WIM DEHAEN

ADVANCED ORGANIC CHEM ISTRY

1

Chapter 1 Concerted reactions

During concerted reactions the cleavage of the bonds of the starting materials and the

formation of the new bonds of the product happen at the same time (in other words in concert)

without the occurrence of discrete intermediates. A very important class of concerted

reactions is formed by the pericyclic reactions. The latter are characterized by a cyclic

transition state. In the text below we will discuss the different types of pericyclic reactions at

length. In a second part of the chapter others examples of concerted reactions are given,

together with the consequences for the stereochemistry of the products formed.

1.1 Pericyclic reactions : properties and types

-During the course of the reaction no (high-energy) radical, carbocation or carbanion

intermediates are formed. In many cases, the activation energy will be rather low as a

consequence. In general, there are no important solvent effects observed in these reactions

because during the reaction no (large) changes in polarity occur.

-The cyclic transition state implies a large degree of organisation of the reagents, so the

reaction entropy will be negative.

-The pericyclic reactions will in many cases lead to the stereo- and regioselective formation of

products even if several isomers would be possible.

-The reactions are activated by heating (thermally) or by irradiation with UV- or visible light

(photochemically).

h

photochemical [2+2]cycloaddition

R

R

+

R

R

SO2 SO2

+

Synthesis of cyclopropanes from carbenes

transformation of sulfolene to butadiene and SO2

+

thermal Diels-Alder cycloaddition

2

We can distinguish three types of pericyclic reactions:

-Cycloadditions: two separate molecules or fragments form a new cyclic system, and during

this process two -bonds disappear and two -bonds are formed. An example is the

photochemical [2+2] dimerisation of alkenes to form cyclobutanes or the thermal [4+2] Diels-

Alder cycloaddition reaction. Cheletropic reactions and the reverse process, the extrusion

reactions, form a special case in which the two -bonds are formed (respectively cleaved) at

the same atom. These [n+1] processes will for instance take place for the addition of carbenes

(see later) to alkenes and the formation of butadiene and SO2 from sulfolene.

-Electrocyclic reactions: within a single, conjugated open chain system with n -bonds a

transformation occurs to a cyclic system with (n-1) bonds and one (1) newly formed -

bond. In function of the reaction circumstances, the reverse reaction (ring opening) may take

place. The reaction takes place thermally or photochemically.

butadienecyclobutene

-Sigmatropic rearrangements: during the reaction, a group R migrates over a conjugated -

system, of which the bonds shift during the migration. Thus, the total amount of - -bonds

does not change during these reactions. An example is the Claisen rearrangement, in which an

allyl group shifts over an enolate system, resulting in the formation of an unsaturated carbonyl

compound. This is an example of a [3,3]-sigmatropic rearrangement.

OO

Claisen rearrangement

3

1.2 Pericyclic reactions : general principles

1.2.1 Molecular orbitals

Molecular orbitals are obtained by linear combination of atomic orbitals (LCAO). Atomic

orbitals can be seen as wave functions, combining in-phase (bonding interaction) or out-of-

phase (antibonding interaction). If two p-orbitals are combined following the long axis, this

results in the formation of a bonding -orbital and an antibonding * -orbital. The latter has a

higher energy and the orbitals with the lowest energy are the first to be filled with electrons.

These two simple orbitals are symmetric in relation to the bond axis, while in regard to the

nodal plane (m, the plane perpendicular to the bond axis) the -orbital is symmetric (S) and

the * -orbital antisymmetric (A). In relation to the C2-axis perpendicular to the bond axis this

is the same: the -orbital is symmetric (S) and the * -orbital antisymmetric (A).

The - and * -orbitals are formed by lateral overlapping (respectively bonding and

antibonding) of two p-orbitals. These orbitals are both antisymmetric in regard to the bond

axis, and in relation to the nodal plane m the -orbital is symmetric and the * -orbital

antisymmetric. In relation to C2 this situation is reversed.

Energy

C-C bondaxial overlap

C=C bondlateral overlap

The wave function 1 = c1 1 + c2 2 for the bonding - and -orbitals,

and the wave function 2 = c1 1 - c2 2 for the antibonding * - and * -orbitals.

4

The numbers c1 and c2 are the orbital coefficients. Visually, these coefficients are shown by

the size of the orbital lobes. For symmetric compounds (e.g. ethene) c1 = c2, in other cases

(e.g. CH2=O) the two coefficients are different.

Ethene has both (*) - and (*) -orbitals. The energy of the - en * -orbitals is given in

theoretical discussions as respectively + and - , in which is the energy of the original

p-orbital and the energy difference by delocalisation of the electrons over the two atoms of

the molecule. Both and are negative energy values.

The -orbital is in this case the highest occupied molecular orbital (HOMO), and the * -

orbital is the lowest unoccupied molecular orbital (LUMO). Both are the frontier orbitals.

Energy

HOMO

LUMO

Electronic configuration of ethene

In linearly conjugated systems there are several (>2) p-orbitals that simultaneously enter in

lateral interaction with each other. The electrons of the resulting molecular orbitals are

delocalised over all the participating atoms. A prerequisite is that the conjugated system is

not interrupted by sp3-hybridised atoms. Atomic orbitals that are perpendicular (as in allenes

or cumulenes) can not overlap and are not conjugated. Examples of simple linearly

conjugated systems are butadiene (n = 4) and allyl (n =3) (cation, radical or anion). 1,4-

Pentadiene has two localised double bonds, therefore it is not conjugated.

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butadiene

H2C C CH2 allene

1,4-pentadiene

isolated double bonds

CH2 allyl anion

conjugated systems

The n different wave functions of a system with n atoms are described according to LCAO for

the j-th orbital as:

j = c1j 1 + c2j 2 + c3j 3 +... + cnj 3

The coefficients for polyene systems with n atoms can be theoretically calculated (the so-

called Hckel approach) whereby a coefficient crj of the r-th atom orbital in the j-th molecular

orbital is given by:

crj = (2/n+1)0.5

x sin rj /n+1

Example: the coefficient for the third atomic orbital in the fourth wave function of a four atom

system is 0.6.

and the energy of a molecular orbital j is given in general by

E = + m in which m = 2 cos(j /n+1). If m = 0 the orbital is non-bonding.

This approach gives information on the relative contribution of the atomic orbitals in a certain

molecular orbital (size of lobes = orbital coefficients) and also shows if the interaction is

bonding, antibonding or not-bonding. At the same time the amount of knots (electron density

= 0), and their position in the molecule, can be determined.

Application of these formulas on ethene (n =2) leads to m = 1 and c1 = c2 = 0.707.

The following system is this with n = 3, the allyl system. In this case we have three molecular

orbitals 1, (E = + 1.414 ), 2 (E = ) and 3 (E = - 1.414 ). Thus, the molecular orbital

2 is non-bonding.

6

An allyl cation has electron configuration 12

20, an allyl radical 1

221, and an allyl anion

12

22. The allyl group is bent because the central carbon atom has sp

2-hybridisation and thus

the angle is 120.

The orbital coefficient c22 = 0, in other words a knot is localised on the central atom of the

second orbital of the allyl system. The other two coefficients are c21 = c12= c32 = c23 = 0.707

and c11 = c31 = c13 = c33 = 0.5. The molecular orbital 2 is the LUMO for the allyl cation, and

the HOMO for the allyl anion. The molecular orbital 1 has no knots, and the molecular

orbital 3 has two knots, in between atoms 1-2 and 2-3. In general, a linearly conjugated

system in the n-th molecular orbital has n-1 knots.

Energy

Symmetry

m C2

S A

A S

S A

Molecular orbitals of allyl

The most stable conformation of butadiene (n = 4) is a zigzag structure. With LCAO four

molecular orbitals can be formed, in which four -electrons are accommodated. Thus, the

HOMO is the 2-orbital (one knot) and the LUMO is the 3-orbital (two knots). The

difference in energy between HOMO and LUMO is for butadiene (n = 4) 1.236, this is less

than the -LUMO- for the allyl cation (n = 3, 1.414) or ethene (n = 2, 2 ). Thus,

the longer is the conjugation, the smaller is the distance between HOMO and LUMO.

The Hckel calculations predict two orbital coeffici ents 0.6 and 0.371. In the two frontier

orbitals the coeffici ents on the two outer atoms is larger than those on the central. In the

different molecular orbitals of butadiene the knots are always located between the carbon

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atoms, and this is typical for linearly conjugated systems with an even amount of carbon

atoms.

Furthermore, the two occupied molecular orbitals 1 and 2 show respectively a bonding and

antibonding interaction between the central atomic orbitals on C-2 and C-3. The relevant

coefficients are larger for 1 which makes the interaction more bonding. Thus, we can say

that the C-2-C-3 bond in butadiene has partial double-bond-character.

We would like to mention that in simplified representations of the molecular orbitals of

conjugated systems often all orbitals are shown with the same coeffici ents. It is important to

keep in mind that this does not completely correspond to reality.

Energy

Symmetry

m C2

A S

S A

A S

S A

Below are shown the simplified representations (orbitals, energies, symmetry) of the next

homologous systems with n = 5 (pentadienyl) and n = 6 (1,3,5-hexatriene), following the

same logic. The HOMO-LUMO gap is further reduced, respectively to (n = 5 ) and 0.890

(n = 6).

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Energy

Symmetry

m C2

S A

A S

S A

A S

S A

Energy

Symmetry

m C2

A S

S A

A S

S A

A S

S A

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For cyclic conjugated systems other rules apply. The Hckel orbital theory describes the

energy of planar polycyclic polymethines (CH)n ([n]annulenes) as:

E = + 2 cos 2 r/n

with n = number of C-atoms ; r = 0, 1, 2, ...n-1

Mnemotechnically, one can obtain the energy levels by representing the molecule as a regular

polygon that is circumscribed by a circle with diameter 4. The lowest atom (situation for r =

0) should always be placed at the bottom of the circle, and the corresponding lowest energy

level is + 2 . A difference with the linear polymethines is that molecular orbitals with the

same energy (degenerate systems) can occur. In the figure below, the Hckel energy levels

are given for planar, cyclic conjugated systems of n = 3 to n = 8.

Carrying out the calculation for a six-membered ring (benzene) shows the occurrence of 6

orbitals with r = 0, 1 , 2 , 3, 4, 5. The Hckel energies are respectively +2 , + , - , -2 ,

- and + .

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1.2.2 Aromaticity

Hckel : Planar, fully conjugated systems with (4n + 2) electrons have all binding

orbitals filled and thus are very stable. These systems are aromatic. The analogous systems

with 4n electrons are anti-aromatic (n is in both cases an integer).

Aromatic systems are significantly more stable in comparison with the linear analogs and

have a diamagnetic ring current. Anti-aromatic systems are less stable than the linear analogs

and the system will assume a non-aromatic structure whenever possible, for instance by loss

of planarity as in cyclooctatetraene.

This rule can be further explained after a closer look at the energy levels in the figures above

and after a comparison of the stabilisation energies of the filled orbitals of the cyclic and non-

cyclic systems.

We can define for cyclic polyenes a Hckel system in which the base orbital, in other words

the lowest filled -level ( 1) has p-lobes that overlap in-phase.

On the other hand, in a Mbius- or anti-Hckel-system one end of the chain has been turned

over 180 (or n ), so we have a phase dislocation. These definitions can be expanded by

stating that a system with an even amount of phase dislocations is a Hckel system, and a

system with an odd amount of phase dislocations is a Mbius system.

Mbius-systemHckel-system

A so-called Mbius ring can be prepared by turning a strip of paper at one end over 180 and

then joining the ends. Note that a Mbius ring has only one side.

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Evidently, such twisted compounds have large strain, making them unstable. Therefore,

Mbius systems have never been isolated, but are rather of theoretical interest to describe the

transition states of pericyclic reactions.

Hckel systems as before are aromatic with 4n +2 -electrons, Mbius systems on the other

hand are aromatic when they possess 4n -electrons.

1.2.3 Aromaticity principle for the description of pericyclic reactions

This approach was first used by Zimmerman and Dewar on cyclic transition states in

pericyclic reactions. These transition states can be seen as aromatic (favourable) or anti-

aromatic (unfavourable). The derivated rule is the following :

Pericyclic reactions occur thermally (are allowed) when an aromatic transition state can be

formed.

This aromatic transition state is attained for a Hckel system with 4n +2 -electrons or a

Mbius system with 4n -electrons. For photochemical processes that occur via the lowest

excited state, this rule is reversed : the allowed processes are Hckel systems with 4n -

electrons or Mbius systems with 4n + 2 -electrons.

A few pointers when applying this aromaticity rule:

-In the transition state the base orbitals are used (ground orbitals of the reacting systems, -,

p- of -orbitals) with the corresponding phase signs. (Do not use frontier orbitals !)

-the number of electrons and the number of phase dislocations are determined.

-from these data can be determined if the reaction is allowed or not.

1.2.4. Frontier orbital approach

During chemical reactions, and especially pericyclic reactions, the process of overlapping

between the filled orbitals of a substrate and the empty orbitals of a reagent (and vice versa)

determines the course of the reactions.

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The result of an interaction between two filled orbitals is repulsive because the combination

leads to a bonding and antibonding orbital that are both occupied. The resulting energy effect

is unfavorable. The destabilisation by the antibonding orbital is larges than the stabilisation

caused by the bonding orbital because of the coulombic repulsion of the two atoms. Empty

orbitals of two reagents have no stabilising effect because they contain no electrons.

HOMO-1

HOMO-2

LUMO-2

LUMO-1

HOMO-1

HOMO-2

LUMO-2

LUMO-1

HOMO-1

HOMO-2

LUMO-2

LUMO-1

The interaction between filled and empty orbitals will be stronger (leads to more stabilisation,

lowering of energy) if these orbitals are closer to each other in energy. Therefore, it is mainly

the frontier orbitals (HOMO and LUMO) that will have an influence on the chemical reaction.

Electron poor reagents have a relatively low LUMO and will specifically use this frontier

orbital in their reactions. Electron rich products have a relatively high HOMO, giving the

strongest interactions.

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The frontier orbital approach states that HOMO and LUMO, other than being close in energy,

should also have a comparable symmetry. The symmetry of the two frontier orbitals should be

such that the two ends combine in a bonding interaction (the same phase sign).

LUMO

HOMO

LUMO

HOMO

bonding interaction

antibonding interaction

1.2.5 Woodward-Hoffmann rules

Fukui and Hoffmann obtained the Nobel prize in 1981 for their theoretical application of

orbital symmetry to pericyclic reactions. Woodward, who co-developed this approach, had

already died in 1979 but did obtain the Nobel prize in 1965 for his synthetic work. A

summary of this work is given by the Woodward-Hoffmann rules:

In a thermal pericyclic reaction the total amount of (4q+2)s and (4r)a components should be

odd.

This short sentence needs some further explanation. The components mentioned are bonds or

orbitals that participate in a pericyclic reaction as a separate unit. The 4q+2 and 4r refer to the

number of participating electrons, q are r integer, in most cases 0, 1 or (sometimes) 2. The

suffixes suprafacial, respectively a antarafacial component. For a

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suprafacial component, the new bonds are formed on the same side of the component, and for

an antarafacial component the new bonds are formed on opposite sides.

1.3 Cycloadditions

1.3.1 Diels-Alder reaction

The most famous cycloaddition reaction is the Diels-Alder reaction. This is a concerted [4+2]

cycloaddition, in which 4 and 2 refer to the respective amount of -electrons participating in

the reaction. This reaction is thermally allowed. An example is the reaction of butadiene with

maleic anhydride. In a stereospecific manner, a bicyclic product is formed, that can be

transformed to the fungicide Captan, used in agriculture.

Obviously, the transition state has 6 -electrons, and no phase dislocation. According to the

aromaticity principle, this is indeed a thermally allowed process, as empirically found.

O

O

O

+ O

O

O

H

H

N

O

O

H

H

S

CCl3

Captan

Hckel type aromatic TS (6 electrons)

A second approach uses the frontier orbital method. For the reaction of butadiene with ethene

one can involve either the HOMO (butadiene)/LUMO (ethene) interaction or the HOMO

(ethene)/LUMO (butadiene) interaction. Both interactions are favourable, in other words the

frontier orbitals have compatible symmetry. It is said that the reaction is symmetry- allowed.

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HOMO butadiene

(

LUMO ethene

(

LUMO butadiene

(

HOMO ethene

(

m (A) ; C2 (S)

m (A) ; C2 (S)

m (S) ; C2 (A)

m (S) ; C2 (A)

Finally, according to the Woodward-Hoffmann rules, the Diels-Alder reaction is a supra-

supra 4s +

2s process, and hence allowed. Supra-supra means that the bonds are broken or

formed on the same side, which explains the cis-stereospecificity.

In many cases it is possible to form two isomers as a result of the Diels-Alder reaction,

namely an exo- and an endo-isomer. In many cases, the latter isomer is preponderantly or

even specifically formed, even if this is the isomer that suffers the most from steric hindrance.

The names endo and exo refer to the spatial relation between the groups on the dienophile and

the newly formed bond on the diene. When these groups are on the same side, this is the

endo-adduct, otherwise this is the exo-adduct. As an example we can consider the reaction

between cyclopentadiene and maleic anhydride, leading specifically to the endo-product. On

the other hand, the reversible Diels-Alder reaction of furan with maleic anhydride affords

mainly the exo-adduct. This is a typical example of kinetic versus thermodynamic control.

O

H

H

O

O H

H

O

O

O

endo-adduct

O

H

H

O

O

exo-adduct(not formed)

O O

H

H

O

OO

H

H

O

O

O

endo-adductkinetic product

O

O

H

H

O

O

exo-adductthermodynamic product

fastslow

furan(aromatic)

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The endo-specificity for irreversible reactions can be explained by frontier orbital theory. For

instance, during the formation of the endo-product from the dimerisation of cyclopentadiene

we can consider, next to the expected favourable interactions between the frontier orbitals, the

occurrence of secondary interactions (separately shown) that have bonding character and thus

favour the reaction kinetically. Obviously, the secondary interactions do not lead to bond

formation but they will lower the energy of the transition state (and hence the activation

energy). These secondary interactions are not possible during the formation of the exo-adduct.

HOMOcyclopentadiene(reacts as diene)

LUMOcyclopentadiene("dienophile")

secondaryinteractions(bonding)

Another possibility to form isomers as a result of the Diels-Alder reaction occurs if both

reaction partners, diene and dienophile, are nonsymmetrically substituted. In this case there is

the possibility of two regioisomers that differ in the relative place of the substituents of the

product obtained. In practise, often regioselectivity is observed: one of the possible

regioisomers is preferentially formed. This is a result of the electronic complementarity of the

reagents. The most common situation is the one where an electron rich diene is combined

with an electron rich dienophile. Because the reagents are non-symmetrical, some of the

orbital coeffici ents will be larger than others. The size of these orbital coeffici ents can be

calculated but often a logic is followed that can be derived from well-known considerations of

resonance or chemical reactivity. As an example we look at the reaction between methyl

acrylate (methyl propenoate) and 4-methyl-1,3-pentadiene. Methyl acrylate is the dienophile

and thus will react via a LUMO ( *) with low energy. The orbital with the largest coefficient

is located on the -carbon atom. This corresponds to the most reactive (most electrophilic)

site. The 4-methylpentadiene is more electron rich than butadiene by hyperconjugation

involving the two methyl groups. The HOMO ( 2) has a significantly larger coefficient on the

unsubstituted end of the diene. Again, this is the most reactive (most nucleophilic) site.

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Since both reaction partners are nonsymmetrical, the reaction itself loses it symmetry. This

reaction stays concerted but in de transition state the formation of the bond between the

termini with the larger orbital coeffici ents is much further advanced in comparison with the

-bond. This is an explanation of the unexpected regioselectivity, forming the 1,2-

disubstituted product with the most steric hindrance.

The two remaining termini can bear a stabilised, complementary partial charge in the

transition state, without loss of stereoselectivity in the final product (where appropriate). This

is a so-called asynchronous process: the formation of the bonds does not occur at the same

moment although the reaction stays concerted.

O

OCH3

LUMOmethyl acrylaat

CH3

CH3

HOMO4-methyl-1,3-pentadiene

CH3

CH3

O

OCH3

transition state

-

1,2 ("ortho")

Another possibility is the reaction of 2-methoxybutadiene with acrylonitrile (propenenitrile).

In this case the substituents are in 1,4-relation to each other in the cyclohexene formed. This

again is a consequence of the orbital coeffici ents. It is said that the Diels-Alder reaction

orients ortho para

O

OCH3

LUMOacrylonitrile

HOMO2-methoxy-1,3-butadiene

O

OCH3

transition state

H3CO

H3CO

1,4 ("para")

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Lewis acids in combination with dienophiles further lower the LUMO in energy by

complexation with the heteroatoms present, and also the orbital coeffici ent (at the position

in relation to this heteroatom) will increase. Thus, the reactions will be faster and with higher

regioselectivity. Isoprene (2-methylbutadiene) reacts with methyl vinyl ketone (1-propen-3-

one) only after heating in toluene in a closed reaction vessel, and an isomer mixture of the

1,4- and 1,3-substituted product is formed in a 71:29 ratio. After addition of SnCl4.5H2O the

reaction becomes possible at 0C, and the ratio improves to 93:7.

O

CH3

H3CH3C

O

CH3

and

O

H3C

+

toluene, 120C 71 : 29

SnCl4.5H2O, 0C93 : 7

1.3.2. [2+2]Cycloadditions

After irradiation of alkenes with UV-light, cyclobutane derivates may form. This is a

pericyclic reaction that normally does not occur when alkenes are heated (normally alkenes

polymerize on heating). Thus, the photochemical dimerisation reaction is allowed.

Application of the aromaticity rule shows that a supra-supra approach implies a Hckel anti-

aromatic system, thus thermally the reaction is forbidden. An alternative approach, supra-

antara in which the two alkenes approach in a perpendicular fashion in the transition state,

leads to an aromatic 4 -electron Mbius system (one phase dislocation) but this is difficult to

realise by ring strain and steric hindrance of the substituents on the alkenes in the transition

state.

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+

cyclobutaneHckel anti-aromatic

1 phase dislocation4 electrons

Mbius aromatic

=

perpendicular approach

Via the frontier orbital approach it is possible to see that the photochemical reaction is indeed

allowed. After irradiation and absorption of a photon an electron is promoted from the - to

the * -orbital, which now is the HOMO. If we combine this excited molecule with a molecule

in the ground state, the symmetry of the frontier orbitals identical. For two molecules in the

ground state, the symmetry of the frontier orbitals is opposite and this reaction is forbidden.

HOMO alkene, m

LUMO alkene

*, C2

HOMO alkene (excited state)

* , C2

LUMO alkene

* , C2

thermally : symmetry-forbidded photochemically : symmetry-allowed

Ketenes or other electron poor cumulenes (such as isocyanates RN=C=O) will smoothly

undergo thermal [2+2] cycloadditions with electron rich alkenes. The perpendicular approach

of the two reagents gives a situation in which the frontier orbitals (LUMO of ketene, HOMO

of alkene) are stabilised by the p-orbital on the central carbon, that is part of the C=O bond.

The latter orbital is perpendicular to the p-orbitals of the C=C bond and therefore is

overlapping with the HOMO of the alkene. Moreover, the central carbon atom of the ketene is

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sp-hybridised and unsubstituted is, minimising the steric interactions in the transition state

and the product. An example is the cycloaddition of dichloroketene with cyclopentadiene.

Notably, the [2+2]-cycloaddition takes preference over the [4+2]-cycloaddition !

+

O

C

C

ClCl

H

H

O

Cl

Cl

HOMO

p orbital

bonding (stabilising) interactions

antibondinginteraction

LUMO

frontier orbitals of the cycloaddition of a ketene and an alkene

1.3.3 Other cycloadditions

There exists a large variety of higher cycloadditions, to which the principles discussed earlier

can be applied. For instance, cyclopentadiene reacts with tropone (cycloheptatrienone) in a

thermally allowed 6s +

4s addition. The exo-adduct is formed preferentially because the

secondary interactions during the formation of the endo-isomer are antibonding.

O +

O

ENDO

O

EXO

+

(main product)

O

bonding interactions

antibonding interactionsX X

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1,3-Dipolar cycloaddition reactions occur via molecules that are similar to the allyl anion,

thus they have 4 -electrons and they can react with a suitable unsaturated compound, then

named a dipolarophile (mostly alkenes or alkynes). The mechanism bears analogy to the

Diels-Alder cycloaddition. Well-known 1,3-dipoles are diazoalkanes, azides, and ozone.

Ozonolysis is a 1,3-dipolar cycloaddition which occurs via a 1,2,3-trioxolane, that undergoes

a cycloreversion (the opposite of a cycloaddition) to a new, very reactive 1,3-dipole, a

carbonyl oxide, and a ketone. Alternative 1,3-dipolar cycloaddition affords the ozonide (a

1,2,4-trioxolane), that can be reduced, for instance with dimethyl sulfide, to aldehydes (or

ketones for tri- or tetra substituted alkenes).

R

N N N

R

N N N

azides

R

C N N

R

C N N

R

R

diazoalkanes

O

O

O

O

O

O

ozone

O

O

O

O

O

O O

O

O

OO

O

O O+

DMS -DMSO

isoozonide

ozonidecarbonyl oxide1,3-dipole

1,3-DC 1,3-DC

1.3.4 The ene reaction

This reaction was discovered by Alder and named the ne -reaction to distinguish it from the

ne -reaction reported earlier by Diels and himself. From the name we can guess that this

is a reaction involving alkenes. It is possible to look at this reaction as an analog of the Diels-

Alder reaction in which a C-H -bond replaces a double bond of the diene. In this reaction, no

ring is formed, but rather a new C-C bond, and a hydrogen atom is relocated through space.

22

As concerns the orbitals, there are clear differences between the ene reaction and the Diels-

Alder reaction. The C-H bond is parallel to the p-orbitals of the (alk)ene, in such a way that

after the reaction a new double bond may be formed. The two molecules approach each other

in parallel planes. The ene has two components, a 2- and a

2-component. Next to these we

have a 2-component of the alkene (anhydride). The latter is in most cases an electron poor

alkene, reacting via its LUMO with the HOMO of the 2- and

2-components of the ene.

These electron poor reagents are called enophiles.

The three components are all of the (4q+2)s type, and application of the Woodward-Hoffmann

rules confirms that the reaction is thermally allowed. The aromaticity rule (no phase

dislocation, 6 electrons) and the frontier orbital theory are also in agreement with this.

O

O

O

H

O

O

O

O

O

O

H

H

H

O

O

O

H

H

Diels-Alder reaction Alder ene reaction

O

O

O

HHOMO ( )

HOMO ( )

LUMO ( *)

bonding

bonding

"ene"

(electron poor)alkene

enophile

A carbonyl group is a good enophile and the corresponding reactions with alkenes are called

carbonyl-ene reactions. Lewis acids will further increase the reactivity of the carbonyl group.

An example is the intramolecular carbonyl ene reaction of (R)-citronellal, a terpene

compound. This reaction is catalysed by the Lewis acid ZnBr2, which affords isopulegol, that

by reduction can be transformed into (-)-menthol. The stereochemistry of the carbonyl ene

reaction is explained by the occurrence of a trans-decaline transition state, in which the larger

substituents (methyl, hydroxy, isopropenyl) assume an equatorial position. Al though menthol

is found in Nature, most of the commercial menthol is prepared in this way.

23

O

H

ZnBr2

OH

H2/Ni

OH

(-)mentholisopulegol(R)-citronellal

H

O

Me

H

Me

H

ZnBr2

transition state :trans-decaline system

1.3.5 Cheletropic reactions

These are cycloaddition reactions in which two new -bonds are created on the same atom. A

non-bonding orbital (named ) that participates in these reactions can form bonds via one

lobe (suprafacially) or via both lobes (antarafacially). The reaction of an alkene with a sp2-

hybridised carbene (see later in this text) will occur via a non-linear approach. The linear

approach is not allowed for reasons of (orbital) symmetry. Further along the reaction course,

the CH2-groep will turn to minimise the strain in the final product (Skell mechanism).

According to the Woodward-Hoffmann rules, this is an allowed 2s +

2a-process, and the

aromaticity principle allows us to see the TS as a Mbius 4 -system. More applications of

this reaction follow in the part on carbenes and nitrenes.

H

HH H

2s +

2a

2s +

2s

non-linear approachallowed

linear approachforbidden

Woodward-Hoffmann approach

H

H

H

H

HOMO LUMO

LUMOcarbene

HOMOcarbene

C2

C2

m

m

Frontier orbital approach

24

The addition of SO2 to dienes can be used to prepare sulfolenes. This cheletropic

cycloaddition occurs via a linear approach. The SO2 molecule is electron poor and thus reacts

via its LUMO, which is analogous to that of the allyl anion. At higher temperatures, the

equilibrium is shifted from the sulfolenes to the dienes and SO2, as a consequence of the

increasing effect of the entropy factor. This is an extrusion reaction, and can be used as a

possible synthetic route towards substituted dienes. Thus, the diene is protected first as a

sulfolene, and later synthetic transformations can be carried out without interference of the

chemically labile diene system. In the last step, the diene is released by heating. In the

example below, sulfolene is transformed in the anion (well stabilised by the sulfone function)

and alkylated with 6-bromo-1-hexene. Thermolysis yields the substituted butadiene, which

will undergo an intramolecular cycloaddition (via a chair-type conformation) to a trans-fused

bicyclic system.

LUMOHOMO

+ SO2 SO2

SO2

H

H

thermolysis180C

Base

6-bromohexene

Diels-Alder reaction

1.4 Sigmatropic rearrangements

In a [i,j] -sigmatropic rearrangement, a group migrates within a -system, in which the double

bonds shift during the migration. The number i refers to the (carbon) atom of the migrating

group, and j is the number if the migration terminus. The two atoms that form the original -

bond are given number 1. The total amount of - and -bonds does not change during a

25

sigmatropic rearrangement. It is possible to say that a -binding shifts within an unsaturated

system, hence the name sigmatropic rearrangement.

1.4.1 Hydrogen shifts

From experiments it was shown that 1,3-H-shifts, involving two electron pairs, are thermally

non-concerted, while 1,5-, 1,9-,... H-migrations occur thermally concerted, as well as the 1,7-,

1,9-,... H-shifts.

According to the frontier orbital theory, a migration can be seen as a cycloaddition of a -

bond to a -system. Depending on the case, this may be an interaction between the -orbital

and the LUMO of the unsaturated system, or between the * -orbital and the HOMO of the

unsaturated system.

Applied to a 1,3-H-migration, this means that the suprafacial interaction is forbidden, and the

antarafacial interaction that is allowed according to theory is difficult to realise because of

geometry constraints. Photochemically, the 1,3-H-migration can occur in a suprafacial

fashion. According to the Woodward-Hoffmann rules, this thermal 1,3-H shift is a 2s +

2s-

system.

X

geometrically very difficult

LUMO

HOMO X

geometrically very difficult

HOMO

LUMO

LUMO

HOMO

photochemical 1,3-H-shiftthermal 1,3-H-shift

The thermal suprafacial interaction is allowed for a 1,5-H-shift, on the other hand the

antarafacial interaction that would have to occur in a photochemical shift suffers from

geometric constraints. For a 1,7-H-migration, a thermal antarafacial interaction is possible,

and a photochemical suprafacial interaction. In (substituted) cyclopentadienes, the 1,5-H-

migration occurs readily at room temperature, and this may lead to isomerisation.

26

LUMO

HOMO

LUMO

HOMOgeometrically difficult

thermal 1,5-H-shift photochemical 1,5-H-shift

4s +

2a

4s +

2s

LUMO

HOMO

thermal 1,7-shift

6a +

2s

geometrically possible

HR

H

H

R R

H

H1,5-H-shift 1,5-H-shift

1.4.2 Migrations of carbon fragments

A carbon atom of a migrating alkyl group will do this using a sp3-orbital, in contrast to a

hydrogen atom that uses a centrosymmetric 1s-orbital. This means that for these carbon

substituents both suprafacial and antarafacial interactions are possible. If the reaction occurs

suprafacially in relation to the -bond, then the configuration at both atoms will be retained,

or both centres will be inverted. An antarafacial reaction results in inversion on one of the

carbon atoms and retention on the other. This is of importance if chiral centres are present.

2 x retention 2 x inversion

2s

2a

retention, inversion inversion, retention

27

If the alkyl group migrates with retention of configuration (the lobe of the carbon atom bound

to the migration origin is the same lobe that overlaps with the migration terminus) then the

same rules apply as for H-migrations : 1,5-, 1,7-, ...suprafacial migrations are thermally

allowed; as are antarafacial 1,3-(but : geometrically difficult), 1,7- ...migrations.

If the alkyl group migrates with inversion of configuration, these rules are reversed: 1,3-, 1,7-

,.. suprafacial (relative to the -system) migration is thermally allowed; as are 1,5-

(geometrically difficult), 1,9-,... antarafacial migrations. This is in agreement with the frontier

orbital theory and the Woodward-Hoffmann rules.

HOMO LUMO*

LUMO*

HOMO

2s +

2a (allowed)

HOMO

4s +

2s (allowed)

LUMO

3

1,5-alkyl migration with retention of configurationThe 1,5-migration with inversion (antarafacial) is also allowed but geometrically difficult

1,3-alkyl migration with inversion of configuration

A few examples of alkyl migrations are the 1,5-suprafacial migration with retention of

configuration in norcaradiene systems, and the 1,3-suprafacial alkyl migration with inversion

of configuration. These reactions occur smoothly as a result of the rigid ring system which

entropically favours the rearrangement.

H3C

NC CN

H3CCN

CN55C

H3C

CN

CN

55C

HOAc

HDH

HD

OAc

inversion

28

The [3,3]-sigmatropic rearrangements are well known and the Claisen- and Cope-

rearrangements belong to this class. The transition state is a six-membered ring with a chair

conformation as in cyclohexane. This allows us to determine the stereochemistry in relevant

cases. The Claisen-rearrangement is a general synthetic method of , -unsaturated carbonyl

compounds. If the enol ether is part of an aromatic system, an allylphenol is formed after 1,7-

H-migration (and rearomatisation) of the initially formed cyclohexadienone. Cope-

rearrangements are very efficient if the -bond is part of a strained cyclopropane ring,

resulting in the formation of a cycloheptadiene.

According to the Woodward-Hoffmann rules, three components are involved in these

reactions, namely a 2a-,

2a- and

2s-component (or alternatively a

2s-,

2a- and

2a-

component). Thus, the thermal reaction is allowed. The aromaticity principle confirms this

because the TS is a 6-electron system with two phase dislocations (Hckel system). From the

frontier orbital treatment it is possible to recognise a bonding interaction between the -bond

and the LUMO-orbitals of the alkene involved ( *).

O O

Cope rearrangement Claisen rearrangement

2a

2a

2s

O O OH

H

Claisen-rearrangement

1,7-H-shift

LUMO*

LUMO*

HOMO

Cope- rearrangement

[3,3]-Sigmatropic rearrangements are applied in the industrial production of citral, an

important intermediate in the synthesis of Vitamin A. In the first step of the reaction, an enol

29

ether is prepared staring from an aldehyde and an allyl alcohol (prenyl alcohol) via azeotropic

removal of water. After Claisen rearrangement, an aldehyde is formed, which in its turn will

undergo a Cope rearrangement. The prenyl group thus moves from one end of the molecule to

the other, and is twice inverted.

The Fischer-indole synthesis is an example of a [3,3]-sigmatropic rearrangements in which

nitrogen atoms are involved. A phenylhydrazone can be transformed (tautomerized to an

enehydrazine in acidic medium. The latter enehydrazine undergoes the rearrangement and the

unstable bisimine will first aromatise (catalysed by acid) and then cyclise with release of

ammonia.

CHO

OH

O

CHO

CHO

citral

Cope

rearrangement

Claisen

rearrangement-H2O

NH

N

H3C COOCH3

NH

NH

H2C COOCH3

[3,3]NH

NH

H2C COOCH3

NH2

NH

H2C COOCH3

NH

COOCH3-NH3

30

[2,3]-Sigmatropic rearrangements are quite common and they take place via charged

intermediates or products with free electron pairs on heteroatoms. As an example we can refer

to an anionic rearrangement of allyl ethers, forming 4-butenols. This reaction can again be

seen as a 2a +

2s +

2a process, which is thermally allowed.

A second possibility is a rearrangement of allyl sulfenate esters to allyl sulfoxides. After

proton abstraction and alkylation, the reverse reaction can be carried out. Al though the

equilibrium lies to the left, it can be forced right by adding trimethyl phosphite, a compound

that removes the sulfenyl group. The overall result is an alkylation of the allyl alcohol.

O

Ph

BuLi

O

Ph Ph

O

[2,3]

Ph

2a

2a

2s

R OH R O

SPh

heat

[2,3]

R

S

OPh

BuLi

R

S

OPh

R'

O

R

R

SPh

RX

P(OMe)3OH

R

R

1.5. Electrocyclic reactions

In these reactions, a ring is formed (or broken) starting from a single compound or fragment,

in contrast to a cycloaddition reaction. A -bond is transformed in a -bond (or vice versa).

Electrocyclic reactions are a class within the pericyclic reactions and as such can be studied

according to the same principles (aromaticity rule, frontier orbital theory, Woodward-

Hoffmann rules).

A simple case is the ring closure of butadiene to cyclobutene. The molecular orbitals that are

involved are from the - and -type and according to the Woodward-Hoffmann rules this

should happen, in the case of an allowed thermal process, via a 2s +

2a interaction.

31

In other words, the -bond opens along lobes with opposite sign (antarafacially), and the

separated orbitals turn in the same sense. This is a conrotatory ring opening and will have an

effect on the stereochemistry of substituted butadienes / cyclobutenes. For instance, starting

from cis (or Z-)-3,4-dimethylcyclobutene the E,Z-hexa-2,4-diene will be formed (in two

possible ways). On the other hand, starting from trans- (or E-)-3,4-dimethylcyclobutene the

E,E-hexa-2,4-dienz will be formed. Theoretically, it is possible to form Z,Z-hexa-2,4-diene,

but because of steric hindrance this isomer will not be obtained (or in much less amount).

LUMO

HOMO

conrotatory

B

A A

B A B

AB

2s +

2a

CH3

H

H

CH3

CH3

H

CH3

H

H

CH3

H

CH3

+

Z,E-hexa-2,4-diene

CH3

CH3

H

H

CH3

H

H

CH3

H

CH3

CH3

H

+

E,E-hexa-2,4-diene Z,Z-hexa-2,4-diene(minor isomer)

175C

175C

The corresponding photochemical reaction takes place with another stereochemistry because

now this is a 2s +

2s process. The ring opening is disrotatory. Note that although the two

lobes (same sign) are turning to the same side (up or down), one movement will be clockwise

and the other counter clockwise (or vice versa). In this case, the E,E-hexa-2,4-diene is formed

by irradiation of cis-3,4-dimethylcyclobutene (or the reverse reaction). In the frontier orbital

32

treatment, the * -orbital of the alkene part is seen as the HOMO-component, and the * -

orbital of the single bond is seen as the LUMO-component.

In the thermal or photochemical reactions of cyclobutene/butadiene and other conjugated

systems either conrotatory or disrotatory processes are possible, depending on the case. In

many cases, only one isomer is formed if this compound is more stable because of steric

reasons or ring strain (see formation of E,E-hexa-2,4-diene).

LUMO

HOMO

disrotatory

B

A A

B B B

AA

2s +

2a

CH3

H

H

CH3

CH3

H

CH3

CH3

E,E-hexa-2,4-diene

CH3

CH3

H

H

CH3

H

CH3

H

H

CH3

H

CH3

+

E,Z-hexa-2,4-diene

or

A A

BB

h

h

A second electrocyclisation is the reversible transformation of hexatriene to 1,3-

cyclohexadiene. Now the thermal reaction is a disrotatory process, involving a diene system

and a -bond. As the frontier orbitals we take the LUMO of the diene system and the HOMO

of the -bond (or vice versa). Such a 4s +

2s process is thermally allowed. The

corresponding photochemical reactions with hexatriene/1,3-cyclohexadiene are conrotatory.

This explains some stereospecific transformations of 2,4,6-octatrienes to

dimethylcyclohexadienes.

33

B B

AA

thermal

BAB

A

or

ABA

B

disrotatory

H

CH3

H

CH3CH3

CH3

CH3

H

H

CH3

H

H

CH3

H

H

CH3and

H

CH3

CH3

H

h

130C

178C

The rules for the reaction path followed for electrocyclic reactions are summarized in the

following table :

# -electrons # electron pairs reaction circumstances overlap process

4n even thermal conrotatory

4n even photochemical disrotatory

4n+2 odd thermal disrotatory

4n+2 odd photochemical conrotatory

The same insights can be reached by using the aromaticity principle. Conrotatory ring

openings agree with Mbius systems, and therefore the ones with 4n electrons are thermally

allowed, and these with 4n+2 electrons are photochemically allowed. Disrotatory ring

openings agree with Hckel systems and therefore are thermally allowed for 4n+2 electrons,

while these with 4n electrons occur on irradiation.

34

Other electrocyclisations will follow the above rules, for instance the ring opening of

cyclopropyl cations (2 electrons involved, so the thermal reaction occurs disrotatory) to allyl

cations. In substitution reactions of cyclopropyl halides in many cases allyl derivates are

obtained.

The Nazarov cyclisation, that occurs with doubly unsaturated ketones in acid media is

conrotatory (4 electrons) when thermal and cyclopentenones are formed after tautomerisation

of the intermediate enols.

The cyclooctadienyl anion (6 electrons) smoothly ring closes thermally in a disrotatory

process, after which the cis-fused hexahydropentalenyl anion is formed. The corresponding

photochemical ring closure is not possible because the product formed would have a trans-

fusion, leading to too much strain.

ClR

RCl

R

RR R

R R

O

H

OHOH

H H

- H

OH

H H

tautomerisation

O

H H

H

H

H

BuLi

0C

35

The formation of Vitamin D2 starting from ergosterol (derived by biosynthesis from

cholesterol) is a nice example of a few pericyclic reactions occurring in Nature. First, an

electrocyclic ring opening occurs under the influence of sunlight, and provitamin D2 is

formed in a conrotatory (photochemically, 6 electron) process. A (thermal) disrotatory process

is not possible because in this case the double bond in the C-ring (third ring of the steroid)

would be trans, and this is obviously impossible. The provitamin D2 then undergoes an

allowed 1,7-H-shift (antarafacial, thermal) to form Vitamin D2.

H

Me

HO

Me

H

Me Me

Me

Me

electrocyclic reactionh , conrotatory

CH2

HO

Me

H

Me Me

Me

MeH

1,7-H-shift (thermal, antarafacial)

CH2

HO

Me

H

Me Me

Me

Meergosterol provitamin D2

Vitamin D2

2. Stereochemistry in concerted addition-, substitution- and elimination reactions

The Woodward-Hoffmann-rules can also provide insight in the stereospecificity of other

concerted reactions (other than pericyclic). In the transition state of these reactions a

symmetry plane m or rotation-axis C2 may be present and the following rules can be

formulated for thermal reactions:

1. If the total number of participating electron pairs is odd (e.g. 4n+2 electrons), then a

suprafacial reaction (symmetry plane m) is allowed. In other words the bonds are

formed or broken on the same side of the reaction centre.

2. If the total number of participating electron pairs is even (e.g. 4n electrons, then an

antarafacial reaction (C2 axis) is allowed.

36

Below are a few examples.

2.1 Substitutions

In the classical SN2-reaction, two electron pairs are involved, that belong to the attacking and

leaving group. Thus, we have an antarafacial attack and an inversion of the stereocentre, if

present. This can also be related to the frontier orbital theory.

XY

antara

Y

YX

HOMOLUMO

antara

Y

X

HOMO

LUMO

supra (bonding and antibonding)

The related SN -type substitutions can take place for allyl systems. In this case, three electron

pairs are involved and the substitution occurs according to a stereospecifically syn suprafacial

attack, resulting in retention of conformation.

OCOAr

Me

Me

NH

Me

Me

NMe Me

+ ArCOOH

In electrophilic SE2 reactions, only one electron pair is involved: a suprafacial reaction is

allowed. The LUMO of the electrophile interacts with the site that is the most rich in electrons

and the -bond is the HOMO-orbital. Therefore, protonation of organometals or nitration of

alkanes takes place with retention of configuration.

37

HgX + H H + HgX

H + NO2NO2 + H

2.2 Additions

1,2-Additions to alkenes and 1,4-additions to dienes can take place in a concerted way, the

reactions then are respectively anti (antarafacial, 4 electrons) and syn (suprafacial, 6

electrons). However, often this type of reactions involve reaction intermediates (e.g.

carbocations)

H

X

H

Xantara

D X

supra

D X

2.3 Eliminations

The E2-reaction in the presence of a base can be regarded as a process with 6 electrons: one

pair of the base and two pairs of the substrate. The process is twice antarafacial and thus

equivalent to a suprafacial process. Therefore, H and X are anti(periplanar) to each other.

Analogously, 1,4-eliminations take place via a syn-position of H and X because 8 electrons

are involved.

38