ORGANIC CHEMISTRY II (CHEM 220W)
SUBSTITUTION AND ELIMINATION OF ALKYL HALIDES
Prescribed textbook: Organic Chemistry, 8th ed (Paula Y Bruice)
Alternative recommended textbook: Any other organic textbook that you have
Dr Matshawe Tukulula: H-Block, Room 3-037 ([email protected])
Consultation times: Any time when I am in the office (8:30 to 16:30)
REACTIONS OF ALKYL HALIDES
SPECIFIC OUTCOMES
- Predict the products of the reactions of alkyl halides
- Explain the differences in mechanisms of nucleophilic substitution (SN1 vs SN2) and elimination (E1 vs
E2) reactions
- Explain the reaction kinetics and factors influencing the rate of the substitution and elimination
reactions
- Be able to predict whether a reaction will undergo SN1 or E1 or SN2 or E2 OR mixture of four
reactions
REACTIONS OF ALKYL HALIDES (R-X): NUCLEOPHILIC
SUBSTITUTION AND ELIMINATION REACTIONS
Characteristic reactions of alkyl halides are substitution and elimination reactions:
In an elimination reaction, a halogen is removed from one carbon and a hydrogen is removed
from an adjacent carbon to form a double bond (Removal of HX or dehydrohalogenation)
- Two types: Elimination unimolecular (E1) and Elimination bimolecular (E2)
ELIMINATION REACTIONS: E2 REACTION MECHANISM
Lets recap SN2 reaction mechanism: Rate = k[R-Hal][Nu]
Concerted reaction: New bonds
forming and old bonds breaking occur
simultaneously
E2 reaction mechanism: Rate = k [R-Hal][Base]
This is also a concerted
reaction
NB! SN2 and E2 competes with each other, so its NB to note factors that favour one over the other!
ELIMINATION REACTIONS: E2 REACTION ENERGY DIAGRAM
COMPETITION BETWEEN E2 vs SN2 REACTION
Depends on the nature of the substrate
Depends on the Nature of the Substrate
CN
CH3CH2CH2CH2Br CH3CH2CH2CH2CN
str. nuc.; wk. base
1o 100% SN2
(CH3)3CBr CN CH2=C(CH3)2
3o 100% E2
Conclusion: 1o substrates favour SN2 while bulky substrates favour E2. Remember SN2 does not occur on
3o substrates!!
COMPETITION BETWEEN E2 vs SN2 REACTION
Depends on the nature of the substrate
Depends on the Nature of the Substrate
CN
CH3CH2CH2CH2Br CH3CH2CH2CH2CN
str. nuc.; wk. base
1o 100% SN2
(CH3)3CBr CN CH2=C(CH3)2
3o 100% E2
Conclusion: 1o substrates favour SN2 while bulky substrates favour E2. Remember SN2 does not occur on
3o substrates!!
COMPETITION BETWEEN E2 vs SN2 REACTION
Depends on the nature of the nucleophile/base
Substitution Elimination
CH3CO2 OAc
wk. base CH3CHCH 3 CH2=CHCH 3
Br 100% 0%
CH3CHCH 3
OEt
CH3CH2O
CH3CHCH 3 CH2=CHCH 3
str. base
20% 80%
Conclusion: Weak bases (but stronger nucleophiles) favour SN2 while stronger bases (whether weaker
or stronger nucleophiles) favour E2
COMPETITION BETWEEN E2 vs SN2 REACTION
Depends on the size of the base
Depends on the Size of the Base
CH3CH2O
CH3CH2CH2CH2OEt CH3CH2CH=CH 2
str. base
90% 10%
CH3CH2CH2CH2Br
(CH3)3CO
CH3CH2CH2CH2OtBu CH3CH2CH=CH 2
str. bulky base 15% 85%
Conclusion: smaller, stronger bases favour SN2 when using 1o alkyl halide while stronger bases bulky
bases (but weaker nucleophiles) favour E2
COMPETITION BETWEEN E2 vs SN2 REACTION
Depends on the nature of the leaving group
Just liKe in SN2, the weaker the base, the better it is as a leaving group
Conclusion: For both E2 and SN2 the weaker the base, the better it is as a leaving. Remember basicity
decreases down the group in the periodic table
ZAITSEV’S (OR SAYTREFF’S) RULE TO PREDICT ALKENE PRODUCTS
An E2 reaction is regioselective: The major product is the more substituted
alkene
The more stable alkene has the more stable transition state
ZAITSEV (OR SAYTZEFF) RULE TO PREDICT ALKENE PRODUCTS
The more substituted alkene product is obtained when a proton is removed from the β-carbon that
is bonded to the fewest hydrogens:
The most stable alkene is generally (but not always) the most substituted alkene
WORKED EXAMPLE ON PREDICTING THE OUTCOME OF THE
REACTIONS
Predict the major product(s) in the following E2 reaction:
-Answer:
EXCEPTIONS 1 TO ZAITSEV (OR SAYTZEFF’S) RULE
Conjugated alkene products are preferred over the more substituted alkene product:
Conclusion: Do not use Zaitsev’s rule to predict the major product in these cases
EXCEPTIONS 2 TO ZAITSEV (OR SAYTZEFF’S) RULE
Bulky substrates and bulky bases form the less substituted (or stable) alkene called the Hoffman
product as a major product: Hofmann product
However a less bulky substrate and a bulky base still forms a Zaitsev product as the major product:
Zaitsev product
EXCEPTIONS 2 TO ZAITSEV (OR SAYTZEFF’S) RULE
Bulky substrates and bulky bases form the less substituted (or stable) alkene called the Hoffman
product as a major product: Hofmann product
However a less bulky substrate and a bulky base still forms a Zaitsev product as the major product:
Zaitsev product
EXCEPTIONS 3 TO ZAITSEV (OR SAYTZEFF’S) RULE
When the fluoride ion (F-) is the leaving group in an E2 reaction, the major product is a Hoffman
product: Why?
- (i) F- is a strong base, so the reaction is not concerted (meaning the rate of proton abstraction by
the base is different from the rate of the C-F bond breaking)
- (ii) The transition state is similar to the carbanion, and since the 1o carbanion is more stable than 2o
and 3o carbanion (reverse of carbocation trend!), the main product is the less substituted alkene:
EXCEPTIONS 3 TO ZAITSEV (OR SAYTZEFF’S) RULE
When the fluoride ion (F-) is the leaving group in an E2 reaction, the major product is a Hoffman
product: Why?
- (i) F- is a strong base, so the reaction is not concerted (meaning the rate of proton abstraction by
the base is different from the rate of the C-F bond breaking)
- (ii) The transition state is similar to the carbanion, and since the 1o carbanion is more stable than 2o
and 3o carbanion (reverse of carbocation trend!), the main product is the less substituted alkene:
EXCEPTIONS 3 TO ZAITSEV (OR SAYTZEFF’S) RULE
Relative stabilities of carbanions
3o 2o 1o Methyl
carbanion carbanion carbanion anion
Most
Least
stable
stable
This trend is opposite to that of carbocation stability
STEROECHEMISTRY OF AN E2 REACTION
The transition state of an E2 reactions four atoms from alkyl halide: one H atom, 2 carbon atoms
and the leaving group X all aligned in a plane
- Thus there are two way for C-H and C-X bonds to be coplanar
- Anti periplanar geometry is the most preferred arrangement for an alkyl halide undergoing E2
reaction regardless of whether cyclic or acyclic
- This stereochemical requirement has important consequences for compounds containing 6-
membered rings!
STEROECHEMISTRY OF AN E2 REACTION
You are asked to give an E2 product of the following reactions (the alkyl halides are diastereomers
of each other):
- Its very NB to note that they don’t give you the same product, what are the products?
STEROECHEMISTRY OF AN E2 REACTION
You are asked to give an E2 product of the following reactions (the alkyl halides are diastereomers
of each other):
- Its very NB to note that they don’t give you the same product, what are the products?
STEROECHEMISTRY OF AN E2 REACTION
Again you are asked to predict E2 products from the two cyclic compounds: How do you go about
that?
Bottom line: Stereochemical factors play a huge role in the E2 reaction and its very important to
remember that!
STEROECHEMISTRY OF AN E2 REACTION
Again you are asked to predict E2 products from the two cyclic compounds: How do you go about
that?
Bottom line: Stereochemical factors play a huge role in the E2 reaction and its very important to
remember that!
ELIMINATION REACTIONS: E1 REACTION MECHANISM
Lets recap SN1 reaction mechanism: Rate = k[R-Hal]
Two step reaction, involves a
carbocation intermediate
E1 reaction mechanism: Rate = [R-Hal]
This is also a two step
reaction; also involves a
carbocation intermediate
NB! SN1 and E1 competes with each other a lot, so its NB to note that in both reactions the stability of
the carbocation is key!
ELIMINATION REACTIONS: E1 REACTION ENERGY DIAGRAM
Stability of the carbocation and rearrangement (1,2-hydride shift)
Br H H
CH3 C C CH3 CH3 C C CH3
H CH3 H CH3
H H
CH3 C C CH3 CH3 C C CH3
H CH3 H CH3
NB!: E1 and SN1 reactions go via a carbocation intermediate that rearranges from less stable
carbocation to more stable one before substitution or elimination can occur
Stability of the carbocation and rearrangement (1,2-Methyl shift)
Br CH3 CH3
CH3 C C CH3
Occurs when there is no hydrogen on the adjacent CH3 C C CH3
carbon (sometimes called β-carbon) H CH3 H CH3
CH3 CH3
CH3 C C CH3 CH3 C C CH3
H CH3 H CH3
NB!: E1 and SN1 reactions go via a carbocation intermediate that rearranges from less stable
carbocation to more stable one before substitution or elimination can occur
Stability of the carbocation
Ring expansion: 6-membered rings are more stable Ring contraction: 6-membered rings are more
than 5-membered stable than 7-membered
a
a
c
hydride
c shift
b a
b
b
H
o o
2 2
ring
contraction a
b
NB!: E1 and SN1 reactions go via a carbocation intermediate that rearranges from less stable
carbocation to more stable one before substitution or elimination can occur
Stability of the carbocation
Ring expansion: 6-membered rings are more stable Ring contraction: 6-membered rings are more
than 5-membered stable than 7-membered
a
a
c
hydride
c shift
b a
b
b
H
o o
2 2
ring
contraction a
b
NB!: E1 and SN1 reactions go via a carbocation intermediate that rearranges from less stable
carbocation to more stable one before substitution or elimination can occur
WORKED EXAMPLE ON PREDICTING THE OUTCOME OF THE
REACTIONS
Predict the major product(s) in the following E1 reaction:
-Answer:
COMPETITION BETWEEN E1 vs SN1 REACTION
SN1 and E1 are less common in organic chemistry compared to SN2 and E2
Typically SN1 and E1 go hand in hand, and they compete because:
(i) They share similar characteristics and (ii) conditions that favour one also favour the other:
Most of the time we don’t know which reaction will yield a major product. How do you make E1 a
major product?
COMPETITION BETWEEN E1 vs SN1 REACTION
Heat favours E1 over SN1 reaction
E1 VS E2 REACTIONS: SUBSTRATE/ALKYL HALIDE
E1 will not occur on 1o substrate because in solution you cannot stabilize 1o carbocation
(similar to SN1 reaction)
Note: AgNO3 and heating aprotic solvents can allow 1o Substrates to undergo E1 and SN1
reactions!!
E1 VS E2 REACTIONS: Base strength
The relative rates of E2 reactions depend on the identity of the base—more specifically, on the
strength of the base:
- Thus, stronger bases generally favour E2 over E1 (Just like nucleophile strength affects SN2 more
than SN1)
The rate of an E1 reaction is not influenced by the base, just weaker based disfavor E2 and favour
E1!
E1 VS E2 REACTIONS: Base strength
The relative rates of E2 reactions depend on the identity of the base—more specifically, on the
strength of the base:
- Thus, stronger bases generally favour E2 over E1 (Just like nucleophile strength affects SN2 more
than SN1)
The rate of an E1 reaction is not influenced by the base, just weaker based disfavor E2 and favour
E1!
E1 VS E2 REACTIONS: Base strength
The relative rates of E2 reactions depend on the identity of the base—more specifically, on the
strength of the base:
- Thus, stronger bases generally favour E2 over E1 (Just like nucleophile strength affects SN2 more
than SN1)
The rate of an E1 reaction is not influenced by the base, just weaker based disfavor E2 and favour
E1!
E1 VS E2 REACTIONS: Solvent effects
The choice of the solvent can have an effect on the outcome of the substitution and elimination
reactions:
KEY POINTS FOR COMPARISON OF E1 VS E2 REACTIONS
DISTINGUISHING BETWEEN SN1, SN2, E1 AND E2 REACTIONS
WORKED EXAMPLE ON PREDICTING THE OUTCOME OF THE
REACTIONS
Predict the major product(s) of the following reaction, and indicate the mechanism (SN1, SN2, E1 or
E2) that are likely responsible for their formation:
-Answer:
* Note that NaOCH3 is a strong base and strong nucleophile, suggesting SN2 and E2 are likely reactions!
* Also note that SN2 cannot happen on 3o substrates, thus leaves only E2
* NaOCH3 is not bulky, thus Zaitsev’s rule can be used to predict major product!
Can we explain why the second reaction forms 100% by E2? Why
no SN1 or E1 product
Depends on the nature of the substrate
Depends on the Nature of the Substrate
CN
CH3CH2CH2CH2Br CH3CH2CH2CH2CN
str. nuc.; wk. base
1o 100% SN2
(CH3)3CBr CN CH2=C(CH3)2
3o 100% E2
WORKED EXAMPLE ON PREDICTING THE OUTCOME OF THE
REACTIONS
Predict the major product(s) of the following reaction, and indicate the mechanism (SN1, SN2, E1 or
E2) that are likely responsible for their formation:
-Answer:
* Akyl halide is 2o, so all reactions can occur!
* There is no strong nucleophile/bases, thus SN1 and E1 are mixture of products is likely (and thus
rearrangement!!)
* For E1 products Zaitsev’s rule can be used to predict the major alkene products!
WORKED EXAMPLE ON PREDICTING THE OUTCOME OF THE
REACTIONS
Predict the major product(s) of the following reaction, and indicate the mechanism (SN1, SN2, E1 or
E2) that are likely responsible for their formation:
-Answer:
* Akyl halide is 2o, so all reactions can occur!
* There is no strong nucleophile/bases, thus SN1 and E1 are mixture of products is likely (and thus
rearrangement!!)
* For E1 products Zaitsev’s rule can be used to predict the major alkene products!
WORKED EXAMPLE ON PREDICTING THE OUTCOME OF THE
REACTIONS
Predict the major product(s) of the following reaction, and indicate the mechanism (SN1, SN2, E1 or
E2) that are likely responsible for their formation:
-Answer:
* Akyl halide is 2o, so all reactions can occur!
* NaOCH3 is strong nucleophile/bases, thus SN2 and E2 products is likely
* NaOCH3 is not bulky, thus Zaitsev’s rule can be used to predict the major alkene products!
WORKED EXAMPLE ON PREDICTING THE OUTCOME OF THE
REACTIONS
Use reaction mechanism to justify the formation of the products given in the following reaction:
-Answer:
* Akyl halide is 1o but because of AgNO3 it can form a 1o carbocation!
* CH3OH is a weak nucleophile and base, thus suggesting SN1 and E1 product mixtures are likely
WORKED EXAMPLE ON PREDICTING THE OUTCOME OF THE
REACTIONS
Use reaction mechanism to justify the formation of the products given in the following reaction:
Remember both SN1 and E1
cannot occur on 1o carbocation
-Answer:
* Akyl halide is 1o but because of AgNO3 it can form a 1o carbocation!
* CH3OH is a weak nucleophile and base, thus suggesting SN1 and E1 product mixtures are likely
End of PART B of substitution and Elimination of alkyl
halides and end of unit 5
