Forming Nitrogen Heterocycles from Aliphatic Amino Acids

nitrogen heterocyclesHow are nitrogen heterocycles formed from aromatic amines?

Aliphatic hydrocarbons¹ take a number of forms. The simplest is written CH₃(CH₂)nCH₃, where n is a positive integer.²  Replace a hydrogen atom at one end of the chain with a carboxylic acid group (-COOH) and a hydrogen atom at the other end with an amino group (-NH₂), and you have a straight chain amino acid.

For instance, choose n = 3. That gives the molecule

HOOC-CH₂-CH₂-CH₂-CH₂-NH₂

Its name is 5-aminopentanoic acid or 5-aminovaleric acid.

nitrogen heterocyclesCyclization

Under the right conditions, this species can be cyclized to form an amine salt. The salt is then converted to a cyclic amide, a delta lactam. The lactam is next reduced to the amine piperidine. The overall process is illustrated in Fig. 1.

Nitrogen Heterocycles

A cyclic amine, a compound with nitrogen in the ring, is a nitrogen heterocycle. The prefix hetero- means “other.” Nitrogen “another” non-carbon atom. If the nitrogen is not within the ring, but is merely atttached to the ring, it is not a heterocycle. So aminocyclohexane, a six carbon atom ring with an attached amino group, is not a heterocycle.

nitrogen heterocyclesAdditional Examples

Another example is 2-methylpyrrolidine. It is prepared from 3-methyl-3-aminobutyric acid. The reaction is illustrated in Fig. 2.
A final example is the cyclization and reduction of 3-chloro-4-methyl-5-aminovaleric acid to form 2-methyl-3-chloro-piperidine. See Figure 3.

¹ An aliphatic compound is an organic compound characterized by an open chain, not rings.
² The letter C stands for carbon; the letter H stands for hydrogen.

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One thought on “Forming Nitrogen Heterocycles from Aliphatic Amino Acids

  • I ought to include an explanation of the amino acid becoming an amine salt. At that step, the acid -COOH group combines loosely with the amino group -NH2, to give -COO with a minus charge and -NH3 with a plus charge. Heating that releases water, producing the group -CONH- which is like the clasp on a string of beads. That structure, upon reduction, produces -CH2-NH- (in other words, the heterocyclic amine structure).

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