derivatives of carboxylic acids
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Derivatives of Carboxylic Acids
Nucleophilic Acyl Substitution
Derivatives of Carboxylic Acids Made Directly from Acids
CH3C NH2
O
CH3C OR
O
CH3C Cl
O
CH3C O
O
CR
O
CH3C OH
O
acid chloride
acid anhydride ester
amide
Preparation of Acid Chlorides Directly from Acids
CH3C OH
O
CH3C Cl
OSOCl2
or PCl3or oxalyl chloride
Preparation of Acid Anhydrides Directly from Acids
CH3C OH
O H+
200oCCH3C O
O
CCH3
O
CO2H
CO2H
H+
200oC
H+
200oC
H+
200oCO
O
Ophthalic acid
acetic acid
Good for acetic and 5- and 6-membered ring anhydrides
+ H2O
+ H2O
Preparation of Esters Directly from Acids
CH3CH2CH2C
O
O- Na+CH3I
CH3CH2CH2C
O
OCH3
SN2 ; Williamson-like
CH3CH2CH2C
O
OH + CH3OH
Direct (Fisher) acid catalyzed esterification
CH3CH2CH2C
O
OH + CH2N2
OCH3
O
CH3CH2CH2C
OCH3
O
CH3CH2CH2C
Diazomethane
H + H2O
Preparation of Amides Directly from Acids
CH3CNH2 + H2O
O
CH3CO- NH4+
O
CH3COH + NH3
O
CH3CO- NH4+
O
(not generally useful, however, due to high temperature needed)
Overview of Reactions of Derivatives of Acids:
CH3C L
O
H2O
RNH2
R'OH [H]
R'MgX
CH3C OR'
O
CH3C OH
O
CH3C NHR'
O CH3C H
O
CH3C R'
O
CH3C H
OH
H
or
CH3C R'
OH
R'
or
All have a Common Mechanism!
RC L
O
:Nu
RC L
O-
Nu
RC Nu
O
+ L-
2-step Acyl Substitution:1. Addition to C=O (to create a tetrahedral C) 2. Elimination of the best L to reform the C=O
(gem diol-like intermediate; unstable w/rto reformation of the carbonyl group & displacement of the best leaving group)
Relative Reactivity
Acid Chlorides > Acid Anhydrides > Thioesters > Esters > Acids > Amides
(inversely related to basicity of leaving group)
CH3C Cl
O
CH3C SR'
O
CH3C NHR'
O
CH3C OR'
O
CH3C O
O
CCH3
O
>
> >
>
Reactions of Acid Chlorides
or CH3C R'
OH
R'
or CH3C H
OH
H
CH3C R'
O
CH3C H
O
CH3C NHR'
O
CH3C OH
O
CH3C OR'
O
R'MgX
[H]R'OHRNH2
H2OCH3C Cl
O
w/ LiAlH(t-OBu)3 w/ LiAlH4
w/ R2CuLi or2
Application: Synthesis of Nylon
H2N (CH2)6 NH2 (CH2)4 C ClCCl
O O+
(CH2)4 CC
O O
(CH2)6 NHHN(CH2)6 NHHN
Nylon 6,6
hexamethylenediamine a dipic acid dichloride
n
Reactions of Anhydrides
or CH3C R'
OH
R'
or CH3C H
OH
H
CH3C R'
O
CH3C H
O
CH3C NHR'
O
CH3C OH
O
CH3C OR'
O
R'MgX
[H]R'OHRNH2
H2OCH3C O
O
CCH3
O
2
w/ LiAlH4
w/ Na2Fe(CO)4
( low T)
Applications: Synthesis of Analgesics
HO
NH2 CH3COCCH3
O O
HO
NHCCH3
O
CH3COH
O
acetaminophen (Tylenol)
CH3COH
O
acetylsalicylic acid (aspirin)
CH3COCCH3
O OC
O
OH
OH+
C
O
OH
OCCH3
O
Reactions of Esters
H2O
RNH2
R'OH [H]
R'MgX
CH3C OR'
O
CH3C OH
O
CH3C NHR'
O CH3C H
O
CH3C R'
O
CH3C H
OH
H
or
CH3C R'
OH
R'
or
CH3C O
O
CH2CH3
w/ LiAlH4 w/ DIBAH; AlH(i-Bu)2
( low T)
Application: Synthesis of Polyethyleneterephthalate (PET)
CCCH3O OCH3
O O
CC OCH2CH2O
O O
+ HOCH2CH2OH
n
CH3OH+
Review: Oxidation at Benzylic Position, Esterification
CH3 CH3 C C
O
OH
O
HOO2 (air)
metal catalyst
C C
O
OH
O
HOH
CH3OHC C
O
OCH3
O
CH3O
p-xylene terephthalic acid
dimethyl terephthalate (DMT)
(4 million pounds produced by Invista per year)
Reactions of Amides (unreactive)
CH3CNH2
O
H2O
CH3COH
O
No Rxn No Rxn
No Rxn
RMgX
LiAlH4
CH3CH2NH2
ROHRNH2
Reactions of Nitriles
RC N
H2O(H+ or OH- cat.) [H]
LiAlH4
[H]DIBAH, then H2O
R'MgXthen H2O
RCR'
O
RCOH
O
RCH2NH2 RCH
O
(nitrile)
The nitrile is an anhydride of an amide; the CN group is a polar group; nucleophiles add to the CN triple bond as they add to a carbonyl group.
Thiol Esters (thioesters)
Intermediate in reactivity between anhydrides and esters...ideal for biological acylation reactions: stable to hydrolysis, yet reasonably reactive
R C SR' Example: Acetyl CoenzymeA,
O
involved in fatty acid biosynthesisto be studied later
Summary of Reactions ofDerivatives of Acids
Derivative H2O ROH NH3 [H] RMgX
Acid Chloride acid ester amide (ald)/alc (ket)/alc
Anhydride acid ester amide (ald)/alc (ket)/alc
Ester acid ester amide (ald)/alc (ket)/alc
Amide acid (NR) (NR) amine (NR)
Nitrile amide ester (NR) amine/ ketone
/acid (ald)
IR Spectroscopy of Carbonyl- Containing Compounds
RCOOCOR (anhydride) ~1820 & 1760 cm-1
RCOCl (acid chloride) ~1800 cm-1
RCO2R’ (ester) ~1740 cm-1
RCHO (aldehyde) ~1730 cm-1
RCOR’ (ketone) ~1715 cm-1
RCO2H (acid...dimer) ~1710 cm-1
RCONH2 (1o amide) ~1690 cm-1
RCONR2 (3o amide) ~1650 cm-1
RC
O
RC
O
ClCl
Explanation of Carbonyl Stretching Frequency
The polarity of the C-Cl bond increases the positive chargeon the carbon in the dipolar resonance form. This raises its energy, resulting in a resonance hybrid with little C-O (single) bond character. The result is mostly C=O (double) bond character and a high C=O bond stretching frequency.
Explanation of Carbonyl Stretching Frequency...
Amide resonance results in an additional resonance form. Two of the resonance forms have C-O single bond character. The result is a lower C=O bond stretching frequency.
RC
O
NH2 RC
O
NH2 RC
O
NH2
C=O (2)1822 &1756 cm-1
C=O1792 cm-1
C=O1739 cm-1
C-O1189 cm-1
C=O1716 cm-1
C-O1240 cm-1
O-H3500-2500 cm-1
C=O1690 cm-1
N-H (2)3363 & 3192 cm-1
C=O1669 cm-1
CN2248 cm-1
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