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)

3. 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
7. Vinil Halida
8. Aril Halida
Dalam Pembahasan Tersendiri

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

6. 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.

7. Substitution Reaction with Halides
(1)
(2)
bromomethane
methanol
Rate law:
rate = k [bromoethane][OH-]
this reaction is an example of a SN2 reaction.
S stands for substitution
N stands for nucleophilic
2 stands for bimolecular

8. 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

9. 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.

10. Mechanism of SN2 Reactions
Steric effect
activation
energy: DG2
Energy
activation
energy: DG1
reaction coordinate
reaction coordinate
Inversion of configuration
(S)-2-bromobutane
(R)-2-butanol

11. Factor Affecting SN2 Reactions
The leaving group
relative rates of reaction pKa HX
HO- + RCH2I RCH2OH + I
HO- + RCH2Br RCH2OH + Br
HO- + RCH2Cl RCH2OH + Cl
HO- + RCH2F RCH2OH + F
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

13. 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.

14. Mechanism of SN1 Reactions
Alkyl halide
Relative rate
≈ 0 * 12
The rate of reaction depends on the concentrations of the alkyl halide only.
When the methyl groups of 1-bromo-1,1-dimethylethane 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

15. Mechanism of SN1 Reactions
nucleophile attacks the carbocation
slow
C-Br bond breaks
fast
Proton dissociation

16. Mechanism of SN1 Reactions
Rate determining step
Carbocation intermediate DG
R++ X- +
R-OH2
R-OH

17. Mechanism of SN1 Reactions
Inverted configuration relative the alkyl halide
Same configuration as the alkyl halide

18. 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

19. 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 > 2o > 1o > methyl
methyl > 1o > 2o > 3o

20. Kestabilan Karbokation

22. 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 mechanism shows that an E2 reaction is a one-step reaction
The E2 Reaction
A proton is removed
Br- is eliminated
The mechanism shows that an E2 reaction is a one-step reaction

24. 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.

25. 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

26. Products of Elimination Reaction
30%
50%
80%
2-butene
2-bromobutane
20%
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

27. ELIMINATION REACTIONS: ALKENES, ALKYNES

28. Elimination Reactions
Dehydrohalogenation (-HX) and
Dehydration (-H2O) are the main types of elimination reactions.

29. Dehydrohalogenation (-HX)

30. The E2 mechanism
This reaction is done in strong base at high concentration, such as 1 M NaOH in water. _

31. Kinetics
The reaction in strong base at high concentration is second order (bimolecular):
Rate law: rate = k[OH-]1[R-Br]1

32. The E1 mechanism
This reaction is done in strong base such as 0.01 M NaOH in water!! Actually, the base solution is weak!

33. Kinetics
The reaction in weak base or under neutral conditions will be first order (unimolecular):
Rate law: rate = k [R-Br]1
The first step (slow step) is rate determining!

34. The E2 mechanism Mechanism Kinetics Stereochemistry of reactants
Orientation of elimination (Zaitsev’s rule)
Stereochemistry of products
Competing reactions

35. E2 mechanism
This reaction is done in strong base at high concentration, such as 1 M NaOH in water.

36. Kinetics of an E2 reaction
The reactions are second order (bimolecular reactions).
Rate = k [R-Br]1[Base]1
second order reaction (1 + 1 = 2)
High powered math!!

37. d-
Transition State
energy
Reaction coordinate

38. 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.

39. Stereochemistry of E2 Reaction
H and Br are anti structure in conformation!!!!!!!!!

40. (S,S)-diastereomer

41. This one is formed!

42. (R,S)-diastereomer

43. This one is formed!

44. Orientation of elimination: regiochemistry/ Zaitsev’s 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

45. Product formed from previous slide
More substituted alkene is more stable!!!!!!!!

46. Typical bases used in E2 reactions
High concentration of the following >1M
If the concentration isn’t given, assume
that it is high concentration!
Na+ -OH
K+ -OH
Na+ -OR
Na+ -NH2

47. Orientation of elimination: regiochemistry/ Zaitsev’s Rule
Explaination of Zaitsev’s 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.

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

50. The E1 mechanism Mechanism Kinetics Stereochemistry of reactants
Orientation of elimination (Zaitsev’s rule)
Stereochemistry of products
Competing reactions

51. 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).

54. However!!!!
With strong base (i.e. >1M), goes by E2

55. Structure of the Carbocation Intermediate

56. Carbocation stability order
Tertiary (3o) > secondary (2o) > 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-X]1
The solvent helps to stabilize the carbocation, but it doesn’t appear in the rate law!!

58. d- d+ d+ d+ +
energy
intermediate
Reaction coordinate

59. 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 Zaitsev’s 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!

63. Whenever there are carbocations…
They can undergo elimination (E1)
They can undergo substitution (SN1)
They can rearrange
and then undergo elimination
or substituion

64. Rearrangements
Alkyl groups and hydrogen can migrate in rearrangement reactions to give more stable intermediate carbocations.
You shouldn’t 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.

66. 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 don’t give rearrangement
Alcohol dehydration reactions are E1

67. Bulky leaving groups Hofmann Elimination
This give the anti-Zaitsev product (least substituted product is formed)!

68. Orientation of elimination: regiochemistry/ Hofmann’s 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

69. 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.

71. Comparing Ordinary and Bulky Bases

72. 1-butene: watch out for competing reactions!

73. Highlights Dehydrohalogenation -- E2 Mechanism Zaitsev’s Rule
Carbocation Rearrangements -- E1
Elimination with Bulky Leaving Groups and Bulky Bases -- Hofmann Rule -- E2

74. Competition Between SN2/E2 and SN1/E1
rate = k1[alkyl halide] + k2[alkyl halide][nucleo.] + k3[alkyl halide] + k2[alkyl halide][base]
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

75. Competition Between Substitution and Elimination
SN2/E2 conditions:
In a SN2 reaction: 1o > 2o > 3o
In a E2 reaction: 3o > 2o > 1o
10%
90%
75%
25%
100%

76. 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%)

77. 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

78. REAKSI ADISI ALKENA

79. 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

80. Addition of Halogens to Alkenes
+ X2 X C
electrophilic addition to double bond
forms a vicinal dihalide
X2 = Cl2 or Br2
F2; explosive I2 ; endothermic 2

81. Example
Br2
CH3CH
CH3CHCHCH(CH3)2
CHCH(CH3)2 Br Br
(100%) 4

82. anti addition Stereochemistry of Halogen Addition Br2
trans-1,2-Dibromocyclopentane 80% yield; only product H Br
Anti Addition ; Two Bromines add to opposite
sides of the ring 6

83. Example H Cl H
Cl2 H
trans-1,2-Dichlorocyclooctane 73% yield; only product 6

84. 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
CH2=CH2 + Br2 -> Br-CH2-CH2-Br 8

85. Step 1a: Formation of Bromonium Ion– + Br
Mutual polarization of electron distributions of Br2 and alkene
Electrons flow from alkene toward Br2 11

86. Step 1b; Electrophilic Addition to form Bromonium Ion
Part i
+ Br-

87. Step 1b; Lone Pair on Bromine Stabalizes Carbocation and Forms Cyclic Bromonium Ion
Part ii
+ Br- Br +

88. Step 2; Bromide Ion Must Attack from Oppositte Side of Cyclic Bromonium Ion (anti addition)+ Br

89. Example Br H
Br2 H
trans-1,2-Dibromocyclopentane 80% yield; only product 6

90. C C
+ X2 X X
alkenes react with X2 to form vicinal dihalides
alkenes react with X2 in water to give vicinal halohydrins C C
+ X2
+ H2O X OH
+ H—X 2

91. Examples H2O H2C CH2 + Br2 BrCH2CH2OH (70%) OH Cl H Cl2 H H2O
anti addition: only product 6

92. Mechanism; 1) Cl2 is polarized and adds across double bond
Mechanism; 1) Cl2 is polarized and adds across double bond. 2) Ion formed is stabalized by lone pair of Cl. 26

93. 3) Water attacks chloronium ion from side opposite (anti addition) carbon-chlorine bond. This gives trans isomer 29

94. Regioselectivity
CH3 OH C
CH2Br
H3C C
CH2
Br2
H2O
(77%)
Markovnikov's rule applied to halohydrin formation: the halogen adds to the carbon having the greater number of hydrogens. 32

95. Hydrogenation (Reduction, +H2) of Ethylene
Metal
Catalyst H C H H  C   
+ H—H
exothermic H° = –136 kJ/mol
catalyzed by finely divided Pt, Pd, Rh, Ni 4

96. Two spatial (stereochemical) aspects of alkene 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
CO2CH3
H2, Pt H 18

97. syn-Additon versus anti-Addition
syn addition
anti addition 18

98. syn-Addition; Metal catalyst breaks H-H bonds.X H H H H 9

99. syn-Addition; Addition of H2 across double bonds takes place in two steps.X Y H H 9

100. Example of Stereoselective Reaction
H3C
CH3 H
Example of Stereoselective Reaction
H2, cat
CH3
H3C H
CH3
H3C H
Both products correspond to syn addition of H2. 21

101. Example of Stereoselective Reaction
H3C
CH3 H
Example of Stereoselective Reaction
H2, cat
Top face of double bond blocked by this methyl group
CH3
H3C H
But only this one is formed.
H2 adds to bottom face of double bond. 21