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Nu + R – X R – Nu + X
Alkyl halide Product Leaving Group
Nucleophile
(substrate) In this example a halide
heterolysis or carbon
halogen bond breaks
H H
δ+ δ-
C L Nu C L
Nu
H H
H H
Inversion
Electrons are transferred from the nonbonding electrons in a filled molecular orbital of
the nucleophile to the empty antibonding molecular orbital of the Lewis acid.
C L
Base Acid
donates Nu Empty orbital
accepts
electrons electrons
σ*
Filled
LUMO
HOMO
Transition State
high energy the carbon is surrounded by three
coplanar groups with 10e¯ around it
concerted reaction.
∆G‡
∆G‡ = Free energy of activation
∆G° = Free energy change
Nu C L
σ* ∆G°
Nu C L
Reactants
Products
Reaction Coordinate
This is a very large Keq which means the reaction will go to completion
Remember the equilibrium always favors the species lower in energy or less reactive
Exergonic: The free energy level of the products is lower than that of the reactants
For many reactions taking place at room temperature, a 10°C increase in temperature
will the cause the reaction rate to double.
The rate increases because more molecules have sufficient kinetic energy to
surmount the energy barrier (∆G‡).
T1 < T2
Nu
-
δ+ δ
Nu C L
Nu
-
the only way in δ+ δ
Nu C L
- δ+
δ
Nu C L Nu C + L
Transition state
High energy Inversion
10 electrons around carbon What happens at a stereogenic carbon?
H3 C Br
CH3CH2S Na H3C
H acetone O H
H
solvent H
cis-1-bromo-3-cyclopentane H3C C CH3
What is the stereochemistry at the
stereogenic centers? lone pair of Transition State
electrons from
sulfur makes new
H3C Br σ bond
+
+ Na Br
flip
-1-(ethylthio)-3-methylcyclopentane
H
SCH2CH3
H3C
NaOH + CH3 Br
Na Br + CH3 OH
H2SO4
CH3OH Na Br
C6H13
C NaOH C
H C
Br
H3C
-(–)- 2-bromooctane
-(–)-2-octanol
transition state
[α] = - 9.90°
[α] = - 34.25°
enantiomeric purity = 100%
Start with enantiomeric purity = 100%
C
C
inversion of configuration
H2O
(CH3)3C-Cl + OH¯ (CH3)3C-OH + Cl¯
acetone
Step 3
+
H +
H H
H H H O OH
O
O O H C
C H
C H3C
H3C CH3
CH3 H3C H3 C
H3 C base CH3
H3 C
+ H3O+ + Cl¯
acid
Sec. 8 - SN2/SN1 Forsey 21
Stability of Carbocations
What is the
hybridization of the
positively charged
carbon?
H
2p2 2p empty
H C sp3
H
potential energy
2sp2 H
2s2 sp3 C C sp2
H
H
1s2 1s2 H C sp3
C+ C+ H
H
Alkyl groups are electron donating. Hyperconjugation donates electron
density via a partial overlap the adjacent sigma bonds. Any time a charge is
dispersed or delocalized the system will be stabilized. The more interactions
of this kind that are possible, the more stable the ion. Thus tertiary cations
will be more stable than secondary and secondary cations are more stable
than primary cations
Sec. 8 - SN2/SN1 Forsey 22
Stability of Carbocations
No hyperconjugation
Will not form in a solution
CH3
+ +
+ +
(CH3)3C + CH3+
A
Br
H
C H2O +
O
H3C C
CH2CH2CH3 acetone H
H3CH2C
(R)-3-bromo-3-methylhexane B
B
optically active A use instead of last step
-H+
-H+
C
( )-3-methyl-3-hexanol
flip
( )-3-methyl-3-hexanol
C C
Energy
barrier too
large
Free Energy
∆G‡ = for a
reaction
to occur
Energy
barrier too
large
Free Energy
∆G‡ = for a
reaction
to occur
H L
H C
C C H
H
Nu
H
H C +
+ H
H
CH3 H3C C +
+ +
CH3
H3C C +
H
H3C C +
+
H
Free Energy
CH3 ∆G‡ =
+
+
Free Energy
∆G‡ ∆G°
Reaction coordinate
CH3 The formation of the ions in the 1st step in a SN1
+
reaction is both endergonic and endothermic and
C Cl
the transition state for this process should show a
H3C CH3 strong resemblance to the product of that step.
Thus when you think about what stabilizes the
intermediate the same processes (delocalization of
bond breaking
carbocation) will help stabilize the transition state
the carbocation must be
and will help the reaction proceed.
somewhat stable or the bond
will not break.
Generally the transition state looks most like the species it is closest to in energy
∆G‡ = δ−
H H δ+ C Br
Free Energy
δ− δ+
Nu C Br
H
H A methyl carbocation is
very unstable and
H3C H3C destabilizes the transition
state – increases ∆G‡
δ− δ+
Reaction coordinate
Nu C Br
H3C CH
Free Energy
3
H3C
δ−
The steric interaction between the δ+ C Br
nucleophile and the Lewis acid Reaction coordinate
generates more strain in the
transition state – increases ∆GSec.
‡
8 - SN2/SN1 H3Forsey
C 34
Relative Reactivity
Relatively
stable Highly unstable carbocation
carbocation
Efficiency of No SN1 No SN1
SN1
CH3 H H H
H3C C L H3C C L H C L H C L
3° 2° 1° methyl
No SN2 Efficiency of
SN2
Steric Little steric interaction
interaction
CH3
Why does this
CH3
+ methanide + happen?
H3C C C CH3 H3C C C CH3
migration H
2° 3° H
H
CH3 H CH3 H
H C C
H
+ H
C C
CH3 CH3 H3C
+
methanide +
H3C H
H3C C CH2 H3 C C CH2 Lewis
Lewis
1° migration 3° acid
CH3 CH3 base
H
H H H
H H
+
hydride + C CH3
CH3CH2 CH CH2 CH3CH2 CH CH2 H2C +
migration 2° H C C
1°
H2C H
CH3 Br
CH3OH
H3C C C CH3
weak base
CH3 H poor nucleophile
conc. H2SO4
OH O
Br sp3
Br Br
+
+ Br
sp3
Nu
allylic SN1
SN2
resonance benzylic
hyperconjugation
stabilized
vinyl and aryl compounds are very nonreactive in both SN1 and SN2
sp2 +
Br
+ Br Br
Br sp2
vinyl
+
SN1 Br aryl
empty p orbital is at sp2 short strong bond
90° w.r.t. π bond and will Under most conditions a
not resonate nucleophile will not displace
The cation will not the leaving group in a SN2 reaction
form under most conditions
Sec. 8 - SN2/SN1 Forsey 39
Other Factors
What effect does the concentration and strength of the nucleophile have on the
rate of reaction?
Trend → Nucleophilicity increases down the periodic tab following the increase
in size and polarizability (in solvents that can hydrogen bond).
I ¯ > Br¯ > Cl ¯ > F ¯ HSe¯ > HS ¯ > HO ¯ R3P > R3S
t-butoxide is a stronger
H3 C
base CH3CH2O Strong base
Strong base H3C O than ethoxide but
poor nucleophile because it is hindered ethoxide good nucleophile
H3C
t-butoxide is a weaker
t-butoxide nucleophile
When bulky groups interfere with a reaction because of their size we call this
steric hindrance. Steric hindrance has little effect on basicity because basicity
usually involves attack on an unhindered proton. Thus by choosing a less
hindered or hindered base you can make the attacking species act like a
nucleophile and perform a SN2 reaction or react as a Bronsted-Lowry base and
abstract a proton. We will talk more about this later
Sec. 8 - SN2/SN1 Forsey 42
Nucleophilicity increases down the periodic tab following the increase in size
and polarizability (in solvents that can hydrogen bond). Why?
All strong bases are good nucleophiles but not all weak bases are poor
nucleophiles. Why is iodide such a strong nucleophile compared to fluoride
even though it is a very weak base?
Polarizability
Iodine’s electrons are far away from the nucleus, are loosely held and are polarizable.
Its electrons can move freely towards a positive charge and can engage in partial
bonding as it attacks the electrophilic carbon atom. Remember from Hammond-
Leffler Postulate that for a exergonic reaction the transition state resembles the
reactants and bond formation and breaking is less than half formed.
H H H H
Free Energy
δ−
“hard” non δ+
C Br C Br
polarizable valence
shell H little bonding H
F
Reaction coordinate
H H
Free Energy
“soft” H H δ−
δ+
polarizable C Br C Br
valence shell
H H Reaction coordinate
more bonding
I Transition State
∆G‡ =
Sec. 8 - SN2/SN1 Forsey 43
Remember bonding occurs between the highest occupied molecular orbital of
the nucleophile and the lowest unoccupied molecular orbital of the Lewis acid.
The table below shows some nucleophiles segregated into categories. It is not
possible to do much better than this as nucleophilicity is a property that
depends on the reaction partner. A good nucleophile with respect to carbon
may or may not be a good nucleophile with respect to displacement on some
other atom. Energy matching is important in the reaction. If we change the
reaction partner and thus the energy of the orbitals involved, we will change
the stabilization involved as well
Polar Protic
Small “hard” ions form stronger hydrogen bonds
than larger polarizable “soft” ions. Thus for an
strong H ion like F¯ is hindered and must shed or displace
bonding the solvent as the ion is attacking the
electrophilic carbon
H
H
H O
H
O
H O
O
H
H
H O
H
O
O
H
H
H H
H H
H
H
H
H
O O
O
H O
H
H
H H
H
O
O H
H H
H C Br H
O
H
H
H
H O O
H
O
O
H H H O H
H
H
H O H
H
O
O
O H
H
O
H
Sec. 8 - SN2/SN1 Forsey 45
H
H
H
H
H
H
Polar Protic Solvents
Larger nucleophilic atoms are less solvated and therefore more reactive in
polar protic solvents
Larger nucleophiles are also more polarizable and can donate more electron density
Relative nucleophilicity in polar solvents:
Polar aprotic solvents not only make the anion less stable or more reactive, polar
aprotic solvents help stabilize the slightly polar transition state of an SN2 reaction.
O δ- O δ-
C δ+ δ+
H3 C δ+ CH3 Diethylether
Acetone
Remember: Like Dissolves Like
Cl Cl δ +
H 3C
C C CH 3 Cl
δ+ H 3C
H 3C H 3C
CH 3 CH 3
H 3C H 3C
Low pka values (strong acids) good leaving groups, L ¯ → weak base
High pka values (weak acids) poor leaving groups. L ¯→ strong base
Acid pka Leaving Name
Group
Stereochemistry
SN2
SN1
acetone
Br + NaC≡N
Br
+ CH3OH
Cl + CH3OH
Br
NH2
+
a lot missing
Sec. 8 - SN2/SN1 Forsey 52
What are the products of the following reactions ?
OH
Na SCH3 +
Br
NaH + CH3CH2C≡C-H
hexane
O
O
O S CH3 acetic acid
+
O O
a lot missing
Sec. 8 - SN2/SN1 Forsey 53
What are the products of the following reactions ?
O
ClCH2CH2CH2COOH + Na OH
Cl CH2CH2CH2C O Na + H2O
acid-base reaction 4 3 2 1
very fast 1°
Intramolecular ring formation reactions are more favorable than
SN2 intermolecular reactions (between two different molecules) because
the nucleophile is held in close proximity to the electrophile by the
carbon chain at all times. Thus attaining the proper orientation
required for the SN2 reaction is much more probable than for a
a lactone intermolecular reaction. For example:
is 5000 O
CH3CH2O + CH3CH2Cl CH3CH2OCH2CH3 + Cl times
slower Cl O + Cl
intermolecular than
Intramolecular
+ CH3CH2OH
Br