Electrophilic aromatic substitution reactions

This is Power Point Presentation on Topic "Electrophilic Aromatic Substitution Reactions" as per syllabus of "University of Mumbai" for S.Y. B. Pharmacy (Sem.: IV) students.

1. Electrophilic Aromatic Substitution Reactions Dr. Firoz Khan Assistant Professor AIKTC, School of Pharmacy, Panvel, Navi Mumbai, India. https://scholar.google.co.in/citations?user=FkGHPWQAAAAJ&hl=en

2. Generalized electrophilic aromatic substitution:

3. Nitration Reaction: Mechanism σ Complex Nitro group can often be reduced to the amine group using tin or iron and HCl . Ar-NO 2 Ar-NH 2 σ Complex

4. Sulfonation Reaction: Mechanism

5. Halogenation Reaction: Mechanism

6. Friedel -Crafts Alkylation Mechanism

7. Friedel -Crafts Acylation Mechanism

8. Kolbe reaction It is also known as Kolbe-Schmitt reaction (named after Hermann Kolbe and Rudolf Schmitt). When Phenol reacts with Sodium hydroxide , gives Sodium phenoxide which undergoes electrophilic substitution with CO 2 and Salicylic acid is formed. Reaction

9. Reaction Mechanism Application: Salicylic acid is used as Precursor/ starting material for synthesis of Aspirin.

10. Reimer- Tiemann Reaction Reimer- Tiemann reaction is an chemical reaction where Phenol is converted into an ortho-hydroxy benzaldehyde ( Salicylaldehyde ) using chloroform and base. Reaction Application: It is starting material for synthesize coumarin and which is used to synthesize Warfarin .

11. Reaction Mechanism

12. Orientation and Reactivity of mono and di -substituted Benzenes Orientation

13. Mechanism of Electrophilic Aromatic Substitution Without any substituents With a substituent group G Depending on the nature of the substituent, the substituent G may stabilize the carbocation intermediate and therefore speed the reaction . Substituents that make the ring react faster (than benzene) with electrophiles are called activators ; those that make the ring react slower (than benzene) are called deactivators .

14. Products of Nitration

15. Substituent Effects All activators direct incoming electrophiles to the ortho - and the para -positions. Most deactivators direct incoming electrophiles to the meta position. The exceptions are the halogens, which are weakly deactivating yet ortho-para directing . Classification of Substituents

16. 3º, especially stable 3º, especially stable o & p-Activators (alkyl & aryl groups) Inductive effect and stability of carbocation will direct the electrophile for o & p substitution.

17. o,p -Activators with a lone pair of electrons More number of resonating structures, more is the stability

18. o,p -Deactivators (Halogens) 4 resonance forms 4 resonance forms o- m- p- Chlorine is electronegative element and therefore it will donate the paired electrons towards positive centre.

19. Summary for o & p directing groups (Activators) When the substituent is R (alkyl) or Ar (aryl), the resonance hybrid cation intermediate has three resonance forms. For attack of the electrophile at the ortho or para positions, one of these is a 3º carbocation , which is especially stable. This lowers the energy of the intermediate, thus facilitates (speeds) the substitution reaction at the o - and p - positions. When the substituent has a lone pair of electrons , such as the halogens, oxygen (OH) or nitrogen (NH 2 ), the resonance hybrid for attack of the electrophile at the ortho and para positions has four resonance forms . This lowers the energy of the those intermediates, thus facilitates (speeds) the substitution reaction at the o - and p - positions.

20. meta-directing Deactivators Especially UNSTABLE** Especially UNSTABLE** o- m- p- Carbocations formed are unstable because of the electron withdrawing effect.

21. Summary for meta (m) directing groups (Deactivators) It will not form the o & p substitution product because of the formation of unstable carbocation (energy level will be too high). Meta substitution product will be formed. Energy level will be less as compared to o & p substitutions. But reaction will be slow one. nitro group sulfonic acid ketone nitrile

22. Rule 1: If the directing effects of two substituents reinforce each other, the predicted product predominates . (o,p) (m)

23. Rule 2: If the directing effects of two substituents oppose each other, the more activating group dominates , but mixtures often result. (o,p; STRONG activator) ( o,p ; weak activator) Ortho to CH 3 - product will be formed but in very less quantity.

24. Rule 3: Substitution almost never occurs between two substituents meta to each other. (o,p) (o,p) X (too crowded)

25. Rule 4: With a bulky o,p - director and/or a bulky electrophile, para substitution predominates. Ortho- product will be formed but in very less quantity.