Chapter 7
Alcohols, 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
O
sp3
sp3
H
104.5°
H
sp2
sp3
O
O
CH3
108.9°
CH3CH2
H
H
H
ethanol
乙醇
methanol
甲醇
sp2
H2C
O
tautomerism
H3C
互变异构
O
C
H
Enol (烯醇)
Phenol
苯酚
H
O
C
H
Aldehyde (醛)
2. Classification of alcohols
• According to the type of carbinol carbon atom
alcohols can be classified as follows:
H
R
C
R
H
OH
H
primary alcohol
(伯醇)
1°
R
C
OH
R
secondary alcohol
(仲醇)
2°
R
C
OH
R
tertiary alcohol
(叔醇)
3°
3. Nomenclature of Alcohols
IUPAC names:
alkane
Common names:
alkyl alcohol
中文:
CH3OH
methanol
(methyl alcohol)
甲醇
XX醇
CH3CH2OH
ethanol
(ethyl alcohol)
乙醇
alkanol
OH
CH3CHCH3
2-propanol
propan-2-ol
(isopropyl alcohol)
2-丙醇; 异丙醇
CH3 CH2 CH2 CH2 OH
1-butanol
butan-1-ol
(n-butyl alcohol)
1-丁醇; (正丁醇)
CH3 CH CH2 OH
CH3
2-methyl-1-propanol
2-methylpropan-1-ol
iso-butyl alcohol
2-甲基-1-丙醇; (异丁醇)
CH3 CH2 CH OH
CH3
2-butanol
butan-2-ol
(sec-butyl alcohol)
2-丁醇; (仲丁醇)
CH3
CH3 C OH
CH3
2-methyl-2-propanol
2-methylpropan-2-ol
t-butyl alcohol
2-甲基-2-丙醇; (叔丁醇)
The order of precedence
of functional groups for
assigning IUPAC names
Acids
Esters
Aldehydes
Ketones
Alcohols
Amines
Alkenes
Alkynes
Alkanes
Ethers
Halides
CH2 CHCH2CHCH3
OH
4-penten-2-ol
pent-4-en-2-ol
4-戊烯-2-醇
Decreasing
priority
CH3 OH H
CH3 C
CH C O
CH3
2-hydroxy-3,3-dimethylbutanal
2-羟基-3,3-二甲基丁醛
CH2OH
phenylmethanol
(benzyl alcohol)
苯甲醇
苄(基)醇
H2C
CHCH2OH
2-propenol
(allyl alcohol)
2-丙烯醇
烯丙醇
HC
2-propynol
2-丙炔醇
炔丙醇
H
OH
OH
H
Br
cyclohexanol
环已醇
CCH2OH
trans- 2-bromocyclohexanol
(1R,2R)-2-bromocyclohexanol
Names of diols
CH2 CH2
OH OH
ethane-1,2-diol
(ethylene glycol)
乙二醇
CH3 CH CH CH3
OH OH
butane-2,3-diol
2,3-丁二醇
glycol (甘醇)= 1,2-diol = vicinal diol, 邻位二醇
Names of phenols
Br
OH
OH
OH
Br
Br
2-bromophenol
3-bromophenol
(ortho-bromophenol) (meta-bromophenol)
2-溴苯酚
3-溴苯酚
邻溴苯酚
间溴苯酚
o-, m-, p邻, 间, 对
4-bromophenol
(para-bromophenol)
4-溴苯酚
对溴苯酚
4. Physical properties of alcohols
R 
O
hydrophobic region
H
疏水区
 
H O
R
hydrophilic region
亲水区
 Boiling points: Alcohols have much higher boiling
points than ethers or hydrocarbons having similar
molecular weight.
 Solubility: C1-3, miscible with water.
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
CO
+
2 H2
300-400oC
200-300atm
ZnO-Cr2O3
CH3OH
Methanol is highly toxic,it can cause blindness or death.
Ethanol
C6H12O6
Sugar
Yeast ½Íĸ
CH2=CH2 + H2O
CH3CH2OH
95%
+ CO2
H+
acid
CH3CH2OH
Ethanol
5. Synthesis of alcohols
1) Synthesis of alcohol from alkyl halide
SN2 reaction
2) Synthesis of alcohols from alkenes
 (A) Hydration of alkenes
H+
+
H2O
H OH
C+ intermediate
(B) oxymercuration-Demercuration(羟汞化－脱汞)
+ H2O
( 1 ) Hg(OAc)2 / THF
Oxymercuration
( 2 ) NaBH4 / H2O
Demercuration (ÍÑHg)
OHH
anti addtion
follow Mar’s rule
OHHgOCOCH3
(C) Hydroboration-oxidation (硼氢化-氧化反应)
+ H B
Alkene
H
Hydroboration
H
THF
Boron hydride
H2O2, NaOH
C C
H OH
C C
H B
Organoborane
syn addition
anti Mar’s product
Problem: (10-37)
Show how you would synthesize the following alcohols
from appropriate alkenes.
OH
CH3
OH
OH
OH
3) Synthesis of alcohols from carbonyl compounds
(由羰基化合物制醇）
R
R
C O
C O
C O
R'
H
carbonyl group
羰基
aldehyde
醛
ketone
酮
R
R
C O
C O
HO
carboxylic acid
羧酸
R'O
carboxylic ester
羧酸酯

Nu:-
C

O
Nu
C
Nucleophilic addition
(亲核加成)
H2O or H3O+
Nu
O
alkoxide ion
C
OH
(A) Reaction of carbonyl compounds with
organometallic reagents to give alcohols
R1
R1
R
C
C +
C
O
R
C
R2
H3O+
C
R2
R1
R
C
C
C
C
R2
alkynol (炔醇)
OH
O
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+
+ C: M
M = Mg or Li
(Primarily ionic)
(a) highly reactive Nu;
(b) powerful B.
(a) great important in organic
synthesis;
(b) relatively stable in ether solutions.
C
M
M = Pb, Sn, Hg, or TI
(Primarily covalent)
(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）
R X
Ar X
+
2 Li
RLi + LiX
(or ArLi)
The order of reactivity of halides is:
RI > RBr > RCl
CH3CH2CH2CH2Br + 2 Li
(Butyl bromide)
- 10oC
Et2O
CH3CH2CH2CH2Li + LiBr
Butyllithium
(80-90%)
Grignard reagents （格利雅试剂, 格氏试剂）
RX + Mg
Et2O
RMgX
or THF
ArX + Mg
Et2O
Grignard reagents
ArMgX
or THF
Et2O
CH3MgI
or THF Methylmagnesium iodide
(95%)
Et2O
C6H5Br + Mg
C6H5MgBr
or THF
Phenylmagnesium bromide
(95%)
CH3I + Mg
Grignard reagents are stable in ether
R
H3CH2C
O
H3CH2C
Mg
CH2CH3
O
CH2CH3
X
R
O
Mg
X
O
Preparation of alcohols by the addition of
Grignard reagents to carbonyl compounds
- +
RMgX +
O
+
C
Et2O
RC OMgX
Aldehyde or Ketone or ester
H+
H2O
RC OH
Alcohols
Nucleophilic addition
Formaldehyde
Grignard reagent
Higher aldehyde
Ketone
Primary alcohol
Grignard reagent
Grignard reagent
Secondary alcohol
Tertiary alcohol
H 
 
C
C6H5MgBr +
H
 
CH3CH2MgBr
H3C
+
 Et2O
O
C6H5CH2OMgBr

C

O
Et2O
CH3
H+
Acetaldehyde
乙醛


O
cyclohexanone
»· ¼ºÍª
H2O
C6H5CH2OH
CH3CH2CHOMgBr
H
 
C6H5MgBr +
H+
H2O
Et2O
OMgBr
H+
H2O
OH
CH3
CH3CH2CHOH

 
R''MgBr

R
+


C


O
R''
Et2O
R'O
esters
RC
R''
O
C
MgBr
OR'
Br
 Mg
OR'
R''MgBr
C
OMgBr
Ketones
H+
H 2O
R
C
OH
R''
R''
Grignard reagent
ester
R
R''
R''
R
O
Grignard reagent
ketone
tertiary alcohol
Organolithium reagents (RLi) react with carbonyl
compounds in the same way as Grignard reagents.

RLi +
 
C O
 
H3C  
CH3Li +
C O
H3C
R
C OLi
CH3
H3C C OLi
CH3
H3O+
H3O+
R
C OH
CH3
H3C C OH
CH3
Attention!!!
Side reactions of organometallic reagents
OH
+
CH3MgI
CH3MgI
+
H2O
HOCH3
CH4 + Mg
CH4
I
+
OCH3
Mg
I
R C CH + R'MgX
R
C
CH + R'Li
R' H + R C CMgX
R' H + R
C
CLi
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.
CH3
CH3MgBr + HOCH2CH2CCH3
O
CH3MgBr + HOCH2CH2CCH3
O
X
HOCH2CH2C
CH3
OMgBr
CH4 + BrMgOCH2CH2CCH3
O
2) Reduction of carbonyl compounds to give
alcohols (10-11, 11-1)
O
R C H
[H]
Reduction
Aldehyde
O
R
C R
Ketone
[H]
Reduction
R CH2OH
1o Alcohols
OH
R CH R
2o Alcohols
O
[H]
R CH2OH
R C OH
Reduction
1o Alcohols
Carboxylic acid
O
R
C
[H]
OR' Reduction
R CH2OH + R'OH
1o Alcohols
(A)
LiAlH4
lithium aluminum hydride
氢化铝俚，四氢铝锂
NaBH4
sodium borohydride
硼氢化钠
LiAlH4
aldehydes
ketones
acids
esters
NaBH4
LiAlH4
NaBH4
-
[H ]
C
O
hydride transfer
nucleophile addition
H
C
HOH
-
O
H
C
OH
Reduction
CH3CH2CH2CHO + NaBH4
CH3CH2CH2CH2OH
H2O
Butanal
1-Butanol
Sodium
Borohydride
O
OH
Reduction
CH3CH2CCH3 + NaBH4
CH3CH2CHCH3
H2O
Butanone
Sodium
2-Butanol
Borohydride
O
CH3 C OH
Acetic acid
1. LiAlH4 / Et2O
2. H2O
CH3 CH2OH
Ethanol
CH3
CH3
1. LiAlH4 / Et2O
CH3
COOH
CH3
CH2OH
2. H2O
CH3
CH3
2,2-Dimethylpropanoic acid
Neopentyl alcohol ÐÂÎì ´¼
(92%)
LiAlH4 + H2O
NaBH3 + H2O
fast
slow
H2 + LiOH + Al(OH)3
H2 + NaOH + B(OH)3
LiAlH4: dry Et2O, THF as solvents
NaBH4: EtOH, MeOH, etc. as solvents
(B) Catalytic hydrogenation of aldehydes and ketones
O
C
CH2
+
H2
CH3 O
CH CH2 C C + H2
CH3 H
Raney Ni
Raney Ni
OH
CH
CH3
CH3 CH2 CH2 C CH2OH
CH3
Problems: give the main products.
O
OH
O
CH3CH2CH
i. NaBH4
ii. H2O, pH = 7
CHCHO
LiAlH4
H2O
Summary for alcohols synthesis
 Synthesis 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 1,2diols
 carbonyl compounds

addition of Grignard reagents

reduction with NaBH4 and LiAlH4
 alkyl halides
Assignments
Text 1: 10-31, 33, 38, 44, 49
7. Reactions of alcohols
•
•
•
•
Oxidation (氧化)
substitution
dehydration (脱水)
Esterification （酯化）
R O H
1) Oxidation of alcohols (11-1, 2, 3)
Oxidation-Reduction reactions in organic chemistry
 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)
O
oxygen content decreases O
[H]
R
C
OH
R
Aldehyde
hydrogen content increases
[H]
R
H
Reduction
Carboxylic acid
O
C
C-O, 3→2
C
H
R
CH2OH
Reduction
C-O, 2→1
Alcohol
Aldehyde
oxygen content decreases
[H]
R
CH2OH
Alcohol
R
CH3
Reduction
Alkanes
C-O, 1→0
R CH3
Alkanes
[O]
[H]
[O]
[O]
R
CH2Cl
[H]
Problem 11-1 p 446
RCHCl2
[H]
RCCl3
[O]
[O]
R
1o Alcohol
R'
R
R
R CHO
Aldehyde
CH2OH
CHOH
Carboxylic acid
R'
[O]
R
2o alcohol
Primary alcohols
Secondary alcohols
Tertiary alcohols
COOH
O
C
ketone
aldehydes
carboxylic acids
ketones
difficult to be oxidized.
(A) Oxidization with Cr(VI) (11-2)
Oxidants:
 K2Cr2O7 or Na2Cr2O7 / H2SO4
 CrO3/ H2SO4
H2CrO4
OH
O
Acetone 35 °C
Cyclooctanol
»·ÐÁ́¼
CH3CH2CH2CH2OH
1-Butanol
K2Cr2O7
H2SO4
K2Cr2O7
H2SO4
Cyclooctanone
»·ÐÁͪ
CH3CH2CH2CHO
Butanal
CH3CH2CH2COOH
butyric acid
Mechanism of chromate oxidations
（铬酸氧化机理）
Step 1
R
O
O
H
C
R
Step 2
R
HO Cr OH
O
R
O
R
H
H2O
Cr OH
H
O
O
6+
Cr OH
O
R
C
R
Cr 6+
Chromate ester (¸õËáõ¥£©
+ H2O
Chromate ester (¸õËáõ¥£©
C
R
O
C
+
H
O
Cr4+
4+
+
O + HCrO3 + H3O
Ketone
Or
A Chemical test for
1°, 2°, and 3° alcohols
Reagent: CrO3 / aqueous H2SO4
or Na2Cr2O7 / aqueous H2SO4
alcohol
phenomenon
1°
greenish opaque solution Cr3+
2°
greenish opaque solution Cr3+
3°
No reaction
PCC (Pyridinium chlorochromate, 吡啶三氧化铬)
PDC (Pyridinium dichromate, 重铬酸吡啶盐)
PCC
CH3CH2CH2CH2OH
CH3CH2CH2CHO
o
CH2Cl225 C
1-Butanol
Butanal
CrO3 + HCl +
N
Pyridine
CrO3Cl-
+
N
H
Pyridinium chlorochromate
ßÁà¤ÈýÑõ»¯¸õ
Oxidation with KMnO4, or HNO3 (11-3)
CH3CH2CH2CH2OH
1-Butanol
KMnO4, KOH
CH3CH2CH2COOK
HCl
CH3CH2CHCH3
KMnO4, KOH
OH
2-Butanol
CH3CH2CH2COOH
CH3CH2CCH3
O
Butanone
If the conditions are not controlled, KMnO4 or HNO3 will
cleave the carbon-carbon bonds.
OH
KMnO4
COOH
COOH
Catalytic dehydrgenation (11-3)
CH3CH2OH
Cu
o
CH3CHO + H2
300 C
Dehydrogenation
Swern oxidation:
convert alcohols to aldehyde or ketone
DMSO/(COCl)2/Et3N/CH2Cl2
2) Substitution

C

O

H
C-O bond are polarized
O-H bond
Hydrogen can be replaced by
sodium (Na) and potassium (K)
The hydroxyl group can be
replaced by other groups.
(1) Acidity of alcohols and phenols (10-6)
ROH
+
Na
RONa +
ROH
+
K
ROK +
reactivity of alcohols:
(CH3)3COH + KH
H2
CH3OH > 1°> 2° > 3°
(CH3)3COK + H2
ONa
OH
+ NaOH
pKa = 10
H2
+ H2O
(2) Conversion of alcohols into alkyl halides
A. R
OH + HX
R
(NaX + H2SO4)
C
O
H + H
X
X + H2O
1° alcohols, SN2
3° alcohols, SN1
C
+
O
H + X-
H
Alcohol
Strong acid
Protonated alcohol
ÖÊ×Ó»¯µÄ́¼
reactivity :
HI > HBr > HCl
3° > 2 ° > 1 °
CH3CH2CH2CH2OH
CH3CH2CH2CH2OH
CH3CH2CH2CH2OH
(CH3)3COH
HI
heating
HBr, H2SO4
heating
HCl, ZnCl2
heating
concd HCl
r.t.
CH3CH2CH2CH2I + H2O
CH3CH2CH2CH2Br + H2O
CH3CH2CH2CH2Cl + H2O
(CH3)3CCl + H2O
The Lucas reagent: HCl / ZnCl2
CH3
H C OH
CH3
ZnCl2
CH3
CH3
ZnCl2
H C
H C O
CH3 H
Cl
CH3
carbocation
CH3
H C Cl
CH3
+
HO ZnCl2
The Lucas test:
To distinguish 1°, 2°, and 3° alcohols
Time to react
(min)
phenomenon
1°
>6
No reaction
or react very slow
2°
1~5
Emulsion (乳状)
<1
The second phase to
separate (分层)
alcohol
3°
Wagner－Meerwerin Rearrangement
H
H3C
H
OH
C
CHCH3
HCl
CH3
H3C
H
O+ H
C
CHCH3
CH3
CH3
H
H3C
C
CH3
+
CHCH3
H3C
C
+
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．
B.
o
o
(1 or 2 )
RCH2OH +
R OH + PCl3
RCl + H3PO3
R OH + PBr3
RBr + H3PO3
R OH + PCl5
RCl + POCl3
R OH + P + I2
RI
Br
P
Br
Br
+ RCH2
+
O
P
H
Br
P
Br + Br-
H Br
A good leaving group
Br
-
+
RCH2O
+ H3PO3
Br
SN2 reaction
RCH2Br + HOPBr2
3R
C.
3 RCl + SO2 + HCl
OH + SOCl2
(1o or 2o)
thionyl chloride
Advantages to use SOCl2 as chloride reagents:
1) no rearrangement; 2) high yield;
3) easily to separate.
Stereochemistry
CH3
H
OH
SOCl2
CH3
H
H
OH
CH2CH3
configuration retention
CH2CH3
CH2CH3
CH3
Cl
SOCl2
pyridine
CH3
Cl
H
CH2CH3
pyridine (吡啶) is present,
configuration inversion
Cl
RCH2OH +
Cl
S
Cl
+
RCH2O
H
O
R
CH2
S
Cl
O-
Cl
Cl
O S
( + HCl)
O
Alkyl chlorosulfite
RCH2Cl + O=S=O
Alkyl chloride
R
CH2
S

O
ion pair
O
Cl
RCH2OH +
Cl
S
Cl
H
O
R
CH2
Cl
O-
( + HCl)
O
Alkyl chlorosulfite
O
S
Cl
O S
Cl- + RCH2
+
RCH2O
S
Cl
O
A good leaving group
N

Cl
H
RCH2Cl + O=S=O + ClAlkyl chloride
Give the major product of the following reactions.
Neighboring group participation (邻基参与)
CH3
Br:
H
H
OH
CH3
CH3
Br
H
H
Br
CH3
HBr
-H2O
CH3
H
Br
H
CH3
H+
CH3
H
Br
H
OH
CH3
CH3
Br
 H
HO
CH3
H
Br-
Br、O、N、C=C、
cyclopropyl (环丙基)、
aryl (芳基), etc.
CH3
H
Br
H
Br
CH3
HBr
CH3
Br
+ H
Br
H
CH3
configuration retention
构型保持
CH3
H
-H2O
H
H3C
Br
H
Br
CH3
H
Br
Br
CH3
H
CH3
Br
H
H3C
Br
H
(3) Conversion of alcohols into mesylates （甲磺酸
酯）and tosylates（苯磺酸酯）
R—OH
R—OH
R—OMs
R—OTs
NuNu-
OTs, OMs are good
leaving groups
R—Nu
R—Nu
O
O
Ms
CH3 S
CH3 S
O
O
Methanesulfonyl
甲磺酰基
Methanesulfonate esters
甲磺酸酯
O
O
H3C
MsOR
OR
S
O
p-Toluenesulfonyl
对甲苯磺酰基
Ts
H3C
S
OR
TsOR
O
p-Toluenesulfonate esters
对甲苯磺酸酯
O
S
H3C
O
Cl + H
OCH2CH3
-HCl
O
RCH2
OCH2CH3
CH3CH2—OTs
solvent: pyridine
or Et3N/CH2Cl2
Nu:
S
O
p-Toluenesulfonyl chloride
对甲苯磺酰氯
-+
H3C
OTs
Ethyl p-toluenesulfonate
(ethyl tosylate)
对甲苯磺酸乙酯
SN2
NuCH2R + -OTs
3) Acid-catalyzed dehydration
H2SO4
CH3CH2OH
CH2=CH2 + H2O
180°C
Ethene
H2SO4
CH3CH2OCH2CH3 +
140°C
Diethyl ether
H2O
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)
Alcohol dehydration: An E1 reaction
CH3
H3C
C
OH
H2SO4 or H3PO4 H3C
C
H3C
CH2
CH3
Step 3
Step 1
fast
H+
Step 2
CH3
H3C
C
CH3
fast
+
OH
H
- H2O
Slow
CH3
H3C
C+
CH2 H
rearrangement
and
orientation
Propose a mechanism for each reaction.
H 3 O+
(1)
H2SO4, heat
(2)
H2SO4
heat
(3)
OH
(4)
CH2OH
H2SO4
heat
+
+
4) Esterification (酯化反应)
Carboxylic acids react with alcohols to form esters
through a condensation reaction known as esterification
(Fischer esterification):
O
O
R
C
OH + HOR'
H+
R
Esterification
C
H2O
O
O
R
C OR' +
Ester
õ¥
Cl
+ HOR'
R
C OR' +
Ester
õ¥
HCl
Carboxylic ester
Phosphate esters (烷基磷酸酯)
O
CH3CH2OH + HO
O
CH3CH2O P OH
P OH
OH
Phosphoric acid
CH3CH2OH
O
CH3CH2O
P OCH2CH3
OH
Diethyl hydrogen
phosphate
Á×ËáÇâ¶þÒÒ
õ¥
OH
Ethyl dihydrogen
phosphate
Á×Ëá¶þÇâÒÒ
õ¥
O
CH3CH2OH
CH3CH2O
P
OCH2CH3
OCH2CH3
Triethyl phosphate
Á×ËáÈýÒÒ
õ¥
base
O
O
P
O
H
O
HO
O
O
H
H
H
H
H
O
phosphate ester
Linkage in DNA
OH
H
H
H
H
H
H
O
O
H
O
base
O
P
O
H
base
O
P
O
H
H
O
O
base
H
H
H
H
O
O
P
O
H
O
base
O
H
OH
H
H
H
Sulfate esters (硫酸酯)
(Notice!! sulfonate esters, 磺酸酯, S—C bond)
O
H3C
O
H
H
O
S
O
O
O
H
H2O
H3C
O
S
O
methyl sulfate
CH3OH
H2O
O
H3C
O
S
O
O
dimethyl sulfate
(硫酸二甲酯)
甲基化试剂, 毒！
CH3
Sulfate ions are
also excellent
leaving group.
O
H
O
H3C O S O CH3 + NH3
O
O
H
H3C O S O + H3C N H
O
methylsulfate ion
甲基硫酸离子
H
methylammonium ion
甲铵离子
Nitrate esters (硝酸酯)
O
R
O
H
H
O
N
O
R
O
O
+ H2O
N
O
alkyl nitrate esters
CH2 OH
CH OH
+
HO
NO2
CH2 OH
炸药
治心绞痛药
CH2 O
NO2
CH O
NO2
CH2 O
NO2
Glyceryl trinitrate
(nitroglycerine)
硝酸甘油
5) Unique reaction of diols (11-11)
CH3 CH3
H3C C
C CH3
OH OH
H
CH3 CH3
CH3 CH3
-H2O
H3C C
C CH3
H3C C
C CH3
OH OH2
OH
Pinacol(频那醇)
~CH3
H3C C
OH
CH3
C CH3
CH3
H3C C
OH
CH3
-H
C CH3
CH3
 The Pinacol rearrangement
 (频那醇重排, 邻二叔醇重排)
CH3
H3C C C CH3
O CH3
Pinacolone
(频那酮)
Propose a mechanism for each reaction.
H+
(1)
CH3
CH3
CH3
OH OH CH3
O
O
O
H2SO4
(2)
OH
Ph
Ph
Ph
Ph
OH
O
OH
(3)
H+
+
CH3CH3
 Periodic acid (HIO4) cleavage of glycols
(高碘酸氧化邻位二醇)
C
C
HIO4
C
OH OH
O
+
O
C
ketones or aldehydes
C
C
O
O
I
O
OH
O
CH2OH
OH
HIO4
CH3
Ph C CH(OH)CH2CH3
OH
OH
OH
H
H
HIO4
H
H C
O
O
+
CH3
HIO4
Ph C
O
+
CHCH2CH3
O
O
O
H
H
APPLICATION:
To identify the structure of the vicinal diols.
Determining the structure of sugars.
Summary for reactions of alcohols
 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
Outline a multistep synthesis for the following
transformation.
Assignments
• Text 1: 11-42, 46, 47, 48, 53, 54, 56
II. Ethers (醚)
1.
Structure and physical properties
of ethers
O
R
R'
R, R’ = alkyl or aryl
• 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 IUPAC names:
alkyl alkyl ether
alkoxy alkane
simple ethers
complex ethers
CH3OCH2CH3
Common:
IUPAC:
ethyl methyl ether
(甲基乙基醚)
methoxyethane
(甲氧基乙烷)
Acids
Esters
Aldehydes
Ketones
Alcohols
Amines
Alkenes
Alkynes
Alkanes
Ethers
Halides
Decreasing
priority
The order of precedence of
functional groups for assigning
IUPAC names
Chain ethers
CH2=CHCH2OCH3
Allyl methyl ether
甲基烯丙基醚
3-methoxypropene
CH3CHCH2CH2CH3
OCH3
2-Methoxypentane
2-甲氧基戊烷
CH3O
Methyl phenyl ether
苯甲醚
Methoxybenzene
CH3OCH2CH2OCH3
Ethylene glycol dimethyl ether
乙二醇二甲醚
1,2-Dimethoxyethane
1，2-二甲氧基乙烷
Cyclic ethers (环醚)
CH3
O
O
tetrahydrofuran
四氢呋喃
THF
oxacyclopentane
氧杂环戊烷
tetrahydropyran
(THP)
四氢吡喃
Heterocyclic compounds
（杂环化合物）
O: Heteroatom （杂原子）
O
3-methyl-tetrahydropyran
O
O
1,4-dioxane
二噁烷
1,4-dioxacyclohexane
1,4-二氧六环
O
Oxirane
(环氧乙烷)
Epoxide
环氧化物
O
Oxetane
1,3-epoxypropane
1,3-环氧丙烷
O
O
O
O
12-crown-4
12-冠-4
Crown ethers
冠醚
3. Synthesis of ether
1) Ethers by bimolecular dehydration of alcohols
(醇的分子间脱水制醚）
ROH + HOR
H+
H2SO4
180oC
CH3CH2OH
ROR + H2O
CH2=CH2
R: Primary
alkyl group
+ H2O
Ethene
H2SO4
140oC
CH3CH2OCH2CH3 +
H2 O
Diethyl ether
Suitable for symmetrical ether (对称醚) synthesis
SN2
CH3CH2OH
H
H
C
+
O
H
+
CH3CH2OCH2CH3 + H2O
H
CH3 H
Protonated alcohol
ÖÊ×Ó»¯µÄÒÒ́¼
-H+
CH3CH2OCH2CH3
Diethyl ether
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）
RONa
+ R'
L
SN2
Sodium alkoxide
L = Br, I, OSO2R'', or OSO2OR''
ROR'
+ NaL
unsymmetrical ethers
R’: Primary alkyl group
Williamson ether synthesis:
Suitable for unsymmetrical ethers (不对称醚)
synthesis
How to synthesize ethyl propyl ether?
(CH3CH2OCH2CH2CH3)
Way 1:
CH3CH2CH2ONa + 1/2 H2
CH3CH2CH2OH + Na
Propyl alcohol
Sodium propoxide
CH3CH2CH2ONa +
CH3CH2
SN2 reaction
I
CH3CH2CH2OCH2CH3 + NaI
Way 2:
CH3CH2ONa + CH3CH2CH2
SN2 reaction
I
CH3CH2CH2OCH2CH3 + NaI
How to synthesize tert-butyl ethyl ether ?
CH3
CH3
CH2
O C CH3
CH3
CH3
CH3
CH2
O C CH3
a
b CH
3
CH3
CH3
a:
H3C C O
CH3
CH2
CH3
Br
CH2
b
CH
3
CH3
CH3
CH3
b:
CH3
O C CH3
CH2
O
H3C C
Br
X
CH3
CH2
O C CH3
CH3
CH3
Notice: Hindered, no reaction!!!
CH3
CH3
CH2
O
H
CH2 C
Br
H2C
b
CH
3
Elimination
C CH3 + CH CH OH + Br
3
2
CH3
Conclusion
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.
Propose a Williamson synthesis of
3-butoxy-1,1-dimethylcyclohexane
from 3,3-dimethyl-cyclohexanol and butanol.
Synthesis of phenyl ethers ( 苯醚)
OBun
O Na
OH
n-Bu-I
NaOH
Phenoxide ion
OH
O
NaOH-H2O
+
CH3OSO2OCH3
dimethyl sulfate
硫酸二甲酯
ONa
Br
+ CH3OSO2ONa
methyl phenyl ether
苯甲醚
O
Cu
+
CH3
210 °C
phenyl bromide
溴苯
diphenyl ether
二苯醚
Ullmann reaction
3) Alkoxymercuration-demercuration
+ ROH
( 1 ) Hg(OAc)2 / THF
Alkoxymercuration
RO
HgOCOCH3
( 2 ) NaBH4 / H2O
Demercuration (ÍÑHg)
OR H
ether
Anti addition(反式加成)
Follow Markovnikov rule(符合马氏规则)
4. Reactions of ethers
1) Cleavage of ethers(醚键的断裂) by HBr and HI
HI or HBr (very strong acids)
R O R'
RX + R'X
Heating
Very strong conditions;
Reactivity: HI > HBr >> HCl.
The molecule must not contain any acid-sensitive
functional group!!
CH3CH2OCH2CH3 + HBr
2 CH3CH2Br + H2O
(HI)
+
CH3CH2O
CH3CH2OCH2CH3 + HBr
CH2CH3 + Br-
H
An oxonium salt
SN2
CH3CH2OH
+ CH3CH2Br
HBr
+
CH3CH2OH
H
BrSN2
CH3CH2Br
CH3
CH3
O C CH3
CH3
HI
CH3OH
I
HI
CH3
CH3
O C CH3
H CH3
CH3
+ I C CH3
CH3
SN1
CH3OH +
CH3
C CH3
CH3
The order of C-O cleavage : 3 > 2 > 1 > Ph-O
Br
Phenyl ethers
HBr
O
CH2CH3
H
Ethyl phenyl ether
Br
H
O
Br
CH2CH3
Protonated ether
Ether cleavage:
1°alkyl ether: SN2
3°alkyl ether: SN1
alkyl phenyl ether: give phenol
and alkyl halide.
No
further
reaction
OH
+ CH3CH2Br
Phenol + ethyl bromide
O
?
diphenyl ether
二苯醚
Propose a mechanism.
2) Autoxidation of ethers
O2
CH3CH2OCH2CH3
autoxidation
CH3CH2OCHCH3
O OH
a hydroperoxide
+
CH3CH2O
OCH2CH3
diethyl peroxide
Add FeSO4 to remove a hydroperoxide!!
Peroxides test: KI/starch(淀粉), or FeSO4/KSCN, etc.
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!
Crown Ethers （冠醚）
Structural characteristic:
Containing more than three –OCH2CH2O- units in
one molecule.
Nomenclature: x-crown-y
x----total atom number in the ring
y----oxygen atom number
O
O
O
O
12-crown-4
12-冠-4
O
O
O
O
OO O O O
O
15-crown-5
15-冠-5
O
O
O
O
O
O
18-crown-6
O
O
O
O
O
O
O
Dibenzo-18-crown-6
二苯基-18-冠-6
O
O
O
O
O
Dicyclohexyl-18-crown-6
二环己基-18-冠-6
0.4
K+
0.3
0.2
NH4+
12-C-4
15－C－5
18－C－6
21－C－7
Na+
Li+
0.1
0
腔体直径 金属离子直径
O
O
K+
O
O
O
O
Phase-Transfer catalysis (PTC) (相转移催化）
18-Crown-6
C6H5CH2Cl + KCN
SN2
18-Crown-6
C6H5CH2Cl + KF
SN2
C6H5CH2CN + KCl
C6H5CH2F + KCl
100%
CH3(CH2)5CH=CH2 + KMnO4
18-Crown-6
O
O
O
O
O
O
O
CH3(CH2)5COOH
+
K
MnO4-
K+CN-
O
O
K+
O
O
O
Crown ethers are used as phase-transfer
catalysts.
MnO4－
(or CN－)
Q+X- (¼¾
ï§ ÑΣ©
RX + NaCN
Q+X-
RCN + NaX
SN2 reaction
(CH3(CH2)3)4N+X-
(CH3(CH2)3)4N+Cl- (ËĶ¡»ùÂÈ»¯ï§ £©
Summary for ethers
 Nomenclature: “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-demercuration
 Reactions
• Cleavage of ethers by HBr and HI
• Autoxidation of ethers
 Application
• Solvents: stable, low bp., diethyl ether, THF, 1,4-dioxane
• Crown ethers: as PTC
Epoxides 环氧化物
C
C
O
O
IUPAC: oxirane
Common: Ethylene oxide
环氧乙烷
an epoxide
环氧化物
H
MCPBA
H
O
H
H3C
H
cyclohexene oxide
H
(H3C)2HC
O
CH2CH3
CH2CH3
O
H
trans-1,2-epoxy-4methylcyclohexane
trans-4-甲基-1,2-环氧环己烷
2,2-diethyl-3-isopropyloxirane
2,2-二乙基-3-异丙基环氧乙烷
1. Synthesis of epoxides
1) Epoxidation of alkenes
O
C
C
+ R
O
O
C O O
+ R
H
C O H
2) Base-Promoted cyclization of halohydrins
O
C
X
C
H
O
NaOH
C
C
+ HX
O
C
O-
H
C
+
-
O
H
C
X
X
O
X = Cl, Br, I
C
C
C
2. Reactions of epoxides
1) Acid-catalyzed ring opening (review)
H+
C
C
C
C
+
O
H
O
- H+
C
C
OH
OH
1,2-Diols
H2O
C
C
OH +OH2
Nu: H2O
ROH
HX
Orientation of acid-catalyzed epoxides opening
CH3
CH3CH2OH
H2C
CH3
C
+
O
H
HOCH2C
CH3
SN2
CH3
+OCH2CH3
H
HOCH2CH(CH3)2 + H+
OCH2CH3
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
-
RO
-
C C
O
ROH
RO C C O
RO C C OH + RO-
An alkoxide ion
Nu: OH-, RO-,
NH3
Orientation of base-catalyzed epoxides opening
Less hindered
CH3CH2O
-
H2C
H
C
CH3CH2OCH2CHCH3
CH3
OAn alkoxide ion
O
Methyloxirane
CH3CH2OH
CH3CH2OCH2CHCH3
+ CH3CH2O-
OH
碱性条件下, 亲核试剂进攻位阻较小的碳。
3) Reaction of organometalic reagents with
oxiranes
C6H5MgI
Et2O
+
C6H5CH2CH2OMgI
O
H+
H2O
Give primary alcohols
C6H5CH2CH2OH
primary alcohol
CH3
C6H5MgI
Et2O
+
C6H5CH2CHOMgI
O
Attact the less hindered carbon
CH3
H
+
H2O
CH3
C6H5CH2CHOH
secondary alcohol
Problem 1: Give the structures of A and B:
Problem 2: Explain the following results:
O
O
anhydrous HBr
concd aqueous HBr
BrCH2CH2Br
HOCH2CH2OH
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(asymmetric
epoxidation) 。1980年，由Sharpless K.B. 等研究发现。
R2
OH
R3
R2
R3
t-BuOOH, Ti(OPri)
R1
L-(+)-tartrate(洒石酸二酯)
t-BuOOH, Ti(OPri)
R1
OH
D-(-)-tartrate(洒石酸二酯)
R2
O
R1
OH
R3
R2
O
R3
R1
OH
Summary for epoxides
 Synthesis
•
Peroxyacid epoxidation
•
Base-Promoted cyclization of halohydrins
 Reactions
•
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