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Pyridine is a basic heterocyclic organic compound with the chemical formula C5H5N. It is structurally related to benzene, with one methine group (=CH−) replaced by a nitrogen atom. It is a highly flammable, weakly alkaline, water-miscible liquid with a distinctive, unpleasant fish-like smell. Pyridine is colorless, but older or impure samples can appear yellow. The pyridine ring occurs in many important compounds, including agrochemicals, pharmaceuticals, and vitamins. Historically, pyridine was produced from coal tar. Today it is synthesized on the scale of about 20,000 tons per year worldwide.

Properties

Physical properties

The molecular electric dipole moment is 2.2 debyes. Pyridine is diamagnetic and has a diamagnetic susceptibility of −48.7 × 10−6 cm3·mol−1. The standard enthalpy of formation is 100.2 kJ·mol−1 in the liquid phaseLide, p. 5-28 and 140.4 kJ·mol−1 in the gas phase. At 25 °C pyridine has a viscosity of 0.88 mPa/s and thermal conductivity of 0.166 W·m−1·K−1. The enthalpy of vaporization is 35.09 kJ·mol−1 at the boiling point and normal pressure. The enthalpy of fusion is 8.28 kJ·mol−1 at the melting point. The critical parameters of pyridine are pressure 6.70 MPa, temperature 620 K and volume 229 cm3·mol−1. In the temperature range 340–426 °C its vapor pressure ''p'' can be described with the Antoine equation :$\log_ p = A-\frac$ where ''T'' is temperature, ''A'' = 4.16272, ''B'' = 1371.358 K and ''C'' = −58.496 K.

Structure

Pyridine ring forms a C5N hexagon. Slight variations of the C-C and C-N distances as well as the bond angles are observed.

Crystallography

Pyridine crystallizes in an orthorhombic crystal system with space group ''Pna21'' and lattice parameters ''a'' = 1752 pm, ''b'' = 897 pm, ''c'' = 1135 pm, and 16 formula units per unit cell (measured at 153 K). For comparison, crystalline benzene is also orthorhombic, with space group ''Pbca'', ''a'' = 729.2 pm, ''b'' = 947.1 pm, ''c'' = 674.2 pm (at 78 K), but the number of molecules per cell is only 4. This difference is partly related to the lower symmetry of the individual pyridine molecule (C2v vs D6h for benzene). A trihydrate (pyridine·3H2O) is known; it also crystallizes in an orthorhombic system in the space group ''Pbca'', lattice parameters ''a'' = 1244 pm, ''b'' = 1783 pm, ''c'' = 679 pm and eight formula units per unit cell (measured at 223 K).

Spectroscopy

The optical absorption spectrum of pyridine in hexane contains three bands at the wavelengths of 195 nm (π → π* transition, molar absorptivity ''ε'' = 7500 L·mol−1·cm−1), 251 nm (π → π* transition, ''ε'' = 2000 L·mol−1·cm−1) and 270 nm (n → π* transition, ''ε'' = 450 L·mol−1·cm−1). The 1H nuclear magnetic resonance (NMR) spectrum of pyridine contains three signals with the integral intensity ratio of 2:1:2 that correspond to the three chemically different protons in the molecule. These signals originate from the α-protons (positions 2 and 6, chemical shift 8.5 ppm), γ-proton (position 4, 7.5 ppm) and β-protons (positions 3 and 5, 7.1 ppm). The carbon analog of pyridine, benzene, has only one proton signal at 7.27 ppm. The larger chemical shifts of the α- and γ-protons in comparison to benzene result from the lower electron density in the α- and γ-positions, which can be derived from the resonance structures. The situation is rather similar for the 13C NMR spectra of pyridine and benzene: pyridine shows a triplet at ''δ''(α-C) = 150 ppm, δ(β-C) = 124 ppm and δ(γ-C) = 136 ppm, whereas benzene has a single line at 129 ppm. All shifts are quoted for the solvent-free substances. Pyridine is conventionally detected by the gas chromatography and mass spectrometry methods.

Chemical properties

Because of the electronegative nitrogen in the pyridine ring, the molecule is relatively electron deficient. It, therefore, enters less readily into electrophilic aromatic substitution reactions than benzene derivatives. Correspondingly pyridine is more prone to nucleophilic substitution, as evidenced by the ease of metalation by strong organometallic bases. The reactivity of pyridine can be distinguished for three chemical groups. With electrophiles, electrophilic substitution takes place where pyridine expresses aromatic properties. With nucleophiles, pyridine reacts at positions 2 and 4 and thus behaves similar to imines and carbonyls. The reaction with many Lewis acids 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 oxides (''N''-oxides), is also a feature of tertiary amines. The nitrogen center of pyridine features a basic lone pair of electrons. This lone pair does not overlap with the aromatic π-system ring, consequently pyridine is basic, having chemical properties similar to those of tertiary amines. Protonation gives pyridinium, C5H5NH+.The p''K''a of the conjugate acid (the pyridinium cation) is 5.25. The structures of pyridine and pyridinium are almost identical. The pyridinium cation is isoelectronic with benzene. Pyridinium ''p''-toluenesulfonate (PPTS) is an illustrative pyridinium salt; it is produced by treating pyridine with ''p''-toluenesulfonic acid. In addition to protonation, pyridine undergoes N-centred alkylation, acylation, and ''N''-oxidation.

Bonding

Pyridine has a conjugated system of six π electrons that are delocalized over the ring. The molecule is planar and, thus, follows the Hückel criteria for aromatic systems. In contrast to benzene, the electron density is not evenly distributed over the ring, reflecting the negative inductive effect of the nitrogen atom. For this reason, pyridine has a dipole moment and a weaker resonant stabilization than benzene (resonance energy 117 kJ·mol−1 in pyridine vs. 150 kJ·mol−1 in benzene). The ring atoms in the pyridine molecule are sp2-hybridized. The nitrogen is involved in the π-bonding aromatic system using its unhybridized p orbital. The lone pair is in an sp2 orbital, projecting outward from the ring in the same plane as the σ bonds. As a result, the lone pair does not contribute to the aromatic system but importantly influences the chemical properties of pyridine, as it easily supports bond formation via an electrophilic attack. However, because of the separation of the lone pair from the aromatic ring system, the nitrogen atom cannot exhibit a positive mesomeric effect. Many analogues of pyridine are known where N is replaced by other heteroatoms (see figure below). Substitution of one C–H in pyridine with a second N gives rise to the diazine heterocycles (C4H4N2), with the names pyridazine, pyrimidine, and pyrazine.

History

Impure pyridine was undoubtedly prepared by early alchemists by heating animal bones and other organic matter, but the earliest documented reference is attributed to the Scottish scientist Thomas Anderson. In 1849, Anderson examined the contents of the oil obtained through high-temperature heating of animal bones. Among other substances, he separated from the oil a colorless liquid with unpleasant odor, from which he isolated pure pyridine two years later. He described it as highly soluble in water, readily soluble in concentrated acids and salts upon heating, and only slightly soluble in oils. Owing to its flammability, Anderson named the new substance ''pyridine'', after gr|πῦρ (pyr) meaning ''fire''. The suffix ''idine'' was added in compliance with the chemical nomenclature, as in ''toluidine'', to indicate a cyclic compound containing a nitrogen atom. The chemical structure of pyridine was determined decades after its discovery. Wilhelm Körner (1869) and James Dewar (1871) suggested that, in analogy between quinoline and naphthalene, the structure of pyridine is derived from benzene by substituting one C–H unit with a nitrogen atom. The suggestion by Körner and Dewar was later confirmed in an experiment where pyridine was reduced to piperidine with sodium in ethanol. In 1876, William Ramsay combined acetylene and hydrogen cyanide into pyridine in a red-hot iron-tube furnace. This was the first synthesis of a heteroaromatic compound. The first major synthesis of pyridine derivatives was described in 1881 by Arthur Rudolf Hantzsch. The Hantzsch pyridine synthesis typically uses a 2:1:1 mixture of a β-keto acid (often acetoacetate), an aldehyde (often formaldehyde), and ammonia or its salt as the nitrogen donor. First, a double hydrogenated pyridine is obtained, which is then oxidized to the corresponding pyridine derivative. Emil Knoevenagel showed that asymmetrically-substituted pyridine derivatives can be produced with this process. The contemporary methods of pyridine production had a low yield, and the increasing demand for the new compound urged to search for more efficient routes. A breakthrough came in 1924 when the Russian chemist Aleksei Chichibabin invented a pyridine synthesis reaction, which was based on inexpensive reagents. This method is still used for the industrial production of pyridine.

Occurrence

Pyridine is not abundant in nature, except for the leaves and roots of belladonna (''Atropa belladonna'') and in marshmallow (''Althaea officinalis''). Pyridine derivatives, however, are often part of biomolecules such as alkaloids. In daily life, trace amounts of pyridine are components of the volatile organic compounds that are produced in roasting and canning processes, e.g. in fried chicken, sukiyaki, roasted coffee, potato chips, and fried bacon. Traces of pyridine can be found in Beaufort cheese, vaginal secretions, black tea, saliva of those suffering from gingivitis, and sunflower honey. File:4-Bromopyridine.svg|4-bromopyridine File:2,2'-Bipyridine.svg|2,2'-bipyridine File:Dipicolinic acid.svg|pyridine-2,6-dicarboxylic acid (dipicolinic acid) File:PyridiniumVerbindungen.svg|General form of the pyridinium cation

Production

Historically, pyridine was extracted from coal tar or obtained as a byproduct of coal gasification. The process was labor-consuming and inefficient: coal tar contains only about 0.1% pyridine, and therefore a multi-stage purification was required, which further reduced the output. Nowadays, most pyridine is produced synthetically using various name reactions, and the major ones are discussed below. In 1989, 26,000 tonnes of pyridine was produced worldwide. Among the largest 25 production sites for pyridine, eleven are located in Europe (as of 1999). The major producers of pyridine include Evonik Industries, Rütgers Chemicals, Jubilant Life Sciences, Imperial Chemical Industries, and Koei Chemical. Pyridine production significantly increased in the early 2000s, with an annual production capacity of 30,000 tonnes in mainland China alone. The US–Chinese joint venture Vertellus is currently the world leader in pyridine production.

Chichibabin synthesis

The Chichibabin pyridine synthesis was reported in 1924 and is still in use in industry. In its general form, the reaction can be described as a condensation reaction of aldehydes, ketones, α,β-unsaturated carbonyl compounds, or any combination of the above, in ammonia or ammonia derivatives. In particular, unsubstituted pyridine is produced from formaldehyde and acetaldehyde, which are inexpensive and widely available. First, acrolein is formed in a Knoevenagel condensation from the acetaldehyde and formaldehyde. The acrolein is then condensed with acetaldehyde and ammonia to give dihydropyridine, which is oxidized with a solid-state catalyst to pyridine. This process is carried out in a gas phase at 400–450 °C. The product consists of a mixture of pyridine, simple methylated pyridines (picolines and lutidines); its composition depends on the catalyst used and can be adapted to the needs of the manufacturer. The catalyst is usually a transition metal salt such as cadmium(II) fluoride or manganese(II) fluoride, but cobalt and thallium compounds can also be used. The recovered pyridine is separated from byproducts in a multistage process. Practical application of the traditional Chichibabin pyridine synthesis are limited by its consistently low yield, typically about 20%. This low yield, together with the high prevalence of byproducts, render unmodified forms of Chichibabin's method unpopular.

Dealkylation of alkylpyridines

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, by vapor-dealkylation on nickel-based catalyst, or hydrodealkylation with a silver- or platinum-based catalyst. Yields of pyridine up to be 93% can be achieved with the nickel-based catalyst.

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 Reppe synthesis can be activated either by heat or by light. While the thermal activation requires high pressures and temperatures, the photoinduced cycloaddition proceeds at ambient conditions with CoCp2(cod) (Cp = cyclopentadienyl, cod = 1,5-cyclooctadiene) as a catalyst, and can be performed even in water. 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 α-bromoesters give the related pyridinium salt, wherein the methylene group is highly acidic. This species undergoes a Michael-like addition to 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. The Ciamician–Dennstedt rearrangement entails the ring-expansion of pyrrole with dichlorocarbene to 3-chloropyridine. In the Gattermann–Skita synthesis, a malonate ester salt reacts with dichloromethylamine. Another method is the Boger pyridine synthesis. Pyridine can also be produced by the decarboxylation of nicotinic acid with copper chromite.

Biosynthesis

Several pyridine derivatives play important roles in biological systems. While its biosynthesis is not fully understood, nicotinic acid (vitamin B3) occurs in some bacteria, fungi, and mammals. Mammals synthesize nicotinic acid through oxidation of the amino acid tryptophan, where an intermediate product, aniline, creates a pyridine derivative, kynurenine. On the contrary, the bacteria ''Mycobacterium tuberculosis'' and ''Escherichia coli'' produce nicotinic acid by condensation of glyceraldehyde 3-phosphate and aspartic acid.

Reactions

Despite the structural and bonding commonalities of benzene and pyridine, their reactivity differ significantly. Instead, in terms of its reactivity, pyridine more closely resembles nitrobenzene.

Electrophilic substitutions

Owing to the decreased electron density in the aromatic system, electrophilic substitutions are suppressed in pyridine and its derivatives. 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. Direct nitration of pyridine is sluggish. Pyridine derivatives wherein the nitrogen atom is screened sterically and/or electronically can be obtained by nitration with nitronium tetrafluoroborate (NO2BF4). In this way, 3-nitropyridine can be obtained via the synthesis of 2,6-dibromopyridine followed by debromination. Sulfonation of pyridine is even more difficult than nitration. However, pyridine-3-sulfonic acid can be obtained. Reaction with the SO3 group also facilitates addition of sulfur to the nitrogen atom, especially in the presence of a mercury(II) sulfate catalyst. In contrast to the sluggish nitrations and sulfonations, the bromination and chlorination of pyridine proceed well.

Pyridine-N-oxide

Oxidation of pyridine occurs at nitrogen to give pyridine-N-oxide. The oxidation can be achieved with peracids: :C5H5N + RCO3H → C5H5NO + RCO2H 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.

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. 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 compounds. The nucleophilic attack compounds may be alkoxides, thiolates, amines, and ammonia (at elevated pressures). 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 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. Analogous to benzene, nucleophilic substitutions to pyridine can result in the formation of pyridyne intermediates as heteroaryne. 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.

Pyridine supports a series of radical reactions, which is used in its dimerization to bipyridines. Radical dimerization of pyridine with elemental sodium or Raney nickel selectively yields 4,4'-bipyridine, or 2,2'-bipyridine, 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%.Joule, pp. 125–141

Reactions on the nitrogen atom

Lewis acids easily add to the nitrogen atom of pyridine, forming pyridinium salts. The reaction with alkyl halides 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

Piperidine is produced by hydrogenation of pyridine with a nickel-, cobalt-, or ruthenium-based catalyst at elevated temperatures. The hydrogenation of pyridine to piperidine releases 193.8 kJ·mol−1, which is slightly less than the energy of the hydrogenation of benzene (205.3 kJ·mol−1). 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. Selective synthesis of 1,4-dihydropyridine is achieved in the presence of organometallic complexes of magnesium and zinc, and (Δ3,4)-tetrahydropyridine is obtained by electrochemical reduction of pyridine.

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 C-B plots. One example is the sulfur trioxide pyridine complex (melting point 175 °C), which is a sulfation agent used to convert alcohols to sulfate esters. Pyridine-borane (C5H5NBH3, melting point 10–11 °C) is a mild reducing agent. Transition metal pyridine complexes are numerous. Typical octahedral complexes have the stoichiometry MCl2(py)4 and MCl3(py)3. Octahedral homoleptic complexes of the type M(py)6+ are rare or tend to dissociate pyridine. Numerous square planar complexes are known, such as Crabtree's catalyst. The pyridine ligand replaced during the reaction is restored after its completion. The ''η''6 coordination mode, as occurs in ''η''6 benzene complexes, is observed only in sterically encumbered derivatives that block the nitrogen center.

Applications

Pesticides

The main use of pyridine is as a precursor to the herbicides paraquat and diquat. The first synthesis step of insecticide chlorpyrifos consists of the chlorination of pyridine. Pyridine is also the starting compound for the preparation of pyrithione-based fungicides. Cetylpyridinium and laurylpyridinium, which can be produced from pyridine with a Zincke reaction, are used as antiseptic in oral and dental care products. Pyridine is easily attacked by alkylating agents to give ''N''-alkylpyridinium salts. One example is cetylpyridinium chloride.

Solvent

Pyridine is used as a polar, basic, low-reactive solvent, for example in Knoevenagel condensations. It is especially suitable for the dehalogenation, where it acts as the base of the elimination reaction and bonds the resulting hydrogen halide to form a pyridinium salt. In esterifications and acylations, pyridine activates the carboxylic acid halides or anhydrides. Even more active in these reactions are the pyridine derivatives 4-dimethylaminopyridine (DMAP) and 4-(1-pyrrolidinyl) pyridine. Pyridine is also used as a base in condensation reactions. It is also used in the textile industry to improve network capacity of cotton.

Specialty reagents based on pyridine

As a base, pyridine can be used as the Karl Fischer reagent, but it is usually replaced by alternatives with a more pleasant odor, such as imidazole. Pyridinium chlorochromate, pyridinium dichromate, and the Collins reagent (the complex of chromium(VI) oxide are used for the oxidation of alcohols.

Hazards

Pyridine is added to ethanol to make it unsuitable for drinking. In low doses, pyridine is added to foods to give them a bitter flavor, and such usage was approved by the US Food and Drug Administration and is still considered safe by the agency even though external lobbying forced it to ban pyridine's use as a synthetic flavor in 2018. The detection threshold for pyridine in solutions is about 1–3 mmol·L−1 (79–237 mg·L−1). Pyridine has a flash point of 17 °C and is, therefore, highly flammable. Its ignition temperature is 550 °C, and mixtures of 1.7–10.6 vol% of pyridine with air are explosive. The thermal modification of pyridine starts above 490 °C, resulting in bipyridine (mainly 2,2'-bipyridine and to a lesser extent 2,3'-bipyridine and 2,4'-bipyridine), nitrogen oxides, and carbon monoxide. Pyridine easily dissolves in water and harms both animals and plants in aquatic systems. The permitted maximum allowable concentration of pyridine was 15–30 parts per million (ppm, or 15–30 mg·m−3 in air) in most countries in the 1990s, but was reduced to 5 ppm in the 2000s. For comparison, indoor air contaminated with tobacco smoke may contain up to 16 µg·m−3 of pyridine, and one cigarette contains 21–32 µg.

Health issues

Nomenclature

The systematic name of pyridine, within the Hantzsch–Widman nomenclature recommended by the IUPAC, is ''azinine''. However, systematic names for simple compounds are used very rarely; instead, heterocyclic nomenclature follows historically established common names. IUPAC discourages the use of ''azinine''/''azine'' in favor of ''pyridine''. The numbering of the ring atoms in pyridine starts at the nitrogen (see infobox). An allocation of positions by letter of the Greek alphabet (α-γ) and the substitution pattern nomenclature common for homoaromatic systems (''ortho'', ''meta'', ''para'') are used sometimes. Here α (''ortho''), β (''meta''), and γ (''para'') refer to the 2, 3, and 4 position, respectively. The systematic name for the pyridine derivatives is ''pyridinyl'', wherein the position of the substituted atom is preceded by a number. However, the historical name ''pyridyl'' is encouraged by the IUPAC and used instead of the systematic name. The cationic derivative formed by the addition of an electrophile to the nitrogen atom is called ''pyridinium''.

* 6-membered aromatic rings with one carbon replaced by another group: borabenzene, silabenzene, germabenzene, stannabenzene, pyridine, phosphorine, arsabenzene, stibabenzene, bismabenzene, pyrylium, thiopyrylium, selenopyrylium, telluropyrylium * 6-membered rings with two nitrogen atoms: diazines * 6-membered rings with three nitrogen atoms: triazines * 6-membered rings with four nitrogen atoms: tetrazines * 6-membered rings with five nitrogen atoms: pentazine * 6-membered rings with six nitrogen atoms: hexazine

References

Bibliography

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