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)

Concerted A/D D/A

PentavalentIntermediate

Nu LC

TrivalentIntermediate

CNu LC

TransitionState

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

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

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

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