Chichibabin pyridine synthesis
Encyclopedia
The Chichibabin pyridine synthesis -chē-bā-bēn) is a method for synthesizing pyridine
rings. In its general form, the reaction can 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
. It was reported by Aleksei Chichibabin
in 1924.
, and initiating the ring-synthesis step, a Michael reaction
.
, 4-methylpyridine
and 2-ethyl-5-methylpyridine exhibit widespread use in syntheses of latex
es, ion-exchange matrixes
, and photography materials.
The high proportion of byproducts and low yield are explained by the easily-reversible nature of the aldol condensation
, and carbonyl chemistry in general. For instance, the following side-reactions could lead to byproduct formation:
Immine formation steps:
1.Nucleophillic attack
of ammonia at the β-, rather than α-carbon
will prevent enamine
/imine
formation
2.Nucleophilic attack of ammonia on the enamine or imine
Aldol condensation step
3.(In the case of asymmetric ketones), abstraction of the non-preferred β-Hydrogen
4.Enolate ion attack of the enamine or imine carbon
5.Enolate ion attack of an unintended aldehyde- or keto-carbonyl
Pyridine synthesis step
6. Immine attack of carbonyl-, rather than γ-carbon
7. Immine attack at an enamine or imine carbon
In the case of simple aldehydes and, and particularly in the case of α,β-Unsaturated carbonyl compounds, polymerization of starting materials can occur frequently and is shown to significantly decrease yields.
increases product yields
2. Use of paraldehyde
as a source of gradually-available ethanal
3. Large (>3x catalytic) excess of aqueous ammonia, with catalytic amounts of ammonium acetate
4. Conducting the reaction in the gas phase and passing-over a number of catalysts including aluminium(III) oxide
(yield 65% at 600 K), zeolite
(yield 98.9 % at 500 K), and many others.
5. Increased pressures and temperature
, (deaminated lysine) from bovine ligamentum nuchae elastin
fibers appeared to be pyridine cross-linked. The structures of these cross-linked amino acids had 3,4,5- and 2,3,5-trisubstituted pyridine skeletons, specifically pyridinated desmosine
(DESP) and pyridinated isodesmosine
(IDP).
Extrapolating from an in-vitro elastin model under physiological conditions, the researchers found that the ratios of IDP to DESP corresponded extremely closely with values based on both a calculation of a theoretical Chichibabin pyridine synthesis of 3 mol allysine
and 1 mol ammonia, and reported ratios of 2,3,5- to 3,4,5-trisubstituted pyridine ratios of a Chichibabin pyridine synthesis involving phenylacetaldehyde
. They concluded with relative certainty that the pyridine cross-links found in elastin were, in fact, due to an in-vitro Chichibabin pyridine synthesis of ammonia and allysine.
Pyridine
Pyridine is a basic heterocyclic organic compound with the chemical formula C5H5N. It is structurally related to benzene, with one C-H group replaced by a nitrogen atom...
rings. In its general form, the reaction can can be described as a condensation reaction
Condensation reaction
A condensation reaction is a chemical reaction in which two molecules or moieties combine to form one single molecule, together with the loss of a small molecule. When this small molecule is water, it is known as a dehydration reaction; other possible small molecules lost are hydrogen chloride,...
of aldehydes, ketones, α,β-Unsaturated carbonyl compounds, or any combination of the above, in ammonia
Ammonia
Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...
or ammonia derivatives
Amine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
. It was reported by Aleksei Chichibabin
Aleksei Chichibabin
For the poet, see Boris Chichibabin.Alekséy Yevgényevich Chichibábin was a Soviet/Russian organic chemist. His name is also written Alexei Yevgenievich Chichibabin and Alexei Euguenievich Tchitchibabine.- Life :...
in 1924.
Reaction mechanism
The elementary contributing steps of the reaction mechanism can be classified as more familiar name reactions, including an immine synthesis, a base-catalyzed aldol condensationAldol condensation
An aldol condensation is an organic reaction in which an enol or an enolate ion reacts with a carbonyl compound to form a β-hydroxyaldehyde or β-hydroxyketone, followed by a dehydration to give a conjugated enone....
, and initiating the ring-synthesis step, a Michael reaction
Michael reaction
The Michael reaction or Michael addition is the nucleophilic addition of a carbanion or another nucleophile to an alpha, beta unsaturated carbonyl compound. It belongs to the larger class of conjugate additions. This is one of the most useful methods for the mild formation of C-C bonds...
.
Fundamental reaction steps
Detailed reaction mechanism
Showing detailed curved-arrow electron pushing steps, formal charges, and categorized steps of the reaction.Synthetic applications
Alkyl-substituted pyridines show widespread uses among multiple fields of applied chemistry, including the polymer and pharmaceutical industries. For example, 2-methylpyridine2-Methylpyridine
2-Methylpyridine, or 2-picoline, is the compound described with formula C6H7N. 2-picoline is a colorless liquid that has an unpleasant odor similar to pyridine. Pyridines including 2-picoline are most crudely prepared by the reaction of acetylene and hydrogen cyanide.-Synthesis:2-Picoline was the...
, 4-methylpyridine
4-Methylpyridine
4-Methylpyridine is the organic compound with the formula CH3C5H4N. It is one of the three isomers of methylpyridine. This colourless pungent liquid is a building block for the synthesis of other heterocyclic compounds...
and 2-ethyl-5-methylpyridine exhibit widespread use in syntheses of latex
Latex
Latex is the stable dispersion of polymer microparticles in an aqueous medium. Latexes may be natural or synthetic.Latex as found in nature is a milky fluid found in 10% of all flowering plants . It is a complex emulsion consisting of proteins, alkaloids, starches, sugars, oils, tannins, resins,...
es, ion-exchange matrixes
Ion exchange resin
An ion-exchange resin or ion-exchange polymer is an insoluble matrix normally in the form of small beads, usually white or yellowish, fabricated from an organic polymer substrate. The material has highly developed structure of pores on the surface of which are sites with easily trapped and...
, and photography materials.
Limitations
One of the chief limitations of practical application of the traditional Chichibabin pyridine synthesis is it's consistently low product yield. With the exception of two experimental runs, Chichibabin himself was unable to obtain product yields in excess of 20% across a variety of reactants, solvents, and other experimental conditions. This, in concert with the high prevalence of byproducts, which would require a multitude of purification steps to isolate pure pyridine product, render unaltered forms of Chichibabin's method unsuitable for applied chemistry.The high proportion of byproducts and low yield are explained by the easily-reversible nature of the aldol condensation
Aldol condensation
An aldol condensation is an organic reaction in which an enol or an enolate ion reacts with a carbonyl compound to form a β-hydroxyaldehyde or β-hydroxyketone, followed by a dehydration to give a conjugated enone....
, and carbonyl chemistry in general. For instance, the following side-reactions could lead to byproduct formation:
Immine formation steps:
1.Nucleophillic attack
Nucleophilic substitution
In organic and inorganic chemistry, nucleophilic substitution is a fundamental class of reactions in which an electron nucleophile selectively bonds with or attacks the positive or partially positive charge of an atom or a group of atoms called the leaving group; the positive or partially positive...
of ammonia at the β-, rather than α-carbon
Alpha carbon
The alpha carbon in organic chemistry refers to the first carbon that attaches to a functional group . By extension, the second carbon is the beta carbon, and so on....
will prevent enamine
Enamine
An enamine is an unsaturated compound derived by the reaction of an aldehyde or ketone with a secondary amine followed by loss of H2O.The word "enamine" is derived from the affix en-, used as the suffix of alkene, and the root amine. This can be compared with enol, which is a functional group...
/imine
Imine
An imine is a functional group or chemical compound containing a carbon–nitrogen double bond, with the nitrogen attached to a hydrogen atom or an organic group. If this group is not a hydrogen atom, then the compound is known as a Schiff base...
formation
2.Nucleophilic attack of ammonia on the enamine or imine
Aldol condensation step
3.(In the case of asymmetric ketones), abstraction of the non-preferred β-Hydrogen
4.Enolate ion attack of the enamine or imine carbon
5.Enolate ion attack of an unintended aldehyde- or keto-carbonyl
Pyridine synthesis step
6. Immine attack of carbonyl-, rather than γ-carbon
7. Immine attack at an enamine or imine carbon
In the case of simple aldehydes and, and particularly in the case of α,β-Unsaturated carbonyl compounds, polymerization of starting materials can occur frequently and is shown to significantly decrease yields.
Ways to overcome limitations
1. Protection of the carbonylProtecting group
A protecting group or protective group is introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction...
increases product yields
2. Use of paraldehyde
Paraldehyde
Paraldehyde is the cyclic trimer of acetaldehyde molecules. Formally, it is a derivative of 1,3,5-trioxane. The corresponding tetramer is metaldehyde. A colourless liquid, it is sparingly soluble in water and highly soluble in alcohol. Paraldehyde slowly oxidizes in air, turning brown and producing...
as a source of gradually-available ethanal
Acetaldehyde
Acetaldehyde is an organic chemical compound with the formula CH3CHO or MeCHO. It is one of the most important aldehydes, occurring widely in nature and being produced on a large scale industrially. Acetaldehyde occurs naturally in coffee, bread, and ripe fruit, and is produced by plants as part...
3. Large (>3x catalytic) excess of aqueous ammonia, with catalytic amounts of ammonium acetate
Ammonium acetate
Ammonium acetate is a chemical compound with the formula CH3COONH4 . It is a white solid, which can be derived from the reaction of ammonia and acetic acid...
4. Conducting the reaction in the gas phase and passing-over a number of catalysts including aluminium(III) oxide
Aluminium oxide
Aluminium oxide is an amphoteric oxide with the chemical formula 23. It is commonly referred to as alumina, or corundum in its crystalline form, as well as many other names, reflecting its widespread occurrence in nature and industry...
(yield 65% at 600 K), zeolite
Zeolite
Zeolites are microporous, aluminosilicate minerals commonly used as commercial adsorbents. The term zeolite was originally coined in 1756 by Swedish mineralogist Axel Fredrik Cronstedt, who observed that upon rapidly heating the material stilbite, it produced large amounts of steam from water that...
(yield 98.9 % at 500 K), and many others.
5. Increased pressures and temperature
Evidence of this mechanism in-vivo
In vivo, deamination of the α-amino group of amino acids produces small amounts of ammonia. Researchers found that protein-incorporated allysineAllysine
Allysine is a derivative of Lysine, used in the production of elastin and collagen. It is produced by the actions of the enzyme lysyl oxidase in the extracellular matrix and is essential in the crosslink formation that stabilizes collagen and elastin....
, (deaminated lysine) from bovine ligamentum nuchae elastin
Elastin
Elastin is a protein in connective tissue that is elastic and allows many tissues in the body to resume their shape after stretching or contracting. Elastin helps skin to return to its original position when it is poked or pinched. Elastin is also an important load-bearing tissue in the bodies of...
fibers appeared to be pyridine cross-linked. The structures of these cross-linked amino acids had 3,4,5- and 2,3,5-trisubstituted pyridine skeletons, specifically pyridinated desmosine
Desmosine
A desmosine cross-link is formed from three allysyl side chains plus one unaltered lysyl side chain from the same or neighbouring polypeptides.It is found in elastin. Desmosine causes a yellow color....
(DESP) and pyridinated isodesmosine
Isodesmosine
Isodesmosine is a lysine derivative found in elastin....
(IDP).
Extrapolating from an in-vitro elastin model under physiological conditions, the researchers found that the ratios of IDP to DESP corresponded extremely closely with values based on both a calculation of a theoretical Chichibabin pyridine synthesis of 3 mol allysine
Allysine
Allysine is a derivative of Lysine, used in the production of elastin and collagen. It is produced by the actions of the enzyme lysyl oxidase in the extracellular matrix and is essential in the crosslink formation that stabilizes collagen and elastin....
and 1 mol ammonia, and reported ratios of 2,3,5- to 3,4,5-trisubstituted pyridine ratios of a Chichibabin pyridine synthesis involving phenylacetaldehyde
Phenylacetaldehyde
Phenylacetaldehyde is an aromatic compound found in buckwheat, chocolate and many other foods and flowers.It is also responsible for the antibiotic activity of maggot therapy and it is also a compound that is added to cigarettes to improve their aroma....
. They concluded with relative certainty that the pyridine cross-links found in elastin were, in fact, due to an in-vitro Chichibabin pyridine synthesis of ammonia and allysine.
Related reactions
- Chichibabin ReactionChichibabin reactionThe Chichibabin reaction -chē-bā-bēn) is a method for producing 2-aminopyridine derivatives by the reaction of pyridine with sodium amide. It was reported by Aleksei Chichibabin in 1914. The following is the overall form of the general reaction:...
- Gattermann-Skita synthesis
- Hantzsch pyridine synthesisHantzsch pyridine synthesisThe Hantzsch pyridine synthesis or Hantzsch dihydropyridine synthesis is a multi-component organic reaction between an aldehyde such as formaldehyde, 2 equivalents of a β-keto ester such as ethyl acetoacetate and a nitrogen donor such as ammonium acetate or ammonia. The initial reaction product is...
- Ciamician-Dennstedt rearrangement