Organic Chemistry, Heterocyclic Compounds, Lec.8 PDF

Organic Chemistry III Heterocyclic Compounds Thiophene | Lec.8 Heterocyclic Compounds | Thiophene Contents : Introduction 3 Properties of Thiophene 4 Thiophene aromaticity 7 Synthesis of Thiophene 11 Reactions of Thiophene 18 Medical uses of Thiophene 30 Heterocyclic Compounds | Thiophene Introducti...

Organic Chemistry III Heterocyclic Compounds Thiophene | Lec.8 Heterocyclic Compounds | Thiophene Contents : Introduction 3 Properties of Thiophene 4 Thiophene aromaticity 7 Synthesis of Thiophene 11 Reactions of Thiophene 18 Medical uses of Thiophene 30 Heterocyclic Compounds | Thiophene Introduction: 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. Properties of Thiophene Heterocyclic Compounds | Thiophene Properties: 1. Aromaticity Heterocyclic Compounds | Thiophene Properties of Thiophene: 1. At room temperature, thiophene is a colorless liquid with a mildly pleasant odor reminiscent of benzene. 2. It’s boiling point is 84°C. 3. It is insoluble in water but freely soluble in ethanol, ether and acetone. 4. The high reactivity of thiophene toward sulfonation is the basis for the separation of thiophene from benzene. Thiophene aromaticity Heterocyclic Compounds | Thiophene Thiophene aromaticity: Thiophene have 4C and 1S, all are sp2 hybridized. sp² hybridization is planar, it makes a planar thiophene ring structure. Each ring atom also contains unhybridized p orbital that is perpendicular to the plane of σ bonds (plane of ring). Here p orbitals are parallel to each other, so overlapping btwn p orbitals is possible. The total nu of non bonding e- are 6 (4 of four C, 2 from one S). The resonance of 6 e- follows the Hückel's rule. So the thiophene is aromatic. Heterocyclic Compounds | Thiophene Thiophene aromaticity: Furan is less aromatic/ thiophene is more aromatic. This order depends on order of electronegativity of heteroatoms. The more e-ve is the atom → the more tightly holds its lone pair of e → more reduce the ease of delocalization (aromaticity). Heterocyclic Compounds | Thiophene So most e-ve O in furan most decrease aromaticity & Least e-ve S in thiophene least decrease aromaticity. Thus …… Or we can say, As Sulphur is less electronegative as compared to nitrogen and oxygen, it has a greater electron donating tendency. And these donated electrons take part in delocalization in the ring. Synthesis of Thiophene Heterocyclic Compounds | Thiophene Synthesis: From N-butane (Commercial method) By reaction of sulphur with n-butane in the gas phase at 650 °C Heterocyclic Compounds | Thiophene From Acetylene Thiophene can be prepared by passing a mixture of acetylene and hydrogen sulphide through a tube containing aluminium oxide at 600°C. Heterocyclic Compounds | Thiophene Synthesis: 1. Paal-Knorr synthesis of thiophene The condensation of 1,4-dicarbonyl compounds with sulfur sources gives thiophene. Heterocyclic Compounds | Thiophene Mechanism Heterocyclic Compounds | Thiophene 2. From sod. Succinate Laboratory synthesis. Heating a mix. of sod. succinate and phosphorus trisulfide. Heterocyclic Compounds | Thiophene 3. Hinsberg Synthesis Condensation between a 1,2-dicarbonyl compound and diethyl thiodiacetate in presence of strong base give thiophene 2,5- diacids (-diketone). Reaction of Thiophene Heterocyclic Compounds | Thiophene Reactions: 1. Electrophilic substitution: Thiophene is more easily substituted than benzene but less vigorously than furan and pyrrole. The new substituent usually enters on the 2-position. If the 2-positions are occupied then on 3-position. Heterocyclic Compounds | Thiophene Thiophene undergoes electrophilic substitution reaction at 2nd position. 2 reasons... C2 attack gives more resonance contributing structures than C3. Extra stable contributing structure generates upon C2 attack Heterocyclic Compounds | Thiophene Very strongly acidic conditions lead to acid - catalysed polmerization. The action of hot phosphoric acid on thiophene leads to a trimer. Heterocyclic Compounds | Thiophene Heterocyclic Compounds | Thiophene Friedel-crafts acylation Chloromethylation Heterocyclic Compounds | Thiophene Reaction with organolithium or 2- lithiumthiophene Heterocyclic Compounds | Thiophene Reactions: 2. Reduction: Partial reduction in acidic media Heterocyclic Compounds | Thiophene The differences between furan and thiophene reduction using Raney Ni: On the other hand thiophene can not be reduced under the same conditions as in furan due to sulfur poison the catalyst and desulphurization occurs with ring opening. However, partial reduction can take place by metals in acidic medium, given in the previous slide. Heterocyclic Compounds | Thiophene Reactions: 3. Oxidation: Thiophene does not oxidised, but tetrahydrothiophene oxidised to respective sulphone. Heterocyclic Compounds | Thiophene Electrophilic Substitution in subst. Furan and subs. Thiophene: a) Monosubstituted furan & thiophene with electron withdrawing groups such as COOH, CHO, CN, COR, SO3H are less reactive than unsubstitutted compounds Heterocyclic Compounds | Thiophene Electrophilic Substitution in subst. Furan and subs. Thiophene: b) Monosubstituted furan & thiophene with electron donating groun such as CH3, OH, NH2 , OCH3. Medical uses Heterocyclic Compounds | Thiophene Medical uses: 1. Sitaxsentan: Cardiovascular Agent, used in pulmonary artery hypertension. 2. Tiagabine: Anticonvulsant Agent, used in the treatment of epilepsy Heterocyclic Compounds | Thiophene 3. Cephalothin New semisynthetic antibacterial agent structurally related to Pencillins. It is effective against penicillinase- producing staphylococci as well as other gram-positive and gram-negative organisms.