Medicinal Chemistry - INTRODUCTION TO KINETICS

lecture notes supplement (2010)

Lecturer: Dr. Cheang Khoo

A. Introduction

Chemical kinetics is the study of the rate (or speed) of chemical reactions and the factors
influencing the rate. The rate of a chemical reaction is important for several reasons. For
example, if an explosive reaction is required then a reaction that produces a great deal of
energy in a very short time (µs→ms) is required. Sometimes a slightly slower reaction
rate is required – for example when rocket fuel is burned to produce gases that propel the
rocket, the reaction needs to be fast but an explosive reaction is not desired. A slow
reaction is desired if the aim is to prevent reactions like rusting (an oxidation reaction) or
food spoilage.

The rate of a chemical reaction may be described by the rate of the reactant(s)
disappearing or the rate of the product(s) (of the reaction) appearing. The rate of reactant
disappearance or product appearance will depend on the reaction stiochiometry (or
reaction ratios) as shown in the given example:

Example 1:

For the general reaction:

2A + B → 3C + D

where A and B are the reactants and C and D are the products of the reaction and the
numbers indicate the reaction stiochiometry. The rate expression (do not confuse with
rate law) is given by the expression:

Rate = - 1 d[A] = - d[B] = + 1 d[C] = + d[D] -------------- (i)

2 dt dt 3 dt dt

where d[A] = change in concentration of A ; with similar definitions for B, C, D.

time interval for change

A and B are reactants and are therefore decreasing in concentration with time, hence the
(-)ve sign while C and D are products and therefore increasing in concentration, hence
the (+)ve sign.

Since 2 A’s react with 1 B, for every decrease of 1 unit of B, 2 units of A will decrease.
Thus if we want to write a mathematical expression equating the rate of change of A and
B, we have to multiply the rate of change of A by ½ , as shown in equation (i), or multiply
the rate of change of B by 2.

Comparing the change in concentration of products and reactants over time, the following
plot may be observed:

1
 Concentration of product D

Concentration Axis of symmetry

when stoichiometries
of B & D are the
same.

Concentration of reactant B

Time

The curves are symmetrical about the horizontal intersection point if their reaction
stoichiometries (and therefore rate coefficients) are equal (as is the case for B and D).

Exercise questions:

Exercise A1:
For a general reaction 2A + B → 3C, express the rate of the reaction in the differential
form with respect to each of the species involved.
(Answer: -1/2 d[A]/dt = -d[B]/dt = 1/3 d[C]/dt )

Exercise A2:
For the reaction A + 3B → 2C + 2D, write the rate expression.
(Answer: -d[A]/dt = -1/3 d[B]/dt = ½ d[C]/dt = ½ d[D]/dt)

Exercise A3:
For the reaction A + ½B → 3C + ¼D, write the rate expression.
(Answer: -d[A]/dt = -2 d[B]/dt = 1/3 d[C]/dt = 4 d[D]/dt)

Exercise A4:
Write a stoichiometric equation for the general reaction whose rate is expressed as:

Rate = -d[A] = -½ d[B] = -2 d[C] = d[D] = 2 d[E]

dt dt dt dt dt
(Answer: A + 2B + ½ C → D + ½ E)

Exercise A5:
Write a stoichiometric equation for the general reaction whose rate is expressed as:

Rate = -d[A] = -¼ d[B] = ½ d[C] = d[D] = 3 d[E]

dt dt dt dt dt
(Answer: A + 4B → 2C + D + 1/3 E)

Exercise A6:
The following reaction occurs consecutively:

2
 k1 k2
A → B → C where the reaction rate constants k1 = k2 (that is, the reaction rates
are the same)

Draw a graph for the time variation of the concentrations of A, B and C (concentration y-
axis, time x-axis).

B. Rate Law and Reaction Order

1. Definition and introduction

For the general reaction:

aA + bB + cC + ……… → Product(s),

where A, B, C…. are the reactants and a, b, c are the reaction stoichiometries, the
rate law expression is:

Rate = k[A]x[B]y [C]z

where k = rate constant,

x,y,z… are the orders of the reaction with respect to A, B, C…. respectively.

The overall order of the reaction is the sum of the individual orders, namely x + y + z
+…… The values of x, y, z are usually (though not always) small integers (whole
numbers) and can also include zero.

If x = 1, then the order of the reaction with respect to A is said to be first order. If x = 2,
then it is second order, if x = 3 it is third order and so on.

Note that the orders of the reaction (x, y, z…) do not necessarily follow the reaction
stiochiometries (a, b, c…). The orders of the reaction can only be determined
experimentally and is not obtained by theoretical calculation.

If the order of the reaction is the same as their respective reaction stiochiometries (that is
Rate = k[A]a [B]b [C]c) then the reaction may occur via a single step – that is the a-
number molecules of A, collide with b-number of molecules of B and c-number of
molecules of C to give the products. Single step reactions are uncommon as they are
statistically unfavourable.

2. Rate law determination

The rate law can only be determined experimentally. It cannot be calculated from theory.
That is, the values of k and the orders of the reactant(s) can only be found by conducting
an experiment.

Example 1:
Determine the rate law for the reaction:

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 A + 2B → C + D

from the experimental data obtained:

___________________________________________________
Concentration (M) Rate of formation of C (M s-1)___
A B
0.10 0.10 2.0 x 10-4
0.10 0.20 4.0 x 10-4
0.20 0.20 1.6 x 10-3
0.30 0.20 3.6 x 10-3______________

That is, for the expression: Rate = k[A]x [B]y, determine the values of k, x, and y.

Answer:
From the first and second experimental data, it is observed that keeping [A] constant (0.10
M) while [B] is doubled (from 0.10 to 0.20 M), the rate also doubles (2.0 x 10-4 to 4.0 x
10-4). That is,

‘ [B](concentration) x 2’ leads to ‘rate x 2’; or 2j(concentration) = 2(rate),

therefore j = 1 since 21 = 2. That is, rate α [B]1. (α is the symbol for ‘proportional to’)

The order for [A] may be obtained by using any combination of the last three data sets.
Using the second and third data sets, if [B] is kept constant at 0.20 M and [A] is doubled
from 0.10 to 0.20 M, the rate changes by [(1.6 x 10-3) ÷ (4.0 x 10-4)] or 4 times. Thus

2j(concentration) = 4(rate), therefore j = 2 (since 22 = 4)

That is rate α [A]2.

The same relationship for [A] may be obtained by using the last two data sets where, if
the concentration of [A] is increase 1.5 times (from 0.30 ÷ 0.20), the rate increases 2.25
times (from (3.6 x 10-3) ÷ (1.6 x 10-3)). Thus

1.5j(concentration) = 2.25(rate), therefore j = 2 since 1.52 = 2.25.

That is rate α [A]2, which is the same result as obtained for [A]x earlier.

The rate expression obtained so far is:

Rate = k[A]2 [B]

The value of the rate constant ‘k’ may be obtained by substituting the [A], [B] and rate
values from any one of the data sets. The same k value should be obtained for any data set
used. Using the second data set as an example,

k = __Rate_ = __4.0 x 10-4_(M s-1)____ = 0.20 M-2 s-1

[A]2 [B] [0.10]2 [0.20] ([M]2 [M])

Note therefore that the units for k will depend on the order of the rate expression.

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Exercise questions:

Exercise B1:
For the decomposition of hydrogen peroxide in solution at 25 oC:
2 H2O2 → 2 H2O + O2 (g), the following data was obtained:

Experiment [H2O2] -d[H2O2]/dt

number mmol L-1 mmol L-1 s-1
__________________________________
1 14.45 6.70 x 10-3
2 28.90 13.3 x 10-3
3 57.80 26.7 x 10-3_

a. What is the order of the reaction?

b. What is the rate equation for the reaction?
c. Determine the rate constant for the reaction (at 25 oC)
d. Determine the decomposition rate (at 25 oC) when [H2O2] = 10.0 mmol L-1.
e. Does the rate increase, decrease or remains unchanged as the reaction proceeds?
(Answer: c. 4.6 x 10-4 s-1; d. 4.6 x 10-6 mol L-1 s-1)

Exercise B2:
At 27 oC, the reaction:
2 NOCl → 2 NO + Cl2
is observed to exhibit the following dependence on rate of reaction:

Initial NOCl concentration Initial rate of NO formation

[mmol dm-3] [mmol dm-3 s-1]
0.30 3.60 x 10-9
0.60 1.44 x 10-8
0.90 3.24 x 10-8

a. What is the rate law for the reaction?

b. What is the rate constant?
c. By what factor would the rate increase if the initial concentration of NOCl was
increased from 0.30 to 0.45 M?
(Answer: b. 4.0 x 10-8 L mmol-1 s-1; c. 2.25 times faster)

C. Measurement of reaction rates

Three methods will be discussed. These are the ‘initial rate method’, the ‘integrated rate
law method’ and the ‘half-life’ method.

1. Initial rate method

For this method the initial rate of reaction is determined for various combinations of
reactant concentration. The rate of a reaction is not constant over time since initial
reactant(s) concentration(s) change as the reaction proceeds. If only the initial rate is
measured (that is, the rate at the start of the reaction), the known initial reactant(s)

5
concentration(s) can be assumed to not have changed significantly and the initial
concentration(s) can be used in the rate calculations.

The rate of reaction may be monitored either by measuring the rate of appearance of a
product or the rate of disappearance of a reactant.

Example 1:
Determine the rate for the reaction:

2I- + S2O82- → I2 + 2S2O82-

by measuring the initial rate of formation of the product, I2. We therefore need a method
to determine how long it takes for a certain amount of I2 to form, or the amount of I2
formed in a given time.

In the experiment that will be performed in the laboratory class, the method that will be
used for rate determination for this reaction is the time it takes for a given amount of I2 to
form. This is achieved by placing some starch solution in the reaction mix (that is, starch
+ I- + S2O82-) so that the formation of I2 can be easily detected as it reacts with starch to
form an intense blue colour. However this arrangement does not enable us to know when
a certain concentration of I2 has been reached. This problem is solved by placing in the
reaction mix, a small; accurately known amount of a substance (which is S2O32-) which
quickly reacts with I2 as it is formed (that is the S2O32- uses up the I2 as soon as it is
formed). When all the S2O32- has all been used up, free I2 enters the solution and it reacts
with the starch to give a dark blue colour. Thus the time it takes for the initially clear
solution to go dark, is the time taken for a certain amount of I2 to form. That certain
amount of I2 formed is directly related to the amount of S2O32- added. This amount of
S2O32- takes part in what is referred to as the ‘indicator reaction’.

These reactions are summarised by the following equations:

1. 2I- + S2O82- → I2 + 2SO42- } Reaction being measured

2. I2 + 2S2O32- → 2I- + S4O62- } Indicator reaction

Reaction 2 is much faster than reaction 1.

As mentioned previously, the rate of the reaction is measured by the time it takes for a
predetermined quantity of I2 to form. This quantity of I2 is equal to half the quantity of
S2O32- added as shown in equation 2.

That is: Rate (of I2 formation) = ½ d[S2O32-]

dt

The rate is determined for a given set of [I-] and [S2O82-] concentrations. During the
course of the reaction, [I-] remains absolutely constant while [S2O82-] remains
approximately constant. The concentration [S2O82-] is, of course, known.

Refer to your practical notes for a full discussion of this experiment.

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2. Integrated rate law method

This method of rate law determination shows how the concentration(s) of reactant(s) vary
with time.

For a general reaction: A → products

The half-life (t1/2) of a chemical reaction is the time it takes for the concentration of a
reactant to reach half of its initial concentration.

(a) Zero order rate law:

This is when the order for the reaction is zero. For a zero order rate law reaction (see also
later discussion on page 9), the reaction rate is independent of the concentration of the
reactants as described by the equation:

Rate = k (reaction depends on the rate constant k only)

The integrated rate equation is:

t = time; [A]t = conc. A after time t;
[A]t = -kt + [A]o
[A]0 = conc. A at time 0 (initial conc.)
Compare with y = -mx + c which is the equation for a straight line and
k is given by the slope as shown in the figure:

Slope = -k (mol L-1 s-1)

[A]

t1/2 = [A]o/2k

time (t)

(b) First order rate law:

For a first order reaction where [A] is the concentration of reactant A and k is the rate
constant, then

Rate = d[A] = k[A]

dt dt

From calculus, ln [A]t = -k1t + ln [A]o

Compare with y = -mx + c which is the equation for a straight line.

7
Where [A]t = concentration of A after time t
[A]o = concentration of A at time 0 (that is initial concentration of A)

Thus for a first order reaction, a plot of ln [A] versus t will give a straight line with the
rate constant obtained from the slope of the line (without the (-) sign) as shown in the
figure:

Slope = -k (s-1)

ln [A]
time (t) t1/2 = 0.693/k

(c) Second order rate law:

For a second order reaction the rate law expression is:

Rate = k2[A]2.

Or _1_ = k2t + _1_

[A]t [A]o which is comparable to the equation for a straight line:

y = mx + c

Thus a plot of 1/[A]t versus t yields a straight line with the rate constant, k2, obtained
from the slope of the line as shown in the figure:

_1_
[A] Slope = k (L mol-1 s-1) t1/2 = _1__
k[A]o

time (t)

3. Half life method:

The half life, t1/2, of a chemical reaction is the time taken for a given reactant to be
reduced to half its initial concentration.

(a) For a zero order reaction where [A] is the concentration of reactant A and k is the rate
constant, the rate expression is:

8
 Rate = k (mol L-1 s-1)

and t1/2 = [A]o/2k

(b) For a first order reaction where [A] is the concentration of reactant A and k is the rate
constant, the rate expression is:

Rate = k1[A]

From calculus, ln [A]t = -k1t + ln [A]o

Or ln [[A]o/[A]t] = k1t

At t1/2 [A] = ½[A]o

Therefore, ln [[A]o/½ [A]t] = k1t1/2

That is, ln 2 = k1t1/2

Or 0.693 = k1t1/2

Or, t1/2 = 0.693

k1

Therefore it will be observed that for a first order reaction, t1/2 is independent of the
concentration of A as the term “[A]” is absent from the expression.

(c) For a second order reaction:

t1/2 = __1__
k2[A]o

so that for a second order reaction, t1/2 is dependent on the initial concentration of A (that
is, the t1/2 is dependent on [A]o) . If [A]o (the initial concentration of A) is doubled, t1/2 is
halved.

General comment on zero order reactions:

It is generally observed that the concentrations of reactants affect the rate of a chemical
reaction but there a few reactions whose rates are independent of concentration. In such
cases, the reaction proceeds at a constant rate. That is,

rate of reaction = k = constant.

This can arise if all the orders of the reactants are zero. The reaction is said to follow zero
order kinetics.

A plot of concentration of reactant versus time gives a straight line with a negative slope:

9
 [A]o

[A]

[A] = 0

Time

[A] decreases from a maximum value of [A]o at time t = 0 till [A] = 0. The rate constant, k
= - slope. That is, the rate of reaction which remains constant throughout and the reaction
rate is the negative of the slope of the straight line graph.

The units of k are the same as the units of the rate of a reaction, namely mol L-1 (time)-1,
for example, M s-1.

Summary of graphical method to determine order of a reaction:

1. If a plot of [A] versus time gives a straight line, the reaction is zero order.
2. If a plot of ln[A] versus time gives a straight line, the reaction is first order.
3. If a plot of 1/[A] versus time gives a straight line, the reaction is second order

Exercise questions:

Exercise C1:
The half life for the 1st order reaction:
SO2Cl2 → SO2 + Cl2
is 8.0 min. How long will it take for the concentration of SO2Cl2 to be reduced to 1% of
the original concentration? (hint: the relevant formula is: ln [[A]o/[A]t] = -k1t)
(Answer: 53 min)

Exercise C2:
The 1st order rate constant for the conversion of cyclobutane to ethylene at 100 oC is
87 s-1:

H H
H C C H H H
2 C C
H C C H H H
H H
cyclobutane ethylene

a. What is the half life of this reaction at 1000 oC?

10
b. If the initial quantity of cyclobutane is 1.00 g, how long will it take to consume 0.70 g
of it?
c. How much of an initial quantity of 1.00 g cyclobutane remain after 1.00 x 10-2 s?
(Answer: a. 8.0 x 10-3 s; b. 0.0138 s; c. 0.419 g)

Exercise C3:
The molecule (CH2CO2H2)2CO undergoes 1st order decomposition in aqueous solution
according to the equation:

(CH2CO2H2)2CO → (CH3)2CO + 2 CO2

a. Give the rate law expression

b. If the rate constant, k1 is 5.48 x 10-2 s-1 at 60 oC, what is the t1/2 at 60 oC?
c. If the rate constant, k2 is 2.46 x 10-5 s-1 at 0 oC, what is the t1/2 at 0 oC?
d. Are the calculated t1/2’s in accordance with the statement:

“In general, the speed of a chemical change approximately doubles for each 10 oC rise
in temperature”
(Answer: a. 12.65 s; b. 2.8 x 104 s)

D. Factors influencing the rate of a chemical reaction

1. Introduction:

There are four factors that influence the rate of a chemical reaction. These are:
(i) The chemical nature of the reactants and products
(ii) The concentration of the reactants
(iii) The temperature of the reaction environment
(iv) The presence of a catalyst

2. Collision rates:

Not all collisions between reactants lead to product formation. For a successful collision
(that is, one that leads to product formation) the molecules must collide with:

(i) Correct orientation and

(ii) Sufficient energy

(i) Correct orientation:

Consider the reaction of nitrogen oxide with ozone:

NO(g) + O3(g) → NO2(g) + O2(g)

Orientation leading to product formation:

11
 Nitrogen O
N O
oxide O
N
N O Reaction
O O
O O
O O O
Ozone O
Before collision Collision After collision

Orientation not leading to product formation:

N
O N N
O
O No reaction
O O
O O O
O O O
O
Before collision Collision After collision

Figures showing requirement for correction orientation of colliding reactant molecules

(ii) Collision with sufficient energy:

Even with the correct orientation, the reactants must collide with sufficient energy for
product to form. Otherwise the colliding molecules will simply bounce apart without
reacting.

Collision with sufficient energy is necessary because, for new bonds to form to give the
product, old bonds must be broken and bond breaking requires energy. If the collision
process does not provide sufficient energy for this bond breaking to occur, the product
does not form and the colliding molecules move apart chemically unchanged.

This process is illustrated in the given diagram:

12
 Old bond breaks

O: New bond forms

:O: ::O: N:. O::

Activated complex
Potential
Energy
(P.E.) .:N=O::
+ EA(F) EA(R)
O:
:O: .
:O: :O:: N
+
Reactants ∆H :O: ::O: :O:
Products

Reaction coordinate

EA(F) = Energy of activation for the forward reaction

EA(R) = Energy of activation for the reverse reaction
∆H = Enthalpy of reaction which is (-)ve in this example
(exothermic reaction, P.E. of products lower than
P.E. of reactants)

Potential energy plot for an exothermic ((-)ve ∆H) reaction

Whether the reaction is exo- or endothermic, the activated complex, which is a transition
state product, will have P.E. greater than either the P.E. of the reactant(s) or product(s).

In the course of a reaction, bond breaking occurs as new ones are formed. The process of
bond breaking requires energy input whereas the process of bond formation releases
energy. The difference in energy absorbed and energy released is the enthalpy change
(∆H) for the reaction. If more energy is released during bond formation that was put in for
the process of bond breaking, then a (-)ve ∆H is observed and vice versa.

The activated complex is the transitory molecular arrangement at the point of bond
breaking, just before new bonds are formed. It is therefore the point where it has the
highest P.E. The activation energy (EA) comes from the kinetic energy (K.E.) of the
reacting molecule. Note that K.E. = ½ mv2 (m = mass, v = velocity), thus the kinetic
energy is strongly dependent on the velocity of the molecule. Since the K.E. is the energy
the molecule has due to its motion, the K.E. is therefore temperature dependent (higher
temperature, higher velocity, higher K.E.). At the point of collision, the K.E. is converted
to P.E., thereby providing the energy necessary to climb the EA ‘hill’.

The P.E. plot for an endothermic ((+)ve ∆H) has the P.E. of the products higher than the
P.E. of the reactants as shown in the given figure:

13
 Activated complex

Potential EA(R)
Energy
(P.E.)
EA(F)
Products
∆H

Reactants

Reaction coordinate

Potential energy plot for an endothermic ((+)ve ∆H) reaction

Spontaneous endothermic reactions are driven by entropy (∆S) since for a spontaneous
reaction to occur, the Gibbs free energy (∆G) must be negative (note: ∆G = ∆H - T∆S),
thus the ∆S must be large enough (or positive enough) to overcome the positive ∆H.

(iii) Presence of a catalyst

A catalyst is a substance that increases the rate of a chemical reaction without being used
up in the reaction. The catalyst takes part in the chemical reaction but it is regenerated at
the end, resulting in no net change in the amount of catalyst present.

A catalyst functions by lowering the activation energy, EA, by providing an alternative

(lower EA) pathway or mechanism for the reaction to proceed.

A catalyst does not alter the equilibrium constant (K) for the reaction because the forward
and reverse reaction rates are increased equally. The enthalpy of reaction (∆H) also
remains unchanged.

The effect of a catalyst on EA on the P.E. versus reaction coordinate plot is shown in the
given figure:

14
 Activated complex
Potential
Catalyst lowers EA
Energy
(P.E.)
EA(without catalyst)
EA(with catalyst)

Reactants ∆H
Products

Reaction coordinate

Potential energy plot for an exothermic ((-)ve ∆H) reaction in presence of a catalyst

Homogeneous and heterogeneous catalysts:

Catalysts may be classified as homogeneous (where the catalyst is in the same phase as
the reactant(s)) or heterogeneous (where the catalyst is in a different phase to the
reactants).

An example of a homogeneous catalyst is the catalytic decomposition of vitamin C by

Cu2+ ions in solution. An example of a heterogeneous catalyst is the use of finely divided
Ni metal for the hydrogenation of oils in the production of margarine.

Examples of mechanisms of how catalysts work are given in the following examples.

Example of how a homogeneous catalyst works:

Formic acid can decompose to water and carbon monoxide according to the equation:

O
H-C-O-H → H2O + CO
In the un-catalysed reaction the process occurs as shown in the figure:

15
 Activated
complex

Potential C
Energy HOH
(P.E.)
O
H C=O
C EA &
HOH
OH

Reaction coordinate

Figure showing un-catalysed decomposition of formic acid

The decomposition of formic acid to water and carbon monoxide is catalysed by acid. In
the catalysed reaction the process occurs as shown in the figure:

EA is lowered in the
presence of the catalyst (H+)
Activated
Potential complex
Energy O
H O
(P.E.) O
H C C
O C
+
&
H H+
C HOH
+ HOH HOH
EA
H + OH

Reaction coordinate
Figure showing catalysed decomposition of formic acid

Example of how a heterogeneous catalyst works:

The exact mechanism of how a heterogeneous catalysts is not completely clear but it
appears that the availability of d-electrons and d-orbitals on atoms at the surface of the
catalyst plays an important role. A large number to transition elements and their
compounds show catalytic activity.

For a heterogeneous catalyst to work, the reactants (which may be gas or liquid) must be
adsorbed on the surface of the catalyst. Not all atoms at the surface of the catalyst is
effective – those that are called active sites.

The sequence of events that take place in the action of a catalyst is:

16
Step 1. Adsorption of the reactants
Step 2. Diffusion of the reactants along the catalyst surface
Step 3. Reaction at an active site of the catalyst to form the adsorbed product
Step 4. Desorption of the product

This sequence of events is illustrated in the example involving the rhodium (Rh) catalysed
reaction between carbon monoxide and nitric oxide to produce carbon dioxide and water
according to the reaction:
Rh
2CO + 2NO → 2CO2 + N2

Step 1: Two molecules each of CO and NO are adsorbed on the Rh surface:

O O O O O O O O

C C N N N N C C
Rh Rh

Step 2: The adsorbed NO molecules dissociate into adsorbed N and O atoms and diffuse
along the surface of the catalyst:

O O O O

C N O N N O N C
Rh Rh

Step 3: The adsorbed CO molecules and O atoms combine to form CO2 molecules which
desorb from the catalyst surface as the gas. The two adsorbed N atoms combine and
desorb as the N2 molecule:

CO2 CO2

N2
O O

C O N N O C
Rh Rh

Enzymes as catalysts:

17
Catalysts associated with chemical reactions in living organisms are called enzymes which
are high molecular weight proteins. Enzymes are very specific in the reactions they
catalyse.

For example, in alcoholic fermentation, the six-carbon compound glucose is broken down
to give two molecules of ethanol. This is a 12 enzymic step process, the last of which
catalysed by the enzyme alcohol dehydrogenase.

In the simplest mechanism of enzyme action, known as the Michaelis-Menten

mechanism, a reactant species called the substrate (S) attaches itself to an active site on
the enzyme (E). The result is an enzyme-substrate complex (ES) which dissociates to
produce a product species (P) and the originals enzyme (E). This two step mechanism
may be summarised in the given equations:

S + E ↔ ES
ES ↔ E + P

A plot of reaction rate as a function of time for an enzyme catalysed reaction which
follows the Michaelis-Menten mechanism of enzyme action is shown:

First order

Zero
Rate of order
reaction

Concentration of substrate [S]

Figure showing Michaelis-Menten mechanism of enzyme action

Along the rising portion of the curve the reaction is 1st order with respect to substrate
concentration S because the rate at which the complex [ES] forms is proportional to [S].

That is, Rate = k[S]

At high substrate S concentration the reaction is zero order. The enzyme E is saturated
and adding more substrate does not increase reaction rate, therefore:

Rate = k1[S]0 = k1

Toxicokinetics:
This is the study of changes of toxin or drug concentration in the body as a function of
time.

18
Most drugs used in modern medicine bind very loosely with their receptors. For example
cimetidine binds to the histamine receptor.

The structure of cimitidine is:

H3C CH2-S-CH2-CH2-NH-C-NH-CH3

N-CN

HN N

The substances can usually be easily washed off their receptors which the stops to trigger
the effects of the substance. However some xenobiotics (for example, organophosphate
pesticides) are able to form covalent bonds with the receptors and the effects of these are
more difficult to reverse.

Therefore the physiological effect of a toxin may result from either

1. a reversible reaction between an active agent and a receptor (the target molecule) or
2. an irreversible interaction between the two.

In the first example the intensity of the toxic effect depends on the number of target
molecules (T) that have been bound to the toxin or active agent (A):

A + T A-T → toxic effect

The position of the equilibrium depends on the concentration of A and the strength of the
A-T bond.

The blood concentration of A at the site of the action changes with time, therefore the
intensity of the effect as a function of time can also be described by the change in blood
concentration of A as a function of time.

If a toxic effect is a result of covalent A-T bond, then the reaction is essentially
irreversible and the number of adduct molecules (molecules formed by combination of
precursor molecules, for example, A-T) and hence by the amount of active agent (A).

The mechanism by which a chemical species reaches a particular blood concentration in

the body is difficult to describe as it depends on a variety of factors, for example nature of
the substances involved, its absorption, distribution, biotransformation and excretion.

Despite the complexity described the body can often be presented schematically by a so-
called ‘compartment model’ for the purposes of fitting to a mathematical model.

This toxicokinetic (or pharmacokinetic) concept of compartment applies to all tissues,

organs and fluids in the body that do not differ from each other in terms of kinetics.
Toxicokinetics mainly deals with reversible reactions though toxicology often involves
irreversible reactions (which involve covalent bonding).

If a substance, after entering the circulation, is rapidly distributed throughout the

organism, and if the substance is readily exchanged between the circulating blood and the
rest of the body (for example the fatty or adipose tissue), then the organism can be
described as a two-compartment model. In this case the two compartments are the adipose
tissue (often referred to as the peripheral or tissue compartment, T) and the circulation

19
plus other organs and tissues (often referred to as the central compartment, C). Whether a
number of organs, tissues and body fluids constitute a compartment depends of the nature
and extent of the organs and tissues and the physiochemical properties (for example,
hydrophobic/hydrophilic nature, binding affinity) of the substance concerned.

(iv) Effect of temperature on reaction rates and the measurement of EA

An increase in the temperature of the reaction environment leads to increased K.E. of

reactant molecules, thus increasing the fraction of molecules with K.E. > EA, thereby
increasing the number of molecules that can have a collision that leads to product
formation. This increase in the fraction of molecules with P.E. > EA, with increased
temperature is illustrated in the given figure:

K.E. distribution at
higher temperature
K.E. distribution at
lower temperature
Kinetic Number of molecules
EA with P.E. > EA
energy

Number of molecules

Kinetic energy distribution of molecules at two different temperatures

The Arrhenius equation gives the relationship between the rate constant, k, energy of
activation, EA, and temperature (in K):

-EA/RT
k = Ae

where R = gas constant

e = base of natural log
A = proportionality constant whose value is determined by the collision
frequency and molecular orientation during collision

Taking logs on both sides, the equation becomes:

20
 ln k = ln A - EA . 1
R T

y = c -m . x which is the equation for a straight line.

Thus by plotting ln k versus 1/T, a straight line should be obtained, with a slope equal to
-EA/R and ln A is obtained where the line cuts the y-axis. This is illustrated in the given
figure:

Plot of ln k versus 1/T to determine EA

ln k
Slope = ∆ln k = - EA
∆(1/T) R

1/T (K-1)

The slope is measured, the gas constant, R, is known and therefore can be determined.

Other than the graphical method just described, the value of EA can also be determined by
mathematical calculation if the rate constant, k, is determined at two different
temperatures. The calculation for this is shown:

If k1 is the rate constant at temperature T1 (K) and k2 is the rate constant at temperature
T2, then the following expressions may be written:

21
 k1 = Ae -EA/RT1

-EA/RT2
k2 = Ae
EA 1 - 1
k1 R T1 T2
= e
k2

k1 EA 1 - 1
ln k =
2 R T2 T1

OR

log k1 = EA 1 - 1
k2 2.303R T2 T1

If EA is in joules (J), then R = 8.314 J K-1 mol-1.

Examples of calculations using the Arrhenius equation:

Example 1:
The rate constant for a reaction was determined to be 1.3 x 10-5 L mol-1 s-1 at 15 oC
and 8.0 x 10-3 L mol-1 s-1 at 50 oC. Determine the EA (in kJ mol-1) for the reaction.

Answer:
Using the equation

k1 EA 1 - 1
ln k =
2 R T2 T1

-5 -1 -1
ln 1.3 x 10-3 (L mol-1 s-1) =
EA __ ___
-1 -1
__ 1 - 1_____
8.0 x 10 (L mol s ) 8.314 (J K mol ) 50 + 273 (K) 15 + 273 (K)

Solving, EA = 142 kJ mol-1 (always check for consistency of units)

Example 1:
The EA for a particular reaction is 105 kJ mol-1. At 25 oC the rate constant is 2.0 x 10-3 s-1.
Determine the rate constant at 50 oC.

Answer:
k1 = 2.0 x 10-3 s-1 at 25 oC (T1)
k2 = ? at 50 oC (T2)
-1
EA = 105 kJ mol

22
ln 2.0 x 10-3 (s-1) = ___105 (kJ mol-1)_____ ___1 _____ - ____1_____
k2 (s-1) 8.31 x 10-3 (kJ K-1 mol-1) 50 + 273 (K) 25 + 273 (K)

= ___ 105 (kJ mol-1)_____ [-2.597 x 10-4 (K)]

8.31 x 10-3 (kJ K-1 mol-1)

ln 2.0 x 10-3 = -3.282

k2

2.0 x 10-3 = 0.0376

k2 (s-1)

k2 = 5.3 x 10-2 s-1

Note that R = 8.314 kJ K-1 mol-1 has been converted to kJ to be consistent with the units
of EA which is in kJ.

Exercise questions:

Exercise D1:
For the reaction:
OCl- (aq) → Cl- (aq) + ½ O2 (g),
the ∆Hreaction = -51 kJ mol-1 and the EA = 47 kJ mol-1.

Draw a diagram plotting potential energy (P.E.) versus reaction coordinate, clearly
labelling the diagram to show the ∆Hreaction, EA, the activated complex and the reactant
and products.

Exercise D2:
The activation energy, EA for the decomposition of hydrogen iodide, HI:

2 HI (g) → H2 (g) + I2 (g)

is 182 kJ mol-1. The rate constant, k, for the reaction at 700 oC is 1.57 x 103 dm3 mol-1 s-1.
What is the rate constant at 600 oC?
(Answer: 1.19 x 10-4 dm3 mol-1 s-1)

Exercise D3:
What activation energy, EA, should a reaction have so that raising the temperature
from 0 oC to 10 oC would triple the reaction rate?
(Answer: 7.06 x 104 J mol-1)

Exercise D4:
The following reaction follows 1st order kinetics:
FClO2 (g) → FClO (g) + O (g)
The EA for the reaction is 186 kJ mol-1 and the k at 322 oC is 6.76 x 10-4 s-1.

(i) What is the k at 25 oC?

(ii) What temperature of reaction is required to achieve a k = 4.00 x 10-2 s-1?

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(Answer: (i) 3.38 x 10-20 s-1; (ii) 394 oC)

E. Reaction mechanisms

A balanced chemical equation does not provide information on how a reaction occurs. It is
merely a summary of the reaction. Reaction mechanisms can be deduced by studying their
rates and rate law.

A balanced chemical equation can provides information on how a reaction occurs if it is a

single step reaction – that is the product(s) are formed by direct collision of the molecules
as written in the equation. However, most reactions follow a multi step mechanism.

1. Single step reactions:

In a single step reaction the reactant molecules collide as written in the equation.

For single step reactions, the rate law has orders of reaction which correspond to the
relevant reaction stoichiometries.

For the general reaction:

aA + bB → cC

Rate = k [A]a [B]b for a single step reaction.

2. Multi step reactions:

For multi step reactions, the rate law does not correspond to the balanced equation for the
reaction.

For the reaction:

2 N2O5 (g) → 4 NO2 (g) + O2 (g)

The rate law was found to be

Rate = k [N2O5]

(rather than rate = k [N2O5]2 as would be observed if it were a single step reaction)

The given reaction there does not occur via a single step but follows a multi step
mechanism such as the one given:

2 [N2O5 → NO2 + NO3] (slow reaction)

NO2 + NO3 → NO + NO2 + O2 (fast reaction)
NO + NO3 → 2 NO2 (fast reaction)
2 N2 O5 → 2 NO2 + O2 (overall reaction)

24
The different steps of a multi step may have very different rates. The overall rate cannot
exceed the rate of the slowest step in the reaction mechanism. The slowest step is called
the rate determining step. The rate determining step of a reaction mechanism gives the
rate law for the reaction. Thus for the given example:

Rate = k [N2O5] since it is the rate expression for the rate determining step.

Where the rate expression for the slowest step does not involve a reactant that appears in
the equation for the overall reaction, substitutions using the equilibrium constant (K)
expressions may be used to place the reactant into the equation for the rate determining
step.

Each of the three individual steps shown in the example is called an elementary process,
step or reaction. All the three steps taken together is called the reaction mechanism.
Elementary steps are almost always unimolecular (that is, involving only one species) and
bimolecular (that is, involving two species) and rarely termolecular (that is, involving
three species). These are described in greater detail in the next section.
In multi step reactions, species are often formed in the elementary steps which do not
appear in the final products (as shown in the overall reaction). Such species (for example,
NO3) are called reaction intermediates. Some reaction intermediates are odd-electron
species called free radicals.

(i) Unimolecular reactions

These are reactions that result from the decomposition or internal rearrangement of a
single molecule, for example:

H3 C CH3 H3 C H
C=C C=C
H H
H CH3
Cis-2-butene Trans-2-butene

The rate law was observed to be:

Rate = k[cis-2-butene]

A unimolecular reaction has first order rate law.

(ii) Bimolecular reactions

These reactions are a result of a successful collision between two molecules, for example:

NO (g) + O3 (g) → NO2 (g) + O2 (g)

The rate law was observed to be:

25
 Rate = k [NO][O3]

A bimolecular reaction has second order rate law.

(iii) Termolecular reactions

These occur by successful simultaneous collision between three molecules and would
have a third order rate law. These reactions are uncommon because of probability
considerations.

3. Chain reactions:

A chain reaction is a multi step reaction in which a free radical is formed and this free
radical initiates a series of two or more reactions in which the products are formed and the
free radical is regenerated as shown in the given example:

H2 + Br2 → 2 HBr (the overall reaction)

which occurs via the following mechanism:

Br2 → 2 Br. } chain initiation

Br. + H2 → HBr + H. } chain propagation
H. + Br2 → HBr + Br. } chain propagation
Br. + Br. → Br2 } chain termination
H2 + Br2 → 2 HBr______ } overall reaction

Exercise questions:

Exercise E1:
The proposed mechanism for a gaseous reaction is:
O3 → O2 + O
O + O3 → 2 O2
a. What is the observed overall reaction being studied?
b. What is the role of O in the reaction?

Exercise E2:
What is the overall reaction for the following postulated mechanism?

Cl2 + AlCl3 → AlCl4- + Cl+

Cl+ + C6H6 → C6H5Cl + H+
H+ + AlCl4- → AlCl3 + HCl

What is the role of AlCl3 in this reaction?

Exercise E2:
Ozone, O3 in the stratosphere can be decomposed by reaction with nitrogen oxide, NO
(commonly called nitric oxide), from high flying jet aircraft, following the equation:

26
 O3(g) + NO(g) → NO2(g) + O2(g)

The rate expression is: Rate = k [O3][NO].

Which of the following mechanisms are consistent with the observed rate expression?

A: NO + O3 → NO3 + O slow
NO3 + O → NO2 + O2 fast___
_O3 + NO → NO2 + O2 overall

B: NO + O3 → NO2 + O2 slow (one step)

C: O3 → O2 + O slow
O + NO → NO2 fast___
O3 + NO → NO2 + O2 overall_

D: NO → N + O slow
O + O3 → 2 O2 fast
O2 + N → NO2 fast__
O3 + NO → NO2 + O2 overall

E: NO → N + O fast
O + O3 → 2 O2 slow
O2 + N → NO2 fast__
O3 + NO → NO2 + O2 overall

Exercise E3:
Do you expect the equation for the combustion of ethene,

C2H4(g) + 3 O2(g) → 2 CO2(g) + 2 H2O(g)

to represent the mechanism by which ethene burns (that is, would you expect the
reaction to be a single step process)? Explain your answer.

Exercise E4:
The proposed mechanism for a gaseous reaction is given as:

Step 1: NO + Cl2 → NOCl2 Fast

Step 2: NOCl2 + NO → 2 NOCl Slow

a. Write the equation for the overall reaction.

b. What is the rate determining step in the mechanism
c. What is the molecualrity of Step 1 and of Step 2?
d. If the proposed mechanism is correct, would the rate equation be in terms of the overall
reactants?
(Hint: Use equilibrium constant (K) expression for Step 1 to get the rate
expression to be in terms of the reactants in the overall equation)
e. If the concentrations of both reactants NO and Cl2 were doubled, by what factor would
the rate increase?

27
f. The rate constant, k, varies with temperature in a manner described by the Arrhenius
equation:
-EA/RT
k = Ae
A plot of ln k versus 1/T for the reaction gives a straight line with slope = -9.99 x 103 K.
Calculate the EA for the reaction at 25 oC.
(Answer: EA = 83 kJ mol-1)

F. Nucleophilic substitution at a saturated carbon

1. Introduction:

The term ‘nucleophilic’ means nucleus (that is, (+)ve charge) seeking. The nucleophilic
species is therefore a (-)ve charged species and is called a nucleophile or nucleophilic
reagent. The opposite of a nucleophile is an electrophile which is species which seeks
after a (-)ve charge and it is therefore a (+)ve charged species.

A saturated carbon is a carbon atom with four bonds attached to it. A substitution reaction
is the substitution or replacement of one atom or a group of atoms in a molecule with
another atom or group of atoms.

Nucleophilic substitution reactions may be classified as:

1. Unimolecular (or first order) or
2. Bimolecular (or second order)

If unimolecular, the reaction is referred to as a SN1 (substitution, nucleophilic, 1st order).

If bimolecular, the reaction is referred to as SN2 (substitution, nucleophilic, 2nd order).

The designations SN1 or SN2 do not reveal the reaction mechanism – it only states the type
of nucleophilic substitution occurring at the saturated carbon. The favoured pathway
(whether SN1 or SN2) is determined by the nature of the substituents on the saturated
carbon and on the experimental conditions.

2. SN1 reactions:

Consider the reaction whereby Br is substituted for OH in t-butyl bromide:

CH3 CH3

H3 C C Br + OH - H3 C C OH + Br -
nucleophile

CH3 CH3

t-butyl bromide t-butyl alcohol

28
The rate law was found to have 1st order kinetics, that is:

Rate = k [(CH3)3CBr]

and not Rate = k [(CH3)3CBr][OH-]. Therefore the reaction rate is dependent on the
concentration of t-butyl bromide only and independent of [OH-] concentration.

The observed rate law is consistent with the following reaction mechanism:

CH3
CH3
H3 C C Br
H3 C C+ + Br - [Slow step]
CH3
t-butyl bromide CH3

Indicates movement
of electron pair
Carbocation species

CH3 CH3

H3 C C+ + OH- H3 C C OH [Fast step]

nucleophile
CH3 CH3

t-butyl alcohol

Figure showing mechanism for SN1 reaction

Since the slow step (the rate determining step) determines the reaction rate, then the rate
law expression is:

Rate = k[t-butyl bromide]

A substitution reaction will tend top proceed via the SN1 pathway if the molecular
structure favours the formation of the carbocation species. Alkyl groups (for example,
-CH3) are electron releasing and can thus help stabilise the (+)ve carbocation.

3. SN2 reactions:

Consider the reaction of methyl bromide with the hydroxide ion (OH-):

29
 H H

H C Br + OH- H C OH + Br -
nucleophile

H H
Methyl bromide Methyl alcohol

The rate law was found to have 2nd order kinetics, that is:

Rate = k [CH3Br][OH-]

Since the rate is influenced by both the [CH3Br] and [OH-] concentrations, the reaction
probably proceeds in a single step involving a collision between the two reactant
molecules.

The observed law is consistent with the following mechanism:

Back of molecule Front of molecule (the 3-H’s and C are on one plane)

H H
H

OH- + H C Br OH- C Br

H
H
Reactants Activated complex

OH C H + Br-
-

H
Products
(tetrahedral shaped molecule)

Figure showing mechanism for SN2 reaction

The 3-H’s attached to the C-atom flip over to the other side of C and the product is thus
inverted because the nucleophile (for example OH -) attacks from the back side of the

30
molecule. This aspect of inversion is not important in the given example as the product is
the same whether or not there is inversion.

The SN2 mechanism is favoured when the groups attached to the C-atom are not bulky
(like, for example, H atom instead of CH3 or other bulkier alkyl groups) so that they can
be easily flipped over to the other side of the C-atom.

The rate of an SN2 reaction is largely influenced by stearic (or spatial) factors whereas the
rate of an SN1 reaction is largely affected by electronic (or electrical charge distribution)
factors.
4. SN1 versus SN2 pathways:

Some reactions proceed via both the SN1 versus SN2 pathways. The reactivity towards
each mechanism is given by the summary:

SN2 increases
RX = CH3X 1o 2o 3o X = halide
SN1 increases

Most typically for halides, going along the series CH3, 1o, 2o, 3o, the following
mechanisms apply:

CH3X > 1o > 2o < 3o

SN 2 SN 2 Mixed SN 1

(Note: 1o = CH3XH3, 2o = (CH3)2XH2, 3o = (CH3)3XH representing primary, secondary

and tertiary methyl halides respectively)

Exercise question:

Exercise F1:
Briefly describe what is meant by a SN1 and SN2 reaction. Give an example of each,
showing clearly the mechanism of reaction in each case.

Examples of multiple choice questions:

1. For the reaction between gaseous chlorine and nitrogen monoxide:

2NO + Cl2 → 2NOCl
It was found that doubling the concentration of both reactants increased the rate
by a factor of eight, but doubling the chlorine concentration alone only doubles
the rate.
(i) What is the order of the reaction with respect to NO and Cl2?
(ii) State the overall order and molecularity of the reaction.

(a) (i) Rate = k[NO]2[Cl], (ii) termolecular

31
 (b) (i) Rate = k[NO] [Cl]2, (ii) termolecular
(c) (i) Rate = k[NO] [Cl], (ii) bimolecular
(d) (i) Rate = k[NO] [Cl]2, (ii) bimolecular

2. For the decomposition of hydrogen peroxide in solution at 25oC:

2H2O2 → 2H2O(g) , the following data was recorded:

Experiment number: [H2O2] mmol L-1 -d[H2O2]/dt mmol L-1s-1

1 14.45 6.70 x 10-3

2 28.90 13.3 x 10-3
3 57.80 26.7 x 10-3

(i) What is the rate equation for the reaction?

(a) Rate = k[H2O2]0 (c) Rate = k[H2O2]2
(b) Rate = k[H2O2] (d) Rate = k[H2O2]1/2

(ii) What is the order of the reaction?

(a) 0 order (c) 2nd order
(b) 1st order (d) 3rd order

(iii) Calculate the rate constant (k) for the reaction at 25oC.
(a) 1.3 x 10-2 mmol L-1 s-1 (c) 4.6 x 10-4 mmol L-1
(b) 1.3 x 10-2 mmol (d) 4.6 x 10-4 s-1

(iv) Calculate the decomposition rate (in mol L-1 s-1) at 25oC when [H2O2] = 10 mmol
L-1.
(a) 4.6 x 10-4 (c) 4.6 x 10-5
-3
(b) 4.6 x 10 (d) 4.6 x 10-6

(v) How does the rate change as the reaction proceeds?

(a) increases (c) increases then decreases
(b) decreases (d) decreases then increases

3. At 27oC, the reaction 2NOCl → 2NO + Cl2, is observed to exhibit the following
dependence of rate on concentration:

Initial NOCl concentration [mol dm-3] Initial rate of NO formation [mol dm-3 s-1]
0.30 3.60 x 10-9
0.60 1.44 x 10-8
0.90 3.24 x 10-8

(i) What is the rate law for the reaction?

(a) R = k[NOCl] (c) R = k[NOCl]1/2
(b) R = k[NOCl]2 (d) R = k[NOCl]3

(ii) What is the rate constant, k?

32
 (a) 4.0 x 10-8 L mol-1 s-1 (c) 4.0 x 10-6 L mol-1 s-1
(b) 3.5 x 10-8 L mol-1 s-1 (d) 3.5 x 10-8 L mol-1 s-1

(iii) By what factor would the rate increase if the initial concentration were increased
from 0.30 to 0.45 M
(a) 1.5 times faster (c) 5.0 times faster
(b) 0.675 times faster (d) 2.25 times faster

(Answers: 1a; 2 (i)b, (ii)b, (iii)d, (iv)d, (v)b; 3 (i)b, (ii)a, (iii)d)

33