Chapter 17
Introduction
• Alcohols are compounds with a OH group bonded to
a saturated C (sp3-hybridized)
• Phenols are compounds with a OH group bonded to
a carbon in a benzene ring
•
Alcohols are abundant in nature; they are important
solvents and synthesis intermediates
–
Methanol, CH3OH, called methyl alcohol, is a common
solvent, a starting material and a fuel additive; it is
produced in large quantities by catalytic reduction
–
Ethanol, CH3CH2OH, called ethyl alcohol, is a solvent, fuel,
beverage; it is produced in large quantities by acidcatalyzed hydration of ethylene
•
Phenol, C6H5OH (“phenyl alcohol”) is abundant in
nature; it has diverse uses
–
It gives its name to the general class of compounds
flavoring agent
(oil of wintergreen)
allergens
(poison oak or ivy )
1.
Naming Alcohols and Phenols
• Alcohols are classified as primary (1°), secondary
(2°), or tertiary (3°) based on substitution on C to
which OH is attached
– Primary (1°) (C has two H’s, one R)
– Secondary (2°) (C has one H, two R’s)
– Tertiary (3°) (C has no H, 3 R’s)
Naming Alcohols
•
Alcohols are named according to the IUPAC system
1. Select the longest carbon chain containing the OH group,
and derive the parent name by replacing the -e ending of
the corresponding alkane with -ol
2. Number the chain from the end nearer the OH group
3. Number substituents according to position on chain,
listing the substituents in alphabetical order
•
Many alcohols have common names, accepted by
IUPAC
Naming Phenols
•
Phenols are named according to the IUPAC system
1. Use “phene” (the French name for benzene) as the
parent hydrocarbon name, not benzene, followed by the
suffix –ol to indicate the OH substituent
2. Number substituents on aromatic ring by their position
from OH
Practice Problem: Give IUPAC names for the following
compounds
Practice Problem: Draw structures corresponding to the following
IUPAC names
a. 2-Ethyl-2-buten-1-ol
b. 3-Cyclohexen-1-ol
c. trans-3-Chlorocycloheptanol
d. 1,4-Pentanediol
e. 2,6-Dimethylphenol
f.
o-(2-Hydroxyethyl)phenol
2.
Properties of Alcohols and Phenols:
Hydrogen Bonding
• The geometry around the O atom of an alcohol
(ROH) and phenol (ArOH) is similar to that of
water (HOH)
– The C-O-H bond angle has the tetrahedral
value
– The O atom is sp3-hybridized
•
Alcohols and phenols have much higher boiling points
than alkanes and alkyl halides with similar MW
•
Alcohols and phenols have high boiling points because
they form hydrogen bonds (like H2O) in solution
–
A hydrogen bond is a weak attraction between a H bonded
to an electronegative atom and an electron lone pair on
another electronegative atom
–
This intermolecular force elevates the boiling point
–
The attraction of a d+ H atom of OH from one molecule to a
lone pair of electrons on a d- O atom of another molecule
produces a force that holds the two molecules together
–
This intermolecular attraction (present in solution but not in
the gas phase) must be overcome for the molecules to
enter the gas phase, thus elevating the boiling point of the
solution
Practice Problem: The following data for isomeric four-carbon
alcohols show that there is a decrease in
boiling point with increasing substitution. How
might you account for this trend?
1-Butanol, bp 117.5oC
2-Butanol, bp 99.5oC
2-Methyl-2-propanol, bp 82.2oC
3.
Properties of Alcohols and Phenols:
Acidity and Basicity
• Alcohols and phenols are both weakly basic
and weakly acidic
– They act as Brønsted bases in the presence of
a strong acid
– They act as Brønsted acids in the presence of a
strong base
•
Alcohols and phenols are weak Brønsted bases
– They are protonated by strong acids to yield
oxonium ions, ROH2+
•
Alcohols and phenols are weak Brønsted acids
–
They can transfer a proton to water to a very small extent
–
They produce H3O+ and an alkoxide ion, RO-, or a
phenoxide ion, ArO-
Brønsted Acidity Measurements
•
The acidity constant, Ka, measures the extent to
which a Brønsted acid transfers a proton to water
HA + H2O

A- + H3O+
[A-] [H3O+]
Ka = Keq [H2O] = —————
[HA]
• A larger value of Ka indicates a stronger acid
pKa – The acid strength scale
• Acid strength is expressed using pKa values:
pKa = - log Ka
• The free energy in an equilibrium is related to -ln
of Keq:
DG = -RT ln Keq
• Relative acidities are more conveniently presented
on a logarithmic scale, pKa, which is directly
proportional to the free energy of the equilibrium
• Differences in pKa correspond to differences in free
energy
DpKa = log Keq2/Keq1
 DpKa can be used to calculate the extent of H+
transfer
• H+ will always go from the stronger acid to the
stronger base
• The stronger the acid, the weaker its conjugate
base. The weaker the acid, the stronger the
conjugate base.
The larger the Ka, the smaller the pKa, the stronger the acid
Alcohol Acidity
•
Simple alcohols are about as acidic as water
–
–
–
•
pKa H2O = 15.74
pKa CH3OH = 15.54
pKa CH3CH2OH = 16.00
Factors that affect alcohol acidity include:
– Alkyl Substitution (Steric Effects)
– Inductive Effects
Effect of Alkyl Substitution
–
Higher alkyl groups decrease the acidity of an alcohol
due to decreased solvation of the alkoxide ion
•
–
The less easily the alkoxide ion is solvated by water, the less
stable, the less its formation is energetically favored, the lower
the acidity
Steric hindrance on alkoxide ion decreases solvation
–
Steric hindrance on alkoxide ion decreases solvation


CH3OH has an unhindered O on the methoxide ion, CH3O(CH3)3OH has a hindered O on the t-butoxide ion, (CH3)3O-
Inductive Effects
–
Electron-withdrawing groups make an alcohol a
stronger acid by stabilizing the conjugate base
(alkoxide)
Nonafluoro-t-butoxide ion
t-butoxide ion
Alcohols generate alkoxides
•
Alcohols are weak acids. They require a strong base
•
They form alkoxides upon reaction with:
–
–
–
–
•
alkali metals,
sodium hydride (NaH),
sodium amide (NaNH2), and
Grignard reagents (RMgX)
Alkoxides are used as basic reagents in organic
chemistry
Alcohols form alkoxides upon reaction with: alkali metals, NaH,
NaNH2, and Grignard reagents (RMgX)
Phenol Acidity
•
Phenols (pKa ~10) are much more acidic than
alcohols (pKa ~ 16) due to resonance stabilization of
the phenoxide ion
•
The resonance-stabilized phenoxide anion is more stable
than the methoxide anion. The negative charge in phenoxide
is delocalized (spread over) from O to the ring.
•
Phenols react with NaOH solutions (but alcohols do not),
forming salts that are soluble in dilute aqueous solutions
•
A phenolic component can be separated from an organic
solution by extraction into basic aqueous solution followed
by addition of acid into the solution
Effect of Substitution on phenol acidity
Substituted phenols can be more or less acidic than
phenol itself
–
An electron-withdrawing substituent makes a phenol
more acidic because it delocalizes the negative charge
–
An electron-donating substituent makes a phenol less
acidic because it concentrates the charge
Nitro phenols
–
Phenols with nitro groups at the ortho and para
positions are much stronger acids
–
The pKa of 2,4,6-trinitrophenol is 0.6, a very strong
acid
Practice Problem: Is p-cyanophenol more acidic or less acidic
than phenol?
CN, an electron-withdrawing group, increases the
acidity of phenol by stabilizing the negative charge
on the phenoxide ion.
Practice Problem: Rank the following substances in order of
increasing acidity:
a. (CH3)2CHOH, HCCH, (CF3)2CHOH, CH3OH
b. Phenol, p-methylphenol, p-(trifluoromethyl)phenol
c. Benzyl alcohol, phenol, p-hydroxybenzoic acid
Practice Problem: p-Nitrobenzyl alcohol is more acidic than
benzyl alcohol but p-methoxybenzyl alcohol is
less acidic. Explain
4.
Preparation of Alcohols: A Review
• Alcohols are very useful in synthesis because:
– They can be derived from many types of
compounds
– They can be converted to many other types of
compounds (with different functional groups)
Preparation of Alcohols by Regiospecific Hydration of
Alkenes
•
Hydroboration/oxidation: syn, non-Markovnikov hydration
•
Oxymercuration/reduction: Markovnikov hydration
Preparation of 1,2-Diols
•
Cis-1,2-diols: Hydroxylation of an alkene with OsO4
followed by reduction with NaHSO3
•
Trans-1,2-diols: Acid-catalyzed hydrolysis of epoxides
•
There is a new nomenclature for cis and trans diols:
–
–
Select a reference substituent r (with lowest sequence
number or with higher Cahn-Ingold-Prelog priority)
Assign the other either cis (c) or trans (t) to the reference
1-methyl-r1,c2-cyclo-hexanediol
1-methyl-r1,t2-cyclo-hexanediol
Practice Problem: Predict the products of the following reactions:
(c) cis-5-decene
1. OsO4
2. NaHSO3
?
5.
Alcohols from Reduction of Carbonyl
Compounds
• Reduction of a carbonyl compound in general
gives an alcohol
– Note that organic reduction reactions add the equivalent
of H2 to a molecule
Reduction of Aldehydes and Ketones
•
•
Aldehydes are reduced to give primary alcohols
Ketones are reduced to give secondary alcohols
Reduction Reagent: Sodium Borohydride (NaBH4)
•
NaBH4 is not sensitive to moisture and it does not
reduce other common functional groups
–
It adds the equivalent of “H-”
Reduction Reagent: Lithium Aluminum Hydride (LiAlH4)
•
LiAlH4 is more powerful, less specific, and very
reactive with water
–
Like NaBH4, it adds the equivalent of “H-”
Reduction of Carboxylic Acids and Esters
•
Carboxylic acids and esters are reduced to give
primary alcohols
–
LiAlH4 is used because NaBH4 is not effective for
carboxylic acids and esters
Reduction Reagent: Lithium Aluminum Hydride (LiAlH4)
•
LiAlH4 is used because NaBH4 is not effective
–
It adds the equivalent of two “H-”
Mechanism of Reduction
•
The mechanism involves:
–
Addition of nucleophilic hydride ion, H-, to the positively
polarized electrophilic carbon of C=O to form an
alkoxide ion intermediate
–
Protonation of the alkoxide ion intermediate
Practice Problem: What carbonyl compounds would you reduce
to obtain the following alcohols?
Practice Problem: What reagent would you use to accomplish
each of the following reactions?
Practice Problem: What carbonyl compounds give the following
alcohols on reduction with LiAlH4? Show all
possibilities
6.
Alcohols from Reaction of Carbonyl
Compounds with Grignard Reagents
• Alkyl, aryl, and vinylic halides react with Mg in ether
or THF to generate Grignard reagents, RMgX
• Grignard reagents react with carbonyl compounds
to yield alcohols
Grignard addition to carbonyl compounds
•
Formaldehydes react with Grignard reagents to give
primary alcohols
Formaldehyde
•
Aldehydes react with Grignard reagents to give
secondary alcohols
•
Ketones react with Grignard reagents to give tertiary
alcohols
Examples of Reactions of Grignard Reagents with Carbonyl Compounds
•
Esters react with Grignard reagents to give tertiary
alcohols in which two of the substituents R on OHbearing carbon come from the Grignard reagent
•
Grignard reagents do not add to carboxylic acids
–
Base
They undergo an acid-base reaction, generating the
hydrocarbon of the Grignard reagent and the
carboxylic acid salt
+
Acid

Hydrocarbon
+
Salt
Limitations of the Grignard Reaction
•
Grignard reagents can't be prepared from alkylhalides
if there are reactive functional groups, FG, in the
same molecule, including proton donors:
Mechanism of the Addition of a Grignard Reagent
•
There are two steps:
–
Grignard reagents act as nucleophilic carbon anions
(carbanions, : R-) in adding to a carbonyl group
–
The intermediate alkoxide is then protonated to produce
the alcohol
Practice Problem: How would you use the addition of a Grignard
reagent to a ketone to synthesize 2-phenyl-2propanol?
Practice Problem: How would you use the reaction of a Grignard
reagent with a carbonyl compound to
synthesize 2-methyl-2-pentanol?
OR
Practice Problem: Show the products obtained from addition of
methylmagnesium bromide to the following
compounds:
a. Cyclopentanone
b. Benzophenone (diphenyl ketone)
c. 3-Hexanone
Practice Problem: Use a Grignard reaction to prepare the
following alcohols:
a. 2-Methyl-2-propanol
b. 1-Methylcyclohexanol
c. 3-Methyl-3-pentanol
d. 2-Phenyl-2-butanol
e. Benzyl alcohol
Practice Problem: Use the reaction of a Grignard reagent with a
carbonyl compound to synthesize the
following compound:
7.
Some Reactions of Alcohols
• There are two general classes of alcohol reactions:
– At the carbon of the C–O bond
– At the proton of the O–H bond
Dehydration of Alcohols to Yield Alkenes
•
Dehydration of alcohol involves loss of O-H and H of
the neighboring C–H to give a  bond (an alkene)
•
Specific reagents are needed:
– Acid catalysts (H3O+)
– Phosphorus oxychloride in pyridine (POCl3/pyridine)
Acid-Catalyzed Dehydration
•
Acid-catalyzed dehydration usually follows Zaitsev’s
rule
–
It produces the more stable (more highly substituted)
alkene
• It is an E1 process
with a three-step
mechanism:
– protonation of the
alcohol O
– spontaneous loss
of H2O to yield a
carbocation
intermediate
– loss of proton H+
from the
neighboring carbon
•
The reactivity order for acid-catalyzed dehydration is:
–
Tertiary alcohols are readily dehydrated with acid
–
Secondary alcohols require severe conditions (75%
H2SO4, 100°C) - Sensitive molecules don't survive
–
Primary alcohols require very harsh conditions –
Impractical
•
The reactivity order is the result of the stability of
the carbocation intermediate
Primary
Carbocation
<
Secondary
Carbocation
<
Tertiary
Carbocation
Dehydration with POCl3
•
Phosphorus oxychloride POCl3 in the amine solvent
pyridine can lead to dehydration of secondary 2o
and tertiary 3o alcohols at low temperatures
• It is an E2 process
via an intermediate
ester of POCl2:
– reaction of the
alcohol O with
POCl3 to form a
dichlorophosphate
intermediate
– abstraction of H+ by
pyridine and loss of
OPOCl2
Practice Problem: What product(s) would you expect from
dehydration of the following alcohols with
POCl3 in pyridine? Indicate the major product
in each case.
Conversion of Alcohols into Alkyl Halides
•
3° alcohols are converted into alkyl halides by HCl
or HBr at low temperature
SN1
•
1° and 2o alcohols are resistant to acid – They are
converted into alkyl halides by SOCl2 or PBr3
SN2
• The reaction of 3o
alcohol with HX
occurs by an SN1
mechanism:
– protonation of the
alcohol O
– spontaneous loss
of H2O to yield a
carbocation
intermediate
– Attack by
nucleophilic halide
ion on the
carbocation
•
The reactions of 1o and 2o alcohols with SOCl2 or PBr3
occur by SN2 mechanisms:
– Reaction of SOCl2 or PBr3 converts the OH into OSOCl or
OPBr2 (better leaving groups than OH)
– Backside nucleophilic substitution of Cl- or Br- expels
OSOCl or OPBr2
Conversion of Alcohols into Tosylates
•
Alcohols react with p-toluenesulfonyl chloride (tosyl
chloride, p-TosCl) in pyridine to yield alkyl tosylates,
ROTos
–
Formation of the tosylate does not involve the C–O
bond so configuration at a chirality center is maintained
–
Alkyl tosylates behave like alkyl halides (SN1 and SN2
reaction)
•
Stereochemical Uses of Tosylates
–
The SN2 reaction of an alcohol via an alkyl halide
proceeds with two inversions, giving product with same
absolute stereochemistry as starting alcohol
–
The SN2 reaction of an alcohol via a tosylate, produces
one inversion at the chirality center, giving product with
opposite absolute stereochemistry to starting alcohol
Practice Problem: How would you carry out the following
transformation, a step used in the synthesis
of (S)-ibuprofen?
8.
Oxidation of Alcohols
• Alcohols undergo oxidation reactions to yield
carbonyl compounds
•
•
•
Primary alcohols yield aldehydes or carboxylic acids
Secondary alcohols yield ketones
Tertiary alcohols do not react with oxidizing agents
•
The oxidation of primary and secondary alcohols can
be accomplished by inorganic reagents, such as
KMnO4, CrO3, and Na2Cr2O7 or by more selective,
expensive reagents
Oxidation of Primary Alcohols
•
Primary alcohols are converted to
– aldehydes via pyridinium chlorochromate (PCC,
C5H6NCrO3Cl) in dichloromethane
– carboxylic acids via other reagents (CrO3, …)
Oxidation of Secondary Alcohols
•
Secondary alcohols are converted to ketones
– This is effective with inexpensive reagents such as
Na2Cr2O7 in acetic acid
– PCC is used for sensitive alcohols at lower
temperatures
Mechanism of Chromic Acid Oxidation
•
It is an E2-like mechanistic pathway:
–
•
Alcohol reacts with Cr(VI) to form a chromate ester
followed by elimination of H+s and expulsion of Cr (the
leaving group) to give carbonyl product
The mechanism was determined by observing the
effects of isotopes on rates
Practice Problem: What alcohols would give the following
products on oxidation?
Practice Problem: What products would you expect from
oxidation of the following compounds with
CrO3 in aqueous acid? With pyridinium
chlorochromate?
a. 1-Hexanol
b. 2-Hexanol
c. Hexanal
9.
Protection of Alcohols
• Hydroxyl groups can easily transfer their proton to
a basic reagent
– This can prevent desired reactions
• Converting the hydroxyl to a (removable) functional
group without an acidic proton protects the alcohol
•
When one functional group in a molecule interferes
with an intended reaction, it is possible to avoid the
problem by protecting the interfering functional group
by:
1. introducing a protecting group to block the
interfering function
1. carrying out the desired reaction
1. removing the protecting group
Common Method to Protect Alcohols
•
Reaction with chlorotrimethylsilane in the presence of
base yields an unreactive trimethylsilyl (TMS) ether
–
The base (usually triethylamine) helps to form the
alkoxide anion and to remove the HCl by-product
•
The ether can be cleaved with acid or with fluoride
ion to regenerate the alcohol
–
The ether has no acidic H’s and is protected from
oxidizing agents, reducing agents, and Grignard reagents
Protection-Deprotection: An Example
•
Use of TMS-alcohol protection during Grignard
reaction of 3-bromo-1-propanol to acetaldehyde
•
A nucleophile reacts with Si of TMS via SN2 even
though Si is a 3o center
– Si is less hindered. It is larger than C and forms
longer bonds
Practice Problem: TMS ethers can be removed by treatment
with fluoride ion as well as by acid-catalyzed
hydrolysis. Propose a mechanism for the
reaction of cyclohexyl TMS ether with LiF.
Fluorotrimethylsilane is a product.
10. Preparation and Uses of Phenols
• Phenols can be prepared by:
– reaction of chlorobenzene with NaOH at high
temperature and pressure
– reaction of cumene (isopropylbenzene) with O2,
followed by treatment with acid
– alkali fusion of aryl sulfonate
•
Phenol is prepared on an industrial scale by treatment
of chlorobenzene with dilute aqueous NaOH at 340°C
under high pressure
• Another industrial process of phenol synthesis
involves readily available cumene and O2/H3O+
– It forms cumene hydroperoxide with O2 at high
temperature
– It is converted into phenol and acetone by acid (H3O+)
• Cumene hydroperoxide
is acid-catalyzed to form
phenol:
– protonation of O
– rearrangement of the
phenyl group from C to O
with simultaneous loss of
H 2O
– readdition of H2O then
yields a hemiacetal
intermediate, which breaks
down to phenol and
acetone
• A laboratory preparation of phenols involves melting
aromatic sulfonic acids with NaOH at high
temperature
– It is limited to the preparation of alkyl-substituted phenols
• Phenol is the starting material for synthesis of
– chlorinated phenols (eg. pentachlorophenol, 2,4-D,
hexachlorphene,…)
• Phenol is the starting material for synthesis of
– food preservatives BHT (butylated hydroxytoluene)
and BHA (butylated hydroxyanisole)
Practice Problem: p-Cresol (p-methylphenol) is used both as
an antiseptic and as a starting material to
prepare the food additive BHT. How would
you prepare p-cresol from benzene?
Practice Problem: Show the mechanism of the reaction of pmethylphenol with 2-methylpropene and
H3PO4 catalyst to yield the food additive BHT
11. Reactions of Phenols
• Phenols can undergo:
– Electrophilic Aromatic Substitution Reactions
– Oxidations
Electrophilic Aromatic Substitution Reactions
•
The hydroxyl group is strongly activating, ortho- and
para-directing
•
Phenols are highly reactive substrates for electrophilic
aromatic reactions:
– halogenation,
– nitration,
– sulfonation, and
– Friedel–Crafts reactions
Oxidation of Phenols: Quinones
•
Reaction of a phenol with strong oxidizing agents
yields a quinone (or 2,5-cyclohexadiene-1,4-dione)
–
Fremy's salt [(KSO3)2NO, potassium nitrosodisulfonate]
works under mild conditions through a radical
mechanism
Oxidation-reduction of quinones
•
Quinones can be easily reduced to hydroquinones
(p-dihydroxybenzenes) by NaBH4 or SnCl2
•
Hydroquinones can be easily reoxidized to quinones
by Fremy's salt
Quinones in nature
•
Ubiquinones, also called coenzymes Q, mediate
electron-transfer processes involved in energy
production through their redox reactions
12.
Spectroscopy of Alcohols and Phenols
• Alcohols and phenols can be identified by
– Infrared Spectroscopy
– Nuclear Magnetic Resonance Spectroscopy
– Mass Spectrometry
Infrared Spectroscopy
•
Alcohols have a characteristic O–H stretching
absorption at 3300 to 3600 cm-1 in the IR spectrum
–
Sharp absorption near 3600 cm-1 except if H-bonded:
then broad absorption 3300 to 3400 cm-1 range
–
Strong C–O stretching absorption near 1050 cm-1
Cyclohexanol
•
Phenol OH absorbs near 3500 cm-1
Practice Problem: Assume that you need to prepare 5-cholestene3-one from cholesterol. How could you use IR
spectroscopy to tell whether the reaction was
successful? What differences would you look for
in the IR spectra of starting material and
product?
Nuclear Magnetic Resonance Spectroscopy
•
13C
NMR: C bonded to electron-withdrawing -OH
is deshielded and absorbs at a lower field, d 50 to
80
•
•
1H
NMR: H bonded on the O-bearing C is deshielded
by electron-withdrawing effect of the nearby O; it
absorbs at d 3.5 to 4.5
–
Usually no spin-spin coupling between O–H proton
and neighboring protons on C due to exchange
reactions with moisture or acids
–
Spin–spin splitting is observed between protons on the
oxygen-bearing carbon and other neighbors
Phenol O–H protons absorb at d 3 to 8
–
Usually no spin-spin coupling between O–H proton
and neighboring protons on C due to exchange
reactions with moisture or acids
Adding D2O makes the OH proton absorption disappear
–
Spin–spin splitting is observed between protons on the
oxygen-bearing carbon and other neighbors
Example: 1-propanol
Practice Problem: When the 1H NMR spectrum of an alcohol is
run in DMSO solvent rather than chloroform,
exchange of the OH proton is slow and spinspin splitting is seen between the OH proton
and CH protons on the adjacent carbon. What
spin multiplicities would you expect for the
hydroxyl protons in the following alcohols?
a. 2-Methyl-2-propanol
d. 2-propanol
b. Cyclohexanol
e. Cholesterol
c. Ethanol
f.
1-Methylcyclohexanol
Mass Spectrometry
•
Alcohols undergo:
– alpha () cleavage, a C–C bond nearest the
hydroxyl group is broken, yielding a neutral radical
plus a charged oxygen-containing fragment
– dehydration, loss of H-OH yielding an alkene
radical cation
– alpha () cleavage: a C–C bond nearest the
hydroxyl group is broken, yielding a neutral radical
plus a charged oxygen-containing fragment
– Dehydration: loss of H-OH yielding an alkene
radical cation
•
Example: Mass spectrum of 1-butanol
Chapter 17