Friedel-Crafts alkylation of phenols

The product is a substituted phenol, whose -OH group directs the orientation of the -C(CH3)3 groups. The precursor to MON-0585 is synthesized by a Friedel-Crafts alkylation of phenol by the appropriate hydrocarbon halide. This compound is synthesized by NBS bromination of the product of alkylation of benzene with 2-chloropropane. 

Alkylphenols can be prepared by Friedel>Crafts alkylation of phenols, but the yields are often poor. 

The Friedel-Crafts alkylation of phenol and p-cresol with tert-butanol, isopropanol and n-propanol was investigated [50, 51] (Scheme 14.6). At 275 °C, concentrations of H3O+ and OH reached a maximum, this is therefore the temperature applied for this acid-catalyzed reactions. The fastest alkylation of phenol was the reaction of tert-butanol with phenol. After a short reaction time, up to 17 % 2-tert-butyl-phenol was found. This yield decreases to the equihbrium value of aroimd 10 % (yields relative to initial phenol content). The yield of 4-tert-butylphenol reaches 20 % and the residual phenol content was around 70 % after attaining equilibrium. 

Alkylphenol ethoxylates are important kinds of nonionic surfactants. A characteristic feature of the catalytic ethoxylation of alkylphenols is the enhanced reactivity of phenol hydroxyl for ethylene oxide in comparison with alcohols. Esters of ethylene glycol and alkylphenol behave already as an alcohol. Therefore di-, tri-, and m-mers are allowed to form only after the complete consumption of the starting material. All commercial ethoxylated alkylphenols are mixtures of oligomer-homologues having a Poisson-like distribution with some PEG and catalyst as impurities. Both alkylphenols and dialkylphenols are useful for ethoxylation as a hydrophobic moiety. Among the alkylphenols, isooctylphenol and isononylphenol are most widely used. They are synthesized by the Friedel-Crafts alkylation of phenol with butene dimer and mixture of propene trimers, respectively. 

A range of PILs was trialed in the Friedel—Craft alkylation of phenol with tert-butyl alcohol to produce tert-butyl alcohol as mentioned in section 6.1. These included a series of pyridinium PILs specifically designed for use as acid catalysts by Duan et al. and SO3H functionalized Bronsted acidic AILs. " It was shown successfully from the pyridinium PILs that a range of PILs could be easily produced that modified the acidities, catalytic activities, and, hence, selectivities and conversions for this reaction type, with the best performance by 2-methylpyridinium, with a conversion of 95%, and a selectivity toward 2,4-di- r butylphenol of 82%. In general, the SO3H functionalized AILs led to comparable selectivities and conversions for this reaction as the PILs. " Some nonstoichiometric salts containing pyridinium cations with HF anions have been used successfully as the catalyst and reaction media for the isobutane—olefin alkylation reactions. 

Scheme 8.40. A representation of the Friedel-Crafts alkylation of phenol by chloromethane (CH3CI) in nitrobenzene solvent in the presence of aluminum trichloride (AlClj).

SCHEME 5.14 Asymmetric oiganocatalyzed aza-Friedel-Crafts alkylations of phenols, naphthols, and sesamols. 

Tris(nonylphenyl)phosphate (TNPP) is a common commercial phosphite. Note that this is not n-nonyl, hut rather a mixture of branched C9 isomers. Nonylphenol is commercially synthesized through Friedel-Crafts alkylation of phenol with nonene. Technical nonene ( propylene trimer ) is a mixture of predominantly C9-olefins with varying degrees of branching. The resulting nonylphenol is mainly a mixture of 4-substituted monoalkylphenols with various isomeric, branched nonyl groups [13]. Tris(2,4-di-t-butylphenyl)phosphite is another commonly used phosphite. 

Cumene. Cumene (qv) is produced by Friedel-Crafts alkylation of benzene by propylene (103,104). The main appHcation of cumene is the production of phenol (qv) and by-product acetone (qv). Minor amounts are used in gasoline blending (105). 

For example /-butyl phenyl ether with aluminium chloride forms para-t-butyl phenol155. Often the de-alkylated phenol is also formed in considerable quantity. The reaction formally resembles the Fries and Claisen rearrangements. Like the Fries rearrangement the question of inter- or intramolecularity has not been settled, although may experiments based on cross-over studies156, the use of optically active ethers157 and comparison with product distribution from Friedel-Crafts alkylation of phenols158 have been carried out with this purpose in view. 

Cumene (isopropylbenzene) is made by Friedel-Crafts alkylation of benzene with propylene. Although cumene is a high-octane automotive fuel, almost all of the cumene produced is used to make phenol (C6H5OH) and acetone [(CH3)2CO]. Cumene is easily oxidized to the corresponding hydroperoxide, which is readily cleaved in dilute acid, to yield phenol and acetone. 

Cumene capacity topped 9.5 million metric tons in 1998 and is projected to reach 10.4 million metric tons by the end of 2003 (19). Like ethylbenzene, cumene is used almost exclusively as a chemical intermediate. Its primary use is in the coproduction of phenol and acetone through cumene peroxidation. Phenolic resins and bisphenol A are the main end uses for phenol. Bisphenol A, which is produced from phenol and acetone, has been the main driver behind increased phenol demand. Its end use applications are in polycarbonate and epoxy resins. The growth rate of cumene is closely related to that of phenol and is expected to be approximately 5.1% per year worldwide over the next five years. Process technologies for both chemicals have been moving away from conventional aluminum chloride and phosphoric acid catalyzed Friedel-Crafts alkylation of benzene, toward zeolite-based processes. 

Protection of phenols by the foregoing methods is complicated by the rapid Friedel-Crafts rearrangement of the nascent rm-butyl ether. By using trifluoro-methanesulfonic add at -78 PC, the rate of /erf-butyl ether formation is fast and the Friedel-Crafts alkylation does not compete [Scheme 4.126].226 Similarly, attempts to deprotect phenol ferf-butyl ethers with trifluoroacetic acid or titanium tetrachloride may give complex mixtures, again as a result of Friedel-Crafts alkylation of the phenol but this side reaction can be suppressed by using a catalytic amount of trifluoromethanesulfonic acid in 2.2,2-trifluoroethanol as solvent at -5 DC. 

We see here a situation exactly analogous to one we have encountered several times before in 1,2- and 1,4-addition to conjugated dienes (Sec. 8.22), in Friedel-Crafts alkylation of toluene (Sec. 12.11), and in sulfonation of phenols (Problem 24.13, p. 803). At low temperatures the controlling factor is rate of reaction, at high temperatures, position of equilibrium,... 

Isopropylation of toluene by isopropyl halo- and alkyl-sulfonates (equation 54) has been performed by Olah et al. A variety of cattdysts, such as AlCb, AlCb-MeNOa and Nafion-H were employed, and the isomer distribution (o, m, p) in the product was determined. Sartori et al have recently reported an unusual Friedel-Crafts alkylation of lithium phenolates with ethyl pyruvate in the presence of AlCb to afford a-(2-hydroxyphenyl)ethyl lactates (22), which are the precursors of 3-methyl-2,3-dihydrobenzo-furan-3-ols (23 Scheme 6). 

Friedel-Crafts alkylation of dicyclopentadiene with phenol nsing boron triflnoride-etherate as the catalyst gives 2-[4-(2-hydroxyphenyl)tricyclo[5.2.1.0(2, 6)]dec-8-yl]phenol, which can be used in the preparation of the phenol-formaldehyde resins (eqnation 3f. 

Whereas the Friedel-Crafts alkylations require only catalytic quantities of the Lewis acidic AICI3 catalyst, Friedel-Crafts acylations of phenols require excess Lewis acids, due to the complex formation of the Lewis acids with the hydroxyl group . Boron trifluoride-phosphoryl chloride, in stoichiometric amounts, is used for the Fridel-Crafts reaction of phenol with /3,/S-dimethylacrylic acid to give the acrylophenone. ... 

Very recently, the enantioselective Friedel-Crafts alkylation of the simple phenols 157 with trifluoropyruvate was also accomplished by using the bifunctional quinidine... 

The process is based upon three different reactions (i) Friedel-Crafts alkylation of benzene with propene to afford cumene (isopropylbenzene) (ii) cumene oxidation with oxygen to give cumyl hydroperoxide and (iii) cleavage of cumyl hydroperoxide in acidic medium to afford phenol and acetone (Equation 13.2) ... 

Introduction. Hiils has produced cumene since 1954 at its site in Marl. The current production capacity is 150 000 t/a. Cumene is used mainly in the production of acetone and phenol, and also in the production of cumene sulfonate, which is a raw material for detergents. It is produced by Friedel-Crafts alkylation of benzene by propene, catalyzed by aluminum chloride, which does not give cumene exclusively, but also produces di- and tiisopropylbenzene. 

Friedel-Crafts alkylations of arenes with mesylates, benzyl or allyl alcohols, aldehyde/diol combinations (reductive alkylation), 1,3-dienes, or alkenes in an ionic liquid are also effectively catalyzed by Sc(OTf)3. Sc(OTf)3 works as an efficient catalyst for the condensation reaction of trimethylhydroquinone with isophytol to afford a-tocopherol. 2-Aminoalkylation of phenols with a-iminoacetates (or glyoxylate/amine) is catalyzed by Sc(OTf)3 to produce amino acid derivatives. The Sc(OTf)3-catalyzed alkylations of indoles with a-hydroxy esters, aziri-dines, acetals, and aldehydes have been utilized as key steps of total syntheses as exemplified in eq 15. ... 

An additional difficulty in the Blanc reaction is the tendency for activated aromatic rings to undergo polychloromethylation under the typically harsh reaction conditions. For example, in the chloromethylation of benzene, the product benzylchloride (4) is often accompanied by small amounts of / -xylylene dichloride 10, as well as a small amoxmt of diphenylmethane, the product resulting from Friedel-Crafts alkylation of benzene with benzylchloride (4). With more activated ring systems, such as phenols, the reaction is increasingly difficult to control, resulting often in the formation of polymeric materials. ... 

Friedel-Crafts alkylation of benzene, toluene, or phenol gives a variety of diaryl products (245) ... 

As already noted in Scheme 8.24, substitution of hydrogen by an alkyl group can also be effected. Generally, such Friedel-Crafts alkylations with phenols require catalysis by Lewis acids just as they did with unsubstituted and alkyl-substituted arenes (Chapter 6). Despite the fact that the nonbonded electrons on the hydroxyl... 

Phenol production is typically carried out by add induced conversion of cumene hydroperoxide to phenol and acetone (Hock process). Cumene hydroperoxide is obtained by oxidation of cumene. The cumene feedstock for the latter reaction is provided by Friedel-Crafts alkylation of benzene with propene. Alternative routes (chlorobenzene hydrolysis, cydohexanol dehydrogenation, oxidative decarboxylation of benzoic acid) exist but are of much lower industrial relevance. 

Lewis acids supported on graphite as well as the perfluorinated resin sulfonic acids (Nafion-H) have been studied for their abilities to perform Friedel-Crafts alkylation of benzene and transalkylation of alkylbenzenes (Olah et aL, 1977). The graphite-supported materials were less stable than the perfluorinated resin sulfonic acid. Subsequent studies investigated the use of this latter resin in the methylation of phenols, benzene, and alkylbenzenes (Kaspi and Olah, 1978 Kaspi et aL, 1978), the nitration of aromatics (Olah et aL, 1978a), the rearrangement of allyl alcohols to aldehydes (Olah et al., 1978b), the pinacolone rearrangement (Olah and Meidar, 1978) and isomerizations of alkylbenzenes (Olah and Kaspi, 1978). 

From Cumene Hydroperoxide. This process illustrates industrial chemistry at its best. Overall, it is a method for converting two relatively inexpensive organic compounds— benzene and propene—into two more valuable ones—phenol and acetone. The only other substance consumed in the process is oxygen from air. Most of the worldwide production of phenol is now based on this method. The synthesis begins with the Friedel-Crafts alkylation of benzene with propene to produce cumene (isopropylbenzene) ... 

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