Halogen bonding in complexes of proteins and non-natural amino acids

In this work, we have analyzed the influence of halogen bonding to the stability of 44 complexes of proteins and non-natural amino acids. Fluorine- and chlorine-containing non-natural amino acids are more prevalent in the dataset, and an even larger number of contacts made by iodine-containing ligands are found. Only few halogen bonds with the hydroxyl oxygens and carboxylate side chains are found in the dataset. Halogen bonds with the nitrogen-containing side chains have higher occurrence than other acceptors. Backbone carbonyl oxygens and nitrogens are to a substantial extent involved in our dataset. We have observed a small percentage of interactions involving water as hydrogen bond donors. Additionally, most of the interacting residues comprising the interfaces also show a great degree of conservation. There is a clear interaction hot spot at distances of 3.5–3.7 Å and Θ₁ angles of 100–120°. There is also a cluster of contacts featuring short distances (2.6–2.9 Å) but only nearly optimal Θ₁ angles (140–160°). 51.3% of stabilizing residues are involved in building halogen bonds with the non-natural amino acids. We discovered three types of structural motifs significantly over-represented: beta-turn-ir, beta-turn-il and niche-4r. The halogen-bonding statistics of the dataset do not show any preference for α-helices (36%), β-sheets (36%), or turns/coils (28%) structures. Most of the amino acid residues that were involved in halogen bonds prefer to be in the solvent excluded environment (buried). Furthermore, we have shown that in amino acid–protein complexes halogen atoms can sometimes be involved in hydrogen bonding interactions with hydrogen bonding-donors. The results from this study might be used for the rational design of halogenated ligands as inhibitors and drugs, and in biomolecular engineering.     

Halogen bonding: a paradigm in supramolecular chemistry

The term halogen bonding describes the tendency of halogen atoms to interact with lone pair possessing atoms. The binding features and structural properties of halogen bonding are discussed and applied to drive the intermolecular self-assembly of hydrocarbons and perfluorocarbons in chemo-, site-, and enantioselective supramolecular synthesis. The halogen bonding is thus an effective and reliable tool in crystal engineering at the disposal of the supramolecular chemist.     

Halogen bonding in solution

Halogen bonding is the electron density donation based weak interaction of halogens with Lewis bases. Its applicability for molecular recognition processes long remained unappreciated and has so far mostly been studied in silico and in solid state. As most physiological processes and chemical reactions take place in solution, investigations in solutions are of highest relevance for its use in the pharmaceutical and material scientific toolboxes. Following a short discussion of the phenomenon of halogen bonding, this tutorial review presents an overview of the methods hitherto applied for gaining an improved understanding of its behaviour in solutions and summarizes the gained knowledge in order to indicate the scope of the techniques and to facilitate exciting future developments.     

Halogen bonding in supramolecular chemistry

Halogen bonding is the noncovalent interaction where halogen atoms function as electrophilic species. The energetic and geometrical features of the interaction are described along with the atomic characteristics that confer molecules with the specific ability to interact through this interaction. Halogen bonding has an impact on all research fields where the control of intermolecular recognition and self-assembly processes plays a key role. Some principles are presented for crystal engineering based on halogen-bonding interactions. The potential of the interaction is also shown by applications in liquid crystals, magnetic and conducting materials, and biological systems.     

Halogen bonding and chalcogen bonding mediated sensing

Sigma–hole interactions, in particular halogen bonding (XB) and chalcogen bonding (ChB), have become indispensable tools in supramolecular chemistry, with wide-ranging applications in crystal engineering, catalysis and materials chemistry as well as anion recognition, transport and sensing. The latter has very rapidly developed in recent years and is becoming a mature research area in its own right. This can be attributed to the numerous advantages sigma–hole interactions imbue in sensor design, in particular high degrees of selectivity, sensitivity and the capability for sensing in aqueous media. Herein, we provide the first detailed overview of all developments in the field of XB and ChB mediated sensing, in particular the detection of anions but also neutral (gaseous) Lewis bases. This includes a wide range of optical colorimetric and luminescent sensors as well as an array of electrochemical sensors, most notably redox-active host systems. In addition, we discuss a range of other sensor designs, including capacitive sensors and chemiresistors, and provide a detailed overview and outlook for future fundamental developments in the field. Importantly the sensing concepts and methodologies described herein for the XB and ChB mediated sensing of anions, are generically applicable for the development of supramolecular receptors and sensors in general, including those for cations and neutral molecules employing a wide array of non-covalent interactions. As such we believe this review to be a useful guide to both the supramolecular and general chemistry community with interests in the fields of host–guest recognition and small molecule sensing. Moreover, we also highlight the need for a broader integration of supramolecular chemistry, analytical chemistry, synthetic chemistry and materials science in the development of the next generation of potent sensors.

Sigma–hole mediated detection of anions is rapidly emerging as a new paradigm in supramolecular sensor chemistry. Herein, we provide an overview of this field including halogen bonding and chalcogen bonding optical, electrochemical and other sensors.     

Halogen bonding: a new interaction for liquid crystal formation

It is shown for the first time that liquid crystal behavior can be induced through halogen bonding. Thus, mixing the nonmesomorphic components 4-alkoxystilbazole with pentafluoroiodobenzene leads to a 1:1 halogen-bonded complex whose integrity is shown by X-ray single-crystal analysis and which shows thermotropic smectic A and nematic phases.     

Halogen bonding in DNA base pairs

Halogen bonding (R-X···Y) is a qualitative analogue of hydrogen bonding that may prove useful in the rational design of artificial proteins and nucleotides. We explore halogen-bonded DNA base pairs containing modified guanine, cytosine, adenine and thymine nucleosides. The structures and stabilities of the halogenated systems are compared to the normal hydrogen bonded base pairs. In most cases, energetically stable, coplanar structures are identified. In the most favorable cases, halogenated base pair stabilities are within 2 kcal mol(-1) of the hydrogen bonded analogues. Among the halogens X = Cl, Br, and I, bromine is best suited for inclusion in these biological systems because it possesses the best combination of polarizability and steric suitability. We find that the most stable structures result from a single substitution of a hydrogen bond for a halogen bond in dA:dT and dG:dC base pairs, which allows 1 or 2 hydrogen bonds, respectively, to complement the halogen bond.     

Dinuclear complexes of a pseudocalixarene macrocycle: structural consequences of intramolecular hydrogen bonding

A series of dinuclear complexes of a pseudocalixarene macrocycle H6L containing two 2,2'-methylenediphenol groups have been synthesised and structurally characterised. Using divalent metal ions, complexes containing a common hyperbolic paraboloid (saddle) M2(H4L)2+ core are formed. The structure is controlled by two strong O-H-O interactions resulting from metal ion-promoted monodeprotonation of the methylenediphenol units. The metal ions are located in a cleft within which neutral or anionic guests can bind. Use of trivalent metal ions leads to complete deprotonation of the phenol groups and loss of the saddle conformation.     

Halogen bonding in mono- and dihydrated halobenzene

Density functional theory calculations were performed on halogen-bonded and hydrogen-bonded systems consisting of a halobenzene (XPh; X = F, Cl, Br, I, and At) and one or two water molecules, using the M06-2X density functional with the 6-31+G(d) (for C, H, F, Cl, and Br) and aug-cc-pVDZ-PP (for I, At) basis sets. The counterpoise procedure was performed to counteract the effect of basis set superposition error. The results show halogen bonds form in the XPh-H₂O system when X > Cl. There is a trend toward stronger halogen bonding as the halogen group is descended, as assessed by interaction energy and X•••O_w internuclear separation (where O_w is the water oxygen). For all XPh-H₂O systems hydrogen-bonded systems exist, containing a combination of CH•••O_w and O_wH_w•••X hydrogen bonds. For all systems except X = At the X•••H_w hydrogen-bonding interaction is stronger than the X•••O_w halogen bond. In the XPh-(H₂O)₂ system halogen bonds form only for X > Br. The two water molecules prefer to form a water dimer, either located around the C H bond (for X = Br, At, and I) or located above the benzene ring (for all halogens). Thus, even in the absence of competing strong interactions, halogen bonds may not form for the lighter halogens due to (1) competition from cooperative weak interactions such as C H•••O and OH•••X hydrogen bonds, or (2) if the formation of the halogen bond would preclude the formation of a water dimer. © 2018 Wiley Periodicals, Inc.     

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.     

Halogen bonding as a new driving force for layer-by-layer assembly

A new approach for fabricating a layer-by-layer polymer film was explored, which was based on the halogen bonding between poly(4-(4-iodo-2,3,5,6-tetrafluorophenoxy)-butyl acrylate) and poly(4-vinylpyridine). Layer-by-layer assembly of two polymers was confirmed by UV-vis spectroscopy and quartz crystal microbalance measurements. The interaction between the two polymers was identified as halogen bonding by X-ray photoelectron spectroscopy. The surface of the multilayer film is flat, and the thickness of one bilayer is about 1.3 nm. We also compared the stability of a halogen-bonded multilayer film in methanol with that of a hydrogen-bonded multilayer film.     

Halogen bonding interaction between fluorohalides and isocyanides

The optimized geometries and corresponding binding energies of complexes between fluorohalides, FX (X = Cl, Br, and I), and isocyanides, CNY (Y = CN, NC, NO(2), F, CF(3), Cl, Br, H, CCF, CCH, CH(3), SiH(3), Li, and Na), were calculated at the MP2(Full)/aug-cc-pVTZ (aug-cc-pVTZ-PP on I) level of theory, without and with basis set superposition error (BSSE) corrections through the counterpoise (CP) method. The optimized complex geometries were analyzed through the Steiner-Limbach relationship, which can be used to establish correlations between the F-X and X-C bond lengths. For all complexes, the correlations were shown to improve considerably when using optimized geometries including BSSE corrections. It was shown that further improvements can be achieved through the introduction of an extended four-parameter form of the Steiner-Limbach relationship which accounts for all differences between the valences associated with the two bonds involving the halogen in an A-X···B complex. The results indicate that chlorine as a halogen bond donor is affected by the basicity of the isocyanides and forms different types of halogen bonds as the F-Cl bond lengthens in parallel with the shortening of the distance between Cl and the isocyanide carbon. This is not observed for iodine and bromine as halogen-bond donors, which is illustrated by the low levels of correlation obtained when applying the standard and extended Steiner-Limbach relationships to the corresponding complexes.     

Halogen bonding driven self-assembly of fluorocarbons and hydrocarbons

Halogen bonding, the interaction between halogen atoms and lone pair possessing atoms, overcomes the low affinity existing between perfluorocarbon and hydrocarbon derivatives. This interaction effectively drives the self-assembly of materials wherein perfluorocarbon and hydrocarbon layers alternate thanks to a remarkable module segregation. The approach has been exploited in supramolecular polymer coating.     

Theoretical study of the structural character of weakly bonding silicon carbonyl complexes

The structures, properties and the bonding character for sub-carbonyl Si, SiCO and Si(CO)₂, in singlet and triplet states have been investigated using complete-active-space self-consistent field (CASSCF), density functional theory and second-order M?ller–Plesset methods with a 6-311+G* basis set. The results indicate that the SiCO species possesses a ³∑⁻ ground state, and the singlet ¹Δ excited state is higher in energy than the ³∑⁻ state by 17.3 kcalmol⁻¹ at the CASSCF–MP2/6-311+G* level and by 16.4 kcalmol⁻¹ at the CCSD(T)/6-311+G* level. The SiCO ground state may be classified as silene (carbonylsilene), and its CO^δ− moiety possesses CO⁻ property. The formation of SiCO causes the weakening of CO bonds. The Si–C bond consists of a weak σ bond and two weak π bonds. Although the Si–C bond length is similar to that of typical Si–C bonds, the bond strength is weaker than the Si–C bonds in Si-containing alkanes; the calculated dissociation energy is 26.2 kcalmol⁻¹ at the CCSD(T)/6-311+G* level. The corresponding bending potential-energy surface is flat; therefore, the SiCO molecule is facile. For the bicarbonyl Si systems, Si(CO)₂, there exist two V-type structures for both states. The stablest state is the singlet state (¹A₁), and may be referred to the ground state. The triplet state (³B₁) is energetically higher in energy than the ¹A₁ state by about 40 kcalmol⁻¹ at the CCSD(T)/6-311 + G* level. The bond lengths in the ¹A₁ state are very close to those of the SiCO species, but the SiCO moieties are bent by about 10°, and the CSiC angles are only about 78°. The corresponding ³B₁ state has a CSiC angle of about 54° and a SiCO angle of about 165°, but its Si–C and C–O bonds are longer than those in the ¹A₁ state by about 0.07 and 0.03 ?, respectively. This Si(CO)₂ (¹A₁) has essentially silene character and should be referred to as a bicarbonyl silene. Comparison of the CO dissociation energies of SiCO and Si(CO)₂ in their ground states indicates that the first CO dissociation energy of Si(CO)₂ is smaller by about 7 kcalmol⁻¹ than that of SiCO; the average one over both CO groups is also smaller than that of SiCO. A detailed bonding analysis shows that the possibility is small for the existence of polycarbonyl Si with more than three CO. This prediction may also be true for similar carbonyl complexes containing other nonmetal and non-transition-metal atoms or clusters. Received: 17 April 2002 / Accepted: 11 August 2002 / Published online: 4 November 2002 Acknowledgements. This work was supported by the National Natural Science Foundation of China (29973022) and the Foundation for Key Teachers in University of the State Ministry of Education of China. Correspondence to: Y. Bu e-mail: byx@sdu.edu.ch     

Halogen bonding: a theoretical study based on atomic multipoles derived from quantum theory of atoms in molecules

Atomic multipole moments derived from quantum theory of atoms in molecules are used to study halogen bonds in dihalogens (with general formula YX, in which X refers to the halogen directly interacted with the Lewis base) and some molecules containing C–X group. Multipole expansion is used to calculate the electrostatic potential in a vicinity of halogen atom (which is involved in halogen bonding) in terms of atomic monopole, dipole, and quadrupole moments. In all the cases, the zz component of atomic traceless quadrupole moments (where z axis taken along Y–X or C–X bonds) of the halogens plays a stabilizing role in halogen bond formation. The effects of atomic monopole and dipole moments on the formation of a halogen bond in YX molecules depend on Y and X atoms. In Br₂ and Cl₂, the monopole moment of halogens is zero and has no contribution in electrostatic potential and hence in halogen bonding, while in ClBr, FBr, and FCl it is positive and therefore stabilize the halogen bonds. On the other hand, the negative sign of dipole moment of X in all the YX molecules weakens the corresponding halogen bonds. In the C–X-containing molecules, monopole and dipole moments of X atom are negative and consequently destabilize the halogen bonds. So, in these molecules the quadrupole moment of X atom is the only electrostatic term which strengthens the halogen bonds. In addition, we found good linear correlations between halogen bonds strength and electrostatic potentials calculated from multipole expansion.     

LZnX complexes of tripodal ligands with intramolecular RN-H hydrogen bonding groups: structural implications of a hydrogen bonding cavity, and of X/R in the hydrogen bonding geometry/strength

Tripodal ligands N(CH2Py)3-n(CH2Py-6-NHR)n(R=H, n=1-3 L1-3, n=0 tpa; R=CH2tBu, n=1-3 L'1-3) are used to investigate the effect of different hydrogen bonding microenvironments on structural features of their LZnX complexes (X=Cl-, NO3-, OH-). The X-ray structures of [(L2)Zn(Cl)](BPh4)2.0.5(H2O.CH3CN), [(L3)Zn(Cl)](BPh4)3.CH3CN, [(L'1)Zn(Cl)](BPh4) 1', [(L'2)Zn(Cl)](BPh4)2'.CH3OH, and [(L'3)Zn(Cl)](BPh4)3' have been determined and exhibit trigonal bipyramidal geometries with intramolecular (internal) N-HCl-Zn hydrogen bonds. The structure of [(L'2)Zn(ONO2)]NO3 4'.H2O with two internal N-HO-Zn hydrogen bonds has also been determined. The axial Zn-Cl distance lengthens from 2.275 A in [(tpa)Zn(Cl)](BPh4) to 2.280-2.347 A in 1-3, 1'-3'. Notably, the average Zn-N(py) distance is also progressively lengthened from 2.069 A in [(tpa)Zn(Cl)](BPh4) to 2.159 and 2.182 A in the triply hydrogen bonding cavity of 3 and 3', respectively. Lengthening of the Zn-Cl and Zn-N(py) bonds is accompanied by a progressive shortening of the trans Zn-N bond from 2.271 A in [(tpa)Zn(Cl)](BPh4) to 2.115 A in 3 (2.113 A in 3'). As a result of the triply hydrogen bonding microenvironment the Zn-Cl and Zn-N(py) distances of 3 are at the upper end of the range observed for axial Zn-Cl bonds, whereas the axial Zn-N distance is one of shortest among N4 ligands that induce a trigonal bipyramidal geometry. Despite the rigidity of these tripodal ligands, the geometry of the intramolecular RN-HX-Zn hydrogen bonds (X=Cl-, OH-, NO3-) is strongly dependent on the nature of X, however, on average, similar for R=H, CH2tBu.     

Halogen bonding in ligand-receptor systems in the framework of classical force fields

Halogen bond is an important non-covalent interaction which is receiving a growing attention in the study of protein-ligand complexes. Many drugs are halogenated molecules and it has been recently shown that many halogenated ligands establish halogen bonds with biomolecules. As the halogen bond nature is due to an anisotropy of the electrostatic potential around halogen atoms, it is not possible to use traditional force fields based on a set of atom-centred charges to study halogen bonds in biomolecules. We show that the introduction of pseudo-atoms on halogens permits us to correctly describe the anisotropy of the electrostatic potential and to perform molecular dynamics simulations on complexes of proteins with halogenated ligands that reproduce experimental values. The results are compared with crystallographic data and with hybrid quantum mechanics/molecular mechanics calculations.     

Ligand structural effects on Cu2S2 bonding and reactivity in side-on disulfido-bridged dicopper complexes

To assess supporting ligand effects on S-S bond activation, a series of [Cu2(mu-eta2:eta2-S2)]2+ complexes supported by various beta-diketiminate or anilido-imine ligands (L) were synthesized via the reaction of Cu(I) precursors LCu(CH(3)CN) with S8. For the cases where L = beta-diketiminate, the syntheses were complicated by formation of clusters [Cu(SR)]4, where SR represents the ligand functionalized by sulfur at the central methine position. The [Cu2(mu-eta2:eta2-S2)]2+ products were characterized by X-ray crystallography and electronic absorption and resonance Raman spectroscopy. Correlations among the Cu-S, Cu-Cu, and S-S distances and the nu(S-S) values were observed and interpreted within the framework of a previously described bonding picture (Chen, P.; Fujisawa, K.; Helton, M. E.; Karlin, K. D.; Solomon, E. I. J. Am. Chem. Soc. 2003, 125, 6394). Comparison of these data to those for other relevant species revealed a remarkable degree of S-S bond activation in the compounds supported by the beta-diketiminate and anilido-imine ligands, which through strong electron donation increase backbonding from the copper ions into the S-S sigma* orbital and cause S-S bond weakening. Reactions of one of the complexes supported by an anilido-imine ligand with PPh(3) and xylyl isocyanide were explored, revealing facile transfer of sulfur to PPh(3) but only displacement of sulfur to yield a LCu(I)-CNAr (Ar = xylyl) complex with the isocyanide.     

Halogen bonding and pi...pi stacking control reactivity in the solid state

The halogen bonding and the pi...pi stacking interactions induce the noncovalent self-assembly of modules into photoreactive supramolecular architecture. The pi...pi interaction pre-organizes the template, and the halogen bonding aligns the olefins to conform to the topochemical principle for photoreaction. The UV irradiation of the crystal resulted in a cyclization product with quantitative yield and stereospecificity.