Lecture 8: Pericyclic Reactions I

E. Kwan

Key Questions
(1) Explanation?

Pericyclic Reactions I
Eugene E. Kwan
September 17, 2010
CH3

CH3

CH3

CH3

CH3

CH3

CH3

CH3

Dewar-Zimmerman
model

the endo
rule
the frontier MO
perspective

CH3

but
not

CH3

(2) Which is favored?

R

both
clockwise

both
counter-

Scope of Lecture

endiandric acids

Chem 106

electrocyclizations

clockwise

con-in
R

con-out

(3) Mechanism?

pericyclic reactions I
Me2AlCl

Me

torquoselectivity
the Diels-Alder
reaction

H
CO2Et

CO2Et
Me

(4) Mechanism?
Ph

Helpful References
1. Carroll, F.A. Perspectives on Structure and Mechanism in
Organic Chemistry. Pacific Grove, California, Brookes/Cole
Publishing Company, 1998. (Chapter 11 - Concerted Rxns)
2. Fleming, I. Molecular Orbitals and Organic Chemical
Reactions (Student Edition). Wiley, 2009. (Chapter 6 Thermal Pericyclic Reactions)
3. Bachrach, S.M. Computational Organic Chemistry
Wiley, 2007. (Chapter 3 - Pericyclic Reactions)

CO2R

H
CO2H

H
Ph

I thank Professor David A. Evans (Harvard) for helpful

discussions and the use of some material in the
preparation of this lecture. Many of the stereochemical
analyses here are taken from Chem 206.

Lecture 8: Pericyclic Reactions I

E. Kwan, D.A. Evans

Pericyclic Reactions
In the 1960s, a wide variety of reactions involving olefins were
known, but there was no obvious connection between their
behavior:

Chem 106

Similarly, the cycloaddition of two ethylene molecules is

forbidden. If it did occur, it would go through an antiaromatic
transition state:
is considered
analogous to

but
not

(Hckel anti-aromatic)
CH3

CH3

CH3

CH3

but
not

CH3
CH3

In transition states, it is much easier to get to a Mbius

topology. For example, dienes are known to close to
cyclobutanes. We can draw arrows for this process:

In the next few lectures, we will consider such thermal,

pericyclic reactions, which involve the concerted, cyclic
flow of electrons.

We already discussed the concept of aromaticity in the

ground state:
Aromatic

Anti-aromatic

Hckel Topology

4n+2

4n

Mbius Topology

4n

4n+2

However, the cyclic redistribution of -electrons in a pericyclic

reaction can also be considered in the same terms:

However, the curly arrows don't give any guidance for

whether the R groups end up syn or anti to each other.
In fact, they end up syn. How did that happen?
R

conrotatory

R
R

R
R

disrotatory

R
R

is considered
analogous to

If both R groups turn counterclockwise ("conrotatory"),

then syn product is produced; if the R groups turn in
opposite directions, then anti product is obtained.

(Hckel aromatic)
transition state

ground state

Thus, we want to know if these reactions are

aromatic (allowed) or antiaromatic (not allowed).

Lecture 8: Pericyclic Reactions I

E. Kwan, D.A. Evans

Dewar-Zimmerman Model
To analyze this or any pericyclic reaction, we can perform a
Dewar-Zimmerman analysis as described below. These
reactions are also described by the Woodoward-Hoffman rules,
which are conceptually appealing, but operationally complex
symmetry-based arguments (we will not consider them in this
course). The Fukui frontier molecular orbital approach is
perhaps easier to explain and apply, but is somewhat limited
in scope (we will return to it a bit later).
Step by Step:
Let us consider the allowed conrotatory closure of a butadiene:
R

R
R

1. Draw p orbitals on all the atoms involved in the reaction

(use s orbitals for hydrogens; there aren't any in this
example, but there might be for, say, a [1,5]-shift). Do this
in three dimensions:

Chem 106

3. Now think of the transition state or product, and connect any

lobes which were not connected in the starting material:

R
R

4. The red "X" marks a phase inversion. Go along the lines

you have drawn and count up how many times the phase
inverts. Note that phase inversions within an orbital don't
count.
5. Here, there was one phase inversion. An odd number of
inversions is considered Mbius topology; an even number
of inversions is considered Hckel topology. If you shade
the orbitals differently, you won't affect the topology:
different
three inversions or
one inversion makes
no difference: it's still
R
the Mbius topology
R

6. Finally, decide how many -electrons are involved. Here,

there are four. As stated earlier:

2. The phase of each orbital is arbitrary. Now, draw lines

connecting the orbitals in the starting material. Only do this
on one side.

R
R

Aromatic
(allowed)

Anti-aromatic
(not allowed)

Hckel Topology

4n+2

4n

Mbius Topology

4n

4n+2

So this reaction is "symmetry allowed." Oddly enough,

reactions which are "disallowed" can actually occur; they just
can't occur through a concerted mechanism (maybe they go
through a radical pathway instead).

Lecture 8: Pericyclic Reactions I

E. Kwan, D.A. Evans

Torquoselectivity
Of course, if an electrocyclic ring closure is allowed, then so
is its microscopic reverse, electrocyclic ring opening:

Electrocyclic Reactions
The corresponding disrotatory closure is forbidden:

R
R

one phase inversion

Mbius topology,
4 e, allowed

zero inversions
Hckel topology,
4 e, forbidden

(The rightmost p orbital has simply been turned the other way.)
In general, here are the selection rules for thermal electrocyclic
reactions:
4n electrons, conrotatory
4n+2 electrons, disrotatory
For example, what is the outcome of this reaction?
CH3

CH3

CH3

CH3

CH3

or

Chem 106

CH3

This is a 6 e cyclization, which means 4n+2 (n=1) electrons,

and therefore a disrotatory closure:
CH3
CH3

That's like saying that the easiest walk from home to school
can't be uphill both ways. But just because both the forward
and reverse reactions are allowed doesn't mean they have
the same barrier.
There is an additional wrinkle, however. The opening of
cyclobutenes must be conrotatory; that is, everything is turning
the same way. But this doesn't tell us which way (clockwise or
counterclockwise) everything is turning:
R

both
clockwise

both
counterclockwise

con-in
R
R

con-out

Is it just a 50/50 chance either way? In fact, the answer is no,

and the torquoselectivity depends on what R is:
(1) if R is electron donating, con-out is preferred
(2) if R is electron withdrawing, con-in preferred

The easiest way to remember this is to memorize the outcome

of one reaction, and then remember that changing one
parameter "toggles" the outcome. For example, if you
remembered that 4cyclizations are disrotatory, then changing
the number of electrons to 6 toggles the outcome to conrotatory.

So what's going on? It definitely can't be just sterics.

Lecture 8: Pericyclic Reactions I

E. Kwan, D.A. Evans

Torquoselectivity
The fact that torquoselectivity is not just related to steric effects
was not appreciated until the mid-1980s. For example:
Me

Me

Me

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However, if R is not very electron-withdrawing, then the

increased sterics of this trajectory make it unfavorable:
X

Me

Me
Me

Conversely, if the group rotates outwards, then the donoracceptor interaction is not as good, but the sterics are relieved:

Me

Me

con-out rotation
to avoid severe
strain in product
F3C F
F

not observed

product

Criegee Chem Ber 1965 98 2339

F

F F

F3C

CF3

con-in rotation:
why?

F
R R

F F

CF3

R=CF3

Knowing this, can you predict how substituted cyclopropyl

tosylates will solvolyze? (This was known in the 1960s, even
though it didn't yet have a cool name: DePuy ACR 1968 1 33.)
Me

major
product

Me

Dolbier JACS 1984 106 1871

Houk and coworkers have studied this extensively (see ACR
1996 29 471 and references therein). To understand their
explanation, consider the donor-acceptor interactions that
develop in both transition states.

OTs

The tosylate solvolyzes to an allyl cation in a disrotatory

fashion:
X

dis-out

Me

Me

Suppose R is an electron-withdrawing group; i.e., a good

acceptor.

con-in

Me
X

If R rotates inwards, a stabilizing

donor-acceptor interaction builds up.

favored

Me

dis-in
=
to *(C-X)
donation is
stabilizing

Me

disfavored
Me

Me
Me

This expels the tosylate to give the E,E-cation in a dis-out

fashion. Another perspective: having the donor on the inside
leads to an "antiaromatic" 3c/4e bond.

Lecture 8: Pericyclic Reactions I

E. Kwan

Practice With Torquoselectivity

1. What is the outcome of this reaction? (Werstiuk, Chem.
Commun. 2002, 648.)
O

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4. However, this reaction is not as selective. Why?

SiMe3

Me3Si

PhMe2C

69:31

Electron-withdrawing substituents prefer the con-in pathway

to maximize donation from the breaking bond into the
adjacent * antibond of the substituent:
O

R
R

PhMe2C

PhMe2C

Evidently, the con-in preference of the TMS group is just not

very strong. With the con-out preference of the alkyl group
in the previous example, the effects reinforce each other.
5. The con-in vs con-out preferences for a variety of groups
have been studied theoretically by Houk (JACS 2003 125
5072). 3-aminocyclobutene is predicted to be quite
selective. Does the amino group prefer con-in or con-out?
NH2

H2N

Carbon is more electronegative. Pauling values: 1.90 (C),

2.55 (Si). Therefore, the Si-C bond (which you can think of
analogous to a C-X bond) is a good acceptor.
3. Given this knowledge, what is the outcome of this reaction?
SiMe2Ph
n-C8H17

The Si-C bonds are good acceptors, so con-in rotation is

preferred:

con-out

con-in

Con-out is preferred by quite a bit (16.2 kcal/mol; B3LYP/

6-311++(3d,3p)). It's argued that the lone pair of the
nitrogen can donate into the * of the breaking bond.
(See next page for NBO analysis.)
6. How about the ammonium derivative?
NH3

H3N

NH3

con-in

con-out

H
R

R3Si

NH2

2. Which is more electronegative, silicon or carbon?

SiMe3

SiR3

Alternatively, one can think of the bulky alkyl group as

preferring con-out rotation. (Murakami ACIE 2001 40 189()

The preference is now only 6.2 kcal/mol. There's no lone

pair, so the preference is purely steric in origin.

E. Kwan

Lecture 8: Pericyclic Reactions I

3-Aminocyclobutene
Con-in mode TS (nN to *C-C: 8.4 kcal/mol)

Chem 106

Con-out mode TS (nN to *C-C: 39.0 kcal/mol)

NBO Cartoon for Torquoselectivity

energy

*CC
sp3

sp3
CC

energy

enhanced
acceptor

*CC

acceptor*
CC
enhanced
donor

bond
breaking

As the bond breaks,

its energy rises (the
bonding electrons
are going up in
energy). (In the limit,
these are two radicals.)

- the antibond goes

down, making it a
better acceptor
- the bond goes up,
making it a better
donor donor
- only stabilizing two
electron interactions
are being invoked

Lecture 8: Pericyclic Reactions I

E. Kwan

The Nazarov Reaction

The Nazarov reaction is a 4 electrocyclization that occurs in
a five orbital system:
O

OH

OH
H

R
R

conrotatory
closure

The resulting allyl cation can be captured by a nucleophile,

eliminated, or rearrange further. Because of the carbonyl
group, these reactions can be catalyzed by Lewis acids.
Can you propose a concerted mechanism for this reaction?
(Trauner ACIE 2003 42 549)
Me2AlCl

Me
H

CO2Et

CO2Et
Me

This is a sort of vinylogous Nazarov reaction with a

concomittant (or possibly stepwise) migration:
R

Me

Chem 106

The Diels-Alder Reaction

Of course, the most famous pericyclic reaction is the DielsAlder reaction. The reaction is not only one of the most
synthetically useful ones known, but has also been the object
of intense mechanistic and computational study.
The prototypical reaction is that between butadiene and
ethylene:

Ea = 27.5 kcal/mol (experimental)

The relatively efficient DFT method B3LYP/6-31g(d) places
this barrier at 23.3 kcal/mol. The good performance of B3LYP
in pericyclic reactions has probably led to its widespread use
in computational chemistry (possibly in unrelated areas where
it might not be so good). (Houk J Phys Chem A 2003 107
11445).
The Dewar-Zimmerman analysis of the concerted pathway is
fairly trivial:
0 inversions, 6,
Hckel-aromatic

Me

R
R

EtO
Me
[Al]

Nazarov: 1 inversion, 4
Mbius-aromatic

EtO
Me
O
[Al]

orthogonal
-systems

cyclopropane: 0 inversions, 2, Hckel-aromatic

However, it also instructive to consider the Fukui frontier

orbital analysis. The idea is that reactions in which the HOMO
of one partner is symmetry-matched with the LUMO of the
other will be allowed.
Think of the HOMO of butadiene and LUMO of ethylene now.
(A reversed choice of HOMO/LUMO gives the same answer.)

Lecture 8: Pericyclic Reactions I

E. Kwan, D.A. Evans

Frontier Orbital Analysis of the Diels-Alder Reaction

The easiest way to draw the HOMO of a -system is to simply
put nodes where the single bonds are:

We can also draw the LUMO this way, by drawing the HOMO
and then adding an extra node to go up one level. For
ethylene, this is rather trivial:

HOMO

Chem 106

Since ethylene is also reacting in a suprafacial manner, we can

denote this reaction "4s + 2s." In general:
m+n

allowed

forbidden

4q

s+a/a+s

s+s/a+a

4q+2

s+s/a+a

s+a/a+s

In this case, this is a (4q+2)-type cycloaddition (q=1), which

can proceed with suprafacial/suprafacial (s+s) geometry as
drawn. In principle, it could also occur in an antarafacial/
antarafacial mode:

LUMO

Now we line up the reactants and see that the symmetries

are matched:
matched phases,
symmetry-allowed

We can consider the two termini of each reactant, and ask

if the other reactant is interacting with lobes that are on the
same side ("suprafacial") or the opposite side ("antarafacial").
For example, for butadiene:

Of course, this is not a very good geometry for this reaction,

which just illustrates the point that just because a reaction
pathway is symmetry-allowed doesn't mean it actually happens
that way.
Dienes and Dienophiles
In a "normal electron demand" Diels-Alder, the diene is
electron-rich while the dienophile is electron-poor, so it
makes sense to consider the HOMO of the former and
the LUMO of the latter:

MeO

lobes being interacted

with are on the same
side, so suprfacial

CO2Me

CO2Me

diene:
electron
rich

MeO

dienophile:
electron
poor

Lecture 8: Pericyclic Reactions I

E. Kwan

Dienes and Dienophiles

In contrast, "inverse electron demand" Diels-Alder reactions
occur with electron poor dienes and electron rich dienophiles.
These are less common, and usually involve heteroatoms:
CO2Et

Regioselectivity
Thinking of Diels-Alder reactions in HOMO-LUMO terms can
help us understand the issue of regiocontrol:

MeO

diene:
electron
poor

MeO

OEt

dienophile:
electron
rich

N
OEt
SO2Ph

>20:1 regiocontrol
>20:1 endo/exo

CHO

CHO

CO2Et

N
SO2Ph

Chem 106

MeO

MeO

favored

CHO

disfavored

The sense of regiocontrol is dictated by the relative

sizes of the HOMO and LUMO lobes:

small

Boger JACS 1995 117 11839

We will examine the issue of selectivity momentarily. Both the
"normal" and "inverse" modes decrease the HOMO-LUMO gap:
LUMO

LUMO
HOMO
acrolein

butadiene

ethylene

large
B3LYP/6-31g(d)

LUMO
HOMO
HOMO
vinyl ether

butadiene

ethylene

Lecture 8: Pericyclic Reactions I

E. Kwan

Regioselectivity
In general, one can divide vinyl substituents into three
categories:

Chem 106

1-Substituted Dienes

X: electron withdrawing (e.g., Cl)

C: conjugating group (e.g., vinyl)
Z: electron donating (e.g., OMe)
Houk has calculated the energies of such systems and plotted
them on the same scale (eV, Fleming, ref. edition, pg 297).
Each circle represents the size, or more precisely, the
coefficient, of one p orbital (they're not s orbitals). In general,
1-substituted dienes: form "ortho" adducts
2-substituted dienes: form "para" adducts
X-diene + X-dienophile: "meta" products, but slow reaction
Dienophiles

more reactive
here

X/C/Z

2-Substituted Dienes

C/Z

attacks
here

attacks
here

more reactive
here
X/C/Z

Lecture 8: Pericyclic Reactions I

E. Kwan

The Endo Rule

The classic example of exo vs. endo selectivity is the DielsAlder reaction between cyclopentadiene and maleic anhydride:
O

favored by
3.8 kcal/mol
over

O
O

endo: CH2
over the ring
(disfavored)

This is the "maximum accumulation of double bonds" proposed

by Alder and Stein (Liebigs Ann Chem 1934 514 1). Woodward
and Hoffman proposed that this endo preference is the result
of secondary orbital interactions (SOIs) (JACS 1965 87 4388):

HOMO

secondary
interaction

primary
interaction

Unfortunately, the existence of SOIs is controversial:

"The Existence of Secondary Orbital Interactions." Schleyer
et al. J Comput Chem 2006 28 344. (for SOIs)
"Do Secondary Orbital Interactions Really Exist?" Salvatella
et al. Acc Chem Res 2000 33 658-664. (against SOIs)

endo: diene
over the ring
(favored)

Chem 106

The endo preference has been variously attributed to:

- van der Waals attractions
- charge transfer
- volumes of activation
- etc., etc...
For example: cyclopropene + butadiene (JOC 1989 54 5264)
favored
over

In fact, only one stereoisomer can be detected by NMR. The

SOI interpretation is that the CH2 group has -character (to
be discussed in a later lecture) and this engages butadiene's
LUMO:
LUMO

LUMO

O
O

HOMO
Instead of considering the LUMO to be a two-center system
H
analogous to ethylene, in this picture, the LUMO is a four-center
system including two "empty" p orbitals on the carbonyl carbons.
This four-center system still has two electrons in it, so the LUMO
However, some people think that cyclopropene's CH2 repels
has one node in it.
butadiene's CH2's in the exo transition state or that C-H/
hydrogen bonding is involved in the endo transition state.

Lecture 8: Pericyclic Reactions I

E. Kwan

Synthesis of Endiandric Acids

A beautiful example of the power of electrocyclic reactions
and Diels-Alder cycloadditions is the synthesis of the endiandric
acids:
Ph

Ph
H

CO2H

HO2C
H

con

H
CO2H

H
H

endiandric acid C

Ph

H
H
HO2C

6
H

dis
CW/CCW

Ph

Black's Proposal
The endiandric acids are secondary metabolites from an
Australian plant. Interestingly, these compounds are all
found as racemates even though they have eight stereoeight stereogenic centers. Black proposed that

The termini are Z,Z-substituted, but you can see what's

happening better if you consider the E,E-hydrogens:
6

endiandric acid D

This is the work of Black, who proposed the biosynthetic

relationship between these compounds, and Nicolaou, who
proved it in the lab (Classics in Total Synthesis I, Nicolaou and
Sorenson, Chapter 17).

these compounds arise from achiral, polyunsaturated

precursors, which cyclize through a nonenzymatic
8/ 6/ Diels-Alder pathway.

Of course, this is not enzymatic, so both enantiomers are

produced. Next, there are two disrotatory 6 possibilities:

X
H
H

endiandric acid B

endiandric acid A
H

Here is the idea drawn out. First, a conrotatory 8 cyclization

occurs:
8
X Y

Chem 106

dis
H CW/CCW

CW CCW
The reverse case gives a diastereomer:
6
dis
CCW/CW
X

H
X

inverted
maintained

And if either X or Y contain a dienophile, it can react in an

intramolecular sense with the cyclohexadiene.

Lecture 8: Pericyclic Reactions I

E. Kwan

Chem 106

Synthesis of Endiandric Acids A-D

E,E

E,E

Z,Z

Z,Z

CO2H

CO2H

CO2H

8
con

Ph

8
con

Ph

Ph

Ph

8
con

CO2H

CO2H

CO2H
Ph

Ph

RO2C

Ph

diastereomers

endiandric acid D

HO2C

- chart adapted from

Classics I, page 266)

H
H

HO2C

endiandric acid F

Ph
H

H
CO2H

endiandric acid A

endiandric acid G
Diels-Alder

HO2C
H

H
H

Ph

Diels-Alder

Diels-Alder

CO2H

HO2C

endiandric acid E

Ph

diastereomers

H
H

CO2R

diene and dienophile

on opposite sides;
can't do Diels-Alder

6
dis

6
dis
H
H

CO2H
Ph

6
dis

6
dis

H
H

8
con

enantiomers

enantiomers

Ph

CO2H

H
H

H
CO2H

endiandric acid B

endiandric acid C

Ph