Phenols nucleophilic aromatic substitution

Preparation of Phenols Nucleophilic Aromatic Substitution Useful new methods for synthesizing benzene derivatives. 

Bifunctional catalysis in nucleophilic aromatic substitution was first observed by Bitter and Zollinger34, who studied the reaction of cyanuric chloride with aniline in benzene. This reaction was not accelerated by phenols or y-pyridone but was catalyzed by triethylamine and pyridine and by bifunctional catalysts such as a-pyridone and carboxylic acids. The carboxylic acids did not function as purely electrophilic reagents, since there was no relationship between catalytic efficiency and acid strength, acetic acid being more effective than chloracetic acid, which in turn was a more efficient catalyst than trichloroacetic acid. For catalysis by the carboxylic acids Bitter and Zollinger proposed the transition state depicted by H. 

A one-pot three-step conversion of aryl fluorides to phenols based on a consecutive nucleophilic aromatic substitution/isomerization/hydrolysis sequence has been reported by Levin and Du (Scheme 6.126) [256], The authors discovered that 2-butyn-l-ol can function as a hydroxyl synthon through consecutive SNAr displacement, in situ isomerization to the allenyl ether, and subsequent hydrolysis, to afford phenols rapidly and in good yields. In most cases, excesses of 2-butyn-l-ol (1-2 equivalents) and potassium tert-butoxidc (2-4 equivalents) were required in order to achieve optimum yields. 

It might be expected that the activating effect of p-NO2 on nucleophilic aromatic substitution would be related to the a value of the substituent. From various studies of nucleophilic aromatic substitution, Miller and Parker213 obtained a <7 value for /2-NO2 of 1.27, very close to the values based on the ionization of substituted phenols or anilinium ions (Section ELD). 

Spurred by our desire to avoid use of expensive dipolau aprotic solvents in nucleophilic aromatic substitution reactions, we have developed two alternative phase transfer systems, which operate in non-polar solvents such as toluene, chlorobenzene, or dichlorobenzene. Poleu polymers such as PEG are Inexpensive and stable, albeit somewhat inefficient PTC agents for these reactions. N-Alkyl-N, N -Dialkylaminopyridinium salts have been identified as very efficient PTC agents, which are about 100 times more stable to nucleophiles than Bu NBr. The bis-pyridinium salts of this family of catalysts are extremely effective for phase transfer of dianions such as bis-phenolates. 

General. Toluene, chlorobenzene, and o-dichlorobenzene were distilled from calcium hydride prior to use. 4-Dimethylaminopyridine (Aldrich Chemical Co) was recrystalled (EtOAc), and the other 4-dialkylaminopyridines were distilled prior to use. PEG S, PEGM s, PVP s, and crown ethers were obtained from Aldrich Chemical Co., and were used without purification. BuJ r and BU. PBr were recrystallized (toluene). A Varian 3700 VrC interfaced with a Spectraphysics SP-4000 data system was used for VPC analyses. A Dupont Instruments Model 850 HPLC (also interfaced with the SP-4000) was used for LC analyses. All products of nucleophilic aromatic substitution were identified by comparison to authentic material prepared from reaction in DMF or DMAc. Alkali phenolates or thiol ates were pre-formed via reaction of aqueous NaOH or KOH and the requisite phenol or thiophenol in water under nitrogen, followed by azeotropic removal of water with toluene. The salts were transferred to jars under nitrogen, and were dried at 120 under vacuum for 20 hr, and were stored and handled in a nitrogen dry box. 

Aryl halides bearing strong electron-withdrawing groups and thus allowing nucleophilic aromatic substitution can be used for the arylation of azinone anions. 4-(4-Hydroxy-3-methylphenyl)phthalazin-l(2//)-one has been arylated simultaneously at N-2 and at the phenolic OH with 4-chlorobenzonitrile and potassium carbonate in dimethyl-acetamide (DMA) <2005CHJ200>. 

One solution for this problem, the most optimistic, suggested the existence of three independent sets of o--constants. The first set, the Hammett constants, would be applicable to side-chain reactions in which resonance interactions between the substituent and the side-chain were either small or insignificant. The second set, the w-constants, would apply to side-chain reactions of phenols and anilines and nucleophilic aromatic substitution reactions in which a negative charge was introduced in the aromatic nucleus (Miller, 1956). A third set, the c7+-constants, would apply to electrophilic substitution and electrophilic side-chain reactions for which resonance interactions between the reaction site and the substituent were important. 

Kita and Tohma found that exposure of p-substituted phenol ethers to [bis(tri-fluoroacetoxy)iodo]benzene 12 in the presence of some nucleophiles in polar, less nucleophilic solvents results in direct nucleophilic aromatic substitution [Eq. (84)] [156]. Involvement of a single-electron transfer (SET) from phenol ethers to A3-iodane 12 generating arene cation radicals was suggested by the detailed UV-vis and ESR studies. SET was involved in the oxidative biaryl coupling of phenol ethers by 12 in the presence of BF3-Et20 [157]. 

The kinetics of polycondensation hy nucleophilic aromatic substitution in highly polar solvents and solvent mixtures to yield linear, high molecular weight aromatic polyethers were measured. The basic reaction studied was between a di-phenoxide salt and a dihaloaromatic compound. The role of steric and inductive effects was elucidated on the basis of the kinetics determined for model compounds. The polymerization rate of the dipotassium salt of various bis-phenols with 4,4 -dichlorodiphenylsulfone in methyl sulfoxide solvent follows second-order kinetics. The rate constant at the monomer stage was found to be greater than the rate constant at the dimer and subsequent polymerization stages. 

Aromatic compounds undergo many reactions, but relatively few reactions that affect the bonds to the aromatic ring itself. Most of these reactions are unique to aromatic compounds. A large part of this chapter is devoted to electrophilic aromatic substitution, the most important mechanism involved in the reactions of aromatic compounds. Many reactions of benzene and its derivatives are explained by minor variations of electrophilic aromatic substitution. We will study several of these reactions and then consider how substituents on the ring influence its reactivity toward electrophilic aromatic substitution and the regiochemistry seen in the products. We will also study other reactions of aromatic compounds, including nucleophilic aromatic substitution, addition reactions, reactions of side chains, and special reactions of phenols. 

The addition-elimination mechanism for nucleophilic aromatic substitution requires strong electron-withdrawing substituents on the aromatic ring. Under extreme conditions, however, unactivated halobenzenes react with strong bases. For example, a commercial synthesis of phenol (the Dow process ) involves treatment of chlorobenzene with sodium hydroxide and a small amount of water in a pressurized reactor at 350 °C ... 

Nucleophilic aromatic substitution provides one of the common methods for making phenols. (Another method is discussed in Section 19-17.) Show how you would synthesize the following phenols, using benzene or toluene as your aromatic starting material, and explain why mixtures of products would be obtained in some cases. 

Replacement of the Diazonium Group by Hydroxide Hydrolysis Hydrolysis takes place when the acidic solution of an arenediazonium salt is warmed. The hydroxyl group of water replaces N2, forming a phenol. This is a useful laboratory synthesis of phenols because (unlike nucleophilic aromatic substitution) it does not require strong electron-withdrawing substituents or powerful bases and nucleophiles. 

In al this we have estimated the stability of a carbonium ion on the same basis the dispersal or concentration of the charge due to electron release or electron withdrawal by the substituent groups. As wc shall see, the approach that has worked so well for elimination, for addition, and for electrophilic aromatic substitution works for still another important class of organic reactions in which a positive charge develops nucleophilic aliphatic substitution by the S l mechanism (Sec. 14.14). It works equally well for nucleophilic aromatic substitution (Sec. 25.9), in which a negative charge develops. Finally, we shall find that this approach will help us to understand acidity or basicity of such compounds as carboxylic acids, sulfonic acids, amines, and phenols. 

This phenol synthesis is different from the nucleophilic aromatic substitutions discussed in the previous section because it takes place by an elimination addition mechanism rather than an addition/elimination. Strong base first causes the elimination of HX from halobenzene in an E2 reaction, yielding a highly reactive benzyne intermediate, and a nucleophile then adds to benzyne in a second step to give the product. The two steps are similar to those in other nucleophilic aromatic substitutions, but their order is reversed elimination before addition for the benzyne reaction rather than addition before elimination for the usual reaction. 

Star-shaped molecules containing cationic arene complexes of iron and ruthenium have been reported by Astruc and co-workers.298 Utilizing the activating nature of the cyclopentadienyliron moiety on the complexed arene, 260 was converted into 262 via bromobenzylation. The photolysis of 262 gave 263, which was subsequently reacted with 264 to give the hexametallic complex 265. Further nucleophilic aromatic substitution reactions with phenol 266 gave the allyl-substituted complex 267 (Scheme 2.70). 

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