Reactions - Lesson 2 - Aromatic Substitution, Electrophilic - Introduction - March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (2013)

March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (2013)

Part II. Introduction

Chapter 11. Aromatic Substitution, Electrophilic

11.F. Reactions

The reactions in this chapter are classified according to leaving group. Hydrogen replacements are treated first, and then rearrangements in which the attacking entity is first cleaved from another part of the molecule (hydrogen is also the leaving group in these cases), and finally replacements of other leaving groups.

11.F.i. Hydrogen as the Leaving Group in Simple Substitution Reactions

A. Hydrogen as the Electrophile

11-1 Hydrogen Exchange

Deuterio-de-hydrogenation or Deuteriation

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Aromatic compounds can exchange hydrogen atoms when treated with acids. The reaction is used chiefly to study mechanistic questions111 (including substituent effects), but can also be useful to deuterate (add 2img) or tritiate (add 3img) aromatic rings selectively. The usual directive effects apply and, for example, phenol treated with D2O gives slow exchange on heating, with only ortho and para hydrogen atoms being exchanged.112 Strong acids, of course, exchange faster with aromatic substrates, and this exchange must be taken into account when studying the mechanism of any aromatic substitution catalyzed by acids. There is a great deal of evidence that exchange takes place by the ordinary arenium ion mechanism. Among the evidence are the orientation effects noted above and the finding that the reaction is general acid catalyzed, which means that a proton is transferred in the slow step113 (Sec. 8.D). Furthermore, many examples have been reported of stable solutions of arenium ions formed by attack of a proton on an aromatic ring.5 Simple aromatic compounds can be extensively deuterated in a convenient fashion by treatment with D2O and BF3.114 It has been shown that tritium exchange takes place readily at the 2 position of 31, despite the fact that this position is hindered by the bridge. The rates were not very different from the comparison compound 1,3-dimethylnaphthalene.115

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Hydrogen exchange can also be effected with strong bases116 (e.g., NH2). In these cases, the slow step is the proton transfer:117

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so the SE1 mechanism and not the usual arenium ion mechanism is operating.118 Aromatic rings can also be deuterated by treatment with D2O and a Rh(III) chloride119 or Pt120 catalyst or with C6D6 and an alkylaluminum dichloride catalyst,121 though rearrangements may take place during the latter procedure. Tritium (3img, abbreviated T) can be introduced by treatment with T2O and an alkylaluminum dichloride catalyst.121 Tritiation at specific sites (e.g., >90% para in toluene) has been achieved with T2 gas and a microporous aluminophosphate catalyst.122

B. Nitrogen Electrophiles

11-2 Nitration or Nitro-de-hydrogenation

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Most aromatic compounds, whether of high or low reactivity, can be nitrated, because a wide variety of nitrating agents is available.123 For benzene, the simple alkylbenzenes, and less reactive compounds, the most common reagent is a mixture of concentrated nitric and sulfuric acids,124 but for active substrates, the reaction can be carried out with nitric acid alone,125 or in water, acetic acid, acetic anhydride, or chloroform.126 Milder conditions are necessary for active compounds (e.g., amines, phenols, and pyrroles), since reaction with mixed nitric and sulfuric acids would oxidize these substrates. With active substrates, (e.g., anilines127 and phenols,128 nitration can be accomplished by nitrosation under oxidizing conditions with a mixture of dilute nitrous and nitric acids.129 Trimethoxybenzenes were nitrated easily with ceric ammonium nitrate on silica gel,130 and mesitylene was nitrated in an ionic liquid using nitric acid–acetic anhydride.131 Phenol can also be nitrated in an ionic liquid.132 An alternative route for the nitration of activated aromatic compounds (e.g., anisole), used a nitrate ester (RONO2) with triflic acid in an ionic liquid for ortho-selective nitration.133

For nitration reactions of “normal” aromatic compounds, representative nitrating agents are NaNO2 and trifluoroacetic acid,134 N2O4/O2 and a catalytic amount of zeolite Hβ,135 Yb(OTf)3,136 Bi(NO3)3√5H2O,137 ceric ammonium nitrate,138 urea nitrate and nitrourea,139 and nitronium salts.140 A mixture of NO2 and ozone has also been used.141 Nitric acid, in the presence of P2O5 supported on SiO2, is useful for the nitration of aromatic compounds under solvent-free conditions.142 Nitration of styrene poses a problem since addition occurs at the C=C unit to give a 1-nitroethyl aryl.143 Deactivated aromatic rings, as in acetophenone, were nitrated with N2O5 and Fe(acac)2(acac=acetylacetone).144 Heterocycles (e.g., pyridine) are nitrated with N2O5 and SO2.145

When anilines are nitrated under strong acid conditions, meta orientation is generally observed, because the ammonium salt is the species undergoing nitration, which is the conjugate acid of the amine. If the conditions are less acidic, the free amine is nitrated and the orientation is ortho–para. Although the free base may be present in much smaller amounts than the conjugate acid, it is far more susceptible to aromatic substitution (see also, Sec. 11.B.i). Because of these factors and because they are vulnerable to oxidation by nitric acid, primary aromatic amines are often protected before nitration by treatment with acetyl chloride (Reaction 16-72) or acetic anhydride (Reaction 16-73). Nitration of the resulting acetanilide derivative avoids all these problems. There is evidence that when the reaction takes place on the free amine, it is the nitrogen that is attacked to give an N-nitro compound (Ar–NH–NO2), which rapidly undergoes rearrangement (see Reaction 11-28) to give the product.146

Since the nitro group is deactivating, it is usually easy to stop the reaction after one group has entered the ring, but a second and a third group can be introduced if desired, especially when an activating group is also present. Even m-dinitrobenzene can be nitrated if vigorous conditions are applied. This has been accomplished with NO2+ BF4 in FSO3H at 150 °C.147

With most of the reagents mentioned, the attacking species is the nitronium ion (NO2+). Among the ways in which this ion is formed are

1. In concentrated sulfuric acid, by an acid–base reaction in which nitric acid is the base:

equation

This ionization is essentially complete.

2. In concentrated nitric acid alone,148 by a similar acid–base reaction in which one molecule of nitric acid is the acid and another the base:

equation

This equilibrium lies to the left (~ 4% ionization), but enough NO2+ is formed for nitration to occur.

3. The equilibrium just mentioned occurs to a small extent even in organic solvents.

4. With N2O5 in CCl4, there is spontaneous dissociation:

equation

but in this case there is evidence that some nitration also takes place with undissociated N2O5 as the electrophile.

5. When nitronium salts are used, NO2+ is of course present to begin with. Esters and acyl halides of nitric acid ionize to form NO2+.

There is a great deal of evidence that NO2+ is present in most nitration reactions and that it is the attacking entity,149 for example,

1. Nitric acid has a peak in the Raman spectrum. When nitric acid is dissolved in concentrated sulfuric acid, the peak disappears and two new peaks appear, one at 1400 cm−1 attributable to NO2+ and one at 1050 cm−1 due to HSO4.150

2. On addition of nitric acid, the freezing point of sulfuric acid is lowered about four times the amount expected if no ionization has taken place.151 This means that the addition of one molecule of nitric acid results in the production of four particles, which is strong evidence for the ionization reaction between nitric and sulfuric acids given above.

3. The fact that nitronium salts in which nitronium ion is known to be present (by X-ray studies) nitrate aromatic compounds shows that this ion does attack the ring.

4. The rate of the reaction with most reagents is proportional to the concentration of NO2+, not to that of other species.152 When the reagent produces this ion in small amounts, the attack is slow and only active substrates can be nitrated. In concentrated and aqueous mineral acids, the kinetics are second order: first order each in aromatic substrate and in nitric acid (unless pure nitric acid is used in which case there are pseudo-first-order kinetics). But in organic solvents (e.g., nitromethane, acetic acid, and CCl4), the kinetics are first order in nitric acid alone and zero order in aromatic substrate, because the rate-determining step is formation of NO2+ and the substrate does not take part in this.

In a few cases, depending on the substrate and solvent, there is evidence that the arenium ion is not formed directly, but via the intermediacy of a radical pair (see Sec. 11.D), such as 32.153

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Arylboronic acids have been shown to react with ammonium nitrate and trifluoroacetic acid to give the corresponding nitrobenzene.154

OS I, 372, 396, 408 (see also, OS 53, 129); II, 254, 434, 438, 447, 449, 459, 466; III, 337, 644, 653, 658, 661, 837; IV, 42, 364, 654, 711, 722, 735; V, 346, 480, 829, 1029, 1067.

11-3 Nitrosation or Nitroso-de-hydrogenation

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Ring nitrosation155 with nitrous acid is normally carried out only with active substrates (e.g., amines and phenols). However, primary aromatic amines give diazonium ions (Reaction 13-19) when treated with nitrous acid,156 and secondary amines tend to give N-nitroso rather than C-nitroso compounds (Reaction 12-50); hence this reaction is normally limited to phenols and tertiary aromatic amines. Nevertheless, secondary aromatic amines can be C-nitrosated in two ways. The N-nitroso compound first obtained can be isomerized to a C-nitroso compound (Reaction 11-29), or it can be treated with another equivalent of nitrous acid to give an N,C-dinitroso compound. Also, a successful nitrosation of anisole has been reported, where the solvent was CF3COOH–CH2Cl2.157

Much less work has been done on the mechanism of this reaction than on Reaction 11-2.158 In some cases, the attacking entity is NO+, but in others it is apparently NOCl, NOBr, N2O3, and so on, in each of which there is a carrier of NO+. Both NOCl and NOBr are formed during the normal process of making nitrous acid (the treatment of sodium nitrite with HCl or HBr). Nitrosation requires active substrates because NO+ is much less reactive than NO2+. Kinetic studies have shown that NO+ is at least 1014 times less reactive than NO2+.159 A consequence of the relatively high stability of NO+ is that this species is easily cleaved from the arenium ion, so that k−1 competes with k2 (Sec. 11.A.i) and isotope effects are found.160 With phenols, there is evidence that nitrosation may first take place at the OH group, after which the nitrite ester thus formed rearranges to the C-nitroso product.161 Tertiary aromatic amines substituted in the ortho position generally do not react with HONO, probably because the ortho substituent prevents planarity of the dialkylamino group, without which the ring is no longer activated. This is an example of steric inhibition of resonance (Sec. 2.F).

OS I, 214, 411, 511; II, 223; IV, 247.

11-4 Diazonium Coupling

Arylazo-de-hydrogenation

equation

Aromatic diazonium ions normally couple only with active substrates (e.g., amines and phenols).162 Many of the products of this reaction are used as dyes (azo dyes).163 Presumably because of the size of the species attacked by the aromatic ring, substitution is mostly para to the activating group, unless that position is already occupied, in which case ortho substitution takes place. The pH of the solution is important both for phenols and amines. For amines, the solutions may be mildly acidic or neutral. The fact that amines give ortho and para products shows that even in mildly acidic solution they react in their un-ionized form. If the acidity is too high, the reaction does not occur, because the concentration of free amine becomes too small. Phenols must be coupled in slightly alkaline solution where they are converted to the more reactive phenoxide ions, because phenols themselves are not active enough for the reaction. However, neither phenols nor amines react in moderately alkaline solution, because the diazonium ion is converted to a diazo hydroxide (Ar–N=N–OH). Primary and secondary amines face competition from attack at the nitrogen.164 However, the resulting N-azo compounds (aryl triazenes) can be isomerized to C-azo compounds (Reaction 11-30). In at least some cases, even when the C-azo compound is isolated, it is the result of initial N-azo compound formation followed by isomerization. It is therefore possible to synthesize the C-azo compound directly in one laboratory step.165 Acylated amines and phenolic ethers and esters are ordinarily not active enough for this reaction, though it is sometimes possible to couple them (as well as such polyalkylated benzenes as mesitylene and pentamethylbenzene) to diazonium ions containing electron-withdrawing groups in the para position, since such groups increase the concentration of the positive charge and thus the electrophilicity of the ArN2+. Some coupling reactions that are otherwise very slow (in cases where the coupling site is crowded) are catalyzed by pyridine for reasons discussed in Section 11.A.i. Phase-transfer catalysis has also been used.166

Coupling of a few aliphatic diazonium compounds to aromatic rings has been reported. All the examples reported so far involve cyclopropanediazonium ions and bridgehead diazonium ions, in which loss of N2 would lead to very unstable carbocations.167 Azobenzenes have been prepared by Pd catalyzed coupling of aryl hydrazides with aryl halides, followed by direct oxidation.168

The mechanism of (Z/E) isomerization in Ar–N=NAr systems has been studied.169

OS I, 49, 374; II, 35, 39, 145.

11-5 Direct Introduction of the Diazonium Group

Diazoniation or Diazonio-de-hydrogenation

equation

Diazonium salts can be prepared directly by replacement of an aromatic hydrogen without the necessity of going through the amino group.170 The reaction is essentially limited to active substrates (amines and phenols), since otherwise poor yields are obtained. Since the reagents and the substrate are the same as in Reaction 11-3, the first species formed is the nitroso compound. In the presence of excess nitrous acid, this is converted to the diazonium ion.171 The reagent (azidochloromethylene)dimethylammonium chloride [Me2N=C(Cl)N3 Cl] can also introduce the diazonium group directly into a phenol.172 A synthesis of solid aryldiazonium chlorides is now available.173

11-6 Amination or Amino-de-hydrogenation174

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Aromatic compounds can be converted to primary aromatic amines in 10–65% yields, by treatment with hydrazoic acid (HN3) in the presence of AlCl3 or H2SO4.175 Higher yields (>90%) have been reported with trimethylsilyl azide (Me3SiN3) and triflic acid (F3CSO2OH).176 Treatment of an aromatic compound with tetramethylhydrazonium iodide and then ammonium also gives the aryl amine.177 Tertiary amines have been prepared in ~50–90% yields by treatment of aromatic hydrocarbons with N-chlorodialkylamines; by heating in 96% sulfuric acid; or with AlCl3 or FeCl3 in nitroalkane solvents; or by irradiation.178 Treatment of an aryl halide with an amine and a Pd catalyst leads to the aniline derivative.179

Tertiary (and to a lesser extent, secondary) aromatic amines can also be prepared in moderate-to-high yields by amination with an N-chlorodialkylamine (or an N-chloroalkylamine) and a metallic-ion catalyst (e.g., Fe2+, Ti3+, Cu+, Cr2+) in the presence of sulfuric acid.180 The attacking species in this case is the aminium radical ion (R2NH√) formed by181

equation

Because attack is by a positive species (even though it is a free radical), orientation is similar to that in other electrophilic substitutions (e.g., phenol and acetanilide give ortho and para substitution, mostly para). When an alkyl group is present, attack at the benzylic position competes with ring substitution. Aromatic rings containing only meta-directing groups do not give the reaction at all. Fused-ring systems react well.182

Unusual orientation has been reported for amination with haloamines and with NCl3 in the presence of AlCl3. For example, toluene gave predominately meta amination.183 It has been suggested that initial attack in this case is by Cl+ and that a nitrogen nucleophile (whose structure is not known but is represented here as NH2 for simplicity) adds to the resulting arenium ion, so that the initial reaction is addition to a carbon–carbon double bond followed by elimination of HCl from 33.184

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According to this suggestion, the electrophilic attack is at the para position (or the ortho, which leads to the same product) and the meta orientation of the amino group arises indirectly. This mechanism is called the σ-substitution mechanism.

Diphenyliodonium salts react with amines in the presence of a Cu catalyst. Diphenyliodonium tetrafluoroborate, (Ph2I+ BF4), reacts with indole in DMF at 150 °C with a Cu(OAc)2 catalyst (e.g., to give N-phenylindole).185

Aromatic compounds that do not contain meta-directing groups can be converted to diarylamines by treatment with aryl azides in the presence of phenol at −60 °C: ArH + Ar′N3 → ArNHAr′.186 Diarylamines are also obtained by the reaction of N-arylhydroxylamines with aromatic compounds (benzene, toluene, anisole) in the presence of F3CCO2H: ArH + Ar′NHOH → ArNHAr′.187

Direct amidation can be carried out if an aromatic compound is heated with a hydroxamic acid (34) in polyphosphoric acid, but the scope is essentially limited to phenolic ethers.188 Naphthol reacted with a substituted hydrazine to give the 1-amino derivative.189 The formation of hydroindole derivatives was accomplished by reaction of a N-carbamoyl phenylethylamine derivative with phenyliodine (III) diacetate, followed by Bu4NF.190 Direct amidation via ipso substitution by nitrogen was accomplished when a N-methoxy arylethylamide (35) was treated with [hydroxyl(tosyloxy)iodo]benzene (HTIB) in 2,2,2-trifluoroethanol, giving a N-methoxy spirocylcic amide (36).191

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Aromatic compounds add to DEAD, in the presence of InCl3–SiO2 and microwave irradiation, to give the N-aryldiamino compound [ArN(CO2Et)–NHCO2Et].192 An interesting variation in the alkylation reaction used 5 equiv of aluminum chloride in a reaction of N-methyl-N-phenylhydrazine and benzene to give N-methyl-4-phenylaniline.193

Also see, Reactions 13-5 and 13-16.

C. Sulfur Electrophiles

11-7 Sulfonation or Sulfo-de-hydrogenation

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The sulfonation reaction is very broad in scope and many aromatic hydrocarbons (including fused-ring systems), aryl halides, ethers, carboxylic acids, amines,194 acylated amines, ketones, nitro compounds, and sulfonic acids have been sulfonated.195 Phenols can also be successfully sulfonated, but attack at oxygen may compete.196 Sulfonation is often accomplished with concentrated sulfuric acid, but it can also be done with fuming H2SO4, SO3, ClSO2OH, ClSO2NMe2/In(OTf)3,197 or other reagents.198 A FeCl3 based ionic liquid has been used for the sulfonation of aromatic compounds.199 As with nitration (Reaction 11-2), reagents of a wide variety of activity are available to suit both highly active and highly inactive substrates. Since this reaction is reversible (see Reaction 11-38), it may be necessary to drive the reaction to completion. However, at low temperatures the reverse reaction is very slow and the forward reaction is practically irreversible.200 Sulfur trioxide reacts much more rapidly than sulfuric acid with benzene (it is nearly instantaneous). Sulfones are often side products. When sulfonation is carried out on a benzene ring containing four or five alkyl and/or halogen groups, rearrangements usually occur (see Reaction 11-36).

A great deal of work has been done on the mechanism, chiefly by Cerfontain and co-workers.201 Mechanistic study is made difficult by the complicated nature of the solutions. Indications are that the electrophile varies with the reagent, though SO3 is involved in all cases, either free or combined with a carrier. In aq H2SO4 solutions, the electrophile is thought to be H3SO4+ (or a combination of H2SO4 and H3O+) at concentrations below ~80–85% H2SO4, and H2S2O7 (or a combination of H2SO4 and SO3) at concentrations higher than this202 (the changeover point varies with the substrate203). Evidence for a change in electrophile is that in both the dilute and the concentrated solutions the rate of the reaction was proportional to the activity of H3SO4+ and H2S2O7, respectively. Further evidence is that with toluene as substrate the two types of solution gave very different ortho/para ratios. The mechanism is essentially the same for both electrophiles and may be shown as202:

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The other product of the first step is HSO4 or H2O from H2S2O7 or H3SO4+, respectively. Path a is the principal route, except at very high H2SO4 concentrations, when path b becomes important. With H3SO4+ the first step is rate determining under all conditions, but with H2S2O7 the first step is the slow step only up to ~96% H2SO4, when a subsequent proton transfer becomes partially rate determining.204 The H2S2O7 is more reactive than H3SO4+. In fuming sulfuric acid (H2SO4 containing excess SO3), the electrophile is thought to be H3S2O7+ (protonated H2S2O7) up to ~104% H2SO4 and H2S4O13 (H2SO4 + 3 SO3) beyond this concentration.205 Finally, when pure SO3 is the reagent in aprotic solvents, SO3 itself is the actual electrophile.206 Free SO3 is the most reactive of all these species, so that attack here is generally fast and a subsequent step is usually rate determining, at least in some solvents.

OS II, 42, 97, 482, 539; III, 288, 824; IV, 364; VI, 976.

11-8 Halosulfonation or Halosulfo-de-hydrogenation

equation

Aromatic sulfonyl chlorides can be prepared directly, by treatment of aromatic rings with chlorosulfuric acid.207 Since sulfonic acids can also be prepared by the same reagent (Reaction 11-7), it is likely that they are intermediates, being converted to the halides by excess chlorosulfuric acid.208 The reaction has also been effected with bromo- and fluorosulfuric acids. Sulfinyl chlorides (ArSOCl) have been prepared by the reaction of thionyl chloride and an aromatic compound on Montmorillonite K-10 clay.209

OS I, 8, 85.

11-9 Sulfonylation

Alkylsulfonylation or Alkylsulfo-de-hydrogenation

equation

Diaryl sulfoxides can be prepared by the reaction of aromatic compounds with thionyl chloride and triflic acid.210 Diaryl sulfones have also been prepared using thionyl chloride with the ionic liquid [bmim]Cl√AlCl3.211 Diaryl sulfones can be formed by treatment of aromatic compounds with aryl sulfonyl chlorides and a Friedel–Crafts catalyst.212 This reaction is analogous to Friedel–Crafts acylation with carboxylic acid halides (Reaction 11-17). In a better procedure, the aromatic compound is treated with an aryl sulfonic acid and P2O5 in polyphosphoric acid.213 Still another method uses an arylsulfonic trifluoromethanesulfonic anhydride (ArSO2OSO2CF3) (generated in situfrom ArSO2Br and CF3SO3Ag) without a catalyst.214 Indium tris(triflate)215 and indium trichloride216 leads to sulfonation of aromatic compounds with sulfonyl chlorides. Indium bromide was used with indoles.217 A ferric chloride catalyzed reaction with microwave irradiation has also been reported,218 as has the use of zinc metal with microwave irradiation.219 The reaction can be extended to the preparation of alkyl aryl sulfones by the use of a sulfonyl fluoride.220

Direct formation of diaryl sulfones from benzenesulfonic acid and benzene was accomplished using Nafion-H.221 Aryl halides react with sulfinic acid salts, via a proline-promoted CuI catalyzed coupling reaction.222 Arylboronic acids (see Reaction 10-73) are sulfonated in ionic liquids, using a Cu catalyst.223

OS X, 147.

D. Halogen Electrophiles

11-10 Halogenation224

Halo-de-hydrogenation

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1. Chlorine225 and Bromine.226 Aromatic compounds can be brominated or chlorinated by treatment with bromine or chlorine in the presence of a catalyst.227 For amines and phenols the reaction is so rapid that it is carried out with a dilute solution of Br2 or Cl2 in water at room temperature, or with aqueous HBr in DMSO.228 Typically, it is not possible to stop the reaction with anilines before all the available ortho and para positions are substituted, because the initially formed haloamines are weaker bases than the original amines and are less likely to be protonated by the liberated HX.229 For this reason, the corresponding anilides are used if monosubstitution is desired. With phenols it is possible to stop after one group has entered.230 The rapid room temperature reaction with amines and phenols is often used as a test for these compounds. In general, for active substrates including anilines, phenols, naphthalene, and polyalkylbenzenes231 (e.g., mesitylene and isodurene), no catalyst is needed. The overall effectiveness of reagents in aromatic substitution is Cl2 > BrCl > Br2 > ICl > I2. A mixture of ZnBr2/diazene has been suggested for the regioselective para-bromination of activated aromatic substrates.232

When chlorination or bromination is carried out at high temperatures (e.g., 300–400 °C), ortho–para directing groups direct meta and vice versa.233 A different mechanism operates here, which is not completely understood. It is also possible for bromination to take place by the SE1 mechanism, for example, in the t-BuOK catalyzed bromination of 1,3,5-tribromobenzene.234

For less activated aromatic rings, iron was commonly used at one time for halogenation, but the real catalyst was shown not to be the iron itself, but rather the ferric bromide or chloride formed in small amounts from the reaction between iron and the reagent. Indeed, ferric chloride and other Lewis acids are typically directly used as catalysts, as is iodine. Many Lewis acids can be used, including thallium(III) acetate, which promotes bromination with high regioselectivity para to an ortho–para directing group.235 A mixture of Mn(OAc)3 and acetyl chloride, with ultrasound, chlorinates anisole with high selectivity.236

Other reagents can be used to promote chlorination or bromination. copper(II)-catalyzed chlorination has been reported using dioxygen as an oxidant.237 N-Bromosuccinimide under photochemical conditions238 brominates aromatic compounds, as does pyridinium bromide perbromide,239 and NBS in acetic acid with ultrasound is effective.240 Both NCS and NBS with aq BF3 gave the respective chloride or bromide.241 The NBS in an ionic liquid242 gave the brominated aromatic, and para-bromination of aniline was reported by mixing aniline with the ionic liquid, bmim Br2.243 Similarly, hmim Br3244 without another reagent is a brominating agent. Bromine on silica gel245 or with SO2Cl2246 gave good yields of the brominated aromatic compound. Majetich et al.247 reported the use of HBr/DMSO for the remarkably selective bromination of aniline. Highly para-selective bromination was accomplished using dioxane dibromide, under solvent free conditions.248

Other reagents have been used for chlorination and bromination. If the substrate contains alkyl groups, side-chain halogenation (Reaction 14-1) is possible with most of the reagents mentioned, including chlorine and bromine. Since side-chain halogenation is catalyzed by light, the reactions should be run in the absence of light wherever possible. Sulfuryl chloride (SO2Cl2) in acetic acid chlorinates anisole derivatives,249 and acetyl chloride with a catalytic amount of ceric ammonium nitrate also converted aromatic compounds to the corresponding chlorinated derivative.250 A mixture of KCl and Oxone® chlorinated activated aromatic compounds.251 Oxone and KBr gave good para-bromination of anisole,252 as does NH4Br/Oxone.253 Dibromoisocyanuric acid in H2SO4 is a very good brominating agent254 for substrates with strongly deactivating substituents.255 N-Chlorosuccinimide in isopropyl alcohol256 chlorinates aniline derivatives, and KBr/NaBO3√4 H2O has been used for the bromination of aniline derivatives.257 Conversion of aniline to the N-SnMe3 derivative allowed in situ bromination with bromine, with high para selectivity after conversion to the free amine with aq KF.258 Pyridinium bromochromate converted phenolic derivatives to brominated phenols.259

Predominant ortho chlorination260 of phenols has been achieved with chlorinated cyclohexadienes,261 while para chlorination of phenols, phenolic ethers, and amines can be accomplished with N-chloroamines262 and with N-chlorodimethylsulfonium chloride (Me3S+Cl Cl).263 The last method is also successful for bromination when N-bromodimethylsufonium bromide is used. Highly selective ortho chlorination of acetanilides has been reported, using a combination of P and Cu catalysts.264 Iridium-catalyzed borylation of arenes leads to meta-halogenation.265 Certain alkylated phenols can be brominated in the meta positions with Br2 in the superacid solution SbF5–HF.266 It is likely that meta orientation is the result of conversion by the superacid of the OH group to the OH2+ group, which should be meta-directing because of its positive charge. Bromination and the Sandmeyer reaction(14-20) can be carried out in one laboratory step to give 37 by treatment of an aromatic primary amine with CuBr2 and tert-butyl nitrite, for example,267

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With deactivated aromatic derivatives, NBS and H2SO4 is an effective reagent, giving the meta-brominated product.268 Bromination at C-6 of 2-aminopyridine was accomplished with NBS.269 An alternative route reacted pyridine N-oxide with POCl3 and triethylamine to give 2-chloropyridine.270

For reactions in the absence of a catalyst, the attacking entity is simply Br2 or Cl2 that has been polarized by the ring.271

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Evidence for molecular chlorine or bromine as the attacking species in these cases is that acids, bases, and other ions, especially chloride ion, accelerate the rate about equally, though if chlorine dissociated into Cl+ and Cl, the addition of chloride should decrease the rate and the addition of acids should increase it. Intermediate 38 has been detected spectrally in the aqueous bromination of phenol.272

When a Lewis acid catalyst273 is used with chlorine or bromine, the attacking entity may be Cl+ or Br+, formed by FeCl3 + Br2 → FeCl3Br + Br+, or it may be Cl2 or Br2, polarized by the catalyst. With other reagents, the attacking entity in brominations may be Br+ or a species (e.g., H2OBr+, the conjugate acid of HOBr), in which H2O is a carrier of Br+.274 With HOCl in water the electrophile may be Cl2O, Cl2, or H2OCl+; in acetic acid it is generally AcOCl. All these species are more reactive than HOCl itself.275 It is extremely doubtful that Cl+ is a significant electrophile in chlorinations by HOCl.275 It has been demonstrated in the reaction between N-methylaniline and calcium hypochlorite that the chlorine entity is attacked by the nitrogen to give N-chloro-N-methylaniline, which rearranges (as in Reaction 11-31) to give a mixture of ring-chlorinated N-methylanilines in which the ortho isomer predominates.276 In addition to hypohalous acids and metal hypohalites, organic hypohalites are reactive. An example is tert-butylhypobromite (t-BuOBr), which brominated toluene in the presence of zeolite (HNaX).277

Furan and thiophene are known to polymerize in the presence of strong acid, both Brimgnsted–Lowry and Lewis. For such highly reactive heteroaromatic systems, alternative halogenating reagents are commonly used. Furan was converted to 2-bromofuran with a bromine•dioxane complex (e.g., at <0 °C.278 3-Butylthiophene reacted with NBS/acetic acid to give 2-bromo-3-butylthiophene.279 N-Methylpyrrole reacted with NBS and a catalytic amount of PBr3, at −78 °C → −10 °C, to give N-methyl-3-bromopyrrole.280

2. Iodine. Iodine is the least reactive of the halogens in aromatic substitution.281 Except for active substrates, an oxidizing agent must normally be present to oxidize I2 to a better electrophile.282 Examples of such oxidizing agents used with I2 are HNO3, SO3, hypervalent iodine compounds [e.g., PhI(OTf)2,283 NaIO4,284 ammonium iodide and H2O2,285 ceric ammonium nitrate,286 peroxydisulfates,287 and a mixture of NaIO4/KI/NaCl].288 A solvent-free iodination used I2 and AgNO3.289 The reagent ICl is a better iodinating agent than iodine itself.290 A mixture of ICl/In(OTf)3 has also been used.291 Iodination can also be accomplished by treatment of the substrate with NCI and H2SO4,292 N-Iodosuccinamide and trifluoroacetic acid,293 KI/KIO3 in aq methanol,294 KI and H2O2,295 and NaI with an iron catalyst.296 Sodium periodate and iodine was used to iodinate β-carbolines.297 A solvent-free iodination was accomplished using NaICl2 and an N-bromoammonium salt.298 Another solvent-free iodination used I2 with Bi(NO3)3 on silica gel.299 A mixture of iodine/pyridine/dioxane leads to selective para-iodination of aniline derivatives.300 Selective ortho cyanation allows the reaction with iodine to give the corresponding aryl iodide.301 Iodination of activated aromatics has been reported using KI and ammonium peroxodisulfate.302 N-Iodosuccinimide and p-toluenesulfonic acid give regioselective iodination of phenol and related compounds.303

The actual attacking species is less clear than with bromine or chlorine. Iodine itself is too unreactive, except for active species (e.g., phenols), where there is good evidence that I2 is the attacking entity.304 There is evidence that AcOI may be the reactive entity when peroxyacetic acid is the oxidizing agent,305 and I3+ when SO3 or HIO3 is the oxidizing agent.306 The I+ ion has been implicated in several procedures.307 For an indirect method for accomplishing aromatic iodination see (Reaction 12-31).

3. Fluorine. Direct fluorination of aromatic rings with F2 is not feasible at room temperature, because of the extreme reactivity of F2.308 It has been accomplished at low temperatures (e.g., −70 to −20 °C, depending on the substrate),309 but the reaction is not yet of preparative significance. Fluorination has also been reported with acetyl hypofluorite (CH3CO2F, generated from F2 and sodium acetate),310 and with an N-fluoroperfluoroalkyl sulfonamide [e.g., (CF3SO2)2NF].311 Pyridine has been converted to 2-fluoropyridine with F2/I2/NEt3 in 1,1,2-trichloro-1,2,2-trifluoroethane.312 However, none of these methods seems likely to displace the Schiemann reaction(13-23; heating diazonium tetrafluoroborates) as the most common method for introducing fluorine into aromatic rings.

OS I, 111, 121, 123, 128, 207, 323; II, 95, 97, 100, 173, 196, 343, 347, 349, 357, 592; III, 132, 134, 138, 262, 267, 575, 796; IV, 114, 166, 256, 545, 547, 872, 947; V, 117, 147, 206, 346; VI, 181, 700; VIII, 167; IX, 121, 356. Also see, OS II, 128.

E. Carbon Electrophiles

A new carbon–carbon bond is formed in the reactions in this section. With respect to the aromatic ring, they are electrophilic substitutions, because a positive species attacks the ring. We treat them in this manner because it is customary. However, with respect to the electrophile, most of these reactions are nucleophilic substitutions, and what was said in Chapter 10 is pertinent to them.

11-11 Friedel–Crafts Alkylation

Alkylation or Alkyl-de-hydrogenation

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The alkylation of aromatic rings, called Friedel–Crafts alkylation, is a reaction of very broad scope.313 Catalytic asymmetric Friedel–Crafts alkylation reactions are known.314 The most important reagents are alkyl halides, alkenes, and alcohols, but other types of reagent have also been employed.313 Tertiary halides are particularly good substrates since they form relatively stable tertiary carbocations. When alkyl halides are used, the reactivity order is F > Cl > Br > I.315 This trend can be seen in reactions of dihalo compounds (e.g., FCH2CH2CH2Cl), which react with benzene to give PhCH2CH2CH2Cl316 when the catalyst is BCl3. By the use of this catalyst, it is therefore possible to place a haloalkyl group on a ring (see also, Reaction 11-14).317 Di- and trihalides, when all the halogens are the same, usually react with more than one molecule of an aromatic compound; it is usually not possible to stop the reaction earlier.318 Thus, benzene with CH2Cl2 gives not PhCH2Cl, but Ph2CH2; benzene with CHCl3 gives Ph3CH. With CCl4, however, the reaction stops when only three rings have been substituted to give Ph3CCl. Functionalized alkyl halides [e.g., ClCH(SEt)CO2Et] undergo Friedel–Crafts alkylation.319 Montmorillonite clay-(K10) is an effective medium for alkylation reactions.320

Alkenes are especially good alkylating agents, generally proceeding by formation of an intermediate carbocation that reacts with the electron-rich aromatic ring, and the final product (39) incorporates a H and Ar from ArH to a C=C double bond. Many variations are possible. This reaction has been accomplished in an ionic liquid, using Sc(OTf)3 as the catalyst.321 Other catalysts include Sm(OTf)3.322 Intramolecular versions lead to polycyclic aromatic compounds.323 Benzene reacted with 1,2,3,6-tetrahydropyridine in the presence of trifluoromethanesulfonic acid to give 4-phenylpiperidine.324

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When 4-methoxyphenol reacted with isobutylene (electrolysis with 3 M LiClO4 in nitromethane and acetic acid), initial reaction with the phenolic oxygen generated an ether moiety and the resulting carbocation was attacked by the aromatic ring to form a benzofuran.325 Enantioselective alkylations have been reported for pyrroles and indoles, using a chiral Pybox–Cu complex.326

Acetylene reacts with 2 mol of aromatic compound to give 1,1-diarylethanes, and phenylacetylene reacted to give 1,1-diarylethenes with a Sc(OTf)3 catalyst.327 Variations are possible here as well. Phenol reacted with trimethylsilylethyne, in the presence of SnCl4 and 50% BuLi, at 105 °C, to give the 2-vinyl phenolic derivative.328 A Ru catalyzed intramolecular reaction with a pendant alkyne unit led to a dihydronapthalene derivative,329 and a Rh catalyzed reaction led to indanone derivatives.330 An acidic fluoroantimonate(V) ionic liquid has been used as a catalyst.331

Alcohols are more active than alkyl halides, but if a Lewis acid catalyst is used more catalyst is required, since the catalyst complexes with the OH group. However, proton acids (e.g., H2SO4) are often used to catalyze alkylation with alcohols. An intramolecular cyclization was reported from an allylic alcohol, using P2O5, to give indene derivatives.332 Secondary alcohols are coupled to aromatic compounds using a heterobimetallic Ir–Sn complex.333Molecular iodine has been used to catalyze benzylation of arenes with benzylic alcohols.334 A “contra Friedel–Crafts” tert-butylation has been reported.335 Diastereoselective alkylation is possible from alcohol precursors. High facial diastereoselectivity was reported with “chiral benzylic cations”, for example.336

When carboxylic esters are the reagents, there is competition between alkylation and acylation (Reaction 11-17). This competition can often be controlled by choice of catalyst, and alkylation is usually favored, but carboxylic esters are not often employed in Friedel–Crafts reactions. Other alkylating agents are ethers,337thiols, sulfates, sulfonates, alkyl nitro compounds,338 and even alkanes and cycloalkanes, under conditions where these are converted to carbocations. Notable here are ethylene oxide, which puts the CH2CH2OH group onto the ring,339 and cyclopropyl340 units. For all types of reagent, the reactivity order is allylic ~ benzylic > tertiary > secondary > primary. Alkyl mesylates undergo alkylation reaction with benzene rings in the presence of Sc(OTf)3.341 Allylic acetates undergo alkylation with Mo(CO)6342 and allylic chlorides react in the presence of ZnCl2/SiO2.343

Naphthalene and other fused ring compounds are so reactive that they react with the catalyst, and therefore tend to give poor yields in Friedel–Crafts alkylation. Heterocyclic rings also tend to be poor substrates for the reaction. Although some furans and thiophenes have been alkylated, polymerization is quite common, and a true alkylation of a pyridine or a quinoline has never been described.344 N-Methylpyrrole reacted with the C=C unit of methacrolein in the presence of a chiral catalyst (a chiral Friedel–Crafts catalyst) to give the 2-alkylated pyrrole, with good enantioselectivity.345 Alkylation at C-5 of 2-trimethylsilylfuran was accomplished using the carbocation [(p-MeOC6H4)2CH+ OTf] and Proton Sponge (see Sec. 8.F, category 6).346 The reaction of isoquinoline with ClCO2Ph and AgOTf, followed by reaction with an allylic silane, led to a 2-allylic dihydroisoquinoline.347

Regardless of which reagent is used, a catalyst is nearly always required.348 Lewis acid catalysts (e.g., aluminum chloride and boron trifluoride) are the most common, but many other Lewis acids have been used,349 and also proton acids (e.g., HF and H2SO4).350 Calcium has been used to catalyze Friedel–Crafts alkylation reactions, at room temperature.351 For active halides, a trace of a less active catalyst (e.g., ZnCl2) may be enough. For an unreactive halide (e.g., chloromethane), a more powerful catalyst (e.g., AlCl3) is needed, and in larger amounts. In some cases, especially with alkenes, a Lewis acid catalyst causes reaction only if a small amount of proton-donating cocatalyst is present. Catalysts have been arranged in the following order of overall reactivity: AlBr3 > AlCl3 > GaCl3 > FeCl3 > SbCl5352 > ZrCl4, SnCl4 > BCl3, BF3, SbCl3353; but the reactivity order in each case depends on the substrate, reagent, and conditions. Other Lewis acids have been used, of course, including SeCl2,354 InCl3,355 and enantiopure cycloalkyldialkylsilyl triflimide catalysts.356

Friedel–Crafts alkylation is unusual among the principal aromatic substitutions in that the entering group is activating (the product is more reactive than the starting aromatic substrate), and di- and polyalkylation are frequently observed. However, the activating effect of simple alkyl groups (e.g., ethyl and isopropyl) is only ~1.5–3 times as fast as benzene for Friedel–Crafts alkylations,357 so it is often possible to obtain high yields of monoalkyl product.358Actually, the fact that di- and polyalkyl derivatives are frequently obtained is not due to the small difference in reactivity, but to the circumstance that alkylbenzenes are preferentially soluble in the catalyst layer, where the reaction actually takes place.359 This factor can be removed by the use of a suitable solvent, by high temperatures, or by high-speed stirring.

It is important to note that the OH, OR, NH2, and so on, groups do not facilitate the reaction, since most Lewis acid catalysts coordinate with these basic groups. Although phenols give the usual Friedel–Crafts reactions, orienting ortho and para, the reaction is very poor for aniline derivatives. However, amines can undergo the reaction if alkenes are used as reagents and aluminum anilides as catalysts.360 In this method, the catalyst is prepared by treating the amine to be alkylated with one-third equiv of AlCl3. A similar reaction can be performed with phenols, though here the catalyst is Al(OAr)3.361 Primary aromatic amines (and phenols) can be methylated regioselectively in the ortho position by an indirect method (see Reaction 11-23). For an indirect method for regioselective ortho methylation of phenols, see Reaction 15-65.

In most cases, meta-directing groups make the ring too inactive for alkylation. Nitrobenzene cannot be alkylated, and there are only a few reports of successful Friedel–Crafts alkylations when electron-withdrawing groups are present.362 This is not because the attacking species is not powerful enough; indeed we have seen (Sec. 11.D) that alkyl cations are among the most powerful of electrophiles. The difficulty is caused by the fact that, with inactive substrates, degradation and polymerization of the electrophile occurs before it can attack the ring. However, if an activating and a deactivating group are both present on a ring, Friedel–Crafts alkylation can be accomplished.363Aromatic nitro compounds can be methylated by a nucleophilic mechanism (Reaction 13-17).

The intermediate for Friedel–Crafts alkylation is a carbocation, and rearrangement to a more stable cation can be quite facile. Therefore, rearrangement of the alkyl substrate occurs frequently and is an important synthetic limitation of Friedel–Crafts alkylation. For example, benzene treated with n-propyl bromide gives mostly isopropylbenzene (cumene) and much less n-propylbenzene. Rearrangement is usually in the order primary → secondary → tertiary and usually occurs by migration of the smaller group on the adjacent carbon. Therefore, in the absence of special electronic or resonance influences on the migrating group (e.g., phenyl), H migrates before methyl, which migrates before ethyl, and so on (see discussion of rearrangement mechanisms in Chap 18). It is therefore not usually possible to put a primary alkyl group (other than methyl364 and ethyl) onto an aromatic ring by Friedel–Crafts alkylation. Because of these rearrangements, n-alkylbenzenes are often prepared by acylation (Reaction 11-17), followed by reduction (Reaction 19-61).

An important use of the Friedel–Crafts alkylation reaction is to effect ring closure,365 via an intramolecular process.366 The most common method is to heat an aromatic compound with aluminum chloride having a halogen, hydroxy, or alkene group in the proper position, as, for example, in the preparation of tetralin (40).

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Another way of effecting ring closure through Friedel–Crafts alkylation is to use a reagent containing two groups (e.g., 41). These reactions are most successful for the preparation of six-membered rings,367 though five- and seven-membered rings have also been closed in this manner. For other Friedel–Crafts ring-closure reactions, see Reactions 11-15, 11-13, and 11-17. An interesting variation in this reaction showed that N-acyl aniline derivatives, upon treatment with Et2P(=O)H in water and a water soluble initiator (V-501) led to an intramolecular alkylation reaction to give an amide.368

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As mentioned above, the electrophile in Friedel–Crafts alkylation is a carbocation, at least in most cases.369 This is in accord with the knowledge that carbocations rearrange in the direction primary → secondary → tertiary (see Chap 18). In each case, the cation is formed from the attacking reagent and the catalyst. For the three most important types of reagent these reactions are

From alkyl halides

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From alcohols370 and Lewis acids

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From alcohols and protonic acids

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From alkenes (a supply of protons is usually required)


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There is direct evidence, from IR and NMR spectra, that the tert-butyl cation is quantitatively formed when tert-butyl chloride reacts with AlCl3 in anhydrous liquid HCl.371 In the case of alkenes, Markovnikov's rule (Sec. 15.B.ii) is followed. Carbocation formation is particularly easy from some reagents, because of the stability of the cations. Triphenylmethyl chloride372 and 1-chloroadamantane373 alkylate activated aromatic rings (e.g., phenols and amines) with no catalyst or solvent. Ions as stable as this are less reactive than other carbocations and often attack only active substrates. The tropylium ion, for example, alkylates anisole, but not benzene.374 Note in Section 10.F that relatively stable vinylic cations can be generated from certain vinylic compounds. These have been used to introduce vinylic groups into aryl substrates.375 Lewis acids (e.g., BF3376 or AlEt3377 can also be used for alkylation of aromatic rings with alkene units.

There is considerable evidence that many Friedel–Crafts alkylations, especially with primary reagents, do not go through a completely free carbocation. The ion may exist as a tight ion pair with, say, AlCl4 as the counterion or as a complex. Among the evidence is that methylation of toluene by methyl bromide and methyl iodide gave different ortho/para/meta ratios,378 although the same ratios are expected if the same species are attacked in each case. Other evidence is that, in some cases, the reaction kinetics are third order; first order each in aromatic substrate, attacking reagent, and catalyst.379 In these instances, a mechanism in which the carbocation is slowly formed and then rapidly attacked by the aromatic ring is ruled out since, in such a mechanism, the substrate would not appear in the rate expression. Since it is known that free carbocations, once formed, are rapidly attacked by the ring (acting as a nucleophile), there are no free carbocations here. Another possibility (with alkyl halides) is that some alkylations take place by an SN2 mechanism (with respect to the halide), in which case no carbocations would be involved at all. However, a completely SN2 mechanism requires inversion of configuration. Most investigations of Friedel–Crafts stereochemistry, even where an SN2 mechanism might most be expected, have resulted in total racemization, or at best a few percent inversion. A few exceptions have been found,380 most notably where the reagent was optically active propylene oxide, in which case 100% inversion was reported.381

Rearrangement is possible even with a non-carbocation mechanism. The rearrangement could occur before the attack on the ring takes place. It has been shown that treatment of CH314CH2Br with AlBr3 in the absence of any aromatic compound gave a mixture of the starting material and 14CH3CH2Br.382 Similar results were obtained with PhCH214CH2Br, in which case the rearrangement was so fast that the rate could be measured only below −7°.383Rearrangement could also occur after formation of the product, since alkylation is reversible (see Reaction 11-33).384

See Reaction 11-17 for Friedel–Crafts acylation. See Reaction 14-17 and 14-19 for free radical alkylation.

OS I, 95, 548; II, 151, 229, 232, 236, 248; III, 343, 347, 504, 842; IV, 47, 520, 620, 665, 702, 898, 960; V, 130, 654; VI, 109, 744.

11-12 Hydroxyalkylation or Hydroxyalkyl-de-hydrogenation

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When an aldehyde, ketone, or other carbonyl-containing substrate is treated with a protonic or Lewis acid, an oxygen-stabilized cation is generated. In the presence of an aromatic ring, Friedel–Crafts type alkylation occurs. The condensation of aromatic rings with aldehydes or ketones is called hydroxyalkylation.385 The reaction can be used to prepare alcohols,386 though more often the alcohol initially produced reacts with another molecule of aromatic compound (Reaction 11-11) to give diarylation. For this the reaction is quite useful, an example being the preparation of 1,1,1-trichloro-2,2′-bis(p-chlorophenyl)ethane DDT, 44:

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The diarylation reaction is especially common with phenols (the diaryl product here is called a bisphenol). The reaction is normally carried out in alkaline solution on the phenolate ion.387 Another variation involved Friedel–Crafts coupling of an aldehyde to an activated aromatic compound (an aniline derivative) to give diaryl carbinols that exhibited atropisomerism (see Sec. 4.C, category 5).388 When the reaction was done with a chiral aluminum complex, modest enantioselectivity was observed.

The hydroxymethylation of phenols with formaldehyde is called the Lederer–Manasse reaction. This reaction must be carefully controlled,389 since it is possible for the para and both ortho positions to be substituted and for each of these to be rearylated, so that a polymeric structure (45) is produced. However, such polymers, which are of the Bakelite type (phenol–formaldehyde resins, 45), are of considerable commercial importance.

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The attacking species is the carbocation (R2(OH)C+) formed from the aldehyde or ketone and the acid catalyst, except when the reaction is carried out in basic solution.

When an aromatic ring is treated with diethyl oxomalonate [(EtOOC)2C=O)], the product is an arylmalonic acid derivative [ArC(OH)(COOEt)2], which can be converted to an arylmalonic acid [ArCH(COOEt)2].390 This is therefore a way of applying the malonic ester synthesis (Reaction 10-67) to an aryl group (see also, Reaction 13-14). Of course, the opposite mechanism applies here: The aryl species is the nucleophile.

Two methods, both involving boron-containing reagents, have been devised for the regioselective ortho hydroxymethylation of phenols or aromatic amines.391 Conjugated aldehydes undergo Friedel–Crafts alkylation with aryltrifluoroborate salts, in the presence of a catalytic amount of an imidazolidinone.392

OS III, 326; V, 422; VI, 471, 856; VIII, 75, 77, 80. Also see, OS I, 214.

11-13 Cyclodehydration of Carbonyl-Containing Compounds

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As described in Reaction 11-12, the reaction of carbonyl-containing functional groups with protonic or Lewis acids lead to oxygen-stabilized carbocations. When generated in the presence of an aromatic ring, Friedel–Crafts alkylation occurs to give an alcohol or an alkene, if dehydration occurs under the reaction conditions. When an aromatic compound contains an aldehyde or ketone function in a position suitable for closing a suitably sized ring, treatment with acid results in cyclodehydration. The reaction is a special case of 11-12, but in this case dehydration almost always takes place to give a double bond conjugated with the aromatic ring.393 The method is very general and is widely used to close both carbocyclic and heterocyclic rings.394 Polyphosphoric acid is a common reagent, but other acids have also been used. In a variation known as the Bradsher reaction,395 diarylmethanes, which contain a carbonyl group in the ortho position, can be cyclized to anthracene derivatives (46). In this case, 1,4-dehydration takes place, at least formally.

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An intramolecular cyclization of an aryl ether to the carbonyl of a pendant aryl ketone, on clay with microwave irradiation, led to a benzofuran via Friedel–Crafts cyclization and elimination of water.396

A variation of this reaction involves acylation of a β-keto ester, followed by Friedel–Crafts cyclization of the ketone moiety. The product is a coumarin (43), in what is known as the Pechmann condensation.397 Isolation of esters (e.g., 42) is not always necessary, and protonic acids can be used rather than Lewis acids. The Pechmann condensation is facilitated by the presence of hydroxyl (OH), dimethylamino (NMe2), and alkyl groups meta to the hydroxyl of the phenol.398 The reaction has been accomplished using microwave irradiation on graphite/Montmorillonite K-10.399 Pechmann condensation in an ionic liquid using ethyl acetate has also been reported.400

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The carbonyl unit involved in the cyclization process is not restricted to aldehydes and ketones. The carbonyl of acid derivatives (e.g., amides) also can be utilized. One of the more important cyclodehydration reactions is applied to the formation of heterocyclic systems via cyclization of β-aryl amides, in what is called the Bischler–Napieralski reaction.401 In this reaction, amides of the type 47 are cyclized with phosphorous oxychloride or other reagents, including polyphosphoric acid, sulfuric acid, or phosphorus pentoxide, to give a dihydroisoquinoline (48). The Bischler–Napieralski reaction has been done in ionic liquids using POCl3.402 The reaction has also been done using solid-phase (see Sec. 9.D.iv) techniques.403

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If the starting compound contains a hydroxyl group in the α position, an additional dehydration takes place and the product is an isoquinoline.404 Higher yields can be obtained if the amide is treated with PCl3 to give an imino chloride (ArCH2CH2N=CR–Cl), which is isolated and then cyclized by heating.405 In this latter case, a nitrilium ion (ArCH2CH2+NimgCR) is an intermediate.

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Another useful variation is the Pictet–Spengler isoquinoline synthesis, also known as the Pictet–Spengler reaction.406 The reactive intermediate is an iminium ion (49) rather than an oxygen-stabilized cation, but attack at the electrophilic carbon of the C=N unit (see Reaction 16-31) leads to an isoquinoline derivative. When a β-arylamine reacts with an aldehyde, the product is an iminium salt, which cyclizes with an aromatic ring to complete the reaction and generate a tetrahydroisoquinoline.407 Metal-catalyzed reactions are known, including the use of AuCl3/AgOTf.408 A variety of aldehydes can be used, and substitution on the aromatic ring leads to many derivatives. When the reaction is done in the presence of a chiral catalyst, good enantioselectivity was observed.409

Another variation in this basic procedure leads to tetrahydroisoquinolines. When phenethylamine was treated with N-hydroxymethylbenzotriazole and then AlCl3 in chloroform, cyclization occurred, and reduction with sodium borohydride gave the 1,2,3,4-tetrahydro-N-methylisoquinoline.410

OS I, 360, 478; II, 62, 194; III, 281, 300, 329, 568, 580, 581; IV, 590; V, 550; VI, 1. Also see, OS I, 54.

11-14 Haloalkylation or Haloalkyl-de-hydrogenation

equation

When certain aromatic compounds are treated with formaldehyde and HCl, the CH2Cl group is introduced into the ring in a reaction called chloromethylation. The reaction has also been carried out with other aldehydes and with HBr and HI. The more general term haloalkylation covers these cases.411 The reaction is successful for benzene, and alkyl-, alkoxy-, and halobenzenes. It is greatly hindered by meta-directing groups, which reduce yields or completely prevent the reactions. Amines and phenols are too reactive and usually give polymers unless deactivating groups are also present, but phenolic ethers and esters successfully undergo the reaction. Compounds of lesser reactivity can often be chloromethylated with chloromethyl methyl ether (ClCH2OMe) or methoxyacetyl chloride (MeOCH2COCl).412 Zinc chloride is the most common catalyst, but other Friedel–Crafts catalysts are also employed. As with Reaction 11-12 and for the same reason, an important side product is the diaryl compound Ar2CH2 (from formaldehyde).

Apparently, the initial step involves reaction of the aromatic compound with the aldehyde to form the hydroxyalkyl compound, exactly as in Reaction 11-12, and then the HCl converts this to the chloroalkyl compound.413 The acceleration of the reaction by ZnCl2 has been attributed414 to the raising of the acidity of the medium, causing an increase in the concentration of HOCH2+ ions.

OS III, 195, 197, 468, 557; IV, 980.

11-15 Friedel–Crafts Arylation: The Scholl Reaction

De-hydrogen-coupling

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The coupling of two aromatic molecules by treatment with a Lewis and a proton acid is called the Scholl reaction.415 Yields are low and the synthesis is seldom useful. High temperatures and strong-acid catalysts are required, and the reaction fails for substrates that are destroyed by these conditions. The reaction becomes important with large fused-ring systems, so ordinary Friedel–Crafts reactions (11-11) on these systems are rare. For example, naphthalene gives binaphthyl under Friedel-Crafts conditions. Yields can be increased by the addition of a salt (e.g., CuCl2 or FeCl3), which acts as an oxidant.416 Rhodium417 and Ru catalysts418 have also been used.

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Intramolecular Scholl reactions (e.g., formation of 50 from triphenylmethane) are much more successful than the intermolecular reaction. The mechanism is not clear, but it may involve attack by a proton to give an arenium ion of type 12 (Sec. 11.A.i, category 2), which would be the electrophile that attacks the other ring.419 Sometimes arylations have been accomplished by treating aromatic substrates with particularly active aryl halides, especially fluorides. For free radical arylations, see Reactions 12-15, 13-26, 13-27, 13-10, 14-17, and 14-18.

OS IV, 482; X, 359. Also see, OS V, 102, 952.

11-16 Arylation of Aromatic Compounds by Metalated Aryls

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Many metalated aryl compounds are known to couple with aromatic compounds. Aniline derivatives react with ArPb(OAc)3, for example, to give the 2-arylaniline.420 Phenolic anions also react to form biaryls, with modest enantioselectivity in the presence of brucine.421 A Mn(III) mediated synthesis of biaryls used microwave irradiation for the coupling reaction.422 The homocoupling reaction of aryl Grignard reagents in the presence of TEMPO is known.423

Phenylboronates [ArB(OR)2] react with electron-deficient aromatic compounds (e.g., acetophenone) to give the biaryl.424 Arylboronates also react with π-allyl Pd complexes to form the alkylated aromatic compound.425Arylboronic acids are also coupled in the presence of metal catalysts.426 Organoborates can be coupled using an oxovanadium catalyst,427 and potassium phenyltrifluoroborates can be coupled to aromatics using a combination of Pd and Cu catalysts.428

A Cu catalyzed coupling reaction with hypervalent arylated iodine derivatives is known.429

See Reactions 13-9, 13-11, and 13-12.

11-17 Friedel–Crafts Acylation

Acylation or Acyl-de-hydrogenation

equation

The most important method for the preparation of aryl ketones is known as Friedel–Crafts acylation.430 The reaction is of wide scope. Reagents other than acyl halides can be used,431 including carboxylic acids,432 anhydrides, and ketenes. Oxalyl chloride has been used to give diaryl 1,2-diketones.433 Carboxylic esters usually give alkylation as the predominant product (see Reaction 11-11).434 N-Carbamoyl β-lactams reacted with naphthalene in the presence of trifluoromethanesulfonic acid to give the keto-amide.435

The alkyl group (R in RCOCl) may be aryl as well as alkyl.436 The major disadvantages of Friedel–Crafts alkylation, polyalkylation, and rearrangement of the intermediate carbocation, are not a problem in Friedel–Crafts acylation. Rearrangement of the alkyl group (R in RCOCl) is never found because the intermediate is an acylium ion (an acyl cation, RCimgO+, see below), which is stabilized by resonance. Because the RCO group is deactivating, the reaction stops cleanly after one group is introduced. All four acyl halides can be used, though chlorides are most commonly employed. The order of activity is usually, but not always, I > Br > Cl > F.437 Catalysts are Lewis acids,438 similar to those in Reaction 11-11, but in acylation a little >1 equiv of catalyst is required per mole of reagent, because the first mole coordinates with the oxygen of the reagent [as in R(Cl)C=O+−AlCl3].439 A reusable catalyst [Ln(OTf)3–LiClO4] has been developed.440 Ferric chloride in an ionic liquid has also been used.441 The HY-Zeolite has also been used to facilitate the reaction with acetic anhydride.442 Catalyts include a Pd catalyst, which was used with acetic anhydride,443 TiCl4,444 SmI2,445 In metal,446 acetyl chloride, and zinc powder with microwave irradiation.447 Friedel–Crafts acylation using a carboxylic acid with a catalyst called Envirocat-EPIC (an acid-treated clay-based material) was reported.448 Friedel–Crafts acylation was reported in an ionic liquid.449 An interesting acylation reaction was reported that coupled trichlorophenylmethane to benzene, giving benzophenone in the presence of the ionic liquid AlCl3–BPC.450 (butylpyridiniumchloroaluminate = BPC). Acylation has been accomplished in carbon disulfide.451 An interesting variation couples a conjugated acid chloride with benzene, in the presence of AlCl3 and microwave irradiation, to give an indanone.452

Protonic acids can be used as catalysts when the reagent is a carboxylic acid.453 Triflic anhydride promotes dehydrative acylation of carboxylic acids,454 as does P2O5/SiO2.455 An aryl carboxylic acid can be converted to the acid chloride in situ with cyanuric chloride and AlCl3, leading to Friedel–Crafts acylation.456 A solvent-free method is also available using tosic acid/graphite.457

The mixed carboxylic sulfonic anhydrides (RCOOSO2CF3) are extremely reactive acylating agents and can smoothly acylate benzene without a catalyst.458 With active substrates (e.g., aryl ethers, fused-ring systems, thiophenes), Friedel–Crafts acylation can be carried out with very small amounts of catalyst, often just a trace, or even sometimes with no catalyst at all.

The reaction is quite successful for many types of substrate, including fused ring systems, which give poor results in Reaction 11-11. Compounds containing ortho–para directing groups, including alkyl, hydroxy, alkoxy, halogen, and acetamido groups, are easily acylated and give mainly or exclusively the para products, because of the relatively large size of the acyl group. However, aromatic amines give poor results. With amines and phenols there may be competition from N- or O-acylation; however, O-acylated phenols can be converted to C-acylated phenols by the Fries rearrangement (Reaction 11-27). Friedel–Crafts acylation is usually prevented by meta-directing (deactivating) groups. Indeed, nitrobenzene is often used as a solvent for the reaction. Many heterocyclic systems, including furans, thiophenes, pyrans, and pyrroles459 but not pyridines or quinolines, can be acylated in good yield. Initial reaction of indole with Et2AlCl460 or SnCl4,461 followed by acetyl chloride leads to 3-acetylindole. By comparison, the reaction of N-acetylindole with acetic anhydride and AlCl3 gave N,6-diacetylindole.462 Acetylation at C-3 was also accomplished with acetyl chloride in the ionic liquid emimcl–AlCl3.463 Gore, in Ref. 430 (pp. 36–100; with tables, pp. 105–321), presents an extensive summary of the substrates to which this reaction has been applied.

Friedel–Crafts acylation can be carried out with cyclic anhydrides,464 in which case the product contains a carboxyl group in the side chain (53). When succinic anhydride is used, the product is ArCOCH2CH2CO2H. This can be reduced (Reaction 19-61) to ArCH2CH2CH2CO2H, and can then be cyclized by an internal Friedel–Crafts acylation to give 54. The total process is called the Haworth reaction:465

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When a mixed-anhydride (RCOOCOR′) is the reagent, two products are possible: ArCOR and ArCOR′. Which product predominates depends on two factors. If R contains electron-withdrawing groups, then ArCOR′ is chiefly formed, but if this factor is approximately constant in R and R′, the ketone with the larger R group predominantly forms.466 This means that formylations of the ring do not occur with mixed anhydrides of formic acid (HCOOCOR).

An important use of the Friedel–Crafts acylation is to effect ring closure.467 This closure can be accomplished if an acyl halide, anhydride, or carboxylic acid468 group is in the proper position. An example is the conversion of 51to 52. The reaction is used mostly to close six-membered rings, but has also been done for five- and seven-membered rings, which close less readily. Even larger rings can be closed by high-dilution techniques.469 Tricyclic and larger systems are often made by using substrates containing one of the acyl groups on a ring. Many fused-ring systems are made in this manner. If the bridging group is CO, the product is a quinone.470 One of the most common catalysts for intramolecular Friedel–Crafts acylation is polyphosphoric acid471 (because of its high potency), but AlCl3, H2SO4, and other Lewis and proton acids are also used, though acylations with acyl halides are not generally catalyzed by proton acids.

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Thioesters are coupled to arylboronic acids in the presence of a Pd catalyst, in a Friedel–Crafts acylation-type coupling.472 Acyl halides are coupled to arylboronic acids under microwave irradiation.473

The mechanism of Friedel–Crafts acylation is not completely understood,474 but at least two mechanisms probably operate, depending on conditions.475 In most cases, the attacking species is the acyl cation, either free or as an ion pair, formed by476

equation

If R is tertiary, RCO+ may lose CO to give R+, so that the alkyl arene ArR is often a side product or even the main product. This kind of cleavage is much more likely with relatively unreactive substrates, where the acylium ion has time to break down. For example, pivaloyl chloride (Me3CCOCl) gives the normal acyl product with anisole, but yields the alkyl product (Me3CPh) with benzene. In the other mechanism, an acyl cation is not involved, but the 1:1 complex (55) attacks directly.477 Free-ion attack is more likely for sterically hindered R.478 The ion CH3CO+ has been detected (by IR spectroscopy) in the liquid complex between acetyl chloride and aluminum chloride, and in polar solvents (e.g., nitrobenzene); but in nonpolar solvents (e.g., as chloroform) only the complex and not the free ion is present.479 In any event, 1 molar equivalent of catalyst certainly remains complexed to the product at the end of the reaction. When the reaction is performed with RCO+ SbF6, no catalyst is required and the free ion480 (or ion pair) is undoubtedly the attacking entity.481 The use of LiClO4 on the metal triflate catalyzed Friedel–Crafts acylation of methoxynaphthalene derivatives has been examined. The presence of the lithium salt leads to acylation in the ring containing the methoxy unit, whereas reaction occurs in the other ring in the absence of lithium salts.482 Note that lithium perchlorate forms a complex with acetic anhydride, which can be used for the Friedel–Crafts acetylation of activated aromatic compounds.483

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A related reaction couples an acid chloride with an aromatic compound in the presence of a Rh catalyst, but the coupling reaction involves a decarbonylation to give a biaryl.484

OS I, 109, 353, 476, 517; II, 3, 8, 15, 81, 156, 169, 304, 520, 569; III, 6, 14, 23, 53, 109, 183, 248, 272, 593, 637, 761, 798; IV, 8, 34, 88, 898, 900; V, 111; VI, 34, 618, 625 X, 125.

Reaction 11-18 is a direct formylation of the ring.485 Reaction 11-17 has not been used for formylation, since neither formic anhydride nor formyl chloride is stable at ordinary temperatures. Formyl chloride has been shown to be stable in chloroform solution for 1 h at −6°,486 but it is not useful for formylating aromatic rings under these conditions. Formic anhydride has been prepared in solution, but has not been isolated.487 Mixed anhydrides of formic and other acids are known488 and can be used to formylate amines (see Reaction 16-73) and alcohols, but no formylation takes place when they are applied to aromatic rings. See Reaction 13-17 for a nucleophilic method for the formylation of aromatic rings.

A related reaction involves a biaryl, where one ring is a phenol. Treatment with BCl3 and an AlCl3 catalyst, followed by reaction with CO and Pd(OAc)2, led to carbonylation and acylation to give the corresponding lactone.489Carbonylation of aromatic compounds can lead to aryl ketones. Heating an aromatic compound with Ru(CO)12, ethylene and 20 atm. of CO gave the corresponding aryl ethyl ketone.490

11-18 Formylation

Formylation or Formyl-de-hydrogenation

equation

The reaction with disubstituted formamides (R2N–CHO) and phosphorus oxychloride, called the Vilsmeier or the Vilsmeier–Haack reaction,491 is the most common method for the formylation of aromatic rings.492 However, it is applicable only to active substrates (e.g., amines and phenols). An intramolecular version is also known.493 Aromatic hydrocarbons and heterocycles can also be formylated, but only if they are much more active than benzene (e.g., azulenes and ferrocenes). Although N-phenyl-N-methylformamide is a common reagent, other arylalkyl amides and dialkyl amides are also used.494 Phosgene (COCl2) has been used in place of POCl3. The reaction has also been carried out with other amides to give ketones (actually an example of Reaction 11-17), but not often. The attacking species495 is 56,496 and the mechanism is probably that shown to give 57, which is unstable and easily hydrolyzes to the product. Either formation of 56 or the reaction of 56 with the substrate can be rate determining, depending on the reactivity of the substrate.497

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When (CF3SO2)2O was used instead of POCl3, the reaction was extended to some less-active compounds, including naphthalene and phenanthrene.498

In a related reaction, paraformaldehyde can be used, with MgCl2-NEt3, to convert phenol to phenol 2-carbaldehyde.499 Another variation treated acetanilide with POCl3–DMF and generated 2-chloroquinoline-3-carboxaldehyde.500Used in conjunction with conjugated hydroxylamines, a tandem Vilsmeier–Beckman reaction (see Reaction 18-17 for the Beckman rearrangement) leads to pyridines (2-chloro-3-carboxaldehyde).501 A chain-extension variation has been reported in which an aryl alkyl ketone is treated with POCl3/DMF on silica with microwave irradiation to give a conjugated aldehyde [ArC(=O)R → ArC(Cl)=CHCHO].502

OS I, 217; III, 98, IV, 331, 539, 831, 915.

equation

Formylation with Zn(CN)2 and HCl is called the Gatterman reaction503 and can be applied to alkylbenzenes, phenols and their ethers, as well as many heterocyclic compounds. However, it cannot be applied to aromatic amines. In the original version of this reaction, the substrate was treated with HCN, HCl, and ZnCl2, but the use of Zn(CN)2 and HCl (HCN and ZnCl2 are generated in situ) makes the reaction more convenient to carry out and yields are not diminished. The mechanism of the Gatterman reaction has not been investigated very much, but it is known that an initially formed, but not isolated nitrogen-containing product, is hydrolyzed to aldehyde. This product is presumed to be ArCH=NH2+Cl, as shown. When benzene was treated with NaCN under superacid conditions (F3CSO2OH–SbF5, see Sec. 5.A.ii), a good yield of product was obtained, leading to the conclusion that the electrophile in this case was +C(H)=N+H2.504 The Gatterman reaction may be regarded as a special case of Reaction 11-24.

Another method, formylation with CO and HCl in the presence of AlCl3 and CuCl505 (the Gatterman–Koch reaction), is limited to benzene and alkylbenzenes.506 Aryl halides are converted to aryl aldehydes with CO/H2 in the presence of a Pd catalyst.507

OS II, 583; III, 549.

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In the Reimer–Tiemann reaction, aromatic rings are formylated by reaction with chloroform and hydroxide ion.508 The method is useful only for phenols and certain heterocyclic compounds (e.g., pyrroles and indoles). Unlike the previous formylation methods (Reaction 11-18), this one is conducted in basic solution. Yields are generally low, seldom rising >50%.509 The incoming group is directed ortho, unless both ortho positions are filled, in which case the attack is para.510 Certain substrates have been shown to give abnormal products instead of or in addition to the normal ones. For example, 58 and 60 gave, respectively, 59 and 61, as well as the normal aldehyde products. From the nature of the reagents and

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from the kind of abnormal products obtained, it is clear that the reactive entity in this reaction is dichlorocarbene (CCl2).511 This product is known to be produced by treatment of chloroform with bases (see Reaction 10-3); it is an electrophilic reagent and is known to give ring expansion of aromatic rings (see Reaction 15-64), accounting for products like 58. The mechanism of the normal reaction is thus something like512:

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The formation of 61 in the case of 60 can be explained by attack of some of the CCl2 ipso to the CH3 group. Since this position does not contain a hydrogen, normal proton loss cannot take place and the reaction ends when the CCl2moiety acquires a proton.

A method closely related to the Reimer–Tiemann reaction is the Duff reaction, in which hexamethylenetetramine [(CH2)6N4] is used instead of chloroform. This reaction can be applied only to phenols and amines; ortho substitution is generally observed and yields are low. A mechanism513 has been proposed that involves initial aminoalkylation (Reaction 11-22) to give ArCH2NH2, followed by dehydrogenation to ArCH=NH and hydrolysis of this to the aldehyde product. When (CH2)6N4 is used in conjunction with F3CCO2H, the reaction can be applied to simple alkylbenzenes; yields are much higher and a high degree of regioselectively para substitution is found.514 In this case too, an imine seems to be an intermediate.

OS III, 463; IV, 866

equation

Besides Reaction 11-18, several other formylation methods are known.515 In one of these, dichloromethyl methyl ether formylates aromatic rings with Friedel–Crafts catalysts.516 The ArCHClOMe compound is probably an intermediate. Orthoformates have also been used.517 In another method, aromatic rings are formylated with formyl fluoride (HCOF) and BF3.518 Unlike formyl chloride, formyl fluoride is stable enough for this purpose. This reaction was successful for benzene, alkylbenzenes, PhCl, PhBr, and naphthalene. Phenols can be regioselectively formylated in the ortho position in high yields by treatment with 2 molar equivalents of paraformaldehyde in aprotic solvents in the presence of SnCl4 and a tertiary amine.519 Phenols have also been formylated indirectly by conversion to the aryllithium reagent followed by treatment with N-formyl piperidine.520 See also, the indirect method mentioned at Reaction 11-23. Aryl halides are converted to the corresponding aldehyde in a related reaction.521

OS V, 49; VII, 162.

Reactions 11-19 and 11-20 are direct carboxylations522 of aromatic rings.523

11-19 Carboxylation with Carbonyl Halides

Carboxylation or Carboxy-de-hydrogenation

equation

Phosgene, in the presence of Friedel–Crafts catalysts, can carboxylate the ring. This process is analogous to Reaction 11-17, but the ArCOCl initially produced hydrolyzes to the carboxylic acid. However, in most cases the reaction does not take this course, but instead the ArCOCl is attacked by another ring to give a ketone ArCOAr. A number of other reagents have been used to get around this difficulty, including oxalyl chloride, urea hydrochloride, chloral (Cl3CCHO),524 carbamoyl chloride (H2NCOCl), and N,N-diethylcarbamoyl chloride.525 With carbamoyl chloride the reaction is called the Gatterman amide synthesis and the product is an amide. Among compounds carboxylated by one or another of these reagents are benzene, alkylbenzenes, and fused ring systems.526

Although mechanistically different, other methods are available to convert aromatic compounds to aromatic carboxylic acids. The Pd catalyzed reaction of aromatic compounds and formic acid leads to benzoic acid derivatives.527Diphenyliodonium tetrafluoroborate (Ph2I+ BF4) reacts with CO and In in DMF, with a Pd catalyst, to give benzophenone.528

OS V, 706; VII, 420.

11-20 Carboxylation with Carbon Dioxide: The Kolbe–Schmitt Reaction

Carboxylation or Carboxy-de-hydrogenation

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Sodium phenoxides can be carboxylated, mostly in the ortho position, by CO2 (the Kolbe–Schmitt reaction). The mechanism is not clearly understood, but apparently some kind of a complex is formed between the reactants,529making the carbon of the CO2 more positive and putting it in a good position to attack the ring. Potassium phenoxide, which is less likely to form such a complex, is chiefly attacked in the para position. There is evidence that, in the complex formed from potassium salts, the bonding is between the aromatic compound and the carbon atom of CO2.530 At least part of the potassium p-hydroxybenzoate that forms comes from a rearrangement of initially formed potassium salicylate (sodium salicylate does not rearrange).531 Carbon tetrachloride can be used instead of CO2 under Reimer–Tiemann (Reaction 11-18) conditions.

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Sodium or potassium phenoxide can be carboxylated regioselectively in the para position in high yield by treatment with sodium or potassium carbonate and carbon monoxide.532 The img labeling showed that it is the carbonate carbon that appears in the p-hydroxybenzoic acid product.533 The CO is converted to sodium or potassium formate. Carbon monoxide has also been used to carboxylate aromatic rings with Pd compounds as catalysts.534 In addition, a Pd catalyzed reaction has been used directly to prepare acyl fluorides ArH → ArCOF.535 Molybdovanadophosphates have been used for anisole in the presence of CO and O2.536 A Pd catalyzed carboxylation has been reported using Ag2CO3 and CO.537

An enzymatic carboxylation was reported, in supercritical CO2 (see Sec. 9.D.ii), in which exposure of pyrrole to Bacillus megaterium PYR2910 and KHCO3 gave the potassium salt of pyrrole 2-carboxylic acid.538

OS II, 557.

11-21 Amidation

N-Alkylcarbamoyl-de-hydrogenation

equation

N-Substituted amides can be prepared by direct attack of isocyanates on aromatic rings.539 The R group may be alkyl or aryl, but if the latter, dimers and trimers are also obtained. Isothiocyanates similarly give thioamides.540 The reaction has been carried out intramolecularly both with aralkyl isothiocyanates and acyl isothiocyanates.541 In the latter case, the product is easily hydrolyzable to a dicarboxylic acid; this is a way of putting a carboxyl group on a ring ortho to one already there (62 is prepared by treatment of the acyl halide with lead thiocyanate). The reaction gives better yields with substrates of the type ArCH2CONCS, where six-membered rings are formed. An intramolecular reaction of 2-amido biaryls leads to carbazoles in the presence of Pd and Cu catalysts.542

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There are interesting transition metal catalyzed reactions that lead to aryl amides. The use of POCl3 and DMF, with a Pd catalyst, converts aryl iodides to benzamides.543 Carbonylation is another method that generates amides. When an aryl iodide was treated with a secondary amine and Mo(CO)6, in the presence of 3 equiv of DBU, 10% Pd(OAc)2, with microwave irradiation at 100 °C, the corresponding benzamide was obtained.544 Aminocarbonylation is accomplished with microwave irradiation using hydroxylamine as an ammonia equivalent.545

OS V, 1051; VI, 465.

Reactions 11-1211-23 involve the introduction of a CH2Z group, where Z is halogen, hydroxyl, amino, or alkylthio. They are all Friedel–Crafts reactions of aldehydes and ketones and, with respect to the carbonyl compound, additions to the C=O double bond. They follow mechanisms discussed in Chapter 16.

11-22 Aminoalkylation and Amidoalkylation

Dialkylaminoalkylation or Dialkylamino-de-hydrogenation

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Phenols, secondary and tertiary aromatic amines,546 pyrroles, and indoles can be aminomethylated by treatment with formaldehyde and a secondary amine. Other aldehydes have sometimes been employed. Aminoalkylation is a special case of the Mannich reaction (16-19). When phenols and other activated aromatic compounds are treated with N-hydroxymethylchloroacetamide, amidomethylation takes place547 to give 63, which is often hydrolyzed in situto the aminoalkylated product. Other N-hydroxyalkyl and N-chlorinated compounds have also been used.379 Nitroethane in polyphosphoric acid can be used for the acetamidation of aromatic compounds.548

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Aryl halides are aminomethylated with potassium organotrifluoroborates.549

OS I, 381; IV, 626; V, 434; VI, 965; VII, 162.

11-23 Thioalkylation

Alkylthioalkylation or Alkylthioalkyl-de-hydrogenation

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A methylthiomethyl group can be inserted into the ortho position of phenols by heating with DMSO and 1,3-dicyclohexylcarbodiimide (DCC).550 Other reagents can be used instead of DCC, among them SOCl2,551 or acetic anhydride.552 Alternatively, the phenol can be treated with DMS and NCS, followed by triethylamine.553 The reaction can be applied to amines (to give o-NH2C6H4CH2SMe) by treatment with t-BuOCl, Me2S, and NaOMe in CH2Cl2.554 Aromatic hydrocarbons have been thioalkylated with ethyl α-(chloromethylthio)acetate (ClCH2SCH2CO2Et) to give ArCH2SCH2CO2Et,555 and with methyl methylsulfinylmethyl sulfide (MeSCH2SOMe) or methylthiomethyl p-tolyl sulfone (MeSCH2SO2C6H4Me) to give ArCH2SMe,556 in each case with a Lewis acid catalyst.

OS VI, 581, 601.

11-24 Acylation with Nitriles: The Hoesch Reaction

Acylation or Acyl-de-hydrogenation

equation

Friedel–Crafts acylation with nitriles and HCl is called the Hoesch or the Houben–Hoesch reaction.557 In most cases, a Lewis acid is necessary; zinc chloride is the most common. The reaction is generally useful only with phenols, phenolic ethers, and some reactive heterocyclic compounds (e.g., pyrrole), but it can be extended to aromatic amines by the use of BCl3.558 Acylation in the case of aniline derivatives is regioselectively ortho. Monohydric phenols, however, generally do not give ketones559 but are attacked at the oxygen to produce imino esters. Many nitriles have been used. Even aryl nitriles give good yields if they are first treated with HCl and ZnCl2, and then the substrate added at 0 °C.560 In fact, this procedure increases yields with any nitrile. If thiocyanates (RSCN) are used, thiol esters (ArCOSR) can be obtained. The Gatterman reaction (Reaction 11-18) is a special case of the Hoesch synthesis.

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The reaction mechanism is complex and not completely settled.561 The first stage consists of an attack on the substrate by a species containing the nitrile and HCl (and the Lewis acid, if present) to give an imine salt (66). Among the possible reactive species are 64 and 65. In the second stage, the salts are hydrolyzed to the products, first the iminium salt, and then the ketone. Ketones can also be obtained by treating phenols or phenolic ethers with a nitrile in the presence of F3CSO2OH.562 The mechanism in this case is different.

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OS II, 522.

11-25 Cyanation or Cyano-de-hydrogenation

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Aromatic hydrocarbons (including benzene), phenols, and phenolic ethers can be cyanated with trichloroacetonitrile, BrCN, or mercury fulminate [Hg(ONC)2].563 In the case of Cl3CCN, the actual attacking entity is probably Cl3C–C+=NH, formed by addition of a proton to the cyano nitrogen. Secondary aromatic amines (ArNHR), as well as phenols, can be cyanated in the ortho position with Cl3CCN and BCl3.564

Note that aryl triflates are converted to the aryl nitrile by treatment with Zn(CN)2 and a Pd catalyst.565

OS III, 293.

F. Oxygen Electrophiles

Oxygen electrophiles are very uncommon, since oxygen does not bear a positive charge very well. However, there is one reaction that can be mentioned.

11-26 Hydroxylation or Hydroxy-de-hydrogenation

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There have been only a few reports of direct hydroxylation566 by an electrophilic process (see, however, 14-5).567 In general, poor results are obtained, partly because the introduction of an OH group activates the ring, which suppresses further reaction. Quinone formation is common. However, alkyl-substituted benzenes (e.g., mesitylene or durene) can be hydroxylated in good yield with trifluoroperacetic acid and boron trifluoride.568 In the case of mesitylene, the product (67) is not subject to further attack.

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In a related procedure, even benzene and substituted benzenes (e.g., PhMe, PhCl, and xylenes) can be converted to phenols in good yields with sodium perborate–F3CSO2OH.569 Aromatic amines, N-acyl amines, and phenols were hydroxylated with H2O2 in SbF5-HF.570 Pyridine and quinoline were converted to their 2-acetoxy derivatives in high yields with acetyl hypofluorite (AcOF) at −75 °C.571

Another hydroxylation reaction is the Elbs reaction.572 In this method, phenols can be oxidized to p-diphenols with K2S2O8 in alkaline solution.573 Primary, secondary, or tertiary aromatic amines give predominant or exclusive ortho substitution unless both ortho positions are blocked, in which case para substitution is found. The reaction with amines is called the Boyland–Sims oxidation. Yields are low with either phenols or amines, generally <50%. The mechanisms are not clear,574 but for the Boyland–Sims oxidation there is evidence that the S2O82− ion attacks at the ipso position, and then a migration follows.575

Electrolysis of benzene, in the presence of trifluoroacetic acid and triethylamine, leads to a 73% yield of phenol.576 Photolytic hydroxylation of benzene has been reported in the presence of mesoporous TiO2.577 Deactivated rings (e.g., nitrobenzene) are selectively ortho hydroxylated by molecular oxygen in the presence of H5PV2Mo10O40 polyoxometalate.578 Nitrous oxide has been used as an oxidant, in the presence of FeAlPO catalysts.579

G. Metal Electrophiles

Reactions in which a metal replaces the hydrogen of an aromatic ring are considered along with their aliphatic counterparts in Chapter 12 (Reactions 12-22 and 12-23).

11.F.ii. Hydrogen as the Leaving Group in Rearrangement Reactions

In these reactions, a group is detached from a side chain and then reattached the ring, but in other aspects they resemble the reactions already treated in this chapter.580 Since a group moves from one position to another in a molecule, these are rearrangements (also see Chap 18). In all these reactions, the question arises as to whether the group that cleaves from a given molecule is attacked by the same molecule or another one; that is, Is the reaction intramolecular or intermolecular? For intermolecular reactions, the mechanism is the same as ordinary aromatic substitution, but for intramolecular cases the migrating group could never be completely free, or else it would be able to react with another molecule. Since the migrating species in intramolecular rearrangements is thus likely to remain near the atom from which it cleaved, it has been suggested that intramolecular reactions are more likely to lead to ortho products than are the intermolecular type. This characteristic has been used, among others, to help decide whether a given rearrangement is inter- or intramolecular, though there is evidence that at least in some cases, an intermolecular mechanism can still result in a high degree of ortho migration.581

The Claisen (Reaction 18-33) and benzidine (Reaction 18-36) rearrangements, which superficially resemble those in this section, have different mechanisms and are treated in Chapter 18.

A. Groups Cleaving from Oxygen

11-27 The Fries Rearrangement

1/C-Hydro,5/O-acyl-interchange582

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Phenolic esters can be rearranged by heating with Friedel–Crafts catalysts in a synthetically useful reaction known as the Fries rearrangement.583 Both o- and p-acylphenols can be produced, and it is often possible to select conditions so that either one predominates. The ortho/para ratio is dependent on the temperature, solvent, and amount of catalyst used. Exceptions are known, but low temperatures generally favor the para product and high temperatures favor the ortho product. The R group may be aliphatic or aromatic. Any meta-directing substituent on the ring interferes with the reactions, as might be expected for a Friedel–Crafts process. In the case of aryl benzoates treated with F3CSO2OH, the Fries rearrangement was shown to be reversible and an equilibrium was established.584 Transition metal catalyzed Fries rearrangements have been reported.585

Questions remain about the exact mechanism.586 Opinions have been expressed that it is completely intermolecular,587 completely intramolecular,588 and partially inter- and intramolecular.589 One way to decide between inter- and intramolecular processes is to run the reaction of the phenolic ester in the presence of another aromatic compound, say, toluene. If some of the toluene is acylated, the reaction must be, at least in part, intermolecular. If the toluene is not acylated, the presumption is that the reaction is intramolecular, though this is not certain, for it may be that the toluene is not attacked because it is less active than the other. A number of such experiments (called crossover experiments) have been carried out; sometimes crossover products have been found and sometimes not. As in Reaction 11-17, an initial complex (68) is formed between the substrate and the catalyst, so that a catalyst/substrate molar ratio of at least 1:1 is required. In the presence of aluminum chloride, the Fries rearrangement can be induced with microwave irradiation.590 Simply heating phenyl acetate with microwave irradiation gives the Fries rearrangement.591 The Fries rearrangement has been carried out in ionic melts.592

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The Fries rearrangement can also be carried out with UV light, in the absence of a catalyst.593 This reaction, called the photo-Fries rearrangement,594 is predominantly an intramolecular free radical process. Both ortho and para migration are observed.595 Unlike the Lewis acid catalyzed Fries rearrangement, the photo-Fries reaction can be accomplished, though often in low yields, when meta-directing groups are on the ring. The available evidence strongly suggests the following mechanism involving formation of the excited state ester followed by dissociation to a radical pair596 for the photo-Fries rearrangement597 (illustrated for para attack).

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The phenol ArOH is always a side product, resulting from some ArO√ that leaks from the solvent cage and abstracts a hydrogen atom from a neighboring molecule. When the reaction was performed on phenyl acetate in the gas phase, where there are no solvent molecules to form a cage (but in the presence of isobutane as a source of abstractable hydrogen atoms), phenol was the chief product and virtually no o- or p-hydroxyacetophenone was found.598Other evidence599 for the mechanism is that CIDNP has been observed during the course of the reaction600 and that the ArO√ radical has been detected by flash photolysis601 and by nanosecond time-resolved Raman spectroscopy.602

A LDA-mediated anionic Fries rearrangement of aryl carbamates has been reported.603 The so-called anionic Snieckus–Fries rearrangement has also been discussed.604

Treatment of O-arylsulfonate esters with AlCl3–ZnCl2, on silica with microwave irradiation, leads to 2-sulfonyl phenols in a thia-Fries rearrangement.605 A similar reaction was reported with O-arylsulfonamides.606

OS II, 543; III, 280, 282.

B. Groups Cleaving from Nitrogen607

It has been shown that PhNH2D rearranges to o- and p-deuterioaniline.608 The migration of OH, formally similar to Reactions 11-2811-32, is a nucleophilic substitution and is treated in Chapter 13 (13-32).

11-28 Migration of the Nitro Group

1/ C-Hydro,3/N-nitro-interchange

img

N-Nitro aromatic amines rearrange on treatment with acids to o- and p-nitroamines with the ortho compounds predominating.609 Aside from this indication of an intramolecular process, there is also the fact that virtually no meta isomer is produced in this reaction,610 although direct nitration of an aromatic amine generally gives a fair amount of meta product. Thus a mechanism in which NO2+ is dissociated from the ring and then is attacked by another molecule must be ruled out. Further results indicating an intramolecular process include the observation that rearrangement of several substrates in the presence of K15NO3 gave products containing no img,611 and that rearrangement of a mixture of PhNH15NO2 and unlabeled p-MeC6H4NHNO2 gave 2-nitro-4-methylaniline containing no img.612 On the other hand, rearrangement of

img

69 in the presence of unlabeled PhNMeNO2 gave labeled 70, which did not arise by displacement of F.613 The R group may be hydrogen or alkyl. Two principal mechanisms have been suggested, one involving cyclic attack by the oxygen of the nitro group at the ortho position before the group cleaves,614 and the other involving a cleavage into a radical and a radical ion held together in a solvent cage.615 Among the evidence

img

for the latter view616 are the effects of substituents on the rate of the reaction,617 15N and 14C kinetic isotope effects that show nonconcertedness,618 and the fact that both N-methylaniline and nitrous acid are produced in sizable and comparable amounts in addition to the normal products o- and p-nitro-N-methylaniline.619 These side products are formed when the radicals escape from the solvent cage.

11-29 Migration of the Nitroso Group: The Fischer–Hepp Rearrangement

1/ C-Hydro-5/N-nitroso-interchange

img

The migration of a nitroso group, formally similar to Reaction 11-28, is important because p-nitroso secondary aromatic amines cannot generally be prepared by direct C-nitrosation of secondary aromatic amines (see Reaction 12-50). The reaction, known as the Fischer–Hepp rearrangement,620 is brought about by treatment of N-nitroso secondary aromatic amines with HCl. Other acids give poor or no results. In benzene systems, the para product is usually formed exclusively.621 The mechanism of the rearrangement is not completely understood. The fact that the reaction takes place in a large excess of urea622 shows that it is intramolecular623 since, if NO+, NOCl, or some similar species were free in the solution, it would be captured by the urea, preventing the rearrangement.

11-30 Migration of an Arylazo Group

1/C-Hydro-5/ N-arylazo-interchange

img

Rearrangement of aryl triazenes can be used to prepare azo derivatives of primary and secondary aromatic amines.624 These are first diazotized at the amino group (see Reaction 11-4) to give triazenes, which are then rearranged by treatment with acid. The rearrangement always gives the para isomer, unless that position is occupied.

11-31 Migration of Halogen: The Orton Rearrangement

1/C-Hydro-5/N-halo-interchange

img

Migration of a halogen from a nitrogen side chain to the ring by treatment with HCl is called the Orton rearrangement.625 The main product is the para isomer, though some ortho product may also be formed. The reaction has been carried out with N-chloro- and N-bromoamines and less often with N-iodo compounds. The amine must be acylated, except that PhNCl2 gives 2,4-dichloroaniline. The reaction is usually performed in water or acetic acid. There is considerable evidence (cross-halogenation, labeling, etc.) that this is an intermolecular process.626 First, the HCl reacts with the starting material to give ArNHCOCH3 and Cl2; then the chlorine halogenates the ring as in Reaction 11-10. Among the evidence is that chlorine has been isolated from the reaction mixture. The Orton rearrangement can also be brought about photochemically627 and by heating in the presence of benzoyl peroxide.628 These are free radical processes.

11-32 Migration of an Alkyl Group629

1/C-Hydro-5/N-alkyl-interchange

img

When HCl salts of arylalkylamines are heated at ~200–00 °C, migration occurs in what is called the Hofmann–Martius reaction. It is an intermolecular reaction, since crossing is found. For example, methylanilinium bromide gave not only the normal products o- and p-toluidine, but also aniline and di- and trimethylanilines.630 As would be expected for an intermolecular process, there is isomerization when R is primary.

With primary R, the reaction probably goes through the alkyl halide formed initially in an SN2 reaction:

equation

Evidence for this view is that alkyl halides have been isolated from the reaction mixture and that Br, Cl, and I gave different ortho/para ratios, which indicates that the halogen is involved in the reaction.630 Further evidence is that the alkyl halides isolated are not rearranged (as would be expected if they are formed by an SN2 mechanism), even though the alkyl groups in the ring are rearranged. Once the alkyl halide is formed, it reacts with the substrate by a normal Friedel–Crafts alkylation process (Reaction 11-11), accounting for the rearrangement. When R is secondary or tertiary, carbocations may be directly formed so that the reaction does not go through the alkyl halides.631

It is also possible to carry out the reaction by heating the amine (not the salt) at a temperature between 200 and 350 °C with a metal halide (e.g., CoCl2, CdCl2, or ZnCl2). When this is done, the reaction is called the Reilly–Hickinbottom rearrangement. Primary R groups larger than ethyl give both rearranged and unrearranged products.632 The reaction is not generally useful for secondary and tertiary R groups, which are usually cleaved to alkenes under these conditions.

When acylated arylamines are photolyzed, migration of an acyl group takes place633 in a process that resembles the photo-Fries reaction (11-27).

11.F.iii. Other Leaving Groups

Three types of reactions are considered in this section.

1. Reactions in which hydrogen replaces another leaving group:

equation

2. Reactions in which an electrophile other than hydrogen replaces another leaving group:

equation

3. Reactions in which a group (other than hydrogen) migrates from one position in a ring to another. Such migrations can be either inter- or intramolecular:

img

The three types are not treated separately, but reactions are classified by leaving group.

A. Carbon Leaving Groups

Reversal of Friedel–Crafts Alkylation

Hydro-de-alkylation or Dealkylation

equation

Alkyl groups can be cleaved from aromatic rings by treatment with proton and/or Lewis acids. Tertiary R groups are the most easily cleaved; because this is true, the tert-butyl group is occasionally introduced into a ring, used to direct another group, and then removed.634 For example, 4-tert-butyltoluene (71) reacted with benzoyl chloride and AlCl3 to give the acylated product, and subsequent treatment with AlCl3 led to loss of the tert-butyl group to give 72.635

Secondary R groups are harder to cleave, and primary R harder still. Because of this reaction, care must be taken when using Friedel–Crafts catalysts (Lewis or proton acids) on aromatic compounds containing alkyl groups. True cleavage, in which the R becomes an alkene, occurs only at high temperatures, >400 °C.636 At ordinary temperatures, the R group attacks another ring, so that the bulk of the product may be dealkylated, but there is a residue of heavily alkylated material. The isomerization reaction, in which a group migrates from one position in a ring to another or to a different ring, is therefore more important than true cleavage. In these reactions, the meta isomer is generally the most favored product among the dialkylbenzenes; and the 1,3,5-product the most favored among the trialkylbenzenes, because they have the highest thermodynamic stabilities. Alkyl migrations can be inter- or intramolecular, depending on the conditions and on the R group. The following experiments can be cited: Ethylbenzene treated with HF and BF3 gave, almost completely, benzene and diethylbenzenes637 (entirely intermolecular); propylbenzene labeled in the β position gave benzene, propylbenzene, and di- and tripropylbenzenes, but the propylbenzene recovered was partly labeled in the α position and not at all in the γ position638 (both intra- and intermolecular); o-xylene treated with HBr and AlBr3 gave a mixture of o- and m- but no p-xylene, while p-xylene gave p- and m- but no o-xylene, and no trimethyl compounds could be isolated in these experiments639 (exclusively intramolecular rearrangement). Apparently, methyl groups migrate only intramolecularly, while other groups may follow either path.640

img

img

The mechanism641 of intermolecular rearrangement can involve free alkyl cations, but there is much evidence to show that this is not necessarily the case. For example, many of them occur without rearrangement within the alkyl group. The following mechanism has been proposed for intermolecular rearrangement without the involvement of carbocations that are separated from the ring.642

Evidence for this mechanism is that optically active PhCHDCH3 labeled in the ring with 14C and treated with GaBr3 in the presence of benzene gave ethylbenzene containing no deuterium and two deuterium atoms and that the rate of loss of radioactivity was about equal to the rate of loss of optical activity.642 The mechanism of intramolecular rearrangement is not very clear. 1,2 shifts of this kind have been proposed:643

img

There is evidence from img labeling that intramolecular migration occurs only through 1,2-shifts.644 Any 1,3- or 1,4-migration takes place by a series of two or more 1,2-shifts.

Phenyl groups have also been found to migrate. Thus o-terphenyl, heated with AlCl3–H2O, gave a mixture containing 7% o-, 70% m-, and 23% p-terphenyl.645 Alkyl groups have also been replaced by groups other than hydrogen (nitro groups).

Unlike alkylation, Friedel–Crafts acylation has been generally considered to be irreversible, but a number of instances of electrofugal acyl groups have been reported,646 especially where there are two ortho substituents (e.g., the hydro-de-benzoylation of 73).647

img

OS V, 332. Also see, OS III, 282, 653; V, 598.

11-34 Decarbonylation of Aromatic Aldehydes

Hydro-de-formylation or Deformylation

equation

The decarbonylation of aromatic aldehydes with sulfuric acid648 is the reverse of the Gatterman–Koch reaction (11-18). It has been carried out with trialkyl- and trialkoxybenzaldehydes. The reaction takes place by the ordinary arenium ion mechanism: The attacking species is H+ and the leaving group is HCO+, which can lose a proton to give CO or combine with OH from the water solvent to give formic acid.649 Aromatic aldehydes have also been decarbonylated with basic catalysts.650 When basic catalysts are used, the mechanism is probably similar to the SE1 process of Reaction 11-35 (see also, Reaction 14-32).

11-35 Decarboxylation of Aromatic Acids

Hydro-de-carboxylation or Decarboxylation

equation

The decarboxylation of aromatic acids is most often carried out by heating with copper and quinoline. However, two other methods can be used with certain substrates. In one method, the salt of the acid (ArCOO) is heated, and in the other the carboxylic acid is heated with a strong acid, often sulfuric. The latter method is accelerated by the presence of electron-donating groups in ortho and para positions and by the steric effect of groups in the ortho positions; in benzene systems it is generally limited to substrates that contain such groups. In this method, decarboxylation takes place by the arenium ion mechanism,651 with H+ as the electrophile and CO2 as the leaving group.652Evidently, the order of electrofugal ability is CO2 > H+ > COOH+, so that it is necessary, at least in most cases, for the COOH to lose a proton before it can cleave.

img

When carboxylate ions are decarboxylated, the mechanism is entirely different, being of the SE1 type. Evidence for this mechanism is that the reaction is first order and that electron-withdrawing groups, which would stabilize a carbanion, facilitate the reaction.653

img

Despite its synthetic importance, the mechanism of the copper–quinoline method has been studied very little, but it has been shown that the actual catalyst is cuprous ion.654 In fact, the reaction proceeds much faster if the acid is heated in quinoline with cuprous oxide instead of copper, provided that atmospheric oxygen is rigorously excluded. A mechanism has been suggested in which it is the cuprous salt of the acid that actually undergoes the decarboxylation.654 It has been shown that cuprous salts of aromatic acids are easily decarboxylated by heating in quinoline655 and that arylcopper compounds are intermediates that can be isolated in some cases.656 Metallic silver has been used in place of copper, with higher yields.657 Silver acetate has also been used to promote decarboxylation.658 A photolytic decarboxylation also has been reported, under a dioxygen atmosphere in the presence of HgF2.659

In certain cases, the carboxyl group can be replaced by electrophiles other than hydrogen (e.g., NO,657 I,660 Br,661 or Hg).662 Although closely related to reactions in Chapter 13 (Reactions 13-9, 13-11, and 13-12), a decarboxylative coupling reaction of aryl halides and arylcarboxylic acids has been reported, using Pd and Cu catalysts, to give the corresponding biaryl.663

Rearrangements are also known to take place. For example, when the phthalate ion is heated with a catalytic amount of cadmium, the terphthalate ion (74) is produced:664

img

In a similar process, potassium benzoate heated with Cd salts disproportionates to benzene and 74. The term Henkel reaction (named for the company that patented the process) is used for these rearrangements.665 An SE1 mechanism has been suggested.666 The terphthalate is the main product because it crystallizes from the reaction mixture, driving the equilibrium in that direction.667

For aliphatic decarboxylation, see Reaction 12-40.

OS I, 274, 455, 541; II, 100, 214, 217, 341; III, 267, 272, 471, 637; IV, 590, 628; V, 635, 813, 982, 985. Also see, OS I, 56.

11-36 The Jacobsen Reaction

img

When polyalkyl- or polyhalobenzenes are treated with sulfuric acid, the ring is sulfonated, but rearrangement also takes place. The reaction, known as the Jacobsen reaction, is limited to benzene rings that have at least four substituents, which can be any combination of alkyl and halogen groups, where the alkyl groups can be ethyl or methyl and the halogen iodo, chloro, or bromo. When isopropyl or tert-butyl groups are on the ring, these groups are cleaved to give alkenes. Since a sulfo group can later be removed (Reaction 11-38), the Jacobsen reaction can be used as a means of rearranging polyalkylbenzenes. The rearrangement always brings the alkyl or halo groups closer together than they were originally. Side products in the case illustrated above are pentamethylbenzenesulfonic acid, 2,4,5-trimethylbenzenesulfonic acid, and so on, indicating an intermolecular process, at least partially.

The mechanism of the Jacobsen reaction is not established,668 but there is evidence, at least for polymethylbenzenes, that the rearrangement is intermolecular, and that the species to which the methyl group migrates is a polymethylbenzene, not a sulfonic acid. Sulfonation takes place after the migration.669 It has been shown by labeling that ethyl groups migrate without internal rearrangement.670

Isomerization of alkyl groups in substituted biphenyls has been observed671 when the medium is a superacid (see Sec. 5.A.ii).

B. Oxygen Leaving Groups

11-37 Deoxygenation

equation

In a few cases, it is possible to remove an oxygen substituent directly from the aromatic ring. Treatment of an aryl mesylate (ArOMs) with a Ni catalyst in DMF, for example, leads to the deoxygenated product, Ar-H.672

C. Sulfur Leaving Groups

11-38 Desulfonation or Hydro-de-sulfonation

equation

The cleavage of sulfo groups from aromatic rings is the reverse of Reaction 11-7.673 By the principle of microscopic reversibility, the mechanism is also the reverse.674 Dilution is generally used, as the reversibility of sulfonation decreases with increasing H2SO4 concentration. The reaction permits the sulfo group to be used as a blocking group to direct meta and then to be removed. The sulfo group has also been replaced by nitro and halogen groups. Sulfo groups have also been removed from the ring by heating with an alkaline solution of Raney nickel.675 In another catalytic process, aromatic sulfonyl bromides or chlorides are converted to aryl bromides or chlorides, respectively, on heating with an Rh catalyst.676 This reaction is similar to the decarbonylation of aromatic acyl halides mentioned in Reaction 14-32.

equation

OS I, 388; II, 97; III, 262; IV, 364. Also see, OS I, 519; II, 128; V, 1070.

D. Halogen Leaving groups

11-39 Dehalogenation or Hydro-de-halogenation

equation

Aryl halides can be dehalogenated by Friedel–Crafts catalysts. Iodine is the most easily cleaved. Dechlorination is seldom performed and defluorination apparently never. The reaction is most successful when a reducing agent, say, Br or I is present to combine with the I+ or Br+ coming off.677 Except for deiodination, the reaction is seldom used for preparative purposes. Migration of halogen is also found,678 both intramolecular679 and intermolecular.680The mechanism is probably the reverse of that of Reaction 11-10.681 Debromination of aromatic rings having two attached amino groups was accomplished by refluxing in aniline containing acetic acid/HBr.682

Rearrangement of polyhalobenzenes can also be catalyzed by very strong bases (e.g., 1,2,4-tribromobenzene) is converted to 1,3,5-tribromobenzene by treatment with PhNHK.683 This reaction, which involves aryl carbanion intermediates (SE1 mechanism), has been called the halogen dance.684

Removal of halogen from aromatic rings can also be accomplished by various reducing agents, among them Bu3SnH,685 catalytic-hydrogenolysis,686 catalytic-transfer hydrogenolysis,687 Na–Hg in liquid NH3,688 LiAlH4,689 NaBH4and a catalyst,690 NaH,691 HCO2H692 or aq HCO2693 with Pd/C,694 ammonium formate in aq isopropyl alcohol with a Pd catalyst,695 and Raney nickel in alkaline solution,696 the last method being effective for fluorine as well as for the other halogens. Aryl iodides are reduced with DMAP methiodide salt.697 Carbon monoxide, with potassium tetracarbonylhydridoferrate [KHFe(CO)4] as a catalyst, specifically reduces aryl iodides.698 Not all of these reagents operate by electrophilic substitution mechanisms. Some are nucleophilic substitutions and some are free radical processes. Photochemical699 and electrochemical700 reduction are also known. Halogen can also be removed from aromatic rings indirectly by conversion to Grignard reagents (Reaction 12-38) followed by hydrolysis (Reaction 11-41).

OS III, 132, 475, 519; V, 149, 346, 998; VI, 82, 821.

11-40 Formation of Organometallic Compounds

equation

These reactions are considered along with their aliphatic counterparts at Reactions 12-38 and 12-39.

E. Metal Leaving Groups

11-41 Hydrolysis of Organometallic Compounds

Hydro-de-metalation or Demetalation

equation

Organometallic compounds can be hydrolyzed by acid treatment. For active metals (e.g., Mg, Li, etc.), water is sufficiently acidic. The most important example of this reaction is hydrolysis of Grignard reagents, but M may be many other metals or metalloids. Examples are SiR3, HgR, Na, and B(OH)2. Since aryl Grignard and aryllithium compounds are fairly easy to prepare, they are often used to prepare salts of weak acids (e.g., alkynes).

equation

Where the bond between the metal and the ring is covalent, the usual arenium ion mechanism operates.701 Where the bonding is essentially ionic, this is a simple acid–base reaction. For the aliphatic counterpart of this reaction, see Reaction 12-24.

Other reactions of aryl organometallic compounds are treated with their aliphatic analogues: Reactions 12-2512-27 and 12-3012-37.

Notes

1. For a review of electrophilic aromatic reactions in ionic liquids, see Borodkin, G.I.; Shubin, V.G. Russ. J. Org. Chem. 2006, 42, 1745.

2. See Taylor, R. Electrophilic Aromatic Substitution, Wiley, NY, 1990; Katritzky, A.R.; Taylor, R. Electrophilic Substitution of Heterocycles: Quantitative Aspects (Vol. 47 of Adv. Heterocycl. Chem.), Academic Press, NY, 1990; Taylor, R. in Bamford, C.H.; Tipper, C.F.H. Comprehensive Chemical Kinetics, Vol. 13, Elsevier, NY, 1972, pp. 1–406.

3. This mechanism is sometimes called the SE2 mechanism because it is bimolecular, but in this book we reserve that name for aliphatic substrates (see Chap 12).

4. See Olah, G.A. J. Am. Chem. Soc. 1971, 94, 808.

5. See Brouwer, D.M.; Mackor, E.L.; MacLean, C. in Olah, G.A.; Schleyer, P.v.R. Carbonium Ions, Vol. 2, Wiley, NY, 1970, pp. 837–897; Perkampus, H. Adv. Phys. Org. Chem. 1966, 4, 195.

6. Also see de la Mare, P.B.D. Acc. Chem. Res. 1974, 7, 361.

7. Berglund-Larsson, U.; Melander, L. Ark. Kemi 1953, 6, 219. See also, Zollinger, H. Adv. Phys. Org. Chem. 1964, 2, 163.

8. See Hammett, L.P. Physical Organi Chemistry, 2nd ed.; McGraw-Hill, NY, 1970, pp. 172–182.

9. Zollinger, H. Helv. Chim. Acta 1955, 38, 1597, 1617, 1623.

10. Snyckers, F.; Zollinger, H. Helv. Chim. Acta 1970, 53, 1294.

11. See Myhre, P.C.; Beug, M.; James, L.L. J. Am. Chem. Soc. 1968, 90, 2105; Márton, J. Acta Chem. Scand. 1969, 23, 3321, 3329.

12. Bott, R.W.; Eaborn, C.; Greasley. P.M. J. Chem. Soc. 1964, 4803.

13. See Koptyug, V.A. Top. Curr. Chem. 1984, 122, 1; Bull. Acad. Sci. USSR Div. Chem. Sci. 1974, 23, 1031; Shteingarts, V.D. Russ. Chem. Rev. 1981, 50, 735; Farcasiu, D. Acc. Chem. Res. 1982, 15, 46.

14. Olah, G.A.; Kuhn, S.J. J. Am. Chem. Soc. 1958, 80, 6541. See Effenberger, F. Acc. Chem. Res. 1989, 22, 27.

15. Olah, G.A.; Schlosberg, R.H.; Porter, R.D.; Mo, Y.K.; Kelly, D.P.; Mateescu, G.D. J. Am. Chem. Soc. 1972, 94, 2034.

16. Olah, G.A.; Staral, J.S.; Asencio, G.; Liang, G.; Forsyth, D.A.; Mateescu, G.D. J. Am. Chem. Soc. 1978, 100, 6299.

17. Lyerla, J.R.; Yannoni, C.S.; Bruck, D.; Fyfe, C.A. J. Am. Chem. Soc. 1979, 101, 4770.

18. Dewar, M.J.S. Electronic Theory of Organic Chemistry; Clarendon Press: Oxford, 1949.

19. See Hubig, S.M.; Kochi, J.K. J. Org. Chem. 2000, 65, 6807.

20. See Gallivan, J.P.; Dougherty, D.A. Org. Lett. 1999, 1, 103; Rosokha, S.V.; Kochi, J.K. J. Org. Chem. 2002, 67, 1727.

21. Kilpatrick, M.; Luborsky, F.E. J. Am. Chem. Soc. 1953, 75, 577.

22. Brown, H.C.; Brady, J.D. J. Am. Chem. Soc. 1952, 74, 3570.

23. Laali, K.K.; Okazaki, T.; Harvey, R.G. J. Org. Chem. 2001, 66, 3977.

24. Condon, F.E. J. Am. Chem. Soc. 1952, 74, 2528.

25. Brown, H.C.; Stock, L.M. J. Am. Chem. Soc. 1957, 79, 1421.

26. Olah, G.A.; Kuhn, S.J.; Flood, S.H.; Hardie, B.A. J. Am. Chem. Soc. 1964, 86, 2203.

27. Olah, G.A.; Kuhn, S.J.; Flood, S.H. J. Am. Chem. Soc. 1961, 83, 4571, 4581.

28. Olah, G.A.; Kuhn, S.J.; Flood, S.H.; Hardie, B.A. J. Am. Chem. Soc. 1964, 86, 1039, 1044.

29. Rys, P.; Skrabal, P.; Zollinger, H. Angew. Chem. Int. Ed. 1972, 11, 874. See also, DeHaan, F.P.; Covey, W.D.; Delker, G.L.; Baker, N.J.; Feigon, J.F.; Miller, K.D.; Stelter, E.D. J. Am. Chem. Soc. 1979, 101, 1336; Santiago, C.; Houk, K.N.; Perrin, C.L. J. Am. Chem. Soc. 1979, 101, 1337.

30. See Ridd, J.H. Acc. Chem. Res. 1971, 4, 248; Taylor, R.; Tewson, T.J. J. Chem. Soc., Chem. Commun. 1973, 836; Naidenov, S.V.; Guk, Yu.V.; Golod, E.L. J. Org. Chem. USSR 1982, 18, 1731. Also see Olah, G.A. Acc. Chem. Res. 1971, 4, 240; Olah, G.A.; Lin, H.C. J. Am. Chem. Soc. 1974, 96, 2892; Sedaghat-Herati, M.R.; Sharifi, T. J. Organomet. Chem. 1989, 363, 39; Banthorpe, D.V. Chem. Rev. 1970, 70, 295, especially Sections VI and IX.

31. See Stock, L.M. Prog. Phys. Org. Chem. 1976, 12, 21; Ridd, J.H. Adv. Phys. Org. Chem. 1978, 16, 1.

32. Holman, R.W.; Gross, M.L. J. Am. Chem. Soc. 1989, 111, 3560.

33. Also see Eaborn, C.; Hornfeld, H.L.; Walton, D.R.M. cgqtBunnett, J.F.; Miles J.H.; Nahabedian, K 1967, 1036.

34. See Hoggett, J.G.; Moodie, R.B.; Penton, J.R.; Schofield, K. Nitration and Aromatic Reactivity, Cambridge University Press, Cambridge, 1971, pp. 122–145, 163–220.

35. For a computational approach to evaluate substituent constants, see Galabov, B.; Ilieva, S.; Schaefer III, H.F. J. Org. Chem. 2006, 71, 6382.

36. Fierz, H.E.; Weissenbach, P. Helv. Chim. Acta 1920, 3, 312.

37. Witt, O.N. Ber. 1915, 48, 743.

38. It must be remembered that in acid solution amines are converted to their conjugate acids, which for the most part are meta directing (type 2). However, unless the solution is highly acidic, there will be a small amount of free amine present, and since amino groups are activating and the conjugate acids deactivating, ortho–para direction is often found even under acidic conditions.

39. See Chuchani, G. in Patai, S. The Chemistry of the Amino Group, Wiley, NY, 1968, pp. 250–265; for ether groups see Kohnstam, G.; Williams, D.L.H. in Patai, S. The Chemistry of the Ether Linkage, Wiley, NY, 1967, pp. 132–150.

40. Tomoda, S.; Takamatsu, K.; Iwaoka, M. Chem. Lett. 1998, 581.

41. Tarbell, D.S.; Herz, A.H.J. Am. Chem. Soc. 1953, 75, 4657. Ring substitution is possible if the SH group is protected. See Walker, D. J. Org. Chem. 1966, 31, 835.

42. Carroll, T.X.; Thomas, T.D.; Bergersen, H.; Bimgrve, K.J.; Sæthre, L.J. J. Org. Chem. 2006, 71, 1961.

43. See Castagnetti, E.; Schlosser, M. Chem. Eur. J. 2002, 8, 799.

44. See Gilow, H.M.; De Shazo, M.; Van Cleave, W.C. J. Org. Chem. 1971, 36, 1745; Hoggett, J.G.; Moodie, R.B.; Penton, J.R.; Schofield, K. Nitration and Aromatic Reactivity, Cambridge University Press, Cambridge, 1971, pp. 167–176.

45. Hartshorn, S.R.; Ridd, J.H. J. Chem. Soc. B 1968, 1063. Also see Ridd, J.H. in Aromaticity, Chem. Soc. Spec. Publ., no. 21, 1967, pp. 149–162.

46. Brickman, M.; Utley, J.H.P.; Ridd, J.H. J. Chem. Soc. 1965, 6851.

47. For a discussion of the substituents effect of the methyl group, see Myrseth, V.; Sæthre, L.J.; Bimgrve, K.J.; Thomas, T.D. J. Org. Chem. 2007, 72, 5715.

48. Spryskov, A.A.; Golubkin, L.N. J. Gen. Chem. USSR 1961, 31, 833. Since the CO2 group is present only in alkaline solution, where electrophilic substitution is not often done, it is seldom encountered.

49. See, however, Schubert, W.M.; Gurka, D.F. J. Am. Chem. Soc. 1969, 91, 1443; Himoe, A.; Stock, L.M. J. Am. Chem. Soc. 1969, 91, 1452.

50. See Effenberger, F.; Maier, A.J. J. Am. Chem. Soc. 2001, 123, 3429.

51. Stock, L.M.; Himoe, A. J. Am. Chem. Soc. 1961, 83, 4605.

52. Olah, G.A. Acc. Chem. Res. 1970, 4, 240, p. 248.

53. Ansell, H.V.; Le Guen, J.; Taylor, R. Tetrahedron Lett. 1973, 13.

54. Hoggett, J.G.; Moodie, R.B.; Penton, J.R.; Schofield, K. Nitration and Aromatic Reactivity, Cambridge University Press, Cambridge, 1971, pp. 176–180.

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56. Breslow, R.; Campbell, P. J. Am. Chem. Soc. 1969, 91, 3085; Bioorg. Chem. 1971, 1, 140. See also, Komiyama, M.; Hirai, H. J. Am. Chem. Soc. 1983, 105, 2018; 1984, 106, 174; Chênevert, R.; Ampleman, G. Can. J. Chem.1987, 65, 307; Komiyama, M. Polym. J. (Tokyo) 1988, 20, 439.

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