Chapter 19 Carboxylic Acid Derivatives Nucleophilic Acyl Substitution

1. Chapter 19Carboxylic Acid DerivativesNucleophilicAcyl Substitution

2. Nomenclature 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 p-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 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

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 by -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 by 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 by -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. Structure of Carboxylic Acid Derivatives

16. The key to this chapter is the next slide.It lists the various carboxylic acids in order of decreasing reactivity toward their fundamental reaction type (nucleophilic acyl substitution).The other way to read the list is in order of increasing stabilization of the carbonyl group.

17. Mostreactive Leaststabilized O O O O O O CH3C CH3C CH3C CH3C CH3C Cl NH2 SCH2CH3 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 SR' SR' R R •• •• Thioesters • Sulfur (like chlorine) is a third-row element.Electron donation to C=O from third-row elementsis not very effective.Resonance stabilization of C=O in thioesters isnot significant.

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

29. – •• •• 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

30. O RCCl O O RCOCR' O O RCOR' RCSR' least stabilized C=O most stabilized C=O

31. – •• •• 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

32. – •• •• 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

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

34. – •• •• O O •• •• •• – •• C C O O R R •• •• •• •• Carboxylate ions • very efficient electron delocalization and dispersalof negative charge • maximum stabilization

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

36. 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

37. •• •• 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

38. O RCCl O O RCOCR' O O O RCOR' RCSR' 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

39. General MechanismforNucleophilicAcyl Substitution

40. •• •• 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

41. •• 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.

42. •• 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

43. •• 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

44. •• 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.

45. •• 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.

46. 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

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

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

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

50. Nucleophilic Substitutionin Acyl Chlorides