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OC II (FS 2013) Lecture 1 Prof. Bode Oxidation 1 Oxidation State Of OC II (FS 2013) Lecture 1 Prof. Bode Oxidation 1 Oxidation state of carbon Oxidation is a process in which a chemical species loses electron. Reduction is a process in which a chemical species gains electron. HO H H3C H3C OH H2C O C O O C O H methane methanol formaldehyde carbon dioxide formic acid most reduced most oxidized Other functional groups with equivalent oxidation state O R R N C O R R' C N R isocyanate alkene alkyne H amide R O C N R SH OR' R N cyanate thiol R OR' acetal nitrile R N C N R R X OR' carbodiimide O R OR' X = halide, R S C S OH, or OR OR' epoxide orthoester carbon disulfide 2 Functional group interconversion Key to organic synthesis is the interconversion of functional groups. Oxidation and reduction allow for the change up and down the oxidantion ladder. Part of organic chemistry is learning how to master the manipulation of oxidation state and knowing the appropriate reagent for the desired transformation. For example: H oxidant A OH oxidant B oxidant C O OH O oxidant D 3 Oxidizing agents Oxidizing agents increases the oxidation state of the substrate but itself undergoes a reduction. The net process is called a redox reaction. There are many oxidants available in the “tool box.” Here we are categorizing them based on their mode of action (mechanism). Some class of oxidizing agents: [Metal] O "X-Y" organic oxidant DDQ: TEMPO: MnO2 IBX: DMDO: Me2S Cl Br2 PCC: O O RuO4 O N NaClO I2 OH N Me Me 2 I O Me Cl N O H Me Me KMnO4 O O Me O Cr Cl HO OH Cl2 CrO Cl O 3 N O O 1 OC II (FS 2013) Lecture 1 Prof. Bode 3.1 Oxidation of alcohol to carbonyl compounds 3.1.1 TEMPO oxidation O Me Me N Me Me H HO O O O OMe (catalytic) OMe HO HO Me NaOCl [O] Me base Mechanism Me Me N Me Me O oxidation NaOCl Me Me Me Me N oxidation Me N Me Me Me OH O Me Me O R OH base N O R H base-H Me Me H 3.1.2 Swern oxidation and other variants Swern oxidation: (COCl)2 DMSO Me Me Et3N Ph OH Ph O CH2Cl2 -78oC Mechanism: O O O Me O Cl Cl- S S Cl S Cl Me Me Me Me Me O O O less acidic base-H+ base Me H H Me H H Me H H S S S R O CH2 R O Me R OH Me Cl CO2 + CO H H more acidic base H H CH CH H 2 H H 2 S S S Me Me R O Me R O Me R O ene-like Other varients Moffatt oxidation: DCC acitivation DCC H H DMSO H Me N OH N N cat. H+ O S O C N Me Et Et 2 OC II (FS 2013) Lecture 1 Prof. Bode Corey-Kim oxidation: NCS acitivation O Ph NCS Ph Me Me Me S 2 S Cl N S Me OH Me O Me Me Cl O 3.1.3 TPAP oxidation Pr4N RuO4 (TPAP, 5 mol%) O N O (NMO, 1.5 eq.) Me Et OH Et O O CH2Cl2, 4Å MS O Mechanism Et OH Et O O O O O Ru O O O H O O O H Ru Ru Et O OH Et O O O O O O O OH Ru O H O catalyst O O Ru O reoxidation O Ru H2O O O O N Me O N O Me Other metal oxides oxidation (i.e. Cr or Mn) have similar mechanism. A special feature of MnO2 oxidation is a mild and selective oxidation of unsaturated system. H Cl 20 equiv. MnO2 Cl OH CH2Cl2 O Cl room temp Cl 3.1.4 Dess-Martin and IBX oxidation O IBX: OH Dess-Martin AcO OAc I (DMP): I OAc O O O O OBn OBn Me Me O DMP O Et Et OH O H 3 OC II (FS 2013) Lecture 1 Prof. Bode Mechanism: OH AcO OAc I OAc H H AcO H R O R O R OAc O I I O OAc H H O O O O 3+ I5+ I OAC 3.2 Oxidation of aldehyde (or equivalent) to carboxylic acid derivative 3.2.1 Pinnick oxidation also sometime known as Lindgren oxidation O O OH NaClO2 NaH2PO4 tBuOH/H2O OMe HClO or 2-Me-Butene OMe (as scavenger) OH OH Mechanism ClO2 + H2PO4 2 ClO2 + Cl + OH 2 ClO2 O R H O R H O R Cl H O Cl H Cl HClO R H O O O O O HO O H 3.2.2 Oxidation by N-heterocyclic carbene (NHC) S N Bn O O (5 mol %) + MeOH Common oxidant: Ph H 1.0 equiv [O] Ph OMe Et3N (7.5 mol %) MnO + MeOH 2 S N Bn tBu tBu O OH O O O H+ transfer [O] S S S Ph Ph Ph H SET? tBu tBu N N N Bn Bn Bn Breslow intermediate activated carboxylate 3.2.3 Oxidative amidation This reaction is mechanistically similar to other metal oxides with the Ru cat performing two oxidations: first on the alcohol to aldehyde and second on the hemiaminal to the amide. It is a nice example of catalytic amidation reaction – a problem with few satisfactory results (See Milstein Science 2007, 317, 790). tBu N P tBu Ru H N OH CO O Et Et R2 NH2 R2 R R1 N 1 1 mol% H reflux-tol O O O Bn 96% Ph 58% 99% C H N C H N N 6 13 5 11 H H H OMe 4 OC II (FS 2013) Lecture 1 Prof. Bode Mechanism tBu tBu tBu tBu N P N P - H2 N P N P O tBu Ru tBu Ru H Ru tBu Ru tBu Et H Et H Et H R2 OC N OC H R NH N OH OC R1 N N O 2 2 CO N O H Et Et H Et Et O Et R1 R1 NHR2 R1 R1 NHR2 hemiaminal 3.2.4 Formal oxidation of aldehyde to nitrile This is technically an elimination reaction with the net outcome of oxidation of C=O to CΞN bond OH O N O N Cl S OH NH2OH O elimination oxime nitrile 3.3 C-H oxidation 3.3.1 Radical halogenation mechanism: H Cl Cl2 H Cl Cl hv - HCl Cl 3.3.2 Dehydrogenation: alkane to alkene Pt Δ 3.3.3 Allylic C-H oxidation OH SeO2, H2O2 Me Me tBuOH, H2O Hartshorn and Masamune Org. Synth., 1988, 6 , 946. Me 40 - 50oC Me β-pinene trans-pinocarveol Mechanism O Se O H O O H hydrolysis Se H Se O O OH R R' R R' R R' R R' 3.3.4 Benzylic C-H oxidation Many strong oxidants such as KMnO4, IBX or H2O2 may be used for benzylic oxidation O KMnO4 / MnO2 Shaabania Tetrahedron, 2004, 60, 11415 O OH I O O Me Me Nicolaou JACS 2002, 124, 2245 DMSO O 5 OC II (FS 2013) Lecture 1 Prof. Bode 3.4 Alkene oxidation 3.4.1 Epoxidation by mCPBA - This reaction is stereospecific Me Me Me Me m-CPBA 24 h dr > 9:1 O Stereochemistry: Cl Preferred reactive conformation 120° OH Me O O m-CPBA H Me O H H H O O Me OH Me H Me OH R Me R dr = 95:5 R A1,3-strain minimized 3.4.2 Dihydroxylation - This reaction is also stereospecific Me 1 mol% OsO4 HO OH Me NMO, H2O Me Me mechanism R R R O R OOs O O O O OH R R Os O O HO OH 2 OH− O O 2 OH− HO OH 2- HO O 2- 2 H2O Os Os HO OH HO O O O NMO NMM 3.4.3 Wacker oxidation - This reaction generally follows Markovnikov selectivity 10% Pd(OAc)2 CuCl O R H O, O R R 2 2 R + O Cu + O2 Pd0 HX R PdX2 R R R β-hydride elim. then tautomerization R R R PdX2 H2O R OH PdX Markov- H O H nikov PdX H 3.4.4 Ozonolysis 6 OC II (FS 2013) Lecture 1 Prof. Bode 1) O Ph Ph 3 Ph Ph CH2Cl2 O O Me 2) PPh3 Me H or Me2S mechanism Ph O H H O O O O O H O HO Ph O O O O O Ph reduced = O Ph O O Me O O O Ph Ph Ph Me H Me H Me Me O Ph Ph Ph Ph Ph Me Ph Ph Me H secondary ozonide primary ozonide 3.5 Baeyer-Villiger oxidation This reaction is stereoretentive O O O HO O O Me steps Me Me HO O Me HO O O H H mCPBA O Ph O HO O HO Me O Me O Me H Ph N O Me H H OH O Me O OH O O Taxol Ph mechanism RS O O H O Ar O RS O Ar OH RL O O RL R R Ar O H L S O O O RL migrates R larger than R L S faster than RS 4 Heteroatom oxidation 4.1 Borane oxidation (in hydroboration sequence) MOMO MOMO MOMO 9-BBN H2O2 NaOH Me N Me N BR2 Me N OH Boc Boc Boc mechanism R R RO H O O OH BR2 RO OR 2 BR BR B ROH + B(OH)3 2 O 2 OH OR 4.2 Fleming-Tamao oxidation Me 1) BF3-AcOH Si HO Me N 2) H2O2, N O NaHCO3 O Ph Ph mechanism O R R Me Me O Si O Me Me O Ar O Me E-X X Si Me base Si O ROH Me R Si O O Me R O Ar Ar 5 Other functional groups and their oxidation state 7 OC II (FS 2013) Lecture 1 Prof.
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