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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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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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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-HOMO interaction.
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) if bonding electron density increases (or decreases) and/orantibonding electron density decreases (or increases) between the extremities.
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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.
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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Frontier Orbital Interactions and What We Can Do with Them?
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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Frontier Orbital Interactions and What We Can Do with Them?
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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Frontier Orbital Interactions and What We Can Do with Them?
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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Frontier Orbital Interactions: Stereoselectivity
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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Frontier Orbital Interactions: Stereoselectivity
pericyclic reactions
Electrocyclic reactions
Torquoselectivity, basic Rondan-Houk treatment
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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Frontier Orbital Interactions: Stereoselectivity
pericyclic reactions
Electrocyclic reactions
Torquoselectivity, basic Rondan-Houk treatment
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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Frontier Orbital Interactions: Stereoselectivity
pericyclic reactions
Electrocyclic reactions
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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Frontier Orbital Interactions: Stereoselectivity
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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Frontier Orbital Interactions: Stereoselectivity
cycloaddition reactions
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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Frontier Orbital Interactions: Stereoselectivity
cycloaddition reactions
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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Frontier Orbital Interactions: Stereoselectivity
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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Frontier Orbital Interactions: Stereoselectivity
addition reactions - Nucleophilic additions
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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Frontier Orbital Interactions: Stereoselectivity
addition reactions - Nucleophilic additions
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 4tertbutylcyclohexanone by LiAlH4
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Frontier Orbital Interactions: Stereoselectivity
addition reactions - Nucleophilic additions
1,2 Asymmetric inductions
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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Frontier Orbital Interactions: Stereoselectivity
addition reactions - Nucleophilic additions
1,2 Asymmetric inductions
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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Frontier Orbital Interactions: Stereoselectivity
addition reactions - Nucleophilic additions
1,2 Asymmetric inductions
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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Frontier Orbital Interactions: Stereoselectivity
addition reactions - Nucleophilic additions
1,2 Asymmetric inductions
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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Frontier Orbital Interactions: Stereoselectivity
addition reactions - Nucleophilic additions
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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Frontier Orbital Interactions: Stereoselectivity
addition reactions - Nucleophilic additions
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
Nguyen. A. T. et al, Tet. Let.1976, 17, 159"Axial attack is favored by flattenedor flexible rings"
Nu
better for electronic transfer andminimizes the torisional repulsions.
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Frontier Orbital Interactions: Stereoselectivity
addition reactions - Nucleophilic additions
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
Nguyen. A. T. et al, Tet. Let.1976, 17, 159"Axial attack is favored by flattenedor flexible rings"
Nu
better for electronic transfer andminimizes the torisional repulsions.
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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