Cooperativity in Photofoldamer Chloride Double Helices Turned On with Sequences and Solvents, Around with Guests, and Off with Light.

Photofoldamers are sequence-defined receptors capable of switching guest binding on and off. When two foldamer strands wrap around the guest into 2:1 double helical complexes, cooperativity emerges, and with it comes the possibility to switch cooperativity with light and other stimuli. We use lessons from nonswitchable sequence isomers of aryl-triazole foldamers to guide how to vary the sequence location of azobenzenes from the end (FEND) to the interior (FIN) and report their impact on the cooperative formation of 2:1 complexes with Cl-. This sequence change produces a 125-fold increase from anti-cooperative (α = 0.008) for FEND to non-cooperative with FIN (α = 1.0). Density functional theory (DFT) studies show greater H-bonding and a more relaxed double helix for FIN. The solvent and guest complement the synthetic designs. Use of acetonitrile to enhance solvophobicity further enhances cooperativity in FIN (α = 126) but lowers the difference in cooperativity between sequences. Surprisingly, the impact of the sequence on cooperativity is inverted when the guest size is increased from Cl- (3.4 Å) to BF4- (4.1 Å). While photoconversion of interior azobenzenes was poor, the cis-cis isomer forms 1:1 complexes around chloride consistent with switching cooperativity. The effect of the guest, solvent, and light on the double-helix cooperativity depends on the sequence.

Revealing the Hidden Costs of Organization in Host-Guest Chemistry Using Chloride-Binding Foldamers and Their Solvent Dependence.

Preorganization is a key concept in supramolecular chemistry. Preorganized receptors enhance binding by minimizing the organization costs associated with adopting the conformation needed to orient the binding sites toward the guest. Conversely, poorly organized receptors show affinities below what is possible based on the potential of their specific binding interactions. Despite the fact that the organization energy is paid each time like a tax, its value has never been measured directly, though many compounds have been developed to measure its effects. We present a method to quantify the hidden costs of receptor organization by independently measuring the contribution it makes to chloride complexation by a flexible foldameric receptor. This method uses folding energy to approximate organization energy and relies on measurement of the coil-helix equilibrium as a function of solvent. We also rely on the finding, established with rigid receptors, that affinity is inversely related to the solvent dielectric and expect the same for the foldamer's helically organized state. Increasing solvent polarity across nine dichloromethane-acetonitrile mixtures we see an unusual V-shape in affinity (decrease then increase). Quantitatively, this shape arises from weakened hydrogen-bonding interactions with solvent polarity followed by solvent-driven folding into an organized helix. We confirm that dielectric screening impacts the stability of host-guest complexes of flexible foldamers just like rigid receptors. These results experimentally verify the canonical model of binding (affinity depends on the sum of organization and noncovalent interactions). The picture of how solvent impacts complex stability and conformational organization thereby helps lay the groundwork for de novo receptor design.

Polarity-Tolerant Chloride Binding in Foldamer Capsules by Programmed Solvent-Exclusion.

Persistent anion binding in a wide range of solution environments is a key challenge that continues to motivate and demand new strategies in synthetic receptor design. Though strong binding in low-polarity solvents has become routine, our ability to maintain high affinities in high-polarity solvents has not yet reached the standard set by nature. Anions are bound and transported regularly in aqueous environments by proteins that use secondary and tertiary structure to isolate anion binding sites from water. Inspired by this principle of solvent exclusion, we created a sequence-defined foldameric capsule whose global minimum conformation displays a helical folded state and is preorganized for 1:1 anion complexation. The high stability of the folded geometry and its ability to exclude solvent were supported by solid-state and solution phase studies. This capsule then withstood a 4-fold increase in solvent dielectric constant (εr) from dichloromethane (9) to acetonitrile (36) while maintaining a high and solvent-independent affinity of 105 M-1; ΔG ∼ 28 kJ mol-1. This behavior is unusual. More typical of solvent-dependent behavior, Cl- affinities were seen to plummet in control compounds, such as aryl-triazole macrocycles and pentads, with their solvent-exposed binding cavities susceptible to dielectric screening. Finally, dimethyl sulfoxide denatures the foldamer by putative solvent binding, which then lowers the foldamer's Cl- affinity to normal levels. The design of this capsule demonstrates a new prototype for the development of potent receptors that can operate in polar solvents and has the potential to help manage hydrophilic anions present in the hydrosphere and biosphere.

Nanoporous Thin Films Formed from Photocleavable Diblock Copolymers on Gold Substrates Modified with Thiolate Self-Assembled Monolayers.

Nanoporous thin films formed on electrodes are considered functional elements of electrochemical sensing systems, thus motivating methods for their development. We report a preparative strategy detailing the effects of surface modification of gold substrates with thiolate self-assembled monolayers (SAMs) on the properties of nanoporous thin films derived from polystyrene-block-poly(ethylene oxide) having a photocleavable o-nitrobenzyl ester junction (PS-hν-PEO). Two PS-hν-PEO having similar PEO volume fractions (≈0.2) but different molecular weights (10 and 23 kg/mol) were used to prepare films (30-100 nm thick) spin-cast on gold substrates unmodified and modified with cysteamine, thioctic acid, and 6-hydroxy-1-hexanethiol SAMs. Solvent vapor annealing followed by PEO removal led to the formation of nanopores with average diameters of 12 and 19 nm from the smaller and larger PS-hν-PEO, respectively. Cyclic voltammograms of 1,1'-ferrocenedimethanol showed that nanoporous films on cysteamine SAMs afforded nanopores reaching the underlying substrates at higher density than those on the other substrates. This result was attributed to balanced affinity of the cysteamine SAM surface with PS and PEO, which enhanced the vertical orientation of PEO microdomains. The generation of carboxyl groups associated with the photocleavage reaction was revealed by pH-dependent changes in the voltammogram of Fe(CN)63- that reflected electrostatic effects regulated by the protonation state of the carboxyl groups. The SAMs underneath the nanoporous films could be replaced by treatment with a thiol solution, as verified by voltammograms of l-ascorbic acid. These results suggest that thiolate SAM modification provides a simple means to control the interfacial orientation of PEO microdomains in thin PS-hν-PEO films.

Allosteric Control of Photofoldamers for Selecting between Anion Regulation and Double-to-Single Helix Switching.

Allosteric regulation of protein structure and function is a hallmark of biology. The structures of protein-like abiological foldamers have been subject to allosteric control, however, regulation of their function is rare. We report this behavior using a photoactive foldamer following the discovery that small and large anions select between single and double helical structures, respectively. Correspondingly, these anions activate different functions in the photofoldamer; small anions turn on photoregulation of anion concentrations while large anions turn on chiroptical switching of quaternary structure. For this demonstration, we used an aryl-triazole based photofoldamer in which the light-driven trans-cis isomerization of azobenzenes alters intrastrand π-π contacts while the triazoles define the allosteric anion-binding site. Binding to 11 anions of increasing size was quantified (Cl-, Br-, NO2-, I-, NO3-, SCN-, BF4-, ClO4-, ReO4-, PF6-, SbF6-). Contrary to expectations that single helices will expand to accommodate larger and larger guests, this behavior only occurs for smaller anions (Cl- to NO3-; <45 Å3) beyond which the larger anions form double helices (SCN- to SbF6-; >45 Å3). With small anions, the single helix regulates anion concentrations when the azobenzenes are photoswitched. The binding of large anions favors a chiral double helix and activates light-driven switching into racemic single helices thereby modulating the quaternary structure and chiroptical activity. This work shows how complex multifunctional outcomes emerge when allosteric changes in structure are expressed in intrinsically functional foldamers.

Sequence-Controlled Stimuli-Responsive Single-Double Helix Conversion between 1:1 and 2:2 Chloride-Foldamer Complexes.

The primary sequence in biopolymers carries the information to direct folded secondary structures, to modulate their stabilities, and to control the resultant functions. Our ability to encode such information into nonbiological oligomers and polymers, however, is still limited. Here, we describe a C2-symmetric aryl-triazole foldamer that assembles into a chloride-templated 2:2 double helix, and the discovery that its interconversion with the simpler 1:1 single helix can be driven by solvent quality, temperature, and concentration. We use single-site substitutions in the 13-residue sequence (two terminal sites and one central site) to reveal that the stability of the double helix is largely dictated by the differences in the anion binding power between single and double helices as well as the location of the modified residues. Specifically, placement of stabilizing CH···Cl- hydrogen-bonding interactions at the chain ends in the form of bisamide phenylene residues is found to highly favor the double helix. While the burial of π surfaces and the solvophobic effect also help to stabilize the double helix, their role was found to be less sensitive to the modifications considered. This understanding of how chemical information is programmed into the primary sequence provides a powerful tool for controlling structure and properties of abiological foldamers.