Course code : CHEM 43244

Course title : Advanced Organic Chemistry I

Physical Organic Chemistry (15 h)

Dr. Dinesh Pandithavidana

E-mail: dinesh@kln.ac.lk

Mobile: 0777-745-720

Office: B1 222/3

Stereochemical Principles

Stereoselective Reactions:

• A stereoselective reaction can produce multiple stereoisomers theoretically, but

more of some produced than others

Br Br

+

(2R)-2-bromo-1,1-dimethylcyclohexane

base

(1Z)-3,3-dimethylcyclohexene(2R)-2-bromo-1,1-dimethylcyclohexane

+(2S)-2-bromo-1,1-dimethylcyclohexane

(1Z)-3,3-dimethylcyclohexene

no E (trans) isomer is formed

Stereospecific Reactions:

• A stereospecific reaction produces different stereoisomer products from

different stereoisomer reactants.

SN2 mechanism

stereospecific

SN1 mechanism

non-stereospecific

Regioselective Reactions:

• A regioselective reaction is one

in which multiple constitutional

isomers possible, but more of

some formed than others.

HBr

Br Br

+

major product no measurable quantity formed

DefinitionsProchiral:

• A molecule is prochiral if the addition of a new group or an exchange of one

group on the molecule would create a new stereocenter and, therefore, a chiral

molecule. A prochiral atom must be bonded to three different groups before any

change is made.

O

The molecule on the left is prochiral because a new stereocenter can be made by

replacing one group on the carbon marked with an asterisk (*) with a new one.

The molecule on the right is prochiral because a new stereocenter can be made

by adding a new group to the carbon marked with an asterisk.

* *

Proton Equivalence

• Proton NMR is much more sensitive than 13C and the active nucleus (1H) is

nearly 100 % of the natural abundance.

• Shows how many kinds of nonequivalent hydrogens are in a compound.

• Theoretical equivalence can be predicted by seeing if replacing each H with

“X” gives the same or different outcome.“X” gives the same or different outcome.

• Equivalent H’s have the same signal while nonequivalent are “different” and

as such may cause additional splitting (diastereotopic effect).

– There are degrees of nonequivalence

Nonequivalent Hydrogens

• Replacement of each H with “X” gives a different constitutional isomer.

• Then the Hydrogens are in constitutionally heterotopic environments

and will have different chemical shifts – they are nonequivalent under all

circumstances.

Equivalent Hydrogens

• Two H’s that are in identical environments (homotopic) have the same NMR signal.

• Test by replacing each with X

– if they give the identical result, they are equivalent

– Protons are considered homotopic

Enantiotopic Distinctions

• If Hydrogens are in environments that are mirror images of each other, they are

enantiotopic.

• Replacement of each H with X produces a set of enantiomers.

• The Hydrogens have the same NMR signal in the absence of chiral materials

(optically active solvents, co-solvents or Lewis acids)

Diastereotopic Distinctions

• In a chiral molecule, paired hydrogens can have different environments and different shifts.

• Replacement of a pro-R hydrogen with X gives a different diastereomer than replacement of the pro-S hydrogen.

• Diastereotopic hydrogens are distinct chemically and spectrocopically.

Symmetry in NMR Spectra

• Protons and other nuclei in NMR spectra can be classified as heterotopic,

diastereotopic, enantiotopic and homotopic.

• Heterotopic and diastereotopic protons will have different chemical shifts and

couplings to neighboring magnetic nuclei.

• Enantiotopic and homotopic protons will have identical chemical shifts. They may or

may not have identical couplings to other nuclei.

• Distinction can be made by the substitution test.

The Substitution Test for Equivalance of Protons:

For a pair of protons to be tested, replace one with another group

(which is not present in the molecule). Compare the two structures formed:

• If they are identical, the protons are homotopic,

• If they are enantiomers, the protons are enantiotopic.

• If they are diastereomers then the protons are diastereotopic.

• If they are structural isomers, the protons are heterotopic.

Correlation of Structures with Reactivity

• The structural changes which are used to bring about electronic perturbations are

substituent groups, which may be introduced , near to the reaction center and

which do not themselves take part directly in the reaction being considered.

• It is the change in reaction, brought about by substitution, which are of interest, so

structural changes must be determined relative to some standard substituent

which is electronically neutral. Hydrogen is normally adopted as the “zero”

substituent. substituent.

• This is because that most reactions studied, occur at carbon as one reaction

center, and the electronegativities of carbon & hydrogen are almost equal. So that

C ̶ H bond has no polarity. Furthermore, the hydrogen substituent has no

unshared pairs of π-electrons.

O

O

X

H

O

H

H

O

O

X O

H

H

H+ +

ka

• We can measure the ionization of substituted benzoic acid in water and then

determine equilibrium constant, Ka.

O

O

X

H

O

H

H

O

O

X O

H

H

H+ +

ka

X NO2 CN Cl H CH3 OCH3

Log Ka -3.45 -3.56 -4.00 -4.20 -4.37 -.4.47

Ka has been increased by substitution of H for an electron-withdrawing groups which

weakens the O-H bond, and conversely decreased by an electron donating group.

This reveals the carboxylic acid acts as a the electrophile and water acts as the nucleophile.

Relative to hydrogen, in this series, electron withdrawing sustituents increase the acidity and

electron donating susbtituents decrease the acidity.

Log Ka -3.45 -3.56 -4.00 -4.20 -4.37 -.4.47

σ +0.75 +0.64 +0.2 0.00 -0.17 -0.27

• Quantitatively, the effect of each substituent, relative to that of hydrogen,

may be obtained by a comparison of ∆G for dissociation constants of

substituted benzoic acid (KX) with that of the parent compound (non

substituted benzoic acid) KH.

• Substituent effect =

• σ is called substituent constant because it’s value depends on the nature of

substituent.

σ=

=∆−∆

H

X

HX

K

KGG log

Energy

O

O-

O

O-

O2N

HG∆

XG∆

• For Hydrogen, as a reference point; σ = 0.0

Because if so if there is no substituent, 01loglog ==

H

H

K

K

O H O H

H

X

K

Klog

.. .

.m-Br, Cl

p-NO2

m-CNO

O

X

H

O

H

H

O

O

X O

H

H

H+ +

ka

σ

..

..

...

.. .

m-OMe

m-I

p-F

m-Mep-OMe

p-I

p-Cl

m-Br, Cl

p-Br

H

electron withdrawing groupselectron donating groups

Gradient = 1

Let’s see the hydrolysis of methyl benzoate and ionization of phenyl acetic

acid with compared to ionization of benzoic acid.

O

O CH3

O

O

OH

X X

Rates are evidently increased by electron withdrawing substituents on the ester,

which must accordingly be the electrophiles.which must accordingly be the electrophiles.

In case of phenyl acetic acid, ionization center, COOH and benzene ring with the

substituent have been isolated by the –CH2- group. So the reaction is less

sensitive to substituents than benzoic acid ionization reaction.

X O

H

H

X+

ka

O

O

H

O

O

H

X

K

Klog

for Benzoic acid (m = 1)

for Methyl benzoate (m > 1)

Hammett Plot

σelectron withdrawing groupselectron donating groups

for Phenyl acetate (m < 1)

*** This σ corresponds to ionization of Benzoic

acid which is our standard reaction

• Now it is evident that the linear relationship of previous plots implies;

• Introducing a constant of proportionality, ρ , known as the reaction constant.

ασ

H

X

K

Klog

σρ.log =

H

X

K

K

• Introducing a constant of proportionality, ρ , known as the reaction constant.

The Hammett Equation:

The equation describing the straight line correlation between a series of reactions

with substituted aromatics and the hydrolysis of benzoic acids with the same

substituents is known as the Hammett Equation.

The reaction constant, ρ, describes the susceptibility of the reaction to

substituents, compared to the ionization of benzoic acid. It is equivalent to the

slope of the Hammett plot. Information on the reaction and the associated

mechanism can be obtained based on the value obtained for ρ.

If the value of:

• ρ>1, the reaction is more sensitive to substituents than benzoic acid and

negative charge is built during the reaction (or positive charge is lost).

• 0<ρ<1 , the reaction is less sensitive to substituents than benzoic acid

and negative charge is built (or positive charge is lost).

• ρ=0, no sensitivity to substituents, and no charge is built or lost.

• ρ<0, the reaction builds positive charge (or loses negative charge).

Significance of ρ

Resonance Effect (R)

Reaction center is perturbed by the substituents through,

1) Inductive effect

2) Resonance effect

3) Filed effect

The effect is described as a +R effect, if it results in donation of electrons from

substituent to reaction center.

And a – R effect, if a withdrawal of electron results.And a – R effect, if a withdrawal of electron results.

Donor groups typically possess unshared π-electron pairs or electrons on an atom

directly attached to the ring.

E.g.

These groups are all capable of exerting +R effect which stabilizes an acceptor

center when they are at ortho- or para- positions.

-NR2 , -OR, -SR, -PR2, -X , HC CH2

Stabilization via +R effect

� Substituents which have π-acceptor center, adjacent to the ring, which can act

as electron acceptors.

E.g:

C

OCH3

C

OCH3

C N C NE.g:

C

C

C

CO O

Stabilization via -R effect

CO

CO

C N C N

• In case of Resonance Effect, many substituents give rise to a perturbation

which is greater when they are located at ortho- or para- than they are at

meta- position.

This is because little interactions

between donor and acceptor centers

will occur, if they are located at meta,

so resonance structures cannot be

drawn due to the presence of high

energy.

C C

O

CH3

O

CH33 3

Inductive Effect & Field Effect

• Inductive effect is caused by differences in electronegativity which polarize

both σ and π bonds. This also depends on number of bonds between the

reaction center and substituent.

Me3N

C

CField effect

Inductive effect +δ

+δδ

• The Field effect is propagated through space and depends more for its

intensity and proximity than on the number of bonds between the reaction

center and substituent.

• When inductive effect is there, field effect is also should be associated with

it.

Field effect

Can you explain differences of σ values?

σ = 0.15 σ = 0.34

F C

O

O

C

O

O

F

HO C

O

O

C

O

O

HO

σ = - 0.4 σ = + 0.12

Deviations from Linearity in Hammett Plots

Modified Substituent Constants σ_

Scale:

• We can develop new σ values for these substrates by separating out these through-

conjugation effects from inductive effects.

• Develop line with ρ value based on m-substituents only, which cannot exhibit

resonance effects. The amount by which certain substituents deviate from the line

can be added to their σ values to produce a new scale of σ_

value.

Substituent effect by the enhanced resonance = ( σ͞ ̶ σ)

Modified Substituent Constants σ+

Scale:

• Similarly, in some cases,we find that strongly electron-donating substituents don’t fall

on the line predicted by the Hammett correlation.

Example: SN1

solvolysis of p-substituted tertiary halides

Substituent effect by the enhanced resonance = ( σ+ ̶ σ)

Uses of Hammett Plots

(1) Calculation of k or K for a specific reaction of a specific compound:

If we know ρ for a particular reaction, then we can

calculate the rate or equilibrium constant for any substituent relative to that

for the unsubstituted compound (because we also know σ for the

σρ.log =

H

X

K

K

for the unsubstituted compound (because we also know σ for the

substituent).

(2) To provide information about reaction pathways:

� Magnitude and sign of ρ tell about development of charge at reaction

centre.

� If σ+ or σ͞ gives a better correlation than σ , then we know we have

a reaction where through conjugation is important.

The Hammond Postulate

29

The Hammond PostulateG

• In an endothermic reaction, the transition state resembles the products more than the

reactants, so anything that stabilizes the product stabilizes the transition state also. Thus,

lowering the energy of the transition state decreases Ea, which increases the reaction rate.

30

• If there are two possible products in an endothermic reaction, but one is more stable than

the other, the transition state that leads to the formation of the more stable product is lower

in energy, so this reaction should occur faster.

The Hammond PostulateG.

• In the case of an exothermic reaction, the transition state resembles the reactants

more than the products. Thus, lowering the energy of the products has little or no effect

on the energy of the transition state.

• Since Ea is unaffected, the reaction rate is unaffected.

• The conclusion is that in an exothermic reaction, the more stable product may or may

not form faster, since Ea is similar for both products.

31

• The Hammond postulate estimates the relative energy of transition states,

and thus it can be used to predict the relative rates of two reactions.

• According to the Hammond postulate, the stability of the carbocation

determines the rate of its formation.

The Hammond Postulate:

32

Energy diagram for

carbocation

formation in two

different SN1 reactions