Indol

The indol is a Composé aromatic organics heterocyclic. The name indol is derived from the Indigo, a blue pigment whose molecule contains two grouping welded indols. It can be described schematically as being formed of a benzene cycle and a coupled cycle pyrrole. The electronic doublet carried by the Atome of Azote in the Représentation of Lewis takes part in the aromatic delocalization. Contrary to the traditional amine S, indol is thus not a base since the aromatic character is lost in the event of Chemical reaction bringing into play this doublet.

Indol is a solid compound with the room temperature, which has an intense odor of fecal Matière. On the other hand with weak concentrations, it has a flowered odor, and is constituent of a great number of perfumes.

Indol is naturally present in the coal tar. The structure indol is present in many organic compounds like the Tryptophane (an Amino-acid ) like in the Protéine S containing of tryptophan, in Alcaloïde S and Pigment S.

Indol can undergo a aromatic Substitution électrophile, mainly in position 3. The compounds of substituted the indol type constitute the basic blocks of alkaloids of the type Tryptamine like the Sérotonine (a Neurotransmetteur), the Mélatonine, the Psilocybine (a substance Hallucinogène), the Diméthyltryptamine, the 5-MeO-DMT or LSD. Among the others made up derived from indol, one can quote the Auxine (a Hormone of the Plante S), the Indométacine (an anti-inflammatory drug) or the Pindolol (a Bêta-bloquant)

History

The chemistry of indol started to develop with the study of the Indigo, pigment of blue color. This one was transformed into Isatine then in Oxindole (Oxyde of indol). In 1866, Adolf von Baeyer (Nobel Prize of chemistry in 1917), managed to to reduce the indol oxindole by using dust of Zinc like reducer. He proposed a Chemical formula for this new compound in 1869 (left).

Some derived from indol were used as dyes until the end of the 19th century. The interest for made up increased during the years 1930, when it was discovered that indol is a brick constitutive of a great number of Alcaloïde S, as well as Auxine S and Tryptophane. Indol remains a compound very studied and used at present.

Synthesis and production of indol

The principal industrial method of production of indol is the Distillation coal tar, whose indol is one of the important components. Indol is contained in the fraction of distillate obtained between 220°C and 260°C.
Indol and its derivatives can also be synthesized by a large variety of chemical reactions. This chapter does not present all the techniques of synthesis in an exhaustive way but a historical panorama.

Synthesis of Bischler-Möhlau

Developed during the decade 1880, the method of Bischler-Möhlau is one of the very first techniques of synthesis of indol. During the reaction, α-bromo- Acétophénone reacts with an excess of Aniline in medium Acide to form an 2-aryl-indol. However, it does not make it possible to directly prepare indol not substituted.

Mechanism of the synthesis of Bischler-Möhlau

Although the reaction implements simple reagents, its mechanism is relatively complex. The first two stages are consisted the reaction of α-bromo-acetophenone with two aniline molecules to form the intermediary 4 . In this intermediary, aniline charged positively is a good group therefore and the compound can cycliser to form the intermediary 5 . This one undergoes a fast deprotonation which makes it aromatic, then a Tautomérie leading to substituted indol.

References

Bischler, A. and Al ; Chemische Berichte 1892 , 25 , 2860.
Bischler, A. and Al ; Chemische Berichte 1893 , 26 , 1336.
Möhlau, R.; Chemische Berichte 1881 , 14 , 171.
Möhlau, R.; Chemische Berichte 1882 , 15 , 2480.

Synthesis of Fischer

Synthesis of Reissert

Proposed in 1897, the synthesis of Reissert is one of the first to allow the indol synthesis not substituted , in three stages starting from ortho-nitrotoluene ( 1 ).

Mechanism of the synthesis of Reissert

During the first stage, the grouping Méthyle of ortho-nitrotoluene ( 1 ) is déprotoné in strongly basic medium (presence of éthanolate in the NaOEt form), which allows its condensation with the diéthyloxalate ( 2 ) to form the éthyl o-nitrophénylpyruvate ( 3 ) (with regeneration of NaOEt). The second stage consists of a reduction /cyclisation in the presence of Zinc in the acetic Acid to form 2-carboxy-indol ( 4 ). This one can be décarboxylé by simple heating to form indol ( 5 ).

Reference

Reissert, A. Chemische Berichte 1897 , 30 , 1030.

Synthesis of Madelung

The synthesis of Madelung, developed in 1912, is a reaction allowing the manufacture of indol (substituted or not substituted) by the intramolecular cyclization of N-phénylamide. It is done at high temperature in the presence of a bases strong.

This method with the disadvantage of being carried out starting from a starting reagent having to be itself synthesized. It thus constitutes only the last stage of a feedback path passing by N-phénylamide.

References

Madelung, W.; Chemische Berichte 1912 , 45 , 1128.

Synthesis of Leimgruber-Batcho

The method of synthesis of the indol of Leimgruber-Batcho, discovered and patented in 1976, makes it possible to prepare indol and derivatives substituted with a good output. It is particularly used in the drug company to prepare Médicaments of which the structure contains derivatives indols.

This synthesis is carried out in two stages, starting from ortho-nitrotoluene. This one is initially transformed into a énamine, which is then reduced to obtain indol.

The stage of reduction above (2 to 3) uses Nickel of Raney and Hydrazine. Those can be replaced indifferently by Chlorure of tin II or Fer in the acetic Acid .

This synthesis was very much used in industry well before the method is published in the scientific literature. The good control of a method of synthesis of indol is indeed important for the drug company, of many derivatives of indol being used like active ingredient in drugs. This method became a very popular alternative to the method of Fischer, because of many derivatives of ortho-nitrotoluene are available commercially or easy to prepare. Moreover, this method is characterized by an output raised under conditions of synthesis " douces".

Mechanism of the synthesis of Leimgruber-Batcho

During the first stage of the reaction (formation of the énamine), the Pyrrolidine reacts with the diméthylformamide diméthylacétal while eliminating from the Diméthylamine (DMA, gas), which makes it possible to make it more reactive. The grouping Méthyle of nitrotoluene can be déprotoné, and the Carbanion which results from it can attack activated pyrrolidine, which leads to the énamine with a simultaneous elimination of Méthanol. The reaction can also be implemented without pyrrolidine by using NR, N-diméthylenamine, but the reaction is then definitely slower.

During the second stage, grouping - NO₂^- is reduced in - NH₂ by using Dihydrogène and Nickel of Raney as Catalyze ur, reduction followed by a elimination of pyrrolidine leading to indol. The dihydrogene is generally produced in-situ by the spontaneous decomposition of the Hydrazine in the presence of nickel.

References

Batcho, A.D.; Leimgruber, W.U.S. Obvious # 3,976,639
Batcho, A.D.; Leimgruber, W. Organic Syntheses 1985 , 63 , 214-220. (Article)

Use of Indol

The natural gasoline of Jasmin used in Parfum ery contains approximately indol 2,5%. The production of 1 kg of natural gasoline requires several million flowers and costs about 10.000 $. Indol is thus used (among others made up) to manufacture synthetic jasmine perfume, at a cost of about 10 $/kg.

Indol is égalment the starting reagent of the synthesis of a great number of organic compounds: Pigment S, components of Perfume S, Drug S…

Chemical reactions bringing into play Indol

Basic character of the doublet of nitrogen

Although the Atome of Azote has a free doublet (two electron S not taking part in the chemical bonds), indol is definitely less Basique that the amine S or that the Aniline. Indeed, this doublet of electron is delocalized and takes part in the aromaticity of the system. The basic form (indol) is thus definitely more stable than the form Acide (protonic) for which the aromaticity is lost. The protonic form has a constant acidity pKa=-3,6. It is thus necessary to use a Strong acid (like the Hydrochloric acid ), for protoner a significant fraction of indol.

Aromatic substitution électrophile

Because of its aromatic character , indol can undergo a aromatic Substitution électrophile (substitution of an atom of Hydrogène by a grouping électrophile. The most reactive position with respect to aromatic substitution électrophile is the position C-3 (which is approximately 1000 times more reactive than those located on the benzene cycle). For example, at the time of a formylation of Vilsmeier-Haack carried out with the room temperature, only the C-3 position is substituted (see diagram).

The positions located on the cycle Pyrrole being more reactive, aromatic substitutions électrophiles of the benzene cycle can take place only when the positions N-1, C-2 and C-3 underwent a substitution.

Among the compounds obtained by this type of reactions one can quote the Gramine, an important intermediary of synthesis, manufactured starting from indol, of Diméthylamine and Formaldéhyde by the Réaction of Mannich.

Acid character of the hydrogen atom related to nitrogen

The hydrogen atom carried by nitrogen has a weak character Acide, with a constant of acidity pKa=21 in DMSO. The deprotonation of the nitrogen atom thus requires the use of a bases very strong like the Hydrure of sodium or the Butyl lithium, and a medium completely Anhydre. The salts resulting from the deprotonation can react in two manners. Ionic salts very like salts of Sodium or Potassium react preferentially by an attack électrophile on the nitrogen atom (way of left on the diagram). Contrary, covalent salts more , in particular the Organo-magnesian S (reactive of Hard grindstone) and the complex containing Zinc, react preferentially via carbon C-3 (way of right-hand side on the diagram). In the same way, the Solvant used influences the reaction: the solvents Polar S and Aprotique S like DMF or DMSO support a reaction by the nitrogen atom, while the non-polar solvents as the Toluène support a reaction by C-3 carbon.

Acidity of carbon, lithiation of position 2

In term of Acidity, the most acid hydrogen atom after that related to the nitrogen atom is that related to the carbon atom in position 2. On the condition of carrying out a protection of the nitrogenized function initially, it is thus possible of déprotoner carbon in position 2, by using for example Butyl lithium or Diisopropylamide lithium (LDA). The resulting Carbanion is nucleophilic very powerful, which can thus react with compounds électrophiles. (example:

Oxidation of indol

Indol is a compound rich in electron S (10 electrons delocalized on the cycles) which can be easily oxidized. For example, the N-Bromosuccinimide makes it possible to oxidize indol ( 1 ) in a selective way to form the Oxindole ( 4 in balance with 5 ).

Cycloadditions

The connections π carried by the carbon atoms in positions C-2 and C-3 can react in reactions of the type cycloaddition (Réaction of Diels-Alder). The intermolecular reactions are not favorable. On the other hand, the intramolecular reactions (using substituted derivatives of indol) make it possible to obtain good outputs. In the example presented below, indol is the Diénophile and the 2-aminofurane is the Diène.

Safety

Indol can strongly react with the Oxydant S forts. It is a compound irritating for the eyes. In the event of ingestion, it is irritating for the mouth, the throat, the esophagus and the digestive tract.

Sentences of risk and councils of prudence

R: 21/22 (Harmful by contact with the skin and ingestion)
R: 36 (Irritating for the eyes)
R: 50 (Very toxic for the watery organizations)
S: 36/37 (To wear clothing protective and gloves suitable)
S: 61 (To avoid the rejection in the environment. To consult the instructions spéciales/la card of data of safety)

General references

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