Marc Camats

Daniel Pla

Montserrat Gómez

Copper nanocatalysts applied in coupling reactions: a mechanistic insight

Copper-based nanocatalysts have seen a great interest in synthetic applications since the early 20th century, as evidenced by the exponential number of contributions reported (since 2000, more than 48,000 works published out of about 81,300 since 1900; results of SciFinder using "copper nanocatalysts in organic synthesis" as keywords). These huge efforts are mainly based on two key aspects: i) copper is an earth abundant metal with low toxicity, leading to inexpensive and eco-friendly catalytic materials; and ii) copper can stabilize different oxidation states (0 to +3) for molecular and nanoparticle-based systems, which promotes different types of metal-reagent interactions. This chemical versatility allows different pathways, involving radical or ionic copper-based intermediates. Thus, copper-based nanoparticles have become convenient catalysts, in particular for couplings (both homo and hetero-couplings), transformations present in a remarkable number of processes affording organic compounds, which find interest in different fields (medicinal chemistry, natural products, drugs, materials…). Clearly, this richness in reactivity makes understanding the mechanisms more complex. The present review focuses on the analysis of reported contributions using monometallic copper-based nanoparticles as catalytic precursors applied in coupling reactions, paying attention to those shedding light on the reaction mechanism.

Introduction

Coupling reactions are known since the middle of the 19 th century when Charles A. Wurtz described in 1855 the homocoupling of alkyl halides using sodium as reducing agent. 1 Later, in 1869, Carl A. Glaser reported the coupling of terminal alkynes using stoichiometric amounts of copper 2 and in 1901, Fritz Ullmann published the coupling of aryl halides. 3 Cross-couplings promoted by copper were first described by F. Ullmann 4 and Irma Golberg 5 in 1905 and 1906, respectively. Despite these relevant contributions, copper was not largely applied in organic synthesis until the 1960's, probably due to experimental limitations associated with pioneer works, such as high temperature, high metal loading, reaction hazards and relatively low tolerance to functional groups. 6 Advances in innovative ligands and a better understanding of reaction mechanisms facilitated the design of copper-based catalysts overcoming the initial issues. On top of that, copper is a relatively abundant metal (70 ppm of the earth's crust versus 0.015 ppm for Pd) with low toxicity, resulting in less expensive and more sustainable catalysts than those involving heavier transition metals. Currently, copper represents a competitive alternative to palladium, from an environmental and economical point of view. This trend is clearly evidenced by the exponential reported contributions since 2000 (Fig. 1). From a mechanistic point of view, the interest of copper in organic synthesis is mainly motivated by two key aspects. First, copper is capable of stabilizing different oxidation states (from 0 to +3) permitting both one-and two-electron transfer (i.e. radical and polar) pathways. Second, copper can easily bind to heteroatoms and favour both -and -interactions with unsaturated functional groups. Furthermore, copper exhibits the ability to form coordination and organometallic complexes, and also well-defined nanoparticles, tuning their structures and compositions due to the copper oxidation state and the nature of ancillary ligands (or stabilisers for metal-based nanoparticles). In terms of applications view, the use of both heterogenised molecular-based catalytic systems and copperbased (un)supported nanoparticles allow a straight-forward catalyst recycling, working under batch or flow conditions.

Fig. 1 Publications in the period 1905-August 2021 using "copper nanocatalysts in organic synthesis" as search topic (data collected from SciFinder database).

a. Laboratoire Hétérochimie Fondamentale et Appliquée, UMR CNRS 5069, Université Toulouse 3 -Paul Sabatier, 118 route de Narbonne, 31062 Toulouse cedex 9, France. Email: pla@lhfa.fr; gomez@chimie.ups-tlse.fr

Nanocatalysis using metal nanoparticles as catalytic precursors represents a fast developing area with broad applications in chemical synthesis. [START_REF] Heiz | Nanocatalysis[END_REF] Small-sized metal nanoparticles ranging from 1-10 nm in diameter exhibit distinct catalytic activities, often better than the parent molecular complexes or heterogeneous catalysts. This catalytic behaviour is mainly due to the extended surface areas of nanomaterials, which compared to bulk materials, exhibits a higher concentration of defects at the surface and low-coordinated metal centres providing a high concentration of highly reactive sites. The small size of nanoparticles does provide a particular set of electronic and quantum effects which may unlock catalytic pathways only allowed by the use of nanocatalysis. Metal nanoparticles immobilised both in solution and solid supports, find efficient applications due to their facile recovery without losing their catalytic properties, which makes them environmentally friendly. [START_REF] Nasrollahzadeh | [END_REF] Current methods of metal-based nanoparticles encompass catalyst preparation by reduction of Cu(I) and Cu(II) salts and organometallic complexes (such as CuI, mesitylcopper(I), Cu(OAc)2 or Cu(NO3)2) in the presence of solid supports or liquid phases. 9 Despite copper species shall be completely reduced to zero-valent copper nanoparticles, electron deficient Cu δ+ sites via the loss of electrons at the Fermi level or even residual cationic copper species (showing different oxidation states) may be of paramount importance in enabling reactivity and selectivity trends. This nanoparticle feature induces a certain flexibility at the metal centres, in terms of charge stabilisation, especially important throughout electron transfer steps, from both thermodynamic and kinetic point of view. The soft Lewis acidity of such cationic species on small Cu nanoparticles may be responsible for the catalytic activity. Despite the elucidation of the catalytic active species is challenging because the variety of copper oxidation states (i.e. 0, +1, +2 and +3) and many organic reactions can be catalysed by Cu(I), Cu(II) or Cu(III) complexes and by copper-based nanoparticles (Cu(0), CuxOy, CuxSy…), the rational design of catalytic systems is key towards reaction optimization and catalytic performance enhancement (e.g. conversion and selectivity) of nanocatalysts, required to move forward more sustainable applications. 10 From a mechanistic point of view, nanoparticles morphology (i.e. size, shape and structure) is crucial for understanding the catalytic reactivity, in particular the recognition and quantification of the active sites. 11 Regarding size, small nanoparticles (1-5 nm) exhibits a suitable compromise between active surface and structure stability. However, MNPs morphology often varies during the catalytic reaction, due to the formation of diverse intermediates that can trigger morphological changes (Fig. 2). 12 For these purposes, modelling studies represent an essential tool which enables correlating calculations with experimental data. Recently, Maestri, Mpourmpakis and co-workers have modelled the catalytic reactivity and morphology of MNPs under reaction conditions (in particular for RhNPs applied to the dissociation of CO), by Boltzmann statistics and DFT calculations, for the most stable nanoparticles and the ensemble of nanoparticles. The correlation between reactivity in terms of different active sites was in good agreement with experimental data. 13 However, the multi-component reactions make these methods difficult, due to the multiple interactions to be considered. Zheng and coworkers have carried out a meaningful work on coordination of organic molecules to defined metallic clusters with the aim of using them as models for surface coordination chemistry of MNPs. 14 On the other hand, the incessant progresses on characterization techniques, in particular those based on real-time approaches, lead to a better understanding of the catalytic transformations.

In this review, advances in mono-metallic copper-based nanocatalysts for organic synthesis purposes are discussed, highlighting those contributions with mechanistic approaches.

Homocoupling reactions

C(sp)-C(sp) homocoupling reactions

Since the first copper-mediated acetylenic homo-coupling reaction reported by Glaser back in 1869, where copper(I) phenylacetylide underwent dimerization under aerobic conditions to deliver diphenyldiacetylene, 2,15 followed by a catalytic version (Hay modification) using nitrogen donor ligands such as N,N,N',N'-tetramethylethylenediamine (TMEDA) which facilitated the reaction under homogeneous and aerobic conditions, 16 progress has been made on the elucidation of activation mechanisms of terminal alkynes via σand π-bond coordination modes with low-valent Cu catalysts, namely Cu(0) or Cu2O, but the higher complexity of nanostructured systems in comparison to classical molecular or heterogeneous systems demands cutting-edge characterization methods to speed innovation in this field. Copper nanocatalysts, mainly immobilised systems, have provided a greener route towards the production of 1,3-diynes, allowing metal recovery and catalyst reusability and at the same time providing safer procedures. Often being able to replace the use of pure oxygen by air and avoiding refluxes of flammable solvents. Thus, this section summarizes the recent advances in Cu(0) and Cu2O NPs catalysed C(sp) homocoupling reactions to Please do not adjust margins Please do not adjust margins yield symmetrical 1,3-diynes products with special emphasis on the catalyst morphology, oxidation state and support. Although the specific role of small nanoparticles (1-10 nm) in the reaction mechanisms is challenging to ascertain, such nanoparticles have been demonstrated to exhibit unique catalytic properties. Radivoy and co-workers have reported the use of very reactive and monodisperse (3.0 ± 1.5 nm), spherical low valent copper nanoparticles in-situ generated from anhydrous CuCl2 and lithium sand (in equimolar amounts). 17 Despite the lack of stabilizing agents triggered particles agglomeration (up to 15-30 nm diameter sizes after THF reflux for 6 h), this catalytic system permitted the homocoupling of traditionally sluggish alkylacetylenes under N2 (Scheme 1). The authors have validated the role of the base in enhancing reaction rates and propose the formation of alkynyl-Cu complexes, but claim for further studies to ascertain the differential reaction mechanism of Cu(0) NPs versus the classical one via Cu(I)-acetylide intermediates. Indeed, the role of lithium alone via the formation of more complex bimetallic systems could not be excluded at this time.

Scheme 1 Homocoupling of alkynes. 17 These authors have adapted their methodology to support Cubased NPs (ca. 3 nm) on silica-coated maghemite supports of nanometric size ranging from 5-30 nm in particle size. 1819 The asprepared composite catalyst showed easy catalyst recovery and negligible leaching of metal species. A similar strategy has been used by Alonso, Yus and co-workers for the immobilization of Cu2O nanoparticles onto a high surface area TiO2 support (featuring 60% anatase and 40% rutile polymorphs). 1918 Despite doubling the amount of reducing agent (lithium powder) to reduce CuCl2 in comparison to the precedent report, the copper catalyst was mainly in the form of ultrafine Cu2O NPs of 1.0 ± 0.4 nm average diameter size (Fig. 3), as denoted by the analysis of the Auger spectrum and the absence of satellite peaks of Cu(II) species in the XPS spectrum. Mechanistic studies on the nature of the catalytic process pointed to a surface catalysed reaction as a slight conversion increase was observed after reuse of the catalyst upon removal of the supernatant solution with a negligible copper leaching (45 ppb of copper detected by ICP-MS analyses). As in the parent non-supported catalyst, catalysis takes place under inert atmosphere, overriding the need of oxygen and no alkynyl radicals could be detected.

In addition, alternative bottom-up chemical methods have been mostly used for the preparation of low-valent Cu-based NPs systems in combination with either solid supports such as SiO2 (Scheme 2), 20 covalent organic frameworks 21 or ionic liquids. 22 Thus, Luque and co-workers have described the preparation of highly active Cu2O-CuO NPs on self-assembled silica nanotubes exhibiting high surface areas (90-500 m 2 g -1 ). 20 The synthesis of the catalyst composite featuring Cu2O NPs (34 ± 4 nm average size) was achieved in one pot by reaction of CuCl2, Si(OEt)4 and dodecylamine at temperatures ranging from 80 to 110 °C under microwave irradiation. High reaction conversions (>90%) and good homocoupling selectivity (75%) is obtained. However, the presence of mixed oxidation states in the catalyst composition (up 40% of Cu(II) species as determined by XPS analysis) may merit further investigation in terms of reaction selectivity improvement.

Scheme 2. Proposed mechanism of tubular nanostructure formation via the reduction of Cu(II) species by silanol groups promoted under microwave irradiation. Reprinted from 20 with permission from the Royal Society of Chemistry.

Bottom-up approaches have also been used for the preparation of low-valent Cu-based NPs systems in combination with polymeric supports. Thus, as reported by Zuraev and coworkers, Cu(0) NPs supported on polymer matrixes exhibit higher stability of the particles and protection against oxidation despite their inherent sensitivity to oxygen and water. 23 In addition, the nitrogenated matrix prepared by thermolysis of a copper(II) poly-5-vinyltetrazolate polymer enhanced mass transfer of substrate during the reaction resulting in high catalytic activities. PXRD analysis of the catalytic material revealed only the presence of Cu(0) nanocrystalline phases of 30 nm average diameter size, however the authors do not report XPS data that could take into account amorphous copper phases. Moreover, the formation of well-dispersed Cu nanoparticles of 6.5 ± 1.5 nm average diameter size supported in a polyaniline matrix has been reported by Ul Islam and coworkers. 24 They used an in situ polymerisation approach using CuSO4 as the oxidizing agent encompassing the formation of a 27 as first reported by Eglinton in the late 1950s. 28 In particular, two key mechanistic steps have been described for this coupling type under homogeneous conditions, namely a π-bond coordination of the triple bond to electrophilic Cu(II) species that weakens the terminal C-H bond, thus facilitating its deprotonation by a base, as well as a final reductive elimination step from a dinuclear copper(II) acetylide species (Scheme 3). 27,29 Scheme 3. Bohlmann mechanism for the Glaser homocoupling of acetylenes (B = N ligand). 29 Note: for each proposed intermediate, the oxidation state on the copper sites is indicated on each copper ion (roman numbers); the total charge of intermediates is indicated together with the square brackets.

Hitherto, only copper oxide based nanocatalytic systems have been described featuring Cu(II) species for applications in homocoupling reactions (Fig. 4). 30 As an example, Kaur and coworkers have described the synthesis of uniformly distributed CuO NPs (6 ± 3 nm size) on an Amberlite XAD-4 polystyrene resin featuring nitro group functionalization. 30a The nitro groups played an important role in the coordination of copper(II) cations from Cu(OAc)2 precursor on the resin, which was then subjected to NaBH4 treatment. XPS and XRD analyses of the asprepared material revealed the presence of core-shell structure, featuring a Cu(0) core covered with an oxide layer on the surface.

Fig. 4 TEM micrograph of CuOx NPs@Fe3O4 (a) and its particle size distribution graphic (b); TEM micrograph of CuOx-Fe3O4 NPs@graphene (c) and its particle size distribution graphic (d). Reproduced from 30d with permission of Elsevier and Copyright Clearance Center (license number: 5160240128897) 2017.

Jones and co-workers assessed the heterogeneity of CuO NPs (17-72 nm in size) supported on both γ-Al2O3 and TiO2 precatalysts in ethynylbenzene oxidative homocoupling in the presence of piperidine as a base, 30b revealing that the formation of soluble molecular copper-piperidine complexes at elevated temperature was needed to form the catalytically active species, so the reaction could then proceed even at room temperature with good conversions towards the homocoupling product. Besides, Serp, Raspolli-Galletti and co-workers 30d have successfully prepared magnetic copper oxide based nanoparticles on nanosized magnetite supports. The catalyst composite (featuring 9-13 nm particles of both CuOx and Fe3O4) exhibit high selectivity towards phenylacetylene oxidative homocoupling in the absence of an external base, and thus probably precluding both metal leaching and formation of molecular copper-base complexes thanks to synergistic effects between CuOx and magnetite support. XPS data revealed the presence of mostly Cu(II) on the catalysts surface, but the characteristic face centred cubic Cu2O peaks were also detected by PXRD. In addition, it has been shown by Rossi, Suib and coworkers for analogous CuO@MnOx catalytic systems that the support (manganese oxide) assists the re-oxidation of lowvalent Cu species formed during catalysis in air. 30c To illustrate the oxidative coupling of alkynes on the CuO@MnOx surface, the authors propose that the π-[Cu II (HC≡CH)(H2O)4] 2+

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Please do not adjust margins interaction via a three-electron stabilizing interaction (Fig. 5a, analogous to a molecular Glaser-Hay mechanism) is more stable than the corresponding Cu(I) one. In addition, the authors propose a model system involving a η 2 :η 2 -peroxo motif (Fig. 5b), but further mechanistic studies are required to assess the higher activities and maximize the synergistic effects operating in MnOx since Mn atoms from the support may not only form stable Mn III O2(H2O)n in the presence of air, which are capable of proton abstraction from bonded acetylene units in close proximity, but also these Mn sites neighbouring active Cu atoms may interact with the approaching acetylide anionic fragments and accommodate the two discarded electrons arising from the oxidation of acetylide anions via Mn available 3d orbital, as discussed by the authors. 30c Adapted with permission from 30c . Copyright 2016 American Chemical Society.

C(sp 2 )-C(sp 2 ) homocoupling

Cu-catalysed C(sp 2 )-C(sp 2 ) homocoupling reactions pioneered by Ullmann in 1901 for the synthesis of symmetrical bis-aryls, 3 represent a distinctive activation mode that has been widely applied in synthesis. Despite the broad substrate scope for this transformation, comprising aryl halides, arylboronic acid derivatives, or other organometallic reagents, and even unactivated arenes, correlation studies taking into account the catalyst nature (phase, oxidation state, synergistic effects…) and mechanistic insights are key to the development of novel catalyst systems with enhanced properties in terms of activity, selectivity and recyclability. Although this reactivity has been known for a long time and is still, the progress on the development of well-defined catalysts at the nanometric scale urges fundamental studies to elucidate the reaction mechanisms governing these type of transformations. Thus, this section summarizes the recent advances in Cu-based NPs catalysed C(sp 2 ) homocoupling reactions to yield symmetrical bisaryls products with special emphasis on the catalyst morphology (particle size, shape, homogeneity…), oxidation state and support (Scheme 4).

Scheme 4 C-C homo-coupling reactions catalysed by Cu-based NPs covered in this review (reaction conditions and concomitant products have been omitted).

The catalyst system developed by Chu, Sun and co-workers by reduction of CuSO4 with ascorbic acid in the presence of graphene oxide in N-methylpyrrolidone as solvent at 90 °C for 2 h featured Cu(0) NPs (ca. 8 nm in size, Scheme 5). 31 Despite the synthesis conditions triggered a partial reduction of the graphene oxide support, the as-prepared catalyst composite resulted highly active towards the homocoupling of aryl halides. Despite the high efficiency obtained for the conversion of both aryl iodides and bromides bearing electrodonating and electrowithdrawing groups in DMF, DMSO or a mixture of 1butyl-3-methylpyridinium bis(trifluormethylsulfonyl)imide and water as solvent under microwave irradiation (70-90 W) for 30 min, aryl chlorides were also reactive substrates albeit in moderate yields. This catalyst composite showed high activity towards the homocoupling reaction of boronic acid substrates, but further studies towards the elucidation of the differential elementary steps (oxidative addition, transmetallation…) involved in the activation of both types of substrates are needed. In an analogy with homogeneous systems, Ph-B(OH)2 bond activation via transmetallation is the key step in the oxidative homocoupling of organoboronic acid derivatives. 32 Cu(0) nanocatalysts generated by reduction of CuCl2 precursor with Li powder have also been proposed by Radivoy and coworkers as active catalysts for the homocoupling of aryl, heteroaryl and alkenyl Grignard reagents (Fig. 6). 33 As discussed in the previous section for analogous catalysts prepared by this methodology, further studies to assess the role of lithium cooperative effects and the mechanism of transmetallation are needed. Core-shell Cu-Cu2O based nanocatalytic systems featuring a Cu(0) metal core (with crystallite size of 8-12 nm in diameter) encapsulated by a layer of amorphous copper oxide (20-45 nm overall diameter size) have been prepared by Klabunde and coworkers via the solvated metal atom dispersion (SMAD) method. 34 The authors could establish a positive correlation between the chemical reactivity towards Ullmann reaction and the surface area of the as-prepared catalytic systems. Parvulescu, Garcia and co-workers have recently prepared graphene-film supported Cu2O nanoplatelets (8 nm in size) by one-step pyrolysis of Cu(NO3)2 embedded in chitosan at 900 °C under inert atmosphere that were active towards the homocoupling of iodobenzene in the absence of base. 35 Studies on the catalytic regimes of Cu2O-nanoparticle-catalysed C-C couplings carried out by Andiappan and co-workers 36 indicate that Cu2O systems can catalyze homocoupling reactions precluding the need of ligands or base via surface reactivity, enabling their implementation in flow applications.

The heterogeneous nature of analogous CuO nano-rod shaped catalysts has been reported by Veer and co-workers in the oxidative homocoupling of arylboronic acids via hot filtration tests and the absence of copper leaching. 37 Thus, upon removal of the nanocatalyst, no further reaction conversion was observed in the filtrates (monitoring during 6 h). Despite the lack of appreciable changes in the CuO PXRD pattern of the fresh and the reused catalyst after the 5 th run, the authors proposed a mechanism based on a monometallic active center encompassing a double transmetallation on a Cu(II) site, followed by air oxidation to generate the corresponding bis-aryl Cu(III) reactive intermediate that undergoes reductive elimination, generating biphenyl as a product and reduced Cu(I) species (Scheme 6). While this is in agreement with precedent mechanisms described for the oxidative homocoupling of arylboronic acids under homogeneous regimes, 38 the possibility of cooperative effects among neighbouring copper atoms cannot be ruled out. 37

Scheme 6 Proposed mechanism for the oxidative homocoupling of arylboronic acids based on a monometallic active centre. Adapted from 38b with permission from the Royal Society of Chemistry.

C-C cross-couplings

Alkyne cross-coupling

Unsymmetrical 1,3-diynes are present in many intermediates involved in organic synthesis and also appear as structural motifs in functional materials and natural products. 41 The most important challenge in the heterocoupling of two different terminal alkynes catalysed by homogeneous or heterogeneous systems, is the chemoselectivity, often controlled by using a large excess of the less reactive alkyne (i.e. more electron rich reagent). 42 Thus, this challenge often turns the catalyst design into a game of kinetics and statistics.

Although high selectivity towards unsymmetrical diynes is not trivial to be achieved, some Cu-based nanocatalysts have been recently reported, obtaining high isolated yields. 21,43 Fig. 7 Substrate scope for the synthesis of unsymmetrical diynes catalysed by Cu/Cu2O nanoparticles immobilised on phenol-pyridiyl covalent organic frameworks (COF). 21 This journal is © The Royal Society of Chemistry 2021 Nanoscale, 2021, 00, 1-18 | 7

Please do not adjust margins Please do not adjust margins From a mechanistic point of view, it is important to highlight the contribution of Vinod, Vaidhyanathan and co-workers, which prepared Cu/Cu2O NPs (mean size Cu-based NPs: 2-3 nm determined by HRTEM analyses) confined on covalent organic frameworks (COF), exhibiting H-protonable pyridyl-lined and Hbonding hydroxyl pores. 21 This catalytic material was successfully applied in heterocouplings of terminal alkynes using a nearly equimolar ratio of both alkynes: 0.5/0.42 (Fig. 7). This hybrid catalyst was able to stabilize Cu-Cl based clusters formed from chloroform (used as solvent), which were responsible of the observed reactivity.

A thorough characterization study of the catalytic material (cyclic voltammetry, XPS, IR) at different reaction times evidenced the presence of high-valent metal species, observing a reversible oxidation of Cu(0)/Cu2O into Cu(II) and Cu(III)), where the COF structure tunes the redox activity (Fig. 8). DFT calculations suggested that the functionalized pores of the support favour the interaction of hetero-substrates (two different alkynes) with the catalyst rather than with homosubstrates (two identical alkynes), in agreement with the experimental results.

Sonogashira-type couplings

C-C cross-couplings involving terminal alkynes and aryl or vinyl halides (or triflates) mainly catalysed by palladium and copper species also including palladium-and copper-free versions, represent a valuable and widely used tool for the synthesis of biologically active molecules, natural products, molecular electronics and polymers, through C(sp 2 )-C(sp) bond formation reactions. [START_REF] Chinchilla | For selected reviews[END_REF] For Cu-catalysed Sonogashira reactions, many research works have been reported in the literature, most of them concerning Cu(I) or Cu(II) salts and coordination complexes as catalytic precursors, 45 designing catalysts and reaction conditions in order to avoid the competing Glaser-Hay homocoupling and to allow working under safe conditions (some Cu(I)-acetylene organometallic complexes can be explosive). From a mechanistic point of view, a homogeneous pathway is generally accepted involving Cu(I) and Cu(II) intermediate species 46 or concerted activation of C-halide bond and C-C bond formation. 47 The use of copper-based nanoparticles as catalytic precursors has been less applied. Rothenberg and co-workers reported for the first time Sonogashira-type couplings with different aryl iodides and bromides catalysed by copper clusters, proposing a mechanism where the positive charge generated on copper in the oxidative addition step can be shared among the metal atoms of the cluster, in contrast to happen using homogenous systems, and without formation of high-valent copper species. Thus, this elementary transformation is kinetically favoured, which is often the rate determining step (Fig. 9). 48 It is important to highlight that reagents/metal surface interactions were not deeply studied; it is suggested that phenylacetylene coordinates to the metal cluster leading to an alkenyl-Cu intermediate (probably by a σ bond between Cu and the alkenyl group), and the corresponding aryl halide probably coordinates to copper by π interaction involving several metal centres. This journal is © The Royal Society of Chemistry 2021

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Please do not adjust margins Later on, Cu-based nanoparticles were efficiently applied in this type of couplings, both unsupported 36,49 and immobilised on inorganic solids such as silica 50 and graphene. 51 Andiappan and co-workers were interested in proving the nature of the catalytically active species, i.e. molecular-versus surface-like reactivity. 36 In other words, in proving the lack of copper atoms leaching from the metallic surface. Cu2O nanoparticles were prepared by microemulsion methodology and characterized by TEM (mean size: 34 nm) and PXRD (only presence of Cu2O crystalline cubic phase). The authors proved (by different techniques applied to the catalytic reactions: UVvis extinction spectroscopy, ESI-MS, FAAS and TEM) that in the absence of base, molecular species could not be detected, in contrast to the tests carried out in the presence of a base.

Suzuki-type couplings

Analogously to Sonogashira and Heck reactions, cross-couplings between aryl halides and aryl boronic acids are a useful synthetic methodology, together with Ullmann-type reactions, for the synthesis of bis-aryl compounds, which are present in a wide panel of commercially available products. [START_REF] Miyaura | For selected reviews[END_REF] As known, these cross-couplings are commonly catalysed by palladium-based systems, both homogeneous and heterogeneous ones. Despite the efficiency of this process (wide scope, high TON, vast applications), in the current trend to replace noble metals by earth-abundant and low-cost metals, innovative catalytic systems are developed. In addition to this reason, copper has been proven to be more efficient than palladium for Suzuki cross-couplings involving highly fluorinated boronate esters. 53 Concerning nanocatalysts, in 2002, Rothenberg and co-workers reported Suzuki couplings catalysed by copper nanoclusters, both monometallic and also polymetallic systems, which exhibited a relative high catalytic activity. 54 More recently, some works have been reported involving preformed Cu(0) and Cu2O nanoparticles in Suzuki reactions, using low copper loading (less than 0.5 mol%) under relative smooth conditions. 55 The in situ formation of Cu2O nanoparticles has been evidenced by XPS and PXRD analyses, using CuCl2 as catalytic precursor and K3PO4 as a base for the synthesis of diarylpyridines. 56 Based on these characterization data and the catalytic behaviour, the authors proposed that the nano-material is responsible of the reactivity observed via a Cu(I)-Cu(III) mechanism (Fig. 10). Copyright 2017 American Chemical Society.

Cross-dehydrogenative couplings

As very well-known, methodologies for forming C-C bonds represent a decisive role in synthesis design, finding extensive applications in academia and industry. 57 Mostly, these approaches require two functionalized reagents, resulting in the stoichiometric formation of by-products. Since 1990's, a huge work has been developed concerning the activation of C-H bonds, avoiding pre-functionalizations and significantly reducing the generation of wastes. [START_REF] Shilov | For selected reviews[END_REF] In the frame of these environmentally and economically attractive approaches, the C-H/C-H cross-dehydrogenative coupling (CDC) is a powerful tool for the formation of C-C bonds through the activation of two C-H bonds under oxidative conditions, 59 being copper a versatile catalyst for this type of transformations mainly using metal salts as catalytic precursors. 60 In the last years, the application of well-defined copper-based nanoparticles has been reported, [START_REF] Marset | [END_REF] with limited mechanistic studies. [START_REF] Tsang | For a revision concerning CDC mechanism under homogeneous regime[END_REF] Alonso and co-workers described the CDC of terminal alkynes and tertiary amines catalysed by Cu-based NPs immobilised on different solids, being the most catalytically active and selective system (no formation of diynes) when zeolite was used as support (mean diameter of Cu-based NPs: 1.7 nm). [START_REF] Alonso | [END_REF] XPS analyses showed that copper was mainly constituted of CuO with the presence of Cu2O. The authors were interested in studying the mechanism of the reaction. They proved that the reaction occurred under heterogeneous conditions. Thus, the catalyst was separated by filtration from the resulting organic phase at low conversion (ca. 5%), evidencing that this solution, under optimized catalytic conditions, did not work (its copper content was negligible: 0.78 ppb by ICP-MS analyses). Control tests with different radical scavengers proved the formation of methyl radicals, coming from the -cleavage of tbutylhydroxyperoxide (TBHP), used as oxidizing agent. XPS analyses of the catalytic material demonstrated that, contrarily to the starting catalytic material, Cu2O was the main copper phase which was easily re-oxidized with TBHP.

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Please do not adjust margins On the basis of all control tests, the authors proposed the mechanism represented in Fig. 11. The SET (Single Electron Transfer) and HAT (Hydrogen-Atom Transfer) sequence proposed seems to be the most plausible (more than the inverse one, HAT-SET), because no dimers arising from dimethylphenylamine radicals were detected. Jain and co-workers have reported Cu7S4 NPs immobilised on graphene oxide applied in the ortho-aminomethylation of phenols through C(sp 2 )-H-C(sp 3 )-H CDC. 61b Curiously, this reactivity was only observed using copper sulphides as catalytic precursors (including bulk materials such as CuS and Cu2S); however, Cu2O did not promote this transformation. Different control experiments, including the addition of radical scavenger (TEMPO) to the catalytic reaction, HR-MS and time-dependent 1 H NMR analyses of intermediates (evidencing the formation of an iminium cation) and the lack of reactivity when anisole was employed instead of phenol, permitted to the authors to propose a plausible surface-like pathway (Fig. 12). Zero-valent copper nanoparticles (mean diameter 1.7 nm determined by TEM) synthesized under hydrogen atmosphere in glycerol, using PVP as stabiliser, and fully characterized (XPS and electrochemical studies proved the exclusive presence of Cu(0), together with the surface plasmon resonance evidenced by UV-vis; Fig. 13), were also efficiently applied in CDC reactions, leading to the synthesis of propargylamines from tertiary amines and terminal alkynes. 9a When Nmethylphenylaniline (a secondary amine) was used, Nmethylation was also observed, indicating that TBHP acts as both methylating and oxidizing agent, in agreement with previous reported works by Phan, Truong and co-workers using copper ferrite and copper MOF as catalysts. 64 This catalytic system was also applied in the synthesis of propargylamines and N-containing heterocycles by A 3 (aldehyde, alkyne and amine) couplings. This catalyst was also active in KA 2 (ketone, alkyne and amine) couplings, taking into account that ketones are more reluctant than aldehydes in this type of three-component reactions (Scheme 7). This journal is © The Royal Society of Chemistry 2021

Please do not adjust margins Please do not adjust margins Copper is one of the most applied catalyst in theses multicomponent transformations, but mainly using homogeneous species. [START_REF] Volkova | For selected reviews[END_REF] In the last decade, several nano-catalysts have been applied in this reactivity, but few of them using preformed copper-based nanoparticles; scarce mechanistic studies can be found. 66 Spectroscopic studies (IR and UV-vis) were carried with Cu(0) NPs in glycerol in the presence of phenylacetylene without observing the formation of Cu(I)-alkyne molecular species, even in the presence of morpholine. These data together with the negligible copper detected in the extracted organic compounds after catalysis (ICP-AES analyses), suggest that a copper surface-like reactivity takes place. Based on these observations, the authors suggested a plausible mechanism for the synthesis of heterocycles, where the alkyne is activated at the metal surface taking advantage of the electronic density of the nanoparticle then reacting with the iminium formed by condensation of the amine and aldehyde; the resulting propargylamine intermediate can give the cycloaddition promoted by the copper-alkyne interaction (Fig. 14). Alonso and co-workers proposed a similar mechanism for the synthesis of propagylamines catalysed by Cu2O NPs supported on titania. 67

C-heteroatom cross-couplings

The copper effect on C-heteroatom bond formation was first reported by Ullmann for the synthesis of diarylamines using super-stoichiometric amount of copper, 68 followed by the independent works of Ullmann 4 and Goldberg 5 reporting the first Cu-catalysed processes for the synthesis of bisaryl ethers and arylation of amines/amides, respectively. 69 As mentioned before, the high-energy demanding initial conditions employed in these transformations together with the relative low functional group tolerance, Cu-based catalysts were scarcely studied during the long decades. In the nineties, Buchwald 70 and Hartwig 71 independently applied homogeneous Pd-based catalysts in the synthesis of amines by coupling of aryl halides and primary or secondary amines; this methodology has been successfully applied including C-O and C-S cross-coupling reactions, proving the versatility of palladium catalytic systems. 72 With the aim of using more convenient catalysts, since 2000 copper, including heterogeneous systems in particular copper-based nanoparticles, have been largely developed for C-heteroatom bond formations. Please do not adjust margins Please do not adjust margins couplings with a special insight in the study of mechanisms are described.

C-N bond formation: cross-dehydrogenative couplings

As previously mentioned, CDC reactions represent a sustainable tool for synthetic purposes (see above section 3.4). In particular N-H/C-H CDC has emerged as an effective way for the synthesis of N-containing compounds, scaffolds present in many natural products and pharmaceutical compounds. [START_REF] Srivastava | Heterocycles via Cross Dehydrogenative Coupling[END_REF] In 2010, Li and co-workers reported for the first time the direct amidation of aryl pyridines by a Cu-catalysed oxidative C-N bond formation using di-tert-butyl peroxide as oxidant and CuBr as catalytic precursor, by activation of N-H and C-H bonds. [START_REF] Shuai | [END_REF] CuO nanoparticles on carbon nano-powder (two populations of particles observed by TEM with mean sizes of 10 and 27 nm) were applied in the synthesis of imines by both self-coupling of a large variety of amines and cross-coupling of primary amines and aniline, using air as oxidant (Fig. 15). 76 Wang and coworkers developed CuO nanoparticles supported on kaolin for the synthesis of quinazolines (Scheme 8). 77 The authors evidenced the leaking of CuO NPs from the support during the reaction, precluding an efficient recycling. Scheme 8 Synthesis of quinazolines catalysed by CuO nanoparticles supported on kaolin. 77 Phan and co-workers described CuO NPs supported on porous metal-organic framework for the synthesis of -ketoamides through oxidative CDC of amines and -carbonyl aldehydes under aerobic conditions (Scheme 9); 78 the authors postulated a heterogeneous catalytic pathway based on the control filtration test (after removing the catalyst, the solution did not progress towards the expected product under catalytic conditions and <10 ppm of Cu was detected in the filtrate by ICP-MS analysis) and an efficient recycling (the catalyst was reused up to 9 runs without activity loss). Please do not adjust margins Please do not adjust margins

C-N bond formation: Ullmann couplings

Cross-couplings between aryl halides and N-based reagents (anilines, amides…) catalysed by copper precursors have been extensively studied in the literature, mainly involving copper molecular species as catalytic precursors. 80 Due to the relative stability of copper species exhibiting different oxidation states (from Cu(0) to Cu(III)), both ionic (involving oxidative addition/reductive elimination steps) and radical (involving single electron transfer steps) mechanisms have been proposed based on different types of control experiments and theoretical calculations. 69 In 2009, Sreedhar and co-workers reported for the first time the use of CuI NPs in C-N and C-O bond formation under ligand-free conditions. 81 The authors proposed a mechanism based on the CuI NPs stabilization by DMF and the amines and alcohols used as reagents. Hot filtration test (no reaction after catalyst removal from the catalytic solution at the first half of reaction time) and TEM analysis after several catalytic runs (catalyst did not exhibit changes in morphology) pointed to a surface-like reactivity (Fig. 17). They assumed that the cross-coupling proceeds by oxidative addition of the aryl halide at the nanoparticle surface promoted by electronic density sharing on neighbouring copper atoms. Later, Xu, Feng and co-workers reported the use of CuI NPs in the chemoselective synthesis of anilines, phenols and thiophenols in aqueous medium, using aryl halides (bromo and iodo derivatives) and n-tetrabutylammonium hydroxide as base. 82 In the presence of ammonia or sulphur, the corresponding anilines and thiophenols were obtained without observing the formation of the corresponding phenols.

In the last decade, several works have been described using as catalytic precursors well-defined CuO NPs, both unsupported and supported on solids, some of them containing mechanistic studies. 10f Kavermbu and co-workers reported the N-arylation of benzimidazole using unsupported CuO NPs (mean size determined by TEM and PXRD: 6-8 nm) as catalyst, 83 showing up the activation of aryl fluorides (containing electron withdrawing groups) along with bromo and chloro derivatives.

Authors proposed an ionic pathway without reporting experimental controls.

Ahamed, Sen, Islam and co-workers have reported the synthesis of unsupported CuO NPs (mean diameter ca. 5 nm) prepared in water in the presence of Ocimum Sanctum leaf extract, acting as both reducing agent (high content on polyphenols) and nanoparticles stabiliser. 84 The as-prepared catalytic material was applied in the N-arylation of a large variety of amides and aryl/styryl halides (iodo and bromide derivatives) (Fig. 18).

Fig. 18 CuO NPs catalysed C-N cross-couplings. Reprinted with permission from 84 .

Copyright 2017 American Chemical Society.

The authors carried out some tests with the aim of obtaining inputs concerning the mechanism of these Cu-catalysed crosscouplings. Thus, the addition of a radical scavenger (TEMPO) did not influence on the catalytic reaction. Furthermore, when trans-styryl halides were used, the products showed full retention of configuration (presence of vinyl radical intermediates would lead to a mixture of stereoisomers). 85 These observations ruled out a radical pathway. Concerning copper, four-line hyperfine EPR spectra of the catalyst for fresh and intermediate stages, indicated the quantitative presence of Cu(II). Taking into account that the oxidative addition on Cu(II) seems quite doubtful, the authors proposed a mechanism consisting of a first coordination of the amide to Cu(II) metal centres (N-H activation) followed by a coordination of the aryl halide leading to a transient intermediate which evolves towards the C-X activation, forming the corresponding Nfunctionalized amide and the corresponding salt from the base (scavenger of HX) (Fig. 19). Please do not adjust margins

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CuO NPs immobilised on silica (mean size of nanoparticles: ca. 30 nm) were efficiently applied in C-N cross-couplings of aryl halides (iodo, bromo and chloro derivatives) and various disubstituted amines (anilines, benzylamines, alkylamines). 86 The authors proposed a mechanism through oxidative addition/reductive elimination steps, assuming a prior reduction of CuO in the reaction medium probably promoted by the base (with formation of peroxides from KOH). CuO NPs supported on multi-walled carbon nanotubes (mean diameter of CuO NPs ca. 4.6 nm) were applied in the N-arylation of 2phenylindoles. 87 From a mechanistic approach, the authors proposed a Cu(I)/Cu(III) heterogeneous mechanism, also presuming an in situ reduction of CuO in Cu(I) species (promoted by the base, in this case NaOtBu). Cu2O NPs supported on ascorbic acid coated magnetite (mean diameter in the range of 8-15 nm) were catalytically active for C-N (and also for C-O) cross-couplings, using aryl halides (iodo, bromo and chloro derivatives) and aniline, imidazole and alkyl amines. 88 The authors proposed a heterogeneous reactivity based on hot filtration tests and ICP analyses of the organic extracts. Cu2O-based NPs were applied in the synthesis of diarylamines; the most active catalytic system was that constituted of a mixture of unsupported Cu(0) and Cu2O NPs prepared by a polyol approach (1,3-propanediol used as solvent and reducing agent) from copper(II) acetate; the structure of the catalyst cannot be inferred from the reported characterization data (core-shell or mixture of independent Cu(0) and Cu(I) nanoparticles). 89 Cu(0) NPs supported on alumina/silica support were also active for the cross-couplings between aryl chlorides and N-heterocyclic and aromatic amines. 90 Patel and co-workers applied unsupported CuO NPs for the synthesis of a large panel of quinazolinones (31 examples, yields in the range 39-85%) through a sequential Ullmann coupling followed by intramolecular oxidative C-H amidation, affording better yields than when copper salts were used as catalytic precursors; after catalysis, TEM analyses evidenced catalyst agglomeration, in agreement with the inefficient recycling, results pointing to a plausible copper leaching during the reaction. 91

C-N bond formation: Chan-Lam couplings

In 1998, Chan 92 and Lam 93 independently reported crosscouplings between aryl boronic acids and nitrogen-based nucleophiles, mediated by copper acetate and working under smooth conditions (often at room temperature). This methodology was quickly optimized and applied by several groups, becoming a valuable methodology for C-N bond formation, 94 mainly involving homogenous catalysts. 95 Well-defined unsupported CuO NPs have been efficiently applied in N-arylation of imidazoles and anilines under mild conditions (methanol or methanol/water as solvent and temperatures in the range rt to 60 °C), 96 even working in the absence of added base. 96a Moreover, supported Cu(0) nanoparticles on N-enriched graphene oxide found applications in the synthesis of diarylamines, suggesting a mechanistic pathway based on ligand exchange, followed by transmetallation, reductive elimination and oxidation; these elementary steps are proposed that occur at the metal surface of Cu(0) NPs immobilised on the graphene-based support and consequently excluding any metal leaching; unfortunately no mechanistic studies are described. Guo and co-workers reported a visible-light photocatalytic approach by Cu(0) NPs on graphene, taking advantage of the surface plasmon effect of the Cu NPs (Scheme 11). 97 This catalyst exhibited a relative high activity (TOF = 25.4 h -1 ); working under optimized irradiation of 520-600 nm for the N-arylation of phenylboronic acid and imidazole; it was also efficient for the synthesis of diarylethers and dithioarylethers by C-O and C-S cross-coupling of arylboronic acids with phenols and thiophenol, respectively. The catalyst was characterized after being used in catalysis without observing any morphology change (TEM and powder XRD analyses); XPS evidenced a slight shift on the binding energy of Cu 2p3/2 pointing to the formation of Cu(I) species. The catalyst showed good recyclability up to the fifth run; after that, the catalytic activity was recovered by treatment of the catalyst under H2 atmosphere. The catalytic behaviour observed for Cu NPs@graphene together with the catalyst characterisation (before and after reaction) strongly point to a surface reactivity.

Scheme 11 Cu NPs@graphene catalysed Chan-Lam N-arylation of imidazole derivatives and arylboronic acids under visible light irradiation. 97

C-N bond formation: alkyne-azide cycloaddition

Certainly, azide-alkyne cycloadditions (AAC) represent one of the most fruitful applications of copper-catalysed organic reactions, which belong to the transformations named "click chemistry". 98 The effect of copper in AAC (1,3-dipolar cycloadditions firstly described by Huisgen in 1963 under metal-free conditions and thus leading to mixture of regioisomers), 99 Please do not adjust margins Please do not adjust margins times) under inert conditions (in the presence of air, copper oxides are assumed to be formed, justifying the dramatic activity decrease). 103 Scaiano and co-workers studied the catalytic nature of copper species by single-molecule studies by Total Internal Reflection Fluorescence Microscopy (TIRFM), using well-defined Cu2O NPs as catalytic precursors, both colloidal and supported systems (MCM-41 used as support) 98b . Authors proved that the as-prepared NPs were able to catalyse the AAC on mole and single-molecule scales, in this latter case monitored by TIRFM involving Förster Resonance Energy (FRET) activation via formation of the corresponding triazoles that contain donor-acceptor dyes in close proximity. These singlemolecule studies proved that the reaction initially proceeds through the formation of Cu-acetylides on the nanoparticle surface followed by azide attack, without copper ion leaching from the NPs. Gómez and co-workers reported the synthesis of Cu2O NPs stabilised by PVP and immobilised in glycerol (mean diameter: 4.7 nm), being a versatile catalyst for the synthesis of a wide panel of triazole-containing compounds, including one-pot AAC/C-N cross-coupling tandem processes. 104 The catalyst was recycled up to ten runs without evidencing activity loss, pointing to a surface reactivity. The same group evidenced the formation of CuI NPs in glycerol using CuI salt as catalytic precursor in the presence of long-alkyl-chain amines (such as oleylamine). In the absence of these amines, no formation of nanoparticles was observed and the amine-free CuI/glycerol system was not catalytically active, proving the crucial role of the Cu(I)-based nanoparticles. 105 Alonso, Yus and co-workers prepared Cu-based NPs on active carbon (mean diameter: ca. 6 nm) constituted of Cu2O and CuO NPs and efficiently applied in multi-component synthesis of βhydroxy-1,2,3-triazoles from epoxides, alkynes and sodium azide in water (Fig. 20). 106 Deuteration control experiments evidenced the formation of Cu-acetylide intermediates, probably at the surface of the catalyst. Cu(0) 109 and Cu(II) based NPs 110 have been also efficiently used as catalytic precursors for AAC, without evidences of the corresponding pathways, which probably generate Cu(I) intermediate species under catalytic conditions.

C-P bond formation

Alkynylphosphonates exhibit an increased interest due to the phosphonic functional group (acid or ester) present in natural and synthetic bioactive compounds. 111 Moglie and co-workers described the straightforward synthesis of alkynylphosphonates via cross-coupling between terminal alkynes and H-phosphonates catalysed by commercial Cu2O, under base-free conditions and avoiding the use of moisturesensitive reagents (such as metal acetylides and phosphonic halides). 112 Later on, Lu and co-workers used well-defined copper-based NPs immobilised on Nb2O5. 113 The full characterization of the catalytic material revealed that the metal nanoparticles are mainly constituted of Cu2O together with Cu(0) (XPS analysis), very well-dispersed on the support (TEM analysis) exhibiting a mean size of 3.5 nm. Compared with other supports (such as ZrO2, SiO2, Al2O3), Nb2O5 gave the highest catalytic activity, depending on the nature of the solvent. The authors suggested that this catalytic behaviour can be attributed by the strong adsorption of diethylphosphite on Nb2O5 due to its Lewis acid nature (FT-IR controls). Concerning the copper sites, the requirement of oxygen to lead to an efficient coupling seems to point that Cu(I) sites are the catalytic centers and a Cu(I)/Cu(II) mechanism seems to operate. Taking into account that no alkyne homocoupling was detected, Cuphosphonate intermediates were probably formed instead of copper-alkynyl ones. Hot filtration experiment pointed to a surface-like catalytic reactivity. Based on these experimental evidences, a cross-coupling alkyne/H-phosphonate pathway was proposed (Fig. 21).

This journal is © The Royal Society of Chemistry 2021

Nanoscale, 2021, 00, 1-18 | 15

Please do not adjust margins Please do not adjust margins Building C-heteroatom bonds, in particular C-N, C-O and C-S bonds, represents a prevailing approach in the synthesis of polymers, natural products and fine chemicals. One of the most classical methodologies is the copper-promoted Ullmann couplings. 52b, 69,80,114 Catalytic systems working at moderate temperatures have been developed, reducing both energy consumption and waste production (low E-factor). Among them, Cu-based nanomaterials have led to efficient processes for the production of ethers, amines and thioethers. 10f, 73,115 . The catalytic reactivity observed using Cu2O@graphene 119 or Cu2O@TiO2 as catalysts 120 for the coupling of halo-arenes with phenols corroborates the requirement of Cu(I) species. Accordingly, CuO@MnOx should be reduced by the reagent with the concomitant formation of the corresponding peroxide or disulfide. Moreover, the control experiment using a radical scavenger (phenotriazine) ruled out the presence of radical intermediates. From kinetic studies, the Hammet analysis pointed to an oxidative addition of the aryl iodide to Cu(I) (ρ = +1.0) and a coordination of the phenol to Cu(I) (ρ = -2.9), by comparison with Rh(I), 121 Ni(0) 122 and Pd(0) 123 homogenous catalysts. Reported mechanistic studies using homogeneous catalysts proved that oxidative addition takes place prior to the nucleophilic addition. 124 Furthermore, the heterogeneous nature of the catalyst was proven by the lack of copper leaching in a hot filtration experiment. Based on these experimental results, including DFT calculations, the authors proposed a Cu(I)/Cu(III) pathway (Fig. 22). As proposed by Sreedhar and coworkers for C-O and C-N couplings, the presence of a base (such as K2CO3) acts as HX scavenger adsorbed on Cu-based nanoparticles. 81 Other than Cu(II)-and Cu(I)-based catalysts, Cu(0)nanocatalysts have been also applied in Ullmann-type couplings. Obora and co-workers prepared colloidal Cu(0) NPs in DMF under surfactant-free conditions. 125 Their characterization proved that the as-prepared zero-valent CuNPs (mean diameter ca. 2 nm, determiner by TEM) were capped by a copper oxide shell (XPS analysis). This catalytic system was active for the synthesis of diaryl ethers, from both bromo-and iodo-arene reagents. Cu(0)NPs immobilised on nafion-graphene nanoribbons, exhibiting a mean size of ca. 26 nm (determined by TEM and PXRD), were successfully applied in a wide-ranging scope of aryl halides (iodo-and bromo-based substrates) and phenols, 126 under both base-and oxygen-free conditions. Kassaee and co-workers prepared Cu(0)NPs immobilised on Fe3O4 nanoparticles decorated by chitosan, from CuCl2 in the presence of the support using hydrazine hydrate as reducing agent. 127 This catalyst was active for a large variety of phenols and iodo-aryls. The authors proposed a Cu(0)/Cu(II) pathway, but no mechanistic studies are described. In addition, Sharma, Gawande and co-workers reported a magnetically retrievable catalyst nanocomposite made of Cu(0) and maghemite exhibiting excellent catalytic activities towards C-O and C-S bond-formation reactions and reusability. 128 XPS, TEM and highangle annular dark-field scanning transmission electron microscopy with energy-dispersive spectroscopy atomic absorption spectroscopy were used for the full characterization of the nanocatalyst (Fig. 23). Thorough mechanistic insights using a catalyst composite made of ultra-small Cu NPs of 1-2 nm embedded in a matrix of chitosan microspheres have been recently reported by García and co-workers for the synthesis of diaryl sulphides from This journal is © The Royal Society of Chemistry 2021

Please do not adjust margins Please do not adjust margins thiophenol and iodoaryls (or bromo-and chloroaryls bearing electron withdrawing groups). 10b

This nanocatalyst system was prepared in a stepwise manner consisting of solvothermal reduction of Cu(NO3)2 in ethylene glycol at 150 °C (polyol reduction method), affording Cu NPs, which were then supported on chitosan via hydrogel formation under acidic media, followed by microsphere precipitation with a NaOH solution. 10b Detailed XPS characterization of the fresh catalysts and after reaction revealed the loss of nitrogen content of the chitosan matrix as well as the presence of Cu in low oxidation states, probably Cu(I) and Cu(0). Although the overall concentration of surface Cu atoms remains unchanged after reaction, the contribution of Cu 2p peak at 931.5 eV and the observation of the Auger peak at 916.5 eV evidence the implication of Cu(I) as active catalyst. The authors proposed two concomitant surface processes on low valent copper atoms: on the one hand, a multiatomic oxidative addition of the aryl halide substrate, as well as the coordination of the thiophenolate anion leading to a reductive elimination of the corresponding diphenyl sulfide product (Fig. 24). 10b Not only the oxidative addition is easier for aryl iodides in comparison to bromides and chloride counterparts, but also the weaker binding energy of the concomitant copper halide species > Cu-Br > Cu-I) may preclude deleterious catalyst passivation pathways. In particular, the binding energy of the concomitant copper halide species (Cu-Cl > Cu-Br > Cu-I) has been identified as a key parameter in the optimization of catalytic processes due to its relevance in terms of both the leaching of molecular copper species and catalyst poisoning. Despite moderate activity decrease after the first run, the catalytic activity of the recycled catalyst remains consistently stable after 5 runs. 10b Moreover, spherical Cu2O nanocatalysts (4.7 ± 1.5 nm mean size) immobilised in glycerol have also exhibited excellent selectivity and conversions towards unsymmetrical diaryl sulphides and alkyl aryl sulphides from thiols and aryl iodides. 104 Despite the good reaction selectivity towards unsymmetrical diaryl sulphides obtained with nanocatalyst composites of Cu NPs (2-3 nm in size) immobilised on hexagonal microporous silica, the formation of disulphides via oxidative homocoupling was also identified as reported by Luque, Macquarrie and coworkers. 129 The heterogeneity in copper oxidation states of the catalyst could be responsible of the different selectivity outcomes, namely 60% of the copper content corresponded to Cu(0) (XPS peak centred at 931.8 eV), together with Cu(I) and Cu(II) oxidation states (at 934.1 and 942.2 eV, respectively). However, alternative reaction manifolds may be possible for Cu(II) nanocatalysts to enable Ullmann-type C-S cross coupling reactions as reported by Wang and co-workers for a catalyst system made of CuO nanoparticles (12.6 ± 3 nm of size determined by TEM, 2p3/2 and 2p1/2 XPS peaks 934.8 and 955 eV) immobilised on mesoporous nitrogen-doped carbon materials of high specific surface areas (from 373 to 488 m 2 g-1 ), as the oxidative reaction conditions using DMSO at 100 °C may preclude potential contributions of low-valent Cu species in such transformation. 130 Analogous results in DMSO have been obtained with a catalyst nanocomposite featuring spherical CuO nanoparticles (55 ± 15 nm diameter) supported on graphene oxide (Fig. 25). 10d The use of telescoped processes for the synthesis of symmetrical and unsymmetrical diaryl sulfides has also been achieved with CuO nanocatalysts with thiourea as an effective sulfur surrogate and aryl iodides substrates in DMSO as solvent. 131 However further mechanistic insights taking into account the thiophilicity of copper nanocatalysts and their role in the cascade reactions needs to be further studied. Thus far, literature reports by Kakulapati and co-workers on the synthesis of diarylsulfides and alkylarylsulfides from iodo-and bromoaryls with ethyl potassium xanthogenate and a commercial CuO nanocatalyst system (<50 nm) not only identified the leaching of copper species by ICP-AES (0.8 and 1.2 ppm after first and second run), but also demonstrated the negligible role in catalysis of such molecular species in catalysis upon removal of CuO nanoparticles. 132 Recent results on the encapsulation of CuO nanoparticles inside metal-organic frameworks (MOF) point out the relevance of structural confinement towards the preparation of size defined copper nanoparticles featuring a superficial layer of CuO from 2.1 ± 0.6 nm to 4.4 ± 0.9 nm, depending on the preparation Please do not adjust margins Please do not adjust margins conditions. 133 The as-prepared MOF embedded catalytic systems showed excellent activity towards the formation of diaryl sulphides via C-S cross-coupling reactions and was reused up to four times without nanoparticle aggregation. These results shed light on the active role of metal nanoparticle systems and their oxides to enable substrate activation via surface mechanisms. Despite the fact that C-Se cross coupling reactions have been less explored with nanocatalytic systems, a few reports on CuO nanoparticle catalytic systems (up to 40 nm) with selenourea 134 or N,N-diethyl selenoformamide 135 their use towards the synthesis of diaryl selenides and diaryl diselenides, the latter being a reaction intermediate in the synthesis of the former via the cleavage of the Se-Se bond as decribed by Rama Rao and coworkers with analogous CuO under basic conditions. 136

Summary and outlook

This review considers reported contributions related to monometallic copper-based nanocatalysts applied in organic synthesis, in particular in coupling reactions, which contribute to rationalise the catalytic behaviour observed in this multifaceted reactivity. Advances on operando techniques (so far more developed for homogeneous catalytic processes) adapted to coupling reactions involving metal nanoparticles under catalytic conditions, represent a foremost challenge for evidencing metal-reagent interactions and intermediates (such as the work developed by Scaiano's team) 98b by a straightforward way, together with theoretical approaches taking into account the simultaneous presence of different reagents and additives, other than solvents. Given the versatility in structure and oxidation states ranging from zero-valent to Cu(III) species, the development of Cubased catalytic systems capable to selectively enable one-or two-electron processes shall be key for the rational design of efficient nanocatalytic systems towards sustainable applications.

Fig. 2 .

 2 Fig. 2. Some examples of MNP morphology changes produced under catalytic conditions. Adapted from 12 with permission of Elsevier and Copyright Clearance Center (license number: 5160190892244) 2021.

Fig. 3

 3 Fig.3TEM micrograph of Cu2O NPs@TiO2 catalyst and size distribution analysis for 125 nanoparticles randomly selected. Adapted from19 with permission of John Wiley and Sons and Copyright Clearance Center (license number: 5143150408233) 2011.

Fig. 5

 5 Fig. 5 Model systems of CuO@MnOx surface in the oxidative coupling of alkynes: (a) Cu atoms in adjacent positions to each other; (b) O2 as bridging ligand between Cu sites. Adapted with permission from 30c . Copyright 2016 American Chemical Society.

Fig. 6 . 6 |Scheme 5 .

 665 Fig. 6. TEM image of Cu NPs their and size-distribution graphic (out of 200 particles). Reprinted from 33 with permission from Taylor & Francis Ltd (www.tandfonline.com).

  Since 1960's, C-C cross-coupling reactions applied in organic synthesis have been generally associated to palladiumcatalysed processes, internationally recognized with the Nobel Prize in Chemistry 2010 awarded to R. F. Heck, E.-I. Negishi and A. Suzuki.39 Although the copper ability to form C-C and C-N bonds is known since 1905 and 1906 by the pioneer works independently published by F. Ullmann4 and I. Goldberg5 respectively, Cu-catalysed cross-couplings have been extensively developed from the end of the 20 th century (more than 105,000 reports have been found in SciFinder database in the period 2000-2021, answering to the topic "copper-catalysed cross-couplings" versus 99,883 reports for a similar search concerning palladium). 6c,[START_REF] Wang | Copper-Mediated Cross-Coupling Reactions[END_REF] In this section, C-C cross-couplings are described. C-heteroatom bond formation processes are presented in section 4 (see below).

Fig. 8

 8 Fig. 8 Characterisation of Cu-based NPs supported on COF (Cu@COF): Cyclic voltammetry of Cu@COF showing the reversible formation of Cu(0)-Cu(I)-Cu(II)-Cu(0) species (A and B: O means oxidation wave; R, reduction wave); XPS spectra at the Cu 2p binding energy region for Cu@COF (t = 0 min) and at different stages of the reaction (C-F); IR spectra of the catalyst at different reaction times showing no change of COF (H); XPS spectrum at Cl 2p binding energy region of an isolated sample of Cu@COF during the catalytic reaction, proving the presence of Cu-Cl species (I). Reprinted with permission from 21 . Copyright 2019 American Chemical Society.

Fig. 9

 9 Fig.9 Proposed cycle for Cu-catalysed Sonogashira coupling. Reproduced from48 with permission from the Royal Society of Chemistry.

Fig. 10 .

 10 Fig. 10. Top: General scheme corresponding to the synthesis of biarylpyridines. Bottom: XPS spectrum of Cu2O nanoparticles at the Cu 2p binding energy region (left); proposed Cu(I)-Cu(III) mechanism for the catalytic reaction. Reprinted with permission from 56 . Copyright 2017 American Chemical Society.

Fig. 11 .

 11 Fig. 11. Proposed mechanism for cross-dehydrogenative coupling of phenylacetylene and N,N-dimethylaniline catalysed by Cu-based nanoparticles supported on zeolite. Reproduced from 63 with permission of John Wiley and Sons and Copyright Clearance Center (license number: 5142910077768) 2015.

Fig. 12

 12 Fig.12 Plausible radical mechanism for the Cu7S4 NPs on graphene oxide catalysed orthoaminomethylation of phenol using TBHP as oxidising agent. Reproduced from 61b with permission from the Royal Society of Chemistry.

Fig. 13 a

 13 Fig. 13 a) Synthesis of Cu(0) NPs (CuA) prepared in glycerol; b) UV-vis spectra recorded at different times during the synthesis of CuA; c) HR-TEM micrograph of CuA including the crystallographic planes spots (Fast Fourier Transform from one selected nanoparticle); d) High-resolution XPS spectra at the Cu 2p binding energy region for CuA (red trace) and its precursor [Cu( 2 -N,N,N',N'-TMEDA)(-OH)]2Cl2 (blue trace); e) Cyclic voltammetry of CuA in glycerol (the ornge dot indicates the starting point of the experiment). Adapted from 9a with permission of John Wiley and Sons and Copyright Clearance Center (license number: 5142920864622) 2017.

Fig. 14

 14 Fig. 14 Proposed mechanism for the synthesis of quinolones catalysed by zero-valent copper nanoparticles in glycerol, assisted by morpholine, via a tandem A 3 coupling/cycloisomerisaton process. 9a Reproduced from 9a with permission of John Wiley and Sons and Copyright Clearance Center (license number: 5142920864622) 2017.

  8a, 73 In this section, the works involving Cu-based NPs catalysed hetero-This journal is © The Royal Society of Chemistry 2021 Nanoscale, 2021, 00, 1-18 | 11

Fig. 15

 15 Fig. 15 TEM micrographs (a) Carbon nanopowder and (b, c and d) CuO NPs@Carbon nanopowder, and (d) size distribution histogram of CuO NPs. Reproduced from 76 with permission of Elsevier and Copyright Clearance Center (license number: 5160200537079) 2017.

Scheme 9 79 Scheme 10

 97910 Scheme 9 CuO NPs on MOF catalysed the synthesis of -ketoamides through oxidative CDC of aliphatic and aromatic amines with phenylglyoxal.78

Fig. 16

 16 Fig.16 Proposed pathway for oxidative amination of N,N-dimethylbenzylamines catalysed by Cu2S nanoparticles. Reprinted with permission from79 . Copyright 2018 American Chemical Society

Fig. 17 .

 17 Fig. 17. Plausible mechanism for C-N and C-O bond formation in arylation processes. Reprinted with permission from 81 . Copyright 2009 American Chemical Society.

Fig. 19 .

 19 Fig. 19. Plausible mechanism for C-N and C-O bond formation in arylation processes. Reprinted with permission from 84 . Copyright 2017 American Chemical Society.

Fig. 20

 20 Fig. 20 Multicomponent synthesis of 1,4-disubstituted 1,2,3-triazoles catalysed by Cu2O/CuO nanoparticles supported on activated carbon. Reprinted with permission from 106 . Copyright 2011 American Chemical Society.

4. 6 .

 6 C-O, C-S and C-Se bond formation

Fig. 22

 22 Fig. 22 Plausible pathway for Ullmann coupling reactions catalysed by CuO nanoparticles supported on MnOx. Reprinted with permission from 116 . Copyright 2017 American Chemical Society

Fig. 23

 23 Fig. 23 HAADF-STEM images of Cu-maghemite nanocatalyst; a) HAADF image; b) Distribution of Cu by HAADF; c) Distribution of Fe by HAADF; d) Distribution of O by HAADF; e) Distribution of Cu, Fe, and O together by HAADF; f) EDS spectrum indicating the presence of Cu. Reprinted from 128 with permission of John Wiley and Sons and Copyright Clearance Center (license number: 5160250578857) 2015.

Fig. 24

 24 Fig. 24 Simplified mechanistic proposal for C-S cross-coupling on Cu NPs. i) Ph-I cleavage on low-coordinated surface Cu sites; ii) Adsorption of thiophenoalete on the surface; iii) PhSPh desorption; iv) Iodide desorption. Reprinted from 10b with permission of John Wiley and Sons and Copyright Clearance Center (license number: 5143520480932) 2015.

Fig. 25

 25 Fig.25 Synthesis of aryl sulphides catalysed by CuO NPs@ graphene oxide (GO). 10d

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	Cu(I)-composite material which was then subjected to NaBH4
	reduction to form Cu(0) NPs@polyaniline. The authors
	confirmed that the homocoupling of terminal alkynes was
	facilitated under aerobic conditions, arguably due to the fact
	that the base and oxygen present in air helps the formation of
	Cu(I)-acetylide intermediate species capable to deliver the
	homocoupling product by reductive elimination. Analogously,
	Yao and co-workers described the synthesis of low-valent Cu
	NPs by NaBH4 reduction of Cu(OAc)2 in EtOH at 40 °C for 20 h in
	the presence of ordered mesoporous carbon nitride materials
	(OMCN, prepared by polymerization of 2,4,6-trichlorotriazine
	with benzidine in the presence of SBA-15 as template). 25 The
	PXRD pattern of the prepared Cu NPs@OMNC showed the
	characteristic two diffraction peaks at 43.6° and 50.5°
	corresponding to the (111) and (200) lattice planes of metallic
	Cu fcc structure, but the appearance of Cu2O (111) was also
	observed. TEM analysis of the Cu-based NPs@OMCN showed
	the copper nanoparticles successfully supported on the
	hexagonal mesopores of 4.7 nm pore size. Balova and co-
	workers have recently reported the preparation of C(sp)
	homocoupling-selective copper-based nanocatalysts by ex situ
	laser-induced methods from copper precursors such as CuCl2
	and Cu(OAc)2. 26 This methodology adds up to the classical
	bottom-up approaches.
	Differential activation pathways under molecular regimes have
	been reported for Cu(II)-mediated oxidative homocoupling of
	terminal alkynes in the presence of pyridine as ligand,
	Please do not adjust margins

  OES analyses of the catalytic solutions after catalyst removal, and catalyst recycling (up to 5 This journal is © The Royal Society of Chemistry 2021

	was independently
	reported by Meldal 100 and Sharpless 101 in 2002. Since then, the
	regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles has
	found worthy applications in different areas (drug design,
	macromolecules, biochemistry, materials). 102 Despite this vast
	scope and range of conditions and solvents, both aprotic and
	protic ones including water, mechanistic studies continue being
	of interest from a fundamental point of view.
	Cu-based NPs have been applied in AAC processes, in many
	cases without concluding if the nanoparticles operate as true
	catalyst (surface reactivity) or as reservoir of molecular
	catalytically active species. One of the first reported works
	proving a heterogeneous reactivity was that published by
	Moores and co-workers using CuFe bimetallic magnetic
	nanoparticles constituted by a Fe(0) core and a Cu(I) shell; this
	conclusion was based on ICP-

Scheme 7 Synthesis of propargylamines by A 3 coupling catalysed by preformed Cu(0) nanoparticles.9a

Scope of the cross-coupling between phosphite esters Cu-based nanoparticles immobilised on Nb2O5 (top) and a proposed mechanism for this coupling (bottom). Adapted from 113 with permission from the Royal Society of Chemistry.

Acknowledgements

The Centre National de la Recherche Scientifique (CNRS) and the Université Toulouse 3 -Paul Sabatier are gratefully acknowledged for their financial support. M. C. thanks the Ministère de l'Enseignement Supérieur et de la Recherche of the French government for a PhD scholarship.

Author Contributions

The authors have equally contributed to the writing of this review.

Conflicts of interest

The authors declare that there is no conflict of interest.