1. Chapter 19 Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

2. 19.1 Nomenclature of Carboxylic Acid Derivatives

3. Acyl Halides RC O X 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. Acyl Halides CH 3 CCl O Acetyl chloride 3-butenoyl chloride or but-3-enoyl chloride O H2CH2C CHCH 2 CCl O CBr F p-fluorobenzoyl bromide or 4-fluorobenzoyl bromide

5. 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. RCOCR' OO

6. Acid Anhydrides Acetic anhydride Benzoic anhydride Benzoic heptanoic anhydride CH 3 COCCH 3 OO C 6 H 5 COCC 6 H 5 OO C 6 H 5 COC(CH 2 ) 5 CH 3 OO

7. Esters Name as alkyl alkanoates. 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. RCOR' O

8. Esters CH 3 COCH 2 CH 3 O Ethyl acetate Methyl propanoate 2-chloroethyl benzoate O CH 3 CH 2 COCH 3 COCH 2 CH 2 Cl O

9. Amides Having an NH 2 Group Identify the corresponding carboxylic acid. Replace the -ic acid or -oic acid ending with –amide. RCNH 2 O

10. Amides Having an NH 2 Group CH 3 CNH 2 O Acetamide 3-Methylbutanamide O (CH 3 ) 2 CHCH 2 CNH 2 CNH2CNH2 O Benzamide

11. 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). RCNHR' O and RCNR' 2 O

12. Amides Having Substituents on N CH 3 CNHCH 3 O N-Methylacetamide N-Isopropyl-N-methylbutanamide CN(CH 2 CH 3 ) 2 O N,N-Diethylbenzamide O CH 3 CH 2 CH 2 CNCH(CH 3 ) 2 CH 3

13. 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). RC N

14. Nitriles CH 3 C N Ethanenitrile or: Acetonitrile or: Methyl cyanide C6H5CC6H5C N Benzonitrile N C CH 3 CHCH 3 2-Methylpropanenitrile or: Isopropyl cyanide

15. 19.2 Structure and Reactivity of Carboxylic Acid Derivatives

16. Figure 19.1 The key to managing the information in this chapter is the same as always: structure determines properties. The key structural feature is how well the carbonyl group is stabilized. The key property is reactivity in nucleophilic acyl substitution.

17. CH 3 C O Cl CH 3 C O OCCH 3 O CH 3 C O OCH 2 CH 3 CH 3 C O NH 2 Most reactive Least reactive Least stabilized Most stabilized

18. RC O 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: – RC O X + RC O X + –

19. 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 RC O X – RC O X + RC O X + –

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

21. Orbital Overlaps in Carboxylic Acid Derivatives lone pair orbital of substituent

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

23. Acyl chlorides have the least stabilized carbonyl group. Delocalization of lone pair of Cl into C=O group is not effective because C—Cl bond is too long. Acyl Chlorides C O R Cl C O R Cl + –

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

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

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

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

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

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

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

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

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

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

34. Reactivity is Related to Structure RCOCR' OO RCCl O RCOR' O RCNR' 2 O Stabilization very small small large moderate Relative rate of hydrolysis 10 11 10 7 < 10 -2 1.0 The more stabilized the carbonyl group, the less reactive it is.

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

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