Bischler-Napieralski reaction
Encyclopedia
The Bischler–Napieralski reaction is an intramolecular electrophilic aromatic substitution
reaction that allows for the cyclization of β-arylethylamides or β-arylethylcarbamates. It was first discovered in 1893 by August Bischler
and Bernard Napieralski, in affiliation with Basle Chemical Works and the University of Zurich
. The reaction is most notably used in the synthesis of dihydroisoquinolines, which can be subsequently dehydrated
to isoquinolines.
Two types of mechanisms have appeared in literature for the Bischler–Napieralski reaction. Mechanism I involves a dichlorophosphoryl imine-ester intermediate, while Mechanism II involves a nitrilium ion intermediate (both shown in brackets). This mechanistic variance stems from the ambiguity over the timing for the elimination
of the carbonyl
oxygen in the starting amide
. In Mechanism I, the elimination occurs with imine
formation after cyclization; while in Mechanism II, the elimination yields the nitrilium intermediate prior to cyclization. Currently, it is believed that different reaction conditions affect the prevalence of one mechanism over the other (see reaction conditions).
In certain literature, Mechanism II is augmented with the formation of an imidoyl chloride intermediate produced by the substitution
of chloride for the Lewis acid
group just prior to the nitrilium ion.
Because the dehydroisoquinoline nitrogen is basic, neutralization is necessary to obtain the deprotonated product.
(POCl3) is widely used and cited for this purpose. Additionally, SnCl4 and BF3 etherate have been used with phenethylamides, while Tf2O and polyphosphoric acid (PPA, a.k.a. Eaton's reagent
) have been used with phenethylcarbamates. For reactants lacking electron-donating groups on the benzene
ring, phosphorus pentoxide
(P2O5) in refluxing POCl3 is most effective. Depending on the dehydrating reagent used, the reaction temperature varies from room temperature to 100°C.
proceeds from a β-arylamine via condensation
with an aldehyde
. The Picter-Gams reaction proceeds from an α-hydroxy-β-phenethylamide and culminates in isoquinoline via condensation instead of dehydrogenation.
There are documented variations on the Bischler–Napieralski reaction whose products differ in virtue of either the structure of the initial reactant, the tailoring of reaction conditions, or both. For example, research done by Doi and colleagues suggests that the presence or absence of electron-donating groups on the aryl
portion of β-arylethylamides and the ratio of dehydrating reagents influence the patterns of ring closure via electrophilic aromatic substitution
, leading to two possibilities for product (see below). Other research on the variations on the Bischler-Napieralski Reaction have investigated the effects of nitro
and acetal
aryl groups on product formation (for further information, see references).
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...
reaction that allows for the cyclization of β-arylethylamides or β-arylethylcarbamates. It was first discovered in 1893 by August Bischler
August Bischler
August Bischler was a Crimea German, Swiss chemist who together with Bernard Napieralski discovered the Bischler-Napieralski reaction.-Life:...
and Bernard Napieralski, in affiliation with Basle Chemical Works and the University of Zurich
University of Zurich
The University of Zurich , located in the city of Zurich, is the largest university in Switzerland, with over 25,000 students. It was founded in 1833 from the existing colleges of theology, law, medicine and a new faculty of philosophy....
. The reaction is most notably used in the synthesis of dihydroisoquinolines, which can be subsequently dehydrated
Dehydration reaction
In chemistry and the biological sciences, a dehydration reaction is usually defined as a chemical reaction that involves the loss of water from the reacting molecule. Dehydration reactions are a subset of elimination reactions...
to isoquinolines.
Mechanisms
Two types of mechanisms have appeared in literature for the Bischler–Napieralski reaction. Mechanism I involves a dichlorophosphoryl imine-ester intermediate, while Mechanism II involves a nitrilium ion intermediate (both shown in brackets). This mechanistic variance stems from the ambiguity over the timing for the elimination
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...
of 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....
oxygen in the starting 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...
. In Mechanism I, the elimination occurs with 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...
formation after cyclization; while in Mechanism II, the elimination yields the nitrilium intermediate prior to cyclization. Currently, it is believed that different reaction conditions affect the prevalence of one mechanism over the other (see reaction conditions).
In certain literature, Mechanism II is augmented with the formation of an imidoyl chloride intermediate produced by the substitution
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...
of chloride for 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,...
group just prior to the nitrilium ion.
Because the dehydroisoquinoline nitrogen is basic, neutralization is necessary to obtain the deprotonated product.
General Reaction Reagents/Conditions
The Bischler–Napieralski reaction is carried out in refluxing acidic conditions and requires a dehydrating agent. Phosphoryl chloridePhosphoryl chloride
Phosphoryl chloride is a colourless liquid with the formula 3. It hydrolyses in moist air to phosphoric acid to release choking fumes of hydrogen chloride. It is manufactured industrially on a large scale from phosphorus trichloride and oxygen or phosphorus pentoxide...
(POCl3) is widely used and cited for this purpose. Additionally, SnCl4 and BF3 etherate have been used with phenethylamides, while Tf2O and polyphosphoric acid (PPA, a.k.a. Eaton's reagent
Eaton's reagent
Eaton's reagent is used as an alternative to polyphosphoric acid in chemical synthesis to promote acylation reactions....
) have been used with phenethylcarbamates. For reactants lacking electron-donating groups on the benzene
Benzene
Benzene is an organic chemical compound. It is composed of 6 carbon atoms in a ring, with 1 hydrogen atom attached to each carbon atom, with the molecular formula C6H6....
ring, phosphorus pentoxide
Phosphorus pentoxide
Phosphorus pentoxide is a chemical compound with molecular formula P4O10 . This white crystalline solid is the anhydride of phosphoric acid. It is a powerful desiccant.-Structure:...
(P2O5) in refluxing POCl3 is most effective. Depending on the dehydrating reagent used, the reaction temperature varies from room temperature to 100°C.
Related Reactions and Variations
Several reactions that are related to the Bischler–Napieralski reaction are known. The Pictet-Spengler reactionPictet-Spengler reaction
The Pictet–Spengler reaction is a chemical reaction in which a β-arylethylamine such as tryptamine undergoes ringclosure after condensation with an aldehyde or ketone. Usually an acidic catalyst is employed and the reaction mixture heated, but some reactive compounds give good yields even at...
proceeds from a β-arylamine via condensation
Condensation
Condensation is the change of the physical state of matter from gaseous phase into liquid phase, and is the reverse of vaporization. When the transition happens from the gaseous phase into the solid phase directly, the change is called deposition....
with 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....
. The Picter-Gams reaction proceeds from an α-hydroxy-β-phenethylamide and culminates in isoquinoline via condensation instead of dehydrogenation.
There are documented variations on the Bischler–Napieralski reaction whose products differ in virtue of either the structure of the initial reactant, the tailoring of reaction conditions, or both. For example, research done by Doi and colleagues suggests that the presence or absence of electron-donating groups on the aryl
Aryl
In the context of organic molecules, aryl refers to any functional group or substituent derived from an aromatic ring, be it phenyl, naphthyl, thienyl, indolyl, etc....
portion of β-arylethylamides and the ratio of dehydrating reagents influence the patterns of ring closure via 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...
, leading to two possibilities for product (see below). Other research on the variations on the Bischler-Napieralski Reaction have investigated the effects of 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...
and acetal
Acetal
An acetal is a molecule with two single-bonded oxygen atoms attached to the same carbon atom.Traditional usages distinguish ketals from acetals...
aryl groups on product formation (for further information, see references).