Neighboring-Group Mechanism

Neighboring-Group Participation/ Anchimeric assistance ( Anchi is neighbor in Greek)

3-bromo-2-butanol when treated with HBr
threo dl Pair

Symmetrical bromonium ion is intermediate

Rearranged products possible if the intermediate is not symmetrical

erythro dl Pair

Meso

Solvolysis of the cis and trans isomers of 2-acetoxycyclohexyl p-toluenesulfonate

retention of configuration
an enantiomerically pure reactant with two stereogenic centers
solvolysis gives a racemic mixture of products

inversion of configuration

acetoxonium ion
the anchimeric assistance occurs in the rate-determining step involving leaving
group departure, not after formation of the carbonium ion
Following reaction is an evidence for acetoxonium ion
if reaction is carried out in presence of small amount of water or ethanol

cyclic orthoester

trans acetate reacts faster in the acetolysis

reaction of 2-substituted cyclohexyl
brosylates than a cis acetate.
trans acetoxy group participate in
the ionization process

Both reactants are less active than a simple

cyclohexyl derivative due to the electron
withdrawing acetate groups

But entropy of activation is more negative for trans, indicating a more organized
transition state due to the anchimeric assistance.

Solvolysis of cis- and trans-2-halocyclohexyl brosylates in acetic acid

Rel.rates of
reaction

X=H

X = trans-Cl

4.8 104

X = cis-Cl

1.3

X = trans-Br

0.10

Inductive effects of halogen atom

Anchimeric assistance by haolgen atom

104

X = cis-Br

1.2 104

X = trans-I

1.2 103

X = cis-I

ktrans /
kcis

4.3 104

800

3 106

Effectiveness of halogens as neighboring

groups I>Br>Cl

a neighboring group lends assistance in proportion to the need for such assistance

when 5-chloro-2-hexyl tosylate is solvolyzed in acetic acid,

there is little participation by the Cl,
but when the solvent is trifluoroacetic acid, which is much less nucleophilic,
neighboring-group participation by the Cl becomes the major reaction pathway

OH group in trans- 2-hydroxycyclopentyl arenesulfonates acts as a neighboring

group when the leaving group is tosylate
but not when it is nosylate, apparently because the nosylate group leaves so rapidly
that it does not require assistance

Neighboring-Group Participation
consists essentially of two SN2 substitutions, each causing an inversion, net result is
retention of configuration
in the first step the neighboring group (Z) acts as a nucleophile, pushing out the
leaving group but still retaining attachment to the molecule
in the second step, the external nucleophile (Y) displaces the neighboring
group by a backside attack
first-order rate law is followed in the neighboring group mechanism , Y does not take
part in the rate-determining
rate of reaction is greater than expected( > ~50 times)
A reaction between the substrate and Y involves a large decrease in entropy of
activation S, since the reactants are far less free in the transition state than before.
In general reaction of Z involves a much smaller loss of S
there is usually a group with an unshared pair of electrons to the leaving group (or
sometimes farther away)
some of the important
neighboring groups:
COO , COOR, COAr, OCOR,
OR, OH, O ,
NH2, NHR, NR2, NHCOR,
SH, SR, S , SO2Ph,
I , Br, and Cl

acetolysis of both 4-methoxy-1-pentyl brosylate

and 5-methoxy- 2-pentyl brosylate gives the same mixture of products
a cyclic oxonium ion is the intermediate

Relative Solvolysis Rates of Some -Methoxyalkyl p- Bromobenzenesulfonates

in Acetic Acid

the maximum rate is usually observed for the five- and six-membered rings
strain that develops in the closure of small rings (ring size 3,4) (H )
decreased probability of encounter of the reaction centers (for ring sizes
greater than 7 (S )

Solvolysis of 4- chlorobutanol in water gives tetrahydrofuran as the product

Sulfur Mustards (R-S-CH2 CH2 -X) as neighboring groups

mustard gas - used in World War I as a chemical warfare agent in the form of an
aerosol
Bis(2,2)-(chloroethyl)sulfide

Hydrolyzes much more rapidly than its analog 1,5-dichloropentane

Hydrolysis proceeds by first order kinetics, very rapid, rate unaffected by addition of
other nucleophiles
Cyclic sulfonium ion reacts extremely rapidly, reacts with a variety of nucleophiles,
including water, and also proteins and other biomolecules
cause DNA damage by permanent alkylation of the guanine nucleotide in DNA strands
These reactions create HCI, which severely burns and blisters the skin.
Find few other sulfur mustards

Nitrogen Mustards (R-NR-CH2 CH2 -X) as neighboring groups

Cyclic ammonium ions are relatively stable compared to cyclic sulfonium or bromonium ions
May not react very rapidly with weak nucleophiles,like water
In absence of powerful nucleophiles nitrogen mustard reaction may exhibit complex kinetics.
High concentrations of good nucleophile, react rapidly with cyclic ammonium ions ,making
the intra molecular displacement as the rate determining step.
Addition of good nucleophiles and more likely the first order kinetics followed!!!!!! An
interesting paradox

Rates of formation of cyclic ammonium salts in water at 25 C

3-membered rings have less unfavorable entropies of activation

Enthalpies of formation of relatively strain free 5- and 6-memberd rings
significantly lower than that for 3-membered rings
Rate of formation of cyclic sulfonium salts in 20% auqeous dioxane at 100o C

Normal bond angles of divalent sulfur is much smaller (~ 100) than trivalent nitrogen (~109)
Less bond distortion and strain in formation 3-membered sulfonium ions

participation of aromatic electron

solvolysis of 3-phenyl-2-butyl tosylates
a spirooctadienyl cation

Phenonium ions are derivatives spirooctadienyl cation

They are related to the Wheland complexes of electrophilic aromatic substitution
Reactions resulting in three membered cyclic phenonium ions can be compared to
Intramolecular Friedel Crafts reactions

Phenethyl tosylate solvolyzes in CF3CO2H orders of magnitude faster than ethyl tosylate
The intermediacy of a phenonium ion in the solvolysis of phenethyl tosylate was proven
by isotope labeling

Solvolysis rate studies in 2-arylethyl systems

for primary and secondary systems, two pathways can exist

Solvent and the nature of the aryl group

affect the

EtOH<CH3COOH<HCOOH<CF3COOH
solvolysis of 1-phenyl- 2-propyl tosylate at 50o C shows percentage of retention as
in EtOH 7%, CH3COOH 35%, HCOOH 85%, CF3COOH 100 %

For tertiary systems,the mechanism is SN1 and open carbocations ArCH2CR2+ are
intermediates

Approximate k/ks Ratios for Acetolysis of p-ZC6H4CH2CH2OTs at 90o C

Percentage of k

k changes substantially as Z is changed from activating to deactivating

ks is fairly constant, remote field effect of Z
Relative importance of aryl participation is a function of the substituents on
the ring
Relative extent of participation of the -phenyl groups is highly dependent on the solvent

In solvents of good nucleophilicity (e.g., ethanol), the normal solvent displacement

mechanism makes a larger contribution.
As solvent nucleophilicity decreases, the relative extent of aryl participation increases.

Participation of electrons of carbon-carbon double bonds

The electrons of carbon-carbon double bonds can also become involved in
nucleophilic substitution reactions. This participation can facilitate the ionization step
if it leads to a carbocation having special stability

7-norbornenyl tosylates

Anti 7-norbornenyl tosylates

Syn7-norbornenyl tosylates

In acetolysis anti-tosylateis is 1011 more reactive than the saturated 7-norbornyl

analog
The syn isomer reacts 107 times slower than the anti isomer.
The rate data is strong evidence that the
the OTs

group assists in the departure of

intermediate nonclassical bishomocyclopropenyl cation involved

reaction product in thise case of syn isomer is derived from a rearranged carbocation
ion that is stabilized by virtue of being allylic

Non classical nature of 7-norbornenyl cation

homoallylic carbocation -homoallylic refers to the

position on a carbon skeleton next to an allylic position
very strong interaction between C7, which carries the formal cationic center, and the C2C3 double bond
these three carbons linked together by two electrons: three center-two electron bonding
situation
electrons may be cyclically delocalised making the cation a bishomo analogue of the
aromatic cyclopropenyl cation (bishomoaromatic ring system)
the C2-C3 double bond is longer than a typical double bond, because
electron density has been removed from the C2-C3 bonding region and delivered to C7

Non classical nature of 7-norbornenyl cation was contested by H C Brown

Refer bernard miller

Homoaromaticity refers to a special case of aromaticity in which conjugation

is interrupted by a single sp3 hybridized carbon atom
3-bicyclo[3.1.0]hexyl cation--tris-homocyclopropenyl cation

As in an aromatic cyclopropenyl cation, positive

charge is delocalised over three equivalent
carbons containing two electrons.
Only that this conjugation is interrupted by
three -CH2 groups
It is tris-homo counterpart to the cyclopropenyl
cation

Neighboring group participates only when there is sufficient demand for it

Participation by a potential neighboring group can be reduced or eliminated
if an outside nucleophile is present that is more effective than the neighboring group in
attacking the central carbon, or
if a sufficiently good leaving group is present,or
if the stability of the potential carbocation is increased
Presence of a p-anisyl group at the 7 position exerts a powerful leveling effect on the
rate difference

High solvolysis rate

solvolysis in acetone water at 85oC
of norbornadienyl derivative
was only 2.5 times faster than
that of the saturated analogue

Both the norbornadienyl derivatives give

the same mixture of solvolysis products,
i.e., stereoselectivity is not present

stabilization by the p-anisyl group is so great that further stabilization that would come
from participation by the C=C bond is not needed

Ability of C=C to serve as a neighboring group can depend on its electron density

Two CF3 groups completely remove the ability of the C=C bond to act as a neighboring
group, solvolysis rate was about the same as (actually 17 times slower than) the rate for
the saturated substrate

How about the solvolysis rate of 7-chloronorbornadiene compared to

anti-7-chloronorbornene??

Reacts about 750 times faster than anti-7-chloronorbornene in acetic

acid solution
Do the double bonds participate as shown below?

Studies show that the orbital at C7 interacts with only one double bond at a time.
Activation energy of around 19.5 kcal/mol is required to flip the C7 bridge from
interaction with one double bond to interact with the other.
Then why the higher rate??

Aromatic rings fused to anti-7-norbornenyl rings participating in the displacement of

groups at C7

But degree of participation is

much smaller than that by a
double bond

Cycloheptatrienyl cations also acts as neighboring groups in the 7-norbornyl system

-(syn-7-norbornenyl)ethyl brosylate at 25o C

undergoes acetolysis 140,000 times faster than the
saturated analog

Participation of carbon-carbon double bonds in solvolysis reactions is revealed

in some cases by isolation of products with new carbon-carbon bond
solvolysis of 2-cyclopent-3-enylethyl tosylate
formation of the bicyclo[2.2.1]heptane ring

norbornyl cation

CarbonCarbon Single Bond as a Neighboring Group

2-Norbornyl System

exo-2-norbornyl brosylate

solvolysis in acetic acid of optically active exo-2-norbornyl brosylate gave a racemic

mixture of the two exo acetates; no endo products formed

endo-2-norbornyl brosylate solvolyzed 350 times slower than the exo isomer

1,6 bond assists in the departure of the leaving group

a nonclassical intermediate is involved

nonclassical
Intermediate
1 and 2 positions are equivalent
attacked by the nucleophile with equal facility

solvolysis of the endo Isomer is not assisted by the 1,6 bond because it is not in a
favorable position for backside attack

Acetolysis of the endo isomer also leads exclusively to the exo acetates!

A Classical ion first formed

and then converted to the more stable
Nonclassical intermediate
Support??product is not racemic but contains somewhat more B than A (corresponding
to 313% inversion,depending on the solvent), suggesting that some of the classical ion ,
gives B before it can collapse to the nonclassical intermediate

solvolysis of exo-2-chloronorbornane (rate five times that of cyclopentyl chloride

And 500 times that of endo-2-chloronorbornane)
Only exo products are obtained
the product is racemic, suggesting an intermediate with a plane of symmetry

the endo face of the bicyclic system is protected by the bonding geometry of the
intermediate carbocation

concepts of participation and the nonclassical intermediate challenged? (H.C. Brown)

The experimental observations could alternatively be explained by invoking
two classical carbocations rapidly equilibrating as shown below for endo-brosylate,
that would give the same racemic products

Present only as aTS, not as intermediate?

stereochemical outcome due to an exclusive exo attack to be expected from any 2norbornyl system not only for the cation but even for reactions not involving cations,
because of steric hindrance to attack from the endo side?
the high exo/endo rate ratios because the exo rate that is normal and the endo rate
abnormally low, because of steric hindrance to removal of the leaving
group in that direction

hydride shjfts of the norbornyl cation

hydride shifts alone cannot explain the products found from the solvolysis of
2-norbornyl systems
predicted carbon label positions are not in the same positions as experimentally
observed

the conventional Wagner-Meerwein carbon shift as proposed by Brown

would give racemic products with the label in the correct positions
If the hydride shifts and carbon shift are all facile, all the carbons and all the hydrogens
of 2-norbornyl cation will become equivalent.
Infact, both the 1H and 13C NMR spectra show only one line at room temperature in
stable ion media.

Studies that support the bridged non-classical structure

gas phase hydride ion affinity (HIA)
kcal/ mol

kcal/ mol

typical HIA 2 I 3 energy difference is 17 kcal I mol.

The substantially smaller value in this case indicates a special stabilization of this 2 ion
X ray studies :Geometry of methylnorbornyl cation
substantial lengthening of the C1-C6 bond and
shortening of C1-C2 bond
lower temperatures solution NMR of 2-norbornyl ion in stable ion media(temperatures
below -150oC in SbF5 - SO2 and FSO3HSbF5 - SO2) where hydride shifts are absent
shows equivalence of C1 and C2 ---- stable structure is the symmetrical
bridged ion, or the barrier to the reaction so small
solid state NMR spectrum of 2-norbornyl cation taken at 5 K----- the system still appears
to be a single, symmetrical ion.
Donation of filled orbitals to empty orbitals is always stabilizing, and when the filled
orbitals are aligned with the empty p orbital of a carbocation, this donation can and
will occur.

The Cyclopropylmethyl (cyclopropylcarbinyl )System

cyclopropylmethyl substrates solvolyze with abnormally high rates
products often a mixture of unrearranged cyclopropylmethyl, cyclobutyl and
homoallylic compounds

solvolysis of cyclopropylcarbinyl tosylate is approximately 106 times faster than that of

isobutyl tosylate

Cyclobutyl and certain homoallyl substrates also solvolyze abnormally rapidly and give
similar products. (all undergo solvolysis faster than analogous structures)
Reactions carried out with labeled substrates showed considerable scrambling into all
of the carbons of all three products.

an intermediate where many of

the carbons become equivalent?

key carbocationic intermediates that could be involved in these solvolysis reactions

Conventional carbonium ions as

But a common intermediate present in these cases?

the less conventional bicyclobutonium ion??

This common intermediate could

then be obtained by three routes

The CH2+can "lean" to the left

or to the right
Two different bicyclobutoniums can form
The interconversion of the two bicyclobutonium ions places partial positive charge
on each carbon of the cyclopropane ring.

Bicyclobutonium from the homoallyl cation

Special stability of cyclopropylmethyl cations (more stable than the benzyl cations)
explaines as due to conjugation between the bent orbitals of the cyclopropyl rings
and the vacant p orbital of the cationic carbon that lies parallel to the C-2,C-3
bond of the cyclopropane ring and not perpendicular to it

parallel

Substantial p character in the bonding orbitals

of the ring.
The C -C bonding MOs do not lie along the line
connecting carbons of the ring, instead bulge
out and away from the ring.
The electrons in these cyclopropane C-C bonds
are higher in energy than in standard alkanes
(the ring is strained).
These orbitals interact with an empty p orbital

Cyclopropyl as a Neighboring Group

endo-anti-tricyclooctan-8-yl p-nitrobenzoate
solvolyzed ~1014 times faster than

Need for a suitably placed cyclopropyl ring

solvolyzed only about five times

faster than

solvolyzed three times slower than

Methyl as a Neighboring Group

Can a C-C bond lend anchimeric assistance even in a simple open-chain compound?
On solvolysis, neopentyl systems undergo almost exclusive rearrangement

Is the departure of the leaving group concerted with the formation of the CH3 C bond?
Does the methyl participate?
Support from isotope effect studies, that indicates that the methyl group in the
neopentyl system does indeed participate although it may not greatly enhance the rate
Is

an intermediate or only a transition state?

small amounts of cyclopropanes (1015%) can be isolated

Hydrogen as a Neighboring Group

Does the hydrogen participate in the departure of the leaving group?

Is

an intermediate or only a transition state?

solvolysis of deuterated sec-butyl tosylate in trifluoroacetic acid

Product an equimolar mixture of 1 & 2, but no 3 & 4 formed
If reaction did not involve
neighboring hydrogen at
all (pure SN2 or SN1), the
product would be only 1

if hydrogen does migrate, but only open cations are involved all four products possible

Effect of Substrate Structure on SN reactions

Branching at the and Carbons
Effect on SN2 ----- crowded transition statedecreased rate
Average Relative SN2 Rates for Some Alkyl Substrates

transition state is more crowded when

larger groups are close to the central carbon

Branching at the Carbons

Effect on SN1---increases the rate for SN1
stability order of alkyl cations (tertiary>secondary>primary)

branching
B strain (back strain) relieved by ionization to the carbocation
the rate smoothly rises with the increasing number of ethyl
groups,but increase in rate is relatively small, and caused
by normal field and resonance (hyperconjugation) effects.
Substitution with the second isopropyl group the crowding
is great enough to cause B strain, and the rate is increased
10-fold.
Except where B strain is involved, branching has little
effect on the SN1 mechanism, except that carbocations
with branching undergo rearrangements readily.

2-adamantyl system is a secondary system that reacts by the SN1 mechanism

because backside attack is hindered for steric reasons

a methyl group at the 2- position increases solvolysis rates by a factor of ~ 108

SN1 mechanism is important under all conditions only for tertiary substrates.
Wherever a hydrogen is present, elimination becomes a dominant reaction with tertiary
substrates.
Secondary substrates generally react by the SN2 mechanism, but SN1 mechanism may
become important at high solvent polarities
Simple primary substrates react by the SN2 mechanism even when solvolyzed in solvents
of very low nucleophilicity ( CF3 COOH, CF3 CCH2OH) even with very good leaving groups
(e.g., OSO2F)

Unsaturation at the Carbon

HRC

CHX

RC CX

Very unreactive toward nucleophilic substitutions

Electronegativity of carbons follow the order sp > sp2 > sp3
Simple SN2 mechanism has never been convincingly demonstrated for vinylic substrates
Vinylic substrates can be made to undergo SN1 reactions (even then rates are generally low
compared to saturated compounds)
a) when substituents that stabilize the cation are present as in -aryl vinylic halides
or RCBr=CR2 ,where R = cyclopropyl, vinylic, alkynyl
or R2C= C =CRX
b) even without a stabilization, by the use of a very good leaving group, OSO2CF3 triflate)
vinylic cations are linear
empty p orbital lies in the plane of the double bond
a cis or a trans substrate often gives a 1:1 mixture of cis and trans products,
reactivity in cycloalkenyl systems decreases with decreasing ring size
the relative size of R1 and R2 can influence the entry of nucleophile giving
preference of one product over the other

Unsaturation at the Carbon.

double bond in the position
The SN1 rates are increased when there is a double bond in the position
allylic and benzylic substrates react rapidly
Relative Rates for the SN1 Reaction between ROTs and Ethanol at 25oC
SN1 rates at an allylic substrate are increased by
any substituent in the 1 or 3 position that can
further stabilize the carbocation by resonance or
hyperconjugation, like alkyl, aryl, and halo groups.

triple bonds in the position (in propargyl systems)

have about the same effect of rate enhancement as double bonds

Unsaturation at the Carbon.

double bond in the position
SN2 rates for allylic and benzylic systems are increased by double bond in the position
probably owing to resonance possibilities in the transition state
rate of this reaction was 8000 times
slower than the rate of (PhCH2)2SEt+
It does not have the proper
geometry for conjugation in the
transition state.

Alkyl, aryl, halo, and cyano groups,in the 3 position of allylic substrates increase SN2 rates,
due to increased resonance in the transition state.
but alkyl and halo groups in the 1 position decrease the rates because of steric hindrance.

 Substituents

Compounds of the formula ZCH2X, where Z has unshared pair of electrons (as in Z = RO,
RS, orR2N) undergo SN1 reactions very rapidly because of the increased resonance in the
carbocation. resonance effect dominate field effects for these groups
When Z in ZCH2X is RCO, HCO, ROCO, NH2CO, NC, or F3C, SN1 rates are
decreased compared to CH3X due to the electron-withdrawing field
effects of these groups
the partial positive charge on the adjacent carbon destabilizes the
carbocation

In solvolysis of these molecules

C=O group exhibits a
retardation effect of 107.3

Resonance stabilization may offset

the inductive destabilization
making the rate retarding effect negligible
in cases

When Z is SOR or SO2R SN1 is retarded by the electron-withdrawing effect of the SOR
or SO2R group,
and the SN2 mechanism is retarded presumably by the steric effect.

 Substituents
SN1 rates are generally lower for compounds of the type ZCH2CH2X, than for
unsubstituted systems, because the resonance effects are absent, but the field effects
are still there, although smaller, unless they behave as neighboring groups and enhance
the rate
Substitution do not have much effect on SN2 rates unless they behave as neighboring
groups and enhance the rate or unless their size causes the rates to decrease for
steric reasons.

The SNi Mechanism

(substitution nucleophilic internal)

D N + AND e

alkyl chlorosulfites forms in a second order reaction

then dissociate into an intimate ion pair
part of the leaving group attacks, from the front as it is unable to get to the rear

nucleophilic substitution proceeds with retention of configuration

Evidence for the mechanism:
the addition of pyridine to the mixture of alcohol and thionyl chloride results in the
formation of alkyl halide with inverted configuration.
pyridine reacts with ROSOCl to give ROSONC5H5. The Cl freed attacks from the rear
decomposition of ROCOCl (alkyl chloroformates) into RCl and CO2 also follows SNi
mechanism

Nucleophilic Substitution at an Allylic Carbon: Allylic Rearrangements

under SN1 conditions (

Mechanism) 1/DN+3/AN

Free carbocation ?? Or Ion pair?

Exhibits product spread in the direction of starting compound.

product spread decreases with increasing polarity of solvent, stabilising the free carbocation

Why the product spread?

Formation of an unsymmetrical intimate ion pair in the first step (different for
different starting compound)
a considerable amount of internal return of this ion pair
the counterion remains close to the carbon from which it departed.
The field of the anion polarizes the allylic cation, making the nearby carbon atom
more electrophilic,it has a greater chance of attracting the nucleophile

on acetolysis gave not only both the acetates, but also

the isomerization was faster than the acetate formation
the rate of formation of the rearranged chloride was unaffected
by the addition of external Cl-

3/1/ANDN
allylic rearrangements can also take place under SN2 conditions,
the nucleophile attacks at the carbon rather than the usual position
Occurrs where SN2 conditions hold but where sterically retarded by the normal SN2
mechanism

Increasing the size of the nucleophile increases the extent of the SN2' reaction at
the expense of the SN2

leaving group can also have an affect on whether the rearrangement occurs

nucleophile to attack at the position instead of the position

2-buten-1-ol and 3-buten-2-ol, both gave 100% allylic rearrangement when treated
with thionyl chloride in ether
Ordinary allylic rearrangements (SN1') or SN2' mechanisms could not be expected to
give 100% rearrangement