Carboxyl Derivatives

1
Carboxyl Derivatives

• Classes shown, formally, via dehydration.

2
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 -oic acid to -oyl
  halide.

3
Related Sulfonyl Chlorides

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

4
Structure Acid Anhydrides

• 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.

5
Acid Anhydrides

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

6
Related Phosphoric Anhydrides

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

7
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.

8
Esters Lactones

• Lactone A cyclic ester.
• name the parent carboxylic acid, drop the suffix
  -ic acid and add -olactone.

9
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-.

10
Amides

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

ethanamide
11
Amides resonance
12
Amides Characteristics
13
Amides Lactams

• Lactams A cyclic amides are called lactams.
• Name the parent carboxylic acid, drop the suffix
  -ic acid and add -lactam.

Indicates where the N is located.
14
Imides

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

15
Related 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.

16
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.

17
Acidity of N-H bonds

• Effect of neighboring carbonyl groups.

1.0
18
Acidity of N-H

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

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. More resonance delocalization of the negative
  charge.

20
Lab related Sulfonamides (Hinsberg)
Experimental test to distinguish primary,
secondary and tertiary amines.
1
soluble
insoluble
2
insoluble
3
soluble
In acid
In base
Reaction replaces one H with the sulfonyl group.
In an H remains it is soluble in base.
Aq. base
21
Characteristic Reactions Ketones Aldehydes

• Nucleophilic acyl Addition

Protonation makes carbonyl better electrophile.
Ok with poor nucleophile.
Carbonyl weaker electrophile. Need good
nucleophile.
22
Characteristic Reactions Derivatives

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

Dominant for derivatives due to good leaving
group (Y), uncommon for ketones or aldehydes.
23
Characteristic Reactions

• Poor bases make good leaving groups.

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
Water and 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
Water and Anhydrides

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

26
Mechanism- Anhydrides

• Step 1 Addition of H2O to give a TCAI.
  (Addition)

Acid makes carbonyl better electrophile.
27
Mechanism- Anhydrides

• Step 2 Protonation and collapse of the TCAI.
  (Elimination)

Acid sets up better leaving group.
28
Water and 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.
• acid catalyst protonates the carbonyl oxygen and
  increases 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.

29
Mechanism Acid/H2O - Esters (1o and 2o alkoxy)

• Acid-catalyzed ester hydrolysis.

Acid makes carbonyl Better electrophile.
Acid sets up leaving group.
30
Mechanism Reaction with Acid/H2O Esters (3o
alkoxy)
But wait!!!!!!!
water
alcohol
31
Reaction with Base/H2O - Esters

• Saponification The hydrolysis of an esters in
  aqueous base.
• Each mole of ester hydrolyzed requires 1 mole of
  base
• For this reason, ester hydrolysis in aqueous base
  is said to be base promoted.

32
Mechanism of Reaction with Base/H2O Esters

• Step 1 Attack of hydroxide ion (a nucleophile)
  on the carbonyl carbon (an electrophile).
  (Addition)
• Step 2 Collapse of the TCAI. (Elimination)
• Step 3 Proton transfer to the alkoxide ion this
  step is irreversible and drives saponification to
  completion.

33
Acidic Reaction with H2O - Amides

• Hydrolysis of an amide in aqueous acid requires
  one 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.

34
Basic Reaction with H2O - Amides

• Hydrolysis of an amide in aqueous base requires
  one mole of base per mole of amide.
• Reaction is driven to completion by the
  irreversible formation of the carboxylate salt.

35
Mechanism Acidic H2O - Amides

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

36
Acidic 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.
  (Elimination)

37
Mechanism Reaction with Basic H2O - Amides
Amide
hydroxide ion
Dianion!
38
Acidic H2O and 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.

Acid Ammonium ion
39
Basic H2O and Nitriles

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

40
Synthesis Reaction with H2O - Nitriles

• Hydrolysis of nitriles is a valuable route to
  carboxylic acids.

41
Synthesis Grignards Nitriles -gtketone 1
R'MgX
H2O
diethylether

• Grignard reagents add to carbon-nitrogen
  triplebonds in the same way that they add to
  carbon-oxygen double bonds.
• The product of the reaction is an imine.

42
Synthesis Grignards Nitriles -gtketone 2
R'MgX
H2O
diethylether
H3O
Imines hydrolyzed to ketones.
43
Reaction of Alcohols and Acid Halides

• 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.

44
Reaction with Alcohols, Sulfonic Esters

• Sulfonic acid esters are prepared by the reaction
  of an alkane- or arenesulfonyl chloride 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.

45
Reaction of Alcohols and Acid Anhydrides

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

46
Reaction of Alcohols and Esters

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

47
Reaction of Ammonia, etc. and Acid Halides

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

48
Reaction of Ammonia, etc. and Anhydrides.

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

49
Ammonia, etc. and Esters

• Esters react with ammonia and with 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 with 1 or 2
  amines.

50
Acid Chlorides with Salts

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

51
Interconversions of Acid Derivatives
52
Grignard and an Ester.Look for two kinds of
reactions.
Substitution
Any alcohol will do here.
But where does an ester come from?
Acid chloride
Perhaps this carboxylic acid comes from the
oxidation of a primary alcohol or reaction of a
Grignard with CO2.
Addition
53
Grignard Reagents and Formic Esters

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

54
Reactions with RLi

• Organolithium compounds are even more powerful
  nucleophiles than Grignard reagents.

55
Gilman Reagents

• Acid chlorides at -78C react with Gilman
  reagents to give ketones.

Gilman Reagents do not react with acid
anhydrides, esters, amides or nitriles under
these conditions. Selective reaction.
56
Synthesis Reduction - Esters by LiAlH4

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

57
Mechanism Reduction - Esters by LiAlH4

• Reduction occurs in three steps plus workup
• Steps 1 and 2 reduce the ester to an aldehyde.
• Step 3 Work-up gives a 1 alcohol derived from
  the carbonyl group.

58
Synthesis Selective Reduction by NaBH4

• NaBH4 reduces aldehydes and ketones. It does not
  normally reduce esters. LiAlH4 reduces all.
• Selective reduction is often possible by the
  proper choice of reducing agents and experimental
  conditions.

59
Synthesis Reduction - Esters by DIBAlH -gt
Aldehyde

• 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
Synthesis 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.

61
Synthesis Reduction - Nitriles by LiAlH4

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

Can use catalytic hydrogenation also.
62
Interconversions

• Problem Show reagents and experimental
  conditions to bring about each reaction.