Reactions of Alcohols Synthesis

Reactions of Alcohols Synthesis

Reactions of Alcohols Oxidation R-X, Ether, and Ester Preparation Protection of Alcohols Synthesis The Logic of Mechanisms Alcohols are Synthetically Versatile Oxidation levels of oxygen- halogen- and nitrogencontaining molecules CH2=CH2 CH3CH3 [O]

CH3CH2OH HC [O] CH CH3CH=O [O] CH3CO2H CH3CH2Cl

CH3CHCl2 CH3CCl3 CH3CH2NH2 CH3CH=NH CH3CN Oxidation Reduction Oxidation - Reduction Oxidation of 2 Alcohols with

Cr(VI) o Mechanism Na2Cr2O7 + H2O + 2 H2SO4 O OH + HO o 2 alcohol

O Cr OCrO3H OH O Chromic Acid (Cr VI) CrO3H H 2 H2CrO4 + 2 NaHSO 4

+ H2O Chromate ester O OH2 + H3O + HCrO 3 ketone (Cr IV) Oxidation of 1 Alcohols o PCC oxidizes 1 Alcohols to Aldehydes

o CrO3Cl N PCC H pyridinium chlorochromate Pyridinium Chlorochromate (PCC) PCC is a complex of chromium trioxide, pyridine, and HCl. Oxidizes primary alcohols to aldehydes. Oxidizes secondary alcohols to ketones.

Oxidation of 1 Alcohols to Aldehydes: PCC o 3 Alcohols Cannot Be Oxidized Carbon does not have hydrogen, so oxidation is difficult and involves the breakage of a CC bond. Chromic acid test is for primary and secondary alcohols because tertiary alcohols do not react. Orange color of Cr(VII) turns green - Cr(III); 3o alcohol is not oxidized, therefore no color change. Sodium Hypochlorite (NaOCl)

Sodium hypochlorite (household bleach) can oxidize alcohols without heavy metals or generating hazardous waste. This is a much better option for acid-sensitive compounds. 2013 Pearson Education, Inc. Chapter 11 12 Swern Oxidation Dimethylsulfoxide (DMSO), with oxalyl chloride and hindered base, oxidizes 2 alcohols to ketones and 1 alcohols to aldehydes (same as PCC).

2013 Pearson Education, Inc. Chapter 11 13 Oxidation Summary CH2CO2H Na2Cr2O7 H2SO4 CH2CH2OH NH

CrO3Cl OO DMSO, ClCCCl (CH3CH2)3N, in CH2Cl2 CH2CHO CH2CHO Reduction Summary CH2CO2H 1) LiAlH 4 2) H3O

CH2CH2OH + 1) NaBH 4 2) H3O CH2CHO + or H2, Raney Ni CH2CHO

Conversion of Alcohol into a Leaving Group Form Tosylate (p-TsCl, pyridine) Use strong acid (H3O+) Convert to Alkyl Halide (HX, SOCl2, PBr3) Formation of p-Toluenesulfonate Esters Substitution and Elimination Reactions Using Tosylates Summary of Tosylate Reactions Best to use p-TsCl with pyridine

CH3 OH CH3 O CH3 + ClS O p-toluenesulfonyl chloride OS N pyridine reacts with

HCl as it forms O O N H Cl CH3 Reactions of Tosylates: Reduction, Substitution, Elimination CH3 OH

CH3 O + ClS O CH3 O OS pyr: CH3

O 1) LiAlH4 KI NaOCH3 CH3 CH3 CH3 I H + LiOTs Reduction of Alcohols

Dehydrate with concentrated H2SO4, then add H2. Make a tosylate, then reduce it with LiAlH4. Alcohols to Alkyl Halides OH HX (HCl or HBr) rapid SN1 o X + HOH

3 alcohol OH HX moderate SN1 o 2 alcohol X + HOH Reaction of Alcohols with Acids

The hydroxyl group is protonated by an acid to convert it into a good leaving group (H2O). Once the alcohol is protonated, a substitution or elimination reaction can take place. 2013 Pearson Education, Inc. Chapter 11 24 Reaction of Alcohols with HBr OH of alcohol is protonated. OH2+ is good leaving group. 3 and 2 alcohols react with Br via SN1. 1 alcohols react via SN2.

SN1 Mechanism Step 1: Protonation. Step 2: Formation of the carbocation. Step 3: Bromide attacks the carbocation. SN1: Carbocations can Rearrange HO Br Br HBr

+ cis & trans HO Br Br H-Br + cis & trans H Br

HO - H2O H Br Solved Problem 2 When 3-methyl-2-butanol is treated with concentrated HBr, the major product is 2-bromo-2methylbutane. Propose a mechanism for the formation of this product. Solution The alcohol is protonated by the strong acid. This protonated secondary alcohol loses water to form a secondary carbocation. Solved Problem 2 (Continued)

Solution (Continued) A hydride shift transforms the secondary carbocation into a more stable tertiary cation. Attack by bromide leads to the observed product. Lucas Test CH3 ZnCl2 12M HCl CH3COH CH3 CH3CCl forms in seconds CH3 + HOZnCl2 CH3

CH3 CH3C CH3 OZnCl2 CH3 H CH3C CH3 Cl SN2 Reaction with the Lucas Reagent

Primary alcohols react with the Lucas reagent (HCl and ZnCl2) by the SN2 mechanism. Reaction is very slow. The reaction can take from several minutes to several days. 2013 Pearson Education, Inc. Chapter 11 32 Qualitative test for Alcohol Characterization primary OH secondary OH

tertiary OH >10 minutes (if at all) ZnCl2, HCl Cl Cl <5 minutes Cl 1-2 seconds

Other Simple Qualitative Tests Alkenes Br Br2 reddish-brown OH colorless Br O

Alcohols Na2Cr2O7 OH H2SO4 orange Cr(VI) green Cr(IV) CO2H 1 and 2 Alcohols: best to use SOCl2, PBr3, or P/I2 o

o All are SN2 Reactions SOCl2 pyridine OH PBr3 P, I2 (in situ prep. of PI3) Cl Br I

Examples Thionyl chloride mechanism in Pyridine SN2, Inversion O Cl OH O O H S S

Cl SOCl 2 Cl + SO2 + HCl pyridine O Cl O Cl H

N S Cl -H + O Cl O S

Cl Dehydration of Alcohols Alcohol dehydration generally takes place through the E1 mechanism. Rearrangements are possible. The rate of the reaction follows the same rate as the ease of formation of carbocations: 3o > 2o > 1o. Primary alcohols rearrange, so this is not a good reaction for converting 1 alcohols into alkenes. 2013 Pearson Education, Inc. Chapter 11

38 Dehydration of Alcohols E1 OH H H2SO4 (aq) cat. + H2O H regenerated H O

HSO4 or H2O H -H2O H Methide Shift is Faster than + Loss of H OH CH3 CH3

CH3 CH3 CH3 H2SO4 (aq) CH3 + distill major minor

+ H2O Dimerization of Alcohols: Symmetrical Ethers Dehydration o 2 CH3CH2CH2OH H2SO4, 125-140 C CH3CH2CH2OCH2CH2CH3 + H2O Mechanism

Dehydration, Acid-Catalyzed o H2SO4, 125-140 C 2 CH3CH2CH2OH H CH3CH2CH2-OH CH3CH2CH2OH CH3CH2CH2OCH2CH2CH3 + H2O loss of H2O

CH3CH2CH2OCH2CH2CH3 H 2O H Esterification Fischer: Alcohol + carboxylic acid Tosylate esters Sulfate esters Nitrate esters

Phosphate esters Fischer Esterification Reaction of an alcohol and a carboxylic acid produces an ester. Sulfuric acid is a catalyst. The reaction is an equilibrium between starting materials and products, and for this reason the Fischer esterification is seldom used to prepare esters. 2013 Pearson Education, Inc. Chapter 11 44

Nitrate Esters The best-known nitrate ester is nitroglycerine, whose systematic name is glyceryl trinitrate. Glyceryl nitrate results from the reaction of glycerol (1,2,3-propanetriol) with three molecules of nitric acid. 2013 Pearson Education, Inc. Chapter 11 45 Phosphate Esters Phosphate Esters in DNA

Protection of Alcohols Suppose you wanted to carry out the following transformation: CH2OH CH2OH CH3 O OH Would the following Grignard sequence work? 1) CH3MgBr 2) H3O Nope.

+ Alcohol is acidic enough to react preferentially. CH2OH CH2OMgBr 1) CH3MgBr 2) H3O O + CH4 +

O Chlorotrimethylsilane (TMS-Cl) Protecting groups temporarily convert reactive functional groups into unreactive groups in a simple, high-yielding reaction. ROH + ClSi(CH 3)3 TMS-Cl pyridine or Et3N dilute H3O +

deprotection ROSi(CH 3)3 + HCl Mechanism is SN2 OH CH3 CH3 CH3 H Si Cl

O SN2 Cl Si(CH3)3 OSi(CH3)3 + HCl Protect as trimethylsilyl ether CH2OH CH2OH CH3

O + 3) H3O protonates & deprotects 1) ClSi(CH 3)3 in pyridine CH2OSi(CH3)3 CH2OSi(CH3)3

2) CH3MgBr dry ether O OH OMgBr CH3 Give the Reagents OH O OCH3

No Protection needed OH O 1) Na metal 2) CH3I 3) CH3CH2MgBr 4) H3O 5) TsCl, pyridine + 6) LiAlH4 7) H3O OCH3 + Road Map Problem

Br A MgBr B O 1) CH3CH2CH 2) H3O + C

Na2Cr2O7 H2SO4 D 1) CH3MgBr 2) H3O + E Mechanisms Thinking Logically Do not use reagents that are not given. Is the product a result of a rearrangement? Only

intermediates can rearrange. Is one of the reagents H3O+? If so, use it in the 1st step. Do not create negatively charged species in acid. CH 2 H3C CH3 CH3 OH +

H , heat H3C CH3 + H2O Only Five Arrows CH2 H3C CH3 CH3 OH

+ H , heat CH3 H3C + H2O H2O H3C CH3 CH3 OH

H H3C CH3 CH3 H H3C CH2 CH3 Propose a Mechanism OCH2CH3

H3O Where do you protonate? + O + CH3CH2OH Both approaches seem logical H H OCH2CH3 +

OCH2CH3 H OCH2CH3 + H OCH2CH3 H Take the Blue Route OCH2CH3 H3O

H O + + CH3CH2OH + OCH2CH3 H2O H O

OH2 O H CH2CH3 H HOCH2CH3 H

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