Communication pubs.acs.org/JACS
Cite This: J. Am. Chem. Soc. 2017, 139, 16446-16449
Decomposition of Olefin Metathesis Catalysts by Brønsted Base: Metallacyclobutane Deprotonation as a Primary Deactivating Event Gwendolyn A. Bailey,† Justin A. M. Lummiss,† Marco Foscato,‡ Giovanni Occhipinti,‡ Robert McDonald,§ Vidar R. Jensen,‡ and Deryn E. Fogg*,† †
Center for Catalysis Research and Innovation, and Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa K1N 6N5, Canada ‡ Department of Chemistry, University of Bergen, Allégaten 41, N-5007 Bergen, Norway § X-Ray Crystallography Laboratory, University of Alberta, Edmonton, Alberta T6G 2G2, Canada S Supporting Information *
abstract the benzylidene moiety from GII5d and HII,8a or the methylidene ligand from Ru-1.5c For PCy3-stabilized catalysts, associative binding of sterically accessible Lewis donors accelerates loss of PCy3, and hence loss of the methylidene ligand from Ru-1.5,6 Less is yet understood about the pathways operative for Brønsted bases, but multiple studies attest to their negative impact.1,4,8 Nitrogen bases of widely varying strength (DBU, pKa 24; NEt3, pKa 18) were shown to decompose GII and HII during macrocyclization5d or styrene metathesis,8a via pathways hitherto conjectural.9 Likewise, yields in acrylate metathesis catalyzed by GII are severely reduced relative to those attainable with the phosphine-free Hoveyda catalyst HII.8c The latter problem was traced to highly basic10 enolates formed by reaction of acrylate with liberated PCy3 (Scheme 1).8b
ABSTRACT: Brønsted bases of widely varying strength are shown to decompose the metathesis-active Ru intermediates formed by the second-generation Hoveyda and Grubbs catalysts. Major products, in addition to propenes, are base·HCl and olefin-bound, cyclometalated dimers [RuCl(κ 2 -H 2 IMes−H)(H 2 CCHR)] 2 Ru-3. These are generated in ca. 90% yield on metathesis of methyl acrylate, styrene, or ethylene in the presence of either DBU, or enolates formed by nucleophilic attack of PCy3 on methyl acrylate. They also form, in lower proportions, on metathesis in the presence of the weaker base NEt3. Labeling studies reveal that the initial site of catalyst deprotonation is not the H2IMes ligand, as the cyclometalated structure of Ru-3 might suggest, but the metallacyclobutane (MCB) ring. Computational analysis supports the unexpected acidity of the MCB protons, even for the unsubstituted ring, and by implication, its overlooked role in decomposition of Ru metathesis catalysts.
Scheme 1. Enolates and Phosphonium Salts Generated During Acrylate Metathesis When PCy3 Is Present
W
ith the advent of Ru-catalyzed olefin metathesis in pharmaceutical manufacturing,1 the need to understand the fundamental pathways governing catalyst decomposition2 takes on new prominence. Decomposition limits metathesis productivity: as well, because decomposed catalyst can promote non-metathetical side-reactions, it affects selectivity and reproducibility.3 Particularly important are decomposition pathways triggered by even trace amounts of base, a recurring problem for metathesis in process chemistry in pharma.1,4 Sterically accessible Lewis bases are now known to play an important role in decomposition of the leading metathesis catalysts of Chart 1.5−7 Small nucleophiles (e.g., NH2nBu)
Here we demonstrate that the negative impact of Brønsted bases on GII and HII in metathesis is due to metallacyclobutane (MCB) deprotonation, which triggers elimination of the ring hydrocarbons as propene(s). Computational analysis substantiates the implied acidity of the MCB protons, even for unsubstituted Ru-2 (Chart 1). These findings highlight the significance of the MCB moiety in decomposition by base, and of MCB protection in catalyst redesign. We began by isolating the Ru decomposition products formed in reactions with enolate. On treating GII with methyl acrylate (Scheme 2a), cyclometalated dimer Ru-3a deposited in ca. 60% yield, accompanied by phosphonium salts A−C. This reaction was cleaner when PCy3 and methyl acrylate were
Chart 1. Metathesis Catalysts and Key Active Species
Received: August 11, 2017 Published: November 3, 2017 © 2017 American Chemical Society
16446
DOI: 10.1021/jacs.7b08578 J. Am. Chem. Soc. 2017, 139, 16446−16449
Communication
Journal of the American Chemical Society
Ph) led us to suspect that MCB deprotonation might be more general. X-ray quality crystals of Ru-3b deposited from a macrocyclization reaction promoted by GII in the presence of DBU (Figures S1, S16).5d The styrene ligand presumably originates in the first cycle of metathesis. Deliberate reaction of HII with styrene and DBU at RT (Scheme 4) enabled isolation of Ru-3b in 86% yield. In situ
Scheme 2. Formation of Ru-3a from GII and HII
Scheme 4. Isolation of Dimers Ru-3b and Ru-3c
a
NMR analysis indicated near-quantitative co-formation of DBU·HCl. Experiments with D2CCDPh (not shown) revealed 80% deuterium incorporation into DBU·DCl, confirming that this proton originates in the MCB ring.18 Remarkably, even protons on the unsubstituted ring are sufficiently acidic to participate. Thus, ca. 90% DBU·HCl was also observed in the corresponding reaction with ethylene, and known6b ethylene adduct Ru-3c was isolated in 93% yield. On replacing DBU with NEt3, yields of both Ru-3c and base·HCl drop to ca. 50%, consistent with the lower basicity of NEt3 (and, potentially, competing decomposition of Ru-1). To validate the acidity of the protons in the unsubstituted MCB ring, and to exclude the alternative possibility of methylidene deprotonation,20 we undertook computational analysis. Ground-state structures for Ru-1, Ru-2, and their deprotonated derivatives appear in Figure 1. Density functional
ORTEP plot shown with Gaussian ellipsoids at 50% probability level; hydrogen atoms omitted.
added to the faster-initiating11,12 catalyst HII (Scheme 2b). Dimeric Ru-3a then precipitated quantitatively. NMR and Xray analysis support the acrylate-bound structure depicted. Strong back-donation onto acrylate is indicated by the elongated CC distance (1.426(3) Å, vs 1.337(7) Å for free methyl acrylate).13−15 The cyclometalated structure of Ru-3a suggests that decomposition by enolate commences with abstraction of an o-methyl proton from the H2IMes ligand.16 To probe this point, we reacted methyl acrylate with GII-d22, in which the mesityl rings are perdeuterated,17 and deprotonation should thus generate A−C-d1.8b However, limited deuteration was observed by quantitative MALDI-MS analysis (e.g., 80% propenyl products (chiefly 1,3-diphenylpropene, as well as β-methylstyrene) are observed on metathesis of styrene in the presence of DBU or NEt3.8a Loss of propene has also been reported in Ru-catalyzed metathesis in the absence of base,24 and in metathesis via d0 catalysts.25 The accepted pathway involves proton migration from the β-position of the MCB, and subsequent elimination (with, in the d0 systems, an intervening C2H4 insertion step).26 The tendency of Brønsted base to promote this pathway is plausibly due to a reduced energy barrier for transformation of the MCB into a π-allyl species when β-deprotonation is involved, rather than β-H migration. The foregoing demonstrates that the MCB ring is the primary site of attack in decomposition of metathesis-active intermediates by Brønsted base. Cyclometalation of the Nheterocyclic carbene ligand is not a primary deactivating event, as hitherto believed, but an ensuing, opportunistic step. Importantly, the susceptibility to deprotonation by base is not limited to MCBs formed by metathesis of electron-deficient olefins. MCB deprotonation proves an unexpectedly general feature, most notably for the unsubstituted MCB Ru-2. We conclude that protection of the MCB ring is an important, overlooked priority in improving the lifetime and productivity of ruthenium metathesis catalysts. 16448
DOI: 10.1021/jacs.7b08578 J. Am. Chem. Soc. 2017, 139, 16446−16449
Communication
Journal of the American Chemical Society
Am. Chem. Soc. 2002, 124, 4944−4945. (f) Phillips, N.; Tang, C. Y.; Tirfoin, R.; Kelly, M. J.; Thompson, A. L.; Gutmann, M. J.; Aldridge, S. Dalton Trans. 2014, 43, 12288−12298. (g) Chilvers, M. J.; Jazzar, R. F. R.; Mahon, M. F.; Whittlesey, M. K. Adv. Synth. Catal. 2003, 345, 1111−1114. (17) For the synthesis of H2IMes-d22, see: Leitao, E. M.; Dubberley, S. R.; Piers, W. E.; Wu, Q.; McDonald, R. Chem. − Eur. J. 2008, 14, 11565−11572. (18) Much smaller proportions (ca. 20%) of the non-labeled base· HCl salts were observed. We suspect that these arise from H/D exchange pathways, though the possibility of direct mesityl deprotonation cannot be completely ruled out. (19) The corresponding benzylidene complex does not undergo deprotonation by DBU, instead forming the stable adduct RuCl2(H2IMes)(DBU)(=CHPh). See ref 5d. (20) Deprotonation of Ru benzylidene species can occur, where steric pressure drives intramolecular α-elimination. See: (a) Conrad, J. C.; Amoroso, D.; Czechura, P.; Yap, G. P. A.; Fogg, D. E. Organometallics 2003, 22, 3634−3636. (b) Coalter, J. N.; Bollinger, J. C.; Eisenstein, O.; Caulton, K. G. New J. Chem. 2000, 24, 925−927. (21) Gordon, C. P.; Yamamoto, K.; Liao, W.-C.; Allouche, F.; Andersen, R. A.; Copéret, C.; Raynaud, C.; Eisenstein, O. ACS Cent. Sci. 2017, 3, 759−768. (22) Because acidity is a thermodynamic property, defined via the equilibrium constant, we calculate pKa values from the most stable acid−base pairs. For Ru-4, this means using the cis-Cl2 isomer. The mechanistic investigation instead focuses on the trans-Cl2 isomer, as the kinetic product of deprotonation. The two are denoted Ru-4 and Ru-4′, respectively. (23) The structural similarity of these acid−base pairs aids in evaluating the relative pKas of Ru-2 and Ru-1. See SI. (24) (a) Romero, P. E.; Piers, W. E. J. Am. Chem. Soc. 2007, 129, 1698−1704. (b) Nizovtsev, A. V.; Afanasiev, V. V.; Shutko, E. V.; Bespalova, N. B. NATO Sci. Ser. II 2007, 243, 125−135. (c) van Rensburg, W. J.; Steynberg, P. J.; Meyer, W. H.; Kirk, M. M.; Forman, G. S. J. Am. Chem. Soc. 2004, 126, 14332−14333. (25) See ref 2a and: (a) Schrock, R. R.; Copéret, C. Organometallics 2017, 36, 1884−1892. (b) Solans-Monfort, X.; Copéret, C.; Eisenstein, O. J. Am. Chem. Soc. 2010, 132, 7750−7757. (26) A related pathway in alkyne metathesis involves β-H transfer from the MCB, and reductive elimination of an anionic ligand X as HX. See: (a) Heppekausen, J.; Stade, R.; Kondoh, A.; Seidel, G.; Goddard, R.; Fürstner, A. Chem. − Eur. J. 2012, 18, 10281−10299. (b) McCullough, L. G.; Listemann, M. L.; Schrock, R. R.; Churchill, M. R.; Ziller, J. W. J. Am. Chem. Soc. 1983, 105, 6729−6730.
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DOI: 10.1021/jacs.7b08578 J. Am. Chem. Soc. 2017, 139, 16446−16449
