English: The reaction mechanism for the Combes Quinoline Synthesis. Date, 9 December , Source, Own work. Author, Sunlk Acid-catalyzed condensation of anilines and β-diketones to assemble quinolines. Cf. Conrad–Limpach reaction. Combes Quinoline Synthesis. A. Combes, Bull. Soc. Chim. France 49, 89 (). Formation of quinolines by condensation of β-diketones with primary.
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The Combes quinoline synthesis is a chemical reactionwhich was first reported by Combes in An intramolecular proton transfer is followed by an E2 mechanismwhich causes a molecule of water quimoline leave.
Deprotonation at the nitrogen atom generates a Schiff basewhich tautomerizes quimoline form an enamine that gets protonated via the acid catalyst, which is commonly concentrated sulfuric acid H 2 SO 4.
The second major step, which is also the rate-determining stepis the annulation of the molecule. Immediately following the annulationthere is a proton transfer, which eliminates the positive formal charge on the nitrogen atom. The alcohol is then protonated, followed by the dehydration of the molecule, resulting in the end product of a substituted quinoline.
The formation of the quinoline product is influenced quiboline the interaction of both steric and electronic effects. In a recent study, Sloop  investigated how substituents would influence the regioselectivity of the product as well as the rate of reaction during the rate-determining step in a modified Combes pathway, which produced trifluoromethyl quinoline as the product.
One modification to the generic Combes quinoline synthesis was the use of a mixture of polyphosphoric acid PPA and various alcohols Sloop used ethanol in his synthhesis.
Combes quinoline synthesis – WikiVisually
The mixture produced a polyphosphoric ester PPE catalyst that proved to be more effective as the dehydrating agent than concentrated sulfuric acid H 2 SO 4which is commonly used in the Combes quinoline synthesis.
Using the modified Combes synthesis, two possible regioisomers were found: It was observed that the steric effects of the substituents play a more important role in the electrophilic aromatic annulation step, which is the rate-determining stepcompared to the initial nucleophilic addition of the aniline to the di ketone.
It was also observed that increasing the bulk of the R group on the di ketone and using methoxy -substituted anilines leads to the formation of 2-CF 3 – quinolines. If chloro – or fluoro anilines are used, the major product would be the 4-CF 3 regioisomer.
The study concludes that the interaction of steric and electronic effects leads to the preferred formation of 2-CF 3 – quinolineswhich provides us with some information on how to manipulate the Combes quinoline synthesis to form a desired regioisomer as the product. There are multiple ways to synthesize quinolineone of which is the Combes quinoline synthesis. The synthesis of quinoline derivatives has been prevalent in biomedical studies due to the efficiency of the synthetic methods as well as the relative low-cost production of these compounds, which can also be produced in large scales.
Quinoline is an important heterocyclic derivative that serves as a building block for many pharmacological synthetic compounds. Quinoline and its derivatives are commonly used in antimalarial drugs, fungicides, antibiotics, dyes, and flavoring agents.
Combes quinoline synthesis – Wikipedia
Additionally, researchers, such as Luo Zai-gang et quuinoline. They also looked at how the substituent placement on the quinoline derivatives affected the primary anti-HIV inhibitory activity. From Wikipedia, the free encyclopedia. Pyridine, Quinoline, and Isoquinoline”.
File:Combes Quinoline Synthesis Mechanism.png
Moscow University Chemistry Bulletin. Department of Chemistry, Stanford University. Retrieved 7 December Retrieved from ” https: Carbon-carbon bond forming reactions Condensation reactions Quinoline forming reactions Name reactions. Pages with citations lacking titles.
Combes quinoline synthesis
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