Bis(Cyclic Alkyl Amino Carbene) Ruthenium Complexes: A Versatile, Highly Efficient Tool for Olefin Metathesis

Turner Z.R.

A cyclic (alkyl)(amino)carbene (CAAC) was found to undergo unprecedented rearrangements and transformations of its core structure in the presence of Group 1 and 2 metals. Although the carbene was also found to be prone to intramolecular C-H activation, it was competent for intermolecular activation of a variety of sp-, sp(2) -, and sp(3) -hybridized C-H bonds. Double C-F activation of hexafluorobenzene was also observed in this work. These processes all hold relevance to the role of these carbenes in catalysis, as well as to their use in the synthesis of new and unusual main group or transition metal complexes.

Bidange J., Fischmeister C., Bruneau C.

Remarkable innovations have been made in the field of olefin metathesis due to the design and preparation of new catalysts. Ethenolysis, which is cross-metathesis with ethylene, represents one catalytic transformation that has been used with the purpose of cleaving internal carbon-carbon double bonds. The objectives were either the ring opening of cyclic olefins to produce dienes or the shortening of unsaturated hydrocarbon chains to degrade polymers or generate valuable shorter terminal olefins in a controlled manner. This Review summarizes several aspects of this reaction: the catalysts, their degradation in the presence of ethylene, some parameters driving their productivity, the side reactions, and the applications of ethenolysis in organic synthesis and in potential industrial applications.

Lummiss J.A., Perras F.A., McDonald R., Bryce D.L., Fogg D.E.

The dramatic reactivity difference between the Grubbs metathesis catalysts and their resting-state methylidene derivatives was probed in an integrated crystallographic, solid-state NMR and localized molecular orbital analysis study. A principal focus was the second-generation Grubbs system RuCl2(H2IMes)(PCy3)(═CHR) (GII, R = Ph; GIIm, R = H); supporting studies were carried out with the first-generation species RuCl2(PCy3)2(═CHR) (GI, GIm). The compiled rate constants for PCy3 dissociation demonstrate the limited lability of the methylidene complexes (e.g., ca. 275-fold lower for GIIm than GII and nearly 2000 times lower for the IMes analogue GIIm′). This is important because it impedes catalyst re-entry from the resting state into the active cycle. The 31P chemical shift (CS) tensors for the PCy3 ligand exhibited the expected changes (i.e., those characteristic of an increased Ru–P orbital interaction) in GIIm relative to GII, as did GIm vs GI. Greater insight was offered by the 13C CS tensors. Whereas c...

Higman C.S., Lummiss J.A., Fogg D.E.

Dieser Kurzaufsatz behandelt die kurzliche Einfuhrung molekularer Metathesekatalysatoren in die Produktion von Spezialchemikalien und Pharmazeutika.

Higman C.S., Lummiss J.A., Fogg D.E.

The recent uptake of molecular metathesis catalysts in specialty-chemicals and pharmaceutical manufacturing is reviewed.

Bidal Y.D., Lesieur M., Melaimi M., Nahra F., Cordes D.B., Athukorala Arachchige K.S., Slawin A.M., Bertrand G., Cazin C.S.

The synthesis and characterization of abnormal N-heterocyclic carbene, cyclic (alkyl)(amino)carbene, and mesoionic carbene copper(I) complexes are reported. These organometallic species are obtained via a versatile and inexpensive synthetic pathway using readily available reactants, namely copper oxide and iminium salts. The catalytic activity of this series of complexes was evaluated in the [3+2] cycloaddition of alkynes with azides (CuAAC). Outstanding catalytic properties were observed for the abnormal NHC- and triazolylidene-based copper(I) complexes.

Lummiss J.A., Higman C.S., Fyson D.L., McDonald R., Fogg D.E.

Strong σ-donation from NHC ligands (NHC = N-heterocyclic carbene) is shown to have profoundly conflicting consequences for the reactivity of transition-metal catalysts. Such donation is regarded as central to high catalyst activity in many contexts, of which the second-generation Grubbs metathesis catalysts (RuCl2(NHC)(PCy3)([double bond, length as m-dash]CHPh), GII) offer an early, prominent example. Less widely recognized is the dramatically inhibiting impact of NHC ligation on initiation of GII, and on re-entry into the catalytic cycle from the resting-state methylidene species RuCl2(NHC)(PCy3)([double bond, length as m-dash]CH2), GIIm. Both GII and the methylidene complexes are activated by dissociation of PCy3. The impact of NHC donicity on the rate of PCy3 loss is explored in a comparison of s-GIIm, vs.u-GIIm, in which the NHC ligand is saturated H2IMes or unsaturated IMes, respectively. PCy3 loss is nearly an order of magnitude slower for the IMes derivative (a difference that is replicated, albeit smaller, for the benzylidene precatalysts GII). Proposed as an overlooked contributor to these rate differences is an increase in the Ru-PCy3 bond strength arising from π-back-donation onto the phosphine ligand. Strong σ-donation from the IMes ligand, coupled with the inability of this unsaturated NHC to participate in significant π-backbonding, amplifies Ru → PCy3 π-back-donation. The resulting increase in Ru-P bond strength greatly inhibits entry into the active cycle. For s-GII, in contrast, the greater π-acceptor capacity of the NHC ligand enables competing Ru → H2IMes back-donation (as confirmed by NOE experiments, which reveal restricted rotation about the Ru-NHC bond for H2IMes, but not IMes). Ru → PCy3 back-donation is thus attenuated in the H2IMes complexes, accounting for the greater lability of the PCy3 ligand in s-GIIm and s-GII. Similarly inhibited initiation is predicted for other metal-NHC catalysts in which a π-acceptor ligand L must be dissociated to permit substrate binding. Conversely, enhanced reactivity can be expected where such L ligands are pure σ-donors. These effects are expected to be particularly dramatic where the NHC ligand has minimal π-acceptor capacity (as in the unsaturated Arduengo carbenes), and in geometries that maximize NHC-M-L orbital interactions.

Ireland B.J., Dobigny B.T., Fogg D.E.

Reactions are described of the second-generation Hoveyda catalyst HII with amines, pyridine, and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), in the presence and absence of olefin substrates. These nitrogen bases have a profoundly negative impact on metathesis yields, but in most cases, they are innocuous toward the precatalyst. HII adducts were formed by primary and secondary amines (n-butylamine, sec-butylamine, benzylamine, pyrrolidine, morpholine), pyridine, and DBU at room temperature. No reaction was evident for NEt3, even at 60 °C. On longer reaction at RT, unencumbered primary amines abstract the benzylidene ligand from HII. With 10 equiv of NH2nBu, this process was complete in 12 h, affording NHnBu(CH2Ar) (Ar = o-C6H4–OiPr) and [RuCl(H2IMes)(NH2nBu)4]Cl. For benzylamine, benzylidene abstraction occurred over days at RT. No such reaction was observed for sec-butylamine, secondary amines, NEt3, pyridine, or DBU. All of these bases, however, strongly inhibited metathesis of styrene by HII, with a gener...

Marx V.M., Sullivan A.H., Melaimi M., Virgil S.C., Keitz B.K., Weinberger D.S., Bertrand G., Grubbs R.H.

An expanded family of ruthenium-based metathesis catalysts bearing cyclic alkyl amino carbene (CAAC) ligands was prepared. These catalysts exhibited exceptional activity in the ethenolysis of the seed-oil derivative methyl oleate. In many cases, catalyst turnover numbers (TONs) of more than 100 000 were achieved, at a catalyst loading of only 3 ppm. Remarkably, the most active catalyst system was able to achieve a TON of 340 000, at a catalyst loading of only 1 ppm. This is the first time a series of metathesis catalysts has exhibited such high performance in cross-metathesis reactions employing ethylene gas, with activities sufficient to render ethenolysis applicable to the industrial-scale production of linear α-olefins (LAOs) and other terminal-olefin products.

Marx V.M., Sullivan A.H., Melaimi M., Virgil S.C., Keitz B.K., Weinberger D.S., Bertrand G., Grubbs R.H.

Soleilhavoup M., Bertrand G.

ConspectusCarbenes are compounds that feature a divalent carbon atom with only six electrons in its valence shell. In the singlet state, they possess a lone pair of electrons and a vacant orbital and therefore exhibit Lewis acidic and Lewis basic properties, which explains their very high reactivity. Following the preparation by our group in 1988 of the first representative, a variety of stable carbenes are now available, the most popular being the cyclic diaminocarbenes.In this Account, we discuss another class of stable cyclic carbenes, namely, cyclic (alkyl)(amino)carbenes (CAACs), in which one of the electronegative and π-donor amino substituents of diaminocarbenes is replaced by a σ-donating but not π-donating alkyl group. As a consequence, CAACs are more nucleophilic (σ-donating) but also more electrophilic (π-accepting) than diaminocarbenes. Additionally, the presence of a quaternary carbon in the position α to the carbene center provides steric environments that differentiate CAACs dramatically from all other ligands. We show that the peculiar electronic and steric properties of CAACs allow for the stabilization of unusual diamagnetic and paramagnetic main group element species. As examples, we describe the preparation of room temperature stable phosphorus derivatives in which the heteroatom is in the zero oxidation state, nucleophilic boron compounds, and phosphorus-, antimony-, boron-, silicon-, and even carbon-centered neutral and cationic radicals. CAACs are also excellent ligands for transition metal complexes. The most recent application is their use for the stabilization of paramagnetic complexes, in which the metal is often in a formal zero oxidation state. Indeed, bis(CAAC)M complexes in which the metal is gold, copper, cobalt, iron, nickel, manganese, and zinc have been isolated. Depending on the metal, the majority of spin density can reside either on the metal or on the carbene carbons and the nitrogen atoms of the CAAC ligand. In contrast to diaminocarbenes, the higher basicity of CAACs makes them poor leaving groups, and thus they cannot be used for classical organocatalysis. However, because of their superior electrophilicity and smaller singlet–triplet gap, CAACs can activate small molecules at room temperature, such as CO, H2, and P4, as well as enthalpically strong bonds, such as B–H, Si–H, N–H, and P–H. Lastly, excellent results have been obtained in palladium, ruthenium, and gold catalysis. CAAC–metal complexes are extremely thermally robust, which allows for their utilization in harsh conditions. This property has been used to perform a variety of gold-catalyzed reactions in the presence of basic amines, including ammonia and hydrazine, which usually deactivate catalysts.

Khan R.K., Torker S., Hoveyda A.H.

The origins of the unexpected finding that Ru catechothiolate complexes, in contrast to catecholate derivatives, promote exceptional Z-selective olefin metathesis reactions are elucidated. We show that species containing a catechothiolate ligand, unlike catecholates, preserve their structural integrity under commonly used reaction conditions. DFT calculations indicate that, whereas alkene coordination is the stereochemistry-determining step with catecholate complexes, it is through the metallacyclobutane formation that the identity of the major isomer is determined with catechothiolate systems. The present findings suggest that previous models for Z selectivity, largely based on steric differences, should be altered to incorporate electronic factors as well.

Rouen M., Queval P., Falivene L., Allard J., Toupet L., Crévisy C., Caijo F., Baslé O., Cavallo L., Mauduit M.

An unexpected cationic bis-N-heterocyclic carbene (NHC) benzylidene ether based ruthenium complex (2 a) was prepared through the double incorporation of an unsymmetrical unsaturated N-heterocyclic carbene (U2 -NHC) ligand that bore an N-substituted cyclododecyl side chain. The isolation and full characterization (including X-ray diffraction studies) of key synthetic intermediates along with theoretical calculations allowed us to understand the mechanism of the overall cationization process. Finally, the newly developed complex 2 a displayed interesting latent behavior during ring-closing metathesis, which could be "switched on" under acidic conditions.

Szczepaniak G., Kosiński K., Grela K.

The increasing use of olefin metathesis in practical syntheses led to a greater demand for tailored catalysts that offer not only high reactivity and stability in the presence of impurities, but also improved handling characteristics, such as custom solubility profiles, simpler post-reaction workup and easier removal of ruthenium residues from the products. Due to mechanistic considerations, the most appropriate way to create such compounds is to decorate known catalysts with utility related tags placed in nonlabile ligands. This critical review summarizes how the NHC ligand can be modified to confer novel auxiliary traits and examines the practical consequences of these modifications.

Bates J.M., Lummiss J.A., Bailey G.A., Fogg D.E.

A long-standing question in olefin metathesis centers on whether the “release–return” (boomerang) mechanism contributes to the productivity of Hoveyda-class catalysts. According to this mechanism, a molecule of o-isopropoxystyrene (A) is liberated during catalyst initiation, but recaptures the active catalyst following metathesis. The relevance of this pathway for the second-generation Hoveyda catalyst HII was assessed in metathesis of 1,1- and 1,2-disubstituted olefins. Crossover studies with 13C-labeled A*, as well as competition experiments involving ring-closing or cross metathesis (RCM, CM) in the presence of A (equimolar with HII) indicated rapid reuptake of styrenyl ether. The crossover studies indicated highly efficient catalyst initiation, with the entire catalyst charge being activated before metathesis was complete. In a comparative study involving CM of anethole with methyl acrylate, sustained activity was shown for HII, whereas the second-generation Grubbs catalyst GII was rapidly deactivated...

Yang Y., Jang M., Kang H., Choe S., Lee E., Choi T.

AbstractCyclic polymers are very attractive due to their unique properties; however, so far, they have simple and less reactive backbone structures due to synthetic limitations, restricting their further post‐modification. Notably, allenes present a potentially useful platform in polymer chemistry due to their well‐established toolbox in organic chemistry. Nevertheless, the biggest challenge remains in synthesizing poly(allenamer)s with high allene contents or polymerization efficiency, as well as synthesizing different types of cyclic poly(allenamer)s. Herein, we synthesized linear and cyclic poly(allenamer)s via ring‐opening metathesis polymerization (ROMP) and ring‐expansion metathesis polymerization (REMP), employing highly efficient cyclic–alkyl–amino–carbene (CAAC) ruthenium catalysts. Mechanistic studies suggested CAAC ligands enhanced stability of propagating Ru vinylidene, enabling various linear and cyclic poly(allenamer)s with turnover number up to 1360 and molecular weight reaching 549 kDa. Their cyclic architecture was thoroughly characterized by multiangle light scattering size‐exclusion chromatography (MALS SEC) with viscometer. Moreover, controlled ROMP of a highly reactive α‐substituted cyclic allene was achieved using third‐generation Grubbs' catalyst. Finally, we demonstrated highly efficient and selective post‐modifications on poly(allenamer)s with primary and secondary alcohols. This broadens the scope of cyclic polymers with improved efficiency and structural control, affording a practical platform for diverse macromolecules.

Yang Y., Jang M., Kang H., Choe S., Lee E., Choi T.

AbstractCyclic polymers are very attractive due to their unique properties; however, so far, they have simple and less reactive backbone structures due to synthetic limitations, restricting their further post‐modification. Notably, allenes present a potentially useful platform in polymer chemistry due to their well‐established toolbox in organic chemistry. Nevertheless, the biggest challenge remains in synthesizing poly(allenamer)s with high allene contents or polymerization efficiency, as well as synthesizing different types of cyclic poly(allenamer)s. Herein, we synthesized linear and cyclic poly(allenamer)s via ring‐opening metathesis polymerization (ROMP) and ring‐expansion metathesis polymerization (REMP), employing highly efficient cyclic–alkyl–amino–carbene (CAAC) ruthenium catalysts. Mechanistic studies suggested CAAC ligands enhanced stability of propagating Ru vinylidene, enabling various linear and cyclic poly(allenamer)s with turnover number up to 1360 and molecular weight reaching 549 kDa. Their cyclic architecture was thoroughly characterized by multiangle light scattering size‐exclusion chromatography (MALS SEC) with viscometer. Moreover, controlled ROMP of a highly reactive α‐substituted cyclic allene was achieved using third‐generation Grubbs' catalyst. Finally, we demonstrated highly efficient and selective post‐modifications on poly(allenamer)s with primary and secondary alcohols. This broadens the scope of cyclic polymers with improved efficiency and structural control, affording a practical platform for diverse macromolecules.

Zhang Y., Tao Q., Li Q., Jin Z., Long Y., Zhou X.

AbstractTransition metal‐catalyzed cross‐coupling reactions have emerged as one of the most attractive methods in organic synthesis in recent years. However, due to the inertness of C−C bonds, C−C bond activation enabled cross‐coupling reactions are far less common. In this work, the first example of palladium‐catalyzed cross‐coupling of ynones with aryl bromides for the synthesis of diarylacetylenes via C(O)‐C(sp) bond activation was described. The reaction exhibited directing group‐free unstrained C−C bond activation, wide substrate scope, and good functional group tolerance. Preliminary mechanistic studies suggested that a cross‐electrophile coupling reaction pathway might be involved rather than the conventional nucleophilic addition/β‐C elimination pathway.

Jang M., Jung E., Yang Y., Noh J., Song H., Kim H., Kang H., Choe S., Choi T., Lee E.

Ivchenko P.V., Nifant'ev I.E.

In this tutorial review, the most important and actual issues of oleochemistry, including the preparation of oleates and related compounds and their transformation with and without breaking of the CC bond, are addressed and discussed.

Luo Y., Liu G., Zhang P., Zhou B., Zhang P., Xu P., Qiu Z., Xie Z., Mei L.

Boisvert E.Y., Castellanos R.R., Ferguson M.J., Fogg D.E.

AbstractThe small, lipophilic tetrafluoroborate anion is ubiquitous in the imidazol(in)ium and iminium precursors to N‐heterocyclic carbenes (NHCs), including cyclic (alkyl)(amino)carbenes (CAACs). Its symmetrical distribution of charge over four highly electronegative fluorine atoms confers high stability, attenuating basicity while shielding the boron center. Here we report that this inertness does not withstand the nucleophilicity of free carbenes, when combined with a polarizing lithium cation. Reaction of CAAC ⋅ HBF4 salts with LiN(SiMe3)2, a protocol widely used to liberate free CAACs, generates zwitterionic CAAC‐BF3 adducts within minutes at 80 °C, or hours at room temperature, even for bulky N‐diisopropylphenyl (DIPP) CAACs. Imidazol(in)ium tetrafluoroborates likewise form NHC‐BF3 adducts in excellent yields.

Krajczy P., Meyners C., Repity M., Hausch F.

AbstractAccess to small, rigid, and sp3‐rich molecules is a major limitation in the drug discovery for challenging protein targets. FK506‐binding proteins hold high potential as drug targets or enablers of molecular glues but are fastidious in the chemotypes accepted as ligands. We here report an enantioselective synthesis of a highly rigidified pipecolate‐mimicking tricyclic scaffold that precisely positions functional groups for interacting with FKBPs. This was enabled by a 14‐step gram‐scale synthesis featuring anodic oxidation, stereospecific vinylation, and N‐acyl iminium cyclization. Structure‐based optimization resulted in the discovery of FKBP inhibitors with picomolar biochemical and subnanomolar cellular activity that represent the most potent FKBP ligands known to date.

Farkas V., Csókás D., Erdélyi Á., Turczel G., Bényei A., Nagy T., Kéki S., Pápai I., Tuba R.

AbstractIsomerization Metathesis (ISOMET) reaction is an emerging tool for “open loop” chemical recycling of polyethylene to propylene. Novel, latent N‐Alkyl substituted Cyclic(Alkyl)(Amino)Carbene (CAAC)–ruthenium catalysts (5a‐Ru, 3b‐Ru – 6c‐Ru) are developed rendering “inverted” chemical structure while showing enhanced ISOMET activity in combination with (RuHCl)(CO)(PPh3)3 (RuH) double bond isomerization co‐catalyst. Systematic investigations reveal that the steric hindrance of the substituents on nitrogen and carbon atom adjacent to carbene moiety in the CAAC ligand have significantly improved the catalytic activity and robustness. In contrast to the NHC‐Ru and CAAC‐Ru catalyst systems known so far, these systems show higher isomerization metathesis (ISOMET) activity (TON: 7400) on the model compound 1‐octadecene at as low as 3.0 bar optimized pressure, using technical grade (3.0) ethylene. The propylene content formed in the gas phase can reach up to 20% by volume.

Zier M., Planer S., Czeluśniak I., Marczyk A., Młodzikowska-Pieńko K., Trzaskowski B., Bockfeld D., Tamm M., Kajetanowicz A.

AbstractA Grubbs‐type ruthenium complex bearing a tridentate anionic bisfluoroalkoxy‐carbene was synthesised and fully characterised. Under standard conditions, it proved to be inactive in olefin metathesis reactions, but the addition of HCl triggers its activity and allows the synthesis of a series of cyclic olefins and ethers as well as a stereoregular polynorbornene with an unexpectedly high content of trans‐configured double bonds, as found in commercially available polynorbornene (Norsorex®). Detailed structural studies and DFT calculations showed that the complex enters the catalytic cycle, but instead of performing a full turnover, it is caught as a stable intermediate that does not undergo further reactions. The addition of HCl causes dissociation of the fluoroalkoxy units, resulting in a compound that behaves similarly to standard Grubbs‐type complexes. To further understand this phenomenon, the corresponding Hoveyda‐Grubbs complex was also obtained and studied in detail; due to the absence of the phosphine ligand, its behaviour was different from that of its Grubbs‐type counterpart.

Purohit V.B., Pięta M., Pietrasik J., Plummer C.M.

Over the past century the advancement of polymer chemistry has provided civilization with a plethora of plastic products that have significantly contributed to day-to-day life and the general well-being of humanity. However, the disposal of used plastic has led to an accumulation of plastic waste in the environment which can destroy fragile ecosystems. It is therefore imperative that viable alternatives to the presently used non–degradable polymers are developed. Two emerging approaches for addressing the contemporary plastic waste crisis are the development of degradable and chemically recyclable polymers. Among the various polymerization techniques, ring–opening metathesis polymerization (ROMP) remains a viable candidate for the design and preparation of such next-generation polymers. Within this review article an overview is presented regarding the history, mechanism and catalyst developments in ROMP, detailing significant developments over the previous decades which reassert the importance of ROMP in designing advanced polymers. Moreover, this article aims to explore the chemistry involved in ROMP by summarizing the state-of-the-art, as well as providing an overview of the fundamental challenges involved in synthesizing such next-generation polymers, including potential future directions.

Talcik J., Serrato M., Del Vecchio A., Colombel-Rouen S., Morvan J., Roisnel T., Jazzar R., Melaimi M., Bertrand G., Mauduit M.

The synthesis of ruthenium-complexes with cyclic (amino)(barrelene)carbenes (namely CABCs) as ligand is reported. Isolated in moderate to good yields, those new complexes showed an impressive thermal stability at 110 °C...

Cheng-Sánchez I., Moya-Utrera F., Sarabia F.

Gawin R., Tracz A., Krajczy P., Kozakiewicz-Piekarz A., Martínez J.P., Trzaskowski B.

Sytniczuk A., Struzik F., Grela K., Kajetanowicz A.

A tunable family of ibuprofen intermediate-derived CAAC-base complexes for different applications, dependent from the size of the N-aryl substituent.