The Chemistry of Polynuclear Silver N-Heterocyclic Carbene Complexes

Abstract

Polynuclear (tri-, tetra-, penta-, hexa-, polymeric-) silver N-heterocyclic carbene (Ag-NHC) complexes can be synthesized by reacting imidazolium salts (e.g., Cl, Br, PF₆) with Ag₂O, followed by anionic exchanges in some cases. The first polynuclear (tetra-) Ag-NHC complex was reported in 2002. Since then, these complexes have been explored in the literature for a variety of applications, including transmetallation, sensing, antimicrobial agents, and anticancer treatments, owing to their versatile properties. The labile silver-carbene bonds facilitate efficient ligand exchange with other transition metals such as Au, Cu, and Pd providing an efficient route to a variety of transition metal-NHC complexes with diverse applications. Tetranuclear Ag-NHC complexes that exhibit substantial fluorescence intensity have been used as sensors to detect persistent pollutants like 2,6-dichloronitroaniline with high sensitivity. Additionally, some trinuclear Ag-NHC complexes have demonstrated better antiproliferative activity than known chemotherapeutic drugs like 5-fluorouracil and cisplatin, highlighting the potential of these complexes as more stable and selective therapeutic agents. Overall, this review underscores the versatility of polynuclear Ag-NHC complexes across diverse fields, while emphasizing the importance of structural modifications to optimize their efficacy and minimize toxicity.

1. Introduction

The field of N-heterocyclic carbene (NHC) metal complexes has witnessed substantial development since Wanzlick's first mention of nucleophilic carbenes in 1962 [1], and his subsequent synthesis of the first NHC in 1963 [2]. The field took a significant leap forward a year later when Fischer and Maasböl transformed organometallic chemistry with the discovery of metal-carbene complexes [3]. In parallel, Bauman and Wang reported the first imidazole-silver (Ag) complex [4]. In 1968, Wanzlick [5] synthesized the first mercury and Öfele [6] the first chromium NHC complexes, marking another milestone in NHC chemistry. Years later, Arduengo succeeded in isolating the first stable NHC in 1991 [7]. Following this, he published the first mononuclear Ag-NHC complex in 1993 [8]. In 1995, Herrmann made significant strides by reporting the first reaction involving an NHC-metal (Pd) complex [9]. The following year, Lin observed an anomaly in the ¹³C NMR spectra of one of his mononuclear Ag-NHC complexes, leading him to suggest the potential for a dinuclear Ag-NHC complex [10]. However, it wasn’t until 2000 that Danopoulos fully characterized the first dinuclear Ag-NHC complex [11]. In 2023, Catalano reported the synthesis of the first trinuclear Ag-NHC complex [12], just a year after Lin documented the preparation of the first tetranuclear Ag-NHC complex [13]. Also in 2023, Zhang characterized the first polymeric Ag-NHC complex [14]. Early in 2009, Chen published an X-ray crystal structure of a pentanuclear Ag-NHC complex, which may represent a polymeric compound [15]. Most recently, Hahn and Peris [16] revealed the first hexanuclear Ag-NHC complex (Figure 1). These groundbreaking and pioneering reports have spurred a vast body of literature, with approximately 15,000 publications on NHCs, of which around 1,500 specifically address Ag-NHC complexes, and 89 publications delve into the characterization of polynuclear (3 or more Ag)-NHC complexes, as compiled from a SciFinder search and depicted in Figure 1.

Figure 1.

The history of polynuclear Ag-NHC complexes

This review focuses on the synthesis, characterization, and application of polynuclear (three or more Ag)-NHC complexes. While several examples of polynuclear Ag-NHC complexes have been reported in the literature, the majority of the articles have concentrated on tri- and tetra-, and only a few on penta-, hexa-, and polymeric Ag-NHC complexes, as described in the following sections. To provide a systematic and updated analysis of polynuclear Ag-NHC complexes, integrating structural features with catalytic and functional outcomes, and highlighting trends not previously compiled in a unified framework. These polynuclear Ag-NHC complexes have exhibited unique structural and reactivity characteristics. They serve as valuable intermediates in transmetallation reactions [17], facilitating the efficient synthesis of a diverse range of metal complexes[18–20]. Such transformations play a crucial role in the generation of catalytically active species for numerous synthetic and biological applications, including; hydrogen evolution [21], fluorescence [22], luminescence [23], antimicrobial, anticancer [24,25], and sensing research, demonstrating a wide range of bioactive properties [26–28]. Despite the increasing number of reported structures, the relationship between nuclearity and functional reactivity in Ag-NHC complexes remains poorly defined in the literature. In particular, the influence of silver nuclearity on electronic communication, ligand rigidity, and catalytic potential has not been comprehensively addressed. The versatility of these complexes is largely due to the influence of NHC ligands on the electronic environment and coordination of the metals. This effect can be fine-tuned through ligand structural modifications, thus expanding their utility in various fields.

2. Scope

This review manuscript provides an in-depth exploration of the synthesis, properties, and diverse applications of polynuclear Ag-NHC complexes. Working on the design and discovery of NHC-metal complexes, my group has devoted significant time and effort to exploring their potential as bioactive molecules and catalysts for various organic transformations [29–31]. We have also conducted an extensive review of the antimicrobial and anticancer properties of mononuclear NHC-metal complexes [32–34], as well as dinuclear silver NHC complexes [35]. In continuation of our work, the focus of this review is on the role of polynuclear Ag-NHC complexes in transmetallation reactions [36], where they act as intermediates in the formation of highly reactive mononuclear or polynuclear metal species [37]. Furthermore, we highlight their catalytic potential and explore their expanding roles in biomedical and materials science. This review aims to emphasize the increasing significance of polynuclear Ag-NHC complexes in both.

2. Synthesis and classification

Polynuclear Ag-NHC complexes have been synthesized using methods similar to those reported for mononuclear Ag-NHC complexes [32–34]. Generally, polynuclear Ag-NHC complexes can be prepared through a simple method [38] and its variants as outlined in scheme 1. A) reacting imidazolium salts II (e.g., Cl, Br, I) with Ag₂O to form polynuclear complexes such as III [39–41], B) reacting imidazolium salts (e.g., Cl, Br, I) with Ag₂O followed by counterion exchange with more labile anions (e.g., KPF₆, NaBF₄ ,AgBF₄, AgPF₆) to make polynuclear complexes IV [42–44], C) Reversing the order of steps, where a counterion exchange of imidazolium salts (e.g., Cl, Br, I) with a more labile anion (e.g., NH₄PF₆) is performed first, followed by reaction with Ag₂O [45,46].

Scheme 1.

Traditional approaches to polynuclear Ag-NHC complexes

The synthesis of a diverse array of chemical structures depends on many factors, including but not limited to the geometry of the ligand, the equivalences of silver oxide used, and, in some cases, the solvent employed in the reaction or during recrystallization as well as the ligand’s substitution. Illustrations of the reported shapes are classified in Figure 2. For instance, trinuclear silver webs with a medial triangle, such as complex 1, have been synthesized in a myriad of ways such as salt metathesis of mononuclear NHC-Ag-Cl species [15], and the reaction of various equivalences of silver oxide with NHC containing ligands [47–49]. Yields were reported to range from 38–83% with no clear advantage of one method over the other [15,47–49].

Figure 2.

Classes of polynuclear Ag-NHC complexes.

The ligand geometry likely plays a predominant role in the synthesis of trinuclear webs, with nitrogen, carbon, nitrogen donors separated by methylene spacers being the most commonly reported [15,47–49]. Here, the solvent is important too, as reactions taking place in an aqueous environment seem to afford dimeric mononuclear complexes [48]. Additionally, the silver complexes are light sensitive, requiring protection from it for the reaction to run to completion and for its longevity in storage [15,47–49]. Rigid tridentate ligands, on the other hand, facilitate the linear arrangement of silver atoms, producing ‘sandwich’ structures. Ye et al. [50] synthesized complex 2 via metalation of a carbene with Ag₂O in acetonitrile with 85% yield, a synthetic method which can be extended to other ligands [18].

Tetranuclear ‘sandwich’ structures of dimeric dinuclear reacted with at least two times the equivalences of silver oxide at complexes have also been reported with specific N-position moderate temperatures, 55 °C, produce modest yields of so called substitution on the imidazole [51]. Cyclic tetradentate ligands ‘tetranuclear sandwiches’ [52,53], as depicted by complex 3. The complexes are generally unstable, dissociating to a dinuclear complex in the presence of light [53]. The formation of the ‘sandwich’ architecture is also solvent dependent, wherein metalation reactions performed in water rather than DMSO yield a dinuclear silver complex [53]. Tetranuclear Ag-NHC complexes can additionally possess a cuboid stack arrangement of silver atoms through the reaction of acyclic, tetradentate, pyrazole ligands with one equivalent of Ag₂O [54–56], see complex 4. Reactions to synthesize these structures are reported to occur at room temperatures [54,56] with yields upwards of 67% [54]. Formations of these structures are fairly sensitive to substitution, as slight variations in ligand bulkiness have been reported to shift the complex structure from a tetranuclear “box” to a hexanuclear Ag-NHC complex [56].

Sandwiches with separation between silver atoms have also been synthesized in yields upwards of 95% [57–59]. In some instances, the reaction of equal equivalents of ligand and Ag₂O at room temperature is sufficient to form these architectures [57,58]. Interestingly, dinuclear complexes of similar structure have been reported to rapidly interconvert in acetonitrile to tetranuclear metalla[2]catenanes [60]. NHC motifs separated by large organic spacers with three, and sometimes four, arms form organometallic cages. Complex 5 was synthesized by Mejuto et al. [61] through the reaction of 1.5 equivalences of Ag₂O at 60 °C. This a common method used to synthesize three armed cages with yields ranging from 42% to upwards of 90% [62–66]. Four-armed cages are typically synthesized under similar conditions, using two equivalences of a tetradentate ligand and four of Ag₂O, with yields ranging from 68–94% [41,67–70]. Moreover, N-substitution of the imidazole nitrogen has been reported to influence the nuclearity of the silver complex regardless of the equivalences of reactants employed [41]. Improved yields of three- and four-armed cages are also reported when performing the metalation reaction with the exclusion of light [65,66,69] and under and inert atmosphere [69,70]. It is common to utilize these architectures as scaffolding for the synthesis of organic cages via [2+2] cycloaddition of olefins embedded in the arms of the ligand [68,71] or condensation of free amines and ligand-aldehyde end groups through a “facile three-step procedure” [65]. The supramolecular assembly of ligands in solution offers the opportunity to create unique heteroligand [63] and triply interlocked cages [66]. Schulte to Brinke and Hahn synthesized complex 6, a prototypical metallocylinder [72–74]. Cyclic tetracarbene ligands are typically reacted with at least 2 equivalents of Ag₂O to form tetranuclear cylinders in good yields, from 51–96% [72–75]. These architectures are also often synthesized at room temperature [72,74,75]. Interestingly, in DMF and with the appropriately long aliphatic length between the ligand’s NHC centers, reactions of the cyclic ligands with Ag₂O yields hexanuclear cylinders [76].

Halogen atoms, notably iodine and bromine, often coordinate to silver atoms in the core of polynuclear NHC complexes. Crystallization in DCM after a reaction of half equivalences of Ag₂O or greater with a NHC ligand gives bridged tetrasilver polyhalogen structures, such as complex 7 [13,77–81]. In some reports, yields between 76–95% [13,79,81] are obtained, even at room temperature [13]. Interesting supramolecular structures like lamellae assemble spontaneously for complexes possessing long aliphatic N-substituents on the imidazole group [13,78]. This bridge structure can be modified to resemble a cube-like structure, such complex 8a, through reactions of equal equivalences of Ag₂O with NHC-hybrid ligands as reported by Braunstein and coworkers [19,82]. Additionally, recrystallization in DMSO, a hexane/acetone mixture, or DCM [77,83,84] with excess Ag₂O and molecular sieves affords the highest yields reported [84] of cascade-like structure, such complex 8b. These complexes can also assemble, forming polymers through silver-halogen bonds [77,83]. The synthesis of chairs, bridges, and cubes reflect the fine control over the organometallic architecture of polynuclear halide-Ag-NHC complexes.

Higher silver nuclei content complexes can also be synthesized in a similar manner. For example, Peris has reported a couple of hexanuclear Ag-NHC complexes such as 9 using also Ag₂O in methanol [16]. Although the yields are modest (32–44%), 9 crystalized in a beautiful cistern like structure [16,85]. A liner pentanuclear Ag-NHC X-ray structure was reported by Chen that hints to be polymeric [15]. Truly polymeric Ag-NHC complex 11 was synthesized by Wang et al. through the reaction of silver triflate with a ligand bearing three NHC centers [86]. Additionally, these polymeric compounds have been reportedly synthesized via salt metathesis of mononuclear NHC-Ag-Cl with silver tetrafluoroborate in acetonitrile [15]. Lastly. in a recent study, Gan and coworkers [87] synthesized bio-mimetic helicates, showcasing exceptional control over the structure of polynuclear Ag-NHC complexes and the diversity of structures which can be created through them. Unfortunately, there is not much research into the applications of these polymers, but the moderate conditions required to synthesize them could warrant further investigation.

4. Applications of Polynuclear Ag-NHC complexes

As established in the prior sections, polynuclear Ag-NHC complexes are relatively easy complex to prepare and have exposed a several applications as follows:

4.1. Transmetallation

Ag-NHC complexes are commonly used in transmetallation reactions to access NHC complexes of other metals due to NHC-silver bonds being labile and, when reacted with chloride salts of the metal of interest, formation of insoluble AgCl drives the reaction to completion [88]. In this section, notable examples of polynuclear Ag-NHC complexes are presented to demonstrate their synthetic utility as transmetallation agents and the potential applications of the resulting metal complexes. To better visualize the presented compounds, all trinuclear complexes are included in Schemes 3 and 4 and representations of all complexes with four or more metal nuclei are contained in Schemes 5 and 6. Additionally, a summary of all complexes in this section is presented in Table 1.

Scheme 3.

Trinuclear Ag-NHC Complexes used in transmetallation

Scheme 4.

Trinuclear Ag-NHC Complexes used in transmetallation (cont.)

Scheme 5.

Polynuclear Ag-NHC Complexes used in transmetallation

Scheme 6.

Polynuclear Ag-NHC Complexes used in transmetallation.

Table 1.

Polynuclear Ag-NHC complexes and their transmetallation products.

Complex(es)	Type	Transition metals	Polynuclear after TM	Application(s) of Ag-NHC	Ref.
12	Trinuclear	Pd	No	Norbornene polymerization	[89]
13	Trinuclear	Pd	No	Suzuki coupling	[91]
14	Trinuclear	Pd	No	Suzuki and Heck coupling	[92]
15–16	Trinuclear	Pd	No	NR	[88]
17–21	Trinuclear	Cu	Yes	Luminescence	[93]
22	Trinuclear	Au	Yes	Luminescence	[94]
23	Trinuclear	Au	Yes	Luminescence	[95]
24	Trinuclear	Au	Yes	Luminescence	[96]
25–27	Trinuclear	Au	No	Luminescence	[97]
28	Trinuclear	Cu, Au	Yes	NR	[98]
29–31	Trinuclear	Cu, Au	Yes	NR	[99]
32–35	Trinuclear	Au	Yes	NR	[100]
36	Trinuclear	Cu, Au	Yes	NR	[101]
37	Trinuclear	Pd	No	Anticancer agent	[102]
38	Trinuclear	Au	No	Antibacterial, anticancer agent	[103]
39	Trinuclear	Cu, Au	Yes	NR	[59]
40	Tetranuclear	Pd	No	Suzuki coupling	[104]
41	Tetranuclear	Pd	No	Suzuki and Heck coupling	[92]
42	Tetranuclear	Au	Yes	Luminescence	[105]
43	Tetranuclear	Au, Ni, Pd, Pt	Yes (Au only)	Luminescence	[106]
45–46	Tetranuclear	Au	No	Anticancer agent	[107]
47–49	Tetranuclear	Cu, Au	Yes	NR	[99]
50	Tetranuclear	Ir	No	NR	[108]
51	Tetranuclear	Cu, Au	Yes	NR	[101]
52–54	Tetranuclear	Au	Yes	NR	[109]
55	Tetranuclear	Cu, Au, Ni, Pd, Pt, Fe	Yes (Cu, Au)	NR	[110]
56	Tetranuclear	Au	No	NR	[111]
57	Tetranuclear	Rh, Pd	No	NR	[112]
58–61	Tetranuclear	Rh	No	NR	[113]
62–64	Hexanuclear	Au	Yes	NR	[114]

TM = Transmetallation. NR = None reported.

Trinuclear Ag-NHC complexes are versatile transmetallation agents which have been used to prepare metal complexes with multiple applications. Transition metal complexes are often used as catalysts for organic reactions. Wang and coworkers [89] synthesized complex 12, a trinuclear silver complex with an iodine core and pyridine-functionalized imidazolium ligands. Transmetallation of this complex with Pd resulted in a mononuclear complex obtained in 76% yield. Complex 12 was found to have moderate activity towards ethylene polymerization, while its derivative Pd complex was found to be highly active as catalyst precursor in norbornene polymerization. The observed catalytic activity of trinuclear complex 12 is in accordance with other reports of catalytic activity observed in mono and dinuclear Ag-NHC complexes [90]. Another example of trinuclear Ag-NHC complexes as precursors to catalysts can be found in a report by Li and colleagues [91] who prepared trinuclear silver complex 13 using benzimidazole-functionalized imidazolium ligands. Transmetallation of complex 13 with Pd produced a mononuclear complex in ca. 67% yield which was found to be effective in Suzuki coupling. Pd complexes are common targets for transmetallation of Ag-NHC complexes, for instance, Thapa and Kilyanek [92] synthesized trinuclear Ag-NHC complex 14, using a 20-membered macrocyclic bis-NHC-bis-amino ligand. The structure of complex 14 consists of two equivalent cationic macrocyclic-bis(NHC)silver(I) complexes linked through an anionic AgBr₂⁻ core and a second AgBr₂⁻ unit present in the unit cell with no contacts to the main structure. This complex was used to produce a mononuclear Pd species in 58% yield through transmetallation. This Pd species was screened for activity as precatalyst for Suzuki and Heck cross-coupling reactions with favorable results. Another example of transmetallation to Pd of trinuclear Ag-NHC complexes can be found in the work by Kim and collaborators [88] who reported the synthesis of trinuclear complexes 15 and 16 using pyridine-substituted NHC ligands. These complexes with a web-like structure underwent transmetallation with palladium to form a dinuclear complex in 75% yield with potential catalytic or luminescent applications which weren’t elaborated on by the authors of the study.

Short metal-metal interactions within group 11 metal complexes are often responsible for luminescent activity observed in these compounds [93]. NHCs are perfect ligands to form polynuclear structures incorporating these interactions which has led to the exploration of trinuclear Ag-NHC complexes and their transmetallation derivatives with Au or Cu for diverse luminescence-related applications. An example of this can be found in a study by Catalano and collaborators [93], in which they synthesized a series of trinuclear Ag-NHC complexes 17–21 with web-like structures, by employing several pyridine-functionalized ligands. They also prepared Cu versions of each Ag complex, only one of which was obtained in 79% yield by transmetallation of 21 since it couldn’t be obtained by direct reaction of Cu₂O with the ligand, illustrating the advantages of using silver complexes as transmetallation agents to access metal complexes difficult to prepare by other means. The photoluminescent properties of the Ag and Cu complexes were studied and it was found that Ag complexes are weakly photoluminescent, but Cu complexes are intensely active blue emitters, a relatively rare kind of emitter useful in OLED production. Transmetallation of trinuclear Ag-NHC complexes to gold complexes with photoluminescent properties has also been reported. Bestgen and coworkers [94] prepared a trinuclear Au complex incorporating phosphinoethyl-tethered imidazolium salts from transmetallation of the corresponding Ag trinuclear species 22 which was not isolated. The Au complex synthesized was obtained in around 30% yield and showed relatively bright photoluminescence in the solid state even at ambient temperature with a photoluminescence efficiency as high as 37%. On a similar note, Ai et al [95] prepared trinuclear Ag complex 23 with a different diphosphine-containing NHC ligand. Transmetallation of 23 yielded a trinuclear Au complex in high yield (80%), which possessed excellent photophysical properties which were retained in the solid state. The authors developed a proof-of-concept OLED with the gold complex, demonstrating its potential interest as a deep-blue emitter in solution-processed OLEDs. Luminescent activity has also been observed in bimetallic complexes, as reported by Sahu and colleagues [96]. In their study, trinuclear Ag-NHC complex 24 was synthesized employing N-methylbenzimidazole-substituted imidazolium ligands. Reaction of silver complex 24 with Au(SMe₂)Cl resulted in a heterobimetallic trinuclear complex incorporating two Ag and one Au ions respectively, obtained in 72% yield. The photophysical properties of both the silver and the bimetallic complexes were investigated and it was determined that they are both highly fluorescent species. Macrocyclic ligands have also been incorporated in trinuclear Ag-NHC complexes that undergo transmetallation to Au species, as illustrated by Lu and coworkers [97] who synthesized trinuclear complexes 25–27 and tetranuclear complex 44 using macrocyclic NHC ligand precursors. Complexes 25, 26 and 44 form a sandwiched structure, coordinated by two macrocyclic NHC ligands; while compound 27 adopts a structure with all Ag cores located inside the macrocyclic cavity due to its larger size. Complexes 25 and 26 served as transmetallation agents to form dinuclear Au complexes in 22 and 28% yield respectively. The Au complexes were luminescent, emitting blue to green light in the solid state at room temperature and 77 K.

Synthesis of supramolecular architectures has attracted the interest of many researchers due to their potential uses as molecular hosts and by allowing selected catalytic transformations within their cavities [98]. Polynuclear Ag-NHC complexes have been reported as adopting several interesting supramolecular assemblies, which can often be retained upon transmetallation with other metals. For example, Sinha and collaborators [98] synthesized nanometer-sized trinuclear cylindrical supramolecular assembly 28 with the three Ag ions sandwiched in between two symmetric tris-NHC ligands. Transmetallation of this complex afforded the Au, and Cu derivatives in 70 and 63% yield, respectively with retention of the cylindrical structure. The authors noted that developing methods to control the shape and volume of cavities is crucial to designing supramolecular structures with potential applications in selective catalysis. Another example of a cylindrical supramolecular assembly can be found in the report of Rit et al [99] who synthesized trinuclear Ag-NHC complexes 29–31 from polyimidazolium salts. Transmetallation of 29–31 with Cu and Au yielded the respective complexes maintaining the same cylindrical structure with reported yields around 70% for Cu complexes and over 60% for Au complexes. The authors’ rationale for expanding the size of the ligands used was the generation of complexes with larger cavities to encapsulate selected substrates. In a later study, Sinha and coworkers [100] followed-up by preparing cylinder-like trinuclear Ag-NHC complexes 32–33 that incorporate coumarin-functionalized tris-NHC ligands. Post synthetic modification of these complexes by irradiation with UV light (365 nm) led to a photochemical intramolecular [2+2] cycloaddition to afford complexes 34–35, which contain three cyclobutane rings each, making them the first reported examples of organometallic complexes bearing cage-like three-dimensional hexacarbene ligands, motifs which are difficult to produce by classical organic synthetic methods. All compounds 32–35 were subjected to transmetallation with Au to form the respective trinuclear complexes which retained the precursors’ cylindrical structures, affirming once again the versatility of NHC-silver complexes as transmetallating agents. Finally, it is worth noting that, when studying the processes that govern the self-assembly of supramolecular structures, Nishad and coworkers [101] observed that when forming Ag complexes with bis-NHC ligands, trinuclear complex 36 and tetranuclear complex 51 existed in temperature- and concentration-dependent equilibrium in solution. Interestingly, the metal plays a fundamental role in this behavior, since transmetallation to Au and Cu derivatives generated discrete tetranuclear forms, in 62 and 76% yield respectively, with no equilibrium observed.

Transmetallation of trinuclear NHC-silver complexes has also been implemented in the search for anticancer and antibacterial agents. Salman and Haque [102] report the synthesis of complex 37, a trinuclear Ag-NHC complex with imidazolium ligands and a chloride ion core. Transmetallation of compound 37 afforded a mononuclear Pd species, a cis-platinum analogue, in 69% yield which was tested against HCT116 cancer cells. Surprisingly, trinuclear silver complex 37 was found to have higher anticancer potential than the Pd derivative. On the same note, Jakob et al. [103] performed the synthesis of a tridentate gold complex via transmetallation of the silver complex 38 using Au(tht)Cl under mild conditions at room temperature for 16 hours. The reaction yielded a good result of 61%, with the structural characteristics closely resembling those of its silver analog, complex 38. While the physicochemical properties of the gold complex were very similar to the silver complex, its biological applications revealed a stark contrast. In antibacterial assays against E. coli and S. aureus, as well as in cytotoxicity tests against HeLa and MCF7 cancer cell lines, the gold complex was considered inactive, unlike the silver complex, which exhibited favorable results which will be discussed in subsequent sections.

To round up this account of the transmetallation reactions of trinuclear Ag-NHC complexes, a study by Li et al. [59] reports the synthesis of trinuclear Ag-NHC complex 39 with picolyl-functionalized imidazolium ligands. Transmetallation of 39 with Cu and Au produced a linear one-dimensional chain structure for Cu in 70% yield and a tetranuclear Au structure in 65% yield respectively, showcasing the influence of the metal on the resulting structure of the complex obtained.

NHC-silver complexes bearing four or more silver centers have also been used as transmetallation agents for a variety of applications. Morgan and coworkers [104] designed a wide bite angle ligand using a terphenyl, trans-spanning scaffold, due to reports of this ligand type exhibiting improved regioselectivity on catalytic processes. Using this trans-chelating bis-NHC ligand, they synthesized tetranuclear Ag complex 40 and carried out its transmetallation with Pd to produce a mononuclear species in 80.9% yield which demonstrated high catalytic activity in Suzuki-Miyaura coupling reactions. Another example of transmetallation of tetranuclear Ag-NHC complexes for catalytic applications is found in the previously cited work of Thapa and Kilyanek [92] who reported macrocyclic-bis-NHC silver complex 41 which underwent transmetallation with Pd to yield a mononuclear complex in 55% yield that was demonstrated to be an active precatalyst for Heck and Suzuki cross-coupling reactions. Though not as active as current state-of-the-art Pd coupling systems, the reported Pd derivatives of trinuclear complex 14 and tetranuclear complex 41 showed improved yields at shorter reaction times compared to other reported macrocyclic Pd compounds.

Tetranuclear Ag-NHC complexes have also been used as a source of complexes with photoluminescent properties via transmetallation. Zhou and Chen [105] prepared tetranuclear Ag complex 42 incorporating pyrazole-linked bis-NHC ligands. Transmetallation of 42 generated the corresponding isostructural Au derivative in ca. 50% yield. Both Ag and Au complexes are luminescent in solid state. Since macrocyclic ligands tend to form complexes with a higher stability than their acyclic analogues, Altmann et al. [106] synthesized tetranuclear Ag-NHC complex 43 presenting a box-like structure bearing a macrocyclic tetracarbene ligand. Complex 43 was employed as a transmetallation agent to prepare Au, Ni, Pd, and Pt derivatives. Reported yields for the complexes obtained are 85% for Au, 61% for Ni, 68% for Pd, and 65% for Pt. The group 10 metal complexes adopted an almost square planar coordination geometry, while the Au complex retained the box-like structure. Additionally, the Au complex was found to have photoluminescent activity as a blue emitter.

Transmetallation of tetranuclear Ag-NHC complexes has also been employed in an attempt to produce anticancer agents. Van der Westhuizen and coworkers [107] reported tetranuclear Ag-NHC complexes 45–46 with carbazole-derivatized NHC ligands. Unfortunately, the instability of complex 46 didn’t allow for its transmetallation, but complex 45 was successfully converted to a dinuclear Au derivative in a modest 28% yield. Nevertheless, the Au derivative’s insolubility precluded its use in biological studies.

Supramolecular structures adopted by tetranuclear Ag-NHC complexes and their transmetallation derivatives are also known in the literature. The aforementioned study by Rit and colleagues [99] also reports the synthesis of cylindrical tetranuclear Ag-NHC complexes 47–49 from polyimidazolium ligands. Complexes 48 and 49 underwent transmetallation with Au to produce derivatives, which retained the supramolecular structure, in 65 and 66% yield respectively. Other types of supramolecular structures of tetranuclear Ag-NHC complexes have been reported. For instance, Hua et al [108] prepared tetranuclear tubular metallacage Ag complex 50. Transmetallation with Ir generated a dinuclear derivative containing CNC-pincer-ligated Cp*Ir fragments in 60% yield. On another note, Gan and coworkers [109] reported the synthesis of supramolecular helical tetranuclear Ag-NHC complexes 52–54 employing tridentate CNC pincer units and NHC ligands. Complexes 52 and 53 are double helicates, while compound 54 is a double mesocate. Transmetallation of complex 52 with Au resulted in a change in its supramolecular structure from a helicate to a mesocate, which was obtained in 85% yield.

Other reports of the use of tetranuclear Ag-NHC complexes as transmetallation agents include the study by Weiss and collaborators [110] who used flexible ligand structures to investigate new coordination modes of tetra-NHC complexes. Using an open-chain tetra-NHC ligand they synthesized linear tetranuclear Ag-NHC complex 55. To assess the versatility of 55 as a transmetallation agent, reactions with Cu, Au, Ni, Pd, Pt and Fe were carried out. The resulting Cu and Au complexes retained the linear structure of their precursor and were obtained in 74 and 94% yield respectively. Ni, Pd and Pt complexes were mononuclear with distorted square planar geometries and were obtained in yields of 97% for both Ni and Pd and 91% for Pt. Finally, the resulting Fe complex was obtained in 85% yield and presented both a sawhorse-type and equatorial coordination with two additional acetonitrile ligands coordinated. Ligands incorporating both an NHC and a phosphine moiety have also been incorporated in tetranuclear Ag-NHC complexes. Simler at al [111] employed a P-NHC hybrid ligand to prepare tetranuclear silver complex 56 with a cubane-like structure. Transmetallation of the complex with gold, resulted in the transfer of both donor groups, producing a linear dinuclear complex in 97% yield, the authors mention that ligand alterations are necessary to favor chelating and/or pincer rather than bridging coordination to produce complexes with catalytic potential in the future. Another P-NHC hybrid ligand was utilized by Benaissa and coworkers [112] who synthesized tetranuclear complex 57, producing an unprecedented doubly zwitterionic structure with no bond between the Ag ions and phosphorus. Transmetallation of this unique species with Rh and Pd resulted in mononuclear complexes in 87 and 88% yields respectively, confirming that even this unconventional Ag-NHC complex structure can function as a transmetallation agent. Finally, Komori et al [113] reported the synthesis of tetranuclear box-like Ag-NHC complexes 58–61 using macrocyclic tetraimidazolium ligands. These complexes were obtained as an isomeric mixture from reaction of the respective macrocyclic ligand with Ag(OAc). Attempting transmetallation of the PF₆ complexes 58 and 60 with Rh resulted in the formation of a complicated mixture. On the other hand, transmetallation of the TFSI complexes 60 and 61 with Rh resulted in a mixture of dinuclear Rh complexes in 40 and 32% yields respectively.

Polynuclear NHC-silver complexes of greater nuclearity have also been used as transmetallation agents. Zhang and coworkers [114] designed tridentate ligands containing a central triazine moiety covalently connected by phenylene spacers to three imidazo [1,5-a] NHC precursors. These tridentate ligands were used to synthesize hexanuclear Ag complexes 62–64 presenting a three-dimensional triply interlocked catenane supramolecular structure. All complexes readily undergo transmetallation to produce the corresponding hexanuclear Au complexes with retention of the supramolecular structure. As can be seen from the presented examples, transmetallation of polynuclear Ag-NHC complexes is a reliable strategy to access a variety of metal complexes with varying structures and applications.

4.2. Sensors

Luminescent molecules of polynuclear coordination complexes with NHCs are pivotal in material science due to their light-emitting capabilities. These properties make them ideal for applications in optoelectronic devices, such as OLEDs, and biological sensors. NHCs enhance stability and allow for tuning electronic properties, rendering these complexes versatile for advanced technologies and energy transfer studies. In this context, Yongbo Zhou et al. [115] designed and synthetized four trinuclear and tetranuclear Ag-NHC complexes 65-68 by functionalizing NHC-N-alkylimidazolium ligands (Scheme 7). The luminescent properties of complexes 65 and 68 were evaluated, revealing that the trinuclear complex 65 exhibited a single emission band at 401 nm when excited at 363 nm, while the tetranuclear complex 68 displayed two emission bands at 362 and 463 nm when excited at 318 nm. This data provides insight into the low-energy emission bands for both complexes 65 and 68, which feature orthogonal silver nuclei, indicating that the silver atoms are arranged such that their interactions or bonds form angles close to 90° with each other, which were confirmed by X-ray crystallography. The complexes were characterized, although the nature of the emission mechanism remains unclear, only confirming photoluminescent properties.

Scheme 7.

Polynuclear Ag-NHC polymer complexes used in sensors.

In 2015, Qing-Xiang Liu et al. [116] synthesized and studied the luminescent properties of four tetranuclear Ag-NHC complexes 69-72. These complexes were evaluated for intermolecular π-π and π-Ag interactions involving anthracene and benzimidazole structures. Complex 69 demonstrated two types of interactions: carbene carbons coordinating to silver and carbene bridges forming with another silver atom, detectable by NMR. Notably, π-Ag interactions with anthracene were identified, enhancing electron flow and luminescence. Complexes 70-72 exhibited similar characteristics, with π-π interactions between anthracene and benzimidazole rings. All complexes showed pentacoordination of silver with carbenes, pyridine nitrogen, DMSO oxygen, and Ag-Ag interactions. Luminescence studies, excited at 283 nm, revealed emission bands in the 380–564 nm range, corresponding to n-π and π-π* transitions. Complexes 69 and 70 had weaker red emissions due to metal perturbation of interligand processes, while complexes 71 and 72 showed stronger emissions, up to four times more intense, due to extended π-π interactions. This research underscores the importance of intermolecular interactions and electron movement in photoluminescence.

Ag-NHC complexes have garnered significant interest due to their photoluminescent properties, particularly in polynuclear ligands. Philipp J. Altmann et al. [106] synthesized and evaluated the photoluminescent properties of a tetranuclear Ag-NHC complex 43. The spectral analysis revealed absorption bands in the 200 to 330 nm range, which are indicative of π-π interactions. Notably, these transitions exhibited a red shift when interacting with the silver core, in contrast to the initial ligands. The emission spectrum of the complex displayed a prominent peak at 442 nm, consistent with previously reported values for such complexes. The structural characterization of complex 43 reveals it as a molecular box type, where the silver atoms are positioned within close Van der Waals radii. This arrangement suggests unique in-plane Ag-Ag interactions, which are critical in defining the complex's photophysical behavior. To the similar way Prioti Choudhury Purba et al. [117] designed and synthesized a novel ligand based on triphenylamine tetraimidazolium salt, designated as NHCTPA 73. Upon coordination with silver, the emission spectra of the resulting complex were enhanced ninefold in dilute solution, with the fluorescence quantum yield increasing from 0.55% to 5.42%. This significant enhancement in fluorescent properties is primarily attributed to the increased rigidity introduced by the Ag-carbene junctions, where the silver atoms play a crucial role in augmenting the structural stiffness. This silver-induced rigidity effectively restricts internal molecular motions such as rotation and vibration, thereby blocking nonradiative decay pathways and facilitating energy dissipation through radiative decay. The UV-Vis spectral analysis revealed absorbance maxima at 337 nm and 335 nm for the free ligand and the silver complex, respectively. These absorption peaks are characteristic of the π-π* transitions within the triphenylamine-based ligand moiety. To further corroborate these findings, TD-DFT calculations were performed using the B3LYP/LANL2DZ method in the ground state. The molecular orbital (MO) distribution pattern of the Ag-NHCTPA complex indicated that the electron density is primarily localized within the ligand centers (HOMO, LUMO), with minimal contribution from the metal centers. Additionally, the complex was evaluated for its efficacy in detecting picric acid, demonstrating high efficiency and selectivity in this application. UV-Vis spectra revealed the formation of charge-transfer complexes between picric acid and the Ag-NHCTPA complex, as evidenced by the appearance of a new absorption peak around 425 nm. This interaction was further supported by a decrease in the complex's excited-state lifetime, indicating the involvement of an active dynamic quenching mechanism by picric acid.

In 2024, Pranay Kumar Maitra et al. [118] designed a luminescent tetranuclear silver(I)-octacarbene metal-organic cage 74 that significantly enhances emission properties, showing a 36-fold increase in fluorescence intensity compared to the free ligand in dilute solutions. This remarkable enhancement is primarily due to the increased rigidity induced by the Ag-carbene coordination, which effectively suppresses intramolecular motions and nonradiative decay pathways. The UV–vis spectra in dilute solutions showed a band at 358 nm for both the metallacage 74 and ligand. This band is attributed to the π−π* transition stemming out of the ligand backbone. As a result, the fluorescence quantum yield of the complex improved dramatically, rising from 2.1% to 40.8%. Leveraging these enhanced photophysical properties, the researchers explored the application of complex 74 as a sensitive sensor for detecting environmental contaminants, particularly focusing on 2,6-dichloronitroaniline (DCN), a persistent pesticide. During titration experiments, a drastic reduction in emission intensity was observed with the incremental addition of DCN, achieving a 90.5% quenching efficiency. The Stern-Volmer plot indicated a predominantly static quenching mechanism at lower concentrations of DCN, which was further supported by TD-DFT calculations. These calculations revealed that the LUMO of complex 74 lies below the HOMO level of DCN, suggesting a possible electron transfer that contributes to the observed quenching effect.

Polymeric NHCs represent a robust class of surface ligands that offer superior colloidal stability for metallic nanoparticles (NPs) under a variety of adverse conditions. Studies carried out by Yu Nong et al. [119] evaluated the fluorescent properties of one polymeric NHC, specifically complex 75, and investigated the potential optical behaviors of polymeric Ag-NHC complexes. The results demonstrated that the precursor to the polymeric complex, 75, exhibited broad emission bands at 352 nm upon excitation at 288 nm. Upon complexation with silver, the Ag-NHC complex, 75, displayed broad emission bands at 319 nm, indicating a blue shift of approximately 33 nm compared to its precursor. This observed blue shift in emission wavelength generally suggests the occurrence of a metal-to-ligand charge transfer (MLCT) in the coordination between the Ag atom and the carbenic carbon of the triazole ring within the one-dimensional linear polymeric Ag-NHC structure. Such charge-transfer phenomena have been reported in previous studies, wherein the interplay between charge transfer and polymeric arrangement results in shorter emission wavelengths. Furthermore, polymeric NHC complexes exhibit good potential in the design of advanced nanomaterials with tailored fluorescent behaviors.

4.3. Antimicrobial

Bacterial resistance to antibiotics continues to rise, the need for new alternatives to combat infections and diseases caused by microbial pathogens becomes increasingly urgent. Recently, multidentate NHC complexes have garnered significant attention in the field of bioinorganic chemistry due to their high stability under physiological conditions. There is growing interest in the synthesis of polynuclear transition metal NHC complexes, which have demonstrated promising antimicrobial properties. Christian H.G. Jakob et al. [103] investigated the antimicrobial efficacy of a macrocyclic tetracarbene silver complex 38 (Scheme 8). Their studies revealed that the IC₅₀ values against E. coli and S. aureus were comparable to those of AgNO₃, a standard antimicrobial agent, with no significant strain dependence observed between Gram-positive and Gram-negative bacteria (Table 2). The minimum inhibitory concentrations (MIC) for both bacterial strains were approximately 30 μM, like those observed for AgNO₃. These findings highlight the moderate effectiveness of complex 38 in inhibiting the growth of both E. coli and S. aureus, positioning it as a viable candidate in the search for new antimicrobial agents.

Scheme 8.

Polynuclear Ag-NHC Complexes used in antimicrobial.

Table 2.

Antimicrobial activity of dinuclear NHCs-silver complexes.

Complex(es)	Bacteria screened (n)	Fungi screened (n)	Superior Complex(es)	Highest activity against	Concentration	Activity inhibition zone (mm)	Ref.
38	2	0	38	S. Aureus	30 μM	MIC	[103]
78	3	1	78	C. Albicans	0.125 mg/mL	MIC	[120]
79 – 82	2	0	79	S. Aureus	10 μg	MIC	[121]

MIC = Minimum inhibitory concentration.

Privileged chemical structures with well-established biological properties, such as N-substituted benzimidazolium frameworks bearing alkyl groups, have served as a foundational scaffold for designing novel bioactive compounds. Building on this concept, A.G. Bharathi Dileepan et al. [120] synthesized a hexacarbene Ag(I) NHC complex 76 aimed at enhancing its antimicrobial efficacy (Scheme 8). The study employed the agar well diffusion method on Mueller Hinton plates, targeting Vibrio cholerae (−), Shigella flexneri (−), Bacillus megaterium (+), and the fungal pathogen Candida albicans. The antimicrobial activity was benchmarked against fluconazole for C. albicans and nalidixic acid for the bacterial strains. The results demonstrated that complex 76 exhibited comparable inhibition to amphotericin B against C. albicans, with minimum inhibitory concentrations (MICs) of 0.125 mg/mL and 0.062 mg/mL, respectively, whereas the ligand alone showed a significantly higher MIC of 2 mg/mL. The inhibition zone diameters were measured, with complex 76 showing a maximum inhibition zone of approximately 21 mm for C. albicans, 13 mm for V. cholerae, 11 mm for S. flexneri, and 14 mm for B. megaterium. To know the mechanism of action of complex 76, Scanning Electron Microscopy (SEM) was employed to examine the morphological changes in C. albicans and the bacterial cells. The SEM analysis revealed distinct differences between the control cells, which maintained smooth surfaces, and those treated with the ligand and complex 76. Post-incubation, the treated cells exhibited significant morphological alterations, including surface roughening and structural collapse, with some cells showing loss of their extracellular matrix. These observations suggest that the antimicrobial activity of complex 76 may be attributed to its ability to disrupt cell membrane integrity, leading to cellular collapse and death.

Natural product-based antimicrobials, such as coumarins, have led to extensive research in the field. Erika Mooney et al. [121] designed silver(I) coumarin-carbene hybrids 77–80 as promising antimicrobial agents, building on the known activity of coumarins substituted at positions 6, 7, and 8 with methoxy groups (Scheme 8). The goal was to enhance their effect by incorporating silver nuclei, allowing for continuous release of both coumarin and silver ions. These complexes were tested against E. coli and S. aureus at two concentrations, 5 μg and 10 μg, evaluating the inhibition zone. For E. coli, the ligands alone exhibited complete inactivity, while complex 78 demonstrated the highest activity with an inhibition zone of 9.5 mm at 10 μg. Complexes 77, 79, and 80 showed good inhibition, with zones ranging from 8.3 to 8.7 mm. Against S. aureus, complex 77 stood out with an inhibition zone of 13.4 mm at 10 μg, while complexes 78–80 ranged between 9.7 and 10.2 mm. These findings highlight the potential of hybrid complexes as therapeutic agents against E. coli and S. aureus, showing superior antimicrobial activity compared to their parent ligands. All tested polynuclear Ag-NHC adducts differed only in the substituents on the core coumarin framework. Interestingly, these variations had no significant influence on the overall antimicrobial activity, which remained within a narrow range. In fact, the unsubstituted NHC adduct, complex 77, exhibited the best activity against S. aureus. However, the significantly improved solubility and stability profiles of these complexes, combined with their demonstrated antimicrobial properties, suggest further potential for exploration in other areas of interest.

4.4. Anticancer

NHCs, despite being studied for many years, have recently garnered renewed interest due to their diverse applications, particularly in medicinal chemistry. The incorporation of noble metals, such as silver (Ag), has enhanced the pharmacological properties of NHC-based compounds, amplifying their efficacy as potential anticancer agents. Salmas and Haque [122] designed a benzyl-Ag-NHC complex 37 (Scheme 4) as a promising anticancer agent against HTC 116 human colorectal carcinoma cells. This trinuclear Ag-NHC complex exhibits a unique structural arrangement that significantly contributes to its potent anticancer properties. The coordination of silver ions with N-heterocyclic carbenes is critical to its biological activity. The complex demonstrated remarkable cytotoxicity, with an IC₅₀ value of 0.40 μM, which is superior to the positive control, 5-fluorouracil, which had an IC₅₀ of 5.2 μM (Table 3). The proposed mechanism of complex 37, as indicated by MTT assays, involves its ability to induce apoptosis in cancer cells. This apoptotic pathway is likely mediated through mitochondrial dysfunction, leading to cell death. Such disruption of mitochondrial function not only enhances the cytotoxic effects but also increases the selectivity of complex 37 towards cancer cells over healthy cells, thereby minimizing potential side effects. The trinuclear structure of complex 37 confers enhanced stability through interactions with multiple silver nuclei, increasing its rigidity and thereby facilitating its interaction with cellular targets. This structural rigidity results in greater efficacy compared to mononuclear analogs, which are reported to be less rigid. These findings open new avenues for the development of polynuclear NHC complexes with unique characteristics and potential for high selectivity against cancer cells, warranting further investigation into their mechanisms of action.

Table 3.

Anticancer activity of polynuclear Ag-NHC complexes: Effect of the compounds on viability of HCT 116, MCF-7, HeLa, HL 60 and MDA-MB-231.

Compound	IC50 (μM)	Cell linea	Superior Complex(es)	Highest activity against	Ref
37	0.40	HCT 116a	37	HCT 116	[122]
81–85	0.26	HCT 116a, EA.hy92b, MCF-7c, HeLad	85	HCT 116	[123]
38	3.03	MCF-7c, HeLad	38	MCF-7	[103]
86–90	4.08	HeLad	88	HeLa	[124]
91	0.08	HCT 116a, HL 60e	91	HL 60	[125]
75	ndg	MCF-7c	75	MCF-7	[119]
92	4.41	MDA-MB-231f, HCT-116a	92	MDA-MB-231	[128]

^aHCT-116 = colorectal carcinoma cells;

^bEA.hy92 = ovarian cancer metastasis cells;

^cMCF-7= breast carcinoma cells;

^dHeLa = cervical carcinoma cells;

^eHL 60 = promyelocytic leukemia;

^fMDA-MB-231 = breast carcinoma cells.

^gnd = not determined due to insufficient solubility.

The study conducted by Tabinda Fatima et al. [123] delved into the anticancer activity of a series of trinuclear Ag-NHC complexes. These ligands, derived from tris-benzimidazolium salts, were strategically designed with varying N-alkyl and N-alkyl substituents (benzyl, n-butyl, cyclopentyl, 2-methylenebenzonitrile, n-decyl) 81-85 to evaluate their influence on the biological activity of the resulting Ag-NHC complexes, both individually and as part of the complexes (Scheme 9s). The results demonstrated that the trinuclear Ag-NHC complexes exhibited significant cytotoxicity against HCT 116 (colorectal cancer), EA.hy92 (umbilical vein), MCF-7 (breast cancer), and HeLa (cervical cancer) cell lines. Complexes with longer carbon side chains or specific functional groups were particularly noteworthy for their superior anticancer efficacy. For instance, complex 84, containing a 2-methylenebenzonitrile group, and complex 68, with an n-decyl substituent, showed potent cytotoxic effects that even surpassed the standard drugs 5-fluorouracil and tamoxifen. The findings of the study underscore the critical role of Ag(I) ions in enhancing the anticancer properties of NHC ligands. Notably, most compounds were inactive against HCT 116, with the exception of the individual ligand and complexes 84 and 85. Conversely, all complexes demonstrated activity against EA.hy926 cells, with complex 82 exhibiting an IC50 of 6.16 μM, which is lower than tamoxifen’s IC50 of 7.5 μM. In the HeLa cell line, complexes 81, 82, 83, and 85 displayed lower IC50 values (2.77 μM, 8.65 μM, 0.40 μM, and 1.51 μM, respectively) compared to 5-fluorouracil, except for complex 84, which showed a similar IC₅₀ of 10.89 μM. Among these, complex 83 stood out for its exceptionally low IC₅₀. However, complex 85 was active across all cell lines, demonstrating a higher percentage inhibition of proliferation at all doses compared to both 5-fluorouracil and tamoxifen. This enhanced activity is likely attributed to the increased lipophilicity associated with longer carbon chains in certain complexes, which may improve drug absorption and consequently enhance cytotoxicity against cancer cells. These results open avenues for further exploration of the mechanisms underlying the observed anticancer activity, particularly in relation to the role of lipophilicity and its impact on cellular uptake and efficacy.

Scheme 9.

Polynuclear Ag-NHC complexes used in anticancer.

The antiproliferative activity of metal-based complexes is heavily influenced by the choice of metal. Christian H.G. Jakob et al. [103] explored the properties of trinuclear NHC/urea Ag(I) macrocyclic complexes and designed complex 38 to evaluate its anticancer potential in HeLa and MCF7 cell lines. The silver complex 38 exhibited high antiproliferative activity against these cancer cell lines, with IC₅₀ values of 3.61 μM for HeLa and 3.03 μM for MCF7, surpassing the results obtained with the control drug Cisplatin, which had IC₅₀ values of 39.9 μM for HeLa and 18.1 μM for MCF7. This demonstrates a strong antiproliferative effect, where the cyclic urea moiety positively impacts the pharmacokinetic properties of the complex. Additionally, the increased rigidity provided by the three silver nuclei enhances the stability of the structure. This study also explores different types of bonding within the carbene structures, illustrating how the arrangement of these structures can benefit the potential therapeutic applications of Ag-NHC complexes.

Most studies on NHC-metal complexes focus on mononuclear complexes to evaluate their properties and potential applications in medicinal chemistry. However, Abdurrahman et al. [124] investigated how increasing the number of NHC units and the number of bound silver(I) ions leads to more reactive complexes against various cancer cells, specifically trinuclear Ag-NHC complexes 86–90. In this study, the N-carbene group was modified with different alkyl chains (methyl, ethyl, propyl, butyl, and pentyl) to assess their antiproliferative potential in HeLa cervical cancer cell lines. The significance of forming silver complexes lies primarily in the well-known properties they impart, such as enhanced stability, rigidity, and the slow release of silver ions, in contrast to other silver-based drugs that rapidly lose their effectiveness as the silver ions are depleted. The results were promising, indicating lower IC₅₀ values for all compounds, with complex 88 showing an IC₅₀ of 4.08 μM and complex 86 with 5.44 μM, both significantly outperforming Etoposide, which had an IC₅₀ of 19.51 μM. Based on this study, complexes 86 and 88 demonstrated superior anticancer activity compared to the positive control, corresponding to lower compound concentrations that resulted in antiproliferative activities of 94.57% and 95.89%, respectively. However, at low concentrations, the complexes exhibited acceptable viability, and as the concentration increased, the survival rate decreased, confirming that tri-NHC trinuclear silver(I) complexes possess potent anticancer properties. The presence of the silver core is crucial as it enhances both stability and efficacy, making these complexes highly viable candidates for further development in cancer treatment.

Muhammad et al. [125] conducted a comprehensive screening of complex 91 on HCT 116 and HL 60 cancer cell lines, using 5-fluorouracil as a positive control. The study provided valuable insights into the anticancer activity of the benzimidazolium salt and its Ag(I) complex, highlighting the influence of silver on cytotoxicity and selectivity. While the benzimidazolium ligand alone exhibited antiproliferative activity, complex 91 demonstrated six times greater efficacy, with an IC₅₀ value of 0.08 μM in HL 60 cells, and 0.3 μM in HCT 116 cells, indicating higher inhibition in HL 60. However, the results of the viability and selectivity assays revealed that complex 91 was cytotoxic to both cancerous and normal cells, particularly in HCT 116 lines, where treated cells displayed an abnormally large number of cytoplasmic vacuoles, indicating signs of autophagy. Additionally, the cells showed markers of apoptosis induction. In contrast, the imidazolium salt alone only caused minor morphological alterations in most cells, suggesting that the enhanced cytotoxicity is primarily attributable to the presence of silver. This aligns with previous studies linking silver nitrate with similar cellular damage, further emphasizing the role of Ag(I) in the observed effects. These findings underscore the dual impact of silver complexes, offering potent anticancer activity but raising concerns about off-target effects, which demand for further studies to optimize therapeutic applications while minimizing damage to healthy cells.

The discovery of innovative supramolecular anticancer agents with high efficacy and minimal toxicity has become increasingly critical due to the rising incidence of cancer worldwide. In this context, Yu Nong et al. [119] evaluated the supramolecular Ag-NHC complex 75 on the MCF-7 breast cancer cell line. The results indicated significant variations in cell viability at lower concentrations. In antiproliferation assays, the complex exhibited primarily proliferative activity at low concentrations of around 900 nM, while at higher concentrations of 5 μM, no substantial increase in antiproliferative activity was observed. It was suggested that the structural configuration of the N-benzyl groups in the complex may limit supramolecular interactions with cancer cells, contributing to increased rigidity of the complex. This rigidity could potentially be a limiting factor in its cytotoxic effect. The study concludes that modifying these structural features could enhance the cytotoxic activity of the Ag-NHC complex 75 against the MCF-7 cancer cell line, providing new insights into the design of more effective anticancer agents.

Several research groups have tested a range of NHC salts and Ag-NHC complexes derived from imidazoles (with diverse structural modifications) against various cancer cell types [126,127]. Aqsa Habib et al. [128] investigated the cytotoxic activity of polymeric imidazolium-based Ag-NHC complex 92 against breast cancer cells (MDA-MB-231) and human colon cancer cells (HCT-116) to evaluate its antiproliferative potential. Complex 92 exhibited enhanced activity, with IC₅₀ values of 4.41 μM and 7.91 μM against MDA-MB-231 and HCT-116 cells, respectively, which is attributed to its polymeric structure. Furthermore, the study explored the mechanism of action, concluding that the anticancer activity of NHC ligands and silver complexes is associated with the silver-ligand bond, which enhances the biopotential by preventing the rapid release of Ag ions in biological systems. Instead, a gradual release of Ag ions is observed, which can be attributed to the weak π-acceptor and strong σ-donor nature of the Ag-NHC complexes. It was also demonstrated that the anticancer effect of complex 92 primarily occurs via the apoptotic pathway. The ligand structure plays a crucial role in lipophilicity, with the benzyl group allowing for greater cell permeability, enabling the slow release of Ag ions within the cell. This slow-release mechanism further enhances the biopotency of Ag-NHC complexes, making them more effective in anticancer treatments.

Conclusion

It can be stated that substantial advances in the chemistry of polynuclear Ag-NHC complexes have been achieved resulting in diverse emerging applications for these organometallic species. Transmetallation of Ag-NHC complexes to generate complexes of other transition metals such as platinum, copper, and gold is highly favored due to the labile nature of carbene-silver bonds. The resulting transition metal complexes often exhibit promising catalytic, luminescent, antibacterial, or anticancer properties. Transmetallation to gold and copper complexes in particular often results in retention of the polynuclearity of the silver compound precursor, with complete structural retention of the ligand framework observed in many cases such as with the gold derivatives of hexanuclear compound 62 [114]. Polynuclear Ag-NHC complexes exhibit enhanced luminescent, antimicrobial, and anticancer properties due to their unique molecular structures. The Ag-carbene coordination increases molecular rigidity, creating metal-organic cages that suppress non-radiative decay. Notably, complex 74 achieved a quantum yield over 40% and an extinction rate of 90%, making it highly efficient for luminescence applications. In antimicrobial studies, these complexes disrupt bacterial membranes and release silver ions, effectively combating multidrug-resistant pathogens [118]. Complex 76 showed potent activity with an lower MIC, comparable to amphotericin B, causing severe membrane damage and cell collapse, positioning it as a viable antibiotic alternative [120]. Furthermore, anticancer research, trinuclear Ag-NHC complexes disrupt mitochondrial function, inducing apoptosis and exhibiting high selectivity toward cancer cells. For instance, complex 37 exhibited IC₅₀ values so low that outperformed 5-fluorouracil and cisplatin standards, underscoring the role of silver ions and structural rigidity in developing more stable and selective anticancer agents with reduced side effects [102].

In summary, a plethora of polynuclear Ag-NHC complexes with diverse architectures have been reported over the past two decades. Their straightforward synthesis has fueled a surge of research studies, enabling the development of novel structures with broad applicability. It is expected that structural diversity will continue to expand in the near future—initially through analogs inspired by mononuclear and binuclear Ag–NHC complexes with similar applications. This will likely be followed by the design of complexes incorporating other types of carbenes, multinuclear and/or heteronuclear frameworks [129], or the use of solid-supported resins for catalytic applications, as recently demonstrated in Sonogashira couplings [130]. Therefore, a deeper understanding of structure–activity relationships remain essential, particularly in fields such as pharmaceutical synthesis. The ability to tailor the structure of silver complexes holds promise for the development of advanced materials, effective drugs, and efficient catalysts, among other valuable applications.

HIGHLIGHTS:

• Polynuclear Ag-NHC complexes are easily prepared by reacting imidazolium salts with Ag₂O and sometimes undergoing anionic exchanges.

• The first polynuclear tetra-Ag-NHC complex was reported in 2002, marking the beginning of their exploration in various fields.

• These Ag-NHC complexes are used in a range of applications including transmetallation, sensing, antimicrobial agents, and anticancer treatments.

• Tetranuclear Ag-NHC complexes exhibit significant fluorescence intensity increases and can detect pollutants like 2,6-dichloronitroaniline with high quenching efficiency.

• Trinuclear Ag-NHC complexes have shown IC₅₀ values lower than 5-fluorouracil and cisplatin.