Synthesis of electrochemically responsive TTF-based molecular tweezers: evidence of tight intramolecular TTF pairing in solution

We report the synthesis and conformational studies of TTF-containing molecular tweezers based on a 1,2,4,5-tetramethylbenzene scaffold. In the neutral form the tweezers are expected to adopt the closed conformation, while, upon oxidation, the open conformation should be preferred due to electrostatic repulsion between the oxidized TTF moieties. Cyclic voltammetry studies demonstrate electronic pairing with formation of mixed-valence [TTF]₂⁺ species and opening of the tweezers upon the full oxidation of the TTF groups. Variable-temperature (VT) NMR studies evidence tight intramolecular TTF pairing at low temperature. Molecular modeling studies showed clear preference for an open conformation of tweezers in a fully oxidized state.     

Molecular Tweezers: Concepts and Applications

Taken to the molecular level, the concept of “tweezers” opens a rich and fascinating field at the convergence of molecular recognition, biomimetic chemistry and nanomachines. Composed of a spacer bridging two interaction sites, the behaviour of molecular tweezers is strongly influenced by the flexibility of their spacer. Operating through an “induced‐fit” recognition mechanism, flexible molecular tweezers select the conformation(s) most appropriate for substrate binding. Their adaptability allows them to be used in a variety of binding modes and they have found applications in chirality signalling. Rigid spacers, on the contrary, display a limited number of binding states, which lead to selective and strong substrate binding following a “lock and key” model. Exquisite selectivity may be expressed with substrates as varied as C₆₀, nanotubes and natural cofactors, and applications to molecular electronics and enzyme inhibition are emerging. At the crossroad between flexible and rigid spacers, stimulus‐responsive molecular tweezers controlled by ionic, redox or light triggers belong to the realm of molecular machines, and, applied to molecular tweezing, open doors to the selective binding, transport and release of their cargo. Applications to controlled drug delivery are already appearing. The past 30 years have seen the birth of molecular tweezers; the next many years to come will surely see them blooming in exciting applications.     

Redox responsive molecular tweezers with tetrathiafulvalene units: synthesis, electrochemistry, and binding properties

Several new molecular tweezers with tetrathiafulvalene (TTF) arms as well as mono-TTF derivatives bearing 3,5-di-tert-butylbenzylthio groups to provide enhanced solubility were prepared starting from a bis-cyanoethyl-protected tetrathiafulvalene derivative. The X-ray crystallographic analysis of 3 and 7a showed highly distorted TTF groups and absence of close TTF-TTF contacts in the crystalline state. Comparative cyclic voltammetry (CV) measurements demonstrated that through space distance-dependent TTF-TTF interactions take place in the TTF-containing molecular tweezers, leading to electronic pairing with formation of mixed valence [TTF]₂⁺ species and splitting of the first oxidation wave. TTF-containing molecular tweezers were successfully tested as receptors for several electron-deficient substances.     

A photoswitchable strapped calix[4]pyrrole receptor: highly effective chloride binding and release

A stiff-stilbene strapped calix[4]pyrrole receptor can be reversibly switched by light between a strong chloride-binding Z-isomer and a very weakly binding E-isomer. The light-induced switching process is monitored by UV-Vis and ¹H NMR spectroscopy and chloride binding is studied in detail using both ¹H NMR and ITC titrations in DMSO and MeCN. In DMSO, at millimolar concentrations, switching from a fully bound to an almost fully unbound state can be triggered. Quantification of the binding constants in MeCN reveals an extraordinary 8000-fold affinity difference between the Z- and E-isomer. Single crystal X-ray crystallographic analysis gives insight into the structure of the photogenerated E-isomer and the geometry of the chloride-bound receptors is optimized by DFT calculations. The highly effective control of binding affinity demonstrated in this work opens up new prospects for on demand binding and release in extractions and photocontrol of membrane transport processes, among other applications.

A reconfigurable calix[4]pyrrole receptor containing a stiff-stilbene strap can be switched by light between a strong and weak binding form, showing an 8000-fold affinity difference for chloride.     

Molecular clips and tweezers with corannulene pincers

Application of the synthetic methodology developed in our laboratory yields molecular clips and tweezers with corannulene pincers and cyclooctadiene or cyclooctatetraene tethers. These highly nonplanar systems possess a potential for binding guest molecules of various sizes. One of the clips, bis(benzocorannulene)[a,e]cyclooctadiene, exists in a ‘open’ chair conformation encapsulating solvating nitrobenzene in the solid state, while it is expected to prefer an internally π-π stacked twist-boat conformation in the gas phase.     

Drug release by pH‐responsive molecular tweezers: Atomistic details from molecular modeling

pH‐responsive molecular tweezers have been proposed as an approach for targeting drug‐delivery to tumors, which tend to have a lower pH than normal cells. We performed a computational study of a pH‐responsive molecular tweezer using ab initio quantum chemistry in the gas‐phase and molecular dynamics (MD) simulations in solution. The binding free energy in solution was calculated using steered MD. We observe, in atomistic detail, the pH‐induced conformational switch of the tweezer and the resulting release of the drug molecule. Even when the tweezer opens, the drug molecule remains near a hydrophobic arm of the molecular tweezer. Drug release cannot occur, it seems, unless the tweezer is in a hydrophobic environment with low pH. © 2014 Wiley Periodicals, Inc.     

Measurement of Ibuprofen Binding to Mixed Monolayers Containing β-Cyclodextrin Active Sites

A molecular imprinting method involving a three-step sequential self-assembly procedure was applied to prepare gold electrodes responsive towards ibuprofen. The electrode modified with the cyclodextrin derivative binds ferrocene to form an electroactive complex with the ferrocene oxidation current decreasing in the presence of ibuprofen in the solution. The competition of ferrocene and ibuprofen for the cyclodextrin cavities in the monolayer provided a means for the determination of the binding constants of ibuprofen with two derivatives of lipoylamide β-cyclodextrin of different hydrophobicity.     

Photoelectrochemical water oxidation improved by pyridine N-oxide as a mimic of tyrosine-Z in photosystem II

Artificial photosynthesis provides a way to store solar energy in chemical bonds with water oxidation as a major challenge for creating highly efficient and robust photoanodes that mimic photosystem II. We report here an easily available pyridine N-oxide (PNO) derivative as an efficient electron transfer relay between an organic light absorber and molecular water oxidation catalyst on a nanoparticle TiO₂ photoanode. Spectroscopic and kinetic studies revealed that the PNO/PNO⁺˙ couple closely mimics the redox behavior of the tyrosine/tyrosyl radical pair in PSII in improving light-driven charge separation via multi-step electron transfer. The integrated photoanode exhibited a 1 sun current density of 3 mA cm⁻² in the presence of Na₂SO₃ and a highly stable photocurrent density of >0.5 mA cm⁻² at 0.4 V vs. NHE over a period of 1 h for water oxidation at pH 7. The performance shown here is superior to those of previously reported organic dye-based photoanodes in terms of photocurrent and stability.

Stable and high photocurrent for water oxidation was achieved by an organic dye-sensitized photoanode with a pyridine N-oxide derivative as an efficient electron relay between the chromophore and molecular water oxidation catalyst.     

Mutually exclusive hole and electron transfer coupling in cross stacked acenes

The topology of frontier molecular orbitals (FMOs) induces highly sensitive charge transfer coupling with variation in the intermolecular arrangement. A consistent optoelectronic property correlated to a specific aggregate architecture independent of the nature of the monomer is a rare phenomenon. Our theoretical investigation on stacked dimeric systems of linear [n]acenes (n = 2–5) and selected non-linear acenes with a D_2h point group reveals that the Greek cross (+) stacked orientation, irrespective of the molecular candidate, exhibits mutually exclusive hole and electron transfer couplings. The deactivation of either hole or electron transfer coupling is a consequence of the zero inter-orbital overlap between the highest occupied molecular orbitals (HOMOs) or lowest unoccupied molecular orbitals (LUMOs) of the monomers possessing gerade symmetry. In the Greek cross (+) stacked alignment, the (4n + 2) π-electronic acene systems with an odd number of benzenoids exhibit exclusive electron transfer coupling, while the even numbered acenes exhibit selective hole transfer coupling. The trend is reversed for representative 4n π-electronic acene systems. The effect of mutually exclusive charge transfer coupling in the hopping regime of charge transport was evaluated using semiclassical Marcus theory, and selective charge carrier mobility was exhibited by the Greek cross (+) stacks of the considered acene candidates. Additionally, the characteristic charge transfer coupling of the orthogonal acene stacks resulted in negligible short-range exciton coupling, inciting null exciton splitting at short interplanar distances. Engineering chromophores in precise angular orientations ensuring characteristic emergent properties can have tremendous potential in the rational design of advanced optoelectronic materials.

Acenes in the Greek cross (+) stack orientation exhibit selective hole and electron transfer coupling based on gerade symmetry in frontier molecular orbitals.     

胆甾类分子钳对氨基酸衍生物的对映选择性识别

用差紫外光谱滴定法考察了以脱氧胆酸作spacer的手性分子钳1～3对一系列α-氨基酸甲酯的对映选择性识别性能。结果表明,分子钳1和2与客体氨基酸甲酯形成1:1型超分子配合物,并显示较好的手性识别能力。分钳3对所考察的氨基酸甲酯均没有明显的识别作用。讨论了主-客体间尺寸/形状匹配、几何互补等因素对形成超分子配合物的影响,并利用计算机模拟作辅助手段对实验结果和现象进行了解释。     

Light-driven release of cucurbit[8]uril from a bivalent cage

Temporal control over supramolecular systems has great potential for the modulation of binding and assembly events, such as providing orthogonal control over protein activity. Especially light controlled triggering provides unique entries for supramolecular systems to interface in a controlled manner with enzymes. Here we report on the light-induced release of cucurbit[8]uril (CB[8]) from a bivalent cage molecule and its subsequent activation of a proteolytic enzyme, caspase-9, that itself is unresponsive to light. Central to the design is the bivalent binding of the cage with high affinity to CB[8], 100-fold stronger than the UV-inactivated products. The affinity switching occurs in the (sub-)micromolar concentration regime, matching the concentration characteristics required for dimerizing and activating caspase-9 by CB[8]. The light-responsive caged CB[8] concept presented offers a novel platform for tuning and application of switchable cucurbiturils and beyond.

Photo-switchable supramolecular systems offer unique entries to control biomolecular process, as illustrated via the light-induced release of cucurbit[8]uril from a bivalent cage molecule and its subsequent activation of the caspase-9 enzyme.     

Tailoring the optical and dynamic properties of iminothioindoxyl photoswitches through acidochromism

Multi-responsive functional molecules are key for obtaining user-defined control of the properties and functions of chemical and biological systems. In this respect, pH-responsive photochromes, whose switching can be directed with light and acid–base equilibria, have emerged as highly attractive molecular units. The challenge in their design comes from the need to accommodate application-defined boundary conditions for both light- and protonation-responsivity. Here we combine time-resolved spectroscopic studies, on time scales ranging from femtoseconds to seconds, with density functional theory (DFT) calculations to elucidate and apply the acidochromism of a recently designed iminothioindoxyl (ITI) photoswitch. We show that protonation of the thermally stable Z isomer leads to a strong batochromically-shifted absorption band, allowing for fast isomerization to the metastable E isomer with light in the 500–600 nm region. Theoretical studies of the reaction mechanism reveal the crucial role of the acid–base equilibrium which controls the populations of the protonated and neutral forms of the E isomer. Since the former is thermally stable, while the latter re-isomerizes on a millisecond time scale, we are able to modulate the half-life of ITIs over three orders of magnitude by shifting this equilibrium. Finally, stable bidirectional switching of protonated ITI with green and red light is demonstrated with a half-life in the range of tens of seconds. Altogether, we designed a new type of multi-responsive molecular switch in which protonation red-shifts the activation wavelength by over 100 nm and enables efficient tuning of the half-life in the millisecond–second range.

Protonation of an ITI molecular photoswitch shifts its absorption to the orange/red part of the spectrum and allows for manipulation of the thermal half-life of the photogenerated E-isomer over three orders of magnitude.     

Molecular recognition in molecular tweezers systems: quantum-chemical calculation of NMR chemical shifts

Quantum-chemical calculations for molecular tweezers systems are presented, where the focus is not only on the recognition process in the host-guest systems, but on the self aggregation of the tweezers host as well. Such intermolecular interactions influence the corresponding NMR spectra strongly by up to 6 ppm for proton chemical shifts, since ring-current effects are particularly important. The quantum-chemical results allow one to reliably assign the spectra and to gain information both on the structure and on the importance of intra- and intermolecular interactions. In addition, we study the accuracy of a variety of density functionals for describing the present host-guest systems, where we observe a considerable underestimation of ring-current effects on (1)H NMR chemical shifts at the density functional theory (DFT) level using smaller basis sets such as 6-31G**, so that larger bases like TZP are required. This stands in contrast to the behavior of the Hartree-Fock scheme, where small basis sets, such as 6-31G**, provide reliable (1)H NMR shieldings for molecular tweezers systems.     

Photochromic and molecular switching behaviour of Schiff base-containing pyrazolone ring

A new Schiff base compound, 4-[[(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)methylidene] amino]-1,5-dimethyl-2-phenyl-2,3-dihydro-1H-pyrazol-3-one (I), was synthesised and characterised by elemental analysis and LC-MS, FTIR and ¹H NMR spectra. The photochromic property of the synthesised compound investigated under 365 nm UV irradiation can be observed by solid state absorption and fluorescence spectra. The kinetic study showed that the photochromic reaction was of the pseudo-first-order. The photo-isomerisation was due to photo-induced intermolecular hydrogen bonding, which resulted in enol to keto transformation. The molecular switching behaviour was studied in solution with two inputs in three different systems (OH^? and Ag⁺), (OH^? and Cd²⁺) and (OH^? and Th⁴⁺) based on the UV absorption spectra. It exhibited the logic behaviour of XNOR, AND and NOR for Ag⁺,Cd²⁺ and Th⁴⁺ in alkaline media, respectively.     

Mechanofluorochromism of heteropolycyclic donor-π-acceptor type fluorescent dyes

This paper reports that mechanofluorochromism is found for a series of benzofuro[2,3-c]oxazolo[4,5-a]carbazole-type fluorophores (1a-5a) with different p-substituted phenyl groups as acceptor and dibutylamino groups as donor. Grinding of as-recrystallized dyes 1a-3a with strong electron-accepting group induces a fluorescent color change with an enhanced quantum yield and the fluorescent color is recovered by heating or exposure to solvent vapor. On the basis of experimental results and semi-empirical molecular orbital calculations (AM1 and INDO/S), we clarified that the mechanofluorochromism is attributed to a reversible switching between crystalline and amorphous states with changes of dipole-dipole interaction and intermolecular π-π interaction by changes of the densities of the solids before and after grinding.     

Uncovering the interactions driving carotenoid binding in light-harvesting complexes

Carotenoids are essential constituents of plant light-harvesting complexes (LHCs), being involved in protein stability, light harvesting, and photoprotection. Unlike chlorophylls, whose binding to LHCs is known to require coordination of the central magnesium, carotenoid binding relies on weaker intermolecular interactions (such as hydrogen bonds and van der Waals forces), whose character is far more elusive. Here we addressed the key interactions responsible for carotenoid binding to LHCs by combining molecular dynamics simulations and polarizable quantum mechanics/molecular mechanics calculations on the major LHC, LHCII. We found that carotenoid binding is mainly stabilized by van der Waals interactions with the surrounding chlorophyll macrocycles rather than by hydrogen bonds to the protein, the latter being more labile than predicted from structural data. Furthermore, the interaction network in the binding pockets is relatively insensitive to the chemical structure of the embedded carotenoid. Our results are consistent with a number of experimental data and challenge the role played by specific interactions in the assembly of pigment-protein complexes.

Carotenoids are essential constituents of plant light-harvesting complexes. This in silico study shows that carotenoid binding is mainly driven by van der Waals interactions with the surrounding chlorophylls rather than hydrogen bonds to the protein.     

Mapping the cooperativity pathways in spin crossover complexes

Crystal packing energy calculations are applied to the [Fe(PM-L)₂(NCS)₂] family of spin crossover (SCO) complexes (PM-L = 4-substituted derivatives of the N-(2-pyridylmethylene)-4-aminobiphenyl ligand) with the aim of relating quantitatively the cooperativity of observed SCO transitions to intermolecular interactions in the crystal structures. This approach reveals a linear variation of the transition abruptness with the sum of the magnitudes of the interaction energy changes within the first molecular coordination sphere in the crystal structure. Abrupt transitions are associated with the presence of significant stabilising and destabilising changes in intermolecular interaction energies. While the numerical trend established for the PM-L family does not directly extend to other classes of SCO complex in which the intermolecular interactions may be very different, a plot of transition abruptness against the range of interaction energy changes normalised by the largest change shows a clustering of complexes with similar transition abruptness. The changes in intermolecular interactions are conveniently visualised using energy difference frameworks, which illustrate the cooperativity pathways of an SCO transition.

The abruptness of spin crossover (SCO) is related to intermolecular energy changes occurring over the course of an SCO transition. Crossover is abrupt when SCO-induced strain is accommodated synergistically in a few key interactions.     

Recognition competes with hydration in anion-triggered monolayer formation of cyanostar supra-amphiphiles at aqueous interfaces

The triggered self-assembly of surfactants into organized layers at aqueous interfaces is important for creating adaptive nanosystems and understanding selective ion extraction. While these transformations require molecular recognition, the underlying driving forces are modified by the local environment in ways that are not well understood. Herein, we investigate the role of ion binding and ion hydration using cyanosurf, which is composed of the cyanostar macrocycle, and its binding to anions that are either size-matched or mis-matched and either weakly or highly hydrated. We utilize the supra-amphiphile concept where anion binding converts cyanosurf into a charged and amphiphilic complex triggering its self-organization into monolayers at the air–water interface. Initially, cyanosurf forms aggregates at the surface of a pure water solution. When the weakly hydrated and size-matched hexafluorophosphate (PF₆⁻) and perchlorate (ClO₄⁻) anions are added, the macrocycles form distinct monolayer architectures. Surface-pressure isotherms reveal significant reorganization of the surface-active molecules upon anion binding while infrared reflection absorption spectroscopy show the ion-bound complexes are well ordered at the interface. Vibrational sum frequency generation spectroscopy shows the water molecules in the interfacial region are highly ordered in response to the charged monolayer of cyanosurf complexes. Consistent with the importance of recognition, we find the smaller mis-matched chloride does not trigger the transformation. However, the size-matched phosphate (H₂PO₄⁻) also does not trigger monolayer formation indicating hydration inhibits its interfacial binding. These studies reveal how anion-selective recognition and hydration both control the binding and thus the switching of a responsive molecular interface.

The selective binding of anions transform macrocycles into amphiphiles that form monolayers on the surface of water depending upon the relative roles of anion hydration and anion recognition.     

Molecular clips and tweezers hosting neutral guests

Intense current interest in supramolecular chemistry is devoted to the construction of molecular assemblies displaying controlled molecular motion associated to recognition. On this ground, molecular clips and tweezers have focused an increasing attention. This tutorial review points out the recent advances in the construction of always more sophisticated molecular clips and tweezers, illustrating their remarkably broad structural variety and focusing on their binding ability towards neutral guests. A particular attention is brought to recent findings in dynamic molecular tweezers whose recognition ability can be regulated by external stimuli. Porphyrin-based systems will not be covered here as this very active field has been recently reviewed.     

Desymmetrised pentaporphyrinic gears mounted on metallo-organic anchors

Mastering intermolecular gearing is crucial for the emergence of complex functional nanoscale machineries. However, achieving correlated motion within trains of molecular gears remains highly challenging, due to the multiple degrees of freedom of each cogwheel. In this context, we designed and synthesised a series of star-shaped organometallic molecular gears incorporating a hydrotris(indazolyl)borate anchor to prevent diffusion on the surface, a central ruthenium atom as a fixed rotation axis, and an azimuthal pentaporphyrinic cyclopentadienyl cogwheel specifically labelled to monitor its motion by non-time-resolved Scanning Tunneling Microscopy (STM). Desymmetrisation of the cogwheels was first achieved sterically, i.e. by introducing one tooth longer than the other four. For optimal mechanical interactions, chemical labelling was also investigated as a preferential way to induce local contrast in STM images, and the electronic properties of one single paddle were modulated by varying the porphyrinic scaffold or the nature of the central metal. To reach such a structural diversity, our modular synthetic approach relied on sequential cross-coupling reactions on a penta(p-halogenophenyl)cyclopentadienyl ruthenium(ii) key building block, bearing a single pre-activated p-iodophenyl group. Chemoselective Sonogashira or more challenging Suzuki–Miyaura reactions allowed the controlled introduction of the tagged porphyrinic tooth, and the subsequent four-fold cross-couplings yielded the prototypes of pentaporphyrinic molecular gears for on-surface studies, incorporating desymmetrised cogwheels over 5 nm in diameter.

Star-shaped cogwheel prototypes incorporating one sterically- or chemically-labelled porphyrinic paddle were designed and synthesised with the aim of achieving intermolecular gearing on surfaces.