derivatives of carboxylic acids
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Derivatives of Carboxylic Acids
Derivatives of Carboxylic Acids
Nucleophilic Acyl SubstitutionNucleophilic Acyl Substitution
Derivatives of Carboxylic Acids Made Directly from AcidsDerivatives 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 AcidsPreparation of Acid Chlorides Directly from Acids
CH3C OH
O
CH3C Cl
OSOCl2
or PCl3or oxalyl chloride
Preparation of Acid Anhydrides Directly from AcidsPreparation 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
Preparation of Esters Directly from AcidsPreparation 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
Preparation of Amides Directly from AcidsPreparation 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: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!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 Relative Reactivity
Acid Chlorides > Acid Anhydrides > Acid Chlorides > Acid Anhydrides >
Thioesters > Esters > Acids > AmidesThioesters > 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 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'OH
RNH2
H2OCH3C Cl
O
w/ LiAlH(t-OBu)3 w/ LiAlH4
w/ R2CuLi or2
Application: Synthesis of Nylon 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
Reactions of Anhydrides 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'OH
RNH2
H2OCH3C O
O
CCH3
O
2
w/ LiAlH4w/ Na2Fe(CO)4
( low T)
Applications: Synthesis of Analgesics 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 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;LiAlH2(i-Bu)2
( low T)
Application: Synthesis of Polyethyleneterephthalate (PET) Application: Synthesis of Polyethyleneterephthalate (PET)
CCCH3O OCH3
O O
CC OCH2CH2O
O O
+ HOCH2CH2OH
n
CH3OH+
Review: Oxidation at Benzylic Position, Esterification Review: Oxidation at Benzylic Position, Esterification
CCCH3O OCH3
O O
CH3 CH3
O2
metal cat.CCHO OH
O O
H+
CH3OH
toluene terephthalic acid
dimethyl terephthalate (DMT)
4 million pounds per year p roduced by Hoechst-CelaneseK OSA
p-xylene
Reactions of NitrilesReactions of Nitriles
RC N
H2O
(H+ or OH- cat.) [H]LiAlH4
[H]DIBAH, then H2O
R'MgX
then H2ORCR'
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 bond.
Thiol Esters (thioesters)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 AcidsSummary 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/ ket /acid (ald)
IR Spectroscopy of Carbonyl- Containing CompoundsIR Spectroscopy of Carbonyl- Containing Compounds
RCOCl (acid chloride) ~1800 cm-1
RCO2R’ (ester) ~1735 cm-1
RCHO (aldehyde) ~1725 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
Explanation of Carbonyl Stretching FrequencyExplanation of Carbonyl Stretching Frequency
R C
O
Cl
The polarity of the carbon-chlorine bond raises the energy of the dipolar resonance form, which results in it contributing LESS to the resonance hybrid than the double bonded form. The CO stretching frequency is greater the more the double bonded formcontributes to the resonance hybrid. Acid chlorides have HIGHC=O stretching frequencies.
R C
O
Cl
Explanation of Carbonyl Stretching Frequency...Explanation of Carbonyl Stretching Frequency...
R C NH2
O
R C NH2
O
Amide resonance DECREASES the double bond character of the CO bond by stabilizingthe dipolar resonance form. This results in DECREASING its stretching frequency.
,
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