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Nucleophilic Substitution
Reactions:
SN2 Mechanism
The SN2 Mechanism of
Nucleophilic Substitution
Concerted One Step - Bimolecular
Reactions
Kinetics
Many nucleophilic substitutions follow a
second-order rate law.
CH3Br + HO –
CH3OH + Br –
rate = k [CH3Br] [HO – ]
What is the reaction order of each starting material?
What can you infer on a molecular level?
What is the overall order of reaction?
Bimolecular mechanism
one step
concerted
HO – + CH3Br
HOCH3 +
Br –
Bimolecular mechanism
one step
concerted
HO – + CH3Br
HOCH3 +
Br –
Bimolecular mechanism
dHO
dBr
CH3
transition state
one step
concerted
HO – + CH3Br
HOCH3 +
Br –
Question
Assuming the reaction below takes place by a concerted process,
which mechanistic scheme is correct?
NaCN
CN
Cl
+ NaCl
A.
NaCN
Cl
CN
+ NaCl
CN
+ NaCl
CN
+ NaCl
NC
B.
CN
NaCN
Cl
CN
Cl
C.
CN
NaCN
Cl
Stereochemistry of SN2 Reactions
Generalization
Nucleophilic substitutions that exhibit
second-order kinetic behavior are
stereospecific and proceed with
inversion of configuration.
Inversion of Configuration
nucleophile attacks carbon
from side opposite bond
to the leaving group
Inversion of Configuration
nucleophile attacks carbon
from side opposite bond
to the leaving group
three-dimensional
arrangement of bonds in
product is opposite to
that of reactant
Inversion of configuration (Walden inversion) in an SN2
reaction is due to back side attack
Stereospecific Reaction
A stereospecific reaction is one in which
stereoisomeric starting materials give
stereoisomeric products.
The reaction of 2-bromooctane with NaOH
(in ethanol-water) is stereospecific.
(+)-2-Bromooctane
(–)-2-Octanol
(–)-2-Bromooctane
(+)-2-Octanol
Stereospecific Reaction
H (CH2)5CH3
CH3(CH2)5 H
NaOH
C
Br
CH3
(S)-(+)-2-Bromooctane
HO
C
CH3
(R)-(–)-2-Octanol
1) Draw the Fischer projection formula for (+)-S-2-bromooctane.
2) Write the Fischer projection of the
(–)-2-octanol formed from it by nucleophilic substitution
with inversion of configuration.
CH3
H
CH3
Br
CH2(CH2)4CH3
HO
H
CH2(CH2)4CH3
A.) R- ? or B.) S- ?
A conceptual view of SN2 reactions
Why does the nucleophile attack from the back side?
Why does the nucleophile attack from the back side?
“Roundabout” SN2 Reaction
Mechanism
SN2 Reaction Mechanisms: Gas Phase (2008)
http://pubs.acs.org/cen/news/86/i02/8602notw1.html
Traditional
Physicist Roland Wester and his team in Matthias Weidemüller's group
at the University of Freiburg, in Germany, in collaboration with William
L. Hase's group at Texas Tech University, provide direct evidence for
this mechanism in the gas phase. However, they also detected an
additional, unexpected mechanism. In this new pathway, called the
roundabout mechanism, chloride bumps into the methyl group and
spins the entire methyl iodide molecule 360° before chloride
substitution. Data at lower collision energies support the traditional
SN2 mechanism. However, at higher collision energies, about 10% of
the iodide ions fell outside of the expected distribution.
Roundabout
Roundabout SN2
Mechanism
Traditional SN2 Mechanism
Fig. 1. Calculated MP2(fc)/ECP/aug-cc-pVDZ Born-Oppenheimer potential energy along the reaction
coordinate g = RC-I - RC-Cl for the SN2 reaction Cl- + CH3I and obtained stationary points
J. Mikosch et al., Science 319, 183 -186 (2008)
Published by AAAS
Fig. 2. (A to D) Center-of-mass images of the I- reaction product velocity from the reaction of Cl- with
CH3I at four different relative collision energies
J. Mikosch et al., Science 319, 183 -186 (2008)
Published by AAAS
Fig. 3. View of a typical trajectory for the indirect roundabout reaction mechanism at 1.9 eV that
proceeds via CH3 rotation
J. Mikosch et al., Science 319, 183 -186 (2008)
Published by AAAS
Steric Effects in SN2 Reactions
Crowding at the Reaction Site
The rate of nucleophilic substitution
by the SN2 mechanism is governed
by steric effects.
Crowding at the carbon that bears
the leaving group slows the rate of
bimolecular nucleophilic substitution.
Reactivity toward substitution by the SN2
mechanism
RBr + LiI
RI + LiBr
Alkyl
bromide
Class
Relative
rate
CH3Br
Methyl
221,000
CH3CH2Br
Primary
1,350
(CH3)2CHBr
Secondary
1
(CH3)3CBr
Tertiary
too small
to measure
A bulky substituent in the alkyl halide reduces the
reactivity of the alkyl halide: steric hindrance
Decreasing SN2 Reactivity
CH3Br
CH3CH2Br
(CH3)2CHBr
(CH3)3CBr
Decreasing SN2 Reactivity
CH3Br
CH3CH2Br
(CH3)2CHBr
(CH3)3CBr
Reaction coordinate diagrams for (a) the SN2 reaction of
methyl bromide and (b) an SN2 reaction of a sterically
hindered alkyl bromide
Crowding Adjacent to the Reaction Site
The rate of nucleophilic substitution
by the SN2 mechanism is governed
by steric effects.
Crowding at the carbon adjacent
to the one that bears the leaving group
also slows the rate of bimolecular
nucleophilic substitution, but the
effect is smaller.
Effect of chain branching on rate of SN2
substitution
RBr + LiI
RI + LiBr
Alkyl
bromide
Structure
Relative
rate
Ethyl
CH3CH2Br
1.0
Propyl
CH3CH2CH2Br
0.8
Isobutyl
(CH3)2CHCH2Br
0.036
Neopentyl
(CH3)3CCH2Br
0.00002
Question
Which reaction will have the fastest rate of reaction?
A)
B)
C)
Putting things together
IUPAC Nomenclature
of Alkyl Halides
IUPAC Nomenclature
There are several kinds of IUPAC nomenclature.
The two that are most widely used are:
functional class nomenclature
substituent nomenclature
Both types can be applied alkyl halides and
to alcohols.
Functional Class Nomenclature of Alkyl Halides
Name the alkyl group and the halogen as
separate words (alkyl + halide).
CH3F
CH3CH2CHCH2CH2CH3
Br
CH3CH2CH2CH2CH2Cl
H
I
Functional Class Nomenclature of Alkyl Halides
Name the alkyl group and the halogen as
separate words (alkyl + halide).
CH3F
CH3CH2CH2CH2CH2Cl
Methyl fluoride
Pentyl chloride
CH3CH2CHCH2CH2CH3
Br
1-Ethylbutyl bromide
H
I
Cyclohexyl iodide
Substituent Nomenclature of Alkyl Halides
Name as halo-substituted alkanes.
Number the longest chain containing the
halogen in the direction that gives the lowest
number to the substituted carbon.
CH3CH2CH2CH2CH2F
CH3CHCH2CH2CH3
Br
CH3CH2CHCH2CH3
I
Substitutive Nomenclature of Alkyl Halides
Name as halo-substituted alkanes.
Number the longest chain containing the
halogen in the direction that gives the lowest
number to the substituted carbon.
CH3CH2CH2CH2CH2F
1-Fluoropentane
CH3CH2CHCH2CH3
I
3-Iodopentane
CH3CHCH2CH2CH3
Br
2-Bromopentane
Substitutive Nomenclature of Alkyl Halides
Cl
CH3
CH3
Cl
Halogen and alkyl groups
are of equal rank when
it comes to numbering
the chain.
Number the chain in the
direction that gives the
lowest number to the
group (halogen or alkyl)
that appears first.
Substitutive Nomenclature of Alkyl Halides
Cl
5-Chloro-2-methylheptane
CH3
CH3
2-Chloro-5-methylheptane
Cl
Question
Name the compound on the right according to
the IUPAC system.
A)
B)
C)
D)
4-bromo-5-ethyl-2-methylheptane
4-bromo-3-ethyl-6-methylheptane
4-bromo-5-diethyl-2-methylpentane
4-bromo-3-ethyl-6-dimethylhexane
Question
Br
Cl
What is the correct IUPAC name for the ABOVE
structure?
A. (3S,4S)-3-bromo-4-chlorohexane
B. (3S,4S)-3,4-dibromochloroheptane
C. (3R,4R)-3-chloro-4-bromohexane
D. (3R,4R)-3-bromo-4-chlorohexane
E. (3S,4S)-4-bromo-3-chlorohexane
Classes of Alkyl Halides
Classification
Alkyl halides & alcohols are classified as
primary
secondary
tertiary
according to their "degree of substitution."
Degree of substitution is determined by counting
the number of carbon atoms directly attached to
the carbon that bears the halogen or hydroxyl group.
Different Kinds of Alkyl Halides
Classification
H
CH3CH2CH2CH2CH2F
OH
primary alkyl halide
secondary alcohol
CH3
CH3CHCH2CH2CH3
Br
secondary alkyl halide
CH3CCH2CH2CH3
OH
tertiary alcohol
Question
What type of alcohol is 2-methyl-3-pentanol?
A) primary (1°)
B) secondary (2°)
C) tertiary (3°)
D) quaternary (4°)