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Chem 634
Carboxylate Chemistry
Reading: C&S B 3.4
Announcements
Seminar: Prof. Michael Neidig, University of Rochester
Wed, 4pm, 219 BRL
Organic Journal Club
Thursdays, 12:30-1:30pm
219 BRL
Carboxylate chemistry
O
O
R
OR
R
O
NR2
R
Cl
Esters
Fisher Esterification
O
+
R
OH
O
R
MeOH
heat
H
O
R
OH
O
H Cl
R
OMe
H
O
R
OH
OMe
H
OH
OMe
H
MeOH
Cl
OH2
HCl
R
OH
OMe
– H2O
O
R
H
OMe
Cl
O
R
OMe
Note: Reaction is an equilibrium process driven by concentrations...
Excess alcohol is required!
Esters
Transesterification
O
R
+
OMe
EtOH
O
H+, heat
R
OEt
Note: Reaction is an equilibrium process driven by concentrations...
Excess alcohol is required!
Esters
Activation by Acid Chloride
O
O
R
Cl
Cl
O
O
OH
R
(oxalyl chloride)
Cl
– HCl, CO2, CO
Cl
O
R
O
H
O
O
O
Cl O
Cl
O
R
O
H
O
Cl
O
O
R
Cl
O
O
Cl
Also works with thionyl chloride (SOCl2), etc.
Cl
R
Cl
O
O
O
Esters
Reaction of acyl chlorides with alcohols:
O
+ BuOH
R
Cl
O
O
Cl
R
OBu
H
Et3N
Et3N
R
Cl
OBu
O
R
OBu
Esters
Acyl Transfer Catalysis
NMe2
(DMAP)
O
+ Nuc
R
O
N
Et3N
Cl
R
O
R
Nuc
O
Cl
N
R
N
NMe2
Nuc
NMe2
speeds reaction
N
Related: HOBT for peptide coupling.
N
N
OH
Esters
Mixed Anhydrides – Yamaguchi Lactonization
Cl
O
Cl
HO
OH
n
Cl
O
Cl
O
DMAP
n-3
O
via:
OH
O
O
O
+
Cl
Cl
Cl
Cl
O
OH
Cl
Good for large ring synthesis.
Cl
Esters
Diazo methane (methyl esters only)
H
N
N
C
N
N
H
H
H
N
N
O
R
H
OH
O
H
+
R
O
N2
CH3
O
R
OMe
CAUTION! CH2N2 explodes very easily, need special glassware.
Amides
From Acids:
O
O
+
R
BuNH2
OH
R
O
+
BuNH3
Amides not formed except under very forcing conditions.
From Esters:
O
O
+
R
OMe
BuNH2
+ MeOH
R
NHBu
Amide formation can work with small, nucleophilic amines and
non-sterically hindered esters, but often requires heat.
Amides
Classic: Schotten-Baumann
O
R
+
Cl
BuNH2
O
NaOH
or Et3N
R
NHBu
+ H2O/NaCl
or Et3NHCl
Note: Amines nucleophilic enough rxn can be run in water.
Amides
Carboimide Couplings
DCC =
BuNH2
O
R
OH
O
DCC
O
+
R
NHBu
CyHN
NHCy
Et
EDCI =
Mechanism:
H
R
R
N C N
NMe2
B
O
N C N
N C N
R
O
R
R
N
O
O
NR
R
OH
O
R
R
O
O
NH
R
NR
O
NHR2
RHN
NR
NHR2
H
R
O
N
HB
NR
Amides
Many
Similar
Methods:
N
Me
Mukayama, TL, 1970, 1901
HNMe2
O
R
Cl
O
R
pyridine
OH
NMe2
aromaticity
broken
R
H2N
Cl
N
Me
Cl
O
OH
Cl
N
Me
O
R
O
H
N
Me
O
R
N
O
Me
N
Me
O
R
O
aromaticity
restored
–
H+
Me
O
H
O
N
R
N
Me
O
R
N
H
Me +
O
N
Me
Amides
AlMe3 Activation
HNR2
O
R
OMe
AlMe3
O
+
R
NR2
Me2Al OMe
Likely via:
AlMe3 + HNR2
O
Me2Al NR2
Good for Weinreb Amides:
Me
Me
R
OMe
N
Me
Al
O
R
NMe2
OMe
Weinreb (Penn State), TL, 1977, 4171