The Bischler–Napieralski reaction is an intramolecular
electrophilic aromatic substitution
Electrophilic aromatic substitution (SEAr) is an organic reaction in which an atom that is attached to an aromatic ring, aromatic system (usually hydrogen) is replaced by an electrophile. Some of the most important electrophilic aromatic substitut ...
reaction that allows for the
cyclization
A cyclic compound (or ring compound) is a term for a compound in the field of chemistry in which one or more series of atoms in the compound is connected to form a ring. Rings may vary in size from three to many atoms, and include examples where ...
of β-arylethylamides or β-arylethylcarbamates. It was first discovered in 1893 by
August Bischler
August Bischler (29 April 1865 – 26 May 1957) was a Russian Empire-born ethnic Crimea German chemist who later emigrated to Switzerland. He discovered the Bischler–Möhlau indole synthesis reaction in 1892 and, together with Bernard Napier ...
and , in affiliation with
Basel
Basel ( ; ), also known as Basle ( ), ; ; ; . is a city in northwestern Switzerland on the river Rhine (at the transition from the High Rhine, High to the Upper Rhine). Basel is Switzerland's List of cities in Switzerland, third-most-populo ...
Chemical Works and the
University of Zurich
The University of Zurich (UZH, ) is a public university, public research university in Zurich, Switzerland. It is the largest university in Switzerland, with its 28,000 enrolled students. It was founded in 1833 from the existing colleges of the ...
. The reaction is most notably used in the synthesis of dihydroisoquinolines, which can be subsequently
oxidized
Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...
to
isoquinolines
Isoquinoline is an individual chemical specimen - a heterocyclic aromatic organic compound - as well as the name of a family of many thousands of natural plant alkaloids, any one of which might be referred to as "an isoquinoline". It is a struc ...
.
Mechanisms
Two types of mechanisms have appeared in the 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
In organic chemistry, a carbonyl group is a functional group with the formula , composed of a carbon atom double bond, double-bonded to an oxygen atom, and it is divalent at the C atom. It is common to several classes of organic compounds (such a ...
oxygen in the starting
amide
In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a chemical compound, compound with the general formula , where R, R', and R″ represent any group, typically organyl functional group, groups or hydrogen at ...
.

In Mechanism I, the elimination occurs with
imine
In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bon ...
formation ''after'' cyclization; while in Mechanism II, the elimination yields the nitrilium intermediate ''prior'' to cyclization. Currently, it is believed that reaction conditions affect the prevalence of one mechanism over the other (see
reaction conditions
A chemical reaction is a process that leads to the chemical transformation of one set of chemical substances to another. When chemical reactions occur, the atoms are rearranged and the reaction is accompanied by an energy change as new products ...
).

In certain literature, Mechanism II is augmented with the formation of an
imidoyl chloride Imidoyl chlorides are organic compounds that contain the functional group RC(NR')Cl. A double bond exist between the R'N and the carbon centre. These compounds are analogues of acyl chloride. Imidoyl chlorides tend to be highly reactive and are m ...
intermediate produced by the
substitution
Substitution may refer to:
Arts and media
*Substitution (poetry), a variation in poetic scansion
* Substitution (theatre), an acting methodology
Music
*Chord substitution, swapping one chord for a related one within a chord progression
*Tritone ...
of chloride for the
Lewis acid
A Lewis acid (named for the American physical chemist Gilbert N. Lewis) is a chemical species that contains an empty orbital which is capable of accepting an electron pair from a Lewis base to form a Lewis adduct. A Lewis base, then, is any ...
group just prior to the nitrilium ion.
Because the dihydroisoquinoline nitrogen is basic, neutralization is necessary to obtain the deprotonated product.
General reaction reagents and conditions
The Bischler–Napieralski reaction is carried out in
refluxing
Reflux is a technique involving the condensation of vapors and the return of this condensate to the system from which it originated. It is used in industrial and laboratory distillations. It is also used in chemistry to supply energy to reactions ...
acidic conditions and requires a
dehydrating agent.
Phosphoryl chloride
Phosphoryl chloride (commonly called phosphorus oxychloride) is a colourless liquid with the formula . It hydrolyses in moist air releasing phosphoric acid and fumes of hydrogen chloride. It is manufactured industrially on a large scale from phosp ...
(POCl
3) is widely used and cited for this purpose. Additionally,
SnCl4 and
BF3 etherate have been used with phenethylamides, while
Tf2O and
polyphosphoric acid
In chemistry, a phosphoric acid, in the general sense, is a phosphorus acid, phosphorus oxoacid in which each phosphorus (P) atom is in the oxidation state +5, and is chemical bond, bonded to four oxygen (O) atoms, one of them through a double b ...
(PPA) have been used with phenethylcarbamates. For reactants lacking
electron-donating
Electron-rich is jargon that is used in multiple related meanings with either or both kinetic and thermodynamic implications:
* with regards to electron-transfer, electron-rich species have low ionization energy and/or are reducing agents. Tetr ...
groups on the
benzene
Benzene is an Organic compound, organic chemical compound with the Chemical formula#Molecular formula, molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar hexagonal Ring (chemistry), ring with one hyd ...
ring,
phosphorus pentoxide
Phosphorus pentoxide is a chemical compound with molecular formula Phosphorus, P4Oxygen, O10 (with its common name derived from its empirical formula, P2O5). This white crystalline solid is the anhydride of phosphoric acid. It is a powerful desic ...
(P
2O
5) in refluxing POCl
3 is most effective. Depending on the dehydrating reagent used, the reaction temperature varies from room temperature to 100 °C.
Related reactions
Several reactions that are related to the Bischler–Napieralski reaction are known. In the
Morgan–Walls reaction
Phenanthridine is a nitrogen heterocyclic compound with the formula . It is a colorless solid, although impure samples can be brownish. It is a precursor to DNA-binding fluorescent dyes through intercalation. Examples of such dyes are ethidiu ...
, the linker between the aromatic ring and the amide nitrogen is an ''ortho''-substituted aromatic ring. This ''N''-acyl 2-aminobiphenyl cyclizes to form a
phenanthridine
Phenanthridine is a nitrogen heterocyclic compound with the formula . It is a colorless solid, although impure samples can be brownish. It is a precursor to DNA-binding fluorescent dyes through intercalation. Examples of such dyes are ethidiu ...
. The
Pictet–Spengler reaction
The Pictet–Spengler reaction is a chemical reaction in which a β-arylethylamine undergoes Condensation reaction, condensation with an aldehyde or ketone followed by ring closure. The reaction was first discovered in 1911 by Amé Pictet and The ...
proceeds from a β-arylamine via
condensation
Condensation is the change of the state of matter from the gas phase into the liquid phase, and is the reverse of vaporization. The word most often refers to the water cycle. It can also be defined as the change in the state of water vapor ...
with an
aldehyde
In organic chemistry, an aldehyde () (lat. ''al''cohol ''dehyd''rogenatum, dehydrogenated alcohol) is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred ...
. These two components form an imine, which then cyclizes to form a tetrahydroisoquinoline.
Pictet–Gams reaction
The Pictet–Gams reaction proceeds from an β-hydroxy-β-phenethylamide. It involves an additional dehydration under the same conditions as the cyclization, giving an
isoquinoline
Isoquinoline is an individual chemical specimen - a heterocyclic aromatic organic compound - as well as the name of a family of many thousands of natural plant alkaloids, any one of which might be referred to as "an isoquinoline". It is a struc ...
.
As with the Bischler–Napieralski reaction, the Pictet–Gams reaction requires a strongly dehydrating Lewis acid, such as phosphoryl chloride or phosphorus pentoxide.
Structural effects and alternate products
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
In organic chemistry, an aryl is any functional group or substituent derived from an aromatic ring, usually an aromatic hydrocarbon, such as phenyl and naphthyl. "Aryl" is used for the sake of abbreviation or generalization, and "Ar" is used ...
portion of β-arylethylamides and the ratio of dehydrating reagents influence the patterns of ring closure via
electrophilic aromatic substitution
Electrophilic aromatic substitution (SEAr) is an organic reaction in which an atom that is attached to an aromatic ring, aromatic system (usually hydrogen) is replaced by an electrophile. Some of the most important electrophilic aromatic substitut ...
, leading to two possible products (see below). Other research on the variations on the Bischler-Napieralski Reaction have investigated the effects of
nitro
Nitro may refer to:
Chemistry
*Nitrogen, a chemical element and a gas except at very low temperatures, with which many compounds are formed:
**Nitro compound, an organic compound containing one or more nitro functional groups, -NO2
**Nitro ligand ...
and
acetal
In organic chemistry, an acetal is a functional group with the connectivity . Here, the R groups can be organic fragments (a carbon atom, with arbitrary other atoms attached to that) or hydrogen, while the R' groups must be organic fragments n ...
aryl groups on product formation (see
references
A reference is a relationship between Object (philosophy), objects in which one object designates, or acts as a means by which to connect to or link to, another object. The first object in this relation is said to ''refer to'' the second object. ...
).
:
See also
*
Pomeranz–Fritsch reaction
The Pomeranz–Fritsch reaction, also named Pomeranz–Fritsch cyclization, is a named reaction in organic chemistry. It is named after Paul Fritsch (chemist), Paul Fritsch (1859–1913) and Cäsar Pomeranz (1860–1926). In general it is a synth ...
References
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{{DEFAULTSORT:Bischler-Napieralski Reaction
Nitrogen heterocycle forming reactions
Heterocycle forming reactions
Name reactions