651.06
Nucleophilic Aliphatic Substitution
Nuc
C LG
+
Nuc
LG
There are two different mechanistic possibilities:
SN2:
Nuc
k2
C LG
Nuc
+
LG
rate = k2[Nuc:][C-LG]
SN1:
C LG
k1
slow - r.d.s.
C
+
LG
Nuc
Nuc
rate = k1[C-LG]
Hughes & Ingold, J. Chem. Soc. 1933, 526
Leaving groups:
-typically, they are electronegative or positively charged atoms
examples:
N2+> R2O+> R2S+> OTf > OMs, OTs, OBs > I > Br >> Cl, OAc, OBz >> F
[note: OH is a poor leaving group under anionic conditions because it deprotonates]
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SN2
MO description:
LG
C
!*
LG
Nuc
C
Nuc
C
LG
LG
C
Nuc
!
LG
C
Nuc
From the MO diagram, we can view the SN2 as an interaction between the non-bonded
electrons on the nucleophile with σ*C-LG orbital. Thus, the nucleophile approaches from
theback side to afford the best overlap with σ*.
Energy Diagram:
Nuc
C
LG
E
SM
product
X
Note that the position of the transition state is not necessarily exactly halfway between
s.m. & product. Both early & late transition states are possible in the SN2.
Features:
1) Stereochemical inversion at C
2) pentacoordinate t.s. will be sensitive to sterics: as substituent size increases,
ΔG‡ increases and rate decreases.
3) t.s. has substantial charge delocalization; should be stabilized by polar solvents.
4) rate affected by LG ability and nucleophilicity of nucleophile
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SN1
I
!G‡
E
SM
product
Χ
The rate determing step is the dissociation to a carbocationic intermediate. From the
Hammond postulate, we know that carbocation stability should be a good
index into transition state stability, i.e. rate.
Features:
1) Stereochemical scrambling upon formation of carbocation
2) carbocation stability should govern ΔG‡ and rate
3) the t.s. greatly stabilized by polar media
4) rate affected by LG ability, but not by nucleophilicity
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Single Electron Transfer (SET) - a third possibility
remember that anions are also reducing agents
So, what about:
Nuc
R X
+
SET
Nuc
+
R X
-X
Nuc
+
R
+X
Nuc
R Nuc
Nuc R
-R X
Features:
1)R-X bond must be weak
_
2) Nuc must be unstable anion (good reducing agent)
3) racemization at R
4) other radical reactions of R• or Nuc• may compete & R-R or Nuc-Nuc may be
side products
original proposal: Kornblum, JACS 1965, 87, 4520
JACS 1966, 88, 5660, 5662
evidence:
Nuc
Nuc
X
-X
X
--
Nuc = RS , R2C--NO2, Li+AlH4
X = I, OTs
_
Ashby, Accts. Chem. Res. 1988, 21, 414
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Mechanisms in Between SN1 and SN2
For many reactions, the question of SN1 vs. SN2 is not so clear:
Ph
CH3
Ph
K OAc
HOAc, 50o
Cl
CH3
Ph
+
CH3
OAc
OAc
42.5%
57.5%
-not pure racemization; nor pure inversion
Ph
CH3
Ph
Et4 N OAc
Cl
CH3
Ph
+
OAc
O
CH3
OAc
17.5%
82.5%
Hammett, JACS 1937, 59, 2536
How to explain? We must develop a unified mechanism:
R X
R
Nuc
Nuc
Nuc
Nuc
RX
X
SOH
Nuc
Nuc
RNuc + X solv
"SN2"
Rsolv + X solv
SOH
ROS + Hsolv + X solv
"SN1"
Nuc
SOH
Nuc R X
Nuc R
X
Several different species are introduced here:
config.
lability
R X
- "tight" or "intimate" ion pair
R
- "loose" or "solvent-separated" ion pair
X
Rsolv + X solv
- fully dissociated & solvated ions
This scheme results primarily from the work of Saul Winstein:
Bartlett, JACS 1972, 94, 2161
Sneen has even proposed that all nucleophilic substitutions go via ion pairs:
Sneen, Accts. Chem. Res. 1973, 6, 46
Conclusion - There is a spectrum of reactivity from SN1 to SN2 - every nucleophilic
substitution has some amount of SN1 & SN2 character.
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Factors influencing Reaction Rate
Steric factors in the SN2
R Cl
NaI
R I
O
R
rel. rate
CH3
93
CH2CH3
1
CH2CH2CH3
0.0076
Conant, JACS 1925, 47, 476
LiCl
RCH2 Br
RCH2 Cl
O
R
k x 105 (M-1• s-1)
H
600
CH3
9.9
Et
6.4
iPr
1.5
tBu
0.00026
JACS 1975, 97, 3694
compare to an SN1:
RCH 2 OTs
HOAc
RCH 2 OAc
R
k x 105 (M-1• s-1)
H
0.052
CH3
0.044
Et
-
iPr
0.018
tBu
0.0042
_
note that for bulkier nucleophiles than Cl , the steric difference will be even greater
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Electronic effects of substituents:
R Br
LiCl
DMF
R Cl
R
Relative Rate
CH3
1
CH2CH3
3.3 x 10-2
CH2CH2CH3
1.3 x 10-2
iPr
8.3 x 10-4
tBu
5.5 x 10-5 (JCS, B, 1968, 142)
3.3 x 10-7
tBuCH2
1.3
PhCH2
4.0
Streitwieser, Solvolytic Displacement Reactions, 1962
Why the increased reactivity of allylic and benzylic electrophiles?
Could be simple stabilization of ionized R Br
RH 2C Cl
I
, but:
RH 2C I
R
rel. rate
n-Pr
1
PhSO2-
0.25
3.5 x 104
O
H3 CC
NC-
3 x 103
EtO2C-
1.7 x 103
Bordwell, JACS 1964, 86, 4545
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So, it must be more complex:
X
O
!
X
!
O
!
(resonance explanation)
!
!
Nuc
!
Nuc
MO picture:
"*
X
X
!*
Nuc
X
!
X
"
interaction between π* & nucleophile is stronger than σ* with nucleophile
⇒ SN2 transition state is more stable
⇒ reaction is faster
Another feature is the SN2′ reaction:
Nuc
X
Nuc
-for allyl halides, the SN2 and SN2′ products are the same
200
+
X
651.06
But:
H
Et2 NH
D
Et 2N
Cl
H D
+
Et 2N
D
H
-both products arise from SN2′, occuring with syn stereochemistry (they arise from
different rotomers)
JACS 1979, 101, 2107
Why syn? View it as an allyl cation interacting with two σ orbitals:
(reproduced from Lowry & Richardson, Mechanism and Theory in Organic Chemistry,
3rd Ed., HarperCollins, New York, 1987.)
Yates, JACS 1975, 97, 6615
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Solvent:
SN1 reactions have a highly polar transition state ⇒ polar solvents speed SN1’s
SN2’s are more complex...
It has been predicted that, because the transition state of most SN2 reactions has greater
charge dispersion, it should react slower in polar solvents!
Why the choice of “polar aprotic” solvents?
O
H
N
H3 C
O
S
O
N P N
N
CH3
DMSO
DMF
HMPA
(best)
They are all Lewis basic ⇒ solvate cations well, but not anions
Result:
NaI in DMSO:
S
O
S O
Na
O
S
solvated Na+ and dissociated I
O S
I
_
⇒ very reactive anions in these solvents
see Chem. Rev. 1969, 69, 1 for details of solvation
Nucleophilicity - already discussed
only a factor in SN2 reactions
One feature of nucleophilicity - the “α effect”
OOH
>
H2NNH2
OH
>
NH3
-this arises from destabilization of HOMO due to lone pair / lone pair repulsion
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Neighboring Group Effects:
nucleophilic substitution can be accelerated by participation of nearby electrons (nonbonded, π or σ)
ex:
R OBs
NaI
O
R
R I
rel. rate
1
0.28
O
0.63
O
6.57
O
123
O
1.2
O
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Neighboring Group Participation:
O
OTs
O
O
O
O
O
O
O
OTs
O
O
O
O
O
O
1
O
OH
cis
O
O
670
O
OH
trans
Observations
1) rates of solvolysis differ by a factor of 670
2) cis gives trans diacetate (inversion)
3) trans gives trans diacetate (retention)
4) optically active trans gives racemic product
O
H
O
O
O
O
O S PhCH3
O O
O
O
H
H
O S PhCH3
O
H
H
O
O
O
O
(S N2)
H
O
achiral intermediate
--racemization
H
O
O
O
O
O
H
H
O
O
O
H
H
trans
O
O
proceeded
through double
inversion
--retention
1
H
O
O S PhCH
3
670
-rate determining activation barriers are lowered
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π bond participation:
starting material
products
rel. rate of
intermediate
acetolysis
OTs
OAc
104
OTs
AcO
1
TsO
TsO
10
OAc
205
3
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X
Phenonium Ion
H
H
H
H3C
H
H3C
OAc
CH3
H
H3C
OTs
racemic
H
CH3
CH3
H
OAc
threo
H3C
H
H3C
CH3
H
AcO
CH3
H
OTs
H
H3C
H
H
CH3
H
CH3
CH3
retention
erythro
H
H3C
CH 3
H
OAc
X
OSO2PhCH3
X
extent of aryl participation
NO2
0
CF3
0
Cl
7
H
21
CH3
63
OCH3
93
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σ bond participation:
reaction
rate of
argued evidence
acetolysis
H
O
O S
O
Br
HOAc
KOAc
OAc
350
1) high exo / endo rate ratios
2) predominant capture of the
H
O O
S
O
HOAC
KOAc
1
cation from the exo direction
OAc
Br
O
H
O S
O
Br
nonclassical carbonium ion
or
classical carbonium ions
NMR - at temperatures as low as 5K no evidence for two structures observed
Stereochemistry:
bicyclo[2.2.2]octyl brosylate
racemic products
classical
achiral
H
OBs
nonclassical
stereochemical integrity
chiral
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HOAc
~ 80%
OBs
OAc
Retention of configuration ⇒ nonclassical!
Do not presume that nonclassical carbonium ions are universal!
In bridged systems:
tertiary carbocation
more stable than bridged, nonclassical
benzylic carbocation
carbocation ⇒ classical carbenium ion
primary carbocation
less stable than bridged, nonclassical
carbocation ⇒ nonclassical carbenium ion
secondary carbocation
borderline, can be either classical or
nonclassical
208