Download Oxidations - Chem.iitb

Oxidations
Oxidation is one of the most important & useful reactions in
chemistry
Most of the chemicals are obtained by the oxidation of
petrochemicals
Definition:
Inorganic Chemists & Organic Chemists differ in defining oxidation
Inorganic Chemists:
(1) Loss of electrons
(2) Increase in oxidation number
Organic Chemists:
The same rules can not be applied because
(1) Mechanisms of most of the oxidation reactions do
not involve a direct electron transfer
(2) It is also not possible to apply oxidation number
uniformly
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 1 Oxidations
Addition of Oxygen
H3C CH3
H3C C
H2
OH
H3C CHO
H3C CO2H
Replacement of hydrogen atom bonded to carbon with another,
more electronegative element like oxygen
Elimination of Hydrogen
H3C CH3
H2C CH2
HC CH
Simplest Definition
Most oxidations in organic chemistry involve a gain of oxygen
and/or a loss of hydrogen
The reverse is true for reduction
There is no oxidation without a concurrent reduction
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 2 Oxidations
Oxidation
At single carbon
Vicinal Carbon
Hetero atom
Unfunctionalized
Carbon atom Reagents
1. Metal based
2. Non-metal based
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 3 Metal Based Oxidations
Chromium based oxidation
Manganese based oxidation
Ruthenium based oxidation
Osmium based oxidation
Molybdenum based oxidation
Lead based oxidation
Titanium based oxidation
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 4 Metal Based Oxidations
Chromium Based Reagents
CrO3
Jones oxidant
PCC
PDC
Collins reagent
Chromyl chloride
Reactivity & selectivity depends on the (1) Solvents & (2) Chromium
ligands
Substantial selectivity can be achieved by choice of the particular
reagent or conditions
The most widely employed transition metal oxidations are Cr(VI)
based reagents
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 5 Oxidations
CrO3
O
CrO3
+
HO Cr O
H2O
O
O
O
O
O Cr O Cr O
2 HO Cr O
O
O
+ H2O
O
In dilute solution the chromate ion is present. As concentration
increases the dichromate ion dominates
The extent of protonation of these ions depend on the pH
In acetic acid, CrO3 exists as mixed anhydride of acetic acid &
chromic acid
O
CH3COOH + CrO3
O
OH
Cr
O
O
O
O
O
Cr
O
O O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 6 Oxidations
CrO3
In pyridine, CrO3 exists as an adduct involving Cr-N bond
O
N Cr O
N + CrO3
O
The most common transformation effected on with Cr(VI) is the
convertion of the alcohols into ketones or aldehydes
H
R
OH
CrO3
R
O
O
Cr OH
R
O
+
H2CrO3
O
A variety of experimental conditions have been used for
oxidation of alcohols by Cr(VI) on a synthetic scale
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 7 Chromium Based Oxidation
Jones Oxidation
Jones Reagent: Acidic aqueous solution of chromic acid. Generally
added to an acetone solution of the alcohol
CrO3 + H2SO4
+
H2O
Use: For simple, unfunctionalized alcohols Jones reagent can be used
O
OH
Jones reagent
Acetone
OH
Jones
Reagent
O
Jones
Reagent
OH
O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 8 Chromium Based Oxidation
Jones Oxidation
Advantages:
(1)
Cr(III)
Cr(VI)
Precipitate
Acetone can be decanted. Easy to work up
(2) Good reagent to oxidize primary alcohol to acid
Disadvantages:
(1) Saturated primary alcohols are oxidized to carboxylic acids
R
OH
H
R
Jones reagent
Acetone
O
R
OH
Hydration
O
OH
R
OH
(2) Not good method for acid sensitive groups & compounds
(3) Under acidic condition dehydration may also take place
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 9 Chromium Based Oxidation
CrO3. 2Pyridine (Collins Reagent)
Preparation:
CrO3 +
(anh.)
2 Pyridine
(anh.)
CrO3. 2pyridine
(Solid)
Uses:
(1) Where other functional groups are susceptible to
oxidation
(2) When the molecule is sensitive to strong acid
(3) Primary & secondary alcohols are oxidized to aldehydes &
ketones in non-aqueous solution (Generally DCM was used)
without over oxidation
(4) Neither markedly basic, nor acidic
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 10 Chromium Based Oxidation
CrO3. 2Pyridine (Collins Reagent)
OH
O
CrO3. Py
OH
Ph
Ph
CrO3. Py
O
Ph
Ph
O
O
CrO3. Py
OH
O
The double bond did not migrate
Disadvantages:
(1) Must use a large excess of the reagent
(2) It is moisture sensitive & loses its activity in aqueous solution
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 11 Chromium Based Oxidation
Pyridinium Chlorochromate (PCC)
Preparation:
O
CrO3
+
6N HCl
HO Cr Cl
O
O
Pyridine
N
O Cr Cl
H
O
Orange-yellow
crystalline solid,
Less hygroscopic
Advantages:
(1) Reagent can be used in stoichiometric amounts with substrate
(2) It is less hygroscopic. So, it can be stored for a long time
(3) PCC is slightly acidic, but can be buffered with NaOAc
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 12 Chromium Based Oxidation
Pyridinium Chlorochromate (PCC)
O
O
OH
PCC
O
CH2Cl2
O
PCC
OH
O
PCC
O
Ph
Ph
OH
O
Oxidation of Organoboranes:
R
(2) PCC,
R
O
(1) BH3.THF
0oC
R
R
Deoximation:
R1
R2
N
OH
O
PCC
R1
R2
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 13 Chromium Based Oxidation
Pyridinium Chlorochromate (PCC)
Oxidation of Tertiary Allylic Alcohols:
OH
PCC
CH2Cl2
O
O
O Cr O PyH
O
O
O Cr O PyH
O
O
O
1. MeMgBr, CeCl3
2. PCC, CH2Cl2
O
O
1. MeMgBr, CeCl3
2. PCC, CH2Cl2
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 14 Chromium Based Oxidation
Pyridinium Chlorochromate (PCC)
Oxidation of Tertiary Allylic Alcohols:
OH
PCC
OH
O
PCC
O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 15 Chromium Based Oxidation
Pyridinium Chlorochromate (PCC)
Oxidative Cationic Cyclization:
PCC
CH2Cl2
OH
O
Oxidation
ene reaction
O
OH
H
O
OH
PCC
OH
PCC
O
CH2Cl2
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 16 Chromium Based Oxidation
Pyridinium Chlorochromate (PCC)
Oxidation of Enol Ethers to Lactones:
PCC
CH2Cl2
O
R
Cr
O
H
R
OR'
O
O
Cl
PyH
O
O
O
O
H
O
Cl
PCC
Cr
O
O
R
OR'
R
PyH
O
H3C
O
HO
OH
R
H3C
O
O
O
Cr
Cl O
OH
O
OR'
Oxidation of Furan Ring System:
H3C
O
O
R
H3C
O
O HO
R
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 17 Chromium Based Oxidation
Pyridinium Chlorochromate (PCC)
Oxidation of Active Methylene Group:
PCC
O
O
O
PCC
O
O
O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 18 Chromium Based Oxidation
Pyridinium Dichromate (PDC)
Preparation:
O
2CrO3 + H2O
O
HO Cr O Cr OH
O
O
O
Pyridine
O
O Cr O Cr O
N
H
O
O
N
H
Solubility:
Soluble in water, DMF, DMSO, dimethylacetamide. It is
sparingly soluble in dichloromethane
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 19 Chromium Based Oxidation
Pyridinium Dichromate (PDC)
Advantages:
(1) Excellent reagent for oxidation of allylic alcohols
(2) There is no over-oxidation of aldehydes
PDC
OH
CHO
DCM
(3) No E/Z-isomerization
(4) Unlike conjugated aldehydes non-conjugated aldehydes are
readily oxidized to acids by PDC in DMF at 25oC
HO
HO
O
PDC
DMF
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 20 Chromium Based Oxidation
Pyridinium Dichromate (PDC)
Uses:
R
OH
R
OH
R'
R
OH
PDC
CH2Cl2
PDC
CH2Cl2
PDC
CH2Cl2
R
O
R
O
R'
R
O
O
OH
PDC
DCM
O
CH2OH
PDC
O
CHO
DCM
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 21 Chromium Based Oxidation
Pyridinium Dichromate (PDC)
O
PDC
CH2Cl2
PDC
OH
DMF
O
OH
PCC
CH2Cl2
O
This reaction is
complicated by the
cationic cyclization
when PCC was used
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 22 Chromium Based Oxidation
Miscellaneous Oxidation of CrO3
CrO3/AcOH
HO2C
CO2H
H2O
O
CrO3/AcOH
H2O
O
OH
O
Cr
O
HO2C
H2O
CO2H
O
O
H2O
C
O
HO
O
Cr
OH
O
O
O
O
CO2H
HO3Cr
O
O
H2O
O
O
Cr
O H
O
O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 23 Chromium Based Oxidation
Etard Reaction
CHO
CrO2Cl2
CH2Cl2
OR
OR
CH3
CHO
CrO3
Ac2O
CrO3
Ac2O
AcO H OAc
C
CHO
Hydrolysis
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 24 Chromium Based Oxidation
Supported Reagents
(1) PCC on alumina
(2) PCC on polyvinylpyridine
H2 H
C C
H2 H
C C
n
n
CrO3.HCl
Cross link
O
R2CHOH
R
N
N
.
CrO3.HCl
N
H2 H
C C
N
n
1) Remove CrO3
2) HCl wash
3) KOH wash
4) H2O wash
H2 H
C C
R
n
N
.
Cr(III)
Advantage:
Improved yields due to simplified work up
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 25 Chromium Based Oxidation
Transformation
Chromium Reagents
R CHO
PCC, Collins reagent,
PDC in DCM
R
OH
OH
R
R
R'
OH
O
R
R'
R COOH
PCC, Collins reagent,
PDC, Jones reagent
Jones reagent, PDC
in DMF
CHO
Etard reaction
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 26 Manganese Based Oxidation
Mn(OAc)3
MnO2
KMnO4
Potassium Permanganate (KMnO4)
Under mild condition KMnO4 can effect conversion of alkenes to
glycol
KmnO4 is such a powerful oxidant that it can cleave the glycol
further. So, careful control is required
R'
R'
+ KMnO4
R
R
R'
R
H
O O
Mn
O O-K+
R'
O O
Mn
O O-K+
R'
OH
+
R
R
OH
OH
O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan HO O
Mn
HO O-K+
R'
O
R
O
27 Manganese Based Oxidation
Potassium Permanganate (KMnO4)
In Water Medium:
R
R
O
O
R'
R'
R
R'
OH
O
OH
R'
R
HO
KMnO4, H2O
Ar
Ar
KMnO4, H2O
CH3
KMnO4, H2O
ArCO2H
ArCO2H
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 28 Manganese Based Oxidation
Potassium Permanganate (KMnO4)
In Organic Solvents:
3.3 mol KMnO4
Benzene polyether
OH
O
1.0 mol KMnO4
OH
O
R4NCl
Oxidation of Acetylenes:
Ph
CH2CH2CH3
KMnO4
Ph
CH2CH2CH3
R4N+, DCM
HO
OH
Ph
O
Ph
O
CH2CH2CH3
OH
CH2CH2CH3
O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 29 Manganese Based Oxidation
Potassium Permanganate (KMnO4)
Oxidation of Aromatic Side Chain:
KMnO4
Ar
R
Ar
CO2H
Oxidation of Amino Compounds:
KMnO4
R3C NO2
R3C NH2
Tertiary alkylamines can be oxidized to nitro compounds
Oxidation of Sulphides:
NO2
O2N
S
KMnO4
NO2
O
O2N
S
O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 30 Manganese Based Oxidation
Potassium Permanganate (KMnO4)
Oxidation of Terminal Alkynes:
KMnO4
CO2H
Application in the Synthesis of Saccharin:
Me
Me
(NH4)2CO3
SO2NH2
SO2Cl
O
KMnO4
CO2
OH-
SO2NH2
Na
NH
S
O2
Saccharin
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 31 Manganese Based Oxidation
Uses:
Manganese dioxide (MnO2)
Selective oxidation of allylic & benzylic alcohols
O
OH
Excess of MnO2
is required
MnO2
CH2Cl2
OH
OH
MnO2, KCN
CN
EtOH
O
O
EtOH
OEt
CN
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 32 Manganese Based Oxidation
Manganese dioxide (MnO2)
OH
MnO2
ROH
CO2R
NaCN
OH
MnO2
H
CN
CN
O
OH
MnO2
OR
R OH
O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan CN
O
33 Manganese Based Oxidation
Manganese dioxide (MnO2)
CH2OH
CHO
MnO2
OH
MnO2
CHO
DCM
O
HO
OH
MnO2
MnO2, CH2Cl2
CHO
OH
OH
OH
OH
OH
OH
MnO2
HO
CHCl3
O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 34 Manganese Based Oxidation
Manganese(lll) acetate Mn(OAc)3
O
O
OAc
Mn(OAc)3
O
OH
O
Mn(OAc)2
O
O
Mn(OAc)3 Mn(OAc)3
Mn(OAc)2
Mn(OAc)2
O
OAc
O
O
Mn(OAc)3
AcO
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 35 Manganese Based Oxidation
Manganese(lll) acetate Mn(OAc)3
OH
O
Mn(OAc)3
N
O
N
Me
N
O
Me
OH
O
OH
Mn(OAc)3
N
O
Mn(OAc)2
Me
OH
O
O
Me
OH
OH
OH
N
Me
O
O
N
O
Me
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 36 Silver-Based Oxidation
Ag2O
Mild oxidant to oxidize aldehyde to carboxylic acid
O
R
O
Ag2O
R
H
OH
+
2 Ag
CO2H
CHO Ag O
2
NaOH
Ag2CO3 on Celite (Fetizon’s Reagent)
Conversion of diols to lactones
OH
OH
O
OH
OH
O
Fetizon's
reagent
Fetizon's
reagent
O
O
O
OH
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 37 Silver-Based Oxidation
Ag2CO3 on Celite (Fetizon’s Reagent)
Highly Selective:
OH
OH
Fetizon's
reagent
OH
OH
O
OH
Mono-Oxidation:
OH
Fetizon's
reagent
OH
Fetizon's
reagent
O
OH
O
OH
OH
OH
Mechanism:
H
R
R
O
H
H
Ag+ -O
O- Ag+
O
R
R
O
H
Ag
Ag+
O
O
O
R
R
H2O + CO2 + 2Ag
O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 38 Silver-Based Oxidation
Silver acetate
R
R
R'
R'
R
OAc
-OAc
OAc
I
R'
O
R
O
I
Ag(OAc) or
Ag(O2CPh)
R'
R
R
I2
R'
O
O
CH3
O
R'
OH
R'
OH
trans product
In presence of water,
Woodwards hydroxylation,
cis-product
CH3
CH3
H2O
In absence of water, Prevost
Hydroxylation, trans-product
R
O
R
OH
R'
OH
cis product
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 39 Other Metal-Based Oxidation
Hunsdiecker Reaction:
CO2Ag
X2
RCOOX
RCOO
R
RCOOX
∇
RCOOAg
Br2
Br
RCOOX
AgX
RCOO
X
R
CO2
RX
RCOO
(Initiation)
(Propagation)
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 40 Ruthenium & Osmium tetroxide Oxidation
Mechanism seems to be same in both cases
MO4
O
M
O
O
Hydrolysis
O
OH
HO
M
OH
HO
O
O
Reoxidation
O
M
O
O
O
Uses:
Alkenes are generally oxidized to cis-diols
Alkynes are oxidized to diketones as in case of KMnO4
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 41 Ruthenium & Osmium tetroxide Oxidation
Osmium tetraoxide (OsO4)
R
R
OH
R'
OH
Syn
OsO4
R'
OsO4 is highly toxic, cannot
be used at industrial scale
O
Use of NMO as co-oxidant along with catalytic amount
of OsO4 can be used for higher scale
NMO
N
O
Selectivity:
Directed by hydroxyl group
OsO4
NMO
O
HO
Pyridine
HO
HO
OsO4
O
HO
HO
HO
OsO4
NMO
O
TMSO
OH
OH
Pyridine
HO
HO
O
TMSO
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 42 Ruthenium & Osmium tetroxide Oxidation
Ruthenium tetroxide (RuO4)
Prepared in-situ by mixing RuCl3, NaIO4, CH3CN, CCl4, H2O
Primary Alcohols:
H
RuO4
H
H
OH
O
H
O
CO2H
Secondary Alcohols:
Secondary alcohols oxidized to ketones
HO
RuCl3, NaIO4
CCl4, H2O, CH3CN
O
O
O
O
Diols:
O
Diols are further oxidized to carboxylic acids
OH
Ph
OH
RuO4, NaIO4
CCl4, H2O, CH3CN
O
Ph
OH
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 43 Ruthenium & Osmium tetroxide Oxidation
Ruthenium tetroxide (RuO4)
Oxidation of Ethers:
RuO4
O
O
OAc
O
OAc
RuO4
O
O
AcO
O
OAc
O
RuCl3, NaIO4
OMe
OMe
CCl4, MeCN
H2O
Oxidation of Phenyl Groups:
RuCl3, NaIO4
R
CCl4, H2O, CH3CN
R CO2H
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 44 Ruthenium & Osmium tetroxide Oxidation
Tetra-n-propylammonium perruthenate (TPAP)
A catalytic amount of TPAP with NMO as the co-oxidant oxidizes
a range of functional groups
The performance of this reagent is improved by the addition of MS
HO
TPAP
NMO
O
OTBDPS
OHC
O
DCM
OTBDPS
TPAP
NMO
THPO
OH
DCM
THPO
CHO
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 45 Ruthenium & Osmium tetroxide Oxidation
Tetra-n-propylammonium perruthenate (TPAP)
Groups Tolerant are:
Alkenes
THP ethers
Epoxides
Lactones
Silyl ethers
Indoles
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 46 Other Metal-Based Oxidation
Lead tetraacetate, LTA ,Pb(OAc)4
Lead tetraacetate is a very good reagent for glycol
cleavage
Particularly LTA is useful for glycols that have low
solubility in aqueous media
OH
O
Pb(OAc)4
O
O
OH
O
Carboxylic acids are oxidized by LTA
CO2H
LTA
CHCl3
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 47 Other Metal-Based Oxidation
Lead tetraacetate, LTA ,Pb(OAc)4
Pb(OAc)4 + RCO2H
RCOO-Pb(OAc)3 + CH3COOH
RCOO-Pb(OAc)3
R + CO2 + Pb(OAc)3
R + Pb(OAc)3
R+ + Pb(OAc)2 + CH3COO-
The reductive step is promoted by hydrogen donor
solvents
Acetate arise by the capture of an acetate ion
In presence of lithium chloride, the product is the
corresponding chloride
Cl
Cl
Cl
H3C
CO2H
CH2CO2Me
Pb(OAc)4
Cl
LiCl
H3C
Cl
CH2CO2Me
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 48 Other Metal-Based Oxidation
α- hydroxy carboxylic acids undergo oxidative decarboxylation to
give ketone
O H
O H
O
+ CO2 + Pb(OAc)2 + CH3CO2H
O Pb(OAc)
3
OH
O
O
γ- keto carboxylic acid preferentially yield α,β– unsaturated
ketone
HO2C
Pb(OAc)4
Cu(OAc)2
O
O
Presumably it goes via oxidation of carboxylic acid to the carbocation
followed by deprotonation
O
H
O Pb(OAc)3
O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 49 Other Metal-Based Oxidation
Lead tetraacetate, LTA ,Pb(OAc)4
O
O
O
OAc
LTA, AcOH
OAc
LTA is toxic in nature
OH
O
O
AcOH
O
R
O
LTA
OH
R+ + AcO- + Pb(OAc)2
AcO
+
+
Pb(OAc)2
Pb(OAc)3
+
+
AcOH
Pb(OAc)4
R
O
Pb(OAc)3
+
AcOH
CO2 + Pb(OAc)3 + R
R OAc
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 50 Other Metal-Based Oxidation
Lead tetraacetate, LTA ,Pb(OAc)4
O
O
O
O
O
Pb(OAc)4
O
Pyridine
O
O
O
O R R O
H O C
O Pb(OAc)3
CO2 + Alkene + Pb(OAc)2 + CH3CO2H
R R
O
CO2H
O Pb(OAc)3
H
O
O
+ Pb(OAc)2
O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan + CO2 + AcOH
51 Other Metal-Based Oxidation
Lead tetraacetate, LTA ,Pb(OAc)4
O
CO2H
O Pb(OAc)3
LTA
O
CO2H
H
+ AcOH
O
O H
LTA
O H
O Pb(OAc)3
OH
O
+ 2CO2 + Pb(OAc)2
O
O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 52 Other Metal-Based Oxidation
Oxymercuration
Addition of water to an alkene
Hg2+
Hg(OAc)2
R
R
Hg2+
R
Mercurinium
ion
When water is used as solvent, it opens the mercurinium
ion and give alcohols
OH
Hg(OAc)2
R
H2O
R
HgOAc
OH
NaBH4
R
CH3
C-Hg bond is very weak and it can be easily replaced with
hydrogen by reducing agents. Generally NaBH4 is used
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 53 Other Metal-Based Oxidation
Oxymercuration
Addition of water to an alkyne
Hg(OAc)2
R
R
H2O
Hg2+
HgOAc
HO
R
This is what we should have expected. But what we get is a ketone
R
HgOAc
HO
Isomerizes to
R
HgOAc
O
Since AcOH is the byproduct, this protonates the carbonyl group
R
O
R
R
HgOAc
HO
O
CH3
H
For hydration of alkynes, we do not need NaBH4. Moreover, if you
use NaBH4 in the last step, it will reduce the ketone
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 54 Other Metal-Based Oxidation
Oxymercuration
OH
Hg(OAc)2
Hg
AcO
O
OH
NaBH4
O
OH
O
AcOHg
OH
O
OH
OMe O
OH
Hg(OAc)2
OH O
H2O
OMe O
OH
Deoxydaunomycinone
OH
Hg(OAc)2
H2SO4
OH
-H2O
O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan O
55 Other Metal-Based Oxidation
Wacker Oxidation
O2, HCl
PdCl2
CuCl2
R
Pd0 + HCl
PdIICl
HPdIICl
O
HO
β- elimination
R
R
R
H
H2O
PdIICl
HO
O
O
HO
MgBr
Wacker
oxidation
HO
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 56 Other Metal-Based Oxidation
Molybdenum Peroxy Complexes:
MoOPH (MoO5. Py. HMPA complex)
It contains two electrophilic bridged peroxy ligands and a single oxounit
O
O
O
+
Li
O
Mo
O
LDA
L
R'
R'
O
O
O
R
R'
L= HMPA
L'= Pyridine
O
O
OH
R
R'
L' O
H
OH
O
CH3
O
O
L'
O
Mo
L
O
O
R
R
O
CH3
LDA
MoOPH
O
O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 57 Non-Metal Based Oxidation
Activated Dimethyl Sulfoxide (DMSO)
H R
E
S O
+
E+
S O
Electrophiles
SOCl2, (COCl)2, Cl2,
TsCl, (CH3CO)2O,
SO3/pyridine, CF3SO3H
O
R
R2CHOH
S O
R
R
Me2S
Nucleophiles
ROH, PhOH, PhNH2,
R2C=N-OH, Enols
Swern Oxidation
Moffatt Oxidation
Kornblum Oxidation
Most of these
reactions take place at
very low temperature
Corey-Kim Oxidation
DMSO-Ac20
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 58 Non-Metal Based Oxidation
Swern Oxidation
Cl
Cl
S O
+
O
O
-Cl-
O
Cl
S Cl
-CO2, -CO
S O
O
Cl
O
S O
-HCl
R
R
Et3N
OH
H
H
R
O
DMSO, (COCl)2
OH
CH2Cl2, Et3N
Cl
O
O
Trifluoroacetic anhydride also can be used instead of (COCl)2
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 59 Non-Metal Based Oxidation
Swern Oxidation
Survives protecting groups
CH(OEt)2
Swern
Oxidation
CH(OEt)2
OH
O
O
O
O
O
No epimerization of aldehydes
H
CH3
Swern
Oxidation
CH3
CHO
OH
Swern
Oxidation
OH
H
H
O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 60 Non-Metal Based Oxidation
Moffatt Oxidation
R
H
O
R
RHN
S O
NR
R N C N R
S O
R
O
R
R
O
Me2S
O
O
R
O
S
R
R
H
Base
O
O
DMSO
O
O
OH
CO2Me
DCC
OAc OH
OAc O
O
S
DMSO
O
CO2Me
DCC
O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan S
61 Non-Metal Based Oxidation
DMSO, Ac2O R
S O
+ Ac2O
-OAc-
S OAc
-OAc-
S O
R
R'
H
O
OAc
OH
R'
+ Me2S
+ AcOH
R'
R
Disadvantage: Alcohol may attack acetate
DMSO- SO3- Py
N
O S O
O
O
S
O S O
O
RCH2OH
R
H
S
O
S
Py
RCHO + Me2S
O
OH
DMSO
OH
SO3, Py
OH
O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 62 Non-Metal Based Oxidation
Kornblum Oxidation
Oxidation of alkyl halides to aldehydes
O
R
S
RCH2Br
H
O
NaHCO3
S
RCHO + Me2S
Base
Corey-Kim Oxidation
O
S
Cl
N
R
S Cl
R
H
O
S
R
O
Base
HO
R
R2CO + Me2S
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 63 Non-Metal Based Oxidation
Hypervalent Iodine(V) Containing Oxidizing Agents
O
O
O
I
O
O
I
OAc
AcO OAc
OH
IBX
DMP
2-Iodoxybenzoic acid (IBX) Preparation:
Oxone, H2O
COOH
O
70 °C
O
I
KBrO3
I
O
OH
2N H2SO4, 75 °C
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 64 Non-Metal Based Oxidation
2-Iodoxybenzoic acid (IBX) Mechanism:
OH
O
OH
I
R1
O
R1
R2
H
O
O
I
R2
OH
O
O
R1
R2
O
O
O
O
I
Uses:
1. Oxidation of Alcohols:
OH
R2
MeO
O
O
IBX
R2
O
DMSO
R1
MeO
O
O
R1
OH
H
O
O
OH
IBX
H
DMSO
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan OH
H
O
H
65 Non-Metal Based Oxidation
2-Iodoxybenzoic acid (IBX) 2. Introduction of Unsaturation:
OH
O
O
O
IBX (2 eqv)
IBX (2 eqv)
Toluene-DMSO
Toluene-DMSO
IBX (4 eqv)
OH
N
Toluene-DMSO
O
N
3. Selective Oxidation of Benzylic Carbon:
O
IBX (4 eqv)
Ar
R
Fluorobenzene-DMSO
Ar
R
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 66 Non-Metal Based Oxidation
Dess-Martin Periodinane (DMP) Preparation:
O
OH
I
O
Ac2O
O
AcO OAc
OAc
I
O
O
Mechanism:
AcO OAc
OAc
I
O
O
HO
R
O
AcO O
H
O
I
O R
O
OAc
O
I
O
R
H
O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 67 Non-Metal Based Oxidation
Dess-Martin Periodinane (DMP) Uses:
OH
OH
DMP
OH
O
TBSO
TBSO
OH
Ph
DMP
O
Ph
CF3
O
CF3
DMP
O
O
O
HO
O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 68 Non-Metal Based Oxidation
Tetramethylpiperidine nitroxide (TEMPO)
N O
HO
R
It is a stable
nitroxide and is
the active reagent
in oxidizing
alcohols
O
OH R
N
O
H
N OH
TEMPO can be
used in catalytic
amount if NaOCl
or NCS is used in
stoichiometric
amount
R
H
NaOCl
N O
TEMPO
(2 mol%)
PhCH2O(CH2)2CH2
OH
NaOCl
PhCH2O(CH2)2
CHO
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 69 Non-Metal Based Oxidation
Tetramethylpiperidine nitroxide (TEMPO)
This reagent can selectively oxidize primary alcohols in the
presence of secondary alcohols
TEMPO
(10 mol%)
CH3CH(CH)8CH2 OH
NCS(1.5 eq)
TBACl
OH
CH3CH(CH)8CHO
OH
It can also oxidize primary alcohols to carboxylic acids by a
subsequent oxidation with hypochlorite ion
TEMPO
RCH2OH
NaOCl (3 eq)
TBACl
RCOOH
CHO
N
CO2tBu
OH
N
CO2tBu
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 70 Non-Metal Based Oxidation
Epoxidation
R
O
H
O
O
O
Nu
R
OH
Nu O
R = EWG
Stabilized
Electron rich substrate and electrophilic reagent
electron rich
Electron deficient substrate and nucleophilic reagent
O
electron deficient
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 71 Non-Metal Based Oxidation
Epoxidation
Electrophilic Reagents:
1. Peracetic acid 2. Perbenzoic acid 3. m-CPBA 4. KHSO5 (Oxone) 5. Dimethyldioxirane (DMDO)
Peracids
Peracids can be prepared from the corresponding acids & H2O2
RCO2H
+
H2O2
RCO3H
+
H2O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 72 Non-Metal Based Oxidation
Peracids
Mechanism:
R
O
H
O
O
R
R
R
R
R
O
R
R
+ RCOOH
R
It is believed to be a concerted process
Stereospecific syn addition is constantly observed
Epoxides are always syn. Trans epoxide means substituents are trans
The rate of epoxidation
The reactivity of the peracid is increased by EWG’s
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 73 Non-Metal Based Oxidation
Stereoselectivity:
R'
m-CPBA
H
O
R
R
Peracids
m-CPBA
R'
R
H
R'
H
O
R
H
R'
Addition of oxygen comes preferentially from the less hindered
side of the molecule
H
H
O
m-CPBA
H
O
+
H
2 : 1
H
H
m-CPBA
O
H
H
Regioselectivity:
m-CPBA
O
More electron rich double bond participated in epoxidation
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 74 Non-Metal Based Oxidation
Henbest Epoxidation:
Peracids
Epoxidation directed by a polar group
Hydrogen bonding between hydroxyl group & the reagent stabilizes
the transition states
R
OH
OH
O
m-CPBA
H
O
H
O
O H
O
H
OAc
OAc
OAc
m-CPBA
O
+
O
(57:43)
NHAc
NHAc
m-CPBA
O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 75 Non-Metal Based Oxidation
Peracids
Henbest Epoxidation:
CO2Me
CO2Me
m-CPBA
OH
HO
HO
H
O
RO
H
H
O
O
O
H
m-CPBA
H
RO
OH
O
H
H
m-CPBA
O
O
H
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 76 Non-Metal Based Oxidation
Peracids
Rubottom Oxidation:
O
OTMS
TMSO
m-CPBA
OAc
AcO
O
O
H+
O
O
O
O
OH
O
OAc
Epoxides derived from vinyl silanes are converted into aldehydes
or ketones under mild acidic condition
TMS
H
O
R
R
H+, H2O
R2CH-CHO
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 77 Non-Metal Based Oxidation
Can you do epoxidation in non-acidic medium?
Yes
Nitrile & H2O2
NH
R C N + H2O2
R
R
R
R
R
R
O
R
O
O
O
R
R
H
R
NH2
Peroximidic
acid
By product is
amide, not acid
DCC-H2O2
H2O2
N C N
MeOH
N
H
N C
O
O
R
H
O
R
DCU
(neutral)
Looks like peracid
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 78 Non-Metal Based Oxidation
Methyltrioxorhenium (MeReO3)
Ph
Ph
MeReO3
O
Py, CH2Cl2
30% H2O2
Dioxiranes (Murray’s Reagent)
KHSO5
(Oxone)
O
O
O
H2O2
F3C
F3C
O
Uses:
F3C
F3C
O
O
Dimethyldioxirane (DMDO)
More reactive analogue
of DMDO
Epoxidation of olefins
Oxidizes sulfides to sulfoxides & sulfones
Oxidation of amines to amino N-oxides
Oxidation of aldehydes to carboxylates
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 79 Non-Metal Based Oxidation
Dioxiranes (Murray’s Reagent)
Mechanism:
O
O
C12H25
H3C
N
O , KHSO5
O
N,N-Dialkylpiperidin-4-one salts are
also good catalysts for epoxidation
The quarternary nitrogen enhances the reactivity of the ketone
towards nucleophilic addition
F
OH
Ph
H3C
O
H3C
F
KHSO5
K2CO3
O
Ph
OH
93%
89% ee
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 80 Non-Metal Based Oxidation
Epoxidation of Electrophilic Alkenes
O
O
H2O2
O
NaOH
O
O
O
O
O O
H
O O
H
O
O
H
KOH
O
H
H2O2
H
O
O
H
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 81 Non-Metal Based Oxidation
Epoxidation of Electrophilic Alkenes
O
O
H2O2/NaOH
O
O
m-CPBA
O
Strong EWG attached to olefin makes it less reactive
CF3CO3H
CO2Me
O
CO2Me
O
R
O
OMe
CF3CO2H
R
O
OMe
H2O2/NaOH cannot be used as ester will get hydrolyzed and
m-CPBA is unreactive
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 82 Non-Metal Based Oxidation
Baeyer- Villiger oxidation
O
R
O
R'CO3H
R
R
R
H
O
O
R'
O
R
OR
+ R'COOH
O
O H
O
O
O
O O
CO3H
CO2H
O
O
CH3CO3H
O
O
O
O
CF3CO3H
O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 83 Non-Metal Based Oxidation
Transformation of Epoxides
Nu
R
Nu
R
O
R
BF3.Et2O
O
CH3
O
O BF3
O BF3
R
H
O
H3C
H3C
OH
R
R
H2O2
OH
HCO2H
OH
H
H2SO4
H3C
H3C
OH
MeOH
MeO
CH3
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 84 Non-Metal Based Oxidation
Transformation of Epoxides
Base catalyzed ring opening of epoxides leads to allylic
alcohols
O
Base
HO
LDA
LiClO4, CF3SO3Li, Mg(ClO4)2, Zn(OTf)2, Yb(OTf)3 catalyze the
epoxide ring opening.
OH
O
NR2
R2NH
LAH acts as a nucleophilic agent & attacks at the less
substituted carbon atom of the epoxide ring. DIBAL-H also
serves the purpose
O
R
OH
LAH
R
CH3
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 85 Non-Metal Based Oxidation
Oxidation with Singlet Oxygen
Generation of Singlet Oxygen:
Photosensitizer
1
3
hν
+
1
3
[Photosensitizer]*
[Photosensitizer]*
H2O2 +
(RO)3P + O3
Ph
+
[Photosensitizer]*
3
O2
Photosensitizer
-OCl
1O
(RO)3P
[Photosensitizer]*
O
O
2
1
O2
+ H2O + Cl-
O
(RO)3P=O +
1O
2
Ph
O O
Ph
+
1O
2
Ph
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 86 Non-Metal Based Oxidation
Oxidation with Singlet Oxygen
Mechanism:
1. Concerted mechanism
O
O
H
O
OH
2. Perepoxide-intermediate mechanism
O
O
O H
O H
O
OH
There is a preference for removal of a hydrogen from
more congested side of the double bond
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 87 Non-Metal Based Oxidation
Oxidation with Singlet Oxygen
(PhO)3P
O OH
O
O
O
-OCl
O OH
H2O2
-35 oC
O
O
OCH3
1O
2
O O
O OH
MeOH
OCH3
OCH3
OCH3
CH3CHO
OCH3
O O
O
CH3
OCH3
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 88 Non-Metal Based Oxidation
SeO2 Oxidation
H
2. H2O2
R
Mechanism:
O
H
Se
OH
R'
O
OH
1. SeO2
R
R'
H
Se
O
R
R
HO
OH
O
Se
Se
R'
R
H
R
R'
O
HO
Se
O
R'
R'
O
Cat. SeO2
t-BuOOH
SeO2
R
HO
R'
R
R
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 89 Non-Metal Based Oxidation
SeO2 Oxidation
OAc
OAc
1. SeO2
2. NaBH4
HO
PhSeCl Oxidation
O
SePh
1. LDA
O
Ph
O
O
Se
H2O2
2. PhSeCl
O
+ PhSeOH
H
Phenyl Sulfoxide Oxidation
O
O
O
SPh
1. LDA
m-CPBA
O
Ph
S
O
Δ
2. Ph-S-S-Ph
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 90 Elimination Reactions
N
Cope Elimination
O
H
O
O
O
SePh
LDA
Ph
Se
1 eq. NaIO4
PhSeSePh
O
O
H
OAc
SMe
O
OH
S
CS2, MeI
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 91 Non-Metal Based Oxidation
NaIO4 Oxidation
R
R
HO
IO4
R
-
2 RCHO + H2O + IO3-
O
O
I
O
O
HO OH
OH
O
IO4O
R
OH-
HO
O
O
O
O
I
O
O
OH
O O
I O
O O
OH
H2O
2 CH3COOH + IO3- + H2O
OH
O OH
I O
O
O
OH
OH
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 92 Non-Metal Based Oxidation
Ozonolysis
O
O3
R
O
R
O
O
R
[3+2]
O
R
R'
O
R
Retro
[3+2]
O
O
+
H
O
O
+
H
R
O
O
R
R
R'
R
+
R
O
O
[3+2]
2 RCHO + Me2S=O
Me2S
O
O
R
O
R
PPh3
Ph3P=O
Zn
Ozonide
ZnO
NaBH4
EtOH
RCH2OH
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 93 Non-Metal Based Oxidation
Ozonolysis
MeO
OMe
Reductive Workup:
will undergo ozonolysis
faster than other
1. O3
N
2. Na2SO3
N
O
Oxidative Workup:
O
O
1. O3, HCOOH
HO2C
CO2H
2. H2O2
HO2C
CO2H
O
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 94 Non-Metal Based Oxidation
Oxidation with N-sulfonyloxaziridines
O
1. KHMDS
O
2.
NSO2Ph
Ph
NSO2
NSO2
H
R
O
Me2HC
O
R
O
PhCH2OCH2O
CH2CO2Me
Me
O
H
R
R
O
1. KHMDS
2.
Ph
OH
R
HO
H
R
O
PhCH2OCH2O
OH
Me2HC
O
NSO2Ph
CO2Me
Me
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 95 Non-Metal Based Oxidation
Oxidation of Unfunctionalized Carbon
Barton Reaction:
OH
NOCl
O
NO
H
hν
O
Py
NOH
OH
NO
OH
NO
OH
O
OH
CH-­‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 96