Catalysis with chalcogen bonds: neutral benzodiselenazole scaffolds with high-precision selenium donors of variable strength.

The benzodiselenazoles (BDS) introduced in this report fulfill, for the first time, all the prerequisites for non-covalent high-precision chalcogen-bonding catalysis in the focal point of conformationally immobilized σ holes on strong selenium donors in a neutral scaffold. Rational bite-angle adjustment to the long Se-C bonds was the key for BDS design. For the unprecedented BDS motif, synthesis of 12 analogs from o-xylene, crystal structure, σ hole variation strategies, optoelectronic properties, theoretical and experimental anion binding as well as catalytic activity are reported. Chloride binding increases with the depth of the σ holes down to KD = 11 µM in THF. Catalytic activities follow the same trend and culminate in rate enhancements for transfer hydrogenation of quinolines beyond 100 000.

Catalysis with Chalcogen Bonds.

Herein, we introduce catalysts that operate with chalcogen bonds. Compared to conventional hydrogen bonds, chalcogen bonds are similar in strength but more directional and hydrophobic, thus ideal for precision catalysis in apolar solvents. For the transfer hydrogenation of quinolines and imines, rate enhancements well beyond a factor of 1000 are obtained with chalcogen bonds. Better activities with deeper σ holes and wider bite angles, chloride inhibition and correlation with computed anion binding energies are consistent with operational chalcogen bonds. Comparable to classics, such as 2,2'-bipyrroles or 2,2'-bipyridines, dithieno[3,2-b;2',3'-d]thiophenes (DTTs), particularly their diimides, but also wide-angle cyclopentadithiazole-4-ones are identified as privileged motifs to stabilize transition states in the focal point of the σ holes on their two co-facial endocyclic sulfur atoms.

Asymmetric Anion-π Catalysis on Perylenediimides.

Anion-π catalysis, that is the stabilization of anionic transition states on π-acidic aromatic surfaces, has so far been developed with naphthalenediimides (NDIs). This report introduces perylenediimides (PDIs) to anion-π catalysis. The quadrupole moment of PDIs (+23.2 B) is found to exceed that of NDIs and reach new records with acceptors in the core (+70.9 B), and their larger surface provides space to better accommodate chemical transformations. Unlike NDIs, the activity of PDI catalysts for enolate and enamine addition is determined by the twist of their π surface rather than their reducibility. These results, further strengthened by nitrate inhibition and circular dichroism spectroscopy, support an understanding of anion-π interactions centered around quadrupole moments, i.e., electrostatic contributions, rather than redox potentials and charge transfer. The large PDI surfaces provide access to the highest enantioselectivities observed so far in anion-π catalysis (96 % ee).

Anion Transport with Chalcogen Bonds.

In this report, we introduce synthetic anion transporters that operate with chalcogen bonds. Electron-deficient dithieno[3,2-b;2',3'-d]thiophenes (DTTs) are identified as ideal to bind anions in the focal point of the σ holes on the cofacial endocyclic sulfur atoms. Anion binding in solution and anion transport across lipid bilayers are found to increase with the depth of the σ holes of the DTT anionophores. These results introduce DTTs and related architectures as a privileged motif to engineer chalcogen bonds into functional systems, complementary in scope to classics such as 2,2'-bipyrroles or 2,2'-bipyridines that operate with hydrogen bonds and lone pairs, respectively.

Enolate Stabilization by Anion-π Interactions: Deuterium Exchange in Malonate Dilactones on π-Acidic Surfaces.

Of central importance in chemistry and biology, enolate chemistry is an attractive topic to elaborate on possible contributions of anion-π interactions to catalysis. To demonstrate the existence of such contributions, experimental evidence for the stabilization of not only anions but also anionic intermediates and transition states on π-acidic aromatic surfaces is decisive. To tackle this challenge for enolate chemistry with maximal precision and minimal uncertainty, malonate dilactones are covalently positioned on the π-acidic surface of naphthalenediimides (NDIs). Their presence is directly visible in the upfield shifts of the α-protons in the (1) H NMR spectra. The reactivity of these protons on π-acidic surfaces is measured by hydrogen-deuterium (H-D) exchange for 11 different examples, excluding controls. The velocity of H-D exchange increases with π acidity (NDI core substituents: SO2 R>SOR>H>OR>OR/NR2 >SR>NR2 ). The H-D exchange kinetics vary with the structure of the enolate (malonates>methylmalonates, dilactones>dithiolactones). Moreover, they depend on the distance to the π surface (bridge length: 11-13 atoms). Most importantly, H-D exchange depends strongly on the chirality of the π surface (chiral sulfoxides as core substituents; the crystal structure of the enantiopure (R,R,P)-macrocycle is reported). For maximal π acidity, transition-state stabilizations up to -18.8 kJ mol(-1) are obtained for H-D exchange. The Brønsted acidity of the enols increases strongly with π acidity of the aromatic surface, the lowest measured pKa =10.9 calculates to a ΔpKa =-5.5. Corresponding to the deprotonation of arginine residues in neutral water, considered as "impossible" in biology, the found enolate-π interactions are very important. The strong dependence of enolate stabilization on the unprecedented seven-component π-acidity gradient over almost 1 eV demonstrates quantitatively that such important anion-π activities can be expected only from strong enough π acids.

Big, strong, neutral, twisted, and chiral π acids.

General synthetic access to expanded π-acidic surfaces of variable size, topology, chirality, and π acidity is reported. The availability of π surfaces with these characteristics is essential to develop the functional relevance of anion-π interactions with regard to molecular recognition, translocation, and transformation. The problem is that, with expanded π surfaces, the impact of electron-withdrawing substituents decreases and the high π acidity needed for strong anion-π interactions can be more difficult to obtain. To overcome this problem, it is herein proposed to build large surfaces from smaller fragments and connect these fragments with bridges that are composed only of single atoms. Two central surfaces for powerful anion-π interactions, namely, perfluoroarenes and naphthalenediimides (NDIs), were selected as fragments and coupled with through sulfide bridges. Their oxidation to sulfoxides and sulfones, as well as fluorine substitution in the peripheral rings, provides access to the full chemical space of relevant π acidities. According to cyclic voltammetry, LUMO levels range from -3.96 to -4.72 eV. With sulfoxide bridges, stereogenic centers are introduced to further enrich the intrinsic planar chirality of the expanded surfaces. The stereoisomers were separated by chiral HPLC and characterized by X-ray crystallography. Their topologies range from chairs to π boats, and the latter are reminiscent of the cation-π boxes in operational neuronal receptors. With pentafluorophenyl acceptors, the π acidity of NDIs with two sulfoxide groups in the core reaches -4.45 eV, whereas two sulfone moieties give a value of -4.72 eV, which is as low as with four ethyl sulfone groups, that is, a π superacid near the limit of existence. Beyond anion-π interactions, these conceptually innovative π-acidic surfaces are also of interest as electron transporters in conductive materials.

Anion-π and cation-π interactions on the same surface.

Herein, we address the question whether anion-π and cation-π interactions can take place simultaneously on the same aromatic surface. Covalently positioned carboxylate-guanidinium pairs on the surface of 4-amino-1,8-naphthalimides are used as an example to explore push-pull chromophores as privileged platforms for such "ion pair-π" interactions. In antiparallel orientation with respect to the push-pull dipole, a bathochromic effect is observed. A red shift of 41 nm found in the least polar solvent is in good agreement with the 70 nm expected from theoretical calculations of ground and excited states. Decreasing shifts with solvent polarity, protonation, aggregation, and parallel carboxylate-guanidinium pairs imply that the intramolecular Stark effect from antiparallel ion pair-π interactions exceeds solvatochromic effects by far. Theoretical studies indicate that carboxylate-guanidinium pairs can also interact with the surfaces of π-acidic naphthalenediimides and π-basic pyrenes.

Anion-π catalysis.

The introduction of new noncovalent interactions to build functional systems is of fundamental importance. We here report experimental and theoretical evidence that anion-π interactions can contribute to catalysis. The Kemp elimination is used as a classical tool to discover conceptually innovative catalysts for reactions with anionic transition states. For anion-π catalysis, a carboxylate base and a solubilizer are covalently attached to the π-acidic surface of naphthalenediimides. On these π-acidic surfaces, transition-state stabilizations up to ΔΔGTS = 31.8 ± 0.4 kJ mol(-1) are found. This value corresponds to a transition-state recognition of KTS = 2.7 ± 0.5 µM and a catalytic proficiency of 3.8 × 10(5) M(-1). Significantly increasing transition-state stabilization with increasing π-acidity of the catalyst, observed for two separate series, demonstrates the existence of "anion-π catalysis." In sharp contrast, increasing π-acidity of the best naphthalenediimide catalysts does not influence the more than 12 000-times weaker substrate recognition (KM = 34.5 ± 1.6 µM). Together with the disappearance of Michaelis-Menten kinetics on the expanded π-surfaces of perylenediimides, this finding supports that contributions from π-π interactions are not very important for anion-π catalysis. The linker between the π-acidic surface and the carboxylate base strongly influences activity. Insufficient length and flexibility cause incompatibility with saturation kinetics. Moreover, preorganizing linkers do not improve catalysis much, suggesting that the ideal positioning of the carboxylate base on the π-acidic surface is achieved by intramolecular anion-π interactions rather than by an optimized structure of the linker. Computational simulations are in excellent agreement with experimental results. They confirm, inter alia, that the stabilization of the anionic transition states (but not the neutral ground states) increases with the π-acidity of the catalysts, i.e., the existence of anion-π catalysis. Preliminary results on the general significance of anion-π catalysis beyond the Kemp elimination are briefly discussed.

Catalysis with anion-π interactions.

The conclusion is inevitable: Increasing stabilization of an anionic transition state with increasing π-acidity of the catalyst is observed; thus, anion-π interactions can contribute to catalysis.

Enthalpy-entropy compensation combined with cohesive free-energy densities for tuning the melting temperatures of cyanobiphenyl derivatives.

This work illustrates how minor structural perturbations produced by methylation of 4'-(dodecyloxy)-4-cyanobiphenyl leads to enthalpy-entropy compensation for their melting processes, a trend which can be analyzed within the frame of a simple intermolecular cohesive model. The transformation of the melting thermodynamic parameters collected at variable temperatures into cohesive free-energy densities expressed at a common reference temperature results in a novel linear correlation, from which melting temperatures can be simply predicted from molecular volumes.

Synthetic ion transporters that work with anion-π interactions, halogen bonds, and anion-macrodipole interactions.

The transport of ions and molecules across lipid bilayer membranes connects cells and cellular compartments with their environment. This biological process is central to a host of functions including signal transduction in neurons and the olfactory and gustatory sensing systems, the translocation of biosynthetic intermediates and products, and the uptake of nutrients, drugs, and probes. Biological transport systems are highly regulated and selectively respond to a broad range of physical and chemical stimulation. A large percentage of today's drugs and many antimicrobial or antifungal agents take advantage of these systems. Other biological transport systems are highly toxic, such as the anthrax toxin or melittin from bee venom. For more than three decades, organic and supramolecular chemists have been interested in developing new transport systems. Over time, curiosity about the basic design has evolved toward developing of responsive systems with applications in materials sciences and medicine. Our early contributions to this field focused on the introduction of new structural motifs with emphasis on rigid-rod scaffolds, artificial ß-barrels, or π-stacks. Using these scaffolds, we have constructed selective systems that respond to voltage, pH, ligands, inhibitors, or light (multifunctional photosystems). We have described sensing applications that cover the three primary principles of sensor development: immunosensors that use aptamers, biosensors (an "artificial" tongue), and differential sensors (an "artificial" nose). In this Account, we focus on our recent interest in applying synthetic transport systems as analytical tools to identify the functional relevance of less common noncovalent interactions, anion-π interactions, halogen bonds, and anion-macrodipole interactions. Anion-π interactions, the poorly explored counterpart of cation-π interactions, occur in aromatic systems with a positive quadrupole moment, such as TNT or hexafluorobenzene. To observe these elusive interactions in action, we synthesized naphthalenediimide transporters of increasing π-acidity up to an unprecedented quadrupole moment of +39 Buckinghams and characterized these systems in comparison with tandem mass spectrometry and computational simulations. With π-acidic calixarenes and calixpyrroles, we have validated our results on anion-π interactions and initiated our studies of halogen bonds. Halogen bonds originate from the σ-hole that appears on top of electron-deficient iodines, bromines, and chlorines. Halogen-bond donors are ideal for anion transport because they are as strong and at least as directional as hydrogen-bond donors, but also hydrophobic. The discovery of the smallest possible organic anion transporter, trifluoroiodomethane, illustrates the power of halogen-bond donors. This molecule contains a single carbon atom and is a gas with a boiling point of -22 °C. Anion-macrodipole interactions, finally, differ significantly from anion-π interactions and halogen bonds because they are important in nature and cannot be studied with small molecules. We have used anion-transporting peptide/urea nanotubes to examine these interactions in synthetic transport systems. To facilitate the understanding of the described results, we also include an in-depth discussion of the meaning of Hill coefficients. The use of synthetic transport systems to catch less common noncovalent interactions at work is important because it helps to expand the collection of interactions available to create functional systems. Progress in this direction furthers fundamental knowledge and invites many different applications. For illustration, we briefly discuss how this knowledge could apply to the development of new catalysts.

Transmembrane anion transport mediated by halogen-bond donors.

In biology and chemistry, the transport of anions across lipid bilayer membranes is usually achieved by sophisticated supramolecular architectures. Significant size reduction of transporters is hampered by the intrinsically hydrophilic nature of typical anion-binding functionalities, hydrogen-bond donors or cations. To maximize the atom efficiency of anion transport, the hydrophobic nature, directionality, and strength of halogen bonds seem promising. Unlike the ubiquitous, structurally similar hydrogen bonds, halogen bonds have not been explored for anion transport. Here we report that transport across lipid bilayers can be achieved with small perfluorinated molecules that are equipped with strong halogen-bond donors. Transport is observed with trifluoroiodomethane (boiling point=-22 °C); that is, it acts as a 'single-carbon' transporter. Contrary to the destructive action of small-molecule detergents, transport with halogen bonds is leakage-free, cooperative, non-ohmic and highly selective, with anion/cation permeability ratios <37.

Self-organizing surface-initiated polymerization: facile access to complex functional systems.

Facile access to complex systems is crucial to generate the functional materials of the future. Herein, we report self-organizing surface-initiated polymerization (SOSIP) as a user-friendly method to create ordered as well as oriented functional systems on transparent oxide surfaces. In SOSIP, self-organization of monomers and ring-opening disulfide exchange polymerization are combined to ensure the controlled growth of the polymer from the surface. This approach provides rapid access to thick films with smooth, reactivatable surfaces and long-range order with few defects and high precision, including panchromatic photosystems with oriented four-component redox gradients. The activity of SOSIP architectures is clearly better than that of disordered controls.

Silver baits for the "miraculous draught" of amphiphilic lanthanide helicates.

The axial connection of flexible thioalkyls chains of variable length (n=1-12) within the segmental bis-tridentate 2-benzimidazole-8-hydroxyquinoline ligands [L12(Cn) -2 H](2-) provides amphiphilic receptors designed for the synthesis of neutral dinuclear lanthanides helicates. However, the stoichiometric mixing of metals and ligands in basic media only yields intricate mixtures of poorly soluble aggregates. The addition of Ag(I) in solution restores classical helicate architectures for n=3, with the quantitative formation of the discrete D(3) -symmetrical [Ln(2) Ag2(L12(C3) -2 H)(3) ](2+) complexes at millimolar concentration (Ln=La, Eu, Lu). The X-ray crystal structure supports the formation of [La(2) Ag(2) (L12(C3) -2 H)(3) ][OTf](2) , which exists in the solid state as infinite linear polymers bridged by S-Ag-S bonds. In contrast, molecular dynamics (MD) simulations in the gas phase and in solution confirm the experimental diffusion measurements, which imply the formation of discrete molecular entities in these media, in which the sulfur atoms of each lipophilic ligand are rapidly exchanged within the Ag(I) coordination sphere. Turned as a predictive tool, MD suggests that this Ag(I) templating effect is efficient only for n=1-3, while for n>3 very loose interactions occur between Ag(I) and the thioalkyl residues. The subsequent experimental demonstration that only 25 % of the total ligand speciation contributes to the formation of [Ln(2) Ag(2) (L12(C12) -2 H)(3) ](2+) in solution puts the bases for a rational approach for the design of amphiphilic helical complexes with predetermined molecular interfaces.

Experimental evidence for the functional relevance of anion-pi interactions.

Attractive in theory and confirmed to exist, anion-pi interactions have never really been seen at work. To catch them in action, we prepared a collection of monomeric, cyclic and rod-shaped naphthalenediimide transporters. Their ability to exert anion-pi interactions was demonstrated by electrospray tandem mass spectrometry in combination with theoretical calculations. To relate this structural evidence to transport activity in bilayer membranes, affinity and selectivity sequences were recorded. pi-acidification and active-site decrowding increased binding, transport and chloride > bromide > iodide selectivity, and supramolecular organization inverted acetate > nitrate to nitrate > acetate selectivity. We conclude that anion-pi interactions on monomeric surfaces are ideal for chloride recognition, whereas their supramolecular enhancement by pi,pi-interactions appears perfect to target nitrate. Chloride transporters are relevant to treat channelopathies, and nitrate sensors to monitor cellular signaling and cardiovascular diseases. A big impact on organocatalysis can be expected from the stabilization of anionic transition states on chiral pi-acidic surfaces.

Core-substituted naphthalenediimides.

This feature article reviews research of core-substituted naphthalenediimides (cNDIs) in a comprehensive yet easily readable manner. Their synthesis, electrochemistry and spectroscopy are covered first with emphasis on the ability of cNDIs with electron donating substituents to absorb and fluoresce in all colors without global structural changes and cNDIs with electron withdrawing substituents to reach unprecedented extents of pi-acidity. The section on supramolecular chemistry covers face-to-face pi-stacks and peripheral hydrogen bonds, that on molecular recognition moves from pH and fluoride sensors to the binding to telomeric DNA in vivo and intercalation into pi-stacks and sticky tweezers. cNDIs can recognize and transport anions by functional anion-pi interactions. The section on electron transport describes cNDIs as air-stable n-semiconductors with high charge mobility and use as OFETs. Photoinduced electron transport by rainbow cNDIs has been used for the creation of artificial photosystems in solution, in bilayer membranes and on solid substrates. Examples include multicolor light harvesting architectures, organic solar cells, photosystems that can open up into ion channels, and supramolecular n/p-heterojunctions with antiparallel redox gradients. The review is highly interdisciplinary but should appeal most to organic, biosupramolecular and physical chemists.

Supramolecular n/p-heterojunction photosystems with antiparallel redox gradients in electron- and hole-transporting pathways.

Lessons from nature call for supramolecular n/p-heterojunctions with oriented multicolored antiparallel redox gradients (OMARG-SHJs) as "ideal" photosystems. Their design combines advantages of bilayer and bulk n/p-heterojunction (BHJ) solar cells for the directional separation of photogenerated charges before recombination can occur. Although conceptually attractive, OMARG-SHJs have remained beyond reach because of unresolved challenges in synthetic organic and supramolecular chemistry. Here we report the first OMARG-SHJs with two-component redox gradients in both the electron- and hole-transporting pathways. They were obtained by zipper assembly of stacks of red naphthalenediimide (NDI) electron donors along strings of oligophenylethynyl hole acceptors on top of yellow NDI electron acceptors along p-oligophenyl hole donors. The presence of both gradients is shown to be essential for achieving photoinduced charge separation over very long distances.