What is the initiation step of the Grubbs-Hoveyda olefinmetathesiscatalyst?

Hillier I.H., Pandian S., Percy J.M., Vincent M.A.

The potential energy surfaces for ring-closing metathesis reactions of a series of simple α,ω-dienes which lead to 5-10 membered ring products, have been explored using density functional theory methods. We have investigated both the conformational aspects of the hydrocarbon chain during the course of the reactions, as well as the stationary structures on the corresponding potential energy surfaces. Extensive conformational searches reveal that the reaction proceeds via the conformation that would be expected for the cycloalkene product, though most unexpectedly, cyclohexene forms via complexes in boat-like conformations. The M06-L density functional has been used to map out the potential energy surfaces, and has identified metallocyclobutane fragmentation as being generally the highest barrier along the pathway. The structural variations along the pathway have been discussed for the reactant hydrocarbons of differing chain length to identify points at which cyclisation events may begin to affect reaction rates. Our study provides an excellent starting point from which to begin to learn about the way RCM reaction outcomes are controlled by diene structure.

Vorfalt T., Wannowius K., Plenio H.

Solans-Monfort X., Pleixats R., Sodupe M.

The catalytic activity and catalyst recovery of two heterogenized ruthenium-based precatalysts (H and NO(2)(4)) in diene ring-closing metathesis have been studied by means of density functional calculations at the B3LYP level of theory. For comparison and rationalization of the key factors that lead to higher activities and higher catalyst recoveries, four other Grubbs-Hoveyda complexes have also been investigated. The full catalytic cycle (catalyst formation, propagation, and precatalyst regeneration) has been considered. DFT calculations suggest that either for the homogeneous and heterogenized systems the activity of the catalysts mainly depends on the ability of the precursor to generate the propagating carbene. This ability does not correlate with the traditionally identified key factor, the Ru...O interaction strength. In contrast, precatalysts with lower alkoxy-dissociation energy barriers and lower stabilities compared with the propagating carbene also present larger C1-C2 bond length (i.e., lower pi character of the C-C bond that exists between the metal-carbene (Ru=C) and the phenyl ring of the Hoveyda ligand). Catalyst recovery, regardless of whether a release-return mechanism occurs or not, is also mainly determined by the pi delocalization. Therefore, future Grubbs-Hoveyda-type catalyst development should be based on fine-tuning the pi-electron density of the phenyl moiety, with the subsequent effect on the metalloaromaticity of the ruthenafurane ring, rather than considering the modification of the Ru...O interaction.

Vougioukalakis G.C., Grubbs R.H.

The fascinating story of olefin (or alkene) metathesis (eq 1) began almost five decades ago, when Anderson and Merckling reported the first carbon-carbon double-bond rearrangement reaction in the titanium-catalyzed polymerization of norbornene. Nine years later, Banks and Bailey reported “a new disproportionation reaction . . . in which olefins are converted to homologues of shorter and longer carbon chains...”. In 1967, Calderon and co-workers named this metal-catalyzed redistribution of carbon-carbon double bonds olefin metathesis, from the Greek word “μeτάθeση”, which means change of position. These contributions have since served as the foundation for an amazing research field, and olefin metathesis currently represents a powerful transformation in chemical synthesis, attracting a vast amount of interest both in industry and academia.

Pandian S., Hillier I.H., Vincent M.A., Burton N.A., Ashworth I.W., Nelson D.J., Percy J.M., Rinaudo G.

Using density functional theory employing the M06 functional, we predict the reaction path energetics of ring formation via diene ring closing metathesis (RCM) reactions, and thence the effective molarity (EM) for the formation of cyclohexene, which is in good accord with the experimental lower limit which we report here.

Benitez D., Tkatchouk E., Goddard III W.A.

Using density functional theory with the B3LYP and M06 functionals, we show conclusively that the (H(2)IMes)(Cl)(2)Ru olefin metathesis mechanism is bottom-bound with the chlorides remaining trans throughout the reaction, thus attempts to effect diastereo- and enantioselectivity should focus on manipulations that maintain the trans-dichloro Ru geometry.

Vougioukalakis G., Grubbs R.

A series of ruthenium-based olefin metathesis catalysts coordinated with unsymmetrical N-heterocyclic carbene (NHC) ligands has been prepared and fully characterized. These complexes are readily accessible in one or two steps from commercially available [(PCy(3))(2)Cl(2)Ru==CHPh]. All of the complexes reported herein promote the ring-closing of diethyldiallyl and diethylallylmethallyl malonate, the ring-opening metathesis polymerization of 1,5-cyclooctadiene, and the cross metathesis of allyl benzene with cis-1,4-diacetoxy-2-butene, in some cases surpassing in efficiency the existing second-generation catalysts. Especially in the cross metathesis of allyl benzene with cis-1,4-diacetoxy-2-butene, all new catalysts demonstrate similar or higher activity than the second-generation ruthenium catalysts and, most importantly, afford improved E/Z ratios of the desired cross-product at conversion above 60 %. The influence of the unsymmetrical NHC ligands on the initiation rate and the activation parameters for the irreversible reaction of these ruthenium complexes with butyl vinyl ether were also studied. Finally, the synthesis of the related chlorodicarbonyl(carbene) rhodium(I) complexes allowed for the study of the electronic properties of the new unsymmetrical NHC ligands that are discussed in detail.

Zhao Y., Truhlar D.G.

Second-generation ruthenium carbenoid catalysts for olefin metathesis are a hundred to a thousand times more active than first-generation catalysts, despite a slower initiation step. A new density functional capable of treating medium-range correlation energy shows that the relative rates of generation of the catalyst are determined by attractive noncovalent interactions.

Sanford M.S., Love J.A., Grubbs R.H.

This report details the effects of ligand variation on the mechanism and activity of ruthenium-based olefin metathesis catalysts. A series of ruthenium complexes of the general formula L(PR(3))(X)(2)Ru=CHR(1) have been prepared, and the influence of the substituents L, X, R, and R(1) on the rates of phosphine dissociation and initiation as well as overall activity for olefin metathesis reactions was examined. In all cases, initiation proceeds by dissociative substitution of a phosphine ligand (PR(3)) with an olefinic substrate. All of the ligands L, X, R, and R(1) have a significant impact on initiation rates and on catalyst activity. The origins of the observed substituent effects as well as the implications of these studies for the design and implementation of new olefin metathesis catalysts and substrates are discussed in detail.

Sanford M.S., Ulman M., Grubbs R.H.

Over the past two decades, olefin metathesis has emerged as a mild and efficient method for the formation of carbon−carbon double bonds. In particular, (PCy_3)_2(Cl)_2RuCHPh (1)^2 has found extensive use in organic and polymer chemistry due to its high reactivity with olefins in the presence of a diverse array of functional groups. Recently, a new family of ruthenium-based olefin metathesis catalysts have been prepared by the substitution of a single PCy_3 ligand of 1 with an N-heterocyclic carbene. These new alkylidenes, particularly [Figure 1], exhibit dramatically increased activity over the parent system in ring-opening metathesis polymerization, ring-closing metathesis,4a and cross metathesis reactions. The mechanism of olefin metathesis reactions catalyzed by 1 has received intense investigation in our group and others and early studies established that phosphine dissociation is a crucial step along the reaction coordinate. As such, it has been suggested that the high activity of 2 and its analogues is due to their increased ability to promote this critical phosphine dissociation step. We report herein a detailed mechanistic study of phosphine exchange and initiation kinetics in alkylidenes 1 and 2. This study provides new and surprising evidence concerning the origin of the large activity differences between these two catalysts.

Garber S.B., Kingsbury J.S., Gray B.L., Hoveyda A.H.

Several highly active, recoverable and recyclable Ru-based metathesis catalysts are presented. The crystal structure of Ru complex 5, bearing a 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene and styrenyl ether ligand is disclosed. The heterocyclic ligand significantly enhances the catalytic activity, and the styrenyl ether allows for the easy recovery of the Ru complex. Catalyst 5 promotes ring-closing metathesis (RCM) and the efficient formation of various trisubstituted olefins at ambient temperature in high yield within 2 h; the catalyst is obtained in >95% yield after silica gel chromatography and can be used directly in subsequent reactions. Tetrasubstituted olefins can also be synthesized by RCM reactions catalyzed by 5. In addition, the synthesis and catalytic activities of two dendritic and recyclable Ru-based complexes are disclosed (32 and 33). Examples involving catalytic ring-closing, ring-opening, and cross metatheses are presented where, unlike monomer 5, dendritic 33 can be readily recovered.

Kingsbury J.S., Harrity J.P., Bonitatebus P.J., Hoveyda A.H.

A Ru carbene (8, Scheme 2) that contains an internal metal−oxygen chelate is an active metathesis catalyst and is readily obtained by the sequential treatment of Cl2Ru(PPh3)3 with (2-isopropoxyphenyl)diazomethane and PCy3. This Ru-carbene complex offers excellent stability to air and moisture and can be recycled in high yield by silica gel column chromatography. The structures of this and related complexes have been unambiguously established by NMR and single-crystal X-ray diffraction studies.

Kinugawa T., Mitsusada S., Orito N., Matsuo T.

Basak T., Trzaskowski B.

Medley A.W., Patel D., Utne C., Bender T.A.

Antonova Alexandra S., Zubkov Fedor I.

Catalytic olefin metathesis using Hoveyda-Grubbs type ruthenium complexes is a powerful tool for creating complex molecules possessing a variety of practically useful properties. This method is also applied for obtaining modern polymer materials from low-demand petroleum products. Among all ruthenium complexes containing five- or six-membered chelate rings, the commercially available HG-II catalyst is the most common. In addition, other Hoveyda-Grubbs type complexes, which include a Het→Ru donor–acceptor bond in the chelate ring, often exhibit metathesis activity equal to or superior to that of HG-II. This review considers second-generation N-heterocyclic ruthenium carbene Hoveyda-Grubbs type complexes with donor–acceptor bonds such as O→Ru, S→Ru, Se→Ru, N→Ru, P→Ru and Hal→Ru in the chelate ring. Methods of preparation, analysis of stability and catalytic activity of such complexes are compared, and examples of the application of these organometallic ruthenium derivatives in the synthesis of practically relevant products are provided. The literature from 2010 to 2023 is summarized, making this review useful for a broad audience of chemists working in heterocyclic and organometallic chemistry, as well as practitioners involved in the production of catalysts and polymers.The bibliography includes 174 references.

Mitan C., Filip P., Delaude L., Dragutan V.

Ring-closing enyne metathesis (RCEYM) is a powerful synthetic strategy to build complex molecular architectures, including carbocycles and heterocycles, which are crucial for natural product synthesis. In this review, we delve into the mechanistic nuances of RCEYM, with a focus on the role of the well-defined Grubbs and Hoveyda-Grubbs ruthenium-alkylidene catalysts. Notably, integrating computational and experimental findings, we highlight how the sophisticated interplay of catalytic and substrate variables orchestrate the RCEYM process thus dictating reaction pathways and selectivity.

Ou X., Occhipinti G., Boisvert E.Y., Jensen V.R., Fogg D.E.

Marczyk A., Mukherjee N., Trzaskowski B.

• The initation rate is an important characteristic of olefin metathesis catalysts • Electron-withdrawing –NO, –NO 2 and –SO 2 C 4 F 9 groups were introduced to all possible positions of the benzylidene ring of the Hoveyda-Grubbs complex • DFT calculations predict increased initation rates of such systems • The –SO 2 C 4 F 9 -substituted derivatives were predicted to be the fastest-initaitng in the series The initiation rate of ruthenium metathesis catalysts is one of their most important characteristics from the applicational point of view due to the fact, that initiation is often the rate-limiting step of the entire catalytic cycle. Such initiation rate can be adjusted by introducing various modifications to the commonly used Grubbs-like and Hoveyda-Grubbs-like catalysts. Using a DFT approach, we predicted the initiation rates of the 2nd generation Hoveyda-Grubbs catalyst analogues substituted with electron-withdrawing –NO, –NO 2 , and –SO 2 C 4 F 9 groups in all positions of the phenyl ring in the benzylidene part. We show that some of the modifications should result in very fast-initiating catalysts. In particular, the –SO 2 C 4 F 9 -substitued derivatives are predicted to be the fastest-initiating in the series. We also found correlations between the selected computed parameters such as the Gibbs free energy barrier for initiation and ruthenium-oxygen bond strengths which, combined with distortion energy analysis, allowed us to provide an explanation of the main driving force behind fast initiation.

Młodzikowska-Pieńko K., Trzaskowski B.

Rajkiewicz A.A., Kajetanowicz A., Grela K.

New ruthenium olefin metathesis catalysts containing N-heterocyclic carbene (NHC) connected by a linker tether to a benzylidene ligand were studied. Such obtained self-chelated Hoveyda–Grubbs type complexes existed in the form of an organometallic polymer but could still catalyze olefin metathesis after being dissolved in an organic solvent. Although these polymeric catalysts exhibited a slightly lower activity compared to structurally related nonpolymeric catalysts, they were successfully used in a number of ring-closing metathesis reactions leading to a variety of heterocyclic compounds, including biologically and pharmacologically related analogues of cathepsin K inhibitor and sildenafil (Viagra™). In the last case, a good solubility of a polymeric catalyst in toluene allowed the separation of the product from the catalyst via simple filtration.

Martínez J.P., Trzaskowski B.

The dissociative mechanism of initiation for a series of Hoveyda-Grubbs type metathesis catalysts modified at the para and meta positions in the isopropoxybenzylidene ligand is investigated by means of DFT calculations. The electron donating/withdrawing capacity of the ligand was screened through the incorporation of various substituents such as halogens, nitro, alkoxides, ketones, esters, amines, and amides. Variations in structural parameters, energy barriers for the Ru-O bond dissociation, and Ru-O bond strength were examined as a function of the Hammett constant. It was found that electronic properties of the catalysts such as chemical potential, hardness, and electrophilicity correlate linearly with the dissociative energy barriers. These findings enable a systematic rationalization and prediction of rate of precatalyst initiation through the calculation of only the HOMO-LUMO gap of catalysts, as the faster the initiation, the more electrophilic the catalyst.

Martínez J.P., Trzaskowski B.

Although highly selective complexes for the cross-metathesis of olefins, particularly oriented toward the productive metathesis of Z-olefins, have been reported in recent years, there is a constant need to design and prepare new and improved catalysts for this challenging reaction. In this work, guided by density functional theory (DFT) calculations, the performance of a Ru-based catalyst chelated to a sulfurated pincer in the olefin metathesis was computationally assessed. The catalyst was designed based on the Hoveyda-Grubbs catalyst (SIMes)Cl2Ru(═CH-o-OiPrC6H4) through the substitution of chlorides with the chelator bis(2-mercaptoimidazolyl)methane. The obtained thermodynamic and kinetic data of the initiation phase through side- and bottom-bound mechanisms suggest that this system is a versatile catalyst for olefin metathesis, as DFT predicts the highest energy barrier of the catalytic cycle of ca. 20 kcal/mol, which is comparable to those corresponding to the Hoveyda-Grubbs-type catalysts. Moreover, in terms of the stereoselectivity evaluated through the propagation phase in the metathesis of propene-propene to 2-butene, our study reveals that the Z isomer can be formed under a kinetic control. We believe that this is an interesting outcome in the context of future exploration of Ru-based catalysts with sulfurated chelates in the search for high stereoselectivity in selected reactions.

Böth A.D., Sauer M.J., Reich R.M., Kühn F.E.

This chapter represents a comprehensive review of organometallic ruthenium and osmium complexes containing N-heterocyclic carbene as well as π-acid ligands, such as heavier tetrylenes, nitrogen and/or phosphorous coordinating ligands. Relevant literature is discussed between the years 2006 and 2020. Novel structures, reactivities and properties of these organometallic complexes are emphasized.

Grela K., Kajetanowicz A., Szadkowska A., Czaban‐Jóźwiak J.

This chapter describes olefin cross‐metathesis (CM) reactions catalyzed by ruthenium, molybdenum, and tungsten complexes and surveys the literature from 1993 through 2020. Cross‐metathesis has been applied to the synthesis of a wide range of functionalized alkenes, including natural and biologically active products. Due to its simplicity and inherit atom economy, CM has found applications in the preparation of fine chemicals and various building blocks, and in transformations of biomass. Tandem reactions involving CM as the key step are also reviewed. Examples discussed in this chapter serve to illustrate how the reactivity of alkene substrates in CM depends on the presence of functional groups and steric congestion in the proximity of the reacting double bonds. A discussion of the mechanism of olefin metathesis is also included.

Wei W., Jia G.

The coordination chemistry of ruthenium, osmium, technetium and rhenium with carbon-based ligands covering the literature from 2003 to 2018 is discussed. These metals form a vast number of coordination compounds with carbon-based ligands ranging from a single carbon atom (a carbido ligand) to polydentate hydrocarbon chains, and from monodentate organometallic ligands such as carbenes to multidentate ligands such as pincers and macrocycles. Particular focus of this review is given to syntheses, properties and applications of complexes with popular carbon-based ligands such as monodentate N-heterocyclic carbenes (NHCs), cyclometallated bidentate ligands, tridentate pincers and porphyrin-like macrocycles.

Patra S.G., Das N.K.

N -heterocyclic carbene (NHC) containing Ru catalysts are highly efficient in olefin metathesis. The computational investigation has been employed to understand the mechanism. NHC increases the catalyst efficiency through easily accessible rotameric conformation. The reaction proceeds through metallacyclobutane intermediate. Using bulky substituents over NHC and other anionic ligands leads to the chemo-, stereo-, and regio-selective product formation. The presence of alcohol, amines leads to catalyst decomposition through β hydride elimination. • Mechanistic study of the olefin metathesis using N -heterocyclic carbene (NHC) containing Ru catalyst. • NHC increases efficiency and stability through trans effect and active conformation. • Associative, dissociative, and interchange pathways of initiation. • A stable metallacyclobutane intermediate is formed, which governs product formation. • NHC types govern the chemo-, stereo, regio-selectivity of the product olefine. The second-generation Grubbs catalyst contains N -heterocyclic carbene (NHC) coordinated to Ru center. Various such complexes have been employed as catalysts for the olefin metathesis reaction. Based on experimental results and theoretical analysis, it has been established that a cyclic four-membered metallacyclobutane is formed as an active intermediate. The use of the right computational recipe is prescribed in the context of the Grubbs catalyst. The carbene electronic structure in the catalyst and the course of the reaction are discussed. A recent computational study examined the possibility of an oxidation state as +2 or +4 in a comparative manner. Further, the role of catalysts in the chemo, regio, and stereoselectivity are also discussed. In particular, in recent years, Z selective catalysts (cyclometalated and dithiolate-containing) were developed through an in-depth understanding of the electronic and steric principles. Besides, the substituents present on the NHC carbene also plays an important role. Furthermore, the presence of a chiral backbone leads to stereoselectivity in the product. Studies also predict a more suitable catalyst for certain types of substrates. In a recent study, the effect of aromaticity while discussing alkene vs. arene substrate has been considered. Catalyst undergoes decomposition in the presence of primary alcohol and Brønsted/Lewis base. Mechanism of such type of deterioration via β hydride elimination of the metallacyclobutane intermediate are discussed. Finally, catalyst decomposition involving chelated complexes are also emphasized. Thus, such theoretical studies may help the experimental chemist reduce their effort in choosing a suitable catalyst. In this review article, recent advancements in the olefin metathesis mechanistic studies by Grubbs catalyst are comprehensively summarized.