Organic reactions usually end up with products that are in line with the unanimously accepted mechanisms. Consequently the products are often called “normal products”. In many instances, reactions do not give exclusively and solely the expected products, but may lead to other ones that stem from mechanistically different pathways. These unexpected products are referred to as “abnormal products” or “rearranged products”. The rearranged product is sometimes not only the abnormal but also the major one. This may result from a plausible rearrangement occurring during the mechanistic course to fulfill the principle of the minimum energy state of the whole system, that is, of the transition state. A certain energetic relief or a certain ease of the system must manifest to yield the stable product, the rearrangement product.
This can be provided through several phenomena: a) a delocalization of the generated radical, cation or anion species over the atoms of the molecules with the mostly probable localization on the thermodynamically favored site, a phenomenon called resonance; this final stage of the intermediate, that is, the activated complex, would resemble the resulted product in accord with the Hammond postulate, b) a shift or a migration of one atom or a group of atoms (radical) from one site to another via a breaking-forming bond rule. Overall, all these mechanistic phenomena are likely to occur intramolecularly. In many cases, the rearrangement affords products of an isomerization, coupled with some stereochemical changes. An energetic requirement is also observed in order for a rearrangement to take place; that is, the rearrangement usually involves a heat evolution to be able to yield a more stable compound. For instance, the energy difference between the tertiary and the secondary carbocations and between the secondary and the primary ones are about 16 kcal/mole.
The keto-enol tautomerization shown in equation (1) can be viewed as an example of an intramolecular rearrangement in which the keto form of the equilibrium is always the most thermodynamically favored, frequently in proportion higher than 99%. A very related rearrangement is the early Lobry de Bruyn – van Eckenstein rearrangement (1895) of the glyceraldehyde to dihydroxyacetone as indicated in equation (2).
There are cases where, acidic, alkaline, thermal or photochemical treatment (or combination of these) of an organic compound leads to a product which is actually the rearranged starting material with an unabated molecular formula (an isomerization). A quite of few related examples can be found in Tables 3,4, and 5.
This article is but intended to sum up the well-known rearrangements in order to bring them closer to the chemist reader in general and particularly to serve as a handout to the undergraduate and graduate students. It is not within the scope of this manuscript, however, to present an up-to-dated review on this special topic.
Rearrangements on Deficient Carbons
A series of most known rearrangements are based on the carbonium intermediate. Moreover, the carbocation species can now be readily evidenced by some spectroscopic analyses; for example, Olah reported the infrared and Raman spectra of (CH3)3C+ which were similar to those of its isoelectronic compound, (CH3)3B . Olah was also able to record the ESCA spectrum of t-butyl cation , another stark and unshakable proof (ESCA: electronic spectroscopy of chemical analysis). In addition, 2-norbornyl cation and C4H7+ ion, the longstanding controversy ion, were unambiguously approved by isotopic tracer experiments, solvolytic studies, and, more interesting, by the 13C CPMAS NMR spectroscopy (cross-polarization magic angle spinning), a powerful analysis arsenal . The carbonium ions as involved in the nucleophilic substitution SN1, in the elimination reaction E1, and in the addition reaction to double bond, often undergo rearrangements. Of these the Wagner-Meerwein rearrangement is by far the most interestingly spread one.
Rearrangements that occur with elimination of water in the dehydration of an alcohol, of hydrogen halide in the dehydrohalogenation of an alkyl halide, ….etc., are commonly referred to as “Wagner-Meerwein rearrangement” (W-M rearrangement) . The W-M rearrangement is sometimes named “retrogade pinacol rearrangement” because it is the exact reverse of the pinacol rearrangement discussed below. The most illustrative example of this type of a rearrangement is the formation of tetramethylethylene as the main product of the acid-catalyzed dehydration of methyl-t-butyl carbinol (pinacoyl rearrangement), equation (3). The rearrangement is in a good agreement with the stability feature of Saytzev olefin.
This rearrangement is characterized by a 1,2-shift of an aryl or an alkyl group R (the migrating species is shown in bold throughout this paper) from an α-carbon to the carbonium ion site either in a stepwise mechanism, a classical ion, or in a concerted one, a non-classical ion as depicted in Scheme 1 .
Besides the energetic requirement for a 1,2-shift to take place, the stereochemical one should also be considered. As to the latter, the bond C – R in the above scheme (R is a migrating group) must lie in the plane of the empty p orbital consisting of the positive charge, that is, the dihedral angle between C – R and the vacant orbital must be nil. The solvolysis of neopentyl iodide in the presence of silver nitrate undergoes a WagnerMeerwein rearrangement as traced in equation (4), called “neopentyl rearrangement”.
Scheme 1: Classical and non-classical carbonium ions
A parent rearrangement was observed earlier on the deamination of the neopentylamine upon treatment with nitrous acid. The literature is replete with many examples of such rearrangement often coined the Demjanow rearrangement .
One distinct feature of the W-M rearrangement is that it provides, in some cases, a ring expansion as well as a ring closure which may have a valuable synthetic interest. Indeed the solvolysis of some cyclic compounds yields the unrearranged products and products from ring enlargement or ring contraction visibly through a 1,2-shift. For example, the hydrolysis of cyclocarbinyl chloride leads to a mixture of the unrearranged alcohol and cyclobutanol, the rearranged alcohol, equation (5) .
It is worthwhile to recall that the deamination of both cyclopropyl carbinyl amine and cyclobutyl amine affords the same products in nearly the same ratio . In order to explain the distribution of these products, a valuable proposal was advanced by Roberts who states that a set of charge-delocalized carbonium ions C4H7+ existing in a rapid equilibrium are the actual intermediates among which two are depicted in Scheme 2; according to the nonclassical ion concept, these carbonium ions were called “bicyclobutonium ions” which have been later found to be bisected cyclocarbinyl cations .
Scheme 2: Possible bicyclobutonium ions
Good examples are by far those of the bicycloalkyl systems such as the norbornyl and the bicyclo[2.2.2] octyl systems .
Bicyclic terpenes are prone to W-M rearrangement when subjected to some reaction conditions . The treatment of α- and β-pinenes with hydrogen chloride at temperature 0°C gives the pinene hydrochloride, the normal product, equation (6). However, at higher temperatures, bornyl chloride is obtained as a rearranged product.
A “Nametkin isomerization” is defined as a W-M double rearrangement . An example of this isomerization is the acidic hydrolysis of an borneol-type substance to give camphene-like structures, the W-M rearrangement (camphene rearrangement type I) and the Nametkin isomerization (camphene rearrangement type II) products respectively. A successive Nametkin isomerization takes place in the fascinating example shown in equation (7) where flower petals are formed by expansion of the cyclobutyl rings .
A 1,2-hydrogen shift to a deficient carbon center has been also found to occur on some organometallic reactions. For instance, the reaction of methyllithium with (CO)5W=C(OMe)(Ph), a Fischer carbene, ends up with products that stem from a WagnerMeerwein rearrangement . Interesting is the formation of a valuable polymer starting material, styrene, when a phenyl group is present in the Fischer carbene.
The intramolecular rearrangement of a 1,2-shift occurs frequently in the cationic polymerization of α-olefins either by a hydride or an alkyl shift, equation (8). For example, the polymerization of 3-methyl-1-butene with coordination catalysts (Ziegler-Natta) yields the conventional 1,2-polymer. However, with Lewis acids as initiators at –130°C, the polymerization of this monomer gives a high molecular weight and crystalline 1,3-polymer which results from a hydride shift, a structure actually suggested by 1H NMR spectrum revealing two singlet peaks . Interesting is the fact that, at relatively high temperature (-100°C), a copolymer of 1,2 and 1,3 units is obtained as an amorphous material. The alkyl shift is also observed in the cationic polymerization of 3,3-dimethyl-1-butene at –130°C or lower affording exclusively the 1,3-polymer . A set of examples of polymers which are the results of such rearrangement can be found in reference .
(R = hydrogen or methyl)
In some cases, the rearrangement is a result of a nucleophilic assistance of a neighboring group (an intramolecular assistance) to the departure of a leaving group: this
phenomenon is called ìneighboring group participationî or ìanchimeric assistanceî. An illustrative example is the solvolysis of β,β,β-triphenylethyl chloride in formic acid which
involves the participation of one of the phenyl groups as shown in equation (9) . Cram finically analyzed the acetolysis products of the L-threo and erythro -3-phenyl-2-
butyltosylate and the results were consistent with the ìphenonium ionî proposal . The Cramís findings were further buttressed by Winsteinís results on kinetic studies of this
solvolysis . Notwithstanding these convincing evidences, a tremendous controversy has lasted for decades as to the existence of this intermediate species . Herbert C. Brown approved it by performing thorough and sound studies on the rates and the products of acetolysis of threo-3-phenyl-2-butyltosylate with a number of substituents on the phenyl group . For example, he reported that the rate constant of the acetolysis of threo-3-anisyl- 2-butyltosylate is about 99% of the aryl assistance.
A similar radical feature is also observed in the Urry-Karasch rearrangement, equation (10), where the rearrangement is promoted by the mixture of cobaltous chloride and
a Grignard reagent to give a set of rearranged products in 30 to 50% yields .
In a 1,2-shift the stereochemistry at the migration terminus is bound to the relative departure time of the leaving group in the picture (Scheme 1). That is, if R migrates before the departure of X, an inversion at the carbon terminus can be observed. If, however, the leaving group X begins to depart first, the migrating R starts also to move, and consequently, both inversion and retention are probable. In some cases, a racemization may result.
An intensive research on the chemistry of short-bridged [n]cyclophanes is now going on. One of their chemistry features is their propensity towards rearrangement upon an acid catalysis. Indeed the rapid Wagner-Meerwein rearrangement observed in such compounds discloses unscrupulously their strong deviation from the normal, planar aromatics . Such rearrangement of these compounds are typified by the example shown in equation (11).
In 1860 Rudolph Fittig reported one of the earliest rearrangements in organic chemistry. It consisted of the transformation of pinacol to pinacolone under acidic treatment
as shown in equation (12) . Nowadays the pinacol rearrangement encompasses all α-glycols other than methyl-containing ones. The driving force of the rearrangement is likely the carbonyl formation. Electrophilic reagents such as Lewis acids can also promote this kind of rearrangement.
Studies on pinacol rearrangement using 18O-labeled water showed, besides the pinacolone formation, the presence of a 18O-labeled pinacol which may result from the attack
of the carbocation by H2O18 before a methyl shifting . These results demonstrate clearly that no anchimeric assistance by methyl group can ensue in the pinacol rearrangement but the carbocation formation. In 1989, two French research groups studied the clay montmorillonite- promoted pinacol rearrangement shown in equation (12) providing that the monmorillonite acidity is similar to that of sulfuric acid based on the Hammett function acidity scale .
A semipinacol rearrangement is the rearrangement that results from the deamination of a β-aminoalcohol by nitrous acid as in equation (13) . The analogous β-
sulfonatealcohol undergoes similar reaction which has been vastly employed in terpene synthesis .
In 1975 D tz found that alkynes can be inserted into the Fischer carbenes, (CO)5M = C R1R2 (M= W, Cr), leading to a benzannulation when R1 or R2 is a phenyl group .
Recently, a tandem alkyne insertionñsemipinacol rearrangement has been observed by Zora and Herdon when carrying reaction of chromium carbene complexes with 1-
alkynylcyclobutenols producing 2-alkenyl-4-cyclopentene-1,3-diones in quantitative yields , 76%, as traced in equation (14) .
In the pinacol rearrangement, it is questionable as to which of the β-groups will preferentially migrate to the carbocation. As a general rule and in respect with the carbocation
stability, the migratory aptitude is as follows: hydrogen > aryl > alkyl; yet, the steric factors may make the inverse aptitude prevail. To assess the migratory aptitude of different
substituted aryl groups, Bachmann and Ferguson undertook a careful study of pinacol rearrangement of a series of symmetrical pinacols .
A striking difference has been found in migratory aptitudes of the aryl groups between the pinacol and the semipinacol rearrangements . It has been generally observed that the deamination reactions show lower selectivity than other Wagner-Meerwein rearrangements. These results can be explained by the "hot carbocation theory.
A paramount application of an acid-catalyzed rearrangement is the design of chemical amplification resist systems, the lithographic imaging. A stringent requirement for such
application is the polarity change of the system, that is, from a polar to a nonpolar environment or vice-versa. For this purpose, the pinacol rearrangement is well suited for the
design of aqueous base-developable negative resists because a polarity change is expected from a vic-diol (glycol) system to a ketone or an aldehyde. For instance, the copolymer of styrenic pinacol and 4-acetoxystyrene undergoes a facile acid-catalyzed pinacol rearrangement as described in Scheme 3 to afford negative resists
Scheme 3 : Pinacol rearrangement in resist design.