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H3C
H3C
Cl
EN (F-C) =
EN (Cl-C) =
H3C
Br
EN (Br-C) =
H3C
EN (I-C) =
pKb = 23
-
I
30,000
pKb = 22
-
Br
10,000
pKb = 21
-
Cl
200
pKb = 11
F
1
pKb = -1.7
HO
0
The poorest
leaving
groups are
the strongest
bases.
Nu:
..
Br
.. :
..
: Br
.. :
H
-
Nu
2) elimination
H
-
Nu:
X-
C
X
X-
Nu
Nu:
C
X
X-
Nu
Note that the nucleophile must hit the back side of the -carbon.
The nucleophile to C bond forms as the C to X bond breaks.
No C+ intermediate forms. An example is shown on the next slide.
:O
H
H +
..
..
Br :
..
..O
H
C
..
Br :
..
..
..O
H
C
HH
..
+ : Br :
..
transition state
>>
>>
>>
While a methyl halides reacts quickly in SN2 reactions, a 3 does not react.
The back side of an -carbon in a 3 alkyl halide is completely blocked.
H3C
H3C
Br
methyl bromide
H3C
CH2
CH
Br
H3C
Br
Br
H3C
H3C
ethyl bromide
isopropyl bromide
t-butyl bromide
Back side of -C
of a methyl halide
is unhindered.
Me>>
Back side of -C of a
1 alkyl halide is
slightly hindered.
>>
Back side of -C of a
2 alkyl halide is
mostly hindered.
>>
Back side of -C of a
3 alkyl halide is
completely blocked.
H2C
CH
Br
Br
vinyl bromide
bromobenzene
Nu:H2C
CH
Br
Nu:Br
The overlapping p-orbitals that form the -bonds in vinyl and aryl halides
completely block the access of a nucleophile to the back side of the
-carbon.
Reactivity
Nu:-
Relative Reactivity
very weak
< 0.01
weak
ROH
HOH, NO3-
100
F-
500
Cl-, RCOO-
20 103
NH3, CH3SCH3
300 103
N3-, Br-
600 103
OH-, CH3O-
2 106
fair
good
very good
increasing
The better the nucleophile, the faster the rate of SN2 reactions.
The table below show the relative power or various nucleophiles.
The best nucleophiles are the best electron donors.
pKb = 23
pKb = 22
pKb = 21
pKb = 11
pKb = -1.7
pKb = -2
pKb = -21
I-
Br -
Cl-
F-
HO-
RO-
H2N-
30,000
10,000
200
Polar aprotic solvents like acetone, which contain strong dipoles but no
OH or NH2 groups. Polar aprotic solvents speed up SN2 reactions.
Non polar solvents, e.g., hydrocarbons. SN2 reactions are relatively slow
in non polar solvents.
Protic solvents (e.g., H2O, MeOH, EtOH, CH3COOH, etc.) cluster around the
Nu:- (solvate it) and
its energy (stabilize it) and reduce its reactivity via
+ lower
H-bonding.
OR
H
RO H
+
X:
+
H
H OR
+
OR
10
CH3
N:
acetonitrile
: O:
H3C
CH3
acetone
Polar Aprotic Solvents solvate the cation counterion of the nucleophile but
not the nucleophile.
Examples include acetonitrile (CH3CN), acetone (CH3COCH3),
dimethylformamide (DMF) [(CH3)2NC=OH], dimethyl sulfoxide, DMSO
[(CH3)2SO], hexamethylphosphoramide, HMPA {[(CH3)2N]3PO} and
dimethylacetamide (DMA).
:O :
H
..
: O:
CH3
H3C
CH3
S
..
.. ..
[(CH3)2N]3P O
..
CH3
.. _
+
:
CH3C O
.. Na
CH3CN :
H3C
HMPA
DMSO
DMF
:O:
H3C
CH3
DMA
:O:
Na
CH3
C CH3
N
..
+
C N:
..
: N C CH3
+
.. _
:
CH3C O
..
..
N C CH3
+
11
Non polar solvents (benzene, carbon tetrachloride, hexane, etc.) do not solvate
or stabilize nucleophiles.
SN2 reactions are relatively slow in non polar solvents similar to that
in protic solvents.
Cl
benzene
Cl
Cl
CH3CH2CH2CH2CH2CH3
C
Cl
n-hexane
carbon
tetrachloride
12
3
C
CH3
rapid
Br
H3C
Na+ I-
Na+ Br-
CH3
CH3
>
2
R2HC-Br
>
1
RH2C-Br
>
vinyl
CH2=CH-Br
>
phenyl
-Br
>
Me
H3C-Br
13
1.
- Br -
CH3
H3C
C+
CH3
rapid
2.
..
Na+ :I :..
CH3
H3C
..
..I :
Na+ Br-
CH3
3 C+
Reaction Steps
1.
the slower, rate-limiting dissociation of the alkyl halide forming a C+
intermediate
2.
a rapid nucleophilic attack on the C+
Note that the nucleophile is not involved in the slower, rate-limiting step.
14
more
stable
CH3
CH3
H3C
C+
H3C
tertiary
3
CH3
C+
CH3
>
secondary
2
less
stable
H
C+
H
>
primary
1
C+
H
>
methyl
15
Stability of Carbocations
Alkyl groups are weak electron donors.
They stabilize carbocations by donating electron density by induction
(through bonds)
CH3
H3C
Inductive effects:
Alkyl groups donate (shift) electron
density through sigma bonds to
electron deficient atoms.
This stabilizes the carbocation.
C+
CH3
overlap (hyperconjugation)
sp 2
hybridized
carbocation
..
C
Csp3-Hs
sigma bond
orbital
H
H
HYPERCONJUGATION
16
Stability of Carbocations
Allyl and benzyl halides also react quickly by SN1 reactions because
their carbocations are unusually stable due to their resonance forms
which delocalize charge over an extended system
H2C
CH
CH2
HC CH2
H2C
H2C
CH
1 allyl carbocation
H2C+
CHR
HC CHR
2 allyl carbocation
1 benzylic
+
C
C
H
+
C
H
2 benzylic
H
H
C
H
+
C
R
17
+
C HR
+
C R2
3 C +
3 benzylic
CH3
C+
CH3
3 allylic
2 C +
1 C +
CH3
CH3
>
+
CH2 CH CR2
1 benzylic
2 benzylic
+
CH2 CH CHR
2 allylic
>
CH3
C+
H
>
CH3
C+
H
>
+
CH2 CH
vinyl C
+
>
>
+
phe nyl
H C+
H
+
m ethyl C
+
CH2 CH CH2
1 allylic
Note that 1 allylic and 1 benzylic C+s are about as stable as 2alkyl C+s.
Note that 2 allylic and 2 benzylic C+s are about as stable as 3 alkyl C+s.
Note that 3 allylic and 3 benzlic C+s are more stable than 3 alkyl C+s
Note that phenyl and vinyl C+s are unstable. Phenyl and vinyl halides do not
usually react by SN1 or SN2 reactions
18
pKb = 23
pKb = 22
pKb = 21
pKb = 11
pKb = -1.7
pKb = -2
pKb = -21
I-
Br -
Cl-
F-
HO-
RO-
H2N-
30,000
10,000
200
Iodine (-I) is a good leaving group because iodide (I-) is non basic.
The hydroxyl group (-OH) is a poor leaving group because hydroxide (OH-) is
a strong base.
19
EtOH
100
20
dielectric constant
name
aprotic solvents
dielectric constant
protic solvents
hexane
1.9
acetic acid
6.2
benzene
2.3
acetone
20.7
diethyl ether
4.3
ethanol
24.3
chloroform
4.8
methanol
33.6
HMPA
30
formic acid
58.0
DMF
38
water
80.4
DMSO
48
21
CH3
Na+ I-
H3C
CH3
Na+ Br-
K+ Br-
CH3
CH3
CH3
3
H3C C Br
CH3
K+ F-
H3C
CH3
22
:O
H
H +
..
..
Br :
..
..O
H
C
..
Br :
..
..
..O
HH
H
C
H
..
+ : Br :
..
transition state
Also recall our study of the preparation of alkenes. When a 2 or 3 alkyl halide
is treated with a strong base such as NaOH, dehydrohalogenation occurs
producing an alkene an elimination (E2) reaction.
KOH in ethanol
Br
bromocyclohexane
KBr
H2O
-HBr
KOH
23
E2 Reaction Mechanism
There are 2 kinds of elimination reactions, E1 and E2.
E2 = Elimination, Bimolecular (2nd order). Rate = k [RX] [Nu:-]
E2 reactions occur when a 2 or 3 alkyl halide is treated with a strong
base such as OH-, OR-, NH2-, H-, etc.
H
OH-
Br
Br- +
HO H
All strong bases, like OH-, are good nucleophiles. In 2 and 3 alkyl halides
the -carbon in the alkyl halide is hindered. In such cases, a strong base
will abstract (remove) a hydrogen ion (H+) from a -carbon, before it hits
the -carbon. Thus strong bases cause elimination (E2) in 2 and 3 alkyl
halides and cause substitution (SN2) in unhindered methyl and 1 alkyl
halides.
24
E2 Reaction Mechanism
In E2 reactions, the Base to H bond formation, the C to H bond breaking,
the C to C bond formation, and the C to Br bond breaking all occur
simultaneously. No carbocation intermediate forms.
B:H
R
C
C
R
+
R
H
R
R
C
C
R
B H +
X-
CH3CH2O-Na+
CH3CH
CH3CH2CHCH3
EtOH
CHCH3
2-butene
major product
( > 80%)
CH3CH2CH
CH2
1-butene
minor product
( < 20%)
25
B:H
R
C
C
R
+
R
H
R
C
R
B H +
X-
26
H
H
H
Cl
Na+ OHE2
H3C
H
H
3-methylcyclopentene
NaCl
HOH
H3C
H
1-methylcyclopentene
27
E1 Reactions
Just as SN2 reactions are analogous to E 2 reactions, so SN1 reactions have
an analog, E1 reaction.
E1 = Elimination, unimolecular (1st order); Rate = k [RX]
CH3
CH3
C Br
CH3
CH3
slow
- Br-
CH3
H
rapid
C+
C
H
CH3
C
H
B:-
CH3
B H
Br
28
E1 Reactions
As with E2 reactions, E1 reactions also produce the more highly substituted
alkene (Zaitsevs rule). However, unlike E2 reactions where no C + is
produced, C+ rearrangements can occur in E1 reactions.
e.g., t-butyl chloride + H2O (in EtOH) at 65 C t-butanol + 2-methylpropene
CH3
CH3
C Cl
CH3
H2O, EtOH
65C
CH3
CH3
C OH
CH3
64%
S N1
product
CH3
C
+
CH3
C
H
36%
E1
product
29
30
alkyl
halide
(substrate)
good Nu
strong base
e.g., bromide
e.g., ethoxide
Br
C2H5O
(CH3)3CO
Me
SN2
SN2
SN2
no reaction
SN2
SN2
E2 (SN2)
no reaction
SN2
E2
E2
SN1, E1
SN1
E2
E2
SN1, E1
good Nu
good Nu
nonbasic
very poor Nu
nonbasic
CH3COOH
Strong bulky bases like t-butoxide are hindered. They have difficulty hitting
the -carbon in a 1 alkyl halide. As a result, they favor E2 over SN2
products.
31
alkyl
halide
(substrate)
v. gd. Nu
..
moderate
. .base
e.g., cyanide
CN-
4.7
pkb =
v. gd. Nu
..
moderate
.. base
fair Nu
..
weak base
..
e.g., carboxylate
6.0 /
pkb =
RCOO
9
pkb =
alcohol
(substrate)
HI
HBr
HCl
Me
SN2
7.0
SN2
SN2
Me
SN2
SN2
SN2
SN2
SN2
SN2
SN2
E2
SN1
E2
E2
E2
SN1
32
Alkylation of Alkynides
Recall the preparation of long alkynes.
1. A terminal alkyne (pKa = 25) is deprotonated with a very strong base
R-C C-H
NaNH2
R-C C-CH2CH3
NaX
The reaction is straightforward with Me and 1 alkyl halides and proceeds via
an SN2 mechanism
Alkynide anions are also strong bases (pKb = -11) as well as good Nu: -s, so
E2 competes with SN2 for 2 and 3 alkyl halides
33
+
(CH3)3C OH
.. 2
Cl
- H2O
..
:
(CH3)3C Cl
..
(CH3)3C +
H2O
.. : Cl :
..
CH3CH2
..
OH
..
Cl
CH3CH2
OH2+
.. : Cl :
..
CH3CH2Cl
H2O
34
CH3(CH2)4CH2
:P
..
OH
..
Br
Br
ether
CH3(CH2)4CH2
+ PBr 2
O
..
H
CH3(CH2)4CH2Br
Br
35
KBr
H2O
-HBr
bromocyclohexane
KOH
36
methyl
CH3
CH3
C Br
H
CH3
C Br
H
CH3
C Br
H
CH3
C Br
CH3
37
CN-
I-
CH3O-
HO-
NH3
Cl-
H2O
125,000
125,000
100,000
25,000
16,000
1000
700
Note that poor nucleophiles that are also weak bases (H2O, ROH, CH3COOH,
etc.) do not undergo any reaction unless a C+ is formed first. If a C+ can form
(as with a 2, 3, any benzylic, or any allylic halides), then E1 and SN1 generally
occur together.
pKb = 22
pKb = 21
pKb = 11
pKb = -1.7
pKb = -2
pKb = -21
I-
Br -
Cl-
F-
HO-
RO-
H2N-
30,000
10,000
200
38