Alpha Effect
Encyclopedia
The alpha effect refers to the increased nucleophilicity
of a molecule
due to the presence of an adjacent (alpha) atom
with lone pair
electron
s. The molecule does not necessarily exhibit increased basicity compared with a similar molecule without the adjacent, electron donating atom. The effect is well established with many theories to explain the effect but without a clear winner.
The effect was first observed by Jencks and Carriuolo in 1960 in a series of chemical kinetics
experiments involving the reaction of the ester
p-nitrophenyl acetate with a range of nucleophiles. Regular nucleophiles such as the fluoride
anion, aniline
, pyridine
, ethylene diamine
and the phenolate ion were found to have pseudo first order reaction rates corresponding to their basicity as measured by their pKa
. Other nucleophiles however reacted much faster than expected based on this criterium alone. These include hydrazine
, hydroxylamine
, the hypochlorite
ion and the hydroperoxide anion.
In 1962 Edwards and Pearson
(the latter of HSAB theory
fame) introduced the phrase alpha effect for this anomaly. He offered the suggestion that the effect was caused by a transition state
(TS) stabilization effect: on entering the TS the free electron pair on the nucleophile moves away from the nucleus causing a partial positive charge which can be stabilized by an adjacent lone pair
as for instance happens in any carbocation
.
Over the years many additional theories have been put forward attempting the effect. A ground state stabilizing effect assumes that the alpha lone-pair and nucleophilic electron pair destabilize each other by electronic repulsion thereby increasing the ground state and making it more reactive. Stabilization of the transition state is possible by assuming some TS free radical character or assuming that the TS has more advanced nucleophile-substrate bond formation. The polarizability
of the nucleophile or involvement of intramolecular
catalysis
also plays a role. One recent in silico
contribution did find a correlation between the alpha effect and the so-called deformation energy which is the electronic energy required to bring the two reactants together in the transition state.
The alpha effect is also dependent on solvent
but not in a predictable way: it can increase or decrease with solvent mix composition or even go through a maximum.
Nucleophile
A nucleophile is a species that donates an electron-pair to an electrophile to form a chemical bond in a reaction. All molecules or ions with a free pair of electrons can act as nucleophiles. Because nucleophiles donate electrons, they are by definition Lewis bases.Nucleophilic describes the...
of a molecule
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...
due to the presence of an adjacent (alpha) atom
Atom
The atom is a basic unit of matter that consists of a dense central nucleus surrounded by a cloud of negatively charged electrons. The atomic nucleus contains a mix of positively charged protons and electrically neutral neutrons...
with lone pair
Lone pair
In chemistry, a lone pair is a valence electron pair without bonding or sharing with other atoms. They are found in the outermost electron shell of an atom, so lone pairs are a subset of a molecule's valence electrons...
electron
Electron
The electron is a subatomic particle with a negative elementary electric charge. It has no known components or substructure; in other words, it is generally thought to be an elementary particle. An electron has a mass that is approximately 1/1836 that of the proton...
s. The molecule does not necessarily exhibit increased basicity compared with a similar molecule without the adjacent, electron donating atom. The effect is well established with many theories to explain the effect but without a clear winner.
The effect was first observed by Jencks and Carriuolo in 1960 in a series of chemical kinetics
Chemical kinetics
Chemical kinetics, also known as reaction kinetics, is the study of rates of chemical processes. Chemical kinetics includes investigations of how different experimental conditions can influence the speed of a chemical reaction and yield information about the reaction's mechanism and transition...
experiments involving the reaction of the ester
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
p-nitrophenyl acetate with a range of nucleophiles. Regular nucleophiles such as the fluoride
Fluoride
Fluoride is the anion F−, the reduced form of fluorine when as an ion and when bonded to another element. Both organofluorine compounds and inorganic fluorine containing compounds are called fluorides. Fluoride, like other halides, is a monovalent ion . Its compounds often have properties that are...
anion, aniline
Aniline
Aniline, phenylamine or aminobenzene is an organic compound with the formula C6H5NH2. Consisting of a phenyl group attached to an amino group, aniline is the prototypical aromatic amine. Being a precursor to many industrial chemicals, its main use is in the manufacture of precursors to polyurethane...
, pyridine
Pyridine
Pyridine is a basic heterocyclic organic compound with the chemical formula C5H5N. It is structurally related to benzene, with one C-H group replaced by a nitrogen atom...
, ethylene diamine
Ethylene diamine
Ethylenediamine is the organic compound with the formula C2H42. This colorless liquid with an ammonia-like odor is a strongly basic amine. The liquid fumes upon contact with humid air...
and the phenolate ion were found to have pseudo first order reaction rates corresponding to their basicity as measured by their pKa
PKA
PKA, pKa, or other similar variations may stand for:* pKa, the symbol for the acid dissociation constant at logarithmic scale* Protein kinase A, a class of cAMP-dependent enzymes* Pi Kappa Alpha, the North-American social fraternity...
. Other nucleophiles however reacted much faster than expected based on this criterium alone. These include hydrazine
Hydrazine
Hydrazine is an inorganic compound with the formula N2H4. It is a colourless flammable liquid with an ammonia-like odor. Hydrazine is highly toxic and dangerously unstable unless handled in solution. Approximately 260,000 tons are manufactured annually...
, hydroxylamine
Hydroxylamine
Hydroxylamine is an inorganic compound with the formula NH2OH. The pure material is a white, unstable crystalline, hygroscopic compound. However, hydroxylamine is almost always provided and used as an aqueous solution. It is used to prepare oximes, an important functional group. It is also an...
, the hypochlorite
Hypochlorite
The hypochlorite ion, also known as chlorate anion is ClO−. A hypochlorite compound is a chemical compound containing this group, with chlorine in oxidation state +1.Hypochlorites are the salts of hypochlorous acid...
ion and the hydroperoxide anion.
In 1962 Edwards and Pearson
Ralph Pearson
Ralph G. Pearson is a physical inorganic chemist best known for the development of the concept of hard and soft acids and bases ....
(the latter of HSAB theory
HSAB theory
The HSAB concept is an acronym for 'hard and soft acids and bases. Also known as the Pearson acid base concept, HSAB is widely used in chemistry for explaining stability of compounds, reaction mechanisms and pathways....
fame) introduced the phrase alpha effect for this anomaly. He offered the suggestion that the effect was caused by a transition state
Transition state
The transition state of a chemical reaction is a particular configuration along the reaction coordinate. It is defined as the state corresponding to the highest energy along this reaction coordinate. At this point, assuming a perfectly irreversible reaction, colliding reactant molecules will always...
(TS) stabilization effect: on entering the TS the free electron pair on the nucleophile moves away from the nucleus causing a partial positive charge which can be stabilized by an adjacent lone pair
Lone pair
In chemistry, a lone pair is a valence electron pair without bonding or sharing with other atoms. They are found in the outermost electron shell of an atom, so lone pairs are a subset of a molecule's valence electrons...
as for instance happens in any carbocation
Carbocation
A carbocation is an ion with a positively-charged carbon atom. The charged carbon atom in a carbocation is a "sextet", i.e. it has only six electrons in its outer valence shell instead of the eight valence electrons that ensures maximum stability . Therefore carbocations are often reactive,...
.
Over the years many additional theories have been put forward attempting the effect. A ground state stabilizing effect assumes that the alpha lone-pair and nucleophilic electron pair destabilize each other by electronic repulsion thereby increasing the ground state and making it more reactive. Stabilization of the transition state is possible by assuming some TS free radical character or assuming that the TS has more advanced nucleophile-substrate bond formation. The polarizability
Polarizability
Polarizability is the measure of the change in a molecule's electron distribution in response to an applied electric field, which can also be induced by electric interactions with solvents or ionic reagents. It is a property of matter...
of the nucleophile or involvement of intramolecular
Intramolecular
Intramolecular in chemistry describes a process or characteristic limited within the structure of a single molecule, a property or phenomenon limited to the extent of a single molecule.- Examples :...
catalysis
Catalysis
Catalysis is the change in rate of a chemical reaction due to the participation of a substance called a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. A catalyst may participate in multiple chemical transformations....
also plays a role. One recent in silico
In silico
In silico is an expression used to mean "performed on computer or via computer simulation." The phrase was coined in 1989 as an analogy to the Latin phrases in vivo and in vitro which are commonly used in biology and refer to experiments done in living organisms and outside of living organisms,...
contribution did find a correlation between the alpha effect and the so-called deformation energy which is the electronic energy required to bring the two reactants together in the transition state.
The alpha effect is also dependent on solvent
Solvent
A solvent is a liquid, solid, or gas that dissolves another solid, liquid, or gaseous solute, resulting in a solution that is soluble in a certain volume of solvent at a specified temperature...
but not in a predictable way: it can increase or decrease with solvent mix composition or even go through a maximum.