Macromolecules with programmable shape, size, and chemistry · Macromolecules with programmable...

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Macromolecules with programmable shape, size, and chemistry Dylan J. Walsh a and Damien Guironnet a,1 a Department of Chemical and Biomolecular Engineering, University of Illinois UrbanaChampaign, Urbana, IL 61801 Edited by David A. Weitz, Harvard University, Cambridge, MA, and approved December 17, 2018 (received for review October 15, 2018) Shape, size, and composition are the most fundamental design features, enabling highly complex functionalities. Despite recent advances, the independent control of shape, size, and chemistry of macromolecules remains a synthetic challenge. We report a scalable methodology to produce large, well-defined macromolecules with programmable shape, size, and chemistry that combines reactor engineering principles and controlled polymerizations. Specifically, bottlebrush polymers with conical, ellipsoidal, and concave architec- tures are synthesized using two orthogonal polymerizations. The chemical versatility is highlighted by the synthesis of a compositional asymmetric cone. The strong agreement between predictions and experiments validates the precision that this methodology offers. reactor engineering | polymer nanostructure | bottlebrush polymers T uning the shape, size, and chemical composition is a way to mediate the function of molecules to biological structures (1). An example eliciting this can be seen in the shape of viruses (e.g., conical shape of HIV-1 capsid or the bullet shape of a rabies-related virus), in which the virulence is dictated by the shape of the pathogen, or in antibodies where complementary antigen targets in specific locations are required for activity (14). Given the importance of controlling the function of materials, scientists have developed various synthetic strategies to control the shape, size, and chemistry of nanomaterials. Most notably, advancements in colloidal particle synthesis have enabled the tuning of physical, electrical, and chemical properties of inorganic nanomaterials by varying their shape, size, and composition (57). Today, these hard particles find diverse applications varying from quantum dots for portable displays to biological systems for im- aging, detecting, and treating diseases (1, 8). In soft materials the independent control of shape, size, and composition of macro- molecules remains nontrivial, which overall limits our ability to realize and mediate advanced functionalities (9). Dendrimers and hyperbranched polymers have been synthe- sized with some tunability (10, 11). Low-generation dendrons (5 nm) with variable shapes and chemistries have been syn- thesized, and modification of their composition was shown to provide unique control on their molecular assemblies (10, 12). High-generation dendrimers of variable size (up to 30 nm) and chemistry but fixed shape (spherical) have been intensely in- vestigated over the years in drug delivery, gene transfection, and imaging (13). Recently, cylindrical-shaped macromolecules with variable size (up to 1,000 nm) and chemistry have been accessed through the synthesis of high graft density branched polymers, called bottlebrush polymers (14, 15). The steric encumbrance of the densely packed brushes forces the polymer to adopt a semirigid 3D cylindrical conformation (1517). Sequenced graft- through polymerization of macromonomers with different lengths has been implemented to reach a limited number of blocky shapes (1821). The potential of these materials is highlighted by the wide range of available chemistries that have been applied to the synthesis and functionalization of bottlebrush polymers, which have translated into remarkable attributes for drug de- livery, biomimicry, photonic materials, and soft elastomers (15, 16, 22, 23). Here we present a methodology for the synthesis of bottlebrush polymers with programmable shape, size, and chemistry. Bottle- brush polymers with conical, ellipsoidal, and concave architectures (Fig. 1, Right) are synthesized with a size up to 300 nm using ring- opening polymerization (ROP) in tandem with ring-opening me- tathesis polymerization (ROMP) on gram scale. The essence of shape stems from varying the brush length along the polymer backbone, which is achieved by varying the rate of addition of the growing macromonomer solution into a graft-through polymeri- zation (semibatch setup, Fig. 1, Left). Beyond the control of shape and size, this approach is compatible with a variety of chemistries; as exemplified by the synthesis of a compositionally asymmetric cone containing both asymmetric shape and chemical contrast within a single macromolecule. Results and Discussion We envisioned that the shape and size of bottlebrush polymers could be programmed by implementing a computer-controlled semibatch reactor setup in conjunction with a graft-through polymerization (Fig. 1, Left). With this approach, the flowrate profile of the solution of growing macromonomer would directly translate into the shape of the bottlebrush polymer, i.e., each flowrate profile will result in a unique polymer shape. The re- actor setup consists of a syringe/syringe pump as the first reaction vessel, and a flask as the second vessel. In the first vessel, the macromonomers are synthesized via a controlled polymerization, while the solution is continuously fed into the second reaction vessel. The brush growth is immediately quenched upon addition to the second vessel, and the macromonomers are rapidly and quantitatively incorporated into the growing bottlebrush polymer via a graft-through polymerization. Over time, the length of the Significance Tuning shape, size, and chemical composition elicits a way to mediate function. In soft materials, the establishment of these structurefunction relationships has been hampered by the in- ability to independently control the shape, size, and composition of macromolecules. Here, we establish a synthetic methodology combining a computer-controlled process and two controlled polymerizations to yield macromolecules with any monotonic axisymmetric shape up to 300 nm in size. The methodology has a simple and scalable setup to yield gram quantities of macro- molecules from commercially available materials. This approach provides a unique material platform to study the impact of shape, size, and composition of macromolecules. Author contributions: D.J.W. and D.G. designed research; D.J.W. performed research; D.J.W. and D.G. analyzed data; and D.J.W. and D.G. wrote the paper. Conflict of interest statement: An invention disclosure related to this work has been filed: D.G. and D.J.W. filed a US Patent Application, January 2018. This article is a PNAS Direct Submission. Published under the PNAS license. 1 To whom correspondence should be addressed. Email: [email protected]. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. 1073/pnas.1817745116/-/DCSupplemental. Published online January 17, 2019. 15381542 | PNAS | January 29, 2019 | vol. 116 | no. 5 www.pnas.org/cgi/doi/10.1073/pnas.1817745116 Downloaded by guest on May 26, 2020

Transcript of Macromolecules with programmable shape, size, and chemistry · Macromolecules with programmable...

Page 1: Macromolecules with programmable shape, size, and chemistry · Macromolecules with programmable shape, size, and chemistry Dylan J. Walsha and Damien Guironneta,1 aDepartment of Chemical

Macromolecules with programmable shape, size,and chemistryDylan J. Walsha and Damien Guironneta,1

aDepartment of Chemical and Biomolecular Engineering, University of Illinois Urbana–Champaign, Urbana, IL 61801

Edited by David A. Weitz, Harvard University, Cambridge, MA, and approved December 17, 2018 (received for review October 15, 2018)

Shape, size, and composition are the most fundamental designfeatures, enabling highly complex functionalities. Despite recentadvances, the independent control of shape, size, and chemistry ofmacromolecules remains a synthetic challenge. We report a scalablemethodology to produce large, well-defined macromolecules withprogrammable shape, size, and chemistry that combines reactorengineering principles and controlled polymerizations. Specifically,bottlebrush polymers with conical, ellipsoidal, and concave architec-tures are synthesized using two orthogonal polymerizations. Thechemical versatility is highlighted by the synthesis of a compositionalasymmetric cone. The strong agreement between predictions andexperiments validates the precision that this methodology offers.

reactor engineering | polymer nanostructure | bottlebrush polymers

Tuning the shape, size, and chemical composition is a way tomediate the function of molecules to biological structures

(1). An example eliciting this can be seen in the shape of viruses(e.g., conical shape of HIV-1 capsid or the bullet shape of arabies-related virus), in which the virulence is dictated by theshape of the pathogen, or in antibodies where complementaryantigen targets in specific locations are required for activity (1–4). Given the importance of controlling the function of materials,scientists have developed various synthetic strategies to controlthe shape, size, and chemistry of nanomaterials. Most notably,advancements in colloidal particle synthesis have enabled thetuning of physical, electrical, and chemical properties of inorganicnanomaterials by varying their shape, size, and composition (5–7).Today, these hard particles find diverse applications varying fromquantum dots for portable displays to biological systems for im-aging, detecting, and treating diseases (1, 8). In soft materials theindependent control of shape, size, and composition of macro-molecules remains nontrivial, which overall limits our ability torealize and mediate advanced functionalities (9).Dendrimers and hyperbranched polymers have been synthe-

sized with some tunability (10, 11). Low-generation dendrons(∼5 nm) with variable shapes and chemistries have been syn-thesized, and modification of their composition was shown toprovide unique control on their molecular assemblies (10, 12).High-generation dendrimers of variable size (up to 30 nm) andchemistry but fixed shape (spherical) have been intensely in-vestigated over the years in drug delivery, gene transfection, andimaging (13). Recently, cylindrical-shaped macromolecules withvariable size (up to 1,000 nm) and chemistry have been accessedthrough the synthesis of high graft density branched polymers,called bottlebrush polymers (14, 15). The steric encumbranceof the densely packed brushes forces the polymer to adopt asemirigid 3D cylindrical conformation (15–17). Sequenced graft-through polymerization of macromonomers with different lengthshas been implemented to reach a limited number of blocky shapes(18–21). The potential of these materials is highlighted by thewide range of available chemistries that have been applied tothe synthesis and functionalization of bottlebrush polymers,which have translated into remarkable attributes for drug de-livery, biomimicry, photonic materials, and soft elastomers (15,16, 22, 23).

Here we present a methodology for the synthesis of bottlebrushpolymers with programmable shape, size, and chemistry. Bottle-brush polymers with conical, ellipsoidal, and concave architectures(Fig. 1, Right) are synthesized with a size up to 300 nm using ring-opening polymerization (ROP) in tandem with ring-opening me-tathesis polymerization (ROMP) on gram scale. The essence ofshape stems from varying the brush length along the polymerbackbone, which is achieved by varying the rate of addition of thegrowing macromonomer solution into a graft-through polymeri-zation (semibatch setup, Fig. 1, Left). Beyond the control of shapeand size, this approach is compatible with a variety of chemistries;as exemplified by the synthesis of a compositionally asymmetriccone containing both asymmetric shape and chemical contrastwithin a single macromolecule.

Results and DiscussionWe envisioned that the shape and size of bottlebrush polymerscould be programmed by implementing a computer-controlledsemibatch reactor setup in conjunction with a graft-throughpolymerization (Fig. 1, Left). With this approach, the flowrateprofile of the solution of growing macromonomer would directlytranslate into the shape of the bottlebrush polymer, i.e., eachflowrate profile will result in a unique polymer shape. The re-actor setup consists of a syringe/syringe pump as the first reactionvessel, and a flask as the second vessel. In the first vessel, themacromonomers are synthesized via a controlled polymerization,while the solution is continuously fed into the second reactionvessel. The brush growth is immediately quenched upon additionto the second vessel, and the macromonomers are rapidly andquantitatively incorporated into the growing bottlebrush polymervia a graft-through polymerization. Over time, the length of the

Significance

Tuning shape, size, and chemical composition elicits a way tomediate function. In soft materials, the establishment of thesestructure–function relationships has been hampered by the in-ability to independently control the shape, size, and compositionof macromolecules. Here, we establish a synthetic methodologycombining a computer-controlled process and two controlledpolymerizations to yield macromolecules with any monotonicaxisymmetric shape up to 300 nm in size. The methodology has asimple and scalable setup to yield gram quantities of macro-molecules from commercially available materials. This approachprovides a unique material platform to study the impact ofshape, size, and composition of macromolecules.

Author contributions: D.J.W. and D.G. designed research; D.J.W. performed research;D.J.W. and D.G. analyzed data; and D.J.W. and D.G. wrote the paper.

Conflict of interest statement: An invention disclosure related to this work has been filed:D.G. and D.J.W. filed a US Patent Application, January 2018.

This article is a PNAS Direct Submission.

Published under the PNAS license.1To whom correspondence should be addressed. Email: [email protected].

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1817745116/-/DCSupplemental.

Published online January 17, 2019.

1538–1542 | PNAS | January 29, 2019 | vol. 116 | no. 5 www.pnas.org/cgi/doi/10.1073/pnas.1817745116

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macromonomer increases in the first vessel, and the processresults in a shaped bottlebrush polymer in the second vessel.To implement the proposed shape-controlled synthesis, a few

polymerizations selection criteria are considered. First, the twopolymerizations should be fully compatible and orthogonal. Sec-ond, the macromonomer synthesis should be quenched readily inthe second vessel. Third, the graft-through polymerization shouldhave a very high rate of polymerization to prevent the accumu-lation and scrambling of macromonomers of different lengths.Grubbs third-generation (G3) catalyzed ROMP of norbornene-type monomers was selected for the graft-through polymeriza-tion (the backbone-forming reaction), as it results in very narrowpolymer molecular weight dispersities at very high monomerconversion (24, 25). The ROP of lactide catalyzed by a 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was selected for the brushsynthesis as an orthogonal and quenchable polymerization (26).The polymerization rates for both brush and backbone reac-

tions were determined to ensure the control over the bottle-brush’s shape and size was maintained. The rate constant ofROP of lactide (kp = 200 M−2·min−1; SI Appendix, section 3) wasdetermined and extremely narrow polymer dispersities wereachieved (Mw/Mn = Ɖ < 1.1) (26). The narrow polymer dispersitiesare a key element for maintaining shape control, as a broadpolymer distribution would reduce the shape resolution. The ratesof polymerization of G3-initiated ROMP of macromonomers (nor-PLA) were measured over a broad range of molecular weights (SIAppendix, section 5). In all cases, the rates of polymerization werevery fast (kobs > 1.5 min−1) compared with ROP (∼102× faster).This large difference in polymerization rates is important to ensurethat the macromonomer growth and thus the feed rate of macro-monomers is slow enough so that the fast ROMP is able to maintaina high macromonomer conversion; i.e., prevent the accumulationand scrambling of brushes of various lengths in the ROMP pot.To ensure the orthogonality of ROMP and ROP a study was

conducted to explore the compatibility of both polymerizationsin detail. A model system using nor2 [(bicyclo[2.2.1]hept-5-en-2-yl)methyl benzoate] as a monomer for ROMP was implementedto probe the effect of ROP reagents on ROMP (SI Appendix,section 4). Only DBU was identified to be an inhibitor. There-fore, DBU must be quantitatively scavenged out of solution uponaddition to the second vessel (27). Boric acid was found to bevery efficient in this role as it fully quenched ROP without af-fecting the ROMP (with respect to rate and polymer dispersity)prior to and post-DBU quenching. Finally, we demonstrated that

ROMP remained controlled under semibatch conditions byslowly feeding a solution of 500 eq of nor2 to a solution of G3over the course of 1 h. Full monomer conversion was achieved,and the isolated polymer had the same molecular weight, as inthe batch experiment (Mn = 113 kg/mol, Ɖ = 1.03).A key feature of the methodology is that the molecular shape is a

direct result of the flowrate profile [ϑo(flow rate) vs. t(time)] of liquidfrom vessel 1 to vessel 2. We chose to target three specific geometricshapes (cone, ellipsoid, and concave elliptical cone) to establish themethodology. However, the method can in principle be used tosynthesize any axisymmetric monotonic geometry. The flowrateequations/profiles were derived using a constraint that describesthe relationship between brush length with respect to backboneposition (i.e., shape). A unique feature of this is that each shape andsize has a different characteristic flowrate profile. The constraint fora cone, for example, is a constant, “A” (Eq. 1), which embodies thecone angle. The flowrate equation for the cone is presented in Eq.2. A detailed derivation of the flowrate equations for all of thetargeted geometries can be found in SI Appendix, section 9.

Constant≡A=Nbrush

Nbb, [1]

ϑo =�Nsyn,max

brush

Nsyn,maxbb

��V1

A

�ðKROPÞe−KROPt. [2]

The flowrate equation is the only mathematical frameworkneeded to synthesize shaped bottlebrush polymers. Additionally,it is possible to predict the polymerization outcomes (i.e.,conversion of lactide and norbornene in both reaction vesselsand Mn of brushes and bottlebrush polymers) at any time pointby combining the flowrate equation with the rate laws, and thedesign equations for semibatch reactors (SI Appendix, section 9)(26, 28). The use of a mathematical framework to predict thepolymerization outcomes provides a first-principle methodologyfor proving precise shape and size control. Each shape and sizehas its own flowrate equation and its own characteristic predic-tion profiles. A match between the experimental data and thepredictions would validate a successful synthesis of a shapedbottlebrush, as no other macromolecule could have been synthe-sized. To that end, a MATLAB code was written to numericallysolve the design equations (SI Appendix, section 10) and generatethe predictions.

Fig. 1. (Left) Schematic of the programable semibatch reactor system. (Right) Shaped bottlebrush polymers.

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To compare an experiment directly with our predictions, weperformed the synthesis of a conical-shaped polymer (Nmax

brush = 50,Nbb = 185) multiple times, quenching the polymerizations at dif-ferent reaction time points by simultaneously halting the flow ofmacromonomer and injecting vinyl ether to stop ROMP. Thecrude polymer mixtures were analyzed by gel permeation chro-matography (GPC) and NMR spectroscopy to determine thesystem outcomes (Fig. 2 and SI Appendix, section 6). First, theconversion of lactide and lactide buildup proceeded as predicted,which confirms that the macromonomers fed out of the syringehad the desired conical profile. Second, no residual macro-monomer was detected in the graft-through polymerization vessel

at any time point (macromolecule conversion >98%, SI Appendix,section 11 for detection limit) providing proof of rapid in-corporation of the macromonomers into the growing bottlebrush,thus ensuring that no scrambling of brushes of different lengthsoccurs. Third, the experimental and the predicted bottlebrushmolecular weights were in close agreement, and all bottlebrushpolymers had narrow molecular weight distributions (Ɖ < 1.1).Altogether the strong agreement between prediction and experi-ment validates the shape and size control of the process.The precision and flexibility of the methodology was further

illustrated by synthesizing a series of conical-shaped bottlebrushpolymers with different sizes, backbone lengths, and cone angles

Reactor: ROMP

Syringe: ROP

Brush Synthesis

Graft Through Polymerization

1

0.8

0.6

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00 20 40 60 80

Lactide Buildup

Time (min)

Rat

io

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.vnoC

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Time (min)

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4

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Time (min)

MW

(100

kg/

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)Data from NMRData from NMR Data from GPC

Lactide Buildup ∝∝Rate of ROP & Flow Rate

Macromolecule Conv. ∝Rate of ROMP & Flow Rate

Bottlebrush MW ∝Rate of ROP & Rate of

ROMP & Flow Rate

Data from GPC

Lactide Conv. ∝ Rate of ROP

Fig. 2. Process flow diagram with predicted (line) and experimental (dots) data for the synthesis of conical bottlebrush.

Table 1. Predicted and experimental data for the synthesis of shape-controlled bottlebrush polymers

Entry Shape Composition

Prediction Experimental data

Nbb Mn,brush,max Lac buildup, % Mn,BB Mn,brush,max* Lac buildup†, % Mn,BB‡ Ɖ‡ Nor conv. (NMR)†, %

1 Conical PLA 100 3.63 81.7 200 3.59 81.3 178 1.07 >982 PLA 200 3.63 81.7 400 3.55 80.7 515 1.12 >983 PLA 500 3.63 81.7 998 3.59 81.7 895 1.09 >984 Ellipsoid PLA 200 2.48 81.7 400 2.44 81.5 522 1.13 >985 Concave

elliptical conePLA 200 6.27 81.7 400 6.34 81.2 521 1.14 >98

6 Conical PDMS 200 6.73 — 767 6.72 — 153* 1.18* >98

Mn are in kg/mol and reaction conditions can be found in SI Appendix.*Data collected from GPC with respect to PLA standards for PLA and PS standards for PDMS.†Calculated from 1H NMR.‡Data collected from triple-detect GPC.

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(Table 1 and SI Appendix, section 6). In all cases, the predictedparameters (molecular weights and conversions) matched theexperimental values well, no residual macromonomers are de-tected, and the polymers remained narrowly dispersed (Ɖ ≤1.12). Next, the methodology was expanded to ellipsoid andconcave elliptical cone shapes (Table 1). This was achieved bysimply implementing the corresponding flowrate equations.Once again, NMR and GPC were used to analyze the products ofthe reactions. Narrow molecular weight distributions and strongagreement with predictions establish the exquisite control overshape and size. To further validate the methodology, atomicforce microscopy (AFM) images of a conical-shaped polymerwere collected. The size and shape observed are consistentwith theoretical calculations of size (Fig. 3 and SI Appendix,section 13).The generality of the synthetic strategy was further showcased

by expanding the chemical versatility of the process. The anionicROP of cyclic siloxanes for the synthesis of PDMS brushes wasused in place of the ROP of lactide (29). A detailed kineticanalysis and chemical compatibility study was performed, whichidentified trimethylsilyl chloride (TMSCl) as an effective quenchingagent (SI Appendix, section 7). Polydimethylsiloxane (PDMS)conical bottlebrushes were successfully synthesized with nar-row molecular weight distributions (Ɖ ≤ 1.2) and no detect-able unreacted macromonomer was observed (Table 1 and SIAppendix, section 7).Finally, as a second example illustrating the chemical versatility

of the process, a compositional asymmetric cone was synthesized(30–32). This was achieved by cofeeding two macromonomerssynthesis reaction mixtures, one for PLA and one for PDMS, intoa single vessel of G3, boric acid, and TMSCl (Fig. 4 and SI Ap-pendix, section 8). Analysis of the crude reaction mixture

confirmed that the experimental conversions matched the pre-dicted values, while maintaining a narrow polymer dispersity (Ɖ =1.19). The precision of the synthesis of this complex molecularobject exemplifies the chemical flexibility and shape control of themethodology. Moreover, this one-step synthesis was completed inless than 2 h, using exclusively commercially available reagents.

ConclusionThis work establishes a scalable strategy to synthesize macro-molecules with programmable shape, size, and composition.Reactor engineering principles and controlled polymerizations areleveraged to achieve the continuous control of brush length alongthe polymer backbone. This allowed for the programming of shapeand size simply by changing the flowrate, as any particular flowrateprofile will yield a bottlebrush polymer with a unique architecture.Macromolecules with conical, ellipsoidal, and concave architec-tures were synthesized and a mathematical model was used toconfirm that precise synthetic control was achieved. The chemicalversatility of the method was illustrated by the synthesis of acompositional asymmetric cone containing both asymmetric shapeand compositional contrast within a single macromolecule. Overallthis methodology provides an ability to independently probe theimpact of macromolecules shape, size, and chemistry for the devel-opment of new materials.

Methods and MaterialsDetails of all procedures can be found in SI Appendix.

The general procedure for the synthesis of shaped bottlebrushes is asfollows: To a glass vial, lactide and nor1 are dissolved in THF. The poly-merization was initiated by adding DBU dissolved in THF. This reactionmixture was immediately sucked up into a syringe and the needle waspushed through a septum of a round-bottom flask containing B(OH)3 and G3

Fig. 3. AFM height maps for PLA cone bottlebrush on silicon surface. The blue line in the plot is the theoretical shape profile for the imaged bottlebrush.

Fig. 4. Synthesis of a compositional asymmetrical cone composed of PLA and PDMS arms.

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in THF. This setup (syringe and round-bottom flask) was set in a syringepump. The reaction mixture was added according to a specified flow profile.At the end of the reaction a large excess of ethyl vinyl ether (large excesswith respect to [Ru]) was immediately added to the reaction mixture. Thereaction mixture was poured into methanol and a centrifuge was used toisolate the resulting polymer.

ACKNOWLEDGMENTS. PolyAnalytik Inc. is acknowledged for performingtriple-detection GPC. AFM was carried out at Frederick Seitz MaterialsResearch Laboratory Central Research Facilities, University of Illinois. Majorfunding for the 500-MHz Bruker CryoProbe was provided by the Roy J.Carver Charitable Trust to the School of Chemical Sciences NMR Labora-tory. We acknowledge NSF Grant DMR-1727605. We thank Umicore for thegenerous gift of Grubbs catalysts.

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