Nucleophilic aromatic substitution water

If one limits the consideration to only that limited number of reactions which clearly belong to the category of nucleophilic aromatic substitutions presently under discussion, only a few experimental observations are pertinent. Bunnett and Bernasconi30 and Hart and Bourns40 have studied the deuterium solvent isotope effect and its dependence on hydroxide ion concentration for the reaction of 2,4-dinitrophenyl phenyl ether with piperidine in dioxan-water. In both studies it was found that the solvent isotope effect decreased with increasing concentration of hydroxide ion, and Hart and Bourns were able to estimate that fc 1/ for conversion of intermediate to product was approximately 1.8. Also, Pietra and Vitali41 have reported that in the reaction of piperidine with cyclohexyl 2,4-dinitrophenyl ether in benzene, the reaction becomes 1.5 times slower on substitution of the N-deuteriated amine at the highest amine concentration studied. 

It is more difficult to interpret micellar effects upon reactions of azide ion. The behavior is normal , in the sense that k /kw 1, for deacylation, an Sn2 reaction, and addition to a carbocation (Table 4) (Cuenca, 1985). But the micellar reaction is much faster for nucleophilic aromatic substitution. Values of k /kw depend upon the substrate and are slightly larger when both N 3 and an inert counterion are present, but the trends are the same. We have no explanation for these results, although there seems to be a relation between the anomalous behavior of the azide ion in micellar reactions of aromatic substrates and its nucleophilicity in water and similar polar, hydroxylic solvents. Azide is a very powerful nucleophile towards carboca-tions, based on Ritchie s N+ scale, but in water it is much less reactive towards 2,4-dinitrohalobenzenes than predicted, whereas the reactivity of other nucleophiles fits the N+ scale (Ritchie and Sawada, 1977). Therefore the large values of k /kw may reflect the fact that azide ion is unusually unreactive in aromatic nucleophilic substitution in water, rather than that it is abnormally reactive in micelles. 

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 most broadly useful intermediates for nucleophilic aromatic substitution are the aryl diazonium salts. Aryl diazonium ions are usually prepared by reaction of an aniline with nitrous acid, which is generated in situ from a nitrite salt.75 Unlike aliphatic diazonium ions, which decompose very rapidly to molecular nitrogen and a carbocation (see Section 10.1), aryl diazonium are stable enough to exist in solution at room temperature and below. They can also be isolated as salts with nonnucleophilic anions, such as tetrafluoroborate or trifluoroacetate.76 The steps in forming a dizonium ion are addition of the nitrosonium ion, +NO, to the amino group, followed by elimination of water. 

In an extension of the ideas of Bar and Drummond (115), Wolfenden (116) suggested the rate limiting formation of a tetrahedral intermediate at the 6 position of purine involving enzyme or enzyme bound water and substrate similar to the type of intermediates generally encountered in nucleophilic aromatic substitution as indicated in (I). 

Selectivities for alcohol-water mixtures depend strongly on the pH of the solution. If the pH is sufficiently high that the alcohol and water are partially deprotonated, then alkoxide and hydroxide will be effective nucleophiles, and their concentrations will depend on the p Kz values of the alcohol and water. For relatively acidic alcohols, calculation of S using Equation 2.9 could then give S values over 1000, e.g. nucleophilic aromatic substitutions, including the dyeing of cotton using fibre-reactive dyes [42]. 

Generation of quinone methides by nucleophilic aromatic substitution of water at carbocations 59... 

The quinone methide 48 was generated by nucleophilic aromatic substitution of water at Me-48+ as shown in Scheme 23,89 and its reaction with solvent and added nucleophiles studied in water and in 50/50 (v/v) H20/trifluoroethanol at 25°C.4,67,89,91 The addition of a pair of strongly electron-deficient q -CF3 groups to the parent unsubstituted pura-quinone methide p-1 should increase the... 

During my early years as an assistant professor at the University of Kentucky, I demonstrated the synthesis of a simple quinone methide as the product of the nucleophilic aromatic substitution reaction of water at a highly destabilized 4-methoxybenzyl carbocation. I was struck by the notion that the distinctive chemical reactivity of quinone methides is related to the striking combination of neutral nonaromatic and zwitterionic aromatic valence bond resonance structures that contribute to their hybrid resonance structures. This served as the starting point for the interpretation of the results of our studies on nucleophile addition to quinone methides. At the same time, many other talented chemists have worked to develop methods for the generation of quinone methides and applications for these compounds in organic syntheses and chemical biology. The chapter coauthored with Maria Toteva presents an overview of this work. 

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 ... 

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. 

A new solvent was investigated for the introduction of amine nucleophiles onto the selenophene nucleus via nucleophilic aromatic substitution. Treatment of 5-bromoselenophene-2-carboxaldehyde 53 with secondary amines in water produced 5-aminoselenophenes 54 (Equation 6) <1999T6511>. 

The full structure of glutathione (p. 1356) is a tripeptide but the reactive group is a thiol (SH) on a cysteine in the middle. We shall represent glutathione as GSH. The first compound reacts by nucleophilic aromatic substitution (pp. 590-5) aided by the nitro groups. After the reaction, the dangerously electrophilic dinitrochlorobenzene cannot react with enzymes or DNA but is carried away attached to a short water-soluble peptide. 

The mechanism was postulated to involve a Cu(l)-carboxylate as the active species, which promotes oxidative addition of the thioimide. Subsequent transme-talation and C-S reductive elimination generates the thioether product. An excess of boronic acid is often required, as copper catalysts may competitively oxidize aryl substituted boronic acids to the corresponding phenol in the presence of adventitious water [21]. The rate of acceleration observed with amino acids and carboxylate-based ligands, such as 3-methylsalicylate, is attributed to stabilization of a 7i-Cu intermediate generated through a nucleophilic aromatic substitution type mechanism (Scheme 1) [72]. The amino acid or carboxylate ligand may also simply stabilize putative Cu(lll) intermediates. 

Y. -L. Zhong, et al.. Tetrahedron Lett., 50, 2293-2297 (2009). These Merck researchers were evaluating a series of compounds for antiviral activity. They performed nucleophilic aromatic substitution with a hindered amine preferentially at the less hindered aryl fluoride followed by a second nucleophilic aromatic substitution at the hindered aryl fluoride. After condensation and loss of water, the product is formed. Draw the product. 

Oxidative addition of substrates possessing C-X or H-X bonds of medium polarity and of substrates possessing Ar-X bonds that cannot undergo S 2 pathways often occur by concerted pathways involving three-centered transition states more like those of the oxidative additions of nonpolar substrates. The clearest cases in which reactions occiu by concerted pathways are the oxidative additions of aryl halides and sulfonates to paUadium(0) complexes. These reactions have been studied extensively because they are the first step of transition-metal-catalyzed nucleophilic aromatic substitution reactions called cross couplings. The oxidative additions of the O-H and N-H bonds in water, alcohols, and amines also appear to occur by concerted three-centered transition states in many cases. 

A different kind of nucleophilic aromatic substitution reaction, namely cyanation reactions, was described by Kitamura and coworkers [49]. Thqr investigated the photocyanation of pyrene by mixing an aqueous solution of NaCN and a propylene carbonate solution of pyrene and 1,4-dicyanobenzene in Y-shaped microfluidic chips made of polymers (Scheme 4.26). Since the reaction takes place at the oil-water interface, an increase in interfadal area was a major driver for employing microreactors. 

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