CH3CH_2CH2 + CH3CH_2CH2 + δ δ H δ δ H BrC O BrC O th H H Organic Chemistry, 6 Edition H H H H L. G. Wade, Jr. Types of Reactions

• Dehydration to • Oxidation to aldehyde, ketone Chapter 11 • Substitution to form alkyl halide Reactions of • Reduction to alkane • Esterification • Tosylation

Jo Blackburn • Williamson synthesis of ether => Richland College, Dallas, TX Dallas County Community College District © 2006, Prentice Hall Chapter 11 2

CH3CH_2CH2 + CH3CH_2CH2 + δ δ H δ δ H BrC O BrC O H H Summary Table H H Oxidation States H H • Easy for inorganic salts 2- ¾CrO4 reduced to Cr2O3

¾KMnO4 reduced to MnO2

• Oxidation: loss of H2, gain of O, O2, or X2 - • Reduction: gain of H2 or H , loss of O, O2, or X2 + • Neither: gain or loss of H , H2O, HX =>

Chapter 11 3 => Chapter 11 4

1 CH3CH_2CH2 + CH3CH_2CH2 + δ δ H δ δ H BrC O BrC O H H 1º, 2º, 3º Carbons H H H H Oxidation of 2° Alcohols • 2° alcohol becomes a ketone

• Reagent is Na2Cr2O7/H2SO4

• Active reagent probably H2CrO4 • Color change: orange to greenish-blue

OH O Na2Cr2O7 / H2SO4 CH3CHCH2CH3 CH3CCH2CH3

=> => Chapter 11 5 Chapter 11 6

CH3CH_2CH2 + CH3CH_2CH2 + δ δ H δ δ H BrC O BrC O H H Oxidation of 1° Alcohols H H 3° Alcohols Don’t Oxidize H H • 1° alcohol to aldehyde to carboxylic acid • Cannot lose 2 H’s • Difficult to stop at aldehyde • Basis for chromic acid test • Use pyridinium chlorochromate (PCC) to limit the oxidation. • PCC can also be used to oxidize 2° alcohols to ketones.

OH NHCrO3Cl O

CH3CH2CH2CH2 CH3CH2CH2CH => => Chapter 11 7 Chapter 11 8

2 CH3CH_2CH2 + SOLVED PROBLEM 11-1 CH3CH_2CH2 + δ δ H δ δ H BrC O Suggest the most appropriate method for each of the following laboratory syntheses. BrC O H (a) ––––––> cyclopentanone H H H H H Other Oxidation Reagents Solution Many reagents are available to oxidize a simple secondary alcohol to a ketone. For a laboratory • Collins reagent: Cr2O3 in pyridine(1° to synthesis, however, dehydrogenation is not practical, and cost is not as large a factor as it would be in industry. Most labs would have chromium trioxide or sodium dichromate available, and the chromic aldh) acid oxidation would be simple. PCC and the Swern oxidation would also work, although these • Jones reagent: chromic acid in acetone reagents are more complicated to prepare and use.

•KMnO4 (strong oxidizer) • Nitric acid (strong oxidizer) • CuO, 300°C (industrial dehydrogenation) • Swern oxidation: dimethylsulfoxide, with oxalyl chloride and hindered base, oxidizes 2° alcohols to ketones and 1° alcohols to aldehydes. => Chapter 11 9 Chapter 11 10

SOLVED PROBLEM 11-1 (continued) CH3CH_2CH2 + CH3CH_2CH2 + δ δ H δ δ H (b) 2-octen-l-ol ––––––> 2-octenal (structure below) BrC O BrC O H Biological Oxidation H Solution H H H H This synthesis requires more finesse. The aldehyde is easily over-oxidized to a carboxylic acid, and the double bond reacts with oxidants such as KMnO4. Our choices are limited to PCC or the Swern • Catalyzed by ADH, alcohol dehydrogenase. oxidation. • Oxidizing agent is NAD+, nicotinamide adenine dinucleotide. • oxidizes to acetaldehyde, then acetic acid, a normal metabolite. • oxidizes to formaldehyde, then formic acid, more toxic than methanol. • oxidizes to oxalic acid, toxic. • Treatment for poisoning is excess ethanol. =>

Chapter 11 11 Chapter 11 12

3 CH3CH_2CH2 + CH3CH_2CH2 + δ δ H δ δ H BrC O BrC O H H Alcohol as a Nucleophile H H Alcohol as an Electrophile H H •OH- is not a good H leaving group unless it H is protonated, but most O nucleophiles are strong O C RX bases which would ∂ + C remove H+. • Convert to tosylate • ROH is weak nucleophile (good leaving group) to - C-Nuc bond forms, •ROis strong nucleophile react with strong C-O bond breaks • New O-C bond forms, O-H bond breaks. nucleophile (base). => => Chapter 11 13 Chapter 11 14

CH3CH_2CH2 + CH3CH_2CH2 + δ δ H δ δ H BrC O BrC O H H H H H H Formation of Tosylate Ester SN2 Reactions of Tosylates H C C O Cl C H O O • With hydroxide produces alcohol O S O N O SO O S O • With cyanide produces nitrile • With halide ion produces alkyl halide • With alkoxide ion produces ether CH CH 3 3 CH3 • With ammonia produces amine salt p-toluenesulfonyl chloride ROTs, TsCl, “tosyl chloride” a tosylate ester • With LiAlH4 produces alkane => =>

Chapter 11 15 Chapter 11 16

4 CH3CH_2CH2 + CH3CH_2CH2 + δ δ H δ δ H BrC O BrC O H H Summary of Tosylate H H Reduction of Alcohols H H Reactions • Dehydrate with conc. H2SO4, then add H2

• Tosylate, then reduce with LiAlH4

OH H2SO4 H2 CH3CHCH3 CH2 CHCH3 CH CH CH Pt 3 2 3 alcohol alkene alkane

OH OTs TsCl LiAlH4 CH3CHCH3 CH3CHCH3 CH3CH2CH3 => alcohol tosylate alkane

=> Chapter 11 17 Chapter 11 18

CH3CH_2CH2 + SOLVED PROBLEM 11-2 CH3CH_2CH2 + δ δ H δ δ H BrC O When 3-methyl-2- is treated with concentrated HBr, the major product is 2-bromo-2-BrC O H methylbutane. Propose a mechanism for the formation of this product. H Reaction with HBr H H H H

• -OH of alcohol is protonated + •-OH2 is good leaving group • 3° and 2° alcohols react with Br- via S 1 Solution N The alcohol is protonated by the strong acid. This protonated secondary alcohol loses water to form a secondary carbocation. • 1° alcohols react via SN2

+ H - H3O Br ROH ROH RBr =>

Chapter 11 19 Chapter 11 20

5 SOLVED PROBLEM 11-2 (continued) CH3CH_2CH2 + CH3CH_2CH2 + δ δ H δ δ H Solution (continued) BrC O BrC O H H A hydride shift transforms the secondary carbocation into a more stable tertiary cation. AttackH by H Reaction with HCl H H bromide leads to the observed product. • Chloride is a weaker nucleophile than bromide.

• Add ZnCl2, which bonds strongly with -OH, to promote the reaction. • The chloride product is insoluble.

• Lucas test: ZnCl2 in conc. HCl ¾1° alcohols react slowly or not at all. ¾2° alcohols react in 1-5 minutes. ¾3° alcohols react in less than 1 minute. =>

Chapter 11 21 Chapter 11 22

CH3CH_2CH2 + CH3CH_2CH2 + δ δ H δ δ H BrC O BrC O H H H H Reactions with H H Limitations of HX Reactions Phosphorus Halides • HI does not react • Good yields with 1° and 2° alcohols • Poor yields of 1° and 2° chlorides •PCl3 for alkyl chloride (but SOCl2 better) • May get alkene instead of alkyl halide • PBr for alkyl bromide • Carbocation intermediate may 3 rearrange. • P and I2 for alkyl iodide (PI3 not stable)

=> =>

Chapter 11 23 Chapter 11 24

6 CH3CH_2CH2 + CH3CH_2CH2 + δ δ H δ δ H BrC O BrC O H Reaction with H Mechanism with PBr3 H H H H Thionyl Chloride

• Produces alkyl chloride, SO2, HCl - • P bonds to -OH as Br- leaves • S bonds to -OH, Cl leaves - •Cl- abstracts H+ from OH •Brattacks backside (SN2) • C-O bond breaks as Cl- transferred to C • HOPBr2 leaves => Chapter 11 25 Chapter 11 26=>

CH3CH_2CH2 + CH3CH_2CH2 + δ δ H δ δ H BrC O BrC O H H Dehydration Reactions H H Dehydration Mechanisms H H H OH OH • Conc. H2SO4 produces alkene H2SO4 CH3CHCH3 CH3CHCH3 CH3CHCH3 • Carbocation intermediate alcohol

H2O • Zaitsev product CH2 CHCH3 + • Bimolecular dehydration produces ether H3O CH3OH CH3 OH2 CH3 O CH3 • Low temp, 140°C and below, favors ether H

• High temp, 180°C and above, favors CH3OH CH3OCH3 H O alkene => 2 =>

Chapter 11 27 Chapter 11 28

7 CH3CH_2CH2 + SOLVED PROBLEM 11-3 CH3CH_2CH2 + δ δ H δ δ H BrC O Predict the products of sulfuric acid-catalyzed dehydration of the following alcohols. BrC O H (a) 1-methylcyclohexanol (b) H Energy Diagram, E1 H H H H Solution (a) 1-Methylcyclohexanol reacts to form a tertiary carbocation. A proton may be abstracted from any one of three carbon atoms. The two secondary atoms are equivalent, and abstraction of a proton from one of these carbons leads to the trisubstituted double bond of the major product. Abstraction of a methyl proton leads to the disubstituted double bond of the minor product.

=> Chapter 11 29 Chapter 11 30

SOLVED PROBLEM 11-3 (continued) CH3CH_2CH2 + CH3CH_2CH2 + δ δ H δ δ H Solution (continued) BrC O BrC O H H (b) Neopentyl alcohol cannot simply ionize to form a primary cation. Rearrangement occursH as theH H H leaving group leaves, giving a tertiary carbocation. Loss of a proton from the adjacent secondary Unique Reactions of Diols carbon gives the trisubstituted double bond of the major product. Loss of a proton from the methyl group gives the disubstituted double bond of the minor product. • Pinacol rearrangement (Dehydration) • Periodic acid cleavage (Aldehydes and ketones

=>

Chapter 11 31 Chapter 11 32

8 CH3CH_2CH2 + CH3CH_2CH2 + δ δ H δ δ H BrC O BrC O H H Pinacol Rearrangement H H Periodic Cleavage H H of Glycols • Pinacol: 2,3-dimethyl-2,3-butanediol Same products formed as from ozonolysis • Dehydration with sulfuric acid of the corresponding alkene. CH CH CH CH CH 3 3 + 3 3 3 H CH3 H CH CH C CCH CH C CCH CH C C 3 CH3 3 3 3 3 3 HIO4 CH3 H OH OH OH OH OH CH3 C CCH3 CH3 C + C CH3 H OH OH O O CH CH 3 3 CH3 CH3 CH C C OsO4 O3 3 CH3 C CCH3 CH3 C CCH3 CH3 H2O2 (CH3)2S OH OH CH3 OH CH3 CH H 3 CH3 CC => CH3 C CCH3 => H3C CH3 O CH3 Chapter 11 33 Chapter 11 34 pinacolone

CH3CH_2CH2 + CH3CH_2CH2 + δ δ H δ δ H BrC O BrC O H H Esterification H H Fischer Esterification H H • Acid + Alcohol yields Ester + Water • Fischer: alcohol + carboxylic acid • Sulfuric acid is a catalyst. • Tosylate esters • Each step is reversible. • Sulfate esters O CH + O CH3 • Nitrate esters 3 H CH3 COH + H O CH2CH2CHCH3 CH3C OCH2CH2CHCH3 • Phosphate esters + HOH => =>

Chapter 11 35 Chapter 11 36

9 CH3CH_2CH2 + CH3CH_2CH2 + δ δ H δ δ H BrC O BrC O H H Tosylate Esters H H Sulfate Esters H H • Alcohol + p-Toluenesulfonic acid, TsOH Alcohol + Sulfuric Acid • Acid chloride is actually used, TsCl

O + O O H HO S OH + HOCH2CH3 HO S OCH2CH3 CH CH OH + HO S CH 3 2 3 O O O

O O O H+ CH3CH2OH+ HO S OCH2CH3 CH3CH2OSOCH2CH3 CH3CH2 OS CH3 => O O O => + HOH Chapter 11 37 Chapter 11 38

CH3CH_2CH2 + CH3CH_2CH2 + δ δ H δ δ H BrC O BrC O H H Nitrate Esters H H Phosphate Esters H H

O H+ O NOH + HOCH2CH3 N OCH2CH3 O O

=> => Chapter 11 39 Chapter 11 40

10 CH3CH_2CH2 + CH3CH_2CH2 + δ δ H δ δ H BrC O BrC O H H Phosphate Esters in DNA H H H H Alkoxide Ions O CH base 2 O H H H • ROH + Na (or NaH) yields sodium alkoxide CH base O O 2 O - P •RO+ 1° alkyl halide yields ether (Williamson OO H H H ether synthesis) O O CH base 2 O P OO H H H O O CH base CH3 2 O P CH CH CHCH CH CH Br 3 2 3 + 3 2 CH2CH2CH OCH2CH3 OO H H H O O O => P OO => Chapter 11 41 Chapter 11 42

CH3CH_2CH2 + δ δ H BrC O H H H

End of Chapter 11

Chapter 11 43

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