1. 7
Neighboring Group
Effect and Nonclassical
Cations

2. Substitution with Retention of Configuration
SN2 reaction at chiral carbons yield products with inverted
configuration. SN1 reaction normally yield at least partially
racemized products.
However, if b-carbon has a substituent with unshared
electron pairs, nuclephilic substitution reactions proceed
with retention of configuration.
trans-2-iodocyclohexanol

3. Substitution with Retention of Configuration
bromohydrin
Stereospecifically inversion
Stereospecifically inversion
Cyclic bromonium ion

4. Substitution with Retention of Configuration

5. Substitution with Retention of Configuration
Although cyclic halonium ions are only short-lived
intermediates, they have much longer lifetimes in less
nucleophilic solvents such as superacids.

6. Substitution with Retention of Configuration
Similar reaction occurred if other atoms that may act
as nuclephiles, such as oxygen atoms, are located on
carbons linked to carbons bearing leaving groups.

7. Sulfur and Nitrogen Mustards
Anchimeric Assistance
Neighboring group effect
Retention of configuration
(2) Acceleration of rates

8. Sulfur and Nitrogen Mustards
Anchimeric Assistance
Like other displacement reactions involving neighboring
groups, the substitution reactions of sulfur mustards
proceed with overall retention of configuration.

9. Sulfur and Nitrogen Mustards
Anchimeric Assistance
Like their sulfur analogs, primary alkyl halides with dialkyl-
amino groups on b-carbons under rapid intramolecular
reactions to form cyclic ammonium ions which are relative
stable and may proceed slowly with weak nucleophiles.

10. Sulfur and Nitrogen Mustards
Effects of Ring Size
On the rates of formation of cyclic sulfonium and of cyclic
ammonium salts

11. Sulfur and Nitrogen Mustards
Effects of Ring Size
On the rates of formation of cyclic sulfonium and of cyclic
ammonium salts

12. Sulfur and Nitrogen Mustards
Effects of Ring Size
3-Membered ammonium rings are formed more rapidly
than 4- or 7-membered rings.
(2) The 5- and 6-membered rings are formed much faster
than the 3-membered ammonium salts.
However,
3-Membered sulfonium rings are formed faster than
sulfonium rings of any other size.
- Normal bond angles of divalent sulfur atoms are much
smaller than bond angles of trivalent nitrogen atoms.

13. Trans/Cis Rate Ratios

14. Trans/Cis Rate Ratios Summary from Table 7.3
trnas-2-bromocyclohexyl brosylate undergoes solvolysis
in acetic acid at only one-tenth the rate of cyclohexyl
brosylate
(2) trnas-2-chlorocyclohexyl brosylate undergoes solvolysis
in acetic acid at only one-thousandth the rate of
cyclohexyl brosylate
(3) The trans isomer reacts more rapidly than the cis isomer
(4) The difference in rates between the two isomers is small
for 2-chlorocyclohexyl brosylate, indicating that the
chlorine atom is not an effective neighboring group

15. Trans/Cis Rate Ratios
Whether in open-chain or cyclic molecules, neighboring
group effects will be most evident when the leaving group
and the neighboring group can easily be placed in a trans,
coplanar arrangement.
4a reacts rapidly when heated in
acetic acid, but 4b is quite unreactive
under the same conditions.

16. Trans/Cis Rate Ratios
Summary of neighboring group effects

17. Neighboring Acetoxy Groups
The displacement of tosylate by the neighboring acetoxy
group yields the cyclic five-membered acetoxonium ion 6
rather than a three-membered ring.

18. Cyclic Phenonium Ions Participation by Aromatic Rings
Displacement of leaving groups can be assisted by
neighboring groups with lacking unshared electrons.
Donald Cram suggested
the formation of cyclic
phenonium ions as
intermediates

19. Cyclic Phenonium Ions Participation by Aromatic Rings
If the reactions were stopped before they were complete and
unreacted 10 and 11 were recovered, 10 was recovered in a
completely racemic form, while tosylate 11 had retained its
optical activty.
Intimate ion pair

20. Cyclic Phenonium Ions Migration of Aryl Groups
The migrations of aryl groups usually yield rearrangement
products with inverted configurations at both the migration
origins and the migration termini.

21. Double Bonds As Neighboring Groups
The Iso-Cholesterol Rearrangement
Double bonds would be expected to participate in displace-
ment reactions even more effectively than aromatic rings.
Iso-cholesterol
rearrangement
Cholesteryl tosylate
Cyclopropyl ring is formed by
displacement of the leaving group
with inversion of geometry of the
chiral carbon

22. Double Bonds As Neighboring Groups
The Iso-Cholesterol Rearrangement
Displacement reactions of cholesteryl tosylate are about
100 times as rapid as reactions of cyclohexyl tosylate.
Double bond participates in displacement of the leaving
group to form allylcarbinyl (homoallylic) cation.

23. Double Bonds As Neighboring Groups
The Iso-Cholesterol Rearrangement
Tosylate 12 was found to react about 1200 times as rapidly
as ethyl tosylate. The reaction yielded a cyclopropane
derivatives as well as the simple displacement product.

24. Double Bonds As Neighboring Groups
7-Norbornenyl Cations
The largest rate enhancement caused by a neighboring
double bond is observed in the solvolysis of anti-7-
norbornenyl tosylate (13), which reacts 107 times as
rapidly as its syn isomer (14), and 1011 times as rapidly
as 7-norbornyl tosylate (15).

25. Double Bonds As Neighboring Groups
7-Norbornenyl Cations
Proposed mechanism
intermediate
Cyclopropane-like characteristics is formed

26. Double Bonds As Neighboring Groups
7-Norbornenyl Cations
Several factors for the contribution of rapid reaction rate of
anti-7-norbornenyl derivatives
The developing cation at C7 of the 7-norbornenyl system
can interact with center of the double bond having the
region of greatest electron density.
(2) In norbornenyl ring systems, the five-membered rings
are distorted far from planarity, so that C7 is relatively
close to the double bond.
(3) The cyclic array of three p orbitals containing two
electrons in the 7-norbornenyl cation can be regared as
a “bishomoaromatic” ring system.

27. Double Bonds As Neighboring Groups
7-Norbornenyl Cations
H.C. Brown suggested that it might be a rapidly
equilibrating mixture of cations 16b and 16c.

28. Double Bonds As Neighboring Groups
7-Norbornenyl Cations
Paul G, Gassman tested this possibility by introducing
methyl groups onto the double bond of 7-norbornenyl
derivative.

29. Double Bonds As Neighboring Groups
7-Norbornenyl Cations
The solvolysis reactions of the anti-7-norbornenyl
derivatives 19 yielded products that retained the original
anti configurations

30. Double Bonds As Neighboring Groups
7-Norbornenyl Cations
Mixtures of anti and syn-isomers were formed when the
substituents were p-dimethylamino or p-methoxy groups

31. Double Bonds As Neighboring Groups
7-Norbornenyl Cations
Aromatic rings fused to anti-7-norbornenyl rings can also
participate in displacement of leaving group at C7, although
the degree of anchimeric assistance is much smaller than
for participation by a double bond.

32. Double Bonds As Neighboring Groups
7-Norbornenyl Cations
Cycloheptatrienyl cations can also act as neighboring
groups in the 7-norbornyl system

33. Double Bonds As Neighboring Groups
7-Norbornenyl Cations
7-Chloronorbornadiene (20) reacts about 750 times as
Rapidly as anti-7-chloronorbornene in acetic acid solution.
It was originally suggested that both double bonds might
Assist in stabilizing the carbocation 21, or that they might
Interact with each other as well, in structure 22.