Lecture4: 123.312


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Finishing off the reactions of carboxylic acid derivatives (well the substitution reactions) and introducing oxidation and reduction. Then looking at the oxidation of alkenes (epoxidation and dihydroxylation) and alcohols (the usual suspects).

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Lecture4: 123.312

  1. 1. 123.312FUNCTIONALGROUP previously... INTERCONVERSIONS O functional group we have looked at CHAPTER6 functional group interconversions interconversions... R Cl O O R OH R OH R NH2 CHAPTER six oxidation and O reduction ...& then alcohols, carboxylic acids & their derivatives... E R OR2 1 2 3 ©jspace3@flickr oxidation: PERMITS THE but its formal INTRODUCTION OF FUNCTIONALITY definition is... tion: on Oxidaally, o xidatcitrons form s when ele m a look at oxidation of organic compounds first (& not inorganic compounds like R H oxidation R Y H M M 22+ occur emoved fro e- aremrpound co the rust shown here!) to the organic chemist oxidation is the addition of now turn our attention to oxidation electronegative atoms & reduction 4 5 6 A more useful definition: reduction is the opposite... reduction : PERMITS THE removal OF FUNCTIONALITY Oxygen is gained Hydrogen is lost Y reduction R H R H or electrons lost electronegative element gained removing an electronegative atom/bond... ©David Reeves from Flickr ©smig44 uk@flickr 7 8 9
  2. 2. the formal A more useful definition: oxidation definition is... tion: n Reduc lly, reductio R H Cl R R N O C O formas when a s O O O Oxygen - is lost R OH occur ound gain R1/H R R OH H2N NH2 Hydrogen is gained 2 comprons M2 Cl Cl O Cl Cl e- M R NH2 elect or electrons gained R R R O OR1 Cl Cl R1O OR1 electronegative element R Cl lost R R R NH2 a generalisation... Reduction ©David Reeves from Flickr 10 11 12 a simple method to oxidise electron neutral or rich alkenes is with a peracid Text O O oxidation of O alkenes O R O H R O H peracids are often unstable/explosive 13 14 15 meta-chloroperoxybenzoic acid electrophilic Epoxidation with reaction proceeds with retention (mcpba) peracid of stereochemisrty O R2 O R2 OH RCO3H RCO3H O O O H O R1 R1 O RCO3H O Cl most common reagent normally sold as reaction is concerted R1 R2 (bonds made & broken at same Cl 70% in water (still a white time), which has an important start with a cis alkene R1 R2 powder) get a cis epoxide consequence... 16 17 18
  3. 3. antibacterial: O OH epoxidation in nucleophilic Epoxidation with indolizomycin total synthesis peroxide N OH OH H O O H O O mCPBA O H O N N R R2 NaOH R R2 H 84% H TEOC TEOC O still explosive...still SiMe3 sold in water very different ©http://www.flickr.com/photos/ajc1/534413333/sizes/o/ O mechanism... 19 20 21 nucleophilic Epoxidation with ...reaction is stepwise so... chemoselectivity peroxide H O O O O H O O O H O O R R2 O H O R R2 R R2 NaOH R R2 free rotation in this intermediate means there is no A reaction that you control of stereochemistry (trans predominates) O hydrogen peroxide only peracid reverses this have/will do in the 312 lab. it is O reacts with activated selectivity (only reacts very different to the previous (electron poor) alkenes with electron rich alkenes) epoxidation R R2 very different ...no control of mechanism... stereochemistry ©gillonde@Flickr 22 23 24 epoxides are useful intermediates OH O Nuc R examples R Nuc what is all the fuss about ring strain makes epoxides? normally get good epoxides very reactive stereo- & regio-control on addition of a ©ultrabobban@Flickr nucleophile 25 26 27
  4. 4. reaction with reducing agents... madagascar periwinkle use of epoxides in total synthesis OH NsHN O Ns O LiAlH4 N OH Et Et K2CO3 N OH Et 82% N R R H N H N Boc MeO2C Boc MeO2C N TBDPSO OTBDPS H H MeO2C Et OAc formation of an alcohol MeO large (& medium) rings are normally hard with control (retention) of H NOH to form due to both entropic & enthalpic stereochemistry Me CO2Me factors vinblastine ©TusharKumar@Flickr 28 29 30 use of epoxides in total synthesis dihydroxylation of alkenes concerted reaction... O O O O Os Os i. OsO4 ii. NaOH / H2O HO OH NsHN Ns O O O O O Et K2CO3 N R R OH NaOH R R N 82% N Et H2O i. OsO4 Boc Boc R ii. NaOH / H2O HO OH MeO2C MeO2C OTBDPS two oxygen atoms can be TBDPSO added to an alkene OH R R R ...as a results we note retention of observe retention of stereochemistry at oxygen stereochemistry start with a cis alkene centre OH get a cis epoxide 31 32 33 3 how many compounds? OH OH OH OH OH OH osmium tetroxide is vile! volatile & toxic at levels below that which can be smelt. it also stains the cornea OH OH ©cayusa@Flickr not four 34 35 36
  5. 5. OH OH OH OH OH OH ! ! ! OH OH OH OH OH OH meso meso these two are identical due to a plane of symmetry enantiomers 37 38 39 4 how many compounds? OH OH OH OH OH OH broken the OH OH symmetry ©arkadyevna@Flickr 40 41 42 how would you make the two the cis compound is easy... trans isomer... different diastereoisomers? O OH OH O O OH O Os O OH O O OH OH OH Cl simple...just takes more than just worried about the one step ... relative stereochemistry dihydroxylation but what about epoxidation first the other then... diastereoisomer? 43 44 45
  6. 6. Ring open epoxide we can fully oxidise an alkene by breaking the double bond OH KOH OH ! O OH how would we form OH just one enantiomer? ©wonderferret@Flickr ©e-magic@Flickr 46 47 48 ozonolysis: reductive work-up other reagents can also achieve mechanism can be this transformation a little daunting! O3 then Me2S or Ph3P CHO CHO ozonolysis: oxidative work-up O3 then H2O2 / HCO2H CO2H CO2H ©clappstar@Flickr ©Jasoon@Flickr 49 50 51 mechanism... mechanism... mechanism... O O this then O O O O O O fragments O O O O before... O O O O O O cyclisation to give a compound called an first step is a ozonide cycloaddition O O O O O O O O O O O O O O O O O O 52 53 54
  7. 7. Reductive work-up: oxidative work-up: oxidative work-up: H2O2 O H+ O O O OH O O H O O O H O H O O O H O O OH O OH H O H O O O mechanism isn’t so O O S clear...I’m ok up to the H H O S aldehyde then made it up ... O H H H O O O OH H O H O O H O O repeat O H O O O CO2H CO2H OH the ozonide is then OH OH oxidation could occur via a broken down on hydride shift or it could work-up be radical 55 56 57 Care must be taken in the Chromium-based oxidation oxidation of alcohols... reagents: Jones reagent always goes to carboxylic acid H H [O] H [O] OH CrO3, H H H2SO4 OH R OH R O R O oxidation of R OH R O R H [O] R alcohols often hard to stop oxidation at aldehyde CrO3, R OH R O stage R H H2SO4 R R R X [O] R OH R O probably should have a bottle of can oxidise tertiary alcohols vinegar here... R OH but it requires C-C bonds to be broken harsh, acidic conditions limit its use 58 59 60 Chromium-based oxidation Cl Chromium-based O O reagents: Pyridinium oxidation reagents: Cr O Cr O Cr O chlorochromate O O N Pyridinium N O H Dichromate O O H 2 H H PCC H H H PDC PDC R OH NO H2O R O DCM R OH DMF H OH R H PCC R R O R O R OH R O many chromium reagents are less acidic (but still acidic!) carcinogens mild & interesting selectivity 61 62 63
  8. 8. Mechanism of chromium oxidations fragmentation common to most oxidations O O H H O H H O O OH Cr H O H H O O Cr OH Cr Cr O O R O H O R OH O O OH R H R OH R H OH H Y general mechanism for all these reagents O H Mechanism for aldehyde O remember, if X HO Cr OH R O oxidation (normally needs water) R OH R something is oxidised something is reduced O ©nesster@Flickr 64 65 66 the Swern oxidation the Swern oxidation Text dmso is methyl sulfoxide DMSO, H H (COCl)2, Et3N H R OH R O one example of a class of mild & selective oxidations... never goes to the acid ©natashalcd@Flickr ©rantz@Flickr 67 68 69 complex mechanism mechanism of the swern oxidation: mechanism of the swern oxidation: O O H H H Cl H H :NEt3 S O H H Cl H H S Cl S S O O R O R O O O Cl S CO2 H CO S H H Cl R O only two problems: the H H R OH Cl smell of dimethylsulfide & S S the potential racemisation R O of alpha stereocentres 70 71 72
  9. 9. fragmentation common Activated DMSO reactions... you do not need to to many oxidations Text remember names just Swern the general principle O O Cl Et3N S Cl H H O H H O Pfitzner–Moffatt Cr O H H R O S O N OH S C TFA / pyridine R O N organic chemistry is just a few basic parikh-doering concepts repeated over & over. It’s what you O N O can do with those concepts that is so S Et3N fascinating S O O ©Graham Johnson, Graham Johnson Medical Media, Boulder, Colorado 73 74 75 Aldehydes readily oxidised to acids: Jones reagent CrO3, oxidation of H H2SO4 OH aldehydes & ketones R O R O already seen this reaction during the many reagents oxidation of alcohols can promote this ©nezume you@Flickr tranformation 76 77 78 The baeyer-villiger oxidation mechanism mechanism O O O O H a 1,2-shift then occurs to H HO O O O O O R R O O insert an oxygen HO O C-C R R O into a O RCO3H RCO3H O RCO3H bond O HO HO R2 R R2 R O first the ketone is O activated by protonation & O then undergoes nucleophilic addition of the peracid RCO3H H H O O O O O O O O O ketones can also be oxidised but this involves breaking C-C bonds 79 80 81
  10. 10. the more substituted side migrates the more substituted side migrates X O O R R Ph Ph O O O O O !– O O O O RCO3H !+ RCO3H Ph HO O HO O O Ph !+ Ph O Ph O there is a build up of methyl group least stable O positive charge (2e shared +ve so benzylic group O question over 3 atoms) so the group that can migrates stabilise a positive charge note: retention of which product is stereochemistry ©carbonnyc@Flickr formed? migrates 82 83 84 what would happen in what would happen in what would happen in the following the following the following reaction? reaction? reaction? ? ? ? O O O RCO3H RCO3H RCO3H under acidic conditions carbonyl protonated & get question of baeyer-villiger otherwise chemoselectivity epoxidation 85 86 87 madagascar periwinkle the baeyer-Villiger N OH Et oxidation in total H synthesis N H N H Et MeO2C OAc MeO N OH H Me CO2Me OH O O Et N Et O Et mCPBA, H AcOH N H N H OH OH MeO2C Et OAc MeO N H OH OTBDPS note: retention of OTBDPS Me CO2Me stereochemistry vinblastine ©TusharKumar@Flickr 88 89