Nucleophilic Substitution Reactions - SN2 and SN1
The Energy Diagrams
What is a Substitution Reaction?
bond-forming
In a substitution reaction, one group replaces another one:
bond-breaking
H H
CN
K CN
+
K Br
State
The species that attacks with a lone pair and expels the leaving group is the nucleophile
SN2
The Br- in this reaction is the leaving group (LG) which is kicked out by the nucleophile.
interest).
H
Exothermic
reactants
The substrate in substitution reactions is the electrophile (electron-deficient).
H
products
SH >
simultaneously (concerted mechanism) - as one comes, the other one leaves. This is the SN2
nucleophile attacks.
stepwise - SN1 mechanism. Let's discuss both mechanisms one-by-one.
+
SN2
2) The leaving group leaves first, and only after this steps, the nucleophile can attack. This is the
+
OH
The SN2 Mechanism
Cl
The carbocation formed in the first step is attacked from both sides and as a result, SN1 reactions
BrH
Br
SN2 is a bimolecular mechanism. This means the rate of the reaction depends on the
concentration of both, the substrate and the nucleophile.
O
O
R
sp2
carbocation
*If there was an
unreactive chiral center in
the substrate,
diastereomers would form.
O
O
O
R
SN1
O
+
S
Racemic mixture
+
order. Below is the rate law equation:
The Role of the Solvent On Nucleophilicity
In the previous section, we said that stronger bases are better nucleophiles and also larger
atoms are better nucleophiles. What if you compare F- and I- ions? F- is as stronger base, while
I- is a larger atom, so which one is a better nucleophile?
The answer is it depends on the solvent. There are two types of polar solvents used in the
substitution reactions: 1-polar protic solvents, 2-polar aprotic solvents.
increases 9 times
of halides is reversed in polar aprotic solvents.
2o - both
SN2 and SN1
3o - NO SN2
R
R
R
Nu
C X
R H
1o
<
2o
<
Methyl
only SN2
R
H2C X
R
C X
3o
1o,
H3C X
<
I
caged
I
still reactive
>>
1o
carbocation, the more stable it is:
SN1 is a unimolecular (first order) mechanism and the rate of the reaction depends only on
R
R
H
C
R
>
R
3o
the concentration of the substrate.
R' R"
R Nu
H
stronger nucleophile (less H-bonding)
is the stronger nucleophile
LG +
R
C
R
>
2o
H
C
R
OK
1o
Hypercojugation
[Nu] has no effect on the rate
Poor
(Never)
in SN1 or SN2
bond to the empty p orbital of the carbocation.
Intermediate
if [Substrate] doubles, rate doubles
Excellent
Good
more stable
Hyperconjugation is the charge-stabilization by pushing some electron density of the adjacent
No hyperconjugation
Rate = k Substrate
>
I
R
Nu
Nu
+
LG
effects and hyperconjugation.
Alkyl groups are electron donors by the inductive effect, so the more alkyl groups on the
Substrate
Br
Good leaving groups are the ones that stabilize negative charge, so the weaker the LG as a base,
the better it is as leaving group. Weak bases are good leaving groups.
The reason is the higher stability of more substituted carbocations originating from inductive
group. When the leaving group is gone, there is a carbocation formed. This is the intermediate.
Nu
>
the stronger base
and methyl don't do SN1 (at least in undergard courses)
The first, and the rate determining (slowest) step in SN1 mechanism is the loss of the leaving
R"
> Cl
F
> Cl > F
Increasing rate of an SN2 reaction
I.e. 3o > 2o
R
Br
the weaker base is the
Methyl
Oppsite to SN2 reactions, SN1 reactions go faster with increasing the alkyl substitution.
-LG
>
What Makes a Good Leaving Group?
Because SN2 is a concerted mechanism, there is only one step, so there are no
R' R"
R LG
Polar aprotic solvent
Polar protic solvent
-
F-
Both the substrate and the nucleophile appear in the transition state of the rate determining step.
The SN1 Mechanism
electronegative atom).
Polar protic solvent
still able to act as a nucleophile because of its larger/polarizable orbitals. So, the nucleophilicity
cannot attack
intermediaries in the reaction.
(no proton on an
H
So, sterically unhindered species are more reactive/mobile and prefer SN2.
if both tripled,
if [Nu] doubles, rate doubles
make hydrogen bonds
Nu
SN2 reactions go faster as the size of the substrate (and the nucleophile) get smaller.
too hindered
Nu
H
Now, because F- is smaller it gets caged by the molecules of polar protic solvent, while the I- is
increases 4 times
if [RLG] doubles, rate doubles
Aprotic solvents do not
H
H
Reactivity of Substrates in SN2 and SN1 Reactions
LG
if both doubled,
LG
CN > HCN
PH3 > NH3
> Br > Cl > F,
decrease its nucleophilicity.
The reaction is first order in the substrate and the nucleophile and overall it is second
R'
I
hydrogen bonds with the nucleophile and
breaks the C-LG bond
makes the Nu-C bond
Rate = k R
OH,
Polar protic solvents are capable of making
leaving group
Nu
SH,
S
S
R
proceed with racemization of that stereogenic center.
R
>
NH2,
OH
Cl
mechanism.
Nu
>
NH
OH,
rows in the periodic table, classify the larger atom/greater polarizability as a better nucleophile.
The Stereochemistry
SN2 reactions proceed with inversion of configuration at the stereogenic center where the
LG +
>
Another factor is the polarizability of the nucleophilic atom: When comparing atoms of different
Rxn coordinate
Two steps - one intermediate
1) The nucleophile attacks and kicks out the leaving group. In other words, this happens
R
OH
Nucleophilicity increases going down the periodic table.
There are two ways the swap can happen - two mechanisms:
Loss of a
NH2 >
2) Charged species are better nucleophiles.
O
product and do not make an influence on the course of the reaction.
Nucleophilic attack
NH,
products
Exothermic
Rxn coordinate
One step - no intermediate
is the counterion. Counterions are often omitted since they are not part of the organic
R'
R R"
reactants
H
The molecule with the leaving group is generally classified as the substrate (molecule of
Ea2
Ea1
>
HC C
SN1
Ea
reactants
products
1) Stronger bases, in general, are better nucleophiles.
LG
Intermediate
Endothermic if
(electron-rich, likes a nucleus since it is positively charged).
K+
R
Transition
R
Energy
+
Like for basicity, larger electron density increases the nucleophilicity. So, two implications here:
R' R"
LG
Nu
Br
What Makes a Good Nucleophile?
Too unstable
+
H C H
H
H
H C
+
C H
H
H
sp3 sp2
More alkyl groups -
TsO MsO
I
H2O
Br
Cl
OH
R2N
AcO
OR F
RNH R
I
-10
Br
-8
Cl
-7
TsO
-3
MsO
-3
H2O
F
-1.7
3.2
AcO
4
pKa of the cojugate acid
Most of the time you can follow the pKa pattern to
determine the leaving propensity. However, for different
reasons, there are deviations. For example, F- is not a
leaving group since it makes a strong bond with carbon.
These are NOT leaving groups (for most cases in undergraduate courses), so whenever you see
them marked as "poor leaving groups", read it as "not a leaving group".
more hyperconjugation
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Elimination Reactions - E2 and E1
Stereospecificity of E2 Reactions
General Features of Elimination Reactions
Regioselectivity of E1 Reactions
In stereospecific reactions, only one isomer can be formed dictated by the mechanism of the
In an elimination reaction, a new
bond is formed by a loss of elements from the substrate.
LG
Like the E2 reaction, E1 reaction is regioselective as well.
reaction and the stereochemistry of the starting material. It is not a preferential formation of one
R
R
+
B
R
R
H
BH
+
+
LG
hydrogen
MeOH
The E2 reactions are stereospecific if there is only one -hydrogen present. The reason for this
bond formed
disubstituted-more stable
monosubstituted
Br
over the other - there is no choice.
H
Zaitsev product
+
H
is the requirement of a parallel alignment between the -hydrogen and the leaving group in the E2
major product
mechanism. This can be syn-periplanar or anti-periplanar. The anti-periplanar alignment
The carbon bonded to the leaving group is called
-carbon. The adjacent carbon(s) is called a
determines the stereochemistry of the product for a stereospecific reaction.
carbon. The hydrogen(s) on the -carbon is called a -hydrogen.
eclipsed conformation
The presence of a -hydrogen is a must (unless rearrangements are possible) and because of
LG
LG H
this, they are called -elimination or 1,2-elimination reactions.
H
If the leaving group is a halogen, the elimination is also called dehydrohalogenation.
Cl
H
H
LG
LG
Cl
B
H2O
+
LG
*
*
H
H
anti-periplanar
1) E2 is a concerted mechanism where all the bonds are broken and formed in a single step.
Cl
LG
anti-periplanar
Cl
H
Br
H
H
syn-periplanar
The E2 Mechanism
E1 reactions are also stereoselective, so the more stable stereoisomer is the major product:
H
or
H
Like in substitution, there is a bimolecular (E2) and a unimolecular mechanism (E1).
Stereoselectivity of E1 Reactions
staggered conformation
*
major product
*
H
*
*
*
H
Rearrangements in E1 and SN1 Reactions
*
Watch out for rearrangements in SN1 and E1 since there is a carbocation intermediate formed:
H2O
R
R" + OH
R
R' H
Strong base
Substrate
Cl
R"
R'
+
The leaving group and the -hydrogen must be anti-periplanar:
Br
E2 reactions are favored by strong bases such as MeO-, EtO-, tBuOK, DBN and DBU
E2 is a second order reaction and the rate depends on the concentration of both, the substrate
H
H Br
H
H
3o
shift
carbocation
Elimination Reactions of Alcohols
Only the red H can be removed regardless of what base is used since it is periplanar to the Br.
Remember, the -OH by itself is a very poor leaving group. Removing the -OH can be done in the
following ways:
1) By converting it into a good leaving group:
The first, and the rate determining (slowest), step in E1 mechanism is the loss of the leaving group.
mainly E1: ROH or H2O and heat
Once the carbocation has formed, the base attacks and deprotonates it and the alkene(s) is formed.
Br
Sterically unhindered bases produce the more substituted/stable alkene as the major product.
+
EtO Na
R
R'
+
E2
OTs
Py
tBuOK
Hofmann
E1 reactions are favored by weak bases. Most common weak bases are water and alcohols.
20%
OH
OH2
R'
fast
R"
R"
Zaitsev product
+
H
H
disubstituted-more stable
OH
H
Br-
Zaitsev
TsCl
R
slow
H
R
R' R"
or other unhindered bases
like -OH, MeO-
EtO- Na+
Regioselectivity is the preferential formation of one regio/constitutional isomer over the other.
When there are two or more -hydrogens present, the E2 reaction is regioselective.
E1
observed
The E1 Mechanism
monosubstituted
expected
H2O
not
H
Rate = k Substrate Base
Regioselectivity of E2 Reactions
SN1
a rearrengement
and the base.
Br
OH
H
H
Br
H
1,2-hydride
carbocation
H
MeO-
2o
- Cl
OH
H
H
E2 Reactions of Cyclohexanes
Br
+
H2O
sterics
2) By Using fuming H2SO4 or H3PO4 or POCl3 for
1o
or other hindered bases
like DIPEA, DBU, DBN
, 2o , and 3o alcohols:
80%
Sterically hindered/bulky bases produce the less substituted alkene as the major product.
H2SO4
E1 is a unimolecular (first order) mechanism and the rate of the reaction depends only on
OH
the concentration of the substrate.
conc.
Zaitsev
Regio- and
stereoselective.
or by POCl3 and
pyridine
Br
+
OK
+
Hofmann product
20%
H
H
Rate = k Substrate
80%
How to Know if the Reaction is E1 or E2?
Short answer:
Unhindered base - Zaitsev
OH
H3C O
Reactivity of Substrates in E2 and E1 Reactions
Hindered base - Hofmann
N
O
N
O
N
N
O
DBN
tBuOK
DBU
E2 reactions are also stereoselective, meaning that the more stable (E) alkene is the
major product.
Stereoisomers
R
+
B
R
R
Z-isomer
+
R
mechanisms. For E2, it increases because the transition state is better stabilized as it resembles a more
More details in the next part - competition between SN1, SN2, E1 and E2.
substituted alkene.
3o
R"
R
R' H
>
2o
1o (no E1 for primary substrates)
>
The E1CB Mechanism
Br
+
OH
R
R' H
This is an example of -OH and -OR groups being leaving groups when they are next to an
R
R"
R'
R"
acidic proton at
R
E-isomer
O
E alkene- more stable
major product
carbonyl position.
OH
more alkyls - more stable the transition state
LG
R
E1 reactions are favored by weak bases. Most common weak bases are water and alcohols.
Br
Stereoselectivity of E2 Reactions
E2 reactions are favored by strong bases and polar aprotic solvents.
The reactivity increases with more substituted alkyl halides (or other substrates) for both E2 and E1
B
O
OR
O
+
-OR
H
For the E1, it increses because the itermediate carbocation is better stabiized with more
alkyl groups by inductive effect and hyperconjugation (check the SN2 and SN1 guide):
OR
The product,
unsaturated carbonyl
is a conjugated system
which have additional
stability.
This stability is the driving force pf the reaction despite having an -OH or -OR as a leaving group.
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Competition Between Substitution and Elimination Reactions: SN1, SN2, E1 and E2
SN1 vs SN2
SN1/E1 vs SN2/E2
If you are asked to choose between SN1 and SN2, consider these factors in the following
What if you get a question asking you to choose between SN1, SN2, E1 and E2?
order of priority:
Here is one good way to approach this. First, you want to remember that SN2 and E2 are bimolecular reactions favored by strong nucleophiles or bases, while SN1 and E1 are unimolecular reactions favored by
1) The Substrate. This is the most important and often decisive.
weak nucleophiles and bases. Now, because of these different conditions, you are not going to get a SN1/E2 or SN2/E1 competition. So, the question here is to decide between SN2/E2 and SN1/E1.
If methyl or primary, then it is SN2.
To determine the mechanism, classify first the nucleophile/base as strong or weak and follow the diagram once on the left or the right side:
If tertiary, then it is SN1. No question, you are done.
Increasing rate of an SN1 reaction
NO SN1
only SN1
R
SN2 and SN1
X
H3C X
R
1o
2o
Strong - bimolecular: SN2 or E2
Nucleophile/Base
H2O or alcohols
R
X
R
R
3o
NO SN2
only SN2
R
X
Bulky strong bases
Weak - unimolecular: SN1 or E1
O
Non-bulky
tBuOk
SN1/E1 mixture obtained
Methyl
N
E2 Only
Br
OH
Strong, non-basic Nucleophiles
2) The Nucleophile. Strong nucleophiles favor SN2, weak nucleophiles favor SN1.
O
Oxygen and nitrogen are
+
OH
Strong Nu - SN2
H2O
OH
-OH
I
Halides, -CN, -SR, -SH, RSH
Br
H2O
OH
+
+
2o
Racemizaion of the chiral center
Br
-CN
can do SN2 and E2.
Cl
RNH2, RNH-, -NH2,
and bases.
CN
+
solvent
Br-
SN2
CH3OH
DMSO
1
1500
rate
E2
bulky
SN2 - No elimination
3) The Solvent. Polar aprotic solvents favor SN2, polar protic solvents favor SN1.
-CN
+
Basic Nucleophiles
E1-major
Inversion of the chiral center
Alcohols are also weak nucleophiles
Br
Br
O
CN
Remember, however, if it is a tertiary
R
+
E2
2o
, -OH, -OR
R
substrate, SN2 is impossible, only SN1.
Bulkiness and temperature determine:
R
+
R
Cl
SN2
1o
1o- SN2, 2o, 3o- E2
A better leaving group (LG) increases the rate of both, SN1 and SN2, so no need to consider it
O
SN2
E2-major
bulky
negativelly charged.
(No Elimination)
heat
N
Li
LDA
N
H
DIPEA
Br
basic especially if
Weak Nu - SN1
DBN
be non-basic and basic.
SN2 Only
SN1-major
N
DBU
The strong nucleophile can
H2O
The issue is with secondary substrates. They can do both, so other factors need to be considered.
N
Nucleophilic base
(Basic Nucleophile)
Non-Basic
Heat favors Elimination
Increasing rate of an SN2 reaction
N
O
Bulky
* Keep in mind that Heat and Bulkiness/Steric hindrance favor elimination over
* Any combination of Strong-Bulky gives E2. Doesn't matter if it is the substrate or the base that is bulky.
substitution for any of the mechanisms.
Molecules do not know that we classify them into substrates and bases.
when deciding between SN1 and SN2.
Benzylic and Allylic Halides
E1 vs E2
Solvents
Benzylic and allylic substrates are quite reactive in SN2 and E2 reactions. They also undergo SN1 and E1
Choosing between E1 and E2 is easier since the reactivity pattern is the same for both; the
Polar aprotic solvents favor bimolecular SN2 and E2 mechanisms.
reactions because of the stability of the benzylic carbocation.
rate of E1 and E2 increase with the degree of substitution.
Polar protic solvents favor unimolecular SN1 and E1 mechanisms.
The only restriction here is that 3o benzylic substrates cannot undergo SN2
R
2o
X
R O
- no carbocation
R
R
3o
CH3
R'
SN1
R Br
R
E1
The key factor here is the strength of the base.
CH3O-
CH3OH
1o, 2o, 3o
heat
R
R'
Also, polar aprotic solvents favor the E2 mechanism since it is a bimolecular mechanism.
R'
E2
heat
R
R O
CH3OH
R'
R'
+
R + S, E + Z
R'
H2O
Solvolysis-
Br
tBuOK
R'
O
S
(DMSO)
CH3OH
O
R'
+
R'
H
Methanol (MeOH)
N
Acetonitirile (MeCN) CH3CN
Hexamethylphosphoramide
N
(HMPA)
Combination
regioisomers.
R
R
(DMF)
Water (H2O)
O
Acetone (Me2CO)
O
P N
N
Ethanol (EtOH)
Ammoina (NH3)
OH
tert-Butanol (tBuOH)
O
Acetic acid (AcOH) CH3COOH
A mess.
or
Note: This may vary from textbook-to-textbook. For example, in some, it is stated that secondary substrates do not undergo SN1 reactions and in this case, it would be easier to determine the mechanism. In any case,
DMSO
polar aprotic solvent
H2O is the base and the solvent
R
Strong base - E2
Dimethylformamide
of stereo- and
R Br
Weak base - E1
Dimethyl sulfoxide
When allylic substrates undergo E1 or SN1, a mixture is obtained because of different resonance contributors:
E2 reactions are favored by strong bases. E1 reactions are favored by weak bases.
Polar protic solvents
Polar aprotic solvents
SN2
R
R'
elimination - only one carbon.
CH3
R'
R=H
R'
Methyl substrates, obviously, cannot do
Increasing rate of E1 and E2 reaction
R O
CH3O-
CH3OH
Increasing Polarity
X
X
1o
1o substrates can only do E2
R
R
R
if unhindered base
is used
you need follow as your instructor teaches.
Note: In real life, a mixture of compounds is obtained in most cases. Here we only talk about general traits and major products. Don't take words like
"never" "always" literally. There is always an exception, if not more than one.
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