Heterocyclic chemistry Flashcards
Benzene structure
- 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
Huckels rule
Aromatic compounds must have 4n+2 pi electrons e.g. (6,10,14,20)
what are nucleophiles
- 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
what are electrophiles
- positively charged or neutral species
- must have a vacant/ low energy molecular orbital into which an electron pair can be donated
pyrrole basics
- 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
Base chemistry of pyrrole
- 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
Acid chemistry of pyrrole
- Pyrrole is also a weak acid
- deprotination doesn’t disrupt aromaticity
- deprotination of N-H can occur with strong base (e.g. n-BuLi)
Why C-2 subsitution is better than C-3 substitution (pyrrole)
-increased resonance stabilisation for C-2 meaning greater delocalisation (donation of electron density)
meaning more low energy resonance forms can exist
-
when can you get selective C-3 substitution (pyrrole)
when you attatch a bulky group to the nitrogen atom e.g. TIPS = Tri-isopropylsilyl, using TIPSCl = Tri-Isopropyl Silyl Chloride and NHNH2
structure of furan
- 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
structure of thiophene
- 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
order of reactivity for pyrolle, thiophene and furan towards electrophillic substitution reactions
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)
Acid-base chemistry of Furan
- 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
Reactivity of thiophene
- Thiophene can undergo Friedel-Crafts acylation
* Pyrrole and Furan do not undergo reliable Friedel-Crafts reactions.
Structure of pyridone
- 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
pyridinium cations
- retain their aromaticity but protination further decreases electron density in the ring
reactivity of pyridine (electrophillic aromatic substitution)
Generally unreactive towards EAS
- Salt formation via N-lone pair
- Very forcing conditions required, generally not synthetically useful
- “Electron poor” aromatic system
Reactivity of pyridine (NAS) - regioselectivity
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.
quinoline structure
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)
Reactivity of Quinoline (electrphillic aromatic substitution)
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
Regioselectivity of EAS (Quinoline)
substitution towards C-5 and C-8 favoured
substitution towards C-6 and C-7 disfavoured
due to resonance
where does nucleophillic aromatic substitution occur (quinoline)
C-2 and C-4
Structure of Indole
• Indole (benzopyrrole)
• Fused benzoaromatic:
-Benzene ring attatched to pyrrole like ring
• The nitrogen of indole contributes a lone pair to the aromaticity/is delocalized
reactivity of indole
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
