Cation-pi interaction
Encyclopedia
Cation–π interaction, also known as the Dougherty effect, is a noncovalent molecular interaction
between the face of an electron-rich π system
(e.g. benzene
, ethylene
) with an adjacent cation (e.g. Li+, Na+). This unusual interaction is an example of noncovalent bonding between a monopole (cation) and a quadrupole (π system). Cation–π interaction energies are of the same order of magnitude as hydrogen bond
s or salt bridges
and play an important role in molecular recognition
.
, the model π system, has no permanent dipole moment, as the contributions of the weakly polar carbon–hydrogen bonds cancel due to molecular symmetry
. However, the electron-rich π system above and below the benzene ring hosts a partial negative charge. A counterbalancing positive charge is associated with the plane of the benzene atoms, resulting in an electric quadrupole (a pair of dipoles, which do not cancel each other). The negatively charged region of the quadrupole can then interact favorably with positively charged species; a particularly strong effect is observed with cations of high charge density
.
. Several criteria influence the strength of the bonding: the nature of the cation, the subsitutents
on the π system, and the solvent.
(Coulomb's law
), a smaller and more positively charged cations lead to larger electrostatic attraction. The following table shows a series of Gibbs free energy
changes for the interaction of benzene with several alkaline metals in the gas phase. The influence of the ionic radius
,
, is evident.
s also have an influence on the strength of the attraction. Electron withdrawing groups
(for example, cyano
−CN) weaken the interaction, while electron donating substituents
(for example, amino −NH2) strengthen the cation–π binding. This relationship is illustrated quantitatively in the margin for several substituents. The origin of this effect is often attributed to donation into or out of the π system, although recent computational results indicate that it is primarily due to direct through-space interactions between the substituents and the cation.
.
side chains of tryptophan
and tyrosine
or the DNA bases are capable of binding to cationic species (not only metal ions, but also charged amino acid side chains, ...). Therefore, cation–π interactions can play an important role in stabilizing the three dimensional structure of a protein
. An alternative role of the cation–π interaction is seen in the nicotinic acetylcholine receptor
which binds its endogenous ligand
, acetylcholine
(a positively charged molecule), via a cation–π interaction to the quaternary ammonium.
along the π system (e. g. hexafluorobenzene
). The anion–π effect is advantageously exploited in chemical sensors for specific anions.
Chemical bond
A chemical bond is an attraction between atoms that allows the formation of chemical substances that contain two or more atoms. The bond is caused by the electromagnetic force attraction between opposite charges, either between electrons and nuclei, or as the result of a dipole attraction...
between the face of an electron-rich π system
Aromaticity
In organic chemistry, Aromaticity is a chemical property in which a conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibit a stabilization stronger than would be expected by the stabilization of conjugation alone. The earliest use of the term was in an article by August...
(e.g. benzene
Benzene
Benzene is an organic chemical compound. It is composed of 6 carbon atoms in a ring, with 1 hydrogen atom attached to each carbon atom, with the molecular formula C6H6....
, ethylene
Ethylene
Ethylene is a gaseous organic compound with the formula . It is the simplest alkene . Because it contains a carbon-carbon double bond, ethylene is classified as an unsaturated hydrocarbon. Ethylene is widely used in industry and is also a plant hormone...
) with an adjacent cation (e.g. Li+, Na+). This unusual interaction is an example of noncovalent bonding between a monopole (cation) and a quadrupole (π system). Cation–π interaction energies are of the same order of magnitude as hydrogen bond
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...
s or salt bridges
Salt bridge (protein)
Salt bridges fall into the broader category of noncovalent interactions. A salt bridge is actually a combination of two noncovalent interactions: hydrogen bonding and electrostatic interactions . This is most commonly observed to contribute stability to the entropically unfavorable folded...
and play an important role in molecular recognition
Molecular recognition
The term molecular recognition refers to the specific interaction between two or more molecules through noncovalent bonding such as hydrogen bonding, metal coordination, hydrophobic forces, van der Waals forces, π-π interactions, electrostatic and/or electromagnetic effects...
.
Origin of the effect
BenzeneAromaticity
In organic chemistry, Aromaticity is a chemical property in which a conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibit a stabilization stronger than would be expected by the stabilization of conjugation alone. The earliest use of the term was in an article by August...
, the model π system, has no permanent dipole moment, as the contributions of the weakly polar carbon–hydrogen bonds cancel due to molecular symmetry
Molecular symmetry
Molecular symmetry in chemistry describes the symmetry present in molecules and the classification of molecules according to their symmetry. Molecular symmetry is a fundamental concept in chemistry, as it can predict or explain many of a molecule's chemical properties, such as its dipole moment...
. However, the electron-rich π system above and below the benzene ring hosts a partial negative charge. A counterbalancing positive charge is associated with the plane of the benzene atoms, resulting in an electric quadrupole (a pair of dipoles, which do not cancel each other). The negatively charged region of the quadrupole can then interact favorably with positively charged species; a particularly strong effect is observed with cations of high charge density
Charge density
The linear, surface, or volume charge density is the amount of electric charge in a line, surface, or volume, respectively. It is measured in coulombs per meter , square meter , or cubic meter , respectively, and represented by the lowercase Greek letter Rho . Since there are positive as well as...
.
Influences on the strength of the cation–π interaction
The cation–π interaction is comparable in strength to hydrogen bonding and can, in some cases, be a decisive intermolecular forceIntermolecular force
Intermolecular forces are forces of attraction or repulsion which act between neighboring particles: atoms, molecules or ions. They are weak compared to the intramolecular forces, the forces which keep a molecule together...
. Several criteria influence the strength of the bonding: the nature of the cation, the subsitutents
Substituent
In organic chemistry and biochemistry, a substituent is an atom or group of atoms substituted in place of a hydrogen atom on the parent chain of a hydrocarbon...
on the π system, and the solvent.
Nature of the cation
From electrostaticsElectrostatics
Electrostatics is the branch of physics that deals with the phenomena and properties of stationary or slow-moving electric charges....
(Coulomb's law
Coulomb's law
Coulomb's law or Coulomb's inverse-square law, is a law of physics describing the electrostatic interaction between electrically charged particles. It was first published in 1785 by French physicist Charles Augustin de Coulomb and was essential to the development of the theory of electromagnetism...
), a smaller and more positively charged cations lead to larger electrostatic attraction. The following table shows a series of Gibbs free energy
Gibbs free energy
In thermodynamics, the Gibbs free energy is a thermodynamic potential that measures the "useful" or process-initiating work obtainable from a thermodynamic system at a constant temperature and pressure...
changes for the interaction of benzene with several alkaline metals in the gas phase. The influence of the ionic radius
Ionic radius
Ionic radius, rion, is the radius of an atom's ion. Although neither atoms nor ions have sharp boundaries, it is important to treat them as if they are hard spheres with radii such that the sum of ionic radii of the cation and anion gives the distance between the ions in a crystal lattice...
,
, is evident.
M+ Li+ Na+ K+ Rb+ - G [kcal/mol]
38 27 19 16 [pm]
76 102 138 152
Substituents on the π system
The electronic properties of the substituentSubstituent
In organic chemistry and biochemistry, a substituent is an atom or group of atoms substituted in place of a hydrogen atom on the parent chain of a hydrocarbon...
s also have an influence on the strength of the attraction. Electron withdrawing groups
Inductive effect
In chemistry and physics, the inductive effect is an experimentally observable effect of the transmission of charge through a chain of atoms in a molecule by electrostatic induction...
(for example, cyano
Nitrile
A nitrile is any organic compound that has a -C≡N functional group. The prefix cyano- is used interchangeably with the term nitrile in industrial literature. Nitriles are found in many useful compounds, one example being super glue .Inorganic compounds containing the -C≡N group are not called...
−CN) weaken the interaction, while electron donating substituents
Inductive effect
In chemistry and physics, the inductive effect is an experimentally observable effect of the transmission of charge through a chain of atoms in a molecule by electrostatic induction...
(for example, amino −NH2) strengthen the cation–π binding. This relationship is illustrated quantitatively in the margin for several substituents. The origin of this effect is often attributed to donation into or out of the π system, although recent computational results indicate that it is primarily due to direct through-space interactions between the substituents and the cation.
Influence of the solvent
Additionally, the nature of the solvent also determines the relative strength of the bonding. Most data on cation–π interaction is acquired in the gas phase, as the attraction is most pronounced in that case. Any intermediating solvent molecule will attenuate the effect, which is why it becomes less pronounced with increasing solvent polarityChemical polarity
In chemistry, polarity refers to a separation of electric charge leading to a molecule or its chemical groups having an electric dipole or multipole moment. Polar molecules interact through dipole–dipole intermolecular forces and hydrogen bonds. Molecular polarity is dependent on the difference in...
.
Cation–π interactions in nature
Nature’s building blocks consist of aromatic moieties, too. Amino acidAmino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
side chains of tryptophan
Tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
and tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
or the DNA bases are capable of binding to cationic species (not only metal ions, but also charged amino acid side chains, ...). Therefore, cation–π interactions can play an important role in stabilizing the three dimensional structure of a protein
Protein structure
Proteins are an important class of biological macromolecules present in all organisms. Proteins are polymers of amino acids. Classified by their physical size, proteins are nanoparticles . Each protein polymer – also known as a polypeptide – consists of a sequence formed from 20 possible L-α-amino...
. An alternative role of the cation–π interaction is seen in the nicotinic acetylcholine receptor
Nicotinic acetylcholine receptor
Nicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...
which binds its endogenous ligand
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
, acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
(a positively charged molecule), via a cation–π interaction to the quaternary ammonium.
Anion–π interaction
In many respects, anion–π interaction is the opposite of cation–π interaction, although the underlying principles are identical. Significantly fewer examples are known to date. In order to attract a negative charge, the charge distribution of the π system has to be reversed. This is achieved by placing several strong electron withdrawing substituentsInductive effect
In chemistry and physics, the inductive effect is an experimentally observable effect of the transmission of charge through a chain of atoms in a molecule by electrostatic induction...
along the π system (e. g. hexafluorobenzene
Hexafluorobenzene
Hexafluorobenzene, HFB, , or perfluorobenzene is an organic, aromatic compound. In this derivative of benzene all hydrogen atoms have been replaced by fluorine atoms. The technical uses of the compound are limited, although it is recommended as a solvent in a number of Photochemical reactions...
). The anion–π effect is advantageously exploited in chemical sensors for specific anions.