Alcohol Vs Amine: Which Makes A Better Nucleophile?

Amines and alcohols are both nucleophiles, commonly used in laboratory and biochemical reactions. However, amines are considered better nucleophiles than alcohols. The nitrogen atom on an amide is less nucleophilic than the nitrogen on an amine due to the resonance stabilization of the nitrogen lone pair provided by the amide carbonyl group. The Mayr nucleophilicity factors can be used to determine the order of magnitude of electronic and steric effects. The Mayr tables indicate that the higher the number, the better the nucleophile. The nucleophilicity of a molecule is also dependent on the solvent used in the reaction.

Amines are better nucleophiles than alcohols

Amines are considered better nucleophiles than alcohols. Nucleophilicity is the tendency of a nucleophile to react with an electrophile. The nitrogen atom in an amine is more nucleophilic than the oxygen atom in an alcohol due to the resonance stabilization of the nitrogen lone pair provided by the amide carbonyl group.

In biological chemistry, where the solvent is protic (water), thiols are more powerful nucleophiles than alcohols. The thiol group in a cysteine amino acid is a potent nucleophile and often acts as a nucleophile in enzymatic reactions. However, hydroxyl groups on serine, threonine, and tyrosine also act as nucleophiles.

The Mayr nucleophilicity factors can be used to compare the nucleophilicity of tertiary amines to secondary amines. In general, tertiary amines are more sterically hindered than secondary amines, reducing their nucleophilicity. However, in acetonitrile, tertiary amines are significantly more nucleophilic than secondary amines.

Amines are also better nucleophiles than alcohols because they are less electronegative, meaning they hold on to their electrons less tightly and are theoretically better nucleophiles. Additionally, the basicity of atoms decreases when moving vertically down a column on the periodic table. This trend can be explained by the increasing size of the 'electron cloud' around larger ions, which increases stability and reduces basicity.

Furthermore, the use of amines as nucleophiles has some advantages over alcohols. Neutral amines are good enough nucleophiles for most purposes, and using an amide base does not offer a significant advantage. However, the potential drawback of using amide bases is that acid-base reactions tend to be fast, and side reactions can occur.

Mayr nucleophilicity factors

In general, amines are better nucleophiles than alcohols. This is because the nitrogen atom in an amine is less nucleophilic than the nitrogen atom in an amide due to the resonance stabilisation of the nitrogen lone pair provided by the amide carbonyl group.

The Mayr nucleophilicity factors are a set of reactivity scales that can be used to determine the order of magnitude of electronic and steric effects on nucleophilicity. Mayr's scale is likely the most complete collection of reactivity data, with over 1200 nucleophiles. The higher the number on the Mayr scale, the better the nucleophile. The Mayr factors work best with non-sterically hindered electrophiles.

The Mayr nucleophilicity factors can be used to determine whether tertiary amines or secondary amines are better nucleophiles. Tertiary amines are more sterically hindered than secondary amines, which reduces their nucleophilicity. In acetonitrile, tertiary amines are at least one, if not two, orders of magnitude more nucleophilic than secondary amines.

The key descriptors of the model are the proton affinity, solvation energies, and sterics of the nucleophile. The nucleophile proton affinity and the solvation energy of both the nucleophile and the addition product appear as the main parameters. These coincide with the pKa, suggesting that thermodynamics is a key factor contributing to the reaction rate constant.

The Mayr nucleophilicity factors are useful for understanding the relative reactivity of different nucleophiles, which is important in chemistry as nucleophilicity is at the basis of most chemical transformations.

The alpha-effect

Amines are generally considered better nucleophiles than alcohols. The "alpha-effect" refers to the increased nucleophilicity of an atom due to the presence of an adjacent atom with lone pair electrons. This adjacent atom is known as an "alpha" atom. The alpha effect was first observed by Jencks and Carriuolo in 1960 through a series of chemical kinetics experiments. In 1962, Edwards and Pearson introduced the term alpha effect to describe this anomaly.

The alpha effect is an important concept in mechanistic chemistry and biochemistry, and it has been observed in various chemical reactions. The effect is characterized by higher nucleophilicity than expected based on the Brønsted basicity. For example, the hydroxyl group on serine, threonine, and tyrosine can act as nucleophiles, but the presence of an adjacent electron-donating atom increases their nucleophilicity. This deviation from the classical Brønsted-type reactivity-basicity relationship is a key feature of the alpha effect.

The origin of the alpha effect is still a subject of debate, with several theories proposed to explain it. One theory suggests that the electron-electron repulsion between the alpha lone pair and the nucleophilic electron pair increases reactivity by decreasing the activation barrier. Another theory, known as the secondary orbital interactions theory, emphasizes the role of the electron-donating heteroatom in the alpha position, which contributes to increased orbital interaction with the substrate, stabilizing the transition state. Barroso-Flores explains that the alpha heteroatom polarizes the HOMO (highest occupied molecular orbital) at the nucleophilic centre, reducing its size and lowering steric repulsion, ultimately leading to increased reactivity.

The alpha effect is also influenced by the solvent but in an unpredictable manner. It can increase or decrease with changes in solvent composition or even go through a maximum. Some studies suggest that the alpha effect may be primarily a solvation effect, as it has been observed to disappear in gas-phase reactions. However, the presence of similar alpha effects in different solvent systems challenges this explanation.

While the exact mechanism of the alpha effect remains elusive, it has been established as a significant phenomenon in chemistry, particularly in understanding the reactivity of nucleophiles. The classification of nucleophiles into those exhibiting the alpha effect, those that don't, and those exhibiting the inverse alpha effect provides a framework for predicting reactivity in fundamental reactions.

Acid-base side reactions

Amines are generally considered to be better nucleophiles than alcohols. This is because amines are more basic than alcohols, which affects the stability of the leaving group. The reaction with the amine can eliminate the carboxylate ion without protonation, as the amine is a strong enough base to stabilize the leaving group.

Amines are also more nucleophilic than alcohols because the nitrogen atom on an amide is less nucleophilic than the nitrogen of an amine due to the resonance stabilization of the nitrogen lone pair provided by the amide carbonyl group. Steric hindrance is another important consideration when evaluating nucleophilicity. For example, tertiary amines should be more sterically hindered than secondary amines, reducing nucleophilicity.

In biological chemistry, where the solvent is protic (water), thiols are more powerful nucleophiles than alcohols. The thiol group in a cysteine amino acid is a powerful nucleophile and often acts as a nucleophile in enzymatic reactions.

When considering acid-base side reactions, it is important to note that extremely strong bases, such as NaNH2, can lead to acid-base side reactions rather than the desired reaction with the electrophile. For example, trying to do an SN2 reaction on an alkyl halide with an amine may result in the desired product, but it also has the potential to deliver an elimination product as well. This is because acid-base reactions tend to be fast relative to reactions at carbon.

A substitution reaction of amines with alcohols for N-alkylated amines has been developed using inexpensive AlCl3 without any ligand or additive. This is an atom-efficient and environmentally benign process that can be catalyzed by iron, an inexpensive and readily available metal.

SN2 reactions

Amines are better nucleophiles than alcohols. This is because the nitrogen atom in an amine is less nucleophilic than the nitrogen atom in an amide due to the resonance stabilisation of the nitrogen lone pair provided by the amide carbonyl group. The SN2 reaction, or "bimolecular nucleophilic substitution", is one of the most important reactions in organic chemistry. It involves the substitution of a nucleophile upon an alkyl halide. The rate of the SN2 reaction depends on the concentration of the nucleophile and the substrate.

The SN2 mechanism proceeds through a concerted backside attack of the nucleophile on the alkyl halide. The nucleophile approaches the alkyl halide 180° from the carbon-halogen bond, and as the carbon-nucleophile bond forms, the carbon-leaving group bond breaks. This results in an inversion of stereochemistry. For example, (S)-2-bromobutane becomes (R)-2-methylbutanenitrile. The geometry of the transition state is trigonal bipyramidal, and the three groups flip over as the leaving group leaves.

The SN2 mechanism is a second-order reaction, meaning that the overall rate depends on a step in which two separate molecules (the nucleophile and the electrophile) collide. The mechanism starts when lone pair electrons from the nucleophile attack the electrophilic carbon of the alkyl halide to form a C-nucleophile sigma bond. Simultaneously, the carbon-leaving group bond is broken as the electrons are pushed onto the leaving group. Overall, during this mechanism, a set of lone pair electrons are transferred from the nucleophile to the leaving group.

The SN2 reaction is stereoselective, meaning that when the substitution takes place at a stereocenter, the stereochemical configuration of the product can be predicted. For example, if the reaction starts with the R enantiomer as the substrate, the product will be the S enantiomer. If it starts with the S enantiomer, the product will be the R enantiomer. This also applies to substrates that are cis or trans.

The rate of an SN2 reaction can be decreased by steric hindrance. For example, the rate decreases 50-80 fold when going from methyl to ethyl or ethyl to isopropyl. Tertiary amines are more sterically hindered than secondary amines, reducing their nucleophilicity. However, in some solvents, such as acetonitrile, tertiary amines can be one to two orders of magnitude more nucleophilic than secondary amines.

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