Download Learning Guide for Chapter 16

Learning Guide for Chapter 16 - Ethers and Epoxides
I. Introduction to ethers, sulfides, and epoxides
II. Nomenclature of ethers
III. Synthesis of ethers and sulfides
IV. Reactions of ethers and sulfides
V. Synthesis of epoxides
VI. Reactions of epoxides
VII. Review of reactions
I. Introduction to ethers, epoxides, and thioethers
Defintion and examples of ethers and thioethers
Describe an ether functional group:
contains C-O-C w/no C=O on those C's
How is an ether different from an ester or anhydride?
O
O
O
O
O
ether
ester
O
anhydride
What is the most common ether? What is it used for?
diethyl ether
O
solvent, starter fluid, early general anesthetic
What ether is used as an additive in gasoline? Why? Why has its use declined?
MTBE
O
increases octane rating; environmental concerns
What does a thioether look like? What else are they called?
S
also called sulfides
What do thioethers often smell like?
oysters that have been left in the fridge too long
What thioether did we use in the reaction of alkenes with ozone?
S
= (CH3)2S
dimethyl sulfide
LG Ch 16 p 2
Classifications of Ethers
Draw an example of each of the following:
alkyl ether
alkyl groups on both sides
O
O
aryl group directly attached to the O
aryl ether
cyclic ether
O
THF
O
epoxide
O in a ring 4 or more
O in a three-membered ring
What are crown ethers useful for?
O
O
K+
O
O
CN-
O
O
O
O
Li+
O
O
[18]-crown-6
F-
removing ions from solution
carrying anions into solution
[12]-crown-4
Physical Properties of Ethers
Put the following compounds in order of their boiling points.
3
5
2
1
O
O
H
4
OH
H
O
dipole
Van der Waals
H-bonding
dipole
H-bonding
66oC
-42oC
100oC
-25oC
78oC
Why are ethers good solvents?
intermediate polarity - can dissolve nonpolar and polar compounds
LG Ch 16 p 3
Can ethers undergo hydrogen bonding with each other? What about with water?
no H-bonding - no H on EN atom
O
O
O
O
H
can H-bond w/ H2O
and other H-bonding donors
H
How can ethers stabilize electron deficient compounds?
O
H
+
H
Are ethers flammable?
B
H
O
B
H
H
H
yes! and very volatile
What can happen when ethers are exposed to air for a long time?
form organic peroxides - shock sensitive
O2
O
O
O
(slow)
sold with inhibitors; don't open old bottles!
Reactivity of Ethers and Thioethers
Which of the following will ethers react with?
acids
bases
nucleophiles
electrophiles
oxidizing
agents
reducing
agents
least reactive functional group!
(another thing that makes them good solvents)
H-base
O
O
H
what happens next depends on the
conjugate base of the acid
pKa - 3.6 so H-base has to have a pKa less than -3.6
LG Ch 16 p 4
Which of the following will epoxides react with?
acids
bases
nucleophiles
H
H-base
O
electrophiles
Nu
O
Nu
weak
Nu
Nu
O
strong
H3O+
O
OH
Nu
OH
IR Spectra of Ethers
What band do ethers have that alkanes don't?
C-O 1300-1000 cm-1
What other compounds have this band? How can they be distinguished from ethers?
esters - also have C=O band
alcohols - also have OH band
anhydrides - also have 2 C=O bands
NMR Spectra of Ethers
What chemical shift are the H's next to the O in an ether? 3-4 ppm
H
H H
O
H
4H quartet at 3-4 ppm
LG Ch 16 p 5
How will the spectra of a symmetrical ether and a nonsymmetrical ether be different?
symmetrical - 1 peak at 3-4 ppm; unsymmetrical - 2 peaks at 3-4 ppm
H
H H
H
O
q and s at 3-4 ppm (might overlap)
H
What will happen with an aryl ether?
O
s at 4-6 ppm
no H's next to O on aryl side
Deduce the structure of the compound which gave the following spectrum.
C7H7BrO
a - 2H d ~7 ppm
aromatic
b - 2H d ~7 ppm
4 aromatic H's - 2 substituents
c - 3H s 3-4 ppm
3H's next to O
O
4-bromoanisole
Br
LG Ch 16 p 6
II. Nomenclature of ethers
Common names
How are common names for ethers constructed?
substituent + substituent + "ether"
Give common names for the following ethers.
O
O
O
methyl propyl ether
dimethyl ether
methyl phenyl ether
O
O
O
tert-butyl methyl ether
MTBE - oops
benzyl methyl ether
IUPAC names
Are ethers principle groups?
diallyl ether
no - don't change the ending
What part of the ether is considered a substituent?
the O plus the smallest carbon chain connected to it
How are ether substituents named?
O
change "yl" to "oxy"
methylcyclohexane
methoxycyclohexane
Name the following compounds.
O
Br
O
ethoxycyclohexane
1-bromo-2-methoxycyclohexane
O
OH
O
O
3,4-dimethoxy-1-cyclohexene
2-methoxy-1-cyclohexanol
LG Ch 16 p 7
O
O
O
1-ethoxy-4-methoxybutane
3-ethoxyhexane
OH
O
5-methoxy-2-vinyl-2-cyclopentene-1-ol
Draw structures for the following:
1-ethoxypropane
1-butoxy-1-ethanol
4-propoxy-1-butene
O
O
O
OH
1,3-dimethoxypropane
O
3-bromo-1,1-dimethoxycyclopentane
O
O
O
Br
III. Synthesis of ethers and sulfides
What starting materials and reagents are needed for each of the methods of ether synthesis?
Williamsen ether synthesis
Br
SN2
+
alkyl halide
or tosylate
O
O
alkoxide
SN2 reaction
alkoxymercuration-reduction
1. Hg(OAc)2
+
alkene
OH
O
2. NaBH4
alcohol
oxymercuration-reduction
with an alcohol instead of water
LG Ch 16 p 8
What is the main limitation of the Williamsen ether synthesis?
the alkyl halide or tosylate must be 1o
Synthesize the following ether by the Williamsen ether synthesis.
1o
aryl
OH
O
Br
O
O
Br
O
NaOH
good
+
no reaction
Br
O
What is the main limitation of the alkoxymercuration-reduction reaction?
ether always goes to the more substituted side of the alkene
equally substituted - two products
Synthesize the following ether by alkoxymercuration-reduction.
wrong product
OH
O
good
HO
1. Hg(OAc)2
+
HO
2. NaBH4
no base!
O
LG Ch 16 p 9
Synthesize the following ethers by either the Williamsen ether synthesis or
alkoxymercuration-reduction. Explain why the other won't work!
O
Williamsen
NaH
OH
+
O
alkoxymercurationreduction
OH
Br
1. Hg(OAc)2
O
2. NaBH4
wrong product
O
Br
Williamsen
no reaction
or E2 products as well
Br
2o
aryl
OH
alkoxymercurationreduction
good
2 products
Which of these methods works for synthesis of sulfides?
SN2
What effect does the lower acidity of thiolate ions have? no E2, even with 2o RX or ROTs
Synthesize the following sulfide.
S
SH
Cl
S
NaOH
+
NaOH
+
SH
S
OTs
LG Ch 16 p 10
IV. Reactions of ethers and sulfides
Reactions of Ethers
Are ethers highly reactive, or highly unreactive functional groups?
What kind of reagents do ethers react with? strong acids
H-base
H
O
+
base
O
pKa = -3.6
Which of the following will give a new product?
H2SO4
H
+ HSO4-
O
O
protonates, that's all
alcohol will also react
H
H
Br
+
O
O
Br
OH
conj base is a Nu
H2O +
Br
2 eq HBr
O
2
if
SN2
o
if 3 , SN1
if 2o, both
2 eq HBr
+ H2O
Br
Br
Br
OH2
1o,
What products would the following ethers give?
O
H
+
if symmetrical - one RX
Br
+
+ H2O
Br
if unsymmetical, two RX
O
2 eq HI
OH
I
Is this a good way to make alkyl halides?
not really - makes two products, harder to make the ether first
aromatic ethers give
phenol, can't react
LG Ch 16 p 11
Reactions of Sulfides
What reaction can sulfides undergo that ethers cannot?
oxidation
What can they be oxidized to?
H2O2
S
CH3COOH
2 H2O2
S
O
O
S
CH3COOH
sulfoxides
S
sulfones
O
Which is a better nucleophile, S or O? S - larger
What happens when a sulfide acts as a nucleophile towards an alkyl halide?
CH3I
S
I
S
alkylating agent
see biochem application p 642
LG Ch 16 p 12
V. Synthesis of Epoxides
What are the two ways in which epoxides may be formed?
1) alkene + peroxy acid --> epoxide
2) halohydrin + base --> epoxide
Epoxidation of alkenes
What do peroxyacids look like?
O
R
O
O
H
COOH with an extra O
Which of the following peroxy acids are soluble in water or alchols? Which in low polarity
solvents? How are they abbreviated?
O
O
O
O
O
H
MMPP
O
O
H
O
O
peroxyacidic acid
peroxybenzoic acid
water, alcohols
O
O
H
H
O
Mg+2
O
O
O
O
magnesium monoperoxyphthalate
when used in low polarity solvents
CH3CO3H
PhCO3H
product crystallizes out
Write a reaction of an alkene with a peroxy acid to form an epoxide.
low polarity solvents
O
+
O
O
OH
O
+
oxidized
reduced
What gets oxidized and reduced in the reaction above?
What stereochemistry does this reaction have? Why?
H
PhCO3H
O
meso
H
syn addition - O added to the same side
mechanism is electrocyclic, O connects to both C's at the same time
OH
LG Ch 16 p 13
PhCO3H
O
PhCO3H
O
+
O
O
+
if you want this
result, how do you
get it?
Cyclization of halohydrins
We have seen how alkoxides react with alkyl halides to form ethers in the Williamson ether
synthesis. How could this be used to make an epoxide?
Cl
+
O
O
Cl
O
O
O
Cl
O
O
O
Cl
Cl
O
O
What is the stereochemistry of this reaction? Why?
H
Cl
H
O
O
inversion - SN2, attacks from the opposite side of the halogen
LG Ch 16 p 14
What does the starting material look like before the H is removed to make the alkoxide?
What is this functional group called?
Cl
Cl
reagent we need:
halohydrin
starting material:
O
OH
Write the entire reaction starting with the neutral starting material.
Cl
Cl
NaH
O
(or K)
OH
O
Where do halohydrins come from?
Cl2
Cl
H2O
OH
halohydrin
So, how are the two epoxide syntheses related?
X2, water
NaH
epoxide
alkene
peroxyacid
Show two ways each of the following epoxides could be formed from an alkene.
O
1)
2)
PhCO3H
Br2
OH
H2O
Br
NaH
O
1)
PhCO3H
Cl
2)
Cl2
H2O
NaH
OH
LG Ch 16 p 15
VI. Reactions of Epoxides
Reaction of epoxides with strong nucleophiles
Why are epoxides good electrophiles, while ethers are not?
Nu
O
+
O
Nu
O
Nu
O
Nu
O
no rxn - O- is not a good LG
Nu
Nu
O
no rxn - same as above
O- is still formed,
but ring strain is also released
How do their energy diagrams compare?
O
epoxide: small Ea = fast - !H = exothermic
Ea
105 kJ/mol
ring strain!
ether:
!H -
large Ea = slow + !H = endothermic
Ea
!H +
O
since the epoxide starts out so much higher, it is
it is ok to form a charged product
What needs to happen to complete the reaction?
alkoxide needs to be protonated
source of H will depend on the Nu
What product is formed when each of the following nucleophiles is reacted with ethylene
oxide? What is the proton source in each case?
O
NaOH
O
H2O
O
CH3ONa
CH3MgBr
2)
H3O+
OH
vicinal diol
solvent
O
CH3OH
O
HO
OH
O
HO
O
2-alkoxy alcohol
solvent
O
HO
alcohol
acid added as 2nd step
LG Ch 16 p 16
What other nucleophiles would attack epoxides?
any SN2 Nu
C
R
N
R
acetylide ions
cyanide
S
thiolate ions
If the epoxide is not equally substituted, which side will be attacked?
attack at C2
attack at C1
O
1
2
CH3ONa
O
CH3OH
1
OH
OH
1
2
O
2
not formed
Write the two possible products.
How could we figure out which will be formed? by experiment
Knowing the answer, how can we make sense of it? sterics - less hindered
side is attacked
Reactions of protonated epoxides with weak nucleophiles
How can an epoxide react with an acid?
H
O
base
H
O
+
base
Which is a better electrophile, a neutral epoxide or a protonated one? Which requires a
stronger nucleophile?
Nu
O
O
Nu
forms alkoxide - charged
HO
Nu
forms alcohol - neutral
less reactive strong
H
O
Nu
weak
more reactive
What kinds of weak nucleophiles would work?
SN1 Nu
water, alcohols
LG Ch 16 p 17
Show how a protonated epoxide would form, then react with water or an alcohol. What
product is formed?
diol
H
H2SO4
O
OH2 H2O
HO
O
HO
OH
+H3O+
H2O
2-alkoxy alcohol
H2SO4
O
O
H
HO
HO
CH3OH
HO
O
CH3OH
What do you notice about the acid?
catalytic
If the epoxide is not equally substituted, which side will be attacked?
attack at C1
O
1
2
H2SO4
O
CH3OH
1
attack at C2
OH
OH
O
1
2
2
not formed
Write the two possible products.
How could we figure out which will be formed? by experiment
Knowing the answer, how can we make sense of it?
O
H
more substituted C has more of the + charge
!+ !+
Synthesis using epoxides
What kinds of products can be made using epoxides?
compounds with an alcohol next to something that can be attached using a Nu
N
HO
OH
HO
S
R
HO
C
R
HO
O
R
HO
R
HO
LG Ch 16 p 18
What steps should you take when designing a synthesis using an epoxide?
1) determine where the epoxide was
2) figure out what Nu(s) could be used
3) determine if the Nu will attack the correct side
What reaction could be used to form the following products?
O
OH
H2SO4
or
OH
H2O
NaOH
H2O
since both sides end up the same, it doesn't matter which
side the Nu attacks
O
O
OH
H2SO4
or
CH3OH
CH3ONa
CH3OH
since the ether is on the more substituted side, acid and a
weak Nu must be used
O
OH
H2SO4
or
O
CH3OH
1
2
3
4
5
6
6
4
5
2
3
OH
epoxide
1
2
Li
3
O
OH
1
4
5
CH3OH
now the ether is on the less substituted side, so a strong Nu
must be used
epoxide
Nu
CH3ONa
2) H3O+
6
6
Nu
1
2
3
4
O
5
Li
2) H3O+
Nu must attack the more substituted side, but either side
could be the Nu
LG Ch 16 p 19
Stereochemistry of epoxide reactions
What is the stereochemistry of the addition of the Nu to an epoxide?
the carbon which is attacked it inverted; the other carbon stays the same
C
N
C
N
OH
H2O
OH
C
meso
C
one enantiomer
H2O
C
chiral
O
N
OH
OH
N
H2O
chiral
N
OH
N
O
C
racemic mixture
of enantiomers
+
O
C
chiral
C
N
constitutional
isomers
N
chiral
the idea is not to memorize these examples, but use the principles to predict
stereochemical results in multiple situatons
Compare the stereochemistry of the following reactions.
OH
KMnO4
H2O, NaOH
OH
PhCO3H
NaOH
OH
OH
OH
OH
O
H2O
How are these two reactions complementary?
hydroxylation gives cis diols
epoxidation, then hydrolysis gives trans diols