Under the Influence of Water: Molecular Recognition of Organic Hydrophilic Molecules in Water with a Prismarene Host Driven by Hydration Effects.

A water-soluble prism[5]arene host can form endo-cavity complexes with hydrophilic organic substances in water by displacing frustrated water molecules from its deep cavity. Water molecules structured at both rims of the prismarene host can mediate hydrogen bonding interactions with the guest. Water-mediated hydrogen bonding interactions were invoked here to elucidate the elevated binding affinities and selectivity of the prismarene host toward hydrophilic organic guests. We show that water at the interface of a host-guest complex can act as an extension of the host structure, facilitating the accommodation of neutral guests within the binding site. This study highlights the crucial role of water in facilitating supramolecular interactions between a deep-cavity prismarene host and organic hydrophilic guests in aqueous medium.

The Resorcinarene Hexameric Capsule as a Supramolecular Photoacid to Trigger Olefin Hydroarylation in Confined Space.

The self-assembled resorcinarene capsule C6 shows remarkable photoacidity upon light irradiation, which is here exploited to catalyze olefin hydroarylation reactions in confined space. An experimental pKa* value range of -3.3--2.8 was estimated for the photo-excited hexameric capsule C6*, and consequently an increase in acidity of 8.8 log units was observed with respect to its ground state (pKa=5.5-6.0). This makes the hexameric capsule the first example of a self-assembled supramolecular photoacid. The photoacid C6* can catalyze hydroarylation reaction of olefins with aromatic substrates inside its cavity, while no reaction occurred between them in the absence of irradiation and/or capsule. DFT calculations corroborated a mechanism in which the photoacidity of C6* plays a crucial role in the protonation step of the aromatic substrate. A further proton transfer to olefin with a concomitant C-C bond formation and a final deprotonation step lead to product releasing.

Deep-Cavity Calix[4]naphth[4]arene Macrocycles: Synthesis, Conformational Features, and Solid-State Structures.

We recently introduced calix[n]naphth[m]arenes as a novel class of deep-cavity hybrid macrocycles constituted by phenol (n) and naphthalene (m) units. In this study, we report the synthesis, conformational analysis, spectroscopic properties, and solid-state structures of calix[4]naphth[4]arene (C4N4) and its permethylated analog (C4N4-Me), thereby expanding the calix[n]naphth[m]arene family. C4N4 was synthesized through a 2 + 2 fragment coupling macrocyclization under acidic conditions, where the solvent played a crucial role in selectively forming the C4N4 derivative. The X-ray structure of C4N4 reveals a chair-like 1,2,3,4-alternate conformation characterized by two opposing 3/4-cone moieties stabilized by intramolecular hydrogen bonds. In contrast, the X-ray structure of C4N4-Me exhibits a 1,3,5,7-alternate conformation.

Hexahexyloxycalix[6]arene, a Conformationally Adaptive Host for the Complexation of Linear and Branched Alkylammonium Guests.

Hexahexyloxycalix[6]arene 2b leads to the endo-cavity complexation of linear and branched alkylammonium guests showing a conformational adaptive behavior in CDCl3 solution. Linear n-pentylammonium guest 6a+ induces the cone conformation of 2b at the expense of the 1,2,3-alternate, which is the most abundant conformer of 2b in the absence of a guest. In a different way, branched alkylammonium guests, such as tert-butylammonium 6b+ and isopropylammonium 6c+, select the 1,2,3-alternate as the favored 2b conformation (6b+/6c+⊂2b1,2,3-alt), but other complexes in which 2b adopts different conformations, namely, 6b+/6c+⊂2bcone, 6b+/6c+⊂2bpaco, and 6b+/6c+⊂2b1,2-alt, have also been revealed. Binding constant values determined via NMR experiments indicated that the 1,2,3-alternate was the best-fitting 2b conformation for the complexation of branched alkylammonium guests, followed by cone > paco > 1,2-alt. Our NCI and NBO calculations suggest that the H-bonding interactions (+N-H···O) between the ammonium group of the guest and the oxygen atoms of calixarene 2b are the main determinants of the stability order of the four complexes. These interactions are weakened by increasing the guest steric encumbrance, thus leading to a lower binding affinity. Two stabilizing H-bonds are possible with the 1,2,3-alt- and cone-2b conformations, whereas only one H-bond is possible with the other paco- and 1,2-alt-2b stereoisomers.

The Odd Couple(s): An Overview of Beta-Lactam Antibiotics Bearing More Than One Pharmacophoric Group.

ß-lactam antibiotics are among the most important and widely used antimicrobials worldwide and are comprised of a large family of compounds, obtained by chemical modifications of the common scaffolds. Usually these modifications include the addition of active groups, but less frequently, molecules were synthesized in which either two ß-lactam rings were joined to create a single bifunctional compound, or the azetidinone ring was joined to another antibiotic scaffold or another molecule with a different activity, in order to create a molecule bearing two different pharmacophoric functions. In this review, we report some examples of these derivatives, highlighting their biological properties and discussing how this strategy can lead to the development of innovative antibiotics that can represent either novel weapons against the rampant increase of antimicrobial resistance, or molecules with a broader spectrum of action.

Kinetic and Thermodynamic Modulation of Dynamic Imine Libraries Driven by the Hexameric Resorcinarene Capsule.

The composition of dynamic covalent imine libraries (DCL) adapts to the presence of the hexameric resorcinarene capsule. In the presence of the self-assembled capsule, a kinetic and thermodynamic modulation of the imine constituents of the DCLs was observed, which was induced by an unusual predatory action of the capsule on specific imine constituents. More complex 2 × 2 DCLs also adapt to the presence of the hexameric capsule, showing a thermodynamic and kinetic modulation of the constituents induced by the predatory action of the capsule. By cross-referencing experimental data, a good selectivity (up to 66%) for one constituent can be induced in a 2 × 2 DCL.

Prismarenes: A New Class of Macrocyclic Hosts Obtained by Templation in a Thermodynamically Controlled Synthesis.

The novel title macrocycles, based on methylene-bridged 1,5-naphthalene units, have been obtained by template effect in a thermodynamically controlled synthesis. In detail, the prism[5]arene 1 or the prism[6]arene 3 was selectively removed from the equilibrium mixture by using the complementary ammonium-templating agent. When only the solvent 1,2-DCE was used, the 1,4-confused derivative 2 was obtained. The prism[5]arene here described shows a deep π-electron-rich aromatic cavity that exhibits a great affinity for the quaternary ammonium guests, originating from favorable cation···π and +NC-H···π interactions. This recognition motif is the basis of the templated synthesis of the prism[n]arenes here reported.

New compounds for a good old class: Synthesis of two Β-lactam bearing cephalosporins and their evaluation with a multidisciplinary approach.

Antimicrobial resistance is spreading massively in the world and is becoming one of the main health threats of the 21st century. One of the possible strategies to overcome this problem is to modify the known classes of antibiotics in a rational way, with the aim of tuning their efficacy. In this paper, we present the synthesis and the evaluation of the biological activity of a series of two ß-lactam bearing cephalosporin derivatives, in which an additional isolated azetidinone ring, bearing different substituents, is joined to the classical cephalosporanic nucleus by a chain of variable length. A computational approach has been also applied in order to predict the molecular interactions between some representative derivatives and selected penicillin-binding proteins, the natural targets of ß-lactam antibiotics. All these derivatives are active against Gram-positive bacteria, with MIC100 comparable or even better than that of the reference antibiotic ceftriaxone, and show no or very low cytotoxic activity on different cell lines. Overall, these molecules appear to be able to exert their activity in particular against microorganisms belonging to some of the species more involved in the development of multidrug resistance.

Synergic Interplay Between Halogen Bonding and Hydrogen Bonding in the Activation of a Neutral Substrate in a Nanoconfined Space.

The principle of amplified halogen bonding (XB) in a small space is exploited as a catalytic tool for the activation of an XB acceptor substrate in a nanoconfined environment. The inner cavity of the resorcinarene capsule has been equipped with an XB catalyst bearing an ammonium unit acting as a Trojan horse to drive the catalyst inside the capsule. In the presence of a specific XB catalyst, the capsule is able to catalyze a Michael reaction between N-methylpyrrole and methyl vinyl ketone. In the bulk medium in absence of the resorcinarene capsule, the XB catalyst is catalytically ineffective. Quantum-mechanical investigations highlight that the Michael reaction proceeds through the activation of the carbonyl group by synergistically enhanced halogen/hydrogen-bonding interactions and takes place in an open pentameric capsule.

The Hexameric Resorcinarene Capsule at Work: Supramolecular Catalysis in Confined Spaces.

The hexameric resorcinarene capsule reported by Atwood in 1997 is able to act as a supramolecular catalyst. Its inner cavity provides a unique environment, in which organic reactions can be efficiently catalyzed, thanks to the confinement effect of the substrates. In addition, different stereo- and regiochemical outcomes can be observed with respect to reactions in the bulk solvent. The hexameric capsule shows some catalytic features reminiscent of natural enzymes. In particular, highlights of the capsule discussed herein include 1) its ability to recognize the substrates (substrate selectivity), 2) the possibility of stabilizing the transition states and intermediates through secondary interactions, 3) an inherent Brønsted acidity, and 4) its ability to act as a hydrogen-bond catalyst. In addition, it is also shown how the catalytic activity of the hexameric capsule can be modulated in the presence of competitive alkylammonium guests, which show high affinities for its internal cavity. These aspects are discussed through a critical examination of data reported in the literature in recent years.