It is good to be bold.
Fruits by the Numbers
part I
My Favorite Fruits
- strawberries
- apples
- pears
- peaches
Fruits in any Order
part II
Fruits I do not like
- bananas
- durians
Section Two
part III
Further studies and reviews of the Combes quinoline synthesis and its variations have been published by Alyamkina et al. [1] , Bergstrom and Franklin [2] , Born [3] , and Johnson and Mathews [4] .
The Combes quinoline synthesis is often used to prepare the quinoline backbone and is unique in that it uses a β-di ketone substrate, which is different from other quinoline preparations, such as the Conrad-Limpach synthesis and the Doebner reaction.
Mechanism
The reaction mechanism [5] undergoes three major steps, the first one being the protonation of the oxygen on the carbonyl in the β-di ketone, which then undergoes a nucleophilic addition reaction with the aniline. An intramolecular proton transfer is followed by an E2 mechanism, which causes a molecule of water to leave. Deprotonation at the nitrogen atom generates a Schiff base, which tautomerizes to form an enamine that gets protonated via the acid catalyst, which is commonly concentrated sulfuric acid (H2SO4). The second major step, which is also the rate-determining step, is the annulation of the molecule. Immediately following the annulation, there 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.
Regioselectivity
The formation of the quinoline product is influenced by the interaction of both steric and electronic effects. In a recent study, Sloop [6] 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. Sloop focused specifically on the influences that substituted trifluoro-methyl-β-di ketones and substituted anilines would have on the rate of quinoline formation. 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 experiment). The mixture produced a polyphosphoric ester (PPE) catalyst that proved to be more effective as the dehydrating agent than concentrated sulfuric acid (H2SO4), which is commonly used in the Combes quinoline synthesis. Using the modified Combes synthesis, two possible regioisomers were found: 2-CF3- and 4-CF3-quinolines. 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 step, compared 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-CF3- quinolines. If chloro- or fluoro anilines are used, the major product would be the 4-CF3 regioisomer. The study concludes that the interaction of steric and electronic effects leads to the preferred formation of 2-CF3- quinolines, which provides us with some information on how to manipulate the Combes quinoline synthesis to form a desired regioisomer as the product.
See Also
Notes
-
^ Alyamkina, EA (2010). "Comparison of peak performance measures in children ages 6 to 8, 9 to 10, and 11 to 13 years". Moscow University Chemistry Bulletin. 65 (5): 402–408.
{{ cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) ( help) -
^ Bergstrom, FW and Franklin, EC (1944). Hexacyclic Compounds: Pyridine, Quinoline, and Isoquinoline in Heterocyclic Nitrogen Compounds. California: Department of Chemistry, Stanford University. p. 156.
{{ cite book}}: CS1 maint: multiple names: authors list ( link) - ^ Born, JL (1972). "The mechanism of formation of benzo[g]quinolines via the Combes reaction". J. Org. Chem. 37 (24): 3952–3953. doi: 10.1021/jo00797a045.
-
^ Johnson, WS (1944). "Cyclization studies in the benzoquinoline series". J. Am. Chem. Soc. 66 (2): 210–215.
doi:
10.1021/ja01230a016.
{{ cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) ( help) - ^ Li, J.J. (2009). In "Combes Quinoline Synthesis"; Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications. Springer. pp. 131–132. ISBN 978-3-642-01053-8.
- ^ Sloop, JC (2009). "Quinoline formation via a modified Combes reaction: examination of kinetics, substituent effects, and mechanistic pathways". J. Phys. Org. Chem. 22 (2): 110–117. doi: 10.1002/poc.1433.
It is good to be bold.
Fruits by the Numbers
part I
My Favorite Fruits
- strawberries
- apples
- pears
- peaches
Fruits in any Order
part II
Fruits I do not like
- bananas
- durians
Section Two
part III
Further studies and reviews of the Combes quinoline synthesis and its variations have been published by Alyamkina et al. [1] , Bergstrom and Franklin [2] , Born [3] , and Johnson and Mathews [4] .
The Combes quinoline synthesis is often used to prepare the quinoline backbone and is unique in that it uses a β-di ketone substrate, which is different from other quinoline preparations, such as the Conrad-Limpach synthesis and the Doebner reaction.
Mechanism
The reaction mechanism [5] undergoes three major steps, the first one being the protonation of the oxygen on the carbonyl in the β-di ketone, which then undergoes a nucleophilic addition reaction with the aniline. An intramolecular proton transfer is followed by an E2 mechanism, which causes a molecule of water to leave. Deprotonation at the nitrogen atom generates a Schiff base, which tautomerizes to form an enamine that gets protonated via the acid catalyst, which is commonly concentrated sulfuric acid (H2SO4). The second major step, which is also the rate-determining step, is the annulation of the molecule. Immediately following the annulation, there 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.
Regioselectivity
The formation of the quinoline product is influenced by the interaction of both steric and electronic effects. In a recent study, Sloop [6] 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. Sloop focused specifically on the influences that substituted trifluoro-methyl-β-di ketones and substituted anilines would have on the rate of quinoline formation. 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 experiment). The mixture produced a polyphosphoric ester (PPE) catalyst that proved to be more effective as the dehydrating agent than concentrated sulfuric acid (H2SO4), which is commonly used in the Combes quinoline synthesis. Using the modified Combes synthesis, two possible regioisomers were found: 2-CF3- and 4-CF3-quinolines. 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 step, compared 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-CF3- quinolines. If chloro- or fluoro anilines are used, the major product would be the 4-CF3 regioisomer. The study concludes that the interaction of steric and electronic effects leads to the preferred formation of 2-CF3- quinolines, which provides us with some information on how to manipulate the Combes quinoline synthesis to form a desired regioisomer as the product.
See Also
Notes
-
^ Alyamkina, EA (2010). "Comparison of peak performance measures in children ages 6 to 8, 9 to 10, and 11 to 13 years". Moscow University Chemistry Bulletin. 65 (5): 402–408.
{{ cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) ( help) -
^ Bergstrom, FW and Franklin, EC (1944). Hexacyclic Compounds: Pyridine, Quinoline, and Isoquinoline in Heterocyclic Nitrogen Compounds. California: Department of Chemistry, Stanford University. p. 156.
{{ cite book}}: CS1 maint: multiple names: authors list ( link) - ^ Born, JL (1972). "The mechanism of formation of benzo[g]quinolines via the Combes reaction". J. Org. Chem. 37 (24): 3952–3953. doi: 10.1021/jo00797a045.
-
^ Johnson, WS (1944). "Cyclization studies in the benzoquinoline series". J. Am. Chem. Soc. 66 (2): 210–215.
doi:
10.1021/ja01230a016.
{{ cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) ( help) - ^ Li, J.J. (2009). In "Combes Quinoline Synthesis"; Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications. Springer. pp. 131–132. ISBN 978-3-642-01053-8.
- ^ Sloop, JC (2009). "Quinoline formation via a modified Combes reaction: examination of kinetics, substituent effects, and mechanistic pathways". J. Phys. Org. Chem. 22 (2): 110–117. doi: 10.1002/poc.1433.