derivatives of carboxylic acids
DESCRIPTION
Derivatives of Carboxylic Acids. Nucleophilic Acyl Substitution. Derivatives of Carboxylic Acids Made Directly from Acids. Preparation of Acid Chlorides Directly from Acids. Preparation of Acid Anhydrides Directly from Acids. + H 2 O. + H 2 O. - PowerPoint PPT PresentationTRANSCRIPT
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