Lectures Ch4 Ns PDF

ORGANIC CHEMISTRY
Chapter 4
ALKYL HALIDES:
Nucleophilic Substitution
and Elimination
Hortensia Rodriguez
[email protected]
ALKYL HALIDES
1. Reactions of alkyl halides: nucleophilic substitutions and eliminations, SN2, SN1,
E2, and E1 reactions with stereochemical consequences, mechanisms, transition
states, and intermediates.
LECTURE 1
Bibliography: Organic Chemistry, F.A. Carey, Chapter 4, 5 and 8

Organic Chemistry, Clayden-Warren, Chapter 16
Classes of Halides
H H I
Halogen, X, is
H C C Br directly bonded HALIDES X is bonded to
sp2 carbon on
H H to sp3 carbon.
alkyl halide
benzene ring.
aryl halide
H H
C C X is bonded to sp2
H Cl carbon of alkene.
vinyl halide
ALKYL HALIDES
Alkyl halides are a class of compounds where a halogen atom or atoms are bound to an sp3
orbital of an alkyl group.
CHCl3 (Chloroform: organic solvent) CF2Cl2 (Freon-12: refrigerant CFC)
CF3CHClBr (Halothane: anesthetic)

Polarity and Reactivity
• Halogens are more electronegative than C.

• Carbon—halogen bond is polar, so carbon has partial positive
charge.
• Carbon can be attacked by a nucleophile.
• Halogen can leave with the bond electron pair.
Polarity and Reactivity
• The electronegative halogen atom in alkyl halides creates a polar C—X
bond, making the carbon atom electron deficient. Electrostatic potential
maps of four simple alkyl halides illustrate this point.
Electrostatic potential maps of

four halomethanes (CH3X)
IUPAC Nomenclature
• Name as haloalkane.
• Choose the longest carbon chain, even if the halogen is not
bonded to any of those C’s.
• Use lowest possible numbers for position.
1 2
Cl CH2CH2F
CH3CHCH2CH3 CH3CH2CH2CHCH2CH2CH3
1 2 3 4 1 2 3 4 5 6 7
2-chlorobutane 4-(2-fluoroethyl)heptane
Examples
CH3 Br
CH3CHCH2CH2CH2CHCH2CH2CH3
1 2 3 4 5 6 7 8 9
6-bromo-2-methylnonane Br
1 H
3
F H
cis-1-bromo-3-fluorocyclohexane
Systematic Common Names
• The alkyl groups is a substituent on halide.
• Useful only for small alkyl groups.
CH3 CH3 CH3

CH3CHCH2 Br CH3CH2CH Br CH3C Br
iso-butyl bromide sec-butyl bromide

CH3
tert-butyl bromide
Common Names of Alkyl Halides
• CH2X2 called methylene halide.
• CHX3 is a haloform.
• CX4 is carbon tetrahalide.

• Common halogenated solvents:
CH2Cl2 is methylene chloride
CHCl3 is chloroform
CCl4 is carbon tetrachloride.
Alkyl Halides Classification
• Methyl halides: halide is attached to a methyl group.
• Primary alkyl halide: carbon to which halogen is bonded is attached to only
one other carbon.
• Secondary alkyl halide : carbon to which halogen is bonded is attached to
two other carbons.
• Tertiary alkyl halide : carbon to which halogen is bonded is attached to three
other carbon.
Primary, Secondary, Tertiary Alkyl Halides
CH3 CH3
CH3CHCH2 Br CH3CH2CH Br
* *
primary alkyl halide secondary alkyl halide
CH3
CH3C* Br
CH3
tertiary alkyl halide
Types of Dihalides
• Geminal dihalide: two halogen atoms are bonded to the same carbon.
Br
CH3 CH Br
geminal dihalide
• Vicinal dihalide: two halogen atoms are bonded to adjacent carbons.
Br CH2CH2 Br
vicinal dihalide
Physical Properties
• Alkyl halides are weak polar molecules. They exhibit dipole-dipole
interactions because of their polar C—X bond, but because the rest of the
molecule contains only C—C and C—H bonds, they are incapable of
intermolecular hydrogen bonding.
Dipole Moments
Dipole Moments
1 D = 3,34 x 10-30 Culombio x m
• Electronegativities of the halides:

F > Cl > Br > I
• Bond lengths increase as the size of the halogen increases:
C—F < C—Cl < C—Br < C—I
• Bond dipoles:
C—Cl > C—F > C—Br > C—I
1.56 D 1.51 D 1.48 D 1.29 D
• Molecular dipoles depend on the geometry of the molecule.
Bond strength
1 D = 3,34 x 10-30 Culombio x m
Physical Properties
Preparation of Alkyl Halides
• Free radical halogenation

• Chlorination produces a mixtures of products. This reaction is not a good lab
synthesis, except in alkanes where all hydrogens are equivalent.
• Bromination is highly selective.
3º carbons > 2º carbons > 1º carbons
• Free radical allylic halogenation

• Halogen is placed on a carbon directly attached to the double bond (allylic).
• Free radical allylic halogenation
Halogen is placed on a carbon directly attached to the double bond (allylic).
• Allylic radical is resonance stabilized.

• Bromination occurs with good yield at the allylic
position (sp3 C next to C C).
Free radical allylic halogenation, Reaction Mechanism
• The mechanism involves an allylic radical stabilized by resonance.

• Both allylic radicals can react with bromine.
Free radical allylic intermediate, Molecular Orbitals
SOMO
Reaction of Alkyl Halides
Competitive Reactions
a a sustitución
Substitution
B: +

C GS
LG
b
H C b eliminación
Elimination
+

Reaction of Alkyl Halides
• The halogen atom on the alkyl halide is replaced with

a nucleophile (Nuc-).
• Since the halogen is more electronegative than
carbon, the C—X bond breaks heterolytically and X-
leaves.
• Elimination reactions produce double bonds.

• The alkyl halides loses a hydrogen and the halide.
• Also called dehydrohalogenation (-HX).
General Features of Nucleophilic Substitution
Three components are necessary in

any substitution reaction.
24
Reaction of Alkyl Halides,
• Negatively charged nucleophiles like HO¯ and HS¯ are used as salts with Li+, Na+, or K+
counterions to balance the charge. Since the identity of the counterion is usually
inconsequential, it is often omitted from the chemical equation.
• When a neutral nucleophile is used, the substitution product bears a positive charge.
• Furthermore, 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.
• 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.
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:¯. 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.
The Leaving Group
The Leaving Group

v
v
The Nucleophile
• Nucleophiles and bases are structurally similar: both have a lone pair or a
 bond. They differ in what they attack.
v
Although nucleophilicity and basicity are interrelated, they are fundamentally different.
Basicity is a measure of how readily

Nucleophilicity is a measure of how
an atom donates its electron pair to a
readily an atom donates its electron
proton. It is characterized by an
v pair to other atoms.
v It is characterized
equilibrium constant, Ka in an acid-
by a rate constant, k, making it a
base reaction, making it a
kinetic property.
thermodynamic property.
Nucleophilicity and basicity
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 = 14, and
CH3COOH = 4.8). HO¯ is a stronger base and stronger nucleophile than CH3COO¯.
2. A negatively charged nucleophile is always a stronger nucleophile than its conjugate
acid.
HO¯ is a stronger base and stronger nucleophile than H2O.
3. Right-to-left-across a row of the periodic table, nucleophilicity increases as basicity
increases:
Nucleophilicity and basicity
• Nucleophilicity does not parallel basicity when steric hindrance becomes important.
• Steric hindrance is related to 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.
32
Nucleophiles
Trends in Nucleophilicity
• A negatively charged nucleophile is stronger than its neutral counterpart:
OH- > H2O HS-> H2S NH2- > NH3

• Nucleophilicity decreases from left to right :
OH- > F- NH3 > H2O
• Increases down Periodic Table, as size and polarizability increase:
I- > Br- > Cl-

Mechanisms of Nucleophilic Substitution
But what is the order of bond making and bond breaking? In theory,
there are two possibilities.
[1] Bond making and bond breaking occur at the same time.
In this scenario, the mechanism is comprised of one step. In such a bimolecular reaction, the
rate depends upon the concentration of both reactants, that is, the rate equation is second
order.
But what is the order of bond making and bond breaking? In theory,
there are two possibilities.
[2] Bond breaking occurs before bond making.
In this scenario, 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.
Consider reaction [1] below:
Kinetic data show that the rate of reaction [1] depends on the concentration of both
reactants, which suggests a bimolecular reaction with a one-step mechanism.
This is an example of an SN2 (bimolecular nucleophilic substitution) mechanism.
Consider reaction [2] below:
Kinetic data show that the rate of reaction [2] depends on the concentration of only the
alkyl halide. This suggests a two-step mechanism in which the rate-determining step
involves the alkyl halide only.
This is an example of an SN1 (unimolecular nucleophilic substitution) mechanism.
SN2 SN1
S N1
SN2
• Bimolecular reaction with a one-step mechanism
• The two reagents are involves in the slowest step of the reaction.
• The TS included both species.
Mechanisms of Nucleophilic Substitution, SN2
The mechanism of an SN2 reaction would be drawn as follows. Note the curved arrow
notation that is used to show the flow of electrons.
•The pair of electrons on the nucleophile almost always comes from the highest-energy occupied molecular
orbital (HOMO) of the nucleophile. Why? Because these are the electrons that are the least tightly held.
• The orbital on the electrophile that accepts the pair of electrons is almost always the lowest-energy
unoccupied molecular orbital (LUMO), because this will result in the lowest-energy transition state (and the
fastest reaction).
Homo-Lumo Interactions in SN2
•The pair of electrons on the nucleophile almost always comes from the highest-energy occupied molecular
orbital (HOMO) of the nucleophile. Why? Because these are the electrons that are the least tightly held.
• The orbital on the electrophile that accepts the pair of electrons is almost always the lowest-energy
unoccupied molecular orbital (LUMO), because this will result in the lowest-energy transition state (and the
fastest reaction).
The back-side attack actually occurs in the SN2 reaction.

Steric hindrance between the

nucleophile and the leaving group
Energy diagram for the SN2 reaction:
• In the TS, the C-Br bond is partiallly

broken, the C-O bond is partially
formed, and both the attacking
nucleophile and the departing
leaving group bear a partial
negative charge.
Stereochemistry
Stereochemistry of the SN2 reaction
• All SN2 reactions proceed with backside attack of the nucleophile, resulting in inversion of
configuration at a stereogenic center.
Stereochemistry of the SN2 reaction, examples.
The bond to the nucleophile in

the product is always on the
opposite side relative to the
bond to the leaving group in
the starting material
• Methyl and 1° alkyl halides undergo easily SN2 reactions.

• 2° Alkyl halides react more slowly.
• 3° Alkyl halides do not undergo SN2 reactions. This order of reactivity can be
explained by steric effects. Steric hindrance caused by bulky R groups makes
nucleophilic attack from the backside more difficult, slowing the reaction rate.
Steric effects in the SN2 reaction
Electrostatic potential maps illustrate the effects of steric hindrance around the
carbon bearing the leaving group in a series of alkyl halides.
• The higher the Ea, the slower the reaction rate. Thus, any factor that increases Ea decreases
the reaction rate. Steric effects in the S 2 reaction
N
Steric effects in the SN2 reaction
• Increasing the number of R groups on the carbon with the leaving group increases
crowding in the transition state, thereby decreasing the reaction rate.
• The SN2 reaction is fastest with unhindered halides.
Polarizability Effect in SN2 mechanism
Bigger atoms have a soft shell which can start to overlap the carbon atom from a farther
distance.
S N2 S N1
• Unimolecular reaction with at least two-step mechanism
• The alkyl halide is the only reagent involves in the slowest
step of the reaction.
• The TS included only the R-X species.
Key features of the SN1 mechanism are that it has two steps, and carbocations are formed as
reactive intermediates.
Homo-Lumo interactions in SN1
Energy diagram for the SN1 reaction:
• Two energy barriers
• DHoverall is a negative value.
• Ea(1)>Ea(2) since 1st step involves

bond breaking and 2nd step involves
bond formation. In each step only one
bond is broken or formed, so de TS for
each state has one partial bond.
Step 1
rate 1st orders kinetics
Step 2
Step 3
Energetic Diagram
Step 1 Step 2
Step 3
Stereochemistry
Stereochemistry
To understand the stereochemistry of the SN1 reaction, we must examine the geometry of
the carbocation intermediate.
Stereochemistry
•Loss of the leaving group in Step [1] generates a planar carbocation that is achiral. In Step
[2], attack of the nucleophile can occur on either side to afford two products which are a
pair of enantiomers.
•Because there is no preference for nucleophilic attack from either direction, an equal
amount of the two enantiomers is formed—a racemic mixture. We say that racemization
has occurred.
Stereochemistry
Two examples of racemization in the SN1 reaction
•The rate of an SN1 reaction is affected by the type of alkyl halide involved.
•This trend is exactly opposite to that observed in SN2 reactions.

Carbocation Stability
• The effect of the type of alkyl halide on SN1 reaction rates can be explained by
considering carbocation stability.
• Carbocations are classified as primary (1°), secondary (2°), or tertiary (3°), based
on the number of R groups bonded to the charged carbon atom. As the number of
R groups increases, carbocation stability increases.
•The order of carbocation stability can be rationalized through inductive effects and
hyperconjugation.
Inductive effects are electronic effects that occur through  bonds. Specifically, the inductive
effect is the pull of electron density through  bonds caused by electronegativity differences
between atoms.
Electrostatic potential maps for
differerent carbocations
• Alkyl groups are electron donating groups that

stabilize a positive charge.
• The greater the number of alkyl groups attached to
a carbon with a positive charge, the more stable
will be the cation.
•Hyperconjugation is the spreading out of charge by the overlap of an empty p orbital with
an adjacent  bond. This overlap (hyperconjugation) delocalizes the positive charge on the
carbocation, spreading it over a larger volume, and this stabilizes the carbocation.
•Example: CH3+ cannot be stabilized by hyperconjugation, but (CH3)2CH+ can.
Just as aryl and vinyl carbocations are not stabilized by
resonance, they are also not stabilized by hyperconjugation:
Considering these effects, we can arrange the different types of carbocations on the :
3 w/out resonance 2 w/out resonance vinyl

3 w/ resonance > or > or >> 1 w/out resonance > methyl > or
2 w/ resonance 1 w/ resonance aryl
The type of carbon atoms highlighted in

red do not form carbocations in most cases
SN1 - Rearrangements
One consequence of reactions proceeding via carbocation intermediates is the occurrence of rearrangement
side reactions. Consider the following reaction:
The substitution product is a constitutional isomer of the product expected. Propose a mechanism for the
above reaction:
SN1 - Rearrangements
It is worth noting that carbocation rearrangements can

involve shifting either a hydride ion or a methyl anion.
In either case, you will always be forming a more stable
carbocation.
Pay close attention to the way curly arrows are drawn

when proposing a hydride or methyl shift. We should be
able to tell if you’re proposing a hydride shift or generation
of a pi bond.
SN1 and SN2 reactions – Solvent Effects
SN1 reactions are typically done in polar protic solvents. Polar protic solvents are used because they help
stabilize the transition state during the process of forming the carbocation intermediate. The more stabilized
the transition state, the faster the carbocation will form:
Some common polar protic solvents:

O
OH
C OH CH3CH2OH CH3OH H2O
H3C OH
Acetic Acid t-Butanol Methanol
AcOH Isopropanol Ethanol Water
(t-BuOH) (iPrOH) (EtOH) (MeOH)
SN1 and SN2 reactions – Solvent Effects
Polar aprotic solvents favor SN2 reactions because nucleophiles are not well solvated, and therefore, are
more nucleophilic.
• Polar protic solvents have acidic hydrogens (O—H or N—H) which can solvate the nucleophile reducing
their nucleophilicity.
SN1 vs. SN2 reactions – Comparison
SN2 SN1
Reaction Order second order reaction first order reaction
Minimum # Steps 1 or more steps 2 or more steps
Intermediates? not necessarily carbocation
Stereochemical stereospecific inversion of racemization (full or partial)

Consequences configuration at electrophilic site at electrophilic site
Importance of very important; no reaction unimportant

Nucleophile Strength for weak nucleophiles like H2O
Importance of very important; no reaction for very important; no reaction for
Leaving Group weak leaving groups like HO- weak leaving groups like HO-
Substrate Structure avoid steric hindrance; need carbocation stabilization;
Dependence CH3 > 1 > 2(slow) > 3 (no); 3 > 2 (slow) > 1 (no);
no reaction for aryl/vinyl resonance stabilization helps;
no reaction for aryl/vinyl
Rearrangements None Possible
Solvent polar aprotic polar protic

Predicting the Likely Mechanism of a
Substitution Reaction.
• Four factors are relevant in predicting whether a given reaction is likely to proceed by an SN1 or
an SN2 reaction.
The identity of the alkyl halide (the most important)
The nature of the nucleophile
The Leaving group
The nature of the solvent

The identity of the alkyl halide (the most important)
• Strong nucleophiles (which usually bear a negative charge) present in high concentrations favor SN2
reactions.
• Weak nucleophiles, such as H2O and ROH favor SN1 reactions by decreasing the rate of any competing SN2
reaction.
• Let us compare the substitution products formed when the 2° alkyl halide A is treated with either the
strong nucleophile HO¯ or the weak nucleophile H2O. Because a 2° alkyl halide can react by either
mechanism, the strength of the nucleophile determines which mechanism takes place.
• The strong nucleophile favors an SN2 mechanism.
• The weak nucleophile favors an SN1 mechanism.
81
The Leaving group • A better leaving group increases the rate of both
SN1 and SN2 reactions.
The nature of the solvent
• Polar protic solvents like H2O and ROH favor SN1 reactions because the
ionic intermediates (both cations and anions) are stabilized by solvation.
• Polar aprotic solvents favor SN2 reactions because nucleophiles are not well
solvated, and therefore, are more nucleophilic.
ALKYL HALIDES
1. Reactions of alkyl halides: nucleophilic substitutions and eliminations, SN2, SN1,
E2, and E1 reactions with stereochemical consequences, mechanisms, transition
states, and intermediates.
LECTURE 2
Elimination Reactions
Bibliography: Organic Chemistry, F.A. Carey, Chapter 4, 5 and 8

Organic Chemistry, Clayden-Warren, Chapter 16

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ORGANIC CHEMISTRY

Bibliography: Organic Chemistry, F.A. Carey, Chapter 4, 5 and 8

CHCl3 (Chloroform: organic solvent) CF2Cl2 (Freon-12: refrigerant CFC)

CF3CHClBr (Halothane: anesthetic)

• Halogens are more electronegative than C.

Electrostatic potential maps of

CH3 CH3 CH3

iso-butyl bromide sec-butyl bromide

• CX4 is carbon tetrahalide.

• Vicinal dihalide: two halogen atoms are bonded to adjacent carbons.

• Electronegativities of the halides:

• Free radical halogenation

3º carbons > 2º carbons > 1º carbons

• Free radical allylic halogenation

• Allylic radical is resonance stabilized.

• The mechanism involves an allylic radical stabilized by resonance.

• The halogen atom on the alkyl halide is replaced with

• Elimination reactions produce double bonds.

Three components are necessary in

• To draw any nucleophilic substitution product:

The Leaving Group

Basicity is a measure of how readily

OH- > H2O HS-> H2S NH2- > NH3

OH- > F- NH3 > H2O

• Increases down Periodic Table, as size and polarizability increase:

I- > Br- > Cl-

[2] Bond breaking occurs before bond making.

The back-side attack actually occurs in the SN2 reaction.

Steric hindrance between the

• In the TS, the C-Br bond is partiallly

The bond to the nucleophile in

• Methyl and 1° alkyl halides undergo easily SN2 reactions.

• Two energy barriers

• DHoverall is a negative value.

• Ea(1)>Ea(2) since 1st step involves

rate 1st orders kinetics

•This trend is exactly opposite to that observed in SN2 reactions.

• Alkyl groups are electron donating groups that

3 w/out resonance 2 w/out resonance vinyl

The type of carbon atoms highlighted in

It is worth noting that carbocation rearrangements can

Pay close attention to the way curly arrows are drawn

Some common polar protic solvents:

Minimum # Steps 1 or more steps 2 or more steps

Intermediates? not necessarily carbocation

Stereochemical stereospecific inversion of racemization (full or partial)

Importance of very important; no reaction unimportant

Rearrangements None Possible

Solvent polar aprotic polar protic

The identity of the alkyl halide (the most important)

The nature of the nucleophile

The Leaving group

The nature of the solvent

• The strong nucleophile favors an SN2 mechanism.

• The weak nucleophile favors an SN1 mechanism.

The nature of the solvent

Bibliography: Organic Chemistry, F.A. Carey, Chapter 4, 5 and 8

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