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 nitrogen- containing molecules

Oxidation - Reduction

Oxidation of 2 o Alcohols with Cr(VI)

Mechanism

Oxidation of 1 o Alcohols

PCC oxidizes 1 o Alcohols to Aldehydes

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 o Alcohols to Aldehydes: PCC

3° Alcohols Cannot Be Oxidized Carbon does not have hydrogen, so oxidation is difficult and involves the breakage of a C—C 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); 3 o alcohol is not oxidized, therefore no color change.

© 2013 Pearson Education, Inc. Chapter 1112 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 1113 Swern Oxidation Dimethylsulfoxide (DMSO), with oxalyl chloride and hindered base, oxidizes 2  alcohols to ketones and 1  alcohols to aldehydes (same as PCC).

Oxidation Summary

Reduction Summary

Conversion of Alcohol into a Leaving Group Form Tosylate (p-TsCl, pyridine) Use strong acid (H 3 O + ) Convert to Alkyl Halide (HX, SOCl 2, PBr 3 )

Formation of p-Toluenesulfonate Esters

Substitution and Elimination Reactions Using Tosylates

Summary of Tosylate Reactions

Best to use p-TsCl with pyridine

Reactions of Tosylates: Reduction, Substitution, Elimination

Reduction of Alcohols Dehydrate with concentrated H 2 SO 4, then add H 2. Make a tosylate, then reduce it with LiAlH 4.

Alcohols to Alkyl Halides

© 2013 Pearson Education, Inc. Chapter 1124 Reaction of Alcohols with Acids The hydroxyl group is protonated by an acid to convert it into a good leaving group (H 2 O). Once the alcohol is protonated, a substitution or elimination reaction can take place.

Reaction of Alcohols with HBr –OH of alcohol is protonated. –OH 2 + is good leaving group. 3° and 2° alcohols react with Br – via S N 1. 1° alcohols react via S N 2.

Step 1: Protonation. Step 2: Formation of the carbocation. Step 3: Bromide attacks the carbocation. S N 1 Mechanism

S N 1: Carbocations can Rearrange

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

A hydride shift transforms the secondary carbocation into a more stable tertiary cation. Attack by bromide leads to the observed product. Solved Problem 2 (Continued) Solution (Continued)

Lucas Test

© 2013 Pearson Education, Inc. Chapter 1132 S N 2 Reaction with the Lucas Reagent Primary alcohols react with the Lucas reagent (HCl and ZnCl 2 ) by the S N 2 mechanism. Reaction is very slow. The reaction can take from several minutes to several days.

Qualitative test for Alcohol Characterization

Other Simple Qualitative Tests

1 o and 2 o Alcohols: best to use SOCl 2, PBr 3, or P/I 2

Examples

Thionyl chloride mechanism in Pyridine – S N 2, Inversion

© 2013 Pearson Education, Inc. Chapter 1138 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: 3 o > 2 o > 1 o. Primary alcohols rearrange, so this is not a good reaction for converting 1° alcohols into alkenes.

Dehydration of Alcohols – E1

Methide Shift is Faster than Loss of H +

Dimerization of Alcohols: Symmetrical Ethers

Mechanism

Esterification Fischer: Alcohol + carboxylic acid Tosylate esters Sulfate esters Nitrate esters Phosphate esters

© 2013 Pearson Education, Inc. Chapter 1144 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 1145 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.

Phosphate Esters

Phosphate Esters in DNA

Protection of Alcohols

Alcohol is acidic enough to react preferentially.

Chlorotrimethylsilane (TMS-Cl)

Mechanism is S N 2

Protect as trimethylsilyl ether

Give the Reagents…

No Protection needed

Road Map Problem

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 H 3 O + ? If so, use it in the 1 st step. Do not create negatively charged species in acid.

Only Five Arrows

Propose a Mechanism

Both approaches seem logical

Take the Blue Route