Chapter 20 Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution

1. Chapter 20Carboxylic Acid Derivatives:Nucleophilic Acyl Substitution

2. 20.1Nomenclature of Carboxylic Acid Derivatives

3. O RC X Acyl Halides • Name the acyl group and add the word chloride, fluoride, bromide, or iodide as appropriate. • Acyl chlorides are, by far, the most frequently encountered of the acyl halides.

4. O CH3CCl O H2C CHCH2CCl O F CBr Acyl Halides Acetyl chloride 3-butenoyl chloride or but-3-enoyl chloride p-fluorobenzoyl bromide or 4-fluorobenzoyl bromide

5. O O RCOCR' Acid Anhydrides • When both acyl groups are the same, name the acid and add the word anhydride. • When the groups are different, list the names of the corresponding acids in alphabetical order and add the word anhydride.

6. O O CH3COCCH3 O O C6H5COCC6H5 O O C6H5COC(CH2)5CH3 Acid Anhydrides Acetic anhydride Benzoic anhydride Benzoicheptanoic anhydride

7. O RCOR' Esters • Name as alkylalkanoates. • Cite the alkyl group attached to oxygen first (R'). • Name the acyl group second; substitute the suffix-ate for the -ic ending of the corresponding acid.

8. O CH3COCH2CH3 O CH3CH2COCH3 O COCH2CH2Cl Esters Ethyl acetate Methyl propanoate 2-chloroethyl benzoate

9. O RCNH2 Amides Having an NH2 Group • Identify the corresponding carboxylic acid. • Replace the -ic acid or -oic acid ending with –amide.

10. O CH3CNH2 O (CH3)2CHCH2CNH2 O CNH2 Amides Having an NH2 Group Acetamide 3-methylbutanamide Benzamide

11. O O RCNHR' RCNR'2 Amides Having Substituents on N • Name the amide as before. • Precede the name of the amide with the name of the appropriate group or groups. • Precede the names of the groups with the letter N- (standing for nitrogen and used as a locant). and

12. O CH3CNHCH3 O CN(CH2CH3)2 O CH3CH2CH2CNCH(CH3)2 CH3 Amides Having Substituents on N N-methylacetamide N,N-diethylbenzamide N-isopropyl-N-methylbutanamide

13. RC N Nitriles • Add the suffix -nitrile to the name of the parent hydrocarbon chain (including the triply bonded carbon of CN). • or: Replace the -ic acid or -oic acid name of the corresponding carboxylic acid with –onitrile. • or: Name as an alkyl cyanide (functional class name).

14. CH3C N C6H5C N CH3CHCH3 C N Nitriles Ethanenitrileor: Acetonitrileor: Methyl cyanide Benzonitrile 2-methylpropanenitrileor: Isopropyl cyanide

15. 20.2Structure and ReactivityofCarboxylic Acid Derivatives

16. Figure 20.1 The key to managing the information inthis chapter is the same as always:structure determines properties. The key structural feature is how well thecarbonyl group is stabilized. The key property is reactivity in nucleophilicacyl substitution.

17. Mostreactive Leaststabilized O O O O O CH3C CH3C CH3C CH3C NH2 Cl OCH2CH3 OCCH3 Leastreactive Moststabilized

18. – – •• •• •• O O O •• •• •• •• •• + •• •• RC X RC X RC X + Electron Delocalization and the Carbonyl Group • The main structural feature that distinguishes acyl chlorides, anhydrides, thioesters, esters, and amides is the interaction of the substituent with the carbonyl group. It can be represented in resonance terms as:

19. – •• •• •• O O O •• •• •• •• •• + •• •• RC X RC X RC X + Electron Delocalization and the Carbonyl Group • The extent to which the lone pair on X can be delocalized into C=O depends on: • 1) The electronegativity of X • 2) How well the lone pair orbital of X interacts with the  orbital of C=O –

20. Orbital Overlaps in Carboxylic Acid Derivatives • orbital of carbonyl group

21. Orbital Overlaps in Carboxylic Acid Derivatives • lone pair orbitalof substituent

22. Orbital Overlaps in Carboxylic Acid Derivatives • electron pair of substituent delocalized into carbonyl orbital

23. •• O •• R C Cl •• •• •• Acyl Chlorides – •• O •• •• • Acyl chlorides have the least stabilized carbonylgroup. • Delocalization of lone pair of Cl into C=O group isnot effective because C—Cl bond is too long. R C + Cl •• ••

24. O RCCl least stabilized C=O most stabilized C=O

25. – •• •• •• •• O O O O •• •• •• •• •• + •• C C C C O O R R R R •• •• Acid Anhydrides • Lone pair donation from oxygen stabilizes thecarbonyl group of an acid anhydride. • The other carbonyl group is stabilized in ananalogous manner by the lone pair.

26. O RCCl O O RCOCR' least stabilized C=O most stabilized C=O

27. – •• •• O O •• •• •• + •• C C OR' OR' R R •• •• Esters • Lone pair donation from oxygen stabilizes thecarbonyl group of an ester. • Stabilization greater than comparable stabilizationof an anhydride or thioester.

28. O RCCl O O RCOCR' O RCOR' least stabilized C=O most stabilized C=O

29. – •• •• O O •• •• •• + •• C C NR'2 NR'2 R R Amides • Lone pair donation from nitrogen stabilizes thecarbonyl group of an amide. • N is less electronegative than O; therefore, amides are stabilized more than esters and anhydrides.

30. – •• •• O O •• •• •• + •• C C NR'2 NR'2 R R Amides • Amide resonance imparts significant double-bondcharacter to C—N bond. • Activation energy for rotation about C—N bondis 75-85 kJ/mol. • C—N bond distance is 135 pm in amides versusnormal single-bond distance of 147 pm in amines.

31. O RCCl O O RCOCR' O O RCOR' RCNR'2 least stabilized C=O most stabilized C=O

32. – •• •• O O •• •• •• – •• C C O O R R •• •• •• •• Carboxylate Ions • Very efficient electron delocalization and dispersalof negative charge • Maximum stabilization

33. O RCCl O O RCOCR' O O RCOR' RCNR'2 O RCO– least stabilized C=O most stabilized C=O

34. Relative rateof hydrolysis O 1011 RCCl O O 107 RCOCR' O 1.0 RCOR' O < 10-2 RCNR'2 Reactivity is Related to Structure Stabilization • The more stabilized the carbonyl group, the less reactive it is. very small small moderate large

35. •• •• O O •• •• C C R R X Y Nucleophilic Acyl Substitution In general: • Reaction is feasible when a less stabilized carbonyl is converted to a more stabilized one (more reactive to less reactive). + HY + HX

36. O RCCl O O RCOCR' O O RCOR' RCNR'2 O RCO– most reactive A carboxylic acid derivative can be converted by nucleophilic acyl substitution to any other type that lies below it in this table. least reactive