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The central goal of this unit is to help you identify the environmental and structural factors that can

be used to control chemical reactions.

Unit 6How do we control chemical change?

In order to control chemical processes, we

need to consider two important factors:

STRUCTURE

ReactantsProducts

CONDITIONS

T and PSolvent

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How do we control chemical change?

M4. Selecting the Reactants

M2. Changing the Environment .

M3. Analyzing the ProductsAnalyzing the effect of charge

stability.

Exploring the influence of external factors.

Evaluating the impact of electronic and steric effects.

M1. Characterizing InteractionsRecognizing interactions

between reacting molecules.

FOUR MAIN MODULES

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Context

To illustrate the power of chemical ideas and models in controlling chemical change, we will focus our

attention in understanding the synthesis and properties of drugs and the way they interact inside

our body.

Why do you think drug designers and pharmacists may be interested in learning how to control chemical

reactions ?Why do

we care?

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The Problem

Drugs are chemical compounds that interact with a biological system to produce a biological response.

It is thus of central importance to know how to control their synthesis as well as their chemical

behavior inside our body.

Drugs should be able to resist decomposition inside our body and target specific

organs or sites without affecting others.

Tetracycline

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How do we control chemical change?

Module 1: Characterizing Interactions

Central goal:

To characterize the nature and effect of

interactions between polar molecules and

water.

-

+

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The Challenge

Drugs interact with a variety of systems in our body: in the stomach, in the bloodstream,

inside cells. Drug action and delivery depends on the nature and effect of these interactions.

TransformationHow do I change it?

How can we predict the types of interactions

that drugs will have with their surroundings?

Recognizing potential interactions between substances is crucial in controlling chemical reactions.

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The Setting

The structure that drugs adopt inside our body depends on their interactions with substances such

as water, lipids, proteins, and nucleic acids.

How do drugs react with water?

How can we predict the outcome?

In most cases, the interaction of drugs with water produces a chemical reaction that alters the charge

distribution in these molecules. This in turn affects the way drugs interact

with other substances.

-

+

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Water molecules are polar and many chemical reactions in which these molecules participate are

driven by interactions with their positive and negative charge centers.

Polar Water

-

+

H2O - +

Proton (H+) transfer is common in water. This is a FAST process (equilibrium is reached quickly)

that leads to redistribution of charge.

H3O+

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Liquid Water

Proton transfer even occurs between two water molecules :

H2O (l) + H2O(l) H3O+(aq) + OH-(aq)

22

3

][

]][[

OH

OHOHKc

Auto-ionization is not thermodynamically favored, though. In pure liquid water:

[H3O+] = [OH-] = 1.0 x 10-7 M at 25 oC

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]][[][ 32

2 OHOHOHKK cw

Given that [H2O] does not change much by auto-ionization, we can take it as a constant and include it as part of the auto-ionization equilibrium constant:

Water’s Auto-Ionization

H2O (l) + H2O(l) H3O+(aq) + OH-(aq)

Kw = [H3O+][OH-] = (1.0 x 10-7)2 = 1 x 10-14

The value of the auto-ionization constant Kw for water at 25 oC is then:

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pH and pOH

It is common to express and monitor the concentrations of H3O+ and OH- in water solutions

using pH or pOH values:

pH = -log [H3O+]

pOH = -log[OH-]

Given that Kw = [H3O+][OH-] = 1 x 10-14

ALWAYS in water solutions:

pH + pOH = 14 in water solutions.

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Water as a ReactantMany substances react with water via proton transfer

and alter the concentration of H3O+ and OH- ions in solution (change the pH).

pH scale

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ILet’s Think

The pH of Milk of Magnesia is close to 10.5; that of our stomach is close to 2.0.

How many times larger is [H3O+] in our stomach compared to [OH-] in Milk of Magnesia?

6.311016.3

1000.1

10

10

10

10

][

][4

2

145.10

23

x

x

OH

OHpOH

pH

H3O+(aq) + OH-(aq) 2 H2O (l)Given that the reaction:

is pretty favored.

What would you expect to happen when equal amounts of these two solutions are mixed?

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Those substances that react with water via proton transfer are classified as

Brønsted-Lowry acids or bases:

Acid-Base Reactions

B-L AcidsProton Donors(Increase H3O+)

HCl(g) + H2O(l)

-

+

B-L BasesProton Acceptors

(Increase OH-)NH3(g) + H2O(l)

-

+

Cl (aq) + H3O+(aq)

Hydronium Ion

NH4+(aq) + OH (aq)

Hydroxide ion

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Predict the outcome of the reaction of these drugs with water. Determine whether they behave as

acids or bases in this solvent.

B-L AcidProton Donor

+ H3O+(aq) -+ H2O(l)

Aspirin

+ H2O(l)

Ephedrine

+ OH-(aq)

B-L BaseProton Acceptor

2+

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Conjugate Species

HCl(g) + H2O(l) Cl (aq) + H3O+(aq)

Conjugate AcidBaseConjugate BaseAcid

In these reactions, new acids and bases are formed:

Acid

Conjugate AcidBase

Cl-(aq) + H2O HCl(aq) + OH-(aq)

Conjugate BaseBase Conjugate Acid

NH3(g) + H2O(l) NH4+(aq) + OH-(aq)

What happens

in this case?

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The solubility and activity of most drugs strongly depends on their acid-base properties.

Identify all of the conjugate pairs in these acid-base equilibria involving common drugs?

C4H4N2O3(aq) + H2O(l) C4H3N2O3 (aq) + H3O+(aq)

C17H19NO3(aq) + C6H8O6(aq) C17H20NO3+(aq) + C6H7O6(aq)

Barbituric Acid Barbiturate Ion (Base)

Morphine

(Base)

Morphine Ion

(Acid)

C9H8O4(aq) + C6H7O7+(aq) C9H7O4

(aq) + C6H8O7(aq) Acetylsalicylic

AcidAcetylsalicylate Ion

(Base)

Ascorbic Acid

Ascorbate Ion (Base)

Citrate Ion (Base)

Citric Acid

Base Acid

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StrengthThe extent to which an acid or base reacts with water

determines its strength.

HCl(g) + H2O(l) Cl (aq) + H3O+(aq)

HCl is a strong acid.

1][

]][[ 3

HA

AOHKa

For a strong acid HA:

HA(aq) + H2O(l) A-(aq) + H3O+(aq)

HCl, HNO3, H2SO4

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Weak acids are much less than 100% ionized in water.

1][

]][[ 3

HA

AOHKa

Strength

Similar ideas can be applied to evaluate the strength of basic substances.

HA(aq) + H2O(l) A (aq) + H3O+(aq)

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HA(aq) + H2O(l) A (aq) + H3O+(aq)

In general, we can use the value of these dissociation constants to judge acid/base strength.

Strength

If we take, Ka x Kb for a conjugate pair, we see that:

The larger the value of Ka (the stronger the acid), the smaller Kb (the weaker the conjugate base).

][

]][[ 3

HA

AOHKa

][

]][[

A

OHHAKb

wba KOHOHA

OHHAx

HA

AOHKK

]][[][

]][[

][

]][[ x 3

3

A (aq) + H2O(l) HA(aq) + OH-(aq)

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C4H4N2O3/C4H3N2O3

Identify the “strongest” species

in each pair.

C17H20NO3+/C17H19NO3

C9H8O4/C9H7O4

Barbituric/Barbiturate

Morphine Ion/Morphine

Acetylsalicylic/Acetylsalicylate

Ka = 9.77 x 10-5

Kb = 7.4 x 10-7

Ka = 3.16 x 10-4

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IpKa and pKb

It is common to express the strength of an acid or a base using these quantities:

pKa = - log (Ka)

pKb = - log (Kb)

The larger the value of pKa, the weaker the acid.The larger the value of pKb, the weaker the base.

For a conjugate acid/base pair:

pKa + pKb = 14

Let’s Think

pKa = 7.4pKa = 8.1

Pentobarbital Phenobarbital

Which is a stronger acid?

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Let′s apply!

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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.

The strongest acids tend to be carboxylic acids (pka ~ 4) ; the weakest tend to be

barbiturates.

pKa ~ 8

Most of the basic drugs contain amine groups.

pKa ~ 9

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The analysis of the acid-base properties of drugs is crucial to understand and control their

behavior in our body.

For example, in the stomach, drugs such

as morphine and aspirin mainly exist in their “acid” form.

MorphineC17H20NO3

+

AspirinC9H8O4This determines which

will be absorbed faster.

Drugs’ Behavior

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MorphineC17H20NO3

+

AspirinC9H8O4

Let′s apply! Predict

Which of these two drugs will be absorbed at a faster rate through stomach cell membranes

(made of lipids)?

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Drugs’ Behavior

Ionic forms are more likely to be soluble in water and insoluble in cell membranes, made of non-polar lipids. Thus, charged species tend to be

absorbed at a slower rate.

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Let′s apply! Infer

OH

CHCH

C

CH CH

C NH

C

CH3

O

CH

CH CH

CH

CC

C

O

OH O C

CH3

O

CH

C

CH CH

C

CH

CH

CH3

C OH

O

CH2

CHCH3

CH3

Tylenol

Aspirin

Ibuprofen

Which proton are these drugs likely to transfer

to water? Write the chemical equation of

their reaction with water.

All of these analgesics are acidic.

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Let′s apply! Identify

OH

CHCH

C

CH CH

C NH

C

CH3

O

CH

CH CH

CH

CC

C

O

OH O C

CH3

O

CH

C

CH CH

C

CH

CH

CH3

C OH

O

CH2

CHCH3

CH3

Tylenol

Aspirin

Ibuprofen

Which is stronger, the acid form of each analgesic or its

conjugate base?

pKa = 3.5pKa = 4.5

pKa = 9.1

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Discuss with a partner what are the main differences between a weak

acid and a strong base.

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Characterizing Interactions

Summary

Many substances react with water via proton transfer and alter the concentration of H3O+ and OH- ions in

solution (change the pH).

These reactions are driven by the interactions between + and – charge centers.

-

+

Brønsted-Lowry AcidsProton Donors(Increase H3O+)

Brønsted-Lowry BasesProton Acceptors

(Increase OH-)

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Dissociation

Although acids and bases change [H3O+] and [OH-] in water, the concentration of these ions is related by:

Kw = [H3O+][OH-] = 1 x 10-14 in water at 25 oC.

We can use the value of equilibrium dissociation constants to judge acid and base strength:

HA(aq) + H2O(l) A (aq) + H3O+(aq)][

]][[ 3

HA

AOHKa

][

]][[

B

OHBHKb

B(aq) + H2O(l) BH+(aq) + OH-(aq)

Acid Conjugate Base

Base Conjugate Acid

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For next class,

Investigate how changes in concentration and temperature affect acid-base reactions.

How does chemical equilibrium shift in an acid-base reaction when the concentration of

reactants or products are changed?