High-Affinity Hybridization of Complementary Aromatic Oligoamide Strands in Water.

We prepared a series of water-soluble aromatic oligoamide sequences all composed of a segment prone to form a single helix and a segment prone to dimerize into a double helix. These sequences exclusively assemble as antiparallel duplexes. The modification of the duplex inner rim by varying the nature of the substituents borne by the aromatic monomers allowed us to identify sequences that can hybridize by combining two chemically different strands, with high affinity and complete selectivity in water. X-ray crystallography confirmed the expected antiparallel configuration of the duplexes whereas NMR spectroscopy and mass spectrometry allowed us to assess precisely the extent of the hybridization. The hybridization kinetics of the aromatic strands was shown to depend on both the nature of the substituents responsible for strand complementarity and the length of the aromatic strand. These results highlight the great potential of aromatic hetero-duplex as a tool to construct non-symmetrical dynamic supramolecular assemblies.

Controlling aromatic helix dimerization in water by tuning charge repulsions.

Several helically folded aromatic oligoamides were designed and synthesized. The sequences were all water-soluble thanks to the charged side chains borne by the monomers. Replacing a few, sometimes only two, charged side chains by neutral methoxy groups was shown to trigger the formation of various aggregates which could be tentatively assigned to head-to-head stacked dimers of single helices, double helical duplexes and a quadruplex, none of which would form in organic solvent with organic-soluble analogues. The nature of the aggregates was supported by concentration and solvent dependent NMR studies, 1H DOSY experiments, mass spectrometry, and X-ray crystallography or energy-minimized models, as well as analogies with earlier studies. The hydrophobic effect appears to be the main driving force for aggregation but it can be finely modulated by the presence or absence of a small number of charges to an extent that had no precedent in aromatic foldamer architectures. These results will serve as a benchmark for future foldamer design in water.

High-affinity single and double helical pseudofoldaxanes with cationic guests.

Two aromatic oligoamides, the 8-residue H8 and 16-residue H16, that adopt stable, cavity-containing helical conformations were examined for their complexation of a rodlike dicationic guest, octyl viologen (OV2+) and para-bis(trimethylammonium)benzene (TB2+). Studies based on 1D and 2D 1H NMR, isothermal titration calorimetry (ITC), and X-ray crystallography demonstrated that H8 and H16 wraps around two OV2+ ions as a double helix and a single helix, respectively, resulting in 2 : 2 and 1 : 2 complexes. Compared to H8, the longer H16 binds the OV2+ ions with much higher binding affinity and with extraordinary negative cooperativity. In contrast to its 1 : 2 binding with OV2+, the binding of helix H16 with the bulkier guest TB2+ shows a 1 : 1 ratio. Host H16 also selectively binds OV2+ in the presence of TB2+. This novel host-guest system features pairwise placement of the otherwise strongly repulsive OV2+ ions in the same cavity, strong negative cooperativity, and mutual adaptability of hosts and guests. The resultant complexes are highly stable [2]-, [3]-, and [4]pseudo-foldaxanes with few known precedents.

Combining local conformational preferences and solvophobic effects in helical aromatic oligoamide foldamers.

Aromatic oligoamide foldamers were designed using a newly-developed monomer so that helical folding was promoted by both local conformation preferences and solvophobic effects. Solid phase synthesis provided quick access to the desired sequences. Sharp solvent-driven conformational transitions that depended on sequence length were evidenced by both NMR and UV absorption spectroscopies.

CPL-active water-soluble aromatic oligoamide foldamers.

A series of enantiopure water-soluble quinoline-based foldamers were prepared and their optical and chiroptical properties in water were investigated. The new hexameric sequences incorporated either cationic or anionic water-solubilizing chains, and one of the oligomers was additionally functionalized by an electron donating moiety to further modulate the optoelectronic properties. A systematic study revealed strong electronic circular dichroism and circularly-polarized luminescence properties in water, with dissymmetry factors up to 2 × 10-2 in absorption and 5 × 10-3 in emission, regardless of the nature of the solubilizing chains and functions. This study therefore highlights new opportunities for the development of water-soluble and chiroptically-active artificial systems towards chirality-associated applications in aqueous or biological media.

A pH- and Metal-Actuated Molecular Shuttle in Water.

The structure of the Viologen-Phenylene-Imidazole (VPI) guest, previously shown to be bound by cucurbit[7]uril (CB[7]) with binding modes depending on pH and silver ions, has been extended by adding hydrophobic groups on the two extremities of VPI before investigations of CB[7] binding by NMR, ITC, X-ray diffraction, UV-vis and fluorescence spectroscopies. With an imidazole station extended by a naphthalene group (VPI-N), binding modes of CB[7] are similar to those previously observed. However, with the viologen extended by a tolyl group (T-VPI), CB[7] preferentially sits on station T, shuttling between the T and P stations at acid pH or after Ag+ addition. The CB[7] ⋅ T-VPI complex thus behaves as a metal-actuated thermodynamic stop-and-go molecular shuttle featured by fast and autonomous ring translocation between two stations and a continuum for fractional station occupancy solely and easily controlled by Ag+ concentration.

Operating room design using agent-based simulation to reduce room obstructions.

This study seeks to improve the safety of clinical care provided in operating rooms (OR) by examining how characteristics of both the physical environment and the procedure affect surgical team movement and contacts. We video recorded staff movements during a set of surgical procedures. Then we divided the OR into multiple zones and analyzed the frequency and duration of movement from origin to destination through zones. This data was abstracted into a generalized, agent-based, discrete event simulation model to study how OR size and OR equipment layout affected surgical staff movement and total number of surgical team contacts during a procedure. A full factorial experiment with seven input factors - OR size, OR shape, operating table orientation, circulating nurse (CN) workstation location, team size, number of doors, and procedure type - was conducted. Results were analyzed using multiple linear regression with surgical team contacts as the dependent variable. The OR size, the CN workstation location, and team size significantly affected surgical team contacts. Also, two- and three-way interactions between staff, procedure type, table orientation, and CN workstation location significantly affected contacts. We discuss implications of these findings for OR managers and for future research about designing future ORs.

[3]Foldarotaxane-mediated synthesis of an improbable [2]rotaxane.

The wrapping of an aromatic oligoamide helix around an active ester-containing [2]rotaxane enforced the sliding and the sequestration of the surrounding macrocycle around a part of the axle for which it has no formal affinity. The foldamer-mediated compartmentalization of the [2]rotaxane shuttle was subsequently used to prepare an improbable rotaxane.

Self-assembling figure-of-eight and pseudoplectoneme aromatic oligoamide ribbons.

Two oligoamide macrocycles composed of eight and twelve 7-amino-8-fluoro-2-quinolinecarboxylic acid monomers were synthesised despite the propensity of their acyclic precursors to fold and self-assemble into double helices. Macrocyclisations were made possible through the transient use of helicity disruptors. The resulting macrocyclic ribbons were found to adopt figure-of-eight and pseudoplectoneme shapes that maintain an ability to self-assemble.

Selective and Cooperative Photocycloadditions within Multistranded Aromatic Sheets.

A series of aromatic helix-sheet-helix oligoamide foldamers composed of several different photosensitive diazaanthracene units have been designed and synthesized. Molecular objects up to 7 kDa were straightforwardly produced on a 100 mg scale. Nuclear magnetic resonance and crystallographic investigations revealed that helix-sheet-helix architectures can adopt one or two distinct conformations. Sequences composed of an even number of turn units were found to fold in a canonical symmetrical conformation with two helices of identical handedness stacked above and below the sheet segment. Sequences composed of an odd number of turns revealed a coexistence between a canonical fold with helices of opposite handedness and an alternate fold with a twist within the sheet and two helices of identical handedness. The proportions between these species could be manipulated, in some cases quantitatively, being dependent on solvent, temperature, and absolute control of helix handedness. Diazaanthracene units were shown to display distinct reactivity toward [4 + 4] photocycloadditions according to the substituent in position 9. Their organization within the sequences was programmed to allow photoreactions to take place in a specific order. Reaction pathways and kinetics were deciphered and product characterized, demonstrating the possibility to orchestrate successive photoreactions so as to avoid orphan units or to deliberately produce orphan units at precise locations. Strong cooperative effects were observed in which the photoreaction rate was influenced by the presence (or absence) of photoadducts in the structure. Multiple photoreactions within the aromatic sheet eventually lead to structure lengthening and stiffening, locking conformational equilibria. Photoproducts could be thermally reverted.

Foldaxanes: Rotaxane-like Architectures from Foldamers.

Mechanically interlocked molecules such as rotaxanes and catenanes contain free-moving components that cannot dissociate and have enabled the investigation and control of various translational and rotational molecular motions. The architecture of pseudo-rotaxanes and of some kinetically labile rotaxanes is comparable to that of rotaxanes but their components are reversibly associated and not irreversibly interlocked. In other words, pseudo-rotaxanes may fall apart. This Account focuses on a peculiar family of rotaxane-like architectures termed foldaxanes.Foldaxanes consist of a helically folded oligomer wound around a rod-like dumbbell-shaped guest. Winding of the helix around the rod thus entails an unwinding-rewinding process that creates a kinetic barrier. It follows that foldaxanes, albeit reversibly assembled, have significant lifetimes and may not fall apart while defined molecular motions are triggered. Foldaxanes based on helically folded aromatic oligoamide hosts and oligo(alkyl carbamate) guests can be designed rationally through the inclusion of complementary binding motifs on the rod and at the inner rim of the helix so that helix length and rod length match. Single helical foldaxanes (bimolecular species) and double helical foldaxanes (trimolecular species) have thus been produced as well as poly[n]foldaxanes, in which several helices bind to long rods with multiple binding stations. When the binding stations differ and are organized in a certain sequence, a complementary sequence of different stacked helices, each matching with their binding station, can be assembled, thus reproducing in an artificial system a sort of translation process.Foldaxane helix handedness may be controlled by stereogenic centers on the rod-like guest. Handedness can also be transmitted from helix to helix in polyfoldaxanes. Foldaxane formation has drastic consequences for the rod properties, including its stiffening and the restriction of the mobility of a macrocycle already interlocked on the rod. Fast translation (without dissociation) of helices along rod-like guests has been demonstrated. Because of the helical nature of the hosts, translation may be accompanied by rotation in various sorts of screw-like motions. The possibility, on longer time scales, for the helix to dissociate from and reassociate to the rod has allowed for the design of complex, kinetically controlled supramolecular pathways of a helix on a rod. Furthermore, the design of helices with a directionality, that is, with two distinct termini, that bind to nonsymmetrical rod-like guests in a defined orientation makes it possible to also control the orientation of molecular motion. Altogether, foldaxanes constitute a distinct and full-of-potential family of rotaxane-like architectures that possess designer structures and allow orchestration of the time scales of various supramolecular events.

Stable pseudo[3]rotaxanes with strong positive binding cooperativity based on shape-persistent aromatic oligoamide macrocycles.

New aromatic oligoamide macrocycles with C3-symmetry bind a bipyridinium guest (G) to form compact pseudo[3]rotaxanes involving interesting enthalpic and entropic contributions. The observed high stabilities and strong positive binding cooperativity are found in few other host-guest systems.

Sensing a binding event through charge transport variations using an aromatic oligoamide capsule.

The selective binding properties of a 13-mer oligoamide foldamer capsule composed of 4 different aromatic subunits are reported. The capsule was designed to recognize dicarboxylic acids through multiple-point interactions owing to a combination of protonation/deprotonation events, H-bonding, and geometrical constraints imparted by the rigidity of the foldamer backbone. Compared to tartaric acid, binding of 2,2-difluorosuccinic acid or 2,2,3,3-tetrafluorosuccinic acid resulted in symmetry breaking due to deprotonation of only one of the two carboxylic acid groups of the encapsulated species as shown by NMR studies in solution and by single-crystal X-ray diffraction in the solid state. An analogous 14-mer foldamer capsule terminated with a thiol anchoring group was used to probe the complexation event in self-assembled monolayers on Au substrates. Ellipsometry and polarization-modulation infrared absorption-reflection spectroscopy studies were consistent with the formation of a single molecule layer of the foldamer capsule oriented vertically with respect to the surface. The latter underwent smooth complexation of 2,2-difluorosuccinic acid with deprotonation of one of the two carboxylic acid groups. A significant (80-fold) difference in the charge transport properties of the monolayer upon encapsulation of the dicarboxylic acid was evidenced from conducting-AFM measurements (S = 1.1 × 10-9 vs. 1.4 × 10-11 ohm-1 for the empty and complexed capsule, respectively). The modulation in conductivity was assigned to protonation of the aromatic foldamer backbone.

Accessing Improbable Foldamer Shapes with Strained Macrocycles.

The alkylation of some secondary amide functions with a dimethoxybenzyl (DMB) group in oligomers of 8-amino-2-quinolinecarboxylic acid destabilizes the otherwise favored helical conformations, and allows for cyclization to take place. A cyclic hexamer and a cyclic heptamer were produced in this manner. After DMB removal, X-ray crystallography and NMR show that the macrocycles adopt strained conformations that would be improbable in noncyclic species. The high helix folding propensity of the main chain is partly expressed in these conformations, but it remains frustrated by macrocyclization. Despite being homomeric, the macrocycles possess inequivalent monomer units. Experimental and computational studies highlight specific fluxional pathways within these structures. Extensive simulated annealing molecular dynamics allow for the prediction of the conformations for larger macrocycles with up to sixteen monomers.

Influence of Positional Isomerism on the Chiroptical Properties of Functional Aromatic Oligoamide Foldamers.

A series of functionalized quinoline-based aromatic oligoamide foldamers were prepared in their two enantiomeric forms, comprising an enantiopure terminal camphanyl chiral inducer, which governed the adjacent (P-/M-) helical-handedness. Hierarchical chirality transfer was further investigated in chromophore-appended variants via a range of electronic and vibrational spectroscopic techniques, including circularly polarized luminescence, vibrational circular dichroism and fluorescence. Intense total and polarized photoluminescence (up to Φlum =0.39, glum =1.5×10-3 ) was observed in the visible region from these modular multicomponent architectures and a significant influence of positional isomerism was evidenced. The optimal position of a fluorophore substituent on the quinoline hexamers was determined as being position 2 over position 6, as stronger chiroptical features were systematically observed with the 2-positioned derivatives.

Interplay between a Foldamer Helix and a Macrocycle in a Foldarotaxane Architecture.

The design and synthesis of a novel rotaxane/foldaxane hybrid architecture is reported. The winding of an aromatic oligoamide helix host around a dumbbell-shaped thread-like guest, or axle, already surrounded by a macrocycle was evidenced by NMR spectroscopy and X-ray crystallography. The process proved to depend on the position of the macrocycle along the axle and the associated steric hindrance. The macrocycle thus behaves as a switchable shield that modulates the affinity of the helix for the axle. Reciprocally, the foldamer helix acts as a supramolecular auxiliary that compartmentalizes the axle. In some cases, the macrocycle is forced to move along the axle to allow the foldamer to reach its best recognition site.

Light-mediated chiroptical switching of an achiral foldamer host in presence of a carbohydrate guest.

A photoresponsive diarylethene was incorporated in an achiral helical foldamer container. A carbohydrate guest was found to induce opposite handedness upon binding to the open and closed forms of the diarylethene-containing foldamer, thus enabling chiroptical switching of an achiral host mediated by a chiral guest.

Multiturn Hollow Helices: Synthesis and Folding of Long Aromatic Oligoamides.

Aromatic oligoamides adopting helical conformations are synthesized by coupling carboxyl-terminated basic units having two, four, and eight residues to amine-terminated oligomer precursors. Coupling yields show no noticeable reduction with the size of the basic units or the final product. One- and two-dimensional NMR spectroscopy and computational studies demonstrate the reliable helical folding of these oligomers. The X-ray structure of 16mer 7 reveals a compact, multiturn helix having a 9 Å inner pore.

Aromatic foldamers as scaffolds for metal second coordination sphere design.

As metalloproteins exemplify, the chemical and physical properties of metal centers depend not only on their first but also on their second coordination sphere. Installing arrays of functional groups around the first coordination sphere of synthetic metal complexes is thus highly desirable, but it remains a challenging objective. Here we introduce a novel approach to produce tailored second coordination spheres. We used bioinspired artificial architectures based on aromatic oligoamide foldamers to construct a rigid, modular and well-defined environment around a metal complex. Specifically, aza-aromatic monomers having a tethered [2Fe-2S] cluster have been synthesized and incorporated in conical helical foldamer sequences. Exploiting the modularity and predictability of aromatic oligoamide structures allowed for the straightforward design of a conical architecture able to sequester the metal complex in a confined environment. Even though no direct metal complex-foldamer interactions were purposely designed in this first generation model, crystallography, NMR and IR spectroscopy concurred to show that the aromatic oligoamide backbone alters the structure and fluxional processes of the metal cluster.

Hyper-Rayleigh Scattering as a New Chiroptical Method: Uncovering the Nonlinear Optical Activity of Aromatic Oligoamide Foldamers.

Molecular helices based on self-organized aromatic oligoamide foldamers have been designed and prepared in their two enantiomeric forms in order to probe their second-order nonlinear chiroptical properties in solution. The quinoline oligoamides were rationally functionalized by electron-donating and electron-withdrawing groups to afford a gradual increase of the electronic polarization of the helical architectures. Their hyper-Rayleigh scattering (HRS) responses in solution were accordingly assessed, using either linearly polarized or circularly polarized incident light. Both methods allowed us to observe nonlinear optical activity that was quantified, for the first time for molecular systems, through circular differential scattering intensity ratios. The hyper-Rayleigh optical activity study reveals important charge-transfer differences within the aromatic oligomers, depending on the helix handedness and on the extent of electronic polarization induced by the appended substituents. The origin of the enantiomeric difference is discussed considering both achiral and chiral contributions. Overall, using aromatic oligoamide foldamers as a chiral model, we demonstrate the capabilities of HRS as a complementary chiroptical method, ideally suited for the analysis of various chiral molecular and supramolecular systems in solution. The reliability and chiral discrimination sensitivity of the method can be further improved through dynamic measurements using standard polarization modulation and heterodyning techniques.