CH-420: Principles of Organic Chemistry

Dr. Krishna P. Bhabak

Assistant Professor
Department of Chemistry
Indian Institute of Technology Guwahati
 Lead tetraacetate, LTA, [Pb(OAc)4]
-LTA (Criegee reagent) is a powerful oxidizing agent
-It is very toxic, hygroscopic colorless crystals
-However, it can decompose in air to produce Pb(OAc)2 that is brown in color. Generally stored with added Acetic acid
-It must be used with precautions in a ventilated fume hood.

Oxidation of alcohols
-Alcohols are oxidized to aldehydes or ketones in the presence of pyridine
-1,2-diols undergo oxidative cleavage to produce aldehydes or ketones
-cis-diols react faster than the trans-diols
-reaction goes via cyclic intermediates
-very useful reagent for the glycols that have low solubility in aqueous media
-reactions are generally performed in organic solvents
 Lead tetraacetate, LTA, [Pb(OAc)4]
The proposed mechanism of
oxidation of cis- and trans-diols are
shown to be different

The saturated alcohols having δ-

hydrogen atom undergoes cyclization
to produce tetrahydrofuran ring in the
presence of LTA.

The reaction likely to proceed via

radical pathway.
Mechanism
 Lead tetraacetate, LTA, [Pb(OAc)4]
Carboxylic acids undergo
decarboxylation to produce alkenes

1,2-dicarboxylic acids undergo oxidative

decarboxylation to form alkenes

α-hydroxy carboxylic acids undergo

oxidative decarboxylation to produce
ketones

γ-keto carboxylic acids undergo

oxidation followed by deprotonation to
produce α,β-unsaturated ketones
 Aluminium Alkoxide (Oppenauer Oxidation)
-Aluminium triisopropoxide or aluminium
tributoxide act as oxidizing agents for
oxidation of alcohols
-Secondary alcohols are oxidized to ketones
in the presence of an excess amount of
acetone
-Inert solvent such as benzene, toluene or
dioxane minimizes the side products
-The β,γ-double bond generally migrates to
α,β-position of the carbonyl group during
oxidation.
-Cyclohexanone acts as hydrogen acceptor
here.
 Aluminium Alkoxide (Oppenauer Oxidation)
Synthesis of
Analgesic and
Hormones

Mechanism
Proceeds via six-membered cyclic transition
state
Acetone acts as oxidizing agent and gets
reduced to isopropyl alcohol
 Ruthenium-based Oxidants
Tetrapropyl ammonium perruthenate (TRAP) [Ley-Griffith Oxidation]
Mild oxidant for alcohols to carbonyl compounds
Over-oxidizes primary alcohols to carboxylic acids in the presence of water
Can be used in stoichiometric amount or catalytic amount with NMO as co-oxidant
Reagent performs better in the presence of molecular sieves
Pr4N+ RuO4-
Has good tolerance of other functional groups such as alkenes, THP ethers, silyl
ethers, lactones, epoxides etc
Mechanism
 Ruthenium-based Oxidants
Tetrapropyl ammonium perruthenate (TRAP) [Ley-Griffith Oxidation]

Primary alcohols are over-oxidized to carboxylic acids in the

presence of catalytic TRAP and co-oxidant NMO in the presence
of water. Oxidation goes through intermediates A and B.
 Non-metal-based Oxidants
Oxidation by Activated Dimethyl Sulfoxide (DMSO)

-Mild oxidizing agents

-Primary alcohols are oxidized to aldehydes and secondary alcohols to ketones
-No overoxidation
-less toxic to environment than many metal-based oxidants

General mechanism

Development of DMSO-based oxidation process

E+ = SOCl2, Cl2, (COCl)2, TsCl, Ac2O, CF3SO3H etc

 Kornblum Oxidation
• This was discovered in 1959

• A primary tosylate is heated at 150 oC to cause SN2 displacement by the oxygen of dimethyl sulfoxide
(DMSO) in the presence of NaHCO3.

• The reaction was shown to work with alkyl bromides also.

• The reaction time is only few minutes.

Disadvantages: High reaction temperature

 Barton Modification
 Modification was done in 1964 by Barton and co-workers
• Sulfenate salts were generated by treating alkyl chloroformates with DMSO after loss of CO2
• The chloroformates can be prepared by treating alcohols with phosgene.
• The final oxidized product is generated upon the addition of trimethylamine.
• This procedure was an improvement of the harsh conditions of the Kornblum procedure.

Mechanism

-CO2
 Moffatt-Pfitzner Oxidation
 Was discovered by J. Moffatt and his student K. Pfitzner in 1963
 DMSO is activated by DCC in the presence of phosphoric acid to generate the intermediate 2
 Intermediate 2 is again protonated to facilitate addition of the alcohol oxygen on the sulfur atom
 Stable dicyclohexyl urea 4 is formed along with sulfenate salt 3
 Sulfenate salt 3 produces the carbonyl compound in the presence of dihydrogen phosphate anion
 Although H3PO4 and pyridinium trifluoroacetate can catalyze the reaction, H2SO4, HCl or CF3CO2H do not work
 It is critical that the conjugate base of the acid is basic enough to effect the last step of the reaction

Mechanism

J. Am. Chem. Soc. 1963, 85, 3027–3028

 Parikh-Doering Oxidation
 Was discovered in 1967
 This oxidation utilizes the pyridine sulfur trioxide complex as the activator of DMSO
 Alcohols attack the electrophilic S-center with the displacement of SO42- group
 Finally, the sulfenate salt is decomposed in the presence of NEt3 to produce an aldehyde or ketone

Mechanism
 Corey-Kim Oxidation
 Was discovered in 1972 by E. J. Corey and C. U. Kim
 Here Dimethyl sulfide (DMS) is activated by N-chlorosuccinimide to generate the activated sulfenium
species
 The alcohol attacks at the S-center with the removal of succinimidyl group
 Finally, the sulfenate intermediate decomposes in the presence of NEt3 forming aldehyde/ketone as the
oxidizing species.
Limitations
 The reaction needs a carefully
controlled condition and low
temperature (-25 oC) in non-polar
solvents
 Highly reactive alcohols (benzyl/allyl)
generate the corresponding halides
 In polar solvents, thioether product
is also formed

J. Am. Chem. Soc. 1972, 94, 7586–7587

 Swern Oxidation
 The reaction is named after Daniel Swern, American Chemist
 In 1976, early Swern oxidation was reported that employed trifluoroacetic anhydride at -50 oC to activate
DMSO
 The sulfenate intermediate was formed upon the attack of alcohol at S-center with the replacement of
CF3COO- group.
 The ketone/aldehyde is produced in the usual fashion in the presence of triethylamine
 Swern Oxidation
 In 1978, a more convenient Swern oxidation was reported
 Here, DMSO was activated with Oxalyl chloride to generate Chloro(dimethyl)sulfonium chloride
intermediate at low temperature (-78 oC)
 Addition of the primary or secondary alcohol followed by deprotonation of sulfenate salt with
triethylamine leads to the desired aldehyde or ketone, respectively.

J. Org. Chem. 1979, 44, 4148–4150

Swern Oxidation
 2-Iodoxybenzoic Acid (IBX)
 Was first prepared in 1893 by Hartman and Meyer
 Oxidizes primary alcohols to aldehydes and secondary alcohols to ketones
 Has good functional group tolerance
 Insoluble in many organic solvents except polar solvents like DMSO

J. Org. Chem. 2011, 76, 9852-9855

Condition a): IBX, DMSO, THF, 4h

 Dess-Martin Periodinane (DMP)
 DMP is a hypervalent iodine compound developed by Daniel Benjamin Dess and James Cullen Martin
 It is a selective oxidizing agent and works under essentially neutral conditions
 Oxidizes primary alcohols to aldehydes and secondary alcohols to ketones
 Mild reaction condition, high chemoselectivity, no need for a co-oxidant

Preparation
 Treatment of 2-Iodobenzoic acid with Potassium bromate produces 2-Iodoxybenzoic acid, which is then
acetylated with acetic anhydride in the presence of catalytic amount of p-Toluenesulphonic acid
 In a sealed condition, the reagent is stable for very long time, however, tends to undergo hydrolysis in
the presence of moisture

DMP is more soluble than

IBX in organic solvents due
to the presence of acetate
groups 80 oC
IBX Yield: 93% DMP
 Dess-Martin Periodinane (DMP)

Mechanism

CH2Cl2 CH2Cl2
 TEMPO [2,2,6,6-Tetramethylpiperidin-1-oxyl ]
 TEMPO was prepared by Lebedev and Kazarnowskii in 1960 by the oxidation of 2,2,6,6-
tetramethylpiperidine.
 TEMPO is a heterocyclic organic compound bearing a radical oxygen atom.
 This reagent provides mild conditions for oxidations and works in combination with
other co-oxidants (NaOCl, NCS, PIDA [phenyliodine(III) diacetate], KBrO3 etc)
 1o alcohols could be chemoselectively oxidized in the presence of 2o alcohols.

Preparation
 TEMPO [2,2,6,6-Tetramethylpiperidin-1-oxyl ]
Mechanism

N-oxoammonium salt
 Cerium(IV) Ammonium Nitrate [(NH4)2Ce(NO3)6], CAN
• An inorganic cerium (IV) salt of the formula (NH4)2Ce(NO3)6 ; Lanthanide compound
• Commercially available and air-stable compound used as single-electron oxidant in organic chemistry
• Highly soluble in water and some extent in polar organic solvents
• It is mostly used in a catalytic amount in the presence of another co-oxidant

Oxidation of alcohols
1o alcohols (allylic or benzylic) can be oxidized to aldehydes and 2o alcohols to ketones
However, 2o alcohols can be oxidized selectively in the presence of 1o alcohols
 Cerium(IV) Ammonium Nitrate [(NH4)2Ce(NO3)6], CAN
Aerial Oxidation of alcohols using CAN and TEMPO
1o or 2o benzylic alcohols can be oxidized in the presence of a catalytic amount of both CAN and TEMPO in the presence
of O2
Rate of oxidation of 2o alcohols were higher than that of 1o alcohols

Synthesis, 2003, No. 14, pp 2135–2137

 Cerium(IV) Ammonium Nitrate [(NH4)2Ce(NO3)6], CAN

Oxidation of epoxides and aziridines

Synthesis, 2003, No. 14, pp 2135–2137

Tetrahedron Letters, 2005, 46, 4111–4113

 Peracids
• General molecular formula: RCO3H
• Commonly used for the oxidation of various organic compounds
• Some of the common peracids are: peracetic acid (CH3CO3H), perbenzoic acid (PhCO3H), trifluoroacetic
acid (CF3CO3H) and m-chloroperbenzoic acid (m-ClC6H4CO3H, mCPBA)
• Can be prepared in situ by the oxidation of corresponding carboxylic acid with H2O2

Epoxidation
 Epoxides serve as very important precursors in organic synthesis as they can react with a variety of
nucleophiles with the opening of epoxide ring
 A convenient method for the synthesis of epoxides is the direct conversion of alkenes to epoxides using
peracids as oxidizing agent (mCPBA). The carboxylic acid by-product can be removed by washing the
reaction mixture with saturated NaHCO3 solution.

Concerted addition
Stereospecific syn-addition
 Epoxidation
 The epoxidation is stereospecific in nature, leading to the syn-addition of the oxygen atom to alkene.
 For example, cis-alkene gives cis-epoxide; trans-alkene gives trans-epoxide

 The electron rich alkene shows higher reactivity than the electron deficient alkene toward peracids.
 Thus, terminal alkenes exhibit slower reactivity compared alkyl substituted alkenes.
 Whereas, Peracid having electron withdrawing substituent exhibits higher reactivity than that containing
electron donating group. For an example, reactivity order: m-CPBA >> PhCO3H

Relative reactivity order towards a Peracid

Regioselectivity

Electron rich vs electron deficient alkenes Terminal vs internal alkenes

 Henbest Epoxidation
 Epoxidation of allylic alcoholic double bonds gets influenced by the H-bonding interaction with –OH
group.
 Thus the peracid approaches from the same side of alcohol with the stabilization of TS geometry
 Henbest Epoxidation

While –OH group directs the epoxidation

via syn-face with H-bonding interactions,
the –OAc group blocks the approach of
peracid owing to the lack of H-bonding
interaction and additional dipole-dipole
interaction and steric crowding, preferring
the anti-face apporach

Reagents and conditions: (i) PhCO3H, C6H6, 0 °C, 2.5 h; (ii)

PhCO3H, C6H6, 0 °C, 31 h

Org. Biomol. Chem., 2014,12, 4544-4549

 Peracids: Oxidation of Ketones
Baeyer-Villiger oxidation
Adolf von Baeyer (Nobel, 1905, German Scientist); Victor Villiger, Swiss born German Scientist

Acyclic ketones undergo reaction with peracids to give esters and cyclic ketones produce lactones

Important features
-Retention of the stereochemistry of the migrating group
-In the RDS, the migration of the migrating group and departure of the leaving group happens in a concerted
manner
-The migrating group should adopt anti-periplaner origentation to the O-O bond of the leaving group
-Relative migratory aptitude: tert. alkyl > cyclohexyl > sec. alkyl > phenyl > prim. alkyl > CH3 > H
-preference for the migration of aryl groups is p-OMeC6H4 > C6H5 > p-NO2C6H4
Presence of EWG on the peracid enhances the rate of rearrangement
 Baeyer Villiger Oxidation
The proposed mechanism for the acid-catalyzed oxidation of acylic and cyclic ketones are shown below

Mechanism

RDS

RDS
 Baeyer Villiger Oxidation
Acyclic ketones produce Esters
Cyclic ketones produce lactones with ring expansion
1,2-diketones produce anhydrides due to the higher stability of the generated carbocation upon acyl group migration
 Ozonolysis
 Ozone (O3) is triatomic oxygen species with a characteristic smell and pale blue colored gas.
 It is less stable and highly reactive and slightly soluble in water but more soluble in non-polar solvents
such as carbon tetrachloride
 O3 is a powerful oxidant in organic chemistry

Ozonolysis: The alkenes react with ozone and can produce either of aldehydes/ketones or carboxylic
acids depending on the reaction conditions and reagents.
The reaction is generally carried out at lower temperature (-78 °C) in common solvents such as
dichloromethane, methanol and acetone.
 Ozonolysis
Mechanism

molozonide

ozonide

The alkene reacts with ozone via 1,3-dipolar cycloaddition to form the primary ozonide (molozonide), which is
highly unstable and undergoes retro 1,3-dipolar cycloaddition to form the carbonyl compound and a carbonyl
oxide. The carbonyl oxide, which has a dipole undergoes 1,3-dipolar cycloaddition with aldehyde to generate more
stable ozonide. The ozonide can react with oxidizing or reducing agents to produce carboxylic acids or
aldehydes/ketones
 Ozonolysis

 Ozonolysis of alkynes leads to oxidative

cleavage of the triple bond.
 Internal alkynes are oxidized to
carboxylic acids (RCOOH), whereas
terminal alkynes afford carboxylic acids
and CO2.
 Selenium Dioxide (SeO2)
 Selenium dioxide (SeO2) is a colorless crystalline solid.
 It is soluble in solvents like dioxane, ethanol, acetic acid and acetic anhydride.
 Can work in stoichiometric as well as in catalytic amount (with co-oxidant)
Allylic Oxidation
 Oxidation of Carbonyl Compounds (Riley Oxidation)
 The methyl group or any active methylene group adjacent to a carbonyl group reacts with SeO2 and
produces 1,2-dicarbonyl compounds.
 This reaction is called Riley oxidation

Acidic proton
 Sodium Periodate (NaIO4)
 Sodium periodate (NaIO4) is a sodium salt of periodic acid (HIO4)
 It is soluble in water and converts to sodium iodate (NaIO3) on heating
 NaIO4 acts as oxidizing agent and mostly is used as a co-oxidant in oxidation reactions
 The NaIO4 can cleave 1,2-diol to give carbonyl compounds (Similar like Lead tetracetate, LTA)
 Used mostly for water soluble substrates such as sugars

Often used as a co-oxidant for a variety of metal catalyzed

oxidation processes. It oxidizes the reduced metal to its active
oxidation state, thereby reduces the use of stoichiometric
amount of metal salt.
 2,3-Dichloro-5,6-Dicyanobenzoquinone, DDQ
 The reagent is highly reactive and undergoes decomposition in water
 Reactions are generally done in inert condition in organic solvents such as THF, Dioxane, Benzene
etc
 Used for dehydrogenation of hydroaromatic compounds and carbonyl compounds, oxidative
coupling reactions, cyclization reactions etc.
 Decomposition in water leads to the generation of HCN gas having some toxicity issues
Mechanism
Aromatization

Tetralin Naphthalene

Acenaphthene Acenaphthalene
 2,3-Dichloro-5,6-Dicyanobenzoquinone, DDQ
Formation of conjugated double bonds

Original Commentary about DDQ by Derek R. Buckle