Anion⋯anion self-assembly under the control of σ- and π-hole bonds.

The electrostatic attraction between charges of opposite signs and the repulsion between charges of the same sign are ubiquitous and influential phenomena in recognition and self-assembly processes. However, it has been recently revealed that specific attractive forces between ions with the same sign are relatively common. These forces can be strong enough to overcome the Coulomb repulsion between ions with the same sign, leading to the formation of stable anion⋯anion and cation⋯cation adducts. Hydroden bonds (HBs) are probably the best-known interaction that can effectively direct these counterintuitive assembly processes. In this review we discuss how σ-hole and π-hole bonds can break the paradigm of electrostatic repulsion between like-charges and effectively drive the self-assembly of anions into discrete as well as one-, two-, or three-dimensional adducts. σ-Hole and π-hole bonds are the attractive forces between regions of excess electron density in molecular entities (e.g., lone pairs or π bond orbitals) and regions of depleted electron density that are localized at the outer surface of bonded atoms opposite to the σ covalent bonds formed by atoms (σ-holes) and above and below the planar portions of molecular entities (π-holes). σ- and π-holes can be present on many different elements of the p and d block of the periodic table and the self-assembly processes driven by their presence can thus involve a wide diversity of mono- and di-anions. The formed homomeric and heteromeric adducts are typically stable in the solid phase and in polar solvents but metastable or unstable in the gas phase. The pivotal role of σ- and π-hole bonds in controlling anion⋯anion self-assembly is described in key biopharmacological systems and in molecular materials endowed with useful functional properties.

Chalcogen and Hydrogen Bond Team up in Driving Anion⋠⋠⋠Anion Self-Assembly.

H-selenite anions (HSeO3 - ) form in the solid unprecedented anionic supramolecular chains wherein single units are assembled via alternating short Se⋅⋅⋅O and H⋅⋅⋅O contacts. Crystallographic analyses and computational studies (the quantum theory of "atoms-in-molecules", QTAIM, and the noncovalent interaction plot, NCIPlot) consistently prove the attractive nature of these chalcogen bonds (ChBs) and hydrogen honds (HBs), the Janus-type character of HSeO3 - anions which act as both donors and acceptors of ChB and HB, and the possible stability of anion dimers in solution. The effectiveness of the ChBs herein described may lead to consider the HSeO3 - moiety as a new entry in the toolbox of crystal engineering based on ChB.

Osme Bond: Geometric and Energetic Features in the Adducts between OsO4 and Lewis Bases.

Adducts between OsO4 and Lewis bases exert a role in important oxidation processes such as epoxidation and dihydroxylation. It has been shown that the attractive interaction driving the formation of these adducts is a σ-hole bond involving the metal as the electrophilic species; the term Osme Bond (OmB) was proposed for designating it. Here some new adducts between OsO4 and various bases have been characterized through single crystal x-ray diffraction (XRD) and computational studies (density functional theory, DFT), confirming the existence of a robust correlation between σ-hole interaction energy and deformation of the tetrahedral geometry of OsO4. Also, some adducts formed by RuO4 with nucleophiles were investigated computationally.

Erythronium Bonds: Noncovalent Interactions Involving Group†5 Elements as Electron-Density Acceptors.

Analyses of the Cambridge Structural Database and theoretical calculations (PBE0-D3/def2-TZVP level, atoms-in-molecules, natural bond orbital studies) prove the formation of net attractive noncovalent interactions between group 5 elements and electron-rich atoms (neutral or anionic). These kinds of bonding are markedly different from coordination bonds formed by the same elements and possess the distinctive features of σ-hole interactions. The term erythronium bond is proposed to denote these bonds. X-ray structures of vanadate-dependent bromoperoxidases show that these interactions are present also in biological systems.

Chalcogen Bonding (ChB) as a Robust Supramolecular Recognition Motif of Benzisothiazolinone Antibacterials.

1,2-benzisothiazol-3(2H)-one derivatives are highly active against a broad spectrum of fungi as well as Gram positive and Gram negative bacteria. For this reason they are extensively used, for example, as additives in detergents, leather products, paper coatings, and antifouling paintings. In this paper experimental findings are reported proving that the sulfur atom of benzisothiazolinones have a remarkable tendency to form short and directional chalcogen bondings on the extension of the covalent N-S bond and, to a lesser extent, of the C-S bond. Analyses of the Cambridge Structural Database confirm the interaction as a primary recognition motif of these systems. The electrophilicity of sulfur is crucial in the chemical reactions initiating the cascade of events resulting in the biopharmacological activities of benzisothiazolinones. The reported results suggest that the electrophility of sulfur may play a role also at earlier stages than the reactive ones, namely it may pin the compounds at the active site of target enzymes via chalcogen bondings that preorganize the system in the conformation required for the bonds formation/cleavage determining the biopharmacological activity.

Halogen Bonding Assembles Anion⋠⋠⋠Anion Architectures in Non-centrosymmetric Iodate and Bromate Crystals.

Single crystal X-ray diffraction of iodate and bromate salts shows that the I and Br atoms in IO3 - and BrO3 - anions form short and linear O-I/Br⋅⋅⋅O contacts with the O atoms of nearby anions. Non-centrosymmetric systems are formed wherein anions are orderly aligned into supramolecular 1D and 2D networks. Theoretical evidences, namely the outcome of QTAIM and NCIplot studies, prove the attractive nature of these contacts and the ability of iodate and bromate anions to act as robust halogen bond (HaB) donors. The HaB is proposed as a general and effective assisting tool to control the architecture of acentric iodate salts.

Stacking Interactions: A Supramolecular Approach to Upgrade Weak Halogen Bond Donors.

The co-crystallization of tetracyanobenzene (TCB) with haloarenes ArX provided six new co-crystals TCB ⋅ ArX (ArX=PhCl, PhBr, 4-MeC6 H4 Cl, 4-MeC6 H4 Br, 4-MeOC6 H4 Cl, 1,2-Br2 C6 H4 ) which were studied by X-ray diffraction. In these systems, the strong collective effect of π⋅⋅⋅π stacking interactions and lone pair-(X)⋅⋅⋅π-hole-(C) bondings between TCB and ArX promote the strength of X⋅⋅⋅Ncyano halogen bonding (HaB). Theoretical studies showed that the stacking interactions affect the σ-hole depth of the haloarenes, thus significantly boosting their ability to function as HaB donors. According to the molecular electrostatic potential calculations, the σ- hole-(Cl) value (1.5 kcal/mol) in the haloarene 4-MeOC6 H4 Cl (featuring an electron-rich arene moiety and exhibiting very poor σ-hole-(Cl) ability) increases significantly in the stacked trimer (TCB)2 ⋅ 4-MeOC6 H4 Cl (12.5 kcal/mol). Theoretical DFT calculations demonstrate the dramatic increase of X⋅⋅⋅Ncyano HaB strength for stacked trimers in comparison with parent unstacked haloarenes.

The N,N,N-trimethylammonium moiety as tetrel bond donor site: crystallographic and computational studies.

Five structures bearing the N,N,N-trimethylammonium unit have been investigated to address the ability of the N+-CH3 unit to function as a tetrel bond donor site. Charged and neutral electron density donors display close contacts with different carbon atoms of methyl groups on the ammonium moiety. The Hirshfeld atom refinement (HAR) technique was used on selected structures to accurately and precisely determine the hydrogen atom positions and, consequently, to get better insights into the N+-C⋯Nu (Nu = nucleophile) interactions occurring in the crystals. In particular, the performed analyses highlighted specific geometrical features of the moieties involved in the interactions and allowed distinguishing between tetrel and hydrogen bonds.

Anion⋠⋠⋠Anion Interactions Involving σ-Holes of Perrhenate, Pertechnetate and Permanganate Anions.

In this communication experimental and theoretical results are reported affording strong evidence that interactions between electron rich atoms and the metal of tetroxide anions of group 7 elements are a new case of attractive and σ-hole interactions. Single crystal X-ray analyses, molecular electrostatic potentials, quantum theory of atoms-in-molecules, and noncovalent interaction plot analyses show that in crystalline permanganate and perrhenate salts the metal in Mn/ReO4- anion can act as electron acceptors, the oxygen of another Mn/ReO4- anion can act as the donor and supramolecular anionic dimers or polymers are formed. The name matere bond (MaB) is proposed to categorize these noncovalent interactions and to differentiate them from the classical metal-ligand coordination bond.

Anion⋠⋠⋠Anion Coinage Bonds: The Case of Tetrachloridoaurate.

Interactions in crystalline tetrachloridoaurates of acetylcholine and dimethylpropiothetine are characterized by Au⋅⋅⋅Cl and Au⋅⋅⋅O short contacts. The former interactions assemble the AuCl4 - units into supramolecular anionic polymers, while the latter interactions append the acetylcholine and propiothetine units to the polymer. The distorted octahedral geometry of the bonding pattern around the gold center is rationalized on the basis of the anisotropic distribution of the electron density, which enables gold to behave as an electrophile (π-hole coinage-bond donor). Computational studies prove that gold atoms in negatively charged species can function as acceptors of electron density. The attractive nature of the Au⋅⋅⋅Cl/O interactions described here complement the known aurophilic bonds involved in gold-centered interactions.

Molecular Electrostatic Potential and Noncovalent Interactions in Derivatives of Group 8 Elements.

This communication reports experimental and theoretical evidences of σ-hole interactions in adducts between nitrogen or oxygen nucleophiles and tetroxides of osmium or other group 8 elements. Cocrystals between pyridine or pyridine N-oxide derivatives and osmium tetroxide are characterized through various techniques and rationalized as σ-hole interactions using DFT calculations and several other computational tools. We propose the term "osme bond" (OmB, Om=Fe, Ru, Os, (Hs)) for naming the noncovalent interactions wherein group 8 elements have the role of the electrophile. The word osme is the transcription of ὀσµÎ®, the ancient Greek word for smell that was used to name the heaviest group 8 element in relation to the smoky odor of its tetroxide.

The Chalcogen Bond in Crystalline Solids: A World Parallel to Halogen Bond.

The distribution of the electron density around covalently bonded atoms is anisotropic, and this determines the presence, on atoms surface, of areas of higher and lower electron density where the electrostatic potential is frequently negative and positive, respectively. The ability of positive areas on atoms to form attractive interactions with electron rich sites became recently the subject of a flurry of papers. The halogen bond (HaB), the attractive interaction formed by halogens with nucleophiles, emerged as a quite common and dependable tool for controlling phenomena as diverse as the binding of small molecules to proteinaceous targets or the organization of molecular functional materials. The mindset developed in relation to the halogen bond prompted the interest in the tendency of elements of groups 13-16 of the periodic table to form analogous attractive interactions with nucleophiles. This Account addresses the chalcogen bond (ChB), the attractive interaction formed by group 16 elements with nucleophiles, by adopting a crystallographic point of view. Structures of organic derivatives are considered where chalcogen atoms form close contacts with nucleophiles in the geometry typical for chalcogen bonds. It is shown how sulfur, selenium, and tellurium can all form chalcogen bonds, the tendency to give rise to close contacts with nucleophiles increasing with the polarizability of the element. Also oxygen, when conveniently substituted, can form ChBs in crystalline solids. Chalcogen bonds can be strong enough to allow for the interaction to function as an effective and robust tool in crystal engineering. It is presented how chalcogen containing heteroaromatics, sulfides, disulfides, and selenium and tellurium analogues as well as some other molecular moieties can afford dependable chalcogen bond based supramolecular synthons. Particular attention is given to chalcogen containing azoles and their derivatives due to the relevance of these moieties in biosystems and molecular materials. It is shown how the interaction pattern around electrophilic chalcogen atoms frequently recalls the pattern around analogous halogen, pnictogen, and tetrel derivatives. For instance, directionalities of chalcogen bonds around sulfur and selenium in some thiazolium and selenazolium derivatives are similar to directionalities of halogen bonds around bromine and iodine in bromonium and iodonium compounds. This gives experimental evidence that similarities in the anisotropic distribution of the electron density in covalently bonded atoms translates in similarities in their recognition and self-assembly behavior. For instance, the analogies in interaction patterns of carbonitrile substituted elements of groups 17, 16, 15, and 14 will be presented. While the extensive experimental and theoretical data available in the literature prove that HaB and ChB form twin supramolecular synthons in the solid, more experimental information has to become available before such a statement can be safely extended to interactions wherein elements of groups 14 and 15 are the electrophiles. It will nevertheless be possible to develop some general heuristic principles for crystal engineering. Being based on the groups of the periodic table, these principles offer the advantage of being systematic.

Charge-Assisted Chalcogen Bonds: CSD and DFT Analyses and Biological Implication in Glucosidase Inhibitors.

This study reports a combined Cambridge Structural Database and theoretical DFT study of charge assisted chalcogen bonds involving sulfonium, selenonium, and telluronium cations. The chalcogen bond has been recently defined by IUPAC as the net attractive interaction between an electrophilic region associated with a chalcogen atom in a molecular entity and a nucleophilic region in another, or the same, molecular entity. Divalent chalcogen atoms typically have up to two σ-holes and forms up to two ChBs; the same holds for tetravalent chalcogens which adopt a seesaw arrangement. In sulfonium, selenonium, and telluronium salts chalcogen atoms form three covalent bonds, three σ-holes are located opposite to these bonds, and up to three charge assisted ChBs can be formed between these holes and the counterions. The covalent bond arrangement around these chalcogen atoms is similar to trivalent pnictogen atoms and translates into a similar pattern of noncovalent interactions. We have found and studied this type of charge-assisted chalcogen bonds in various sulfonium ion-containing inhibitors of glucosidase, for example, salacinol and kotalanol.

The Relevance of Size Matching in Self-assembly: Impact on Regio- and Chemoselective Cocrystallizations.

Decamethonium diiodide is reported to perform the chemo- and regioselective encapsulation of para-dihalobenzenes through the competitive formation of halogen-bonded cocrystals starting from solutions that also contain ortho and meta isomers. Selective caging in the solid occurs even when an excess ortho or meta isomers, or even a mixture of them, is present in the solution. A prime matching between the size and shape of the dication and the formed dianions plays a key role in enabling the selective self-assembly, as proven by successful encapsulation of halogen-bond donors as weak as 1,4-dichlorobenzene and by the results of cocrystallization trials involving mismatching tectons. Encapsulated para-dihalobenzenes guest molecules can be removed quantitatively by heating the cocrystals under reduced pressure and be recovered as pure materials. The residual decamethonium diiodide can be recycled with no reduction in selectivity.

Resonance Assisted Chalcogen Bonding as a New Synthon in the Design of Dyes.

Intramolecular chalcogen bonding in arylhydrazones of sulfamethizole is strengthened by conjugation in the π-system of a noncovalent five-membered ring. The S⋅⋅⋅O distance in the sulfamethizole moiety of these compounds ranges from 2.698(3) to 2.806(15) Å, which indicates its strong dependence on the attached arylhydrazone fragments. Information on the nature of the intramolecular chalcogen bond was afforded by DFT calculations.

Radicalradical chalcogen bonds: CSD analysis and DFT calculations.

This manuscript reports a combination of crystallographic analysis (Cambridge Structural Database) and theoretical DFT calculations in chalcogen bonding interactions involving radicals in both the Ch bond (ChB) donor and acceptor. As a radical ChB acceptor (nucleophile) we have used benzodithiazolyl radical (BDTA) and as Ch bond donors (electrophile) we have used dithiadiazolyl and diselenadiazolyl radicals of the general formula p-X-C6F4-CNChChN (Ch = S, and Se). We have evaluated how the para substituent (X) affects the interaction energy, spin density and charge/spin transfer from the electron rich BDTA radical to the electron poor dichalcogenadiazolyl ring. The ability of the latter rings to form ChBs in the solid state has been examined by a comprehensive search in the CSD; several cases are used to exemplify the preferred geometric features of the complexes and they are compared with the theory. The molecular surface electrostatic potentials calculated for these ChB donors allow for a very precise rationalization of the self-assembly motifs most frequently adopted in the crystalline state and of their relative robustness.

Unexpected chalcogen bonds in tetravalent sulfur compounds.

In this manuscript we have combined a CSD (Cambridge Structural Database) analysis with theoretical calculations (RI-MP2/def2-TZVP level of theory) to study the importance of polarizability in chalcogen bonding interactions. It is well known that chalcogen bonds are stronger for less electronegative chalcogen atoms, i.e., S < Se < Te, and in the presence of electron-withdrawing substituents at the chalcogen. Herein, we report experimental and theoretical evidence (RI-MP2/def2-TZVP) that the chalcogen bond acceptor (Lewis base) has a preference in some cases for the σ-hole that is opposite to the more polarizable group instead of the more electron withdrawing one, as confirmed by Natural Bond Orbital (NBO) and Bader's theory of "atoms-in-molecules" computational tools.

Molecular Bases for Anesthetic Agents: Halothane as a Halogen- and Hydrogen-Bond Donor.

Although instrumental for optimizing their pharmacological activity, a molecular understanding of the preferential interactions given by volatile anesthetics is quite poor. This paper confirms the ability of halothane to work as a hydrogen-bond (HB) donor and gives the first experimental proof that halothane also works as a halogen-bond (HaB) donor in the solid state and in solution. A halothane/hexamethylphosphortriamide co-crystal is described and its single-crystal X-ray structure shows short HaBs between bromine, or chlorine, and the phosphoryl oxygen. New UV/Vis absorption bands appear upon addition of diazabicyclooctane and tetra(n-butyl)ammonium iodide to halothane solutions, indicating that nitrogen atoms and anions may mediate the HaB-driven binding processes involving halothane as well. The ability of halothane to work as a bidentate/tridentate tecton by acting as a HaB and HB donor gives an atomic rationale for the eudismic ratio shown by this agent.

The Halogen Bond.

The halogen bond occurs when there is evidence of a net attractive interaction between an electrophilic region associated with a halogen atom in a molecular entity and a nucleophilic region in another, or the same, molecular entity. In this fairly extensive review, after a brief history of the interaction, we will provide the reader with a snapshot of where the research on the halogen bond is now, and, perhaps, where it is going. The specific advantages brought up by a design based on the use of the halogen bond will be demonstrated in quite different fields spanning from material sciences to biomolecular recognition and drug design.

Dicarboxylic Acid Separation by Dynamic and Size-Matched Recognition in Solution and in the Solid State.

Bis(trimethylammonium) alkane diiodides dynamically encapsulate dicarboxylic acids through intermolecular hydrogen bonds between the I- anions of the hosts and the carboxylic OH groups of the guests. A selective recognition is realized when the size of the I- ⋅⋅⋅HOOC(CH2 /CF2 )n COOH⋅⋅⋅I- superanion matches the dication alkyl chain length. Dynamic recognition is also demonstrated in solution, where the presence of the size-matching organic salt boosts the acid solubility profile, thus allowing efficient mixture separation.