Chap 3-1

Chapter 3

Understanding the Acid/Base Chemistry of Functional Groups in Organic
Molecules

The ability of functional groups in organic molecules to act as acids and/or bases is
a key factor in defining their solubility properties in both aqueous and nonaqueous
solutions and in defining the types of reactions they will undergo. Because the vast
majority of drugs are organic molecules, a thorough understanding of the acid/base
properties of the functional groups is essential to understanding and predicting the
solubility and reactivity of drug molecules. In this chapter we will:

review the basic principles of acid/base chemistry:
- acid/base equilibria
- acid dissociation constant K
a
,
- pK
a
definition and dominant species at pH > pK
a
and pH < pK
a


learn approximate pK
a
values of common isolated functional groups

develop a conceptual understanding of their relative values

examine how changes in molecular structure alter pK
a
values

look at several examples of drug molecules where we will apply the concepts
developed above to identify and understand which functional groups are associated
with the reported pK
a
values from the literature.

These concepts form the foundation for understanding the reactivity of organic,
i.e., drug molecules, and will be emphasized and reiterated throughout the
remainder of this course and all of your Pharm Chem courses discussing the
chemistry of drug molecules.

RECOMMENDED READING in Dewick:
1) The functional groups in Chap. 1, Table 1.1, pp 5-6
2) Background in Chapter 2, especially sections 2.7-2.10
3) **All of Chapter 4 on Acids and Bases the same principles from the syllabus are
presented in a different but useful manner. (Ignore K
b
and pK
b
in section 4.4)
4) **Sections in Chap. 11 on Heterocycles for more on the pKas of NH, OH and SH groups in
heterocyclic molecules: Sec. 11.2, p 405; Sec. 11.4, pp 408, 416-418; Sec. 11.5, pp 420-421;
Sec. 11.6, pp 427, 430; Sec. 11.7, pp 432-433; Sec. 11.9, p 450.

Problem Sets: PS3 on website; and in Dewick: 16.09, pp 630-633 & 16.22, pp 666-668
Chap 3-2
Connecting to Chemistry of Medicines for Chapter 3

Recall the following molecules from the prologue on Odanacatib:


N
H
H
N
O
C
N
HN
CF
3
N
N
H
H
N
O
C
S
CF
3
N
O O




Which of the above was highly selective for its target in vitro? Why?
Was it more or less selective in vivo? Why?
Which one caused undesirable side effects? Why?
How/why did the structural changes shown alter the properties?




Ar N
H
H
N
O
C
CF
3
N
Ar N
H
H
N
O
C
CH
3
N




What property of the above two analogues is different? Why?
Which one was a better inhibitor of the cathepsin K target?

Chap 3-3
HO
HO
O
OH
NH
2
pKa's
2.3
8.7
9.7
13.4


OH O OH O O
NH
2
OH
N
H
3
C CH
3
OH
H
N
H
3
C CH
3
pKa's
2.8
5.0
7.8
9.5

N
O
Cl
O
OH
H
3
CO
CH
3
pKa
4.5

N
H
NH
O
O
O
CH
3
CH
2 pKa
7.5





OH
O
OH
NH
2
O
OH
OH
O
O
O
CH
3
pKa's
3.0
13.4
pKa
8.1
pKa
3.5


H
3
C S
O
O
N
H
N
H
O
CH
2
CH
2
CH
2
CH
3
pKa
5.3

N
H
N
O
2
N
O
Cl
pKa's
1.5
10.5

tolbutamide (hypoglycemic agent) clonazepam (anti-seizure)
salicylic acid acetylsalicylic
acid
salicylamide
analgesic and antipyretic
Indomethacin
(anti-inflammatory) phenobarbital (sedative)
L-dopa (precursor of
neurotransmitter
dopamine used for
Parkinsons disease)
minocycline (antibiotic)
A FEW DRUG COMPOUNDS
& THEIR pKas
SHOWN IN THEIR
NON-IONIZED STATES
Chap 3-4
Brnsted-Lowry Acids and Bases (Dewick Sections 4.1, 4.2 & 4.4)
Two general types of Acid/Base pairs
Acid = proton donor Base = proton acceptor




Although we often write acid/base equilibria as if the H
+
simply dissociates, acids actually never
lose a free proton H
+
. Instead H
+
is always transferred between lone pairs of electrons on two
different bases reaching an equilibrium that is dependent on the relative strengths of the two
acids:







Neutral water molecules can act as both a neutral base (:B) and as a neutral acid (HA). In
physiological systems, where water is the solvent at ~ 55 M, it serves as the main acid and
base with which other acids and bases equilibrate. So what we are interested in is the strength
of the various types of acids and bases relative to the protonated BH+form of water (hydronium
ion: H
3
O
+
), which is the strongest acidic species that can exist in water, and the deprotonated A

form of water (hydroxide: OH

), which is the strongest basic species that can exist in water.

So acids that are stronger than H
3
O
+
are completely dissociated in water:












and bases that are weaker than OH

are always completely protonated in water:

Chap 3-5
As noted in the examples above, the main acids that are stronger than H
3
O
+
have inorganic
anions as conjugate bases (Cl

, Br

, I

, HSO
4

), and some of the main bases that are stronger

than OH

(and thus typically do not form under physiological conditions) are carbanions (R
3
C

).

However, most of the functional groups in organic molecules that have acid/base properties are
either HA or BH+acids that are weaker than H
3
O
+
and have conjugate bases (A

or :B) that are

weaker bases than OH

.

As a result, these weak acids are incompletely dissociated in aqueous solution.

e.g.: dissociation of acetic acid

OH O
+ H
3
O
+
O O
+ H
2
O







e.g., dissociation of an alkyl ammonium ion


NH
3
NH
2
+ H
3
O
+
+ H
2
O








This follows the general principle that in any equilibrium between two acids and their conjugate
bases, the equilibrium will always lie in favor of the combination of weaker acid + weaker base:


stronger acid + stronger base weaker base + weaker acid





The question of interest then is to what extent are different HA and BH+ acids dissociated, i.e.,
what are the relative equilibrium constants for these proton transfer processes?

Or asked another way - What are their relative strengths and what scale do we use to define their
relative strengths?
Chap 3-6
Recall from thermodynamics: (Dewick Section 4.8)


HA + H
2
O A
-
+ H
3
O
+
K
eq



K
eq
=
[H
3
O
+
] [A
-
]
[H
2
O] [HA]




K
eq
[H
2
O] = K
a
=
[H
3
O
+
] [A
-
]
[HA]

____________________

Henderson- Hasselbach eqn
- log K
a
= - log [H
3
O
+
] - log
[A
-
]
[HA]




pK
a
= pH - log
[A
-
]
[HA]


rearranging

pH - pK
a
= log
[A
-
]
[HA]



By definition, the pK
a
of an acid is equal to the pH at which 50% of the acid
is dissociated, i.e. when pH =pKa [A-]/[HA] =1.




pH - pKa =
pKa
0 +1 +2 +3 -1 -2 -3
dominant
species
=
% acid
form
=

The pK
a
is a
quantitative measure
of the strength of an
acid.

The lower the pK
a
,
the stronger the acid.

Stronger acids lose
their protons more
easily.
Chap 3-7
Recall that using the Henderson-Hasselbach Equation you can: (Dewick Section 4.9)

calculate the pH, given a known mixture of acid and base forms of an ionizable species
determine whether the predominant species at any given pH will be charged or neutral.

Of interest to us:
At any given pH, where are we relative to the pKa of the functional group of interest?
Is the predominant species at that pH charged or uncharged?

To answer this, we need to know what the acid form and base form are for the
functional group of interest:

FOR HA ACIDS:

A
-
+ H
3
O
+
K
a
HA



pK
a
= pH - log
[A
-
]
[HA]

pH - pK
a
= log
[A
-
]
[HA]



pH pKa pH >pKa pH <pKa
dominant
species
charged? or
uncharged?


FOR BH+ ACIDS:

B: + H
3
O
+
K
a
BH
+



pK
a
= pH - log
[B:]
[BH
+
]

pH - pK
a
= log
[B:]
[BH
+
]



pH pKa pH >pKa pH <pKa
dominant
species
charged? or
uncharged?

Chap 3-8
With WATER is the main solvent for physiological conditions
The questions of interest are:
What are the pKa values of H
3
O
+
and OH

?
What functional groups have pKa values within those limits?
or stated another way:
What groups will vary in ionization state in the physiological pH range?
What groups will remain in one ionization state in that range?
Acid pKa Conjugate base
ethane
Table 3.1 pKa Values for Some Organic and Inorganic Acids
H
2
C H
H
2
C C
H
H
2
N
H
H
3
N
H
2
O
I
HC C
H
H
H
H
H
HO H
H
H
Br H
Cl H
O
2
C O H
HO
2
C O H
H
2
O
3
P O H
ethylene
ammonia
hydrogen
acetylene
ethanol
WATER
bicarbonate ion
ammonium ion
carbonic acid
phosphoric acid
HYDRONIUM ION
sulfuric acid
hydrogen chloride
hydrogen bromide
hydrogen iodide
H
2
C CH
NH
2
H
NH
3
H
2
O
I
HC C
OH
Br
Cl
O
2
C O
HO
2
C O
H
3
C CH
2
H
3
C
O H H
3
CH
2
C O H
3
CH
2
C
51
44
38
35
25
15.9
15.74
10.33
9.24
6.36
2.1
1.74
5.2
7
8
9
acetic acid O H H
3
CCO O H
3
CCO 4.76
benzoic acid O H C
6
H
5
CO O C
6
H
5
CO 4.2
H
2
O
3
P O
HO
3
S O H HO
3
S O

This chart gives us a qualitative view and emphasizes two points:
- Acids with inorganic ions as the base component are typically stronger than organic acids
- Most carbon acids are very weak acids with very high pKas and very strong conjugate bases.
These two points will resurface later in our discussions of molecular reactivity.

What are the functional groups of most interest to pharmacists or stated
another way, what functional groups appear most often in drug molecules?
Stronger
base
Weaker
acid
Weaker
base
Stronger
acid
Chap 3-9
**Typical Acids and Bases in Organic Compounds** **Two Pages To Remember**

Main types of acidic bonds in the functional groups: O-H, S-H and N-H

Acid Name Acid form Base form starting point pKa

alcohol R-OH R-O

(alkoxide) 15.2
guanidinium ion see below 13.6
alkyl ammonium ion R-NH
3
+
R-NH
2
(amine) 10.6
thiol R-SH R-S

(thiolate) 10.5
sulfonamide see below 10.4
phenol Ar-OH Ar-O

(phenoxide) 10.0
imide see below 9.6
iminium ion see below 8-9
imidazolium ion see below 7.0
thiophenol Ar-SH Ar-S

(thiophenoxide) 6.5
pyridinium ion see below 5.2
carboxylic acid R-COOH R-COO

(carboxylate) 4.8
anilinium ion Ar-NH
3
+
Ar-NH
2
(aniline) 4.6
sulfonic acid RSO
3
H R-SO
3

(sulfonate) 2.6


Structures Referred to Above

R =alkyl, e.g. Ar =aryl =
H
3
C


iminium ion <===> imine guanidinium ion <===> guanidine

N N
R H R

NH
2
N
H
NH
2
R
NH
2
N
H
NH
R


pyridinium ion <===> pyridine imidazolium ion <===> imidazole


N
H
N

NH HN NH N


sulfonamide <===> sulfonamide anion imide <===> imide anion

S
R
O O
NH
2
S
R
O O
NH
or Ar

N
H
R
O O
R N R
O O
R

Chap 3-10
If we group the functional groups in a different way, we see some trends in the
variation of the pKas:

Acid Name Acid form Base form starting point pKa

O-H acids (sp
3
hybridized O)

alcohol R-OH R-O
-
(alkoxide) 15.2
phenol Ar-OH Ar-O
-
(phenoxide) 10.0
carboxylic acid R-COOH R-COO
-
(carboxylate) 4.8
sulfonic acid RSO
3
H R-SO
3
-
(sulfonate) 2.6

S-H acids (sp
3
hybridized S)

thiol R-SH R-S
-
(thiolate) 10.5
thiophenol Ar-SH Ar-S
-
(thiophenoxide) 6.5

N-H acids of the BH+ type
sp
3
hybridized N
alkyl ammonium ion R-NH
3
+
R-NH
2
(amine) 10.6
anilinium ion Ar-NH
3
+
Ar-NH
2
(aniline) 4.6

sp
2
hybridized N
guanidinium ion see prev. page 13.6
iminium ion see prev. page 8-9
imidazolium ion see prev. page 7.0
pyridinium ion see prev. page 5.2

N-H acids of the HA type

sulfonamide see prev. page 10.4
imide see prev. page 9.6

Observations:

1) acidity varies for different X-H bonds in the same molecular context, e.g,
compare R-OH & R-SH this is due to Intrinsic differences in the properties of
the elements

2) acidity of a given type of X-H bond varies with molecular context, e.g. compare
O-H acids attached to alkyl versus aryl, carbonyl and sulfonyl groups where
resonance delocalization of negative charge becomes increasingly available

3) acidity of X-H bonds varies with the hybridization state of X, e.g. compare
alkyl ammonium where N is sp
3
and iminium where N is sp
2


Lets look at these factors in more detail
Chap 3-11
1) Intrinsic properties of the elements that control their relative X-H acidity:

1a) Differences in intrinsic polarity of X-H as defined by the electronegativity of X vs H

1b) Differences in overlap of orbitals on X and H

X-H bonds of most interest in drug compounds: O-H, S-H, N-H and occasionally C-H

1a) Electronegativity of X vs H (Dewick, Section 2.7, 4.3.1, & 4.5.1)

Paulings electronegativity scale

H
2.1

Li C N O F
1.0 2.5 3.0 3.5 4.0

Na Si P S Cl
0.9 1.8 2.1 2.5 3.0

K Br
0.8 2.8







H C H N H O H F
+ + + +
weakly polar polar very polar v. very polar
H CH
3
H NH
2
H OH H F
H CH
3
H NH
2
H OH H F
pK
a
=
~48
~38 15.7 ~3.2
2.1 2.5 2.1 2.1 2.1 3.0 3.5 4.0

bonding orbitals
or valence shell
on X
2s, 2p
Chap 3-12
1) Intrinsic factors of the elements (contd)

1b) Differences in Orbital Overlap in X-H bonds for elements in different rows
(Dewick Section 4.3.2)

Based only on the differences in electronegativities on the previous page, the H-S bond
should be less acidic than the H-O bond in the same structural context:


H S
+
weakly polar
2.1 2.5
bonding orbitals
or valence shell
on X
3s, 3p

H O
+
very polar
2.1 3.5
bonding orbitals
or valence shell
on X
2s, 2p



However,


H
3
C S
H
H
3
C S + H
3
O
+
H
3
C O
H
H
3
C O + H
3
O
+
pK
a
~11 pK
a
~15.2





S
H

O
H




Since the 3
rd
shell has a larger volume than the 2
nd
shell for electrons to occupy:

- less of the S electron density is shared with H in the S-H bond compared with the
amount of O electron density shared with H in the O-H bond

With less shared electron density, the S-H bond is weaker and S lets go of its H
+
more
easily than O, therefore

the S-H bond is more acidic, which means it has a lower pKa
the O-H bond is less acidic, which means it has a higher pKa
S uses 3
rd
shell
sp
3
orbitals
O uses 2
nd
shell
sp
3
orbitals
Chap 3-13
2) Effects of Molecular Structure on pKas of the functional groups

2a) Increasing resonance delocalization of negative charge or lone pairs of electrons in a base
stabilizes or weakens the base and therefore strengthens its conjugate acid which results in a
lower pKa. (see pp 45-49 of Dewick for review of resonance)

Compare the following O-H acids:

O H H
3
C O H
3
C
pKa = 15.2
alcohol
H +


phenol
O H O
pKa = 10
H +









carboxylic acid
H
3
C
O
O H H
3
C
O
O
pKa = 4.8
H +






sulfonic acid
H
3
C
S
O
O H
O
H
3
C
S
O
O
O
pKa = 2.6
H +

Chap 3-14
2a) Increasing resonance delocalization of negative charge or lone pairs of electrons in a base
stabilizes or weakens the base and therefore strengthens its conjugate acid which results in a
lower pKa.

The same effect can be seen in the S-H acids (note thiocarboxylic acids and thiosulfonic
acids are not sufficiently stable to be found as functional groups in drug molecules):

S H H
3
C S H
3
C
pKa ~ 10.5
H +

thiol

S H S
pKa ~ 6.5
H +

thiophenol








and also in the sp
3
hybridized BH+ type N-H acids:

N
H
2
H
H
3
C NH
2
H
3
C
pKa ~ 10.6
H +

alkyl ammonium ion

N
H
2
H
NH
2
pKa ~ 4.6
H +

anilinium ion








note that if we follow the trend of the O-H acids, the next two species we would expect in
the sp
3
hybridized BH+ type N-H acids would be protonated amides and sulfonamides
Chap 3-15
however, protonated amides and sulfonamides behave somewhat differently than
carboxylic acids and sulfonic acids:

These species that are protonated on the NH
2
group NEVER form!

NH
3
O

S
O O
NH
3


Instead, the lone pair of electrons on the N of the NH
2
or NR
2
group is stongly resonance
delocalized into the bond of the C=O so that negative charge tends to build up on the
more electronegative oxygen. For example


NH
2
O
O
NH
2

amide



As a result, when an amide gets protonated the proton adds to the O, not the N


NH
2
OH
+ H
3
O
+
+ H
2
O
NH
2
O
pK
a
~ -1.0





Note the pKa is very low (1) so very little of this exists at physiological pH values.
Be sure to learn to distinguish an amide from an amine in other molecular structures.

Following the trend of the O-H acids, the pKa for a protonated sulfonamide would be very
much lower than 1 so essentially NONE of that would exist at physiological pH values
Chap 3-16
in fact, instead of seeing a protonated sulfonamide (BH+ type) in our list of pKa values,
we see the sulfonamide listed as an N-H acid of the HA type! We also see an imide as an
HA type acid, but not a simple amide (nor an aniline or amine). Here again the trend
results from increased resonance of the electrons onto the much more electronegative O
atoms in the imide and sulfonamide relative to that in the others:

N
H
H H
3
C NH H
3
C
pKa ~ 38
amine
H +


N
H
H NH
pKa ~ 28
H +

aniline
H
3
C
O
N
H
H H
3
C
O
NH
pKa ~ 17-18
H +

amide very, very little at physiological pH

NONE of the anionic forms of the amine or the aniline would be formed at physiological pH
values and only very tiny amounts of the deprotonated amide would be formed. However, the
added resonance with two C=O or S=O bonds available lowers the pKas for formation of
the anionic bases of the imide and sulfonamide into the physiological range:

R
O
N
H
R
O
N
pKa ~ 9.6
H +
R
O
R
O

imide






S
O
N
H
H
O
S
O
NH
O
pKa ~ 10.4
H +
H
2
N

sulfonamide
Chap 3-17
3) Effects of the Hybridization state of X on the pKas of X-H groups

As the hybridization of X changes from sp
3
-> sp
2
-> sp, all X-H bonds become stronger
acids (i.e., have lower pKa values) if the rest of the molecular context stays the same.
(Bewick - Sections 4.S.4 & 4.S.S) Consider the following series of related acids in each
column in the table below:

C H
stronger
acids
weaker
acids
H
3
C C
H
2
H
H
2
C
C
H
H
HC C H
sp
3
sp
2
sp
N H
R
2
HC N
H
2
H
R
2
C
N
H
H
pKa
~ 50
~ 44
~ 25
pKa
10 - 11
~ 8
O H
R
2
HC O
H
H
R
2
C
O
H
pKa
2 to 3
7


This is the empirical observation. Why is this the case?

One idea to explain this: As the orbital that the X-H bond occupies increases in its percentage of
s character (i.e., an sp
3
orbital is only 25% s while an sp
2
orbital is 33% s), the electrons in
that orbital are held more closely to the positively charged nucleus in X. As a result of
feeling more positive charge, those negatively charged electrons become less basic. If the
base is weaker, then the corresponding acid will be stronger and the pKa will be lower.

**Note from the values in the above table that the only sp
2
hybridized X atom that has a
pKa in the physiological range is N with N-H acids of the BH+ type**

iminium ion sp
2
hybridized N vs alkyl ammonium ion sp
3
hybridized N


N
R H
N
R

N
R
H
N
R
H
H


pKa ~ 8 pKa ~ 10

With a pKa of ~ 8, significant amounts of both the acid (iminium ion) and base (imine)
forms of this simple molecule would be present at physiological pH values. With their very
high pKa values, none of the C-H acids would be deprotonated. In contrast, with their very low
pKa values, only tiny amounts of the protonated O-H acids will form, but as we will see in
Chapter 6, these are important for the reactivity of carbonyl (C=O) compounds.

We will look at the other sp
2
hybridized N-H acids a little later
Chap 3-18
2) Effects of Molecular Structure on pKas of the functional groups

In the above pages we examined the three factors (intrinsic elemental differences, variable
resonance interactions, and hybridization differences) that give rise to the differences in
pKa values for the different functional groups when they are found in simple molecules
with no other substituents.

However, this is rarely the case in drug molecules where the molecular structures are
typically complex with two or more different types of functional groups present.
Frequently, these functional groups (or substituents) alter the electronic properties of
each other so that the reactivities of each group and their acid/base properties deviate
from those of the isolated functional groups we examined above.

On the following pages we examine the two types of Electronic Effects:

2b) inductive electronic effects of substituents that occur through bonds (electron
donating EDG and electron withdrawing EWG groups (Dewick Secs 4.3.3 & 4.5.2)

2c) resonance electronic effects with EDG and EWG substituents attached to aromatic
rings and other double- or triple-bonded systems
(Dewick Secs 4.3.5 & 4.5.4)


2b) Examples of Inductive Electronic Effects

In Alcohols

Observations:

1) Alkyl groups are inductively electron donating (EDG).
They push electron density towards the C-O-H group,
which increases the negative charge on O making it a
stronger base, which raises the pKa of the alcohol O-H
group relative to that of the unsubstituted CH
3
-OH.

2) Highly electronegative fluorine (F) is inductively a
strong electron withdrawing group (EWG). It pulls
electron density towards itself and away from the C-O-H
group. This places + charge on the C, which stabilizes the
negative charge on O making it a weaker base. This lowers
the pKa of the alcohol O-H group relative to that in CH
3
-
OH.
H
2
C OH H
H
2
C OH H
3
C
C OH H
3
C
H
2
C OH F
3
C
CH
3
CH
3
pKa
15.2
~16
~20
12.4
Chap 3-19
2b) Examples of Inductive Electronic Effects (cont)


In Carboxylic acids

C
OH F
3
C
pKa
~3.8
4.8
4.2
0.25
O
C
OH H
O
C
OH H
3
C
O
C
OH
O




In Alkyl Ammonium ions

H NH
3
H
2
C NH
3
H
3
C
H
2
C NH
3
H
2
C
pKa
9.24
10.6
7.9
NC


Chap 3-20
however, when multiple alkyl groups are present on an alkyl ammonium
ion, the EDG effects are no longer additive:


H
2
C N H
3
C
pKa
10.6
H
2
C
N
H
3
C
C
H
2
H
3
C
H
2
C
N
H
3
C
C
H
2
H
3
C CH
2
CH
3
11.0
10.7
H
H
H
H
H
H






In general, for charged species to be stabilized in aqueous solution, they need to
be solvated, i.e., form H-bonds (which we will discuss more in Chapter 4). As
more alkyl groups are added, fewer H-bonds can be formed with water, so the
charged ammonium ions become less stable. This means they will lose their
protons more easily to become the uncharged base, which means they are more
acidic and therefore have lower pKa values.
Chap 3-21
A Schematic Approach to Inductive Electronic Effects


INDUCTIVE ELECTRONIC EFFECTS, which occur through bonds, are the same in
any molecular context. They can be largely attributed to the polarity of the bond that
results from the difference in electronegativity of the atoms making the bond.


RECALL from the Table of Electronegativities on p. 3-11:

Atom H C N O F Cl Br I
Electronegativity 2.1 2.5 3.0 3.5 4.0 3.2 3.0 2.7



Qualitative strength of polarity (length of arrow) of various bonds based on above:


C X
C H
C C
C N
C O
C F
relative polarity
nonpolar
C O
C N
N O
C Cl
C Br
C I
similar
inductive effect
ED
EW
EW
EW
EW
EW
EW
EW
EW
EW
neither
ED =electron donating
EW =electron withdrawing


Chap 3-22
Qualitative Strength of Inductive
Effects of Common Alkyl Substituents
NR
3
+
NO
2
C N
CF
3
C
O
C
O
F
Cl Br
I
OR
SR
C C
C C
C
6
H
5
electron
withdrawing
(EWG)
electron
donating
(EDG)
R
,
C
O
O
Strong
Weak
RO
R


Multiple EWGs have combined effect, e.g., compare strength of F versus CF
3





Inductive effects fall off with increased distance from XH, e.g.







Note: Table 4.7 in Dewick, p. 126
groups the inductive effects, but
does NOT list them in order of
qualitative strength as done here.
Chap 3-23
2b,c) Examples of Inductive & Resonance Electronic Effects in Aromatic Rings

Consider the observations in substituted phenols
pKa = 10.0
OH O
H +

OH
pKa
10.2 9.95
OH
F
OH
9.3
F
H
3
CO
OH
7.0
O
2
N
pKa




in substituted anilines
pKa = 4.6
NH
3
NH
2
H +

OH
pKa
5.29 1.74
OH
NC
OH
2.76
CN
H
3
CO
OH
4.20
pKa
OCH
3


Chap 3-24
in substituted benzoic acids

pKa = 4.20
C
OH
O
C
O
O
H +



C
OH
pKa
4.57
4.08
4.14
O
C
OH
O
C
OH
O
F
C
OH
3.86
O
F
HO
OH
C
OH
3.42
O
O
2
N
pKa
C
OH
3.49
O
NO
2
C
OH
4.37
O
H
3
C
C
OH
4.27
O
CH
3



How can we explain these diverse effects?
Chap 3-25

Hammett constants An empirical scale for quantifying electron donating
(EDG) and withdrawing (EWG) effects in aromatic rings

In the 1930s Hammett noted these effects of substituents on the acid dissociation
constant K
a
of benzoic acid and developed a scale of substituent constants,
values, to quantify their relative electron donating or withdrawing strength.



O
OH
O
O
+ H
K
a
X X




values are derived from the free
energy relationship below, which
compares the acid dissociation constant
for a substituted benzoic acid (log K
aX
)
with that for benzoic acid (log K
aH
).


logK
aX
= + logK
aH
where measures the sensitivity of the
reaction to the substituent effect and is
defined as = 1.0 for the above reaction.

= 0.0 for the reference compound
benzoic acid (X = H)

Rearranging and recalling that logK
a
=pK
a
, we obtain this relationship in terms of pK
a
values
for unsubstituted vs substituted benzoic acid:

-logK
aH
+logK
aX
=

pK
aH
- pK
aX
=

Since = 1.0, and

electron withdrawing substituents (EWG) stabilize negative charge, they favor loss of an
acidic proton and lower the pK
aX
relative to the pK
aH
of benzoic acid, so

pK
aX
< pK
aH
and values for EWGs are positive ( + )

electron donating substituent (EDG) disfavor loss of an acidic proton and raise the pK
aX

relative to the pK
aH
of benzoic acid, so

pK
aX
> pK
aH
and values for EDGs are negative ( )
For benzoic acid,
X = H and logK
aH

Chap 3-26

O
OH
para
meta
meta ortho
ortho

________________________________________________
values for common substituents
(reviewed in Hansch, et al., (1991) Chem Rev 91, 165-195)_
Substituent para meta
____________________________________________
:NH
2
0.66 0.16
:OH 0.37 +0.12
:OCH
3
0.27 +0.12
CH
3
0.17 0.07
Ph 0.01 +0.06
H 0.00 +0.00
CO
2

0.00 0.10
:F +0.06 +0.34
:I +0.18 +0.35
:Br +0.23 +0.39
:Cl +0.23 +0.37
CO
2
H * +0.45 +0.37
CO
2
Me * +0.45 +0.37
COCH
3
* +0.50 +0.38
CF
3
+0.54 +0.43
CN * +0.66 +0.56
NO
2
* +0.78 +0.71

Why do the effects vary with position?

and why are some substituents that are inductively electron withdrawing on alkyl
chains become electron donating at the para position of an aromatic ring?

because the overall effect results from a combination of inductive and
resonance interactions that sometimes work together and sometimes are opposed
as we noted in the p- vs m-
examples above, the pK
a
values
and, hence, the values vary
with position

Observations:

1) Some substituents have
stronger effects (larger
values) in meta vs para

2) Some substituents have
stronger effects in para vs
meta

3) Some substituents are
EDGs ( value) in one
position but EWGs (+
value) in the other

Chap 3-27
RESONANCE ELECTRONIC EFFECTS TWO TYPES WHAT ARE THEY

EFFECTS STRONGEST WITH SUBSTITUENT AT PARA POSITION (VS META) - WHY

When substituents are attached to a double bond, such as occurs in an aromatic ring,
resonance interactions become possible in two types of situations:

1) RESONANCE DONORS WORK AGAINST INDUCTIVE ELECTRON
WITHDRAWING EFFECT - substituents that have an sp
3
hybridized atom with a lone
pair of electrons directly attached to the double bond of the ring can participate in
resonance with the double bond as electron donors. The lone pair of electrons is
conjugated with the double bond and can push electrons into it:

For example:


C
OH
C
OH
O OH O OH
C
OH
O OH
C
OH
O OH
Resonance donation
from the para position
places negative charge
directly on the C with the
acidic group so the effect
is stronger than donation
from the meta position
where the negative charge
is not directly interacting



So then


Chap 3-28
what substituents are resonance donors and what are their overall
electronic effects?

The resonance ED is shown schematically here with a curved arrow from a lone pair of
electrons towards the C of the aromatic ring. The length of the arrow qualitatively
represents the strength of the atom (or group) as a resonance donor. The final two
columns show the overall combined effect of the substituent when it is attached either
para or meta to the acidic group of interest. The corresponding constants for each
substituent are shown in parentheses and give a more quantitative measure of the
overall effect at each position.


C NH
2
C OR
C F
C Cl
C Br
C I
inductive EW resonance ED
overall effect
para (
para
) meta (
meta
)
v.strong
EDG
(-0.66)
medium
EDG
(-0.16)
strong
EDG
(-0.27
-0.37)
medium
EWG
(+0.12)
v.weak
EWG
(+0.06)
strong
EWG
(+0.34)
med str.
EWG
(+0.23)
strong
EWG
(+0.37)
med str.
EWG
(+0.23)
strong
EWG
(+0.39)
med str.
EWG
(+0.18
+0.27)
strong
EWG
(+0.35)


(Note: the
para
value for the Iodide substituent is less well determined than the
para

values for the other halogens, so the two values reported in the literature are given
here. Refs: L.P. Hammett (1937) J. Am. Chem. Soc. 59, 96; D.H. McDaniel & H.C.
Brown (1958) J. Org. Chem. 23, 420.)


Chap 3-29
2) RESONANCE ACCEPTORS ENHANCE INDUCTIVE ELECTRON WITHDRAWING
EFFECT - substituents that have a doubly bonded atom (sp
2
hybridized) directly
attached to the double bond of the ring can participate as electron acceptors
withdrawing electron density from the ring through resonance. The double bond of the
substituent is conjugated with the double bond of the ring extending the system.

For example:


C
C
C
C
O OH O OH
C
C
O OH
C
C
O OH
Resonance withdrawal
from the para position
places positive charge
directly on the C with
the acidic group so the
effect is stronger than
withdrawal from meta
position where the
positive charge is not
directly interacting
O
O
O
O



So then...

Chap 3-30
what substituents are resonance acceptors and what are their
overall electronic effects?

The resonance EW is shown schematically here with a curved arrow from a lone pair of
electrons (although the electron pair comes from the bond of the ring), but now the
arrow is flipped in orientation to be the same as the inductive EW effect. The length of
the arrow qualitatively represents the strength of the group as a resonance acceptor.
The final two columns show the overall combined effect of the substituent when it is
attached either para or meta to the acidic group of interest. The corresponding
constants for each substituent are shown in parentheses and give a more quantitative
measure of the overall effect at each position.


C C
C C
C C
C C
C N
C S
inductive EW resonance EW
overall effect
para (
para
) meta (
meta
)
stronger
EWG
(+0.45)
strong
EWG
(+0.37)
stronger
EWG
(+0.45) strong
EWG
(+0.37)
stronger
EWG
(+0.50)
strong
EWG
(+0.38)
v. strong
EWG
(+0.66)
stronger
EWG
(+0.56)
even
stronger
EWG
(+0.78)
v. strong
EWG
(+0.71)
stronger
EWG
(+0.57)
strong
EWG
(+0.46)
O
OH
OR
O
R
O
N
O
O
NH
2
O
O

Chap 3-31
Returning to the substituted phenols
pKa = 10.0
OH O
H +


OH
F
OH
F

OH
OCH
3
OH
NO
2

pKa = 9.3 pKa = 9.95 pKa = 10.2 pKa ~ 7.0
(
meta
+0.34) (
para
+0.06) (
para
-0.27) (
para
-0.78)




















Chap 3-32
The Key Concept regarding both inductive and resonance electronic effects in
both alkyl and aromatic systems:

Regardless of whether the effect is inductive or through resonance:

EWG - stabilize negative () charge and destabilize positive charge so
they lower pKa values of any type of acid relative to the
unsubstituted acid

or stated another way:

EWGs make acids stronger relative to the unsubstituted acid and
conjugate bases weaker relative to the unsubstituted base

For example:

A H
H
2
O
A
H
3
O +
A H
H
2
O
A
H
3
O +
EWG EWG
stronger
relative to A-H
(lower pKa)
weaker
relative to A-
B H
H
2
O
B
H
3
O +
B H
H
2
O
B
H
3
O +
EWG EWG
stronger
relative to B-H+
(lower pKa)
weaker
relative to B:



Chap 3-33
Conversely,

EDG stabilize positive (+) charge and destabilize negative charge so
they raise pKa values of any type of acid relative to the
unsubstituted acid

or stated another way:

EDGs make acids weaker relative to the unsubstituted acid and
conjugate bases stronger relative to the unsubstituted base

For example:

A H
H
2
O
A
H
3
O +
A H
H
2
O
A
H
3
O +
EDG EDG
weaker
relative to A-H
(higher pKa)
stronger
relative to A-
HB H
H
2
O
B
H
3
O +
B H
H
2
O
B
H
3
O +
EDG EDG
weaker
relative to B-H+
(higher pKa)
stronger
relative to B:




These principles not only underlie the effects on pKa values as further
exemplified on the following pages, but also underlie the reactivity of
molecules in many different reactions as we will see later in Chapters 5 & 6.
Chap 3-34
A Few Final Examples of EDG & EWG effects

in sp
2
hybridized N-H BH+ acids

When EDGs with lone pairs of electrons are attached to an iminium ion, they participate
in resonance with the double bond and increase the electron density on the N which raises
the pKa of the protonated form.

Compare the pKas of:

iminium ion sp
2
hybridized N

N
R H
N
R


pKa ~ 8 vs guanidinium ion with two EDGs



N
H
NH
2
N
H H
NH
2
N
H
N
H
R
R


pKa 13.6




N
N
N





** The lone pairs on the EDGs are in p orbitals, they are not basic because they are in
resonance.
**The lone pair in the sp
2
hybridized orbital is basic, i.e., the site of protonation.
Chap 3-35
In the aromatic pyridinium and imidazolium heterocycles, the N of the acidic N-H group is also
sp
2
hybridized.

The pKa of the pyridinium N-H is quite low because the electron deficient double bonds of the
ring act as EWGs:


N
H
N

pKa 5.2




The pKa of the sp
2
hybridized N-H group in the imidazolium ring is similarly low, but now the
lone pair in the p orbital on the 2nd NH is an EDG in resonance which raises the pKa relative
to the pyridinium pKa just as in the case of guanidinium vs iminium above.



NH HN NH N

pKa 7.0







Note the different behavior between the lone pairs of electrons in the sp
2
vs p orbitals on
the two Ns in imidazole:





N
N H


Chap 3-36
Examples of Ionizable Groups in Drugs effect of structural complexity on
pKas


example 1: indomethacin
pKa =4.5
N
O
Cl
O
OH
H
3
CO
CH
3






example 2a,b,c:

salicylic acid - pKas acetylsalicylic acid pKa salicylamide - pKa
3.0 3.5 8.1
13.4

OH
O
OH
NH
2
O
OH
OH
O
O
O
CH
3

Chap 3-37
example 3: phenobarbital pKa =7.5

N
H
NH
O
O
O




















example 4: tolbutamide pKa =5.3
H
3
C S
O
O
N
H
O
N
H












Chap 3-38
example 5: nicotine


N
N
CH
3




















example 6: procaine


H
2
N
O
O
N

pKa type
3.1 BH+
8.0 BH+
pKa type
2.5 BH+
9.0 BH+
Chap 3-39
example 7: clonazepam


N
H
N
O
2
N
O
Cl
pKa type
1.5 BH+
10.5 HA
Chap 3-40
example 8: sulfasalazine


HO
2
C
HO N N S
O
O
N
H
N




















pKa type
0.6 HA
2.4 BH+
9.7 HA
11.8 HA
Chap 3-41
example 9: minocycline this is a complicated structure!













OH O OH O O
NH
2
OH
N
H
3
C CH
3
OH
H
N
H
3
C CH
3


pKa type
2.8 HA
5.0 BH+
7.8 HA
9.5 BH+
Chap 3-42
example 10: L-DOPA



HO
HO
O
OH
NH
3
+























pKa type
2.3 HA
8.7 BH+
9.7 HA
13.4 HA
Chap 3-43
example 11: penicillamine sometimes pKa values are macroscopic and not as easily
assigned to one specific group


O
OH
NH
3
+
CH
3
H
3
C
HS


































pKa type
1.8 HA
7.9 BH+ ?
10.5 HA ?