Exploiting and Understanding the Selectivity of Ru-N-Heterocyclic

Article pubs.acs.org/JACS

Exploiting and Understanding the Selectivity of Ru-N-Heterocyclic Carbene Metathesis Catalysts for the Ethenolysis of Cyclic Olefins to α,ω-Dienes Pascal S. Engl,† Celine B. Santiago,‡ Christopher P. Gordon,† Wei-Chih Liao,† Alexey Fedorov,*,† Christophe Copéret,*,† Matthew S. Sigman,*,‡ and Antonio Togni*,† †

Department of Chemistry and Applied Biosciences, ETH Zürich, Vladimir-Prelog-Weg 2, CH-8093 Zürich, Switzerland Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112, United States

‡

S Supporting Information *

ABSTRACT: A library of 29 homologous Ru-based olefin metathesis catalysts has been tested for ethenolysis of cyclic olefins toward the goal of selectively forming α,ω-diene using cis-cyclooctene as a prototypical substrate. Dissymmetry at the N-heterocyclic carbene (NHC) ligand was identified as a key parameter for controlling the selectivity. The best-performing catalyst bearing an N-CF3 group significantly outperformed the benchmark second-generation Grubbs catalyst in the ethenolysis of cis-cyclooctene. Application of this optimal catalyst to the ethenolysis of various norbornenes allows the efficient synthesis of valuable diene intermediates in good yields. The observed ligand effect trends could be rationalized through univariate and multivariate parameter analysis involving steric and electronic descriptors of the NHC ligand in the form of the buried volume and the 77Se NMR chemical shift, in particular the σyy component of the shielding tensor of [Se(NHC)] model compounds, respectively. Natural chemical shift analysis of this chemical shielding tensor shows that σyy probes the π-acceptor property of the NHC ligand, the essential electronic parameter that drives the relative rate of degenerate metathesis and selectivity in ethenolysis with catalysts bearing dissymmetric NHC ligands.

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With the prominent exception of thiolate Ru catalysts,7c,9 most of the recent progress in developing Ru metathesis catalysts tailored for a particular application relies on modifying the structure of the NHC ligand.1a,10 The identification of a specific ancillary ligand for the Grubbs-type catalyst is mostly a tedious, empirical endeavor if the parent H2IMes Ru catalyst does not provide the desired product in high yield and/or selectivity. Unfortunately, despite extensive effort,11 there are no general rules that govern rational ligand design of the optimal catalyst for the wide variety of metathesis reactions. A better understanding of the ligand effects and structural features controlling activity and selectivity is therefore required in order to develop either specific improvements or even de novo design of next generation olefin metathesis catalysts. In this context, we selected to explore the development of selective ethenolysis of cyclic alkenes to yield valuable acyclic α,ω-dienes with Ru metathesis catalysts based on structure− activity relationships. While ethenolysis of linear olefins such as oleate esters has been widely studied, predominantly with Ru catalysts,5,8a,12 there are only a few reports on ethenolysis of cyclic olefins with Ru initiators.13 This is presumably due to the

INTRODUCTION

Transition-metal-catalyzed olefin metathesis is an atomeconomical approach to form carbon−carbon double bonds, widely exploited both in academia and industry.1,2 Research in the last two decades has yielded highly active and stable welldefined metathesis catalysts.3 Particularly compelling examples are the ruthenium benzylidenes containing N-heterocyclic carbene (NHC) ligands, (NHC)(Cl)2RuCHPh(PCy3), often called the Grubbs second-generation catalysts, with the NHC typically being 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene (H2IMes).4 These catalysts combine high activity in olefin metathesis with functional group tolerance as well as excellent moisture and air stability in the solid state. While highly active Ru catalysts requiring as little as 1 ppm catalyst loadings to achieve up to 340 000 turnovers in cross-metathesis reactions of methyl oleate with ethylene (ethenolysis) have been reported,5 the development of selective catalysts remains one of the most challenging goals in this field.6 Accordingly, current efforts have focused on enhancing the control over stereoselectivity, for both Z- and E-selectivity of olefin products,7 as well as chemoselectivity in olefin crossmetathesis,8 the latter by avoiding secondary metathesis reactions.3a © 2017 American Chemical Society

Received: July 4, 2017 Published: August 18, 2017 13117

DOI: 10.1021/jacs.7b06947 J. Am. Chem. Soc. 2017, 139, 13117−13125

Article

Journal of the American Chemical Society

obtained for a broad range of second-generation Grubbs catalysts. In order to rationalize the empirical structure−activity results, a multivariate analysis is carried out and shows a good correlation between the selectivity and two descriptors: one electronic, namely the 77Se NMR chemical shift, in particular the σyy component of the shielding tensor of [Se(NHC)] model compounds, and one steric in the form of the buried volume of the ancillary NHC ligand. Detailed scrutiny of the Se chemical shift anisotropy in [Se(NHC)] model compounds by natural chemical shift analysis (NCS) demontrates that the N-CF3 substituent in the dissymmetric NHC ligands provide strong π-acceptor properties, significantly enhancing the rates of degenerate metathesis in ring closing metathesis (RCM), which correlates with selectivity in ethenolysis reactions.

high activity of Ru catalysts toward the competitive ringopening metathesis polymerization (ROMP), that depletes the yield of terminal dienes. Herein, we assess a library of 29 homologous Ru complexes with various NHC ligands in the ethenolysis of cis-cyclooctene used as a prototypical substrate with the objective to determine which structural features of an NHC ligand provide selectivity in ethenolysis of cyclic olefins. Below, we demonstrate that catalysts bearing an unsymmetrical ligand (R1 ≠ R2, Scheme 1) and an N-CF3 group are Scheme 1. Ethenolysis of cis-cyclooctenea

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RESULTS AND DISCUSSION Library of Ruthenium Metathesis Catalysts. We tested various Ru benzylidene complexes bearing NHC ligands that differ in steric and electronic properties in the ethenolysis of ciscyclooctene (Scheme 2). This library can be subdivided into five distinct groups according to the substitution pattern on the NHC backbone or at the nitrogen atoms. Group 1 is based on the parent H2IMes Grubbs catalyst and contains electron-rich to electron-neutral substituents in the para-position of the Naryl groups (Ru-1−5). The NHC ligands in Ru-6−10 of Group 2 feature an unsymmetrical nitrogen substitution pattern of the imidazolidine ring.14 We selected to include Ru catalysts with

a 1

R , R2, R3 = aryl, heteroaryl, cycloalkyl, alkyl, X = C, N.

particularly selective in the ethenolysis of cyclic olefins, including norbornene derivatives, producing α,ω-dienes in preference to polymers. Such selectivity contrasts with what is

Scheme 2. Library of Ru Metathesis Catalysts Tested in the Ethenolysis of cis-Cyclooctene

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Journal of the American Chemical Society unsymmetrical NHC ligands as they have shown improved selectivities in various metathesis reactions10d,15 including ethenolysis.5,12d,16 In the specific case of Ru-10, asymmetry is induced through a Ru−F interaction that occurs with one of the ortho-F substituents of the N-aryl group after PCy3 dissociation.17 Complexes Ru-11−15 of Group 3 have imidazolium rather than imidazolinium rings and generally two different Nsubstituents on the NHC ligands, with exception of Ru-13. Catalysts with underexplored N-trifluoromethyl NHC ligands are represented by Ru-16−21 (Group 4). Finally, Group 5 includes ruthenium complexes bearing miscellaneous NHCs (Ru-22−29), which diverge more significantly from the NHC ligands of Groups 1−4 in terms of substituent size, backbone substitution, and the type of heterocyclic carbene ligand employed. Most of the Ru catalysts were synthesized according to literature reports or were commercial; new Ru complexes were fully characterized (see SI). Evaluation of NHC-Based Ru Metathesis Catalysts in Ethenolysis of cis-Cyclooctene. We tested catalysts Ru-1− 29 in the ethenolysis of cis-cyclooctene for selective ethenolysis to 1,9-decadiene. All catalytic tests were performed by injecting 210 ppm catalyst in toluene to 0.95 mL of neat cis-cyclooctene pressurized to 10 bar ethylene (99.995% purity) at 35 °C, and the reaction progress was monitored via ethylene uptake at a constant pressure in all runs (see SI). Gas uptake experiments were recorded at least twice with reproducible results. Four catalytic tests were conducted with different reaction times (5, 30, 180, and 300 min) for every catalyst and this data is presented in the Supporting Information. Yields of 1,9decadiene (2) and the side product (3) formed from 2 via self-metathesis were determined by GC-FID using cyclooctane as internal standard; the yield of poly(COE) (4) is based on the isolated polymer. Reproducibility tests were routinely performed to ensure robustness of the results. Ru-1−5 bearing symmetrical saturated NHCs (Group 1) afforded mainly poly(COE) in preference to the desired ethenolysis product 2 (3−12%, Figure 1). This demonstrates that electronic modification of the para-substituent of the N-aryl groups does not enhance the yield of 2. The introduction of asymmetry in the NHC ligands in Ru-6−10 (Group 2) improves selectivity for 2, which is in the 15−35% range. A significant enhancement of the initial selectivity for 2 was observed with Ru-9 featuring a N-cyclohexyl substituent on the NHC ligand.14b However, this initial selectivity decreases with increasing conversion of 1 (Figure 1B). A reduced overall conversion of 1 was observed for Ru-7 bearing an electronically depleted N-aryl group on the NHC ligand, which might be due to partial catalyst decomposition under the applied conditions. Complexes Ru-11−15 of Group 3 containing unsaturated NHC ligands exhibit a reduced catalytic activity compared to the catalysts of Groups 1 and 2, but Ru-12 with an N-butyl substituent displays increased initial selectivity for 2. Remarkably, with the exception of Ru-19, catalysts of Group 4 bearing unsymmetrical N-trifluoromethyl NHC ligands yield fair to high conversions of 1 (59−98%) and good selectivity (50−68%) to the terminal diene 2 after 5 h, showing no detectable ROMP activity. Initial selectivity of these catalysts exceeds 95% (Figure 1A). Whereas trifluoromethyl and isopropyl groups are sterically similar,18 the replacement of CF3 in Ru-17 by iPr in Ru-25 results in a significantly diminished selectivity (54% for Ru-17; 6% for Ru-25) for 2, while the overall conversion of 1 is comparable (75% for Ru-

Figure 1. Selectivity vs conversion plots for the ethenolysis of ciscyclooctene (1) to 1,9-decadiene (2) after 5 min (A) and 5 h (B) as well as the ROMP selectivity (C). 13119


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Journal of the American Chemical Society 17; 64% for Ru-25). This result highlights the importance of the electronic effect of the CF3 group and, possibly of the F− Ru interaction found crystallographically in Group 4 catalysts.19 The yield of poly(COE) decreases in the row Ru-22 > Ru-3 > Ru-23 > Ru-26, which correlates with the increasing size at the NHC ligand; the latter catalyst shows no conversion of ciscyclooctene under our conditions. Modifying the NHC backbone via cyclohexyl or chloro groups in Ru-24 and Ru27 improves neither selectivity nor conversion. Both the sixmembered NHC ligand in Ru-28 or the triazole ligand in Ru29 reduce the overall conversion of 1. Interestingly, poly(COE) formed during ethenolysis of 1 with Ru-28 contains an unusually high number of cis double bonds (86%). Such cis-content is difficult to achieve with simple cyclic olefins even using the new generation of powerful Zselective Ru metathesis catalysts.20 Repeating the reaction without ethylene pressure yields only 17% cis-content and >99% yield of the poly(COE) (Table S36). Univariate and Multivariate Parameter Analysis. In order to rationalize the non-obvious dependence of selectivity on structure in the ethenolysis of 1, we sought to delineate which properties of the NHC ligand21 influence the reaction pathway. Therefore, various steric22 and electronic23 descriptors of the NHC ligands were obtained computationally and evaluated to identify parameters that impact the selectivity for 2. Since the isotropic 77Se NMR chemical shift (δiso) of corresponding NHC selenium adducts has been shown to be a useful parameter to describe the electronic properties of NHC ligands (vide inf ra),24 we evaluated the selectivity of 2 as a function of the chemical shift of the corresponding NHC selenium derivatives. After performing linear regression analysis, a modest trend (R2 = 0.46, Figure 2A,B) was found between the computationally derived isotropic 77Se NMR chemical shift (δiso) and the selectivity for the ethenolysis product 2 at t = 180 min for catalysts Ru-1−29 (excluding Ru-26 that gave no conversion of cis-cyclooctene). However, since chemical shift is an average of the three principal components of the chemical shift tensor (CST), wherein each component provides a valuable source of information on the local electronic structure (Figure 2A),25,26 we investigated the correlation of the selectivity with each principal component of CST of the corresponding [Se(NHC)] analogues of Ru-1−29. As a benchmark for our calculations, we measured the chemical shift tensor of Se-1−8 by solid state NMR (Table 1), which agreed well with calculated values. The principal components of the calculated shielding tensor were mostly oriented as shown in Figures 2A and S143−147. While the σxx and σzz components of the shielding tensor change only marginally with the nature of the NHC ligand, σyy, the component oriented along the SeC bond, constitutes the main contribution to the isotropic 77Se NMR chemical shift. This is thus the key element for distinguishing the CSA fingerprint of the [Se(NHC)] model compounds. With the principal components and their orientation determined, we found a significantly improved correlation in relation to the experimental ethenolysis selectivity (R2 = 0.61, t = 180 min, Figure 2C). In contrast, the σxx and σzz components correlate poorly with the ethenolysis selectivity (Figures S150 and S151). Further univariate analyses of ethenolysis selectivity (t = 180 min) led to the finding of a selectivity trend with the percent buried volume, %Vbur (R2 = 0.23, Figure 3). Note that an enhanced linear correlation can be obtained after removal of the miscellaneous ruthenium complexes of Group 5 leading to a

Figure 2. (A) Description of the chemical shift anisotropy and orientation of the 77Se chemical shielding tensor of [Se(NHC)] complexes. Univariate correlations of the isotropic 77Se NMR chemical shift δiso (B) and the σyy component of the chemical shielding tensor (C) of [Se(NHC)] model compounds for ethenolysis product 2 at t = 180 min for catalysts Ru-1−29 (excluding Ru-26).

correlation coefficient R2 = 0.65 (see Figure S152). The percent buried volume27 describes the volume occupied by the NHC in an abstract sphere of defined radius (r = 3.5 Å) with the metal atom at the center. The %Vbur values were calculated using the selenium atom as a substitute for the metal center. Intuitively, one might expect that an increased %Vbur of the NHC ligand would prevent the catalyst from engaging with the monomeric alkene, either substrate or the ethenolysis product, thereby inhibiting homometathesis and ROMP pathways. The obtained negative correlation for %Vbur implies that sterically more demanding NHC ligands result in a diminished chemoselectivity for the terminal diene 2. However, this correlation 13120


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Table 1. Experimental and Calculated Chemical Shifts and Principal Components of CSA of Selected [Se(NHC)] Complexesa

δiso (σiso) [ppm] entry

[Se]

meas.

calc.

1 2 3 4 5 6 7

Se-1 Se-2 Se-3 Se-4 Se-5 Se-6 Se-7

150 (1703) 241 (1612) 179 (1674) 45 (1808) 33 (1814) 114 (1739) 336 (1517)

8

Se-8

95 ± 3 122 ± 4 102 ± 2 26 ± 3 −20 ± 3 26 ± 26 171 ± 2 181 ± 2 184 ± 2 212 ± 2 162 ± 3 152 ± 3

280 (1573)

δxx (σxx) [ppm] meas. 473 504 474 454 423 378 459 482 473 472 458 469

± ± ± ± ± ± ± ± ± ± ± ±

δyy (σyy) [ppm]

calc. 3 4 2 3 3 3 2 2 2 2 3 3

653 722 677 577 560 546 713

(1200) (1131) (1176) (1276) (1293) (1307) (1140)

688 (1185)

δzz (σzz) [ppm]

meas.

calc.

meas.

−93 ± 3 15 ± 4 −25 ± 2 −132 ± 3 −138 ± 3 −109 ± 3 191 ± 2 223 ± 2 239 ± 2 299 ± 2 218 ± 3 178 ± 3

−71 (1924) 171 (1682) 49 (1804) −143 (1996) −118 (1971) 61 (1792) 519 (1334)

−93 ± 3 −151 ± 4 −144 ± 2 −245 ± 3 −344 ± 3 −190 ± 3 −136 ± 2 −163 ± 2 −159 ± 2 −133 ± 2 −189 ± 3 −191 ± 3

414 (1439)

calc. −132 −171 −192 −300 −325 −264 −224

(1985) (2024) (2045) (2153) (2178) (2117) (2077)

−243 (2096)

δii are the principal components of the selenium chemical shift tensor such that δiso = (δxx + δyy + δzz)/3. σii are the principal components of the shielding tensor. The computationally derived chemical shifts are referenced to SeMe2

a

multivariate models suggest an additive effect between the electronic and steric influences from the NHC ligand. However, the electronic nature of the NHC ligand, characterized by the isotropic 77Se NMR chemical shift, as well as by the σyy component of the shielding tensor of [Se(NHC)] derivatives, describes the ethenolysis selectivity to a much greater extent as indicated by the larger R2 values, obtained from the univariate regression models (Figures 2 and 3). The removal of the miscellaneous ruthenium complexes of Group 5 (Ru-22−29) resulted in greatly improved correlations (R2 = 0.87 for δiso, Figure 4A and R2 = 0.89 for σyy, Figure 4B). Natural Chemical Shift Analysis. To further understand the electronic structure associated with the observed shielding, the shielding tensor of selenium in [Se(NHC)] model compounds was decomposed into its individual orbital contributions in a Natural Chemical Shift (NCS) analysis.25,29 This analysis allows identifying the occupied orbitals (bonds and lone pairs) contributing to the chemical shift. This procedure is particularly informative since the contributions of an occupied orbital depend on the energy and symmetry of the occupied as well as the coupled vacant orbitals, allowing the direct examination of a molecule’s electronic structure. Generally, a large deshielding along an axis is expected if a high-lying occupied orbital can be coupled with a low-lying vacant orbital upon action of the angular momentum operator, which can be pictorially viewed as the superposition of these orbitals of p-character upon rotation around this axis by 90°. For [Se(NHC)] compounds, deshielding along the y axis (σyy) is mainly associated with a coupling of the lone pair on selenium lpx(Se) with the vacant π*(SeC) orbital by action of the angular momentum operator Ly (Figure 5). An additional contribution to shielding arising from the π(SeC) orbital is significantly smaller in magnitude (Table

Figure 3. Univariate correlations of the percent buried volume (%Vbur) with selectivity for ethenolysis product 2 at t = 180 min for Ru-1−29 (excluding Ru-26).

is strongly influenced by the NHC ligands of Group 4 featuring a small N-CF3 group and should therefore be considered with caution. We next developed multivariate regression models,28 vetted on experimental ethenolysis selectivity, to identify possible interrelations between both electronic and steric molecular features. A moderate correlation was observed for a multivariate model consisting of either δiso (R2 = 0.63, Figure S153) or σyy (R2 = 0.67, Figure S154) and the %Vbur in relation to ethenolysis selectivity (selectivity for 2 at t = 180 min). Additionally, a leave-one-out validation was performed for both models as represented by the correlation coefficient Q2. These 13121


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Productive versus Nonproductive Metathesis Selectivity. The nature of the NHC ligands has a profound influence on the selectivity of Ru-based olefin metathesis catalysts to undergo either productive or degenerate (nonproductive) metathesis events.3a,31 It has been reported that Ru catalysts with unsymmetrical NHC ligands promote more degenerate catalysis than productive turnover to product, compared to catalysts with symmetrical NHC ligands.31 A rationale for this observation has thus far not been provided. Understanding such degenerate metathesis activity could provide valuable insights into relevant catalyst attributes for metathesis reactions, such as ethenolysis.12d For instance, the remarkable activity and selectivity of CAAC containing ruthenium metathesis catalysts in ethenolysis of methyl oleate has been linked to enhanced levels of degenerate metathesis, as compared to previously reported NHC ligands.12d We were therefore interested in evaluating the influence of the N-trifluoromethyl group of our optimal catalyst Ru-20 on the relative rates of degenerate and productive metathesis in RCM of isotopically labeled diethyl diallyl malonate 5-d2 (Figure 6A). The overall conversion to 6 was monitored via gas chromatography (GC), while the

Figure 4. Multivariate models of predicted selectivity vs measured selectivity for ethenolysis product 2 at t = 180 min for ruthenium complexes Ru-1−21.

Figure 5. Relevant orbital interactions along the σyy component of the shielding tensor.

S45). Therefore, deshielding for σyy on Se probes mainly the πaccepting ability of the NHC ligands because higher deshielding is associated with a lower energy π*(Se=C) orbital and hence, the greater π-acceptor properties of the respective NHC ligands. The superior selectivity of the catalysts of Group 4 can therefore be attributed to the enhanced π-acceptor properties of N-trifluoromethyl NHCs, which is a result of the diminished π-overlap of the nitrogen lone pair at the N-CF3 moiety with the p-orbital of the carbene carbon, due to hyperconjugation of the nitrogen lone pair into the σ*(C−F) antibonding orbital of the CF3 group.30

Figure 6. (A) Productive versus nonproductive conversion for the RCM of 5-d2. (B) Interconversion between two diastereomeric methylidene species via metathesis with ethylene. (C) Comparison between productive and nonproductive metathesis activity of Ru-3, Ru-9, and Ru-20 with 5-d2. 13122


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Journal of the American Chemical Society amount of degenerate metathesis was determined from the relative isotopologue counts of 5-d0 and 5-d4 using mass spectrometry (MS) (see SI for details). While Ru-20 displays significant levels of degenerate metathesis amounting to a degenerate to productive ratio of ca. 1:2 (Figure 6C), the benchmark catalyst Ru-3 shows a much higher preference for productive metathesis (ratio of ca. 1:10). Interestingly, CAAC ligands feature enhanced π-accepting properties,32 similar to our N-trifluoromethyl NHC ligands of Group 4, thereby suggesting a relationship between the electronic properties of the NHC ligand and the relative rate of degenerate metathesis for dissymmetric NHC ligands. The replacement of one of the N-mesityl groups in Ru-3 by a N-cyclohexyl group (Ru-9) increases the propensity of the catalyst for degenerate metathesis (ratio of ca. 1:5). In comparison, CAAC-based Ru metathesis catalysts, which are very active in ethenolysis, achieve ratios of nearly 1:1.31b In addition, we note that since catalysts with dissymmetric NHC ligands feature two diastereomeric forms of the catalytically active methylidene species due to the high rotational barrier around the Ru−CNHC bond,33 the nonproductive metathesis turnover with ethylene interconvert such diastereomeric methylidene species (Figure 6B). The distinct reactivity of diastereomeric Ru alkylidenes34 is the basis of the concept of diastereomeric site control of selectivity, a design principle that have been exploited for chemoselective alternating copolymerization of cis-cyclooctene and norbornene.35 Importantly, the N-CF3 Ru catalysts are highly selective in the aforementioned alternating copolymerization,19 as well as other Ru catalysts with dissymmetric NHC ligands36 akin to selective ethenolysis catalysts.12d Furthermore, while dissymmetric catalysts of Groups 2 and 3 feature two rotamers as discerned by NMR spectroscopy (see SI for details), catalysts of Group 4 exist as a single rotamer in solution and in the solid state, probably because of the enhanced π-acceptor properties of such N-trifluoromethyl NHCs with the benzimidazole core, augmented by a Ru−F interaction.19 This enhancement in rotational barrier of the NHC ligands correlates with the improved selectivity in ethenolysis (vide supra). Both Ru-937 and Ru-1238 were reported to exist as a single rotational isomer in solution, which is consistent with their higher selectivity in ethenolysis as compared to catalysts Ru-6−8 and Ru-14−15 existing as mixtures of rotational isomers. Application to the Ethenolysis of Norbornene Derivatives. The superior activity of Ru metathesis catalysts featuring unsymmetrical N-trifluoromethyl NHC ligands in ethenolysis of 1 prompted us to further investigate the performance of our optimal catalyst Ru-20 in the ethenolysis of norbornene derivatives (Table 2). These substrates are particularly challenging, as they readily undergo ROMP due to their extensive ring strain. Nevertheless, ethenolysis of norbornenes constitutes a simple and attractive route for accessing valuable functionalized α,ω-dienes.39 Ru-3 shows high activity toward ROMP of norbornene (NBE) under ethenolysis conditions, yielding polynorbornene as the only reaction product (Table 2; entry 1). Ethenolysis of norbornene with 0.02 mol% of Ru-20 gives 1,3-divinylcyclopentane 7 as the only detectable product according to GC-MS; precipitation from the reaction mixture using methanol does not lead to any poly(NBE). Conducting this reaction in C6D6 and analyzing the reaction mixture by NMR confirms formation of monomer 7 (70% yield by 1H NMR; Table 2; entry 6), whereas a small amount of the

Table 2. Ethenolysis of Norbornene Derivatives with Ru-3 and Ru-20

entrya diene b

1 2 3 4 5 6b 7 8 9 10

7 8f 9f 10f 11 7 8f 9f 10f 11

[Ru] Ru-3 Ru-3 Ru-3 Ru-3 Ru-3 Ru-20 Ru-20 Ru-20 Ru-20 Ru-20

conv. [%]c S. for diene [%]d Y. of diene [%]e >99 >99 >99 82 >99 >99 42 >99 94 89

− 14 − 16 3 70 45 73 95 85

− 14 − 13 3 70 19 73 89 75

a

Reaction conditions: norbornene derivative = 2.124 mmol, [Ru] = 1000 ppm (0.1 mol%), 10 bar C2H4, 4 mL toluene, 50 °C. bReaction condition: norbornene = 2.124 mmol, [Ru] = 210 ppm (0.02 mol%), 10 bar C2H4, 4 mL C6D6, 35 °C; conversion and yield determined by 1 H NMR. cConversion of functionalized norbornenes determined by recovering the remaining cyclic olefin from the reaction mixture. d Selectivity (S.) = yield of diene/conversion × 100. eIsolated yields (Y.) for terminal dienes 8−11. fExo-isomer of the starting norbornene was used.

homometathesis side product is also detected (see SI for details). Fractional distillation of the reaction mixture after standard quenching with excess ethyl vinyl ether yields the homometathesis side product in 73% isolated yield, showing a very high propensity of 7 toward homometathesis in the absence of ethylene even with trace amounts of the metathesisactive Ru species in the reaction mixture. We next turned our attention to the ethenolysis of functionalized norbornene derivatives40 and were intrigued to find that Ru-20 gives 42% conversion and 45% selectivity toward 1,3-divinylcyclopentane 8 with an anhydride functionality at 0.1 mol % catalyst loading after 5 h at 50 °C and 10 bar ethylene (Table 2; entry 7). While Ru-3 completely converts the starting material under these conditions, its selectivity to 8 is only 14% (Table 2; entry 2). Furthermore, Ru-20 exhibits a surprisingly high activity and selectivity for the corresponding 1,3-divinylcyclopentanes 9− 11, significantly outperforming Ru-3 (73−89% isolated yield; 73−95% selectivity; vs 0−13% isolated yield; 0−16% selectivity; see Table 2 and Table S38 for optimization details). Compound 10 featuring a β-lactam scaffold has already been used as a precursor for the synthesis of novel functionalized carbocyclic β-amino acids.41

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CONCLUSIONS In summary, evaluation of a library of 29 homologous Ru metathesis catalysts featuring various NHC ligands identifies the dissymmetric NHC ligand with a N-CF3 group as in Ru-20 to be the essential structural feature for the selective ethenolysis of cyclic diene toward α,ω-dienes 2 (96% conversion of 1; 53% selectivity for 2). In comparison to benchmark catalyst Ru-3, 13123


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1) for financial support of the high throughput catalyst screening facility (HTE@ETH). P.S.E., C.P.G., W.C.L. and A.T. thank the SNSF for a research grants (200020_156989, 200021_169134 and 200020_149704). A.F. thanks Holcim Stiftung for a habilitation fellowship and Prof. Mikhail A. Kuznetsov (SPbSU) for helpful discussions. Research at the University of Utah was supported by the NSF through a grant to M.S.S. (CHE-1361296). The support and resources from the Center of High Performance Computing at the University of Utah is gratefully acknowledged.

which mainly affords poly(COE) 4 in preference to the desired ethenolysis product 2 (12% selectivity), Ru-20 showed no detectable ROMP activity in the absence of ethylene. This remarkable activity and selectivity of Ru-20 in ethenolysis was thus exploited for functionalized norbornenes allowing the preparation of highly valuable 1,3-divinylcyclopentanes in synthetically useful yields, typically exceeding 70%. Through the utilization of univariate and multivariate linear regression analysis, we identified the 77Se NMR chemical shift δiso and more precisely the σyy component of the shielding tensor of selenium in [Se(NHC)] derivatives, as well as the percent buried volume %Vbur as electronic and steric descriptors of NHC ligands, respectively, for the selective ethenolysis to cyclic dienes. The major role in controlling the selectivity can thereby be mostly ascribed to the electronic accepting property of the NHC ligand according to NCS analysis of the chemical shift tensor of the corresponding [Se(NHC)] derivatives. This π-acceptor ability appears to be the key driver for increasing the relative rate of degenerate metathesis as well as the ethenolysis selectivity toward dienes vs ROMP. This enhanced π-accepting character of N-CF3 NHCs presumably increases the rotation barrier around the Ru−CNHC bond thereby increasing the configurational stability of diastereomeric methylidene species present due to the dissymmetry of the NHC ligand. The latter is likely vital for selective metathesis reactions under conditions of diastereomeric site control of selectivity. Our groups are currently investigating the wider generality of this concept for catalyst design.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b06947. Full experimental and computational details and catalytic data (PDF)

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REFERENCES

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AUTHOR INFORMATION

Corresponding Authors

*[email protected] *[email protected] *[email protected] *[email protected] ORCID

Christopher P. Gordon: 0000-0002-2199-8995 Wei-Chih Liao: 0000-0002-4656-6291 Alexey Fedorov: 0000-0001-9814-6726 Christophe Copéret: 0000-0001-9660-3890 Matthew S. Sigman: 0000-0002-5746-8830 Antonio Togni: 0000-0003-3868-1799 Author Contributions

The synthetic part of the work was carried out by P.S.E.; C.B.S. carried out the multivariate analyses; C.P.G. and W.C.L. carried out the solid-state NMR and NCS analysis; A.F., C.C., M.S.S. and A.T. supervised the project. All authors contributed to the writing of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are grateful to the Scientific Equipment Program of ETH Zürich and the SNSF (R’Equip grant 206021_150709/ 13124


Article

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Exploiting and Understanding the Selectivity of Ru-N-Heterocyclic

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