Pyridine


Pyridine is a basic heterocyclic organic compound with the chemical formula. It is structurally related to benzene, with one methine group 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 commercial compounds, including agrochemicals, pharmaceuticals, and vitamins. Historically, pyridine was produced from coal tar. As of 2016, it is synthesized on the scale of about 20,000 tons per year worldwide.

Properties

Physical properties

Pyridine is diamagnetic. Its critical parameters are: pressure 5.63 MPa, temperature 619 K and volume 248 cm3/mol. In the temperature range 340–426 K its vapor pressure p can be described with the Antoine equation
where T is temperature, A = 4.16272, B = 1371.358 K and C = −58.496 K.

Structure

Pyridine ring forms a hexagon. Slight variations of the and distances as well as the bond angles are observed.
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. For comparison, crystalline benzene is also orthorhombic, with space group Pbca, a = 729.2 pm, b = 947.1 pm, c = 674.2 pm, but the number of molecules per cell is only 4. This difference is partly related to the lower symmetry of the individual pyridine molecule. A trihydrate 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.

Spectroscopy

The optical absorption spectrum of pyridine in hexane consists of bands at the wavelengths of 195, 251, and 270 nm. With respective extinction coefficients of 7500, 2000, and 450 L·mol−1·cm−1, these bands are assigned to π → π*, π → π*, and n → π* transitions. The compound displays very low fluorescence.
The 1H nuclear magnetic resonance spectrum shows signals for α-, γ- and β-protons. By contrast, the proton signal for benzene is found at δ7.27. 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 = 150 ppm, δ = 124 ppm and δ = 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.

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.
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 from the same column of the Periodic Table of Elements. Substitution of one C–H in pyridine with a second N gives rise to the diazine heterocycles, 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 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 and James Dewar 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, an aldehyde, 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.
File:Hantzsch pyridine synthesis.svg|class=skin-invert-image|800px|thumb|center|Hantzsch pyridine synthesis with acetoacetate, formaldehyde and ammonium acetate, and iron chloride as the oxidizer.
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 and in marshmallow. 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.
Trace amounts of up to 16 μg/m3 have been detected in tobacco smoke. Minor amounts of pyridine are released into environment from some industrial processes such as steel manufacture, processing of oil shale, coal gasification, coking plants and incinerators. The atmosphere at oil shale processing plants can contain pyridine concentrations of up to 13 μg/m3, and 53 μg/m3 levels were measured in the groundwater in the vicinity of a coal gasification plant. According to a study by the US National Institute for Occupational Safety and Health, about 43,000 Americans work in contact with pyridine.

In foods

Pyridine has historically been added to foods to give them a bitter flavour, although this practise is now banned in the U.S. It may still be added to ethanol to make it unsuitable for drinking.

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, 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 reactions are also known, but they are not practiced on scale.
In 1989, 26,000 tonnes of pyridine was produced worldwide. Other major derivatives are 2-, 3-, 4-methylpyridines and 5-ethyl-2-methylpyridine. The combined scale of these alkylpyridines matches that of pyridine itself. Among the largest 25 production sites for pyridine, eleven are located in Europe. 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 the basic approach underpins several industrial routes. In its general form, the reaction involves the condensation reaction of aldehydes, ketones, α,β-unsaturated carbonyl compounds, or any combination of the above, in ammonia or ammonia derivatives. Application of the Chichibabin pyridine synthesis suffer from low yields, often about 30%, 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 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 °C. Typical catalysts are modified forms of alumina and silica. The reaction has been tailored to produce various methylpyridines.