Structure-based ligand design in medicinal chemistry and crop protection relies on the identification and quantification of weak noncovalent interactions and understanding the role of water. Small-molecule and protein structural database searches are important tools to retrieve existing knowledge. Thermodynamic profiling, combined with X-ray structural and computational studies, is the key to elucidate the energetics of the replacement of water by ligands. Biological receptor sites vary greatly in shape, conformational dynamics, and polarity, and require different ligand-design strategies, as shown for various case studies. Interactions between dipoles have become a central theme of molecular recognition. Orthogonal interactions, halogen bonding, and amide⋅⋅⋅π stacking provide new tools for innovative lead optimization. The combination of synthetic models and biological complexation studies is required to gather reliable information on weak noncovalent interactions and the role of water.

Molecular capsules based solely on the interaction of halogen bonding (XB) are presented along with their host-guest binding properties in solution. The first example of a well-defined four-point XB supramolecular system is realized by decorating resorcin[4]arene cavitands with polarized halogen atoms for dimerization with tetra(4-pyridyl) resorcin[4]arene cavitands. NMR binding data for the F, Cl, Br, and I cavitands as the XB donor show association constants (Ka ) of up to 5370 M(-1) (ΔG283 K =-4.85 kcal mol(-1) , for I), even in XB-competitive solvent, such as deuterated benzene/acetone/methanol (70:30:1) at 283 K, where comparable monodentate model systems show no association. The XB capsular geometry is evidenced by two-dimensional HOESY NMR, and the thermodynamic profile shows that capsule formation is enthalpically driven. Either 1,4-dioxane or 1,4-dithiane are encapsulated within each of the two separate cavities within the XB capsule, with of up to Ka =9.0 10(8)  M(-2) (ΔG283 K =-11.6 kcal mol(-1) ).

Three series of stable, neutral, π-extended bispentalene derivatives, with two pentalenes fused to a central benzene or naphthalene moiety, have been prepared through a modified double carbopalladation cascade reaction. While these chromophores feature skeletons with [4n+2] π-electron perimeters, the two 8 π-electron pentalene subunits strongly influence bonding and spectral properties. (1)H NMR spectra showed large upfield shifts of the protons in the pentalene moieties, comparable to antiaromatic monobenzopentalenes. Further investigations on magnetic ring currents through NICS-XY-scans suggest a global paratropic current and a local diatropic current at the central benzene ring in two of the series, while the third series, with a central naphthalene ring, showed more localized ring currents, with stronger paratropic ring currents on the pentalene moieties. X-ray diffraction analyses revealed planar bispentalene cores with large double- and single-bond alternation in the pentalene units, characteristic for antiaromaticity, and small alternation in the central aromatic rings. In agreement with TD-DFT calculations, both optical and electrochemical data showed much smaller HOMO-LUMO energy gaps compared to other neutral, acene-like hydrocarbons with the same number of fused rings. Both experimental and computational results suggest that the molecular properties of the presented bispentalenes are dominated by the antiaromatic pentalene-subunits despite the [4n+2] π-electron perimeter of the skeletons.

Halogen bonding (XB) between (iodoethynyl)benzene donors and quinuclidine in benzene affords binding free enthalpies (ΔG, 298 K) between -1.1 and -2.4 kcal mol(-1), with a strong LFER with the Hammett parameter σpara. The enthalpic driving force is compensated by an unfavorable entropic term. The binding affinity of XB acceptors increases in the order pyridine < C═O < S═O < P═O < quinuclidine. Diverse XB packing motifs are observed in the solid state.

Self‐assembly is a bioinspired strategy to craft materials for renewable and clean energy technologies. In plants, the alignment and assembly of the light‐harvesting protein machinery in the green leaf optimize the ability to efficiently convert light from the sun to form chemical bonds. In artificial systems, strategies based on self‐assembly using noncovalent interactions offer the possibility to mimic this functional correlation among molecules to optimize photocatalysis, photovoltaics, and energy storage. One of the long‐term objectives of the field described here as supramolecular energy materials is to learn how to design soft materials containing light‐harvesting assemblies and catalysts to generate fuels and useful chemicals. Supramolecular energy materials also hold great potential in the design of systems for photovoltaics in which intermolecular interactions in self‐assembled structures, for example, in electron donor and acceptor phases, maximize charge transport and avoid exciton recombination. Possible pathways to integrate organic and inorganic structures by templating strategies and electrodeposition to create materials relevant to energy challenges including photoconductors and supercapacitors are also described. The final topic discussed is the synthesis of hybrid perovskites in which organic molecules are used to modify both structure and functions, which may include chemical stability, photovoltaics, and light emission.