e m organic chemistry ch-401 course i t bether.chem.iitb.ac.in/~kpk/metal_based_oxidation.pdfin...

Krishna P. Kaliappan, Department of Chemistry, IIT Bombay

CH E

MII T B

Organic Chemistry CH-401 Course

1

Krishna P. KaliappanDepartment of Chemistry

Indian Institute of Technology-BombayMumbai 400 076 INDIA

http://www.chem.iitb.ac.in/[email protected]

9/18/20

Oxidation

CH (401) slides should not be used for commercial purposes

CH-401 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

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

3

Oxidation

(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


Addition of oxygen

H3C CH3 H3C CH2

OHH3C CHO H3C CO2H

Elimination of hydrogen

H3C CH3 H2C CH2 HC CH

Replacement of hydrogen atom bonded to carbon with another, more electronegative element like oxygen

Simplest DefinitionMost 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. In organic chemistry, oxidation means organic substrate is oxidized

4

Oxidation


Reagents Based Classification

At Single carbon Vicinal Carbon

1. Metal based

2. Non-metal based

Hetero atom UnfunctionalizedCarbon atom

Substrates Based Classification

5

Classification


Chromium based oxidation

Manganese based oxidation

Titanium based oxidation

Ruthenium based oxidation

Osmium based oxidation

Molybdenum based oxidation

Lead based oxidation

6

Metal Based Oxidation


CrO3

The most widely employed transition metal oxidations are Cr(VI) based reagents

Reactivity & selectivity depends on the (1) Solvents & (2) Chromium ligands

Substantial selectivity can be achieved by choice of the particular reagent or conditions

Jones reagent

PCC

PDC

Collins reagent

Chromyl chloride

7

Chromium Based Reagents


The extent of protonation of these ions depend on the pH

In acetic acid, CrO3 exists as mixed anhydride of acetic acid & chromic acid

CH3COOH + CrO3

O

OCrO OH

O

O

OCrO O

O O

In dilute solution the chromate ion is present. As concentration increases the dichromate ion dominates

CrO3

CrO3 + H2O CrO

OHO O

Cr OHOO

O2 Cr OO

O

OCr OO

O+ H2O

8

Chromium Trioxide


R OH CrO3 R O

H

CrO

OOH

The most common transformation effected on with Cr(VI) is the conversion of alcohols into ketones or aldehydes

N + CrO3 N Cr OO

O

In pyridine, CrO3 exists as an adduct involving Cr-N bond

CrO3

A variety of experimental conditions have been used for oxidation of alcohols by Cr(VI) on a synthetic scale

9

R O H2CrO3+

Chromium Trioxide


CrO3 H2SO4 H2O+ +

Jones Oxidation

Utility: Jones reagent can be used for oxidation of simple unfunctionalized secondary alcohols to ketones

Jones Reagent: Acidic aqueous solution of chromic acid. Generally added to an acetone solution of the alcohol

10

Chromium Based Oxidation


OH

Jones reagentAcetone

O

O

O

OHJonesReagent

OH

JonesReagent

11

Jones Oxidation


Jones reagentAcetoneR OH

R OH

O

(3) Under acidic condition dehydration may also take place

Disadvantages:(1) Saturated primary alcohols are oxidized to carboxylic acids

Hydration

R OH

OH

R O

H

(2) Not good for acid sensitive groups & compounds

Advantages:(1) Cr(VI) Cr(III)

Precipitate

Acetone can be decanted. Easy to work up(2) Good reagent to oxidize primary alcohol to acid

12

Jones 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 respectively in non-aqueous solution (Generally DCM was used) without over oxidation

(4) Neither markedly basic, nor acidic

13

Collins Reagent


Disadvantages:(1) Must use a large excess of the reagent

(2) It is moisture sensitive & loses its activity in aqueous solution

O

OH

CrO3. Py

O

OH

CrO3. Py

O

PhPh

OHCrO3. Py

O

PhPh

O

The double bond did not migrate

14

Collins Reagent


Pyridinium Chlorochromate (PCC)

CrO3 6N HCl+ CrO

OHO Cl

Pyridine CrO

OO Cl

NH

Orange-yellowcrystalline solid,Less hygroscopic

Preparation:

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

15

Pyridinium Chlorochromate


O

O O

O

O OH

PCC

CH2Cl2

OH PCC O

PhOH

PCCPh

O

16



Oxidation of Organoboranes:

R

R (1) BH3.THF

(2) PCC, 0oC

O

RR

Deoximation:O

R2R1

Pyridinium Chlorochromate (PCC)

17

N

R1 R2

OH

PCC



OH

CH2Cl2

PCC

O

Oxidation of tertiary allylic alcohols:

18

O CrO

OO PyH

O CrO

OO PyH




19

O1. MeMgBr, CeCl32. PCC, CH2Cl2

O

O

1. MeMgBr, CeCl32. PCC, CH2Cl2

O




OHPCC O

OHPCC

O

20



OH

PCCCH2Cl2

O

OH

Oxidative cationic cyclization:

ene reaction

Oxidation

21

OH



Oxidative cationic cyclization:

O

PCCCH2Cl2

OH O

22

PCC

OH



R O

OR'

Oxidation of enol ethers to lactones:

O

PCCCH2Cl2 O O

O

PCC

O O

23

CrO O

Cl O PyH

R H

OR'OCrO

R H

OR'

Cl O PyH



Oxidation of furan ring system:

OH3CR

OHO

O

H3C

HOR

24

OH3CR

OHO OCr

Cl O

O

RO

H3C

HO



Oxidation of active methylene group:

O

PCCO

O

O

PCC

O O

25



O CrO

OO Cr

O

OO

NH

NH

Preparation:

2CrO3 H2O+ HO CrO

OO Cr

O

OOH

Pyridine

Solubility:

Soluble in water, DMF, DMSO, dimethylacetamide. It is sparingly soluble in dichloromethane

26


Pyridinium Dichromate (PDC)


Advantages:

(1) Excellent reagent for oxidation of allylic alcohols

(2) There is no over-oxidation of aldehydes

OH

PDC

DCM CHO

(3) No E/Z-isomerization(4) Unlike conjugated aldehydes non-conjugated aldehydes are readily oxidized to acids by PDC in DMF at 25oC

HO

PDC

DMF

HO O

27

Pyridinium Dichromate


R OHPDCCH2Cl2

R O

R OH R OPDCCH2Cl2

R OH

R'PDCCH2Cl2 R O

R'

Utility:

28

OHPDC

DCM

O

O CH2OH PDC

DCMO CHO



OHO

PDCDMF

PDCCH2Cl2 O

OH

29

PCCCH2Cl2

O

This reaction is complicated by the cationic cyclization when PCC was used


CrO

O

O OOHO

OHO3Cr

H2O

CH-401 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan30

O

CrO3/AcOHH2O

CO2HHO2C

OHO

CrO

O

OOCrO

O

OH

H2OO

HOO

O

CO2HC

O

CrO3/AcOHH2O

CO2HHO2C

H2O


CH 401Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

OR

CHO

OR

CrO2Cl2CH2Cl2

31

Etard Reaction

H

CrO

O

Cl

Cl

Ene

Reaction

OR

CrO Cl

ClOH

[2,3]

Sigmatropicrearrangement

OROCr

OH

ClCl

H

OR

CHO

+ CrHO Cl

OR

Mechanism:

CH 401Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan32

CH3

CrO3

Ac2O

CHO

CrO3Ac2O

HC

AcO OAc

Hydrolysis

CHO

Etard Reaction


Supported Reagents

Improved yields due to simplified work up

(1) PCC on alumina

(2) PCC on polyvinylpyridine

Advantage:

33

N

Cross link

N

HC

H2C n

CrO3.HCl

N

HC

H2C n

CrO3.HCl.

N

HC

H2C n

.

R2CHOH O

RR

Cr(III)

1) Remove CrO32) HCl wash

3) KOH wash4) H2O washN

HC

H2C n



R OH R CHO

OH

R R'

O

R R'

R OH R COOH

Transformation Chromium reagentPCC, Collins reagent, PDC in DCM

PCC, Collins reagent, PDC, Jones reagent

Jones reagent, PDC in DMF

CHO

Etard reaction



KMnO4 MnO2 Mn(OAc)3

Potassium permanganate (KMnO4)

R'

RKMnO4+

R'

R OMnO O

O-K+

R'

R OH

OH

HOMn

HO O

O-K++

R'

R OMnO O

O-K+H

R'

R O

OH R'

R O

O

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

35

Manganese Based Oxidation


R R'KMnO4, H2O

R R'

HO OH

R

R'O

O

R R'

O OH

ArKMnO4, H2O ArCO2H

CH3Ar KMnO4, H2OArCO2H

In water medium:

36

Potassium Permanganate


In Organic Solvents:

3.3 mol KMnO4

Benzene polyether

1.0 mol KMnO4

R4NCl

OH

OH

O

O

Oxidation of acetylenes:

Ph CH2CH2CH3

KMnO4

R4N+, DCM HO

CH2CH2CH3

OH

Ph

O

CH2CH2CH3

OH

Ph

O

CH2CH2CH3

O

Ph

37



Oxidation of aromatic side chain:

Ar R Ar CO2HKMnO4

R3C NH2 R3C NO2KMnO4

Oxidation of amino compounds:

Tertiary alkylamines can be oxidized to nitro compounds

Oxidation of sulphides:

S

NO2

O2N S

NO2

O2NO

O

KMnO4

38



Application in the synthesis of Saccharin:

Me

SO2NH2

KMnO4

OH-

CO2

SO2NH2

Na

SO2

NH

O

Saccharin

Oxidation of terminal alkynes:

CO2H

39

Me

SO2Cl

(NH4)2CO3

KMnO4



Manganese dioxide (MnO2)

Excess of MnO2is required

O

MnO2, KCNOH

EtOH

OH

CN

Utility:Selective oxidation of allylic & benzylic alcohols

O

CN

MnO2

CH2Cl2

OH

40

O

OEtEtOH



OH

MnO2ROH

NaCNCO2R

OH MnO2

O

H

CN OH

CN

MnO2

O

CN

O

OR R OH

Manganese Dioxide


CH2OH CHO

MnO2 OHCHO

MnO2

DCM

OHCHO

MnO2 MnO2, CH2Cl2

HO

OH

O

OH

42

OH

HO

MnO2

CHCl3

OH OH

O

OH

Manganese Dioxide


Manganese(lll) acetate [Mn(OAc)3]O

Mn(OAc)3

OOAc

OOAcOMn(OAc)3

43

OHO OMn(OAc)2

Mn(OAc)3

Mn(OAc)2

OMn(OAc)3

O

Mn(OAc)2

OOAc



OH

44

Mn(OAc)3

NMe

O

OH

NMe

O

O

NMe

O

O OH

NMe

O

O OHMn(OAc)3

Mn(OAc)2

NMe

O

OH OH

NMe

O

OOH

Manganese Triacetate


R

O

H

Ag2OR

O

OH+ 2 Ag

Ag2O

Mild oxidant to oxidize aldehyde to carboxylic acid

CHO Ag2O

NaOH

CO2H

45

Silver Based Oxidation


Ag2CO3 on Celite (Fetizon’s reagent)

OHOH

Fetizon's reagent O

O

Fetizon's reagent

O

OH

OH O

OH

O

Conversion of diols to lactones

46



Ag2CO3 on Celite (Fetizon’s reagent)

Highly selective:

Mono-oxidation:

OH OH OH

Fetizon's reagent

OH O OH

OHOH

Fetizon's reagent

OHO

Fetizon's reagent

OH

OH

O

OH

47



R

R'I

O

OR

R'CH3

O

OR

R'CH3

R

R'

OAc

OAc

-OAc

In the absence of water, Prevost Hydroxylation, trans-product

In the presence of water, Woodwards hydroxylation,

cis-product48

R

R'

I2Ag(OAc) or Ag(O2CPh)

Silver AcetateR

R'

I

O CH3

O

H2O

R

R'

OH

OHcis product

R

R'

OH

OHtrans product


CO2Ag BrBr2

RCOOAg X2 RCOOX AgX

∇RCOOX RCOO X (Initiation)

RCOO R CO2

R RCOOX RX RCOO (Propagation)

Hunsdiecker Reaction


Mechanism seems to be same in both cases

Uses:

Alkenes are generally oxidized to cis-diols

Alkynes are oxidized to diketones as in case of KMnO4

50

Ruthenium & Osmium Based Oxidation

MO4

OM

O O

OHydrolysis

OH

OH

HOM

HO O

O

Reoxidation

OM

O O

O


Osmium tetraoxide (OsO4)

OsO4 is highly toxic, cannot be used at industrial scale

Use of NMO as co-oxidant along with catalytic amount of OsO4can be used for higher scale

51

Osmium Tetraoxide

R

R'

OsO4R

R'

OH

OHSyn

N

O

O

NMO


Directed by hydroxyl group

52

OHO

OsO4NMO

PyridineO

HO

HO

HO

OH

OsO4

OH

HO

HO

OTMSO

OsO4NMO

PyridineO

TMSO

HO

HO

Osmium Tetraoxide


Ruthenium Based OxidationRuthenium tetroxide (RuO4)

Prepared in-situ by mixing RuCl3, NaIO4, CH3CN, CCl4, H2O

Primary Alcohols:

Secondary Alcohols:Secondary alcohols oxidized to ketones

O

HH

OH

RuO4

O

HHCO2H

OO

HORuCl3, NaIO4

CCl4, H2O, CH3CN OO

O


Ruthenium Based OxidationRuthenium tetroxide (RuO4)

Diols:Diols are further oxidized to carboxylic acids

Oxidation of Phenyl Groups:

RuCl3, NaIO4

CCl4, H2O, CH3CNPh OH

OHPh

O

OH

RRuCl3, NaIO4

CCl4, H2O, CH3CNR CO2H


Oxidation of Ethers:

55

Ruthenium Tetroxide

O O O

RuO4

OAc

OAc

O

AcO OAc

OO

RuO4

RuCl3, NaIO4

CCl4, H2O, CH3CNOMe OMe

O


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

56

Ruthenium Based Oxidation

HO

OTBDPSO TPAP

NMO, DCM

O

OTBDPSO

TPAP

NMO, DCMTHPO OH THPO O


Tetra-n-propylammonium perruthenate (TPAP)

Groups tolerant are:

Epoxides

Alkenes

THP ethers

Lactones

Silyl ethers

Indoles

57

TPAP


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

Carboxylic acids are oxidized by LTA

58

Lead Based Oxidation

O

OH

OH

Pb(OAc)4

O

O

O

Pb(OAc)4CO2H

CHCl3


Lead Tetraacetate, LTA ,Pb(OAc)4

The reductive step is promoted by hydrogen donor solvents

Acetate arise by the capture of an acetate ion

In the presence of lithium chloride, the product is the corresponding chloride

59

Lead Tetraacetate

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-

CO2HCH2CO2Me

ClClH3C

Pb(OAc)4

LiClClCH2CO2Me

ClClH3C


α- hydroxy carboxylic acids undergo oxidative decarboxylation to give ketone

γ- keto carboxylic acid preferentially yield α,β– unsaturated ketone

Presumably it goes via oxidation of carboxylic acid to the carbocation followed by deprotonation

60

HOH

O

O

HO

O

OPb(OAc)3

O+ CO2 + Pb(OAc)2 + CH3CO2H

O

HO2C

Pb(OAc)4

Cu(OAc)2 O

O

OO

Pb(OAc)3H

Lead Tetraacetate


LTA is toxic in nature

61

O

LTA, AcOH

OOAc

OH

LTA

O

+ Pb(OAc)3 + AcOHAcOH

.

Pb(OAc)2..

OAc +O

OAc

Lead Tetraacetate


R

O

OH R

O

OPb(OAc)3 + AcOH

LTA

KOAc

R+CO2 Pb(OAc)3 +

R+ Pb(OAc)2AcO-+ +

R OAc

Lead Tetraacetate


O

CO2H

O

O

OO Pb(OAc)3

H

O

Pb(OAc)2 CO2 AcOH+ + +

+

Lead Tetraacetate


O

O

O

O

O

O Pb(OAc)4

Pyridine

H

H

O

O

O

RRR

R

OOH

OOPb OAc

AcO OAc

CO2 + Alkene + Pb(OAc)2 + CH3CO2H

CO2H

CO2H

Lead Tetraacetate


Oxymercuration

Addition of water to an alkene

When water is used as solvent, it opens the mercurinium ion and give alcohols

C-Hg bond is very weak and it can be easily replaced with hydrogen by reducing agents. Generally NaBH4 is used

65

Mercury Based Oxidation

R

Hg(OAc)2R

Hg2+ Hg2+

R

Mercuriniumion

RHg(OAc)2

H2OR

HgOAcOH NaBH4

R CH3

OH


Addition of water to an alkyne

This is what we should have expected. But what we get is a ketone

Since AcOH is the byproduct, this protonates the carbonyl group

For hydration of alkynes, we do not need NaBH4. Moreover, if you use NaBH4in the last step, it will reduce the ketone

Isomerizes to

66

Oxymercuration

RHg(OAc)2 Hg2+

R

H2OHO

HgOAcR

HOHgOAc

R

OHgOAc

R

H2OO

HgOAcR

HHO

R

O CH3

R


OH Hg(OAc)2OH

HgAcO Hg OAc

O

O

AcOHg

ONaBH4

OH Hg(OAc)2

H2SO4

OH

O O

-H2O

Oxymercuration


O

OOMe

OH

OH

OHHg(OAc)2

H2O

O

OOMe

OH

OH

OH

Deoxydaunomycinone

O

Oxymercuration


Palladium Based Oxidation

RPdCl2

CuCl2, H2O R

O

Wacker Process

O

MgBr

HO

HOO

PdCl2CuCl2, H2O

O

MgBrHO Hg(OAc)2

H2SO4


Palladium Based Oxidation

Wacker Process

PdCl2

PdCl2 R

PdIICl

H2O

PdIICl

HO HR

β- eliminationHO

R

O

R

HPdIICl

Pd0 + HCl

CuCl2

O2, HCl


Molybdenum Peroxy Complexes:MoOPH (MoO5. Py. HMPA complex)

It contains two electrophilic bridged peroxy ligands and a single oxo-unit

71

Molybdenum Based Oxidation

O

RR'

LDA O

RR'

Li+

MoO

O O

O

L L'

O

L= HMPAL'= Pyridine

RO

Mo

O

R'O

OO

O

L L'

O

RR'

OH

OO

CH3

HO

LDA

MoOPH

OO

CH3

OHO

CH-401Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

NO

H

Cope elimination

72

Elimination Reactions

OLDA

PhSeSePhor

PhSecl

OSePh O

SePh

O

H

OH2O2 OR

m-CPBA ORNaIO4

O

LDAPhSSPh

OSPh

H2O2 OR

m-CPBA ORNaIO4

OSPh

O

H

O

e m organic chemistry ch-401 course i t bether.chem.iitb.ac.in/~kpk/metal_based_oxidation.pdfin...

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