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 o • A primary tosylate is heated at 150 C 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 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 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)