sign in sign up
<<
Home , Oppenauer oxidation, Peracetic acid, Swern oxidation

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 -It must be used with precautions in a ventilated fume hood.

Oxidation of -Alcohols are oxidized to or in the presence of pyridine -1,2- 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- 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

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 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 -Inert solvent such as , toluene or dioxane minimizes the side products -The β,γ-double bond generally migrates to α,β-position of the 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 -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, , 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 (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

o • A primary tosylate is heated at 150 C to cause SN2 displacement by the 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 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

2-  Alcohols attack the electrophilic S-center with the displacement of SO4 group

 Finally, the sulfenate salt is decomposed in the presence of NEt3 to produce an or

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

 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 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 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 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 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 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 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 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 .  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

(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- 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