Nucleophilic displacement reactions assemblies

The majority of enzymes that are apt to be mentioned in any discussion of metabolism catalyze nucleophilic displacement reactions (Type 1, Table 10-1). These include most of the reactions by which the energy of ATP cleavage is harnessed and by which polymers are assembled from monomers. They include reactions by which pieces, large or small, are transferred onto or off of polymers as well as the reactions by which polymers are cleaved into pieces.1 3,1... 

In one route, tidopidine (1) was assembled via Sn2 displacement of 2-chlorobenzyl chloride (9) with 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (8). " The nucleophile 8 was synthesized by heating 2-thiophen-2-yl-ethylamine (6) with 1,3-dioxolane in the presence of concentrated hydrochloric acid. 1,3-Dioxolone gave better yields than with formaldehyde, paraformaldehyde and 1,3,5-ttioxane. The interesting transformation 6 —> 8 first involved the formation of the corresponding Mannich base 7, which then underwent a Pictet-Spengler type reaction to afford the ring-closure product 8. It was of interest to note that a possible intramolecular aminomethylation did not take place. 

Data assembled by Parker (201 demonstrate these effects for bimolecular reactions involving sulfur nucleophiles and haloaliphatic substrates. As an illustration for the case of Reactions 4, the S 2 displacement of iodide from CH3I by SCN at 25°C is accelerated relative to its rate in water tty 0.2 log units in methanol, by 1.1 log units in 10% aqueous dimethyl sulfoxide (v/v), and tty approximately 2.4 log units in dimethyl formamide (DMF). Furthermore, the rates of bimolecular elimination and substitution of cyclohexyl bromide in the presence of thiophenolate at 25°C both increase by 2.7 log units when the solvent is changed from ethanol to dimethylfonnamide (20). 

A different way to produce chemical microarrays in situ is spot synthesis of combinatorial libraries on cellulose sheets [56]. Spot synthesis is configured as an open system to be operated at room temperature. Despite attempts to replace cellulose with polypropylene as a synthesis support [57], cellulose is still the support of choice for spot synthesis, and reaction conditions have to be compatible with the restricted chemical stability of cellulose. Due to the acid labihty of such membranes, the diversity content of these arrays was initially restricted to the synthesis of peptides. Recently, a method was described that could widen the scope of spot synthesis arrays. Germeroth and coworkers [57] succeeded in the assembly of a library of 8000 cellulose-bound 1,3,5-triazines under mild reaction conditions. They employed a strategy that took advantage of a temperature-dependent, successive displacement of cyanuric chlorides by different nucleophiles in a first report of the synthesis of smaU organic compounds on ceUulose sheets. 

The emergence of catalytic asymmetric methods to effect the Staudinger reaction appears to have largely displaced further efforts to identify new methodology based on the use of chiral auxiliaries. These methods rely on the nucleophilic activation of the ketene to form a zwitterionic enolate, which then undergoes nucleophilic addition to the imine, followed by cyclization. While the assembly of enantiodifferentiated transition states using Lewis acid catalysis has been well developed, the use of Lewis base catalysts to accomplish the same purpose is a relatively recent development and well suited to the Staudinger reaction. 

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