Chapter 11 Alcohols & Ethers

Home , Epoxide, Peroxy acid

Ch. 11 - 1 1. Structure & Nomenclature

 Alcohols have a hydroxyl (–OH) group bonded to a saturated carbon atom (sp3 hybridized)

OH OH OH 1o 2o 3o Ethanol 2-Propanol 2-Methyl- (isopropyl 2-propanol alcohol) (tert-butyl alcohol) Ch. 11 - 2 OH OH

2-Propenol 2-Propynol (allyl alcohol) (propargyl alcohol)

Benzyl alcohol

Ch. 11 - 3  Phenols ● Compounds that have a hydroxyl group attached directly to a benzene ring

OH OH Cl OH

H3C

Phenol 4-Methylphenol 2-Chlorophenol

Ch. 11 - 4  Ethers ● The oxygen atom of an ether is bonded to two carbon atoms O CH O 3

Diethyl ether tert-Butyl methyl ether

O O

Divinyl ether Ethyl phenyl ether Ch. 11 - 5 1A. Nomenclature of Alcohols  Rules of naming alcohols ● Identify the longest carbon chain that includes the carbon to which the –OH group is attached ● Use the lowest number for the carbon to which the –OH group is attached ● Alcohol as parent (suffix)  ending with “ol”

Ch. 11 - 6  Examples

OH OH

OH OH 2-Propanol 1,2,3-Butanetriol (isopropyl alcohol)

Ch. 11 - 7  Example

OH 3-Propyl-2-heptanol

7 wrong or 6 1 5 7 3 1 2 3 4 6 5 4 2

OH OH Ch. 11 - 8 1B. Nomenclature of Ethers  Rules of naming ethers ● Similar to those with alkyl halides

 CH3O– Methoxy  CH3CH2O– Ethoxy

 Example

Ethoxyethane (diethyl ether) Ch. 11 - 9  Cyclic ethers O O

Oxacyclopropane Oxacyclobutane or oxirane or oxetane (ethylene oxide)

O O Oxacyclopentane 1,4-Dioxacyclohexane (tetrahydrofuran or THF) (1,4-dioxane) Ch. 11 - 10 2. Physical Properties of Alcohols and Ethers

 Ethers have boiling points that are roughly comparable with those of hydrocarbons of the same molecular weight (MW)  Alcohols have much higher boiling points than comparable ethers or hydrocarbons

Ch. 11 - 11  For example

O OH

Diethyl ether Pentane 1-Butanol (MW = 74) (MW = 72) (MW = 74) b.p. = 34.6oC b.p. = 36oC b.p. = 117.7oC

 Alcohol molecules can associate with each other through hydrogen bonding, whereas those of ethers and hydrocarbons cannot

Ch. 11 - 12  Water solubility of ethers and alcohols ● Both ethers and alcohols are able to form hydrogen bonds with water ● Ethers have solubilities in water that are similar to those of alcohols of the same molecular weight and that are very different from those of hydrocarbons ● The solubility of alcohols in water gradually decreases as the hydrocarbon portion of the molecule lengthens; long- chain alcohols are more “alkane-like” and are, therefore, less like water

Ch. 11 - 13  Physical Properties of Ethers

Name Formula mp bp (oC) (oC) (1 atm)

Dimethyl ether CH3OCH3 -138 -24.9

Diethyl ether CH3CH2OCH2CH3 -116 34.6

Diisopropyl ether (CH3)2CHOCH(CH3)2 -86 68

1,2-Dimethoxyethane CH3OCH2CH2OCH3 -68 83 (DME) O Oxirane -112 12

Tetrahydrofuran (THF) -108 65.4

O Ch. 11 - 14  Physical Properties of Alcohols

Name Formula mp bp (oC) * (oC) (1 atm)

Methanol CH3OH -97 64.7 inf. Ethanol CH3CH2OH -117 78.3 inf. Isopropyl alcohol CH3CH(OH)CH3 -88 82.3 inf. tert-Butyl alcohol (CH3)3COH 25 82.5 inf. Hexyl alcohol CH3(CH2)4CH2OH -52 156.5 0.6

Cyclohexanol OH 24 161.5 3.6

OH Ethylene glycol HO -12.6 197 inf.

* Water solubility (g/100 mL H2O) Ch. 11 - 15 4. Synthesis of Alcohols from Alkenes

 Acid-catalyzed Hydration of Alkenes

H C C C C H O ⊕ 2 H H OH

H2O

C C C C

H H2O H O H H Ch. 11 - 16  Acid-Catalyzed Hydration of Alkenes

● Markovnikov regioselectivity

● Free carbocation intermediate

● Rearrangement of carbocation possible

Ch. 11 - 17  Oxymercuration–Demercuration

OH OH Hg(OAc)2 NaBH4 C C C C C C H2O, THF NaOH HgOAc H

● Markovnikov regioselectivity ● Anti stereoselectivity ● Generally takes place without the complication of rearrangements ● Mechanism  Discussed in Section 8.6 Ch. 11 - 18  Hydroboration–Oxidation

OH 1. BH3 THF H 2. H2O2, OH

● Anti-Markovnikov regioselectivity ● Syn-stereoselectivity ● Mechanism  Discussed in Section 8.7

Ch. 11 - 19 Markovnikov regioselectivity OH + H , H2O or R 1. Hg(OAc)2, H2O, THF 2. NaBH , NaOH 4 H

1. BH3 • THF H 2. H2O2, NaOH OH R Anti-Markovnikov regioselectivity Ch. 11 - 20  Example Synthesis? (1) OH

Synthesis? (2)

Ch. 11 - 21  Synthesis (1) H OH

● Need anti-Markovnikov addition of H–OH ● Use hydroboration-oxidation

H OH

1. BH3 • THF 2. H2O2, NaOH Ch. 11 - 22  Synthesis (2) OH H

● Need Markovnikov addition of H–OH ● Use either  acid-catalyzed hydration or  oxymercuration-demercuration ● Acid-catalyzed hydration is NOT desired due to rearrangement of

carbocation Ch. 11 - 23  Acid-catalyzed hydration HO

H⊕

H2O

H Rearrangement of carbocation (2o cation)

Ch. 11 - 24  Oxymercuration-demercuration OH H

Hg(OAc)2 OH NaBH4 H2O, THF NaOH

HgOAc

Ch. 11 - 25 5. Reactions of Alcohols

 The reactions of alcohols have mainly to do with the following ● The oxygen atom of the –OH group is nucleophilic and weakly basic ● The hydrogen atom of the –OH group is weakly acidic ● The –OH group can be converted to a leaving group so as to allow substitution or elimination reactions

Ch. 11 - 26 δ− δ+ O C–O & O–H bonds of an H + δ alcohol are polarized

 Protonation of the alcohol converts a poor leaving group (OH⊖) into a good

one (H2O) H C O H + H A C O H + A

alcohol strong protonated acid alcohol Ch. 11 - 27  Once the alcohol is protonated substitution reactions become possible

H H SN2 Nu + C O H Nu C + O H

protonated alcohol The protonated –OH group is a good leaving

group (H2O)

Ch. 11 - 28 6. Alcohols as Acids

 Alcohols have acidities similar to that of water

pK a Values for Some Weak Acids

Acid pKa

CH3OH 15.5

H2O 15.74

CH3CH2OH 15.9

(CH3)3COH 18.0 Ch. 11 - 29  Relative Acidity H2O & alcohols are the strongest acids in this series H2O > ROH > RC CH > H2 > NH3 > RH

Increasing acidity

 Relative Basicity OH⊖ is the weakest acid in this series

R > NH2 > H > RC C > RO > HO

Increasing basicity Ch. 11 - 30 7. Conversion of Alcohols into Alkyl Halides

R OH R X

● HX (X = Cl, Br, I)

● PBr3 ● SOCl2

Ch. 11 - 31  Examples

OH conc. HCl Cl + HOH 25oC

(94%)

OH PBr3 Br

(63%)

Ch. 11 - 32 8. Alkyl Halides from the Reaction of Alcohols with Hydrogen Halides

R OH + HX R X + H2O

 The order of reactivity of alcohols ● 3o > 2o > 1o < methyl  The order of reactivity of the hydrogen halides ● HI > HBr > HCl (HF is generally unreactive) Ch. 11 - 33 R OH + NaX No Reaction! OH⊖ is a poor leaving group

H R OH + NaX R X

X R O H ⊕ H3O is a good H leaving group Ch. 11 - 34 8A. Mechanisms of the Reactions of Alcohols with HX

 Secondary, tertiary, allylic, and benzylic alcohols appear to react by a mechanism that involves the formation of a carbocation  Step 1

H + H O H H + O H O O H fast H H Ch. 11 - 35  Step 2

H + O H O slow H H

 Step 3

+ Cl fast Cl

Ch. 11 - 36  Primary alcohols and methanol react to form alkyl halides under acidic

conditions by an SN2 mechanism

H H H H X + R C O H X C R + O H

H H (a good protonated 1o alcohol leaving group) or methanol

Ch. 11 - 37 9. Alkyl Halides from the Reaction

of Alcohols with PBr3 or SOCl2

 Reaction of alcohols with PBr3

3 R OH + PBr3 R Br + H3PO3 (1o or 2o)

● The reaction does not involve the formation of a carbocation and usually occurs without rearrangement of the carbon skeleton (especially if the temperature is kept below 0°C) Ch. 11 - 38  Reaction of alcohols with PBr3

● Phosphorus tribromide is often preferred as a reagent for the transformation of an alcohol to the corresponding alkyl bromide

Ch. 11 - 39  Mechanism

Br PBr2 R OH + P R O + Br Br Br H protonated alkyl dibromophosphite

PBr2 Br + R O R Br + HOPBr2 H a good leaving group Ch. 11 - 40  Reaction of alcohols with SOCl2 o o ● SOCl2 converts 1 and 2 alcohols to alkyl chlorides

● As with PBr3, the reaction does not involve the formation of a carbocation and usually occurs without rearrangement of the carbon skeleton (especially if the temperature is kept below 0°C)

● Pyridine (C5H5N) is often included to promote the reaction Ch. 11 - 41  Mechanism

O H O Cl R O H + Cl S Cl R O S Cl

N − Cl

(C5H5N) O H O N + R O S Cl R O S Cl

Ch. 11 - 42  Mechanism

O O − Cl N + R O S Cl R O S N

Cl⊖

O + O O + N S R Cl O S N

Ch. 11 - 43 10. Tosylates, Mesylates, & Triflates: Leaving Group Derivatives of Alcohols O

OTs = O S CH3 (Tosylate) O

OMs = O S CH3 (Mesylate) O

Ch. 11 - 44  Direct displacement of the –OH group

with a nucleophile via an SN2 reaction is not possible since OH⊖ is a very poor leaving group

OH + Nu No Reaction!

 Thus we need to convert the OH⊖ to a better leaving group first

Ch. 11 - 45  Mesylates (OMs) and Tosylates (OTs) are good leaving groups and they can be prepared easily from an alcohol

(methane sulfonyl chloride) O pyridine OH + CH3 S Cl O

O O S CH + + Cl 3 N O same as H

OMs (a mesylate) Ch. 11 - 46  Preparation of Tosylates (OTs) from an alcohol (p-toluene sulfonyl chloride) O pyridine OH + H3C S Cl O

O O S CH + + Cl 3 N O same as H

OTs (a tosylate) Ch. 11 - 47  SN2 displacement of the mesylate or tosylate with a nucleophile is possible

OTs + Nu

Nu + OTs

Ch. 11 - 48  Example Retention of OH OTs configuration TsCl pyridine

NaCN DMSO

Inversion of configuration CN + NaOTs

Ch. 11 - 49  Example Retention of configuration OH OMs MsCl pyridine

NaSMe DMSO Inversion of configuration SMe

Ch. 11 - 50 11. Synthesis of Ethers 11A. Ethers by Intermolecular Dehydration of Alcohols

H2SO4 180oC Ethene OH

H2SO4 O 140oC Diethyl ether

Ch. 11 - 51  Mechanism

OH + H OSO3H O H + OSO3H H

O O + H2O H H2O ● This method is only good for synthesis of symmetrical ethers Ch. 11 - 52  For unsymmetrical ethers

H2SO4 + O ROH R'OH R R' + o 1 alcohols O Mixture R R of ethers + O R' R'

Ch. 11 - 53  Exception

cat. H2SO4 R OH + R O HO + HO H (good yield) H

R OH Ch. 11 - 54 11B. The Williamson Synthesis of Ethers

R'O R X R O R' (SN2)

o  Via SN2 reaction, thus R is limited to 1 (but R' can be 1o, 2o or 3o)

Ch. 11 - 55  Example 1

Na H O O Na + H2 H

Ch. 11 - 56  Example 2

Cl NaOH Cl HO H2O O

Ch. 11 - 57  Example 3

I NaOH O H2O OH

 However

I NaOH No epoxide observed! H2O OH

Ch. 11 - 58 11C. Synthesis of Ethers by Alkoxy- mercuration–Demercuration Markovnikov regioselectivity

OR' 1. Hg(O2CCF3)2, R'OH R R 2. NaBH4, NaOH

(1) (2) OR'

Hg(O2CCF3) Ch. 11 - 59  Example

i 1. Hg(O2CCF3)2, PrOH O

2. NaBH4, NaOH

Ch. 11 - 60 11D. tert-Butyl Ethers by Alkylation of Alcohols: Protecting Groups

H2SO4 R OH + R O

 A tert-butyl ether can be used to tert-butyl “protect” the hydroxyl group of a 1o protecting alcohol while another reaction is carried group out on some other part of the molecule  A tert-butyl protecting group can be removed easily by treating the ether with dilute aqueous acid Ch. 11 - 61  Example

Synthesis of 1 3 5 HO 2 4

1 3 from HO Br 2

5 and BrMg 4

Ch. 11 - 62 ● Direct reaction will not work BrMg (Not Formed) + ☓ HO HO Br ● Since Grignard reagents are basic and alcohols contain acidic proton BrMg

+ BrMg O Br H O Br + H Ch. 11 - 63 ● Need to “protect” the –OH group first tert-butyl protected alcohol

1. H2SO4 HO Br O Br 2.

BrMg

H HO O H2O deprotonation Ch. 11 - 64 11E. Silyl Ether Protecting Groups

 A hydroxyl group can also be protected by converting it to a silyl ether group

Me Me imidazole Me Me R O H + Si R Si Cl tBu DMF O tBu (−HCl) tert-butylchloro ( R O T B S ) dimethylsilane (TBSCl)

Ch. 11 - 65  The TBS group can be removed by treatment with fluoride ion (tetrabutyl- ammonium fluoride or aqueous HF is frequently used)

+ − Me Me Bu4N F Me Me R Si R O H + Si O tBu THF F tBu

( R O T B S )

Ch. 11 - 66  Example

2 4 6 Synthesis of HO Ph 5 1 3

2 4 from HO 1 3 I

and Ph Na 6 5

Ch. 11 - 67 ● Direct reaction will not work

Ph Na (Not Formed) + ☓ HO Ph O H I

● Instead

Na Ph H Ph O + + O O H I I Ch. 11 - 68 ● Need to “protect” the –OH group first

HO TBSCl TBSO I I imidazole DMF Na Ph

TBSO Ph

Bu4N F THF

HO Ph

Ch. 11 - 69 12. Reactions of Ethers

 Dialkyl ethers react with very few reagents other than acids

O + HBr O + Br H an oxonium salt

Ch. 11 - 70 12A. Cleavage of Ethers

 Heating dialkyl ethers with very strong

acids (HI, HBr, and H2SO4) causes them to undergo reactions in which the carbon–oxygen bond breaks

O + 2 HBr 2 Br + H2O

Cleavage of an ether

Ch. 11 - 71  Mechanism

O + H Br O + Br H

Br H H O + Br O + Br H

O H H + Br Ch. 11 - 72 13. Epoxides

 Epoxide (oxirane) ● A 3-membered ring containing an oxygen

Ch. 11 - 73 13A. Synthesis of Epoxides: Epoxidation  Electrophilic epoxidation

peroxy O C C C C acid

Ch. 11 - 74  Peroxy acids (peracids)

O R C O OH

● Common peracids

Cl O O

C O OH H3C C O OH

meta-chloroperbenzoid acid peracetic acid (MCPBA) Ch. 11 - 75  Mechanism

R R carboxylic R peroxy acid acid O O O O O O O O O H H H

epoxide alkene concerted transition state Ch. 11 - 76 13B. Stereochemistry of Epoxidation  Addition of peroxy acid across a C=C bond  A stereospecific syn (cis) addition O MCPBA

(trans) (trans)

O MCPBA

(cis) (cis) Ch. 11 - 77  Electron-rich double reacts faster

MCPBA O (1 eq.)

Ch. 11 - 78 14. Reactions of Epoxides

 The highly strained three-membered ring of epoxides makes them much more reactive toward nucleophilic substitution than other ethers

Ch. 11 - 79  Acid-catalyzed ring opening of epoxide

C C + H O H C C + O H O H O H H O H H O H H H H + O H O H C C C C H O H O Ch. 11 - 80  Base-catalyzed ring opening of epoxide

RO R O + C C C C O O

R O H

RO C C + R O OH Ch. 11 - 81  If the epoxide is unsymmetrical, in the base-catalyzed ring opening, attack by the alkoxide ion occurs primarily at the less substituted carbon atom EtO Et O + O O 1o carbon atom is EtOH less hindered EtO + Et O OH Ch. 11 - 82  In the acid-catalyzed ring opening of an unsymmetrical epoxide the nucleophile attacks primarily at the more substituted carbon atom cat. HA MeOH + O MeO OH

MeOH + O MeO OH (protonated epoxide) H H o This carbon resembles a 3 carbocation Ch. 11 - 83 15. Anti 1,2-Dihydroxylation of Alkenes via Epoxides

 Synthesis of 1,2-diols − OH cold KMnO4, OH or

1. OsO4 OH 2. NaHSO3

1. MCPBA OH + 2. H , H2O

OH Ch. 11 - 84  Anti-Dihydroxylation ● A 2-step procedure via ring-opening of epoxides

H H MCPBA H+ O O H H2O H H

OH H2O

OH Ch. 11 - 85 16. Crown Ethers

 Crown ethers are heterocycles containing many oxygens

 They are able to transport ionic compounds in organic solvents – phase transfer agent

Ch. 11 - 86  Crown ether names: x-crown-y ● x = ring size ● y = number of oxygen

O O O O O O O O O O O O O O O (18-crown-6) (15-crown-5) (12-crown-4)

Ch. 11 - 87  Different crown ethers accommodate different guests in this guest-host relationship ● 18-crown-6 for K+ ● 15-crown-5 for Na+ ● 12-crown-4 for Li+

 1987 Nobel Prize to Charles Pedersen (Dupont), D.J. Cram (UCLA) and J.M. Lehn (Strasbourg) for their research on ion transport, crown ethers Ch. 11 - 88  Many important implications to biochemistry and ion transport

O O O O O O KMnO4 K MnO benzene 4 O O O O O O

(18-crown-6) (purple benzene)

Ch. 11 - 89  Several antibiotics call ionophores are large ring polyethers and polylactones

Me Me O

O O O O Me Me O Me O Me O O O O

O Me Me

Nonactin Ch. 11 - 90 17. Summary of Reactions of Alkenes, Alcohols, and Ethers  Synthesis of alcohols X OH

O OH 1. 1. BH3 THF 2. H2O 2. H O , NaOH (1o alcohol) 2 2

MgBr Ch. 11 - 91  Synthesis of alcohols

1. BH3 THF 2. H2O2, NaOH

OH 1. Hg(OAc)2, H2O + H , H2O 2. NaBH4 (2o alcohol)

Ch. 11 - 92  Synthesis of alcohols

H2O

1. Hg(OAc)2, H2O + H , H2O OH 2. NaBH4 (3o alcohol)

Ch. 11 - 93  Reaction of alcohols OR Br

1. base PBr3 2. R-X H+, heat

OH TsCl SOCl2 (1o alcohol) pyridine

Cl H-X OTS

X Ch. 11 - 94  Synthesis of ethers

conc. H SO R O R 2 4 RO 140oC

R X R OH

 Cleavage reaction of ethers

H X X R O R' R O R' ROH+R'X H Ch. 11 - 95  END OF CHAPTER 11 

Ch. 11 - 96