Chapter Four

Substitution Reaction
Substitution reaction is a type of reaction that a replacement of one group by
another group occurs.
Or one in which the Lewis base act as a nucleophile to substituent for the halide
substituent on carbon.
General schematic representation of nucleophlic substitution reaction:

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  Nucleophile is a species with a shared electron pair(lone pair) react with an alkyl
halide(substrate) by replacing the halogen substitution.

 To draw any nucleophilic substitution product:

• Find the sp3 hybridized carbon with the leaving group.
• Identify the nucleophile, the species with a lone pair or  bond.
• Substitute the nucleophile for the leaving group and assign charges (if necessary) to
any atom that is involved in bond breaking or bond formation.
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 Negatively charged nucleophiles like HO¯ and HS¯ are used as salts with Li +,
Na+, or K+ counter ions to balance the charge.
 Since the identity of the counter ion is usually inconsequential, it is often omitted
from the chemical equation.
 When a neutral nucleophile is used, the substitution product bears a positive
charge

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 when the substitution product bears a positive charge and also contains a proton
bonded to O or N, the initially formed substitution product readily loses a proton in
a BrØnsted-Lowry acid-base reaction, forming a neutral product.

 Alkyl halides are used as the starting material for the synthesis of many compound
and, it is usually called the substrate.
 The Leaving Group: In a nucleophilic substitution reaction of R—X, the C—X
bond is heterolytically cleaved, and the leaving group departs with the electron pair
in that bond, forming X:¯.

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 The more stable the leaving group X:¯, the better able it is to accept an electron
pair.

 For example, H2O is a better leaving group than HO¯ because H2O is a weaker
base
 There are two mechanisms in substitution reaction

1.SN1 mechanism (Unimolecular Nucleophilic Substitution)

2. SN2 mechanism (bimolecular Nucleophilic Substitution)

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SN1 mechanism

 Unimolecular ,1st order means only one molecule is involved in the rate
determining step.
Rate = k [R-X]
Note: only the substrate (RX) shows up in the rate equation
 Bond breaking occurs before bond making.
 The mechanism has two steps and a carbocation is formed as an intermediate.
Because the first step is rate-determining, the rate depends on the
concentration of RX only; that is, the rate equation is first order.
 Note that the nucleophile is not involved in the slower, rate-limiting step, so its
concentration has no effect on the rate of reaction

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7
An energy diagram for the SN1 reaction

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 The mechanism of 1st order reaction is based on the ff experimental evidence.

1.The rate of reaction is depend on only the concentration of alkyl halide

2. When the methyl group of tert butyl bromide are successively replaced by
hydrogens the rat of SN1 reaction decrease progressively
 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

3. The reaction of an alkyl halide in which the halogen is bonded to an asymmetric

carbon form two stereoisomerism
 One the same with starting material retained end the other is inverted
configuration.

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 Recall that carbocations are planar, so the nucleophile can approach both sides of
the empty “p” orbital, from the “top” or from the “bottom.”

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 SN2 mechanisms
 Bimolecular, 2nd order means two molecule are involved in the rate determining step.
rate = [alkyl halide][nucleophile]
 Note: both the substrate (RX) and the nucleophile (Nu-) show up in the rate equation.
 General mechanism of SN2

 Note the following features from the above mechanism:

 bond making and breaking occur at the same time.

 Note that the nucleophile must hit the back side of the alpha-carbon.
 The nucleophile to C bond forms as the C to X bond breaks.
 No intermediate forms. 11
 Rate law tells us which molecule are involved in the transition state of rate
determining step
 Hughes and Ingold based their mechanism for an reaction on the following
three pieces of experimental evidence.

1. The rate of the reaction depends on the concentration of the alkyl halide and on

the concentration of the nucleophile. This means that both reactants are involved

in the rate-determining step.

2. When the hydrogens of methyl bromide are successively replaced with methyl

groups, the rate of the reaction with a given nucleophile becomes progressively

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  Unhindered alkyl halides, those in which the back side of the a-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 a-carbon in a 3° alkyl halide is completely blocked.

3. The reaction of an alkyl halide in which the halogen is bonded to an asymmetric

carbon leads to the formation of only one stereoisomer, and the configuration of
the asymmetric carbon is inverted relative to its configuration in the reacting
alkyl halide.

Therefore, Hughes and Ingold proposed that an reaction is a concerted reaction it

takes place in a single step, so no intermediates are formed.

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 Eg
An energy diagram for the SN2 reaction:

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 All SN2 reactions proceed with backside attack of the nucleophile, resulting in
inversion of configuration at a stereogenic center.

Stereochemistry of the SN2 reaction

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Factors Affecting The Rates Of SN1 And SN2 Reactions

1. The concentration and reactivity of the nucleophile (for bimolecular reactions).

2. The structure of the substrate.

3. The effect of the solvent.

4. The nature of the leaving group.

1. Nucleophiles and bases are structurally similar: both have a lone pair or a  bond.
They differ in what they attack.

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  Basicity is a measure of how readily an atom donates its electron
pair to a proton. It is characterized by an equilibrium constant, Ka in
an acid-base reaction, making it a thermodynamic property.
 Nucleophilicity is a measure of how readily an atom donates its
electron pair to other atoms. It is characterized by a rate constant, k,
making it a kinetic property.
• Nucleophilicity parallels basicity in three instances:

1. For two nucleophiles with the same nucleophilic atom, the stronger base is the
stronger nucleophile.

 The relative nucleophilicity of HO¯ and CH3COO¯, two oxygen nucleophiles,

is determined by comparing the pKa values of their conjugate acids (H2O =

15.7, and CH3COOH = 4.8). HO¯ is a stronger base and stronger nucleophile
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 2. A negatively charged nucleophile is always a stronger nucleophile than its
conjugate acid.

 HO¯ is a stronger base and stronger nucleophile than H 2O.

3. Right-to-left-across a row of the periodic table, nucleophilicity increases as

basicity increases
• Nucleophilicity does not parallel basicity when steric hindrance becomes important.
• Steric hindrance is a decrease in reactivity resulting from the presence of bulky
groups at the site of a reaction.
• Steric hindrance decreases nucleophilicity but not basicity.
• Sterically hindered bases that are poor nucleophiles are called non nucleophilic
bases.

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2. substrate
• Alkyl halides(substrate) are organic molecules containing a halogen atom
bonded to an sp3 hybridized carbon atom.

• Alkyl halides are classified as primary (1°), secondary (2°), or tertiary

(3°), depending on the number of carbons bonded to the carbon with the
halogen atom.

• The halogen atom in halides is often denoted by the symbol “X”. 20

 There are other types of organic halides. These include vinyl halides, aryl halides,
allylic halides and benzylic halides.

 Vinyl halides have a halogen atom (X) bonded to a C—C double bond.

 Aryl halides have a halogen atom bonded to a benzene ring.

 Allylic halides have X bonded to the carbon atom adjacent to a C—C double bond.
 Benzylic halides have X bonded to the carbon atom adjacent to a benzene ring.

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 Four types of organic halides (RX) having X near a π bond

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  system

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 H2C CH +
CH2 H2C+ HC CH2 H2C CH +
CHR H2C+ HC CHR

1º allyl carbocation 2º allyl carbocation

Increasing C+ stability and rate of SN1 reaction

+
+ C H2
C HR

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 phenyl and vinyl C+’s are unstable. Phenyl and vinyl halides
do not usually react by SN1 or SN2 reactions
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 Effect of nature of substrate on rate of SN2 reactions:

 Since the energy of the transition state is significant in determining the rate of
the reaction, a primary substrate will react more rapidly than secondary.

R Br + Cl R Cl + Br
6
Rate: ~0 1 500 40,000 2 x 10
(CH3)3CBr (CH3)3CCH2Br (CH3)2CHBr CH3CH2Br CH3Br
tertiary neopentyl secondary primary methyl

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3.Leaving Group

Nu + R-Y  R-Nu + Y –
(so Y needs to be able to stabilize a negative charge)

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Con’t

 R-Y  Y – (so Y needs to be able to stabilize a negative charge)

 OH- F- < Cl- < Br- < I- < -OTos

 NH2- bad best O

 OR- O S

O
 (Can’t leave)

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 4. solvent
 There are the ff 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

H OR
via H-bonding. + -
 A solvated anion (Nu:-) has reduced nucleophilicity,
RO H X:
-
H OR reduced reactivity and increased stability
- +
 
H OR
+ -
 
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 Effect of the solvent on rate of SN2 reactions:

 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).
- +
 
Polar aprotic solvents solvate metal cations N.. C CH3
leaving the anion counterion (Nu: -) bare and
thus more reactive + - :O:
  .. _
+
H3C C N : Na : N C CH3 + CH3C O.. :
:O: - +
.. _ CH3CN :  
+
CH3C O.. : Na
..
N C CH3
- +
 
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 Non polar solvents (benzene, carbon tetrachloride, hexane, etc.) do not solvate or
stabilize nucleophiles.

 SN 2 reactions are relatively slow in non polar solvents similar to that in protic solvents.

Effect of the solvent on rate of SN1 reactions:

 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

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 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

 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.
 Or Dielectric constant: a measure of a solvent’s ability to insulate opposite
charges from each other.
 Polar solvents are good electric insulators because their dipoles surround and
associate with charged species.

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 The SN2 reaction is a key step in the laboratory synthesis of many important
drugs.
 Figure Nucleophilic substitution in the synthesis of two useful drugs

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 Nucleophilic substitution reactions are important in biological systems as well.

 This reaction is called methylation because a CH3 group is transferred from one
compound (SAM) to another (:Nu¯).

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 Adrenaline synthesis
from noradrenaline in
response to stress

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 summary: SN1 versus SN2

 Reactions of alkyl halides by an SN1 mechanism are favored by the use of:

1) substrates that can form relatively stable carbocations.

2) weak nucleophiles.

3) highly ionizing solvent.

 2. Reactions of alkyl halides by an SN2 mechanism are favored by the use of:

1) relatively unhindered alkyl halides.

2) strong nucleophiles.

3) polar aprotic solvents.

4) high concentration of nucleophiles.

 3. The effect of the leaving group is the same in both SN1 and SN2

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