Coniine is a poisonous chemical compound, an alkaloid present in and isolable from Conium ( Conium maculatum), where its presence has been a source of significant economic, medical, and historico-cultural interest; coniine is also produced by the Sarracenia flava ( Sarracenia flava), and fool's parsley ( Aethusa cynapium). Its ingestion and extended exposure are toxic to humans and all classes of livestock; its mechanism of poisoning involves disruption of the central nervous system, with death caused by respiratory paralysis. The biosynthesis of coniine contains as its penultimate step the non-enzyme cyclisation of 5-oxooctylamine to γ-coniceine, a Schiff base differing from coniine only by its carbon-nitrogen double bond in the cyclic compound. This pathway results in natural coniine that is a mixture—a racemate—composed of two enantiomers, the ( S)-(+)-coniine and ( R)-(−)-coniine, depending on the direction taken by the chain that branches from the ring. Both enantiomers are toxic, with the ( R)-enantiomer being the more biologically active and toxic of the two in general. Coniine holds a place in organic chemistry history as being the first of the important class of to be synthesized, by Albert Ladenburg in 1886, and it has been synthesized in the laboratory in a number of unique ways through to modern times.
Hemlock poisoning has been a periodic human concern, a regular veterinary concern, and has had significant occurrences in human and cultural history. Notably, in 399 BC, Socrates was sentenced to death by drinking a coniine-containing mixture of Conium maculatum.
Coniine is also found in Sarracenia flava, the yellow pitcher plant. The yellow pitcher plant is a carnivorous plant endemism to the southeastern United States. The plant uses a mixture of sugar and coniine to simultaneously attract and poison insects, which then fall into a digestive tube. Coniine is also found in Aethusa cynapium, commonly known as fool's parsley.
Hemlock has had a limited medical use throughout history. The Greeks used it not just as capital punishment, but also as an antispasmodic and treatment for arthritis. Books from the 10th century attest to medical use by the Anglo-Saxons. In the Middle Ages it was believed that hemlock could be used to cure rabies; in later European times it came to be associated with in witchcraft. Native Americans used hemlock extract as arrow poison.
Sarracenia flava, or Sarracenia flava, contains coniine.Mody, N. V.; Henson, R.; Hedin, P. A.; Kokpol, U.; Miles, D. H. (1976). "Isolation of the insect paralyzing agent coniine from *Sarracenia flava*". *Experientia*, 32(7), 829–830. doi:10.1007/BF01942981. Aethusa cynapium contains cynopine, which is similar to coniine.Dwivedi, H., Bhardwaj, M., & Kumar, G. (2021). A Comprehensive Study of Poisonous Plants of Family Apiaceae. In Apiaceae: Ecology, Uses and Toxicity (pp. 1–14). Nova Publisher, New York.
Coniine, as racemate or as pure enantiomer, begins by binding and stimulating the nicotinic receptor on the post-synaptic membrane of the neuromuscular junction. The subsequent depolarization results in nicotinic toxicity; as coniine stays bound to the receptor, the nerve stays depolarized, inactivating it. This results, systemically, in a flaccid paralysis, an action similar to that of succinylcholine since they are both depolarizing neuromuscular blockers. Symptoms of paralysis generally occur within a half-hour, although death may take several hours. The central nervous system is not affected: the person remains conscious and aware until respiratory paralysis results in cessation of breathing. The flaccid, muscular paralysis is an ascending paralysis, lower limbs being first affected. The person may have a hypoxic convulsion just prior to death, disguised by the muscular paralysis such that the person may just weakly shudder. Cause of death is lack of oxygen to the brain and heart as a consequence of respiratory paralysis, so that a poisoned person may recover if artificial ventilation can be maintained until the toxin is removed from the victim's system.
The values (in mouse, i.v. administered) for the R-(−) and S-(+) enantiomers, and the racemate, are approximately 7 and 12, and 8 milligrams per kilogram, respectively.
D-( S)-Coniine has since been determined to be a colorless alkaline liquid, with a penetrating odour and a burning taste; has D0° 0.8626 and D19° 0.8438, refractive index n23°D 1.4505, and is dextrorotatory, α19°D +15.7° (see related comments under Specific rotation section below). L-( R)-Coniine has α21°D 15° and in other respects resembles its D-isomer, but the salts have slightly different melting points; the platinichloride has mp. 160 °C (Löffler and Friedrich report 175 °C), the aurichloride mp. 59 °C.Ahrens, Ber., 1902, 35, 1330Löffler and Friedrich, Ber., 1909, 42, 107.
The scheme proposed by Ladenburg gave poor yields, so the quest for alternative routes was open. A slightly better yield is observed if 2-methylpyridine and acetaldehyde are heated in a sealed tube with hydrochloric acid for 10 hours. A mixture of 2-propenylpyridine and 2-chloropropylpyridine is formed and is subsequently reduced by sodium in ethanol to give rac-coniine. Note: although the scheme below shows a single enantiomer of coniine, the final reaction produces a racemic mixture that is then separated
In 1907, another route with better yield was proposed. First, 2-(2'-hydroxypropyl)pyridine is reduced with phosphorus and fuming hydroiodic acid at 125 °C. Second, the product is treated with zinc dust and water. Finally, the product of the second step is treated with sodium in ethanol. Note: although the graphic below shows a single enantiomer of coniine, this reaction produces a racemic mixture that is then purified and separated.
A number of other syntheses of coniine have been effected, of which that of Diels and Alder is of special interest.Diels and Alder, Annalen, 1932, 498, 16. The initial adduct of pyridine and dimethyl acetylenedicarboxylate is tetramethylquinolizine-1,2,3,4-tetracarboxylate, which on oxidation with dilute nitric acid is converted into trimethyl indolizine-tricarboxylate. This, on hydrolysis and decarboxylation, furnishes indolizine, the octahydro-derivate of which, also known as octahydropyrrocoline is converted by the cyanogen bromide method successively into the bromocyanamide, cyanamide and rac.-coniine. A synthesis of the alkaloid, starting from indolizine (pyrrocoline) is described by Ochiai and Tsuda. Ber., 1934, 67, 1011.
The preparation of L-( R)-coniine by the reduction of β-coniceine (L-propenylpiperidine) by Löffler and Friedrich provides means for converting conhydrine to L-( R)-coniine. Hess and Eichel reported, Ber., 1917, 50, 1192, 1386. incorrectly,Pelletierine is now known to be 1-(2-piperidinyl)-2-propanone; see: The Merck Index, 15th Ed. (2013), p. 1314, Monograph 7181, O'Neil: The Royal Society of Chemistry. Available online at: http://www.rsc.org/Merck-Index/monograph/mono1500007181 that pelletierine was the aldehyde (β-2-piperidyl-propaldehyde) corresponding to coniine, and yielded rac-coniine when its hydrazone was heated with sodium ethoxide in ethanol at 156–170 °C. According to these authors, D-( S)-coniine is rendered almost optically inactive when heated with barium hydroxide and alcohol at 180–230 °C. Leithe Ber., 1932, 65, 927. has shown by observation of the optical rotation of (+)-pipecolic acid (piperidine-2-carboxylic acid) and some of its derivatives under varying conditions, that it must belong to the D-series of .
Currently, Coniine, and many other alkaloids, can be synthesized stereoselectively. For example, Pd-catalyzed 1,3-chirality transfer reaction can stereospecifically transform a single enantiomer of an allyl alcohol into a cyclic structure (in this case a piperidine). In this way, starting from (S)-alcohol an (S)-enantiomer of Coniine is obtained and vice versa. Remarkably, the separation of racemic alcohol into different enantiomers is done with the help of Candida antarctica lipase.
Further elongation of butyryl-CoA using 2 malonyl-CoA forms 5-ketooctanal. Ketooctanal then undergoes transamination using alanine:5-keto-octanal aminotransferase. The amine then spontaneously cyclizes and is dehydrated to form the coniine precursor γ–coniceine. This is then reduced using NADPH dependent y-coniceine reductase to form coniine.
The R and S 2-Propylpiperidine stereoisomers are a neurotoxin present in a slug-like lifeform in The Expanse. The toxin is shown as causing almost instant death upon skin contact in the show.
Chemical properties
Solubility
Crystallization
Color changes
Specific rotation
Synthesis
Biosynthesis
[[Image:Coniine1.gif|center|750px]]
In popular culture
Further reading
External links
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