Coniine

[koh-nee-een, -in, -neen]

Coniine is a poisonous alkaloid found in poison hemlock and the Yellow Pitcher Plant, and contributes to hemlock's fetid smell. It is a neurotoxin which disrupts the peripheral nervous system. It is toxic to humans and all classes of livestock; less than 0.2g (0.007oz) is fatal to humans, with death caused by respiratory paralysis. Socrates was put to death by way of this poison in 399 BC. Coniine has two stereoisomers: (S)-(+)-coniine (CAS 458-88-8), which is the natural isomer present in hemlock and (R)-(-)-coniine (CAS 5985-99-9). Coniine was first synthesized by Albert Ladenburg in 1886; it was the first of the alkaloids ever synthesized as well.

Synthesis

In the original synthesis of this piperidine by Ladenburg, he heated methylpyridinium iodide at 300 °C to obtain 2-methylpyridine (α-picoline). 2-Methylpyridine was reacted with acetaldehyde in the presence of a base to 2-propenylpyridine in a Knoevenagel condensation. This intermediate was reduced with metallic sodium in ethanol to racemic (±) coniine (reduction by hydrogen gas is also possible). Enantiopure Coniine was obtained by chiral resolution — fractional crystallisation of the diastereoisomers of the salt obtained with (+)-tartaric acid.

Pharmacology

Coniine paralyzes muscles by blocking the nicotinic receptor on the post-synaptic membrane of the neuromuscular junction causing a flaccid paralysis. This action is similar to that of curare. Symptoms of paralysis occur within a half hour, and death may take several hours. As the central nervous system is not affected the person remains conscious and aware until respiratory paralysis results in cessation of breathing. The muscular paralysis is an ascending flaccid paralysis as the lower limbs are affected first. The person may have an hypoxic convulsion just prior to death but this is greatly disguised by the muscular paralysis and the person may just weakly shudder. The cause of death is lack of oxygen to the brain and heart as a consequence of respiratory paralysis. A poisoned person will recover if artificial ventilation (breathing) is maintained until the toxin is removed from the receptor.

There have been a number of cases of poisoning in certain regions of Italy due to the consumption of larks and chaffinches, which eat the buds of poison hemlock during April and May. Also, the alkaloid appears to have an addictive effect: goats, cows and pigs have all shown a preference for conium-containing foliage (up to the point of eventual death) if they survive initial exposure.

Coniine in Literature

Coniine is the poison used to kill Amyas Crale in Five Little Pigs (published in 1943), also known as Murder in Retrospect, one of Agatha Christie's Hercule Poirot mysteries.