Derivatives of Carboxylic Acid

1
Derivatives of Carboxylic Acid
carboxylate
acid chloride
nitrile
acid anhydride
amide
ester
2
Nomenclature of Acid Halides

• IUPAC alkanoic acid ?? alkanoyl halide
• Common alkanic acid ? alkanyl halide

I 3-aminopropanoyl chloride
I 4-nitropentanoyl chloride
c b-aminopropionyl chloride
c g-nitrovaleryl chloride
I hexanedioyl chloride
c adipoyl chloride
Rings (IUPAC only) ringcarbonyl halide
I benzenecarbonyl bromide
c benzoyl bromide
I 3-cylcopentenecarbonyl chloride
3
Nomenclature of Acid Anhydrides

• Acid anhydrides are prepared by dehydrating
  carboxylic acids

acetic anhydride
ethanoic anhydride
ethanoic acid
I butanedioic anhydride
I benzenecarboxylic anhydride
I butanedioic acid
c succinic anhydride
c benzoic andhydride
c succinic acid
Some unsymmetrical anhydrides
I cis-butenedioic anhydride
c maleic anhydride
I benzoic methanoic anhydride
I ethanoic methanoic anhydride
c benzoic formic anhydride
c acetic formic anhydride
4
Nomenclature of Esters

• Esters occur when carboxylic acids react with
  alcohols

I phenyl methanoate
I t-butyl benzenecarboxylate
I methyl ethanoate
c phenyl formate
c methyl acetate
c t-butyl benzoate
I dimethyl ethanedioate
I isobutyl cyclobutanecarboxylate
c dimethyl oxalate
c none
I cyclobutyl 2-methylpropanoate
c cyclobutyl a-methylpropionate
5
Nomenclature of Cyclic Esters, Lactones
Cyclic esters, lactones, form when an open
chain hydroxyacid reacts intramolecularly. 5 to
7-membered rings are most stable.
I 4-hydroxybutanoic acid
I 4-hydroxybutanoic acid lactone
c g-hydroxybutyric acid
c g-butyrolactone

• lactone is added to the end of the IUPAC acid
  name.
• olactone replaces the ic acid of the common
  name and hydroxy is dropped but its
  locant must be included.

I 5-hydroxypentanoic acid lactone
I 4-hydroxypentanoic acid lactone
c d-valerolactone
c g-valerolactone
I 3-hydroxypentanoic acid lactone
c b-valerolactone
I 6-hydroxy-3-methylhexanoic acid lactone
c b-methyl-e-caprolactone
6
Nomenclature of Amides
1 amide
3 amide N,N-disubstituted amide
2 amide N-substituted amide

• 1 amides alkanoic acid amide ??
  alkanamide
• a ring is named ringcarboxamide

I butanamide
I p-nitrobenzenecarboxamide
I 3-chlorocyclopentanecarboxamide
c butyramide
c p-nitrobenzamide
c none

• 2 and 3 amides are N-substituted amides

I N-phenylethanamide
c N-phenylacetamide
I N,2-dimethylpropanamide
c acetanilide
c N,a-dimethylpropionamide
I N-ethyl-N-methylcyclobutanecarboxamide
c none
7
Nomenclature of Cyclic Amides, Lactams
Cyclic amides, lactams, form when an open chain
aminoacid reacts intramolecularly. 5 to
7-membered rings are most stable.
I 4-aminobutanoic acid
I 4-aminobutanoic acid lactam
c g-aminobutyric acid
c g-butyrolactam

• lactam is added to the end of the IUPAC acid
  name.
• olactam replaces the ic acid of the common
  name and amino is dropped but its locant
  must be included.

I 3-amino-2-bromopropanoic acid lactam
c a-bromo-b-propionolactam
I 5-aminohexanoic acid lactam
c d-caprolactam
I 4-amino-3-methylbutanoic acid lactam
c b-methyl-g-butyrolactam
8
Nomenclature of Nitriles
Nitriles are produced when 1 amides are
dehydrated with reagents like POCl3

• IUPAC alkane nitrile ?? alkanenitrile
• IUPAC rings ringcarbonitrile
• Common alkanic acid onitrile ?
  alkanonitrile

I 4-iodobutanenitrile
I p-thiobenzenecarbonitrile
I ethanenitrile
c g-iodobutyronitrile
c p-mercaptobenzonitrile
c acetonitrile
I 3-methoxycyclohexanecarbonitrile
I 2-cyanocyclopentanecarboxylic acid
c none
c none
9
Nomenclature Practice Exercise
I bromomethyl ethanoate
I cyclobutanecarbonitrile
I sodium ethanoate
c bromomethyl acetate
c sodium acetate
c none
I 3-bromo-N-methylpentanamide
c b-bromo-N-methylvaleramide
I pentanedioic anhydride
I 3-oxobutanoyl chloride
c glutaric anhydride
c b-oxobutyryl chloride
I 6-amino-6-chlorohexanoic acid lactam
I 2-ethyl-5-hydroxypentanoic acid lactone
c e-chloro-e-caprolactam
c a-ethyl-d-valerolactone
10
Relative Reactivity of Carbonyl Carbons

• Nucleophiles (electron donors), like OH-, bond
  with the sp2 hybridized carbonyl carbon.
• The order of reactivity is shown.

11
Nucleophilic Addition to Aldehydes and Ketones

• Recall that electron donors (Nu -s) add to the
  electrophilic carbonyl C in aldehydes and
  ketones. The CO p bond breaks and the pair of
  electrons are stabilized on the electronegative O
  atom.
• R (alkyl groups) and hydrogens (H) bonded to the
  CO carbon remain in place. R- and H- are too
  reactive (pKb of 40 and -21). R and H are not
  leaving groups, so the carbonyl group becomes an
  alkoxide as the sp2 C becomes a tetrahedral sp3
  C.

tetrahedral alkoxide with sp3 carbon.

• A second addition of a nucleophile cannot occur
  since alkoxides are not nucleophilic. The
  reaction is usually completed by protonation of
  the alkoxide with H3O forming an alcohol. This
  later reaction is simply an acid/base reaction.
• The characteristic reaction of aldehydes and
  ketones is thus nucleophilic addition.

12
Nucleophilic Acyl Substitution in Acid
Derivatives

• Carboxylic acid derivatives commonly undergo
  nucleophilic substitution at the carbonyl carbon
  rather than addition. The first step of the
  mechanism is the same.
• The CO p bond breaks and the pair of electrons
  are stabilized on the electronegative O atom. A
  tetrahedral alkoxide is temporarily formed.

Chlorine is a fair leaving group.
sp2 carbonyl reforms
alkoxide C js sp3
sp2 carbonyl C

• In carboxylic acid derivates, one of the groups
  that was bonded to the carbonyl C is a leaving
  group. When this group leaves, the sp3
  tetrahedral alkoxide reverts back to an sp2 CO
  group. Thus substitution occurs instead of
  addition.
• In many cases, the substitution product contains
  a carbonyl that can react again.

Note that because the CO group reforms, the
nucleophile can react a second time.
13
Nucleophilic Acyl Substitution in Acid Derivatives

• In carboxylic acid derivatives, the acyl group
  (RCO) is bonded to a leaving group (-Y).

Draw the mechanism.

• The leaving group (-Y) becomes a base (Y-) .
  The acid derivative is reactive If the base
  formed is weak (unreactive). Weak bases are
  formed from good leaving groups.
• For the carboxylic acid derivatives shown, circle
  the leaving group. Then draw the structure of
  the base formed, give its pKb, and describe it as
  a strong or weak base.

acid derivative leaving group pKb strength as base




21
non basic
weak base
9
-2
strong base
-21
v. strong base
14
Nucleophilic Acyl Substitution in Acid Derivatives

• We will study the reaction of only a few
  nucleophiles with various carboxylic acid
  derivatives and we will see that the same kinds
  of reactions occur repeatedly.

• Hydrolysis Reaction with water to produce a
  carboxylic acid
• Alcoholysis Reaction with an alcohol to produce
  an ester
• Aminolysis Reaction with ammonia or an amine to
  produce an amide
• Grignard Reaction Reaction with an
  organometallic to produce a ketone or alcohol
• Reduction Reaction with a hydride reducing
  agent to produce an aldehyde or alcohol

Draw the structures of the expected products of
these nucleophilic substitution reactions, then
circle the group that has replaced the leaving
group (-Y)
hydrolysis
alcoholysis
aminolysis
Grignard reduction
hydride reduction
15
Nucleophilic Acyl Substitution of Carboxylic Acids

• Nucleophilic acyl substitution converts
  carboxylic acids into carboxylic acid
  derivatives, i.e., acid chlorides, anhydrides,
  esters and amides.

NH3, D, -H2O
SOCl2
amide
acid chloride
ROH H
D -H2O
acid anhydride
ester
16
Conversion of Carboxylic Acids to Acid Halides

• The S atom in SOCl2 is a very strong
  electrophile. S is electron deficient because it
  is bonded to 3 electronegative atoms (Cl and O).
  Cl is a leaving group.
• The hydroxyl O atom in a carboxylic acid has non
  bonded pairs of electrons, making it a
  nucleophile. This O atom bonds with S (replacing
  a Cl) and forming a chlorosulfite intermediate.
  The chlorosulfite group is a very good leaving
  group. It is easily displaced by a Cl- ion via an
  SN2 mechanism yielding an acid chloride.
• Use curved arrows to draw the initial steps of
  the mechanism shown below.

• PBr3 will substitute Br for OH converting a
  carboxylic acid to an acid bromide
• Draw and name the products of the following
  reactions.

I p-methylbenzenecarbonyl chloride
c p-methylbenzoyl chloride
I ethanoyl chloride
c acetyl chloride
17
Conversion of Carboxylic Acids to Acid Anhydrides

• High temperature dehydration of carboxylic acids
  results in two molecules of the acid combining
  and eliminating one molecule of water.

acetic anhydride
ethanoic anhydride
ethanoic acid

• Cyclic anhydrides with 5 or 6-membered rings are
  prepared by dehydration of diacids.

I butanedioic acid
I butanedioic anhydride
c succinic acid
c succinic anhydride

• Draw a reaction showing the preparation of
  cyclohexanecarboxylic anhydride.

18
Conversion of Carboxylic Acids to Esters

• Two methods are used SN2 reaction of a
  carboxylate and Fischer Esterification
• SN2 reaction of a carboxylate with a methyl
  halide or 1? alkyl halide is straightforward.
  2? and 3? alkyl halides are not used because
  carboxylate is only a fair nucleophile and is
  basic enough (pKb 9) that elimination of HX
  from the alkyl halide will compete with
  substitution. The carboxylate will be protonated
  and the alkyl halide eliminates HX becoming an
  alkene.

E2
sodium propionoate
isobutylene
I 5-bromopentanoic acid
I 5-hydroxypentanoic acid lactone
I sodium 5-bromopentanoate
c d-bromovaleric acid
c d-valerolactone
c sodium d-bromovalerate
19
Conversion of Carboxylic Acids to Esters
20
Conversion of Carboxylic Acids to Esters

1. Fischer Esterification (RCOOH ? RCOOR)
   Esters are produced from carboxylic acids by
   nucleophilic acyl substitution by a methyl or 1º
   alcohol. Heating the acid and alcohol in the
   presence of a small quantity of acid catalyst
   (H2SO4 or HCl (g)) causes ester formation
   (esterification) along with dehydration. The
   equilibrium constant is not large (Keq 1) but
   high yields can be obtained by adding a large
   excess of one of the reactants and removing the
   H2O formed. The reaction is reversible. A large
   excess of H2O favors the reverse reaction. Bulky
   (sterically hindered) reagents reduce yields.
   Since alcohols are weak nucleophiles, acid
   catalyst is used to protonate the carbonyl oxygen
   which makes the carbonyl C a better electrophile
   for nucleophilic attack by ROH. Proton transfer
   from the alcohol to the hydroxyl creates a better
   leaving group (HOH). Learn the mechanism since
   it is common to other reactions.

• The net effect of Fischer esterification is
  substitution of the OH group of a carboxylic
  acid with the OR group of a methyl or 1 alcohol.

21
Conversion of Carboxylic Acids to Esters

• Draw and name the products of the following
  reactions.

I diethyl propanedioate
I propanedioic acid
c diethyl malonate
c malonic acid
cyclopentylmethyl benzoate

• Draw the reagents that will react to produce the
  following ester.

Why will an SN2 reaction of a carboxylate and an
alkyl halide not work here?
I isopropyl 2-methylpropanoate
Isopropyl bromide is a 2 alkyl halide and would
undergo an E2 rather than SN2 reaction.
c isopropyl isobutyrate

• Draw the complete mechanism for Fischer
  esterification of benzoic acid with methanol.

22
Conversion of Carboxylic Acids to Amides

• Amides are difficult to prepare by direct
  reaction of carboxylic acids with amines (RNH2)
  because amines are bases that convert carboxylic
  acids to non electrophilic carboxylate anions and
  themselves are protonated to non nucleophilic
  amine cations, (RNH3)

• High temperatures are required to dehydrate these
  quaternary amine salts and form amides. This is
  a useful industrial method but poor laboratory
  method.
• In the lab amides are often prepared from acid
  chloride after converting the carboxylic acid to
  the acid chloride.

Proton (H) acceptor

• Explain why methylamine is a Bronsted base.
• Explain why methylamine is a Lewis base.
• Explain why methylamine is not an Arrhenius base

Electron pair donor
Has no OH- group
23
Synthesis Problems Involving Carboxylic Acids

• Write equations showing how the following
  transformations can be carried out. Form a
  carboxylic acid at some point in each question.

24
Chemistry of Acid Halides

• In the same way that acid chlorides are produced
  by reacting a carboxylic acid with thionyl
  chloride (SOCl2), acid bromides are produced by
  reacting a carboxylic acid with phosphorus
  tribromide (PBr3).

Reactions of Acid Halides Acid halides are among
the most reactive of the carboxylic acid
derivatives and are readily converted to other
compounds. Recall that acid chlorides add to
aromatic rings via electrophilic aromatic
substitution (EAS) reactions called
Friedel-Crafts Acylation with the aid of
Friedel-Crafts catalysts.
25
Chemistry of Acid Halides

• Draw a reaction showing how propylbenzene can be
  produced by a Friedel Crafts acylation reaction.

I 1-phenyl-1-propanone
c ethyl phenyl ketone

• Most acid halide reactions occur by a
  nucleophilic acyl substitution mechanism. The
  halogen can be replaced by -OH to produce an
  acid, -OR to produce an ester, -NH2 to produce an
  amide. Hydride reduction produces a 1? alcohol,
  and Grignard reaction produces a 3? alcohol.

26
Hydrolysis Conversion of Acid Halides into Acids

• Acid chlorides react via nucleophilic attack by
  H2O producing carboxylic acids and HCl.

• Tertiary amines, such as pyridine, are sometimes
  used to scavenge the HCl byproduct and drive the
  reaction forward. 3º amines will not compete
  with water as a nucleophile because their
  reaction with acid halide stops at the
  intermediate stage (there is no leaving group).
  Eventually, water will displace the amine from
  the tetrahedral intermediate, regenerating the 3º
  amine and forming the carboxylic acid.

• Draw the mechanism of the reaction of
  cyclopentanecarbonyl chloride with water.

27
Alcoholysis Conversion of Acid Halides into
Esters

• Acid chlorides react with alcohols producing
  esters and byproduct HCl by the same mechanism as
  hydrolysis above.
• Draw and name the products of the following
  reaction.

I isopropyl ethanoate
I ethanoyl chloride
c isopropyl acetate
c acetyl chloride

• Draw the mechanism of the reaction of benzoyl
  chloride and ethanol.

• Once again, 3º amines such as pyridine may be
  used to scavenge the HCl byproduct or for water
  insoluble acid halides, aqueous NaOH can be used
  to scavenge HCl since it will not enter the
  organic layer and attack the electrophile (thus
  it cannot compete with the alcohol as the
  nucleophile).

28
Practice on Synthesis of Esters

• Write equations showing all the ways that benzyl
  benzoate can be produced. Consider Fischer
  esterification, SN2 reaction of a carboxylate
  with an alkyl halide, and alcoholysis of an acid
  chloride.

• Answer the same question as above but for t-butyl
  butanoate

This is the only method that will work.

• Explain why the other methods will fail.

29
Aminolysis Conversion of Acid Halides into Amides

• Acid chlorides react rapidly with ammonia or 1?
  or 2? but not 3? amines producing amides. Since
  HCl is formed during the reaction, 2 equivalents
  of the amine are used. 1 equivalent is used for
  formation of the amide and a second equivalent to
  react with the liberated HCl, forming an ammonium
  chloride salt. Alternately, the second
  equivalent of amine can be replaced by a 3º amine
  or an inexpensive base such as NaOH (provided it
  is not soluble in the organic layer). Using NaOH
  in an aminolysis reaction is referred to as the
  Schotten-Baumann reaction.

I N,N-dimethylbenzenecarboxamide
c N,N-dimethylbenzamide

• Write equations showing how the following
  products can be made from an acid chloride.

N-methylacetamide
propanamide
30
Reduction of Acid Chlorides to Alcohols with
Hydride

• Acid chlorides are reduced by LiAlH4 to produce
  1? alcohols. The alcohols can of course be
  produced by reduction of the carboxylic acid
  directly.
• The mechanism is typical nucleophilic acyl
  substitution in which a hydride (H-) attacks the
  carbonyl C, yielding a tetrahedral intermediate,
  which expels Cl-. The result is substitution of
  -Cl by -H to yield an aldehyde, which is then
  immediately reduced by LiAlH4 in a second step to
  yield a 1? alcohol.

• Draw the reaction and name the product when
  2,2-dimethylpropanoyl chloride is reduced with
  LiAlH4

I 2,2-dimethyl-1-propanol
c neopentyl alcohol
31
Reduction of Acid Chlorides to Aldehydes with
Hydride

• The aldehyde cannot be isolated if LiAlH4 (and
  NaBH4) are used. Both are too strongly
  nucleophilic.
• However, the reaction will stop at the aldehyde
  if exactly 1 equivalent of a weaker hydride is
  used, i.e., diisobutylaluminum hydride (DIBAH) at
  a low temperature (-78C).
• Under these conditions, even nitro groups are not
  reduced.

• DIBAH is weaker than LiAlH4. DIBAH is neutral
  LiAlH4 is ionic.
• DIBAH is similar to AlH3 but is hindered by its
  bulky isobutyl groups.
• Only one mole of H- is released per mole of
  DIBAH.

p-nitrobenzaldehyde
32
Reduction of Acid Chlorides to Alcohols with
Grignards

• Grignard reagents react with acid chlorides
  producing 3? alcohols in which 2 alkyl group
  substituents are the same. The mechanism is the
  same as with LiAlH4 reduction. The 1st
  equivalent of Grignard reagent adds to the acid
  chloride, loss of Cl- from the tetrahedral
  intermediate yields a ketone, and a 2nd
  equivalent of Grignard immediately adds to the
  ketone to produce an alcohol.

I 2-phenyl-2-propanol

• The ketone intermediate cant be isolated with
  Grignard reaction but can be with Gilman reagent
  (diorganocopper), R2CuLi. Only 1 equivalent of
  Gilman is used at -78C to prevent reaction with
  the ketone product. Recall the preparation of
  ketones (Ch. 19). This reagent does not react
  other carbonyl compounds (although it does
  replace halogens in alkyl halides near 0?C)

I 3-methyl-2-butanone
c isopropyl methyl ketone
33
Practice Questions for Acid Chloride Reductions

• Draw the reagents that can be used to prepare the
  following products from an acid chloride by
  reduction with hydrides, Grignards and Gilman
  reagent. Draw all possible combinations.

I ethanoyl chloride
I 1,1-dicyclopentylethanol
I 1-phenyl-1-propanone
c ethyl phenyl ketone
I 2,2-dimethylpropanoyl chloride
I 2,2-dimethyl-1-propanol
I cyclohexanecarbonyl chloride
I cyclohexanecarbaldehyde
34
Preparations of Acid Anhydrides
Preparation of Acid Anhydrides Dehydration of
carboxylic acids as previously discussed is
difficult and therefore limited to a few cases.
acetic anhydride
A more versatile method is by nucleophilic acyl
substitution of an acid chloride with a
carboxylate anion. Both symmetrical and
unsymmetrical anhydrides can be prepared this way.

• Draw all sets of reactants that will produce the
  anhydride shown with an acid chloride.

35
Reactions of Acid Anhydrides
The chemistry of acid anhydrides is similar to
that of acid chlorides except that anhydrides
react more slowly. Acid anhydrides react with
HOH to form acids, with ROH to form esters, with
amines to form amides, with LiAlH4 to form 1?
alcohols and with Grignards to form 3? alcohols.
Note that ½ of the anhydride is wasted so that
acid chlorides are more often used to acylate
compounds. Acetic anhydride is one exception in
that it is a very common acetylating agent.

• Write the mechanism for the following reactions
  and name all products
• aniline with acetic anhydride (2 moles aniline
  are needed or use 1 mole aq. NaOH)
• cyclopentanol with acetic formic anhydride (the
  formic carbonyl is more reactive).
• methyl magnesium bromide with acetic propanoic
  anhydride (Grignards are not nucleophilic enough
  to react with carboxylate by products)
• lithium aluminum hydride with acetic formic
  anhydride (LiAlH4 is so powerful a nucleophile
  that it will reduce even carboxylates).

36
Practice Questions for Acid Anhydrides

• Show the product of methanol reacting with
  phthalic anhydride

2-(methoxycarbonyl)benzoic acid

• Draw acetominophen formed when p-hydroxyaniline
  reacts with acetic anhydride

N-(4-hydroxyphenyl)acetamide
37
Chemistry of Esters

• Esters are among the most widespread of all
  naturally occurring compounds. Most have
  pleasant odors and are responsible for the
  fragrance of fruits and flowers. Write chemical
  formulas for the following esters

Flavor Name Structure
pineapple methyl butanoate
bananas isopentyl acetate
apple isopentyl pentanoate
rum isobutyl propanoate
oil of wintergreen methyl salicylatemethyl 2-hydroxybenzoate)
nail polish remover ethyl acetate
new car smell(plasticizer for PVC) dibutyl phthalate
38
Preparation of Esters

1. SN2 reaction of a carboxylate anion with a methyl
   or 1? alkyl halide
2. Fischer esterification of a carboxylic acid
   alcohol acid catalyst
3. Acid chlorides react with alcohols in basic media

39
Reactions of Esters

• Esters react like acid halides and anhydrides but
  are less reactive toward nucleophiles because the
  carbonyl C is less electrophilic. Both acyclic
  esters and cyclic esters (lactones) react
  similarly. Esters are hydrolyzed by HOH to
  carboxylic acids, react with amines to amides,
  are reduced by hydrides to aldehydes, then to
  1?alcohols, and react with Grignards to 3?
  alcohols.

40
Base Hydrolysis of Esters

• Esters are hydrolyzed (broken down by water) to
  carboxylic acids or carboxylates by heating in
  acidic or basic media, respectively.
• Base-promoted ester hydrolysis is called
  saponification (Latin soap-making). Boiling
  animal fat (which contains ester groups) in an
  aqueous solution of a strong base (NaOH, KOH,
  etc.) makes soap. A soap is long hydrocarbon
  chain with an ionic end group.

I sodium dodecanoate
c sodium laurate

• The mechanism of base hydrolysis is nucleophilic
  acyl substitution in which OH- adds to the ester
  carbonyl group producing a tetrahedral
  intermediate. The carbonyl group reforms as the
  alkoxide ion leaves, yielding a carboxylate.

c potassium laurate

• The leaving group, methoxide (OCH3-), like all
  alkoxides, is a strong base (pKb -2). It will
  deprotonate the carboxylic acid intermediate
  converting it to a carboxylate. The alkoxide,
  when neutralized, becomes an alcohol.

41
Acid Hydrolysis of Esters

• Acidic hydrolysis of an ester yields a carboxylic
  acid (and an alcohol). The mechanism of acidic
  ester hydrolysis is the reverse of Fischer
  esterification. The ester is protonated by acid
  then attacked by the nucleophile HOH. Transfer
  of a proton and elimination of ROH yields the
  carboxylic acid. The reaction is not favorable.
  It requires at least 30 minutes of refluxing.
• Draw the complete mechanism of acid hydrolysis of
  methyl cyclopentanecarboxylate.

• Acid hydrolysis of an ester can be reversed by
  adding excess alcohol. The reverse reaction is
  called Fischer Esterification. Explain why base
  hydrolysis of an ester is not reversible.

42
Alcoholysis of Esters

• Nucleophilic acyl substitution of an ester with
  an alcohol produces a different ester. The
  mechanism is the same as acid hydrolysis of
  esters except that that the nucleophile is an
  alcohol rather than water. A dry acid catalyst
  must be used, e.g., HCl(g) or H2SO4. If water is
  present, it will compete with the alcohol as the
  nucleophile producing some carboxylic acid in
  place of the ester product.
• The process is also called Ester Exchange or
  Transesterification

dicyclobutyl 1,4-benzenedicarboxylate
dicyclobutyl terephthalate
diethyl 1,4-benzenedicarboxylate
diethyl terephthalate
cyclobutanol
43
Aminolysis of Esters

• Amines can react with esters via nucleophilic
  acyl substitution yielding amides but the
  reaction is difficult, requiring a long reflux
  period. Aminolysis of acid chlorides is
  preferred.
• Draw the mechanism aminolysis of methyl
  isobutyroxide with ammonia.

I 2-methylpropanamide
c a-methylpropionamide

• Write an equation showing how the following amide
  can be prepared from an ester.

• Note that the amide intermediate must deprotonate
  to form a stable, neutral amide. Thus the amine
  must have at least one H. NH3, 1 and 2 amines
  will work but not 3.

44
Hydride Reduction of Esters

• Esters are easily reduced with LiAlH4 to yield 1?
  alcohols. The mechanism is similar to that of
  acid chloride reduction. A hydride ion first
  adds to the carbonyl carbon temporarily forming a
  tetrahedral alkoxide intermediate. Loss of the
  OR group reforms the carbonyl creating an
  aldehyde and an OR - ion. Further addition of H
  - to aldehyde gives the 1? alcohol. Draw the
  mechanism and show all products.

• Draw and name the products.

I 1,4-butanediol
I 4-hydroxybutanoic acid lactone
c none
c g-butyrolactone

• The hydride intermediate can be isolated if DIBAH
  is used as a reducing agent instead of LiAlH4. 1
  equivalent of DIBAH is used at very low temp.
  (-78 ?C).

I 4-hydroxypentanal
I 4-hydroxypentanoic acid lactone
c g-hydroxyvaleraldehyde
c g-valerolactone
45
Grignard Reduction of Esters

• Esters and lactones react with 2 equivalents of
  Grignard reagent to yield 3? alcohols in which
  the 2 substituents are identical. The reaction
  occurs by the usual nucleophilic substitution
  mechanism to give an intermediate ketone, which
  reacts further with the Grignard to yield a 3?
  alcohol.

triphenylmethoxide
methyl benzoate
benzophenone
triphenylmethanol
I 4-hydroxybutanoic acid lactone
4-methyl-1,4-pentanediol
c g-butyrolactone
46
Practice with Esters

• What ester and Grignards will combine to produce
  the following

2-phenyl-2-propanol
1,1-diphenylethanol
47
Chemistry of Amides

• Amides are usually prepared by reaction of an
  acid chloride with an amine. Ammonia,
  monosubstituted and disubstituted amines (but not
  trisubstituted amines) all react.

• Amides are much less reactive than acid
  chlorides, acid anhydrides, or esters. Amides
  undergo hydrolysis to yield a carboxylic acids
  plus an amine on heating in either aqueous acid
  or aqueous base.
• Basic hydrolysis occurs by nucleophilic addition
  of OH- to the amide carbonyl, followed by
  elimination of the amide ion, NH2-,(a very
  reactive base a difficult step requiring
  reflux)

I sodium cyclohexanecarboxamide
48
Hydrolysis of Amides

• Acidic hydrolysis occurs by nucleophilic addition
  of HOH to the protonated amide, followed by loss
  of a neutral amine (after a proton transfer to
  nitrogen).

N-methylcyclohexanecarboxamide
cyclohexanecarboxylic acid
5-aminopentanoic acid lactam
d-valerolactam
49
Alcoholysis of Amides (to Esters)

• Alcoholysis of amides occurs by the same acid
  catalyzed mechanism as acid hydrolysis except
  that the amido group of the amide is replaced
  with by an alcohol rather than water. Dry acid,
  e.g., HCl(g) or H2SO4 must be used otherwise
  water would compete with the alcohol as the
  nucleophile producing some carboxylic acid
  product in place of an ester.
• The reaction will require a long reflux period
  because amides are weak electrophiles and
  alcohols are weak nucleophiles.

N,N-dimethylcyclopentanecarboxamide
sec-butyl cyclopentanecarboxylate

• Write a mechanism for this reaction. Refer to
  acid hydrolysis mechanism if necessary.

50
Hydride Reduction of Amides

• Amides are reduced by LiAlH4. The product is an
  amine rather than an alcohol. The amide carbonyl
  group is converted to a methylene group (-CO ?
  -CH2). This is unusual. It occurs only with
  amides and nitriles. Initial hydride attack on
  the amide carbonyl eliminates the oxygen. A
  second hydride ion is added to yield the amine.
  The reaction works with lactams as well as
  acyclic amides.

N,N-dimethylcyclopentanecarboxamide

• Write equations showing how the above
  transformation can be carried out.

benzoyl chloride
N-methylbenzamide
51
Grignard Reduction of Amides

• Grignards deprotonate 1º and 2º amides and are
  not reactive enough to add to the imide ion
  product. N-H protons are acidic enough (pKa 17)
  to be abstracted by Grignards.

• Write equations showing how the following
  transformation can be carried out.

52
Chemistry of Nitriles

• The carbon atom in the nitrile group is
  electrophilic because it is bonded to an
  electronegative N atom and a ? bond in the
  nitrile is easily broken, i.e., as if it were
  providing a leaving group.

• Preparation of Nitrile
• Nitriles are easily prepared by SN2 reaction of
  cyanide ion (CN-) with methyl halides or a 1?
  alkyl halide. 2º alkyl halides also work but
  some E2 product also forms. 3º alkyl halides
  will result in mostly an alkene (E2) product
  instead of a nitrile. (pKb of CN- 4.7)

propanenitrile
bromoethane
ethyl bromide

1. Another method of preparing nitriles is by
   dehydration of a 1? amide using any suitable
   dehydrating agent such as SOCl2, POCl3, P2O5, or
   acetic anhydride. Initially, SOCl2 reacts with
   the amide oxygen atom and elimination follows.
   This method is not limited by steric hindrance.

53
Reactions of Nitriles

• Like carbonyl groups, the nitrile group is
  strongly polarized and the nitrile C is
  electrophilic. Nucleophiles thus attack yielding
  an sp2 hybridized imine anion.

• Nitriles are hydrolyzed by HOH to amides and
  subsequently to carboxylic acids, reduced by
  hydrides to amines or aldehydes, and by Grignards
  to ketones.

54
Hydrolysis of Nitriles into Carboxylic Acids

• Nitriles are hydrolyzed in either acidic or basic
  aqueous solution to yield carboxylic acids plus
  ammonia or an amine.

• In acid media, protonation of N produces a cation
  that reacts with water to give an imidic acid (an
  enol of an amide). Keto-enol isomerization of
  the imidic acid gives an amide. The amide is
  then hydrolyzed to a carboxylic acid and ammonium
  ion. It is possible to stop the reaction at the
  amide stage by using only 1 mole of HOH per mole
  of nitrile. Excess HOH forces carboxylic acid
  formation.

55
Hydrolysis of Nitriles into Carboxylate Salts

• In basic media, hydrolysis of a nitrile to a
  carboxylic acid is driven to completion by the
  reaction of the carboxylic acid with base. The
  mechanism involves nucleophilic attack by
  hydroxide ion on the electrophilic C producing a
  hydroxy imine, which rapidly isomerizes to an
  amide. Further hydrolysis yields the carboxylate
  salt.

• Show how the following transformation can be
  carried out without using a Grignard.

56
Reduction of Nitriles
Alcoholysis of Nitriles doesnt work. Alcohols
are weak nucleophiles and nitriles are weak
electrophiles Aminolysis of Nitriles doesnt
work. Amines are weak nucleophiles and nitriles
are weak electrophiles. Reduction with
Hydrides Reduction of nitriles with 2
equivalents of LiAlH4 gives 1? amines. LiAlH4 is
a very good nucleophile and can break 2 ? bonds
forming a dianion.

• If less powerful DIBAH is used, only 1 equivalent
  of hydride can add. Subsequent addition of HOH
  yields the aldehyde.

2-methylbenzaldehyde
57
Reduction of Nitriles with Grignards

• Grignards add to nitriles giving intermediate
  imine anions which when hydrolyzed yield ketones.
  The mechanism is similar to hydride reduction
  except that the attacking nucleophile is a
  carbanion (R-). Grignards are not as strongly
  nucleophilic as LiAlH4 and so can only add once
  a dianion is not formed.

1-phenyl-1-propanone
ethyl phenyl ketone
58
Multistep Synthesis Problems

• Write equations to show how the following
  transformations can be carried out.