Structure Elucidation and Synthesis of Nicotine

Nicotine is a naturally occurring alkaloid found in tobacco plants (Nicotiana tabacum) in a range of 0.5 to 7.5% depending on variety. Nicotine is also found in the leaves of Nicotiana rustica, in amounts of 2–14%. Nicotine is a colorless leavorotatory liquid having molecular formula C₁₀H₁₄N₂ and has a boiling point of about 246°C. It acts as a stimulant in small doses, affecting the central nervous system by binding to nicotinic acetylcholine receptors. Natural form of nicotine is (-) –form with specific rotation value -169°.

Structure Elucidation of Nicotine

1. Elemental analysis and molecular weight determine the molecular formula of nicotine is C₁₀H₁₄N₂.

2. Both the nitrogen atoms found to be present at tertiary because nicotine takes up two molecules of methyl iodide to form a dimethiodide. Under suitable conditions it also forms two isomeric monomethiodides. One of the tertiary nitrogen atoms is found to be N-methyl group.

3. Nicotine on oxidation gives nicotinic acid (pyridine 3-carboxylic acid) indicating that nicotine is 3-substituted pyridine.
By subtracting the molecular formula of a substituted pyridine (C₅H₄N) from the molecular formula of nicotine (C₁₀H₁₄N₂) it is obvious that the side chain at position 3 is C₅H₁₀N.

4. Position and Nature of Side Chain:

A. Nicotine absorbs only three molecules of hydrogen to form hexahydro derivative suggesting that the side chain is saturated since three moles of hydrogen are required by pyridine nucleus of the nicotine.

B. Now since, the nitrogen atom of pyridine moiety is present as —N=, the nitrogen atom of the side chain must possess the methyl group (point 2). This is confirmed by the fact that when nicotine is heated with concentrated hydroidic acid at 150°, methyl iodide is formed. Thus, the side chain having N-methyl group can be extracted as C₄H₇NCH₃. C. Nicotine forms an addition product zincichloride with zinc chloride. The zincichloride product on heating with lime gives pyridine, pyrrole and methyl amine.

This step clearly indicated that the side chain is pyrrole derivative but we have already pointed out that the side chain is reduced and has one N-CH₃ group. It is N-methyl pyrrolidine.
The point of attachment of the side chain (N-methylprrolidine) to the 3-position of the pyridine nucleus could be either 2 or 3 (α or β). Thus the side chain of nicotine may be represented as below-

4. On treatment with methyl iodide, nicotine hydrochloride gives nicotine nicotine isomethiodide which on oxidation with potassium ferricycanide followed by dichromate oxidation gives N-methylproline (hygrinic acid). The formation of N-methylproline suggests beyond doubt that the pyrrolidine unit is attached to position-3 of the pyridine nucleus by means of α-position.

5. On the basis of above points nicotine may be written as below which explains all the reactions.

The above structure of nicotine was confirmed by its synthesis

Synthesis of Nicotine

Synthesis of Nicotine by Spath et al. (1982)

This synthesis involves the claisen condensation of ethyl nicotinate with N-methyl-2-pyrrolidone.

Synthesis of Nicotine by Craig et al. (1933)

Source: Chemistry of Organic Natural Products Vol.-1 O. P. Agrawal