Methyl nucleophilic attack

As we have seen the nucleophile attacks the substrate m the rate determining step of the Sn2 mechanism it therefore follows that the rate of substitution may vary from nucleophile to nucleophile Just as some alkyl halides are more reactive than others some nucleophiles are more reactive than others Nucleophilic strength or nucleophilicity, is a measure of how fast a Lewis base displaces a leaving group from a suitable substrate By measuring the rate at which various Lewis bases react with methyl iodide m methanol a list of then nucleophihcities relative to methanol as the standard nucleophile has been compiled It is presented m Table 8 4... 

Nucleophilic Reactions. The strong electronegativity of fluorine results in the facile reaction of perfluoroepoxides with nucleophiles. These reactions comprise the majority of the reported reactions of this class of compounds. Nucleophilic attack on the epoxide ring takes place at the more highly substituted carbon atom to give ring-opened products. Fluorinated alkoxides are intermediates in these reactions and are in equiUbrium with fluoride ion and a perfluorocarbonyl compound. The process is illustrated by the reaction of methanol and HFPO to form methyl 2,3,3,3-tetrafluoro-2-methoxypropanoate (eq. 4). 

A related but distinct rhodium-catalyzed methyl acetate carbonylation to acetic anhydride (134) was commercialized by Eastman in 1983. Anhydrous conditions necessary to the Eastman acetic anhydride process require important modifications (24) to the process, including introduction of hydrogen to maintain the active [Rhl2(CO)2] catalyst and addition of lithium cation to activate the alkyl methyl group of methyl acetate toward nucleophilic attack by iodide. 

Methylpyridinium quaternary salts, such as (12), undergo oxidation in alkaline solution in the presence of potassium ferricyanide to give 2-pyridones, eg, A/-methyl-2-pyridone [694-85-9] (16). Frequendy nucleophilic attack at position 2 by excess hydroxide leads to ring opening this and synthetically useful recycli2ations have been reviewed (17). 

Reaction of various pyridazine derivatives with nitromethane or nitroethane in DMSO affords the corresponding 5-methyl and 5-ethyl derivatives. The reaction proceeds as a nucleophilic attack of the nitroalkane at the position 5. In this way, 3,6-dichloro-4-cyano-pyridazine, 4-carboxy- and 4-ethoxycarbonyl-pyridazin-3(2//)-ones and 4-carboxy- and 4-ethoxycarbonyl-pyridazin-6(lH)-ones can be alkylated at position 5 (77CPB1856). 

In many cases, substituents linked to a pyrrole, furan or thiophene ring show similar reactivity to those linked to a benzenoid nucleus. This generalization is not true for amino or hydroxyl groups. Hydroxy compounds exist largely, or entirely, in an alternative nonaromatic tautomeric form. Derivatives of this type show little resemblance in their reactions to anilines or phenols. Thienyl- and especially pyrryl- and furyl-methyl halides show enhanced reactivity compared with benzyl halides because the halogen is made more labile by electron release of the type shown below. Hydroxymethyl and aminomethyl groups on heteroaromatic nuclei are activated to nucleophilic attack by a similar effect. 

Bromine in chloroform and bromine in acetic acid are the reagents used most often to brominate pyrazole. When nitric acid is used as a solvent, both bromine and chlorine transform pyrazoles into pyrazolones (Scheme 24). Thus 3-methyl-l-(2,4-dinitrophe-nyOpyrazole is brominated at the 4-position (309). The product reacts with chlorine and nitric acid to give the pyrazolone (310). The same product results from the action of bromine and nitric acid on (311). The electrophilic attack of halogen at C-4 is followed by the nucleophilic attack of water at C-5 and subsequent oxidation by nitric acid. 

Electrophilic attack on the sulfur atom of thiiranes by alkyl halides does not give thiiranium salts but rather products derived from attack of the halide ion on the intermediate cyclic salt (B-81MI50602). Treatment of a s-2,3-dimethylthiirane with methyl iodide yields cis-2-butene by two possible mechanisms (Scheme 31). A stereoselective isomerization of alkenes is accomplished by conversion to a thiirane of opposite stereochemistry followed by desulfurization by methyl iodide (75TL2709). Treatment of thiiranes with alkyl chlorides and bromides gives 2-chloro- or 2-bromo-ethyl sulfides (Scheme 32). Intramolecular alkylation of the sulfur atom of a thiirane may occur if the geometry is favorable the intermediate sulfonium ions are unstable to nucleophilic attack and rearrangement may occur (Scheme 33). 

Azetidine, 7V-bromo-, 7, 240 Azetidine, AT-r-butyl- N NMR, 7, 11 Azetidine, AT-t-butyl-3-chloro-transannular nucleophilic attack, 7, 25 Azetidine, 3-chloro-isomerization, 7, 42 Azetidine, AT-chloro-, 7, 240 dehydrohalogenation, 7, 275 Azetidine, 7V-chloro-2-methyl-inversion, 7, 7 Azetidine, 3-halo-synthesis, 7, 246 Azetidine, AT-halo-synthesis, 7, 246 Azetidine, AT-hydroxy-synthesis, 7, 271 Azetidine, 2-imino-stability, 7, 256 Azetidine, 2-methoxy-synthesis, 7, 246 Azetidine, 2-methyl-circular dichroism, 7, 239 optical rotatory dispersion, 7, 239 Azetidine, AT-nitroso-deoxygenation, 7, 241 oxidation, 7, 240 synthesis, 7, 246 Azetidine, thioacyl-ring expansion, 7, 241 Azetidine-4-carboxylic acid, 2-oxo-oxidative decarboxylation, 7, 251 Azetidine-2-carboxylic acids absolute configuration, 7, 239 azetidin-2-ones from, 7, 263 synthesis, 7, 246... 

Benzothiazole, 2-methyl-2-phenyl-2,3-dihydro-synthesis, 6, 325 Benzothiazole, 2-nitro-reactions, 6, 285 Benzothiazole, 5-nitro-nucleophilic attack, 5, 62 reactions... 

Isoxazole, 3-acetyl-4-chloro-5-methyl-oxidation, 6, 27, 53 Isoxazole, 3-acetyl-4,5-dimethyl-oxidation, 6, 27, 53 Isoxazole, 5-acetyl-3-methoxy-reactions, 6, 53 Isoxazole, 3-acyl-furazans from, 6, 417 nucleophilic attack, S, 93 reactions with bases, 6, 30... 

H-Pyrido[2,l-i]purine-9-carboxylic acid, 7-oxo-methyl ester, 5, 566 Pyrido[2,3-6]pyrazine, amino-nucleophilic attack, 3, 253 Pyrido[2,3-h]pyrazine, 6-chloro-reactions... 

Pyridopyridazines, hydroxyalkyl-nucleophilic attack, 3, 241 Pyridopyridazines, methyl-electrophilic reactions, 3, 240 Pyrido[2,3-6]pyridazines nucleophilic substitution, 3, 253-254 Pyrido[2,3-c]pyridazines, 3, 232-233 benzo fused, 3, 233 N-oxide... 

Pyrrolo[2,3-d]pyrimidine, 5-cyano-bromination, 4, 506 Pyrrolo[2,3-d]pyrimidine, 5-nitroso-nucleophilic reactions, 4, 507 Pyrrolo[l, 2- c]pyrimidine-3-carboxylic acids methyl ester synthesis, 4, 293 Pyrrolopyrimidine-2,4-diones Mannich reaction, 4, 504 Vilsmeier reaction, 4, 505 Pyrrolopyrimidines synthesis, 4, 514, 517, 524, 527 Pyrrolopyrimidines, chloro-nucleophilic attack, S, 312 Pyrrolo[2,3-d]pyrimidines NMR, 4, 500... 

Sulfonates react with a variety of nucleophiles. Synthesis of M A -bis(trifluoro-methyl)aminotnfluoromethanesulfonate and its reactions with nucleophiles were investigated [33] (equation 31) (Table 13). Nucleophilic attack occurs at either nitrogen or sulfur amines give complex mixtures [33]. Polyfluoroalkyl fluorosul-fates react with amines, alcohols, or alkoxides to yield polyfluoroalkyl sulfamates and dialkyl sulfates, respectively [34] (equation 32) (Table 13). In these reactions. 

The addition of primary amines to fluoroolefins under anhydrous conditions yields imines The hexafluoropropene dimer, perfluoro-2-methyl-2-pcntcne, and ten butylamine react to yield a mixture of two compounds m a 9 4 ratio [4] (equation 3) rather than just the major keteiiimme-imine, as previously reported [5] It IS claimed that this result is possible by means of isomerization to the terminally unsaturated difluoromethylene isomer prior to nucleophilic attack Secondary amines add to fluoroolefins under anhydrous conditions to give fluonnated ternary amines m good yields If the fluoroolefin is added to the amine without cooling the reaction mixture, or if an excess of the secondary armne is used, there is a tendency toward dehvdrofluonnation of the ternary amine The products... 

Diffusion-limited rate control at high basicity may set in. This is more eommonly seen in a true Br nsted plot. If the rate-determining step is a proton transfer, and if this is diffusion controlled, then variation in base strength will not affect the rate of reaction. Thus, 3 may be zero at high basicity, whereas at low basicity a dependence on pK may be seen. ° Yang and Jencks ° show an example in the nucleophilic attack of aniline on methyl formate catalyzed by oxygen bases. 

Examine the highest-occupied molecular orbital (HOMO of cyanide anion. Is the larger lobe on carbon or nitrogen Would you expect cyanide to act as a carbon or nitrogei nucleophile Does this lead to the lower energy transitioi state (compare the energy of cyanide-l-methyl iodide ( attack and cyanide+methyl iodide N attack) ... 

LUMO of methyl bromide reveals the likely site of nucleophilic attack. 

Molecules that possess more than one nucleophilic si are referred to as ambident nucleophiles. Sn2 reactioi involving these nucleophiles may lead to mixtures i products. For example, nucleophilic attack by nitrite c methyl bromide gives both nitromethane and methyl nitrit... 

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