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KOT 222 ORGANIC CHEMISTRY II CHAPTER 11 REACTIONS OF ALCOHOLS KOT 222 Chapter 11 1 The hydroxyl group of alcohols can be converted to almost any other functional group. R-OH R-Y KOT 222 Chapter 11 2 Types of Alcohol Reactions KOT 222 Chapter 11 3 Oxidation of Alcohols In organic chemistry, increasing the number of bonds to oxygen is considered an oxidation. KOT 222 Chapter 11 4 Oxidizing reagents: Chromium reagent Permanganate Nitric acid Even household bleach (NaOCl). KOT 222 Chapter 11 5 o Oxidation of 2 Alcohols 2o alcohols are oxidized to ketones. Best oxidizing agent: Chromic acid reagent (Na2Cr2O7 or CrO3) Reactive reagent probably is chromic acid (H2CrO4). Orange in color. KOT 222 Chapter 11 6 Mechanism: Observation: Color change from orange to greenish blue. KOT 222 Chapter 11 Cr3+ 7 o Oxidation of 1 Alcohols 1o alcohols is oxidized to aldehydes then to carboxylic acids. KOT 222 Chapter 11 8 Use pyridinium chlorochromate (PCC) to limit the oxidation. PCC also can be used to oxidized 2o alcohol to ketones. KOT 222 Chapter 11 9 o Oxidation of 3 Alcohols Can?? A tertiary alcohol lacks a hydrogen bonded to the carbon attached to the OH group, therefore… KOT 222 Chapter 11 10 3o alcohols do not undergo oxidation. KOT 222 Chapter 11 11 Other Oxidation Reagents Collins reagent: Cr2O3 in pyridine. Jones reagent: chromic acid in acetone KMnO4 (strong oxidizer) Nitric acid (strong oxidizer) Dehydrogenation (CuO, 300°C ) KOT 222 Chapter 11 12 Swern oxidation: dimethyl sulfoxide, with oxalyl chloride and hindered base. oxidizes 2o alcohols to ketones and 1o alcohols to aldehydes. KOT 222 Chapter 11 13 Alcohols as Nucleophiles Alcohols are weak nucleophiles: R R C O O C R H O C H R O H Alkoxide ions are strong nucleophiles: Na R O H R R C O O X R O C H KOT 222 Chapter 11 14 Alcohols as Electrophiles Alcohols are weak electrophiles as –OH is a poor leaving group. -OH becomes good leaving group (H2O) when being protonated. Example: KOT 222 Chapter 11 15 Protonating the alcohols : need a strong acidic solution. and most nucleophiles are strong bases which would remove H+ and protonated. H R O H C X C H R O H + HC C H To overcome this, convert to tosylate (good leaving group) to react with strong nucleophile (base). KOT 222 Chapter 11 16 Formation of Tosylate Ester By condensation of alcohol with: 1. p-toluenesulfonic acid (TsOH) KOT 222 Chapter 11 17 2. tosyl chloride (TsCl) H C O C C H O O Cl O S O N O CH3 S O CH3 p-toluenesulfonyl chloride TsCl, “tosyl chloride” O S O CH3 ROTs, a tosylate ester This reaction gives much higher yields than the reaction with TsOH itself. KOT 222 Chapter 11 18 Reactions of Tosylates Tosylate group (-OTs) is a good leaving group. The tosylate ester can undergo: Elimination (R is a bulky group) C C Substitution, SN2 (R is 1o or 2o alkyl) KOT 222 Chapter 11 19 SN2 reactions of tosylates inverted configuration The tosylate ion is a resonance-stabilized anion KOT 222 Chapter 11 20 SN2 reactions of tosylates With hydroxide produces alcohol With cyanide produces nitrile With halide ion produces alkyl halide With alkoxide ion produces ether With ammonia produces amine salt With LiAlH4 produces alkane KOT 222 Chapter 11 21 Reduction of Alcohols Two methods: 1. Dehydrate with conc. H2SO4 or H3PO4, then add H2 OH CH3CHCH3 H2SO4 ∆ alcohol CH2 H2 CHCH3 Pt alkene E1 dehydration CH3CH2CH3 alkane hydrogenation 2. Tosylate, then reduce with LiAlH4 OH CH3CHCH3 alcohol TsCl pyridine OTs CH3CHCH3 tosylate KOT 222 Chapter 11 LiAlH4 CH3CH2CH3 alkane 22 Reactions of Alcohols with Acids Alcohols react with hydrohalic acids (HX) to give alkyl halides. (X=Br, Cl) In acidic solution of hydrohalic acid, alcohol is protonated. Halide ions, X- react as nucleophiles and attack the protonated alcohol. SN1: with 2o and 3o alcohols. SN2: with 1o alcohols. KOT 222 Chapter 11 23 Reactions with HBr -OH of alcohols is protonated become a good leaving group, -OH2+. 2o and 3o alcohols react via SN1. 1o alcohol react via SN2. KOT 222 Chapter 11 24 Reactions with HCl Chloride is a weaker nucleophile than bromide. ZnCl2 is added to promote the reactions - it bonds more strongly than proton. The reagent composed of HCl and ZnCl2 = Lucas reagent. Lucas test: ZnCl2 in conc. HCl – 1°alcohols react slowly or not at all. – 2° alcohols react in 1-5 minutes. – 3° alcohols react in less than 1 minute. KOT 222 Chapter 11 25 Secondary and tertiary alcohols reacts with the Lucas reagent (HCl and ZnCl2) by the SN1 mechanism. KOT 222 Chapter 11 26 Primary alcohols react with the Lucas reagent (HCl and ZnCl2) by the SN2 mechanism. KOT 222 Chapter 11 27 Limitations of HX Reactions HI does not react Poor yields of 1°and 2°chlorides May get alkene instead of alkyl halide Carbocation intermediate may rearrange. KOT 222 Chapter 11 28 Reactions of Alcohols with Phosphorus Halides A better way to convert alcohols to alkyl halides. Work well with 1o and 2o alcohols. - no carbocation rearrangement. Work poorly with 3o alcohol. - alkyl groups hinder SN2 reaction. KOT 222 Chapter 11 29 PCl3 for alkyl chloride (but SOCl2 better) 3 R-OH + PCl3 → 3 R-Cl + P(OH)3 R-OH + PCl5 → R-Cl + POCl3 + HCl PBr3 for alkyl bromide 3 R-OH + PBr3 → 3 R-Br + P(OH)3 P and I2 for alkyl iodide (PI3 not stable) 6 R-OH + 2 P + 3 I2 → 6 R-I + 2 P(OH)3 KOT 222 Chapter 11 30 SN2 Mechanism with PBr3 • P bonds to -OH as Br- leaves • Br- attacks backside (SN2) • HOPBr2 leaves KOT 222 Chapter 11 31 Reaction with Thionyl Chloride SOCl2 is often the best reagent to give alkyl chloride from an alcohol. The reactant and product (RCl) have the same configuration. Byproducts (SO2 and HCl) are gaseous – no reverse reaction. Work best with 1o and 2o alcohols. Also work with 3o alcohols. KOT 222 Chapter 11 32 Mechanism (SN1): Step 1: The oxygen atom attacks the sulfur of thionyl chloride. A chloride is eliminated followed by the loss of a proton to give a chlorosulfite ester. Step 2: This ester (when R = 2o or 3o) ionizes and the sulfur atom delivers a chloride to the carbocation. If the alkyl group is primary, ionization does not occur, instead the Cl probably bonds to the carbon at the same time the C-O bond is breaking. KOT 222 Chapter 11 33 Dehydration of Alcohols A) Acid catalyzed dehydration: E1 elimination of the protonated alcohol. Ease of dehydration follows the ease of formation of carbocation: 3o > 2o > 1o Carbocation rearrangement especially with 1o alcohol. Follow Zaitsev rule: major product is the highly substituted alkene. KOT 222 Chapter 11 34 The major product is the most stable alkene product The most stable alkene product has the most stable transition state KOT 222 Chapter 11 35 B) Bimolecular dehydration to form ethers: synthesize symmetrical dialkyl ether from simple, unhindered 1o alcohol. Involve SN2 mechanism CH3OH H3O + CH3 OH2 CH3 O CH3 H CH3OH H2O KOT 222 Chapter 11 CH3OCH3 36 Under acidic dehydration, E1 and SN2 compete: SN2 when T ≤ 140 oC 2 CH3CH2OH H2SO4 140 oC CH3CH2-O-CH2CH3 + H20 E1 when T ≥ 180 oC CH3CH2OH H2SO4 180 oC CH2=CH2 + H20 KOT 222 Chapter 11 37 Reactions of Diols Pinacol rearrangement Periodic acid cleavage of glycols KOT 222 Chapter 11 38 Pinacol Rearrangement vicinal diol converts to the ketone (pinacolone) under acidic conditions and heat. Formally an acid-catalyzed dehydration. KOT 222 Chapter 11 39 Mechanism: Step 1&2: Protonation of a hydroxyl group and loss of water. CH3 CH3 CH3 C C CH3 OH OH H CH3 CH3 CH3 + CH3 C C CH3 OH OH CH3 C C OH CH3 CH3 H Step 3: Methyl migration to form a resonance-stabilized carbocation. CH3 CH3 C C OH CH3 CH3 CH3 CH3 C C CH3 OH CH3 CH3 CH3 C C CH3 OH CH3 CH3 Step 4: Deprotonation CH3 KOT 222 Chapter 11 C C O CH3 pinacolone CH3 40 Periodic Acid Cleavage of Glycols Glycols can be oxidatively cleaved by periodic acid (HIO4) to form the corresponding ketones and aldehydes. CH3 H CH3 C C CH3 OH OH Hydroxylation alkene HIO 4 CH3 H C O O3 (CH3)2S OsO 4 H2O 2 H C H3C C CH3 + O C CH3 Ozonolysis-reduction of the corresponding alkene CH3 CH3 KOT 222 Chapter 11 41 Esterification of Alcohols Fischer: alcohol + carboxylic acid Tosylate esters Sulfate esters Esters of inorganic acids Nitrate esters Phosphate esters KOT 222 Chapter 11 42 Fischer Esterification Acid-catalyzed reaction between alcohols and carboxylic acids to form esters + water. Sulfuric acid is a catalyst. The reaction is reversible. O CH3 C OH CH3 + H O CH2CH2CHCH3 + H O CH3 CH3C OCH2CH2CHCH3 + HOH The equilibrium can be shifted to the right by adding excess alcohol / acid or by adding dehydrating agent to remove the water. KOT 222 Chapter 11 43 Tosylate Esters Alcohol + p-Toluenesulfonic acid, TsOH Acid chloride is actually used, TsCl O CH3CH2 O H + HO S CH3 O O CH3CH2 O S O CH3 + HOH Tosylate ester (ROTs) KOT 222 Chapter 11 44 Sulfate Esters Alcohol + Sulfuric acid. O HO S O + OH H + H O CH2CH3 HO O S OCH2CH3 O O CH3CH2O H + HO O + S OCH2CH3 H CH3CH2O O H H N H O S OCH2CH3 O O CH3CH2 S H O CH2CH3 H O N O CH2CH3 O H ethylammonium ion KOT 222 Chapter 11 S O CH2CH3 O ethylsulfate ion 45 Nitrate Esters Alcohols + nitric acid. O O + N OH + H O CH2CH3 H O N OCH2CH3 O Glyceryl nitrate results from the reaction of glycerol (1,2,3propanetriol) with three molecules of nitric acid. KOT 222 Chapter 11 46 Phosphate Esters Alcohol + phosphoric acid. KOT 222 Chapter 11 47 Phosphate esters in DNA O CH2 base O H H H O O CH2 O H P O base O H H O O CH2 O H P O base O H H O O CH2 O H P Phoaphate ester linkage – bond the individual nucleotides together in DNA KOT 222 Chapter 11 O base O H H O O P O O 48 Alkoxides Ions How to form alkoxide ions? R OH O- +Na + 1/2 H2 (g) + Na R + K R 3C 1o/2o alcohol R3C OH O- + K + 1/2 H2 (g) 3o alcohol R OH + NaH THF KOT 222 Chapter 11 R O- +Na + H2 (g) 49 Reaction of Alkoxides Williamson ether synthesis: SN2 displacement reaction. works better with primary alkyl halides to facilitate back-side attack. If a secondary or tertiary alkyl halide is used the alkoxide will acts as a base and an elimination will take place. KOT 222 Chapter 11 50 KOT 222 Chapter 11 51