Polysaccharide‐based chiral stationary phases as halogen bond acceptors: A novel strategy for detection of stereoselective σ‐hole bonds in solution

In the last few years, halogen bonds have been exploited in a variety of research areas both in the solid state and in solution. Nevertheless, several factors make formation and detection of halogen bonds in solution challenging. Moreover, to date, few chiral molecules containing electrophilic halogens as recognition sites have been reported. Recently, we described the first series of halogen‐bond‐driven enantioseparations performed on cellulose tris(3,5‐dimethylphenylcarbamate) by high‐performance liquid chromatography. Herein the performances of amylose tris(3,5‐dimethylphenylcarbamate) as halogen bond acceptor were also investigated and compared with respect to cellulose tris(3,5‐dimethylphenylcarbamate). With the aim to explore the effect of polysaccharide backbone on the enantioseparations, the thermodynamic parameters governing the halogen‐dependent enantioseparations on both cellulose and amylose polymers were determined by a study at variable temperature and compared. Molecular dynamics were performed to model the halogen bond in polysaccharide‐analyte complexes. Chiral halogenated 4,4′‐bipyridines were used as test compounds (halogen bond donors). On this basis, a practical method for detection of stereoselective halogen bonds in solution was developed, which is based on the unprecedented use of high‐performance liquid chromatography as technical tool with polysaccharide polymers as molecular probes (halogen bond acceptors). The analytical strategy showed higher sensitivity for the detection of weak halogen bonds.     

Intermolecular Halogen Bond Detected in Racemic and Optically Pure N-C Axially Chiral 3-(2-Halophenyl)quinazoline-4-thione Derivatives

The halogen bond has been widely used as an important supramolecular tool in various research areas. However, there are relatively few studies on halogen bonding related to molecular chirality. 3-(2-Halophenyl)quinazoline-4-thione derivatives have stable atropisomeric structures due to the rotational restriction around an N-C single bond. In X-ray single crystal structures of the racemic and optically pure N-C axially chiral quinazoline-4-thiones, we found that different types of intermolecular halogen bonds (C=S⋯X) are formed. That is, in the racemic crystals, the intermolecular halogen bond between the ortho-halogen atom and sulfur atom was found to be oriented in a periplanar conformation toward the thiocarbonyl plane, leading to a syndiotactic zig-zag array. On the other hand, the halogen bond in the enantiomerically pure crystals was oriented orthogonally toward the thiocarbonyl plane, resulting in the formation of a homochiral dimer. These results indicate that the corresponding racemic and optically pure forms in chiral molecules are expected to display different halogen bonding properties, respectively, and should be separately studied as different chemical entities.     

The Halogen Bond: An Emerging Supramolecular Tool in the Design of Functional Mesomorphic Materials

Owing to their dynamic attributes, non-covalent supramolecular interactions have enabled a new paradigm in the design and fabrication of multifunctional material systems with programmable properties, performances, and reconfigurable traits. Recently, the “halogen bond” has become an enticing supramolecular synthetic tool that displays a plethora of promising and advantageous characteristics. Consequently, this versatile and dynamic non-covalent interaction has been extensively harnessed in various fields such as crystal engineering, self-assembly, materials science, polymer chemistry, biochemistry, medicinal chemistry and nanotechnology. In recent years, halogen bonding has emerged as a tunable supramolecular synthetic tool in the design of functional liquid-crystalline materials with adjustable phases and properties. In this Concept article, the use of halogen bond in the field of stimuli-responsive smart soft materials, that is, liquid crystals is discussed. The design, synthesis and characterization of molecular and macromolecular liquid crystalline materials are described and the modulation of their properties has been emphasized. The power of halogen bonding in offering a large variety of functional liquid crystalline materials from readily accessible mesomorphic and non-mesomorphic complementary building blocks is highlighted. The article concludes with a perspective on the challenges and opportunities in this emerging endeavor towards the realization of enabling and elegant dynamic functional materials.     

Effects of solvent on weak halogen bonds: Density functional theory calculations

In recent years, many applications of solution‐phase halogen bonding in anion recognition, catalysis, and pseudorotaxane formation have been reported. Moreover, a number of thermodynamic data of halogen bonding interactions in organic solution are now available. To obtain detailed information of the influence of the surrounding medium on weak halogen bonds, a series of dimeric complexes of halobenzene (PhX) with three electron donors (H₂O, HCHO, and NH₃) were investigated by means of DFT/PBE calculations in this work. The PCM implicit solvation approach was utilized to include the effects of three solvents (cyclohexane, chloroform, and water) as representatives for a wide range of dielectric constant. In some cases, halogen‐bond distances are shown to shorten in solution, accompanied by concomitant elongation of the C? X bonds. For the remaining systems, the intermolecular distances tend to increase or remain almost unchanged under solvent effects. In general, the solvent has a slight destabilizing effect on weak halogen bonds; the strength order of halogen bonds observed in vacuum remains unchanged in liquid phases. Particularly, the interaction strength attenuates in the order I > Br > Cl in solution, consistent with the experimental measurements of weak halogen bond door abilities. The similarities between halogen and hydrogen bonding in solution were also elucidated. The results presented herein would be very useful in future applications of halogen bonding in molecular recognition and medicinal chemistry. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2012     

Competition between Halogen,Hydrogen and Dihydrogen Bonding in Brominated Carboranes

Halogen bonds are a subset of noncovalent interactions with rapidly expanding applications in materials and medicinal chemistry. While halogen bonding is well known in organic compounds, it is new in the field of boron cluster chemistry. We have synthesized and crystallized carboranes containing Br atoms in two different positions, namely, bound to C‐ and B‐vertices. The Br atoms bound to the C‐vertices have been found to form halogen bonds in the crystal structures. In contrast, Br atoms bound to B‐vertices formed hydrogen bonds. Quantum chemical calculations have revealed that halogen bonding in carboranes can be much stronger than in organic architectures. These findings open new possibilities for applications of carboranes, both in materials and medicinal chemistry.     

Does Fluorine Participate in Halogen Bonding?

When R is sufficiently electron withdrawing, the fluorine in the R?F molecules could interact with electron donors (e.g., ammonia) and form a noncovalent bond (F ??? N). Although these interactions are usually categorized as halogen bonding, our studies show that there are fundamental differences between these interactions and halogen bonds. Although the anisotropic distribution of electronic charge around a halogen is responsible for halogen bond formations, the electronic charge around the fluorine in these molecules is spherical. According to source function analysis, F is the sink of electron density at the F ??? N BCP, whereas other halogens are the source. In contrast to halogen bonds, the F ??? N interactions cannot be regarded as lump–hole interactions; there is no hole in the valence shell charge concentration (VSCC) of fluorine. Although the quadruple moment of Cl and Br is mainly responsible for the existence of σ‐holes, it is negligibly small in the fluorine. Here, the atomic dipole moment of F plays a stabilizing role in the formation of F ??? N bonds. Interacting quantum atoms (IQA) analysis indicates that the interaction between halogen and nitrogen in the halogen bonds is attractive, whereas it is repulsive in the F ??? N interactions. Virial‐based atomic energies show that the fluorine, in contrast to Cl and Br, stabilize upon complex formation. According to these differences, it seems that the F ??? N interactions should be referred to as “fluorine bond” instead of halogen bond.     

An Unprecedented Interconversion Between Non-covalent and Covalent Interactions Driven by Halogen Bonding

The spontaneous interconversion between covalent forces and noncovalent counterparts remains an unexplained mystery to date. Here we have discovered a marvelous transformation between them through halogen bonding using NI₃ as a prototype. Our results show that the interaction strength of the NI₃ dimer is 7.01 kcal mol⁻¹, demonstrating that it is a quite strong halogen bond. Molecular orbital analyses indicate that the frontier molecular orbitals result from strong mixing of the fragment orbitals, which may be the electronic structure basis for interconversion. Further studies on a series of NI₃ oligomers (5-, 10-, 15-, 20-, 26-, 30-mer) show that the interconversion occurs approximately at 26-mer on the basis on bond distance, ELF, etc.; the interconversion is a gradual transformation and not a sudden one. This study provides more insights into the halogen bonding and the high explosivity of NI₃ containing species.     

The many flavours of halogen bonds – message from experimental electron density and Raman spectroscopy

Experimental electron‐density studies based on high‐resolution diffraction experiments allow halogen bonds between heavy halogens to be classified. The topological properties of the electron density in Cl…Cl contacts vary smoothly as a function of the interaction distance. The situation is less straightforward for halogen bonds between iodine and small electronegative nucleophiles, such as nitrogen or oxygen, where the electron density in the bond critical point does not simply increase for shorter distances. The number of successful charge–density studies involving iodine is small, but at least individual examples for three cases have been observed. (a) Very short halogen bonds between electron‐rich nucleophiles and heavy halogen atoms resemble three‐centre–four‐electron bonds, with a rather symmetric heavy halogen and without an appreciable σ hole. (b) For a narrow intermediate range of halogen bonds, the asymmetric electronic situation for the heavy halogen with a pronounced σ hole leads to rather low electron density in the (3,?1) critical point of the halogen bond; the properties of this bond critical point cannot fully describe the nature of the associated interaction. (c) For longer and presumably weaker contacts, the electron density in the halogen bond critical point is only to a minor extent reduced by the presence of the σ hole and hence may be higher than in the aforementioned case. In addition to the electron density and its derived properties, the halogen–carbon bond distance opposite to the σ hole and the Raman frequency for the associated vibration emerge as alternative criteria to gauge the halogen‐bond strength. We find exceptionally long C—I distances for tetrafluorodiiodobenzene molecules in cocrystals with short halogen bonds and a significant red shift for their Raman vibrations.     

Comparative Study of Halogen‐ and Hydrogen‐Bond Interactions between Benzene Derivatives and Dimethyl Sulfoxide

The halogen bond, similar to the hydrogen bond, is an important noncovalent interaction and plays important roles in diverse chemistry‐related fields. Herein, bromine‐ and iodine‐based halogen‐bonding interactions between two benzene derivatives (C₆F₅Br and C₆F₅I) and dimethyl sulfoxide (DMSO) are investigated by using IR and NMR spectroscopy and ab initio calculations. The results are compared with those of interactions between C₆F₅Cl/C₆F₅H and DMSO. First, the interaction energy of the hydrogen bond is stronger than those of bromine‐ and chlorine‐based halogen bonds, but weaker than iodine‐based halogen bond. Second, attractive energies depend on 1/rⁿ, in which n is between three and four for both hydrogen and halogen bonds, whereas all repulsive energies are found to depend on 1/r^8.5. Third, the directionality of halogen bonds is greater than that of the hydrogen bond. The bromine‐ and iodine‐based halogen bonds are strict in this regard and the chlorine‐based halogen bond only slightly deviates from 180°. The directional order is iodine‐based halogen bond>bromine‐based halogen bond>chlorine‐based halogen bond>hydrogen bond. Fourth, upon the formation of hydrogen and halogen bonds, charge transfers from DMSO to the hydrogen‐ and halogen‐bond donors. The CH₃ group contributes positively to stabilization of the complexes.     

Ab initio study of the complexes of halogen-containing molecules RX (X=Cl, Br, and I) and NH3: towards understanding the nature of halogen bonding and the electron-accepting propensities of covalently bonded halogen atoms

Ab initio calculations have been performed on a series of complexes formed between halogen-containing molecules and ammonia to gain a deeper insight into the nature of halogen bonding. It appears that the dihalogen molecules form the strongest halogen-bonded complexes with ammonia, followed by HOX; the charge-transfer-type contribution has been demonstrated to dominate the halogen bonding in these complexes. For the complexes involving carbon-bound halogen molecules, our calculations clearly indicate that electrostatic interactions are mainly responsible for their binding energies. Whereas the halogen-bond strength is significantly enhanced by progressive fluorine substitution, the substitution of a hydrogen atom by a methyl group in the CH(3)X...NH(3) complex weakened the halogen bonding. Moreover, remote substituent effects have also been noted in the complexes of halobenzenes with different para substituents. The influence of the hybridization state of the carbon atom bonded to the halogen atom has also been examined and the results reveal that halogen-bond strengths decrease in the order HC triple bond CX > H(2)C=CHX approximately O=CHX approximately C(6)H(5)X > CH(3)X. In addition, several excellent linear correlations have been established between the interaction energies and both the amount of charge transfer and the electrostatic potentials corresponding to an electron density of 0.002 au along the R-X axis; these correlations provide good models with which to evaluate the electron-accepting abilities of the covalently bonded halogen atoms. Finally, some positively charged halogen-bonded systems have been investigated and the effect of the charge has been discussed.     

Motional Dynamics of Halogen‐Bonded Complexes Probed by Low‐Field NMR Relaxometry and Overhauser Dynamic Nuclear Polarization

Halogen bonding is a subject of considerable interest owing to wide‐ranging chemical, materials and biological applications. The motional dynamics of halogen‐bonded complexes play a pivotal role in comprehending the nature of the halogen‐bonding interaction. However, not many attempts appear to have been made to shed light on the dynamical characteristics of halogen‐bonded species. For the first time, we demonstrate here that the combination of low‐field NMR relaxometry and Overhauser dynamic nuclear polarization (ODNP) makes it possible to obtain a cogent picture of the motional dynamics of halogen‐bonded species. We discuss here the advantages of this combined approach. Low‐field relaxometry allows us to infer the hydrodynamic radius and rotational correlation time, whereas ODNP probes the molecular translational correlation times (involving the substrate as well as the organic radical) with high sensitivity at low field.     

Source of Cooperativity in Halogen‐Bonded Haloamine Tetramers

Inspired by the isostructural motif in α‐bromoacetophenone oxime crystals, we investigated halogen–halogen bonding in haloamine quartets. Our Kohn–Sham molecular orbital and energy decomposition analysis reveal a synergy that can be traced to a charge‐transfer interaction in the halogen‐bonded tetramers. The halogen lone‐pair orbital on one monomer donates electrons into the unoccupied σ*_N?X orbital on the perpendicular N?X bond of the neighboring monomer. This interaction has local σ symmetry. Interestingly, we discovered a second, somewhat weaker donor–acceptor interaction of local π symmetry, which partially counteracts the aforementioned regular σ‐symmetric halogen‐bonding orbital interaction. The halogen–halogen interaction in haloamines is the first known example of a halogen bond in which back donation takes place. We also find that this cooperativity in halogen bonds results from the reduction of the donor–acceptor orbital‐energy gap that occurs every time a monomer is added to the aggregate.     

Halogen bonding in polymer science: towards new smart materials

The halogen bond is a special non-covalent interaction, which can represent a powerful tool in supramolecular chemistry. Although the halogen bond offers several advantages compared to the related hydrogen bond, it is currently still underrepresented in polymer science. The structural related hydrogen bonding assumes a leading position in polymer materials containing supramolecular interactions, clearly indicating the high potential of using halogen bonding for the design of polymeric materials. The current developments regarding halogen bonding containing polymers include self-assembly, photo-responsive materials, self-healing materials and others. These aspects are highlighted in the present perspective. Furthermore, a perspective on the future of this rising young research field is provided.

The incorporation of halogen bonding into polymer architectures is a new approach for the design of functional materials. This perspective emphasizes the current development in the field of halogen bonding featuring polymer materials.     

Cooperative and substitution effects in enhancing strengths of halogen bonds in FCl⋯CNX complexes

In this paper, the cooperative effect of halogen bond with hydrogen bond has been used to make a halogen bond in FCl-CNH dimer vary from a chlorine-shared one to an ion-pair one. The halogen bond is strengthened in FCl-CNH-CNH trimer and its maximal interaction energy equals to -76 kJ∕mol when the number of CNH in FCl-CNH-(CNH)(n) polymer approaches infinity. Once the free H atom in FCl-CNH-CNH trimer is replaced with alkali metals, the halogen bond becomes strong enough to be an ion-pair one in FCl-CNH-CNLi and FCl-CNH-CNNa trimers. An introduction of a Lewis acid in FCl-CNH dimer has a more prominent effect on the type of halogen bond. A prominent cooperative effect is found for the halogen bond and hydrogen bond in the trimers. FH-FCl-CNH-CNH and FH-FCl-CNH-CNLi tetramers have also been studied and the interaction energy of halogen bonding in FH-FCl-CNH-CNLi tetramer is about 12 times as much as that in the FCl-CNH dimer. The atoms in molecules and natural bond orbital analyses have been carried out for these complexes to understand the nature of halogen bond and the origin of the cooperativity.     

A Halogen‐Bonded Dimeric Resorcinarene Capsule

Iodine (I₂) acts as a bifunctional halogen‐bond donor connecting two macrocyclic molecules of the bowl‐shaped halogen‐bond acceptor, N‐cyclohexyl ammonium resorcinarene chloride 1 , to form the dimeric capsule [(1,4‐dioxane)₃@ 1 ₂(I₂)₂]. The dimeric capsule is constructed solely through halogen bonds and has a single cavity (V=511 ų) large enough to encapsulate three 1,4‐dioxane guest molecules.     

Iodoalkyne‐Based Catalyst‐Mediated Activation of Thioamides through Halogen Bonding

Halogen bonding catalysis has recently gained increasing attention as a powerful tool to activate organic molecules. However, the variety of the catalyst structure has been quite limited so far. Herein, we report the first example of the use of an iodoalkyne as a halogen bond donor catalyst. By using an iodoalkyne bearing a pentafluorophenyl group as a catalyst, thioamides were efficiently activated and reacted with 2‐aminophenol to generate benzoxazoles in good yield. Mechanistic studies, including ¹³C NMR spectroscopic analysis and several control experiments, provided concrete evidence that this catalytic activation is based on halogen bonding. Thus, the results obtained in this study demonstrate that iodoalkynes can serve as a new scaffold for future development of halogen bonding catalysis.     

Visible‐Light‐Driven Halogen Bond Donor Based Molecular Switches: From Reversible Unwinding to Handedness Inversion in Self‐Organized Soft Helical Superstructures

Visible‐light‐driven molecular switches endowing reversible modulation of the functionalities of self‐organized soft materials are currently highly sought after for fundamental scientific studies and technological applications. Reported herein are the design and synthesis of two novel halogen bond donor based chiral molecular switches that exhibit reversible photoisomerization upon exposure to visible light of different wavelengths. These chiral molecular switches induce photoresponsive helical superstructures, that is, cholesteric liquid crystals, when doped into the commercially available room‐temperature achiral liquid crystal host 5CB, which also acts as a halogen‐bond acceptor. The induced helical superstructure containing the molecular switch with terminal iodo atoms exhibits visible‐light‐driven reversible unwinding, that is, a cholesteric–nematic phase transition. Interestingly, the molecular switch with terminal bromo atoms confers reversible handedness inversion to the helical superstructure upon irradiation with visible light of different wavelengths. This visible‐light‐driven, reversible handedness inversion, enabled by a halogen bond donor molecular switch, is unprecedented.     

Interplay between halogen bond and lithium bond in MCN-LiCN-XCCH (M = H, Li, and Na; X = Cl, Br, and I) complex: the enhancement of halogen bond by a lithium bond

Quantum chemical calculations have been performed to study the complex of MCN-LiCN-XCCH (M = H, Li, and Na; X = Cl, Br, and I). The aim is to study the cooperative effect between halogen bond and lithium bond. The alkali metal has an enhancing effect on the lithium bond, making it increased by 77 and 94% for the Li and Na, respectively. There is the cooperativity between the lithium bond and halogen bond. The former has a larger enhancing effect on the latter, being in a range of 11.7-29.4%. The effect of cooperativity on the halogen bond is dependent on the type of metal and halogen atoms. The enhancing mechanism has been analyzed in views with the orbital interaction, charge transfer, dipole moment, polarizability, atom charges, and electrostatic potentials. The results show that the electrostatic interaction plays an important role in the enhancement of halogen bond.     

Benchmarking of Halogen Bond Strength in Solution with Nickel Fluorides: Bromine versus Iodine and Perfluoroaryl versus Perfluoroalkyl Donors

The energetics of halogen bond formation in solution have been investigated for a series of nickel fluoride halogen bond acceptors; trans-[NiF(2-C₅NF₄)(PEt₃)₂] ( A1 ), trans-[NiF{2-C₅NF₃(4-H)}(PEt₃)₂] ( A2 ), trans-[NiF{2-C₅NF₃(4-NMe₂)}(PEt₃)₂] ( A3 ) and trans-[NiF{2-C₅NF₂H(4-CF₃)}(PCy₃)₂] ( A4 ) with neutral organic halogen bond donors, iodopentafluorobenzene ( D1 ), 1-iodononafluorobutane ( D2 ) and bromopentafluorobenzene ( D3 ), in order to establish the significance of changes from perfluoroaryl to perfluoroalkyl donors and from iodine to bromine donors. ¹⁹F NMR titration experiments have been employed to obtain the association constants, enthalpy, and entropy for the halogen bond formed between these donor-acceptor partners in protiotoluene. For A2 – A4 , association constants of the halogen bonds formed with iodoperfluoroalkane ( D2 ) are consistently larger than those obtained for analogous complexes with the iodoperfluoroarene ( D1 ). For complexes formed with A2 – A4 , the strength of the halogen bond is significantly lowered upon modification of the halogen donor atom from I (in D1 ) to Br (in D3 ) (for D1 : 5≤K₂₈₅≤12 m ⁻¹, for D3 : 1.0≤K₁₉₃≤1.6 m ⁻¹). The presence of the electron donating NMe₂ substituent on the pyridyl ring of acceptor A3 led to an increase in −ΔH, and the association constants of the halogen bond complexes formed with D1 – D3 , compared to those formed by A1 , A2 and A4 with the same donors.     

Nature of the Hydrogen Bond Enhanced Halogen Bond

The factors responsible for the enhancement of the halogen bond by an adjacent hydrogen bond have been quantitatively explored by means of state-of-the-art computational methods. It is found that the strength of a halogen bond is enhanced by ca. 3 kcal/mol when the halogen donor simultaneously operates as a halogen bond donor and a hydrogen bond acceptor. This enhancement is the result of both stronger electrostatic and orbital interactions between the XB donor and the XB acceptor, which indicates a significant degree of covalency in these halogen bonds. In addition, the halogen bond strength can be easily tuned by modifying the electron density of the aryl group of the XB donor as well as the acidity of the hydrogen atoms responsible for the hydrogen bond.