Heteroaromatic Chemistry- Quinoline

Question 1

What is quinoline

Answer 1

1. A fused bicyclic heteroaromatic compound

2. Benzene + pyridine

Question 2

Describe properties of quinoline

Answer 2

1. 10 pi-electron system
2. Nitrogen lone pair perpendicular to pi-system
3. Similar chemistry to pyridine
4. Additional benzene ring reduces aromaticity

Question 3

What are the two structural isomers or quinoline

Answer 3

1. Quinoline- N adjacent to join with benzene

2. Isoquinoline- N opposite

Question 4

Can quinoline undergo SEAr

Answer 4

1. Can on benzenoid ring
2. Only nitration or sulfonation not others
3. Not ideal
4. Add HNO3 + H2SO4 rt for nitration

Question 5

Describe regio control of SEAr of quinoline

Answer 5

1. Poor regio control- 1:1

2. NO2 adds to position 5 and 8

Question 6

Describe region control for SEAr of isoquinoline

Answer 6

1. More control is observed
2. Only position 5 - opposite to side with N
3. 0 degrees

Question 7

How can you carry out SEAr on pyridine ring or quinoline

Answer 7

1. Need to activate it - form N-oxide
2. N-oxide- adds group to nitrogen which delocalises negative charge into pi system
3. Wheland intermediate governs regiochemistry

Question 8

Describe SNAr in quinoline

Answer 8

1. The benzenoid ring makes nucleophilic substitution easier
2. Same positions as for pyridine are active- position 2 and 4
3. Nucleophilic substitution can take place without need for leaving group- unlike pyridine
4. Because LUMO is low- easy for nuc chem - addition of ring further stabilises

Question 9

Describe how to add chlorine into quinoline

Answer 9

1. Same methods as used for synthesising halopyridines
2. PCl3 onto activated quinoline or
3. POCl3 if carbonyl group on position 2
4. Much faster rate of reaction- LUMO lower in energy

Question 10

What is special about protons in the pridyl position of alkylated quinolines

Answer 10

1. Quinolines and pyridines with alkyl groups at C2/4 position can undergo interesting chemistry
2. Protons in pridyl position are acidic so can deprotonate and form a stable carbanion- the negative charge can delocalise so stable

Question 11

What does deprotonation of alkyl group in alkylated quinolines allow

Answer 11

1. Form enolate looking thing
2. Can treat with electrophile
3. Can do Claisen condensation etc

Question 12

How can you reduce quinoline

Answer 12

1. It has reduced aromaticity so the rings can be hydrogenated
2. Either reduce benzene ring or pyridine ring depending on conditions
3. Pt Under strong acidic- back ring- benzene
4. Pt under neutral- reduce pyridine ring

Question 13

What does retrosynthesis of quinoline produce

Answer 13

1. 1,3-diketone and aniline

Question 14

What does retrosynthesis of isoquinoline produce

Answer 14

1. Homobenzylic amine acid and acid chloride

Question 15

Describe Combes reaction

Answer 15

1. Quinoline synthesis
2. Use aniline and 1,3-dicarbonyl
3. Requires extensive heating and acid catalysis
4. Allows installation of functionality on quinoline- preinstall in aniline

Question 16

Describe the Skraup/Doebner Miller

Answer 16

1. Quinoline synthesis
2. Heating of aniline with glycerol with sulphuric acid and an oxidising agent
3. Doebner and Miller came up with heating aniline with an alpha/beta unsaturated aldehyde and oxidising agent - start with enone instead of glycerol

Question 17

Describe Bischler-Napieralski

Answer 17

1. Synthesis of isoquinolines via acylated phenylethylamine
2. Key ring forming reaction is a Friedel-Crafts reaction
3. Forms dihydroisoquinoline that requires further oxidation
4. Preinstall functionality provides groups you can’t get by reactions onto isoquinoline