acyl substitution

8/12/2019 Acyl Substitution

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Chapter 21. Carboxylic Acid

Derivatives and NucleophilicAcyl Substitution Reactions


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Carboxylic Compounds

Acyl group bonded to Y, an electronegative atom orleaving group

Includes: Y = halide (acid halides), acyloxy(anhydrides), alkoxy (esters), amine (amides),

thiolate(thioesters), phosphate(acyl phosphates)


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General Reaction Pattern

Nucleophilic acyl substitution


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21.1 Naming Carboxylic Acid

Derivatives

Acid Halides, R-CO-X

Derived from the carboxylic acid name by replacing the

-ic acid ending with -yl or the -carboxylic acid ending

with carbonyl and specifying the halide


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Naming Acid Anhydrides, RCO2COR' If symmetricalreplace acidwith anhydridebased

on the related carboxylic acid (for symmetricalanhydrides)

From substituted monocarboxylic acids: use bis-ahead of the acid name

Unsymmetrical anhydrides cite the two acidsalphabetically


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Naming Amides, RCONH2

With unsubstitutedNH2group. replace -oic acidor-ic acid with -amide, or by replacing the -carboxylicacidending with carboxamide

If the N is further substituted, identify the substituent

groups (preceded by N) and then the parent amide


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Naming Esters, RCO2R

Name Rand then, after a space, the carboxylic acid

(RCOOH), with the -ic acid ending replaced by -

ate


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21.2 Nucleophilic Acyl Substitution

Carboxylic acid

derivatives have an acyl

carbon bonded to a

group Y that can leave

A tetrahedral

intermediate is formed

and the leaving group is

expelled to generate a

new carbonyl compound,leading to substitution


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Substitution in Synthesis

We can readily convert a more reactive acidderivative into a less reactive one

Reactions in the opposite sense are possible butrequire more complex approaches


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General Reactions of Carboxylic Acid

Derivatives

watercarboxylic acid

alcoholsesters

ammonia or an

aminean amide hydridesource

an aldehydeor analcohol

Grignard reagenta ketoneoranalcohol


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Conversion of Carboxylic Acids into

Acid Chlorides

Reaction with thionyl chloride, SOCl2


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Mechanism of Thionyl Chloride

Reaction Nucleophilic acyl substitution pathway

Carboxylic acid is converted into an acyl chlorosulfite

which then reacts with chloride


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i . Conversion of Carboxylic Acids into

AcidAnhydrides

Heat cyclic dicarboxylic acids that can form five- orsix-membered rings

Acyclic anhydrides are not generally formed this way- they are usually made from acid chlorides and

carboxylic acids


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ii. Conversion of Carboxylic Acids

into Esters

a) Methods include reaction of a carboxylate anion witha primary alkyl halide


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Fischer Esterification

b) Heating a carboxylic acid in an alcohol solvent

containing a small amount of strong acid produces

an ester from the alcohol and acid


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Mechanism of the Fischer

Esterification

The reaction is an acid-catalyzed, nucleophilic acylsubstitution of a carboxylic acid

When 18O-labeled methanol reacts with benzoic acid,the methyl benzoate produced is 18O-labeled but the

water produced is unlabeled


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Fischer Esterification: Detailed

Mechanism

1

2

3

4


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i i i. Conversion of Carboxylic Acids

into AmidesThe reaction can not be achieved easily by direct reaction between

carboxylic acids and amines as the latter is a base and resultsin the formation of un-reactive carboxylate anion. In practice,amides are usually prepared by treating the carboxylic acidwith dicyclohexylcarbodiimide (DCC) to activate it, followed by

addition of the amine. The overall reaction is the formation ofthe amide linkage (-CO-NH-) and the water molecule is addedto the DCC converting it into dicyclohexylurea.

CN N

O

OH

NH2

CH3+ +HH

O

CN N

Dicyclohexyl carbodiimide (DCC)Dicyclohexyl urea

NH

CH3

O


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iv. Conversion of Carboxylic Acids

into AlcoholsThe reaction can be achieved by either LiAlH4, a strong reducing

agent, converting the (-COOH) into (-CH2-OH) OR BH3/THF,followed by treatment with dilute acid solution, which is a moremilder reducing agent, which will reduce ONLY the (COOH)into (CH2-OH) and leaving any other group in the molecule

unaffected at the given reaction condition. This is anadvantageous selective reduction reaction.

O

OH

N+

O-

O

1) BH3/THF

2) H3O+

LiAlH4

HH

OH

NH H

HH

OH

N+

O-

O


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21.4 Chemistry of Acid Halides

Acid chlorides are prepared from carboxylic acids byreaction with SOCl2

Reaction of a carboxylic acid with PBr3yields the acidbromide


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Reactions of Acid Halides

Nucleophilic acyl substitution

Halogen replaced by OH, by OR, or by NH2

Reduction yields a primary alcohol

Grignard reagent yields a tertiary alcohol


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i . Hydrolysis: Conversion of Acid

Halides into Acids

Acid chlorides react with water to yield carboxylic

acids

HCl is generated during the hydrolysis: a base is

added to remove the HCl


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ii. Conversion of Acid Halides to

Esters

Esters are produced in the reaction of acid chlorideswith alcohols in the presence of pyridineor NaOH

The reaction is better with less sterically hindered(OH) groups.


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i i i. Aminolysis: Conversion of Acid

Halides into Amides

Amides result from the reaction of acid chlorides withNH3, primary (RNH2) and secondary amines (R2NH)

The reaction with tertiary amines (R3N) gives an

unstable species that CAN NOTbe isolated

HCl is neutralized by the excess amine or addedbase


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iv. Reduction: Conversion of Acid

Chlorides into Alcohols

LiAlH4reduces acid chlorides to yield aldehydes and

then primary alcohols


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v. Reaction of Acid Chlorides with

Organometallic Reagents (GR)

Grignard Reagents react with acid chlorides to yieldtertiary alcohols in which two of the substituents arethe same


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vi. Formation of Ketonesfrom Acid

Chlorides Reaction of an acid chloride with a lithium

diorganocopper(Gilman reagent), Li+R2Cu

Addition produces an acyl diorganocopper

intermediate, followed by loss of RCu and formation

of the ketone


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vii. Conversion of Acid Halides to

Anhydrides

Reaction between metal carboxylate and acidehalides facilitated the preparation of anhydrides atmuch lower temperatures than the direct severheating method to eliminate H2O molecule.

This method is also a very useful route to prepareunsymmetricalanhydrides.

H

OO

-Na

+

O

Cl

CH3

+ EtherO

H O

O

CH3

Formic propanoic anhydridePropanoyl chlorideSod. formate


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21.5 Chemistry of Acid Anhydrides

Prepared by nucleophilic acyl substitution of

an acid chloride with a carboxylate anion.

Both symmetricaland unsymmetricalacid

anhydrides are prepared by this method.


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Reactions of Acid Anhydrides

The chemistry of acid anhydrides is similar tothat of acid chlorides. Although anhydrides

react more slowly than acid chlorides.


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Acetylation

Acetic anhydride forms acetate esters fromalcoholsand N-substitutedacetamidesfromamines


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21.6 Chemistry of Esters

Many esters are pleasant-smelling liquids: fragrantodors of fruits and flowers that are naturally occuring.

Also present in fats and vegetable oils


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The chemical industry uses esters for a variety

of purposes e.g. ethyl acetate is a commonly

used solvent, dioctyl phthalate DOPordiisooctyl phthalate DIOPhas been used for

along time as a plasticizerfor PVC, beside

other dialkyl phthalate.

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O

O

O

O

CH3 CH3

CH3 CH3

Diisooctyl phthalate DIOP

O

O

O

O

CH3 CH3

Dibutyl phthalate


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Preparation of Esters

Esters are usually prepared from carboxylic acids


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Reactions of Esters

Less reactive toward nucleophiles than are acid

chloridesor anhydrides, see the reactivity chart!!!.

Cyclicesters are called lactonesand react similarly to

acyclicesters

-Valerolactone


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i . Hydrolysis: Conversion of Esters

into Carboxylic Acids

An ester is hydrolyzed by aqueous baseor aqueousacidto yield a carboxylic acid plus an alcohol.

Alkaline hydrolysis of esters is the basic reaction forsoapindustry which in fact is made by boiling animal

fat with a base to hydrolyze the ester linkages givingalcohol and metal-carboxylate salt (soap).

M h i f E H d l i d


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Mechanism of Ester Hydrolysis under

basic condition

Hydroxide anion is the nucleophilic attacking species.

1

2

3

4


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Evidence from Isotope Labelling

18Oin the ether-like oxygen in ester winds up

exclusively in the ethanol product

None of the label remains with the propanoic acid,

indicating that saponification occurs by cleavage of

the CORbond rather than the CORbond

M h i f E t H d l i d


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Mechanism of Ester Hydrolysis under

acidic condition


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ii. Conversion of Ester into Alcohols

Esters (cyclic and acyclic) are easily reduced

completely by treatment with LiAlH4/ether to yield

primary alcohols.

Controlled or partial reduction of esters (cyclic and

acyclic) is possible if 1equivalentof [DIBAH/toluene,

-78 C, followed by treatment with H3O+] was applied.


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Mechanism of Reduction of Esters

Hydride ion adds to the carbonyl group, followed by

elimination of alkoxide ion to yield an aldehyde

Reduction of the aldehyde gives the primary alcohol


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Partial Reduction to Aldehydes

Use one equivalent of diisobutylaluminum hydride(DIBAH = ((CH3)2CHCH2)2AlH)) instead of LiAlH4

Low temperature to avoid further reduction to thealcohol


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iii. Aminolysis of Esters

Ammonia, primary and secondary amines react with

estersto form amides. The reaction is not very

common as this preparation is usually carried out by

reacting the more reactive species, like acid chloride,

instead.

i f i h i d


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iv. Reaction of Esters with Grignard

Reagents: conversion into alcohols

React with 2 equivalents of a Grignard reagent to

yield a tertiary alcohol


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21.7 Chemistry of Amides

Amides, like esters, are abundant in all livingorganisms-proteins, nucleic acids and manypharmaceuticals.

The reason for this abundance of amides is thatbecause they are the least reactive species ofcarboxylic acid derivatives, and hence the moststable to the conditions found in living organisms.


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Preparation of Amides

Prepared by reaction of an acid chloride withammonia, mono-substituted amines 1, or di-

substituted amines 2.

R ti f A id


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Reactions of Amides,

i(a). Acid Hydrolysis Heating in either aqueous acidor aqueous base

produces a carboxylic acid and amine

Acidic hydrolysis by nucleophilic additionof water tothe protonatedamide, followed by loss of ammonia


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i(b). Basic Hydrolysis of Amides

Addition of hydroxide and loss of amide ion

ii R d ti C i f A id


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ii. Reduction: Conversion of Amides

into Amines

Reduced by LiAlH4 to an aminerather than an

alcohol

The net effect is to converts C=OCH2. This

reaction is very specific for amides and does NOT

occur with other carboxylic acid derivatives.


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Mechanism of Reduction

Addition of hydride to carbonyl group

Expulsion of the oxygen as an aluminate anion

leaving group to give an iminium ion intermediate

which is then further reduced by another molecule of

LiAlH4to yield the amine


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Uses of Reduction of Amides

Works with cyclic and acyclic

Good route to cyclic amines

21 9 P l id d P l t St


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21.9 Polyamides and Polyesters: Step-

Growth Polymers

Reactions occur in distinct linear steps, NOTas chainreactions

Reaction of a diamine and a diacid chloride gives anongoing cycle that produces a polyamide

A diol with a diacid leads to a polyester


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Polyamides (Nylons)

Heating a diamine with a diacid produces apolyamide called Nylon

Nylon 66is from adipic acid and hexamethylene-diamine at 280C


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Polyesters

The polyester from dimethyl terephthalate and

ethylene glycol is called Dacronand Mylarto make

fibers

21 10 Spectroscopy of Carboxylic


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21.10 Spectroscopy of Carboxylic

Acid Derivatives

Infrared Spectroscopy

Acid chlorides absorb near 1800cm1

Acid anhydrides absorb at 1820cm1and also at1760cm1

Esters absorb at 1735cm1

, higher thanaldehydes or ketones

Amides absorb near the low end of the carbonylregion

Nuclear Magnetic Resonance


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Nuclear Magnetic Resonance

Spectroscopy

Hydrogens on the carbon next to a C=O are near 2in the 1H NMR spectrum.

All acid derivatives absorb in the same range soNMR does not distinguish them from each other


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13C NMR

13C NMR is useful for determining the presence orabsence of a carbonyl group in a molecule of

unknown structure

Carbonyl carbon atoms of the various acid

derivatives absorb from 160 to 180


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Suggested Problems:

21.1-.5

21.7, .9, .12, .15, .17,

21.18-.21, 21.23-.25

21.36, .55

acyl substitution

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