View source for Coniine

{{chembox
| Verifiedfields = changed
| Watchedfields  = changed
| verifiedrevid  = 456491703
| ImageFile      = Coniin - Coniine.svg
| ImageFile2     = Coniine-3D.png
| ImageCaption   = (''S'')-Coniine
| IUPACName      = (''2S'')-2-Propylpiperidine
| Section1       = {{Chembox Identifiers
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 389878
| ChEMBL2_Ref = {{ebicite|correct|EBI}}
| ChEMBL2 = 2287063
| InChI = 1/C8H17N/c1-2-5-8-6-3-4-7-9-8/h8-9H,2-7H2,1H3/t8-/m0/s1
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = C479P32L2D
| UNII1_Ref = {{fdacite|correct|FDA}}
| UNII1 = 04R53ZF48T
| UNII2_Ref = {{fdacite|correct|FDA}}
| UNII2 = QKK1SI92BR
| SMILES = CCCC1CCCCN1
| SMILES1 = N1[C@@H](CCC)CCCC1
| SMILES2 = N1[C@H](CCC)CCCC1
| InChIKey = NDNUANOUGZGEPO-QMMMGPOBBO
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo = 3238-60-6
| index_label = (''R''/''S'')
| CASNo1_Ref = {{cascite|correct|CAS}}
| CASNo1 =  5985-99-9
| index1_label = (''R'')
| CASNo2_Ref = {{cascite|correct|PubChem}}
| CASNo2 =  458-88-8
| index2_label = (''S'')
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 28322
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C8H17N/c1-2-5-8-6-3-4-7-9-8/h8-9H,2-7H2,1H3/t8-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = NDNUANOUGZGEPO-QMMMGPOBSA-N
| PubChem = 9985
| PubChem2 = 441072
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = C06523
| EC_number2 = 207-282-6
  }}
| Section2       = {{Chembox Properties
|C=8|H=17|N=1
|Appearance = Colorless, oily liquid
|MeltingPtC = -2
|BoilingPtC = 166 to 167
|RefractIndex= 1.4505
  }}
}}

'''Coniine''' is a poisonous [[chemical compound]], an [[alkaloid]] present in and isolable from [[Conium|poison hemlock]] (''[[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|yellow 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 by [[respiratory paralysis]]. The [[biosynthesis]] of coniine contains as its penultimate step the non-[[enzyme|enzymatic]] cyclisation of [[5-oxooctylamine]] to γ-coniceine, a [[Schiff base]] differing from coniine only by its carbon-nitrogen double bond in the [[cyclic compound|ring]]. This pathway results in natural coniine that is a mixture—a [[racemate]]—composed of two enantiomers, the [[stereoisomer]]s (''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 [[alkaloid]]s 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 [[Trial of Socrates|sentenced to death]] by drinking a coniine-containing mixture of [[Conium maculatum|poison hemlock]].

==Natural origins==
[[File:Conium.jpg|thumb|left|alt=A The poison hemlock plant.|The poison hemlock plant.]]
[[Poison hemlock]] (''Conium maculatum'') contains highly [[toxic]] 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.<ref>{{Cite journal|last1=Peters|first1=Amy|last2=Bouska|first2=Cassie|title=Poison Hemlock|url=http://extension.oregonstate.edu/coos/Forage/PoisonHemlock|journal=Osu Extension Service|access-date=3 May 2015}}</ref> The coniine is present in ''Conium maculatum'' as a mixture of the R-(−)- and S-(+)-[[enantiomer]]s<!--, although the S-enantiomer predominates STATEMENT CANNOT BE MADE WITHOUT VERY SPECIFIC STATEMENT OF CULTIVAR, TIME OF YEAR, OTHER DETAILS-->.<ref name = Lee>{{cite journal |author1=Stephen T. Lee |author2=Benedict T. Green |author3=Kevin D. Welch |author4=James A. Pfister |author5=Kip E. Panter |year=2008 |title=Stereoselective potencies and relative toxicities of coniine enantiomers |journal=[[Chemical Research in Toxicology]] |volume=21 |issue=10 |pages=2061–2064 |doi=10.1021/tx800229w|pmid=18763813 }}</ref> 
 
[[File:Sarracenia Flava JPG01.jpg|thumb|right|alt=A The yellow pitcher plant.|The yellow pitcher plant]]

Coniine is also found in ''[[Sarracenia flava]]'', the yellow pitcher plant.<ref>{{cite journal |author1=N. V. Mody |author2=R. Henson |author3=P. A. Hedin |author4=U. Kokpol |author5=D. H. Miles |year=1976 |title=Isolation of the insect paralyzing agent coniine from ''Sarracenia flava'' |journal=[[Experientia]] |volume=32 |issue=7 |pages=829–830 |doi=10.1007/BF02003710|s2cid=38319708 }}</ref><ref name=Hotti>{{cite journal |first1=Hannu |last1=Hotti |first2=Heiko |last2=Rischer |date= 2017 |title=The killer of Socrates: Coniine and Related Alkaloids in the Plant Kingdom |journal=Molecules |volume=22 |issue=11 |page=1962 |doi=10.3390/molecules22111962 |pmid=29135964 |pmc=6150177 |doi-access=free }}</ref> The yellow pitcher plant is a [[carnivorous plant]] [[endemism|endemic]] 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.<ref>{{cite web|last1=Mackie|first1=Robin|title=Yellow Pitcher Plant or Trumpets|url=http://www.fs.fed.us/wildflowers/plant-of-the-week/sarracenia_flava.shtml|website=United States Department of Agriculture|publisher=United States Department of Agriculture Forest Service|access-date=3 May 2015}}</ref> Coniine is also found in ''[[Aethusa cynapium]]'', commonly known as fool's parsley.<ref>{{Cite book | author = Clapham, Tutin, & Warburg | title = Flora of the British Isles | edition = 2nd | page = 524 }}</ref>

==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.<ref>{{cite EB1911|wstitle=Conine|volume=6|page=942}}</ref> 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 [[Lesbos]] who also consumed quail suffered from the same poisoning, causing [[myoglobinuria]] and [[acute kidney injury]].<ref>{{Cite web|title=Massachusetts Medical Society: Don't Eat the Quails|url=https://www.massmed.org/about/mms-leadership/history/don-t-eat-the-quails/|access-date=2021-07-30|website=www.massmed.org}}</ref> 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.<ref>{{cite journal |author=James Warren |year=2001 |title=Socratic suicide |journal=[[Journal of Hellenic Studies]] |volume=121 |pages=91–106 |pmid=19681231 |doi=10.2307/631830|jstor=631830 |s2cid=24221544 }}</ref><ref>{{cite journal |author=R. G. Frey |s2cid=170399183 |year=1978 |title=Did Socrates commit suicide? |journal=[[Philosophy (journal)|Philosophy]] |volume=53 |issue=203 |pages=106–108 |doi=10.1017/S0031819100016375}}</ref><ref>{{Cite EB1911 |last=Jackson |first=Henry |authorlink=Henry Jackson (classicist)  |wstitle=Socrates |accessdate= |volume=25 |pages=331–338 |quote=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 }}</ref> Hemlock juice was often used to execute criminals in [[ancient Greece]].<ref>{{cite web|title=The Suicide of Socrates|url=http://www.eyewitnesstohistory.com/socrates.htm|website=EyeWitness to History|access-date=3 May 2015}}</ref>

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.<ref>{{cite book|last1=Grieve|first1=M.|title=A Modern Herbal|date=1971|publisher=Dover Publications|location=Mineola, N.Y.|isbn=978-0-486-22798-6|page=392|edition=2nd|url=https://books.google.com/books?id=tLWve-VvBLoC&q=anglo+saxons+hemlock&pg=PA392|access-date=3 May 2015}}</ref> 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 [[flying ointment]]s in witchcraft. [[Indigenous peoples of the Americas|Native Americans]] used hemlock extract as [[arrow poison]].<ref name="native">{{cite web|last1=Moser|first1=L|last2=Crisp|first2=D|title=Poison Hemlock|url=http://sbsc.wr.usgs.gov/research/projects/swepic/factsheets/coma2sf_info.pdf|publisher=San Francisco Peaks Weed Management|access-date=3 May 2015}}</ref>

[[Sarracenia flava|Yellow pitcher plant]], or ''Sarracenia flava'', contains coniine.<ref>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.</ref> ''[[Aethusa cynapium]]'' contains [[cynopine]], which is similar to coniine.<ref>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.</ref>

==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).<ref name = Lee/>

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.<ref>{{cite book |last1=Goldrank |first1=Lewis |last2=Nelson |first2=Lewis |title=Toxicologic Emergencies |publisher=McGraw-Hill |location=New York |pages=Chapter 118: Plants |edition=11th }}</ref> 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 [[hypoxia (medical)|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 {{LD50}} 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.<ref name = Lee/>

==Chemical properties==
(+/–)-Coniine was first [[Chemical substance#Isolation, purification, characterization, and identification|isolated]] by Giesecke,<ref>Giseke, Aug. Lud. (1827) [https://babel.hathitrust.org/cgi/pt?id=chi.63391235;view=1up;seq=117 "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 [https://babel.hathitrust.org/cgi/pt?id=chi.095492268;view=1up;seq=103 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.)</ref> but the formula was suggested by Blyth<ref>Blyth, J. (1849) [https://babel.hathitrust.org/cgi/pt?id=umn.319510009023537;view=1up;seq=357 "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):  C<sub>17</sub>H<sub>17</sub>N.  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.</ref> and definitely established by [[August Wilhelm von Hofmann|Hofmann]].<ref>Hofmann, A. W. (1881) [https://babel.hathitrust.org/cgi/pt?id=mdp.39015026349442;view=1up;seq=713 "Einwirkung der Wärme auf die Ammoniumbasen:  2. Coniin"] (Effect of heat on ammonium bases:  2. Coniine), ''Berichte der deutschen chemischen Gesellschaft'', '''14''' :  705–713.</ref><ref>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),  [https://books.google.com/books?id=79i9mfl2PO4C&pg=PA116 p. 116.]</ref>

<small>D</small>-(''S'')-Coniine has since been determined to be a colorless alkaline liquid, with a penetrating odour and a burning taste; has <small>D</small><sup>0°</sup>&nbsp;0.8626 and <small>D</small><sup>19°</sup>&nbsp;0.8438, refractive index ''n''<sup>23°</sup><sub>D</sub> 1.4505, and is dextrorotatory, [α]<sup>19°</sup><sub>D</sub> +15.7° (see related comments under [[Specific rotation]] section [[#Specific rotation|below]]). <small>L</small>-(''R'')-Coniine has [α]<sup>21°</sup><sub>D</sub> 15° and in other respects resembles its <small>D</small>-isomer, but the salts have slightly different melting points; the platinichloride has mp. 160&nbsp;°C (Löffler and Friedrich report 175&nbsp;°C), the aurichloride mp. 59&nbsp;°C.<ref>Ahrens, ''Ber.'', 1902, '''35''', 1330</ref><ref name="Löffler">Löffler and Friedrich, ''Ber.'', 1909, '''42''', 107.</ref>

===Solubility===
Coniine is slightly soluble (1 in 90) in cold water, less so in hot water, so that a clear cold solution becomes [[Turbidity|turbid]] when warmed. On the other hand, the base dissolves about 25% of water at room temperature. It mixes with [[ethanol|alcohol]] in all proportions, is readily soluble in [[diethylether|ether]] and most organic solvents. Coniine dissolves in [[carbon disulfide]], forming a complex thiocarbamate.<ref>Melzer, ''Arch. Pharm.'', 1898, '''236''', 701</ref><ref>cf. Dilling, ''Pharm. J.'', 1909, [iv], '''29''', 34, 70, 102.</ref>

===Crystallization===
{{one source | section |date=January 2017}}
<!--is all of this information really all from this one Ber. source?-->
Coniine solidifies into a soft crystalline mass at −2&nbsp;°C. It slowly [[oxidize]]s 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&nbsp;°C, [α]<sup>20°</sup><sub>D</sub> +10.1°; the hydrobromide, in needles, mp. 211&nbsp;°C, and the <small>D</small>-acid tartrate, B•C<sub>4</sub>H<sub>6</sub>O<sub>6</sub>•2&nbsp;H<sub>2</sub>O, in rhombic crystals, mp. 54&nbsp;°C. The platinichloride, (B•HCl)<sub>2</sub>•PtCl<sub>4</sub>•H<sub>2</sub>O, separates from concentrated solution as an oil, which solidifies to a mass of orange-yellow crystals, mp. 175&nbsp;°C (dry). The aurichloride, B•HAuCl<sub>4</sub>, crystallizes on standing, mp. 77&nbsp;°C. The [[picrate]] forms small yellow needles, mp. 75&nbsp;°C, from hot water. The 2,4-dinitrobenzoyl- and 3,5-dinitrobenzoyl-derivates have mps. 139.0–139.5&nbsp;°C and 108–9&nbsp;°C respectively.<ref>Späth, Kuffner and Ensfellner, ''Ber.'', 1933, '''66''', 596.</ref> The precipitate afforded by potassium cadmium iodide solution is crystalline, mp. 118&nbsp;°C, while that given by [[nicotine]] with this reagent is amorphous.

===Color changes===
Coniine gives no coloration with [[sulfuric acid|sulfuric]] or [[nitric acid]]. [[Sodium nitroprusside]] gives a deep red color, which disappears on warming, but reappears on cooling, and is changed to blue or violet by [[aldehyde]]s.<ref>Gabutti, ''Chem. Soc. Abstr.'', 1906, [ii], 711.</ref>

===Specific rotation===
The [[stereochemical]] composition of "coniine" is a matter of some importance, since its two enantiomers do not have identical biological properties,<ref name = Lee/> and many of the older [[pharmacology|pharmacological]] studies on this compound were carried out using the naturally occurring [[isomeric]] mixture.{{Citation needed|date=January 2017}} ''S''-(+)-Coniine has a specific rotation, [α]<sub>D</sub>, of +8.4° (c = 4.0, in CHCl<sub>3</sub>).<ref>{{cite journal |author1=Craig J. Cymerman |author2=A. R. Pinder |year=1971 |title=Improved method resolution of coniine |journal=[[Journal of Organic Chemistry]] |volume=36 |issue=23 |pages=3648–3649 |doi=10.1021/jo00822a051}}</ref> These authors note that Ladenburg's value,<ref>A. Ladenburg (1888) ''Justus Liebig's Ann. Chem.'' '''247''' 1-98.</ref> +15°, is for a "neat", i.e. undiluted, sample. A similarly high value of +16° for the [α]<sub>D</sub> of "coniine" is given, without explicit citation of the source, in [[Merck Index|The Merck Index]].<ref>''[[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</ref> The value of +7.7° (c = 4.0, CHCl<sub>3</sub>) for synthetic S-(+)-coniine and -7.9° (c = 0.5, CHCl<sub>3</sub>) for synthetic R-(−)-coniine is given by other chemists.<ref name = Enders>D. Enders and J. Tiebes (1993) ''Liebig's Ann. Chem.'' 173-177.</ref> The hydrochloride salts of the (''S'')-(+) and (''R'')-(−) enantiomers of coniine have values of [α]<sub>D</sub> of +4.6° and -5.2°, respectively (c = 0.5, in methanol).<ref name = Lee/>

==Synthesis==

The original synthesis (shown below) of Coniine was performed by Ladenburg in 1886.<ref name=Ladenburg>{{Cite journal|last=Ladenburg|first=A.|date=1886-01-01|title=Versuche zur Synthese des Coniin|journal=Berichte der Deutschen Chemischen Gesellschaft|volume=19|issue=1|pages=439–441|doi=10.1002/cber.188601901108|issn=0365-9496}}</ref> Ladenburg heated N-methylpyridine iodide to 250&nbsp;°C, to obtain [[2-Methylpyridine|2-methylpyridine]]. He then performed a [[Knoevenagel condensation]] with [[acetaldehyde]] in anhydrous [[zinc chloride]] to yield 2-propenylpyridine. In fact, Ladenburg used [[paraldehyde]], a cyclic trimer of acetaldehyde that readily forms acetaldehyde upon heating. Finally, 2-propenylpyridine was [[Reducing agent|reduced]] with metallic [[sodium]] in [[ethanol]] to provide [[racemate|racemic]] (±) coniine. [[fractional crystallization (chemistry)|Fractional crystallisation]] of racemic coniine with (+)-[[tartaric acid]] yielded [[Enantiomer|enantiopure]] coniine.

[[File:Coniine Synthesis by Ladenburg.png|alt=a graphical representation of synthesis described in the article|center|thumb|600x600px|Original Synthesis by Ladenburg]]

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

:[[Image:Coniinsynthese2.svg|center|450px]]

In 1907, another route with better yield was proposed. First, 2-(2'-hydroxypropyl)pyridine is reduced with [[phosphorus]] and fuming [[hydroiodic acid]] at 125&nbsp;°C. Second, the product is treated with [[zinc]] dust and water. Finally, the product of the second step is treated with sodium in ethanol.<ref>{{Cite journal|last=Ladenburg|first=A.|date=1907-06-01|title=Noch ein Wort über das Isoconlin. 14. Mitteilung über den asymmetryschen Stickstoff|journal=Berichte der Deutschen Chemischen Gesellschaft|volume=40|issue=3|pages=3734–3736|doi=10.1002/cber.190704003170|issn=0365-9496|url=https://zenodo.org/record/2045027}}</ref> Note: although the graphic below shows a single enantiomer of coniine, this reaction produces a racemic mixture that is then purified and separated. 

:[[Image:Coniinsynthese3.svg|center|450px]]

A number of other syntheses of coniine have been effected,<ref>{{Cite journal|last1=Denić|first1=Marija|last2=Blagojević|first2=Polina|last3=Radulović|first3=Niko|date=2013|title=Synthetic approaches to coniine and other 2-alkyl piperidines|url=http://www.doiserbia.nb.rs/Article.aspx?ID=0354-46561301001D|journal=Facta universitatis - series: Physics, Chemistry and Technology|volume=11|issue=1|pages=1–26|doi=10.2298/FUPCT1301001D|doi-access=free}}</ref> of which that of Diels and Alder is of special interest.<ref>Diels and Alder, ''Annalen'', 1932, '''498''', 16.</ref> 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<ref>{{cite journal |author1=G. R. Clemo |author2=G. R. Ramage |year=1932 |title=Octahydropyrrocoline |journal=[[Journal of the Chemical Society]] |pages=2969–2973 |doi=10.1039/JR9320002969}}</ref> 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.<ref>''Ber.'', 1934, '''67''', 1011.</ref>

:[[Image:Coniinsynthese4.svg|center|450px]]

The preparation of <small>L</small>-(''R'')-coniine by the reduction of β-coniceine (<small>L</small>-propenylpiperidine) by Löffler and Friedrich<ref name="Löffler"/> provides means for converting [[conhydrine]] to <small>L</small>-(''R'')-coniine.<ref>{{Citation|last1=Talapatra|first1=Sunil Kumar|title=Coniine, Conhydrine, and Pseudoconhydrine (The C-Skeleton Derived from a C8-Fatty Acid and N from Transamination)|date=2015|work=Chemistry of Plant Natural Products: Stereochemistry, Conformation, Synthesis, Biology, and Medicine|pages=733–748|editor-last=Talapatra|editor-first=Sunil Kumar|publisher=Springer|language=en|doi=10.1007/978-3-642-45410-3_17|isbn=978-3-642-45410-3|last2=Talapatra|first2=Bani|editor2-last=Talapatra|editor2-first=Bani}}</ref> Hess and Eichel reported,<ref>''Ber.'', 1917, '''50''', 1192, 1386.</ref> incorrectly,<ref>Pelletierine is now known to be 1-(2-piperidinyl)-2-propanone;{{according to whom|date=January 2017}} see: ''The Merck Index'', '''15th Ed.''' (2013), p. 1314,{{Original research inline|date=January 2017}} Monograph '''7181''', O'Neil: The Royal Society of Chemistry. Available online at: http://www.rsc.org/Merck-Index/monograph/mono1500007181</ref> 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&nbsp;°C. According to these authors, <small>D</small>-(''S'')-coniine is rendered almost optically inactive when heated with [[barium hydroxide]] and alcohol at 180–230&nbsp;°C. Leithe<ref>''Ber.'', 1932, '''65''', 927.</ref> has shown by observation of the optical rotation of (+)-[[pipecolic acid]] (piperidine-2-carboxylic acid) and some of its derivatives under varying conditions,<ref>{{cite journal |author=George William Clough |year=1918 |title=The relationship between the optical rotatory powers and the relative configurations of optically active compounds. The influence of certain inorganic haloids on the optical rotatory powers of α-hydroxy-acids, α-amino-acids, and their derivatives |journal=[[Journal of the Chemical Society, Transactions]] |volume=113 |pages=526–554 |doi=10.1039/CT9181300526|url=https://zenodo.org/record/2142175 }}</ref> that it must belong to the <small>D</small>-series of [[amino acid]]s.

Currently, Coniine, and many other alkaloids, can be synthesized [[Enantioselective synthesis|stereoselectively]].<ref name = Enders/> 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).<ref>{{Cite journal|last1=Hande|first1=Sudhir M.|last2=Kawai|first2=Nobuyuki|last3=Uenishi|first3=Jun’ichi|date=2009-01-02|title=An Efficient Synthesis of 2- and 2,6-Substituted Piperidines Using PdII-Catalyzed 1,3-Chirality Transfer Reaction|journal=The Journal of Organic Chemistry|volume=74|issue=1|pages=244–253|doi=10.1021/jo801926g|pmid=19012434|issn=0022-3263}}</ref> 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]].

==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,<ref>{{cite journal | url=https://pubs.acs.org/doi/10.1021/ja01066a039 | doi=10.1021/ja01066a039 | title=Biosynthesis of the Hemlock Alkaloids. The Incorporation of Acetate-1-C<sup>14</sup> into Coniine and Conhydrine | date=1964 | last1=Leete | first1=Edward. | journal=Journal of the American Chemical Society | volume=86 | issue=12 | pages=2509–2513 | bibcode=1964JAChS..86.2509L | url-access=subscription }}</ref> it is in fact derived from two malonyl and a butyryl CoA, which are derived in the usual way from acetyl-CoA.<ref>{{cite journal | url=https://febs.onlinelibrary.wiley.com/doi/full/10.1111/febs.13410 | doi=10.1111/febs.13410 | title=Polyketide synthases from poison hemlock ( ''Conium maculatum'' L.) | date=2015 | last1=Hotti | first1=Hannu | last2=Seppänen-Laakso | first2=Tuulikki | last3=Arvas | first3=Mikko | last4=Teeri | first4=Teemu H. | last5=Rischer | first5=Heiko | journal=The FEBS Journal | volume=282 | issue=21 | pages=4141–4156 | pmid=26260860 }}</ref>
 [[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.<ref>{{cite journal | url=https://www.sciencedirect.com/science/article/abs/pii/S0031942200896892 | doi=10.1016/S0031-9422(00)89689-2 | bibcode=1978PChem..17..107R | title=Separation of the formation of γ-coniceine and aliphatic amines from got activity in Conium maculatum | last1=Roberts | first1=Margaret F. | journal=Phytochemistry | date=1978 | volume=17 | issue=1 | page=107 | url-access=subscription }}</ref> 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.

[[Image:Coniine2.gif|center|750px]]

==In popular culture==
Coniine is the murder weapon in [[Agatha Christie]]'s mystery novel ''[[Five Little Pigs]]''.<ref>{{Cite book |title=A is for Arsenic: The Poisons of Agatha Christie |last=Harkup |first=Kathryn |publisher=Bloomsbury |year=2015 |isbn=9781472911308 |location=New York, NY |pages=132}}</ref>

== References ==
{{reflist|32em}}

==Further reading==
*{{cite journal|author1= Green, Benedict T. |author2=Lee, Stephen T. |author3=Panter, Kip E. |author4=Brown, David R.  | year = 2012 | title =  Piperidine Alkaloids: Human and Food Animal Teratogens | journal = Food and Chemical Toxicology | volume = 50 | issue = 6 | pages = 2049–2055 | url = https://naldc.nal.usda.gov/download/57683/PDF | archive-url = https://web.archive.org/web/20170202032321/https://naldc.nal.usda.gov/download/57683/PDF | url-status = dead | archive-date = February 2, 2017 | doi = 10.1016/j.fct.2012.03.049 | pmid = 22449544 | format = PDF | access-date = January 23, 2017}}

== External links ==
* [http://www.chm.bris.ac.uk/motm/hemlock/intro.htm Information on hemlock] from the [[University of Bristol]]
* [https://web.archive.org/web/20060908113444/http://students.ou.edu/T/Mitchel.L.Tucker-1/episode_1.html  Mitch Tucker student work, Hemlock and Death of Socrates, at the University of Oklahoma]

{{ancient anaesthesia-footer}}

[[Category:Neurotoxins]]
[[Category:Piperidine alkaloids]]
[[Category:Nicotinic antagonists]]
[[Category:Plant toxins]]
[[Category:2-Piperidinyl compounds]]