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A halogen bond occurs when there is evidence of a net attractive interaction between an
electrophilic In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carri ...
region associated with a
halogen The halogens () are a group in the periodic table consisting of five or six chemically related elements: fluorine (F), chlorine (Cl), bromine (Br), iodine (I), astatine (At), and tennessine (Ts). In the modern IUPAC nomenclature, this group is ...
atom in a molecular entity and a
nucleophilic In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...
region in another, or the same, molecular entity. Like a
hydrogen bond In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a ...
, the result is not a formal
chemical bond A chemical bond is a lasting attraction between atoms or ions that enables the formation of molecules and crystals. The bond may result from the electrostatic force between oppositely charged ions as in ionic bonds, or through the sharing o ...
, but rather a strong
electrostatic Electrostatics is a branch of physics that studies electric charges at rest (static electricity). Since classical times, it has been known that some materials, such as amber, attract lightweight particles after rubbing. The Greek word for ambe ...
attraction. Mathematically, the interaction can be decomposed in two terms: one describing an electrostatic, orbital-mixing charge-transfer and another describing electron-cloud dispersion. Halogen bonds find application in
supramolecular chemistry Supramolecular chemistry refers to the branch of chemistry concerning chemical systems composed of a discrete number of molecules. The strength of the forces responsible for spatial organization of the system range from weak intermolecular forces, ...
;
drug design Drug design, often referred to as rational drug design or simply rational design, is the invention, inventive process of finding new medications based on the knowledge of a biological target. The drug is most commonly an organic compound, organi ...
and
biochemistry Biochemistry or biological chemistry is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology and ...
;
crystal engineering Crystal engineering studies the design and synthesis of solid-state structures with desired properties through deliberate control of intermolecular interactions. It is an interdisciplinary academic field, bridging solid-state and supramolecular c ...
and
liquid crystal Liquid crystal (LC) is a state of matter whose properties are between those of conventional liquids and those of solid crystals. For example, a liquid crystal may flow like a liquid, but its molecules may be oriented in a crystal-like way. Th ...
s; and organic
catalysis Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
.


Definition

Halogen bonds occur when a halogen atom is electrostatically attracted to a partial negative charge. Necessarily, the atom must be covalently bonded in an antipodal σ-bond; the electron concentration associated with that bond leaves a positively charged "hole" on the other side. Although all halogens can theoretically participate in halogen bonds, the σ-hole shrinks if the electron cloud in question polarizes poorly or the halogen is so
electronegative Electronegativity, symbolized as , is the tendency for an atom of a given chemical element to attract shared electrons (or electron density) when forming a chemical bond. An atom's electronegativity is affected by both its atomic number and the d ...
as to polarize the associated σ-bond. Consequently halogen-bond propensity follows the trendAlthough hydrogen is sometimes considered a halogen, convention excludes
hydrogen bonds In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a ...
from the category of halogen bonds. For a complete analysis, see .
F < Cl < Br < I. There is no clear distinction between halogen bonds and
expanded octet In chemistry, a hypervalent molecule (the phenomenon is sometimes colloquially known as expanded octet) is a molecule that contains one or more main group elements apparently bearing more than eight electrons in their valence shells. Phosphorus pe ...
partial bonds; what is superficially a halogen bond may well turn out to be a full bond in an unexpectedly relevant
resonance structure In chemistry, resonance, also called mesomerism, is a way of describing bonding in certain molecules or polyatomic ions by the combination of several contributing structures (or ''forms'', also variously known as ''resonance structures'' or ...
.


Donor characteristics

A halogen bond is almost
collinear In geometry, collinearity of a set of points is the property of their lying on a single line. A set of points with this property is said to be collinear (sometimes spelled as colinear). In greater generality, the term has been used for aligned ...
with the halogen atom's other, conventional bond, but the geometry of the electron-charge donor may be much more complex. * Multi-electron donors such as
ether In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula , where R and R′ represent the alkyl or aryl groups. Ethers can again b ...
s and
amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent suc ...
s prefer halogen bonds collinear with the
lone pair In chemistry, a lone pair refers to a pair of valence electrons that are not shared with another atom in a covalent bondIUPAC ''Gold Book'' definition''lone (electron) pair''/ref> and is sometimes called an unshared pair or non-bonding pair. Lone ...
and donor nucleus. *
Pyridine Pyridine is a basic heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom. It is a highly flammable, weakly alkaline, water-miscible liquid with ...
derivatives tend to donate halogen bonds approximately coplanar with the ring, and the two CN \cdots X angles are about 120°. *
Carbonyl In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containing a ...
, thiocarbonyl-, and selenocarbonyl groups, with a trigonal planar geometry around the Lewis donor atom, can accept one or two halogen bonds.
Anions An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...
are usually better halogen-bond acceptors than neutral species: the more dissociated an ion pair is, the stronger the halogen bond formed with the anion.


Comparison to other bond-like forces

A parallel relationship can easily be drawn between halogen bonding and
hydrogen bonding In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a ...
. Both interactions revolve around an
electron donor In chemistry, an electron donor is a chemical entity that donates electrons to another compound. It is a reducing agent that, by virtue of its donating electrons, is itself oxidized in the process. Typical reducing agents undergo permanent chemi ...
/
electron acceptor An electron acceptor is a chemical entity that accepts electrons transferred to it from another compound. It is an oxidizing agent that, by virtue of its accepting electrons, is itself reduced in the process. Electron acceptors are sometimes mista ...
relationship, between a halogen-like atom and an electron-dense one. But halogen bonding is both much stronger and more sensitive to direction than hydrogen bonding. A typical hydrogen bond has energy of formation ; known halogen
bond energies In chemistry, bond energy (''BE''), also called the mean bond enthalpy or average bond enthalpy is the measure of bond strength in a chemical bond. IUPAC defines bond energy as the average value of the gas-phase bond-dissociation energy (usually at ...
range from 10–200 kJ/mol. The σ-hole concept readily extends to pnictogen, chalcogen and aerogen bonds, corresponding to atoms of Groups 15, 16 and 18 (respectively).


History

In 1814, Jean-Jacques Colin discovered (to his surprise) that a mixture of dry gaseous ammonia and iodine formed a shiny, metallic-appearing liquid. Frederick Guthrie established the precise composition of the resulting I2···NH3 complex fifty years later, but the physical processes underlying the molecular interaction remained mysterious until the development of
Robert S. Mulliken Robert Sanderson Mulliken Note Longuet-Higgins' amusing title for reference B238 1965 on page 354 of this Biographical Memoir. The title should be "Selected papers of Robert S Mulliken." (June 7, 1896 – October 31, 1986) was an American ph ...
's theory of inner-sphere and outer-sphere interactions. In Mulliken's categorization, the intermolecular interactions associated with small partial charges affect only the "inner sphere" of an atom's electron distribution; the electron redistribution associated with Lewis adducts affects the "outer sphere" instead. Then, in 1954, Odd Hassel fruitfully applied the distinction to rationalize the
X-ray diffraction X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angle ...
patterns associated with a mixture of 1,4-dioxane and bromine. The patterns suggested that only 2.71 Å separated the dioxane oxygens and bromine atoms, much closer than the sum (3.35 Å) of the atoms' van der Waals radii; and that the angle between the O−Br and Br−Br bond was about 180°. From these facts, Hassel concluded that halogen atoms are directly linked to electron pair donors in a direction with a bond direction that coincides with the axes of the orbitals of the lone pairs in the electron pair donor molecule. For this work, Hassel was awarded the 1969
Nobel Prize in Chemistry ) , image = Nobel Prize.png , alt = A golden medallion with an embossed image of a bearded man facing left in profile. To the left of the man is the text "ALFR•" then "NOBEL", and on the right, the text (smaller) "NAT•" then "M ...
. Dumas and coworkers first coined the term "halogen bond" in 1978, during their investigations into complexes of CCl4, CBr4, SiCl4, and SiBr4 with
tetrahydrofuran Tetrahydrofuran (THF), or oxolane, is an organic compound with the formula (CH2)4O. The compound is classified as heterocyclic compound, specifically a cyclic ether. It is a colorless, water-miscible organic liquid with low viscosity. It is ma ...
,
tetrahydropyran Tetrahydropyran (THP) is the organic compound consisting of a saturated six-membered ring containing five carbon atoms and one oxygen atom. It is named by reference to pyran, which contains two double bonds, and may be produced from it by addin ...
,
pyridine Pyridine is a basic heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom. It is a highly flammable, weakly alkaline, water-miscible liquid with ...
,
anisole Anisole, or methoxybenzene, is an organic compound with the formula CH3OC6H5. It is a colorless liquid with a smell reminiscent of anise seed, and in fact many of its derivatives are found in natural and artificial fragrances. The compound is ma ...
, and di-n-butyl ether in organic solvents. However, it was not until the mid-1990s, that the nature and applications of the halogen bond began to be intensively studied. Through systematic and extensive
microwave spectroscopy Microwave spectroscopy is the spectroscopy method that employs microwaves, i.e. electromagnetic radiation at GHz frequencies, for the study of matter. History The ammonia molecule NH3 is shaped like a pyramid 0.38 Å in height, with an equilatera ...
of gas-phase halogen bond adducts, Legon and coworkers drew attention to the similarities between halogen-bonding and better-known hydrogen-bonding interactions. In 2007, computational calculations by Politzer and Murray showed that an anisotropic electron density distribution around the halogen nucleus — the "σ-hole" — underlay the high directionality of the halogen bond. This hole was then experimentally observed using Kelvin probe force microscopy.


Applications


Crystal engineering

The strength and directionality of halogen bonds are a key tool in the discipline of
crystal engineering Crystal engineering studies the design and synthesis of solid-state structures with desired properties through deliberate control of intermolecular interactions. It is an interdisciplinary academic field, bridging solid-state and supramolecular c ...
, which attempts to shape crystal structures through close control of intermolecular interactions. Halogen bonds can stabilize copolymers or induce mesomorphism in otherwise isotropic
liquids A liquid is a nearly incompressible fluid that conforms to the shape of its container but retains a (nearly) constant volume independent of pressure. As such, it is one of the four fundamental states of matter (the others being solid, gas, an ...
. Indeed, halogen bond-induced liquid crystalline phases are known in both alkoxystilbazoles and silsesquioxanes (pictured). Alternatively, the steric sensitivity of halogen bonds can cause bulky molecules to crystallize into porous structures; in one notable case, halogen bonds between
iodine Iodine is a chemical element with the symbol I and atomic number 53. The heaviest of the stable halogens, it exists as a semi-lustrous, non-metallic solid at standard conditions that melts to form a deep violet liquid at , and boils to a vi ...
and
aromatic In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satu ...
π-orbitals caused molecules to crystallize into a pattern that was nearly 40%
void Void may refer to: Science, engineering, and technology * Void (astronomy), the spaces between galaxy filaments that contain no galaxies * Void (composites), a pore that remains unoccupied in a composite material * Void, synonym for vacuum, a s ...
.


Controlled polymerization

Conjugated polymers offer the tantalizing possibility of organic molecules with a manipulable
electronic band structure In solid-state physics, the electronic band structure (or simply band structure) of a solid describes the range of energy levels that electrons may have within it, as well as the ranges of energy that they may not have (called ''band gaps'' or '' ...
, but current methods for production have an uncontrolled
topology In mathematics, topology (from the Greek words , and ) is concerned with the properties of a geometric object that are preserved under continuous deformations, such as stretching, twisting, crumpling, and bending; that is, without closing h ...
. Sun, Lauher, and Goroff discovered that certain
amides In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is ...
ensure a linear polymerization of poly(diiododiacetylene). The underlying mechanism is a self-organization of the amides via hydrogen bonds that then transfers to the diiododiacetylene monomers via halogen bonds. Although pure diiododiacetylene crystals do not
polymerize In polymer chemistry, polymerization (American English), or polymerisation (British English), is a process of reacting monomer molecules together in a chemical reaction to form polymer chains or three-dimensional networks. There are many for ...
spontaneously, the halogen-bond induced organization is sufficiently strong that the cocrystals do spontaneously polymerize. Monomerand6.jpg, The catalyst-monomer cocrystal. Units repeat every 5.25 Å and are oriented at 51.3˚. PIDA.jpg, Post-polymerization crystal structure: the oxygen atom (purple) forms a hydrogen bond (blue dashed line) and a weak halogen bond with the polymer's iodine substituents. Iodine may also form a halogen bond with the terminal nitriles (red dashed line).


Biological macromolecules

Most biological macromolecules contain few or no halogen atoms. But when molecules do contain halogens, halogen bonds are often essential to understanding molecular conformation. Computational studies suggest that known halogenated
nucleobases Nucleobases, also known as ''nitrogenous bases'' or often simply ''bases'', are nitrogen-containing biological compounds that form nucleosides, which, in turn, are components of nucleotides, with all of these monomers constituting the basic ...
form halogen bonds with
oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as well ...
,
nitrogen Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at sevent ...
, or
sulfur Sulfur (or sulphur in British English) is a chemical element with the symbol S and atomic number 16. It is abundant, multivalent and nonmetallic. Under normal conditions, sulfur atoms form cyclic octatomic molecules with a chemical formula ...
''in vitro''. Interestingly, oxygen atoms typically do not attract halogens with their
lone pairs In chemistry, a lone pair refers to a pair of valence electrons that are not shared with another atom in a covalent bondIUPAC ''Gold Book'' definition''lone (electron) pair''/ref> and is sometimes called an unshared pair or non-bonding pair. Lone ...
, but rather the π electrons in the
carbonyl In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containing a ...
or amide group. Halogen bonding can be significant in
drug design Drug design, often referred to as rational drug design or simply rational design, is the invention, inventive process of finding new medications based on the knowledge of a biological target. The drug is most commonly an organic compound, organi ...
as well. For example, inhibitor IDD 594 binds to human
aldose reductase In enzymology, aldose reductase (or aldehyde reductase) () is a cytosolic NADPH-dependent oxidoreductase that catalyzes the reduction of a variety of aldehydes and carbonyls, including monosaccharides. It is primarily known for catalyzing the r ...
through a bromine halogen bond, as shown in the figure. The molecules fail to bind to each other if similar aldehyde reductase replaces the enzyme, or
chlorine Chlorine is a chemical element with the symbol Cl and atomic number 17. The second-lightest of the halogens, it appears between fluorine and bromine in the periodic table and its properties are mostly intermediate between them. Chlorine is ...
replaces the drug halogen, because the variant geometries inhibit the halogen bond.


Notes


References


Further reading

* An early review: {{chemical bonds Chemical bonding Intermolecular forces