Nucleophilic acyl substitution
Encyclopedia
Nucleophilic acyl substitution describes the substitution reaction
involving nucleophile
s and acyl
compounds. Acyl compounds are carboxylic acid
derivatives including ester
s, amide
s and acid halides. Nucleophiles include anionic reagents such as alkoxide
compounds and enolates or species of high basicity, such as amine
s.
with a polar carbonyl
group such as a ketone
or an aldehyde
results in nucleophilic addition
with a tetrahedral
alkoxide as primary reaction product. However, in acyl
compounds the carbonyl group is bonded to a substituent
that can act as a leaving group
. Upon attack of the nucleophile at the carbonyl group, as before, a tetrahedral intermediate is formed with the nucleophile, the leaving group and the oxygen anion attached to the central carbon atom. The alkoxy group can now revert back to the carbonyl
group and at the same time expel the leaving group
. The nucleophile has taken the position previously occupied by the leaving group.
This mechanism is supported by isotope labeling experiments. The 18O labeled ethoxy oxygen atom in ethyl propionate
(leaving group = EtO) winds up exclusively in the ethanol product in a reaction with NaOH .
Acyl substitution is basically a two-step nucleophilic addition
and elimination reaction
. Both reaction steps are reversible reaction
s. The relative strength of both nucleophilic species determines the reaction outcome, but in practical reactions the leaving group is by far the poorest nucleophile.
Carboxylic acids as well as the related esters and amides are often insufficiently reactive to undergo nucleophilic substitution. The carboxylic acid is often activated by conversion to the acyl chloride using thionyl chloride
.
s are nucleophilic acyl substitutions. Carboxylic acid
s react with chlorine donors such as thionyl chloride
or phosphorus trichloride
to acid chlorides, with alcohol
s to ester
s in esterfication and carboxylic acids selfcondense
to acid anhydrides. With amine
s they form amide
s. Esters react with Grignard reagents in a nucleophilic acyl substitution, leading to ketones, followed by a nucleophilic addition
, leading to tertiary alcohols. Esters also react with Enolate nucleophiles. For example ethyl acetate
reacts with acetone
to acetylacetone
.
The Baker-Venkataraman rearrangement
is a nucleophilic acyl substitution used in the synthesis of flavones. In the Weinreb ketone synthesis
ketones are synthesized from carboxylic acid
precursors. An unusual intramolecular acyl substitution is the Chan rearrangement
.
Substitution reaction
In a substitution reaction, a functional group in a particular chemical compound is replaced by another group. In organic chemistry, the electrophilic and nucleophilic substitution reactions are of prime importance...
involving nucleophile
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...
s and acyl
Acyl
An acyl group is a functional group derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids.In organic chemistry, the acyl group is usually derived from a carboxylic acid . Therefore, it has the formula RCO-, where R represents an alkyl group that is...
compounds. Acyl compounds are carboxylic acid
Carboxylic acid
Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...
derivatives including 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...
s, amide
Amide
In chemistry, an amide is an organic compound that contains the functional group consisting of a carbonyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds. The term amide also refers to deprotonated form of ammonia or an...
s and acid halides. Nucleophiles include anionic reagents such as alkoxide
Alkoxide
An alkoxide is the conjugate base of an alcohol and therefore consists of an organic group bonded to a negatively charged oxygen atom. They can be written as RO−, where R is the organic substituent. Alkoxides are strong bases and, when R is not bulky, good nucleophiles and good ligands...
compounds and enolates or species of high basicity, such as amine
Amine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
s.
Reaction mechanism
The reaction of a nucleophileNucleophile
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...
with a polar carbonyl
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....
group such as a ketone
Ketone
In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...
or an aldehyde
Aldehyde
An aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....
results in nucleophilic addition
Nucleophilic addition
In organic chemistry, a nucleophilic addition reaction is an addition reaction where in a chemical compound a π bond is removed by the creation of two new covalent bonds by the addition of a nucleophile....
with a tetrahedral
Tetrahedral molecular geometry
In a tetrahedral molecular geometry a central atom is located at the center with four substituents that are located at the corners of a tetrahedron. The bond angles are cos−1 ≈ 109.5° when all four substituents are the same, as in CH4. This molecular geometry is common throughout the first...
alkoxide as primary reaction product. However, in acyl
Acyl
An acyl group is a functional group derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids.In organic chemistry, the acyl group is usually derived from a carboxylic acid . Therefore, it has the formula RCO-, where R represents an alkyl group that is...
compounds the carbonyl group is bonded to a substituent
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...
that can act as a leaving group
Leaving group
In chemistry, a leaving group is a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. Leaving groups can be anions or neutral molecules. Common anionic leaving groups are halides such as Cl−, Br−, and I−, and sulfonate esters, such as para-toluenesulfonate...
. Upon attack of the nucleophile at the carbonyl group, as before, a tetrahedral intermediate is formed with the nucleophile, the leaving group and the oxygen anion attached to the central carbon atom. The alkoxy group can now revert back to the carbonyl
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....
group and at the same time expel the leaving group
Leaving group
In chemistry, a leaving group is a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. Leaving groups can be anions or neutral molecules. Common anionic leaving groups are halides such as Cl−, Br−, and I−, and sulfonate esters, such as para-toluenesulfonate...
. The nucleophile has taken the position previously occupied by the leaving group.
This mechanism is supported by isotope labeling experiments. The 18O labeled ethoxy oxygen atom in ethyl propionate
Ethyl propionate
Ethyl propionate is a compound with formula C2H5. It is the ethyl ester of propionic acid. It smells fruity....
(leaving group = EtO) winds up exclusively in the ethanol product in a reaction with NaOH .
Acyl substitution is basically a two-step nucleophilic addition
Nucleophilic addition
In organic chemistry, a nucleophilic addition reaction is an addition reaction where in a chemical compound a π bond is removed by the creation of two new covalent bonds by the addition of a nucleophile....
and elimination reaction
Elimination reaction
An elimination reaction is a type of organic reaction in which two substituents are removed from a molecule in either a one or two-step mechanism...
. Both reaction steps are reversible reaction
Reversible reaction
A reversible reaction is a chemical reaction that results in an equilibrium mixture of reactants and products. For a reaction involving two reactants and two products this can be expressed symbolically as...
s. The relative strength of both nucleophilic species determines the reaction outcome, but in practical reactions the leaving group is by far the poorest nucleophile.
Carboxylic acids as well as the related esters and amides are often insufficiently reactive to undergo nucleophilic substitution. The carboxylic acid is often activated by conversion to the acyl chloride using thionyl chloride
Thionyl chloride
Thionyl chloride is an inorganic compound with the formula SOCl2. It is a reactive chemical reagent used in chlorination reactions. It is a colorless, distillable liquid at room temperature and pressure that decomposes above 140 °C. Thionyl chloride is sometimes confused with sulfuryl...
.
Reactions
Many condensation reactionCondensation reaction
A condensation reaction is a chemical reaction in which two molecules or moieties combine to form one single molecule, together with the loss of a small molecule. When this small molecule is water, it is known as a dehydration reaction; other possible small molecules lost are hydrogen chloride,...
s are nucleophilic acyl substitutions. Carboxylic acid
Carboxylic acid
Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...
s react with chlorine donors such as thionyl chloride
Thionyl chloride
Thionyl chloride is an inorganic compound with the formula SOCl2. It is a reactive chemical reagent used in chlorination reactions. It is a colorless, distillable liquid at room temperature and pressure that decomposes above 140 °C. Thionyl chloride is sometimes confused with sulfuryl...
or phosphorus trichloride
Phosphorus trichloride
Phosphorus trichloride is a chemical compound of phosphorus and chlorine, having chemical formula PCl3. Its shape is trigonal pyramidal. It is the most important of the three phosphorus chlorides. It is an important industrial chemical, being used for the manufacture of organophosphorus compounds...
to acid chlorides, with alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
s to 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...
s in esterfication and carboxylic acids selfcondense
Self-condensation
Self-condensation is an organic reaction in which a chemical compound containing a carbonyl group acts both as the electrophile and the nucleophile in an aldol condensation...
to acid anhydrides. With amine
Amine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
s they form amide
Amide
In chemistry, an amide is an organic compound that contains the functional group consisting of a carbonyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds. The term amide also refers to deprotonated form of ammonia or an...
s. Esters react with Grignard reagents in a nucleophilic acyl substitution, leading to ketones, followed by a nucleophilic addition
Nucleophilic addition
In organic chemistry, a nucleophilic addition reaction is an addition reaction where in a chemical compound a π bond is removed by the creation of two new covalent bonds by the addition of a nucleophile....
, leading to tertiary alcohols. Esters also react with Enolate nucleophiles. For example ethyl acetate
Ethyl acetate
Ethyl acetate is the organic compound with the formula CH3COOCH2CH3. This colorless liquid has a characteristic sweet smell and is used in glues, nail polish removers, and cigarettes...
reacts with acetone
Acetone
Acetone is the organic compound with the formula 2CO, a colorless, mobile, flammable liquid, the simplest example of the ketones.Acetone is miscible with water and serves as an important solvent in its own right, typically as the solvent of choice for cleaning purposes in the laboratory...
to acetylacetone
Acetylacetone
Acetylacetone is an organic compound that famously exists in two tautomeric forms that rapidly interconvert. The less stable tautomer is a diketone formally named pentane-2,4-dione. The more common tautomer is the enol form. The pair of tautomers rapidly interconvert and are treated as a single...
.
The Baker-Venkataraman rearrangement
Baker-Venkataraman rearrangement
The Baker–Venkataraman rearrangement is the chemical reaction of 2-acetoxyacetophenones with base to form 1,3-diketones.This rearrangement reaction proceeds via enolate formation followed by acyl transfer...
is a nucleophilic acyl substitution used in the synthesis of flavones. In the Weinreb ketone synthesis
Weinreb ketone synthesis
The Weinreb ketone synthesis is a chemical reaction used in organic chemistry to make carbon–carbon bonds. It was discovered in 1981 by Steven M. Weinreb and Steven Nahm as a method to synthesize ketones...
ketones are synthesized from carboxylic acid
Carboxylic acid
Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...
precursors. An unusual intramolecular acyl substitution is the Chan rearrangement
Chan rearrangement
The Chan rearrangement is a chemical reaction that involves rearranging an acyloxy acetate in the presence of a strong base to a 2-hydroxy-3-keto-ester .This procedure was rediscovered and employed in the Holton Taxol total synthesis....
.
See also
- The substitution reactionSubstitution reactionIn a substitution reaction, a functional group in a particular chemical compound is replaced by another group. In organic chemistry, the electrophilic and nucleophilic substitution reactions are of prime importance...
s in organic chemistryOrganic chemistryOrganic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, composition, reactions, and preparation of carbon-based compounds, hydrocarbons, and their derivatives...
are nucleophilic acyl substitution, nucleophilic aliphatic substitution and nucleophilic aromatic substitutionNucleophilic aromatic substitutionright|300px|Aromatic nucleophilic substitutionA nucleophilic aromatic substitution is a substitution reaction in organic chemistry in which the nucleophile displaces a good leaving group, such as a halide, on an aromatic ring...
.
External links
- Reaction of ethyl acetateEthyl acetateEthyl acetate is the organic compound with the formula CH3COOCH2CH3. This colorless liquid has a characteristic sweet smell and is used in glues, nail polish removers, and cigarettes...
with acetoneAcetoneAcetone is the organic compound with the formula 2CO, a colorless, mobile, flammable liquid, the simplest example of the ketones.Acetone is miscible with water and serves as an important solvent in its own right, typically as the solvent of choice for cleaning purposes in the laboratory...
in Organic SynthesesOrganic SynthesesOrganic Syntheses is a scientific journal that since 1921 has provided the chemistry community with annual collections of detailed and checked procedures for the organic synthesis of organic compounds. The journal is peer reviewed...
Coll. Vol. 3, p.16; Vol. 20, p.6 Article