651.06

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Pericyclic Reactions

-describes a family of reactions, all concerted, which proceed through a transition state

involving the cyclic movement of electrons

3 types:

electrocyclic reaction cycloaddition

( 1 ring 0 ring ) ( 2 mol. 1 ring )

conversion of σ−>π bond conversion of π −> 2 σ bonds

sigmatropic rearrangement

( acyclic acyclic )

no change in bonding

Electrocyclic Reactions

-formation of single bond between ends of a linear π system or the reverse process

ex:

175o

one interesting feature is its stereospecificity:

651.06

140

175o

cis-3,4-dimethylcyclobutene (E,Z)-2,4-hexadiene

175o

trans (E, E)

Winter, TL 1965, 1207

What accounts for this specificity?

-Woodward & Hoffman proposed the “conservation of orbital symmetry”

see: Hoffman & Woodward, Accts. Chem. Res. 1968, 1, 17

c2

!'

!

symmetry elements present in s.m. & pdt

H

H

H

H

651.06

141

!*

"*

"

!

"4*

"3*

"2

"1

Now consider the likely transition states for this reaction:

(the π orbitals of c1 & c4 must rotate to form σ orbital)

vs.

conrotatory disrotatory

note that not all symmetry elements are maintained in the two transition states:

conrotatory has only a c2 axis

disrotatory has only the σ plane

Now we classify orbitals on the basis of these symmetry elements:

651.06

142

!*

"*

"

!

"4*

"3*

"2

"1

A

S

A

S

S

A

S

A

c2 c2

conrotatory process

(note that orbitals of like symmetry are correlated & that correlation lines of like

symmetry do not cross)

Note that bonding orbitals in s.m. correlate with bonding orbitals in pdt

⇒ symmetry allowed

Now, let’s see the disrotatory process:

!*

"*

"

!

"4*

"3*

"2

"1

A

A

S

S

A

S

A

S

! !

disrotatory process

651.06

143

Note that, due to symmetry considerations, π2 correlates with π3*, meaning that the

product is in an excited (higher energy) state

⇒ THIS IS THERMALLY FORBIDDEN

Thus, electrocyclic ring opening of cyclobutene is predicted to be conrotatory

Another formulation used to explain these process was created by Dewar & Zimmerman:

Dewar, M.J.S. Angew. Chem. Int. Ed. Engl. 1971, 10, 761

Zimmerman, H.E. JACS 1966, 1564, 1566

Zimmerman, H.E. Accts. Chem. Res. 1971, 4, 272

This approach uses interaction diagrams

consider s.m. as a series of basis (p) orbitals:

look at both transition states and connect lobes which were bonded:

vs.

conrotatory disrotatory

Note that in the conrotatory diagram, the interaction path must travel across the plane of

the ring, while disrotatory path is on the same side. This can be seen more clearly by

ignoring the molecular framework altogether & simply tracing a path between orbitals:

651.06

144

conrotatory vs. disrotatory

These two situations are referred to as Huckel (disrotatory) & anti-Huckel or Mobius

(conrotatory)

Now, let’s phase the orbitals:

Möbius Hückel

(1phase inversion) (0 phase inversions)

No matter what the phasing, the Möbius has one inversion

For Hückel transition states, we know how to define aromaticity:

4n+2 electrons ⇒ aromatic

4n electrons ⇒ anti-aromatic

What about Möbius transition states?

The Hückel 4n+2 rule is reversed:

4n+2 electrons ⇒ anti-aromatic

4n electrons ⇒ aromatic

Heilbronner, TL 1964, 1923

651.06

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Conclusion:

4n+2 systems: Hückel thermally allowed, Möbius thermally forbidden

4n systems: Möbius thermally allowed, Hückel thermally forbidden

Caveats:

1) these rules apply to thermal, ground state reactions

2) these rules only consider electronics; steric strain can change things

651.06

146

Now let’s consider a second case:

!

HH H

HH

H HH

H

H

H

H

c2 (conrotatory)

!6*

!5*

!4*

!3

!2

!1

S

A

S

A

S

A

S

A

S

A

S

A "*

!d*

!c*

!b*

!a*

"

⇒ thermally forbidden

651.06

147

HH H

HH

H HH

H

H

H

H

!

(disrotatory)

σ σ

!6*

!5*

!4*

!3

!2

!1

"*

!d*

!c*

!b

!a

"

A

S

A

S

A

S

S

S

A

S

A

A

⇒ thermally allowed

651.06

148

Theory predicts the electrocyclic ring closure of 1,3,5-hexatriene should be disrotatory

-what about experiment?

132o

178o

disrotatory

TL 1965, 385, 391

another ex:

O O

O

O

O

O

H

H H

H

H

H

h!

(photochemicaldisrotatoryclosure)

- 2CO2- H2

Pb(OAc)4

H

H

“Dewar benzene”

C6H6 - isomer of benzene

H

H

25o

t1/2 = 2d

ΔH‡ = 23 kcal / mol

JACS 1977, 99, 8112

this is an example of a thermally forbidden, disrotatory ring opening

an important variant - the Nazarov reaction

OO

H

H H

H3PO4

651.06

149

mechanism:

O

H

OH OH

HH

OH

H H

O

H H

O

H

4! e- system

conrotatory 4!

electron

electrocyclic ring

closure

HH2PO4

"-elimination

H

H2PO4

H

H H

651.06

150

Cycloadditions

Now look at the interaction of 2 π systems:

[2 + 2]+

indicates # of atoms in each component

stereochemistry -

vs.

suprafacial antarafacial

(0 phase inversions) (1 phase inversion)

two transition states for [2+2]:

Hb Hd

Hb Hd

Ha Hc

HcHa

!2s

!2s

+

Hb

Hb

Hd

Hd

Hc

Hc

Ha

Ha

or

Hb Hd

HcHa

Ha Hb

Hc Hd

Hb

Ha

Hd

Hc

Hc

Hd

Ha

Hb

Möbius (π2s + π2a)

651.06

151

From Dewar-Zimmerman theory, we know the π2s + π2a transition state to be the

thermally allowed one.

What do Woodward-Hoffman rules say?

!'

!

(π2s + π2s)

!!' !!'

AA

AS

SA

SS

SS

AS

SA

AA

⇒ THERMALLY FORBIDDEN

651.06

152

Now look at (π2s + π2a) cycloaddition:

c2 (π2s + π2a)

c2 c2

A

S

A

S

A

S

A

S

!4*

!3*

!2

!1

end-on view

of orbital

"d*

"c*

"b

"a

thermally allowed

651.06

153

A third possibility: (π2a + π2a)

c2 (π2a + π2a)

c2 c2

thermally forbidden

If we consider the reaction from the Dewar-Zimmerman perspective, we have:

(π2s + π2s) (π2s + π2a) (π2a + π2a) (0 phase inversions) (1 p.i.) (2 p.i.) Hückel Möbius Hückel

For a 4 electron process, the Möbius transition state is preferred

A

S

A

S

A

A

S

S

!4*

!3*

!2

!1

"d*

"c*

"b

"a

651.06

154

Thus, both methods support the same conclusion:

thermal [2+2] cycloaddition occur via a (π2s + π2a) pathway

What does experiment show?

Thermal [2+2] are rare, owing to forbidden nature of (π2s + π2s)

cyclization & steric problems of (π2s + π2a) pathway

Most thermal [2+2]’s are not concerted:

F F

F F

H D

H D

F

F

F

F+

!+

F

F

F

F

D

D D

D

~ 1 : 1

F F

F F

D H

H D

F

F

F

F+

!+

F

F

F

F

D

D D

D

same product distribution

Why?

F F

F F

H D

H D

F

F

F

F

D

D

F

F

F

F

H

D

D

H

free to rotate

free to invert

651.06

155

The only thermal [2+2]’s are those of ketenes:

RCl

OR

NEt3

O

H

RO

HH

H HO

R

NEt3

heat Cl

- Et3NHCl

[2+2]

B

cyclobutanone

Is it (π2s + π2a)?

O

EtO

H

CH3H3C

H3C CH3

EtO O

+

JACS 1970, 92, 1766

Why this isomer?

we can generalize as

O

L'

S'

LL

L L

L' O

+

S

S

S'

S S

look at (π2s + π2a) transition state:

S

L

S

L

L' S'

S

L

S

L

L' S'

O

!2s + !2a

O

L L

L' O

S

S

S'

651.06

156

Application of ketene [2+2] cycloadditions in synthesis:

O O

OBn

Cl

O

h!, PhHO O

OBn

+

Cl

O

[2+2]

O O

OBn

O

ClPhCH3, 110°

O O OCl

OBn

O OCl

OBn

HO

Danhesier, Org. Lett. 2000, 2, 3407

Most other [2+2] process are photochemical & proceed through a photochemically

allowed (π2s + π2s) transition state:

OTMS PhCHO, h!

(250-325 nm)

OTMS

O

H

PhHH

25:1 this diastereomer; single regioisomer (40%)

Schreiber, TL 1988, 29, 6689

651.06

157

[4+2] Cycloadditions

the most familiar is the Diels-Alder reaction

6! e-

heat

(100-300o)

The reaction is stereospecific: CO2Me

CO2Me

CO2Me

CO2Me

+

CO2Me CO2Me

CO2Me

+

MeO2C

It’s also regioselective:

Y Y

+

X X

1- substituted

diene+

X

Y “ortho” “meta”

typically 9 : 1

Y Y

+2- substituted

diene+

Y

X XX

“meta” “para”

1 : ~ 6-10

It’s also stereoselective:

Y Y

+

X X

+

X

Y

“endo” “exo” “endo” isomer normally predominates

651.06

158

!

π2s + π4s

σ σ

!6*

!5*

!4*

!3

!2

!1

"d*

"c*

!b*

!a

"b

"a

S

S

S

A

AS

S A

A

A

A

S

651.06

159

+

+1.0eV (LUMO)

-9.05eV (HOMO)

+1.5eV

-10.52eV

Rate Effects in Diels-Alder Reaction

10.53eV

Rate ! 1/"Ehomo/lumo Need "E < 10eV

11.52eV

651.06

160

Electron Demand in Diels-Alder Reactions

EDG

EWG

HOMO

Reduced !E

1

LUMO

2

EWG

Normal Electron Demand (HOMOdiene-controlled)

EDG

Inverse Electron Demand (LUMOdiene-controlled)

LUMO

HOMO

LUMO

LUMO

HOMO

Reduced opposite !E

EDG=OMe, OR, R

EWG=COX, CN, NO2, SO3R, Ph

651.06

161

O

O

O

MeO Cl

Factors affecting the rate of the Diels-Alder Reaction

1 Diene

Rate of Reaction with

>> > > > > > > >

O

110 2.2 2 1

OO O

>

a) Aromaticity

>>

Inert

O

O

O

0.1

borderline

locked into s-cis

b) Conformation

krel 1348 12 5 3.3

O

s-cis

Ph

Ph

s-trans

>>

>

Reactive :

H

Aromatizes upon Diels-Alder

also unreactive

651.06

162

CNNC

CNNC

COCl SO2Ph NO2 COCH3CO2Me CN

W

Factors affecting the rate of the Diels-Alder Reaction

W

W

2 Dieneophile

Rate of Reaction with

W

krel

W

4.3x107

W

6700

W

155

W

4

R

R R

1

>> >> >> >

O O O

a) Sterics

>

O

>

O

> >

Do Not React

O

! - Bad

O

" - OK

Good

Doubly activated

planar - Sterically unencumbered

Quinones

#TCNE #

`

651.06

163

O

CN

O

CN

O

CN

O

CN

Rate Acceleration with High Pressure

O

+

CO2Me

.001 Kbar

+

15 Kbar

RT, 4hr, CH2Cl2

O

RT, 5wk, neat

CO2Me

39%

55%

O +

CO2Me

.001 Kbar

+

15 Kbar

RT, 4hr

O

40˚C, 1mo

CO2Me

18%

62%

651.06

164

O

O

O

Hydrophobic Acceleration of Diels-Alder

++

EndoExo

Solvent k x 105 M-1S-1

isooctane 5.94

CH3OH 75.5

H2O 4,410

H2O/LiCl 10,800

H2O,

NH2

H2N NH

2Cl

4,300

H2O/β-CD 10,900

Breslow, JACS, 1980, 102, 7816

OMe

OH

CO2R

OMe

OH

OMe

OH

CHO

H

H

CHO

CO2R

+ +

endo

exo

CO2R

CHO

R Solvent time Yield Endo:Exo

Et PhH 288h 52% 1:1.18

Et H2O 168h 82% 1.3:1

H H20 17h 85% 1.5:1

Na H20 5h 100% 3:1

Grieco, TL, 1983, 24, 1897

651.06

165

E

AlCl3

(HOMO) (HOMO)

OMe

!E = 2.2eV

Examples

++

Lewis Acid Catalysis of the Diels-Alder Reaction

2.2eV

-14.3eV

1.9eV

O

H

-14.6eV

OMe

O

H

Lewis Acid

+0.5eV

!E =

9.2

eV

-16.6eV

2.2eV

-14.3eV

-4.0eV

-20.6eV

OMe

O

-9.2eV-9.2eV

-7.0eV

+0.5eV

O

0.0eV

140˚C

OMe

-10.9eV

O

8-10h

+

75%

CH2Cl25˚C, 1h

O

+

75%

a)

b)

(LUMO)

(LUMO)

H+ for

calculations

MeO

MeO

E

651.06

166

Regiochemistry of Diels-Alder

OCH3

CH3

+CO2Et

Et

OCH3

CH3

CO2Et

Et

OCH3

CH3

Et

CO2Et

or

How to precdict the regiochemical outcome?

OCH3

CH3

OCH3

CH3

OCH3

CH3

OCH3

CH3

O

CH3

OCH3

CH3

OCH3

CH3

CH3..

..: : :

::

:

:

Best; no separationof charge.

Good charge separated form; positive charge next tolone pairs on oxygen.

important overlap with lone pair on oxygen

Negative chargenext to lone pairs;bad repulsion.

10 electrons aroundoxygen; violates octet rule.

Resonance forms of E,E-1-methoxy-1,3-pentadiene.

.. ..

....

651.06

167

C

O

OCH3C

O

OCH3

Et Et

C

O

OCH3

Et

C

O

OCH3

Et

C

O

OCH3

Et

Good form; negativecharge delocalized ontoan electronegative atom.

: : : : : :

: :: :

Best form;no charge separation.

Good dipolar form;negative charge adjacentto carbonyl group

Bad form; placespositive chargeadjacent tocarbonyl group.

Bad form; placing positivecharge on the oxygen atom.

Resonance forms of a vinyl ester.

651.06

168

MeO CHO MeO CHOMeO

CHO

+Diels-Alder +

"Para" "Meta"

+0.4eV (LUMO)

MeO

-9.1eV (HOMO)

CHO

0.0eV

-10.9eV

.67

.42

-.28

-.41

MeO-.43

CHO.63

.67

-.41

.63

-.43

Frontier Orbital Explanation of Diel-Alder Regioselectivity

!E=11.3eV

!E=9.1eV

651.06

169

-.51

CHO

-.51

.60-.43

+.63

O

Lewis Acid

93

O

O

O

+

H

.60

71

Diels-Alder

:

SnCl4, 25˚C, PhH

+

29

O

O

H3CO

! = 0.20

-.03

+.58

O

O

H3CO

: 7JACS, 1964, 86, 3899

O

O

H3CO

+

Improved Regioselectivity with Lewis Acid in Diels-Alder

120˚C, PhCH3

+

! = 0.55

None 1 :

BF3•OEt2

1

4 : 1

100˚C

-16˚C

SnCl4 -16˚C 1 : 20

Hendrickson, Chem. Comm., 1983, 837

Lewis Acid T

651.06

170

Y

XX

Y

X

Y

CO2Me

CO2Me

H

CO2MeH

CO2Me

CO2Me

H

CO2Me

H

Stereoselectivity of Diels-Alder Reaction

++!

"endo" "exo"

Major Minor

+ !

MeO2 C

MeO2 C

+

KOt-Bu

CO2Me

CO2Me

t-BuOH

endo

CHO

OAc

+ !"endo"

Predicted Major isomer

R

Minor

VS.

Major

OAc

CHO

R

Thermodynamic

Kinetic

exoendo

Kinetic

exo

Transition State

Alder's endo rule

651.06

171

OBn

CHOOBn

CHO

Endo Selectivity with Lewis Acid

+ +

Endo Exo

0˚, 10d 66 34

200˚, 6h

34 66

BF3•OEt2(-20˚, 5min)

90 10

CHO

OBn

Kabalke, JACS, 1970,92, 6548

651.06

172

Factors Affecting Endo/Exo Product Ratio

1 Endo adduct is often increased by Lewis Acid catalysis.

2 Pressure

OHC

vs.

CHO

endo

more compact

exo

!V = -25 to -38cm3 mol-1

T.S. smaller than SM

3

!!V Favors endo pressure endo:exo

Temperature

CO2H

CO2H+

CO2H HO2C

CO2H CO2H

endo exo

Temperature (˚C) Endo Exo

75˚ exclusively

90˚ 7 1

100˚ 4.5 1

110˚ 2 1

130˚ 1 1

651.06

173

Ph

CHO

Ph Ph

CHO CHO

CHO

CHO

OHO2C

O

O

O

O

O

HO2C

O O

O

O

O

O

O

O

H

H

O

OO O

O

O

O

O

H

H

O

O

O

O

H

H

5

Steric Factors

O

O

O

6

100˚C

+

Isomerization

Reversibility

130˚C

Ph

Ph

4

O

O

O

H

H

rt, Et2O

exo endo

+

Factors Affecting Endo/Exo Product Ratio

+ O

O

O

H

H

!

exo

+

H+or

OH-

endo

Et2O+

Example:

endo exoT

25˚C 100

:

: 0

140˚C

Ph Ph Ph Ph

29 : 71

H200˚C

exo

651.06

174

1,3 Dipolar Cycloaddition

YX Z

YX Z

YX Z

YX Z

“1,3-dipole”

examples:

O

O O ozone

N N

Rdiazoalkane

NO

Rnitrone

R'

R N N N azide

R C N O nitrile oxide

NR R azomethine ylide

vinylcarbene

OR R carbonyl ylide

-these can all be 4π e_ systems, so use them in [π4s + π2s] cycloadditions

1

4 5

32 1

4 5

32

1

4 5

32

"[3+2]"

651.06

175

5-membered ring (heterocyclic) products are the usual signatures of [3+2] cycloadditions.

familiar examples:

O

OO

O3

[3+2] retro - [3+2]

[3+2]

mol-ozonide

O

O

OO O

O

OO

O

O

O

more synthetically important examples:

nitrile oxides

R NO2RCNO

R R'

O OH

R R'

O O

R'

R' C CH

N O

N O

R

R'

R'

R

isoxazoline

isoxazole

Zno

HCl

1O2

[4+2]

PhNCO

50o

651.06

176

mechanism:

R NO

O

Ph N C OR N

O

O O

NPh

R NO

O O

HNPh

H

R NO

HPhHN O

O

R C N O

H

nitrones

N

O

RR'

RNH

OH O

H R

+

application:

N

MOMO

CHO

HOHN N

R

MOMO

NR'

O

[3+2]

ONR'

H H

HR

(-)-pyrodemin Org. Lett. 2003, 5, 2611.

651.06

177

azides

N

N

N

R

N

N

N

R

N

N

N

R

CO2Me

NN

NR

CO2Me

NR CO2Meh!

(-N2)

triazoline Wolff, 1912

R R

O

CO2EtOO O

CO

2E

t

OO

OO OO OO

EWG

R

EWGOO

OOEWG

EWG

R

How do they work?

75˚C, PhH

PhH, 75˚C

45%

vinylcarbenes

[3+2]

Boger, JACS 1985

651.06

178

Sigmatropic Rearrangements

-definition: movement of a σ bond across a π system

2 typical forms:

2

3 4

51

2

345

1

[2,3]

2

345

61 2

345

61

[3,3]

-both are 6 e_ processes

nomenclature specifies the positions of breaking and forming bonds

i.e.,

R R3

11

2 2

3[1,3]

(π2 + σ2)

3

2

1

3

21

3

21

3

21[3,3]

(π2 + π2 + σ2)

1

23

5

4

3

1

2

1

23

5

4

3

1

2

[3,5]

(π2 + π4 + σ2)

(by convention, lower number is given first)

651.06

179

[1,n] rearrangements

Like cycloadditions, sigmatropic rearrangements can be suprafacial or antarafacial. For

example, consider a [1,5] rearrangement:

a bc

[1,5]

a bc

(retention)

(σ2s + π4s)

a bc

[1,5]

abc

(retention)

(σ2s + π4a)

a bc

[1,5]

c ba

(inversion)

(σ2a + π4s)

When a σ bond participates in antarafacial fashion in a [1,n] sigmatropic rearrangement,

inversion occurs at the migrating center. Thus, we might expect 4 and 8 electron [1,n]

processes to show inversion.

651.06

180

[1,2] shifts

Two electron versions are cationic: H3C H

[1,2]

!2s

CH3H

H

“1,2 - hydride shift”

[1,2]

!2s “Wagner - Meerwein shift”

-note the suprafacial nature of this shift

HH

H

σ2s - thermally allowed (Hückel)

More complex example:

H3C H

H H

CH3

OH

40% H2SO4

THF, -5 °C -> 25 °C H3C H

H H

CH3

1,2-shiftH

OH

H3C CH3

H H

+H2O

(-H+)

caryophyllenealcohol

Corey, JACS 1964, 86, 1652; JACS1965, 87, 5733.

Four-electron [1,2] shifts must be antarafacial and are difficult to achieve:

O

R

R

O

[1,2] Wittig rearrangement

-these processes typically occur via radical intermediates

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[1,3] rearrangements

These are 4 e_ processes, so they must employ a Möbius transition state choices: π2s + σ2a or π2a + σ2s (suprafacial/inversion) (antarafacial/retention) “si” “ar”

ex:

H

AcO

H

H

OAc

H

HCH3

!

[1,3]

OAc

HH3C H OAc

CH3

H OAcCH3H

H

("2s + #2a)

note that this transition state is feasible only because a hydrogen atom is pointed toward

the cyclopentene in the transition state

!

[1,3]AcO

H

H

OAc

H

HCH3

retention!

-this is thermally forbidden, but occurs due to steric crowding in the allowed transition

state:

H OAc

H

CH3

(!2s + "2a)

way too big!

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The best studied [1,3] rearrangement is the vinylcyclopropane rearrangement (useful for

making 5-memebered rings):

300o

this is also predicted to go by a π2s + σ2a pathway

The experimental result:

296o

+ + +

65% 8% 22% 5%(!2s + "2a) (!2a + "2s) (!2s + "2s) (!2a + "2a)

allowed forbidden

J.E. Baldwin, JACS 1976, 98, 6705

so, the question is: is this reaction pericyclic, or does it proceed via the diradical

intermediate:

?

The most likely answer is: both; see JACS 1997, 119, 10543, 10545

[1,5] rearrangements

H H

[1,5] as drawn, this is a degenerate rearrangement

(product 6 e_: (π4s + σ2s) - Hückel is identical to starting material)

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to examine, look at:

DCH3 CH2CH3

CH3 CH3 CH3

CH3CH2CH3CH2CH3

D

CH3

D

+250o

We rationalize this result as follows:

D

CH3H3CH2C

CH3

H

D

CH3H3CH2C

CH3

H CH3D

CH3

CH2CH3

D

CH3

CH2CH3H3C

HD

CH3

CH2CH3H3C

H CH2CH3D

CH3

CH3

both of these pathways are π4s + σ2s

but is this process concerted?

kH / kD = 12.2 at 25oC; ΔH‡ = 30 kcal/mol; ΔS‡ = -5 to -10 cal/(mol·K)

-these are all consistent with the concerted pathway

Winstein, TL 1966, 999

Roth, Justus Liebigs Ann. Chem. 1964, 671, 25

Roth, Justus Liebigs Ann. Chem. 1966, 699, 24

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[1,7] rearrangement - 8 e_ process

H H

[1,7]

!6a + "2s

unlike [1,3] hydride shifts, [1,7] hydride shifts occur, as the 8-membered ring can

adopt an antarafacial transition state:

H

Möbius π6a + σ2s transition state

ex:

HO

C9H17

H2C H H

HO

C9H17

H[1,7] shift

Vitamin D

[2,3] rearrangements - 6 electron suprafacial / suprafacial π2s + ω2s +σ2s

X YY

X[2,3]

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ex:

EWG

O

EWG

OLDA

[2,3]

EWG O

“[2,3] - Wittig rearrangement”

(EWG = Ph, CO2R, alkene, alkyne)

-this reaction is irreversible due to product stability

O

SPh SPhO OHP(OMe)3

irrev.

[2,3]

sulfoxide sulfenate

“Mislow rearrangement”

ylides also undergo [2,3] rearrangements:

SS

S

KOtBu

- 40o

[2,3]

Vedejs, JOC 1978, 43, 1185

(note: the ylide shown is not the most stable one, but it is the needed intermediate)

Neutral species can also undergo a [2,3] rearrangement:

OHCl P(OPh)2 O P

OPh

OPhP

O

OPh

OPh

[2,3]

N -reaction favors products owing to stability of P(V) and P+ _ O_ bond

-note participation of alkyne to yield an allene

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Internal Eliminations

H

Y

X YX H"Ei"

-this looks like a [2,3] rearrangement where a π bond is replaced by a σ bond to H

ex:

N

O

H

+ Me2NOH!

N-oxide

“Cope Elimination”

O OLi O

SePh

O

Se

Ph

O

H

O

LDA PhSeBr H2O2

-sulfoxides also eliminate but need elevated temperature

I

O O

I O O IO

Hdimethyldioxirane

(source of O)

(DMDO)

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[3,3] rearrangements

!

“Cope Rearrangement”

Org. React. 1975, 22, 1

-degenerate reaction ⇒ reversible

does reaction proceed via chair - or boat - like transition state?

DD

D

D

D

D

D

D

230o

(enantiomer of s.m.)

What do the two transition states predict?

HH

HDD

DH

DH

DH

H

H

DD

D DH

DH D

H

D

HD

D

D

D"chair"

D

H

H

D

D

D D

D

H

H

D

D

D

DD

D

H

H

D

D

D

D

"boat"

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Also:

225o

6h (E,Z)-2,6-octadiene (99.7% E,Z)

Doering & Roth, Tet 1962, 18, 67

-this reaction is limited by its reversible nature, but it can be made essentially

irreversible: OH OH O

tautomerize200o

[3,3]

this is the sole product

“oxy-Cope” reaction

even more remarkable:

O O O

H2O60o

OHKH, 18-crown-6

- 25o

“anionic oxy-Cope” ⇒ results in a 1010 - 1017 rate acceleration

Evans, JACS 1975, 97, 4765

Evans, JACS 1978, 100, 2242

What is responsible for such a rate acceleration?

The transition state can be considered as a radical pair (if bond breaking is early)

for anionic oxy-Cope:

O

The difference is that between allyl radical & O

(a radical anion) ⇒ the electron donating of alkoxide stabilizes radical

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we can observe facile Cope rearrangements by geometric constraint

ex:

RT[3,3]

(ΔG‡ = 20 kcal/mol)

cis-divinylcyclopropane

JCS Chem. Comm. 1973, 319

-note boat-like transition state

(trans isomer requires 190o to rearrange, presumably via cis)

0o

(rapid equilibrium between degenerate forms)

Doering & Roth, ACIEE 1963, 2, 115

- 55o

O O

(Ea = 8.1 kcal/mol)

Lambert, TL 1963, 1901

Claisen Rearrangement

O O150o - 200o

[3,3]

Historically, it was the first known [3,3] rearrangement

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O

O

OH!

[3,3]

tautomerize

(Claisen, 1912)

Org. React. 1944, 2, 1

Org. React. 1975, 22, 1

para isomer is also observed:

O O OH

Cope taut.

Claisen also proceeds via chair-like transition state:

O O

O O180o

[3,3]

trans(E,E)

-note that we chose the diequatorial chair t.s.

chair is preferred to boat by ~ 6 kcal/mol: Houk & Borden, JACS 1988, 110, 2314 (This implies that steric considerations can override this preference)

A Claisen rearrangement is also catalyzed by the enzyme chorismate mutase as part of

the biosynthesis of aromatic amino acids: HO2C

O

OHCO2H

chorismatemutase

HO2C

O

CO2H

OH

chorismate prephenate

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Ene Reaction

H H(!2s + "2s + !2s)

this is not formally a sigmatropic rearrangement, but is closely related to a [3,3] process:

both are π2s + σ2s + π2s

ex:

OO

H

O

O

O

O

200o

+

JACS 1950, 72, 2871

intramolecular:

H

490o

Stork, JACS 1976, 98, 6747

O

H

OH

180o

+ 3 isomers

60% 40%

Ohloff, Helv. Chim. Acta 1967, 50, 153

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Lewis acids have been shown to accelerate ene reactions:

H

CO2Me CO2Me

+

230o

+ 3% isomer

47%

H

CO2Me CO2Me

+AlCl3

sole product

61%

25o

Snider, JOC 1974, 39, 255

JOC 1976, 41, 3061

JACS 1979, 101, 5283

There are also 6-membered ring cyclic eliminations:

H O

X

Y X

O

Y

H

-this looks like a retro-ene reaction

ex: CO2Et

OAc

CO2Et300o

JACS 1959, 81, 2126

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why this isomer? H

H

HO

O

CO2EtCO2Et- HOAc

only H near to OAc

Also:

O SMe

S150

o

+

xanthate

“Chugaev reaction”

JOC 1962, 27, 2007