Substitution and Elimination

1
Substitution and Elimination

• Reaction of Alkyl Halides
• By Ismiyarto, MSi

2
ALKIL HALIDA

• Manfaat (Pestisida, Bahan Dasar Sintesis Alkohol,
  Alkena)
• Struktur (Metil, Primer, Sekunder, Tersier,
  Benzil dan Vinil)
• Reaksi (SN-2, SN-1, E-2 dan E-1)

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PETA REAKSI ALKIL HALIDA
SN-2

• Metil Halida
• Alkil halida Primer
• Alkil Halida Sekunder
• Alkil Halida Tersier
• Alil Halida
• Benzil Halida

SN-2
SN-2, SN-1 dan E-2
SN-2, SN-1 dan E-2
SN-2, SN-1
SN-2, SN-1
4
Organic compounds with an electronegative atom or
an electron-withdrawing group bonded to a sp3
carbon undergo substitution or elimination
reactions
-
Substitution
Elimination
Halide ions are good leaving groups. Substitution
reaction on these compounds are easy and are used
to get a wide variety of compounds
alkyl fluoride
alkyl chloride
alkyl bromide
alkyl iodide
5
Alkyl Halides in Nature
Synthesized by red algae
red algae
Synthesized by sea hare
a sea hare
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Substitution Reaction with Halides
(1)
(2)
bromomethane
methanol
If concentration of (1) is doubled, the rate of
the reaction is doubled.
If concentration of (1) and (2) is doubled, the
rate of the reaction quadruples.
If concentration of (2) is doubled, the rate of
the reaction is doubled.
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Substitution Reaction with Halides
(1)
(2)
bromomethane
methanol
Rate law rate k bromoethaneOH- this
reaction is an example of a SN2 reaction. S
stands for substitution N stands for nucleophilic
2 stands for bimolecular
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Mechanism of SN2 Reactions
Alkyl halide Relative rate
1200
40
1
0
The rate of reaction depends on the
concentrations of both reactants.
When the hydrogens of bromomethane are replaced
with methyl groups the reaction rate slow down.
The reaction of an alkyl halide in which the
halogen is bonded to an asymetric center leads to
the formation of only one stereoisomer
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Mechanism of SN2 Reactions
Hughes and Ingold proposed the following
mechanism
Transition state
Increasing the concentration of either of the
reactant makes their collision more probable.
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Mechanism of SN2 Reactions
Steric effect
activation energy DG2
activation energy DG1
Energy
reaction coordinate
reaction coordinate
Inversion of configuration
(S)-2-bromobutane
(R)-2-butanol
11
Factor Affecting SN2 Reactions
The leaving group
The nucleophile
In general, for halogen substitution the
strongest the base the better the nucleophile.
pKa
Nuclephilicity
12
SN2 Reactions With Alkyl Halides
an alcohol
a thiol
an ether
a thioether
an amine
an alkyne
a nitrile
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Substitution Reactions With Halides
1-bromo-1,1-dimethylethane
1,1-dimethylethanol
Rate law rate k 1-bromo-1,1-dimethylethane
this reaction is an example of a SN1
reaction. S stands for substitution N stands for
nucleophilic 1 stands for unimolecular
If concentration of (1) is doubled, the rate of
the reaction is doubled.
If concentration of (2) is doubled, the rate of
the reaction is not doubled.
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Mechanism of SN1 Reactions
Alkyl halide Relative rate
0
0
12
1 200 000
The rate of reaction depends on the
concentrations of the alkyl halide only.
When the methyl groups of 1-bromo-1,1-dimethyletha
ne are replaced with hydrogens the reaction rate
slow down.
The reaction of an alkyl halide in which the
halogen is bonded to an asymetric center leads to
the formation of two stereoisomers
a small rate is actually observed as a result
of a SN2
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Mechanism of SN1 Reactions
nucleophile attacks the carbocation
slow
C-Br bond breaks
fast
Proton dissociation
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Mechanism of SN1 Reactions
Rate determining step
Carbocation intermediate
DG
R X-

R-OH2
R-OH
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Mechanism of SN1 Reactions
Inverted configuration relative the alkyl halide
Same configuration as the alkyl halide
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Factor Affecting SN1 reaction

• Two factors affect the rate of a SN1 reaction
• The ease with which the leaving group
  dissociate from the carbon
• The stability of the carbocation

The more the substituted the carbocation is, the
more stable it is and therefore the easier it is
to form.
As in the case of SN2, the weaker base is the
leaving group, the less tightly it is bonded to
the carbon and the easier it is to break the bond
The reactivity of the nucleophile has no effect
on the rate of a SN1 reaction
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Comparison SN1 SN2
SN1 SN2
A two-step mechanism A one-step mechanism
A unimolecular rate-determining step A bimolecular rate-determining step
Products have both retained and inverted configuration relative to the reactant Product has inverted configuration relative to the reactant
Reactivity order 3o gt 2o gt 1o gt methyl Reactivity order methyl gt 1o gt 2o gt 3o
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Kestabilan Karbokation
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(No Transcript)
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Elimination Reactions
1-bromo-1,1-dimethylethane
2-methylpropene
Rate law rate k 1-bromo-1,1-dimethylethane
OH- this reaction is an example of a E2
reaction. E stands for elimination 2 stands for
bimolecular
23
The E2 Reaction
A proton is removed
Br- is eliminated
The mechanism shows that an E2 reaction is a
one-step reaction
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Elimination Reactions
1-bromo-1,1-dimethylethane
2-methylpropene
Rate law rate k 1-bromo-1,1-dimethylethane
this reaction is an example of a E1 reaction. E
stands for elimination 1 stands for unimolecular
If concentration of (1) is doubled, the rate of
the reaction is doubled.
If concentration of (2) is doubled, the rate of
the reaction is not doubled.
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The E1 Reaction
The base removes a proton
The alkyl halide dissociate, forming a carbocation
The mechanism shows that an E1 reaction is a
two-step reaction
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Products of Elimination Reaction
50
30
80
2-butene
20
2-bromobutane
1-butene
The most stable alkene is the major product of
the reaction for both E1 and E2 reaction
The greater the number of alkyl substituent the
more stable is the alkene
For both E1 and E2 reactions, tertiary alkyl
halides are the most reactive and primary alkyl
halides are the least reactive
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ELIMINATION REACTIONSALKENES, ALKYNES
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Elimination Reactions
Dehydrohalogenation (-HX) and Dehydration (-H2O)
are the main types of elimination reactions.
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Dehydrohalogenation (-HX)
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The E2 mechanism

• This reaction is done in strong base at high
  concentration, such as 1 M NaOH in water.

_
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Kinetics

• The reaction in strong base at high concentration
  is second order (bimolecular)
• Rate law rate kOH-1R-Br1

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The E1 mechanism

• This reaction is done in strong base such as 0.01
  M NaOH in water!! Actually, the base solution is
  weak!

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Kinetics

• The reaction in weak base or under neutral
  conditions will be first order (unimolecular)
• Rate law rate k R-Br1
• The first step (slow step) is rate determining!

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The E2 mechanism

• Mechanism
• Kinetics
• Stereochemistry of reactants
• Orientation of elimination (Zaitsevs rule)
• Stereochemistry of products
• Competing reactions

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E2 mechanism

• This reaction is done in strong base at high
  concentration, such as 1 M NaOH in water.

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Kinetics of an E2 reaction

• The reactions are second order (bimolecular
  reactions).
• Rate k R-Br1Base1
• second order reaction (1 1 2)
• High powered math!!

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Transition State
energy
Reaction coordinate
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Stereochemistry of reactants

• E2 reactions must go by an anti elimination
• This means that the hydrogen atom and halogen
  atom must be 180o (coplanar) with respect to each
  other!!
• Draw a Newman projection formula and place the H
  and X on opposite sides.

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Stereochemistry of E2 Reaction
H and Br are anti structure in conformation!!!!!!!
!!
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(S,S)-diastereomer
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This one is formed!
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(R,S)-diastereomer
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This one is formed!
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Orientation of elimination regiochemistry/
Zaitsevs Rule

• In reactions of removal of hydrogen halides from
  alkyl halides or the removal of water from
  alcohols, the hydrogen which is lost will come
  from the more highly-branched b-carbon.

More branched
Less branched
A. N. Zaitsev -- 1875
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Product formed from previous slide
More substituted alkene is more stable!!!!!!!!
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Typical bases used in E2 reactions

• High concentration of the following gt1M
• If the concentration isnt given, assume
• that it is high concentration!
• Na -OH
• K -OH
• Na -OR
• Na -NH2

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Orientation of elimination regiochemistry/
Zaitsevs Rule

• Explaination of Zaitsevs rule
• When you remove a hydrogen atom from the more
  branched position, you are forming a more highly
  substituted alkene.

48
Stereochemistry of products

• The H and X must be anti with respect to each
  other in an E2 reaction!
• You take what you get, especially with
  diastereomers! See the previous slides of the
  reaction of diastereomers.

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Competing reactions

• The substitution reaction (SN2) competes with the
  elimination reaction (E2).
• Both reactions follow second order kinetics!

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The E1 mechanism

• Mechanism
• Kinetics
• Stereochemistry of reactants
• Orientation of elimination (Zaitsevs rule)
• Stereochemistry of products
• Competing reactions

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E1 mechanism

• This reaction is done in strong base at low
  concentration, such as 0.01 M NaOH in water)

52
E1 Reactions

• These reactions proceed under neutral conditions
  where a polar solvent helps to stabilize the
  carbocation intermediate.
• This solvent also acts as a weak base and removes
  a proton in the fast step.
• These types of reactions are referred to as
  solvolysis reactions.

53

• tertiary substrates go by E1 in polar solvents,
  with little or no base present!
• typical polar solvents are water, ethanol,
  methanol and acetic acid
• These polar solvents help stabilize carbocations
• E1 reactions also occur in a low concentration of
  base (i.e. 0.01M NaOH).

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However!!!!

• With strong base (i.e. gt1M), goes by E2

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Structure of the Carbocation Intermediate
56
Carbocation stability order

• Tertiary (3o) gt secondary (2o) gt primary (1o)
• It is hard (but not impossible) to get primary
  compounds to go by E1. The reason for this is
  that primary carbocations are not stable!

57
Kinetics of an E1 reaction

• E1 reactions follow first order (unimolecular)
  kinetics
• Rate k R-X1
• The solvent helps to stabilize the carbocation,
  but it doesnt appear in the rate law!!

58
d-
d
d
d

energy
intermediate
Reaction coordinate
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Stereochemistry of the reactants

• E1 reactions do not require an anti coplanar
  orientation of H and X.
• Diastereomers give the same products with E1
  reactions, including cis- and trans products.
• Remember, E2 reactions usually give different
  products with diastereomers.

60
Orientation of elimination

• E1 reactions faithfully follow Zaitsevs rule!
• This means that the major product should be the
  product that is the most highly substituted.

61
Stereochemistry of products

• E1 reactions usually give the thermodynamically
  most stable product as the major product. This
  usually means that the largest groups should be
  on opposite sides of the double bond. Usually
  this means that the trans product is obtained.

62
Competing reactions

• The substitution reaction (SN1) competes with the
  elimination reaction (E1).
• Both reactions follow first order kinetics!

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Whenever there are carbocations

• They can undergo elimination (E1)
• They can undergo substitution (SN1)
• They can rearrange
• and then undergo elimination
• or substituion

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Rearrangements

• Alkyl groups and hydrogen can migrate in
  rearrangement reactions to give more stable
  intermediate carbocations.
• You shouldnt assume that rearrangements always
  occur in all E1 reactions, otherwise paranoia
  will set in!!

65
Comparison of E2 / E1

• E1 reactions occur under essentially neutral
  conditions with polar solvents, such as water,
  ethyl alcohol or acetic acid.
• E1 reactions can also occur with strong bases,
  but only at low concentration, about 0.01 to 0.1
  M or below.
• E2 reactions require strong base in high
  concentration, about 1 M or above.

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Comparison of E2 / E1

• E1 is a stepwise mechanism (two or more)
• Carbocation intermediate!
• E2 is a concerted mechanism (one step)
• No intermediate!
• E1 reactions may give rearranged products
• E2 reactions dont give rearrangement
• Alcohol dehydration reactions are E1

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Bulky leaving groupsHofmann Elimination

• This give the anti-Zaitsev product (least
  substituted product is formed)!

68
Orientation of elimination regiochemistry/
Hofmanns Rule

• In bimolecular elimination reactions in the
  presence of either a bulky leaving group or a
  bulky base, the hydrogen that is lost will come
  from the LEAST highly-branched b-carbon.

More branched
Less branched
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Product from previous slide
70
Elimination with bulky bases

• Non-bulky bases, such as hydroxide and ethoxide,
  give Zaitsev products.
• Bulky bases, such as potassium tert-butoxide,
  give larger amounts of the least substituted
  alkene (Hoffmann) than with simple bases.

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Comparing Ordinary and Bulky Bases
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1-butene watch out for competing reactions!
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Highlights

• Dehydrohalogenation -- E2 Mechanism
• Zaitsevs Rule
• Dehydrohalogenation -- E1 Mechanism
• Carbocation Rearrangements -- E1
• Elimination with Bulky Leaving Groups and Bulky
  Bases -- Hofmann Rule -- E2

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Competition Between SN2/E2 and SN1/E1
SN1
SN2
E1
E2
rate k1alkyl halide k2alkyl
halidenucleo. k3alkyl halide k2alkyl
halidebase

• SN2 and E2 are favoured by a high concentration
  of a good nucleophile/strong base
• SN1 and E1 are favoured by a poor
  nucleophile/weak base, because a poor
  nucleophile/weak base disfavours SN2 and E2
  reactions

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Competition Between Substitution and Elimination

• SN2/E2 conditions

In a SN2 reaction 1o gt 2o gt 3o In a E2
reaction 3o gt 2o gt 1o
10
90
75
25
100
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Competition Between Substitution and Elimination

• SN1/E1 conditions

All alkyl halides that react under SN1/E1
conditions will give both substitution and
elimination products (50/50)
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Summary

• Alkyl halides undergo two kinds of nucleophilic
  subtitutions SN1 and SN2, and two kinds of
  elimination E1 and E2.
• SN2 and E2 are bimolecular one-step reactions
• SN1 and E1 are unimolecular two step reactions
• SN1 lead to a mixture of stereoisomers
• SN2 inverts the configuration od an asymmetric
  carbon
• The major product of a elimination is the most
  stable alkene
• SN2 are E2 are favoured by strong
  nucleophile/strong base
• SN2 reactions are favoured by primary alkyl
  halides
• E2 reactions are favoured by tertiary alkyl
  halides

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REAKSI ADISI ALKENA
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Addition Reaction of Alkene

• HX Addition
• Electrophilic Addition (Markovnikov Product)
• Free Radical Mechanism (Anti-Mark Product)
• Hydration ( H2O)
• Halogenation/ Hydrohalogenation
• Reduction or Hydrogenation ( H2 )
• Oxidation
• Multi-step Synthesis

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Addition of Halogens to Alkenes

• electrophilic addition to double bond
• forms a vicinal dihalide

X2 Cl2 or Br2
F2 explosive I2 endothermic
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Example
Br2
CH3CHCHCH(CH3)2
CH3CH
CHCH(CH3)2
Br
Br
(100)
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Stereochemistry of Halogen Addition

• anti addition

Anti Addition Two Bromines add to opposite
sides of the ring
83
Example
H
Cl2
H
trans-1,2-Dichlorocyclooctane73 yield only
product
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Mechanism is electrophilic addition

• Br2 is not polar, but it is polarizable
• two steps (1) formation of bromonium ion
• electrophilic attack
• (2) nucleophilic attack on bromonium ion by
  bromide

NET REACTION
CH2CH2 Br2 -gt Br-CH2-CH2-Br
85
Step 1a Formation of Bromonium Ion
Mutual polarizationof electron distributionsof
Br2 and alkene
Electrons flow from alkenetoward Br2
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Step 1b Electrophilic Addition to form Bromonium
Ion
Part i
Br-
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Step 1b Lone Pair on Bromine Stabalizes
Carbocation and Forms Cyclic Bromonium Ion
Part ii
Br-
88
Step 2 Bromide Ion Must Attack from Oppositte
Side of Cyclic Bromonium Ion (anti addition)
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Example
Br2
trans-1,2-Dibromocyclopentane80 yield only
product
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X2
X
X
alkenes react with X2 to form vicinal dihalides
alkenes react with X2 in water to give vicinal
halohydrins
H2O
X2
X
OH
HX
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Examples
H2O

H2C
BrCH2CH2OH
Br2
CH2
(70)
Cl2
H2O
anti addition only product
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Mechanism 1) Cl2 is polarized and adds across
double bond. 2) Ion formed is stabalized by lone
pair of Cl.
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3) Water attacks chloronium ion from side
opposite (anti addition) carbon-chlorine bond.
This gives trans isomer
94
Regioselectivity
(77)

• Markovnikov's rule applied to halohydrin
  formation the halogen adds to the carbon having
  the greater number of hydrogens.

95
Hydrogenation (Reduction, H2) of Ethylene
Metal Catalyst
?
?
?
?
HH

• exothermic ?H 136 kJ/mol
• catalyzed by finely divided Pt, Pd, Rh, Ni

96
Two spatial (stereochemical) aspects ofalkene
hydrogenation

• (1) syn addition of both H atoms to double bond
• (2) hydrogenation is stereoselective,
  corresponding to addition to less crowded face of
  double bond

97
syn-Additon versus anti-Addition
syn addition
anti addition
98
syn-Addition Metal catalyst breaks H-H bonds.
B
Y
C
C
A
X
99
syn-Addition Addition of H2 across double bonds
takes place in two steps.
100
Example of Stereoselective Reaction
H2, cat
Both productscorrespond tosyn additionof H2.
101
Example of Stereoselective Reaction
H2, cat
Top face of doublebond blocked bythis methyl
group
But only thisone is formed.
H2 adds to bottom face of double bond.