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Organic Chemistry 236!
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• Do not memorize everything!
• Practice writing mechanisms and “talking” yourself through the steps.
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• Work as many problems as you can.
• Do not hesitate to visit me during office hours for assistance.
• A free tutoring service is available through the LRC.
Fall 2011
Dr. Halligan
CHM 236
Chapter 10
• Reactions of Alcohols, Ethers, Epoxides,
Amines, and Sulfur-Containing
Compounds
Ch. 10 Overview
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Conversion of Alcohols to Alkyl Halides and Sulfonate Esters
Substitution reactions of activated alcohols (ROH with better LG’s)
Dehydration of alcohols via Elimination Reactions
Oxidation of Alcohols
Nucleophilic Substitution Reactions of Ethers
• Nucleophilic Substitution Reactions of Epoxides
• Amines Do Not Undergo Substitution or Elimination Reactions
• Quaternary Ammonium Hydroxiudes Undergo Elimination
Reactions
• Phase-Transfer Catalysts
• Thiols, Sulfides, and Sulfonium Salts
Substitution Reactions of Alcohols
• The OH group of an alcohol is a terrible LG. Why?
• We must convert the OH group to a better LG before doing a substitution
reaction.
• In this chapter, we will use HCl, HBr, HI, ZnCl2, PBr2, SOCl2, and R’SO2Cl/py
to convert OH to a better LG.
OH
+
Br
Br
+
OH
strong base
(you need a weak/stable base)
Alcohols and ethers have to be activated before they can undergo a
substitution or an elimination reaction:
Convert the strongly basic leaving group (OH–) into the good
leaving group, H2O (a weaker base):
Only weakly basic nucleophiles can be used
6
Primary, secondary, and tertiary alcohols all undergo
nucleophilic substitution reactions with HI, HBr, and HCl:
7
Secondary and tertiary alcohols undergo SN1 reactions
with hydrogen halides:
8
Primary alcohols undergo SN2 reactions with hydrogen halides:
Reaction carried out in 48% aqueous HBr. Recall that Br– is an
excellent nucleophile in water.
9
ZnCl2 can be used to catalyze certain SN2 reactions:
ZnCl2 functions as a Lewis acid that complexes strongly with the lonepair electrons on oxygen:
10
The Lucas Reagent
Anhydrous ZnCl2 in conc HCl
Distinguishes primary, secondary, and tertiary low-molecularweight alcohols
The Lucas reaction:
ZnCl2
ROH + HCl
RCl
Positive test: Solution
becomes cloudy
Test results and mechanisms at room temperature:
SN 2
• Primary: No reaction
SN2 and SN1
• Secondary: Reaction in ~5 minutes
• Tertiary, allylic, and benzylic: Reaction immediate
SN 1
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Look out for rearrangement product in the SN1 reaction
of the secondary or tertiary alcohol:
12
Other Methods for Converting Alcohols
into Alkyl Halides
Utilization of phosphorus tribromide:
Other phosphorus reagents can be used:
PBr3, phosphorus tribromide
PCl3, phosphorus trichloride
PCl5, phosphorus pentachloride
POCl3, phosphorus oxychloride
13
Activation by SOCl2
Pyridine is generally used as a solvent and also acts as a base:
14
The Artificial Sweetener Splenda
(Sucralose)
Could Splenda be a cellular alkylating agent?
No, it is too polar to enter a cell.
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Summary: Converting of Alcohols
to Alkyl Halides
Recommended procedures:
17
Converting Alcohols into Sulfonate Esters
18
Several sulfonyl chlorides are available to
activate OH groups:
19
Dehydration of Secondary and Tertiary
Alcohols by an E1 Pathway
To prevent the rehydration of the alkene product, one
needs to remove the product as it is formed
20
The major product is the most stable alkene product:
The most stable alkene product has the most stable
transition state
21
The rate of dehydration reflects the ease with which the
carbocation is formed:
22
Look out for carbocation rearrangement:
23
Complex Alcohol Rearrangements in Strong Acid
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Pinacol Rearrangement
Protonate alcohol:
Eliminate water:
Rearrange carbocation:
Deprotonate:
H3 C
CH3
H 3C
Resonance-stabilized
oxocarbocation
CH3
O
25
Ring Expansion and Contraction
Show the mechanism for this
reaction:
•Protonate the alcohol.
•Eliminate water.
•Rearrange carbocation to
afford the more stable
cyclohexane ring.
•Deprotonate.
26
Primary Alcohols Undergo Dehydration by
an E2 Pathway
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The Stereochemical Outcome of
the E1 Dehydration
Alcohols and ethers undergo SN1/E1 reactions unless
they would have to form a primary carbocation
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A Milder Way to Dehydrate an Alcohol
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Oxidation by Chromium (VI)
30
Primary alcohols are oxidized to aldehydes and
eventually carboxylic acids:
Mechanism:
31
The oxidation of aldehydes to acids requires the
presence of water:
In the absence of water, the oxidation stops at the aldehyde:
PCC, a methylene chloride–soluble reagent:
No water present
32
A tertiary alcohol cannot be oxidized and is converted to a
stable chromate ester instead:
O
O Cr O
O
No hydrogen on
this carbon
Di-tert-Butyl Chromate
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Amines do not undergo substitution reactions because
NH2– is a very strong base (a very poor leaving group):
Protonation of the amine moiety does not solve the
problem:
34
Nucleophilic Substitution Reactions of Ethers
Ethers, like alcohols, can be activated by protonation:
35
Ether cleavage: an SN1 reaction:
Ether cleavage: an SN2 reaction:
36
Reagents such as SOCl2 and PCl3 can activate alcohols but not ethers
Ethers are frequently used as solvents because only they
react with hydrogen halides
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Nucleophilic Substitution
Reactions of Epoxides
Recall Section 4.9
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Epoxides are more reactive than ethers in nucleophilic
substitution reactions because of ring strain:
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Acid-Catalyzed Epoxide Ring Opening
Stereospecificity of epoxide ring opening:
Reason: Back-side attack of
water on protonated epoxide:
A trans diol
40
Reaction of an epoxide in the presence of
methanol and acid
Regioselectivity:
Mechanism:
41
When a nucleophile attacks an unprotonated
epoxide, the reaction is a pure SN2 reaction:
Therefore:
42
Epoxides Are Synthetically
Useful Reagents
Enantiomers
43
Epoxy resins are the strongest adhesives known:
Amine nucleophile
mediated epoxide
ring opening:
44
Arene Oxides:
Arene oxides are versatile compounds with interesting
chemistries.
They are compounds in which one of the “double bonds” of the
aromatic ring has been converted into an epoxide.
What happens to aromatic compounds when they enter the body
as a foreign substance (such as cigarette smoke, drugs, charcoalbroiled meats or automobile exhaust)?
45
Arene Oxide Reactions
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•
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Arene oxides participate in two types of reactions.
They undergo nucleophilic attacks of the epoxide ring to form addition products
(unlike regular epoxides).
They can also undergo a rearrangement reaction to form a phenol.
Whether or not a certain arene oxide is carcinogenic depends its subsequent
reaction pathway (rearrangement or nucleophilic substitution).
If it proceeds through the rearrangement pathway, non-carcinogenic phenols will
be produced.
However, if it undergoes nucleophilic attack by DNA, this can lead to carcinogenic
products.
Y
OH
Y
addition product
O
OH
rearranged product
Mechanism for arene oxide rearrangement:
47
How Do Arene Oxides Cause Cancer?
DNA
backbone
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BENZO[a]PYRENE EPOXIDATION
Not all smokers
get cancer
Benzopyrenes in chimneys
were responsible for cancer
of the scrotum in “chimneyboys.” The connection
between cancer and chimney
soot was made by Percivall
Pott in 1775.
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Reactions of 4° Ammonium Hydroxides
• A fully alkylated amino group (quaternary), makes a good enough
LG for the “E2” Hofmann Elimination Reaction.
• If the 4° amino group was protonated, the E2 base, would just
deprotonate the 4° amino group and there would be no E2
reaction.
Hofmann Elimination Favors anti-Zaitsev Products
• Do you remember the 3 exceptions for E2 reactions in terms of
predicting the major products?
• Usually, the more substituted alkene is the major product except if
there is a big bulky base, possibility of conjugation or a Fluorine LG.
• Here, the quaternary ammonium salt is a relatively slow LG just
like Fluorine. As the E2 base comes in to abstract the proton, a
negative charge starts to build up on the B-carbon. Remember that
carbanion stability is the opposite of carbocation stability.
Crown Ethers
The ability of a host to bond only certain guests is an
example of molecular recognition
52
Crown Ether Reactions
•
Crown ethers serve as excellent phase-transfer catalysts for reactions.
•
The crown ether enables a reaction to be carried out in two phases (polar and
nonpolar).
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•
This is exemplified in the reaction of 1-bromohexane with acetate ion.
The acetate ion is only soluble in water whereas the 1-bromohexane is only
soluble in nonpolar solvents.
The crown ether helps dissolve the acetate by binding the inorganic ion species
(e.g. Na+ or K+) in its cavity and then the whole crown-guest complex is soluble in
the nonpolar solvent (benzene in this case).
•
Thiols are sulfur analogs of alcohols:
Thiols form strong complexes with heavy metal cations
Thiols are stronger acids (pKa = 10) than alcohols
Thiols are not good at hydrogen bonding
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Thiols, Sulfides, and Sulfonium Salts
•
Thiols are sulfur analogs of alcohols
with SH replacing the OH of the
alcohol.
•
Thiols are also known as mercaptans
because they form stable heavy
metal derivatives with species such
as mercuric and arsenic ions.
•
Low MW thiols have strong and
offensive odors, such as those
present in onions, garlic and skunks.
•
The –SH group ranks just below an
alcohol in terms of naming.
In protic solvent, thiolate ions are better
nucleophiles than alkoxide ions:
Sulfur is an excellent nucleophile because its
Electron cloud is polarized
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