Nucleophile intermolecular nucleophilic displacement

The formation of ethyl cyano(pentafluorophenyl)acetate illustrates the intermolecular nucleophilic displacement of fluoride ion from an aromatic ring by a stabilized carbanion. The reaction proceeds readily as a result of the activation imparted by the electron-withdrawing fluorine atoms. The selective hydrolysis of a cyano ester to a nitrile has been described. (Pentafluorophenyl)acetonitrile has also been prepared by cyanide displacement on (pentafluorophenyl)methyl halides. However, this direct displacement is always aecompanied by an undesirable side reaetion to yield 15-20% of 2,3-bis(pentafluoro-phenyl)propionitrile. 

Ring closure of 2-chloro-l-phenethylpyridinium ion (247) (prepared in situ) to l,2-dihydro-3,4-benzoquinolizium ion involves intramolecular nucleophilic displacement of the chloro group by the phenyl 77-electrons. A related intermolecular reaction involving a more activated pyridine ring and more nucleophilic 7r-electrons is the formation of 4-( -dimethylaminophenyl)pyridine (and benzaldehyde) from dimethylaniline and 1-benzoylpyridinium chloride (cf. Section III,B,4,c). 

For neutral nucleophiles (e.g. amines, alcohols, water) there is much evidence that the addition-elimination mechanism depicted in equation 1 fits very well most of the intermolecular and intramolecular nucleophilic displacements involving nitro-activated aromatic substrates1. 

Studies of gas-phase S"n2 reactions at sp carbon have been made by Fourier transform ion cyclotron resonance mass spectrometry (FTlCRMS) and complemented by both semiempirical and ab initio MO calculations. The particular processes of interest involved intramolecular reactions in which neutral nucleophiles displace neutral leaving groups within cationic substrates, e.g. A-(2-piperidinoethyl)-2,4,6-triphenylpyridinium cation (59), in which the piperidino moiety is the nucleophile and 2,4,6-triphenylpyridine (60) is the leaving group. No evidence has been obtained for any intermolecular gas-phase 5) 2 reaction involving a pyridine moiety as a leaving group. The quantum mechanical treatments account for the intramolecular preference. 

Intramolecular nucleophilic displacements of halogen from u> -halohexylamines is an obvious route to saturated azepines and was the route by which hexamethyleneimine was first prepared. The method has since been superseded as a route to simple hexamethyl-eneimines but is still used for highly substituted derivatives (67MI51600). However, high dilution techniques are necessary in order to avoid polymerization intermolecular N-alkylations are minimized by using amine protecting groups, e.g. Af-tosyl. 

Several mechanisms have been proposed for the intriguing interconversions of sulfur (or selenium) rings. These include the formation of (i) radicals by homolytic S-S bond cleavage, (ii) thiosulfoxides of the type S =S via ring contraction (an intramolecular process) or (iii) spirocyclic sulfuranes (or sele-nanes) via an intermolecular process. A fourth alternative (iv) invokes nucleophilic displacement reactions. Generic examples of mechanisms (ii)-(iv) for homoatomic sulfur or selenium rings are depicted in Scheme 12.1. 

Intramolecular nucleophilic displacements, such as those in lactone formation, have faster reaction rates than intermolecular S,42 reactions because the latter require two species to collide. The neighboring participant is said to furnish anchimeric assistance. 

According to this equation, the product is indeed produced by an SN reaction because the nucleophile displaces an oxyanion as a leaving group from the attacked C atom. Nonetheless this oxyanion is still a part of the reaction product. In this respect this reaction can also be considered to be an addition reaction. An intermolecular addition reaction is one that involves the combination of two molecules to form one new molecule. An intramolecular addition reaction is one that involves the combination of two moieties within a molecule to form one new molecule. 

General base catalysis of the Sn2 reaction is not generally observed, for various reasons. Amine nucleophiles do not need it, and hydroxy groups are very weakly nucleophilic towards soft, polarisable centers like sp -carbon. The only well-authenticated example of an intermolecular general base catalyzed nucleophilic displacement at sp -hybridized carbon is the trifluoroethanolysis of the benzylsul-... 

Below, the usefulness of nucleophile- and base-labile linkers and resins is reviewed in the preparation of various organic compounds. First, intermolecular nucleophilic displacement (saponification, transesterification and amminolysis and related reactions) are analyzed. Finally, the obtention of cyclic products by intramolecular nucleophilic reactions is reviewed. 

Nucleophilic Substitution, Metallation, and Halogen-Metal Exchange.—Direct nucleophilic displacement of the 7-chloro-group of 7-chloro-3-methyl-benzo[b]thiophen has been achieved. 3-Bromobenzo[b]thiophen was reduced to the 3-deuterio-derivative by the reaction with sodium borodeuteride and palladium chloride. Meisenheimer complexes were formed in the reaction of methoxide ion with 2-methoxy-3-nitro- and 3-methoxy-2-nitrobenzo[b]thiophen. Rate and equilibrium data were determined in methanol at 25 C. On treatment of 2-bromobenzo[b]thiophen with potassium amide in liquid ammonia, bromine migration to the adjacent carbon atom was observed. Considerable evidence for the occurrence of an intermolecular transbromination was obtained. The reaction of 3-bromo-benzo[b]thiophen with piperidine has been reinvestigated and found to give primarily the normal, but also some of the cine-substitution product, which is the only product obtained in the reaction of 2-bromobenzo[b]thiophen. Possible mechanisms for some of these reacticms are suggested. 

Aminomethylindoles are particularly important synthetic intermediates. 3-Dimethyl-aminomethylindole (gramine) (153) and especially its quaternary salts readily undergo displacement reactions with nucleophiles (Scheme 60). Indole-2,3-quinodimethanes, generated from 2-methylgramine as shown in Scheme 61, undergo intermolecular cycloaddition reactions with dienophiles to yield carbazole derivatives (82T2745). 

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