Organic Chemistry18-*
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.
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Related: Sulfonyl Chlorides
Replacement of -OH in a sulfonic acid by -Cl gives a sulfonyl chloride.
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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.
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Acid Anhydrides
Cyclic anhydrides are named from the dicarboxylic acids from which they are derived.
5.cdx
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Related: Phosphoric Anhydrides
A phosphoric anhydride contains two phosphoryl groups bonded to an oxygen atom.
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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.
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Lactone: A cyclic ester.
name the parent carboxylic acid, drop the suffix -ic acid and add -olactone.
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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-.
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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
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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.
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Imides
The functional group of an imide is two acyl groups bonded to nitrogen.
Both succinimide and phthalimide are cyclic imides.
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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.
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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.
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1.0
6.cdx
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Acidity of N-H
Imides such as phthalimide readily dissolve in aqueous NaOH as water-soluble salts.
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Imides are more acidic than amides because
1. the electron-withdrawing inductive of the two adjacent C=O groups weakens the N-H bond, and
2. More resonance delocalization of the negative charge.
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In acid
In base
Reaction replaces one H with the sulfonyl group. In an H remains it is soluble in base.
1
2
3
Carbonyl weaker electrophile.
Need good nucleophile.
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.
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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.
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Low-molecular-weight acid chlorides react rapidly with water.
Higher molecular-weight acid chlorides are less soluble in water and react less readily.
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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.
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Step 1: Addition of H2O to give a TCAI. (Addition)
Acid makes carbonyl better electrophile.
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Acid sets up better leaving group.
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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.
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Acid-catalyzed ester hydrolysis.
Acid makes carbonyl
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alcohol
water
Each mole of ester hydrolyzed requires 1 mole of base
For this reason, ester hydrolysis in aqueous base is said to be base promoted.
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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.
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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.
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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.
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Step1: Protonation of the carbonyl oxygen gives a resonance-stabilized cation intermediate.
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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)
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Amide
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
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.
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Hydrolysis of nitriles is a valuable route to carboxylic acids.
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Grignard reagents add to carbon-nitrogen triple
bonds in the same way that they add to carbon-
oxygen double bonds.
R'MgX
H2O
diethyl
ether
NH
RCR'
N
RC
NMgX
RCR'
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R'MgX
H2O
diethyl
ether
H3O+
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.
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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.
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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.
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Reaction of Alcohols and Esters
Esters react with alcohols in the presence of an acid catalyst in an equilibrium reaction called transesterification.
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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.
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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.
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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.
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Acid Chlorides with Salts
Acid chlorides react with salts of carboxylic acids to give anhydrides.
Most commonly used are sodium or potassium salts.
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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.
Substitution
Addition
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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.
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Gilman Reagents
Acid chlorides at -78°C react with Gilman reagents to give ketones.
Gilman Reagents do not react with acid anhydrides, esters, amides or nitriles under these conditions. Selective reaction.
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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.
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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.
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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.
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Synthesis: Reduction - Esters by DIBAlH -> Aldehyde
Diisobutylaluminum hydride (DIBAlH) at -78°C selectively reduces an ester to an aldehyde.
At -78°C, the TCAI does not collapse and it is not until hydrolysis in aqueous acid that the carbonyl group of the aldehyde is liberated.
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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.
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Synthesis: Reduction - Nitriles by LiAlH4
The cyano group of a nitrile is reduced by LiAlH4 to a 1° amine.
Can use catalytic hydrogenation also.
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Interconversions
Problem: Show reagents and experimental conditions to bring about each reaction.
O
OO
aceticpropionicanhydride
NH
2
pK
a
=38
O
NH
2
NH
O
O
amine
amide
imide
pK
a
=15-17
pK
a
=8-10
OH
O
OH
pK
a
=16
pK
a
=5
S
O
O
OH
pK
a
=10
N-Hacidity
O-Hacidity
R'OEt
O
R-Mg-X
R'OEt
O
R
R'R
O
R-Mg-X
R'R
OMgX
R
R'R
OH
R
R'COCl
EtOH
R'CO
2
H
SOCl
2
H