Organohalides: Nucleophilic

Substitution and Elimination Reactions

NH
HO

HO
OH

Adrenaline

Ms Mputumana
Office 3-501
Learning Outcomes

 Explain the reactivity of the C-X bond

 Name the alkyl halides according to the IUPAC system
 Propose reactions to prepare alkyl halides
 Predict the products of the reactions of alkyl halides
 Explain the mechanisms of nucleophilic substitution
(including Walden inversion of configuration) and elimination reactions
 Explain the reaction kinetics and factors influencing the rate of the substitution
and elimination reactions
 Use the simple reactions of methods to prepare and transform alkyl halides
as part of multi-step synthetic proposals of more elaborate molecules
 Classes of Halides

• Alkyl: Halogen, X, is directly bonded to sp3

carbon.
• Vinyl: X is bonded to sp2 carbon of alkene.
• Aryl: X is bonded to sp2 carbon on the benzene ring.
• Allylic: X bonded to the carbon atom adjacent to
a C—C double bond.
• Benzylic: X bonded to the carbon atom adjacent to
a benzene ring.

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 Classes of Halides
Examples:
 Classes of Alkyl Halides

• Methyl halides: only one C, CH3X

• Primary: C to which X is bonded has only one C-C bond.
• Secondary: C to which X is bonded has two C-C bonds.
• Tertiary: C to which X is bonded has three C-C bonds.

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 Dihalides
• Geminal dihalide: two halogen atoms are bonded to the
same carbon
• Vicinal dihalide: two halogen atoms are bonded to
adjacent carbons.

H H H H

H C C Br H C C H

H Br Br Br

geminal dihalide vicinal dihalide 6

 IUPAC Nomenclature

• Name as haloalkane.
• Choose the longest carbon chain, even if the halogen is not
bonded to any of those C’s.
• Use the lowest possible numbers for position.

CH2CH2Br

H 3C CH CH2 CH3 CH3(CH2)2CH(CH2)2CH3

Cl
4-(2-bromoethyl)heptane
2-chlorobutane

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 Alkyl Halides and Nucleophilic Substitution

Physical Properties
 Alkyl Halides and Nucleophilic Substitution

Interesting Alkyl Halides

Chloromethane: is produced by giant kelp and algae and also

found in emissions of volcanoes such as Hawaii’s Kilauea.

Dichloromethane (or methylene chloride) is an important

solvent, once used to decaffeinate coffee.

Halothane is a safe general anesthetic

 Alkyl Halides and Nucleophilic Substitution
Interesting Alkyl Halides
 Preparation of RX

• Free radical halogenation

□ produces mixtures, not good lab synthesis
□ unless: all H’s are equivalent, or
□ halogenation is highly selective.
• Free radical allylic halogenation
□ produces alkyl halide with a double bond on the neighboring
carbon.

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 Halogenation of Alkanes

• All H’s equivalent. Restrict the amount of halogen to prevent di-

or trihalide formation

• Highly selective: bromination of 3° C

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 Preparation of RX

• Reaction of alcohols with HX

• Reaction of 1o and 2o alcohols with PBr3

• Reaction of 1o and 2o alcohols with SOCl2

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 Reaction of alkyl halides:
Organometallic reagents
• Carbon is bonded to a metal (Mg or Li).
• Carbon is nucleophilic (partially negative).
• It will attack a partially positive carbon.
□ C-X
□ C=O
• A new carbon-carbon bond forms.

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 Reaction of alkyl halides:
Organometallic reagents
• Alkyl halides react with magnesium metal in ether or
tetrahydrofuran (THF) to form alkylmagnesium halides, RMgX.

• The products are called Grignard reagents after their

discoverer, Victor Grignard.

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 Grignard Reagents

• Formula R-Mg-X (reacts like R:- +MgX)

• Stabilized by anhydrous ether
• The halogens can be Cl, Br or I. Iodides most
reactive
• May be formed from any halide
□ primary
□ secondary
□ tertiary
□ vinyl
□ aryl

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 Grignard Reagents
• Grignard reagent is the magnesium salt, R3C- +MgX of a
carbon acid, R3C-H, and is thus a carbon anion, or a
carbanion (C-). But because hydrocarbons are such weak
acids carbon anions are very strong bases.

• Therefore, Grignard reagents must be very protected from

atmospheric moisture to prevent their being protonated and
destroyed.
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 Some Grignard Reagents

How would you synthesize hexane from 1-bromohexane?

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 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 electron pair.

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Nucleophilic Substitution Reactions

Three components are necessary in any substitution reaction.

sp3 hybridized C
leaving group

nucleophile

• The halogen atom on the alkyl halide is replaced with

another group.
• Since the halogen is more electronegative than carbon, the
C-X bond breaks heterolytically and X- leaves.
• The group replacing X- is a nucleophile.
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 Alkyl Halides and Nucleophilic Substitution
General Features of Nucleophilic Substitution

• 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.
 Alkyl Halides and Nucleophilic Substitution General
Features of Nucleophilic Substitution
• 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:

o Find the sp3 hybridized carbon with the leaving group.
o Identify the nucleophile, the species with a lone pair or π bond.
o Substitute the nucleophile for the leaving group and assign
charges (if necessary) to any atom that is involved in bond
breaking or bond formation.
 SN2: Nucleophilic Strength

• Stronger nucleophiles react faster.

• Strong bases are strong nucleophiles, but not all strong
nucleophiles are basic.
• A negatively charged nucleophile is always a stronger
nucleophile than its conjugate acid.
Common Nucleophiles, Listed decreasing order of
Nucleophilicity in hydroxylic solvents such as water and the
alcohols

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 SN2: Nucleophilic Strength

Common Nucleophiles, Listed in decreasing order of

Nucleophilicity in hydroxylic solvents such as water and the
Alcohols.

Strong nucleophiles: Moderate Nucleophiles:

Weak nucleophiles:

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 Uses for SN2 Reactions
• Synthesis of other classes of compounds.
• Halogen exchange reaction.

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 Bulky Nucleophiles
Sterically hindered for attack on carbon, so weaker
nucleophiles.

CH3 CH2 O
ethoxide (unhindered)
weaker base, but stronger nucleophile

CH3

CH3 C O

CH3
t-butoxide (hindered)
stronger base, but weak nucleophile
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 Solvent Effects (1)
• Polar protic solvents (O-H or N-H) reduce the strength of the
nucleophile. Hydrogen bonds must be broken before
nucleophiles can attack the carbon.

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 Solvent Effects (2)
• Polar aprotic solvents (no O-H or N-H) do not form
hydrogen bonds with nucleophile
• Examples:

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Solvent Effects (2)

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 Leaving Group Ability
• Electron-withdrawing
• Stable once it has left (not a strong base)
• Polarizable to stabilize the transition state.

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 Alkyl Halides and Nucleophilic
Substitution The Leaving Group
• There are periodic trends in leaving group ability:
 Alkyl Halides and Nucleophilic Substitution

The Leaving Group

Alkyl Halides and Nucleophilic Substitution
Mechanisms for Nucleophilic Substitution
In a nucleophilic substitution:

But what is the order of bond making and bond breaking? In theory,
there are three possibilities.
[1] Bond making and bond breaking occur at the same time (SN2).

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.
 SN2 Mechanism

• Bimolecular nucleophilic substitution.

• Concerted reaction: new bond forming and old
bond breaking at same time.
• Rate is first order in each reactant.
• Walden inversion.

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 Alkyl Halides and Nucleophilic Substitution
Mechanisms of Nucleophilic Substitution
• All SN2 reactions proceed with backside attack of the nucleophile,
resulting in inversion of configuration at a stereogenic center.
Stereochemistry of SN2
Walden inversion

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 SN2 Energy Diagram

• One-step reaction.
• Transition state is highest in energy. 37
 Alkyl Halides and Nucleophilic Substitution
Mechanisms of Nucleophilic Substitution
 Alkyl Halides and Nucleophilic Substitution
Mechanisms of Nucleophilic Substitution
 SN2: Reactivity of Substrate

• Carbon must be partially positive.

• Must have a good leaving group
• Carbon must not be sterically hindered.

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 Structure of Substrate

• Relative rates for SN2:

CH3X > 1° > 2° >> 3°

• Tertiary halides do not react via the SN2 mechanism, due

to steric hindrance.
• Steric hindrance caused by bulky R groups makes nucleophilic
attack from the backside more difficult, slowing the reaction
rate.

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 Alkyl Halides and Nucleophilic Substitution
Mechanisms for Nucleophilic Substitution
[2] Bond breaking occurs before bond making (SN1).

• Unimolecular nucleophilic substitution.

• Two step reaction with carbocation intermediate.
• Rate is first order in the alkyl halide, zero order in the nucleophile
• Racemization occurs.
 SN1 Mechanism (1)
• Formation of carbocation (slow)

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 SN1 Mechanism (2)
• Nucleophilic attack

• Loss of H+ (if needed)

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 SN1 Energy Diagram
• Forming the carbocation is endothermic
• Carbocation intermediate is in an energy well.

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 Rates of SN1 Reactions

• 3° > 2° > 1° >> CH3X

□ Order follows stability of carbocations (opposite to SN2)
□ More stable ion requires less energy to form
• Better leaving group, faster reaction (like SN2)
• Polar protic solvent best: It solvates ions strongly with
hydrogen bonding.

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 Stereochemistry of SN1
• Racemization: inversion and retention

=>
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 Stereochemistry of SN1
• Racemization: inversion and retention

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 SN2 or SN1?
• Primary or methyl • Tertiary
• Strong nucleophile • Weak nucleophile (may
also be solvent)
• Polar aprotic solvent
• Polar protic solvent, silver
• Rate = k[halide][Nuc] salts
• Inversion at chiral • Rate = k[halide]
carbon • Racemization of optically
• No rearrangements active compound

• Rearranged products

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 Elimination Reactions

• The alkyl halide loses halogen as a halide ion, and also loses
H+ on the adjacent carbon to a base.
• A pi bond is formed. Product is alkene.
• Also called dehydrohalogenation (-HX).

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 E1 Reaction

• Unimolecular elimination
• Two groups lost (usually X- and H+)
• Nucleophile acts as base
• Also have SN1 products (mixture)

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 E1 Mechanism

• Halide ion leaves, forming carbocation.

• Base removes H+ from adjacent carbon.
• Pi bond forms.
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A Closer Look

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 Alkyl Halides and Elimination Reactions
Mechanisms of Elimination—E1

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 E2 Reaction

• Bimolecular elimination
• Requires a strong base
• Halide leaving and proton abstraction happens simultaneously
- no intermediate.

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E2 Mechanism

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 Saytzeff’s Rule
Alkenes—The Products of Elimination
• Alkenes are classified according to the number of carbon
atoms bonded to the carbons of the double bond.

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 Saytzeff’s Rule

• If more than one elimination product is possible, the most-

substituted alkene is the major product (most stable).
• A reaction is regioselective when it yields predominantly or
exclusively one constitutional isomer when more than one is
possible. Thus, the E2 reaction is regioselective.

minor major 60
Saytzeff’s Rule

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E2 Stereochemistry

Chapter 6 62
 E1 or E2?
• Tertiary > Secondary • Tertiary > Secondary
• Weak base • Strong base required
• Good ionizing solvent • Solvent polarity not
important
• Rate = k[halide] • Rate = k[halide][base]
• Saytzeff product • Saytzeff product
• No required geometry • Coplanar leaving groups
(usually anti)
• Rearranged products • No rearrangements

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 Substitution or Elimination?

• Strength of the nucleophile determines order: Strong nuc.

will go SN2 or E2.
• Primary halide is usually SN2.
• Tertiary halide mixture of SN1, E1 or E2
• High temperature favors elimination.
• Bulky bases favor elimination.
• Good nucleophiles, but weak bases, favor substitution.

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 Secondary Halides?
Mixtures of products are common.

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 Alkyl Halides and Elimination Reactions

Mechanisms of Elimination—E1
• E1 reactions are regioselective, favoring formation of the
more substituted, more stable alkene.
• Zaitsev’s rule applies to E1 reactions also.

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