Decomposition of Ruthenium Olefin Metathesis Catalyst

Home , Agostic interaction, Buchner ring expansion, Catalytic cycle, Cycloheptatriene, Dehydrohalogenation, Grubbs catalyst

catalysts

Review Decomposition of Ruthenium OleﬁnOlefin Metathesis CatalystMetathesis Catalyst

Magdalena Jawiczuk 1,, Anna Anna Marczyk Marczyk 1,21,2 andand Bartosz Bartosz Trzaskowski Trzaskowski 1,* 1,* 1 1 CentreCentre of of New New Technologies, Technologies, University University of of Warsaw, Warsaw, Banacha Banacha 2c, 2c, 02-097 02-097 Warsaw, Warsaw, Poland; [email protected]@cent.uw.edu.pl (M.J.); (M.J.); [email protected] [email protected] (A.M.) (A.M.) 2 Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland 2 Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland * Correspondence: [email protected] * Correspondence: [email protected] Received: 28 28 June 2020; Accepted: 02 2 AugustAugust 2020;2020; Published:Published: 5date August 2020

Abstract: RutheniumRuthenium olefin olefin metathesis metathesis catalysts catalysts are are one one of of the most commonly used class of catalysts. There There are are multiple multiple reviews reviews on on their their us useses in in various branches of chemistry and other sciences but a detailed review of their decomposition is missing, despite a large number of recent and important advances advances in in this this field. field. In In particular, particular, in in the the last last five five years years several several new new mechanism mechanism of decomposition,of decomposition, both both olefin-driven olefin-driven as well as well as induc as induceded by external by external agents, agents, have have been been suggested suggested and usedand usedto explain to explain differences differences in the decomposition in the decomposition rates and rates the metathesis and the metathesis activities activitiesof both standard, of both N-heterocyclicstandard, N-heterocyclic carbene-based carbene-based systems and systems the recently and the developed recently developed cyclic alkyl cyclic amino alkyl carbene- amino containingcarbene-containing complexes. complexes. Here we Here present we present a revi aew review which which explores explores the thelast last 30 30years years of of the decomposition studied on ruthenium olefin olefin metathesis catalyst driven by both intrinsic features of such catalysts as well as external chemicals.

Keywords: decomposition;decomposition; ruthenium; olefin oleﬁn metathesis; catalysis

1. Introduction Introduction While the importance of ruthenium for olefin olefin me metathesis,tathesis, one of the most prominent methods to form new C–C bonds, was realized already in the 196 1960s0s [1,2], [1,2], the true dawn of the ruthenium-driven metathesis olefin olefin catalysis catalysis came came in in 1992 1992 with with the the synthesis synthesis of the of first the firstwell-defined well-defined complex complex [3]. This [3]. Thisbreakthrough breakthrough complex, complex, synthesized synthesized in the inGrubbs the Grubbs group, group, had many had manyof the ofstructural the structural features features found infound modern, in modern, highly highly efficient effi andcient specialized and specialized metathesis metathesis catalysts. catalysts. WhatWhat followed followed were werethe 1st the (GI 1st),( 2ndGI), (2ndGII ()GII and) and3rd 3rd(GIII (GIII) generation) generation catalysts catalysts [4–8] [4– 8and] and Hoveyda-Grubbs Hoveyda-Grubbs catalyst catalyst (HG (HG) )[[9]9] which which gave gave rise toto hundredshundreds of of precatalysts precatalysts with with very very distinct dist structuralinct structural features features but always but always based on based the essential, on the 16-electronessential, 16-electron skeleton with skeleton the Ru with atom the at Ru its atom core [at10 its–14 core] (Figure [10–14]1). Nowadays,(Figure 1). Nowadays, ruthenium metathesisruthenium metathesiscatalysts are catalysts used in are all used branches in all branches of chemistry, of chemistry, ranging fromranging pharmaceutical from pharmaceutical sciences sciences [15–19] [15– and 19]synthesis and synthesis of macrocyclic of macrocyclic musks [ 20musks,21] to [20,21] the petrochemical to the petrochemical industry industry [22–24]. [22–24].

N N N N N N N N PCy3 Cl Cl Cl Cl Cl Ru Ru Ru N Ru Ru Cl Cl Ph Cl Ph Cl Ph Cl Ind O PCy3 PCy3 N PCy3

GI GII GIII IndII HGII Figure 1. Common ruthenium metathesis catalysts.

Soon after after the the discovery discovery of of first ﬁrst ruthenium ruthenium metath metathesisesis catalysts catalysts it was it was realized realized that that they they do not do easilynot easily undergo undergo decomposition, decomposition, though though there there are are va variousrious external external agents agents that that can can degrade degrade these

Catalysts 2020, 10, x; doi: FOR PEER REVIEW www.mdpi.com/journal/catalysts Catalysts 2020, 10, 887; doi:10.3390/catal10080887 www.mdpi.com/journal/catalysts Catalysts 2020, 10, 887 2 of 56 Catalysts 2020, 10, x FOR PEER REVIEW 2 of 60 catalysts asas wellwell asas several several chemical chemical groups groups that that are are not not compatible compatible with with them. them. These These studies studies were were very veryvaluable, valuable, since since by proposing by proposing the probable the probable decomposition decomposition mechanisms mechanisms they inspiredthey inspired and guided and guided other othergroups groups in the in synthesis the synthesis of new, of new, modified modified catalysts catalysts with with improved improved stabilities stabilities and and less less vulnerable vulnerable to todegradation. degradation. As As a result a result of theseof these over over 30-year 30-year long long investigations, investigations, we we have have today today vastly vastly improved improved our ourunderstanding understanding of how of structuralhow structural features features of ruthenium of ruthenium complexes complexes affect their affect stabilities their andstabilities reactivities and reactivitiesas well as what as well are theas majorwhat decompositionare the major decomp routes ofosition metathesis routes catalysts. of metathesis A good catalysts. understanding A good of understandingthe entire catalytic of the cycle entire of metathesis, catalytic cycle first of proposed metathesis, by Chauvinfirst proposed and presented by Chauvin in Figure and presented2, was also in Figurevital for 2, these was also findings vital [for25]. these findings [25].

Figure 2. SchematicSchematic representation representation of the metathesis catalytic cycle; ( a) initiation, ( b,c) propagation.

The review is organizedorganized inin thethe followingfollowing manner.manner. First, we discuss the available scientificscientific literature on on the the decomposition decomposition routes routes of of ruthenium ruthenium metathesis metathesis catalysts catalysts which which are are common common for forall catalyst,all catalyst, such such as Ru as = Ru C =doubleC double bond bond and anddo not do depend not depend on the on specific the specific structural structural features features of such of catalysts,such catalysts, such as such different as diff erentauxiliary auxiliary ligands ligands These These include include the olefin-driven the olefin-driven decomposition decomposition as well as wellas decomposition as decomposition initiated initiated by various by various external external agents agents and and solvents, solvents, divided divided by by their their chemical properties. Next Next we we focus focus on on two two main main classes classes of of metathesis metathesis catalysts—phosphine-containing catalysts—phosphine-containing and and n- heterocyclicn-heterocyclic carbene carbene (NHC)-containing (NHC)-containing ones ones and and review review most most known known decomposition decomposition routes routes which are either phosphine-driven or NHC-driven. Finally we provide a summary and a future outlook for the decomposition studies of this important family ofof widelywidely usedused catalysts.catalysts. The most recentrecent reviewreview onon ruthenium ruthenium metathesis metathesis catalysts’ catalysts’ decomposition decomposition was was reported reported in 2014in 2014 by byNolan Nolan group group and and dealt dealt mostly mostly with with C–H C–H activation, activation, shortly shortly mentioning mentioning several several other other mechanisms mechanisms of ofdegradation degradation [26 ].[26]. Since Since then then a large a large number number of new of ruthenium new ruthenium metathesis metathesis catalysts catalysts has been has designed been designedand there and have there been have a plethora been ofa plethora works presenting of works newpresenting results new on their results decomposition, on their decomposition, therefore we thereforebelieve that we a believe new review that a on new this review topic ison timely this topic and is relevant. timely and relevant.

2. Non-Specific Non-Specific Decomposition Routes In this section we describe the current state of knowledgeknowledge for thethe non-specificnon-specific decompositiondecomposition routes of ruthenium metathesis catalysts. These These include all the decomposition pathways which are driven byby externalexternal agents agents and and do do not not depend depend on theon specificthe specific features features of certain of certain catalysts catalysts but are possiblebut are possiblefor all catalysts for all catalysts due to structural due to stru featuresctural andfeatures metathesis and metathesis mechanisms mechanisms shared by shared all of them.by all of them.

Catalysts 2020, 10, x FOR PEER REVIEW 3 of 60 Catalysts 2020, 10, 887 3 of 56

2.1. Olefin-Driven Self-Degradations 2.1. Olefin-Driven Self-Degradations Historically the decomposition studies of Grubbs-type complexes have been initiated by Grubbs and co-workers,Historically thewho decomposition investigated the studies phosphine-dr of Grubbs-typeiven decomposition complexes have of been 1st and initiated 2nd generation by Grubbs andGrubbs co-workers, complexes; who this investigated is described the later phosphine-driven in this review. Soon decomposition after their studies of 1st andvan 2ndRensburg generation et al. Grubbsshowed, complexes; however, that this for is describedthese catalysts later a in substrat this review.e-induced Soon pathway after their is also studies viable.van In Rensburg their seminal et al. showed,work authors however, of this that study for these performed catalysts density a substrate-induced functional (DFT) pathway calculations is also viable. on the In their1st and seminal 2nd workgeneration authors Grubbs of this complexes study performed and showed density that functionalin both cases (DFT) the calculationsGibbs free energy on the barriers 1st and of 2nd β- generationhydride transfer Grubbs from complexes metallacyclobutane and showed thatare relatively in both cases low the (16.9 Gibbs kcal/mol free energy for 1st barriers generation of β-hydride Grubbs transfercatalyst fromand 24.3 metallacyclobutane kcal/mol for 2nd are generation relatively one) low (16.9[27] (Scheme kcal/mol 1). for To 1st confirm generation these Grubbs findings catalyst they andalso 24.3performed kcal/mol ruthenium for 2nd generationmethylidene-catalyzed one) [27] (Scheme metathesis1). To of confirm ethylene these which findings yielded, they among also performedother olefins, ruthenium 1-propene methylidene-catalyzed and different isomers metathesis of butane, of which ethylene is whichpossible yielded, only via among β-hydride other olefins,transfer. 1-propene It is worth and mentioning different here, isomers that of a butane,different which mechanism is possible for olelfin only viaisomerizationβ-hydride (but transfer. not Itcatalyst is worth decomposition) mentioning here,was proposed that a diff 2erent years mechanism earlier by Nolan for olelfin and Prunet isomerization [28]. Van (but Rensburg not catalyst et al. decomposition)also found that 38% was proposedof the starting 2 years 2nd earlier generation by Nolan methylidene and Prunet has [28 decomposed]. Van Rensburg after et 16 al. h also exposure found thatto excess 38% ofethylene the starting in 40 2nd°C. This generation work marked methylidene the first has study decomposed where the after evidence 16 h exposure of olefin-driven to excess ethylenedecomposition in 40 ◦ C.of Thisruthenium work marked metathesis the firstcatalyst study has where been the given, evidence together of olefin-driven with a feasible decomposition mechanistic ofexplanation. ruthenium It metathesis was followed catalyst in 2006 has by been a DFT given, study together from the with same a feasible group where mechanistic the decomposition explanation. Itpathways was followed of first-generation in 2006 by a DFTand second-generation study from the same Grubbs group catalyst where theas well decomposition as two isomeric pathways Phobcat of first-generationcatalysts were studied and second-generation [29]. In this work Grubbs the entire catalyst decomposition as well as two pathway isomeric with Phobcat ethylene, catalysts starting were studiedfrom precatalysts [29]. In this and work ending the entire at the decomposition propene-asso pathwayciated catalyst, with ethylene, was explored. starting The from results precatalysts were andsimilar ending to the at the previous propene-associated study, as the catalyst, transition was explored. state leading The results to the were β-hydride similar totransfer the previous from study,metallacyclobutane as the transition was state in each leading case the to the rate-limitingβ-hydride step transfer of the from decomposition, metallacyclobutane with values was ranging in each casefrom the 23.4 rate-limiting to 26.9 kcal/mol. stepof the decomposition, with values ranging from 23.4 to 26.9 kcal/mol.

Scheme 1. The van Rensburg decomposition mechanism for the 1st generation and 2nd generationgeneration

Grubbs catalysts. L2 = PCyPCy33, ,numbers numbers represent represent relative relative Gibbs Gibbs free free energies energies at the density functional (DFT)(DFT) levellevel ofof theorytheory inin kcalkcal/mol./mol.

In the same year an interesting experimental study performed in the continuous flow reactor In the same year an interesting experimental study performed in the continuous flow reactor by by Lysenko et al. showed that ethylene pretreatment of the 1st generation Grubbs catalyst induces Lysenko et al. showed that ethylene pretreatment of the 1st generation Grubbs catalyst induces catalyst’s deactivation [30]. Interestingly, similar pretreatment with cis-2-butene had little effect on catalyst’s deactivation [30]. Interestingly, similar pretreatment with cis-2-butene had little effect on the catalyst activity. Authors of this investigation concluded that the methylidene species generated the catalyst activity. Authors of this investigation concluded that the methylidene species generated from the catalyst and ethylene is unstable and promotes catalyst loss, while ruthenium alkylidene from the catalyst and ethylene is unstable and promotes catalyst loss, while ruthenium alkylidene derived from 2-butene is rather stable and allows to sustain catalyst integrity. This was the first derived from 2-butene is rather stable and allows to sustain catalyst integrity. This was the first indication that various olefins may deactivate/decompose metathesis catalysts with a different rate or indication that various olefins may deactivate/decompose metathesis catalysts with a different rate to a different extent. or to a different extent. In 2007, Nizovtsev et al. perform a similar study to the original work of van Rensburg but using In 2007, Nizovtsev et al. perform a similar study to the original work of van Rensburg but using the Hoveyda-Grubbs catalyst [31]. They showed that in a metathesis reaction with ethylene a mixture the Hoveyda-Grubbs catalyst [31]. They showed that in a metathesis reaction with ethylene a mixture of olefins is obtained. with a preferable formation of propylene. Based on these results they postulated of olefins is obtained. with a preferable formation of propylene. Based on these results they that the decomposition route utilizing the -hydride transfer is preferred, although suggested also postulated that the decomposition route βutilizing the β-hydride transfer is preferred, although other mechanism leading to for example, diruthenium species. suggested also other mechanism leading to for example, diruthenium species. Due toto the the improvements improvements in computational in computationa techniquesl techniques more and more more and complex more and complex sophisticated and studiessophisticated of ruthenium studies of catalysts ruthenium became catalysts possible became in the possible next decade. in the next One decade. of the One most of prominent the most worksprominent dealing works with dealing Ru metathesis with Ru catalysts metathesis decomposition catalysts decomposition from that time from is the that investigation time is the by Ashworthinvestigation etal. bydescribing Ashworth the competitionet al. describing between the the metathesiscompetition and between isomerization the [metathesis32]. In this workand authorsisomerization computationally [32]. In this investigated work authors three computationa different, completelly investigated routes of three propylene different, isomerization complete routes using

Catalysts 2020, 10, 887x FOR PEER REVIEW 4 of 60 56 of propylene isomerization using the van Rensburg mechanism, Nolan-Prunet mechanism and finallythe van a Rensburgdirect hydride mechanism, transfer Nolan-Prunet from a ruthenium mechanism hydride and species. finally (Scheme a direct 2). hydride They found transfer very from high a energyruthenium barriers hydride of hydrogen species. (Scheme transfer2). to They methylidene found very for high the energyNolan-Prunet barriers ofmechanism hydrogen (over transfer 28 kcal/molto methylidene with respect for the to Nolan-Prunet methylidene), mechanism which were (over much 28 higher kcal/mol than with those respect for the to van methylidene), Rensburg whichmechanism. were They much concluded higher than that those the methylidene for the van Rensburgroute using mechanism. the van Rensburg They concluded mechanism that is the mostmethylidene favorable route from using the theenergy van Rensburgpoint of view mechanism and once is the again most reaffirmed favorable that from metallacyclobutane the energy point of viewdecomposition and once is again the rate-limiting reaffirmed that step metallacyclobutane of this decomposition decomposition path. They also is the showed rate-limiting that for stepolefins of (suchthis decomposition as allylbenzene) path. the They barrier also of showed the van that Rens forburg olefins transition (such as state allylbenzene) is much higher the barrier (around of the 8 vankcal/mol Rensburg higher transition than for state ethylene). is much This higher finding (around was 8 kcal later/mol confirmed higher than by forTrzaskowski ethylene). Thiset al., finding who wasstudied later the confirmed impact of by structural Trzaskowski changes et al., in who the olefin, studied as the well impact as in the of structural carbene part changes of the in catalyst the olefin, on theas well energetics as in the ofcarbene van Rensbu partrg’s of the decomposition catalyst on the [33,34]. energetics of van Rensburg’s decomposition [33,34].

Scheme 2. TheThe Nolan-Prunet Nolan-Prunet mechanism mechanism of of propylene propylene isomer isomerizationization with relative Gibbs free energies based on DFT results (in kcalkcal/mol)./mol).

The most most thorough thorough computational computational analysis analysis of many of possible many possible decomposition decomposition routes of Hoveyda- routes of GrubbsHoveyda-Grubbs complexes complexes has been haspresented been presented in 2017 in in the 2017 work in the from work Jensen from Jensenlaboratory laboratory [35]. In [ 35this]. Instudy this DFTstudy approach DFT approach has been has beenused used to explore to explore all allpossi possibleble events events during during metathesis metathesis catalytic catalytic cycle, cycle, including deactivation, decomposition, decomposition, regeneration regeneration,, isomerization isomerization and and the the proper proper catalysis catalysis itself. itself. From the decomposition point of view this investigation is particularly valuable, since it deals with almost all theoretically plausible degradation pathways, including those those very unlikely (due to very high energy barriers) and therefore rarely/never rarely/never studied.studied. These included, for example, example, the the previously previously mentioned Nolan-PrunetNolan-Prunet mechanism, mechanism, the the C–H C–H activation activation of precatalyst of precatalyst and methylidene, and methylidene, the formation the formationof diruthenium of diruthenium species and aspecies few other and mechanisms. a few other Nevertheless,mechanisms. itNevertheless, was shown again it was that shown for ethylene again thatthe lowest for ethylene Gibbs freethe energylowest barrierGibbs free of decomposition energy barrier is of associated decomposition with the is van associated Rensburg with mechanism. the van Additionally,Rensburg mechanism. it was also Additionally, demonstrated it thatwas the also analogous demonstrated barrier ofthat decomposition the analogous with barrier a larger of decompositionolefin, allylbenzene, with a is larger 7.7 kcal olefin,/mol allylbenzene, higher with respectis 7.7 kcal/mol to the precatalyst. higher with (Schemerespect to3) the Finally, precatalyst. a new (Schememechanism 3) Finally, of decomposition a new mechanism was proposed of decompositio for olefins composedn was proposed of at least for olefins three carbon composed atoms, of namelyat least 1-alkene-triggeredthree carbon atoms, decomposition, namely 1-alkene-triggered which proceeds decomposition, via a trigonal bipyramidal which proceeds metallacyclopentane via a trigonal bipyramidalintermediate metallacyclopentane (Scheme3). The energy intermediate barrier for (Scheme the rate-limiting 3). The energy step of barrier this path for was the estimatedrate-limiting at step29.5 kcalof this/mol path with was allylbenzene, estimated at around 29.5 kcal/mol 3 kcal/mol with lower allylbenzene, than for the around van Rensburg 3 kcal/mol route, lower rendering than for thethis van mechanism Rensburg likely. route, rendering this mechanism likely. The final, for now, piece of olefin-driven decomposition puzzle was discovered in 2018 when a new mechanism involving bimolecular coupling has been suggested by Fogg and Jensen [36]. The experiments and identification of ruthenium decomposition products of Hoveyda-Grubbs catalyst allowed them first to rule out the Buchner expansion and NHC cyclometallation pathways due to the fact that the NHC remained intact. On the other hand combined kinetic and DFT mechanistic studies allowed them to suggest three different bimolecular complexes bridged either by two Cl, two ethylene or one –CH2– group. The final conclusion of this work was that the CH2–bridged complex is the only likely candidate for the further decomposition, as this transition state had a relatively low Gibbs free energy barrier (Scheme4). These findings were further supported by experimental data from decomposition experiments of Hoveyda-Grubbs and usually more stable cyclic alkyl amino carbene (CAAC) catalysts [37]. As expected, CAAC catalysts were shown to undergo little or no β-hydride elimination via the van Rensburg mechanism, contrary to the Hoveyda-Grubbs catalyst. Surprisingly, CAAC catalysts were found to be more susceptible to bimolecular coupling than the Hoveyda-Grubbs catalyst. The final conclusion of the study was that CAAC catalyst offer a very

Catalysts 2020, 10, x FOR PEER REVIEW 5 of 60

Catalysts 2020, 10, 887 5 of 56 high productivity combined with little decomposition particularly at ppm loadings, since at such low Catalystscatalysts 2020 concentrations, 10, x FOR PEER the REVIEW impact of bimolecular coupling is relatively low. 5 of 60

Scheme 3. (a) The ethylene-driven and allylbenzene-driven decomposition of metathesis catalysts using van Rensburg decomposition pathway and (b) 1-alkene-triggered catalyst decomposition for allylbenzene with DFT-based relative Gibbs free energies (in kcal/mol).

The final, for now, piece of olefin-driven decomposition puzzle was discovered in 2018 when a new mechanism involving bimolecular coupling has been suggested by Fogg and Jensen [36]. The experiments and identification of ruthenium decomposition products of Hoveyda-Grubbs catalyst allowed them first to rule out the Buchner expansion and NHC cyclometallation pathways due to the fact that the NHC remained intact. On the other hand combined kinetic and DFT mechanistic studies allowed them to suggest three different bimolecular complexes bridged either by two Cl, two ethylene or one –CH2– group.Scheme The final 4. The conclusion bimolecular of coupling this work mechanism. was that the CH2–bridged complex is the only likely candidate for the further decomposition, as this transition state had a relatively low Gibbs2.2. Alcohol free energyand Alkoxy-Driven barrier (Scheme Decomposition 4). These findings were further supported by experimental data from decomposition experiments of Hoveyda-Grubbs and usually more stable cyclic alkyl amino Despite the excellent tolerance of various functional groups to ruthenium metathesis catalysts, carbeneconducting (CAAC) such acatalysts transformation [37]. As inexpected, water or CAAC protic catalysts solvents, were such shown as alcohols, to undergo remains little a challenge. or no β- hydrideconducting elimination such a transformation via the van Rensburg in water ormechanism, protic solvents, contrary such to as the alcohols, Hoveyda-Grubbs remains a challenge. catalyst. Alcohols and water can act as either Lewis acids or bases but in the presence of metathesis catalysts Surprisingly,they usually actCAAC as a Lewiscatalysts acids, were abstracting found to abe chloride more susceptible from the catalyst. to bimolecular On the othercoupling hand than simple the Hoveyda-Grubbs catalyst. The final conclusion of the study was that CAAC catalyst offer a very high alkoxides are strong bases and act a Lewis bases, usually attacking directly the ruthenium core bearing productivitythe formal + 2combined charge. Here with we little will decomposition describe research particularly focused on at theppm understanding loadings, since of mechanismsat such low catalystsgoverning concentrations the decomposition the impact of metathesis of bimolecular catalysts. coupling is relatively low. One of the ﬁrst degradation mechanism of 1st generation Grubbs catalysts in the presence of the alcohols was proposed by Dinger and Mol [38]. The research was mainly dictated by the curiosity to explain the formation of ruthenium hydride 1, a potential isomerization catalyst. The authors observed the formation of 1 from GI in primary alcohol/toluene solution at 70–75 ◦C overnight (Scheme5) and noticed that this reaction was accelerated by addition of appropriate bases (such as Et3N, CH3ONa, NaOH, K2CO3). Moreover, based on labeling experiments, they conﬁrmed that the source of hydrogen in the reaction is alcohol dehydrogenation occurring in a non-catalytic manner. Scheme 4. The bimolecular coupling mechanism.

2.2. Alcohol and Alkoxy-Driven Decomposition Despite the excellent tolerance of various functional groups to ruthenium metathesis catalysts, conducting such a transformation in water or protic solvents, such as alcohols, remains a challenge. Alcohols and water can act as either Lewis acids or bases but in the presence of metathesis catalysts

Catalysts 2020, 10, x FOR PEER REVIEW 6 of 60 they usually act as a Lewis acids, abstracting a chloride from the catalyst. On the other hand simple alkoxides are strong bases and act a Lewis bases, usually attacking directly the ruthenium core bearing the formal +2 charge. Here we will describe research focused on the understanding of mechanisms governing the decomposition of metathesis catalysts. One of the first degradation mechanism of 1st generation Grubbs catalysts in the presence of the alcohols was proposed by Dinger and Mol [38]. The research was mainly dictated by the curiosity to explain the formation of ruthenium hydride 1, a potential isomerization catalyst. The authors observed the formation of 1 from GI in primary alcohol/toluene solution at 70–75 °C overnight (Scheme 5) and noticed that this reaction was accelerated by addition of appropriate bases (such as Et3N, CH3ONa, NaOH, K2CO3). Moreover, based on labeling experiments, they confirmed that the CatalystsEt3N, CH20203ONa,, 10, 887 NaOH, K2CO3). Moreover, based on labeling experiments, they confirmed that6 ofthe 56 source of hydrogen in the reaction is alcohol dehydrogenation occurring in a non-catalytic manner.

Scheme 5.5. Catalysts degradation in primary alcohols. L = SIMesSIMes or or SIPr. SIPr.

The postulated mechanism suggests that the hydrochloride isis eliminated asas Et3N*HCl as a result The postulated mechanism suggests that the hydrochloride is eliminated as Et33N*HCl as a result of alcohol dehydrogenation. At At the same time, aldehy aldehyde,de, formed in this stage, reacts with the metal center, whichwhich after after decarbonylation decarbonylation gives gives carbonyl carbonyl and and ruthenium ruthenium hydride hydride species species (Scheme (Scheme6). It needs 6). It needsto be highlighted to be highlighted that when that reacting when reacting with longer with aliphatic longer aliphatic alcohols, besidealcohols,1, toluenebeside 1 was, toluene formed was as formedthe main as by-product. the main by-product. This results This implies results that imp thelies above-mentioned that the above-mentioned mechanism mechanism cannot be cannot directly be directlyextended extended to other alcoholsto other alcohols with longer with aliphatic longer alip chainshatic and chains is valid and only is valid for smallonly for and small simple and alcohols. simple Additionally,alcohols. Additionally, under the under same reactionthe same conditions reaction conditions benzyl alcohol benzyl gave alcohol an unexpected gave an unexpected complex 2, complexinconsistent 2, inconsistent with last step with of thelast proposedstep of the mode proposed of action mode (Scheme of action5). (Scheme 5).

Scheme 6. PostulatedPostulated alcohol-driven degradat degradationion mechanism by Dinger and Mol. nd The same group extended this research to 2 nd generation Grubbs (GII) complexes [39,40]. As in The same group extended this research to 2nd generation Grubbs (GII) complexes [39,40]. As in the case of the GII complex, the formation of the corresponding ruthenium hydride 3 was also observed the case of the GII complex, the formation of the corresponding ruthenium hydride 3 was also but two other hydrides were also found (Scheme5). One of them was unidentified and the other observed but two other hydrides were also found (Scheme 5). One of them was unidentified and the turned out to be complex 1, resulting likely from the exchange of the N-heterocyclic carbene (NHC) other turned out to be complex 1, resulting likely from the exchange of the N-heterocyclic carbene ligand for phosphine [39]. The authors emphasized, however, that the relatively long time needed (NHC) ligand for phosphine [39]. The authors emphasized, however, that the relatively long time to create this complex limited its potential role in competitive reactions. Notwithstanding, when the needed to create this complex limited its potential role in competitive reactions. Notwithstanding, reaction with alcohol, including benzyl alcohol, was subjected to GII_SIPr, only the formation of an when the reaction with alcohol, including benzyl alcohol, was subjected to GII_SIPr, only the analogous product 3 was observed [40]. formation of an analogous product 3 was observed [40]. At around the same time Wolf and co-workers conducted very similar studies but with focus on the reaction of ruthenium GI with allyl alcohols at room temperature [41]. In the presence of the allylic alcohol, the GI catalyst gave first the hydroxymethyl carbene 4, which further decomposed in solution to an inactive carbonyl species 5, propanal and small amounts of ethane and propenal (Scheme7). The mechanism of this transformation (Scheme8) starts with the β-hydrogen transfer from CH2 of alkylidene group to the ruthenium center and the formation of an hydride intermediate which, after reductive elimination, gives a metal π-complex with enol. In the next step, such a complex isomerizes to aldehyde and, via the C-H bond oxidative addition, an (acyl)hydrideruthenium species is formed. In the final step a methyl migration and elimination yields ruthenium carbonyl complex 5. Catalysts 2020, 10, x FOR PEER REVIEW 7 of 60 Catalysts 2020, 10, x FOR PEER REVIEW 7 of 60

At around the same time Wolf and co-workers conducted very similar studies but with focus on the reaction of ruthenium GI with allyl alcohols at room temperature[41]. In the presence of the allylic alcohol, the GI catalyst gave first the hydroxymethyl carbene 4, which further decomposed in solution to an inactive carbonyl species 5, propanal and small amounts of ethane and propenal (Scheme 7). The mechanism of this transformation (Scheme 8) starts with the β-hydrogen transfer from CH2 of alkylidene group to the ruthenium center and the formation of an hydride intermediate from CH2 of alkylidene group to the ruthenium center and the formation of an hydride intermediate which, after reductive elimination, gives a metal π-complex with enol. In the next step, such a complex isomerizes to aldehyde and, via the C-H bond oxidative addition, an (acyl)hydrideruthenium species is formed. In the final step a methyl migration and elimination yields Catalysts(acyl)hydrideruthenium2020, 10, 887 species is formed. In the final step a methyl migration and elimination yields7 of 56 ruthenium carbonyl complex 5.

Scheme 7. Reaction of GI catalyst with the allyl alcohol in solution or in solid state. Scheme 7. Reaction of GI catalyst with the allyl alcohol in solution or in solid state.

SchemeScheme 8. PrimaryPrimary allyl allyl alcohol alcohol driven driven degradation degradation in in solution solution postulated by Werner and Wolf. Scheme 8. Primary allyl alcohol driven degradation in solution postulated by Werner and Wolf. The same ruthenium complex 4 can follow a different deactivation pathway in the solid state The same ruthenium complex 4 can follow a different deactivation pathway in the solid state to to rearrange into carben 6. As a possible explanation for these observations authors suggested a rearrange into carben 6. As a possible explanation for these observations authors suggested a nucleophilic attack of the OH group of CH2OHOH at at the carbene carbon to form a protonated oxirane, nucleophilic attack of- the OH group of CH2OH at the carbene carbon to form a protonated oxirane, where [RuCl[RuCl22(PCy33)2]]- actsacts as as a a substituent substituent of of the the three-memb three-memberedered ring. Next, Next, opening opening of epoxide and where [RuCl2(PCy3)2]- acts as a substituent of the three-membered ring. Next, opening of epoxide and 6 hydrogen transfer to CH2 moiety occurs, which leads to the formation of complex 6 (Scheme8 8).). hydrogen transfer to CH2 moiety occurs, which leads to the formation of complex 6 (Scheme 8). While Mol and co-workers noted that secondary alcohols were ineffective in the reaction with While Mol and co-workers noted that secondary alcohols were ineffective in the reaction with [RuCl2(PCy(PCy33))2],2], Wolf’s Wolf’s Group Group presented presented a afull full reaction reaction pa pathwaythway using using 3-buten-2-ol 3-buten-2-ol as asan anexample example of [RuCl2(PCy3)2], Wolf’s Group presented a full reaction pathway using 3-buten-2-ol as an example of of such reaction (Scheme9). The main di fference, compared to the previously suggested primary such reaction (Scheme 9). The main difference, compared to the previously suggested primary alcohol-driven mechanism, was the inability of acetone to undergo oxidative addition, which allowed alcohol-driven mechanism, was the inability of acetone to undergo oxidative addition, which allowed the formation of a π-complex with a substrate molecule. The following β-hydride transfer to ruthenium the formation of a π-complex with a substrate molecule. The following β-hydride transfer to yields a π-allyl-derivative, which could rearrange to a Ru-enol complex. The only product observed in ruthenium yields a π-allyl-derivative, which could rearrange to a Ru-enol complex. The only product this reaction was butanon, which was formed as a consequence of rapid tautomerization of the starting observed in this reaction was butanon, which was formed as a consequence of rapid tautomerization enol molecule, coinciding with the exchange of acetone. of theCatalysts starting 2020 enol, 10, x FORmolecule, PEER REVIEW coinciding with the exchange of acetone. 8 of 60

SchemeScheme 9. The 9. secondaryThe secondary allyl allyl alcohol-driven alcohol-driven degradation degradatio inn in solution solution postulated postulated by by Werner Werner andand Wolf. Wolf. Detailed experimental studies on the conditions required for the benzylidene ligand abstraction of 1st andDetailed 2nd generation experimental Grubbs studies catalysts on the byconditions reacting required with the for excess the benzylidene of methoxide ligand were abstraction investigated by Foggof 1st and and co-workers 2nd generation [42,43 ].Grubbs They catalysts showed by that reacting at ambient with temperaturesthe excess of rutheniummethoxide were catalysts investigated by Fogg and co-workers [42,43]. They showed that at ambient temperatures ruthenium treated with NaOCH3, used to eliminate nonessential byproducts derived from thermal decomposition, catalysts treated with NaOCH3, used to eliminate nonessential byproducts derived from thermal decomposition, decompose to different hydrogen species depending on the nature of the catalyst [43]. Under these conditions, GI was transformed promptly into two hydride complexes 8 and 9 (Scheme 10), while the second generation GII_IMes gave one stable methoxyhydride species 10, in contrast with previous observations [39,40]. In this case, the relative ease of methanol undergoing β- elimination prevents the formation of carbynes and bisalkoxide complexes, in contrast with analogous reactions with other alkoxides [44–47]. Additionally, phosphine addition delayed the consumption of the GI catalyst, while the rate of the GII_IMes decomposition was not affected by it. This finding was associated with a higher lability of PCy3 moiety in 1st generation catalysts and an easier formation of a four-coordinated intermediate [Ru(Cl2)(=CHPh)L] (path 1, Scheme 11). Subsequent steps of the suggested mechanism begin with the reaction of the metathesis catalyst via exchange of the chloride ligands followed by the transfer of a hydrogen atom from attached methoxy group to the benzylidene. Next, formaldehyde coordination, insertion of CO, abstraction of benzyl moiety as toluene and rebinding of PCy3 occurs, which is in line with previous observations made by Mol et al. [38]. The formation of a four-coordinate compound as a result of phosphine dissociation is highlighted as the crucial decomposition pathway [43]. A plausible mechanism of conversion of complex 7 to a six-coordinated species 8 and 9 is multi-step and starts with the introduction of an additional methoxide ligand as shown also on Scheme 11.

Scheme 10. The reaction of Grubbs-type catalyst with methoxides.

Catalysts 2020, 10, x FOR PEER REVIEW 8 of 60

Scheme 9. The secondary allyl alcohol-driven degradation in solution postulated by Werner and Wolf.

Catalysts 2020Detailed, 10, 887 experimental studies on the conditions required for the benzylidene ligand abstraction8 of 56 of 1st and 2nd generation Grubbs catalysts by reacting with the excess of methoxide were investigated by Fogg and co-workers [42,43]. They showed that at ambient temperatures ruthenium decomposecatalysts to treated different with hydrogen NaOCH3, speciesused to dependingeliminate nonessential on the nature byproducts of the catalystderived [from43]. Underthermal these conditions,decomposition,GI was transformeddecompose to promptlydifferent hydrogen into two spec hydrideies depending complexes on the8 andnature9 (Scheme of the catalyst 10), while[43]. the secondUnder generation these conditions,GII_IMes GI gavewas transformed one stable promptly methoxyhydride into two hydride species complexes10, in contrast 8 and with9 (Scheme previous observations10), while [39 the,40 second]. In this generation case, the GII_IMes relative easegave ofone methanol stable methoxyhydride undergoing β -eliminationspecies 10, in preventscontrast the with previous observations [39,40]. In this case, the relative ease of methanol undergoing β- formation of carbynes and bisalkoxide complexes, in contrast with analogous reactions with other elimination prevents the formation of carbynes and bisalkoxide complexes, in contrast with alkoxidesanalogous [44– 47reactions]. Additionally, with other phosphinealkoxides [44–47]. addition Additionally, delayed the phosphine consumption addition of delayed the GI catalyst,the whileconsumption the rate of the of GII_IMesthe GI catalyst,decomposition while the rate was of the not GII_IMes affected bydecomposition it. This finding was wasnot affected associated by it. with a higherThis lability finding of was PCy associated3 moiety in with 1st a generation higher lability catalysts of PCy and3 moiety an easier in 1st formation generation of catalysts a four-coordinated and an intermediateeasier formation [Ru(Cl2 )(of= CHPh)L]a four-coordinated (path 1, Scheme intermediate 11). Subsequent [Ru(Cl2)(=CHPh)L] steps of the(path suggested 1, Scheme mechanism 11). beginSubsequent with the reaction steps of ofthe the suggested metathesis mechanism catalyst begin via exchange with the reaction of the chloride of the metathesis ligands followedcatalyst via by the transferexchange of a hydrogen of the chloride atom ligands from attachedfollowed by methoxy the transfer group of a tohydrogen the benzylidene. atom from attached Next, formaldehyde methoxy group to the benzylidene. Next, formaldehyde coordination, insertion of CO, abstraction of benzyl coordination, insertion of CO, abstraction of benzyl moiety as toluene and rebinding of PCy3 occurs, whichmoiety is in lineas toluene with previous and rebinding observations of PCy3 occurs, made which by Mol is etin al.line [38 with]. The previous formation observations of a four-coordinate made by Mol et al. [38]. The formation of a four-coordinate compound as a result of phosphine dissociation is compound as a result of phosphine dissociation is highlighted as the crucial decomposition pathway [43]. highlighted as the crucial decomposition pathway [43]. A plausible mechanism of conversion of A plausiblecomplex mechanism 7 to a six-coordinated of conversion species of complex8 and 9 is 7multi-stepto a six-coordinated and starts with species the introduction8 and 9 is multi-stepof an and startsadditional with methoxide the introduction ligand as of shown an additional also on Scheme methoxide 11. ligand as shown also on Scheme 11.

SchemeScheme 10. 10.The The reaction reaction ofof Grubbs-typeGrubbs-type catalyst catalyst with with methoxides. methoxides.

In 2020, Fogg’s group reported a study on the degradation of the 2nd generation Hoveyda-Grubbs catalyst induced by the hydroxide ion [48]. In this work a new pathway of decomposition was proposed (Scheme 12) which differed from the previously proposed decomposition driven by hydroxide in methanol [43]. In the latter work the catalysts (Schemes 10 and 11) were transformed into Ru-hydride species via β-elimination of a methoxide adduct [43]. In the present work, however, the ring-closing n metathesis (RCM) reaction of diethyl diallylmalonate in the presence of [N Bu4][OH] showed a rapid decrease in the catalytic activity of HGII complex. An instant quenching of a similar experiment without the olefin suggested that hydroxide ion attacked precatalyst, yielding the product, which either decomposed during the first catalytic cycle or was inactive in metathesis. The authors synthesized the putative bis-hydroxide complex HGII-OH in 85% yield (Scheme 12) and it demonstrated an almost complete lack of reactivity (<3%) in model RCM reactions. The synthesized bis-hydroxide complex HGII-OH gave styrene ether as the product of metathesis exchange and propenes E/E’ bya β-elimination of a corresponding metallacyclobutane. Since the identified products referred to only 50% of HGII-OH used in the reaction, it was suggested that the bimolecular coupling of bis-hydroxide ruthenium methylidene adduct HGIIm-OH might be responsible for a further decomposition of this species. Computational comparison of the dimerization and the ethylene binding indicated that the hetero-coupling is indeed preferred by ca. 12.4 kcal/mol (Scheme 12). This results was in line with kinetics studies showing that the rate-limiting step of the reaction was the formation of an essential methylidene intermediate HGIIm-OH. Two stable isomers were predicted, transoid- and cisoid-Ru. Additionally, the capture and decomposition of HGII-OH by an already decomposed ruthenium species were noted and explained by a H-bonding capacity of the hydroxide ligand. Catalysts 2020, 10, 887 9 of 56 Catalysts 2020, 10, x FOR PEER REVIEW 9 of 60

SchemeScheme 11. The 11. The proposed proposed mechanism mechanism of of formation formation of ruthenium ruthenium complexes complexes 7–107– due10 due to a tomethoxide a methoxide attackCatalystsattack on 2020 Grubbs-type on, 10 Grubbs-type, x FOR PEER complexes. REVIEWcomplexes. 10 of 60

In 2020, Fogg’s group reported a study on the degradation of the 2nd generation Hoveyda- Grubbs catalyst induced by the hydroxide ion [48]. In this work a new pathway of decomposition was proposed (Scheme 12) which differed from the previously proposed decomposition driven by hydroxide in methanol [43]. In the latter work the catalysts (Schemes 10 and 11) were transformed into Ru-hydride species via β-elimination of a methoxide adduct [43]. In the present work, however, the ring-closing metathesis (RCM) reaction of diethyl diallylmalonate in the presence of [NnBu4][OH] showed a rapid decrease in the catalytic activity of HGII complex. An instant quenching of a similar experiment without the olefin suggested that hydroxide ion attacked precatalyst, yielding the product, which either decomposed during the first catalytic cycle or was inactive in metathesis. The authors synthesized the putative bis-hydroxide complex HGII-OH in 85% yield (Scheme 12) and it demonstrated an almost complete lack of reactivity (<3%) in model RCM reactions. The synthesized bis-hydroxide complex HGII-OH gave styrene ether as the product of metathesis exchange and propenes E/E’ bya β-elimination of a corresponding metallacyclobutane. Since the identified products referred to only 50% of HGII-OH used in the reaction, it was suggested that the bimolecular coupling of bis-hydroxide ruthenium methylidene adduct HGIIm-OH might be responsible for a further decomposition of this species. Computational comparison of the dimerization and the ethylene binding indicated that the hetero-coupling is indeed preferred by ca. 12.4 kcal/mol (Scheme 12). This results was in line with kinetics studies showing that the rate-limiting step of the reaction was the formation of an essential methylidene intermediate HGIIm-OH. Two stable isomers were predicted, transoid- and cisoid-Ru. Additionally, the capture and decomposition of HGII-OH by an already decomposed ruthenium species were noted and explained by a H-bonding capacity of the hydroxide ligand.

SchemeScheme 12. The 12. The degradation degradation mechanism mechanism inin presencepresence of of hy hydroxidedroxide ion ion proposed proposed by Fogg by Fogg et al. et with al. with

DFT-basedDFT-based relative relative Gibbs Gibbs free free energies energies (in (in kcal kcal/mol)./mol).

In silico studies of the alcohol-driven decomposition mechanism proposed by Mol [39] for the benzylidene 2nd generation Grubbs-type catalyst was conducted by Young et al. [49] Authors considered two possible decomposition mechanism dubbed phosphine-off and phosphine-on (Scheme 13), which correspond to either a dissociative or an associative metathesis mechanism, respectively. The initial assumption made by authors was that the associative pathway has the advantage of saving the cost of phosphine dissociation but the calculated energy barriers for individual transition states were higher than for the dissociative path, thereby indicating the dissociative mechanism as the preferred one. The value of the estimated Gibbs free energy barrier for limiting transition state (methoxide reaction with benzylidene via hydride transfer) of 55.8 kcal/mol, with respect to the initial complex is, however, at least puzzling. The authors explained this result by noting, that the reverse reaction from the –OCH3 adduct is highly unlikely, thus formally resetting the energy of this adduct to zero, resulting in the final Gibbs free energy barrier of only 25.2 kcal/mol. The last step of this pathway proceeds through an unstable intermediate 11, which converts immediately to ruthenium hydride complex 3, rather than through 12, due to a favorable position of the CHO ligand for hydrogen abstraction.

Catalysts 2020, 10, 887 10 of 56

In silico studies of the alcohol-driven decomposition mechanism proposed by Mol [39] for the benzylidene 2nd generation Grubbs-type catalyst was conducted by Young et al. [49] Authors considered two possible decomposition mechanism dubbed phosphine-oﬀ and phosphine-on (Scheme 13), which correspond to either a dissociative or an associative metathesis mechanism, respectively. The initial assumption made by authors was that the associative pathway has the advantage of saving the cost of phosphine dissociation but the calculated energy barriers for individual transition states were higher than for the dissociative path, thereby indicating the dissociative mechanism as the preferred one. The value of the estimated Gibbs free energy barrier for limiting transition state (methoxide reaction with benzylidene via hydride transfer) of 55.8 kcal/mol, with respect to the initial complex is, however, at least puzzling. The authors explained this result by noting, that the reverse reaction from the –OCH3 adduct is highly unlikely, thus formally resetting the energy of this adduct to zero, resulting in the ﬁnal Gibbs free energy barrier of only 25.2 kcal/mol. The last step of this pathway proceeds through an unstable intermediate 11, which converts immediately to ruthenium hydride complex 3, rather than through 12, due to a favorable position of the CHO ligand for hydrogen abstraction. Catalysts 2020, 10, x FOR PEER REVIEW 11 of 60

Scheme 13.SchemeTwo 13. mechanisms Two mechanisms of alcoholysisof alcoholysis and Gibbs Gibbs free free energy energy profile proﬁle (in kcal/mol) (in kcal for /mol)the for the phosphine-ophosphine-offﬀ mechanism mechanism obtained obtained at the at the DFT DFT level level of theory theory (blue (blue route route via 11). via 11).

The influence of the indenylidene ligand on decomposition process was examined by Nolan’s The inﬂuencegroup [50]. ofA quantitatively the indenylidene receivedligand and rath oner unexpected decomposition product processfrom a reaction was examinedof M10 with bya Nolan’s group [50].stoichiometric A quantitatively amount receivedof Et3N in and ethanol rather (Scheme unexpected 14) demons producttrated fromdifferent a reactiondecomposition of M10 with a 5 stoichiometricbehavior amount compared of Et to3 otherN in metathesis ethanol (Scheme catalysts investigated 14) demonstrated so far. The di newﬀerent η -ruthenium decomposition complex behavior comparedwas to formed other metathesisthrough the phosphine catalysts dissociation investigated and rearrangement so far. The to new an indenylη5-ruthenium complex 13. complexThe was overall reaction rate, determined by means of nuclear magnetic resonance (NMR), was phosphine formed throughindependent, the phosphine although its dissociationexcess decreases and the rate rearrangement of reaction. to an indenyl complex 13. The overall

Catalysts 2020, 10, 887 11 of 56 reaction rate, determined by means of nuclear magnetic resonance (NMR), was phosphine independent, although its excess decreases the rate of reaction. Catalysts 2020, 10, x FOR PEER REVIEW 12 of 60

Scheme 14.SchemeThe alcoholysis 14. The alcoholysis decomposition decomposition products products of of thethe Grubbs-type indenylidene indenylidene precatalyst precatalyst in in (a) (a) RCH2OH and (b) iPrOH. RCH2OH and (b) iPrOH. The same group performed also theoretical DFT studies to evaluate energetic cost of such The same group performed also theoretical DFT studies to evaluate energetic cost of such transformation (Scheme 15) using methanol as the model alcohol. The suggested mechanism starts transformationwith the (Scheme substitution 15 of) usingthe phosphine methanol by an as alcoho thel modelmolecule alcohol. and proton The transfer suggested from the mechanismmethanol starts with the substitutionto the base through of the transition phosphine state TS by AB an (12.9 alcohol kcal/mol), molecule yielding and an protonintermediate transfer with PPh from3 ligand the methanol trans to MeO. Additionally, methoxy group and adjacent Cl ligand interacting via hydrogen bond to the base through transition state TS AB (12.9 kcal/mol), yielding an intermediate with PPh3 ligand with Et3NH+ force the loss of Et3NH+Cl- via TS BC (24.0 kcal/mol) transition state, giving intermediate trans to MeO. Additionally, methoxy group and adjacent Cl ligand interacting via hydrogen bond with C with the simultaneous shift of the methoxy group into the vacant cis position with respect to the + + - Et3NH forcephosphine. the loss The ofrebinding Et3NH ofCl phosphinevia TS allows BC (24.0 for an kcal energy/mol) gain transition of 19.6 kcal/mol. state, Based giving on intermediatethe C with theanalysis simultaneous of the entire shift cycle, of it the was methoxy suggested groupthat the intorate-limiting the vacant step ofcis thisposition reaction withis the respectfinal to the phosphine.hydrogen The rebinding transfer from of the phosphine methoxy ligand allows to the for ylidene an energy carbon atom gain (TS of D 19.6→E) and kcal the/mol. release Based of on the formaldehyde. The last isomerization step from η1-species to a more thermodynamically stable form analysis of the entire cycle, it was suggested that the rate-limiting step of this reaction is the final 13 was shown to be practically barrierless. The impact of the base on this mechanism was found to hydrogen transfer from the methoxy ligand to the ylidene carbon atom (TS D E) and the release of be significant, since it lowers the energy barrier of initial TS BC by ca. 16 kcal/mol, compared→ to direct formaldehyde.H transfer The from last MeOH isomerization to Cl. This is step in good from agreementη1-species with experimental to a more thermodynamicallyevidence of base-promoted stable form 13 was shownalcoholysis to be [38,43] practically and the barrierless. determined activation The impact energy of (25.7 the kcal.mol) base on [50]. this mechanism was found to be significant, since it lowers the energy barrier of initial TS BC by ca. 16 kcal/mol, compared to direct H transfer from MeOH to Cl. This is in good agreement with experimental evidence of base-promoted alcoholysis [38,43] and the determined activation energy (25.7 kcal.mol) [50]. The use of an analogous methodology for obtaining ‘piano-stool’ complexes for other ruthenium catalysts containing the indenylidene fragment was further tested in later studies (Scheme 15)[51,52]. It was shown that complex M1/IndII/M20 followed an analogous decomposition pathway as previously observed for GI, while M11 gave, very similar to 13, a η5-ylidenyl complex 14 in the form of a mixture of rotamers. The ‘piano-stool’ geometry was preserved, with phosphines in the cis-orientation but it seemed that bulky Phoban-type ligands preferred the smaller hydride over the chloride. This finding 5 appears to be confirmed by obtaining corresponding hydride [Ru(H)(η -3-phenyl-indenyl)(PPh3)2] by prolong reaction time of 13. The final conclusion of the study is that depending on the alkylidene moiety and the phosphine ligand, different decomposition processes can occur for similar catalysts. Scheme 15. The energy profile of M10 formation from the two different DFT methods (in kcal/mol). Extension of the initial stability research to basic solution of secondary alcohols by Nolan resulted in a corresponding dihydrogen hydride 15 for M1 and IndII catalyst [52]. The same dihydrogen decomposition product gave methylidene derivatives [RuCl2(=CH2)(PCy3)2], as well as 1st and 2nd generation metathesis precatalyst (Scheme 14), in contrary to earlier reports by Mol [38]. The fact that the characteristic decomposition product of hydrogenolysis, complex 15, is formed in an alcohol-driven decomposition reaction and the possibility of its transformation into a hydridocarbonyl species using Catalysts 2020, 10, x FOR PEER REVIEW 12 of 60

Scheme 14. The alcoholysis decomposition products of the Grubbs-type indenylidene precatalyst in

(a) RCH2OH and (b) iPrOH.

The same group performed also theoretical DFT studies to evaluate energetic cost of such Catalysts 2020, 10, 887 12 of 56 transformation (Scheme 15) using methanol as the model alcohol. The suggested mechanism starts with the substitution of the phosphine by an alcohol molecule and proton transfer from the methanol to the base through transition state TS AB (12.9 kcal/mol), yielding an intermediate with PPh3 ligand methanoltrans [53] impliedto MeO. Additionally, similarities methoxy of both group processes and adjacent [52]. Cl The ligand computational interacting via modellinghydrogen bond of the entire i decompositionwith Et3 pathwaysNH+ force the for lossM1 of Et(PCy3NH+Cl3)- via and TSM11 BC (24.0( Bu-Phoban) kcal/mol) transition conﬁrmed state, giving that intermediate hydrogen transfer from the alkoxideC with the tosimultaneous the indenylidene shift of the ligandmethoxyTS grouphas into the the highest vacant cis energy position barrier. with respect It was to the also found phosphine. The rebinding of phosphine allows5 for an energy gain of 19.6 kcal/mol. Based on the that for smaller phosphines, such as PPh3, the η -chloro complex was more stable than the starting analysis of the entire cycle, it was suggested that the rate-limiting step of this reaction is the final rutheniumhydrogen carbene transfer catalyst, from while the methoxy for complexes ligand to the containing ylidene carbon the atom PCy 3(TSor D Phoban→E) and groupsthe release the of formation of the intermediateformaldehyde.G Thewas last unfavored isomerization by step around from η 5–111-species kcal to /amol. more Furtherthermodynamically part of the stable DFT form calculation suggested13 the was favorable shown to be formation practicallyof barrierless. hydride The14 impa(intermediatect of the baseF on) for thisM11 mechanism(Scheme was 16found). These to results were consistentbe significant, with thesince experimentally it lowers the energy observed barrier of initial formation TS BC by of ca.14 16instead kcal/mol, of compared chloride to complexdirect 13 for H transfer from MeOH to Cl. This is in good agreement with experimental evidence of base-promoted the catalystalcoholysis bearing [38,43] a Phoban and the ligand. determined activation energy (25.7 kcal.mol) [50].

SchemeCatalysts 15.Scheme 2020The, 10 energy15., x FORThe energyPEER proﬁle REVIEW profile of M10 of M10formation formation from the the two two differ dientﬀerent DFT methods DFT methods (in kcal/mol). (in14 kcal of 60/mol).

Scheme 16. TheScheme energy 16. The proﬁle energy of profileM11, ofM10 M11, M1, M10formation, M1 formation from from the the DFT DFT calculations calculations (values (values in in kcal/mol). kcal/mol). In 2016, Rouen et al. also noticed the formation of a bisphosphine hydride complexes from an In 2016, Rouen et al. also noticed the formation of a bisphosphine hydride complexes from an unsymmetricalunsymmetrical 2nd generation 2nd generation idenylidene idenylidene catalysts in the in thepresence presence of an alcohol of an [54], alcohol similar [to54 the], similar to the previousprevious works works of Cavalloof Cavallo and and others others [[52].52]. The The authors authors explained explained the formation the formation of the complex of the complex [RuCl(H)(CO)(PCy[RuCl(H)(CO)(PCy3)2] by3 the)2] by protonolysis the protonolysis of of the the NHCNHC ligand ligand in compound in compound 17, the17 formation, the formation of which of which in the reaction was not observed but only inferred on the basis of the identical reaction of the M1 catalyst (see Scheme 14). DFT calculations of the substitution of N-heterocyclic carbene by an ethanol molecule indicated that for a less crowded, unsymmetrical ligand, the energy barrier of the crucial transition state was 3.9 kcal/mol lower than for the standard SIMes carbene (Scheme 17).

Catalysts 2020, 10, 887 13 of 56 in the reaction was not observed but only inferred on the basis of the identical reaction of the M1 catalyst (see Scheme 14). DFT calculations of the substitution of N-heterocyclic carbene by an ethanol molecule indicated that for a less crowded, unsymmetrical ligand, the energy barrier of the crucial transitionCatalysts 2020 state, 10, x was FOR 3.9PEER kcal REVIEW/mol lower than for the standard SIMes carbene (Scheme 17). 15 of 60

Scheme 17.17. ComparisonComparison ofof the the alcohol-driven alcohol-driven decomposition decomposition of (ofa) ( symmetrica) symmetric and and (b) asymmetric(b) asymmetric 2nd generation2nd generation indenylidene indenylidene catalysts catalyst withs with the Gibbs the Gibbs free energiesfree energies (in kcal (in/ mol)kcal/mol) calculated calculated at the at DFT the levelDFT oflevel theory. of theory. 2.3. Phenols 2.3. Phenols Phenols are a distinct class of compounds from alcohols due to their different chemical properties. Phenols are a distinct class of compounds from alcohols due to their different chemical In the case of ruthenium metathesis catalysts they mode of action is, however, similar to alcohols properties. In the case of ruthenium metathesis catalysts they mode of action is, however, similar to and based on Lewis acidity. In 2005 Forman et al. reported suppression of metathesis carbene alcohols and based on Lewis acidity. In 2005 Forman et al. reported suppression of metathesis carbene catalyst by the addition of phenol [55]. An unexpected beneficial effect of enhanced activity and catalyst by the addition of phenol [55]. An unexpected beneficial effect of enhanced activity and lifetime of active catalyst form was observed for the GI catalyst in the self-metathesis of 1-octene. lifetime of active catalyst form was observed for the GI catalyst in the self-metathesis of 1-octene. A A similar effect was observed, though to a lesser extent, for very acidic alcohols such as trifluoroethanol, similar effect was observed, though to a lesser extent, for very acidic alcohols such as trifluoroethanol, perfluoro-tert-butyl alcohol or hexafluoro-2-propanol. Grubbs 2nd generation catalysts showed lower activity in the self-metathesis reaction but a significant improvement in the cross-metathesis with methyl acrylate in the presence of phenols. The NMR kinetic studies revealed that the type of phenol used alters the phosphine dissociation rate and in high concentrations it may sequester it in the form of (PhOH)nPCy3. In general, the 1st generation catalyst with less acidic phenols exhibited excellent performance in metathesis, which resulted from impeding of the phosphine rebinding to

Catalysts 2020, 10, 887 14 of 56 perfluoro-tert-butyl alcohol or hexafluoro-2-propanol. Grubbs 2nd generation catalysts showed lower activity in the self-metathesis reaction but a significant improvement in the cross-metathesis with methyl acrylate in the presence of phenols. The NMR kinetic studies revealed that the type of phenol used alters the phosphine dissociation rate and in high concentrations it may sequester it in the form ofCatalysts (PhOH) 2020n, PCy10, x 3FOR. In PEER general, REVIEW the 1st generation catalyst with less acidic phenols exhibited excellent16 of 60 performance in metathesis, which resulted from impeding of the phosphine rebinding to ruthenium. Basedruthenium. on the Based experimental on the resultsexperimental and additional results and DFT additional calculations, DFT a mechanism calculations, for a metathesis mechanism in thefor presencemetathesis of in phenols the presence was proposed of phenols (Scheme was 18prop). Computationalosed (Scheme 18). study Computational pointed to 18a study( 11.7 pointed kcal/mol) to − as18a the (−11.7 more kcal/mol) favored modeas the ofmore coordination favored mode over 1of8b coordination( 3.9 kcal/mol) over and 18b at ( the−3.9 same kcal/mol) time showedand at the an − increasesame time in showed the stability an increase of active in the catalyst stability with of a active growing catalyst number with of a growing coordinated number phenols of coordinated molecules (phenols20 26.3kcal molecules/mol > (2019a −26.3kcal/mol16.6kcal/mol > 19a> 19b −16.6kcal/mol8.0kcal/mol). > 19b The −8.0kcal/mol). energy barriers The for energy the dissociation barriers for − − − ofthe model dissociation PMe3 forof model both 1st PMe and3 for 2nd both generation 1st and 2nd catalyst generation was higher catalyst when was phenolhigher when was coordinated. phenol was Moreover,coordinated. the Moreover, carbene carbon the carbene atom was carbon activated atom by wa enhancings activated its by electrophilicity, enhancing its as electrophilicity, demonstrated byas thedemonstrated charge distribution by the charge analysis. distribution The proposed analysis equilibrium. The proposed between equilibriu intermediatesm betweenA and intermediatesB promotes theA and latter B promotes one and prevents the latter the one decomposition and prevents ofthe the decomposition 14-electron species of the A14-electron. species A.

Scheme 18.18.The The mechanism mechanism of metathesisof metathesis in the in presence the pres of phenolsence of with phenols suggested with PhOH suggested coordination PhOH structurescoordination to activatedstructures catalyst. to activated catalyst. 2.4. Water-Mediated Degradation 2.4. Water-Mediated Degradation Ruthenium-based olefin metathesis catalysts are usually non-soluble in water and specific Ruthenium-based olefin metathesis catalysts are usually non-soluble in water and specific modifications to their structure need to be introduced to make them water-soluble. Even in such cases modifications to their structure need to be introduced to make them water-soluble. Even in such cases water, however, can degrade these complexes. Similarly to previously described alcohols, water can act water, however, can degrade these complexes. Similarly to previously described alcohols, water can as either Lewis acid or base, though in the reported decomposition studies it usually acts via OH- ions. act as either Lewis acid or base, though in the reported decomposition studies it usually acts via OH- In 2000 Grubbs and co-workers observed the decomposition of the 1st generation ruthenium ions. metathesis catalysts, while studying the polymerization reaction in protic solvents. The degradations In 2000 Grubbs and co-workers observed the decomposition of the 1st generation ruthenium was furthermore promoted by hydroxide ions [56]. As a result of the stoichiometric reaction of the metathesis catalysts, while studying the polymerization reaction in protic solvents. The degradations ruthenium carbene complex with NaOD in D O, a new product without the ylidene substituent was was furthermore promoted by hydroxide ions2 [56]. As a result of the stoichiometric reaction of the formed, which further decomposed to a mixture of unknown products. Unfortunately, the nature ruthenium carbene complex with NaOD in D2O, a new product without the ylidene substituent was of this transformation and the exact structure of the decomposition product were unknown at that formed, which further decomposed to a mixture of unknown products. Unfortunately, the nature of time. It was also suggested that the presence of acid additives prevents the catalyst decomposition by this transformation and the exact structure of the decomposition product were unknown at that time. avoiding hydroxide ions formation in the reaction of phosphines with water. It was also suggested that the presence of acid additives prevents the catalyst decomposition by The idea of conducting metathesis in protic solvents and water was later grasped by many groups avoiding hydroxide ions formation in the reaction of phosphines with water. and a number of reports can be found in the literature experimenting with this approach [57–69]. The idea of conducting metathesis in protic solvents and water was later grasped by many groups and a number of reports can be found in the literature experimenting with this approach [57– 69]. They main focus of these studied is on introducing various modifications to the catalyst structure to improve their solubilities, testing different co-solvents [70] and checking their effectiveness in model reactions. One of the more interesting findings in this area is the observation made by Raine that ethers used as co-solvents with water give the highest RCM metathesis yields. Authors suggested that ethers are more likely to coordinate to the active intermediates and thus protecting it from water and maintaining the catalyst in the solution [70].

Catalysts 2020, 10, 887 15 of 56

They main focus of these studied is on introducing various modifications to the catalyst structure to improve their solubilities, testing different co-solvents [70] and checking their effectiveness in model reactions. One of the more interesting findings in this area is the observation made by Raine that ethers used as co-solvents with water give the highest RCM metathesis yields. Authors suggested that ethersCatalysts are 2020 more, 10, x likelyFOR PEER to coordinateREVIEW to the active intermediates and thus protecting it from water17 of and 60 maintaining the catalyst in the solution [70]. Hirota andand Matsuo Matsuo used used an interestingan interesting approach approa to thech problem to the ofproblem ruthenium of catalysts’ruthenium degradation catalysts’ indegradation water [71]. in They water applied [71]. aThey strategy applied consisting a strategy of suppressing consisting theof suppressing loss of chlorine the ligandsloss of andchlorine thus increasingligands and the thus activity increasing of the the Hoveyda-Grubbs-type activity of the Hoveyda-Grubbs-type ruthenium catalysts ruthenium in water. catalysts Their assumption in water. wasTheir based assumption on a widely was acceptedbased on facta widely that the accepted ligand fa exchangect that the modifies ligand rutheniumexchange modifies metathesis ruthenium catalysts performancemetathesis catalysts [72–75], performance as well as on [72–75], earlier reports as well indicating as on earlier that thereports ligand indicating replacement that couldthe ligand lead toreplacement the formation could of lead an inactiveto the formation product orof an precatalyst inactive product dimer [72 or,74 precatalyst,76–78]. UV-Vis dimer [72,74,76–78]. spectroscopy investigationUV-Vis spectroscopy of HG stabilityinvestigation in neutral of HG aqueous stability solutionin neutral without aqueous KCl solution showed without the decrease KCl showed of a characteristicthe decrease of metal-to-ligand a characteristic chargemetal-to-ligand transfer absorptioncharge transfer band absorption (ca. 373 nm)band and (ca. the373 formationnm) and the of aformation product whichof a product showed which no activity showed in no RCM. activity There in RCM. were noThere intensity were changesno intensity of the changes band inof the presenceband in the of presence the salt even of the after salt 16h. even Based after 16h. on these Based results, on these a mechanism results, a mechanism of chloride of ligand chloride effect ligand was proposedeffect was (Scheme proposed 19 ),(Scheme in which 19), the in presence which ofthe the pres saltence changes of the the salt equilibrium changes the toward equilibrium chloride-bound toward complex,chloride-bound while itscomplex, absence while facilitates its absence the substitution facilitates of the one substitution chloride ligand of one with chloride water or ligand hydroxide with ion,water ultimately or hydroxide leading ion, to ultimately the deactivation leading of theto the catalyst. deactivation The structure of the ofcatalyst. the final The Ru-species structure was of notthe determinedfinal Ru-species but authorswas notspeculated determined that but the authors formation speculated of a Cl-bridged that the formation dimer or oxo-bridgedof a Cl-bridged form dimer was likely.or oxo-bridged Although form the exchangewas likely. reaction Although is not the a decompositionexchange reaction reaction, is not thea decomposition loss of the ligand reaction, may lead the toloss less of stablethe ligand intermediates may lead andto less introduce stable intermediates new degradation and introduce pathways. new degradation pathways.

Scheme 19. A schematic representation of the equilibrium step with salt during conversion to the inactive form of the catalyst.catalyst. 2.5. Phosphines and General Routes to Metallacyclobutane Deprotonation 2.5. Phosphines and General Routes to Metallacyclobutane Deprotonation The risks associated with the use of the phosphine-containing catalysts for olefin metathesis are The risks associated with the use of the phosphine-containing catalysts for olefin metathesis are reviewed later. It is worth noting, however, that phosphine can be added to the Hoveyda-Grubbs reviewed later. It is worth noting, however, that phosphine can be added to the Hoveyda-Grubbs catalyst as an external agent, what was reported by Bailey and Fogg [79]. They demonstrated that the catalyst as an external agent, what was reported by Bailey and Fogg [79]. They demonstrated that the phosphine is able to attack the olefin and form zwitterion A (Scheme 20), which can then undergo a phosphine is able to attack the olefin and form zwitterion A (Scheme 20), which can then undergo a number of side reactions which lead to catalyst degradation. It was observed that the main reaction is number of side reactions which lead to catalyst degradation. It was observed that the main reaction the attack on the acrylate molecule and the elimination of the B+Cl salt, which occurs only in the is the attack on the acrylate molecule and the elimination of the B+Cl−− salt, which occurs only in the presence of ruthenium species as a source of hydrogen and chloride anion. In addition, zwitterion A presence of ruthenium species as a source of hydrogen and chloride anion. In addition, zwitterion A competes in this reaction with the proton source, as confirmed by the formation of A+. The authors competes in this reaction with the proton source, as confirmed by the formation of A+. The authors suggest that the metallacyclobutane intermediate (MCB) is a likely target of phosphine attack, while suggest that the metallacyclobutane intermediate (MCB) is a likely target of phosphine attack, while the attack on the resting state intermediate is likely less preferred due to steric hindrances. These results the attack on the resting state intermediate is likely less preferred due to steric hindrances. These confirm that the superiority of Hoveyda-Grubbs-type catalysts, relative to GII, in the analogous results confirm that the superiority of Hoveyda-Grubbs-type catalysts, relative to GII, in the analogous metathesis reaction results from the lack of phosphine and not from the postulated boomerang effect [79,80].

Catalysts 2020, 10, 887 16 of 56

Catalysts 2020, 10, x FOR PEER REVIEW 18 of 60 metathesis reaction results from the lack of phosphine and not from the postulated boomerang eCatalystsﬀect [79 2020,80, ].10, x FOR PEER REVIEW 18 of 60

Scheme 20. The formation of phosphonium salt and the mechanism of acrylate-induced decomposition. Scheme 20.20.The The formation formation of phosphonium of phosphonium salt and thesalt mechanism and the ofmechanism acrylate-induced of acrylate-induced decomposition. decomposition.Consecutive studies of Fogg et. al. on Broensted bases—induced degradation of metathesis catalystsConsecutive verified studiesthe previous of Fogg hypothesis et. al. on of Broenstedmetallacyclobutane bases—induced deprotonation degradation [81]. Dimer of metathesis 21 was catalystsisolatedConsecutive from veriﬁed reac thestudiestion previous mixtures of Fogg hypothesis of et.GII al. and on of HGII metallacyclobutaneBroens withted bases—inducedmethyl acrylate deprotonation (Schemedegradation [81 21),]. Dimeroftogether metathesis21 withwas isolatedcatalystssalts A–C from verified. Based reaction theon theprevious mixtures experiments ofhypothesisGII and withHGII of deuterated metallacyclobutanewith methyl olefins acrylate and deprotonation deuterated (Scheme 21 ),mesityl [81]. together Dimer rings with 21 it saltswaswas A–Cisolatedsuggested. Based from that on reac thethetion experiments initial mixtures deprotonation with of GII deuterated and site HGII is oleﬁnsthe withmetallacyclobutane and methyl deuterated acrylate mesityl intermediate (Scheme rings 21), it rather wastogether suggested than with the thatsaltsNHC theA–C ligand. initial. Based deprotonation on the experiments site is the with metallacyclobutane deuterated olefins intermediate and deuterated rather thanmesityl the NHCrings ligand.it was suggested that the initial deprotonation site is the metallacyclobutane intermediate rather than the NHC ligand.

SchemeScheme 21.21. TheThe methyl-acrylatemethyl-acrylate inducedinduced formationformation ofof rutheniumruthenium dimers.dimers.

DFTDFT calculationcalculationScheme ofof acidity21.acidity The methyl-acrylate ofof protonsprotons inin induced activeactive intermediates intermediatesformation of ruthenium MCBMCB andand dimers. methylidenemethylidene speciesspecies showedshowed lowerlower acidity acidity of of H Hαα compared toto HHββ and,and, thus, thus, excluded excluded the deprotonation of the methylidene restingrestingDFT statestate calculation as aas competitive a ofcompetitive acidity path. of Moreover,prpath.otons Moreover in estimated active, intermediatesestimated energy barriers energy MCB ofthe andbarriers further methylidene transformationsof the speciesfurther aftershowedtransformations the lower deprotonation acidity after ofthe of H deprotonationMCBα comparedand the toloss Hofβ MCBand, of chloride thus, and theexcluded and loss allyl of the chloride group deprotonation to and dimer allyl21 of groupwere the methylidenelow to dimer and the 21 entirerestingwere low process state and wastheas entire founda competitive process to be eff wasortless path. found (Scheme Moreover to be effortless22)., Thus, estimated (Scheme the MCB energy22).deprotonation Thus, barriers the MCB turnedof deprotonation the out further to be a generaltransformationsturned featureout to be of after Broensteda general the deprotonation featur basese and of notBroensted of onlyMCB restricted and bases the and loss to electron-deficientnot of chlorideonly restricted and allyl olefins. to group electron-deficient to dimer 21 wereolefins. low and the entire process was found to be effortless (Scheme 22). Thus, the MCB deprotonation turned out to be a general feature of Broensted bases and not only restricted to electron-deficient olefins.

Catalysts 2020, 10, 887x FOR PEER REVIEW 1917 of 60 56 Catalysts 2020, 10, x FOR PEER REVIEW 19 of 60

Scheme 22. The amine-driven decomposition of metallacyclobutane with the Gibbs free energy profileScheme obtained 22.22. TheThe amine-drivenat amine-driven the DFT level decomposition decompositionof theory. of metallacyclobutaneof metallacyclobutane with with the Gibbs the Gibbs free energy free energy profile obtainedprofile obtained at the DFT at the level DFT of level theory. of theory. In 2017 Fogg presented a method of overcoming the catalysts’ decomposition in demanding metathesisIn 2017 reactions FoggFogg presentedpresented with electron-deficient aa methodmethod ofof overcomingovercoming olefins [82]. thetheIn this catalysts’catalysts’ new approach decompositiondecomposition phenol-functionalized inin demandingdemanding resinsmetathesis were reactionsused to quench with electron-deficientelectron-deficient the enolate, produced olefinsolefins during [[82].82]. In metathesis this new approach reaction (Scheme phenol-functionalized 23). The cross metathesisresins were of used GII to and quench IndII the with enolate, acrylate produced at low catalyst during metathesisloadings in reaction toluene (Scheme(Schemeand at 70 2323). °C). indicated The cross thatmetathesis the sacrificial ofof GIIGIIand and protonIndII IndII sourcewith with acrylate acrylateis the atprimary at low low catalyst catalystfunction loadings loadings of the in resin,toluenein toluene rather and and at than 70 at◦ C70the indicated °C previously indicated that reportedthethat sacrificial the sacrificialprotonation proton proton source of the source isphosphine the primaryis the [55].primary function Proton fu ofnctionation the resin,ofof thethe rather enolateresin, than rather anion the than previouslyconverts the previously it reported into an unreactiveprotonationreported protonation phosphonium of the phosphine of thesalt boundphosphine [55]. Protonationto resin, [55]. thus Proton ofimpeding theation enolate of the the catalyst anion enolate converts decomposition. anion it converts into an Authors unreactiveit into also an suggestedphosphoniumunreactive that phosphonium saltin the bound case tosaltof resin,the bound macrocyclization thus to impedingresin, thus the reactionimpeding catalyst phenol the decomposition. catalyst resin may decomposition. remove Authors polar also Authors impurities suggested also throughthatsuggested in the hydrogen that case in of the theinteractions. case macrocyclization of the Replacingmacrocyclization reaction the resin phenol reaction with resinwater phenol may as aresin removesource may of polar remove the hydrogen impurities polar impurities leads through to a furtherhydrogenthrough decomposition hydrogen interactions. interactions. of Replacing the catalyst, Replacing the resinmost thewith likely resin water as wi ath asresult water a source of as the a of source formation the hydrogen of the of hydrogen the leads hydroxide to leads a further ion.to a Thedecompositionfurther presence decomposition of of the the resin catalyst, of reducesthe mostcatalyst, also likely themost as harmful a likely result ofeasffects thea result formation of water of the by of formation thecompeting hydroxide of with the ion. hydroxideit Thein a presencereaction ion. withofThe the presence the resin enolate. reduces of the alsoresin the reduces harmful also eff ectsthe harmful of water e byffects competing of water with by competing it in a reaction with with it in the a reaction enolate. with the enolate.

Scheme 23. AA schematic schematic representation representation of role of ph phenolenol during olefin olefin metathesis reaction. Scheme 23. A schematic representation of role of phenol during olefin metathesis reaction. 2.6. Amines Amines 2.6. Amines Although well-defined well-defined metathesis catalysts catalysts ar aree compatible with with many many functional groups, groups, continuousAlthough reactions well-defined with nitrogen-containing metathesis catalysts olef olefins insare such compatible as amines with or heteroaromatic many functional compounds groups, remaincontinuous a challenge reactions [83]. [83 with]. There There nitrogen-containing are are two two main main modes olefins of ofsuch action as amines of amines, or heteroaromatic which as both compounds Lewis and Broenstedremain a challenge basesbases maymay [83]. directly directly There attack attack are thetwo the ruthenium main ruthenium modes core coreof of action catalysts of catalysts of amines, as well as aswell which abstract as asabstract hydrogenboth Lewishydrogen atoms and atomsfromBroensted the from crucial bases the crucial metallacyclobutanemay directly metallacyclobutane attack intermediates. the ruthenium intermediates. core of catalysts as well as abstract hydrogen atomsDuring from theexamination examination crucial metallacyclobutane of ofthe the degradation degradation intermediates. products products of ruthenium of ruthenium methylidene methylidene complexes, complexes, Grubbs etGrubbs al. Duringnoticed et al. examinationthenoticed formation the of formation of the a tripyridinedegradation of a tripyridine complex products in complex ofthe ruthenium presence in the of methylidene presenceamine excess of complexes, amine [84] (Scheme excess Grubbs [24),84] (Schemewhileet al. noticed the 24 benzylidene), whilethe formation the catalyst benzylidene of a gave tripyridine a catalyst stable complex bispyridine gave a stablein the adduct bispyridinepresence in previous of amine adduct studies excess in previous [8].[84] Interestingly, (Scheme studies 24), [8]. theInterestingly,while 3rd the generation benzylidene the 3rd Grubbs generation catalyst catalyst gave Grubbs GIIIa stable catalystwere bispyridine alsoGIII susceptiblewere adduct also toin susceptible theprevious degradation studies to the degradation and[8]. Interestingly,a tripyridine and a complextripyridinethe 3rd generation in complexreaction Grubbs with in reaction ethylene catalyst with was GIII ethylene obtained. were was also obtained. susceptible to the degradation and a tripyridine complex in reaction with ethylene was obtained.

Catalysts 2020, 10, 887 18 of 56 Catalysts 2020, 10, x FOR PEER REVIEW 20 of 60

Scheme 24. AnAn amine-driven amine-driven decomposition product obtained with the excess of pyridine.

In 20092009 MooreMoore and and co-workers co-workers presented presented a study a stud ony the on stabilitythe stability of 1st of and 1st 2nd and generation 2nd generation Grubbs Grubbscarbenes carbenes with respect with torespect primary to primary amines amines [85,86]. [85,86]. The influence The influence of both ofn -butylamineboth n-butylamine [85] and [85] DETA and (diethylenetriamine)DETA (diethylenetriamine) [86] on the[86] catalysts on the were catalysts tested inwere ring-opening tested metathesisin ring-opening polymerization metathesis of polymerizationdicyclopentadiene of anddicyclopentadiene monitored by means and ofmonito the diffrederential by means scanning of calorimetry the differential (DSC) andscanning NMR calorimetrytechniques. (DSC) For the and 1st NMR generation techniques. catalysts For the the decomposition 1st generation catalysts together the with decomposition the detection together of a free withPCy3 theand detection other phosphine-containing of a free PCy3 and productsother phosphine-containing was observed within pr 10oducts min. Atwas the observed same time, within the 2nd 10 min.generation At the NHC-containing same time, the 2nd catalysts generation (Scheme NHC- 25)containing formed a newcatalysts carbene (Scheme species 25) accompanied formed a new by carbenephosphine species dissociation. accompanied Based by onphosphine these results dissociatio it wasn. suggested Based on these that the results replacement it was suggested of the PCy that3 theby areplacement primary amine of isthe the PCy first3 by step a inprimary the bimolecular amine iscoupling the first degradation.step in the bimolecular It was also concluded coupling degradation.that the greater It was steric also hindrance concluded of thethat NHC the greater ligand steric and its hindrance lower propensity of the NHC to exchange ligand and with its aminelower propensityprevents the to decomposition exchange with of amine the 2nd prevents generation the de catalysts.composition As an of indirect the 2nd evidence generation for thecatalysts. proposed As andegradation indirect evidence pathway, for new the ruthenium proposed complexes degradation were pathway, synthesized new with ruthenium an excess complexes of amine. Stablewere synthesizedcomplexes 22 withand an23 excesswere obtainedof amine. but Stable the complexes structure of 22 the and second 23 were one obtained has not beenbut the unequivocally structure of theconfirmed. second one However, has not thebeen early unequivocally decomposition confirmed. of catalyst However,23 in thethe presenceearly decomposition of n-butyloamine of catalyst and 23diethyl in the diallylmalonate presence of n-butyloamine indicated that and the diethyl methylidene diallylmalonate intermediate indicated is less stablethat the compared methylidene to its intermediatebenzylidene analogue.is less stable compared to its benzylidene analogue. A complementary study by Fogg’s group devoted to the decomposition of metathesis catalysts was reported in 2014. The authors of this investigation showed the impact of different amines on GII and its key intermediates formed in the catalytic cycle, that is, the methylidene resting state (GIIm) and the metallacyclobutane MCB (Scheme 26)[87]. First, GII was reacted with various amines and the resulting products were examined by means of NMR. In accordance with the earlier work of Moore [85], it was found that the less sterically hindered n-buthylamine (a) yielded the N-benzyl-N-buthylamine and bisamine complex, which further decomposed via a nucleophilic attack of another amine molecule on the benzylidene carbon atom. More bulky amines, such as pyrrolidine (b), morpholine (c) and DBU (diazabicycloundecene) (d) reacted slower and formed stable mono-amine adducts at room temperature (Scheme 26). Next, the authors investigated the sensitivity of the methylidene species to the presence of primary amines (Scheme 26). In all of these cases, reactions proceeded faster than for GII, even when using 1.1 equivalent of amine. Estimated half-lives of the resting states (a (12 min) > b (1.5 h) > c (14 h) > d (>24 h)) showed that the steric hindrance of amine is the crucial factor, as well as that DBU (d) + induced virtually no decomposition. Interestingly the phosphonium chloride MePCy3 Cl−, found as one of the byproducts, indicated a degradation path through a nucleophilic attack of the PCy3 on the methylidene released by the ligand exchange with amine and not from the attack of amine itself. This was further confirmed in studies of the 13C-labeled methylidene resting state with n-butyloamine,

Catalysts 2020, 10, x FOR PEER REVIEW 21 of 60

Catalysts 2020, 10, 887 19 of 56 as well as the predominance of a phosphine attack over an amine attack revealed by the 7:3 ratio of + n resultingCatalysts 2020 products,, 10, x FOR MePCy PEER REVIEW3 Cl− and CH3NH Bu, respectively [88]. 21 of 60

Scheme 25. The structure of investigated catalysts and obtained amine adducts in the study of ruthenium complexes stability towards amines.

A complementary study by Fogg’s group devoted to the decomposition of metathesis catalysts was reported in 2014. The authors of this investigation showed the impact of different amines on GII and its key intermediates formed in the catalytic cycle, that is, the methylidene resting state (GIIm) and the metallacyclobutane MCB (Scheme 26) [87]. First, GII was reacted with various amines and the resulting products were examined by means of NMR. In accordance with the earlier work of Moore [85], it was found that the less sterically hindered n-buthylamine (a) yielded the N-benzyl-N- buthylamine and bisamine complex, which further decomposed via a nucleophilic attack of another amine molecule on the benzylidene carbon atom. More bulky amines, such as pyrrolidine (b), morpholineScheme ( 25.25.c) and TheThe DBU structure structure (diazabicycloundecene) of investigated catalysts (d) reactedand obtained slower amine and formedadducts stablein the mono-amine study of adductsruthenium at room complexescomplexes temperature stabilitystability (Scheme towardstowards 26). amines.amines.

A complementary study by Fogg’s group devoted to the decomposition of metathesis catalysts was reported in 2014. The authors of this investigation showed the impact of different amines on GII and its key intermediates formed in the catalytic cycle, that is, the methylidene resting state (GIIm) and the metallacyclobutane MCB (Scheme 26) [87]. First, GII was reacted with various amines and the resulting products were examined by means of NMR. In accordance with the earlier work of Moore [85], it was found that the less sterically hindered n-buthylamine (a) yielded the N-benzyl-N- buthylamine and bisamine complex, which further decomposed via a nucleophilic attack of another amine molecule on the benzylidene carbon atom. More bulky amines, such as pyrrolidine (b), morpholine (c) and DBU (diazabicycloundecene) (d) reacted slower and formed stable mono-amine adducts at room temperature (Scheme 26).

Scheme 26. The amine-driven decomposition of ruthenium complexes studied by Fogg.

The inﬂuence of amines on the RCM reaction were also tested (Scheme 27) and the results showed an accelerated catalyst degradation compared to the control reaction. The presence of a phosphonium salt in reactions with amines a–c indicated, that the deactivation occurs through the decomposition of the resting state. In the presence of DBU an instant decomposition was observed with no trace of salt but only free PCy3. Thus, the deprotonation of the metallacyclobutane MCB by this highly

Scheme 26. The amine-driven decomposition of ruthenium complexes studied by Fogg.

Catalysts 2020, 10, x FOR PEER REVIEW 22 of 60

Next, the authors investigated the sensitivity of the methylidene species to the presence of primary amines (Scheme 26). In all of these cases, reactions proceeded faster than for GII, even when using 1.1 equivalent of amine. Estimated half-lives of the resting states (a (12 min) > b (1.5 h) > c (14 h) > d (>24 h)) showed that the steric hindrance of amine is the crucial factor, as well as that DBU (d) induced virtually no decomposition. Interestingly the phosphonium chloride MePCy3+Cl−, found as one of the byproducts, indicated a degradation path through a nucleophilic attack of the PCy3 on the methylidene released by the ligand exchange with amine and not from the attack of amine itself. This was further confirmed in studies of the 13C-labeled methylidene resting state with n-butyloamine, as well as the predominance of a phosphine attack over an amine attack revealed by the 7:3 ratio of resulting products, MePCy3+Cl− and CH3NHnBu, respectively [88]. The influence of amines on the RCM reaction were also tested (Scheme 27) and the results showed an accelerated catalyst degradation compared to the control reaction. The presence of a Catalystsphosphonium2020, 10, 887salt in reactions with amines a–c indicated, that the deactivation occurs through20of the 56 decomposition of the resting state. In the presence of DBU an instant decomposition was observed with no trace of salt but only free PCy3. Thus, the deprotonation of the metallacyclobutane MCB by basicthis highly amine basic was amine suggested was suggested as the true as mechanism the true mechanism of decomposition. of decomposition. It was also It was concluded also concluded that the highthat the basicity high ofbasicity amines of together amines withtogether thebulkiness with the ofbulkiness the ylidene of the moiety ylidene are themoiety critical are parametersthe critical inparameters this phenomenon. in this phenomenon. These results These were alsoresults in agreementwere also in with agreement the observed with ligandthe observed exchange ligand and amine-adductsexchange and amine-adducts formation for secondaryformation aminesfor secondary and GII amines[84,87] and and GII the precatalyst[84,87] and degradationthe precatalyst by unhindereddegradation primaryby unhindered amines. primary amines.

SchemeScheme 27.27. The proposed mechanism of amine-induced decomposition in conditions of ring-closing metathesis (RCM). metathesis (RCM).

The same group carriedcarried out thethe reactionreaction ofof thethe benzylidenebenzylidene andand methylidenemethylidene derivativesderivatives of Grubbs catalyst withwith pyridinepyridine (py).(py). While reacting this nitrogen-containingnitrogen-containing heterocyclic base with resting statesstates of of 1st 1st generation generation catalysts, catalysts, a rapid a ra disappearancepid disappearance of the of ylidene the ylidene functionality functionality was noticed was togethernoticed together with simultaneous with simultaneous formation formation of a new adduct of a new bearing adduct three bearing pyridine three molecules pyridine24 molecules(Scheme 28 24). Both the 1st and 2nd generation precatalyst provided bis-pyridine carbene complexes, as reported previously [89,90], implying the absence of the phosphine attack on benzylidene. Adduct 24 completely + decomposed within 18 h at 60 ◦C to free PCy3, MePCy3 Cl− and three other, unidentiﬁed compounds, which probably come from other co-existing decay paths. The authors were not able to connect any of these products with the CH2 = PCy3 ylide, as proposed in the prior work of Grubbs [84]. Instead, + they associated the production of MePCy3 Cl− with an intermolecular proton abstraction. Catalyst GI, under metathesis condition of diethyl diallylmalonate RCM, gave ca. 80% of 24, showing that the main attack was at the resting state and not at the metallacyclobutane. The principal conclusion of this work is that any donor able to replace the phosphine ligand and stabilize the methylidene species may cause the deactivation of the catalyst using the same route. Catalysts 2020, 10, x FOR PEER REVIEW 23 of 60

(Scheme 28). Both the 1st and 2nd generation precatalyst provided bis-pyridine carbene complexes, as reported previously [89,90], implying the absence of the phosphine attack on benzylidene. Adduct 24 completely decomposed within 18 h at 60 °C to free PCy3, MePCy3+Cl− and three other, unidentified compounds, which probably come from other co-existing decay paths. The authors were not able to connect any of these products with the CH2 = PCy3 ylide, as proposed in the prior work of Grubbs [84]. Instead, they associated the production of MePCy3+Cl− with an intermolecular proton abstraction. Catalyst GI, under metathesis condition of diethyl diallylmalonate RCM, gave ca. 80% of 24, showing that the main attack was at the resting state and not at the metallacyclobutane. The principalCatalysts 2020 conclusion, 10, 887 of this work is that any donor able to replace the phosphine ligand and stabilize21 of 56 the methylidene species may cause the deactivation of the catalyst using the same route.

Scheme 28. The donor-induced decomposition of 1st1st generation generation ruthenium ruthenium carbene carbene catalysts. catalysts.

Similar resultsresults werewere obtained obtained by by Fogg’s Fogg’s group group for Hoveyda-Grubbsfor Hoveyda-Grubbs catalyst catalyst treated treated withthe with excess the excessof diﬀerent of different nitrogen nitrogen bases in bases the presence in the presence or absence or of absence the oleﬁn of the [91]. olefin Non-bulky [91]. Non-bulky primary amines primaryf,g aminesformed mono-f,g formed and bisaminobenzylidene mono- and bisaminobenzylidene complexes with HGIIcomplexes, which furtherwith HGII decomposed, which tofurther25/250 decomposedand NH2CH2 toAr 25/25 amine′ and (Scheme NH2CH 29).2Ar The aminen-butylamine (Scheme 29). derivative The n-butylamine25 was also derivative isolated, starting 25 wasfrom also isolated,either the startingHGII or fromGII eithercatalysts. the HGII On the or other GII catalysts. hand the On sterically the other crowded hand thesec -butylaminesterically crowded gave only sec- butylaminethe single-substituted gave only derivative,the single-substituted which was derivative, resistant to which further was degradation resistant to (Scheme further 29 degradation). Reaction with(Scheme secondary 29). Reaction amines, pyridinewith secondary or DBU (amines,a–d) led topyridine stable complexesor DBU ( containinga–d) led to one stable amine complexes molecule containingcoordinated one to amine ruthenium molecule (two coordinated in the case to of ruthenium pyridine) for(two all in cases, the case apart of pyridine) from Et3N, for for all whichcases, n apartno reaction from Et was3N, observed.for which no The reaction dependence was observed. the on spatial The dependence hindrance (theNH 2onBu spatial>> NH hindrance2CH2Ph) (NHcorresponds2nBu >> NH to the2CH proposed2Ph) corresponds loss of the to benzylidene the proposed ligand loss asof athe result benzylidene of a nucleophilic ligand as attack a result through of a nucleophilicconcerted pathways attack through presented concerte in Schemed pathways 30. presented in Scheme 30.

Catalysts 2020, 10, x FOR PEER REVIEW 24 of 60 Catalysts 2020, 10, 887 22 of 56 Catalysts 2020, 10, x FOR PEER REVIEW 24 of 60

SchemeScheme 29. 29. HGII HGII and and GIIGII reactionsreactions with with secondary secondary amines amines and and DBU. DBU.

Scheme 30. The reaction of HGII with primary amines. Scheme 30. The reaction of HGII with primary amines.

TheThe addition addition of of amines amines to to styrene styrene self-metathesisself-metathesis reaction resulted resulted in in the the decrease decrease of ofyield yield with with theThe increase addition of Broensted of amines basicity to styren of thee self-metathesis amines. The detailed reaction decomposition resulted in the pathways decrease were of yieldstudied with the increase of Broensted basicity of the amines. The detailed decomposition pathways were studied thefor increase pyrrolidine, of Broensted DBU and basicity NEt3, which of the were amines. found The to detailed be the most decomposition detrimental basespathways for this were process. studied for pyrrolidine, DBU and NEt3, which were found to be the most detrimental bases for this process. forThe pyrrolidine, major organic DBU product and NEt observed3, which during were foundthe decomposition to be the most was detrimental (E)-PhCH = basesCHCH for2Ph, this with process. the The major organic product observed during the decomposition was (E)-PhCH = CHCH2Ph, with the Theadditional major organic presence product of (E)-PhCH observed = CHCH during3 when the decomposition NEt3 were used. was To explain(E)-PhCH these = CHCH observations,2Ph, with the the additional presence of (E)-PhCH = CHCH when NEt were used. To explain these observations, additionalauthors proposedpresence aof deactivation (E)-PhCH = mechanismCHCH3 when3 involving NEt3 were3 the deprotonationused. To explain of athese sterically observations, accessible the theauthors authors proposed proposed a deactivation a deactivation mechanism mechanism involving involving the the deprotonation deprotonation of of a a sterically sterically accessible

Catalysts 2020, 10, 887 23 of 56 CatalystsCatalysts 20202020,, 1010,, xx FORFOR PEERPEER REVIEWREVIEW 2525 ofof 6060 metallacyclobutanemetallacyclobutane intermediateintermediate (Scheme(Scheme 31 31),31),), toto generategenerate anan anionic anionic ruthenium rutheniumruthenium complex complex 2626 andand then, then, throughthrough thethe subsequentsubsequent protonationprotonationprotonation andandand elimination,elimination,elimination, the thethe release releaserelease of ofof ( (E(EE)-PhCH)-PhCH)-PhCH= == CHCHCHCH222Ph.Ph. Traces Traces ofof thethe transtrans-propenylbenzene-propenylbenzene suggests suggests that, that, in in the the casecase ofof thethe lesslessless basicbasicbasic NEtNEtNEt333,, the the deprotonationdeprotonation of of thethe monosubstitutedmonosubstituted metallacyclobutanemetallacmetallacyclobutaneyclobutane occurred.occurred.

SchemeScheme 31.31. TheThe proposed proposed mechanismmechanism ofof deactivationdeactivation ofof HGIIHGII byby amine.amine.

InIn anotheranother workwork devoteddevoted toto metathesismetathesismetathesis catalysts’catalysts’catalysts’ decomposition,decomposition,decomposition, Fogg’s Fogg’s groupgroup confirmedconfirmedconfirmed anan earlierearlier assumptionassumptionassumption that thatthat the thethe presence presencepresence of Lewis ofof LewisLewis donor donordonor accelerates acceleratesaccelerates the loss the ofthe methylidene lossloss ofof methylidenemethylidene from phosphine fromfrom stabilizedphosphinephosphine complexes stabilizedstabilized complexes[complexes92]. The previously [92].[92]. TheThe previouslypreviously proposed mechanism proposedproposed mechanismmechanism of the nucleophilic ofof thethe nucleophilicnucleophilic attack of the attackattack free phosphineofof thethe freefree onphosphinephosphine the methylidene onon thethe methylidenemethylidene moiety, resulting moiety,moiety, in the resultingresulting loss of thisinin thethe functionality lossloss ofof thisthis with functionalityfunctionality phosphonium withwith saltphosphoniumphosphonium [CH3PR3]Cl saltsalt release [CH[CH33PR (SchemePR33]Cl]Cl releaserelease 28), was (Scheme(Scheme also shown 28),28), waswas to operate alsoalso shownshown for weaker toto operateoperate Lewis forfor donors, weakerweaker such LewisLewis as THF,donors,donors, H2 O,suchsuch MeOH, asas THF,THF, MeCN, HH22O,O, DMSO, MeOH,MeOH, as MeCN,MeCN, well as DMSO,DMSO, a series asas of wellwell 2nd generationasas aa seriesseries Grubbsofof 2nd2nd generation catalyst,generation including GrubbsGrubbs benzylidenecatalyst,catalyst, includingincluding and indenylidene benzylidenebenzylidene derivatives andand indenylideneindenylidene (Scheme derivatives derivatives32). The lack (Scheme(Scheme of a significant 32).32). TheThe elacklackffect ofof on aa the significantsignificant catalyst degradationeffecteffect onon thethe catalystcatalyst of such degradationdegradation donors as NH ofof suchsuch3, urea donorsdonors or phosphoramide asas NHNH33,, ureaurea oror wasphosphoramidephosphoramide consistent with waswas consistent theconsistent previously withwith observedthethe previouslypreviously lack ofobservedobserved degradation lacklack ofof of degradationdegradation the GII catalyst ofof thethe by GIIGII DBU catalystcatalyst [87] byby and DBUDBU indicates [87][87] andand that indicatesindicates Lewis that basicitythat LewisLewis is irrelevant,basicitybasicity isis irrelevant, ifirrelevant, steric hindrance ifif stericsteric hindrance preventshindrance the prevenpreven approachtsts thethe to approachapproach the metal toto center. thethe metalmetal Moreover, center.center. Moreover, theMoreover, formation thethe offormationformation a hitherto ofof undetected aa hithertohithertoσ -alkylundetectedundetected intermediate σσ-alkyl-alkyl 27 intermediateintermediatewas confirmed 2727 inwaswas labelled confirmedconfirmed NMR in experimentsin labelledlabelled NMRNMR with complexexperimentsexperiments bearing withwith andcomplexcomplex IMes bearingbearing ligand and and IMesIMes pyridine ligandligand at and 50and◦ pyridineC.pyridine The unsuccessful atat 5050 °C.°C. TheThe attempts unsuccessfulunsuccessful to detect attemptsattempts this complextoto detectdetect thisusingthis complexcomplex SIMes adducts usingusing SIMesSIMes were adductsadducts explained werewere by explainedexplained a short life byby of aa the shortshort resulting lifelife ofof thethe species resultingresulting and by speciesspecies effortless andand C–Hbyby effortlesseffortless activation C–HC–H of activation theactivation methyl ofof group thethe methylmethyl in the grouporthogroupposition inin thethe orthoortho of the positionposition mesityl ofofsubstituent. thethe mesitylmesityl substituent. Thus,substituent. elimination Thus,Thus, byeliminationelimination proton abstraction byby protonproton fromabstractionabstraction the NHC fromfrom was ththe promotede NHCNHC waswas as promotedpromoted a consequence asas aa consequenceconsequence of π-backbonding ofof ππ-backbonding-backbonding onto SIMes ligand,ontoonto SIMesSIMes which ligand,ligand, was reflected whichwhich waswas in anreflectedreflected inhibited inin anan rotation inhibitedinhibited (Scheme rotationrotation 33)[ (Scheme(Scheme93]. 33)33) [93].[93].

SchemeScheme 32.32. TheThe rate-limiting rate-limiting step step for for thethe donor-accelerateddonor-accelerated lossloss ofof methylidene.methylidene.

Catalysts 2020, 10, 887 24 of 56 Catalysts 2020, 10, x FOR PEER REVIEW 26 of 60

Scheme 33.33.The The rate rate limiting limiting step step for thefor donor-acceleratedthe donor-accele lossrated of loss methylidene of methylidene based on based the inhibition on the ofinhibition the carbene of the rotation. carbene rotation.

Based on the rate at whichwhich thethe decompositiondecomposition occursoccurs and on the influenceinfluence ofof donorsdonors bulkinessbulkiness and stoichiometry authors assumed that the observed degradation proceeds is an an associative associative process. process. The established reaction rate for DMSO showed a first-orderfirst-order dependencedependence on its concentrationconcentration for both tested complexes, GII and the 1st generation methylidene complex GIm. Additional Additional deuterium- deuterium- labelling studiesstudies confirmed confirmed that that the rate-determiningthe rate-determining step here step is thehere ligand is the binding ligand for binding the methylidene for the complexmethylideneGIIm complexand the GIIm C-H and activation the C-H for activation the unsaturated for the unsaturatedGIIm_IMes GIIm_IMes(Scheme 32 (Scheme). It was 32). also It demonstratedwas also demonstrated that ethylidene that ethylidene ligand introduced ligand introduced to GII in the to reactionGII in the with reaction 2-butene with prevents 2-butene the donor-inducedprevents the donor-induced ylidene abstraction, ylidene as evidenced abstractio byn, theas lackevidenced of the [EtPCyby the3]Cl lack production. of the [EtPCy3]Cl production. 2.7. N-Heterocyclic Carbenes 2.7. N-HeterocyclicWhile N-heterocyclic Carbenes carbenes are often used as auxiliary ligands in ruthenium metathesis catalysts, they canWhile also N-heterocyclic act as a Lewis basescarbenes and are accelerate often used the decomposition as auxiliary ligands of such complexesin ruthenium when metathesis added to thecatalysts, reaction they mixture. can also Recently act as a Fogg’sLewis bases group and showed accelerate that small the decomposition NHC ligand in of ruthenium such complexes catalyst when may expediteadded to itsthe decomposition reaction mixture. [94]. Recently During theFogg’s attempts group to showed synthesize that the small methylidene NHC ligand complex in ruthenium with the truncatedcatalyst may IMe expedite4 ligand fromits decomposition the 1st generation [94]. complex During GImthe ,attempts a stable four-coordinatedto synthesize the Ru(Cl) methylidene2(IMe)4 complex 28 was observed, instead of the expected ligand exchange product (Scheme 34). This species complex with the truncated IMe4 ligand from the 1st generation complex GIm, a stable four- was additionally accompanied by a free PCy and ethylimidazolium salt A. The reaction completed coordinated Ru(Cl)2(IMe)4 complex 28 was3 observed, instead of the expected ligand exchange rapidly in less than 5 min at 80 C. The formation of product A was confirmed independently by product (Scheme 34). This− species◦ was additionally accompanied by a free PCy3 and NMRethylimidazolium experiments salt with A labeled. The reaction methylidene completedGIm rapidlyand synthesis. in less than Further 5 min DFT at − calculations80 °C. The formation indicated thatof product complex A was28 was confirmed formed byindependently the nucleophilic by NMR IMe4 experimentsligand attack with on the labeled methylidene methylidene carben GIm carbon, and rather than the phosphine exchange, for which the estimated energy barrier is 5–6 kcal/mol higher. synthesis. Further DFT calculations indicated that complex 28 was formed by the nucleophilic IMe4 Inligand the suggested attack on mechanismthe methylidene (Scheme carben 34) it carbon, was noted rather that than the resultedthe phosphine adduct exchange, [Ru-CH2IMe for4 ]which preferred the theestimated elimination energy reaction barrier is which 5–6 kcal/mol leads to higher.N-heterocyclic In the suggested olefin (NHO mechanism) over the (Scheme protonolysis 34) it was and noted the release of [CH IMe ]Cl. Calculations provided also the evidence that the NHO may be involved that the resulted3 adduct4 [Ru-CH2IMe4] preferred the elimination reaction which leads to N- in further catalyst degradation as a potential nucleophile (Scheme 34b). Complex 29, produced in heterocyclic olefin (NHO) over the protonolysis and the release of [CH3IMe4]Cl. Calculations thisprovided reaction also and the bearing evidence highly that basicthe NHO CH2CH may2IMe be4 ligandinvolved undergoes in further the catalyst protonolysis degradation to give as salt a Apotential, likely proceedednucleophile by (Scheme PCy3/ IMe34b).4 exchange.Complex 29, Additionally, produced in analogousthis reaction reaction and bearing of IMe highly4 with basic the methylidene complex of 2nd generation carbene GIIm resulted in adduct 28 instead of the expected CH2CH2IMe4 ligand undergoes the protonolysis to give salt A, likely proceeded by PCy3/IMe4 RuCl (SIMes)(IMe ) product, in contrast to standard, larger NHC. The estimated energetic cost of the exchange.2 Additionally,4 n analogous reaction of IMe4 with the methylidene complex of 2nd generation attack of SIMes on the methylidene was found to be higher than for a small ligand such as IMe and carbene GIIm resulted in adduct 28 instead of the expected RuCl2(SIMes)(IMe4)n product, in contrast4 introducesto standard, significant larger NHC. geometric The estimated strain, therefore energetic no co suchst of the decomposition attack of SIMes was on observed the methylidene for SIMes. was found to be higher than for a small ligand such as IMe4 and introduces significant geometric strain, therefore no such decomposition was observed for SIMes.

Catalysts 2020, 10, 887 25 of 56 Catalysts 2020, 10, x FOR PEER REVIEW 27 of 60

Scheme 34. TheThe decomposition decomposition pathway pathway of ofthe the methylidene methylidene active active species species by bysmall small ligands: ligands: (a)

(tetramethylimidazol-2-ylidenea) tetramethylimidazol-2-ylidene IMe IMe4 and4 and (b ()b N-heterocyclic) N-heterocyclic olefin olefin CH CH2 2== IMeIMe4,4 ,with with the the Gibbs Gibbs free energy profileprofile fromfrom DFTDFT calculations.calculations. 2.8. Acrylonitrile 2.8. Acrylonitrile The next external agent which was found to cause ruthenium catalysts decomposition, The next external agent which was found to cause ruthenium catalysts decomposition, is is acrylonitrile. It is an interesting example since it is a very weak base, that is not able to abstract acrylonitrile. It is an interesting example since it is a very weak base, that is not able to abstract hydrogen atoms and can rarely form stable adducts after attack on the ruthenium core. Nevertheless it hydrogen atoms and can rarely form stable adducts after attack on the ruthenium core. Nevertheless was found that at elevated temperature such adducts can be formed. In 2011 Zhao, Wang and Guo it was found that at elevated temperature such adducts can be formed. In 2011 Zhao, Wang and Guo presented electrospray ionization tandem mass spectrometry (ESI-MS/MS) study with off-line and presented electrospray ionization tandem mass spectrometry (ESI-MS/MS) study with off-line and on-line detection of the degradation of the 1st generation ruthenium complexes under the influence on-line detection of the degradation of the 1st generation ruthenium complexes under the influence of acrylonitrile [95]. In the first, control experiment with GI in CH2Cl2 they observed the formation of acrylonitrile [95]. In the first, control +experiment with GI in CH2Cl2 they observed the formation of of a phosphine product (PhCH2PCy+ 3) , which was consistent with previous work of Grubbs [96]. a phosphine product (PhCH2PCy3) , which was consistent with previo+ us work of Grubbs [96]. Shortly Shortly after the addition of acrylonitrile, signals form+ (HPCy3) ion and the relative abundance after the addition of acrylonitrile,+ signals form (HPCy3) ion and the relative abundance increase of increase of (PhCH2PCy3) were observed (Scheme 35). Within 15 min catalyst decomposed entirely (PhCH2PCy3)+ were observed (Scheme 35). Within 15 min catalyst decomposed entirely and a new and a new signal of ruthenium decomposition products 30a–d and 33a–d arose. Complexes 30c signal of ruthenium decomposition products 30a–d+ and 33a–d arose. Complexes 30c+ and 30d were and 30d were identified as [RuCl(CH3CN)4PCy3] and [RuCl(CH3CN)3(PCy3)2] based on their identified as [RuCl(CH3CN)4PCy3]+ and [RuCl(CH3CN)3(PCy3)2]+ based on their isotopic patterns. isotopic patterns. Accordingly, structures 30a and 30b in equilibrium with 30c–d were established Accordingly, structures+ 30a and 30b in equilibrium+ with 30c–d were established as as [RuCl(CH3CN)2PCy3] and [RuCl(CH3CN)3PCy3] . Ru-species 33a–b were suggested to appear [RuCl(CH3CN)2PCy3]+ and [RuCl(CH3CN)3PCy3]+. Ru-species 33a–b were suggested to appear from from the C-H activation but this assumption was ambiguously proved. It was further postulated the C-H activation but this assumption was ambiguously proved. It was further postulated that a that a higher concentration of acrylonitrile promoted a faster loss of chloride and phosphine ligands, higher concentration of acrylonitrile promoted a faster loss of chloride and phosphine ligands, as as evidenced by the formation of compound 31d. Moreover, the presence of 31a–d was detected only evidenced by the formation of compound 31d. Moreover, the presence of 31a–d was detected only in in the early stage of the catalyst decomposition, indicating that these were transient intermediates. the early stage of the catalyst decomposition, indicating that these were transient intermediates. These results allowed to propose the predominant mechanism of degradation promoted by acrylonitrile These results allowed to propose the predominant mechanism of degradation promoted by presented on Scheme 35 path A, which was consistent with the slow degradation in CH Cl observed acrylonitrile presented on Scheme 35 path A, which was consistent with the slow degradation2 2 in earlier [97]. A second possible decomposition pathway (path B in Scheme 35) was associated with the CH2Cl2 observed earlier [97]. A second possible decomposition pathway (path B in Scheme 35) was formation of compound 32a through the loss of toluene from 31a and its appropriate CH CN adducts associated with the formation of compound 32a through the loss of toluene from 3 31a and its 32b–c. The authors assumed that the C-H activation was the result of an agostic interaction between appropriate CH3CN adducts 32b–c. The authors assumed that the C-H activation was the result of an the Ru atom and one of the cyclohexyl ring, which was made possible due to a greater steric freedom agostic interaction between the Ru atom and one of the cyclohexyl ring, which was made possible of the resulting species after the loss of phosphine and chloride. due to a greater steric freedom of the resulting species after the loss of phosphine and chloride.

Catalysts 2020, 10, 887 26 of 56 Catalysts 2020, 10, x FOR PEER REVIEW 28 of 60

Scheme 35.35. The mechanism of acrylonitrile driven decomposition proposed byby GuoGuo etet al.al.

Comprehensible,Comprehensible, real-time monitoring droplet spray ionizationionization tandem massmass spectrometryspectrometry (DSI-MS)(DSI-MS) studiesstudies onon thethe behaviorbehavior ofof thethe 2nd2nd generationgeneration catalystscatalysts inin thethe presencepresence ofof acrylonitrileacrylonitrile werewere conductedconducted byby JinJin inin 20172017 [[98].98]. The obtainedobtained results were veryvery similarsimilar toto thosethose forfor thethe 1st1st generationgeneration catalysts.catalysts. The decomposition pathwa pathwayy proposed by authors starts with a heterolyticheterolytic bondbond cleavagecleavage andand aa lossloss ofof chlorinechlorine ((3434)) andand thenthen thethe dissociationdissociation ofof thethe phosphinephosphine formingforming complexcomplex 3535.. AtAt thisthis point,point, two degradation pathways pathways are are possible possible (Scheme (Scheme 36). 36 ).Path Path A Aincludes includes Ph-CH Ph-CH = H=2IMesH2IMes ion loss ion losswith with simultaneous simultaneous attachment attachment of acrylonitrile of acrylonitrile molecules molecules and SIMes and SIMescarbene carbene to give to37 give. Then,37 .a Then,series aof series capture of capture and release and release of CH of3CN CH 3moleculesCN molecules followed followed finally ﬁnally by bya PCy a PCy3 3rebindingrebinding leads leads to to thethe formationformation ofof aa veryvery stablestable hexacoordinatedhexacoordinated complexcomplex 3838.. ItIt isis worthworth notingnoting thatthat thethe detachmentdetachment ofof oneone acrylonitrileacrylonitrile moleculemolecule fromfrom37 37results results in in the the formation formation of of compound compound39 ,39 which, which was was not not considered considered for thefor earlierthe earlier generation generation of ruthenium of ruthenium carbenes. carbenes In the. secondIn the routesecond (Scheme route 36(Scheme) a series 36) of subsequenta series of subsequent coordination of acrylonitrile molecules combined with phosphine association leads to compound 36, which can also be formed directly from complex 34.

Catalysts 2020, 10, 887 27 of 56 coordination of acrylonitrile molecules combined with phosphine association leads to compound 36, whichCatalysts can2020 also, 10, xbe FOR formed PEER REVIEW directly from complex 34. 29 of 60

Scheme 36. TheThe mechanism mechanism of of decomposition decomposition of GII by CH CH33CNCN based based on on mass mass spectrometry spectrometry analysis. analysis.

The latestlatest theoretical theoretical studies studies on theon stabilitythe stability of Hoveyda-Grubbs-type of Hoveyda-Grubbs-type catalyst catalyst under the under inﬂuence the influenceof acrylonitrile of acrylonitrile were presented were bypresented Trzaskowski’s by Trzaskowski’s group [99]. group In this [99]. work In the this reaction work the of acrylonitrile reaction of acrylonitrileself-metathesis self-metathesis as well as possible as well decomposition as possible routes decomposition with standard routes Hoveyda-Grubbs with standard catalyst Hoveyda- and Grubbstwo CAAC catalyst derivatives and two were CAAC investigated. derivatives Three were ways investigated. of degradation Three wereways considered—throughof degradation were considered—throughβ-elimination of metallacyclobutane β-elimination usingof metallacyclobutane van Rensburg mechanism using van (oleﬁn-driven), Rensburg mechanism via Buchner (olefin- ring driven),expansion via leading Buchner to ring cycloheptatriene expansion leading and through to cycloheptatriene the direct attack and through of the nitrile the direct molecule. attack Since of the it wasnitrile concluded molecule. that Since the mostit was likely concluded mechanism that isthe via most the Buchnerlikely mechanism ring expansion is via and the depends Buchner on ring the expansionstructure of and the depends catalyst, on it is the reviewed structure in of the the next catalyst, part of it this is reviewed study. in the next part of this study.

2.9. CO and O2 2.9. CO and O2 There are two more compounds known to cause ruthenium metathesis catalysts’ decomposition. There are two more compounds known to cause ruthenium metathesis catalysts’ decomposition. One is CO, a potent Lewis acid, commonly found in various transition metal complexes. Similarly to One is CO, a potent Lewis acid, commonly found in various transition metal complexes. Similarly to acrylonitrile, however, CO act as a complexing agent which enables deactivation and decomposition of acrylonitrile, however, CO act as a complexing agent which enables deactivation and decomposition ruthenium NHC complexes via Buchner-type expansion. The second species is O2 known to promote of ruthenium NHC complexes via Buchner-type expansion. The second species is O2 known to the C–H activation also mostly in the NHC-containing complexes. Due to this features, investigations promote the C–H activation also mostly in the NHC-containing complexes. Due to this features, on the CO-driven and O2-dependent decomposition are reviewed in the next section. investigations on the CO-driven and O2-dependent decomposition are reviewed in the next section. In 2003, Trnka and Grubbs observed the effect of traces of oxygen on the synthesis of the GII catalyst (Scheme 37) and they were able to isolate this compound from the reaction mixture, which was formed as a result of the C–H activation of ortho methyl group in mesityl substituent [100]. Dinger and Mol conducted similar experiment as previously with primary alcohols using water but it did not bring the expected results, since no ruthenium hydride was formed. Instead the tricyclohexylphosphane oxide was obtained together with a one-phosphorus compound that was

Catalysts 2020, 10, 887 28 of 56

In 2003, Trnka and Grubbs observed the effect of traces of oxygen on the synthesis of the GII catalyst (Scheme 37) and they were able to isolate this compound from the reaction mixture, which was formed as a result of the C–H activation of ortho methyl group in mesityl substituent [100]. Dinger and Mol conducted similar experiment as previously with primary alcohols using water but it did not bring theCatalysts expected 2020, 10 results,, x FOR PEER since REVIEW no ruthenium hydride was formed. Instead the tricyclohexylphosphane30 of 60 oxide was obtained together with a one-phosphorus compound that was neither hydride nor carbene andneither which hydride structure nor carbene was not and determined which structure [38]. They was also not carrieddetermined out the [38]. reaction They also of GI carriedwith oxygenout the lookingreaction forof aGI source with ofoxygen oxygen looking to form for ruthenium a source carbonylof oxygen5. Theto form maximum ruthenium yield carbonyl in solution 5. wasThe aroundmaximum 15% yield for 5in(Scheme solution 37 was), while around the 15% same for reaction 5 (Scheme performed 37), while overnight the same with reaction a solid performed sample at 40overnight bar of O with2 at 60 a ◦solidC gave sample 75% ofat the40 desiredbar of O product.2 at 60 °C Second gave generation75% of the Grubbsdesired catalysts product. behaved Second ingeneration a similar Grubbs manner, catalysts although behaved they reacted in a similar more ma slowlynner, (3although days, at they 50 barreacte O2d, 60more◦C) slowly and with (3 days, less eatffi 50ciency bar O (29%2, 60 of °C) phenyl and with Ru-complex) less efficiency (Scheme (29% 37)[ of39 phenyl]. It was Ru-complex) suggested that (Scheme the final 37) Ru [39]. species It was is formedsuggested by that the oxygenthe final attack Ru species at the is benzylidene formed by group.the oxygen attack at the benzylidene group.

Scheme 37. The reactions of ruthenium Grubbs carbenes in presence ofof OO22.

The decompositiondecomposition of of Hoveyda-type Hoveyda-type complexes complexes under under air, air, reported reported by Blechert,by Blechert, is mentioned is mentioned later inlater this in review this review in the in C-H the activation C-H activation section. section. Later, Cazin’sLater, Cazin’s Group studiedGroup studied the effect the of effect air on of the air catalytic on the performancecatalytic performance of commercially of commercially available available ruthenium ruthenium catalysts catalysts by systematically by systematically changing changing the reaction the conditionsreaction conditions [101]. The [101]. RCM The reaction RCM forreaction N-tosyldiallylamine for N-tosyldiallylamine was conducted was conducted in non-degassed in non-degassed solvents, lowsolvents, catalyst low loading catalyst in loading air and in its air components and its components (N2, CO2 ,O(N2,,H CO2O2, O and2, H dry2O and air). dry It was air). shown It was thatshown for allthat tested for all catalysts, tested catalysts, the influence the influence of oxygen of and,oxygen in second and, in place, second carbon place, dioxide, carbon dioxide, were less were harmful less thanharmful expected. than expected. The most The deleterious most deleterious effect was effe assignedct was to assigned water and to thiswater results and wasthis additionallyresults was confirmedadditionally by confirmed the decrease by ofthe the decrease reaction of conversion. the reaction Moreover, conversion. these Moreover, results were these in agreementresults were with in relativelyagreement high with amounts relatively of high catalyst amounts which of need catalyst to be which used in need metathesis to be used in aqueous in metathesis media in [67 aqueous]. mediaRecently, [67]. Ton and Fogg reported investigations on the impact of oxygen on various ruthenium catalysts,Recently, including Ton and those Fogg bearing reported CAACs investigations [102]. In all on cases, the impact the decrease of oxygen in ring on various closing metathesisruthenium productivitycatalysts, including was observed those bearing under 8% CAACs of oxygen [102]. in In Ar. all A cases, comparison the decrease with a simultaneouslyin ring closing metathesis conducted reactionproductivity under was nitrogen observed showed unde thatr CAAC-bearing8% of oxygen catalystsin Ar. A were comparison the most Owith2-resistant a simultaneously and gave the highestconducted metathesis reaction yields. under Basednitrogen on theshowed inhibition that CAAC-bearing of degradation catalysts by PCy3 additionwere the authorsmost O suggested2-resistant thatand thegave products the highest of oxidative metathesis degradation yields. Base operated on throughthe inhibition a four-coordinated of degradation ruthenium by PCy3 complexaddition bothauthors in their suggested experiments that the as wellproducts as in those of oxidative described degradation by Mol [39] andoperate Trnka through and Grubbs a four-coordinated [100]. As such, threeruthenium different complex transformation both in their paths experiments were proposed as we (Schemell as in 38 those)—(a) described a benzylidene by Mol attack [39] byand O 2Trnka, (b) a [2and+2] Grubbs cycloaddition [100]. As of such, O2—proposed three different by analogy transformation to molybdenum paths were Schrock-catalysts proposed (Scheme [103 ]38)—(a) and (c) a bimolecularbenzylidene degradationattack by O with2, (b) stilbenea [2+2] release.cycloaddition of O2—proposed by analogy to molybdenum Schrock-catalysts [103] and (c) a bimolecular degradation with stilbene release.

Catalysts 2020, 10, 887 29 of 56 Catalysts 2020, 10, x FOR PEER REVIEW 31 of 60

SchemeScheme 38. 38.Three Three proposed proposed reaction reaction of of Ru-catalyst Ru-catalyst under under oxygen,oxygen, n.d.n.d. == notnot determined; determined; (a)( a) a

benzylidenebenzylidene attackattack by O O2,2 ,((b)b a) [2+2] a [2+ cycloaddition2] cycloaddition of O of2, (c O) 2a,( bimolecularc) a bimolecular degradation degradation with stilbene with stilbene release. release.

TheThe experimentalexperimental analysisanalysis ofof thethe productsproducts ledled toto thethe conclusionconclusion thatthat thethe degradationdegradation throughthrough cycloadditioncycloaddition is is the the dominant dominant reaction reaction but withbut alsowith some also carbon some attackcarbon on theattack alkylidene on the substituent.alkylidene In addition, under the conditions of the experiment, oxygen also acts as the PCy scavenger, facilitating substituent. In addition, under the conditions of the experiment, oxygen 3also acts as the PCy3 degradationscavenger, facilitating via bimolecular degradation coupling. via bimolecular In view of these coupling. results, In theview remarkable of these results, oxygen the tolerance remarkable of CAACoxygen ligand tolerance catalysts of CAAC is unexpected ligand catalysts and its is originunexpected is under and further its origin investigation. is under further investigation. 2.10. CO 2.10. CO There is one more compounds known to cause ruthenium metathesis catalysts’ decomposition, There is one more compounds known to cause ruthenium metathesis catalysts’ decomposition, namely CO, a potent Lewis acid, commonly found in various transition metal complexes. Similarly to namely CO, a potent Lewis acid, commonly found in various transition metal complexes. Similarly acrylonitrile, however, CO act as a complexing agent which enables deactivation and decomposition to acrylonitrile, however, CO act as a complexing agent which enables deactivation and of ruthenium NHC complexes exclusively via the Buchner-type expansion. Due to this feature, decomposition of ruthenium NHC complexes exclusively via the Buchner-type expansion. Due to investigations on the CO-driven decomposition are reviewed in the next section. this feature, investigations on the CO-driven decomposition are reviewed in the next section. 3. Decomposition Routes Depending on the Ligands of Catalysts 3. Decomposition Routes Depending on the Ligands of Catalysts Most ruthenium-based metathesis catalysts are synthesized in the form of precatalysts which requireMost initiation ruthenium-based and dissociation metathesis of one ofcatalysts the Ru-P are/O /synthesizedN bonds. For in phosphine-containing the form of precatalysts complexes which itrequire results ininitiation the liberation and ofdissociation the phosphine, of one which of canthe act Ru-P/O/N as decomposing bonds. agent. For Replacingphosphine-containing phosphines bycomplexes NHCs solves it results this problem in the butliberation also causes of the a diphosphine,fferent one, which sincemany can act NHCs as candecomposing readily undergo agent. eitherReplacing C–H phosphines activation or by Buchner-type NHCs solves expansion this problem of the but aromatic also causes ring. a Heredifferent we willone, review since many the studied NHCs relatedcan readily to these undergo subjects. either C–H activation or Buchner-type expansion of the aromatic ring. Here we will review the studied related to these subjects. 3.1. Phosphine-Driven Decomposition 3.1. Phosphine-Driven Decomposition Almost as soon as the first ruthenium metathesis catalysts were synthesized, the first degradation studiesAlmost of these as systems soon as were the reported. first ruthenium In 1999 Ulman metath andesis Grubbs catalysts reported were the synthesized, thermolysis ofthe the first 1st generationdegradation metathesis studies catalystsof these [97systems]. Based were on the repo NMRrted. measurements, In 1999 Ulman half-lives and ofGrubbs selected reported complexes the thermolysis of the 1st generation metathesis catalysts [97]. Based on the NMR measurements, half- were estimated at 55 ◦C in C6D6. The decomposition product or products in this reaction were not determinedlives of selected due to complexes a large number were ofestimated phosphines at 55 signals °C in arisingC6D6. The during decomposition the course of product the decomposition or products processin this reaction (Scheme were 39). Authorsnot determined of this workdue to concluded a large number that in of most phosphines cases the si methylidenegnals arising complexesduring the undergocourse of a the unimolecular decomposition degradation, process (Scheme while alkylidene 39). Authors complexes of this awo bimolecularrk concluded one. that in most cases the methylidene complexes undergo a unimolecular degradation, while alkylidene complexes a bimolecular one.

Catalysts 2020, 10, x FOR PEER REVIEW 32 of 60 Catalysts 2020, 10, 887 30 of 56 Catalysts 2020, 10, x FOR PEER REVIEW 32 of 60

Scheme 39. The temperature-induced 1st generation Grubbs catalyst decomposition route.

The exceptionScheme 39. to The the temperature-induced proposed rule was 1st observed generation by Grubbs Forman catalystcatalyst and decompositiondecomposition co-workers [104].route.route. Thermal decomposition of deuterated complex of (PhobCy)2Cl2Ru = CD2 in benzene at 50 °C was monitored by meansTheThe exception exceptionof the 2H totoNMR. thethe proposedproposedSignal analysis rulerule was wasallowed observedobserved to id entifybyby FormanForman the deuterated andand co-workersco-workers ethylene [104[104]. (CD]. 2 ThermalThermal = CD2), indicatingdecompositiondecomposition a bimolecular ofof deuterateddeuterated decomposition complexcomplex ofof pathway. (PhobCy)(PhobCy) 2Author2ClCl22Ru =s= suggestCD2 inin benzene benzenethat the at phosphabicyclononane 50 ◦°CC was monitored 2 ligandbyby meansmeans was ofof responsible thethe 2HH NMR.NMR. for SignalchangesSignal analysisanalysis in the relative allowedallowed rates toto identifyid ofentify competing thethe deuterateddeuterated degradation ethyleneethylene routs (CDobserved(CD22 == CDCD for22), otherindicatingindicating bis-phosphine aa bimolecularbimolecular catalysts. decompositiondecomposition pathway.pathway. AuthorsAuthors suggestsuggest thatthat thethe phosphabicyclononanephosphabicyclononane ligandligandAt waswas around responsibleresponsible the same forfor time changeschanges Nolan inin theetthe al. relativerelative found ratesratesthat ofrutheniumof competingcompeting complexes degradationdegradation bearing routsrouts NHC observedobserved ligands forfor exhibitotherother bis-phosphinebis-phosphine higher thermal catalysts.catalysts. stability compared to their bis-phosphine analogs [5,105]. Toluene solution of the 1stAtAt aroundaroundgeneration the the same sameGrubbs time time Nolanbenzylidene Nolan et al. et foundal. and found thatvinylmethylene rutheniumthat ruthenium complexes complexes complexes bearing showed bearing NHC 75% ligands NHC and ligands exhibit 90% decompositionhigherexhibit thermalhigher thermal stabilityrates, respectively, stability compared compared toupon their heatingto bis-phosphine their bis-phosphinefor 1 h analogs at 100 analogs [°C,5,105 while]. [5,105]. Toluene their Toluene solutionIMes derivatives solution of the 1st of remainedgenerationthe 1st generation intact. Grubbs The benzylidene Grubbshigher stabi benzylidene andlity vinylmethyleneof the IMes-containingand vinylmethylene complexes complexe showed complexess was 75% attributed andshowed 90% to decomposition75% an enhancedand 90% stericrates,decomposition protection respectively, rates, of the upon respectively, active heating 14-electron for upon 1 h interm atheating 100ediates◦ C,for while 1 formedh at their 100 after IMes°C, the while derivatives phosphine their IMes remained dissociation derivatives intact. by NHCTheremained higher ligand. intact. stability The of higher the IMes-containing stability of the IMes-containing complexes was attributed complexe tos was an enhanced attributed steric to an protection enhanced ofsteric theAlso activeprotection during 14-electron ofthat the timeactive intermediates Grubbs 14-electron and formed co-workersinterm afterediates the synthesized phosphine formed after dissociationvarious the phosphine ruthenium by NHC dissociation electron-rich ligand. by carbeneNHCAlso ligand. complexes during that [Ru time = Grubbs CHER], and where co-workers ER synthesized= OR, NR, variousSR and ruthenium characterized electron-rich their thermal carbene decompositioncomplexesAlso during [Ru product= CHER],that timeas wherecarbonyl Grubbs ER hydride =andOR, co-workers NR,species SR (Scheme and synthesized characterized 40 [106,107]. various their Th rutheniume thermal spectroscopic decomposition electron-rich analysis (IR,productcarbene NMR, ascomplexes GC/MS) carbonyl of [Ru hydride 13C-labelled = CHER], species and where (Scheme deuterated ER 40 =[ Ru(TFA)106OR,,107 NR,].2(PPh TheSR 3) spectroscopicand2 = CHOCH characterized2Ph analysis complexes their (IR, thermal found NMR, 13 signalsGCdecomposition/MS) from of theC-labelled product carbonyl as and ligandcarbonyl deuterated and hydride showed Ru(TFA) species the2 (PPhformation (Scheme3)2 = 40CHOCHof [106,107].toluene2Ph and Th complexes ebenzyl spectroscopic trifluoroacetate found analysis signals byproductsfrom(IR, NMR, the carbonyl GC/MS)and, thus, ligand of supported 13C-labelled and showed the and proposed the deuterated formation decomposition Ru(TFA) of toluene2(PPh mechan and3 benzyl)2 = ismCHOCH trifluoroacetateshown2Ph on complexes Scheme byproducts 41 found[106]. Inand,signals this thus, frommechanism, supported the carbonyl the proposedphosphineligand and decomposition dissociationshowed the formationand mechanism the βof-alkyl showntoluene elimination onand Scheme benzyl leads 41 trifluoroacetate[ 106 to]. formyl In this intermediatesmechanism,byproducts and, the 40 phosphine thus,, which supported after dissociation the the removal proposed and theof decomposition βbe-alkylnzyl eliminationtrifluoroacetate mechan leadsism TFACHto shown formyl2 onPh intermediates Schemetransform 41 [106]. into40, whichruthenium(II)In this after mechanism, the complex. removal the Further of benzylphosphine rearrangements trifluoroacetate dissociation in TFACH thisand complex the2Ph transformβ-alkyl may resultelimination into in ruthenium(II) the carbonylleads to complex. speciesformyl 41Furtherintermediates. Another rearrangements path, 40, withwhich the in afterthis reductive complexthe removal elimination may resultof be of innzyl toluene the trifluoroacetate carbonyl from speciesintermediate TFACH41. Another 402Ph to transformyield path, carbonyl with into the adductreductiveruthenium(II) 42 elimination, was complex. also proposed. of tolueneFurther fromProlongedrearrangements intermediate heating in40 thisofto the yieldcomplex bis-phosphine carbonyl may adductresult ethoxy in42 the, was carbene carbonyl also proposed.complex species RuClProlonged41. Another2(PCy3 heating) 2 path,= CHOEt with of the in the benzene bis-phosphine reductive allowed elimination ethoxy Grubbs carbene ofet al.toluene to complex isolate from a RuCl rutheniumintermediate2(PCy3 )hydride2 = 40CHOEt to 1yield in in69% carbonyl benzene yield, furtherallowedadduct characterized42 Grubbs, was also et al. byproposed. tomeans isolate of Prolonged X-ray a ruthenium [107]. heating The hydride obtained of the1 bis-phosphinein hydride 69% yield, complex furtherethoxy 1 was characterizedcarbene a subject complex of the by previouslymeansRuCl2(PCy of X-ray 3proposed)2 = CHOEt [107]. mechanism, in The benzene obtained whichallowed hydride confirmed Grubbs complex et it sal. validity. to1 wasisolate aThesubject a ruthenium remaining of the hydride Fischer previously carbenes1 in 69% proposed yield,gave numerousmechanism,further characterized signals which in confirmed the by NMR means its spectrum validity.of X-ray from The[107]. remaining the The re sultingobtained Fischer degradation hydride carbenes complex products, gave numerous 1 was suggesting a subject signals several of in the competingNMRpreviously spectrum degradationproposed from themechanism, pathways. resulting which degradationBased confirmed on the products, established its validity. suggesting half-lives, The remaining several the thermal competing Fischer stability carbenes degradation of gave the derivativespathways.numerous Basedsignalswas found on in thethe to establishedNMR be in spectrumthe order half-lives, offrom E = theN >re thermal Csulting > S > stabilityO. degradation of the products, derivatives suggesting was found several to be incompeting the order degradation of E = N > C pathways.> S > O. Based on the established half-lives, the thermal stability of the derivatives was found to be in the order of E = N > C > S > O.

Scheme 40. TheThe thermal thermal degradation degradation of Fisher carbenes generated from GII catalyst.

Scheme 40. The thermal degradation of Fisher carbenes generated from GII catalyst.

Catalysts 2020, 10, 887 31 of 56 Catalysts 2020, 10, x FOR PEER REVIEW 33 of 60

Ph3P Ph3P Ph3P Ph3P TFA O TFA TFA TFA O + PPh Ru Ru Ru 3 Ru CO -CH Ph TFA OCH2Ph - PPh3 TFA H TFA 3 TFA PPh3 CH2Ph PhCH2 H PPh3 40 42

- TFACH2Ph

Ph3P Ph3P TFA O + PPh 3 Ru CO Ru(0) species Ru H - TFAH H TFA PPh3 41 Scheme 41. TheThe thermal thermal decomposition of the Fischer-type carbene.

Early thermal stability studies of the 2nd generati generationon ruthenium catalyst were reported by Hong and Grubbs [96]. [96]. The methylidene complex complex GIImGIIm was heated at 55 °C◦C in benzene and after 72 h the + diruthenium compound 4343 werewere isolatedisolated in in 46% 46% yield, yield, together together with with CH CH3PCy3PCy3 3+ClCl−−.. Complex Complex 43 isis an interesting speciesspecies that that can can be be characterized characterized by theby lossthe ofloss the of alkylidene the alkylidene functionality functionality and the presenceand the 6 presenceof the hydride of the ligand hydride on ligand one ruthenium on one ruthenium atom as well atom as aasη well-interaction as a η6-interaction of the second of the ruthenium second rutheniumcenter to one center of the to mesitylene one of the moietiesmesitylene (Scheme moieties 42). (Scheme The authors 42). The of this authors study of proposed this study a multi-stepproposed adegradation multi-step pathwaydegradation based pathway on chemistry based establishedon chemistry for established other ruthenium for other carbene ruthenium complexes carbene [108] + - complexesand formation [108] of and the formation CH3PCy3 ofCl thesalt. CH3 InPCy this3+Cl pathway,- salt. In this a phosphine pathway, attacka phosphine on the attack methylidene on the methylidenecomplex was complex suggested was as thesuggested first step, as whichthe first than step, releases which the than CH releases2 = PCy 3theylide CH and2 = PCy the3 12-electron ylide and thespecies 12-electron44. Further, species it was44. Further, suggested it was that suggested intermediate that intermediate44 may bind 44 one may of thebind mesityl one of substituentthe mesityl substituentof methylidene of methylidene complex leading complex to a leading dimer withto a dimer two chloride with two bridges, chloride followed bridges, by followed HCl abstraction by HCl + abstractionthrough ylide, through forming ylide, CH 3formingPCy3 Cl CH− and3PCy an3+ alkylidyneCl− and an adduct.alkylidyne Transformation adduct. Transformation of the latter systemof the latterinto the system final complexinto the 43finalwas complex elucidated 43 bywas the elucidated migration by of chloridethe migration ligands of and chloride an oxidative ligands addition and an oxidativeof alkylidyne. addition The formationof alkylidyne. of proposed The formation intermediates of proposed was, intermediates however, speculative was, however, since they speculative have not sincebeen observedthey have experimentally. not been observed Considering experimentally the time. Considering scale of the degradation the time scale process of the (which degradation usually processtake days) (which and metathesisusually take reaction days) (whichand metathesis is usually reac finishedtion (which in hours), is usually it can probably finished bein hours), assumed it thatcan probablyit has no significantbe assumed impact that onit has the courseno significant of the metathesis impact on reaction. the course However, of the as metathesis later work reaction. showed, However,the proposed as later nucleophilic work showed, attack the on theproposed methylidene nucleophilic is the primaryattack on vector the methylidene of the active is methylidenethe primary vectorspecies of degradation the active methylidene [88,109]. species degradation [88,109]. In continuation of these works Grubbs et al. screened thermal stabilities of a series of methylidene complexes (Schemes 42 and 43)[84]. The results confirmed that phosphine catalysts are subject to a first-order degradation rate, which is not affected by the excess of phosphine. Moreover, based on half-lives of NHC-catalysts authors leaned more towards a mechanism involving the dissociation followed by the phosphine attack, rather than a mechanism involving an internal attack of the phosphine on the methylidene species (Scheme 42). In the same work authors investigated also the degradation of an active methylidene species under metathesis reaction with ethylene in toluene. Different behavior was observed for PPh3-containing derivatives with respect to the PCy3-containing ones. Two major products were characterized as + methyltriphenylphosphonium chloride CH3PCy3 Cl− and diruthenium complex 45, which structure was confirmed by the X-ray analysis. The proposed mechanism of this reaction is presented on Scheme 44. It is interesting to note that the same reaction carried out in CD2Cl2 allowed to identify the formation of complex 46, whose existence was suggested by the authors in an earlier work [96]. Interestingly, in the presence of ethylene at 40 C this intermediate can revert to an active methylidene − ◦ to give the metallocycobutane. Additionally, the decomposition of a phosphine-free Hoveyda-Grubbs catalyst with ethylene in C6D6 at 55 ◦C resulted in an unidentified hydride species.

Catalysts 2020, 10, x FOR PEER REVIEW 34 of 60

Catalysts 2020, 10, 887 32 of 56 Catalysts 2020, 10, x FOR PEER REVIEW 34 of 60

Scheme 42. The proposed mechanism of the thermolysis of the 2nd generation Grubbs carbenes.

In continuation of these works Grubbs et al. screened thermal stabilities of a series of methylidene complexes (Schemes 42 and 43) [84]. The results confirmed that phosphine catalysts are subject to a first-order degradation rate, which is not affected by the excess of phosphine. Moreover, based on half-lives of NHC-catalysts authors leaned more towards a mechanism involving the dissociation followed by the phosphine attack, rather than a mechanism involving an internal attack of the phosphineScheme 42.42. onThe the proposed methylidene mechanism species of theth (Schemee thermolysis 42). of the 2nd generationgeneration GrubbsGrubbs carbenes.carbenes.

Scheme 43. The decomposition rates of ruthenium methylidene complexes.

InspiredIn the same by thework aforementioned authors investigated work, Metzger also the anddegradation Wang conducted of an active a spectroscopic methylidene analysis, species usingunder electrospraymetathesis ionizationreaction with mass ethylene spectrometry in to (ESI-MS),luene. Different of bis-phosphine behavior oleﬁnwas observed catalyst systems for PPhGI3- andcontainingGIv in RCMderivatives reaction with with respect oleﬁns, presentedto the PCy on3-containing Scheme 45[ 110ones.]. Although Two major the authorsproducts failed were to identifycharacterized any degradation as methyltriphenylphosphonium products containing ruthenium, chloride they CH3 werePCy3+ ableCl− and to determine diruthenium both complexcis and trans 45, stilbenewhich structure in CH2Cl was2 solution confirmed of catalyst by theGI X-ray, indicating analysis a. bimolecularThe proposed degradation mechanism with of this organic reaction dimer is + formation.presented on For Scheme allScheme investigated 44. 43. It Theis interesting decomposition complexes to the note rates methylphosphonium that of rutheniumthe same reactionmethylidene cation carried complexes. CH 3outP Cyin CD3 (at2Clm2/ zallowed295) as wellto identify as the benzylidenetrialkylphosphinethe formation of complex 46, whose (at m/z existence374), which was represents suggested products by the ofauthors phosphine-driven in an earlier degradation,In the same were work detected. authors investigated also the degradation of an active methylidene species under metathesis reaction with ethylene in toluene. Different behavior was observed for PPh3- containing derivatives with respect to the PCy3-containing ones. Two major products were characterized as methyltriphenylphosphonium chloride CH3PCy3+Cl− and diruthenium complex 45, which structure was confirmed by the X-ray analysis. The proposed mechanism of this reaction is presented on Scheme 44. It is interesting to note that the same reaction carried out in CD2Cl2 allowed to identify the formation of complex 46, whose existence was suggested by the authors in an earlier

Catalysts 2020, 10, x FOR PEER REVIEW 35 of 60 work [96]. Interestingly, in the presence of ethylene at −40 °C this intermediate can revert to an active Catalystsmethylidene2020, 10 ,to 887 give the metallocycobutane. Additionally, the decomposition of a phosphine-free33 of 56 Hoveyda-Grubbs catalyst with ethylene in C6D6 at 55 °C resulted in an unidentified hydride species.

Scheme 44.44. The suggested paths of thethe decompositiondecomposition of thethe methylenemethylene complexcomplex underunder metathesismetathesis Catalystsreaction 2020, 10 withwith, x FOR ethylene.ethylene. PEER REVIEW 36 of 60

Inspired by the aforementioned work, Metzger and Wang conducted a spectroscopic analysis, using electrospray ionization mass spectrometry (ESI-MS), of bis-phosphine olefin catalyst systems GI and GIv in RCM reaction with olefins, presented on Scheme 45 [110]. Although the authors failed to identify any degradation products containing ruthenium, they were able to determine both cis and trans stilbene in CH2Cl2 solution of catalyst GI, indicating a bimolecular degradation with organic dimer formation. For all investigated complexes the methylphosphonium cation CH3P+Cy3 (at m/z 295) as well as the benzylidenetrialkylphosphine (at m/z 374), which represents products of phosphine-driven degradation, were detected.

Scheme 45. The structures of (a) investigatedinvestigated ruthenium 1st generation catalysts and (b) identiﬁedidentified decomposition species.

3.2. C-H Activation Metal-promoted C-H bond activation is a very active research area and holds great potential in organic chemistrychemistry [[111–115].111–115]. TheThe C–HC–H activation activation of of complexes complexes bearing bearing unsubstituted unsubstitutedortho orthopositions positions in thein theN-alkyl N-alkyl and andN-aryl N-aryl groups groups result result in decomposition, in decomposition, which which can occur can occur even ineven mild in conditions mild conditions and is oftenand is reversible, often reversible, therefore therefore diﬃcult to difficult detect. Itto is detect. also accompanied It is also accompanied by the formation by ofthe transient formation metal of hydridestransient metal aﬀecting hydrides the catalytic affecting activity the catalytic of the catalyst. activity of the catalyst. Grubbs et al. first reported the insertion of ruthenium into one of the NHC methyl C–H bond of the second generation Grubbs catalyst [100]. This C-H oxidative addition and loss of the alkylidene ligand was promoted by air, forming a catalyst in which the C–H bond activation of the mesityl ortho- methyl group occurred (Scheme 46). The decomposition product was air-stable in solution and solid state. All bonds linked to the ruthenium in the new 16-electron complex became shorter but the mechanism, at that time, was still unknown.

Scheme 46. The C–H activation of Grubbs catalyst.

Whittlesey’s group treated the mono-carbene species Ru(IMes)(PPh3)2(CO)H2 with trimethylvinylsilane at room temperature, also observing the intramolecular C–H activation of an ortho-methyl group in the NHC ligand, reversible on the use of hydrogen [116]. The same group observed the activation of ruthenium chelating P-P and P-As complexes 47 and 48, which share many structural features with metathesis catalysts, induced by trimethylvinylsilane, which yielded complex 49 with Me3SiEt at 100 °C as well as a mixture of three regioisomers 50a–c at 85 °C, respectively (Scheme 47, part a) [117]. Heating under hydrogen reformed the dihydride precursors. Their later theoretical studies showed that the C–H activation occurred through a Ru(0) intermediate formed by the olefin, which acts as hydrogen acceptor [118]. The precatalyst reformed on addition of the hydrogen is useful in catalytic transfer hydrogenation involving alcohols [119–121]. The C–H activation of 51 took place through the thermal reductive elimination, forming reactive Ru(0) intermediates (Scheme 47, part b). This process may occur at the six-coordinate complex to give a four-coordinate complex 52 or at the five-coordinate transition state 53, to give the 3-coordinate complex 54. The latter can also be obtained by the loss of phosphine from 52. When any of the 52 or 54 systems are formed, they undergo a rapid C–H activation. It was also proven that the solvation by benzene does not have any impact in stabilizing species 52, 53 or 54. Similar complexes were also studied theoretically by the groups of Houk and Trzaskowski using computational methods to further elucidate the details of the reaction/decomposition mechanisms [122,123].

Catalysts 2020, 10, x FOR PEER REVIEW 36 of 60

Scheme 45. The structures of (a) investigated ruthenium 1st generation catalysts and (b) identified decomposition species.

3.2. C-H Activation Metal-promoted C-H bond activation is a very active research area and holds great potential in organic chemistry [111–115]. The C–H activation of complexes bearing unsubstituted ortho positions

Catalystsin the N2020-alkyl, 10, 887and N-aryl groups result in decomposition, which can occur even in mild conditions34 of 56 and is often reversible, therefore difficult to detect. It is also accompanied by the formation of transient metal hydrides affecting the catalytic activity of the catalyst. Grubbs et al. first ﬁrst reported the insertion of ru rutheniumthenium into one of the NHC methyl C–H bond of the second generation Grubbs catalystcatalyst [[100].100]. This C-H oxidative addition and loss of the alkylidenealkylidene ligand was was promoted promoted by by air, air, forming forming a catalyst a catalyst in which in which the C–H the C–H bond bond activation activation of the ofmesityl the mesityl orthoortho-methylmethyl group groupoccurred occurred (Scheme (Scheme 46). The 46 ).decomposition The decomposition product product was air-stable was air-stable in solution in solution and solid and solidstate. state.All bonds All bonds linked linked to the to theruthenium ruthenium in the in the new new 16-electron 16-electron complex complex became became shorter shorter but but the mechanism, at that time, was still unknown.

Scheme 46. The C–H activation of Grubbs catalyst.

Whittlesey’s group treatedtreated thethe mono-carbenemono-carbene speciesspecies Ru(IMes)(PPhRu(IMes)(PPh3)32)2(CO)H(CO)H22 with trimethylvinylsilane at at room room temperature, temperature, also also observing observing the the intramolecular intramolecular C–H C–H activation activation of an of anorthoortho-methyl-methyl group group in inthe the NHC NHC ligand, ligand, reversible reversible on on the the use use of of hydrogen hydrogen [116]. [116]. The The same same group observed the activation of ruthenium chelating P-P and P-As complexes 47 and 48, which which share share many many structural featuresfeatures with with metathesis metathesis catalysts, catalysts, induced induced by trimethylvinylsilane, by trimethylvinylsilane, which yieldedwhich complexyielded 49complexwith Me493 SiEtwith atMe 1003SiEt◦C at as 100 well °C as as a mixturewell as ofa mixture three regioisomers of three regioisomers50a–c at 85 ◦50a–cC, respectively at 85 °C, (Schemerespectively 47a) (Scheme [117]. Heating 47, part under a) [117]. hydrogen Heating reformed under thehydrogen dihydride reformed precursors. the dihydride Their later precursors. theoretical studiesTheir later showed theoretical that the studies C–H activationshowed that occurred the C–H through activation a Ru(0) occurred intermediate through formeda Ru(0) byintermediate the oleﬁn, whichformed acts by the as hydrogenolefin, which acceptor acts as [hydrogen118]. The accept precatalystor [118]. reformed The precatalyst on addition reformed of the on hydrogen addition of is usefulthe hydrogen in catalytic is useful transfer in hydrogenationcatalytic transfer involving hydrogenation alcohols [involving119–121]. Thealcohols C–H [119–121]. activation ofThe51 C–Htook placeactivation through of 51 the took thermal place reductive through elimination, the thermal forming reductive reactive elimination, Ru(0) intermediates forming reactive (Scheme Ru(0) 47b). Thisintermediates process may (Scheme occur 47, at thepart six-coordinate b). This process complex may occur to give at a the four-coordinate six-coordinate complex complex52 toor give at the a ﬁve-coordinatefour-coordinate transition complex state52 or53 at, to the give five-coordinate the 3-coordinate transition complex state54. The 53, latterto give can the also 3-coordinate be obtained bycomplex the loss 54 of. The phosphine latter can from also52 be. When obtained any by of thethe 52lossor of54 phosphinesystems are from formed, 52. When they undergoany of the a rapid52 or C–H54 systems activation. are formed, It was also they proven undergo that a the rapid solvation C–H activa by benzenetion. It doeswas notalso have proven any that impact the insolvation stabilizing by speciesbenzene52 does, 53 ornot54 have. Similar any impact complexes in stabilizing were also species studied 52 theoretically, 53 or 54. Similar by the complexes groups of Houkwere also and Trzaskowskistudied theoretically using computational by the groups methods of Houk to further and elucidateTrzaskowski the details using of computational the reaction/decomposition methods to mechanismsfurther elucidate [122 ,the123 ].details of the reaction/decomposition mechanisms [122,123]. This research topic was continued by Morris et al., who observed the cyclometalation of an ortho-methyl group when reacting RuHCl(PPh3)3 with SIMes, IMes or imidazolium salt precursors (Scheme 48)[124]. The reaction of 55 with CO at 20 ◦C yielded a complex with an attached CO group, whereas at 68 ◦C the Ru(0) complex saturated with three CO groups and a reformed IMes ligand was obtained. Protonation of the cyclometalated IMes ligand by phenol, apart from associating a 5 η -bonded phenoxide group, also caused the reformation of the IMes ligand. Reaction of RuHCl(PPh3)3 with ItBu and later with hydrogen produced a mixture of two isomers 56a and 56b of the dihydride Ru(H)2(ItBu)(PPh3)2, both with activated C-H bonds. This study proved that IMes and PPh3 ligands do not bind to 55. A year later, Whittlesey described trimethylvineylsilane-promoted activation of the alkyl NCH2CH2-H activation of 57 (Scheme 49)[125]. A metalated, 5-membered ring of the IEt2Me2 ligand was formed with a Ru–C–C angle similar to that of an unstrained sp3-hybridized methylene group (58). Since complexes in Morris’ work were more electron-rich, the key role in permitting the C–H activation in complexes 57 and 58 was assigned to the CO ligand. Reaction with hydrogen or benzene/alcohol solutions in room temperature caused precipitation of 59 but complex 57 was reformed in alcohol with an increasing rate in MeOH< EtOH < iPrOH. Catalysts 2020, 10, 887 35 of 56 Catalysts 2020, 10, x FOR PEER REVIEW 37 of 60

Scheme 47.47. ((a)) TheThe C-HC-H activationactivation ofof thethe P-PP-P andand P-AsP-As complexescomplexes andand ((bb)) thethe proposedproposed mechanismmechanism

forfor thethe C-HC-H activationactivation ofof six-coordinatesix-coordinate complex with additional PPh3 (blue) and IMes ligand (red), withwith thethe GibbsGibbs freefree energiesenergies estimatedestimated atat thethe DFTDFT levellevel ofof theorytheory (in(in kcalkcal/mol)./mol).

GrubbsThis research also reported topic was decomposition continued by via Morris the C–H et al., activation who observed of the secondthe cyclometalation generation Grubbs of an catalyst leading to complex 45 [84]. The decomposition occurred after 5 days in toluene at 23 C and ortho-methyl group when reacting RuHCl(PPh3)3 with SIMes, IMes or imidazolium salt precursors◦ was(Scheme initiated 48) [124]. by the The dissociation reaction of of 55 the with phosphine. CO at 20 The°C yielded presence a complex of ethylene with facilitated an attached its subsequent CO group, attackwhereas on at the 68 methylidene°C the Ru(0) complex of GIIm saturated(Scheme 44with)[100 three,119 CO]. The groups formed and a complex reformed44 IMesin the ligand presence was ofobtained. two Ph 3ProtonationP = CH2 molecules of the cyclometalated underwent C–H IMes activation, ligand producingby phenol, theapart dinuclear from associating catalyst 45 aand 5- methyl-trihenylphosphonium chloride. bonded phenoxide group, also caused the reformation of the IMes ligand. Reaction of RuHCl(PPh3)3 with TheItBu same and later group with reported hydrogen the doubleproduced C-H a bondmixture activation of two isomers of a phenyl-substituted 56a and 56b of the NHC dihydride in 2nd generation Grubbs catalyst 60 [126]. In complex 61 one can observe an inserted benzylidene carbon Ru(H)2(ItBu)(PPh3)2, both with activated C-H bonds. This study proved that IMes and PPh3 ligands 6 atomdo not into bind the to ortho55. C–H bond of the N-phenyl ring, as well as a η binding of ruthenium to the benzylidene phenyl group and the loss of phosphine (Scheme 50). Catalysts with NHC ligands

Catalysts 2020, 10, 887 36 of 56

Catalysts 2020, 10, x FOR PEER REVIEW 38 of 60 containing phenyl instead of mesityl groups were more prone to the C–H activation, as further insertion of ruthenium into another phenyl group and the formation of a ﬁve-membered metallacycle produced complex 62. It was suggested that the ﬂexibility of the N-phenyl groups play the key role in the initiation and propagation of this reaction [127]. Heating of complex 60 in benzene at 60 ◦C under inert conditions led to product 61 after three days (58% yield) with traces of 62. Faster decomposition of this complex occurred in DCM, however, after 12 h at 40 ◦C the main product was 62 (38% yield) with 61 in 24% yield. After a week in 40 ◦C 61 turned into 62, while after adding phosphine it turned into 62 at room temperature only in three days. Catalysts 2020, 10, x FOR PEER REVIEW 38 of 60

Scheme 48. The C-H activation of ruthenium hydride complexes.

A year later, Whittlesey described trimethylvineylsilane-promoted activation of the alkyl NCH2CH2-H activation of 57 (Scheme 49) [125]. A metalated, 5-membered ring of the IEt2Me2 ligand was formed with a Ru–C–C angle similar to that of an unstrained sp3-hybridized methylene group (58). Since complexes in Morris’ work were more electron-rich, the key role in permitting the C–H activation in complexes 57 and 58 was assigned to the CO ligand. Reaction with hydrogen or benzene/alcohol solutions in room temperature caused precipitation of 59 but complex 57 was reformed in alcohol withScheme an increasing 48.48. The C-H rate activation in MeOH< of rutheniumruth EtOHenium < hydride iPrOH. complexes.

Scheme 49. The C–H activation of CO-containing complexes.

Grubbs suggestedalso reported a mechanism decomposition for decomposition via the C–H activation of 60, diﬀerent of the from second the previousgeneration one Grubbs due to catalystno attack leading of the phosphine.to complex In45 this[84]. mechanism, The decomposition immediately occurred after after the loss 5 days of the in phosphinetoluene at 23 (initiating °C and wasthe metathesis),initiated by the the dissociationortho C–H bond of the of phosphine. the N-phenyl The grouppresence adds of ethylene to the ruthenium facilitated center its subsequent forming attacka ruthenium on the hydridemethylidene complex of GIIm63. In(Scheme the next 44) step, [100,119]. the hydride The formed inserts complex at the benzylidene 44 in the presenceα-carbon of twoatom Ph giving3P = CH complex2 molecules64 and underwent a reductive C–H elimination activation, between producing the metalated the dinuclearN-phenyl catalyst carbon 45 atom and methyl-trihenylphosphoniumand benzylidene α-carbon atom chloride. generates 61. Lastly, a C-H insertion of the second N -phenyl ring and phosphine-mediatedThe same group reportedScheme elimination 49.the The double C–H of HCl activationC-H yields bond of ac62 CO-containingtivation. Intermediates of a complexes.phenyl-substituted63-65 were not NHC observed in 2nd by generationspectroscopic Grubbs methods, catalyst most 60 probably [126]. In duecomplex to their 61 shortone can lifetimes. observe an inserted benzylidene carbon atomGrubbs into the also ortho reported C–H bond decomposition of the N-phenyl via the ring, C–H as activation well as a of 6the binding second of generation ruthenium Grubbs to the benzylidenecatalyst leading phenyl to complex group 45and [84]. the The loss decomposition of phosphine occurred(Scheme after50). 5Catalysts days in toluenewith NHC at 23 ligands °C and containingwas initiated phenyl by the instead dissociation of me ofsityl the phosphine.groups were Th moree presence prone of to ethylene the C–H facilitated activation, its subsequent as further insertionattack on of the ruthenium methylidene into ofanother GIIm phenyl(Scheme group 44) [100,119]. and the formation The formed of acomplex five-membered 44 in the metallacycle presence of two Ph3P = CH2 molecules underwent C–H activation, producing the dinuclear catalyst 45 and methyl-trihenylphosphonium chloride. The same group reported the double C-H bond activation of a phenyl-substituted NHC in 2nd generation Grubbs catalyst 60 [126]. In complex 61 one can observe an inserted benzylidene carbon atom into the ortho C–H bond of the N-phenyl ring, as well as a 6 binding of ruthenium to the benzylidene phenyl group and the loss of phosphine (Scheme 50). Catalysts with NHC ligands containing phenyl instead of mesityl groups were more prone to the C–H activation, as further insertion of ruthenium into another phenyl group and the formation of a five-membered metallacycle

Catalysts 2020, 10, x FOR PEER REVIEW 39 of 60

produced complex 62. It was suggested that the flexibility of the N-phenyl groups play the key role in the initiation and propagation of this reaction [127]. Heating of complex 60 in benzene at 60 °C under inert conditions led to product 61 after three days (58% yield) with traces of 62. Faster decomposition of this complex occurred in DCM, however, after 12 h at 40 °C the main product was Catalysts62 2020(38%, 10 yield), 887 with 61 in 24% yield. After a week in 40 °C 61 turned into 62, while after adding37 of 56 phosphine it turned into 62 at room temperature only in three days.

SchemeScheme 50. The 50. C–HThe activationC–H activation of the of second the second generation generati Grubbson Grubbs catalysts catalysts containing containing phenyl-substituted phenyl- NHCsubstituted ligand. NHC ligand. Grubbs suggested a mechanism for decomposition of 60, different from the previous one due to Suresh et al. further investigated this mechanism using theoretical methods and also highlighted no attack of the phosphine. In this mechanism, immediately after the loss of the phosphine (initiating the key role of the flexibility of N-phenyl groups in the initiation and propagation of this reaction [128]. the metathesis), the ortho C–H bond of the N-phenyl group adds to the ruthenium center forming a Theirruthenium work was hydride extended complex later by63. In Cavallo the next et step, al., whothe hydride also theoretically inserts at the studiedbenzylidene the mechanismα-carbon atom of this doublegiving C–H complex activation 64 and [129 a]. reductive They presented elimination a low between energy the pathway metalated of formationN-phenyl carbon of 62, displayingatom and the importancebenzylidene of phosphine α-carbon atom in the generates propagation 61. Lastly, of this a C-H step insertion (Scheme of 51 the). second The first N-phenyl step starts ring fromand the elongationphosphine-mediated of the C–H bond elimination in 14 electron of HCl complex yields 6562,. afterIntermediates dissociation 63-65 of thewere phosphine, not observed followed by by the transferspectroscopic of the agosticmethods, hydrogen most probab to thely due benzylide to theirα short-carbon lifetimes. atom through a transition state (oxidative addition).Suresh The benzylidene et al. further investigated group turns this into mechanis a benzylm groupusing theoretical and a new methods bond betweenand also highlighted ruthenium and the orthothe keycarbon role atomof theof flexibility the N-phenyl of N-phenyl ring is groups formed. in the Complex initiation64 and(suggested propagation by Grubbs) of this reaction is higher in [128]. Their work was extended later by Cavallo et al., who also theoretically studied the mechanism energy than 65 and is stabilized by the double bond between ruthenium and the benzyl carbon atom. of this double C–H activation [129]. They presented a low energy pathway of formation of 62, The benzyl α-hydrogen transfers to ruthenium through a transition state forming complex 63, which is displaying the importance of phosphine in the propagation of this step (Scheme 51). The first step unstable and prone to undergo a σ-bond insertion between the ruthenium and the N-phenyl ortho starts from the elongation of the C–H bond in 14 electron complex 65, after dissociation of the carbon atom forming ruthenium hydride 66, previously not postulated by Grubbs. phosphine, followed by the transfer of the agostic hydrogen to the benzylide α-carbon atom through Ina transition the second state part (oxidative of the addition). mechanism, The benzylidene the ruthenium group hydride turns into bond a benzyl is broken group byand a a reductive new elimination,bond between forming ruthenium a complex and stabilized the ortho carbon by a strong atom of interaction the N-phenyl with ring the is former formed. benzylidene Complex 64 Cipso atom.(suggested Intermediates by Grubbs)610-61 is0” higherwerepreviously in energy than not postulated65 and is stabilized [128], probably by the double due to bond the highbetween stability of 61.ruthenium Lastly, more and stablethe benzyl complex carbon62 atom.is formed The benzyl via an α interaction-hydrogen transfers of one chloride to ruthenium atom withthrough the a other N-phenyltransitionortho statehydrogen forming atom complex and the63, which elimination is unstable of HCl. and Experimentsprone to undergo confirmed a σ-bond that insertion complex 61 was onlybetween thermodynamically the ruthenium and stable the without N-phenyl a Lewis ortho base, carbon that atom is, phosphine, forming ruthenium otherwise hydride the equilibrium 66, was shiftedpreviously towards not postulated62 [128]. by During Grubbs. the C-H activation the N-phenyl rings maintain their aromaticity, being the key feature for this reaction. The benzylidene phenyl ring plays a role in stabilizing the various isomers of 61 by a strong electron donation to ruthenium center, which reduces its aromaticity but this is compensated by binding to the metal and elongating the C–C bond. In another work devoted to the issue, Blechert et al. observed the decomposition of the Hoveyda-type complex after two weeks under air forming an intramolecular bond between the ortho position of the N-aryl ligand and the benzylidene carbon atom, the length of which was between that of a single and double bond [130]. This type of decomposition was also observed for another Hoveyda-Grubbs-type complex bearing an unsymmetrical NHC in DCM after a few hours under air, proving that presence of oxygen and less steric N-substituent allows the formation of a bond between the benzylidene carbon atom and β-position of the N-aryl ligand [131]. The postulated mechanism follows a sequence of a reversible pericyclic cyclization of A to form B, followed by an irreversible Catalysts 2020, 10, 887 38 of 56 oxidation with oxygen to C. An elimination and re-aromatization finally causes the insertion, giving product D (Scheme 52). Catalysts 2020, 10, x FOR PEER REVIEW 40 of 60

N N N N N N N N Cl Cl Cl Cl Ru Ru Ru Ru Cl Cl Cl Cl H H 66 61''' 0.0 4.9 -7.8 2.8

N N N N N N N N Cl Cl Cl Cl Ru Ru Ru Ru Cl Cl Cl Cl

61' -7.1 -7.2 -0.1 -9.7

N N N N N N Cl Cl Cl 62 + HCl Cl Ru Ru Ru H -26 Cl + - 61 62 +HPCy3 Cl -30.9 -2.5 -34 SchemeScheme 51. The51. The mechanism mechanism of of the the C–H C–H activation activation of ca catalyststalysts containing containing phenyl-substituted phenyl-substituted NHC NHC ligandsCatalystsligands 2020 with, 10with the, x FOR relativethe PEERrelative GibbsREVIEW Gibbs free free energies energies (in (in kcalkcal/mol),/mol), as as proposed proposed by by Cavallo. Cavallo. 41 of 60

In the second part of the mechanism, the ruthenium hydride bond is broken by a reductive elimination, forming a complex stabilized by a strong interaction with the former benzylidene Cipso atom. Intermediates 61′-61′’’ were previously not postulated [128], probably due to the high stability of 61. Lastly, more stable complex 62 is formed via an interaction of one chloride atom with the other N-phenyl ortho hydrogen atom and the elimination of HCl. Experiments confirmed that complex 61 was only thermodynamically stable without a Lewis base, that is, phosphine, otherwise the equilibrium was shifted towards 62 [128]. During the C-H activation the N-phenyl rings maintain their aromaticity, being the key feature for this reaction. The benzylidene phenyl ring plays a role in stabilizing the various isomers of 61 by a strong electron donation to ruthenium center, which reduces its aromaticity but this is compensated by binding to the metal and elongating the C–C bond. In another work devoted to the issue, Blechert et al. observed the decomposition of the Hoveyda- type complex after two weeks under air forming an intramolecular bond between the ortho position of the N-aryl ligand and the benzylidene carbon atom, the length of which was between that of a single and double bond [130]. This type of decomposition was also observed for another Hoveyda- Grubbs-type complex bearing an unsymmetrical NHC in DCM after a few hours under air, proving that presence of oxygen and less steric N-substituent allows the formation of a bond between the benzylidene carbon atom and β-position of the N-aryl ligand [131]. The postulated mechanism follows a sequence of a reversible pericyclic cyclization of A to form B, followed by an irreversible oxidation with oxygen to C. An elimination and re-aromatization finally causes the insertion, giving product D (SchemeSchemeScheme 52). 52. 52.The The mechanism mechanism forfor insertion reac reactiontion proposed proposed by byBlechert. Blechert.

TheThe following following year, year, McDonald McDonald et et al. al. reported a athermal thermal decomposition decomposition of phosphonium of phosphonium alkylidene catalysts in the presence of 1,1-dichloroethylene and B(C6F5)3, yielding a trichloro-bridged alkylidene catalysts in the presence of 1,1-dichloroethylene and B(C6F5)3, yielding a trichloro-bridged dimerdimer (Scheme (Scheme 53 a)53, [ part132]. a) C-H[132]. activationC-H activation of theof the mesityl mesitylortho ortho methyl group group through through the addition the addition across the Ru = C phosphonium alkylidene bond was the rate-determining step of this process [116]. across the Ru = C phosphonium alkylidene bond was the rate-determining step of this process [116]. The ruthenium intermediate IV eliminates the methyl phosphonium to give the alkylidene complex The ruthenium intermediate IV eliminates the methyl phosphonium to give the alkylidene complex V V and after the cross metathesis with the trapping olefin, the dichlorocarbene and styrenic vinyl and aftergroups the are cross formed metathesis in intermediate with the VI trapping. Then, after oleﬁn, the loss the dichlorocarbeneof chloride, the dimerization and styrenic occurs vinyl and groups

the ion exchange gives 67 and a methylphosphonium salt [H3CPR3][Cl]. Intermediates IV-VI were not directly observed, however the mechanism for the formation of V could be the one postulated previously by Blechert et al. [130]. After 1–2 days at room temperature, a mixed dimer 68 was observed after „self-trapping” of V by 69 (Scheme 53, part B). It was, however, noted that these catalysts exhibited higher initiation rates than the rate-limiting step in decomposition. In the same year, Piers et al. observed the same dimerization of this catalyst after two days at room temperature, where the C-H insertion occurred through the alkylidene moiety under air [133].

Catalysts 2020, 10, 887 39 of 56 are formed in intermediate VI. Then, after the loss of chloride, the dimerization occurs and the ion exchange gives 67 and a methylphosphonium salt [H3CPR3][Cl]. Intermediates IV–VI were not directly observed, however the mechanism for the formation of V could be the one postulated previously by Blechert et al. [130]. After 1–2 days at room temperature, a mixed dimer 68 was observed after „self-trapping” of V by 69 (Scheme 53b). It was, however, noted that these catalysts exhibited higher initiation rates than the rate-limiting step in decomposition. In the same year, Piers et al. observed the same dimerization of this catalyst after two days at room temperature, where the C-H insertion occurredCatalysts through 2020, 10, thex FOR alkylidene PEER REVIEW moiety under air [133]. 42 of 60 Catalysts 2020, 10, x FOR PEER REVIEW 42 of 60

Scheme 53. (a) The proposed mechanism of the decomposition of phosphonium complexes and (b) SchemeScheme 53. ( a53.) The(a) The proposed proposed mechanism mechanism of of the the decomposition decomposition of of phosphoniumphosphonium complexes and and (b (b) ) the the self-trapping of the proposed intermediate V. self-trappingthe self-trapping of the proposed of the proposed intermediate intermediateV. V. In the consecutive studies, Severin et al. observed that treatment of complex 70 with one In theIn consecutive the consecutive studies, studies, Severin Severin et al. et observed al. observed that treatmentthat treatment of complex of complex70 with 70 onewith equivalent one equivalent of PCy3 in dioxane at 70 °C for 3 days yielded a chiral dinuclear, chloro-bridged product of PCyequivalentin dioxane of PCy at370 in dioxaneC for 3 at days 70 °C yielded for 3 days a chiral yielded dinuclear, a chiral dinuclear, chloro-bridged chloro-bridged product product71 in which 713 in which a η2-bound◦ cyclohexene group, attained from the phosphine ligand after partial η2 71 in which a η2-bound cyclohexene group, attained from the phosphine ligand after partial a -boundhydrogenation, cyclohexene was coordinated group, attained to the ruthenium from the center phosphine (Scheme ligand54) [134]. after Two partialdiastereoisomers hydrogenation, of hydrogenation, was coordinated to the ruthenium center (Scheme 54) [134]. Two diastereoisomers of was coordinated71 were obtained to the due ruthenium to chirality center of the dehydrogenated (Scheme 54)[134 PCy]. Two2(C6H diastereoisomers9) ligand with ruthenium of 71 were acting obtained as 71 were obtained due to chirality of the dehydrogenated PCy2(C6H9) ligand with ruthenium acting as due tothe chirality stereogenic of thecenter. dehydrogenated The formation of PCy complex2(C6H 719) through ligand withthe intramolecular ruthenium acting C-H activation as the stereogenic of the the stereogenic center. The formation of complex 71 through the intramolecular C-H activation of the center.cyclohexane The formation group of proved complex the71 existencethrough theof intramoleculara very reactive C-H intermediate activation [(cymene)Ru( of the cyclohexaneμ- cyclohexane group proved the existence of a very reactive intermediate [(cymene)Ru(μ- groupCl) proved3RuCl(PCy the3 existence)], with one of cymene a very ligand reactive replaced intermediate by phosphine, [(cymene)Ru( which wasµ-Cl) possible3RuCl(PCy to capture3)], with by one Cl)3RuCl(PCy3)], with one cymene ligand replaced by phosphine, which was possible to capture by addition of the dihydrogen. cymeneaddition ligand of replacedthe dihydrogen. by phosphine, which was possible to capture by addition of the dihydrogen.

Scheme 54. The decomposition of the diruthenium chloro-bridged complex. SchemeScheme 54. 54. The Thedecomposition decomposition ofof the diruthenium chloro-bridged chloro-bridged complex. complex. Grubbs and Houk contributed to the topic by studying the decomposition of Z-selective Grubbs and Houk contributed to the topic by studying the decomposition of Z-selective metathesis catalysts with chelating ligands resulting from the carboxylate-driven C-H bond insertion metathesis catalysts with chelating ligands resulting from the carboxylate-driven C-H bond insertion [135]. According to their results, the C–H activation occurred in THF at room temperature between [135]. According to their results, the C–H activation occurred in THF at room temperature between the N-adamantyl alkyl C–H bond and the carboxylate ligand bound to ruthenium, involving a four- the N-adamantyl alkyl C–H bond and the carboxylate ligand bound to ruthenium, involving a four- or six-membered transition step (Scheme 55) [136]. A subsequent hydride elimination depends on or six-membered transition step (Scheme 55) [136]. A subsequent hydride elimination depends on many steric and electronic factors. Compared to the oxidative addition mechanism, this carboxylate- many steric and electronic factors. Compared to the oxidative addition mechanism, this carboxylate-

Catalysts 2020, 10, 887 40 of 56

Grubbs and Houk contributed to the topic by studying the decomposition of Z-selective metathesis catalysts with chelating ligands resulting from the carboxylate-driven C-H bond insertion [135]. According to their results, the C–H activation occurred in THF at room temperature between the N-adamantyl alkyl C–H bond and the carboxylate ligand bound to ruthenium, involving a four- or six-membered transition step (Scheme 55)[136]. A subsequent hydride elimination depends on many stericCatalysts and electronic 2020, 10, x FOR factors. PEER REVIEW Compared to the oxidative addition mechanism, this carboxylate-driven43 of 60 process allowed for isolation of active complexes without the formation of a ruthenium hydride [127]. Treatmentdriven ofprocess72 with allowed the excess for isolation carbon of monoxide active complexes at 78 Cwithout led to the a 1,1-insertion formation of of a COruthenium ligand into − ◦ the Ru-Chydride bond [127]. of theTreatment NHC ligand.of 72 with In the the excess next carbon step the monoxide alkylidene at −78 moiety °C led decomposedto a 1,1-insertion and of anCO alkyl rutheniumligand complexinto the Ru-C saturated bond withof the CO NHC ligands ligand. was In ﬁnallythe next formed step the with alkylidene the N-adamantyl moiety decomposed group bound and an alkyl ruthenium complex saturated with CO ligands was finally formed with the N-adamantyl to the former alkylidene carbon. Substitution by the π-acidic CO ligands decreased the stabilization of group bound to the former alkylidene carbon. Substitution by the π-acidic CO ligands decreased the the alkylidene carbon via backbonding [137]. stabilization of the alkylidene carbon via backbonding [137].

SchemeScheme 55. ( 55.a) The(a) The synthesis synthesis of theof the C-H C-H activated activated catalyst catalyst 72 72 andand itsits decomposition via via exposure exposure to to an excessan CO; excess (b ,CO;c) the (b, C-Hc) the activation C-H activation via t BuCOOAg.via tBuCOOAg.

SuchSuch alkylidene alkylidene insertion insertion could could be be also also possible possible for for C–H C–H activated activated catalystscatalysts in the absence of of CO. It wasCO. proposed It was proposed that similar that ruthenium-alkylsimilar ruthenium-alkyl complexes complexes could could undergo undergo a hydride a hydride elimination elimination when when not saturated with CO ligands leading to inactive catalysts. Treatment of catalyst 73 with silver not saturated with CO ligands leading to inactive catalysts. Treatment of catalyst 73 with silver pivalate pivalate (tBuCOOAg) produced the η2-bound olefin complex 74, through the ligand exchange of (tBuCOOAg) produced the η2-bound oleﬁn complex 74, through the ligand exchange of chlorides for chlorides for pivalates and the generation of silver chloride. The C–H activation occurred through pivalatesthe alkylidene and thegeneration insertion and of the silver β-hydride chloride. elimination The C–H (Scheme activation 55, part occurred b). This through group also the studied alkylidene insertionthe decomposition and the β-hydride of complex elimination 75 through (Scheme the alkylidene 55b). Thisinsertion group and alsothe α studied-hydride theelimination, decomposition by treatment with tBuCOOAg, resulting in a bond formation between the benzylidene carbon and ortho carbon of the N-aryl ligand, keeping the alkylidene group (Scheme 55, part c). The mechanism of this reaction was not carboxylate-driven and the reaction occurred only in the presence of oxygen. The initial product was complex 76 which, by treatment with methylene chloride/pentane mixture, gave

Catalysts 2020, 10, 887 41 of 56 of complex 75 through the alkylidene insertion and the α-hydride elimination, by treatment with tBuCOOAg, resulting in a bond formation between the benzylidene carbon and ortho carbon of the N-aryl ligand, keeping the alkylidene group (Scheme 55c). The mechanism of this reaction was not carboxylate-driven and the reaction occurred only in the presence of oxygen. The initial product was complexCatalysts76 2020which,, 10, x FOR by PEER treatment REVIEW with methylene chloride/pentane mixture, gave product44 of77 60 with replaced pivalates for chloride ligands [138,139]. The formed pivalic acid was a proof of the C–H activationproduct followed 77 with replaced by the catalyst pivalates decomposition. for chloride ligands [138,139]. The formed pivalic acid was a proof of the C–H activation followed by the catalyst decomposition. Cavallo performed DFT studies on the first steps of the C–H activation, the formation of bond Cavallo performed DFT studies on the first steps of the C–H activation, the formation of bond N betweenbetween the rutheniumthe ruthenium and and the the N-phenyl-phenyl ortho ortho methylmethyl group group (Scheme (Scheme 56) 56 [140].)[140 The]. The second second step of step of this mechanismthis mechanism was was the the formation formation of of a benzyla benzyl group group through through anan activated proton proton transfer. transfer. A Avariety variety of substituentsof substituents in the in NHC the NHC backbone backbo didne did not not have have a stronga strong e ffeffectect on on thethe decomposition pathway pathway and, and, in manyin cases, many thecases, energy the energy of the of transition the transition state state65–65 65–065decreased′ decreased for for the theortho ortho isopropylisopropyl groups, groups, while while the methylthe substituents methyl substituents had no effhadect. no For effect. the rate For limiting the rate transition limiting statetransition650–64 state, the 65 NHC′–64, substituentsthe NHC in intermediate 65 had a larger effect on the decomposition. substituents0 in intermediate 65′ had a larger effect on the decomposition.

SchemeScheme 56. The 56. The initial initial step step of of the the deactivation deactivation pathway for for complexes complexes containing containing phenyl-substituted phenyl-substituted NHCNHC ligands ligands with with relative relative Gibbs Gibbs free free energies energies fromfrom the DFT DFT calculations calculations (in (in kcal/mol). kcal/mol).

To studyTo study the the inﬂuence influence ofof the ruthenium-yliden ruthenium-ylidenee bond, bond, Ru-benzylidene, Ru-benzylidene, Ru-indenylidene, Ru-indenylidene, Ru- Ru-methylidenemethylidene andand trimethylphosphonium Ru-alkylid Ru-alkylideneene bonds bonds were were compared compared in the in same the samework. work. Transition states 65–65′ and 65′–64 were found to be more stable for the Ru-Ind system than the Ru- Transition states 65–650 and 650–64 were found to be more stable for the Ru-Ind system than the Ru-benzylidenebenzylidene one, suggesting that that the the catalysts catalysts wi withth indenylidene indenylidene group group were were more more prone prone to this to this decomposition. For the Ru-alkylidene system, the second transition state was less stable, though, on decomposition. For the Ru-alkylidene system, the second transition state was less stable, though, the other hand, a very stable complex 64 was formed. Catalysts with methylidene and benzylidene on the other hand, a very stable complex 64 was formed. Catalysts with methylidene and benzylidene group showed similar results, suggesting that they undergo a similar decomposition pathway. group showedRecently, similar Fogg results, et al. observed suggesting a rapid that theydecomposition undergo a of similar complex decomposition GIIm through pathway. the C-H Recently,activation Foggof mesityl et al. ortho observed-methyl a group, rapid decompositionby the treatment of with complex a 10-foldGIIm excessthrough of pyridine the C-H [92]. activation The of mesitylsaturatedortho NHC-methyl was group,found to by be the more treatment prone to with the activation a 10-fold excessdue to ofa π pyridine-back-donation [92]. Thefrom saturated the NHCruthenium was found to to the be NHC, more slowing prone to down the activation the rotation due around to a π this-back-donation bond [141–144]. from The the corresponding ruthenium to the NHC,σ-alkyl slowing intermediate down the 27 rotation was in a around conformation this bond that favored [141–144 the]. interaction The corresponding between theσ-alkyl σ-alkyl intermediate carbon 27 wasand in the a conformationmesityl group [134,137], that favored while therotating interaction about the between C–N mesityl the σbond-alkyl [145,146]. carbon The and rapid the mesitylC- groupH [134activation,137], whilesuggested rotating the aboutpresence the of C–N only mesityl starting bond methylidene [145,146 ].complex The rapid GIIm C-H and activation the decomposition product [MePCy3]Cl (Scheme 32). The C-H activation was slower for 27_IMes due to suggested the presence of only starting methylidene complex GIIm and the decomposition product the rotation of IMes ligand (after 15 min). The treatment with a 3-fold excess of pyridine retarded the decomposition of GIIm_IMes, while the decomposition of 27_IMes was slower than its formation. In all cases the rate-determining step of the decomposition was either pyridine binding or C–H

Catalysts 2020, 10, 887 42 of 56

[MePCy3]Cl (Scheme 32). The C-H activation was slower for 27_IMes due to the rotation of IMes ligand (after 15 min). The treatment with a 3-fold excess of pyridine retarded the decomposition of GIIm_IMes, while the decomposition of 27_IMes was slower than its formation. In all cases the rate-determining step ofCatalysts the decomposition 2020, 10, x FOR PEER was REVIEW either pyridine binding or C–H activation, indicating that the45 energeticof 60 barriersactivation, for both indicating processes that were the very energetic similar. barriers The entirefor both decomposition processes were was very completed similar. The within entire 75 min and smalldecomposition amounts was of the completed free phosphine within 75 suggestedmin and sm anall additional,amounts of the unknown free phosphine pathway. suggested an additional, unknown pathway. 3.3. Buchner-Type Expansion fo NHCs Interaction3.3. Buchner-Type between Expansion the electrophilic fo NHCs carbene and the aromatic ring of the NHC may lead to carbene insertionInteraction into the aromatic between ringthe electrophilic system, also carbene known and as the the aromatic Buchner ring ring of expansion.the NHC may This lead reaction to is usuallycarbene found insertion when into isocyanides the aromatic or ring carbon system, monoxide, also known widely as the used Buchner as ligands ring expansion. in transition This metal complexesreaction due is usually to their foundσ-donor when strength isocyanides and or weak carbonπ acidity,monoxide, are widely complexed used as to ligands Ru [141 in ,transition147–150]. Themetal group complexes led by due Diver to wastheir the σ-donor first to strength propose and a decomposition weak π acidity, pathway are complexed for 2nd to generation Ru[141,147– Grubbs 150]. II catalysts involving carbene insertion into the mesityl group of NHC ligand, promoted by carbon The group led by Diver was the first to propose a decomposition pathway for 2nd generation monoxideGrubbs or II isocyanides, catalysts involving also known carbene as insertion Buchner into reaction the mesityl [151 ,group152]. Theof NHC general ligand, mechanism promoted consistsby here ofcarbon two steps—first,monoxide or theisocyanides, aromatic also ring known undergoes as Buchner a cyclopropanation reaction [151,152]. which, The general after rearrangement mechanism by 6π electrocyclization,consists here of two forms steps—first, a cycloheptatriene. the aromatic Two ring years undergoes later, Grubbs a cyclopropanation reported the loss which, of CH after2 = PPh3 in secondrearrangement generation by catalyst6π electrocyclization, decomposition forms [84 a]. cycloheptatr The Diveriene. group Two proved years thatlater, in Grubbs the first reported generation complexesthe loss the of CH ylide2 = PPh transfers3 in second from generation the ruthenium catalyst to decomposition the phosphorus [84]. of The the Diver phosphine group proved [153,154 that]. After treatmentin the with first CO,generation two molecules complexes coordinate the ylide transf to rutheniumers from the already ruthenium bearing to threethe phosphorus chloride ligands of the and the wholephosphine complex [153,154]. is anionic After withtreatment a phosphonium with CO, two counterion. molecules coordinate The addition to ruthenium of an aryl already isocyanide bearing three chloride ligands and the whole complex is anionic with a phosphonium counterion. p-ClC6H4NC to the 1st generation Grubbs complex also caused loss of benzylidne resulting in a The addition of an aryl isocyanide p-ClC6H4NC to the 1st generation Grubbs complex also caused complex with three isocyanides added to the ruthenium in a mer arrangement. The first isocyanide loss of benzylidne resulting in a complex with three isocyanides added to the ruthenium in a mer moleculearrangement. coordinates The tofirst the isocyanide metal in the moletransculeposition coordinates to the to benzylidene the metal in (Athe, Schemetrans position 57), which to the causes an intramolecularbenzylidene (A migration, Scheme 57), of which phosphine causes by an aintramolecular 1,2-shift and migration produces of intermediate phosphine byB a. The1,2-shift binding of theand second produces isocyanide intermediate ligand B. The forms binding the intermediate of the second Cisocyanide, which after ligand ylide forms elimination the intermediate produces C, 78 and 79which. after ylide elimination produces 78 and 79.

SchemeScheme 57. The 57. mechanismThe mechanism of isocyanide-promoted of isocyanide-promoted ylidene yliden transfere transfer to to phosphorus phosphorus proposed proposed by by Diver. Diver. Later, the same group synthesized polar isocyanide 80 and used it to remove Ru from metathesis reaction mixturesLater, the same [131]. group The synthesized isocyanide-promoted polar isocyanide carbene 80 and insertion used it to inremove the 2nd Ru from generation metathesis Grubbs catalystreaction (Scheme mixtures 58) [131]. resulted The inisocyanide-promoted a rapid quenching carbene of the insertion carbene in reactivity.the 2nd generation In a reaction Grubbs with catalyst (Scheme 58) resulted in a rapid quenching of the carbene reactivity. In a reaction with p- p-chlorophenyl isocyanide 81, complex 82 was formed, in which two molecules of the isocyanide chlorophenyl isocyanide 81, complex 82 was formed, in which two molecules of the isocyanide were were added to the Ru center and the benzylidene formally inserted into one of the Mes groups, added to the Ru center and the benzylidene formally inserted into one of the Mes groups, similar to similarearlier to earlier findings ﬁndings with CO with [151]. CO The [151 same]. The insertion same insertionwas triggered was by triggered the polar by isocyanide the polar 80, isocyanide which 80, whichconferred conferred greater greater polarity polarity to the to he thexacoordinate hexacoordinate Ru complex, Ru complex, facilitating facilitating the loss of catalyst’s the loss ofactivity catalyst’s activityand and its removal its removal from fromthe organic the organic products products of metathesis. of metathesis.

Catalysts 2020, 10, 887 43 of 56 Catalysts 2020, 10, x FOR PEER REVIEW 46 of 60

Scheme 58. TheThe isocyanide-promoted isocyanide-promoted ligand insertion into GII complex.

In consecutive studies, the Cavallo group performed DFT calculations for the Buchner ring expansion andand highlighted highlighted the the significance significance of the ofπ -acidthe π CO-acid binding CO binding to the trans to positionthe trans to benzylideneposition to benzylideneligand in catalyst’s ligand decompositionin catalyst’s decomposition [155]. The creation [155]. ofThe a cyclopropanone-containingcreation of a cyclopropanone-containing complex was complexconfirmed was by otherconfirmed groups by [156 other–162 groups]. The group [156–162]. ruled The out thegroup possibility ruled out of athe free possibility carbene release of a free as a carbeneresults of release CO binding as a results on the of ground CO binding of the on endothermicity the ground of of the the endothermicity reaction. In the of proposed the reaction. mechanism In the proposedfirst, the CO mechanism molecule coordinatesfirst, the CO to themoleculetrans position coordinates to the to ylidene the trans bond position which elongatesto the ylidene and pushes bond whichthe phosphine elongates almost and pushes opposite the tophosphine the NHC almost ligand o (Schemepposite to59 the). The NHC Ru-NHC ligand (Scheme and Ru-P 59). bonds The alsoRu- NHCelongate, and whileRu-P bonds the NHC-Ru also elongate,= CH2 whileangle the is reduced,NHC-Ru causing= CH2 angle the reactiveis reduced, methylidene causing the ligand reactive to methylideneget closer to theligand aromatic to get NHCcloser ring. to the The aromatic cyclopropanation NHC ring. occursThe cyclopropa in two steps—annation occurs attack in of two the steps—anmethylidene attack group of onthe the methylidene Cipso atom group forming on a the more Cipso stable atom83 forming, still containing a more stable a Ru-CH 83,2 stillbond containing and then athe Ru-CH breaking2 bond of thisand bond then withthe breaking an attack of of this the bond methylidene with an carbon attack onof the one methylidene of the ortho carbon carbon atoms on one of ofthe the mesityl ortho ring.carbon Intermediate atoms of the84 mesityl, with a ring. vacant Intermediatetrans position 84, towith CO a is vacant formed trans and position the coordination to CO is formedof a second and COthe coordination molecule is energetically of a second CO comparable molecule tois energetically the first binding, comparable leading to the first intermediate binding, leading85. The openingto the intermediate of the cyclopropane 85. The opening ring gives of the the final cyclopropane product 86 .ring Noteworthy, gives the withfinal onlyproduct one CO86. Noteworthy,molecule attached with toonly Ru, one the CO system molecule must overcomeattached to a Ru, larger the barrier, system collapsing must overcome to intermediate a larger barrier,87 and, collapsingafter binding to intermediate of second CO, 87 the and, final after product binding86 isof formed. second CO, Due the to a final relatively product small 86 is energy formed. barrier Due for to athe relatively84-to-87 smallstep, theenergy second barrier CO moleculefor the 84 may-to-87 coordinate step, the second after the CO ring molecule expansion. may coordinate after Catalysts 2020, 10, x FOR PEER REVIEW 47 of 60 the ring expansion.

Scheme 59. The CO-driven deactivation pathway of GII with L = PMe3 or CO, with Gibbs free Scheme 59. The CO-driven deactivation pathway of GII with L = PMe3 or CO, with Gibbs free energies energies (in kcal/mol) based on DFT calculations. (in kcal/mol) based on DFT calculations. The first step of cyclopropanation with no ligand trans to the Ru-ylidene bond was investigated with ethylene as a model olefin, in the presence of pyridene, PMe3 or PF3 phosphine (L2, π-acids weaker than CO), also varying ligands opposite the NHC (L1). With no L2 ligand or when L2 = py, the C–H activated complex was unstable. For L2 = PMe3 or PF3, the complex with the associated L2 ligand and the C–H activated catalyst were both stable, whereas the latter was favored for more acidic PF3 than PMe3 (similarly to CO). Additional studies showed that the PH3 ligand favorably binds in the trans position to the Ru-methylidene bond, pointing out that the NHC mesityl rings shield that position. When L1 = PMe3 or pyridine, the system behaved in a similar fashion, whereas using a stronger π-acids like CO or PF3 as L1 and L2 reduced the energy barriers between the precatalyst and the C–H activated complex, the latter becoming the only stable structure. The more electrophilic the catalyst containing L2, the more reactive the methylidene group is towards the Cipso. Moreover, the results showed that when both the precatalyst and the C–H activated complex were stable, the energy barrier for the conversion was rather small. Grela and co-workers expanded the topic by applying amine-containing isocyanides, also known as scavengers, in quenching metathesis reactions and removing ruthenium from the product mixture [163–165]. In one of their studies they observed a coordination of such ligands to ruthenium in the second generation complexes, initiating Buchner reaction and inserting the benzylidene group into the N-aryl moiety [163] forming a decomposed complex 88. In the absence of the NHC, the treatment with isocyanide generated an inactive complex 89 and phosphine ylide 90 (Scheme 60). Among the three new metal scavengers I-III proposed by this group which contained a polar fragment with a tertiary nitrogen atom, II decomposed much faster than the ethyl vinyl ether (EVE). Unlike EVE, CO and D1, isocyanide II seemed to be an ideal olefin metathesis quenching agent, as proposed by Fogg et al. [166].

Catalysts 2020, 10, 887 44 of 56

The first step of cyclopropanation with no ligand trans to the Ru-ylidene bond was investigated with ethylene as a model olefin, in the presence of pyridene, PMe3 or PF3 phosphine (L2, π-acids weaker than CO), also varying ligands opposite the NHC (L1). With no L2 ligand or when L2 = py, the C–H activated complex was unstable. For L2 = PMe3 or PF3, the complex with the associated L2 ligand and the C–H activated catalyst were both stable, whereas the latter was favored for more acidic PF3 than PMe3 (similarly to CO). Additional studies showed that the PH3 ligand favorably binds in the trans position to the Ru-methylidene bond, pointing out that the NHC mesityl rings shield that position. When L1 = PMe3 or pyridine, the system behaved in a similar fashion, whereas using a stronger π-acids like CO or PF3 as L1 and L2 reduced the energy barriers between the precatalyst and the C–H activated complex, the latter becoming the only stable structure. The more electrophilic the catalyst containing L2, the more reactive the methylidene group is towards the Cipso. Moreover, the results showed that when both the precatalyst and the C–H activated complex were stable, the energy barrier for the conversion was rather small. Grela and co-workers expanded the topic by applying amine-containing isocyanides, also known as scavengers, in quenching metathesis reactions and removing ruthenium from the product mixture [163–165]. In one of their studies they observed a coordination of such ligands to ruthenium in the second generation complexes, initiating Buchner reaction and inserting the benzylidene group into the N-aryl moiety [163] forming a decomposed complex 88. In the absence of the NHC, the treatment with isocyanide generated an inactive complex 89 and phosphine ylide 90 (Scheme 60). Among the three new metal scavengers I-III proposed by this group which contained a polar fragment with a tertiary nitrogen atom, II decomposed much faster than the ethyl vinyl ether (EVE). Unlike EVE, CO and D1, isocyanide II seemed to be an ideal olefin metathesis quenching agent, as proposed by

FoggCatalysts et 2020 al. [,166 10, x]. FOR PEER REVIEW 48 of 60

SchemeScheme 60. The reactivity of isocyanides towards the ﬁrstfirst andand second generation metathesis catalysts.

FurtherFurther work of thethe DiverDiver groupgroup focusedfocused onon thethe kineticskinetics ofof thethe BuchnerBuchner reaction,reaction, thisthis timetime triggeredtriggered byby alkylalkyl andand arylaryl isocyanidesisocyanides [[167].167]. For all isocyanides,isocyanides, product 91 waswas thethe initialinitial reactionreaction productproduct (Scheme 61,61a). part It a). was It was the the only only product product for for alkyl alkyl isocyanides isocyanides at at 0 0◦ C°C and and arylaryl isocyanides, whereaswhereas atat higherhigher temperaturestemperatures oror forfor slowerslower BuchnerBuchner reactions,reactions, complexcomplex 9292 withwith threethree isocyanideisocyanide groupsgroups waswas formed.formed. Such product existing as aa mixturemixture ofof cycloheptatrienylcycloheptatrienyl ringring isomersisomers hashas beenbeen obtainedobtained previouslypreviously [156 [156]] in ain reaction a reaction of Hoveyda-Blechert of Hoveyda-Blechert catalyst 4catalystwith 4-chlorophenyl 4 with 4-chlorophenyl isocyanide (Schemeisocyanide 61b). (Scheme It was also 61, shownpart b). that Itat was higher also temperatures shown that the at phosphine higher temperatures dissociative mechanismthe phosphine was favoreddissociative over mechanism the associative was one.favored When over the the Buchner associat reactionive one. was When faster the than Buchner isocyanide reaction substitution was faster forthan PCy isocyanide3, the reaction substitution with the for second PCy isocyanide3, the reaction molecule with causedthe second Buchner isocyanide insertion molecule and binding caused of theBuchner third molecule,insertion and generating binding the of finalthe third tris(isocyanide) molecule, generating complex. Despitethe final faster tris(isocyanide) dissociation complex. of PPh3 withDespite respect faster to dissociation PCy3, such modificationof PPh3 with ofrespect the phosphine to PCy3, such ligand modification did not affect of the carbenephosphine insertion. ligand However,did not affect it was the acarbeneffected byinsertion. the ligand However,trans to it thewas NHC, affected since by itsthe electron ligand trans donating to the/withdrawing NHC, since propertiesits electron modulated donating/withdrawing the reactivity ofproperties ruthenium modulated towards thethe Buchner reactivity reaction. of ruthenium towards the Buchner reaction.

Scheme 61. The mechanism for the CNR-promoted Buchner insertion proposed by Diver for (a) GII and (b) HGII.

Catalysts 2020, 10, x FOR PEER REVIEW 48 of 60

Scheme 60. The reactivity of isocyanides towards the first and second generation metathesis catalysts.

Further work of the Diver group focused on the kinetics of the Buchner reaction, this time triggered by alkyl and aryl isocyanides [167]. For all isocyanides, product 91 was the initial reaction product (Scheme 61, part a). It was the only product for alkyl isocyanides at 0 °C and aryl isocyanides, whereas at higher temperatures or for slower Buchner reactions, complex 92 with three isocyanide groups was formed. Such product existing as a mixture of cycloheptatrienyl ring isomers has been obtained previously [156] in a reaction of Hoveyda-Blechert catalyst 4 with 4-chlorophenyl isocyanide (Scheme 61, part b). It was also shown that at higher temperatures the phosphine dissociative mechanism was favored over the associative one. When the Buchner reaction was faster than isocyanide substitution for PCy3, the reaction with the second isocyanide molecule caused Buchner insertion and binding of the third molecule, generating the final tris(isocyanide) complex. Despite faster dissociation of PPh3 with respect to PCy3, such modification of the phosphine ligand did not affect the carbene insertion. However, it was affected by the ligand trans to the NHC, since Catalysts 2020its electron, 10, 887 donating/withdrawing properties modulated the reactivity of ruthenium towards the 45 of 56 Buchner reaction.

SchemeScheme 61. The 61. mechanism The mechanism for for the the CNR-promoted CNR-promoted Buchne Buchnerr insertion insertion proposed proposed by Diver by Diverfor (a) GII for (a) GII and (b) HGII. and (b) HGII.

In these studies it was also shown that both steric and electronic properties of the isocyanide have an impact on the decomposition of ruthenium catalysts. Due to the constrained vacant coordination, the site positioned between a mesityl and cyclohexyl group was the most accessible to less sterically-hindered ligands, which was confirmed by Fogg et al. [88,101] Aromatic isocyanides presented in this work most probably accelerated the Buchner reaction compared to highly congested aryl isocyanides, as did electron-withdrawing isocyanide substituents. Moreover, to accommodate quenching the ligand must possess strong σ-donor and π-acceptor properties. Strong σ donation only resulted in the metal binding but was not itself sufficient to cause the Buchner insertion. Lack of the π accepting properties, on the other hand, gave rise to a decomposition pathway different from Buchner reaction, as reported by Grubbs et al. [84] The electronic environment of the metal in the complex also played a key role, since previous study [156] showed that electron-rich metal carbenes, such as Fischer carbenes, do not undergo the Buchner reaction but instead, a π conjugation may take place, that is, for a vinyl carbene. Furthermore, Diver group emphasized the most favorable mechanism in which one isocyanide molecule is reversibly coordinated, the benzylidene is added to the mesityl group (rate-limiting step), followed by next fast steps. The electrophilicity of the carbene was the rate-determining factor of the process. The isocyanide addition most probably occurred in the trans position to the carbene, forming an 18-electron species 93 and altering the electronic nature of the carbene. It was suggested that the π orbital of the benzylidene carbene carbon was destabilized, weakening the bond with ruthenium and making the carbene more electrophilic [168]. The 16-electron intermediate 94 was formed on account of proximal mesityl group cyclopropanation, followed by the addition of a second isocyanide and ring opening, forming metallocyclic intermediate 95 [155]. Recently, the Trzaskowski group performed computational studies on the decomposition of Hoveyda-Grubbs catalysts promoted by acrylonitrile and also considered Buchner ring expansion, keeping in mind the possibility of generating complexes with two acrylinitrile ligands [99]. Acrylonitrile may interact with ruthenium complexes by attacking the π-bond of benzylidene and one chloride ligand, possibly leading to chloride abstraction and catalyst decomposition. Calculations were also performed for similar systems of phosphine-containing ruthenium complex coordinating the CO molecule [155]. Removing or substitution of the CO ligand with acrylonitrile caused intermediate 83 to become unstable and form back to the original complex or the cyclopropane intermediate Catalysts 2020, 10, 887 46 of 56

(Scheme 62). It was shown that the decomposition pathway with one acrylonitrile was very unlikely from the energetic point of view. When two acrylonitrile ligands were attached to the complex through Ru-N interactions, most energy barriers were lower compared to complexes with one acrylonitrile. Decomposition of HGII with two acrylonitrile moieties through Buchner ring expansion was possible in room temperature through methylidene or cyanomethylidene species. It was, however, unlikely for CAAC systems, for which energy barriers were of at least 39.0 kcal/mol. It was speculated that the opposite trends of TONs for these catalysts versus HGII could be caused by the fact that metathesis may be much faster (usually 0.5–2 h) than decomposition (usually hours/days). Grela’s group earlier showed that CAAC Hoveyda-Grubbs-like catalysts decompose by 5% in 12 h, whereas analogues of HGII decomposes much faster (45% catalyst left after 4 h, 30% after 12 h) [169]. The high/low TONs for metathesis reactions may also be caused by catalyst being stuck in a non-productive cycle with no ability to form the ﬁnal product. Catalysts 2020, 10, x FOR PEER REVIEW 50 of 60

Scheme 62.SchemeThe Gibbs62. The freeGibbs energy free energy proﬁle profile of of decomposition decomposition of ofHGIIHGII and andCAAC-containing CAAC-containing catalysts catalysts via Buchner ring expansion with either (a) one or (b) two acrylonitrile ligands. via Buchner ring expansion with either (a) one or (b) two acrylonitrile ligands. The results obtained by Trzaskowski et al. showed different behavior of CAAC-containing The resultscatalysts obtainedand HGII in by the Trzaskowski presence of acrylonitrile et al. showed[99]. It was di suggestedﬀerent behaviorthat low barriers of CAAC-containing for HGII catalysts andmayHGII be indue the presenceto strong of acrylonitrileinteraction between [99]. It wasacrylonitrile suggested ligand that low trans barriers to fortheHGII may be due to strongmethylidene/cyanomethylidene interaction between and acrylonitrile mesityl group. ligand This interactiontrans to exists the methylidene in the key transition/cyanomethylidene states for system 96 and 97 but not for 98. This transition state was also stabilized by the mesityl/phenyl- and mesityl group. This interaction exists in the key transition states for system 96 and 97 but acrylonitrile interactions, while the methyl-acrylonitrile interaction destabilized that intermediate in not for 98.98 This. Energy transition barriers were state estimated was also to be stabilized very similar by for the catalysts mesityl 98 and/phenyl-acrylonitrile 97 and lower for 96. In the interactions, while the methyl-acrylonitrilecase of the Buchner ring expansion, interaction the destabilizedhigher stability thatof 98 intermediatein the presence of in acrylonitrile98. Energy may barriers be were estimatedcaused to be veryby minimizing similarfor interactions catalysts between98 and th97e NHC/CAACand lower forside 96groups. In theand case the acrylonitrile of the Buchner ring molecule. It was also suggested that the NHC/CAAC electronic properties and not only steric ones, itself may have an effect on the decomposition.

Catalysts 2020, 10, 887 47 of 56 expansion, the higher stability of 98 in the presence of acrylonitrile may be caused by minimizing interactions between the NHC/CAAC side groups and the acrylonitrile molecule. It was also suggested that the NHC/CAAC electronic properties and not only steric ones, itself may have an eﬀect on the decomposition.

4. Conclusions and Future Outlook

OverCatalysts 30 2020 years, 10, x FOR after PEER the REVIEW synthesis of the first, well-defined ruthenium metathesis catalyst51 of 60 [3], our knowledge and understanding of the decomposition pathways of this important family of complexes4. Conclusions is very broad.and Future Over Outlook 150 studies cited in this review shed more light on the relationship between theOver structure 30 years andafter decompositionthe synthesis of the mechanisms first, well-defined and rates ruthenium of these metath systems,esis catalyst which [3], gave our rise to the synthesisknowledge of and even understanding more efficient of the catalysts, decomposition less prone pathways to decomposition. of this important While family around of complexes five years ago itislooked very broad. like Over we have 150 studies a very cited good in understanding this review shed ofmore all thelight major on thedecomposition relationship between processes the of rutheniumstructure metathesis and decomposition catalyst, some mechanisms newer and studied rates inof thisthese field systems, showed which that gave we rise were to the and synthesis may still be, far fromof even knowing more efficient the complete catalysts, picture. less prone Of the to manydecomposition. interesting While studied around reviewed five years here, ago a it few looked warrant like we have a very good understanding of all the major decomposition processes of ruthenium a special attention of the reader. These include definitely the seminal study by the Fogg group on metathesis catalyst, some newer studied in this field showed that we were and may still be, far from the general Broensted base-driven decomposition pathway, valid for a broad range of Grubbs-class knowing the complete picture. Of the many interesting studied reviewed here, a few warrant a special catalystsattention [81]. of This the studyreader. does These not include simply definitely provide the new seminal data study for yet by anotherthe Fogg decompositiongroup on the general pathway underBroensted a new external base-driven agent decomposition but addresses pathway, the decomposition valid for a broad problem range of for Grubbs-class a broader catalysts range of [81]. external agentsThis and study catalysts, does not providing simply provide mechanistic new data insight for yet into another the actiondecomposition of an entire pathway class under of compounds. a new A secondexternal study agent likely but addresses to have the a large decomposition impact on prob thelem catalytic for a broader society range is the of external discovery agents of theand new, bimolecularcatalysts, decomposition providing mechanistic pathway insight [36]. Combinedinto the action with of thean entire older class studies of compounds. of van Rensburg A second [27] this workstudy allows likely toinvestigate to have a large the impact two major on the decomposition catalytic society routes is the discovery for both oldof the and new, new bimolecular catalysts and alreadydecomposition made possible pathway to explain [36]. Combined the diff witherences the older in action studies between of van Rensburg the standard [27] this Hoveyda-Grubbs work allows to investigate the two major decomposition routes for both old and new catalysts and already made catalysts and newer CAAC-based ones. They also pave a way for developing new catalysts, even less possible to explain the differences in action between the standard Hoveyda-Grubbs catalysts and prone to degradation in the presence of olefins. newer CAAC-based ones. They also pave a way for developing new catalysts, even less prone to Ondegradation the other in hand the presence there are of stillolefins. some unresolved problems and questions waiting for an answer. These includeOn the for other example, hand there the possibleare still some decomposition unresolved problems pathways and of questions NHC-containing waiting for catalysts an answer. in only aproticThese solutions, include without for example, any the presence possible of decomposition olefin or external pathways agents of known NHC-containing to cause decomposition catalysts in only [169]. Oneaprotic possible solutions, decomposition without any mechanism presence of in olefin such or setup external could agents include known ato bimolecular cause decomposition coupling of benzylidenes,[169]. One insteadpossible decomposition of methylidenes, mechanism following in such a pathway setup could summarized include a bimolecular in Scheme coupling 63. One of can also expectbenzylidenes, soon newinstead studied of methylidenes, on the more following and morea pathway commonly summarized used in CAAC-containing Scheme 63. One can catalysts’also and theirexpect susceptibility soon new studied to various on the externalmore and agents, more commonly similar to used former, CAAC-containing analogous studies catalysts’ for and Grubbs their susceptibility to various external agents, similar to former, analogous studies for Grubbs and and Hoveyda-Grubbs complexes. We are certain, that in the next 5–10 years a new review on the Hoveyda-Grubbs complexes. We are certain, that in the next 5–10 years a new review on the decomposition pathways of ruthenium metathesis catalysts will be again timely, as there will be new, decomposition pathways of ruthenium metathesis catalysts will be again timely, as there will be new, interestinginteresting results results on thison this topic. topic.

SchemeScheme 63. The63. The hypothetical hypothetical bimolecular bimolecular couplingcoupling mechanism mechanism for for activated activated benzylidenes. benzylidenes.

Author Contributions: Design, B.T.; Bibliographic research and Writing-Review, M.J, A.M and B.T; Editing, B.T. All authors have read and agreed to the published version of the manuscript.

Funding: The authors acknowledge research support from the National Science Centre grant UMO- 2016/22/E/ST4/00573.

Catalysts 2020, 10, 887 48 of 56

Author Contributions: Design, B.T.; Bibliographic research and Writing-Review, M.J., A.M. and B.T.; Editing, B.T. All authors have read and agreed to the published version of the manuscript. Funding: The authors acknowledge research support from the National Science Centre grant UMO-2016/22/E/ST4/00573. Conﬂicts of Interest: The authors declare no conﬂict of interest.

References

1. Rinehart, R.E.; Smith, H.P. The emulsion polymerization of the norbornene ring system catalyzed by noble metal compounds. J. Polym. Sci. B 1965, 3, 1049–1052. [CrossRef] 2. Michelotti, F.W.; Keaveney, W.P. Coordinated polymerization of the bicyclo-[2.2.1]-heptene-2 ring system (norbornene) in polar media. J. Polym. Sci. A 1965, 3, 895–905. [CrossRef] 3. Nguyen, S.T.; Johnson, L.K.; Grubbs, R.H.; Ziller, J.W. Ring-opening metathesis polymerization (ROMP) of norbornene by a Group VIII carbene complex in protic media. J. Am. Chem. Soc. 1992, 114, 3974–3975. [CrossRef] 4. Schwab, P.; France, M.B.; Ziller, J.W.; Grubbs, R.H. A Series of Well-Deﬁned Metathesis Catalysts–Synthesis

of [RuCl2(=CHR0)(PR3)2] and Its Reactions. Angew. Chem. Int. Ed. Engl. 1995, 34, 2039–2041. [CrossRef] 5. Huang, J.; Stevens, E.D.; Nolan, S.P.; Petersen, J.L. Olefin Metathesis-Active Ruthenium Complexes Bearing a Nucleophilic Carbene Ligand. J. Am. Chem. Soc. 1999, 121, 2674–2678. [CrossRef] 6. Scholl, M.; Trnka, T.M.; Morgan, J.P.; Grubbs, R.H. Increased ring closing metathesis activity of ruthenium-based olefin metathesis catalysts coordinated with imidazolin-2-ylidene ligands. Tetrahedron Lett. 1999, 40, 2247–2250. [CrossRef] 7. Ackermann, L.; Fürstner, A.; Weskamp, T.; Kohl, F.J.; Herrmann, W.A. Ruthenium carbene complexes with imidazolin-2-ylidene ligands allow the formation of tetrasubstituted cycloalkenes by RCM. Tetrahedron Lett. 1999, 40, 4787–4790. [CrossRef] 8. Love, J.A.; Morgan, J.P.; Trnka, T.M.; Grubbs, R.H. A Practical and Highly Active Ruthenium-Based Catalyst that Effects the Cross Metathesis of Acrylonitrile. Angew. Chem. Int. Ed. 2002, 41, 4035–4037. [CrossRef] 9. Garber, S.B.; Kingsbury, J.S.; Gray, B.L.; Hoveyda, A.H. Efficient and Recyclable Monomeric and Dendritic Ru-Based Metathesis Catalysts. J. Am. Chem. Soc. 2000, 122, 8168–8179. [CrossRef] 10. Vougioukalakis, G.C.; Grubbs, R.H. Ruthenium-Based Heterocyclic Carbene-Coordinated Olefin Metathesis Catalysts. Chem. Rev. 2010, 110, 1746–1787. [CrossRef] 11. Samojłowicz, C.; Bieniek, M.; Grela, K. Ruthenium-Based Olefin Metathesis Catalysts Bearing N-Heterocyclic Carbene Ligands. Chem. Rev. 2009, 109, 3708–3742. [CrossRef][PubMed] 12. Lozano-Vila, A.M.; Monsaert, S.; Bajek, A.; Verpoort, F. Ruthenium-Based Olefin Metathesis Catalysts Derived from Alkynes. Chem. Rev. 2010, 110, 4865–4909. [CrossRef][PubMed] 13. Hamad, F.B.; Sun, T.; Xiao, S.; Verpoort, F. Olefin metathesis ruthenium catalysts bearing unsymmetrical heterocylic carbenes. Coord. Chem. Rev. 2013, 257, 2274–2292. [CrossRef] 14. Nolan, S.P.; Clavier, H. Chemoselective olefin metathesis transformations mediated by ruthenium complexes. Chem. Soc. Rev. 2010, 39, 3305. [CrossRef] 15. Higman, C.S.; Lummiss, J.A.M.; Fogg, D.E. Olefin Metathesis at the Dawn of Implementation in Pharmaceutical and Specialty-Chemicals Manufacturing. Angew. Chem. Int. Ed. 2016, 55, 3552–3565. [CrossRef] 16. Hughes, D.; Wheeler, P.; Ene, D. Olefin Metathesis in Drug Discovery and Development—Examples from Recent Patent Literature. Org. Process Res. Dev. 2017, 21, 1938–1962. [CrossRef] 17. Yu, M.; Lou, S.; Gonzalez-Bobes, F. Ring-Closing Metathesis in Pharmaceutical Development: Fundamentals, Applications, and Future Directions. Org. Process Res. Dev. 2018, 22, 918–946. [CrossRef] 18. Turczel, G.; Kovács, E.; Merza, G.; Coish, P.; Anastas, P.T.; Tuba, R. Synthesis of Semiochemicals via Olefin Metathesis. ACS Sustain. Chem. Eng. 2019, 7, 33–48. [CrossRef] 19. Flick, A.C.; Leverett, C.A.; Ding, H.X.; McInturff, E.; Fink, S.J.; Helal, C.J.; O’Donnell, C.J. Synthetic Approaches to the New Drugs Approved During 2017. J. Med. Chem. 2019, 62, 7340–7382. [CrossRef] 20. Sytniczuk, A.; Milewski, M.; Kajetanowicz, A.; Grela, K. Preparation of macrocyclic musks via olefin metathesis: Comparison with classical syntheses and recent advances. Russ. Chem. Rev. 2020, 89, 469–490. [CrossRef] Catalysts 2020, 10, 887 49 of 56

21. Montgomery, T.P.; Johns, A.M.; Grubbs, R.H. Recent Advancements in Stereoselective Olefin Metathesis Using Ruthenium Catalysts. Catalysts 2017, 7, 87. [CrossRef] 22. Chikkali, S.; Mecking, S. Refining of Plant Oils to Chemicals by Olefin Metathesis. Angew. Chem. Int. Ed. 2012, 51, 5802–5808. [CrossRef][PubMed] 23. Winkler, M.; Meier, M.A.R. Olefin cross-metathesis as a valuable tool for the preparation of renewable polyesters and polyamides from unsaturated fatty acid esters and carbamates. Green Chem 2014, 16, 3335–3340. [CrossRef] 24. Vignon, P.; Vancompernolle, T.; Couturier, J.-L.; Dubois, J.-L.; Mortreux, A.; Gauvin, R.M. Cross-Metathesis of Biosourced Fatty Acid Derivatives: A Step Further Toward Improved Reactivity. ChemSusChem 2015, 8, 1143–1146. [CrossRef] 25. Jean-Louis Hérisson, P.; Chauvin, Y. Catalyse de transformation des olefines par les complexes du tungstene II. Telomerisation des oleffines cycliques en presence d’olefines acycliques. Makromol. Chem. 1971, 141, 161–176. [CrossRef] 26. Nelson, D.J.; Manzini, S.; Urbina-Blanco, C.A.; Nolan, S.P. Key processes in ruthenium-catalysed olefin metathesis. Chem. Commun. 2014, 50, 10355. [CrossRef] 27. Janse van Rensburg, W.; Steynberg, P.J.; Meyer, W.H.; Kirk, M.M.; Forman, G.S. DFT Prediction and Experimental Observation of Substrate-Induced Catalyst Decomposition in Ruthenium-Catalyzed Olefin Metathesis. J. Am. Chem. Soc. 2004, 126, 14332–14333. [CrossRef]

28. Bourgeois, D.; Pancrazi, A.; Nolan, S.P.; Prunet, J. The Cl2(PCy3)(IMes)Ru(=CHPh) catalyst: Olefin metathesis versus olefin isomerization. J. Organomet. Chem. 2002, 643–644, 247–252. [CrossRef] 29. van Rensburg, W.J.; Steynberg, P.J.; Kirk, M.M.; Meyer, W.H.; Forman, G.S. Mechanistic comparison of ruthenium olefin metathesis catalysts: DFT insight into relative reactivity and decomposition behavior. J. Organomet. Chem. 2006, 691, 5312–5325. [CrossRef] 30. Lysenko, Z.; Maughon, B.R.; Mokhtar-Zadeh, T.; Tulchinsky, M.L. Stability of the first-generation Grubbs metathesis catalyst in a continuous flow reactor. J. Organomet. Chem. 2006, 691, 5197–5203. [CrossRef] 31. Bespalova, N.B.; Nizovtsev, A.V.; Afanasiev, V.V.; Shutko, E.V. Metathesis Catalysts Stability and Decomposition Pathway. In Metathesis Chemistry; Imamoglu, Y., Dragutan, V., Karabulut, S., Eds.; Springer: Dordrecht, The Netherlands, 2007; pp. 125–135. 32. Ashworth, I.W.; Hillier, I.H.; Nelson, D.J.; Percy, J.M.; Vincent, M.A. Searching for the Hidden Hydrides: The Competition between Alkene Isomerization and Metathesis with Grubbs Catalysts. Eur. J. Org. Chem. 2012, 2012, 5673–5677. [CrossRef] 33. Jawiczuk, M.; Młodzikowska-Pieńko,K.; Trzaskowski, B. Impact of the olefin structure on the catalytic cycle and decomposition rates of Hoveyda–Grubbs metathesis catalysts. Phys. Chem. Chem. Phys. 2020, 22, 13062–13069. [CrossRef][PubMed] 34. Jawiczuk, M.; Marczyk, A.; Młodzikowska-Pieńko,K.; Trzaskowski, B. Impact of the Carbene Derivative Charge on the Decomposition Rates of Hoveyda–Grubbs-like Metathesis Catalysts. J. Phys. Chem. A 2020, acs.jpca.0c03096. [CrossRef][PubMed] 35. Engel, J.; Smit, W.; Foscato, M.; Occhipinti, G.; Törnroos, K.W.; Jensen, V.R.Loss and Reformation of Ruthenium Alkylidene: Connecting Olefin Metathesis, Catalyst Deactivation, Regeneration, and Isomerization. J. Am. Chem. Soc. 2017, 139, 16609–16619. [CrossRef] 36. Bailey, G.A.; Foscato, M.; Higman, C.S.; Day, C.S.; Jensen, V.R.; Fogg, D.E. Bimolecular Coupling as a Vector for Decomposition of Fast-Initiating Olefin Metathesis Catalysts. J. Am. Chem. Soc. 2018, 140, 6931–6944. [CrossRef] 37. Nascimento, D.L.; Fogg, D.E. Origin of the Breakthrough Productivity of Ruthenium–Cyclic Alkyl Amino Carbene Catalysts in Olefin Metathesis. J. Am. Chem. Soc. 2019, 141, 19236–19240. [CrossRef] 38. Dinger, M.B.; Mol, J.C. Degradation of the First-Generation Grubbs Metathesis Catalyst with Primary Alcohols, Water, and Oxygen. Formation and Catalytic Activity of Ruthenium(II) Monocarbonyl Species. Organometallics 2003, 22, 1089–1095. [CrossRef] 39. Dinger, M.B.; Mol, J.C. Degradation of the Second-Generation Grubbs Metathesis Catalyst with Primary Alcohols and Oxygen—Isomerization and Hydrogenation Activities of Monocarbonyl Complexes. Eur. J. Inorg. Chem. 2003, 2827–2833. [CrossRef]

40. Banti, D.; Mol, J.C. Degradation of the ruthenium-based metathesis catalyst [RuCl2(CHPh)(H2IPr)(PCy3)] with primary alcohols. J. Organomet. Chem. 2004, 689, 3113–3116. [CrossRef] Catalysts 2020, 10, 887 50 of 56

41. Werner, H.; Grünwald, C.; Stüer, W.; Wolf, J. Deactivation of the Grubbs Carbene Complex

[RuCl2(CHPh)(PCy3)2] by Allylic Alcohols. Organometallics 2003, 22, 1558–1560. [CrossRef] 42. Beach, N.J.; Camm, K.D.; Fogg, D.E. Hydrogenolysis versus Methanolysis of First- and Second-Generation Grubbs Catalysts: Rates, Speciation, and Implications for Tandem Catalysis. Organometallics 2010, 29, 5450–5455. [CrossRef] 43. Beach, N.J.; Lummiss, J.A.M.; Bates, J.M.; Fogg, D.E. Reactions of Grubbs Catalysts with Excess Methoxide: Formation of Novel Methoxyhydride Complexes. Organometallics 2012, 31, 2349–2356. [CrossRef] 44. Coalter, J.N.; Bollinger, J.C.; Eisenstein, O.; Caulton, K.G. R-Group reversal of isomer stability for

RuH(X)L2(CCHR) vs. Ru(X)L2(CCH2R): Access to four-coordinate ruthenium carbenes and carbynes. New J. Chem. 2000, 24, 925–927. [CrossRef] 45. Sanford, M.S.; Henling, L.M.; Day, M.W.; Grubbs, R.H. Ruthenium-Based Four-Coordinate Olefin Metathesis Catalysts. Angew. Chem. Int. Ed. 2000, 39, 3451–3453. [CrossRef] 46. Conrad, J.C.; Amoroso, D.; Czechura, P.; Yap, G.P.A.; Fogg, D.E. The First Highly Active, Halide-Free Ruthenium Catalyst for Olefin Metathesis. Organometallics 2003, 22, 3634–3636. [CrossRef] 47. Caskey, S.R.; Stewart, M.H.; Ahn, Y.J.; Johnson, M.J.A.; Kampf, J.W. Dehydrohalogenation by a Germylene: Conversion of Carbene Ligands into Carbynes at Ruthenium. Organometallics 2005, 24, 6074–6076. [CrossRef] 48. Goudreault, A.Y.; Walden, D.M.; Nascimento, D.L.; Botti, A.G.; Steinmann, S.N.; Michel, C.; Fogg, D.E. Hydroxide-Induced Degradation of Olefin Metathesis Catalysts: A Challenge for Metathesis in Alkaline Media. ACS Catal. 2020, 3838–3843. [CrossRef] 49. Young, A.; Vincent, M.A.; Hillier, I.H.; Percy, J.M.; Tuttle, T. Forming a ruthenium isomerisation catalyst from Grubbs II: A DFT study. Dalton Trans. 2014, 43, 8493–8498. [CrossRef] 50. Manzini, S.; Urbina-Blanco, C.A.; Poater, A.; Slawin, A.M.Z.; Cavallo, L.; Nolan, S.P. From Olefin Metathesis Catalyst to Alcohol Racemization Catalyst in One Step. Angew. Chem. Int. Ed. 2012, 51, 1042–1045. [CrossRef] 51. Manzini, S.; Nelson, D.J.; Lebl, T.; Poater, A.; Cavallo, L.; Slawin, A.M.Z.; Nolan, S.P. From ruthenium olefin metathesis catalyst to (η5-3-phenylindenyl)hydrido complex via alcoholysis. Chem. Commun. 2014, 50, 2205–2207. [CrossRef] 52. Manzini, S.; Poater, A.; Nelson, D.J.; Cavallo, L.; Slawin, A.M.Z.; Nolan, S.P. Insights into the Decomposition of Olefin Metathesis Precatalysts. Angew. Chem. Int. Ed. 2014, 53, 8995–8999. [CrossRef] 53. Beach, N.J.; Blacquiere, J.M.; Drouin, S.D.; Fogg, D.E. Carbonyl-Amplified Catalyst Performance: Balancing Stability against Activity for Five-Coordinate Ruthenium Hydride and Hydridocarbonyl Catalysts. Organometallics 2009, 28, 441–447. [CrossRef] 54. Rouen, M.; Queval, P.; Borré, E.; Falivene, L.; Poater, A.; Berthod, M.; Hugues, F.; Cavallo, L.; Baslé, O.; Olivier-Bourbigou, H.; et al. Selective Metathesis of α-Olefins from Bio-Sourced Fischer–Tropsch Feeds. ACS Catal. 2016, 6, 7970–7976. [CrossRef] 55. Forman, G.S.; McConnell, A.E.; Tooze, R.P.; Janse van Rensburg, W.; Meyer, W.H.; Kirk, M.M.; Dwyer, C.L.; Serfontein, D.W. A Convenient System for Improving the Efficiency of First-Generation Ruthenium Olefin Metathesis Catalysts. Organometallics 2005, 24, 4528–4542. [CrossRef] 56. Lynn, D.M.; Mohr, B.; Grubbs, R.H.; Henling, L.M.; Day, M.W. Water-Soluble Ruthenium Alkylidenes: Synthesis, Characterization, and Application to Olefin Metathesis in Protic Solvents. J. Am. Chem. Soc. 2000, 122, 6601–6609. [CrossRef] 57. Dowden, J.; Savović,J. Olefin metathesis in non-degassed solvent using a recyclable, polymer supported alkylideneruthenium. Chem. Commun. 2001, 37–38. [CrossRef] 58. Van Veldhuizen, J.J.; Garber, S.B.; Kingsbury, J.S.; Hoveyda, A.H. A Recyclable Chiral Ru Catalyst for Enantioselective Olefin Metathesis. Efficient Catalytic Asymmetric Ring-Opening/Cross Metathesis in Air. J. Am. Chem. Soc. 2002, 124, 4954–4955. [CrossRef] 59. Connon, S.J.; Rivard, M.; Zaja, M.; Blechert, S. Practical Olefin Metathesis in Protic Media under an Air Atmosphere. Adv. Synth. Catal. 2003, 345, 572–575. [CrossRef] 60. Binder, J.B.; Guzei, I.A.; Raines, R.T. Salicylaldimine Ruthenium Alkylidene Complexes: Metathesis Catalysts Tuned for Protic Solvents. Adv. Synth. Catal. 2007, 349, 395–404. [CrossRef] 61. Vila, A.M.L.; Monsaert, S.; Drozdzak, R.; Wolowiec, S.; Verpoort, F. New Indenylidene-Schiff Base-Ruthenium Complexes for Cross-Metathesis and Ring-Closing Metathesis. Adv. Synth. Catal. 2009, 351, 2689–2701. [CrossRef] Catalysts 2020, 10, 887 51 of 56

62. Burtscher, D.; Grela, K. Aqueous Olefin Metathesis. Angew. Chem. Int. Ed. 2009, 48, 442–454. [CrossRef] [PubMed] 63. Kniese, M.; Meier, M.A.R. A simple approach to reduce the environmental impact of olefin metathesis reactions: A green and renewable solvent compared to solvent-free reactions. Green Chem. 2010, 12, 169–173. [CrossRef] 64. Skowerski, K.; Szczepaniak, G.; Wierzbicka, C.; Gułajski, Ł.; Bieniek, M.; Grela, K. Highly active catalysts for olefin metathesis in water. Catal. Sci. Technol. 2012, 2, 2424–2427. [CrossRef] 65. Skowerski, K.; Kasprzycki, P.; Bieniek, M.; Olszewski, T.K. Efficient, durable and reusable olefin metathesis catalysts with high affinity to silica gel. Tetrahedron 2013, 69, 7408–7415. [CrossRef] 66. Occhipinti, G.; Hansen, F.R.; Törnroos, K.W.; Jensen, V.R. Simple and Highly Z-Selective Ruthenium-Based Olefin Metathesis Catalyst. J. Am. Chem. Soc. 2013, 135, 3331–3334. [CrossRef] 67. Tomasek, J.; Schatz, J. Olefin metathesis in aqueous media. Green Chem. 2013, 15, 2317–2338. [CrossRef] 68. Skowerski, K.; Białecki, J.; Tracz, A.; Olszewski, T.K. An attempt to provide an environmentally friendly solvent selection guide for olefin metathesis. Green Chem. 2014, 16, 1125–1130. [CrossRef] 69. Ablialimov, O.; K˛edziorek, M.; Malińska,M.; Wo´zniak,K.; Grela, K. Synthesis, Structure, and Catalytic Activity of New Ruthenium(II) Indenylidene Complexes Bearing Unsymmetrical N-Heterocyclic Carbenes. Organometallics 2014, 33, 2160–2171. [CrossRef] 70. Binder, J.B.; Blank, J.J.; Raines, R.T. Olefin Metathesis in Homogeneous Aqueous Media Catalyzed by Conventional Ruthenium Catalysts. Org. Lett. 2007, 9, 4885–4888. [CrossRef] 71. Matsuo, T.; Yoshida, T.; Fujii, A.; Kawahara, K.; Hirota, S. Effect of Added Salt on Ring-Closing Metathesis Catalyzed by a Water-Soluble Hoveyda–Grubbs Type Complex to Form N-Containing Heterocycles in Aqueous Media. Organometallics 2013, 32, 5313–5319. [CrossRef] 72. Tanaka, K.; Böhm, V.P.W.; Chadwick, D.; Roeper, M.; Braddock, D.C. Anionic Ligand Exchange in Hoveyda Grubbs Ruthenium(II) Benzylidenes. Organometallics 2006, 25, 5696–5698. [CrossRef] − 73. Zirngast, M.; Pump, E.; Leitgeb, A.; Albering, J.H.; Slugovc, C. Pyridine as trigger for chloride isomerisation in chelated ruthenium benzylidene complexes: Implications for olefin metathesis. Chem. Commun. 2011, 47, 2261–2263. [CrossRef] 74. Keitz, B.K.; Endo, K.; Patel, P.R.; Herbert, M.B.; Grubbs, R.H. Improved Ruthenium Catalysts for Z-Selective Olefin Metathesis. J. Am. Chem. Soc. 2012, 134, 693–699. [CrossRef][PubMed] 75. Falivene, L.; Poater, A.; Cazin, C.S.J.; Slugovc, C.; Cavallo, L. Energetics of the ruthenium—Halide bond in olefin metathesis (pre)catalysts. Dalton Trans. 2013, 42, 7312–7317. [CrossRef][PubMed] 76. Wappel, J.; Urbina-Blanco, C.A.; Abbas, M.; Albering, J.H.; Saf, R.; Nolan, S.P.; Slugovc, C. Halide exchanged Hoveyda-type complexes in olefin metathesis. Beilstein J. Org. Chem. 2010, 6, 1091–1098. [CrossRef] [PubMed] 77. Krause, J.O.; Nuyken, O.; Wurst, K.; Buchmeiser, M.R. Synthesis and Reactivity of Homogeneous and Heterogeneous Ruthenium-Based Metathesis Catalysts Containing Electron-Withdrawing Ligands. Chem. Eur. J. 2004, 10, 777–784. [CrossRef] 78. Pump, E.; Fischer, R.C.; Slugovc, C. Halide Exchange in Second-Generation cis-Dihalo Ruthenium Benzylidene Complexes. Organometallics 2012, 31, 6972–6979. [CrossRef] 79. Bailey, G.A.; Fogg, D.E. Acrylate Metathesis via the Second-Generation Grubbs Catalyst: Unexpected Pathways Enabled by a PCy3-Generated Enolate. J. Am. Chem. Soc. 2015, 137, 7318–7321. [CrossRef] 80. Bates, J.M.; Lummiss, J.A.M.; Bailey, G.A.; Fogg, D.E. Operation of the Boomerang Mechanism in Olefin Metathesis Reactions Promoted by the Second-Generation Hoveyda Catalyst. ACS Catal. 2014, 4, 2387–2394. [CrossRef] 81. Bailey, G.A.; Lummiss, J.A.M.; Foscato, M.; Occhipinti, G.; McDonald, R.; Jensen, V.R.; Fogg, D.E. Decomposition of Olefin Metathesis Catalysts by Brønsted Base: Metallacyclobutane Deprotonation as a Primary Deactivating Event. J. Am. Chem. Soc. 2017, 139, 16446–16449. [CrossRef] 82. Santos, A.G.; Bailey, G.A.; Dos Santos, E.N.; Fogg, D.E. Overcoming Catalyst Decomposition in Acrylate

Metathesis: Polyphenol Resins as Enabling Agents for PCy3-Stabilized Metathesis Catalysts. ACS Catal. 2017, 7, 3181–3189. [CrossRef] 83. Compain, P. Oleﬁn Metathesis of Amine-Containing Systems: Beyond the Current Consensus. Adv. Synth. Catal. 2007, 349, 1829–1846. [CrossRef] Catalysts 2020, 10, 887 52 of 56

84. Soon, H.H.; Wenzel, A.G.; Salguero, T.T.; Day, M.W.; Grubbs, R.H. Decomposition of ruthenium olefin metathesis catalysts. J. Am. Chem. Soc. 2007, 129, 7961–7968. [CrossRef] 85. Wilson, G.O.; Porter, K.A.; Weissman, H.; White, S.R.; Sottos, N.R.; Moore, J.S. Stability of Second Generation Grubbs’ Alkylidenes to Primary Amines: Formation of Novel Ruthenium-Amine Complexes. Adv. Synth. Catal. 2009, 351, 1817–1825. [CrossRef] 86. Wilson, G.O.; Caruso, M.M.; Reimer, N.T.; White, S.R.; Sottos, N.R.; Moore, J.S. Evaluation of Ruthenium Catalysts for Ring-Opening Metathesis Polymerization-Based Self-Healing Applications. Chem. Mater. 2008, 20, 3288–3297. [CrossRef] 87. Lummiss, J.A.M.; Ireland, B.J.; Sommers, J.M.; Fogg, D.E. Amine-mediated degradation in olefin metathesis reactions that employ the second-generation Grubbs catalyst. ChemCatChem 2014, 6, 459–463. [CrossRef] 88. Lummiss, J.A.M.; Botti, A.G.G.; Fogg, D.E. Isotopic probes for ruthenium-catalyzed olefin metathesis. Catal. Sci. Technol. 2014, 4, 4210–4218. [CrossRef] 89. Sanford, M.S.; Love, J.A.; Grubbs, R.H. A Versatile Precursor for the Synthesis of New Ruthenium Olefin Metathesis Catalysts. Organometallics 2001, 20, 5314–5318. [CrossRef] 90. Getty, K.; Delgado-Jaime, M.U.; Kennepohl, P. Assignment of pre-edge features in the Ru K-edge X-ray absorption spectra of organometallic ruthenium complexes. Inorganica Chim. Acta 2008, 361, 1059–1065. [CrossRef] 91. Ireland, B.J.; Dobigny, B.T.; Fogg, D.E. Decomposition of a Phosphine-Free Metathesis Catalyst by Amines and Other Bronsted Bases: Metallacyclobutane Deprotonation as a Major Deactivation Pathway. ACS Catal. 2015, 5, 4690–4698. [CrossRef] 92. McClennan, W.L.; Rufh, S.A.; Lummiss, J.A.M.; Fogg, D.E. A General Decomposition Pathway for Phosphine-Stabilized Metathesis Catalysts: Lewis Donors Accelerate Methylidene Abstraction. J. Am. Chem. Soc. 2016, 138, 14668–14677. [CrossRef][PubMed] 93. Lummiss, J.A.M.; Higman, C.S.; Fyson, D.L.; McDonald, R.; Fogg, D.E. The divergent effects of strong NHC donation in catalysis. Chem. Sci. 2015, 6, 6739–6746. [CrossRef][PubMed] 94. Rufh, S.A.; Goudreault, A.Y.; Foscato, M.; Jensen, V.R.; Fogg, D.E. Rapid decomposition of olefin metathesis catalysts by a truncated N-heterocyclic carbene: Efficient catalyst quenching and n-heterocyclic carbene vinylation. ACS Catal. 2018, 8, 11822–11826. [CrossRef] 95. Zhao, Z.-X.; Wang, H.-Y.; Guo, Y.-L. Studies on CH3CN-assisted decomposition of 1st Grubbs catalyst by electrospray ionization tandem mass spectrometry. Rapid Commun. Mass Spectrom. 2011, 25, 3401–3410. [CrossRef] 96. Hong, S.H.; Day, M.W.; Grubbs, R.H. Decomposition of a Key Intermediate in Ruthenium-Catalyzed Olefin Metathesis Reactions. J. Am. Chem. Soc. 2004, 126, 7414–7415. [CrossRef] 97. Ulman, M.; Grubbs, R.H. Ruthenium Carbene-Based Olefin Metathesis Initiators: Catalyst Decomposition and Longevity. J. Org. Chem. 1999, 64, 7202–7207. [CrossRef] 98. Jiang, J.; Zhao, D.; Zhang, H.; He, J.; Li, N. In situ analysis and real-time monitoring of the decomposition of

the 2nd Grubbs catalyst in CH3CN by droplet spray ionization tandem mass spectrometry. Anal. Methods 2017, 9, 4201–4206. [CrossRef] 99. Jawiczuk, M.; Młodzikowska-Pieńko,K.; Osella, S.; Trzaskowski, B. Molecular Modeling of Mechanisms of Decomposition of Ruthenium Metathesis Catalysts by Acrylonitrile. Organometallics 2020, 39, 239–246. [CrossRef] 100. Trnka, T.M.; Morgan, J.P.; Sanford, M.S.; Wilhelm, T.E.; Scholl, M.; Choi, T.L.; Ding, S.; Day, M.W.; Grubbs, R.H. Synthesis and activity of ruthenium alkylidene complexes coordinated with phosphine and N-heterocyclic carbene ligands. J. Am. Chem. Soc. 2003, 125, 2546–2558. [CrossRef] 101. Guidone, S.; Songis, O.; Nahra, F.; Cazin, C.S.J. Conducting Olefin Metathesis Reactions in Air: Breaking the Paradigm. ACS Catal. 2015, 5, 2697–2701. [CrossRef] 102. Ton, S.J.; Fogg, D.E. The Impact of Oxygen on Leading and Emerging Ru-Carbene Catalysts for Olefin Metathesis: An Unanticipated Correlation Between Robustness and Metathesis Activity. ACS Catal. 2019, 9, 11329–11334. [CrossRef] 103. Feast, W.J.; Gibson, V.C.; Khosravi, E.; Marshall, E.L.; Mitchell, J.P. Bimolecular termination in living ring opening metathesis polymerization. Polymer 1992, 33, 872–873. [CrossRef] Catalysts 2020, 10, 887 53 of 56

104. Forman, G.S.; McConnell, A.E.; Hanton, M.J.; Slawin, A.M.Z.; Tooze, R.P.; van Rensburg, W.J.; Meyer, W.H.; Dwyer, C.; Kirk, M.M.; Serfontein, D.W. A Stable Ruthenium Catalyst for Productive Olefin Metathesis. Organometallics 2004, 23, 4824–4827. [CrossRef] 105. Huang, J.; Schanz, H.-J.; Stevens, E.D.; Nolan, S.P. Influence of Sterically Demanding Carbene Ligation on Catalytic Behavior and Thermal Stability of Ruthenium Olefin Metathesis Catalysts. Organometallics 1999, 18, 5375–5380. [CrossRef] 106. Wu, Z.; Nguyen, S.T.; Grubbs, R.H.; Ziller, J.W. Reactions of Ruthenium Carbenes of the Type

(PPh3)2(X)2Ru:CH-CH:CPh2 (X = Cl and CF3COO) with Strained Acyclic Olefins and Functionalized Olefins. J. Am. Chem. Soc. 1995, 117, 5503–5511. [CrossRef] 107. Louie, J.; Grubbs, R.H. Metathesis of Electron-Rich Olefins: Structure and Reactivity of Electron-Rich Carbene Complexes. Organometallics 2002, 21, 2153–2164. [CrossRef] 108. Hansen, S.M.; Rominger, F.; Metz, M.; Hofmann, P. The first grubbs-type metathesis catalyst with cis 2 stereochemistry: Synthesis of [(n -dtbpm)Cl2Ru=CH-CH=CMe2] from a novel, coordinatively unsaturated dinuclear ruthenium dihydride. Chem. Eur. J. 1999, 5, 557–566. [CrossRef] 109. Lummiss, J.A.M.; McClennan, W.L.; McDonald, R.; Fogg, D.E. Donor-induced decomposition of the Grubbs catalysts: An intercepted intermediate. Organometallics 2014, 33, 6738–6741. [CrossRef] 110. Wang, H.; Metzger, J.O. ESI-MS Study on First-Generation Ruthenium Olefin Metathesis Catalysts in Solution: Direct Detection of the Catalytically Active 14-Electron Ruthenium Intermediate. Organometallics 2008, 27, 2761–2766. [CrossRef] 111. Labinger, J.A.; Bercaw, J.E. Understanding and exploiting C–H bond activation. Nature 2002, 417, 507–514. [CrossRef] 112. Bergman, R.G. C–H activation. The stability of the chemical bonds in saturated hydrocarbons makes them generally unreactive. But the invention of processes in which carbon–hydrogen (C–H) bonds in hydrocarbons can be activated is allowing chemists to exploit organic compounds in previously unimaginable ways. Nature 2007, 446, 391–393. [PubMed] 113. Forsman, Å.; Grimvall, A. Reduced models for efficient simulation of spatially integrated outputs of one-dimensional substance transport models. Environ. Model. Softw. 2003, 18, 319–327. [CrossRef] 114. Dyker, G. Transition Metal Catalyzed Coupling Reactions under C-H Activation. Angew. Chem. Int. Ed. 1999, 38, 1698–1712. [CrossRef] 115. Guari, Y.; Sabo-Etienne, S.; Chaudret, B. Catalytic Formation of Carbon-Carbon Bonds by Activation of Carbon-Hydrogen Bonds. Eur. J. Inorg. Chem. 1999, 1999, 1047–1055. [CrossRef] 116. Jazzar, R.F.R.; Macgregor, S.A.; Mahon, M.F.; Richards, S.P.; Whittlesey, M.K. C-C and C-H bond activation reactions in N-heterocyclic carbene complexes of ruthenium. J. Am. Chem. Soc. 2002, 124, 4944–4945. [CrossRef] 117. Chilvers, M.J.; Jazzar, R.F.R.; Mahon, M.F.; Whittlesey, M.K. Reversible C-H Bond Activation

Reactions of theN-Heterocyclic Carbene Ligands in Ru(Ph2PCH2CH2CH2PPh2)(IMes)(CO)H2 and Ru(Ph2AsCH2CH2PPh2)(IMes)(CO)H2 (IMes=1,3-Dimesityl-1,3-dihydro-2H-imidazol-2-ylidene). Adv. Synth. Catal. 2003, 345, 1111–1114. [CrossRef] 118. Diggle, R.A.; Macgregor, S.A.; Whittlesey, M.K. Computational study of C-C activation of 1,3-dimesitylimidazol-2-ylidene (IMes) at ruthenium: The role of Ligand bulk in accessing reactive intermediates. Organometallics 2008, 27, 617–625. [CrossRef] 119. Edwards, M.G.; Jazzar, R.F.R.; Paine, B.M.; Shermer, D.J.; Whittlesey, M.K.; Williams, J.M.J.; Edney, D.D. Borrowing hydrogen: A catalytic route to C–C bond formation from alcohols. Chem. Commun. 2004, 4, 90–91. [CrossRef] 120. Burling, S.; Whittlesey, M.K.; Williams, J.M.J. Direct and transfer hydrogenation of ketones and imines with a ruthenium N-heterocyclic carbene complex. Adv. Synth. Catal. 2005, 347, 591–594. [CrossRef] 121. Burling, S.; Paine, B.M.; Nama, D.; Brown, V.S.; Mahon, M.F.; Prior, T.J.; Pregosin, P.S.; Whittlesey, M.K.; Williams, J.M.J. C-H activation reactions of ruthenium N-heterocyclic carbene complexes: Application in a catalytic tandem reaction involving C-C bond formation from alcohols. J. Am. Chem. Soc. 2007, 129, 1987–1995. [CrossRef] 122. Wenz, K.M.; Liu, P.; Houk, K.N. Intramolecular C-H Activation Reactions of Ru(NHC) Complexes Combined with H2 Transfer to Alkenes: A Theoretical Elucidation of Mechanisms and Eﬀects of Ligands on Reactivities. Organometallics 2017, 36, 3613–3623. [CrossRef] Catalysts 2020, 10, 887 54 of 56

123. Młodzikowska-Pieńko,K.; Trzaskowski, B. Rate-limiting Steps in the Intramolecular C-H Activation of Ruthenium N-Heterocyclic Carbene Complexes. J. Phys. Chem. A 2020, 124, 3609–3617. [CrossRef][PubMed] 124. Abdur-Rashid, K.; Fedorkiw, T.; Lough, A.J.; Morris, R.H. Coordinatively unsaturated hydridoruthenium(II) complexes of N-heterocyclic carbenes. Organometallics 2004, 23, 86–94. [CrossRef] 125. Burling, S.; Mahon, M.F.; Paine, B.M.; Whittlesey, M.K.; Williams, J.M.J. Reversible intramolecular Alkyl C-H bond activation, alcohol dehydrogenation, and trans-Cis dihydride isomerization in ruthenium N-heterocyclic carbene complexes. Organometallics 2004, 23, 4537–4539. [CrossRef] 126. Hong, S.H.; Chlenov, A.; Day, M.W.; Grubbs, R.H. Double C-H activation of an N-heterocyclic carbene ligand in a ruthenium olefin metathesis catalyst. Angew. Chem. Int. Ed. 2007, 46, 5148–5151. [CrossRef] 127. Sandford, M.S.; Love, J.A.; Grubbs, R.H. Mechanism and activity of ruthenium olefin metathesis catalysts. J. Am. Chem. Soc. 2001, 123, 6543–6554. [CrossRef][PubMed] 128. Mathew, J.; Koga, N.; Suresh, C.H. C-H bond activation through σ-bond metathesis and agostic interactions: Deactivation pathway of a Grubbs second-generation catalyst. Organometallics 2008, 27, 4666–4670. [CrossRef] 129. Poater, A.; Cavallo, L. Mechanistic insights into the double C-H (de)activation route of a Ru-based olefin metathesis catalyst. J. Mol. Catal. Chem. 2010, 324, 75–79. [CrossRef] 130. Vehlow, K.; Gessler, S.; Blechert, S. Deactivation of ruthenium olefin metathesis catalysts through intramolecular carbene-arene bond formation. Angew. Chem. Int. Ed. 2007, 46, 8082–8085. [CrossRef] 131. Galan, B.R.; Kalbarczyk, K.P.; Szczepankiewicz, S.; Keister, J.B.; Diver, S.T. A rapid and simple cleanup procedure for metathesis reactions. Org. Lett. 2007, 9, 1203–1206. [CrossRef] 132. Leitao, E.M.; Dubberley, S.R.; Piers, W.E.; Wu, Q.; McDonald, R. Thermal decomposition modes for four-coordinate ruthenium phosphonium alkylidene olefin metathesis catalysts. Chem. Eur. J. 2008, 14, 11565–11572. [CrossRef] 133. Van Der Eide, E.F.; Romero, P.E.; Piers, W.E. Generation and spectroscopic characterization of ruthenacyclobutane and ruthenium olefin carbene intermediates relevant to ring closing metathesis catalysis. J. Am. Chem. Soc. 2008, 130, 4485–4491. [CrossRef]

134. Solari, E.; Gauthier, S.; Scopelliti, R.; Severin, K. Multifaceted chemistry of [(Cymene)RuCl2]2 and PCy3. Organometallics 2009, 28, 4519–4526. [CrossRef] 135. Herbert, M.B.; Lan, Y.; Keitz, B.K.; Liu, P.; Endo, K.; Day, M.W.; Houk, K.N.; Grubbs, R.H. Decomposition pathways of Z-selective ruthenium metathesis catalysts. J. Am. Chem. Soc. 2012, 134, 7861–7866. [CrossRef] 136. Endo, K.; Grubbs, R.H. Chelated ruthenium catalysts for Z-selective olefin metathesis. J. Am. Chem. Soc. 2011, 133, 8525–8527. [CrossRef] 137. Weng, W.; Parkin, S.; Ozerov, O.V. Double C-H activation results in ruthenium complexes of a neutral PCP ligand with a central carbene moiety. Organometallics 2006, 25, 5345–5354. [CrossRef] 138. Oliván, M.; Caulton, K.G. C-(halide) oxidative addition routes to ruthenium carbenes. Inorg. Chem. 1999, 38, 566–570. [CrossRef] 139. Prechtl, M.H.G.; Ben-David, Y.; Giunta, D.; Busch, S.; Taniguchi, Y.; Wisniewski, W.; Görls, H.; Mynott, R.J.; Theyssen, N.; Milstein, D.; et al. Synthesis and characterisation of nonclassical ruthenium hydride complexes containing chelating bidentate and tridentate phosphine ligands. Chem. Eur. J. 2007, 13, 1539–1546. [CrossRef] 140. Poater, A.; Bahri-Laleh, N.; Cavallo, L. Rationalizing current strategies to protect N-heterocyclic carbene-based ruthenium catalysts active in olefin metathesis from C-H (de)activation. Chem. Commun. 2011, 47, 6674–6676. [CrossRef] 141. Fernández, I.; Lugan, N.; Lavigne, G. Effects of attractive through space π-π* Interactions on the structure, reactivity, and activity of Grubbs II complexes. Organometallics 2012, 31, 1155–1160. [CrossRef] 142. Comas-Vives, A.; Harvey, J.N. How important is backbonding in metal complexes containing N-heterocyclic carbenes? Structural and NBO analysis. Eur. J. Inorg. Chem. 2011, 5025–5035. [CrossRef] 143. Vummaleti, S.V.C.; Nelson, D.J.; Poater, A.; Gómez-Suárez, A.; Cordes, D.B.; Slawin, A.M.Z.; Nolan, S.P.; Cavallo, L. What can NMR spectroscopy of selenoureas and phosphinidenes teach us about the π-accepting abilities of N-heterocyclic carbenes? Chem. Sci. 2015, 6, 1895–1904. [CrossRef][PubMed] 144. Credendino, R.; Falivene, L.; Cavallo, L. π-face donation from the aromatic N-substituent of N-heterocyclic carbene ligands to metal and its role in catalysis. J. Am. Chem. Soc. 2012, 134, 8127–8135. [CrossRef] [PubMed] 145. Gallagher, M.M.; Rooney, A.D.; Rooney, J.J. Variable temperature 1H NMR studies on Grubbs catalysts. J. Organomet. Chem. 2008, 693, 1252–1260. [CrossRef] Catalysts 2020, 10, 887 55 of 56

146. Kotyk, M.W.; Gorelsky, S.I.; Conrad, J.C.; Carra, C.; Fogg, D.E. Geometric and electronic structure of a C1-symmetric ruthenium-Aryloxide metathesis catalyst: An experimental and computational study. Organometallics 2009, 28, 5424–5431. [CrossRef] 147. Song, B.; Xu, B. Metal-catalyzed C-H functionalization involving isocyanides. Chem. Soc. Rev. 2017, 46, 1103–1123. [CrossRef] 148. Boyarskiy, V.P.; Bokach, N.A.; Luzyanin, K.V.; Kukushkin, V.Y. Metal-mediated and metal-catalyzed reactions of isocyanides. Chem. Rev. 2015, 115, 2698–2779. [CrossRef] 149. Chakrabarty, S.; Choudhary, S.; Doshi, A.; Liu, F.Q.; Mohan, R.; Ravindra, M.P.; Shah, D.; Yang, X.; Fleming, F.F. Catalytic isonitrile insertions and condensations initiated by RNC-X complexation. Adv. Synth. Catal. 2014, 356, 2135–2196. [CrossRef] 150. Vlaar, T.; Ruijter, E.; Maes, B.U.W.; Orru, R.V.A. Palladium-catalyzed migratory insertion of isocyanides: An emerging platform in cross-coupling chemistry. Angew. Chem. Int. Ed. 2013, 52, 7084–7097. [CrossRef] 151. Galan, B.R.; Gembicky, M.; Dominiak, P.M.; Keister, J.B.; Diver, S.T. Carbon monoxide-promoted carbene insertion into the aryl substituent of an N-heterocyclic carbene ligand: Buchner reaction in a ruthenium carbene complex. J. Am. Chem. Soc. 2005, 127, 15702–15703. [CrossRef] 152. Buchner, E.; Curtius, T. Ueber die Einwirkung von Diazoessigäther auf aromatische Kohlenwasserstoffe. Berichte Dtsch. Chem. Ges. 1885, 18, 2377–2379. [CrossRef] 153. Galan, B.R.; Pitak, M.; Keister, J.B.; Diver, S.T. Isocyanide-promoted ylidene transfer to phosphorus: Rearrangement in the first-generation grubbs complex. Organometallics 2008, 27, 3630–3632. [CrossRef] 154. Johnson, L.K.; Frey, M.; Ulibarri, T.A.; Virgil, S.C.; Grubbs, R.H.; Ziller, J.W. Alkylidene Transfer from Phosphoranes to Tungsten(IV) Imido Complexes. J. Am. Chem. Soc. 1993, 115, 8167–8177. [CrossRef] 155. Poater, A.; Ragone, F.; Correa, A.; Cavallo, L. Exploring the reactivity of ru-based metathesis catalysts with a π-acid ligand trans to the Ru-ylidene bond. J. Am. Chem. Soc. 2009, 131, 9000–9006. [CrossRef][PubMed] 156. Galan, B.R.; Pitak, M.; Gembicky, M.; Keister, J.B.; Diver, S.T. Ligand-promoted carbene insertion into the aryl substituent of an n-heterocyclic carbene ligand in ruthenium-based metathesis catalysts. J. Am. Chem. Soc. 2009, 131, 6822–6832. [CrossRef][PubMed] 157. Monnier, F.; Castillo, D.; Dérien, S.; Toupet, L.; Dixneuf, P.H. Addition of Diazoalkanes to Enynes Promoted by a Ruthenium Catalyst: Simple Synthesis of Alkenyl Bicyclo[3.1.0]hexane Derivatives. Angew. Chem. Int. Ed. 2003, 42, 5474–5477. [CrossRef] 158. Peppers, B.P.; Diver, S.T. Tandem cyclopropanation/ring-closing metathesis of dienynes. J. Am. Chem. Soc. 2004, 126, 9524–9525. [CrossRef] 159. Kitamura, T.; Sato, Y.; Mori, M. Unexpected results of enyne metathesis using a ruthenium complex containing an N-heterocyclic carbene ligand. Chem. Commun. 2001, 1258–1259. [CrossRef] 160. Nishiyama, H.; Itoh, Y.; Matsumoto, H.; Park, S.B.; Itoh, K. New Chiral Ruthenium Bis(oxazolinyl)pyridine Catalyst. Efficient Asymmetric Cyclopropanation of Olefins with Diazoacetates. J. Am. Chem. Soc. 1994, 116, 2223–2224. [CrossRef] 161. Anciaux, A.J.; Demonceau, A.; Noels, A.F.; Hubert, A.J.; Warin, R.; Teyssié, P. Transition-Metal-Catalyzed Reactions of Diazo Compounds. 2.1 Addition to Aromatic Molecules: Catalysis of Buchner’s Synthesis of Cycloheptatrienes. J. Org. Chem. 1981, 46, 873–876. [CrossRef] 162. Basato, M.; Tubaro, C.; Biffis, A.; Bonato, M.; Buscemi, G.; Lighezzolo, F.; Lunardi, P.; Yianini, C.; Benetollo, F.; Del Zotto, A. Reactions of diazo compounds with alkenes catalysed by [RuCl(cod)(Cp)]: Effect of the substituents in the formation of cyclopropanation or metathesis products. Chem. Eur. J. 2009, 15, 1516–1526. [CrossRef][PubMed] 163. Szczepaniak, G.; Urbaniak, K.; Wierzbicka, C.; Kosiński,K.; Skowerski, K.; Grela, K. High-Performance Isocyanide Scavengers for Use in Low-Waste Purification of Olefin Metathesis Products. ChemSusChem 2015, 8, 4139–4148. [CrossRef][PubMed] 164. Szczepaniak, G.; Noga´s,W.; Piatkowski, J.; Ruszczyńska,A.; Bulska, E.; Grela, K. Semiheterogeneous Purification Protocol for the Removal of Ruthenium Impurities from Olefin Metathesis Reaction Products Using an Isocyanide Scavenger. Org. Process. Res. Dev. 2019, 23, 836–844. [CrossRef] 165. Szczepaniak, G.; Ruszczyńska,A.; Kosiński,K.; Bulska, E.; Grela, K. Highly efficient and time economical purification of olefin metathesis products from metal residues using an isocyanide scavenger. Green Chem. 2018, 20, 1280–1289. [CrossRef] Catalysts 2020, 10, 887 56 of 56

166. Blacquiere, J.M.; Jurca, T.; Weiss, J.; Fogg, D.E. Time as a dimension in high-throughput homogeneous catalysis. Adv. Synth. Catal. 2008, 350, 2849–2855. [CrossRef] 167. Griﬃths, J.R.; Hofman, E.J.; Keister, J.B.; Diver, S.T. Kinetics and Mechanism of Isocyanide-Promoted Carbene Insertion into the Aryl Substituent of an N-Heterocyclic Carbene Ligand in Ruthenium-Based Metathesis Catalysts. Organometallics 2017, 36, 3043–3052. [CrossRef] 168. Klose, A.; Solari, E.; Hesschenbrouck, J.; Floriani, C.; Re, N.; Geremia, S.; Randaccio, L. Ruthenium-carbene functionality bonded to dibenzotetramethyltetraaza[14]annulene: Metal-to-macrocycle ligand-induced carbene migration. Organometallics 1999, 18, 360–372. [CrossRef] 169. Małecki, P.; Gajda, K.; Gajda, R.; Wo´zniak,K.; Trzaskowski, B.; Kajetanowicz, A.; Grela, K. Specialized ruthenium oleﬁn metathesis catalysts bearing bulky unsymmetrical NHC Ligands: Computations, synthesis, and application. ACS Catal. 2019, 9, 587–598. [CrossRef]

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).