Chapter 7Alcohols, Ethers, and Epoxides

( 醇、醚、环氧化物 )Text 1: Chapter 10, 11, 14

I. Alcohol ( 醇 )• The origins of alcohols Ethyl alcohol (ethanol): grain alcohol （酒精） Methyl alcohol (methanol): wood alcohol （木

醇）

• Role of alcohols Reagents Solvents Synthetic intermediates ( 合成中间体 )

1. Structure of alcohols

HO

H104.5°

OH

methanol甲醇 Phenol

苯酚

CH

OH3CCH

OH

H2C

Enol ( 烯醇 ) Aldehyde ( 醛 )

sp3

sp2

sp2

tautomerism互变异构

sp3

CH3CH2

OHCH3

OH

108.9°

ethanol乙醇

sp3

2. Classification of alcohols

• According to the type of carbinol carbon atom alcohols can be classified as follows:

C

H

R

H

OH C

H

R

R

OH C

R

R

R

OH

primary alcohol( 伯醇 )

1°

secondary alcohol( 仲醇 )

2°

tertiary alcohol( 叔醇 )

3°

3. Nomenclature of Alcohols

CH3OH

IUPAC names: alkane alkanol

Common names:

中文 :

alkyl alcohol

XX 醇

methanol(methyl alcohol)甲醇

CH3CH2OH

ethanol(ethyl alcohol)乙醇

CH3CHCH3

OH

2-propanolpropan-2-ol(isopropyl alcohol)2- 丙醇 ; 异丙醇

CH3 CH2 CH2 CH2 OH

1-butanolbutan-1-ol(n-butyl alcohol)1- 丁醇 ; ( 正丁醇 )

CH3 CH2 CH OH

CH3

2-butanolbutan-2-ol(sec-butyl alcohol)2- 丁醇 ; ( 仲丁醇 )

CH3 CH CH2 OH

CH3

2-methyl-1-propanol2-methylpropan-1-oliso-butyl alcohol2- 甲基 -1- 丙醇 ; ( 异丁醇 )

CH3 C OH

CH3

CH3

2-methyl-2-propanol2-methylpropan-2-olt-butyl alcohol2- 甲基 -2- 丙醇 ; ( 叔丁醇 )

CH2 CHCH2CHCH3

OH

4-penten-2-olpent-4-en-2-ol4- 戊烯 -2- 醇

CH3 C CH

OH

CH3

CH3

C O

H

2-hydroxy-3,3-dimethylbutanal2- 羟基 -3,3- 二甲基丁醛

The order of precedence of functional groups for assigning IUPAC names

AcidsEstersAldehydesKetonesAlcoholsAminesAlkenesAlkynesAlkanesEthersHalides

Decreasing priority

CH2OH H2C CHCH2OH HC CCH2OH

phenylmethanol(benzyl alcohol)苯甲醇苄 ( 基 ) 醇

2-propenol(allyl alcohol)2- 丙烯醇 烯丙醇

2-propynol2- 丙炔醇炔丙醇

cyclohexanol环已醇

OH

H

H

Br

OH

trans- 2-bromocyclohexanol(1R,2R)-2-bromocyclohexanol

Names of diols

CH3 CH CH

OH

CH3

OH

butane-2,3-diol2,3- 丁二醇

CH2 CH2

OHOH

ethane-1,2-diol(ethylene glycol)乙二醇

glycol ( 甘醇 )= 1,2-diol = vicinal diol, 邻位二醇

OH OH OH

Br

Br

Br

2-bromophenol(ortho-bromophenol)2- 溴苯酚邻溴苯酚

3-bromophenol(meta-bromophenol)3- 溴苯酚间溴苯酚

4-bromophenol(para-bromophenol)4- 溴苯酚对溴苯酚

Names of phenols

o-, m-, p-邻 , 间 , 对

4. Physical properties of alcohols

Boiling points: Alcohols have much higher boiling points than ethers or hydrocarbons having similar molecular weight.

Solubility: C1-3, miscible with water.

RO

H

H OR

hydrophobic region 疏水区

hydrophilic region亲水区

Problem 10-34

Predict which member of each pair has the higher bp, and explain the reasons for your predictions.

(a)1-hexanol or 3,3-dimethyl-1-butanol(b)2-hexanone or 2-hexanol(c)2-hexanol or 1,5-hexanediol(d)2-pentanol of 2-hexanol

Important alcohols

Methanol is highly toxic,it can cause blindness or death.

Methanol

Ethanol YeastCH3CH2OHC6H12O6 + CO2

Sugar

½Íĸ

95%

CO + 2 H2

300-400oC200-300atm

ZnO-Cr2O3CH3OH

CH3CH2OHCH2=CH2Ethanol

+ H2OH+

acid

5. Synthesis of alcohols

(A) Hydration of alkenes

+ H2OH+

H OH

2) Synthesis of alcohols from alkenes

1) Synthesis of alcohol from alkyl halide

SN2 reaction

C+ intermediate

(B) oxymercuration-Demercuration( 羟汞化－脱汞 )

+ H2O( 1 ) Hg(OAc)2 / THF

OHHgOCOCH3Oxymercuration

( 2 ) NaBH4 / H2O

OHHDemercuration (ÍÑHg)

anti addtionfollow Mar’s rule

(C) Hydroboration-oxidation ( 硼氢化 - 氧化反应 )

+ H BH

H

Hydroboration C CH B

OrganoboraneBoron hydrideAlkene

THF

H2O2, NaOHC CH OH

syn additionanti Mar’s product

Problem: (10-37)

Show how you would synthesize the following alcohols from appropriate alkenes.

OH CH3

OH

OHOH

3) Synthesis of alcohols from carbonyl compounds ( 由羰基化合物制醇）

carbonyl group 羰基

carboxylic ester羧酸酯

aldehyde醛

ketone酮

carboxylic acid羧酸

C OR

CH

O

RC

R'O

RC

HOO

RC

R'OO

C O

Nu:- Nu C O

Nucleophilic addition( 亲核加成 )

Nu C OHH2O or H3O+

alkoxide ion

(A) Reaction of carbonyl compounds with organometallic reagents to give alcohols

C O

R2

R1

R C C + C C

R1

R2

OCR

C C

R1

R2

OHCR H3O+

alkynol ( 炔醇 )

Organometallic compounds （有机金属化合物）

Compounds that contain carbon-metal bonds (C-M) are called organometallic compounds.

C:- M+

M = Na+ or K+

(Primarily ionic)

(a) highly reactive Nu;(b) powerful B.

C: M

M = Mg or Li

+ -

(a) great important in organic synthesis; (b) relatively stable in ether solutions.

(Primarily covalent)

C M

M = Pb, Sn, Hg, or TI

(a) much less reactive;(b) often volatile ( 挥发性的 ) and are stable in air; (c) all poisonous;(d) generally soluble in nonpolar solvents.

Tetraethyllead has been used as an "antiknock" compound in gasoline.

Preparation of organolithium and organomagnesium compounds

Organolithium compounds ( 有机锂化合物）

(Butyl bromide)

CH3CH2CH2CH2Br + 2 Li- 10oC

Et2OCH3CH2CH2CH2Li + LiBr

Butyllithium(80-90%)

The order of reactivity of halides is:

R X

X

+ 2 Li RLi + LiX

(or ArLi)Ar

RI > RBr > RCl

Grignard reagents （格利雅试剂 , 格氏试剂）

RX + Mg RMgXEt2O

or THF

ArX + MgEt2O

or THFArMgX

Grignard reagents

CH3I + Mg CH3MgIEt2O

or THF

C6H5Br + MgEt2O

or THFC6H5MgBr

Methylmagnesium iodide(95%)

Phenylmagnesium bromide(95%)

R

Mg

X

O O

R

Mg

X

H3CH2C

O

H3CH2C

O

CH2CH3

CH2CH3

Grignard reagents are stable in ether

Preparation of alcohols by the addition of Grignard reagents to carbonyl compounds

Nucleophilic addition

+RMgX+ -+- H+

RCEt2O

H2OC O

Aldehyde or Ketone or ester Alcohols

OHRC OMgX

Formaldehyde Primary alcoholGrignard reagent

Higher aldehyde Secondary alcoholGrignard reagent

Ketone Tertiary alcoholGrignard reagent

+C6H5MgBr

Et2OHC

HO C6H5CH2OMgBr

H+

C6H5CH2OHH2O

Acetaldehyde乙醛

+CH3CH2MgBr

Et2OH3CC

HO CH3CH2CHOMgBr

CH3

H+

CH3CH2CHOHH2O

CH3

+C6H5MgBr

Et2O

cyclohexanone»·¼ºÍª

OOMgBr

H+

H2O OH

+R''MgBr Et2ORC

R'OO

esters

RC

OR'

R''

O MgBrBr

MgOR'

R''

C

R

O

Ketones

R''MgBrR C

R''

R''

OMgBrH+

H2OR C

R''

R''

OH

Grignard reagentester ketone tertiary alcohol

Grignard reagent

Organolithium reagents (RLi) react with carbonyl compounds in the same way as Grignard reagents.

RLi + C O

R C OLiH3O+

R C OH

CH3Li +H3C

CH3C

O

H3C C

CH3

CH3

OLiH3O+

H3C C

CH3

CH3

OH

R C CH + R'MgX R' H + R C CMgX

R C CH + R'Li R' H + R C CLi

CH3MgI + H2O CH4 + MgOH

ICH3MgI + HOCH3 CH4 + Mg

OCH3

I

Side reactions of organometallic reagents

体系中不能有活泼氢 , 如 O-H, N-H, S-H, -C≡C-H;底物中不能含有其它极性多重键 , 如 C=O, C=N, C≡N, S=O, N=O.

Attention!!!

CH3MgBr HOCH2CH2CCH3

O

HOCH2CH2C

OMgBr

CH3

CH3

+

CH3MgBr + HOCH2CH2CCH3

O

CH4 + BrMgOCH2CH2CCH3

O

X

R C

O

OH[ H ]

ReductionR CH2OH

Carboxylic acid 1o Alcohols

R C

O

OR'[ H ]

ReductionR CH2OH

1o Alcohols

+ R'OH

R C

O

H[ H ]

Reduction R CH2OH

Aldehyde 1o Alcohols

R C

O

R[ H ]

ReductionR CH

Ketone 2o Alcohols

OHR

2) Reduction of carbonyl compounds to give alcohols (10-11, 11-1)

LiAlH4

lithium aluminum hydride 氢化铝俚，四氢铝锂　

NaBH4

sodium borohydride 硼氢化钠

aldehydes ketones acids esters

NaBH4

LiAlH4

C OLiAlH4

NaBH4

[H-] C O-HHOH

C OHHhydride transfer

nucleophile addition

(A)

CH3 C

O

OH CH3 CH2OH

CH3

CH3

COOH

2,2-Dimethylpropanoic acid

1. LiAlH4 / Et2O

2. H2OAcetic acid Ethanol

CH3

1. LiAlH4 / Et2O

2. H2OCH3

CH3

CH2OH

CH3

Neopentyl alcohol ÐÂÎì ´¼ (92%)

CH3CH2CH2CHO

Butanal 1-Butanol

ReductionNaBH4

SodiumBorohydride

H2O+ CH3CH2CH2CH2OH

CH3CH2CCH3

Butanone 2-Butanol

ReductionNaBH4

SodiumBorohydride

H2O+ CH3CH2CHCH3

O OH

LiAlH4 + H2O H2 + LiOH + Al(OH)3

NaBH3 + H2O H2 + NaOH + B(OH)3

fast

slow

LiAlH4: dry Et2O, THF as solventsNaBH4: EtOH, MeOH, etc. as solvents

O

C + H2Raney Ni

OH

CH

(B) Catalytic hydrogenation of aldehydes and ketones

CH2 CHCH2 C

CH3

CH3

CO

H+ H2

Raney NiCH3 CH2CH2 C

CH3

CH3

CH2OH

Problems: give the main products.

CH3CH2CH CHCHOLiAlH4 H2O

O

OH

O

i. NaBH4

ii. H2O, pH = 7

Summary for alcohols synthesisSynthesis of alcohol from: alkenes acid-catalyzed hydration ( 酸催化的水化反应 ) hydroboration-oxidation ( 硼氢化反应 ) oxymercuration-demercuration ( 汞氧化反应 ) hydroxylation ( 羟化反应 ) to prepare 1,2-diols carbonyl compounds addition of Grignard reagents reduction with NaBH4 and LiAlH4

alkyl halides

Assignments

Text 1: 10-31, 33, 38, 44, 49

• Oxidation ( 氧化 )• substitution• dehydration ( 脱水 )• Esterification （酯化）

7. Reactions of alcohols

R O H

Reduction ( 还原 )of an organic molecule usually corresponds to increasing its hydrogen content or to decreasing its oxygen content.( 加氢、去氧或去卤素 , 增加Ｃ－Ｈ键数或减少Ｃ－Ｏ键数 )

Oxidation ( 氧化 ): increasing the oxygen content of an organic molecule or decreasing its hydrogen content.( 加氧或加卤素、去氢，减少Ｃ－Ｈ键数或增加Ｃ－Ｏ键数 )

Oxidation-Reduction reactions in organic chemistry

1) Oxidation of alcohols (11-1, 2, 3)

R C

O

OH[ H ]

ReductionR C

O

H

Carboxylic acid Aldehyde

oxygen content decreases

R C

O

H[ H ]

ReductionR CH2OH

Aldehyde Alcohol

hydrogen content increases

[ H ]

ReductionR CH3

Alcohol Alkanes

oxygen content decreases

R CH2OH

C-O, 3→2

C-O, 2→1

C-O, 1→0

[ O ]R CH2Cl

AlkanesR CH3

[ H ]

[ O ]

[ H ]RCHCl2

[ O ]

[ H ]RCCl3

Problem 11-1 p 446

R CHOH[ O ]

R C

2o alcohol ketone

R' R'

O

R CH2OH[ O ]

R CHO R COOH

1o Alcohol Aldehyde Carboxylic acid

[ O ]

Tertiary alcohols

Primary alcohols aldehydes carboxylic acids

Secondary alcohols ketones

difficult to be oxidized.

(A) Oxidization with Cr(VI) (11-2)

Oxidants: K2Cr2O7 or Na2Cr2O7 / H2SO4

CrO3/ H2SO4

OH

Cyclooctanol

H2CrO4

Acetone 35 °CO

Cyclooctanone

»·ÐÁ́¼ »·ÐÁͪ

CH3CH2CH2CH2OH

1-Butanol

K2Cr2O7

H2SO4CH3CH2CH2CHO

Butanal

K2Cr2O7

H2SO4CH3CH2CH2COOH butyric acid

Mechanism of chromate oxidations （铬酸氧化机理）

Step 1

RC

R

O H

H+

HO Cr

O

O

OH RC

R

O

H

Cr

O

O

OH+ H2O

Chromate ester (¸õËáõ¥£©

RC

R

O

H

Cr

O

O

OH RC

RO + HCrO3

- + H3O+

Step 2

KetoneCr 6+ Cr4+

6+4+

H2O

Chromate ester (¸õËáõ¥£©

Or

A Chemical test for 1°, 2°, and 3° alcohols

alcohol phenomenon

1° greenish opaque solution Cr3+

2° greenish opaque solution Cr3+

3° No reaction

Reagent: CrO3 / aqueous H2SO4

or Na2Cr2O7 / aqueous H2SO4

CH3CH2CH2CH2OH1-Butanol

CH3CH2CH2CHOButanal

PCC

25 oCCH2Cl2

CrO3 + HCl +N N

H

CrO3Cl-+

Pyridinium chlorochromate

ßÁà¤ÈýÑõ»¯̧ õ

Pyridine

PCC (Pyridinium chlorochromate, 吡啶三氧化铬 ) PDC (Pyridinium dichromate, 重铬酸吡啶盐 )

Oxidation with KMnO4, or HNO3 (11-3)

CH3CH2CHCH3

OH2-Butanol

KMnO4, KOHCH3CH2CCH3

OButanone

CH3CH2CH2CH2OH

1-Butanol

CH3CH2CH2COOKKMnO4, KOH

HClCH3CH2CH2COOH

If the conditions are not controlled, KMnO4 or HNO3 will cleave the carbon-carbon bonds.

OH KMnO4

COOH

COOH

CH3CH2OHCu

300 oCCH3CHO + H2

Dehydrogenation

Catalytic dehydrgenation (11-3)

Swern oxidation: convert alcohols to aldehyde or ketone

DMSO/(COCl)2/Et3N/CH2Cl2

CO

H

C-O bondO-H bond

are polarized

Hydrogen can be replaced by sodium (Na) and potassium (K)

The hydroxyl group can be replaced by other groups.

2) Substitution

ROH + Na RONa + H2

ROH + K ROK + H2

reactivity of alcohols: CH3OH > 1°> 2° > 3°

(CH3)3COH + KH (CH3)3COK + H2

OH+ NaOH

ONa+ NaOH + H2O

(1) Acidity of alcohols and phenols (10-6)

pKa = 10

(2) Conversion of alcohols into alkyl halides

R OH HX+ R X + H2O

(NaX + H2SO4)

A.

C O H + H X

Strong acidAlcohol

C O H

H

+

Protonated alcoholÖÊ×Ó» µ̄Ä́¼

+ X-

1° alcohols, SN23° alcohols, SN1

reactivity : HI > HBr > HCl

3° > 2 ° > 1 °

HICH3CH2CH2CH2OH CH3CH2CH2CH2I + H2Oheating

HBr, H2SO4CH3CH2CH2CH2OH CH3CH2CH2CH2Br + H2Oheating

HCl, ZnCl2CH3CH2CH2CH2OH CH3CH2CH2CH2Cl + H2Oheating

+ H2O(CH3)3COHconcd HCl

(CH3)3CClr.t.

The Lucas reagent: HCl / ZnCl2

H C

CH3

CH3

OH ZnCl2H C

CH3

CH3

OZnCl2

HC

CH3

CH3

H

carbocation

ClH C

CH3

CH3

Cl + HO ZnCl2

The Lucas test: To distinguish 1°, 2°, and 3° alcohols

alcoholTime to react

(min)phenomenon

1° >6No reaction

or react very slow

2° 1~5 Emulsion ( 乳状 )

3° <1The second phase to sep

arate ( 分层 )

Wagner － Meerwerin Rearrangement

H3C C

CH3

H

CHCH3

OHHCl

H3C C

CH3

H

CHCH3

O+

H

H

H3C C

CH3

H

CHCH3+

H3C C

CH3

CH2CH3+

1,2-rearrangement

当伯醇或仲醇的 β- 碳原子具有二个或三个烷基或芳基时 , 在酸作用下都能发生分子重排反应 . 亲核能力强的或能使碳正离子更稳定的基团优先迁移．

RCH2OH + Br P

Br

Br RCH2O

H

+P Br

Br

+ Br-

A good leaving group

O

H

+P Br

Br

Br- + RCH2 RCH2Br + HOPBr2SN2 reaction

B. R OH

(1o or 2o)

+ PCl3 RCl + H3PO3

R OH + PBr3 RBr + H3PO3

R OH + PCl5 RCl + POCl3

R OH + P + I2 RI + H3PO3

3R OH

(1o or 2o)

+ SOCl2 3 RCl + SO2 + HCl

thionyl chloride

Stereochemistry

configuration retention

CH3

OHH

CH2CH3

SOCl2

pyridine

CH3

HCl

CH2CH3

pyridine ( 吡啶 ) is present,configuration inversion

CH3

OHH

CH2CH3

SOCl2CH3

ClH

CH2CH3

C.

Advantages to use SOCl2 as chloride reagents:1) no rearrangement; 2) high yield; 3) easily to separate.

RCH2OH + Cl S

O

Cl RCH2O

H

+S Cl

O-

Cl

O SCl

O

( + HCl)

Alkyl chlorosulfite

CH2R

O

S

Cl

OCH2R

ion pair

RCH2Cl + O=S=O

Alkyl chloride

RCH2OH + Cl S

O

Cl RCH2O

H

+S Cl

O-

Cl

O SCl

O

( + HCl)

Alkyl chlorosulfite

CH2R

ClN

H

O S Cl

O

Cl- + RCH2 RCH2Cl + O=S=O + Cl-

A good leaving group

Alkyl chloride

Give the major product of the following reactions.

Neighboring group participation ( 邻基参与 )

Br 、 O 、 N 、 C=C 、cyclopropyl ( 环丙基 ) 、aryl ( 芳基 ), etc.

configuration retention构型保持

CH3

Br

OH

CH3

H

H

HBrCH3

Br

Br

CH3

H

H

CH3

Br

CH3

H

H

HO

H

-H2O

CH3

Br

H

H

H3C

CH3

Br

CH3

H

H

Br

CH3

H

Br

H

Br

H3C

Br

Br-

CH3

H

H

CH3

Br

H+

-H2O

CH3

H

OH

CH3

Br:

H

CH3

H

Br

CH3

Br

H

HBrCH3

Br

H

CH3

H

Br+

(3) Conversion of alcohols into mesylates （甲磺酸酯） and tosylates （苯磺酸酯）

R—OH R—OTsR—OH R—OTs

R—OH R—OMs R—NuNu-

R—NuNu-

OTs, OMs are good leaving groups

CH3 S

O

O

CH3 S

O

O

ORMs MsOR

S

O

O

H3C

Methanesulfonyl甲磺酰基

Ts

p-Toluenesulfonyl对甲苯磺酰基

S

O

O

ORH3C TsOR

Methanesulfonate esters　甲磺酸酯

p-Toluenesulfonate esters对甲苯磺酸酯

p-Toluenesulfonyl chloride对甲苯磺酰氯

S

O

O

Cl + OCH2CH3-HCl

HH3C S

O

O

OCH2CH3H3C

Ethyl p-toluenesulfonate(ethyl tosylate)对甲苯磺酸乙酯

solvent: pyridine or Et3N/CH2Cl2

CH3CH2—OTs

OTsRCH2Nu:- + NuCH2R + -OTsSN2

3) Acid-catalyzed dehydration

Intramolecular dehydration yield alkenes.Intermolecular dehydration yield ethers. (bimolecular dehydration, unhindered primary alcohols, 非位阻的伯醇才能反应生成醚 )

CH3CH2OH

CH2=CH2 + H2O

CH3CH2OCH2CH3 + H2O

Ethene

Diethyl ether

H2SO4

180°C

H2SO4

140°C

Alcohol dehydration: An E1 reaction

H3C C

CH3

CH3

OHH2SO4 or H3PO4 H3C

CH3C

CH2

H+

H3C C

CH3

CH3

OHH

+

Step 1fast

H3C C +

CH2

CH3

H

- H2O

Step 2

Slow

Step 3 fast

rearrangementand orientation

H2SO4, heat

Propose a mechanism for each reaction.

H3O+

OH

H2SO4

heat

CH2OHH2SO4

heat+ +

(1)

(2)

(3)

(4)

4) Esterification ( 酯化反应 )

Carboxylic acids react with alcohols to form esters through a condensation reaction known as esterification (Fischer esterification):

R C

O

OH + HOR'H+

R C

O

OR' + H2OEsterification Ester

õ¥

Carboxylic ester

R C

O

Cl + HOR' R C

O

OR' + HClEsterõ¥

Phosphate esters ( 烷基磷酸酯 )

HO P

OH

O

OH+CH3CH2OH

Phosphoric acid

P

OH

O

OH

Ethyl dihydrogen phosphateÁ×Ëá¶þÇâÒÒõ¥

CH3CH2O

CH3CH2OHP

OH

O

OCH2CH3

Diethyl hydrogen phosphateÁ×ËáÇâ¶þÒÒõ¥

CH3CH2OCH3CH2OH

P

OCH2CH3

O

OCH2CH3CH3CH2O

Triethyl phosphateÁ×ËáÈýÒÒõ¥

baseO

HOH

HH

HH

O

P

O

O O

baseO

H

HH

HH

O

P

O

O O

baseO

H

HH

HH

O

P

O

O O

baseO

H

HH

HH

O

P

O

O OO

HOH

HH

HH

HObase

phosphate ester Linkage in DNA

Sulfate esters ( 硫酸酯 )

methyl sulfate

dimethyl sulfate( 硫酸二甲酯 )甲基化试剂 , 毒！

(Notice!! sulfonate esters, 磺酸酯 , S—C bond)

O S

O

O

OH HH3C O H O S

O

O

OH3C H H2O

CH3OHO S

O

O

OH3C CH3 H2O

Sulfate ions are also excellent leaving group.

NH3H3C O S O CH3

O

O+

H3C O S O

O

O

H3C N

H

H

H

+

methylsulfate ion甲基硫酸离子

methylammonium ion甲铵离子

Nitrate esters ( 硝酸酯 )

CH2

CH

CH2

OH

OH

OH + HO NO2

CH2

CH

CH2

O

O

O

NO2

NO2

NO2

Glyceryl trinitrate(nitroglycerine)硝酸甘油

R O H O N

O

O

H O N

O

O

R + H2O

alkyl nitrate esters

炸药治心绞痛药

The Pinacol rearrangement ( 频那醇重排 , 邻二叔醇重排 )

Pinacol( 频那醇 )

Pinacolone( 频那酮 )

5) Unique reaction of diols (11-11)

H3C C

CH3

OH

C CH3

CH3

OH

HH3C C

CH3

OH

C CH3

CH3

OH2

-H2OH3C C

CH3

OH

C CH3

CH3

~CH3 H3C C

OH

C CH3

CH3

CH3

H3C C

OH

C CH3

CH3

CH3

-HH3C C

O

C CH3

CH3

CH3

Propose a mechanism for each reaction.

OHPh

OHPh

O

Ph

Ph

H2SO4

CH3OH OH CH3 O CH3

CH3

CH3CH3

O

+H+

(1)

(2)

OH H+

O

(3)

Periodic acid (HIO4) cleavage of glycols( 高碘酸氧化邻位二醇 )

C C

OHOH

HIO4C O CO+

C C

O O

IO O

OH

ketones or aldehydes

APPLICATION: To identify the structure of the vicinal diols. Determining the structure of sugars.

CH2OHOH HIO4

Ph C

CH3

CH(OH)CH2CH3

OH

HIO4

OH

HOH

H

HIO4

H CO

H+

O

Ph C

CH3

CHCH2CH3

O O

+

O

HO

H

oxidation

Cr(VI), PCC (PDC); KMnO4

substitution RO-Na+

HBr, PBr3, SOCl2 (to prepare alkyl halides)

ROTs, ROMs dehydration E1, yield alkenes SN2, yield ethers (primary ROH)

esterification unique reactions of diols pinacol rearrangment; HIO4 cleavage

Summary for reactions of alcohols

Outline a multistep synthesis for the following transformation.

Assignments

• Text 1: 11-42, 46, 47, 48, 53, 54, 56

1. Structure and physical properties of ethers

RO

R' R, R’ = alkyl or aryl

II. Ethers ( 醚 )

• Having much lower bp than alcohols of similar formula weight.

• Polar solvents, aprotic solvents• Lewis base: Coordination with H+, B, Mn+, etc.

2. Nomenclature of ethers

Common names

simple ethers

IUPAC names:

alkyl alkyl ether alkoxy alkane

complex ethers

AcidsEstersAldehydesKetonesAlcoholsAminesAlkenesAlkynesAlkanesEthersHalides

Decreasing priority

The order of precedence of functional groups for assigning IUPAC names

ethyl methyl ether

( 甲基乙基醚 )

methoxyethane

( 甲氧基乙烷 )

Common:

IUPAC:

CH3OCH2CH3

Chain ethersChain ethers

Methyl phenyl ether苯甲醚Methoxybenzene

Allyl methyl ether甲基烯丙基醚3-methoxypropene

CH3OCH2=CHCH2OCH3

CH3CHCH2CH2CH3

OCH3

2-Methoxypentane2- 甲氧基戊烷

CH3OCH2CH2OCH3

1,2-Dimethoxyethane1 ， 2- 二甲氧基乙烷

Ethylene glycol dimethyl ether乙二醇二甲醚

Cyclic ethers ( 环醚 )

oxacyclopentane氧杂环戊烷

Heterocyclic compounds（杂环化合物）O: Heteroatom （杂原子）

O

tetrahydrofuran四氢呋喃

THF

Otetrahydropyran

(THP)四氢吡喃

O

CH3

3-methyl-tetrahydropyran

O

O

1,4-dioxane二噁烷

1,4-dioxacyclohexane1,4- 二氧六环

O O

O O

OO

Oxirane( 环氧乙烷 )

Oxetane1,3-epoxypropane1,3- 环氧丙烷

12-crown-412- 冠 -4

Crown ethers 冠醚

Epoxide环氧化物

3. Synthesis of ether

ROH + HORH+

ROR + H2O

CH3CH2OH

CH2=CH2 + H2O

CH3CH2OCH2CH3 + H2O

Ethene

Diethyl ether

H2SO4

180oC

H2SO4

140oC

1) Ethers by bimolecular dehydration of alcohols

( 醇的分子间脱水制醚）

Suitable for symmetrical ether ( 对称醚 ) synthesis

R: Primary alkyl group

H C

H

CH3

O H

H

+

Protonated alcoholÖÊ×Ó» µ̄ÄÒÒ́¼

SN2

+ H2O

CH3CH2OCH2CH3

Diethyl ether

CH3CH2OH CH3CH2OCH2CH3H

+

-H+

Can we use this method to synthesize the unsymmetrical ethers?

CH3CH2OCH2CH2CH3 ?

2) The Williamson synthesis of ethers ( 醚的威廉姆逊合成）

Williamson ether synthesis: Suitable for unsymmetrical ethers ( 不对称醚 ) synthesis

R’: Primary alkyl group

RONa + R' LSN2

ROR' + NaL

Sodium alkoxide unsymmetrical ethers

L = Br, I, OSO2R'', or OSO2OR''

How to synthesize ethyl propyl ether?(CH3CH2OCH2CH2CH3)

CH3CH2CH2OH + Na

Propyl alcohol

CH3CH2CH2ONa

Sodium propoxide

+ 1/2 H2

Way 1:

CH3CH2ONa + CH3CH2CH2 I

SN2 reactionCH3CH2CH2OCH2CH3 + NaI

Way 2:

CH3 CH2 O C

CH3

CH3

CH3

How to synthesize tert-butyl ethyl ether ?

CH3 CH2 O C

CH3

CH3

CH3

a b

CH3 CH2 O C

CH3

CH3

CH3CH3 CH2 BrOC

CH3

CH3

H3C

b

BrC

CH3

CH3

H3CCH3 CH2 O CH3 CH2 O C

CH3

CH3

CH3

Elimination

BrC

CH3

CH3

CH2

b

CH3 CH2 O H2C C

CH3

CH3H + CH3CH2OH + Br

a:

b:

Notice: Hindered, no reaction!!!

X

To convert two alcohols to an ether: Convert the more hindered alcohol to its alkoxide. Convert the less hindered alcohol to its tosylate (OTs, or an alkyl halide). Make sure the tosylate or halide is a good SN2 substrate.

Conclusion

Propose a Williamson synthesis of 3-butoxy-1,1-dimethylcyclohexane from 3,3-dimethyl-cyclohexanol and butanol.

Synthesis of phenyl ethers ( 苯醚 )

OH

NaOH

O Na

n-Bu-I

OBun

OH+ CH3OSO2OCH3

NaOH-H2O OCH3

+ CH3OSO2ONa

dimethyl sulfate硫酸二甲酯

methyl phenyl ether苯甲醚

Phenoxide ion

ONa O+

Br Cu

210 °C

diphenyl ether二苯醚

phenyl bromide溴苯

Ullmann reaction

3) Alkoxymercuration-demercuration

+ ROH( 1 ) Hg(OAc)2 / THF

RO HgOCOCH3Alkoxymercuration

( 2 ) NaBH4 / H2O

OR HDemercuration (ÍÑHg)

Anti addition( 反式加成 )Follow Markovnikov rule( 符合马氏规则 )

ether

4. Reactions of ethers

1) Cleavage of ethers( 醚键的断裂 ) by HBr and HI

R O R'HI or HBr (very strong acids)

HeatingRX + R'X

Very strong conditions;

Reactivity: HI > HBr >> HCl.

The molecule must not contain any acid-sensitive fu

nctional group!!

CH3CH2OCH2CH3 + HBr

(HI)

2 CH3CH2Br + H2O

CH3CH2OCH2CH3 + HBr CH3CH2O

H

+CH2CH3 + Br-

An oxonium saltSN2

CH3CH2OH + CH3CH2Br

HBr

CH3CH2OHH

+ Br-

CH3CH2BrSN2

CH3 O C

CH3

CH3

CH3

HI

CH3 O C

CH3

CH3

CH3

HI

H

CH3OH + C

CH3

CH3

CH3

SN1

CH3OH + I C

CH3

CH3

CH3

I

The order of C-O cleavage : 3 > 2 > 1 > Ph-O

Phenyl ethers

OCH2CH3

H Br OCH2CH3

H BrOH

+ CH3CH2Br

Ethyl phenyl ether Protonated ether Phenol + ethyl bromide

HBr

Br

No further reaction

Ether cleavage: 1°alkyl ether: SN2 3°alkyl ether: SN1 alkyl phenyl ether: give phenol and alkyl halide.

O

diphenyl ether二苯醚

?

Propose a mechanism.

CH3CH2OCH2CH3

O2

CH3CH2OCHCH3

O OHa hydroperoxide

autoxidation

CH3CH2O OCH2CH3+

diethyl peroxide

Add FeSO4 to remove a hydroperoxide!!Peroxides test: KI/starch( 淀粉 ), or FeSO4/KSCN, etc.

2) Autoxidation of ethers

5. Important ethers

• Diethyl ether: bp 35 ºC, polar solvent

• THF: bp 66 ºC, strong polar solvent

• Crown ethers: as PTC ( 相转移催化剂 )

使用乙醚注意事项

• 蒸馏时不能蒸干！• 蒸馏时尾接管要通下水道！• 周围不能有明火！• 不能在冰箱里敞口存放！• 萃取时要及时放气 !

Structural characteristic: Containing more than three –OCH2CH2O- units in

one molecule.

O O

OO

O O

OO

O OO OOO

12-crown-412- 冠 -4

15-crown-515- 冠 -5

Crown Ethers （冠醚）

Nomenclature: x-crown-y x----total atom number in the ring

y----oxygen atom number

OO

O

OOO

OO

O

OOO

18-crown-6

Dibenzo-18-crown-6二苯基 -18- 冠 -6

Dicyclohexyl-18-crown-6二环己基 -18- 冠 -6

OO

O

OOO

金属离子直径金属离子直径

LiLi++NaNa++

KK++NH4

+

K+O

OO

OOO

Phase-Transfer catalysis (PTC) ( 相转移催化）

C6H5CH2Cl + KCNSN2

18-Crown-6C6H5CH2CN + KCl

C6H5CH2Cl + KF C6H5CH2F + KCl

100%

CH3(CH2)5CH=CH2 + KMnO4 CH3(CH2)5COOH

18-Crown-6

SN2

18-Crown-6

MnO4－

(or CN － )

O

O

O

OO

O

K+MnO4-

K+CN-

O

O

O

OO

O

K+

Crown ethers are used as phase-transfer catalysts.

RX + NaCNQ+X- (¼¾ï§ ÑΣ©

RCN + NaXSN2 reaction

Q+X- (CH3(CH2)3)4N+X-

(CH3(CH2)3)4N+Cl- (ËĶ¡»ùÂÈ» ï̄§ £©

Summary for ethersNomenclature: “alkyl alkyl ether”, “alkoxy alkane”(IUPAC)Synthesis• Ethers by intermolecular dehydration of alcohols ( 醇的分子

间脱水制醚）• The Williamson synthesis of ethers ( 醚的威廉姆逊合成）• Alkoxymercuration-demercurationReactions• Cleavage of ethers by HBr and HI• Autoxidation of ethersApplication• Solvents: stable, low bp., diethyl ether, THF, 1,4-dioxane• Crown ethers: as PTC

Epoxides 环氧化物

O

H

H

MCPBA

cyclohexene oxide

O

H

H

H

H3C

trans-1,2-epoxy-4-methylcyclohexanetrans-4- 甲基 -1,2- 环氧环己烷

OH

(H3C)2HC

CH2CH3

CH2CH32,2-diethyl-3-isopropyloxirane2,2- 二乙基 -3- 异丙基环氧乙烷

C C

O

an epoxide环氧化物

O

IUPAC: oxiraneCommon: Ethylene oxide 环氧乙烷

1. Synthesis of epoxides

1) Epoxidation of alkenes

2) Base-Promoted cyclization of halohydrins

C C + R C O O H

O OR C O H

O

+

C C

X

O H

C C

ONaOH

+ HX

C C

X

O H

X = Cl, Br, I

+ -O H C C

X

O-

C C

O

2. Reactions of epoxides

1) Acid-catalyzed ring opening (review)

C C

O

H+

C C

OH

+

H2OC C

OH +OH2

- H+

C C

OH OH

1,2-Diols

Nu: H2O ROH HX

Orientation of acid-catalyzed epoxides opening

SN2

H2C CCH3

O

CH3CH2OH

CH3

H

+HOCH2C CH3

OCH2CH3

CH3

H+

HOCH2CH(CH3)2

OCH2CH3

+ H+

酸性条件下 , 亲核试剂进攻取代基多的碳，即带正电多的碳 .

2) Based-Catalyzed Ring Opening

Nu: OH-, RO-, NH3

C CO

RO C C O-RO-

An alkoxide ion

RO C C OHROH

+ RO-

Orientation of base-catalyzed epoxides opening

H2CHC CH3

O

CH3CH2O-

Methyloxirane An alkoxide ion

CH3CH2OCH2CHCH3

O-

Less hindered

CH3CH2OHCH3CH2OCH2CHCH3

OH

+ CH3CH2O-

碱性条件下 , 亲核试剂进攻位阻较小的碳。

3) Reaction of organometalic reagents with oxiranes

Give primary alcohols

+C6H5MgIO

Et2OCH3

C6H5CH2CHOMgI

CH3

H+

C6H5CH2CHOHH2O

CH3

+C6H5MgIO

Et2OC6H5CH2CH2OMgI

H+

C6H5CH2CH2OHH2O

primary alcohol

secondary alcohol

Attact the less hindered carbon

Oanhydrous HBr

BrCH2CH2Br

O concd aqueous HBr HOCH2CH2OH

Problem 2: Explain the following results:

Problem 1: Give the structures of A and B:

Sharpless 不对称环氧化反应

• 烯丙醇及其衍生物在钛酸酯参与下的不对称环氧化反应称为 Sharpless 环氧化反应，简称为 AE 反应 (asymmetr

ic epoxidation) 。 1980 年，由 Sharpless K.B. 等研究发现。

R2 R1

R3OH

t-BuOOH, Ti(OPri)

L-(+)-tartrate(洒石酸二酯)

R2 R1

R3OH

O

R2 R1

R3OH

t-BuOOH, Ti(OPri)

D-(-)-tartrate(洒石酸二酯)

R2 R1

R3OH

O

Summary for epoxides

Synthesis• Peroxyacid epoxidation • Base-Promoted cyclization of halohydrinsReactions• 　 acid-catalyzed ring opening• base-catalyzed ring opening• reaction with Grignard reagents

Assignments

• T.1 14-32, 33, 37, 39, 41, 43

• T.2(selected) 4, 8, 9, 10, 13, 15, 16, 19, 22