Download Organic Chemistry Second Edition

Organic Chemistry
Second Edition
David Klein
Chapter 13
Alcohols and Phenols
Copyright © 2015 John Wiley & Sons, Inc. All rights reserved.
Klein, Organic Chemistry 2e
13.1 Alcohols and Phenols
• Alcohols possess a hydroxyl group (-OH)
• Hydroxyl groups are extremely common in natural
compounds
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Klein, Organic Chemistry 2e
13.1 Alcohols and Phenols
• Hydroxyl groups in natural compounds
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13-3
Klein, Organic Chemistry 2e
13.1 Alcohols and Phenols
• Phenols possess a hydroxyl group directly attached to an
aromatic ring
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13-4
Klein, Organic Chemistry 2e
13.2 Acidity of Alcohols and Phenols
•
A strong base is usually necessary to deprotonate an
alcohol
•
A preferred choice to create an alkoxide is to treat the
alcohol with Na, K, or Li metal. Show the mechanism for
such a reaction
•
Practice with conceptual checkpoint 13.4
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13-5
Klein, Organic Chemistry 2e
13.2 Acidity of Alcohols and Phenols
•
•
Recall from chapter 3 how ARIO is used to qualitatively
assess the strength of an acid
Lets apply these factors to alcohols and phenols
–
Atom
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13-6
Klein, Organic Chemistry 2e
13.2 Acidity of Alcohols and Phenols
•
Lets apply these factors to alcohols and phenols
–
Resonance
–
Explain why phenol is 100 million times more acidic than
cyclohexanol
Show all relevant resonance contributors
–
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13-7
Klein, Organic Chemistry 2e
13.2 Acidity of Alcohols and Phenols
•
Lets apply these factors to alcohols and phenols
–
Induction: unless there is an electronegative group nearby,
induction won’t be very significant
–
Orbital: in what type of orbital do the alkoxide electrons
reside? How does that effect acidity?
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13-8
Klein, Organic Chemistry 2e
13.2 Acidity of Alcohols and Phenols
•
•
•
Solvation is also an important factor that affects acidity
Water is generally used as the solvent when measuring
pKa values
Which of the alcohols below is stronger?
•
ARIO cannot be used to explain the difference
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13-9
Klein, Organic Chemistry 2e
13.2 Acidity of Alcohols and Phenols
•
Solvation explains the difference in acidity
•
Draw partial charges on the solvent molecules to show
how solvation is a stabilizing effect
Practice with SkillBuilder 13.2
•
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13-10
Klein, Organic Chemistry 2e
Copyright © 2015 John Wiley & Sons, Inc. All rights reserved.
Klein, Organic Chemistry 2e
13.3 Preparation of Alcohols
•
•
•
We saw in chapter 7 that substitution reactions can
yield an alcohol
What reagents did we use to accomplish this
transformation?
We saw that the substitution can occur by SN1 or SN2
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13-12
Klein, Organic Chemistry 2e
13.3 Preparation of Alcohols
•
•
The SN1 process generally uses a weak nucleophile
(H2O), which makes the process relatively slow
Why isn’t a stronger nucleophile (-OH) used under SN1
conditions?
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13-13
Klein, Organic Chemistry 2e
13.3 Preparation of Alcohols
•
In chapter 9, we learned how to make alcohols from
alkenes
•
Recall that acid-catalyzed hydration proceeds through a
carbocation intermediate that can possibly rearrange
How do you avoid rearrangements?
Practice with checkpoints 13.7 and 13.8
•
•
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13-14
Klein, Organic Chemistry 2e
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Klein, Organic Chemistry 2e
13.4 Alcohol Prep via Reduction
•
•
•
•
A third method to prepare alcohols is by the reduction
of a carbonyl. What is a carbonyl?
Reductions involve a change in oxidation state
Oxidation state are a method of electron bookkeeping
Recall how we used formal charge as a method of
electron bookkeeping
–
–
Each atom is assigned half of the electrons it is sharing with
another atom
What is the formal charge on carbon in methanol?
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13-16
Klein, Organic Chemistry 2e
13.4 Alcohol Prep via Reduction
•
For oxidation states, we imagine the bonds breaking
heterolytically, and the electrons go to the more
electronegative atom
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13-17
Klein, Organic Chemistry 2e
13.4 Alcohol Prep via Reduction
•
•
•
•
•
Each of the carbons below have zero formal charge, but
they have different oxidation states
Calculate the oxidation number for each
Is the conversion from formic acid  carbon dioxide an
oxidation or a reduction?
What about formaldehyde  methanol?
Practice with SkillBuilder 13.3
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13-18
Klein, Organic Chemistry 2e
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Klein, Organic Chemistry 2e
13.4 Alcohol Prep via Reduction
•
The reduction of a carbonyl requires a reducing agent
•
•
Is the reducing agent oxidized or reduced?
If you were to design a reducing agent, what element(s)
would be necessary?
Would an acid such as HCl be an appropriate reducing
agent? WHY or WHY NOT?
•
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13-20
Klein, Organic Chemistry 2e
13.4 Alcohol Prep via Reduction
•
There are three reducing agents you should know
1. We have already seen how catalyzed hydrogenation can
reduce alkenes. It can also work for carbonyls
–
Forceful conditions (high temperature and/or high pressure)
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13-21
Klein, Organic Chemistry 2e
13.4 Alcohol Prep via Reduction
•
Reagents that can donate a hydride are generally good
reducing agents
2. Sodium borohydride
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13-22
Klein, Organic Chemistry 2e
13.4 Alcohol Prep via Reduction
•
Reagents that can donate a hydride are generally good
reducing agents
3. Lithium aluminum hydride (LAH)
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13-23
Klein, Organic Chemistry 2e
13.4 Alcohol Prep via Reduction
•
•
Note that LAH is significantly more reactive that NaBH4
LAH reacts violently with water. WHY?
•
How can LAH be used with water if it reacts with water?
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13-24
Klein, Organic Chemistry 2e
13.4 Alcohol Prep via Reduction
•
Hydride delivery agents will somewhat selectively
reduce carbonyl compounds
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13-25
Klein, Organic Chemistry 2e
13.4 Alcohol Prep via Reduction
•
The reactivity of hydride delivery agents can be finetuned by using derivatives with varying R-groups
–
–
–
Alkoxides
Cyano
Sterically hindered groups
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13-26
Klein, Organic Chemistry 2e
13.4 Alcohol Prep via Reduction
•
LAH is strong enough to also reduce esters and
carboxylic acids, whereas NaBH4 is generally not
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13-27
Klein, Organic Chemistry 2e
13.4 Alcohol Prep via Reduction
•
To reduce an ester, 2 hydride equivalents are needed
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13-28
Klein, Organic Chemistry 2e
13.4 Alcohol Prep via Reduction
•
To reduce an ester, 2 hydride equivalents are needed
•
Which steps in the mechanism are reversible?
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13-29
Klein, Organic Chemistry 2e
13.4 Alcohol Prep via Reduction
•
Predict the products for the following processes
•
Practice with SkillBuilder 13.4
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13-30
Klein, Organic Chemistry 2e
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Klein, Organic Chemistry 2e
13.5 Preparation of Diols
•
Diols are named using the same method as alcohols,
except the suffix, “diol” is used
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13-32
Klein, Organic Chemistry 2e
13.5 Preparation of Diols
•
If two carbonyl groups are present, and enough moles
of reducing agent are added, both can be reduced
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13-33
Klein, Organic Chemistry 2e
13.5 Preparation of Diols
•
Recall the methods we discussed in chapter 9 to
convert an alkene into a diol
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13-34
Klein, Organic Chemistry 2e
13.6 Grignard Reactions
•
•
•
Grignard reagents are often used in the synthesis of
alcohols
To form a Grignard, an alkyl halide is treated with Mg
metal
How does the oxidation state of the carbon change
upon forming the Grignard?
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13-35
Klein, Organic Chemistry 2e
13.6 Grignard Reactions
•
The electronegativity difference between C (2.5) and
Mg (1.3) is great enough that the bond has significant
ionic character
•
The carbon atom is not able to effectively stabilize the
negative charge it carries
Will it act as an acid, base, electrophile, nucleophile,
etc.?
•
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13-36
Klein, Organic Chemistry 2e
13.6 Grignard Reactions
•
If the Grignard reagent reacts with a carbonyl
compound, an alcohol can result
•
Note the similarities between the Grignard and LAH
mechanisms
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13-37
Klein, Organic Chemistry 2e
13.6 Grignard Reactions
•
Because the Grignard is both a strong base and a strong
nucleophile, care must be taken to protect it from
exposure to water
•
If water can’t be used as the solvent, what solvent is
appropriate?
What techniques are used to keep atmospheric
moisture out of the reaction?
•
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13-38
Klein, Organic Chemistry 2e
13.6 Grignard Reactions
•
Grignard examples
•
With an ester substrate, excess Grignard reagent is
required. WHY? Propose a mechanism
List some functional groups that are NOT compatible
with the Grignard
Practice with SkillBuilder 13.5
•
•
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13-39
Klein, Organic Chemistry 2e
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Klein, Organic Chemistry 2e
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Klein, Organic Chemistry 2e
13.7 Protection of Alcohols
•
Consider the reaction below. WHY won’t it work?
•
The alcohol can act as an acid, especially in the
presence of reactive reagents like the Grignard reagent
The alcohol can be protected to prevent it from reacting
•
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13-42
Klein, Organic Chemistry 2e
13.7 Protection of Alcohols
•
A three-step process is required to achieve the desired
overall synthesis
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13-43
Klein, Organic Chemistry 2e
13.7 Protection of Alcohols
•
One such protecting group is trimethylsilyl (TMS)
•
The TMS protection step requires the presence of a
base. Propose a mechanism
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13-44
Klein, Organic Chemistry 2e
13.7 Protection of Alcohols
•
•
Evidence suggests that substitution at the Si atom
occurs by an SN2 mechanism
Because Si is much larger than C, it is more open to
backside attack
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13-45
Klein, Organic Chemistry 2e
13.7 Protection of Alcohols
•
•
The TMS group can later be removed with H3O+ or FTBAF is often used to supply fluoride ions
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13-46
Klein, Organic Chemistry 2e
13.7 Protection of Alcohols
•
Practice with conceptual checkpoint 13.18
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13-47
Klein, Organic Chemistry 2e
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Klein, Organic Chemistry 2e
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Klein, Organic Chemistry 2e
13.9 Reactions of Alcohols
•
Recall this SN1 reaction from section 7.5
•
For primary alcohols, the reaction occurs by an SN2
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13-50
Klein, Organic Chemistry 2e
13.9 Reactions of Alcohols
•
The SN2 reaction also occurs with ZnCl2 as the reagent
•
Recall from section 7.8 that the –OH group can be
converted into a better leaving groups such as a tosyl
group
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13-51
Klein, Organic Chemistry 2e
13.9 Reactions of Alcohols
•
SOCl2 can also be used to convert an alcohol to an alkyl
chloride
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13-52
Klein, Organic Chemistry 2e
13.9 Reactions of Alcohols
•
PBr3 can also be used to convert an alcohol to an alkyl
bromide
•
Note that the last step of the SOCl2 and PBr3
mechanisms are SN2
Practice with SkillBuilder 13.6
•
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13-53
Klein, Organic Chemistry 2e
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Klein, Organic Chemistry 2e
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Klein, Organic Chemistry 2e
13.9 E1 and E2 Reactions of Alcohols
•
In section 8.9, we saw that an acid (with a nonnucleophilic conjugate base) can promote E1
•
•
Why is E2 unlikely?
Recall that the reaction generally produces the more
substituted alkene product
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13-56
Klein, Organic Chemistry 2e
13.9 E1 and E2 Reactions of Alcohols
•
If the alcohol is converted into a better leaving group,
then a strong base can be used to promote E2
•
•
E2 reactions do not involve rearrangements. WHY?
When applicable, E2 reactions also produce the more
substituted product
Practice with conceptual checkpoint 13.21
•
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13-57
Klein, Organic Chemistry 2e
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Klein, Organic Chemistry 2e
13.10 Oxidation of Alcohols
•
•
We saw how alcohols can be formed by the reduction
of a carbonyl
The reverse process is also possible with the right
reagents
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13-59
Klein, Organic Chemistry 2e
13.10 Oxidation of Alcohols
•
Oxidation of primary alcohols proceed to an aldehyde
and subsequently to the carboxylic acid
–
•
Very few oxidizing reagents will stop at the aldehyde
Oxidation of secondary alcohols produces a ketone
–
Very few agents are capable of oxidizing the ketone
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13-60
Klein, Organic Chemistry 2e
13.10 Oxidation of Alcohols
•
Tertiary alcohols generally do not undergo oxidation.
WHY?
•
There are two main methods to produce the most
common oxidizing agent, chromic acid
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13-61
Klein, Organic Chemistry 2e
13.10 Oxidation of Alcohols
•
When chromic acid reacts with an alcohol, there are
two main steps
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13-62
Klein, Organic Chemistry 2e
13.10 Oxidation of Alcohols
•
Chromic acid will generally oxidize a primary alcohol to
a carboxylic acid
•
PCC (pyridinium chlorochromate) can be used to stop
at the aldehyde
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13-63
Klein, Organic Chemistry 2e
13.10 Oxidation of Alcohols
•
PCC (pyridinium
chlorochromate) is
generally used with
methylene chloride as
the solvent
•
Both oxidizing agents
will work with
secondary alcohols
•
Practice with SkillBuilder 13.7
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13-64
Klein, Organic Chemistry 2e
Copyright © 2015 John Wiley & Sons, Inc. All rights reserved.
Klein, Organic Chemistry 2e
13.10 Oxidation of Alcohols
•
Predict the product for the following reaction
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13-66
Klein, Organic Chemistry 2e
13.13 Synthetic Strategies
•
Recall some functional group conversions we learned
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13-67
Klein, Organic Chemistry 2e
13.13 Synthetic Strategies
•
Classify the functional groups based on oxidation state
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13-68
Klein, Organic Chemistry 2e
13.13 Synthetic Strategies
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13-69
Klein, Organic Chemistry 2e
13.13 Synthetic Strategies
•
Give necessary reagents for the following conversions
•
Practice with SkillBuilder 13.8
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13-70
Klein, Organic Chemistry 2e
Copyright © 2015 John Wiley & Sons, Inc. All rights reserved.
Klein, Organic Chemistry 2e
Copyright © 2015 John Wiley & Sons, Inc. All rights reserved.
Klein, Organic Chemistry 2e
13.13 Synthetic Strategies
•
Recall the C-C bond forming reactions we learned
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13-73
Klein, Organic Chemistry 2e
13.13 Synthetic Strategies
•
What if you want to convert an aldehyde into a ketone?
•
What reagents are needed for the following
conversion?
•
Practice with conceptual checkpoint 13.27 and
SkillBuilder 13.9
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13-74
Klein, Organic Chemistry 2e
Copyright © 2015 John Wiley & Sons, Inc. All rights reserved.
Klein, Organic Chemistry 2e
Copyright © 2015 John Wiley & Sons, Inc. All rights reserved.
Klein, Organic Chemistry 2e
Additional Practice Problems
•
Name the following molecule
•
Draw (1R,2R)-1-(3,3-dimethylbutyl)-3,5-cyclohexadien1,2-diol
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13-77
Klein, Organic Chemistry 2e
Additional Practice Problems
•
Use ARIO and solvation to rank the following molecules
in order of increasing pKa
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13-78
Klein, Organic Chemistry 2e
Additional Practice Problems
•
Predict the products for the following processes
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13-79
Klein, Organic Chemistry 2e
Additional Practice Problems
•
Design a synthesis for the following molecule starting
from an alkyl halide and a carbonyl, each having 5
carbons or less
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13-80
Klein, Organic Chemistry 2e
Additional Practice Problems
•
Give necessary reagents for the multi-step synthesis
below
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13-81
Klein, Organic Chemistry 2e