Methods of Determining Reaction Mechanisms

Meaning of Reaction Mechanism

Reaction mechanism is the step by step sequence of elementary reactions by which overall
chemical change occurs. Although only the net chemical change is directly observable for
most chemical reactions, experiments can often be designed that suggest the possible
sequence of steps in a reaction mechanism.

A reaction mechanism is only a guess at how a reaction proceeds. Therefore, even if a

mechanism agrees with the experimental results of a reaction, it cannot be proved to be
correct.

Electrophile
Positively charged or neutral species are called electrophiles that are deficient in electrons
and can accept a pair of electrons. These are also called species that love electrons (philic).
 The term electrophile can be split into “electro” derived from electron and “phile”
which means loving.
 They are electron deficient and hence love to accept electrons (electrons loving).
 They are positively charged or neutral.
 They attract electrons. The movement of electrons depends on the density.
 They move from high-density area to low density area.
 They undergo electrophilic addition and electrophilic substitution reactions.
 An electrophile is also called Lewis acid.

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Nucleophile
A nucleophile is a reagent comprising a negative charge or lone pair of electrons. As a
nucleophile is rich in electron, it looks for electron-deficient locations. Nucleophiles act as
Lewis bases, i.e, species which can donate a pair of electrons.
 The term nucleophile can be split into “nucleo” derived from the nucleus and “phile”
which means loving.
 They are electron-rich and hence nucleus loving. They are negatively charged or
neutral.
 They donate electrons.
 The movement of electrons depends on the density.
 They move from low-density area to high-density area.
 They undergo nucleophilic addition and nucleophilic substitution reactions.
 A nucleophile is also called a Lewis base.

Classes of Reaction Mechanism

1. Substitution
2. Addition
3. Elimination
4. Rearrangement

Substrate
Substrate is a compound with which a reagent reacts.

Reagents
Reagent is a substance, chemical, or solution used in the laboratory to detect, measure, or
otherwise examine other substances, chemicals, or solutions.

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Important Symbols for Describing Reaction Mechanism

Symbols Meaning
Irreversible reaction to product

Reaction which does not proceed

Forward and backward reaction

Reaction with more than one step

Reversible reaction

Reversible reaction: Equilibrium favors product

Reversible reaction: Equilibrium favors reactant

Resonance

Electron Movement
Curved arrows indicate breaking and forming of bonds
Arrowhead with a “half” head (“fish-hook”) indicates hemolytic and
homogenic steps (called ‘radical processes’)
Arrowhead with a complete head indicates heterolytic and heterogenic
steps (called ‘polar processes’)

 Curved arrows are a way to keep track of changes in bonding in polar reaction
 The arrows track “electron movement”
 Electrons always move in pairs
 Charges change during the reaction
 One curved arrow corresponds to one step in a reaction mechanism
 The arrow goes from the nucleophilic reaction site to the electrophilic reaction site

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 Curved arrows depict the flow of electrons

‘Tail’ ‘Head’
source destination
(Electron donor) (Electron acceptor)

As with resonance, there are really only three classes of reaction arrow:

lone pair  bond bond  lone pair bond  bond

Aside from a handful of problematic cases, the movement of electrons in every

reaction can be shown through a combination of these three ‘moves’

First, there are arrows that form bonds (lone pair to bond)
The source of our electrons here is a lone pair of electrons, and this lone pair is accepted by a
second atom. The result is the formation of a bond.

Arrows that form bonds (lone pair to bond)

Start Finish Example

lone pair  bond

lone pair  bond

Secondly, there are arrows that break bonds (bond to lone pair)
The source of our electrons here is a bond, and the pair of electrons moves to one atom. This
leaves the second atom bereft of electrons. The source of electrons can be either a  bond or a
π bond:

Arrows that form bonds (bond to lone pair)

Start Finish Example

 bond lone pair

 bond lone pair

Again, the formal charge of the atom that accepts the electrons becomes more negative by
one, and the formal charge of the atom which loses the electrons becomes more positive by
one.

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The third types of arrows are those which both break and form bonds.
We can also break  or π bonds to form a new  or π bond. Note that in contrast to the first
two situations (which involve two atoms), these arrows involve three atoms. The atom in the
“middle” sees its charge remain the same, while the atoms on either end see their charges
changing by plus or minus one.

Arrows that form and break bonds (bond to bond)

Start Finish Example

 bond  bond

 bond  bond

 bond  bond

 bond  bond

Reaction Energetics

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 The highest energy point in a reaction step is called the Transition State.
 The energy needed to go from reactant to transition state is the Activation Energy
(Ea).
 If a reaction occurs in more than one step, it must involve species that are neither the
reactant nor the final product. These are called reaction intermediates or simply
“Intermediates”.
 Each step has its own free energy of activation.
 The complete diagram for the reaction shows the free energy changes associated with
an intermediate.

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 Explanation of Thermodynamic Quantities: G = H  TS
Term Name Explanation
The energy difference between reactants and products.
When G is negative, the reaction is exothermic, has a
Gibbs free-energy favorable equilibrium constant, and can occur
G
Change spontaneously. When G is positive, the reaction is
endothermic, has an unfavorable equilibrium constant,
and cannot occur spontaneously.
The heat of reaction, or difference in strength between
the bonds broken in a reaction and the bonds formed.
H Enthalpy change When H is negative, the reaction releases heat and is
exothermic. When H is positive, the reaction absorbs
heat and is endothermic.
The change in molecular randomness during a reaction.
S Entropy change When S is negative, randomness decreases; when S
is positive, randomness increases.

Reaction kinetics
Chemical kinetics is the study and discussion of chemical reactions with respect to reaction
rates, effect of various variables, rearrangement of atoms, formation of intermediates etc.
There are many topics to be discussed, and each of these topics is a tool for the study of
chemical reactions. By the way, the study of motion is called kinetics, from Greek kinesis,
meaning movement.

At the macroscopic level, we are interested in amounts reacted, formed, and the rates of their
formation. At the molecular or microscopic level, the following considerations must also be
made in the discussion of chemical reaction mechanism.

 Molecules or atoms of reactants must collide with each other in chemical reactions.
 The molecules must have sufficient energy (discussed in terms of activation energy)
to initiate the reaction.
 In some cases, the orientation of the molecules during the collision must also be
considered.

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Reaction rates
Consider a chemical reaction
A+B → C+D
Rate = k[A] ------------------------- (1)
or Rate = k[A][B] ------------------ (2)
From Eqn (1), it is observed that the reaction is depended on the concentration of A, so the
reaction is first order or unimolecular.
From Eqn (2), it is observed that the reaction is depended on the concentration of A and B, so
the reaction is second order or bimolecular.

Rate limiting (determining) step

The rate determining step is the slowest step of a chemical reaction that determines the speed
(rate) at which the overall reaction proceeds.
The rate determining step is important in deriving the rate equation of a chemical reaction.
For example, consider a multi-step reaction:
A+B → C+D
Assume the elementary steps for this reaction are the following:

Step 1: Slow A+A → C+E (with a rate constant, k1)

Step 2: Fast E + B → A+D (with a rate constant, k2)

where E is an intermediate, the product in step 1 and a reactant in step 2 that does not show
up in the overall reaction. This is because when steps 1 and 2 are added, intermediate
E cancels out, along with the extra reactant A from step 1. Note that intermediate reactions do
not show up in the overall reaction.
In the case of this hypothetical reaction, if step 1 is the slow step and step 2 is the fast step of
the reaction, then the overall reaction rate depends on step 1; the slow step in a reaction is
always the rate-limiting step, another name for the rate determining step.

Kinetic versus thermodynamic control

The potential outcome of a reaction is usually influenced by two factors:
1. The relative stability of the products (i.e., thermodynamic factors)
2. The rate of product formation (i.e., kinetic factors)
The following simple reaction coordinate diagram provides a basis for the key issues about
kinetic and thermodynamic control:

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Consider the case where a starting material, SM, can react in a similar manner to give two
different products, P1and P2 via different (competing) pathways.

Reaction 1 via pathway 1 (green) generates product 1 (P1) via transition state 1 (TS1). This
will be the faster reaction since it has a lower energy (more stable) transition state, and
therefore a lower activation barrier. Therefore, product 1, P1 is the kinetic product (the
product that forms the fastest).

Reaction 2 via pathway 2 (blue) generates product 2 (P2) via transition state 2 (TS2). P2 is
the more stable product since P2 is at a lower energy than P1. Therefore, P2 is
the thermodynamic product (the more stable product).

We now need to consider how the outcome of this situation changes with the competing
reactions of the starting material as we alter the reaction temperature and therefore the
average energy of the molecules changes.
1. At low temperature, the average energy of the molecules is low and more molecules have
enough sufficient energy cross activation energy EA1 than EA2. Therefore the reaction
preferentially proceeds along the green path to P1. The reaction is not reversible since the
molecules lack sufficient energy to reverse to SM, i.e., it is irreversible, so the product ratio
of the reaction is dictated by the rates of formation of P1 and P2, k1: k2.

2. At some slightly higher temperature, reaction 1 will become reversible when sufficient
molecules have enough energy to cross the reverse reaction barrier for reaction 1, while
reaction 2 remains irreversible. So although P1 may form initially, over time it will revert
to SM and react to give the more stable P2.

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3. At high temperature, both reaction 1 and 2 are reversible and the product ratio of the
reaction is dictated by the equilibrium constants for P1 and P2, K1: K2.

Summary
 At low temperature, the reaction is under kinetic control (rate, irreversible
conditions) and the major product is that from the fastest reaction.
 At high temperature, the reaction is under thermodynamic control (equilibrium,
reversible conditions) and the major product is the more stable system.

Methods of determining reaction mechanism

Identification of products
The most fundamental information about a reaction is provided by establishing the structure
of the products that are formed during its course, and relating this information to the structure
of the starting material. Where, as is often the case with organic reactions, more than one
product is obtained then it is usually an advantage to know also the relative proportions in
which the products are obtained, e.g., in establishing, among other things, whether kinetic or
thermodynamic control is operating.

Information about the products of a reaction can be particularly informative when one of
them is quite unexpected. Thus the reaction of 4-chloromethylbenzene (p-chlorotoluene, 1)
with amide ion, NH2 in liquid ammonia is found to lead not only to the expected 4-
methylphenylamine (p-toluidine, 2), but also to the quite unexpected 3-methylphenylamine
(m-toluidine, 3), which is in fact the major product:
Cl NH2
NH2
NH2 in liq. NH3
+

CH3 CH3 CH3

1 2 3
Expected Unexpected

The latter clearly cannot be obtained from (1) by a simple substitution process, and either
must be formed from (1) via a different pathway than (2), or if the two products are formed
through some common intermediate then clearly (2) cannot be formed by a direct substitution
either.

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The importance of establishing the correct structure of the reaction product is best illustrated
by the confusion that can result when this has been assumed, wrongly, as self-evident, or
established erroneously. Thus the yellow triphenylmethyl radical, obtained from the action of
silver on triphenylmethyl chloride in 1900, readily forms a colorless dimer which was
reasonably enough assumed to be hexaphenylethane (5) with thirty 'aromatic' hydrogen
atoms. Only after nearly seventy years (in 1968) did the NMR spectrum of the dimer (with
only twenty-five 'aromatic' (H), four 'dienic' (H), and one 'saturated' (H), hydrogen atoms)
demonstrate that it could not have the hexaphenylethane structure (5) and was, in fact (6):

Study of intermediates
Possible intermediates
Among the most concrete evidence obtainable about the mechanism of a reaction is that
provided by the actual isolation of one or more intermediates from the reaction mixture. Thus
in the Hofmann reaction by which amides are converted into amines, it is, with care, possible
to isolate the N-bromoamide, RCONHBr, its anion, RCONBr , and an isocyanate, RNCO;
thus going some considerable way to elucidate the overall mechanism of the reaction. It is of
course necessary to establish beyond all doubt that any species isolated really is an
intermediateand not merely an alternative productby showing that it may be converted,
under the normal reaction conditions, into the usual reaction products at a rate at least as fast
as the overall reaction under the same conditions. It is also important to establish that the
species isolated really is on the direct reaction pathway, and not merely in equilibrium with
the true intermediate.

Detection of intermediates and their trapping

Where we have reason to suspect the involvement of a particular species as a labile

intermediate in the course of a reaction, it may be possible to confirm our suspicions by
introducing into the reaction mixture, with malice aforethought, a reactive species which we
should expect our postulated intermediate to react with particularly readily. It may then be

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possible to divert the labile intermediate from the main reaction pathwayto trap itand to
isolate a stable species into which it has been unequivocally incorporated. Thus in the
hydrolysis of trichloromethane with strong bases, the highly electron-deficient
dichlorocarbene, :CCl2, which has been suggested as a labile intermediate, was 'trapped' by
introducing into the reaction mixture the electron-rich species cis-2-butene (1), and then
isolating the resultant stable cyclopropane derivative (2), whose formation can hardly be
accounted for in any other way:

Isotopic labeling
It is often a matter of some concern to know whether a particular bond has, or has not, been
broken in a step up to and including the rate-limiting step of a reaction. Simple kinetic data
cannot tell us this, and further refinements have to be resorted to. If, for example, the bond
concerned is CH, the question may be settled by comparing the rates of reaction, under the
same conditions, of the compound in which we are interested, and its exact analogue in which
this bond has been replaced by a CD linkage. The two bonds will have the same chemical
nature as isotopes of the same element are involved, but their vibration frequencies, and
hence their dissociation energies, will be slightly different because atoms of different mass
are involved: the greater the mass, the stronger the bond. This difference in bond strength
will, of course, be reflected in different rates of breaking of the two bonds under comparable
conditions: the weaker CH bond being broken more rapidly than the stronger CD bond;
quantum mechanical calculation suggests a maximum rate difference, kH/kD,  7 at 25 °C.

Thus in the oxidation

It is found that Ph2CHOH is oxidized 6ꞏ7 times as rapidly as Ph2CDOH; the reaction is said
to exhibit a primary kinetic isotope effect, and breaking of the CH bond must clearly be
involved in the rate-limiting step of the reaction.

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Isotopes can also be used to solve mechanistic problems that are non-kinetic. Thus the
aqueous hydrolysis of esters to yield an acid and an alcohol could, in theory, proceed by
cleavage at (a) alkyl/oxygen fission, or (b) acyl oxygen fission:

If the reaction is carried out in water enriched in the heavier oxygen isotope 18O, (a) will lead
18 18
to an alcohol which is O enriched and an acid which is not, while (b) will lead to an O
18
enriched acid but a normal alcohol. Most simple esters are in fact found to yield an O
enriched acid indicating that hydrolysis, under these conditions, proceeds via (b) acyl/oxygen
fission. It should of course be emphasized that these results are only valid provided that
neither acid nor alcohol, once formed, can itself exchange its oxygen with water enriched in
18
O, as has indeed been shown to be the case.

Stereochemical Studies
Information about the stereochemical course followed by a particular reaction can also
provide useful insight into its mechanism, and may well introduce stringent criteria that any
suggested mechanistic scheme will have to meet. Thus the fact that the base-catalyzed
bromination of an optically active stereoisomer of the ketone (1) leads to an optically
inactive racemic product, indicates that the reaction must proceed through a planar
intermediate, which can undergo attack equally well from either side leading to equal
amounts of the two mirror-image forms of the product.

Then again, the fact that cyclopentene (2) adds on bromine under polar conditions to yield the
trans-dibromide (3) only, indicates that the mechanism of the reaction cannot simply be
direct, one-step addition of the bromine molecule to the double bond, for this must lead to the
cis-dibromide (4):

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The addition must be at least a two-step process. Reactions like this, which proceed so as to
give largely-or even wholly-one stereoisomer out of the two alternatives possible, are said to
be stereoselective.

Kinetic Studies
The largest body of information about reaction pathways has come and still does come- from
kinetic studies as we shall see, but the interpretation of kinetic data in mechanistic terms is
not always quite as simple as might at first sight be supposed. Thus the effective reacting
species, whose concentration really determines the reaction rate, may differ from the species
that was put into the reaction mixture to start with, and whose changing concentration we are
actually seeking to measure. Thus in aromatic nitration the effective attacking species is
usually NO2, but it is HNO3 that we put into the reaction mixture, and whose changing
concentration we are measuring; the relationship between the two may well be complex and
so, therefore, may be the relation between the rate of reaction and [HNO3]. Despite the fact
that the essential reaction is a simple one, it may not be easy to deduce this from the
quantities that we can readily measure.

Then again, if the hydrolysis in aqueous solution of the alkyl halide, RHal, is found to follow
the rate equation,
Rate = k1[RHal]

It is not necessarily safe to conclude that the rate-determining step does not involve the
participation of water, simply on the grounds that [H2O] does not appear in the rate equation;
for if water is being used as the solvent it will be present in very large excess, and its
concentration would remain virtually unchanged whether or not it actually participated in the

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rate-limiting stage. The point could perhaps be settled by carrying out the hydrolysis in
another solvent, e.g., HCO2H, and by using a much smaller concentration of water as a
potential nucleophile. The hydrolysis may then be found to follow the rate equation,

Rate = k2[RHal][H2O]

But the actual mechanism of hydrolysis could well have changed on altering the solvent, so
that we are not, of necessity, any the wiser about what actually went on in the original
aqueous solution.

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