Kelly M. Wiggins

Unclicking the Click: Mechanically Facilitated 1,3-Dipolar Cycloreversions

Application of ultrasound can cleanly reverse a widely used chemical coupling reaction. The specific targeting of covalent bonds in a local, anisotropic fashion using mechanical methods offers useful opportunities to direct chemical reactivity down otherwise prohibitive pathways. Here, we report that embedding the highly inert 1,2,3-triazole moiety (which is often prepared using the canonical “click” coupling of azides and alkynes) within a poly(methyl acrylate) chain renders it susceptible to ultrasound-induced cycloreversion, as confirmed by comprehensive spectroscopic and chemical analyses. Such reactivity offers the opportunity to develop triazoles as mechanically labile protecting groups or for use in readily accessible materials that respond to mechanical force.

Methods for activating and characterizing mechanically responsive polymers

Mechanically responsive polymers harness mechanical energy to facilitate unique chemical transformations and bestow materials with force sensing (e.g., mechanochromism) or self-healing capabilities. A variety of solution- and solid-state techniques, covering a spectrum of forces and strain rates, can be used to activate mechanically responsive polymers. Moreover, many of these methods have been combined with optical spectroscopy or chemical labeling techniques to characterize the products formed via mechanical activation of appropriate precursors in situ. In this tutorial review, we discuss the methods and techniques that have been used to supply mechanical force to macromolecular systems, and highlight the advantages and challenges associated with each.

Mechanically Facilitated Retro [4 + 2] Cycloadditions

Poly(methyl acrylate)s (PMAs) of varying molecular weights were grown from a [4+2] cycloaddition adduct of maleimide with furan containing two polymerization initiators. Subjecting the corresponding PMA (>30 kDa) chains to ultrasound at 0 °C resulted in a retro [4+2] cycloaddition reaction, as observed by gel permeation chromatography (GPC) and UV-vis spectroscopy, as well as labeling of the liberated maleimide and furan moieties with appropriate chromophores featuring complementary functional groups. Similar results were obtained by sonicating analogous polymers that were grown from a thermally robust [4+2] cycloaddition adduct of maleimide with anthracene. The generation of anthracenyl species from these latter adducts allowed for the rate of the corresponding mechanically activated retro [4+2] cycloaddition reaction to be measured. No reduction in the number average molecular weight (M(n)) or liberation of the maleimide, furan, or anthracene moieties was observed (i) for polymers containing the cycloaddition adducts with M(n) < 20 kDa, (ii) for high molecular weight PMAs (M(n) > 60 kDa) featuring terminal cycloaddition adducts, or (iii) when the cycloaddition adducts were not covalently linked to a high molecular weight PMA. Collectively, these results support the notion that the aforementioned retro [4+2] cycloaddition processes were derived from a vectorially opposed mechanical force applied to adducts embedded within the polymer chains.

Mechanical activation of catalysts for C-C bond forming and anionic polymerization reactions from a single macromolecular reagent.

Coupling of pyridine-capped poly(methyl acrylate)s, PyP(M) (where M corresponds to the number average molecular weight in kDa), to the SCS-cyclometalated dipalladium complex [(1)(CH(3)CN)(2)] afforded organometallic polymers [(1)(PyP(M))(2)] with a concomitant doubling in molecular weight. Ultrasonication of solutions containing [(1)(PyP(M))(2)] effected the mechanical scission of a palladium-pyridine bond, where the liberated PyP(M) was trapped with excess HBF(4) as the corresponding pyridinium salt, harnessed to effect the stoichiometric deprotonation of a colorimetric indicator, or used to catalyze the anionic polymerization of α-trifluoromethyl-2,2,2-trifluoroethyl acrylate. The mechanically induced chain scission also unmasked a catalytically active palladium species which was used to facilitate carbon-carbon bond formation between benzyl cyanide and N-tosyl imines. Spectroscopic and macromolecular analyses as well as a series of control experiments demonstrated that the aforementioned structural changes were derived from mechanical forces that originated from ultrasound-induced dissociation of the polymer chains connected to the aforementioned Pd complexes.

Molecular catch bonds and the anti-Hammond effect in polymer mechanochemistry.

While the field of polymer mechanochemistry has traditionally focused on the use of mechanical forces to accelerate chemical processes, theoretical considerations predict an underexplored alternative: the suppression of reactivity through mechanical perturbation. Here, we use electronic structure calculations to analyze the mechanical reactivity of six mechanophores, or chemical functionalities that respond to mechanical stress in a controlled manner. Our computational results indicate that appropriately directed tensile forces could attenuate (as opposed to facilitate) mechanochemical phenomena. Accompanying experimental studies supported the theoretical predictions and demonstrated that relatively simple computational models may be used to design new classes of mechanically responsive materials. In addition, our computational studies and theoretical considerations revealed the prevalence of the anti-Hammond (as opposed to Hammond) effect (i.e., the increased structural dissimilarity between the reactant and transition state upon lowering of the reaction barrier) in the mechanical activation of polyatomic molecules.

Retracted article: Design, synthesis, and study of benzobis- and bibenz(imidazolium)-based ionic liquid crystals

The Royal Society of Chemistry hereby wholly retracts this Journal of Materials Chemistry article with the agreement of Christopher W. Bielawski and Kelly M. Wiggins (other co-authors could not be reached) due to data fabrication as detailed below. This retraction supersedes the information provided in the Expression of Concern related to this article. The Royal Society of Chemistry has been contacted by the corresponding author of this article and the Research Integrity Officer at The University of Texas at Austin regarding concerns of scientific misconduct affecting this article. The Research Integrity Officer has informed us that an investigation to ascertain the validity of the work reported has found that scientific misconduct by one of the articles co-authors has taken place as follows: the thermal plots in this article were falsified from original data – the enumerated figures do not accurately reflect the raw data. Specifically, the thermal data in Figure 2 was falsified. The thermal data in Supplementary Figures S1-S3 was also falsified. The original data in Figure 2 and Supplementary Figures S1-S3 was manipulated to make the peaks appear larger or smaller than they originally were. The signing authors would like to apologise for this and any consequent inconvenience to authors and readers. Signed: Christopher W. Bielawski and Kelly M. Wiggins, March 2015

A mechanochemical approach to deracemization.

The synthesis and isolation of enantiopure compounds remains an important challenge for many applications in medicinal, materials, and synthetic chemistry. In general, chiral molecules of high enantiopurity are prepared by asymmetric synthesis or the resolution of their respective racemates. The latter approach is more common but can be tedious, and the yields of isolated products are inherently restricted to, at best, 50%. An ideal solution to this problem is to reconfigure the stereochemistry of the undesired enantiomer during the resolution process. While dynamic kinetic resolution (DKR) or attrition-enhanced deracemization methods may be used to overcome this fundamental limitation, the substrate scope for these methods is confined to compounds that can be chemically or thermally racemized. Given the recent advances in mechanochemistry, 17] where the mechanical force generated under ultrasound may be used to surmount thermally inaccessible isomerization barriers, we envisioned a new method for enriching the enantiopurity of optically active species. Herein we report a cooperative method that combines a mechanically facilitated reconfiguration process with stereoselective enzymatic hydrolysis to isolate (S)-1,1’-bi-2-naphthol ((S)binol) in 90 % yield with an enantiopurity of higher than 98% from a racemic precursor. Chiral molecules that are devoid of stereogenic centers and the asymmetry of which is derived from hindered rotation around single bonds are known as atropisomers. These compounds have been successfully used as scaffolds for materials with molecular recognition capabilities and serve as the basis for many chiral ligands used to confer enantioselectivity to catalytically active metals. 25] (S)-binol, in particular, is an essential component used in the preparation of (S)-2,2’-bis(diphenylphosphino)-1,1’-binaphthyl (Sbinap), 26] which is critical for the large-scale synthesis of ( )-menthol and other industrially important and biologically active compounds. Enantiopure atropisomers, including (S)-binol, are typically isolated by the resolution of a racemic precursor and are therefore subject to the fundamental and practical constraints described above. Recently, we demonstrated that mechanical force may be used to reconfigure atropisomers. By growing poly(methyl acrylate) (PMA) chains from enantiopure (R)or (S)-binol and subjecting solutions of these materials to ultrasound, we were able to convert one stereoisomer to the other in an iterative process that ultimately produced racemic mixtures. Because of their high isomerization barriers (> 30 kcal mol ), upon heating these same materials to temperatures exceeding 250 8C for longer than 72 h no isomerization was observed. To deracemize rac-binol, we envisioned using the aforementioned mechanical isomerization methodology in conjunction with the enzyme cholesterol esterase, which is known to stereoselectively hydrolyze esters of (S)-binol. We hypothesized that in a racemic mixture of polymer-embedded binol units, the enzyme would selectively cleave the polymer chains connected to an (S)-binol derivative (i.e., PMA(S)-binol, Scheme 1). Subsequent mechanically induced reconfiguration of the residual enantiomer (i.e., PMA(R)-binol) [21] followed by in situ enzymatic hydrolysis should then repeat until (S)binol, which is not of sufficient molecular weight to experience ultrasound-induced isomerization, is formed as the exclusive chiral product (Scheme 1). In addition to establishing a new method for enriching the enantiopurity of optically active compounds, we reasoned that the solubility differences between high-molecular-weight polymers and small molecules would allow the isolation of the enantiopure products. To test our hypothesis, a polymerization initiator amenable to hydrolysis by cholesterol esterase was required. As summarized in Scheme 2, coupling 3-(2-bromo-2-methylpropanoyloxy) propanoic acid with rac-binol using 1-ethyl-3-(3dimethylaminopropyl)carbodiimide (EDC) and catalytic amounts of 4-dimethylamino pyridine (DMAP) afforded a racemic initiator, rac-I. PMA chains were then grown from this difunctional initiator using a copper(0)-catalyzed controlled radical polymerization (CRP). 30] The resulting polymer, PMArac-binol, was isolated by precipitation into methanol and subsequent filtration. Analysis of the isolated material by gel permeation chromatography (GPC) revealed that it possessed a number average molecular weight (Mn) of 67 kDa and a polydispersity index (PDI) of 1.3 (Figure 1a, blue trace) and therefore was of sufficient size to undergo an ultrasound-induced mechanochemical activation process. As expected, the circular dichroism (CD) profile of this racemic material exhibited no significant optical activity (Figure 1b, blue). With the desired material in hand, a biphasic solution of PMArac-binol (50 mg mL ) in methyl isobutyl ketone and phosphate buffer (pH 7.0; 1:1 v/v) containing cholesterol esterase (2 U) and deoxycholic acid (6.3 mm) was prepared. 29] The mixture was then subjected to pulsed ultrasound at 9 8C (conditions: 1 s on, 1 s off; power density = [*] K. M. Wiggins, Prof. C. W. Bielawski Department of Chemistry & Biochemistry The University of Texas at Austin 1 University Station, A1590, Austin, TX, 78712 (USA) E-mail: bielawski@cm.utexas.edu Homepage: http://bielawski.cm.utexas.edu

Retracted article: Selective scission of pyridine–boronium complexes: mechanical generation of Brønsted bases and polymerizationcatalysts

The Royal Society of Chemistry hereby wholly retracts this Journal of Materials Chemistry article with the agreement of Christopher W. Bielawski, Andrew G. Tennyson and Kelly M. Wiggins (other co-authors could not be reached) due to data fabrication as detailed below. This retraction supersedes the information provided in the Expression of Concern related to this article. The Royal Society of Chemistry has been contacted by the corresponding author of this article and the Research Integrity Officer at The University of Texas at Austin regarding concerns of scientific misconduct affecting this article. The Research Integrity Officer has informed us that an investigation to ascertain the validity of the work reported has found that scientific misconduct by one of the articles co-authors has taken place as follows: the kinetics data and plots in this article were fabricated. Specifically, the rates and associated data in the Results and Discussion section were fabricated. The data acquired from the kinetics experiments discussed in the Supporting Information section entitled “3. Polymer Chain Scission Experiments: Kinetic Analyses”, was fabricated. The data found in Figures 1B, 1C, and 1D, Supplementary Figures S5 and S6, and Supplementary Table S2 was fabricated. In addition, all of the Gel Permeation Chromatographs presented in this article and the accompanying Supplementary Information were smoothed. The signing authors would like to apologise for this and any consequent inconvenience to authors and readers. Signed: Christopher W. Bielawski, Andrew G. Tennyson and Kelly M. Wiggins, March 2015

Retracted Article: Homonuclear bond activation using a stable N,N′-diamidocarbene

The activation of molecules possessing homonuclear bonds (i.e., X–X, where X = Br, O, S, or C) using a stable N,N′-diamidocarbene (DAC) is described. Exposing bromine to the DAC at 25 °C afforded a substituted tetrahydropyrimidinium salt in good yield (70%). In contrast, treatment of the DAC with benzoyl peroxide or various disulfides afforded the corresponding diamidoketal or diamidothioketal products, respectively, under mild conditions (25 °C) and in good yield (60–80%). Mechanistic and kinetic studies of the latter reactions were consistent with a concerted process involving the nucleophilic attack of the DAC on the aforementioned substrates. While the diamidoketal decomposed to the corresponding urea (91% yield) at 25 °C, the diamidothioketals produced a thiolate which induced rearrangement to the corresponding ring-opened thioesters (78–90% yield) at elevated temperatures (60 °C). The DAC also inserted into the C(O)–C(O) bond of cyclic and acyclic diones as well as the C(O)–CR bond of a cyclopropenone under mild conditions (25–60 °C); the corresponding products were subsequently isolated in good yield (75–90%).

Squeezing New Life Out of Polymers

The field of polymer mechanochemistry, 2] wherein macroscopic forces are translated into chemical transformations within polymeric matrices, is witnessing a rebirth. Unique or otherwise kinetically inaccessible chemical reactions are now possible when mechanically labile functionalities, termed mechanophores, are embedded within polymers and then subjected to exogenous mechanical forces. Paradigms in the field are shifting, however, and efforts are now focusing on using force as a method for driving the production of reactive chemical species. In particular, polymers that generate acids or redox reagents under the action of mechanical force are of interest, as such materials could find utility in applications that range from self-healing systems that undergo spontaneous repair through acid-catalyzed cross-linking reactions to mechanically driven syntheses. The production of valuable small molecules from mechanically activated polymers is still in its infancy, and reported methods for achieving this goal often require a thermal or chemical treatment step. 7] Designing materials that extrude well-defined chemical entities solely under mechanical force has proven considerably more challenging. In a seminal contribution, Moore and co-workers showed that dinitrogen could be expelled from a centrally positioned diazo unit in a poly(ethylene glycol) chain under ultrasonication. Although the chemical inertness of dinitrogen precluded its use in further reactions, this example laid the groundwork for two recent reports from the Moore and Grzybowski laboratories that beautifully demonstrated how reactive chemical reagents can be generated from mechanically responsive materials. The Moore group focused on generating Brønsted acids by compressing appropriately functionalized polymers. The design of the mechanically responsive materials was based on previous studies from Craig et al., who demonstrated that polymers containing multiple gem-dihalocyclopropane (gDHC) moieties could undergo mechanically facilitated electrocyclic rearrangements to afford dihaloalkenes. Subsequent thermal treatment (165 8C) of the olefinic products resulted in the extrusion of mineral acids (e.g., HCl). To reduce the temperature required for the elimination reaction, Moore et al. envisaged an indene-based analogue that could drive the rearrangement of the gDHC moieties and the elimination of HCl through aromatization (Scheme 1).