FURANSubmitted by

Vayu ChaurasiyaM.Sc Chemistry 4th Semester

MS14CHM016

CHEMISTRY OF HETEROCYCLIC COMPOUNDS

Furan is a Heterocyclic organic compound, consisting of a five-membered aromatic ring with four carbon atoms and

one oxygen. The class of compounds containing such rings are also referred to as furans

Physical Properties:• It is colorless, flammable and highly volatile

liquid.• Melting point: -85.6°C• Boiling Point: 31.3°C• Soluble in alcohol, ether and acetone but

slightly soluble in water• Toxic and may be carcinogenic

Interesting Furan Containing Drugs

RanbezolidAnti-bacterial Drug

NifurzideAnti-Infective Drug

Ranitidine (Zantac)H2 histamine receptor

antagonist

FuraneolPerfume distilled from

Strawberries

Synthesis of Furan1. From Pentosans

2. From Oxidation of cis-but-2-ene-1,4-diol

Pentosans are hydrolyzed to Xylose followed by dehydration and cyclization to give furfural

3. From diacetosuccinic ester:

When diacetosuccinic ester is heated with dilute sulphuric acid, 2,5-dimethylfuran-3,4-dicarboxylic acid is obtained.

4. From Alkynes

5. Ring opening of Epoxide in presence of Lewis acid BF3

Name Reactions for Furan Synthesis6. Paal-Knorr Synthesis:The acid-catalyzed cyclization of 1,4-dicarbonyl compounds in presence of acid or lewis acid

Mechanism:

7. Feist–Benary synthesisIt is Organic reaction between α-haloketones and β-dicarbonyl compounds to substituted furan compounds.This condensation reaction is catalyzed by base.

Mechanism:This classical synthesis rests on an initial aldol condensation at the carbonyl carbon of a 2 - halo - arbonyl-component; ring closure is achieved via intramolecular displacement of halide by enolate oxygen.

Aromaticity of Furan

The resonance energy of furan is 67 kJ (16 kcal)/mol.

The oxygen within the cyclic structure can assume an sp2 hybridization.

With sp2 , one of the two lone pairs occupies a pz orbital, allowing oxygen to contribute to the continuous loop of pz orbitals and maintains the ring’s flat shape.

The other lone pair occupies an sp2 orbital, perpendicular to the pi electron cloud. This pair is not involved in the pi electron cloud.

Furan also obeys Hückel’s rule (4n + 2 = 6 pi electrons, n = 1). Because furan has a continuous, closed loop of pz orbitals, planarity, and obeys Hückel’s rule, it is aromatic.

Chemical Properties of Furan

• It appears that structure (I), (II) and (III) are the main contributing structures since 2- (or 5-) substitution (with electrophile) occur more readily.

• (IV) and (V) would account for 3-substitution when the 2- and 5-positions are both occupied.

• Calculations of the bond lengths and comparison with the measured values show that (I) contributes about 85%, to the resonance hybrid.

• It is considerably more reactive than Benzene in electrophilic substitution reactions, due to the electron-donating effects of the oxygen heteroatom. Examination of the resonance contributors shows the increased electron density of the ring, leading to increased rates of electrophilic substitution.

Furan behaves as resonance hybrid.

Reactions of Furan1. Reactions of Protonated FuransThe hydrolysis (or alcoholysis) of furans involves nucleophilic addition of water (or an alcohol) to an initially formed cation, giving rise to open - chain 1,4 -dicarbonyl compounds or derivatives

2. Nitration

3. Sulphonation

4. HalogenationFuran reacts vigorously with chlorine and bromine at room temperature to give polyhalogenated products, but does not react at all with iodine.

If the bromination is conducted in an alcohol, trapping of the intermediate by C - 5 addition of the alcohol, then alcoholysis of C - 2 - bromide, produces 2,5 - dialkoxy - 2,5 - dihydrofurans, as mixtures of cis - and trans isomers;

• Hydrogenation of these species affords 2,5 - dialkoxy – tetrahydrofurans.The 2,5 - dialkoxy -2,5 - dihydrofurans are also useful for the synthesis of 2 - substituted furans, for example with benzenethiol or phenylsulfinic acid, 2 - sulfur - substituted furans are formed.

The reaction of furfural with excess halogen to produce mucobromic acid which reacts with formamide to provide a useful synthesis of 5 – bromopyrimidine.

5. Acylation:Carboxylic acid anhydrides or halides normally require the presence of a Lewis acid (often boron trifluoride) for Friedel – Crafts acylation of furans, trifluoroacetic anhydride will react alone

6. Vilsmeier Haack Formylation

7. Alkylation

8. AlkenylationIntramolecular alkenylation at a furan α- or β- position by an alkyne occurs, with the formation of bicyclic derivatives, when promoted by mercury(II) acetate (or Hg(OAc)(OTf), generated in situ from mercuric acetate and scandium triflate)

9. Mannich Reaction

10. Mercuration

Mercuration takes place very readily with replacement of hydrogen, or carbon dioxide from an acid.

11. Reaction with Oxidizing agents

12. Achmatowicz ReactionIt is an organic synthesis in which a furan is converted to a dihydropyran.Furfuryl alcohol is reacted with bromine in methanol to 2,5-dimethoxy-2,5-dihydrofuran which rearranges to the dihydropyran with dilute sulphuric acid followed by alcohol protection with methyl orthoformate and boron trifluoride and ketone reduction with sodium borohydride.

13. Reaction with Nucleophilic reagents Simple furans do not react with nucleophiles by addition or by substitution. Nitro substituents activate the displacement of halogen

14. Direct Ring C – H Metallation

Lithium diisopropylamide can effect C - 2 - deprotonation of 3 - halofurans. With furoic acid and two equivalents of lithium diisopropylamide, selective formation of the 5 - lithio lithium 2 - carboxylate takes place, whereas n- butyllithium, via ortho- assistance, produces the 3 - lithio lithium 2 – carboxylate.

15. Reaction with Reducing Agents

16. Diels-Alder Reaction Furan serves as a diene in Diels-Alder reactions with electron-

deficient dienophiles such as ethyl (E)-3-nitroacrylate. The reaction product is a mixture of isomers with preference for the endo isomer:

17. Paterno-Buchi reactionThe cycloaddition of diaryl ketones and some aldehydes across the furan 2,3 - double bond proceeds regioselectively to afford oxetano - dihydrofurans, proton - catalyzed cleavage of the acetal linkage in which produces 3 - substituted furans.

Synthesis of Furaneol Furaneol is a natural flavour principle, isolated from pineapple and strawberry, and used in the food and

beverage industries

Synthesis of Ranitidine Ranitidine is one of the most commercially successful medicines ever developed; it is

used for the treatment of stomach ulcers and has been synthesized from furfuryl alcohol.