Editing Pyridine (section)

==Production==
Historically, pyridine was extracted from [[coal tar]] or obtained as a byproduct of coal [[gasification]]. The process is labor-consuming and inefficient: [[coal tar]] contains only about 0.1% pyridine,<ref>{{cite book|first=A. |last=Gossauer |title=Struktur und Reaktivität der Biomoleküle |date=2006 |page=488 |publisher=Wiley-VCH |location=Weinheim |isbn=3-906390-29-2}}</ref> and therefore a multi-stage purification was required, which further reduced the output. Nowadays, most pyridines are synthesized from ammonia, aldehydes, and nitriles, a few combinations of which are suited for pyridine itself.   Various [[name reaction]]s are also known, but they are not practiced on scale.<ref name=ul>{{Ullmann|first1=S. |last1=Shimizu |first2=N. |last2=Watanabe |first3=T. |last3=Kataoka |first4=T. |last4=Shoji |first5=N. |last5=Abe |first6=S. |last6=Morishita |first7=H. |last7=Ichimura |title=Pyridine and Pyridine Derivatives |doi=10.1002/14356007.a22_399}}</ref>

In 1989, 26,000 tonnes of pyridine was produced worldwide.  Other major derivatives are [[2-methylpyridine|2-]], [[3-methylpyridine|3-]], [[4-methylpyridine]]s and [[5-ethyl-2-methylpyridine]].  The combined scale of these alkylpyridines matches that of pyridine itself.<ref name=ul/> Among the largest 25 production sites for pyridine, eleven are located in Europe (as of 1999).<ref name=osha/> The major producers of pyridine include [[Evonik Industries]], Rütgers Chemicals, [[Jubilant Life Sciences]], [[Imperial Chemical Industries]], and Koei Chemical.<ref name=ul/> Pyridine production significantly increased in the early 2000s, with an annual production capacity of 30,000 tonnes in mainland China alone.<ref>{{cite web |url=http://www.agrochemex.net/en/press/2010/05/11/Pyridine_s_Development_in_China/ |title=Pyridine's Development in China |publisher=[[AgroChemEx]] |date=11 May 2010 |access-date=7 January 2011 |archive-url=https://web.archive.org/web/20180920134906/http://www.agrochemex.net/en/press/2010/05/11/Pyridine_s_Development_in_China/ |archive-date=20 September 2018 |url-status=dead }}</ref> The US–Chinese joint venture Vertellus is currently the world leader in pyridine production.<ref>{{cite web |url=http://www.vertellus.com/company.aspx |title=About Vertellus |website=vertellus.com |access-date=7 January 2011 |archive-url=https://archive.today/20120918012717/http://www.vertellus.com/company.aspx |archive-date=18 September 2012 |url-status=dead }}</ref>

===Chichibabin synthesis===
The [[Chichibabin pyridine synthesis]] was reported in 1924 and the basic approach underpins several industrial routes.<ref name=tschi/> In its general form, the reaction involves the [[condensation reaction]] of [[aldehydes]], [[ketones]], [[α,β-Unsaturated carbonyl compound|α,β-unsaturated carbonyl compounds]], or any combination of the above, in [[ammonia]] or [[amine|ammonia derivatives]]. Application of the Chichibabin pyridine synthesis suffer from low yields, often about 30%,<ref name='Frank1949'>{{cite journal
|last1=Frank|first1= R. L. |last2=Seven|first2= R. P.| title = Pyridines. IV. A Study of the Chichibabin Synthesis
| journal = Journal of the American Chemical Society
| year = 1949
| volume = 71
| issue = 8
| pages = 2629–2635
| doi = 10.1021/ja01176a008}}</ref> however the precursors are inexpensive. In particular, unsubstituted pyridine is produced from [[formaldehyde]] and [[acetaldehyde]]. First, [[acrolein]] is formed in a [[Knoevenagel condensation]] from the acetaldehyde and formaldehyde. The acrolein then [[condensation reaction|condenses]] with acetaldehyde and ammonia to give [[dihydropyridine]], which is oxidized to pyridine. This process is carried out in a gas phase at 400–450&nbsp;°C. Typical catalysts are modified forms of [[alumina]] and [[silica]]. The reaction has been tailored to produce various [[methylpyridine]]s.<ref name=ul/>

[[File:AcroleinDarstellung.svg|class=skin-invert-image|500px|center|thumb|Formation of acrolein from acetaldehyde and formaldehyde]]
[[File:Pyridin aus Acrolein.svg|class=skin-invert-image|500px|center|thumb|Condensation of pyridine from acrolein and acetaldehyde]]

===Dealkylation and decarboxylation of substituted pyridines===
Pyridine can be prepared by dealkylation of alkylated pyridines, which are obtained as byproducts in the syntheses of other pyridines. The oxidative dealkylation is carried out either using air over [[vanadium(V) oxide]] catalyst,<ref>{{cite patent|status=patent |country=DE |number=1917037 |gdate=1968|title=Verfahren zur Herstellung von Pyridin und Methylpyridinen|inventor=Swift, Graham}}</ref> by vapor-dealkylation on [[nickel]]-based catalyst,<ref>{{cite patent|status=patent |inventor=Nippon Kayaku |country=JP |number=7039545 |gdate=1967|title=Electrically-assisted bicycle, driving system thereof, and manufacturing method}}</ref><ref>{{cite patent|status=patent |country=BE |number=758201 |gdate=1969|title=Procede de preparation de bases pyridiques|inventor=
Koei Chemical}}</ref> or hydrodealkylation with a [[silver]]- or [[platinum]]-based catalyst.<ref>{{cite journal|title=Hydrodealkylierung von Pyridinbasen bei Normaldruck|author=Mensch, F. |year=1969|journal= Erdöl Kohle Erdgas Petrochemie|volume= 2|pages= 67–71}}</ref> Yields of pyridine up to be 93% can be achieved with the nickel-based catalyst.<ref name=ul/> Pyridine can also be produced by the [[decarboxylation]] of [[nicotinic acid]] with [[copper chromite]].<ref>{{cite journal|title = A method for the Degradation of Radioactive Nicotinic Acid|journal = Biochemical Journal|volume=102|issue=1|pages=87–93|author1=Scott, T. A.|doi=10.1042/bj1020087|pmc = 1270213|year = 1967|pmid=6030305}}</ref>

===Bönnemann cyclization===
[[File:BönnemannEn.png|class=skin-invert-image|thumb|Bönnemann cyclization]]
The [[trimerization]] of a part of a [[nitrile]] molecule and two parts of [[acetylene]] into pyridine is called '''Bönnemann cyclization'''. This modification of the [[Walter Reppe|Reppe synthesis]] can be activated either by heat or by [[Photochemistry|light]]. While the [[thermal activation]] requires high pressures and temperatures, the photoinduced [[cycloaddition]] proceeds at ambient conditions with CoCp<sub>2</sub>(cod) (Cp = cyclopentadienyl, cod = [[1,5-cyclooctadiene]]) as a catalyst, and can be performed even in water.<ref>{{cite book|last=Behr |first=A. |date=2008 |title=Angewandte homogene Katalyse |page=722 |publisher=Wiley-VCH |location=Weinheim |isbn=978-3-527-31666-3}}</ref> A series of pyridine derivatives can be produced in this way. When using [[acetonitrile]] as the nitrile, 2-methylpyridine is obtained, which can be dealkylated to pyridine.

===Other methods===
The [[Kröhnke pyridine synthesis]] provides a fairly general method for generating substituted pyridines using pyridine itself as a reagent which does not become incorporated into the final product. The reaction of pyridine with bromomethyl ketones gives the related [[pyridinium]] salt, wherein the [[methylene group]] is highly acidic. This species undergoes a [[Michael addition|Michael-like addition]] to [[Α,β-Unsaturated carbonyl compound|α,β-unsaturated carbonyls]] in the presence of [[ammonium acetate]] to undergo ring closure and formation of the targeted substituted pyridine as well as pyridinium bromide.<ref>{{cite journal|first=Fritz |last=Kroehnke |title=The Specific Synthesis of Pyridines and Oligopyridines |journal=Synthesis |date=1976 |volume=1976 |issue=1 |pages=1–24 |doi=10.1055/s-1976-23941|s2cid=95238046 }}.</ref>
[[File:Kroehnke Pyridine Figure 1.png|class=skin-invert-image|600px|Figure 1|center]]
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The Ciamician–Dennstedt rearrangement<ref>{{Cite journal |last1=Ciamician |first1=G. L. |last2=Dennstedt |first2=M. |date=1881 |title=Ueber die Einwirkung des Chloroforms auf die Kaliumverbindung Pyrrols |url=https://onlinelibrary.wiley.com/doi/10.1002/cber.188101401240 |journal=Berichte der Deutschen Chemischen Gesellschaft |language=en |volume=14 |issue=1 |pages=1153–1163 |doi=10.1002/cber.188101401240 |issn=0365-9496}}</ref> entails the ring-expansion of [[pyrrole]] with [[dichlorocarbene]] to [[3-Chloropyridine|3-chloropyridine]].<ref>{{cite journal|doi=10.1021/ja01541a070|last1=Skell |first1=P. S. |last2=Sandler |first2=R. S. |journal= Journal of the American Chemical Society |volume=80|pages= 2024 |year=1958|issue=8|title=Reactions of 1,1-Dihalocyclopropanes with Electrophilic Reagents. Synthetic Route for Inserting a Carbon Atom Between the Atoms of a Double Bond}}</ref><ref>{{cite journal|doi=10.1039/J39690002249|title=Mechanism of heterocyclic ring expansions. Part III. Reaction of pyrroles with dichlorocarbene|year=1969|last1=Jones|first1=R. L.|last2=Rees|first2=C. W.|journal=Journal of the Chemical Society C: Organic|issue=18|pages=2249}}</ref><ref>{{cite journal|last1=Gambacorta |first1=A. |last2=Nicoletti |first2=R. |last3=Cerrini |first3=S. |last4=Fedeli |first4=W. |last5=Gavuzzo |first5=E. |doi=10.1016/S0040-4039(01)94795-1|title=Trapping and structure determination of an intermediate in the reaction between 2-methyl-5-''t''-butylpyrrole and dichlorocarbene|year=1978|journal=Tetrahedron Letters|volume=19|issue=27|pages=2439}}</ref>
[[File:Ciamician-Dennstedt Rearrangement.png|class=skin-invert-image|500px|center|Ciamician–Dennstedt Rearrangement]]
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In the Gattermann–Skita synthesis,<ref>{{cite journal|title = Eine Synthese von Pyridin-Derivaten|trans-title = A synthesis of pyridine derivatives|journal = Chemische Berichte|volume = 49|issue = 1|year = 1916|pages = 494–501|last1 = Gattermann|first1 = L.|last2 = Skita|first2 = A.|doi = 10.1002/cber.19160490155|url = https://zenodo.org/record/1426601|access-date = 29 June 2019|archive-date = 25 September 2020|archive-url = https://web.archive.org/web/20200925145302/https://zenodo.org/record/1426601|url-status = live}}</ref> a [[Malonic ester synthesis|malonate ester]] salt reacts with dichloro[[methylamine]].<ref>{{cite web|archive-url=https://web.archive.org/web/20060616020955/http://www.pmf.ukim.edu.mk/PMF/Chemistry/reactions/gattermann-skita.htm |url=http://www.pmf.ukim.edu.mk/PMF/Chemistry/reactions/gattermann-skita.htm |title=Gattermann–Skita |publisher=Institute of Chemistry, Skopje |archive-date=2006-06-16}}</ref>
[[File:Gattermann-Skita Syntesis.png|class=skin-invert-image|500px|center|Gattermann–Skita synthesis]]
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Other methods include the [[Boger pyridine synthesis]] and [[Diels–Alder reaction]] of an [[alkene]] and an [[oxazole]].<ref>{{Cite journal |author1=Karpeiskii, Y.|author2=Florent'ev V. L. |date=1969 |title=Condensation of Oxazoles with Dienophiles — a New Method for the Synthesis of Pyridine Bases |journal=Russian Chemical Reviews |volume=38 |issue=7 |pages=540–546 |doi=10.1070/RC1969v038n07ABEH001760 |bibcode=1969RuCRv..38..540K |s2cid=250852496 }}</ref>

===Biosynthesis===
Several pyridine derivatives play important roles in biological systems. While its biosynthesis is not fully understood, [[nicotinic acid]] (vitamin B<sub>3</sub>) occurs in some [[bacteria]], [[fungi]], and [[mammal]]s. Mammals synthesize nicotinic acid through oxidation of the [[amino acid]] [[tryptophan]], where an intermediate product, the [[aniline]] derivative [[kynurenine]], creates a pyridine derivative, [[quinolinate]] and then nicotinic acid. On the contrary, the bacteria ''[[Mycobacterium tuberculosis]]'' and ''[[Escherichia coli]]'' produce nicotinic acid by condensation of [[glyceraldehyde 3-phosphate]] and [[aspartic acid]].<ref>{{cite journal|doi=10.1104/pp.69.3.553|last1=Tarr|pmc=426252|pmid=16662247|first1=J. B.|year=1982|pages=553–556|issue=3|volume=69|last2=Arditti|journal=Plant Physiology|first2=J.|title=Niacin Biosynthesis in Seedlings of ''Zea mays''}}</ref>