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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
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.
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
Intermolecular Substitution
Intramolecular Substitution
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
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.
Neutral substrates
Polar solvents increase the rate by stabilization of TS
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.
[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.
intimate,
contact, or
tight ion pair
loose, or
solvent-separated
ion pair
dissociated ions
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
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
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.
CH2Br
Me2N
MeO
N
C
H2
Me
Conc. of (Z)-substituted
N,N-dimethyl anilines
Mechanism corresponding to these observations can be expressed by the scheme given below
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)
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
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.
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
binding pocket in macrocycle 1 accelerates the reaction and distorts the halide
leaving group order