Questions for home study and tutorial discussion:
(1) How does the nature of the leaving-group affect SN2 reactions?
(2) How does the nature of the solvent affect SN2 reactions?
(3) How does the nature of the leaving-group affect SN1 reactions?
(4) How does the nature of the solvent affect SN1 reactions?
Revising SN2 Substitution Reactions:
As the nucleophile approaches the
reaction centre its own excess
H
Nu-:
C
Ph
X
sp3
CH3
sp2
H
Nu
X
C
Ph
CH3
sp3
H
Nu
C
Ph
CH3
+ X-
electron density repels the electrons
in the bonds at the central carbon
forcing them back in the direction
of the departing leaving group.
In the transition state the
hybridisation at carbon has now
changed from tetrahedral sp3 to
planar sp2 with both the
nucleophile and the leaving group
sharing an unhybridised p orbital.
As the nucleophile moves even closer to
the reaction centre - and the leaving
group simultaneously moves off - the
sp2 transition state collapses to sp3 again
in the direction of the departing leaving
group so that the substitution product
forms with inverted configuration at
carbon.
Rate = k x [RX] x [Nucleophile]
SN2 substitutions are inhibited by steric crowding at the reacting carbon
Reactivity CH3X > 1° RX >> 2° RX >>> 3° RX
(1) How does the nature of the leaving-group affect SN2 reactions?
H
C6 H 5
C
Br + Nu-
CH3
H
Desirable
?
Not
Desirable
CH3
C
Nu
+ Br-
C6H5
For an SN2 reaction to give the maximum yield of product the leaving
group should be a much poorer nucleophile than the incoming (i.e.
attacking) nucleophile - otherwise the substitution reaction would tend
to go backwards leading to an equilibrium between starting material and
substitution product.
Good nucleophiles are usually also strong bases, hence poor
nucleophiles are usually weak bases.
Therefore good leaving groups (i.e. poor nucleophiles) will usually be
weak bases i.e. the anions of strong acids.
Conversely poor leaving groups (i.e. good nucleophiles) will usually be
strong bases i.e. the anions of weak acids:
HOH N-
Cl-
Br-
I-
TsO-
1 x 104
3 x 104
6 x 104
2
CH3O<< 1
Poor
2 x 102
Good
Reactivity as leaving group
Anion of strong acid = Good leaving group
Acidity:
H2O > HCl > HBr > HI > TsOH
Leaving group ability: OH– < Cl– <
Br– <
I– <
TsO–
TsO- = p-toluenesulphonate = tosylate anion =
O
S
CH3
-
O
O
O
CH3
S
OH
toluenesulphonic = tosic acid
O
Ts = toluenesulphonyl = tosyl
(2) How does the nature of the solvent affect SN2 reactions?
The nucleophile in an SN2 reaction is very commonly the anion of an
ionic reactant - e.g. CN- from NaCN or OH- from KOH.
Ionic
compounds are insoluble in non-polar solvents such as alkanes, ethers
or benzene. These solvents are not suitable for SN2 reactions which are
usually carried out in polar solvents which dissolve the ionic reactant.
The effect of solvent on an SN2 reaction depends on whether the solvent
is a protic polar solvent or an aprotic polar solvent.
Protic polar solvents - solvents having protons attached to
electronegative atoms like oxygen or nitrogen, e.g. water, alcohols or
amines - inhibit SN2 reactions of ionic nucleophiles:
- OR
+ H
RO
H
Nu
H
Solvation of an anionic
H OR
nucleophile by hydrogen
bonding with a protic
solvent.
OR
The nucleophile is stabilised - i.e. made less reactive - by solvation.
The attached solvent molecules also make it more difficult for the
nucleophile to approach the electrophile and this also inhibits SN2
reactivity.
In contrast aprotic polar solvents - polar solvents without OH or NH
groups - increase the reactivity of ionic nucleophiles and enhance the
SN2 reaction. Among such solvents are:
Acetonitrile, Me-CN:
O
N,N-Dimethylformamide (DMF), Me2 NCHO, H
C
NMe2
and -
Dimethylsulphoxide (DMSO), Me2SO, Me2S
O
These solvents enhance SN2 reactions. Firstly the lack of acidic protons
means no unhelpful solvation of the nucleophile.
Secondly, the electron rich nitrogen (MeCN) or oxygen (HCONMe2 or
Me2SO) atoms solvate the cation of ionic nucleophiles. As a result
anion-cation interactions are removed and the reactivity of the anion is
increased.
M
+ Nu-
Cation/nucleophile
ion pair
S
S
+ S
M
Nu
S
S
S
Cation solvated by aprotic
solvent with more reactive
'bare' anionic nucleophile
Revising SN1 Substitution Reactions:
H
+
Slow
C
Ph
H
Br
C
RDS
CH3
Ph
+ Br
-
CH3
Planar
sp2 hybridised
CARBOCATION
(R)-1-Bromo-1phenylethane
N
H
Ph
C
_
_
C
H
+
CN
CH3
(R)-1-Cyano-1phenylethane
C
C
Ph
N
H
NC
C
CH3
RACEMISATION
50%
CH3
(S)-1-Cyano-1phenylethane
50%
Rate = k x [RX]
Ph
(3) How does the nature of the leaving-group affect SN1 reactions?
Slow
(CH3 )3C
X
Rate-determining
step.
+
(CH3)3 C + X
Rapid Nu-
(CH3 )3C
CARBOCATION
intermediate
Nu
As the departure of the leaving group is involved in the RDS of SN1
substitution then the reaction will be enhanced by good leaving groups
and inhibited by poor leaving groups. As with SN2 reactions:
Good leaving groups (i.e. poor nucleophiles) will be weak bases i.e. the
anions of strong acids.
Poor leaving groups (i.e. good nucleophiles) will be strong bases i.e. the
anions of weak acids.
See Question (1) above for more details and some examples of good and poor - leaving groups.
(4) How does the nature of the solvent affect SN1 reactions?
Slow
(CH3 )3C
+
(CH3)3 C + X
X
Rate-determining
step.
Rapid Nu-
(CH3 )3C
CARBOCATION
intermediate
Nu
Since the RDS of the SN1 reactions produces two ions a solvent which
can stabilise those ions will facilitate the reaction. Polar solvents - both
protic and aprotic can do this - the negative end of the solvent dipole
solvating and stabilising the carbocation (the most important effect)
and the positive end doing the same for the anionic leaving-group:
+
H
:
O
+
+
+
X
+
+
+
+
+
+
R
+
:
H
Comparison of SN1 and SN2 substitution reactions:
Variable
Substrate structure:
Methyl or 1°
Secondary
Tertiary
Stereochemistry
Nucleophile
Leaving group
Solvent
SN1
SN2
Does not occur except for 1° allyl and
1° benzyl - methyl or
1° carbocations are
insufficiently stable.
Yes - but mainly for
allylic and benzylic
systems
Common - minimal
steric hindrance to
the rearward
approach of
nucleophile
Yes - unless substrate
is very sterically
crowded.
Common - highly
stabilised tertiary
carbocations
Does not occur - too
much steric
hindrance
to rearward approach
by nucleophile
Racemisation
Inversion
Rate independent of
Rate dependent on
concentration and
concentration and
nature of the nucleo- nature of the nucleophile since the latter is phile since the latter
not involved in the
is involved in the
RDS.
RDS- anionic nucleophiles especially
favour SN2
Reaction favoured by As for SN1 reaction
good leaving groups anions of strong acids
Favoured by polar
Favoured by aprotic
solvents and inhibited polar solvents,
by non-polar solvents. inhibited by protic
polar solvents.