Structure Elucidation and Synthesis of Nicotine

Structure Elucidation of Nicotine

1. Elemental analysis and molecular weight determination shows that the molecular formula of nicotine is C₁₀H₁₄N₂.
2. Both the nitrogen atoms are found to be present as tertiary because it takes up two molecules of methyl iodide to form a dimethiodide. From Herzig-Meyer reaction, one of the tertiary nitrogen is found to be –NCH₃ group.

C₁₀H₁₄N₂ + 2CH₃I → C₁₀H₁₄(N-CH₃)₂

3. On oxidation with KMnO₄ or Chromic acid, nicotinic acid is formed which indicates that nicotine is 3-substituted pyridine. This indicates the side chain at position 3 is C₅H₁₀N.

Structure of Side Chain

A. Nicotine absorbs only three moles of hydrogen to form hexahydro derivative suggesting that the side chain is saturated.

B. Nicotine forms an addition product zincichloride with zinc chloride which on heated with lime gives pyridine, pyrrol and methyl amine.

This step indicates that the side chain is pyrrole derivatives and according to step two, the nitrogen of pyrrole is as –NCH₃.
C. The point of attchment of side chain to the 3rd position of pyridine is eithe r 2 or 3(α or β), Thus the side chain may be written as-

D. On treatment with methyl iodide, nicotine hydriodide gives nicotine isomethiodide which on oxidation with potassium ferricynide followed by dichromate oxidation gives N-methyl proline (hygrinic acid). This indicates that the pyrrolidine ring is bonded to pyridine ring through 2-position.

4. On the basis of above facts nicotine may be written as-

Finally the structure of nicotine was confirmed by the following synthesis accomplished by Spath(1928).

Synthesis of Nicotine