chapter 11
DESCRIPTION
Chapter 11. Alcohols & Ethers. About The Authors. These Powerpoint Lecture Slides were created and prepared by Professor William Tam and his wife Dr. Phillis Chang. - PowerPoint PPT PresentationTRANSCRIPT
Created byProfessor William Tam & Dr. Phillis
Chang Ch. 11 - 1
Chapter 11
Alcohols & Ethers
About The AuthorsThese Powerpoint Lecture Slides were created and prepared by Professor William Tam and his wife Dr. Phillis Chang.
Professor William Tam received his B.Sc. at the University of Hong Kong in 1990 and his Ph.D. at the University of Toronto (Canada) in 1995. He was an NSERC postdoctoral fellow at the Imperial College (UK) and at Harvard University (USA). He joined the Department of Chemistry at the University of Guelph (Ontario, Canada) in 1998 and is currently a Full Professor and Associate Chair in the department. Professor Tam has received several awards in research and teaching, and according to Essential Science Indicators, he is currently ranked as the Top 1% most cited Chemists worldwide. He has published four books and over 80 scientific papers in top international journals such as J. Am. Chem. Soc., Angew. Chem., Org. Lett., and J. Org. Chem.
Dr. Phillis Chang received her B.Sc. at New York University (USA) in 1994, her M.Sc. and Ph.D. in 1997 and 2001 at the University of Guelph (Canada). She lives in Guelph with her husband, William, and their son, Matthew. Ch. 11 -
2
Ch. 11 - 3
OH OH OH
1. Structure & Nomenclature 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)
Ch. 11 - 4
OHOH
OH
2-Propenol(allyl alcohol)
2-Propynol(propargyl alcohol)
Benzyl alcohol
Ch. 11 - 5
Phenols●Compounds that have a
hydroxyl group attached directly to a benzene ringOH
Phenol
OH
4-Methylphenol
OH
2-Chlorophenol
Cl
H3C
Ch. 11 - 6
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
Ch. 11 - 7
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 - 8
ExamplesOH
OHOH
OH
2-Propanol(isopropyl alcohol)
1,2,3-Butanetriol
Ch. 11 - 9
Example
OH
OH
12 3 4
56
7
OH
125 4
3
67
8
or wrong
3-Propyl-2-heptanol
Ch. 11 - 10
1B.Nomenclature of Ethers Rules of naming ethers
●Similar to those with alkyl halides CH3O– Methoxy CH3CH2O– Ethoxy
Example O
Ethoxyethane(diethyl ether)
Ch. 11 - 11
Cyclic ethers
Oxacyclopropaneor oxirane
(ethylene oxide)
O O
O O
O
Oxacyclobutaneor oxetane
Oxacyclopentane(tetrahydrofuran or THF)
1,4-Dioxacyclohexane(1,4-dioxane)
Ch. 11 - 12
2. Physical Properties ofAlcohols 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 - 13
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 Alcohol molecules can associate
with each other through hydrogen bonding, whereas those of ethers and hydrocarbons cannot
Ch. 11 - 14
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 - 15
Physical Properties of Ethers
Dimethyl etherDiethyl etherDiisopropyl ether1,2-Dimethoxyethane
CH3OCH3CH3CH2OCH2CH3(CH3)2CHOCH(CH3)2CH3OCH2CH2OCH3
-138-116-86-68
-24.934.6
6883
O
O
(DME)
Oxirane
Tetrahydrofuran (THF)
-112
-108
12
65.4
Name Formula mp(oC)
bp (oC)(1 atm)
Ch. 11 - 16
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)
Ch. 11 - 17
4. Synthesis of Alcohols from Alkenes Acid-catalyzed Hydration of
AlkenesC C H
H2OC C
OHH
C COHH
HC CH
H⊕
H2O
H2O
Ch. 11 - 18
Acid-Catalyzed Hydration of Alkenes
●Markovnikov regioselectivity
●Free carbocation intermediate
●Rearrangement of carbocation possible
Ch. 11 - 19
Oxymercuration–Demercuration
●Markovnikov regioselectivity●Anti stereoselectivity●Generally takes place without
the complication of rearrangements
●Mechanism Discussed in Section 8.6
C C H2O, THF C CHgOAc
OHHg(OAc)2 C CH
OH
NaOHNaBH4
Ch. 11 - 20
Hydroboration–Oxidation
●Anti-Markovnikov regioselectivity
●Syn-stereoselectivity●Mechanism
Discussed in Section 8.7
1. BH3 THF2. H2O2, OH
OH
H
Ch. 11 - 21
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
Ch. 11 - 22
Example
OH
OHSynthesis?
(1)
Synthesis?(2)
Ch. 11 - 23
Synthesis (1)
OHH
●Need anti-Markovnikov addition of H–OH
●Use hydroboration-oxidation
OHH
1. BH3 • THF2. H2O2, NaOH
Ch. 11 - 24
Synthesis (2)H
OH
●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 - 25
H
H⊕
H2O
HO
Rearrangementof carbocation
(2o cation)
Acid-catalyzed hydration
Ch. 11 - 26
HOH
HgOAc
OHHg(OAc)2H2O, THF
Oxymercuration-demercuration
NaBH4NaOH
Ch. 11 - 27
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 - 28
OH
C–O & O–H bonds of an
alcohol are polarized
Protonation of the alcohol converts a poor leaving group (OH⊖) into a good one (H2O)
C O+ HH
C O H H A A+
alcohol strongacid
protonatedalcohol
Ch. 11 - 29
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)
Ch. 11 - 30
6. Alcohols as Acids 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
Ch. 11 - 31
Relative Acidity
H2O > ROH > > H2 > NH3 > RHRC CH
H2O & alcohols are thestrongest acids in this series
Increasing acidity
Relative Basicity
R > NH2 > H > > RO > HORC C
OH⊖ is the weakestacid in this series
Increasing basicity
Ch. 11 - 32
7. Conversion of Alcohols intoAlkyl Halides
●HX (X = Cl, Br, I)●PBr3●SOCl2
R OH R X
Ch. 11 - 33
OH Clconc. HCl25oC
+ HOH
(94%)
Examples
OH Br
(63%)
PBr3
Ch. 11 - 34
8. Alkyl Halides from the Reaction ofAlcohols with Hydrogen Halides
The order of reactivity of alcohols●3o
The order of reactivity of the hydrogen halides●HI > HBr > HCl (HF is generally
unreactive)
R OH R XHX+ + H2O
> 2o > 1o< methyl
Ch. 11 - 35
R OH NaX+ No Reaction!OH⊖ is a poorleaving group
R OH NaX+ H R X
R O HH
X
H3O⊕ is a goodleaving group
Ch. 11 - 36
8A.Mechanisms of the Reactions ofAlcohols with HX Secondary, tertiary, allylic, and
benzylic alcohols appear to react by a mechanism that involves the formation of a carbocation
Step 1
H O HHO
H + O HHO
H +
Hfast
Ch. 11 - 37
Step 2
OH
H
O HH
+slow
Step 3
+ ClClfast
Ch. 11 - 38
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)
Ch. 11 - 39
9. Alkyl Halides from the Reaction of Alcohols with PBr3 or SOCl2
Reaction of alcohols with PBr3
R OH R Br3 + + H3PO3PBr3(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 - 40
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 - 41
Mechanism
R OHBrP
Br Br+ R O
PBr2
HBr
protonatedalkyl dibromophosphite
+
R OPBr2
HBr
a goodleaving group
+ R Br + HOPBr2
Ch. 11 - 42
Reaction of alcohols with SOCl2●SOCl2 converts 1o and 2o
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 - 43
Mechanism
OOSCl Cl+HR O SR
H OClCl
O SRH O
Cl
Cl
O SRO
Cl+N
N
(C5H5N)
Ch. 11 - 44
+ O SRO
NCl
Mechanism
Cl⊖
O SRO
Cl+N
+ SO ON
ClO SR
ON
Ch. 11 - 45
10. Tosylates, Mesylates, & Triflates:Leaving Group Derivatives of Alcohols
OMs =
OTs = O SO
OCH3
O SO
OCH3
(Tosylate)
(Mesylate)
Ch. 11 - 46
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 + No Reaction!Nu
Thus we need to convert the OH⊖ to a better leaving group first
Ch. 11 - 47
Mesylates (OMs) and Tosylates (OTs) are good leaving groups and they can be prepared easily from an alcohol
OHOSCH3 ClO
OS CH3OO
NH
Cl
OMs
+
+ +
same as
(a mesylate)
pyridine(methane sulfonyl chloride)
Ch. 11 - 48
Preparation of Tosylates (OTs) from an alcohol
OHOS ClO
OSOO
NH
Cl
OTs
+
+ +
same as
(a tosylate)
pyridineH3C
CH3
(p-toluene sulfonyl chloride)
Ch. 11 - 49
SN2 displacement of the mesylate or tosylate with a nucleophile is possible
OTs
Nu
Nu
OTs
+
+
Ch. 11 - 50
Example
+ NaOTs
OHTsCl
pyridine
OTs
NaCNDMSO
CN
Retention ofconfiguration
Inversion ofconfiguration
Ch. 11 - 51
Example
MsClpyridine
NaSMeDMSO
OH OMs
SMe
Retention ofconfiguration
Inversion ofconfiguration
Ch. 11 - 52
11.Synthesis of Ethers
OH
O
180oCH2SO4
H2SO4140oC
Ethene
Diethyl ether
11A. Ethers by Intermolecular Dehydration of Alcohols
Ch. 11 - 53
OH
H + OSO3H
OH
+ H2O
Mechanism+OH H OSO3H
OH
H2O
O
●This method is only good for synthesis of symmetrical ethers
Ch. 11 - 54
For unsymmetrical ethers
+R
OR'ROH + R'OH
+R
OR
R'O
R'
H2SO4
Mixtureof ethers
1o alcohols
Ch. 11 - 55
Exception
+R OH HOcat. H2SO4
R O
+ HO H
H
R OH
(good yield)
Ch. 11 - 56
R X R O R'R'O
(SN2)
11B. The Williamson Synthesis of Ethers
Via SN2 reaction, thus R is limited to 1o (but R' can be 1o, 2o or 3o)
Ch. 11 - 57
Example 1
OH
Na H O Na + H2
Br
O
Ch. 11 - 58
Example 2
NaOHH2OHO
Cl
O
Cl
O
Ch. 11 - 59
Example 3
NaOHH2OOH
IO
However
NaOHH2OOH
INo epoxide observed!
Ch. 11 - 60
R1. Hg(O2CCF3)2, R'OH2. NaBH4, NaOH
11C. Synthesis of Ethers by Alkoxy- mercuration–Demercuration
R
OR'
Hg(O2CCF3)
(1) (2)
R
OR'Markovnikov regioselectivity
Ch. 11 - 61
Example
O1. Hg(O2CCF3)2, iPrOH2. NaBH4, NaOH
Ch. 11 - 62
R OH R OH2SO4+
tert-butylprotecting
group
11D. tert-Butyl Ethers by Alkylation of Alcohols: Protecting Groups
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 A tert-butyl protecting group can be removed easily by treating the ether with dilute aqueous acid
Ch. 11 - 63
Example
Synthesis ofHO
HO Br
BrMg
from
and
1
2
3
4
5
1
2
3
4
5
Ch. 11 - 64
●Direct reaction will not work
HOHO Br
BrMg
+ ☓(Not Formed)
●Since Grignard reagents are basic and alcohols contain acidic proton
O Br
BrMg
+H
BrMg O Br+ H
Ch. 11 - 65
●Need to “protect” the –OH group first
HO Br1. H2SO42. O Br
BrMg
OHOH H2O
tert-butyl protected alcohol
deprotonation
Ch. 11 - 66
+
tert-butylchlorodimethylsilane
(TBSCl)
R O HCl
Si tBu
Me Me
OSi tBu
Me MeR
imidazoleDMF
( HCl) R O TBS( )
11E. Silyl Ether Protecting Groups A hydroxyl group can also be
protected by converting it to a silyl ether group
Ch. 11 - 67
+R O HF
Si tBu
Me Me
OSi tBu
Me MeR
R O TBS( )
Bu4NF
THF
The TBS group can be removed by treatment with fluoride ion (tetrabutyl-ammonium fluoride or aqueous HF is frequently used)
Ch. 11 - 68
Example
Synthesis of HO
HO
Ph
from
and
1
2
3
4
5
1
2
3
5
Ph6
I4
Na6
Ch. 11 - 69
HO Ph
●Direct reaction will not work
+O
Ph
I
Na
H☓
(Not Formed)
●Instead
+O
Ph
I
Na
HO
I
H Ph+
O
Ch. 11 - 70
I IHO TBSOTBSCl
imidazoleDMF
●Need to “protect” the –OH group first
Na Ph
TBSOPh
Bu4N FTHF
HOPh
Ch. 11 - 71
12.Reactions of Ethers
O + HBr BrOH
+
an oxonium salt
Dialkyl ethers react with very few reagents other than acids
Ch. 11 - 72
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 H2O+Br2
Cleavage of an ether
Ch. 11 - 73
BrOH
+ OH + Br
Mechanism
H BrO + BrOH
+
HBr
Br+HO
H
Ch. 11 - 74
13.Epoxides
O
Epoxide (oxirane)●A 3-membered ring containing
an oxygen
Ch. 11 - 75
13A. Synthesis of Epoxides: Epoxidation
C C C COperoxy
acid
Electrophilic epoxidation
Ch. 11 - 76
R CO
O OH
Peroxy acids (peracids)
●Common peracids
H3C CO
O OHCO
O OH
Cl
meta-chloroperbenzoid acid(MCPBA)
peracetic acid
Ch. 11 - 77
O
O H
O
R
Mechanism
O
O H
O
R
O
O H
O
Rperoxy acid
alkeneconcertedtransition
state
carboxylicacid
epoxide
Ch. 11 - 78
13B. Stereochemistry of Epoxidation
O
O
MCPBA
MCPBA
(trans)
(cis)
(trans)
(cis)
Addition of peroxy acid across a C=C bond
A stereospecific syn (cis) addition
Ch. 11 - 79
OMCPBA(1 eq.)
Electron-rich double reacts faster
Ch. 11 - 80
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 - 81
+ O HH
CCOH
O HH
+ HCCO
Acid-catalyzed ring opening of epoxide
O HH
C CO
O HH
H
O HH+
H
C CO
O H
H
Ch. 11 - 82
+ CCO
OR
Base-catalyzed ring opening of epoxide
CCRO
O
OR H
+CCRO
OHOR
Ch. 11 - 83
+O
OEt
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
EtO
OH+ OEt
EtOH1o carbon atom isless hindered
Ch. 11 - 84
+O
MeOHMeO OH
cat. HA
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)
Ch. 11 - 85
15.Anti 1,2-Dihydroxylation of Alkenes via Epoxides
Synthesis of 1,2-diolsOH
OH
OH
OH
1. MCPBA2. H, H2O
cold KMnO4, OH or1. OsO42. NaHSO3
Ch. 11 - 86
Anti-Dihydroxylation●A 2-step procedure via ring-
opening of epoxides H
H
OMCPBA
H
H
O HH
H2O
H2OOH
OH
Ch. 11 - 87
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 - 88
Crown ether names: x-crown-y●x = ring size●y = number of oxygen
OO
O
OO
O
O O
O OO O
OOO
(18-crown-6) (15-crown-5) (12-crown-4)
Ch. 11 - 89
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 - 90
Many important implications to biochemistry and ion transport
OO
O
OO
OK
OO
O
OO
O
KMnO4benzene MnO4
(18-crown-6) (purple benzene)
Ch. 11 - 91
Several antibiotics call ionophores are large ring polyethers and polylactones
O
OO
O
Me
O
O
O Me
O OO
Me
O
Me
Me
O
Me
Me Me
Nonactin
Ch. 11 - 92
17.Summary of Reactions of Alkenes, Alcohols, and Ethers
Synthesis of alcohols
OH
(1o alcohol)
XOH
1. BH3 THF2. H2O2, NaOH
MgBr
1. 2. H2O
O
Ch. 11 - 93
Synthesis of alcohols
OH
(2o alcohol)
1. BH3 THF2. H2O2, NaOH
1. Hg(OAc)2, H2O2. NaBH4
or
H+, H2O
Ch. 11 - 94
Synthesis of alcohols
(3o alcohol)OH
H2OX
1. Hg(OAc)2, H2O2. NaBH4H+, H2O
Ch. 11 - 95
Reaction of alcohols
OH
(1o alcohol)
OR
1. base2. R-X H+, heat
OTS
TsClpyridineSOCl2
Cl
X
H-X
Br
PBr3
Ch. 11 - 96
Synthesis of ethers
R O R
R OH
conc. H2SO4140oC
R X
RO
Cleavage reaction of ethers
R O R' H X X ROH+R'XR O R'H
Ch. 11 - 97
END OF CHAPTER 11