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 sigma 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, sigma 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 s holes down to K-D = 11 mu M in THF. Catalytic activities follow the same trend and culminate in rate enhancements for transfer hydrogenation of quinolines beyond 100 000.

The benzodiselenazoles (BDS) introduced in this report fulfill, for the first time, all the prerequisites for noncovalent high-precision chalcogen-bonding catalysis in the focal point of conformationally immobilized s 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, s 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 s holes down to KD 1⁄4 11 mM in THF. Catalytic activities follow the same trend and culminate in rate enhancements for transfer hydrogenation of quinolines beyond 100 000.

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.

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).

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.

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.

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.

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.

The introduction of new noncovalent interactions to build functional systems is of fundamental importance. We here report experimental and theoretical evidence that anion-pi 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-pi catalysis, a carboxylate base and a solubilizer are covalently attached to the pi-acidic surface of naphthalenedfimides. On these pi-acidic surfaces, transition-state stabilizations up to Delta Delta G(TS) = 31.8 +/- 0.4 kJ mol(-1) are found. This value corresponds to a transition-state recognition of K-TS = 2.7 +/- 0.5 mu M and a catalytic proficiency of 3.8 x 10(5) M-1. Significantly increasing transition-state stabilization with increasing pi-acidity of the catalyst, observed for two separate series, demonstrates the existence of "anion-pi catalysis." In sharp contrast, increasing if-acidity of the best naphthalenediimide catalysts does not influence the more than 12000-times weaker substrate recognition (K-M = 34.5 +/- 1.6 mu M). Together with the disappearance of Michaelis-Menten kinetics on the expanded pi-surfaces of perylenediimides, this finding supports that contributions from pi-pi interactions are not very important for anion-pi catalysis. The linker between the pi-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 pi-acidic surface is achieved by intramolecular anion-pi 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 pi-acidity of the catalysts, i.e., the existence of anion-pi catalysis. Preliminary results on the general significance of anion-pi catalysis beyond the Kemp elimination are briefly discussed.

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.

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.

Die zunehmende Stabilisierung eines anionischen Übergangszustands mit steigender π-Acidität eines neuen Katalysators belegt beispiellos auf experimentelle Weise, dass Anion-π-Wechselwirkungen zur Katalyse beitragen können. In ihrer Zuschrift auf S. 10124 ff. zeigen S. Matile et al. ferner anhand von theoretischen Simulationen zur Anion-π-Katalyse, dass die negative Ladung über die π-acide Oberfläche des Naphthalindiimid-Katalysators gleitet.

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.

The expansion of the number of intermolecular interactions available to create molecular functional systems is of paramount importance. Quite recently, we have identified synthetic transport systems as attractive tools to elaborate on interactions that are otherwise difficult to detect. Realized examples include anion–p interactions, halogen bonds, and anion–macrodipole interactions. Intriguing results with transport promised attractive applications to catalysis, because evidence for anion binding in the ground state implied that anionic transition states could be similarly stabilized. Anion–p interactions were particularly interesting for this purpose because wonderful examples exist for catalysis with complementary cation–p interactions, reaching from carbocation stabilization in terpenoid and steroid cyclization to surprisingly rare and recent use in organocatalysis. Anion–p interactions, however, have essentially not been used in catalysis. This is understandable, because experimental evidence for their functional relevance appeared only recently, and discussions concerning their nature and significance continue. The poor development of the field presumably originates from the limited occurrence, availability, and diversity of the required p-acids, that is aromatic rings with strong enough electron-withdrawing substituents to invert their usually negative quadrupole moments into positive ones. The Kemp elimination is an established tool to develop conceptually innovative catalysts. Useless with regard to applications in organocatalysis, this reaction has served well to elaborate on theoretically designed enzymes, catalytic antibodies, promiscuous proteins, synthetic polymers, macrocyclic model systems, vesicles, micelles, and non-specific medium effects. The key step is the deprotonation of a carbon in the benzisoxazole substrate S by a general base (Figure 1). The reaction then proceeds with a single anionic transition state to afford the nitrophenolate either as intermediate or product, depending on conditions. There is general agreement that catalysis in its most general sense occurs by transition-state stabilization. The anionic nature of the transition state thus qualified the Kemp elimination as a valid tool to identify contributions from anion–p interactions to catalysis. Herein, we report that p-acidic naphthalenediimides (NDIs) with a covalently attached carboxylate base can catalyze the Kemp elimination and, most importantly, that the stabilization of the anionic transition state of this transformation increases with increasing p-acidity of the new catalysts. The key to “anion–p catalysis” was to take the p-acidic surface of an NDI (variable and strong), and to attach a carboxylate base on one side and a solubilizing tail on the other side (Figure 2). With this design, p-stacking between substrate and catalyst should hold throughout the transformation. The onset of anion–p interactions between the compound in transformation and the catalyst C (Figure 1), however, should coincide exactly with the key step, that is the injection of a negative charge from the proximal carboxylate into the substrate. The translocation of this negative charge over five atoms (from the carboxylate oxygen to the Figure 1. Catalysis of the Kemp elimination with anion–p interactions. A carboxylate is placed as general base near the p-acidic surface of catalyst C to 1) couple deprotonation with the onset of anion–p interactions for transition-state (TS) stabilization, and 2) protonate the phenolate in the reactive intermediate (RI) to avoid product inhibition. blue = electron deficient, red = electron rich, S = substrate, P= product, CS = catalyst–substrate complex, CP = catalyst–product complex.

Lipophilic methyl-substituted cyanobiphenyls can be considered as molecular salmon that jump out of the condensed phase, but are limited by an increase in size of their rigid core. The concept of cohesive free-energy densities applied to melting processes correlates the molecular volumes of the constituents with the macroscopic enthalpic and entropic changes that accompany the phase transitions of the bulk materials. For more details see the Full Paper by E. Terazzi, C. Piguet et al. on page 8447 ff. Lipophilic methyl-substituted cyanobiphenyls can be considered as molecular salmon that jump out of the condensed phase, but are limited by an increase in size of their rigid core. The concept of cohesive free-energy densities applied to melting processes correlates the molecular volumes of the constituents with the macroscopic enthalpic and entropic changes that accompany the phase transitions of the bulk materials. For more details see the Full Paper by E. Terazzi, C. Piguet et al. on page 8447 ff. Drug Protection Skin photosensitivity remains one of the main limitations in photodynamic therapy. In this Concept article by B. Therrien on page 8378 ff., a strategy is described to overcome this limitation, in which the photosensitizer is hidden inside the hydrophobic cavity of a water-soluble organometallic cage. The metallacage not only protects the photosensitizer from light, but also facilitates its delivery to cancer cells.1 Nanoparticle Functionalization A photochemical thiol-yne reaction was used to functionalize iron oxide nanoparticles with various thiols. This metal-free click reaction is easy to use, versatile, chemoselective, and applicable to biomolecules. In their Communication on page 8388 ff., E. Guénin et al. show that this technique can be used to perform chemoselective double functionalization of nanoparticle surfaces.1 Heterobimetallic Cuprates Several bimetallic silyl halido cuprates of the general formula [CuX{Si(3,5-Me2pz)3Mo(CO)3}]− are reported in the Full Paper by F. Breher et al. on page 8436 ff. The electronic and structural properties of the complexes were probed in detail by X-ray diffraction analysis, IR-induced multiphoton dissociation studies, cyclic voltammetry, gas-phase photoelectron spectroscopy, UV/Vis and fluorescence spectroscopy. The picture shows a van der Waals plot of the silyl chloro cuprate in the background and the different characterization techniques applied in the foreground.1

Recently, our group reported on the development of an unprecedented process in copper-catalyzed Asymmetric Allylic Alkylation. This method allowed for the quantitative transformation of a racemic substrate into an enantioenriched product. While a high level of asymmetric induction (up to 99% ee) was observed, the mechanistic understanding of the reaction remained fuzzy. In the present article, a thorough mechanistic analysis, based on computational investigations, led to the identification of the reaction pathway. Notably, it uncovered that both enantiomers of the starting material converged independently to the same product via two different mechanistic routes. This specific feature established this process as a rare example of Direct Enantioconvergent Transformation. Finally, the modelling results prompted a valuable improvement of the reaction, relying on the use of a more accessible range of substrates.

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.