1.4.1 Definition of rearrangement reactions
Rearrangement reactions play a vital role in modern synthetic chemistry. A simple definition would describe a rearrangement reaction as the migration of a group from one atom to another atom within the same molecule.[83] Rearrangements have long been known, with many important examples having been discovered in the 19th century long before the introduction of modern organic theory, such as the Benzil-Benzilic Acid rearrangement first observed by Liebig in 1838.[84]
The departing segment moves from what is named the migration origin 87 (atom A) and after rearrangement is bonded to the migration terminus 88 (atom B).
A B Y
A B Y
87 88
In any rearrangement there are two possible modes of reaction, one possiblility involves the complete removal of Y from the atom A with Y becoming attached to atom B of another molecule.
Normally intermolecular rearrangements are considered along with intramolecular rearrangements even though they do not strictly fall under the above definition. The second mode of reaction involves the movement of Y from A to B within the same molecule, an intramolecular rearrangement. Migrations are almost always from one atom to an adjacent atom (1,2-migrations) however longer movements can be achieved through a series of [1,2]-migrations. Rearrangements can be classified broadly as nucleophilic, electrophilic, pericyclic or free radical. In a nucleophilic rearrangement, the migrating group Y moves with its electron pair. In an electrophilic rearrangement, the migrating group Y moves without its electron pair and finally in a free radical rearrangement, the migrating group moves with a single electron. Nucleophilic rearrangements are by far the most common type and the reason for this can be seen from consideration of the transition states 89 involved.
A B Y
Nucleophilic Free radical Electrophilic 89
antibonding orbital bonding orbital
The transition state (or intermediate) for all three cases is represented by 89 with the two electron A-Y bond overlapping with an orbital on atom B, which contains zero, one or two electrons, in the case of nucleophilic, free radical and electrophilic respectively. With a nucleophilic rearrangement only two electrons are involved with both occupying a bonding orbital which translates to a low energy transition state. However with a free radical or electrophilic rearrangement there are three or four electrons respectively which must be occupied in antibonding orbitals thus raising the energy of the transition state 89. When these rearrangements are observed, the migrating group is normally aromatic, the aryl group being able to accomodate the extra electron. Pericyclic rearrangements proceed through cyclic transition states and are classified by a system based on migration of a sigma bond. Either end of the sigma bond which rearranges is numbered unity and each carbon atom is then numbered sequentially. The final location of the sigma bond determines the classification of the reaction e.g. these include [1,5]-, [2,3]-, and [3,3]-sigmatropic rearrangements among others.
1 8
1.4.2 Sigmatropic rearrangements
Sigmatropic rearrangements have been defined as:[85]
“The migration, in an uncatalysed intramolecular process of a σ bond, adjacent to one or more π systems, to a new position in a molecule, with the π systems becoming reorganised in the process.”
These reactions are called sigmatropic because a σ-bond appears to move from one place to another throughout the course of the reaction. A numbering system has been developed to identify the order of sigmatropic reactions. The rearrangement of 90 into 91 is known as a [3,3]-sigmatropic rearrangement, each terminus of the sigma bond drawn in red for 90 is numbered 1, simply counting to the ends of the new sigma bond in 91 gives the order of the reaction.
R R
R R
1 2
3
1
2 3 1
2 3 1
2 3
90 91
1.4.2.1 The Claisen rearrangement
The first sigmatropic rearrangement was reported by Claisen in 1913[86] when an aryl allyl ether 92 was heated without solvent to give an ortho-allyl phenol 94. Aryl allyl ethers which bear substituents in both ortho positions undergo allyl migration to the para position. The mechanism is a concerted pericyclic [3,3] sigmatropic rearrangement requiring no catalyst. If the α-carbon next to the oxygen atom bears a non-hydrogen substituent then stereoisomers will be generated.
In the majority of cases the resulting double bond will be trans since the Claisen rearrangement proceeds through a cyclic chairlike transition state 93,[87,88] and any substituent R will adopt an equatorial position which is retained in the final product.
O O
old bond breaking
new bond forming
O
H
OH
92 93 94
H-transfer
Ethers which contain an alkyl group in the γ-position sometimes rearrange to give so-called abnormal products such as 97.[89] These are postulated to arise from the initial formation of the normal rearranged products such as 95 which subsequently rearrange to cyclopropane intermediates like 96[90] which can undergo a [1,5]- sigmatropic hydrogen shift to form the
“abnormal” products such as 97.
O H O H OH
95 96 97
Rearrangements in organic synthesis
The mechanism of the Claisen rearrangement does not involve ions and theoretically it should not be dependent to a great extent on the presence or absence of electron donating/withdrawing substituents. Electron donating substituents have been found to increase the rate whereas electron withdrawing substituents have been found to decrease it.[91-93] However the effect is small and solvent effects have been shown to be much more important[94,95] with highly polar solvents like trifluoroacetic acid being especially effective even at room temperature.[96] Normally Claisen rearrangements are performed without catalysts but recent research has focused on the use of catalysts such as BF3 and AlCl3 to effect rearrangement at lower reaction temperatures.[97] The presence of an aromatic ring is not necessary for the Claisen rearrangement with the same reaction also proceeding with aliphatic ethers. The reaction is then either known as an aliphatic Claisen rearrangement or as a Claisen-Cope rearrangement. [3,3]-Sigmatropic rearrangements which only contain carbon atoms in the intermediate chair transition state ring are known as Cope rearrangments.[98]
A discussion of the stereochemistry of sigmatropic rearrangements normally includes consideration of the frontier orbitals involved. It should be recognised that a sigmatropic migration can occur by two distinct routes. When the migrating group remains associated with the same face of the conjugated π system 99 during the course of the rearrangement then the migration is termed suprafacial. Alternatively the term antarafacial is employed when the migrating group moves to the opposite face of the π system 101 during the course of the migration.
d
In order to determine whether a rearrangement will proceed by suprafacial or antarafacial migration, a detailed examination is conducted of the orbital symmetry requirements between the π system and the orbitals from the migrating fragment. A frontier orbital analysis of the simple 1,3-H shift can be thought of as a hydrogen atom interacting with an allyl radical. The HOMO for an allyl radical is the only frontier orbital we need consider for the rearrangement.
The hydrogen atom has only a 1s orbital which has only one lobe. Sigmatropic rearrangements of hydrogen follow a rule stating that the hydrogen atom must move from a plus to a plus or from a minus to a minus lobe, of the HOMO; it cannot move to a lobe of opposite sign. This follows from the rule that bonds form from the overlap of orbitals of the same sign. Since this is a concerted reaction, the hydrogen orbital in the transition state must overlap simultaneously with one lobe from the migration origin and one from the terminus. Clearly these orbitals must have the same sign.
H H
suprafacial antarafacial
The 1,3-suprafacial hydrogen shift is forbidden by orbital symmetry considerations. Therefore for a 1,3-H migration only the antarafacial is allowed, however because the transition state contained a rigid three carbon chain the 1,3-antarafacial rearrangement is not observed in practice which is convenient otherwise double bonds would easily migrate around organic molecules.
2 0
A similar analysis of the 1,5-sigmatropic rearrangement of hydrogen leads to the opposite conclusion. In this case the suprafacial process is allowed whereas the antarafacial process is now forbidden.
H
Thermally allowed 1,5-suprafacial hydrogen shift in 1,3-pentadiene
Photochemistry changes all these observations due to the promotion of an electron into the former LUMO. Thus thermal 1,3-H shifts by the antarafacial route are unknown however the photochemical 1,3-H suprafacial shift contains a few examples in the literature.[99] The situation is reversed for 1,5-H shifts. Thermal suprafacial shifts are very common with photochemical antarafacial shifts being much less common.[100]
1.4.3 The Conia rearrangement
The thermal cyclisation of unsaturated carbonyl compounds as a method for the formation of carbon-carbon σ-bonds is sometimes called the Conia rearrangement. The rearrangement can be thought of as an intramolecular variant of the “Ene” reaction[101] where an alkene can add to another alkene, with the formal addition of RH to a double bond. This is a useful method for the construction of cyclic systems α to an aldehyde or ketone. Conceptually the ene reaction can be classified by six different cyclisations; Mikami[102] provides a short discussion on ene nomenclature.
The intramolecular thermal reaction of unsaturated carbonyl compounds leads to considerable changes in structure without the need for expensive catalysts or additives, with the formation of cycloalkyl ketones, cycloalkanones and bridged bicycloalkanes having been prepared by this method.[103] The mechanism of the Conia rearrangement implies an enol tautomer 103 which is formed in catalytic amounts by a [1,3]-hydrogen displacement at elevated temperatures. The hydrogen from the enol can then be transfered to the terminus of the double bond with formation of a new carbon-carbon sigma bond.
O R
O
R H
R O
102 103 104
R = H, alkyl, aryl
∆ ∆
A single non-epimerisable product 104 is formed when R = CH3 with the methyl group that is formed in the cyclisation step having a cis relationship with the acyl group. The formation of a five ring always proceeds with a cis relationship between the newly formed alkyl group and the acyl group.[104] The presence or absence of substituents in the compound has no effect on this outcome. In certain cases observation of products containing the trans relationship between the new alkyl group and the acyl group can be detected. Formation of the trans isomer has been explained by assuming that the cis isomer is formed initially which under the elevated reaction temperatures is able to re-enolise in the direction of the newly formed ring. Reformation of the Rearrangements in organic synthesis
keto group leads to the thermodynamically more stable trans isomer being formed. This explanation does not hold for all observations of the trans product, with examples known that result from the different orientations of the two allyl groups in the transition state.
Bridged carbonyl compounds can be formed in good yields by a Conia rearrangement of 3-alkyl acetylcyclohexane 105 to give the corresponding 1-acetylbicyclo[3.2.1] alkane 106. Only one stereoisomer, with the methyl group cis with respect to the acetyl group, appears to be formed in this reaction.[105]
O O
H O
105 106
By a similar mode of action spiro compounds of type 108 can be synthesised from substituted 2-alkenylcycloalkanones such as 107. The ring size of the starting ketone is not important with both cyclopentane and cyclohexane rings having been used; the nature of the side chain is more important. Hex-ω-enyl ketones of type 107 lead to two products, cis-6-methyl-spiroketones 108 and compound 109. 109 is formed as a result of the cyclic ketone enolising to the α’-carbon followed by ring closure to give a [5.2.1]-bicycle 109.[106] Numerous examples exist of so-called α’-cyclisations where the enol intermediate is orientated or forced to the opposite side followed by the cyclisation step.[104] When the side chain contains a terminal alkyne as opposed to an alkene the formation of spiro systems containing an exo double bond is observed and represents an excellent method for the generation of spirodiketones.
O
H O
H O
O
O
∆
∆ 107
90%
10%
108
109
2 2