2. Three major types of elimination reactions are:
1) α-elimination: two atoms or groups are removed from the
same atom. It is also known as 1,1-elimination.
2) β-elimination: loss of atoms or groups on adjacent atoms.
It is also known as 1, 2- elimination.
3) g-elimination: loss of atoms or groups from the 1st and 3rd
positions as shown below.
3.
4. The Mechanisms of Elimination
What is the mechanism for elimination?
What is the order of bond breaking and bond making?
Is the reaction a one-step process or does it occur in many steps?
There are two mechanisms for elimination—E2 and E1
The E2 and E1 mechanisms differ in the timing of bond cleavage
and bond formation.
5.
6. Figure 5.1. An energy diagram for an E2 reaction:
(CH3)3CBr + –OH → (CH3)2C═CH2 + H2O + Br–
7. E2 reactions are generally run with strong, negatively charged bases like
–OH and –OR.
Two strong, sterically hindered nitrogen bases, called DBN and DBU,
are also sometimes used.
DBN=1,5-diazabicyclo[4.3.0]non-5-ene,
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene.
There are close parallels between the E2 and SN2 mechanisms in how the
identity of the base, the leaving group, and the solvent affect the rate.
8.
9. Because polar aprotic solvents like (CH3)2C═O do not solvate anions well, a
negatively charged base is not “hidden” by strong interactions with the solvent,
and the base is stronger.
Then, a stronger base increases the reaction rate.
10. Why does increasing alkyl substitution increase the rate of an E2 reaction?
In the transition state, the double bond is partially formed, so increasing the
stability of the double bond with alkyl substituents stabilizes the transition state.
11. The Zaitsev Rule
A mixture of alkenes can form from the dehydrohalogenation of
alkyl halides having two or more different β carbon atoms.
When this occurs, one of the products usually predominates.
The major product is the more stable product—the one with the more
substituted double bond─Zaitsev Rule
A reaction is regioselective when it yields predominantly or exclusively one
constitutional isomer when more than one is possible.
E2 reaction is regioselective
12. Exception:
The less stable alkene is the major product if the base in an E2 reaction is
sterically bulky!
The bulky base picks easily accessible proton and less substituted alkene is
formed predominantly.
13. When a mixture of stereoisomers is possible from dehydrohalogenation,
the major product is the more stable stereoisomer-trans alkene.
A reaction is stereoselective when it forms predominantly or exclusively
one stereoisomer when two or more are possible.
The E2 reaction is stereoselective because one stereoisomer is formed
preferentially.
14.
15.
16. Figure 5.2: Energy diagram for an E1 reaction:
(CH3)3CI + H2O(CH3)2C═CH2 + H3O+ + I–
17. Increasing alkyl substitution has the same effect on the rate of both an
E1 and E2 reaction; increasing rate of the E1 and E2 reactions:
RCH2X (1°) <R2CHX (2°) < R3CX (3°).
19. 5.2. Evidences for mechanisms of elimination reaction
Evidences for E2 mechanism
1) There is kinetic isotopic effect
2) Kinetic data shows second order kinetics
3) There is no rearrangement
21. This clearly indicate that in E2 elimination, breaking of Cβ-H bond must
occurs in the slow step (RDS).
22. Kinetic study shows that doubling the concentration of one reactant
doubles the rate of the reaction and
Doubling the concentration of both reactants increases the reaction rate
by a factor of four.
This indicate that the rate of the reaction depends on the concentration
of both reactants (both of them appear in the RDS).
Therefore, it exhibits second order kinetics & must follow E2
mechanism.
2) Kinetic data shows second order kinetics
3) Absence of rearrangement:
indicates that the reaction doesn’t involve carbocation formation and
therefore it occurs through E2 mechanism.
23. 1) No kinetic isotopic effect
2) Kinetic data shows first order kinetics
3) There is rearrangement
Evidences for E1 mechanism
24. 5.3. El versus E2
1) When Is the Mechanism E1 or E2?
This depends on the nature of alkyl halide, the base & the solvent.
Primary alkyl halides undergo only E2 elimination reaction.
They can not undergo E1 reaction.
For those alkyl halides that can undergo both E2 and E1 reactions (i.e. 1o&2o)
E2 reaction is favored by a high concentration of a strong base and
polar aprotic solvent (e.g., DMSO or DMF).
E1 reaction is favored by a weak base and a polar protic solvent
(e.g.,H2O or ROH).
25. Predicting the substitution and elimination products of a reaction can then
be organized by the type of alkyl halide, as shown in the following table.
5.4. Elimination versus substitution
How do we know if a given alkyl halide will undergo substitution or
elimination with a given base or nucleophile, and by what mechanism?
To determine the product of a reaction with an alkyl halide:
26.
27.
28.
29. Exercise:
Draw the products of the following reaction, and include the mechanism showing
how each product is formed.
A)
B)
C)
30. 5.5. Applications of elimination reactions
A) Dehydration of alcohols: Synthesis of alkenes
31.
32.
33. Dehydration follows Zaitsev’s rule
This depends on carbocation stability
This depends on alkene stability
30 alcohols dehydrate easily.
35. A very strong base such as -NH2 or K+ -OC(CH3)3 in DMSO is needed for the
second elimination since vinyl halide intermediate is less reactive.
If a weaker base, the reaction will stop at the vinylic halide and no alkyne will
be formed.
Vicinal dihalides can undergo two consecutive E2 dehydrohalogenations,
giving alkynes.
B) Dehydrohalogenation of Vicinal Dihalides: Synthesis of alkynes
36. C) Hofmann Elimination: Synthesis of alkenes
The reaction of a quaternary ammonium ion with hydroxide ion is known as a
Hofmann elimination reaction.
The leaving group in a Hofmann elimination reaction is a tertiary amine.
A Hofmann elimination reaction is an E2 reaction.
37. Regiochemistry of Hofmann Elimination
The less substituted alkene is the major product (anti Zaitsev’s rule)!
Why do quaternary amines violate the rule?
Steric factor is the main reason (bulky leaving group).
Steric factor in the Hofmann reaction favors anti-Zaitsev’s product.
38. D) Acetate pyrolysis: Synthesis of alkene
Is heat induced intramolecular syn-elimination of acetate ester with β-
hydrogen to form alkene product.
A concerted reaction via a cyclic transition state.
An intramolecular proton transfer is accompanied by syn-elimination to form
a new carbon-carbon double bond.
The carboxylic acid corresponding to the ester is a byproduct.
39. If more than 1 β hydrogen is present then mixtures of alkenes are generally
formed.
The loss of the β-hydrogen occurs preferably from the most unhindered
position (Acetate pyrolysis obeys Hofmann rule).
40. E) Cope elimination reaction: Synthesis of alkenes
Amine oxides undergo a reaction similar to the Hofmann elimination
reaction, called a Cope elimination reaction.
Intramolecular E2 reaction.
Major product of Cope elimination is like that of the Hofmann elimination.
41. F) Applications of elimination reaction in drug synthesis & metabolism
E2 reaction is used in the synthesis of quinine, a naturally occurring antimalarial
drug.
Bonds and atoms in quinine that originate in
the alkene intermediate are shown in red.
42. Atracurium (muscle relaxant drug)- useful during surgery when the
patient needs to be immobilised.
The effect of such drugs should be wear off after surgery and unless it
can cause respiratory depression.
The effect would only wear off after the drug gets metabolised – that is it
gets changed in the body – to a not active form.
One such change involves an elimination reaction of the quarternary
ammonium group of the drug.
Elimination reaction in drug metabolism.
