Reaction mechanisms, SNAr

Substrate binding and activation are followed by attack of the carboxylate side chain of Asp-145 at the benzoyl C-4 atom to give an enzyme-stabilized Meisenheimer intermediate (EMc) (Figure 8). Indeed, a site-directed mutant in which Asp-145 has been replaced by an alanine is catalytically inactive." Ketonization of the EMc results in rearomatization of the benzoyl ring and expulsion of the chloride. This nucleophilic addition-elimination mechanism (SNAr-type reaction) results in a second covalent (aryl-enzyme) intermediate, which is subsequently hydrolyzed by a water molecule that is activated by His-90 to give the free enzyme and the product. The existence of a covalent aryl-enzyme intermediate has been inferred from 0-labeling studies (similar to those described for haloalkane and haloalcohol dehalogenase) and from the direct measurement of the aryl-enzyme... 

Sn2 and SNAr Reactions In these reactions the metal atom attacks aliphatic or aromatic carbon bonded to X, respectively. A stronger nucleophilic metal as well as a better leaving group X (I>Br>Cl>F) facilitates, whereas steric hindrance in R slows these types of oxidative addition [193, 194]. SNAr reactions are favored by electron-withdrawing substituents Y in the case of the substrates 4-YQH4X [2], Sn2 [27, 29, 89, 117, 180, 181] and SNAr [31, 33, 62-67, 95, 100, 107-109] mechanisms have been suggested frequently for zerovalent d10 complexes such as [L M] (M = Ni, Pd, Pt L=tertiary phosphine =2,3,4). For example ... 

The C-F bond activations in C6F6 and related compounds with ruthenium [200, 201] and rhodium [17, 78, 201] complexes, for which an SNAr mechanism is energetically unfavorable, have been explained by SET pathways. Both SN2 [128, 129, 131, 170-174, 199, 202] and SET [130, 132, 199] mechanisms have been proposed for the reaction of Co(I) complexes with alkyl and vinyl halides. 

The reaction labelled IPSO substitution is only applicable to species like OH - and NH2" and corresponds to a special case of the SNAr mechanism. 

Step 1 of the SNAr mechanism has been studied for the reaction between picryl chloride (as well as other substrates) and OH ions (3-1), and spectral evidence has been reported15 for two intermediates, one a ir complex (p. 505), and the other a radical ion-radical pair ... 

The fact that the order of halide reactivity is Br > I > Cl > F (when the reaction is performed with KNHi in liquid NH3) shows that the SNAr mechanism is not operating here.31... 

There is no clear-cut proof that a one-step Sn2 mechanism, so important at a saturated carbon, ever actually occurs with an aromatic substrate. The hypothetical aromatic Sn2 process is sometimes called the one-stage mechanism to distinguish it from the two-stage SNAr mechanism. Some of the reactions in this chapter operate by still other mechanisms, among them an addition-elimination mechanism (see 3-17). 

The reaction with ammonia or amines, which undoubtedly proceeds by the SNAr mechanism, is catalyzed by copper8" and nickel105 salts, though these are normally used only with rather unreactive halides.106 This reaction, with phase transfer catalysis, has been used to synthesize triarylamines.107 Copper ion catalysts (especially cuprous oxide or iodide) also permit the Gabriel synthesis (0-58) to be applied to aromatic substrates. Aryl bromides or iodides are refluxed with potassium phthalimide and Cu 0 or Cul in dimethylacetamide to give N-aryl phthalimides, which can be hydrolyzed to primary aryl amines.108... 

The neat resin preparation for PPS is quite complicated, despite the fact that the overall polymerization reaction appears to be simple. Several commercial PPS polymerization processes that feature some steps in common have been described (1,2). At least three different mechanisms have been published in an attempt to describe the basic reaction of a sodium sulfide equivalent anddichlorobenzene these are S Ar (13,16,19), radical cation (20,21), and Bunnett s (22) S l radical anion (23—25) mechanisms. The benzyne mechanism was ruled out (16) based on the observation that the para-substitution pattern of the monomer, j -dichlorobenzene, is retained in the repeating unit of the polymer. Demonstration that the step-growth polymerization of sodium sulfide and A dichlorobenzene proceeds via the SNAr mechanism is fairly recent (1991) (26). Further complexity in the polymerization is the incorporation of comonomers that alter the polymer structure, thereby modifying the properties of the polymer. Additionally, post-polymerization treatments can be utilized, which modify the properties of the polymer. Preparation of the neat resin is an area of significant latitude and extreme importance for the end user. 

Studies of the SN Ar mechanism have involved theuse of 2,4-dtnitrqfluoroben-zene as a substrate The SNAr reaction of fluoroaromatics is catalyzed by both aromatic and alphatic amines [42, 43 44, 45, 46 47, 48, 49] Diamines [50] and... 

The most important experimental data about NMR, IR, and UV spectroscopy have been reported in CHEC-I. In addition, an AMI SCF-MO study has been published <88JOC3900>. The relaxed reaction profile for aromatic nucleophilic substitution of some chloropyrimido[4,5-J]pyridazine has been investigated using the MNDO procedure <90JST(63)45>. Kinetic measurements and MNDO calculations show that the C-8 position of the pyridazine ring is more reactive than C-5 in nucleophilic substitution reactions, and these follow a two-step SNAr mechanism <89T4485>. 

Chromium tricarbonyl-complexed aryl fluorides undergo nucleophilic substitution reactions. The substitution is not a straightforward SNAr mechanism as can be seen using, for example, 4-methoxy-l-fluorobenzene complex (71). Reaction of (71) with acetylide (72) gives a 1 2 mixture of the 1,2 and 1,3 products (73) and (74) (Scheme 115). Other leaving groups include halogens, alkoxides, and amines. Indazoles can be prepared by reaction with hydrazine followed by acidic deprotection-decomplexation (Scheme 116). 

The reaction between aryl halides and cuprous cyanide is called the Rosenmund-von Braun reaction Reactivity is in the order I > Br > Cl > F, indicating that the SNAr mechanism does not apply. Other cyanides (e.g., KCN and NaCN) do not react with aryl halides, even activated ones. This reaction has been done in ionic liquids using CuCN. ° The reaction has also been done in water using CuCN, a phase transfer catalyst, and microwave irradiation. 

The reactions may occur by nucleophilic attack of the second nucleophilic center of the binucleophile at the ortho-fiuorine atom of the aromatic ring as in the usual SNAr mechanism. However, an alternative mechanism is an attack of the ipso-carbon atom at the second nucleophilic center, generating an intermediate... 

The basic concepts of nucleophilic substitution reactions appeared in the first semester of organic chemistry. These reactions follow SN1 or SN2 mechanisms. (In aromatic nucleophilic substitution mechanism, we use the designation SNAr.) In SN1 and SN2 mechanisms, a nucleophile attacks the organic species and substitutes for a leaving group. In aromatic systems, the same concepts remain applicable, but with some differences that result from the inherent stability of aromatic systems. 

An SNAr mechanism is an addition/elimination, not an elimination/addition reaction. 

Now you have three basic mechanisms for aromatic rings — electrophilic aromatic substitution, SNAr, and elimination/addition. How do you choose among these The first consideration is what types of other reagents are present. If the reagents include an electrophile, then the reaction will be electrophilic aromatic substitution. The presence of a nucleophile may lead to either SNAr or elimination/addition. If the system meets the three requirements for SNAr, then the reaction will follow that mechanism. If not, it will be an elimination/addition. 

C-0 bond cleavage of aryl triflates or tosylates is also studied in relation to Mizoroki-Heck type reactions [101], Oxidative addition of PhOTf to Pd(PPh3)4 is 10 times slower than that of Phi. Since similar trend is observed for the catalytic Mizoroki-Heck reaction, the oxidative addition of aryl compound is considered to be the rate-determining step in the overall catalytic process. This feature suggests that the C-0 bond cleavage of aryl triflate proceeds by the concerted SNAr mechanism. However, since the triflate normally acts as a non-coordinating anion, thermally unstable cationic arylpalladium(II) complexes are formed in this reaction (Scheme 3.54). 

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