Nucleophilicity of reagents

When S 2 reactions are carried out in aprotic solvents, the nucleophilicity of reagents is dramatically different from that in protic solvents, and the n and tzCh3i values of Tables 4.4 and 4.5 do not apply. The requirement that a base must be polarizable in order to be a good nucleophile becomes much less important, and there is a better correlation between proton basicity and nucleophilicity. For example, SeCN reacts 4000 times as fast as Cl- with methyl iodide in methanol at 0°C, but in dimethylformamide (DMF) also at 0°C, Cl reacts twice as fast as SeCN-.46 Even the order of halide reactivity can be reversed. Bromide reacts 18 times as fast as Cl- with methyl iodide in methanol, but in DMF, Cl- reacts twice as fast as Br-.47... 

The formation of new stereogenic centers using chemical intermediates such as free radicals, carbanions, or carbocations can be influenced by many factors such as solvents, electronic effects, the electrophilicity or nucleophilicity of reagents, and the presence of Lewis acid. Of course, the intrinsic reactivity of the intermediate used will also affect the outcome of the reaction. Still, the general principles governing the induction of diastereoselectivity remain the same for all of the above-mentioned species. 

Two main topics are usually distinguished the influence of the catalyst in proton-transfer reactions showing general acid or general base catalysis (the Bronsted equation) and the nucleophilicity of reagents in bimolecular reactions. These topics, however, are not totally unconnected. 

These compounds are sources of the nucleophilic anion RC=C and their reaction with primary alkyl halides provides an effective synthesis of alkynes (Section 9 6) The nucleophilicity of acetylide anions is also evident m their reactions with aldehydes and ketones which are entirely analogous to those of Grignard and organolithium reagents... 

Alkyl azides prepared by nucleophilic substitution of alkyl halides by sodium azide as shown m the first entry of Table 22 3 are reduced to alkylammes by a variety of reagents including lithium aluminum hydride... 

A soft (nucleophilic) Grignard reagent has been developed (82—84). The value of this reaction is demonstrated ia acylation reactions (82). 

Nucleophilic Addition. Reagents with labile hydrogen atoms, such as alcohols, thiols, phenols, carboxyHc acids and amines, add to ketenes giving the corresponding carboxyHc acid derivatives (1) as shown ia Figure 1 (38). Not many are of practical importance, as there are better ways to such... 

Displacement Reactions. Cyclopentadienyltitanium haUdes undergo displacements with a wide variety of nucleophiles. HydroxyUc reagents cleave Ti—R bonds (317,318) ... 

In forcing conditions with excess of reagents the 5,8-bis derivative was obtained in the above cases, with hydrazine and with sulfur nucleophiles. Other authors have also observed selective reactions in the pyrido[2,3-[Pg.242]

In contrast to electrophilic reagents, the highly -tt-deficient character of the pteridine nucleus is responsible for its vulnerability towards nucleophilic attack by a wide variety of reagents. The direct nucleophilic substitution of pteridine itself in a Chichibabin-type reaction with sodamide in diethylaniline, however, was unsuccessful (51JCS474). Pteridin-6-one, on the other hand, yielded pteridine-6,7-dione under the same conditions, via a still unknown reaction mechanism. 

Scheme 6 depicts a typical penicillin sulfoxide rearrangement (69JA1401). The mechanism probably involves an initial thermal formation of a sulfenic acid which is trapped by the acetic anhydride as the mixed sulfenic-acetic anhydride. Nucleophilic attack by the double bond on the sulfur leads to an episulfonium ion which, depending on the site of acetate attack, can afford either the penam (19) or the cepham (20). Product ratios are dependent on reaction conditions. For example, in another related study acetic anhydride gave predominantly the penam product, while chloroacetic anhydride gave the cepham product (7lJCS(O3540). The rearrangement can also be effected by acid in this case the principal products are the cepham (21) and the cephem (22 Scheme 7). Since these early studies a wide variety of reagents have been found to catalyze the conversion of a penicillin sulfoxide to the cepham/cephem ring system (e.g. 77JOC2887).

In contrast to pyridine-hydrogen fluoride, which is acidic and acts as a protonating agent, in alkylamine-hydrogen fluoride complexes, fluorine is a nucleophile. The difference of the nature of these two types of reagents has been... 

It was soon learned that the nucleophilic parameter WMcBr is not a universal measure of reagent nucleophilicity, and Edwards took a more fundamental approach, writing a two-term LFER, Eq. (7-70),... 

The o-nitrobenzenesulfenamide has been used for the protection of amino acids. o-Nitrobenzenesulfenamides, B, are also cleaved by acidic hydrolysis (HCl/Et20 or EtOH, 0°, 1 h, 95% yield)" by nucleophiles (13 reagents, 5 min-12 h, 90% cleaved) by PhSH or HSCH2CO2H, 22°, 1 h by 2-mercaptopyri-dine/CH2Cl2, 1 min, 100% yield) by NH4SCN, 2-methyl-1-indolylacetic acid and by catalytic desulfurization (Raney Ni/DMF, column, a few hours, satisfactory yield). 

In addition to the synthesis of heterocycles, the Corey-Chaykovsky reaction bestows an entry to carbocycles as well. The reaction of (trialkylsilyl)vinylketene 89 with substituted ylide 90 led exclusively to rrans-4,5-dimethyl cyclopentenone 91. The substituted ylide 90 here serves as a nucleophilic carbenoid reagent in the formal [4 +1] annulation reaction. 

As pointed out by Chapman et the steric requirements of the reagents and the degree of solvation of the substrate at the reacting center should also be considered when comparing the nucleophilicities of different amines toward different substrates. The large number of factors which may be involved clearly call for much more work in this area. 

In spite of the potential complexity of the general problem, even when restricted to the reagent family of amines, the nucleophilicities of such series as meta- and pom-substituted pyridines and anilines appear to correlate very closely with the expected substituent effects and with the basicities. This has been verified in the following cases (i) The reaction of pyridines (R = H, m- andp-CHs) with 2-chloro-3-nitro-, 2-chloro-5-nitro-, and 4-chloro-3-nitro-pyridines. ... 

When a positively charged substituent such as the trimethylam-monio group is anywhere on the ring, but most effectively when it is ortho to the leaving group, it can favorably affect the entropy of activation with anionic nucleophiles and accelerate reaction. A recent example of reagent-substituent interaction is the electrophilic substitution of 2-carboxybiphenyl, nitration (non-polar solvent) of which occurs only at the 2 -position and not the 4 -position and has been postulated to be due to the interaction of the nitronium ion with the carboxyl group. 

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