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Nucleophilic Aliphatic Substitution
Nuc C LG Nuc + LG
There are two different mechanistic possibilities:
SN2:
Nuc C LG Nuc + LGk2
rate = k2[Nuc:][C-LG]
SN1: C LGk1
C + LGNuc
Nucslow - r.d.s.
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:
C
C
C
C
C
LG
!
!*LG
Nuc
LG Nuc
LG Nuc
LG 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:
E
CNuc LG
SMproduct
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
E
SMproduct
I!G‡
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:
R X
Nuc R
Nuc SET+ R XNuc +
- X
Nuc + R + X
Nuc
- R X
R Nuc
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:
X
Nuc
X
Nuc
- X
X = I, OTs Nuc = RS--, R2C--NO2, Li+AlH4_
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 CH3 Ph CH3
Cl OAcOAc
+K OAc
HOAc, 50o
57.5% 42.5%
-not pure racemization; nor pure inversion
Ph CH3 Ph CH3 Ph CH3
Cl OAcOAc
+Et4N OAc
82.5% 17.5%
O
Hammett, JACS 1937, 59, 2536
How to explain? We must develop a unified mechanism:
RNuc Xsolv+
R X R X
RX
Nuc R X
Nuc
Nuc
Nuc
"SN2"
NucNuc
Nuc R X
Nuc
Nuc
"SN1"
Rsolv Xsolv
SOH
SOH
SOHROS+ + Hsolv + Xsolv
Several different species are introduced here:
R X
R X
Rsolv Xsolv+
config.lability
- "tight" or "intimate" ion pair
- "loose" or "solvent-separated" ion pair
- 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 R I
O
NaI
R rel. rate
CH3 93
CH2CH3 1
CH2CH2CH3 0.0076
Conant, JACS 1925, 47, 476
RCH2 Br RCH2 Cl
LiCl
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:
RCH2 OTs RCH2 OAcHOAc 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 R ClLiCl
DMF
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)
tBuCH2 3.3 x 10-7
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
, but:
RH2C Cl RH2C II
R rel. rate
n-Pr 1
PhSO2- 0.25 O
H3CC 3.5 x 104
NC- 3 x 103
EtO2C- 1.7 x 103
Bordwell, JACS 1964, 86, 4545
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So, it must be more complex:
OX
Nuc
!
!
!
OX
Nuc
!
!
!
(resonance explanation)
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:
X Nuc+ X
Nuc
-for allyl halides, the SN2 and SN2′ products are the same
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But:
H
D
Et2N Et2N
H DD H
Cl
+Et2NH
-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
NHS
CH3H3C
OP
O
NNN
DMF DMSO HMPA (best)
They are all Lewis basic ⇒ solvate cations well, but not anions
Result: NaI in DMSO:
O
Na OO
O
S
S
S
S
I
solvated Na+ and dissociated 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 OH H2NNH2 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 (non-
bonded, π or σ)
ex:
R OBsO
R INaI
R rel. rate
1
O 0.28
O 0.63
O 6.57
O 123
O 1.2
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Neighboring Group Participation:
OTs
O
O
OTs
O
O
O
O
O O
O
OH
O
O
O
O O
O
O
O
OH
O
cis
1
trans
670
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
HH
O
O
S
O
O
PhCH3
O
O
HO
O
H
O
HO
H
O S
O
O
PhCH3
O
H
H
O S PhCH3
O
O
O
O O
HH
O
O
O
O
HO
H
O
O
O
(SN2)
trans
achiral intermediate--racemization
proceededthrough doubleinversion--retention
1670
-rate determining activation barriers are lowered
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π bond participation:
starting material products rel. rate of
acetolysis
intermediate
OTs
OAc
104
OTs
AcO
1
TsO
OAc
103 TsO
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Phenonium Ion X
OTsH3C
CH3
H
H
H3C CH3
H H
OTsH3C
HH
CH3
H3C HH CH3
OAcH3C
CH3
H
H
OAcH3C
HH
CH3
OAc
AcO
H3C
CH3
HCH3
H
H
CH3
H
threo
erythro
racemic
retention
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
acetolysis
argued evidence
H
O
OAc
S
O
O
BrHOAc
KOAc
350
1) high exo / endo rate ratios
H
OOAcS
O
O
Br
HOAC
KOAc
1
2) predominant capture of the
cation from the exo direction
H
O S
O
O
Br
or
nonclassical carbonium ion
classical carbonium ions
NMR - at temperatures as low as 5K no evidence for two structures observed
Stereochemistry: bicyclo[2.2.2]octyl brosylate
OBs
H
classical
achiral
chiral
racemic products
stereochemical integritynon-classical
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OBs OAc
HOAc~ 80%
Retention of configuration ⇒ nonclassical!
Do not presume that nonclassical carbonium ions are universal!
In bridged systems:
tertiary carbocation
benzylic carbocation
more stable than bridged, nonclassical
carbocation ⇒ classical carbenium ion
primary carbocation less stable than bridged, nonclassical
carbocation ⇒ nonclassical carbenium ion
secondary carbocation borderline, can be either classical or
nonclassical
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