18- 18- 1 1 Carboxyl Derivatives Carboxyl Derivatives Classes shown, formally, via dehydration. H -NH 2 H -Cl H -OR' RC- OH O H -OCR' O RC=N HO H RC- OH O RC- OH O RC- OH O - H 2 O - H 2 O - H 2 O - H 2 O - H 2 O RC N RCNH 2 O RCCl O RCO R' O RCOCR' O O The enolof an am ide A n acid chloride A n ester A n acid anhydride A n am ide A nitrile
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18-1 Carboxyl Derivatives Classes shown, formally, via dehydration.
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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-oic acid to -oyl halide-oyl halide.
Nucleophilic acyl substitutionNucleophilic acyl substitution:: An addition-elimination sequence resulting in substitution of one nucleophile for another.
Tetrahedral carbonyladdition intermediate
++ CNuR
CY R
CNuR
O
Y
O
:Nu :Y
Substitution product
O
Dominant for derivatives due to good leaving group (Y), uncommon for ketones or aldehydes.
18-18-2323
Characteristic ReactionsCharacteristic Reactions
Poor bases make good leaving groups.
R2N- RO-
O
RCO- X-
Increasing basicity
Increasing leaving ability
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.
18-18-2424
Water and Acid ChloridesWater 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.
CH3CClO
H2O CH3COHO
HCl++
Acetyl chloride
18-18-2525
Water and AnhydridesWater 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.
CH3COCCH3
O OH2O CH3COH
OHOCCH3
O++
Acetic anhydride
18-18-2626
MechanismMechanism- Anhydrides- Anhydrides
• Step 1: Addition of H2O to give a TCAI. (Addition)
O
CH3-C-O-C-CH3
H
H
O-H
O
O HH
CH3-C-O-C-CH3
H
H
O-H
CH3-C-O-C-CH3
O
OH
H
H-O-HH
++
+
Tetrahedral carbonyladdition intermediate
+
OO
Acid makes carbonyl better electrophile.
18-18-2727
MechanismMechanism- Anhydrides- Anhydrides
• Step 2: Protonation and collapse of the TCAI. (Elimination)
O
CH3-C-O-C-CH3
O
HOH
H+ O
H H
CH3 C
O
O
O C
O
CH3
H
HOH
H+
CH3 C O
O
O
C CH3
OH
H
H
H
H+ H
+O
Acid sets up better leaving group.
18-18-2828
Water and EstersWater 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.
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MechanismMechanism: Acid/H: Acid/H22O - Esters (O - Esters (11oo and 2 and 2oo alkoxy alkoxy))
Acid-catalyzed ester hydrolysis.
R OCH3
CO
H2OH+
OHC
ROCH3
OHH+
R OHCO
CH3OH+ +
Tetrahedral carbonyladdition intermediateAcid makes
carbonylBetter electrophile.
Acid sets up leaving group.
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Mechanism:Mechanism: Reaction with Acid/H Reaction with Acid/H22O – Esters (O – Esters (33oo alkoxy alkoxy))
alcohol
water
But wait!!!!!!!
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Reaction with Reaction with BaseBase/H/H22O - EstersO - Esters
SaponificationSaponification: 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.O
RCOCH3 NaOHH2O
O
RCO- Na
+ CH3OH++
18-18-3232
MechanismMechanism of Reaction with Base/H of Reaction with Base/H22O – EstersO – 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.
R-C-OCH3
O
OH R-C
O
OHOCH3
R-C
O
OH
R-C
O
O
HOCH3(1)
+(2) (3)+ +OCH3
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Acidic Reaction with HAcidic Reaction with H22O - AmidesO - 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.
2-Phenylbutanoic acid2-Phenylbutanamide
++ +heat
H2 O HClH2 O
NH4+ Cl
-
PhNH2
O
PhOH
O
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Basic Reaction with HBasic Reaction with H22O - AmidesO - 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
Mechanism:Mechanism: Acidic H Acidic H22O - AmidesO - Amides
• Step1: Protonation of the carbonyl oxygen gives a resonance-stabilized cation intermediate.
R C
O
NH2 OH H
H
O
C NH2R
HO
C NH2R
H
C
O
NH2R
H
H2O
Resonance-stabilized cation intermediate
+
+
++
++
18-18-3636
Acidic HAcidic H22O - AmidesO - 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)
R C
OH
C OHRNH3
H
C
O
NH3+R
OH
NH4+++
O+
OH
++ O
H
H C
OH
NH2RO
H H
C
OH
NH3+R
O
+C
OH
NH2R
H
proton transfer from
O to N
18-18-3737
Mechanism:Mechanism: Reaction with Basic H Reaction with Basic H22O - AmidesO - Amides
Amide
hydroxide ion
Dianion!
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Acidic HAcidic H22O and NitrilesO 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.
Ph CH2C N 2H2O H2SO4H2O
Ph CH2COH
O
NH4+HSO4
-
Ammoniumhydrogen sulfate
Phenylaceticacid
Phenylacetonitrile
+heat
++
R-C N H2O H+
NH
OH
R-C R-C-NH2
O
An imidic acid(enol of an amide)
+
An amide
Acid+Ammoniumion
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Basic HBasic H22O and NitrilesO 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.
CH3(CH2)9C NNaOH, H2O
O
CH3(CH2)9COH
CH3(CH2)9CO-Na
+O
HCl H2O
NaCl
NH3
NH4Cl
Sodium undecanoate Undecanenitrile
+heat
Undecanoic acid
+ +
18-18-4040
SynthesisSynthesis: : Reaction with HReaction with H22O - NitrilesO - Nitriles
• Hydrolysis of nitriles is a valuable route to carboxylic acids.
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.
Imines hydrolyzed to ketones.Imines hydrolyzed to ketones.
18-18-4343
Reaction of Alcohols and Acid HalidesReaction 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.
Butanoylchloride
Cyclohexyl butanoate
+
Cyclohexanol
HO HClCl
O
+ O
O
18-18-4444
Reaction with Alcohols, Sulfonic EstersReaction 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.