Alkyl Halides: Nucleophilic Substitutions and Eliminations

Contributed by:

Jonathan James Mon, Jan 17, 2022 06:14 PM UTC

The highlights are:
1. Nucleophilic substitution, base induced elimination are among the most widely occurring and versatile reaction types in organic chemistry
2. Reactions will be examined closely to see:
- How they occur
- What their characteristics are
- How they can be used

1. 11. Reactions of Alkyl Halides:
Nucleophilic Substitutions and
Eliminations
Based on McMurry’s Organic Chemistry, 7th edition

2. Alkyl Halides React with
Nucleophiles and Bases
 Alkyl halides are polarized at the carbon-halide bond,
making the carbon electrophilic
 Nucleophiles will replace the halide in C-X bonds of
many alkyl halides(reaction as Lewis base)
 Nucleophiles that are Brønsted bases produce
elimination
2

3. Why this Chapter?
 Nucleophilic substitution, base induced
elimination are among most widely occurring
and versatile reaction types in organic
chemistry
 Reactions will be examined closely to see:
- How they occur
- What their characteristics are
- How they can be used
3

4. 11.1 The Discovery of Nucleophilic
Substitution Reactions
 In 1896, Walden showed that (-)-malic acid could be
converted to (+)-malic acid by a series of chemical
steps with achiral reagents
 This established that optical rotation was directly
related to chirality and that it changes with chemical
alteration
 Reaction of (-)-malic acid with PCl5 gives (+)-
chlorosuccinic acid
 Further reaction with wet silver oxide gives (+)-malic
acid
 The reaction series starting with (+) malic acid gives (-)
acid
4

5. Reactions of the Walden Inversion
5

6. Significance of the Walden
 The reactions alter the array at the chirality center
 The reactions involve substitution at that center
 Therefore, nucleophilic substitution can invert the
configuration at a chirality center
 The presence of carboxyl groups in malic acid led to
some dispute as to the nature of the reactions in
Walden’s cycle
6

7. 11.2 The SN2 Reaction
 Reaction is with inversion at reacting center
 Follows second order reaction kinetics
 Ingold nomenclature to describe characteristic step:
 S=substitution
 N (subscript) = nucleophilic
 2 = both nucleophile and substrate in
characteristic step (bimolecular)
7

8. Kinetics of Nucleophilic
 Rate (V) is change in concentration with time
 Depends on concentration(s), temperature, inherent
nature of reaction (barrier on energy surface)
 A rate law describes relationship between the
concentration of reactants and conversion to
products
 A rate constant (k) is the proportionality factor
between concentration and rate
Example: for S converting to P
V = d[S]/dt = k [S]
8

9. Reaction Kinetics
 The study of rates of reactions is called kinetics
 Rates decrease as concentrations decrease but the
rate constant does not
 Rate units: [concentration]/time such as L/(mol x s)
 The rate law is a result of the mechanism
 The order of a reaction is sum of the exponents of the
concentrations in the rate law – the example is
second order
9

10. SN2 Process
 The reaction involves a transition state in which both
reactants are together
10

11. SN2 Transition State
 The transition state of an SN2 reaction has a planar
arrangement of the carbon atom and the remaining
three groups
11

12. 11.3 Characteristics of the SN2
 Sensitive to steric effects
 Methyl halides are most reactive
 Primary are next most reactive
 Secondary might react
 Tertiary are unreactive by this path
 No reaction at C=C (vinyl halides)
12

13. Reactant and Transition State
Energy Levels Affect Rate
Higher reactant
energy level (red
curve) = faster
reaction (smaller
Higher transition
state energy level
(red curve) =
slower reaction
(larger G‡).
13

14. Steric Effects on SN2 Reactions
The carbon atom in (a) bromomethane is readily accessible
resulting in a fast SN2 reaction. The carbon atoms in (b) bromoethane
(primary), (c) 2-bromopropane (secondary), and (d) 2-bromo-2-
methylpropane (tertiary) are successively more hindered, resulting in
successively slower SN2 reactions.
14

15. Order of Reactivity in SN2
 The more alkyl groups connected to the reacting
carbon, the slower the reaction
15

16. The Nucleophile
 Neutral or negatively charged Lewis base
 Reaction increases coordination at nucleophile
 Neutral nucleophile acquires positive charge
 Anionic nucleophile becomes neutral
 See Table 11-1 for an illustrative list
16

17. Relative Reactivity of Nucleophiles
 Depends on reaction and conditions
 More basic nucleophiles react faster
 Better nucleophiles are lower in a column of the
periodic table
 Anions are usually more reactive than neutrals
17

18. The Leaving Group
 A good leaving group reduces the barrier to a
reaction
 Stable anions that are weak bases are usually
excellent leaving groups and can delocalize charge
18

19. Poor Leaving Groups
 If a group is very basic or very small, it is prevents reaction
 Alkyl fluorides, alcohols, ethers, and amines do not typically undergo S N2 reactions.
19

20. The Solvent
 Solvents that can donate hydrogen bonds (-OH or –NH)
slow SN2 reactions by associating with reactants
 Energy is required to break interactions between reactant
and solvent
 Polar aprotic solvents (no NH, OH, SH) form weaker
interactions with substrate and permit faster reaction
20

21. 11.4 The SN1 Reaction
 Tertiary alkyl halides react rapidly in protic solvents by a
mechanism that involves departure of the leaving group prior
to addition of the nucleophile
 Called an SN1 reaction – occurs in two distinct steps while
SN2 occurs with both events in same step
 If nucleophile is present in reasonable concentration (or it is
the solvent), then ionization is the slowest step
21

22. SN1 Energy Diagram
V = k[RX]
 Rate-determining step is formation of carbocation
22

23. Rate-Limiting Step
 The overall rate of a reaction is controlled by
the rate of the slowest step
 The rate depends on the concentration of the
species and the rate constant of the step
 The highest energy transition state point on
the diagram is that for the rate determining
step (which is not always the highest barrier)
23

24. Stereochemistry of SN1
 The planar
intermediate
leads to loss of
chirality
 A free
carbocation is
achiral
 Product is
racemic or has
some inversion
24

25. SN1 in Reality
 Carbocation is biased to react on side opposite
leaving group
 Suggests reaction occurs with carbocation loosely
associated with leaving group during nucleophilic
addition
 Alternative that SN2 is also occurring is unlikely
25

26. Effects of Ion Pair Formation
 If leaving group remains
associated, then
product has more
inversion than retention
 Product is only partially
racemic with more
inversion than retention
 Associated carbocation
and leaving group is an
ion pair
26

27. 11.5 Characteristics of the SN1
 Tertiary alkyl halide is most reactive by this mechanism
 Controlled by stability of carbocation
 Remember Hammond postulate,”Any factor that stabilizes a high-
energy intermediate stabilizes transition state leading to that
intermediate”
27

28. Allylic and Benzylic Halides
 Allylic and benzylic intermediates stabilized by
delocalization of charge
 Primary allylic and benzylic are also more reactive
in the SN2 mechanism
28

29. Effect of Leaving Group on SN1
 Critically dependent on leaving group
 Reactivity: the larger halides ions are better
leaving groups
 In acid, OH of an alcohol is protonated and leaving
group is H2O, which is still less reactive than halide
 p-Toluensulfonate (TosO-) is excellent leaving group
29

30. Nucleophiles in SN1
 Since nucleophilic addition occurs after
formation of carbocation, reaction rate is not
normally affected by nature or concentration
of nucleophile
30

31. Solvent in SN1
 Stabilizing carbocation also stabilizes associated transition state and controls rate
 Solvent effects in the SN1 reaction are due largely to stabilization or destabilization
of the transition state
31

32. Polar Solvents Promote Ionization
 Polar, protic and unreactive Lewis base solvents facilitate
formation of R+
 Solvent polarity is measured as dielectric polarization (P)
 Nonpolar solvents have low P
 Polar solvents have high P values
32

33. 11.6 Biological Substitution
 SN1 and SN2 reactions are well known in
biological chemistry
 Unlike what happens in the laboratory,
substrate in biological substitutions is often
organodiphosphate rather than an alkyl halide
33

34. 11.7 Elimination Reactions of
Alkyl Halides: Zaitsev’s Rule
 Elimination is an alternative pathway to substitution
 Opposite of addition
 Generates an alkene
 Can compete with substitution and decrease yield,
especially for SN1 processes
34

35. Zaitsev’s Rule for Elimination
 In the elimination of HX from an alkyl halide, the more
highly substituted alkene product predominates
35

36. Mechanisms of Elimination
 Ingold nomenclature: E – “elimination”
 E1: X- leaves first to generate a carbocation
 a base abstracts a proton from the carbocation
 E2: Concerted transfer of a proton to a base and
departure of leaving group
36

37. 11.8 The E2 Reaction and the
Deuterium Isotope Effect
 A proton is
transferred to base
as leaving group
begins to depart
 Transition state
combines leaving of
X and transfer of H
 Product alkene forms
stereospecifically
37

38. Geometry of Elimination – E2
 Antiperiplanar allows orbital overlap and minimizes
steric interactions
38

39. E2 Stereochemistry
 Overlap of the developing  orbital in the transition
state requires periplanar geometry, anti arrangement
39

40. Predicting Product
 E2 is stereospecific
 Meso-1,2-dibromo-1,2-diphenylethane with base gives
cis 1,2-diphenyl
 RR or SS 1,2-dibromo-1,2-diphenylethane gives trans
1,2-diphenyl
40

41. 11.9 The E2 Reaction and
Cyclohexane Formation
 Abstracted proton and leaving group should
align trans-diaxial to be anti periplanar (app)
in approaching transition state
 Equatorial groups are not in proper alignment
41

42. 11.10 The E1and E1cB Reactions
 Competes with SN1 and E2 at 3° centers
 V = k [RX], same as SN1
42

43. Comparing E1 and E2
 Strong base is needed for E2 but not for E1
 E2 is stereospecifc, E1 is not
 E1 gives Zaitsev orientation
43

44. E1cB Reaction
 Takes place through a carbanion
intermediate
44

45. 11.11 Biological Elimination
 All three elimination reactions occur in
biological pathways
 E1cB very common
 Typical example occurs during biosynthesis
of fats when 3-hydroxybutyryl thioester is
dehydrated to corresponding thioester
45

46. 11.12 Summary of Reactivity: SN1,
SN1, E1,E1cB, E2
 Alkyl halides undergo different reactions in competition,
depending on the reacting molecule and the conditions
 Based on patterns, we can predict likely outcomes
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