α Effect
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The alpha effect refers to the increased
nucleophilicity 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 ...
of an
atom Atoms are the basic particles of the chemical elements. An atom consists of a atomic nucleus, nucleus of protons and generally neutrons, surrounded by an electromagnetically bound swarm of electrons. The chemical elements are distinguished fr ...
due to the presence of an adjacent (alpha)
atom Atoms are the basic particles of the chemical elements. An atom consists of a atomic nucleus, nucleus of protons and generally neutrons, surrounded by an electromagnetically bound swarm of electrons. The chemical elements are distinguished fr ...
with
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 ...
electron The electron (, or in nuclear reactions) is a subatomic particle with a negative one elementary charge, elementary electric charge. It is a fundamental particle that comprises the ordinary matter that makes up the universe, along with up qua ...
s. This first atom does not necessarily exhibit increased
basicity In chemistry, there are three definitions in common use of the word "base": ''Arrhenius bases'', ''Brønsted bases'', and ''Lewis bases''. All definitions agree that bases are substances that react with acids, as originally proposed by Guilla ...
compared with a similar atom without an adjacent electron-donating atom, resulting in a deviation from the classical Brønsted-type reactivity-basicity relationship. In other words, the alpha effect refers to nucleophiles presenting higher nucleophilicity than the predicted value obtained from the Brønsted basicity. The representative examples would be high nucleophilicities of
hydroperoxide Hydroperoxides or peroxols are Chemical compound, compounds of the form ROOH, where R stands for any group, typically Organic compound, organic, which contain the hydroperoxy functional group (). Hydroperoxide also refers to the hydroperoxide anio ...
(HO2) and
hydrazine Hydrazine is an inorganic compound with the chemical formula . It is a simple pnictogen hydride, and is a colourless flammable liquid with an ammonia-like odour. Hydrazine is highly hazardous unless handled in solution as, for example, hydraz ...
(N2H4). The effect is now well established with numerous examples and became an important concept in mechanistic chemistry and biochemistry. However, the origin of the effect is still controversial without a clear winner.


Background


Experiment

The effect was first observed by Jencks and Carriuolo in 1960 in a series of
chemical kinetics Chemical kinetics, also known as reaction kinetics, is the branch of physical chemistry that is concerned with understanding the rates of chemical reactions. It is different from chemical thermodynamics, which deals with the direction in which a ...
experiments involving the reaction of the
ester In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...
p-nitrophenyl acetate with a range of nucleophiles. Regular nucleophiles such as the
fluoride Fluoride (). According to this source, is a possible pronunciation in British English. is an Inorganic chemistry, inorganic, Monatomic ion, monatomic Ion#Anions and cations, anion of fluorine, with the chemical formula (also written ), whose ...
anion,
aniline Aniline (From , meaning ' indigo shrub', and ''-ine'' indicating a derived substance) is an organic compound with the formula . Consisting of a phenyl group () attached to an amino group (), aniline is the simplest aromatic amine. It is an in ...
,
pyridine Pyridine is a basic (chemistry), basic heterocyclic compound, 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, weak ...
,
ethylene diamine Ethylenediamine (abbreviated as en when a ligand) is the organic compound with the formula C2H4(NH2)2. This colorless liquid with an ammonia-like odor is a basic amine. It is a widely used building block in chemical synthesis, with approximately 5 ...
and the
phenolate Phenolates (also called phenoxides) are anions, salt (chemistry), salts, and esters of phenols, containing the phenolate ion. They may be formed by reaction of phenols with strong base. Properties Alkali metal phenolates, such as sodium phenoxi ...
ion were found to have
pseudo first order reaction In chemistry, the rate equation (also known as the rate law or empirical differential rate equation) is an empirical differential mathematical expression for the reaction rate of a given reaction in terms of concentrations of chemical species and ...
rates corresponding to their basicity as measured by their pKa. Other nucleophiles however reacted much faster than expected based on this criterion alone. These include
hydrazine Hydrazine is an inorganic compound with the chemical formula . It is a simple pnictogen hydride, and is a colourless flammable liquid with an ammonia-like odour. Hydrazine is highly hazardous unless handled in solution as, for example, hydraz ...
,
hydroxylamine Hydroxylamine (also known as hydroxyammonia) is an inorganic compound with the chemical formula . The compound exists as hygroscopic colorless crystals.Greenwood and Earnshaw. ''Chemistry of the Elements.'' 2nd Edition. Reed Educational and Prof ...
, the
hypochlorite In chemistry, hypochlorite, or chloroxide is an oxyanion with the chemical formula ClO−. It combines with a number of cations to form hypochlorite salts. Common examples include sodium hypochlorite (household bleach) and calcium hypochlorite ...
ion and the
hydroperoxide Hydroperoxides or peroxols are Chemical compound, compounds of the form ROOH, where R stands for any group, typically Organic compound, organic, which contain the hydroperoxy functional group (). Hydroperoxide also refers to the hydroperoxide anio ...
anion.


α-effect

In 1962, Edwards and Pearson (the latter of
HSAB theory HSAB is an acronym for "hard and soft (Lewis) acids and bases". HSAB is widely used in chemistry for explaining the stability of compounds, reaction mechanisms and pathways. It assigns the terms 'hard' or 'soft', and 'acid' or 'base' to chemical ...
) introduced the phrase ''alpha effect'' for this anomaly. He offered the suggestion that the effect was caused by a
transition state In chemistry, 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 potential energy along this reaction coordinate. It is often marked w ...
(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 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 ...
as for instance happens in any
carbocation Carbocation is a general term for ions with a positively charged carbon atom. In the present-day definition given by the IUPAC, a carbocation is any even-electron cation with significant partial positive charge on a carbon atom. They are further ...
.


Theory

Over the years, many additional theories have been put forward attempting to explain the effect.


Ground state destabilization

The ground state destabilization theory proposes that the electron-electron repulsion between the alpha lone-pair and nucleophilic electron pair destabilize each other by electronic repulsion (filled–filled orbital interaction) thereby decreasing the activation barrier by increasing the ground state energy and making it more reactive. This explains the higher reactivity of α-nucleophiles, however, this electronic mechanism should also increase the basicity and, therefore, cannot fully explain the α-effect.


Transition state stabilization

Many explanations fall into this category. First, the secondary orbital interactions theory emphasized that electron-donating heteroatom in the α-position could contribute to increased orbital interaction with the substrate, which stabilizes the transition state (TS) and gives greater reactivity. Second, the electron transfer (ET) mechanism presents that the heteroatom in the α position could stabilize the SN2 transition state which has a single electron transfer (free radical) character. Other driving forces including the tighter transition state and higher polarizability of α-nucleophiles, involvement of intramolecular
catalysis Catalysis () is the increase in rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recycles quick ...
also plays a role. Another
in silico In biology and other experimental sciences, an ''in silico'' experiment is one performed on a computer or via computer simulation software. The phrase is pseudo-Latin for 'in silicon' (correct ), referring to silicon in computer chips. It was c ...
study 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.


Thermodynamic product stability

This explanation proposes that a stable product could contribute to the alpha effect, however, this factor could not be the sole factor.


Solvent-induced effects

The alpha effect is also dependent on
solvent A solvent (from the Latin language, Latin ''wikt:solvo#Latin, solvō'', "loosen, untie, solve") is a substance that dissolves a solute, resulting in a Solution (chemistry), solution. A solvent is usually a liquid but can also be a solid, a gas ...
but not in a predictable way: it can increase or decrease with solvent mix composition or even go through a maximum. At least in some cases, the alpha effect has been observed to vanish if the reaction is conducted in the gas phase, leading some to conclude that it is primarily a solvation effect. However, this explanation has limitations since similar alpha effects could be found in different solvent systems and also because the solvation affects both the basicity and the nucleophilicity of the nucleophile.


Pauli repulsion and HOMO-LUMO overlap

In the recent article published in 2021, Hansen and Vermeeren proposed the two requirements for an α-nucleophile to present the α-effect. The two proposed requirements were (1) minimization of steric Pauli repulsion via small HOMO lobes on the nucleophilic center and (2) small HOMO-LUMO orbital energy gap that ensures orbital overlap with the substrate. It was proposed that both of these two requirements should be fulfilled to have an α-effect, otherwise, the nucleophiles would show no or inverse α-effect (Figure 2). In this recent work, the six normal nucleophiles (HO, CH3O, H2N, CH3HN, CH3S, HS) followed the Brønsted-type correlation. α-nucleophiles with O, HN, and S in the α position were classified into three groups according to their degree and pattern of deviation from the Brønsted-type correlation in SN2 reactions with the substrate, ethyl chloride (C2H5Cl) (Figure 3). First, the α-nucleophiles with downward deviation, in other words, higher reactivity shown considering the basicity or lower basicity given the reactivity, were grouped as nucleophiles showing α-effect. The second group had nucleophiles with small or no deviation from the line plotted by six normal nucleophiles. Lastly, the third group had nucleophiles showing inverse α-effect, meaning that they are above the plotted line or have less reactivity considering their high basicity. Relative density functional theory,
activation strain model The activation strain model, also referred to as the distortion/interaction model, is a computational tool for modeling and understanding the potential energy curves of a chemical reaction as a function of reaction coordinate (ζ), as portrayed i ...
, energy decomposition analysis, and Kohn-Sham molecular orbital analysis the three groups had a distinction in HOMO lobes and HOMO-LUMO gaps. To elaborate on the first requirement, the electronegative heteroatom reduces the electron density of the atom that attacks the nucleophile making the HOMO lobe smaller. This minimizes the Pauli repulsion between the substrate and the nucleophile. Nonetheless, these small HOMO lobes don't mean less orbital interaction than the parent normal nucleophile. This is because α-nucleophiles showing the α-effect have smaller HOMO(nucleophile)-LUMO(substrate) gap, in other words, high HOMO energy level that allows more orbital interaction. Examples of α-nucleophiles with α-effects are shown in Figure 4. The α-nucleophiles have smaller HOMO lobes than the parent normal nucleophile. Examples of α-nucleophiles with α-effect and inverse α-effect are shown in Figure 5.


See also

*
SN2 reaction The bimolecular nucleophilic substitution (SN2) is a type of reaction mechanism that is common in organic chemistry. In the SN2 reaction, a strong nucleophile forms a new bond to an sp3-hybridised carbon atom via a backside attack, all while t ...
*
Nucleophile 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 ...


References

{{DEFAULTSORT:Alpha Effect Physical organic chemistry