1. Unit 6 How do we control chemical change?
The central goal of this unit is to help you identify the structural and environmental factors that can be used to control chemical reactions.
Recognizing interactions between reacting molecules.
M1. Characterizing Interactions
Exploring the influence of external factors. .
M2. Changing the Environment
Every Course Unit includes a brief description of the central learning objectives of each Module in the Unit
M3. Analyzing the Products
Analyzing the effect of charge stability.
Evaluating the impact of electronic and steric effects.
M4. Selecting the Reactants

2. How do we control chemical change? Module 4: Selecting the Reactants
Unit 6
How do we control chemical change?
Module 4: Selecting the Reactants
Central goal:
To identify the steric and electronic factors that determine the outcome of chemical processes.
Each Module begins with a description of the central learning objective for the Module.

3. Transformation How do I change it?
The Challenge
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.
“The Challenge” describes the types of problems or questions that we would like to be able to answer by the end of the Module.
Questions in green are rhetorical questions. They are included to invite students to think and brainstorm initial ideas.
How can we design and synthesize drugs with specific binding capacities?

4. 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.
Dispersion
H-bonding
Ion-Ion O H
H3N + -

5. Amoxicillin: An antibiotic
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.
Let′s think!
Amoxicillin: An antibiotic

6. Amine (H-bonding and Ion-Ion) Carboxyl (H-bonding and Ion-Ion)
Binding Groups
Amine (H-bonding and Ion-Ion)
Alkyl (Dispersion)
Phenyl (Dispersion)
Ketone (H-bonding)
Carboxyl (H-bonding and Ion-Ion)
Hydroxyl (H-bonding)
Amoxicillin

7. Polar Reactions
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).
Nucleophile (Negative or with high e- density) d- d+
Electrophile (Positive or with low e- density) d- d+

8. 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: X
Imagine that we were interested in introducing an hydroxyl –OH group to enhance H-bonding in a drug. d+
Electrophile d-
Electronegative
We could try to use:
HO:
Nucleophile

9. Under some conditions: Under other conditions:
Experiments
R-X + Nu:  R-Nu + X:
Kinetic experiments indicate that there are two main routes through which this reaction may happen:
Under some conditions:
Rate = k [Nu-][R-X]
2nd Order
Change in Chirality
Under other conditions:
Rate = k [R-X]
1st Order
Racemization
How do we explain it?

10. Mechanism 1 One possibility is: x x x One-Step Bimolecular process:
Transition State x x
One-Step Bimolecular process:
Rate = k[OH-][R-X]
2nd Order
Important:
The configuration of the carbon atom is inverted in this process.
(Configuration Inversion)
SN2

11. SN2
DGrxn Ea DG

12. Mechanism 2
A second possibility for this reaction, is a two-step mechanism:
Step 2 Fast
Intermediate +
Step 1 Slow x
Two-step process:
Rate = k [R-X]
1st Order
Important:
The reaction produces both enantiomers.
(Racemization)
SN1

13. SN1
Ea1
Ea2
DGrxn DG
Rate Limiting

14. How can we control whether the reaction mechanism is SN1 or SN2?
Reaction Control
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).

15. Let’s Think x
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
Transition State +
SN1
Intermediate
What characteristics (composition, structure) of the reactants may influence the formation and stability of the transition state or the intermediate?

16. Major Effects
The formation and stability of different chemical species is essentially determined by:
Electronic Effects
How is the charge distributed among atoms?
Steric Effects
How do different parts of a molecule interact with others?

17. How bulky is the electrophile (or substrate)?
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.
Primary
Secondary
Tertiary
Let′s think!
How do you explain these trends?
Rate
1o o o
SN2
1o o o
SN1 x +
(Hint: Think of the these species’ stability.)

18. How bulky is the electrophile (or substrate)?
Factor 1
How bulky is the electrophile (or substrate)?
The bulkier the electrolyte, the more difficult for the nucleophile to attack (steric effects).
SN2 Ea
Rate
Nu:
Substituents can stabilize the carbocation by charge induction or delocalization (electronic effects). +
Nu:
Planar Trigonal
Rate Ea
SN1

19. Which of these precursors is your best option? Why?
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.
Which of these precursors is your best option? Why?

20. Factor 2 How strong is the nucleophile?
The strength of nucleophiles depends on their charge and the stability of such a charge:
Weak:
Same period: Nucleophilicity increases with basicity.
Same group: Nucleophilicity increases with polarizability.
Moderate: Cl Br I
Strong: HO

21. How strong is the nucleophile?
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?
SN2
SN1
Rate
Let′s think!
S M W
S M W
More reactive nucleophiles tend to be less stable.
Rate Ea

22. How stable is the leaving group? Increasing Leaving Ability
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. F Cl Br I HO
Bad
Excellent
Increasing Leaving Ability
Let′s think!
How would you explain this trend? How would you expect this factor to affect the SN2 and SN1 mechanisms?

23. Factor 3 How stable is the leaving group? Rate
SN2
SN1
Rate
Ex Good Bad
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.

24. 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?

25. How can we explain these results?
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).
Polar (protic) DG
Reaction Progress
Polar (aprotic)
SN2
H2O CH3OH DG
Reaction Progress
Less Polar
More Polar
SN1
How can we explain these results?

26. Factor 4 What is the solvent?
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.

27. Reaction Control
The analysis in this module reveals central issues in the prediction and control of chemical reactions:
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.

28. Let′s apply!
Assess what you know

29. Drug Development
In general, chemical reactions can be used to introduce structural changes that:
Increase activity;
Reduce side-effects;
Facilitate drug administration.
Derivatives
Morphine
Receptor
Main strategies
Variation of substituents;
Structural extension and rigidification.
Receptor 2
Receptor 1

30. 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.
OH-
Nuc-
Solvent
DMSO
H2O

31. What reactants and reactions conditions would you choose:
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:
Nuc-: OH-, H2O, R-O-
Solvent- H2O, DME

32. Work in pairs to complete the summary table below
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-

33. Selecting the Reactantsd-
Summary
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.

34. Substitution Reactions
For example, substitution reactions are used to “substitute” one nucleophile for another in a molecule.
R-X + Nu:  R-Nu + X:
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

35. Are You Ready?

36. Malic Acid
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.

37. In particular, malic acid is a diprotic acid.
Polyprotic Acids
Malic acid is a polyprotic acid (an acid that can lose more than one proton)
In particular, malic acid is a diprotic acid.
Identify the two acidic protons in this molecule and decide which is more acidic. Justify your reasoning.
Let′s think!

38. 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 -
+ H3O+ 1)
+ H2O
K2 = 7.94x10-6 -
+ H3O+
+ H2O 2)
Calculate the pKa and identify the conjugate acid/base pairs in each case.

39. pH
The average concentration of malic acid (C4H6O5) in apple juice is close to 8.0 g/L.
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).
Let′s think!
C4H6O5 + H2O   C4H5O5- + H3O+
Co = 8.0/ = 6.0x  x
pH = -log (x) = 2.3

40. The dissociation of malic acid in water can be represented as:
H2A + H2O   HA- + H3O+
HA- + H2O   A2- + H3O+
How many times larger is the concentration of H2A than HA- in our stomach (pH = 2.0) when we drink apple juice?
Let′s think!

41. Malic acid has one chiral carbon
Chirality
Malic acid has one chiral carbon
Which is it?
Let′s think! L D
In Nature, almost all malic acid appears in the L- form.
Malic acid is produced commercially in the D-/L- racemic mixture.

42. Justify your reasoning.
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 Cl
How could you ensure the formation of the right optical isomer using a substitution reaction?
What nucleophile would you use?
What solvent?
Justify your reasoning.
Let′s think!