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

Site selectivity of halogen oxygen bonding in 5- and 6-haloderivatives of uracil

Seven 5-and 6-halogenated derivatives of uracil or 1-methyluracil (halogen = Cl, Br, I) were studied by single crystal X-ray diffraction. In contrast with pure 5-halouracils, where the presence of N-H…O and C-H…O hydrogen bonds prevents the formation of other intermolecular interactions, the general ability of pyrimidine nucleobases to provide electron donating groups to halogen bonding was confirmed in three crystals and cocrystals containing uracil with the halogen atom at the C6 position. In the latter compounds, among the two nucleophilic oxygen atoms in the C=O moiety, only the urea carbonyl oxygen O1 can act as halogen bond acceptor, being not saturated by conventional hydrogen bonds. The halogen bonds in pure 6-halouracils are all rather weak, as supported by Hirshfeld surface analysis. The strongest interaction was found in the structure of 6- iodouracil, which displayed the largest (13%) reduction of the sum of van der Waals (vdW) radii for the contact atoms. Despite this, halogen bonding plays a rol

Structure energy relationship of biological halogen bonds

2012 Summer.Includes bibliographical references.The primary goal of the studies in this thesis is to derive a set of mathematical models to describe the anisotropic atomic nature of covalent bound halogens and by extension their molecular interactions. We use a DNA Holliday junctions as a experimental model system to assay the structure energy relationship of halogen bonds (X-bonds) in a complex biological environment. The first chapter of this dissertation is reserved for a review on DNA structure and the Holliday Junction in context of other DNA conformations. The conformational isomerization of engineered Holliday junctions will be established as a means to assay the energies of bromine X-bonds both in crystal and in solution. The experimental data are then used in the development of anisotropic force fields for use in the mathematical modeling of bromine halogen bonds, serving as a foundation to model all biological halogen interactions. The DNA Holliday junction experimental system is expanded to compare and contrast halogens from fluorine to iodine. This comprehensive study is used to determine the effects of polarization on the structure-energy relationship of biological X-bonds in solid state and solution phase. The culmination of the work in this thesis, in addition to previously published studies, provides a growing set of principles to guide knowledge-based application of halogens in drug design. These principles are applied to the selection of X-bond acceptors in a protein binding pocket, optimal placement of the halogen on the lead compound, and which halogen is best suited for a particular interaction

Substituent Effects on the Binding of Halides by Neutral and Dicationic Bis-Triazolium Receptors

The effects of substituent and overall charge upon the binding of a halide anion by a bis-triazolium receptor are studied by M06-2X DFT calculations, with the aug-cc-pVDZ basis set. Comparison is also made between a receptor that engages in H-bonds, with a halogen-bonding species. Fluoride is clearly most strongly bound, followed by Cl-, Br-, and I- in that order. The dicationic receptor engages in stronger complexes, but not by a very wide margin compared to its neutral counterpart. The binding is enhanced as the substituent on the two triazolium rings becomes progressively more electron-withdrawing. Halogen-substituted receptors, whether neutral or cationic, display a greater sensitivity to substituent than do their H-bonding counterparts. Both Coulombic and charge transfer factors obey the latter trends but do not correctly reproduce the stronger halogen vs hydrogen bonding. Both H-bonds and halogen bonds are nearly linear within the complexes, due in part to bond rotations within the receptor that bring the two triazole rings closer to coplanarity with the central benzene ring

Gallic Acid Dimer As a Double π−Hole Donor: Evidence from X‑ray, Theoretical Calculations, and Generalization from the Cambridge Structural Database

In this work, we demonstrate that the centrosymmetric eight-membered supramolecular ring R2 2 (8) that is formed upon dimerization of benzoic acids has a marked tendency to establish π−hole interactions with electron-rich atoms. We have used the Cambridge Structural Database to demonstrate the preference of carboxylic acid dimers to form donor−acceptor interactions involving π−holes located at the C atoms above and below the molecular plane. Moreover, we have carried out DFT calculations (PBE0-D3/def2-TZVP) to investigate the geometric and energetic features of these interactions and how they are affected by the substituents of the aromatic ring. Finally, as an example we report the synthesis and X-ray characterization of a solvate of gallic acid with dioxane, where two molecules of dioxane are located above and below the eight-membered supramolecular ring, forming two symmetrically equivalent O···C π−hole interactions

Computational Study About Noncovalent Bonding Systems Involving Halogen, Chalcogen and Pnicogen Bonds

First terms used in this thesis are introduced and defined as follows. In the periodic table, the elements in the 17th column are named halogen including fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). The elements in the 16th column are named chalcogen including oxygen (O), sulfur (S), selenium (Se) and tellurium (Te). The elements in the 15th column are named pnicogen including nitrogen (N), phosphorus (P), arsenic (As) and antimony (Sb). After hydrogen bonds (B-H⋅⋅⋅B) are well studied and understood by scientists and researchers, halogen bonds (R-X⋅⋅⋅B) have drawn attention due to the similarities in bonding format and geometries. However, it is not straightforward to understand how the overall negative halogen atoms interact with the electronegative chemical group, which is usually a Lewis base until scientists proved the existence of the positive region surrounding the halogen atom X directly opposite the R group by Molecular Electrostatic Potential analysis. This thesis studied the detailed structural, geometric and spectroscopic features quantitatively by computational chemistry. The research studied the halogen transfer in symmetric (between two same molecules) and asymmetric systems (between two different molecules). In either case, the potential contains a single symmetric well for short halogen bond length and transferred to a double well when the distance was increased. Furthermore, the partial transfer calculations of halogen as bridging atom between two molecules suggests the degree of halogen transfer to form an ion pair is small even when a strong acid is combined with a strong base. Moreover, the thesis extended the application of Badger-Bauer rules from hydrogen bonds to halogen, chalcogen and pnicogen bonds. Badger-Bauer rules states the spectroscopic change were linearly related to the bond strength of hydrogen bonds. The theory extension will improve the understanding of bond strength of a specific bond in the complicated systems by detecting the spectroscopic change

Enol intermediates derived from carboxylic acids, esters and amides

A kinetic investigation into the enolisation mechanism and enol contents of simple carboxylic acids, esters and amides has been undertaken. Measurement of the enolisation rate constants for malonic acid, ethylhydrogenmalonate and 2- carboxyacetamide were obtained. The halogenation reactions were carried out under conditions where the rate determining step was the enolisation and the reactions were zero order in halogen. The measurements were carried out using u.v./visible spectrophotometry. Results obtained for malonic acid and ethylhydrogenmalonate support the idea of an intramolecular acid catalysed mechanism involving a hydrogen bonded six membered transition state. The enolisation mechanisms were investigated in a number of buffer solutions and were found to be catalysed by general bases. Catalytic coefficients for the following bases were calculated, HO(_2)CCH(_2)CO(_2)-, EtO(_2)CCH(_2)CO(_2)-,ClCH(_2)CO(_2)-, and H(_2)O. Deuterium exchange reactions were monitored using (^1)H N.M.R. and enolisation rate constants for cyano-containing esters and amides were calculated. The results show that the enolisation of amides occurs via an acid catalysed process whereas the enolisation of carboxylic acids and esters proceeds by an intramolecular acid catalysed or a general base catalysed mechanism. Enol contents for simple carboxylic acid derivatives were determined from their reactions with halogens under conditions where the reaction of the halogen with the enol is rate limiting and the reaction is found to be first order in the halogen. It was demonstrated that chlorine, bromine and iodine react with carboxylic ester enols at or very close to the diffusion controlled limit (ca 5x10(^9) 1 mol(^-1) sec(^-1)). The enol contents measured were found to be greater than expected, with the enol content of malonic acid very similar to that of acetone. An estimate of the acidity of carboxylic acid enols has shown them to be strong acids with pK(_a) values in the region 2-5