Designing Sequence Selectivity into a Ring-Opening Metathesis

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Designing Sequence Selectivity into a Ring-Opening Metathesis Polymerization Catalyst Published as part of the Accounts of Chemical Research special issue “Computational Catalysis for Organic Synthesis”. Peter Chen* Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 2, CH-8093 Zürich, Switzerland CONSPECTUS: The development of a chemoselective catalyst for the sequence-selective copolymerization of two cycloolefins by ring-opening metathesis polymerization is described, starting with the mechanistic work that established the structure of the key metallacyclobutane intermediate. Experimental and computational investigations converged to a conclusion that the lowest energy metallacyclobutane intermediate in the ruthenium carbene-catalyzed metathesis reaction had the four-membered ring trans to the phosphine or NHC ligand. The trans-metallacyclobutane structure, for the case of a degenerate metathesis reaction catalyzed by a Grubbs first-generation complex, necessitated a rotation of the 3-fold symmetric tricyclohexylphosphine ligand, with respect to the 2-fold symmetric metallacyclobutane substructure. The degeneracy could be lifted by constraining the rotation. Lifting the degeneracy created the possibility of chemoselectivity. This mechanistic work led to a concept for the “tick-tock” catalyst for a chemoselective, alternating copolymerization of cyclooctene and norbornene from a mixture of the two monomers. The design concept could be post facto elaborated in terms of stereochemistry and topological theory, both viewpoints providing deeper insight into the design of selectivity into the catalytic reaction. The iterative interaction of theory and experiment provided the basis for the rational design and optimization of a new selectivity into an existing catalytic system with decidedly modest structural modifications of the original carbene complex.

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INTRODUCTION The history of catalysis is more a chronicle of discovery than one of design, with the archetypical story of the Haber−Bosch catalyst being representative. In the period between 1909 and 1912, Dr. Alwin Mittasch and co-workers screened 2500 formulations in 6500 experiments to find an optimized catalyst for the Haber−Bosch ammonia synthesis.1 Whereas technological improvements since then have made the screening process faster and more efficient,2 the fundamental issue remains that catalysts are most typically found rather than designed. This issue of Accounts of Chemical Research is devoted to the application of theory to molecular design in homogeneous catalysis. In this Account, we take one particular case, the engineering of chemoselectivity into a catalyst for sequenceselective ring-opening metathesis polymerization (ROMP), to illustrate the productive interaction of theory with design at several levels of sophistication. Theory can be understood to mean many things. We take a deliberately broad view of theory, encompassing explicitly computational methods, as well as structural and topological approaches. We consider also non-numerical methods, with the argument that computation delivers numbers, but the numbers alone become relevant only within a conceptual framework, © XXXX American Chemical Society

which itself is not numerical. Accordingly, the structural and topological approaches must be seen as integral to any consideration of theory in catalysis. In this Account, conceptual models of increasing sophistication will be treated. Roughly, the same catalyst design will be considered from the point-of-view of the “tick-tock” catalyst, diastereomeric site control of selectivity, and topological analysis.

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MECHANISTIC AND THEORETICAL BACKGROUND Subsequent to the discovery of the homogeneous olefin metathesis reaction by researchers at Goodyear Tire & Rubber Company,3 there were a number of mechanistic proposals. The key observation, a double-labeling experiment, solidified the mechanism proposed by Chauvin,4 which calls for transition metal carbene complexes and metallacyclobutane intermediates in the catalytic cycle. The preparation of well-characterized carbene complexes and their application as catalysts in olefin metathesis were honored by the Nobel Prize in 2005.5 Whereas the basic features of the Chauvin mechanism are well-established, the details for any given structural class of Received: February 16, 2016

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DOI: 10.1021/acs.accounts.6b00085 Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Accounts of Chemical Research

Scheme 1. Original Proposal for the Mechanism of Olefin Metathesis Catalyzed by Ruthenium Carbenes by Way of a cisMetallacyclobutane Intermediate7

catalysts presented a further challenge. For the class of discrete, isolable ruthenium carbene complexes commonly known as Grubbs first- and second-generation (G1 and G2) catalysts, there were multiple, possible diastereomeric carbene complexes and, more importantly, multiple, diastereomeric metallacyclobutanes.6 For the carbene complexes themselves, structures could be determined by X-ray crystallography, which eventually removed any ambiguity as to their stereochemistry. For the metallacyclobutanes, though, it was more difficult. For example, the putative parent metallacyclobutane, produced by what would be a degenerate cross-metathesis if a ruthenium methylidene were to react with ethylene, could have the metallacyclobutane ring situated either cis or trans to the supporting phosphine (1st generation, G1) or N-heterocyclic carbene (2nd generation, G2) ligand. The original mechanism proposed by Grubbs, shown in Scheme 1, made the eminently reasonable proposal that the metallacyclobutane should be cis, based on arguments of least motion and microscopic reversibility, although, admittedly, the primary concern of that work was the distinction between associative and dissociative mechanisms.7 The proposed structures, with the cis-metallacyclobutane (key for the present discussion), persisted for some years, for example, in an ab initio molecular dynamics study,8 as well as in other places.9,10 Two lines of work converged to present an opportunity for design of new selectivity into Ru metathesis catalysts, although that connection was not envisioned at the time. Purely as mechanistic investigations, both theory and experiment pointed to trans-metallacyclobutanes as the key intermediate in the metathesis reaction catalyzed by the G1 and G2 catalysts. A number of groups had begun computational studies of the intermediates in the Chauvin mechanism, as they would apply to the G1 and G2 catalysts. Prior to 2000, a single DFT study, interestingly coupled with Car−Parrinello ab initio molecular dynamics to simulate solvation effects, was undertaken.8 Early studies by Chen,10 Cavallo,11 Straub,12 and Thiel13 were instructive, with a highlight being the identification of the 14electron carbene intermediate, that is, a dissociative mechanism in which a phosphine ligand departs prior to coordination of olefin and formation of the metallacyclobutane, a conclusion that was supported experimentally by Grubbs14 and by Chen.9,10,15 In all of the early computational studies, however, the phosphine ligands, especially tricyclohexylphosphine, were truncated, in the extreme to PH3, to reduce the size of the calculation.16 Moreover, DFT was typically employed, despite the absence of validation of the adequacy of any of this class of methods for the problem at hand.17 There was simply no better choice. In 2004, Adlhart reported a comprehensive QM/MM computational study of the G1 and G2 catalysts with the full ligand sphere, including consideration of, and a search through, the conformations in the coordinated tricyclohexylphosphine.6,18 An exhaustive search for possible metallacyclobutane structures and transition states connecting them was done, as shown in Scheme 2. Among the conclusions19 was a prediction

Scheme 2. Possible Trigonal Bipyramidal and Square Pyramidal Structures for the Metallacyclobutane and Their Interconversions18

that the kinetically and thermodynamically favorable metathesis pathway proceeded via the trans-metallacyclobutane in both G1 and G2 catalysts. Furthermore, interconversion between the trans- and cis-metallacyclobutanes was ruled out. The most recent computational study, in 2014, reconfirms the preference for the trans-metallacyclobutane.20 In 1997, Snapper reported an X-ray structure of a Ru carbene complex, related to the G1 catalysts, in which a tethered olefin was bound trans to the tricyclohexylphosphine ligand.21 The tethered olefin was designed to stop at the intermediate stage, not being able to proceed to product, and despite its odd, strained structure, the result called the previously assumed cismetallacyclobutane structures into question. More compellingly, Piers reported a novel preparation of the metallacyclobutane derived from a G2 catalyst, whose low-temperature NMR spectrum was consistent only with a transmetallacyclobutane.22 The latter experiment was confirmed and extended by Wenzel,23 who also found that the 2 + 2 cycloreversion of the metallacyclobutane was fast and reversible, even at −95 °C. The structures are shown in Scheme 3. It should be noted that cis-metallacyclobutanes have been indicated for some cases, especially when there is a chelating ligand, for example, a catecholate,24 in place of the two chlorides, but these special structures do not change the more general result favoring the trans isomer for the “ordinary” G1 and G2 catalysts. A further significant computational result was the finding that the hypothetical degenerate metathesis reaction of a Ru carbene B


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Scheme 3. Structurally Characterized Olefin π-Complexes and Metallacyclobutanes Derived from G1 and G2 Catalysts21−23

Scheme 4. Simplified Representation of a Degenerate Cross-Metathesis, Shown As a Newman-Like Projection, Sighting along the Ru−P Bond, Starting and Ending with a 14-Electron G1 Catalyst, and Showing the Rotation of the Tricyclohexylphosphine Ligand at the trans-Metallacyclobutane Stage25

monomers. While the biological functions of the copolymers do depend on the substituents, it is the control of higher-order structure via the primary sequence of the copolymer that gives the biopolymer unique properties. In polyolefins, sequence control in the polymerization reaction is not the usual case, although enantiomorphic site control does show that control of polymer microstructure by the catalyst (in a homopolymerization) is possible.27 Sequence control in two copolymers, Carilon, a 1:1 alternating copolymer of ethylene and CO from Shell,28 and the polycarbonates produced as copolymers of epoxides and CO2,29 has been demonstrated, but a catalystcontrolled (as opposed to the growing chain end control in some radical polymerizations30) alternating copolymerization of two chemically similar monomers had not been shown. We judged a chemoselective, for example, alternating, ROMP reaction to be a sufficiently ambitious design target. After an initial publication of a slightly modified G1 catalyst that produced substantially alternating copolymers of cyclooctene and norbornene,31 the Chen group published improved versions leading to a catalyst with essentially complete chemoselectivity, as judged by 13C NMR of the obtained polymer.32 A number of subsequent reports by Buchmeiser and Blechert produced similar results with G2 frameworks.33 While the copolymer has no particularly special properties derived from the sequence-controlled copolymerization, the concept of sequence-selective copolymerization can be generalized, in principle, to build more complicated polymers from functionalized monomers. Such a generalization to ester- and ethersubstituted cycloalkene monomers has indeed been reported recently by Sampson.34 The simplest rationale for the catalyst design relied on theory to the extent that the computational study had identified the trans-metallacyclobutane, as well as the importance of ligand rotation in a degenerate metathesis reaction. Given the latter, the question arose as to what would happen if the monodentate tricyclohexylphosphine and one of the two chlorides in a firstgeneration catalyst were replaced with a P,O bidentate ligand, especially for the case where the remaining two substituents on

with an olefin proceeded with rotation of the tricyclohexylphosphine ligand in the metallacyclobutane intermediate.25 While Scheme 4, in which the complex is depicted in a Newman-like projection, shows that the ligand must rotate at some point during the reaction, the computational study found that the most favorable place was at the metallacyclobutane structure. A significant barrier for the rotation is perhaps not so surprising, tricyclohexylphosphine having a Tolman cone angle of 170°.26 Rotation of the ligand would mean that the large alkyl substituents must squeeze past the large chloride ligands. The transition state for the rotation of the tricyclohexylphosphine ligand on a trans-metallacyclobutane intermediate was found to lie on the reaction coordinate and, furthermore, to be the highest point or one of the highest points for the degenerate metathesis by a G1 catalyst. The computational study reconciled, in this case, the trans-metallacyclobutane with the microscopic reversibility argument,7 the latter becoming unproblematic because of an additional, kinetically relevant step, that is, the ligand rotation, in the mechanism. It also reconciled the computational results with the kinetic isotope effects observed for the forward and reverse reactions in the gas phase.10 What if the ligand were to be prevented from rotating? A conformationally fixed phosphine would mean that an otherwise degenerate metathesis would no longer be degenerate. Each turnover of the catalyst would switch the catalyst between two nonequivalent states. From this structural argument, which itself derived from a computational study of the potential surface for the metathesis reaction, we built a concept for a chemoselective catalyst that could assemble an alternating copolymer, meaning an ABABAB sequence, from a mixture of two monomers in one pot.

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DESIGNING CHEMOSELECTIVE COPOLYMERIZATION: SEQUENCE CONTROL FROM SEVERAL PERSPECTIVES Consider proteins, DNA, and even polysaccharides. These biopolymers are copolymers of fairly simply substituted C


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Scheme 5. Original Catalytic Cycle for the Alternating Ring-Opening Metathesis Copolymerization of a Strained and an Unstrained Cyclic Olefin31

eliminated an undesired C−H agostic interaction by the remaining tricyclohexylphosphine that produced an unexpected X-ray structure and lowered selectivity in the polymerization. The same P,O-chelating ligand but with two tert-butyl substituents on phosphorus rather than one phenyl and one tertiary alkyl gave no alternating copolymerization at all, the catalyst homopolymerizing norbornene instead. The unsymmetrical substitution, giving alternately two different active sites, unambiguously causes the chemoselective copolymerization. A more abstract treatment of the fruitful design concept of the tick-tock catalyst looks at the catalyst from the point-ofview of stereochemistry. Considering the tetracoordinate 14electron carbene complex derived from the Grubbs firstgeneration catalyst, one sees immediately that it is achiral, at least to the extent that the carbene moiety can itself rotate. Replacing one of the chlorides with the phenolic oxygen of a P,O bidentate ligand makes the Ru center stereogenic. Making the two remaining substituents on the phosphine different renders the phosphine furthermore P-stereogenic. Structural theory teaches us that a molecule with two stereogenic centers can occur as two diastereomeric pairs of enantiomers. Furthermore, whereas the reactivity of enantiomers with respect to achiral substrates should be identical, there is no reason that diastereomers should show the same reactivity. Differential reactivity by diastereomeric carbene complexes has been examined very recently as a basis for reactivity and selectivity in metathesis, in general.35 In the present chemoselective, alternating copolymerization, the stereochemical point-of-view gives a unique insight. The Chauvin mechanism via a trans-metallacyclobutane means that the Ru center inverts its absolute configuration with each turnover of the catalyst. The phosphine remains, however, unchanged, meaning that each turnover converts one diastereomer of the active 14-electron carbene complex into the other diastereomer. Whereas the stereochemical point-ofview does not give a specific prediction as to what the selectivity will be, it does indicate that an alternating 1:1 copolymer should be accessible. This point-of-view highlights

the phosphine were sterically different. For an ordinary crossmetathesis reaction with a first- or second-generation catalyst, the intermediate metallacyclobutane cleaves to form a Ru carbene and an olefin, with the preference for the forward or reverse direction along the reaction coordinate being small, cross-metathesis of unstrained, acyclic olefins having been shown to produce equilibrium mixtures of olefins because of the reversibility of the reaction. For the cleavage of the metallacyclobutane derived from the modified catalyst with the P,O bidentate ligand, the two directions are no longer equivalent. Cleavage in one direction places the nascent carbene moiety near a phenyl substituent, while cleavage in the other direction swings the carbene into a position near to a tert-butyl group. The latter is sterically disfavored, so the metathesis reaction should proceed preferentially to put the carbene on the side of the phenyl group. In practical terms, this means that that the modified complex with the carbene on the sterically less encumbered side should not make a homopolymer from any cyclic olefin, as was in fact demonstrated for cyclooctene. The sterically less encumbered Ru carbene should, however, still ring-open strained cycloolefins, the release of ring strain paying the price for putting the carbene on the sterically more encumbered side. These considerations led to the proposal of the catalytic cycle shown in Scheme 5. The catalyst with the carbene on the phenyl side, in a mixture of cyclooctene and norbornene, ring-opens norbornene selectively because of its ring strain. The resulting complex with the carbene on the tert-butyl side then ring-opens cyclooctene preferentially because it is available in large molar excess of cyclooctene over norbornene. Turnover in the proposed catalytic cycle (going around the cycle clockwise in Scheme 5) would produce a 1:1 alternating copolymer of the two cycloolefins. Because the carbene swings from one side to the other in a manner reminiscent of a pendulum, the catalyst was called a “tick-tock catalyst”. The initially achieved degree of alternation, approximately 60% according to 13C NMR,31 could be improved to nearly 100% by adjustment of the steric bulk of the substituents.32 Moreover, replacement of the Grubbs firstgeneration framework with a Grubbs−Hoveyda variant D


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Accounts of Chemical Research an analogy to the well-established mechanism for stereoselective polymerization of propylene by C2- or Cs-symmetric metallocenes.27 At each turnover, there is a stereochemical inversion at the metal center, which leads to enantiomorphic site control to form either isotactic or syndiotactic polypropylene, depending on the symmetry of the ligands on the metallocene. A similar mechanism, also identified as enantiomorphic site control, occurs in the stereoselective ring-opening polymerization of propylene oxide by certain multinuclear zinc alkoxide complexes, as reported by Tsuruta.36 In analogy, therefore, one can designate the chemoselective, alternating ring-opening metathesis copolymerization of two cycloolefins with the ticktock catalyst to occur with diastereomeric site control. Computational chemistry can also contribute a semiquantitative prediction of selectivity via the relative stability of the two diastereomers. In principle, one should calculate the entire potential surface, but the energy difference between two equilibrium structures is already sufficiently diagnostic to guide catalyst design. In this way, the best selectivity, with the two variable substituents on the phosphine being phenyl and 1,1,2,2-tetramethylpropyl was ascertained.32 Synthesis and characterization of that catalyst and testing in the ROMP of cyclooctene and norbornene produced the above-mentioned nearly 100% alternating copolymer (to within the detection limits of 13C NMR) at room temperature and a decidedly modest molar excess, 20:1 of cyclooctene over norbornene. One should mention Buchmeiser and Blechert’s G2-based systems with unsymmetrical substituents on the N-heterocyclic carbene supporting ligand also produced alternating copolymers of norbornene and cyclooctene.33 If one takes again the analogy to the stereocontrolled homopolymerization of propylene again, then the mechanism proposed for the G2based systems more closely resembles a chain-end control mechanism rather than a diastereomeric site control that was established for the Chen group G1 cases. One should note that the G2-based system could also function by diastereomeric site control if the rotation of the unsymmetrically substituted Nheterocyclic carbene ligand were to be slow relative to the metathesis reaction itself. Buchmeiser and Blechert measured the rotation rate by peak coalescence in variable temperature NMR and established, for the precatalyst, that it is fast.33 They comment, however, that their experiment does not prove that the rotation is equally fast at the metallacyclobutane structure. One should note in this particular context that the comparable variable temperature NMR experiment from Wenzel found that the 2 + 2 cycloreversion of the G2 metallacyclobutane is, in fact, fast and reversible and, in particular, faster than rotation of the N-heterocyclic carbene ligand.23 Lastly, a structurally and electronically analogous G2 active species, and therefore an analogous metallacyclobutane, is presumably formed in the reported alternating copolymerization of norbornene and cyclooctene by a G2 catalyst with a tethered, chelating Nheterocyclic carbene ligand,37 for which chemoselectivity was admittedly modest. The ligand cannot rotate in the tethered case, so the mechanism for that particular G2 system is more likely the diastereomeric site control, growing chain end control with ligand rotation being ruled out for the chelating ligand. As a contrast, one should note that alternating ROMP without an unsymmetrically substituted ligand on ruthenium has been reported for a mixture of two olefinic monomers that are electronically very different.38 The chemoselectivity in this instance can only come from chain-end control. Lastly, a very recent example of alternating ROMP, again with electronically

dissimilar olefinic monomers, has been reported with a Mo carbene.39 The mechanism of chemoselectivity is proposed to arise from syn- and anti-configured carbenes, the steric interaction with a bulky imido ligand, and ring strain, which cannot be classified cleanly as either diastereomeric site control or growing chain-end control, the mechanism having elements of both, although the switching between diastereomeric active species with each turnover has been used to achieve stereoselective ROMP with related Mo carbenes.40 Having regarded the chemoselectivity from the simple “ticktock” point-of-view and then generalizing it as a case of diastereometric site control, one can proceed further with another theoretical analysis pertinent to the catalyst design, that is, the role of topological considerations. It is perhaps obvious in hindsight, but one must consider that chemoselectivity in the case of the Ru-catalyzed ROMP requires that a pentacoordinate intermediate, the metallacyclobutane, maintain its configurational integrity over the time scale of the reaction. If the metallacyclobutane itself were to isomerize rapidly, then neither the tick-tock mechanism, in particular, nor diasteromeric site control, in general, should give alternation in the copolymerization. The problem that fluxionality poses for stereoselectivity in reactions proceeding via pentacoordinate intermediates was already identified explicitly by Muetterties.41 His early work, as well as that by Westheimer and co-workers,42 gave rise to the general argument that the small energy difference between trigonal bipyramidal and square pyramidal structures should make intramolecular stereomutation fast for pentavalent phosphorus compounds, for example, by a Berry pseudorotation.43 Experimental confirmation followed for other pentacoordinate main group compounds44 and, importantly, for important classes of transition metal complexes.45 Facile stereomutation was reported for monocyclic and even spirocyclic systems.46 Muetterties moreover presented a systematic classification of multiple mechanisms for intramolecular stereomutation of pentacoordinate compounds,47 the first two of five theoretically possible mechanisms being Berry pseudorotation43 and the Ugi turnstile mechanism.48 Simultaneous recognition by Prelog49 and by Mislow50 that vertices of a topological object, the Desargues−Levi graph,51 corresponded one-to-one with the 20 unique stereoisomers of a general pentacoordinate molecule provided for systematic designations, that is, naming, for those stereoisomers.52 Moreover, each of the edges in a Desargues−Levi graph maps onto a Berry pseudorotation, which would interconvert the stereoisomers corresponding to the vertices connected by that edge. The system remained, however, merely a formal map because the Berry pseudorotation was understood to be only one of five possible mechanisms for stereomutation. Theory makes a decisive contribution at this point. In a key computational study by Couzijn et al.,53 all five stereomutation mechanisms, including the Ugi turnstile mechanism, could be shown to be comprised of sequential Berry pseudorotations. The key recognition was a representation of the atomic motions for each of the stereomutation mechanisms in terms of a set of internal coordinates, which separated intramolecular distortions from rotation of the molecule as a whole in a manner reminiscent of the separation of internal degrees of freedom from overall rotation by the Eckhart equations in molecular spectroscopy.54 The consequence for the topological representation of the stereomutation reactions by a Desargues− Levi graph cannot be underestimated.55 If all stereomutation E


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Scheme 6. Desargues−Levi Graph with the Designations of the 20 Isomeric Trigonal Bipyramids Connected by Berry Pseudorotations, Showing the trans-Metallacyclobutane 13 and the Reduction to the Geometrically Possible Isomeric Structures Taking into Account That a Bidentate Ligand Cannot Span Axial Positions

equatorial positions, based on observed structures and simple molecular orbital arguments.59 Accordingly, one sees that the gateway structures 25 and 42 should be high-energy isomers of the trans-metallacyclobutane 13. If one were to perform explicit quantum chemical calculations, one would need to compute the relative energy of the single, additional (gateway) structure, beyond that of the original trans-metallacyclobutane, to decide whether or not there is kinetically significant fluxionality. The same conclusion could be read from Scheme 2, but the search for plausible reaction pathways in that case proceeded by brute force. The topological approach substantially reduces the scale of the numerical calculations that must be done to achieve certainty of stereochemical integrity. Given that any other (possibly) low energy stereoisomers can only be accessed via a high-energy intermediate, topological theory, combined with a defined and modest computational effort, establishes that the key pentacoordinate intermediate in the chemoselective, alternating ROMP is indeed configurationally stable, in contrast to the usual argument that pentacoordinate complexes are fluxional. Although this conclusion postdates the design of this particular catalyst, one can easily see how the application of topological concepts could provide for a rigorous way to limit the number of quantum chemical calculations required a priori in the process by which a selective catalyst would be designed.

mechanisms in a trigonal bipyramid can be reduced to a series of sequential Berry pseudorotations, then the Desargues−Levi graph becomes an exhaustive and exclusive map of all possible reactions that interconvert stereoisomers in a pentacoordinate molecule. Previously, the topological object provided only a systematic method for naming the stereoisomers. With the realization that there are only Berry pseudorotations, it becomes the map of all possible reactions. In the specific application of the topological model to the case of the chemoselective, alternating ROMP reaction by our ruthenium complex, consider the metallacyclobutane intermediate. For the nomenclature, the five substituents are ranked according to Cahn−Ingold−Prelog priority (1 = highest, 5 = lowest). The stereoisomer is designated according to the priority of the ligands in the two axial positions of the trigonal bipyramid, with the three ligands in the equatorial positions ordered in the clockwise direction, when viewed from the direction of the highest priority axial ligand, as shown in Scheme 6. As a spirocyclic, pentacoordinate complex, the transmetallacyclobutane, designated as stereoisomer 13, can still undergo stereomutation reactions, in principle. However, many of the potential stereoisomers, even if they are energetically low-lying, can be predicted to be inaccessible kinetically. The two atoms directly bound to the ruthenium in bidentate ligands, that is, the chelating P,O ligand and the four-membered ring of the metallacyclobutane itself, cannot occupy sites trans to each other, which can be represented on the Desargues−Levi graph by removing the vertices corresponding to stereoisomers 23, 32, 45, and 54, as shown in Scheme 6. Necessarily, one also removes all of the edges connected to vertices that are removed. The reduced subgraph is a map of all theoretically remaining stereomutation reactions of the metallacyclobutane intermediate. Concretely, starting with the initially formed trans-metallacyclobutane, stereoisomer 13, an examination of the subgraph indicates that all possible stereomutations must proceed via isomers 25 and 42, which, upon closer examination, represent the same structure as long as there are no substituents on the metallacyclobutane ring. Expanding on earlier concepts like apicophilicity (developed for pentacoordinate main group structures),56−58 qualitative arguments applied specifically to the d4 metallacyclobutane structures predict a preference of electronegative ligands (Cl or O, in the present case) in apical, and π-acceptor or sterically bulky ligands (the phosphine) in

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CONCLUSION The process by which a chemoselective ROMP catalyst was designed, with an omnipresent interaction with theory at many levels, spanned more than a decade. Importantly, the chronology emphasizes that the process is iterative, in that there is no algorithm for even the more modest goal of designing chemoselectivity into an existing catalyst, much less designing catalytic activity de novo using theory alone. This is the state-of-the-art. It is furthermore important to see that theory means much more than numerical computations. Computers and programs spit out numbers, but the conceptual framework, in which the numbers are meaningful at all, is given by structural theory and, in this case, even topological theory, areas where there are still no algorithmic approaches. Nevertheless, the end-result speaks for itself. The computational studies arguably stimulated the more detailed examination of experimental work that produced the structural models that were further elaborated synthetically and theoretically. The F


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Metathesis Reactions (Nobel Lecture). Angew. Chem., Int. Ed. 2006, 45, 3748−3759. (6) (a) Adlhart, C.; Chen, P. Mechanism and Activity of Ruthenium Olefin Metathesis Catalysts: The Role of Ligands and Substrates from a Theoretical Perspective. J. Am. Chem. Soc. 2004, 126, 3496−3510. (b) Adlhart, C.; Chen, P. Intrinsic Reactivity of Ruthenium Carbenes. In Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH, Weinheim, Germany, 2003; Vol. 1, pp 132−172. (7) Dias, E. L.; Nguyen, S. T.; Grubbs, R. H. Well-Defined Ruthenium Olefin Metathesis Catalysts: Mechanism and Activity. J. Am. Chem. Soc. 1997, 119, 3887−3897. (8) (a) Aagaard, O. M.; Meier, R. J.; Buda, F. Ruthenium-Catalyzed Olefin Metathesis: A Quantum Molecular Dynamics Study. J. Am. Chem. Soc. 1998, 120, 7174−7182. (b) Meier, R. J.; Aagaard, O. M.; Buda, F. First principles molecular dynamics applied to homogeneous catalysis: on ethylene insertion mechanism and metathesis. J. Mol. Catal. A: Chem. 2000, 160, 189−197. (9) Hinderling, C.; Adlhart, C.; Chen, P. Olefin Metathesis by a Ruthenium Carbene Complex by Electrospray Ionization in the Gas Phase. Angew. Chem., Int. Ed. 1998, 37, 2685−2689. (10) Adlhart, C.; Hinderling, C.; Baumann, H.; Chen, P. Mechanistic Studies of Olefin Metathesis by Ruthenium Carbene Complexes using Electrospray Ionization Tandem Mass Spectrometry. J. Am. Chem. Soc. 2000, 122, 8204−8214. (11) Cavallo, L. Mechanism of Ruthenium-Catalyzed Olefin Metathesis Reactions from a Theoretical Perspective. J. Am. Chem. Soc. 2002, 124, 8965−8973. (12) Straub, B. F. Origin of the High Activity of Second-Generation Grubbs Catalysts. Angew. Chem., Int. Ed. 2005, 44, 5974−5978. (13) Vyboishchikov, S. F.; Bühl, M.; Thiel, W. Mechanism of Olefin Metathesis with Catalysis by Ruthenium Carbene Complexes: Density Functional Studies on Model Systems. Chem. - Eur. J. 2002, 8, 3962− 3975. (14) (a) Sanford, M. S.; Ulman, M.; Grubbs, R. H. New Insights into the Mechanism of Ruthenium-Catalyzed Olefin Metathesis Reactions. J. Am. Chem. Soc. 2001, 123, 749−750. (b) Love, J. A.; Sanford, M. S.; Day, M. W.; Grubbs, R. H. Synthesis, Structure, and Activity of Enhanced Initiators for Olefin Metathesis. J. Am. Chem. Soc. 2003, 125, 10103−10109. (15) Torker, S.; Merki, D.; Chen, P. Gas-Phase Thermochemistry of Ruthenium Carbene Metathesis Catalysts. J. Am. Chem. Soc. 2008, 130, 4808−4814. (16) For example, the B3LYP/LANL2DZ calculation in ref 10 modeled PCy3 with PH3. (17) The first, quantitative one-to-one validation was reported by Truhlar in a comparison to gas-phase bond strengths. Zhao, Y.; Truhlar, D. G. Attractive Noncovalent Interactions in the Mechanism of Grubbs Second-Generation Ru Catalysts for Olefin Metathesis. Org. Lett. 2007, 9, 1967−1970. (18) Adlhart, C. A. Intrinsic Reactivity of Ruthenium Carbenes: A Combined Gas Phase and Computational Study. Dissertation No. 15073, ETH Zürich, 2003. (19) A further important conclusion was that the apparent inconsistency between the rate of phosphine dissociation (activation) and the overall catalyst activity could be explained by the degree of catalyst “commitment” in G1 (low commitment) vs G2 (high commitment). (20) Poater, A.; Correa, A.; Pump, E.; Cavallo, L. cis/trans Coordination in Olefin Metathesis by Static and Molecular Dynamic DFT Calculations. Chem. Heterocycl. Compd. 2014, 50, 389−395. (21) Tallarico, J. A.; Bonitatebus, P. J.; Snapper, M. L. Ring-Opening Metathesis. A Ruthenium Catalyst Caught in the Act. J. Am. Chem. Soc. 1997, 119, 7157−7158. (22) (a) Romero, P. E.; Piers, W. E. Direct Observation of a 14Electron Ruthenacyclobutane Relevant to Olefin Metathesis. J. Am. Chem. Soc. 2005, 127, 5032−5033. (b) Romero, P. E.; Piers, W. E. Mechanistic Studies on 14-Electron Ruthenacyclobutanes: Degenerate Exchange with Free Ethylene. J. Am. Chem. Soc. 2007, 129, 1698− 1704. (c) van der Eide, E. F.; Romero, P. E.; Piers, W. E. Generation

alternating copolymerization of two monomers in one pot could be designed into the catalyst with modifications to the ligands that can only be described as modest, which testifies to the fruitful interaction of theory and experiment in the design of new selectivity in a catalyst.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Funding

This work was generously supported by the ETH Zürich and the Schweizerischen Nationalfonds. Notes

The authors declare no competing financial interest. Biography Prof. Peter Chen, B.S. Chicago 1982, Ph.D. Yale 1987, was Assistant Professor (1988−1991) and Associate Professor (1991−1994) at Harvard University and Professor of Physical Organic Chemistry at the ETH Zürich since 1994. He was Vice President for Research and Corporate Relations at the ETH, 2007−2009. He was a member of the Research Council of the Swiss NSF, 2010−2015, and member of its Executive Board, 2012−2015. His research and teaching centers on reactive intermediates and reaction mechanisms, often using new physical methods, with a present focus on homogeneous catalysis. Among other mandates, he is a Director of Clariant Ltd., a leading specialty chemicals company. Of the numerous honors, Prof. Chen is most proud of the “Golden Owl” in 2005 and 2015, awarded for the best teaching in each department at the ETH.

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ACKNOWLEDGMENTS The author acknowledges the contributions of the all of the students, postdoctoral researchers, and scientific collaborators who contributed to the project over nearly two decades: Christian Hinderling, Christian Adlhart, Harold Baumann, Marc Bornand, Sebastian Torker, Daniel Merki, André Müller, Raphael Sigrist, Marija Jovic, Juan Manuel Sarria Toto, Erik Couzijn, Martin Volland, and Peter Hofmann.

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REFERENCES

(1) Ertl, G. Elementary Steps in Heterogeneous Catalysis. Angew. Chem., Int. Ed. Engl. 1990, 29, 1219−1227. (2) Schunk, S. A.; Böhmer, N.; Futter, C.; Kuschel, A.; Prasetyo, E.; Roussière, T. High throughput technology: approaches of research in homogeneous and heterogeneous catalysis. Catalysis 2013, 25, 172− 215. (3) (a) Calderon, N.; Chen, H. Y.; Scott, K. W. Olefin Metathesis − A Novel Reaction for Skeletal Transformations of Unsaturated Hydrocarbons. Tetrahedron Lett. 1967, 8, 3327−3329. (b) Calderon, N.; Ofstead, E. A.; Judy, W. A. Ring-Opening Polymerization of Unsaturated Alicyclic Compounds. J. Polym. Sci., Part A-1: Polym. Chem. 1967, 5, 2209−2217. (c) Calderon, N.; Ofstead, E. A.; Ward, J. P.; Judy, W. A.; Scott, K. W. Olefin Metathesis I. Acyclic Vinylenic Hydrocarbons. J. Am. Chem. Soc. 1968, 90, 4133−4140. (4) Hérisson, P. J.- L.; Chauvin, Y. Catalyse de transformation des oléfines par les complexes du tungstène. Makromol. Chem. 1971, 141, 161−176. (5) (a) Chauvin, Y. Olefin Metathesis: the Early Days (Nobel Lecture). Angew. Chem., Int. Ed. 2006, 45, 3740−3747. (b) Grubbs, R. H. Olefin Metathesis Catalysts for the Preparation of Molecules and Materials (Nobel Lecture). Angew. Chem., Int. Ed. 2006, 45, 3760− 3765. (c) Schrock, R. R. Multiple Metal-Carbon Bonds for Catalytic G


Article

Accounts of Chemical Research and Spectroscopic Characterization of Ruthenacyclobutane and Ruthenium Olefin Carbene Intermediates Relevant to Ring Closing Metathesis Catalysis. J. Am. Chem. Soc. 2008, 130, 4485−4491. (23) (a) Wenzel, A. G.; Grubbs, R. H. Ruthenium Metallacycles Derived from 14-Electron Complexes. New Insights into Olefin Metathesis Intermediates. J. Am. Chem. Soc. 2006, 128, 16048−16049. (b) Wenzel, A. G.; Blake, G.; VanderVelde, D. G.; Grubbs, R. H. Characterization and Dynamics of Substituted Ruthenacyclobutanes Relevant to the Olefin Cross-Metathesis Reaction. J. Am. Chem. Soc. 2011, 133, 6429−6439. (24) Khan, R. K. M.; Torker, S.; Hoveyda, A. H. Reactivity and Selectivity Differences between Catecholate and Catecholthiolate Ru Complexes. Implications Regarding Design of Stereoselective Olefin Metathesis Catalysts. J. Am. Chem. Soc. 2014, 136, 14337−14340. (25) Adlhart, C.; Chen, P. Ligand Rotation Distinguishes First- and Second-Generation Ruthenium Metathesis Catalysts. Angew. Chem., Int. Ed. 2002, 41, 4484−4487. (26) Tolman, C. A. Steric Effects of Phosphorus Ligands in Organometallic Chemistry and Homogeneous Catalysis. Chem. Rev. 1977, 77, 313−348. (27) (a) Corradini, P.; Guerra, G.; Cavallo, L.; Moscardi, G.; Vacatello, M. Models for the Explanation of the Stereospecific Behavior of Ziegler-Natta Catalysts. In Ziegler Catalysts; Fink, G.; Mülhaupt, R., Brintzinger, H.H., Eds.; Springer Verlag: Berlin, 1995; Chapter 13, pp 237−249. (b) Brintzinger, H. H.; Fischer, D.; Mülhaupt, R.; Rieger, B.; Waymouth, R. M. Stereospecific Olefin Polymerization with Chiral Metallocene Catalysts. Angew. Chem., Int. Ed. Engl. 1995, 34, 1143−1170. (c) Gómez, F. J.; Waymouth, R. M. Catalysts Rise to the Challenge. Science 2002, 295, 635−636. (28) Drent, E.; van Broekhoven, J. A. M.; Doyle, M. J. Efficient palladium catalysts for the copolymerization of carbon monoxide with olefins to produce perfectly alternating polyketones. J. Organomet. Chem. 1991, 417, 235−251. (29) (a) Darensbourg, D. J.; Holtcamp, M. W. Catalysts for the reactions of epoxides and carbon dioxide. Coord. Chem. Rev. 1996, 153, 155−174. (b) Darensbourg, D. J.; Yarbrough, J. C. Mechanistic Aspects of the Copolymerization Reaction of Carbon Dioxide and Epoxides, Using Chiral Salen Chromium Chloride Catalyst. J. Am. Chem. Soc. 2002, 124, 6335−6342. (30) Matyjaszewski, K.; Davis, T. P. Handbook of Radical Polymerization; Wiley-VCH: Weinheim, Germany, 2002. (31) Bornand, M.; Chen, P. Mechanism-Based Design of a ROMP Catalyst for Sequence-Selective Copolymerization. Angew. Chem., Int. Ed. 2005, 44, 7909−7911. (32) (a) Torker, S.; Müller, A.; Sigrist, R.; Chen, P. Tuning the Steric Properties of a Metathesis Catalyst for Copolymerization of Norbornene and Cyclooctene toward Complete Alternation. Organometallics 2010, 29, 2735−2751. (b) Torker, S.; Müller, A.; Chen, P. Building Stereoselectivity into a Chemoselective Ring-Opening Metathesis Polymerization Catalyst for Alternating Copolymerization. Angew. Chem., Int. Ed. 2010, 49, 3762−3766. (c) Jovic, M.; Torker, S.; Chen, P. Non-Innocent Character of Oxyanions in Ruthenium Metathesis Catalysts. Organometallics 2011, 30, 3971−3980. (33) Lichtenheldt, M.; Wang, D.; Vehlow, K.; Reinhardt, I.; Kühnel, C.; Decker, U.; Blechert, S.; Buchmeiser, M. R. Alternating RingOpening Metathesis Copolymerization by Grubbs-Type Initiators with Unsymmetrical N-Heterocyclic Carbenes. Chem. - Eur. J. 2009, 15, 9451−9457. (34) Song, A.; Parker, K. A.; Sampson, N. S. Synthesis of Copolymers by Alternating ROMP (AROMP). J. Am. Chem. Soc. 2009, 131, 3444− 3445. (35) Torker, S.; Khan, R. K. M.; Hoveyda, A. H. The Influence of Anionic Ligands on Stereoisomerism of Ru Carbenes and Their Importance to Efficiency and Selectivity of Catalytic Olefin Metathesis Reactions. J. Am. Chem. Soc. 2014, 136, 3439−3455. (36) (a) Hagiwara, T.; Ishimori, M.; Tsuruta, T. 13C NMR Study on the Mechanism of Stereoselective Polymerization of Methyloxirane Catalyzed by a Model Compound for Enantiomorphic Catalysts. Makromol. Chem. 1981, 182, 501−511. (b) Yoshino, N.; Suzuki, C.;

Kobayashi, H.; Tsuruta, T. Some features of a novel organozinc complex, [{MeOCH 2 CH(Me)OZnOCH(Me)CH 2 OMe} 2 • {EtZnOCH(Me)CH2OMe}2], as an enantiomorphic catalyst for stereoselective polymerization of propylene oxide. Makromol. Chem. 1988, 189, 1903−1913. (c) Hasebe, Y.; Tsuruta, T. Mechanism of stereoselective polymerization of propylene oxide with [{MeOCH2CH(Me)OZnOCH(Me)CH2OMe}2 • {EtZnOCH(Me)CH2OMe}2] as initiator. Makromol. Chem. 1988, 189, 1915−1926. (37) (a) Kong, Y.; Xu, S.; Song, H.; Wang, B. Synthesis, Structures, and Norbornene ROMP Behavior of o-Aryloxide-N-Heterocyclic Carbene p-Cymene Ruthenium Complexes. Organometallics 2012, 31, 5527−5532. (b) Kong, Y.; Tang, Y.; Wang, Z.; Xu, S.; Song, H.; Wang, B. Ruthenium Ring-Opening Metathesis Polymerization Catalysts Bearing o-Aryloxide-N-Heterocyclic Carbenes. Macromol. Chem. Phys. 2013, 214, 492−498. (38) Ilker, M. F.; Coughlin, E. B. Alternating Copolymerizations of Polar and Nonpolar Cyclic Olefins by Ring-Opening Metathesis Polymerization. Macromolecules 2002, 35, 54−58. (39) Jeong, H.; John, J. M.; Schrock, R. R.; Hoveyda, A. H. Synthesis of Alternating trans-AB Copolymers through Ring-Opening Polymerization Initiated by Molybdenum Alkylidenes. J. Am. Chem. Soc. 2015, 137, 2239−2242. (40) Schrock, R. R. Synthesis of Stereoregular Polymers through Ring-Opening Metathesis Polymerization. Acc. Chem. Res. 2014, 47, 2457−2466. (41) Muetterties, E. L.; Schunn, R. A. Pentacoordination. Q. Rev., Chem. Soc. 1966, 20, 245−299. (42) Westheimer, F. H. Pseudo-Rotation in the Hydrolysis of Phosphate Esters. Acc. Chem. Res. 1968, 1, 70−78. (43) Berry, R. S. Correlation of Rates of Intramolecular Tunneling Processes, with Applications to some Group V Compounds. J. Chem. Phys. 1960, 32, 933−938. (44) (a) Boyer, J.; Corriu, R. J. P.; Kpoton, A.; Mazhar, M.; Poirier, M.; Royo, G. Hydrogenosilanes: Pentacoordination and Pseudorotation. J. Organomet. Chem. 1986, 301, 131−135. (b) Kumara Swamy, K. C.; Satish Kumar, N. New Features in Pentacoordinate Phosphorus Chemistry. Acc. Chem. Res. 2006, 39, 324−333. (45) (a) Muetterties, E. L. Topological Representation of Stereoisomerism. II. The Five-Atom Family. J. Am. Chem. Soc. 1969, 91, 4115−4122. (b) Osborn, J. A.; Shapley, J. R. Rapid Intramolecular Rearrangements in Pentacoordinate Transition Metal Compounds. On the Rearrangement Mechanism of Some Fluxional Iridium(I) Complexes. J. Am. Chem. Soc. 1970, 92, 6976−6978. (c) Haake, P.; Pfeiffer, R. M. Ligand-Complex Interaction in Tetragonal Planar Complexes and the Mechanism of Catalyzed Isomerization. J. Am. Chem. Soc. 1970, 92, 4996−4997. (d) Darensbourg, D. J.; Dobson, G. R.; Moradi-Araghi, A. Evidence for the Fluxionality and Structure in Solution of Intermediates of the Type W(CO)4(L) (L = Lewis Base). J. Organomet. Chem. 1976, 116, C17−C20. (46) (a) Hellwinkel, D.; Lindner, W.; Schmidt, W. 1H-NMRUntersuchung mit sterisch überbesetzten asymmetrischen Phosphoranen, Arsoranen und Stiboranen. Chem. Ber. 1979, 112, 281−291. (b) Kojima, S.; Kajiyama, K.; Nakamoto, M.; Matsukawa, S.; Akiba, K. The Ligand-Exchange Process of P-Hapical Phosphoranes and the Thermal Formation and Pseudorotation of Anti-Apicophilic Spirophosphoranes. Eur. J. Org. Chem. 2006, 2006, 218−234. (47) (a) Muetterties, E. L. Topological Representation of Stereoisomerism. I. Polytopal Rearrangements. J. Am. Chem. Soc. 1969, 91, 1636−1643. (b) Meakin, P.; Muetterties, E. L.; Jesson, J. P. Intramolecular Rearrangement Mechanisms in Five-Coordinate Complexes. J. Am. Chem. Soc. 1972, 94, 5271−5285. (48) Ugi, I.; Marquarding, D.; Klusacek, H.; Gokel, G.; Gillespie, P. Chemistry and Logical Structures. Angew. Chem., Int. Ed. Engl. 1970, 9, 703−730. (49) Dunitz, J. D.; Prelog, V. Ligand Reorganization in the Trigonal Bipyramid. Angew. Chem., Int. Ed. Engl. 1968, 7, 725−726. (50) Mislow, K. Role of Pseudorotation in the Stereochemistry of Nucleophilic Displacement Reactions. Acc. Chem. Res. 1970, 3, 321− 331. H


Article

Accounts of Chemical Research (51) Randic, M. Symmetry Properties of Graphs of Interest in Chemistry. II. Desargues-Levi Graph. Int. J. Quantum Chem. 1979, 15, 663−682. (52) A similar systematic was described by Lauterbur, P. C.; Ramirez, F. Pseudorotation in Trigonal-Bipyramidal Molecules. J. Am. Chem. Soc. 1968, 90, 6722−6726. (53) Couzijn, E. P. A.; Slootweg, J. C.; Ehlers, A. W.; Lammertsma, K. Stereomutation of Pentavalent Compounds: Validating the Berry Pseudorotation, Redressing Ugi’s Turnstile Rotation, and Revealing the Two- and Three-Arm Turnstiles. J. Am. Chem. Soc. 2010, 132, 18127−18140. (54) Wilson, E. B.; Decius, J. C.; Cross, P. C. Molecular Vibrations: The Theory of Infrared and Raman Vibrational Spectra; McGraw-Hill: New York, 1955. (55) Moberg, C. Stereomutation in Trigonal-Bipyramidal Systems: A Unified Picture. Angew. Chem., Int. Ed. 2011, 50, 10290−10292. (56) Hoffmann, R.; Howell, J. M.; Muetterties, E. L. Molecular Orbital Theory of Pentacoordinate Phosphorus. J. Am. Chem. Soc. 1972, 94, 3047−3058. (57) Holmes, R. R. A Model for Calculating Conformational Energies in Pentacoordinate Phosphorus Compounds. J. Am. Chem. Soc. 1978, 100, 433−445. (58) McDowell, R. S.; Streitwieser, A. A Theoretical Study of Model Substituted Phosphoranes, PH4X: Apicophilicities, Geometries, and Electron Densities. J. Am. Chem. Soc. 1985, 107, 5849−5855. (59) Rossi, A. R.; Hoffmann, R. Transition Metal Pentacoordination. Inorg. Chem. 1975, 14, 365−374.

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Designing Sequence Selectivity into a Ring-Opening Metathesis

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