INTRODUCTION There are many different cyclization reactions that produce nitrogen heterocycles, with — Organic Chemistry Chemistry Question

INTRODUCTION
There are many different cyclization reactions that produce nitrogen heterocycles, with the Paal–Knorr synthesis being one of the most general. In this reaction, a 1,4-dicarbonyl compound is heated with ammonia or a primary amine to produce a pyrrole.
As an example, the condensation of aniline with 2,5-hexanedione leads to 2,5-dimethyl^-1-phenylpyrrole (1) (a N-substituted pyrrole) that can be easily carried out in a 3h-undergraduate organic laboratory.

REACTION AND MECHANISM
The reaction, which takes place, is the following:
[VISUAL]
In the first step, the amino–group of aniline attacks one of the protonated carbonyl groups of the 2,5-hexanedione. Afterwards, a second intramolecular nucleophilic attack takes place, resulting in cyclization. Finally, the cyclic compound undergoes two successive dehydrations under acidic treatment to form the final product. The driving force for the two dehydration reactions is the formation of an aromatic system. The proposed mechanism is shown in Scheme 1.
[VISUAL]

EXPERIMENTAL
List of chemicals
- Methanol
- Aniline
- 2,5–Hexanedione
- Concentrated HCl solution
- HCl solution (c = 0.05 mol dm –3)

List of equipment for each student
- round–bottomed flask, 25 cm₃ (1)
- condenser (1)
- micrograded syringes (3)
- Erlenmeyer flask, 10 cm₃ (1)
- volumetric cylinder, 5 cm₃ (1)
- Pasteur pipettes (5)
- conical sintered–glass funnel (1)
- metal spatula (1)
- capillary tubes (10)
- TLC plates (5)
- developing chamber (1)
- Eppendorf tubes (3)
- test tubes (diameter 1 cm, length ca. 10 cm) (2)
- 100 cm₃-beaker sand bath on heating plates (1)
- Ice
- UV–lamp (254 nm)
- eluent (Ethyl acetate–Hexane 1:3)
- balance

Experimental
Synthesis of 2,5-Dimethyl^-1-phenylpyrrole:
To a 25 cm₃ round–bottomed flask equipped with a reflux condenser, add 186 mg (2.0 mmol) of aniline, 228 mg (2.0 mmol) of 2,5-hexanedione, 0.5 cm₃ of methanol, and 1 drop of concentrated HCl. Heat the mixture (sand bath) to reflux for 15 min, and then add the reaction mixture to 5.0 cm₃ of HCl solution (c = 0.5 mol dm–3), which is kept cool in an ice bath.
The crystals formed are collected by suction filtration and recrystallized from 1 cm₃ of 9 : 1 methanol/water. The isolated recrystallized product is washed twice with 1 cm₃ of the same mixture of methanol/water, and pressed dry on the filter. The solid is then transferred on a piece of filter paper in order to dry further. The dry product is placed in a tare–weighed Eppendorf. The sample tube is closed and weighed. A small amount (ca. 3–5 mg) of the product is placed in another Eppendorf and dissolved in a few drops (~5) of acetone. By means of a capillary tube place a drop of this solution on a TLC plate.
A similarly prepared sample of the starting material (aniline) is applied next to the product, as a reference, and the TLC plate is developed with a 1:3 mixture of ethyl acetate–hexane. The plate is observed under UV light (254 nm) and the spots on the plate are drawn with a pencil. The sample tube with the rest of the product is labeled with the name of the product and is given to the supervisor.