Ethers &
Epoxides
Chapter 11
11--1
11
Structure
‹ The
functional group of an ether is an oxygen
atom bonded to two carbon atoms
• in dialkyl ethers, oxygen is sp3 hybridized with bond
angles of approximately 109.5°.
• in dimethyl ether
ether, the C
C-O-C
O C bond angle is 110
110.3
3°
H
H
••
H
C
H
O
••
C
H
H
11--2
11
Structure
• in other ethers, the ether oxygen is bonded to an sp2
hybridized carbon
• in
i ethyl
th l vinyl
i l ether,
th
for
f example,
l the
th ether
th oxygen is
i
bonded to one sp3 hybridized carbon and one sp2
hybridized carbon
Ethoxyethene
CH3 CH2 -O-CH=CH2
(Eth yl vinyl ether)
11--3
11
Nomenclature: ethers
‹ IUPAC: the longest carbon chain is the parent
• name the OR group as an alkoxy substituent
‹
Common names: name the groups bonded to oxygen in
alphabetical order followed by the word ether
OH
CH3 OCCH3
CH3 CH2 OCH 2 CH3
OCH2 CH3
Ethoxyethane
(Diethyl ether)
CH3
trans-2-Ethoxycyclohexanol
CH3
2-Methoxy-2methylpropane
(tert-Butyl methyl ether)
11--4
11
Nomenclature: ethers
‹ Although
cyclic ethers have IUPAC names, their
common names are more widely used
• IUPAC: prefix ox
ox-- shows oxygen in the ring
• the suffixes -irane
irane, -etane
etane, -olane
olane, and -ane
ane show three,
four five,
four,
five and six atoms in a saturated ring
2
O
3
1O
O
O
O
O
Oxirane
Oxetan e
Oxolane
Oxan e
1,4-D ioxane
(Ethylene oxid e)
(Tetrahydrofuran) (Tetrahydropyran)
11--5
11
Physical Properties
‹ Although
ethers are polar compounds, only weak
dipole-dipole attractive forces exist between their
molecules in the pure liquid state
11--6
11
Physical Properties
‹ Boiling
points of ethers are
• lower than alcohols of comparable MW
• close to those of hydrocarbons of comparable MW
‹ Ethers
are hydrogen bond acceptors
• they are more soluble in H2O than are hydrocarbons
11--7
11
Preparation of Ethers
1) Williamson ether synthesis: SN2 displacement of
halide, tosylate, or mesylate by alkoxide ion
CH3
-
CH3 CHO N a
Sodium
isopropoxide
+
+
CH3 I
SN 2
Iodomethane
(Methyl iodide)
CH 3
CH3 CHOCH3
+
+ -
Na I
2-Methoxypropane
(Isopropyl methyl ether)
11--8
11
Preparation of Ethers
• yields are highest with methyl and 1° halides,
• lower with 2° halides (competing β-elimination)
• reaction fails with 3° halides (β-elimination only)
CH3
CH3
SN2
CH3 CO- K+ +
CH3 Br
CH3 COCH3 + K+ BrCH3
CH3
Potass ium
Bromometh ane
2-Meth oxy-2-meth ylp ropan e
t ert-bu toxid e (Meth yl b romid e)
(t ert -Bu tyl methyl ether)
CH3
CH3 CBr
+
CH3
2-Bromo-2methylprop ane
-
CH3 O Na
+
Sodium
methoxide
E2
CH3
CH3 C
C=CH
CH2 + CH3 OH + Na+ Br2-Methylprop ene
11--9
11
Preparation of Ethers
2) AcidAcid-catalyzed dehydration of alcohols
• diethyl ether and several other ethers are made on an
industrial scale this way
• a specific example of an SN2 reaction in which a poor
leaving group (OH-) is converted to a better one (H2O)
2 CH3 CH2 OH
Ethanol
H2 SO4
140°C
CH3 CH2 OCH2 CH3 + H2 O
D iethyl eth er
11--10
11
Preparation of Ethers
• Step 1: proton transfer gives an oxonium ion
fas t and
reversib le
O
CH3 CH2 -O-H + H-O-S-O-H
O
O
+
CH3 CH2 -O-H + O-S-O-H
O
H
An oxon ium ion
• Step 2: nucleophilic displacement of H2O by the OH
group
g
p of the alcohol gives
g
a new oxonium ion
+ SN2
CH3 CH2 -O-H + CH3 CH2 -O-H
H
+
CH3 CH2 -O-CH2 CH3 +
O-H
H
A new oxonium ion
H
11--11
11
Preparation of Ethers
Step 3: proton transfer to solvent completes the reaction
+
CH3 CH2 -O-CH2 CH3 + O-H
H
H
proton
tran sfer
+
CH3 CH2 -O-CH2 CH3 + H O-H
H
11--12
11
Preparation of Ethers
3) AcidAcid-catalyzed addition of alcohols to alkenes
• yields are highest using an alkene that can form a
stable carbocation
• and using methanol or a 1° alcohol that is not prone to
undergo acid-catalyzed dehydration
CH3
CH3 C= CH2 + CH3 OH
acid
catal st
catalyst
CH3
CH3 COCH3
CH3
2-Methoxy-2-methyl
propane
11--13
11
Preparation of Ethers
• Step 1: protonation of the alkene gives a carbocation
CH3
CH3 C=CH2 + H
+
O CH3
CH3
CH3 CCH3 +
+
H
O CH3
H
• Step 2: reaction of the carbocation (an electrophile)
p
) gives
g
an oxonium ion
with the alcohol ((a nucleophile)
CH 3
CH3 CCH3 + HOCH3
+
CH3
CH3 CCH3
+
O
CH3
H
11--14
11
Preparation of Ethers
Step 3: proton transfer to solvent completes the reaction
CH3
CH3
O H + CH3 CCH3
+
O
H
CH3
CH3
+
CH3 O H + CH3 CCH3
H
O CH3
11--15
11
Reactions of ethers: 1) Cleavage of Ethers
‹ Ethers
are cleaved by HX to an alcohol and a
haloalkane
R-O-R + H-X
R-O-H + R-X
• cleavage requires both a strong acid and a good
nucleophile; therefore, the use of concentrated HI
(57%) and HBr (48%)
• cleavage by concentrated HCl (38%) is less effective,
primarily because Cl- is a weaker nucleophile in water
than either I- or Br-
11--16
11
Cleavage of Ethers
‹A
dialkyl ether is cleaved to two moles of
haloalkane
O
D ib utyl
t l ether
th
+ 2 HBr
heat
2
Br + H2 O
1-Bromob utane
11--17
11
Cleavage of Ethers
‹ 3°,
allylic, and benzylic ethers are particularly
sensitive to cleavage by HX
• tert-butyl ethers are cleaved by HCl at room temp
• in this case, protonation of the ether oxygen is
followed by C-O
C O cleavage to give the tert-butyl
tert butyl cation
O
+ HCl
A tert -butyl
ether
+ Cl -
OH
+
SN1
Cl
A 3° carbocation
intermed iate
11--18
11
Reactions of ethers: 2) Oxidation of Ethers
‹ Ethers
react with O2 at a C-H bond adjacent to
the ether oxygen to give hydroperoxides
• reaction occurs by a radical chain mechanism
O-O-H
+ O2
O
D iethyl ether
+ O2
O
D iisopropyl ether
‹ Hydroperoxide:
O
A h yd roperoxide
O-O-H
O
A hydroperoxid e
a compound containing the OOH
group
11--19
11
Ether Safety Alert: Flammability and Formation of Hydroperoxides
Two hazards must be avoided when working with
diethyl ether and other low-molecular-weight
ethers:
1) These ethers have low boiling points and are
hi hl flammable.
highly
fl
bl Open
O
fl
flames
and
d electric
l ti
appliances with sparking contacts must be
avoided
2) These ethers for hydroperoxides, which are
dangerous because they are explosive
11--20
11
Silyl Ethers as Protecting Groups
‹ When
dealing with compounds containing two or
more functional groups, it is often necessary to
protect one of them (to prevent its reaction) while
reacting at the other
• suppose you wish
i h to
t carry outt this
thi transformation
t
f
ti
OH
?
OH
H
4-Pentyn-1-ol
4-Heptyn-1-ol
11--21
11
Silyl Ethers as Protecting Groups
• the new C-C bond can be formed by alkylation of an
alkyne anion
• the
th OH group, however,
h
is
i more acidic
idi (pK
( Ka 16-18)
16 18) than
th
the terminal alkyne (pKa 25)
• treating the compound with one mole of NaNH2 will
give the alkoxide anion rather than the alkyne anion
pK a 16-18
pK a 25
H
O-Na+
OH
+
+ N
Na NH2
H
+ NH3
11--22
11
Silyl Ethers as Protecting Groups
‹A
protecting group must
• add easily to the sensitive group
• be resistant to the reagents used to transform the
unprotected functional group(s)
• be removed easily to regenerate the original functional
group
‹ In
this chapter, we discuss trimethylsilyl (TMS)
and other trialkylsilyl ethers as OH protecting
groups
11--23
11
Silyl Ethers as Protecting Groups
‹ Silicon
is in Group 4A of the Periodic Table,
immediately below carbon
• like carbon, it also forms tetravalent compounds such
as the following
O=Si=O
S ilicon dioxide
H
H-Si-H
H
Silane
CH3
CH3
CH3 -Si-CH3
CH3 -Si-Cl
CH3
Tetramethylsilane
CH3
Ch lorotrimethylsilane
11--24
11
Silyl Ethers as Protecting Groups
‹ An
-OH group can be converted to a silyl ether by
treating it with a trialkylsilyl chloride in the
presence of a 3° amine
CH3
RCH2 OH + Cl-Si-CH3 + Et 3 N
CH3
Chlorotri- Triethylmethylsilane amin e
CH3
RCH2 O-Si-CH3 + Et 3 NH+ ClCH3
A trimeth yls ilyl
Triethylether
ammonium
chloride
11--25
11
Silyl Ethers as Protecting Groups
• replacement of one of the methyl groups of the TMS
group by tert-butyl gives a tert-butyldimethylsilyl
(TBDMS) group
group, which is considerably more stable
than the TMS group
• other common silyl protecting groups include the TES
and TIPS groups
Me
Me Si Cl
Me
Trimethylsilyl
chlorid
hl id e
(TMSCl)
Et
Et Si Cl
Et
Me
Si Cl
Me
Trieth yls ilyl t -Butyldimethylsilyl
chlorid
hl id e
chloride
hl id
(TESCl)
(TBD MS Cl)
Si Cl
Triis op ropylsilyl
chloride
hl id
(TIPS Cl)
11--26
11
Silyl Ethers as Protecting Groups
• silyl ethers are unaffected by most oxidizing and
reducing agents, and are stable to most
nonaqueous acids and bases
• the TBDMS group is stable in aqueous solution
within the pH range 2 to 12, which makes it one of
the most widely used -OH protecting groups
• silyl blocking groups are most commonly removed
by treatment with fluoride ion,
ion generally in the
form of tetrabutylammonium fluoride
RCH2 O Si
+
-
F
+ -
Bu4 N F
RCH2 OH + F Si
THF
A TBD MS-protected
p
alcohol
11--27
11
Silyl Ethers as Protecting Groups
• we can use the TMS group as a protecting group in the
conversion of 4-pentyn-1-ol to 4-heptyn-1-ol
CH3
O Si CH3
CH3
OH
1 . ( CH3 ) 3 SiCl
H
H
2 . Na+ NH2 Br
3.
4-Pentyn-1-ol
CH3
O Si CH3
CH3
+ -
4 . Bu4 N F
OH
4-Hep tyn -1-ol
CH3
+ F Si CH3
CH3
11--28
11
Epoxides
‹ Epoxide:
a cyclic ether in which oxygen is one
atom of a three-membered ring
• simple epoxides are named as derivatives of oxirane
• where the epoxide is part of another ring system, it is
shown by the prefix epoxy
epoxy-• common names are derived from the name of the
p
is formally
y derived
alkene from which the epoxide
2
H2 C
3
CH 2
1O
Oxirane
(Ethylene oxide)
H3 C
H
H
C
C
CH 3
O
cis-2,3-Dimethyloxirane
(cis-2-Butene oxide)
1
H
O
2
H
1,2-Epoxycyclohexane
(Cyclohexene oxide)
11--29
11
Synthesis of Epoxides
‹ Ethylene
oxide, one of the few epoxides
manufactured on an industrial scale, is prepared
by air oxidation of ethylene
2 CH2 = CH2 + O2
Ag
2 H2 C
CH2
O
Oxirane
(Ethylene oxide)
11--30
11
Synthesis of Epoxides
‹ The
most common laboratory
oxidation
of
an
alkene
peroxycarboxylic acid (a peracid)
O
COOH
Cl
meta-chloroperoxybenzoic
be
o c acid
ac d
(MCPBA)
O
COOH
CO
O
Mg
2
2+
method
using
is
a
O
CH 3 COOH
Peroxyacetic acid
(Peracetic acid)
Magnesium
monoperoxyphthalate
(MMPP)
11--31
11
Synthesis of Epoxides
‹ Epoxidation
+
C cloh exene
Cycloh
e ene
of cyclohexene
O
RCOOH
H
CH2 Cl2
A p eroxyero
carboxylic acid
O
+
O
RCOH
H
1 2 Ep oxycyclohexan
1,2-Ep
o c clohe an e A carboxylic
carbo lic
(Cycloh exene oxide)
acid
11--32
11
Synthesis of Epoxides
‹ Epoxidation
is stereospecific:
• epoxidation of cis-2-butene gives only cis-2,3dimethyloxirane
• epoxidation of trans-2-butene gives only trans-2,3dimethyloxirane
H
CH3
C
H3 C
RCO3 H
C
H
trans-2-Buten e
H
H3 C
C
C
CH3
H
O
+
H
H3 C
C
O
t rans-2,3-D imethyloxirane
((a racemic mixture))
C
H
CH3
11--33
11
Synthesis of Epoxides
‹A
mechanism for alkene epoxidation must take
into account that the reaction
• takes place in nonpolar solvents, which means that no
ions are involved
• is stereospecific with retention of the alkene
configuration, which means that even though the pi
bond is broken, at no time is there free rotation about
the remaining sigma bond
11--34
11
Synthesis of Epoxides
‹A
mechanism for alkene epoxidation
R
O
C
O
3
2
H
R
O
O
H
O
4
O
1
C
C
C
C
C
The concerted formation of the two C-O bonds of the
epoxide ensures that the reaction is stereospecific
11--35
11
Synthesis of Epoxides
‹ Epoxides
are can also be synthesized via
halohydrins
CH3 CH=CH2
Cl2 , H2 O
Propene
OH
O
NaOH, H2 O
CH3 CH-CH2
CH 3 CH CH2
SN 2
Cl
A chlorohydrin
Meth yloxiran e
(racemic)
(racemic)
• the second step is an internal SN2 reaction
O
O
C
C
Cl
internal S N 2
C
C
+ Cl
A n epoxide
11--36
11
Synthesis of Epoxides
• halohydrin formation is both regioselective and stereoselective;
for alkenes that show cis,trans isomerism, it is also stereospecific
(Section 6.3F)
• conversion of a halohydrin to an epoxide is stereoselective
‹
Problem: account for the fact that conversion of cis-2cis 2
butene to an epoxide by the halohydrin method gives
only cis-2,3-dimethyloxirane
H
H3 C
H
1 . Cl 2 , H 2 O
C C
CH 3 2 . NaOH, H O
2
cis-2-Butene
H3 C
H
C
C
H
CH 3
O
cis-2,3-Dimethyloxirane
11--37
11
Synthesis of Epoxides
‹ Sharpless
epoxidation
• stereospecific and enantioselective
T i( O-iPr) 4
R2
(-)-D iethyl
tartrate
R1
+
R3
T i(( O-iPr)) 4
tert -Bu tyl
h yd roperoxid e
(+)-D iethyl
tartrate
OH
Et OOC
O
R3
+
OH
+
OH
OH
A
OOH
OH
A n allylic
alcoh ol
R1
R2
R2
R1
O
R3
OH
B
OH
COOEt
OH
(2S,3S)-(-)-D iethyl tartrate
Et OOC
COOEt
OH
(2R,3R)-(+)-D iethyl tartrate
11--38
11
ChemActivity 18: Ring opening
‹ Split
quickly in groups of 4
‹ Read Hand-out
Hand out Chem Activity 18 (model 1)
‹ Work on the critical thinking questions (1-7)
‹ You have 10-15
10 15 min
‹ We will discuss the questions in 5 min
11--39
11
Reactions of Epoxides
‹ Ethers
are not normally susceptible to attack by
nucleophiles
‹ Because of the strain associated with the threemembered ring, epoxides readily undergo a
variety
i t off ring-opening
i
i
reactions
ti
Nu
C
C
O
+ HN u :
C
C
HO
11--40
11
Reactions of Epoxides
‹ Acid-catalyzed
ring opening
• in the presence of an acid catalyst, such as sulfuric
acid, epoxides are hydrolyzed to glycols
O + H2 O
Oxirane
(Ethylene oxide)
H+
HO
OH
1,2-Ethanediol
(Ethylene glycol)
11--41
11
Reactions of Epoxides
Step 1: proton transfer to oxygen gives a bridged
oxonium ion intermediate
St
Step
2 backside
2:
b k id attack
tt k by
b water
t (a
( nucleophile)
l
hil ) on
the oxonium ion (an electrophile) opens the ring
Step 3:proton transfer to solvent completes the
reaction
H
H
2
H2 C
CH2
H2 C
O
1
+
H O H
(1)
CH2
O+
H
2
O
H
H
H
+O 3
CH2 CH2
OH
O
H
3
OH
CH2 CH2 + H3 O+
OH
H
11--42
11
Reactions of Epoxides
‹ Attack
of the nucleophile on the protonated
epoxide shows anti stereoselectivity
• hydrolysis of an epoxycycloalkane gives a trans-1,2diol
+
O +
H2 O
11,2-Epoxycyclop
2-Epoxycyclop entan e
(Cyclopen tene oxide)
(achiral)
H
OH
OH
+
OH
OH
trans 1 2 Cyclop entaned iol
trans-1,2-Cyclop
(a racemic mixtu re)
11--43
11
Reactions of Epoxides
‹ Compare
the stereochemistry of the glycols
formed by these two methods
H
RCO3 H
O
OH
+
H
H2 O
OH
+
OH
OH
t rans-1,2-Cyclopen tanediol
(formed as a racemic mixtu re)
H
OH
OsO4 , t-BuOOH
OH
cis -1,2-Cyclopentan ediol
(ach iral)
11--44
11
Epoxides
• the value of epoxides is the variety of nucleophiles
that will open the ring and the combinations of
functional groups that can be prepared from them
CH3
HSCH2 CHOH
A β-mercaptoalcohol
CH3
HOCH2 CHOH
A glycol
l
l
CH3
HC CCH2 CHOH
A β-alk yn ylalcoh ol
+
H2 O/ H3 O
+
-
CH3
Na SH / H2 O
H2 C
Na+C N- / H2 O
CH3
N CCH2 CHOH
A β-hydroxynitrile
CH
O
Methyloxiran e
+
1 . HC C Na
2 . H2 O
NH3
CH3
H2 NCH2 CHOH
A β-aminoalcohol
11--45
11
Reactions of Epoxides
‹ Treatment
of an epoxide with lithium aluminum
hydride, LiAlH4, reduces the epoxide to an
alcohol
• the nucleophile attacking the epoxide ring is hydride
ion H:ion,
CH
CH 2
O
Phenyloxirane
(Styrene oxide)
1 . LiAlH4
2 . H2 O
CH- CH 3
CH
OH
1-Phenylethanol
11--46
11
Ethylene Oxide
• ethylene oxide is a valuable building block for organic
synthesis because each of its carbons has a functional
group
OH
N C
(1)
O
+
-
Na CN
CH3 NH2
(3)
H2 / M
(2)
OH
CH3 N
H
-
(8) CH3 C C Na
OH
H2 N
O
(4)
Cl
OH
SOCl2
(6)
CH3 N
CH3 N
Cl
OH
+
(5) H2 SO4
(7) NH3
OH
CH3 N
O
CH3 N
N-H
11--47
11
Ethylene Oxide
• part of the local anesthetic procaine is derived from
ethylene oxide
• the
th hydrochloride
h d
hl id salt
lt off procaine
i is
i marketed
k t d under
d
the trade name Novocaine
O
O
O
H2 N
N
N
OH + HO
H2 N
Procaine
O
Eth ylen e
oxide
+
N
H
D iethylamine
11--48
11
Epichlorohydrin
‹ The
epoxide epichlorohydrin is also a valuable
building block because each of its three carbons
contains a reactive functional group
• epichlorohydrin is synthesized from propene
Cl
+ HCl
+ Cl2 500°C
Prop ene
3-Chlorop ropen e
(Allyl chloride)
OH
Step 2: Cl
Cl
Cl + HCl
+ Cl2 / H2 O
Step 1:
OH
Step 3: Cl
Cl + Ca(OH) 2
Cl
O
+ CaCl2
Ep ichloroh yd rin
(racemic)
11--49
11
Epichlorohydrin
• the characteristic structural feature of a product
derived from epichlorohydrin is a three-carbon unit
with -OH
OH on the middle carbon,
carbon and a carbon,
carbon nitrogen,
nitrogen
oxygen, or sulfur nucleophile on the two end carbons
Cl
O
Nu
Nu
O
OH
Nu
Nu
Nu
Epichlorohydrin
11--50
11
Epichlorohydrin
• an example of a compound containing the threecarbon skeleton of epichlorohydrin is nadolol, a βadrenergic blocker with vasodilating activity
Cl
O
HO
N
OH H
HO
N adolol
(racemic)
O
-
O
HO
HO
a nu cleophile d erived
b y removal of th e acidic
H from an -OH
OH group
H2 N
the nitrogen
nu cleophile
of a 1° amin e
11--51
11
Thioethers
‹ The
sulfur analog of an ether
• IUPAC name: select the longest carbon chain as the
parent and name the sulfur-containing substituent as
an alkylsulfanyl group
• common name: list the groups bonded to sulfur
followed by the word sulfide
S
Ethylsulfanylethan e
(D ieth yl s ulfide)
S
2-Eth yls ulfanylprop ane
(Eth yl is op ropyl su lfid e)
11--52
11
Nomenclature
‹ Disulfide:
contains an -S-S- group
• IUPAC name: select the longest carbon chain as the
parent and name the disulfide-containing substituent
as an alkyldisulfanyl group
• Common name: list the groups bonded to sulfur and
add the word disulfide
S
S
Ethyldis ulfanylethane
(D ieth yl d isulfide)
11--53
11
Preparation of Sulfides
‹ Symmetrical
sulfides: treat one mole of Na2S with
two moles of a haloalkane
2 RX + N a2 S
+ Na2 S
Cl
Cl
,
ichlorob utane
1,4-D
RSR + 2 N aX
A sulfide
SN 2
+
-
+ 2 Na Cl
S
Th iolan e
(Tetrahydrothiophen e)
11--54
11
Preparation of Sulfides
‹ Unsymmetrical
sulfides: convert a thiol to its
sodium salt and then treat this salt with an alkyl
halide (a variation on the Williamson ether
synthesis)
-
+
CH3(CH2)8CH2S Na
Sodium 1-decanethiolate
+ CH3I
SN2
CH3(CH2)8CH2SCH3 + Na+ I1-Methylsulfanyldecane
(D l methyl
(Decyl
th l sulfide)
lfid )
11--55
11
Oxidation Sulfides
‹ Sulfides
can be oxidized to sulfoxides and
sulfones by the proper choice of experimental
conditions
S- CH 3
S
Methyl phenyl
sulfide
O
N aIO 4
S- CH3
o
H2 O2
25oC
25 C
Methyl phenyl
sulfoxide
2 CH3 -S-CH
S CH3 + O2
D imethyl su lfid e
oxides of
g
nitrogen
O
S- CH3
S
O
Methyl phenyl
sulfone
O
2 CH3 -S-CH
S CH3
D imethyl su lfoxide
11--56
11
Ethers
&
Epoxides
End of Chapter 11
11--57
11