When stereoisomeric substrates were examined, the rearrangement proved to be stereospecific, ruling out a common zwitterionic intermediate. The examples in the green-shaded area clearly demonstrate inversion of configuration in the carbon-carbon bond forming step. An application of the Favorskii rearrangement in synthesis will be shown above by clicking on the diagram a second time. In this case cleavage of the cyclopropanol at the more substituted α-carbon probably reflects the inductive effect of the THPO substituent.
Epoxy alcohols undergo reversible intramolecular epoxide opening reactions known as the Payne rearrangement. The following diagram illustrates three such reactions, and a general mechanism is written in the gray-shaded box. The equilibrium usually favors the more highly substituted epoxide moiety. As expected for an SN2, process, these transformations are stereospecific. Although such equilibria may not always lie in the desired direction, subsequent reaction may divert one of the components to a useful product. An example will be shown by clicking on the diagram. Even though the terminal epoxide is a minor component of the Payne equilibrium, its kinetic advantage in the ring opening step determines the final product. The course of reaction in the absence of the Payne rearrangement is displayed in the gray-shaded box.
An interesting and generally useful skeletal transformation, involving specific carbon-carbon bond cleavage with accompanying conversion of certain sigma-bonds to pi-bonds, is known as the Grob fragmentation. As background for discussing this reaction, it is helpful to define the concept of ethylogy, which may be regarded as the sigma-bond equivalent of vinylogy. This is illustrated in the following diagram. Here a simple nucleophilic fragmentation at M is converted to an ethylagous analog by the insertion of a two carbon (ethyl) segment between the reacting moieties.
A simple example of an ethylagous relationship may be found by comparing the acid or base-catalyzed loss of water from a carbonyl hydrate with the retro aldol cleavage reaction. This will be shown above by clicking on the diagram. The carbon atoms of the ethylagous unit are colored green.
Whenever functional group interactions occur through a chain of covalent bonds (sigma or pi), stereoelectronic factors will play an important role. This is demonstrated by the stereoisomeric amino chlorides in the following diagram. The non-ethylagous analog for the reaction is drawn in the gray-shaded box. A Grob fragmentation takes place in the top example, because the orbitals of the bonding and non-bonding electron pairs participating in the reaction are aligned properly. These are the non-bonding pair on nitrogen and the bonding pairs in the green-colored covalent bonds. Their alignment is a function of their relative orientation on the brown-colored bonds. As drawn, the reacting electron pairs on each such bond are anti, the preferred configuration for maximum overlap. In the bottom epimer the chlorine atom is not oriented properly, and a slower bimolecular E2 elimination is observed.
Other examples of Grob fragmentations will be shown above by repeated clicking on the diagram. The first is a useful ring enlargement reaction in which the common bond of a fused bicyclic skeleton is cleaved, yielding a larger carbocycle. Applications of this kind may be initiated in several ways, one interesting case being that shown in part 6 of a curved arrow problem. A second click on the diagram displays a Grob-like fragmentation, favored by the relief of ring strain in the four-membered ring.
A one-pot reaction in which a starting compound is transformed into a skeletally rearranged product by way of several unremarkable steps may appear to be extraordinary and unexpected. One such example is the conversion of the sesquiterpene santonin into santonic acid on heating with base. From the formulas shown in the following equation, this reaction not only adds one equivalent of water (expected if the lactone is opened), but also creates a new carbonyl group and removes both carbon-carbon double bonds. The nature of the transformation of santonin to santonic acid remained unknown for many years, but was resolved in 1948 by the work of R. B. Woodward and coworkers at Harvard. Clicking on the diagram, will display the structures of santonic acid and its oxidative products.
The mechanism by which this remarkable change takes place will be displayed above by a second click on the diagram. Initial hydrolysis of the lactone to santoninic acid is followed by isomerism of the α,β-unsaturation to a β,ν-location and tautomerization. The resulting diketone, in its cis-fused configuration, then undergoes an intramolecular Michael reaction, forming a new five-membered ring (note the colored bond).
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