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.

Mechanism

The reaction likely to proceed via

radical pathway.

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)

Mechanism

Proceeds via six-membered cyclic transition

state

Acetone acts as oxidizing agent and gets

reduced to isopropyl alcohol

Synthesis of

Analgesic and

Hormones

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

Has good tolerance of other functional groups such as alkenes, THP ethers, silyl

ethers, lactones, epoxides etcMechanism

Pr4N+ RuO4

-

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

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

Development of DMSO-based oxidation process

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

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

Preparation

80 oC

IBX DMPYield: 93%

DMP is more soluble than

IBX in organic solvents due

to the presence of acetate

groups

Mechanism

Dess-Martin Periodinane (DMP)

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 alcohols1o 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 TEMPO1o or 2o benzylic alcohols can be oxidized in the presence of a catalytic amount of both CAN and TEMPO in the presence

of O2Rate 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

Synthesis, 2003, No. 14, pp 2135–2137

Tetrahedron Letters, 2005, 46, 4111–4113

Oxidation of epoxides and aziridines

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

Electron rich vs electron deficient alkenes Terminal vs internal alkenes

Regioselectivity

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

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

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

Peracids: Oxidation of Ketones

Baeyer-Villiger oxidation

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

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

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

Aromatization

Tetralin Naphthalene

Acenaphthene Acenaphthalene

Mechanism

2,3-Dichloro-5,6-Dicyanobenzoquinone, DDQ

Formation of conjugated double bonds

Original Commentary about DDQ by Derek R. Buckle