Lecture Summary 29
November 3, 2006
Chapter 11 - Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations
SN2 Reaction Details - Leaving Group
The leaving group has a big influence on the substitution reaction as well. The weaker the bond
(longer bonds are weaker), the better a leaving group is. Also, the more stable the leaving group is
after the bond has broken, the easier it can come off. Thus, more stable anions will be better
leaving groups. The tosylate group (-OTos) is one of the best leaving groups.
LEAVING GROUP
TosO-
I-
Br-
Cl-
F-
HO-
NH2-
RELATIVE RATE
FOR SN2
60,000
30,000
10,000
200
1
<1
<1
O
S
TosO-
=
O
Tosylate (p-toluenesulfonate)
O
SN2 Reaction Details - Solvents
Solvents play a role in dissolving the reactants, stabilizing intermediates and can have positive or
negative effects on a reaction. We will discuss the details next time. Here are some examples of
common solvents. Note that ‘protic’ solvents can hydrogen bond with lone pairs.
non-polar
solvents
alkanes
polar protic
solvents
polar aprotic solvents
CH3 OH
CH3 C
O
N
(CH3)2N
acetonitrile
CH3CH2 OH
HMPA N(CH3)2 hexamethylphosphortriamide
N(CH3)2
P
O
H2O
CH3
S
O
CH3
DMSO dimethylsulfoxide
H
C
N
CH3 DMF dimethylformamide
CH3
SOLVENT
RELATIVE RATE
FOR SN2
CH3OH
H2O
DMSO
DMF
CH3CN
HMPA
1
7
1300
2800
5000
200,000
SN2 Reaction Details - Solvents
Solvents play a role in dissolving the reactants, stabilizing intermediates and can have positive or
negative effects on a reaction. In the SN2 reaction, the nucleophile strength is important. While
solvents that are polar help any substitution reaction, protic solvents will retard the rate of SN2
reactions. This is because the acidic nature of the protons on water or alcohols will surround the
nucleophile to stabilize it and render it less reactive. Polar aprotic solvents are best for SN2.
©2006 Gregory R. Cook
North Dakota State University
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Chem 341
CH3
H3C
δ+ S
CH3
H3C
Na
δO
δS
O
δ+
CH3
S
CH3 δ+ CH3
O
Polar aprotic solvents can
separate and stabilize ionic
reagents.
Nuc
δ+ CH3
S
CH3
O δ-
O
H
H
H
H O
Nuc
O H
S
δ+
CH3
H
H O
H
H3C
CH3
δδ+
O S
CH3
δO
S CH3
δ+
CH3
δ- O
δO
δO
δ+ CH
3
S
H
Polar protic solvents like water will surround a
nucleophile making it less reactive. Thus, protic
solvents retard the rate of SN2 reactions.
H
H
H
H O
O H
SN1 Reaction Details - Substrate
Since the nucleophile is not involved in the rate determining step of the SN1 reaction, the
important feature here is the stability of the carbocation intermediate that is being formed. Tertiary
substrates are best for this reaction. Secondary substrates are very slow, however if they are next
to an alkene, resonance can greatly stabilize the carbocation and make SN1 more favorable.
H
SUBSTRATE
RELATIVE RATE
FOR SN1
R
C
H
H
C
I
methyl
R
H
H
1
1
C
I
1°
R
R
H
12
C
I
2°
R
R
I
3°
1,200,000
Br
©2006 Gregory R. Cook
North Dakota State University
page 2
Chem 341
SN1 Reaction Details - Nucleophile
The nucleophile is not very important for a SN1 reaction. This is because it is not involved in the
rate determining step. Even weak nucleophiles like neutral water will react with a carbocation
when it’s formed. The major concern is problems with competing elimination reactions when the
nucleophile is too basic.
SN1 Reaction Details - Leaving Group
The leaving group has a big influence on the substitution reaction for SN1 just as we saw with SN2
since the leaving group leaves in the rate determining step. The weaker the bond (longer bonds
are weaker), the better a leaving group is. Also, the more stable the leaving group is after the bond
has broken, the easier it can come off. Thus, more stable anions will be better leaving groups. The
tosylate group (-OTos) is one of the best leaving groups.
SN1 Reaction Details - Solvents
What was bad for the nucleophile in SN2 reactions is great for the leaving group as it comes off.
The protic solvents will stabilize the anion with it’s acidic protons. Also, the polar solvents will
stabilized the carbocation when it’s formed. Thus, polar protic solvents are best for aiding the rate
determining step of the SN1 reaction.
H
H
H
O H
δ−
H
O
δ−
H
O δ−
δ−
O
R
H
H
H
δ−
O
H
δ−
O H
Polar solvents
stabilize the
carbocation by
surrounding it with
the negatively
charged oxygens
H
O
H
O
H
O
H
H
H
H O
Br
O H
H
Protic solvents
stabilize the leaving
group by
surrounding it with
acidic protons
H
H
H
H
H O
O H
Stereochemistry of Substitution Reactions
SN2 reactions on chiral substrates will proceed with complete inversion of the stereochemistry. In a
SN1 reaction, stereochemistry is lost when you form the planar (achiral) carbocation. The
nucleophile may approach from either side with equal probability. Thus, racemic products are
formed.
Br
CN
NaCN
DMSO
SN2
Br
OAc
NaOAc
Acetic Acid
OAc
+
SN1
50 : 50
©2006 Gregory R. Cook
North Dakota State University
page 3
Chem 341
SN1 and SN2 Comparison
Below is a table comparing the features important for each mechanism for substitution. The
substrate type is probably the most important factor.
SN1
SN2
SUBSTRATE
3° >> 2° > 1°
1° > 2° >> 3°
NUCLEOPHILE
Weak OK
Strong
LEAVING GROUP
Stable Anions
Stable Anions
SOLVENT
Polar Protic
Polar Aprotic
STEREOCHEM
Racemic
100% inversion
Here are some examples of the affects of these mechanisms on the reaction of an alcohol. Note
that carbocations generated during SN1 reactions can undergo rearrangements. An alcohol can be
activated into a leaving group two ways . . making a tosylate or making a halide. Note that the
tosylate formation does not alter the C-O bond stereochemistry whereas PBr3 or SOCl2 will invert
the alcohol stereochemistry when the halide is formed. Nucleophiles and halides in the same
molecule can undergo cyclization reactions.
carbocation
rearrangement
OH
HBr
O Tos
OH
CN
Tos-Cl
NaCN
pyridine
DMF
inversion
OH
Br
CN
PBr3
NaCN
DMF
inversion
inversion
Br
OH
©2006 Gregory R. Cook
North Dakota State University
Br
NaH
Br
O
O
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Chem 341