Nucleophilic substitution approaches

Perhaps more useful are the transformations of diazonium salts. Imidazole-2-diazonium fluoroborate can be converted into the 2-fluoro- and 2-nitroimidazoles, the former by heating or photolysis, the latter with sodium 

A suspension of 4-nitro-l-(o-nitrobenzenesulfonyl)imidazole (made from 4-nitroimidazole, o-nitrobenzenesulfonyl chloride, and triethylamine) (0.745 g, 2.5mmol) and aniline (l.Og, 11 mmol) in aqueous methanol (1 1 20ml) is stirred and heated at 70°C (2h). The mixture is then steam distilled, and the hot undistilled residue is filtered to give the above product (0.41 g, 87%), m.p. 185-187°C. Cooling of the filtrate results in separation of 

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The nucleophilic substitution approach was also used by several research groups for syntheses of polysulfides with broad variation of the chemical structure and of the reaction conditions [343-352]. For instance, a poly(thioether-ketone) was prepared from DFBP and dry Na2S with variation of the reaction medium [337]. N-Cyclohexylpyrrolidone was found to yield the highest molecular weights. In another publication random copoly(ketone sulfone sulfide)s were prepared by copolycondensation of 4,4 -dichloro-benzophenone and 4,4 -dichlorodiphenylsulfone with NaSH (222) [344]. The crystallinity was found to depend on the molar fraction of benzophenone moieties. 

Microwave radiation can be used in the synthesis of alkyl azides. The microwave-assisted synthesis of j8- and 7-azidoarylketones 89 from haloaryUcetones 88 and NaNs leads to acceleration in reaction rates and yields comparable to the ones using conventional heating. The microwave-enhanced nucleophilic substitution approach to alkyl azides (91, 93 and 95) in aqueous medium from halides or tosylates and NaN3 is also known. The authors observed that a variety of reactive functional groups are tolerated, namely ester, carboxylic acid and imide (Scheme 3.12). 

Scheme 14 Nucleophilic substitution approach to the bis-THP fragment of leucascandrolide A [35]...

Next in what amounts to an intramolecular Williamson ether synthesis the alkoxide oxygen attacks the carbon that bears the halide leaving group giving an epoxide As m other nucleophilic substitutions the nucleophile approaches carbon from the side oppo site the bond to the leaving group... 

An alternative approach is in terms of frontier electron densities. In electrophilic substitution, the frontier electron density is taken as the electron density in the highest filled MO. In nucleophilic substitution the frontier orbital is taken as the lowest vacant MO the frontier electron density at a carbon atom is then the electron density that would be present in this MO if it were occupied by two electrons. Both electrophilic and nucleophilic substitution thus occur at the carbon atom with the greatest appropriate frontier electron density. 

Another approach is therefore to adopt a model process that is very similar to the reactions of interest. Swain and Scott ° selected as a standard reaction the nucleophilic substitution reaction of methyl bromide in water at 25°C. 

The reaction of an alkyl halide or los3 late with a nucleophiJe/base results eithe in substitution or in diminution. Nucleophilic substitutions are of two types S 2 reactions and SN1 reactions, in the SN2 reaction, the entering nucleophih approaches the halide from a direction 180° away from the leaving group, result ing in an umbrella-like inversion of configuration at the carbon atom. The reaction is kinetically second-order and is strongly inhibited by increasing stork bulk of the reactants. Thus, S 2 reactions are favored for primary and secondary substrates. 

How- does this reaction take place Although it appears superficially similar to the SN1 and S 2 nucleophilic substitution reactions of alkyl halides discussed in Chapter 11, it must be different because aryl halides are inert to both SN1 and Sj 2 conditions. S l reactions don t occur wdth aryl halides because dissociation of the halide is energetically unfavorable due to tire instability of the potential aryl cation product. S]sj2 reactions don t occur with aryl halides because the halo-substituted carbon of the aromatic ring is sterically shielded from backside approach. For a nucleophile to react with an aryl halide, it would have to approach directly through the aromatic ring and invert the stereochemistry of the aromatic ring carbon—a geometric impossibility. 

In the skeleton of many chelating diphosphines, the phosphorus atoms bear two aryl substituents, not least because the traditional route to this class of compounds involves the nucleophilic substitution with alkali metal diarylphosphides of enantiopure ditosylates derived from optically active natural precursors, approach which is inapplicable to the preparation of P-alkylated analogs. The correct orientation of these aryl substituents in the coordination sphere has been identified as a stereo chemically important feature contributing to the recognition ability of the metal complex [11,18-20]. 

There are two other approaches to enhancing reactivity in nucleophilic substitutions by exploiting solvation effects on reactivity the use of crown ethers as catalysts and the utilization of phase transfer conditions. The crown ethers are a family of cyclic polyethers, three examples of which are shown below. 

Within the past several years, we have examined the synthesis and reactions of several classes of polymers related to PECH. We have adopted three simple approaches to the preparation of polymeric substrates more reactive than PECH toward nucleophilic substitution. We have i). removed the 8-branch point by extension of the side chain, ii). replaced the chloride leaving group by a more reactive bromide and iii). replaced the backbone oxygen atom by a sulfur atom that offers substantial anchimeric assistance to nucleophilic... 

Two chemical approaches that involve nucleophilic substitution of the chlorine atoms attached to boron with linking reagents are reported in the literature. In both methods, the driving force is the formation of a stable by-product or one that can easily be stabilized. These substances contain chlorine. They can be distinguished by the number of steps, either one or two, required for preparing the polymer, starting from /i-chloroborazine. 

Another approach for oxidative nucleophilic substitution of hydrogen can be carried out with primary amines and CAN in aqueous MeCN (Eq. 9.45).77... 

A similar approach has been described by the same authors for the synthesis of related cyclic peptidomimetics [44]. A set often nucleophiles was employed for the substitution of the chlorine atom of the cyclic triazinyl-peptide bound to the cellulose membrane. By virtue of the aforementioned rate enhancement effects for nucleophilic substitution of the solid-supported monochlorotriazines, these reactions could be rapidly carried out by microwave heating. All products were obtained in high purity, enabling systematic modification of the molecular properties of the cyclic peptidomimetics. 

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