12-02-2019

Kinetic vs. Thermodynamic Control

of Product Composition

There are certainly two factors which decides the outcome of a reaction,
these are:
1. Thermodynamic factor: the relative stability of the products.
2. Kinetic factor: the rate of product formation.

Thermodynamic reaction control or kinetic reaction control in a chemical

reaction can decide the composition in a reaction product mixture when
competing pathways lead to different products and the reaction conditions
influence the selectivity.

Thermodynamics is all about “if”

• if a process or a reaction can occur or not.

• if a systems is in stable or metastable equilibrium.
• if sufficient driving force is present to enforce a favourable transformation.

Kinetics is all about “how”

• how fast or slow a process can occur, i.e., determining the rate
• how transition from nonequilibrium to equilibrium systems, or between
two equilibrium states occurs
• how to overcome the energy barrier to finish the transformation from the
starting (reactant) state to the final (product) state.

For a reaction irreversible under mild conditions and reversible under vigorous
conditions at a certain temperature one product changes to another. At this particular
temperature there is change between a kinetic and a thermodynamic product.

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Figure shows the conditions

under which a kinetic or
thermodynamic product is
preferred. Here
R is the reactant and A or B
are products formed under
different conditions. Figure
shows that
if activation energy is less
kinetic product will form
predominantly.

Case B

The distinction is relevant when product A forms faster than product B

because the activation energy for product A is lower than that for product
B, yet product B is more stable.

In such a case A is the kinetic product and is favoured under kinetic control
and B is the thermodynamic product and is favoured under thermodynamic
control.

This is only true if the activation energy of the two pathways differ, with
one pathway having a lower Ea (energy of activation) than the other.

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The conditions of the reaction, such as temperature, pressure, or solvent,

affect which reaction pathway may be favoured: either the kinetically
controlled or the thermodynamically controlled one.

Prevalence of thermodynamic or kinetic control determines the final

composition of the product when these competing reaction pathways lead to
different products.

The reaction conditions as mentioned above influence the selectivity of the

reaction - i.e., which pathway is taken.

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Whenever competing or successive reaction products can come

to equilibrium, the product composition will reflect relative
stability and be subject to thermodynamic control.

If product composition is governed by competing rates, the

reaction is under kinetic control.

A given reaction may be subject to either thermodynamic or

kinetic control, depending on the conditions.

Short reaction times favour kinetic control, whereas longer

reaction times favour thermodynamic reaction control.

Low temperatures will enhance the selectivity under both sets

of conditions
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In every reaction, the first product formed is that which is most easily formed.
Thus, every reaction a priori starts under kinetic control.

Under kinetic reaction control, the forward reaction is faster than the reverse
reaction.

A necessary condition for thermodynamic control is reversibility or a

mechanism permitting the equilibration between products.

Reactions are considered to take place under thermodynamic reaction control

when the reverse reaction is sufficiently rapid that the equilibrium establishes
itself within the allotted reaction time.

In this way, the thermodynamically more stable product is always favoured.

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Under Kinetic Control

After reaction time t, the product ratio is the ratio of rate constants k and thus a
function of the difference in activation energies Ea or ΔG‡:

Unless equilibration is prevented, pure kinetic control is practically impossible,

because equilibration will have started before the reactants will have been entirely
consumed.

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Under pure thermodynamic reaction control, when the equilibrium has been
reached, the product distribution will be a function of the stabilities G°.

After an infinite amount of reaction time, the ratio of product concentrations

will equal the equilibrium constant Keq and therefore be a function of the
difference in Gibbs free energies.

In general, short reaction times favour kinetic control, whereas longer reaction
times favour thermodynamic reaction control.

Low temperatures will enhance the selectivity under both sets of conditions, since T is in
the denominator in both cases.

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The ideal temperature to optimise the yield of the fastest-forming

product (Kinetic controlled) will be the lowest temperature that will
ensure reaction completion in a reasonable amount of time.

The ideal temperature for a reaction under thermodynamic control is

the lowest temperature at which equilibrium will be reached in a
reasonable amount of time.

If needed, the selectivity can be increased by then slowly cooling the

reaction mixture to shift the equilibrium further toward the most stable
product.

When the difference in product stability is very large, the

thermodynamically controlled product can dominate even under
relatively vigorous reaction conditions. If a reaction is under
thermodynamic control at a given temperature, it will also be under
thermodynamic control at a higher temperature for the same reaction
time.
In the same manner, if a reaction is under kinetic control at a given
temperature, it will also be under kinetic control at any lower
temperature for the same reaction time. 12
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Kinetic vs. Thermodynamic Control - Examples

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Electrophilic addition Reaction

The electrophilic addition reaction of hydrogen bromide to 1,3-butadiene

above room temperature leads predominantly to the thermodynamically
more stable 1,4 adduct, 1-bromo-2-butene, but decreasing the reaction
temperature to below room temperature favours the kinetic 1,2 adduct, 3-
bromo-1-butene.

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Both products result from Markovnikov protonation at position 1, resulting in a

resonance-stabilized allylic cation.

The 1,4 adduct places the larger Br atom at a less congested site and includes a
more highly substituted alkene moiety, while the 1,2 adduct is the result of the
attack by the nucleophile (Br-) at the carbon of the allylic cation bearing the
greatest positive charge (the more highly substituted carbon).

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The transition state for 1,4-addition has positive charge is on less substituted carbon,
therefore its activation energy is large and formed slowly. Whereas, the transition state for
1,2-addition has positive charge on more substituted carbon, and has lesser activation
energy thus formed faster.
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At low temperature -80 or 0 oC the kinetic product is obtained as major due to low Ea. While
at high temperature 40-45 oC the thermodynamic product is major, due to greater stability.
The 1,4-addition product is more stable as greater the number of alkyl groups attached to a
sp2 carbon more stable it is (more substitute alkene). But, 1,2-addition product is formed
faster, as the transition state for formation of 1,2-product is more stable.
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Addition of HCl to conjugated dienes

The addition of HCl to 1,3-butaidene can give two products one is 1,2- and another is 1,4-
addition product. The amount of each will depend upon the reaction conditions. The 1,2-
product is called kinetic product and 1,4- is thermodynamic product.

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The addition of HCN to butenone

There are two electrophilic centres in α,β -unsaturated carbonyl system, the carbonyl carbon
and the terminal carbon of the unsaturated system. The nucleophile may attack to give
either 1,2- or 1,4- addition products.

When HCN is added to α,β-unsaturated carbonyl compounds the cynohydrin (direct

addition) is obtained fast and it is kinetic product. While the β-cyano carbonyl compound
(conjugate addition) is obtained in a slow reaction and it is the thermodynamic product.

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The ‘direct’ addition means that cyanide ion must attack the carbonyl group directly
while the ‘conjugate’ addition means that it must attack the less electrophilic alkene.
The second is a slower reaction but gives the more stable product. Both reactions
have an alkoxide anion as an intermediate.

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The energy profile diagram for these two reactions is quite complicated. The extent of reaction
increases both to the right for thermodynamic control and to the left for kinetic control.

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Points to notice:

• The thermodynamic product has a lower energy than the kinetic product.

• The highest transition state to the right is higher than the highest to the left.

• Initially the reaction will go to the left. If there is enough energy for the kinetic product
to get back to the starting materials, there will be enough energy for some
thermodynamic product to be formed.

• The energy needed for the thermodynamic product to get back to starting materials is
very great.

• At low temperatures direct addition is favoured, but conjugate addition is favoured at

high temperatures

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If sulphonation of naphthalene is carried out under irreversible conditions the kinetic

product (1-substituted) is formed. However, under reversible conditions, the
thermodynamic product (2-substituted) is formed.

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The kinetic product is easier to form because the carbocation leading to its formation is more
stable. The 2-substituted product is more stable and formed at high temperature, because
there is a bulky sulphonic group at 2-position is sterically less hindered. Whereas, in the kinetic
product (1-substituted) the sulphonic group is close to hydrogen at 8-position.

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The Diels-Alder reaction of cyclopentadiene with furan

Diels-Alder reaction of cyclopentadiene with furan can produce two isomeric

products.

At room temperature, kinetic reaction control prevails and the less stable endo
isomer 2 is the main reaction product.

At 81°C and after long reaction times, the chemical equilibrium can assert itself
and the thermodynamically more stable exo isomer 1 is formed.

The exo product is more stable by virtue of a lower degree of steric congestion,
while the endo product is favoured by orbital overlap in the transition state.

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The formation of enolate anions from unsymmetrical ketones

Alkylation of unsymmetrical ketones gives two different products because either of the α-
carbons can be alkylated. As the reaction proceeds via formation of enolate in basic medium
and most ketone can give rise to more than one enolate depending upon the reaction
conditions.

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2-hexanone
For example, in the case of 2-hexanone if a strong and sterically hindered base (lithium
diisopropylamide) and aprotic solvent is used the kinetic enolate is major product. However,
with protic solvent or weak base thermodynamic enolate is predominant.

The formation of different types of enolates can be explained as follows. In 2-hexanone, the
α-hydrogen of methyl groups are less sterically hindered than the α-hydrogen of butyl group.

Thus removal of proton from methyl hydrogen is faster than removal of proton from butyl. In
presence of strong base enolate will not be converted back to ketone as the enolate is a weak
base to regain proton.

With weaker base and protic solvent protons can be transferred reversibly between isomeric
enolates and the base. Under these conditions the more stable enolate will be major as they
are in equilibrium with each other. The more substituted enolate is more stable.
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Enolate of Cyclic Ketones

The methylation of 2-methylcyclohexanone with one equivalent of methyl iodide it

forms both 2,6-dimethylcyclohexanone and 2,2-dimethylcyclohexanone. The relative
amounts of the two products depend on the reaction conditions.

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The enolate leading to 2,6-dimethylcyclohexanone is the kinetic enolate because the α-

hydrogen that is removed to make this enolate is more accessible (particularly if a hindered
base like LDA is used) and slightly more acidic. So 2,6 dimethylcyclohexanone is formed faster
and is the major product if the reaction is carried out at -78 oC.

The enolate leading to 2,2-dimethylcyclohexanone is the thermodynamic enolate because

it has the more substituted double bond, making it the more stable enolate. Therefore,
2,2-dimethylcyclohexanone is the major product if the reaction is carried out under
conditions that cause enolate formation to be reversible and if a less hindered base (KH) is
used.
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Low temperature favours kinetic enolate as the system can not equilibrate to form the more
stable thermodynamic enolate. At high temperature the more stable thermodynamic enolate
is formed predominantly. If a much weaker base is used, the deprotonation will be
incomplete, and there will be an equilibrium between reactants and products.

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Use of low temperatures and sterically demanding bases increases the kinetic selectivity.

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