 (S)-Coniine | |
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| IUPAC name (2S)-2-Propylpiperidine | |
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3D model (JSmol) |
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| ChEBI |
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| ChemSpider |
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| ECHA InfoCard | 100.006.621 |
| EC Number |
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| Properties | |
| C8H17N | |
| Molar mass | 127.231 g·mol−1 |
| Appearance | Colorless, oily liquid |
| Melting point | −2 °C (28 °F; 271 K) |
| Boiling point | 166 to 167 °C (331 to 333 °F; 439 to 440 K) |
Refractive index (nD) | 1.4505 |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
Coniine is a poisonouschemical compound, analkaloid present in and isolable frompoison hemlock (Conium maculatum), where its presence has been a source of significant economic, medical, and historico-cultural interest; coniine is also produced by theyellow pitcher plant (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 byrespiratory paralysis. Thebiosynthesis of coniine contains as its penultimate step the non-enzymatic cyclisation of5-oxooctylamine to γ-coniceine, aSchiff base differing from coniine only by its carbon-nitrogen double bond in thering. This pathway results in natural coniine that is a mixture—aracemate—composed of two enantiomers, thestereoisomers (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 inorganic chemistry history as being the first of the important class ofalkaloids to be synthesized, byAlbert 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 wassentenced to death by drinking a coniine-containing mixture ofpoison hemlock.
Poison hemlock (Conium maculatum) contains highlytoxic 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.[1] The coniine is present inConium maculatum as a mixture of the R-(−)- and S-(+)-enantiomers.[2]
Coniine is also found inSarracenia flava, the yellow pitcher plant.[3][4] The yellow pitcher plant is acarnivorous plantendemic 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.[5] Coniine is also found inAethusa cynapium, commonly known as fool's parsley.[6]
The history of coniine is understandably tied to the poison hemlock plant, since the natural product was not synthesizable until the 1880s.[7] 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 ofLesbos who also consumed quail suffered from the same poisoning, causingmyoglobinuria andacute kidney injury.[8] 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.[9][10][11] Hemlock juice was often used to execute criminals inancient Greece.[12]
Hemlock has had a limited medical use throughout history. The Greeks used it not just as capital punishment, but also as anantispasmodic and treatment forarthritis. Books from the 10th century attest to medical use by the Anglo-Saxons.[13] In theMiddle Ages it was believed that hemlock could be used to cure rabies; in later European times it came to be associated withflying ointments in witchcraft.Native Americans used hemlock extract asarrow poison.[14]
Yellow pitcher plant, orSarracenia flava, contains coniine.[15]Aethusa cynapium containscynopine, which is similar to coniine.[16]
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).[2]
Coniine, as racemate or as pure enantiomer, begins by binding and stimulating thenicotinic receptor on the post-synaptic membrane of theneuromuscular junction. The subsequent depolarization results in nicotinic toxicity; as coniine stays bound to the receptor, the nerve stays depolarized, inactivating it.[17] This results, systemically, in aflaccid paralysis, an action similar to that ofsuccinylcholine 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 ahypoxic 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.
TheLD50 values (in mouse, i.v. administered) for theR-(−) andS-(+) enantiomers, and the racemate, are approximately 7 and 12, and 8 milligrams per kilogram, respectively.[2]
(+/–)-Coniine was firstisolated by Giesecke,[18] but the formula was suggested by Blyth[19] and definitely established byHofmann.[20][21]
D-(S)-Coniine has since been determined to be a colorless alkaline liquid, with a penetrating odour and a burning taste; hasD0° 0.8626 andD19° 0.8438, refractive indexn23°D 1.4505, and is dextrorotatory, [α]19°D +15.7° (see related comments underSpecific rotation sectionbelow).L-(R)-Coniine has [α]21°D 15° and in other respects resembles itsD-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.[22][23]
Coniine is slightly soluble (1 in 90) in cold water, less so in hot water, so that a clear cold solution becomesturbid when warmed. On the other hand, the base dissolves about 25% of water at room temperature. It mixes withalcohol in all proportions, is readily soluble inether and most organic solvents. Coniine dissolves incarbon disulfide, forming a complex thiocarbamate.[24][25]
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Coniine solidifies into a soft crystalline mass at −2 °C. It slowlyoxidizes 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, [α]20°D +10.1°; the hydrobromide, in needles, mp. 211 °C, and theD-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. Thepicrate 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.[26] The precipitate afforded by potassium cadmium iodide solution is crystalline, mp. 118 °C, while that given bynicotine with this reagent is amorphous.
Coniine gives no coloration withsulfuric ornitric acid.Sodium nitroprusside gives a deep red color, which disappears on warming, but reappears on cooling, and is changed to blue or violet byaldehydes.[27]
Thestereochemical composition of "coniine" is a matter of some importance, since its two enantiomers do not have identical biological properties,[2] and many of the olderpharmacological studies on this compound were carried out using the naturally occurringisomeric mixture.[citation needed]S-(+)-Coniine has a specific rotation, [α]D, of +8.4° (c = 4.0, in CHCl3).[28] These authors note that Ladenburg's value,[29] +15°, is for a "neat", i.e. undiluted, sample. A similarly high value of +16° for the [α]D of "coniine" is given, without explicit citation of the source, inThe Merck Index.[30] 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.[31] The hydrochloride salts of the (S)-(+) and (R)-(−) enantiomers of coniine have values of [α]D of +4.6° and -5.2°, respectively (c = 0.5, in methanol).[2]
The original synthesis (shown below) of Coniine was performed by Ladenburg in 1886.[32] Ladenburg heated N-methylpyridine iodide to 250 °C, to obtain2-methylpyridine. He then performed aKnoevenagel condensation withacetaldehyde in anhydrouszinc chloride to yield 2-propenylpyridine. In fact, Ladenburg usedparaldehyde, a cyclic trimer of acetaldehyde that readily forms acetaldehyde upon heating. Finally, 2-propenylpyridine wasreduced with metallicsodium inethanol to provideracemic (±) coniine.Fractional crystallisation of racemic coniine with (+)-tartaric acid yieldedenantiopure 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 withhydrochloric acid for 10 hours. A mixture of 2-propenylpyridine and 2-chloropropylpyridine is formed and is subsequently reduced by sodium in ethanol to giverac-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 withphosphorus and fuminghydroiodic acid at 125 °C. Second, the product is treated withzinc dust and water. Finally, the product of the second step is treated with sodium in ethanol.[33] 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,[34] of which that of Diels and Alder is of special interest.[35] The initial adduct ofpyridine anddimethyl acetylenedicarboxylate is tetramethylquinolizine-1,2,3,4-tetracarboxylate, which on oxidation with dilutenitric acid is converted into trimethyl indolizine-tricarboxylate. This, on hydrolysis and decarboxylation, furnishesindolizine, the octahydro-derivate of which, also known as octahydropyrrocoline[36] is converted by thecyanogen bromide method successively into the bromocyanamide, cyanamide andrac.-coniine. A synthesis of the alkaloid, starting fromindolizine (pyrrocoline) is described by Ochiai and Tsuda.[37]
The preparation ofL-(R)-coniine by the reduction of β-coniceine (L-propenylpiperidine) by Löffler and Friedrich[23] provides means for convertingconhydrine toL-(R)-coniine.[38] Hess and Eichel reported,[39] incorrectly,[40] thatpelletierine was the aldehyde (β-2-piperidyl-propaldehyde) corresponding to coniine, and yieldedrac-coniine when itshydrazone was heated withsodium ethoxide inethanol at 156–170 °C. According to these authors,D-(S)-coniine is rendered almost optically inactive when heated withbarium hydroxide and alcohol at 180–230 °C. Leithe[41] has shown by observation of the optical rotation of (+)-pipecolic acid (piperidine-2-carboxylic acid) and some of its derivatives under varying conditions,[42] that it must belong to theD-series ofamino acids.
Currently, Coniine, and many other alkaloids, can be synthesizedstereoselectively.[31] 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).[43] 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 ofCandida antarcticalipase.
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,[44] it is in fact derived from two malonyl and a butyryl CoA, which are derived in the usual way from acetyl-CoA.[45]
Further elongation of butyryl-CoA using 2 malonyl-CoA forms 5-ketooctanal. Ketooctanal then undergoes transamination using alanine:5-keto-octanal aminotransferase.[46] 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.
Coniine is the murder weapon inAgatha Christie's mystery novelFive Little Pigs.[47]
{{cite book}}: CS1 maint: multiple names: authors list (link)SOCRATES, son of the statuary Sophroniscus and of the midwife Phaenarete, was born at Athens, not earlier than 471 nor later than May or June 469 B.C. ... In 399, four years after the restoration and the amnesty, he was indicted as an offender against public morality. ... The accusation ran thus: "Socrates is guilty, firstly, of denying the gods recognized by the state and introducing new divinities, and, secondly, of corrupting the young." ... Under ordinary circumstances the condemned criminal drank the cup of hemlock on the day after the trial; but in the case of Socrates the rule that during the absence of the sacred ship sent annually to Delos no one should be put to death caused an exceptional