Pharmaceutical &

Biological Chemistry 1
B31B07

Acids and Bases

-Lecture 5-

Electronic and Structural Features that

Influence Basicity

Dr Lim Kuan Hon

Tel: 8208
[email protected]
Aims and Objectives

By the end of this session you will be able to:

Describe the electronic and structural features

that increase the basicity of molecules.
 Basicity
Basicity - ability of a compound to donate its electron pair.
Remember: The more stable the conjugate acid BH+,
the more readily the corresponding base is to donate
its unshared electrons to a proton  stronger base.
Basic strength can be determined by considering the
acidity (pKa) of its conjugate acid, BH+.
Stronger bases will have larger pKa values
Weaker bases will have smaller pKa values
Although we can actually measure basic strength using
pKb, unfortunately this is not the convention now.
To measure the pKa of a conjugate acid, we consider
the following equilibrium:
BH+(aq) + H2O(l) H3O+ (aq) + B(aq)

[B][H3O+]
For which, K a =
[BH+]
It follows that:
a strong base has a small Ka (large pKa),
i.e., BH+ is favoured over B.
a weak base has a large Ka (small pKa),
i.e., B is favoured over BH+.
Just as in the case of acidity, we will look at how
electronic and structural features of a particular
basic compound determine its strength as a base.
 Electronegativity

Recall: The acidity of an acid HA increases as A becomes

more electronegative.
Conversely, basicity will decrease as an atom becomes
more electronegative.

Compare atoms within the same row of the periodic table:

Greater electronegativity  less willing to donate or share
their electrons with a proton  weaker base.

Example: O is more electronegative than N, so oxygen’s

electrons are less likely to be donated to H +.
 H2O (pKa –1.74) is a weaker base than NH3 (pKa 9.24).
 Inductive Effects
Electron-donating groups on N increase the likelihood of
the unshared electrons to be protonated.
Generally, electron-donating groups increase the
strength of a base by stabilizing the conjugate acid.
N N
H H H Me
H H
ammonia methylamine
pK a 9.2 pK a 10.6

This effect is readily seen from the pKa of NH3 (9.2) and
MeNH2 (10.6). The inductive effect of Me increases the
basic strength of MeNH2 over NH3 by 1.4 pKa units,
i.e., by a factor of over 25 (101.4 = 25.1).
 N N N N
H H H Me H Me Me Me
H H Me Me
ammonia methylamine dimethylamine trimethylamine
pK a 9.2 pK a 10.6 pK a 10.7 pK a 9.8

However:
Introduction of a second Me, as in Me2NH, has a
relatively small effect.

Introduction of a third Me, as in Me3N, reduces the basic

strength to weaker than that of methylamine.

How to explain this anomalous observation?

H -bonding stabilizes cations
Me Me Me
N N N
H H H Me Me Me
H
O H O
H  H
O H  H
H H H
H O H O H O
H H H
Stabilized by 3 H2O Stabilized by 2 H2O Stabilized by only 1 H2O

This anomaly is a consequence of measuring pKa of these

conjugate acids in aqueous solutions
 H-bonding with H2O molecules stabilizes the positive
charge on N (conjugate acids).

This additional stabilization from H-bonding with H 2O will

decrease as the number of alkyl groups increases.
The observed pKa are therefore a combination of
increased basicity with increasing alkyl groups
countered by a stabilization of the cation through H-
bonding, which decreases with increasing alkyl groups.
incr ease stabilization due to mor e methyl substituents

Me Me Me
N N N
H H H Me Me Me
H H H
methylammonium dimethylammonium trimethylammonium
pK a 10.6 pK a 10.8 pK a 9.8

incr ease stabilization due to H-bonding with H 2O

When pKa are measured in the gas phase, where there

are no H-bonding, the pKa are found to follow the
predictions based solely on inductive effects.
Electron-withdrawing groups will have the opposite
effect:
Þ Decrease electron density on N  the base is less
likely to pick up a proton  weaker base.

In agreement with this, the conjugate acid BH+ that

would form is also relatively unstable.

For example, groups with strong electron-withdrawing

inductive effects, such as trichloromethyl, decrease
basicity significantly.
Cl H H
Cl H H
N Me N
Cl H H
pK a 5.5 pK a 10.8
Water is a much weaker base than NH 3 because O is
more electronegative than N, and its electrons are thus
less likely to be donated to a proton.
Furthermore, O is so electronegative that inductive
effects from substituents have rather less influence on
its basicity than they would in similar compounds
containing N.

Alcohols are somewhat less basic than water, with ethers

weaker still (this is not due to inductive effects).
H H H3C H H3C CH3
This is precisely O O O
opposite to what H H H
would be expected pK a 1.7 pK a 2.2 pK a 3.8
from the inductive
effects of alkyl groups. Such observations are likely to
be, primarily, the result of solvation effects (H-
bonding).
 Hybridization Effects
Recall: Acidity is influenced by hybridization of the
atom to which the acidic hydrogen is attached.
→ The acidity of a C–H bond decreases as the s-character
of the carbon hybridized orbital decreases.
→ Lesser s-character  less electronegative  less C-H
bond polarization  weaker acid.

Similar reasoning may be applied to basicity.

If a lone pair is in an sp2 or sp orbital, the lone pair is

held closer to the nucleus and thus more difficult to
be protonated than if it is in an sp3 orbital.
Hybridization effects on basicity can be demonstrated by
comparing the pKa values of acetonitrile and ethylamine.

H+ Me N H+ H
Me C N Me C N H H lone pair inMe N
lone pair in H H
H
acetonitrile sp orbital
pK a 10
ethylamine sp3 orbital pK 10.8
(not basic) a

We find that the nitrile nitrogen is not at all basic, while

ethylamine is relatively a lot more basic.
Other examples include:
sp3 orbital sp2 orbital
H
H H H H H H H
N N N N

more
basic than

cyclohexylamine cyclohexanimine pK a 10.6 pK a 9.2

Similarly, alcohols (sp3 hybridization) are more basic than
aldehydes and ketones (sp2 hybridization).

lone pairs in sp3 orbitals

H H+ H
H3C O H3C O
H
ethanol pK a 2.4

lone pairs in sp2 orbitals

H+ H H+ H
O O O O
C C C C
H3C CH3 H3C CH3 H CH3 H CH3
acetone pK a 7.2 acetyldehyde pK a 8
 Resonance/Delocalization
Effects
Recall: For acids, delocalization of charge in the
conjugate base anion contributes to stabilization of the
anion, and thus ionization of the acid is enhanced.

Conversely, delocalization effects in bases are more likely

to stabilize the base rather than the conjugate acid BH +
 reduce the basicity.
Example: Amides are typically less basic than amines.
Compare acetamide (pKa 0.3) with ethylamine (pKa 10.8).
O O
C H C H
H3C N H3C N
H H
acetamide

delocalization of N lone pair

into  system resulting in O
resonance stabilization C H
H3C N
H

The reluctance to protonate the N of acetamide is due to

N lone pair delocalization occurring in the neutral amide
Protonation requires the N lone pair, so delocalization
(resonance stabilization) would not be possible if the N
is protonated.
However, if amides do act as bases, then protonation will
occur at O instead of N.

This is because resonance stabilization can still occur in

the O-protonated amide.

O Protonate N O
C H C H
H3C N H3C N NO resonance stabilization
H
H H
Protonate O

H H
O O
C H C H
H3C N H3C N
H H
pK a 1.4
Protonation of carboxylic acid and ester occurs at the
carbonyl oxygen, despite this oxygen having an sp2
hybridization and the alternative oxygen (-OR) having
an sp3 hybridization. lone pairs in lone pairs in
sp2 orbitals sp3 orbitals

Protonate sp3 O
O O O O
+
H
C R C R C R C R
H3C O H3C O H3C O H3 C O
R = H, carboxylic acid H
R = alkyl/aryl, ester Protonate sp2 O H+ no resonance
stabilization
delocalization of oxygen
lone pair into  system H H
resulting in O O
resonance stabilization C R C R
H3C O H C O
resonance 3
stabilization
pK a about 6
This is the result of delocalization, with resonance
stabilization being possible when the carbonyl
oxygen is protonated, but not possible should the
-OR oxygen become protonated.
O +
O O
H
H3C
C
O
R
H3C
C
O
R
X H3C
C
O
R
H H
resonance stabilization is N ot Possible

This additional resonance stabilization is not pertinent

to aldehydes and ketones, which are thus less basic
than the carboxylic acid derivatives.
However, since these oxygen derivatives are such
weak bases, they are only protonated in the
presence of strong acids.
For the sulfur analogues, thioesters and thioacids, this
delocalization is much less favourable.
Delocalization requires overlap between a sulphur 3p
orbital and a carbon 2p orbital, which is unlikely
because of the size difference between these
orbitals.

O O
C R X C R
H3C S H3C S

resonance of this type is less f avourable

in the sulf ur esters and acids due to the
larger S atom, and less orbital overlap
Amidines are stronger bases than amines.
Amidines are essentially amides where the carbonyl O is
replaced with N (nitrogen analogues of amides).

sp2 orbital H H H H H
N H+ N N
(imine N)
C H C C
Me N Me NH2 Me NH2
H
acetamidine pK a 12.4
(ethanamidine) resonance
sp3 orbital stabilization
(amide N)
Only the imine N can be protonated.
This is true even though the hybridization of the imine N
is sp2, which in theory should be less basic than the
sp3-hybridized amide N.
This can be rationalized using the resonance stabilization
concept.
Protonation of the imine N allows resonance stabilization
in the conjugate acid to occur; not possible if
protonation would to take place at the amide N.

The two resonance structures are identical. This situation

is similarly found in the carboxlyate anion.

H H H H NH2 O
N N
c.f .
C C C C
Me NH2 Me NH2 Me NH2 Me O
resonance structures protonated acetamidine carboxylate anion

Amidines are therefore strong bases, with the electron

delocalization effect dominating over the hybridization
effect.
Guanidines are even stronger bases (pKa = 13.6).
There is delocalization of charge in the conjugate acid
 In each resonance structure, the charge is favourably
associated with one of the 3 N atoms.
H H H
N N H H H H
N N
C C
H2N NH2 H2N NH2 C C
H2N NH2 H2N NH2
guanidine pK a 13.6

No such favourable delocalization is possible in the

neutral molecule, so guanidines are readily protonated
and are therefore strong bases.

Note: Guanidine is more basic than amidine simply

because its conjugate acid has greater resonance
stabilization (three resonance structures can be drawn).
Let’s look at aniline in comparison with cyclohexylamine:
Aniline has pKa 4.6, while cyclohexylamine has pKa 10.6.

The difference in bacisity between the two can be

attributed to:
i. Inductive effect
ii. Resonance effect (to a greater extent)
The phenyl ring in aniline exerts an electron-withdrawing
inductive effect on NH2  reduces the availability of N
lone pair to be donated.
electron-withdrawing
NH2 NH3 inductive ef f ect NH2 NH3

cyclohexylamine pK a 10.6 aniline pK a 4.6

Resonance is the more prominent effect, occurs only in
the unprotonated aniline, not in the conjugate acid.
This increases the stability of the unprotonated aniline,
and consequently aniline is a very weak base.
NH2 NH2 NH2 NH2

resonance stabilization possible in the base,

but not the conjugate acid

NH2 NH3
Y ou can push
electrons around
the ring X

Unprotonated aniline Protonated aniline

This effect of reduced basicity increases when a suitable
electron-withdrawing group is in the ortho or para
position on the aromatic ring.
For examples, p-nitroaniline and o-nitroaniline have pKa 1
and –0.3, respectively.
These aromatic amines are even weaker bases than
aniline, due to improved delocalization in the free base.
NH2 NH2

NH3 NH3 O
etc
N
O
N N
O O O O
p-nitroaniline N
O O
pK a 1.0 pK a 0.3
NH2 O NH2 O
unf avourable conjugate acids due
N N etc to lack of resonance stabilization
O O = very weak f ree bases

o-nitroaniline
The slight decreased in basicity of o-nitroaniline relative to
p-nitroaniline is a result of an additional effect:
The very near inductive effect due to NO2 at the ortho-
position causes o-nitroaniline to be less basic than p-
nitroaniline.

m-Nitroaniline (pKa 2.5) is the most basic nitro-aniline

compound due to the absence of improved delocalization.
It is still less basic than aniline due to the presence of
electron-withdrawing inductive effect from NO2.
NH3 protonated
m-nitroaniline

O
N
pK a 2.5 O
the meta-nitro group does not improve delocalization
of the N lone pair in the neutral molecule
Substituents that act as electron-donating groups via
resonance will give rise to the opposite effect  increase
the basicity of aniline.
Through resonance, OH and OMe distribute their lone pairs
towards the NH2 substituent, facilitating its protonation.
NH3
protonated o-methoxy NH3 p -methoxy NH3 m-methoxy
NH3
aniline OMe

OMe
OMe
pK a 4.6 pK a 4.5 pK a 5.4 pK a 4.2

The pKa for o-methoxyaniline, p-methoxyaniline and m-

methoxyaniline are 4.5, 5.4, and 4.2, respectively.
Why is o-methoxyaniline significantly less basic than
p-methoxyaniline?
Both OH and OMe are electron-withdrawers via inductive
effect and electron-donors via resonance (predominate)
at the same time .
NH3 NH3 NH3 NH3
OMe OH

OMe OH
pK a 5.4 pK a 4.5 pK a 5.5 pK a 4.7

stabilizing resonance ef f ect

destabilizing inductive ef f ect

Therefore, the electron-donating resonance effect is

countered by the electron-withdrawing inductive effects
 makes predictions about basicity become a little
more complex
 Summary
Structural factors affecting pKa
– Electronegativity
– Inductive effects
– Hybridization
– Resonance/delocalization

Directed study

Essentials of Organic Chemistry,

by PM Dewick, 2006 (Wiley), Chap 4.