Reactions

of Alcohols

Alcohols can be oxidized to aldehydes, carboxylic acids, and ketones. Normally, C
H bonds can be converted to CO bonds, but CC bonds cannot. In the oxidation of
alcohols by CrO3, if the alcohol is primary, it will go all the way to the carboxylic
acid. We wont worry about the mechanism, but water is essential in this
conversions. If the reactions conditions are kept dry, the oxidation of a primary
alcohol by CrO3 will proceed to the aldehyde and stop. The conditions used are PCC
and CH2Cl2. CH2Cl2 is an organic solvent that is easy to keep dry. PCC is pyridinium
chlorochromate, effectively a form or variant of CrO3 that is soluble in CH2Cl2.

Addition to carbonyls: Carbonyls are electrophilic. They have a partial positive
charge at the carbonyl carbon as evident by resonance structures. Thus,
nucleophiles can add to them readily. One such nucleophile we will look at later is
water, which is key to the oxidation of aldehydes to carboxylic acids. But we will
start with hydrides, which add to carbonyls and reduce them. A hydride is an H. It
is coordinated to a metal; the nature of this coordination modulates the reactivity of
the hydride. NaBH4 is sodium borohydride. It can reduce a ketone to a secondary
alcohol or an aldehyde to a primary alcohol. Mechanistically, the hydride may be
drawn as if free in solution, but it is always coordinated to a boron. Note that if the
reactive center is a new stereogenic center, the products may be a racemic mixture
or a mixture of diastereomers. In the case of a racemate, addition to the carbonyl
occurs equally to each side, as the (products and the) transition states are
enantiomers of each other and are therefore of equal energy. In the case of
formation of diastereomers, the transition states are diasteromeric, thus of different
energy, and do not form in equal amounts. It is often difficult to predict which
diastereomer will predominate; the ratio may be close to 50:50.

Grignards (Nobel Prize 1912): Grignards are essentially a carbon equivalent of a
hydride. They are carbanions, carbon anions. They are always coordinated to a
metal (Mg for Grignards) as they are too reactive to exist alone. They are still
reactive as nucleophiles (and as bases). They are not stable in protic solvents such
as water and alcohols, as they will act as bases and be neutralized. The pKa of
alkanes are 40-50, whereas that of alcohols are 15-20. The immediate product of
addition of a Grignard to a ketone or aldehyde is an alkoxide, which is neutralized in
a subsequent workup step: some form of acid is added so the neutral product is
formed, which is much easier to isolate. Note that the trajectory of attack of a
nucleophile on a carbonyl is from about 45 to the plane of the carbonyl. This way
the nucleophile can form a bond with the orbital that was a p-orbital and becomes
an sp3 orbital (other anti-bonding orbital overlap arguments are often made).

Organic Synthesis: How do you make complex molecules from simpler precursors?
One approach is to work backwards by doing a retro-synthetic analysis.

Acetals and Hemiacetals: We alluded to water adding to carbonyls (to form
hydrates of carbonyls) in our discussion of oxidation of aldehydes. We will discuss

the analogous reaction with alcohols more explicitly. An alcohol can add to an
aldehyde to yield a hemiacetal. Addition of a second alcohol yields an acetal.
Formation of a hemiacetal is fast and can occur under mildly acidic conditions or
under basic conditions. Hemiacetals are usually not very stable; equilibrium will lie
either toward the aldehyde or the acetal depending on the amount of water/alcohol
present (Le Chatelier). Acetal formation requires moderately strong acidic
conditions. Ketones undergo the same transformation. The corresponding products
are ketals and hemiketals, but it is common to call them acetals and hemiacetals
even though these terms are not precise. Under basic conditions, dilute alkoxide in
alcohol, the alkoxide is present in sufficient concentrations to act as the nucleophile
(over the more abundant but less nucleophilic alcohol). The alkoxide is sufficiently
nucelophilic to attack an aldehyde or ketone. Under mildly acidic conditions, the
nucleophile is the alcohol, which is usually not nucleophilic enough to attack a
neutral carbonyl. The role of the acid is to protonate the carbonyl. This makes the
carbonyl far more electrophilic. Although the amount of protonated carbonyl will be
low, it reacts quickly. Again, hemiacetals are generally not very stable. An exception
is a cyclic hemiacetal (which are crucial in carbohydrate chemistry). Again, acetal
formation requires stronger acid. The reaction is typically driven by the absence of
water (the solvent is typically the alcohol forming the acetal). Hydrolysis of an
acetal, the reverse of its formation, is likewise driven by the preponderance of water
over alcohol.

Carbohydrates: As the name suggests, these are hydrates of carbon. They are
polyhydroxylated aldehydes and ketones. They are one of the three most prevalent
biomolecules (proteins/amino acids and nucleic acids being the other two). Most
sugars exist as cyclic hemiacetals in water, as these are thermodynamically more
stable than the open hydroxyl-carbonyl form. Sugars such as glucose can link to each
other to form oligosaccharides. One example is cellulose, which is found in plants,
paper, and cotton. Cellulose is digested by cows but not humans. Starch (in potatoes,
rice, etc.) is a similar source of energy, but is digestible by humans. Note the small
difference in their structure. Humans have enzymes that recognize starch but not
cellulose, which illustrates the selectivity of enzymes.

H OH
H
H OH
H

H
O

OH

H
H

OH
H

OH

H OH

OH
H

Cellulose

OH

O
H

O
H

OH

OH

OH

Starch

H
OH
O

Carboxylic Acid and Derivatives: Acid chlorides are isolable, but reactive species
that can be converted to many other species.

H2O
R
O

OH
O

R'OH
R

Cl

OR'

R'NH2

The reaction mechanisms all involve addition of a nucleophile to the carbonyl to
yield first a tetrahedral intermediate, which then collapses to reform the carbonyl,
kick out the leaving group (Cl) and reform the sp2 hybridization.

Polyester: Fabrics used in clothing formed by polymerizing a diol (two alcohols in
one molecule) and a di-acid chloride.

R

Cl

NHR'

Cl

OH
HO

O
O

Dacron

Polyamide: Likewise, a diamine and a di-acid chloride can yield a polyamide.
Examples: (1) nylon 66 (Dupont 1935): used in fibers, clothing, tires, bearings,
parachutes (WWII), and stockings.

O
H 2N

(CH 2)6

NH 2

Cl

O
(CH 2)4

O
Cl

HN

(CH 2)6

H
N

O
(CH 2)4

nylon 66
(2) Another polyamide is Kevlar, which is used for body armor as it makes a very
tough material.

H 2N

NH 2
H
N

+
Cl

NH

O
O

n
O

Cl

Kevlar

Proteins, enzymes, and peptides are common biopolymers that are polyamides.
There are 20 common amino acids that comprise proteins. Three are shown below.

The amide bonds that connect amino acids in proteins are called peptide bonds. The
peptide bond is planar due to the significant amount of double-bond character they
have as demonstrated by resonance structures. Likewise, protonation of an amide
will occur at the carbonyl oxygen, not the nitrogen due to the partial negative charge
on the O and the partial positive charge on the N. Finally, rotation about the CN
bond occurs on the seconds to minutes timescale.

R

O
R

CO2H

polymerize

H
N

H 2N
N
H

(enzymes)

NH 2

OH

n
R

Protein, Enzyme, Peptide

Alanine, R = CH3
Serine, R = CH2OH
Glutamic Acid, R = CH2CH2CO2H

Ester Hydrolysis: Esters can be hydrolyzed under either acidic or basic conditions.
The same principles hold that pertained to acetal formation, including the formation
of a tetrahedral intermediate. Under basic conditions, hydroxide is a strong enough
nucleophile to attack an ester carbonyl. Under acidic conditions, there is an
insufficient concentration of hydroxide for the rate of its attack on the carbonyl to
be significant. Water is too weak a nucleophile to attack the carbonyl of an ester.
Protonation of the ester makes the carbonyl far more electrophilic, enough that
water will attack at an appreciable rate. Hydrolysis in base is often called
saponification. Saponification of fats leads to fatty acids (actually their conjugate
bases) and glycerol. The conjugate base of fatty acids have anionic ends and non-
polar ends. In water, they aggregate into a sphere called a micelle that acts as a soap
by positioning the polar ends toward water and their nonpolar ends together in the
center. Nonpolar molecules are thus attracted to and entrapped by the micelle.

O
H 2C

O O

NaOH

HC
O O

H 2C
O

Animal Fat

n
n = 4-12

H 2C

OH

HC

OH

H 2C

OH

glycerol

O
O

Fatty Acid
(Soap)



Esterification: The reverse of ester hydrolysis. The reaction is done in the alcohol
as solvent so as to drive the equilibrium to the ester. It is done under acidic
conditions. Under basic conditions, the carboxylate forms and it is non-electrophilic.

Transesterification: A methyl ester for example can be converted to an ethyl ester.
This can be done under either acidic of basic conditions.

Amide Hydrolysis: Amides can also be hydrolyzed under acidic or basic conditions.
Although amides are more difficult to hydrolyze than esters, sufficient heat gets the
reaction to go.