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Chemistry 125: Lecture 44January 26, 2011
Nucleophilic Substitutionand Mechanistic Tools:
Stereochemistry, Rate Law, Substrate, Nucleophile This
For copyright notice see final page of this file
SN2 Nucleophilic SubstitutionGenerality of Nucleophilic Substitution
Nucleophile Substrate
Solvent
Nu: R-L Nu-R L(+) (-)
the Pragmatic Logicof Proving a Mechanism
with Experiment & Theory
(mostly by disproving all alternative mechanisms)
ProductLeavingGroup
But there are different mechanisms!
"It is an old maxim of mine that when you have excluded the impossible,
whatever remains, however improbable,
must be the truth."
The Adventure of the Beryl Coronet
SN2 Nucleophilic Substitution
Nu: R-L Nu-R L(+) (-)
Break bond (Dissociation)
(mostly by disproving all alternative mechanisms)
Make bond (Association)the Pragmatic Logic
of Proving a Mechanism with Experiment & Theory
D then A A then D Simultaneous“Concerted”
(make-as-you-break)
PentavalentIntermediate
Nu LCNu LC
TransitionState
Nu
TrivalentIntermediate
C
Concerted A/D D/A
Which is it normally?
Unlikely for very exothermic
process(
(Hammond implausibility)
Nu
a b
c
a b
c
a b
c
enantiomers
Stereochemical Implications!
chiral chiral achiral
Tools for Testing(i.e. Excluding) Mechanisms:
Stereochemistry (J&F sec 7.4b)
Rate Law (J&F sec 7.4a)
Rate Constant (J&F sec 7.4cdefg)
StructureX-Ray and Quantum Mechanics
CN L+
Displacement
Nucleophilic Substitution
N + RL L + RN
C LN +
Replacement
C NL +
Walden Inversion (1898) - “the most astoundingdiscovery in stereochemistry since the
groundbreaking work of van’t Hoff.” E. Fischer
Why not avoid acetate steps by
using -OH?
STEREOCHEMISTRYKenyon and Phillips (1923)
H
PhCH2
CH3
CH
O Cl SO2 CH3
PhCH2
CH3
CH
O SO2 CH3
+33°+31°
O
PhCH2
CH3
CH
-7°
CH3CO
O
PhCH2
CH3
CH
O CH3C
O
OHPhCH2
CH3
CH
O CH3C
O
OH
-32°Inversion!(R) (S)
Backside Attack in
nucleophilic substitution at S (A/D, A favored by vacant d orbital of S)
Same as starting
material?
PhCH
CH3
CH
Becauseit attacks H
-OH
(the only step involving chiral C)
H
HCH3
O
OC
Proves nothing
C
C C
nucleophilic substitution at C=O(A/D, A favored by *)
nucleophilic substitution at saturated C.
H
Concerted A/D D/A
Trivalent intermediate could be attacked from either face racemization, not inversion.
PentavalentIntermediate
Nu LC
TrivalentIntermediate
CNu LC
PentavalentTransition State
Stereochemistry
Rate Law
Rate Constant
StructureX-Ray and Quantum Mechanics
Tools for Testing(i.e. Excluding) Mechanisms:
Rate Law
NaOEt + EtBr EtOEt + NaBr
[NaOEt] ( fixed [EtBr] )
rate
Second Order (SN2)
d[EtO-]dt = k2 [EtO-] [EtBr]
0
Nu enters
Concerted A/D D/A
Initial rate-limiting dissociation in D/A would give a rate independent of [Nu], not SN2.
PentavalentIntermediate
Nu LC
TrivalentIntermediate
CNu LC
PentavalentTransition State
Not D/A
Nu enters
Analogy
EtO- + H+ EtOH
EtO: + H+ EtOHH
+
H
EtO- + EtBr EtOEt
EtO: + EtBr EtOEtH
+
H
NaOEt + EtBr EtOEt + NaBrEtOH
+ k1 [EtBr]+ k [EtOH] [EtBr]
First Order (D/A?)Pseudo First Order
pKa15.7
-1.7
k2 = 20,000 k
[NaOEt]
d[EtO-]dtra
te = k2 [EtO-] [EtBr]
Second Order (SN2)
~ const
at equilibrium
Is it reasonable to be so different?
Ratio should be much less drastic
at early SN2
transition state.
1017.4
0
Stereochemistry
Rate Law
Rate Constant
StructureX-Ray and Quantum Mechanics
Tools for Testing(i.e. Excluding) Mechanisms:
Rate Constant
Rate Constant Dependance on
NucleophileLeavingGroup
SolventNu: R-L Nu-R L
(+) (-)
Product
145
0.82
0.0078
0.000012
~ 0.0005 ?
Substrate
Something else happens
LUMO
Surface Potential+26 to -25 kcal/mole
0.036
145x
>15x
128x1.2x
3000x
23x
C-Lantibonding
node
~same
H
[1]
krel
(CH3)2CH
CH3CH2
CH3
(CH3)3CCH2
CH3CH2CH2
R
(CH3)3C
e.g. J&F Table 7.1 p. 275
RBr + I-
acetone / 25°C
(CH3)2CHCH2
-Methylation
Neopentyl
Ethyl [1] n-Propyl 0.82
iso-Butyl 0.0360.000012
No way to avoid the third -CH3
PlanarTrivalent
Intermediate
CNu LC
TransitionState
Backside Attack
Might it be possible to have frontside attack?
Nu
LC
TransitionState
Frontside Attack
or formation of a non-planar cation?
NonplanarTrivalent
Intermediate
+C
(remember planar BH3)
“In 1939 Bartlett and Knox published the account of their work on the bridge-head chloride, apocamphyl chloride. I believed then, and I believe now, that this was a fantastically influential paper. For thirty years afterwards, no one really accepted any mechanism unless it had been tested out on a bridgehead case.
Bartlett and Knox(J.Am.Chem.Soc. - 1939)
Indeed, the Bartlett-Knox paper shaped the interests and viewpoint of many chemists about the kind of physical organic they wanted to do.”
John D. RobertsCaltech1975
Molecule specifically designed and prepared
to test these mechanistic questions
*
Backside of *C-Cl is inaccessible,and inversion would be impossible.
Flattening would generate highly strained angles (estimated >23 kcal/mole).
bicyclo[2.2.1]heptane
Cl
“bridgehead” chloride
boat c-hexanewith a bridge
Bartlett and Knox(J.Am.Chem.Soc. - 1939) Attack would have to be frontside.
Cation would not be planar.
*
H
H
H
Although there are -H atoms, they are not in the anti position necessary to allow CH - *C-X overlap during elimination of H-X to form C=C.
“C=C bonds cannot originate from such a bridgehead.”
(Bredt’s Rule)
Horrid Overlap!
Bartlett and Knox(J.Am.Chem.Soc. - 1939)
Would competition from loss of HCl make it impossible to measure the expected really
slow rate of substitution?*
gauche
R-Cl: + Ag+ R+ + AgCl ()
Bartlett and Knox(J.Am.Chem.Soc. - 1939)
+C>109 slower than from
Et(CH3)2C-Cl 60°cooler and without Ag+
Nu
LC >>106 slower than
typical backside attack
pull on Cl instead of pushing at C
*
increased strain in transition state
Cycloalkyl Halides (e.g. J&F Table 7.2)
krelative
[1]
1.6
0.008
<0.0001
0.01
C HCC
Br
I
120° sp2
60°
90°
109°
strain in starting material
~109°
???
OK bent
LeavingGroupSubstrate
Rate Constant Dependance onSolvent
Nu: R-L Nu-R L(+) (-)
Product
80
1,000
10,000
16,000
126,000
Nucleophile
[1]
krel
Br-
F-
H2O
HO-
Cl-
Nu
HS-e.g. J&F Sec. 7.4d, Table 7.3
I- 80,000
-8
-9
7
-10
3.2
15.7
-1.7
pKa (NuH+)
For first-row elementsnucleophilicity (attack
C-L )
parallels basicity (attack H+).Both require high HOMO.
But as atoms get bigger, they get better at attacking
C-L (compared to attacking H+)
Solvent
LeavingGroupSubstrate
Rate Constant Dependance onNu: R-L Nu-R L
(+) (-)
Nucleophile
80
1,000
10,000
16,000
126,000
[1]
krel
Br-
F-
H2O
HO-
Cl-
Nu
HS-e.g. J&F Sec. 7.4dg
I- 80,000
-8
-9
7
-10
3.2
15.7
-1.7
pKa (NuH+) krel
CH3I in H2O
[1]
14
160
krel
CH3Br in Acetone
11
5
[1]
harderto break H-bonds
to smaller ions
Polar solvents accelerate reactions that generate (or concentrate) charge,
and vice versa.
Sen
sibl
e
Backw
ards
End of Lecture 44Jan. 26, 2011
Copyright © J. M. McBride 2011. Some rights reserved. Except for cited third-party materials, and those used by visiting speakers, all content is licensed under a Creative Commons License (Attribution-NonCommercial-ShareAlike 3.0).
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