Jennifer Morvan

Marc Mauduit

Guy Bertrand

Rodolphe Jazzar

Cyclic (Alkyl)(amino)carbenes (CAACs) in Ruthenium Olefin Metathesis

Keywords: cyclic (alkyl)(amino)carbenes (CAACs), olefin metathesis, homogeneous catalysis, ruthenium catalysts, transition metals

Discovered in 2005, cyclic (alkyl)(amino)carbenes (CAACs) have led to numerous discoveries in the field of ruthenium olefin metathesis, until then largely dominated by the well-known N-heterocyclic carbenes (NHCs). Compared to the latter, CAACs are simultaneously more nucleophilic (σ-donating) and electrophilic (π-accepting), which leads to very strong metal-carbene bonds. Consequently, CAAC-ruthenium complexes are very robust, which leads to enhanced catalytic activities, as exemplified by the industrially relevant ethenolysis of unsaturated fatty acids (up to of 390,000 TON). Herein, we provide a

Introduction

The discovery of stable carbenes at the end of the last century [START_REF] Igau | Analogous ,'-bis-carbenoid, triply bonded species: synthesis of a stable  3 -phosphino carbene- 5 -phosphaacetylene[END_REF][START_REF] Harlow | A stable crystalline carbene[END_REF] has unarguably triggered a profound revolution in transition metal catalysis. Until then, the field was largely dominated by phosphines as ancillary ligands. [START_REF] Brown | Ligand steric properties[END_REF] One of the most prominent examples is witnessed by the evolution of the first generation Grubbs ruthenium olefin metathesis catalyst A. [START_REF] Scholl | Increased ring closing metathesis activity of ruthenium-based olefin metathesis catalysts coordinated with imidazolin-2-ylidene ligands[END_REF] The replacement of one of the two PCy3 ligands in A, by the strong σ-donor and poor π-acceptor 1,3-dimesityl-imidazolin-2-ylidene (IMes), [START_REF] Harlow | A stable crystalline carbene[END_REF] (a carbene from the family of N-heterocyclic carbenes; i.e. NHCs), resulted in the extremely stable, yet very reactive second-generation Grubbs catalyst B (Scheme 1). [START_REF] Vougioukalakis | Ruthenium-based heterocyclic carbene-coordinated olefin metathesis catalysts[END_REF][START_REF] Samojłowicz | Ruthenium-based olefin metathesis catalysts bearing Nheterocyclic carbene ligands[END_REF][START_REF] Zhu | Recent progress on donor and donor-donor carbenes[END_REF][START_REF] Gonzalez | N-Heterocyclic Carbenes in Late Transition Metal Catalysis[END_REF][START_REF] Nolan | Chemoselective olefin metathesis transformations mediated by ruthe-nium complexes[END_REF][START_REF] Ogba | Recent advances in ruthenium-based olefin metathesis[END_REF] The superior catalytic activity of B over A, originally demonstrated in the preparation of di-, tri-, and even tetra-substituted olefins, [START_REF] Scholl | Increased ring closing metathesis activity of ruthenium-based olefin metathesis catalysts coordinated with imidazolin-2-ylidene ligands[END_REF][START_REF] Scholl | Synthesis of Trisubstituted Alkenes via Olefin Cross metathesis[END_REF] was later established across multiple other systems. [START_REF] Vougioukalakis | Ruthenium-based heterocyclic carbene-coordinated olefin metathesis catalysts[END_REF][START_REF] Samojłowicz | Ruthenium-based olefin metathesis catalysts bearing Nheterocyclic carbene ligands[END_REF][START_REF] Zhu | Recent progress on donor and donor-donor carbenes[END_REF] This breakthrough, also referenced as the 00's of metathesis, paved the way for the development of hundreds of metathesis catalysts featuring N-heterocyclic carbene ligands, [START_REF] Gonzalez | N-Heterocyclic Carbenes in Late Transition Metal Catalysis[END_REF][START_REF] Nolan | Chemoselective olefin metathesis transformations mediated by ruthe-nium complexes[END_REF][START_REF] Ogba | Recent advances in ruthenium-based olefin metathesis[END_REF] as seen with the well-known second generation Hoveyda-Grubbs catalysts C. [START_REF] Garber | Efficient and Recyclable Monomeric and Dendritic Ru-Based Metathesis Catalysts[END_REF] Recently, another class of stable singlet carbenes, named cyclic (alkyl)(amino)carbenes (CAACs), have gained considerable momentum in this field and have only briefly been discussed in a few review articles. .13,14,15,16,17 Herein, we provide a comprehensive summary of the impact of CAACs in olefin metathesis, since the first report in 2007, including results which were only reported in patents (the latter are highlighted in pink in the schemes and figures). To understand the advantages and limitations of CAACs versus NHCs in ruthenium olefin metathesis, a brief comparison of their electronic properties and steric contribution is necessary. 18,[START_REF] Lavallo | CO fixation to stable acyclic and cyclic alkyl amino carbenes: Stable amino ketenes with a small HOMO-LUMO gap[END_REF][START_REF] Back | 31 P NMR Chemical Shifts of Carbene-Phosphinidene Adducts as an Indicator of the π-Accepting Properties of Carbenes[END_REF][START_REF] Liske | Determining the π-Acceptor Properties of N-Heterocyclic Carbenes by Measuring the 77 Se NMR Chemical Shifts of Their Selenium Adducts[END_REF] CAACs differ from NHCs by the presence of a σ-donating quaternary carbon α to the carbene center instead of a π-donating and σ-attracting amino group (Figure 1). As a result, CAACs are simultaneously more nucleophilic and electrophilic than traditional NHCs (HOMO: -5.35 vs. -5.82 eV and LUMO: +0.06 vs. +1.00 eV). Also contrasting with NHCs, where the steric contribution is best described as an umbrella with pendant Nsubstituents oriented towards the metal (as opposed to phosphines), the sp [START_REF] Brown | Ligand steric properties[END_REF] -hybridized α carbon of CAACs provides a wall of protection. Additionally, this quaternary carbon provides a mean to introduce chirality much closer to the metal not feasible with conventional NHCs. [START_REF] Pichon | The Debut of Chiral Cyclic (Alkyl)(amino)carbenes (CAACs) in Enantioselective Catalysis[END_REF]

Revised manuscript 5

Figure 1. Electronic and steric properties of CAACs versus NHCs

The preparation of aldiminium cations, the conjugate acids of CAACs, has been achieved by two complimentary synthetic routes (Scheme 2). While both methods involve the addition of electrophiles to aza-allyl anion intermediates, followed by ring closure, they differ in the nature Revised manuscript 6 of the electrophile. For Route 1, the use of epoxides allows for introducing both alkyl and aryl groups at nitrogen but is somewhat restricted to relatively sterically uncongested sp [START_REF] Brown | Ligand steric properties[END_REF] hybridized carbon center. [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] Mandal | Influence of N-Substitution on the Formation and Oxidation of NHC-CAAC-Derived Triazaalkenes[END_REF] On the other hand, Route 2 is limited to N-aryl substituents, but more tolerant to steric congestion at the sp 3 carbon. It proceeds via an allylation followed by an intramolecular hydroiminiumation reaction. 25,[START_REF] Jazzar | Hydroiminiumation and -amidiniumation" of Alkenes: A Convenient, Flexible, and Scalable Route to Cyclic Iminium and Imidazolinium Salts[END_REF] In recent years, Route 2 has been used for the preparation of more ambiphilic CAAC ligands such as the bicyclic (alkyl)(amino)carbenes (BiCAACs) and the 6-membered cyclic (alkyl)(amino)carbenes (CAAC-6s). [START_REF] Tomás-Mendivil | Bicyclic (alkyl)(amino)carbenes (Bi-CAACs): stable carbenes more ambiphilic than CAACs[END_REF]28 In all cases, free CAACs were obtained from the corresponding aldiminium salts by deprotonation with a strong base such as KHMDS or LDA.

Scheme 2. Synthesis of CAACs

Heteroleptic (CAAC)Ruthenium Metathesis Complexes

Hoveyda-Grubbs (CAAC)Ruthenium Type Complexes

Second generation heteroleptic ruthenium metathesis complexes are typically accessed by ligand exchange, reacting the free NHC with inexpensive and readily available first-generation complexes bearing a sacrificial phosphine ligand (e.g. PCy3). With NHC, this route classically relies on in situ generation of free carbenes by treatment of various imidazolinium salts with a strong base. [START_REF] Bantreil | Synthesis of N-heterocyclic carbene ligands and derived ruthenium olefin metathesis catalysts[END_REF] This is also the case with CAACs which can be generated in situ and undergo ligand exchange at room temperature with Hoveyda-Grubbs first generation D [START_REF] Kingsbury | A Recyclable Ru-Based Metathesis Catalyst[END_REF] (Scheme 3). [START_REF] Marx | Cyclic Alkyl Amino Carbene (CAAC) Ruthenium Complexes as Remarkably Active Catalysts for Ethenolysis[END_REF][START_REF] Anderson | Synthesis and reactivity of olefin metathesis catalysts bearing cyclic (alkyl)(amino)carbenes[END_REF][START_REF] Anderson | Kinetic Selectivity of Olefin Metathesis Catalysts Bearing Cyclic (Alkyl)(Amino)Carbenes[END_REF] While yields appear counterintuitively higher with more sterically demanding Revised manuscript 7 ligands, it is likely a consequence of the propensity of some of the metal-free CAACs to degrade via intramolecular insertion into benzylic C(sp [START_REF] Brown | Ligand steric properties[END_REF] )-H bonds of aryl substituents. [START_REF] Turner | Chemically Non-Innocent Cyclic (Alkyl)(Amino)Carbenes: Ligand Rearrangement, C-H and C-F Bond Activation[END_REF] With bulky groups, the aryl moiety is forced to be perpendicular to the CAAC skeleton, which prevents its ortho-substituents from approaching the carbene center. As seen with Ru1-Ru18, most of the modifications of the CAAC ligands in ruthenium complexes have been achieved by changing substituents on the N-Aryl or at the quaternary carbon adjacent to the carbene center. To investigate the influence of the backbone over the catalytic performance of these complexes, Zhang, Shi and coworkers, prepared complexes Ru19-Ru21 bearing a bulky isopropyl group β to the carbene center. [START_REF] Zhang | Ruthenium-catalyzed olefin metathesis accelerated by the steric effect of the backbone substituent in cyclic (alkyl)(amino) carbenes[END_REF] More recently, Tóth, Tuba and coworkers extended the variety of (CAAC)Ru complexes to Ru-22 and Ru-23 in which the CAAC features an amino and an ammonium group on the N-aryl moiety. [START_REF] Nagyházi | Towards Sustainable Catalysis -Highly Efficient Olefin Metathesis in Protic Media Using Phase Labelled Cyclic Alkyl Amino Carbene (CAAC) Ruthenium Catalysts[END_REF] The latter is highly polar and was shown to be soluble in environmentally benign protic media without compromising the high catalytic activity and stability.

Revised manuscript 8

Scheme 3 Synthesis of Hoveyda-Grubbs CAACs

As shown by Olivier-Bourbigou and coworkers, the benzylidene moiety of CAAC derived Hoveyda-Grubbs complexes are readily tunable by simple addition of a chelating olefin (Scheme 4). 37 These authors used this pathway to introduce an amino group on the benzylidene fragment as shown by complexes Ru-24 and Ru-25. In line with a report by Grela, Kirschning and coworkers, [START_REF] Michrowska | A New Concept for the Noncovalent Binding of a Ruthenium-Based Olefin Metathesis Catalyst to Polymeric Phases: Preparation of a Catalyst on Raschig Rings[END_REF] subsequent protonation of the amino substituent of Ru-25 with pTsOH afforded complex Ru-26 which appeared to be more active, probably due to the increased lability of the benzylidene fragment. The benzylidene variants Ru-27 have also been obtained by reacting pre-functionalized 1 st generation precursors with in situ generated CAACs. [START_REF] Patent: Verpoort | Group 8 tansition metal catalysts and method for making same and process for use of same in olefin disproportionation reactions[END_REF] Revised manuscript 9

Scheme 4 Preparation of Ruthenium metathesis CAACs complexes with various benzylidene fragments

These methodologies are not limited to CAAC-5, and can be extended to other motifs of the CAAC family. Indeed, Grubbs and coworkers have recently reported the first example of CAAC-6 ruthenium metathesis complexes Ru-28-31 (Scheme 5). [START_REF] Samkian | Synthesis and Activity of Six-Membered Cyclic Alkyl Amino Carbene-Ruthenium Olefin Metathesis Catalysts[END_REF] Here also, excellent yields were obtained with the sterically hindered cyclohexyl derivatives (>68%), whereas less hindered ethyl derivatives resulted in much lower yields (<30%). Note that the ethyl substituted CAAC-6 is less stable than the CAAC-5 analogues. 28 Moreover, the authors stated that decreasing sterics at nitrogen (e.g., N-mesityl group) or at the quaternary α-carbon (e.g., gemdimethyl) proved challenging, because of the difficulty in preparing the CAAC conjugate acids. 25

Revised manuscript 10

Scheme 5 Preparation of Hoveyda-Grubbs CAAC-6 complexes

As highlighted by Fogg et al., [START_REF] Nascimento | For an overview of problems associated with in-situ generation of NHC from imidazolinium salts[END_REF] numerous issues have been associated with the preparation of (carbene)Ru metathesis pre-catalysts by in situ generation of the free carbene. Looking for alternatives, [START_REF] Sauvage | Imidazol(in)ium-2-carboxylates as N-Heterocyclic Carbene Precursors for the Synthesis of Second Generation Ruthenium Metathesis Catalysts[END_REF][START_REF] Trnka | Synthesis and Activity of Ruthenium Alkylidene Complexes Coordinated with Phosphine and N-Heterocyclic Carbene Ligands[END_REF][START_REF] Blum | Synthesis of N-Heterocylic Carbene-Containing Metal Complexes from 2-(Pentafluorophenyl)imidazolidines[END_REF][START_REF] Jolly | Adducts, NHCs and Azomethine Ylides: Divergence in Wanzlick Equilibrium and Olefin Metathesis Catalyst Formation[END_REF] Grela and coworkers disclosed the use of mechanochemistry (ballmilling) as a mild and solvent free method for the preparation of CAAC Hoveyda-Grubbs complexes (Scheme 6). [START_REF] Mukherjee | A Gentler Touch: Synthesis of Modern Ruthenium Olefin Metathesis Catalysts Sustained by Mechanical Force[END_REF] While the method compares reasonably well with the homogeneous route (55% yield vs. 77% for Ru-2), it arguably opens new prospects for the preparation of Hoveyda-Grubbs complexes of more challenging or low yielding CAAC motifs.

Scheme 6 Mechanochemical preparation of (CAAC)Ru metathesis pre-catalysts.

For its ability to undergo facile ligand exchange with stronger donors, pyridine complex E has also been used as precursor for Hoveyda-Grubbs type (CAAC)Ruthenium pre-catalysts (Scheme 7). [START_REF] Anderson | Synthesis and reactivity of olefin metathesis catalysts bearing cyclic (alkyl)(amino)carbenes[END_REF] As expected, treatment of E with CAACs, generated in situ, afforded the airsensitive pyridine adducts Ru-32 and Ru-33, which were isolated in modest yields. Building upon these results, Lemcoff and coworkers have shown that Ru-32 provides a convenient route to sulfur-chelated ruthenium benzylidenes Ru-34 and Ru-35. [START_REF] Rozenberg | Synthesis and Catalytic Properties of Sulfur-Chelated Ruthenium Benzylidenes Bearing a Cyclic (Alkyl)(amino)carbene Ligand[END_REF] Revised manuscript 11

Indenylidene (CAAC)Ruthenium Type Complexes

Until recently, (CAAC)Ru complexes were mainly obtained using Hoveyda-Grubbs firstgeneration benzylidene complex D (vide supra), the preparation of which can be challenging. [START_REF] Kingsbury | A Recyclable Ru-Based Metathesis Catalyst[END_REF] Aiming to develop a more versatile route, Skowerski and coworkers examined the preparation of CAAC olefin metathesis ruthenium catalysts from readily accessible and patent-free precursors. They considered the indenylidene complex F bearing two triphenyl phosphine ligands. [START_REF] Schanz | Coordinatively Unsaturated 16-Electron Ruthenium Allenylidene Complexes: Synthetic, Structural, and Catalytic Studies[END_REF]49 Excitingly, in contrast with NHCs, [START_REF] Jafarpour | Indenylidene-Imidazolylidene Complexes of Ruthenium as Ring-Closing Metathesis Catalysts[END_REF][START_REF] Keitz | Protonolysis of a Ruthenium-Carbene Bond and Applications in Olefin Metathesis[END_REF] reaction of F with three equivalents of in situ generated CAACs, resulted in the formation of bis(CAAC)Ru indenylidene complexes Ru-36-43 (Scheme 8). [START_REF] Gawin | Cyclic Alkyl Amino Carbene) Ruthenium Complexes: AVersatile, Highly Efficient Tool for Olefin Metathesis[END_REF][START_REF]Note that Ru-43 is commercialized by Apeiron Synthesis[END_REF] Note that higher yields were obtained with the indenylidene complex bearing two tricyclohexyl phosphines, albeit with longer reaction times. Tóth, Tuba and coworkers extended this methodology to CAAC bearing NMe2 Ru-44 and N-Me3 + ammonium Ru-45 groups on the N-aryl moiety (Scheme 9). 36 The propensity of ruthenium bis-NHCs alkylidenes to generate active catalytic species has been discussed. [START_REF] Trnka | Synthesis and Activity of Ruthenium Alkylidene Complexes Coordinated with Phosphine and N-Heterocyclic Carbene Ligands[END_REF][START_REF] Keitz | Protonolysis of a Ruthenium-Carbene Bond and Applications in Olefin Metathesis[END_REF][START_REF] Weskamp | A Novel Class of Ruthenium Catalysts for Olefin Metathesis[END_REF][START_REF] Kamal | Activation of olefin metathesis complexes containing unsymmetrical unsaturated Nheterocyclic carbenes by copper and gold transmetalation[END_REF] To determine whether strongly σ-donating and π-accepting CAACs could impede or facilitate the activation of bis-CAAC-Ru-indenylidene complexes, Skowerski and coworkers next examined their reaction with a doubly chelating olefin. [START_REF] Gawin | Cyclic Alkyl Amino Carbene) Ruthenium Complexes: AVersatile, Highly Efficient Tool for Olefin Metathesis[END_REF] As shown in Scheme 10, reaction of Ru-43 with 1-isopropoxy-2-(propenyl)benzene at 60 o C in toluene led to the clean formation of the Hoveyda-Grubbs derivative Ru-11, which was isolated in 86% yield.

Scheme 8 Preparation of bis(CAAC)Ru indenylidene complexes

Revised manuscript 12

Interestingly, the authors also noted that under the same conditions no conversion was observed with the less sterically hindered Ru-36 even after 48h. However, it was shown that simple addition of CuCl (2 eq.), likely acting as a carbene scavenger, is sufficient to drive the reaction forward, thus affording complex Ru-9 in good yield.

Scheme 10 Accessing Hoveyda-Grubbs type complexes from bis(CAAC)Ru indenylidenes

Capitalizing on these results the same group extended the methodology to other Grela type [START_REF] Grela | A Highly Efficient Ruthenium Catalyst for Metathesis Reactions[END_REF] Hoveya-Grubbs CAAC-ruthenium metathesis complexes Ru-46-52 (Scheme 11), [START_REF] Gawin | Cyclic Alkyl Amino Ruthenium Complexes Efficient Catalysts for Macrocyclization and Acrylonitrile Cross Metathesis[END_REF][START_REF]Note that Ru-50 is commercialized by Apeiron Synthesis[END_REF] as well as Ru-53 and Ru-54-57 which were only reported in a patent (Scheme 12). [START_REF] Patent: Skowerski | Process for producing ruthenium complexes and intermediates thereof and their use in olefin metathesis[END_REF] and Ru-59 are also accessible by this route as a mixture of trans-and cis-isomers (Scheme 13). [START_REF] Rozenberg | Synthesis and Catalytic Properties of Sulfur-Chelated Ruthenium Benzylidenes Bearing a Cyclic (Alkyl)(amino)carbene Ligand[END_REF] The cis/trans ratio could readily be tuned by solvent polarity and temperature, and UV-A irradiation was sufficient to revert from cis to trans.

Revised manuscript 13

Revised manuscript 14

Scheme 13 Preparation and configurational behavior of sulfur-chelated ruthenium benzylidenes

Other Types of (CAAC)Ruthenium Complexes

The development of Z-selective ruthenium-based catalysts bearing cyclometalated NHC ligands [START_REF] Endo | Chelated Ruthenium Catalysts for Z-Selective Olefin Metathesis[END_REF][START_REF] Khan | Z-and Enantioselective Ring-Opening/Cross metathesis with Enol Ethers Catalyzed by Stereogenic-at-Ru Carbenes: Reactivity, Selectivity, and Curtin-Hammett Kinetics[END_REF] has been expanded to CAAC derivatives. [START_REF] Bronner | Ru-based Z-selective metathesis catalysts with modified cyclometalated carbene ligands[END_REF] As shown in Scheme 14, the general synthetic strategy used to access the adamantyl variant Ru-60, involves the exchange of the chlorines of Hoveyda-Grubbs CAAC complex Ru-10 with sodium-pivalate. With NHCs, cyclometalated-nitrato catalyst have been shown to afford more stable and more selective catalysts. [START_REF] Hartung | Highly Z-Selective and Enantioselective Ring-Opening/Cross metathesis Catalyzed by a Resolved Stereogenic-at-Ru Complex[END_REF] The CAAC analogue Ru-61 is readily available in 59% yield by simple treatment of Ru-60 with ammonium nitrate.

Scheme 14 Preparation of CAAC-Ru cyclometalated complexes

As previously mentioned, bis(CAAC)Ru-indenylidene pre-catalysts are rather difficult to initiate, requiring high temperatures or the use of additives such as copper chloride. This Revised manuscript [START_REF] Spekreijse | The future of ethenolysis in biobased chemistry[END_REF] arguably impedes their catalytic activity under mild conditions, because of catalyst degradation. [START_REF] Manzini | Insights into the Decomposition of Olefin Metathesis Precatalysts[END_REF][START_REF] Jawiczuk | Decomposition of Ruthenium Olefin Metathesis Catalyst[END_REF] To circumvent these limitations, Fogg and coworkers reported a novel (CAAC)Ru-indenylidene dimer Ru-62, [START_REF] Nascimento | Integrating Activity with Accessibility in Olefin Metathesis: An Unprecedentedly Reactive Ruthenium-Indenylidene Catalyst DanielL[END_REF] bridged by dative Cl interactions. [START_REF] Weskamp | Highly Active Ruthenium Catalysts for Olefin Metathesis: The Synergy of N-Heterocyclic Carbenes and Coordinatively Labile Ligands[END_REF] To access this species, the bis(CAAC)Ru indenylidene Ru-43 was treated with CuCl in the absence of additional donors in CH2Cl2 (Scheme 15). Under these conditions, trapping of one of the two CAAC ligands afforded Ru-62 in 78% isolated yield.

Scheme 15 Preparation of Fogg's (CAAC)Ru-indenylidene dimer Ru-62

Grubbs and coworkers sought to better understand the influence of CAACs versus NHCs on elementary steps of the RCM catalytic cycle, correlating these effects with the selectivity for either degenerate or productive olefin metathesis. [START_REF] Keitz | Probing the Origin of Degenerate Metathesis Selectivity via Characterization and Dynamics of Ruthenacyclobutanes Containing Variable NHCs[END_REF] For this purpose, they prepared CAAC ethylene ruthenacycles Ru-67,68 via a three-step procedure involving the reaction of Hoveyda-Grubbs type complexes Ru-1,9 with P i Pr3, which afforded carbides Ru-63,64 (Scheme 16).

Following protonation with HBF4, the reactivity of the ensuing Piers type phosphonium alkylidene Ru-65,66 complexes was evaluated under ethene atmosphere to afford Ru-67,68. [START_REF] Romero | Rapidly Initiating Ruthenium Olefin-Metathesis Catalysts[END_REF] It is worth mentioning that these results show that phosphonium alkylidenes are accessible from Hoveyda-type complexes. Note that ethylene ruthenacycles can also be obtained starting from Fogg's (CAAC)Ru-indenylidene dimer Ru-62. [START_REF] Nascimento | Origin of the Breakthrough Productivity of Ruthenium-Cyclic Alkyl Amino Carbene Catalysts in Olefin Metathesis[END_REF]

Revised manuscript 16

Scheme 16 Preparative sequence for accessing ethylene ruthenacycles Ru-67,68

Optically pure (CAAC)Ruthenium Complexes

Owing to their simple accessibility, optically pure NHCs have fostered numerous asymmetric applications in olefin metathesis. 71 , 72 , 73 Recently, it was shown that the highly modular steric environment of CAACs could also provide potent optically pure ligands for asymmetric catalysis. [START_REF] Pichon | The Debut of Chiral Cyclic (Alkyl)(amino)carbenes (CAACs) in Enantioselective Catalysis[END_REF] Eager to streamline the discovery of optically pure CAAC-ruthenium metathesis catalysts, we have shown that preparative high-performance liquid chromatography ( Prep HPLC), [START_REF] Okamoto | Chiral HPLC for efficient resolution of enantiomers[END_REF] provides means for bypassing problems typically associated with the synthesis of chiral catalysts (i.e. multisteps, low yielding, single enantiomers). [START_REF] Morvan | Optically Pure C1-Symmetric Cyclic(alkyl)(amino)carbene (CAAC) Ruthenium-Complexes for Asymmetric Olefin Metathesis[END_REF] Of the several columns evaluated, only amylose chiral stationary phases substituted with chloro-phenylcarbamate allowed for separations with good enantioselectivity and excellent resolution. Using Chiralpak IF® for its antipode's separation, shorter elution time and good loading capacity, (+)-Ru-3 and (-)-Ru-3 enantiomers were isolated in excellent yields (46 and 45%, respectively) and excellent enantiomeric purities (>98% ee) (Scheme 17). This method was successfully extended to Grela type complexes Ru-53 and Ru-69-73. 76 Revised manuscript 17

(CAAC)Ruthenium catalysts in Olefin Metathesis

Application to Self-and Cross metathesis

The cross metathesis (CM) between two different olefins or between the same olefin, known as self-metathesis (SM), offers a straightforward access to higher value, multifunctional compounds. Of course, the latter (SM) competes with the former (CM), thus both processes are often considered in parallel across the literature. To better delineate the specificities of these processes we have chosen to present them separately.

Self-metathesis

In contrast with NHC ruthenium catalysts which are generally known to be very active in selfmetathesis processes reaching up to 640,000 TONs with 1-octene, [START_REF] Dinger | High Turnover Numbers with Ruthenium-Based Metathesis Catalysts[END_REF] CAACs variants are comparatively less efficient. This is apparent in the self-metathesis of type 1 olefins 78 such as olefin 1 which results in lower TONs in the presence of Hoveyda-Grubbs Ru-47, Ru-51 complexes (Scheme 18). [START_REF] Gawin | Cyclic Alkyl Amino Ruthenium Complexes Efficient Catalysts for Macrocyclization and Acrylonitrile Cross Metathesis[END_REF] Contrasting with this statement are bis(CAAC)-indenylidene type complexes such as Ru-43 yielding up to 315,000 (Scheme 19). [START_REF] Gawin | Cyclic Alkyl Amino Carbene) Ruthenium Complexes: AVersatile, Highly Efficient Tool for Olefin Metathesis[END_REF] Such differences likely results from the different initiation modes between these two families of complexes.

Revised manuscript 18

Scheme 18. Activity of CAAC-Ru Grela type complexes in self-metathesis Scheme 19. Activity of bis(CAAC)Ru indenylidenes catalysts in self-metathesis

Despite the moderate activity of CAAC catalysts in the homo-dimerization of olefin, their inherent reactivity provides a convenient tool for reducing isomerization pathways. This was unambiguously established by Lemcoff and coworkers by comparing the Hoveyda-Grubbs 2 nd generation C to the CAAC Ru-5 in the self-metathesis of methyl oleate 5 at 100 °C in the presence of 0.1 mol% catalyst loading (Scheme 20). [START_REF] Butilkov | Highly Selective Olefin Metathesis with CAAC-Containing Ruthenium Benzylidenes[END_REF] These authors showed that after 1 h, up to 40% isomerization was observed with C, whereas it was suppressed almost completely with Ru-5. Interestingly, a similar study performed with thioether chelated precatalysts Ru-34,35, Ru-58,59 cis supported these findings. [START_REF] Rozenberg | Synthesis and Catalytic Properties of Sulfur-Chelated Ruthenium Benzylidenes Bearing a Cyclic (Alkyl)(amino)carbene Ligand[END_REF] Supported by DFT, this selectivity was proposed to originate from the greater difficulty of CAAC ruthenium complexes to form the rutheniumhydride-π-allyl intermediate compulsory to the isomerization mechanism. These results also suggest that the conformation of the catalyst and the nature of the benzylidene moiety should be accounted for when predicting the reactivity of these species. Indeed, marked differences where observed between Ru-58 cis and Ru-59 cis upon performing the reaction at either 100°C Revised manuscript [START_REF] Lavallo | CO fixation to stable acyclic and cyclic alkyl amino carbenes: Stable amino ketenes with a small HOMO-LUMO gap[END_REF] to 120°C, the former yielding up to 47% increase in isomerization products. Moreover, it was shown to also impact the stability of the catalyst as seen with the lack of reactivity of Ru-35.

Scheme 20 CAACs catalysts appear to be more selective that their NHC variant in olefin selfmetathesis

As expected, and as highlighted by Wagener and coworkers, [START_REF] Bell | Bulk Acyclic Diene Metathesis Polycondensation[END_REF] the propensity of CAAC ruthenium catalysts to completely inhibit isomerization processes remains contingent on the nature of the olefin. This was demonstrated in the homodimerization of an anthracene substituted olefin 6 in the presence of Ru-3 at 100 °C, which afforded up to 29% of the isomerization product 7 (Scheme 21).

Scheme 21 CAAC catalyst selectivity is likely contingent to the nature of the olefin

The homo-dimerization of olefins by a CAAC-6 ruthenium complex has also been reported using 1-decene 3a and Ru-31, albeit with moderate (31% conversion after 2h; 4a: E/Z ratio:

Revised manuscript 20 4.7/1) (Scheme 22). [START_REF] Samkian | Synthesis and Activity of Six-Membered Cyclic Alkyl Amino Carbene-Ruthenium Olefin Metathesis Catalysts[END_REF] The reduced catalytic activity and selectivity were proposed to originate from the increased steric bulk of the CAAC-6 ligand. 28 It is worth noting that allylbenzene resulted in significant olefin migration under the same conditions.

Scheme 22 Activity of CAAC-6 Hoveyda-Grubbs type complexes in self-metathesis

To improve the Z-selectivity of the self-metathesis reaction, Grubbs and coworkers compared the activity of several cyclometalated carbene ruthenium complexes. As illustrated by selected examples in Scheme 23, NHC complexes (such as G) were found to outcompete the CAAC ruthenium variant Ru-61 in the self-metathesis of allylbenzene 8. While the lack of reactivity was attributed to the instability of Ru-61, the diminished Z-selectivity was proposed to originate from conformational differences with NHCs variants.

Scheme 23. Activity of cyclometalated CAAC complexes in self-metathesis

Revised manuscript 21

Cross metathesis

The development of E/Z-diastereoselective olefin metathesis catalysts is an area of substantial interest in organic chemistry. [START_REF] Grubbs | Handbook of Metathesis[END_REF][START_REF] Montgomery | Stereoretentive Olefin Metathesis: An Avenue to Kinetic Selectivity[END_REF] Typically, the E/Z diastereoselectivity of an olefin metathesis reaction is controlled by the thermodynamic stability of the olefin isomers rather than the selectivity of the catalyst. Looking to further investigate the influence of CAACs on this predicament, Grubbs and coworkers reported that CAAC-substituted catalysts exhibit lower E/Z ratio of 11 (2:1 at 70% conversion) in the cross metathesis of cis-1,4-diacetoxy-2-butene 10 with allylbenzene 8 (Scheme 24). [START_REF] Anderson | Kinetic Selectivity of Olefin Metathesis Catalysts Bearing Cyclic (Alkyl)(Amino)Carbenes[END_REF] As highlighted by the selectivity of C SIMes , NHCcatalysts are typically more selective towards the most thermodynamically stable E-olefins, whereas CAACs afford higher ratio of Z-olefins. Interestingly, the shorter reaction times observed with the less hindered Ru-9 (at ∼60% conversion after 1 h at 22 °C; vs. 32 h for Ru-1 and 48 h for Ru-2 at 60 °C) indicate that the higher Z selectivity observed with CAACs is a result of the inherent catalyst selectivity, rather than an artefact of a less active catalyst unable to isomerize olefins.

Scheme 24. Cross metathesis with CAAC ruthenium catalysts appears to be more E-selective than with NHC variants

The activity of the CAAC ruthenium catalysts in cross metathesis of methyl oleate 5 has also been achieved with 1,4-diacetoxy-2-butene 10. It was found to be quite straightforward,

Revised manuscript 22

achieving up to 99 % yield of the corresponding olefins 12 and 13 under solvent free conditions with catalyst Ru-44 at 0.05 mol % loading and 65°C (Scheme 25). Note that the reaction can also be achieved under protic conditions in methanol using the more polar Ru-45. [START_REF] Nagyházi | Towards Sustainable Catalysis -Highly Efficient Olefin Metathesis in Protic Media Using Phase Labelled Cyclic Alkyl Amino Carbene (CAAC) Ruthenium Catalysts[END_REF]

Scheme 25 Cross metathesis of methyl oleate with Bis-CAAC-Ru complexes Ru-44 and Ru-45

In recent years, the production of value-added molecules from microalgae including pigments, vitamins, proteins and lipids has shown significant potential. Specifically, [START_REF] Hulatt | Polar snow algae as a valuable source of lipids?[END_REF] for polyunsaturated fatty acids, a class of lipids which are of particular interest given their range of applications in cosmeceuticals, nutraceuticals, fine chemicals, pharmaceuticals, and biodiesel. [START_REF] Hess | Production of chemicals from microalgae lipidsstatus and perspectives[END_REF] Despite the difficulty of transforming such complex molecules, Tuba, Tóth and coworkers have shown that Hoveyda-Grubbs Ru-23 and indenylidene Bis(CAAC)Ruthenium Ru-45 were active in the cross metathesis of 1,4-diacetoxy-2-butene 10 with 1,2-dioleoyl-snglycero-3-phosphocholine 14 (DOPC) (Scheme 26), [START_REF] Nagyházi | Towards Sustainable Catalysis -Highly Efficient Olefin Metathesis in Protic Media Using Phase Labelled Cyclic Alkyl Amino Carbene (CAAC) Ruthenium Catalysts[END_REF] a glycerophospholipid obtained from low value algae.

Revised manuscript 23

Scheme 26 Cross metathesis of polyunsaturated fatty acids

The use of nitriles in olefin metathesis is quite attractive as it offers a convenient access to value-added chemicals such as the Rilsan® Nylon 11 precursor "10-cyanodec-9-enoate" 16, which is obtained by reaction of methyl 9-decenoate 1 with acrylonitrile. Yet, as noted by Fogg and others, [START_REF] Mcclennan | A General Decomposition Pathway for Phosphine-Stabilized Metathesis Catalysts: Lewis Donors Accelerate Methylidene Abstraction[END_REF][START_REF] Malacea | Renewable materials as precursors of linear nitrile-acid derivatives viacross metathesis of fatty esters and acids with acrylonitrile and fumaronitrile[END_REF] traditional NHC ruthenium metathesis catalysts (B, C) are susceptible to decomposition in the presence of nitriles (e.g. acrylonitrile). Looking to improve upon the best NHC catalytic systems in the field, [START_REF] Bidange | Ruthenium-Benzylidenes and Ruthenium-Indenylidenes as Efficient Catalysts for the Hydrogenation of Aliphatic Nitriles into Primary Amines[END_REF][START_REF] Patent: Dubois | Cross metathesis process[END_REF] Skowerski and coworkers envisaged capitalizing on the enhanced activity and stability of Grela-type catalysts bearing CAAC ligands. [START_REF] Gawin | Cyclic Alkyl Amino Ruthenium Complexes Efficient Catalysts for Macrocyclization and Acrylonitrile Cross Metathesis[END_REF] As highlighted in Scheme 27, despite the proficiency of the NHC Grela-type D SIPr , CAAC derived Ru-50 was found to be much more reactive leading up to 24,800 TON. Performing the same reaction with 20 ppm of Ru-50 and at 85 °C led to 30,000 TON and 82% selectivity. In line with previous comments, [START_REF] Marx | Cyclic Alkyl Amino Carbene (CAAC) Ruthenium Complexes as Remarkably Active Catalysts for Ethenolysis[END_REF] the authors proposed that this improved performance originates from higher stability of the active species rather than from better kinetics. This postulate was later supported by a DFT study by Trzaskowski and coworkers, who demonstrated that in marked contrast with NHCs, CAAC-derived ruthenium catalysts were less susceptible to undergo acrylonitrileassisted degradation. [START_REF] Jawiczuk | Molecular Modeling of Mechanisms of Decomposition of Ruthenium Metathesis Catalysts by Acrylonitrile[END_REF] The superior activity of CAAC catalysts in cross metathesis processes Revised manuscript [START_REF] Mandal | Influence of N-Substitution on the Formation and Oxidation of NHC-CAAC-Derived Triazaalkenes[END_REF] with acrylonitrile was successfully extended to methyl oleate 5 and 1-decene 3a affording the corresponding olefins 17 and 18 (Scheme 28). [START_REF] Patent: Skowerski | Use of ruthenium complexes in olefin metathesis reaction[END_REF] Acrylates (type II olefins [START_REF] Chatterjee | A General Model for Selectivity in Olefin Cross Metathesis[END_REF] ) have a significant number of applications, [START_REF] Prunet | Cross metathesis in Natural Products Synthesis in Metathesis in Natural Product Synthesis: Strategies, Substrates, and Catalysts[END_REF] but have poor reactivity in metathesis transformations as shown with Grubbs 2 nd generation catalysts which require activation by a copper additive. [START_REF] Bailey | Acrylate Metathesis via the Second-Generation Grubbs Catalyst: Unexpected Pathways Enabled by a PCy3-Generated Enolate[END_REF][START_REF] Santos | Overcoming Catalyst Decomposition in Acrylate Metathesis: Polyphenol Resins as Enabling Agents for PCy3-Stabilized Metathesis Catalysts[END_REF] Having found that CAAC catalysts allowed for improved catalytic activities in the cross metathesis of ethyl 10-undecenoate 1 with acrylonitrile, [START_REF] Gawin | Cyclic Alkyl Amino Ruthenium Complexes Efficient Catalysts for Macrocyclization and Acrylonitrile Cross Metathesis[END_REF] Skowerski and coworkers naturally extended their study to acrylates. [START_REF] Kaczanowska | Cross metathesis with acrylates: N-heterocyclic carbene (NHC)-versus cyclic alkyl amino carbene (CAAC)-based ruthenium catalysts, an unanticipated influence of the carbene type on efficiency and selectivity of the reaction[END_REF][START_REF] Patent: Skowerski | Use of ruthenium complexes in olefin metathesis reaction[END_REF] Using ethyl 10-undecenoate 1 in the presence of methyl acrylate, these authors compared the activity Revised manuscript 25 of CAACs Ru-46,50 to NHCs D SIMes and D SIPr (Scheme 29). However, with turnovers as high as 34,110, NHC-based catalysts were found to be more selective than CAAC catalysts, which are more prone to undergo self-metathesis. The authors could confirm these results across a larger range of CAAC complexes Ru47-49,51,52,69. [START_REF] Patent: Skowerski | Use of ruthenium complexes in olefin metathesis reaction[END_REF]

Scheme 27 CAAC ruthenium catalysts remain very efficient in

Scheme 29 Cross metathesis with methyl acrylate and CAAC-Ru Grela type complexes

As shown in Scheme 30, these challenging cross metathesis reactions between electrondeficient methyl acrylate and acrylonitrile with methyl 9-undecenoate 3b was readily extended to bis(CAAC)Ru-indenylidene pre-catalysts. [START_REF] Gawin | Cyclic Alkyl Amino Carbene) Ruthenium Complexes: AVersatile, Highly Efficient Tool for Olefin Metathesis[END_REF] Note that in this case the use of the more reactive Ru-43 without the necessity of adding CuCl to activate the catalyst. Extending the field to asymmetric transformations, we recently examined the activity of optically pure CAACs in challenging asymmetric cross metathesis (ACM). [START_REF] Berlin | Highly Active Chiral Ruthenium Catalyst for Asymmetric Cross metathesis and Ring-Opening Cross metathesis[END_REF] As shown in Scheme 31, we found that Grela type enantiopure (CAAC)Ru-(S) Ru-71 afforded 24 with up to 50% ee in the cross metathesis of diene 22 with allyl acetate 23. [START_REF] Morvan | Optically Pure C1-Symmetric Cyclic(alkyl)(amino)carbene (CAAC) Ruthenium-Complexes for Asymmetric Olefin Metathesis[END_REF] Note that these preliminary results surpass state of the art chiral NHC ligands, which suggest that further investigations should be performed to delineate the impact of CAACs in ACM. [START_REF] Hartung | Enantioselective Olefin Metathesis with Cyclometalated Ruthenium Complexes[END_REF] Scheme 31 First application of an optically pure CAAC in asymmetric cross metathesis

Revised manuscript 26

Application to Ring-Closing Metathesis

Small molecules

The catalytic performance of CAAC-based ruthenium catalysts in ring-closing metathesis (RCM) was first established by Grubbs and coworkers in the RCM of diallylmalonate 25. [START_REF] Anderson | Synthesis and reactivity of olefin metathesis catalysts bearing cyclic (alkyl)(amino)carbenes[END_REF] As Revised manuscript [START_REF] Tomás-Mendivil | Bicyclic (alkyl)(amino)carbenes (Bi-CAACs): stable carbenes more ambiphilic than CAACs[END_REF] shown in Scheme 32, pyridine-based CAAC-complexes Ru-32,33 showed moderate reactivities (50% conv. over 24 h), which was attributed to premature catalyst decomposition occurring even at room temperature. As expected, improved efficiencies were observed with the more stable Hoveyda-type derivatives Ru-1,2, reaching almost full conversions with trisubstituted olefin 27, even at 1 mol% catalyst loading, albeit with longer reaction times.

( Scheme 33). As observed between Ru-1,2 and Ru-9 the catalytic activity of CAAC catalysts is largely influenced by sterics. Improving upon these results, Skowerski and coworkers obtained higher activities with the least sterically hindered Ru-9 and Ru-5. [START_REF] Patent: Skowerski | Use of ruthenium complexes in olefin metathesis reaction[END_REF] However, CAAC catalysts could not efficiently perform the RCM of dimethyl diallylmalonate to yield the cyclic tetra-substituted olefin (not shown). Examining the influence of the substitution of the backbone, Zhang, Shi and coworkers obtained higher reactivity with Ru-19-21 featuring an isopropyl instead of their gem-dimethyl analogues (Scheme 33). [START_REF] Zhang | Ruthenium-catalyzed olefin metathesis accelerated by the steric effect of the backbone substituent in cyclic (alkyl)(amino) carbenes[END_REF] While these results clearly highlight the importance of sterics in this process, they also indicate that steric decongestion at the N-aryl ortho-substituent is more critical than on the backbone of the CAAC ligand.

Scheme 32 Ring Closing-Metathesis using pyridine-based CAAC-complexes Ru-32

Revised manuscript 28 (scheme 34). [START_REF] Patent: Skowerski | Process for producing ruthenium complexes and intermediates thereof and their use in olefin metathesis[END_REF] Note that replacing a methyl by a phenyl on the quaternary carbon next to the carbene center also led to a faster RCM (Ru-50,52). Going further, these authors considered the nature of the styrenyl motif (Scheme 35). [START_REF] Patent: Skowerski | Process for producing ruthenium complexes and intermediates thereof and their use in olefin metathesis[END_REF][START_REF] Patent: Skowerski | Use of ruthenium complexes in olefin metathesis reaction[END_REF] Notably, introduction of a modified styrenyl ether ligand, containing the Weinreb-amide functionality, drastically improved the initiation rate of Ru-54-56. Per comparison, N-chelating morpholine moiety (Ru-74) was less efficient, requiring a thermal activation to initiate the RCM. Note that the replacement of chloride by iodide in Ru-55 appeared to be detrimental, while addition of an electron donating methoxy group in Ru-75 led to a severe drop of reactivity in marked contrast with Ru-50 bearing an electron withdrawing group. Such behavior has also been observed with NHC-based Revised manuscript 29 catalysts. [START_REF] Gułajski | New tunable catalysts for olefin metathesis: Controlling the initiation through electronic factors[END_REF] A remarkable initiation rate was also observed with iodine-chelated catalyst Ru-76 reaching full conversion within 10 min.

Scheme 34 Activity of nitro-Grela CAAC catalysts in Ring Closing-Metathesis of diallyl malonate

Scheme 35 Impact of the styrenyl ether ligand on the Ring Closing-Metathesis of diallyl malonate

Revised manuscript 30

As already mentioned, nitriles are known to poison many Ru-based olefin metathesis catalysts. [START_REF] Mcclennan | A General Decomposition Pathway for Phosphine-Stabilized Metathesis Catalysts: Lewis Donors Accelerate Methylidene Abstraction[END_REF][START_REF] Malacea | Renewable materials as precursors of linear nitrile-acid derivatives viacross metathesis of fatty esters and acids with acrylonitrile and fumaronitrile[END_REF] However, Skowerski and coworkers examined the RCM of diallyl malonate 25 in the presence of nitrile additives. They reported that CAAC-Ru-50 was only slightly impacted, maintaining high reactivity at low catalyst loading (0.02 mol%), in marked contrast with Ru-46 NHC-based catalyst C SIPr (Scheme 36). [START_REF] Gawin | Cyclic Alkyl Amino Ruthenium Complexes Efficient Catalysts for Macrocyclization and Acrylonitrile Cross Metathesis[END_REF] Additional experiments and DFT calculations highlighted that some CAAC-Ru catalysts impede the formation of transient ruthenium cyanomethylidenes that are more prone to undergo acrylonitrile-assisted decomposition. [START_REF] Jawiczuk | Molecular Modeling of Mechanisms of Decomposition of Ruthenium Metathesis Catalysts by Acrylonitrile[END_REF] In another report, it was also shown that CAAC-catalysts are tolerant to methyl acrylates (as in 30) another well-known poison for metathesis catalysts. [START_REF] Kaczanowska | Cross metathesis with acrylates: N-heterocyclic carbene (NHC)-versus cyclic alkyl amino carbene (CAAC)-based ruthenium catalysts, an unanticipated influence of the carbene type on efficiency and selectivity of the reaction[END_REF]

Scheme 36 CAAC ruthenium catalysts remain very efficient in Ring Closing Metathesis in the presence of nitriles or acrylates

Recently, Grubbs and coworkers extended these studies to six-membered CAAC-Hoveyda catalysts Ru-28-31 (Scheme 37). [START_REF] Samkian | Synthesis and Activity of Six-Membered Cyclic Alkyl Amino Carbene-Ruthenium Olefin Metathesis Catalysts[END_REF] As with their 5-membered counterparts, some important structure/activity insights were identified through an initiation study involving butyl vinyl ether (not shown), combined with reactive profiles of the benchmark RCM of diallylmalonate 25.

Revised manuscript 31

As expected from more donating ligands, faster catalyst initiation was observed with CAAC-6 complexes (vs. CAAC-5), likely due to a weaker Ru-O bond. For now, CAAC-6 catalysts do not meet the catalytic activities of CAAC-5 motifs. However, given the small range of CAAC-6 studied and the critical influence of subtle steric modifications of the ligand structure in these systems, it seems premature to critically assess the impact of CAAC-6 in olefin metathesis.

Scheme 37 Activity of CAAC-6 Hoveyda-Grubbs catalysts in Ring Closing Metathesis

Lemcoff and coworkers have investigated the reactivity of latent sulfur-chelated Rubenzylidenes containing CAACs in the RCM of tosylsulfonamide 31 (scheme 38). [START_REF] Rozenberg | Synthesis and Catalytic Properties of Sulfur-Chelated Ruthenium Benzylidenes Bearing a Cyclic (Alkyl)(amino)carbene Ligand[END_REF] Under drastic thermal conditions (150 °C), cis and trans Ru-58,59 afforded excellent conversions to 7-membered 32, with extremely low isomerization of the double bond (97% selectivity). This is in marked contrast with the CAAC Hoveyda-type Ru-5 and NHC SIMes cis-variant I, which give significant amounts of isomerized by-products. [START_REF] Butilkov | Highly Selective Olefin Metathesis with CAAC-Containing Ruthenium Benzylidenes[END_REF] Revised manuscript 32

Scheme 38 Activity of sulfur-chelated (CAAC)Ru-benzylidenes in the RCM of tosylsulfonamide

Looking for even more efficient catalysts, Skowerski and coworkers disclosed the remarkable activity of bis(CAAC)Ru indenylidene complexes Ru-36-43 (Scheme 39). [START_REF] Gawin | Cyclic Alkyl Amino Carbene) Ruthenium Complexes: AVersatile, Highly Efficient Tool for Olefin Metathesis[END_REF][START_REF] Patent: Skowerski | Process for producing ruthenium complexes and intermediates thereof and their use in olefin metathesis[END_REF] Compared to traditional Hoveyda-Grubbs CAAC ruthenium complexes, bis(CAAC)Ru indenylidene complexes were shown to be more difficult to activate (Ru-36: 1% in 1 h versus Ru-9: 95% in 15 min). However, this could be overcome by promoting ligand to ligand steric repulsion through the CAAC motifs (Ru-36 vs. Ru-39 or Ru43), or by simple addition of a CuCl additive.

Scheme 39 Activity of Bis(CAAC)Ru-indenylidene complexes in Ring Closing Metathesis

The most performant catalyst Ru-43 was found to outperform the traditional Grubbs II catalyst (50% yield and 8,300 TON, not shown) in the RCM leading to proline derivative 33 (TON 15,300) (Scheme 40). Seven-membered ring azepine derivative 34 and challenging (sterically hindered) tetra-substituted olefin 35 were also efficiently transformed, as well as diallyltosylamine 36. [START_REF] Patent: Skowerski | Use of ruthenium complexes in olefin metathesis reaction[END_REF] Revised manuscript 33 Tuba, Tóth and coworkers examined the catalytic performances of Ru-complexes containing polar tags in protic media such as methanol (Scheme 41). [START_REF] Nagyházi | Towards Sustainable Catalysis -Highly Efficient Olefin Metathesis in Protic Media Using Phase Labelled Cyclic Alkyl Amino Carbene (CAAC) Ruthenium Catalysts[END_REF] It is worth mentioning that both complexes were highly robust toward air and moisture.

Scheme 41 Ring-Closing-Metathesis catalyzed by ammonium-tagged CAAC Ru-complexes

In the case of the indenylidene chloro-bridge dimer complex Ru-62, the high lability of the bridging anionic ligand considerably increased the initiation rate as well as the productivity in the RCM of diallyl malonate 25 (Scheme 41). [START_REF] Nascimento | Integrating Activity with Accessibility in Olefin Metathesis: An Unprecedentedly Reactive Ruthenium-Indenylidene Catalyst DanielL[END_REF] At extremely low catalyst loading (0.005 mol%), it could outperform bis(CAAC)Ru indenylidene complexes Ru-43 and the state of the art NHC-based catalysts (e.g. nitro-Grela, Umicore M2; not shown). Note however that the activity of dimer Ru-62 was comparable (or slightly higher at 9 ppm) than nitro CAAC-catalyst Ru-50. Interestingly, both catalysts remained active in presence of oxygen, even at 1 ppm, attesting of their remarkable robustness. [START_REF] Ton | The Impact of Oxygen on Leading and Emerging Ru-Carbene Catalysts for Olefin Metathesis: An Unanticipated Correlation Between Robustness and Metathesis Activity[END_REF]

Revised manuscript 34

Scheme 42 Fogg's indenylidene chloro-bridge dimer complex Ru-62, a very active RCM catalyst

Macrocycles

Macrocycle cores are ubiquitous in numerous natural molecules, notably in pharmaceutical drugs and cosmetics. In this context, olefin metathesis represents a clean and highly competitive synthetic tool to form macrocycle scaffolds (e.g. ketone, lactone, lactam) even those containing various organic functions. Nevertheless, the high dilutions and catalyst loadings required in these processes remains a major drawback. This limits the usefulness of macro-RCM for any practical industrial developments, especially in the area of macrocyclic fragrance molecules. To confront these challenges, Skowerski and coworkers demonstrated that BisCAAC Ru-43 could efficiently convert diene 37 into 16-membered macrocycle 38, a precursor of highly desirable exaltolide, a musk known for its odorant property (Scheme 43). [START_REF] Gawin | Cyclic Alkyl Amino Carbene) Ruthenium Complexes: AVersatile, Highly Efficient Tool for Olefin Metathesis[END_REF] However, a much more impressive 62,000 TON (TOF 3,000 min -1 ) was achieved with the nitro CAAC-catalyst Ru-50, enabling fast metathetic macrocyclizations at extremely low catalyst loadings (as low as 10 ppm). [START_REF] Gawin | Cyclic Alkyl Amino Ruthenium Complexes Efficient Catalysts for Macrocyclization and Acrylonitrile Cross Metathesis[END_REF] It is worth mentioning that these TONs are the highest reported so far in macro-RCM, outperforming classical NHC-containing catalysts such as Grubbs B, Hoveyda-Grubbs C or nitro-Grela D, as well as other CAAC-complexes (Ru-11,46). At higher Revised manuscript [START_REF] Zhang | Ruthenium-catalyzed olefin metathesis accelerated by the steric effect of the backbone substituent in cyclic (alkyl)(amino) carbenes[END_REF] concentrations, excellent conversions were observed, however at the expense of substantial oligomer formation (up to 31%).

Scheme 43 Activity of nitro-Grela CAAC complexes in Macro-Ring-Closing Metathesis

Using high substrate concentration (i.e. 200 mM; 0.25 mol/kg), reduced pressure and paraffin oil as a solvent, Grela and coworkers investigated the macro-RCM of oleyl derived diene 39 (Scheme 44). Surprisingly compared to NHC J, CAAC-catalysts appeared to be quite inefficient under these specific conditions, both in productivity and selectivity. [START_REF] Patent: Grela | Method of cyclic compounds production in olefine metathesis reaction and use of ruthenium catalysts in production of cyclic olefins in olefine metathesis reaction -WO 2018/197963 A1[END_REF]100

Scheme 44 The activity of CAAC complexes in Macro-Ring-Closing Metathesis

Revised manuscript [START_REF] Nagyházi | Towards Sustainable Catalysis -Highly Efficient Olefin Metathesis in Protic Media Using Phase Labelled Cyclic Alkyl Amino Carbene (CAAC) Ruthenium Catalysts[END_REF] Recently, Jamison, Bio and coworkers described the macro-RCM of diene 40 using a continuous flow olefin metathesis process (Scheme 45). 101 Thanks to a selective membrane allowing a high flux ethylene gas permeation, nitro-CAAC Ru-50 efficiently catalyzed the production of 14-membered macrocyclic lactone 41, a relevant molecule of the fragrance industry. Despite its excellent performance, significant amounts of oligomers were also formed due to high substrate concentration (i.e. 10 mM). Note that similar catalytic performances were also obtained using the a bis-iodo-SIMes nitro-Grela catalyst (not shown).

Scheme 45 Macro-RCM of diene 40 in continuous flow using Ru-50

Fogg's chloro-bridge dimer Ru-62 compared well with nitro CAAC-Ru-50 in the selective formation of exaltolide precursor 37 (i.e. without traces of oligomer) (Scheme 46). [START_REF] Nascimento | Integrating Activity with Accessibility in Olefin Metathesis: An Unprecedentedly Reactive Ruthenium-Indenylidene Catalyst DanielL[END_REF] As an added feature, Ru-62 was shown to be more oxygen tolerant than Hoveyda-Grubbs Ru-50. In marked contrast, bis(CAAC)Ru indenylidene Ru-43 displayed an acute sensitivity to oxygen, [START_REF] Ton | The Impact of Oxygen on Leading and Emerging Ru-Carbene Catalysts for Olefin Metathesis: An Unanticipated Correlation Between Robustness and Metathesis Activity[END_REF] possibly resulting from O2 binding to its sixth vacant coordination site. Factors favoring this degradation pathway have been proposed to result from several factors such as the inherent πacidity of the CAAC ligands, the low ligand lability, and the reduced steric crowding of the indenylidene unit.

Revised manuscript 37

Scheme 46 Fogg's chloro-bridge dimer Ru-62 a competitive catalyst for macro-RCM

Applications in Ethenolysis

Methyl and ethyl Oleate

Cross metathesis involving ethylene, the so-called ethenolysis, has received tremendous attention as means to produce alpha-olefins in high demands for many industrial applications (materials, lubricants, surfactants, plasticizers, antimicrobials, etc.…). In the context of biomass fuel production (biorefinery), the ethenolysis of unsaturated fatty acids/esters derived from natural vegetable oils (preferentially nonedible ones) provides bio-sourced alpha-olefins.

Among the transition-metals able to promote ethenolysis of the biomass, robust and air stable ruthenium alkylidenes complexes rapidly emerged as promising catalyst candidates. However, the instability of propagating methylene species and concurrent inhibition by ethenolysis products only resulted in modest productivity (ca. TON <14,000). 102 Complicating the matter further, second generation NHC-based catalysts were shown to favor undesirable selfmetathesis pathways. In that respect, the discovery of CAAC-based catalysts undeniably contributed to overcome these fundamental issues. In 2008, Schrodi and colleagues examined Revised manuscript [START_REF] Michrowska | A New Concept for the Noncovalent Binding of a Ruthenium-Based Olefin Metathesis Catalyst to Polymeric Phases: Preparation of a Catalyst on Raschig Rings[END_REF] for the first time the reactivity of CAAC-Ru Hoveyda-type complexes in the ethenolysis of methyl oleate 5 (Scheme 47). [START_REF] Anderson | Kinetic Selectivity of Olefin Metathesis Catalysts Bearing Cyclic (Alkyl)(Amino)Carbenes[END_REF] At low catalyst loading (i.e. 100 ppm) and under 10 bar of ethylene, in solvent-free conditions, Ru-1, Ru-2 and Ru-9 exhibited good conversions and selectivity toward the desired terminal olefins 3a and 3b. Reduction of the catalyst loading to 10 ppm even allowed up to 35,000 TON with Ru-9, one of the highest reported at that time.

Under similar conditions, Piers-type CAAC-Ru-65' performed as efficiently, whereas the monosubstituted i Pr-CAACs Ru-19-21 gave excellent performances despite a lower purity (96%) of the methyl oleate and ambient conditions. [START_REF] Zhang | Ruthenium-catalyzed olefin metathesis accelerated by the steric effect of the backbone substituent in cyclic (alkyl)(amino) carbenes[END_REF]103 Comparatively, the Hoveyda catalyst C SIMes gave lower yield and selectivity (20 and 33%, resp.; TON 2,000; not shown). [START_REF] Anderson | Kinetic Selectivity of Olefin Metathesis Catalysts Bearing Cyclic (Alkyl)(Amino)Carbenes[END_REF]

Scheme 47 CAAC Ruthenium catalysts as powerful tools for ethenolysis

Grubbs and coworkers reported an extensive study of the ethenolysis of neat methyl oleate (Scheme 48). [START_REF] Marx | Cyclic Alkyl Amino Carbene (CAAC) Ruthenium Complexes as Remarkably Active Catalysts for Ethenolysis[END_REF] The use of high purity ethylene (99.95%) considerably improved the performance of catalysts reaching 180,000 TONs with Ru-5 and Ru-7. Pushing the system Revised manuscript 39 even further, with even higher ethylene purity (up to 99.995%), allowed reaching 340,000 TON with Ru-5, one of the highest reported to date.

Scheme 48 Importance of the purity of ethylene for improving TON in ethenolysis

This impressive productivity/selectivity was attributed to i) CAAC induced increased electron density at the ruthenium leading to more stable methylidene propagating species and ii) large N-aryl substituents limiting the formation of ruthenium hydrides thereby limiting secondary reaction pathways. Comparison of initiation rates and TONs support this hypothesis, suggesting that an optimal balance must be found to achieve stability and reactivity. Grubbs and coworkers later achieved the low pressure ethenolysis of methyl oleate 5, using continuous flow condition with Ru-9 (Scheme 49). 104 At 50 ppm catalyst loading, Ru-9 surpassed its NHC-counterparts (i.e. Grubbs and Hoveyda-Grubbs) by affording the highest yield (ca. 70%) and a TON of 27,200. Note that this high catalytic performance was achieved using lower purity material (97%). Similarly, Verpoort and coworkers examined the influence of labile benzylether, benzylthioether and benzylamine chelating groups. [START_REF] Patent: Verpoort | Group 8 tansition metal catalysts and method for making same and process for use of same in olefin disproportionation reactions[END_REF] As shown in Scheme 51, all Ru-27 catalysts converted methyl oleate 5 (neat) with excellent selectivity (98%) and impressive

Revised manuscript 40

Revised manuscript 41

TONs (from 180,000 to 210,000), outperforming the Hoveyda complex Ru-3 (150,000, see Scheme 48). The reaction carried out with high purity ethylene gas (99.995%), in the presence of benzylamine-chelated Ru-27e and a Brønsted acid activator (HSiCl3), afforded the highest TON value reported so far (390,000), slightly surpassing the state of art Ru-5 (340,000).

Scheme 51 Benzylether, benzylthioether and benzylamine substited CAAC-Ru catalysts display very reactivities

As depicted in Scheme 52, six-membered CAAC-ligated Ru-catalysts Ru-28-31 displayed much poorer reactivities than their five-membered counterparts in the ethenolysis of neat methyl oleate 5. [START_REF] Samkian | Synthesis and Activity of Six-Membered Cyclic Alkyl Amino Carbene-Ruthenium Olefin Metathesis Catalysts[END_REF] Given a significant drop of activity at elevated temperature, it is likely that the poor catalytic behavior of these complexes could be imparted to their lower stability.

Nevertheless, the authors also noted that CAAC-6 catalysts outperformed CAAC-5 in term of selectivity.

Revised manuscript 42

Scheme 52 Activity of CAAC-6 Hoveyda-Grubbs catalysts in Ethenolysis

Capitalizing on these results, Chen and coworker envisaged combining the Ru-ethenolysis and Pd-copolymerization of internal olefins to generate highly desirable polar functionalized linear low density polyethylene materials. 108 Using neat methyl oleate, and thanks to the high selectivity of CAAC-catalyst in ethenolysis, this tandem catalytic process involving CAAC Ru-11/Pd-1 was able to produce valuable copolymers with high molecular weight and a tunable incorporation of 1-decenoate/1-decene (Scheme 53). It is worth noting that the direct copolymerization route failed due to the steric mismatch between the 1,2-disubstitued olefin and the palladium catalyst.

Scheme 53 Tandem Ru-ethenolysis and Pd-copolymerization of internal olefins towards polyethylene materials

Revised manuscript [START_REF] Trnka | Synthesis and Activity of Ruthenium Alkylidene Complexes Coordinated with Phosphine and N-Heterocyclic Carbene Ligands[END_REF] CAAC-catalysts were also investigated in the ethenolysis of ethyl oleate 5'. The later takes the advantage of a higher boiling point allowing for an easier separation of the corresponding products. 109 In an extensive study, Grela and coworkers reported on the catalytic activity of sixty-five NHC and CAAC Ru-complexes in the ethenolysis of 5' (95% purity; 15 mmol scale) under ambient conditions (Scheme 54). 109 Amongst all the catalysts screened, CAAC Ru-9 and NHC J were shown to be the most efficient (i.e. combining high reactivity and high selectivity).

Note that a lower activity was observed with iodine derived CAAC Ru-78 albeit a higher selectivity (99%). Expanding upon their work, these authors could perform large scale production using Ru-9 as a catalyst (Scheme 55). 110 Note that in this case they relied on SnatchCat as a metal scavenger to facilitate the purification.

Scheme 54 CAAC-Ru catalysts in the ethenolysis of ethyl oleate

Scheme 55 Large scale ethenolysis of ethyl oleate under ambient conditions using Ru-9

Revised manuscript 44 Bis(CAAC)Ru indenylidene complexes developed by Skowerski and workers also proved to be efficient in the ethenolysis of neat methyl oleate 5 affording up to 86,000 TONs (Scheme 56). [START_REF] Gawin | Cyclic Alkyl Amino Carbene) Ruthenium Complexes: AVersatile, Highly Efficient Tool for Olefin Metathesis[END_REF] As expected, higher activities were obtained with the more sterically demanding phenyl substituted CAAC catalysts Ru-41-43 and sterically unbalanced N-aryl Ru-39 and Ru40 reaching 86,000 TONs. Despite such exceptional reactivities, these catalysts remained slightly less reactive than nitro-Grela Ru-48 (TON 94,000).

Scheme 56 Catalytic performances of bis(CAAC)Ru-indenylidene complexes in ethenolysis

With up to 50,000 TON, Fogg's chloro-bridge dimer Ru-62 was also shown to be a very potent catalyst for this transformation, even outperforming the Grela type catalyst Ru-50 (Scheme 57). [START_REF] Nascimento | Integrating Activity with Accessibility in Olefin Metathesis: An Unprecedentedly Reactive Ruthenium-Indenylidene Catalyst DanielL[END_REF] Note however, that with this dimer, the catalytic activity was shown to be largely impacted by ethylene pressures.

Revised manuscript 45

Scheme 57 Fogg's chloro-bridge dimer Ru-62 a competitive catalyst for ethenolysis

Fatty acid methyl esters (FAME) mixture

Given the excellent catalytic performance of CAAC-catalysts in the ethenolysis of oleic esters, the methodology was applied to more valuable raw materials, such as FAME mixtures derived from transesterification of seed oils. The ethenolysis of soy FAME was first studied by Grubbs and coworkers using CAAC-Ru catalysts Ru-5,7 and Ru-17 (Scheme 58). 111 At 3 ppm catalyst loading and 10 bar of extremely pure ethylene (99.995%), the corresponding terminal olefins were produced with high TONs, up to 92,000 with Ru-5. Note that these complexes were also shown to efficiently catalyze the butenolysis of soy FAME 43, delivering terminal and internal olefins in high conversions within 30 min (Scheme 59 ).

Scheme 58 CAAC-Ru complexes in the ethenolysis of soy FAME

Revised manuscript 46

Scheme 59 CAAC-Ru complexes in the butenolysis of soy FAME

More recently, Grela and coworkers reported the catalytic activity of CAAC Ru-9 in the ethenolysis of rapeseed FAME, performed at a 1 liter-scale, under industrially relevant conditions (i.e. ambient conditions, technical grade of oleic raw materials and ethylene). 110 Despite these unfavorable settings, Ru-9 remained very active at 25 ppm loading, affording terminal olefins with high conversion and excellent selectivity (Scheme 60). Weinreb-amide containing CAAC-catalysts Ru-54-56 were used by Skowerski for large-scale transformation of rapeseed FAME but in this case lower productivities were obtained. [START_REF] Patent: Skowerski | Process for producing ruthenium complexes and intermediates thereof and their use in olefin metathesis[END_REF] Revised manuscript 47

Scheme 60 CAAC-Ru complexes in the ethenolysis of rapeseed FAME

In 2017, Goossen and coworkers described the effective conversion of rapeseed FAME into biofuel via a catalytic process taking advantage of three specific catalysts: CAAC-Ru-1 (for ethenolysis), [Pd(I)(µ-Br)( t Bu3P)]2 Pd-2 (for isomerization) and state of the art SIPr-M73 ruthenium catalyst K 112 (for cross-and self-metathesis) (Scheme 61). 113 Used in a 1:4:1 ratio, these three mutually compatible catalysts performed the large scale transformation of rapeseed FAME to produce a mixture of C12-C14 linear internal olefins (monoesters, diesters and hydrocarbons), thus affording an end-product with boiling specifications expected for biodiesel fuels. Advantageously, this eco-friendly and practical process produces no wastes, involves soft conditions (60 °C), and requires no solvent. Note that the use of the highly active ethenolysis catalyst CAAC-Ru-1 was shown to be critical in promoting high ethylene incorporation into the product mixture.

Scheme 61 One-pot, three-catalysts transformation of rapeseed FAME into biofuel

Other substrates

Aside from the transformation of bio-sourced unsaturated fatty esters, the ethenolysis reaction remains widely underexplored. In 2020, Fedorov, Togni and coworkers examined the catalytic activity of a number of ruthenium catalysts in the ethenolysis of inexpensive maleate esters, Revised manuscript 48 competitive alternatives to industrially relevant acrylates. 114,115 In contrast with the promising productivity (up to 5,200 TON) and good selectivity (up to 99%) obtained with Hoveyda-Grubbs catalyst C SIMes in ethenolysis of dimethyl maleate 45, CAAC complexes Ru-2,5 proved to be much less efficient (Scheme 62). Although not discussed by the authors, this unexpected inefficiency, which severely contrasts with high TONs exhibited with fatty esters, could be the result of the rapid deactivation of the transient CAAC-Ru=CHCO2Me. 116

Scheme 62 Carbene-Ru complexes in the ethenolysis of acrylates

Recently, Grela and coworkers reported the ethenolysis of β-caryophyllene E, a bicyclic sesquiterpene, ubiquitous in various essential oils, that is largely used as an additive in food industry and as a fragrance ingredient (Scheme 63). 117 CAAC-Ru-9 showed promising catalytic performance, leading to the expected triene 46 with a TON of 404 (ca. 20% conversion at 0.05 mol%). Note that a lower 4% conversion (TON of 81) was observed with standard Hoveyda C SIMes , while higher TONs (up to 2,876) were reached with a newly designed Ru-catalyst L, containing an unsymmetrical phenanthrene-based NHC. The two-directional desymmetrisation of chains is a popular strategy for the synthesis of complex molecules. Using ring-opening metathesis polymerisation (ROMP) or asymmetric ring-opening cross metathesis (AROCM), cyclic alkenes have been exploited as potential chain precursors. Interestingly, there are much fewer examples involving ring-opening metathesis and double cross metathesis (ROCM). Capitalizing on this approach, Lee and coworkers described a large scale two-directional desymmetrisation of cyclooctene using Soybean oil (Scheme 64). 118 Comparing the catalytic activities of CAAC Ru-63' to the NHC catalyst C SIMes , these authors demonstrated that NHCs perform much more efficiently. However, given the lack of more comprehensive studies, it seems premature to draw some conclusion.

Revised manuscript 49

Scheme 64 Tandem ring-openning cross metathesis with CAAC-Ru Piers type catalyst

Revised manuscript 50

Owing to their unique and highly modular steric environment, chiral NHCs have attracted considerable interests for the development of AROCM transformations. 119,120 Having developed an efficient access to optically pure CAAC ruthenium metathesis catalysts, we evaluated their activity in AROCM. [START_REF] Morvan | Optically Pure C1-Symmetric Cyclic(alkyl)(amino)carbene (CAAC) Ruthenium-Complexes for Asymmetric Olefin Metathesis[END_REF] So far, chiral CAACs catalysts are less reactive and E/Z selective than Hoveyda-Grubbs type chiral catalysts, such as the one developed by Blechert and coworkers C Blechert (Scheme 65). 121 However, they have been shown to trigger asymmetric induction in AROCM up to 92% ee. While the specifics of the chiral induction phenomenon in these C1-symmetric chiral CAAC ligands are still unclear, DFT studies indicate that it likely originates from steric clashing between substituents at the quaternary position to the carbene center and the incoming substrate. Taking advantage of the CAAC framework, the remarkable asymmetric induction is clearly illustrated upon comparing the enantio-and E/Z selectivity obtained with the cyclohexyl derived Ru-73, in comparison to the phenyl derived Ru-69 (Entry e). These catalysts were also evaluated in the challenging AROCM of cyclopropenes for which moderate yields but good Z-selectivity were observed (Scheme 66). It can be expected that further modifications of the CAAC motif will permit more competitive asymmetric inductions. polycondensation. 122,123,124,125,126 The former, which converts cyclic olefins into linear highly unsaturated polymers via chain polymerization, provides a wide range of unique architectures.

Revised manuscript 51

Revised manuscript 52

The latter, involving a step-growth polymerization mechanism is advantageous for the synthesis of polymeric materials containing in-chain functionalities.

Ring Opening Metathesis Polymerization (ROMP)

There are surprisingly very few examples of CAAC metathesis ruthenium complexes applied to ring opening metathesis polymerization. Using bis(CAAC)Ru indenylidene Ru-43, Skowerski and coworkers investigated the formation of polynorbornene (PNB), an elastomer used in the production of a wide variety of rubber goods which is also known as a super absorbent oil binding polymer (up to 30 times its own weight). [START_REF] Gawin | Cyclic Alkyl Amino Carbene) Ruthenium Complexes: AVersatile, Highly Efficient Tool for Olefin Metathesis[END_REF] Under mild conditions and using 1000 ppm of catalyst, up to 87% yield of PNB was obtained (Scheme 67). Extending this study to five typical cyclic olefins (52, 56-59) (Scheme 69), Lemcoff and coworkers looked at the reactivity of sulfur-chelated ruthenium benzylidenes Ru-34,35. [START_REF] Rozenberg | Synthesis and Catalytic Properties of Sulfur-Chelated Ruthenium Benzylidenes Bearing a Cyclic (Alkyl)(amino)carbene Ligand[END_REF] Apart from the most reactive ROMP monomer, norbornene 52, both catalysts showed latency at 35 °C. As expected, performing the reaction at higher temperature (75 °C) resulted in full polymerization of 52, meanwhile other monomers remained poorly reactive. Similar results were obtained with sulfur-chelated cis-ruthenium benzylidenes Ru-58 cis and Ru-59 cis under thermal conditions. However, taking advantage of the photoactivity of these complexes, the authors could trigger significant catalytic activity under irradiation at 350 nm, as illustrated with Ru-58 cis and cyclooctene. Screening additional wavelengths with Ru-58 cis (254 and 419 nm), it was found that visible light at 419 nm resulted in excellent reactivity. The activation of Ru-58 cis with UV-A and visible light arguably marks a new method for the activation of CAAC containing olefin metathesis catalysts. The polymerization of dicyclopentadiene 57, a diene of significant industrial importance was also considered, and complete polymerization was observed with Ru-58 cis upon irradiation at 419 nm or by heating to 80°C.

Revised manuscript 54

. Acyclic Diene Metathesis (ADMET) Polycondensation

The propensity of CAAC ruthenium catalysts to promote the polymerization of dienes has also been used as a mean to improve the acyclic diene metathesis (ADMET) polymerization of Jojoba oil 65. Traditionally this process requires rather high temperatures (i.e. 200 °C) to separate the polyester polymer 66 from the octadec-9-ene (4a) biofuel side product. However, under these demanding conditions traditional NHC ruthenium catalysts are prone to decompose and thus promote undesirable isomerizations. 129 This is well illustrated with Hoveyda-Grubbs C SIMes which only provides up to 28% of 4a (Scheme 71). In marked contrast, under the same conditions, CAAC catalysts Ru-1,5,9 and Ru-36 were shown to suppress the isomerization reaching up to 86% of hydrocarbon 4a. [START_REF] Butilkov | Highly Selective Olefin Metathesis with CAAC-Containing Ruthenium Benzylidenes[END_REF] Revised manuscript 56

Scheme 71 Highly selective ADMET of Jojoba oil catalyzed by CAAC Ru-complexes

The advantage of using CAAC catalysts in the ADMET was also evidenced with 1,5-hexadiene 65, a precursor to polybutadiene 66. As shown in Scheme 72, a more pronounced isomerization can be seen in the C SIMes derived polymer, whereas much fewer defects are observed with Ru-5. [START_REF] Butilkov | Highly Selective Olefin Metathesis with CAAC-Containing Ruthenium Benzylidenes[END_REF] The authors proposed that CAACs afford more stable ruthenium complexes less prone to form the ruthenium-hydride-π-allyl intermediates necessary to promote the double migration.

Revised manuscript 57

Capitalizing on these results Wagener and coworkers extended the study to the bulk polymerization of 1-9 decadiene 67 and bis(pent-4-en-1-yl)sulfone 69 (Scheme 73). [START_REF] Bell | Bulk Acyclic Diene Metathesis Polycondensation[END_REF] While excellent polycondensation results were obtained in both cases, the authors demonstrated the stability of CAAC ruthenium catalyst Ru-3 up to 175 °C, with a slight loss of reactivity at 200 °C. While this later result is presumably due to slow catalyst degradation, it clearly shows that CAAC complexes can retain their activities despite the very high working temperatures necessary to maintain liquid state in high crystallinity polymers.

Scheme 73 Ru-3 catalyzed Bulk Acyclic Diene Metathesis Polycondensation

More recently, Tuba and coworkers have shown that ADMET polymerization of heptadiene-4-ol 71 could be achieved under protic conditions using the very polar CAAC ruthenium Hoveyda-Grubbs Ru-23 and the bis(CAAC)Ru indenylidene Ru-45 (Scheme 74). [START_REF] Nagyházi | Towards Sustainable Catalysis -Highly Efficient Olefin Metathesis in Protic Media Using Phase Labelled Cyclic Alkyl Amino Carbene (CAAC) Ruthenium Catalysts[END_REF] Note that polymer 55 was obtained selectively by ROMP of cyclopent-3-en-1-ol 54 (Scheme 68).

Revised manuscript 58

Scheme 74 ADMET of heptadiene-4-ol 71 using polar ammonium tagged CAAC-based catalysts.

Application to En-Yne Metathesis

The en-yne metathesis is a fundamental chemical transformation involving an alkene and an alkyne to generate a diene. 130,131 Skowerski and coworkers were the first to show that the reactivity of CAACs ruthenium catalysts extends to the intramolecular Ring-Closing En-Yne Metathesis (RCEYM 132 ). [START_REF] Gawin | Cyclic Alkyl Amino Carbene) Ruthenium Complexes: AVersatile, Highly Efficient Tool for Olefin Metathesis[END_REF] In the presence of 250 ppm of the bis(CAAC)Ru indenylidene complex Ru-43, up to 3160 TONs of 1,3-diene 73 were obtained starting from en-yne 72 (Scheme 75). Contrasting with other catalysts, such as Cazin's ruthenium phosphite indenylidene L (907 TON) 133 or benzylidene-oxazinone catalysts M (1,266 TON), 134 these results prompt further investigations on the use of (CAAC)Ru catalysts in en-yne metathesis.

Scheme 75 Comparing the activities of carbene-Ru catalysts in Ring-Closing En-Yne Metathesis

Revised manuscript 59

Activity in Degenerate (Nonproductive) Metathesis

As mentioned previously, CAAC-Ru-complexes have largely outperformed their diamino-NHC counterparts in ethenolysis by remaining highly active at extremely low catalyst loadings (as low as 1 ppm), thus affording the highest TONs reported so far. To explain these remarkable catalytic performance, Grubbs and coworkers compared several catalysts in non-productive (i.e. degenerative) metathesis events occurring during RCM. 135 Investigating the RCM of deuterated diethyl diallyl malonate 25-d2 (Scheme 76-A), they showed that Ru-9 and Hoveyda-type NHC ruthenium complexes C SIPrMe and C SIPrEt displayed almost equal amounts of degenerative vs productive metathesis events (1:1), whereas bulkier C SIMes or C SITol complexes gave a 1:10 ratio (not shown). These contrasting behaviors were also confirmed during the RCM of deuterated dimethyl allylmethallyl malonate 27-d8 (Scheme 76-B), in which a higher amount of non-productive cross metathesis was observed with Ru-9, C SIPrMe and C SIPrEt . To explain these results, the authors proposed that steric interactions in catalysts

Revised manuscript 60

Scheme 76 Nonproductive events in RCM using CAAC catalysts Later, the same authors reported the clean formation of CAAC-based ruthenacyclobutanes Ru-67,68 resulting from the reaction of Piers catalysts Ru-65,66 with an excess of ethylene (Scheme 77). [START_REF] Keitz | Probing the Origin of Degenerate Metathesis Selectivity via Characterization and Dynamics of Ruthenacyclobutanes Containing Variable NHCs[END_REF] Unexpectedly, relatively low exchange rate of α and β methylene protons in ethylene ruthenacycles was found for Ru-67,68 compared to their NHC variant O. Moreover, substituting DEP at nitrogen with DIPP resulted in a remarkable 2.6-fold increase in the exchange rate, suggesting that subtle changes in ligand architecture is sufficient to alter the reactivity and the selectivity of CAAC catalysts. As pointed by the authors, the relatively low exchange rate observed with Ru-67 suggests that CAAC derived metathesis-relevant Revised manuscript 61 ruthenacycles may be viable targets for crystallographic characterization. Additionally, the reaction of Piers catalysts Ru-65,66 with cyclopentene 26 in the presence of one equivalent of ethylene did not lead to the expected substituted ruthenacycle Ru-79,80 (as observed with NHC congeners), [START_REF] Keitz | Probing the Origin of Degenerate Metathesis Selectivity via Characterization and Dynamics of Ruthenacyclobutanes Containing Variable NHCs[END_REF] but to the ethylene ruthenacycles Ru-67,68. The authors noted that this peculiarity, although surprising, could be related to the preferential ability of CAAC-catalysts to propagate as methylidene species in metathesis reactions.

Conclusions and Future Directions

Since stable N-heterocyclic carbenes were discovered in 1991, whereas CAACs were only isolated in 2005, it is not surprising that NHCs are dominant ligands in many transition metal catalyzed reactions. However, the advent of CAACs in olefin metathesis has resulted in numerous achievements and breakthroughs, including in industry, as illustrated by the number of patents. Compared to NHCs, they reveal enhanced metathesis performances in several reactions, in particular in ethenolysis processes (up to of 390,000 TON). In a recent study, Fogg and Nascimoto noted that such a breakthrough can likely be attributed to the remarkable stability of CAAC-ruthenacycles toward β-elimination, and CAAC-ruthenium-methylidenes toward bimolecular decomposition at extremely low catalyst loading. 136 As illustrated by the diversity of complexes obtained so far (>70), with some of them already prepared industrially, Revised manuscript 62 the high structural modularity of the CAAC framework is particularly attractive for olefin metathesis applications. Undoubtedly, we expect the number CAAC-ruthenium catalysts and their ensuing applications to increase significantly with other motifs such as the 6-membered CAAC-6s 28 , the bicylic BiCAACs 27 , the multifunctional FunCAACs [START_REF] Pichon | The Debut of Chiral Cyclic (Alkyl)(amino)carbenes (CAACs) in Enantioselective Catalysis[END_REF]137 , and their chiral variant ChiCAACs [START_REF] Pichon | The Debut of Chiral Cyclic (Alkyl)(amino)carbenes (CAACs) in Enantioselective Catalysis[END_REF][START_REF] Morvan | Optically Pure C1-Symmetric Cyclic(alkyl)(amino)carbene (CAAC) Ruthenium-Complexes for Asymmetric Olefin Metathesis[END_REF] , which have recently been used in asymmetric olefin metathesis.

Thanks to the stability of CAAC ruthenium complexes, we are confident that they will prove invaluable for the solid-state characterization of metathesis-relevant ruthenacycles (achiral and chiral). [START_REF] Keitz | Probing the Origin of Degenerate Metathesis Selectivity via Characterization and Dynamics of Ruthenacyclobutanes Containing Variable NHCs[END_REF] For the same reason, it can be expected that their enantioselective version might shine as air-stable Z-selective 138,139 and stereoretentive 140 catalysts. Finally, much remain to be done in their development as new thermo-and photo-switchable latent catalysts for a highlycontrolled polymerization, 141142 a growing area of research interest. Paul, U. S. D.; Radius, U. What Wanzlick did not dare to dream: Cyclic (alkyl)(amino)carbenes (CAACs) as new key players in transition metal chemistry. Eur. J. Inorg. Chem. 2017, 3362 -3375.

Scheme 1

 1 Scheme 1 The debut of N-heterocyclic carbenes in ruthenium olefin metathesis

Scheme 7

 7 Scheme 7 Preparation of sulfur-chelated ruthenium benzylidene complexes

Scheme 9

 9 Scheme 9 Preparation of bis(CAAC)Ru complexes bearing polar amino substituents

Scheme 11

 11 Scheme 11 Accessing nitro-Grela type complexes from bis(CAAC)Ru indenylidenes

Scheme 17

 17 Scheme 17 Preparation of optically pure (CAAC)Ruthenium complexes

  Scheme 27 CAAC ruthenium catalysts remain very efficient in Cross metathesis in the presence of nitriles

Scheme 30

 30 Scheme 30 Activity of Bis(CAAC)Ru-indenylidene Ru-43 in the Cross metathesis with methyl acrylate and acrylonitrile

Scheme 33

 33 Scheme 33 Activity of Hoveyda-Grubbs CAAC catalysts in Ring Closing-Metathesis of diallyl malonate

Scheme 40

 40 Scheme 40 Bis(CAAC)Ru-indenylidene Ru-43, a powerful catalyst for RCM of azo-dienes

Scheme 49

 49 Scheme 49 Low pressure ethenolysis of methyl oleate 5 in continuous flow using Ru-9

Scheme 63 3 . 4 .

 6334 Scheme 63 Comparing the activities of Carbene-Ru complexes in the ethenolysis of β-caryophyllene E

Scheme 65 First 3 . 5 .

 6535 Scheme 65 First example of CAAC ruthenium catalysts in asymmetric ring-opening cross metathesis of norbornenes

Scheme 67

 67 Scheme 67 Activity of Bis(CAAC)Ru-indenylidene in Ring-Opening Metathesis Polymerization ofNorbornene.

Scheme 69

 69 Scheme 69 Polymerization scope for sulfur-chelated CAAC Ru-benzylidenes

Scheme 72 ADMET

 72 Scheme 72 ADMET of 1,5-hexadiene illustrating the selectivity of Ru-5 versus C SIMes .

  bearing unsymmetrical carbene ligands (i.e. Ru-9, C SIPrMe , C SIPrEt ) could favor the formation of the less sterically hindered β-substituted metallacycle (Path b) over the more productive αsubstituted metallacycle (Path a) (Scheme 76-C).

Scheme 77

 77 Scheme 77 Probing the origin of degenerate metathesis for CAAC-based Ru complexes via the generation of ethylene ruthenacycles

ACKNOWLEGMENT

This work was supported by the Region Bretagne [ARED 2018 "Biometa" N° 601, grant 275 (J.M.)], the Agence Nationale de la Recherche [ANR-19-276 CE07-0017 ChiCAAC (R.J. and M.M.)], and the U.S. Department of Energy, Office of Science, Basic Energy 278 Sciences, Catalysis Science Program, under Award DE-279 SC0009376 (G.B.).

Revised manuscript 63

AUTHOR INFORMATION

Corresponding Authors

*Marc Mauduit: marc.mauduit@ensc-rennes.fr; *Rodolphe Jazzar: rjazzar@ucsd.edu; *Guy Bertrand: gbertrand@ucsd.edu