Polymer Mechanochemistry: Force Enabled Transformations Kelly M. Wiggins, Johnathan N. Brantley, and Christopher W. Bielawski* Department of Chemistry and Biochemistry, University of Texas at Austin, 1 University Station A1590, Austin, Texas 78712, United States ABSTRACT: In this viewpoint, we highlight the ability of mechanical force to overcome the limitations associated with using thermal or photochemical stimuli to facilitate chemical transformations. Emphasis will be directed toward examples of new chemical reactions that are accessed through externally applied mechanical forces, as these are illustrative of the emerging concept of using polymer chemistry to drive the synthesis of small molecules. In parallel, we oﬀer perspectives on the potential applications of polymer mechanochemistry in the development of novel synthetic strategies.
ince the inception of polymer science, which was marked by the seminal work of Staudinger and Carothers showing how organic reactions could be employed to prepare novel polymeric materials,1−3 the relationship between small molecule and macromolecular chemistry has been largely one-sided. Advances in small molecule chemistry have routinely been applied to the design and synthesis of macromolecules. In contrast, developments in polymer chemistry rarely inﬂuence the strategies used to synthesize small molecules (aside from facilitating separations).4 The ﬁeld of polymer mechanochemistry, however, has the potential to change this paradigm by revolutionizing the way chemists think about controlling chemical reactions. For example, while the reactivity of small molecules can be manipulated with photochemical or thermal stimuli, these approaches often require the use of short wavelength irradiation or elevated reaction temperatures to access the desired transformations. Unfortunately, the high energies associated with such processes can also drive the reactions down a variety of decomposition pathways. Mechanical force, however, provides opportunities for circumventing these limitations. While the detailed mechanisms by which various mechanochemical phenomena arise are not always well understood, mechanical forces are capable of eﬀecting novel reactivity. With force, one can eﬀectively shepherd a chemical reaction down speciﬁc reaction pathways (e.g., by selectively lowering the energy of a transition state), thereby avoiding undesired outcomes and enabling the discovery of transformations that are altogether new and otherwise inaccessible (Figure 1). The concept of using force to modify molecular reactivity (i.e., mechanochemistry) has a rich history. As early as 1940, Kauzmann and Eyring proposed that the mechanical perturbation of diatomic molecules could alter the reaction coordinates associated with their homolytic dissociation.5 Recently, the ﬁeld of mechanochemistry has experienced a renaissance, and a variety of techniques (e.g., ball-milling, turbulent ﬂow, atomic force microscopy, etc.) have been used to activate chemical reactions.6−8 Among these methods, the © 2012 American Chemical Society
Figure 1. All chemical reactions, whether facilitated by thermal, photochemical, or mechanical stimuli, proceed via the lowest energy pathway. Polymer mechanochemistry can selectively alter the reaction coordinate along the pathway to a desired product (e.g., through the stabilization of the transition state).
anisotropic distribution of exogenous forces to chemical functionalities embedded within polymer chains (i.e., polymer mechanochemistry) has proven to be one of the most broadly applicable approaches.9−14 Polymer mechanochemistry uses the size of macromolecules to harness externally applied forces and translate them into facilitating chemical reactions.15 Within this growing ﬁeld, ultrasound has emerged as an eﬀective and straightforward progenitor of mechanical forces within polymer chains.16−19 In essence, acoustic ﬁelds created under ultrasound pull the ends of the polymer in opposing directions, generating tensile stress (i.e., force) near the middle of the polymer chain.20−24 In this viewpoint, we will focus on the increasing number of novel mechanochemical transformations accessible through the use of polymers, as they are illustrative of the ability to realize new small molecule chemistry through advancements in macromolecular science. A salient example of using force to overcome thermal and photochemical restrictions involved pericyclic rearrangements, which are governed by the well-established orbital symmetry Received: April 6, 2012 Accepted: April 13, 2012 Published: April 20, 2012 623
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rules (e.g., the Woodward−Hoﬀmann rules).25 While symmetry requirements can be useful for predicting reactivity, they are also prohibitive, particularly for reactions involving the construction or deconstruction of carbocycles. Moore, Sottos, and White, however, showed that mechanical activation could circumvent the aforementioned restrictions and facilitate formally disallowed electrocyclic ring-opening (ERO) reactions. As shown in Figure 2a, the mechanical activation of a mixture of
treatment of the same starting materials, however, generated chemically distinct hexaﬂuorocyclobutenes and diol derivatives (Figure 3a). Our own eﬀorts revealed that a thermally robust [4
Figure 2. (a) Force mediated EROs of benzocyclobutene moieties eﬀectively circumvented orbital symmetry rules. (b) Mechanical isomerization of gDFCs resulted in the formation of the thermodynamically disfavored cis-products. R = poly(methyl acrylate) or poly(ethylene glycol). Red arrows indicate the direction of an externally applied mechanical force.
Figure 3. (a) Mechanical activation of PFCBs aﬀorded products that were distinct from those obtained upon thermolysis (shown). (b) Mechanical force was used to promote thermally inaccessible [4 + 2] cycloreversions. (c) The triazole moieties underwent cycloreversion only under mechanical perturbation. For the transformations depicted in (b) and (c), no reaction was observed when the same materials were heated to elevated temperatures. PMA = poly(methyl acrylate).
cis- and trans-benzocyclobutenes aﬀorded a single ERO product;26 in contrast, subjecting the same starting materials to thermal or photochemical stimuli resulted in a mixture of isomers. Importantly, the reaction achieved under mechanical perturbation represented a novel isomerization that is accessible only via force. The triumph of mechanical activation over the longstanding symmetry rules holds promise for accessing a variety of scaﬀolds that require forbidden reactivity (e.g., antiBaldwin ring closures).27 Craig and Martinez later demonstrated that mechanically facilitated gem-diﬂuorocylcopropane (gDFC) ring openings also proceeded through an unanticipated mechanism (Figure 2b).28 Speciﬁcally, mechanical activation of polymers containing both cis- and trans-gDFCs resulted in thermodynamically disfavored isomerizations that aﬀorded polymers with predominately cisgDFCs. In contrast, thermolysis of the same starting materials yielded predominately trans-gDFC containing polymers. The isomerization was hypothesized to proceed through a radical mechanism, and the putative diradical intermediate of gDFC isomerization was successfully trapped under ultrasound irradiation. Importantly, trapping could not be reproduced in the absence of mechanical activation, which indicated that the forces generated under ultrasonication stabilized the transient diradical species. The ability to extend the lifetime of ﬂeeting intermediates through mechanical stabilization has important implications for the study of small molecule reactions, particularly if transition states could be endowed with suﬃcient longevity to enable their characterization.29,30 Cycloreversions further illustrate the limitations associated with thermally activating chemical systems. High temperatures are often required to promote these reactions, which, as noted above, can promote undesired decomposition processes or preclude cycloreversion altogether.31−36 The speciﬁcity with which chemical systems can be activated through polymer mechanochemistry, however, has been shown to facilitate the cycloreversion of thermally robust moieties. For example, Craig and co-workers found that the mechanical activation of perﬂuorocyclobutanes (PFCBs) resulted in a formal [2 + 2] cycloreversion to yield reactive triﬂuorovinyl ethers.37 Thermal
+ 2] cycloadduct of anthracene and maleimide could also be selectively deconstructed into its starting diene and dienophile with mechanical force (Figure 3b).38 Building on these results, we targeted the mechanical cycloreversion of the 1,2,3-triazole, the familiar product of the Cu-catalyzed azide−alkyne cycloaddition. By incorporating triazoles into polymer chains, we found that this chemically and thermally inert species could be mechanically disassembled into its constituent azide and alkyne (Figure 3c).39 In addition to representing fundamentally new transformations that cannot be accessed using other stimuli, these cycloreversions further illustrate the speciﬁcity with which mechanical forces can guide chemical reactions to desired products. Importantly, all of the aforementioned mechanically facilitated cycloreversions occurred with good selectivity and limited decomposition. As such, these features could render such chemistry amenable for use in a variety of new applications, such as mechanically activated protecting groups (MAPGs) for small molecule synthesis. Ideally, MAPGs would constitute mechanically labile moieties that are otherwise thermally and chemically inert (e.g., 1,2,3-triazoles). Once installed, the MAPG would “protect” sensitive functionalities while desired synthetic transformations were performed. Then, the MAPG could be selectively deconstructed with mechanical force, freeing the protected functionality for further manipulation. For practical reasons, MAPGs would need to be recyclable (i.e., the polymers could be selectively isolated from the desired functionality and then used in subsequent protections). While bond scission has been a primary focus of many eﬀorts in polymer mechanochemistry, we envisioned that nonscissile transformations would expand the utility and scope of mechanochemical phenomena. Controlling the conﬁgurations of atropisomers was of particular interest, as these moieties are prominent in asymmetric syntheses but are challenging to obtain in enantiopure forms.40−42 Indeed, the enantiomers of atropisomers are typically isolated through tedious chiral resolutions of their racemates in yields that are intrinsically limited to 50%.43−45 Our early eﬀorts focused on demonstrat624
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precursors, as such approaches may also lead to novel transformations. Recent work by Grzybowski, for example, showed that the radicals produced by polymers under stress could be used to convert water into reactive peroxides that were later used to drive various chemical processes, including nanoparticle synthesis, dye bleaching, and ﬂuorescence.49 Similarly, the activation of latent metal catalysts represents another intriguing application of mechanochemistry. While a number of mechanically responsive catalysts have been reported, many are based on metal complexes that are also capable of undergoing thermal activation, which, consequently, does not allow selective access to new chemistries.50−53 Polymer mechanochemistry, however, could provide new opportunities for activating metal-based catalysts through thermally inaccessible pathways. For example, mechanically facilitated ligand dissociations that are thermodynamically disfavored could provide access to catalysts that are otherwise unobtainable (Figure 5).
ing that atropisomers with thermally inaccessible isomerization barriers could be reconﬁgured using mechanical force. Initially, we showed that polymer embedded enantiopure 1,1′-binaphthol (binol) derivatives could be isomerized using ultrasound (Figure 4a).46 For comparison, heating the same polymers at
Figure 4. (a) Atropisomers with high thermal isomerization barriers underwent a force-induced racemization. No racemization was observed when the same materials were heated to elevated temperatures. (b) Chiral resolution of atropisomers was achieved using a method that combined mechanochemical isomerization with enzymatic polymer cleavage. PMA = poly(methyl acrylate).
Figure 5. Comparison of catalyst activation using heat vs mechanical force: L = thermally labile ligand; O = mechanically labile ligand.
elevated temperatures for extended periods of time (i.e., 257 °C for 72 h) did not result in any appreciable racemization. In an eﬀort to overcome the inherent restrictions of the current methodologies for chiral resolution, we next sought to harness mechanical isomerizations for the generation and isolation of enantiopure materials. By combining the well-established method of enantioselectively cleaving alkyl esters from Sbinol using Cholesterol esterase47 with the aforementioned mechanical isomerization, we found that the kinetic resolution of S-binol could be achieved in a single vessel (Figure 4b).48 Ultimately, this approach resulted in the exclusive formation of S-binol, which was isolated in good yield (>90%) and high enantiopurity (>98% ee) from a racemic precursor. More broadly, this result demonstrated that a desirable small molecule could be isolated following a polymer-facilitated mechanical activation process. While the isolation described above clearly illustrates the utility of polymer mechanochemistry in small molecule applications, it also raises a few concerns. Namely, isolation is not atom economical, as the byproduct of the reaction is the cleaved polymer chains. For this reason, the synthesis of small molecules using mechanochemical approaches would necessitate the development of “catalytic” polymer mechanochemistry. Here, polymers could be attached to functionalities in situ, facilitate a mechanochemical transformation, and then be selectively cleaved and reattached to a second molecule so that the cycle could be repeated. Beyond reducing waste, catalytic polymer mechanochemistry may also render large scale reactions more feasible. In many examples, each polymer performs only one transformation, which can create scalability and practicality challenges. However, if the polymers eﬀectively served as catalysts, then each chain could facilitate multiple transformations. While the incorporation of multiple mechanically labile functionalities into a single polymer (e.g., the PFCB and gDFC materials) is an alternative solution, the ability to recycle the polymeric actuators is appealing. As the ﬁeld of polymer mechanochemistry continues to develop, we expect that eﬀorts will be directed toward the mechanical generation of reactive species from stable
To further expedite advances in polymer mechanochemistry, computational models, which have already proven valuable in elucidating the mechanism of mechanical activation for a number of systems (e.g., EROs),54−60 should be used to guide the rational design of novel mechanically labile functionalities. Speciﬁcally, in silico high-throughput screening of small molecule transformations under mechanical force could be used to rapidly develop libraries of force responsive scaﬀolds. Computational analyses could also aid in the choice of polymer attachment sites to maximize the desired mechanochemical response. Recent eﬀorts, for example, have shown that attaching polymers to improper positions (i.e., atoms where force is not directed to the appropriate bonds) can result in undesired reactivity,61 and changing the stereochemistry of the attachment sites can signiﬁcantly aﬀect the rate of mechanical activation.62 Although the ﬁeld is still burgeoning, polymer mechanochemistry has already led to the discovery of fundamentally new transformations, including electrocyclic ring-openings that eﬀectively violate orbital symmetry rules, thermally inaccessible isomerizations of optically active molecules, and cycloreversions of thermally and chemically robust moieties. Combined with the ability to selectively remove polymer chains following mechanical activation, polymer mechanochemistry is poised to enable new synthetic methodologies and potentially change the relationship between macromolecular and small molecule chemistry.
*E-mail: [email protected]
The authors declare no competing ﬁnancial interest.
ACKNOWLEDGMENTS This material is based on work supported in part by the U.S. Army Research Oﬃce under Grant No. W911NF-09-1-0446. 625
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Additional support from the Robert A. Welch Foundation (F1621) is also acknowledged.
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