PVP Orbital Stereoselectivity

7/21/2019 PVP Orbital Stereoselectivity

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Frontier Orbital Interactions: Stereoselectivity

Phong V. Pham

MacMillan Group

Group Meeting

Princeton, Feb. 27, 2008

OM

HOMO

O LUMO


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Frontier Orbital Interactions and Applications

Pericyclic Reaction

Addition Reactions

Substitution Reactions

Limitation & Conclusion

Leading Reference:

Anh T. Nguyen,Frontier Orbitals, Wiley, England, 2007

Ian Fleming,Frontier Orbitals and Organic Chemical Reactions, Wiley, England, 2006


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Frontier Orbital Interactionsand What We Can Do with Them?

E

A + B

P

[AB]

Maximumof

MinimaLUMO (A)

HOMO (A)

LUMO (B)

HOMO (B)

HOMO: Highest Occupied Morlecular Orbital

LUMO: Lowest Unoccupied Morlecular Orbital

"... majoyity of chemical reactions should take place at the position and in the direction of maximum overlappingof

the HOMO(or high-lying occupied MO!s) and the LUMO(or low-lying unoccupied MO!s) of the reacting species; in

reacting species possessing a singly occupied (SO) MO, this plays the part of the HOMO or of the LUMO, or of both"

Fukui K., Acc. Chem. Ress.1971, 4. 57


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Frontier Orbital Interactions and What We Can Do with Them?

Study on the Frontier Orbital Interactions Help to Answer Questions of Structureand Reactivity

Standard FO Treatments of Structure

Stable Conformations

Q: Which is the most stable conformation?

A: Formally divide the molecule into two fragments, the most stable conformation will be the onehaving the smallest HOMO-LUMO intereaction.

Reactive Conformation

Q: Which is the most reactive conformation?

A: It is the one having highest lying HOMO and lowest lying LUMO in the transition state.

Structural Anomalies

Q: When might structural anormalies occur?

A: A bond will shorten (or lengthen) of bonding electron density increases (or decreases) and/orantibonding electron density decreases (or increases) between the extremities.


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A: Formally divide the molecule into two fragments, the most stable conformation will be the onehaving the smallest HOMO-HOMO interaction.






A: A bond will shorten (or lengthen) if bonding electron density increases (or decreases) and/orantibonding electron density decreases (or increases) between the extremities.


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N N

F F

N N

F

F

N N

F F

N N

F

FHOMO

LUMO

HOMO

LUMO

The cisisomer is 3 kcal/mol favored at 25o

C

cis trans


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Study on the Frontier Orbital Interactions Help to Answer Questions ofStructureand Reactivity

Standard FO Treatments of Reactivity

Absolute Reactivity

Q: Will A react with B?

A: Reaction is forbiddent if their FO overlap is zero

Relative Reactivity

Q: Will A react preferentially with B1or B2?

A: A reacts preferentially with the molecule whose frontier orbitals are closer in energy to its own.

Regioselectivity

Q:Which reactive site of B will A react preferentially with?

A: A reacts preferentially with the site whose frontier orbital has the largest coefficient.

Stereoselectivity

Q: Which is the best approach for A to attach a given site of B?

A: The preferred trajectory will have the best FO overlap.


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Absolute Reactivity


A: Reaction is forbiddent if their FO overlap is zero.

Relative Reactivity



Regioselectivity

Q:Which reactive site of B will A react preferentially with?


Stereoselectivity




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Absolute Reactivity


A: Reaction is forbiddent if their FO overlap is zero

Relative Reactivity



Regioselectivity

Q: Which reactive site of B will A react preferentially with?


Stereoselectivity




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pericyclic reactions

Electrocyclic reactions

Torquoselectivity, basic Rondan-Houk treatment

R

R

Rcon-out con-in

Et

Etcon-out con-in

Et

1 2.1

iPr

iPrcon-out con-in

iPr

1 1.9


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R

R

Rcon-out con-in

Me

Mecon-out con-in

100% 0%

CHO

CHOcon-out con-in

0% 100%

Me

CHO


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R

R

Rcon-out con-in

HHH H

LUMO LUMOHOMO HOMO

Preferred when R is ED group Preferred when R is EW group

LUMO (R)

LUMO (cyclobutadiene)

HOMO (R)

HOMO (Cyclobutadiene)


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Torquoselectivity, quantitative analysis

CO2

CO2con-out con-in

LUMO (R)

LUMO (cyclobutadiene)

HOMO (R)

HOMO (cyclobutadiene)

CO2

Me

Me

Me

+5.7 kcal/mol (Me)

4.4 kcal/mol (CO2)

1.2 kcal/mol (Me)

+0.7 kcal/mol (CO2)

+1.3 kcal/mol 0.5 kcal/mol

Houk K.N. et al,Tet. Let. 1995, 36, 6201

1 >10


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cycloaddition reactions

Endo-Exoorientation, secondary orbital interactions are important

[4 + 2] and [8 + 2] prefers Endoorientation

[6 + 4] prefers Exoorientation

LUMO

HOMO

HOMO

LUMO

LUMO

HOMO

What do you think about the mechanism of this reaction?

O

O


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Syn-Antiorientation, steric effect vs. secondary orbital interactions

X

X X

syn anti

Steric control Secondary orbital overlap control

OCOCH3

OCOCH3

only one isomer isolated

OMe

OMe

Woodward R.B., J. Am. Chem. Soc.1955, 77, 4183

Et N

O

O

Ph

N

O

O Ph

Et

N

O

O Ph

Et

2.2 1

Burnell J.D, J. Org. Chem. 1997, 62, 7272


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Syn-Antiorientation, steric effect vs. secondary orbital interactions

X

X X

syn anti

Steric control Secondary orbital overlap control

OCOCH3

OCOCH3

only one isomer isolated

OMe

OMe

Woodward R.B., J. Am. Chem. Soc.1955, 77, 4183

Et N

O

O

Ph

N

O

O Ph

Et

N

O

O Ph

Et

2.2 1

Burnell J.D, J. Org. Chem. 1997, 62, 7272


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addition reactions - Nucleophilic additions

The non-perpendicular Dunitz-Burgi attack

O

Nu

Traditional model

O

Dunitz-Burgi study

N~107 o

O LUMO

Nu HOMO

Burgi H.B. et al, JACS1973, 95, 5065Nguyen A.T., TCC1980, 88, 145

Houk and co-workers showed on their calculation that the angles of nucleophilic attacks on alkenes and

alkynes lie in the range 115130 o(lager than the angle of attack on carbonyls.) Can you rationalize the

result? (JACS1982, 104, 7162)

O LUMO

Nu HOMO

LUMO

Nu HOMO


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1,2 Asymmetric inductions

The Cram model

O

R1

R3

R2

S

L (or X)

MO

(I)

L: the bulkiest group

X: electronegative group

preferental attack

L

MS

(II)

Increase the size of R make II become more competitive with I

preferental attackO

R

Cram model cannot explan the outcome of the reduction of 4tertbytylcyclohexanone by LiAlH4


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The Cram model

O

R1

R3

R2

S

L (or X)

MO

(I)

L: the bulkiest group

X: electronegative group

preferental attack

L

MS

(II)

Increase the size of R make II become more competitive with I

preferental attackO

R

Cram model cannot explan the outcome of the reduction of 4tertbutylcyclohexanone by LiAlH4


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The Felkin model

O

R1

R3

R2 S

L

MO

Nu major attack

RR M

L

S O

Nu minor attackR

RCO LMSC

LUMO

HOMO

!* (CO)

!(CO)

"* (CL)

O LUMO

NuHOMO

L

MS

O LUMO

HOMOL

MS

Nu

antiaddition TS

synaddition TS

antiaddtiontransition state

has betterorbital overlapthan synadditiontransition state.


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The Felkin model

O

R1

R3

R2 S

L

MO

Nu major attack

RR M

L

S O

Nu minor attackR

RCO LMSC

LUMO

HOMO

!* (CO)

!(CO)

"* (CL) The energy of "*CXfalls asthe electronegativity of Xincreases. (Except X= F andstrong dipolar stabilization

cases)

The energy of "*CLfalls asthe CL bond weakens

The HOMO-LUMO gap fallsas the number of atoms in S,M or L rises


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The Felkin model

O

R1

R3

R2 S

L

MO

Nu major attack

RR M

L

S O

Nu minor attackR

RCO LMSC

LUMO

HOMO

!* (CO)

!(CO)

"* (CL) The energy of "*CXfalls asthe electronegativity of Xincreases. (Except X= F andstrong dipolar stabilization

cases)

The energy of "*CLfalls asthe CL bond weakens

The HOMO-LUMO gap fallsas the number of atoms in S,M or L rises


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The Felkin model

O

R1

R3

R2 S

L

MO

Nu major attack

RR M

L

S O

Nu minor attackR

RCO LMSC

LUMO

HOMO

!* (CO)

!(CO)

"* (CL)

O LUMO

NuHOMO

L

MS

O LUMO

HOMOL

MS

Nu

antiaddition TS

synaddition TS

antiaddtiontransition state

has betterorbital overlapthan synadditiontransition state.


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O

O

O

H3SnOTBS

1)

2) TESCl

O

O

OTES

OTBSO

O

OTES

OTBS

antiadduct synadduct

Taber D. F., JACS1999, 121, 5589

96 : 4


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Dealing with the cyclic system- the "flattening rule"

Ha

C3He

O

12o7

21o

45o

axialattack

equatorialattack

O

"flatten" the ring

Ha

C3 He

O

12o7 + 21o

45o+ 21o

axialattack

TS in the nucleophilic addition will be strongly stabilized when the C2X and C---Nu bonds areantiperiplanar.

Nu

better for electronic transfer andminimizes the torisional repulsions.


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Ha

C3He

O

12o7

21o

45o

axialattack

equatorialattack

O

"flatten" the ring

Ha

C3 He

O

12o7 + 21o

45o+ 21o

axialattack

Nguyen. A. T. et al, Tet. Let.1976, 17, 159"Axial attack is favored by flattenedor flexible rings"

Nu



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Ha

C3He

O

12o7

21o

45o

axialattack

equatorialattack

O

"flatten" the ring

Ha

C3 He

O

12o7 + 21o

45o+ 21o

axialattack

Nguyen. A. T. et al, Tet. Let.1976, 17, 159"Axial attack is favored by flattenedor flexible rings"

Nu



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Arrange the following compounds in order of increasing preference for axialnucleophilic attack(LiAlH4for example)?

1)

O

O

O

1 2 3

2)

O

O

4 5

O

6

O

7

The experimentally observed percentageges for axialattack

4 5 6 7

LiAlH4

NaBH4

MeMgI

80

78

12

85

88

34

89

90

42

94

94

56

Casadevall E. et al, Tet. Let.1976, 17, 2841

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PVP Orbital Stereoselectivity