The nature and characteristics of the CH/π interaction are discussed by comparison with other weak molecular forces such as the CH/O and OH/π interaction. The CH/π interaction is a kind of hydrogen bond operating between a soft acid CH and a soft base π-system (double and triple bonds, C6 and C5 aromatic rings, heteroaromatics, convex surfaces of fullerenes and nanotubes). The consequences of CH/π hydrogen bonds in supramolecular chemistry are reviewed on grounds of recent crystallographic findings and database analyses. The topics include intramolecular interactions, crystal packing (organic and organometallic compounds), host/guest complexes (cavity-type inclusion compounds of cyclodextrins and synthetic macrocyclic hosts such as calixarenes, catenanes, rotaxanes and pseudorotaxanes), lattice-inclusion type clathrates (including liquid crystals, porphyrin derivatives, cyclopentadienyl compounds and C60 fullerenes), enantioselective clathrate formation, catalytic enantioface discriminating reactions and solid-state photoreaction. The implications of the CH/π concept for crystal engineering and drug design are evident.

CH/π hydrogen bonds in crystals

Molecular recognition in biological systems relies on the existence of specific attractive interactions between two partner molecules. Structure-based drug design seeks to identify and optimize such interactions between ligands and their host molecules, typically proteins, given their three-dimensional structures. This optimization process requires knowledge about interaction geometries and approximate affinity contributions of attractive interactions that can be gleaned from crystal structure and associated affinity data.

Here we compile and review the literature on molecular interactions as it pertains to medicinal chemistry through a combination of careful statistical analysis of the large body of publicly available X-ray structure data and experimental and theoretical studies of specific model systems. We attempt to extract key messages of practical value and complement references with our own searches of the CSDa,(1) and PDB databases.(2) The focus is on direct contacts between ligand and protein functional groups, and we restrict ourselves to those interactions that are most frequent in medicinal chemistry applications. Examples from supramolecular chemistry and quantum mechanical or molecular mechanics calculations are cited where they illustrate a specific point. The application of automated design processes is not covered nor is design of physicochemical properties of molecules such as permeability or solubility.

Throughout this article, we wish to raise the readers’ awareness that formulating rules for molecular interactions is only possible within certain boundaries. The combination of 3D structure analysis with binding free energies does not yield a complete understanding of the energetic contributions of individual interactions. The reasons for this are widely known but not always fully appreciated. While it would be desirable to associate observed interactions with energy terms, we have to accept that molecular interactions behave in a highly nonadditive fashion.3,4 The same interaction may be worth different amounts of free energy in different contexts, and it is very hard to find an objective frame of reference for an interaction, since any change of a molecular structure will have multiple effects. One can easily fall victim to confirmation bias, focusing on what one has observed before and building causal relationships on too few observations. In reality, the multiplicity of interactions present in a single protein−ligand complex is a compromise of attractive and repulsive interactions that is almost impossible to deconvolute. By focusing on observed interactions, one neglects a large part of the thermodynamic cycle represented by a binding free energy: solvation processes, long-range interactions, conformational changes. Also, crystal structure coordinates give misleadingly static views of interactions. In reality a macromolecular complex is not characterized by a single structure but by an ensemble of structures. Changes in the degrees of freedom of both partners during the binding event have a large impact on binding free energy.

The text is organized in the following way. The first section treats general aspects of molecular design: enthalpic and entropic components of binding free energy, flexibility, solvation, and the treatment of individual water molecules, as well as repulsive interactions. The second half of the article is devoted to specific types of interactions, beginning with hydrogen bonds, moving on to weaker polar interactions, and ending with lipophilic interactions between aliphatic and aromatic systems. We show many examples of structure−activity relationships; these are meant as helpful illustrations but individually can never confirm a rule.

http://pubs.acs.org/doi/pdf/10.1021/jm100112j

A Medicinal Chemist’s Guide to Molecular Interactions

In the last decade interactions of fluorine substituents in a variety of organic compounds have gained interest in life science and solid state materials. This review provides knowledge on fluorine interactions classified into phenyl–perfluorophenyl-, C–F⋯H, F⋯F and C–F⋯πF interactions. Except for phenyl–perfluorophenyl stacking featuring a stabilising energy of about 30 kJ·mol−1, interactions involving fluorine are generally weak. Although, there is still no concise understanding of fluorine interactions, there are numerous examples showing the influence of weak synthons on chemical, physical and biological properties.

Fluorine in crystal engineering—“the little atom that could”

The interactions of metal ions with quinolone antibacterial agents

Non-covalent interactions play a crucial role in (supramolecular) chemistry and much of biology. Supramolecular forces can indeed determine the structure and function of a host–guest system. Many sensors, for example, rely on reversible bonding with the analyte. Natural machineries also often have a significant non-covalent component (e.g. protein folding, recognition) and rational interference in such ‘living’ devices can have pharmacological implications. For the rational design/tweaking of supramolecular systems it is helpful to know what supramolecular synthons are available and to understand the forces that make these synthons stick to one another. In this review we focus on σ-hole and π-hole interactions. A σ- or π-hole can be seen as positive electrostatic potential on unpopulated σ* or π(*) orbitals, which are thus capable of interacting with some electron dense region. A σ-hole is typically located along the vector of a covalent bond such as XH or XHlg (X=any atom, Hlg=halogen), which are respectively known as hydrogen and halogen bond donors. Only recently it has become clear that σ-holes can also be found along a covalent bond with chalcogen (XCh), pnictogen (XPn) and tetrel (XTr) atoms. Interactions with these synthons are named chalcogen, pnigtogen and tetrel interactions. A π-hole is typically located perpendicular to the molecular framework of diatomic π-systems such as carbonyls, or conjugated π-systems such as hexafluorobenzene. Anion–π and lone-pair–π interactions are examples of named π-hole interactions between conjugated π-systems and anions or lone-pair electrons respectively. While the above nomenclature indicates the distinct chemical identity of the supramolecular synthon acting as Lewis acid, it is worth stressing that the underlying physics is very similar. This implies that interactions that are now not so well-established might turn out to be equally useful as conventional hydrogen and halogen bonds. In summary, we describe the physical nature of σ- and π-hole interactions, present a selection of inquiries that utilise σ- and π-holes, and give an overview of analyses of structural databases (CSD/PDB) that demonstrate how prevalent these interactions already are in solid-state structures.

The Bright Future of Unconventional σ/π-Hole Interactions

C–halogen···π interactions and their influence on molecular conformation and crystal packing: a database study

Hydrogen bonded networks in hydrophilic channels: crystal structure of hydrated Ciprofloxacin Lactate and comparison with structurally similar compounds

Weak interactions involving organic fluorine: analysis of structural motifs in Flunazirine and Haloperidol

Weak interactions involving fluorine have been analyzed in terms of altered packing modes in the crystalline lattice in four benzodiazepinone drug intermediates which are determined by X-ray diffraction. Two of them are non-fluorinated and the other two are corresponding mono-fluorosubstituted derivatives. The compounds are 2-chloroacetamido-5-chlorobenzophenone (C15H11Cl2NO), 2-chloroacetamido-5-chloro-2'-fluorobenzophenone (C15H10Cl2FNO2), 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzadiazapin-2-one (C15H12ClN2O) and 7-chloro-1,3-dihydro-5-(2'-fluorophenyl)-2H-1,4-benzadiazapin-2-one (C15H11ClN2OF). The conformational features in the first two compounds are essentially governed by strong intramolecular interactions. Specific C-H...F intermolecular interactions along with C-H...π interactions generate altered packing modes in fluorinated intermediates. The latter two compounds have strong N-H...O intermolecular hydrogen bonds as well

Analysis of weak interactions involving fluorine: a comparative study of crystal packing of some benzodiazepinone drug intermediates and their non-fluorinated analogues

M.D. Prasanna

Papers

C–halogen···π interactions and their influence on molecular conformation and crystal packing: a database study

Hydrogen bonded networks in hydrophilic channels: crystal structure of hydrated Ciprofloxacin Lactate and comparison with structurally similar compounds

Weak interactions involving organic fluorine: analysis of structural motifs in Flunazirine and Haloperidol

Analysis of weak interactions involving fluorine: a comparative study of crystal packing of some benzodiazepinone drug intermediates and their non-fluorinated analogues