Nucleophilic Substitution by Proton Abstraction

Copyright 2001 John Wiley Sons, Inc. ISBNs 0-471-35833-9 (Hardback) 0-471-22041-8 (Electronic) 

Orbital Interaction Theory of Organic Chemistry, Second Edition. Arvi Rauk 

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Some typical reactions of 1,1 -difluoroethene with nucleophiles are summarized in Scheme 2.18. Alkoxides [3], trialkylsilyl anion [4], ester enolates [5], and diphenylphosphinyl anion [6] attack the gem-difluorinated carbon of 5. However, it is noteworthy that nucleophilic substitution and proton abstraction are in some cases competitive, and thus s -butyl lithium abstracts the (3 -vinylic proton predominantly to generate vinyllithium. The lithium species can be trapped with an aldehyde, providing difluoroallyl alcohol, which is then hydrolyzed to a, (3-unsaturated carboxylic ester (11) [ 7 ] (Scheme 2.19). Some synthetically useful examples are shown in Schemes 2.20 and 2.21. Tetrathiafulvalene derivative (14) is prepared from difluorinated derivative (13) [8]. An elegant intramolecular version was demonstrated by Ichikawa, which provided a range of cyclized compounds (17), including dihydrofurans, thiophenes, pyrroles, and cyclopentenes, and also corresponding benzo derivatives (20) [2]. 

The primary products from the reactions of thermally equilibrated amide ions with organoelement compounds form via nucleophilic substitution or proton abstraction by amide, or by competition between both reaction channels. Elimination reactions and other secondary processes are observable in some cases see for example [20 to 22]. 

The 5 -0-tosyl derivative of cytidine 227, upon reaction with KF and an azocrown ether, gave, unexpectedly, instead of the nucleophilic substitution product, the oxazocine 228 via nucleophilic attack by the 2-carbonyl oxygen initiated by proton abstraction from N-4 by fluoride (Scheme 46) <1998BML1317>. 

Substitution reactions of allylic halides show diverse character according to the reagent and the position of the allylic system. In buffered aqueous solutions the 3 a- and 3 3-chloro-A -compounds 7) and (8), and also the 4/5-chloro-AS-(10) and 6ji -chloro-A4 compounds (ii) clearly react through common allylic cations (9 and 12, respectively). The product patterns are what one would expect from nucleophilic attack upon these cations by water, accompanied in the case of the C<3) C(4)-C(5) cation (9) by proton abstraction to give a diene. This cation exhibits no preference for either 3 a- or 3jS-attack of the nucleophile but the C(4>-C(5) C(6) cation 12) is attacked... 

An interesting example of an extractant is n-octylphenyl-iV,iV-diisobutylcarbomyl-methylphosphine oxide (Scheme 5) [48]. This nuclear extractant can concentrate nuclear waste by up to 10 and Dr. P. Horwitz from Argonne National Laboratories won a IR-100 award for the development of the TRUEX process [147]. Monitoring the reaction by P-NMR indicates that nucleophilic substitution occurs first, followed by proton abstraction to form the anion [148]. 

Sulfoxides react with organolithium and Grignard reagents by four different reaction pathways. One involves nucleophilic substitution with Walden inversion at the sulfinyl sulfur atom. A second involves a concomitant ligand exchange and disproportionation reactions. A third process, recently discovered, comprises ligand coupling reactions, and the fourth is the formation of a-sulfinyl car-banions by proton abstraction. The four reactions are summarized in Scheme 4. 

The ion-molecule reactions of collisionally relaxed NH2 with typical representatives of organic compounds in the gas phase at ambient temperature are compiled in Table 22. The anions were analyzed by mass spectrometry in early experiments and later by Fourier transform (ion cyclotron resonance) mass spectrometry. More recent investigations usually apply the flowing afterglow technique or its offspring, the selected-ion flow tube (SIFT) technique. These methods allow the identification of anions only the other products have to be deduced from the mass balance. Rate constants were determined by the flowing afterglow and the SIFT techniques. The products frequently form by proton abstraction which may be followed by elimination or by nucleophilic substitution. Reaction enthalpies and... 

With the exception of the nuclear amination of 4-methylthiazole by sodium amide (341, 346) the main reactions of nucleophiles with thiazole and its simple alkyl or aryl derivatives involve the abstraction of a ring or substituent proton by a strongly basic nucleophile followed by the addition of an electrophile to the intermediate. Nucleophilic substitution of halogens is discussed in Chapter V. 

Nucleophilic aromatic substitution by the elimination-addition mechanism is impossible, owing to the absence of any protons that might be abstracted from the substrate. The addition-elimination pathway is available, however. 

The overall reaction involves replacing the halogen atom of the alkyl halide with an NH, unit. Another method is the Gabriel synthesis of amines. This involves treating phthalimide with KOH to abstract the N-H proton. The N-H proton of phthalimide is more acidic (pK9) than the N-H proton of an amide since the anion formed can be stabilised by resonance with both neighbouring carbonyl groups. The phthalimide ion can then be alkylated by treating it with an alkyl halide in nucleophilic substitution. 

So far little information is available on electrophilic substitution reactions these are mainly expected to occur in the azine ring when activated by electron-releasing substituents. Nucleophilic substitution reactions, however, occur readily in either ring. The N—S bond may be cleaved by nucleophilic attack at sulfur and this may be the preferential reaction path in some cases. The N—S bond may also be cleaved as a result of proton abstraction from the azole ring. 

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