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.

34. Cyclopropane Rings as Neighboring Groups
The cyclopropyl group appears to provide greater anchimeric
assistance to the formation of carbocations than any other
hydrocarbon group.
Cyclopropylmethyl bromide reacts about 40 times as rapidly
as allyl bromide in aqueous C2H5OH solution.
Cyclopropylmethyl tosylate undergoes solvolysis in acetic
acid 90 times as rapidly as benzyl tosylate and 123,000 times
as rapidly as ethyl tosylate.

35. Cyclopropane Rings as Neighboring Groups
John D. Roberts examined the products obtained from
Cyclopropylmethyl cations formed by diazotization of
Cyclopropylmethylamine labeled with 14C at C1.
Initial suggestion by Roberts
Dissociation of cyclopropylmethyl derivatives
results in the formation of “tricyclobutonium”
ion, in which the cationic center interacts with
the bond linking the two methylene groups of
the cyclopropane ring.

36. Cyclopropane Rings as Neighboring Groups
However, tricyclobutonium cations should have equal
amount of radioactive label compounds due to the equal
distribution on the three methylene groups of the cations.
Roberts proposed later the formation of “bicyclobutonium”
ion, in which the cationic canter interacts with one
neighboring bond of the cyclopropyl ring.

37. Cyclopropane Rings as Neighboring Groups
NMR spectra of several cations formed from cyclopropyl-
methyl derivatives in superacid solution showed that ions
appear to have structures in which the planes of the
cationic carbons bisect the cyclopropane rings.
The stability of these “bisected” structures may be
attributed to the fact that cationic center can interact
with two “bent bonds” of the cyclopropyl ring.

38. Cyclopropane Rings as Neighboring Groups
The effects of substituents on the solvolysis rates of
cyclopropylmethyl derivatives suggest that the TS for the
reactions are lowest in energy when the developing cationic
center can interact with two sides of the neighboring
cyclopropyl ring rather than one.
More rapid reaction
in acetic acid than
parent compound

39. Cyclopropane Rings as Neighboring Groups
H.C. Brown demonstrated that a cyclopropyl substituent in
para position increase the solvolysis rate of a tertiary
benzylic chloride.
A single methyl substituent at meta position results in a slight further
increase in the rate of reaction. However, a second meta-methyl group
markedly decrease the rate, because it forces the TS to adopt a conformation
similar to that of ion 26 rather than one similar to the bisected ion 27.

40. Cyclopropane Rings as Neighboring Groups

41. Neighboring Alkyl Groups: 2-Norbornyl Cations
Anchimeric Assistance by Alkyl Groups: The “Nonclassical”
Hypothesis
Alkyl groups rarely provide anchimeric assistance to the
formation of carbocations. However, alkyl groups can act
as effective neighboring groups in the 2-norbornyl system.
Solvolysis of exo-2-norbornyl brosylate (28) in acetic acid proceed 350
times as rapidly as solvolysis of its endo isomer yields exclusively exo-2-norbornyl acetate and a completely racemic mixture.

42. Neighboring Alkyl Groups: 2-Norbornyl Cations
Anchimeric Assistance by Alkyl Groups: The “Nonclassical”
Hypothesis
Winstein and Trifan suggested that C1-C6 bond acts as a
neighboring group in reactions of 28, resulting in the
formation of the “nonclassical” cation 30.
A plane of symmetry
Through C4, C5, and C6

43. Neighboring Alkyl Groups: 2-Norbornyl Cations
Anchimeric Assistance by Alkyl Groups: The “Nonclassical”
Hypothesis
J.D. Roberts studied the rearrangements of 2-norbornyl
Derivatives labeled with radioactive carbon at C2.

44. Neighboring Alkyl Groups: 2-Norbornyl Cations
Anchimeric Assistance by Alkyl Groups: The “Nonclassical”
Hypothesis
Why should an alkyl group provide anchimeric assistance?
The C1-C6 bonds in exo-2-norbornyl derivatives are trans
to the bonds between C2 and the leaving groups.
(2) The norbornyl ring system is quite strained and thus the
C1-C6 bond is bent and weak, and its electrons are
relatively available to participate in the displacement of a
leaving group.