Base Catalyzed Rearrangements

Many common rearrangements are induced by the formation of electron deficient sites
which attract neighboring non-bonding or bonding electron pairs. These cationic
rearrangements have been discussed elsewhere. In this chapter rearrangements and
related reactions resulting from anion induced bonding shifts will be examined.

1,2-Group Shifts
Two examples of 1,2-phenyl shifts are shown in the following diagram. In each case the
driving force for the rearrangement is the conversion of a less stable anion into a more
stable one. The reversible addition of hydroxide ion to one of the benzil carbonyl groups
produces an intermediate which undergoes a pinacol-like rearrangement. In contrast to the
carbocation "pull" that initiates the pinacol rearrangement, thisbenzilic acid
rearrangement complements a weak electrophilic pull by the adjacent carbonyl carbon
with the "push" of the alkoxide anion. A rapid proton transfer then forms the relatively
stable carboxylate anion. In the second example, a very reactive 1-carbanion (pK a 45) is
converted to a diphenyl resonance stabilized carbanion (pKa 34).

Similar 1,2-shifts of hydrogen or alkyl groups may also be favored by loss of a stable
anion, as illustrated by the following example. Once again, an alkoxide anion provides a
"push", and loss of the stable tosylate leaving group terminates the rearrangement. The
LiAlH4 reagent not only generates the oxy-anion, but also reduces the resulting carbonyl
products to alcohols. This rearrangement contrasts with the Wagner-Meerwein
rearrangement in which a stable anion leaving group initiates the process by generating a
carbocation species.

Brook Rearrangement
The rearrangement of silicon groups from carbon to oxygen is called the Brook
rearrangement. An important driving force for this shift is the increased bond strength of
the SiO bond (110 Kcal/mol) compared with the SiC bond (76 Kcal/mol). The example
given in the following equation is catalyzed by base, and a cyclic transition state is
indicated by the high entropy of activation. Retention of configuration at the silicon atom
during the rearrangement was demonstrated by the reaction sequence shown by clicking
on the diagram. Since the benzylation of the silyl chloride is known to proceed with
inversion, and the final hydride reduction with retention, the rearrangement itself must
have occurred with retention. Note that the sign of optical rotation for different silyl
derivatives does not necessarily correlate with their configuration.

By clicking on the above diagram a third time, thermal 1,2 and 1,3- silicon rearrangements
to oxygen in silyl esters and ketones will be displayed. When alkoxide base is added to
silyl ketones, hypervalent silicon intermediates may be formed prior to rearrangement, as
shown by one last click on the diagram. Mechanisms for the formation of various products
are given by the curved arrows.

Wittig and Stevens Rearrangement

Three examples of an unusual 1,2 alkyl shift from oxygen to carbon, known as the [1,2]Wittig rearrangement, are shown below. Here a powerful base generates a reactive
carbanion alpha to an ether. An intramolecular shift of an alkyl or aryl group then creates a
much more stable alkoxide anion, which in the last example eliminates cyanide anion.
Many studies of the mechanism of this rearrangement have been conducted, and it has

been established to be intramolecular. The initially created negative charge weakens the
other carbon-oxygen bond, enabling a rapid radical-radical anion dissociationrecombination process to take place (green-shaded box).

A related reaction involving a 1,2-shift from nitrogen to carbon is known as the Stevens
rearrangement. Many aspects of this transformation are similar to the Wittig
rearrangement. Clicking on the above diagram will display examples of the Stevens
rearrangement.

Other Sigmatropic Shifts

Base catalyzed reactions of allylic ethers and amines may take different paths depending
on substitution and conditions. Often [2,3]-sigmatropic shifts occur in preference to others.
The example shown below is illustrative. Both the [2,3]-shift and the minor [1,4]-shift are
regio and stereospecific, suggesting a structured transition state for each.

[2,3]-Sigmatropic shifts of this kind are commonly called [2,3]-Wittig rearrangements. A

general example involving diallyl ethers is shown in the following diagram. By clicking on
the diagram the cyclic chair-like mechanism proposed to account for the stereospecificity
of this reaction will be displayed. A second click on the diagram will show two additional
examples which demonstrate the synthetic utility of the reaction.

Shifts Occurring by Addition-Elimination Mechanisms.

The Sommelet-Hauser rearrangement, a reaction that often competes with the Stevens
rearrangement, might be classified as a [2,3]-sigmatropic shift. However, it may also be
considered an addition-elimination process, as drawn below. A nitrogen ylide, formed by
reaction of a quaternary ammonium salt with strong base, is the reactive intermediate. This
species may be trapped by an electrophile, but normally rearranges in the fashion shown.
The Truce-Smiles rearrangement displayed by clicking on the diagram represents another
such aryl relocation, in this case a 1,4-shift.

The Favorskii Rearrangement

Treatment of -halogenated ketones, having acidic '-hydrogens, with nucleophilic bases
often leads to a skeletal rearrangement known as the Favorskii rearrangement. As
depicted in the following diagram, this reaction is believed to proceed by way of a
cyclopropanone intermediate. Facile conversion of cyclopropanones to hydrates and
hemiacetals (relief of angle strain) occurs, and the cyclopropoxide conjugate base
undergoes ring opening and solvent protonation. In the case of unsymmetrical
cyclopropanones the ring cleavage takes place on the side that yields the more stable
carbanion or leads to elimination of a stable anion (second example). A debate concerning
the nature of the carbon-carbon bond formation step now favors direct (synchronous)
formation of the cyclopropanone by a 1,3-elimination, as shown, rather than initial
ionization of the enolate to a zwitterionic species such as that drawn in the green box.
However, in polar solvents this intermediate may play a role.

By clicking on the above diagram another example of the Favorskii rearrangement will be
displayed. Here the unsymmetrical cyclopropanone opens to favor the less substituted carbon,
reflecting
thecarbanion
stability
order:
1
>
2
>
3 .
When stereoisomeric substrates were examined, the rearrangement proved to be
stereospecific, ruling out a common zwitterionic intermediate. The examples in the greenshaded 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 -carbon probably reflects the inductive effect of the
THPO substituent.

The Payne Rearrangement

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 S N2, 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.

Grob Fragmentation
An interesting and generally useful skeletal transformation, involving specific carboncarbon 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 byclicking 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.

Multistep Transformations

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 ,-unsaturation to a ,-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).