Povarov reaction
Encyclopedia
The Povarov reaction is an organic reaction
described as a formal cycloaddition
between an aromatic imine
and an alkene
. The imine
in this organic reaction
is a condensation reaction
product from an aniline
type compound and a benzaldehyde
type compound . The alkene
must be electron rich which means that functional group
s attached to the alkene must be able to donate electrons. Such alkenes are enol ether
s and enamine
s. The reaction product in the original Povarov reaction is a quinoline
. Because the reactions can be carried out with the three components premixed in one reactor it is an example of a multi-component reaction
.
for the Povarov reaction to the quinoline
is outlined in scheme 1. In step one aniline
and benzaldehyde
react to the Schiff base
in a condensation reaction
. The Povarov reaction requires a lewis acid
such as boron trifluoride
to activate the imine
for an electrophilic addition
of the activated alkene
. This reaction step forms an oxonium ion
which then reacts with the aromatic ring in a classical electrophilic aromatic substitution
. Two additional elimination reaction
s create the quinoline ring structure.
The reaction is also classified as a subset of aza Diels-Alder reaction
s
and an enamine
in the presence of yttrium
triflate
as the lewis acid
. This reaction is regioselective because the iminium
ion preverentially attacks the nitro
ortho position and not the para position. The nitro group is a meta directing substituent but since this position is blocked, the most electron rich ring position is now ortho and not para. The reaction is also diastereoselective
because the enamine addition occurs with a preference for trans
addition without formation of the cis isomer.
gives an intramolecular
reaction with the aryl group, this intermediate can also be terminated by an additional nucleophile
such as an alcohol
. Scheme 3 depicts this 4 component reaction with the ethyl
ester
of glyoxylic acid
, 3,4-dihydro-2H-pyran, aniline
and ethanol
with lewis acid
scandium(III) triflate
and molecular sieve
s.
Organic reaction
Organic reactions are chemical reactions involving organic compounds. The basic organic chemistry reaction types are addition reactions, elimination reactions, substitution reactions, pericyclic reactions, rearrangement reactions, photochemical reactions and redox reactions. In organic synthesis,...
described as a formal cycloaddition
Cycloaddition
A cycloaddition is a pericyclic chemical reaction, in which "two or more unsaturated molecules combine with the formation of a cyclic adduct in which there is a net reduction of the bond multiplicity." The resulting reaction is a cyclization reaction.Cycloadditions are usually described by the...
between an aromatic imine
Imine
An imine is a functional group or chemical compound containing a carbon–nitrogen double bond, with the nitrogen attached to a hydrogen atom or an organic group. If this group is not a hydrogen atom, then the compound is known as a Schiff base...
and an alkene
Alkene
In organic chemistry, an alkene, olefin, or olefine is an unsaturated chemical compound containing at least one carbon-to-carbon double bond...
. The imine
Imine
An imine is a functional group or chemical compound containing a carbon–nitrogen double bond, with the nitrogen attached to a hydrogen atom or an organic group. If this group is not a hydrogen atom, then the compound is known as a Schiff base...
in this organic reaction
Organic reaction
Organic reactions are chemical reactions involving organic compounds. The basic organic chemistry reaction types are addition reactions, elimination reactions, substitution reactions, pericyclic reactions, rearrangement reactions, photochemical reactions and redox reactions. In organic synthesis,...
is a condensation reaction
Condensation 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,...
product from an 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...
type compound and a benzaldehyde
Benzaldehyde
Benzaldehyde is an organic compound consisting of a benzene ring with a formyl substituent. It is the simplest aromatic aldehyde and one of the most industrially useful. This colorless liquid has a characteristic pleasant almond-like odor...
type compound . The alkene
Alkene
In organic chemistry, an alkene, olefin, or olefine is an unsaturated chemical compound containing at least one carbon-to-carbon double bond...
must be electron rich which means that functional group
Functional group
In organic chemistry, functional groups are specific groups of atoms within molecules that are responsible for the characteristic chemical reactions of those molecules. The same functional group will undergo the same or similar chemical reaction regardless of the size of the molecule it is a part of...
s attached to the alkene must be able to donate electrons. Such alkenes are enol ether
Enol ether
An enol ether is an alkene with an alkoxy substituent. The general structure is R_1R_2C=CR_3-O-R_4 with R an alkyl or an aryl group. Enol ethers and enamines are so-called activated alkenes or electron rich alkenes because the oxygen atom donates electrons to the double bond by forming a resonance...
s and enamine
Enamine
An enamine is an unsaturated compound derived by the reaction of an aldehyde or ketone with a secondary amine followed by loss of H2O.The word "enamine" is derived from the affix en-, used as the suffix of alkene, and the root amine. This can be compared with enol, which is a functional group...
s. The reaction product in the original Povarov reaction is a quinoline
Quinoline
Quinoline is a heterocyclic aromatic organic compound. It has the formula C9H7N and is a colourless hygroscopic liquid with a strong odour. Aged samples, if exposed to light, become yellow and later brown...
. Because the reactions can be carried out with the three components premixed in one reactor it is an example of a multi-component reaction
Multi-component reaction
In chemistry, a multi-component reaction , sometimes referred to as a "Multi-component Assembly Process" , is a chemical reaction where three or more compounds react to form a single product...
.
Reaction mechanism
The reaction mechanismReaction mechanism
In chemistry, a reaction mechanism is the step by step sequence of elementary reactions by which overall chemical change occurs.Although only the net chemical change is directly observable for most chemical reactions, experiments can often be designed that suggest the possible sequence of steps in...
for the Povarov reaction to the quinoline
Quinoline
Quinoline is a heterocyclic aromatic organic compound. It has the formula C9H7N and is a colourless hygroscopic liquid with a strong odour. Aged samples, if exposed to light, become yellow and later brown...
is outlined in scheme 1. In step one 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...
and benzaldehyde
Benzaldehyde
Benzaldehyde is an organic compound consisting of a benzene ring with a formyl substituent. It is the simplest aromatic aldehyde and one of the most industrially useful. This colorless liquid has a characteristic pleasant almond-like odor...
react to the Schiff base
Schiff base
A Schiff base, named after Hugo Schiff, is a compound with a functional group that contains a carbon-nitrogen double bond with the nitrogen atom connected to an aryl or alkyl group, not hydrogen....
in a condensation reaction
Condensation 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,...
. The Povarov reaction requires a lewis acid
Lewis acid
]The term Lewis acid refers to a definition of acid published by Gilbert N. Lewis in 1923, specifically: An acid substance is one which can employ a lone pair from another molecule in completing the stable group of one of its own atoms. Thus, H+ is a Lewis acid, since it can accept a lone pair,...
such as boron trifluoride
Boron trifluoride
Boron trifluoride is the chemical compound with the formula BF3. This pungent colourless toxic gas forms white fumes in moist air. It is a useful Lewis acid and a versatile building block for other boron compounds.-Structure and bonding:...
to activate the imine
Imine
An imine is a functional group or chemical compound containing a carbon–nitrogen double bond, with the nitrogen attached to a hydrogen atom or an organic group. If this group is not a hydrogen atom, then the compound is known as a Schiff base...
for an electrophilic addition
Electrophilic addition
In organic chemistry, an electrophilic addition reaction is an addition reaction where, in a chemical compound, a π bond is broken and two new σ bonds are formed...
of the activated alkene
Alkene
In organic chemistry, an alkene, olefin, or olefine is an unsaturated chemical compound containing at least one carbon-to-carbon double bond...
. This reaction step forms an oxonium ion
Oxonium ion
The oxonium ion in chemistry is any oxygen cation with three bonds. The simplest oxonium ion is the hydronium ion H3O+. Another oxonium ion frequently encountered in organic chemistry is obtained by protonation or alkylation of a carbonyl group e.g...
which then reacts with the aromatic ring in a classical electrophilic aromatic substitution
Electrophilic aromatic substitution
Electrophilic aromatic substitution EAS is an organic reaction in which an atom, usually hydrogen, appended to an aromatic system is replaced by an electrophile...
. Two additional 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...
s create the quinoline ring structure.
Aza Diels-Alder reaction
The Aza Diels-Alder reaction converts imines and dienes to tetrahydropyridines. This organic reaction is a modification of the Diels-Alder reaction. The nitrogen atom can be part of the diene or the dienophile....
s
Examples
The reaction depicted in scheme 2 illustrates the Povarov reaction with an imineImine
An imine is a functional group or chemical compound containing a carbon–nitrogen double bond, with the nitrogen attached to a hydrogen atom or an organic group. If this group is not a hydrogen atom, then the compound is known as a Schiff base...
and an enamine
Enamine
An enamine is an unsaturated compound derived by the reaction of an aldehyde or ketone with a secondary amine followed by loss of H2O.The word "enamine" is derived from the affix en-, used as the suffix of alkene, and the root amine. This can be compared with enol, which is a functional group...
in the presence of yttrium
Yttrium
Yttrium is a chemical element with symbol Y and atomic number 39. It is a silvery-metallic transition metal chemically similar to the lanthanides and it has often been classified as a "rare earth element". Yttrium is almost always found combined with the lanthanides in rare earth minerals and is...
triflate
Triflate
Trifluoromethanesulfonate, also known by the trivial name triflate, is a functional group with the formula CF3SO3-. The triflate group is often represented by -OTf, as opposed to -Tf...
as the lewis acid
Lewis acid
]The term Lewis acid refers to a definition of acid published by Gilbert N. Lewis in 1923, specifically: An acid substance is one which can employ a lone pair from another molecule in completing the stable group of one of its own atoms. Thus, H+ is a Lewis acid, since it can accept a lone pair,...
. This reaction is regioselective because the iminium
Iminium
An iminium salt or cation in organic chemistry has the general structure [R1R2C=NR3R4]+ and is as such a protonated or substituted imine. It is an intermediate in many organic reactions such as the Beckmann rearrangement, Vilsmeier-Haack reaction, Stephen reaction or the Duff reaction...
ion preverentially attacks the nitro
Nitro compound
Nitro compounds are organic compounds that contain one or more nitro functional groups . They are often highly explosive, especially when the compound contains more than one nitro group and is impure. The nitro group is one of the most common explosophores used globally...
ortho position and not the para position. The nitro group is a meta directing substituent but since this position is blocked, the most electron rich ring position is now ortho and not para. The reaction is also diastereoselective
Diastereomer
Diastereomers are stereoisomers that are not enantiomers.Diastereomerism occurs when two or more stereoisomers of a compound have different configurations at one or more of the equivalent stereocenters and are not mirror images of each other.When two diastereoisomers differ from each other at...
because the enamine addition occurs with a preference for trans
Geometric isomerism
In organic chemistry, cis/trans isomerism or geometric isomerism or configuration isomerism or E/Z isomerism is a form of stereoisomerism describing the orientation of functional groups within a molecule...
addition without formation of the cis isomer.
Variations
One variation of the Povarov reaction is a four component reaction . Whereas in the traditional Povarov reaction the intermediate carbocationCarbocation
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,...
gives an 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 :...
reaction with the aryl group, this intermediate can also be terminated by an additional 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...
such as an 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....
. Scheme 3 depicts this 4 component reaction with the ethyl
Ethyl group
In chemistry, an ethyl group is an alkyl substituent derived from ethane . It has the formula -C2H5 and is very often abbreviated -Et.Ethylation is the formation of a compound by introduction of the ethyl functional group, C2H5....
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...
of glyoxylic acid
Glyoxylic acid
Glyoxylic acid or oxoacetic acid is an organic compound. Together with acetic acid, glycolic acid, and oxalic acid, glyoxylic acid is one of the C2 carboxylic acids. It is a colourless solid that occurs naturally and is useful industrially....
, 3,4-dihydro-2H-pyran, 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...
and ethanol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
with lewis acid
Lewis acid
]The term Lewis acid refers to a definition of acid published by Gilbert N. Lewis in 1923, specifically: An acid substance is one which can employ a lone pair from another molecule in completing the stable group of one of its own atoms. Thus, H+ is a Lewis acid, since it can accept a lone pair,...
scandium(III) triflate
Scandium(III) triflate
Scandium trifluoromethanesulfonate, commonly called scandium triflate, is a chemical compound with formula Sc3, a salt consisting of scandium cations Sc3+ and triflate SO3CF3− anions....
and molecular sieve
Molecular sieve
A molecular sieve is a material containing tiny pores of a precise and uniform size that is used as an adsorbent for gases and liquids.Molecules small enough to pass through the pores are adsorbed while larger molecules are not. It is different from a common filter in that it operates on a...
s.