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SCH 206 LECTURE NOTES

Research · February 2017

DOI: 10.13140/RG.2.2.30806.24643

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 SCH 206

SCH 206
Course outline
Aldehydes and Ketones;
Carboxylic Acids;
Carboxylic Acids derivatives;
R1
Amines
N R2
and Phenols
R3
Structure,
Nomenclature,
Synthesis and
Dr. Solomon Derese
Reactions 1
 SCH 206

Dr. Solomon Derese; Chemistry Department

Room 118; [email protected]

Recommended text books

1. Organic Chemistry, John McMurry

2. Organic Chemistry, Francis Carry
3. Organic Chemistry, Solomons T.W.G.

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 SCH 206

Science is the knowledge

of consequences and
dependence of one fact
upon another

Thomas Hobbes (1588–1679)

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 O SCH 206

Carbonyl Compounds
R Z
Two broad classes of compounds contain the carbonyl
group:
I. Compounds that have only carbon and hydrogen
atoms bonded to the carbonyl group (Aldehydes and
Ketones).
O

R R'
Aldehyde Ketone
An aldehyde has at least one H atom bonded to the
carbonyl group. A ketone has two alkyl or aryl groups
bonded to the carbonyl group.
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 SCH 206

II. Compounds that contain an electronegative atom

bonded to the carbonyl group (Carboxylic acids and
their derivatives).

Each of these compounds contains an electronegative

atom (Cl, O or N) capable of acting as a leaving group.
The presence or absence of a leaving group on the
carbonyl carbon determines the type of reactions
these compounds undergo.
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 SCH 206

Nature of the Carbonyl Group

The double bond between carbon and oxygen is
similar to an alkene C=C double bond. The carbonyl
carbon is sp2-hybridized and forms three bonds.

R1 R2

R3 R4

Alkene
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 SCH 206

Alkene Carbonyl
p-bond p-bond
d-bond d-bond

C C 120° 120° C O

sp2 orbital sp2 orbital

2p orbital
2p orbital

The C=O double bond is similar to a C=C double

bond, except that it is shorter, stronger, and
polarized.
Bond Bond distance Bond energy Dipole moment
C=C 134 pm 611 KJ/mol 0.3 D
C=O 122 pm 745 KJ/mol 2.5 D
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 SCH 206

The difference between the alkene double bond and

the carbonyl double bond arises from the different
electronegativities of the elements involved. Oxygen is
more electronegative than carbon (3.5 compared with
2.5); therefore, a carbon-oxygen double bond is polar, with
oxygen bearing a partial negative charge and carbon
bearing a partial positive charge.
The carbon carries a partial
positive charge, is an electrophilic
site, and reacts with nucleophiles.
Conversely, oxygen atom carries a
partial negative charge, is a
nucleophilic site, and reacts with
electrophiles.
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 SCH 206

Electronegativity
Nucleophilic (electron rich)
Reacts with electrophiles, e.g. H+

Electrophilic (electron deficient)

Reacts with nucleophiles

Uncrowded SP2 carbon

The electrophilicity of a carbonyl group derives
from resonance effects as well as inductive effects.

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 SCH 206

The reactivity of carbonyl compounds is due to the

polarity of the carbonyl group that results from oxygen
being more electronegative than carbon. The carbonyl
carbon is therefore electron deficient (an electrophile). So
we can safely predict that it will be attacked by
nucleophiles.

As a result, carbonyl compounds react with nucleophiles.

:Nu

Planar (sp2) Tetrahedral intermediate (sp3)

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 SCH 206

When a nucleophile adds to the carbonyl carbon

the weakest bond in the molecule - the carbon-
oxygen double bond (p-bond) breaks forming a
tetrahedral intermediate.
When a carbonyl group is attacked by a
nucleophile, the carbon atom undergoes a change
in hybridization (sp2 to sp3) and geometry (planar
to tetrahedral).
The outcome of nucleophilic attack, however,
depends on the identity of the carbonyl starting
material. It depends on whether Z is a leaving
group or not.
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 SCH 206

I. Reactions of carbonyl compounds when Z is not

a leaving group – Nucleophilic addition

Nucleophilic Addition Reaction

Aldehydes (Z = H) and ketones (Z = R) undergo

nucleophilic addition as neither H or R are leaving
groups.

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 SCH 206

Mechanism of Nucleophilic Addition Reaction

Step I: Nucleophilic attack

Tetrahedral intermediate
The nucleophile (:Nu–H) attacks the electrophilic
carbonyl. As the new bond to the nucleophile forms,
the p bond is broken, moving an electron pair out on
the oxygen atom. This forms an sp3 hybridized
intermediate.
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 SCH 206

Step II: Proton transfer

OH

R1 H (R2)
Nu

Proton (Hydrogen) transfer from the positively

charged nucleophile to the negatively charged
oxygen forming neutral addition product.
The net result is that the p bond is broken, two
new d bonds are formed, and the elements of H
and Nu are added across the p bond.
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 SCH 206

Stereochemistry of the Nucleophilic Addition Reaction

H-Nu:

Racemic
mixture

H-Nu:
The carbonyl carbon is planar and nucleophiles can attack
it from either side (bottom as well as top face) equally. As
a result, the carbonyl addition product will consist of a
racemic mixture.
Dr. Solomon Derese
 SCH 206

II. Reactions of carbonyl compounds when Z is a

leaving group – Nucleophilic Acyl substitution

Z= –OH (carboxylic acid), –OR (ester),

–Cl (acid chloride), –NH2 (amide), or
–OCOR (acid anhydride)

Nucleophilic Acyl Substitution Reaction

Carbonyl compounds that contain leaving groups

(electronegative elements) undergo Nucleophilic
Acyl Substitution Reaction.
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 SCH 206

Mechanism of Nucleophilic Acyl Substitution

Reaction
Step I: Nucleophilic attack

Tetrahedral intermediate
The nucleophile (:Nu–H) attacks the electrophilic
carbonyl, forming an sp3 hybridized intermediate.
This step is identical to nucleophilic addition.
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 SCH 206
Step II: Loss of a leaving group

O
Z

R1 Z:
Nu
H

Because the intermediate contains an electronegative

atom Z which can act as a leaving group. To do so, an
electron pair on oxygen re-forms the p bond, and Z
leaves with the electron pair in the C – Z bond.
The net result is that Nu replaces Z, a nucleophilic
substitution reaction. This reaction is called
Nucleophilic Acyl Substitution.
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 SCH 206

A compound that has an sp3 carbon bonded to an

oxygen atom generally will be unstable if the sp3
carbon is bonded to another electronegative
element. The tetrahedral intermediate, therefore,
is unstable because Z and Nu are both
electronegative atoms.
For an aldehyde or ketone to undergo nucleophilic
acyl substitution reaction, the tetrahedral
intermediate would need to eject a hydride ion
(H:-) or an alkanide ion (R:-). Both are very
powerful bases, and both are, therefore, very
poor leaving groups.
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 SCH 206

Reactions like this do not occur

with aldehydes and ketones
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 SCH 206

Comparison of Carbonyl Reaction Types

I. Nucleophilic addition and nucleophilic acyl
substitution involve the same first step—
nucleophilic attack on the electrophilic carbonyl
carbon to form a tetrahedral intermediate.
II. The difference between the two reactions is
what then happens to the intermediate.
III. Aldehydes and ketones cannot undergo
substitution because they do not have a good
leaving group bonded to the newly formed sp3
hybridized carbon.

Dr. Solomon Derese 21

 SCH 206

Reactivity of carbonyl compounds

The reactivity of the carbonyl group towards
nucleophiles is dependent on:

I. The electrophilicity of the carbonyl carbon

The relative reactivities of carbonyl

O compounds with nucleophiles is mainly
attributed to the amount of positive charge
R1 Z on the carbonyl carbon.
A greater positive charge means higher reactivity. If the
partial positive charge is dispersed throughout the
molecule, then the carbonyl compound is more stable
and less reactive.
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 SCH 206

In general electron withdrawing groups increase

the electrophilicity of the carbonyl carbon while
electron donating groups decrease the
electrophilicity of the carbonyl carbon.
II. The accessibility of the carbonyl carbon
Sterically hindered carbonyl compound react
slower with nucleophiles as a result aldehydes (one
alkyl group) are more reactive than ketones (two
alkyl groups) .

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 SCH 206

In general, aldehydes are more reactive than

ketones toward nucleophilic attack. This
observation can be explained in terms of both steric
and electronic effects.

Aldehydes Ketones
O

R1 R2

Less steric hindrance Only one R stabilizes Two R’s increase Two R’s stabilizes the
with only one R group the positive charge. steric hindrance positive charge.
Less crowded Less stable More crowded More stable
Aldehydes—more reactive Ketones—less reactive
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 SCH 206

Steric effect
The two R groups bonded to the ketone carbonyl group
make it more crowded, so nucleophilic attack is more
difficult.
Electronic effect
Recall that alkyl groups are electron donating. The two
electron-donor R groups stabilize the partial charge on
the carbonyl carbon of a ketone, making it more stable
and less reactive.
The d+ charge of an aldehyde is less stabilized than a
ketone. As a result, aldehydes are more electrophilic
than ketones and therefore more reactive.
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 SCH 206

Thus, carbonyl compounds containing electron-

withdrawing groups are the most electrophilic and
the most reactive, followed in turn by
formaldehyde, other aldehydes, and finally ketones.

Most reactive Least reactive

Aromatic carbonyl compounds are less reactive
than aliphatic carbonyl compounds, for its
delocalized p orbitals can also act as electron
source.
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 SCH 206

The bulkier the alkyl group the less reactive.

> >

This is due to the crowding that results by adding

nucleophiles to the carbonyl carbon.
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 SCH 206
Assignment 1
Which ones are more reactive towards nucleophilic
addition, explain.

a)

b)

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 SCH 206

Carboxylic acid and its derivatives differ greatly in

their reactivity towards nucleophilic acyl
substitution reaction. They have a generalized
structure as follows:

This resonance contribution leads to:

a) Partial double bond character on the C-Y
bond, and
b) Reduced partial positive charge at the
carbonyl carbon.
Dr. Solomon Derese 29
 SCH 206

The particular extent of the effect depends on the type

of derivative. They differ in the degree to which the
atom attached to the carbonyl group can stabilize the
carbonyl group by electron donation.
Electron release from the substituent Z not only
stabilizes the carbonyl group, it decreases the positive
character of the carbonyl carbon and makes the
carbonyl group less electrophilic.
The order of reactivity of carboxylic acid derivatives
toward nucleophilic acyl substitution can be explained
on the basis of the electron-donating properties of
substituent Z. The greater the electron-donating
powers of Z, the slower the rate.
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 SCH 206

a) Acid halide
The halogens have considerable electronegativity.
Plus, their p-orbitals are 3p, 4p, etc. The carbon p-
orbital is 2p. This mismatch will lead to a
relatively poor overlap. All in all the resonance
contribution (overlap) from halogens is weakest.
This would mean that in acyl halide the carbonyl
carbon would have the largest positive charge.

Very small contribution

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 SCH 206

b) Acid anhydride

O O

R O R'

The central oxygen (2p) makes a resonance

contribution, but the effect is shared between
two acyl moieties, so each carbonyl carbon
experiences only half of the overall stabilization.

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 SCH 206

c) Ester/Carboxylic acid

R’ = H = Carboxylic acid
R’ = Alkyl/aryl = Ester
The oxygen atoms lone pair conjugates with the
carbonyl group, causing a significant reduction of
the positive change at the carbonyl carbon.

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 SCH 206

d) Amide

Restricted bond rotation

Since nitrogen is a better electron-donor than
oxygen, the conjugation is more pronounced in
amides. The second resonance structure has such a
significant contribution that the C-N bond acquires
a considerable double bond character; reflected in
the restricted rotation of this bond.
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 SCH 206

The amount of positive charge on the carbonyl

carbon is directly related to its susceptibility to
nucleophilic attack. Due to the above reasons, the
following order of reactivity is observed.

> > > > ≈ >

Most Least
reactive reactive
Least Most
stable stable

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 SCH 206

Carbonyl compounds will react with

nucleophiles without the use of the catalysts
only when the carbonyl carbon is very
electrophilic or the nucleophile is strong.

Otherwise catalysts must be used that will

increase either the electrophilicity of the
carbonyl carbon or the nucleophilicity of the
nucleophile. This can be achieved by using
acid and base catalysts.

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 SCH 206
Acid Catalyzed Nucleophilic Addition Reaction
Step I: Protonation of the carbonyl oxygen
H
O
H H

In the acid catalyzed mechanism the first step is

the protonation of the carbonyl oxygen to give an
oxonium.
A contributing resonance structure puts the
positive charge on the carbonyl carbon. The net
effect of protonation is to make the carbonyl
carbon even more electron deficient than it was.
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 SCH 206

This makes it more susceptible to attack by

nucleophiles in this case a weak nucleophile (e.g.
water/alcohol) will suffice.
Step II: Nucleophilic attack

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 SCH 206

Base Catalyzed Nucleophilic Addition Reaction

A base removes a hydrogen from the nucleophile
(H-Nu:) and generates a strong nucleophile (:Nu:-).

Step I: Nucleophilic attack

O

R1 R2 O

Aldehyde/Ketone R1 R2
Nu
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 SCH 206

Step II: Protonation of the oxygen

R1 R2
Nu

The same argument also applies for nucleophilic

acyl substitution reaction.

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 SCH 206

The Acidity of the a Hydrogens of Carbonyl

Compounds
The a-Hydrogens of
b d carbonyl compounds are
weakly acidic, (pKa 19 - 20).
a c They are unusually acidic for
hydrogen atoms attached to
carbon.
pKa = 16
O pKa = 25 H H
H
H H H
H H
pKa = 20
H pKa = 51
Dr. Solomon Derese
pKa = 44 41
 SCH 206

Why are a-hydrogens of carbonyl compounds

acidic?

An a-hydrogen is more acidic because the negative

charge formed on the a-carbon when a base
abstracts the proton is not localized on this carbon
but through resonance is also on the oxygen.

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 SCH 206

The greater acidity of a-hydrogens arises because

the negative charge on the resulting enolate anion
is delocalized by resonance, thus stabilizing it
relative to an alkane, alkene, or alkyne anion.

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 SCH 206

When an enolate anion reacts with a proton

donor, it may do so either on oxygen or on the a-
carbon. Protonation of the enolate anion on the a-
carbon gives the original molecule, called the keto
form. Protonation on oxygen gives an enol (alkene
alcohol) form. In this way, the keto form of an
aldehyde or ketone can be converted into the enol
catalyzed by base.
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 SCH 206

Aldehydes and ketones with at least one a-

hydrogen are in equilibrium with their enol forms.
The keto and enol forms of carbonyl compounds
are constitutional isomers, but of a special type.
Because they are easily interconverted in the
presence of traces of acids and bases, chemists use
a special term to describe this type of
constitutional isomerism.
Interconvertible keto and enol forms are called
tautomers, and their interconversion is called
tautomerization.
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 SCH 206

Tautomers are constitutional isomers that differ in

the location of a double bond and a hydrogen
atom. Two tautomers are in equilibrium with each
other.

A keto tautomer has a C=O and an additional C – H

bond.
Tautomerization, the process of converting one
tautomer into another, is catalyzed by both base
and acid.
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 SCH 206

Tautomerization under acidic condition.

Tautomerization, the process of converting one

tautomer into another, is catalyzed by both acid
and base. Tautomerization always requires two
steps (protonation and deprotonation), but the
order of these steps depends on whether the
reaction takes place in acid or base.
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 SCH 206

Under most circumstances, we encounter keto–

enol tautomers in a state of equilibrium. It is
difficult to prevent tautomerization even if care is
taken to remove all acids and bases from the
solution. Tautomerization can still be catalyzed by
the trace amounts of acid or base that are
adsorbed to the surface of the glassware.
However, the equilibrium favors the keto form
largely because a C=O is much stronger than a C=C.
Most carbonyl compounds exist almost exclusively
in the keto form at equilibrium, and it’s usually
difficult to isolate the pure enol.
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 SCH 206

0.0001%

The percentage of enol tautomer is even less for

carboxylic acids, esters, and amides. Even though
enols are difficult to isolate and are present only to
a small extent at equilibrium, they are
nevertheless responsible for much of the chemistry
of carbonyl compounds because they are so
reactive.
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 SCH 206
Assignment 2
I. For a long time attempts to prepare compound A were
thwarted by its ready isomerization to compound B. The
isomerization is efficiently catalyzed by traces of base.
Write a reasonable mechanism for this isomerization.

O OH
KOH

H H2O H

OH O
A B

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 SCH 206

II. Consider the ketones piperitone, menthone, and

isomenthone.

Suggest reasonable explanations for each of the following

observations:
a) Optically active piperitone ([a]D=32) is converted to
racemic piperitone on standing in a solution of sodium
ethoxide in ethanol.
b) Menthone is converted to a mixture of menthone and
isomenthone on treatment with 90% sulfuric acid.
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