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FIVE MEMBEREDAROMATIC

HETEROCYCLES

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a-substitution b-substitutionThe Substitution is regioselective to the a position; whenthese positions are occupied, the b-position is substituted.

X = O, S or NH

Electrophilic aromatic substitution reaction of fivemembered aromatic heterocycles

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WHY?The +ve charge is better resonance stabilized whenthe substitution is at the a-position than at b-position.

A more stable intermediate carbocation having 3resonance forms.

only 2 resonance forms

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Common reactions of pyrrole, furan, and thiophene

Electrophilic aromatic substitution reaction is easyand is preferred at a-position; also easy at b-position.

The following reaction are common to the three fivemembered aromatic heterocycles.

A. Electrophilic Aromatic Substitution

Z = O, S, NH

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C. Vilsmeier-Haack reaction

B. Substitution at a-position via a-lithiated Intermediates

Z = O, S, NR

Vilsmeier reaction (Vilsmeier‐Haack reaction) allowsthe formylation (addition of -CHO) of heterocyclicmolecules. The formylating agent, chloroiminiumion, is formed in situ from N,N‐dimethylamide andPOCl3.

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Z = O, S, NH

Example

Vilsmeier-Haack reaction

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Mechanism

Chloroiminium ion

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The reaction of electron rich heterocycles withformaldehyde and primary/secondary amineforming an amino alkylated heterocylcic compoundis called the Mannich reaction.

D. Mannich reaction

Z = O, S, NH

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Mechanism

R1

N

R2

H

H

OH

Z

N R2

R1H

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Furans are volatile, fairly stable compounds withpleasant odours. Furan itself is slightly soluble inwater. It is readily available, and its commercialimportance is mainly due to its role as the precursorof the very widely used solvent tetrahydrofuran(THF).

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By analogy with benzene, furanundergoes reactions with electrophilicreagents, often with substitution.However, it can also react by additionand/or ring-opening depending onreagent and reaction conditions.

Reactions of Furans

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Electrophilic Aromatic Substitution Reaction

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HalogenationFuran can be halogenated at a-position. Bromination andiodination are easy to control as only one halogen atomsadds to furan. In the case of chlorination, di-substitution hasbeen known to occur.

O

OCl O

ClCl+

OBr dioxane

- 40 oC

variable yields

Cl2

Br2

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AcylationAcetyl groups in the presence of phosphoric acid (or a Lewisacid) add at a-position of furans.

In general, position 2 (a-position) is more reactive thanposition 3. When position 2 is blocked, b-acylation canproceed smoothly.

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n-Butyllithium in hexane metalates furan inthe 2-position, while excess of reagent athigher temperature produces 2,5-dilithiofuran.

Metalation

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Addition reactionsFurans yield the corresponding tetrahydrofurans bycatalytic hydrogenation.

In some addition reactions, furans behave as 1,3-dienes. For example, furan reacts with bromine inmethanol in the presence of potassium acetate togive 2,5-dimethoxy-2,5-dihydrofuran by a 1,4-addition:

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Ring-opening reactions

Furans are protonated in the 2-position, and not onthe O-atom, by BRÖNSTED acids:

O

HO

HPOLYMERS

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Thiophene prefers reactionswith electrophilic reagents.Additions and ring-openingreactions are less importantthan with furan, andsubstitution reactions aredominant.

Some additional reactions, such as oxidationand desulfurization, are due to the presenceof sulfur and are thus confined to thiophenes.

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Electrophilic substitutions

Thiophene reacts more slowly than furan but fasterthan benzene. Substitution is regioselective in the 2-or in the 2,5-position.

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Reactions with nucleophilic reagents

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Thiophenes are oxidized by peroxy acids to givethiophene 1,1 –dioxides:

Oxidation

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Pyrrole reacts with sodium, sodium hydride or potassium ininert solvents, and with sodium amide in liquid ammonia, togive salt-like compounds:

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Electrophilic substitution reactions on carbon

Nitration

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Halogenation