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  Reactions of Benzopyrrole, Chemistry tutorial

Introduction:

Indole is the aromatic heterocyclic organic compound. It consists of a bicyclic structure, comprising of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring (figure shown below). Indole is a popular component of fragrances and the precursor to numerous pharmaceuticals. Compounds that have an indole ring are known as Indoles. The indolic amino acid tryptophan is the precursor of the neurotransmitter serotonin. Indole is solid at room temperature. Indole can be prepared by bacteria as a degradation product of the amino acid tryptophan. It takes place naturally in human faeces and consists of an intense faecal odor. At extremely low concentrations, though, it consists of a flowery smell and is a constituent of numerous flower scents (like orange blossoms) and perfumes. It as well takes place in coal tar.

206_Structure of Indole.jpg

Fig: Structure of Indole

General Physical and Chemical Properties of Indoles:

Indole is basically solid at room temperature having a melting point between 52 to 54ºC. Unlike most of the amines, indole is non basic. The bonding situation is entirely analogous to that in pyrrole. Very strong acids like hydrochloric acid are needed to protonate indole. The protonated form consists of a pKa of -3.6. The sensitivity of numerous indolic compounds (example: tryptamines) under acidic conditions is caused via this protonation.

Electrophilic Substitution:

The Electrophiles attack indole at C-3, instead of at C-2. This is the opposite result to that noticed for pyrroles, however can be described if the intermediates for each kind of reaction are considered. For a reaction at C-3, the energy of activation of the intermediate is lowered since it is possible to delocalize the positive charge via resonance comprising the nitrogen lone pair of electrons. This favorable condition is not possible in the corresponding intermediate for attack at C-2. Any effort to delocalize the positive charge would now disrupt the 6π-electron system of the benzene ring (figure shown below). 

1481_Electrophilic Substitution of Indole- C-3 versus C-2.jpg

Fig: Electrophilic Substitution of Indole- C-3 versus C-2

3-Substituted Indoles:

Sulphonation of the indole with pyridinium-N-sulphonate results indolyl-3-sulphonic acid, and bromine in pyridine at 0°C affords 3-bromoindole. Acetylation by a heated mixture of acetic anhydride and acetic acid provides 1,3-diacetylindole. Methylation needs heating by methyl iodide in DMF (N,N-dimethylformamide) at 80 to 90°C and results 3-methylindole. This compound reacts further, giving 2,3-dimethylindole and lastly 1,2,3,3-tetramethyl-3H-indoleninium iodide (figure shown below).

942_Reactions of Indole with Electrophiles.jpg

Fig: Reactions of Indole with Electrophiles

Vilsmeier Formylation:

Whenever DMF and phosphorus oxychloride are reacted altogether in the Vilsmeler reaction, the N,N-dimethylamino(chloro)methyleniminium cation is produced, and this reacts by indole at 5°C to provide 3-(N,N-dimethylaminomethylene)indolenine. Whenever hydrolyzed via treatment with dilute sodium hydroxide, this provides an excellent result of 3-formylindole (figure shown below).

850_Vilsmeier Formylation.jpg

Fig: Vilsmeier Formylation

Reaction with Triethyl Orthoformate (Triethoxymethane):

Triethyl orthoformate is often employed in reactions with enolates and carbanions to form diethyl acetals which on treatment by dilute acid provide the corresponding formyl derivatives.  Though, whenever indole is heated at around 160°C by triethyl orthoformate the locus of reaction is at N-1 instead of at C-3, and 1-(diethoxymethyl)indole is made (figure shown below). The N-substituent is simply eliminated via acidic hydrolysis to reform indole.

2105_Reaction on Indole with Triethyl Orthoformate.jpg

Fig: Reaction on Indole with Triethyl Orthoformate

Mannish Reaction:

The method of the Mannish reaction is identical to that of the Vilsmeier reaction as the electrophile is as well a methyleniminium cation, formed this time from a condensation of dimethylamine and formaldehyde in acetic acid solution (figure shown below). This reacts by indole to result 3-(N,N-dimethylaminomethyl)indole (though not shown, it is possible that initial attack takes place at N-1 and rearrangement of the side chain to C-3 occurs as a follow-up step (figure shown below).

2185_Mannish Reaction.jpg

Fig: Mannish Reaction

Formation of the Indoyl Anion; N-1 versus C-3 Substitution:

The indole anion is simply made up by reactions with bases like sodium hydride, sodamide, Grignard reagents or alkyllithium. However, the indolyl anion is resonance stabilized; the nature of the cation has an effect on the future reactions (as does the solvent utilized). Therefore, if the conjugate cation is not simply polarized, example: a sodium ion (or potassium ion), the indolyl anion is attacked at the site of highest electron density, that is, at N-1. Though, if the metal in the cation is magnesium, then it is supposed that partial covalent bonding to nitrogen prevents attack there. Now the electrophilic attack is diverted to the C-3.

N-Alkylation, -acylation and sulphonation are as well promoted through a polar solvent, like HMPA (hexamethylphosphoric triamide), DMF and DMSO. This acts to solvate the ions (that is, promoting dissociation), however in a non-polar solvent such as toluene, diethylether or tetrahydrofuran (THF), attack via most carbon electrophiles on indolylmagnesium bromide proceeds at C-3 (figure shown below).

652_N-1 versus C-3 Substitution.jpg

Fig: N-1 versus C-3 Substitution

C-2 Lithiation:

=> Carbon acidity and C-2 Lithiation:

After the N-H proton, the hydrogen at C-2 is the subsequent most acidic proton on indole. Reaction of N-protected Indoles by butyl lithium or lithium diisopropylamide yields in Lithiation exclusively at C-2 position. This strong nucleophile can then be employed as such by the other electrophiles.

Bergman and Venemalm developed a method for lithiating the 2-position of unsubstituted indole.

Ring Expansion with Dichlorocarbene:

Indole can be reacted by the dichlorocarbene to result 3-chloroquinoline (figure shown below).  Initially, the carbene adds across the C-2- C-3 double bond to form a cyclopropanoindole, this product then ring-expand by the removal of hydrogen chloride.

1241_Ring Expansion of Indole Ring with Dichlorocarbene.jpg

Fig: Ring Expansion of Indole Ring with Dichlorocarbene  

Reduction of Indole:

Indole can be reduced in Birch conditions (that is, lithium in liquid ammonia having hydrogen donor example: methanol) to provide a 4:1 mixture of 4,7-di and 4,5,6,7-tetrahydroindoles. Sodium cyanoborohydride (NaBH3CN) in acetic acid, though, makes indoline (2,3-dihydroindole). In this reduction, 3-protonation provides the indoleninium salt, which is then 'set-up' to experience hydride transfer at C-2 from the boron reagent (figure shown below).

1295_Reduction of Indole.jpg

Fig: Reduction of Indole

Oxidation of Indole:

Because of the electron-rich nature of indole, it is simply oxidized. Simple oxidants like N-bromosuccinimide will selectively oxidize indole 1 to oxindole (4 and 5).

82_Oxidation of Indole.jpg

Fig: Oxidation of Indole

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