Reactions - Lesson 5 - Substitution Reactions: Radical - 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 14. Substitution Reactions: Radical

14.B. Reactions

The reactions in this chapter are classified according to leaving group. The most common leaving groups are hydrogen and nitrogen (generally the diazonium ion); these are considered first.

14.C.i Hydrogen as a Leaving Group

A. Substitution by Halogen

14-1 Halogenation at an Alkyl Carbon144

Halogenation or Halo-de-hydrogenation

equation

Alkanes can be chlorinated or brominated by treatment with chlorine or bromine in the presence of visible or UV light, or with heat145 These reactions require an added chemical reagent as the radical chain initiator, or exposure to light, or higher temperatures.146 The reaction can also be applied to alkyl chains containing many functional groups. The chlorination reaction is usually not useful for preparative purposes precisely because it is so general: Not only does substitution take place at virtually every alkyl carbon in the molecule, but di- and polychloro substitution almost invariably occur even if there is a large molar ratio of substrate to halogen. Note that benzylic halogenation (e.g., the Wohl–Ziegler bromination) is discussed in Reaction 14-3.

When functional groups are present, the principles are those outlined in Section 14.B.i. Tertiary carbons are most likely to be functionalized and primary are least likely. Favored positions are those α to aromatic rings, while positions α to electron-withdrawing groups are least likely to be substituted. Hydrogen atoms α to an OR group are very readily replaced. Nevertheless, mixtures are nearly always obtained. This can be contrasted to the regioselectivity of electrophilic halogenation (Reactions 12-412-6), which always takes place α to a carbonyl group (except when the reaction is catalyzed by AgSbF6). Of course, if a mixture of chlorides is wanted, the reaction is usually quite satisfactory. For obtaining pure compounds, the chlorination reaction is essentially limited to substrates with only one type of replaceable hydrogen (e.g., ethane, cyclohexane, and neopentane). The most common are methylbenzenes and other substrates with methyl groups on aromatic rings, since few cases are known where halogen atoms substitute at an aromatic position.147 Of course, ring substitution does take place in the presence of a positive-ion-forming catalyst (Reaction 11-10). In addition to mixtures of various alkyl halides, traces of other products are obtained. These include H2, alkenes, higher alkanes, lower alkanes, and halogen derivatives of these compounds. Solvent plays an important role in this process.148

The bromine atom is much more selective than the chlorine atom. As indicated in Section 14.B.iv, it is often possible to brominate tertiary and benzylic positions selectively. High regioselectivity can also be obtained where the neighboring-group mechanism (Sec 14.A.iv) can operate.

As already mentioned, halogenation can be performed with chlorine or bromine. Fluorine has also been used,149 but seldom, because it is too reactive and hard to control.150 It often breaks carbon chains down into smaller units, a side reaction that sometimes becomes troublesome in chlorinations as well. Fluorination151 has been achieved by the use of chlorine trifluoride (ClF3) at −75°C.152 For example, cyclohexane gave 41% fluorocyclohexane and methylcyclohexane gave 47% 1-fluoro-1-methylcyclohexane. Fluoroxytrifluoromethane (CF3OF) fluorinates tertiary positions of certain molecules in good yields with high regioselectivity.153 For example, adamantane gave 75% 1-fluoroadamantane. Fluorine at −70 °C, diluted with N2,154 and bromine trifluoride at 25–35 °C155 are also highly regioselective for tertiary positions. These reactions probably have electrophilic,156 not free radical mechanisms. In fact, the success of the F2 reactions depends on the suppression of free radical pathways, by dilution with an inert gas, by working at low temperatures, and/or by the use of radical scavengers. Fluorination of 1,3-dicarbonyl compounds and activated aromatic compounds was achieved under solvent-free conditions using Selectfluor™ F–TEDA–BF4.157

Iodine can be used if the activating light has a wavelength of 184.9 nm,158 but iodinations using I2 alone are seldom attempted, largely because the HI formed reduces the alkyl iodide. The direct free radical halogenation of aliphatic hydrocarbons with iodine is significantly endothermic relative to the other halogens, and the requisite chain reaction does not occur.159 On the other hand, when iodine (CCl4•2 AlI3) reacts with an alkane in dibromomethane at −20 °C, good yields of the iodoalkane are obtained.160 The reaction of an alkane with tert-butylhypoiodite (t-BuOI) at 40 °C gave the iodoalkane in good yield.161 The reaction of alkanes with iodine and PhI(OAc)2 generates the iodoalkane.162 A radical protocol was developed using CI4 with base. Cyclohexane could be iodinated, for example, with CI4 in the presence of powdered NaOH.163 The reaction led to the use of iodoform on solid NaOH as the iodination reagent of choice. A base-induced bromination has been reported. 2-Methyl butane reacts with 50% aq NaOH and CBr4, in a phase-transfer catalyst, to give a modest yields of 2-bromo-2-methylbutane. α-Iodo ethers and α-iodolactones have been prepared from the parent ether or lactone via treatment with Et4N4 HF under electrolytic conditions.164

Many other halogenation agents have been employed, and a common reagent is sulfuryl chloride (SO2Cl2).165 Among other agents used have been NBS (see Reaction 14-3), CCl4,166 PCl5,167 N-haloamines, and sulfuric acid.168 In all these cases, an initiator is required, usually peroxides or UV light.169

When chlorination is carried out with N-haloamines and sulfuric acid (catalyzed by either UV light or metal ions), selectivity is much greater than with other reagents.168 In particular, alkyl chains are chlorinated with high regioselectivity at the position next to the end of the chain (the ω - 1 position).170 Some typical selectivity values are171

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Ref. 172

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Ref. 173

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Ref. 174

Furthermore, di- and polychlorination are much less prevalent.Dicarboxylic acids are predominantly chlorinated in the middle of the chain,175 and adamantane and bicyclo[2.2.2]octane at the bridgeheads176 by this procedure. The reasons for the high ω - 1 specificity are not clearly understood.177Alkyl chlorides can be converted to vic-dichlorides by treatment with MoCl5.178 Enhanced selectivity at a terminal position of n-alkanes has been achieved by absorbing the substrate onto a pentasil zeolite.179 For regioselective chlorination at certain positions of the steroid nucleus, see Reaction 19-2.

In almost all cases, the mechanism involves a free radical chain:

equation

When the reagent is halogen, initiation occurs as shown above.180 When it is another reagent, a similar cleavage occurs (catalyzed by light or, more commonly, peroxides), followed by propagation steps that do not necessarily involve abstraction by halogen. For example, the propagation steps for chlorination by tert-butyl hypochlorite (t-BuOCl) have been formulated as:181

equation

and the abstracting radicals in the case of N-haloamines are the aminium radical cations (R2NH•+, Reaction 11-5), with the following mechanism (in the case of initiation by Fe2+)168:

equation

This mechanism is similar to that of the Hofmann–Löffler Reaction (18-40).

The two propagation steps shown above for X2 are those that lead directly to the principal products (RX and HX), but many other propagation steps are possible and many occur. Similarly, the only termination step shown is the one that leads to RX, but any two radicals may combine (H, CH3, Cl, CH2CH3 in all combinations). Thus, products like H2, higher alkanes, and higher alkyl halides can be accounted for. When methane is the substrate, the rate-determining step is

equation

since an isotope effect of 12.1 was observed at 0 °C.182 For chlorinations, chains are very long, typically 104–106 propagations before a termination step takes place.

The order of reactivity of the halogens can be explained by energy considerations. For the substrate methane, ΔH values for the two principal propagation steps follow:

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In each case, D for CH3–H is 105 kcal mol−1 (438 kJ mol−1), while D values for the other bonds involved are given in Table 14.4.183 Fluorine (F2) is so reactive184 that neither UV light nor any other initiation is needed (total ΔH = −101 kcal mol−1, −425 kJ mol−1)185; while Br2 and I2 essentially do not react with methane. The second step is exothermic in all four cases, but it cannot take place before the first, and it is this step that is very unfavorable for Br2and I2. It is apparent that the most important single factor causing the order of halogen reactivity to be F2 > Cl2 > Br2 > I2 is the decreasing strength of the HX bond in the order HF > HCl > HBr > HI. The increased reactivity of secondary and tertiary positions is in accord with the decrease in D values for R–H in the order primary > secondary > tertiary (Table 5.3). (Note that for chlorination, step 1 is exothermic for practically all substrates other than CH4, since most other aliphatic C–H bonds are weaker than those in CH4.)

Table 14.4 Some D Valuesa

D

Bond

(kcal mol−1)

(kJ mol−1)

H–F

136

570

H–Cl

103

432

H–Br

88

366

H–I

71

298

F–F

38

159

Cl–Cl

59

243

Br–Br

46

193

I–I

36

151

CH3–F

108

452

CH3–Cl

85

356

CH3–Br

70

293

CH3–I

57

238

Reprinted with permission from Lide, D.R. (Ed.), Handbook of Chemistry and Physics, 87th ed., CRC Press, Boca Raton, FL, 2007, pp. 5-4–5-42. Copyright © 2007, with permission from Taylor & Francis Group LLC.

a. See Ref. 183.

Metal mediated halogenation reactions are known. Heating alkenes with bromine in the presence of MnO2 leads to monobromination.186 Hydrogen peroxide–HBr in water has been used for radical bromination.187 Bromination and chlorination of alkanes and cycloalkanes can also take place by an electrophilic mechanism if the reaction is catalyzed by AgSbF6.188 Direct chlorination at a vinylic position by an electrophilic mechanism has been achieved with benzeneseleninyl chloride [PhSe(O)Cl] and AlCl3 or AlBr3.189 However, while some substituted alkenes give high yields of chloro-substitution products, others (e.g., styrene) undergo addition of Cl2 to the double bond (Reaction 15-39).151 Electrophilic fluorination has already been mentioned (Sec. 14.C.i).

OS II, 89, 133, 443, 549; III, 737, 788; IV, 807, 921, 984; V, 145, 221, 328, 504, 635, 825; VI, 271, 404, 715; VII, 491; VIII, 161.

14-2 Halogenation at Silicon

Halogenation or Halo-de-hydrogenation

equation

Just as free radical halogenation occurs at the carbon of an alkane, via hydrogen abstraction to form the radical, a similar reaction occurs at silicon. When triisopropylsilane (iPr3Si–H) reacts with tert-butyl hypochlorite at −10 °C, the product is triisopropylchlorosilane (iPr3Si–Cl).190

14-3 Allylic and Benzylic Halogenation

Halogenation or Halo-de-hydrogenation

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This reaction is a special case of Reaction 14-1, but is important enough to be treated separately.191 Alkenes can be brominated in the allylic position and also a benzylic position by a number of reagents, of which NBS192 is by far the most common. When this reagent is used, the reaction is known as Wohl–Ziegler bromination. A nonpolar solvent is used, most often CCl4, but the reaction has been done in an ionic liquid.193 A variation in the reaction used NBS with 5% Yb(OTf)3 and 5% ClSiMe3.194 Other N-bromo amides have also been used. With any reagent an initiator is needed; this is usually AIBN (1), a peroxide (e.g., di-tert-butyl peroxide) or benzoyl peroxide or, less often, UV light. Boron trifluoride has been used for benzylic bromination.195

1,3-Dibromo-5,5-dimethylhydantoin (DBDMH) has been used for benzylic bromination in the presence of a Lewis acid (e.g., ZrCl4).196 Similarly, N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate, in the presence of a Pd catalyst and microwave irradiation, led to benzylic fluorides.197

Allylic chlorination has also been carried out198 with NCS and either arylselenyl chlorides (ArSeCl), aryl diselenides (ArSeSeAr), or TsNSO as catalysts. Allylic chlorination has been carried out with tert-butyl hypochlorite199 or NaClO/CeCl3•7H2O.200

The reaction is usually quite specific at an allylic or benzylic position and good yields are obtained. However, when the allylic radical intermediate is unsymmetrical, allylic rearrangements can take place, so that mixtures of both possible products are obtained (23 and 24). Use of the selenium catalysts produces almost entirely the allylically rearranged chlorides in high yields. With TsNSO the products are the unrearranged chlorides in lower yields. Dichlorine monoxide (Cl2O), with no catalyst, also leads to allylically rearranged chlorides in high yields.201 A free radical mechanism is unlikely in these latter reactions.

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When a double bond has two different allylic positions (e.g., CH3CH=CHCH2CH3), a secondary position is substituted more readily than a primary. The relative reactivity of tertiary hydrogen is not clear, though many substitutions at allylic tertiary positions have been performed.202 It is possible to brominate both sides of the double bond.203 Because of the electron-withdrawing nature of bromine, the second bromine substitutes on the other side of the double bond rather than α to the first bromine. Molecules with a benzylic hydrogen (e.g., toluene) react rapidly to give α-bromomethyl benzene (e.g., PhCH3 → PhCH2Br).

N-Bromosuccinimide is a highly regioselective brominating agent at other positions, including positions α to a carbonyl group, to a C≡C triple bond, and to an aromatic ring (benzylic position). When both a double and a triple bond are in the same molecule, the preferred position is α to the triple bond.204

Dauben and McCoy205 demonstrated that the mechanism of allylic bromination is of the free radical type, showing that the reaction is very sensitive to free radical initiators and inhibitors and indeed does not proceed at all unless at least a trace of initiator is present. Subsequent work indicated that the species that actually abstracts hydrogen from the substrate is the bromine atom. The reaction is initiated by small amounts of Br. Once it is formed, the main propagation steps are

Step 1 img

Step 2 img

The source of the Br2 is a fast ionic reaction between NBS and the HBr liberated in step 1:

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The function of the NBS is therefore to provide a source of Br2, as shown in the reaction, in a low, steady-state concentration, which effectively uses up the HBr liberated in step 1.206 The main evidence for this mechanism is that NBS and Br2 show similar selectivity207 and that the various N-bromo amides also show similar selectivity,208 which is consistent with the hypothesis that the same species is abstracting in each case.209

It may be asked why, if Br2 is the reacting species, it does not add to the double bond, either by an ionic or by a free radical mechanism (see Reaction 15-39). Apparently, the concentration is too low. In bromination of a double bond, only one atom of an attacking bromine molecule becomes attached to the substrate, whether the addition is electrophilic or free radical:

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The other bromine atom comes from another bromine-containing molecule or ion. This result is clearly not a problem in reactions with benzylic species since the benzene ring is not prone to such addition reactions. If the concentration is sufficiently low, there is a low probability that the proper species will be in the vicinity once the intermediate forms. The intermediate in either case reverts to the initial species and the allylic substitution competes successfully. If this is true, it should be possible to brominate an alkene in the allylic position without competition from addition, even in the absence of NBS or a similar compound, if a very low concentration of bromine is used and if the HBr is removed as it is formed so that it is not available to complete the addition step. This has indeed been demonstrated.210

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When NBS is used to brominate non-alkenyl substrates (e.g., alkanes) another mechanism, involving abstraction of the hydrogen of the substrate by the succinimidyl radical211 25 can operate.212 This mechanism is facilitated by certain solvents (e.g., CH2Cl2, CHCl3, or MeCN) in which NBS is more soluble, and by the presence of small amounts of an alkene that lacks an allylic hydrogen (e.g., ethene). The alkene serves to scavenge any Br that forms from the reagent. Among the evidence for the mechanism involving 25 are abstraction selectivities similar to those of Cl atoms and the isolation of β-bromopropionyl isocyanate (BrCH2CH2CONCO), which is formed by ring opening of 25.

Allyl silanes react with transition metals bearing chlorine ligands to give allyl chlorides, where a chlorine replaces a Me3Si unit.213

OS IV, 108; V, 825; VI, 462; IX, 191.

14-4 Halogenation of Aldehydes

Halogenation or Halo-de-hydrogenation

equation

The α-halogenation reaction of carbonyl compounds was mentioned in Reaction 14-2. A different halogenation reaction is possible in which aldehydes can be directly converted to acyl chlorides by treatment with chlorine, but the reaction operates only when the aldehyde does not contain an α hydrogen and even then it is not very useful. When there is an α hydrogen, α halogenation (Reactions 14-2 and 12-4) occurs instead. Other sources of chlorine have also been used, among them SO2Cl2214 and t-BuOCl.215 The mechanisms are probably of the free radical type. N-Bromosuccinimide, with AIBN (Sec. 14.A.i) as a catalyst, has been used to convert aldehydes to acyl bromides.216 In the presence of benzoyl peroxide as an initiator, Br3CCO2Et converts aldehydes to acyl bromides under radical conditions.217

OS I, 155.

B. Substitution by Oxygen

14-5 Hydroxylation at an Aromatic Carbon218

Hydroxylation or Hydroxy-de-hydrogenation

equation

A mixture of hydrogen peroxide and ferrous sulfate,219 called Fenton's reagent,220 can be used to hydroxylate aromatic rings, although yields are usually not high.221 Biaryls are typical side products.222 Among other reagents used H2O2 and titanous ion; O2 and Cu(I)223 or Fe(III),224 a mixture of ferrous ion, oxygen, ascorbic acid, and ethylenetetraaminetetraacetic acid (Udenfriend's reagent)225; O2 and KOH in liquid NH3226; and peroxyacids (e.g., peroxynitrous and trifluoroperoxyacetic acids).

Much work has been done on the mechanism of the reaction with Fenton's reagent, and it is known that free aryl radicals (formed by a process, e.g., HO + ArH → AR + H2O) are not intermediates. The mechanism is essentially that outlined in Section 14.A.iii, with HO as the attacking species,227 formed by

equation

The rate-determining step is formation of HO and not its reaction with the aromatic substrate.

An alternative oxidation of arene to phenol was reported using Cu(NO3)3 H2O, 30% hydrogen peroxide and a phosphate buffer.228

See also, Reaction 11-26

14-6 Formation of Cyclic Ethers

(5)OC-cyclo- Alkoxy-de-hydro-substitution

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Alcohols with hydrogen in the δ position can be cyclized with lead tetraacetate.229 The reaction is usually carried out at ~ 80 °C (most often in refluxing benzene), but can also be done at room temperature if the reaction mixture is irradiated with UV light. Tetrahydrofurans are formed in high yields. Little or no four- and six-membered cyclic ethers (oxetanes and tetrahydropyrans, respectively) are obtained even when γ and ε hydrogen atoms are present. The reaction has also been carried out with a mixture of halogen (Br2 or I2) and a salt or oxide of silver or mercury (especially HgO or AgOAc),230 with iodosobenzene diacetate and I2,231 and with ceric ammonium nitrate (CAN).232 The following mechanism is likely for the lead tetraacetate reaction233:

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although 26 has never been isolated. The step marked A is a 1,5-internal hydrogen abstraction. Such abstractions are well known (see Reaction 18-40) and are greatly favored over 1,4 or 1,6 abstractions (the small amounts of tetrahydropyran formed result from 1,6-abstractions).234

Oxidation to the aldehyde or acid (Reactions 19-3 and 19-22) and fragmentation of the substrate sometimes compete. When the OH group is on a ring of at least seven members, a transannular product can be formed, as in the cyclization reaction of 1-octanol to 27.235 β-Hydroxy ethers can give cyclic acetals (e.g., 28).236

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There are no references in Organic Syntheses, but see OS V, 692; VI, 958, for related reactions.

14-7 Formation of Hydroperoxides

Hydroperoxy-de-hydrogenation

equation

The slow atmospheric oxidation (slow meaning without combustion) of C–H to C–O–O–H is called autoxidation.237 The reaction occurs when compounds are allowed to stand in air and is catalyzed by light, so unwanted autoxidations can be greatly slowed by keeping the compounds in dark places. Most autoxidations proceed by free radical chain processes that involve peroxyl radicals.238 To suppress autoxidation, an antioxidant can be added that will prevent or retard the reaction with atmospheric oxygen.239 Although some lactone compounds are sold as antioxidants, many radicals derived from lactones show poor or no reactivity toward oxygen.239 The hydroperoxides produced often react further to give alcohols, ketones, and more complicated products, so the reaction is not often used for preparative purposes, although in some cases hydroperoxides have been prepared in good yield.240 It is because of autoxidation that foods, rubber, paint, lubricating oils, and so on deteriorate on exposure to the atmosphere over periods of time. On the other hand, a useful application of autoxidation is the atmospheric drying of paints and varnishes. As with other free radical reactions of C–H bonds, some bonds are attacked more readily than others,241 and these are the ones seen before (Sec. 14.B.i), although the selectivity is very low at high temperatures and in the gas phase. The reaction can be carried out successfully at tertiary (to a lesser extent, secondary), benzylic,242 and allylic (though allylic rearrangements are common) R.243 2-Phenylpropane reacted with oxygen to give PhMe2C–OOH, for example. Another susceptible position is aldehydic C–H, but the peroxyacids so produced are not easily isolated244 since they are converted to the corresponding carboxylic acids (Reaction 19-23). The α positions of ethers are also easily attacked by oxygen [RO–C–H → RO–C–OOH], but the resulting hydroperoxides are seldom isolated. However, this reaction constitutes a hazard in the storage of ethers since solutions of these hydroperoxides and their rearrangement products in ethers are potential spontaneous explosives.245

Oxygen itself (a diradical) is not reactive enough to be the species that actually abstracts the hydrogen. But if a trace of free radical (say R′) is produced by some initiating process, it reacts with oxygen246 to give R′–O–O; since this type of radical does abstract hydrogen, the chain is

equation

In at least some cases (in alkaline media),247 the radical R can be produced by formation of a carbanion and its oxidation (by O2) to a radical, such as allylic radical 29.248 Autoxidations in alkaline media can also proceed by a different mechanism: R–H + base → R- + O2 → ROO-.249

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When alkenes are treated with oxygen that has been photosensitized (Sec. 7.A.vi, category 6), they are substituted by OOH in the allylic position in a synthetically useful reaction.250 Although superficially similar to autoxidation, this reaction is clearly different because 100% allylic rearrangement always takes place. The reagent here is not the ground-state oxygen (a triplet), but an excited singlet state251 (in which all electrons are paired), and the function of the photosensitization is to promote the oxygen to this singlet state. Singlet oxygen can also be produced by nonphotochemical means,252 for example, by the reaction between H2O2 and NaOCl253 or between ozone and triphenyl phosphite.254 Calcium peroxide diperoxohydrate (CaO2•2H2O2) has been reported as a storable compound used for the chemical generation of singlet oxygen.255 The oxygen generated by either photochemical or nonphotochemical methods reacts with alkenes in the same way;256 this is evidence that singlet oxygen is the reacting species in the photochemical reaction and not some hypothetical

img

complex between triplet oxygen and the photosensitizer, as had previously been suggested. The fact that 100% allylic rearrangement always takes place is incompatible with a free radical mechanism. Further evidence that free radicals are not involved comes from the treatment of optically active limonene (30) with singlet oxygen. Among other products is the optically active hydroperoxide 31, though if 32 were an intermediate, it could not give an optically active product since it possesses a plane of symmetry.257 In contrast, autoxidation of 30 gave optically inactive 31 (a mixture of four diastereomers in which the two pairs of enantiomers are present as racemic mixtures). As this example shows, singlet oxygen reacts faster with more highly substituted than with less highly substituted alkenes. The order of alkene reactivity is tetrasubstituted > trisubstituted > disubstituted. Electron-withdrawing substituents deactivate the alkene.258 In simple trisubstituted alkenes, there is a general preference for the hydrogen to be removed from the more highly congested side of the double bond.259 With cis-alkenes of the form RCH=CHR′, the hydrogen is removed from the larger R group.260 Many functional groups in an allylic position cause the hydrogen to be removed from that side rather than the other (geminal selectivity).261 Also, in alkyl-substituted alkenes, the hydrogen that is preferentially removed is the one geminal to the larger substituent on the double bond.262

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Several mechanisms have been proposed for the reaction with singlet oxygen.263 One of these is a pericyclic mechanism, similar to that of the ene synthesis (Reaction 15-23) and to the first step of the reaction between alkenes and SeO2 (Reaction 19-14). However, there is strong evidence against this mechanism,264 and a more likely mechanism involves addition of singlet oxygen to the double bond to give a perepoxide (33),265 followed by internal proton transfer.266

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Still other proposed mechanisms involve diradicals or dipolar intermediates.267

OS IV, 895.

14-8 Formation of Peroxides

Alkyldioxy-de-hydrogenation

equation

Peroxy groups (ROO) can be introduced into susceptible organic molecules by treatment with a hydroperoxide in the presence of cuprous chloride or other catalysts (e.g., cobalt and manganese salts).268 Very high yields can be obtained. The type of hydrogen replaced is similar to that with NBS (Reaction 14-3); that is, mainly benzylic, allylic, and tertiary. The mechanism is therefore of the free radical type, involving ROO formed from ROOH and the metal ion. The reaction can be used to demethylate tertiary amines of the form R2NCH3, since the product R2NHCH2OOR′ can easily be hydrolyzed by acid (Reaction 10-6) to give R2NH.269

14-9 Acyloxylation

Acyloxylation or Acyloxy-de-hydrogenation

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Susceptible positions of organic compounds can be directly acyloxylated270 by tert-butyl peroxyesters, the most frequently used being acetic and benzoic (R′ = Me or Ph).271 The reaction requires a catalyst (cuprous ion is the actual catalyst, but a trace is all that is necessary, and such traces are usually present in cupric compounds, so that these are often used) and without it is not selective. Susceptible positions are similar to those in Reaction 14-6: benzylic, allylic, and the α position of ethers and sulfides. Terminal alkenes are substituted almost entirely in the 3 position; that is, with only a small amount of allylic rearrangement, but internal alkenes generally give mixtures containing a large amount of allylic-shift product. If the reaction with alkenes is carried out in an excess of another acid (R″CO2H), the ester produced is of that acid ROCOR″. Aldehydes give anhydrides:

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Acyloxylation has also been achieved with metallic acetates (e.g., lead tetraacetate,272 mercuric acetate,273 and palladium(II) acetate).274 In the case of the lead and mercuric acetates, not only does the reaction take place at allylic and benzylic positions and at those α to an OR or SR group, but also at positions α to the carbonyl groups of aldehydes, ketones, or esters and at those α to two carbonyl groups (ZCH2Z′). It is likely that in the latter cases it is the enol forms that react. Ketones can be α-acyloxylated indirectly by treatment of various enol derivatives with metallic acetates (e.g., silyl enol ethers with silver carboxylates-iodine,275 enol thioethers with lead tetraacetate,276 and enamines277 with lead tetraacetate).278 Lead tetraacetate even acyloxylates alkanes, in a slow reaction (10 days–2 weeks), with tertiary and secondary positions greatly favored over primary ones.279 α,β-Unsaturated ketones can be acyloxylated in good yields in the α′ position with manganese triacetate.280 Palladium acetate converts alkenes to vinylic and/or allylic acetates.281 Acyloxylation of certain alkanes has also been reported with palladium(II) acetate.282

Studies of the mechanism of the cuprous-catalyzed reaction show that the most common mechanism is the following283:

Step 1 img

Step 2 img

Step 3 img

This mechanism, involving a free radical R, is compatible with the allylic rearrangements found.284 The fact that tert-butyl peroxyesters labeled with 18O in the carbonyl oxygen gave an ester with 50% of the label in each oxygen285is in accord with coupling of R with intermediate 34, in which the Cu is ionically bound, so that the oxygen atoms are essentially equivalent. Other evidence is that tert-butoxy radicals have been trapped with dienes.286 Much less is known about the mechanisms of the reactions with other metal acetates.287

Free radical acyloxylation of aromatic substrates288 has been accomplished with a number of reagents, including copper(II) acetate,289 silver(II) complexes,290 and cobalt(III) trifluoroacetate.291

OS III, 3; V, 70, 151; VIII, 137.

C. Substitution by Sulfur

14-10 Chlorosulfonation or Chlorosulfo-de-hydrogenation

equation

The chlorosulfonation of organic molecules with chlorine and sulfur dioxide is called the Reed reaction.292 In scope and range of products obtained, the reaction is similar to 14-1. The mechanism is also similar, except that there are two additional main propagation steps:

equation

Chlorosulfenation293 can be accomplished by treatment with SCl2 and UV light:

equation

D. Substitution by Nitrogen

14-11 The Direct Conversion of Aldehydes to Amides

Amination or Amino-de-hydrogenation

equation

Aliphatic and aromatic aldehydes have been converted to the corresponding amides with ammonia or a primary or secondary amine, NBS, and a catalytic amount of AIBN (Sec. 14.A.i).294 In a reaction of more limited scope, amides are obtained from aromatic and α,β-unsaturated aldehydes by treatment with dry ammonia gas and nickel peroxide.295 Best yields (80–90%) are obtained at −25 to −20 °C. In the nickel peroxide reaction, the corresponding alcohols (ArCH2OH) have also been used as substrates.

Oxidative amidation of aldehydes has been done using AgIO3 in the presence of a CuI catalyst.296 Similar oxidative amidation was accomplished using H2O2 and a Pd-catalyst.297 Amides were prepared from aldehydes using NBS with a Cu catalyst.298 Hypervalent iodine with a Fe catalyst has also been used.299 Oxidative amidation of aromatic aldehydes using Oxone and ball milling without solvent gave the corresponding amide.300 Amidation using nucleophilic N-heterocyclic carbenes leads to amidation accompanied by ring opening of proximal epoxides301 or cyclopropane moieties.302 Aromatic aldehydes are converted to the corresponding amide by treatment with LiN(TMS)2 in the presence of LnCl3, and a stoichiometric reaction was reported using (Me3Si)2N]3Ln(í-Cl)Li(THF)3.303

The reaction has been performed with MnO2 and NaCN along with ammonia or an amine at 0 °C in isopropyl alcohol.304 Treatment of an aldehyde with iodine in aq ammonia, followed by oxidation with aq H2O2 generates a primary amide.305 Secondary amines react with aldehydes to give an amide using a Pd306 or a Rh catalyst.307 For an indirect way of converting aldehydes to amides, see Reaction 12-32. Thioamides (RCSNR′2) have been prepared in good yield from thioaldehydes (produced in situ from phosphoranes and sulfur) and secondary amines.308

14-12 Amidation and Amination at an Alkyl Carbon

Acylamino-de-hydrogenation

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When alkanes bearing a tertiary hydrogen are exposed to UV light in acetonitrile containing a heteropolytungstic acid, they are amidated.309 The oxygen in the product comes from the tungstic acid. When the substrate bears two adjacent tertiary hydrogen atoms, alkenes are formed (by loss of two hydrogen atoms), rather than amides (Reaction 19-2). Amidyl radicals can be generated by other means.310

14-13 Substitution by Nitro

Nitro-de-carboxylation

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In a reaction termed a “nitro-Hunsdiecker” (see Reaction 14-30), vinyl carboxylic acids (conjugated acids) are treated with nitric acid and a catalytic amount of AIBN (Sec. 14.A.i). The product is the vinyl nitro compound, generated via decarboxylation of a radical intermediate.311

Aryl halides are converted to aromatic nitro compounds via a Cu catalyzed reaction with nitrite salts (Ar–X → Ar–NO2).312 Ceric ammonium nitrate in acetonitrile also facilitates this reaction.313

Conjugated amides were coupled via the γ-carbon to give good yields of the dimeric diamide, with an excess of samarium(II) iodide, and with modest enantioselectivity using a chiral additive.314

E. Substitution by Carbon

In these reactions, a new carbon–carbon bond is formed, and they may be given the collective title coupling reactions. In each case, an alkyl or aryl radical is generated and then combines with another radical (a termination process) or attacks an aromatic ring or alkene to give the coupling product.315

14-14 Simple Coupling at a Susceptible Position

De-hydrogen-coupling

equation

Alkane and alkyl substrates RH are treated with peroxides, which decompose to give a radical that abstracts a hydrogen from RH to give R, which dimerizes. Dialkyl and diacyl peroxides have been used, as well as Fenton's reagent (Reaction 14-5). This reaction is far from general, although in certain cases respectable yields have been obtained. Among susceptible positions are those at a tertiary carbon,316 as well as those α to a phenyl group (especially if there is also an α-alkyl or α-chloro group),317 an ether group,318 a carbonyl group,319 a cyano group,320 a dialkylamino group,321 or a carboxylic ester group (either the acid or alcohol side).322 Cross-coupling is possible in some cases. When toluene was heated with allyl bromide, in the presence of di-tert-butyl peroxide, 4-phenyl-1-butene was formed quantitatively.323

equation

Alkanes can be dimerized by vapor-phase mercury photosensitization324 in a synthetically useful process. Best results are obtained for coupling at tertiary positions, but compounds lacking tertiary hydrogen atoms (e.g., cyclohexane) also give good yields. Dimerization of n-alkanes gives secondary–secondary coupling in a nearly statistical distribution, with primary positions essentially unaffected. Alcohols and ethers dimerize at the position α to the oxygen [e.g., 2 EtOH → MeCH(OH)CH(OH)Me].

img

When a mixture of compounds is treated, cross-dimerization (to give 35) and homodimerization take place statistically. Even with the limitation on yield implied by the statistical process, cross-dimerization is still useful when one of the reactants is an alkane, because the products are easy to separate, and because of the few other ways to functionalize an alkane. The cross-coupling of an alkane with trioxane is especially valuable, because hydrolysis of the product (Reaction 10-6) gives an aldehyde, thus achieving the conversion RH → RCHO. The mechanism probably involves abstraction of H by the excited Hg atom, and coupling of the resulting radicals.

The reaction has been extended to ketones, carboxylic acids and esters (all of which couple α to the C=O group), and amides (which couple α to the nitrogen) by running it in the presence of H2.325 Under these conditions it is likely that the excited Hg abstracts H from H2, and that the remaining H abstracts H from the substrate. Radicals have also been generated at benzylic positions and shown to couple with epoxides, forming an alcohol.326

OS IV, 367; V, 1026; VII, 482.

14-15 Coupling at a Susceptible Position via Silanes

De-silyl-coupling

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Under electrochemical conditions it is possible to couple two silanes. The reaction of 36 and allyltrimethylsilane, for example, gave the corresponding homoallylic ether.327

14-16 Coupling of Alkynes328

De-hydrogen-coupling

equation

Terminal alkynes can be coupled by heating with stoichiometric amounts of cupric salts in pyridine or a similar base. This reaction, which produces symmetrical diynes in high yields, is called the Eglinton reaction.329 The large-ring annulenes (see Sec. 2.K) were prepared by rearrangement and hydrogenation of cyclic polyynes,330 prepared by the Eglinton reaction with terminal diynes to give 37, a cyclic trimer of 1,5-hexadiyne.331 The corresponding tetramers (C24), pentamers (C30), and hexamers (C36) were also formed. The Eglinton reaction is of wide scope and many functional groups can be present on the alkyne. The oxidation is usually quite specific for triple-bond hydrogen.

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Another common procedure is the use of catalytic amounts of cuprous salts in the presence of ammonia or ammonium chloride (this method is called the Glaser reaction). Atmospheric oxygen or some other oxidizing agent (e.g., permanganate or hydrogen peroxide) is required in the latter procedure. This method is not satisfactory for cyclic coupling. Hydrogen peroxide, potassium permanganate, potassium ferricyanide, iodine, or Cu(II) can be used instead of oxygen as oxidants.332 Isolation of copper acetylide during the reaction can be avoided by doing the reaction in pyridine or cyclohexylamine, in the presence of a catalytic amount of CuCl2.333 If the Glaser reaction is done with a N,N,N,N-tetramethylethylenediamine–CuCl complex, the reaction proceeds in good yield in virtually any organic solvent.334 When molecular oxygen is the oxidant, this modification of the Glaser reaction is known as the Hay reaction.

A variation couples terminal alkynes using CuCl2 in supercritical CO2 (see Sec. 9.D.ii),335 and in ionic liquids.336 Coupling was also achieved using CuCl2 on KF–Al2O3 with microwave irradiation.337 A Co catalyzed Glaser coupling has been reported338 and also a transition metal free coupling.339 A modified Glaser coupling has been reported using KF/Alumina.340 Coupling has been achieved under ambient conditions using cupric acetate.341Copper(II) promoted homocoupling of terminal alkynes has been done in supercritical CO2.342 Another variation is a Ni catalyzed cross-coupling.343 Terminal alkynes give 1,3-diynes upon treatment with Cu–iodine.344

Unsymmetrical diynes can be prepared by Cadiot–Chodkiewicz coupling345:

equation

This may be regarded as a variation of Reaction 10-74, but it must have a different mechanism since acetylenic halides give the reaction but ordinary alkyl halides do not, which is hardly compatible with a nucleophilic mechanism. However, the mechanism is not fully understood. One version of this reaction binds the alkynyl bromide unit to a polymer, and the di-yne is released from the polymer after the solid-state transformation.346 Alkynes have also been coupled using CuI and a Pd catalyst.347 A variation of the Cadiot–Chodkiewicz method consists of treating a haloalkyne (R′C≡CX) with a copper acetylide (RC≡CCu).348 The Cadiot–Chodkiewicz procedure can be adapted to the preparation of diynes in which R′=H by the use of BrC≡CSiEt3 and subsequent cleavage of the SiEt3 group.349 This protecting group can also be used in the Eglinton or Glaser methods.350

The mechanism of the Eglinton and Glaserreactions probably begins with loss of a proton

equation

since there is a base present and acetylenic protons are acidic. It is known, of course, that cuprous ion can form complexes with triple bonds. The last step is probably the coupling of two radicals:

equation

but just how the carbanion becomes oxidized to the radical and what part the cuprous ion plays (other than forming the acetylide salt) are matters of considerable speculation,351 and depend on the oxidizing agent. One proposed mechanism postulated Cu(II) as the oxidant.352 It has been shown that molecular oxygen forms adducts with Cu(I) supported by tertiary amines, which might be the intermediates in the Glaser reaction where molecular oxygen is the oxidant.353 For the Hay reaction, the mechanism involves a Cu(I)/Cu(III)/Cu(II)/Cu(I) catalytic cycle, and the key step for this reaction is the dioxygen activation during complexation of two molecules of acetylide with molecular oxygen, giving a Cu(III) complex.354 This mechanism is supported by isolation and characterization of Cu(III) complexes formed under the conditions of the Glaser coupling.

Sonogashira coupling, which involves aryl halides and terminal alkynes in the presence of a Pd catalyst, has been extended to the coupling of two alkynes.355 Indeed, the Pd catalyzed coupling of two alkynes to form a diyne356 is often referred to as Sonogashira cross-coupling, or Sonogashira-like coupling. An example is the conversion of 38 to 39.357 Here rt = room temperature amd DABCO = 1,4-diazabicyclo[2.2.2]octane.

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Terminal alkynes are not the only reaction partners. 1-Trimethylsilyl alkynes (R–C≡C–SiMe3) give the diyne R–C≡C–C≡C–R) upon reaction with CuCl358 or Cu(OAc)2/Bu4NF.359

Alkynylboronates undergo homocoupling to give symmetrical 1,3-diynes in the presence of a Cu salt.360 The Cu-catalyzed homocoupling of alkynyltrifluoroborates leads to 1,3-diynes.361

In related reactions, alkynyltrifluoroborates react with vinylic tellurides to give 1,3-enynes.362 The Pd catalyzed reaction of vinyl bromides and terminal alkynes gives enynes.363 1,3-Dienes are prepared by the Pd catalyzed homocoupling of alkenyltrifluoroborates.364

OS V, 517; VI, 68, 925; VIII, 63.

14-17 Alkylation and Arylation of Aromatic Compounds by Peroxides

Alkylation or Alkyl-de-hydrogenation

img

This reaction is most often carried out with R = aryl, so the net result is the same as in Reaction 13-27, though the reagent is different.365 It is used less often than Reaction 13-27, but the scope is similar. When R = alkyl, the scope is more limited.366 Only certain aromatic compounds, particularly benzene rings with two or more nitro groups, and fused ring systems, can be alkylated by this procedure. 1,4-Quinones can be alkylated with diacyl peroxides or with lead tetraacetate (methylation occurs with this reagent).

The mechanism is as shown in Section 14.A.iii (CIDNP has been observed367); the radicals are produced by

img

Since no relatively stable free radical is present (e.g., O–N=N–Ar in Reaction 13-27), most of the product arises from dimerization and disproportionation.368 The addition of a small amount of nitrobenzene increases the yield of arylation product because the nitrobenzene is converted to diphenyl nitroxide, which abstracts a hydrogen atom and diminishes the extent of side reactions.369 The Pd catalyzed methylation of aromatic rings in the presence of dicumyl peroxide is another variation.370

equation

Aromatic compounds can also be arylated by aryllead tricarboxylates.371 Best yields (~ 70–85%) are obtained when the substrate contains alkyl groups; an electrophilic mechanism is likely. Phenols are phenylated ortho to the OH group (and enols are a phenylated) by triphenylbismuth dichloride or by certain other Bi(V) reagents.372O-Phenylation is a possible side reaction. As with the aryllead tricarboxylate reactions, a free radical mechanism is unlikely.373

OS V, 51. See also, OS V, 952; VI, 890.

14-18 Photochemical Arylation of Aromatic Compounds

Arylation or Aryl-de-hydrogenation

equation

Another free radical arylation method consists of the photolysis of aryl iodides in an aromatic solvent.374 Yields are generally higher than in Reactions 13-27 or 14-17. The aryl iodide may contain OH or COOH groups. The coupling reaction of iodobenzene and azulene to give a phenylazulene was reported (41% conversion and 85% yield).375 The mechanism is similar to that of Reaction 13-27. The aryl radicals are generated by the photolytic cleavage ArI → AR + I. The reaction has been applied to intramolecular arylation (analogous to the Pschorr reaction).376 A similar reaction is photolysis of an arylthallium bis(trifluoroacetate) (12-23) in an aromatic solvent. Here too, an unsymmetrical biaryl is produced in good yields.377 In this case, it is the C–Tl bond that is cleaved to give aryl radicals.

equation

14-19 Alkylation, Acylation, and Carbalkoxylation of Nitrogen Heterocycles378

Alkylation or Alkyl-de-hydrogenation, and so on

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Alkylation of protonated nitrogen heterocycles (e.g., pyridines, quinolines) can be accomplished by treatment with a carboxylic acid, silver nitrate, sulfuric acid, and ammonium peroxydisulfate.379 The R group can be primary, secondary, or tertiary. The attacking species is R, formed by380

equation

A hydroxymethyl group can be introduced (ArH → ArCH2OH) by several variations of this method.381 Alkylation of these substrates can also be accomplished by generating the alkyl radicals in other ways: from hydroperoxides and FeSO4,382 from alkyl iodides and H2O2–Fe(II),383 from carboxylic acids and lead tetraacetate, or from the photochemically induced decarboxylation of carboxylic acids by iodosobenzene diacetate.384

Protonated nitrogen heterocycles (e.g., quinoxaline, 40) can be acylated by treatment with an aldehyde, tert-butyl hydroperoxide, sulfuric acid, and ferrous sulfate, in this case giving 41.385

img

Photochemical alkylation of protonated quinoline occurred with Ph2Se(O2Cc-C6H11)2.386

Other positively charged heterocycles react as well. When N-fluoropyridinium triflate was treated with the enolate anion of acetone, 2-(2-oxopropyl)pyridine was formed in modest yield.387

These alkylation and acylation reactions are important because Friedel–Crafts alkylation and acylation (Reactions 11-11 and 11-17) cannot be applied to most nitrogen heterocycles (see also, Reaction 13-17).

Protonated nitrogen heterocycles can be carbalkoxylated388 by treatment with esters of α-keto acids and Fenton's reagent. Pyridine is carbalkoxylated at C-2 and C-4, for example. The attack is by COOR radicals generated from the esters via a hydroperoxide (42).

img

Similarly, a carbamoyl group can be introduced389 by the use of the radicals img or img generated from formamide or DMF and H2SO4, H2O2, and FeSO4 or other oxidants.

14.C.ii. N2 as Leaving Group390

In these reactions, diazonium salts are cleaved to aryl radicals,391 in most cases with the assistance of copper salts. Reactions 13-27 and 13-26 may also be regarded as belonging to this category with respect to the attacking compound. For nucleophilic substitutions of diazonium salts (see Reactions 13-2013-23). Removal of nitrogen and replacement with a hydrogen atom is a reduction, found in Chapter 19.

14-20 Replacement of the Diazonium Group by Chlorine or Bromine

Chloro-de-diazoniation, and so on

equation

Treatment of diazonium salts with cuprous chloride or bromide leads to aryl chlorides or bromides, respectively. In either case, the reaction is called the Sandmeyer Reaction.392 The reaction can also be carried out with copper and HBr or HCl, in which case it is called the Gatterman Reaction (not to be confused with 11-18). However, a Cu catalyzed Sandmeyer bromination reaction is known.393 The Sandmeyer reaction is not useful for the preparation of fluorides or iodides, but for bromides and chlorides it is of wide scope and is probably the best way of introducing bromine or chlorine into an aromatic ring. The yields are usually high.

The mechanism is not known with certainty, but is believed to take the following course394:

equation

The first step involves a reduction of the diazonium ion by the cuprous ion, which results in the formation of an aryl radical. In the second step, the aryl radical abstracts halogen from cupric chloride, reducing it. CuX is regenerated and is thus a true catalyst.

Aryl bromides and chlorides can be prepared from primary aromatic amines in one step by several procedures,395 including treatment of the amine (1) with tert-butyl nitrite and anhydrous CuCl2 or CuBr2 at 65 °C,396 and (2) with tert-butyl thionitrite or tert-butyl thionitrate and CuCl2 or CuBr2 at room temperature.397 These procedures are, in effect, a combination of Reaction 13-19 and the Sandmeyer Reaction. A further advantage is that cooling to 0 °C is not needed. A mixture of Me3SiCl and NaNO2 was used to convert aniline to chlorobenzene in a related reaction.398

For the preparation of fluorides and iodides from diazonium salts, see Reactions 13-32 and 13-31.

equation

Note that the reaction of aryl diazonium salts with CuCN to give benzonitrile derivatives is also called the Sandmeyer Reaction. It is usually conducted in neutral solution to avoid liberation of HCN.

OS I, 135, 136, 162, 170; II, 130; III, 185; IV, 160. Also see, OS III, 136; IV, 182. For the reaction with CuCN see OS I, 514.

14-21 Replacement of the Diazonium Group by Nitro

Nitro-de-diazoniation

equation

Nitro compounds can be formed in good yields by treatment of diazonium salts with sodium nitrite in the presence of cuprous ion. The reaction occurs only in neutral or alkaline solution. This is not usually called the Sandmeyer Reaction, although, like Reaction 14-20, it was discovered by Sandmeyer. Tetrafluoroborate (BF4) is often used as the negative ion, since the diminished nucleophilicity avoids competition from the chloride ion. The mechanism is probably like that of Reaction 14-20.399 If electron-withdrawing groups are present, the catalyst is not needed; NaNO2 alone gives nitro compounds in high yields.400

An alternative procedure used electrolysis, in 60% HNO3 to convert 1-aminonaphthalene to naphthalene.401

OS II, 225; III, 341.

14-22 Replacement of the Diazonium Group by Sulfur-Containing Groups

Chlorosulfo-de-diazoniation

equation

Diazonium salts can be converted to sulfonyl chlorides by treatment with sulfur dioxide in the presence of cupric chloride.402 The use of FeSO4 and copper metal instead of CuCl2 gives sulfinic acids (ArSO2H)403 (see also, Reaction 13-21).

OS V, 60; VII, 508.

14-23 Conversion of Diazonium Salts to Aldehydes, Ketones, or Carboxylic Acids

Acyl-de-diazoniation, and so on

img

Diazonium salts react with oximes to give aryl oximes, which are easily hydrolyzed to aldehydes (R = H) or ketones.404 A copper sulfate–sodium sulfite catalyst is essential. In most cases, higher yields (40–60%) are obtained when the reaction is used for aldehydes rather than for ketones. In another method405 for achieving the conversion ArN2+ → ArCOR, diazonium salts are treated with R4Sn and CO with palladium acetate as catalyst.406 In a different kind of reaction, silyl enol ethers of aryl ketones (Ar′C(OSiMe3)=CHR) react with solid diazonium fluoroborates (ArN2+ BF4) to give ketones (ArCHRCOAr′).407 This is, in effect, an arylation of the aryl ketone.

Carboxylic acids can be prepared in moderate-to-high yields by treatment of diazonium fluoroborates with carbon monoxide and palladium acetate408 or copper(II) chloride.409 The mixed anhydride (ArCOOCOMe) is an intermediate that can be isolated. Other mixed anhydrides can be prepared by the use of other salts instead of sodium acetate.410 An arylpalladium compound is probably an intermediate.368

OS V, 139.

14.C.iii. Metals as Leaving Groups

14-24 Coupling of Grignard Reagents

De-metallo-coupling

equation

This organometallic coupling reaction is clearly related to the Wurtz coupling, discussed in Reaction 10-56, and the coupling of other organometallic compounds is discussed in Reaction 14-25. Grignard reagents can be coupled to give symmetrical dimers411 by treatment with either thallium(I) bromide412 or with a transition metal halide (e.g., Fe compounds,413 CrCl2, CrCl3, CoCl2, CoBr2, or CuCl2).414 The metallic halide is an oxidizing agent and becomes reduced. Both aryl and alkyl Grignard reagents can be dimerized by either procedure, though the TlBr method cannot be applied to R = primary alkyl or to aryl groups with ortho substituents. Aryl Grignard reagents can also be dimerized by treatment with 1,4-dichloro-2-butene, 1,4-dichloro-2-butyne, or 2,3-dichloropropene.415 Vinylic and alkynyl Grignard reagents can be coupled (to give 1,3-dienes and 1,3-diynes, respectively) by treatment with thionyl chloride.416 Primary alkyl, vinylic, aryl, and benzylic Grignard reagents give symmetrical dimers in high yield (~90%) when treated with a silver(I) salt in the presence of a nitrogen-containing oxidizing agent (e.g., lithium nitrate, methyl nitrate, or NO2).417 This method has been used to close rings of four, five, and six members.418

The mechanisms of the reactions with metal halides, at least in some cases, probably begin with conversion of RMgX to the corresponding RM (Reaction 12-36), followed by its decomposition to free radicals.419

OS VI, 488.

14-25 Coupling of Other Organometallic Reagents332

De-metallo-coupling

equation

Lithium dialkylcopper reagents can be oxidized to symmetrical dimers by O2 at −78 °C in THF.420 The reaction is successful for R = primary and secondary alkyl, vinylic, or aryl. Other oxidizing agents (e.g., nitrobenzene) can be used instead of O2. Vinylic copper reagents dimerize on treatment with oxygen, or simply on standing at 0 °C for several days or at 25 °C for several hours, to yield 1,3-dienes.421 The finding of retention of configuration for this reaction demonstrates that free radical intermediates are not involved.

The coupling reaction of Grignard reagents was discussed in Reaction 14-24. There are iron-catalyzed cross-coupling reactions.422 Lithium organoaluminates (LiAlR4) are dimerized to R–R by treatment with Cu(OAc)2.423Terminal vinylic alanes (prepared by Reaction 15-17) can be dimerized to 1,3-dienes with CuCl in THF.424 Symmetrical 1,3-dienes can also be prepared in high benzylic bromides to give the coupling product.425 Coupling products are obtained by treatment of vinylic mercury chlorides426 with LiCl and a Rh catalyst427 and by treatment of vinylic tin compounds with a Pd catalyst.428 Vinylic, alkynyl, and aryl tin compounds were dimerized with Cu(NO3)2.429Allylindium reagents were coupled to alkyl- and aryllithium compounds can be dimerized by transition metal halides in a reaction similar to Reaction 14-24.430

Unsymmetrical coupling of vinylic, alkynyl, and arylmercury compounds was achieved in moderate-to-good yields by treatment with alkyl and vinylic dialkylcopper reagents (e.g., PhCH=CHHgCl + Me2CuLi → PhCH=CHMe).431 A radical coupling reaction has been reported, in which an aryl halide reacted with Bu3SnH, AIBN, and benzene, followed by treatment with methyllithium to give the biaryl.432

14-26 Coupling of Boranes

Alkyl-de-dialkylboration

img

Alkylboranes can be coupled by treatment with silver nitrate and base.433 Since alkylboranes are easily prepared from alkenes (Reaction 15-16), this is essentially a way of coupling and reducing alkenes; in fact, alkenes can be hydroborated and coupled in the same flask. For symmetrical coupling (R = R′) yields range from 60 to 80% for terminal alkenes and from 35 to 50% for internal ones. Unsymmetrical coupling has also been carried out,434 but with lower yields. Arylboranes react similarly, yielding biaryls.435 The mechanism is probably of the free radical type.

Dimerization of two vinylborane units to give a conjugated diene can be achieved by treatment of divinylchloroboranes (prepared by addition of BH2Cl to alkynes; see Reaction 15-16) with methylcopper. (E,E)-1,3-Dienes are prepared in high yields.436

img

In a similar reaction, symmetrical conjugated diynes RC≡C–C≡CR can be prepared by reaction of lithium dialkyldialkynylborates, Li+ [R′2B(C≡CR)2], with iodine.437

14.C.iv. Halogen as Leaving Group

The conversion of RX to RH can occur by a free radical mechanism, but is treated at Reaction 19-53.

14.C.v. Sulfur as Leaving Group

14-27 Desulfurization

Hydro-de-thio-substitution, and so on

equation

Thiols and thioethers,438 both alkyl and aryl, can be desulfurized by hydrogenolysis with Raney nickel.439 The hydrogen is usually not applied externally, since Raney nickel already contains enough hydrogen for the reaction. Other sulfur compounds can be similarly desulfurized, among them disulfides (RSSR), thiono esters (RCSOR′),440 thioamides (RCDNHR′), sulfoxides, and dithioacetals. The last reaction, which is an indirect way of accomplishing reduction of a carbonyl to a methylene group (see Reaction 19-61), can also give the alkene if a hydrogen atom is present.441 In most of the examples given, R can also be aryl. Other reagents442 have also been used,443 including Sm in acetic acid for desulfurization of vinyl sulfones.444

An important special case of RSR reduction is desulfurization of thiophene derivatives. This proceeds with concomitant reduction of the double bonds. Many compounds have been made by alkylation of thiophene (see 39), followed by reduction to the corresponding alkane.

img

Thiophenes can also be desulfurized to alkenes (RCH2CH=CHCH2R′ from 43) with a nickel boride catalyst prepared from nickel(II) chloride and NaBH4 in methanol.445 It is possible to reduce just one SR group of a dithioacetal by treatment with borane–pyridine in trifluoroacetic acid or in CH2Cl2 in the presence of AlCl3.446 Phenyl selenides (RSePh) can be reduced to RH with Ph3SnH447 and with nickel boride.448

The exact mechanisms of the Raney nickel reactions are still in doubt, though they are probably of the free radical type.449 It has been shown that reduction of thiophene proceeds through butadiene and butene, not through 1-butanethiol or other sulfur compounds; that is, the sulfur is removed before the double bonds are reduced. This was demonstrated by isolation of the olefins and the failure to isolate any potential sulfur-containing intermediates.450

See Chapter 19 for other reduction reactions involving sulfur compounds.

OS IV, 638; V, 419; VI, 109, 581, 601. See also, OS VII, 124, 476.

14-28 Conversion of Sulfides to Organolithium Compounds

Lithio-de-phenylthio-substitution

equation

Sulfides can be cleaved, with a phenylthio group replaced by a lithium,451 by treatment with Li or lithium naphthalenide in THF.452 Good yields have been obtained with R = primary, secondary, or tertiary alkyl, or allylic,453 and containing groups, such as double bonds or halogens. Dilithio compounds can be made from compounds containing two separated SPh groups, but it is also possible to replace just one SPh from a compound with two such groups on a single carbon, to give an α-lithio sulfide.454 The reaction has also been used to prepare α-lithio ethers and α-lithio organosilanes.451 For some of these compounds, lithium 1-(dimethylamino)naphthalenide is a better reagent than either Li or lithium naphthalenide.455 The mechanism is presumably of the free radical type.

14.C.vi. Carbon as Leaving Group

14-29 Decarboxylative Dimerization: The Kolbe Reaction

De-carboxylic-coupling

equation

Electrolysis of carboxylate ions, results in decarboxylation and combination of the resulting radicals to give the coupling product R–R. This coupling reaction is called the Kolbe Reaction or the Kolbe electrosynthesis.456 It is used to prepare symmetrical R–R, where R is straight chained, since little or no yield is obtained when there is a branching. The reaction is not successful for R = aryl. Many functional groups may be present, though many others inhibit the reaction.456 Unsymmetrical R–R′ have been made by coupling mixtures of acid salts. The Kolbe reaction has been done using solid-supported bases.457

A free radical mechanism is involved

equation

There is much evidence458 for this mechanism, including side products (RH, alkenes) characteristic of free radical intermediates and the fact that electrolysis of acetate ion in the presence of styrene caused some of the styrene to polymerize to polystyrene (such polymerizations can be initiated by free radicals, see Sec. 15.B.i). Other side products (ROH, RCO2R) are sometimes found, stemming from further oxidation of the radical R to a carbocation R+.459

When the reaction is conducted in the presence of 1,3-dienes, additive dimerization can occur:460

equation

The radical R adds to the conjugated system to give RCH2CH=CHCH2, which dimerizes. Another possible product is RCH2CH=CHCH2R, from coupling of the two kinds of radicals.461

In a nonelectrolytic reaction, which is limited to R = primary alkyl, the thiohydroxamic esters (44) give dimers when irradiated at −64 °C in an Ar atmosphere:462

img

In another nonelectrolytic process, aryl acetic acids are converted to vic-diaryl compounds (2ArCR2COOH → ArCR2CR2Ar) by treatment with sodium persulfate (Na2S2O8) and a catalytic amount of AgNO3.463 Photolysis of carboxylic acids in the presence of Hg2F2 leads to the dimeric alkane via decarboxylation.464 Both of these reactions involve dimerization of free radicals. In still another process, electron-deficient aromatic acyl chlorides are dimerized to biaryls (Ar–Ar) by treatment with a disilane R3SiSiR3 and a Pd catalyst.465

OS III, 401; V, 445, 463; VII, 181.

14-30 The Hunsdiecker Reaction

Bromo-de-carboxylation

equation

Reaction of a silver salt of a carboxylic acid with bromine is called the Hunsdiecker reaction466 and is a method of decreasing the length of a carbon chain by one unit.467 The reaction is of wide scope, giving good results for n-alkyl R from 2 to 18 carbons and for many branched R too, producing primary, secondary, and tertiary bromides. Many functional groups may be present as long as they are not a substituted. The R group may also be aryl. However, if R contains unsaturation, the reaction seldom gives good results. Although bromine is the most often used halogen, chlorine, and iodine have also been used. Catalytic Hunsdiecker reactions are known,468 and microwave enhancement has been employed.469

When iodine is the reagent, the ratio between the reactants is very important and determines the products. A 1:1 ratio of salt/iodine gives the alkyl halide, as above. A 2:1 ratio, however, gives the ester RCOOR. This is called the Simonini Reaction and is sometimes used to prepare carboxylic esters. The Simonini reaction can also be carried out with lead salts of acids.470 A more convenient way to perform the Hunsdiecker Reaction is by use of a mixture of the acid and mercuric oxide instead of the salt, since the silver salt must be very pure and dry and such pure silver salts are often not easy to prepare.471

Other methods for accomplishing the conversion RCOOH → RX are472 (1) treatment of thallium(I) carboxylates with bromine;473 (2) treatment of carboxylic acids with lead tetraacetate and halide ions (Cl-, Br-, or I-);474 (3) reaction of the acids with lead tetraacetate and NCS, which gives tertiary and secondary chlorides in good yields, but is not good for R = primary alkyl or phenyl;475 (4) treatment of thiohydroxamic esters with CCl4, BrCCl3 (which gives bromination), CHI3, or CH2I2 in the presence of a radical initiator;476 (5) photolysis of benzophenone oxime esters of carboxylic acids in CCl4 (RCON=CPh2 → RCl).477 Alkyl fluorides can be prepared in moderate-to-good yields by treating carboxylic acids (RCOOH) with XeF2.478 This method works best for R = primary and tertiary alkyl, and benzylic. Aromatic and vinylic acids do not react.

The mechanism of the Hunsdiecker reaction is believed to be as follows:

equation

The first step is not a free radical process, and its actual mechanism is not known.479 Compound 45 is an acyl hypohalite and is presumed to be an intermediate, though it has never been isolated from the reaction mixture. Among the evidence for the mechanism is that optical activity at R is lost (except when a neighboring bromine atom is present, see Sec. 14.A.iv); if R is neopentyl, there is no rearrangement, which would certainly happen with a carbocation; and the side products, notably R-R, are consistent with a free radical mechanism. There is evidence that the Simonini reaction involves the same mechanism as the Hunsdiecker reaction, but that the alkyl halide formed then reacts with excess RCOOAg (Reaction 10-17) to give the ester480 (see also, Reaction 19-12).

Vinyl carboxylic acids (conjugated acids) were shown to react with NBS and lithium acetate in aq acetonitrile, to give the corresponding vinyl bromide (C=C–CO2H → C=C–Br), using microwave irradiation.481 A similar reaction was reported using Na2MoO4, KBr and aq H2O2.482

A related reaction reacts the sodium salt of an alkylsulfonic acid with thionyl chloride at 100 °C, to give the alkyl chloride.483

OS III, 578; V, 126; VI, 179; 75, 124; X, 237. See also, OS VI, 403.

14-31 Decarboxylative Allylation

Allyl-de-carboxylation

img

The COOH group of a β-keto acid is replaced by an allylic group when the acid is treated with an allylic acetate and a Pd catalyst at room temperature.484 The reaction is successful for various substituted allylic groups. The less highly substituted end of the allylic group forms the new bond. Thus, both CH2=CHCHMeOAc and MeCH=CHCH2OAc gave O=C(R)-C-CH2CH–CHMe as the product.

14-32 Decarbonylation of Aldehydes and Acyl Halides

Carbonyl-extrusion

equation

Aldehydes, both aliphatic and aromatic, can be decarbonylated485 by heating with a Rh catalyst486 or other catalysts (e.g., Pd).487 The compound RhCl(Ph3P)3 is often called Wilkinson's catalyst.488 In an older reaction aliphatic (but not aromatic) aldehydes are decarbonylated by heating with di-tert-butyl peroxide or other peroxides,489 usually in a solution containing a hydrogen donor, such as a thiol. The reaction has also been initiated with light, and thermally (without an initiator) by heating at ~500 °C.

Wilkinson's catalyst has also been reported to decarbonylate aromatic acyl halides at 180 °C (ArCOX → ArX).490 This reaction has been carried out with acyl iodides,491 bromides, and chlorides. Aliphatic acyl halides that lack a hydrogen also give this reaction,492 but if an α hydrogen is present, elimination takes place instead (Reaction 17-17). Aromatic acyl cyanides give aryl cyanides (ArCOCN → ArCN).493 Aromatic acyl chlorides and cyanides can also be decarbonylated with Pd catalysts.494

It is possible to decarbonylate acyl halides in another way, to give alkanes (RCOCl → RH). This is done by heating the substrate with tripropylsilane (Pr3SiH) in the presence of tert-butyl peroxide.495 Yields are good for R = primary or secondary alkyl and poor for R = tertiary alkyl or benzylic. There is no reaction when R = aryl. (See also, the decarbonylation ArCOCl → Ar–Ar mentioned in Reaction 14-29.)

The mechanism of the peroxide- or light-induced reaction seems to be as follows (in the presence of thiols).496

img

The reaction of aldehydes with Wilkinson's catalyst goes through complexes of the form 46 and 47, which have been trapped.497 The reaction has been shown to give retention of configuration at a chiral R;498 and deuterium labeling demonstrates that the reaction is intramolecular: RCOD give RD.499 Free radicals are not involved.500 The mechanism with acyl halides appears to be more complicated.501

img

For aldehyde decarbonylation by an electrophilic mechanism, see Reaction 11-34.

Notes

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