Nucleophilic aliphatic substitution

Nucleophile [ Y /Nu ]
electron pair donating reagent
brings an electron pair to the substrate
uses this pair to form the new bond
anions or neutral species but not cations
all nucleophiles are Lewis bases
Leaving group [the nucleofuge, X]
comes away with an electron pair

Electrophiles
electron pair acceptors
contain either a deficiency in the valence electron shell of one of the atoms or
valence-saturated but contain an atom from which a bonding electron pair can be
removed as part of a leaving group
cations or neutral compounds but not anions

Different charge types of nucleophilic substitution

Nucleophilic substitution at an alkyl carbon is alkylation of the nucleophile.

Nucleophilic substitution at an acyl carbon is an acylation of the nucleophile.
When Y/ Nu is the solvent, the reaction is called solvolysis as in

MECHANISMS
limiting mechanisms as defined by Hughes and Ingold
Direct displacement mechanism (SN 2, substitution-nucleophilic-bimolecular)
ANDN is the IUPAC designation indicates that bond breaking is concurrent with
bond formation
Ionization mechanism (SN 1, substitution-nucleophilic-unimolecular)
DN+AN or DN+AN indicating former happens first and RDS
The IUPAC system is based on a very simple description of bond changes.
letter A represents formation of a bond (association)
letter D represents breaking of a bond (dissociation)
The basic description of a mechanism consists of these letters, with subscripts
to indicate where the electrons are going.
subscript is N if a core atom is forming a bond to a nucleophile (AN) or breaking a
bond to a nucleofuge (DN).
The core atoms in any mechanism are defined as
the two atoms in a multiple bond that undergoes addition,
the two atoms that will be in a multiple bond after elimination
the single atom at which substitution takes place.

The SN2 Mechanism

In the TS the central carbon atom has changed hybridization from initial sp3 to sp2
One lobe of the p orbital overlaps with the nucleophile and the other with the leaving
group.
three nonreacting substituents and the central carbon are approximately coplanar
backside attack involves the maximum amount of overlap throughout the course of
the reaction.
follow the second order rate expression
inversion of configuration at the reaction centre--Walden inversion
trans-tosylate A
gives exclusively
the cis-cyclohexyl
acetate B
A molecular orbital viewpoint

strongest initial interaction is between the filled orbital on the

nucleophile and the antibonding orbital of C-X

a front-side approach involve

both a bonding and an
antibonding interaction

Evidence that the transition state in an SN2 reaction must be linear

Given reaction of a methyl(arenesulfonate) intermolecular or intramolecular??

Crossover Experiment to determine whether reactions take place intra- or intermolecularly

Two substrates differing from each other by a double substituent variation are reacted as a
mixture.

Intermolecular Substitution

Linear transition state possible

Reaction coordinate-intermolecular

Intramolecular Substitution

Bent transition state enforced

Reaction coordinate-intramolecular

Cyclic six-membered transition state is not favored here at all!!!!

In an SN2 reaction the approach path of the nucleophile must be collinear with the bond
between the attacked C atom and the leaving group

Other evidences for SN2 Mechanism

Reaction between optically active 2-octyl iodide and radioactive iodide ion

Rate of inversion was found to be identical with the rate of uptake of radioactive *I
If started with the pure R isomer, at first each exchange will produce an S isomer
Then with increasing concentration of S isomer, it will compete for I
At the end a racemic mixture is left.
Rate of racemization, was measured which is twice the rate of inversion
Unsuccessful reaction attempts at bridgeheads under SN2 conditions

1-bromo-8,8-dimethylbicyclo [2.2.2]octane

1 - bromobicyclo- [3.3.1]nonan-9-one

Difficulty in approach from the rear for the nucleophile

The effect of solvent /medium on SN 2 reaction

Depends on the charge type of the reaction

Solvent chosen for a given reaction has a strong influence on the course of that reaction.
Protic/aprotic solvents as well as polar/nonpolar solvents can have effects ranging from
solubility to solvent assisted ionization or stabilization of transition states.

Energy profile for SN2 reactions

Polar Versus Nonpolar solvents

Only type II SN 2 reactions, where the both the reactants are uncharged, but the
transition state has developed a charge, is aided by polar solvents
In types I and IV, an initial charge is dispersed in the transition state, so the reaction is
hindered by polar solvents.
In type III, initial charges are decreased in the transition state, so that the reaction
is even more hindered by polar solvents.

Some examples of polar aprotic solvents

Protic Versus Aprotic solvents in SN 2 reactions
For reactions of types I and III ,
dimethylformamide
where the nucleophile is anionic,
(DMF)
TS is more solvated in polar aprotic solvents
than in protic ones,
dimethylacetamide
whereas the charged nucleophile
(DMAC)
is less solvated in aprotic solvents
Small anions are solvated best in protic solvents
dimethyl sulfoxide
large anions are solvated best in aprotic solvents
(DMSO)
Protic solvents have highly developed
structures held together by hydrogen bonds
hexamethylphosphoramide
Aprotic solvents have much looser structures,
(HMPA)
hence easier for a large anion to be fitted in
So the rate of attack by small anions is
propylene carbonate
most greatly increased by the change from
a protic to an aprotic solvent
N-methyl-2-pyrrolidone
Relative rates at 25oC for the reaction between MeI
(NMP)
and Cl are
MeOH - 1 (55.5) HCONH2 (protic but a weaker
acetone, nitromethane,
acid)-12.5 (56.6) HCONHMe - 45.3
nitrobenzene, acetonitrile (CH3CN),
HCONMe2- 1.2 106 (43.8)
benzonitrile

The SN1 Mechanism

substitution, nucleophilic, unimolecular
Ionization is always assisted by solvent
energy necessary to break the bond is largely
recovered by solvation of R+ and of X-

Ionization of t-BuCl to t-Bu+ and Cl

in the gas phase requires
150 kcal mol-1.
In water, this ionization
requires only 20 kcal mol-1

protic solvent pulls the leaving group away

from front side in limiting SN1

Neutral substrates
Polar solvents increase the rate by stabilization of TS

When the substrate is positively charged, the charge is

more spread out in the TS than in the starting ion
Stabilization of T.S is less than for the more polar
reactant.
Polar solvents decrease the rate

Relative Rates of Ionization of p-Methoxyneophyl Toluenesulfonate

list of solvents in order of ionizing power

Trifluoroacetic acid has even greater ionizing

power than any solvent listed in the table
It has very low nucleophilicity and is an excellent
solvent for SN1 solvolyses
Other good solvents for this purpose are
1,1,1-trifluoroethanol CF3CH2OH,
1,1,1,3,3,3-hexafluoro-2-propanol, (F3C)2CHOH

Aspects of kinetics of SN 1 reactions

Pure first-order kinetics may not be followed in SN 1 always!!
If the first step is reversible the X formed in this step competes with Y for the cation.

In the beginning of the reaction, when the concentration of X is very small,

k-1[X ] is negligible and rate equation reduces to
In the later stages of SN1 solvolyses, [X-] becomes large, rate should decrease according to the
above equation .
Solvolysis of diphenylmethyl halides in aqueous acetone follows the above complex kinetics
But tert-butyl halides follow

for entire reaction

diphenylmethyl halides Versus tert-butyl halides What is different about the kinetics??
diphenylmethyl cations more stable than tert-butylcations
tert-butylcations are less selective than diphenylmethy cation
more water available since it is the solvent
halide ion is a much more powerful nucleophile than water
less selective tert-butyl ion does not wait for a reactive but relatively rare halide
ion and combines with the solvent
selective diphenylmethyl cation survives many collisions with solvent molecules
before combining with a reactive halide

How will the rate be affected if some halide is added to the system??
the rate for diphenylmethyl solvolysis decreases by the addition of halide ions
but not the rate for tert-butylhalides.
Common ion effect !!!
retardation of rate by addition of X (leaving ion)

Salt effect?
increase in ionic strength of the solution usually increases the rate of an SN1 reaction
For SN1 reaction of charge type II, where both Y and RX are neutral the ionic
strength increases as the reaction proceeds and this increases the rate.
Fact that addition of outside ions increases the rate of most SN1 reactions makes the
common ion effect especially impressive.

How to tell a pseudo first order SN2 reaction from an an ordinary SN1 reaction?
Common ion effect could be of help.in cases where it works.
Addition of a common ion will not markedly affect the rate of an SN2 reaction beyond the
effect caused by other ions.

SN1 reactions at bridgehead positions??

Difficulty in assuming the planarity required for the cationic center
[2.2.1] (1-norbornyl) systems like this molecule gave no reaction even after
boiling for 48 hrs with aqueous ethanolic silver nitrate, or for 21 hrs with
30% KOH in 80% ethanol although analogous open-chain systems reacted
readily in these conditions
SN1 reactions should be possible with larger rings, if near-planar carbocations could
be formed

[2.2.2] bicyclic systems undergo SN1 reactions much faster than smaller bicyclic
systems, although the reaction is still slower than with open-chain systems.

Ion Pairs in the SN1 Mechanism (Saul Winstein)

many first-order substitutions do give complete racemizationa planar carbocation
But many do not, and give 520% inverted products.

intimate,
contact, or
tight ion pair

loose, or
solvent-separated
ion pair

dissociated ions

a diagram of all the

possibilities for solvolysis
reactions in a solvent SH
it is unlikely
that all these reactions
occur
in any particular case
In internal return the intimate ion pair recombines to give the original substrate

Other evidences for the intervention of ion pairs

Solvolysis of 2-octyl brosylate labeled at the sulfone oxygen with 18O
unreacted brosylate recovered at various stages of solvolysis had considerable 18O scrambling

In an intimate ion pair, the three oxygens become equivalent

The step leading to the scrambling of labeling could be happening at another stage ???
Solvolyzing unlabeled substrate in the presence of labeled HOSO2Ar, showed, though
there is some amount of intermolecular exchange(which cannot be explained by
return at intimate ion pair stage) not enough to account for the extent of scrambling
in the original experiment

Other evidences for the intervention of ion pairs

Special salt effect
The addition of LiClO4 or LiBr in the acetolysis of certain tosylates produced an initial
steep rate acceleration and then decreased to the normal linear acceleration (caused by
the ordinary salt effect).
the ClO4 (or Br ) traps the solvent separated ion pair to give
Which is unstable and goes to product.
Hence, the amount of solvent-separated ion pair that would have returned to the starting
material is reduced, and the rate of the overall reaction is increased.
Partial retention (2050%) of configuration in certain SN1 reactions !!!
Ion pairs have been invoked to explain some of these.
For example, phenolysis of optically active -phenylethyl chloride
Product ether is of net retained configuration.

Mixed SN1 and SN2 Mechanisms

Cases that cannot be characterized easily into pure SN1 or SN2
some intermediate mechanism? a mechanistic borderline region?
or resulting from simultaneous SN1 and SN2 mechanisms??
i)a) intermediate-mechanism theory- neither pure SN1 nor pure SN2
A formulation by Sneen- Ion Pair Mechanism- applies to all nucleophilic substitutions
according to which

in SN1 formation of the ion pair (k1) is rate determining

In SN2 destruction of ion pair (k2) is rate determining
Borderline behavior when the rates of formation and destruction of the ion pair are of
the same order of magnitude.
b) SN2(intermediate) mechanism- Schleyer
Varying degrees of nucleophilic solvent assistance to ion-pair formation

II) borderline behavior resulting from simultaneous SN1 and SN2 mechanisms
Hydrolysis of 4-methoxybenzyl chloride in 70% aqueous acetone
MeO

CH2Cl

70% aq.acetone

MeO

CH2OH
SN1 path

MeO

CH2Cl

70% aq.acetone

MeO

CH2OH + MeO

CH2N3

azide ions

In presence of azide ions

Rate of ionization increases .. the salt effect
Rate of hydrolysis decreases rate of formation of alcohol product decreases..
.. some azide must be formed by SN1 process
Rate of ionization was found to be less than the total rate of reaction
Some azide must also form by an SN2 mechanism

A nucleophilic substitution reaction that seem to involve a borderline mechanism,

but do not
Hydrolysis of optically active 2-octyl brosylate
in 75% aqueous dioxane, gave inverted 2octanol in 77% optical purity.

In presence of sodium azide, 2-octyl azide

and 2-octanol formed, 2-octanol 100%
inverted.

Was 2-octanol produced by two different processes??

an SN2 reaction leading to inverted product,
and another process (SN1) with an intermediate that leads to partial racemization or
retention?
Did azide ions scavenge this intermediate, while the SN2 process went on to give inverted 2octanol?
Arguments against (SN1) process, simultaneously operating in this reaction.
For 2-octyl brosylate or 2-octyl methanesulfonate SN2 mechanism operates in more polar
solvents water or methanol
Solvolysis of 2-RBs in pure methanol gave methyl 2-octyl ether with 100% inversion of
configuration
Solvolysis of 2-RMs in pure water gave 2-octanol, 100% inversion of configuration
Hence unlikely that any SN1 process could occur in 75% aqueous dioxane.

Solvent [NaN3 ], 2%
M
octanol,%
Dioxane
yield

Optical
Purity of 2octanol,%
(inverted)

75

---

100

77

75

0.0126

73

76

75

0.03

35

100

75

0.06

22

100

50

---

100

88

50

0.03

75

75

50

0.09

48

96

25

---

100

95

25

0.03

83

96

25

0.04

78

97

water

---

---

100

water

0.1

---

98

But the following scheme accomodates the inversion of configuration observed for
the azide product. An intimate ion pair is involved.
In absence of azide some part of reaction go by the dioxane attacking the ion pair,
which then goes on to give the alcohol with retention of configuration.

A reaction that is reported to be proceeding by a simultaneous, independent SN1 and SN2

pathway
Br
Me
MeO

CH2Br

Me2N

MeO

N
C
H2
Me

Menschutkin reaction of benzylic systems with aromatic tertiary amines

plots of the pseudo-first order rate constants, kobs Vs
concentrations of nucleophiles in non-solvolyzing solvent,
acetonitrile at 50oC
Slope of the linear parts of these plots gave the secondorder rate constants, k2.
k2 increases with increasing nucleophilicity of Zsubstituted N,N-dimethylanilines as
in the order Z = p-Me > H > p-Br > m-NO2.
The kinetic equation can be seen as the sum of zero and
first-order terms in nucleophile concenteration

Conc. of (Z)-substituted
N,N-dimethyl anilines

Menschutkin reaction of N,N-dimethylanilines

with benzyl bromides less activated than pmethoxybenzyl bromide proceeds entirely by a secondorderprocess (SN2 reaction)

Mechanism corresponding to these observations can be expressed by the scheme given below

Percentage (%) contribution of SN1 process is given by

SN1 ratio increased for the weaker nucleophile

k1 values are independent of the
nucleophilicity
k2 values, are dependent on nucleophilicity

Nucleophiles in SN reactions
Nucleophilicity is the measure of the ability of the nucleophile to make an electron
pair available to the electrophile.
Factors that influence nucleophilicity
solvation energy of the nucleophile
strength of the bond being formed to carbon
electronegativity of the attacking atom
polarizability of the attacking atom
steric bulk of the nucleophile
The relative nucleophilicity of a given nucleophile is a combination of effects of substrate,
solvent, leaving group, hence may be different towards different reactants.
No absolute scale of nucleophilicity.

SwainScott equation :
nucleophilic constant (n)

Empirical measures of nucleophilicity obtained by

comparing relative rates of reaction of a standard
reactant with various nucleophiles

Trends in nucleophilicity
When attacking atom is same
nucleophilicity parallels basicity
decreases going across a row in the
periodic table.
determined by electro negativity and polarizability
increases going down the periodic table
Decrease in electronegativity
greater polarizability
weaker solvation
methanolysis of methyl iodide as the
standard reaction

Alpha effect (-effect )

Enhancement in nucleophilicity when an atom containing one or more unshared
pairs is adjacent to the attacking atom on the nucleophile.

Reason for -effect could be

ground state of the nucleophile is destabilized by repulsion between the adjacent pairs
of electrons
the transition state is stabilized by the extra pair of electrons
adjacent electron pair reduces solvation of the nucleophile
Evidence supporting the third explanation is that there was no alpha effect in the reaction
of HO2 with methyl formate in the gas phase HO2 shows a strong alpha effect in solution.

Effect of Solvation on Nucleophilicity

Relative reactivity order in MeOH
Reactivity order is dominated by solvation in MeOH
N3 and I ions are weakly solvated
The iodide ion is large and very polarizable, anionic charge on the azide ion is
dispersed by delocalization.
Relative reactivity order in DMSO

the effect of solvation is diminished in DMSO, the strength of the bond being formed
now plays a major role.
Enhanced Nucleophilicity in Polar Aprotic Solvents
Anion is more free and cation counterparts such as K+ and Na+ are strongly solvated by
polar aprotic solvents such as DMSO and DMF

When added to nonpolar solvents, the crown ethers increase the solubility of ionic
materials

Macrocyclic polyethers that specifically solvate cations such as Na+ and K+ and
enhance solubility and reactivity.
The complexed cation as it is surrounded by the nonpolar crown ether, gains high
solubility in the nonpolar media.
To maintain electroneutrality the anion is also transported into the solvent.

In the absence of crown ether, potassium fluoride is insoluble in benzene and

unreactive toward alkyl halides.

The Effect of the Leaving Group

Relative Solvolysis Rates of 1-Phenylethyl Esters and Halides in 80% aqueous ethanol at
75o C

The reactivity of the leaving groups generally parallels their electron-accepting capacity.
Sulfonate esters are very useful reactants in nucleophilic substitution
reactions in synthesis. They have a high level of reactivity and can be prepared from
alcohols

the limiting SN 1 and SN 2 mechanisms differ in their sensitivity to the nature of the
leaving group.
SN 1 mechanism should exhibit a greater dependence on leaving-group ability because it
requires cleavage of the bond to the leaving group without assistance by the
nucleophile.
Tosylate/Bromide Rate Ratios for Solvolysis of RX in 80% Ethanol

Relative Reactivity of Leaving Groups in SN2 Substitution Reactions

Bimolecular rate constants at 25 oC

Leaving-group effects are diminished in SN 2 reactions, because the nucleophile

assists in bond breaking
In the aprotic dipolar solvent DMF, the leaving-group order is I >Br >O3SCH3 for both
azide and thiocyanate anions.

Distortion of halide leaving group order in reaction of 4-tert-butylbenzyl (4-t-BuBn) halides

with macrocyclic amine 1

binding pocket in macrocycle 1 accelerates the reaction and distorts the halide
leaving group order

Increased transition-state stabilization due to hydrogen bonding in the

macrocyclic pocket