Rodolphe Jazzar
email: rjazzar@ucsd.edu

Michele Soleilhavoup
email: msoleilhavoup@ucsd.edu

Guy Bertrand
email: gbertrand@ucsd.edu

Cyclic (Alkyl)-and (Aryl)-(amino)carbene Coinage Metal Complexes and their Applications

Cyclic (alkyl)-and (aryl)-(amino)carbenes (CAACs and CAArCs) are stronger sdonors and p-acceptors than imidazol-2-ylidenes and imidazolidin-2-ylidenes, the well-known Nheterocyclic carbenes (NHCs). Consequently, they form strong bonds with coinage metals, and stabilize both low and high oxidation states. This Focus Review shows that CAACs and CAArCs have allowed for the isolation of copper and gold complexes which were believed to be only transient intermediates. This has not only allowed for a better understanding of the mechanism of known processes but has also led to the development of novel coinage metal-catalyzed reactions.

In addition to their role in homogeneous catalysis, CAAC and CAArC coinage metal complexes have recently found applications in medicinal chemistry, as well as in materials science. When possible, the performance of CAAC and CAArC ligands are compared with those of classical NHCs.

Corresponding Author ORCID Notes Biographies

INTRODUCTION

Since their discovery in 2005, 1,2 five-membered cyclic (alkyl)(amino)carbenes (CAAC) 1 have been the subject of several reviews. 3,4,5,[START_REF][END_REF]7,8 However none of them have comprehensively covered their coordination chemistry towards coinage metals. Even more importantly many significant discoveries in this field have been made in recent years and thus have not been discussed in the previous review articles. This Focus Review will not be limited to CAACs 1, but will also include six-membered cyclic (alkyl)(amino)carbenes (CAAC-6) 2, [START_REF] Weinstein | Highly Ambiphilic Room Temperature Stable Six-Membered Cyclic (Alkyl)(amino)carbenes[END_REF] bicyclic (alkyl)(amino)carbenes (BiCAAC) 3, [START_REF] Tomas-Mendivil | Bicyclic (Alkyl)(amino)carbenes (BICAACs): Stable Carbenes more Ambiphilic than CAACs[END_REF] the so-called saturated abnormal NHCs (saNHC) 4, [START_REF] Hashmi | Regioselective Formation of Saturated Abnormal NHC-Gold(I) Complexes by [3+2] Cycloaddition of Azomethine Ylides and Isonitrile Gold(I) Complexes[END_REF] as well as cyclic (aryl)(amino)carbenes (CAArC) 5 [START_REF] Rao | Cyclic (Amino)(aryl)carbenes (CAArCs) as Strong sigma-Donating and pi-Accepting Ligands for Transition Metals[END_REF] and 6, [START_REF] Jothibasu | Versatile Coordination Chemistry of Indazole-Derived Carbenes[END_REF] (Figure 1). Because of the importance of classical NHCs in coinage metal chemistry, [START_REF] Danopoulos | N-Heterocyclic Carbene Complexes of Copper, Nickel, and Cobalt[END_REF][START_REF] Trose | Dinuclear N-Heterocyclic Carbene Copper(I) Complexes[END_REF][START_REF] Lazreg | Copper-NHC Complexes in Catalysis[END_REF][START_REF] Nolan | The Development and Catalytic Uses of N-Heterocyclic Carbene Gold Complexes[END_REF][START_REF] Mora | Recent Advances in Gold-NHC Complexes with Biological Properties[END_REF][START_REF] Marinelli | Recent Advances in Medicinal Applications of Coinage-Metal (Cu and Ag) N-Heterocyclic Carbene Complexes[END_REF] we will compare the results obtained with 1-6 with those of imidazol-2-ylidenes 7 [START_REF] Arduengo | A Stable Crystalline Carbene[END_REF] and imidazolidin-2-ylidenes 8. 21 To understand the advantages and disadvantages of carbenes 1-6 compared to classical NHCs 7 and 8, a comparison of their electronic properties is necessary. This will be only briefly summarized since detailed analyses have already been reported in the previous reviews mentioned above. Although the calculated energy of the HOMO and LUMO of carbenes vary slightly depending on the level of theory, the same trend has been observed. Figure 1 summarizes the results obtained at the B3LYP/def2-TZVPP level of theory with ultrafine grid. With the exception of the so-called saNHC 4, all the cyclic (alkyl)(amino)carbenes 1-3 are both more s-donating and p-accepting than NHCs 7 and 8, [START_REF] Gaggioli | Modulating the Bonding Properties of N-Heterocyclic Carbenes (NHCs): A Systematic Charge-Displacement Analysis[END_REF] because of the presence of the electropositive carbon and of only one p-donor amino group. Cyclic (aryl)(amino)carbenes 5-6 are still strong electron donors, but they are by far more p-accepting than all the other carbenes considered in this review, although less than the diamidocarbenes reported by Hudnall and Bielawski (LUMO: -2 eV). [START_REF] Hudnall | N′-Diamidocarbene: Studies in C-H Insertion, Reversible Carbonylation, and Transition-Metal Coordination Chemistry[END_REF] It is important to note that although carbenes 1-3 as well as NHCs 7 and 8 can be isolated and are stable in solution and in the solid state, carbenes 4- 6 have not yet been isolated.

Figure 1. Calculated energy of the HOMO and LUMO of carbenes 1-6, considered in this Focus Review, and of NHCs 7 and 8 for comparison (B3LYP/def2-TZVPP level of theory with ultrafine grid).

COORDINATION CHEMISTRY OF CYCLIC (ALKYL)-AND (ARYL)-(AMINO)CARBENES WITH COINAGE METALS

Synthesis of (CAAC)MCl (M = Cu, Ag, Au) Complexes

The steric bulk and flexibility of the substituents on the a-carbon of CAACs have a dramatic effect on their complexation to gold [START_REF] Frey | Cyclic (Alkyl)(amino)carbene Gold(I) Complexes: A Synthetic and Structural Investigation[END_REF] and silver [START_REF] Romanov | Synthesis, Structures and Photoluminescence Properties of Silver Complexes of Cyclic (Alkyl)(amino)carbenes[END_REF] (Scheme 1). When bulky and rigid substituents, such as menthyl or adamantyl, are present, the corresponding LAuCl complexes 9a and 9b, as well as

LAgCl 10b can readily be isolated. When the smaller and flexible cyclohexyl, cyclohexylene, ethyl or methyl groups are used, the mono-carbene gold and silver complexes can be observed and utilized as such, but are difficult to isolate; instead, the cationic bis(carbene) complexes such as 11c-e and 12f are obtained. Since cationic bis(carbene) complexes 11 and 12 are certainly more inert than the mono-carbenes counterparts 9 and 10, these findings provide a good indication of the range of substituents, which might allow CAAC gold and silver complexes to find catalytic applications. In contrast, mono-carbene copper complexes are readily isolable even with small CAACs such as 1f as shown by 13f. [START_REF] Hu | Air-Stable (CAAC)CuCl and (CAAC)CuBH4 Complexes as Catalysts for the Hydrolytic Dehydrogenation of BH3NH3[END_REF][START_REF] Bidal | Copper(I) Complexes Bearing Carbenes Beyond Classical N-Heterocyclic Carbenes: Synthesis and Catalytic Activity in "Click Chemistry[END_REF] Note that all these gold, silver and copper complexes can be prepared by simple addition at room temperature of the free carbene 1 to Au(SMe2)Cl, AgCl and CuCl, respectively. Alternatively, following the seminal discovery by Lin et al. [START_REF] Wang | Facile Synthesis of Silver(I)-Carbene Complexes. Useful Carbene Transfer Agents[END_REF] on the ability of Ag(I)-NHC complexes to transfer Ag-bound NHC ligands to another metal, both the silver 10 [START_REF] Romanov | Synthesis, Structures and Photoluminescence Properties of Silver Complexes of Cyclic (Alkyl)(amino)carbenes[END_REF] and even the copper complexes 13 [START_REF] Bidal | Generalization of the Copper to Late-Transition-Metal Transmetallation to Carbenes beyond N-Heterocyclic Carbenes[END_REF] can undergo a transmetallation to give the desired CAACcoinage metal complexes.

Scheme 1. Synthesis of (CAAC)MCl complexes (M = Au, Ag, Cu)

Cyclic (alkyl)(amino)carbene gold complexes have also been prepared via an elegant cyclizationrearrangement cascade (Scheme 2). [START_REF] Kolundzic | A Cyclization-Rearrangement Cascade for the Synthesis of Structurally Complex Chiral Gold(I)-Aminocarbene Complexes[END_REF] This protocol allows for the preparation of a variety of chiral CAAC-gold complexes in a highly stereoselective manner.

Synthesis of (CAAC)CuH Complexes

In contrast to monomeric gold hydrides, which can readily be isolated, [START_REF] Tsui | Reactions of a Stable Monomeric Gold(I) Hydride Complex[END_REF][START_REF] Hashmi | Fire and Ice: A Gold(III) Monohydride[END_REF] copper hydrides have the propensity to aggregate [START_REF] Jordan | Coinage Metal Hydrides: Synthesis, Characterization, and Reactivity[END_REF] as evidenced by the widely used Stryker reagent [(Ph3P)CuH]6. [START_REF] Mahoney | Selective Hydride-Mediated Conjugate Reduction of .Alpha.,.Beta.-Unsaturated Carbonyl Compounds Using[END_REF] With the exception of the recently reported complex 14, 37 featuring the extremely bulky 1,3bis [2,6-bis[di(4-tert-butylphenyl)-methyl]-4-methylphenyl]imidazol-2-ylidene (IPr**), 38 dimeric (NHC)copper hydride complexes are unstable with a few exceptions [START_REF] Mankad | Structure, and Alkyne Reactivity of a Dimeric (Carbene)copper(I) Hydride[END_REF][START_REF] Welle | A Three-Component Tandem Reductive Aldol Reaction Catalyzed by N-Heterocyclic Carbene-Copper Complexes[END_REF][START_REF] Jordan | Synthesis and Reactivity of New Copper(I) Hydride Dimers[END_REF] (Scheme 4). In contrast, the dimeric (CAAC)copper hydride 15 was isolated and can be stored in solution for weeks at aand b-Hydride abstractions from alkyl complexes, affording metal-carbene and metal-alkene complexes, respectively, are well known reactions. However, it was only in 2013 that such processes were reported for gold. [START_REF] Ung | Beta-and Alpha-Hydride Abstraction in Gold(I) Alkyl Complexes[END_REF] When the tert-butyl gold complex 17 was treated with triphenylcarbenium tetrafluoroborate, an instantaneous reaction occurred, affording the gold(I)alkene complex 18, demonstrating the possibility of b-hydride abstraction (Scheme 5). To probe the a-hydride abstraction, the gold(I)-neopentyl complex 19 was reacted with Ph3C + BF4 -, and the two diastereomeric gold(I)-(2-methylbut-2-ene) complexes 21 were isolated, although the reaction was drastically slower than in the case of 17. All attempts to characterize the putative carbene intermediate 20 failed, which is not surprising since, with rare exceptions, [START_REF] Harris | Structure, and Reactivity of a Gold Carbenoid Complex That Lacks Heteroatom Stabilization[END_REF][START_REF] Harris | Gold Carbenes, Gold-Stabilized Carbocations, and Cationic Intermediates Relevant to Gold-Catalysed Enyne Cycloaddition[END_REF][START_REF] Hussong | Isolation of a Non-Heteroatom-Stabilized Gold-Carbene Complex[END_REF][START_REF] Sarria Toro | Gold(I) Carbenoids: On-Demand Access to Gold(I) Carbenes in Solution[END_REF][START_REF] Werle | The First Crystal Structure of a Reactive Dirhodium Carbene Complex and a Versatile Method for the Preparation of Gold Carbenes by Rhodium-to-Gold Transmetalation[END_REF][START_REF] Wang | Gold Carbene or Carbenoid: Is There a Difference?[END_REF][START_REF] Joost | Enhanced pi-Backdonation from Gold(I): Isolation of Original Carbonyl and Carbene Complexes[END_REF] heteroatom substituted carbene gold complexes are very unstable. However, when triphenylcarbenium tetrafluoroborate was reacted with the gold(I) dithianyl complex 22, the expected cationic bis(carbene) gold(I) complex 23 was obtained, demonstrating the a-hydride abstraction process.

Scheme 5. a-and b-hydride abstractions from alkyl gold complexes 17 and 19, respectively, lead to alkene p-complexes, whereas a-hydride abstraction from 22 affords the corresponding carbene complex 23

In addition to alkenes, as in 18 and 21, alkynes and even arenes can give p-complexes with (CAAC)coinage metals. The most striking example is arguably the cationic p,s-bis(copper)

acetylide 25 (Scheme 6). [START_REF] Jin | Isolation of Bis(copper) Key Intermediates in Cu-Catalyzed Azide-Alkyne "Click Reaction[END_REF] Indeed, in 2013, Fokin et al. reported that "monomeric copper-acetylide complexes (similar to 24) are not reactive towards organic azides unless an exogenous copper catalyst is added". [START_REF] Worrell | Direct Evidence of a Dinuclear Copper Intermediate in Cu(I)-Catalyzed Azide-Alkyne Cycloadditions[END_REF] They postulated that the catalytically active complex in the Cu-catalyzed azide-alkyne "click reaction [START_REF] Kolb | Click Chemistry: Diverse Chemical Function from a Few Good Reactions[END_REF][START_REF] Hein | Copper-Catalyzed Azide-Alkyne Cycloaddition (Cuaac) and Beyond: New Reactivity of Copper(I) Acetylides[END_REF][START_REF] Meldal | Cu-Catalyzed Azide-Alkyne Cycloaddition[END_REF] was in fact a cationic p,s-bis(copper) acetylide. They further stated that these dinuclear species were "non-isolable and highly reactive intermediates".

However, in 2015, our group first prepared the mononuclear copper complex 24 by adding lithium phenyl acetylide with (CAAC)CuOAc. Note that with the exceptions of (NHC)copper acetylides, [START_REF] Nolte | Isolation of a Copper(I) Triazolide: A "Click" Intermediate[END_REF] these complexes are usually polymeric. Then, addition of (CAAC)CuOTf to 24 gave the desired cationic dinuclear complex 25, which proved to be air-stable and thermally robust. In solution, a very fast exchange between the two (CAAC)Cu units occurred, but in the solid state an X-ray diffraction study shows two different types of coordination, p and s. The isolation of complex 25 has allowed for a detailed mechanistic study of the Cu-catalyzed azide-alkyne "click reaction" (See Section 3.3.). Scheme 6. Synthesis of the monocopper acetylide 24 and supposedly unstable dinuclear complex 25, which is the catalytically active complex in the Cu-catalyzed azide-alkyne cycloaddition "click reaction"

The most common catalytic systems in gold catalysis involve LAuCl complexes, which through in situ salt metathesis generate the active species, supposedly a cationic monoligated LAu+ complex. Because of their strong s-donating properties, CAACs are certainly good candidates to stabilize such compounds. However, treatment of a toluene suspension of 9b with [(Toluene)SiEt3] + [B(C6F5)4] -cleanly led to complex 26 (Scheme 7). [START_REF] Lavallo | Allene Formation by Gold Catalyzed Cross-Coupling of Masked Carbenes and Vinylidenes[END_REF] Though not a truly "naked" cation, the h 2 -binding mode hardly perturbs the aromatic ring, allowing this complex to behave as the proposed active cation for mechanistic studies. Note that a few similar complexes bearing bulky phosphine ligands have also been isolated. 58 The ability of CAACs to efficiently stabilize metals in low oxidation states has been used to study the complexation of phosphaethynolate salts M + (PCO) -, which are strong reducing agents. [START_REF] Goicoechea | The Chemistry of the 2-Phosphaethynolate Anion[END_REF] It has been found that NaPCO reacts with (CAAC)AuCl and (CAAC)CuO t Bu cleanly affording 27 and 29, respectively (Scheme 8). [START_REF] Liu | Isolation of Au-, Co-η 1 PCO and Cu-η 2 PCO Complexes, Conversion of an Ir-η 1 PCO Complex into a Dimetalladiphosphene, and an Interaction-Free PCO Anion[END_REF] Despite the similarities of the solid state structures, a computational study shows that the coordination modes of PCO with gold and copper are h 1 and h 2 , respectively, which leads to a difference in reactivity. The gold complex 27 is stable in the solid state but rearranges over the course of a week in solution at room temperature into the trinuclear complex 28. The copper complex 29 decomposes in a few hours and is very reactive. A simple addition of free CAAC 1f to 29 gives rise the cationic bis(CAAC)Cu complex 30, in which the PCO fragment is the anionic counterpart. Scheme 8. The coordination modes of PCO with gold and copper are h 1 and h 2 , respectively, which induces different reactivity

Synthesis of CAAC-Coinage Metal(0) Complexes

The applications above highlighted the advantages of the strong electron-donating properties of CAACs. However, their strong p-accepting properties 61 , 62 can also be exploited to stabilize electron-rich centers and paramagnetic species. [START_REF] Martin | Carbene-Stabilized Main Group Radicals and Radical Ions[END_REF][START_REF] Kundu | Stable Cyclic (Alkyl)(amino)carbene (Caac) Radicals with Main Group Substituents[END_REF] Indeed, it has been shown that the cationic bis(CAAC) gold 11c and copper 13f complexes can be reduced by a potassium mirror and KC8, respectively, to offer the bis(CAAC)Au 65 and Cu 66 complexes 31 and 32 with the metal in the formal oxidation state zero (Scheme 9). [START_REF] Jerabek | Coinage Metals Binding as Main Group Elements: Structure and Bonding of the Carbene Complexes[END_REF] In both cases, X-ray diffraction studies revealed a linear geometry with both five-membered ring CAACs being co-planar. The bonding situation for both complexes is very similar. Calculations, using the NBO method, showed that the spin density is localized on the carbene carbons (31: 60 %; 32: 68%) and the nitrogen atoms (31: 20 %; 32: 18%) while only 17 % and 10% resides at gold and copper. The shape of the SOMO indicates that the unpaired electron is delocalized over the p(π) AOs of the carbene and the p(π) AO of Au; consequently, the electronic configuration of gold is d 10 s 0 p 1 . Similarly, in complex 32 the copper center has a d 10 electronic configuration, the unpaired electron being delocalized over two carbene carbon atoms. On the other hand, the reduction of the gold complex 9a, in which the small cyclohexyl-CAAC of 11c has been replaced by the bulky menthyl-CAAC, gave rise to the dinuclear complex 33 (Scheme 9). As predicted by Schwerdtfeger and Boyd 69 for the model compound (H3P)Au-Au(PH3), the C1-Au1-Au2-C2 skeleton is almost linear and the Au-Au bond short [2.552 Å]. Note that naked Au2 has a calculated Au-Au bond length of 2.546 Å, which is very close to that observed in 33.

Interestingly, calculations found that in contrast to the mononuclear complex 31, the Au2 fragment in 33 binds the ligands through its electronic 2 S (d 10 s 1 p 0 , J = 1/2) ground state. It is important to note that before this work, apart from elemental gold, the zero oxidation state had only been found in mixed gold(0)/gold(I) complexes, [START_REF] Raubenheimer | Gold Chemistry Guided by the Isolobality Concept[END_REF] as exemplified by [(Ph3PAu)6] 2+ 2(BF4 -) 71 and [(tBu3PAu)4] 2+ 2(BF4 -). [START_REF] Zeller | Tetrahedral Gold Cluster [Au4] 2+ : Crystal Structure of {[(tert-Bu)3PAu]4} 2+ (BF4 -)2. 2CHCl3[END_REF] A nice demonstration of the efficiency of CAACs to stabilize gold(0) complexes comes from the work of Sadighi et al. [START_REF] Tsui | Reactions of a Stable Monomeric Gold(I) Hydride Complex[END_REF] who have shown that, in contrast to 33, (NHC)Au-Au(NHC) complexes were unstable and led to colloidal gold.

CAACs also allowed for the isolation of neutral, paramagnetic, formally gold(0) (allenylidene)(carbene) and bis(allenylidene) complexes (Scheme 10). [START_REF] Jin | Isolation of Cationic and Neutral (Allenylidene)(carbene) and Bis(allenylidene)gold Complexes[END_REF] Note that although a large number of allenylidene transition metal complexes are known, [START_REF] Roh | Transition Metal Vinylidene-and Allenylidene-Mediated Catalysis in Organic Synthesis[END_REF] this is rare with gold, and all involve gold(I) [START_REF] Hansmann | Gold-Allenylidenes -An Experimental and Theoretical Study[END_REF] and gold(III). [START_REF] Xiao | Platinum(II) and Gold(III) Allenylidene Complexes: Phosphorescence, Self-Assembled Nanostructures and Cytotoxicity[END_REF] The (allenylidene)(carbene)Au(I) complex 34 was obtained in a few steps, and subsequent reduction with one equivalent of KC8 in THF at room temperature, afforded the neutral gold complex 35 as yellow crystals. The Mulliken spin density analysis showed that 93.9% of the spin density resides on the CCC fragment, with only 3.8 and 1.8% located on the CAAC ligand and the Au atom, respectively. Consequently, 35 has very weak gold(0) character, and can be viewed as a gold(I) complex with a paramagnetic anionic ligand.

Scheme 10. Preparation of (allenylidene)(carbene) and bis(allenylidene) gold complexes 35 and 38, respectively

The cationic bis(allenylidene) gold(I) complex 37 can be prepared step by step using the same strategy as for 34, but also by dismutation of complex 36 (Scheme 10). The cyclic voltammogram of 37 showed two well-defined one-electron reversible reductions at -1.69 and -2.04 V versus Fc + /Fc. The first reduction potential is shifted to an even more positive value than that of the (allenylidene)(CAAC)gold(I) complex 34 (-1.73 V) demonstrating that the allenylidene behaves as a stronger p-acceptor than CAACs. However, chemical reduction of 37 resulted in a dark green solution, which was EPR active, but all attempts to grow single crystals of 38 led to decomposition.

Notably, only bis(allenylidene) complexes of Ag, [START_REF] Asay | Synthesis of Allenylidene Lithium and Silver Complexes, and Subsequent Transmetalation Reactions[END_REF] Pd, [START_REF] Asay | Synthesis of Allenylidene Lithium and Silver Complexes, and Subsequent Transmetalation Reactions[END_REF][START_REF] Kessler | Bis(allenylidene) Complexes of Palladium and Platinum[END_REF] Pt, [START_REF] Kessler | Bis(allenylidene) Complexes of Palladium and Platinum[END_REF] and Ru 80 have been isolated so far.

Synthesis of CAAC-Coinage Metal Clusters

A variety of gold clusters, [START_REF] Jin | Atomically Precise Colloidal Metal Nanoclusters and Nanoparticles: Fundamentals and Opportunities[END_REF][START_REF] Du | Atomically Precise Noble Metal Nanoclusters as Efficient Catalysts: A Bridge between Structure and Properties[END_REF] including nanoparticles are available, and have found numerous applications. [START_REF] Zhao | State of The Art in Gold Nanoparticle Synthesis[END_REF][START_REF] Hakkinen | The Gold-Sulfur Interface at the Nanoscale[END_REF][START_REF] Higaki | Atomically Tailored Gold Nanoclusters for Catalytic Application[END_REF] All of these species are positively charged, and the isolation of 31, 33 and 35 indicate that CAACs might also be able stabilize neutral clusters of different sizes, mimicking gold surfaces. Therefore, the preparation of the smallest possible clusters, namely tris(gold) clusters, was attempted. [START_REF] Jin | Trinuclear Gold Clusters Supported by Cyclic (alkyl)(amino)carbene Ligands: Mimics for Gold Heterogeneous Catalysts[END_REF] Note that before this work, there was only one example of such a small cluster, namely the NHC supported cluster 39 reported by Sadighi et al. 87 (Scheme 11). Small phosphinesupported gold clusters are usually prepared by reduction of µ3-oxo complexes [(R3PAu)3O] + X - 42. [START_REF] Nesmeyanov | triphenylphosphinegold)oxonium Salts[END_REF] , 89 Although, it has been reported that the analogous NHC-supported µ3-oxo species cannot be prepared, 87 the reaction of (CAAC)AuCl complex 9c with Ag2O, in presence of NaBF4, cleanly gave rise to the desired cluster 40c. Subsequent reduction with carbon monoxide 90 afforded the cationic tris(gold) cluster 41c. Interestingly, similar CAAC-supported clusters such as 41e and mixed (CAAC)(phosphine)-supported cluster 43 can be obtained by ligand exchange, using the readily available phosphine-supported µ3-oxo complex 42 as a precursor. Unfortunately, all attempts to obtain the corresponding neutral trinuclear Au(0) clusters failed.

Synthesis of HemilabileCAAC-Gold(I) and (III) Complexes. Oxidative addition at

Gold(I)

The hemilabile CAAC 1g has been used as a ligand to access gold(I) complexes, but more interestingly gold(III) complexes (Scheme 13). [START_REF] Chu | Synthesis of Hemilabile Cyclic (Alkyl)(amino)carbenes (CAACs) and Applications in Organometallic Chemistry[END_REF] Indeed, it is recognized that oxidative addition at gold(I) is kinetically and thermodynamically difficult, [START_REF] Hashmi | On Homogeneous Gold/Palladium Catalytic Systems[END_REF][START_REF] Livendahl | Rationale for the Sluggish Oxidative Addition of Aryl Halides to Au(I)[END_REF] but Bourissou et al. [START_REF] Joost | Reactivity of Gold Complexes towards Elementary Organometallic Reactions[END_REF][START_REF] Joost | Oxidative Addition of Carbon-Carbon Bonds to Gold[END_REF] and Toste et al. [START_REF] Wu | Stable Gold(III) Catalysts by Oxidative Addition of a Carbon-Carbon Bond[END_REF] have shown that peculiar cationic gold(I) complexes react with biphenylene to give the corresponding gold(III). 100 The imine nitrogen of 1g does not coordinate the gold(I) center of 44 (Au-N > 3.39 Å). However, upon addition of biphenylene at room temperature, in the presence of KB(C6F5)4, the gold(III) complex 45 was obtained, in which the imine ligand coordinates the gold center (Au-N = 2.25 Å). Since a stoichiometric mixture of monodentate (CAAC)AuCl complex and KB(C6F5)4, does not react with biphenylene even upon heating to 80 °C, it can be concluded that the pendant imine moiety stabilizes the gold(III) center. This result suggests that hemilabile bidentate CAACs should be suitable ligands for catalysis involving high oxidation states and might outcompete the corresponding NHCs. 101 Scheme 13. The imine nitrogen of 1g favors the oxidative addition of biphenylene by stabilizing the resulting gold(III) center

Coordination Chemistry of CAAC-6 and BiCAACs

Six-membered ring CAAC gold(I) complexes have been used to compare the steric properties of CAAC-6 with those of five-membered ring CAACs. [START_REF] Weinstein | Highly Ambiphilic Room Temperature Stable Six-Membered Cyclic (Alkyl)(amino)carbenes[END_REF] From the X-ray data of 9b and 46b, it was found that the corresponding CAAC-6 2b has a percent buried volume (%Vbur ) 102,103,104 of 51.2% compared to 47.8% for CAAC 1b (Figure 2). This is mainly due to the wider carbene bond angle (2b: 117.9 o ; 1b: 106.4 o ). BiCAAC 3, due to its higher HOMO and lower LUMO, forms even stronger gold-carbon bonds than CAAC 1e. [START_REF] Tomas-Mendivil | Bicyclic (Alkyl)(amino)carbenes (BICAACs): Stable Carbenes more Ambiphilic than CAACs[END_REF] Indeed, when one equivalent of BiCAAC 3 was added to the (CAAC)AuPh complex 47, an equilibrium featuring a 65/35 ratio of (BiCAAC)AuPh 48 and (CAAC)AuPh 47, along with free CAAC 1e and BiCAAC 3, was observed after 40 h at 60 ° C (Scheme 14).

Scheme 14. Ligand exchange reactions at gold showing that BiCAAC 3 forms even stronger gold-carbon bonds than CAAC 1e

Synthesis of Saturated Abnormal Carbene and Cyclic (Aryl)(amino)carbene Coinage

Metal Complexes

The so-called saturated abnormal carbenes 4 reported by Hashmi et al. 11,105 have not yet been isolated, nor is its cationic precursor readily prepared. Therefore, saNHC-gold complexes 49 have to be synthesized in the coordination sphere of gold, through a [3+2] dipolar cycloaddition of isonitrile gold complexes to an azomethine ylide, generated from the commercially available Nbenzyl-N-methoxymethyl-N-(trimethylsilyl)methylamine (Scheme 15). Cyclic (amino)(aryl)carbenes 5-6 have never been isolated either, but their cationic precursors are readily available. Gold complexes can be prepared by deprotonation of the corresponding aldiminium salts with LiN(SiMe3)2 at -78 o C in the presence of (Me2S)AuCl as shown for 50a, [START_REF] Rao | Cyclic (Amino)(aryl)carbenes (CAArCs) as Strong sigma-Donating and pi-Accepting Ligands for Transition Metals[END_REF] whereas the copper analogue is obtained by treatment of the salt precursor with CuOAc. 106 Alternatively, a transmetallation route can be used as exemplified by the preparation of 51, [START_REF] Jothibasu | Versatile Coordination Chemistry of Indazole-Derived Carbenes[END_REF]107,108,109 or even by reaction with the Nolan NHC gold(I) hydroxide [IPrAuOH} 32,110 as described by Breher et al 111 for the dinuclear complex 52 (Scheme 16). Note that complexes based on ditopic NHCs, analogous to 52 have been discussed as building blocks for electronically coupled systems. 112,113

Scheme 16. Synthesis of cyclic (amino)(aryl)carbene gold and copper complexes

49 R N C Au Cl + Ph N TMS O TFA (5 mol%) 0 o C Ph N Au Cl N N R Ph N Ph Ph R 50a M = Au 50b M = Cu M Cl N Ph Ph R TfO H N N R TfO H R 2) AuCl•SMe 2 , r.t. 1) Ag 2 O, r.t. N N R 51 R N N R BF 4 H R 2 N N R R H r.t. 2 (NHC)AuOH N N R R N N R R 52 2) CuOAc Au Cl Au NHC NHC Au 1) AuCl•SMe 2 LiN(SiMe 3 ) 2 -78 o C 2 BF 4

CYCLIC (ALKYL)(AMINO)CARBENE COINAGE METAL COMPLEXES IN

CATALYSIS

In the past two decades, efficient and selective gold and copper catalysts have been developed to promote a variety of chemical transformations, as evidenced by the number of reviews summarizing various aspects of this growing field. 114,115,116,117,118,119 Due to the peculiar electronic and steric properties of cyclic (alkyl)(amino)carbenes, their coinage metal complexes were found to be active in new catalytic reactions, which are discussed below.

Catalytic Cross-Coupling of Two Unsaturated Carbon Centers Leading to Allenes

The first breakthrough in catalysis with (CAAC)gold complexes was the serendipitous discovery that the gold cation 26, either isolated or prepared in situ by mixing (CAAC)AuCl 9b with one equivalent of KB(C6F5)4 in toluene, promotes the cross-coupling of enamines and terminal alkynes to yield allenes (Scheme 17). [START_REF] Lavallo | Allene Formation by Gold Catalyzed Cross-Coupling of Masked Carbenes and Vinylidenes[END_REF] This observation was very surprising since this reaction usually affords propargyl amines as observed with other catalysts, 120 including (CAAC)AuCl 9b or (Ph3P)AuCl/KB(C6F5)4. Mono-, di-, and tri-substituted enamines and aryl-, alkyl-, and trimethylsilyl-substituted alkynes can be used, including sterically hindered substrates.

Scheme 17. In contrast with other catalysts, the (CAAC)gold cation 26 promotes the crosscoupling of enamines and terminal alkynes to yield allenes

Gold complex 26 is also a very efficient catalyst for hydroamination of alkynes (see Section 3.2.).

Of particular interest, it promotes the addition of secondary amines, which allowed for the

N R 2 R 3 i Pr R 4 H i Pr R 1 + 90 o C, 16 h (Ph 3 P)AuCl/ KB(C 6 F 5 ) 4 5 mol% C H R 4 R 2 R 3 R 1 + N 90 o C, 16 h 26 or 9b/KB(C 6 F 5 ) 4 5 mol% 20 examples N i Pr i Pr R 1 R 3 R 2 R 4 Au 26 N Dipp B(C 6 F 5 ) 4
20 synthesis of tertiary enamines with alkyl substituents at nitrogen. 121 Therefore, taking into account the results discussed above, a one-pot preparation of allenes was developed by coupling two alkynes, using a sacrificial secondary amine. This synthetic strategy was applied to the homo-and hetero-coupling of alkynes. For example, in the presence 1,2,3,4-tetrahydroisoquinoline as dihydrogen donor, the homocoupling of tert-butylacetylene gave rise to allene 53 in 89% yield (Scheme 18). This allene results from the anti-Markovnikov addition of the amine to the alkyne and the same regioselectivity was observed with trimethylsilylacetylene, probably because of the steric hindrance of both reactants. However, with n-butyl acetylene, the allene 54, resulting from the Markovnikov addition of the amine was formed, whereas with cyclohexylacetylene a 14/86 mixture of the two isomeric allenes 53 and 54 was obtained. For the cross-coupling reaction, a set of four different terminal alkynes was tested with 3-hexyne as an internal alkyne, and again 1,2,3,4tetrahydroisoquinoline as a sacrificial amine. After heating at 130 o C for 16 h, the expected allenes were obtained in good to excellent yields. Scheme 18. One-pot preparation of allenes by homo-and heterocoupling of two alkynes, using a sacrificial secondary amine

The coupling of two alkynes to form allenes is one of the very rare chemical transformations that combines two different reactions, yet relies on a single catalyst. Since gold complexes are known for their excellent functional group tolerance, this one-pot process should find applications in the synthesis of complex molecules.

Gold Catalyzed Hydroamination of Alkynes and Allenes, and Hydroammoniumation and Methylamination of Alkynes

Although various homogeneous catalysts, 122,123 including gold 124 and copper 125 , have been used to effect the so-called hydroamination reaction, the cationic gold complexes 26 and 57 were the first homogeneous catalysts able to promote the catalytic hydroamination of alkynes and allenes with ammonia (Scheme 19). 126 Before this discovery, there were only two publications dealing and Surry and Buchwald 128 reported the palladium-catalyzed coupling of aryl halides with ammonia in the presence of a stoichiometric amount of base. The difficulties in using NH3 as a reagent for transition metals 129 , 130 , 131 stems from the formation of inert Lewis acid-base complexes, the so-called Werner complexes.

R 1 R 2 R 3 H, 130 o C, 16 h C C + R 3 H R 1 R 3 H R 2 R 2 R 1
Despite these challenges, in the presence of 5 mol% of (CAAC)AuNH3 CAACs render the formation of the alkyne complex energetically achievable, despite the stability of the Werner complex, thus enabling for the hydroamination reaction to take place. Nitrogen heterocycles, such as pyrroles, could also be prepared in excellent yields in one step from diynes.

These products result from the Markovnikov addition of NH3, followed by ring-closing hydroamination. The scope of the reaction is not limited to alkynes, complex 57 also promotes the NH3 hydroamination of allenes. For the parent allene and the 1,1-dialkyl substituted derivative, the NH2 group adds exclusively at the less-hindered terminus; however mono-, di-, and other words complexes featuring rather p-accepting carbenes, promote the same reaction at room temperature, although the scope of applications is much narrower. Indeed, with complex 49 the hydrohydrazination of alkyl substituted alkynes as well as internal alkynes does not occur. Lledos et al. 140 performed a very sophisticated computational study and concluded that the mechanism of the hydrazination reaction involved the substitution of the hydrazine ligand by the alkyne, leading to a gold π-complex. After the nucleophilic attack of hydrazine on the activated carbon-carbon triple bond, nitrogen to carbon atom proton transfer occurs assisted by the nucleophile. Then carbon to nitrogen atom gold migration yields the enamine intermediate. Lastly, a second nucleophile-assisted nitrogen to carbon atom proton transfer leads to the more stable imine tautomer.

Scheme 20. (CAAC) and (saNHC) gold complexes 58 and 49 promote the hydrohydrazination of alkynes with parent hydrazine

Secondary dialkylamines are also challenging substrates as they are very basic, and in addition early transition metals cannot be employed to promote hydroamination reactions, because of the In the presence of KB(C6F5)4, complex 9b also promotes the hydroamination of allenes with secondary amines, including dialkylamines. 143 Interestingly, for all the amines considered, the amino fragment always adds to the less substituted terminus of the CCC skeleton, giving access to allyl amines, which are important building blocks.

Scheme 21. CAAC-catalyzed intermolecular hydroamination of alkynes and allenes with secondary dialkylamines

In Scheme 18, it was shown that the ability of (CAAC)Au+ complex 26 to promote the hydroamination of internal alkynes with secondary amines allowed for the one-pot preparation of allenes by coupling two alkynes, using a sacrificial secondary amine. Similarly, following the (large excess) This cyclization tolerates aryl or alkyl substituents on the alkyne, but is limited to N,N'-dimethylbenzenamines.

(NHC)AuCl, AgSbF 6 R N R 1 R 1 CH 3 NHR R 2 R 1 H R 3 R N R 3 R 2 R 1 (Cy 3 P)(CO)(MeCN

Scheme 23. Intramolecular hydroammoniumation and aminomethylation of carbon-carbon triple bonds giving 59 and 60, respectively

Importantly, many of the reactions described in this section required very drastic conditions, as exemplified by the NH3 hydroamination of tetrasubstituted allenes, which requires 44 hours at 175 o C (Scheme 19). This is a clear demonstration of the very unusual thermal stability of cationic (CAAC)gold(I) complexes, which is due to the peculiar electronic properties of CAACs.

(CAAC)-Mono-and -Bis-(copper)acetylide Complexes in Catalysis.

The isolation of the mono-and bis-(copper)acetylide complexes 24 and 25 [START_REF] Jin | Isolation of Bis(copper) Key Intermediates in Cu-Catalyzed Azide-Alkyne "Click Reaction[END_REF] has not only allowed for a better understanding of the mechanism of the Cu-catalyzed azide-alkyne "click reaction", but has also led to the development of novel copper-catalyzed reactions.

For the CuAAC, it has been possible to demonstrate several important features of the mechanism.

Although both 24 and 25 are active in the catalytic cycle, the dinuclear complex 25 is involved in the kinetically favored pathway (Scheme 24). The resting state of the catalytic cycle is the bis(copper) triazole complex 61. Lastly, the alkyne serves as the proton source for the demetallation of 61, which regenerates 25, leaving out the mononuclear complex 24 from the catalytic cycle. The CuAAC reactions promoted by CAAC-supported copper complexes are slow enough to be monitored, and to study the successive steps of the catalytic cycle. Of particular interest, the influence of the X ligand has been investigated by carrying out stoichiometric reactions. 149 For the metalation step giving 24 (step 1), which involves a deprotonation of the alkyne, basic ligands are the most efficient (Scheme 25). Indeed, with X= t BuO, the metalation is fast and irreversible, whereas with PhO, a dynamic equilibrium can only be observed by NMR. Lastly, with TfO, no spectroscopic evidence for the formation of 24 can be found, but the latter can be obtained by adding an external base like triethylamine. In contrast, the formation of the bis(copper)acetylide 25 (step 2) is favored by non-nucleophilic ligands with TfO being the best. For step 3, the bis(copper)triazole 61 was only observed when X = TfO; but when X = Cl, AcO, or PhO, a Cmonometallated triazole was obtained. For the last step of the catalytic cycle, namely the protodemetalation of triazole by the alkyne (step 4), all X ligands performed similarly (kobs between 0.5 10 -4 s -1 and 2.2 10 -4 s -1 ), except for the acetate (kobs > 370 10 -4 s -1 ). This acceleration is characteristic of a base assisted proton transfer mechanism as observed in biological systems. 150

N H R 2 R 1 9b/AgOTf (5 mol %) N R 2 R 3 R 1 59 TfO R 3 TfO Au Cl 9b R 1 ,R 2 ,R 3 =
R 1 N N N Cu R 2 Cu X R 1 N N N H R 2 R 1 H R 1 H + -HX R 1 N N N Cu R 2 LCuX Slow FAST R 1 N N N H R 2 R 1 H R 2 N 3 R 2 N 3 step 1 step 2 step 3 step 4 L = 61 N Et Et Dipp 24 Cu R 1 L Cu Cu R 1 X 25 L L CuX L L L L 1e 29
From these results, it appears that the acetate is a good compromise, basic enough for the metalation step, not too nucleophilic to prevent the formation of the bis(copper)acetylide 25, and very efficient in promoting the proto-demetalation step. This rationalized why the acetate is often used in CuAAC reactions.

Scheme 25. Influence of the X ligand on the first two steps of the CuAAC reaction

The knowledge of the influence of the X ligand 151 on the formation of 24 versus 25 has allowed for the rational design of copper catalysts that selectively promote either the hydroboration 152 or the dehydrogenative borylation 153 of terminal alkynes with pinacolborane (Scheme 26). Indeed, in complexes 24, which can be prepared with LCuOPh, the triple bond is available for hydroboration leading to alkenyl boronic esters 62. In contrast, in dinuclear complexes 25, which are readily obtained by reacting LCuOTf with terminal alkynes in the presence of triethylamine with ammonium triflate as the byproduct, the triple bond is protected. The polarized copper-carbon bond of 25 can undergo a s-bond metathesis with pinacolborane giving rise to the alkynyl boronic ester 63, along with the copper hydride 64 (Scheme 27). The latter reacts with ammonium triflate to regenerate LCuOTf and triethylamine with the elimination of dihydrogen.

Scheme 26. Influence of the X ligand on the fate of the reaction of pinacolborane with phenyl acetylene

+ 24 Both the dehydrogenative borylation and the hydroboration processes are readily applicable to a broad range of terminal alkynes bearing functionalities such as OMe, CN, F, Cl, TMS and CO2Me.

X = PhO X = TfO X = TfO + Et 3 N R H X = t BuO (-Et 3 NH , TfO ) Cu Cu R X 25 L L Cu R L CuX L CuOPh L CuOTf L Ph H + LCuX (2.
Importantly, the alkenyl (62) and alkynyl boronic esters (63) were isolated in good to excellent yields via simple filtration through a short plug of dry neutral alumina. This straightforward protocol allows for gram-scale synthesis of these boronic esters.

Note that the catalytic dehydrogenative borylation of C(sp 3 )-H and C(sp 2 )-H bonds discovered by Hartwig et al. 154 and Smith et al. 155 are well studied. 156 In contrast, there are only a few reports by Ozerov et al. 157,158,159 for C(sp)-H bonds, using iridium and palladium complexes supported by pincer ligands, and one by Tsuchimoto et al. 160 with zinc triflate, which has a rather narrow scope. temperature with a high rate of hydrogen generation is vital for the large-scale application of these inorganic compounds. 162 It was first observed that the CAAC copper complex 13e reacts with BH3NH3 or NaBH4 to give 65 in which two hydrogen atoms of BH4 interact with the metal (Scheme 28). Interestingly, in contrast to other LCuBH4 complexes, as exemplified by (Ph3P)CuBH4 which decomposes at -20 o C, 163 65 is perfectly stable at room temperature. Then, it was found that (CAAC)CuBH4 65 and (CAAC)CuCl 13e complexes are highly efficient catalyst for the hydrolytic dehydrogenation of BH3NH3. [START_REF] Hu | Air-Stable (CAAC)CuCl and (CAAC)CuBH4 Complexes as Catalysts for the Hydrolytic Dehydrogenation of BH3NH3[END_REF] Indeed, when a 1 mol% acetone/water solution of 13e was added to BH3NH3, 2.6 moles of H2 were released per mole of BH3NH3 over 5 minutes, which corresponds to a turnover frequency (TOF) of 3100 mol of H2 per mol of 13e per hour. More impressive, by using 1 mol% of 65, the hydrolytic dehydrogenation reaction was finished within 2 minutes at room temperature, with 2.8 moles of H2 released per mole of BH3NH3, thus giving a TOF of 8400.

(CAAC)-Coinage Metals for the

This TOF is more than 1000 times higher than that reported with CuCl2, 164 and compares well with those obtained in the hydrolytic dehydrogenation of ammonia borane promoted by noble metal catalysts. 161 Importantly, 13e and 65 are very robust. The catalytic solution can be handled in air and recycled more than 15 times without significant loss of activity. to 3,500,000. 167 However, this is not the case with abundant and inexpensive first-row metals such as copper. Indeed, although copper hydrides efficiently insert CO2 as shown by the numerous copper-catalyzed carboxylation reactions, 168 , 169 they have difficulty activating molecular hydrogen; consequently, TONs below 500 are usually obtained. 170 On the other hand, frustrated Lewis pairs (FLPs) 171,172 are well-known to activate H2 173,174 but cannot reduce CO2 catalytically because of the formation of a strong B-O bond. 175 It then became reasonable to believe that a copper hydride activating CO2, working in tandem with a Lewis pair as H2 activator, would provide an efficient synergy for the catalytic reduction of CO2 with H2. Indeed, it was found that using the copper borohydride complex 65 as a copper hydride surrogate and B(C6F5)3/DBU as the frustrated Lewis pair, CO2 was cleanly reduced into the formate after 24 hours at 100 o C with TONs reaching 1880 (Scheme 29). 176,177 Scheme 29. Tandem copper hydride-Lewis pair catalyzed reduction of carbon dioxide into formate with dihydrogen.

Interestingly, the elementary steps of the catalytic cycle were reproduced stoichiometrically (Scheme 30). The copper borohydride complex 65 reacted with CO2 (10 bar) at 80 °C giving the insertion product 66 upon elimination of BH3. Then it was confirmed that a known FLP, namely B(C6F5)3 and 1,2,2,6,6-pentamethylpiperidine (PMP), cleaved molecular hydrogen to give 67. 178 Lastly, it was shown that at room temperature a stoichiometric amount of 66 reacted within minutes with 67 to give the formate and the borane-stabilized monomeric (CAAC)CuH-BCF adduct 68. These results suggest that the synergy between a transition metal center and a Lewis pair could be extended to other reactions.

Trinuclear (CAAC) Gold Clusters as Catalysts for the Carbonylation of Amines

In 2012 Corma et al. 179,180,181 reported that very small metallic gold clusters could display catalytic activities that are much higher than those obtained with gold nanoparticles and mononuclear homogeneous gold catalysts. This striking discovery led to the question of whether very small, well-defined clusters, capped with ligands, such as 40-43 (Scheme 11), could also behave as efficient catalysts. [START_REF] Jin | Trinuclear Gold Clusters Supported by Cyclic (alkyl)(amino)carbene Ligands: Mimics for Gold Heterogeneous Catalysts[END_REF] To tackle this question, the carbonylation of amines, which is the simplest and most environmentally friendly route for the preparation of urea derivatives, 182 was chosen. It was found that 2.5 mol% of trinuclear gold complex 41e catalyzed the carbonylation of cyclohexylamine under 30 psi of CO and 10 psi of O2. After 2 days at 90 o C, the N,N'dicyclohexylurea was formed in 69% yield (Scheme 31). Similarly, benzyl amine and 2phenylethylamine were converted into the corresponding urea in 74% and 72% yields, respectively. In the case of the more sterically hindered substrates, such as 2-adamantylamine, the conversion was significantly decreased, while no reaction was observed with the less basic aniline.

Importantly, no decomposition of 41e could be observed during these reactions, demonstrating its robustness. The well-defined nature of 41e allowed for a mechanistic study of the carbonylation reaction. It has been found that CO does not react with 41e or the amine in the absence of air.

However, 41e reacts with cyclohexylamine in the presence of oxygen, leading after two days at 70 o C to the dinuclear complex 69, which was isolated (Scheme 32). Then, when CO was added to 69, the trinuclear cluster 41e was recovered along with cyclohexyl isocyanate and traces of urea.

Note that upon addition of amine, which transforms 41e into 69, two gold centers are oxidized, while in the addition of CO to 69 giving back 41, two gold centers are reduced. This is a very rare example of a gold catalyzed process involving a definite change of oxidation state of the metal. 183,184,185 Scheme 32. Stoichiometric reactions for a better understanding of the catalytic cycle of the carbonylation of amines

(CAAC)-Gold and -Copper Catalysts for the Hydroarylation of Styrene with

Anilines

Friedel-Crafts reactions, such as the intermolecular hydroarylation of alkenes, 186 , 187 usually require Lewis acid catalysts, and are therefore rarely efficient for basic substrates, such as amines.

However, in the presence of KB(C6F5)4, the (CAAC)AuCl complex 44, featuring the hemilabile CAAC 1g, promoted the hydroarylation of α-methylstyrene with N,N-dimethyl aniline (Scheme 33). [START_REF] Chu | Synthesis of Hemilabile Cyclic (Alkyl)(amino)carbenes (CAACs) and Applications in Organometallic Chemistry[END_REF] A 97% conversion was observed after only 12 h at 120 °C, which is slightly better than that with the CAAC supported gold complex 9e, and even the anti-Bredt gold complex 71, which requires 24 h at 135 °C. 188 Even more striking, the analogous copper complex 70 also promotes the same hydroarylation reaction at 120 o C with a 97% conversion after 12 h. Importantly, under the same experimental conditions, the monodentate CAAC copper complex 13e gave only traces of the hydroarylation product. The superiority of complex 70 over 13e might be due to the presence of a basic moiety on the side chain of the CAAC ligand, which could assist a formal proton transfer.

Although examples of intramolecular copper-catalyzed hydroarylation of alkenes have been reported, 189 70 was the first copper complex able to promote the intermolecular version. 190,191 They reported that a stoichiometric mixture of (CAAC)AuCl 13b and NaBAr F (5 mol%), with Pd2dba3 (2.5 mol%) promotes at room temperature the rearrangement of vinyl aziridines into pyrrolizidine and indolizidine frameworks (Scheme 34). 192 The scope of the reaction is reasonably broad as long as bulky R substituents are used to increase the Thorpe-Ingold effect. Methyl substitution at the internal position of the tethered alkene was tolerated, as well as increasing the olefin tether length.

Scheme 33. Comparison of (carbene)-gold and -copper catalysts for the hydroarylation of a- methylstyrene with anilines

Scheme 34. Gold/palladium promoted rearrangement of vinyl aziridines into pyrrolizidines

Following a very detailed mechanistic study, the authors concluded that the reaction did not proceed through carbophilic Au(I) catalysis. Instead, the Au(I)complex would act as an azaphilic Lewis acid helping the aziridine oxidative addition to Pd(0) (Scheme 35). The resulting Pd(II) intermediate would then undergo a syn-aminometalation, followed by a reductive elimination from the palladacyclic intermediate. This mechanistic hypothesis seems to contradict most of the reports emphasizing the carbophilicity of Au(I) towards carbon-carbon multiple bonds.

However, most of these reports deal with alkynes, and therefore, the competitive binding of gold to heteroatoms should be seriously considered, when alkenes are involved. This reaction appeared very sensitive to the experimental conditions used, especially the solvent and the amount of water, and its scope is rather limited. Interestingly for this Focus Review, a detailed study of the influence of the ligand has been done, and CAACs led to the highest yields, presumably through promotion of reductive elimination after migratory insertion in favor of other processes. It is noteworthy that although the migratory insertion of unsaturated carbon-based species into metal-carbon bonds is well-established for most transition metals, 194 this is not the case for gold, 195,196,197 with rare exceptions. 198 Therefore, as concluded by the authors, "This study paves the way for homogeneous gold-catalyzed processes incorporating carbene migratory insertion steps."

Pd(0) N R R Au N R R Au Pd(II) Au N Pd(II) R R N R R L L L L = 1b Scheme 36.
The superiority of CAAC ligands for the migratory insertion of carbenes generated from diazoalkanes into Au-carbon bonds.

Chiral CAAC Ligands in Enantioselective Catalysis

Chiral NHCs were first used as ligands for transition metal-based catalysts in 1996. 199,200 However, up until now, only imidazol-2-ylidenes 7, imidazolidin-2-ylidenes 8 and 1,2,4-triazol-5-ylidenes (Enders carbene) 201 have been used as ligands for enantioselective transformations. 202 Since CAACs feature a quaternary carbon adjacent the carbene carbon, and thus in closer proximity to the active site than NHCs, it is surprising that the first report of their use as ligands in enantioselective catalysis only appeared in 2019. 203 This is even more astonishing since already in 2005, it has been shown that enantiopure CAACs, such as 1a, could be prepared without enantioor diastereo-selective separations from inexpensive starting materials such as (-)-menthol. 1 The key step of the synthesis of enantiopure CAACs is based on the well-known propensity of bulky reactants to approach the cyclohexane moiety selectively from the equatorial direction, as shown for the menthylCAAC 1a (Scheme 37).

Scheme 37. Synthesis of the enantiopure menthyl-CAAC 1a with the key step

The menthyl-CAAC 1a was benchmarked in the copper-catalyzed asymmetric conjugate borylation reaction, a chemical transformation which allows for the preparation of very useful The absence of enantioselectivity observed with 13a is believed to be due to a conformational inversion of the menthyl ring, 207 since the two conformers have antagonistic stereo-inducing effects (Figure 3). To circumvent this issue, a more rigid chiral CAAC was prepared, using once again a precursor derived from the chiral pool, namely the 5a-cholestan-3-one. The X-ray data of the These results suggest that the use of chiral CAACs should not be overlooked in metalcatalyzed asymmetric transformations. These carbenes are readily available from precursors belonging to the chiral pool, not restricted to chiral amines (as for NHCs), but extends to chiral aldehydes, a much larger feedstock.

BIOLOGICAL APPLICATIONS OF CYCLIC (ALKYL)(AMINO)CARBENE COINAGE METAL COMPLEXES

The biological properties of coinage metal NHC complexes (NHC = imidazol-2-ylidenes 7 and imidazolidin-2-ylidenes 8) have been widely investigated, and are the subject of numerous reviews. 18, 208 , 209 , 210 , 211 NHC-gold complexes show antimicrobial activity in several bacterial strains, they are antioxidant and antiparasitic agents that could be relevant in diseases such as leishmaniasis where there is no optimal drug treatment, and they have antitumor activity. NHC-Ag complexes have been shown to be effective against a wide range of both Gram-positive and Gram-negative bacterial strains, and they feature comparable or better antitumor activity than standard chemotherapeutics such as cisplatin and 5-fluorouracil.

The success of NHC-coinage metal complexes in medicinal applications has been rationalized by their great stability in biological media, which is due to their robustness towards ligand dissociation. Since cyclic (alkyl)-and (aryl)-(amino)carbene-coinage metal bonds are even stronger than those of NHCs, it seems reasonable to believe that these complexes could find medicinal applications. However, this field is still in its infancy.

In 2012, Huynh et al. 212 , 213 studied the cytotoxic activities of gold(I) and gold(III) complexes 76-79, bearing cyclic (amino)carbenes derived from pyrazoles, towards the NCI-H1666 non-small cell lung cancer cell line (Scheme 39). The neutral monocarbene complexes 76 and 78 displayed 2 orders of magnitude lower activity as compared to the cationic bis(carbenes) 77 and 79. This is in line with what has been previously referred to as delocalized lipophilic cations, which readily pass through the lipid membrane of mitochondria and eventually lead to mitochondriainduced apoptosis. Importantly, the cationic bis(carbene) complexes 77 and 79 showed better activities than cisplatin.

Similarly, in 2017, Bochmann et al. 214 prepared a series mono-and bis-CAAC complexes of copper, silver and gold (Scheme 39). They were tested against a panel of human cancer cell lines including leukemia (HL 60), breast adenocarcinoma cells (MCF-7) and human lung adenocarcinoma epithelial cell lines (A549), which are known to have varying degrees of cisplatin resistance. These complexes appeared to be highly cytotoxic, with IC50 values in the submicromolar to ∼100 nanomolar range, even against cisplatin-insensitive MCF-7 and A549 cells.

As in the case of complexes 76-79, cationic bis-carbene complexes of Au, Ag and Cu 11f-13f proved particularly effective with the mixed-carbene gold complex 80 being the most potent of the series (Scheme 39). Interestingly, the authors concluded that although the mechanism of cell growth control by these complexes remains to be established, the inhibition of thioredoxin reductase, which is a common pathway for gold NHC compounds could be ruled out as a primary pathway.

Scheme 39. Cationic bis(carbene) gold 77 and 79 displayed 2 orders of magnitude higher cytotoxicity than the neutral monocarbene complexes 76 and 78, and are more potent than cisplatin towards the NCI-H1666 non-small cell lung cancer cell line. Cationic bis(carbenes) 11f-13f proved particularly effective against cisplatin-insensitive MCF-7 and A549 cells, the mixed-carbene gold complex 80 being the most potent of the series

The CAAC-gold complexes, prepared via a cyclization-rearrangement cascade 30 (Scheme 2), feature CAACs based on indole alkaloid scaffolds, which are by themselves often biologically active, including against cancer cells. It was found that complexes 81 displayed cytotoxicity towards the human ovarian cancer cell line A2780 and colorectal adenocarcinoma cell line HT29 at low micromolar or submicromolar concentration. Some of these complexes such as 81a appeared to have strong but nonselective anticancer activity against all cancer cell lines, while others displayed interesting selectivity (Scheme 40). For example, 81b is cytotoxic to HeLa cells and was the only complex active against the breast cancer cell line MCF7 in micromolar concentration. Overall, these preliminary investigations show that CAAC coinage metal complexes hold promise for medicinal applications.

OPTOELECTRONIC APPLICATIONS OF CYCLIC (ALKYL)(AMINO)CARBENE COINAGE METAL COMPLEXES

Since the pioneering discovery of electroluminescence by French chemist and physicist André Bernanose,215,216 and the preparation of an electroluminescent device using organic materials as the emitting element by Ching Tang and Steven Van Slyke at Eastman Kodak, 217 Organic Light-Emitting Diodes (OLEDs) have become vital components of many current technologies. In part due to their efficiency and greater contrast-ratio (black OLED emits no light), OLEDs are traditionally found in television and smartphone displays. However, with the advent of foldable and rollable OLED displays, or even 3D printing of transparent OLED displays, 218 it is forecast that the global demand in light emitting OLED materials will double by 2023. Traditionally, these devices rely on expensive heavy transition metals such iridium, platinum, and ruthenium, as well as rare metal-based phosphors which intrinsically pose serious economical and sustainable challenges in a global economy. 219 In recent years, focus has been put toward the development of

Scheme 42. Influence of the anionic ligand on the quantum yields

Notwithstanding these promising reports, it is most likely the introduction of a second redox-active ligand, a carbazole moiety, that has so far yielded the most significant advancement in the field of coinage metal-based phosphors (Scheme 43). In 2017 and 2019, Di et al. and Thompson et al. respectively reported that both adamantyl-1b 230 and menthyl-1a 231 CAAC afford very emissive materials when bound to copper with an anionic carbazole moiety. Emission is also tailored to the rigidity of the ligand as in complexes 92-95. Initially believed to originate from rotationally assisted spin-state inversion, 230 the luminescence properties of linear carbene-metal-amide (CMA) complexes were later shown to stem from thermally activated delayed fluorescence (TADF) . This occurs through singlet ligand to ligand charge transfer (LLCT) between the electron rich carbazole (HOMO) and the electron-accepting carbene (LUMO). This is favored by a coplanar ligand conformation and coupling through the metal d orbitals. 231,232,233,234,235

Scheme 43. Carbene metal amides emitters

Thanks to these CMA emitters, OLEDs devices with external quantum efficiencies (EQEs) up to 25% have been reported with Cu,230,231 and Au 236 ,237 , 238 but also with Ag. [START_REF] Romanov | Synthesis, Structures and Photoluminescence Properties of Silver Complexes of Cyclic (Alkyl)(amino)carbenes[END_REF]239 As noted by Thompson et al. in a systematic study, 240 despite blatant structural similarities, group 11 metals CMA emitters display marked photophysical differences. However, the metal ions in CMA are best described as redox "innocent" and only serve as a monatomic electronic conduit that modulates communication between the two redox active ligands. Capitalizing on these properties, emissions across the visible spectrum are readily achieved by simple modification of the carbazole moiety. and allenes with ammonia and parent hydrazine. In addition to their uses in catalysis, recent results

show that their applications in medicinal and materials science holds an even greater potential.

Notably, the extent of the recent breakthroughs made in the preparation of efficient coinage metal OLEDs could have a tangible technological impact on our society.

Altogether, we believe that the results summarized in this review article will lead to even more innovations with the newer members of the CAAC ligand family, namely, the bicyclic CAACs (BiCAACs), the 6-membered CAACs (CAAC-6), the aryl versions (CAArCs), the chiral ChiCAACs, and the bidentate CAACs (BICAACs). His research spans a wide range of topics at the border between organic and inorganic chemistry.

He is a member of the French Academy of Sciences.

Sciences, Catalysis Science Program, under Award # DE-SC0009376. We are grateful to our dedicated coworkers who are co-authors of the papers cited in this review.

  3.3. (CAAC)-Mono-and -Bis-(copper)acetylide Complexes in Catalysis. 3.4. (CAAC) Coinage Metals for the Activation of Small Molecules 3.4.1. (CAAC)CuBH4 Complexes for the Catalytic Hydrolytic Dehydrogenation of BH3NH3 and for the Reduction of CO2 into Formate with H2. 3.4.2. Trinuclear (CAAC) Gold Clusters as Catalysts for the Carbonylation of Amines 3.5. Miscellaneous 3.5.1. (CAAC) Gold and Copper Catalysts for the Hydroarylation of Styrene with Anilines 3.5.2. (CAAC)Gold(I) Complexes in Gold/Palladium Dual Catalysis 3.5.3. (CAAC) Gold(III) Complexes in Migratory Insertion of Carbenes into Au(III)-C Bonds. 3.6. Chiral CAAC Ligands in Enantioselective Catalysis 4. Biological Applications of Cyclic (Alkyl)-and (Aryl)-(Amino)carbene Coinage Metal Complexes 5. Optoelectronic Applications of Cyclic (Alkyl)(amino)carbene Coinage Metal Complexes 6. Conclusions and Outlook Author Information

  Scheme 2. Synthesis of CAACAuCl complexes via a cyclization-rearrangement cascade.

  Scheme 4. The crystalline copper hydride dimer supported by bulky NHCs(14) and CAACs(15), and the unprecedented rearrangement of the latter by addition of a L ligand

  Scheme 7. Synthesis of the crystalline [(CAAC)Au(η 2 -toluene)] + [B(C6F5)4] -complex 26

68

 68

Scheme 9 .

 9 Scheme 9. Synthesis of mononuclear gold(0) and copper(0) complexes 31 and 32; solid state structure and SOMO of 31; synthesis and solid state structure of the dinuclear gold(0) complex 33

Scheme 11 .

 11 Scheme 11. The only known trinuclear Au cluster 39; preparation of CAAC-Au clusters 41e

Scheme 12 .

 12 Scheme 12. Preparation of CAAC copper(I) clusters with main group elements.

Figure 2 .

 2 Figure 2. Probing sterics of CAAC-5 versus CAAC-6. Modified with permission from ref 9. Copyright 2018 American Chemical Society.

Scheme 15 .

 15 Scheme 15. Synthesis of the saturated abnormal carbene-gold complex49

  trisubstituted amines are formed. Tetrasubstituted allenes also undergo hydroamination with ammonia, but a different regioselectivity was observed. The NH2 fragment adds to the central carbon, probably because of steric factors, and only the monohydroamination product was obtained. Scheme 19. (CAAC)AuNH3 complex 57 was the first complex able to promote the hydroamination of alkynes and allenes with ammonia Like NH3, parent hydrazine is a difficult substrate for transition metal catalyzed reactions. Before our work, 133 there was no report on hydroamination reaction with hydrazine, and only one example of transition-metal catalyzed functionalization of H2NNH2, namely the palladium catalyzed crosscoupling with aryl chlorides and tosylates.134 There are several difficulties associated with hydrazine. Akin to ammonia, H2NNH2 forms inert Werner complexes. In addition, hydrazine is known to be a strong reducing reagent that leads to inactive metal(0) particles. As an illustration, the formation of gold particles has been reported in the reaction of gold chloride with hydrazine,135 and cationic trinuclear phosphine-gold complexes of the type (R3PAu)3(O) + X _ have been shown to promote the dehydrogenation of H2NNH2 to give N2 complexes.136 In contrast, a stoichiometric amount of (CAAC)AuCl 9a 133 and KB(C6F5)4 reacts cleanly with hydrazine to give the corresponding Werner complex 58, which is active for the hydrohydrazination of a variety of alkynes and bis(alkynes) at rather high temperatures (90-100 o C) (Scheme 20). Interestingly, in the presence of KB(C6F5)4, (saNHC)AuCl complexes 49137 [or even (anti-Bredt-NHC)AuCl],138,139 in

  or 58 (95% yield), 100 o C, 0.5h 49 (91% yield), 20 o C, 4h [Au]/KB(C 6 F 5 ) 4 (5 mol%) 9b (91% yield), 90 o C, 14h 49 (0% yield), 20 o imido complex (LxM=NR) in the catalytic cycle. 141 Consequently, there are very few examples of intermolecular hydroamination reaction with secondary amines. It was found that a stoichiometric amount of KB(C6F5)4 and gold(I) complex 9b 121 or 9g 142 catalyzes the addition of many types of secondary amines to terminal as well as internal alkynes, including the first examples of intermolecular hydroamination of internal alkynes with secondary alkyl amines (Scheme 21).

  Scheme 22. Comparison of the scope of the previously reported one-pot three-component synthesis of 1,2-dihydroquinolines with that observed with CAAC-gold 9g /KB(C6F5)4

  to the corresponding indoles 60 in very good yields after 20 h at 160 o C.

24 .

 24 Both the mono-copper 24 and the bis-copper acetylide 25 are active in the CuAAC reaction, but the latter is more efficient. The alkyne is the proton source for the demetallation step, which regenerates 25, thereby excluding 24 from the preferred catalytic cycle. Reproduced with permission from ref 51. Copyright 2015 AAAS.

  the Reduction of CO2 into Formate with H2. Ammonia borane (BH3NH3) and metal borohydrides M(BH4)n are excellent hydrogen storage materials. 161 Developing catalysts based on cheap transition metals capable of releasing H2 at room

Scheme 28 .BH

 28 Scheme 28. Preparation of (CAAC)CuBH4 65 and hydrolytic dehydrogenation of BH3NH3

30 .

 30 Stoichiometric reactions mimicking the elementary steps of the catalytic cycle of the tandem copper hydride-Lewis pair catalyzed reduction of carbon dioxide by H2

Scheme 31 .

 31 Scheme 31. Carbonylation of amines catalyzed by the trinuclear gold cluster 41e

44 :

 44 12 h, 97% (1 h, 45%) cat. = 9e: 12 h, 89% (1 h, 33%) cat. = 71: 24 h, 97% but at 135 o C 3.5.2. (CAAC)Gold(I) Complexes in Gold/Palladium Dual Catalysis Blum et al. developed elegant dual-catalytic systems combining the Lewis acidic activity of Au(I) with a Lewis basic transition metal catalyst.

35 .

 35 Postulated catalytic cycle for the gold/palladium promoted rearrangement of vinyl aziridines into pyrrolizidines. Modified with permission from ref 191. Copyright 2012 American Chemical Society.3.5.3. (CAAC)-Gold(III) Complexes in Migratory Insertion of Carbenes into Au(III)-C Bonds.In 2018, Toste et al.193 reported the first examples of migratory insertion of carbenes generated from silyl-or carbonyl-diazoalkanes into Au-carbon bonds. Indeed, abstraction of chloride from 72 with AgNTf2 or NaBAr F followed by addition of ethyl diazoacetate at room temperature, led to the formation of the fluorene derivative 73 as the major product (Scheme 36).

Figure 3 .

 3 Figure 3. Proposed justification for the lack of asymmetric induction with catalyst 13a. Adapted with permission from ref 207. Copyright 2019 American Chemical Society.

  75 show a distinctive orientation of the cholestanyl backbone, which gives rise to the topographic steric map showed in Figure4. As can be seen, the corresponding quadrant diagram suggests facial stereoselectivity in catalyst-substrate adducts. As the menthylCAAC-CuCl 13a, the cholesterolCAAC-CuCl 75 readily promotes the asymmetric conjugate borylation in moderate to good isolated yields (47 to 77%), but with enantiomeric excesses reaching 55% (Scheme 38).

Figure 4 .

 4 Figure 4. X-ray crystal structure of 75 and an overlaid topological steric map with a quadrant diagram. Adapted with permission from ref 207. Copyright 2019 American Chemical Society.

80 Xyl

 80 Scheme 40. Gold complexes based on indole alkaloid scaffolds. 81a displays strong but nonselective anticancer activity, while 81b is cytotoxic to HeLa cells and the breast cancer cell line MCF7

d 10 -

 10 coinage metal alternatives which, aside from their low cost and low toxicity, are inherently more advantageous thanks to their fully filled d-orbitals which prevent internal quenching of excited states by low-lying d*-d transitions.220 In particular, three-and four-coordinate Cu(I) complexes bearing phosphine and N-heterocyclic ligands with good p-acceptor properties lying metal-to-ligand charge-transfer (MLCT) and thermally activated delayed fluorescence (TADF) have been intensely investigated as emitting dopants in OLEDs.

  carbene 91,229 all resulting in distinct changes in photophysical behavior. It is worth mentioning that the introduction of flexible electron-rich N-donors such as the formamidinato 86 extends the photophysical properties toward the development of power-efficient white organic light-emitting diode (WOLEDs).228 With lighting accounting for 15% of global electricity consumption and 5% of worldwide greenhouse gas emissions, the production of WOLEDs based on abundant copper sources could have a substantial environmental and economical impact.

  231 In fact, by combining (1b)gold with sulfone 96, dibenzazepine 97, phenothiazine 98, phenoxazine 99 or phenazine 100, as conformationally flexible 7-membered carbazole surrogates, Romanov et al. could tune the luminescence from blue to deep red (Scheme 43). 241 Note that with these non-rigid anionic ligands, copper analogues were found to be less emissive as illustrated by 96 [ØPL = 89.6% (Au) vs. 49.5% (Cu) -in toluene]. This observation was proposed to parallel the

Scheme 44 .Scheme 45 .

 4445 Scheme 44. Tuning the luminescence from blue to deep red

  mechanistic approach, his research interests are aimed toward the development of new catalytic methodologies, especially the enantioselective versions, using CAACs and other carbene ligands. Michèle Soleilhavoup studied chemistry at the University Paul Sabatier in Toulouse and received her PhD in 1993 under the supervision of Guy Bertrand. From 1993 to 1995, she worked for BASF AG at Ludwigshafen. In 1995, she moved to the University Paris VI as a "Chargée de Recherche CNRS", and from 2000 to 2001, she worked in the Remi Chauvin's group at the Laboratoire de Chimie de Coordination in Toulouse. In 2002, she joined the UCR/ CNRS Joint Research Laboratory at the University of California, Riverside and in 2012 the UCSD/CNRS Laboratory at the University of California, San Diego. Her current research interests are focused on the chemistry of carbenes and their application as tunable ligands for transition metal catalysts. Guy Bertrand was an undergraduate in Montpellier, and obtained his PhD from the University of Toulouse. From 1988 to 1998 he was a "Director of Research" at the Laboratoire de Chimie de Coordination du CNRS, and from 1998 to 2005 the Director of the Laboratoire d'Hétérochimie Fondamentale et Appliquée at the University Paul Sabatier (Toulouse). From 2001 to 2012 he has been at the University of California at Riverside, and since 2012 he is Distinguished Professor and Director of the UCSD/CNRS Joint Research Laboratory at the University of California, San Diego.

  CONTENTS 1. Introduction 2. Coordination Chemistry of Cyclic (Alkyl)-and (Aryl)-(Amino)carbenes with Coinage Metals 2.1. Synthesis of (CAAC)MCl (M = Cu, Ag, Au) Complexes 2.2. Synthesis of Various Gold(I) and Gold(III) Complexes from (CAAC)AuCl and (CAAC)AuOH 2.3. Synthesis of (CAAC)CuH Complexes 2.4. Synthesis of CAAC Coinage Metal Alkene, Alkyne, and Aryl p-Complexes 2.5. Synthesis of CAAC Coinage Metal PCO Complexes 2.6. Synthesis of CAAC Coinage Metal(0) Complexes 2.7. Synthesis of CAAC Coinage Metal Clusters 2.8. Synthesis of HemilabileCAAC-Gold(I) and (III) Complexes. Oxidative addition at Gold(I) 2.9. Coordination Chemistry of CAAC-6 and BiCAAC 2.10. Synthesis of Saturated Abnormal Carbene and Cyclic (Aryl)(amino)carbene Coinage Metal Complexes 3. Cyclic (Alkyl)(Amino)carbene Coinage Metal Complexes in Catalysis 3.1. Catalytic Cross-Coupling of Two Unsaturated Carbon Centers Leading to Allenes 3.2. Gold Catalyzed Hydroamination of Alkynes and Allenes, and Hydroammoniumation and Methylamination of Alkynes

  57, NH3 adds to terminal alkynes at 110 o C leading to the Markovnikov imine, whereas for internal alkynes heating at 160 o C is necessary to obtain the expected tautomer of the corresponding enamines (Scheme 19). A very detailed computational study by Ujaque et al. 132 concluded that the electronic properties of

  works byYi et al. 144 and Che et al., 145 our group developed a one-pot three-component synthesis of 1,2-dihydroquinolines, involving a tandem hydroamination-hydroarylation protocol.142

			Dipp	N	Dipp	N
					Au		Au
					Cl	9b	Cl	9h
	Ph	Ph	+	Et 2 NH	[Au]/KB(C 6 F 5 ) 4 (5 mol%) 90 o C, 20 h 9b (98% yield) 9h (92% yield)	Ph Et 2 N	Ph
	Ph		+	Et 2 NH	[Au]/KB(C 6 F 5 ) 4 (5 mol%) 120 o C, 20 h 9b (89% yield) 9h (90% yield)	Ph Et 2 N 43%	+	Ph 57%	NEt 2
		C	+	Et 2 NH	9b (82% yield) [Au]/KB(C 6 F 5 ) 4 (5 mol%) 150 o C, 24 h		N	Et Et
		C	+	Et 2 NH	[Au]/KB(C 6 F 5 ) 4 (5 mol%) 130 o C, 36 h 9b (98% yield)			N	Et
	Ph	C	+	Et 2 NH	[Au]/KB(C 6 F 5 ) 4 (5 mol%) 165 o C, 24h	Ph		Et	Et
						9b (61% yield)			N
									Et

27. Postulated catalytic cycle for the dehydrogenative borylation of terminal alkynes with pinacolborane.

  Modified with permission from ref 153. Copyright 2017 Royal Chemical Society.

	Scheme
		5 mol%)		BPin	+	Ph	BPin
	O	R.T., 2 h		Ph	62			63
	B	H
	O	X	62	63
		OTf OAc	2 80	98 20			L =	Dipp	N	Et Et
		OPh	98	2

Scheme 38. Comparing menthylCAAC-CuCl 13a, NHC-CuCl 74 and cholesterolCAAC- CuCl 75 in the asymmetric conjugate borylation reaction

  Although the menthyl CAAC copper complex 13a was very active in the addition of bis(pinacolato)diboron to various a,b-unsaturated esters, an almost complete lack of asymmetric induction was observed (Scheme 38). In comparison, Hoveyda reported that the chiral NHC copper complex 74 gave β-boryl carbonyl compounds in up to 96% ee.206

	chiral organoboron building blocks. 204,205
	L						L				L					CO 2 Et
	Au	Cl	AgNTf 2 or NaBArF CO 2 Et N 2		Au	CO 2 Et			Au	CO 2 Et	-	L	Au
	72															73
			L=	Dipp	N	N	Dipp	Dipp	N	N	Dipp	Cy	N	N		Cy	Dipp	N
			73 (% yield)		50%			31%			trace		79%
																selective equatorial
																addition
			OH	i Pr				Dipp	N		i Pr	Dipp	N		i Pr
			(-)-menthol					1a			key
												intermediate

  221 , 222 Recently, two-coordinate copper complexes with linear geometry [(L)CuX], where L is a carbene and X an anionic ligand, have emerged as a new class of strongly photoemissive materials.223 In 2016, Bochmann et al. observed that the adamantylCAAC-CuCl complex 13b displayed unexpected photoactivity (ØPL = 96% in the solid state) in marked contrast with the gold analogue 9b which was found to be comparatively inefficient (Scheme 41).224 As highlighted across several reports, the quantum yield in (CAAC)CuCl complexes is directly linked to the steric environment provided by the ligand in the order 13b 225 > 13e225,226 > 13f,226,227 and is a consequence of the increased rigidity of the system. Moreover, these reports underline for the first time the unique Examining the influence of the anionic ligand,Romanov et al. prepared the phenolato-82, the thiopheno-83 and the amido-85 which displayed moderate photoactivity (Scheme 42); 226 note that the later was reported by Steffen et al. to afford dimer 84 with the smaller CAAC 1f.

	Dipp	N
		Au
		Cl

properties of CAACs (i.e. stronger s-donation destabilizing the M(d) orbitals and pacceptance stabilizing the LUMO) with respect to NHC ligands which are much less efficient. 222 Scheme 41. The quantum yield in (CAAC)CuCl complexes is linked to the sterics (F: Quantum yield; kr: radiative rate constant) 227 However, a diverse array of anionic ligands have since been investigated with coordination geometries varying from hemilabile to linear-monodentate, including the formamidinato 86, 228 phenanthroline 87, 227 the trispyrazolylborate 88-89 225 derivatives, bis-CAAC 90 227 and

Acknowledgments References

ACKNOWLEDGMENTS

Our work on CAAC-coinage metal complexes was supported by the US National Science Foundation (CHE-1661518) and the U.S. Department of Energy, Office of Science, Basic Energy

AUTHOR INFORMATION

ORCID

Rodolphe Jazzar: 0000-0002-4156-7826 Michele Soleilhavoup: 0000-0001-5339-921X Guy Bertrand: 0000-0003-2623-2363

Notes

The authors declare no competing interest.

Biographies


Michele Soleilhavoup
email: msoleilhavoup@ucsd.edugbertrand@ucsd.edu

Guy Bertrand

Carbenes, Nitrenes, Phosphinidenes, and Borylenes: Past and Future

The different modes of stabilization for carbenes is briefly discussed in the context of the discovery of their first stable representatives. Due largely to a diversity of stable carbenes available today, their use has spanned across the chemical sciences, including medicinal, and materials applications. Much less is known about the isolobal group 15 cousins of carbenes, namely nitrenes and phosphinidenes, as only one example of each has been isolated. The difficulties associated with their applications are discussed, and possible solutions are presented.

As for group 13 element carbenoids, two types are considered: mono(Lewis base)-stabilized borylenes that have been recently isolated, and borylenes, the only carbenoids discussed in this article that have eluded the synthetic skills of investigators. This perspective results in a description of potentially attainable targets such as monocoordinated aminocarbanions, aminocarbynes and aminocarbocations, compounds featuring six, five and four valence-electrons, respectively.

The octet rule, one of the fundamental principles of organic chemistry, dates back to Mendeleev at the end of the 19 th century and Abbeg, Lewis and Langmuir at the beginning of the 20 th century. [START_REF] Jensen | Langmuir and the Octet Rule[END_REF] Scientists love challenging rules, and one can argue that this motivated Gomberg to prepare the first stable radical, a species in which a carbon atom has only seven-valence-electrons.

Similarly, Curtius and Staudinger attempted to synthesize carbenes, compounds in which a carbon atom features a six-valence-electron shell. In agreement with the octet rule, they found that carbenes were only transient intermediates which, however, were involved in several important chemical transformations. Then, for many years the quest for stable carbenes became an unreasonable target, until the isolation of a distillable (phosphino)(silyl) carbene 1 in 1988 2 and a crystalline imidazol-2-ylidene 2 in 1991 3 (Figure 1). Interestingly, the mode of stabilization for singlet carbenes 1 and 2 is totally different. In agreement with Pauling's prediction, [START_REF] Pauling | The structure of singlet carbene molecules[END_REF] our group believed that a p-donor and a p-acceptor substituent (a push-pull mesomeric substitution pattern) was necessary to decrease both the Lewis acidity and basicity of the carbene center of 1. However, the isolation of Arduengo's carbene 2, which features two p-donor substituents (a push-push mesomeric substitution pattern), showed that the instability of singlet carbenes was mainly due to their Lewis acid character, although one could argue that the amino groups have an inductive pull effect, decreasing the basicity of the lone pair. During the next decade after the discovery of 1 and 2, it was believed that two electronic active substituents were required to allow for the isolation of carbenes. However, at the beginning of the 21 st century, we showed that a single p-donor phosphino 5 or amino [START_REF] Sole | Amino)(aryl)carbenes: stable singlet carbenes featuring a spectator substituent[END_REF][START_REF] Lavallo | Synthesis, reactivity and ligand properties of a stable alkyl carbene[END_REF] substituent, as exemplified by 3, was enough to extend the life-time of carbenes to weeks, providing that the other substituent was sufficiently bulky.

Very often in chemistry, when a novel type of compound is discovered, it is first considered as a laboratory curiosity, and it sometimes takes decades for the first applications to appear. For example, phosphorus ylides were first synthesized in 1894 by Michaelis and Gimborn, but it is only in 1953 that Wittig and Geissler reported the so-called Wittig reaction, which was soon after used by BASF for the synthesis of Vitamin A. This is not the case for carbenes since, already in 1995, Herrmann et al. reported that the palladium complex 4 bearing the imidazol-2-ylidene 2 as an ancillary ligand promoted the Mizoroki-Heck reaction. [START_REF] Herrmann | Metal complexes of N-heterocyclic carbenes-a new structural principle for catalysts in homogeneous catalysis[END_REF] Following this discovery, transition metal complexes bearing carbene 2 and its saturated version i.e. imidazolin-2-ylidene, [START_REF] Arduengo | A stable diaminocarbene[END_REF] the socalled N-heterocyclic carbenes (NHCs), have been used for a variety of catalytic chemical transformations; 10 the Grubbs second generation olefin metathesis catalyst 5 being the most recognizable example. [START_REF] Scholl | Synthesis and activity of a new generation of ruthenium-based olefin metathesis catalysts coordinated with 1,3-dimesityl-4,5dihydroimidazol-2-ylidene ligands[END_REF] In parallel, the 1,2,4-triazolin-5 ylidene 6, reported by Enders, [START_REF] Enders | Preparation, structure, and reactivity of 1,2,3-triphenyl-4,5-dihydro-1h-1,2,4-triazol-5ylidene, a new stable carbene[END_REF] has been shown to be an excellent organocatalyst on his own, in line with the pioneering work by Breslow on the thiazolydene-catalyzed benzoin condensation. [START_REF] Breslow | On the mechanism of thiamine action. evidence from studies of model systems[END_REF] Nowadays, aside from the carbenes mentioned above, there is a myriad of stable carbenes available with distinct steric and electronic properties. Arguably, the most popular are the cyclic (alkyl)(amino)carbenes (CAACs) 7, [START_REF] Lavallo | Stable cyclic (alkyl)(amino)carbenes as rigid or flexible, bulky, electron-rich ligands for transition-metal catalysts: a quaternary carbon atom makes the difference[END_REF][START_REF] Melaimi | Cyclic (alkyl)(amino)carbenes (CAACs): recent developments[END_REF] N,N'-diamidocarbenes (DACs) 8, [START_REF] Moerdyk | Diamidocarbenes as versatile and reversible [2+1] cycloaddition reagents[END_REF][START_REF] Moerdyk | N,N'-Diamidocarbenes: Isolable divalent carbons with bona fide carbene reactivity[END_REF] benzimidazolylidenes 9, [START_REF] Hahn | N-N '-bis(2,2dimethylpropyl)benzimidazolin-2-ylidene: a stable nucleophilic carbene derived from benzimidazole[END_REF] mesoionic carbenes (MICs) 10a [START_REF] Aldeco-Perez | Isolation of a C5-deprotonated imidazolium, a crystalline "abnormal" Nheterocyclic carbene[END_REF][START_REF] Vivancos | Mesoionic and related less heteroatomstabilized N-heterocyclic carbene complexes: synthesis, catalysis, and other applications[END_REF][START_REF] Sau | Stable abnormal N-heterocyclic carbenes and their applications[END_REF] and 10b, [START_REF] Guisado-Barrios | Crystalline 1H-1,2,3triazol-5-ylidenes: new stable mesoionic carbenes (MICs)[END_REF][START_REF] Guisado-Barrios | 1H-1,2,3-Triazol-5-ylidenes: readily available mesoionic carbenes[END_REF] and the cyclopropenylidene 11. [START_REF] Lavallo | Cyclopropenylidenes: from interstellar space to an isolated derivative in the laboratory[END_REF] As a consequence of this diversity, the use of carbenes disseminated across chemical sciences at large, including medicinal 25 and materials applications. [START_REF] Hopkinson | For on excellent review on the applications of stable carbenes[END_REF] Furthermore, thanks in part to carbene's pronounced ability to reversibly activate enthalpically strong bonds and small molecules, [START_REF] Tolentino | Reductive elimination at carbon under steric control[END_REF][START_REF] Ryu | Redox-and light-switchable Nheterocyclic carbenes: a "soup-to-nuts'' course on contemporary structure-activity relationships[END_REF] there has been significant development towards their use as transition metal surrogates. They can also stabilize organic and inorganic paramagnetic species, [START_REF] Kundu | Stable cyclic (alkyl)(amino)carbene (cAAC) radicals with main group substituents[END_REF] and can be used for the functionalization of nanoscale and bulk surfaces. [START_REF] Zhukhovitskiy | Carbene ligands in surface chemistry: from stabilization of discrete elemental allotropes to modification of nanoscale and bulk substrates[END_REF] They even enabled the preparation of OLEDs based on earth-abundant metals, [START_REF] Di | High-performance light-emitting diodes based on carbene-metal-amides[END_REF][START_REF] Hamze | Quick-Silver" from a systematic study of highly luminescent, 2-coordinate, d10 coinage metal complexes[END_REF] which achieve comparable performance to the stateof-the-art luminescent complexes of iridium, platinum, and ruthenium. As an example, the two-coordinate copper(I) complex 12, achieved photoluminescence efficiencies >99% and microsecond lifetimes, which lead to an efficient blue-emitting OLED. [START_REF] Hamze | Eliminating nonradiative decay in Cu(I) emitters: >99% quantum efficiency and microsecond lifetime[END_REF] The discovery of stable carbenes has been followed by the isolation of their heavier analogues, e.g. silylenes. Indeed, in 1994 Denk et al. reported the isolation of 13, [START_REF] Denk | Synthesis and structure of a stable silylene[END_REF] the design of which was clearly derived from the corresponding NHC 2. Although the applications of silylenes are still very limited, some encouraging results have been obtained when they are used as ligands in transition metal catalysis. 35

Figure 1. Stable group 14 carbenoids and selected complexes

Some of the first isolated carbenes (1-3); catalytically active complexes (4, 5), and organocatalyst 6; some of the most popular carbenes (7-11); an efficient blue-emitting OLED (12); the first stable silylene 13.

Much less is known about the isolobal group 15 cousins of carbenes and silylenes, namely nitrenes and phosphinidenes (Figure 2). In 2012 our group isolated the first nitrene 14. [START_REF] Dielmann | A crystalline singlet phosphinonitrene: a nitrogen atom transfer agent[END_REF] The bonding between phosphorus and nitrogen is analogous to that observed for metallonitrenes, which are postulated as key catalytic species in the industrial Haber-Bosch hydrogenation of N2 into NH3.

However, since its discovery, no striking developments have occurred with 14. This is mainly due to the presence of the phosphino substituent. Indeed, although nitrene 14 can activate small molecules, [START_REF] Dielmann | Reactivity of a stable phosphinonitrene towards small molecules[END_REF] the involvement of the phosphorus in the reaction, as exemplified with CO2, might preclude the use of this nitrene in catalytic processes. We believe, however, that a stable amino nitrene, such as 15 that is derived from Dervan's scaffold, [START_REF] Hinsberg | Direct studies of 1,1-diazenes -Syntheses, infrared and electronic spectra, and kinetics of the thermal decomposition of N-(2,2,6,6-tetramethylpiperidyl)nitrene and N-(2,2,5,5-tetramethylpirrolidyl)nitrene[END_REF] would be a more promising candidate.

P SiMe 3 iPr 2 N iPr 2 N 1 N N Ad Ad
The only isolated phosphinidene (16) to date also features a bulky and strong p-donor phosphino substituent. [START_REF] Liu | A room temperature stable singlet phosphinidene[END_REF] Of particular interest, despite its PP multiple bond character and the presence of a partial negative charge on the terminal phosphorus, 16 behaves as an electrophile, as expected for an atom featuring a formal valence sextet structure. Indeed, 16 reacts with Lewis bases, such as phosphines, with a preference for the more basic PCy3 over PPh3. [START_REF] Hansmann | Singlet (phosphino)phosphinidenes are electrophilic[END_REF] Importantly, phosphinidene 16 resembles, to some extent, a transition metal since it reacts with CO giving 19 and undergoes ligand exchange. [START_REF] Hansmann | The transition metal-like behavior of main group elements: ligand exchange at a phosphinidene[END_REF] For example, 19 reacts with phosphines to afford the corresponding adduct 17.

Similarly, the latter reacts with isonitriles to give 18. It is important to note that these ligand exchange reactions can be performed starting from non-hindered phosphinidene/CO adducts, which are readily available from the reaction of the corresponding chlorophosphine with NaPCO. [START_REF] Goicoechea | The chemistry of the 2-phosphaethynolate anion[END_REF] Just as for nitrenes, amino-substituted phosphinidenes would be attractive targets because they might give the opportunity to isolate both the singlet and triplet states of a given compound, which has never been done with carbenoid species. [START_REF] Perera | Photochemically switching diamidocarbene spin states leads to reversible büchner ring expansions[END_REF][START_REF] Sultane | Cyclic(aryl)(amido)carbenes: NHCs with triplet-like reactivity[END_REF] Indeed, calculations by Nguyen et al. [START_REF] Nguyen | In search of singlet phosphinidenes[END_REF] predicted that the singlet-triplet gap for amino phosphinidenes would be below ±3 kcal/mol, in other words the ground state would have two degenerate orbitals.

Figure 2. Group 15 carbenoids

The isolated nitrene 14 and its reactivity with CO2, exemplifying the non-innocence of the phosphorus center. The aminonitrene 15 is an attractive target. The isolated phosphinidene 16 behaves as an electrophile as shown by the formation of 17 and to some extent as a transition metal, since it reacts with CO giving 19, which undergoes ligand exchange as shown by 17 and 18.

As for group 13 element carbenoids, two species have to be considered: mono-(Lewis base)-stabilized borylenes 21 and borylenes 28 (Figure 3). [START_REF] Soleilhavoup | Borylenes: an emerging class of compound[END_REF] The former is isoelectronic with carbenes with a six-electron valence shell, whereas the latter has only a four-electron valence shell.

The first attempt to isolate a compound of type 21 was reported in 2007 by Robinson et al. [START_REF] Wang | A stable neutral diborene containing a B=B double bond[END_REF] through reduction of the (NHC)BBr3 adduct 20. They isolated the diborene 22, which can be regarded as a dimer of the desired mono-(Lewis base)-stabilized borylene 21a. As already stated, carbenes and related species, featuring a sextet of electrons, need a p-donor substituent to be isolated. Although the (NHC)aminoborylene 21b fulfilled this criterion, it was not isolable, due to an intramolecular CH insertion giving 23. [START_REF] Wang | Carbene stabilization of highly reactive main-group molecules[END_REF] Because of its electropositivity, boron is reluctant to be electron-rich, [START_REF] Segawa | Boryllithium: isolation, characterization, and reactivity as a boryl anion[END_REF] [START_REF] Ledet | Reduction of a diamidocarbene-supported borenium cation: isolation of a neutral boryl-substituted radical and a carbene-stabilized aminoborylene[END_REF][START_REF] Dahcheh | Synthesis and reactivity of a CAAC-aminoborylene adduct: a hetero-allene or an organoboron isoelectronic with singlet carbenes?[END_REF] Unsurprisingly, both compounds feature an almost linear allenic structure (>C=B=NR2), but its flexibility gives rise to a highly electrophilic boron center that has carbenelike behavior. Akin to electrophilic singlet carbenes, 21d can activate small molecules, such as H2, and coordinate an additional ligand such as CO; in other words, compounds 21 are boron metallomimics. Along this line, Braunschweig et al. [START_REF] Braunschweig | Main-group metallomimetics: transition metal-like photolytic CO substitution at boron[END_REF] have shown that the CO ligand of 26 can be removed by photolysis to afford the transient mono-(Lewis base)-stabilized borylenes 21e, which can be trapped by Lewis bases to afford novel bis-(Lewis base)-stabilized borylenes 27. [START_REF] Kinjo | Synthesis and characterization of a neutral tricoordinate organoboron isoelectronic with amines[END_REF][START_REF] Kong | Isolation of a bis(oxazol-2ylidene)-phenylborylene adduct and its reactivity as a boron-centered nucleophile[END_REF] In contrast to the other carbenoids, borylenes 28 have two vacant orbitals. Up until now, they have only been spectroscopically characterized in the gas phase or in inert matrices at very low temperatures. [START_REF] Bettinger | Phenylborylene: direct spectroscopic characterization in inert gas matrices[END_REF] In addition the transient formation of borylenes 28 has been postulated based on their chemical reactivity [START_REF] Krasowska | Ring Enlargement of three-membered boron heterocycles upon reaction with organic π systems: implications for the trapping of borylenes[END_REF] as exemplified with the formation of 29. 57 In conclusion, it appears that borylenes 28 are the only carbenoids discussed in this article, which have eluded the synthetic skills of investigators. However, contrary to carbenes, nitrenes and phosphinidenes, which feature either a singlet or a triplet ground state, all borylenes 28 computationally studied have a singlet ground state; 58 therefore, we believe that with the right substituent they should be isolable. Hope for a stable borylene 28 comes from the recent isolation of the monosubstituted carbene 30 (Figure 4), which demonstrates that a single bulky amino substituent could single-handedly tame the intrinsic tendency of carbenes towards dimerization. [START_REF] Nakano | A crystalline mono-substituted carbene[END_REF] Along this line, we believe that monocoordinated aminocarbanions 31 could be isolated. They

24 18 NR

 2418 and thus more electrophilic carbenes than NHCs seemed more appropriate to stabilize a compound of type 21. Indeed, reduction of the DAC adduct of the diisopropylaminodichloroborane bis(trimethylsilyl)aminodichloroborane 25 afforded the desired mono-(Lewis base)-stabilized borylenes 21c,d.

Figure 3 . 27 .

 327 Figure 3. Group 13 carbenoids The first attempts to prepare mono-(Lewis base)-stabilized borylenes (21a,b), and their isolated counterparts 21c,d, which are metallomimics as shown by their reactivity with H2 and CO. The elimination of CO under irradiation from 26 leads to a transient mono-(Lewis base)-stabilized borylene 21e, which can be trapped by an isonitrile to give the bis-(Lewis base)-stabilized borylene 27. The transient formation of borylenes of type 28 has been postulated based on their chemical reactivity as shown by 29.

16 .

 16 have six-valence electrons, similar to carbenes, and two lone pairs and a vacant orbital, like phosphinidenes It might even be possible to undress carbon even more. What about aminocarbynes 32 and aminocarbocations 33, compounds in which the carbon center formally features only five and four valence-electrons, respectively. These molecules are not only exciting synthetic challenges, but their unique properties should unveil new applications. As an illustration, note that carbenes can simultaneously form two sigma bonds, while monocoordinated compounds could form three,[START_REF] Wang | Generating carbyne equivalents with photoredox catalysis[END_REF] which opens a new mode of reactivity.

Figure 4 .

 4 Figure 4. The stable mono-substituted carbene 30, and future targets

ACKNOWLEDGMENTS

This work was supported by the NSF (CHE-1661518), the ACS-PRF (60776-ND1) and the U.S. Department of Energy, Office of Science, Basic Energy Sciences, Catalysis Science Program, under Award # DE-SC0009376.

AUTHOR CONTRIBUTIONS

M.S. and G.B. wrote the manuscript.

DECLARATION OF INTERESTS

The authors declare no competing interests.