1. Nucleophilic Substitution and Mechanistic Tools:
Chemistry 125: Lecture 44 January 26, 2011
Nucleophilic Substitution and Mechanistic Tools:
Stereochemistry, Rate Law, Substrate, Nucleophile
This
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2. SN2 Nucleophilic Substitution
Generality of Nucleophilic Substitution
Solvent
Nu: R-L
Nu-R L
(+)
(-)
Leaving
Group
Nucleophile
Substrate
Product
But there are different mechanisms!
the Pragmatic Logic of Proving a Mechanism with Experiment & Theory
(mostly by disproving all alternative mechanisms)

3. "It is an old maxim of mine that when you have excluded the impossible, whatever remains, however improbable, must be the truth."
From “Adventure of the Beryl Coronet”. Similar lines in other Holmes adventures.
The Adventure of the Beryl Coronet

4. SN2 Nucleophilic Substitution
Nu: R-L
Nu-R L
(+)
(-)
Break bond (Dissociation)
Make bond (Association)
the Pragmatic Logic of Proving a Mechanism with Experiment & Theory
Simultaneous
“Concerted”
(make-as-you-break)
D then A
A then D
(mostly by disproving all alternative mechanisms)

5. Concerted A/D D/A Nu L C Transition State Pentavalent Intermediate Nu
Trivalent
Intermediate C

6. Concerted A/D D/A chiral chiral achiral Unlikely for
enantiomers a b c Nu L C
Transition
State
Pentavalent
Intermediate Nu L C
Trivalent
Intermediate C Nu Nu
chiral chiral achiral
Unlikely for
very exothermic process (
(Hammond implausibility)
Which is it normally?
Stereochemical Implications!

7. 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)
Structure
X-Ray and Quantum Mechanics

8. Nucleophilic Substitution
Walden Inversion (1898) - “the most astounding
discovery in stereochemistry since the
groundbreaking work of van’t Hoff.” E. Fischer
N RL L RN
Displacement
Replacement

9. STEREOCHEMISTRY Kenyon and Phillips (1923)
PhCH
CH3 CH
nucleophilic substitution at S (A/D, A favored by vacant d orbital of S)
-OH H
PhCH2
CH3 CH O
PhCH2
CH3 CH O
SO2 Cl
SO2
CH3 H
+31°
Why not avoid acetate steps by using -OH?
Backside Attack in
+33°
nucleophilic
substitution at C=O
(A/D, A favored by *)
nucleophilic substitution at saturated C.
CH3 C O
Because
it attacks H C
(the only step involving chiral C)
Same as starting material?
J. Chem. Soc 1923 p. 44 ff. By H Phillips (advised by J. Kenyon) from Battersea Polytech. H
PhCH2
CH3 CH O C OH
PhCH2
CH3 CH O C H
CH3 O C O
PhCH2
CH3 CH OH
Inversion!
(R)  (S)
-7°
-32°
Proves nothing

10. Concerted A/D D/A
Pentavalent
Intermediate Nu L C
Trivalent
Transition State
Trivalent intermediate could be attacked from either face  racemization, not inversion.

11. Tools for Testing (i.e. Excluding) Mechanisms:
Stereochemistry
Rate Law
Rate Law
Rate Constant
Structure
X-Ray and Quantum Mechanics

12. NaOEt + EtBr EtOEt + NaBr
[NaOEt] ( fixed [EtBr] )
rate
Second Order (SN2)
d[EtO-] dt
= k2 [EtO-] [EtBr]

13. Concerted A/D D/A
Pentavalent
Intermediate Nu L C
Trivalent
Transition State
Nu enters
Nu enters
Initial rate-limiting dissociation in D/A would give a rate independent of [Nu], not SN2.
 Not D/A

14. NaOEt + EtBr EtOEt + NaBr
EtOH
Analogy
pKa
Ratio should be much less drastic at early SN2 transition state.
EtO- + H+  EtOH
EtO: + H+  EtOH H +
EtO- + EtBr  EtOEt
EtO: + EtBr  EtOEt H +
15.7
[NaOEt]
d[EtO-] dt
rate
= k2 [EtO-] [EtBr]
Second Order (SN2)
1017.4
at equilibrium
-1.7
+ k1 [EtBr]
+ k [EtOH] [EtBr]
~ const
Pseudo First Order
First Order (D/A?)
k2 = 20,000  k
Is it reasonable to be so different?

15. Tools for Testing (i.e. Excluding) Mechanisms:
Stereochemistry
Rate Law
Rate Constant
Rate Constant
Structure
X-Ray and Quantum Mechanics

16. Rate Constant Dependance on
Nu: R-L
Nu-R L
(+)
(-)
Solvent
Leaving
Group
Nucleophile
Substrate
Product
[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
LUMO
145
C-L
antibonding
node
145x  
1.2x
128x
0.82
~same
H
23x
0.0078
Surface Potential
+26 to -25 kcal/mole
>15x
0.036
3000x
~ ?
Something else happens

17. -Methylation Steric Hindrance Total Density (vdW) Methyl Ethyl
iso-Propyl
t-Butyl
Steric Hindrance
Total Density (vdW)
-Methylation

18. -Methylation LUMO at 0.06 LUMO at 0.04 Total Density (vdW) Methyl
iso-Propyl
t-Butyl
LUMO at 0.06
LUMO at 0.04
Total Density (vdW)
-Methylation

19. -Methylation Surface Potential +26 to -25 kcal/mole Methyl Ethyl
iso-Propyl
t-Butyl
Surface Potential
+26 to -25 kcal/mole
-Methylation

20. -Methylation Neopentyl Ethyl [1] n-Propyl 0.82 iso-Butyl 0.036
(Cl is illustrated in this and previous frames)
By mol mech gauche nPrBr is 1.6 kJ/mole above anti, gauche-gauche I-BuBr is 2.4 kJ/mole above gauche-anti
-Methylation
No way to avoid the third -CH3

21. Might it be possible to have frontside attack?Nu L C
Transition
State
Backside Attack
Planar
Trivalent
Intermediate C
Might it be possible to have frontside attack? Nu L C
Transition
State
Frontside Attack
or formation of a non-planar cation?
Nonplanar
Trivalent
Intermediate + C
(remember planar BH3)

22. Bartlett and Knox (J.Am.Chem.Soc. - 1939)
“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.
Molecule specifically designed and prepared to test these mechanistic questions
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. Roberts
Caltech
1975
Bartlett and Knox (J.Am.Chem.Soc ) *

23. Bartlett and Knox (J.Am.Chem.Soc. - 1939)Cl
“bridgehead” chloride
boat c-hexane
with a bridge
bicyclo[2.2.1]heptane
Flattening would generate highly strained angles (estimated >23 kcal/mole).
Cation would not be planar.
Backside of s*C-Cl is inaccessible,
and inversion would be impossible.
Bartlett and Knox (J.Am.Chem.Soc ) *
Attack would have to be frontside.

24. Bartlett and Knox (J.Am.Chem.Soc. - 1939)
Although there are b-H atoms, they are not in the anti position necessary to allow sCH - s*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!
gauche H
Would competition from loss of HCl make it impossible to measure the expected really slow rate of substitution?
Bartlett and Knox (J.Am.Chem.Soc ) * NO

25. Bartlett and Knox (J.Am.Chem.Soc. - 1939)Nu L C
>>106 slower than
typical backside attack + C
>109 slower than from
Et(CH3)2C-Cl
60°cooler and without Ag+
pull on Cl instead of pushing at C
R-Cl: + Ag+
R+ + AgCl ( )
Bartlett and Knox (J.Am.Chem.Soc ) *

26. Cycloalkyl Halides (e.g. J&F Table 7.2)
krelative C H Br I
[1]
~109°
120°
sp2
60°
90°
109°
<0.0001
strain in starting material
???
increased strain in transition state
0.008
bent OK
1.6
0.01

27. Rate Constant Dependance on
Nu: R-L
Nu-R L
(+)
(-)
Solvent
Leaving
Group
Nucleophile
Substrate
Product
[1]
krel
Br- F-
H2O
HO-
Cl- Nu
HS-
e.g. J&F Sec. 7.4d, Table 7.3 I-
3.2
15.7
-1.7
pKa (NuH+)
For first-row elements
nucleophilicity (attack C-L ) parallels basicity (attack H+).
Both require high HOMO. 80
1,000 -8
10,000 -9
But as atoms get bigger, they get better at attacking C-L (compared to attacking H+)
16,000
80,000
-10
126,000 7

28. Rate Constant Dependance on
Nu: R-L
Nu-R L
(+)
(-)
Solvent
Leaving
Group
Polar solvents accelerate reactions that generate (or concentrate) charge, and vice versa.
Nucleophile
Substrate 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]
harder
to break
H-bonds to smaller ions
Backwards
Sensible

29. End of Lecture 44 Jan. 26, 2011
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