unit 6 how do we control chemical change?

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

be used to control chemical reactions.

Unit 6How 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.

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IUnit 6

How do we control chemical change?

Module 2: Changing the Environment

Central goal:

To analyze the effect concentration,

temperature, and nature of the solvent on reaction extent.

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The Challenge

Drugs must travel through different part of our body before

reaching their final target.

TransformationHow do I change it?

How can we predict the effect of different

environmental conditions on their structure and

properties?

How can we take advantage of this knowledge to control their behavior?

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The extent (Thermodynamics) and rate (Kinetics) to which a substance, like an drug, reacts with

another, like water, depends on the environmental conditions.

Reaction Control

We can affect and control chemical reactions by

changing the concentration of reactants and products, the temperature and pressure of

the surroundings, or the nature of the solvent in which

the process takes place.

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Fast Processes

Proton (H+) transfer in water is a fast process. Thus, we are more interested in controlling the thermodynamics than the kinetics of acid-base

reactions in liquid water.

Thus, we will focus our attention on how

to control reaction extent

in this case.

CONCENTRATION

TEMPERATURE

SOLVENT

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

Let us consider an acidic drug HA that undergoes this type of reaction when dissolved in water:

Concentration Effects

For example, phenobarbital, the most

widely used anticonvulsant worldwide.

pKa = 7.4

][

]][[ 3

HA

AOHKa

What factors will determine the values of [H3O+], [A-], and [HA] at equilibrium?

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The actual concentration of each species at equilibrium depends on the values of Ka and the

initial concentrations [HA]o, [A-]o, and [H3O+]o.

][

]][[ 3

HA

AOHKa

Let us now analyze the case in which the initial values of [A-]o and [H3O+]o are negligible

compared to the value of [HA]o.

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Equilibrium Values (Acids)

If the initial concentration of HA in water is Co(mol/L) and we assume that x amount reacts with water:

Initial Co 0 1 x 10-7

Final Co- x x x + 1 x 10-7

If we assume that x << Co but x >> 1x10-7,

and we know that:

][

]][[ 3

HA

AOHKa

][

]][[

oa C

xxK

2/1)( aoao KCKCx

Higher Co Higher x

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ILet’s Think pKa = 7.4

Phenobarbital (HA) has poor solubility in water ~ 1.0 g/L.

Estimate the pH of a saturated solution of this drug.

2/1)( aoao KCKCx

M(C12H12N2O3) = 232.2 g/mol

M 103.42.232

mol 10.1 3 x

gx

L

gCo

2/14.73 )10103.4( xxx M 103.1 5 xx

Are our assumptions (x >> 1.0 x 10-7) valid?

pH = -log (x) = 4.9

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Equilibrium Values (Bases)

A similar procedure can be followed to determine the equilibrium concentrations when a base reacts

with water:

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



][

]][[

B

OHBHKb

][

]][[

ob C

xxK

2/1)/( awobo KKCKCx wba KKK

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ILet’s Think

Due to the poor solubility of its acid form (HA),

phenobarbital is often administered as an ionic salt of its basic form (A-) (100 times more soluble).

][

]][[

A

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

If we know that this reaction will take place in water:

pKa = 7.4

Estimate the pH of a a saturated solution of sodium phenobarbital (100. g/L).

M(NaC12H11N2O3) = 254.2 g/mol

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



)10/101093.3()/( 4.71412/1 xxKKCKCx awobo

][

]][[

A

OHHAKbM(NaC12H11N2O3) = 254.2 g/mol

M 1093.32.254

mol 1.100 1 x

gx

L

gCo

Let’s Think

][

]][[

ob C

xxK wba KKK

41014.3][ xOHxpOH = 3.5 pH = 10.5

Higher Co Higher x

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Imagine now that you have an acid in equilibrium in aqueous solution and you decide to add more

acid. What would you expect to happen to the concentration of the other species?



]][[ 2OHHAkRate ff

]][[ 3 OHAkRate bb

Increasing [HA] increases Ratef compared to Rateb.

Kinetic ArgumentMore A- and H3O+ will be produced until the rates

become equal again.

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eq

eqeqa HA

AOHK

][

][][ 3

nHA

AOHQ

][

]][[ 3

<Actual Value

Equilibrium Value

Thermodynamic Argument

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CH

CH CH

CH

CC

C

O

OH O C

CH3

O

Imagine you have a 0.125 M aqueous solution of

aspirin, an acid drug with pKa = 3.5, in equilibrium.

Let’s Think

a) Estimate the pH of the solution.

b) Predict what would happen to the pH when:

you add more A-; you add more HA; you add OH-

you add more H2O;

Use both, kinetic and thermodynamic arguments.

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Use the simulation at

http://www.chem./arizona.edu/chemt/C21/sim

Acid

to verify your estimates and predictions.

Let’s Think

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Let’s Think

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Understanding how the concentration of one species affects the concentrations of the others is crucial to predict and control the form that a drug

will take in different parts of our body.

Drugs go through various parts of our body that

have relatively fixed but different values of pH.

How do the drugs change? Where are they

more likely to be absorbed?


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Equilibrium Ratios

The ratio of the conjugate forms of and acid-base pair is determined by the equilibrium constant:

][

]][[ 3

HA

AOHKa

][][

][

3

OH

K

HA

A a

By taking logarithms, this relationship can be transformed into:

pKapHOHKHA

Aa

]log[log][

][log 3

][

][log

HA

ApKapH

Henderson-HasselbalchEquation

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Henderson-Hasselbalch

pKapHHA

A

][

][log

For example, [HA] = [A-] when pH = pKa

How much of a an acid is in A- or HA form depends on the pH of the medium

where we put it.

When analyzing drugs, it is useful to calculate the percentage of the drug that exist in acid or basic form

in different parts of the body:

100][][

][% x

HAA

AA

pHpKa

AHA

101

100

][][

1

100

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% Ionization = % A-

if pH > pKa

[A-] > [HA]

[A-][A-] < [HA]

if pH < pKa

[HA]

pHpKaA

101

100%

Consider a drug with a pKa = 4.0.

AHA %100%

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Let’s Think

Determine the dominant form of each of these drugs in different parts of the body.

What % of the drug is ionized at each point?Where is the drug more likely to be absorbed?

Drug Stomach

(pH = 2.0)

Duodenum

(pH = 6.0)

Jejunum

(pH = 7.5)

Aspirin

(Acid, pKa = 3.5)

Phenobarbital

(Acid, pKa = 7.4)

Ephedrine

(Base, pKa = 9.6)

3.1% A- 99.7% A- 99.99% A-

4x10-4% A- 3.8% A- 55.7% A-

3x10-6% A- 3x10-1% A- 0.8% A-

pHpKaA

101

100%

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Temperature Effects

The extent of a chemical reaction can also be controlled by changing the temperature of the system.

As we have seen before, the higher T the greater

the fraction of molecules with enough energy to

react.

RT

Ea

Aek

k

T

Reaction rate increases with T.

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Temperature Effects

The effect of temperature on reaction rate depends on the activation energy Ea of the reaction.

RT

Ea

Aek

The effect is more pronounced

the higher the value of Ea.

P

R

Ep

Reaction Coordinate

Eaf

Eab

Thus, for a system in equilibrium, the forward and backward rates are not affected in the same proportion and there is a shift in the equilibrium.

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P

R

Ep

Reaction Coordinate

Eaf

Eab

Use a kinetic argument to make a prediction

about the effect on the equilibrium for these two

types of reactions.

P

R

Ep

Reaction Coordinate

Eaf Ea

b

Let’s Think

Endothermic/Exothermic processes

(Ho > 0/Ho < 0) shift towards

products/reactants at higher T.

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Thermodynamic Argument

The same conclusion can be derived by analyzing the

effect of T on the equilibrium constant:

)(RT

Gorxn

eK

Gorxn= Ho

rxn–TSorxn

)(R

S

RT

H orxn

orxn

eK

This approach allows us to see that it is actually the

sign of Horxn which

determines the effect of T.

Exothermic T K

Endothermic T K

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Use the simulation at

http://www.chem./arizona.edu/chemt/C21/sim

Acid

to determine whether the reaction is exothermic or endothermic.

Let’s Think

H2O molecules not shown

in the simulation

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Let’s Think

How does the temperature affect the pH of this solution?

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Solvent Effects

The rate and extent of a reaction can also be controlled by changing the solvent in which the

process takes place.

A given solvent can stabilize or destabilize

the reactants or products of a reaction, or the

transition state.

Thus, they may affect both reaction rate and extent.

PR

G

Reaction Coordinate

Sol1

Sol2

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Solvent Effects

In acid-base reactions, the effect of the solvent is crucial because it is actually one of the reactants:

HA + SH A + SH2+

Let′s think!Many drugs are insoluble in water. Thus, to measure their acid-base it is common to use other solvents,

such as methanol (CH3OH).

The Ka of most carboxylic drugs in CH3OH decreases by a factor of 105

compared to that in water. How do you explain it?

Formation of ions is

less likely in less polar solvents.

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Our analysis reveals the central role that environmental factors play in the extent and rate of

chemical processes:

We can control the extent and rate of chemical reactions by altering the concentration of reactants and products, modifying the temperature and pressure of the system, or changing the solvent in which the reaction takes place.

The effect of these factors is better understood by considering both kinetic and thermodynamic arguments.

Reaction Control

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Let′s apply!

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Amino Acids and ProteinsAs we know, proteins are natural polymers made of

amino acid chains.

Amine Carboxyl

Peptidebond

Amino Acid

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The average pH inside cells is close to 7.4 (similar to blood plasma). Calculate the % ionization of these amino acid residues and predict which of them will

mostly be in their ionized forms.

Let′s apply! Predict

Neutral

AcidpKa = 3.9

AcidpKa = 8.3

BasepKa = 10.8

AcidpKa = 10.1

99.96% 0.2% 11.2% 99.97%

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The presence of charged groups helps the protein to fold due to ion-ion interactions and

ion-dipole interactions between residues.

Protein folding can be represented as a chemical process:

Unfold Fold

Protein Folding

This process is affected by temperature.

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Let′s apply! Predict

The unfolded form of a protein is favored a higher temperatures.

The unfolded species does not have

catalytic properties.

How do you explain the effect of temperature on folding from the kinetic and the thermodynamic perspectives?

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Imagine someone gives you the pKa of a drug. Work with a partner making a list of the things you could tell that person about the properties of the drug outside and inside your body.

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Changing the Environment

Summary

We can control the extent of a reaction by altering the concentration of reactants and products, modifying the temperature, or changing the solvent in which the reactions takes place.

Given the expression and value of the dissociation constant for and acid or base in water (pKa, pKb), we

can evaluate things such as:

pH of solution;Degree of dissociation as function of pH;

Effect on pH of changes in C and T.

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For next class,

Investigate what structural features of substances can be used to predict their relative

acid strength.

How can we predict whether one substance will be a stronger acid than another by analyzing

their molecular structure?

unit 6 how do we control chemical change?

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