CY5013 : CONCEPTUAL ORGANIC CHEMISTRY

Physical organic chemistry: Relationship between thermodynamic stability

and rates of reactions – kinetic and thermodynamic control of product
formation, Hammond’s postulate, Curtin Hammett principle. Catalysis
(acids, bases, and nucleophiles) and isotope effects, importance in the
determination of organic reaction mechanisms, solvent effects, examples from
SN2 and E2 reactions. Introduction to carbon acids, pKa of weak acids.
Conformational analysis: Introduction to conformational analysis, steric,
electronic and stereoelectronic effects in governing the conformation of
acyclic and cyclic (5 and 6 membered rings) systems, A-strains and anomeric
effect, decalins, transannular interactions in medium size rings.
Conformation and reactivity: steric and electronic effects in syn-elimination,
E2 elimination and neighboring group participation (Woodward, Prevost
methods) of acyclic and cyclohexyl systems, esterification, substitution
reaction and formation and opening of epoxide in cyclohexyl systems (Furst
Plattner rule).

Muraleedharan K. M.
Room CB 301
E mail: mkm@iitm.ac.in
Text Books:

1. A. Carey and R. A. Sundberg, Advanced Organic Chemistry, Part A:

Structure and Mechanisms, 5th Edition, Springer, New York, 2007.
2. H. Lowry and K. S. Richardson, Mechanism and theory in organic
chemistry, Second edition, , Harper & Row, New York, 1981.
3. S. Isaacs, Physical Organic Chemistry, , ELBS, Longman, UK, 1987.
4. J. Kirby, Stereoelectronic effects, Oxford Chemistry Primers, 2011.
5. Steric and Stereoelectronic Effects in Organic Chemistry, V. K.
Yadav, Springer, 2016.
6. Nasipuri, Stereochemistry of Organic Compounds. Principles and
Applications, Second Edition, Wiley Eastern Limited, New Delhi,
1994. Ch.2-6 and 9-12.
7. G. Morris, Stereochemistry, RSC Tutorial Chemistry Text 1, 2001
8. L. Eliel and S. H. Wilen, Stereochemistry of Organic Compounds,
John Wiley & Sons, New York, 1994.
9. Reinhard Bruckner, Advanced Organic Chemistry: Reaction
Mechanisms
 • Addition
• Substitution
Chemical reactions • Elimination
• Pericyclic reaction
• Oxidation/reduction
• Rearrangements

A + B C + D
Chemical reactions

Reagent
Catalyst
A + B C + D
Solvent
Polar protic (H2O, MeOH, EtOH)
Polar aprotic (Acetone, DMSO, DMF)
Non-polar aprotic (CCl4, Et2O, hexane)

Reaction conditions
Chemical reactions

Reagent
Catalyst
A + B C + D
Solvent
Reaction conditions Additives
Increase reactivity
Selectivity
Modify pathway
Improve efficiency
Chem. Rev. 2016, 116, 6, 4006–4123
Chem. Commun., 2016,52, 6821-6824
Carbenium ion
(carbocation) Carbanion

Nitrene Benzyne

N
carbene H
S H

H
N H
S

T
Reactivity toward a particular reagent/reactant is influenced by
factors that influence the relative availability of electrons in
particular bonds or atoms.

– Inductive and field effects

– Mesomeric/resonance effects Other effects:
– Hyperconjugation ▪ Hydrogen bonding propensities
– Steric effects ▪ Aromaticity
– Bond energy ▪ Acidity/basicity (pKa)

X COOH
X = H, PKa = 6.04
X = Cl, PKa = 6.25
X = COOCH3, PKa = 6.20
Bond Energy
Formation of H-H Bond
 Potential energy of a diatomic molecule as a function of internuclear separation

Molecule of N atoms: 3N-6 vibrational degrees of freedom; 3N-5 (for linear molecules)

• For a polyatomic molecule, a potential energy curve can be drawn for each of the 3N-6 vibrational modes.
A system with N atoms require 3N-6+1 dimensional space for representation!
 Exothermic Reaction Endothermic Reaction

A+B C+D

Ea = activation energy
 Reaction Energy Diagram for SN1

TS#1 TS#2

R+ + X-
E
NuH
TS#3

R-X
R-NuH+ + X-
R-Nu + H-X

Reaction Coordinate

How many steps are there in this reaction?

What is the highest-energy transitions state?

What is the highest-energy intermediate?

Is this reaction exergonic or endergonic?

Which steps determines the reaction’s rate?
O
COOH
1.tBuOK / tBuOH
Ph

2. H3O O
O Ph

pKa values

20
OH
O
>50
pKa ~20

O
40
35 O
Kinetic and thermodynamic control

--------
R
--------
R --------
-------- A --------
B -------- B
-------- A
A --------
B --------
R
Product distribution Kinetic or
depends on rate Thermodynamic A and B equilibrate
rather than their stability based on conditions faser than the rate of
formation of A;
Product distribution
depends on their
thermodynamic stability
16
Energy profile in the case of Benzene – Addition vs. Substitution

Addition Substitution

DH Ref: Reinhard Bruckner,

H Br Advanced Organic Chemistry:
Reaction Mechanisms

Br H
Br
H H
Br Br
Br -
Br Br-

----------------
---------------- ----------------
+9 kcal/mol
-11 kcal/mol
+ Br2
----------------
AlCl3
Br
+ HBr
Energy profile in the case of Olefins – Addition vs. Substitution

H
Addition Substitution
Br DH
H
Br- H

Br Br-

---------------------------------------------------------------------------

-11 kcal/mol
+ Br2
-27 kcal/mol
Br
+ HBr
Br

Br
Energy profile of aromatic substitution reaction
H E
benzenonium
Transition intermediate
state 1

Transition
state 2

intermediate

H
Ea
+ E activation
energy

E
fast + H
slow
STEP 1 STEP 2
Comparison of Activators and deactivators
Relative energy states of intermediates with respect to that of benzene

Deactivators (m-directing)

Benzene

Activators (o/p directing)

Hammond postulate
If two adjacent states along a reaction path have similar energies, they will
have similar structures (their inter-conversion will involve only a small
Reorganization of molecular structure)

TS TS
TS

B A

A B
A B

TS looks more TS looks more TS looks like

like B like A neither A nor B

Late TS Early TS 21
Chemoselectivity The reagent effects preferentially or exclusively one out of
several types of possible transformations
Hammond postulate: illustration Halogenation of isopentane

X2 X
X + + +
D Cl
X

X = Cl 22% 33% 30% 15%

X = Br 92.2% 7.38% 0.28% 0.14%

RLS: RH + X· → R· + HX

23
Number of H
atoms/statistical

Yields, if all Hs are

8% 17% 50% 25% = 3 x 100
substituted at the same rate
12
Yields on a per-H atom
basis

= 22/5

Relative rate
Number of H
atoms/statistical
8% 17% 50% 25%

Yields on a per-H atom

basis

Relative rate
 H-Cl bond enthalpy =
103 kcal/mol.

H-Br bond enthalpy =

88 kcal/mol

(15 kcal/mol difference)

C H Cl RLS: RH + X· → R· + HX C H Br
26
HBr
81% 19%
0
-80 C
Br
Br

3-bromo-1-butene 1-bromo-2-butene
HBr
44% 56%
0
20 C
Regioselectivity in unsymmetrical Ketones:
Kinetic vs. thermodynamic products

Li O
Li
O O

+ LDA + + [(CH3)2CH]NH

Kinetic product Thermodynamic product

Note: relative energy levels are shown arbitrarily – just consider the relative positions of TSs and enolates
Regioselectivity in unsymmetrical Ketones:
Kinetic vs. thermodynamic products

Li O
Li
O O

+ LDA + + [(CH3)2CH]NH

Kinetic product Thermodynamic product

Non-protic conditions (solvent THF), low temperature (~-78oC), and 1 eq. of LDA
favor the Kinetic enolate

Less than 1 eq. of a base (NaOEt), protic solvent (EtOH), and higher temperature
favor the thermodynamic enolate
 The Curtin–Hammett principle (1950’s) - D H R Barton
Relationship between conformation and chemical reactivity

• If a molecule can exist in two conformational states which individually can give two different
products, will the major conformer give the major reaction product?

• Is it possible to predict the major conformer from the structure of the major reaction product?
 B
Case I.
A
More stable conformer (A) reacts
faster and give major or exclusive
product (C) D
C

NaOEt + +
Br
19%
major minor
2-bromobutane

81%

Suchandra Chakraborty and Chandan Saha,

Resonance, 2016 Feb, p 151
 alkaline Me Cl
+ Me
Cl Me
H H
I II
neomenthyl chloride
Saytzeff’s rule (I:II = 78:22)

Predict the energy profile of the following reaction

Alkaline
condition Me
II Me
Cl Me H
H
Me H
Me
H Cl H
menthyl chloride Cl H Me
Case II.
Less stable conformation reacts
faster and give major or exclusive
product

tropane
Case III –
The free energy of activation of the
reaction A to C is comparable to that
of B to D

equilibrium distribution of the two

conformers decide product ratio

(energy difference
3.16 kcal/mole)
Case IV
A and B are of comparable stability.
The free energy of activation of the
reaction A to C is higher than that of B to
D.

Br K2CO3
O
HO

O
Br OH
Br
O H O
Br Br
Curtin–Hammett principle:

“The relative amounts of product formed from two critical

conformations are completely independent of the relative
populations of the conformations and depend only upon the
difference in free energy of the transition states, provided the
rates of reaction are slower than the rates of conformational
interconversion”
43
 Favored by
DG = -3.0 kcal/mol

THF

a:b = 99:1)

J. Am. Chem. Soc. 1997, 119, 4565-4566