Preparation and Reactions of Ethers

Preparations and
Reactions of Ethers
Olivar Reimos D. Barroga
Instructor
Learning Outcomes
At the end of the lesson, you should be able to:
1. describe the key physical and chemical
properties of ethers;
2. write chemical equations for the synthesis
and reactions of ethers; and
3. discuss the importance of crown ethers.
Ethers
Preparations of Ethers
• Ethers are usually prepared from alcohols or
their conjugate bases.
• One important procedure, known as the
Williamson Ether Synthesis, proceeds by an
SN2 reaction of an alkoxide nucleophile with an
alkyl halide
• Since alkoxide anions are strong bases, the
possibility of a competing E2 elimination must
always be considered.
• Bearing in mind the factors that favor
substitution over elimination, a 1º-alkyl halide
should be selected as a preferred reactant
whenever possible.
Preparation of Ethers
• A second general ether synthesis,
alkoxymercuration, is patterned after the
oxymercuration reaction.
• Note that the alcohol reactant is used as the
solvent, and a trifluoroacetate mercury (II) salt is
used in preference to the acetate
(trifluoroacetate anion is a poorer nucleophile
than acetate).
• The mechanism of alkoxymercuration is similar
to that of oxymercuration, with an initial anti-
addition of the mercuric species and alcohol
being followed by reductive demercuration.
Preparation of Ethers
• Acid-catalyzed dehydration of small 1º alcohols
constitutes a specialized industrial method of
preparing symmetrical ethers.
Questions
When preparing ethers using the Williamson
ether synthesis, what factors are important
when considering the nucleophile and the
electrophile?
Questions
What reagents would you use to perform the
following transformations?
Reactions of Ethers
Acidic Cleavage
• The most common reaction of ethers is cleavage
of the C–O bond by strong acids.
• This may occur by SN1 or E1 mechanisms for
3º-alkyl groups or by an SN2 mechanism for 1º-
alkyl groups.
• The conjugate acid of the ether is an
intermediate in all these reactions, just as
conjugate acids were intermediates in certain
alcohol reactions.
Reactions of Ethers
Acidic Cleavage
Reactions of Ethers
Claisen Rearrangement
• The [3,3] sigmatropic rearrangement of 1,5-
dienes or allyl vinyl ethers, known
respectively as the Cope and Claisen
rearrangements, are among the most
commonly used sigmatropic reactions.
Reactions of Ethers
Claisen Rearrangement
Epoxides
• Epoxides (also known as oxiranes) are
three-membered ring structures in which one
of the vertices is an oxygen and the other two
are carbons.
• The most important and simplest epoxide is

ethylene oxide.
Epoxides
• Ethylene oxide is used as an important
chemical feedstock in the manufacturing of
ethylene glycol, which is used as antifreeze,
liquid coolant and solvent.
• Ethylene glycol is used in the production of
polyester and polyethylene terephthalate
(PET) the raw material for plastic bottles.
Epoxides
• Oxacyclopropane synthesis by
peroxycarboxylic acid requires an alkene and
a peroxycarboxylic acid as well as an
appropriate solvent.
• The peroxycarboxylic acid has the unique
property of having an electropositive oxygen
atom on the COOH group.
Preparation of Alcohols using
Grignard Reagents
• Epoxides can also be synthesized by the
treatment of a halohydrin with a base.
Reactions of Epoxides
• These are both good examples
of regioselective reactions. In a
regioselective reaction, two (or more) different
constitutional isomers are possible as
products, but one is formed preferentially (or
sometimes exclusively).
• There are two electrophilic carbons in the
epoxide, but the best target for the
nucleophile in an SN2 reaction is the carbon
that is least hindered.
• Like in other SN2 reactions, nucleophilic
attack takes place from the backside,
resulting in inversion at the electrophilic
carbon.
Example
Predict the major product(s) of the ring opening
reaction that occurs when the epoxide shown
below is treated with:
• ethanol and a small amount of sodium
hydroxide
• ethanol and a small amount of sulfuric
acid
Anti Dihydroxylation
• Epoxides may be cleaved by aqueous acid to
give glycols that are often diastereomeric with
those prepared by the syn-hydroxylation
reaction.
• Proton transfer from the acid catalyst generates
the conjugate acid of the epoxide, which is
attacked by nucleophiles such as water in the
same way that the cyclic bromonium ion
described above undergoes reaction.
• The result is anti-hydroxylation of the double
bond, in contrast to the syn-stereoselectivity of
the earlier method.
Anti Dihydroxylation
Addition of HX
Examples
Thiols and Sulfides
• Thiols and sulfides are the "sulfur equivalent"
of alcohols and ethers.
• This is because thiols contain the C-S-H
functional group, while sulfides contain the C-
S-C group.
Oxidation States of Sulfur
Compounds
Thiols
• Thiols are often called “mercaptans” a
reference to the Latin term mercurium
captans(capturing mercury), since the -SH group
forms strong bonds with mercury and its ions.
• Thiols are analogous to alcohols.
• They are named in a similar fashion as alcohols
except the suffix -thiol is used in place of -ol.
• By itself the -SH group is called a mercapto
group.
Thiols
Preparation of Thiols
Preparation of Thiols
Disulfides
• Oxidation of thiols and other sulfur
compounds changes the oxidation state of
sulfur rather than carbon.
Disulfide bridges
• Disulfide (sulfur-sulfur) linkages between two
cysteine residues are an integral component of
the three-dimensional structure of many
proteins.
• The interconversion between thiols and disulfide
groups is a redox reaction: the thiol is the
reduced state, and the disulfide is the oxidized
state.
Disulfide bridges
Glutathione (GSH)
Disulfide Exchange
Disulfides
• Disulfide bridges in proteins can also be directly
reduced by another flavin-dependent enzyme
called 'thioredoxin’.
• In both cases, NADPH is the ultimate electron
donor, reducing FAD back to FADH2 in each
catalytic cycle.
Disulfides
• Proteins are often maintained in their reduced
(free thiol) state by incubation in buffer
containing an excess concentration of b-
mercaptoethanol (BME) or dithiothreitol (DTT).
Sulfides
• Sulfur analogs of ethers are called sulfides.
Sulfides are less common than thiols as
naturally occurring compounds.
• However, sulfides—especially disulfides (C-S-S-
C)—have important biological functions, mainly
in reducing agents (antioxidants).
• Sulfides are named using the same rules as
ethers except sulfide is used in the place of
ether.
• For more complex substance alkylthio is used
instead of alkoxy.
Sulfides
SAM methyltransferases
• The most common example of sulfonium ions
in a living organism is the reaction of S-
Adenosylmethionine.
Sulfides
• Sulfides can be easily oxidized.
• Reacting a sulfide with hydrogen peroxide,
H2O2, as room termpeature produces a
sulfoxide (R2SO).
• The oxidation can be continued by reaction
with a peroxyacid to produce the sulfone
(R2SO2).
Sulfoxide
• Dimethyl sulfoxide (DMSO).
• DMSO is polar aprotic solvent.
Summary of Reactions
References:
• Henrickson, C., Byrd, L., & Hunter, N. (2005).
A Laboratory for General, Organic, and
Biochemistry. 4th Ed. McGraw-Hill Higher
Education. New York.
• McMurry, J. (2004). Organic Chemistry. 6th
Ed. Thomson/ Brooks / Cole Publishing Co..
New York.
• Schore, Neil E. and Vollhardt, K. Peter C.
(2007). Organic Chemistry: Structure and
Function. New York: Bleyer, Brennan.
References:
• Denniston, K. (2017). General, Organic and
Biochemistry 9th Edition.
• Winter, Arthur (2005). Organic Chemistry for
Dummies. Hoboken, New Jersey: Wiley,.
• Pellegrini, Frank (200). Cliffs Quick Review
Organic Chemistry II. Foster City, CA: Wiley.
• TAN, T., et. al. (2018). Biochemistry. NC -
Creative Commons.
References:
• TAN, T., et. al. (2018). Biochemistry. NC -

Creative Commons.
• Laurence M, et. al. (2012). Principles of
Biochemistry 5th Edition. Published by
Pearson (September 1st 2011) - Copyright ©
2012.

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Preparations and

• The most important and simplest epoxide is

• TAN, T., et. al. (2018). Biochemistry. NC -

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