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20.3 General Mechanism for Nucleophilic Acyl Substitution

20.3 General Mechanism for Nucleophilic Acyl Substitution. ••. ••. O. O. • •. • •. C. C. R. R. X. Nu. Nucleophilic Acyl Substitution. Reaction is feasible when a less stabilized carbonyl is converted to a more stabilized one (more reactive to less reactive). + H Nu. + H X.

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20.3 General Mechanism for Nucleophilic Acyl Substitution

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  1. 20.3General MechanismforNucleophilic Acyl Substitution

  2. •• •• O O •• •• C C R R X Nu Nucleophilic Acyl Substitution • Reaction is feasible when a less stabilized carbonyl is converted to a more stabilized one (more reactive to less reactive). + HNu + HX

  3. •• OH •• O O HNu -HX •• •• R C C C Nu R X R Nu X General Mechanism for Nucleophilic Acyl Substitution Involves formation and dissociationof a tetrahedral intermediate Both stages can involve several elementary steps.

  4. •• OH O HNu •• R C C Nu R X X General Mechanism for Nucleophilic Acyl Substitution First stage of mechanism (formation of tetrahedralintermediate) is analogous to nucleophilic additionto C=O of aldehydes and ketones.

  5. •• OH •• O O HNu -HX •• •• R C C C Nu R X R Nu X General Mechanism for Nucleophilic Acyl Substitution Second stage is restoration of C=O by elimination. Complicating features of each stage involveacid-base chemistry.

  6. •• OH •• O O HNu -HX •• •• R C C C Nu R X R Nu X General Mechanism for Nucleophilic Acyl Substitution Acid-base chemistry in first stage is familiar in thatit has to do with acid/base catalysis of nucleophilic addition to C=O.

  7. •• OH •• O O HNu -HX •• •• R C C C Nu R X R Nu X General Mechanism for Nucleophilic Acyl Substitution Acid-base chemistry in second stage concernsform in which the tetrahedral intermediate existsunder the reaction conditions and how it dissociatesunder those conditions.

  8. Tetrahedral Intermediate (TI) H H •• •• O O •• •• •• – •• •• •• R R O •• •• C C C R Nu Nu •• Nu X X Conjugate acid of tetrahedral intermediate (TI+) Conjugate base of tetrahedral intermediate (TI–) + X H •• The Tetrahedral Intermediate

  9. O B •• •• •• H X + +B—H + •• C R Nu •• Dissociation of TI—H+ •• O H •• R X C H + Nu ••

  10. •• O H O •• R B •• X C •• •• Nu •• •• – + X +B—H + •• •• C R Nu •• Dissociation of TI

  11. •• – O O •• •• R X C •• •• Nu •• •• – + X •• •• C R Nu •• Dissociation of TI–

  12. 20.4Nucleophilic Acyl Substitutionin Acyl Chlorides

  13. O O (CH3)2CHCOH (CH3)2CHCCl Preparation of Acyl Chlorides From carboxylic acids and thionyl chloride(Section 12.7) SOCl2 + + SO2 HCl heat (90%)

  14. O RCCl O O RCOCR' O RCOR' O RCNR'2 O RCO– Reactions of Acyl Chlorides

  15. O O O O RCOCR' RCCl R'COH H O O via: R OCR' C Cl Reactions of Acyl Chlorides Acyl chlorides react with carboxylic acids to giveacid anhydrides: + + HCl

  16. O O CH3(CH2)5CCl CH3(CH2)5COH O O CH3(CH2)5COC(CH2)5CH3 Example + pyridine (78-83%)

  17. O O RCOR' RCCl H O via: R OR' C Cl Reactions of Acyl Chlorides Acyl chlorides react with alcohols to give esters: + + R'OH HCl

  18. O O C6H5COC(CH3)3 C6H5CCl Example pyridine + (CH3)3COH (80%)

  19. O O RCNR'2 RCCl H O via: R NR'2 C Cl Reactions of Acyl Chlorides Acyl chlorides react with ammonia and aminesto give amides: + + R'2NH + HO– H2O + Cl–

  20. O O C6H5CN C6H5CCl HN Example NaOH + H2O (87-91%)

  21. O O RCOH RCCl O O RCO– RCCl Reactions of Acyl Chlorides Acyl chlorides react with water to givecarboxylic acids (carboxylate ion in base): + + H2O HCl + + 2HO– Cl– + H2O

  22. O O RCOH RCCl H O R OH C Cl Reactions of Acyl Chlorides Acyl chlorides react with water to givecarboxylic acids (carboxylate ion in base): + + H2O HCl via:

  23. O O C6H5CH2COH C6H5CH2CCl Example + + H2O HCl

  24. O C6H5CCl Reactivity • Acyl chlorides undergo nucleophilic substitution much faster than alkyl chlorides. C6H5CH2Cl Relative rates ofhydrolysis (25°C) 1,000 1

  25. 20.5Nucleophilic Acyl Substitution in Acid Anhydrides • Anhydrides can be prepared from acyl chlorides as described in Table 20.1.

  26. O O O O CH3COCCH3 O O O O Some Anhydrides are Industrial Chemicals Aceticanhydride Phthalicanhydride Maleicanhydride

  27. O O H COH H C tetrachloroethane O 130°C C H H COH O O From Dicarboxylic Acids • Cyclic anhydrides with 5- and 6-membered rings can be prepared by dehydration of dicarboxylic acids: + H2O (89%)

  28. O O RCOCR' O RCOR' O RCNR'2 O RCO– Reactions of Anhydrides

  29. O O O O RCOR' RCOCR RCOH Reactions of Acid Anhydrides Carboxylic acid anhydrides react with alcoholsto give esters: • Normally, symmetrical anhydrides are used(both R groups the same). • Reaction can be carried out in presence of pyridine (a base) or it can be catalyzed by acids. + + R'OH

  30. O O O O RCOR' RCOCR RCOH H O R OR' C OCR O Reactions of Acid Anhydrides Carboxylic acid anhydrides react with alcoholsto give esters: + + R'OH via:

  31. O O + CH3CHCH2CH3 CH3COCCH3 OH O CH3COCHCH2CH3 CH3 Example H2SO4 (60%)

  32. O O O O RCNR'2 RCO– RCOCR H + O R'2NH2 R NR'2 C via: OCR O Reactions of Acid Anhydrides Acid anhydrides react with ammonia and aminesto give amides: + + 2R'2NH

  33. O O H2N CH(CH3)2 CH3COCCH3 O CH3CNH CH(CH3)2 Example + (98%)

  34. O O O RCOCR O O O RCOCR Reactions of Acid Anhydrides Acid anhydrides react with water to givecarboxylic acids (carboxylate ion in base): + H2O 2RCOH + + 2HO– 2RCO– H2O

  35. O O O RCOCR H O R OH C OCR O Reactions of Acid Anhydrides Acid anhydrides react with water to givecarboxylic acids (carboxylate ion in base): + H2O 2RCOH

  36. O O COH O COH O O Example + H2O

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