Organic Chemistry

1
Organic Chemistry

• William H. Brown
• Christopher S. Foote
• Brent L. Iverson

2

• Functional
• Derivatives of
• Carboxylic Acids

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
Structure Acid Chlorides

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

5
Sulfonyl Chlorides

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

6
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

7
Acid Anhydrides

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

O
O
O
O
O
O
O
O
O
8
Phosphoric Anhydrides

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

O
O
O
O
O
O
O
O
O
O
Triphosphoric acid
Triphosphate ion
9
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

10
Esters

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

11
Esters of Phosphoric Acid

• phosphoric acid forms mono-, di-, and triesters
• name by giving the name of the alkyl or aryl
  group(s) bonded to oxygen followed by the word
  phosphate
• in more complex phosphoric esters, it is common
  to name the organic molecule and then indicate
  the presence of the phosphoric ester by the word
  phosphate or the prefix phospho-

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
Cephalosporins

• the cephalosporins are also ?-lactam antibiotics

16
Imides

• The functional group of an imide is two acyl
  groups bonded to nitrogen
• both succinimide and phthalimide are cyclic imides

17
Nitriles

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

18
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

19
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

20
Acidity of N-H

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

O
O


O
O
21
Characteristic Reactions

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

22
Characteristic Reactions

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

23
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

24
Reaction with H2O - Acid Chlorides

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

25
Reaction with H2O - Anhydrides

• 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

26
Reaction with H2O - Anhydrides

• Step 1 addition of H2O to give a TCAI
• Step 2 protonation followed collapse of the TCAI

27
Reaction 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 (a weak
  nucleophile) to form a tetrahedral carbonyl
  addition intermediate
• collapse of this intermediate gives the
  carboxylic acid and alcohol

28
Reaction with H2O - Esters

• Acid-catalyzed ester hydrolysis

29
Reaction 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

30
Reaction with H2O - Esters

• Step 1 attack of hydroxide ion (a nucleophile)
  on the carbonyl carbon (an electrophile)
• Step 2 collapse of the TCAI
• Step 3 proton transfer to the alkoxide ion this
  step is irreversible and drives saponification to
  completion

31
Reaction with H2O - Amides

• Hydrolysis of an amide in aqueous acid requires 1
  mole of acid per mole of amide
• reaction is driven to completion by the acid-base
  reaction between the amine or ammonia and the acid

32
Reaction with H2O - Amides

• Hydrolysis of an amide in aqueous base requires 1
  mole of base per mole of amide
• reaction is driven to completion by the
  irreversible formation of the carboxylate sale

33
Reaction with H2O - Amides

• Step1 protonation of the carbonyl oxygen gives a
  resonance-stabilized cation intermediate

34
Reaction with H2O - Amides

• Step 2 addition of water (a nucleophile) to the
  carbonyl carbon (an electrophile) followed by
  proton transfer gives a TCAI
• Step 3 collapse of the TCAI and proton transfer

35
Reaction with H2O - Nitriles

• The cyano group is hydrolyzed in aqueous acid to
  a carboxyl group and ammonium ion
• protonation of the cyano nitrogen gives a cation
  that reacts with water to give an imidic acid
• keto-enol tautomerism gives the amide

36
Reaction 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
Reaction with H2O - Nitriles

• hydrolysis of nitriles is a valuable route to
  carboxylic acids

38
Reaction 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
Reaction with Alcohols

• sulfonic acid esters are prepared by the reaction
  of an alkane- or arenesulfonyl chloride (Section
  18.1A) with an alcohol or phenol
• the key point here is that OH- (a poor leaving
  group) is transformed into a sulfonic ester (a
  good leaving group) with retention of
  configuration at the chiral center

40
Reaction with Alcohols

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

41
Reaction with Alcohols

• aspirin is synthesized by treating salicylic acid
  with acetic anhydride

O
O

O
O

O
Acetic acid
42
Reaction with Alcohols

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

O

O
O

43
Reaction 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

44
Reaction with Ammonia, etc.

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

45
Reaction 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

46
Acid Chlorides with Salts

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

47
Interconversions
48
Reaction with Grignard Reagents

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

49
Reaction with Grignard Reagents

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

50
Reaction with Grignard Reagents

• 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)

51
Reaction with Grignard Reagents

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

52
Reactions 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

53
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

O
O
2-Hexanone
Pentanoyl chloride
54
Gilman Reagents

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

55
Reduction - 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

O

56
Reduction - Esters by LiAlH4

• Reduction occurs in three steps plus workup
• Steps 1 and 2 reduce the ester to an aldehyde
• Step 3 reduction of the aldehyde followed by work
  up gives a 1 alcohol

57
Reduction - Esters by NaBH4

• 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

58
Reduction - 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

59
Reduction - Amides by LiAlH4

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

60
Reduction - Amides by LiAlH4

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

61
Reduction - Amides by LiAlH4

• Step 3 redistribution of electrons and ejection
  of H3AlO- gives an iminium ion
• Step 4 transfer of a second hydride ion to the
  iminium ion completes the reduction to the amine

62
Reduction - Nitriles by LiAlH4

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

63
Interconversions

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

64

• Derivatives of
• Carboxylic Acids

End Chapter 18