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OXIDATION AND REDUCTION O Cl R R" R R' R" O R O R' R E OH R R"' R' O O R' R R' O R R R' OH R R" R" R R' Nuc R OR" N R' Introduction • Fundamental backbone of organic chemistry is the ability to alter oxidation states • Hydroxyl and carbonyl moiety provide an invaluable means for transforming molecules so the ability to introduce and remove them very important Course Outline Oxidations • alcohol to carbonyl • alkene epoxidation and dihydroxylation • C–H oxidation • miscellaneous Reductions • carbonyl group • hydrogenation • electron transfer • This is not an all inclusive lecture course • To list every reagent would be boring, so I have tried to be selective with the criteria being those that are more common, useful or interesting, but this is just my opinion • As this is a new course, if you feel I have missed out any important examples (or too much detail on others) please tell me: [email protected] Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 1 ALCOHOL OXIDATION • Alcohols can readily be oxidised to the carbonyl moiety • This is an incredibly important reaction - you should realise that the carbonyl group is one of the cornerstones of C–C bond formation (organometallics, neutral nucleophiles, aldol, Julia, Peterson & Wittig reactions) R1 = H OH O R1 R O R1 R R OH • Primary (R1 = H) alcohols – normally more reactive than seconary alcohols on steric grounds • Need to be able to control oxidation of primary alcohols so only obtain aldehyde or acid • Large number of reagents – all have their advantages and disadvantages • Look at some of the more common... General Fragmentation Mechanism EH H E [O] HO E [O] R H O [R] R R O • This fragmentation mechanism is common to most oxidations regardless of the nature of the reagent Chromium (VI) Oxidants General Mechanism Cr(VI) OH2 O Cr O O O H Cr proton transfer H O –H2O O HO Cr(IV) O O HO R Cr O H Cr HO O OH R R O "Overoxidation" formation of carboxylic acids • Invariably achieved in the prescence of H2O and proceeds via the hydrate O O R OH H2O R H O O Cr O H OH R O Cr OH O O R H OH OH Jones Oxidation H2SO 4, CrO3, acetone OH R O H R OH OH R O R1 R R1 • Harsh, acidic conditions limit use of this method Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 2 Pyridinium Chlorochromate (PCC) Cl must avoid water O OH R Cr O O N H O H R OH H O R1 R R1 R • Less acidic than Jones reagent (although still acidic) Pyridinium Dichromate (PDC) O O O Cr O Cr O O O N H 2 • Even milder than PCC and has useful selectivity O R PDC DCM H OH R H PDC DMF O R OH Other Oxidants Manganese Dioxide MnO2 • Mild reagent • Very selective – only oxidises allylic, benzylic or propargylic alcohols HO HO MnO2 only oxidises activated alcohol O OH Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 3 ALCOHOL OXIDATION Activated DMSO Reagent: DMSO, activator (X) and base Transformation: C–OH → C=O (primary or secondary alcohols) General Mechanism H H X S O + X S + O HO R R O S H base • intermediate common to all activated DMSO reactions • 18O labelling has determined mechanism • alternative activation of hydroxyl followed by displacement not occurring O S H H + R H R O O S S Common Side-Reactions Pummerer Reaction R O S R + O R S Displacement Reactions • The cationic intermediate formed is an excellent leaving group Intramolecular OH CH2 OH CH2 OH DMSO / (COCl)2 93% H O O S H H Intermolecular CH2 OH CH2 Cl OBn DMSO / (COCl)2 95% OBn Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 4 Enolisation • Generation of a carbonyl compound in the presence of an amine base is asking for trouble • α-chiral centre can be racemised • Overcome by: keeping temperature low, remove base with cold acid buffer, use Pyr.SO3 system Eliminations • Problem due to mild acidity of earlier steps • or if suitable leaving group present when base added HO OH 1. DMSO / (COCl)2 2. Et3N 72% OMe O OMe O O OMe O O 1. DMSO / (COCl)2 2. Et3N OP TBSO O OH SO2 Ph O + OP OP O TBSO TBSO 67 % O SO2 Ph 28% Activators Pfitzner-Moffatt (DMSO / DCC then base) N C N • The original Pros: mild conditions, normally rt Cons: DCC urea by-product hard to remove frequently generates Pummerer side-product mildly acidic conditions lead to eliminations OH O O O OH DMSO / DCC TFA / Pyr 88 % O O Swern (DMSO / (COCl)2) Cl • active intermediate of Swern reaction S • Most popular, as mild and easy Pros: low temperature reduces enolisation very little Pummerer reaction Cons: Chlorination Parikh-Doering (DMSO / Pyr–SO3) Pros: very mild conditions, very little enolisation very little Pummerer Reaction O TBSO Ph O TBSO O DMSO / Pyr–SO3 Et3N 94% CH2 OH TBSO Ph O TBSO CHO Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 5 Activated DMSO Oxidations in Synthesis 1. DMSO / (COCl)2 2. Et3N 92 % O HO O O O O OTIPS OTIPS • 1,2-diols are not cleaved 1. DMSO / (CF3CO)2O 2. Et3N 90 % HO HO O O • sequential reactions possible due to the high yields and purity of products especially useful when aldehyde readily forms hydrate Me3 Si Me3 Si 1. DMSO / (COCl)2 2. Et3N OH O Ph3P=CMeCO 2Et 54% overall H Me3 Si CO2Et • tertiary alcohols often do not need to be protected OMe H OMe OH OH OH OMe OMe H 1. DMSO / (COCl)2 2. Et3N 81% OMe OMe O O OH • selective oxidations – primary alcohols oxidised much faster • but use of iPr2S and NCS as activator (proceeds via same intermediate as Swern) oxidises primary alcohols at 0˚C but secondary at -78˚C • do not understand this reaction AND it was only a communication 84CC762 that has never been followed up • oxidation in the presence of allylic or benzylic alcohols O O O O S O OH OH MeO H N Me O DMSO / (CF3CO)2O O MeO N Me H O OCOCF3 OCOCF3 O S S MeO H N Me Et3N O • the activity of allylic and benzylic alcohols means they undergo rapid displacement and hence a form of protection O O (±)-tazettine 61 % OH MeO N H Me Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 6 • lactol or lactone formation can be surpressed • most oxidising agents oxidise primary alcohols faster than secondary and this can lead to problems OH OH OH [O] OH O O [O] O O • activated DMSO does not have this problem as aldehyde only formed on addition of base OH OH DMSO / (COCl)2 O S O O Et3N S O • selective oxidation of primary silyl ethers • Mildly acidic nature and the nucleophilic chloride ion generated allows selective deprotection and concomitant oxidation of primary TES & TMS ethers O O 1. DMSO / (COCl)2 2. Et3N 62 % O OTES OTES O O OTES Limitations • activated DMSO systems will not oxidise propargylic alcohols OH OH What have we learnt? • Activated DMSO reactions are generally mild • Offer many advantages of metallic reagents • Drawbacks include a number of possible side-reactions • Will not oxidise propargylic alcohols Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 7 Dess-Martin Periodinane (DMP) (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one) Reagent: OAc I OAc AcO O O Transformation: C–OH → C=O (primary or secondary alcohols) General mechanism • ligand exchange OH OAc AcO I OAc R O H R H OAc • could be intra or intermolecular H I O O AcO O H I O O O O R O H O 2 x AcOH • since introduction in 1983 become one of the most popular oxidants • mild reagent operating at nearly neutral conditions (buffer with NaHCO3 if worried about AcOH) • many very sensitive molecules can be oxidised H O H DEIPSO OTES O O O H TESO H TBSO O tBu tBu O MeO O O Si O 93 % OTES OTES H Preparation O I + KBrO3 CO2H I 0.73 M H2SO4 65˚C AcO OH O O AcOH OAc I OAc O O • mild and extremely reactive oxidant • Insoluble in most organic solvents and impact sensitive Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 8 Use in Synthesis Selectivity • first step is ligand exchange so an inherent steric selectivity exists • primary alcohols oxidised faster than secondary OTBS HO O HO DMP, pyr, DCM, 88% O TBSO OTBS OMe OTBS OTBS HO O O O TBSO OTBS OMe OTBS • Allylic and benzylic alcohols react ≥~5 faster than saturated alcohols O O O O H H DMP, pyr, DCM, rt 2hrs >75% HO HO OH O Advantages: • no over oxidation is ever observed • no enolisation • no oxidation of heteroatoms (eg N or S) Disadvantages: • Behaves like periodate and cleaves 1,2-diols. BUT not always, no consistancy What have we learnt? • DMP is a mild reagent • selective oxidations are possible • 1,2-diols behave unpredictably Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 9 Tetrapropylammonium Perruthenate TPAP Reagent: Pr4N+RuO4– Stoichiometric or catalytic with NMO Transformation: C–OH → C=O (primary or secondary alcohols) C–OH → CO2H (if H2O present) General mechanism • not entirely clear • it is thought that TPAP is a 3e – oxidant but each step is a 2e– process and that radicals / S.E.T. is not involved • due to steric selectivity it is thought that TPAP is a bulky reagent & oxidation occurs primarily through the intermediacy of a ruthenate ester OH R O HO O O Ru O O H H O R O Ru O O O Ru O O O O H H2O R H O Ru O OH2 H H O N O O O Ru O O N O Ru O O O N O Use in Synthesis • Introduced in 1987 • its mildness and practically have made it popular (coupled to its none explosive nature) • should be used dry with 4Åms or get over-oxidation and cleavage of alkenes • mechanism changes in presence of H2O advantages: • good functional group tolerance • no epimerisation of α-chiral centres or double bond isomerisation • no competative β-elimination OPMB O O O OPMB TPAP / NMO, DCM, 4Åms 96% O O OH O O O O O O Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 10 • selectivity for primary hydroxyl group allows lactone preparation OH O TPAP / NMO, DCM / MeCN, 4Åms 91% OH O TPAP OH O O O O • secondary alcohols oxidise far slower but they do oxidise TPAP / NMO, DCM, 4Åms, 73% N OH O N O O Swern Oxidation = 0% PCC = 0% TMS TMS • depending on sterics can get selectivity for least hindered hydroxyl group HO O HO O O H TPAP / NMO, DCM, 4Åms 61% O OH O O H O OH O O O OH O • lactols can be oxidised selectively (again sterics) O O CO2Me OHO O O O O O AcO MeO 2C H CO2Me OHO OH O OH OH TPAP / NMO, MeCN, 4Åms 75% AcO MeO 2C O O H O OH OH O • TPAP oxidises sulfur but not other heteroatoms • again we see how mild TPAP is SMe O SO2 Me TPAP / NMO, MeCN, 4Åms 80% O O O Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 11 O • Sequential reactions – due to ease of w/u and anhydrous conditions, TPAP is well suited to sequential reactions CO2Me CO2Me TPAP / NMO, DCM, 4Åms OH CO2Me Ph3P=CMeCO2tBu O CO2tBu 72% overall • Disadvantages: TPAP can cleave 1,2-diols like other metal oxidants O O HO OH O O O TPAP, NaOCl 93% O O • Disadvantages: can cause retro-aldol reaction OH O O H O O TPAP / NMO, DCM, 4Åms O O O O O H • retro-aldol results in cleavage of β-hydroxyketones What have we learnt? • TPAP is a mild oxidant • Its bulk allows selective reactions • It can be used in catalytic quantities Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 12 Modified Chromium (VI) Oxidants Pyridinium Chlorochromate PCC Reagent: ClCrO3 NH Transformation: C–OH → C=O (primary or secondary alcohols) General Mechanism H R O O O H H O Cr Cl O O R OH Cr O O R H O H HO Cr ≡ CrO2 + H 2O OH H Use in Synthesis • Must be dry, water hampers reaction and can result in the formation of acids (over-oxidation) OH OH PCC, 4Åms, DCM 93% OH H O H • Disadvantages: reagent is acidic Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 13 Pyridinium Dichromate PDC Reagent: NH Cr2O7 2– Transformation: C–OH → C=O (primary or secondary alcohols) Use in Synthesis • Neutral variant of PCC • Addition of SiO 2 to reaction aids work up and addition of pyridinium trifluroracetate increases rate • DCM normal solvent • DMF gives carboxylic acids OH O PDC, DCM 92% O O PDC, DMF 83% OH CO2Me Oxidation to the Acid O R O H R OH • Many variants involving chromium or manganate which proceed via the hydrated aldehyde • But invariably require strongly acidic conditions so not useful in organic synthesis • You can find them yourselves in March or Smith • A mild alternative is: NaClO2, NaH2PO4 O R H OH HO ClO2 R H R O Cl O HOCl O H R OH • HOCl is very unpleasnt so alkene added as a scavenger What have we learnt? • Chromium reagents can be used to oxidise to either aldehyde or carboxylic acid • They are toxic Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 14 Kinetic Resolution by Selective Oxidation • Noyori has developed a method for resolving racemic alcohols via selective oxidation • Uses hydrogen transfer (analgous to Oppenauer oxidation or Meerwein-Ponndorf-Verley reduction) OH OH + Un + R Un O + R Ph OH + R Un R Un = unsaturated group Yield = 43-51 % e.e. = > 90 % OH + Un Ts N Ru N H Ph O R • note you can not get better than 50% with kinetic resolution Mechanism Un Un O R H H R Ru N O NTs H Ru H Un NTs N H Ph Ph O R Ph H Ru H N NTs H Ph Ph Ph O OH O Un O H Ru H H Ru NTs N R O H N NTs H H Ph Ph Ph Ph • More appealing is the desymmetrisation of meso-diols • Theoretical maximum yield is 100 % OH OH H H 70 % 96 % e.e. OH H O H What have we learnt? • Stereoselective oxidations are now possible • Hydrogen transfer allows preparation of enantiopure compounds from racemates • As both reductant and oxidant are organic this type of reaction will be appearing again Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002 15