Chlorobenzene nucleophilic aromatic

Although nucleophilic aromatic substitution by the elimination-addition mecha nism IS most commonly seen with very strong amide bases it also occurs with bases such as hydroxide ion at high temperatures A labeling study revealed that hydroly SIS of chlorobenzene proceeds by way of a benzyne intermediate... 

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. 

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 ... 

The bimolecular displacement mechanism for nucleophilic aromatic substitution (shown here for chlorobenzene) is ... 

Aromatic substitution reactions usually occur by an electrophilic mechanis Ary halides that have electron-withdrawing substituents, however, can also undergo nucleophilic aromatic substitution. For example, 2,4,6-trinitro-chlorobenzene reacts with aqueous NaOH at room temperature to give 2,4,6-trinitrophenol in 100% yield. The nucleophile OH has substituted for Cl". 

Scheme 36, A and Turnover numbers up to approximately 500,000 were reported for the reaction of iodobenzene with methyl acrylate and an impressive nnmber (about 100,000) was also achieved with bromobenzene and 4-methoxy-bromobenzene. Characteristic featnres of these tridentate PCP catalysts are thermal stability and air stability. A competitive experiment, including 4-bromoiodobenzene, iodobenzene, 4-methyliodoben-zene, and 4-methoxy-iodobenzene with methyl acrylate provided a linear correlation with Hammet cr-valnes, which, however, exhibited a low p valne (1.39). It was concluded that nucleophilic aromatic substitution is not rate determining, bnt a snbsequent step with different electronic requirements, such as alkene insertion, may acconnt for this observation. Chlorobenzene could not be coupled with these catalyst. Very recently, Milstein s group reported new cyclopalladated, phosphine-free imine complexes as catalysts in the Heck arylation reaction (Scheme 36, The new dimeric imine complexes show... 

For inserting the long aliphatic chains into the donor group, chlorobenzene was treated with di-n-octylamine and n-BuLi in a nucleophilic aromatic substitution reaction. The resulting N,N-dioctylaniline (2) was converted into the phos-phonium salt (3) in a reaction with HCHO, P(CgH5)3, CH3COOH,... 

Halides derived from certain heterocyclic aromatic compounds are often quite reac tive toward nucleophiles 2 Chloropyridme for example reacts with sodium methoxide some 230 million times faster than chlorobenzene at 50°C... 

Nucleophilic Substitutions of Benzene Derivatives. Benzene itself does not normally react with nucleophiles such as haUde ions, cyanide, hydroxide, or alkoxides (7). However, aromatic rings containing one or more electron-withdrawing groups, usually halogen, react with nucleophiles to give substitution products. An example of this type of reaction is the industrial conversion of chlorobenzene to phenol with sodium hydroxide at 400°C (8). 

The relative inertness of unactivated aromatic halides towards nucleophiles, under normal conditions, is in sharp contrast to their marked reactivity towards nucleophiles that are also very strong bases. Thus chlorobenzene is readily converted into aniline by reaction with eNH2 (NaNH2) in liquid ammonia at — 33° ... 

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