Unit 6
How do we control chemical change?
Chemistry XXI
The central goal of this unit is to help you identify
the structural and environmental factors that can
be used to control chemical reactions.
M1. Characterizing Interactions
Recognizing interactions
between reacting molecules.
M2. Changing the Environment
Exploring the. influence of
external factors.
M3. Analyzing the Products
Analyzing the effect of charge
stability.
M4. Selecting the Reactants
Evaluating the impact of
electronic and steric effects.
Unit 6
How do we control
chemical change?
Chemistry XXI
Module 3: Analyzing the Products
Central goal:
To predict and control
the properties of
chemical products based
on the analysis of charge
stability.
Drugs’ Properties
Chemistry XXI
Predicting and controlling acid-base properties
of drugs is of central importance in drug design.
As we have seen, at a
certain pH in our body
the relative amount of a
drug in its acid or basic
form will be determined
by its pKa or pKb.
A-
HA
How can we predict or control
relative pKa or pKb values?
-
Charge Stability
To judge the potential strength of an acid or a base
we need to analyze the stability of their
conjugate pairs.
HA(aq) + H2O(l)
Chemistry XXI
B(aq) + H2O(l)
A (aq) + H3O+(aq)
HB+(aq) + OH-(aq)
The more stable the conjugate pair,
the stronger the acid or base (larger Ka or Kb).
The central problem is then to predict or control the
stability of the charge in the conjugate species.
Charge Stability
Analyses of charge stability are of central
importance in making decisions about
chemical reactivity.
Factors to consider:
What atom is the charge on?
Chemistry XXI
How delocalized is the charge?
What types of atoms or groups of atoms are nearby?
The influence of these factors are commonly
called “electronic effects.”
Factor 1
What atom is the charge on?
The most important factor for determining charge
stability is what atom is the charge on.
Consider these potential acids:
Chemistry XXI
Acid
pKa
pKa = -log Ka
Let′s think!
CH4
48
NH3
38
H2O
15.7
HF
3.1
Larger Ka  Smaller pKa (stronger acid)
Write the formula of the conjugate
base in each case. How do you
explain this trend in acid strength?
Factor 1
What atom is the charge on?
CH4 + H2O
CH3- + H3O+
pKa = 48
NH3 + H2O
NH2- + H3O+
pKa = 38
H2O + H2O
OH- + H3O+
pKa = 15.7
HF + H2O
F- + H3O+
pKa = 3.1
Chemistry XXI
Electronegativity
For atoms in the same row,
the stability of the negative
charge increases with the
electronegativity of the atom
on which it is on.
Factor 1
What atom is the charge on?
Let′s think!
Acid
pKa
How do you then explain these trends?
HF
3.1
HCl
-7
HBr
-9
HI
-10
Chemistry XXI
Atomic size
For atoms in the same column,
the stability of the negative
charge increases with the size
of the atom on which it is on.
Let’s Think
Consider a drug with these functionalities.
NH2
H
CH
R
same
as
CH2
CH2
OH
N
H
R
O
H
Chemistry XXI
Identify the most “acidic” proton?
R
R
CH
HS
CH2
CH2
OH
same
as
H
S
O
H
Factor 2
How delocalized is the charge?
Negative charge on the conjugate base can be
stabilized if there is a way to “delocalize” or
spread it among different atoms.
Consider these two weak acids:
Chemistry XXI
Acid
Conjugate Base
O
O
O
O
pKa = 4.8
H
How do we
explain it?
O
H
O
pKa = 15.9
Factor 2
How delocalized is the charge?
The charge in this anion can be delocalized between
the two oxygens:
O
O
Two possible
resonance structures.
Chemistry XXI
O
We cannot
delocalize the
charge here:
O
O
To do it, you either
have to break a single
bond or violate the
octet rule.
Let’s Think
Consider drugs with these functionalities:
OH
CH
O
C
HC
CH
C
R
Chemistry XXI
CH
CH2
CH2
OH
C
C
O
CH
R
HO
Identify the most “acidic” proton in each structure?
Factor 3
What types of atoms or groups of atoms are nearby?
Atoms or groups of atoms close to a center of
charge can stabilize or destabilize it.
Consider these carboxylic acids:
O
Cl
C
C
Chemistry XXI
Cl
H
OH
Cl
pKa = 0.70
H
H
C
C
O
O
O
C
C
OH
H
H3C
OH
Cl
H
pKa = 2.9
pKa = 4.8
C
C
H3C
OH
CH3
pKa = 5.0
How would you explain the trend?
Let′s think!
Factor 3
What types of atoms or groups of atoms are nearby?
Nearby atoms or group of atoms can pull or donate
electron density (Induction). These inductive
effects fall off rapidly with distance.
Chemistry XXI
O
Electron withdrawing groups (high
electronegativity) stabilize – charge
and destabilize + charges.
Cl
C
C
Cl
OH
Cl
O
Electron donating groups (such as
alkyl groups) destabilize – charge
and stabilize + charges.
H3C
C
C
H3C
OH
CH3
Let’s Think
Consider drugs with these functionalities:
R
CH
OH
R
CH2
CH
C
Chemistry XXI
H3C
CH3
CH2
HO
C
C
C
C
OH
CH
F
C
OH
F
F
Identify the most “acidic” proton in each structure?
Base Strength
It should be clear that the factors that tend to
stabilize the conjugate base of an acid, make
that base weaker (less likely to accept a proton).
Chemistry XXI
The base properties of
most drugs are the result
of the presence of the
“amine” functional group:
R
NH2
Primary
R
Secondary
NH
The lone pair on the
nitrogen atom makes this
group a good proton
acceptor.
R
R
Tertiary
N
R
R
Base Strength
R
+
NH3
R
NH2
Base
Conjugate acid
Any factors that limit or hinder the availability of
the lone pair for sharing, will reduce base strength.
CH
CH
Chemistry XXI
CH3
Let′s think!
Which basic
center is
stronger? Explain
HC
C
CH
N
C
CH
CH2
R
NH
Base Strength
It is common to
use the pKa of
the conjugate
acid of a base
to indicate its
strength.
CH
Resonance Sterics Induction +
CH
CH3
HC
C
CH
N
pKa ~ 2
C
CH
R
Chemistry XXI
CH2
NH
pKa ~ 8
The larger the pKa, the weaker the
conjugate acid, and the stronger the
base of interest.
Reaction Control
Our analysis of the charge stability of the products
of acid-base reactions reveals central issues in the
prediction and control of chemical processes:
Chemistry XXI
 We can control the properties of chemical
substances by carefully designing their
composition and structure.
 The chemical properties of substances are largely
determined by electronic effects that affect charge
stability (electronegativity, polarizability, induction,
delocalization). Controlling the influence of these
effects is crucial in the design of substances with
the desired properties.
Chemistry XXI
Let′s apply!
Assess what you know
Drugs, Drugs, Drugs
Over 70% of the drugs in the market have acid-base
properties. Of these, close to 60% are bases, around
25% are acids, and the rest are amphoteric.
Chemistry XXI
Most of the basic
drugs contain
amine groups.
pKa ~ 9
The strongest acids
tend to be carboxylic
acids (pka ~ 4) ; the
weakest tend to be
barbiturates.
pKa ~ 8
Many drugs share common structural features
that determine their acid-base properties.
Analyze
Let′s apply!
Barbiturates are drugs that act as central nervous
system depressants (sedatives, anesthetics).
They are derivatives of barbituric acid.
Chemistry XXI
pKa = 7.9
Barbital
pKa = 8.1
Pentobarbital
pKa = 7.4
Phenobarbital
Which of the three analyzed factors influence
the acidity of these drugs?
Identify
Let′s apply!
pKa = 9.1
Identify the most acidic
proton in each of these
analgesics. Which is the
strongest/weakest acid?
CH
HO
H3C
CH
C
C
C
CH
O
NH
CH
Tylenol
CH
CH
Aspirin
CH
Chemistry XXI
HC
C
HO
C
C
CH2
CH3
O
O
pKa = 3.5
CH
CH3
CH
H3C
C
O
HC
C
C
CH
CH3
Ibuprofen
HC
CH
C
OH
O
pKa = 4.5
Explain
Let′s apply!
How would you justify the
relative basicity of these
drugs?
Benzocaine
pKa = 2.5
Demerol
Chemistry XXI
pKa = 8.7
pKa = 9.6
Ephedrine
Chemistry XXI
Summarize the main structural factors
that can be used to make predictions
about relative acid or base strength.
Analyzing the Products
Summary
To judge the potential strength of an acid or a base
we need to analyze the charge stability of their
conjugate pairs.
Factors to consider:
Chemistry XXI
What atom is the charge on?
How delocalized is the charge?
What types of atoms or groups of atoms are nearby?
The influence of these factors are commonly
called “electronic effects.”
Chemistry XXI
For next class,
Investigate what are the main characteristics of
substitution reactions.
What types of reactants are involved in
substitution reactions and how do they affect
the reaction mechanism?