NUCLEOPHILIC SUBSTITUTION, THE CARBON-CARBON

DOUBLE BOND AND THE CHEMISTRY OF ALKENES

Text references: McMrr! "#t$ E%&t&'n( C$)*ters +, , )n% --.
S'/e I/*'rt)nt Def&n&t&'ns:
BASE: Any species that can 'accept' (i.e. form a bond with) a proton.
Since a proton has no electrons the base must be able to provide both
electrons for the proton-base bond. Therefore the atom in the base
which acts as the actual basic site must bear a 0'ne *)&r of electrons.
The ease with which a base accepts a proton is referred to as its basicity.
B
+ H
+
:
B
:
H
[ ]
+
NUCLEOPHILE: ('nucleus-loving') an electron-rich species with a
tendency to 'attack' (i.e. donate an electron pair to) an electron-poor site
in another molecule (called an ELECTROPHILE). The nucleophilic
site in many - though not all - nucleophiles will be an atom bearing a
0'ne *)&r of electrons.
The rapidity with which a nucleophile reacts with a given type of
electrophile is referred to as its nucleophilicity towards that kind of
electrophile. ood nucleophiles (high nucleophilicity) react rapidly
while poor nucleophiles (low nucleophilicity) react slowly.
!otice that a molecule behaving as a base (i.e. donating an electron pair
to a proton) is simply a special category of nucleophilic behaviour
where the electrophile is a proton.
Therefore a base is also usually (though not always) a nucleophile in the
more general sense. Strong bases are usually (though not always) also
strong nucleophiles and vice-versa.
Alkyl halides" #$" and related compounds are a group of very important
electrophiles in organic chemistry%
C
X
+
-
This carbon atom
is electrophilic
&hen alkyl halides react with nucleophiles two different kinds of
reaction can occur%
(')!ucleophilic substitution%
C
X
+
-
+ Nu:
-
C
Nu
+ X
-
(())limination%
C
X
C
H
:Nu
-
C C
+ NuH + X
-
- HX
Alkene
*ere the nucleophile behaves as a base and removes a proton from a
carbon atom ad+acent to the carbon bearing the halogen. The
conse,uence of the reaction is that the elements of a small molecule
(*
-
" $
-
. *$) are split out or eliminated from the alkyl halide and a
new compound with a carbon-carbon double bond is formed.
Nc0e'*$&0&c s1st&tt&'n re)ct&'ns:
/epending on the compounds involved nucleophilic substitution
reactions can involve one of two different kinds of stereochemical
change%
0onsider the following reaction%
C Br
H
C
6
H
5
CH
3
C CN
H
CH
3
C
6
H
5
(R)-1-Bromo-1-phenylethane
(S)-1-Cyano-1-phenylethane
CN
-
The stereochemical configuration at the electrophilic carbon in the
starting material has changed from #- in the starting material to S- in
the product - the nucleophilic substitution occurs with an inversion of
configuration known" after its original discoverer" as the 2)0%en
In3ers&'n.
The kinetic behaviour of this reaction is also of significance. The rate
depends on both the concentration of the alkyl halide and on the
concentration of the nucleophile - i.e. the reaction follows a sec'n%
'r%er r)te 0)4:
#ate . k 1 2#$3 1 2!ucleophile3
Second-order kinetics tell us that the reaction is 1&/'0ec0)r - i.e. two
molecules - the alkyl halide and the nucleophile - are involved in the
slowest (i.e. rate-determining) step of the nucleophilic substitution
reaction.
A /ec$)n&s/ )cc'nt&n5 f'r t$e stere'c$e/&str! )n% 6&net&c
1e$)3&'r 'f t$&s c0)ss 'f nc0e'*$&0&c s1st&tt&'n re)ct&'ns 4)s *t
f'r4)r% &n -78, 1! H5$es )n% In5'0%.
*ughes and 4ngold labelled the process S
N
9 to indicate that it was a
substitution" involved a nucleophile and was 1imolecular.
The crucial feature of the S
N
( mechanism is that the nucleophile attacks
the electrophilic carbon from the rear of the group - called the 0e)3&n5
5r'* - which will be displaced. There is no intermediate - +ust a single
step in which the nucleophile forms a bond to carbon while the leaving
group departs%
C Br
H
Ph
CH
3
C C
H
Ph
CH
3
(R)-1-Bromo-1-phenylethane
(S)-1-Cyano-1-phenylethane
C
H
CH
3
Ph
N C
-
N C Br
- -
N
:
+ Br
-
Transition state
C X
H
Ph
CH
3
C Nu
H
Ph
CH
3
C
H
CH
3
Ph
:
+ X
-
In the transition state the
hybridisation at carbon has
changed from tetrahedral sp
3
to
planar sp
2
with both nucleophile
and leaving group sharing an
unhybridised p orbital.
Nu
-
Nu
X
sp
3
sp
2
sp
3
- -
As the nucleophile approaches it
repels the electrons in the bonds at
the central carbon forcing them
back in the direction of the
departing leaving group.
As the nucleophile moves even
closer to carbon - and the leaving
group moves off - the sp
2
transition state collapses to sp
3
again in the direction of the
departing leaving group forming
the substitution product with
inverted configuration at carbon.
The fact that both nucleophile and substrate are involved in the
transition state e1plains the bimolecular kinetics while the re,uirement
that the nucleophile attack from the rear of the departing leaving group
e1plains the inversion of configuration at the reacting centre.
:)r&)10es &n t$e S
N
9 re)ct&'n
"-( Ster&c effects%
H
C Br
H
H
CH
3
C Br
H
H
CH
3
C Br
CH
3
H
CH
3
C Br
CH
3
CH
3
Methyl Primary Secondary Tertiary
2 x 10
6
500 4 x 10
4
< 1
Relative S
N
2 reactivity
High Low
As the degree of substitution on the halogen-bearing carbon increases
the reactivity towards S
N
( substitution falls off dramatically.
4ncreasing substitution hinders the approach of the nucleophile to the
halogen-substituted carbon.
"9( T$e nc0e'*$&0e:
H
2
O Cl
-
HO
-
CH
3
O
-
I
-
HS
-
1
1 x 10
3
1.6 x 10
4
2.5 x 10
4
1 x 10
5
1.2 x 10
5
Relative nucleophilicity (relative reactivity in S
N
2 substitution)
Weak Powerful
(i) !ucleophilicity parallels basicity - stronger base . better nucleophile
(ii) !egatively charged nucleophiles are more reactive than neutral
(iii) 5or related species 6
t$
row nucleophiles 7 8
r%
row nucleophiles 7
(
n%
row nucleophiles
An nex*ecte% ex*er&/ent)0 res0t:
H
C Br
H
H
CH
3
C Br
H
H
CH
3
C Br
CH
3
H
CH
3
C Br
CH
3
CH
3
Methyl Primary Secondary Tertiary
Relative S
N
2 reactivity
High
Low
R Br
+ H
2
O
R OH
+ HBr
< 1 1 12 1.2 x 10
6
Relative rate of reaction with water:
Less
reactive
More
reactive
9% *ow can this discrepancy be e1plained:
A% The one-step S
N
( process is not the only possible reaction pathway -
nucleophilic substitution can also proceed by a two-step S
N
- mechanism
- unimolecular nucleophilic substitution - with a f&rst 'r%er r)te 0)4:
#ate . k 1 2#$3
;echanism%
(CH
3
)
3
C Br
Slow
(CH
3
)
3
C
+
+ Br
-
Nu
-
Rapid
(CH
3
)
3
C Nu
CARBOCATION
intermediate
Rate-determining
step.
Stereochemical conse,uences of the S
N
' reaction%
C NC
H
Ph
CH
3
C N
C
H
CH
3
Ph
C
H
CH
3
Ph
C N
C Br
H
Ph
CH
3
C CN
H
Ph
CH
3
Slow
PLANAR
sp
2
hybridised
CARBOCATION
+
+ Br
-
(R)-1-Bromo-1-
phenylethane
+
(R)-1-Cyano-1-
phenylethane
(S)-1-Cyano-1-
phenylethane
50% 50%
RACEMISATION
_ _
&here the S
N
( mechanism leads to inversion at the reacting carbon
atom the S
N
' mechanism leads to racemisation" i.e. to the complete loss
of optical activity .
:)r&)10es &n t$e S
N
- Re)ct&'n
(') The structure of the substrate ( i.e. the reactant which is attacked by
the nucleophile)
RX + Nu
-
R
+
+ X
-
RNu + X
-
G

Transition State
Carbocation
intermediate
Free energy
of
activation
Progress of reaction
E
n
e
r
g
y
Tr)ns&t&'n St)te T$e'r!: An! f)ct'r 4$&c$ st)1&0&ses )n &nter/e%&)te
4&00 )0s' st)1&0&se t$e tr)ns&t&'n st)te f'r t$e f'r/)t&'n 'f t$e
&nter/e%&)te )n% &ncre)se t$e r)te 'f t$e re)ct&'n c'ncerne%.
S' - 4$)t f)ct'rs st)1&0&se ) c)r1'c)t&'n;
C
H
H H
+
C
CH
3
H H
+
C
CH
3
CH
3
CH
3
+
C
CH
3
CH
3
H
+
C
C
H
H
Filled C-H
bonding orbital
Empty p-orbital
of carbocation
Donating electrons
via -overlap to:
+
Methyl 1
2 3
Increasing carbocation stability
H
C Br
H
H
CH
3
C Br
H
H
CH
3
C Br
CH
3
H
CH
3
C Br
CH
3
CH
3
Methyl Primary Secondary
Tertiary
Less
reactive
More
reactive
Increasing S
N
1 reactivity
< < <
H
Hyperconjugation
!ote that the structural factors which promote the S
N
' pathway are
e1actly the same factors which inhibit the S
N
( mechanism.