Heterocyclic chemistry

Question 1

Benzene structure

Answer 1

• 6 SP2 hybridised C-atoms
• each C atom has 1 p orbital perpendicular to the plane of the ring
• overlap of these p orbitals leads to electron delocalisation around the ring

Question 2

Huckels rule

Answer 2

Aromatic compounds must have 4n+2 pi electrons e.g. (6,10,14,20)

Question 3

what are nucleophiles

Answer 3

• negatively charge or neutral species
• must have a pair of electrons which are readily donated
• typically a lone pair, a negative charge or a bond

Question 4

what are electrophiles

Answer 4

• positively charged or neutral species

- must have a vacant/ low energy molecular orbital into which an electron pair can be donated

Question 5

pyrrole basics

Answer 5

• 5 membered ring of 4 carbons and 1 nitrogen
• Nitrogen atom has a lone pair at 90 degrres to the plane of the ring, allowing it to be delocalised into the aromatic system
• can be described as an electron rich aromatic

Question 6

Base chemistry of pyrrole

Answer 6

• pyrolle nitrogen is weakly basic - nitrogen lone pair is part of the aromatic ring
• protination disrupts aromaticity
• pyrolle can be protinated with a STRONG ACID, protinates on C-2 atom

Question 7

Acid chemistry of pyrrole

Answer 7

• Pyrrole is also a weak acid
• deprotination doesn’t disrupt aromaticity
• deprotination of N-H can occur with strong base (e.g. n-BuLi)

Question 8

Why C-2 subsitution is better than C-3 substitution (pyrrole)

Answer 8

-increased resonance stabilisation for C-2 meaning greater delocalisation (donation of electron density)
meaning more low energy resonance forms can exist
-

Question 9

when can you get selective C-3 substitution (pyrrole)

Answer 9

when you attatch a bulky group to the nitrogen atom e.g. TIPS = Tri-isopropylsilyl, using TIPSCl = Tri-Isopropyl Silyl Chloride and NHNH2

Question 10

structure of furan

Answer 10

• Furan is a heterocyclic organic compound, consisting of a five-membered aromatic ring with four carbon atoms and one oxygen.
• lone pair in p-orbital part of pi system
• lone pair in sp3 orbital, not part of pi system

Question 11

structure of thiophene

Answer 11

• Thiophene, also commonly called thiofuran, is a heterocyclic compound with the formula C₄H₄S. Consisting of a flat five-membered ring, it is aromatic as indicated by its extensive substitution reactions
• lone pair in p-orbital part of pi system
• lone pair not part of pi system

Question 12

order of reactivity for pyrolle, thiophene and furan towards electrophillic substitution reactions

Answer 12

The order is pyrrole»furan>thiophene. Simply it’s all about electrons. Nitrogen is the best electron donator of the three.

Oxygen is the most electronegative, holding on to it’s electrons tightly making the ring less nucleophilic.

Finally, sulphur has a lone pair in it’s 3p orbital, which leads to poor interactions with the ring, leading to a lower nucleophilicity and thus a lower reactivity than furan or pyrrole. (Clayden page 1159)

Question 13

Acid-base chemistry of Furan

Answer 13

• Furan can be protonated with strong acids, and rapidly reacts with Lewis acids
• Protonation at the C-3 position leads to ring-opening and decomposition
• Deprotonation at C-2 with n-BuLi allows functionalisation of the ring.
• furan can be protinated with strong acids and therefore reacts with lewis acids
• C-2 sub favoured over C-3 AS EXPECTED

Question 14

Reactivity of thiophene

Answer 14

• Thiophene can undergo Friedel-Crafts acylation

* Pyrrole and Furan do not undergo reliable Friedel-Crafts reactions.

Question 15

Structure of pyridone

Answer 15

• 6 membered ring containing 5 carbons and 1 nitrogen
• Nitrogen lone pair is not delocalised, hence pyridine is basic, and nucleophilic
• Can be protinated without loss of aromaticity

Question 16

pyridinium cations

Answer 16

• retain their aromaticity but protination further decreases electron density in the ring

Question 17

reactivity of pyridine (electrophillic aromatic substitution)

Answer 17

Generally unreactive towards EAS

• Salt formation via N-lone pair
• Very forcing conditions required, generally not synthetically useful
• “Electron poor” aromatic system

Question 18

Reactivity of pyridine (NAS) - regioselectivity

Answer 18

Regioselectivity: 4- and 2-/6- substitution favoured over 3-/5- substitution as the negative
charge can be stabilised on the electronegative Nitrogen atom
• However, a leaving group must be present in the position to be substituted - this is
generally only important if you have a choice of leaving group.

Question 19

quinoline structure

Answer 19

Fused benzoaromatic:
benzene ring “fused” to a pyridine like ring
• Basic and nucleophilic, lone pair on nitrogen not delocalized
• Fused aromatic systems often exhibit reactivity associated with the two individual rings
- aromatic (10 pi electrons)

Question 20

Reactivity of Quinoline (electrphillic aromatic substitution)

Answer 20

EAS occurs on the more electron rich benzene like ring, not on the pyridine-like ring
- protination of the nitrogen further deactivates the “pyridine” ring to EAS

Question 21

Regioselectivity of EAS (Quinoline)

Answer 21

substitution towards C-5 and C-8 favoured
substitution towards C-6 and C-7 disfavoured
due to resonance

Question 22

where does nucleophillic aromatic substitution occur (quinoline)

Answer 22

C-2 and C-4

Question 23

Structure of Indole

Answer 23

• Indole (benzopyrrole)
• Fused benzoaromatic:
-Benzene ring attatched to pyrrole like ring
• The nitrogen of indole contributes a lone pair to the aromaticity/is delocalized

Question 24

reactivity of indole

Answer 24

Regioselectivity: C-3 substitution occurs almost exclusively (opposite of pyrrole) due to only 1 resonance form of the C-2 sub being low energy and both the resonance for C-3 sub are low energy

Question 25

rate of formation of saturated ring

Answer 25

1) ring strain
2) entropy - how much order must be imposed on the molecule to attain a reactive conformation ( increases with ring size)