Editing Pyridine (section)

==Reactions==
Because of the [[Electronegativity|electronegative]] [[nitrogen]] in the pyridine ring, pyridine enters less readily into [[electrophilic aromatic substitution]] reactions than benzene derivatives.<ref>{{cite book|last=Sundberg|first=Francis A. Carey; Richard J.|title=Advanced Organic Chemistry : Part A: Structure and Mechanisms|year=2007|publisher=Springer US|location=Berlin|isbn=978-0-387-68346-1|edition=5.|page=794}}</ref> Instead, in terms of its reactivity, pyridine resembles [[nitrobenzene]].<ref>{{cite journal|title=Adrien Albert and the Rationalization of Heterocyclic chemistry|first1=E. |last1=Campaigne|journal=J. Chem. Educ.|year=1986|volume=63|issue=10|page=860|doi=10.1021/ed063p860|bibcode=1986JChEd..63..860C }}</ref>

Correspondingly pyridine is more prone to [[nucleophilic substitution]], as evidenced by the ease of [[metalation]] by strong [[Organometallic chemistry|organometallic]] bases.<ref name=jou10/><ref name=davies/> The reactivity of pyridine can be distinguished for three chemical groups. With [[electrophile]]s, [[electrophilic substitution]] takes place where pyridine expresses aromatic properties. With [[nucleophile]]s, pyridine reacts at positions 2 and 4 and thus behaves similar to [[imine]]s and [[carbonyl]]s. The reaction with many [[Lewis acid]]s results in the addition to the nitrogen atom of pyridine, which is similar to the reactivity of tertiary amines. The ability of pyridine and its derivatives to oxidize, forming [[amine oxide]]s (''N''-oxides), is also a feature of tertiary amines.<ref>{{cite book|first1=R. |last1=Milcent |first2=F. |last2=Chau |title=Chimie organique hétérocyclique: Structures fondamentales |pages=241–282 |publisher=EDP Sciences |date=2002 |isbn=2-86883-583-X}}</ref>

The nitrogen center of pyridine features a basic [[lone pair]] of [[electron]]s. This lone pair does not overlap with the aromatic π-system ring, consequently pyridine is [[Base (chemistry)|basic]], having chemical properties similar to those of [[tertiary amine]]s. [[Protonation]] gives [[pyridinium]], C<sub>5</sub>H<sub>5</sub>NH<sup>+</sup>.The [[pKa|p''K''<sub>a</sub>]] of the [[conjugate acid]] (the pyridinium cation) is 5.25. The structures of pyridine and pyridinium are almost identical.<ref>{{cite journal|last1=Krygowski |first1=T. M. |last2=Szatyowicz |first2=H. |last3=Zachara |first3=J. E. |journal = J. Org. Chem.|doi = 10.1021/jo051354h|pmid = 16238319|title = How H-bonding Modifies Molecular Structure and π-Electron Delocalization in the Ring of Pyridine/Pyridinium Derivatives Involved in H-Bond Complexation|year = 2005|volume = 70|issue = 22|pages = 8859–8865}}</ref> The pyridinium cation is [[isoelectronic]] with benzene. Pyridinium ''p''-[[toluenesulfonic acid|toluenesulfonate]] (PPTS) is an illustrative pyridinium salt; it is produced by treating pyridine with [[P-Toluenesulfonic acid|''p''-toluenesulfonic acid]]. In addition to [[protonation]], pyridine undergoes N-centred [[alkylation]], [[acylation]], and [[N-oxidation|''N''-oxidation]]. Pyridine and poly(4-vinyl) pyridine have been shown to form conducting [[Molecular wire|molecular wires]] with remarkable polyenimine structure on [[UV irradiation]], a process which accounts for at least some of the visible light absorption by aged pyridine samples. These wires have been theoretically predicted to be both highly efficient electron donors and acceptors, and yet are resistant to air oxidation.<ref>{{Cite journal |last1=Vaganova |first1=Evgenia |last2=Eliaz |first2=Dror |last3=Shimanovich |first3=Ulyana |last4=Leitus |first4=Gregory |last5=Aqad |first5=Emad |last6=Lokshin |first6=Vladimir |last7=Khodorkovsky |first7=Vladimir |date=January 2021 |title=Light-Induced Reactions within Poly(4-vinyl pyridine)/Pyridine Gels: The 1,6-Polyazaacetylene Oligomers Formation |journal=Molecules |language=en |volume=26 |issue=22 |pages=6925 |doi=10.3390/molecules26226925 |pmid=34834017 |pmc=8621047 |issn=1420-3049|doi-access=free }}</ref>

===Electrophilic substitutions===
Owing to the decreased electron density in the aromatic system, [[electrophilic substitution]]s are suppressed in pyridine and its derivatives. [[Friedel–Crafts reaction|Friedel–Crafts alkylation or acylation]], usually fail for pyridine because they lead only to the addition at the nitrogen atom. Substitutions usually occur at the 3-position, which is the most electron-rich carbon atom in the ring and is, therefore, more susceptible to an electrophilic addition.

[[File:Pyridine-EAS-2-position-2D-skeletal.png|class=skin-invert-image|520px|center|substitution in the 2-position]]
[[File:Pyridine-EAS-3-position-2D-skeletal.png|class=skin-invert-image|500px|center|substitution in the 3-position]]
[[File:Pyridine-EAS-4-position-2D-skeletal.png|class=skin-invert-image|430px|center|Substitution in 4-position]]

Direct [[nitration]] of pyridine is sluggish.<ref>{{cite journal|last1=Bakke|first1=Jan M.|last2=Hegbom|first2=Ingrid|title=Dinitrogen Pentoxide-Sulfur Dioxide, a New nitrate ion system|journal=Acta Chemica Scandinavica|volume=48|pages=181–182|year=1994|doi=10.3891/acta.chem.scand.48-0181|last10=Stidsen|first10=Carsten E.|doi-access=free}}</ref><ref>{{cite journal|last1=Ono|first1=Noboru|last2=Murashima|first2=Takashi|last3=Nishi|first3=Keiji|last4=Nakamoto|first4=Ken-Ichi|last5=Kato|first5=Atsushi|last6=Tamai|first6=Ryuji|last7=Uno|first7=Hidemitsu|title=Preparation of Novel Heteroisoindoles from nitropyridines and Nitropyridones|journal=Heterocycles|volume=58|pages=301|year=2002|doi=10.3987/COM-02-S(M)22|doi-access=free}}</ref> Pyridine derivatives wherein the nitrogen atom is screened sterically and/or electronically can be obtained by nitration with [[nitronium tetrafluoroborate]] (NO<sub>2</sub>BF<sub>4</sub>). In this way, 3-nitropyridine can be obtained via the synthesis of 2,6-dibromopyridine followed by nitration and debromination.<ref>{{cite journal|last1=Duffy |first1=Joseph L. |last2=Laali |first2=Kenneth K. |title=Aprotic Nitration ({{chem|NO|2|+|BF|4|−}}) of 2-Halo- and 2,6-Dihalopyridines and Transfer-Nitration Chemistry of Their ''N''-Nitropyridinium Cations|journal=The Journal of Organic Chemistry|volume=56|pages=3006|year=1991|doi=10.1021/jo00009a015|issue=9}}</ref><ref>[[#Joule|Joule]], p.&nbsp;126</ref>

[[Sulfonation]] of pyridine is even more difficult than nitration.   However, pyridine-3-sulfonic acid can be obtained. Reaction with the SO<sub>3</sub> group also facilitates addition of sulfur to the nitrogen atom, especially in the presence of a [[mercury(II) sulfate]] catalyst.<ref name=jou10/><ref>{{cite journal|last1=Möller|first1=Ernst Friedrich|last2=Birkofer|first2=Leonhard|title=Konstitutionsspezifität der Nicotinsäure als Wuchsstoff bei ''Proteus vulgaris'' und ''Streptobacterium plantarum''|trans-title=Constitutional specificity of nicotinic acid as a growth factor in ''Proteus vulgaris'' and ''Streptobacterium plantarum''|journal=Berichte der Deutschen Chemischen Gesellschaft (A and B Series)|volume=75|pages=1108|year=1942|doi=10.1002/cber.19420750912|issue=9}}</ref>

In contrast to the sluggish nitrations and sulfonations, the [[bromination]] and [[chlorination reaction|chlorination]] of pyridine proceed well.<ref name=ul/>
[[File:simple chlorination.png|class=skin-invert-image|500px|center]]

====Pyridine ''N''-oxide====
[[File:Pyridine N-oxide.png|class=skin-invert-image|thumb|upright=.4|Structure of pyridine ''N''-oxide]]
Oxidation of pyridine occurs at nitrogen to give [[Pyridine-N-oxide|pyridine ''N''-oxide]]. The oxidation can be achieved with [[peracid]]s:<ref name = "pyridine-N-oxide hydrochloride">{{cite journal |first1 = H. S.|last1 = Mosher |first2 = L.|last2 = Turner |first3 = A.|last3 = Carlsmith |title = Pyridine-''N''-oxide |journal=Org. Synth. |year = 1953 |volume=33 |page=79 |doi = 10.15227/orgsyn.033.0079}}</ref>
:C<sub>5</sub>H<sub>5</sub>N + RCO<sub>3</sub>H &rarr; C<sub>5</sub>H<sub>5</sub>NO +  RCO<sub>2</sub>H

Some electrophilic substitutions on the pyridine are usefully effected using pyridine ''N''-oxide followed by deoxygenation. Addition of oxygen suppresses further reactions at nitrogen atom and promotes substitution at the 2- and 4-carbons. The oxygen atom can then be removed, e.g., using zinc dust.<ref>{{cite journal|title=Synthesis of 2-aryl Pyridines By Palladium-catalyzed Direct Arylation of Pyridine ''N''-oxides|author1=Campeau, Louis-Charles |author2=Fagnou, Keith |journal=Org. Synth.|year=2011|volume=88|pages=22|doi=10.15227/orgsyn.088.0022|doi-access=free}}</ref>

===Nucleophilic substitutions===
In contrast to benzene ring, pyridine efficiently supports several nucleophilic substitutions. The reason for this is relatively lower electron density of the carbon atoms of the ring. These reactions include substitutions with elimination of a [[hydride]] ion and elimination-additions with formation of an intermediate [[aryne]] configuration, and usually proceed at the 2- or 4-position.<ref name=jou10/><ref name=davies>{{cite book|first=D. T. |last=Davies |title=Aromatic Heterocyclic Chemistry |publisher=Oxford University Press |date=1992 |isbn=0-19-855660-8}}</ref>

[[File:Pyridine-NA-2-position.svg|class=skin-invert-image|500px|center|Nucleophilic substitution in 2-position]]
[[File:Pyridine-NA-3-position.svg|class=skin-invert-image|500px|center|Nucleophilic substitution in 3-position]]
[[File:Pyridine-NA-4-position.svg|class=skin-invert-image|500px|center|Nucleophilic substitution in 4-position]]

Many nucleophilic substitutions occur more easily not with bare pyridine but with pyridine modified with bromine, chlorine, fluorine, or sulfonic acid fragments that then become a leaving group. So fluorine is the best leaving group for the substitution with [[organolithium compound]]s. The nucleophilic attack compounds may be [[alkoxide]]s, thiolates, [[amine]]s, and ammonia (at elevated pressures).<ref>[[#Joule|Joule]], p.&nbsp;133</ref>

In general, the hydride ion is a poor leaving group and occurs only in a few heterocyclic reactions. They include the [[Chichibabin reaction]], which yields pyridine derivatives [[Amination|aminated]] at the 2-position. Here, [[sodium amide]] is used as the nucleophile yielding 2-aminopyridine. The hydride ion released in this reaction combines with a proton of an available amino group, forming a hydrogen molecule.<ref name=davies/><ref>{{cite journal|last1=Shreve|first1=R. Norris|last2=Riechers|first2=E. H.|last3=Rubenkoenig|first3=Harry|last4=Goodman|first4=A. H.|title=Amination in the Heterocyclic Series by Sodium amide|journal=Industrial & Engineering Chemistry|volume=32|pages=173|year=1940|doi=10.1021/ie50362a008|issue=2}}</ref>

Analogous to benzene, nucleophilic substitutions to pyridine can result in the formation of [[pyridyne]] intermediates as hetero[[aryne]]. For this purpose, pyridine derivatives can be eliminated with good leaving groups using strong bases such as sodium and [[potassium tert-butoxide]]. The subsequent addition of a nucleophile to the [[triple bond]] has low selectivity, and the result is a mixture of the two possible adducts.<ref name=jou10/>

===Radical reactions===
Pyridine supports a series of radical reactions, which is used in its [[Dimer (chemistry)|dimerization]] to bipyridines. Radical dimerization of pyridine with elemental [[sodium]] or [[Raney nickel]] selectively yields [[4,4'-bipyridine]],<ref>{{cite book|last1=Badger|first1=G|last2=Sasse|first2=W|chapter=The Action of Metal Catalysts on Pyridines|volume=2|pages=179–202|year=1963|doi=10.1016/S0065-2725(08)60749-7|title=Advances in Heterocyclic Chemistry Volume 2|pmid=14279523|isbn=9780120206025}}</ref> or [[2,2'-bipyridine]],<ref>{{cite journal|author=Sasse, W. H. F.|title=2,2'-bipyridine|journal=Organic Syntheses|year=1966|volume=46|pages=5–8|doi=10.1002/0471264180.os046.02|df=dmy-all}}</ref> which are important precursor reagents in the chemical industry. One of the [[name reactions]] involving free radicals is the [[Minisci reaction]]. It can produce 2-''tert''-butylpyridine upon reacting pyridine with [[pivalic acid]], [[silver nitrate]] and [[ammonium]] in [[sulfuric acid]] with a yield of 97%.<ref name=jou10>[[#Joule|Joule]], pp. 125–141</ref>

===Reactions on the nitrogen atom===
[[File:Pyridine-complex.svg|class=skin-invert-image|thumb|upright=1.5|Additions of various [[Lewis acid]]s to pyridine]]
[[Lewis acid]]s easily add to the nitrogen atom of pyridine, forming pyridinium salts. The reaction with [[alkyl halide]]s leads to [[alkylation]] of the nitrogen atom. This creates a positive charge in the ring that increases the reactivity of pyridine to both oxidation and reduction. The [[Zincke reaction]] is used for the selective introduction of radicals in pyridinium compounds (it has no relation to the chemical element [[zinc]]).

===Hydrogenation and reduction===
[[File:Piperidin Reaktionsschema.svg|class=skin-invert-image|left|thumb|Reduction of pyridine ('''1''') to piperidine ('''2''') with [[Raney nickel]]]]

[[Piperidine]] is produced by [[hydrogenation]] of pyridine with a [[nickel]]-, [[cobalt]]-, or [[ruthenium]]-based catalyst at elevated temperatures.<ref>{{Ullmann|last1=Eller |first1=K. |last2=Henkes |first2=E. |last3=Rossbacher |first3=R. |last4=Hoke |first4=H. |title=Amines, aliphatic}}</ref> The hydrogenation of pyridine to piperidine releases 193.8&nbsp;kJ/mol,<ref name="Cox">{{cite book|last1=Cox |first1=J. D. |last2=Pilcher |first2=G. |date=1970 |title=Thermochemistry of Organic and Organometallic Compounds |publisher=Academic Press |location=New York |pages=1–636 |isbn=0-12-194350-X}}</ref> which is slightly less than the energy of the hydrogenation of [[benzene]] (205.3&nbsp;kJ/mol).<ref name="Cox"/>

Partially hydrogenated derivatives are obtained under milder conditions. For example, reduction with [[lithium aluminium hydride]] yields a mixture of 1,4-dihydropyridine, 1,2-dihydropyridine, and 2,5-dihydropyridine.<ref>{{cite journal|last1=Tanner|first1=Dennis D.|last2=Yang|first2=Chi Ming|title=On the structure and mechanism of formation of the Lansbury reagent, lithium tetrakis(''N''-dihydropyridyl) aluminate|journal=The Journal of Organic Chemistry|volume=58|pages=1840|year=1993|doi=10.1021/jo00059a041|issue=7}}</ref> Selective synthesis of 1,4-dihydropyridine is achieved in the presence of organometallic complexes of [[magnesium]] and [[zinc]],<ref>{{cite journal|last1=De Koning|first1=A.|title=Specific and selective reduction of aromatic nitrogen heterocycles with the bis-pyridine complexes of bis(1,4-dihydro-1-pyridyl)zinc and bis(1,4-dihydro-1-pyridyl)magnesium|journal=Journal of Organometallic Chemistry|volume=199|pages=153|year=1980|doi=10.1016/S0022-328X(00)83849-8|issue=2|last2=Budzelaar|first2=P. H. M.|last3=Boersma|first3=J.|last4=Van Der Kerk|first4=G. J. M.}}</ref> and (Δ3,4)-tetrahydropyridine is obtained by electrochemical reduction of pyridine.<ref>{{cite journal | last=Ferles | first=M. | title=Studies in the pyridine series. II. Ladenburg and electrolytic reductions of pyridine bases | journal=Collection of Czechoslovak Chemical Communications | publisher=Institute of Organic Chemistry & Biochemistry | volume=24 | issue=4 | year=1959 | doi=10.1135/cccc19591029 | pages=1029–1035}}</ref> [[Birch reduction]] converts pyridine to dihydropyridines.<ref>{{cite journal |doi=10.1021/ol0065930|title=Partial Reduction of Electron-Deficient Pyridines |year=2000 |last1=Donohoe |first1=Timothy J. |last2=McRiner |first2=Andrew J. |last3=Sheldrake |first3=Peter |journal=Organic Letters |volume=2 |issue=24 |pages=3861–3863 |pmid=11101438 }}</ref>

===Lewis basicity and coordination compounds===
Pyridine is a [[Lewis base]], donating its pair of electrons to a Lewis acid. Its Lewis base properties are discussed in the [[ECW model]]. Its relative donor strength toward a series of acids, versus other Lewis bases, can be illustrated by [[ECW model|C-B plots]].<ref>Laurence, C. and Gal, J-F. (2010) ''Lewis Basicity and Affinity Scales, Data and Measurement''. Wiley. pp. 50–51. {{ISBN|978-0-470-74957-9}}</ref><ref>{{cite journal|author1=Cramer, R. E. |author2=Bopp, T. T. |year=1977|title= Graphical display of the enthalpies of adduct formation for Lewis acids and bases |journal= Journal of Chemical Education |volume=54|pages=612–613|doi= 10.1021/ed054p612}} The plots shown in this paper used older parameters. Improved E&C parameters are listed in [[ECW model]].</ref> One example is the [[sulfur trioxide pyridine complex]] (melting point 175&nbsp;°C), which is a [[sulfation]] agent used to convert alcohols to [[sulfate ester]]s. Pyridine-[[borane]] ({{chem2|C5H5NBH3}}, melting point 10–11&nbsp;°C) is a mild reducing agent.

[[File:Crabtree.svg|class=skin-invert-image|thumb|structure of the [[Crabtree's catalyst]]]]

[[Transition metal pyridine complexes]] are numerous.<ref name =nakamoto>{{cite book|last=Nakamoto|first=K.|title=Infrared and Raman spectra of Inorganic and Coordination compounds|edition=5th|series=Part A|year=1997|publisher=Wiley|isbn=0-471-16394-5}}</ref><ref>{{cite book|last=Nakamoto|first=K.|title=Infrared and Raman spectra of Inorganic and Coordination compounds|edition=5th|series=Part B|isbn=0-471-16392-9|page=24|date=31 July 1997}}</ref> 
Typical octahedral complexes have the stoichiometry {{chem2|MCl2(py)4}} and {{chem2|MCl3(py)3}}. Octahedral homoleptic complexes of the type {{chem2|M(py)6(+)}} are rare or tend to dissociate pyridine. Numerous square planar complexes are known, such as [[Crabtree's catalyst]].<ref>{{cite journal |last1=Crabtree |first1=Robert |title=Iridium compounds in catalysis |journal=Accounts of Chemical Research |volume=12 |pages=331–337 |year=1979 |doi=10.1021/ar50141a005|issue=9}}</ref> The pyridine ligand replaced during the reaction is restored after its completion.

The ''η''<sup>6</sup> coordination mode, as occurs in ''η''<sup>6</sup> benzene complexes, is observed only in [[Steric effects|sterically encumbered]] derivatives that block the nitrogen center.<ref name="Elschenbroich 2008 524–525">{{cite book|last=Elschenbroich |first=C. |title=Organometallchemie |edition=6th |pages=524–525 |publisher=Vieweg & Teubner |date=2008 |isbn=978-3-8351-0167-8}}</ref>