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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 4: Selecting the Reactants
Central goal:
To identify the steric and
electronic factors that
determine the outcome
of chemical processes.
Chemistry XXI
The Challenge
Transformation
How do I change it?
Many drugs work by
binding to the active site of
enzymes and receptors in
our body, stimulating or
inhibiting their function.
Binding occurs through
intermolecular forces
between the drug molecule
and atoms in the target site.
How can we design and synthesize
drugs with specific binding capacities?
Binding Forces
The forces that bind drugs to active sites or receptors
are the same as those that control from phase
behavior to the tertiary structure of proteins: ionic,
hydrogen bonding, and dispersion interactions.
H-bonding H
O
Chemistry XXI
O
C
H3C
Dispersion
O
C
O
--
+
H3N
Ion-Ion
Binding Groups
In developing drugs, we may be interested in
introducing or eliminating different binding groups to
enhance the pharmacological activity of a substance
Identify the main functional groups with binding
capacity and the types of intermolecular forces
they may able to establish.
Chemistry XXI
NH2
CH
HC
Let′s think!
C
HO
CH
C
CH
CH3
S
NH
C
HC
HC
C
O
C
N
HC
CH
C
O
Amoxicillin: An antibiotic
CH3
O
OH
Binding Groups
Alkyl
(Dispersion)
Amine
(H-bonding and Ion-Ion)
NH2
CH
HC
Chemistry XXI
C
HO
Hydroxyl
(H-bonding)
CH
C
CH
CH3
S
NH
C
HC
HC
C
O
C
N
HC
CH
Phenyl
(Dispersion)
C
O
OH
O
Ketone
(H-bonding)
Amoxicillin
CH3
Carboxyl
(H-bonding
and Ion-Ion)
Polar Reactions
Chemistry XXI
Chemists have developed a wide variety of
reactions to introduce or eliminate specific binding
groups in molecules.
Most of these synthesis
reactions result from
the interaction between
electron-rich sites in a
molecule
(the nucleophile)
and electron-poor sites
in another molecule
(the electrophile).
d-
Nucleophile
(Negative or with
high e- density)
d+
d-
Electrophile
d+
(Positive or with
low e- density)
Substitution Reactions
To illustrate some of the central ways of thinking in
the synthesis of new substances, let us analyze a
class of reactions that allow to “substitute” one
nucleophile for another in a molecule.
R-X + Nu:  R-Nu + X:
Chemistry XXI
Electronegative
Imagine that we were
interested in
introducing an
hydroxyl –OH group
to enhance
H-bonding in a drug.
We could try to use:
H3C
HO:
Nucleophile
C
H
R
Br
X
d+
Electrophile
d-
Experiments
R-X + Nu:  R-Nu + X:
Chemistry XXI
Kinetic experiments indicate that there are
two main routes through which this reaction
may happen:
Under some
conditions:
Under other
conditions:
Rate = k [Nu-][R-X]
Rate = k [R-X]
2nd Order
1st Order
Change in Chirality
Racemization
How do we explain it?
Mechanism 1
One possibility is:
CH3
H3C
HO
-
+
C
H
x
Br
HO
R
-
C
H
-
CH3
x
HO
C
H
+x
R
R
Chemistry XXI
Transition State
One-Step Bimolecular
process:
Rate = k[OH-][R-X]
2nd Order
SN2
Important:
The configuration of the
carbon atom is inverted
in this process.
(Configuration Inversion)
Chemistry XXI
SN2
DG
Ea
DGrxn
Mechanism 2
A second possibility for this reaction, is a
two-step mechanism:
HO
-
+
C
H
R
CH3
CH3
H3C
x
-
C+
Br
Step 1
Slow
H
C
R
Step 2
Fast
HO
R
H
Chemistry XXI
Intermediate
Two-step process:
Important:
Rate = k [R-X]
The reaction produces
both enantiomers.
1st Order
SN1
(Racemization)
SN1
DG
Rate
Limiting
Ea2
Chemistry XXI
Ea1
DGrxn
Reaction Control
Chemistry XXI
Given that drugs act by
interacting with active sites
that can be expected to be
chiral, controlling their
“stereochemistry” is of
central importance during
the development process.
How can we control whether the reaction
mechanism is SN1 or SN2?
We may try to control the rate of each type of
process (kinetic control).
Let’s Think
CH3
Chemistry XXI
SN2
If we are able to reduce
the activation energy
required to form either the
transition state in SN2 or
the intermediate
carbocation in SN1 we
may favor one mechanism
over the other
HO
-
C
-
H
x
R
Transition State
CH3
SN1
-
C+
H
R
Intermediate
What characteristics (composition, structure) of the
reactants may influence the formation and stability of
the transition state or the intermediate?
Major Effects
The formation and stability of different chemical
species is essentially determined by:
Electronic Effects
Chemistry XXI
How is the charge distributed
among atoms?
Steric Effects
How do different parts of a molecule
interact with others?
Factor 1
How bulky is the electrophile (or substrate)?
The degree of substitution on the carbon that is
attacked by the nucleophile has a strong influence
on the reaction rate via SN2 and SN1 mechanisms.
H
Primary
Secondary
C
H
X
R1
Chemistry XXI
C
R2
X
R2
C
X
R1
R1
Rate
Let′s think!
SN2
SN1
-
C
H
1o
-
How do you explain
these trends?
CH3
CH3
HO
R3
Tertiary
H
x
C
-
+
H
R
2o
3o
1o
2o
R
3o
(Hint: Think of the these
species’ stability.)
Factor 1
How bulky is the electrophile (or substrate)?
The bulkier the electrolyte, the more difficult for
the nucleophile to attack (steric effects).
SN2
R3
R2
Nu:
Chemistry XXI
C
X
Ea
Rate
R1
Substituents can stabilize the carbocation by charge
induction or delocalization (electronic effects).
Planar Trigonal
R3
C+
Ea
+
SN1
Nu:
R1
R2
Rate
Let’s Think
Imagine that you have three possible drug
precursors that you want to modify to generate an
H-bonding product with well defined chirality.
Chemistry XXI
Br
CH
Which of
these
precursors
is your best
option?
Why?
C
HC
Br
CH
CH
CH
CH
CH
CH2 HC
CH
CH
Br
CH3
C
HC
CH
CH
H2C
CH2
CH2
CH2
CH3
Factor 2
How strong is the nucleophile?
The strength of nucleophiles depends on their
charge and the stability of such a charge:
Weak:
H
H
Moderate:
Chemistry XXI
N
O
H
H
H
R
H
O
Cl
C
R
Strong:
N
O
HO
Br
I
-
R
-
-
N
O
R
R
H
Same period:
Nucleophilicity
increases with
basicity.
Same group:
Nucleophilicity
increases with
polarizability.
Factor 2
How strong is the nucleophile?
How would you expect the rate to change with the
strength of the nucleophile? How would the
strength affect the energy profile for the reaction?
Chemistry XXI
Rate
SN2
SN1
W
S
Let′s think!
S
M
More reactive nucleophiles
tend to be less stable.
M
Ea
W
Rate
Factor 3
How stable is the leaving group?
We can expect that the more stable a leaving group
is, the easier will be to displace it.
-
HO
N
R
F
R
Cl
Br
H
Bad
Chemistry XXI
N
O
I
H
H
H
Excellent
Increasing Leaving Ability
Let′s think!
H
How would you explain this trend?
How would you expect this factor to
affect the SN2 and SN1 mechanisms?
Factor 3
How stable is the leaving group?
SN2
Rate
Chemistry XXI
Ex
Good
Bad
SN1
Ex
Good
Bad
The effect is similar, but more pronounced for the
SN1 mechanism.
The rate limiting step in SN1 is precisely the loss of
the leaving group.
Let’s Think
Imagine that in the synthesis of a drug you were
interested in substituting one of the groups
attached to the ring. Which one would be easier
to eliminate? Why?
CH3
O
H3C
CH2
CH2
S
O
Chemistry XXI
O
HC
CH
CH2
O
O
CH2
H3C
CH2
N
H3C
HC
CH2
CH
CH2
CH2
C
NH
CH3
Factor 4
What is the solvent?
The solvent in which the reaction takes place may
have a strong impact on the reaction mechanism.
A solvent’s effect depends on its ability to stabilize
the nucleophile (SN2) or the transition state (SN1).
Chemistry XXI
DG
Less Polar
DG
SN2
SN1
More Polar
Reaction Progress
Polar (aprotic)
Polar (protic)
H 2O
CH3OH
Reaction Progress
How can we explain these results?
Factor 4
What is the solvent?
Chemistry XXI
Polar solvents stabilize the
carbocation in SN1, reducing
Ea and increasing the rate.
Polar protic solvents tend to trap
negatively charged nucleophiles.
They stabilize the nucleophile,
increasing Ea in SN2 mechanisms
and thus reducing the rate.
Polar aprotic solvents leave the nucleophile free,
favoring an SN2 mechanism.
Reaction Control
The analysis in this module reveals central issues in
the prediction and control of chemical reactions:
Chemistry XXI
 All of the factors that influence a chemical
reaction can be identified and understood by
carefully examining the reaction mechanism.
 The outcome of a chemical reaction is largely
controlled by steric (exclusion factors) and
electronic (charge stability) effects.
 By changing the composition and structure of
the reactants, or of their environment, we can control
both the extent (DGrxn; thermodynamic control) and
rate (Ea, mechanism; kinetic control) of a reaction.
Chemistry XXI
Let′s apply!
Assess what you know
Drug Development
In general, chemical reactions can be used to
introduce structural changes that:
 Increase activity;
 Reduce side-effects;
 Facilitate drug administration.
Derivatives
Morphine
Chemistry XXI
Main strategies
 Variation of substituents;
Receptor
 Structural extension and
rigidification.
Receptor 1
Receptor 2
Predict
Let′s apply!
The following processes have been chosen to
introduce structural changes in some drugs.
Predict whether the reaction will proceed via
SN1 or SN2 mechanisms.
CH2
CH2
HC
H2C
CH2
Chemistry XXI
H2C
Cl
CH2
OH- Nuc-
DMSO
Solvent
CH2
CH2
CH3
H2C
C
H2C
CH2
CH2
Br
H2O
Design
Let′s apply!
Imagine that you need to add a H-bonding site to a
specific region of a drug molecule.
You want also to produce a chiral product.
What reactants and
reactions conditions
would you choose:
Chemistry XXI
Cl
CH
H3C
CH3
CH2
Nuc-: OH-, H2O, R-OSolvent- H2O, DME
Chemistry XXI
Work in pairs to complete
the summary table below. In
each case, indicate the type
of mechanism, SN1 or/and
SN2, that is favored.
Substrate
Nucleophile
Leaving Group
Solvent
1o-
Strong-
Bad-
Polar protic-
2o-
Moderate-
Good-
Polar aprotic-
3o-
Weak-
Excellent-
Selecting the Reactants
d-
Summary
Chemistry XXI
Many chemical reactions result from
the interaction between electron-rich
sites in a molecule (the nucleophile)
and electron-poor sites in another
molecule (the electrophile).
d+
d-
d+
The extent and rate of these processes are influenced
by multiple factors that can be classified into two
main groups: electronic and steric effects.
The effect of these factors may be identified and
understood by carefully examining the
reaction mechanism.
Substitution Reactions
For example, substitution reactions are used to
“substitute” one nucleophile for another in a molecule.
R-X + Nu:  R-Nu + X:
Chemistry XXI
They may occur via SN1 or SN2 mechanisms,
depending on the effect of these types of factors:
Substrate
Nucleophile
Leaving Group
Solvent
1o- SN2
Strong- SN2
Bad- Neither
Polar protic- SN1
2o- Both
Moderate- Both
Good- Both
Polar aprotic- SN2
3o- SN1
Weak- SN1
Excellent- SN1
Chemistry XXI
Are You Ready?
Malic Acid
Chemistry XXI
Malic acid is a weak carboxylic acid. It is a
common ingredient in many sour or tart foods.
Malic acid is found mostly in unripe fruits and it
is an important intermediate in many
biochemical cycles.
Polyprotic Acids
Malic acid is a polyprotic acid
(an acid that can lose more than one proton)
Chemistry XXI
In particular, malic acid
is a diprotic acid.
Let′s think!
Identify the two acidic protons in this
molecule and decide which is more
acidic. Justify your reasoning.
Let’s Think
Write the chemical equations that represent the
two dissociation processes undergone by
malic acid when dissolved in water.
K1 = 3.98x10-4
Chemistry XXI
1)
-
+ H2O
+ H3O+
K2 = 7.94x10-6
2)
-
+ H2O
-
-
+ H3O+
Calculate the pKa and identify the conjugate
acid/base pairs in each case.
pH
The average concentration of malic acid (C4H6O5)
in apple juice is close to 8.0 g/L.
Chemistry XXI
Let′s think!
Estimate the pH of this solution by
assuming that the acidity of the solution
is determined by the first dissociation of
malic acid (pK1 = 3.4).
C4H6O5 + H2O   C4H5O5- + H3O+
Co = 8.0/134.09 = 6.0x10-2

x  Co K a  (Co K a )1/ 2  4.9 x103
x
pH = -log (x) = 2.3
Dissociation
The dissociation of malic acid in water can be
represented as:
H2A + H2O   HA- + H3O+
Chemistry XXI
HA-
Let′s think!
+ H2O  
A2-
+
H3O+
K1  103.4
K 2  10 5.1
How many times larger is the concentration
of H2A than HA- in our stomach (pH = 2.0)
when we drink apple juice?
[ H 2 A]
pK1  pH
1.4

10

10
~ 25

[ HA ]
Chirality
Malic acid has one chiral carbon
Which is it?
Chemistry XXI
Let′s think!
In Nature, almost all malic
acid appears in the L- form.
L
Malic acid is produced
commercially in the
D-/L- racemic mixture.
D
Synthesis
The presence of D-malic acid in juice or wine thus
indicates that artificial flavor has been added.
Imagine you want to synthesize
L-malic acid using this reactant
Chemistry XXI
Cl
How could you ensure the formation of the right
optical isomer using a substitution reaction?
a) What nucleophile would you use?
b) What solvent?
Justify your reasoning.
Let′s think!