Unit 11 : Ethers

Structure
 Formula r-O-r’
 r a n d r ’ a r e a l k yl o r a r yl
 a r yl : p h e n yl g r o u p
 O x yg e n s p 3 h yb r i d i z e d
 Bent molecular geometry
 Tetrahedral c-O-C angle
 ~110°
 C-O bonds are polar

Properties
 Polar aprotic
 Boiling points
 Higher than alkanes (non-polar)
 Lower than alcohols (polar protic)
 H yd r o g e n b o n d i n g
 E t h e r s c a n h yd r o g e n b o n d w i t h w a t e r
and alcohols, but not other ether
molecules
 H-bond acceptor, but not donator
 Solvation
 Good solvents because
 Dissolve both polar and
nonpolar substances
 Unreactive toward strong bases
 Stabilize both nucleophiles and
electrophiles
 Crown ethers


 Named #-crown-#
 First number in number of
atoms in the entire ring
 Second number is the
number of o atoms
 Above is 18-crown-6
 Solvates small cations, but not
anions

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  Allows anions to act as
nucleophiles
 S i z e o f r i n g d e t e r m i n e s t yp e o f
solvated cation
 12-crown-4: Li(+)
 15-crown-5: Na(+)
 18-crown-6: K(+)
 Allows salts to dissolve in
nonpolar solvents

Nomenclature
 Common names
 N a m e 2 a l k yl g r o u p s a t t a c h e d t o t h e
o x yg e n a n d a d d t h e w o r d “ e t h e r ”
 E x . e t h yl m e t h yl e t h e r
 E x . t e r t - b u t yl m e t h y l e t h e r
 Name the groups in alphabetical
order
 I f s ym m e t r i c a l , u s e d i a l k yl ( o r
j u s t a l k yl )
 E x . d i e t h yl e t h e r o r e t h yl
ether
 IUPAC names
 More complex alkyl group is the
parent alkane name (parent -o-r)
 Smaller group (with the O) becomes
a n “ a l k o x y” s u b s t i t u e n t
 Ex. ethoxy pentane
 E x . 2 - m e t h yl - 2 - m e t h o x yp r o p a n e
 E x . m e t h o x yc y c l o h e x a n e
 Cyclic ethers
 H e t e r o c yc l i c
 Non-carbon atom is part of the
ring
 3-membered: epoxides
(oxiranes)
 4-membered: Oxetanes
 5-membered: Oxolanes
 Ex. THF
 With 2 double bonds:
furans
 6-membered
 With 2 double bonds:
pyrans
 With 1 O: oxanes
 With 2 O: dioxanes
 Epoxides
 Common
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 Name the starting alkene and
add “oxide”
 IUPAC
 I f o x yg e n i s c o n s i d e r e d a
substituent, it is called epoxy
 Numbers specify positions
 If the 3-membered ring is the main
chain, then it is called oxirane
 O is 1, C are 2, 3
 Substituents named in alphabetical
order

Synthesis of ethers
 Williamson Ether synthesis (review)
 Alkoxide is made by deprotonation of
alcohol by Na, K, NaH
 P r i m a r y s u b s t r a t e ( h a l i d e o r t o s yl a t e ) :
SN2 displacement reaction
 r-CH2-X + r-O(-) -> r-CH2-O-R
 Secondary or tertiary substrate: E2
elimination takes place
 P h e n yl e t h e r s
 Phenoxide
 Phenolic proton is acidic
(pKA ~10)
 Easy to produce phenoxide
using NaOH
 P h e n u l h a l i d e s o r t o s yl a t e s
cannot be used
 Positive charge on
phenolic carbon is
not easily attacked
 Ph-O(-) + r-CH2-X -> Ph-O-CH2-
r
 Nucleophile (alkoxide) is from
the more hindered alcohol
 E l e c t r o p h i l e ( t o s yl a t e o r a n
a l k yl h a l i d e ) i s f r o m t h e l e s s
hindered alcohol
 Alkoxymercuration -demercuration
(review)
 Avoids rearrangements
 Step 1: Add Hg(OAc)2 to alkene
 Markovnikov
 OH to more substituted C
 H to less substituted c
 Instead of H2O, use r-O-H

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 Step 2: NaBH4 to replace Hg-OAc
with H
 Anti addition
 Industrial synthesis (review)
 N o t g o o d l a b s yn t h e s i s
 Bimolecular condensation of primary
alcohols
 If temperature is too high, or alcohol
i s n o t p r i m a r y, a n a l k e n e f o r m s d u e t o
elimination
 E x . 2 - p r o p yl a l c o h o l - H 2 S O 4 , h e a t
( ! 4 0 ° C ) - > n - p r o p yl e t h e r + H 2 O
 H i g h e r h e a t ( 1 8 0 ° C ) yi e l d s
alkene
 E x . i s o p r o p yl a l c o h o l - H 2 S O 4 , h e a t - >
H2C≡CH-CH3 + H2O
 u n i m o l e c u l a r d e h yd r a t i o n ( n o
ether formed)
 Mechanism
 Lone pair on O attacks H on
H3O(+) (loss of water)
 Water acts as leaving group
 Carbocation attacked by lone
pair on o (from alcohol)
 O is deprotonated by alcohol
 Formation of ether

Reactions of ethers
 Cleavage of ethers
 Cleaved by heating with concentrated
HBR and HI
 R e a c t i v i t y: H I > H B R
 Mechanism
 r-O-r
 Lone pair on O attacks H on H -
BR
 Br(-) attacks R group; R -O bond
kicked off to O (loss R-OH)
 This happens to the other r
group as well
 O is protonated again,
water leaves as BR attacks
r group
 Forms r-BR
 rOH is a good LG
 SN2 mechanism
 2 m o l e s a l k yl b r o m i d e p r o d u c e d

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 Cleavage of phenyl ethers
 Phenol cannot react further to form a
halide because an SN2 reaction cannot
occur on an sp2 carbon
 Autoxidation of ethers
 H yd r o p e r o x i d e s a n d d i a l k yl p e r o x i d e s
are highly explosive
 Precautions:
 A v o i d d i s t i l l a t i o n t o d r yn e s s
 Store tightly in bottles
 Avoid exposure to flame
 E x . d i e t h yl e t h e r – [ O ] ( e x c e s s O 2 ) - >
CH3-CHOOH-Or –[O]-> CH3CH2-O-O-
r (peroxide)
 O-O bonds are easily broken and can
create explosions

Synthesis of epoxides
 Synthesis of epoxides by Peroxyacids
(review)
 M o s t c o m m o n l y u s e d p e r o x ya c i d i s
M C P B A ( m e t a - c h l o r o p e r o x yb e n z o i c
acid)
 Epoxidation is regioselective; most
electron-rich double bond reacts
faster
 A n o t h e r l e s s t o x i c p e r o x ya c i d t h a t
may be used is MMPP (Magnesium
mono peroxy phthalate)
 Synthesis of epoxides by halohydrin
cyclization
 Stronger base than OH (-) not required
b e c a u s e a c i d i t y o f h a l o h yd r i n s i s
higher due to the inductive effect
(from X)
 Alkoxide and halogen are on the same
molecule
 This mechanism represents an
intramolecular SN2 attack
 Mechanism
 Begin with alkene, X-X
 Pi electrons on double bond
attack X, X(-) leaves
 Electrons from BR on alkane
attack carbocation and form C -
BR-C ring

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  Lone pair on O (water) attacks
more substituted carbon (anti
attack)
 Water is deprotonated, resulting
i n h a l o h yd r i n
 Add base (OH(-))
 O H ( - ) d e p r o t o n a t e s t h e h yd r o x yl
group
 BR leaves as lone pair from O
attacks that carbon

Reactions of epoxides
 Acid-catalyzed opening of epoxides
(review)
 S yn t h e s i s o f t r a n s - 1 , 2 - d i o l
 alkene -MCPBA-> epoxide
 epoxide -H3O(+)-> alcohol
 Epoxide: weak electrophile
 H3O(+) protonates to make
strong electrophile
 Water attacks more substituted
C, C-O bond kicked off onto O
 Water deprotonated, resulting in
diol
 Anti addition
 S yn t h e s i s o f a l k o x y a l c o h o l
 Lone pair on O attacks H on
H3O(+)
 Lone pair on r -OH attacks more
substituted c
 r-OH is deprotonated by r -OH
 Base-catalyzed opening of epoxides
 Epoxide C is attacked by lone pair of
OH(-)
 Attacks less substituted C, kick
O-C bond onto O
 O (-)
is protonated (with water)
 Epoxide opening is
t h e r m o d yn a m i c a l l y f a v o r e d d u e t o
ring strain
 Regioselectivity
 A c i d c a t a l ys i s : a t t a c k o n m o r e
substituted C
 B a s e c a t a l ys i s : a t t a c k o n l e s s
substituted C
 Opening of epoxides with organometallics
(review)
 Attack at less hindered carbon
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  This reaction is important for
s yn t h e s i s :
 Produces alcohol with 1 or 2
branches
 Lengthens carbon chain by 2
carbons
 Mechanism
 Begin with epoxide
 Add Grignard (r attacks less
hindered C)
 C-O bond kicked off onto O
 O is protonated (H3O(+))
 Ether as solvent

Thioethers
 r-S-r’: an analog of ether
 Sulfides are named like ethers:
 IUPAC: Alkoxy replaced by alkylthio
 E x . 5 - e t h yl t h i o - 4 - m e t h yl h e x - 2 -
ene
 Common: ether is replaced by sulfide
 E x . d i e t h yl s u l f i d e
 E x . c yc l o h e x yl i s o p r o p yl s u l f i d e
 Synthesis of Thioethers
 S i m i l a r t o W i l l i a m s o n e t h e r s yn t h e s i s
 Nucleophile: thiolate ion (r-S(-))
 Mechanism
 Thiolate ion attacks alpha
carbon as leaving group leaves
 Oxidation of Thioethers
 Sulfide –[O]-> sulfoxide –[O]->
sulfone
 R e v i e w : o z o n o l ys i s o f a l k e n e s
 Alkene -O3-> [Intermediate
o z o n i d e ] - > k e t o n e / a l d e h yd e
 Mechanism not needed for
o z o n i d e - > k e t o n e / a l d e h yd e
 If using KMnO4 and OH(-), then
c a r b o x yl i c a c i d w o u l d f o r m
 Alkylating agents
 Sulfide + primary halide -> sulfonium
salt
 Lone pair on sulfide attacks primary
halide while X leaves (SN2)
 Nucleophile attacks C on sulfonium
salt, C-S bond gets kicked off onto S
 Nucleophile ex: (-)OH, (-)Or, (-
)
NH2, (-)Nr2, etc.
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  Results in Nu-CH3 + CH3-S-CH3
 Sulfide is good LG

Silyl ethers
 Resistant to some acids, bases, and
oxidizing agents
 E a s i l y f o r m e d a n d e a s i l y h yd r o l yz e d
 Used as protecting groups for alcohols
 r3-Si-Or
 Alcohol-protecting groups
 G r i g n a r d c a n n o t r e a c t w i t h c a r b o n yl
in a molecule with =O and -OH
 W i l l p i c k u p h yd r o g e n o f f o f
h yd r o x yl b e f o r e i t i n t e r a c t s w i t h
c a r b o n yl
 Must be protected for Grignard to
i n t e r a c t w i t h c a r b o n yl
 TIPS
 C h l o r o t r i i s o p r o p yl s i l a n e
 i s o P r o p yl 3 - S i - C l
 Et3N: added as base
 T a k e s H o f f o f h yd r o x yl
 Cl leaves off of TIPS
 Lone pair on O attacks Si
 R e s u l t s i n r - O - S i - i s o p r o p yl 3 ( r -
O-TIPS)
 Add Grignard (interacts with
c a r b o n yl )
 A d d b u t yl 4 N ( + ) F ( - ) , H 2 O t o d e p r o t e c t
 Results in r-OH
 S i l yl e t h e r g r o u p c a n b e r e m o v e d i n
aqueous or organic solvents

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