18 acid derivatives
TRANSCRIPT
18-18-11
Carboxyl DerivativesCarboxyl Derivatives
Classes shown, formally, via dehydration.
H-NH2H-Cl H-OR'RC-OHO
H-OCR'O
RC=NHO H
RC-OHO
RC-OHO
RC-OHO
-H2O -H2O -H2O -H2O-H2O
RC NRCNH2
ORCClO
RCOR'O
RCOCR'O O
The enol ofan amide
An acidchloride
An esterAn acidanhydride
An amide A nitrile
18-18-22
Structure: Acid ChloridesStructure: 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-oic acid to -oyl halide-oyl halide.
CH3CClOO
RC-Cl
OCl
O
Cl
O
Benzoyl chlorideEthanoyl chloride(Acetyl chloride)
An acyl group
Hexanedioyl chloride(Adipoyl chloride)
18-18-33
RelatedRelated: Sulfonyl Chlorides: Sulfonyl Chlorides
• Replacement of -OH in a sulfonic acid by -Cl gives a sulfonyl chloride.
SOHH3C
O
O
CH3SOH
O
O
SClH3C
O
O
CH3SCl
O
O
Methanesulfonicacid
p-Toluenesulfonic acid
Methanesulfonyl chloride(Mesyl chloride, MsCl)
p-Toluenesulfonyl chloride (Tosyl chloride, TsCl)
18-18-44
Structure: Acid AnhydridesStructure: 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 acidacid of the parent acid by anhydrideanhydride.
COC
O O
CH3COCCH3
O O
Benzoic anhydrideAcetic anhydride
18-18-55
Acid AnhydridesAcid Anhydrides
Cyclic anhydrides are named from the dicarboxylic acids from which they are derived.
Maleic anhydride
O
O
O
Phthalic anhydride
Succinicanhydride
O
O
O
O
O
O
O
O O
acetic propionic anhydride
18-18-77
Esters 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-ic acid to -ate-ate.
O
OEtO
O
OEtO
O
O
Ethyl ethanoate(Ethyl acetate)
Diethyl butanedioate(Diethyl succinate)
Isopropyl benzoate
18-18-88
Esters; Lactones Esters; Lactones
LactoneLactone: A cyclic ester.• name the parent carboxylic acid, drop the suffix -ic -ic
acidacid and add -olactone-olactone.
4-Butanolactone-Butyrolactone)
3-Butanolactone-Butyrolactone)
O O
O O
H3C
23
12
1
3 4
6-Hexanolactone-Caprolactone)
O
O2
134
5 6
18-18-1010
AmidesAmides
The functional group of an amide is an acyl group bonded to a nitrogen atom.• drop -oic acidoic acid from the name of the parent acid and
add -amide-amide. (For the common acid name, drop -ic ic of 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 NN--.
CH3CNH2
OCH3C-N
H
CH3
OH-C-N
CH3
CH3
O
N-Methylacetamide(a 2° amide)
Acetamide(a 1° amide)
N,N-Dimethyl-formamide (DMF)
(a 3° amide)ethanamide
18-18-1111
Amides: resonanceAmides: resonance
18-18-1212
Amides; CharacteristicsAmides; Characteristics
18-18-1313
Amides; LactamsAmides; Lactams
Lactams: A cyclic amides are called lactams.• Name the parent carboxylic acid, drop the suffix -ic -ic
acidacid and add -lactam-lactam.
6-Hexanolactam-Caprolactam)
H3C
O
NH
O
NH1
2 1
234
5 63
3-Butanolactam-Butyrolactam)
Indicates where the N is located.
18-18-1414
ImidesImides
The functional group of an imide is two acyl groups bonded to nitrogen.• Both succinimide and phthalimide are cyclic imides.
PhthalimideSuccinimide
NH NH
O O
OO
18-18-1515
Related: Related: NitrilesNitriles
The functional group of a nitrile is a cyano group
• IUPAC names: name as an alkanenitrilealkanenitrile.• common names: drop the -ic acid-ic acid and add -onitrile-onitrile.
CH3C N C N CH2C N
Ethanenitrile(Acetonitrile)
Benzonitrile Phenylethanenitrile(Phenylacetonitrile)
18-18-1616
Acidity of N-H bondsAcidity of N-H bonds
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.
CH3CNH2
O
O
O
SNH2 NH
O
O
NH
O
O
pKa 8.3pKa 9.7pKa 10PhthalimideSuccinimideBenzenesulfonamideAcetamide
pKa 15-17
18-18-1717
Acidity of N-H bondsAcidity of N-H bonds
Effect of neighboring carbonyl groups.
NH2
pKa = 38
O
NH2 NH
O
O
amine amide imide
pKa = 15 - 17 pKa = 8 - 10
OH
O
OH
pKa = 16 pKa = 5
S
O
O
OH
pKa = 10
N-H acidity
O - H acidity
1.0
18-18-1818
Acidity of N-HAcidity of N-H
• Imides such as phthalimide readily dissolve in aqueous NaOH as water-soluble salts.
(stronger acid)
(weakeracid)
(weakerbase)
(strongerbase)
pKa 15.7pKa 8.3
++
O
O
NH N- Na
+
O
O
NaOH H2 O
18-18-1919
Acidity of N-H bondsAcidity of N-H bonds
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.
O
O
N N
O
O
A resonance-stabilized anion
N
O
O
18-18-2020
Lab related: Lab related: Sulfonamides (Hinsberg)Sulfonamides (Hinsberg)
Experimental test to distinguish primary, secondary and tertiary amines.
In acidIn base
Reaction replaces one H with the sulfonyl group. In an H remains it is soluble in base.
1
2
3
soluble
soluble
insoluble
insoluble
18-18-2121
Characteristic Reactions: Characteristic Reactions: Ketones & AldehydesKetones & Aldehydes
Nucleophilic acyl AdditionNucleophilic acyl Addition::
Protonation makes carbonyl better electrophile. Ok with poor nucleophile.
Carbonyl weaker electrophile. Need good nucleophile.
18-18-2222
Characteristic Reactions: Characteristic Reactions: DerivativesDerivatives
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.
18-18-2929
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.
18-18-3030
Mechanism:Mechanism: Reaction with Acid/H Reaction with Acid/H22O – Esters (O – Esters (33oo alkoxy alkoxy))
alcohol
water
But wait!!!!!!!
18-18-3131
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
18-18-3333
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
18-18-3434
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
formation of the carboxylate salt.
CH3CNH
O
NaOHH2O
CH3CO-Na+
OH2N
AnilineSodiumacetate
N-Phenylethanamide(N-Phenylacetamide, Acetanilide)
++heat
18-18-3535
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!
18-18-3838
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
18-18-3939
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.
CHO HCN, KCN CN
OH
H2 SO4, H2O COOH
OH
heat
Benzaldehyde Benzaldehyde cyanohydrin(Mandelonitrile)
(racemic)
2-Hydroxyphenylacetic acid(Mandelic acid)
(racemic)
ethanol,water
CH3(CH2)8CH2Cl KCN H2SO4, H2OCH3(CH2)9COH
heatethanol, water
O
CH3(CH2)9C N1-Chlorodecane Undecanenitrile Undecanoic acid
18-18-4141
RCR'RCR'
NNHH
SynthesisSynthesis: : Grignards + Nitriles ->ketone 1Grignards + Nitriles ->ketone 1
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.
RCRC NNR'MgXR'MgX
RCR'RCR'
NNMgXMgX
HH22OO
diethyldiethyletherether
18-18-4242
SynthesisSynthesis: : Grignards + Nitriles ->ketone 2Grignards + Nitriles ->ketone 2
RCRC NNR'MgXR'MgX
RCR'RCR'
NNMgXMgX
HH22OORCR'RCR'
NNHH
diethyldiethyletherether
RCR'RCR'
OO
HH33OO++
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.
(R)-2-Octanolp-Toluenesulfonylchloride
(Tosyl chloride)
(R)-2-Octyl p-toluenesulfonate[(R)-2-Octyl tosylate]
OH
+ TsCl pyridineOTs
18-18-4545
Reaction of Alcohols and Acid AnhydridesReaction 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.
(sec-Butyl hydrogenphthalate
2-Butanol(sec-Butyl alcohol)
+
Phthalicanhydride
O
O
O
OOHHO
O
O
Acetic acidEthyl acetateEthanolAcetic anhydride
++CH3COCCH3 HOCH2CH3 CH3COCH2CH3 CH3COHO O OO
18-18-4646
Reaction of Alcohols and EstersReaction of Alcohols and Esters
Esters react with alcohols in the presence of an acid catalyst in an equilibrium reaction called transesterificationtransesterification.
Butyl propenoate(Butyl acrylate)
(bp 147°C)
1-Butanol(bp 117°C)
Methyl propenoate(Methyl acrylate)
(bp 81°C)
+
+ HCl
CH3OHMethanol(bp 65°C)
OCH3
O
HO
O
O
18-18-4747
Reaction of Ammonia, etc. and Acid HalidesReaction 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.
Cl
O
2NH3 NH2
O
NH4+Cl
-+ +
Hexanoylchloride
Ammonia Hexanamide Ammoniumchloride
18-18-4848
Reaction of Ammonia, etc. and AnhydridesReaction 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.
CH3COCCH3
O O2NH3 CH3CNH2
OCH3CO-NH4
+O
+ +
Aceticanhydride
Ammonia Acetamide Ammoniumacetate
18-18-4949
Ammonia, etc. and EstersAmmonia, 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.
PhOEt
O
NH3Ph
NH2
O
EtOH
PhenylacetamideEthyl phenylacetate
+ +
Ethanol
18-18-5050
Acid Chlorides with SaltsAcid Chlorides with Salts
Acid chlorides react with salts of carboxylic acids to give anhydrides. • Most commonly used are sodium or potassium salts.
+ +CH3 CCl -OC CH3 COC Na+Cl -Na+O O O O
Acetylchloride
Sodiumbenzoate
Acetic benzoicanhydride
18-18-5151
Interconversions of Acid DerivativesInterconversions of Acid Derivatives
18-18-5252
Grignard and an Ester.Grignard and an Ester.Look for two kinds of reactions.Look for two kinds of reactions.
R' OEt
OR-Mg-X
R' OEt
O
RR' R
O
R-Mg-X
R' R
OMgX
R
R' R
OH
R
But where does an ester come from?
R'COCl
EtOH
Acid chloride
R'CO2H
SOCl2 Perhaps this carboxylic acid comes from the oxidation of a primary alcohol or reaction of a Grignard with CO2.
Substitution
Addition
Any alcohol will do here.
18-18-5353
Grignard Reagents and Formic EstersGrignard Reagents and Formic Esters
• Treating a formic ester with two moles of Grignard reagent followed by hydrolysis in aqueous acid gives a 2° alcohol.
HCOCH3
O2RMgX
H2O, HClHC-R
R
OHCH3OH+
magnesium alkoxide salt
A 2° alcoholAn ester offormic acid
+
18-18-5454
Reactions with RLiReactions with RLi
Organolithium compounds are even more powerful nucleophiles than Grignard reagents.
RCOCH3
1. 2R'Li
2. H2O, HClR-C-R'
O
R'
OH
+ CH3OH
18-18-5555
Gilman ReagentsGilman Reagents
Acid chlorides at -78°C react with Gilman reagents to give ketones.
1. (CH3)2CuLi, ether, -78°C
2. H2OPentanoyl chloride 2-Hexanone
Cl
O O
Gilman Reagents do not react with acid anhydrides, esters, amides or nitriles under these conditions. Selective reaction.
18-18-5656
Synthesis: Synthesis: Reduction - Esters by LiAlHReduction - Esters by LiAlH44
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.
Methanol2-Phenyl-1-propanol(racemic)
Methyl 2-phenyl-propanoate(racemic)
+1. LiAlH4 , ether
2. H2O, HCl
CH3OHPhOCH3
O PhOH
18-18-5757
MechanismMechanism: Reduction - Esters by LiAlH: Reduction - Esters by LiAlH44
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.
A 1° alcohol
R C
H
O+ H
(3)R C H
O
H
(4)R C H
OH
H
A tetrahedral carbonyladdition intermediate
(1)R C OR'
O
+ H R C OR'
O
H
R C
H
O(2)
OR'+
18-18-5858
Synthesis: Synthesis: Selective Selective Reduction by NaBHReduction by NaBH44
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.
OEt
O O NaBH4
EtOH OEt
OH O
(racemic)
18-18-5959
Synthesis: Synthesis: Reduction - Esters by DIBAlH -> AldehydeReduction - 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.
Hexanal
Methyl hexanoate
+
1. DIBALH, toluene, -78°C
2. H2O, HCl
CH3OH
OCH3
O
H
O
18-18-6060
Synthesis: Synthesis: Reduction - Amides by LiAlHReduction - Amides by LiAlH44
LiAlH4 reduction of an amide gives a 1°, 2°, or 3° amine, depending on the degree of substitution of the amide.
NH2
O1. LiAlH42. H2O
1. LiAlH4
2. H2ONMe2
ONMe2
NH2
Octanamide 1-Octanamine
N,N-Dimethylbenzamide N,N-Dimethylbenzylamine
18-18-6161
Synthesis: Synthesis: Reduction - Nitriles by LiAlHReduction - Nitriles by LiAlH44
The cyano group of a nitrile is reduced by LiAlH4 to a 1° amine.
6-Octenenitrile
6-Octen-1-amine
CH3CH=CH(CH2)4C1. LiAlH4
2. H2O
CH3CH=CH(CH2)4CH2NH2
N
Can use catalytic hydrogenation also.
18-18-6262
InterconversionsInterconversions
Problem:Problem: Show reagents and experimental conditions to bring about each reaction.
PhOH
O
OMe
OPh
PhOH
PhCl
O
PhNH2
PhNH2
O
Phenylacetic acid
(a) (b) (c)
(d) (e)
(f)
(g) (h)