Organic

1

• Organic
• Chemistry

William H. Brown Christopher S. Foote
2

• Carboxyl
• Derivatives

3
Carboxyl Derivatives

• In this chapter, we study five classes of organic
  compounds
• under the structural formula of each is a drawing
  to help you see its relationship to the carboxyl
  group

4
Carboxyl Derivatives

• an amide is formally related to a carboxyl group
  by loss of -OH from the carboxyl and -H from
  ammonia
• loss of -OH and -H from an amide gives a nitrile

5
Structure Acid Chlorides

• The functional group of an acid halide is an acyl
  group bonded to a halogen
• to name, change the suffix -ic acid to -yl halide

6
Acid Chlorides

• replacement of -OH in a sulfonic acid by -Cl
  gives a sulfonyl chloride

7
Acid Anhydrides

• The functional group of an acid anhydride is two
  acyl groups bonded to an oxygen atom
• the anhydride may be symmetrical (two identical
  acyl groups) or mixed (two different acyl groups)
• to name, replace acid of the parent acid by
  anhydride

8
Acid Anhydrides

• Cyclic anhydrides are named from the dicarboxylic
  acids from which they are derived

9
Acid Anhydrides

• A phosphoric acid anhydride contains two
  phosphoryl groups bonded to an oxygen atom

10
Esters

• The functional group of an ester is an acyl group
  bonded to -OR or -OAr
• name the alkyl or aryl group bonded to oxygen
  followed by the name of the acid
• change the suffix -ic acid to -ate

11
Esters

• Cyclic esters are called lactones
• name the parent carboxylic acid, drop the suffix
  -ic acid, and add -olactone

12
Amides

• The functional group of an amide is an acyl group
  bonded to a nitrogen atom
• IUPAC drop -oic acid from the name of the parent
  acid and add -amide
• if the amide nitrogen is bonded to an alkyl or
  aryl group, name the group and show its location
  on nitrogen by N-

13
Amides

• Cyclic amides are called lactams
• Name the parent carboxylic acid, drop the suffix
  -ic acid and add -lactam

14
Penicillins

• The penicillins are a family of ?-lactam
  antibiotics

15
Penicillins

• Amoxicillin

16
Cephalosporins

• The cephalosporins are also ?-lactam antibiotics

17
Cefetamet
18
Nitriles

• The functional group of a nitrile is a cyano
  group
• IUPAC name as an alkanenitrile
• Common drop the -ic acid and add -onitrile

19
Acidity of N-H bonds

• Amides are comparable in acidity to alcohols
• water-insoluble amides do not react with NaOH or
  other alkali metal hydroxides to form water
  soluble salts
• Sulfonamides and imides are more acidic than
  amides

20
Acidity of N-H bonds

• Imides are more acidic than amides because
• 1. the electron-withdrawing inductive of the two
  adjacent CO groups weakens the N-H bond, and
• 2. the imide anion is stabilized by resonance
  delocalization of the negative charge

21
Acidity of N-H

• imides such as phthalimide readily dissolve in
  aqueous NaOH as water-soluble salts

22
IR Spectroscopy
23
NMR Spectroscopy

• 1H-NMR
• H on the ?-carbon to a CO group are slightly
  deshielded and come into resonance at ? 2.1-2.6
• H on the carbon of the ester oxygen are more
  strongly deshielded and come into resonance at ?
  3.7-4.7
• 13C-NMR
• the carbonyl carbons of esters show
  characteristic resonance at ? 160-180

24
Characteristic Reactions

• Nucleophilic acyl substitution an
  addition-elimination sequence resulting in
  substitution of one nucleophile for another

25
Characteristic Reactions

• in this general reaction, we have shown the
  leaving group as an anion to illustrate an
  important point about them the weaker the base,
  the better the leaving group

26
Characteristic Reactions

• halide ion is the weakest base and the best
  leaving group acid halides are the most reactive
  toward nucleophilic acyl substitution
• amide ion is the strongest base and the poorest
  leaving group amides are the least reactive
  toward nucleophilic acyl substitution

27
Rexn with H2O - RCOCl

• low-molecular-weight acid chlorides react rapidly
  with water
• higher molecular-weight acid chlorides are less
  soluble in water and react less readily

28
Rexn with H2O - RCO2OR

• low-molecular-weight acid anhydrides react
  readily with water to give two molecules of
  carboxylic acid
• higher-molecular-weight acid anhydrides also
  react with water, but less readily

29
Rexn with H2O - Esters

• Esters are hydrolyzed only slowly, even in
  boiling water
• Hydrolysis becomes more rapid if they are heated
  with either aqueous acid or base
• Hydrolysis in aqueous acid is the reverse of
  Fischer esterification
• the role of the acid catalyst is to protonate the
  carbonyl oxygen and increase its electrophilic
  character toward attack by water to form a
  tetrahedral carbonyl addition intermediate
• collapse of this intermediate gives the
  carboxylic acid and alcohol

30
Rexn with H2O - Esters

• Acid-catalyzed ester hydrolysis

31
Rexn with H2O - Esters

• Hydrolysis of an esters in aqueous base is often
  called saponification
• each mole of ester hydrolyzed requires 1 mole of
  base for this reason, ester hydrolysis in
  aqueous base is said to be base promoted
• hydrolysis of an ester in aqueous base involves
  formation of a tetrahedral carbonyl addition
  intermediate followed by its collapse and proton
  transfer

32
Rexn with H2O - Amides

• Hydrolysis of an amide in aqueous acid requires 1
  mole of acid per mole of amide

33
Rexn with H2O - Amides

• Hydrolysis of an amide in aqueous base requires 1
  mole of base per mole of amide

34
Rexn with H2O - Nitriles

• The cyano group is hydrolyzed in aqueous acid to
  a carboxyl group and ammonium ion

35
Rexn with H2O - Nitriles

• protonation of the cyano nitrogen gives a cation
  that reacts with water to give an imidic acid
• keto-enol tautomerism of the imidic acid gives
  the amide

36
Rexn with H2O - Nitriles

• hydrolysis of a cyano group in aqueous base gives
  a carboxylic anion and ammonia acidification
  converts the carboxylic anion to the carboxylic
  acid

37
Rexn with H2O - Nitriles

• Hydrolysis of nitriles is a valuable route to
  carboxylic acids

38
Rexn with Alcohols

• Acid halides react with alcohols to give esters
• acid halides are so reactive toward even weak
  nucleophiles such as alcohols that no catalyst is
  necessary
• where the alcohol or resulting ester is sensitive
  to HCl, reaction is carried out in the presence
  of a 3 amine to neutralize the acid

39
Rexn with Alcohols

• sulfonic acid esters are prepared by the reaction
  of an alkane- or arenesulfonyl chloride with an
  alcohol or phenol

40
Rexn with Alcohols

• Acid anhydrides react with alcohols to give one
  mole of ester and one mole of carboxylic acid

41
Rexn with Alcohols

• cyclic anhydrides react with alcohols to give one
  ester group and one carboxyl group

42
Rexn with Alcohols

• aspirin is synthesized by treatment of salicylic
  acid with acetic anhydride

43
Rexn with Alcohols

• Esters react with alcohols in the presence of an
  acid catalyst in a reaction called
  transesterification, an equilibrium reaction

44
Rexn with Ammonia, etc.

• Acid halides react with ammonia, 1 amines, and
  2 amines to form amides
• 2 moles of the amine are required per mole of
  acid chloride

45
Rexn with Ammonia, etc.

• Acid anhydrides react with ammonia, and 1 and 2
  amines to form amides.
• 2 moles of ammonia or amine are required

46
Rexn with Ammonia, etc.

• Esters react with ammonia, and 1 and 2 amines
  to form amides
• esters are less reactive than either acid halides
  or acid anhydrides
• Amides do not react with ammonia, or 1 or 2
  amines

47
Interconversions
48
Acid Chlorides with Salts

• Acid chlorides react with salts of carboxylic
  acids to give anhydrides
• most commonly used are sodium or potassium salts

49
Rexns with Grignards

• treatment of a formic ester with 2 moles of
  Grignard reagent followed by hydrolysis with
  aqueous acid gives a 2 alcohol

50
Rexn with Grignards

• treatment of an ester other than formic with a
  Grignard reagent followed by hydrolysis in
  aqueous acid gives a 3 alcohol

51
Rexns with Grignards

• 1. addition of 1 mole of RMgX to the carbonyl
  carbon gives a TCAI
• 2. collapse of the TCAI gives a ketone (an
  aldehyde from a formic ester)

52
Reaction with Grignards

• 3. reaction of the ketone with a 2nd mole of RMgX
  gives a second TCAI
• 4. treatment with aqueous acid gives the alcohol

53
Rexns with RLi

• Organolithium compounds are even more powerful
  nucleophiles than Grignard reagents
• they react with esters to give the same types of
  2 and 3 alcohols as do Grignard reagents
• and often in higher yields

54
Gilman Reagents

• Acid chlorides at -78C react with Gilman
  reagents to give ketones.
• under these conditions, the TCAI is stable, and
  it is not until acid hydrolysis that the ketone
  is liberated

55
Gilman Reagents

• Gilman reagents react only with acid chlorides
• they do not react with acid anhydrides, esters,
  amides, or nitriles under the conditions described

56
Redn - Esters by LiAlH4

• Most reductions of carbonyl compounds now use
  hydride reducing agents
• esters are reduced by LiAlH4 to two alcohols
• the alcohol derived from the carbonyl group is
  primary

57
Redn - Esters by LiAlH4

• Reduction occurs in three steps plus workup

58
Redn - Esters by LiAlH4

• NaBH4 does not normally reduce esters, but it
  does reduce aldehydes and ketones
• Selective reduction is often possible by the
  proper choice of reducing agents and experimental
  conditions

59
Redn - Esters by DIBAlH

• Diisobutylaluminum hydride (DIBAlH) at -78C
  selectively reduces an ester to an aldehyde
• at -78C, the TCAI does not collapse and it is
  not until hydrolysis in aqueous acid that the
  carbonyl group of the aldehyde is liberated

60
Redn - Amides by LiAlH4

• LiAlH4 reduction of an amide gives a 1, 2, or
  3 amine, depending on the degree of substitution
  of the amide

61
Redn - Amides by LiAlH4

• The mechanism is divided into 4 steps
• Step 1 transfer of a hydride ion to the carbonyl
  carbon
• Step 2 formation of an oxygen-aluminum bond

62
Redn - Amides by LiAlH4

• Step 3 redistribution of electrons gives an
  iminium ion
• Step 4 transfer of a second hydride ion
  completes the reduction to the amine

63
Redn - Nitriles by LiAlH4

• The cyano group of a nitrile is reduced by LiAlH4
  to a 1 amine

64
Interconversions

• Problem show reagents and experimental
  conditions to bring about each reaction

65
Hofmann Rearrangement

• When a 1 amide is treated with bromine or
  chlorine in aqueous NaOH or KOH,
• the carbonyl carbon is lost as carbonate ion, and
• the amide is converted to an amine of one fewer
  carbon atoms

66
Hofmann Rearrangement

• Stage 1 acid-base reaction gives an amide anion,
  which reacts as a nucleophile with Br2
• Stage 2 a 2nd acid-base reaction followed by
  elimination of Br- gives a nitrene, an
  electron-deficient species, that rearranges to an
  isocyanate

67
Hofmann Rearrangement

• Stage 3 reaction of the isocyanate with water
  gives a carbamic acid
• Stage 4 decarboxylation of the carbamic acid
  gives the primary amine

68
Prob 18.19

• Propose a structural formula for each compound.

69
Prob 18.19 (contd)

• Propose a structural formula for each compound.

70
Prob 18.20

• Draw a structural formula for the product formed
  on treatment of benzoyl chloride with each
  reagent.

71
Prob 18.26

• Draw a structural formula for the product of
  treating this a,b-unsaturated ketone with each
  reagent.

72
Prob 18.28

• Draw a structural formula for the product of
  treating this anhydride with each reagent.

73
Prob 18.31

• Show how to bring about each step in this
  conversion of nicotinic acid to nicotinamide.

74
Prob 18.32

• Complete these reactions.

75
Prob 18.35

• Draw structural formulas for the products of
  complete hydrolysis of each compound in hot
  aqueous acid.

76
Prob 18.36

• Show reagents to bring about each step in this
  synthesis of anthranilic acid.

77
Prob 18.37

• Propose a mechanism for each step in this
  sequence.

78
Prob 18.38

• Propose a mechanism for each step in this
  sequence.

79
Prob 18.39

• Show how to prepare the insect repellent DEET
  from 3-methyltoluic acid.

80
Prob 18.40

• Show how to prepare isoniazid from
  4-pyridinecarboxylic acid.

81
Prob 18.41

• Show how to bring about this conversion.

82
Prob 18.42

• Propose a mechanism for the formation of this
  bromolactone, and account for the observed
  stereochemistry of each substituent on the
  cyclohexane ring.

83
Prob 18.43

• Propose a mechanism for this reaction.

84
Prob 18.44

• Propose a synthesis of this b-chloroamine from
  anthranilic acid.

85
Prob 18.45

• Show reagents for the synthesis of 5-nonanone
  from 1-bromobutane as the only organic starting
  material.

86
Prob 18.46

• Describe a synthesis of procaine from the three
  named starting materials.

87
Prob 18.47

• The following sequence converts (R)-2-octanol to
  (S)-2-octanol. Propose structural formulas for A
  and B, and specify the configuration of each.

88
Prob 18.48

• Propose a mechanism for this reaction.

89
Prob 18.49

• Propose a mechanism for this reaction.

90
Prob 18.50

• Show how each hypoglycemic drug can be
  synthesized by converting an appropriate amine to
  a carbamate ester, and then treating its sodium
  salt with a substituted benzenesufonamide.

91
Prob 18.51

• Propose a mechanism for Step 1, and reagents for
  Step 2 in the synthesis of the antiviral agent
  amantadine.

92
Prob 18.52

• Propose structural formulas for intermediates A-F
  and for the configuration of the bromoepoxide.

93
Prob 18.53

• Show reagents for the synthesis of
  (S)-Metolachlor from the named starting materials

94

• Derivatives of
• Carboxylic Acids

End Chapter 18