Organic Chemistry
Second Edition
David Klein
Chapter 14
Ethers and Epoxides; Thiols and Sulfides
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Klein, Organic Chemistry 2e
14.1 Introduction to Ethers
• An ether group includes an oxygen atom that is bonded
to TWO –R groups
• -R groups can be alkyl, aryl, or vinyl groups
• Would the compound below be considered an ether?
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Klein, Organic Chemistry 2e
14.1 Introduction to Ethers
• Compounds containing ether groups are quite common
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Klein, Organic Chemistry 2e
14.2 Naming Ethers
• Common names are used frequently
1. Name each –R group
2. Arrange them alphabetically
3. End with the word, “ether”
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Klein, Organic Chemistry 2e
14.2 Naming Ethers
• IUPAC systematic names are often used as well
1. Make the larger of the –R groups the parent chain
2. Name the smaller of the –R groups as an alkoxy substituent
• Practice with SkillBuilder 14.1
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Klein, Organic Chemistry 2e
14.2 Naming Ethers
• Name the following molecule
• Draw the structure for (R)-1-methoxycyclohexen-3-ol
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Klein, Organic Chemistry 2e
14.3 Structure and Properties of Ethers
• The bond angle in ethers is very similar to that found in
water and in alcohols
• Is the oxygen atom in an ether sp3, sp2, or sp hybridized?
• How do the –R groups affect the bond angle?
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Klein, Organic Chemistry 2e
14.3 Structure and Properties of Ethers
• In chapter 13, we learned that due to H-bonding,
alcohols have relatively high boiling points
• What is the maximum number of H-bonds an alcohol
can have?
• Draw an H-bond between an ether and an alcohol
• What is the maximum number of H-bonds an ether can
have?
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Klein, Organic Chemistry 2e
14.3 Structure and Properties of Ethers
• In chapter 13, we learned that due to H-bonding,
alcohols have relatively high boiling points
• Would you expect the boiling point of an ether to be
elevated similar to alcohols?
• WHY or WHY not?
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Klein, Organic Chemistry 2e
14.3 Structure and Properties of Ethers
• Explain the boiling point trends below using all relevant
intermolecular attractions
– Trend 1
– Trend 2
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Klein, Organic Chemistry 2e
14.3 Structure and Properties of Ethers
• Ethers are often used by organic chemists as solvents
– Relatively low boiling points allow them to be evaporated
after the reaction is complete
– Their dipole moment allows them to stabilize charged or
partially charged transition states. HOW?
– They are NOT protic. WHY is that an advantage for a solvent
in many reactions?
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Klein, Organic Chemistry 2e
14.4 Crown Ethers
• Metal atoms with a full or partial positive charge can be
stabilized by ether solvents
• Ethers are generally used as the solvent in the Grignard
reaction
• Give another reason why an ether makes a good solvent
in this reaction
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Klein, Organic Chemistry 2e
14.4 Crown Ethers
• Crown ethers have been shown to form especially
strong attractions to metal atoms. WHY?
• Note how many carbon atoms separate the oxygens
• Why are they called CROWN ethers?
• Explain the numbers found in their names
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Klein, Organic Chemistry 2e
14.4 Crown Ethers
• The size of the metal must match the size of the crown
to form a strong attraction
• 18-crown-6 fits a K+ ion just right
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Klein, Organic Chemistry 2e
14.4 Crown Ethers
• Normally metal ions are not soluble in low polarity
solvents. WHY?
• The crown ether – metal complex should dissolve nicely
in low polarity solvents. WHY?
• Imagine how a crown ether
could be used to aid reactions
between ion (especially anions)
and low polarity organic
substrates
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Klein, Organic Chemistry 2e
14.4 Crown Ethers
• The F- ion below is ready to react because the K+ ion is
sequestered by the crown ether
• Without the crown ether, the solubility of KF in benzene
is miniscule
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Klein, Organic Chemistry 2e
14.4 Crown Ethers
• Generally, F- ion is not used as a nucleophile, because it
is strongly solvated by polar solvents
• Such solvation greatly reduces its nucleophilic strength
• In the presence of the crown ether, it is soluble enough
in a nonpolar solvent that it can readily attack an
electrophile
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Klein, Organic Chemistry 2e
14.4 Crown Ethers
• Smaller crown ethers bind smaller cations
• Practice with conceptual checkpoint 14.4
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Klein, Organic Chemistry 2e
14.5 Preparation of Ethers
• Diethyl ether is prepared industrially by the acidcatalyzed dehydration of ethanol
• How is it a dehydration?
• Can this method be used
to make asymmetrical
ethers?
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Klein, Organic Chemistry 2e
14.5 Preparation of Ethers
• The Williamson ether synthesis is a viable approach for
many asymmetrical ethers
• What happens to the halide?
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Klein, Organic Chemistry 2e
14.5 Preparation of Ethers
• The Williamson ether synthesis is a viable approach for
many asymmetrical ethers
• The alkoxide that forms in step 1 is also a strong base
• Are elimination products likely for methyl, primary,
secondary, or tertiary alkyl halides?
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Klein, Organic Chemistry 2e
14.5 Preparation of Ethers
• Use the Williamson ether approach to prepare MTBE
• Consider a retrosynthetic disconnect on the t-butyl side
• It is better to make your retrosynthetic disconnect on
the methyl side. WHY?
• Practice with SkillBuilder 14.2
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Klein, Organic Chemistry 2e
14.5 Preparation of Ethers
• Use the Williamson ether approach to synthesize the
following molecule
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Klein, Organic Chemistry 2e
14.5 Preparation of Ethers
• Recall from section 9.5 that oxymercurationdemercuration can be used to synthesize alcohols
• Is the addition Markovnikov or anti-Markovnikov?
• Is the addition syn or anti?
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Klein, Organic Chemistry 2e
14.5 Preparation of Ethers
• Similarly, alkoxymercuration-demercuration can be used
to synthesize ethers
• Is the addition Markovnikov or anti-Markovnikov?
• Is the addition syn or anti?
• Practice conceptual checkpoints 14.8–14.10
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Klein, Organic Chemistry 2e
14.6 Reactions of Ethers
• As we mentioned earlier, because they are aprotic,
ethers are generally unreactive
• However, ethers can react under the right conditions
• Consider the ether below
• Where are the most reactive sites?
• Is it most likely to react as an acid, base, nucleophile,
electrophile, etc.?
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Klein, Organic Chemistry 2e
14.6 Reactions of Ethers
• Ethers can undergo acid-promoted cleavage
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Klein, Organic Chemistry 2e
14.6 Reactions of Ethers
• Draw a complete mechanism and predict the products
for the following acid-promoted cleavage
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Klein, Organic Chemistry 2e
14.6 Reactions of Ethers
• To promote cleavage, HI and HBr are generally effective
• HCl is less effective, and HF does not cause significant
cleavage
• Explain the trend above considering the relative
strength of the halide nucleophiles
• Why is the cleavage considered acid-promoted rather
than acid-catalyzed?
• Practice with conceptual checkpoint 14.11
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Klein, Organic Chemistry 2e
14.6 Reactions of Ethers
• Predict products for the reaction below, and draw a
complete mechanism
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Klein, Organic Chemistry 2e
14.6 Reactions of Ethers
• Recall from section 11.9 that ethers can undergo
autooxidation
• Hydroperoxides can be explosive, so laboratory samples
of ether must be frequently tested for the presence of
hydroperoxides before they are used
• The autooxidation occurs through a free radical
mechanism – see next few slides
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Klein, Organic Chemistry 2e
14.6 Reactions of Ethers
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Klein, Organic Chemistry 2e
14.6 Reactions of Ethers
• Recall that the net reaction is the sum of the
propagation steps
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Klein, Organic Chemistry 2e
14.7 Naming Epoxides
• For cyclic ethers, the size of the ring determines the
parent name of the molecule
• Oxiranes are also known as epoxides
• Which cyclic ether system do you think is most reactive?
WHY?
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14-34
Klein, Organic Chemistry 2e
14.7 Naming Epoxides
• An epoxide can have up to 4 –R groups
• Although they are unstable, epoxides are found
commonly in nature
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Klein, Organic Chemistry 2e
14.7 Naming Epoxides
• There are two methods for naming epoxides
1. The oxygen is treated as a side group, and two numbers are
given as its locants
2. Oxirane is used as the parent name
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Klein, Organic Chemistry 2e
14.7 Naming Epoxides
• Name the molecules below by both methods if possible
• Practice conceptual checkpoints 14.12 and 14.13
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14-37
Klein, Organic Chemistry 2e
14.8 Preparation of Epoxides
• Recall from section 9.9 that epoxides can be formed
when an alkene is treated with a peroxy acid
• MCPBA and peroxyacetic acid are most commonly used
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Klein, Organic Chemistry 2e
14.8 Preparation of Epoxides
• Recall that the process is stereospecific
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Klein, Organic Chemistry 2e
14.8 Preparation of Epoxides
•
•
•
•
Epoxides can also be formed from halohydrins
What is a halohydrin?
How are halohydrins formed from alkenes?
When a Halohydrin is treated with NaOH, a ring-closing
reaction can occur
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Klein, Organic Chemistry 2e
14.8 Preparation of Epoxides
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Klein, Organic Chemistry 2e
14.8 Preparation of Epoxides
• Assess the overall stereochemistry of the epoxidation
that occurs through the halohydrin intermediate
• Practice with SkillBuilder 14.3
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14-42
Klein, Organic Chemistry 2e
14.9 Enantioselective Epoxidation
• The epoxidation methods we have discussed so far are
NOT enantioselective
• Draw the products
racemic mixture
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Klein, Organic Chemistry 2e
14.9 Enantioselective Epoxidation
• The epoxidation forms a racemic mixture, because the
flat alkene can react on either face
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Klein, Organic Chemistry 2e
14.9 Enantioselective Epoxidation
• To be enatioselective at least one of the reagents (or
catalyst) in a reaction must be chiral
• The Sharpless catalyst forms such a chiral complex with
an allylic alcohol
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Klein, Organic Chemistry 2e
14.9 Enantioselective Epoxidation
• The desired epoxide can be formed if the right catalyst is
chosen. Note the position of the –OH group
• How does the catalyst favor just one epoxide product?
• Practice with conceptual checkpoint 14.16
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14-46
Klein, Organic Chemistry 2e
14.10 Ring-opening of Epoxides
• Because of their significant ring strain, epoxides have
great synthetic utility as intermediates
• Propose some reagents that might react with an
epoxide to provide a specific functional group
• Propose some reagents that might react with an
epoxide to alter the carbon skeleton
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14-47
Klein, Organic Chemistry 2e
14.10 Ring-opening of Epoxides
• Strong nucleophiles react readily with epoxides
• Predict whether each step is product or reactant
favored, and explain WHY
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14-48
Klein, Organic Chemistry 2e
14.10 Ring-opening of Epoxides
• In general, alkoxides are not good leaving groups
• The ring strain associated with the epoxide increases its
potential energy making it more reactive– see the
energy diagram on the next slide
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14-49
Klein, Organic Chemistry 2e
14.10 Ring-opening of Epoxides
• The epoxide reaction
is both more
kinetically and more
thermodynamically
favored. WHY?
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14-50
Klein, Organic Chemistry 2e
14.10 Ring-opening of Epoxides
• Epoxides can be opened by many other strong
nucleophiles as well
• Both regioselectivity and stereoselectivity must be
considered – see next few slides
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14-51
Klein, Organic Chemistry 2e
14.10 Ring-opening of Epoxides
• Given that the epoxide ring-opening is SN2, predict the
outcome of the following reactions
• Pay attention to regio- and stereoselectivity. EXPLAIN
WHY
• Practice with SkillBuilder
14.4
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14-52
Klein, Organic Chemistry 2e
14.10 Ring-opening of Epoxides
• Acidic conditions can also be used to open epoxides
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14-53
Klein, Organic Chemistry 2e
14.10 Ring-opening of Epoxides
• Water or an alcohol can also be used as the nucleophile
under acidic conditions
• Predict the products and draw a complete mechanism
• Antifreeze (ethylene glycol) is made industrially by this
method
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14-54
Klein, Organic Chemistry 2e
14.10 Ring-opening of Epoxides
• Propose an explanation for the following regiochemical
observations
• Consider both steric and electronic effects (induction)
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14-55
Klein, Organic Chemistry 2e
14.10 Ring-opening of Epoxides
• If the nucleophile preferentially attacks the tertiary
carbon under acidic conditions, is the mechanism likely
SN1 or SN2?
• Considering the observations below, is the mechanism
likely SN1 or SN2?
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14-56
Klein, Organic Chemistry 2e
14.10 Ring-opening of Epoxides
• When the nucleophile attacks a tertiary
center of the epoxide, the intermediate
it attacks takes on some carbocation
character (SN1), but not completely
• Give reaction conditions for the following reaction
• Practice with SkillBuilder 14.5
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14-57
Klein, Organic Chemistry 2e
14.11 Thiols and Sulfides
• Sulfur appears just under oxygen on the periodic table
• Sulfur appears in thiols as an –SH group analogous to
the –OH group in alcohols
• The name of a compound with an –SH group ends in
“thiol” rather than “ol”
• Note that the “e” of butane is not dropped in the name
of the thiol
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14-58
Klein, Organic Chemistry 2e
14.11 Thiols and Sulfides
• Thiols are also known as mercaptans
• The –SH group can also be named as part of a side
group rather than as part of the parent chain
• The mercaptan name comes from their ability to
complex mercury
• 2,3-dimercapto-1-propanol is used to treat mercury
poisoning. WHY? Draw its structure
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14-59
Klein, Organic Chemistry 2e
14.11 Thiols and Sulfides
• Thiols are known for their unpleasant odor
• Skunks use thiols as a defense mechanism
• Methanethiol is added to natural gas (methane) so that
gas leaks can be detected
• Your nose is a very sensitive instrument
• The hydrosulfide ion (HS-) is a strong nucleophile and a
weak base
• HS- promotes SN2 rather than E2
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14-60
Klein, Organic Chemistry 2e
14.11 Thiols and Sulfides
• Predict the outcome of the following reactions, and
draw a complete mechanism
• Practice with conceptual checkpoint 14.22
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14-61
Klein, Organic Chemistry 2e
14.11 Thiols and Sulfides
• Thiols have a pKa of about 10.5
• Recall that water has a pKa of 15.7
• Predict whether the equilibrium below will favor
products or reactants and draw the mechanism
thiolate ion
• Thiolates are excellent nucleophiles
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14-62
Klein, Organic Chemistry 2e
14.11 Thiols and Sulfides
• A thiolate can attack Br2 to produce a disulfide
• How does the oxidation number change?
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14-63
Klein, Organic Chemistry 2e
14.11 Thiols and Sulfides
• Disulfides can be reduced by the reverse reaction
• The interconversion between thiol and disulfide can also
occur directly via a free radical mechanism. Propose a
mechanism
• The bond dissociation energy of a S-S bond is only about
53 kcal/mol. WHY is that significant?
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14-64
Klein, Organic Chemistry 2e
14.11 Thiols and Sulfides
• Sulfur analogs of ethers are called sulfides or thioethers
• Sulfides can also be named as a side group
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14-65
Klein, Organic Chemistry 2e
14.11 Thiols and Sulfides
• Sulfides are generally prepared by nucleophilic attack of
a thiolate on an alkyl halide
• How are thiolates generally prepared?
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Klein, Organic Chemistry 2e
14.11 Thiols and Sulfides
• Sulfides undergo a number of reactions
1. Attack on an alkyl halide
– The process produces a strong alkylating reagent that can
add an alkyl group to a variety of nucleophiles
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Klein, Organic Chemistry 2e
14.11 Thiols and Sulfides
2. Sulfides can also be oxidized
•
Sodium meta-periodiate can be used to form the
sulfoxide
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Klein, Organic Chemistry 2e
14.11 Thiols and Sulfides
2. Sulfides can also be oxidized
•
Hydrogen peroxide can be used to give the sulfone
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Klein, Organic Chemistry 2e
14.11 Thiols and Sulfides
•
•
Sulfoxides and sulfones have very little double bond
character
Which resonance contributor for each is the major
contributor, and WHY?
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14-70
Klein, Organic Chemistry 2e
14.11 Thiols and Sulfides
•
•
Because sulfides are readily oxidized, they make good
reducing agents
Recall the ozonolysis reaction from section 9.11
•
Practice with conceptual checkpoint 14.23
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14-71
Klein, Organic Chemistry 2e
14.11 Thiols and Sulfides
•
Predict any products or necessary reagents in the
reaction sequence below
•
Verify the formal charge on the sulfur in the final
product above
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14-72
Klein, Organic Chemistry 2e
14.12 Synthetic Strategies
Involving Epoxides
•
Epoxides can be used to install functional groups on
adjacent carbons
•
Give necessary reagents for the reaction below
•
Practice with SkillBuilder 14.6
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14-73
Klein, Organic Chemistry 2e
14.12 Synthetic Strategies
Involving Epoxides
•
By reacting an epoxide with a Grignard reagent, the
carbon skeleton can be modified
•
You may think of an epoxide as the starting material
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14-74
Klein, Organic Chemistry 2e
14.12 Synthetic Strategies
Involving Epoxides
•
An epoxide can be used to install a
two carbon chain between an R
group and an OH group
•
Recall that a carbonyl can be used to install a one
carbon chain between an R group and an OH group
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14-75
Klein, Organic Chemistry 2e
14.12 Synthetic Strategies
Involving Epoxides
•
Give necessary reagents for the reaction below
•
Practice with SkillBuilder 14.7
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14-76
Klein, Organic Chemistry 2e
Additional Practice Problems
• Name the following molecule
• Draw the structure for (4-methylcyclohexyl)phenylether
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14-77
Klein, Organic Chemistry 2e
Additional Practice Problems
• Fill in the missing intermediates and reagents in the
scheme below
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14-78
Klein, Organic Chemistry 2e
Additional Practice Problems
• Fill in the missing intermediates and reagents in the
scheme below
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Klein, Organic Chemistry 2e
Additional Practice Problems
• Give necessary reagents to complete the synthesis
below
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Klein, Organic Chemistry 2e