Chem 634 Fall 2014
Pericyclic Reactions
Reading:
CS-B Chapter 6
Grossman Chapter 4
Announcements
•  Presentations due to Mary via email by Thurs, 5pm. (Will be compiled and
sent to you by Fri, 5pm.)
•  Presentations: Saturday, 11/22, 9am, 221 BRL.
•  Seminar: Prof. Matt Kanan (Stanford), Fri, 4pm!
Pericyclic Reactions
Definition: Continuous, concerted reorganization of electrons
cyclic
transition
state
no intermediate,
single transition state
Bond breaking & bond making occur at the same time.
Can be synchronous (equal extent of breaking & making in TS) or
asynchronous (unequal extent of breaking & making in TS).
Fukui & Hoffmann: Nobel Prize in Chemistry, 1981, “for… their theories,
developed independently, concerning the course of chemical
reactions” (Woodward dies in 1979)
5 Types
1.  Electrocyclic
2.  Cycloadditions
3.  Sigmatropic
4.  Chelatropic
5.  Group Transfer
We’ll go through them all!
3 Theories
All 3 theories are correct!
1.  Woodward–Hoffmann: Conservation of Orbital Symmetry
•  1st historically
•  Uses correlation diagrams
2.  Fukui: Frontier Molecular Orbital Theory
•  Easier than Woodward–Hoffmann (usually)
•  Based on HOMO/LUMO interactions
3.  Dewar–Zimmerman: Aromatic Transition State
•  Easiest to apply for all reaction types, but not intuitive to understand why
it’s valid
3 Things Matter
1.  Number of electrons involved
2.  Stereospecificity
3.  Conditions: heat (Δ) vs. light (hυ)
Type 1: Electrocyclic Reactions
-  Ring openings and closures
-  Exchange π-bond for σ-bond
-  Classified by number of electrons
R
R
4e-
favored by release of ring strain
R
6e-
R
π-bond (~75 kcal/mol) –> σ-bond (~88 kca/mol)
2e-
Diastereoselectivity – Observations
Case 3: Case 1: Δ
R
R
Δ
4e-
R
R
R
H H
(±)
R
6eR
R
H
R
HH
R
R
disrotatory
H
H
R
R
Case 4: Case 2: hυ
hυ
R
R
H
R
conrotatory
R
R
6e-
4e-
R
R
R
R
R
R
(±)
H
R
H H
H
R
disrotatory
R
R
R
HH
R
conrotatory
R
H
H
R
General Phenomenon… Woodward–Hoffmann Rules
Number of electrons Thermal Photochemical 4n Con Dis 4n+2 Dis con (n = integer)
6 points for a touchdown –> 6e-, thermal, disrotatory
... But why???
Theory #1: Woodward–Hoffmann Correlation Diagrams
Angew. Chem. Int. Ed. 1969, 8, 781.
•
•
•
•
•
Consider all molecular orbitals (MO’s) involved
Consider symmetry of MO’s in starting material, product, and transition state.
Orbitals of different symmetry can cross (orthogonal orbitals).
Orbitals of same symmetry cannot cross (extreme energetic cost).
We are about orbitals where electrons end up.
Example of W–H Correlation Diagrams
C2 axis of symmetry
σ-plane of symmetry
Each MO is either symmetric (S)
or anti-symmetric (A) with respect
to these symmetry elements.
disrotatory TS
σSM
conrotatory TS
σP
σ∗
A
A
Ψ4
π∗
A
S
Ψ3
π
S
A
σ
S
S
Ψ2
Ψ1
Example of W–H Correlation Diagrams: Thermal Conditions
C2 axis of symmetry
σ-plane of symmetry
disrotatory TS
σ∗
π∗
conrotatory TS
σSM
σP
C2-SM
C2-P
A
A
A
S
A
S
S
A
π
S
A
A
S
σ
S
S
S
A
dis pathway
disfavored
con pathway
favored
Ψ4
Ψ3
Ψ2
Ψ1
Example of W–H Correlation Diagrams: Photochemical Conditions
C2 axis of symmetry
σ-plane of symmetry
disrotatory TS
σ∗
π∗
conrotatory TS
σSM
σP
C2-SM
C2-P
A
A
A
S
A
S
S
A
π
S
A
A
S
σ
S
S
S
A
dis pathway
favored
con pathway
disfavored
Ψ4
Ψ3
Ψ2
Ψ1
Electrocyclic Reactions in Synthesis
H
H
Ph
CO2H
H
O
OSiR3
CN
CO2H
H
(±)-endiandic acid D
H
H
H
H
H
OH
OH
OSiR3
CN
H
=
OH
H
H
HO
Lindlar
H2
HO
OH
HO
OH
retro 6edis, Δ
OH
HO
retro 8econ, Δ
CuI, O2
OH
(x 2)
Nicolaou JACS 1982, 104, 5555
Electrocyclic Reactions in Synthesis
Z
E
Me
Δ
Me
Me
6edis
Me
Ts
N
MeO2C
H
Δ
H
CO2Me
4econ
Ts
N
MeO2C
CO2Me
H
azomethine ylide
Cycloadditions & Cycloreversions
-  Union of 2 π-systems
-  Exchange π-bonds for σ-bonds
-  Classified by [m+n], m & n = # of conjugated atoms in each π-system
[4+2]
4 atoms
2 atoms
Diels–Alder Reaction!
Note: 6 eGreat way to make cyclohexenes & cyclohexanes
Fukui: Frontier Molecular Orbital (FMO) Theory
The idea: Use FMO’s (HOMO + LUMO)
In this case, it doesn’t
matter… HOMO/LUMO
gaps are the same.
LUMO
LUMO
nonbonding level
E
Which HOMO & LUMO?
HOMO
HOMO
E
EA – EB
ΔE
diene
dienophile
geometrical/spatial
overlap
ΔE ∝
orbital overlap
EA – EB
If closer in energy,
then more stability
by forming a
covalent bond.
Types of Diels–Alder Reactions
Normal electron demand = HOMO of diene + LUMO of dienophile
Inverse electron demand = HOMO of dienophile + LUMO of diene
Net Bonding Interaction?
The idea: Use FMO’s (HOMO + LUMO)
LUMO
LUMO
nonbonding level
E
HOMO
HOMO
diene
dienophile
YES!
Diastereoselectivity: Endo vs. Exo
Me
Me
O
OMe
+
O
[4+2]
Me
OMe
OMe
+
Me
Me
Me
Me
Me
minor
exo
Me
major
endo
(favored)
Me
Me
Me
O
OMe
Me
O
Me
MeO
O
Me
Why? … Secondary Orbital Interactions
Me
Me
O
O
OMe
OMe
Me
Me
Me
LUMO
HOMO
Me
stabilizing 2°
orbital overlap
Me Me
exo
Me
Me
OMe
O
Me
Me
MeO
O
endo
Regioselectivity & Rates: Substituent Effects
Rates depend on HOMO/LUMO gap.
Perturba4on HOMO LUMO extra conjuga7on   electron-­‐withdrawing group   electron-­‐dona7ng group   Effects apply to both dienes & dienophiles.
Effect of substitution is biggest if on C1 of diene.
R1
R2
2
3
1
4
bigger effect
Examples
O
+
O
O
O
+
O
rt, 24 h
O
100%
165 °C
12,600 psi
17 h
78%
Regioselectivity
Related to polarization of HOMO and/or LUMO
OMe
+
OMe O
O
OMe
H
H
vs.
H
O
minor
major
Quick prediction: “imaginary intermediate”
(push arrows to get maximum effect of substituents)
OMe
O
OMe O
H
OMe
H
OMe
H
O
CH2
H
O
more stable
… but remember
these reactions
are concerted!!!
Lewis Acid Effects
One of the first Lewis acid-accelerated organic transformations!
O
O
O
+
O
O
Ph
O
O
t1/2
none
2400 h
AlCl3 (1 equiv) < 1 min
CH2Cl2
25 °C
O
Ph
Ph
OMe
+
additive
OMe
additive
1,4 : 1,3
none
80 : 20
AlCl3
97 : 3
additive
endo:exo
none
82 : 18
AlCl3·OEt2 (1 equiv)
99 : 1
OMe
+
O
1,3
1,4
O
+
H
H
OMe
endo
CO2Me
CO2Me
H
+
exo
H
Lewis acid increases rate, endo/exo selectivity & regioselectivity!
Yates, Eaton. JACS 1960, 82, 4436
Why???
MO perturbation!
O
AlCl3
OMe
O
AlCl3
OMe
more reactive, more like
O
Explains rates, but what about selectivity issues???
Houk JACS 1973, 95, 4094
Why???
Bigger difference in lobe size on C1
vs. C2 = better regioselectivity
Lower LUMO = faster rate
Bigger lobe on C=O carbon =
bigger 2° orbital interactions =
better endo/exo selectivity
Houk JACS 1973, 95, 4094
One More Consideration: S-cis vs. S-trans
krel
vs.
O
S-cis
reactive
S-trans
not reactive!
+
O
O
O
O
Me
Me
O
O
+
Me
O
O
Me
+
H
O
O
O
Me
1
4
O
Me
O
O
O
O
10–3
O
O
+
H
H
O
O
O
O
O
103
Synthetic Considerations: Important Dienes
OMe
OMe
Me
Me
CHO
CHO
+
Δ
TBSO
Δ
TBSO
Danishefsky's
diene
Me
CHO
H3O+
O
Acc. Chem. Res. 1981, 14, 400
Tetrahedron 1997, 53, 8689
Me
AcO
E
+
Me
CHO
AcO
Δ
PhS
MeOH
PhS
Trost
diene
Mg(OMe)2
(E = ester)
O
PhS
Me
CHO
NaIO4
O
Me
CHO
Δ
J. Am. Chem. Soc. 1980, 102, 3554
J. Am. Chem. Soc. 1976, 98, 5017
Hetero-Diels–Alder Reactions
Normal Electron Demand
OMe
OMe
H
R
ZnCl2
+
O
TBSO
R
TBSO
H3O+
O
Δ
R
O
O
Danishefsky's
diene
Inverse Electron Demand
+
Me
O
OAc
Me
O
OAc
J. Am. Chem. Soc. 1984, 49, 1955
J. Am. Chem. Soc. 1985, 107, 1246
Intramolecular Diels–Alder Reactions
Type I
or
fused
(most common)
bridged
(needs long tether,
>5 atoms)
Type II
needs long tether to
avoid anti-Bredt olefin
transannular
Diels–Alder in Synthesis (Corey)
Cu(BF4)2 MeO
+
NC
OMe
Cl
KOH
Cl
90%
MeO
80%
O
CN
O
MeO
HO
m-CPBA
O
95%
KOH
O
KI, I2
OMe
90%
NaHCO3
OH
HO2C
HO
O
O
O
O
OMe
OMe
I
OH
OAc
n-Hex
HO
HO
prostaglandin F2α
Asymmetric Diels–Alder Reactions
Option 1: Chiral auxiliary control (see Carreira, Ch 17)
Et
Et
O
O
Me
N
O
Et2AlCl
–100 °C
Bn
O
Me
Al
N
Me
H
O
O
Bn
blocks rear face
Xc
O
97:3 dr
55:1 endo:exo
Evans J. Am. Chem. Soc. 1984, 106, 4261
Asymmetric Diels–Alder Reactions
Option 2: Asymmetric Catalysis (many catalysts!)
Me
blocks front face
O
O
O
N
Me
O
N
O
10 mol % [(t-Bu-Box)Cu(OTf)2
N
Cu
t-Bu
O
O
N
O
Ph
O
Ph
O
+
H
Bn
Me
N Me
N
H
t-Bu
O
O
O
N
O
O
· HCl
Me
(20 mol %)
Bn
NMe
Me
N Me
H
Me
Me
O
Ph
CHO
Ph
Me
75%
35:1 exo:endo
96% ee
MacMillan J. Am. Chem. Soc. 2000, 122, 4243