Coniine is a toxic alkaloid obtained from poisonous hemlock plants. It is a secondary amine and its molecular structure was determined to be 2-propylpiperidine. A series of chemical reactions on coniine and its derivatives such as conyrine revealed that the side chain is a propyl group. Historically, coniine was used to execute prisoners in ancient Greece by poisoning. Two major syntheses of coniine are the Ladenberg and Bergmann syntheses which involve rearrangement and substitution reactions to construct the 2-propylpiperidine core structure.

1. Chemistry of Natural
Products (CHEM4119)
Coniine

2. ALKALOIDS

3. ⚫ Obtained from the plants Conium maculatum (hemlock
poison), Sarracenia flava, Aethusa cynapium.
⚫ Highly toxic
⚫ disruption of the central nervous system
⚫ Death occurs by respiratory paralysis

4. ⚫Mol. Formula: C8H17N.
⚫RXN I:
⚫ Reacting with benzoyl chloride, a mono benzoyl derivative is
obtained, which on further treatment with phosphorous
tribromide gives dihalo compound and benzonitrile.
⚫ This reaction is characteristic of cyclic 20 amines. (Von-
Braun’s 2nd method)

5. ⚫Hence, this reaction indicated the presence of
secondary nitrogen atom in the ring.
⚫RXN : II
On reaction with Zinc, it gives conyrine (C8H11N).
This on further oxidation with KMNO4 gives pyridine-2-
carboxylic acid.
⚫Conyrine must be 2- substituted pyridine. (C6H5NO2)
⚫There must be an alkyl group having three carbons in
the side chain. (2nd position)

6. ⚫ Conyrine –pyridine derivative.
⚫ Coniine –Six hydrogens more than
conyrine.
piperidine derivative.
⚫ Comparing M.F. of conyrine C8H11N and pyridine-2-carboxylic
acid C6H5NO2
⚫ A shortage of 2carbons and 6 hydrogens.
⚫ The side chain have the composition C3H7.
⚫ Two Possibilities:
⚫
n- propyl Iso propyl

7. ⚫ RXN: III
⚫ Heating with hydroiodic acid at 3000C gives n- octane.
⚫ RXN: IV
⚫ Hofmann’s exhaustive degradation gives n-octane.
⚫ Iso-propyl group iso-octane.
⚫ Hence, the side group in coniine is n-propyl group.

8. 2-propylpiperidiene

9. ⚫used to kill condemned prisoners in ancient Greece
⚫Greek philosopher Socrates was executed to death by
drinking poison Hemlock. (399BC)

10. ⚫Ladenberg synthesis
⚫1886
⚫Bergmann synthesis
⚫1932

11. I Step: n-methylpyridiniumiodide to
2-methyl pyridine
Ladenberg Rearrangement
Mechanism: Hofmann-Martius rearrangement
II Step: 2-methylpyridine to
2-propenyl pyridine
Knoevenagel type

12. Methylpyridinium iodide was heated at 3000C to obtain 2-methylpyridine. This
On treatment with acetaldehyde with Lewis base to give 2-propenyl pyridine.
Reduction of the 2-propenyl pyridine yielded coniine.
2-propenyl pyridine coniine
III Step: reduction by metal/alcohol to form alkyl compound

13. I Step: 2-methyl pyridine to alkyl lithium compound
II.step: Nu. Substitution to form
2-propylpyridine
III.Step: Reduction of pyridine moiety