Chemistry 125: Lecture 44 January 27, 2010 Nucleophilic Substitution and Mechanistic Tools: Rate Law...
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Transcript of Chemistry 125: Lecture 44 January 27, 2010 Nucleophilic Substitution and Mechanistic Tools: Rate Law...
Chemistry 125: Lecture 44January 27, 2010
Nucleophilic Substitutionand Mechanistic Tools:
Rate Law & Rate Constant
This
For copyright notice see final page of this file
F CH2
CH2 H :OH
"E2 Elimination"
ABNABN
AON
Make TwoBreak TwoF
H OH
CH2
CH2
Nucleophilic Substitutionand -Elimination
Chapter 7
F H :OH
F H OH
"Acid-Base"
F CH3 :OH
CH3 OHF
"SN2 Substitution"
ABN
Make & BreakSame
(Cf. Lecture 16)
All are Nucleophilic SubstitutionWilliamson Ether Synthesis (1852)
O- Na+ EtBr+ OEt Na+ Br-+
Finkelstein Reaction (1910)
Na+ Cl-Na+ I- + RCl RI +also RBr Na+ Br-
Menschutkin Reaction (1890)
Et3N + RI Et3N-R + I-+
ExchangeIons
(Double Decomposition)
CreateIons
DestroyIons
Breaking apartby solvent
Solvolysis
(CH3)3C-BrEtOH
HBr +(CH3)3C-OEt
Generalization
Meerwein Reagent (1940s)
RO- Na+ (CH3)3O BF4+ ROCH3 Na+ BF4 ++ - -
()acetone
*
*
*
*
*
LUMOHOMO
+ -
Generality of Nucleophilic Substitution
CH3
+
Nucleophile Substrate
Solvent
Nu: R-L Nu-R L(+) (-)
S-Adenosylmethionine
ARGININE
:
H
+
Biological Methylation(Post-Transcriptional Protein Modification, etc.)
Product
ARGININE
LeavingGroup
METHIONINEOH
ADENOSINE
ADENINEH OH
SubstituteNR2
for OH
SubstituteSR2 for “OH”
RIBOSE::
But different mechanisms are involved!
SubstituteNHR2 for SR2
SubstituteBase for NR3
SN2 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
"It is an old maxim of mine that when you have excluded the impossible,
whatever remains, however improbable,
must be the truth."
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 A/D D/A
PentavalentIntermediate
Nu LC
TrivalentIntermediate
CNu LC
TransitionState
Nu
Concerted A/D D/A
PentavalentIntermediate
Nu LC
TrivalentIntermediate
CNu LC
PentavalentTransition State
Which is it normally?
Unlikely for exothermic
process(Hammond
implausibility)
Nu
a b
c
a b
c
a b
c
enantiomers
stereochemical proof !
Tools for Testing(i.e. Excluding) Mechanisms:
Stereochemistry (sec 7.4b)
Rate Law (sec 7.4a)
Rate Constant (sec 7.4cdefg)
StructureX-Ray and Quantum Mechanics
HCH3
O
OC
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)
nucleophilic substitution at C=O (A/D, A favored by *)
nucleophilic substitution at saturated C.
Same as starting
material?
PhCH
CH3
CH
Why not avoid acetate steps by
using -OH? Becauseit attacks H.
-OH
(only step involving chiral C)
H
H
Proves nothing
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:
NaOEt + EtBr EtOEt + NaBr
[NaOEt] ( fixed [EtBr] )
rate
Second Order (SN2)
d[EtO-]dt = k2 [EtO-] [EtBr]
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
SN2 transition state.1017.4
Stereochemistry
Rate Law
Rate Constant
StructureX-Ray and Quantum Mechanics
Tools for Testing(i.e. Excluding) Mechanisms:
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
[1]
krel
(CH3)2CH
CH3CH2
CH3
(CH3)3CCH2
CH3CH2CH2
R
(CH3)3C
Cf. Table 7.1 p. 275
RBr + I-
acetone / 25°C
(CH3)2CHCH2
0.036
145x
>15x
128x1.2x
3000x
23x
C-Lantibonding
node
~same
H
Methyl Ethyl iso-Propyl
t-Butyl
-Methylation
Total Density (vdW)
Steric Hindrance
Methyl Ethyl iso-Propyl
t-Butyl
-Methylation
LUMO at 0.04LUMO at 0.06Total Density (vdW)
Methyl Ethyl iso-Propyl
t-Butyl
-Methylation
Surface Potential+26 to -25 kcal/mole
-Methylation
Neopentyl
Ethyl [1] n-Propyl 0.82
iso-Butyl 0.0360.000012
No way to avoid the third -CH3
increased strain in transition state
Cycloalkyl Halides (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°
End of Lecture 44Jan. 27, 2010
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