Advanced organic chemistry wim dehaen

1.2 Pericyclic reactions : general principles 1.2.1 Molecular orbitals Molecular orbitals are obtained by linear combination of atomic orbitals LCAO.. This approach gives information on

WIM DEHAEN

ADVANCED ORGANIC CHEMISTRY

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 +

transformation of sulfolene to butadiene and SO2+

thermal Diels-Alder cycloaddition

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

-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 - or π-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

-O

O

Claisen rearrangement

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

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

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

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

so-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

 is non-bonding

An allyl cation has electron configuration 1220, an allyl radical 1221, and an allyl anion

1222 The allyl group is bent because the central carbon atom has sp2-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

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 “HOMO-LUMO-gap” 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 Hückel calculations predict two orbital coefficients 0.6 and 0.371 In the two frontier orbitals the coefficients 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

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 coefficients It is important to keep in mind that this does not completely correspond to reality

(n = 6)

For cyclic conjugated systems other rules apply The Hückel 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 Hückel energy levels are given for planar, cyclic conjugated systems of n = 3 to n = 8

1.2.2 Aromaticity

Hückel’s rule : 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 Hückel 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 Möbius- or anti-Hückel-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 Hückel system, and a system with an odd amount of phase dislocations is a Möbius system

Möbius-system Hückel-system

A so-called Möbius ring can be prepared by turning a strip of paper at one end over 180° and then joining the ends Note that a Möbius ring has only one side

Evidently, such twisted compounds have large strain, making them unstable Therefore, Möbius systems have never been isolated, but are rather of theoretical interest to describe the transition states of pericyclic reactions

Hückel systems as before are aromatic with 4n +2 -electrons, Möbius 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 Hückel system with 4n +2 -electrons or a Möbius system with 4n -electrons For photochemical processes that occur via the lowest excited state, this rule is reversed : the allowed processes are Hückel systems with 4n -electrons or Möbius 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

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

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)

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 “s” and “a” refer to a suprafacial, respectively a antarafacial component For a

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

Hückel 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

HOMO butadiene

( 

LUMO ethene ( 

LUMO butadiene ( 

HOMO ethene ( 

s 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

endo-adduct

O

H H

O

O

exo-adduct (not formed)

H

H O

H

O

O O

endo-adduct kinetic product

furan (aromatic)

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

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 coefficients will be larger than others The size of these orbital coefficients 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

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 coefficients is much further advanced in comparison with the other σ-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

LUMO methyl acrylaat

CH 3

CH3

HOMO 4-methyl-1,3-pentadiene

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 coefficients It is said that the Diels-Alder reaction orients “ortho” and “para”

O

OCH3

LUMO acrylonitrile

HOMO 2-methoxy-1,3-butadiene

Lewis acids in combination with dienophiles further lower the LUMO in energy by complexation with the heteroatoms present, and also the orbital coefficient (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 0°C, and the ratio improves to 93:7

Application of the aromaticity rule shows that a supra-supra approach implies a Hückel 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 Möbius 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

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

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

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 Cl Cl

X X

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)

O O O

O

O

O O

1,3-dipole

1.3.4 The ene reaction

This reaction was discovered by Alder and named the “ene”-reaction to distinguish it from the

“diene”-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 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

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

Diels-in parallel planes The ene has two components, a 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

H HOMO (  )

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 Although menthol

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

O ZnBr2

OH

H2/Ni

OH

(-)menthol isopulegol

(R)-citronellal

H O

Me H

Me

H

ZnBr 2 transition state : trans-decaline system

1.3.5 Cheletropic reactions

These are cycloaddition reactions in which two new σ-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 2

s + 2

a-process, and the aromaticity principle allows us to see the TS as a Möbius 4-system More applications of this reaction follow in the part on carbenes and nitrenes

non-linear approach

allowed

linear approach forbidden Woodward-Hoffmann approach

H H

H

H

LUMO carbene

HOMO carbene

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

LUMO HOMO

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 2

s + 2

ssystem

-X

geometrically very difficult

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

s +  2 s

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

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-, , 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

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

H 3 C

NC CN

CN 55°C

H3C

CN

CN 55°C

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

Cope-According to the Woodward-Hoffmann rules, three components are involved in these reactions, namely a 2

[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

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

Claisen rearrangement -H2O

N

N

H3C COOCH3

N NH

H2C COOCH3

[3,3]

NH NH

H2

NH2NH

H2

N COOCH3-NH3

[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 2

a + 2

s + 2

a 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 Although 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

Ph

 2 a

 2 a

 2 s

SPh heat [2,3]

R

S O Ph

BuLi

R

S O Ph

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 2

s + 2

a interaction

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)

CH 3

H H

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

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)

h 

h 

A second electrocyclisation is the reversible transformation of hexatriene to 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

1,3-of the -bond (or vice versa) Such a 4

s + 2

s 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

B B

A A

thermal

B A

or

A B

# -electrons # electron pairs reaction circumstances overlap process

The same insights can be reached by using the aromaticity principle Conrotatory ring openings agree with Möbius 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 Hückel systems and therefore are thermally allowed for 4n+2 electrons, while these with 4n electrons occur on irradiation

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 fusion, leading to too much strain

0°C

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

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

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

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

The related SN2’-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

HgX + H H + HgX

+ 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)

Excercises Chapter 1

1 * A rather complicated natural product is prepared by three consecutive pericyclic reactions Starting and final product are given below What are the intermediates A and B and explain the stereochemistry of the final product One of the ways of solving this is to start from the final product and to think back (« retrosynthetic analysis ») until returning to the starting material

N Ph

Ph

+ N

N Ph

Ph + N2

3* Explain the reaction below with frontier orbitals and the aromaticity principle :