1

Chapter 6Alkyl Halides: Nucleophilic Substitution

and Elimination

Alkyl Halides and Reactions Slide 6-2

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 benzene ring. Examples:

C

H

H

H

C

H

H

Br

alkyl halide

C C

H

H

H

Cl

vinyl halide

I

aryl halide

2

Alkyl Halides and Reactions Slide 6-3

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.

Alkyl Halides and Reactions Slide 6-4

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.

CH3 CH CH2CH3

Cl CH3(CH2)2CH(CH2)2CH3

CH2CH2Br

2-chlorobutane 4-(2-bromoethyl)heptane

3

Alkyl Halides and Reactions Slide 6-5

Systematic Common Names• Name as alkyl halide.• Useful only for small alkyl groups.• Name these:

CH3 CH CH2CH3

Cl

(CH3)3CBr

CH3 CH

CH3

CH2F

Alkyl Halides and Reactions Slide 6-6

“Trivial” Names

• CH2X2 called methylene halide.• CHX3 is a haloform.• CX4 is carbon tetrahalide.• Examples:

CH2Cl2 is methylene chlorideCHCl3 is chloroformCCl4 is carbon tetrachloride.

4

Alkyl Halides and Reactions Slide 6-7

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.

Alkyl Halides and Reactions Slide 6-8

Dihalides

• Geminal dihalide: two halogen atoms are bonded to the samecarbon

• Vicinal dihalide: two halogen atoms are bonded to adjacentcarbons.

C

H

H

H

C

H

Br

Br

geminal dihalide

C

H

H

Br

C

H

H

Br

vicinal dihalide

5

Alkyl Halides and Reactions Slide 6-9

Uses of Alkyl Halides

• Solvents - degreasers and dry cleaning fluid• Reagents for synthesis of other compounds• Anesthetics: Halothane is CF3CHClBr

CHCl3 used originally (toxic and carcinogenic)• Freons, chlorofluorocarbons or CFC’s

Freon 12, CF2Cl2, now replaced with Freon 22,CF2CHCl, not as harmful to ozone layer.

• Pesticides - DDT banned in U.S.

Alkyl Halides and Reactions Slide 6-10

Dipole Moments

• µ = 4.8 x δ x d, where δ is the charge (proportional to ΔEN) and d is the distance (bond length) in Angstroms.

• Electronegativities: F > Cl > Br > I• Bond lengths: 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 shape, too!

6

Summary: Preparation of RX

Alkyl Halides and Reactions Slide 6-12

Preparation of RX via Free Radicals• Free radical halogenation (Chapter 4)

produces mixtures, not good lab synthesisunless: all H’s are equivalent, orhalogenation is highly selective (like bromination).

• Free radical allylic halogenationproduces alkyl halide with double bond on the

neighboring carbon (allyl halides).

7

Alkyl Halides and Reactions Slide 6-13

Halogenation of Alkanes• All H’s equivalent. Restrict amount of halogen to prevent di- or

trihalide formation

• Highly selective: bromination of 3° C

+ HBr

H

Brh!

Br2+

H

H

90%

+ HBrCH3 C

CH3

CH3

Brh!

Br2+CH3 C

CH3

CH3

H

Alkyl Halides and Reactions Slide 6-14

Allylic Halogenation• Allylic radical is resonance stabilized.• Bromination occurs with good yield at the allylic position (sp3

C next to C=C).• Avoid a large excess of Br2 by using

N-bromosuccinimide (NBS) to generate Br2 as product HBr isformed.

=>

8

Alkyl Halides and Reactions Slide 6-15

Reaction MechanismFree radical chain reaction (from before)

initiation, propagation, termination.

H H

Br

H

+ HBr

Br

Br

H Br

+ Br

2BrBr2h!

Alkyl Halides and Reactions Slide 6-16

Substitution Reactions

• The halogen atom on the alkyl halide is replaced with anothergroup.

• Since the halogen is more electronegative than carbon, the C-Xbond breaks heterolytically and X- leaves.

• The group replacing X- is a nucleophile.

C C

H X

+ Nuc:-

C C

H Nuc

+ X:-

9

Alkyl Halides and Reactions Slide 6-17

Elimination Reactions

• The alkyl halide loses halogen as a halide ion, and also losesH+ on the adjacent carbon to a base.

• A pi bond is formed. Product is an alkene.• Also called dehydrohalogenation (-HX).

C C

H X

+ B:-

+ X:- + HB C C

Alkyl Halides and Reactions Slide 6-18

• Bimolecular nucleophilic substitution.• Concerted reaction: new bond forming and

old bond breaking at same time.• Rate is first order in each reactant.• Walden inversion.

SN2 Mechanism

C

H

Br

HH

H O CHO Br

H

HH

CHO

H

HH

+ Br-

10

Alkyl Halides and Reactions Slide 6-19

SN2 Energy Diagram

• One-step reaction.• Transition state is highest in energy. =>

Alkyl Halides and Reactions Slide 6-20

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

=>

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Alkyl Halides and Reactions Slide 6-21

SN2: Nucleophilic Strength• Stronger nucleophiles react faster.• Strong bases are strong nucleophiles, but not all strong

nucleophiles are basic.

=>

Alkyl Halides and Reactions Slide 6-22

Trends inNucleophilic Strength

• Of a conjugate acid-base pair, the base is stronger: OH- >H2O, NH2

- > NH3

• Decreases left to right on Periodic Table. Moreelectronegative atoms less likely to form new bond: OH- >F-, NH3 > H2O

• Increases down Periodic Table, as size and polarizabilityincrease: I- > Br- > Cl-

=>

12

Alkyl Halides and Reactions Slide 6-23

Polarizability Effect

=>

Alkyl Halides and Reactions Slide 6-24

Bulky NucleophilesSterically hindered for attack on carbon, so weaker

nucleophiles.

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

C

CH3

H3C

CH3

O

t-butoxide (hindered)stronger base, but weaker nucleophile

13

Alkyl Halides and Reactions Slide 6-25

Solvent Effects (1)Polar protic solvents (O-H or N-H) reduce the strength of the

nucleophile. Hydrogen bonds must be broken beforenucleophile can attack the carbon.

=>

Alkyl Halides and Reactions Slide 6-26

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

nucleophile.• Examples:

CH3 C N

acetonitrile

C

O

H3C CH3

acetone

=>dimethylformamide (DMF)

CH

O

NCH3

CH3

14

Alkyl Halides and Reactions Slide 6-27

Crown Ethers• Solvate the cation, so

nucleophilic strength of theanion increases.

• Fluoride becomes a goodnucleophile.

O

O

O

O

O

O

K

+

1 8 - c r o w n - 6

CH2Cl

KF, (18-crown-6)

CH3CN

CH2F

=>

Alkyl Halides and Reactions Slide 6-28

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 Reactions Slide 6-29

Structure of Substrate• Relative rates for SN2:

CH3X > 1° > 2° >> 3°

• Tertiary halides do not react via the SN2mechanism, due to steric hindrance.=>

Structure of Substrate

Alkyl Halides and Reactions Slide 6-30

Steric Hindrance

• Nucleophile approaches from the back side.• It must overlap the back lobe of the C-X sp3 orbital.

=>

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Alkyl Halides and Reactions Slide 6-31

Stereochemistry of SN2

Walden inversion

=>

Alkyl Halides and Reactions Slide 6-32

SN1 Reaction

• Unimolecular nucleophilic substitution.• Two step reaction with carbocation intermediate.• Rate is first order in the alkyl halide, zero order in the

nucleophile.• Racemization occurs.

=>

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Alkyl Halides and Reactions Slide 6-33

SN1 Mechanism (1)Formation of carbocation (slow)

(CH3)3C Br (CH3)3C+

+ Br-

=>

Alkyl Halides and Reactions Slide 6-34

SN1 Mechanism (2)• Nucleophilic attack

(CH3)3C+

+ H O H (CH3)3C O H

H

(CH3)3C O H

H

H O H+ (CH3)3C O H + H3O+

=>

• Loss of H+ (if needed)

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Alkyl Halides and Reactions Slide 6-35

SN1 Energy Diagram• Forming the carbocation is

endothermic• Carbocation intermediate is

in an energy well.

=>

Alkyl Halides and Reactions Slide 6-36

Rates of SN1 Reactions

• 3° > 2° > 1° >> CH3XOrder 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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Alkyl Halides and Reactions Slide 6-37

Stereochemistry of SN1Racemization:

inversion and retention

=>

Alkyl Halides and Reactions Slide 6-38

Rearrangements• Carbocations can rearrange to form a more stable

carbocation.• Hydride shift: H- on adjacent carbon bonds with C+.• Methyl shift: CH3

- moves from adjacent carbon if no H’s areavailable.

=>

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Alkyl Halides and Reactions Slide 6-39

Hydride Shift

CH3 C

Br

H

C

H

CH3

CH3CH3 C

H

C

H

CH3

CH3

CH3 C

H

C

H

CH3

CH3CH3 C

H

C

CH3

CH3

H

CH3 C

H

C

CH3

CH3

H

NucCH3 C

H

C

CH3

CH3

H Nuc

=>

Alkyl Halides and Reactions Slide 6-40

Methyl Shift

CH3 C

Br

H

C

CH3

CH3

CH3CH3 C

H

C

CH3

CH3

CH3

CH3 C

H

C

CH3

CH3

CH3CH3 C

H

C

CH3

CH3

CH3

CH3 C

H

C

CH3

CH3

CH3

NucCH3 C

H

C

CH3

CH3

CH3 Nuc

=>

21

Alkyl Halides and Reactions Slide 6-41

SN2 or SN1?

• Primary or methyl• Strong nucleophile

• Polar aprotic solvent

• Rate = k[halide][Nuc]• Inversion at chiral carbon• No rearrangements

• Tertiary• Weak nucleophile (may also be

solvent)

• Polar protic solvent, silver salts• Rate = k[halide]• Racemization of optically active

compound

• Rearranged products =>

Alkyl Halides and Reactions Slide 6-42

E1 Reaction• Unimolecular elimination• Two groups lost (usually X- and H+)• Nucleophile acts as base• Also have SN1 products (mixture)

=>

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Alkyl Halides and Reactions Slide 6-43

E1 Mechanism

• Halide ion leaves, forming carbocation.• Base removes H+ from adjacent carbon.• Pi bond forms. =>

O

H

H

C

H

H

H

C CH3

CH3

C C

H

CH3

CH3

H+ H3O

+

H C

H

H

C

CH3

CH3

Br

C

H

H

H

C CH3

CH3

Alkyl Halides and Reactions Slide 6-44

A Closer LookO

H

H

C

H

H

H

C CH3

CH3

C C

H

CH3

CH3

H+ H3O

+

=>

23

Alkyl Halides and Reactions Slide 6-45

E1 Energy Diagram

Note: first step is same as SN1=>

Alkyl Halides and Reactions Slide 6-46

Zaitsev’s Rule

• If more than one elimination product is possible, the most-substitutedalkene is the major product (most stable).

• R2C=CR2 > R2C=CHR > RHC=CHR > H2C=CHR tetra > tri > di > mono

C C

Br

H

C

H

CH3

H

H

H

CH3

OH-

C C

H

HC

H H

CH3

CH3

C

H

H

H

C

H

C

CH3

CH3

+

=>minor major

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Alkyl Halides and Reactions Slide 6-47

E2 Reaction• Bimolecular elimination• Requires a strong base• Halide leaving and proton abstraction happens

simultaneously - no intermediate. =>

Alkyl Halides and Reactions Slide 6-48

E2 Mechanism

H C

H

H

C

CH3

CH3

Br

C C

H

CH3

CH3

H

O

H

+ H2O Br-

+

=>

• Order of reactivity: 3° > 2 ° > 1°• Mixture may form, but Zaitsev productpredominates.

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Alkyl Halides and Reactions Slide 6-49

E2 Stereochemistry

=>

Alkyl Halides and Reactions Slide 6-50

E1 or E2?

• Tertiary > Secondary• Weak base• Good ionizing solvent

• Rate = k[halide]• Zaitsev product• No required geometry

• Rearranged products

• Tertiary > Secondary• Strong base required• Solvent polarity not important• Rate = k[halide][base]• Zaitsev product• Coplanar leaving groups

(usually anti)• No rearrangements

=>

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Alkyl Halides and Reactions Slide 6-51

Substitution or Elimination?

• Strength of the nucleophile determines order: Strongnucleophile, bimolecular, SN2 or E2.

• Primary halide 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.

=>

Alkyl Halides and Reactions Slide 6-52

Secondary Halides?

Mixtures of products are common.

=>

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Alkyl Halides and Reactions Slide 6-53

Chapter 6 Homework Problems

43-46, 49, 50, 52, 54, 56, 57, 58, 61, 64,66, 67, 71-73, 75