induction of apoptosis in neuroblastoma cells by [Cu(S₂CNEt₂)₂] has been shown to result from increasing levels of intracellular copper concentrations, which triggers the release of cytochrome c and capase activation [253], and it has also been shown to be an activator of Nrf2 in cultured vascular endothelial cells [283].

8.2. Antimicrobial, Antibacterial, Antioxidant and SOD-like Activity

Antimicrobial and antibacterial properties of dithiocarbamate complexes, including those of copper, have recently been reviewed by Tiekink and co-workers [284] and hence this section will cover only a brief overview of selected examples. Antimicrobial resistance is a major societal problem, with increasing resistance to so-called last-resort antibiotics such as carbapenems being of particular concern. Metallo-β-lactamases (MβLs) hydrolyse carbapenems, penicillins and cephalosporins, and consequently the inhibition of MβLs is a topic of considerable interest. In a recent communication, Yang and co-workers have shown that both disulfiram and [Cu(S₂CNEt₂)₂] are potent MβL inhibitors [285]. While the former acts selectively on New Delhi metallo-β-lactamase (NDM-1) via covalently binding to the Cys208 residue leading to release of Zn(II), the copper complex is active at nanomolar levels against a range of MβLs, a process that does not lead to loss of Zn(II). The mechanism of action remains to be fully elucidated, but X-ray photoelectron spectroscopy (XPS) suggests that a reduction of Cu(II) to Cu(I) occurs, a process that has been associated with oxidation of a Zn(II)-thiolate centre in the active site of NDM-1. As the redox chemistry of the copper centre is easily tuned via judicious choice of dithiocarbamate substituents, this suggests that further work in this area should be highly productive.

Dithiocarbamate salts have been studied for the management and control of bacteria [286], and Cu(II) bis(dithiocarbamate) complexes also show antibacterial activity, although it is normally lower than that of the free ligand [287]. This is the case for [Cu(S₂CNC₅H₁₀O)₂], which shows moderate inhibitory activity against both Gram-positive and Gram-negative bacteria [287] and a small library of N’N-diarylformamidine-derived dithiocarbamates, the activity of which is influenced by the presence of chloro-substituents [288]. In contrast, Onwudiwe and Ekennia [24] have reported that the antibacterial activity of NaS₂CNEtPh is enhanced across a broad spectrum of the bacteria even after Cu(II) complexation. Further studies are required to ascertain if the activity of [Cu(S₂CNR₂)₂] simply relates to loss of free ligand, for example upon oxidation to Cu(II). The antibacterial activity of Cu(I)-phosphine complexes has also been explored, with [Cu(PPh₃)₂(S₂CN(R)CH₂CH₂OH)] being selective against Gram-positive bacteria (R = Cy, iPr) [127]. Related N,N′-diarylformamidine-derived dithiocarbamate complexes (Figure 2d) have also been investigated but show poor activity, possibly resulting from their inability to penetrate bacterial cell walls [289].

The release of hydrogen atoms close to the coordination core of metal complexes is responsible for the radical scavenging effect of metal complexes [290]. The presence of copper boosts the antioxidant activity of the ligands as their proton-donor capacity is enhanced, as does the presence of electron-donating groups at carbon [291,292]. The antioxidant activity of a series of copper dithiocarbamates has been reported by Oladipo et al. Using a standard assay, it was noted that their activity was significantly enhanced as compared to the free ligands [19]. Similarly, copper complexes with N’N-diarylformamidine dithiocarbamate ligands (Figure 2d) show enhanced antioxidant activity, being higher for those with symmetrical vs. unsymmetrical ligands [288]. The in vitro antioxidant activity of [Cu(S₂CNEtPh)₂] is also greater than that of the uncoordinated dithiocarbamate salt [24].

Superoxide dismutase (SOD) is a copper-containing enzyme that catalyses the conversion of superoxide to oxygen and peroxide via a Cu(II)–Cu(I) redox couple. The SOD-like activity of Cu(II) dithiocarbamate complexes has been extensively studied by Cao and co-workers [293,294,295,296,297,298] and others [267]. In order to enhance their water solubility, they prepared a range of cyclodextrin [293,297] and α-amino-acid [295] functionalised dithiocarbamates and their Cu(II) complexes. For the latter, structure–activity relationships were established between −log IC₅₀ values and the molar refraction of the amino acid substituents, and also the Cu(II)–Cu(I) redox potentials. The complex derived from l-glutamic acid showed especially high SOD-like activity interpreted on the basis of EPR spectroscopy to its distorted ground-state geometry [295].

8.3. Applications in Medical Imaging

Copper has several positron-emitting radionuclides, ⁶⁰Cu, ⁶¹Cu, ⁶²Cu and ⁶⁴Cu, with a range of half-lives that are suitable for applications in molecular imaging, and radiolabelling/biodistribution of ⁶²Cu-dithiocarbamate has been studied by an in vitro evaluation using non-radioactive Cu-glycine. ⁶²Cu forms stable and neutral dithiocarbamate complexes, with a brain accumulation that is much higher than that reported for ⁶²Cu-glycine [299]. ⁶⁴Cu emits a low-energy positron (0.65 MeV) that allows for high-resolution positron emission tomography (PET) imaging, and the relatively long half-life (12.7 h) enhances its application in preclinical studies and applications in which prolonged scanning (beyond 24 h) is required [300]. Hence, there is a growing interest in the use of the cyclotron-produced ⁶⁴Cu for diagnostic purposes [301]. Due to their ability to cross the blood brain barrier, lipophilicity, kinetic lability and potential to be easily absorbed and trapped in cells, both [⁶⁴Cu(S₂CNR₂)₂] RR = Me, Et) have been used as brain perfusion imaging agents [302],. Charoenphun et al. [303] reported their use in labelling a mouse macrophage cell line (J774), which showed enhanced efficiency dependent on the dithiocarbamate utilised. Thus, while [⁶⁴Cu(S₂CNMe₂)₂] exhibited the fastest and most efficient uptake, the rates of wash-out were too fast for in vivo imaging cell trafficking. The results were similar to other reported complexes of diethyldithiocarbamate and diphenyl dithiocarbamate, which suggest a rapid intracellular dissociation process.

Bifunctional dithiocarbamates, which incorporate bis(phosphonate) group(s), have been developed by de Rosales et al. [38] who prepared a dual-modality complex for medical imaging, utilising the high soft-tissue resolution of magnetic resonance imaging (MRI) and the sensitive signal of PET. The ⁶⁴Cu complex (Figure 2g) was synthesised and conjugated with superparamagnetic Fe₂O₃ nanoparticles as a Dual-Modality PET–MRI Agent. The ligand was designed to bind to Cu(II) through the dithiocarbamate, leaving the bis(phosphonate) ends free to bind to the surface of the Fe₂O₃ nanoparticle [304,305] (Figure 29) and was successfully used in a mouse model to image draining lymph nodes.

9. Other Applications

9.1. Removal of Cu(II) and Environmental Remediation

Due to continued increases in world population and industrialisation, environmental pollution presents a global challenge, and the identification and removal of inorganic and organic pollutants has become a major research area. The main area of environmental applications of dithiocarbamates concern the adsorption of metal ions, with the high binding constants for Cu(II) and aqueous insolubility of [Cu(S₂CNR₂)₂] making dithiocarbamates attractive reagents for the removal of Cu(II) [9]. The normal approach here is to functionalise cheap and highly stable materials such as lignin [306] and starch [307]. A similar approach can also be used to remove copper from pharmaceutical reaction media down to <10 ppm, with [NH₄][S₂CNC₄H₈] being most widely used [11]. Polymeric Cu(II) N,N′-bis(dithiocarboxy)piperazine ([CuBDP]_n) has been shown to be effective for the removal of Acid Red 73 from wastewater, with absorption being as high as 364 mg g⁻¹, being significantly better than either [Cu(S₂CNMe₂)₂] or [Cu(S₂CNEt₂)₂], which are able to absorb up to 37.8 and 42.9 mg·g⁻¹, respectively [308]. The Cu(III) complex [Cu{S₂CN(CH₂CH₂OH)₂}₂]₃[PW₁₂O₄₀] (Figure 30) shows high sono-catalytic activity for Rhodamine B dye degradation and a nanohybrid obtained from [Cu{S₂CN(CH₂CH₂OH)₂}₂], and H₃PW₁₂O₄₀ has high activity as an adsorbent for the removal of methylene blue, with 95% removal being achieved within 50 min [85].

9.2. Photovoltaic Cells

Dye sensitisation is an important technique in improving the efficiency of TiO₂-based solar cells, with potential alternatives to Si-based solar cells due to their ease of fabrication, low cost and adaptability [309]. Metal dithiocarbamate complexes have been explored as dye-sensitising agents because of their ease of functionalisation, which can lead to improved absorption and adsorption capacity of TiO₂. Additionally, the d⁹ electronic configuration of Cu(II) may facilitate agostic interactions, supramolecular architecture stabilisation and the formation of important intermediates [21]. Maner and co-workers [21] have reported the photosensitising activity of five Cu(II) dithiocarbamate complexes [21], with 4-N,N-diethylbenzyl-N-methyl substituents having the highest conversion efficiency of 3.62%, being comparable to values obtained from a standard ruthenium dye. The phot-sensitising activity of the complexes appears to depend primarily on structural features, interfacial charge recombination and electron lifetime. The activity of ferrocenyl-functionalised dithiocarbamates has also been reported [310], with their efficiency as photosensitisers depending upon the nature of the heteroaromatic conjugated linkers. Similarly, the dye-photosensitising ability of a ferrocenyl-substituted dithiocarbamate complex, possessing an –OH group to anchor onto the TiO₂ surface, was reported by Yadav [311]. Its activity is influenced by the nature of the absorption, dye-loading ability and the anchoring geometry of the complex. Compared to cobalt analogues, the efficiency of the copper complex is lower, however, but higher than related nickel species.

9.3. Applications in Organic Transformations and Homogeneous Catalysis

Over the past decade, a number of organic transformations have been shown to occur in the presence of copper ions (both Cu(I) and Cu(II)) and NR₂H-CS₂-base, conditions associated with the formation of [Cu(S₂CNR₂)₂] and/or [Cu(S₂CNR₂)]₄. As far as we are aware, the first of these was reported in 2011 by Ma and co-workers, who showed that mixtures of secondary amines CS₂ and K₂CO₃ in the presence of a range of stoichiometric amounts of copper halides efficiently affords 2-N-substituted benzothiazoles (Figure 31) [312].

Copper dithiocarbamates have not found widespread use in homogeneous catalysis, despite having many of the attributes associated with good catalysts such as a range of accessible oxidation states and coordinative unsaturation. While the reaction discussed above is formally catalytic, the amounts of copper used are near to stoichiometric; nevertheless, there soon followed a range of related transformations in which much smaller amounts of copper were utilised either in the presence of dithiocarbamates [313,314] or thiuram disulfides [315,316,317,318]. By way of example, Bolm and co-workers have reported that Cu₂O is an efficient catalyst for the formation of aryl dithiocarbamates from the coupling of thiuram disulfides and aryl iodides [315]. While mechanistic details have not been fully elucidated, one proposed route is via a Cu(II) species [CuAr(S₂CNR₂)], which undergoes reductive-elimination of the product. This seems unlikely, and a second radical-initiated route whereby reduction of Cu(I) affords aryl radicals, which subsequently add to the thiuram disulfide, seems more plausible. In closely related transformations, Cu(III) intermediates, [CuI(Ar)(S₂CNR₂)], have been postulated, with reductive-elimination regenerating Cu(I), and this seems at least plausible [316,317].

Copper dithiocarbamates have been implicated as catalysts in living free radical polymerisation reactions [152,319,320,321]. For example, in the presence of 2,2′-bipyridine and AIBN, [CuCl(S₂CNEt₂)Cl]₂ has been shown to catalyse the reverse atom-transfer radical polymerisation of vinyl monomers affording polymers with low polydispersity [152]. A likely catalytic species is [CuCl(S₂CNEt₂)(2,2′-bipy)] in which a dithiocarbamate radical shuttles between the copper centre and the developing polymer chain.

Both [Cu(S₂CNR₂)₂] and [Cu(S₂CNR₂)]₄ are active catalysts for the conversion of alkenes into aziridines using the hyper-valent iodine compound [PhI=NTs]_n as the nitrene source [75]. Reactions occur rapidly at room temperature in CH₂Cl₂ and are easily monitored by the dissolution of oligomeric [PhI=NTs]_n, which leads to the initially cloudy solution turning clear. Cu(I) complexes are the most active catalysts and Cu(II) also work, but [Cu(S₂CNR₂)₂][ClO₄] are inactive [322,323]. The mechanism remains unknown but may involve initial coordination of PhI=NTs to a Cu(I) centre. Unfortunately, their utility is stifled by a secondary reaction between catalyst and PhI=NTs, which leads to the formation of insoluble and catalytically inactive Cu(II) amides (Figure 8) possibly via the addition of NTs to sulfur followed by ring expansion.

10. Summary and Conclusions

In this review, we have attempted to give an overview of the coordination chemistry and various applications of copper dithiocarbamates. Some aspects of this work, such as the synthesis of Cu(II) bis(dithiocarbamates), [Cu(S₂CNR₂)₂], are very mature, and their ease of synthesis and robustness to a wide-range of variation in substituents means that they have found applications in a wide range of different areas, including materials science and medicine. Over the last decade, the most widely exploited application is their thermal decomposition to afford copper sulfides, the size, phase and morphology of which can be tuned via judicious choice of reaction conditions. This approach has been further extended to the synthesis of technologically important ternary and quaternary sulfides, most notably Cu₂ZnSnS₄ (CZTS), which results from the co-decomposition of copper, zinc and tin dithiocarbamates. Another important development is the realisation that [Cu(S₂CNEt₂)₂] is formed in the biological domain when the anti-alcohol drug disulfiram is taken, and that it shows anticancer behaviour, leading to detailed investigation of the biological role of Cu(II) bis(dithiocarbamates). While still not fully understood, there is strong evidence that it functions as a proteasome inhibitor, specifically targeting the ubiquitin–proteasome pathway and inducing apoptosis. A major problem with using [Cu(S₂CNEt₂)₂] and most other derivatives as drugs is their extremely low water solubility, and this is being addressed using a Trojan Horse strategy to deliver [Cu(S₂CNEt₂)₂] or to generate it in situ within the cell from reaction between Cu(II) ions and disulfiram. Thus, an “old” molecule finds new relevance bringing an “old” branch of coordination chemistry back to life. In doing the latter, over the past decade, a wide range of novel new Cu(I) dithiocarbamate clusters have been discovered. Their structures are novel, with some being in the nanoscale domain, and understanding how to control their specific size and shape, for example by using different dithiocarbamate substituents and/or other ancillary ligands to generate bespoke clusters in high yields, remains an exciting challenge. Given the widespread development of simple Cu(II) and Cu(I) complexes as SSPs to nanoscale copper sulfides, these clusters might be viewed as intermediates in this process or could be potential SSPs themselves, an area that appears to be totally unexplored to date. We look forward to these exciting new developments and hope that in 10–20 years a researcher scanning this review will find it useful background reading but quite out of date since the field will have moved on enormously.