Phenols Friedel-Crafts alkylation

Other typical electrophilic aromatic substitution reactions—nitration (second entry) sul fonation (fourth entry) and Friedel-Crafts alkylation and acylation (fifth and sixth entnes)—take place readily and are synthetically useful Phenols also undergo elec trophilic substitution reactions that are limited to only the most active aromatic com pounds these include mtrosation (third entry) and coupling with diazomum salts (sev enth entry)... 

All lation of Phenols. The approach used to synthesize commercially available alkylphenols is Friedel-Crafts alkylation. The specific procedure typically uses an alkene as the alkylating agent and an acid catalyst, generally a sulfonic acid. Alkene and catalyst interact to form a carbocation and counter ion (5) which interacts with phenol to form a 7T complex (6). This complex is held together by the overlap of the filled TT-orbital of the aromatic... 

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). 

Friedel-Crafts alkylation Alcohols in combination with acids serve as sources of carbocations. Attack of a carbocation on the electron-rich ring of a phenol brings about its alkylation. 

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. 

A similar problem of complex formation may be encountered if either amino or phenol groups are present in the substrate, and the reaction may fail. Under such circumstances, these groups need to be blocked (protected) by making a suitable derivative. Nevertheless, Friedel-Crafts acylations tend to work very well and with good yields, uncomplicated by multiple acylations, since the acyl group introduced deactivates the ring towards further electrophilic substitution. This contrasts with Friedel-Crafts alkylations, where the alkyl substituents introduced activate the ring towards further substitution (see Section 8.4.3). 

Cumene is an important intermediate in the manufacture of phenol and acetone. The feed materials are benzene and propylene. This is a Friedel-Crafts alkylation reaction catalyzed by solid phosphoric acid at 175-225 °C and 400-600 psi. The yield is 97% based on benzene and 92% on propylene. Excess benzene stops the reaction at the monoalkylated stage and prevents the polymerization of propylene. The benzene propylene ratio is 8-10 1. 

Alkylation. Friedel-Crafts alkylation (qv) of benzene with ethylene or propylene to produce ethylbenzene [100-41 -4], CgH10, or isopropylbenzene [98-82-8], C9H12 (cumene) is readily accomplished in the liquid or vapor phase with various catalysts such as BF3 (22), aluminum chloride, or supported polyphosphoric acid. The oldest method of alkylation employs the liquid-phase reaction of benzene with anhydrous aluminum chloride and ethylene (23). Ethylbenzene is produced commercially almost entirely for styrene manufacture. Cumene [98-82-8] is catalytically oxidized to cumene hydroperoxide, which is used to manufacture phenol and acetone. Benzene is also alkylated with C1Q—C20 linear alkenes to produce linear alkyl aromatics. Sulfonation of these compounds produces linear alkane sulfonates (LAS) which are used as biodegradable deteigents. 

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. 

Phenols are such good nucleophiles that protonated carbonyl compounds functionalize two phenol molecules. The first phenol molecule reacts in an Ar-SE reaction by the carboxonium ion formed in an equilibrium reaction. Subsequently, the second equivalent of phenol becomes the substrate of a Friedel-Crafts alkylation. The electrophile is the benzyl cation that is formed from the initially obtained benzyl alcohol and the acid. Protonated acetone is only a weak electrophile for electronic and steric reasons it contains two electron-donating and relatively large... 

Bakelite, the first synthetic polymer, is an example of a thermoset polymer. It is prepared by the polymerization of phenol and formaldehyde in the presence of ail acid. Carbocations produced by protonation of formaldehyde bond to the ortho and para positions of the highly reactive phenol molecules in a Friedel-Crafts alkylation reaction. The benzylic alcohols that are produced in this step react to produce carbocations that then alkylate additional phenol molecules. A mechanism for the first few steps of this polymerization process is shown in Figure 24.4. 

O The electrophilic carbon of a protonated formaldehyde molecule adds to phenol in a Friedel-Crafts alkylation reaction. The hydroxy... 

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. 

The synthesis of 2,4-diarylchromen-2-ols through the reaction of phenols with an excess of a chalcone in TFA involves sequential Friedel-Crafts alkylation, cyclisation to a 4/7-1-benzo-pyran, an intermolecular hydrogen transfer generates the 4-arylflavylium ion which is hydrated to give the final product (Scheme 12) <07JOC9383>. 

Electron-rich phenols react with isoprene in ionic liquids and with added Sc(OTf)3 to give 2,2-dimethylchromans <07SL3050>. Ionic liquids also promote the one-pot synthesis of 4-arylchromans from benzaldehydes, phenols and allyl bromide which involves sequential Barbier allylation, Friedel-Crafts alkylation and an intramolecular hydroalkoxylation <07SL1357>. 

Phenol > Toluene > p-Bromotoluene > Bromobenzene Aniline and nitrobenzene don t undergo Friedel-Crafts alkylations. 

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. 

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. 

In other systems, such as in some Friedel-Crafts alkylations, ortho-substitution is desirable. For example, extensive alkylation at both the ortho-and para-positions of phenol with formaldehyde in the presence of an acid catalyst yields highly branched novolac phenolic resin prepolymers [Eq. (26)]. 

Synthesis in presence of phenol and alkylphenols, which leads to Friedel-Crafts alkylation by the cationic propagating chain ends (Aromatic C9, 1C, pure monomer resins, polyterpenes). 

Phenol is a nucleophilic aromatic compound (p. 557) and reacts even with acetone in acidic solution. The second reaction with a tertiary benzylic alcohol, is a more conventional Friedel-Crafts alkylation. Phenol is ortho, paro-directing and the para product is favoured in both cases for steric reasons. 

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

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). 

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