Lecture4: 123.312
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The document discusses the oxidation and reduction processes within organic chemistry, detailing functional group interconversions, particularly focusing on alkenes and their transformations through oxidation techniques using peracids and chromium-based reagents. It emphasizes the significance of epoxides as intermediates in synthesis and highlights the mechanisms involved in various oxidation reactions, including the Swern oxidation and the Baeyer-Villiger oxidation. Various reagents, their selectivity, and the implications of stereochemistry during these processes are explored.
![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](https://image.slidesharecdn.com/lecture4-090507231640-phpapp01/85/Lecture4-123-312-7-320.jpg)
Lecture4: 123.312
- 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. 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. 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. 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. 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. 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. 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. 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. 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. 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