Phenoxides, alkylation with

Ethers can be prepared by reaction of an alkoxide or phenoxide ion with a primary alkyl halide. Anisole, for instance, results from reaction of sodium phenoxide with iodomethane. What kind of reaction is occurring Show the mechanism. 

Unlike the acid-catalyzed ether cleavage reaction discussed in the previous section, which is general to all ethers, the Claisen rearrangement is specific to allyl aryl ethers, Ar—O—CH2CH = CH2. Treatment of a phenoxide ion with 3-bromopropene (allyl bromide) results in a Williamson ether synthesis and formation of an allyl aryl ether. Heating the allyl aryl ether to 200 to 250 °C then effects Claisen rearrangement, leading to an o-allylphenol. The net result is alkylation of the phenol in an ortho position. 

The solvent can also affect regioselectivity. Consider O- vs C-alkylation of phenoxide ion with allyl chloride or bromide. In water, with allyl chloride the O- to C-alkylation ratio is 49 41 with phenol as a solvent it is 22 78 with methanol, dimethylformamide, and dioxane 100% O-alkylation is achieved. The selective solvation of the more electronegative O by the more protic solvents perhaps leads to some C-alkylations. 

Although there have been few new developments in the period since 1993, halogenopyrazines 42 have been convenient precursors for a variety of pyrazine derivatives. For example, the halogenopyrazines 42 are cyanated by palladium-catalyzed cross-coupling with alkali cyanide or by treatment with copper cyanide in refluxing picoline, to yield cyanopyrazines 48. Alkoxypyrazines 49 are produced by treatment with alkoxide-alcohol, and aminopyrazines 50 are prepared by amination with ammonia or appropriate amines. The nucleophilic substitution of chloropyrazine with sodium alkoxide, phenoxide, alkyl- or arylthiolate is efficiently effected under focused microwave irradiation <2002T887>. 

A slow non-competing liquid/liquid reaction with no catalyst present gave only 78 % O-alkylation. Thus the active site of the lipophilic phosphonium ion catalysts appears to be aprotic, just as in analogous phase transfer catalyzed alkylations with soluble quaternary ammonium salts 60), Regen 78) argued that the onium ion sites of both the 17% and the 52% RS tri-n-butylphosphonium ion catalysts 1 are hydrated, on the basis of measurements of water contents of the resins in chloride form. Mon-tanari has reported measurements that showed only 3.0-3.8 mols of water per chloride ion in similar 25 % RS catalysts 74). He argued that such small hydration levels do not constitute an aqueous environment for the displacement reactions. No measurements of the water content of catalysts containing phenoxide or 2-naphthoxide ions have been reported. 

Phenols can be converted into esters by reaction with acid chlorides or acid anhydrides and into ethers by reaction with alkyl halides in the presence of base (Following fig.). These reactions can be done under milder conditions than those used for alcohols due to the greater acidity of phenols. Thus phenols can be converted to phenoxide ions with sodium hydroxide rather than metallic sodium. 

Although not studied in detail, the mechanism of phenol alkylation with methanol can be formulated on similar grounds by assuming that the initial interaction of phenol and methanol with MgO gives surface phenoxide and methoxide ions and OH groups [these species are known to be formed separately on MgO (263)]. This initial reaction is then followed by elimination of H20 and formation of trialkyl phenol. 

In opposition to the preceding case, the reaction of phenoxides anions with 1-chloroalkyl-N-monoalkyl carbamates leads to acylation instead of alkylation as shown in scheme 137. 

The reaction of phenols with nitrous acid gives the ortho- and para-nitroso products, which are formed through a neutral dienone intermediate, the proton loss from the latter being the rate-limiting step" " . It has been shown that the nitrous acid can act as a catalyst for the formation of the nitro derivatives. Thus the conventional preparation of nitro compounds by the oxidation of nitroso compounds may be replaced by methods using an electron-transfer pathway in certain cases. In the latter method, the phenoxide reacts with nitrosonium ion to give the phenoxy radical and nitric oxide radical. The nitric oxide radical is in equilibrium with the nitronium radical by reaction with nitronium ion. The reaction of the phenoxy radical with the nitroninm radical resnlts in the formation of the ortho- and para-mixo prodncts" . Leis and coworkers carried ont kinetic stndies on the reaction of phenolate ions with alkyl nitrites and fonnd that the initially formed product is the 0-nitrite ester, which evolves by a complex mechanism to give the ortho-and the para-nitro products". ... 

In general, allyl ethers are less reactive than esters and therefore rarely used as substrates in the palladium-assisted alkylation with soft nucleophiles. Phenyl a- or )5-D-eor//jro-hex-2-enopyra-nosides react with a variety of soft carbanions under neutral conditions to give the a- or t -C -g]ycopyranosides, respectively in good to excellent yields both stereoselectively and with complete regioselectivity88. Since the liberated phenoxide ion deprotonates the active methylene compounds, no external base has to be added. 

Phenoxide ion is about 6 pK units less basic than ethoxide. Unlike ethoxide, phenoxide reacts with secondary alkyl halides by substitution, not elimination. 

The study of phenol alkylation has a long history. Claisen and co-workers (178) showed that metal phenoxides react with active alkyl halides (e.g., allyl and benzyl bromides) in nonpolar solvents to give o-alkylphenols. Cyclohexa-dienones may be prepared in this way starting from 2,6-disubstituted phenols... 

In 1974, McKillop and co-workers reported the formation of diphenox3nnethane derivatives from the attempted alkylation of p-Jt-butylphenol with benzyl chloride and a catalytic amount of a phase transfer catalyst (PTC) in methylene chloride. More recently, Dehmlow and Schmidt reported the synthesis of a series of dlalkyl and diaryl formals ( from the reaction of alkoxide and phenoxide anions with methylene chloride in the presence of a phase transfer catalyst (equation 5). For example, reaction of 2,3,5-trimethylphenol, powdered potassium hydroxide... 

It is interesting to note that the very widely used Makosza catalyst , benzyl triethyl ammonium chloride, does not show high efficiency in this study. 4) Phosphonium ions are somewhat more effective and thermally stable than the corresponding ammonium catalysts and both are better than arsonium systems. 5) Substitution of the quaternary ion by alkyl rather than aryl groups yields more effective catalysts. 6) Reaction rates are generally greater in orf/io-dichlorobenzene (and presumably in other chlorocarbon media) than in benzene, and botli are better than heptane. In connection with this latter point, Ugelstad and coworkers have studied the reactions of quaternary ammonium phenoxide ions with alkyl halides in a variety of media and concluded that the... 

The phase transfer method has also been used in the preparation of a variety of phenolic ethers [5]. It is interesting that alkylation of phenoxide anions generally yield products of both C and 0-alkylation with one favored to a greater or lesser extent depending on solvent. Sodium 2-naphthoxide, for example, exclusively C-benzylates in such hydrogen bonding solvents as ethanol [6], whereas 0-alkylation is favored in tetrahydrofuran. As the size of the cation associated with 2-naphthoxide is increased (for example from Li" to R4N ), 0-alkylation tends to be favored. Consistent with these observations is the report that 2-naphthol 0-alkylates under phase transfer conditions [5]. The successful 0-alkylation of the isomeric nitrophenols and salicyl-aldehyde are also noteworthy. These observations are consistent with the view that... 

It seems likely that dichloromethane could be used in this procedure instead of dibromomethane because after the first chlorine has been substituted, the second substitution should be extremely fast. Cyclization to form a five-membered ring is a favorable process and the alkylating reagent at this stage will be an alkoxymethyl halide. Substitution of the first chlorine in dichloromethane is not improbable, especially in light of the known reaction of both alkoxide and phenoxide anions with it under phase transfer conditions to yield symmetrical dialkyl or diaryl acetals of form-... 

These polyethers are prepared in a similar way as that des- cribed for the synthesis of phenol ethers 5 and polyhydroxyethers using PTC conditions. Polycondensation takes place via alkylation of phenoxide ions with chloromethyl groups in the organic phase. A phase transfer catalyst is necessary for the transportation of the bisphenolate ion to the toluene phase in a highly reactive form. 

Montanari and Tundo found 95-98% 0-alkylation of sodium phenoxide in dichloromethane/water using phosphonium catalysts bound to polystyrene but only 74% 0-alkylation with a similar phos-... 

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