Unit Four

Major Organic Reactions

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In a substitution reaction, the electronegative atom or group is
replaced by another atom or group.

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Substitution reactions are important in organic chemistry because
•To get a wide variety of other compounds.
•To make the biological systems more soluble in water by replacing with polar groups.
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 There are two important mechanisms for the substitution reaction:
1. A nucleophile is attracted to electrophiles to form new bond nucleophile: An
electron-rich atom or molecule (e- donors). electrophile: an electron-deficient
atom or molecule (e- acceptors).

2. Breaking of a bond heterolytically without any assistance from the nucleophile and
forming carbocation
A species containing a positively
charged carbon atom is called a
carbocation.

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• Equally dependant both on nucleophiles and electrophiles.
• Relatively strong nucleophile
• In SN2 reaction both the nucleophile and the electrophile are used in rate
determining step 13
PROBLEM 1:
Arrange the following alkyl bromides in order of decreasing reactivity in an SN2 reaction:
1-bromo-2-methylbutane, 1-bromo-3-methylbutane, 2-bromo-2-methylbutane, and 1-
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bromopentane.
 Factors Affecting SN2 Reactions
A. The Leaving Group, B. the nucleophile

The weaker the basicity of a group, the better is its leaving ability
Readiness of a compound (a nucleophile) to attack an electrophile.
I- < Br- < Cl- < F-

weakest base, strongest base,

most stable base least stable base

Therefore, alkyl iodides are the most reactive of the alkyl halides, and alkyl fluorides
are the least reactive.

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To clarify the ambiguity between basicity and nucleophilicity
There is a direct relationship between basicity and
nucleophilicity: Stronger bases are better nucleophiles.

Basicity is a measure of how well a compound (a base)

shares its lone pair with a proton. It is measured by an
equilibrium constant (the acid dissociation constant, Ka )
that indicates the tendency of the conjugate acid of
the base to lose a proton.

Nucleophilicity is a measure of how readily a compound (a

nucleophile) is able to attack an electron-deficient atom.
Nucleophilicity is measured by a rate constant (k).
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 Basicity:
 is a measure of how well a compound (a base) shares its lone pair with a
proton in aqueous solvent.
 The stronger the base, the better it shares its electrons.
 Basicity is measured by equilibrium constant.
Nucleophilicity: is a measure of how readily a compound (a nucleophile) is
able to attack an electron-deficient atom. Nucleophilicity is measured by a rate
constant (k).

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Polarizability :
 Refers to the ability of an atom to become polarized in the presence of external
influences such as solvent effects.
 polarizability increases as electronegativity decreases.
 increases as size of the atom increases b/c the outer electrons are more diffused to
be polarized.
 influenced by solvent effects and hardness or softness of the nucleophilic base. a
hard base is high in electronegativity and low in polarizability. Alternatively, a soft
base is low in electronegativity and high in polarizability.
e.g. F- is considered a hard base because it is high in electronegativity, small in size
and holds its electrons very tightly. On the other hand, I- is considered a soft base
because its large size causes it to hold its electrons loosely and renders it highly
polarizable.
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Order of increasing nucleophilicity of halide ions is influenced by polarizing influences
such as solvent effects. Protic solvents are
polar liquid
Aprotic solvents are compounds that have
polar liquid dissociable hydrogen
compounds that atoms. They form
have no dissociable hydrogen bond because
hydrogen atoms. they have chemical bonds
Aprotic solvents are required for the hydrogen
unable to form bonding, i.e. O-H bond
hydrogen bonds. and N-H bond.
e.g. dichloromethane e.g: water, hydrogen
(DCM), tetrahydrofuran fluoride (HF), ammonia
(THF), ethyl acetate, and (NH3).
acetone

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 The Effect of the Solvent on Nucleophilicity
In protic solvents smallest atoms are poor nucleophiles but
strong base. why?

Answer: protic solvents make stronger bases poor

nucleophiles due to the fact that Because the solvent
shields the nucleophile. When a negatively charged
species is placed in a protic solvent, the ion becomes
solvated. Protic solvents are hydrogen bond donors and
the partially negatively charged species attracts the proton
through ion–dipole interaction
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 Relative Nucleophilicity Toward CH3l in Methanol

There for I- is a better nucleophile than F- in a protic solvent.

 F- ion would be a better nucleophile in a nonpolar solvents b/c
there is no ion–dipole interactions b/n the ion and the solvent.
 However, ionic cpds are insoluble in most nonpolar solvents, but
they can dissolve in aprotic polar solvents, such as DMF or DMSO.
 there are no ion–dipole interactions. therefore, F- is a better
nucleophile in DMSO than it is in water.
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The order of nucleophilicity among these halide ions would expect to be Cl- >Br-> I-.
This is, in fact, the case in the presence of polar aprotic solvents (solvents not
possessing a dissociable proton) such as dimethylformamide. However, in the presence
of polar protic solvents ( solvents possessing a dissociable proton) such as water or
alcohols the order of nucleophilicity is I- > Br- > Cl-.

Question
a. Which is a stronger base (better solvated in aqueous solvent), RO- or RS-?
b. Which is a better nucleophile in an aqueous solution?
Answer: Sulfur atoms are larger than oxygen atoms and hence they are
not solvated as strongly in a protic solvent as oxygen whose charge is
concentrated. Thus, thiols (R SH) are stronger nucleophiles than
alcohols, and RS- anions are better nucleophiles than RO- anions
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SN1: The Following Conditions Favor an SN1 Reaction:
1. A substrate that can form a relatively stable carbocation (such
as a substrate with a leaving group at a tertiary position)
2. A relatively weak nucleophile
3. A polar, protic solvent
SN1 only the electrophile determines the rate limiting step.

A species containing a positively

charged carbon atom is called a
carbocation.

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 The Mechanism of an SN1 Reaction

tert-butyl bromide tert-butyl alcohol

Rate =k [alkyl halide]

1. The reaction depends on the concentration of only one reactant
2. The reaction is a first-order reaction

Relative reactivities of alkyl halides in an SN1 reaction

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 The mechanism of an SN1 reaction is based on the following
experimental evidence:

 The rate of the reaction depends only on the concentration of the

alkyl halide. i.e. rate determining step involves only the alkyl
halide.
 The rate of the SN1 reaction decreases as the alkyl halide
concentration decreases
relative reactivity of alkyl halides in an SN1 reaction

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 Factors Affecting SN1 Reactions
Two factors affect the rate of an SN1 reaction:
• the ease with which the leaving group dissociates from the carbons
• stability of the carbocation that is formed.
Tertiary alkyl halides are more reactive than secondary alkyl
halides, which are more reactive than primary alkyl halides. The more
substituted the carbocation is, the more stable it is.
The reactivity of the nucleophile has no effect on the rate of an SN1
reaction
relative reactivities of alkyl halides in an SN1 reaction

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• PROBLEMs: Arrange the following alkyl bromides in order of decreasing reactivity
in an reaction:

isopropyl bromide, propyl bromide, tert-butyl bromide, methyl bromide.

• The reaction of 2-bromopropane with hydroxide ion forms a substitution product

without any asymmetric carbons. The product, therefore, has no stereoisomers.
Benzylic Halides, Allylic Halides, Vinylic Halides, and Aryl Halides
Benzylic and allylic halides readily undergo SN2 reactions unless they are tertiary.
Tertiary benzylic and tertiary allylic halides,
like other tertiary halides, are unreactive in SN2 reactions because of steric hindrance.

benzyl chloride benzyl methyl ether

1-bromo-2-butene 2-buten-1-ol
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Table 4.3. Comparison of SN2 and SN1 Reactions
SN2 SN1
A one-step mechanism A stepwise mechanism that forms a
carbocation intermediate
Bimolecularrate-determining step A unimolecular rate-determining step

No carbocation rearrangements Carbocation rearrangements

Product has inverted configuration Products have both retained and inverted
relative to the reactant configurations relative to the reactant

Reactivity order: Reactivity order:

methyl > 1° > 2° > 3° 3° > 2° > 1° > methyl

In summary:
• An SN2 reaction is favored by a high concentration of a good nucleophile.
• An SN1 reaction is favored by a low concentration of a nucleophile or by a poor
nucleophile. 31
Rate law for an SN2 reaction = k2 [alkyl halide] [nucleophile]

Rate law for SN1 reaction = k1 [alkyl halide]

From the rate law, you can see that increasing the concentration
of the nucleophile increases the rate of an SN2 reaction but has
no effect on the rate of an SN1 reaction.

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 Problem
Which reaction in each of the following pairs will take place more rapidly?

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 Application of substitution reaction
Alcohol
An alkohol cannot undergo a nucleophilic substitution reaction
because it has a strongly basic leaving group that cannot be
displaced by a nucleophile.

The substitution will be possible if its OH group is converted into a

better leaving group (H2O). First protonation then displaced by a
nucleophile.

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 Amines
Alcohols are much less reactive than alkyl halides in substitution
reactions. Amines are even less reactive than alcohols. The relative
reactivities of an alkyl fluoride (the least reactive of the alkyl
halides), an alcohol, and an amine can be appreciated by comparing
the values.

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 Epoxides

Ethers in which the oxygen atom is incorporated into a three-

membered ring are called epoxides or oxiranes.

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Substitution reaction of carboxylic acid

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Ester formation from carboxylic acids

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Acid anhydride formation from carboxylic acids

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 Amide formation from carboxylic acids

The order of reactivity of various carboxylic acid derivatives

towards nucleophilic substitution is as follows:
Acid halide > acid anhydride > thioester > ester > amide

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