Conformational, Steric, and Stereo-electronic Effects Part C

1- Anomeric effect
 The incorporation of heteroatom results in Stereo electronic effects,
conformation changes and affects the reactivity.
 From carbohydrate chemistry , pyranose sugar substituted with electron
withdrawal ( e.g. halogen and alkoxy ) at carbon 1 is
more stable in the axial than in equatorial ( Anomeric
effect)

 Anomeric effect also occurs in simple ring system as 2-substituted

tetrahydropyrans

 Anomeric effect is due to :

1. Localized valence bond Terminology :
Dipole-dipole repulsion between polar bonds at the anomeric carbon in
the equatorial conformation which is
reduced in the axial conformation
(solvent also has effect on stabilizing this
interaction).

2. molecular orbital viewpoint :

Interaction between the lone-pair electrons on the pyran oxygen and
Orbital of the electronega ve C2 substituent.
When the C‫ـــ‬X bond axial interaction is possible
{antibonding Orbital of C‫ـــ‬X and the
occupied p-type orbital on the oxygen (lone-pair
electron)}.
 The magnitude of Anomeric effect depends on
1. the nature of the substituent
the more electronegative substituent, the great anomeric effect
and the weaker bond of the substituent( easily removed).
dielectric constant of the medium.
2. Anomeric effect decreases with increasing dielectric constant of
the medium (stabilizing effect of the medium will abolish the
stability difference between axial and equatorial conformation
(anomeric effect explana on 1 above ).
 Anomeric effect also present in acyclic systems and stabilize
conformation that allow antiperiplanar alignment of C‫ـــ‬X bond with the
lone-pair orbital of the heteroatom.(Exp. Conformation of Acetals ,
Amine ).

 Because of the donor-acceptor nature of the interaction it is enhanced

in the order F <O < N for the donor (D)(heteroatom ) and N > O > F for
the acceptor (A) (EW substituent)
 2- Conformational effect on reactivity.
 Difference in the axial and equatorial environment (Stability) has significant
differences in the reaction rate.
 Cyclohexane is rapidly change between axial and equatorial conformation
(equilibrium) So large substituent (ter-butyl substituent) or rigid ring system(Trans
decalin ) used as conformation lock to ease the effect of each conformer on the
reaction rate.

 The effect of conformation on the reaction rate depends on the mechanism of the
reaction:

Axial more reactive for oxidation lower in acetylation than equatorial this is
associated to the details of the mechanism( free energy of activation for the rate
determining step):
1. Oxidation(chromic acid oxidation):
The rate determining step is breakdown of chromate ester
intermediate. The reaction goes to the same product in both axial
and equatorial conforma on (product with Sp2 hyperdization, with
no conformational interaction of hydroxyl group { Diaxial
interaction}).
 From energy diagram axial conformer has higher energy than
equatorial one thus has lower activation energy.

2. Acetylation :
The rate determining step is nucleophilic attack of hydroxyl group on
the carbonyl group of the acetic anhydride to form tetrahedral
intermediate .

Trans isomer have OH in equatorial so more stable (lower in energy).

The intermediate contain acetylating agent in the equatorial (Trans)
more stable (lower in
energy). Energy difference
is greater in case of acetyl
group as it’s more bulky.
So activation energy for
Trans (equatorial) is less
than axial (cis).
Anomeric effect on reactivity Exp. CrO3 can oxidize pyranose acetals leads to Ϭ-ketoesters

Ease of H abstract in axial isomer is more than equatorial conform and hence more
reactive due to anomeric effect.
 3- Angle strain and its effect on reactivity.
 Angle strain : is increase of energy content of the molecule due to distortion
of bond angles .
 Six memberd rings are nearly strain free.
 Angle strain increase ground state energy resulting in reaction which leads to
ring opening proceeds more readily than those of unstrained ring system.
Also it causes qualitative changes in bond hybridization leads to increase
reactivity.
Ex. Saturated hydrocarbons are inert to bromine while cyclopropane reacts
readily.

Ex. Bicyclo [1.1.0] butane has great angle strain, decrease stability and increase
reactivity. The central bond is nearly pure P orbital and reactive towards
electrophiles. Acid-catalyzed hydrolysis gives products characteristic of the
bicyclobutonium Cation.

 Alkene exhibit large strain energy when bonds to the two sp2 –hybridized
carbons not coplanar. Ex. E-cycloheptene:
 Trans geometry not allow coplanar of the double bonds’
which leads to highly strained compound highly reactive to
Diels- Alder reaction.
 With increase ring size amount of strain decrease as double bonds
approaches coplanar geometry.
 Bicyclic rings also distort alkene coplanarity. Ex.
Bicycle[2.2.1]hepta-1-ene:
 Bredt’s rule”absence of bridgehead double bonds” is not absolute as increase
in ring size (>7 carbon) strain is lower and can exist. They are very reactive
toward addition reaction.

4- Relationship between ring size and rate of cyclization.

 Baldwin and co-workers classify ring closure with respect to three factors:
o Ring size .
o Hybridization of the carbon at reaction site.
o Relationship (endocyclic or exocyclic )of reacting bond to the forming
ring.

 Five membered ring endo-trig ring closure is difficult?

 The nucleophile cannot approach in the nodal plane of π system so it must
attack from above or below which leads to distortion of ring geometry.

While 5-end-dig cyclization is feasible as acetylenic system provide orbital in

nearly planar approach.

Ex.

5- Torsional and stereoelectronic effects on reactivity

 Torsional strain nonoptimal arrangement of vicinal bonds.
 Torsional strain in transition state raises the activation energy of the reaction.
 Ex .reaction involve hybridization changes at a ring atom:

In the above reaction sp2 carbon converted to sp3carbon:

 Five-membered ring: this increase Torsional strain.
 Six-membered ring: this decrease Torsional strain (6 strain free).