7. Molecular Rearrangements – Advanced Organic Chemistry

7

Molecular Rearrangements

LEARNING OBJECTIVES

By the end of this chapter you should be familiar with

  • How we can change the connectivity of an existing organic backbone by using reactions that result in skeletal rearrangements.
  • Participation: nucleophiles are more efficient if they are already part of the molecule.
  • Participation means acceleration and retention of stereochemistry and may mean rearrangement. Participating groups can have lone pairs of π electrons.
  • Types of rearrangement. Carbocations often rearrange by alkyl migration.
  • The mechanisms of rearrangements.
  • Ring expansion and contraction by rearrangement and controlling rearrangements.
  • Insertion of O, N, or C next to a ketone.
7.1 INTRODUCTION

There are two types of rearrangements: the first that involves the one-step migration of a hydrogen atom or of a group of atoms within a relatively short-lived intermediate. The second one may be a multistep reaction, including the migration of a hydrogen atom or of a larger molecule fragment in one of its steps. The properties of a molecule are determined by the sequence in which its atoms are attached to one another. Any reaction that shifts the position of a carbon (or other) atom and its substituents within a molecule effects an isomerization that alters the physical and chemical properties of the compound. In this section, we examine the reactions in which a carbon–carbon bond is broken in one part of a molecule and reformed at another place.

7.2 CATIONIC REARRANGEMENTS

The shift of a hydrogen atom from one carbon atom in a carbocation to a neighbouring carbon atom is often quite rapid when a more stable carbocation can be formed from a less stable one. For example, when 2-methyl-1-propanol is treated with aqueous acid, water is lost and a tertiary carbocation is formed, as hydrogen shifts from C-2 to C-1, taking with it the electrons of the C-H σ bond.

The addition of water to the resulting tertiary cation results in the formation of 2-methyl-2-propanol. Because the position of the hydroxyl group in the product alcohol has changed from its original position in starting alcohol, this reaction is classified as an isomerization rather than a rearrangement; the order in which atoms are joined has changed but the carbon skeleton is unchanged. In other words, the identity of the atom to which the functional group is bonded has changed, but the sequence of attachment of carbon atoms along the backbone is the same. However, the skeleton would have been altered if a carbon atom with its substituents, rather than hydrogen, had migrated to the developing carbocationic centre.

7.3 WAGNER–MEERWEIN REARRANGEMENT

In most of the cationic shifts described so far, a hydrogen atom migrates with a pair of bonding electrons (hydride migration). However, alkyl groups also can shift (along with the electrons from the σ bond that connects the group to the adjacent atom). It was George Wagner who observed in 1899 that terpenes undergo skeletal reorganizations. Hans Meerwein provided the second key to the conceptual puzzle in 1922. Later, in 1927, Meerwein generalized the carbocationic mechanism to account for other terpenic rearrangements.

When an alkyl group migrates to a cationic centre, there are changes in the carbon skeleton, and the reaction is referred to as a Wagner–Meerwein rearrangement Alkyl migration occurs in order to make a carbocation more stable; thus, the driving force of the rearrangement is the formation of a carbocation with greater stability. It is a [1,2] rearrangement of H atoms or alkyl group in carbenium ion that is generated in one or more steps, and the rearranged carbenium ion reacts further in one or several steps to give a valence-saturated compound. The rearrangement is catalyzed by Lewis acids like AlCl3, FeCl3, TiCl4 and SnCl4 or by Bronsted acids and is stereospecific. The migrating group approaches the electron-deficient carbon from the direction opposite to that of the leaving group, that is, the SN2 type geometry is needed. The reaction proceeds faster in polar solvents and is consistent with a first order rate law. The order observed for some solvents is SO2 > MeNO2 > MeCN > PhOMe > PhBr > PhH > Et2O. The classical examples are the transformation of camphenilol to santene and camphene hydrochloride to isobornyl chloride. Isobornyl chloride, the exo-isomer (that is, the chlorine atom on the side opposite to the migrating bridge), is the sole product, which slowly rearranges to the thermodynamically more stable endo-isomer (bornyl chloride). Bornyl chloride is also obtained by treatment of α-pinene with HCl.

Another point of interest in the above reaction is reversibility. The migration terminus in the forward process becomes migration origin in the reverse process. It, therefore, follows from the principle of microscopic reversibility that both reactions should have a common reaction mechanism and identical stereochemical rules. One can summarize these rules in the following way. These stereochemical rules have a general applicability for all 1, 2-shifts.

The carbocation may be generated in a variety of ways.

  • From a halide, by using a strongly ionizing solvent or by adding a Lewis acid such as silver ion.
  • By treatment of an alcohol with acid.
  • From an amine by treatment with nitrous acid.
  • From an alkene by protonation.

In the trans-decalin derivative (depicted after this para), the hydroxyl group is held in the equatorial position because the ring system cannot flip. In this situation, there is no hydrogen anti to the hydroxyl, but two of the ring carbon atoms are in the appropriate anti position for rearrangement (that migrates leaving the more stable carbocation) and, in the presence of acid, ring contraction takes place.

Wagner–Meerwein rearrangements of cations are similar in detail to those in which hydrogen atoms migrate: for example, the solvolysis of 1-bromo-2,2-dimethylpropane. Heterolytic cleavage of the C-Br bond of 1-bromo-2,2-dimethylpropane leads not to the primary cation but to the more stable tertiary cation. This cation is produced when a methyl group migrates from C-2 to C-1 as the C-Br bond is broken. The simultaneous migration of the alkyl group and departure of the leaving group to form a tertiary cation is, therefore, faster than the simple loss of the leaving group to form a primary cation.

The products observed are those that result from further reaction of rearranged (tertiary) cation. The alcohol results from reaction of the tertiary cation with water, forming an oxonium ion. Loss of a proton generates the product alcohol with a rearranged carbon skeleton. Alternatively, cation can lose a proton from either of two different adjacent sites to give either the Zaitsev or Hofmann elimination product. All three observed products derive from the rearranged cation, whose carbon skeleton differs from that of the starting material because of migration of methyl group from C-2 to C-1 in a Wagner–Meerwein rearrangement.

When a more stable intermediate can be formed by migration of an alkyl group or hydrogen, rearrangement nearly always occurs. The products formed depend on the structure of the intermediate cation, no matter how this cation is initially formed. For example, the products obtained from the solvolysis of 2-bromo-2-methylbutane are the same as those from the solvolysis of 1-bromo-2,2-dimethylpropane. When a driving force for cation rearrangement exists, migration of an alkyl group almost always takes place faster than trapping of a less stable cation by solvent or another nucleophile.

Ring Expansion. Cation rearrangements can be driven thermodynamically by factors other than the degree of substitution of the cation. For instance, ring strain is also important. As an example, let us consider the treatment of cyclobutylmethanol with strong acid:

Protonation of the hydroxyl oxygen forms an oxonium ion that loses a water molecule, generating a primary cation. The carbinol carbon is next to a strained four-member ring; an adjacent methylene group (CH2) migrates to this centre with the electrons of the C-C σ bond and, at the same time, water is also lost. Both a reduction in strain (a four-member ring becoming a five-member ring) and an increase in the degree of substitution (from a primary to a secondary cation) are accomplished by this migration. The resulting cyclopentyl cation is then captured in a slower step by an external nucleophile. When treated with aqueous, HBr cyclobutylmethanol is converted to cyclopentyl bromide.

In directing the course of the reaction, relief of ring strain can sometimes be more important than the degree of substitution of the carbocationic centre. Consider, for example, the acid-catalyzed solvolysis of α-pinene. Recall that cations can be produced by protonation of alkenes (the first step in electrophilic addition). Protonation of α-pinene forms the tertiary carbocation, which is favoured over the alternative carbocation (recall Markovnikov’s rule). Though the rearrangement step transforms a stable tertiary cation into a less stable secondary cation, relief of strain in expansion from a four- to a five-member ring makes the alkyl migration favourable. The secondary cation is then trapped by water, ultimately producing a product alcohol with a carbon skeleton different from that of the starting material.

A carboxonium ion may become less stable than a carbenium ion only when ring-strain effects dominate. In such cases, carbenium ions can be generated from carboxonium ions by way of a Wagner–Meerwein rearrangement. Thus, the decrease of ring strain can provide a driving force strong enough to overcompensate for the conversion of a more stable into a less stable cationic centre.

A tandem rearrangement and a cascade rearrangement describe sequences of two or more rearrangements taking place more or less directly, one after the other. The following example involves five [1,2]-rearrangements, each one effecting the conversion of a spiro-annulated cyclobutane into a fused cyclopentane.

Every polycyclic hydrocarbon having the molecular formula C10H16 can be isomerized to adamantane. Adamantane, possessing the structure of the repeating unit of the diamond lattice, is the stablest alkane of molecular formula C10H16. All other isomeric tricyclic alkanes are converted to adamantane if subjected to sufficiently vigorous Lewis acid treatment. The minimum number of [1,2]-rearrangements needed in such rearrangements is so high that it can be determined only with the use of a computer program. The rearrangements occur in the presence of catalytic amounts of AlCl3 and tert-BuCl. These isomerizations almost certainly involve [1,2)-shifts of H atoms as well as of alkyl groups. One cannot exclude that [1,3]-rearrangements may also play a role.

A novel application of this rearrangement is the formation of adamantane in 15% yield by treatment of the reduction product of the readily available dimer of cyclopentadiene with AlCl3 at 150–180°C. The reaction product, adamantane, is formed under thermodynamic control. It is the so-called stabilomer (the most stable isomer) of all the saturated hydrocarbons having the molecular formula C10H16.

This impressive cascade reaction begins with the formation of a small amount of the tert-butylcation by reaction of AlCl3 with tert-BuCI. The tert-butylcation abstracts a hydride ion from the substrate C10H16. Thus, a carbenium ion with formula C10H15+ is formed. These carbenium ions C10H15+ are certainly substrates for Wagner–Meerwein rearrangements and also potential substrates for [1,3]-rearrangements, thereby providing various isomeric cations iso-C10H15+. Some of these cations can abstract a hydride ion from the neutral starting material C10H16. The saturated hydrocarbons iso-C10H16 obtained in this way are isomers of the original starting material C10H16. Such hydride transfer, and [1,2]- and [1,3]-shifts, respectively, are repeated until the reaction arrives at adamantane by way of the adamantyl cation.

1,2-Methyl shifts in terpenes: the Nametkin rearrangement This particular type of Wagner–Meerwein shift has special recognition due to its importance in the field of terpene chemistry. For example, the conversion of α-methyl camphene to 4-methylisoborneol involves both a Nametkin and a Wagner–Meerwein rearrangement.

Nametkin rearrangements are commonly encountered in acid-catalyzed dehydrations of 3,3-dimethyl[2.2.1]bicycloheptan-2-ols such as in the camphenilol derivatives shown, and these can be seen to be further examples of rearrangements of neopentyl derivatives.

7.4 PINACOL REARRANGEMENT

This is an acid catalyzed 1,2–migration of a diol to an oxo derivative. When vic–diols (glycols) are treated with acids, they can be rearranged to give aldehydes or ketones. The reaction gets its name from the typical compound pinacol Me2C(OH)C(OH)Me2, which is rearranged to pinacolone Me3CCOCH3. The rearrangement has been carried out with alkyl, aryl, hydrogen and even ethoxy carbonyl (COOEt) as migrating groups. Di–tert–glycols rearrange in the presence of acid to give α–tert–ketones. The reaction takes place in dilute or moderately concentrated acid at higher temperature.

The first step is the reversible protonation of the relatively basic hydroxyl group. This was confirmed by a demonstration that threo- and erythro-1,2-diphenyl-1-p-tolylethylene glycols interconverted in dilute acid more rapidly than they rearranged. The second step is the dehydration, that is, formation of tert-carbenium ion. The carbenium ion rearranges in the third step, into a more stable carboxonium ion via a [1,2]- shift. In the last step the carboxonium ion is deprotonated and the product ketone is obtained. The driving force for this process is the stabilization of the new carboxonium ion by the loss of a proton from the hydroxyl group. The OH group, which forms the most stable carbenium ion, is protonated preferentially and a subsequent intramolecular migration yields the ketone. The reaction is unimolecular with regard to the concentration of the diol.

Glycols in which the four R groups are not identical can give rise to more than one product depending on which group migrates, which depends on the reaction conditions as well as on the nature of the substrate. Thus the action of cold, concentrated H2SO4 on A produces mainly 3,3–diphenyl–2–butanone B (methyl migration), while treatment of A with AcOH containing a trace of H2SO4 gives mainly C (phenyl migration).

Of the two OH groups, the one that forms the more stable carbocation is protonated preferentially. This factor takes precedence over the migratory aptitude factor.

The ease with which any particular group will undergo nucleophilic 1,2-shift is known as its migratory aptitude. There are two ways in which relative migratory aptitudes may be determined. One way involves the comparison of relative rates of rearrangement in a homologous series of substrates, each possessing just one type of migrating group, under exactly the same reaction condition. An alternative method analyzes the product mixtures obtained from a substrate containing two different competing substituents at the migrating origin. A wide range of other factors, such as steric and conformational effects also play an important role in determining whether a particular migration is favoured or not.

The migratory aptitude of the groups decreases in the order aryl > alkyl > hydrogen and amongst the aryl groups p-anisyl > p-tolyl > m-tolyl > m-anisyl > phenyl > p-chlorophenyl > o-anisyl > o-tolyl. The migratory aptitude increases as the aromatic nucleus is made more electron-rich, because the migrating group leaves with its electron-pair and makes a nucleophilic attack at the migration terminus. Electron-withdrawing substituents disfavour delocalization of positive charge to the benzene ring and exert the opposite effect. In unsymmetrical systems, the stability of the intermediate carbenium ion governs the migration of the group and this factor takes precedence over the migratory aptitude factor.

Of course, the way to carry out a direct comparison of relative migratory aptitudes of methyl versus phenyl in the pinacol rearrangement is to use 2,3-diphenylbutan-2,3-diol, as loss of either hydroxyl group generates the same carbocation.

In a crossover experiment, a mixture of di-tert-glycols 1,1-dimethyl-2,2-diphenyl glycol A and 1,1-diethyl-2,2-diphenyl glycol E was rearranged under acidic conditions. The reaction products were the ketones, 3,3-diphenyl-2-butanone C and 4,4-diphenyl-3-haxanone G.

The absence of the crossover products I and J proves the intramolecular nature of the pinacol rearrangement.

This rearrangement follows a definite stereochemical course in that the migrating group enters trans to the departing group, that is, reaction occurs in an anti-manner. This has important consequences in alicyclic systems. For example, cis-1,2-dimethyl-cyclohexane-1,2-diol undergoes a methyl shift to give 2,2-dimethylcyclohaxanone, whereas the trans-isomer undergoes ring contraction to give 1-acetyl-1-methyl cyclopentane. For cyclic diols, the rearrangement results in the contraction or expansion of the ring system, for example, cyclopentylcyclohexane-1,2-diol yields two products, the I being the major one.

Further evidence for carbenium ion formation in the pinacol rearrangement has been obtained by oxygen–exchange experiments. Partial rearrangement of pinacol to pinacolone was carried out in acidic solutions containing H2O18.

It was found that the recovered pinacol contained isotopically labelled oxygen, which established that formation of carbenium ion from pinacol is a reversible process. In this connection, it has been found that under similar experimental conditions, mixtures of pinacol and pinacolone are formed from different precursors.

ß–aminoalcohols, Me2C(OH)C(NH2)Me2, which rearrange on treatment with nitrous acid; iodohydrins, Me2C(OH)C(I)Me2, for which the reagent is Hg2O or AgNO3; ß–hydroxyalkyl selenides, R1R2C(OH)C(SeR5)R3R4 and allylic alcohols may be rearranged with strong acids.

7.5 SEMIPINACOL REARRANGEMENTS

This is a variant of pinacol reaction. By converting a 1,2-diol into its monotosylate, base-catalyzed rearrangement can be brought about. Since the ease of formation of tosylates decreases in the order primary > secondary > tertiary, this provides a means of effecting a rearrangement in the opposite direction from the acid-catalyzed reaction. For example, in the diol below, acid-catalyzed rearrangement occurs with migration of R’ as the tertiary carbocation is formed more readily, whereas in the base-catalyzed process it is R that migrates. Tosylation occurs at the less hindered hydroxyl group of a diol, resulting semipinacol rearrangements more regioselective than pinacol rearrangements and in opposite direction.

Rearrangements that are not pinacol rearrangements but also involve a [1,2]–shift of an H atom or of an alkyl group from an oxygenated carbon atom to a neighbouring carbon atom, that is carbenium ion → carboxonium ion rearrangements, are called semipinacol rearrangements.

Lewis acid catalyzes the ring opening of epoxides. If the carbenium ion is not trapped by a nucleophile, such an epoxide opening initiates a semipinacol rearrangement. There is only a hydrogen atom and no alkyl group available for a [1,2]-migration in the carbenium ion B. This rearrangement is stereogenic and produced stereoselectively.

The glycol monotosylate is deprotonated to give alkoxide in an equilibrium reaction. Under these conditions, other glycol monotosylate would undergo a ring closure delivering the epoxide. However, this compound cannot form an epoxide because the alkoxide O atom is incapable of an attack from the back on the COTs bond. Hence, the tosylated alkoxide has the opportunity for a [1,2]-alkyl shift to occur with concomitant elimination of the tosylate in a stereoselective manner.

7.6 DEMJANOV REARRANGEMENT

When a positive charge is formed on an alicyclic carbon, migration of an alkyl group may occur to give ring contraction by one carbon smaller than the original. This abnormal change involves conversion of more stable secondary carbenium ion to a less stable primary carbenium ion. Similarly, when a positive charge is formed on a carbon α to an alicyclic ring, ring expansion can take place. Both the old and new carbenium ions may give products by combination with a nucleophile, or by elimination. For example, cyclobutylmethylamine and cyclopropylmethylamine give similar mixtures of the two alcohols on treatment with nitrous acid.

When the carbenium ion is formed by diazotization of the amine, the reaction is called the Demjanov rearrangement. The formation of cyclopropylmethyl cation may be due to its relative stability, by significant charge delocalization involving the ring bonds and the positive charge, since the C-C bonds in cyclopropane have appreciable p character.

The expansion reaction has been carried out on rings of the size C3 to C8, but the yields are better with the smaller rings, because relief of small–angle strain provides a driving force for the reaction. The contraction reaction has been applied to four-member rings and to rings of C6 to C8. Treatment of 1–aminomethyl cyclopentanol with nitrous acid gives cyclohexanone in good yields. This reaction is called the Tiffeneau–Demjanov ring expansion. This reaction is of general use for the ring expansion of cycloalkanones to their next higher homologs. Some other examples of cyclic ß–aminoalcohols that undergo Tiffeneau–Demjanov rearrangement are as follows.

Aliphatic diazonium salts are much less stable than aromatic diazonium salts. The first reason for this difference is that aliphatic diazonium salts lack stabilization through resonance. Second, aliphatic diazonium salts release N2 much more readily than their aromatic analogs, as they thus react to give relatively stable alkyl cations. Hence, the decomposition of aliphatic diazonium ion is favoured by product–development control. The molecular nitrogen in aliphatic diazonium ions is an excellent leaving group.

Cyclic bromohydrin on treatment with Grignard reagent gives alkoxide, which upon refluxing undergoes ring expansion. This reaction has been performed with bromohydrins in which the carbon-bearing bromine at least has one phenyl or methyl group, but not when both R and R′ are hydrogen.

A related ring expansion involves treatment of an exocyclic olefin with cyanogen azide. The azide adds to the double bond in a 1,3-dipolar addition to give a triazolidine intermediate which undergoes ring expansion.

Cyclopropyl halides and tosylates give allylic products via allylic cation.

7.7 BAEYER–VILLIGER OXIDATION

The Baeyer–Villiger oxidation (discovered in 1899 by the Germans Adolf van Baeyer, who won the Nobel Prize in 1905, and V. Villiger) involves the reaction of a ketone with H2O2 or a peroxy acid (RCO3H) to give an ester. Here, the starting material is a ketone, in which an oxygen atom is inserted between the carbonyl group and the α carbon to form an ester, that is, it involves 1,2-migration from carbon to electron-deficient oxygen.

Figure 7.1 Sites of oxidation of some representative ketones

The Baeyer–Villiger oxidation begins with nucleophilic attack of the peracid on the ketone carbonyl. It takes place when a ketone is treated with a peracid, a carboxylic acid that has one additional oxygen. Peracids are powerful oxidizing agents, and this reaction is called an oxidation even though, as we will see, it is quite similar mechanistically to the rearrangement already discussed. Carboxylates are not good leaving groups, but the O-O single bond is very weak, and monovalent oxygen cannot bear to carry a positive charge so that once the peracid has added, loss of carboxylate is concerned with a rearrangement, driven, as in the case of pinacol, by formation of a carbonyl group.

In certain instances, information about the movement of atoms between molecules during the course of a reaction can be gained by using compounds containing isotopes of certain of the atoms. These isotopes behave much like the ordinary atoms they replace, but they can be identified by their behaviour. For example, in the hydrolysis of ethyl acetate, it is crucial to a determination of the mechanism to be able to establish which of the two reactants (ethyl acetate or water) provides the oxygen atom that ends up in the product ethyl alcohol. In this case, the use of water labelled with 18O reveals that the oxygen atom in the alcohol comes from the ethyl acetate molecule.

One important piece of evidence for this mechanism is that 18O labelled benzophenone gave ester entirely labelled in the carbonyl oxygen, with none in the alkoxyl oxygen. Carbon-14 isotope–effect studies on acetophenones have shown that migration of aryl groups takes place in the rate-determining step, demonstrating that migration of Ar is simultaneous with the departure of OCOR.

The most common peracids employed for Baeyer–Villiger oxidation are m-chloroperbenzoic acid (MCPBA) and peracetic acid as they are commercially available. MCPBA is crystalline and relatively stable when pure. However, it is somewhat more expensive than peracetic acid, which can be prepared in solution simply by adding a catalytic amount of sulphuric acid to a mixture of acetic acid and hydrogen peroxide. All peracids are very unstable in the presence of metals and metal ions. Even atmospheric dust contains a sufficient concentration of metal ions (such as iron oxides) to catalyze the decomposition of a peracid to form the acid and molecular oxygen.

Other reagents, which have been used to accomplish the same conversion, include H2O2-BF3.Et2O and K2S2O8-H2SO4. One limitation of this reaction is that double bonds present in the molecule are frequently epoxidized, and thioethers are oxidized to sulphoxides or sulphones.

It should be noted that in the Baeyer–Villiger oxidation, if there is competition between two migrating groups, that group migrates which is more nucleophilic of the two. If the migrating group can take some responsibility for the positive charge, the transition state will be more stable. The more stable the charge, the faster the rearrangement. The migrating ability of the aryl groups is increased by electron-donating and decreased by electron-withdrawing groups.

Enolizable ß-diketones do not react and α-diketones can be converted to anhydrides. With aldehydes, migration of hydrogen gives the carboxylic acid; migration of other groups would give formates.

As in the Baeyer–Villiger oxidation, the transition state is cationic, so the cation-stabilizing group migrates more readily. When a phenyl ring migrates, π participation is involved, as the benzene ring acts as a nucleophile and the positive charge can be spread out even further.

Aryl groups migrate more readily than alkyls, and a secondary alkyl more readily than a primary alkyl.

This acid-catalyzed reaction is similar to the formation of a hemiketal or a ketal from a ketone and an alcohol. Protonation of the carbonyl group activates it toward nucleophilic attack by the terminal oxygen of the peracid. Then, via a cyclic transition state, the carbon–oxygen π bond is reformed, with loss of a molecule of carboxylic acid, as the alkyl group migrates to oxygen.

This step is similar to a Beckmann or Hofmann rearrangement, except that the leaving group is a carboxylic acid and the heteroatom to which the group migrates is oxygen. The products of this unimolecular rearrangement are the ester derived from the ketone and the acid derived from the peracid. In 1,2-migrations, the migrating group retains its stereochemistry.

The order, with t-alkyl the best at migrating, then s-alkyl closely followed by Ph, then Et, then Me, very roughly follows the order in which the groups are able to stabilize a positive charge.

Baeyer–Villiger oxidation can be used with either acyclic or cyclic ketones. For example, the Baeyer–Villiger oxidation of cyclohexanone generates a lactone (a cyclic ester). With unsymmetrical ketones, the more substituted carbon migrates preferentially, as in the Beckmann rearrangement.

Unsaturated ketones are not often good substrates for Baeyer–Villiger oxidation. The two factors that matter are: how electrophilic is the ketone and how nucleophilic is the alkene. The following unsaturated bicyclic ketone undergoes Baeyer–Villiger oxidation.

The rate of oxidation is accelerated by electron-donating groups in the ketone and by electron-withdrawing groups in the peracid. The reaction occurs with retention of configuration. As in other 1,2-cationic rearrangements, the migrating group retains its stereochemical configuration. Some of the examples of carbon to electron-deficient oxygen migrations are as follows:

In the rearrangement of trans-9-decalylperbenzoate, the benzoate ion remains intimately associated with the cation at all times. Externally added anions fail to compete and interestingly, the two oxygens of the benzoate ion do not even equilibrate.

Here is an example of regioselective Baeyer–Villiger rearrangement of an electron-rich aromatic aldehyde.

7.8 FRIES REARRANGEMENT

When phenols are treated with acid chlorides or acid anhydrides, esters are obtained. Conversion of phenolic esters, on warming with a Lewis acid (Friedel-Crafts catalyst), to hydroxy ketones is known as Fries rearrangement

It is an acid-catalyzed rearrangement from side chains onto the aromatic ring. Acylation of phenols by Friedel-Crafts reaction also forms the same product mixture but the yield is poor. The relative amounts of ortho– and para–isomers in the product depends on the reaction conditions, that is, temperature, solvent and concentration of catalyst. The two isomers are separable and this is a useful method for the production of phenolic ketones. It has been observed that at low temperature the para–isomer predominates, whereas at higher temperature the more stable ortho is the major product. The para-product can be transformed into the ortho-product on further heating with AlCl3. Although the para–isomer is formed more rapidly, it appears that the greater stability of the ortho–isomer is due to the existence of intramolecular hydrogen bonding. In the presence of AlCl3, the complex formed is stabilized due to the union of two oxygen atoms through aluminium.

The exact mechanism of the Fries rearrangement is still uncertain and has been much disputed, with contradictory evidence being produced, as it is sometimes a one-step and sometimes a two-step process. It is believed that the initial step is probably the formation of a complex between the ester and the catalyst, followed by rearrangement leading to product. Evidence for the intermolecular process has been obtained from trapping experiments. Support for the intramolecular nature of the reaction is a formation of a π-complex intermediate between phenoxytrichloroaluminium and acylium ions. The mechanisms for one-step and two-step processes may be believed to proceed as follows:

Evidence in support of the intermolecular mechanism is the formation of the crossover products.

The Fries reaction can be carried out in the absence of a solvent, but the temperature at which reaction proceeds at a useful rate is lowered by the presence of solvents such as nitrobenzene and carbon disulphide. The usual catalysts are AlCl3, TiCl4, SnCl4 and BF3. The AlCl3 and phenyl ester are generally employed in approximately equimolar quantities.

The presence of a meta-directing group on the aromatic position of the phenyl ester usually interferes with the Fries reaction. For example, the reaction does not occur if the phenolic residue carries a nitro or benzoyl group in either the ortho- or meta-position; the presence of an acetyl or carboxyl group in the ortho-position hinders the reaction and in the para-position prevents it.

α-Naphthyl acetate undergoes Fries rearrangement at low temperature to give mainly 4-acetyl naphthol, but increasing the temperature increases the yields of 2-acetyl and 2,4-diacetyl naphthols.

The Fries rearrangement, carried out with UV light in the absence of a catalyst, and called photo-Fries rearrangement is predominantly an intramolecular free-radical process. Both ortho and para migrations are observed.

The phenol ArOH is always a side product, resulting from some ArO., which leaks from solvent cage and abstracts a hydrogen atom from a neighbouring molecule. When the reaction is performed on phenyl acetate in the gas phase, where there are no solvent molecules to form a cage, phenol is the chief product, and virtually no ortho-or para-hydroxy acetophenone is found. A photochemical variant of the Fries rearrangement is known; it has been shown spectroscopically to proceed via radical intermediates, the majority of which recombine before escaping their solvent cage.

Salbutamol, an anti-asthma drug, is made from aspirin by Fries rearrangement. Halogenation of para–hydroxy ketone gives α–haloketone, which is an excellent electrophile and reacts rapidly with a nucleophile, such as a secondary amine, by the SN2 mechanism. Finally reduction of ketone and acid followed by removal of benzyl-protecting group gives salbutamol.

Some examples of a reverse Fries reaction have been found and this provides evidence to support the view that selective ortho-Fries rearrangement at high temperatures is a consequence of equilibrium via the esters to form the thermodynamically most stable 4-acylphenol. Indeed, 4-acylphenol may be converted to 2-acylphenol on heating with aluminium chloride, although the intermediate ester has never been detected under these conditions.

7.9 DIENONE–PHENOL REARRANGEMENT

Transformation of a diketone to phenol in the presence of acid is known as the Dienone–Phenol rearrangement. As the name implies, this reaction results in the transformation of a quinoid structure to a benzenoid ring. It may be considered as reverse pinacol rearrangement, since pinacol and semipinacol rearrangements are driven by the formation of a carbonyl group. The dienone in acetic anhydride solution is treated with a catalytic amount of sulphuric acid at room temperature. The protonated carbonyl compound rearranges to a tertiary carbocation, which rapidly undergoes elimination of H+ to become aromatic. Thus, the driving force for the overall reaction is the creation of an aromatic ring in the product. In this rearrangement, the migration terminus is not the carbon of a protonated carbonyl group, but rather a carbon in conjugation with it.

In the example just drawn, the ring methylene group migrates in preference to the primary alkyl group. The course of the reaction may be altered by slight structural or electronic changes in the molecule or by employing the aqueous condition. Thus, when R = C2H5, the ethyl group migrates, giving a different product. The group that can best support a positive charge usually prefers to migrate.

One of the important uses of dienone-phenol rearrangement is in the synthesis of a contraceptive pill, 1-methyloestradiol.

The rearrangement has strong connections with natural product chemistry.

The preference for methylene over methyl migration is usually attributed to the greater ease of migration of a branched alkyl group over that of an unbranched alkyl group. Aryl groups migrate more readily than alkyl. Compound C could have been formed by the series of steps shown next.

In aqueous acids the rearrangement places the hydroxyl group meta to the methyl group and in Ac2O solution, the rearrangement places the acetoxy group para to the methyl group.

In a like manner, dienone I yields 6-hydroxytetralin II, and p-toluquinol when heated in aqueous methanol containing sulphuric acid rearranges to 2-methylquinol.

7.10 REARRANGEMENT TO ELECTRON-DEFICIENT NITROGEN

7.10.1 Beckmann Rearrangement

In the Beckmann rearrangement, an oxime is converted to an amide. An oxime is easily obtained by treatment of aldehyde or ketone with hydroxylamine. The OH group of ketoximes R1R2C(=NOH) can become a leaving group. Tosylation is one way to convert this hydroxyl group into a leaving group. The oxime OH group also can become a leaving group if it is either protonated or coordinated by a Lewis acid in an equilibrium reaction. Oximes activated in this fashion may undergo heterolysis. Because the formation of a nitrilium ion needs to be avoided, this heterolysis is accompanied by a simultaneous [1,2]–rearrangement of the group; the group that is attached to the C=N in the trans position with regard to the O atom of the leaving group. This is in complete contrast to the pinacol rearrangement where the nature of the rearrangement depends upon the relative migratory aptitudes of the migrating species. R1 and R2 may be alkyl, aryl, or hydrogen. However, hydrogen rarely migrates, so that the reaction is not generally a means of converting aldoximes to unsubstituted amides RCONH2. A nitrilium ion is formed initially. It reacts with water to form an imidocarboxylic acid, which tautomerizes immediately to an amide. The overall reaction sequence is called the Beckmann rearrangement. The Beckmann rearrangements of cyclic oximes result in lactams. The comparison of the structures of the starting ketone with those of the products reveals that the combination of oxime formation and Beckmann rearrangement accomplishes the insertion of an NH group between the carbonyl carbon and the α carbon.

Beckmann rearrangement of the oxime of cyclohexanone is carried out on a very large scale industrially because the product, caprolactam, is the direct precursor of nylon 6, a versatile polymer that has many applications: for example, the manufacture of fibres for carpeting and other textiles. Concentrated sulphuric acid is used as both the acid catalyst and the solvent for the reaction.

However, because caprolactam is soluble in sulphuric acid, the acid must be neutralized in order to isolate the product. Ammonia is used for this purpose and the large quantity of ammonium sulphate produced as by-product is sold as fertilizer.

The mechanism of the reaction follows the same pattern as a pinacol or Baeyer–Villiger reaction. Acid converts the oxime OH into a leaving group, and an alkyl group migrates on to nitrogen as water departs. The product cation is then trapped by water to give an amide.

Stereospeciflcity in the Beckmann rearrangement is not as general as may be implied in some texts. However, the Beckmann rearrangement in general is stereospecific, and the group trans, that is, anti to the leaving group generally migrates. This method is often used to determine the configuration of the oxime. It has been observed that the migration actually assists ionization that is supported by rate and stereochemical evidences. For example, acetophenone oxime gives only acetanilide. If the migrating group is asymmetric, it retains its configuration during the reaction. Sometimes the group that was syn-to the hydroxyl is found to have migrated and, even more commonly, mixtures of amides may be formed—particularly if R1 and R2 are both alkyl groups.

There are also two possible geometrical isomers of an unsymmetrical oxime. When mixtures of geometrical isomers of oximes are rearranged, mixtures of products result, which ratio mirrors exactly the ratio of the geometrical isomers in the starting materials.

When a mixture of oximes with a tertiary centre next to oxime is subjected to a Beckmann rearrangement, crossover products are obtained showing fragmentation of the protonated oxime.

Oximes derived from aldehydes are not usually good substrates for the Beckmann rearrangement, and yields of primary amides obtained in this manner are commonly poor. However, cyclic ketones undergo a very useful ring enlargement to give cyclic lactams.

Toluene–p–sulphonyl chloride forms the oxime tosylate, which eliminates the stable tosylate anion. PCl5 and SOCl2 induce rearrangement by converting OH to a better leaving group.

Certain ketoximes (oximes of α-diketones, α-keto acids, α-dialkylamino ketones, α-hydroxy ketones, ß-keto ethers) can be converted to nitriles by the action of proton or Lewis acids via fragmentation reactions, which are considered side reactions, often called ‘abnormal’ or ‘second-order’ Beckmann rearrangements.

7.11 HOFMANN, CURTIUS, SCHMIDT AND LOSSEN REARRANGEMENTS

There is a group of closely related rearrangements in which carbon migrates from carbon to nitrogen that may be represented generally as,

where R is an alkyl or aryl group and −X is a leaving group, which may be – Br (Hofmann rearrangement), (Curtius and Schmidt rearrangement) and – OCOR (Lossen rearrangement). In each case, if the migrating group is asymmetric, it retains its configuration.

7.11.1 Hofmann Rearrangement

The Hofmann rearrangement involves conversion of a carboxylic acid amide into an amine with loss of a carbon atom on treatment with aqueous sodium hypobromite (usually generated in situ from bromine and sodium hydroxide). Thus, it results in a shortening of the carbon chain by one atom and a change in the functional group from an amide to an amine. The Hofmann rearrangement occurs through a pathway similar to that for the Beckmann rearrangement.

The first step in the reaction sequence is the formation of the N-bromoamide, which then undergoes removal of the remaining proton on the nitrogen, the acidity of which is enhanced due to the presence of the electronegative bromine in addition to the acyl group. The deprotonated intermediate subsequently undergoes rearrangement by what is generally accepted to be a concerted mechanism, although a two-step process involving loss of bromide and formation of a nitrene would also be compatible with the data available.

The acid amide is treated with sodium hypobromite or bromine in alkali to give N-bromoamide, which reacts with the base to give its conjugate base. Separation of halide ion from the conjugate base gives an electron-deficient species called nitrene within which rearrangement occurs (nitrene is high-energy–neutral species containing a sextet of electrons on nitrogen atom, which is isoelectronic with carbenes).

The rearrangement of nitrene to isocyanate is intramolecular and analogous to the conversion of an acyl carbene to a ketene. Intramolecular process has been established by isotopic labelling: when two amides are rearranged no cross-products are obtained. The isocyanate produced may be isolated in anhydrous conditions, but reaction is generally carried out in aqueous or alcoholic solution in which the isocyanate is converted into an amine or a urethane, respectively. Increase in the nucleophilicity of the migrating group facilitates the reaction.

This rearrangement provides an efficient route for making both aliphatic and aromatic primary amines. Succinimide, on treatment with Br2 and aqueous KOH, yields about 45% ß–alanine.

Anthranilic acid may be obtained in 85% yield in a similar way from phthalimide. Nicotinamide gives ß-aminopyridine (65–70%) that cannot be obtained in good yield via the nitration of pyridine.

An optically active amide (I) gives an optically active amine (II), showing that reaction proceeds through a transition state in which the migratory group is partially bonded to both the migrating origin and the terminus.

(+)-α-Phenylpropionamide, when subjected to sodium hypobromite, gives (−)-α-phenylethylamine with retention of configuration in the migrating group. Bicyclic amide undergoes Hofmann rearrangement with retention of configuration at the migrating atom, because rigidity of the ring system prohibits inversion of configuration.

Meta-bromoaniline can be synthesized from benzoic acid involving Hofmann rearrangement.

α,β-Unsaturated amides give satisfactory yields of urethanes when treated with methanolic sodium hypochlorite. Hydrolysis of these urethanes lead directly to aldehydes, as would be expected, and, therefore, is best carried out in an acid medium.

With α,β-acetylenic amides the Hofmann reaction leads to the formation of nitriles.

It is known that the hydrolysis of benzamides is facilitated by substituents that withdraw electrons from the amide linkage into the ring. It is, therefore, evident that in the Hofmann reaction of 4-nitrophthalimide, the nitro group, by withdrawing electrons at position 1, will cause preferential hydrolysis of the amide linkage at this point, with subsequent rearrangement at position 2.

Furthermore, it is known that a methoxy group in the ortho-position to the amide linkage is much less effective in promoting hydrolysis than in the para-position. For example, in the Hofmann reaction of 3,4-dimethylphthalimide, hydrolysis of amide linkage should occur preferentially at 1-position.

Urea, when subjected to Hofmann reaction, yields 60% hydrazine.

7.11.2 Curtius Degradation (Rearrangement)

Curtius rearrangement involves pyrolysis of an acyl azide that expels molecular nitrogen and, at the same time, rearranges to an isocyanate (the azides may be made by nucleophilic substitution on an acyl chloride by sodium azide or by the reaction of acyl hydrazides with nitrous acid). Azides must be treated with caution as they may decompose explosively. The isocyanate may be isolated by carrying out the reaction in an aprotic solvent such as chloroform, but, generally, alcoholic solvent is used with which the isocyanate reacts to form a urethane.

The addition of water to isocyanate initially results in a carbamic acid, which is unstable and decarboxylate to give amines. The amines formed contain one carbon atom less than the acyl azide substrates. It is due to this feature that the reaction is normally referred to as Curtius degradation rather than Curtius rearrangement

α-Hydroxy azides exhibit a unique behaviour; that is, the intermediate isocyanates lose cyanic acid and aldehydes or ketones are formed. γ-And δ-hydroxy azides revert to the lactone through loss of hydrazoic acid; this reaction occurs less readily when a nonpolar solvent is used in the rearrangement.

Halogenated azides undergo rearrangement in the usual manner to isocyanates, from which halo amines are obtained by hydrolysis. If the halogen is in the α-position, the resulting halogenated isocyanate is hydrolyzed to an aldehyde or ketone.

The Curtius rearrangement has been applied to the synthesis of α-amino acids:

7.11.3 Schmidt Reaction

Carboxylic acids react with hydrazoic acid in the presence of concentrated H2SO4 to give isocyanates directly. The acyl azide is normally not isolated, but allowed to decompose and rearrange in the reaction mixture itself.

The Schmidt reaction is only applicable if the acid does not contain groups that are sensitive to concentrated sulphuric acid. Carbonyl compounds also undergo Schmidt reaction when treated with hydrazoic acid in sulphuric acid. Ketones produce amides, whereas aldehyde generally yields a mixture of the corresponding nitrile and N-formyl derivative.

7.11.4 Lossen Rearrangement

The Lossen rearrangement differs from the Hofmann rearrangement only in the leaving group, which is carboxylate anion rather than bromide ion. The starting material is the ester of hydroxamic acid (RCONHOH) that is decomposed in presence of base. Hydroxamic acids exhibit tautomerism: the keto-form is termed hydroxamic form and the enol-form is called hydroximic acid. As the reaction is normally carried out in water, the process furnishes the amine directly.

Since leaving group R’COO leaves as R’COO, the rearrangement is facilitated by the presence of electron-withdrawing groups in meta- or para-positions. Of these four related processes, the Lossen rearrangement is the least useful in synthesis of amines because of unavailability of hydroxamic acids.

7.12 WOLFF REARRANGEMENT

Wolff rearrangement is an example of nucleophilic rearrangement involving carbene. It is a rearrangement of α-diazoketones leading to carboxylic acid derivatives via ketene intermediates, which is similar to the Curtius rearrangement. It can be achieved with metal catalysis or photochemically. There has been much debate about the timing of the mechanism and many attempts to distinguish between the two-step process involving the intermediacy of a carbene and a concerted process in which migration occurs at the same time as loss of nitrogen. The general consensus appears to be that carbenes are intermediates in the photochemically induced Wolff rearrangement, but there is still controversy about the thermal process.

The above mechanism is supported by the following evidences: (a) the carbonyl carbon in the diazomethyl ketone becomes the carboxyl carbon in the resulting acid shown by 13C studies; (b) the migrating group R- migrates with retention of configuration and (c) in the absence of water or alcohol under favourable conditions, the intermediate ketene may be isolated.

The actual product of the reaction is thus the ketene, which reacts with water, alcohols, or amines to give carboxylic acids, esters or amides, respectively.

Generally, the thermal reaction is carried out in the presence of silver salts, which catalyze the decomposition of the diazoketone. If the rearrangement is carried out in the presence of catalytic amount of silver (I) salts, the dediazotation of α-diazoketone A initially generates the ketocarbene B and/or the corresponding ketocarbenoid C, followed by 1,2-shift of the alkyl group to give the ketene D.

When the rearrangement is carried out photochemically, the same ketene D is formed. In this case, molecular nitrogen (N2) and an excited ketocarbene are formed initially, which may undergo relaxation to the normal ketocarbene B, which can then undergo the 1,2–shift to give the ketene D.

The diazoketone can exist in two conformations, called s-E and s-Z. Studies have shown that the Wolff rearrangement takes place preferentially from the s-Z conformation.

The reaction is of wide scope. R may be alkyl or aryl and may contain many functional groups including unsaturation, but not including groups acidic enough to react with CH2N2 or diazoketones.

Two-fold Wolff rearrangement in the bis-homologation of dicarboxylic acids is reported. The substrate is a cis-disubstituted cyclohexane. The bisketene, which cannot be isolated, must have the same stereochemistry, because the dimethyl ester formed from the bisketene by the addition of methanol still is a cis-disubstituted cyclohexane.

The migrating group migrates with retention of configuration that has been confirmed by the following transformations involving optically active acid.

The acid obtained is degraded to the original acid by Barbier-Weiland degradation. The acid thus obtained is found to have the same configuration as the original acid.

Wolff rearrangements are of particular utility in preparing ring-contracted carboxylic acids via cyclic α-diazoketones.

7.13 ELECTROPHILIC REARRANGEMENTS

7.13.1 Stevens Rearrangement

In the Stevens rearrangement, keto-quaternary ammonium or tertiary sulphonium salts rearrange to amino ketones or mercapto ketones under the influence of strong base. Quaternary ammonium ions, which contain ß-hydrogen atoms undergo E2 (Hofmann) elimination with base:

If, however, none of the alkyl groups possesses a ß-hydrogen atom, but one has a ß-carbonyl group, an α-hydrogen is removed by base to give an ylide followed by rearrangement. The rearrangement does not proceed readily when the benzoyl group is replaced by a phenyl or alkyl group, these being relatively ineffective in ‘labelizing’ the hydrogens on an adjacent methylene group. The reaction is accelerated by base, when slightly more than one equivalent is added.

When the rearrangement is carried out on the optically active ammonium ion, the migrating group migrates with retention of configuration. The migrating group may be of the types allyl, benzhydryl (Ph2CH−) or phenacyl (PhCOCH2−).

When various substituents are placed in the meta- or para- position of the benzyl group, the reaction rate is increased in the order of electron-attracting ability of the substituent. In contrast, para-substituent in the phenacyl group increases the rate of rearrangement with the order of their electron-releasing ability. The rearrangement is retarded by incorporation of electron-attracting substituents in the phenacyl group because of the lower electron density at the negatively charged attacking carbon. The rearrangement is also retarded by incorporation of electron-attracting substituents into the benzoyl group.

The rearrangement occurs in a concerted manner, probably via formation and combination of radical-pairs.

The methylene group of a propargyl moiety is similar in chemical behaviour to an active methylene group adjacent to a carbonyl group because of the acidity of α-carbon atom to the acetylenic function. The propargyl group has been shown to be capable of acting as both the migrating group and the migration terminus in the Stevens rearrangement, that is, it forms a carbanion and promotes the cleavage of C-N bond. In the following example, the propargyl group acts as a migrating group and the phenacyl group as a migration terminus.

Here, the benzyl group acts as a migrating group and the propargyl group as a migration terminus.

Similar rearrangements have been observed with sulphonium salts under sufficiently drastic conditions. For example, benzyl methyl phenacyl sulphonium ion gives α-methyl mercapto-α-benzyl acetophenone.

7.13.2 Wittig Rearrangement

The Wittig rearrangement is directly analogous to the Stevens rearrangement in mechanism and outcome (not to be confused with the better known Wittig reaction) and takes its name from George Wittig who postulated the mechanism of the reaction. It is an example of [2,3] sigmatropic rearrangement in which benzyl and allyl ethers undergo a base-catalyzed rearrangement to α-allyl alkoxides, analogous to the Stevens rearrangement. A benzylic or allylic carbanion is generated by the action of a powerful base such as amide ion or phenyl lithium, and migration of carbon then leads to the more stable oxyanion. The stereochemistry of the Wittig rearrangement can be predicted in terms of a cyclic five-member transition state in which the α substituent prefers an equatorial orientation. Migratory aptitudes are in the order allyl ~ benzyl > alkyl > methyl > aryl, with electron-withdrawing substituents increasing aryl group migratory aptitude.

As with the Stevens rearrangement, there is evidence for a radical-pair mechanism:

[2,3] Sigmatropic rearrangements of anions of N-allyl amines have also been observed and are known as aza-Wittig rearrangements. The reaction requires anion-stabilizing substituents and is favoured by N-benzyl and by silyl or sulphenyl substituents on the allyl group.

7.13.3 Favorskii Rearrangement

α–Halo ketones react with base to give enolates that rearrange to esters via cyclopropanones. The direction of ring opening of the cyclopropanone is determined by which is more stable of the two possible carbanions that can be formed. Alkyl groups destabilize carbanions, whereas aryl groups stabilize them by delocalization of the negative charge. For example, PhCH2−COCH2Cl and PhCHCl−COMe give the same product. Chloroketones are normally preferable to bromoketones as reactants in the Favorskii rearrangement. It can be classified as intramolecular rearrangement from carbon to carbon, involving a migrating group moving without its electron from migrating origin to an electron–rich terminus.

A clear cut case of stereospecific rearrangement has been demonstrated using a pair of epimeric 1-chloro-1-acetyl-2-methylcyclohexanes A and B of proven configuration.

The rearrangement can be employed for bringing about ring contraction in cyclic systems, for example, 2-chlorocyclohexanone and methoxide ion give methyl cyclopentanecarboxylate in 60% yield.

An interesting example is the conversion of the cyclobutyl into the cyclopropyl system, for this must apparently involve the highly strained bicyclobutane system.

The cyclopropanone mechanism for the Favorskii rearrangement is obviously excluded for ketones such as 1-benzoylcyclohexyl chloride, in which the nonhalogenated α-carbon bears no hydrogen atom. Nevertheless, this ketone is found to rearrange with ease to ester. It thus appears that there are at least two distinct paths by which the Favorskii rearrangement may proceed, and that a mechanism analogous to the benzilic acid rearrangement (known as ‘semibenzilic’ rearrangement) may operate when cyclopropanone mechanism may not. If the reaction were concerted, elimination of the other chlorine would be just as favourable and the isomeric product A would be formed.

7.14 SUMMARY

We have seen in this chapter several rearrangement reactions that result in changes in connectivity in a carbon skeleton. These rearrangement reactions take place by the migration of alkyl or aryl groups from one site to an adjacent atom. In the Wagner–Meerwein rearrangement, an alkyl group migrates to an adjacent carbocation (or incipient carbocation). These migrations are controlled by cation stability so as to form the more stable intermediate. The driving force for the key step in pinacol rearrangement is also the formation of a more stable carbocation. Semipinacol rearrangements are pinacol reactions with no choice about which way to go. In 1,2-migrations, the migrating group retains its stereochemistry.

Intramolecular rearrangements are conveniently subdivided into those that occur in electron-deficient systems and those that occur in electron-rich systems. If you see a substitution reaction at a stereogenic saturated carbon atom that goes with retention of stereochemistry, look for neighbouring group participation. Neighbouring groups participate only if they speed up the reaction.

In a number of rearrangements, a group bound to carbon (or an equivalent) migrates to an attached heteroatom (at the α position) that bears a leaving group and a lone pair. Examples of such migrations are the Beckmann rearrangement (converting a ketone through an oxime into an amide), the Hofmann rearrangement (converting an amide into the corresponding amine) and the Baeyer–Villiger oxidation (converting a ketone into an ester). The Tiffeneau-Demjanov rearrangement of diazotized amino alcohols is a reaction that is of general use for the ring expansion of cycloalkanones to their next higher homologs. Wolff rearrangements are rearrangements of α-diazoketones leading to carboxylic acid derivatives via ketene intermediates. Anionic rearrangements are rarer than their cationic counterparts.

PROBLEMS
  1. Propose mechanisms for every step in the following transformations.
  2. Offer explanations for the following:
    1. In the Fries rearrangement ortho-product is formed at higher temperature.
    2. CF3−C(OH)(ϕ)−C(OH)(ϕ)−CF3 is resistant to pinacol rearrangement.
    3. Ketene reacts with diazomethane to give cyclopropanone.
    4. The Beckmann rearrangement of cyclopentanone oxime is slower than that of cyclohexanone oxime, which is much slower than that of the oxime of an acyclic ketone.
    5. The rate of Baeyer–Villiger oxidation of 4-substituted cyclohexanones increases in the order H < Me < t.Bu
  3. Consider the various methods by which 2-butanol can be converted into each of the compounds in parts a through o. In particular, suggest the reagents and conditions necessary to accomplish each of these functional-group conversions.
  4. Specify the reagents and conditions needed to convert cyclohexanone into each of the following products:
  5. What is the starting material needed for the synthesis of the following amides by a Beckmann rearrangement?
  6. Upon dehydration with acid, 2,2-dimethylcyclohexanol forms two alkenes. Both result from rearrangement and one contains a five-member ring. What are their structures?
  7. Both of the diols shown below undergo the pinacol rearrangement. Predict the product in each case and suggest a suitable mechanism.
  8. For the following diols, predict the major rearrangement product formed on treatment with cold dilute acid, and say in each case whether the pathway is a consequence of relative stability of intermediate cations or relative migratory aptitudes of the migrating groups.
    1. 2,3-diphenylbutan-2,3-diol
    2. 1,1-diphenyl-2-methylpropan-1,2-diol
    3. 2-methylpropan-l,2-diol
    4. butan-2,3-diol
  9. Write the major products expected from the following reactions, giving reasons.
  10. Give the products of Baeyer–Villiger rearrangement on these carbonyl compounds.
  11. Formulate mechanisms for the following transformations.
  12. Give the structure of the expected Favorskii rearrangement product of compound A.
OBJECTIVE TYPE QUESTIONS
  1. Unsaturated carbonyl compounds undergo a ring closure reaction with conjugated dienes. This is known as the
    1. Hoffman reaction
    2. Sandmeyer reaction
    3. Diels-Alder reaction
    4. Claisen reaction
  2. Amides may be converted into amines by the reaction named after
    1. Perkin
    2. Claisen
    3. Hoffman
    4. Gatterman
    5. Clemmensen
  3. The most important group of molecular rearrangements involves one of the following shifts
    1. 1,2-shift
    2. 1,3-shift
    3. 1,4-shift
    4. 1,5-shift
  4. Which of the following rearrangements involves a carbene instead of a carbenium ion?
    1. Pinacol rearrangement
    2. Wolff rearrangement
    3. Wagner Meerwein-rearrangement
    4. Hofmann rearrangement
  5. Electron-deficient nitrogen (nitrene) is an intermediate in one of the following rearrangements:
    1. Schmidt rearrangement
    2. Beckmann rearrangement
    3. Baeyer–Villiger oxidation
    4. Stevens rearrangement
  6. Electron-rich skeletal rearrangements occur under
    1. acidic conditions
    2. neutral conditions
    3. basic conditions
    4. under both neutral and acidic conditions
  7. Formation of a cyclopropanone intermediate is observed in
    1. Sommelet rearrangement
    2. Favorskii rearrangement
    3. Benzilic acid rearrangement
    4. Stevens rearrangement
  8. In the presence of strong bases, double bonds will also migrate within carbon skeletons by the
    1. removal of protons
    2. addition of protons
    3. removal and readdition of protons
    4. addition and removal of protons.
  9. Demjanov rearrangement involves the generation of carbenium ion by
    1. deamination of primary amines
    2. dehydration of alcohols
    3. dehydration of 1,2-diols
    4. dehydration of keto-oximes
  10. In most of the rearrangements, the migrating group migrates with
    1. inversion of its configuration
    2. retention of its configuration
    3. racemization of its configuration
    4. none of the above
  11. The rearrangement in which the products are temperature-dependent is
    1. Favorskii rearrangement
    2. Fries rearrangement
    3. Benzidine rearrangement
    4. Sommelet rearrangement
  12. Which one of the following rearrangements is different from the others?
    1. Fries rearrangement
    2. Favorskii rearrangement
    3. Claisen rearrangement
    4. Beckmann rearrangement
  13. Dienone-phenol rearrangement is a
    1. base-catalyzed transformation
    2. acid-catalyzed transformation
    3. transformation catalyzed by both acids and bases
    4. transformation under neutral conditions