KEY CRITERIA FOR CHEMICAL EFFICIENCY

INTRINSIC FACTORS EXTRINSIC FACTORS

chemical reaction reaction processing

yield selectivity time energy equipment

atom economy convergence waste safety natural sources

MODERN
ORGANIC SYNTHESIS

Mechanistic TARGET
interpretation MOLECULES
(single compound or library)
 MAXIMIZING SYNTHETIC EFFICIENCY

EFFICIENCY OF THE REACTION PROCESSING

• solid-phase organic synthesis (SPOS)

• polymer-assisted solution-phase synthesis (PASPS)
• tag-assisted synthesis
• “light” fluorous synthesis
• synthesis in flow-mode

IDEAL SYNTHESIS

EFFICIENCY OF THE CHEMICAL REACTION

• click chemistry
• organocatalysis
• multicomponent reactions (MCRs)
• microwave-assisted synthesis
•domino reactions
• synthesis in flow-mode
Experimental methods in the
determination of
reaction mechanisms

3
Introduction
A reaction mechanism is the better interpretation of the possible routes that involve the
evolution of reactants into the reaction products

These points need to be clarified in the interpretation of a reaction mechanism. The

determination of:

• the number of steps

• the structure of intermediates for multi-step reactions
• the sequence of steps
• the rate-determining step
• overall rate constant and, possibly, rate constant of all steps
• stereochemical requirements of the reaction
• the way by which bonds are formed and broken in the reaction
• effect of variation of the structure of the reactants (substituent effect)
• effect of variation of the reaction conditions (solvent and temperature effects)
• role of the catalyst, if present
4
Introduction
An accepted mechanism for an organic reaction is just a working hypothesis and it is
considered as the more reasonable interpretation, which may justify the available
experimental data

The determination of a reaction mechanism allows for:

• the knowledge of the substrate reactivity

• the prevision of the reaction limits and of the structure of the reaction products
• the improvement of the synthetic procedure
• the conception of new reactions
• the identification of a general reactivity of a given class of compounds

The methods for the determination of a reaction mechanism can be classified into two
categories:

• non-kinetic methods
• kinetic methods

5
Types of mechanism
In most reactions of organic compounds one or more covalent bonds are broken. We
can divide organic mechanisms into three basic types, depending on how the bond
breaks:

1. heterolytic mechanism
2. homolytic or free-radical mechanism
3. pericyclic mechanism

Heterolytic mechanism

The bond breaks in such a way that both electrons remain with one fragment. Such
reactions do not necessarily involve ionic intermediates, though they usually do. For
definition, the electrons are never unpaired. For these reactions it is convenient to call
one reactant the attacking reactant and the other the substrate.
- A reactant that brings an electron pair is called nucleophile and the reaction is
nucleophilic
- A reactant that takes an electron pair is called an electrophile and the reaction is
electrophilic
- In a reaction where the substrate become cleaved, part of it (not containing the
carbon) is called the leaving group 6
Types of mechanism
Homolytic mechanism

If a bond breaks in a such a way that each fragment gets one electron, free radicals
are formed and such reactions are said to take place by homolytic or free-radical
mechanisms

Pericyclic mechanism

If electrons move in a closed ring, and there are not intermediates, ions or free radicals
involved (it is impossible to say whether the electrons are paired or unpaired), this type
of mechanism is named pericyclic

7
Types of reaction
Almost all of the organic reactions can be fitted into the following six categories (all the
species are shown without charges, since differently charged reactants can undergo
analogous changes (the description is purely formal)

8
Types of reaction

9
Types of reaction

1,2 rearrangements are more common, although longer ones are also possible 10
Types of reaction

5. Oxidation and reductions

Many oxidation and reduction reactions fall in one of the four types mentioned above,
but many others do not

6. Combinations of the above

11
Thermodynamic requirements for reaction
In order for a reaction to take place spontaneously, the free energy of the product must
be lower than the free energy of the reactants: ΔG must be negative.
Free energy is made up of two components, enthalpy H and entropy S, which are
related by the equation:

ΔG = ΔH - TΔS

ΔH: difference in bond energies (including resonance, strain, and solvation energy)
between the products and reactants

ΔS: refers to the disorder of the system (the less order in the system, the greater the
entropy)

For many reactions entropy effects are small and its the enthalpy that mainly
determines whether the reaction can take place spontaneously. However, in certain
types of reactions entropy can dominate enthalpy:

1. A reaction in which the reactants are all liquids and one or more of the products is a
gas

2. A ring opening reaction

12
Thermodynamic requirements for reaction
3. A reaction in which the number of product molecules is higher than the number of
reactants molecules (A → B + C)

Not all cleavage reactions take place despite the favorable entropy effect because of
the large increase of enthalpy. Example: the homolytic cleavage of ethane

A bond of ca. 79 Kcal/mol is broken, and no new bond is formed to compensate for this
enthalpy increase. However, ethane can be cleaved at very high temperature, which
illustrates the principle that entropy becomes more important when the temperature
increases (the enthalpy term is independent of temperature)

13
Kinetic requirements for reaction
Just because a reaction has a negative ΔG does not necessarily mean that it will take
place in a reasonable period of time. For example, the reaction between H2 and O2 to
give H2O has a large negative ΔG, but it does not take place at room temperature.
In order for a reaction to occur, free energy of activation ΔG‡ must be added

In the simple case of a single-step reaction, the free energy of activation ΔG‡
corresponds to the energy that must be given to the reactants to reach the transition
state TS
- ΔGr‡ is the energy required to make the system reversible;
- when a reaction between two or more molecules has progressed to the point
corresponding to the top of the curve, the term transition state (TS) is applied to the
position of the nuclei and electrons. The TS possesses a definite geometry and
charge distribution but has no finite existence 14
Kinetic requirements for reaction

Two-step reactions proceed through the formation of an intermediate. In these

reactions there is an energy “well”. There are two TS, each with an energy higher than
the intermediate. The deeper the well, the more stable the intermediate. In reactions
where the second peak is higher than the first, the overall ΔG‡ is less than the sum of
the ΔG‡ values for the two steps.
An intermediate corresponds to a real species which has a finite through a very short
existence. It can be a carbocation, carbanion or free radical. In general, under the
reaction conditions, it does not live long but rapidly goes on to the products 15
Transition state theory
In the transition state theory, the starting material (A) and the transition state are taken
to be in equilibrium, the equilibrium constant designated K‡. For a given reaction
different TS (and also K‡) can be envisaged

According to this theory, all TSs go on to the product at the same rate so that the rate
constant K of the reaction depends only on the position between the starting materials
and the TS, i.e. on the value of K‡.
ΔG‡ is related to K‡ by the equation:

Thus, a higher ΔG‡ is associated with a smaller rate constant K. The higher the
temperature, the lower the value of ΔG‡ and thus the higher the rate constant K 16
Transition state theory
The relation between the rate constant K and free energy of activation ΔG‡ is
controlled by the Eyring equation:

Some reactions have no free energy of activation at all, meaning that K‡ is essentially
infinite and that virtually all collisions lead to reaction. Such processes are said to be
diffusion-controlled 17
Transition state theory
The Eyring equation is a theoretical equation that perfectly corresponds to the
experimental Arrhenius equation:

ΔH‡, the enthalpy of activation is the difference in bond energies (including strain,
resonance and solvation energies) between the TS and the starting compounds. In
many reactions bonds have been broken or partially broken by the time the TS is
reached; the energy necessary for this is ΔH‡
If energy is supplied to form new bonds after the TS, it can affect only ΔH and not ΔH‡

ΔS‡, entropy of activation, is the difference in entropy between the TS and the starting
compounds

18
Transition state theory
ΔS‡ becomes important when two reacting molecules must approach each other in a
specific orientation in order for the reaction to take place

ΔH‡ is not very useful in the determination of a reaction mechanism because of the
influence of solvatation on its value

The sign (+ or -) of ΔS‡ is instead functional because dissociation processes are

generally associated to positive values of ΔS‡

19
Transition state theory
Some examples:

20
Transition state theory
Some considerations:
- Interpretation of the parameters ΔH‡ and ΔS‡ is more complicated in solution than in
gas phase
- Unimolecular reactions that proceed through cyclic TS show negative entropies of
activation because of the loss of conformational degrees of freedom

- Difficult interpretation when are involved charged species. In the example a positive
ΔS‡ is expected because of the formation of two species in the TS; instead, ΔS‡ is
negative because of the reorganization of the solvent molecules in the polar TS

21
Kinetic and thermodynamic control

The figure shows the free-energy profile for the conversion of A where B is
thermodynamically more stable than C (∣ΔGB∣ > ∣ΔGc∣), but C is formed faster (ΔGC‡
< ΔGB‡). If neither reaction is reversible, C will be formed in larger amount because it
is formed faster (C is the kinetic product; the reaction is under kinetic control)

However, if the reaction is reversible (the reaction is permitted to reach the

equilibrium), the predominant or exclusive product is B (B is the thermodynamic
product; the reaction is under thermodynamic control). Under these conditions C that
is first formed reverts to A, while the more stable B does so much less

In many cases the more stable product is also the one that is formed faster
22
The Hammond postulate

Since a TS has zero lifetime, it is impossible to observe it directly and information

about its structure and geometry must be obtained by inference.
The Hammond postulate states that the geometry of the TS for a given step
resembles the side to which it is closer in energy

In the reaction illustrated in the figure, the first transition state (TS1) lies closer in
energy to the intermediate (INT) than to the reactant (A), and we can predict that the
geometry of TS1 resembles that of the intermediate more than it does that of A

Likewise, the second transition state (TS2) also has a free energy closer to that to the
product, so that its geometry resembles that of the intermediate. This is generally the
case of very reactive intermediates 23
Microscopic reversibility

In the course of a reaction the nuclei and electrons assume positions that at each
point correspond to the lowest free energy possible. If the reaction is reversible,
these positions must be the same in the reverse process, too. This means that the
forward and reverse reactions (run under the same conditions) must proceed by the
same mechanism. This is called the principle of microscopic reversibility

For example, if in the reaction A → B there is an intermediate INT, then INT must also
be an intermediate in the reaction B → A

This is a useful principle since it enables us to know the mechanism of reactions in

which equilibrium lies far over the one side

Reversible photochemical reactions are an exception, since a molecule that has

been excited photochemically does not have to lose its energy in the same way
24
Methods of determining reaction mechanisms

1. Non-kinetic methods
1.1 identification of products
1.2. identification of intermediates
1.3. stereochemical outcome
1.4. cross-over experiments
1.5. isotopic labelling
2. Kinetic methods
2.1. single-step reactions
2.2. multi-step reactions
2.3. determination of experimental rate law
2.4. reaction progress kinetic analysis
2.5. isotopic kinetic effect
2.6. reactions with neighboring group participation

25
Non-Kinetic methods
1.1. identification of products

The identification of products is the first step in the determination of the reaction
mechanism. Example: chlorination of methyl benzene

From the analysis of reaction products a different mechanism can be envisaged in

the gas phase (irradiation) and solution phase (in the presence of a Lewis acid) 26
Non-Kinetic methods
1.1. identification of products

Reaction of cyanide with benzylic-type substrates

27
Non-Kinetic methods
1.1. identification of products

A mechanistic proposal has to take into consideration the proportion of the formed
products and the generation of by-products. Example 1: radical halogenation of
methane. The proposed mechanism should explain the formation of ethane

28
Non-Kinetic methods
1.1. identification of products

A mechanistic proposal has to take into consideration the proportion of the formed
products and the generation of by-products. Example 2: Hofmann rearrangement.
The proposed mechanism should explain the formation of CO2

29
Non-Kinetic methods
1.1. identification of products

Sometimes, the absence of an expected product is the basis of a mechanistic

proposal. Example: addition to alkene

The intramolecular attack by oxygen is spatially favored (analysis of the 3D 30

structure)
Non-Kinetic methods
1.2. identification of intermediates
1.2.1. isolable intermediates
If a reaction is a multi-step reaction, it proceeds through the formation of
intermediates. Identification of intermediates may help the mechanistic interpretation.
In the case of isolable intermediates, these should be converted into the final
products with a rate not lower than that observed starting from the reactants. A
strategy for allowing the isolation of intermediates is lowering the temperature (the
energy of the system is diminished) or stopping (quench) the reaction at short times

First example: Friedel-Craft alkylation of 1,3,5-trimethyl benzene

31
Non-Kinetic methods
1.2. identification of intermediates
1.2.1. isolable intermediates
Second example: the Neber rearrangement. Alpha-amino ketones can be prepared
by treatment of ketoxime tosylates with a base as ethoxide or pyridine. The
mechanism became evident after the isolation of a reaction intermediate that reacted
under the reaction conditions to give the target product

32
Non-Kinetic methods
1.2. identification of intermediates
1.2.1. isolable intermediates
Third example: the Reissert reaction for the synthesis of quinoline derivatives

33
Non-Kinetic methods
1.2. identification of intermediates
1.2.1. isolable intermediates
Third example: the Reissert reaction for the synthesis of quinoline derivatives

34
Non-Kinetic methods
1.2. identification of intermediates
1.2.1. isolable intermediates
Fourth example: the Clemmensen reaction. A mechanistic proposal can be based on
the exclusion of an intermediate (here the possible alcohol derivative).

35
Non-Kinetic methods
1.2. identification of intermediates
1.2.1. isolable intermediates
Fifth example: the Hofmann rearrangement. The possible acyl nitrene can be
excluded because it is not reactive with all the involved species (concerted
mechanism)

36
Non-Kinetic methods
1.2. identification of intermediates
1.2.2. detectable intermediates
Different spectroscopic techniques can be used to detect intermediates that cannot
be isolated. First example: detection by NMR analysis of the bromonium ion in
bromide additions to double bonds

Bromonium ion detected by NMR analysis at low temperature in this example

37
Non-Kinetic methods
1.2. identification of intermediates
1.2.2. detectable intermediates
Second example: confirmation of the homolytic scission of Irgacure 651 by EPR
(electron paramagnetic resonance) analysis in the presence of the spin-trapping
agent 2-methyl-2-nitrosopropane (NMP)

38
Non-Kinetic methods
1.2. identification of intermediates
1.2.2. detectable intermediates
Third example: analysis of oxime formation at neutral pH by IR spectroscopy. The
disappearance of the C=O band is faster than the appearance of the C=N band. The
direct conversion into the oxime can be excluded

The step (a) is faster than the acid-catalyzed dehydration (steps (b) and (c) at neutral
pH). Under acidic conditions, the dehydration becomes faster (but the addition of the
39
hydroxylamine is slower)
Non-Kinetic methods
1.2. identification of intermediates
1.2.2. detectable intermediates
Fourth example: discrimination between nucleophilic and basic catalysis in the
hydrolysis of p-nitrophenyl esters promoted by imidazole

40
Non-Kinetic methods
1.2. identification of intermediates
1.2.2. detectable intermediates
The acyl imidazole is formed as an intermediate and it is detected by UV analysis
(increase and then decrease of the absorbance at 254 nm)

41
acyl imidazole
Non-Kinetic methods
1.2. identification of intermediates
1.2.3. trapping of intermediates
First example: bromination of alkenes. Exclusion of the concerted addition of Br2 to
double bonds thanks to the presence of the addition product of methanol

42
Non-Kinetic methods
1.2. identification of intermediates
1.2.3. trapping of intermediates
Second example: nitration of anisole proceeds through a carbocationic intermediate
as demonstrated by an intramolecular trapping experiment starting from a suitable
analog

43
Non-Kinetic methods
1.2. identification of intermediates
1.2.3. trapping of intermediates
Third example: trapping of neutral intermediates. The case of benzyne and Diels-
Alder reaction

(nitrous acid)

44
Non-Kinetic methods
1.2. identification of intermediates
1.2.3. trapping of intermediates
Forth example: trapping of the ortho intermediate in the Claisen rearrangement with
maleic anhydride.

45
Non-Kinetic methods
1.2. identification of intermediates
1.2.4. addition of hypothesized intermediates
If the occurrence of an intermediate is supposed, it can be prepared by a different
strategy and then reacted under the same conditions of the reaction under study. If
the intermediate does not evolve into the product, it means that it is not part of the
reaction. Otherwise, if the product is formed, it is very likely that the intermediate is
involved in the reaction mechanism. Example: the Richter rearrangement.

EWG = electron withdrawing group

46
Non-Kinetic methods
1.2. identification of intermediates
1.2.4. addition of hypothesized intermediates

47
Non-Kinetic methods
1.2. identification of intermediates
1.2.4. addition of hypothesized intermediates
Some evidences: evolution of N2 and positive labelling experiments (vide infra)

48
Non-Kinetic methods
1.3. stereochemical outcome
The stereochemical outcome gives fundamental information on the reaction
mechanism. First example: inversion of configuration in SN2 reactions of
epichlorohydrin

49
Non-Kinetic methods
1.3. stereochemical outcome
Second example: the Wolff rearrangement of a-diazoketones

- HCl

50
Non-Kinetic methods
1.3. stereochemical outcome
Third example: chlorination of an alcohol by thionyl chloride with retention of config.

51
Non-Kinetic methods
1.4. cross-over experiments
In many rearrangements it is necessary to distinguish between inter- or intra-
molecular processes. The migrating group is free during an intermolecular process
while it is never free during an intramolecular one.
First example: the Claisen rearrangement of phenyl ethers

52
Non-Kinetic methods
1.4. cross-over experiments
First example: the Claisen rearrangement of phenyl ethers

53
Non-Kinetic methods
1.4. cross-over experiments
Second example: the Fries rearrangement of phenolic esters

54
Non-Kinetic methods
1.4. cross-over experiments
Second example: the Fries rearrangement of phenolic esters

55
Non-Kinetic methods
1.5. isotopic labelling
The isotopic labelling of a given atom in the substrate can give information on the
reaction mechanism because it is easy to identify that atom in the products.
The use of 14C
In the Claisen rearrangement, the isotopic labelling of the a-carbon of the allyl ether
portion gives a product where the labelled atom is bound to the ortho-position

56
Non-Kinetic methods
1.5. isotopic labelling
The use of 14C
In the Claisen rearrangement, the isotopic labelling of the a-carbon of the allyl ether
portion gives a product where the labelled atom is bound to the ortho-position

57
Non-Kinetic methods
1.5. isotopic labelling
The use of 18O
First example: the use of marked water shows that the basic hydrolysis of pentyl
acetate occurs with scission of acylic C-O bond

58
Non-Kinetic methods
1.5. isotopic labelling
The use of 18O
Second example: mechanism of hydration equilibrium of carbonyl compounds

59
Non-Kinetic methods
1.5. isotopic labelling
The use of 18O
Third example: basic hydrolysis of esters. The occurrence of the tetrahedral
intermediate

60
Non-Kinetic methods
1.5. isotopic labelling
The use of 18O
Third example: basic hydrolysis of esters. The occurrence of the tetrahedral
intermediate. Transfer of the labelled oxygen from ester to hydroxyl anion

61
Non-Kinetic methods
1.5. isotopic labelling
The use of 18O
Forth example: determination of the mechanism of epoxide formation promoted by
Oxone (potassium peroxymonosulfate, KHSO5)

(piperidinium salt)

62
Non-Kinetic methods
1.5. isotopic labelling
The use of 18O
The dioxirane intermediate is the species involved because it justifies the formation
of 50% of marked epoxide as observed by MS analysis

63
Non-Kinetic methods
1.5. isotopic labelling
The use of Deuterium (D or 2H)
The vast use of deuterium is given by the availability of D2O. Example: the
isomerization of (Z)-1-phenyl-butadiene occurs through conjugate addition to H+

64
Methods of determining reaction mechanisms

1. Non-kinetic methods
1.1 identification of products
1.2. identification of intermediates
1.3. stereochemical outcome
1.4. cross-over experiments
1.5. isotopic labelling
2. Kinetic methods
2.1. single-step reactions
2.2. multi-step reactions
2.3. determination of experimental rate law
2.4. reaction progress kinetic analysis
2.5. isotopic kinetic effect
2.6. reactions with neighboring group participation

65
2. Kinetic methods
Introduction
The rate of a homogeneous reaction is the rate of disappearance of a reactant or
appearance of a product.
For a general reaction A + B → C the rate law (the rate of change of concentration
of A with time t) is:

The rate nearly always changes with time, since it is usually proportional to
concentration and the concentration of reactants decreases with time. However, the
rate is not always proportional to the concentration of all reactants. In some cases a
change in concentration of a reactant produces non change at all in the rate, while in
other cases the rate may be proportional to the concentration of a substance (a
catalyst) that does not even appear in the stoichiometric equation 66
2. Kinetic methods
Introduction
If the rate is proportional to the change in concentration of only one reactant (A), the
rate law is:

If the rate is proportional to the change in concentration of two reactants (A and B) or

to the square of the concentration of one (A), the rate law is:

Similar expressions can be written for third-order reactions. A reaction whose rate is
proportional to [A] and to [B] is said to be first order in A and in B, second order
overall 67
2. Kinetic methods
2.1. single-step reactions
The rate law of a reaction is an experimentally determined fact. From this evidence
we attempt to learn the molecularity of the reaction, which may be defined as the
number of molecules that come together to form the transition state (TS). Therefore,
if we know how many (and which) molecules take part in the transition state, we gain
information about the mechanism

The experimentally determined rate order is not necessarily the same as the
molecularity. Any reaction, no matter how many steps are involved, has only one rate
law, but each step of the mechanism has its own molecularity

For reactions that take place in one step (no intermediates) the order is the same as
the molecularity

• a first order, one-step reaction is always unimolecular;

• a one-step reaction that is second order in A always involves two molecules of A;
• a one-step reaction that is first order in A and in B involves a molecule of A that
reacts with one molecule of B in the transition state 68
2. Kinetic methods
2.2. multi-step reactions
For reactions that take place in more than one step, the order of each step is the
same as the molecularity for that step

If any one step of a mechanism is considerably slower than all the others (this is
usually the case), the rate of the overall reaction is essentially the same as the slow
step, which is called the rate-determining step

For reactions that take place in two or more steps, two broad cases can be
distinguished (general reaction: A + 2B → C)

First case: first step is rate-determining

69
2. Kinetic methods
2.2. multi-step reactions
Second case: first step is not rate-determining but a rapid attainment of equilibrium
followed by a second slower reaction

70
2. Kinetic methods
2.2. multi-step reactions
Second case: first step is not rate-determining but a rapid attainment of equilibrium
followed by a second slower reaction

71
2. Kinetic methods
2.2. multi-step reactions
Second case: first step is not rate-determining but a rapid attainment of equilibrium
followed by a second slower reaction.

In order to have mechanistic information, it is necessary to identify limiting cases

where the steady-state equation and the experimental rate law coincide 72
2. Kinetic methods
2.2. multi-step reactions

If this mechanistic hypothesis is correct, we should find an experimental rate law first
order in A and second order in B 73
2. Kinetic methods
2.2. multi-step reactions

If this mechanistic hypothesis is correct, we should find an experimental rate law first
order in A and first order in B (see previous example of page 69) 74
2. Kinetic methods
2.2. multi-step reactions

75
2. Kinetic methods
2.3. determination of experimental rate law
What is being measured is the change in concentration of a product or a reactant
with time. Many methods can be used to make these measurements: the choice
depends on the reaction under study

1. Periodic or continual spectral reading. In many cases the reaction can be carried
out in the cell while it is in the instrument (IR, UV, NMR, ESR spectroscopy,
polarimetry);
2. Quenching and analyzing. A series of reactions can be set up and each stopped
in some way (e.g. by lowering the temperature or adding an inhibitor) after a
different amount of time has elapsed. The material are then analyzed by spectral
reading, titrations, chromatography, polarimetry, or any other method;
3. Removal of aliquots at intervals. Each aliquot is then analyzed as in method 2;
4. Measurements of changes in total pressure. For gas-phase reactions;
5. Calorimetric methods. The output or absorption of heat can be measured at time
intervals;
6. Special methods. For very fast reactions

76
2. Kinetic methods
2.3. determination of experimental rate law
In general, what is obtained is a graph showing how a concentration varies with time

The resulting data must be interpreted to obtain the kinetic law (determination of
reaction orders) and the rate constant K. This can be done using different
techniques depending on the complexity of the reaction under study

If a plot of ln[A] against t is linear, the reaction is first order and K can be 77
obtained from the slope
2. Kinetic methods
2.3. determination of experimental rate law

Thus, under equimolar conditions, if a plot of 1/[A] against t is linear, the reaction is
second order and K can be obtained from the slope
78
2. Kinetic methods
2.4. reaction progress kinetic analysis
Unfortunately, most reactions, especially catalyzed reactions, do not belong to the
above cases

Moreover, in the previous study, we were forced to impose equimolar conditions which
cannot be optimal for performing the reaction (for instance, an excess of B is required
to achieve the best conversion of A)

Therefore, it is important to develop a method to determine the experimental rate law

under synthetically relevant conditions. Very likely , the best method is the Reaction
9051_C027.fm Page 455 Thursday, October 25, 2007 9:50 AM

Progress Kinetic Analysis developed by prof. D. Blackmond

27 Reaction Progress Kinetic

Analysis: A Powerful
Methodology for
Streamlining Pharmaceutical
Reaction Steps
Natalia Zotova, Suju P. Mathew, Hiroshi Iwamura, and
Donna G. Blackmond 79
2. Kinetic methods
2.4. reaction progress kinetic analysis
2.4.1.preliminary operations

Determination of conversion versus time plot using different techniques

80
2. Kinetic methods
2.4. reaction progress kinetic analysis
2.4.1.preliminary operations
• Determination of the reaction stoichiometry and definition of excess [e]

This parameter is the difference between the initial concentration of the two
substrates 1 and 2

This parameter is constant in any given experiment

Excess [e] can be large, small, positive or negative with units of molarity. The
quantity [e] allows to relate the two substrates’ concentration at any point during the
reaction

[1]0 and [2]0 are the initial concentrations of the two substrates.

81
2. Kinetic methods
2.4. reaction progress kinetic analysis
2.4.1.preliminary operations
Most traditional kinetic studies are performed under “pseudo-zero-order” conditions
where one substrate is used in high excess to simplify the rate law

The RPKA method uses substrate concentrations that are only slightly different from
each other

Thus [e] is usually small and the kinetic experiment is performed under synthetically
relevant conditions

82
2. Kinetic methods
2.4. reaction progress kinetic analysis
2.4.2. same excess experiment
• The same excess experiment allows to determine the stability of the catalyst
throughout the reaction

Catalyst stability is one of the most critical aspects related to the reaction mechanism
and robustness (catalyst activation, deactivation, or product inhibition)

• Identify two set of conditions employing the same catalyst concentration but
different initial concentrations of the two reactants chosen such as the value of [e]
is the same in the two experiments

The initial conditions of Exp.2 (blue) are identical to the concentrations of reactants
found in Exp.1 (red) at the point it reaches 50% conversion. From this point onward,
the two experiments exhibit identical [2] at any given [1] throughout the course of both
reactions. The only differences between the two Exps. are that the catalyst performed
more turnovers in Exp.1 and the reaction vial has a greater concentration of product 3
83
in Exp.1
2. Kinetic methods
2.4. reaction progress kinetic analysis
2.4.2. same excess experiment
• Determine the reaction profile ([3] vs. time plot) and convert it in the graphical
rate equation (rate vs. [2] plot)
• Plot together Exp.1 and Exp.2. If the two curves fall on top of one another
(overlay) over the range [2] common to both, it means that the rate is not
significantly influenced by changes in the overall catalyst concentration within the
cycle. Overlay in same excess plots is used to confirm the catalyst robustness

84
2. Kinetic methods
2.4. reaction progress kinetic analysis
2.4.3. different excess experiment
• Determine the reaction orders using the normalized rate equation. It is
necessary to set up at least two experiments with same aldehyde concentration
but different excess (Exps.3 and 4; Exp. 5 is for further confirmation)
• Plot rate/[1]x as the y-axis variable and [2] as the x-axis variable

85
2. Kinetic methods
2.4. reaction progress kinetic analysis
2.4.3. different excess experiment
• Overlay between two curves reveals that the reaction exhibits order x kinetics in
concentration of the normalized substrate (1 in our case)
• The shape of the curve reveals the reaction order in the concentration of the
substrate plotted as the x-axis variable (2 in our case)
• When the overlaid curves give a straight line, this reveals that y =1, meaning that
the reaction exhibits first-order kinetic in [2]. The slope of this straight line equals
k.[4]z
• Reaction orders other than one may be assessed by the shape of the curve
(concave for y < 1; convex for y > 1)
• x and y may also be determined quantitatively and exactly by fitting of the overlaid
curves by the aid of dedicated software

86
2. Kinetic methods
2.5. isotopic kinetic effect
When a hydrogen in a reactant molecule is replaced by deuterium, it can be
observed a change in the reaction rate. Such a change is known as deuterium
isotope effect and is expressed by the ratio KH/KD.

The ground-state vibrational energy (named zero-point vibrational energy) of a bond

depends on the mass of the atoms and it is lower when the the mass atom is higher.
Therefore, D-C, D-O, D-N bonds etc. have lower energies in the ground state than
the corresponding H-C, H-O, H-N bonds. Complete dissociation of a deuterium bond
thus requires more energy than that for the corresponding hydrogen bond in the
same environment.

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2. Kinetic methods
2.5. isotopic kinetic effect

• If a H-C, H-O or H-N bond is broken in the rate-determining step, the rate must be
lowered by the substitution with D.

• Deuterium isotope effects usually range from 1 (no isotopic effect at all: KH/KD = 1)
to about 7 or 8 (KH/KD = 7 or 8).

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2. Kinetic methods
2.5. isotopic kinetic effect

• If H-C, H-O or H-N bond is not broken at all or is broken in a non-rate determining
step, substitution of D for H causes no change in the rate.

• Deuterium isotope effects usually range from 1 (no isotopic effect at all: KH/KD =
1) to about 7 or 8 (KH/KD = 7 or 8).

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2. Kinetic methods
2.5. isotopic kinetic effect
Second example: nitration of benzene

Experimentally, C6H6 and C6D6 undergo nitration with the same rate, thus the C-H
bond is not broken in the rate-determining step (no concerted mechanism). 90
2. Kinetic methods
2.5. reactions with neighboring group participation
If the increase of the reaction rate is due to the stabilizing effect of a neighboring
group in the transition state, we say that group furnishes anchimeric assistance

Evidences of neighboring group participation are:

1. increase of the reaction rate

2. unexpected stereochemical outcome

The migrating groups can be:

1. lone pairs of heteroatoms

2. 𝝅 bonds
3. aromatic systems
4. 𝛔 bonds (C-C and C-H)

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2. Kinetic methods
2.5. reactions with neighboring group participation: evidences
1. increase of the reaction rate

A substituent G with a lone pair can stabilize an electron-deficient center of the

molecule determining an increase of the reaction rate

Example: solvolysis reaction

92
2. Kinetic methods
2.5. reactions with neighboring group participation: evidences
1. increase of the reaction rate

Example: solvolysis reaction

93
2. Kinetic methods
2.5. reactions with neighboring group participation: evidences
1. increase of the reaction rate

Example: solvolysis reaction

94
2. Kinetic methods
2.5. reactions with neighboring group participation: evidences
2. unexpected stereochemical outcome. Example 1

95
2. Kinetic methods
2.5. reactions with neighboring group participation: evidences
2. unexpected stereochemical outcome. Example 1

96
2. Kinetic methods
2.5. reactions with neighboring group participation: evidences
2. unexpected stereochemical outcome. Example 2

97
2. Kinetic methods
2.5. reactions with neighboring group participation: groups
1. lone pairs of heteroatoms
The groups that display a lone pair can use it to form cyclic intermediates. The balance
between enthalpic effects (favorable) and entropic effects (unfavrable) makes the
neighboring group participation particularly efficient for 3-, 5-, and 6-membered rings.
Most common are 3- and 5-membered rings, less common are 6-membered rings

Most common are 3- and 5- membered rings, less common are 6-membered rings.

98
2. Kinetic methods
2.5. reactions with neighboring group participation: groups
1. lone pairs of heteroatoms
Example. Compounds 1 and 2 evolve through the same cyclic intermediate giving the
same product thanks to the anchimeric assistance

99
2. Kinetic methods
2.5. reactions with neighboring group participation: groups
2. 𝝅 bonds
The interaction between 𝝅 bonds and positive centers gives spectacular examples of
anchimeric assistance

100
2. Kinetic methods
2.5. reactions with neighboring group participation: groups
3. aromatic systems
Example 1
Solvolysis of p-bromoethyl phenate at pH =10 is 106 faster than that of (2-
bromoethyl)benzene. This is an example of arylic participation

101
2. Kinetic methods
2.5. reactions with neighboring group participation: groups
3. aromatic systems
Example 2
Participation is suggested in this example by the retention of configuration.
The 𝝅 electrons are involved in an electrophilic aromatic substitution like the Friedel-
Craft alkylation with formation of a delocalized intermediate named phenonium ion

102
2. Kinetic methods
2.5. reactions with neighboring group participation: groups
4. 𝛔 bonds (C-H bond)
• Solvolysis of the suitably prepared labelled tosylate affords two reaction products (1
and 2)
• If no participation of hydride occurs, only one product should be formed (compound
1, normal SN2)

106
2. Kinetic methods
2.5. reactions with neighboring group participation: groups
4. 𝛔 bonds (C-H bond)
• If migration of hydride occurs with formation of open carbocations, four products are
expected

107
2. Kinetic methods
2.5. reactions with neighboring group participation: groups
4. 𝛔 bonds (C-H bond)
• The experimental evidence can be justified by the formation of the non-classical
intermediate (or transition state) displaying a hypervalent H atom

108