chapter 11 1.structure & nomenclature - 건국대학교...

1

Created byProfessor William Tam & Dr. Phillis Chang

Chapter 11

Alcohols & Ethers

Copyright © 2014 by John Wiley & Sons, Inc. All rights reserved.

OH OH OH

1. Structure & Nomenclaturev Alcohols have a hydroxyl (–OH) group

bonded to a saturated carbon atom (sp3 hybridized)

1o 2o 3o

Ethanol 2-Propanol(isopropylalcohol)

2-Methyl-2-propanol

(tert-butyl alcohol)© 2014 by John Wiley & Sons, Inc. All rights reserved.

OHOH

OH

2-Propenol(allyl alcohol)

2-Propynol(propargyl alcohol)

Benzyl alcohol© 2014 by John Wiley & Sons, Inc. All rights reserved.

v Phenols• Compounds that have a hydroxyl

group attached directly to a benzene ring

© 2014 by John Wiley & Sons, Inc. All rights reserved.

2

v Ethers• The oxygen atom of an ether is

bonded to two carbon atoms

Diethyl ether tert-Butyl methyl ether

Divinyl ether

OO

CH3

O O

Ethyl phenyl ether© 2014 by John Wiley & Sons, Inc. All rights reserved.

1A. Nomenclature of Alcoholsv 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)t ending with “ol”


v Examples

OH

OHOH

OH

2-Propanol(isopropyl alcohol)

1,2,3-Butanetriol


v Example

OH

OH

12 3 4

56

7

OH

125 4

3

67

8

or wrong

3-Propyl-2-heptanol


3

1B. Nomenclature of Ethersv Rules of naming ethers

• Similar to those with alkyl halidest CH3O– Methoxyt CH3CH2O– Ethoxy

v ExampleO

Ethoxyethane(diethyl ether)


v Cyclic ethers


2. Physical Properties ofAlcohols and Ethers

v Ethers have boiling points that are roughly comparable with those of hydrocarbons of the same molecular weight (MW)

v Alcohols have much higher boiling points than comparable ethers or hydrocarbons


v For example

O

Diethyl ether(MW = 74)

b.p. = 34.6oC

Pentane(MW = 72)b.p. = 36oC

OH

1-Butanol(MW = 74)

b.p. = 117.7oC

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


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v 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


v Physical Properties of Ethers

Dimethyl ether

Diethyl ether

Diisopropyl ether

1,2-Dimethoxyethane

CH3OCH3

CH3CH2OCH2CH3

(CH3)2CHOCH(CH3)2CH3OCH2CH2OCH3

-138

-116

-86

-68

-24.9

34.6

68

83

O

O

(DME)

Oxirane

Tetrahydrofuran (THF)

-112

-108

12

65.4

Name Formula mp(oC)

bp (oC)(1 atm)


v Physical Properties of Alcohols

MethanolEthanolIsopropyl alcoholtert-Butyl alcoholHexyl alcohol

Cyclohexanol

Ethylene glycol

CH3OHCH3CH2OHCH3CH(OH)CH3(CH3)3COHCH3(CH2)4CH2OH

-97-117-8825

-52

24

-12.6

64.778.382.382.5

156.5

161.5

197

inf.inf.inf.inf.0.6

3.6

inf.

OH

HOOH

Name Formula mp(oC)

bp (oC)(1 atm)

*

* Water solubility (g/100 mL H2O)© 2014 by John Wiley & Sons, Inc. All rights reserved.

3. Important Alcohols & Ethers3A. Methanol

v Methanol is highly toxicv Ingestion of even small quantities of

methanol can cause blindnessv Large quantities cause deathv Methanol poisoning can also occur by

inhalation of the vapors or by prolonged exposure to the skin


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3B. Ethanolv Ethanol can be produced by

• Fermentation

• Acid-catalyzed hydration of ethene


3C. Ethylene and Propylene Glycols

a good automobileanti-freeze

as a low-toxicity, environmentally

friendly alternativeto ethylene glycol


3D. Diethyl Etherv Diethyl ether is a very low boiling,

highly flammable liquid

v Most ethers react slowly with oxygen by a radical process called autoxidation to form hydroperoxidesand peroxides


v Step 1

v Step 2

Hydrogen abstractionadjacent to the ether oxygen

occurs readily


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v Step 3a

orv Step 3b

Hydroperoxides and peroxidescan be explosive

A hydroperoxide

A peroxide© 2014 by John Wiley & Sons, Inc. All rights reserved.

4. Synthesis of Alcohols from Alkenes

v Acid-catalyzed Hydration of Alkenes

C CHH2O

C COHH

C COHH

HC CH

H⊕

H2O

H2O


C C E Nu

EC C

Nu+

1. Addition Reactions of Alkenes


1A. How To Understand Additions to Alkenes

v This is an addition reaction: E–Nuadded across the double bond

C C E Nu

EC C

Nu+

Bonds broken Bonds formed

p-bond s-bond 2 s-bonds


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v Acid-Catalyzed Hydration of Alkenes

• Markovnikov regioselectivity

• Free carbocation intermediate

• Rearrangement of carbocationpossible

© 2014 by John Wiley & Sons, Inc. All rights reserved. © 2014 by John Wiley & Sons, Inc. All rights reserved.

H Br

H H

Br

Br

fast(1o cation)(minor)

slow(r.d.s.)

Br

fast

H

Br

H

(2o cation)(major)

☓

Step 1 Step 2© 2014 by John Wiley & Sons, Inc. All rights reserved. © 2014 by John Wiley & Sons, Inc. All rights reserved.

8

v Oxymercuration–Demercuration

• Markovnikov regioselectivity• Anti stereoselectivity• Generally takes place without the

complication of rearrangements• Mechanism

t Discussed in Section 8.5

C C H2O, THF C CHgOAc

OHHg(OAc)2

C CH

OH

NaOHNaBH4


HgOAc

d+

d+

+AcO

HO

HgOAc

5C. Mechanism of Oxymercurationv Does not undergo a “free carbocation”v H2O attacks the carbon of the bridged Hg ion

that is better able to bear the partial +ve charge

H2O

H2O


v Stereochemistry● Usually anti-addition H2O

OH

CH3

H

Hg(OAc)© 2014 by John Wiley & Sons, Inc. All rights reserved.

v Solvomercuration-Demercuration

OR

Hg(O2CCF3)

NaBH4HO

OR

H

Hg(O2CCF3)2

THF-ROH


9

v Hydroboration–Oxidation

• Anti-Markovnikov regioselectivity• Syn-stereoselectivity• Mechanism

t Discussed in Section 8.7


7A. Mechanism of Hydroboration

H

H3C

H

H

+

H BHH

H

H3C

H

H

H BHH

p complex

H

H3C

H

H

H BHH

HH3C

HH

H BH

H

d+

d-

four-atomconcerted T.S.

HH3C

HH

H BH

Hsyn additionof H and B


7B. Stereochemistry of Hydroboration

v Syn addition

H3C HBH3-THF

H

CH3

BH2

H


● Via

R3B O OHRBR

R O OHR

BOR

R

O OH

ROB

OR

ROHO

RBOR

O ORHO RO

BOR

OR

RBO

R OR

OH


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v Hydrolysis

NaOHH2O

OB

O O

OH + Na3BO33


R

R

OH

H

R

HOH

H+, H2O or1. Hg(OAc)2, H2O, THF2. NaBH4, NaOH

1. BH3 • THF2. H2O2, NaOH

Markovnikov regioselectivity

Anti-Markovnikov regioselectivity© 2014 by John Wiley & Sons, Inc. All rights reserved.

v Example

OH

OHSynthesis?

(1)

Synthesis?(2)


v Synthesis (1)

OHH

• Need anti-Markovnikov addition of H–OH

• Use hydroboration-oxidation

OHH

1. BH3 • THF2. H2O2, NaOH


11

v Synthesis (2)

HOH

• Need Markovnikov addition of H–OH• Thus, could potentially use either

t acid-catalyzed hydration ort oxymercuration-demercuration

• However, acid-catalyzed hydration is NOT reasonable here due to likely rearrangement of carbocation


H

H⊕H2O

HO

Rearrangementof carbocation

(2o cation)

v Acid-catalyzed hydration


HOH

HgOAc

OHHg(OAc)2H2O, THF

v Oxymercuration-demercuration

NaBH4NaOH


5. Reactions of Alcoholsv 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


12

OH

d-

d+d+ C–O & O–H bonds of an

alcohol are polarized

v Protonation of the alcohol converts a poor leaving group (HO⊖) into a good one (H2O)


v Once the alcohol is protonated substitution reactions become possible

C O HH

Nu + CNu + O HH

protonatedalcohol

SN2

The protonated –OHgroup is a good leavinggroup (H2O)


6. Alcohols as Acidsv Alcohols have acidities similar to that of

waterpKa Values for Some Weak AcidsAcid pKa

CH3OH 15.5H2O 15.74CH3CH2OH 15.9(CH3)3COH 18.0


v Relative Acidity

H2O > ROH > > H2 > NH3 > RHRC CH

H2O & alcohols are thestrongest acids in this series

Increasing acidity

v Relative Basicity

R > NH2 > H > > RO > HORC C

HO⊖ is the weakestacid in this series

Increasing basicity© 2014 by John Wiley & Sons, Inc. All rights reserved.

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7. Conversion of Alcohols intoAlkyl Halides

• HX (X = Cl, Br, I)• PBr3• SOCl2

R OH R X


OH Clconc. HCl25oC

+ HOH

(94%)

v Examples

OH Br

(63%)

PBr3


8. Alkyl Halides from the Reactionof Alcohols with HydrogenHalides

v The order of reactivity of alcohols• 3o

v The order of reactivity of the hydrogen halides• HI > HBr > HCl

(HF is generally unreactive)

R OH R XHX+ + H2O

> 2o > 1o < methyl


R OH NaX+ No Reaction!HO⊖ is a poorleaving group

H3O⊕ is a good

leaving group© 2014 by John Wiley & Sons, Inc. All rights reserved.

14

Substitution Reactions of ROH

Why no heat required here?

8A. Mechanisms of the Reactions ofAlcohols with HX

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

v Step 1

H O HH

OH + O H

HO

H +

Hfast


v Step 2

OH

H

O HH

+slow

v Step 3

+ ClClfast


Carbocation rearrangements will occur if it leads to the formation of a more stable carbocation (4.6)

15


v Primary alcohols and methanol react to form alkyl halides under acidic conditions by an SN2 mechanism

+X R C O HH

H

H

protonated 1o alcoholor methanol

RCH

HX O H

H+

(a goodleaving group)


16

9. Alkyl Halides from the Reactionof Alcohols with PBr3 or SOCl2

v Reaction of alcohols 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)


v Mechanism

R OH

BrP

Br Br+ R O

PBr2

H

Br

protonatedalkyl dibromophosphite

+

R OPBr2

H

Br

a goodleaving group

+ R Br + HOPBr2


“Activated” alcohols -conversion to a better leaving group: now allows alcohols to undergo substitution reactions


“Proton sponge”

17

v Mechanism

OOSCl Cl+HR O SR

H OClCl

N

(C5H5N)


+ O SRO

NCl

v Mechanism

Cl⊖O SR

OCl+N

+ SO ON

- ClO SR

ON


10. Tosylates, Mesylates, andTriflates: Leaving Group Derivatives of Alcohols


v Direct displacement of the –OH group with a nucleophile via an SN2 reaction is not possible since HO⊖ is a very poor leaving group

OH + No Reaction!Nu

v Thus we need to convert the HO⊖ to a better leaving group first


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v Mesylates (OMs) and Tosylates (OTs) are good leaving groups and they can be prepared easily from an alcohol

(methanesulfonyl chloride)


v Preparation of Tosylates (OTs) from an alcohol (p-toluenesulfonyl chloride)



v SN2 displacement of the mesylate or tosylate with a nucleophile is possible

OTs

Nu

Nu

OTs

+

+


19

v Example

+ NaOTs

OHTsCl

pyridine

OTs

NaCNDMSO

CN

Retention ofconfiguration

Inversion ofconfiguration


v Example

MsClpyridine

NaSMeDMSO

OH OMs

SMe

Retention ofconfiguration

Inversion ofconfiguration


11. Synthesis of Ethers

OH

O

180oC

H2SO4

H2SO4

140oC

Ethene

Diethyl ether

11A. Ethers by IntermolecularDehydration of Alcohols


Elimination Reactions of ROHE2 Reactions of Alcohols - 1° and 2° alcohols (3° prefer E1):

RULE - 1° alcohols undergoing dehydration have competing E2 and SN2 pathways

20

Elimination Reactions of ROHE1 Reactions of Alcohols - 2° and 3° alcohols:

Notice - no substitution products, because there is no good Nu: in solution

substitution

elimination

carbocationintermediate

Elimination reactions generally have a higher ACTIVATION ENERGY (are more difficult) than

substitution

SUBSTITUTION vs ELIMINATION

HIGHER TEMPERATUREGENERALLY INCREASESTHE AMOUNT OF ELIMINATION

Elimination Reactions of ROH

Why?

RDS of mechanism involves generation of a carbocation intermediate - that which forms fastest is the most stable (3° > 2° > 1°)

3° alcohol dehydration conditions - 50°C in 5% H2SO4

2° alcohol dehydration conditions - 100°C in 75% H2SO4

1° alcohol dehydration conditions - 175°C in 95% H2SO4 - operates via different mechanism because 1° carbocations too unstable….

OH

H + OSO3H

OH

+ H2O

v Substitution Mechanism

+OH H OSO3H

OH

H2O

O

• This method is only good for the synthesis of symmetrical ethers


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v For unsymmetrical ethers

+R

OR'ROH + R'OH

+R

OR

R'O

R'

H2SO4

Mixtureof ethers

1o alcohols


v Exception

+R OH HO

cat. H2SO4R O

+ HO H

H

R OH

(good yield)


R X R O R'R'O

(SN2)

11B. The Williamson Ether Synthesis

v Via SN2 reaction, thus R is limited to 1o

and some 2o (but R' can be 1o, 2o or 3o)


v Example 1

OH

Na H O Na + H2

Br

O


22

v Example 2

NaOH

H2OHOCl

O

Cl

O


v Example 3

NaOH

H2OOH

IO

v However

NaOH

H2OOH

INo epoxide observed!


R1. Hg(O2CCF3)2, R'OH

2. NaBH4, NaOH

11C. Synthesis of Ethers by Alkoxy-mercuration–Demercuration

R

OR'

Hg(O2CCF3)

(1) (2)

R

OR'Markovnikov regioselectivity


v Example

O1. Hg(O2CCF3)2, iPrOH

2. NaBH4, NaOH


23

R OH R OH2SO4+

tert-butylprotecting

group

11D. tert-Butyl Ethers by Alkylationof Alcohols: Protecting Groups

v A tert-butyl ether can be used to “protect” the hydroxyl group of a 1o

alcohol while another reaction is carried out on some other part of the molecule

v A tert-butyl protecting group can be removed easily by treating the ether with dilute aqueous acid


Deprotection

v Example

Synthesis ofHO

HO Br

BrMg

from

and

1

2

3

4

5

1

2

3

4

5


• Direct reaction will not work

HOHO Br

BrMg

+ ☓(Not Formed)

• Reason: Grignard reagents are basic and alcohols contain an acidic proton

O Br

BrMg

+

HBrMg O Br

+ H© 2014 by John Wiley & Sons, Inc. All rights reserved.

24

• Need to “protect” the –OH group first

HO Br1. H2SO4

2. O Br

BrMg

OHOH

H2O

tert-butyl protected alcohol

deprotection© 2014 by John Wiley & Sons, Inc. All rights reserved.

+

tert-butylchlorodimethylsilane

(TBSCl)

R O HCl

Si tBu

Me Me

OSi tBu

Me MeR

imidazole

DMF(-HCl)

R O TBS( )

11E. Silyl Ether Protecting Groupsv A hydroxyl group can also be protected

by converting it to a silyl ether group

v Very common, useful protecting group© 2014 by John Wiley & Sons, Inc. All rights reserved.


+R O HF

Si tBu

Me Me

OSi tBu

Me MeR

R O TBS( )

Bu4N+F-

THF

v The TBS group can be removed by treatment with fluoride ion (tetrabutyl-ammonium fluoride or aqueous HF is frequently used)


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v Example

Synthesis of HO

HO

Ph

from

and

1

2

3

4

5

1

2

3

5

Ph6

I4

Na6


HO Ph

• Direct reaction will not work

+O

Ph

I

Na

H

☓ (Not Formed)

• Instead

+O

Ph

I

Na

HO

I

H Ph+

O


I IHO TBSOTBSCl

imidazoleDMF

• Need to “protect” the –OH group first


12. Reactions of Ethers

O + HBr BrOH

+

an oxonium salt

v Dialkyl ethers react with very few reagents other than acids


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12A. Cleavage of Ethers

v 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 H2O+Br2

Cleavage of an ether


OH + Br

v Mechanism

H BrO + BrOH

+

HBr

Br+HO

H© 2014 by John Wiley & Sons, Inc. All rights reserved.

13. Epoxidesv Epoxide (oxirane)

• A 3-membered ring containing an oxygen


13A. Synthesis of Epoxides:Epoxidation

C C C COperoxy

acid

v Electrophilic epoxidation


27

R CO

O OH

v Peroxy acids (peracids)

• Common peracids


O

OH

O

R

v Mechanism

O

OH

O

R

O

OH

O

Rperoxy acid

alkeneconcertedtransition

state

carboxylicacid

epoxide


13B. Stereochemistry of Epoxidationv Addition of peroxy acid across a C=C

bondv A stereospecific syn (cis) addition


v More electron-rich double reacts faster


28

14. Reactions of Epoxidesv The highly strained three-membered

ring of epoxides makes them much more reactive toward nucleophilic substitution than other ethers


Reactions of EpoxidesEther - acyclic compound with significant rotational freedom - reactant is relatively stable (“inert” solvent)

Epoxide - cyclic compound with significant ring strain - reactant is significantly destabilized (higher in energy)

+ O HH

CCOH

O HH

+ HCCO

v Acid-catalyzed ring opening of epoxide

O HH

C CO

O HH

H

O HH+

H

C CO

O H

H


+ CCO

OR

v Base-catalyzed ring opening of epoxide

CCRO

O

OR H

+CCRO

OHOR


29

+O

OEt

v 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

O

1o carbon atom isless hindered


+O

MeOHMeO OH

cat. HA

v In the acid-catalyzed ring opening of an unsymmetrical epoxide the nucleophile attacks primarily at the more substituted carbon atom

This carbon resembles a 3o carbocation

+O

MeOHMeO OH

H H(protonated

epoxide)


Reactions of EpoxidesA protonated epoxide is so reactive that the C-O bond begins to break even before Nu: attack… the bond that is easier (faster) to break is that which will put a developing charge on a more stable carbon…

.

RULE - Nu: substitution of epoxides is both SN1- and SN2-like - not pure SN1 (no carbocation formed), but not pure SN2 (leaving group begins to depart before Nu: attack)

15. Anti 1,2-Dihydroxylation of Alkenes via Epoxides

v Synthesis of 1,2-diols


30


v Anti-Dihydroxylation• A 2-step procedure via ring-opening

of epoxides

H2OOH

OH© 2014 by John Wiley & Sons, Inc. All rights reserved.

16. Crown Ethers

v Crown ethers are cyclic compounds containing many oxygen atoms

v They are able to transport (i.e. dissolve) ionic compounds in organic solvents – phase transfer agent


v Crown ether nomenclature: x-crown-y● x = # of atoms in ring● y = # of oxygen atoms in ring

OO

O

OO

O

O O

O OO O

OOO

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


31

v 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+

v 1987 Nobel Prize to Charles Pedersen (DuPont), D.J. Cram (UCLA) and J.M. Lehn (Strasbourg) for their research on ion transport, crown ethers


v Many important implications to biochemistry and ion transport

OO

O

OO

OK

OO

O

OO

O

KMnO4

benzene MnO4

(18-crown-6) (purple benzene)


• The ability of crown ethers to complex cations can be exploited in nucleophilic substitution reactions.

v Several antibiotics call ionophores are large ring polyethers and polylactones

O

O

O

O

Me

O

O

O Me

O O

O

Me

O

Me

Me

O

Me

MeMe

Nonactin© 2014 by John Wiley & Sons, Inc. All rights reserved.

32

17. Summary of Reactions of Alkenes, Alcohols, and Ethers

v Synthesis of alcohols

OH

(1o alcohol)

1. BH3 THF2. H2O2, NaOH

MgBr

1. 2. H2O

O



OH

(2o alcohol)

1. BH3 THF2. H2O2, NaOH

1. Hg(OAc)2, H2O2. NaBH4

or

H+, H2O



(3o alcohol)

OH1. Hg(OAc)2, H2O2. NaBH4


v Reaction of alcohols

OH

(1o alcohol)

OR

1. base2. R-X

SOCl2

Cl

Br

PBr3


33

v Synthesis of ethers

R O R

R OH

conc. H2SO4140oC

R X

RO

v Cleavage reaction of ethers

R O R' H X X ROH+R'XR O R'H


If an excess (2 equiv or more) of HI is present, that alcohol can be converted into an alkyl iodide through two subsequent steps (protonation / SN2).


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chapter 11 1.structure & nomenclature - 건국대학교...

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