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Coniine is a poisonous chemical compound, an present in and isolable from ( ), where its presence has been a source of significant economic, medical, and historico-cultural interest; coniine is also produced by the ( ), and fool's parsley ( ). 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 of coniine contains as its penultimate step the non- cyclisation of 5-oxooctylamine to γ-coniceine, a differing from coniine only by its carbon-nitrogen double bond in the . This pathway results in natural coniine that is a mixture—a —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 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, was sentenced to death by drinking a coniine-containing mixture of .


Natural origins
( Conium maculatum) contains highly amounts of coniine. Its presence on farmland is an issue for livestock farmers because animals will eat it if they are not well fed or the hemlock is mixed in with pasture grass. The coniine is present in Conium maculatum as a mixture of the R-(−)- and S-(+)-.

Coniine is also found in , the yellow pitcher plant. The yellow pitcher plant is a carnivorous plant 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 , commonly known as fool's parsley.


History of natural isolates
The history of coniine is understandably tied to the poison hemlock plant, since the natural product was not synthesizable until the 1880s. Jews in the Middle East were poisoned by coniine after consuming quail in the area that usually ate hemlock seeds, and Greeks on the island of who also consumed quail suffered from the same poisoning, causing and acute kidney injury. The most famous hemlock poisoning occurred in 399 BCE, when the philosopher Socrates is believed to have consumed a liquid infused with hemlock to carry out his death sentence, having been convicted of impiety toward the gods, and the corruption of youth. Hemlock juice was often used to execute criminals in .

Hemlock has had a limited medical use throughout history. The Greeks used it not just as capital punishment, but also as an and treatment for . Books from the 10th century attest to medical use by the Anglo-Saxons.

(1971). 9780486227986, Dover Publications. .
In the 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 .

, 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. contains , 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.


Pharmacology and toxicology
The ( R)-(−) enantiomer of coniine is the more biologically active, at least in one system (TE-671 cells expressing human fetal nicotinic neuromuscular receptors), and in mouse bioassay, the same enantiomer and the racemic mixture are about two-fold more toxic than the ( S)-(+) enantiomer (see below).

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 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.


Chemical properties
(+/–)-Coniine was first isolated by Giesecke,Giseke, Aug. Lud. (1827) "Ueber das wirksame Princip des Schierlings, Conium maculatum" (On the active component of hemlock, Conium maculatum), Archiv der Pharmazie, 20 (2) : 97–111. On p. 99, Giseke credits the Swiss apothecary Peschier with coining the name coniin (coniine). See footnote on p. 87 of: Peschier (1821) "Neue analytische Untersuchungen über den unter verschiedenen Himmelsstrichen gebauten Mohn; ferner über einige inländische Narcotica, und Entdeckung neuer Pflanzensäuren und Alkälien in denselben" (New analytical investigations into poppies grown in various climates; furthermore, on some domestic narcotics, and discovery of new plant acids and alkalis in the same), Neues Journal der Pharmacie für Aerzte, Apotheker und Chemiker, 5 (1) : 76–101. From p. 87: "Eine Abbildung der krystallisirten Säure s. Fig. 1 das coniumsaure Natron ist Fig. 2 abgebildet." (An illustration of the crystalline acid, see Fig. 1 ; the sodium salt of conium acid is depicted in Fig. 2.) but the formula was suggested by BlythBlyth, J. (1849) "On the composition of coniine, and its products of decomposition," Quarterly Journal of the Chemical Society of London, 1 : 345–363. Blyth found the empirical formula of coniine to be (p. 351): C17H17N. The error in the amount of carbon is due, in part, to his having assumed that the atomic mass of carbon is 6, not 12 — a common error at the time. and definitely established by Hofmann.Hofmann, A. W. (1881) "Einwirkung der Wärme auf die Ammoniumbasen: 2. Coniin" (Effect of heat on ammonium bases: 2. Coniine), Berichte der deutschen chemischen Gesellschaft, 14 : 705–713.Panter, K. E. and Keeler, R. F., Ch. 5: Piperidine alkaloids of poison hemlock ( Conium maculatum) in: Cheeke, Peter R., ed., Toxicants of Plant Origin: Alkaloids, vol. 1 (Boca Raton, Florida: CRC Press, Inc., 1989), p. 116.

D-( S)-Coniine has since been determined to be a colorless alkaline liquid, with a penetrating odour and a burning taste; has D 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.


Solubility
Coniine is slightly soluble (1 in 90) in cold water, less so in hot water, so that a clear cold solution becomes when warmed. On the other hand, the base dissolves about 25% of water at room temperature. It mixes with in all proportions, is readily soluble in and most organic solvents. Coniine dissolves in , forming a complex thiocarbamate.Melzer, Arch. Pharm., 1898, 236, 701cf. Dilling, Pharm. J., 1909, iv, 29, 34, 70, 102.


Crystallization
Coniine solidifies into a soft crystalline mass at −2 °C. It slowly in the air. The salts crystallize well and are soluble in water or alcohol. The hydrochloride, B•HCl, crystallizes from water in rhombs, mp. 220 °C, α20°D +10.1°; the hydrobromide, in needles, mp. 211 °C, and the D-acid tartrate, B•C4H6O6•2 H2O, in rhombic crystals, mp. 54 °C. The platinichloride, (B•HCl)2•PtCl4•H2O, separates from concentrated solution as an oil, which solidifies to a mass of orange-yellow crystals, mp. 175 °C (dry). The aurichloride, B•HAuCl4, crystallizes on standing, mp. 77 °C. The forms small yellow needles, mp. 75 °C, from hot water. The 2,4-dinitrobenzoyl- and 3,5-dinitrobenzoyl-derivates have mps. 139.0–139.5 °C and 108–9 °C respectively.Späth, Kuffner and Ensfellner, Ber., 1933, 66, 596. The precipitate afforded by potassium cadmium iodide solution is crystalline, mp. 118 °C, while that given by with this reagent is amorphous.


Color changes
Coniine gives no coloration with or . Sodium nitroprusside gives a deep red color, which disappears on warming, but reappears on cooling, and is changed to blue or violet by .Gabutti, Chem. Soc. Abstr., 1906, ii, 711.


Specific rotation
The composition of "coniine" is a matter of some importance, since its two enantiomers do not have identical biological properties, and many of the older studies on this compound were carried out using the naturally occurring mixture. S-(+)-Coniine has a specific rotation, αD, of +8.4° (c = 4.0, in CHCl3). These authors note that Ladenburg's value,A. Ladenburg (1888) Justus Liebig's Ann. Chem. 247 1-98. +15°, is for a "neat", i.e. undiluted, sample. A similarly high value of +16° for the αD of "coniine" is given, without explicit citation of the source, in . The Merck Index, 15th Ed. (2013), p. 446, Monograph 2489, O'Neil: The Royal Society of Chemistry. http://www.rsc.org/Merck-Index/monograph/mono1500002489 The value of +7.7° (c = 4.0, CHCl3) for synthetic S-(+)-coniine and -7.9° (c = 0.5, CHCl3) for synthetic R-(−)-coniine is given by other chemists.D. Enders and J. Tiebes (1993) Liebig's Ann. Chem. 173-177. The hydrochloride salts of the ( S)-(+) and ( R)-(−) enantiomers of coniine have values of αD of +4.6° and -5.2°, respectively (c = 0.5, in methanol).


Synthesis
The original synthesis (shown below) of Coniine was performed by Ladenburg in 1886. Ladenburg heated N-methylpyridine iodide to 250 °C, to obtain 2-methylpyridine. He then performed a Knoevenagel condensation with in anhydrous to yield 2-propenylpyridine. In fact, Ladenburg used , a cyclic trimer of acetaldehyde that readily forms acetaldehyde upon heating. Finally, 2-propenylpyridine was with metallic in to provide (±) coniine. Fractional crystallisation of racemic coniine with (+)- yielded coniine.

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 and fuming at 125 °C. Second, the product is treated with 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 and dimethyl acetylenedicarboxylate is tetramethylquinolizine-1,2,3,4-tetracarboxylate, which on oxidation with dilute is converted into trimethyl indolizine-tricarboxylate. This, on hydrolysis and decarboxylation, furnishes , the octahydro-derivate of which, also known as octahydropyrrocoline is converted by the method successively into the bromocyanamide, cyanamide and rac.-coniine. A synthesis of the alkaloid, starting from (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 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 was the aldehyde (β-2-piperidyl-propaldehyde) corresponding to coniine, and yielded rac-coniine when its was heated with in at 156–170 °C. According to these authors, D-( S)-coniine is rendered almost optically inactive when heated with and alcohol at 180–230 °C. Leithe Ber., 1932, 65, 927. has shown by observation of the optical rotation of (+)- (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 .


Biosynthesis
The biosynthesis of coniine is still being investigated, but much of the pathway has been elucidated. Originally thought to use 4 acetyl groups as feed compounds for the polyketide synthase that forms coniine, it is in fact derived from two malonyl and a butyryl CoA, which are derived in the usual way from acetyl-CoA.
[[Image:Coniine1.gif|center|750px]]
     

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.


In popular culture
Coniine is the murder weapon in 's mystery novel Five Little Pigs.
(2025). 9781472911308, Bloomsbury.

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.


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