Heteroaromatic Chemistry- Pyridine

Question 1

How does the addition of nitrogen into the aromatic ring affect the HOMO and LUMO

Answer 1

1. Lowers the energy of the HOMO and LUMO

2. not good for SeAr reactions

Question 2

What does the nitrogen lone pair mean

Answer 2

1. Even lower HOMO as it interacts with acid needed in SeAr reactions NH+ - Less reactive

Question 3

What does the HOMO and LUMO energy change mean for pyridine chemistry

Answer 3

1. Can’t undergo electrophilic aromatic substitution

Question 4

What does the pKa of the conjugate acid mean about the base

Answer 4

1. The lower the pKa of the conjugate acid the weaker the base

Question 5

What is the pKa of pyridine

Answer 5

1. Around 5.5

Question 6

What is the issue of SeAr with pyridine and what is solution

Answer 6

1. Pi-system is electron deficient

2. Solution is to make aromatic system electron rich

Question 7

How can you make pyridine electron rich

Answer 7

1. Add H2O2 or mCPBA
2. Attaches O- to N+
3. Electron donating O so C2/C4 is now activated- raises HOMO so more reactive

Question 8

How can N-oxide be removed to return to pyridine

Answer 8

1. Ph3P produces original pyridine + Ph3P=O

2. PCl3- chlorinates adjacent to N and cleaves O + Cl3POH

Question 9

Can pyridine undergo nucleophilic substitution

Answer 9

1. Yes- resonance shows positive charge moves across carbons
2. Need suitable leaving group

Question 10

What is different for SNAr with pyridine compared to normal benzene

Answer 10

1. Doesn’t need EWG as already e- deficient species

2. If leaving group is at 2/4 position it forms stable Meisenheimer intermediate

Question 11

What affects rate of SNAr

Answer 11

1. Leaving group and additional substituents

Question 12

What effect would EtO substituent have on rate of SNAr

Answer 12

1. EDG so destabilises intermediate

2. Slower rate

Question 13

What effect would OEt have on rate of SNAr

Answer 13

1. EWG so stabilises intermediate and increases rate

Question 14

What is another method to synthesise a halopyridine

Answer 14

1. Start from hydroxypyridine

2. Add PCl3O

Question 15

Why can’t you use the same rationale for synthesising pyridines as used for imines

Answer 15

1. The forward synthesis of it produces dihydropyridine not pyridine

Question 16

How can you synthesise pyridine

Answer 16

1. Stepwise process- Add NH3 to dicarbonyl and then oxidise (HNO3 or Ce(NO3)6(NH4)2 or DDQ)
2. Or use hydroxylamine as the ammonia source- NH2OH

Question 17

Describe A Hantzsch’s findings

Answer 17

1. Successfully condensed 2 moles of ethyl acetoacetate with one mole of ammonia and acetaldehyde to prepare 1,4-dihydropyridine
2. The dihydropyridine can spontaneously oxidise to the pyridine
3. More stable derivatives require oxidation
4. Can prepare unsymmetrical species, requires synthesis of enone precursor first