Nucleophilic Substitution

Reactions

SN1 and SN2

• A nucleophile, a species with an unshared
electron pair (lone-pair electrons), reacts
with an alkyl halide (substrate) by replacing
the halogen substituent (leaving group).
• In nucleophilic substitution reactions, the
C–X bond of the substrate undergoes
heterolysis, and the lone-pair electrons of the
nucleophile is used to form a new bond to the
carbon atom.
A nucleophile is any negative ion or any neutral
molecule that has at least one
unshared electron pair-General Reaction for
Nucleophilic Substitution of an Alkyl Halide by
Hydroxide Ion.
• To be a good leaving group the substituent
must be able to leave as a relatively stable,
weakly basic molecule or ion.
• In alkyl halides the leaving group is the
halogen substituent –– it leaves as a halide
ion.
• Because halide ions are relatively stable and
very weak bases, they are good leaving
groups.
 NUCLEOPHILIC SUBSTITUTION REACTION
AN SN2 REACTION

• The rate of the reaction depends on the

concentration of methyl chloride and the
concentration of hydroxide ion
• The reaction is second order overall.
• The reaction is first order with respect to
methyl chloride and first order with respect
to hydroxide ion
 MECHANISM FOR THE SN2
REACTION
• The nucleophile attacks the carbon bearing the
leaving group from the back side.
• The bond between the nucleophile and the carbon
atom is forming, and the bond between the carbon
atom and the leaving group is breaking.
• The configuration of the carbon atom becomes
inverted during SN2 reaction.
• Because bond formation and bond breaking occur
simultaneously in a single transition state, the SN2
reaction is a concerted reaction.
Mechanism
Free Energy Diagram
For Methanol
Stereo Chemistry
 Reactions of Alkyl Halides (R-X): [SN1, SN2
d d
reactions]
H3C F EN (F-C) = (4.0 – 2.5) = 1.5
d d
H3C Cl EN (Cl-C) = (3.0 – 2.5) = 0.5
d d
H3C Br EN (Br-C) = (2.8 – 2.5) = 0.3
H3C I
EN (I-C) = (2.5 – 2.5) = 0.0
The -carbon in an alkyl halide is electrophilic (electron
accepting) for either or both of two reasons…
a) the C to X (F, Cl, Br) bond is polar making carbon d+

b) X (Cl, Br, I) is a leaving group

decreasing basicity, increasing stability
The best The poorest
leaving leaving groups
pKb = 23 pKb = 22 pKb = 21 pKb = 11 pKb = -1.7
groups are are the
I- Br - Cl - F- HO - strongest bases.
the weakest
30,000 10,000 200 1 0
bases.

increasing leaving ability 11

 2nd Order Nucleophilic Substitution Reactions, i.e.,
SN2 reactions
H H
.. H .. .. .. .. ..
:O H + C Br : H ..O C Br : H C + : Br :
..
H
.. .. ..O ..
H
H HH H
transition state

The rate of an SN2 reaction depends upon 4 factors:

1. The nature of the substrate (the alkyl halide)
2. The power of the nucleophile
3. The ability of the leaving group to leave
4. The nature of the solvent

1. Consider the nature of the substrate:

 Unhindered alkyl halides, those in which the back side of the -carbon is not blocked,
will react fastest in SN2 reactions, that is:
Me° >> 1° >> 2° >> 3°
 While a methyl halides reacts quickly in SN2 reactions, a 3° does not react. The back
side of an -carbon in a 3° alkyl halide is completely blocked.

12
 Effect of nature of substrate on rate of SN2
reactions:
H C H C 3 3
CH Br H3C C Br
H3C Br H3C CH2 Br
H3C H3C

methyl bromide ethyl bromide isopropyl bromide t-butyl bromide

SPACE FILLING MODELS SHOW ACTUAL SHAPES AND RELATIVE SIZES

Back side of -C of a Back side of -C of a Back side of -C of a Back side of -C of a
methyl halide is 1° alkyl halide is slightly 2° alkyl halide is mostly 3° alkyl halide is
unhindered. hindered. hindered.
completely blocked.

• Me° >> 1° >> 2° >> 3°

decreasing rate of SN2 reactions

13
 Effect of the nucleophile on rate of SN2 reactions:
•The -carbon in vinyl and aryl halides, as in 3° carbocations, is completely hindered and
these alkyl halides do not undergo SN2 reactions.
H2C CH Br Br

vinyl bromide bromobenzene

Nu:- Nu:-
H2C CH Br Br

The overlapping p-orbitals that form the p-bonds in vinyl and aryl halides
completely block the access of a nucleophile to the back side of the
-carbon.

14
 Effect of nature substrate on rate of SN2 reactions:
Consider the power of the nucleophile:
– The better the nucleophile, the faster the rate of SN2 reactions.
– The table below show the relative power or various nucleophiles.
– The best nucleophiles are the best electron donors.

Reactivity Nu:- Relative Reactivity

very weak HSO4-, H2PO4-, RCOOH < 0.01
weak ROH 1

increasing
HOH, NO3- 100
fair F- 500
Cl-, RCOO- 20  103
NH3, CH3SCH3 300  103
good N3-, Br- 600  103
OH-, CH3O- 2  106
very good CN-, HS-, RS-, (CH3)3P:, NH2- ,RMgX, I-, H- > 100  106

15
 Effect of nature of the leaving group on rate of SN2 reactions:

• 3. Consider the nature of the leaving group:

• The leaving group usually has a negative charge
 Groups which best stabilize a negative charge are the best leaving groups, i.e., the
weakest bases are stable as anions and are the best leaving groups.
 Weak bases are readily identified. They have high pKb values.
pKb = 23 pKb = 22 pKb = 21 pKb = 11 pKb = -1.7 pKb = -2 pKb = -21
I- Br - Cl- F- HO- RO- H2N-
30,000 10,000 200 1 0 0 0

Increasing leaving ability

 Iodine (-I) is a good leaving group because iodide (I-) is non basic.
 The hydroxyl group (-OH) is a poor leaving group because hydroxide (OH-) is a strong
base.

16
 Effect of the solvent on rate of SN2 reactions:
• 4. Consider the nature of the solvent:
• There are 3 classes of organic solvents:
 Protic solvents, which contain –OH or –NH2 groups. Protic solvents slow down SN2
reactions.
 Polar aprotic solvents like acetone, which contain strong dipoles but no –OH or –NH2
groups. Polar aprotic solvents speed up SN2 reactions.
 Non polar solvents, e.g., hydrocarbons. SN2 reactions are relatively slow in non polar
solvents.

Protic solvents (e.g., H2O, MeOH, EtOH, CH3COOH, etc.) cluster around the Nu:-
(solvate it) and lower
+ -
its energy (stabilize it) and reduce its reactivity via H-
bonding. d d
H OR
+ d-
d A solvated anion (Nu:-) has reduced nucleophilicity,
RO H X: -
H OR reduced reactivity and increased stability
- + A solvated nucleophile has difficulty
d d
H OR hitting the -carbon.
+ d-
d

17
 : O:
CH3 C N: Effect of the solvent on rate of SN2 C CH3
H3C
acetonitrile
reactions: acetone

 Polar Aprotic Solvents solvate the cation counterion of the nucleophile but not the
nucleophile.
 Examples include acetonitrile (CH3CN), acetone (CH3COCH3), dimethylformamide
(DMF) [(CH3)2NC=OH], dimethyl sulfoxide, DMSO [(CH3)2SO],
hexamethylphosphoramide, HMPA {[(CH3)2N]3PO} and dimethylacetamide (DMA).

:O : : O: :O:
.. CH3 .. .. .. CH3
H C N H3C S CH3 [(CH3)2N]3P O.. H3C C N
..
CH3 CH3
HMPA DMA
DMF DMSO
- +
d d
Polar aprotic solvents solvate metal cations N C CH3
..
leaving the anion counterion (Nu: -) bare and
thus more reactive + - :O:
d d .. _
+
:O: H3C C N: Na : N C CH3 + CH3C O
..
:
- +
.. _ CH3CN : d d
: +
CH3C O
.. Na ..
N C CH3
- +
d d

18
 Effect of the solvent on rate of SN2 reactions:

•Non polar solvents (benzene, carbon tetrachloride, hexane, etc.) do not solvate or
stabilize nucleophiles.

– SN2 reactions are relatively slow in non polar solvents similar to that in protic
solvents.
Cl

C CH3CH2CH2CH2CH2CH3
Cl Cl
Cl
benzene n-hexane
carbon
tetrachloride

19
 Solvent Effect for SN2 reactions
• Requires a polar, aprotic solvent…

• NO alcohols or amines
Why…because hydrogen bonding with
the nucleophile can occur…slowing
down the reaction
Polar, Aprotic Solvents
 SN2 Conditions Summary
 1) Substrate (methyl > primary > secondary >> tertiary)
 2) Nucleophile (negative charge > neutral)
 3) leaving group (Y) (Y stabilizes a negative charge)
 4) solvent (needs to be polar and aprotic)
 AN SN1 REACTION

• THE REACTION OF TERT-BUTYL

CHLORIDE WITH HYDROXIDE ION
 1st Order Nucleophilic Substitution Reactions, i.e.,
SN1 reactions
CH3 CH3
rapid
3° C I Na+ Br-
H3C C Br + Na+ I- H3C +
CH3 CH3

 3 alkyl halides are essentially inert to substitution by the SN2 mechanism

because of steric hindrance at the back side of the a-carbon.
 Despite this, 3 alkyl halides do undergo nucleophilic substitution reactions
quite rapidly , but by a different mechanism, i.e., the SN1 mechanism.
 SN1 = Substitution, Nucleophilic, 1st order (unimolecular).
 SN1 reactions obey 1st order kinetics, i.e., Rate = k[RX].
 The rate depends upon the concentration of only 1 reactant, the
alkyl halide-not the nucleophile
 The order of reactivity of substrates for SN1 reactions is the reverse of SN2
• 3 > 2 > 1 > vinyl > phenyl > Me°
• R3C-Br R2HC-Br RH2C-Br CH2=CH-Br -Br H3C-Br

increasing rate of SN1 reactions

 Mechanism of SN1 reactions
• The mechanism of an SN1 reaction occurs in 2 steps:
CH3 CH3 rapid CH3
3° .. 1. 2. ..
.. : ..I : Na+ Br-
H3C C H3C C+ C
Br
- Br - .. H3C +
Na+ :I :-
CH3 CH3 .. CH3
3° C+

• Reaction Steps …
1. the slower, rate-limiting dissociation of the alkyl halide forming a C+
intermediate
2. a rapid nucleophilic attack on the C+

Note that the nucleophile is not involved in the slower, rate-limiting step.

26
 The Rate of SN1 reactions
• The rate of an SN1 reaction depends upon 3 factors:
1. The nature of the substrate (the alkyl halide)
2. The ability of the leaving group to leave
3. The nature of the solvent
• The rate is independent of the power of the nucleophile.

• 1. Consider the nature of the substrate :

Highly substituted alkyl halides (substrates) form a more stable C+.

increasing rate of SN1 reactions
more less
stable stable
CH3 CH3 CH3 H

H3C C+ H3C C+ H C+ H C+

CH3 H H H
tertiary > secondary > primary > methyl
3º 2º 1º

27
 Stability of Carbocations
• Alkyl groups are weak electron donors.
 They stabilize carbocations by donating electron density by induction (through s
bonds)
CH3
Inductive effects:
Alkyl groups donate (shift) electron
H3C C+ density through sigma bonds to
electron deficient atoms.
This stabilizes the carbocation.
CH3

 They stabilize carbocations by hyperconjugation (by partial overlap of the alkyl C-to-H
bonds with the empty p-orbital of the carbocation).
vacant p orbital overlap (hyperconjugation)
of a carbocation

sp 2 Csp 3-Hs
hybridized sigma bond
carbocation H orbital
..
+
C C H
H

HYPERCONJUGATION
28
 Stability of Carbocations

Allyl and benzyl halides also react quickly by SN1

reactions because their carbocations are
unusually stable due to their resonance forms
which delocalize charge over an extended p
system
+ HC CHR
H2C CH +
CH2 H2C+ HC CH2 H2C CH +
CHR H2C

1º allyl carbocation 2º allyl carbocation

2º benzylic
H H 1º benzylic H H
+ + H
C C C C +
H H H H C
R
+ +

29
 Relative Stability of All Types of Carbocations
Increasing C+ stability and rate of SN1 reaction
+ +
C HR C H2

1º benzylic
+ 2º benzylic
C R2

3º C + 2º C + 1º C + H
3º benzylic
+
CH3 CH3 H + H C+
> > CH2 CH > >
CH3 C+ > CH3 C+ CH3 C+ H
> + +
H H vinyl C
CH3 phenyl m ethyl C
+
+ +
CH2 CH CR2
CH2 CH CHR CH2 CH CH2
3º allylic 2º allylic 1º allylic

Note that 1° allylic and 1° benzylic C+’s are about as stable as 2°alkyl C+’s.
Note that 2° allylic and 2° benzylic C+’s are about as stable as 3° alkyl C+’s.
Note that 3° allylic and 3° benzlic C+’s are more stable than 3° alkyl C+’s
Note that phenyl and vinyl C+’s are unstable. Phenyl and vinyl halides do not
usually react by SN1 or SN2 reactions
30
 Effect of the nucleophile on rate of SN1 reactions:
• Consider the nature of the Nucleophile:
 Recall again that the nature of the nucleophile has no effect on the rate of SN1
reactions because the slowest (rate-determining) step of an SN1 reaction is the
dissociation of the leaving group and formation of the carbocation.
 All carbocations are very good electrophiles (electron acceptors) and even weak
nucleophiles, like H2O and methanol, will react quickly with them.
 The two SN1 reactions will proceed at essentially the same rate since the only
difference is the nucleophile.

CH3 CH3
3° C I Na+ Br-
H3C C Br + Na+ I- H3C +
CH3 CH3

CH3 CH3
3° K+ F- C F K+ Br-
H3C C Br + H3C +
CH3 CH3

31
 Effect of nature of the leaving group on rate of SN1
reactions:
• 2. Consider the nature of the leaving group :
• The nature of the leaving group has the same effect on both SN1 and SN2 reactions.
• The better the leaving group, the faster a C+ can form and hence the faster will be the
SN1 reaction.
• The leaving group usually has a negative charge
 Groups which best stabilize a negative charge are the best leaving groups, i.e., the
weakest bases are stable as anions and are the best leaving groups.
 Weak bases are readily identified. They have high pKb values.

pKb = 23 pKb = 22 pKb = 21 pKb = 11 pKb = -1.7 pKb = -2 pKb = -21

I- Br - Cl- F- HO- RO- H2N-
30,000 10,000 200 1 0 0 0

Increasing leaving ability

 Iodine (-I) is a good leaving group because iodide (I-) is non basic.
 The hydroxyl group (-OH) is a poor leaving group because hydroxide (OH-) is a
strong base.
32
 Effect of the solvent on rate of SN1 reactions:
• 3. Consider the nature of the solvent:
 For SN1 reactions, the solvent affects the rate only if it influences the stability of the
charged transition state, i.e., the C+. The Nu:- is not involved in the rate determining
step so solvent effects on the Nu:- do not affect the rate of SN1 reactions.
 Polar solvents, both protic and aprotic, will solvate and stabilize the charged
transition state (C+ intermediate), lowering the activation energy and accelerating
SN1 reactions.
 Nonpolar solvents do not lower the activation energy and thus make SN1 reactions

relatively slower

The relative rates of an SN1 reaction due to solvent effects are given

(CH3)3C-Cl + ROH  (CH3)3C-OR + HCl

H2O 20% EtOH (aq) 40% EtOH (aq) EtOH

100,000 14,000 100 1
reaction rate increases with polarity of solvent

33
 Effect of the solvent on rate of SN1 reactions:
 Solvent polarity is usually expressed by the “dielectric constant”, , which is a
measure of the ability of a solvent to act as an electric insulator.
 Polar solvents are good electric insulators because their dipoles surround and
associate with charged species.
 Dielectric constants of some common solvents are given in the following table

name dielectric constant name dielectric constant

aprotic solvents protic solvents
hexane 1.9 acetic acid 6.2
benzene 2.3 acetone 20.7
diethyl ether 4.3 ethanol 24.3
chloroform 4.8 methanol 33.6
HMPA 30 formic acid 58.0
DMF 38 water 80.4
DMSO 48

34
HMPA DMSO

35
DMF

36