Nucleophilic acyl substitution reaction Among the most ... · Hydrolysis Most nucleophilic acyl substitution reactions of acyl chlorides are irreversible. SCH 206 ... 3-Methylbutyl

SCH 206

Dr. Solomon Derese

Carboxylic acid derivatives

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Nucleophilic acyl substitution reactionAmong the most important reactions of carboxylicacids are those that convert the carboxyl group intoother acid derivatives by a nucleophilic acylsubstitution reaction.

R O

OH

R O

OR'

R O

OCl

R O

O

R'

O

R N

OR1

R2

SCH 206

Dr. Solomon Derese

Acyl chloride

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Preparation of acyl chloridesAcid chlorides can not be prepared by reaction betweencarboxylic acid and HCl. This is because the carbonylcarbon is not electrophilic enough to be attacked bychloride and also the fact that the hydroxyl group is abad leaving group.

We use PCl5 (an acid chloride of phosphoric acid), PCl3(an acid chloride of phosphorous acid), SOCl2 (Thionylchloride), an acid chloride of sulfurous acid, or oxalylchloride, an acid chloride of oxalic acid.

X

SCH 206

Dr. Solomon Derese 59

PCl3

PCl5

Cl

O

Cl

O

SCH 206


Very reactiveGoodLeavingGroup

Good electrophile

SCH 206

Dr. Solomon Derese

Reaction of acyl chloridesAcyl chlorides are the most reactive of acyl compoundstowards nucleophiles. Lower molecular weight saturatedacyl chlorides react explosively with water, and evenmore rapidly with stronger nucleophiles.

61

Because of their reactivity and the ease with which theycan be prepared from carboxlylic acids, acyl chloridesare the most commonly used starting materials for thesynthesis of carboxylic acid derivatives in general.

SCH 206


O

R ClAcid

chloride

[H]H2O

NR1R2HR'OH

O

R OH

SOCl2

O

R OHHydrolysis

Most nucleophilic acyl substitution reactions of acylchlorides are irreversible.

SCH 206

Dr. Solomon Derese

Acyl chlorides are hydrolyzed by water to give thecorresponding carboxylic acid.

Hydrolysis: Conversion into acids

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N

H2O

O

OH

Pyridine scavenges the HCl

SCH 206

Dr. Solomon Derese

Alcoholysis: Ester formation

In most cases this reaction is carried out in thepresence of a base such as triethylamine, pyridinewhich will scavenge the acid (HCl).

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SCH 206

Dr. Solomon Derese

Ammonlysis: Conversion into amides

The reaction is carried out using an excess of the amine,which serves to remove the acid (HCl) as a salt.

65

Example

DEET, the active ingredient in the most widely usedinsect repellents, is effective against mosquitoes, fleas,and ticks.

SCH 206


Ammonolysis reactions carried with NaOH aresometimes referred to as Schotten – Baumannreaction.

Trimetozine (Opalene, Trimolide, Trioxazine) isa sedative that has been marketed in Europe since1959. It also has mild tranquilizing effects and hasbeen used in the treatment of anxiety.

SCH 206


The search for a synthetic fiber with properties similar to silkled to the discovery of nylon a polyamide. There are severaldifferent kinds of nylon, but the most well known is callednylon 6,6. It can be synthesized from two six-carbonmonomers (hence its name)—adipoyl chloride (ClOC-(CH2)4-COCl) and hexamethylenediamine (H2N(CH2)6NH2).

Application: Nylon 6,6

SCH 206

Dr. Solomon Derese

Example

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The aldehyde intermediate can be isolated if the lesspowerful reducing agent, LiAlH (Ot-Bu)3.

Example

Reduction: Conversion into alcohols

SCH 206

Dr. Solomon Derese

Reaction with aromatic compoundsThe Friedel Crafts acylation

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R Cl

O

R

O

Acyl benzene

R' R'AlCl3

Reaction with Organometallic reagentsGrignard reagent

Organolithiums react similarly to give tertiary alcohols.

SCH 206


Less reactive than Grignard/organolithium reagent and yieldketones rather than tertiary alcohols.

Organocopper (R2CuLi) (Gilman) reagents

Example

The ester functional group is not affected.

SCH 206


R

O

Cl

O

R

R

OH

H

R

O

H

H

1. LiAlH4

2. H2O

R'2CuLiR

O

R'

1. R'M

gBr

R'Li

2. H2O

orR

OH

R"R'

H2OR

O

OH

R'OHPyridine

Pyridine

R

O

OR'

R

O

NR1R2

NHR

1R2

(exc

ess)

AlCl3LiAlH(OtBu)3

Summary of the reactions of acid chlorides

SCH 206


Assignment 21I. How do you achieve the following transformation?

II. Qiana, a polyamide fiber with a silky texture, has thefollowing structure. What are the monomer units usedin the synthesis of Qiana?

SCH 206

Dr. Solomon Derese

Acid anhydrides

The 2nd most reactive carboxylic acid derivatives.

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Preparation of acetic anhydridesFrom acid chlorides

Most commonly used bases are pyridine andtriethylamine.

SCH 206

Dr. Solomon Derese

Example

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MechanismO

O

Cl

O

O

O O

SCH 206

Dr. Solomon Derese

The chemistry of anhydrides is similar to that of acidchlorides except that anhydrides react more slowly, but thekind of reactions the two groups undergo are the same.

Reactions of acid anhydrides

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SCH 206

Dr. Solomon Derese

Examples

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SCH 206

Dr. Solomon Derese

Esters

Many simple low molecular weight esters arepleasant smelling liquids that are responsible for thefragrant odors of fruits and flowers.

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R O

O

R'

Acid component Alcohol component

SCH 206


O

O

Methyl 3-methylbutanoate

O

O

Propyl propionate

O

O

Butyl acetate

O

O

3-Methylbutyl acetate

O

O

Methyl octanoate

O

O

Benzyl butanoate

Commercial applications of estersThe characteristics fruity smell of esters lead to their use inartificial fruit essences.

SCH 206

Dr. Solomon Derese

Preparation of esters Fisher esterification General reaction

Catalyzed by conc. H2SO4 or HCl.

a) Use of excess of acid or alcoholb) Removing water from the reaction mixtures

as it is formed.

Equilibrium reaction and yield can be increased by:

79

SCH 206


R O

O

H

H

OHR1

Mechanism

SCH 206

Dr. Solomon Derese

Carboxylic acids whose molecules have a hydroxyl group ona g- or d- carbon undergo intramolecular esterification togive cyclic esters (Lactones) known as g- or d- lactones.

81

RO

H

OH

OHydroxy acid

O

O

R-Lactone

H3O

Example

SCH 206

Dr. Solomon Derese

From acid chlorides/acid anhydride/carboxylic acid salts

Williamson ester synthesis

General reaction

82

SCH 206

Dr. Solomon Derese

Diazomethane esterification

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R O

O

H H2C N N

Example

Diazomethane, CH2N2, which is best drawn as a hybrid oftwo contributing structures, can be used to synthesize estersfrom carboxylic acid.

N

H

H

N

SCH 206

Dr. Solomon Derese

Reactions of Esters

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SCH 206

Dr. Solomon Derese

Hydrolysis of Esters

Examples

85

Reversible, Why?

Irreversible, Why?

SCH 206


All soaps are salts of fatty acids. The main differencebetween soaps is the addition of other ingredientsthat do not alter their cleaning properties: dyes forcolor, scents for a pleasing odor, and oils forlubrication. Soaps that float are aerated so that theyare less dense than water.

Soaps Saponification

Ester hydrolysis in base

SCH 206

Dr. Solomon Derese

Transesterification is the conversion of an ester intoanother ester by heating it with an excess of eitheran alcohol or a carboxylic acid in the presence of anacid or a base catalyst.

Transesterification

87

In an equilibrium reaction, either the alcohol or theacid portion of the original ester is removed.

SCH 206


The equilibrium is shifted to the right by allowing thelow boiling alcohol to distil from the reactionmixture.

Example

SCH 206


Biodiesel

Biodiesel is produced from renewablesources such as vegetable oils andanimal fats and is a cleanerreplacement for petroleum. It isnontoxic and biodegradable. It hasphysical properties similar to those ofpetroleum diesel.

SCH 206


Assignment 22

Draw a stepwise mechanism for each reaction.

SCH 206


I. The following reactivity order has been found for thesaponification of p-substituted methyl benzoates:

Y = NO2 > Br > H > CH3 > OCH3

How can you explain this reactivity order? Where wouldyou expect Y = CHO and Y = NH2 to be in the reactivity list?

Assignment 23

II. When ethyl benzoate is heated in methanol containing asmall amount of HCl, methyl benzoate is formed.Propose a mechanism for the reaction.

SCH 206


The aldehyde intermediate can be isolated if 1equivalent of the less reactive reducing agentdiisobutylaluminum hydride (DIBAH) is used insteadof LiAlH4. The reaction is carried out at -78°C to avoidfurther reduction to the alcohol.

Reduction of Esters

SCH 206


SCH 206


I. Predict the major product(s) for each of the following reactions:Assignment 24

II. Explain why ester A is more reactive than ester B in nucleophilicsubstitution.

SCH 206


Amides

From acid chlorides

Preparation of amidesNo free rotation across the C-N bond

SCH 206


From acid anhydrides

From esters

SCH 206


Carboxylic acids react with aqueous ammonia toform ammonium salts:

From carboxylic acids

Because of the low reactivity of the carboxylate iontoward nucleophilic substitution reaction, furtherreaction does not usually take place in aqueoussolution.

An ammoniumcarboxylate

SCH 206


Amides are of great importance in life. The linkages that joinindividual amino acids together to form proteins areprimarily amide linkages. Proteins/peptides are formed byreacting the carboxyl group of one amino acid with theamino group another amino acid.

As a consequence, much research has been done to findconvenient and mild ways for amide synthesis.Dialkylcarbodiimides (R-N=C=N=R), for exampledicyclohexylcarbodiimide (DCC), are especially usefulreagents for amide synthesis.

amide linkages

SCH 206


R O

OH N

C

N

Diclohexylcarbodiimide(DCC)

HN

C

N

OR

O

The carbonyl carbon is now moreelectrophilic than the carboxyl andthe bad leaving group –OH isreplaced by a good leaving group.

SCH 206


R N

O

HR1

R2

HN

C

N

O

+

R N

O

R1

R2 +

HN

C

N

OH

SCH 206


The following reaction will not happen as shown.

a. Show what would happen instead.b. How could you obtain the desired product?

Show the reagents to be used and the structures of any intermediates.

Assignment 25

SCH 206

Dr. Solomon Derese

Reactions of amides

HydrolysisAmides are hydrolyzed in either acidic or alkalinesolution. In either case, the acid or base is a reactant,not a catalyst, and must be used in a 1.1 molar ratio orin excess.

102

This property is at most important in biological systemsfor the stability of proteins. If the amide could hydrolyzeeasily we wont even be able to touch water.

SCH 206


Reduction

Mechanism

SCH 206


I. Predict the major product(s) for each of the following reactions:

Assignment 26

II. Propose a mechanism for each of the following transformations:

SCH 206

Dr. Solomon Derese

Preparation of nitriles

I. From dehydration of amides

105

Nitriles

SCH 206


O

H2N

RS

O

ClCl

ON

R

HS

Cl O

Mechanism

Example

SCH 206

Dr. Solomon Derese

SN2 reaction of cyanide ion with primary alkyl halides

107

Example

SCH 206

Dr. Solomon Derese

Reactions of nitriles

108

Hydrolysis of nitrites

Reduction of nitriles

R C N

NH2

RH

H

1. LiAlH4 2. H2O

orH2 / Pd/C

SCH 206


Mechanism

Example

R C N Al

H

HH

H

RCN

H

H

H

SCH 206

Dr. Solomon Derese

Reaction with organometalic reagents

110

An alternative to Friedel-Crafts acylation

SCH 206


CN R

R'

H

HH2O

R R'

OH

NH3

R R'

O

+ NH4

SCH 206


I. Predict the major product(s) for each of thefollowing reactions:

Assignment 27

CN

b)a) CN Br1. LiAlH4

2. H2O 2. MeMgBr

1. NaCN

3. H3O

c) 1. EtMgBr

4. H3O

2. H2O

3. LiAlH4

SCH 206


II. Propose a mechanism for the followingtransformation:

III. Propose an efficient synthesis for each of thefollowing transformations:

SCH 206


IV. Identify compounds A-M in the following reactionsequence.

SCH 206

Dr. Solomon Derese

Reduction of carboxylic acid

General reaction

115

SCH 206

Dr. Solomon Derese

Example

116

BH3 / THFO

HO

Selectively reduces carboxylicacids in the presence ofaldhydes/ketones and esters

SCH 206

Dr. Solomon Derese

Decarboxylation of β-keto acids and β- diacidsAcids whose molecules have a carbonyl group onecarbon removed from the carboxyl group, called β-keto acids, decarboxylate readily when they areheated to 100-150°C.

117

R O

O O

H

- KetoacidH H

SCH 206

Dr. Solomon Derese

There are two reasons for this ease of decarboxylation.1) When the carboxylate ion decarboxylate, it forms a

resonance stabilized enolate anion:

Resonance stabilized anion 118

R O

O O

H

- KetoacidH H

R

O

H

H

R

O

H

H

SCH 206

Dr. Solomon Derese

II. The decarboxylation takes place though a stable six -membered cyclic transition state.

b-Keto carboxylic acid

119

OH

O

O

R

ROH

R

R

Example

SCH 206


Write the organic product(s) and reaction mechanism of thefollowing reaction:

Assignment 28

Nucleophilic acyl substitution reaction Among the most ... · Hydrolysis Most nucleophilic acyl substitution reactions of acyl chlorides are irreversible. SCH 206 ... 3-Methylbutyl

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