Atomically precise nanocluster-catalyzed coupling reactions

Abstract

The application of atomically precise nanocluster-based catalysts in organic synthesis has been practiced for decades. Such nanoclusters have been used as ideal catalysts as their structures are designable at the atomic level, their confined structures are conducive to mechanistic study, and most of them can be recycled during the synthesis process. The catalysis of coupling reactions using nanoclusters is an advanced methodology to build complicated carbohydrate scaffolds in one step. The history of atomically precise nanocluster-catalyzed coupling reactions is short; however, the past decade has witnessed the prosperity of this field-atomically precise nanocluster-catalyzed carbon–carbon coupling reactions including many named reactions, carbon–heteroatom coupling reactions, and multi-component coupling reactions have been reported and extensively applied in medicinal chemistry and materials science. The components and geometries of metal nanoclusters, such as ligands, motifs, metal cores, and supports, affect their catalytic abilities synergistically. This review summarizes carbon–carbon and carbon–heteroatom coupling reactions over atomically precise nanoclusters and highlights the correlations between nanoclusters’ catalytic properties and their specific components. Guidance for choosing suitable nanoclusters for specific coupling reactions and possible research directions in this field have been proposed. We hope that this review will provide researchers attempting to study the coupling reactions catalyzed by metal nanoclusters with a comprehensively catalytic toolbox and insightful research fundamentals, so as to provide tailor-made approaches to achieve more efficient cluster-based catalysts towards coupling reactions.

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Jinhui Hu

Jinhui Hu received his PhD in Organic Chemistry from New Mexico State University, USA, in 2022 (with Prof. James Herndon). He then joined Prof. Manzhou Zhu's group to conduct his postdoctoral research at Anhui University in 2022. His research interests include atomically precise metal cluster-catalyzed coupling reactions and organometallic cyclization reactions.

Xi Kang

Xi Kang is currently a Professor of Chemistry at Anhui University. He received his PhD in Chemistry from Anhui University in 2020 under the supervision of Prof. Manzhou Zhu. His research interests include atomically precise nanoclusters and cluster-based nanomaterials.

Manzhou Zhu

Manzhou Zhu is currently the Changjiang Chair Professor of Chemistry at Anhui University. He received his PhD in Chemistry from the University of Science and Technology of China (USTC) in 2000. He then conducted postdoctoral research at USTC and Carnegie Mellon University (CMU, Pittsburgh, USA). He joined the chemistry faculty of Anhui University in 2010. His current research interests include atomically precise nanoclusters, structure–property correlation of nanoclusters, and applications.

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1. Introduction

Coupling reactions, in general, connect molecules by constructing carbon–carbon bonds or carbon–heteroatom bonds and are usually catalyzed by metals (metal salts,¹ metal complexes,² metal nanoparticles,³ and metal nanoclusters⁴). This type of chemistry might be one of the most significant organic reactions since complicated carbohydrate scaffolds can be built in one step. Many coupling reactions have been named after scientists to recognize their contributions to the development of organic chemistry. The Nobel Prize was awarded to chemists who discovered and developed coupling reactions.⁵ Coupling reactions continue to draw the attention of researchers, motivated by the discovery of better catalysis systems, accurate step-by-step mechanistic study, and the need for waste-reducing and energy-saving methodologies, where atomically precise nanoclusters are prominent because (i) they can be designed and engineered at the atomic level for catalytic performance screening; (ii) the well-defined structure determined by X-ray single-crystal diffraction can be used to unveil the catalytic mechanism both theoretically and experimentally; (iii) nanoclusters, in particular supported nanoclusters, can be recycled easily during catalytic reactions to build a greener catalytic system.⁶

Nanoclusters are optimal catalysts for various homogenous and heterogenous catalytic reactions with their distinct morphology.^6,7 Cross-coupling reactions over supported gold nanoclusters have been reviewed.^8,9 However, many new examples have been reported recently. Thus, it is our intention to highlight the most relevant and recent advances by selecting studies that best represent vital concepts, so as to show the nanocluster family's catalytic potential for organic chemistry. For each report, the assessment is focused on reaction conditions, overall yields, and the relationship between nanoclusters’ structures and their catalytic mechanisms. Examples of nanoclusters with specific metal numbers but no exact chemical formulas are also included in this review to provide a straightforward understanding of the nanocluster catalysis system. Some well-reviewed examples of coupling reactions over nanoclusters are also included but are summarized from different angles and perspectives for the rationalization and completion of the review.

Carbon–carbon and carbon–heteroatom coupling reactions catalyzed by atomically precise nanoclusters are thoroughly reviewed in this article. Most of the examples in each section are listed chronologically to see the development of each system. The catalytic properties of each atomically precise nanocluster are evaluated, and each mechanism is discussed. The application in coupling reactions catalyzed by metal nanoclusters provides opportunities for investigating the correlation between confined structures and physicochemical properties at the atomic level. In this context, this article is intended to guide you in choosing suitable nanoclusters for coupling reactions regarding the metal core, the protecting ligand, and the immobilization support and predict proper catalytic abilities for newly synthesized nanoclusters (Scheme 1).

Scheme 1 Advantages and applications of atomically precise metal nanoclusters.

2. Factors altering nanoclusters’ catalytic properties

The ligand effect, heteroatom doping effect, nanocluster-support synergism, and defective effect have been exploited to dictate the catalytic properties of atomically precise nanoclusters. For instance, homologous gold nanoclusters and gold-base bimetallic nanoclusters behave differently in catalytic performance due to the synergetic effects between gold and foreign atoms.^10,11 Gold-base bimetallic nanoclusters with different foreign atoms show diverse reaction performances.¹² Herein, we list the factors that can alter nanoclusters’ catalytic properties and introduce each of them briefly (Scheme 2).

Scheme 2 Factors altering atomically precise nanocluster's catalytic properties.

2.1 Protecting ligand effect

Protecting ligands as the outmost part of morphology is an essential part of atomically precise nanoclusters to prevent the aggregation of nanoclusters and protect metal motifs and kernels. Commonly used ligands are thiolates, alkynyls, phosphines, and their combinations. Inorganic ligands have also been reported.¹³ All these ligands coordinate with nanoclusters by only one or two atoms (S, P, or C) with mono- or multi-chelation modes. Different protecting ligands could largely influence nanoclusters’ shape and size, as well as their related properties.¹⁴ Engineering nanoclusters by changing their ligands could alter their electronic properties and further influence their catalytic properties.¹⁵ Nanoclusters with different capping ligands could have different total conversion rates, product selectivity, and even reaction directions. There are countless methods of welding capping ligands on nanoclusters, such as simple polydispersity¹⁶ and ligand exchange,¹⁷ indicating that changing the protecting ligands is one of the easiest ways to manipulate nanoclusters’ catalytic properties.

2.2 Doping effect

Alloy is a well-known concept in modern industry to enhance metals’ properties by adding other metal or non-metal materials. The hybrid metal usually represents better oxygen, water, and salt resistance and higher mechanical strength. The same strategy can be extended in nanoscience with various remarkable applications.^18,19 This versatile alloying strategy can drastically increase the nanocluster family's diversity. Sequentially, atomically precise alloy nanocluster-related physicochemical properties can be evaluated at the atomic level owing to their atomically confined structures. Advanced techniques allow scientists to change nanoclusters’ metal atoms one by one. Therefore, some series of nanoclusters can be listed as follows: (1) doping the same parent metal with one hetero-metal atom, for instance, X₁Au₂₄, where X is a foreign metal atom that can be Hg,²⁰ Pd,²¹ Pt,²² Cd,²³etc., based on synthesis procedures and Au is the parent metal atom and (2) doping different numbers of the same foreign metal atom in parent nanoclusters such as Au_25−nAg_n where Au₂₅ is the parent metal kernel, while different numbers of Ag can be doped in it.^24,25 The synergistic effect of hetero atoms is the main reason why their properties changed. Thus, doping hetero-metal atoms to corresponding homologous nanoclusters can improve the physicochemical performance of nanoclusters. Alloying different hetero-metal atoms to the same parent nanocluster could result in different catalytic properties. To date, metals such as Au, Ag, Pt, Pd, Cu, and Cd can be doped into parent homologous nanoclusters to generate bi-, tri-, and multi-metallic alloy nanoclusters.²⁶ The catalytic properties of the alloy nanoclusters can be assessed and predicted according to the metal components before applying them to reactions for saving time and cost.

2.3 Support effect

One of the major limitations of atomically precise nanoclusters is their unstable nature. Even stable nanoclusters can be aggregated, decomposed, or deactivated when they are applied to chemical reaction conditions such as higher or lower PH, extremely high reaction temperature, and long-time exposure to solvent or optical radiation. Immobilizing nanoclusters in support is the most frequently used approach to solve this issue. Common supports are metal oxides such as Ce₂O, Ti₂O, and MgO, porous materials such as activated carbons and carbon nanotubes, and high polymer materials such as poly(N-vinylpyrrolidone). Mounting nanoclusters on supports turns the material into a heterogenous catalyst, which prevents the decomposition of nanoclusters during chemical reactions and keeps them intact during recyclization. Moreover, the porous structure of the support can largely enhance the catalytic properties of nanoclusters by dramatically increasing the contact area between the catalyst and reactant molecules. Some catalytic reactions cannot push forward without the assistance of supports. Moreover, the synergistic effect between nanoclusters and supports can regulate the target reaction's conversion rate and selectivity.^27–29 This approach makes nanoclusters better catalysts with higher efficiency, lower cost, and higher stability.

2.4 Defective effects

Defect is a solid material terminology. It means interruption in the homogenous arrangement of solid building blocks caused by vacancies or other components. The phenomenon results in property changes including electrical and magnetic, which can be utilized to improve their performance. The application of defects is smoothly extended from the macroscopic to the microscopic level, where defect engineering is considered a splendid method to direct electrical, optical, magnetic, and catalytic regulation in nanotechnologies.³⁰ As for nanoclusters, the defect is still a coinage and it usually represents the surface vacancy of nanocluster metal motifs and kernels leading to changes in nanoclusters’ active sites.^31–33 Catalytic reactions occur at the interface between nanoclusters’ metal active sites and reactive species. Hence, defects can directly influence nanoclusters’ catalytic properties by altering the interfacial interaction such as surface adsorption and desorption.³⁴ The imperfection at the atomic level offers new insights into defect chemistry and nanocluster design.

Other characteristics of nanoclusters can also change their catalytic properties, for instance, nanoclusters with less than 10 metal atoms perform differently in chemical reactions from nanoclusters with more than 10 metal atoms due to their coreless nature.³⁵ Nanoclusters catalyze chemical reactions as a whole with their specific morphology including capping ligands, motifs, kernels, and even support. The above-mentioned factors influence nanoclusters’ physicochemical properties collectively. The design and analysis of atomically precise nanoclusters for catalytic coupling reactions require scientists to oversee the catalytic patterns coming from each factor. Their collaborations finally give rise to individual nanocluster's specific catalytic properties and their performance is discussed in section 3 case by case.

3. Catalytic performance

3.1 Carbon–carbon coupling

Carbon–carbon bond formation via coupling reactions is the most versatile and extensively used method to construct carbon scaffolds of organic molecules in organic synthesis. With the rapid development of scientific research, carbon–carbon coupling reactions including Csp³–Csp³, Csp³–Csp², Csp³–Csp, Csp²–Csp², and Csp–Csp bond formation catalyzed by noble metals, inexpensive metals and even without metal have been documented.³⁶ To extend the application of the newly discovered nanomaterial, atomically precise nanoclusters were utilized in carbon–carbon coupling systems to unveil their catalytic abilities.

3.1.1 Ullmann C–C coupling. The classic Ullmann C–C coupling reaction yields biaryls by connecting halogenated aromatic structures (Csp²–Csp²) and is usually catalyzed by copper, nickel, or palladium complexes. In the last two decades, Au₂₅ nanoclusters and M_xAu_(25−x) alloy nanoclusters (M: hetero metal atom) might be the most researched nanoclusters for Ullmann coupling. The synthesis and crystal structure of the Au₂₅(SR)₁₈ nanoclusters (SR: thiolates) were reported by Zhu and Jin's research group^37,38 (Fig. 1a). In general, Au₂₅ nanoclusters have an electron-rich Au₁₃ (Au⁰) core covered by an exterior electron-deficient Au₁₂ shell, where Au atoms carry positive charges. These structures’ intriguing geometry, electron distribution, and thermal stability made them suitable for multiple types of chemical reactions.^39,40 Having the theoretical work in hand, the same group reported the Ullmann-type homocoupling reaction catalyzed by Au₂₅(PET)₁₈ nanoclusters (PET = SCH₂CH₂Ph, 2-phenylethanethiolate).⁴¹ Iodobenzene was converted into a diphenyl product using the nanoclusters and they found that Au₂₅(SR)₁₈ showed decent catalytic ability and excellent recyclability when the nanoclusters were supported by oxides, in particular CeO₂ (conversion rate up to 99.8%). This novel protocol and regular Ullmann coupling reactions shared the same electronic effect, as the electron donating group (EDG) on the aromatic system increased the yield, while the electron-withdrawing group (EWG) decreased the yield (Fig. 1b). A mechanism was proposed for the Ullmann homocoupling reaction based on Au₂₅(SR)₁₈ nanoclusters’ capability of electron transfer³⁸ and density functional theory (DFT) calculations of the formation of the I⋯Au⋯C intermediate.^41,42 Gold atoms in the exterior Au₁₂ shell appeared to be positively charged^38,43 to form the intermediate [Au₂₅R₂]I₂, generating the final product after reductive elimination (Fig. 1c).

Fig. 1 (a) Crystal structure of an Au₂₅(SR)₁₈ cluster (R is the phenylethyl group); (for clarity, only S was shown for ligands; magenta: Au; yellow: S). Reprinted with permission from ref. 38. Copyright 2008 American Chemical Society. (b) Homocoupling of aryl iodides using the Au₂₅(SR)₁₈/CeO₂ catalyst. (c) Proposed mechanism for the Ullmann-type homocoupling reaction of iodobenzene catalyzed by Au₂₅(SR)₁₈ nanoclusters (green: surface Au atoms; yellow: core Au atoms; the thiol ligands are omitted for clarity). Reprinted with permission from ref. 41. Copyright 2012, the Royal Society of Chemistry.

Later the same group investigated the effects of ligand engineering regarding Au₂₅ nanoclusters’ catalytic performance.¹¹ The model reaction they used was the Ullmann hetero coupling reaction between 4-methyl-iodobenzene and 4-nitro-iodobenzene. Au₂₅ nanoclusters with different thiolate ligands were tested under optimized conditions, and the total conversion rate and selectivity towards heterocoupling products were determined (Fig. 2b). According to the results, Au₂₅ protected by aromatic ligands (Fig. 2a) gave the best conversion rate and selectivity, while nanoclusters protected by carbon-chain ligands tended to generate homocoupling products. DFT calculations were used to understand the ligand effects of this system. Jin believed one thiolate ligand was lost, and two gold atoms were exposed to the starting materials during the experiment. Hence, model systems of the iodobenzene with the exposed gold atom of Au₂₅(SCH₃)₂(SH)₁₅ and Au₂₅(SNap)₂(SH)₁₅ (SNap = 1-naphthalenethiolate) were calculated to reduce the computational costs. Aromatic thiolate ligands decreased the activation energy of the C–I bond formation from −4.3 to −7.2 kcal mol⁻¹ compared to aliphatic ligands, making the Ullmann heterocoupling reaction favorable, and meeting the experimental results.

Fig. 2 (a) Structure of the [Au₂₅(SNap)₁₈]⁻[TOA]⁺ nanocluster. Au₂₅S₁₈ is shown in ball-and-stick mode, thiolate ligands, and TOA⁺ in wire-and-stick mode. Gold: green, or orange; sulfur: yellow; carbon: gray; hydrogen: white; TOA⁺: magenta. (b) Catalytic performance of Au₂₅(SR)₁₈/CeO₂ catalysts for Ullmann heterocoupling between 4-methyl-iodobenzene and 4-nitro-iodobenzene. Reprinted with permission from ref. 15. Copyright 2016 American Chemical Society.

The doping effect of the Au_xM_(25−x) alloy nanoclusters in the Ullmann coupling reactions has also been explored.⁴⁴ Li et al. synthesized a group of TiO₂-supported gold-based bimetallic nanoclusters,^44,45 and matrix-assisted laser desorption/ionization-mass spectrum (MALDI-MS) was used to determine their precise formula. Among them, Ag_xAu_(25−x) nanoclusters (x = 0–5) and Cu_xAu_(25−x) nanoclusters (x = 0–6) were mixtures, while the Pt_xAu_(25−x) nanocluster had only one component: Pt₁Au₂₄. They were treated with p-iodoanisole and phenylacetylene in an N₂ atmosphere at 160 °C (Fig. 3a). The Ullmann homocoupling reaction and Sonogashira cross-coupling occurred simultaneously and with different doping hetero atoms, the total conversion rate and selectivity varied. Regarding the Ullmann coupling reaction, none of these bimetallic nanoclusters gave good results except Cu_xAu_(25−x) nanoclusters. It is probably because copper salts and complexes, by themselves, are excellent catalysts for the Ullmann coupling reactions.⁴⁶ The PhC≡C–H/Ph–I pairs are adsorbed on the Au₃ open facet, which leads to the Ullmann homo-coupling reactions (Fig. 3b). The details of the structures of these nanoclusters and the mechanisms of the coupling reactions will be discussed in the Sonogashira coupling reaction section. The results of this study confirmed that doping foreign metal atoms into nanoclusters led to changes in their catalytic performance.

Fig. 3 (a) Catalytic performances of TiO₂-supported M_xAu_25−x(SR)₁₈ nanocluster catalysts for the carbon–carbon coupling reaction between p-iodoanisole and phenylacetylene. (b) Proposed mechanism for the M_xAu_25−x(SR)₁₈-catalyzed-Ullmann coupling reaction. Reprinted with permission from ref. 44. Copyright 2016 Chinese Materials Research Society. Published by Elsevier B.V.

Ehara, Sakurai, and colleagues reported the first Ullmann coupling reactions of chloroarenes under ambient conditions in 2012.⁴⁷ A series of bimetallic nanoclusters Au_xPd_(20−x) supported by poly(N-vinylpyrrolidone) (PVP) were synthesized and tested for Ullmann coupling of 4-chlorotoluenen. Au₁₆Pd₄, Au₁₀Pd₁₀, and Au₄Pd₁₆ showed catalytic abilities under base conditions. With 300 mol% KOH, the Au₁₀Pd₁₀ nanocluster gave the best result: yielding 98% at room temperature in 24 h. The scope of this methodology had been expanded with substituted chloroarenes. Most cases gave excellent yields under optimized conditions within 6–24 h. To further investigate the low-energy cost of this catalyst, computational studies were conducted. The oxidative addition step of the reaction pathway was calculated with model systems of Au₂₀-, Au₁₆Pd₄-, and Au₁₀Pd₁₀. The energy diagram showed that the alloy nanocluster stabilized the intermediate and dramatically reduced the activation energy, while homologous Au₂₀ nanoclusters showed no catalytic ability of this Ullmann coupling reaction at all. It is also worth noting that N,N-dimethylformamide (DMF) played an essential role in this experiment as both a co-solvent and a reductant.

Another smaller gold nanocluster-catalyzed Ullmann coupling reaction has been reported recently.⁴⁸ Mandal's group has synthesized and elucidated the structure of a smaller Au nanocluster, Au₁₁(PPh₃)₇I₃, in detail (Fig. 4a). Since Au₁₁ has a symmetrical core like the Au₁₃ kernel in Au₂₅ nanoclusters,³⁸ the Ullmann C–C coupling reactions were used to test the catalytic ability of the chemical (Fig. 4b). The nanoclusters were supported by CeO₂ and underwent both homocoupling and heterocoupling reactions. The homocoupling reactions followed the same pattern as the Au₂₅ nanoclusters’ catalytic ability with a better total conversion rate. The heterocoupling reactions, however, produced a trace amount of hetero-coupled product. These results were consistent with the ligand effect study conducted by Jin,¹⁵ which confirmed that the protecting ligand of nanoclusters plays an important role in coupling reaction selectivity. DFT calculations have been managed to discover the mechanism of coupling reactions. A simulation of the reaction pathway of C–I bond dissociation was conducted showing that PhI intended to bind the atop site of the optimized Au₁₁ hexagonal close-packed (hcp) structure.⁴⁹ Unlike Au₂₅ nanoclusters’ catalytic performance, the results indicated that the mechanism of this reaction follows the single-atom catalytic behavior, where intermediate I–Au₁₁–Ph is generated. The Au₁₁ nanoclusters cannot bind two aryl compounds simultaneously, which explains why the heterocoupling product was not observed as the key intermediate of the heterocoupling reaction cannot be formed (Fig. 4c).

Fig. 4 (a) Total crystal structure of the Au₁₁(PPh₃)₇I₃ nanocluster (color legends: Au, yellow, purple, blue, bluish-green; P, magenta; I, green; C, gray; H atoms are missing for clarity). (b) Ullmann C–C coupling reaction over Au₁₁. (c) Proposed reaction pathway of C–I bond dissociation using the Au₁₁@CeO₂ catalyst. Reprinted with permission from ref. 48. Copyright 2020 American Chemical Society.

3.1.2 Suzuki–Miyaura coupling. Suzuki–Miyaura (S–M) coupling as one of the most useful C–C connection reactions in organic chemistry has been well researched and established. It is a cross-coupling reaction of aryl halides and arylboronic acids (organoboron compounds) (Csp²–Csp²) usually catalyzed by a palladium (Pd) complex.⁵⁰ Non-precious metal catalysts such as nickel,⁵¹ iron,⁵² and copper⁵³ were proved to be active catalysts for Suzuki–Miyaura coupling reactions.⁵⁴ Au₂₅ nanoclusters once again exhibited their superior ability to catalyze C–C coupling reactions. Jin and Kim's groups managed to link p-iodoanisole and phenylboronic acid using TiO₂-supported Au₂₅(PET)₁₈ nanoclusters as the catalyst.⁵⁵ They noticed that ionic liquids (ILs) are great promoters of the catalytic ability of Au nanoclusters. Before the addition of BMIM·X (BMIM is 1-butyl-3-methylimidazolium and X = Br, Cl, or BF₄), the system only produced a negligible quantity of cross-coupling products. However, when the IL was added to the reaction vial, the yield of biaryls increased dramatically from 0.5% to almost 100% (Fig. 5a). Entry 9 of Table 1 indicated that water was necessary to the system since K₂CO₃ needed to be dissolved to provide a basic condition. Furthermore, a combination of UV-vis spectroscopy, MALDI-MS, DFT calculations, and classical molecular dynamics (MD) simulations was used to study the mechanism of the catalytic reaction thoroughly (Fig. 5b). The imidazolium cations removed the fragments of nanoclusters by bonding to the surface thiolate ligands on the cluster and exposed the gold active sites to catalyze S–M reactions. This study has enlightened the idea of using ILs in hard reactions to improve nanoclusters’ catalytic performance.

Fig. 5 (a) Catalytic performance of thiolate-capped Au₂₅ clusters supported on titania as catalysts for the Suzuki cross-coupling reaction of iodoanisole and phenylboronic acid. (b) Proposed reaction mechanism for the formation of catalytically active sites on the Au₂₅ cluster promoted by imidazolium-based ionic liquids. Reprinted with permission from ref. 55. Copyright 2016 Elsevier Inc.

Table 1 Summary of atomically precise nanocluster-catalyzed coupling reactions

Reaction type	Catalyst	Additives	Conditions	Yield (%)	Ref.
Ullmann C–C coupling	Au25(PET)18/CeO2	K2CO3	130 °C, 2 days	Up to 99.8	38
	CuxAu(25−x)/TiO2	K2CO3	160 °C, 40 h	71.7	44
	Pd10Au10/PVP	K2CO3	40 °C, 24 h	Up to 98	47
	Au11(PPh3)7I3	K2CO3	130 °C, 2 days	>99	48
Suzuki–Miyaura coupling	Au25(PET)18/TiO2	K2CO3, ionic liquid, H2O	90 °C, 18 h	>99	55
	Pd3Cl(PPh2)2(PPh3)3	K2CO3, H2O	r.t., less than 1 h	Up to 99	57
Heck reaction	PdCo/MgAl-LDH	K2CO3, H2O	160 °C, 40 h	Up to 95	73
	Pd3(PPh3)3(PPh2)2/MSNs	NEt3	80 °C, 12 h	Up to 95	74
Sonogashira reaction	Au25(PET)18/CeO2	K2CO3	160 °C, 40 h	Up to 98	27
	Pt1Au24/TiO2	K2CO3	160 °C, 40 h	67.2	44
	Au13Cu2(PPh3)6(SC2H4Ph)6	K3PO4	N2, r.t., 8 h	93	90
	Cu28-PPh2Py	NaOMe	Blue LEDs, 30 °C, 24 h	Up to 82	33
Oxidative coupling	Au1Cu24/AC	Cs2CO3	30 °C, 10 h	Up to 99.7	103
	Cu1Au11(PPh3)7Cl2	K2CO3	120 °C, 10 h	Up to 100	107
C–N coupling	Cu6(GS)2	KOH	120 °C, 7–15 h	Up to 96	123
	Cu61(S^tBu)26S6Cl6H14	K3PO4	N2, Blue LEDs, 34 °C, 24 h	Up to 85	126
C–O coupling	Au4Cu5(Dppm)2(C6H11S)6/AC	Cs2CO3	80 °C, 14 h	Up to 99	131
A^3 coupling	Au13{Sb(p-tolyl)3}8Cl4	Piperidine	50 °C, 12h	92	143
	Au25(PET)18	—	Ar, 60 °C, 24 h	Up to 99	144
	Au25(PPh3)10(C≡CPh)5Cl2/TiO2	Piperidine	N2, 100 °C, 18 h	94	145
	Au38(SC2H4Ph)24	Piperidine	N2, 80 °C, 5 h	Up to 100	146
	[Au13Cd2(PPh3)6(SC2H4Ph)6(NO3)2]2Cd(NO3)4	—	r.t. 10 h	Up to 95	151
	(Au1Ag16Cu12(SSR)12(PPh3)4)	—	130 °C, 3 min	99	154
AHA coupling	Cu6(SC7H4NO)6	Cs2CO3	50 °C, 24 h	99.6	166

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Since the S–M coupling reaction is originally catalyzed by the Pd(0) complex, the Pd nanocluster is a rational catalyst candidate. Corma and colleagues found that regardless of the Pd source (salt, complex, or nanoparticles), the generation of small nanoclusters, particularly three or four Pd atom nanoclusters, is always a prerequisite for the C–C bond formation of halogenated benzenes (Suzuki, Sonogashira, Heck, and so on).⁵⁶ Zhu et al. reported a S–M coupling reaction catalyzed by Pd₃ nanoclusters in 2017.⁵⁷ The trinuclear Pd nanocluster with a BF₄-counteranion was identified decades ago but the crystal structure has not been reported yet.⁵⁸ They composed a novel synthesis method to obtain [Pd₃Cl(PPh₂)₂(PPh₃)₃]⁺[SbF₆]⁻, and X-ray crystallography (Fig. 6b) was utilized to determine its absolute formula. The S–M cross-coupling reactions between various aryl bromides and aromatic boronic acid were conducted to test the catalytic ability of the Pd₃Cl nanocluster. Unlike normal S–M reactions, this experiment required no extra heat, making it even more competitive. The scope of this strategy turned out to be surprisingly wide as substrates with either EWG or EDG gave results in high yields within one hour (Fig. 6a). To deeply understand the mechanism of the Pd₃Cl-catalyzed coupling reaction, electrospray ionization-mass spectroscopy (ESI-MS) was performed. By monitoring the reaction process, intermediates have been captured and an intriguing Pd catalysis mechanism has been discovered (Fig. 6c). Instead of taking the oxidative addition step,⁵⁹ the Pd₃Cl nanocluster broke the C–B bond on phenylboronic acid and generated the intermediate Pd₃Ar. Aryl bromide attacked the Pd₃Ar intermediate to form the final diaryl product along with Pd₃Br, which can be treated similar to Pd₃Cl to participate in another catalytic cycle.

Fig. 6 (a) Catalytic activity of [Pd₃Cl(PPh₂)₂(PPh₃)₃]⁺ in a Suzuki coupling reaction. (b) Crystal structure of the Pd₃Cl catalyst [Pd₃Cl(PPh₂)₂(PPh₃)₃]⁺[SbF₆]⁻. (c) Mechanism of the Suzuki coupling reaction catalyzed by the Pd₃Cl cluster [Pd₃Cl(PPh₂)₂(PPh₃)₃]⁺[SbF₆]⁻. Reprinted with permission from ref. 57. Copyright 2017 American Chemical Society.

The gas-phase nanocluster fabrication technique combined with size-selected soft-landing methods can produce single-sized nanocluster catalysts.⁶⁰ Nakajima et al. applied the combined methodology to generate and separate Pd nanoclusters using a size-selection chamber and a quadrupole ion deflector. Unprotected Pd_n nanoclusters from Pd₁ to Pd₅₅ have been fabricated, sifted, and soft-landed on strontium titanate (STO). These STO-supported Pd nanoclusters were added into an S–M coupling reaction system size by size to investigate the size effect⁶¹ on Pd nanoclusters’ catalytic ability. A Pd₁₃ nanocluster represented an outstanding catalytic ability toward cross-coupling products while other sizes of Pd nanoclusters either gave lower yields or generated hydrolysis products. From the study, they have approved that the partially positive-charged Pd nanoclusters were the key factors of the S–M cross-coupling reaction and the catalytic activity increased as the size of the Pd nanoclusters increased. After comparing the catalytic ability of the Pd₁₃ nanocluster with the M_xPd_(13−x) nanoclusters (M = Cu or W), the relationship between the size-specific activity for n = 13 and the electronic structure is still a myth. Therefore, the authors shed light on the specific geometry of Pd₁₃ nanoclusters and noticed that most of the supported Pd₁₃ nanoclusters consisted of a hemispherical oblate structure.⁶² The geometry of the Pd₁₃ nanocluster supported on STO, however, was observed as a spherical structure. Hence, Nakajima concluded that the excellent performance of the Pd₁₃ nanocluster was due to its site-specific distribution combined with the unique geometric structure.

Some other reports of S–M coupling reactions should be considered to see the big picture of nanocluster-catalyzed C–C coupling reactions between aryl halides and organoboron compounds. In the last decade, composite materials such as Pd/Ni bimetallic nanoclusters,⁶³ PdO nanoclusters supported by WO₃ nanosheet,⁶⁴ α-Fe₂O₃ nanoclusters supported by graphene oxide,⁶⁵ and copper-based mixed nanoclusters^53,66 showed catalytic abilities for various S–M C–C coupling systems. Recently, a novel S–M coupling polymerization reaction to synthesize aromatic polyketones using Pd nanoclusters has been reported.⁶⁷ Even though none of them have a precise crystal structure or an accurate chemical formula, they extended the use of nanoclusters in catalytic C–C coupling reactions.

3.1.3 Heck reaction. The Heck reactions involve the coupling of activated olefins with halogenated aromatic systems or vinyl halides (Csp²–Csp²) usually catalyzed by palladium.^68,69 Scientists have been researching this reaction for decades, and palladium seems to remain the only active catalyst. Chemists are polishing this system by reducing the load of Pd,⁷⁰ lowering the activation energy,⁷¹ and expanding its applicability.⁶⁸ Still, the sustainable use of Pd and the detoxification of the Heck reactions’ waste long for resolution.

Corma's theory was introduced previously,⁵⁶ and they believed that this was also applied to the Heck reaction system. The Heck reactions between vinyl bromide and butyl acrylate with varieties of Pd catalysts were performed to prove their hypothesis. The reaction condition was heating in N-methylpyrrolidone (NMP) with an inorganic base, which was a common condition for the Heck reaction.⁷² Since the premade Pd NP (NP: nanoparticle) required a similar induction period with the Pd salts, they realized that the Pd NPs were not the active species for the Heck reaction. Water was a key ingredient in this recipe since it promoted the formation of Pd nanoclusters. ESI-MS and MALDI-TOF analyses were conducted, and it was found that the reaction started only when Pd nanoclusters with a mass below 500 Da were generated.Although they didn’t identify the exact catalyst for the reaction, they have proved that the active species in the Heck reaction were small Pd nanoclusters. Later, Zhang et al. reported the Heck reactions of iodobenzene and styrene catalyzed by various PdCo alloy nanoclusters in 2019.⁷³ By immobilizing PdCo_r-PVP nanoclusters on layered double hydroxide (LDH), a group of PdCo alloy nanocluster composites, x-PdCo_r/MgAl-LDH, were synthesized (x: Pd loading; r: Co/Pd molar ratio). Among these various sizes of bimetallic nanoclusters, 0.81-PdCo_0.10/MgAl-LDH (2.6 ± 0.6 nm), 0.86-PdCo_0.28/MgAl-LDH (2.3 ± 0.7 nm), and 0.79-PdCo_0.54/MgAl-LDH (3.2 ± 0.9 nm) showed significant catalytic activity for the Heck reaction compared to regular catalysts. According to their results, the smallest competitor 0.86-PdCo_0.28 possessed the highest catalytic ability due to the maximum electron density of the Pd⁰ center and the strongest synergistic effect between the nanoclusters and the supports. Furthermore, the material exhibited great substrate tolerance and recyclability, yet the precise chemical formula has not been identified.

Recently, Gao et al. have reported that the mesoporous silica nanoparticle (MSN)-supported [Pd₃(PPh₃)₃(PPh₂)₂]Cl (Pd₃Cl/MSN) catalyzed the Heck reaction between iodobenzene and styrene.⁷⁴ They have followed Zhu's synthesis method⁵⁷ mentioned in the S–M coupling reaction section. Pd₃Cl was mounted on MSNs by physically mixing and annealing at 100 °C in a vacuum oven before further treatment. Transmission electron microscopy (TEM) and energy-dispersive X-ray spectroscopy (EDX) were performed to confirm the homogenous dispersion of Pd₃Cl on MSNs. During the experiment, the supported nanoclusters showed comparable catalytic activity since they gave the same results as PdCl₂ and their performances were better than the commonly used heterogeneous catalyst Pd/C. It was still intact after three cycles of catalysis. Different substituted iodobenzenes and non-aromatic olefins were used to expand the scope of this protocol. Of note was that only the iodized benzenes gave excellent results, while brominated and chlorinated benzenes were not active in this system because they are not good leaving group in the Heck reaction.

3.1.4 Sonogashira reaction. The Sonogashira cross-coupling reaction constructs carbon–carbon bonds between a terminal alkyne and an aryl or vinyl halide (Csp–Csp²) known as the most widely used approach to synthesize substituted alkynes.⁷⁵ Originally, this coupling reaction was performed with a Pd catalyst, a cuprous salt cocatalyst, and an amine base, and was very sensitive to moisture and oxygen.⁷⁶ Restrictions are less important as chemists developed better experimental procedures for this named reaction.⁷⁷ Moreover, advances in catalyst engineering substitute Pd with copper catalysts, making this system economic and environmentally friendly.^78–80 Rothenberg et al. noticed the catalytic activity of mixed copper and copper-based alloy nanoclusters⁶⁶ in the cross-coupling reactions of aryl halides and terminal alkynes two decades ago.⁸¹ The catalytic cycle was proposed, providing prospects for future research. However, without the isolation of the nanocluster crystal, the mechanism is difficult to confirm.

The theoretical simulation was performed long before experimental research to pave the road for this catalytic system.^82,83 A Au nanorod,⁸⁴ as one of the Au nanoparticles with well-defined surfaces and morphologies, was selected to mimic the performance of Au nanoclusters in catalytic reactions.⁸⁵ Based on Li's group's DFT studies, plausible cross-coupling pathways on the Au(100) and Au(111) facets were proposed.⁸⁶ It was not until 2013 that the first example of the atomically precise nanocluster-catalyzed Sonogashira cross-coupling reaction was published, which revealed the magic power of thiolate-protected Au₂₅(SR)₁₈.²⁷ Jin's group demonstrated that Au₂₅(SR)₁₈ nanoclusters are the “jack of all trades” since they can be used to catalyzed majorities of C–C coupling reactions.⁹ The protecting thiolate-ligand mediated in the Sonogashira cross-coupling reaction system was PET and the immobilizer was still an oxide (Ce₂O, Ti₂O, MgO, or SiO₂). The optimized reaction condition was harsher than other coupling reactions (40 hours of reaction time at 160 °C under basic conditions). First, the support oxides were screened adequately and Au₂₅/CeO₂ gave the best result (Fig. 7a). The recyclability of the composites was examined, and the catalytic performance decreased from 88.1% to 64.5% after 5 cycles, showing that the Au₂₅ nanoclusters cannot endure the harsh reaction conditions and gradually aggregated to larger particles.

Fig. 7 (a) Catalytic performance of Au₂₅(SR)₁₈ supported on various oxides as catalysts for the Sonogashira cross-coupling reaction of p-iodoanisole and phenylacetylene. (b) Proposed mechanism for the Sonogashira-type cross-coupling reaction catalyzed by [Au₂₅] nanoclusters. For simplicity, [Au₂₅] represents Au₂₅(SCH₂CH₂Ph)₁₈. Reprinted with permission from ref. 27. Copyright 2013 Elsevier Inc.

As mentioned in the Ullmann coupling section, the Au₂₅PET₁₈ nanocluster consists of an Au₁₃ kernel surrounded by six “-SR-Au-SR-Au-SR-” staple-like motifs and two facets where three external gold atoms are exposed to the ambience for reactant access. DFT calculations recognized the irreplaceable role of the Au₃⁸⁷ open facet. Aryl iodide (PhI) and phenylacetylene (PA) prefer to adsorb on Au₃ with a total adsorption energy of −0.90 eV. The ideal situation designed by the simulation was: on the Au₃ open facet, (1) PhI adsorbs on one gold atom; (2) PA adsorbs on the adjacent gold atom; and (3) both the triple bond of PA and the halogen group of PhI point toward the third gold atom. The mechanism of this recipe was proposed accordingly (Fig. 7b). After the adsorption, the Ph–I bond was activated to Ph–Au–I, and the C–H bond of PA was activated to Au–C≡CPh. Then, reductive elimination happened to couple –Ph and –C≡CPh to form the final product.

The hetero metal atom doping effect of the Au₂₅ nanocluster in terms of their catalytic abilities in the Sonogashira cross-coupling reaction has been evaluated by Li's group.⁴⁴ Silver-, platinum-, and copper-doped Au₂₅ nanoclusters were synthesized and mounted on TiO₂. The observation suggested that Cu and Ag atoms preferred replacing gold atoms at the Au₁₃ core, while Pt can only stay at the center of the cluster. These materials were treated with p-iodoanisole, phenylacetylene, and K₂CO₃, and stirred under N₂ at 160 °C for 40 h. The Ullmann homocoupling product was the major byproduct in this system. Their catalytic abilities were sorted regarding the generation of cross-coupling products: Ag_xAu_25−x(SR)₁₈ ≈ Au₂₅(SR)₁₈ > Pt₁Au₂₄(SR)₁₈ > Cu_xAu_25−x(SR)₁₈. Even though the doped Pt was located in the very center of the whole structure, it decreased the catalytic ability of Au₂₅. Copper, as a good catalyst for the Ullmann homocoupling, directed the reaction the other way. In conclusion, foreign dopants turned out to drastically influence the catalytic ability of the Au₂₅ nanoclusters, which was consistent with previous research studies.^88,89

Wu et al. have recently reported another atomically precise Au-based bimetallic nanocluster-catalyzed Sonogashira reaction.⁹⁰ They introduced a novel approach to prepare a copper-doped Au₁₃ nanocluster through rapid synthesis. A PPh₃-Cu complex, (Cu(PPh₃)₂NO₃), was applied to decrease the reaction time, so that the decomposition of the Au₁₃ intermediate can be neglected. The ESI-MS spectrum and single-crystal X-ray crystallography (SCXC) confirmed the composition to be [Au₁₃Cu₂(PPh₃)₆(SC₂H₄Ph)₆]⁺[NO₃]⁻, providing the atomically precise structure of Au₁₃Cu₂ (Fig. 8b). Unlike copper-doped Au₂₅ nanoclusters, the copper atoms in Au₁₃Cu₂ did not touch the Au₁₃ icosahedral framework but capped two triangular Au₃ surfaces. They also noticed that the bimetallic nanocluster is much more stable than Au₁₃, which led to better catalytic performance under harsh reaction conditions. In the Sonogashira reaction between p-bromoacetophenone and phenylacetylene, various catalysts were added respectively to highlight the catalytic ability of Au₁₃Cu₂ nanoclusters. Interestingly, the Sonogashira reaction catalyzed by Au₁₃Cu₂ seemed no longer sensitive to air even with a super low catalyst loading (Fig. 8a), showing that the bimetallic nanocluster catalyst was much more active and selective in the Sonogashira coupling reaction. To emphasize the excellent catalytic ability of the nanocluster, various substituted alkynes and aryl halides were tested and compared with regular Sonogashira catalysts. The new catalyst gave a decent yield in almost all cases even when regular catalysts showed bad results. A mechanistic study was proceeded by DFT calculations, and four potential active sites were identified. The energy barrier for the oxidative addition of aryl bromide on these potential active sites was 22.8, 35.0, 34.5, and 25.2 kcal mol⁻¹ respectively. Moreover, the distance between Au₁ and Cu₄ is the closest compared to other gold atoms, which might accelerate the transmetalation step. A hypothesized mechanism was depicted considering the above-mentioned calculations (Fig. 8c). The synergetic effect of Au₁ and Cu₄ played an important role in catalyzing the cross-coupling reaction. Worthy to note is that the gram-scale synthesis of internal alkynes was successfully performed with a great yield and Au₁₃Cu₂ was still intact afterward.

Fig. 8 (a) Catalytic performance of Au₁₃Cu₂ and Pd(PPh₃)₂Cl₂ + CuI in the Sonogashira reaction. (b) X-ray crystal structure of Au₁₃Cu₂ (purple: Au; blue: Cu; yellow: S; red: P). All H and C atoms are omitted for clarity. (c) Proposed mechanism of Sonogashira reaction catalyzed by Au₁₃Cu₂. Reprinted with permission from ref. 90. Copyright 2021 Elsevier Inc.

Scientists recognized the significance of defects in nanotechnology^91,92 and shed light on the surface-defect chemistry in nanoclusters with atomic precision. Very few studies of vacancy defects in well-defined nanoclusters were reported due to the challenges in synthesizing, isolating, and characterizing such defective metal nanoclusters.³² Zhu's group has successfully synthesized the defective atomically precise copper nanoclusters characterized as [Cu₂₈(SC₆H₁₁)₁₈(PPh₂Py)₃H₈]₂⁺ (denoted as Cu₂₈-PPh₂Py).³³ Non-defective nanoclusters [Cu₂₉(SAdm)₁₅Cl₃(P(Ph-Cl)₃)₄H₁₀](PF₆) and [Cu₂₉(SC₆H₁₁)₁₈(P(Ph-pMe)₃)₄H₁₀](BF₄) were synthesized subsequently to examine the surface-defect effect. The research confirmed that the surface defects change the physicochemical properties of the nanoclusters. However, nanoclusters with defectives have not been investigated as model catalysts. A light-induced Sonogashira cross-coupling reaction catalyzed by an atomically precise Copper nanocluster was reported this year by Bakr and Rueping's group.⁹³ Another instance of a defective atomically precise copper nanocluster was synthesized and identified as [Cu₂₈H₁₀(C₇H₇S)₁₈(TPP)₃] (TPP: triphenylphosphine; C₇H₇S: o-thiocresol) (denoted as Cu₂₈TPP). The overall structure of Cu₂₈TTP is a tetrahedral missing in one of the vertices due to the defective copper atom and ligands (Fig. 9b). DFT calculations indicated that the surface vacancy in Cu₂₈TTP can act as a catalytic active site and the Sonogashira cross-coupling reaction proceeded to confirm the simulation. Various catalysts were screened to prominent the catalytic ability of Cu₂₈TPP in the aryl iodide and phenylacetylene. Cu₂₈ gave the best yield and inhibited the formation of the byproduct. The scope and limit of the new methodology were investigated with substituted phenyl iodide and bromide (Fig. 9a). The substrate tolerance of this catalytic system was super broad with both EWG and EDG on aromatic rings. A mechanistic study was conducted and the light induction in the strategy indicated the involvement of the Cu-photoredox chemistry.⁹⁴ Unlike the regular Sonogashira organometallic catalytic cycle, this reaction started with the single-electron-transfer (SET) step (Fig. 9c). Cu₂₈TTP was excited by the blue light and an electron was then transferred to aryl iodide generating a phenyl radical. The triple bond of terminal alkynes could be activated by Cu₂₈TTP via a Cu nanocluster-π-alkynyl complex,⁹¹ which was identified by the Zhu and Sheng's group.⁹⁵ The phenyl radical attacked the activated carbon triple bond to form the vinylic radical intermediate following another SET process to bring Cu₂₈TTP to the ground state. The final product was then generated under basic conditions. The above-mentioned radicals were captured and identified by GC-MS to confirm the radical mechanism.

Fig. 9 (a) Substrate scope of Cu₂₈-catalyzed Sonogashira reactions. (b) Structure of Cu₂₈. All carbon atoms of the surface ligands are omitted for clarity. (c) Proposed reaction mechanism of Cu₂₈-catalyzed Sonogashira reactions. Reprinted with permission from ref. 93. Copyright 2023 Wiley-VCH GmbH.

3.1.5 Oxidative coupling reaction. In general, cross-coupling reactions build bond linkage between nucleophiles and electrophiles. Oxidative coupling reactions, however, construct connections between two nucleophiles, which have received increasing attention over the past few decades.⁹⁶ This type of reaction meets the requirement of the atom-economy principle since no byproduct is generated.⁹⁷ A stoichiometric amount of oxidant is required for the transformation. The oxidative C(sp)–C(sp) coupling reaction catalyzed by copper(I) salts, also known as the Glaser coupling,⁹⁸ is usually the sting of synthesizing substituted alkynes since it is a common side reaction in the Sonogashira reaction. The same situation applied to the atomically precise nanocluster-catalyzed Sonogashira reaction systems due to the involvement of oxygen in air and copper atoms⁹⁹ in nanoclusters. Even though scientists came up with many means to suppress the formation of the homocoupling product, it is still the most efficient way to make 1.3-diynes, which have multiple applications in chemistry and biochemistry,¹⁰⁰ by connecting two terminal alkynes without any waste.

Therefore, copper nanoclusters with precision numbers are the most rational candidates for oxidative C(sp)–C(sp) coupling reactions. Li et al. approved the hypothesis by preparing a new tetranuclear Cu nanocluster protected by bidentate alkyne ligands.¹⁰¹ The synthesis route and characterization were provided in detail and the Cu nanocluster was identified as Cu₄(PPh₃)₄(bis(prop-2-ynyloxy) biphenyl)₂. According to the X-ray diffraction (XRD) analysis, the crystal consists of a new alkynyl-Cu motif and a butterfly-like framework (Fig. 10a). Common oxides were used to immobilize the copper nanoclusters before the composites were examined for the oxidative C(sp)–C(sp) coupling reaction. Cu₄ supported by basic oxide NiO showed the best catalytic ability and recyclability. It is worth noting that if the Cu₄ nanocluster were annealed at 300 °C for 2 h in air, the Cu(I) clusters would convert into the Cu(II) species ending up with zero catalytic ability toward the coupling reaction. Subsequently, several aliphatic alkynes and aromatic alkynes were applied to test this study's scope (Fig. 10b). The electron effect was observed during the experiment where EWG induced the coupling, while EDG decreased the conversion rate.

Fig. 10 (a) Structure of Cu₄ and synthetic protocol of Cu₄(PPh₃)₄L₂ clusters from the Cu^I₂L and triphenylphosphine ligands in the presence of excess copper powder. Color code: Cu atoms, turquoise; P atoms, pink; O atoms, yellow; C atoms, grey. All the H atoms are omitted for clarity. (b) Substrate scope of homocoupling of terminal alkynes over Cu₄/NiO catalysts. Reprinted with permission from ref. 101. Copyright 2020 Wiley-VCH GmbH. (c) Structure of the optimized Cu₆(GS)₂ cluster with selected bond lengths (Å). (d) Substrate scopes for C(sp²)–N(sp³) bond formation reactions catalyzed by Cu₆ nanoclusters. Reprinted with permission from ref. 123. Copyright 2022 American Chemical Society.

Very recently, Zhu and Sheng's group prepared copper-based bimetallic nanoclusters extending the application of atomically precise nanoclusters in making symmetric and asymmetric 1,3-diynes^102,103 The synthetic route of Au_xCu_25−x nanoclusters with 12 (p-FPh)₃P protecting ligands was reported by Zhu's group.¹⁰⁴ One of the objectives of this study was to discover the influence on catalytic performance by the number of ligands on the surface of nanoclusters.¹⁰⁵ Thus, Au₁Cu₂₄H₂₂((p-FPh)₃P)₁₂ was synthesized, supported by activated charcoal (AC), and heated at different temperatures to make a group of catalysts Au₁Cu₂₄/AC-X (X is the heated temperature = 0, 200, 300, 500, and 800) (Fig. 11b). Based on XRD and thermogravimetric analysis (TGA), Au₁Cu₂₄ shed about two ligands at 200 °C, while all of the ligands collapsed after 350 °C. It turned out that the partially exposed nanoclusters, Au₁Cu₂₄/AC-200, showed the best catalytic efficiency of the homocoupling of phenylacetylene. Cu₂₅ and Au₂₅ nanoclusters were prepared accordingly to highlight the synergetic effect of copper and gold in this system. Compared to single-metal nanoclusters, the alloy nanoclusters represented the best catalytic ability and recyclability. Subsequently, various terminal alkynes were treated with optimized reaction conditions to test the adaptive capacity of this strategy (Fig. 11a, 1–6). The oxidative C(sp)–C(sp) cross-coupling reactions were applied to the experiment by overdosing one of the terminal alkynes. The data indicated that Au₁Cu₂₄/AC-200 gave decent yields of cross-coupling products while tolerating halogen groups (Fig. 11a, 7–16). The mechanism of this experiment was referred to previously reported mechanisms.¹⁰⁶ It demonstrated that the unprotected part of the nanocluster core was the active site and oxygen was an indispensable component of this reaction (Fig. 11c).

Fig. 11 (a) Substrate scope of homocoupling and heterocoupling of terminal alkynes catalyzed by Au₁Cu₂₄/AC-200. (b) Schematic diagram of AuCu₂₄/AC-200 and comparison of catalyst synthesis. (c) Proposed mechanism of the Au₁Cu₂₄/AC-200-catalyzed phenylacetylene oxidative homocoupling reaction. Reprinted with permission from ref. 103. Copyright 2023 Wiley-VCH GmbH.

Copper-based nanoclusters showed their privilege in catalyzing the oxidative C(sp)–C(sp) coupling reaction. Furthermore, Mandal et al. have proved that a single copper dopant in nanoclusters could also do the trick by presenting another example of the foreign atom doping effect of atomically precise phosphine-protected Au nanoclusters.¹⁰⁷ Phosphine-protected Au nanoclusters (AuPR₃) are one of the earliest studied nanoclusters^108,109 due to their straightforward Au–P coordination pattern. The applications of AuPR₃,^110,111 however, are limited because the weak Au–P bond lacks stability.¹¹² Doping hetero metal atoms improves the stability and physiochemical properties of Au nanoclusters, which is well demonstrated previously.¹¹³ Hence, they managed to design and synthesize a novel single copper-doped bimetallic AuPR₃ nanocluster (Cu₁Au₁₁(PPh₃)₇Cl₂). The synthesis strategy of the nanoclusters was developed by Zhu.¹¹⁴ After characterization, the crystal structure of Cu₁Au₁₁(PPh₃)₇Cl₂ was depicted as an undeca-gold Au₁₁ core aside by a copper atom (Fig. 12a). Originally, the Sonogashira cross-coupling reaction of 4-methyl iodobenzene and phenylacetylene was used to test the catalytic properties of the newly generated nanoclusters supported by ceria. The results turned out to be a competition between cross-coupling products and homo-coupling of phenylacetylene (PA). For most of the cases, the homo-coupled product diphenylbuta-1,3-diyne was the predominant product, especially when phenylacetylene was substituted by EWG. Control experiments were conducted by synthesizing the parent nanocluster Au₁₁(PPh₃)₇Cl₃ and other related nanoclusters, and none of them showed good catalytic ability toward oxidative C(sp)–C(sp) coupling. Of note, the parent nanocluster Au₁₁(PPh₃)₇Cl₃ had no catalytic activity toward either homo-coupled products or hetero-coupled products whatsoever. DFT calculations were performed, and phenylacetylene adsorption on the nanocluster occurred at the unsaturated Cu atom. This explained why the parent Au₁₁ nanocluster had no catalytic ability since all metal sites were ligated. The computational study also indicated a strong PA–PA interaction, which suggested that the homo-coupled product was the major product (Fig. 12b). This study once again proved that a tiny change in the nanocluster's metal core would lead to a drastic change in catalytic performance.

Fig. 12 (a) Complete structure of Cu₁Au₁₁(PPh₃)₇Cl₂ with halides and triphenyl phosphines attached to 10 outer gold atoms. Color code: Cu atoms, red; P atoms, pink; Au atoms, yellow. All hydrogen atoms are omitted from the phenyl rings for clarity. (b) Reaction free energy profile diagram for the Glaser coupling reaction. ΔΔG^‡_R and ΔG_rxn denote the total reaction free energy barrier and total reaction free energy of the catalytic cycle, respectively. The methyl groups in ligands are omitted for the convenience of visualization. Here, g defines the Glaser coupling. Reprinted with permission from ref. 107. Copyright 2023 American Chemical Society. (c) Structural evolution of organosilver species from organic diide–Ag₄ clusters through nanoclusters to nanoparticles along with the occurrence of coupling reactions at different stages. (d) ESI mass spectra of the acidifying solution samples containing equivalent (1) ^MePyAg₅ and ^n-PrPyAg₅ in acetone, and (2) ^MePyAg₁₃ and ^n-PrPyAg₁₃ in acetone. Reprinted with permission from ref. 115. Copyright 2023 Royal Society of Chemistry.

To the best of our knowledge, oxidative coupling reactions other than the oxidative C(sp)–C(sp) coupling are hardly reported over atomically precise nanocluster systems. Zhao et al. reported an intriguing methodology for making Csp²–Csp² oxidative coupling products while synthesizing atomically precise nanocluster systems.¹¹⁵ Instead of using atomically precise nanoclusters as catalysts, the oxidative coupling reaction occurred during the generation of nanoclusters. First, substituted pyridyl dicarbanion-bonded Ag₄ clusters were synthesized from simple propargylamine and ketones with a special macrocycle ligand, octamethylazacalix[8]pyridine (Py[8]).¹¹⁶ By adding different ketones (acetone, 2-pentanone, and acetophenone respectively), three atomically precise Ag₄ nanoclusters were synthesized: [Ag₅(C₆NH₅)(Py[8])](CF₃SO₃)₃ (denoted as ^MePyAg₅), [Ag₅(C₈NH₉)(Py[8])](CF₃SO₃)₃ (denoted as ^n-PrPyAg₅), and [Ag₅(C₁₁NH₇)(Py[8])](CF₃SO₃)₃ (denoted as ^PhPyAg₅). Three corresponding Ag₁₃ nanoclusters were produced using the Ag₄ nanoclusters and denoted as ^MePyAg₁₃, ^n-PrPyAg₁₃, and ^PhPyAg₁₃ respectively. According to the in situ ESI-MS monitoring, the cross-coupling product 2-methyl-2′-propyl-4,4′-bipyridine and the homo-coupling products 2,2′-dimethyl-4,4′-bipyridine and 2,2′dipropyl-4,4′-bipyridine were observed (Fig. 12d). The oxidative coupling of organic species during the in situ generation of metal subnano- or nano-clusters was proposed before, with uncertain mechanisms and unclear intermediates.^117,118 In this experiment, the removal of the macrocycle Py[8] ligands by protonation led to Ag₄ nanocluster combination. The Ag₄ combination underwent a two-electron oxidative coupling to release the Csp²–Csp² oxidative coupling products while generating low-valence silver atoms. It is worth noting that Ag₁₃ can further aggregate to larger nanoparticles while generating homo-coupling bipyridine products via intra-cluster oxidative coupling (Fig. 12c). It is not a traditional atomically precise nanocluster-catalyzed oxidative coupling reaction, but this study has raised a new idea of generating complex chemicals during the synthesis of nanoclusters.

3.2 Carbon–heteroatom coupling

Compounds containing carbon–heteroatom bonds have extensive applications in agriculture, pharmaceuticals, manufacturing, and material sciences.¹¹⁹ The construction of carbon–heteroatom bonds has been an essential research field in chemistry, and transition metal-catalyzed cross-coupling reactions are the most common methods developed for decades.¹²⁰ However, carbon–heteroatom cross-coupling catalyzed by nanoclusters is uncommon probably because the total development time of nanocluster catalysis is relatively short, let alone this type of reaction usually requires harsher reaction conditions leading to the degradation of nanoclusters.

Before applying atomically precise nanoclusters, metal nanoclusters with uncertain structures have been proven to be active catalysts for carbon–heteroatom cross-coupling reactions. Even though the unclear formula of the nanoclusters restricts the innovation of these novel strategies, they draw scientists’ attention toward the application of nanoclusters in carbon–heteroatom cross-coupling systems. Shimizu et al. noticed that supported Pt nanoclusters showed excellent catalytic properties toward selective cross-coupling of amines compared to the regular strategy.²⁸ They prepared a series of oxide-supported nanoclusters M_x/Oxides-D, where x is the content of (weight%) metal (M) and D is the particle size (nm), and treated them with morpholine and benzylamine.¹²¹ The results indicated that Pd nanoclusters with an average particle size of 1.8 nm supported by Al₂O₃ selectively produce cross-coupling products in a decent yield. Pd nanoclusters with larger average particle sizes would also catalyze this reaction with bad selectivity, while other metals such as Au, Ag, Pt, Rh, and Ru seldom catalyzed this reaction. The scope of the first example of reusable Pd nanocluster catalysts for cross-coupling of amines was expanded. Later, the same group found that alumina-supported Pt nanoclusters with an average particle size of 0.8 nm (Pt/Al₂O₃-0.8) were also effective catalysts for amine cross-coupling in the system of aniline and amine.²⁸

Corma and Leyva-Pérez et al. reported that copper nanoclusters with Cu atoms less than seven have a tremendous ability to activate and catalyze C–N, C–O, C–S, and C–P bond formation.¹²² They noticed that the cross-coupling reaction between iodobenzene and amide did not occur if the solvent was changed from amide (in this case, NMP) to toluene or dioxane when the copper salt was used as the catalyst. Subsequent experiments confirmed the formation of Cu nanoclusters in an amide solvent and the authors proposed that the amide acted as a reducing agent for the Cu nanoclusters. They first proved that Cu nanoparticles were not the active species. Cu nanoclusters with an average size of 5 atoms were proved to be effective catalysts for carbon–heteroatom coupling reactions. This experiment proves the catalytic potential of nanoclusters, in particular Cu nanoclusters, in carbon–heteroatom coupling systems.

3.2.1 Carbon–nitrogen coupling. To further explore Corma's discovery,¹²² Banerjee and Datta's group synthesized a well-defined blue-emitting Cu nanocluster Cu₆(GS)₂ (GS = C₁₀H₁₆N₃O₆S) (Fig. 10c).¹²³ DFT calculations predicted that six copper atoms formed a tetrahedron, while two sulfur atoms coordinated with four of the Cu atoms. The other two copper atoms were stabilized by oxygen atoms from glutathione. Free copper sites are exposed on the nanoclusters due to the arrangements of two glutathione. The Cu₆ nanocluster was then used as a catalyst for the Ullmann C–N coupling reaction. The DMSO-dissolved Cu₆ nanocluster was treated with aryl iodide and cyclohexylamine under strong basic conditions. Substituted iodobenzenes were screened and all of them gave great yields of more than 90% (Fig. 10d). The authors did not propose a plausible mechanism for the C–N coupling reaction. To my knowledge, iodobenzene adsorbed on one copper atom, while amines adsorbed on the adjacent copper. The oxidative addition occurred on both sides to form C–Cu and N–Cu bonds. The final product was generated after reductive elimination.

Copper nanoclusters are reported to have large absorption cross sections under visible light and possess long exited-state lifetimes.^124,125 Rueping's group realized that these properties make Cu nanoclusters as potential modular catalysts for cross-coupling reactions induced by visible light. Their instincts were proved to be right by the research on the Sonogashira cross-coupling reaction catalyzed by atomically precise copper nanocluster mentioned previously.⁹³ The same group also reported another example of using an atomically precise copper nanocluster to activate aryl chlorides to enable Ullmann C–N cross-coupling reactions.¹²⁶ [Cu₆₁(S^tBu)₂₆S₆Cl₆H₁₄]⁺ (denoted as Cu₆₁, –S^tBu: tert-butyl thiolate) was synthesized¹²⁷ and characterized (Fig. 13b). The nanocluster consists of a triangular gyrobicupola Cu₁₉ core and a novel “18-crown-6” metal sulfide-like belt as the shell. The model reaction was designed as follows: amination of carbazole with p-bromobenzonitrile in acetonitrile protected by nitrogen gas at ambient temperature under basic conditions. After optimization, their best yield was 88%, which was much better than the copper salt-catalyzed reactions. The authors spent much time examining the scope of this novel protocol, demonstrating that the Cu₆₁ nanocluster-catalyzed system showed great functional group tolerance (Fig. 13a). Of note, this methodology can be applied to aryl chlorides, which are much harder to activate than aryl bromides. A possible mechanism was proposed based on literature reports of copper-related photoredox chemistry⁹⁴ and their confirmatory experiments (Fig. 13c). The amine adsorption on copper nanoclusters was the first step followed by blue-light irradiation to produce the photoexcited state. A SET process happened to donate an electron to aryl halide, generating an aryl radical species and bringing copper nanoclusters to the ground state spontaneously. The desired C–N coupled product was synthesized by radical–radical bounding, bringing the copper nanocluster to its original form. Copper nanoclusters exhibit a unique role in photocatalysts for coupling reactions. Thus, there is no doubt that more examples of copper nanocluster-related photocatalyst coupling reactions spring out sooner than later.

Fig. 13 (a) Substrate scope of aryl halides catalyzed by Cu₆₁. (b) Well-defined crystal structure of the Cu₆₁ nanocluster. Color legend: green and brown, copper atoms of the core and the shell, respectively; yellow, sulfur; dark blue, chloride; and gray, carbon (c) proposed reaction mechanism of the C–N cross-coupling catalyzed by Cu₆₁. Reprinted with permission from ref. 126. Copyright 2022 American Chemical Society.

3.2.2 Carbon–oxygen coupling. Most reported bimetallic nanoclusters have more than 25 metal atoms consisting of a so-called “core–shell” structure.^44,128 Conversely, the nanoclusters do not have a core–shell scaffold, i.e. “coreless”, when they have less than 10 metal atoms.^129,130 Zhu et al. believed that it is worth researching the catalytic properties of coreless bimetallic nanoclusters owing to the exposure of all metal atoms and the bimetallic synergism. Therefore, Zhu and Sheng's groups reported the first Ullmann C–O coupling reaction catalyzed by coreless atomically precise nanoclusters.¹³¹ To emphasize the catalytic performance of coreless bimetallic nanoclusters, the authors synthesized a group of atomically precise nanoclusters including coreless monometallic nanoclusters,^132,133 coreless bimetallic nanoclusters [Au₄Cu₅(Dppm)₂(C₆H₁₁S)₆]⁺ and [Au₄Cu₄(Dppm)₂(SAdm)₅]⁺ (ref. 129 and 130) (Dppm = bis(diphenylphosphino)methane), core–shell monometallic nanoclusters,^37,104 and core–shell bimetallic nanoclusters.¹⁰⁰ All nanoclusters were mounted on AC to fascinate the heterogeneous catalysts for C–O coupling between phenol and p-nitrobenzaldehyde. The experimental data showed that most of the nanoclusters can catalyze the C–O coupling to some extent, while Au₄Cu₅/AC provided the best result. Under optimized conditions, Au₄Cu₅/AC gave a 98% yield with a turnover number (TON) of 4375 and the catalytic ability was intact even after five cycles. Various substituted nitrobenzenes and substituted phenols were treated with optimized reaction conditions and Au₄Cu₅/AC represented great functional group tolerance (Fig. 14a). DFT calculations and proton NMR analysis were conducted to meet mutual agreement on the mechanism of the C–O coupling catalyzed by Au₄Cu₅ (Fig. 14b). Phenol and p-nitrobenzaldehyde coordinated on two adjacent gold atoms respectively. Then an S_N2 substitution occurred when the PhO-attacking nitrobenzene carbon generated the intermediate. The nitro group left and the biaryl ether was constructed. During the catalytic process, the bond length between Au₂–Cu₂ and Au₂–Cu₃ changed significantly to lower the energy barrier of generating the intermediates. The full exposure of metal active sites due to the coreless arrangement is the key to the functioning of this coupling reaction.

Fig. 14 (a) Scope of the Au₄Cu₅/AC-catalyzed Ullmann C–O coupling. (b) Mechanism of the Ullmann C–O coupling reaction over the Au₄Cu₅ nanocluster. Reprinted with permission from ref. 131. Copyright 2023 Tsinghua University Press. (c) Structure of Au₂₅(PPh₃)₁₀(PA)₅X₂. Color codes: Au, yellow; P, pink; C, gray; X (Cl/Br), green; phenylacetylide, red. (d) Mechanism of the catalyzed A³-coupling reaction over the Au₂₅(PH₃)₁₀(PA)₅Cl₂ cluster. Color code: Au, yellow; P, purple; X, green; N, blue; C, gray; H, white. Only partial gold atoms are shown in 2Im₁, 2Im₂, 2Im₃, and 2Im₄, and other atoms are omitted for clarity. Reprinted with permission from ref. 145. Copyright 2021 Elsevier Inc.

3.3 Multicomponent coupling reactions

The construction of complex molecules from simple and readily available substrates is a major challenge in organic chemistry.¹³⁴ Multicomponent coupling reactions are effective methodologies for generating complex chemical frameworks from simple substrates in a single step. They provide a chance for the formation of multiple bonds simultaneously. Atomically precise nanoclusters seem to be capable of catalyzing this type of coupling reaction effectively owing to their abundant active sites for multiple bond formation. Moreover, the synergistic effect between hetero-metal atoms opens access to the carbon–heteroatom linkage in multicomponent coupling reaction systems.

3.3.1 A³ coupling. The A³ coupling, coined by Li, is a multicomponent coupling reaction connecting an aldehyde, an alkyne, and an amine to product propargylamine.¹³⁵ Moreover, the construction of biologically active compounds and natural products containing nitrogen heterocycles can be started by A³ coupling.¹³⁶ Mechanistically, the alkyne needs to be activated by a metal catalyst (copper,¹³⁶ ruthenium/copper,¹³⁷ iron,¹³⁸ nickel,¹³⁹ silver,¹⁴⁰ and gold¹⁴¹) to a metal acetylide while the amine and aldehyde combine to form an imine. The nucleophilic addition between the metal acetylide and the imine generates a chiral-centered propargylamine. The atomically precise nanoclusters are proven to be efficient media for alkyne activation⁹ and the nucleophilic addition process can be facilitated and accelerated by nanoclusters.¹⁴² Hence, research on A³ coupling catalyzed by atomically precise nanoclusters is a valuable direction to discover the application of nanocluster catalysis.

To our knowledge, almost all reported reactions of atomically precise nanoclusters related to A³ coupling are catalyzed by gold-based nanoclusters.¹⁴³ The Au₂₅ nanoclusters’ high status in nanocluster catalysis is still invincible. Two research groups reported Au₂₅ nanocluster-catalyzed A³ coupling in 2016 independently.^144,145 The protecting ligand used by Obora's group was phenylethanethiol ([Au₂₅(PET)₁₈]), while Li et al. mediated phosphine and phenylacetylide as the ligands (Au₂₅(PPh₃)₁₀(C≡CPh)₅X₂ (X = Cl/Br)) (Fig. 14c). Unlike Obora's strategy, Li immobilized Au₂₅ nanoclusters on TiO₂ but both plans have decent functional group tolerance. It is worth noting that even though both reactions required an external heating source, Li's protocol used water as the solvent, which has zero hazardous concerns compared to toluene. Additionally, Obora noticed that the initial substrate ratio played an important role in the coupling reaction. The access of alkyne increased the yield, while the yield decreased if too much amine was added. Oxygen is an essential additive in Au₂₅(PET)₁₈ systems, while Au₂₅(PPh₃)₁₀(C≡CPh)₅X₂ required an aerophobia environment. Li's group shed light on the mechanism of the A³ coupling over gold nanoclusters by DFT calculations (Fig. 14d). They believed that one of the phosphine ligands was removed exposing the metal site for the catalysis. Terminal alkyne was activated by the open metal site making it easier to be deprotonated by a base. The iminium ion adsorbed on the open site was then attacked by –C≡CPh to form the final product.

Another example of A³ coupling over pure gold nanoclusters was reported in the same year by Jin et al.¹⁴⁶ A bigger thermally stable gold nanocluster Au₃₈(SC₂H₄Ph)₂₄ was synthesized¹⁴⁷ and characterized. According to the X-ray crystallography, the nanocluster was composed of a bi-icosahedral Au₂₃ core, six dimeric Au₂(SR)₃, and three monomeric Au(SR)₂ surface motifs. The authors realized that the catalytic performance would decrease drastically if the protecting thiolate ligands were removed by thermal pretreatment.^148,149 Moreover, the Au(I)-S-C₂H₄Ph complex was synthesized to apply to the same reaction while giving a significantly decreased conversion rate. These two comparison experiments demonstrated that the catalytic property of the Au₃₈ nanoclusters was coming from the entire structure since both the synergistic effect of the thiolate-protected gold surface and the electron-rich Au₂₃ kernel played important roles in their catalytic performance. Of note, this strategy can proceed without any solvent, making it an environmentally friendly method. Later, Leong and Li investigated a smaller-size Au nanocluster in A³ coupling and once again underlined the ligand effects on the nature of nanoclusters’ catalytic ability and efficiency.¹⁴³ They have synthesized an Au₁₃ nanocluster ([Au₁₃{Sb(p-tolyl)₃}₈C_l4][Cl]) stabilized by stibine, which is not a common ligand for Au nanoclusters.¹⁵⁰ The 13 gold atoms formed an icosahedral model with 90 : 10 disorder surrounded by eight SbPh₃ and four chlorides. According to their comparative study, the Au₁₃ nanoclusters have much better catalytic ability than that of previously mentioned Au₂₅ ^144,145 and Au₃₈ ¹⁴⁶ nanoclusters protected by phosphines or thiolates. Au₁₃ nanoclusters managed to catalyze the A³ coupling reaction of benzaldehyde, piperidine, and phenylacetylene with (1) low catalyst loadings; (2) short reaction periods; (3) solvent-free nature; (4) protection-gas-free nature; (5) low reaction temperatures; and (6) high conversion rates. However, the authors did not test the scope and limitations of this protocol leaving blank space for future discovery. We stay tuned for the additional application of this highly effective strategy.

The first atomically precise bimetallic nanocluster-catalyzed A³ coupling was discovered by Wu et al.¹⁵¹ They prepared [Au₁₃Cd₂(PPh₃)₆(SC₂H₄Ph)₆(NO₃)₂]₂Cd(NO₃)₄ (Au₂₆Cd₅) by peeling and doping the well-studied Au₂₅(SCH₂CH₂Ph)₁₈ nanocluster. Au₂₅(SCH₂CH₂Ph)₁₈ can be peeled to Au₁₃(PPh₃)₈(SCH₂CH₂Ph)₃₂⁺via ligand exchange of PPh₃.¹⁵² Two Au₁₃Cd₂ units were formed and linked by Cd(NO₃)₄ when a cadmium salt gets involved. Even though Au₂₅(SCH₂CH₂Ph)₁₈ has no catalytic ability toward A³ coupling, Au₂₆Cd₅ showed exclusive catalytic performance and functional group tolerance. This methodology represented the importance of tuning the nanoclusters’ compositions and structures in improving their catalytic performance. Li et al. synthesized a coreless Au₂Ag₂(C₁₀H₆NO)₄(Ph₃P)₂ bimetallic nanocluster with a well-elucidated crystal structure.¹⁵³ The gold and silver atoms are located in a plane to form a rhombus. The two phosphine and two benzonitrile ligands coordinate with the silver atom through σ-bonds and π-bonds respectively, while the gold atom only coordinates with benzonitrile ligands via σ-bonds (Fig. 15a). Interestingly, the homologous Au₄(C₁₀H₆NO)₄(PPh₃)₂ and Ag₄(C₁₀H₆NO)₄(PPh₃)₂ clusters cannot be prepared via a similar synthetic route. Hence, the triple bond of benzonitrile binding to Au and Ag through σ- and π-bonds respectively, which is considered a novel alkyne-metal coordination mode, is the key to forming the alloy nanocluster. The nanocluster was then immobilized on TiO₂ to catalyze a three-component coupling reaction of benzaldehyde, piperidine, and phenylacetylene. The result indicated that the Au₂Ag₂/TiO₂ did a better job than phosphine-protected Au₂₅ and Au₁₃ nanoclusters owing to the full exposure of metal active sites.

Fig. 15 (a) 1. Full structure of Au₂Ag₂(L)₄(Ph₃P)₂ with 30% probably ellipsoids. 2. Core structure and coordination model in Au₂Ag₂ clusters. Color code: Au, gold; Ag, dark blue; P, pink; O, red; N, blue; C, grey. H atoms are omitted for clarity. Reprinted with permission from ref. 151. Copyright 2017 Royal Society of Chemistry. (b) Illustration of the composition control (innermost kernel, icosahedral edge, and outmost shell) of core–shell nanoclusters to obtain multi-stratified alloy nanoclusters that display enhanced thermal stability, owing to the concentration of free valence electrons to the interior of nanoclusters. (c) Syntheses and crystal structures of monometallic Ag₂₉, bimetallic Ag₁₇Cu₁₂, and trimetallic Au₁Ag₁₆Cu₁₂ nanoclusters. (d) Multicomponent A³ coupling reaction of benzaldehyde, pyrrolidine, and phenylacetylene catalyzed by different nanoclusters. Reprinted with permission from ref. 154. Copyright 2019 American Chemical Society.

The only reaction of A³ coupling over atomically precise nanoclusters that is not catalyzed by a Ag-based nanocluster was reported by Zhu and Kang's groups in 2019.¹⁵⁴ The authors’ indication of designing the specific trimetallic nanocluster (Au₁Ag₁₆Cu₁₂(SSR)₁₂(PPh₃)₄) was to investigate whether rearrangements of free valence electrons could stabilize nanoclusters. Substituting the parent metal with hetero-metal atoms would change the electron distribution probably according to their electronegativity. In other words, doping higher electronegativity metal atoms into the kernel and exchanging the shell with lower electronegativity metal atoms could endow the core–shell nanocluster with a higher partial positive charge (δ⁺) on the surface and partial negative charge (δ⁻) on the kernel (i.e., metallic state M⁰). The highly positive-charged surface would make the nanocluster hard to be further oxidized, leading to better thermostability.¹⁵⁴ The Ag nanoclusters are considered unstable, and doping inert metals into the kernel of Ag nanoclusters could secure thermal stability due to the electron distribution rearrangement.^155,156 Therefore, the design thinking of the groups was manipulating nanoclusters’ stability through valence electron centralization by putting copper (electronegativity is 1.9) into the outmost shell of the core–shell Ag nanocluster (Ag's electronegativity is 1.93) and doping Ag (electronegativity is 2.54) in the innermost core of the Ag nanocluster (Fig. 15b). The bimetallic Ag₁₇Cu₁₂ and trimetallic Au₁Ag₁₆Cu₁₂ nanoclusters were synthesized and determined respectively (Fig. 15c). Thermal stability tests were performed sequentially, showing that free valence electron centralization is a promising means to stabilize nanoclusters. The homologous Ag₂₉ nanocluster lost its original form when heated at 130 °C under vacuum, while Ag₁₇Cu₁₂ remained intact at 150 °C under vacuum. Surprisingly, Au₁Ag₁₆Cu₁₂ retained their original formation even at 175 °C under air. Hence, Au₁Ag₁₆Cu₁₂ can be applied to catalytic reactions with high temperature (175 °C) without protection gas. Thus, a high-temperature three-component coupling reaction of benzaldehyde, pyrrolidine, and phenylacetylene was conducted to demonstrate the extraordinary catalytic nature of Au₁Ag₁₆Cu₁₂ (Fig. 15d). The A³ coupling reaction catalyzed by Au₁Ag₁₆Cu₁₂ can proceed at 130 °C, giving a 99% conversion rate within three minutes. Moreover, the catalytic ability of Au₁Ag₁₆Cu₁₂ remained the same even after five cycles of high-temperature treatment. The intriguing methodology of thermally stabilizing nanoclusters and the stunning catalytic performance of the stabilized nanoclusters provide new insights into the composition-property collaborations that will keep catching scientists’ eyes in materials science.

3.3.2 AHA coupling. Similar to A³ coupling, the multicomponent coupling reaction of alkyne, halomethane, and amine (AHA) produces propargylamines. To date, remarkable efforts have been made on this system by applying metal catalysts such as Cu,^157,158 In,¹⁵⁹ Fe,¹⁶⁰ Co,¹⁶¹ Ni,¹³⁹ Ag,¹⁶² and Au.^163,164 A metal-free version of the AHA coupling was also developed but with mediocre yields.¹⁶⁵ The involvement of dihalomethane, an inexpensive industrial solvent, makes the AHA coupling a valuable methodology for synthesizing propargylamines. Very recently, the example of atomically precise nanocluster-catalyzed AHA coupling has been reported by Zhu and Sheng's groups.¹⁶⁶ Three small nanoclusters with precise structure, namely, Cu₃I₂H(Dppm)₃,¹⁶⁷ Cu₆(SC₇H₄NO)₆,¹⁶⁸ and [Cu₁₁(TBBT)₉ (PPh₃)₆](SbF₆)₂ ¹³³ were synthesized, characterized (Fig. 16a) and supported by AC respectively. Three nanoclusters represented the intrinsic catalytic ability over AHA coupling of phenylacetylene, piperidine, and dichloromethane with a large TON at 50 °C (313.2, 345.8, and 353.5 respectively), while previously reported catalysts gave a super low TON (Fig. 16b). Cu₆/AC was selected as the model catalyst for scope and limitation examination. It turned out that this composite bested almost all non-noble metal catalysts mentioned before in the total conversion rate, functional group tolerance, and TON. During the mechanistic study, GC MS detected methyleneammonium, which was probably generated by the amine and dichloromethane under basic conditions.¹⁶⁹ Hence, the mechanism they proposed accordingly was depicted (Fig. 16c). The copper nanocluster activated the terminal alkyne, while methyleneammonium formed independently. The methyleneammonium was then adsorbed by the nanocluster, providing the site for interaction between methyleneammonium and activated alkyne. The final product was released after reductive elimination.

Fig. 16 (a) Schematic illustration of the formation of Cu_n (n = 3, 6, and 11)/AC. (b) TON value of different catalysts for the AHA coupling reaction. Reaction conditions: 6.6 × 10⁴ mmol Cu catalyst or 3.8 × 10³ mmol copper metal species, phenylacetylene (0.25 mmol), Cs₂CO₃ (0.25 mmol), piperidine (0.56 mmol), dichloromethane (1.0 mL), 50 °C, reacting for 24 h under argon. (c) A plausible mechanism for the synthesis of propargylamines via the coupling of phenylacetylene, piperidine, and dichloromethane using Cu₆/AC. Reprinted with permission from ref. 166. Copyright 2022 Wiley-VCH GmbH.

4. Conclusion and perspectives

Atomically precise nanoclusters have demonstrated their essential position in nanomaterials by representing tremendous applications in thermal-, electrical-, and photo-catalysis reactions.⁶ These catalytic reactions over nanoclusters cover most of the research and application fields of advanced materials, which means atomically precise nanoclusters are all-rounders of academia, industry, agriculture, and pharmacy. Particularly, in the past two decades, the development of confined nanocluster catalysts in coupling reactions has delivered effective, low-cost, and environmentally friendly methodologies for synthesizing complex chemical species from simple molecules. To date, coupling reactions connecting Csp²–Csp², Csp–Csp², Csp–Csp, C–N, C–O, and C–N–C bonds can be mediated by atomically precise nanoclusters (Table 1). Au nanoclusters and Au-based alloy nanoclusters are the most prominent nanocluster catalysts as generalists of almost all coupling reactions mentioned in this review. The higher catalytic activity comes from the distinct electronic properties of Au^8,154 and the superior synergism related to hetero-metal atoms, protecting ligands and supports. The Au–S metallic bond stabilizes the nanoclusters while leaving more room for catalytic active sites. This makes thiolate-protected Au nanoclusters more useful in coupling reactions. The doping effect of hetero-metal atoms makes Au-based alloy nanoclusters suitable for multiple coupling bond formation systems. Au–Cu alloy nanoclusters seem to be rising stars in this field because doping copper in Au nanoclusters decreases the total cost while showing even better catalytic abilities. Of note, CeO₂ and TiO are probably the best assistants for Au nanoclusters under catalytic reaction conditions.^170,171 Pd nanoclusters, in particular small Pd nanoclusters (metal number less than 10), have their unique position in nanocluster-based catalysts since they are still the only active nanoclusters for the Heck reaction, let alone their distinguish catalytic properties in other C–C and C–N connection systems. The development of nanocluster-catalyzed coupling reactions follow the same path as regular coupling reactions³⁶ where the advanced catalysts are transforming from noble metal nanoclusters to non-noble metal nanoclusters. Copper nanoclusters as the most researched non-noble metal nanoclusters demonstrated extraordinary catalytic abilities in coupling reactions. As the price of precious metals continues to rise, copper nanoclusters are bound to become the most popular nanoclusters in the future.

Based on different types of coupling reactions, capping ligands, motifs, kernels, and support influence nanoclusters’ catalytic properties collectively. In general, aromatic protecting ligands tend to give better results in coupling systems compared to aliphatic ligands including thiolate-, phosphine-, and alkyne-aromatic ligands. The synergistic effect between noble metal nanoclusters (Au, Pd, Pt, etc.) and the metal oxide support is obvious, while Cu nanoclusters are usually mounted on porous carbon materials. Nanoclusters with core–shell structures are more stable than coreless nanoclusters, while coreless nanoclusters provide more metal active sites. The hetero metal synergetic effects are an ice breaker in carbon-heteroatom coupling systems. It indicates that nanocluster-catalyzed carbon–heteroatom cross-coupling reactions are size- and support-specific, which emphasizes that the designing of the nanoclusters is the key to altering nanoclusters’ catalytic properties. The atomic-defined nature of atomically precise nanoclusters provides opportunities for trimming and fine-tuning their structures, so that their catalytic properties can be evaluated atom-by-atom and ligand-by-ligand.

Herein, several perspectives regarding atomically precise nanoclusters over coupling reactions are discussed below.

(i) Recommendations for synthesizing atomically precise nanoclusters toward target coupling reactions (and vice versa). Au₂₅ and its alloy nanoclusters are the best shots for the Ullmann C–C coupling reactions. If the designed products are symmetric biaryls (homocoupling products), Cu_xAu_(25−x) bimetallic nanoclusters or Au₁₁ and other smaller Au nanoclusters¹⁷² that behave like single atoms should be considered for the systems. Ce₂O should be considered as the immobilizer if a heterogenous catalyst is needed. As for heterocoupling reactions, Pt_xAu_(25−x) nanoclusters protected by aromatic ligands are the top-one candidates. As for S–M coupling reaction systems, Pd nanoclusters are more effective than other metal nanoclusters. Pd alloy nanoclusters and small Pd nanoclusters should be better candidates for S–M coupling reactions. The Heck reaction is one of the most important paths for coupling sp² carbon with hydrocarbons in one step. Hence, the development of atomically precise nanocluster-catalyzed Heck reaction systems calls for brainstorming despite insufficient examples. From my perspective, future exploration could still be focused on small Pd_n nanoclusters (n = 2–10) and Pd-based alloy nanoclusters such as Pd–Cu nanoclusters. The development of the Sonogashira cross-coupling reaction catalyzed by atomically precise nanoclusters follows the same path as the traditional Sonogashira reaction by moving from expensive noble metal nanoclusters to cheap copper nanoclusters. For future reference, atomically precise copper nanoclusters are still the seeded players in the Sonogashira cross-coupling reaction system. The surface defective effect is calling for a deeper investigation to unveil the relationship between defects and catalytic ability. Copper nanoclusters with precision numbers are still the most rational candidates for oxidative C(sp)–C(sp) coupling reactions. It is still worth optimizing reaction conditions to reduce the reaction temperature and time.

The total development time of C-heteroatom coupling is relatively short. Hence, the time for summarization is not yet ripe. However, based on the limited examples, the atomically precise nanoclusters showed overwhelming catalytic abilities for carbon–heteroatom coupling. Future exploration could focus on coreless alloy nanoclusters since they are much easier to prepare than single-atom catalysts and core–shell nanoclusters. Corma, Leyva-Pérez, et al. have proved the catalytic ability of small Cu nanoclusters in carbon–heteroatom bond formation.¹²² Research related to C-heteroatom bond connection should pay more attention to small Cu and small Cu-based alloy nanoclusters. A³ coupling systems seem to need higher reaction temperatures for the best yield. Thus, thermally stable nanoclusters are the optimal candidates for multicomponent coupling reactions.

In general, even though the majority of reports use bigger nanoclusters with core–shell structures in catalytic systems, we believe that small atomically precise nanoclusters with metal numbers less than 10 will demonstrate a paramount role in catalyzed-coupling reactions in the future because (1) small nanocluster synthesis procedures are much easier than those of bigger nanoclusters; (2) full access to metal-core provides more active sites; (3) the synergistic effect of adjacent metal atoms cannot be interrupted by ligands; (4) calculations and simulations involving fewer atoms are much easier to be conducted for better mechanistic understanding.

(ii) There are still lots of coupling reactions that have not been explored over atomically precise nanoclusters such as Csp³–Csp³, Csp³–Csp², and Csp³–Csp. The activation of Csp and Csp² can be achieved by nanoclusters, while the example of Csp³ activation is less common over atomically precise nanoclusters. The sp³ C–H activation is generally accepted to be much more challenging owing to the low reactivity (high bond energy).¹⁷³ Modern strategies of sp³ C–H functionalization usually rely on SET induced by light-activated catalysts and photoredox catalysis,^174–176 which remind us of the optical properties^124–126 of copper nanoclusters. Therefore, copper nanoclusters with large absorption cross-sections under visible light and longer excited-state lifetimes should be examined for sp³ C–H functionalization systems. Even though only C–N and C–O coupling reactions catalyzed by atomically precise nanoclusters have been discovered, other carbon-heteroatom bond formations such as C–S, C–P, and C–Si should be taken into consideration according to Corma's findings¹¹⁸ to test the catalytic ability of copper coreless alloy nanoclusters.

Catalytic asymmetric coupling reactions, especially the sterically specific Suzuki–Miyaura coupling are one the most useful methods to synthesize chiral biaryls. The most common ligands for asymmetric catalyst metal complexes are optical phosphine ligands,¹⁷⁷ which can be utilized as nanoclusters’ capping ligands as well. Atomically precise nanoclusters possess distinct optical properties,^178,179 while their optical properties can be altered by engineering protecting ligands.¹⁸⁰ Therefore, the development of catalytic asymmetric coupling reactions over atomically precise nanoclusters with optical ligands should be taken into account.

(iii) Keeping nanoclusters stable and active during catalytic reactions are one of the major challenges in practical applications of atomically precise nanoclusters. Zhu and Kang's strategy of generating trimetallic nanoclusters is a prominent protocol to stabilize nanoclusters by rearrangement of free valence electrons.¹⁵⁴ The core–shell nanocluster has a higher partial positive charge (δ⁺) on the surface and partial negative charge (δ⁻) on the kernel. This valence electron centralization pattern should be promoted for the future design of thermostable nanoclusters by doping higher electronegativity metal atoms into the innermost kernel and exchanging the outmost metal shell with lower electronegativity metal atoms.

Another strategy of stabilizing nanoclusters is to immobilize nanoclusters on supports such as metal oxides and porous carbon materials. The synergism effect and host–guest interaction enhance nanoclusters’ catalytic abilities while keeping the nanoclusters intact under various harsh reaction conditions. Modern technology of reticular chemistry offers novel and superior support materials for nanoclusters such as metal–organic frameworks (MOFs), covalent organic frameworks (COFs), and hydrogen-bonded organic frameworks (HOFs). Compared to regular supports, the reticular materials have accurate structures and specific porous sizes that can be designed and modified to cooperate with nanoclusters for optimal catalytic properties. Compositing nanoclusters with MOFs¹⁸¹ and COFs¹⁸² can largely enhance their photostability and photocatalytic performance. Even though there are very few publications on nanocluster/reticular materials in practical applications, we believe that reticular chemistry has great potential in collaboration with atomically precise nanoclusters to rationally design effective catalysts for coupling reactions.

In conclusion, atomically precise nanoclusters hold unlimited potential in catalyzing reactions and understanding reaction processes mechanistically. By designing specific protecting ligands, metal kernels, and support, an effective nanocluster catalyst could be generated for target coupling reactions. There are still some obstacles to apply nanocluster catalysts in complicated reaction conditions, including the instability of nanoclusters and the uncertain synergetic effect between components. With the development of atomically precise nanocluster chemistry and their related nanocomposites, the rational designing of nanoclusters for specific reaction systems could be more regulated and straightforward.

Data availability

This is a Review article, and no data supporting this review have been included. Thus, the section of “Data availability” is not applicable for this work.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We acknowledge the financial support of the NSFC (22371003 and 22101001), the Ministry of Education, the University Synergy Innovation Program of Anhui Province (GXXT-2020-053), the Scientific Research Program of Universities in Anhui Province (2022AH030009), and the Research Program of Wuhu Hangfeng Techo Ltd (2024340104001629).

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