Aromatic electrophilic substitution reactions.pptx

Electrophilic aromatic substitution reactions are organic reactions wherein an electrophile replaces an atom which is attached to an aromatic ring. Commonly, these reactions involve the replacement of a hydrogen atom belonging to a benzene ring with an electrophile

1. Aromatic Electrophilic Substitution reactions Dr. Satyajit Dey Department of Chemistry Tamralipta Mahavidyalaya Tamluk Midnapore (East) Under Graduate SEM-III Organic Chemistry Course

2. The introduction of a formyl group into electron-rich aromatic compounds using N,N- dimethylformanilide and POCl 3 is known as the Vilsmeier-Haack formylation . The reaction between N,N- dimethylformanilide and POCl 3 gave rise to a chloromethyliminium salt ( Vilsmeier reagent), which readily reacts with electron-rich aromatic compounds to yield substituted benzaldehydes . VILSMEIER-HAACK FORMYLATION General features : 1) The Vilsmeier reagent is prepared from any N,N- disubstituted formamide (DMF) by reacting it with an acid chloride (e.g., POCl 3 , SOCl 2 , oxalyl chloride). 2) mostly electron-rich aromatic or heteroaromatic compounds as well as electron-rich alkenes and 1,3-dienes are substrates for the transformation, since the Vilsmeier reagent is a weak electrophile. 3) The transformation is regioselective favoring the less sterically hindered position (this means the para position on a substituted benzene ring); but electronic effects can also influence the product distribution.

3. Mechanism of the reaction Examples:

4. Problems:

5. Mechanism: Reimer- Tiemann reaction In 1876, K. Reimer and F. Tiemann discovered that the treatment of phenol with chloroform in 10% NaOH solution led to the formation of the corresponding o-hydroxy benzaldehyde as the major product. The formylation of phenols and heterocyclic phenols using chloroform in an aqueous alkaline medium is known as the Reimer- Tiemann reaction .

6. Reimer- Tiemann reaction, contd ….. Characteristic features: 1. When o- or p-substituted phenols are subjected to R.T. reaction conditions, 2,2- or 4,4-disubstituted cyclohexadienones may be obtained in addition to normal products. Cause: i ) Insolubility in aq. Base. Ii) sterically hindered iii) not benzylic type 2. it is the only electrophilic aromatic substitution reaction that occurs under basic conditions in a protic solvents, and phenols, naphthols , alkyl-, alkoxy -, and halogenated phenols, salicylic acid derivatives, heterocyclic phenols such as hydroxyquhydroxyquinolines and hydroxypyrimidines , as well as pyrroles and indoles undergo formylation under the reaction conditions.

7. Reimer- Tiemann reaction, contd ….. 3. Besides CHCl 3 , other dichlorocarbene precursors such as chloral, trichloronitromethane , etc. can be used. 5. When o-substituent is a carboxylic acid group (in case of pyrroles), decarboxylation is observed and o- formyl pyrroles are formed. 4. Ortho- formyl products tend to predominate. This is because intramolecular H-bonding makes the o-product thermodynamically more stable. When the ortho -position contains a substituent, then p- formyl phenols are formed. 6. High yield of normal R. T. products is reported under phase transfer catalyst. This is probably due to the increased solubility of phenolate ion and the product in aq. Base, and high concentrations of carbenes are generated under P. T. catalysis.

8. 6. Under the Reimer- Tiemann conditions the potassium salt of pyrroles and indoles and other five membered ring compounds undergo ring- expension to affords ring-expansion products. This transformation is known as Ciamician-Dennstedt rearrangement (also called as the abnormal Reimer- Tiemann reaction). Reimer- Tiemann reaction, contd ….. 7. Other abnormal products such as tropolone and benzoic acid are also formed via the initial carbene insertion reaction on substrate molecules.

9. Reimer- Tiemann reaction : Examples

10. Reimer- Tiemann reaction, contd ….. Problems: Give product and draw a stepwise mechanism for the following reaction.

11. Reimer- Tiemann reaction, Exercize Q. 1 How would you introduce aldehyde group in the aromatic nucleus by a reaction involving carbene intermediate. Give mechanism. Q. 2. Explain why benzene itself does not undergo Reimer- Tiemann reaction with CHCl 3 /Aq. KOH. Q. 3. During the reaction of p-cresol with CHCl 3 and alkali a minor product A of MF C 8 H 8 OCl 2 is formed along with an aldehydic compound. Write down the structure of the product A. Explain its formation. Give mechanism. Q. 4. Give products of the following reaction. Q. 5. Explain why are CHF 3 and CHI 3 not used in Reimer- Tiemann reaction? Q. 6. A small amount of tropolone is formed in the Reimer- Tiemann reaction of phenol with CHCl 3 and aqueous alkali. How it is formed?

12. Reimer- Tiemann reaction, Exercize Q. 7. Explain the following reaction Q. 8. Suggest mechanism for the following reaction. Q. 9. Outline a synthesis for each of the following molecules.

13. The preparation of ortho - or para -substituted aromatic hydroxy acids from the corresponding phenols under basic conditions using gaseous CO 2 is referred to as the Kolbe-Schmitt reaction . Kolbe-Schmitt reaction The general features of this reaction are: phenols, substituted phenols, naphthols , and electron-rich heteroaromatic compounds are good substrates. the size of the alkali metals greatly influences the position of attack, the use of large alkali metal ions such as Rb + or Cs + gives rise to p- hydroxybenzoic acid derivatives, whereas smaller alkali metal ions (Na + or K + ) afford salicylic acid derivatives the presence of even trace amounts of water significantly decreases the yield of the product, so the reactants, reagents, and the solvents should be thoroughly dried before use.

14. Mechanism of the reaction In the mechanism of the Kolbe-Schmitt reaction the CO 2 electrophile attacks the ring directly to afford the corresponding ortho - or para -substituted products. When the counterion is large (e.g., cesium ) the attack of CO 2 at the ortho -position is hindered; therefore, the para -substituted product is the major product. Q. 1. For the synthesis of salicylic acid, Kolbe-Schmidt reaction of sodium phenate is useful but not potassium phenate . Explain. Problems:

15. Gattermann -Koch Formylation The introduction of a formyl group (-CHO) into electron rich aromatic rings by applying CO/HCl/Lewis acid catalyst (AlX 3 , FeX 3 , where X = Cl , Br, I) to prepare aromatic aldehydes is known as the Gattermann -Koch formylation . The general features of this reaction are: at atmospheric pressure activated aromatic compounds can be used as substrates (e.g., alkylbenzenes ) and deactivated aromatic compounds (having meta-directing substituents) cannot be formylated with this method monosubstituted substrates are formylated almost exclusively at the para position, but when there is already a para substituent present in the substrate, the formyl group is introduced at the ortho position

16. Mechanism of the reaction The mechanisms of the Gattermann and Gattermann -Koch formylation belong to the category of electrophilic aromatic substitution ( SEAr ). When carbon monoxide is used, the electrophilic species is believed to be the formyl cation, which is attacked by the aromatic ring to form a -complex. This -complex is then converted to the aromatic aldehyde upon losing a proton. Problems: Give product and draw a stepwise mechanism for the following reaction.

17. Gattermann introduced a modification where HCN is mixed with HCl in the presence of ZnCl 2 to formylate phenols, phenolic ethers and heteroaromatic compounds. This modification is called the Gattermann formylation . The main drawback of the Gattermann formylation was that it called for the use of anhydrous HCN, which is a very toxic compound. To avoid the handling of HCN, R. Adams generated it in situ along with ZnCl 2 by reacting Zn(CN) 2 with HCl in the presence of the aromatic substrate (Adams modification). Gattermann Formylation

18. Mechanism of the reaction The mechanisms of the Gattermann formylation is same as the gattermann -Koch reaction. When HCN is used, the initial product after the SEAr reaction is an imine hydrochloride, which is subsequently hydrolyzed to the product aldehyde . Problems: Give product and draw a stepwise mechanism for the following reaction.

19. Houben-Hoesch Reaction In 1915, K. Hoesch reported the extension of the Gattermann reaction for the preparation of aromatic ketones by using nitriles instead of hydrogen cyanide and replaced the aluminum chloride with the milder zinc chloride. The condensation of nitriles with polyhydroxy - or polyalkoxyphenols to prepare the corresponding polyhydroxy - or polyalkoxyacyloxyphenones is known as the Houben-Hoesch reaction.

20. Mechanism of the reaction The mechanism is very similar to the mechanism of the Gattermann -Koch formylation . The first step is the formation of a nitrilium chloride that is subsequently transformed to an imino chloride from which the reactive species, the iminium ion is generated. Problems: Write down the structure of the missing compounds in the following reaction and draw the mechanism

21. Diazo -Coupling Reaction Diazo coupling is a kind of aromatic electrophilic substitution reaction in which an aryldiazonium cation (an eletrophile ) reacts with the activated aromatic ring (a nucleophile) to produce a covalent diazo -compound. For example, phenol via phenoxide ion couples with diazonium salt at pH 9-10 to afford para-azophenols in good yield. The aromatic diazonium cation is very weak electrophile because the resonance structure I is contributed more due to its octet fulfilled. So the diazonium cation will react with highly reactive aromatic nucleus such as phenols and amines.

22. Diazo -Coupling Reaction, contd …… Introduction of electron withdrawing groups at o- or p- position of the diazonium cation increases electrophilic character of the diazonium cation by resonance. As a result, these diazonium cations reacts with anisole and even with hydrocarbons such as mesitylene . Mechanism of formation of diazonium ion:

23. Diazo -Coupling Reaction, contd …… Effect of pH on diazo -coupling reaction: Diazo -coupling reactions are generally carried out in solution at 4 < pH < 10. In the presence of hydroxide ion, the electrophilic diazonium cation exist in equilibrium with an un-ionized species, Ar -N=N-OH and the salt, Ar -N=N-O - Na + , derived from it. If the diazo -coupling is carried out with amines, the solution is to be made slightly acidic because it increases the conc. of PhN 2 + . However, in strong acid medium the amine is converted into its ammonium ion which because of the positive charge is relatively unreactive towards electrophilic substitution reaction by weakly electrophilic diazonium cation. And the reaction does not occur.

24. Diazo -Coupling Reaction, contd …… Coupling with Phenols: In weakly basic medium, diazo -coupling of phenols takes place almost entirely in the p-position. If, p-position is blocked by stable substituents (for example, alkyl, alkoxy etc.) the coupling occurs in the p-position for steric reasons.

25. Coupling with aromatic amines: Diazo -Coupling Reaction, contd …… With aromatic amines, diazo -coupling reactions occur in mild acidic solution, and coupling occurs on nitrogen for primary andsecondary amines. But with tertiary amines coupling occurs at p-ring carbon. The N-coupling product may be rearranged to the C-coupling product on heating the acid solution.

26. Diazo -Coupling Reaction, contd …… Exception to diazo -coupling test: Why?

27. Diazo -Coupling Reaction, Exercize Q. 1. P-Nitro benzene diazonium salt is 10 4 times more reactive than p- methoxybenzene diazonium salt towards diazo -coupling reaction under the same condition. Explain Q. 2.PhN 2 + Cl - couples with phenol but not with anisole. 2,4-dinitrobenzene diazonium chloride, however couples with anisole. How you account for these differences in behavior. Q. 3. Benzene diazonium salts couple with phenolic compound in weakly basic solution but not in acidic and in strongly basic medium. Explain Q. 4. Give the products in the following reactions and explain. Q. 5. α- Naphthol undergoes diazo coupling reaction at para position whereas β- naphthol gives 1-substituted product. Explain. Q. 6. Between salicylic acid and phenol, which will couples with PhN 2 + Cl - more readily and why?

28. Diazo -Coupling Reaction, Exercize Q. 7. 4-Nitro-2-naphthol does not undergo diazo coupling reaction with PhN 2 + Cl - although its 1-position is free. Give reason. Q. 8. Although N,N-dimethyl aniline couples with PhN 2 + Cl - , its 2,6-dimethyl derivative does not. Explain. Q. 9. P- Toluidine couples with PhN 2 + Cl - to form a compound, which, when heated with H 2 SO 4 , gives four products. What ate the products? Explain.

29. Chloromethylation Reaction The Blanc chloromethylation reaction is the reaction for introducing the chloromethyl group onto aromatic or hetero aromatic rings using formaldehyde (or its synthetic equivalent like MeOCH 2 Cl) and hydrogen chloride in the presence of zinc chloride. Mechanism I: Mechanism II:

30. Ipso-Substitution In some aromatic substitution reactions, the attacking species attacks at the substituent bearing carbon (Ipso position) and results in a displacement of that substituent rather than hydrogen by the attacking species. Such reactions are called Ipso substitution. It can be of two types: Electrophilic Ipso substitution: When the attacking species is an electrophile (E + ), then the aromatic electrophilic substitution is associated with the elimination of Electrofugal group (Y + ). Nucleophilic Ipso substitution: When the attacking species is an Nucleophile (Nu-), then the ipso substitution results in the displacement of Nucleofugal group (X - ).

31. Ipso-Substitution, contd …….. Each of removal of electrofugal group depends on its ability to accommodate a positive charge. In the following example, When X is Br or I, during nitration 30-40 % p- nitroanisole , an ipso substitution product, is formed along with the formation of normal o-nitro derivative. But when X is Cl , no ipso substitution product is formed. Reason: Less electronegative and larger bromide and iodide are best able to stabilize the positive charge in compared to small and more electronegative chlorine atom. Alkyl groups may also be displaced if the resulting alkyl cation is sufficiently stable.

32. Ipso-Substitution, contd …….. Q. 1. What is Ipso substitution? Give one example. Q. 2. Give a possible mechanism for the following reaction. Q. 3. t-Butyl benzene, when treated with Br 2 /FeBr 3 , gives p- bromo t- butylbenzene along with other two products , C and D. Give the structure of the products C and D and explain their formation. Q. 4. When the following compound is heated with mixed acid, a single product of MF C 8 H 8 N 2 O 5 is obtained. Account for this observation.

33. Ipso-Substitution, contd …….. Q. 5. Nitration of p- diisopropyl benzene gives two products, A and B, with the later being formed in major amount. Give the structure of the products and explain their formation. Q. 6. Both salicylic acid and p- hydroxybenzoic acid on treatment with excess bromine in water gives the same product, while m- hydroxybenzoic acid gives different product. Explain. Q. 7. Suggest a probable mechanism for the following reaction. Q. 8. Suggest mechanism for the following reaction.

34. Thanks For Your Attention 34