Special Issue on Synthetic Host Molecules

We are excited to introduce this special issue of the Israel Journal of Chemistry on Synthetic Host Molecules to celebrate the remarkable progress of the field. Featuring eleven scientific reviews and research articles from leading scientists worldwide, the special issue on synthetic host molecules explores the latest advances in some of the host systems developed during the last decades.

This issue also commemorates the milestone of the Joint Conference on Calixarenes and Cucurbiturils (JCCC 2023), which merged the 17^th International Conference on Calixarenes (Calix 2023) and the 7^th International Conference on Cucurbiturils (ICCB 2023) in Tel Aviv in July 2023. This event offered a unique opportunity to unite experts from both subfields, fostering dialogues and collaborations. It was a particularly significant gathering after a hiatus caused by the COVID-19 pandemic, which had disrupted the individual meetings of each conference.

The field of synthetic host molecules originated in the ′60s when Charles J. Pedersen reported the first examples of crown ethers and their remarkable capabilities to bind alkali metal ions according to their cavity size and the metal radii. Shortly after, Jean-Marie Lehn developed cryptands, bicyclic crown ether compounds with higher selectivity. In 1979, Donald Cram introduced spherands, the first examples of synthetic hosts with complete preorganization, significantly reducing the energetic penalty associated with the reorganization and desolvation of crown ethers and cryptands. These groundbreaking contributions earned Pedersen, Lehn, and Cram the Nobel Prize in Chemistry in 1987, officially establishing the field of Supramolecular Chemistry.

Over the last four decades, the field has accelerated rapidly, developing numerous new classes of synthetic host molecules. These systems have evolved from molecules capable of binding organic and inorganic ions to advanced hosts with unique structural, catalytic, optoelectronic, magnetic, and transmembrane transport properties. They can selectively bind myriad organic and bioorganic molecules in diverse media, including water. As a result, these highly functional host molecules have found applications in various fields, including medicine, biotechnology, catalysis, chemical separation, data storage, polymer science, and nanotechnology. This progress has been made possible through interdisciplinary research that merges concepts from synthetic chemistry, physical organic chemistry, computational chemistry, biophysics, and state-of-the-art analytical techniques.

Prof. Pablo Ballester and Dr. Gemma Aragay present an authoritative review on water-soluble aryl- and aryl-extended calix[4]pyrroles. They highlight their achievements over the last two decades to incorporate water-solubilizing groups, enhance the hydrophobic aromatic cavity, and reduce the conformational flexibility of calix[4]pyrroles, resulting in outstanding hosts capable of binding polar organic molecules in aqueous environments. Furthermore, the authors discuss the potential applications of these hosts as protective groups that sequester organic molecules participating in chemical reactions and provide insights into future applications, particularly at the water-solid interface, suggesting the use of calix[4]pyrroles in biotechnological applications.

Prof. Andreas Hening and Justin Neumann present a review that summarises recent achievements in the utility of anionic calixarenes in biomembrane transport of peptides with a strong emphasis on understanding the mechanism of which cell-penetrating peptides (CPPs) are translocated across lipid bilayer membranes. They highlight the use of anionic calixarene derivatives as amphiphilic counterion activators that assist with CPP intake even at catalytic levels. Accordingly, the amphiphilic counterions partitioned into the lipid bilayer membrane and then formed a membrane-bound peptide-counterion complex, which shuttled across the membrane and then released into the vesicle lumen. Further examples of stimulus-responsive membrane transport point that these types of amphiphilic calixarenes enable membrane translocation and cytosolic delivery of hydrophilic molecules. Additionally, they also provide a side-benefit to this developed field that includes the use and standardized membrane transport screening assays.

Inspired by the lessons taught by biological systems, Prof. Agustí Lledo and his team are at the frontier of developing a new class of self-folding hosts based on calix[5]arenes with superior induced fit behavior. In this issue, they review the design principles, synthetic approaches used to obtain these hosts, and strategies for tuning their binding properties with the aid of molecular dynamic simulations. Their work represents a significant step towards understanding and emulating biological receptor dynamics.

Prof. Vladimir Azov and Francois J. De Beer provide a comprehensive review of calix[4]arenes and calix[4]resorcinarene hosts equipped with redox-active moieties, such as ferrocene, tetrathiafulvalene, and quinones. They highlight the ability to develop hosts with switchable properties, particularly emphasizing how the binding and release of guest molecules can be controlled through redox or electrochemical stimuli, which alter the non-covalent interactions between the host and guest or physically change the host‘s cavity. Additionally, the authors discuss the potential of these redox-responsive hosts as a platform for developing innovative electrochemical sensors. They provide valuable insights into the future applications of switchable hosts, such as their integration into molecular machines for object manipulation and other nanotechnological applications.

Prof. Vaidhyanathan Ramamurthy and Amal Sam Sunny report using an octa acid host to investigate the effect of molecular confinement on the Diels-Alder reaction of cyclopentadiene to obtain dicyclopentadiene in aqueous media. Although other hosts have been investigated for this purpose, this particular host is unique because it is fully closed, preventing the guest from interacting with the surrounding water. Through mechanistic investigations, the authors discovered that the reaction occurs at least 2000 times faster than in water, offering insights into the role of non-covalent interactions and molecular confinement in bringing the reactants to optimum proximity.

Prof. Ivan Castillo and Dr. Armando Berlanga-Vázquez report using phenanthroline-functionalized calix[8]arene ligands that form complexes with Mn(I) for the electrocatalytic reduction of CO₂. They successfully reduced CO₂ to CO and H₂, and in some cases, they detected the formation of CH₄. This study highlights the importance of the cavity provided by the calix[8]arene ligands to influence the catalytic behavior of the complex, which is different from the reactivity observed with analogous Mn(I) complexes that do not contain calixarene.

Prof. Mihail Barboiu and his team reported on the ability of a pyrene box to bind various 1,ω-amino acids, differing in the length of their aliphatic chains. The pyrene box, a novel class of self-assembled host developed by this group, consists of two 1,3,5,8-pyrenetetrasulfonate anions laterally capped by H-bonding guanidinium or amino-guanidinium cations. Through NMR studies and analysis of numerous X-ray co-crystal structures, the authors investigated the potential effects of alkali metal countercations on the encapsulation process, system stability, and guest preference during competitive experiments. Additionally, the X-ray co-crystal structures allowed the authors to determine the conformation of guests within the host‘s confinement, providing insights into the system‘s dynamic preference for specific guests. This host represents a new platform to mimic the dynamic nature of some biological hosts.

Prof. Florian Beuerle and Dr. Svetlana Ivanova contribute an in-depth review of covalent organic cages, covering their various classifications, design principles, and their synthesis. They describe how small, rigid molecules, such as cavitands and other building blocks, dynamically self-assemble through covalent bonds to generate shape-persisting cages with small cavities. These individual cages can further assemble into more extensive crystalline porous networks with broad applications. Importantly, the authors explain in detail how different analytical techniques are crucial for the characterization and investigation of these hosts.

Prof. Nuno Basílio and Prof. A. Jorge Parola studied the effect of cucurbit[7]uril (CB[7]) complexation on protonated trans-chalcone dyes pK_a values. They successfully tuned the sign (complexation-induced positive or negative pK_a shifts) and magnitude by systematic engineering of trans-chalcone dyes. Accordingly, one generally observed an increase in the pK_a values of several guests because of the preferential binding of the protonated form over the conjugated base. Nevertheless, by careful modification, some deprotonated trans-chalcone dyes showed a higher affinity towards CB[7] than their protonated counterparts, leading to complexation-induced negative pK_a shifts. These results show that following rational design, the control of equilibria by CB[7] can be achieved.

In the review of Prof. Huijuan Yu, Prof. Yuefei Wang and co-workers, they describe the use of major macrocyclic host families, including cyclodextrins, calixarenes, cucurbiturils and pillararenes, in screening bioactive ingredients from herbal medicines and their druggability enhancement following their encapsulation in the cavity of the host molecules. Applications include developments of screening techniques, enhancement of solubility, stability, and bioavailability, and enhancement of extraction, efficiency.

We would like to thank all the authors of this special issue for their efforts and valuable contributions. We also thank Prof. Ehud Keinan for his leadership on this project and his continued support of the supramolecular community and Dr. Brian Johnson of Wiley-VCH, for his kind and continuous support.