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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.
2
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis
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.
3
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis
2. Electrocyclic reactions
CH n
CH n-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.
4
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).
(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
5
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.
n (no. of π- Condition
Geometry
electrons) s
∆ conrotator
4k y
hν disrotatory
∆ disrotatory
4k+2 hν conrotator
y
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].
6
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis
π-LUMO a ∆
[σ2s + π2a]
σ-HOMO s
π-HOMO s ∆
[σ2a + π2s]
σ-LUMO a
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.)
7
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis
hν ∆
disrot conrot
hν ∆
disrot conrot
hν ∆
disrot conrot
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
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
8
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
hν
(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
9
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis
CF3 F
CF3
F ∆ F ∆ CF3
x F (11)
F F
F
10 11
F F
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
hν ∆
conrot disrot
trans cis
hν ∆
conrot disrot
cis trans
10
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
11
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis
R R R
Me Me Me
Me
∆
1 Me 7
hν
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.
Me
Me Me
2 H2 Me ∆ ∆
Me conrot disrot
(16)
Me
Me
26 H 27
Me 25
12
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.
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
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
13
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis
Cl H H H
H inwards H outwards
H Cl
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
14
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis
Ar
N
H H
100º hν
Ar
con ROOC COOR dis Ar
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
3. Cycloaddition reactions
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.
15
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis
HOMO LUMO
Ψ2 Ψ3
LUMO HOMO
π∗ π
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.
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
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
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.
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.
3.2.1. [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
+
hν
H H ∆ (22)
2 mol
34 35
18
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis
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.
hν H
(24)
H H 37
H
O O O
Me Me Me
Me
hν
Me
not (25)
Me
Me 38 Me Me
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
hν
(29)
Me N Me N
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)
Br
Me Me
tBuO-K+
CHBr3
Me
Br
Me (30)
H H
H H
40
†
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) 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
†
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
CH O CHO
X
(35)
CHO
meta ortho
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
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
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
H CHO
endo CHO exo
CHO H
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)
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.
COOMe H H H
115°
H (37)
H
COOEt H
42 43 COOEt 44 O
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.
(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.
26
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis
∆
A B
A B
(40)
H H
N N HOMO H N N LUMO
H N N H
H
LUMO LUMO HOMO
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).
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
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
28
Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis
[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
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.
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
NC CN
[8+2] (54)
CN
NC CN CN
CN
CN
58 59
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
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
hν
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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