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Polytechnic University of Bucharest

Faculty of Engineering in Foreign Languages


Chemical Engineering Division

Student Communications
May 2003 Edition

Stereochemical
Aspects of
Pericyclic Reactions

Eugen S. Andreiadis
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

1. Introduction

In organic chemistry there exist a number of reactions known as pericyclic† reactions, the
stereochemistry of which depends on the symmetry of the interacting molecular orbitals
(MOs) and not on the overall symmetry of the molecules. These reactions are situated
apart from the more common heterolytic and homolytic transformations since they
don’t involve intermediates of any kind, ionic, radicalic or carbenic. The bond-breaking
and bond-formation process occur (not necessarily synchronous‡) through a cyclic
transition state (TS) accounting for a so-called concert mechanism, the result of which is
the transposition of bonds along a closed curve. They are further characterised by the
fact that their rate is unaffected by the solvent polarity (unless the reactants are charged
– see 1,3 dipolar cycloadditions), the presence of radical initiators (or inhibitors) or
catalysts (exceptions are some acid-catalysed Diels-Alder reactions), and that they take
place thermally or photochemically. The reactions have high (sometimes even total)
stereoselectivity and stereospecificity under kinetically controlled conditions and are of
special interest in organic synthesis. A classical example is the Diels-Alder reaction
between a diene and a substituted alkene (dienophile) in which the 4π-electrons of the
diene and the 2π-electrons of the alkene reorganise thermally through a set of
interacting MOs to the 4σ and 2π-electrons of a cyclohexene (reaction (1)).

X X X

(1)
Y Y Y

Woodward and Hoffmann were the first to deduce a series of rules19-22 to explain
and predict the stereochemistry of the products obtained and the reaction conditions
necessary for a certain transformation to take place. The rules are based on the principle
of conservation of orbital symmetry which may be briefly stated as follows: the
transformations in which the symmetry of the MO is conserved (i.e. the orbitals remain
in phase and thus maintain a degree of bonding during the process) involve a relatively
low energy TS and are called symmetry allowed. On the other hand, in the transformation
in which the symmetry of the orbitals is destroyed by bringing one or more orbitals out
of phase, the energy of the TS becomes very high due to an antibonding interaction and
the reaction is symmetry forbidden. Slight perturbations of the molecular symmetry
caused by a substituent (e.g. CH3) are generally ignored since the mechanism of the
process remains the same. Another important rule referring to the reaction conditions
states that a thermally allowed transformation is forbidden photochemically, and vice
versa, a photochemically allowed process is forbidden thermally, moreover thermal and


from Gr. Perikyklos (peri = around; kyklos = ring).

each bond undergoing change need not necessarily have been made or broken to the same extent by the time the
TS has been reached.

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Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

photochemical reactions give opposite stereochemistry. However, it is important to note


that a forbidden reaction may still take place if nothing easier is available. Three cases
are possible4, with the choice depending on various factors:

a) a nonconcerted reaction may occur to form a discrete intermediate;


b) enough energy may be added to force the reaction to produce via the symmetry forbidden
pathway;
c) the reaction may follow a symmetry-allowed pathway to give an excited state of the
product.

What is meant by forbidden is that the interaction of the orbitals presents an


energy barrier that the ‘allowed’ reactions do not have. It has turned out that, in many
cases, this energy is quite high – examples of allowed transformations are abundant, but
forbidden reactions are few and far between. Equally, the statement that a reaction is
symmetry-allowed does not necessarily guarantee that it will proceed readily in
practice: the attainment of the required geometry in the TS could well be inhibited by
steric factors, such as the size of a ring or the presence of bulk substituents.

Three different models with different degrees of sophistication can now be used
to explain the results of pericyclic reactions: (a) the method based on the principle of
orbital symmetry conservation throughout the reaction (Woodward-Hoffmann); (b) the
method based on aromatic stabilisation of the TS according to Hückel’s MO theory
(Zimmerman and Dewar); and (c) the frontier molecular orbital (FMO) method
(Woodward-Hoffman, Fukui) which, although the simplest, is capable of explaining the
stereochemistry of all pericyclic reactions and is therefore adopted in the present text5.

In this model, one is interested only in the interaction between the highest
occupied molecular orbital (HOMO) of one reactant and the lowest unoccupied molecular
orbital (LUMO) of the other. When two molecules (or appropriate segments thereof)
approach each other in a reaction, pairs of filled MOs which are close in energy interact
to give pairs of hybrid MOs, one bonding and the other antibonding. The energy gained
by a bonding orbital is always slightly less than the energy lost by the antibonding one
so that the energy of the system increases slightly (four electrons are to occupy the two
hybrid MOs) and the cumulative effect constitutes the major part of the activation
energy of the reaction. At the same time, the HOMO of one molecule interacts with the
LUMO of the other but since there are only two electrons (usually), they are
accommodated in the bonding hybrid orbital lowering the activation energy to an
appreciable extent. A third factor, namely, coulombic interaction, has also to be
considered when dealing with charged reacting species. The three combined effects
account for the activation energy of reaction. In order to have appreciable interaction
between the HOMOs and the LUMOs (which is the major consideration in pericyclic
reactions), they must be of comparable energies and above all must belong to the same
symmetry type.

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Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

Theoretically, all pericyclic transformations may be regarded as cycloaddition


reactions or their retrogressions, but they are usually classified into several categories:
electrocyclic, cycloaddition, sigmatropic, cheletropic, and group transfer reactions.
Following, only the first two of these divisions will be analysed and emphasis will be
put on their stereochemical aspects.

2. Electrocyclic reactions

An electrocyclic reaction is one in which the two terminals of a linear conjugated π-


electron system are joined through a single bond, the net change being the conversion of
a π-bond into a σ-bond, or a reversion of this process, i.e. the conversion of a σ-bond
into a π-bond with concomitant ring-opening1. Such a transformation can be
represented generally as below (Figure 1), where n indicates the number of trigonal
carbon atoms in the conjugated polyene and also the number of π-electrons.

CH n
CH n-2

Figure 1. Schematical representation of an electrocyclic reaction

2.1. Frontier Molecular Orbital Approach

In electrocyclic reactions, only one reactant (i.e. a polyene or in the reverse


reaction, a cycloalkene) is involved and thus only the HOMO needs to be considered. If
we take the example of the interconversion of 1,3,5-hexatriene and cyclohexadiene (2),
we can represent the HOMO of the triene as in Figure 2.

(2)

To form a C-C bond on cyclisation, the p orbitals on the terminal atoms have to
rehybridise to sp3 orbitals, and each rotate through 900 to allow of their potential
overlap.

HOMO conrotatory antibonding


(Ψ3) ∆ interaction

HOMO disrotatory bonding


(Ψ3) ∆ interaction

Figure 2. Conrotatory and disrotatory thermal cyclisation of hexatriene

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Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

This rotation could happen in the same direction (conrotatory), or in opposite directions
(disrotatory). Conrotatory movement results in the overlap of sp3 orbitals of opposite
phase, leading to an antibonding situation, while disrotatory movement results in the
overlap of sp3 orbitals of the same phase, leading to a bonding interaction and thus to
the formation of cyclohexadiene. In thermal electrocyclic reactions of a 6 π-electron
system, therefore, only disrotatory motion is allowed and the stereochemistry follows
accordingly (see subchapter 2.2).

On photochemical ring-closure, irradiation results in the promotion of an


electron into the orbital of next higher energy level, i.e. Ψ3 → Ψ4 and the ground state
LUMO (Ψ4) thus now becomes the HOMO* (Figure 3). It is now conrotatory motion that
results in the overlapping of sp3 orbitals of the same phase and a different
stereochemistry follows.

HOMO* conrotatory bonding


(Ψ4) hν interaction

HOMO* disrotatory antibonding


(Ψ4) hν interaction

Figure 3. Conrotatory and disrotatory photochemical cyclisation of hexatriene

If we consider now the case of a 4π-electron system, for example the


interconversion of 1,3-butadiene and cyclobutene (3),

(3)

it is this time conrotatory movement that results in a bonding situation for the ground-
state diene (Figure 4). In the case of photochemical interconversion (which tends to lie
over in favour of the cyclobutene), irradiation of the diene will result in the promotion
of an electron into the orbital of next higher energy level (i.e. Ψ2 → Ψ3) and the ground
state LUMO becomes the HOMO*. It is disrotatory motion that results now in a bonding
interaction and the formation of cyclobutene.

HOMO conrotatory
(Ψ2) ∆

HOMO* disrotatory
(Ψ3) hν

Figure 4. Thermal and photochemical cyclisation of butadiene

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Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

This difference in behaviour derives from the way in which the phases of the
MOs at the termini of the conjugated electronic system are arranged, i.e. their
symmetry. The same phase demand disrotatory movement for bond-making/bond-
breaking to occur, while opposite phases demand conrotatory movement for bond-
making/bond-breaking to occur. The selection rules gathered in Table 1, derived by
Woodward and Hoffmann19, may be stated for all electrocyclic reactions.

Table 1 – Woodward – Hoffmann rules for electrocyclic reactions

n (no. of π- Condition
Geometry
electrons) s
∆ conrotator
4k y
hν disrotatory
∆ disrotatory
4k+2 hν conrotator
y

Electrocyclic reactions, particularly the ring opening of unsaturated cycloalkenes


to polyenes, may be regarded as cycloadditions in which a σ bond and π bond (or a
conjugated system) constitute the two components in addition reaction1. Some notations
that are used in cycloadditions reactions may be defined here to indicate the mode of
addition. If a component undergoes addition (i.e. forms bonds) on the same face, it is
called a suprafacial component, while if a component undergoes addition on opposite
faces, it is called antarafacial component. The two modes of addition are known as
suprafacial and antarafacial respectively. Following this definition, conrotation involves
an antarafacial and disrotation a suprafacial interaction between the two termini of the
reacting species in electrocyclic reactions, as can be clearly seen from Figure 5.

suprafacial interaction antarafacial interaction


disrotatory motion conrotatory motion

Figure 5. Suprafacial and antarafacial interactions in electrocyclic reactions

For example, in the thermal conrotatory ring opening of cyclobutene (Figure 6),
the σ-HOMO of the σ component interacts with the π-LUMO of the π component, the
former behaving as a suprafacial component and the latter as an antarafacial one. The
reaction is designated [σ2s+π2a] (where s and a stand for supra- and antarafacial
respectively). Alternatively, the same reaction may be considered in terms of interaction
between the σ-LUMO (i.e. σ*) and the π-HOMO and thus denoted as [σ2a+π2s].

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Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

π-LUMO a ∆
[σ2s + π2a]
σ-HOMO s

π-HOMO s ∆
[σ2a + π2s]
σ-LUMO a

Figure 6. Thermal ring opening of cyclobutene as a cycloaddition reaction.


Suprafacial / antarafacial nomenclature

2.2. Stereochemical aspects

The stereochemistry of an electrocyclic reaction derives from the conrotatory or


disrotatory mode of ring closure (or ring opening) as permitted by the system under
consideration and the conditions of reaction (thermal or photochemical). For each mode
of reaction, there are two distinct possibilities: the disrotatory process can occur inwards
or outwards, and similarly the conrotatory process can occur towards left or towards right
(Figure 7).

disrotatory R R
inwards
R R

disrotatory
outwards
R R
R R

conrotatory R
twrds right
R R
R
Figure 7. Different possibilities of disrotatory
conrotatory R and conrotatory movement and their
R R
twrd left stereochemical outcome
R

In cases where the two possibilities of a mode give the same product due to an
inherent symmetry of the system or one possibility is forbidden by molecular geometry
or by steric interaction in the TS, almost total diastereoselectivity results.

2.2.1. Four-member rings. The dienes and the cyclobutenes can be interconverted
through electrocyclic transformations. However, the cyclobutenes are
thermodynamically less stable than their partners by some 50 kJ mol , and so the ring
–1

closure cannot practically occur thermally due to reversibility of the process. On the
other hand, the dienes are absorbing light at a much higher wavelength than that of
ordinary alkenes, and it is thus possible for the photochemical cyclisation of dienes to
occur irreversibly. The possible outcomes of such processes, considering the
stereochemistry of the products involved, are represented in Figure 8. (For uniformity,
all disrotatory motions are inward and all conrotatory motions are toward right.)

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Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

hν ∆
disrot conrot

hν ∆
disrot conrot

hν ∆
disrot conrot

Figure 8. Stereochemistry of electrocyclic reactions: four-member rings

Some interesting transformations are depicted below (reactions (4) and (5)).

H O
O O
hν ∆
O disrot O conrot
(4)
impossible
H O
1 2 3
<100o hν
conrot disrot (5)
H H 4 H H
6 5

The lactone 1 undergoes irreversible photochemical cyclisation to give 2. The


reverse reaction cannot occur through the excited pathway because radiation of
convenient wavelength is unavailable, and neither can occur through the thermal
pathway since the conrotatory movement required leads to the unlikely looking lactone
3 containing a trans double bond. In reaction (5), the cyclobutene 5 obtained similarly
through an electrocyclic process from diene 4 is stable at temperatures above 250ºC
because the thermal conrotatory ring opening would also give a geometrically-
impossible trans-cyclohexenic ring. In comparison, the trans-substituted cyclobutene 6
readily undergoes thermal bond cleavage to yield the diene 4.

Dewar benzene 7 was obtained23 through the following reaction (6), using
electrocyclic ring closure.

O
O
hν Pb(OAc)4
O O (6)

O O 7

The direct formation of Dewar benzene derivatives by irradiating the corresponding


aromatic derivatives24 can be accomplished, in spite of the high conjugation energy of

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Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

the latter, for compounds substituted with bulk groups for which the transformation in
Dewar benzene brings a steric relief (reaction (7)).

tBu tBu
tBu
tBu

(7)

tBu tBu

It is interesting to observe that, since benzene is with ~250 kJ mol–1 more stable
than Dewar benzene, the conversion should be facile. However, an activation energy of 96 kJ
mol–1 is required for such a transformation to take place25. The reason, as in the case of
compound 5, is the fact that the allowed thermal conrotatory ring opening produces a
cyclohexatriene with a trans double bond (reaction (8)).

H H
H
∆ not
H
(8)
H H
7

As compared to the electrocyclic ring closure, the ring opening process of four-
member rings has no thermodynamic restrictions, since it goes towards the more stable
product. Thus, it can take place thermally as well as photochemically. The thermal
opening of cis-3,4-dimethylcyclobutene 8 by either of the two possible conrotatory
motions gives Z,E-1,4-dimethylbutadiene, while the photochemical process gives the
E,E-isomer only through a single disrotatory motion in which the substituents move
outwards, because the inward movement implies excessive steric repulsion (reaction
(9)).

Me Me
Me

H hν H ∆ H
Me (9)
H or Me
H
E, E 8 Z, E
Me H

Similarly, the trans-cyclobutene 9 gives only E,E and not Z,Z-butadienes on thermal ring
opening, as shown in reaction (10). However, the outward (or inward) movement of a
substituent is not controlled only by steric factors, but also by electronic effects. Thus an
electro-releasing substituent such as F shows a high affinity for outward rotation26, as
illustrated by reaction (11) in which the fluorinated cyclobutene 10 undergoes ring
cleavage to yield preferentially the diene 11.

Me H
H

H ∆ Me ∆ Me
Me x (10)
H Me
H
E, E 9 Z, Z
Me H

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Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

CF3 F
CF3

F ∆ F ∆ CF3
x F (11)
F F
F
10 11
F F

If we replace the methyl groups of cyclobutene 8 with a polymethylene chain as


in bicycloalkene 12, conrotatory ring opening should give rise to a cyclodiene containing
one E double bond (see reaction (12)).
H
H

H (12)
( )n conrot H ( )n
12

However, this would happen only if the chain is long enough. If it has less than 8
members (as in 13), ring opening takes place only at high temperature (13) through a
non-concerted mechanism which involves the disrotatory movement as the only one
possible geometrically.

H
Me
Me

(13)
disrot
Me Me
H 13

2.2.2. Six-member rings. In hexatrienes-cyclohexadienes interconversion, the


reactions occur thermally disrotatory and photochemically conrotatory. The various
transformations of different isomers of 1,6-dimethyl hexatriene and their stereochemical
outcome are shown in Figure 9.

hν ∆

conrot disrot
trans cis

hν ∆
conrot disrot
cis trans

Figure 9. Stereochemistry of electrocyclic reactions: six-membered rings

These reactions are somewhat different than their four-membered ring


counterparts. First, the difference in thermodynamic stability between the triene and the
cyclodiene is lower than in the previous case, and thus thermal process is an
equilibrium one. Moreover, both the triene and the cyclodiene absorb light at similar
wavelengths, making it impossible to shift the equilibrium eitherway (at least in usual
experimental conditions). However, the triene usually predominates in the reaction

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Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

mixture, both for the thermal as well as for the photochemical transformations. Second,
the polyene must be so disposed as to bring the two termini within reaction distance,
which is equivalent to all-cis geometry except at the marginal double-bonds. However,
in the photochemical conditions, the cis-trans equilibrium occurs easily, and thus the
geometry of the double bonds is of less importance.

It can be observed from the Figure 9 that the disrotatory ring closure of any
polyene brings the two outer and the two inner substituents at the termini close to each
other, i.e. to the same side (cis) of the newly formed σ bond, while the conrotatory ring
closure does the opposite.

The steric repulsion mentioned in the reaction (9) also applies here, forcing the
disrotatory thermal ring opening of the cis isomer of 5,6-dimethyl-cyclohexadiene to
follow only one pathway with both the methyl substituents moving outwards and
forming two marginal trans double bonds. But when the two substituents are apart of a
ring as in the case of bicyclic diene 14, this is no longer the case and the thermal ring
opening takes place inwards, giving an all-cis cyclotriene 15 (reaction (14)). This
happens because there is no longer any steric hindrance and two trans double bonds
cannot be accommodated in a ring unless this is a large one. In the interconversion of
norcaradiene (14, n=1) and cycloheptatriene (15, n=1), the equilibrium is shifted towards
right27. For n>1, interconversious among 14 and other compounds, such as 16 and 17, are
possible.

(CH2)n (CH2)n

14 15

hν hν
(14)

(CH2)n
(CH2)n

17 16

The thermal and photochemical transformations of steroidic derivatives further


illustrate the stereochemistry of these reactions. For example, consider the following
scheme (15) of the processes taking place upon irradiation and heating of ergosterol 18,

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Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

R R R
Me Me Me

Me

1 Me 7

2 6
con [1,7] 20
3
HO HO 5 HO (vit D2)
4 19
18 con hν (precalciferol) ∆
(ergosterol) hν con dis (15)
R
Me
R R R
Me Me Me

Me hν Me Me
con

HO Me HO HO

21 23 24
(lumisterol) (isopyrocalciferol) (pyrocalciferol)
HO 22
(tachisterol)

when a mixture containing ergosterol, precalciferol 19, vitamin D2 20, lumisterol 21 and
tachisterol 22 is obtained28. No matter the starting product, the same equilibrium is
reached, with ergosterol in the smallest yield. What is interesting is that the
photochemical ring closure of 19 to give ergosterol occurs reversibly, while the same
reaction of 22 to yield 21 is irreversible. The reversible process is to be expected, but 22
having a trans double bond cannot react directly, being necessary for it to be converted
first to an excited state in which the rotation around the trans double bond can be
accomplished. This rotation occurs in the direction depicted in the scheme, leading to
lumisterol in order to avoid the steric repulsion between the two methyl groups. Ring
opening of 21 is also a conrotatory process in photochemical conditions and the only
geometrically-allowed pathway gives the precalciferol 19. This can be thermally
converted through a [1,7] sigmatropic transformation to vitamin D2 20 which, on its
turn, can suffer thermal cyclisation to give 23 and 24 in molar ratio 1:1.

Eight-member and higher even-member rings can be treated in a similar fashion.


An interesting example is given in (16).

Me

Me Me
2 H2 Me ∆ ∆
Me conrot disrot
(16)
Me
Me
26 H 27

Me 25

During the syn-hydrogenation of biacetilene 25, surprisingly, the bicycle-


octadiene 27 was isolated. This is explained by the initial formation of tetraene 26,
which undergoes two successive fast conrotatory and disrotatory cyclisations. In this

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Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

case, the stereoselectivity of the reaction was greater than the sensitivity limits available
in conventional product analysis.

2.2.3. Three-member rings. In the case of the even-member rings, the


electrocyclic reaction requires neutral molecules, but for the odd-member rings, it is
necessary to have cations, anions, or radicals. The selection rules also apply to the
concerted reactions of such species. A cyclopropyl cation opens up to an allylic cation (a
2π-electron system) through a thermal disrotatory mode, while a cyclopropyl anion (a
4π-electron system) gives rise to an allylic anion through a thermal conrotatory mode.

For 2,3-disubstituted cations 28, the disrotatory ring opening may proceed in two
ways and after quenching of the allyl cation, lead to either an E or Z olefin (reaction
(17)).

R R R A
A R R
A- outwards inwards A-
R (17)
E R R Z
R 28

E-Z diastereoselectivity is also controlled by other factors, notably by the relative


configuration of the cyclopropane. The preferred direction is the one in which the
emerging lobes of the disappearing σ bond in cyclopropane can compensate (during the
course of the transformation of the σ-bond to a delocalised π-orbital) for the gradual
development of a positive charge at the site of the leaving group (anchimeric assistance
of the σ-bond, see Figure 10). This requires that the substituents cis to the leaving group
(X) turn inwards (approach each other) following the Z pathway, whereas those which
are trans turn outwards (E pathway).

R R R
R - X -
-X R X R
-X

Z route E route
R
X R

Figure 10. The anchimeric assistance of the σ-bond and its possible outcomes.

A proof for this is the difference in the rates of solvolysis of the two isomeric tosylates
29 and 30 where the approaching methyl substituents render the TS derived from the cis
tosylates unfavourable (reaction (18)). The relative acetolysis rates of 29 and 30 are
4500:1 at 1500C.

Me Me Me H
H Me
outwards inwards
Me H H Me OTs H
H
krel = 4500
H
krel = 1 (18)
H Me
H OTs H H
29 Me 30 H

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Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

Even more dramatic is the behaviour of endo- and exo-isomers 31 and 32


(reaction (19)). The endo isomer smoothly undergoes solvolysis at 1250C with
concomitant ring cleavage, while the exo isomer is stable up to 2100C. In this case, it is
the outward movement of the substituents which is prevented since they are
incorporated in a ring. Furthermore, if such movement could occur, the final product
would be an E-cycloheptene (geometrically impossible).

Cl H H H
H inwards H outwards
H Cl

krel = 11000 krel = 1


(19)
H
H H H
endo 31 exo 32

Another similar example is presented in reaction (20). Here, the leaving group is
the endo-Cl substituent, despite it being rather hindered and less reactive that the exo-
Br substituent.

H Cl OH
H Br
AgNO3
Cl X Br (20)
H2O
H
OH 33 H

3-Membered rings with 4 participating π-electrons behave, as expected, in the


opposite manner as compared with corresponding cations. An example (21) is the ring
opening of two diastereomeric aziridines. The resulting 1,3-dipolar ion is subsequently
trapped by a cycloadditions reaction with dimethyl acetylenedicarboxylate, a very good
dipolarophile.

Since the rate of interconversion of the intermediate zwitterions (by C=N+


rotation or carbanion inversion) is slower compared to the rate of cycloaddition, the
later process preserves the geometry of the parent species, and thus the overall reaction
sequence is stereospecific.

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Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

Ar

N
H H
100º hν

Ar
con ROOC COOR dis Ar

H N COOR ROOC N COOR

ROOC H Ar H H
hν N 100º
COOMe H COOR COOMe
dis con
ROOC H (21)
COOMe COOMe

Ar Ar

N N
H COOR ROOC COOR
ROOC H H H

MeOOC COOMe MeOOC COOMe

3. Cycloaddition reactions

A cycloaddition reaction is one in which the terminals of two (or more)


independent and conjugated π-systems combine themselves to form new σ bonds and
thus an additional ring1. The reverse process is known as cycloreversion or retro-
cycloaddition and it proceeds with the breaking of σ bonds. Depending on whether the
two components belong to different molecules or the same, the cycloaddition may be
inter- or intra-molecular. The reaction can be schematically depicted as in Figure 11,
where m and n represent the number of conjugated π electrons in the two components,
respectively, and also the number of trigonal (sp2) carbon atoms.

(CH)m (CH)n (CH)m-2 (CH)n-2

Figure 11. Schematically representation of a cycloaddition reaction

With such a notation, the process can be called a [m+n] addition. The
nomenclature can be extended to include the nature of the participating electrons (σ, π
or ω, the latter being used for electrons occupying a single interacting atomic orbital, as
in carbenes, carbanions or carbocations) and the mode of addition (supra or
antarafacial) on each component, e.g. [πms+πna] addition.

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Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

3.1. Frontier molecular orbital approach

In cycloadditions two components are commonly involved, and the feasibility of


a particular process will be determined by whether overlap can take place between the
HOMO of one component and the LUMO of the other.

The thermal cycloaddition of butadiene and a substituted ethylene (dienophile)


is a classical example of a Diels-Alder reaction (1). The HOMO of butadiene (ψ2) and the
LUMO of ethylene (π*), as also the LUMO of butadiene (ψ3) and the HOMO of ethylene
(π), are represented in Figure 12.

HOMO LUMO
Ψ2 Ψ3

LUMO HOMO
π∗ π

Figure 12. HOMO-LUMO interaction in thermal [π4S+π2S] cycloaddition

It can be observed that, whichever component has the HOMO or the LUMO, this
situation is a bonding one and thus the [π4S+π2S] cycloaddition is thermally allowed.
Since suprafacial-suprafacial (s,s) and antarafacial-antarafacial (a,a) combination give
here the same result, [π4a+π2a] addition is also thermally allowed and proceeds
simultaneously although less effectively, due to unfavourable geometry.

In the cycloaddition of the two substituted ethylene molecules to cyclobutene,


the ground state HOMO-LUMO combination does not permit thermal (s,s) addition
(Figure 13a.)

HOMO HOMO
π (hν) π∗

LUMO LUMO
π∗ π∗
(a) (b)

Figure 13. HOMO-LUMO interactions in thermal (a) and photochemical (b) [π2s+π2s] cycloadditions

However, the cyclodimerisation takes place in the excited state interaction


(photochemical conditions) as can be seen from Figure 13b. The radiant energy is used
to promote an electron of one component into the orbital of the next higher energy level,
i.e. π→π*, and its ground state LUMO (π*) thus now becomes the HOMO, making the
[π2s+π2s] cycloaddition photochemically allowed.

16
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

On the other hand, the ground state interaction allows the [π2s+π2a] cycloaddition
(dotted lines in the Figure 14). In order to afford the orbitals’ overlap, the process goes
through an orthogonal transition state, but even in this disposition the overlap is only
minimal and worsened by the interfering effect of the substituents X and Y. Thermal
[π2s+π2a] are thus very rare.

LUMO
X Y Y
HOMO X X
X 4
X X
X Y
π Y Y ∆ X X X X
1 Y 1 2 Y
2
LUMO Y Y Y Y Y Y 3 4
Y X
π∗ X X HOMO 3
Y
X Y
X

Figure 14. HOMO-LUMO interaction in thermal [π2s+π2a] cyclisations

Such observations lead to the conclusion that the system with total number of
(4k+2) conjugated π-electrons undergo thermal (s,s) cycloaddition, while those with 4k
electrons undergo photochemical (s,s) cycloaddition (Table 2). This prediction is the
particular form of the generalised Woodward-Hoffmann rule according to which a ground
state pericyclic change is symmetry allowed (and so facile) when the total number of
(4i+2)s and (4j)a components, on short, A and B, respectively, is odd. Thus in the
cyclisation of butadiene and ethylene, ethylene serves as the (4i+2)s component (i=0) and
butadiene as the (4j)s component (j=1), i.e. A=0 and B=0 making the total odd and
therefore the thermal ground state addition is symmetry allowed.

Table 2 – Woodward - Hoffmann selection rules for cycloadditions

m+n (no. of Condition


Geometry
π-electrons) s
hν supra - supra
4k ∆ supra -
antara
∆ supra - supra
4k+2 hν supra -
antara

A few relevant points emerge from the above discussion1:


a) for a two component cycloaddition the maximum number of modes of addition is 22:
(s,s), (s,a), (a,s), (a,a); for p components, the number is 2p.
b) only in the (s,s) mode of the addition the two π-systems approach in parallel planes.
In all other modes of addition, the planes are perpendicular.
c) the configuration of the marginal atoms is retained in the case of a suprafacial
component, and is inverted in the case of an antarafacial one.
d) for m>2 or n>2, there are two modes of (s,s) additions, one giving an endo product
and the other an exo product.

17
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

e) the [π4S+π2S] addition is the most facile closely followed by the [π4a+π2a] addition.

3.2. Stereochemical aspects

Concerted cycloadditions are almost totally stereospecific and the


stereochemistry is decided by the mode of addition as permitted by the Woodward-
Hoffmann rules. Some examples are discussed in the following pages.

3.2.1. [2+2] Additions. This type of reactions may involve two alkene fragments
undergoing dimerisation to give cyclobutane derivatives, or one alkene fragment and
another compound containing a double bond (such as ketenes or cumulenes). For the
particular case of the interaction between two molecules of cis-2-butene, Figure 15
presents all the theoretical modes of [π2+π2] addition and their stereochemical outcome2.

Me Me
Me Me Me Me
Me Me s,s s,s
hν hν
Me Me Me Me
Me Me Me Me

Me Me
Me Me Me Me
Me Me s,a s,a
∆ ∆
Me Me Me Me
Me Me Me Me

Me Me
Me Me Me Me
Me Me a,a a,a
hν hν
Me Me Me Me
Me Me Me Me

Figure 15. Possibilities of [π2+π2] addition in the case of cis-2-butene

Thermal [π2s+π2a] cycloaddition leading to cyclobutanes are rare, however,


because of the geometrical restraint in the orthogonal TS discussed before. But if the
double bond in the reacting species is twisted about its axis so that the two p orbitals are
no longer parallel and coplanar (as in compound 34 obtained by the photochemical
[π4s+π4s] addition of benzene and butadiene), there is better overlap of the FMOs and the
addition becomes facile (reaction(22)).

+

H H ∆ (22)
2 mol

34 35

18
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

Actually, the intermediate adduct 34 spontaneously dimerises to 35. In this final


product one side of the cyclobutaric ring retains the trans configuration of the
suprafacial component, while the other becomes cis because of the antara interaction of
the copartner29 (the upward hydrogen atoms are depicted by thick points).

Many of the photochemical [2+2] cycloadditions proceed through biradical or


ionic (in any case, non-concerted) mechanisms, particularly with chloro- and fluoro-
olefins2. A few synthetically useful [π2s+π2s] additions are known (e.g. reaction (23)).

H Me
Me
hν (23)
Me
Me H 36
O O

The process takes place from left to right in spite of the formation of strained
cyclobutanes 36. The reverse reaction is also governed by the W-H rules, and to go back,
the product would have to absorb light. But since it has now lost its π bond, it doesn’t
have any low-lying empty orbitals into which light can promote electrons.

The photochemical cycloreversion of butane can, however, be accomplished by


incorporating into the molecule a double bond serving as photon trap (37, reaction (24)).

hν H
(24)
H H 37
H

Conformational constrains limit the possibilities in the intramolecular reactions.


Formation of the cycloadduct 38 with the methyl group on the cyclobutanic ring on
adjacent carbon (1,2 rather than 1,3) would demand significant twisting of the
methylene tether, corresponding to a higher energy TS (reaction (25)).

O O O
Me Me Me
Me

Me
not (25)
Me
Me 38 Me Me

Ketenes, cumulenes or isocyanates with one or more sp hybridised carbon atoms


lacking a pair of interfering substituents at one of the reacting termini also undergo
[2+2] cycloadditions with olefins relatively easy. The ketenes and cumulenes behave as
antarafacial and the alkenes as suprafacial components. Two stereochemical features
are usually observed: the olefin expectedly retains its configuration but the adduct is the
one which is sterically more congested. The latter fact may be explained considering the
orthogonal TS characteristic to the (s,a) interaction (see figure 16). Consider for example,

19
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

O
Me Me
Me Me H Me Me OEt
C C O H H
(26)
H H EtO H H O
H
EtO H 39

The arrangement in the TS is such that the sp carbon (less hindered) of the ketone is
directed towards the more hindered side of the olefinic double bond (i.e. C=O of the
ketene and the two methyl groups of cis-2-butene are on the same aide). As a result, the
kinetically controlled product of addition 39 becomes sterically more hindered (OEt
ends up on the same side as the Me groups). The stereochemistry thus reflects the
stability of the transition state and not that of the product.

LUMO

LUMO pz
O
Me Me px
HOMO

H H
HOMO

(a) (b)

Figure 16. Molecular orbital interactions for the case of a [π2s+π2a] addition.
(a) top-view; (b) side view.

The intramolecular version of this reaction is usually more efficient than the
intermolecular one. Take for example the following reactions.

R H
R H 3 O
Cl NEt3 6 4 2 ∆ 2 1
1 4
7 C 6 (27)
5 3
O O 5
7
R

Me Me
∆ H

Me
(28)
COOH C
O
O

The intramolecular allene cycloadditions are also important, not only for the
generation of quaternary centers, but also for the construction of highly bridged
molecules. An example of a photochemical transformation from Weisner’s synthesis
of 12-epilycopodine is given in reaction (29).

20
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

O O


(29)
Me N Me N

A final example of [2+2] cycloaddition is the reaction between an alkene and a


singlet carbene (Figure 17.a). The HOMO of the carbene, a σ (usually denoted ω)

orbital with two electrons, adds antarafacial through a non-linear π-approach to the
same side (i.e. suprafacial) of the LUMO of the olefin (Figure 17.b). It is thus a [ω2a+π2s]
addition. In this orientation, the p orbital of carbene is pointing towards the electrons of
the π bond, but this approach is however possible without the creation of a huge
amount of strain in the TS because the p orbital of carbene is empty. The alternative
linear and more symmetrical σ approach (Figure 17.c) is ruled out since it leads to an
antibonding interaction.

H R
LUMO LUMO
HOMO R

R HOMO

H H
(a) (b) (c)

Figure 17. Addition of a carbene to an ethylene

The addition is stereospecific. Z-butene gives 80% cis-cyclopropane 40 upon


treatment with bromoform in a strong basic medium (reaction (30)), while E-butene
forms in the same conditions 68% trans- isomer.

Br
Me Me
tBuO-K+
CHBr3
Me
Br
Me (30)
H H
H H
40

3.2.2. [4+2] Addition. Diels-Alder reaction. Several processes can be included in


this category, but the Diels-Alder transformation is the best known [π4s+π2s]
cycloaddition, proceeding stereospecifically syn with respect to both the diene and
dienophile, as expected from a concerted (s,s) mode of addition. An example was
previously given in reaction (1). The concerted nature of the addition of butadiene and
ethylene has been confirmed using suitably deuterated compounds (reaction (31)), the
product being almost exclusively (> 99%) the cis-isomer 4130.


Triplet carbenes behave more like radicals and do not give concerted cycloadditions.

21
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

D D D
H D D
D ∆ H

D H
(31)
H D D
D D D
41

A few characteristic features need to be emphasised:

a) The diene must be able to react in the s-cis conformation. Those structural elements that
perturb this conformation (voluminous substituents, rings, a.s.o.) inhibit or retard the
reaction. Thus bulky 1-cis substituents slow the process, whereas bulky 2-substituents
speed it up (scheme (32)).

1
2 1 R
2
R R R (32)
3 H H H 3 H
4 4
cisoid transoid transoid cisoid

b) The HOMO of the diene and the LUMO of the dienophile are generally closer in
energy than the HOMO of the dienophile and the LUMO of the diene. Those structural
features which raise the energy of the diene HOMO (e.g. electro-releasing substituents)
and lower the energy of the dienophile LUMO (e.g. electro-withdrawing substituents)
make the reaction procede faster†. The process works only poorly, if at all, in the
absence of the latter. Thus maleic anhydride reacts with butadiene at a much faster rate
than ethylene. In reaction (33), a double bond made strongly dienophile by an adjacent
carbocation gives an intermolecular Diels-Alder reaction31. (Syn or suprafacial addition
of trans alkenes gives a trans ring junction).

OH
Me Me Me Me
CF3SO3H (33)
H
-23°C
H

c) Regioselectivity in Diels-Alder additions (‘ortho’ and ‘para’ effects) is another


characteristic property. Thus dienophiles bearing electro-withdrawing substituents
react with 1-substituted butadienes to give 3,4-disubstituted cyclohexenes, independent
of the nature of the diene substituents (reaction (34)). (Of course, electro-releasing
groups on the diene increase both the rate and the selectivity, by a pull-push
mechanism.) Table 3 sums up a series of experimental results3 related to this behaviour.
For example, 1-methoxybutadiene reacts (35) with acrolein to give exclusively the ortho
but not the meta adduct.


A rarer type of Diels-Alder addition is the reverse electron demand reaction in which the dienophile has electro-
releasing groups and the diene has a conjugated –E group. The interaction is between the HOMO of the dienophile
and the LUMO of the diene.

22
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

R R R
Z Z
(34)
Z
major product

OMe OMe OMe

CH O CHO
X
(35)
CHO
meta ortho

Table 3. Ortho effect in Diels-Alder reactions

Diene subst. (R) Alkene subst. (Z) ortho:meta


Me CHO 8:1
Me CN 10:1
Me COOMe 6.8:1
iPr COOMe 5:1
nBu COOMe 5.1:1

The ortho effect is valid for 1-substituted dienes. In the case of 2-substituted
dienes, one can observe a so-called ‘para’ effect (see Figure 18).

X X
Z Z
ortho

Z Z
para
X X

Figure 18. Regioselectivity in Diels-Alder reactions.


(X stands for an electro-releasing substituent,
while Z denotes an electron-accepting substituent)

Although in many cases the regioselectivity may be determined form the


consideration of electrophilic and nucleophilic centers at the two components (see the
curved arrows in reaction (35)), the effect is primary determined by the coefficient of the
HOMO and LUMO orbitals5.

d) One of the most important characteristics of the Diels-Alder reaction is the ‘endo
rule’ or endo-selectivity. When both the diene and dienophile are substituted, the endo
isomer is the major kinetically controlled product (reaction (36)) even though it may be
thermodynamically less stable than the exo isomer (into which it may be converted by
prolonged heating).

23
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

X
X
(36)
endo X exo

Table 4 presents some experimental results3 showing the preference of the


reaction towards the endo product for various X-substituted olefins.

Table 4. Endo rule in Diels-Alder reactions

Substituent X endo:exo
COOH 75:25
COOMe 76:24
CONH2 10:1
CHO Only endo
CN 60:40
CH2OH 80:20
CH2Br Only endo
CH2NH2 Only endo
CH2CN Only endo
CH2COOH Only endo
NO2 Mostly endo
OAc 81:19
OCHO Only endo
Br Mostly endo

This behaviour can be explained by the presence of a secondary orbital


interaction between non-bond-forming orbital lobes of the same sign in the frontier
MOs. In the reaction between cyclopentadiene and acrolein (Figure 19), this interaction
is shown by a dotted line which is clearly absent in the formation of the exo product.

H CHO
endo CHO exo
CHO H

Figure 19. Endo selectivity in a Diels-Alder reaction

For the thermally allowed [π6s+π4s] cycloaddotion, this interaction has an


antibonding character so that the exo isomer is the kinetically controlled product. A
more general rule for predicting such behaviour was deduced by K.N.Houk3. It states
that, for all allowed [4k+2] cycloaddtions between a (4k) π-electrons polyene and a

24
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

substituted alkene having extended conjugation, the endo transition state is stabilised
by secondary orbital interactions (Figure 20.a), whereas for the allowed [4k+4l+2]
cycloadditions of two polyenes (l ≠ 0) the endo transition state is destabilised (Figure
20.b).

HOMO
HOMO (4k)
(4k) π-el
π-el LUMO
LUMO
(4l+2)
2 π-el π-el

(a) (b)

Figure 20. Secondary orbital interactions in Diels-Alder reactions.


Houk’s general approach

e) Site selectivity is that selectivity shown by a reagent towardss one site (or more) of
a polyfunctional molecule, when several sites are, in principle, available5. In
cycloadditions, site selecivity always involves a pair of sites, e.g. the Diels-Alder
reactions of anthracene generally take place across the 9,10-position than across the 1,4
or 3,9a. The highest coefficients in the HOMO of anthracene are at the 9,10-position, but
the more familiar explanation is that in this way are created two isolated benzene rings,
whereas reaction at the 1,4-position would create a naphthalene ring, less stable an
arrangement than two benzenic rings.

Reaction (37) illustrates an intramolecular Diels-Alder reaction giving a product


which is ultimatelly converted into brexane-2-one 4432. Due to [1,5] H-sigmatropic shifts
(see later), the side chain in the cyclopentadiene may approach any of the five carbon
atoms but it participates in the form 42 with the side chain at C-5 giving the product 43
exclusively.

COOMe H H H

115°
H (37)
H
COOEt H
42 43 COOEt 44 O

Intramolecular Diels-Alder reactions. If the diene and alkene are connected by a


chain of atoms (usually carbon), the Diels-Alder reaction occurs intermoleculary. This
has become one of the most powerful methods in organic synthesis for constructing
carbon bonds with high regio- and stereo-selectivity. Close approach of the diene and
olefin is sometimes inhibited by the atoms which link the two (the tether). The geometry
of the diene and dienophile (cis / trans) also plays a role. Consider for example the
structures 45 and 46.

25
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

45 46

The former compound attains the proper geometry for the reaction, while the latter
requires significant distortion of diene and alkene.

The length of the tether is also important. Small rings are impossible to be
obtained, whereas large rings (8-11 member atoms) are formed with difficulty.

At least 2 different regioisomers are possible for internal Diels-Alder reactions,


depending on the orientation of the alkene as it approaches the diene. If the tether is
short, only 47 is possible, but with longer chains 48 can become a side product or even
the major one.

(38)

47 48

In general, E-dienes do not give products such as 48, although Z-dienes do.
When the reactive termini approach, as in 49, the alkene ‘arm’ can assume an exo mode
(product 50) or an endo mode (product 51). The exo mode leads to a trans product,
while the endo TS leads to a cis product (scheme (39)). The final outcome depends on
the conformational energies of 50 and 51; in general, the exo TS is preferred.

H H

exo

H
H 50 H (39)
H H

H
49 endo

H 51 H
H

The great synthetic advantage of the Diels-Alder reaction is its generality; the
variety of different dienophiles that can be used is very wide indeed (possible variations
in the diene are somewhat less wide), and conditions can usually be found to make the
great majority of such reaction proceeds in good yields and with high stereoselectivity.

3.2.3. Other [2+4] Additions.

26
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

Dipolar cycloadditions. The 4π-electrons component in a [4+2] addition is not


necessary a four-atom system (as in 1,3-dienes), nor it involves carbon atoms only, as
long as the HOMO-LUMO interaction can be achieved. The most common of these non-
dienic 4π-electrons systems involve three atoms and have one or more dipolar
mesomeric structures, hence the term 1,3-dipolar additions. The only significant
difference between these cycloadditions and the Diels-Alder reaction is that they
involve less symmetrical, somewhat dipolar, transition states. The process is thermally
allowed and is highly stereospecific (syn addition to olefins). A general example is given
in reaction (40).


A B
A B
(40)

The alkene or alkyne derivative is called a dipolarophile. A variety of dipolar reagents


can be used, such as diazoalkanes (RCH=N+=N–), nitrile ylids (RC≡N+–CH2), nitrile
oxides (RC≡N+–O–), azides (R–N=N+=N–), nitrones (R1R2C=N+R–O–), and even ozone (–
O–O–O+). In general, the low energy interaction is the one between the LUMO of the
dipole and the LUMO of the alkene. Following the FMO approach, the LUMO interacts
with the HOMO both suprafacially, as can be seen from Figure 21.a for the case of the
diazomethane.

H H
N N HOMO H N N LUMO
H N N H
H
LUMO LUMO HOMO

(a) (b) (c)

Figure 21. Molecular orbital interactions for 1,3-dipolar cycloadditions

For the linear dipoles, the LUMO has a node through one of the terminal atoms
(Figure 22.b). If one needs to consider the alternative HOMO alkene-LUMO dipole
interaction, one must use the next lower unoccupied molecular orbital (NLUMO) instead
(see Figure 22.c).

Both intermolecular and intramolecular reactions are possible. An isomeric


bridged cycloadduct can be produced in this latter process if the tether is long enough
(reaction 41).

A B ∆ A B B
( )n ( )n A (41)
( )n

Using the energies and orbital coefficients for the HOMO and LUMO involved,
accurate predictions of reactivity and regioselectivity can be made. However, these
values are sensitive to structural modifications and it is risky to give general

27
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

predictions, therefore each case should be considered individually. Take for example
the following reactions.

COOMe N
COOMe
N
H2 C N N (42)

COOMe N
COOMe
N
HN N N (43)
HN

O N O
N

N (44)
O

H O OH OH

O O O

(45)
O O O

Cheletropic reactions. A cheletropic reaction is a cycloaddition in which one


component interacts through a single atom, i.e. with ω electrons. The previously
discussed [ω2a+π2s] addition of a carbene to olefins is such a cheletropic reaction. If the
olefin is replaced by a diene, it will be a 6π-electron system and thermal [π4s+ ω2s]
addition would take place. Although the reaction is not known for carbene addition,
sulphur dioxide does react with a diene, e.g. E,E-1,4-dimethylbutadiene (reaction (46))
to form stereoselectively the cis-sulphione 52.

Me Me
H

SO2 SO2
(46)
H

Me
52 Me

The reverse reaction (exclusion of SO2 from the sulphone) is more facile. Similarly, E,Z-
1,4-dimethylbutadiene gives the trans-sulphone or vice versa. One can envisage a
disrotatory motion in the diene component bringing the two methyl groups to their
respective configuration (Figure 22).

Me
H O
S
H
O
Me
LUMO HOMO

Figure 22. Molecular orbital interaction for a cheletropic reaction.

28
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

3.2.4. Higher cycloadditions. Periselectivity

Among the higher cycloadditions, a photochemical [π4s+π4s] addition of


butadiene to benzene has already been mentioned (reaction (22)). Another example is
provided below.

[4+4] (47)

[6+4] Cycloadditions are rare and go by the (s,s) mode, as illustrated in the addition of
cyclopentadiene and tropone 53 (reaction 48).

H
CO
∆ not
exo endo
3 [6+4] H
2 CO
O O
(48)
7 ∆
53 X
[4+2]

54

The product is exclusively the exo isomer which is explained by an unfavourable


interaction between lobes of unlike sign in the HOMO-LUMO combination when
forming the endo TS (see previously Houk’s general approach for secondary orbital
interactions, Figure 20). Moreover the [6+2] addition takes place in preference to a Diels-
Alder [4+2] reaction between the butadiene unit and the C2-C3 bond (both are thermally
allowed). This phenomenon, known as periselectivity, is explained by the fact that the
coefficients of the frontier orbitals of the LUMO of tropone are highest at atoms C2 and
C7 .
In general, the ends of conjugated systems carry the largest coefficients in the
frontier orbitals, and thus the pericyclic reactions use the longest part of conjugated
system according to the Woodward-Hoffmann rules. This proves to be true up to a
point, with the provision that the reactions have also to be geometrically reasonable.
The following cases are all ones where the largest possible numbers of electrons have
beer used, although smaller (but equally allowed) cycloadditions might have taken
place.

N [8+2] N - H2 N (49)
H
H
COOMe COOMe
MeOOC COOMe MeOOC MeOOC

29
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

COOMe
[8+2] COOMe
(50)
COOMe
COOMe

COOEt NCOOEt

N
EtOOC N (51)

NCOOEt

COOMe
N [8+2] NCOOMe
N NCOOMe
(52)
COOMe

In open-chain and in some cyclic systems we can predict that FMO control will
lead the reaction to take the path which uses the longest part of the conjugated system
consistent with a symmetry-allowed reaction, but several other factors, spatial, entropic,
a.s.o., have to be taken into account. However, in some more complicated cases, the
longest conjugated system is not always the one preferred. The following examples
illustrate same of the complexities of such systems.

The reaction (53) between tetracyanoethylene 56 and heptafulvalene 55 is one in


which the geometrical factors outweight the contribution of the frontier orbitals5.

4
NC CN
[14+2]
(53)
3
NC CN
1' 1 2 NC CN
55 56 NC CN

The HOMO coefficients for 55 are highest at the central double bond, but any reaction at
his site would have to be antarafacial on one of the components, and this is sterically
unreasonable. (However, in a carbene cycloaddition, in which an antarafacial element
can be taken up by carbene, it is this central bond that is attacked). The next best
possibility from the FO view point would be a Diels-Alder reaction across the 1,4-
positions, but this was shown not to occur probably because the carbon atoms in the
seven-member cycle are too distant†. The only remaining possibility is the site of lowest
orbital electron density, i.e. the antarafacial reaction across the 1,1’-positions.

Sesquifulvalene 57 presents another case where frontier orbital control is not the
only factor that governs periselectivity.


This is known to influence the rate of Diels-Alder reactions, e.g. cyclopentadiene reacts much faster than
cyclohexadiene, which in its turn reacts much faster than cycloheptatriene.

30
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

10 11

9 12
8

7 2
1

6 3

5 4

57

The sesquifulvalene 58 does give the adduct 59 with tetracyanoethylene by a


[8+2] addition (reaction (54)), as expected from the coefficients of the HOMO of the
unsubstituted system 57, which are greatest for positions C2 and C8.

NC CN
[8+2] (54)
CN
NC CN CN
CN
CN

58 59

However, the sesquifulvalene 60 gives the [4+2] adduct 61 instead, by an


addition (55) across the positions C2 and C5, while the sequifulvalene 62 gives the [12+2]
adduct 63 (reaction (56)) using the orbitals located at C2 and C12. Furthermore, the
sesquifulvalene 64 gives yet another kind of adduct 65 in Diels-Alder reaction (57) when
treated with acetylenedicarboxylic ester. This examples serve to emphasize the pitfalls
of a too easy application of FMO theory.

Ph Ph
Ph Ph

Ph Ph
Ph Ph NC CN
[4+2]
(55)
NC CN CN
CN

61 NC CN
60

H
NC CN CN
[12+2] CN
CN (56)
NC CN CN
H

62 63

31
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

COOMe
COOMe
[4+2]
COOMe
(57)
COOMe 65

64

Cycloadditions of multiple components can also occur, indeed very rarely, in a


bi- or even uni-molecular manner by incorporating two or three of the π-conjugated
systems (in the proper orientation) in a molecular structure. Additions of the type
[π2s+π2s+π2s] are thermally allowed, while those of the type [π2s+ π2s+ π2s+ π2s] are
photochemically allowed. Some examples are presented below (reactions (58), (59) and
(60)).

H O H
∆ H (58)
O
O
O
O
O

NC CN
NC CN
NC CN
∆ (59)
NC CN
O O
O O

MeOOC COOMe


MeOOC COOMe (60)

Conclusion

It is clear from the preceding sections that a wide range of cyclic and polycyclic
molecules can be prepared by pericyclic reactions. In addition, stereocontrolled
syntheses of acyclic molecules are possible via initial cycloaddition, followed by
cleavage of the ring. The power of the reaction lies in the ability to make carbon bonds
with high regio- and stereo-selectivity and specificity. Few synthetic methods allow
access to such a large number of products, with compatibility to a wide range of
functional groups. In conclusion, for power and versatility, few reaction types rival
pericyclic transformations.

32
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

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Work presented at the Student Communications, May 2003 Edition


Copyright © 2003, 2004 by Eugen S. Andreiadis, all rights reserved
Contact: andreiadis@dap.ro

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