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All You Need To Know About Pyridines

Pyridine is the basic heterocyclic compound of the azine kind.  Pyridine is derived from benzene through replacement of the CH group by the N-atom. The Pyridine structure  is analogous to the structure of benzene, because it is related by the replacement of CH group by N. The major differences include:

1. Departure from a perfect regular hexagonal geometry due to the presence of a hetero atom, to be specific, the shorter nitrogen-carbon bonds,
2. Replacement of a hydrogen atom in the ring’s plane with the unshared electron pair, like in the ring’s plane, located in the sp2 hybrid orbital, and not involved in an aromatic p-electron sextet. This nitrogen lone pair the one responsible for basic properties of pyridines,
3. The strong permanent dipole traceable to a higher electronegativity of the nitrogen atom compared with a carbon atom.

Pyridine ring occurs in several crucial compounds, including vitamins niacin, pyridoxine, as well as azines.

A Scottish chemist, Thomas Anderson invented pyridine in 1849 as one of the compounds that constitute bone oil.  After two years, Anderson derived pure pyridine by fractional distillation of bone oil. It is a highly flammable, colorless, water-soluble, weakly alkaline liquid with an unpleasant distinctive, fish-like smell.

Pyridine is always used as a precursor to pharmaceuticals and agrochemicals and is also a crucial reagent and solvent. Pyridine can be added to ethanol if you want to make it unfit for human consumption. It is also applicable in the production of antihistaminic drugs mepyramine and tripelennamine, in vitro synthesis of DNA, in the production of sulfapyridine (medicine for treating viral infections and bacterial infections), as well as bactericides, herbicides, and water repellents.

Most chemical compounds, even though not produced from pyridine, contain a ring structure. Such compounds include B vitamins such as pyridoxine and niacin,  nicotine, nitrogen-containing plant products, and the anti-tuberculosis drug known as isoniazid. Pyridine was historically produced as a byproduct of coal gasification and from coal tar. However, skyrocketing demand for pyridine led to the development of economical methods of production from ammonia and acetaldehyde, and over 20,000 tonnes are produced per year worldwide.

Nomenclature of pyridine

The systematic name of pyridine, according to the Hantzsch–Widman nomenclature suggested by the IUPAC, is azine. But systematic names for basic compounds are used rarely; instead, nomenclature of heterocycles follows established common names. The IUPAC don’t encourage the use of azine when referring to pyridine.

The numbering of the ring atoms in azine begins at the nitrogen. An allocation of the positions by the Greek alphabet letter (α-γ) and the nomenclature substitution pattern typical to the homoaromatic systems (para ortho, meta, ) are used sometimes. Here α, β and γ refer to the two, three, and four positions, respectively.

Systematic name for the derivatives of pyridine is pyridinyl, where a number precedes the substituted atom positionis preceded by a number. But the historical name pyridyl is recommended by the IUPAC and widely used in place of the systematic name. The derivative formed through the addition of an electrophile to the nitrogen atom is known as pyridinium.

4-bromopyridine

2,2′-bipyridine

Dipicolinic acid (pyridine-2,6-dicarboxylic acid)

The basic form of pyridinium cation

 

Production of pyridine

Pyridine was obtained as the byproduct of coal gasification or extracted from coal tar. This method was inefficient and labor-consuming: coal tar have around 0.1 percent pyridine, and thus a multi-stage purification was needed, which reduced the output further. Today, most pyridine is manufactured synthetically using several name reactions, and the most common ones are discussed here below.

Pyridine Synthesis through Bohlmann-Rahtz

Pyridine Synthesis through Bohlmann-Rahtz allows generation of substituted pyridines in two major steps. The condensation of enamines using ethynylketones results in an aminodiene intermediate which, after heat-induced isomerization, undergoes cyclodehydration to produce 2,3,6-trisubstituted pyridines.

Pyridine Synthesis through a Bohlmann-Rahtz mechanism

The mechanism is related to the popular Hantzsch Dihydropyridine Synthesis wherein situ-generated enamine and enone species produce dihydropyridines. Although Bohlmann-Rahtz Synthesis is highly versatile, the purification of intermediate and incredibly high temperatures needed for the cyclodehydration are challenges which have limited its utility. Most of the challenges have been overcomed, making Bohlmann-Rahtz Synthesis more essential in the pyridines generation.

Even though no mechanistic research has been done, intermediates may be characterized by H-NMR. This shows that the major product of the first Michael Addition and the following proton transfer can be a 2Z-4E-heptadien-6-one that is extracted and purified through column chromatography.

Incredibly high cyclodehydration temperatures are thus needed to facilitate Z/E isomerizations which are a prerequisite for heteroannelation.

Several methods which allow synthesis of tetra and trisubstituted pyridines in a single-step process have been developed recently. Instead of making use of butynone as a substrate, Bagley tested various solvents for conversion of less volatile and inexpensive 4-(trimethylsilyl)but-3-yn-2-one. It was demonstrated that only DMSO and EtOH are ideal solvents. EtOH is clearly favored as being polar and protic solvent vs. DMSO as the polar aprotic solvent. In the two solvents, protodesilylation took place spontaneously. Bagley has also demonstrated that acid catalysis allows the cyclodehydration to continue at a lower temperature.

Acid catalysis also boosts the conjugate addition. A wide range of enamines was reacted with ethynyl ketones in the (5:1) mixture of acetic acid and toluene to afford functionalized pyridines in one step in excellent yields.

After the success of the Brønstedt acid catalysis, the chemist investigated the ability of Lewis acid catalysts. Best conditions Used either twenty mol% ytterbium triflate or fifteen mol% zinc bromide in the refluxing toluene.  Even though the mechanistic research was not done, we can assume that the coordination by the catalyst speeds up the cyclodehydration, Michael Addition, and isomerization steps.

The downside is the limited compatibility with the acid-sensitive substrates. For instance, acid-catalyzed decomposition of the enamines takes place with cyano and tert-butylester as electron withdrawing groups. Another mild alternative is the application of Amberlyst-15 ion exchanging reagent which tolerates tert-butylesters.

Since the enamines aren’t readily available, and to enhance the facility of the process, a 3-component reaction was undertaken using ammonium acetate as the source of the amino group. In this effective procedure, enamine is generated in situ which reacts with alkynone present.

In the first trial, ZnBr₂ and AcOH were applied as extra catalysts with toluene as the solvent. However,  it has since been demonstrated that acid-sensitive substrates always react in a mild environment with EtOH as a solvent.

Chichibabin Synthesis

The Chichibabin pyridine synthesis was first reported in 1924 and is still a major application in the chemical industry. It is a ring-forming reaction, which involves the condensation reaction of aldehydes, ketones, α,β-unsaturated carbonyl compounds. Moreover, the overall form of the reaction may include any combination of the above products in pure ammonia or its derivatives.

Formation of Pyridine

Condensation of formaldehyde and acetaldehyde

Formaldehyde and acetaldehyde are mainly the sources of unsubstituted pyridine. At least, they are affordable and quite accessible.

1. The first step involves the formation of acrolein from formaldehyde and acetaldehyde through Knoevenagel condensation.
2. The end product is then condensed from acrolein with acetaldehyde and ammonia, forming dihydropyridine.
3. The final process is an oxidation reaction with a solid-state catalyst to yield pyridine.
4. The above reaction is performed in a gas phase with a temperature range of 400-450°C. The compound formed consists of pyridine, picoline or simple methylated pyridines, and lutidine. However, the composition is subject to the catalyst in use and to some extent, it varies with the demands of the manufacturer. Typically, the catalyst is a transition metal salt. The most common ones are manganese (II) fluoride or cadmium (II) fluoride, although thallium and cobalt compounds can be alternatives.
5. The pyridine is recovered from the by-products in a multistage process.The major limitation of Chichibabin pyridine synthesis is its low yield, translating to about 20% of the end products. For this reason, the unmodified forms of this compound are less prevalent.

Bönnemann cyclization

Bönnemann cyclization is the formation of a trimer from the combination of two parts of acetylene molecule and a part of a nitrile. Actually, the process is a modification of Reppe synthesis.

The mechanism is facilitated by either heat from elevated temperatures and pressure or through photo-induced cycloaddition. When activated by light, Bönnemann cyclization requires CoCp₂ (cyclopentadienyl, 1,5-cyclooctadiene) to act as a catalyst.

This method can produce a chain of pyridine derivatives depending on the compounds used. For instance, acetonitrile will yield 2-methylpyridine, which can undergo dealkylation to form pyridine.

Other methods

The Kröhnke pyridine synthesis

This method uses pyridine as a reagent, though it will not be included in the end product. Contrary, the reaction will generate substituted pyridines.

When reacted with α-bromoesters, pyridine will undergo a Michael-like reaction with the unsaturated carbonyls to form the substituted pyridine and pyridium bromide. The reaction is treated with ammonia acetate within 20-100°C mild conditions.

The Ciamician–Dennstedt rearrangement 

This entails the ring-expansion of pyrrole with dichlorocarbene forming 3-chloropyridine.

Gattermann–Skita synthesis

In this reaction, malonate ester salt reacts with dichloromethylamine in the presence of a base.

Boger pyridine synthesis

Reactions of pyridines

The following reactions can be predicted for pyridines from their electronic structure:

1. The heteroatom makes pyridines very unreactive to normal electrophilic aromatic substitution reactions. Conversely, pyridines are susceptible to nucleophilic attack. Pyridines undergo electrophilic substitution reactions (SEAr) more reluctantly but nucleophilic substitution (SNAr) more readily than benzene.
2.  Electrophilic reagents attack preferably at the Natom and at the b-C-atoms, while nucleophilic reagents prefer the a- and c-C-atoms.

Electrophilic Addition at Nitrogen

In reactions which involve bond formation using the lone pair of electrons on the ring nitrogen, such as protonation and quaternization, pyridines behave just like tertiary aliphatic or aromatic amines.

When a pyridine reacts as a base or a nucleophile, it forms a pyridinium cation in which the aromatic sextet is retained, and the nitrogen acquires a formal positive charge.

Protonation at Nitrogen

Pyridines form crystalline, frequently hygroscopic, salts with most protic acids.

Nitration at Nitrogen

This occurs readily by reaction of pyridines with nitronium salts, such as nitronium tetrafluoroborate. Protic nitrating agents such as nitric acid, of course, lead exclusively to N-protonation.

Acylation at nitrogen

Acid chlorides and arylsulfonic acids react rapidly with pyridines generating 1-acyl- and 1- arylsulfonylpyridinium salts in solution.

Alkyl halides and sulfates react readily with pyridines giving quaternary pyridinium salts.

Nucleophilic Substitutions

Unlike benzene, numerous nucleophilic substitutions can be effectively and efficiently be sustained by pyridine. It is because the ring has a slightly lower electron density of the carbon atoms. These reactions include replacements with the removal of a hydride ion and elimination-additions to obtain an intermediate aryne configuration and usually continue to 2- or 4-position.

Pyridine alone cannot result in the formation of several nucleophilic substitutions. However, modification of pyridine with bromine, sulfonic acid fragments, chlorine, and fluorine can result in a leaving group. The formation of organolithium compounds can be recovered from the best leaving group of fluorine. At high pressure, nucleophilic can react with alkoxides, thiolates, amines, and ammonia compounds.

Few heterocyclic reactions can occur because of using a poor leaving group such as hydride ion. Pyridine derivatives at the 2-position can be obtained through Chichibabin reaction. 2-aminopyridine can continue achieved when sodium amide is used as the nucleophile. The hydrogen molecule is formed when the protons of the amino group combine with hydride ion.

Similar to benzene, pyridines intermediates such as heteroaryne can be obtained through nucleophilic substitutions to pyridine. The use of strong alkalines such as sodium and potassium tert-butoxide can help to get rid of pyridine derivatives when using the right leaving the group.  Following the introduction of the nucleophile to the triple bond, it lowers the selectivity and leads to the formation of a mixture that has two possible adducts.

Electrophilic Substitutions

Several pyridine electrophilic substitutions can either continue up to some point or do not continue entirely. On the other hand, the heteroaromatic element can be stimulated through functionalization of electron-donation. Friedel–Crafts alkylation (acylation) is an example of alkylations and acylations. The aspect fails to undergo pyridine since it results in the addition of nitrogen atom. The substitutions mainly happen at the three-position which is one of the electron-rich carbon atoms located in the ring making it prone to electrophilic addition.

Structure of Pyridine N-Oxide

Electrophilic substitutions can result in the change of position of pyridine at 2- or 4-position due to the adverse σ complex vigorous reaction. However, experimental methods can be used while undertaking electrophilic substitution on pyridine N-oxide. It is later followed by nitrogen atom deoxygenation. Therefore, the introduction of oxygen is known to lower the density on nitrogen and enhance substitution at 2-position and 4-position carbons.

Compounds of divalent sulfur or trivalent phosphorus are known to be easily oxidized hence mainly used to remove oxygen atom. Triphenylphosphine oxide is a compound that is formed after oxidation of Triphenylphosphine reagent. It is another reagent that can be used to get rid of an oxygen atom from another element. The information below describes how ordinary electrophilic substitution reacts with pyridine.

Direct pyridine nitration demands certain harsh conditions, and it generally has little yields. The reaction of dinitrogen pentoxide with pyridine in the presence of sodium can result in the formation of 3-nitropyridine. The derivatives of pyridine can be obtained through nitration of nitronium tetrafluoroborate (NO2BF4) by picking nitrogen atom sterically and electronically. Synthesis of two compounds of 6-dibromo pyridine can result in the formation of 3-nitropyridine after removal of bromine atoms.

Direct nitration is considered to be more comfortable than direct sulfonation of pyridine. Boiling of pyridine at 320 °C can result in pyridine-3-sulfonic acid faster than boiling sulfuric acid at the same temperatures. The addition of the sulfur element to nitrogen atom can be obtained by reacting SO3 group in the presence of mercury (II) sulfate which acts as a catalyst.

Direct chlorination and bromination can continue well unlike nitration and sulfonation. 3-bromopyridine can be obtained through reaction of molecular bromine in sulphuric acid at 130 °C with pyridine. Upon chlorination, the result of 3-chloropyridine can be low in the presence of aluminum chloride which acts as a catalyst at 100 °C. Direct reaction of halogen and palladium (II) can result in both 2-bromopyridine and 2-chloropyridine.

Applications of Pyridine

One of the raw materials that are quite crucial to the chemical factories is pyridine. In 1989, the total production of pyridine worldwide was 26K tonnes.  As of 1999, 11 out of the 25 largest pyridine production sites were situated in Europe. The major pyridine producers included Koei Chemical, Imperial Chemical Industries,  and Evonik Industries.

In the early 2000s, the production of pyridine increased by a high margin. For instance, mainland China alone hit a yearly production capacity of 30,000 tonnes. Today, the joint venture between the U.S and China results in the world’s highest pyridine production.

Pesticides

Pyridine is mainly used as a precursor to two herbicides diquat and paraquat. In the preparation of pyrithione-based fungicides, pyridine is used as the basic compound.

The reaction between Zincke and pyridine results in the production of two compounds – laurylpyridinium and cetylpyridinium. Owing to their antiseptic properties, the two compounds are added to the dental and oral care products.

An attack by an alkylating agent to pyridine results in N-alkylpyridinium salts, cetylpyridinium chloride being one example.

Paraquat Synthesis

Solvent

Another application in which pyridine is used is in Knoevenagel condensations, whereby it’s used as a low-reactive, polar, and basic solvent. Pyridine is particularly ideal for dehalogenation, where it serves as the base of elimination reaction while bonding the resultant hydrogen halide to form pyridinium salt.

In acylations and esterifications, Pyridine activates the anhydrides or carboxylic acid halides. Even more active in these reactions are 4-(1-pyrrolidinyl) pyridine and 4-dimethylaminopyridine (DMAP), which are pyridine derivatives. In condensation reactions, Pyridine is typically applied as a base.

Formation of pyridinium through elimination reaction with pyridine

Pyridine is also an important raw material in the textile industry. Besides being applied as a solvent in the production of rubber and dyes, it’s also used to enhance cotton’s network capacity.

The US Food and Drug Administration approves the addition of pyridine in small quantities to foods in order to provide them with a bitter flavor.

In solutions, the detection threshold of pyridine is around 1–3 mmol·L⁻¹ (79–237 mg·L⁻¹). Being a base, pyridine may be utilized as a Karl Fischer reagent. However, imidazole is usually used as a substitute to pyridine as it (imidazole) has a pleasant odor.

Precursor to Piperidine

Pyridine hydrogenation with ruthenium-, cobalt-, or nickel-based catalyst at high temperatures results in the production of piperidine. This is an essential nitrogen heterocycle that’s a vital synthetic building block.

Specialty Reagents Based on Pyridine

In 1975, William Suggs and James Corey developed pyridinium chlorochromate. It’s applied to oxidize secondary alcohols to ketones and primary alcohols to aldehydes. Pyridinium chlorochromate is customarily obtained when pyridine is added to the solution of concentrated hydrochloric and chromic acid.

C₅H₅N + HCl + CrO₃ → [C₅H₅NH][CrO₃Cl]

With the chromyl chloride (CrO₂Cl₂) being carcinogenic, an alternative route had to be sought. One of them is to use pyridinium chloride to treat chromium (VI) oxide.

[C₅H₅NH⁺]Cl⁻ + CrO₃ → [C₅H₅NH][CrO₃Cl]

The Sarret reagent (the complex of chromium (VI) oxide with pyridine heterocycle in pyridine), pyridinium chlorochromate (PCC), the Cornforth reagent (pyridinium dichromate, PDC), and the Collins reagent (the complex of chromium(VI) oxide with pyridine heterocycle in dichloromethane) are comparable chromium- pyridine compounds. They are also applied for oxidation, such as conversion of secondary and primary alcohols to ketones.

The Sarret and Collins reagents are not only tricky to prepare, but they are also hazardous. They are hygroscopic and are susceptible to igniting during the preparation process. Consequently, use of PDC and PCC was recommended. While the two reagents were heavily utilized in the 70s and 80s, they are rarely used presently due to their toxicity and confirmed carcinogenicity.

The structure of the Crabtree’s catalyst

In coordination chemistry, pyridine is extensively used as a ligand. It’s derivative, as is its derivative 2,2′-bipyridine, comprising of 2 pyridine molecules attached by a single bond, and terpyridine, a molecule of 3 pyridine rings connected together.

A stronger Lewis base can be used as a replacement for a pyridine ligand that’s part of a metal complex. This characteristic is exploited in catalysis of polymerization and hydrogenation reactions, using, for instance, Carabtree’s catalyst. The pyridine Lingard that’s substituted during the reaction is reinstated after its completion.

References

Nomenclature of Organic Chemistry : IUPAC Recommendations and Preferred Names 2013 (Blue Book). Cambridge: The Royal Society of Chemistry. 2014. p. 141.

Anderson, T. (1851). “Ueber die Producte der trocknen Destillation thierischer Materien” [On the products of dry distillation of animal matter]. Annalen der Chemie und Pharmacie. 80: 44.

Sherman, A. R. (2004). “Pyridine”. In Paquette, L. Encyclopedia of Reagents for Organic Synthesis. e-EROS (Encyclopedia of Reagents for Organic Synthesis). New York: J. Wiley & Sons.

Behr, A. (2008). Angewandte homogene Katalyse. Weinheim: Wiley-VCH. p. 722.