Carboxyl Derivatives Classes shown, formally, via dehydration.
O RCCl An acid chloride -H2 O
O RC-OH H-Cl
O O RCOCR' An acid anhydride -H2 O O O RC-OH H-OCR'
O RCOR' An ester
O RC-OH H-OR'
O RCNH2 An amide -H2 O
O RC-OH H-NH2
RC N A nitrile -H2 O HO H RC=N The enol of an amide
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 oic acid oyl halide. oyl halide O
O RCAn acyl group
O Ethanoyl chloride Benzoyl chloride Hexanedioyl chloride (Acetyl chloride) (Adipoyl chloride)
Related: Sulfonyl Chlorides • Replacement of OH in a sulfonic acid by Cl gives a sulfonyl chloride. O CH3SOH O Methanesulfonic acid
O CH3 SCl O Methanesulfonyl chloride (Mesyl chloride, MsCl)
O H3 C
SOH O p-Toluenesulfonic acid
O H3 C
SCl O p-Toluenesulfonyl chloride (Tosyl chloride, TsCl)
Structure: Acid Anhydrides
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. acid anhydride
O O CH3 COCCH3
O O COC
Cyclic anhydrides are named from the dicarboxylic acids from which they are derived. O O O Succinic anhydride
O O O Maleic anhydride
O O O Phthalic anhydride
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 ic acid ate. ate O
O O Ethyl ethanoate (Ethyl acetate)
O Diethyl butanedioate (Diethyl succinate)
Lactone: A cyclic ester. Lactone • name the parent carboxylic acid, drop the suffix ic acid and add olactone. acid olactone
1 2 O 3 4
2 5 6
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 oic acid add amide. (For the common acid name, drop ic of amide ic the acid name and add amide.) amide • an alkyl or aryl group bonded to the N: name the group and show its location on nitrogen by N. O CH3CNH2 Acetamide (a 1° amide)
O H CH3 C-N CH3
O CH3 H-C-N CH3
N-Methylacetamide N,N-Dimethyl(a 2° amide) formamide (DMF) (a 3° amide)
Lactams: A cyclic amides are called lactams. • Name the parent carboxylic acid, drop the suffix ic acid and add lactam. acid lactam O
NH 5 6-Hexanolactam -Caprolactam) 6
Indicates where the N is located.
The functional group of an imide is two acyl groups bonded to nitrogen. • Both succinimide and phthalimide are cyclic imides. O NH O Succinimide
O NH O Phthalimide
The functional group of a nitrile is a cyano group • IUPAC names: name as an alkanenitrile. alkanenitrile • common names: drop the ic acid and add onitrile. ic acid onitrile
CH3 C N Ethanenitrile (Acetonitrile)
C N Benzonitrile
CH2 C N Phenylethanenitrile (Phenylacetonitrile)
Acidity of NH bonds
Amides are comparable in acidity to alcohols. • Waterinsoluble amides do not react with NaOH or other alkali metal hydroxides to form watersoluble salts.
Sulfonamides and imides are more acidic than amides. O O O CH3CNH2 Acetamide pKa 15-17
O O Benzenesulfonamide Succinimide Phthalimide pKa 10 pKa 9.7 pKa 8.3
Acidity of NH bonds
Effect of neighboring carbonyl groups.
Acidity of NH • Imides such as phthalimide readily dissolve in aqueous NaOH as watersoluble salts. O
NH + NaOH O pK a 8.3 (stronger acid)
N Na +
O (stronger base)
pK a 15.7 (weaker acid)
Acidity of NH bonds
Imides are more acidic than amides because 1. the electronwithdrawing inductive of the two adjacent C=O groups weakens the NH bond, and 2. More resonance delocalization of the negative charge. O N O
O N O A resonance-stabilized anion
O N O
Lab related: Sulfonamides (Hinsberg) Experimental test to distinguish primary, secondary and tertiary amines. 1 soluble
Reaction replaces one H with the sulfonyl group. In 1820 an H remains it is soluble in base.
Characteristic Reactions: Ketones & Aldehydes
Nucleophilic acyl Addition:
Protonation makes carbonyl better electrophile. Ok with poor nucleophile.
Carbonyl weaker electrophile. Need good nucleophile.
Characteristic Reactions: Derivatives
Nucleophilic acyl substitution: An addition elimination sequence resulting in substitution of one nucleophile for another. O
Y Tetrahedral carbonyl addition intermediate
Dominant for derivatives due to good leaving group (Y), uncommon for ketones or aldehydes. 1822
Characteristic Reactions Poor bases make good leaving groups. O -
Increasing leaving ability Increasing basicity
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. 1823
Water and Acid Chlorides • Lowmolecularweight acid chlorides react rapidly with water. • Higher molecularweight acid chlorides are less soluble in water and react less readily. O CH3CCl + H2O Acetyl chloride
O CH3COH + HCl
Water and Anhydrides • Lowmolecularweight anhydrides react readily with water to give two molecules of carboxylic acid. • Highermolecularweight anhydrides also react with water, but less readily. O O CH3COCCH3 + H2O Acetic anhydride
O O CH3COH + HOCCH3
Mechanism Anhydrides • Step 1: Addition of H2O to give a TCAI. (Addition) H + O CH3 -C-O-C-CH3 O-H H
O CH3 -C-O-C-CH3 + O H H OH H
O O + CH3 -C-O-C-CH3 + H-O-H O H H Tetrahedral carbonyl addition intermediate
Acid makes carbonyl better electrophile.
Mechanism Anhydrides • Step 2: Protonation and collapse of the TCAI. (Elimination)
H H +O H
H O H O
O CH3 -C-O-C-CH3 H
H + H O
CH3 C O C CH3 H
H H +O H CH3
O O C + O C O
Acid sets up better leaving group. 1827
Water 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. 1828
Mechanism: Acid/H2O Esters (1o and 2o alkoxy)
Acidcatalyzed ester hydrolysis. OH O + H H +H O + CH OH C C 2 3 OH R OCH3 R OH R OCH3 Tetrahedral carbonyl addition intermediate Acid makes O C
carbonyl Better electrophile.
Acid sets up leaving group.
Mechanism: Reaction with Acid/H2O – Esters (3o alkoxy) But wait!!!!!!!
Reaction with Base/H2O Esters
Saponification: The hydrolysis of an esters in Saponification 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 + NaOH
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. O
O O O (1) (2) R-C + OCH3 (3) R-C + HOCH3 R-C-OCH3+ OH R-C OCH3 O O OH H
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 acidbase reaction between the amine or ammonia and the acid. O NH2 + H2 O + HCl
H2 O heat
O OH + NH4
Ph 2-Phenylbutanoic acid
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. O CH3 CNH N-Phenylethanamide (N-Phenylacetamide, Acetanilide)
CH3 CO Na Sodium acetate
Mechanism: Acidic H2O Amides • Step1: Protonation of the carbonyl oxygen gives a resonancestabilized cation intermediate. O + R C NH2 + H O H
H +H O R C NH2
H O R C
H O R C
+ H2 O
Resonance-stabilized cation intermediate
Acidic H2O Amides • Step 2: Addition of water (a nucleophile) to the carbonyl carbon (an electrophile) followed by proton transfer gives a TCAI.
R C NH2 + O H H
R C NH2 O+ H H
proton transfer from O to N
OH R C NH3 + H
• Step 3: Collapse of the TCAI and proton transfer. (Elimination)
R C NH3 OH
O C OH + NH4 +
Mechanism: Reaction with Basic H2O Amides Amide hydroxide ion
Acidic H2O and Nitriles
The cyano group is hydrolyzed in aqueous acid to a carboxyl group and ammonium ion.
Ph CH2C N + 2H2O + H2 SO4 Phenylacetonitrile
O + Ph CH2COH + NH4 HSO4 Phenylacetic acid
Ammonium hydrogen sulfate
• Protonation of the cyano nitrogen gives a cation that reacts with water to give an imidic acid. • Ketoenol tautomerism gives the amide. Acid OH O + + H R-C N + H2 O R-C NH R-C-NH2 Ammonium An imidic acid An amide ion (enol of an amide) 1838
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. CH3(CH2) 9C N Undecanenitrile
NaOH, H2O heat
CH3(CH2)9 CO Na + NH3 Sodium undecanoate HCl H2 O O CH3(CH2) 9COH + NaCl + NH4 Cl Undecanoic acid
Synthesis: Reaction with H2O Nitriles • Hydrolysis of nitriles is a valuable route to carboxylic acids. CH3( CH2 ) 8 CH2 Cl KCN ethanol, 1-Chlorodecane water
CH3 (CH2 ) 9C N Undecanenitrile
H2 SO4 , H2 O heat
O CH3 (CH2 ) 9COH Undecanoic acid
CHO HCN, KCN CN H2 SO4 , H2 O COOH ethanol, heat water Benzaldehyde Benzaldehyde cyanohydrin 2-Hydroxyphenylacetic acid (Mandelonitrile) (Mandelic acid) (racemic) (racemic)
Synthesis: Grignards + Nitriles >ketone 1
R'MgX diethyl ether
Grignard reagents add to carbonnitrogen triple bonds in the same way that they add to carbon oxygen double bonds. The product of the reaction is an imine.
Synthesis: Grignards + Nitriles >ketone 2
R'MgX diethyl ether
Imines hydrolyzed to ketones.
RCR' H3O+ O RCR' 1842
Reaction 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. O
O Cl + HO
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. OTs
(R)-2-Octanol p-Toluenesulfonyl chloride (Tosyl chloride)
(R)-2-Octyl p-toluenesulfonate [(R)-2-Octyl tosylate]
Reaction of Alcohols and Acid Anhydrides
Acid anhydrides react with alcohols to give one mole of ester and one mole of a carboxylic acid. O O CH3 COCCH3 + HOCH2 CH3 Acetic anhydride Ethanol
O O CH3 COCH2 CH3 + CH3 COH Acetic acid Ethyl acetate
• Cyclic anhydrides react with alcohols to give one ester group and one carboxyl group. O
O O O Phthalic anhydride
2-Butanol (sec-Butyl alcohol)
O (sec-Butyl hydrogen phthalate
Reaction of Alcohols and Esters
Esters react with alcohols in the presence of an acid catalyst in an equilibrium reaction called transesterification. transesterification O +
OCH3 Methyl propenoate (Methyl acrylate) (bp 81°C)
HO 1-Butanol (bp 117°C) O
O Butyl propenoate (Butyl acrylate) (bp 147°C)
CH3 OH Methanol (bp 65°C)
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. O
O Cl + 2NH3 Hexanoyl chloride
NH2 + NH4 Cl Hexanamide Ammonium chloride
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. O O CH3 COCCH3 + 2NH3 Acetic Ammonia anhydride
O O + + CH CO NH CH3 CNH2 3 4 Acetamide Ammonium acetate
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. O Ph
O OEt + NH3
Amides do not react with ammonia or with 1° or 2° amines.
Acid Chlorides with Salts
Acid chlorides react with salts of carboxylic acids to give anhydrides. • Most commonly used are sodium or potassium salts. O O + CH3 CCl + Na - OC Acetyl chloride
O O CH3 COC
+ Na+Cl -
Acetic benzoic anhydride
Interconversions of Acid Derivatives
Grignard and an Ester. Look for two kinds of reactions.
Any alcohol will do here.
But where does an ester come from?
R'COCl Acid chloride SOCl2
Perhaps this carboxylic acid comes from the oxidation of a primary alcohol or reaction of a Grignard with CO2.
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. O HCOCH3 + 2RMgX An ester of formic acid
OH magnesium H O, HCl 2 alkoxide HC-R + CH3 OH salt R A 2° alcohol
Reactions with RLi
Organolithium compounds are even more powerful nucleophiles than Grignard reagents.
1. 2R' Li 2. H2 O, HCl
OH R-C-R' + CH3 OH R'
Acid chlorides at 78°C react with Gilman reagents to give ketones.
1. (CH3 ) 2 CuLi, ether, -78°C
Cl 2. H O 2 Pentanoyl chloride
Gilman Reagents do not react with acid anhydrides, esters, amides or nitriles under these conditions. Selective reaction. 1855
Synthesis: Reduction Esters by LiAlH4
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. O Ph
Methyl 2-phenylpropanoate (racemic)
1. LiAlH4 , ether 2. H2 O, HCl
OH + CH3 OH
Mechanism: Reduction Esters by LiAlH4
Reduction occurs in three steps plus workup: • Steps 1 and 2 reduce the ester to an aldehyde. O R C OR' +
O R C OR'
O R C
A tetrahedral carbonyl addition intermediate
• Step 3: Workup gives a 1° alcohol derived from the carbonyl group. O R C H
O R C H H
OH (4) R C H H A 1° alcohol
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. O
OH O OEt (racemic)
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. O OCH3 Methyl hexanoate
1. DIBALH, toluene, -78°C 2. H2 O, HCl O H + CH3 OH Hexanal
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. O NH2 Octanamide
1. LiAlH4 2. H2O
O NMe2 1. LiAlH4 2. H2O N,N-Dimethylbenzamide
Synthesis: Reduction Nitriles by LiAlH4
The cyano group of a nitrile is reduced by LiAlH4 to a 1° amine. 1. LiAlH4 CH3 CH=CH( CH2 ) 4 C N 2. H2 O 6-Octenenitrile CH3 CH=CH(CH2 ) 4 CH2 NH2 6-Octen-1-amine
Can use catalytic hydrogenation also.
Interconversions Problem: Show reagents and experimental conditions to Problem: bring about each reaction. O
OH Phenylacetic acid