Carlos Albizu University Miami Campus Organic Chemistry Worksheet

Organic Chemistry9th Edition
Lecture Presentation
Chapter 15
Conjugated Systems,
Orbital Symmetry, and
Ultraviolet Spectroscopy
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Slide – 1
Conjugated Systems
• Conjugated double bonds are separated by one single bond.
• Isolated double bonds are separated by two or more single bonds.
• Conjugated double bonds are more stable than isolated ones.
• successive double bonds with no intervening single bonds are called cumulated double bonds,
The simplest one is allene,” H2C=C=CH2. cumulated double bonds of allenes are less stable than
isolated double bonds and much less stable than conjugated double bonds.
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Slide – 2
Conjugation (Sect
15-2)
• These two double bonds are isolated (note sp3 carbon
between the double bonds):
• These two double bonds are conjugated (note continuous
array of four sp2 carbons):
• The compound with the conjugated double bonds is more
stable by about 3.6 kcal/mol.
15-4 Allylic Cations
the −CH2−CH=CH2 group is called the allyl group. Many common names use this terminology.
• The allylic carbon is the one directly attached to an sp2 carbon.
When allyl bromide is heated with a good ionizing solvent, it ionizes to the allyl cation, an allyl group with a positive
charge.
More-substituted analogs are called allylic cations.
All allylic cations are stabilized by resonance with the adjacent double bond, which delocalizes the positive charge
over two carbon atoms giving the allyl cation more stability than nonconjugated cations
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Slide – 4
Stability of Carbocations
Because of its resonance
stabilization, the (primary) allyl
cation is about as stable as a
simple secondary carbocation
• Stability of 1° allylic  2° carbocation.
• Stability of 2° allylic  3° carbocation.
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Slide – 5
1,2- and 1,4-Addition to Conjugated Dienes
Electrophilic additions to conjugated dienes usually involve allylic cations as intermediates.
Unlike simple carbocations, an allylic cation can react with a nucleophile at either of its positive centers.
consider the addition of HBr to buta-1,3-diene, an electrophilic addition that produces a mixture of two constitutional isomers.
This product results from
Markovnikov addition across
one of the double bonds.
In this product, the proton and
bromide ion add at the ends of the
conjugated system to carbon atoms
and the double bond shifts to the
C2-C3 position.
The first product results from electrophilic addition of HBr across a double bond. This process is called a 1,2-addition whether or not
these two carbon atoms are numbered 1 and 2 in naming the compound.
In the second product, the proton and bromide ion add at the ends of the conjugated system to carbon atoms with a 1,4-relationship.
Such an addition is called a 1,4-addition whether or not these carbon atoms are numbered 1 and 4 in naming the compound
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Slide – 6
Mechanism of 1,2- and 1,4-Addition
The proton is the electrophile,
adding to the alkene to give the
most stable carbocation.
Bromide can attack this
resonance-stabilized
intermediate at either of the
two carbon atoms sharing
the positive charge.
The allylic cation is stabilized by
resonance delocalization of the positive
charge over two carbon atoms.
Attack by bromide at the
secondary carbon gives 1,2addition
attack at the primary
carbon gives 1,4addition
The key to formation of these two products is the presence of a double bond in position to form a stabilized allylic cation.
Molecules having such double bonds are likely to react via resonance-stabilized intermediates.
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Slide – 7
SN2 Displacement Reactions of Allylic Halides and Tosylates
Allylic halides and tosylates show enhanced reactivity toward nucleophilic displacement reactions by the SN2 mechanism. For
example, allyl bromide reacts with nucleophiles by the SN2 mechanism about 40 times faster than n-propyl bromide.
The enhanced reactivity of allylic halides and tosylates makes them particularly attractive as electrophiles for SN2 reactions.
Allylic halides are so reactive that they couple with Grignard and organolithium reagents, a reaction that does not work well
with unactivated halides.
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Slide – 8
Diels-Alder Reaction
• Named after Otto Diels and Kurt Alder. They received the Nobel prize in 1950.
• In 1928, German chemists Otto Diels and Kurt Alder discovered that alkenes and alkynes with
electron-withdrawing groups add to conjugated dienes to form six-membered rings..
• The Diels–Alder is also called a [4 + 2] cycloaddition because a ring is formed by the interaction of
four pi electrons of the alkene with two pi electrons of the alkene or alkyne.
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Slide – 9
Mechanism of the Diels–Alder Reaction
We can symbolize the Diels–Alder reaction by using
three arrows to show the movement of three pairs of
electrons. This electron movement is concerted, with
three pairs of electrons moving simultaneously.
• Diels–Alder reaction is a one step mechanism.
• the Diels–Alder reaction converts two pi bonds into two sigma bonds.
• Because an electron-poor alkene or alkyne is prone to react with a diene, it is called a dienophile (“lover of dienes”)
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Slide – 10
Examples of Diels–Alder Reactions
The Diels–Alder reaction is similar to a nucleophile–electrophile reaction.
The diene is electron-rich, and the dienophile is electron-poor.
The presence of electron-donating (−D) groups, such as alkyl groups or alkoxy (−OR) groups, further enhance the
reactivity of the diene.
A good dienophile generally has one or more electron-withdrawing groups (−W) pulling electron density away from the pi
bond. Dienophiles commonly have carbonyl-containing (C=O) groups or cyano (−C≡N) groups to enhance their Diels–
Alder reactivity.
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Slide – 11
Organic Chemistry
Lecture Presentation
Chapter 16
Ethers, Epoxides, and
Thioethers
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Slide – 1
Ethers
•
•
The formula is R—O—R where R and R are alkyl or aryl.
The two alkyl groups are the same in a symmetrical ether and different in an unsymmetrical ether.
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Slide – 2
Structure and Polarity
• Oxygen is sp3 hybridized.
• Bent molecular geometry
• Tetrahedral C—O—C angle is 110°.
• Polar C—O bonds
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Slide – 3
14-2B Boiling Points of Ethers; Hydrogen Bonding
• Ethers cannot hydrogen bond with other ether molecules, so they have a lower boiling point than alcohols.
• a hydrogen bond requires both a hydrogen bond ​donor​ and a hydrogen bond ​acceptor​.
• The donor is the molecule with an O−H or N−H group. The acceptor is the molecule whose lone pair of electrons
forms a weak partial bond to the hydrogen atom provided by the donor.
• Ether molecules can hydrogen bond with water and alcohol molecules.
• Ethers are hydrogen bond acceptors.
• Ethers can accept hydrogen bonds but not donate them: melting and boiling points are similar to hydrocarbons of
the same molecular weight
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Slide – 4
Table 14-2. Physical Properties of
Ether
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Slide – 5
14-2C Ethers as Polar Solvents
• Ethers are widely used as solvents because
– they can dissolve nonpolar and polar substances.
– they are unreactive toward strong bases.
14-2D Stable Complexes of Ethers with Reagents
The special properties of ethers (polarity, lone pairs, but
relatively unreactive) enhance the formation and use of
many reagents. For example, Grignard reagents cannot
form unless an ether is present, possibly to share its lone
pairs of electrons with the magnesium atom. This sharing
of electrons stabilizes the reagent and helps keep it in
solution
Complexes with Electrophiles
The ether’s nonbonding electrons stabilize the borane (BH3).
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Slide – 6
Ether Complexes
• Grignard reagents: Complexation
of an ether with a Grignard reagent
stabilizes the reagent and helps
keep it in solution.
• Electrophiles: The ether’s
nonbonding electrons stabilize the
borane (BH3).
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Slide – 7
14-3 Nomenclature of Ethers
14-3A Common Names (Alkyl Alkyl Ether Names)
• Name the two alkyl groups attached to the oxygen and add the word ether.
• Name the groups in alphabetical order but many people still use the old system, which named the groups in order
of increasing complexity, For example, if one of the alkyl groups is methyl and the other is tert-butyl, the current
common name should be “tert-butyl methyl ether,” but most chemists use the older common name, “methyl tertbutyl ether” (or MTBE).
• Symmetrical: Use dialkyl or just alkyl. If just one alkyl group is described in the name, it implies that the ether is
symmetrical, as in “ethyl ether.”
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Slide – 8
The most common ether of all
• Diethyl ether is such a common solvent that it is sold, not
only as “Ethyl ether”, but simply as “ether”.
O
• It has also been used as an anesthetic, and as a drug of
abuse. The quote “there is nothing in the world so helpless
and irresponsible and depraved as a man in the depths of
an ether binge” (Hunter S. Thompson, from Fear and
Loathing in Las Vegas) refers to this ether.
14-3 Nomenclature of Ethers
IUPAC Names: Alkoxy Alkane Names
• IUPAC names use the more complex alkyl group as the root name, and the rest of the ether as an alkoxy group
.
• Base the name on the longest all-carbon chain.
• The “ether linkage” and the other alkyl group on it are named as an “alkoxy” substituent, where the exact name of
the “alk” part of the alkoxy group depends on what the alkyl group is.
• For example, cyclohexyl methyl ether is named “methoxycyclohexane.”
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Slide – 10
14-3 Nomenclature of Ethers
14-3C Nomenclature of Cyclic Ethers
• Cyclic ethers are our first examples of heterocyclic compounds, containing a ring in which a ring atom is an element other than
carbon. This atom, called the heteroatom, is numbered 1 when numbering the ring atoms.
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Slide – 11
14-3 Nomenclature of Ethers
14-3C Nomenclature of Cyclic Ethers
Epoxides (Oxiranes)
• Epoxides are three-membered cyclic ethers.
• formed by peroxyacid oxidation of the corresponding alkenes.
• The common name of an epoxide is formed by adding “oxide” to the name of the alkene that is oxidized.
• One systematic method for naming epoxides is to name the rest of the molecule and use the term epoxy as a substituent,
giving the numbers of the two carbon atoms bonded to the epoxide oxygen.
Another systematic method names epoxides as derivatives of the parent compound, ethylene oxide, using
“oxirane” as the systematic name for ethylene oxide. In this system, the ring atoms of a heterocyclic compound
are numbered starting with the heteroatom and going in the direction to give the lowest substituent numbers.
The “epoxy” system names are also
listed (in blue) for comparison.
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Slide – 12
14-3 Nomenclature of Ethers
14-3C Nomenclature of Cyclic Ethers
Oxetanes : the four-membered cyclic ethers named oxetanes
• Furans (Oxolanes): The five-membered cyclic ethers are commonly named after an aromatic member of this
group, furan. The systematic term oxolane is also used for a five-membered ring containing an oxygen atom.
The saturated five-membered cyclic ether
resembles furan but has four additional
hydrogen atoms. Therefore, it is called
tetrahydrofuran (THF)
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Slide – 13
14-3 Nomenclature of Ethers
14-3C Nomenclature of Cyclic Ethers
• Pyrans (Oxanes): The six-membered cyclic ethers are commonly named as derivatives of pyran, an unsaturated ether.
• The saturated compound has four more hydrogen atoms, so it is called tetrahydropyran (THP).
• Dioxanes: Heterocyclic ethers with two oxygen atoms in a six-membered ring are called dioxanes. The most
common form of dioxane is the one with the two oxygen atoms in a 1,4-relationship
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Slide – 14
14-5 The Williamson Ether Synthesis
• The Williamson ether synthesis is the most reliable and versatile ether synthesis.
• This method involves the attack of an alkoxide ion on SN2 an unhindered primary alkyl halide or tosylate.
• This method involves an SN2 attack of the alkoxide on an unhindered primary halide or tosylate.
• Secondary alkyl halides and tosylates are occasionally used in the Williamson synthesis, but elimination competes, and the
yields are often poor.
• The alkoxide is commonly made by adding Na, K ( an alkali metal) , or NaH ( an alkali metal hydride) to the alcohol
• Of the two partners (the alcohol, and the halide or tosylate), the halide or tosylate must be primary. The intermediate
alkoxide anion is a strong base, and will cause E2 elimination if treated with a secondary or tertiary halide.
• Examples of the Williamson Synthesis:
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Slide – 15
Solved Problem 1
(a)
(b)
(c)
Why is the following reaction a poor method for the synthesis of t-butyl propyl ether?
What would be the major product from this reaction?
Propose a better synthesis of t-butyl propyl ether.
Solution
(a)
The desired SN2 reaction cannot occur on the tertiary alkyl halide.
(b)
The alkoxide ion is a strong base as well as a nucleophile, and elimination prevails.
(c) A better synthesis would use the less hindered alkyl group as the SN2 substrate
and the alkoxide of the more hindered alkyl group.
Problem-Solving HINT
To convert two alcohols to an ether, convert the
more hindered alcohol to its alkoxide. Convert the
less hindered alcohol to its tosylate (or an alkyl
halide). Make sure the tosylate (or halide) is a
good SN2 substrate.
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Slide – 16
14-5 The Williamson Ether Synthesis
Synthesis of Phenyl Ethers
• A phenol (aromatic alcohol) can be used as the alkoxide fragment, but not the halide fragment, for the Williamson ether
synthesis.
• Phenols are more acidic than aliphatic alcohols , and sodium hydroxide is sufficiently basic to form the phenoxide ion.
• As with other alkoxides, the electrophile should have an unhindered primary alkyl group and a good leaving group.
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Slide – 17
14-6 Synthesis of Ethers by Alkoxymercuration–Demercuration
The alkoxymercuration–demercuration process adds a molecule of an alcohol across the double bond of an alkene. The
product is an ether, as shown here.
alkoxymercuration/demercuration will add the elements of H-OR across a C=C double bond, in
Markovnikov fashion
Alkoxymercuration adds the −OR
group of the alcohol to the more
substituted carbon atom of the
C=C double bond.
• Use mercuric acetate with an alcohol. The alcohol will react with the intermediate mercurinium ion
by attacking the more substituted carbon.
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Slide – 18
14-7 Industrial Synthesis: Bimolecular Condensation of Alcohols
The least expensive method for synthesizing simple symmetrical ethers is the acid-catalyzed bimolecular condensation (joining of two
molecules, often with loss of a small molecule such as water)
Industrial method, not good lab synthesis method.
Unimolecular dehydration (to give an alkene) competes with bimolecular condensation.
To form an ether, the alcohol must have an unhindered primary alkyl group, and the temperature must not be allowed to rise too high.
If the alcohol is hindered or the temperature is too high, the delicate balance between substitution and elimination shifts in favor of elimination
Diethyl ether is made industrially, on a huge scale, by this reaction:
Mechanistically, this is an acid-promoted SN2:
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Slide – 19
14-8 Cleavage of Ethers by HBr and HI
• Unlike alcohols, ethers are not commonly used as synthetic intermediates because they do not undergo many reactions. This
unreactivity makes ethers attractive as solvents.
• Ethers are cleaved by heating with HBr or HI to give alkyl bromides or alkyl iodides.
A protonated ether can undergo substitution or elimination with an alcohol serving as a neutral leaving group.
Ethers react with concentrated HBr and HI because these reagents are sufficiently acidic to protonate the ether, whereas bromide and
iodide are good nucleophiles for the substitution.
Under these conditions, the alcohol leaving group usually reacts further with HX to give another alkyl halide.
this reaction converts a dialkyl ether into two alkyl halides.
Iodide and bromide ions are good nucleophiles but weak bases, so they are more likely to substitute by the SN 2 mechanism than to
promote elimination by the E2 mechanism.
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Slide – 20
14-8 Cleavage of Ethers by HBr and HI
Mechanism
• Step 1:​ Protonation of the ether to form a good leaving group.
Step 2:​ SN2 cleavage of the protonated ether.
The halide will attack the carbon and displace
the alcohol (SN2).
The ether is cleaved by a nucleophilic
substitution of Br− or I− on the protonated
ether.
Step 3: Conversion of the alcohol fragment to the alkyl halide.
depending on the structure of the alcohol and the
reaction conditions. The protonated alcohol
undergoes either SN1 or SN2 substitution by
bromide ion.
SEE THE EXAMPLE ON THE NEXT SLIDE
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Slide – 21
14-8 Cleavage of Ethers by HBr and HI
Mechanism
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Slide – 22
14-8 Cleavage of Ethers by HBr and HI
Mechanism
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Slide – 23
14-8 Cleavage of Ethers by HBr and HI
Phenyl Ether Cleavage
• Phenyl ethers (one of the groups bonded to oxygen is a benzene ring) react with HBr or HI to give alkyl halides and
phenols
• Phenols do not react further to give halides because the sp2-hybridized carbon atom of the phenol cannot undergo
the SN2 (or SN1) reaction needed for conversion to the halide.
• Phenol cannot react further to become a halide because an S N2 reaction cannot occur on an sp2 carbon.
In general : HBr and HI convert both alkyl groups (but not aromatic groups) of an
ether to alkyl halides. Phenolic products are unreactive, however.
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Slide – 24
14-9 Autoxidation of Ethers
Peroxide Formation and Explosions
• When ethers are stored in the presence of atmospheric oxygen, they slowly oxidize to
produce hydroperoxides and dialkyl peroxides, both of which are explosive.
Precautions:
– Do not distill to dryness.
– Store in full bottles with tight caps.
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Slide – 25
14-10 Thioethers (Sulfides) and Silyl Ethers
• Thioethers, also called sulfides, are ethers with a sulfur atom replacing the oxygen atom of an ether
• R—S—R, analog of ether
Sulfides are named like ethers, with “sulfide” replacing “ether” in the common names. In the IUPAC (alkoxy alkane)
names, “alkylthio” replaces “alkoxy.”
Sulfides are much more reactive than ethers. In a sulfide, sulfur valence is not necessarily filled: Sulfur can form additional
bonds with other atoms.
• Silyl ethers are ethers with a substituted silicon atom replacing one of the alkyl groups of an ether
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Slide – 26
14-10 Thioethers (Sulfides) and Silyl Ethers
Thioethers (Sulfides)
• Thioethers are easily synthesized by the Williamson ether synthesis using a thiolate ion as the nucleophile.
Thiols are more acidic than water. Therefore, thiolate ions are easily generated by treating thiols with aqueous sodium hydroxide.
Because sulfur is larger and more polarizable than oxygen, thiolate ions are even better nucleophiles than alkoxide ions
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Slide – 27
14-10 Thioethers (Sulfides) and Silyl Ethers
Thioethers (Sulfides)
• Sulfur compounds are more nucleophilic than the corresponding oxygen compounds, because sulfur is larger and more polarizable
and its electrons are less tightly held in orbitals that are farther from the nucleus.
• Although ethers are weak nucleophiles, sulfides are relatively strong nucleophiles. Sulfides attack unhindered alkyl halides to give
sulfonium salts.
Sulfonium Salts as Alkylating Agents:
• Sulfonium salts are strong alkylating agents. The sulfonium salt polarizes the carbon atom, making it electrophilic.
• attack by a nucleophile expels an uncharged sulfide, which is an excellent leaving group, which means that the
leaving group that forms is neutral (a sulfide group in the following example):
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Slide – 28
Alcohol-Protecting Groups
• If the molecule has more than one functional group,
sometimes their reactivity can interfere with the desired
reaction.
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Slide – 29
14-10 Thioethers (Sulfides) and Silyl Ethers
14-10B Silyl Ethers as Alcohol-Protecting Groups
• If we have a compound with two or more functional groups, and we would like to modify just one of those functional groups, we
often must protect any other functional groups to prevent them from reacting as well.
•
For example, if we wanted to add a Grignard reagent to the carbonyl group of a keto-alcohol, the alcohol group would protonate the
Grignard reagent, and the reaction would fail:
• Alcohols must be protected if they are to survive a reaction at another functional group on the molecule.
• A good protecting group must be easy to add to the group it protects, and then it must be resistant to the reagents used to
modify other parts of the molecule
• a good protecting group must be easy to remove to regenerate the original functional group.
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Slide – 30
14-10 Thioethers (Sulfides) and Silyl Ethers
14-10B Silyl Ethers as Alcohol-Protecting Groups
• To accomplish the Grignard reaction shown above, we would need to convert the hydroxy group to something that is resistant to Grignard reagents.
• we might consider using ethers based on silicon to protect a hydroxy group in a Grignard reaction. HOW ?
• We will use the triisopropylsilyl (Tri-Iso-Propyl-Silyl or TIPS) protecting group, of structure R‐O‐Si (i‐Pr)3 as our example. The three bulky isopropyl groups
stabilize this silyl ether by hindering attack by nucleophiles.
• Silyl ethers are commonly formed by the reaction of alcohols with chlorosilanes in the presence of tertiary amines.
• We can form a TIPS ether by a reaction of chlorotriisopropylsilane (TIPSCl) with a tertiary amine such as triethylamine (Et3N :).
• Our keto-alcohol shown above would react with TIPS chloride (TIPSCl) and triethylamine (Et3 N 🙂 to give a protected alcohol. In our
example, we can add a Grignard reagent to the carbonyl group in the presence of the protected alcohol.
• After the Grignard reaction is completed, protonation of the magnesium alkoxide salt and deprotection of the silyl ether gives the desired
product., the deprotection step is done using fluoride ions, in the following reaction Bu4N+ F- is the source of fluoride ions.
Si−F bonds are much stronger than Si−O
bonds, so the deprotection step with fluoride
happens under gentle conditons.
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Slide – 31
14-11 Synthesis of Epoxides
14-11A Peroxyacid Epoxidation
• We’ve seen these before. Direct epoxidation using peroxy acids (sect 14-11A):\
• Peroxyacids are used to convert alkenes to epoxides.
• Most commonly used peroxyacid is meta-chloroperoxybenzoic acid (MCPBA).
• The reaction is carried out in an aprotic acid to prevent the opening of the epoxide.
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Slide – 32
14-11 Synthesis of Epoxides
14-11B Base-Promoted Cyclization of Halohydrins
• This reaction is a variation of the Williamson ether synthesis.
• If an alkoxide and a halogen are located in the same molecule, the alkoxide may displace a halide ion and form a
ring.
• Treatment of a halohydrin with a base leads to an epoxide through this internal SN2 attack.
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Slide – 33
14-11 Synthesis of Epoxides
14-11B Base-Promoted Cyclization of Halohydrins
Remember how we made halohydrins ? Halohydrins are generated by treating alkenes with aqueous solutions of
halogens. Bromine water and chlorine water add across double bonds with Markovnikov orientation.
In this example cyclopentene is reacting
with chlorine water to give the chlorohydrin.
Treatment of the chlorohydrin with
aqueous sodium hydroxide gives the
epoxide.
the ring-closing step is an internal
SN2
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Slide – 34
14-12 Acid-Catalyzed Ring Opening of Epoxides
• Oxiranes (“epoxides”) are more reactive than most ethers, because of their strained three-membered rings; opening
these rings releases the strain energy.
• The products of acid-catalyzed opening depend primarily on the solvent used.
• MECHANISM : Acid-Catalyzed Opening of Epoxides in Water. Acid-catalyzed hydrolysis of epoxides gives glycols with anti
stereochemistry
protonation of oxygen (forming
a good leaving group)
SN2 attack by water. Anti
stereochemistry results from the backside attack of water on the protonated
epoxide.
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Slide – 35
14-12 Acid-Catalyzed Ring Opening of Epoxides
Acid-Catalyzed Opening of Epoxides in Alcohol Solution
• When the acid-catalyzed opening of an epoxide takes place with an alcohol as the solvent, a molecule of alcohol acts as the
nucleophile.
• This reaction produces an alkoxy alcohol with anti stereochemistry.
Mechanism :
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Slide – 36
14-13 Base-Catalyzed Ring Opening of Epoxides
• The reaction of an epoxide with hydroxide ion leads to the same product as the acid-catalyzed opening of the epoxide: a 1,2-diol
(glycol), with anti stereochemistry.
• Mechanism :
opening the epoxide relieves the strain of the threemembered ring. Strong bases can attack and open
epoxides, even though the leaving group is an
alkoxide (a poor leaving group)
• Like hydroxide, alkoxide ions react with epoxides to form ring-opened products
cyclopentene oxide reacts with sodium
methoxide in methanol to give the
same trans-2-methoxycyclopentanol
produced in the acid-catalyzed
opening in methanol.
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Slide – 37
14-14 Orientation of Epoxide Ring Opening
An unsymmetrical epoxide may produce different products under acid-catalyzed and base-catalyzed conditions
Under basic conditions, the alkoxide ion simply attacks the less hindered carbon atom in an SN2 displacement.
basic conditions
Another example:
attack at by the alkoxide happens at the less
substituted epoxide carbon (following the
normal SN2 substrate preference), with
inversion of stereochemistry
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Slide – 38
14-14 Orientation of Epoxide Ring Opening
Under acidic conditions, the alcohol attacks the protonated epoxide.
Attack by the weak nucleophile (ethanol
in this case) is sensitive to the strength of
the electrophile, and it occurs at the more
electrophilic tertiary carbon.
• Attack takes place at the more electrophilic carbon atom, which is usually the more substituted carbon because it can better
support the positive charge.
• Example:
First, acid protonates the oxirane; then, a nucleophile opens the ring. Here, the nucleophile is methanol; in acid, as we
mentioned earlier, the nucleophile attacks the more substituted carbon of the epoxide, with inversion of stereochemistry
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Slide – 39
14-14 Orientation of Epoxide Ring Opening
• In general:
Acid-catalyzed: The nucleophile (solvent) adds to the more substituted carbon, which
bears more + charge.
Base-catalyzed: The nucleophile attacks the less substituted carbon, which is less
hindered.
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Slide – 40
14-15 Reactions of Epoxides with Grignard and Organolithium Reagents
Like other strong nucleophiles, Grignard and organolithium reagents attack epoxides to give (after protonation) ring-opened alcohols.
example, ethylmagnesium bromide reacts
with oxirane (ethylene oxide) to form the
magnesium salt of butan-1-ol. Protonation
gives the neutral alcohol.
• Substituted epoxides can be used in this reaction, with the carbanion usually attacking the less hindered epoxide
carbon atom.
• Examples:
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Slide – 41
Organic Chemistry
Lecture Presentation
Chapter 11
Reactions of Alcohols
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Slide – 1
Types of Alcohol Reactions
• Dehydration to alkene
• Oxidation to aldehyde, ketone
• Substitution to form alkyl halide
• Reduction to alkane
• Esterification
• Tosylation
• Williamson synthesis of ether
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Slide – 2
Summary Table
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Slide – 3
Oxidation States
• Inorganic chemistry:
–Oxidation is a loss of electrons.
–Reduction is a gain of electrons.
• Organic chemistry
–Oxidation: Gain of O, O2, or X2 (halogens); loss of H2
–Reduction: Gain of H2 (or H–); loss of O or O2; and
loss of X2(halogens)
–Neither: The gain or loss of H+, H2O, –OH, HX, etc. is
neither an oxidation nor a reduction.
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Slide – 4
Oxidation States of Carbons
Notice that oxidation of a primary or secondary alcohol forms a
carbonyl (C=O) group by the removal of two hydrogen atoms: one from
the carbinol carbon and one from the hydroxy group. A tertiary alcohol
cannot easily oxidize because there is no hydrogen atom available on
the carbinol carbon.
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Slide – 5
11-2 Oxidation of Alcohols
Oxidation of 2° Alcohols
• A 2° alcohol becomes a ketone.
• Sodium hypochlorite (NaOCl, household bleach) , often used with acetic acid, is an inexpensive and relatively safe
oxidant.
Mechanism :
In the final step, a base such as acetate ion removes a proton
from the carbinol carbon atom, giving it a double bond to
oxygen, which leaves it oxidized. The oxidant (chlorine in this
case) leaves with an additional pair of electrons and fewer bonds
to oxygen, giving it a lower (reduced) oxidation state.
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Slide – 6
11-2 Oxidation of Alcohols
Oxidation of 2° Alcohols
The chromic acid reagent (Na2Cr2O7 / H2SO4)
The chromic acid reagent is prepared by dissolving either sodium dichromate (Na2Cr2O7) or chromium trioxide (CrO3) in a mixture
of sulfuric acid and water.
Oxidation Mechanism:
In the final step, oxidation of the carbon atom
and reduction of the chromium atom take place.
A weak base removes a proton from carbon,
giving it a double bond to oxygen. Chromium
leaves with an additional pair of electrons, going
from Cr(VI) to Cr(IV).
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Slide – 7
11-2 Oxidation of Alcohols
Oxidation of 1° Alcohols
• Oxidation of a primary alcohol initially forms an aldehyde. Unlike a ketone, however, an aldehyde is easily
oxidized further to give a carboxylic acid.
Chromic acid, a powerful oxidant, usually oxidizes a primary
alcohol all the way to the carboxylic acid.
• Can we selectively stop at the aldehyde?
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Slide – 8
11-2 Oxidation of Alcohols
Oxidation of 1° Alcohols
Can we selectively stop at the aldehyde?
Two reagents can be used to oxidize primary alcohols to aldehydes :
Sodium hypochlorite (NaOCl) used with TEMPO ( a stable free radical that catalyzes a variety of oxidations) .
TEMPO (2,2,6,6tetramethylpiperidinyl-1oxy)
The other reagent that can be used is pyridinium chlorochromate (PCC) a complex of chromium trioxide with pyridine and HCl.
PCC can also serve as a mild reagent for oxidizing secondary alcohols to ketones
• Examples:
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Slide – 9
11-2 Oxidation of Alcohols
Oxidation of 3° Alcohols
Resistance of tertiary alcohols to oxidation.
Tertiary alcohols have no hydrogen atoms on the carbinol carbon atom, so oxidation is difficult. Oxidation takes place
by breaking carbon-carbon bonds and require severe conditions.
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Slide – 10
11-3 Additional Methods for Oxidizing Alcohols
• The Swern oxidation uses dimethyl sulfoxide (DMSO) as the oxidizing agent to convert alcohols
to ketones and aldehydes.
• Dimethylsulfoxide (DMSO), with oxalyl chloride and hindered base (The Swern Oxidation)
• oxidizes 2° alcohols to ketones and 1° alcohols to aldehydes.
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Slide – 11
11-3 Additional Methods for Oxidizing Alcohols
• the Dess–Martin periodinane (DMP) reagent
• Can oxidize primary alcohols to aldehydes and secondary alcohols to ketones.
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Slide – 12
11-2 Oxidation of Alcohols
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Slide – 13
Solved Problem 1
Suggest the most appropriate method for each of the following laboratory
syntheses:
(b) 2-octen-l-ol to 2-octenal (structure below)
Solution
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Slide – 14
11-5 Alcohols as Nucleophiles and Electrophiles; Formation of Tosylates
Alcohols can react as both nucleophiles and electrophiles.
Alcohols (ROH) are weak
nucleophiles.
Alkoxides (RO–) are
strong nucleophiles.
An alcohol is a weak electrophile because the hydroxy group is
a poor leaving group. The hydroxy group becomes a good
leaving group (H2O) when it is protonated.
Disadvantage: Most strong nucleophiles are also basic and
will abstract a proton in acid. Once protonated, the reagent is
no longer nucleophilic.
• For example, an acetylide ion would instantly become
protonated if it were added to a protonated alcohol.
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Slide – 15
11-5 Alcohols as Electrophiles; Formation of Tosylates
How can we convert an alcohol to an electrophile that is compatible with basic nucleophiles then?
One solution is to convert the alcohol into a tosylate ester.
A tosylate ester (symbolized
ROTs) is the product of
condensation of an alcohol
with p-toluenesulfonic acid
(symbolized TsOH).
The tosylate group is an
excellent leaving group
Alcohols will react with p-toluenesulfonyl chloride (“tosyl chloride”, often abbreviated TsCl) in the presence of pyridine, to create a “tosylate”:
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Slide – 16
Reactions of Tosylates: Nucleophilic Displacement
Organic tosylates undergo a standard range of SN2 displacements. These work best, as usual, if the original alcohol was
primary or secondary because if substitution is to predominate over elimination the R group of the alcohol must be
unhindered.
• The following reaction shows the SN2 displacement of the tosylate ion (–OTs) from (S)-2-butyl tosylate with inversion of
configuration.
• The tosylate ion is a particularly stable anion, with its negative charge delocalized over three oxygen atoms
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.
Slide – 17
Summary of SN2Tosylate Reactions
Example
Note in this summary that we are using sodium
cyanide, sodium bromide, sodium alkoxide….
Look at the following problems for example:
Example:
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Slide – 18
Reduction of Alcohols via Tosylates (sect 11-6)
The reduction of alcohols to alkanes, HOW ?
One method for reducing an alcohol involves converting the alcohol to the tosylate ester and then using a hydride
reducing agent to displace the tosylate leaving group. This reaction works with most primary and secondary alcohols.
LiAlH4 (a hydride reducing agent) will displace tosylates, to give alkanes. This is useful if you’ve constructed a
carbon skeleton (e.g. by a Grignard synthesis) with an alcohol in a place where you don’t want it, In those cases, we
reduce the −OH group to a hydrogen atom.
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Slide – 19
11-7 Reactions of Alcohols with Hydrohalic Acids, Conversion to Alkyl Halides.
• The hydroxyl group is protonated by an acid to convert it into a good leaving group (H2O).
• Halides are anions of strong acids, so they are weak bases. Solutions of HBr, HCl, or HI contain nucleophilic Br−,
Cl−, or I– ions. These acids are commonly used to convert alcohols to the corresponding alkyl halides.
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Slide – 20
11-7 Reactions of Alcohols with Hydrohalic Acids, Conversion to Alkyl Halides.
11-7A Reactions with Hydrobromic Acid
Secondary alcohols also react with HBr to form alkyl
bromides, usually by the SN1 mechanism. For example,
cyclohexanol is converted to bromocyclohexane using
HBr as the reagent.
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Slide – 21
11-7 Reactions of Alcohols with Hydrohalic Acids, Conversion to Alkyl Halides.
11-7A Reactions with Hydrobromic Acid
• butan-1-ol (a primary alcohol) reacts with sodium bromide in concentrated sulfuric acid to give 1-bromobutane by an SN2
displacement. The sodium bromide/sulfuric acid reagent generates HBr in the solution.
Protonation converts the hydroxy group to
a good leaving group, but ionization to a
primary carbocation is unfavorable.
The protonated primary
alcohol is well suited for the
SN2 displacement, however.
Back-side attack by bromide
ion gives 1-bromobutane.
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Slide – 22
11-7 Reactions of Alcohols with Hydrohalic Acids, Conversion to Alkyl Halides.
11-7b Reactions with Hydrochloric Acid
• Chloride ion is a weaker nucleophile than bromide ion because it is smaller and less polarizable. An additional Lewis acid,
such as zinc chloride (ZnCl2), is sometimes necessary to promote the reaction of HCl with primary and secondary alcohols.
• The reagent composed of HCl and ZnCl2 is called the Lucas reagent.
• Example:
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Slide – 23
11-8 Reactions of Alcohols with Phosphorus Halides
Several phosphorus halides are useful for converting alcohols to alkyl halides, for example Phosphorus tribromide, phosphorus
trichloride, and phosphorus pentachloride
• Phosphorus halides produce good yields of most primary and secondary alkyl halides, but none works well with tertiary
alcohols.
• The following examples show the conversion of primary and secondary alcohols to bromides and iodides by treatment with
PBr3 and P/I2.
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Slide – 24
Examples
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Slide – 25
Mechanism with PBr3
Rearrangements are uncommon because no
carbocation is involved, so there is no
opportunity for rearrangement.
• Br– attacks back-side (SN2).
• The final step is an SN2 displacement where
bromide attacks the back side of the alkyl group.
This attack is hindered if the alkyl group is tertiary.
This explains the poor yields with tertiary alcohols.
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Slide – 26
11-9 Reactions of Alcohols with Thionyl Chloride
• Thionyl chloride (SOCl2) can be used to convert alcohols into the corresponding alkyl chloride in a simple reaction that
produces gaseous HCl and SO2.
• Primary and secondary alcohols are converted to chlorides in good yields, by the combination of thionyl chloride (SOCl2) and
pyridine.
• Examples :
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Slide – 27
11-11 Unique Reactions of Diols
11-11A The Pinacol Rearrangement
Diols sometimes undergo reactions that depend on the presence of two adjacent −OH groups. One of these reactions is
the pinacol rearrangement
The following dehydration is an example of the pinacol rearrangement:
In the pinacol rearrangement, a vicinal diol converts to the ketone (pinacolone) under acidic conditions and heat.
The reaction is classified as a dehydration since a water molecule is eliminated from the starting material.
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Slide – 28
11-11 Unique Reactions of Diols
11-11A The Pinacol Rearrangement
Mechanism
The pinacol rearrangement is formally a dehydration
The reaction is acid-catalyzed, and the first step is
protonation of one of the hydroxy oxygens.
Loss of water gives a tertiary carbocation, as expected
for any tertiary alcohol.
Migration of a methyl group places the positive charge
on the carbon atom bearing the second −OH group,
where oxygen’s nonbonding electrons help to stabilize
the positive charge through resonance.
This extra stability is the driving force for the
rearrangement, which converts a relatively stable 3°
carbocation into an even better resonance-stabilized
carbocation.
Deprotonation of the resonance-stabilized cation gives
the product, pinacolone.
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Slide – 29
• Problem-Solving HINT
If a ring changes size during a reaction, a rearrangement has occurred; specifically, a
ring atom has migrated. In most cases, migration occurs to form a more stable
intermediate, or it may release ring strain in three- and four-membered rings.
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Slide – 30
NAME:
PLEASE READ THE QUESTIONS VERY CAREFULLY BEFORE YOU ANSWER.
Exam 2 is an “assignment on Canvas: when finished, scan or photograph your completed answers and
upload it then submit it on canvas.
1) Give an example of each of the following: (10 points)
a) secondary alcohol
b.) Grignard reagent
d.) a compound with conjugated double bonds
c) Thioether
e) a compound with isolated double bonds
2) Nomenclature: Give the correct IUPAC name and denote all stereochemistry using appropriate descriptors
where possible for the following : (10 points)
3) Reaction Products (30 points)
Fill in the major product(s) including stereochemistry (where appropriate).
4) Write a detailed mechanism for the following reactions (40 points, 10 each).
d) Write the mechanism and the product for the following;
H3CH2C
MgBr
+
1) ether solvent
O
H
+
2) H3O
5) Complete the following synthetic pathways by writing in the empty boxes the chemical structures of the expected
products (10 pints) :
BONUS question ( 5 points).
Write a detailed mechanism for the following reaction:
+
H
H3C
CH3
OH
OH
O
NAME:
PLEASE READ THE QUESTIONS VERY CAREFULLY BEFORE YOU ANSWER.
Exam 2 is an “assignment on Canvas: when finished, scan or photograph your completed answers and
upload it then submit it on canvas.
1) Give an example of each of the following: (10 points)
a) secondary alcohol
b.) Grignard reagent
d.) a compound with conjugated double bonds
c) Thioether
e) a compound with isolated double bonds
2) Nomenclature: Give the correct IUPAC name and denote all stereochemistry using appropriate descriptors
where possible for the following : (10 points)
3) Reaction Products (30 points)
Fill in the major product(s) including stereochemistry (where appropriate).
4) Write a detailed mechanism for the following reactions (40 points, 10 each).
d) Write the mechanism and the product for the following;
H3CH2C
MgBr
+
1) ether solvent
O
H
+
2) H3O
5) Complete the following synthetic pathways by writing in the empty boxes the chemical structures of the expected
products (10 pints) :
BONUS question ( 5 points).
Write a detailed mechanism for the following reaction:
+
H
H3C
CH3
OH
OH
O