CHAPTER 5.

STUDY OF REACTION MECHANISMS

CHAPTER 5. STUDY OF REACTION MECHANISMS

1. THERMODYNAMIC DATA ...................................................................................................... 3

2. KINETIC DATA ........................................................................................................................ 5
2.1. Reaction rate equations ..................................................................................................... 5
2.2. Transition-state theory ..................................................................................................... 16
3. SUBSTITUENT EFFECTS AND LINEAR FREE-ENERGY RELATIONSHIPS .................... 22
4. BASIC MECHANISTIC CONCEPTS ..................................................................................... 37
4.1. Kinetic versus thermodynamic control ............................................................................. 37
4.2. Hammond's Postulate ...................................................................................................... 39
4.3. The Curtin-Hammett Principle .......................................................................................... 43
5. ISOTOPE EFFECTS .............................................................................................................. 45
6. ISOTOPES IN LABELING EXPERIMENTS .......................................................................... 49
7. CHARACTERIZATION OF REACTION INTERMEDIATES .................................................. 50
8. CATALYSIS BY ACIDS AND BASES ................................................................................... 52
8.1. Brönsted acids and bases ................................................................................................ 52
8.2. Lewis Acid Catalysis ........................................................................................................ 57
9. SOLVENT EFFECTS ............................................................................................................. 62
9.1. Polarity ............................................................................................................................. 62
9.2. Enhancement of the nucleophilicity of anions in polar aprotic solvents ........................... 66
9.3. Gas phase versus solution ............................................................................................... 70

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CHAPTER 5. STUDY OF REACTION MECHANISMS

Most organic reactions occur in several steps.

These steps constitute the reaction mechanism.

Examination of the mechanisms of reactions often reveals:

• close relationships between reactions that otherwise might appear to be unrelated;
• the effect of substituents on the rate of related reactions;
• the development of new transformations and improvement of existing ones.

Further reading
1. Advanced Organic Chemistry Part A: Structure and Mechanism R.J. Sundberg, F.A. Carey;
Springer (5ª Ed.), New York, 2007 (Chapter 3). link library
2. Perspectives on Structure and Mechanism in Organic Chemistry F.A. Carroll; Wiley (2nd Ed.)
Hoboken, New Jersey, 2010 (Chapter 6). link library
3. Organic Chemistry An intermediate text. R.V. Hoffman; Wiley (2nd Ed.), New Jersey, 2004
(Chapters 3 and 5). link library
4. Organic Chemistry. Clayden-Greeves-Warren; Oxford University Press (2nd Ed), Oxford
2012 (Chapter 39). link library

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1. THERMODYNAMIC DATA
Any reaction has associated with it changes in enthalpy (ΔH), entropy (ΔS), and free energy
(ΔG). The principles of thermodynamics assure us that ΔH, ΔS, and ΔG are independent of the
reaction path. They are interrelated by the fundamental equation:
ΔG = ΔH -TΔS
Furthermore, the value of ΔG is related to the equilibrium constant K for the reaction:
ΔG = -RT Ln K
Because these various quantities are characteristics of the reactants and products but are
independent of the reaction path, they cannot provide insight into mechanisms.
The enthalpy change of a given reaction can be estimated from tabulated thermochemical data
or from bond-energy data. The example below illustrates the use of bond-energy data for
estimating the enthalpy of a reaction:

𝛥𝐻 = 𝛴𝑏𝑜𝑛𝑑-𝑑𝑖𝑠𝑠𝑜𝑐𝑖𝑎𝑡𝑖𝑜𝑛 𝑒𝑛𝑒𝑟𝑔𝑖𝑒𝑠(𝑏𝑟𝑜𝑘𝑒𝑛) − 𝛴𝑏𝑜𝑛𝑑-𝑑𝑖𝑠𝑠𝑜𝑐𝑖𝑎𝑡𝑖𝑜𝑛 𝑒𝑛𝑒𝑟𝑔𝑖𝑒𝑠(𝑓𝑜𝑟𝑚𝑒𝑑)

Broken bonds (kcal/mol) Formed bonds (kcal/mol)

H-H 103.2 2 C-H 196.4
C=C 145.0 C-C 80.5
248.2 276.9

ΔH = 248.2 - 276.9 = -28.7 kcal/mol

The hydrogenation is therefore calculated to be exothermic by about 29 kcal/mol.

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More accurate calculations can be done on the basis of enthalpies and free energies of
formation of the compound from its constituent elements:
𝛥𝐻 𝑜 = 𝛴𝛥𝐻𝑓𝑜𝑝𝑟𝑜𝑑𝑢𝑐𝑡𝑠 − 𝛴𝛥𝐻𝑓𝑜𝑟𝑒𝑎𝑐𝑡𝑎𝑛𝑡𝑠 𝛥𝐺 𝑜 = 𝛴𝛥𝐺𝑓𝑜𝑝𝑟𝑜𝑑𝑢𝑐𝑡𝑠 − 𝛴𝛥𝐺𝑓𝑜𝑟𝑒𝑎𝑐𝑡𝑎𝑛𝑡𝑠
For example, the enthalpy change associated with hydrogenation of 2-butene can be
estimated:
𝛥𝐻𝑓𝑜 (butane) -30.15 kcal/mol
ΔHºhydrogenation
𝛥𝐻𝑓𝑜 (2-butene) -2.67 kcal/mol
𝛥𝐻𝑓𝑜 (H2) -27.48 kcal/mol
0 kcal/mol

Estimation of the free-energy change associated with a reaction permits the calculation of the
equilibrium position for a reaction and indicates the feasibility of a given chemical process:
• A positive ΔG imposes a limit on the extent to which a reaction can occur.
• An appreciably negative ΔG indicates that the reaction is thermodynamically favourable.
MO calculations provide another approach to obtaining estimates of thermodynamic data. The
accuracy of the semiempirical methods have a reduced range of reliability. The ab initio
method, the 4-31G, 6-31G, G1, and G2 basis sets achieve a level of accuracy that permits
comparison of energy data. Calculations are frequently done on the basis of isodesmic
reactions in order to provide for maximum cancellation of errors in the total energies.

Thermodynamics provides no information about the rates of chemical reactions because they
are independent of the pathways that a potential reaction can follow.
in the absence of a relatively low-energy pathway, two molecules that can
potentially undergo a highly exothermic reaction will coexist without reacting.

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2. KINETIC DATA

2.1. Reaction rate equations

Kinetic data can provide detailed insight into reaction mechanisms.

The rate of a given reaction can be determined by following spectroscopically the
disappearance of a reactant or the appearance of the product.

The goal of a kinetic study is to establish the quantitative relationship between the
concentration of reactants and catalysts and the rate of the reaction. Typically, such a study
involves:
• rate measurements at enough different concentrations of each reactant;
• assessment of the kinetic order with respect to each reactant;
• the reaction is described by a rate law, which is an algebraic expression containing:
- one or more rate constants;
- the concentrations of all reactants that are involved in the rate-determining step
and steps prior to the rate-determining step;
• each concentration has an exponent, which is the order of the reaction with respect to
that component;
• the overall kinetic order of the reaction is the sum of all the exponents.
𝑑[𝐶]
𝑟𝑎𝑡𝑒 = = 𝑘1 [𝐴]𝑛 [𝐵]𝑚
𝑑𝑡

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Example 1. For the reaction sequence

the rates for the successive steps are

𝑑[𝐶]
𝑟𝑎𝑡𝑒1 = = 𝑘1 [𝐴][𝐵] − 𝑘−1 [𝐶]
𝑑𝑡
𝑑[𝐷]
𝑟𝑎𝑡𝑒2 = = 𝑘2 [𝐶]
𝑑𝑡
𝑑[𝐸] 𝑑[𝐹]
𝑟𝑎𝑡𝑒3 = = = 𝑘3 [𝐷]
𝑑𝑡 𝑑𝑡

Let us further specify that the first step is a very rapid but unfavourable equilibrium and that
k2 << k3; i.e., the second step is slow relative to the third step. Under these circumstances, the
overall rate of the reaction will depend on the rate of the second step, and this step is called the
rate-determining step.

Kinetic data provide information only about the rate-determining step and steps
preceding it.

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For the first step of the reaction, the equilibrium constant is:

[𝐶]
𝐾=
[𝐴][𝐵]
At equilibrium the forward and reverse reaction rates are equal:
𝑘−1 [𝐶] = 𝑘1 [𝐴][𝐵]
clearing:
𝑘1
[𝐶] = [𝐴][𝐵]
𝑘−1
and the rate for the second step:

𝑑[𝐷] 𝑘1
= 𝑘2 [𝐶] = 𝑘2 [𝐴][𝐵] = 𝑘𝑜𝑏𝑠 [𝐴][𝐵]
𝑑𝑡 𝑘−1

Experimentally, it would be observed that the reaction rate would be proportional to both [A]
and [B]. The reaction will be first-order in both reactants.

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Example 2. One common kind of reaction involves proton transfer occurring as a rapid
equilibrium preceding the rate-determining step:

There are two steps:

As in example 1, the overall rate being measured is that of step 2, but there may be no means
of directly measuring [𝑅𝑂𝐻2+ ]. The concentration of this protonated intermediate can be
expressed in terms of the concentration of the starting material by taking into consideration the
equilibrium constant, which relates [ROH], [Br-], and [H+]:

[𝑅𝑂𝐻2+ ]
𝐾= [𝑅𝑂𝐻2+ ] = 𝐾[𝑅𝑂𝐻][𝐻 + ]
[𝑅𝑂𝐻][𝐻 + ]

𝑟𝑎𝑡𝑒 = 𝑘2 [𝑅𝑂𝐻2+ ][𝐵𝑟 − ] = 𝑘2 𝐾[𝑅𝑂𝐻][𝐻 + ][𝐵𝑟 − ] = 𝑘𝑜𝑏𝑠 [𝑅𝑂𝐻][𝐻 + ][𝐵𝑟 − ]

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Example 3. A useful approach that is often used in analysis and simplification of kinetic
expressions is the steady-state approximation. The general reaction scheme would be:

If C is a reactive, unstable species, its concentration will never be very large. It must then be
consumed at a rate that closely approximates the rate at which it is formed:
𝑘1 [𝐴][𝐵]
𝑘1 [𝐴][𝐵] = 𝑘2 [𝐶][𝐷] + 𝑘−1 [𝐶] = [𝐶]
𝑘2 [𝐷]+𝑘−1

Therefore, the second step rate can be expressed:

𝑘1 [𝐴][𝐵]
𝑟𝑎𝑡𝑒 = 𝑘2 [𝐶][𝐷] = 𝑘2 [𝐷]
𝑘2 [𝐷] + 𝑘−1
If k2[D] is much greater than k-1 (first step is the rate-determining step) it can be simplified:
𝑘1 𝑘2 [𝐴][𝐵][𝐷]
𝑟𝑎𝑡𝑒 = = 𝑘1 [𝐴][𝐵]
𝑘2 [𝐷]
If k2[D] is much less than k-1 (second step is the rate-determining step):
𝑘1 𝑘2 [𝐴][𝐵][𝐷]
𝑟𝑎𝑡𝑒 =
𝑘−1
The normal course of a kinetic investigation involves postulating likely mechanisms and
comparing the observed rate law with those expected for the various mechanisms. Those
mechanisms that are incompatible with the observed kinetics can be eliminated as possibilities.

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Example 4. At least three possible mechanisms for the aromatic nitration by nitric acid:

A) Protonation of nitric acid and reaction of the protonated species with benzene:

If the first step is fast and reversible:

𝑘 [𝐻𝑂𝑁𝑂2 ]2
𝑘1 [𝐻𝑂𝑁𝑂2 ]2 = 𝑘−1 [𝐻2 𝑂𝑁𝑂2+ ][𝑁𝑂3− ] [𝐻2 𝑂𝑁𝑂2+ ] = 𝑘 1 −
−1 [𝑁𝑂3 ]

and the second step is the rate-determining step:

𝑘2 𝑘1 [𝐻𝑂𝑁𝑂2 ]2
𝑟𝑎𝑡𝑒 = 𝑘2 [𝐻2 𝑂𝑁𝑂2+ ][𝑏𝑒𝑛𝑧𝑒𝑛𝑒] = [𝑏𝑒𝑛𝑧𝑒𝑛𝑒] =
𝑘−1 [𝑁𝑂3− ]
[𝐻𝑂𝑁𝑂2 ]2
= 𝑘𝑜𝑏𝑠 [𝑏𝑒𝑛𝑧𝑒𝑛𝑒]
[𝑁𝑂3− ]

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CHAPTER 5. STUDY OF REACTION MECHANISMS

B) Nitric acid protonation, decomposition of the protonated species, and reaction with benzene

In this case, benzene does appear until after the rate-determining step, so it is not present in
the rate expression:

𝑘1 𝑘2 [𝐻𝑂𝑁𝑂2 ]2 [𝐻𝑂𝑁𝑂2 ]2
𝑟𝑎𝑡𝑒 = 𝑘2 [𝐻2 𝑂𝑁𝑂2+ ] = = 𝑘𝑜𝑏𝑠
𝑘−1 [𝑁𝑂3− ] [𝑁𝑂3− ]

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CHAPTER 5. STUDY OF REACTION MECHANISMS

C) NO2+ formation from two nitric acid molecules:

Now, the rate-determining step is the 3rd one:

𝑟𝑎𝑡𝑒 = 𝑘3 [𝑰]
The σ-complex concentration [I ] can be expressed in terms of the rapid equilibria involved in its
formation:
𝑘 [𝐻𝑂𝑁𝑂2 ]2
𝑘−2 [𝐼] = 𝑘2 [𝑁𝑂2+ ][𝑏𝑒𝑛𝑧𝑒𝑛𝑒] [𝑁𝑂2+ ] = 𝑘 1 −
−1 [𝑁𝑂3 ][𝐻2 𝑂]
2
𝑘2 [𝑏𝑒𝑛𝑧𝑒𝑛𝑒]𝑘1 [𝐻𝑂𝑁𝑂2 ]
𝑟𝑎𝑡𝑒 = 𝑘3
𝑘−2 𝑘−1 [𝑁𝑂3− ][𝐻2 𝑂]
Simplifying:
[𝐻𝑂𝑁𝑂2 ]2 [𝑏𝑒𝑛𝑧𝑒𝑛𝑒] [𝐻𝑂𝑁𝑂2 ]2 [𝑏𝑒𝑛𝑧𝑒𝑛𝑒]
𝑟𝑎𝑡𝑒 = 𝐾 = 𝑘 𝑜𝑏𝑠 𝑖𝑓 [𝐻2 𝑂] >> [𝑏𝑒𝑛𝑧𝑒𝑛𝑒]
[𝑁𝑂3− ][𝐻2 𝑂] [𝑁𝑂3− ]

These mechanisms provide kinetic expressions that are similar in form, although B has the
distinctive feature that it is zero-order in benzene. In fact, this is in agreement with nitration of
benzene in several organic solvents: benzene concentration does not affect the reaction rate.

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CHAPTER 5. STUDY OF REACTION MECHANISMS

Example 5. Let us consider the base-catalyzed reaction of benzaldehyde and acetophenone:

A reasonable sequence of steps can be written, but the relative rates of the steps is an open
question:

Because proton-transfer reactions between oxygen atoms are usually very fast, step 3 can be
assumed to be a rapid equilibrium. If the solvent is EtOH, [EtOH] is almost constant.

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CHAPTER 5. STUDY OF REACTION MECHANISMS

❖ If step 1 is rate-controlling, the rate expression would be:

𝑟𝑎𝑡𝑒 = 𝑘1 [𝑃ℎ𝐶𝑂𝐶𝐻3 ][𝐸𝑡𝑂 − ]

❖ If step 2 is rate-controlling (and step 1 is an equilibrium), we obtain the rate expression:

𝑟𝑎𝑡𝑒 = 𝑘2 [𝑃ℎ𝐶𝑂𝐶𝐻2− ][𝑃ℎ𝐶𝐻𝑂]
As the first step is an equilibrium, [𝑃ℎ𝐶𝑂𝐶𝐻2− ] can be expressed in terms of K1:
[𝑃ℎ𝐶𝑂𝐶𝐻2− ] = 𝐾1 [𝑃ℎ𝐶𝑂𝐶𝐻3 ][𝐸𝑡𝑂− ]
Therefore:
𝑟𝑎𝑡𝑒 = 𝑘2 𝐾1 [𝑃ℎ𝐶𝑂𝐶𝐻3 ][𝐸𝑡𝑂 − ][𝑃ℎ𝐶𝐻𝑂] = 𝑘𝑜𝑏𝑠 [𝑃ℎ𝐶𝑂𝐶𝐻3 ][𝑃ℎ𝐶𝐻𝑂][𝐸𝑡𝑂 − ]

❖ If the final step is rate-controlling, the rate is:

𝑟𝑎𝑡𝑒 = 𝑘4 [𝑭][𝐸𝑡𝑂− ]
The concentration of the intermediate PhCHOHCH2COPh (F) can be expressed in terms of
the three prior equilibria:
[𝑭][𝐸𝑡𝑂 − ] [𝑬]
for the 3rd step 𝐾3 = [𝑬]
and [𝑭] = 𝐾3 [𝐸𝑡𝑂−]

for the 2nd step [𝑬] = 𝐾2 [𝑃ℎ𝐶𝑂𝐶𝐻2− ][𝑃ℎ𝐶𝐻𝑂]

thus,

𝐾2 [𝑃ℎ𝐶𝑂𝐶𝐻2− ][𝑃ℎ𝐶𝐻𝑂]
[𝑭] = 𝐾3
[𝐸𝑡𝑂− ]

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CHAPTER 5. STUDY OF REACTION MECHANISMS

Substituting for [PhCOCH2- ] from the equilibrium expression for step 1 gives:
𝐾2 [𝑃ℎ𝐶𝐻𝑂]
[𝑭] = 𝐾3 𝐾1 [𝑃ℎ𝐶𝑂𝐶𝐻3 ][𝐸𝑡𝑂− ] = 𝐾"[𝑃ℎ𝐶𝐻𝑂][𝑃ℎ𝐶𝑂𝐶𝐻3 ]
[𝐸𝑡𝑂− ]
And this provides the final rate expression as a function of all three reacting species:

𝑟𝑎𝑡𝑒 = 𝑘𝑜𝑏𝑠 [𝑃ℎ𝐶𝐻𝑂][𝑃ℎ𝐶𝑂𝐶𝐻3 ][𝐸𝑡𝑂 − ]

Which is identical to that in the case where the second step was rate-determining.

Experimental studies have revealed that it is third order, indicating that either the second or the
fourth step must be rate-determining.

Two mechanistic proposals that lead to the same rate expression are
"kinetically equivalent".

A choice between them is not possible on the basis of kinetic data. Additional experimental
proofs are required.

Studies on the intermediate F obtained by an alternative synthesis have shown that k4 is about
four times larger than k-3, so that about 80% of the intermediate goes on to product. In addition,
steps 3 and 4 are much faster than the overall reaction under the same conditions. Therefore,
the second step must be rate-controlling.

Although the kinetic data can give the composition of the activated complex for the rate-
determining step and preceding steps, it provides no information about the structure of the
intermediate. Sometimes the structure can be inferred from related chemical experience, but it
is never established by kinetic data alone.

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2.2. Transition-state theory

The transition-state theory is used to analyse the energetic and entropic components of a
reaction. The reaction is assumed to involve the formation of an activated complex that goes on
to product at an extremely rapid rate:

The rate of decomposition of the transition state (T.S.) should be:

𝑟𝑎𝑡𝑒 𝑜𝑓 𝑡𝑟𝑎𝑛𝑠𝑖𝑡𝑖𝑜𝑛 𝑠𝑡𝑎𝑡𝑒 𝑑𝑒𝑐𝑜𝑚𝑝𝑜𝑠𝑖𝑡𝑖𝑜𝑛 = 𝑘 ‡ [𝑇. 𝑆. ]

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CHAPTER 5. STUDY OF REACTION MECHANISMS

The transition-state theory estimates the transition state decomposition rate constant as:
𝜅𝑘𝐵 𝑇
𝑘‡ =
ℎ
where
• κ is the transmission coefficient, which is usually taken to be 1,
• kB is Boltzmann’s constant (1.38 × 1023 m2 kg s-2 K-1)
• h is Planck’s constant (6.626 × 10-34 m2 kg s-1)
• T is the absolute temperature (298 K a 25 ºC)
And therefore, the calculated value of the transition state decomposition rate constant is:

k‡ = 6.2 × 1012 s-1 (a 298 K)

The transition state (T.S.) can be considered to be in equilibrium with the reactants:
[𝑇.𝑆.]
𝐾‡ = [𝑇. 𝑆. ] = 𝐾 ‡ [𝐴][𝐵]
[𝐴][𝐵]

The free energy of activation for this equilibrium between reactants and T.S. should be related
with the temperature, and can be expressed in terms of enthalpy and entropy:

−𝛥𝐺 ‡⁄ −𝛥𝐻 ‡⁄ 𝛥𝑆 ‡⁄
ΔG‡ = - R T lnK‡ = ΔH‡ - TΔS‡ 𝐾‡ = 𝑒 𝑅𝑇 = (𝑒 𝑅𝑇 ) (𝑒 𝑅)

Thus:

−𝛥𝐺 ‡⁄ −𝛥𝐻 ‡⁄ 𝛥𝑆 ‡⁄
[𝑇. 𝑆. ] = 𝑒 𝑅𝑇 [𝐴][𝐵] = (𝑒 𝑅𝑇 ) (𝑒 𝑅 ) [𝐴][𝐵]

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CHAPTER 5. STUDY OF REACTION MECHANISMS

Substituting [T.S.] in the expression for the reaction rate:

𝜅𝑘𝐵 𝑇 −𝛥𝐺 ‡⁄
rate = 𝑘 ‡ [𝑇. 𝑆. ] = 𝑒 𝑅𝑇 [𝐴][𝐵]
ℎ
also:
𝜅𝑘𝐵 𝑇 −𝛥𝐻‡⁄ 𝛥𝑆 ‡⁄
rate = 𝑘 ‡ [𝑇. 𝑆. ] = (𝑒 𝑅𝑇 ) (𝑒 𝑅 ) [𝐴][𝐵]
ℎ
When compared with the form of the expression for the rate of any single step reaction:
rate = 𝑘𝑟 [𝐴][𝐵]
Reveals that the magnitude of ΔG‡ will be the factor that determines the magnitude of kr at any
given temperature:
𝜅𝑘𝐵 𝑇 −𝛥𝐺 ‡⁄ 𝜅𝑘𝐵 𝑇 −𝛥𝐻‡⁄ 𝛥𝑆 ‡⁄
𝑘𝑟 = 𝑒 𝑅𝑇 = (𝑒 𝑅𝑇 ) (𝑒 𝑅)
ℎ ℎ
𝜅𝑘𝐵 𝑇 𝛥𝑆 ‡⁄ −𝛥𝐻 ‡⁄
The term
ℎ
(𝑒 𝑅) varies only slightly with the temperature compared to 𝑒 𝑅𝑇 ,

because of the exponential nature of the latter. To a good approximation, then:

𝑘𝑟 −𝛥𝐻 ‡⁄ 𝑘 −𝛥𝐻 ‡
𝑇
= 𝐶𝑒 𝑅𝑇 𝐿𝑛 ( 𝑇𝑟 ) = 𝑅𝑇
+ 𝐶′

A plot of Ln(kr/T) versus 1/T is then a straight line, and its slope is -H‡/R. Once ΔH‡ is
determined in this manner, ΔS‡ is available from the relationship:
𝛥𝐻 ‡ ℎ𝑘𝑟
𝛥𝑆 ‡ = + 𝑅𝐿𝑛
𝑇 𝜅
𝜅𝑘𝐵 𝑇 −𝛥𝐻 ‡⁄ 𝛥𝑆 ‡⁄
Which can be obtained rearranging the equation 𝑘𝑟 = (𝑒 𝑅𝑇 ) (𝑒 𝑅)
ℎ

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CHAPTER 5. STUDY OF REACTION MECHANISMS

The potential energy diagrams for a hypothetical two-step reaction could be:

The principle of microscopic reversibility arises directly from transition-state theory:

The same pathway that is travelled in the forward direction of a reaction will be travelled in
the reverse direction, since it affords the lowest energy barrier for either process.

Because transition states cannot be observed, there is no experimental method for establishing
their structure.
By applying MO methods, structures can be calculated for successive geometries which
gradually transform the reactants into products.

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CHAPTER 5. STUDY OF REACTION MECHANISMS

By using the above methods, ΔH‡ and ΔS‡ for most organic reactions can be obtained:

ΔH‡ ΔS‡
Reaction T.S.
(KJ mol-1) (J mol-1 K-1)

82 -60
<0

94 +43
>0

46 -75
<0

t
Bu O• +24 t
t
Bu O O tBu 149 >0 Bu O O tBu

218 +80
>0

139 -47
<0

126 -34
<0

65 -142
<0

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CHAPTER 5. STUDY OF REACTION MECHANISMS

The magnitude of ΔH‡ and ΔS‡ reflect transition state structure:

The enthalpy of activation, ΔH‡, reflects the energy required for bond reorganization and
corresponds to the higher energy content of the activated complex.
• Atomic positions in the transition state do not correspond to their positions in the
ground state.
• The reacting bonds are partially formed or partially broken.
‡
ΔH is always positive. The value depends on the ratio of bonds broken and formed, and also
in the degree of conformational change or hybridization during TS. Thus, if the broken and
formed bonds are compensated and there is no conformational or hybridization change, ΔH‡
would be small. On the other hand, if there is no compensation between the broken and formed
bonds and/or there is a conformational or hybridization change in the TS the value of ΔH‡ will
be large.
The relatively low ΔH‡ term for the dimerization of cyclopentadiene is characteristic of
concerted reactions, in which bond making accompanies bond breaking. It differs markedly
from ΔH‡ for the thermal decomposition of 1,1'-azobutane, in which the rate-determining step is
a homolytic cleavage of a C-N bond, with little new bond making to compensate for the energy
cost of the bond breaking.
The entropy of activation, ΔS‡, is a measure of the degree of organization resulting from the
formation of the activated complex:
• If translational, vibrational, or rotational degrees of freedom are lost in going to the
transition state, there is a decrease in the total entropy of the system.
• Conversely, an increase of translational, vibrational, or rotational degrees of freedom
results in a positive entropy of activation.
• For reactions in solution, the organization of solvent contributes to the entropy of
activation.

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CHAPTER 5. STUDY OF REACTION MECHANISMS

3. SUBSTITUENT EFFECTS AND LINEAR FREE-ENERGY RELATIONSHIPS

In order to get some information on the transition state of a reaction, Hammett tried to quantify
the influence of electron withdrawing or electron donor groups.
As a model reaction, the deprotonation benzoic acid derivatives with different substituents in
ortho, meta and para relative positions can be studied and the acidity constants (pKa)
measured.
In this way, it should be possible to relate the acid properties of the model reaction
(deprotonation of benzoic acid) with the behaviour of other reactions, like hydrolysis of esters.

A plot of logk versus pKa gives a random distribution of points:

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CHAPTER 5. STUDY OF REACTION MECHANISMS

However, if aliphatic compounds and aromatics with ortho substituents are excluded, a better
correlation is obtained:

In fact, examples in which there is steric influence have been removed, leaving only the
examples in which electronic effects are dominant. In this way a good correlation is obtained:

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CHAPTER 5. STUDY OF REACTION MECHANISMS

The analysis of many similar examples allowed the generalization of this type of correlation:

• The rates of a series of reactions can be related to the nature of the substituents present
on the substrate.
• This relationship can be expressed quantitatively, and gives information on reaction
mechanisms, rates and equilibria.

One of the best-studied systems relates rates and equilibria of reactions of compounds
containing substituted phenyl groups, like the dissociation of benzoic acids.

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CHAPTER 5. STUDY OF REACTION MECHANISMS

There is a linear relationship between log k/ko and logK/Ko:

2,0 slope  = 2,38

log(k/k0)
p-NO2
m-NO2
m-CN

1,0
m-Cl

p-Cl

-0,4 -0,2 H 0,2 0,4 0,6 0,8 1,0

m-NH2
p-Me log(K/K0)
p-NH2
-1,0

𝑘 𝐾
Hammett equation 𝑙𝑜𝑔 = 𝜌 𝑙𝑜𝑔
𝑘0 𝐾0

Ko y ko are for R=H (benzoic acid), and ρ is the slope of the line.
• the equilibrium constant is related with ΔG of the reaction 𝐾 = 𝑒 −𝛥𝐺/𝑅𝑇
‡
• the rate constant is related with ΔG‡ of the transition state 𝑘 = 𝑘 ‡ 𝑒 −𝛥𝐺 /𝑅𝑇

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CHAPTER 5. STUDY OF REACTION MECHANISMS

Substituting: log k – log k0 = ρ (log K – log K0)

−𝛥𝐺 ‡ −𝛥𝐺0‡ −𝛥𝐺 −𝛥𝐺0
( )−( ) = 𝜌 [( )−( )]
𝑅𝑇 𝑅𝑇 𝑅𝑇 𝑅𝑇
ΔΔG‡ = ρ ΔΔG
The linear correlation therefore indicates that the change in free energy of activation on
introduction of a series of substituent groups is directly proportional to the change in the free
energy of ionization that is caused by the same series of substituents on benzoic acid.
The various correlations arising from such directly proportional changes in ΔG are called linear
free-energy relationships.
The success of the Hammett equation is in the introduction of two parameters: σ and ρ:
𝑘 𝐾
𝑙𝑜𝑔 = 𝜌 𝑙𝑜𝑔 = 𝜌𝜎
𝑘0 𝐾0
σ is the substituent constant, and reflects the effect of substituents on the free energy of
ionization of the substituted benzoic acid
ρ is the reaction constant, reflects the sensitivity of a particular reaction to substituent effects.
ρ =1 for the standard reaction:

First, the values of σ are calculated for several substituents in the previous reaction and once
the σ values are tabulated, the ρ values for other reactions are calculated.

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CHAPTER 5. STUDY OF REACTION MECHANISMS

Example: The pKa of p-chlorobenzoic acid is 3.96; that of benzoic acid is 4.19. Calculate σ for
a chloro group in para position.

𝐾𝑝−𝐶𝑙
𝜎 = 𝑙𝑜𝑔 = 𝑙𝑜𝑔 𝐾𝑝−𝐶𝑙 − 𝑙𝑜𝑔 𝐾𝐻 = − 𝑙𝑜𝑔 𝐾𝐻 − (− 𝑙𝑜𝑔 𝐾𝑝−𝐶𝑙 )
𝐾𝐻
= 𝑝𝐾𝑎𝐻 − 𝑝𝐾𝑎𝑝−𝐶𝑙 = 4.19 − 3.96 = 0.23

The Hammett equation does not take into account steric factors:
it is applied only to meta and para substituents

σ reflects the effect of the substituents: can cause a polarization of electron density around
the ring through the π system in both the reactants and the products:
• can affect the position of the equilibrium
• can have an effect on the transition state, in the energy of activation and in the reaction rate.

The effect of the substituent results from a combination of factors, which fall in three categories:
(a) resonance effect

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CHAPTER 5. STUDY OF REACTION MECHANISMS

(b) field effect

• bond dipoles between groups of different electronegativity perturb the electronic
situation of the reaction site by a through-space electrostatic interaction.
Dipoles that transmit charge density towards electropositive reaction sites (Y) favor the
reaction, and vice versa:

(c) inductive effect

• transmission of bond dipoles through the intervening bonds by successive polarization
of each bond:

The field effect outweighs the inductive effect as the primary means of transmission.
Field effects and inductive effects can be considered together as polar effects

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 CHAPTER 5. STUDY OF REACTION MECHANISMS

Tables of σ and ρ values for many substituents and reactions have been collected

Substituent Constants (σ)

substituent σm σp substituent σm σp
Acetamido CH3CONH 0.21 0.00 Ethynyl HC≡C 0.21 0.23
Acetoxy CH3CO2 0.37 0.45 Fluoro F 0.34 0.06
Acetyl CH3CO 0.38 0.50 Hydrogen H 0.00 0.00
Amino NH2 −0.16 −0.66 Hydroxy OH 0.12 −0.37
Bromo Br 0.37 0.23 Methanesulfonyl CH3SO2 0.60 0.72
t-Butyl (CH3)3C −0.10 −0.20 Methoxy CH3O 0.12 −0.27
Carboxy HO2C 0.37 0.45 Methoxycarbonyl CH3O2C 0.37 0.45
Chloro Cl 0.37 0.23 Methyl CH3 −0.07 −0.17
Cyano CN 0.56 0.66 Methylthio MeS 0.15 0.00
Diazonim N≡N 1.76 1.91 Nitro NO2 0.71 0.78
Dimethylamino Me2N −0.16 −0.83 Phenyl C6H5 0.06 0.01
Ethenyl CH2=CH −0.06 0.04 Trifluoromethyl CF3 0.43 0.54
Ethoxy C2H5O 0.10 −0.24 Trimethylammonium (CH3)3N+ 0.88 0.82
Ethyl C2H5 −0.07 −0.15 Trimethylsilyl (CH3)3Si −0.04 −0.07

• There are no values for ortho-substituents as these can present additional steric factors
that cannot be considered with this analysis;
• electron attractant groups have a favourable polar effect on the reaction site (σ>0);
• when the polar effect is favourable and the resonance effect is unfavourable (as in OH), the
latter prevails in the para position (σp<0)

These constants are useful to predict relative reaction rates.

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CHAPTER 5. STUDY OF REACTION MECHANISMS

Example 1: Let’s consider the saponification of methyl esters.

ρ = 2.38

When the standard reaction is

k = 2x10-4 M-1s-1

Calculate the rate constant for the hydrolysis of methyl m-nitrobenzoate.

Data: ρ value for alkaline hydrolysis of methyl esters of substituted benzoic acids is 2.38 and
from the table in page 29, the σ for a NO2 in meta is σm-NO2=0.71

𝑘𝑚−𝑁𝑂2 𝑘𝑚−𝑁𝑂2
𝑙𝑜𝑔 = 𝜎𝑚−𝑁𝑂2 (𝜌) = (0.71)(2.38) = 1.69 = 49
𝑘𝐻 𝑘𝐻

𝑘𝑚−𝑁𝑂2 = 98𝑥10−4 𝑀−1 𝑠 −1

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CHAPTER 5. STUDY OF REACTION MECHANISMS

Example 2: Using data in tables of page 29, calculate how much faster will hydrolyze in water
p-bromobenzyl chloride than p-nitrobenzyl chloride. (ρ= -1.31 for solvolysis of benzyl chlorides)

ρ = -1.31

𝑘𝑝−𝐵𝑟 𝑘𝑝−𝑁𝑂2
Si X= p-Br: 𝑙𝑜𝑔 = 𝜌𝜎𝑝−𝐵𝑟 Si X= p-NO2: 𝑙𝑜𝑔 = 𝜌𝜎𝑝−𝑁𝑂2
𝑘𝐻 𝑘𝐻

𝑘𝑝−𝐵𝑟 𝑘𝑝−𝑁𝑂2
𝑙𝑜𝑔 = (−1.31)(0.23) 𝑙𝑜𝑔 = (−1.31)(0.78)
𝑘𝐻 𝑘𝐻
𝑙𝑜𝑔 𝑘𝑝−𝐵𝑟 − 𝑙𝑜𝑔 𝑘𝐻 = −0.30 𝑙𝑜𝑔 𝑘𝑝−𝑁𝑂2 − 𝑙𝑜𝑔 𝑘𝐻 = −1.02

𝑙𝑜𝑔 𝑘𝑝−𝐵𝑟 + 0.30 = 𝑙𝑜𝑔 𝑘𝐻 𝑙𝑜𝑔 𝑘𝑝−𝑁𝑂2 + 1.02 = 𝑙𝑜𝑔 𝑘𝐻

𝑙𝑜𝑔 𝑘𝑝−𝐵𝑟 + 0.30 = 𝑙𝑜𝑔 𝑘𝑝−𝑁𝑂2 + 1.02

𝑙𝑜𝑔 𝑘𝑝−𝐵𝑟 − 𝑙𝑜𝑔 𝑘𝑝−𝑁𝑂2 = 0.72

𝑘𝑝−𝐵𝑟
𝑙𝑜𝑔 = 0.72
𝑘𝑝−𝑁𝑂2
𝑘𝑝−𝐵𝑟
= 5.25
𝑘𝑝−𝑁𝑂2

Therefore, p-bromobenzyl chloride solvolyzes 5.25 times faster than p-nitrobenzyl chloride.

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CHAPTER 5. STUDY OF REACTION MECHANISMS

Linear free energy relationships provide information about the reaction mechanism
In the ionization of benzoic acid (ρ = 1) a negative charge is being developed
• σ> 0 for electron withdrawing groups (favour the reaction)
• σ <0 for electron donor groups (disfavour the reaction)
But for the rest of the reactions ρ ≠ 1
• ρ > 0 in reactions favoured by electron-withdrawing groups;
• ρ <0 in reactions favoured by electron releasing groups.

Reaction Constants (ρ)

Reaction 
ArCO2H ArCO2- + H+, water 1.00
ArCO2H ArCO2- + H+, ethanol 1.57
ArCH2CO2H ArCH2CO2- + H+, water 0.56
ArCH2CH2CO2H ArCH2CH2CO2– + H+, water 0.24
ArOH ArO- + H+, water 2.26
ArNH3+ ArNH2 + H+, water 3.19
ArCH2NH3+ ArCH2NH2 + H+, water 1.05
ArCO2C2H5 + -OH ArCO2- + C2H5OH 2.61
ArCH2CO2C2H5 + -OH ArCH2CO2- + C2H5OH 1.00
ArCH2Cl + H2O ArCH2OH + HCl –1.31
ArC(CH3)2Cl + H2O ArC(CH3)2OH + HCl –4.48
ArNH2 + PhCOCl ArNHCOPh + HCl –3.21

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CHAPTER 5. STUDY OF REACTION MECHANISMS

The reaction constant ρ informs about the transition state

Thus, for the saponification of methyl benzoates, ρ = +2.38:
• Electron withdrawing groups facilitate the reaction;
• the reaction is more sensitive to the effects of substituents than the dissociation of
benzoic acid (ρ > ρ0).
This agrees with the proposed tetrahedral intermediate for this reaction:

Electron withdrawing substituents:

• stabilize the negatively charged intermediate;
• enhance the electrophilicity of the carbonyl group of the reagent.

In the solvolysis of diaryl chloromethanes in ethanol ρ = -5.0:

• electron releasing groups speed up the reaction;
• ionization is the rate-determining step.

• the reaction is sensitive to the effects of substituents (|ρ| is relatively high).

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CHAPTER 5. STUDY OF REACTION MECHANISMS

As a general rule:
• ρ > 0 means that a negative charge is developed in the transition state.
• ρ < 0 means that a positive charge is developed in the transition state.
• large values of |ρ| mean greater sensitivity to substituents (transition state with a higher
charge density and well connected to the ring bearing the substituents).

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CHAPTER 5. STUDY OF REACTION MECHANISMS

Some examples:

ρ = 2.26
more influenced by the substituents

ρ = 0.56
less influenced by the substituents

ρ = -1.31 some positive charge (SN2 type)

ρ = -4.48 more positive charge density (SN1 type)

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CHAPTER 5. STUDY OF REACTION MECHANISMS

Some reactions cannot accommodate a Hammett equation because their mechanism may be
different when changing the substituents.
For example, in a multi-step reaction, the rate-determining step can be one or the other
depending on the substituent.

Thus, in the formation of semicarbazones from benzaldehydes:

ρ is 3.5 with electron releasing groups and -0.25 with electron withdrawing groups, which is
justified by a change in the rate-determining step:

(rate-determining step with electron releasing substituents)

(rate-determining step with electron withdrawing substituents)

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CHAPTER 5. STUDY OF REACTION MECHANISMS

4. BASIC MECHANISTIC CONCEPTS

In many reactions, different paths are possible, although with similar energy requirements.
To analyze the factors that may permit a particular reaction path to dominate, it is essential to
know the activation energies in each case.
4.1. Kinetic versus thermodynamic control
When the ratio of the reaction products depends on an equilibrium, we speak of
thermodynamic control.
When the ratio of products depends on the relative rates of formation, we speak of
kinetic control.

case 1. Kinetic control: formation of A and B is effectively irreversible. B can be obtained

exclusively.
case 2. Kinetic or thermodynamic control: If the reaction conditions are carefully adjusted, it will
be possible for A to accumulate and not proceed to B, or with somewhat more
energetic conditions, A and B will equilibrate.
case 3. Thermodynamic control the A:B ratio would be governed by the inherent stability of A
and B and would be independent of the rate of conversion.

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CHAPTER 5. STUDY OF REACTION MECHANISMS

A classic example of kinetic or thermodynamic control is the formation of enolates in

asymmetric ketones:

The hydrogens of α-CH3 are less sterically hindered than the hydrogen in the CH carbon of the
isopropyl group: formation of 3 is faster than formation of 2:
• with a very strong base the enolate cannot revert to the ketone;
• the more hindered the base, the faster the formation of 3 with respect to 2.
The double bond in 2 is more substituted than in 3. This makes 2 the most stable product:
• with a weak base in protic solvents the enolate can revert to the ketone.
Kinetic control (preferential formation of 3): Thermodynamic control (preferential formation of 2):
• strong base; • weak base (similar strength as enolate);
• hindered base; • protic solvent.
• aprotic solvent.
In summary,
• the fastest product to be formed is called kinetic product;
• the most stable product is called thermodynamic product.
In addition,
• when the reaction conditions lead to the kinetic product, we speak of kinetic control;
• when the reaction conditions lead to the thermodynamic product, we speak of
thermodynamic control.

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CHAPTER 5. STUDY OF REACTION MECHANISMS

4.2. Hammond's Postulate

"If two states occur consecutively during a reaction process and have nearly the same energy
content, their interconversion will involve only a small reorganization of molecular structure"

case 1. The transition state will structurally resemble the reactant.

case 2. Neither the reactant nor the product will be a good model of the transition state.
case 3. Transition state structure is similar to that of the product.

The significance of the concept incorporated in Hammond's postulate is that, in appropriate

cases, it permits discussion of transition-state structure in terms of the reactants, intermediates,
or products in a multistep reaction sequence. The appropriate cases are those in which the
transition state is close in energy to the reactant, intermediate, or product.

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CHAPTER 5. STUDY OF REACTION MECHANISMS

In electrophilic aromatic substitution there are ortho-para directing substituents and meta
directing substituents. It is an example of kinetic control:

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CHAPTER 5. STUDY OF REACTION MECHANISMS

At the transition state, a positive charge is present on the benzene ring,

primarily at positions 2, 4, and 6 in relation to the entering bromine.

The electron-releasing methoxy group can stabilize intermediates at ortho or

para from bromine.

As intermediate and transition state are more stable than in the bromination of benzene,
methoxybenzene will react faster than benzene, leading mainly to ortho- and para-isomers.
The nitro group strongly destabilizes the intermediate if the bromine enters ortho or para:

The meta transition state is also destabilized relative to that for benzene, but not as much as
the ortho and para transition states:

Therefore, nitrobenzene is less reactive than benzene, and the bromination product is mainly
the meta isomer.

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CHAPTER 5. STUDY OF REACTION MECHANISMS

The relative energy of the transition states will be:

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CHAPTER 5. STUDY OF REACTION MECHANISMS

4.3. The Curtin-Hammett Principle

Let us consider the effect that conformational equilibria can have on a chemical reaction.
In most cases, the energy of activation for a chemical reaction will be greater than that for a
conformational equilibration,

[𝐴]
𝛥𝐺𝑎‡ 𝑎𝑛𝑑 𝛥𝐺𝑏‡ >> 𝛥𝐺𝑐‡ 𝐾𝑐 =
[𝐵]

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CHAPTER 5. STUDY OF REACTION MECHANISMS

𝑑[𝑃𝐴 ]
𝑟𝑎𝑡𝑒 𝑜𝑓 𝑓𝑜𝑟𝑚𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑝𝑟𝑜𝑑𝑢𝑐𝑡 𝑃𝐴 = = 𝑘𝑎 [𝐴] = 𝑘𝑎 𝐾𝑐 [𝐵]
𝑑𝑡
𝑑[𝑃𝐵 ]
𝑟𝑎𝑡𝑒 𝑜𝑓 𝑓𝑜𝑟𝑚𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑝𝑟𝑜𝑑𝑢𝑐𝑡 𝑃𝐵 = = 𝑘𝑏 [𝐵]
𝑑𝑡
𝑑[𝑃𝐴 ]⁄
𝑝𝑟𝑜𝑑𝑢𝑐𝑡 𝑟𝑎𝑡𝑖𝑜 = 𝑑𝑡 = 𝑘𝑎 𝐾𝑐 [𝐵] = 𝑘𝑎 𝐾𝑐
𝑑[𝑃𝐵 ]⁄ 𝑘𝑏 [𝐵] 𝑘𝑏
𝑑𝑡
The product ratio is therefore determined not by ΔGc, but by the relative energy of the two
transition states A* and B*.
The rate of the formation of the products is dependent upon the relative concentration of the
two conformers A and B. However, as A and B are in a rapid equilibrium, while the one that
reacts faster is being consumed, the equilibrium shifts towards it:
The reaction may proceed through a minor conformation if it is the
one that provides access to the lowest-energy transition state.

Curtin-Hammett principle
The ratio of products formed from conformational isomers is not determined by the
conformation population.
The same arguments can be applied to other energetically facile interconversions of two
potential reactants. For example, many organic molecules undergo rapid proton shifts
(tautomerism).

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CHAPTER 5. STUDY OF REACTION MECHANISMS

5. ISOTOPE EFFECTS
A substituent effect very valuable in the study of reaction mechanisms is the replacement of an
atom by one of its isotopes, most often protium by deuterium (or tritium). When the C-H(D)
bond is broken in the reaction, we can measure primary kinetic isotopic effects.
Any C-H bond has characteristic vibrations which impart some energy to the molecule in its
normal state. This energy is called the zero-point energy.
The energy associated with these vibrations is related to the mass of the vibrating atoms. Due
to the greater mass of deuterium, the vibrations associated with a C-D bond contribute less to
the zero-point energy than those associated with the corresponding C-H bond: replacing H by
D decreases the zero-point energy.
As the transition state has the same energy for the
protonated and deuterated species, the deuterated
molecule will have a higher activation energy to reach
the transition state.
The isotopic effect is defined as the quotient between
the rate constants for the normal and the deuterated
molecules:
kinetic isotope effect = kH/kD
There are isotope effects with nuclei other than
hydrogen, although the quantitative differences are
largest for hydrogen because its isotopes have the largest relative mass differences.
For example, changing a hydrogen atom to deuterium represents a 100% increase in mass,
while substituting 12C with 13C, the mass increases only 8%. The rate of a reaction involving the
breaking of a C-H bond is typically 6 to 10 times faster than that for a C-D bond, while a 12C
reaction is only ~ 1.04 times faster than the equivalent reaction with 13C (although in both cases
the isotope mass increase is one unit).

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CHAPTER 5. STUDY OF REACTION MECHANISMS

How large the rate difference is (>1, maximum 7) depends on the nature of the transition state:
- is large if, in the transition state, the hydrogen
A H B
that is transferred is bound equally to two atoms:
- is small (~1) if the transition state closely
A H B or A H B
resembles the reactants or products:

Two useful pieces of information provided by the isotopic effect:

• When the value is high (kH/kD  2), the C-H bond is broken in the rate-limiting step;
• the magnitude indicates the proximity of the transition state to reactants or products:
- A low primary isotope effect implies that the bond to hydrogen is either only slightly or
nearly completely broken at the transition state.
- An isotope effect near the theoretical maximum is good evidence that the transition state
involves strong bonding of the hydrogen to both its new and its old bonding partners.
Examples of primary kinetic isotopic effects:

reaction kH/kD (ºC)

4.6 77

6.1 25

4.0 191

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Secondary kinetic isotope effects are observed when the substituted hydrogen atom is not
directly involved in the reaction:
• are smaller than primary, in the range kH/kD = 0.7 - 1.5;
Two types:
- normal secondary kinetic isotope effects kH/kD > 1;
- inverse secondary kinetic isotope effects kH/kD < 1;
Are called α or β depending on the distance between the isotopic substitution and the reacting
carbon atom.
The secondary kinetic isotope effects are the result of tightening or loosening of C-H bonds in
the transition state, due to:
• a change the hybridization of the C atom;
• a change the extent of hyperconjugation.

Normal secondary kinetic isotope effects (kH/kD > 1)

• Can be observed when the coordination degree of the reaction center decreases
during the transition state.
• If sp3-hybridized carbon is converted to sp2 as reaction occurs, a hydrogen bound to
the carbon will experience decreased resistance to C-H bending.
• The freeing of the vibration for a C-H bond is greater than that for a C-D bond because
the C-H bond is slightly longer and the vibration therefore has a larger amplitude.

Inverse secondary kinetic isotope effects (kH/kD < 1)

Will occur if coordination at the reaction center increases in the transition state. The bending
vibration will become more restricted.

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Some representative secondary kinetic isotope effects

reaction kH/kD (ºC)

normal (α) 1.30 25

normal (α) 1.37 50

inverse (α) 0.73 25

When carbocations are involved as intermediates, substantial β secondary kinetic isotope

effects are observed, as the hyperconjugative stabilization by the β-H weakens the C-H bond.

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6. ISOTOPES IN LABELING EXPERIMENTS

Isotopes can be used to locate the position of a given atom in a reaction.
As in kinetic experiments, labelling also does not quantitatively affect the course of the reaction.
The most common elements in organic chemistry for labels are deuterium, tritium, 13C, 14C.

Tritium and 14C are radioactive and can be located by measurements of radioactivity, but it is
necessary to degrade the molecule to locate the position of the labelled element.
Deuterium is not observed in normal NMR experiments, but the absence of a hydrogen signal
would indicate the presence of deuterium.
13Cis one of the most useful isotopes because it can be detected directly in NMR, and the
appearance of a very strong signal (compared to the usual one, corresponding to 1% natural
abundance) allows its position to be located.
An example of the use of tritium labelling in the enzymatic hydroxylation of phenylalanine:

The substrate was labelled with tritium in the para position of the aromatic ring, but in the
product the tritium appears in the meta position due to a rearrangement:

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7. CHARACTERIZATION OF REACTION INTERMEDIATES

In a multi-step reaction, the amount of intermediate at a given time will depend on the relative
rates of the different stages:

• if k1 > k2, the concentration of the intermediate increases at the beginning of the reaction,
and it could be possible to isolate it or at least observe it;
• if both k1 and k2 are very large, the reaction proceeds too quickly to allow the isolation of
the intermediates, although they might be observed using spectroscopic techniques;
• if the two steps are equally slow, at any given time there will only be a small proportion of
intermediate, but we could:
❖ stop the reaction by lowering the temperature or adding a reagent that stops the
reaction;
❖ trap the intermediates by reaction with another system, diverting them from the normal
course of reaction.

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The study of intermediates is usually done by spectroscopic methods:

UV-VIS useful for the study of systems containing chromophores that absorb in the range
220 to 700 nm (conjugated systems); detects up to 10-6 M;
IR useful if the intermediates have characteristic bands absent in reactants or products,
as in the following photochemical conversion, in which a band is observed at 2118
cm-1 (ketene) that increases in intensity and decreases as the reaction progresses;

RMN the nuclei with the best sensitivity (to detect low concentrations) are 1H, 19F and 31P;
EPR paramagnetic electron resonance (or spin resonance) is useful to identify radical
intermediates, since it only detects paramagnetic systems;

It must be remembered that simple detection of a species does not prove that it is an
intermediate: It should be proved that the species is converted to product.
• In favorable cases, this may be done by isolation or trapping experiments.
• More often, it may be necessary to determine the kinetic behavior of the appearance
and disappearance of the intermediate and demonstrate that this behavior is consistent
with the species being an intermediate.

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8. CATALYSIS BY ACIDS AND BASES

8.1. Brönsted acids and bases
Catalysts do not affect the equilibrium position but increase the rate of some of the reaction
steps by lowering the activation energy.
Catalysis occurs when the conjugate base or conjugate acid of the substrate is more reactive
than the neutral species.
For example, reactions involving addition of neutral nucleophiles at carbonyl groups are often
accelerated by acids.

On the other hand, the reactions with carbanions can be catalyzed with bases, since the C H
bonds are not very acidic and have little tendency to ionize.
The reaction between acetophenone and benzaldehyde requires a basic catalyst to proceed,
and the kinetics of the reaction show that the rate is proportional to the catalyst concentration.

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Specific acid catalysis:

• is independent of the concentration and nature of the acid;
• is governed by the hydrogen ion concentration in solution (pH):
𝑟𝑎𝑡𝑒 = 𝑘[𝐻 + ][𝑋][𝑌] where [X] and [Y] are the concentration of the reactants

General acid catalysis:

• depends on the concentration and nature of the acid;
• in the rate expression there is a term for each potential proton donor:
𝑟𝑎𝑡𝑒 = 𝑘1 [𝐻 + ][𝑋][𝑌] + 𝑘2 [𝐻𝐴1 ][𝑋][𝑌] + 𝑘3 [𝐻𝐴2 ][𝑋][𝑌]+. . . . +𝑘𝑛 [𝐻𝐴𝑛 ][𝑋][𝑌]
Where HA1, HA2, ..., HAn are all kinetically significant proton donors.

The terms specific base catalysis and general base catalysis apply in the same way to base-
catalyzed reactions.

Acid catalysis is detected by measuring reaction rates at constant pH but with different
concentrations of buffer ([H+] is constant, but [HAn] changes); in that case:
• if the reaction rate changes, there is general acid catalysis;
• if the reaction rate remains constant, there is specific acid catalysis.

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The term specific acid catalysis is used when the reaction rate is dependent on the equilibrium
for protonation of the reactant.

Specific acid catalysis is observed when a reaction proceeds through a protonated intermediate
that is in equilibrium with its conjugate base, Because the position of this equilibrium is a
function of the concentration of solvated protons, only a single acid dependent term appears in
the kinetic expression.

The equilibrium position depends on the proton concentration (pH), which appears in the rate
equation, and is independent of the concentration and specific structure of the various proton
donors present in solution.

An example of a situation with specific acid catalysis:

𝑟𝑎𝑡𝑒 = 𝑘2 [𝐵𝐻 + ][𝐶] = 𝑘2 [𝐶]𝐾[𝐵][𝐻 + ]

𝑟𝑎𝑡𝑒 = 𝑘𝑜𝑏𝑠 [𝐻 + ][𝐵][𝐶]

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General acid catalysis can occur as a result of hydrogen bonding between the reactant R and a
proton donor D-H to form a reactive complex [D-H-R] which then reacts with a substance Z:

In this case the nature of the D-H proton donor will influence the reaction rate.
There is also general acid catalysis when proton exchange is the rate-determining step:

General acid catalysis also occurs if a prior equilibrium between reactant and the acids is
followed by rate-controlling proton transfer. Each individual conjugate base will appear in the
overall rate expression:

• In specific acid catalysis, H+ transfer is not the rate-limiting step;

• In general acid catalysis there is hydrogen transfer in the rate-limiting step.

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There is a relationship between the effectiveness of general acid catalysts and the acid
strength of a proton donor as measured by its acid dissociation constant Ka.
Brönsted catalysis law logkcat =  logKa + b
Therefore, the free energies of activation for the catalytic step for a series of acids are directly
proportional to the free energy of dissociation for the same series of acids. The proportionality
constant α is an indication of the sensitivity of the catalytic step to structural changes.
Protonation of an enol ether with different carboxylic acids is a general acid catalysis process::

The plot shows that the

effectiveness of the various
carboxylic acids as catalysts in the
above reaction is related to their
dissociation constants (α = 0.79):
Because α relates the sensitivity to
structural changes that the proton-
transfer process exhibits to that
exhibited by dissociation of the
acid, it is frequently assumed that
the value of α can be used as an
indicator of transition-state
structure.
The closer α approaches unity, the greater is the degree of proton transfer in the transition state

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8.2. Lewis Acid Catalysis

Lewis acids are defined as molecules that act as electron-pair acceptors. H+ is just an important
special case, but many other species can play an important role
Metal cations Covalent compounds
Li+, Na+, K+, Cs+, Rb+, Mg2+, Ca2+, Zn2+ BF3, AlCl3, TiCl4, SnCl4
Transition metals and lantanides boron, aluminium and titanium derivatives
The catalytic activity of metal ions originates in the formation of a donor-acceptor complex
between the cation and the reactant, which must act as a Lewis base.
Especially prominent in reaction chemistry are:
• carbonyl (sp2) oxygens, hydroxyl and ether (sp3) oxygens;
• nitrogen-, and sulfur-containing functional groups;
• halogen substituents can act as donors to very strong Lewis acids;
• the presence of two potential donor atoms in a favourable geometric relationship
permits formation of bidentate "chelate" structures

If the complexation results in a full covalent bond, there is a net transfer of one unit of formal
charge to the metal ion from the donor atom, which enhances its effective electrophilicity:
• the complexes of carbonyl groups are more reactive to nucleophilic attack.
• hydroxyl groups complexed to metal cations are stronger acids and better leaving groups;
• ether or sulfide groups complexed with metal cations are better leaving groups.
The strength of the complexation is a function of the donor atom, the metal ion and the solvent
(solvent molecules that are potential electron donors can compete for the Lewis acid).

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Qualitative predictions about the strength of donor-acceptor complexation can be made on the
basis of the hard-soft-acid base concept. The better matched the donor and acceptor, the
stronger is the complexation.

Relative Hardness and Softness

Lewis acids Lewis bases

Cationic Neutral Neutral Anionic

Hard H+ BF3, AlCl3 H2O F-, SO42-

Li+, Mg2+, Ca2+, R3B Alcohols Cl-
Na+ ketones, Br-
ethers
Zn2+, Cu2+ Amines N3-
(aliphatic)
Amines
(aromatics)
Pd2+, Hg2+, Ag+ CN-
RS+, RSe+ I-

Soft I+ Sulfides S2-

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Neutral compounds such as boron trifluoride and aluminum chloride form Lewis acid-base
complexes by accepting an electron pair from the donor molecule, which are the same
functional groups that act as lone-pair donors to metal cations.

Because in this case the complex is formed between two neutral species, it too is neutral, but a
formal positive charge develops on the donor atom and a formal negative charge develops on
the acceptor atom.

TiCl4 and SnCl4 can form complexes that are related in character to both those formed by metal
ions and those formed by neutral Lewis acids. Complexation can occur through two ways:
• with an increase in the coordination number at Ti or Sn, or
• with displacement of a chloride from the metal coordination sphere.

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Diels-Alder reactions in the presence of Lewis acids represent a case in which the Lewis acid is
often used in catalytic quantities. The complexed ester (ethyl acrylate in the example given
below) is substantially more reactive than the uncomplexed molecule, and the reaction
proceeds through the complex. The reactive complex is regenerated by exchange of the Lewis
acid from the adduct:

There are more variables to consider in catalysis by Lewis acids than in the case of catalysis by
protons:
• hard/soft relationship;
• steric factors;
• geometric factors;
• stereoelectronic factors

This makes the development of an absolute scale of "Lewis acid strength" difficult, because it
depends on the specific characteristics of the base.

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The table lists the Lewis acid strengths of a number of compounds used commonly in
synthesis. The relative acidity values given are derived from the LUMO energy of the π* orbital
of the compound with the BCl3 complex defined as 1.00 and the uncomplexed 2-butenal LUMO
energy taken as 0.

Relative Lewis Acidity

Acid ΔHa NMR Δδb Relative acidity
BCl3 -6.6 1.35 1.00
AlCl3 -25.6 1.23 0.91
EtAlCl2 -20.0 1.15 0.80
BF3 +4.1 1.17 0.76
Et2AlCl -5.6 0.91 0.71
Et3Al -10.1 0.63 0.63
SnCl4 +10.0 0.87 0.61
a. Enthalpy of interaction in kcal/mol by MNDO.
b. Change in chemical shift of H-3 in 2-butenal.

Stereoelectronic factors are also important in determining the structure and reactivity of
complexes. Complexes of carbonyl groups with trivalent boron and aluminum compounds tend
to adopt a geometry consistent with directional interaction with one of the oxygen lone pairs.
Thus, the C-O-M bond angle tends to be in the trigonal (120-140º) range, and the boron or
aluminum is usually close to the carbonyl plane.

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9. SOLVENT EFFECTS
9.1. Polarity
There are important differences between protic solvents (contain relatively mobile protons i.e.
those bonded to O, N, or S) and aprotic solvents, in which all hydrogens are bound to carbon.
Similarly, polar solvents, those that have high dielectric constants, have effects on reaction
rates that are different from those of nonpolar solvent media.
The dielectric constant is a macroscopic property of a bulk material:
• is a function of both the permanent dipole of the molecule and its polarizability;
• is a good indicator of the ability of the solvent to accommodate separation of charge.

However, it conveys little information about the solvent-solute molecules interactions. These
direct solute-solvent interactions will depend on the specific structures of both molecules.

Dielectric Constants of Some Common Solvents

Aprotic solvents
Protic solvents
Nonpolar Polar
Hexane 1.9 Pyridine 12 CH3CO2H 6.1
CCl4 2.2 Acetone 21 CF3CO2H 8.6
Dioxane 2.2 Hexamethylphosphoramide 30 t-Butyl alcohol 12.5
Benzene 2.3 Nitromethane 36 Ammonia (22)
Et2O 4.3 Dimethylformamide 37 Ethanol 24.5
Chloroform 4.8 Acetonitrile 38 Methanol 32.7
Tetrahydrofuran 7.6 Dimethylsulfoxide 47 Water 78.0

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In the hydrolysis of t-butyl chloride, the transition state must reflect some charge separation
as the reaction leads to a cationic intermediate:

In the intermediate, the solvent molecules can intervene between carbon and chlorine, but not
in the transition state, where they must stabilize the charge development from the periphery.
This interaction depends on:
• of the dielectric constant;
• the nature of both components (intermediate and solvent)
Relative rates using for solvent reference the mixture EtOH:H2O 80:20:
Ethanol-water Methanol-water Other solvents
% ethanol Y % methanol Y Y
100 -2.03 100 -1.09 Acetic acid -1.64
𝑘(𝑠𝑜𝑙𝑣𝑒𝑛𝑡)
𝑌 = 𝑙𝑜𝑔 80 0.00 80 0.38 Formic acid 2.05
𝑘80% (𝐸𝑡𝑂𝐻)
50 1.65 50 1.97 t-butyl alcohol -3.20
20 3.03 10 3.28 90% acetone-water -1.85
0 3.49 90% dioxane-water -2.03

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The Y value reflects primarily the ionization power of the solvent.

• It is largest for polar solvents such as water or formic acid;
• becomes progressively smaller and eventually negative as the solvent becomes less
polar and contains more (or larger) nonpolar alkyl groups.
Nonpolar aprotic solvents are much less effective at stabilizing the development of charge
separation:
• Reactions that involve charge separation in the transition state proceed much more slowly;
• Accelerate reactions in which species with opposite charges approach in the transition state.

Effect of Solvent Polarity on Reactions of Various Charge Types

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The effect of the solvent is not restricted to electrostatic factors, but it also has a structural
component, both in reactants and in the transition state, affecting the energies of both and
therefore the rate of the reaction:

transition state more strongly solvated in reactants more strongly solvated in solvent B,
solvent B, reactivity enhanced in solvent B reactivity decreased in solvent B

Because a solvent may affect the rates of two competing reactions to different extents, a
change in solvent may strongly modify the composition of a product mixture arising from
competing reaction paths.

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9.2. Enhancement of the nucleophilicity of anions in polar aprotic solvents

An important example of solvent effects is the enhanced nucleophilicity of many anions in polar
aprotic solvents as compared with protic solvents.

In protic solvents:
• the anions are strongly solvated by hydrogen bonding, particularly those anions that have
a high concentration of charge on oxygen or nitrogen;
• hydrogen bonding decreases the availability of the electrons of the anion to participate in
reactions as a nucleophile (decreased nucleophilicity);
• the energy required to disrupt hydrogen bonding adds to the activation energy of the reaction.

In aprotic solvents:
• no hydrogens suitable for hydrogen bonding are present;
• the electrons of the anion are more easily available for reaction;
• the anion is at a higher energy level because of the absence of solvent stabilization.

The polarity of the aprotic solvents is important because:

• nonpolar solvents have very low solubility for ionic compounds;
• dissolved ionic compounds are likely to be present as ion pairs or larger aggregates in which
the reactivity of the anion is diminished by the electrostatic interaction with the cation;
• energy must be expended against this electrostatic attraction to permit the anion to react.
Metal cations such as K+ and Na+ are strongly solvated by polar aprotic solvents such as
dimethyl sulfoxide (DMSO) and dimethylformamide. The oxygen atoms in these molecules act
as electron donors toward the cations. The dissolved salts are dissociated, and, as a result, the
anions are highly reactive because they are poorly solvated and not associated with cations.

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Use of crown ethers (macrocyclic polyethers that specifically solvate cations as Na+ and K+):

In nonpolar solvents, crown ethers increase the solubility of ionic materials, such as KF:

In the absence of the polyether, potassium fluoride is insoluble in benzene and unreactive
toward alkyl halides
The solubility and reactivity enhancement result
because the ionic compound is dissociated to a
tightly complexed cation and a "naked" anion.

K+

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Phase transfer catalysts:

Phase-transfer catalysts are salts in which one of the ions (usually the cation) has large
nonpolar substituent groups that confer good solubility in organic solvents

tetraalkylammonium (NR4+) and tetraalkylphosphonium (PR4+) ions are the most common

In two phase systems (water and nonpolar organic solvent) these cations travel from water into
the organic phase, and due to electrical neutrality, the anions travel with them. In this solvent,
the anions are weakly solvated and display high reactivity.

Reactions are carried out between a salt containing the desired nucleophilic anion and an
organic reactant, typically, an alkyl halide. The addition of the phase-transfer catalysts causes
migration of the anion into the organic phase, and, because of the high nucleophilicity of the
anion, reaction occurs under exceptionally mild conditions

Summary:
• solvent effects can modify the energy of both the reactants and the transition state;
• the difference in the two solvation effects is the basis for changes in activation energies
and reaction rates;
• although it is common to express solvent effects solely in terms of reactant solvation or
transition-state solvation, this is usually an oversimplification.

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One case that illustrates this point is the hydrolysis of esters by hydroxide ion:

The reaction is faster in DMSO-H2O than in EtOH-H2O.

By calorimetric measurements (of the heat of solution of the reactants in each solvent system),
the energy difference between transition states and reactives in both solvents is determined:

Both the reactants and the transition state are more strongly solvated in the ethanol-water. The
enhancement in reaction rate comes from the fact that the difference is greater for reactants
(small OH-) than for the T.S (larger anionic species). It is generally true that solvation forces are
strongest for the small, hard anions and decrease with increasing size and softness.

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9.3. Gas phase versus solution

In the gas phase solvation effects are totally eliminated. Thermodynamic data are also different.
Gas-phase substituent effects on simple alcohols change the order of relative acidity.
gas: t-BuOH > EtOH > MeOH >> H2O
This is opposite from the order in solution as revealed by the ΔHo data for the ionization in
water and gas phase:

ΔHo(water) ΔHo(gas)
H2O 21.4 391
MeOH 21.1 379
EtOH 21.7 376
i-PrOH 23.2 374
t-BuOH 26.0 373

In the gas phase, substituent effects can stabilize or destabilize the anion:
• the methyl substituents are better able to undergo local electronic distortion (induced
polarizability) to accommodate the negative charge than is a single hydrogen atom;
• thus, each methyl-for-hydrogen substitution increases gas-phase acidity.

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In solution, these factors are swamped by solvation effects.

Small anions can be better solvated than the more substituted ones, which turns methanol into
the most acidic of this collection of alcohols
Proton transfer between phenol derivatives also has a different behavior in gas phase and in
solution:

Substituent increment (kcal/mol)

X 𝛥𝐺𝑔𝑎𝑠 𝛥𝐻𝑔𝑎𝑠 𝛥𝐺𝐻2𝑂 𝛥𝐻𝐻2𝑂
m-CH3 +0,4 +0,4 +0,18 +0,02
p-CH3 +1,3 +1,3 +0,42 +0,02
m-Cl -7,9 -7,9 -1,2 -0,3
p-Cl -6,6 -6,6 -0,7 -0,2
p-NO2 -25,8 -25,8 -3,8 -0,8

The substituent effect in the gas phase is dominant, as there is no solvation:

• in aqueous solution, the phenolate anion is stabilized by hydrogen bonding;
• there is no such stabilization in the gas phase;
• in solution, the substituent effects are "leveled" to some extent;
• in the gas phase, only the internal substituent effect on the stability of the anion is present.
The importance of the solvation can also be judged by noting that entropy makes a larger
contribution to ΔG than enthalpy for the reaction series in solution. This reflects the extensive
solvent organization that accompanies solvation.

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