Comparison of S

N
2 versus S
N
1 Reactions
Effect of Nucleophile
- S
N
2 is a one step reaction where both the substrate and nucleophile are involved
- S
N
1 is a two step reaction involving the initial formation of a planar carbocation
Therefore:
S
N
2 strong nucleophiles are required
S
N
1 nucleophile strength does not affect rate
Effect of Substrate
Two important considerations:
-as the number of substituents on the carbon increase the stability
of a formed carbocation increases (therefore of lower energy)
For a S
N
1 reaction 3 halides are the best
-as the number of substituents increase, the bulkiness
at the electrophilic carbon increases
For a S
N
2 reaction methyl halides are the best
S
N
1 substrate: 3 > 2 (1 and methyl halide do not react)
S
N
2 substrate: methyl halide > 1 > 2 (3 does not react)
Effect of Leaving Group
-in both reactions the bond between the electrophilic carbon and the leaving group
breaks in the rate determining step
Therefore both S
N
1 and S
N
2 reactions required a good leaving group
Weak bases that are common leaving groups:
Effect of Solvent
In a typical S
N
1 reaction a neutral starting material is ionized to charged intermediates
in the rate determining step
In a typical S
N
2 reaction the charge is kept constant during the rate determining step
(charge changes places, but the total amount of charge is the same)
S
N
1 good ionizing solvent favored
S
N
2 solvent has less of an effect
*Need to compare structures for starting material and transition state for rate determining
step, if the amount of charge changes the effect of solvent on reaction rate will change
Comparison of E1 and E2 Reactions
Effect of Substrate
In a E1 reaction a carbocation is formed
Thus a more substituted carbocation is more stable
In a E2 reaction an alkene is formed in the rate determing step
Follows Zaitsev rule where a more substituted alkene is favored
Therefore both E1 and E2 reactions the rate follows the trend:
3 > 2 > 1 (1 usually will not go by E1)
Effect of Base
Single most important factor for eliminations
If the substrate is suitable for an elimination
then a strong base will favor an E2 mechanism
A weak base will favor ionization (E1) rst
Therefore:
E2 strong base required
E1 base strength unimportant
Orientation of Eliminations
The product with the more substituted double bond will be favored
Zaitsev rule is followed by both E1 and E2
base
Competition Between Substitution and Elimination
A reaction with a given alkyl halide can follow one of four mechanism
(S
N
2, S
N
1, E2, E1) yielded different products
Trends to predict which mechanism will predominate
1) Weakly basic species that are good nucleophiles give predominantly substitution
Examples: halides, RS-, N
3
-, RCO
2
-
Therefore 1 or 2halides yield clean S
N
2
3 halides give predominantly S
N
1 (E1 usually minor pathway)
2) Strongly basic nucleophiles give more eliminations
E2 mechanism starts to compete with S
N
2 as base strength increases
-with methyl halides or 1 halides S
N
2 predominates with strong base (nucleophile)
-with 3 halides S
N
2 mechanism is impossible and E2 predominates with strong base
3) Sterically hindered basic nucleophiles favor eliminations
- Just as elimination becomes favored with sterically hindered substrates
E2 becomes favored with sterically hindered bases
Some common sterically hindered bases
Factors for Substitution versus Elimination
1) Base strength of the nucleophile
Weak
Halides, RS-, N
3
-, NC-, RCO
2
-
Substitution more likely
Strong
HO-, RO-, H
2
N-
Elimination increases
2) Steric hindrance at reacting carbon
Sterically unhindered
Methyl, 1
Substitution predominates
Sterically hindered
Branched 1, 2, 3
Elimination increases
3) Steric hindrance of strongly basic nucleophile
Sterically unhindered
HO-, CH
3
O-, H
2
N-
Substition may occur
Sterically hindered
(CH
3
)
3
CO-, LDA
Elimination favored
Summary of Reactivity of Alkyl Halides
Methyl halide
Reacts only through S
N
2 pathway
- No other possibilities
No adjacent carbons to form ! bond
Methyl cation is too high in energy to go through S
N
1 pathway
Primary Alkyl Halides
Reactivity of R-X with nucleophiles
Unhindered primary R-X
S
N
2 with good nucleophiles that are not strongly basic
S
N
2 with good nucleophile that are also strongly basic
E2 with nucleophiles that are strongly basic and hindered
No, or exceedingly slow, reaction with poor nucleophiles
Branched Primary Alkyl Halides
S
N
2 with good nucleophiles that are not strongly basic
E2 with nucleophiles that are strongly basic
No reaction with poor nucleophiles
Secondary Alkyl Halides
(hardest to predict all four mechanisms are possible)
S
N
1 or E1 with good leaving group in polar solvent with weak nucleophile
S
N
2 with good, weakly basic nucleophiles
E2 with strongly basic nucleophiles
Tertiary Alkyl Halides
S
N
1 and E1 with weak bases
E2 with strong base
As base strength increases, rate of E2 increases
Predicted Mechanisms by which Alkyl Halides React with Nucleophiles (or Bases)
Type of
Alkyl
Halide
Poor NUC
(e.g. EtOH)
Good NUC.
Weak base
(e.g. CH
3
SNa)
Good NUC,
strong,
Unhindered base
(e.g. CH
3
ONa)
Good NUC,
strong,
hindered base
(e.g. (CH
3
)
3
CONa)
methyl No reaction S
N
2 S
N
2 S
N
2
1
unhindered No reaction S
N
2 S
N
2 E2
branched No reaction S
N
2 E2 E2
2 Slow S
N
1, E1 S
N
2 S
N
2 or E2 E2
3 S
N
1, E1 S
N
1, E1 E2 E2
Properties of Each Mechanism
mechanism stereochemistry rate rearrangements
S
N
2 Inversion k[substrate][NUC] never
S
N
1 Racemic,
sometimes inversion
preference
k[substrate] Often, if
possible
E2 Anti-coplanar
Zaitsev rule
k[substrate][base] never
E1 Zaitsev rule k[substrate] Often, if
possible
Description of Electron Control in Organic Chemistry
Stability of an organic compound (or intermediate) is dependent upon the
molecules ability to best fulll the electronic demands throughout the molecule
triuoroacetate acetate
Triuoroacetate is more stable electronically and thus the conjugate is more acidic
Ways to Stabilize Sites
We have learned a couple of ways to stabilize sites electronically
1) Resonance
-stabilizes either electron rich or electron decient sites
2) Substituent Effects
-we have learned about inductive and hyperconjugation effects
For alkyl substituents, more substituents raises the electron density
carbon-carbon bonds are electron donating
For electron decient sites this is good
(therefore radicals and carbocations favor more substituents: 3 > 2 > 1 > methyl)
For electron rich sites this is bad
(therefore carbanions favor less substituents: methyl > 1 > 2 > 3)
Same Considerations for Organic Reactions
Organic reactions quite simply are species with high electron density (nucleophiles)
reacting with species with low electron density (electrophiles)
The FLOW of electrons occur to stabilize the electronic charge
Nucleophiliciy thus merely refers to electron density
-stronger nucleophiles have a higher electron density
Electrophiles thus merely refer to a species with an electron decient center
-stronger electrophiles have a more electron decient center
The only other consideration that we have dealt with is STERICS
Even if the nucleophile would react with the electrophile
they need to be able to reach each other spatially in order to react
Now look at view of nucleophile approach