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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-diketone 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-diketone, 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 trifluoromethylquinoline as the product. Sloop focused specifically on the influences that substituted trifluoro-methyl-β-diketones 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 diketone. It was also observed that increasing the bulk of the R group on the diketone 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.

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.

[1] 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)

[2] 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)

[3] 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.

[4] 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)

[5] 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.

[6] 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.

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