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Transcript
OXIDATION 1 OXIDATION The term oxidation can be defined in different ways: Addition of oxygen to a molecule Removal of hydrogen molecule from a given molecule Loss of electrons Addition of Oxygen i.e. [O] C C C C O An alkene An epoxide or oxirane Removal of Hydrogen from a Molecule OH C C O -H2 H CH C R R Removal of Electron or Loss of Electrons O O . -e Phenoxide anion o Zn Phenoxide radical 2 Zn 2 Calculating Oxidation State of a Particular Carbon Here a question arises how we calculate the oxidation of a carbon bonded with other atoms? For calculating the oxidation state of carbon, we have to consider following two key things. 1 2 Carbon is often more electronegative (2.5) than some of the other atom which it bonds such as hydrogen has electronegativity 2.2. So in this case what we have to do? Unlike metal-metal bond, carbon bonds are found all over the organic chemistry then how can we calculate the oxidation state. There is a simple rule for knowing the oxidation states of an atom in a molecule or over all oxidation state of a reaction. If the number of H atoms bonded to a C decreases, and/or if the number of bonds to more electronegative atoms increases, the Carbon in question will be oxidized (i.e. it will be in a higher oxidation state). How we assign the oxidation state of carbon? 1. Examine the groups attached to a carbon atom. 2. Give the carbon a -1 oxidation number if the each atom attached to less electronegative atom than the carbon in question? 3. Give the carbon a +1 oxidation number if to carbon is attached to more electronegative atom than the carbon in question? 4. Give 0 to each other carbon atom attached to the particular carbon. 5. Give 0 to undefined (R) group attached to particular carbon atom. 6. = Double bond will stand for two single bonds 3 7. ≡ Triple bond will stand for three single bonds 8. Each carbon in a molecule can be labeled with its oxidation state and sum of these oxidation states in a molecule may be compared to the sum in any reaction weather oxidation state increased or decreased. 9. Addition of a species containing XY to a double will not change the overall oxidation state of reaction (sum of the individual carbon states will be remain same). Such as: HBr, HOH, HNO2, HCl, etc 10. Addition of a species Y-Y’ will definitely change the oxidation state of the reaction. Therefore, addition of Y-Y’ (eg. Br-Br) to a double bond is an Oxidation, however, elimination of Y-Y’ from a single bond is reduction. Now let us examine the molecules containing a single carbon Overall oxidation number is -4 4 Why oxidation state is -4? Because carbon is attached with four hydrogen atoms which are less electronegative than carbon Overall oxidation number is -2 Why it is -2? Because oxygen replaced one hydrogen atom and more electronegative than carbon. Overall oxidation number is 0 Why oxidation state is 0? Because two oxygen replaced two hydrogen atoms and oxygen is more electronegative than carbon. Overall oxidation number is +2 Why oxidation state is +2? It is due to the fact that three oxygen replaced three hydrogen atoms 5 Overall oxidation number is +4 Why oxidation state is +4? Because four oxygens replaced four hydrogen atoms Overall oxidation number is +4 Why oxidation state is +4? Because four oxygen atoms replaced four hydrogen atoms Consider molecules with more than one carbon 6 Oxidation number of C = 0 -1 H -1 H H +1 -1 O -1 -1 H C C C C H OH H +1 O +1 C C C +1 -1 +1 H2O H -1 -1H -H2O -1 H -1 H 6 X (-1) = -6 2 X (+1) = +2 TOTAL = -4 C H -1 H H -1 7 X (-1) = -7 3 X (+1) = +3 TOTAL = -4 -1 H +1 Br -1 C -1 -1 H H C +1 -1H C O -1 H -1 H H2O +1 Br C -1 H +1 OH C -1 C H H -1 +1 5 X (-1) = -5 3 X (+1) = +3 TOTAL = -2 -1H +1OH 5 X (-1) = -5 3 X (+1) = +3 TOTAL = -2 7 -1 H -1 H C -1H +1 S +1 -1H C -1 -1 H H C C -1 H C +1 +1 +1 C N H -1 H -1 9 X -1 = -9 5 X +1 = +5 TOTAL = -4 OXIDATION STATE: -4 -3 -2 -1 0 +1 +2 +3 +4 Molecules CH4 RCH3 CH3-OH, R2CH2 RCH2OH CH2O, R2CHOH RCHO, R3COH HCO2H, R2CO RCOOH CO2, CO4 Generally no oxidation state change in the total organic molecule is observed in reaction like Hydrolysis or comparable reactions with alcohols (alcoholysis) or amines (aminolysis) with addition or elimination of HX, HOH, and HOR or with tautomerization but oxidation occurs when oxygen added to the molecule. 8 Are These Oxidations or Not??????????? 9 10 Oxidation of Alkenes Oxidation of alkenes may take place at the double bond or at the adjacent allylic position. Oxidation at Double Bond X H H Alkynes OH Halohydrins, Amino hydroxy O O Dioxetanes HO OH H H H H HO Anti or Trans diol OH Cis diol H Cleavage of Doble Bond Carbonyl and Caboxylic Acid H H O H Epoxide 11 Epoxidation Some oxidation reactions of alkenes give cyclic ethers in which both carbons of a double bond become bonded to the same oxygen atom. These products are called epoxides or oxiranes. An important method for preparing epoxides is by reaction with peracids, RCO3H. The oxygen-oxygen bond of such peroxide derivatives is not only weak (35 kcal/mole), but in this case is polarized so that the acyloxy group is negative and the hydroxyl group is positive. Epoxides or oxiranes are the important intermediates in synthetic organic chemistry. The facile epoxide ring opening is extensive useful in C-C bond formations and diol preparation etc. Epoxidation of alkenes are usually carried out by using peroxy acids. 1. Peracid Reactivity Reactivity Increases R CH3 C6H5 m-ClC6H5 p-NO2C6H5 o-CO2C6H5- CF3 pKa 4.8 4.2 3.9 3.4 2.9 0 The lower the pKa, greater the reactivity. 12 13 The reaction involves the nucleophilic attack on the O-O bond by the π-electron of the double bond. Therefore Epoxidation takes place more rapidly and preferentially at electron rich double bonds. The reaction-rate increase when the substituents on alkenes are electron releasing. This is the basis of regioselectivity in epoxidation. Tetra subs. > Tri subs. > Di subs. > Mono subs. > Unsubs. Similarly, electron withdrawing groups on alkenes decreases the rate of reaction. O F Cis-alkenes give Cis Epoxides Trans-alkenes give Trans Epoxides Concerted reaction at one of the double bonds through cyclic intermediate is the basis of stereocontrol. When two faces of the π-bond are unequally shielded, the two expected stereoisomers will not form to the same extent. 14 The reaction has relatively low steric requirements and even hindered alkenes can be epoxidized easily. Stereochemistry of olefins is maintained: Diasterespecific Reaction rate is insensitive to solvent polarity implying concerted mechanism without intermediacy of ionic intermediate Less hindered face of olefin is epoxide If, R=H 20 min, 25 °C 99% 1% R = CH3 24 h, 25 °C < 10% 90% Epoxidation of an alkene containing one or more chiral centers gives two diastereomeric epoxides, depending on the face from which the reagent approaches the π-bond. This chiral induction is cause of diastereoselectivity in epoxidation. 15 Epoxidation with Organic Peroxy Carboxylic Acid Electron-withdrawing groups on peroxy acids increase the reaction rate. MCPBA is most commonly used reagent in epoxidation. It is fairly stable, solid, and soluble in many organic solvents, such as CH2Cl2, CHCl3. Caution: It is SHOCK SENSATIVE Subsequent work-up depend upon the stability of resulting epoxide. Mechanism: When epoxide react with water in the presence of catalytic amount of acid or base ring opening takes place to afford vicinal diol and it is a well known fact that the epoxide ring opening always takes place in trans manner so we will get an anti diol product in the result of epoxide ring opening e.g. 16 H 3C HO H C H 1) m-CPBA C H3C H 3C 1) m-CPBA C CH3 2) H, H2O C H CH3 OH meso 2,3-butane diol HO H C C CH32) H, H2O Trans 2-butene H H H H3C H C C OH H CH3 + H 3C OH HO C C H CH3 Cis 2-butene (2R,3R)-2,3 butane diol (2S,3S)-2,3 butane diol SALIENT FEATURES OF EPOXIDATION The reactivity of alkene depends on the degree of substitution. 1. Monosubstituted terminal alkenes are least reactive. 17 Substituted versus Terminal Alkene 2. Deactivated double bonds are less reactive. Deactivated Deactivated O C MCPBA, CH2Cl2 OCH3 O F 20 oC C OCH3 O F 70% 3. The oxygen transfer is stereospecifically syn the stereochemistry of the starting alkenes is retained in the product. e.g. D H C C m-CPBA H D Trans alkene H H m-CPBA C C O D C H H D Trans Oxirane O H C D D D Cis alkene C C H D Cis Oxirane 4. Conjugation of alkene double bond with other unsaturated groups such as CN, NO2, COR, COOR, SO2 etc reduce the rate of epoxidation because of the delocalization of π electrons. O OH CH3COOOH 18 It requires strong reagents e.g. MCPBA, triflouro per acetic acid at higher temperature 5. If one or more chiral centers present in substrate the epoxidation will be diastereoselective. SiMe2Ph SiMe2Ph O o MCPBA, CH2Cl2, 20 C + SiMe2Ph O Anti face 67% 33% Peroxy attack takes place majorly from the anti face to the bulky silyl group. 6. In general, for linear chain and flexible cyclic molecule, it is very difficult to predict the stereochemical out come of the reaction. MCPBA, CH2Cl2, 20 oC RO OAc O O + RO RO OAc 47% OAc 53% 19 6. With conformationally rigid cyclic alkenes the epoxidation generally takes place from the less hindered side of the double bond in stereoselective fashion. Less hindered face H O o MCPBA, CH2Cl2, 20 C + O H H H H More hindered face H 94% 6% 20 Equatorial H H Less hindered H H3C H H H H H H3C CH3 H3C O Axial methyl More hindered + O H H 87% CH3 13% Less hindered H3C H3C H3C CH3 CH3 H3C CH3 CH3 CH3 Pseudoaxial CH3 CH3 O MCPBA, CH2Cl2 24 h, r.t. H3C CH3 H3C CH3 93% Axial methyl More hindered CH3 O + H3C CH3 H 3C CH3 7% 21 7. Folded molecules are epoxidized selectively from the less hindered side. More hindered O O O O o O MCPBA, 3 h, 5 C O O O 95% Less hindered H H o O OBn MCPBA, 3 h, 5 C H H OBn OBn H PhSiO PhSiO H OBn 72% 8. Unhindered exomethylenic cyclohexene undergo preferential axial epoxidation More hindered CH3 Ph Ph CH3 Ph CH2 O MCPBA CH3 86% Less hindered 22 9. Stereoselectivity is even more pronounced in polar solvents, since in polar solvents the effective steric bulk of the peroxy acid in the transition state become somewhat greater make attack from hindered side even more difficult. More hindered CH3 H CH2 CH3 H C11H23COOOH H3C O + H3C H3C CH3 H O H3C H3C H3C Less hindered (C2H5)O 65% CH2Cl2 83% 35% 17% 10. The polar substituent at allylic and homoallylic positions influence the direction of the attack. OH OH Cis to OH C6H5COOOH, C6H6, 0 oC O Association of reactant with hydroxyl group of the substrate through hydrogen bonding cause preferential attack from that side. In contrast if no hydrogen bonding occurs than it attacks from less hindered side. 23 OCOCH3 OH OCOCH3 o C6H5COOOH, C6H6, 0 C O Normal Product No hydrogen bonding i.e. attack from less hindered side Mechanism of directive effect: C6H5 C H O O C6H5COOOH CMe3 H C6H6 O H O O H H CMe3 CMe3 H HO + H H H O CMe3 H HO H H O H H 96% 4% H O O O O O H R + C O R 24 The effect is also observed in open chain compounds. CH3 CH3 CH2OH C6H5H2CO CH2Cl2, 0 oC C6H5H2CO CH2OH MCPBA O Coordination of MCPBA with ethereal and hydroxyl oxygen direct the attack from that side. 11. In acyclic alkenes the directive effect of polar allylic substituents is based on the stability of transition state. HO HO HO MCPBA R3 R 1 o CH2Cl2, 0 C O R3 R1 + R2 R O R1 R2 2 Erythro Threo OH H R2 H R3 H R3 R3 R2 H R1 Rotamer for threo R1 OH Rotamer for Erythro Less stable due R1, R3 interaction When R1 and R2 are alkyl more threo will be stable Trisubstituted or Cis - disubstituted Trans - disubstituted or monosubstituted Threo Erythro 12. In cyclohexene system pseudoequatorial hydroxyl is more effective than the pseudoaxial hydroxyl in directing epoxidation. 25 Homoallylic group can also direct the attack. Homoallylic axial hydroxyl can direct the attack, but homoallylic equatorial cannot. Pseudo equatorial (Effective) O OH OH MCPBA, THF, 48 h N r. t. N OH OH Homoallylic equatorial and cannot direct 69% Pseudo axial (not effective) Homoallylic axial (Effective) OH OH HO HO O MCPBA 75% OAc OAc HO HO CO2CH3 CO2CH3 MCPBA, CH2Cl2 0 oC, 1 h O 91% 26 CH3 CH3 OH OH MCPBA, CHCl3 o Ph 0 C, 1 h Ph O 97% Trans CH3 OH Directive effect of hydroxyl is not large enough to overcome the steric interference Ph Less hindered 13. Besides hydroxyl, carbamates, ethers and ketones also direct the epoxidation. O O CH3 O CH3 N O N CH3 CH3 o MCPBA, CH2Cl2, 0 C O 97% Hydrogen bonding between MCPBA and the carbonyl is the basic reaction of directive effect. 27 OSiBuMe2 OSiBuMe2 CF3COOOH, CH2Cl2, -40 oC O Bu Bu OSiBuMe2 + O Bu 7% 93% Directive effect is due to hydrogen bonding between hydroxyl of peroxy and allylic ether. Electrolysis and microorganism such as Corynebactrium equii have also been used for epoxidation. Epoxidation with Metal Complexes H + H H Alkene H O H C R H + O O O H H Per oxy carboxylic acid O H C R H O Epoxide Mechanism O R O H O O + RCOOH Epoxide or Oxirane Per acids are not only way for epoxidations t-BuOOH with V+5 or Mo+6 species are also used for epoxidation. 28 t-BuOOH with Mo+6 species are excellent for epoxidation of isolated double bonds. t-BuOOH with V+5 species are excellent for epoxidation of allylic alcohol and Terminal alkenes. t-BuOOH V+5 O Terminal alkene Difficult to epoxidize with peroxyacid V(acac)2 OH O t-BuOOH OH + O 7% 93% m-MCPBA OH O OH + OH O 65% 35% Effect of polar substituents Controls the stereochemistry of resulting epoxide. Allylic Homollylic Bishomoallylic or even remote position 29 OH OH V(acac)2 t-BuOOH OH O 83% OH Mo(Co)6 t-BuOOH O Precise cause of reaction in not very clear Very fast High stereoselectivity Formation of intermediates Minimum steric interactions R1 L R2 L O V R3 O O t-Bu R4 30 SHARPLESS EPOXIDATION Epoxidation of allylic alcohol t-BuOOH Ti(iPrO)4 Natural L-(+)-diethyl Tartarate Unnatural D-(-)-diethyl Tartarate High optical purity Diseterofacial stereoselectivity Sharpless epoxidation L(+)-Diethyl Tartarate O Ti (iPrO),t-BuOOH 90% R OH Prochiral allylic alcohol R OH D(-)-Diethyl Tartarate O Ti (iPrO),t-BuOOH R OH 90% The discovery of epoxidation. K. B. Sharpless, Chem. Brit. 38. 1986 and references therein. 31 Advantages High asymmetric induction Absolute configuration of product is predictable (+) or (-)- Tartarate ensure one or other epoxide in over 90% optical purity. R2 : : D(-)-Diethyl tartarate (Unnatural) :O: TOP :O: Delivery R1 R2 R1 Ti(iPrO)4, t-BuOOH O o OH R3 CH2Cl2, -20 C OH R3 : : :O: L(+)-Diethyl tartarate (Natural) BOTTOM :O: Delivery Top or Bottom [O] delivery depends on the isomers of tartarate used and depends on pre-existing chirality of substrate. In a recemic Titanium complex reacts with only one enantiomer. 32 Slow Top attack due to bulky R group : D(-)-Diethyl tartarate (Unnatural) :O: Ti(iPrO)4, t-BuOOH O OH OH : :O: R Fast bottom attack due to bulky R group R Ti(iPrO)4 ,t-BuOOH L(+)-Diethyl tartarate (Natural) O OH R : D(-)-Diethyl tartarate (Unnatural) :O: Ti(iPrO)4, t-BuOOH H H Fast top attack due to bulky R group O OH R OH : R :O: Ti(iPrO)4, t-BuOOH L(+)-Diethyl tartarate (Natural) Slow bottom attack due to bulky R group O OH R Diseterefacial stereo selectivity K. B. Sharpless, J. Am. Chem. Soc, 1981, 103, 6237. 33 Loading of complex [Ti(DET) (OR)2] + 2ROH Ti(OR)4 + Diethyl tatarate TBHP ROH ROH [Ti (OR) (TBHP) (DET)] Allylic alcohol [Ti (OR) (Allylic alcohol) (DET)] ROH TBHP ROH Allylic alcohol [Ti (TBHP) (Allylic alcohol) (DET)] "Loaded Complex" [Ti (OR) (epoxy alcohol) (tatarate)] Rapid ligand exchange of Ti(O-i-Pr)4 with DET. The resulting complex further ligand exchange with the alcohol and then THP. The exact structure of the active catalyst is difficult to determine due to rapid exchange but it is likely to have dimeric structure. The hydroperoxide and the allylic alcohol accopy the axial coordination sit on the titanium and this account for the enantionfacial selectivity. Oxygen transfer from TBHP to allylic alcohol to give a complex [Ti(OBu) (epoxy alcohol) (Tatarate)] This is a slow step. Both Ti(OR)4 and Ti(Tartarate) (OR)2 are active epoxidizing catalyst. Ti (Tartarate)2 is catalytically inactive Excess of Ti(OR)4 and its contribution in epoxidation will results in loss of enantioselectivity because it is achiral. Excess of Ti(Tartarate)2 causes a decrease in reaction rate. 34 10-20% mol% excess of tartarates over titanium results in the formation of Ti (tatarate) (OR)2 which gives high enantioselectivity and acceptable rate of reaction. Since the reactions involve a nucleophilic attack on peroxy oxygen in the reactions the electron rich alkene reacts faster than electron deficient alkenes. For example in case of substituted cinnamyl alcohols, an electron-withdrawing (p-nitro) group decreases the reaction rate while electron donating (p-methoxy) increase the rate of reactions. H OH H NO2 OH OMe Slow reacting p-nitro cinnamyl alcohol Fast reacting p-methoxy cinnamyl alcohol Highly subtituted double bond epoxidize prefereably than less substituted OH OH O (CH2)10 (CH2)10 Highly substituted double bond 35 36 E O Ti O (1) E O (2) A reaction path way invoking orbital controlled approach of C-C bond to the peroxide oxygen O(1) in the direction of axis of O(1)-O(2) in the complex has been suggested by Sharpless K. B. Sharpless et. al. Pure and Appl.Chem., (1983) 55, 589. 37 Epoxidation of homoallylic alcohol with other reagents Homoallylic alcohol Transfer of stereochemistry by phosphate and Cyclic iodophosphate formation Treatment of cyclic iodophosphate with ethoxide OP(OR)3, I2, o CH3CN, NaOEt, 25 C OH O OH Mechanism: O P RO OH I I O OR O OR P RO OR O RO P I -RI O O I O O R I O P OR OR O O P O + O OR OR OH O P RO OR RO OR 38 Carbonyl Group Assisted Asymmetric Epoxidation Oxidative cyclization or Iodolactonization I2, CH3CN, 0 oC HO O HO O O Mechanism: HO O I I O I OH O O O I O + I Na2CO3 O H3CO o CH3OH, 25 C O Iodolactone (10:1) What will be the mechanism of last step? 39 Epoxide formation by the action of base on bromohydrins It is very useful method for epoxidation of terminal double bond. OH O B NBS, H2O DME Br Mechanism: O Br N OH2 + H2O Br O OH B O Br 40 Base Catalyzed Ring Opening of Epoxides: OCH3 CH3 H3C CH3 H O NaOMe MeOH CH3 H3C C C CH3 H OH Mechanism: H3C H3C H3C Y H3C O CH3 H Y CH3 H3C O CH3 H Transition state CH3 H3C O H Y Y CH3 OH H CH3 -Substituted alcohol Alkoxide Ion Acid Catalyzed Ring Opening of Epoxide H 3C H O CH3 H2SO4 CH3 MeOH H3C H OCH3 C C OH CH3 CH3 Mechanism: H H 3C H CH3 O CH3 H O Fast Me H 3C CH3 H CH3 O H O Me H CH3 Slow H 3C HO H 3C O CH3 Fast H 3C H 3C O H MeOH HO CH3 CH3 41 Reaction of KMnO4 An aqoues solution of KMnO4 reacts with olefins to add hydroxy function to double bond in a cis manner provided the reaction mixture is alkaline. If the reaction mixture is kept neutrals either by continuous addition of acid or by adding magnesium sulfate the permagnate oxidation results in cleavage or in the formation of α-hydroxy ketone. H H C HO2C(H2C)7 C (CH2)7CO2H HO KMnO4 H NaOH (excess) H 2O OH C C HO2C(H2C)7 H (CH2)7CO2H 81% KMnO4, H2O CH3(CH2)7C (CH2)7CO2H O 75% OH KMnO4 NaOH o H2O, t-BuOH, O C HO H H 40% CHO KMnO4 MnSO4 H2O, AcOH, -15 O o 54-66% CHO 42 Oxidation of Double Bond BY KMnO4 There are two ways Gives vicinal diols R CH CH R (Olefin) R KMnO4 HC HC OH OH R (Cis diol) Mechanism of KMnO4 43 Oxidation of Double Bond with OsO4 Cis vicinal diol Mechanism is very simple Expensive and highly toxic reagent Better yield than KMnO4 Strained and unhindered olefins react rapidly Catalytic amount of OsO4 with less expensive oxidant works well. CH3 CH3 OH OsO4 OH CH3 CH3 70% R R H H C OsO4 C OH C H 2O 2 C OH + H OsO4 H R R Mechanism: R R R O CH CH O O HC R R H2O Os Os O HC O R O O O HC OOsO2 HC OH HC OH HC OH R R 44 Oxidation with Prévost’s Reagent Prévost’s Reagent (I2/CCl4 +AgOAc) or (I2/CCl4 +AgOBz) AcO OH H H O H2 + I2/CCl4 anh ydr ous con dit io n OAc H H AcO Reaction of alkene with Prévost’s reagent in a solution of iodine in CCl4 together with one aqueous solution of silver acetate or silver benzoate under anhydrous condition (Prévost’s conditions) the oxidant directly yields the diacetyl derivative of the trans-glycol. While in the presence of water the monoester of the cis-glycol is obtained (Wood wards conditions) The value of this reagent is due to its specificity and to the mildness of the reaction conditions, free iodine, under these conditions used, hardly affects other sensitive groups present in the molecule. Reaction proceeds through the formation of iodonium ion. 45 Mechanism: O O C O AgO I I C + CH3 AgI I CH3 Iodonium Ion CH3 CH3 CH3 O C C O O O O O Ag I OCOCH3 H 2O H 3C OH OCOCH3 Monoacetyl Cis diol Wood wards Method O OH O OCOCH3 H C C H OCOCH3 Diacetyl Trans diol Prevost Method 46 OZONOLYSIS The most general and mildest method of oxdatively cleavage of alkene to carbonyl compounds is Ozonolysis Alkene is treated with Ozone (O3) at low temperature in solvents like methanol, ethyl acetate and dichloromethane. The first insoluble intermediate ozonide forms which is reduced to the two carbonyl products by different treatment like cat. hydrogenation, Zn/HOAc or by reaction with dimethyl sulfide. O O O3 Reduction O+ O O Ozonide H3C H C2H5 O3, CH2Cl2 O O + H CH3 Zn/HOAc CH3 CH3 O CH Cl 3, 2 2 O H Zn/HOAc O CH3CH 2 O3, CH3OH (CH3)2S CH3O O + H H 47 STEP 1: + O O O O O O O O O Molozonide STEP 2: O (CH3)2S O O O C O C O O + (CH3)2S=O Zn/HOAc O + ZnO + H 2O O H2/Pt Ozonoide Treatment of the ozonoide with NaBH4 leads to alcohols. In this way, a double bond can be oxidatively cleaved to produce two alcohols. CH3(CH2)2CH CHCH2CH2CH3 1. O3, CH2Cl2 2. NaBH4,/CH3OH 2CH3CH2CH2CH2OH O O CH3CH=CH3(CH2)7 C OCH3 1. O3, CH2Cl2 2. NaBH4,/CH3OH C2H5OH + HOCH2(CH2) 48 C OCH3 Photosensitized oxidation of alkenes Iradiation of alkenes and conjugated dienes in the presence of oxygen Hydroperiodes Alkene to allylic alcohols Sensitized Organic dyes (fluorescence derivatives, methyl blue, propylene Reduced to alcohol derivatives No reaction if lack of allylic hydrogen = = = = = = = = = sensitizer = = = = = = = = = O2 = = = = = = = = = light H H C H C OOH O2 C Sensitizer H C H C C H Reduction H OH C H C C H H an allylic hydrogen The position of double bond changes from α, β to β, γ. 49 Reaction mechanism: Generally proceed by a concerted mechanism C C C H O O C H C O Red C O C CH2 OH An allylic alcohol an allylic hydro peroxide H3C CH3 H3C O O CH3 H3C H3C O CH3 O CH2 H H3C H3C CH3 O O CH2 H3C H3C OOH CH3 CH2 H 50 Allylic Oxidation of Alkenes by SeO2 SeO2 is a useful reagent for allylic oxidation of alkenes. Products include allylic alcohols, allylic esters, enals depending upon the nature of substrate and reaction conditions. R H H CH3 R H H CHO H H R CH2OH Basic mechanism consists of three steps: i) An eletrophilic ene reaction with SeO2 Ene reaction: Certain electrophilic double bonds undergo an addition reaction with alkenes in which an allylic hydrogen is transferred to electrophile. O R O Se O R R O H H O Se O H H H Se H Allylic Selenic Acid 51 ii) A sigmatrpic rearrangement that restore the original location of double bond because in the first step the position of double bond has been disposed. OH OH Se R R O R Se OH Se O O H H H Finally hydrolytic breakdown of resulting selenium ether OH R R Se H2O/H + O OH H H Normally an excess amount of this reagent is used due to which resulting alcohols are further oxidized to aldehydes, R R SeO2 O OH H H Therefore, a modification is carried out in order to avoid further oxidation. i) Reaction was carried out in acetic acid as solvent R OH Se R AcOH + Se(OH)2 O H OAc H Allylic acetate ester can be hydrolyzed to required allylic alcohol. ii) Use of catalytic SeO2 along with co-oxidant t-BuOOH which regenerate the catalyst repeatedly and product will be allylic alcohol. 52 Stereoselectivity of the Reaction i) In trisubstituted alkenes, oxidation occurs at more substituted end of the double bond. H3C CH2CH3 H3C H Oxidizable site ii) The oxidized product will be E-allylic alcohol H3C CH2CH3 HOH2C H The observed stereochemistry can be explained by considering the five membered cyclic transition state for sigmatropic rearrangement. H OH Se C2H5 C2H5 HO O O H3C C2H5 Se H HOH2C H3C CH3 Transition state for E-allylic alcohol C2H5 H HO O Se HOH2C H3C C2H5 H CH3 Transition state for Z-allylic alcohol 53 Wacker Oxidation Salient Features: 1. Offers a direct conversion of alkenes to carbonyl compounds. 2. Atmospheric O2 is used in presence of PdCl2 and CuCl2 as catalysts known as Wacker-Smidt process. PdCl2 is used in catalytic amounts while CuCl2 is stoichiometric co-oxidant. 3. Oxidation reaction is carried out in water in the presence of HCl. 4. Terminal alkenes react at much faster rate than internal or 1,1-disubstituted alkenes. 5. α,β-unsaturated ketones and esters are oxidized regioselectively to corresponding β-keto compounds using catalytic amounts of Na2PdCl4 and H2O2 as co-oxidant. The catalytic cycle can also be described as follows: [PdCl4]2 − + C2H4 + H2O → CH3CHO + Pd + 2 HCl + 2 Cl− Pd + 2 CuCl2 + 2 Cl − → [PdCl4]2− + 2 CuCl 2 CuCl + ½ O2 + 2 HCl → 2 CuCl2 + H2O Wacker Oxidation 54 Mechanism 55 Oxidation of Alcohols Several methods → Chemical → Catalytic → Microbial etc → Produces →, Aldehydes → Ketone → Acids Primary alcohols Secondary alcohols → Ketones Tertiary alcohols → Aldehydes or carboxylic acid → Cleavage of C-C bond Oxidation of Alcohols by chromium Primary Alcohols ……………………. Aldehydes, Carboxylic Acids Secondary Alcohols …………………... Ketones Tertiary Alcohols ……………………….. Cleavage of C-C bond Alcohol Oxidation must focus The relative strength of the reagent The condition under which is used Structure variation of the alcohols Oxidizing properties of Chromium with respect to media Chromium (VI) in acidic media Chromium (VI) with heterocyclic nitrogen bases 56 O O HO Cr - O- O O Cr O Cr O O O - + H 2O O J. Am. Chem. Soc., 1958, 80, 2072 J. Am. Chem. Soc., 1960, 82, 290 General Mechanism of Alcohols Oxidation with Chromium CH3 O H H C CH3 OH HO Cr OH CH3 + H -H2O O C O Cr OH CH3 O Chromate ester O O + Cr HO O OH Cr(VI) H 3C CH3 Cr(IV) J. Am. Chem. Soc., 1959, 81, 2116 57 Salient Feature: In cyclohexanol axial OH generally oxidized rapidly than equatorial O O Cr OH OH O Less stable due to 1,3-diaxial interaction Axial O OH O Cr OH O Conformation can be determined Primary → aldehyde → carboxylic acid Continuous distillation of aldehyde Not suitable for alcohols containing acid sensitive group Different solvent combinations Na2Cr2O7/H2O4/H2O CrO3/HOAc/H2O CrO3/H2SO4/H2O/Acetone (Jones Reagent) CrO3/H2O/HCl/Oxalic acid CrO3/DMF CrO3/HMPA CrO3/DMSO/H2SO4 Aqoues / Non aqoues, Heterogeneous, Phase Transfer and Solid Support conditions can also be used. 58 Jones Oxidation Most widely used method of oxidation using Chromic acid/sulfuric acid in aqueous acetone Protect the substrate from over oxidation Multiple bonds are not attacked by Jones reagent O OH J. R. NHTs NHTs H3C 98% H3C CH3 CH3 O OH J. R. CH3 CH3 84% Bu J. R. O Bu O OH 82% 1. J. Org. Chem., 1976, 41, 177. 2. J. Org. Chem., 1971, 36, 387. 3. Can. J. Chem., 1976, 54, 3113. 59 Chromium (VI) with Heterocyclic Nitrogen Bases i) Chromium (VI) oxide forms complex with several nitrogen heterocyclic compounds which show oxidizing properties. ii) They are milder more selective oxidants than acid based reagent systems. iii) Acid sensitive group are tolerated. iv) Preparation of aldehyde is generally easier. Chromium Pyridine Complexes a) Chromium trioxide pyridine complex (Sartt’s reagent) O + N Cr O - O b) Dipyridine chromium (VI) oxide (Collin’s Reagent) O- OCr N N O c) Pyridiium Chlorochromate (Corey’ Reagent) N - ClCrO3 + H 2 d) Pyridinium dichromate - N + Cr2O7 H 60 Reactions OH O O H PCC 3 eq. CH2Cl2, 1 h, r.t. O O O Can. J. Chem., 1987, 65, 195. MeO OMe MeO PCC OH 1.4 eq. CH2Cl2, 2 h, r.t. NaOAc H OMe O J. Am. Chem. Soc., 1980, 102, 1983 Assignment for students having 1/2 solid marks (Propose Mechanisms) Chromium Pyridine Complexes a) Chromium trioxide pyridine complex (Sartt’s reagent) O + N Cr O - O b) Dipyridine chromium (VI) oxide (Collin’s Reagent) O- OCr N N O c) Pyridiium Chlorochromate (Corey’ Reagent) ClCrO3N + H 2 d) Pyridinium dichromate - Cr2O7 N + H 61 Oxidation of Alcohol by Silver Carbonate Ag2CO3 on Celite Fatizon Reagent Solid Support Mild Conditions No Acid No Base Very Selective Other functionalities are unaffected No work-up only filtration. H H C HO H H O H (a) (b) H C O + OAg AgO OAg AgO H C C C O O AgO- OAg C O (c) C + 2Ag + CO2 + H2O O Point to Remember for Ag2CO3-Celite mechanism: Initial step is reversible adsorption of alcohol on the surface of oxidant Formation of covalent bond b/w O of OH and Ag+ Second Ag+ will convert into Ag by heterolytic cleavage of C-H bond and electron transfer and generation H+ CO3-2 pickup H+ and converted to carbonic acid which decomposes to CO2 and H2O 62 H . 63 Ref: A. Mckillop et.al. Synthesis, 401(1979) F.J. Kakis et.al. J. Org. Chem. 523, 3, 39 (1974) M.Fatizon et.al. Tetrahedron Lett., 4445 (1972) Salient Feature Reaction takes place at interface of solid and solution used inert solvent like benzene ith excess of reagent. O selective i.e. alcohols of different type are oxidized at different rate. Benzylic or allylic > secondary > primary Activated alcohols (such as benzylic and allylic alcohols) oxidized faster than saturated alcohols O HO 1oalcohol AgCO3 /Celite Benzene HO HO OH o 2 alcohol O allylic alcohol 1oalcohol O OH HO OH 2 alcohol 70% allylic oxidation AgCO3 /Celite o O HO Benzene HO o OH 48% 1 alcohol Primary alcohols are oxidized more slowly than secondary Highly hindered OH group are unaffected i.e. selectively based on steric crowding. 64 CH3 OH CH3 O H 3C H3C AgCO3 /Celite Benzene H 3C H 3C CH3 OH CH3 OH Diols behaves differently generally only one OH group is oxidized O O H CH2OH CH2OH O Ag2CO3-Celite C6H6, Reflux O H O O H Lctone H One of the OH groups being converted to carboxylic acid and predominantly lactone formation takes place. Other diols (Pir, Sec, e.t.c) give hydroxy ketones. OH OH Ag2CO3-Celite C6H6, Reflux O OH 50% This is an excellent reagent for oxidizing allylic, secondry under essentially neutral conditions. 65 Oxidation of Alcohols Manganese Species KMnO4 and MnO2 KMnO4 is relatively vigorous oxidant than MnO2 MnO2 is mild and more selective KMnO4 oxidation of primary alcohol to carboxylic acids is a synthetically useful reaction. RCH2 OH KMnO4 RCHO RCOOH O HO RCH CH3 RCH CH3 Usually carried out in the presence of alkali hydroxide Also performed in buffer Two phase system containing an aqueous KMnO4 solution and an immiscible solvent such as C6H6, ether can also be used. CH3 (CH2)6 CH2OH Ag KMnO4/ C6H6 + CH3 (CH2)6 COOH BuN Br, RT Solid Support KMnO4 in toluene provides a simple and milder procedure. (CH2)11 CHOH KMnO4/Alumina (CH2)11 C O 66 Mechanism: - (CH2)11CHOH + OH (CH2)11CHO + H2O O O O H3C C H + O Mn O H O Mn O + O O CH3 O H3C CH3 MnO4 abstract the α-hydroxy from alkoxide ion either as an atom (or an electron transfer) or as hydride H ion (two electron transfer) But Hydride shift is more reliable. Permanganate ion is reduced from from Mn(VII) to Mn(V) MnO2 Oxidation Useful oxidizing agent for allylic and benzylic alcohols. Mild and selective than KMnO4 MnO2/CH2Cl2 o 20 C OH H O Neutral solvents are used i.e. benzene, pet. ether, CHCl3 Simple stirring of alcohol in solvent with MnO2 for some hours Used specially prepared MnO2 MnSO4 with KMnO4in alkaline solution produced very active MnO2 This is not clear that actual oxidizing agent is MnO2 or some other manganese species adsorbed on the surface of MnO2 C=C bonds and C HC C C H C remain unaffected by this reagent C CH2OH H MnO2 O HC C C H C CH H 67 Acid or base sensitive subatrate can easily be oxidized by this reagent OH EtOC C C H C CHCH3 H O MnO2 EtOC C C C CHCH3 H Dimethyl Sulfoxide O H 3C S Red H 3C CH3 Dimathyl sulfoxide S CH3 Dimethyl sulfide The development of mild oxidant based on dimethyl sulfoxide for the efficient conversion of alcohols to their corresponding carbonyl compounds was a major breakthrough in synthetic organic chemistry. Wide spread applications Alcohols to corresponding carbonyl compounds Tosylate to = = = = = = = = = = = = = = Halides to = = = = = = = = = = = = = = Epoxide to α-hydroxy ketones H R' Alcohol (CH3)2S=O + Activation R C Base Tosylate RCH2OTs + (CH3)2SO Halide RR'CO + (CH3)2S RCHO + (CH3)2S H R' R OH C + X (CH3)2SO RR'CO + (CH3)2S 68 R R Epoxide HC OH CH + R (CH3)2SO C H O C R + (CH3)2S O Arylic tosylate and halide can also convert into their corresponding carbonyl compounds. The commonly accepted gross mechanism H H3C S O + R2 H3C C R1 H3C X S O C - H H3C R1 X R1 H3C R2 S + H3C C R2 O Alkoxy dimethylsulfonium ion (A key intermediate in all type of DMSO based reagents) R1 = Ar, R2 = H, X = Br R1 = Ar, R2 = H, X = OTs R1 = Alkyl, R2 = H, X = OTs or halide H3C H3C S O +E H3C S OE + R2 H 3C O E H3C H H3C S C R1 H3C OH R1 S O C R2 + HOE H 3C H Alkoxy dimethylsulfonium ion (A key intermediate in all type of DMSO based reagents) E = C6H11N=C=N=C6H11 (DCC) E = (COCl)2 (Oxalyl Chloride) E = Anhydride 69 Decomposition of Alkoxydimethyl sulfonium ion R1 H3C S O H2C H C .. B R1 H3C S R2 O C H2C H R1 H3C R2 S + O R2 H3C H Alkoxy dimethylsulfonium ion (A key intermediate in all type of DMSO based reagents) H H R R + (CH3)2SO OH H C C R H O S R2 O R2 OH O C C H R S H CH2 B CH3 CH2 CH3 R2 OH O C C + (CH3)2S H R C H In final step formation of a ylid which undergoes intermolecular hydrogen transfer with formation of DMS and a carbonyl compound. Ref: C.R. Johnson et.al. J. Org. Chem. 32, 1926, (1976) Various variant of DMSO-based oxidants are available In some cases formation of thio ether are also reported through following mechanism. 70 H3C H3C S O + E S H3C O E H 3C -H H3C S + HOE R1R2CHOH H 2C Methylene Sulfonium Ion H R1 C OCH2 S CH3 R2 Thioether Different combination of DMSO with activators or electrophoiles 1. DMSO-N,N’-Dicyclohexylcarbodiimide (DCC) (Commonly known as Pfitzer-Moffatt Reagent) 2. DMSO-(COCl)2 (Swern Reagent) 3. DMSO-(CH3CO)2O 4. DMSO- (CF3CO)2O 5. DMSO-SO3 6. DMSO-P2O5 7. DMSO-Cl2 SWERN OXIDATION This is one of the best methods of oxidation. In this oxidation oxalyl chloride is used as activator. By reaction of DMSO and oxalyl chloride followed by treatment of the resulting alkoxy sulfonium salt with a base, usually triethylamine, a wide variety of alcohols has been converted into corresponding carbonyl compounds in high yields. 71 O DMSO, (COCl)2 OH H CH2Cl2, Et3N OHC HOH2C DMSO, (COCl)2 O O O O O O O O CH2Cl2, Et3N O O High yield, mild conditions, by-product easily separable Mechanism: H3C H 3C o S O + (COCl)2 CH2Cl2, -60 C S H3C O C C Cl Cl H3C RCHOHR' S S Cl R S O O H3C H3C H3C R H 3C H 3C H2C O O C H C H R' base R R' C O + H3C S CH3 R' Oxidation via alkoxy sulfonium salts A number of methods for oxidation primary and secondary alcohols to aldehyde and ketone by the action of base on the derived alkoxy sulfonium salts differ from 72 each other mainly in the way in which the alkoxy sulfonium salt is obtained from the alcohol. One of the earliest procedure involved reaction of alcohol with dimethylsulfoxide and dicyclohexyl carbodiimide (DCC) in the presence of proton source. R1 C6H11N=C=N-C6H11 CH OH o (CH3)2SO, H3PO4, 75 C R2 R1 O R2 Mechanism: C6H11N=C=N-C6H11 C6H11NH-C=N-C6H11 + O H H 3C R1CHOHR2 S S H 3C O CH3 H3C H 3C R1 O S Base C H 3C + H R2 H O H 3C S H 2C R1 R1 R2 R2 C H O + (CH3)2S (C6H11NH)2CO dicyclohexyl urea The oxidation with DMSO, DCC also known as Pfitzner-Moffat oxidation. A disadvantage of this route is that the product to be separated from the dicyclohexyl urea formed in the reaction. 73 Oppenauer Oxidation Primary and secondary alcohols to ketone Aluminium alkoxide + carbonyl compound Reverse of Meerwein-Pondroff-Verley Reduction Useful in the field of steroids. Al(i-PrO)3, (Al(t-BuO)2, Al(PhO)3 Carbonyl compounds include butanone, benzoquinone, benzophenone, flournone. Flourenone is advantageous due to considerably short time and temperature of reaction α-hydrogen containing carbonyl compounds under alkaline conditions undergo self condensation Use of inert solvent suppresses self condensation. Benzene-acetone and toluene-cyclohexane are commonly used solvents, however, toluene-cyclohexane reduces the time of reactions. Use of flourenone as hydride ion acceptor often reduces the temperature up to room temperature. Use of 1-methyl-4-piperidone as the hydride acceptor allow the easy removal of excess oxidant and corresponding alcohol at the end of reaction by only washing with aqueous acid. 74 Mechanism: Exchange of alkoxide Hydride transfer from alkoxide to carbonyl Pseudocyclic intermediate formation OH R1 O + H3C C R2 CH3 Al(OR')3 R2 H O CH3 O O CH3 + HOR' Al(OR')2 H H3C CH3 O + R1 H3C Al R'O O + H3C C R2 H R1 H R1 C R2 O Al(OR')2 OR' Lead tetraacetate Oxidation Crystalline solid Decomposes at 140 °C Used in Acetic acid or Benzene for Oxidation Widely used for Oxidative cleavage of 1,2-diols, α-hydroxyl ketones, 1,2diketones and α-hydroxy acids Oxidation carried out usually at or near room temperature At elevated temperature the oxidative power dropped considerably Acetic acid is usual solvent for Oxidation Other solvents including Benzene, CH2Cl2, CHCl3, trichloroethane, 1,4-dioxane, ethylacetate, cyclohexane, nitrobenzene and CH3CN are also used. The mechanism aspects of 1,2 diols cleavage with lead tetraacetate are as follows 75 The preferred mechanism for lead tetraacetate cleavage of a diols involves a cyclic transition state. An alternate cyclic mechanism involves coordination of one hydroxy group to lead atom followed by interamolecular proton transfer R2CH OH R2CH OH Pb(OAc)4 2R2CO + Pb (OAc)2 CH3CO2H Mechanism: R R2CH OH + Pb (OAc)4 R2CH R C O R C OH Pb (OAc)3 + HOAc OH R (R)2 O Pb(OAc)2 C 2RC O O + Pb(OAc)2 + CH3CO2H C (R)2 O O C CH3 H In trans diols which cannot rapidly generate a cyclic transition state. The intermediate (b) breaks down with a proton transfer to a base. R H B: R C O O C H R2 Pb (OAc)2 2R2CO + Pb(OAc)2 OAc (b) The oxidation of cyclohexan-1,2-diol is acid catalyzed 76 A strong acid e.g. H2SO4 is a better catalyst. Acid could catalyze the reaction in various ways. It could protonate lead tetraacetate and increases the rate of co-ordination to the diol or it could catalyze the ring closure or its direct decomposition to product. Pb(OAc)4 + H + Pb(OAc)3 + OAc H R2 C R2 OH + R2 C OH R2 C C O C H OH Pb(OAc)3 + Pb(OAc)3O AcH R2 O R2 C O R2 C OH Pb(OAc)2 Pb(OAc)2 R2 C O O+ H Ac 2R2CO α-Hydroxy Acid Lead tetraacetate also cleaves α-hydroxy acids Various mechanisms are proposed for this cleavage. One involves co-ordination of hydroxy group to lead atom, followed by the loss of carbon dioxide Secondly co-ordination of both hydroxyl and carboxyl to the lead followed by the decomposition of cyclic intermediate. 77 H R H C OH + Pb(OAc)4 CO2H R O C O Pb(OAc)2 OAc C O H RCHO + Pb(OAc)2 + HOAc + CO2 H R2 C O O C O Pb(OAc)2 RCHO + CO2 + Pb(OAc)2 78 Periodate reagents Solutions of periodic acid KIO4, NaIO4 in aq. or aq. organic media Co-solvents used methanol, ethanol, t-butanol, 1,4-dioxane, THF, DMF and acetic acid. Co-solvents used less than 50% of the reaction media. Primary use is the cleavage of 1,2-diols, 1-amino-2-hydroxy compounds, αhydroxy ketones, 1,2-diketones. Useful method for water soluble poly-functional compounds such as carbohydrates and certain amino acids. For water-insoluble compounds Pb(OAc)4 is preferable. I I O O + HO + K or Na Periodic salt H (CH3)7 C H C OH O CH3 + I R O OH OH Periodic acid O H 3C O O O O H H C C CH3 O OH O O I O O OH OH Periodic acid O H RCHO + H CC 3 O + I O R O H H C C O CH3 O I O O O 79 Oxidation of Aldehydes O H2CrO4 R C RCOOH H Mechanism OH O HCrO4 R C H + H R RCOOH + HCrO3 C H O CrO3H KMnO4 Oxidation O KMnO4 C6H5 C C6H5COOH H H3O Mechanism O C6H5 C H H2O + + H3O C6H5 CH MnO4 OH H C6H5 C O MnO3 C6H5CO2H + MnO3 OH Oxidation of Ketones Chromic Acid: Cleavage of C-C bond O H2CrO4 HO2C(CH2)4CO2H 80 O OH O H H2CrO4 O CrO3H H OH O + O O O HO Cr HO CrO2 O O OH HO2C(CH2)4CO2H Lead Tetraacetate O CH3CH2 C OCOCH3 CH2CH3 H3C C H C CH2 CH3 C CH CH3 O OCOCH3 + O OCOCH3 H3C C H Mechanism 81 H3C H O C H C OAc CH2CH3 + H3C Pb(OAc)3 H O Pb(OAc)2 C C CH2CH3 OAc OCOCH3 OCOCH3 H3C C H C CH2 CH3 + H3C C H O 31% C CH CH3 O OCOCH3 7% In sterically hindered enols, the acetoxylation procedure is accompanied by a rearrangement. CH3 Pb(OAc)4 O CH3 CH3 CH3 (AcO)2Pb Attack by OAc O O CH3 CH3 OAc OAc CH3 Rearrangement CH3 Shift -H + O CH3 + O H CH3 CH3 82 Bayer-Villiger Oxidation of Ketone Peroxy acids are used as Oxidants. Ketones to Ester or Lactones. Organic peroxy acids i.e, MCPA, Per acetic acid, trifluoroacetic acid give better results. Mild Conditions. Applicable to open chain, cyclic and aromatic ketones. Used to prepare medium and large ring lactones which are difficult to prepare. With unsaturated ketone mixture of products results through competing attack at C—C double bond A new reagent bis(trimethylsilyl)peroxide Me3SiOOSiMe3 eliminate this difficulty, it behaves as masked H2O2 and in the presence of cat. Trifluoromethylmetane sulfonate. It does not affect the double bond. Reaction takes place trough a concerted intermolecular process. Migration of a group from carbon to electron deficient oxygen. In the presence of strong acid, ketone protonated and addition of peroxy acid to ketone. O O O MCPBA Mechanism 83 O OH O H + C2H5 C .. OH O O .. OH O O O C O C2H5 Oxidation of Ethers Interesting reaction of RuO4. Oxidation of aliphatic ethers to esters or lactones in case of cyclic ethers. RuO4 O O O It is used under mild conditions. Reaction stops after first oxidation. Esters or lactones cannot oxidize with RuO4. So attempt prepare succinic anhydride by this way were failed. RuO4 O RuO4 O O O O O 84 A mechanistic study proposed that a hydride from α-position of ether shift to RuO4, then HRuO-4 attacks on the carbonium ion, whish is generated on the α-position of the ether and oxidation takes place. Mechanism of RuO4 Oxidation O HO O H O H Ru + + H O Ru + O O O O O OH O + H2RuO3 Ru O H O O _ O O The formation of 2,5-hexadione by oxidation of 2,5-dimethyl tetrahydrofuran can also be explained by hydride transfer mechanism. 85 HO O H3C H CH3 + H O H 3C CH3 Ru O CH3 Ru + + H O H3C O O O - O H 3C H H O O - O O Ru Ru O O O OH O OH + H2RuO3 O O 86 O Oxidation of Amines Primary amines These are very sensitive to oxidation and generally darken on exposure to air, through auto-oxidation at the surface, to give mixture of complex products. Synthetically useful methods have therefore to be highly selective. The most successful reagents are hydrogen peroxide and per acids. Hydrogen peroxide Hydrogen peroxide converts primary aliphatic amines into aldoxime. n-C3H7CH2NH2 R CH2NH2 + O OH -H2O H2O2 n C3H7CH NOH An Aldoxime RCH2NH H2O2 RCH2N(OH)2 -H2O RCH NOH H OH Oxidation of aromatic amines resulted in formation of nitroso compounds. Perdisulphuric acid HO3S-O-O-SO3H is used as an oxidant. NH2 NO NO2 NO2 HO3S-O-O-SO3H o- Nitrosonitro benzene 87 Nef Reaction Primary and secondary nitroalkanes play an important role in organic synthesis because of their ready transformation into carbonyl compounds. R CH R' RC R' O NO2 Reaction of nitro compounds with base, α-proton is abstracted leads to the formation of resonance stabilized nitronate anions which than hydrolyzed and give a carbonyl compounds. O ' " R R CH :B + N O O ' " RR C N O - OH OH R'R"C ' " O - O O ' " N+ RR C H+ N+ RR C N+ OH H+ .. H2O R C H O R" OH R' C N HO OH Reference Hawthorne, J.Am.Chem.Soc. 1957, 79, pp.2510. Thicde, Ibid. 1952, 74, pp.2615. Folliard, Tetrahedron, 1971, 27, pp.323. 88 R" Oxidation of azobenzene to azoxybenzene Azo compounds may be oxidized to azoxy compounds by per acids. Ar N Ar CH3COOOH N Ar N N Ar O Ar N .. N Ar Ar N N Ar OH O CH3C O OH Ar N N Ar O Oxidation of Isocyanides to Isocyanates Isocyanides have been oxidized to Isocyanates with HgO and with O3 as well as halogen and DMSO. Mechanism involves formation of R-N=CCl2 which hydrolyzed to Isocyanates. R N Cl2 C R O C N Me2SO, H2O Mechanism R C- + N Cl + R Cl CCl N Cl Cl Cl R C N Cl Cl R N HOH C O R N C O H 89 Trifluoroperacetic acid A more powerful oxidant than hydrogen peroxide converts primary amines directly into nitro compounds. The yield with aromatic amines are generally high e.g onitroaniline is oxidized in refluxing CH2Cl2 to o-dinitro benzene in 92% yield. NH2 NO2 NO2 NO2 CF3CO3H With aliphatic amines, however, yields are low. Other oxidants have been used with moderate success e.g. n-hexylamine is oxidized in 33 % yield to the nitro compounds by peracetic acid. Secondary amines Oxidation of secondary amines with H2O2 gives hydroxylamine. R2NH H2O2 R2N OH + H2O Tertiary amines Tertiary amines with H2O2 give their N-oxide hydrates, by nucleophilic displacement as in primary amines. The N-oxides is obtained by warming the hydrate in vacuo. R3N H2O2 R3N OH + OH Heat R3N O Aromatic amines behave similarly e.g. pyridine. 90 The Beckmann Rearrangement The rearrangement of oxime to amide under the influence of acid, Lewis acid is termed as the Beckmann Rearrangement. Commonly H2SO4, PCl5 in Et2O, poly phosphoric acid, aryl sulfonic halides, HCl in HOAc and Ac2O. HCl in HOAc and Ac2O is useful if the starting oxime is insoluble in other medium. 1 2 R CR 2 H+ R C NHR O N OH Mechanism 1 2 R CR 1 2 R CR H+ -H2O 2 + R C NR H 2O 1 2 R C NR 1 N N OH +OH2 +OH2 -H 2 R C 2 + NR 1 1 R C NHR O H O 91 The Schmidt Reaction The acid catalyzed reaction of hydrazoic acid with carboxylic acid to give amines with ketones to give amide and aldehydes to give nitriles are all known as Schmidt reaction. The mechanism of reaction with ketone has similarities with Beckmann rearrangement. Ketone O R" C H+ R' R" C +O N+ N -H2O R" C R' HN N C R' O H R" HN3 N - H N-N2 R' R" + N ' C R R" .. H 2O N CR' OH2 -H R" H O R R" CR' N O O C OH HN3 R -H2O OH2 N _ N H + CR' O H N+ N + O C + R N N -H2O R N C H R C O H R O H N C O N C O .. H-O-H -H H RNH2 + CO2 92 N- Oxidation of Primary Amine (C6H5)3C-NH2 Pb(OAc)4 C6H6, heat (C6H5)2-C=N-C6H5 Mechanism H .. Pb(OAc)4 (C6H5)3C-NH2 (C6H5)2C-N (C6H5)3C-N-Pb(OAc)2 C6H5 O (C6H5)2-C=N-C6H5 CH3-C=O Oxidation of Alkyl Halides C7H15CH2I + (CH3)3N-O Mechanism CHCl3 heat C7H15CHO H C7H15CH2-I + (CH3)3N-O C7H15C O N(CH3)3 H C7H15CHO Aldehyde 93 Oxidation of Sulfur Containing Compounds Oxidation of Thiols: 2RSH H2O2 RSSR Thiols are easily oxidized to disulfides. Many reagents are used to convert them into disulfides. Oxygen in the air oxidizes thiols on standing, if a small amount of base is present. RSH +Base H2O2 RS + BH RS + O2 RS + O2 RS + O2-2 RS + O2 2RS RSSHR -2 O2 + BH OH + B + O2 J. Org. Chem. 1963, 28, 1311. Oxidation of thioethers to sulfoxides and sulfones. O R-S-R R-S-R + H-O-OH H2O2 R-S-R R-S-R O Sulfoxide O Sulfone O .. R-S-R + H-O-O-H R-S-R + H2O R-S-R + OH H O O O R-S-R R-S-R O O-OH O Tetrahedron Lett. 1963, 1479. Ibid, 1966, 1127. Ibid, 1980,3213, J. Chem. Soc, Perkin Tran 2, 1978, 603 J. Chem. Soc, Chem. Commun. 1983, 1203. 94