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Ch. 19-20 Lect. 2 Carboxylic Acids and Derivatives
I. Alkanoyl HalidesA. Preparation
1) Inorganic esters utilized, just as in conversion of alcohols to alkyl halides
2) PBr3, SOCl2 convert carboxylic acids to alkanoyl halides
B. Nomenclature
1) Pentanoic acid becomes pentanoyl chloride
2) Cyclohexane carboxylic acid becomes cyclohexanecarbonyl chloride
O
R OH
SOCl2O
R OSOCl
H+ O
R OSOCl
HCl
OH
OSOCl
Cl
R
O
O
Cl
R
H
S
O
Cl
O
R ClO S O H+Cl-
-HCl
+
+ +
O
CH3CH2CH2CH2 Cl
O
Cl
C. Reactivity: most reactive and useful derivative
1. Modified LiAlH4 reagent LiAl[OC(CH3)3]3H required to prevent over-reduction to alcohols
2. Organocuprates are less reactive alkyl metal reagents to prevent second addition to ketone
3. Amines do addition-elimination to give amides
4. Alcohols do addition-elimination to give esters
5. Acids do addition-elimination to give anhydrides
6. Water does addition-elimination to give acids
II. AnhydridesA. Preparation
1) As just seen, the reaction of an acid and an alkanoyl halide form anhydrides
2) The –OH group of the acid is a weak nucleophile for the reactive alkanoyl halide
3) Dehydration of two carboxylic acids can also work if 5-6 membered ring forms
B. Nomenclature
1) Replace “acid” with “anhydride” for the components
2) Acetic anhydride; Butanedioc anhydride
3) Unsymmetric anhydrides or mixed anhydrides are possible
C. Reactivity
1) All the alkanoyl halides reactions work for anhydrides, but are slower
2) Leaving group is a carboxylate anion, removed by aqueous extraction
3) Use anhydride as an activated substitute for reactions with carboxylic acids
O
R OH
O
R Cl
O
R
O
R O
COOH
COOH-H2O
O
O
O
O
CH3
O
CH3 O
O
CH2CH3
O
CH3 O
Acetic propanoic anhydrideAcetic anhydride
III. EstersA. Preparation
1) As seen, alcohols do addition-elimination to alkanoyl halides to give esters
2) Acid catalyzed addition-elimination of alcohols to carboxylic acids is also useful
3) Esterification (and Ester Hydrolysis) Mechanism
4) Intramolecular esterifications give cyclic esters called lactones
O
R OH
H+
O
R OH
HCH3O H
O
R OH
H
O
HCH3
O
R O
H
HO
CH3
O
R O
H
HO
CH3
H+
O
R O
H
H
O
CH3
H
O
R
H
O CH3
HOCH3
O
R O CH3
+
+
+
+
COOHOH
H2SO4, H2O
-H2O
O
O
Favored for 5-6membered rings
B. Nomenclature: named as alkyl alkanoates
C. Reactivity
1. Ester hydrolysis forms the component alcohol and carboxylic acid
a. Acid catalyzed reaction is the reverse of esterification shown above
b. Base catalyzed ester hydrolysis is also possible
2. Transesterification occurs with alcohols
a. Acid or base catalyzed conversion of one ester to another
b. Control the equilibrium by adding a large excess of the new alcohol
O
O
O
O
O
NH2
OMe
2-methylpropyl propanoate 3-methylbutyl pentanoate methyl 2-aminobenzoate
O
R O CH3
CH3CH2OH
-OCH2CH3
O
R O CH2CH3H+ or
O
R O CH3
-OHO
O
OH
R CH3
O
R O H
-OCH3 -OCH3O
R O
H+, H2O
3. Ester + Amine + Heat gives Amides (amines are more nucleophilic than alcohols)
4. Grignard Reagents + Esters give Alcohols
a. The first reaction is an addition-elimination giving a Ketone product
b. The Ketone reacts with another Grignard molecule giving the alcohol
5. Esters can be reduced by hydrides to alcohols or aldehydes
a. LiAlH4 fully reduced the ester to an alcohol (similar to Grignard above)
b. DIBAL reduces ester only to an aldehyde
O
R O CH3
CH3NH2
O
R N
H
CH3
+
O
CH3 O CH3
RMgBrO
CH3 RRMgBr
OH
R
R
CH3
O
R O CH3
Al
H O
R H
DIBAL = diisobutylaluminum hydride
D. Esters in Nature
1. Esters are important aroma and flavor agents in natural foods
a. Isopentyl acetate = banana oil
b. Octyl acetate = orange oil
c. Methyl salicylate = oil of wintergreen
2. Waxes are long chain esters
a. Beeswax
b. Spermaciti: sperm whale wax
3. Fats and Oils = triesters of glycerol (1,2,3-propanetriol)
O
CH3 O
O
CH3 O
OH
O
O
O
CH3(CH2)24 O (CH2)29CH3 O
CH3(CH2)14 O (CH2)15CH3
CH2OH
CHOH
CH2OH
CH2
CH2
CH
O
O
O
O
O
O
RCOOH
Glycerol
Saturated Fat or Oil
IV. AmidesA. Preparation
1) Amines react with carboxylic acids as bases and as nucleophiles
2) Heating favors the thermodynamic product: amide
3) Amino acids cyclize to give lactams
B. Nomenclature: alkanamides or cycloalkanecarboxamides
O
R O H
:NH3O
R O NH4+Kinetic product
O
R O H
:NH3O
R NH2
Thermodynamic product
COO-H3N+ NH
O
heat, -H2O
O
CH3 NHCH3
N
Br
O
NH2
O
N-methylacetamide4-bromo-N-ethyl-N-methylpentanamide
cyclohexanecarboxamide
C. Reactivity: least reactive of the carboxylic acid derivatives
1. Resonance structures prevent rotation around C—N bond
a. Ea = 21 kcal/mol for rotation about this single bond
b. Two peaks seen in the proton NMR
2. Hydrolysis requires heat and concentrated acid or base
a. Proteins are held together by strong amide bonds; they don’t break easily
3. Reduction to Amine by LiAlH4
O
CH3 N
CH3
CH3
O
CH3 N
CH3
CH3.. +
O
CH3 N
CH3
CH3
H+
-OH
OH2
O
CH3 OH
or
O
CH3 N
CH3
CH3
LiAlH4
H
O
N
H
R
CH3
CH3
Al
NH
R
CH3
CH3 HN
H
R
CH3
CH3H..
+
Iminium ion
V. AlkanenitrilesA. Preparation: SN1 or SN2 reaction of haloalkanes
B. Nomenclature
1) Alkanenitriles or cycloalkanenitriles
C. Reactivity: synthesis of carboxylic acids
1) Acid catalyzed mechanism
2) Similar Base catalyzed mechanism
3) Adds one carbon to the haloalkane, then turns it into carboxylic acid
4) Make derivatives from there; take advantage of all of their reactions
Br -CN N
1
2
3 1
2
3
4
N
N
butanenitrilecyclohexanecarbonitrile
R NH
+
R N H R N HOH2
NH
R OH2+
NH
R OH
H+ NH2+
R OH
NH2
R OH
NH2
R O
H+
OH2 RCOOH
+ -H+
+
-H+
amidehydrolysis
+
