Title: Reversible soft-mechanochemical control of biaryl conformations through crosslinking in a 3D macromolecular network
Abstract: Tuning the dihedral angle (DA) of axially chiral compounds can impact biological activity, catalyst efficiency, molecular motor performance, or chiroptical properties. Herein, we report gradual, controlled and reversible changes in molecular conformation of a covalently linked binaphthyl moiety, within a 3D polymeric network by the application of a macroscopic stretching force. We managed a direct observation of the DA changes by measuring the circular dichroism signal of an optically pure BINOL-crosslinked elastomer network. In accordance with computed spectra, stretching the elastomer resulted in a widening of the DA between naphthyl rings when the BINOL was doubly-grafted to the elastomer network, while no effect was observed when a single naphthyl ring of the BINOL was grafted to the elastomer network. Combining both experimental and theoretical results, we have determined that ~170% extension of the elastomers led to the transfer of a mechanical force to the BINOL moiety of 2.5 kcal*mol-1*Å-1 (~175 pN) in magnitude and results in the opening of the DA of BINOL up to ~130°.
Introduction
Axially chiral moieties play an important role in the bioactivity of many natural products, are highly useful in the design of molecular motors, molecular and/or chiroptical material and lead to powerful ligands for asymmetric catalysis.1 Their ability to induce chiral discrimination arises from a hindered rotation around a congested bond generating a pair of atropisomers, where the presence of a rotational energy barrier avoids racemization. Although this barrier might be overcome by thermal energy in certain compounds such as some biphenyls, binaphthyls and their derivatives have been used extensively because of their resistance to racemization, with isomerization barriers typically exceeding 30 kcal.mol-1.2 Beyond the consideration of this barrier, the precise value of the dihedral angle between naphthyl rings is a key parameter that needs to be controlled for at least two main reasons: this angle value directly impacts both (i) the reactivity and the stereochemical outcome when an atropisomer is involved as ligand in enantioselective catalysis,3 and (ii) the helicity of axially chiral derivatives determines as well their chiroptical properties, a crucial aspect to take into account for chiral material design.4 Conformational control of atropisomers can be done through different environmental stimuli: protonation,5 complexation with metallic ions,6 or solvent polarity7, which can all be efficient triggers when the chiral system studied is in solution but hardly usable for atropisomer-containing materials.
Within the past decade, mechanochemistry has emerged as a new way of conducting chemical reaction by milling, stretching, shearing, pulling, swelling or ultrasonic irradiation.8 In these cases, the mechanical energy allows molecules to overcome high energy barriers that wouldn’t be reachable by thermal or photochemical ways. This results in constitutional changes, where some bonds are cleaved and others are formed in a non-reversible way.9 On top of this, another strategy has recently emerged based on reversible conformational changes of mechano-sensitive molecules, modifying thus properties of the host material they are bound to. Inspired from nature,10 the soft-mechanochemistry field has earned the recognition of community thanks to many successful achievements11 but controls of molecular systems by macroscopic mechanical stimuli remains undoubtedly challenging matters.12 Based on a less energy-demanding process, when the mechanical stimulus is released, the initial state of the considered material can be reversibly restored and the targeted molecule is returned to its initial thermodynamic conformation. This approach was cleverly exploited to design mechanosensitive materials (i) containing enzyme-like artificial cavities, where the application of a mechanical force lead to the selective discrimination between nucleobases,13 (ii) where the applied force controls the fluorescence emission intensity of marked proteins in an hydrogel,14 (iii) where enzymatic biocatalytic activities can be tuned upon stretching or releasing,15 (iv) where polypeptidic conformation and film-nanoorganization can be reversibly modulated upon stretching.16 Through all these contributions, original concepts were reported highlighting the huge potential of soft-mechanochemistry. Nevertheless, the relation between the macroscopic force applied and the resulting observation (supramolecular recognition, chiral discrimination, catalysis, fluorescence and so on) was only expected to occur through a conformational change at the molecular scale and this point was not demonstrated in an unambiguous way. A clue towards this goal was hinted by Balaz and co-workers, when they observed through steady-state and time-resolved emission spectra a distribution change between a planar and a twisted conformation of an embedded porphyrin dimer PVA film. However, in that case, the mechanotransduction was an all or nothing process with intermediate conformations between the two states not being mentioned, and the process showing no reversibility.
Indeed, the efficiency of the mechanotransduction going from the macroscopic mechanical transfer to the molecular deformation depends mainly on two parameters: high displacement and high order. In case of solid-state crystals, the order is large but the displacement is low because of their rigid nature. Although mechanical forces have been largely used to orient molecules embedded in materials,18 in most cases, the rigidity of materials is such that low structural variations are allowed (up to 1% change in volume) prior to loss of crystal integrity.19 On the contrary, for molecules at the 2D interface, where order and displacement can be high, the external force is transferred efficiently to individual molecules and dynamic conformational variation is allowed. This was illustrated using Langmuir monolayers of cholesterol-armed cyclen formed at the air-water interface.20 Unidirectional compression of this 2D organized systems allows tuning the binding constants and the enantioselective recognition between the cyclen and various amino acid guests. Following on this, Ariga and coworkers recently showed a transduction pathway of a mechanical force (compression) to the distortion of the dihedral angle of enantiopure amphiphilic binaphthyl constituting monolayer films.21 The direct observation and the quantification of the molecular conformational change was evidenced using circular dichroism (CD). Though this development is attractive, its application for 3D material still remains highly challenging and has never been reported so far. Soft materials containing conformationally- sensitive molecules, such as polymer-based materials, hydrogels, thin films or liquid crystals, are flexible enough to allow a wide dynamic variation of their structure and a good mechanotransduction of the mechanical stimulus to mechano- sensitive molecules. However, investigating molecular chiral conformation changes within these materials is not obvious because CD signal measurements used to contain huge linear dichroism (LD) and linear birefringence (LB) contributions when the material is mechanically deformed.
Herein, we investigated enantiopure binaphthol derivatives (BINOL) as mechano-sensitive probe mono linked or doubly crosslinked in a 3D macromolecular network. Using polydimethylsiloxane (PDMS) as host elastomer, our goal is to establish unambiguously the transduction’s relation between the macroscopic unidirectional stretching deformation applied and the molecular force involved resulting from dihedral angle changes in the binaphthyl conformation (Scheme 1). Based on a convenient and an easy-to-use optical system, an efficient CD extraction method free from linear contributions was developed. The reversibility and the repeatability of this soft-mechano- transduction process were studied. Quantum molecular calculations (QMC) and molecular dynamic simulation (MDS) have contributed to quantify the molecular force according to the macroscopic mechanical stimulus applied to the BINOL- containing material.
Results and Discussion
Synthesis of BINOL derivatives and preparation of BINOL- crosslinked host materials. PDMS-based material is an elastomer made from the covalent crosslinking of two different kinds of copolymer chains containing either vinyl or hydrogenosilane groups. Hydrosilylation coupling reaction between these two copolymers is catalyzed by an organoplatinum compound leading thus to the formation of a chemical three- dimensional network. Incorporation of BINOL moieties within this polymer architecture was realized thanks to the introduction of vinyl entities at the two phenolic hydroxyl groups. Decenyl chains are long enough spacers placed between the BINOL unit and the reactive terminal double bonds to allow efficient anchoring on the PDMS chains. The reactive R, S and rac-BINOL derivatives leading to R-1, S-1 and rac-1 respectively, were prepared in one step from the commercially available racemic or enantiopure forms R or S of the biaryl starting material (Scheme 2). For control experiments, mono vinyl functionalized BINOL derivatives 2 were also prepared. The nucleophilic substitution of 1 equivalent of BINOL was realized in presence of 1.5 equivalent of 10-bromo-1- decene and potassium carbonate. This 1/1.5 ratio between BINOL/10-bromo-1-decene allowed to isolate the bis vinyl functionalized 1 and the mono vinyl functionalized 2 derivatives in a single step and in one pot conditions through chromatograph column purification. Compounds R-1, S-1, rac-1, R-2, S-2 and yrac-2 were obtained in good to excellent yields ensuring a non- expensive large-scale production necessary for materials preparation (Section 2 in SI). The BINOL-crosslinked PDMS films were prepared using a commercially available kit (Sylgard 184, Dow Corning), incorporating 0.2% in weight of R-1, S-1, rac-1, R- 2, S-2 or rac-2 derivatives, a value that was suitable to avoid signal saturation during optical measurements (Section 3 in SI). Using this method, different transparent and rectangular elastomer samples (3 x 1 cm) displaying ~200 µm of thickness were prepared: R-1@PDMS, S-1@PDMS, rac-1@PDMS, R- 2@PDMS, S-2@PDMS, rac-2@PDMS and an undoped PDMS film lacking any BINOL derivative. Intensive rinsing procedures ensured the removal of unlinked BINOL derivatives and free PDMS chains.
Optical measuring setup. UV-Absorption and CD spectra were both measured for all PDMS films (Fig. S1). Due to the UV cutoff of the PDMS, spectra were recorded between 260 and 380 nm. The measured absorption and CD bands of R-1@PDMS, S- 1@PDMS, R-2@PDMS and S-2@PDMS@ were quite similar to those reported for others binaphthyl-containing materials.4c During stretching experiments, all the LB, CB, LD and CD values were corrected by dividing the intensity measured with the corresponding maximum absorption in order to take into account the film thickness variation, in particular when the PDMS is stretched: LB(λ)*=LB(λ)/Abs. As expected, no CD signal (and no LB or LD as well) arose from rac-1@PDMS and undoped PDMS films, whereas symmetric CD shape curves were obtained for R- and S-doped polymer films. The main issue with CD measurement within materials (i.e. non-isotropic matrix) appeared when the latter was mechanically deformed inducing strong linear contributions coming from LD and LB to the CD signal and leading thus to possible misinterpretation. To decouple LD and LB from CD measurements and access them all independently, we measured all these values at carefully chosen angles compared to the PDMS film orientation (Section 5 in SI). Indeed, using the so-called Mueller matrices method, uniaxial optical material with isotropic chirality and light propagation perpendicular to the optical axis could be simply described without LB and LD cross terms.22 We therefore used a rotating sample holder and the measurements of both first and second harmonic signals to determine LD, LB, CB (circular birefringence) and CD independently on the same set-up without any artefact.23 All measurements were done using a home-made CD spectrophotometer adapted from previous investigations on chiral thin films.4b,c A specific stretching device adaptable to our spectrophotometer and allowing the stretching of PDMS films was also designed (Sections 4 and 5 in SI). The stretching ratio α was defined as the ratio of the lengths of film after and before stretching, multiplied by hundred. Finally, the validity of this approach was carefully checked using rac-1@PDMS, where no CD signals were observed even under high α values (Fig. S2).
Influence of the mechanical stretching on the PDMS chains orientation. The orientation of the PDMS polymer under unidirectional mechanical stretching of films was first investigated. This aspect was evaluated through the LB* measurement because LB* is the refractive index difference between the stretching axis and its 90° counterpart. We thus measured the LB values of undoped PDMS, R-1@PDMS and R-2@PDMS films at rest and at various α stretching ratio, up to 176% (Fig. 1a) and its evolution at λ=340 nm was plotted in Fig. 1b. As expected, strong LB* signals were recorded for all three films. In all cases, LB* spectra were nearly flat all along the spectral window studied between 260 and 380 nm, showing that the BINOL entities, mono or doubly crosslinked in the PDMS network, had no effect on the alignment of the host polymer chains in the stretching direction. Upon stretching from α=0 (when films were at rest), LB* increased linearly for stretching ratio α lower than 80% and the signal saturated with a maximum LB* value around 1 radian. Once again, this behavior was independent of the presence of BINOL and reflected an isotropic distribution of the PDMS chains at rest and an alignment along the stretching axis under high mechanical stress.
Influence of the mechanical stretching on the BINOL entities orientation. While LB, as a refractive index relative measurement, probes the overall PDMS chain orientation, LD*, as an absorption- related measurement, was sensitive to specific chromophore anisotropy, yielding information about the BINOL orientation according to the stretching ratio α (0, 25, 50, 75 and 100%) applied to the host PDMS material.23 The evolution of normalized LD* measured for undoped PDMS, R-1@PDMS and R-2@PDMS films according to the stretching ratio α are given in Fig 1c. Mono- grafted R-2@PDMS and undoped@PDMS films showed LD* signals with intensities ten times weaker than with the double- grafted ones R-1@PDMS. In addition, the spectral profile measured from 260 to 380 nm of R-2@PDMS film was hardly discernable from the one obtained in the case of the undoped@PDMS film revealing that the main contribution in LD signals for the mono-grafted R-2@PDMS film came almost exclusively from the PDMS chains stretching. On the contrary, in the case of the doubly BINOL-grafted R-1@PDMS film, LD* signals were 1 to 2 order of magnitude higher and displayed absorption profile bands as those anticipated for BINOL- containing materials. The evolution of the LD* intensity versus stretching was very similar to that of the LB* versus stretching for the PDMS@undoped films (Fig. 1d). These results highlighted that upon stretching, the mono-grafted BINOL did not follow the stream of the PDMS chains. Indeed, when the BINOLs were bound by only one side to the PDMS network through a long alkyl spacer, they have enough degree of freedom to orient themselves randomly, independently form the stretching state of the host material. Conversely for the R-1@PDMS film, double-grafted BINOL moieties aligned very well with the stretching force applied on their both arms, thus following the alignment of the PDMS chains.
Conformational changes of grafted BINOL through the mechanical stretching of PDMS. CD variation is a powerful tool to evaluate conformational variation of enantiopure compounds especially in the case of axial or helical chirality. In particular, CD activity of biaryl derivatives is known to be directly dependent on the dihedral angle between the aromatic planes and thus BINOL moiety constitutes an ideal probe for conformational changes measurement.21,25 CD* spectra of double-grafted BINOL, R- 1@PDMS and S-1@PDMS films, were recorded (Fig. 2a) and showed a gradual decrease of the CD* signal intensity upon stretching for both enantiomers. The decrease in CD* intensity was linearly dependent with the increase of the stretching ratio α up to 100% before levelling off (Fig. 2b). This CD* variation was in agreement with a conformational change of the BINOL induced by stretching of the host PDMS elastomer. As observed for the LD*, there was no variation of the CD* spectrum upon stretching
for the mono-grafted BINOL unit in R-2@PDMS or S-2@PDMS films (Fig. S3), reflecting that their conformation around the chiral axis of the BINOL was not affected by the applied stretching force. The lack of CD* spectra variation provides a clear evidence that the conformation change of the double grafted BINOL was induced only by the application of a mechanical force through the covalent bonds, rather than other factors, such as localized heating or radical generation from polymer chain cleavage during mechanical deformation.
From macroscopic mechanical stretching to the molecular force applied. Further insights of the mechanical force-induced BINOL conformational changes at the molecular level are obtained through QMC and MDS (see sections 8 and 9 in SI for details). We first optimized via QMC the conformations of the R- BINOL in which the naphthol groups are methoxylated (instead of a long alkyl chain) in order to reduce computational costs. In its most stable conformation the dihedral angle between both naphthalene rings was found to be -88.9° (Fig. S4). Starting from this conformation, the dihedral angle was then rotated by 30° in both clock and anticlockwise directions. Every 5° a geometry optimization was performed keeping the dihedral angle fixed. Hence a total of 11 conformers of R-BINOL with dihedral angles between -58.9° to -128.9° were obtained (Fig. S4 and section 9 in SI). CD spectra for every conformer was then calculated using the sTDA-xtb method.26 Comparison of these theoretical CD spectra with the experimental ones reported above when the R-1@PDMS film was gradually stretched (Fig. 2a) shows marked analogies for these conformers with a dihedral angle larger then -108.9 (Fig. 2c).
Figure 1. Optical linear anisotropy responses of R-1@PDMS and R-2@PDMS and undoped@PDMS films under uniaxial stretching: (a) LB spectra for various stretching ratio α, (b) evolution of LB* with stretching ratio α at λ=340 nm (measurements on different samples were plotted), (c) LD* spectra for various stretching ratio and (d) evolution of LD* intensity (340 nm) versus the stretching ratio α. Points having same color indicate different measurements the same α value of different samples.
Indeed, we observed two positive maxima located at ~270 nm and at ~310 nm, with the former having a higher intensity than the latter. A minimum band was also observed at ~335 nm. By increasing the dihedral angle from -108.9° to -128.9° we observed a simultaneous decrease in the intensity of both maxima (white part of Fig. 2d). This is fully in line with the evolution of the experimental CD spectra when R-1@PDMS film was stretched (Fig. 2a and 2b). For conformers outside this dihedral angle range, i.e. from -58.9° to -108.9°, at least one of these features was missing (grey part in Fig. 2d). Thus, considering that in the R- 1@PDMS film the BINOL dihedral angle should be at least at – 108.9° when the elastomer was at rest, the macroscopic stretching up to 170% results in an increase of the dihedral angle, opening the two naphthyl rings like the opening wings of a butterfly. Evolution of the deformation energy upon variation of the dihedral angle of R-BINOL revealed that a 20° change in the dihedral angle required less than 2 kJ.mol-1 making this conformer largely accessible at room temperature (Fig. S5). The marked difference of the dihedral angle value of above -108.9° when the R-1@PDMS film was at rest and the -88.9° observed for the optimized structure in the gas phase may come from the fact that during the preparation of the material, the crosslinking step between BINOL derivatives 1 and PDMS chains imposed a mechanical tension on the biaryl structure, opening it up from – 88.9° to above -109°. In order to have a rough estimation of the energy transferred at the molecular level when an external force is applied, we performed MDS studies in hexane. Hexane was chosen in order to take into account the highly hydrophobic feature of PDMS chains environment. A R-BINOL with octyl chains linked to each naphthol group was used as a model structure, and an external force in the range of 0.0001 to 4 kcal*mol-1*Å-1 was applied to both terminal methyl carbon atoms of the octyl chains. Each force was directed along the line linking both atoms with opposite directions. Increasing the force applied lead first to a reduction of the mobility of the octyl chains which align along the pulling line and only in a second stage, to the deformation of the dihedral angle of the R-BINOL moiety (Fig. 3a). A force value of about 2.5 kcal*mol-1*Å-1 (~175 pN) was strong enough to open the dihedral angle up to ~130° connecting so the stretching ratio α and the force felt by the BINOL at the molecular scale. Further increasing the applied force up to 4.0 kcal*mol-1*Å- 1 (~280 pN) did only lead to an additional increase in the dihedral angle of about 5° (Fig. S5) which may explain why no significant variation of the experimental CD spectra was observed for stretching the R-1@PDMS film above 100%.This behavior can be explained by the steric hindrance which prevents BINOLs to open more while the PDMS chains can still be stretched over longer distances.
Soft-mechanochemistry allows reversible and repeatable processes. When the R-1@PDMS film was stretched, the dihedral angle of the BINOL was increased and that value was kept as long as the elastomer was in the stretched state. To investigate the reversibility of the conformational change upon stretching, we carried out series of LD, LB CD and absorption measurements according to the stretching-releasing cycles realized using R-1@PDMS and S-1@PDMS. All LD, LB, CD, and absorption were recovered after the releasing of the mechanical stress and no hysteresis was observed, showing the ability of the polymer network to get back to its initial architecture. These data were used to extract CD* values evolution according to the stretching ratio α (Fig. 3b and Fig. S6). First, we observed that increasing α always lead to lower absolute CD* values. Importantly, when returning at rest between stretching steps, initial CD* values were recovered, highlighting the reversibility of the molecular conformation change through the mechanical stretching-releasing cycles of the material. This reversibility shows that the conformation change is only induced by the transduction way going from the macroscopic mechanical force to the BINOL.
Conclusion
The control of conformation changes using a macroscopic mechanical force as external stimulus was already reported in crystals but showing very low variation due to their highly rigid nature.17,18 Using more flexible systems and also well-ordered Langmuir-Blodgett 2D films, conformational changes of biaryl- derived surfactants through compression forces allowed a 10° variation of the dihedral angle.19,20 In this work, we demonstrated the possibility to tune the molecular conformation of BINOL crosslinked within a 3D polymer architecture through macroscopic stretching force applied unidirectionally to the material. Using PDMS as host system, a BINOL probe was disorderly distributed everywhere in the polymer network through a double crosslinking. Thanks to a simple and effective optical measurement set-up, we measured LB, LD and CD through the transparent elastomer according to the stretching degree applied to get information about both the polymer chains and BINOL conformations. The PDMS chains aligned with the stretching direction independently of the presence of BINOL. When stretched up to ~170%, the dihedral angle between the naphthyl- containing plans of BINOL increases continuously from ~110° to ~130°. Less than 2.5 kcal*mol-1*Å-1 was required to ensure this conformational switch of 20° in DA allowing thus a reversibility of the process when the mechanical stress was released, as expected for bioinspired soft-mechanical systems.11 The tuning of the BINOL conformation was controlled through the value of the stretching ratio applied. Other mechano-responsive systems presenting digital changes of BINOL dihedral angle due to phase transition have also been reported.27 In addition to the reversibility observed, all measurements were also repeatable, thus offering an external and easy-to-use mechanical tuning of atropisomers conformation. This paves the way towards the design of original catalytic or chiroptical materials,AUPM-170 fields in which our groups are currently involved.