Andreiadis Pericyclic Reactions

Polytechnic University of Bucharest

Faculty of Engineering in Foreign Languages Chemical Engineering Division

Student Communications May 2003 Edition

SStteerreeoocchheemmiiccaall AAssppeeccttss ooff

PPeerriiccyycclliicc RReeaaccttiioonnss

Eugen S. Andreiadis

Stereochemical Aspects of Pericyclic Reactions – Eugen S. Andreiadis

2

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)).

Y

X

Y

X X

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.

(1)


3

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.


4

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.

nCH n-2CH

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.

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.

conrotatory

∆HOMO(Ψ3)

HOMO(Ψ3)

antibonding interaction

bonding interaction

disrotatory

∆

Figure 2. Conrotatory and disrotatory thermal cyclisation of hexatriene

(2)


5

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.

conrotatory

hν

HOMO*(Ψ4)

bonding interaction

antibonding interaction

disrotatoryHOMO*(Ψ4) hν

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),

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.

conrotatory∆

disrotatory

HOMO(Ψ2)

HOMO*

(Ψ3) hν

Figure 4. Thermal and photochemical cyclisation of butadiene

(3)


6

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-electrons)

Conditions Geometry

∆ conrotatory 4 k

hν disrotatory ∆ disrotatory

4 k + 2 hν conrotatory

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 interactiondisrotatory motion

antarafacial interactionconrotatory 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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[σ2s + π2a]∆π-LUMO

σ-HOMO

a

s

[σ2a + π2s]∆π-HOMO

σ-LUMO

s

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).

Figure 7. Different possibilities of disrotatory and conrotatory movement and their stereochemical outcome

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–1, and so the ring 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.)

R R

disrotatoryinwards

R R

R R

R R

R R

disrotatory

outwards

conrotatorytwrds right

conrotatorytwrd left

R R

R

R

R

R


8

hνdisrot

hνdisrot

hνdisrot

conrot

conrot

conrot

∆

∆

∆

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

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

O

Ohν

disrot O

H

H

O

conrot∆

O

O

impossible1 2 3

HH

conrot<100o

64

hνdisrot

HH5

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

O

hνO

O

O

Pb(OAc)4

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

(4)

(5)

(6)


9

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

tBu

tBu

tBu

hν

tBu

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 H

not

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)).

H

H

Me

Me

hν

Me

H

HMe

∆

Me

H

Me

HE, E Z, E8or

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.

H

H

Me

Me

H

H

MeMe

∆

Me

Me

H

HE, E Z, Z9

∆x

(7)

(8)

(9)

(10)


10

F

F

CF3

F

CF3

F

FF

∆

F

CF3

F

F10

∆x

11

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 ( )n conrot∆

H

H

( )n12

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

H

Me

Medisrot

∆Me

Me13

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

cis

hν

conrot disrot

∆

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

(11)

(12)

(13)


11

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

(CH2)n

hν

∆(CH2)n

hν

14 15

1617

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,

(14)


12

Me

Me

HO

R

3

2

45

6

Me

Me1

HO

R

7

Me

HO

R

Me

Me

HO

RMe R

HO

Me

Me

Me

HO

RMe

Me

HO

R

hν

con

conhν

hνcon

hν

con

∆

[1,7]

dis18

1920

242322

21(lumisterol)

(precalciferol)(ergosterol)

(tachisterol)

(isopyrocalciferol) (pyrocalciferol)

(vit D2)

∆

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

2 H2 Me

Me conrot

∆

H

H

Me

Me disrot

∆Me

Me

25

26 27

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

(15)

(16)


13

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

Rinwardsoutwards

R

R A-

R

RA

Z

R

R

A

R

E

A-

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).

X

R

R -X-

R

R

-X-

R

XR

R

X

RE routeZ route

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.

H

H

Me

Me

Houtwards

Me

H

OTs

H

H

Mekrel = 4500

29Me

Me

H

H

Hinwards

Me

H

H

OTs

H

Mekrel = 1

30

(17)

(18)


14

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

HH

H

inwards

krel = 11000

H

H31endo

H

ClH

H

outwards

krel = 1

32exo

H

H

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

X

ClBrH

H

AgNO3

H2O

H

Br

OH

33 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.

(19)

(20)


15

NH

COOR

H

ROOC

Ar

NCOOR

H

H

ROOC

Ar

N

HH

COORROOC

Ar

N

HROOC

COORH

Ar

COOMe

COOMe

COOMe

COOMe

N

COOMeMeOOC

Ar

HHCOORROOC

N

COOMeMeOOC

Ar

HROOCCOORH

100º

100º

con

hν

dis

dis

hν

con

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.

(21)


16

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.

HOMOΨ2

LUMOπ∗

LUMOΨ3

HOMOπ

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.)

HOMOπ

LUMOπ∗

HOMO(hν) π∗

LUMOπ∗

(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.


17

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.

Y

X X

Y

X

Y Y

X

HOMOπ

LUMOπ∗

∆ X

Y

X

Y

X

X

Y

Y

LUMO

HOMO

1

2

4

3

X

YY

XX

X

Y

Y

1 2

3

XX X

Y X

Y Y

4

Y

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 π-electrons)

Conditions Geometry

hν supra - supra 4 k ∆ supra -

antara ∆ supra - supra

4 k + 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.


18

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

s,shν

MeMe

Me Me

Me Me

Me Me

s,a

MeMe

Me Me

∆

Me Me

Me Me

a,a

MeMe

Me Me

hν

MeMe

MeMe

s,shν

Me Me

MeMe

Me Me

Me Me

s,a

Me Me

MeMe

∆

Me Me

Me Me

a,a

Me Me

MeMe

hν

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)).

+ hν ∆2 mol

34

H H

35

(22)


19

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)).

Me

Me

O

hν

OH

MeH

Me 36

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

HH H 37

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

Me

Me

Me

hνMe

Me

Me

O

not

Me

Me

OMe

38 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,

(23)

(24)

(25)


20

Me

H H

MeC C O

EtO

H Me

H

Me

H

EtO H

O

OEtMe Me

H

H H

O39

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.

Me

H

Me

H

LUMO

HOMO

Opz

px

HOMO

LUMO

(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.

Cl

O

R

NEt37

6

5

4

3

2

C1

O

R H∆

5

62

3

4

7

1

OH

R

Me

COOH

Me

C

O

∆

O

H

Me

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).

(26)

(27)

(28)


21

NMe

O

hν

NMe

O

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.

R

H

(a)

R

H

LUMO HOMO

(b)

R

H

LUMO

HOMO

(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

Br

H

Me

H

Me

40H

MeMe

HCHBr3

tBuO-K+

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.

(29)

(30)


22

D

D

D

D

H D

H D

∆

D D

D D

H

H

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)).

2

34

1

R

H

R

H4

3

1

H

2R

H

R

cisoid transoid cisoidtransoid 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).

MeMeOH

CF3SO3H

-23°C

MeMe

H

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.

(31)

(32)

(33)


23

R

ZR R

Z

Zmajor product

OMe

CHO

X

CH O

OMe OMe

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).

XZ

X

Z

Z Z

X X

ortho

para

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).

(34)

(35)


24

X

X

X

endo 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

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.

CHOH

CHO

CHO

Hendo exo

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

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

(36)


25

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).

(4k)π-el

2 π-el

HOMO

LUMO

(a)

(4k)π-el

HOMO

LUMO

(b)

(4l+2)π-el

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

COOEt

H

115°

H

HCOOEt

H

H

HO42 43 44

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.

(37)


26

H

H

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.

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.

exo

endo

H

H

50

H

H 51

H

H

H

H

H

H

H

H

49

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.

(38)

(39)


27

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

∆ BA

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.

NNH

HHOMO

LUMO

(a)

NNH

H

LUMO

(b)

NNH

HLUMO

HOMO

(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 ∆ BA

( )n ( )n

BA

( )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

(40)

(41)


28

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

H2C N N

COOMe NN COOMe

HN N N

COOMe

HN

NN COOMe

N

O

N O N O

O

O

O

H OH

O

O

OH

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

SO2∆

SO2

Me

Me

H

H52

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

HH

Me

SO

O

LUMO HOMO

Figure 22. Molecular orbital interaction for a cheletropic reaction.

(42)

(43)

(44)

(45)

(46)


29

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]

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

CO

X7

23

OCO

∆

∆

H

H

endoexo

53

[6+4]

[4+2]

not

O

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

COOMeMeOOC

N

COOMeMeOOC

HH

N

COOMeMeOOC

- H2[8+2]

(47)

(48)

(49)


30

COOMe

COOMe

[8+2] COOMe

COOMe

N

COOEt

NEtOOC

NCOOEt

NCOOEt

N

N

COOMe

COOMe

[8+2]

NCOOMe

NCOOMe

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.

[14+2]

1' 1 2

3

4 CNNC

CNNCNC CN

NC CN55 56

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.

(50)

(51)

(52)

(53)


31

5 4

3

217

6

812

1110

9

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.

CNNC

CNNC

[8+2]CN

CN

CNCN

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

PhPh

Ph CNNC

CNNC

[4+2]

60 61

Ph

PhPh

Ph

CN

CNNC

CN

CNNC

CNNC

[12+2]

62

CN

CNCN

CN

H

H

63

(54)

(55)

(56)


32

[4+2]

64

COOMe

COOMe

COOMe

COOMe

65

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)).

O

O

O

H

H ∆

OO

O

HH

∆

OONC CN

CNNC

O O

NC CNNC CN

COOMeMeOOChν

MeOOC COOMe

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.

(57)

(58)

(59)

(60)


33

References

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2. M. Nogradi, Stereochemistry. Basic Concepts and Applications, Pergamon Press, New York, 1981. 3. M.B. Smith, Organic Synthesis, McGraw-Hill, New York, 1994. 4. J.M. Harris, C.C. Wamser, Fundamentals of Organic Reaction Mechanisms, John Wiley & Sons, New

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