ALCOHOLS AND PHENOLS

Organic Chemistry

DITA FLORESYONA
OUTLINE

1. Structure and properties of alcohols 8. Preparation of phenols

2. Acidity of alcohols and phenols 9. Reaction of alcohol: Substitution and
3. Preparation of alcohols via substitution or Elimination
addition 10. Reaction of alcohols: Oxidation
4. Preparation of alcohols via reduction 11. Biological redox reaction
5. Preparation of diols 12. Oxidation of phenols
6. Preparation of alcohols via Grignard reagents 13. Synthesis strategies
7. Protection of alcohols
1. STRUCTURE AND PROPERTIES OF ALCOHOLS
Alcohols are compounds that possess a hydroxyl group (OH) and are characterized by names ending in “ol”:

A vast number of naturally occurring compounds contain the hydroxyl group. Here are just a few examples.
Phenol is a special kind of alcohol. It is comprised of a hydroxyl group attached directly to a phenyl ring. Substituted phenols are
extremely common in nature and exhibit a wide variety of properties and functions, as seen in the following examples.
Commercially Important Alcohols
Methanol (CH3OH)
▪ The simplest alcohol.
▪ It is toxic, and ingestion can cause blindness and death, even in small quantities.
▪ Industrially, methanol is prepared by the reaction between carbon dioxide (CO2) and hydrogen gas (H2) in
the presence of suitable catalysts.

Ethanol (CH3CH2OH)
▪ Obtained from the fermentation of grains or fruits, a process that has been widely used for thousands of years
▪ Industrially, ethanol is prepared via the acid-catalysed hydration of ethylene.

Isopropanol
▪ Also called rubbing alcohol, is prepared industrially via the acid-catalyzed hydration of propylene.
▪ Isopropanol has antibacterial properties and is used as a local antiseptic.
Physical Properties of Alcohols
The physical properties of alcohols are quite different from the physical properties of alkanes or alkyl halides. For
example, compare the boiling points for ethane, chloroethane, and ethanol.

The boiling point of ethanol is much higher than the other two compounds as a result of the hydrogen-bonding
interactions that occur between molecules of ethanol.
Physical Properties of Alcohols

These interactions are fairly strong intermolecular forces, and they are also critical in understanding how alcohols
interact with water.

As the size of the hydrophobic region increases, solubility in water decreases. For example, octanol exhibit
extremely low solubility in water at room temperature. Alcohols with more than eight carbon atoms, such as nonanol
and decanol, are considered to be insoluble in water.
2. ACIDITY OF ALCOHOLS AND PHENOLS
Acidity of the Hydroxyl Functional Groups
The acidity of a compound can be qualitatively evaluated by analysing the stability of its conjugate base:
Acidity of the Hydroxyl Functional Groups
The conjugate base of an alcohol is called an alkoxide ion, and it exhibits a negative charge on an oxygen atom.
A negative charge on an oxygen atom is more stable than a negative charge on a carbon or nitrogen atom but less
stable than a negative charge on a halogen, X

Therefore, alcohols are more acidic than amines and alkanes but less acidic than hydrogen halides
Reagents for Deprotonating an Alcohol
There are two common ways to deprotonate an alcohol, forming an alkoxide ion.

1. A strong base can be used to deprotonate the alcohol. A commonly used base is sodium hydride (NaH), because
hydride (H-) deprotonates the alcohol to generate hydrogen gas, which bubbles out of solution:

2. Alternatively, it is often more practical to use Li, Na, or K. These metals react with the alcohol to liberate hydrogen
gas, producing the alkoxide ion.
Factors Affecting the Acidity of Alcohols and Phenols
1. Resonance. One of the most significant factors affecting the acidity of alcohols is resonance. As a striking
example, compare the pKa values of cyclohexanol and phenol:

When phenol is deprotonated, the conjugate base is stabilized by resonance.

Factors Affecting the Acidity of Alcohols and Phenols

Resonance stabilization of the phenoxide ion explains why phenol is eight orders of magnitude (100,000,000 time)
more acidic than cyclohexanol.As a result, phenol does not need to be deprotonated with a very strong base like
sodium hydride. Instead, it can be deprotonated by hydroxide.
Factors Affecting the Acidity of Alcohols and Phenols
2. Induction. Another factor in comparing the acidity of alcohols is induction. As an example, compare the pKa
values of ethanol and trichloroethanol.

Trichloroethanol is four orders of magnitude (10,000 times) more acidic than ethanol, because the conjugate
base of trichloroethanol is stabilized by the electron-withdrawing effects of the nearby chlorine
atoms.
Factors Affecting the Acidity of Alcohols and Phenols
3. Solvation effects. To explore the effect of alkyl branching, compare the acidity of ethanol and tert-butanol.

This difference in acidity is best explained by a steric effect. The ethoxide ion is not sterically hindered and is therefore
easily solvated (stabilized) by the solvent, while tert-butoxide is sterically hindered and is less easily solvated. The
conjugate base of tert-butanol is less stabilized than the conjugate base of ethanol, endering tert-butanol less acidic.
 3. PREPARATION OF ALCOHOLS VIA SUBSTITUTION OR
ADDITION
Substitution Reactions
Alcohols can be prepared by substitution reactions in which a leaving group is replaced by a hydroxyl group.

A primary substrate will require SN2 conditions (a strong nucleophile), while a tertiary substrate will require SN1
conditions (a weak nucleophile).
Addition Reactions
Several addition reactions that produce alcohols:

Markovnikov addition

Anti-Markovnikov addition
4. PREPARATION OF ALCOHOLS VIA REDUCTION
Involves a change in oxidation state

Oxidation state
Oxidation state
A carbon atom with four bonds will always have no formal charge, but its oxidation state can range anywhere from
−4 to +4.
Reducing Agents

Three reducing agents that can be used to convert a ketone or aldehyde to an alcohol:

1. An alkene can undergo hydrogenation in the presence of a metal catalyst such as platinum, palladium, or nickel. A
similar reaction can occur for ketones or aldehydes, although more forcing conditions are generally required
(higher temperature and pressure).
Reducing Agents
2. Sodium borohydride (NaBH4) is another common reducing agent that can be used to reduce ketones or
aldehydes.

Sodium borohydride functions as a source of hydride (H:−) and the solvent functions as the source of a proton (H+).
The solvent can be ethanol, methanol, or water.
Reducing Agents
3. Lithium aluminum hydride (LAH) is another common reducing agent, and its structure is very similar to NaBH4.

It reacts violently with water, and therefore, a protic solvent cannot be present together with LAH in the reaction
flask. First the ketone or aldehyde is treated with LAH, and then, in a separate step, the proton source is added to the
reaction flask. Water (H2O) can serve as a proton source, although H3O+ can also be used as a proton source:
 When treated with a hydride reducing agent, only the carbonyl
group is reduced. Incontrast, catalytic hydrogenation will also
reduce the C = C bond under the conditions required to
reduce the carbonyl group (high temperature and pressure). For
this reason, hydride reducing agents such as NaBH4 and LAH are
generally preferred over catalytic hydrogenation.

LAH is much more reactive than NaBH4. As a

result, LAH is less selective. LAH will react with a
carboxylic acid or an ester to produce an alcohol,
but NaBH4 will not.
5. PREPARATION OF DIOLS
Diols are compounds with two hydroxyl groups, and the following additional rules are used to name them:
1. The positions of both hydroxyl groups are identified with numbers placed before the parent.
2. The suffix “diol”is added to the end of the name:

Notice that an “e” appears in between the parent and the suffix.In a regular alcohol,the “e” is dropped (i.e., propanol
or hexanol).A few simple diols have common names that are accepted by IUPAC nomenclature.
 6. PREPARATION OF ALCOHOLS VIA GRIGNARD REAGENTS

A Grignard reagent is formed by the reaction between an alkyl halide and magnesium.

A couple of specific examples of Grignard reagents.

A Grignard reagent is characterized by the presence of a C-Mg bond. Carbon is more electronegative than magnesium,
so the carbon atom withdraws electron density from magnesium via induction. This gives rise to a partial negative
charge (δ−) on the carbon atom. In fact, the difference in electronegativity between C and Mg is so large that the bond
can be treated as ionic.
The mechanism is similar to the mechanism of reduction via hydride reagents (LAH or NaBH4). In fact, the reaction here is
also a reduction, but it involves introduction of an R group.

Notice that water is added to the reaction flask in a separate step (similar to reduction with LAH). Water cannot be present
together with the Grignard reagent, because the Grignard reagent is also a strong base and will deprotonate water.
Preparation of Alcohols via Grignard Reagents
A Grignard reagent will react with a ketone or an aldehyde to produce an alcohol.

Grignard reagents also react with esters to produce alcohols, with introduction of two R groups.
Preparation of Alcohols via Grignard Reagents
Preparation of Alcohols via Grignard Reagents
A Grignard reagent will not attack the carbonyl group of a carboxylic acid. Instead, the Grignard reagent will simply
function as a base to deprotonate the carboxylic acid.

In other words, a Grignard reagent is incompatible with a carboxylic acid. For similar reasons, it is not possible to
form a Grignard reagent in the presence of even mildly acidic protons, such as the proton of a hydroxyl group.

This Grignard reagent cannot be formed, as it will simply attack itself to produce an alkoxide.
7. PROTECTION OF ALCOHOLS

To achieve this transformation via a Grignard reaction, the following Grignard reagent would be required:

As we saw in the previous section, it is not possible to form this Grignard reagent, because of incompatibility with
the hydroxyl group. (it will simply attack itself to produce an alkoxide). To circumvent this problem, we employ
a three-step process.
1. Protect the hydroxyl group by removing its proton and converting the hydroxyl group into a new group, called a protecting
group, that is compatible with a Grignard reagent.

2. Form the Grignard reagent and perform the desired Grignard reaction.

3. Deprotect, by converting the protecting group back into a hydroxyl group.

 Protection of Alcohols

The protecting group enables us to perform the desired Grignard reaction.

Protection of Alcohols
One such example of a protecting group is the conversion of the hydroxyl group into a trimethylsilyl ether.

This protecting group is abbreviated as OTMS. The trimethylsilyl ether is formed via the reaction between an
alcohol and trimethylsilyl chloride, abbreviated TMSCl.
Protection of Alcohols
After the desired Grignard reaction has been performed, the trimethylsilyl group can be removed easily with either
H3O+ or fluoride ion.

A commonly used source of fluoride ion is tetrabutylammonium fluoride (TBAF).

Protection of Alcohols
8. PREPARATION OF PHENOLS
Phenol is prepared industrially via a multistep process involving the formation and oxidation of cumene.

❑ A by-product of this process is acetone

❑ Phenol is used as a precursor in the synthesis of a wide variety of pharmaceuticals and other commercially useful
compounds, including bakelite (a synthetic polymer made from phenol and formaldehyde), adhesives for plywood, and
antioxidant food additives
9. REACTION OF ALCOHOLS: SUBSTITUTION AND
ELIMINATION
SN1 Reactions with Alcohols
Tertiary alcohols will undergo a substitution reaction when treated with a hydrogen halide.

We saw that this reaction proceeds via an SN1 mechanism.

SN2 Reactions with Alcohols
1. Primary alcohols will react with HBr via an SN2 process.

This reaction works well for HBr but does not work well for HCl. To replace the hydroxyl group with chloride, ZnCl2
is used as a catalyst.

The catalyst is a Lewis acid that converts the hydroxyl group into a better leaving group.
SN2 Reactions with Alcohols
2. An alcohol can be converted into a tosylate, followed by nucleophilic attack
SN2 Reactions with Alcohols
3. Primary and secondary alcohols react with SOCl2 or PBr3 via an SN2 process
Identify the reagents and draw the mechanism!
10. REACTIONS OF ALCOHOLS: OXIDATION

The outcome of an oxidation process depends on whether the starting alcohol is primary, secondary, or tertiary.
Let’s first consider the oxidation of a primary alcohol.