Methyl iodide nucleophilic substitution

Copolymers consisting of (3-CD and EPI were used for the nucleophilic substitution of halogeno-alkanes [20]. The ratio between CD and EPI varied from 3 to 10. Methylated copolymers were also synthesized from the previous ones by methylation. The nucleophilic substitution of three bromo-alkanes was considered as a model reaction using sodium iodide as nucleophile in the presence of P-CD alone or with the synthesized CD-EPl copolymers (Scheme 2.6). 

Substitution processes focused around the carbonyl group as well as at the carbonyl group are, of course, also possible. Consider the case depicted in item 7 of Table 9.9. As noted immediately above for the intermolecular and intramolecular versions of the Claisen condensation, success depends upon generation of an anion a- to the carbon of the carbonyl. Generation of such anions, particularly at fairly high dilution (where reaction between esters is less likely) with hindered bases, followed by addition of an electrophilic species to the reaction medium, results in overall substitution of the electrophilic species for the proton that was removed. In item 7 of Table 9.9, as shown in Scheme 9.147, the methyl ester of cyclohexanecar-boxylic acid (methyl cyclohexanecarboxylate) does not react with the hindered base (LDA) at the carbon of the carbonyl. Rather, the base removes the proton on the carbon a- to the carbonyl and the carbanion so formed then acts as a nucleophile toward methyl iodide (CH3I). Substitution yields methyl 1-methylcyclohexanecarboxylate, lithium iodide, and recovered base, diisopropylamine [(CH3)2CH]2NH. ... 

Nucleophilic reactivity of the sulfur atom has received most attention. When neutral or very acidic medium is used, the nucleophilic reactivity occurs through the exocyclic sulfur atom. Kinetic studies (110) measure this nucleophilicity- towards methyl iodide for various 3-methyl-A-4-thiazoline-2-thiones. Rate constants are 200 times greater for these compounds than for the isomeric 2-(methylthio)thiazole. Thus 3-(2-pyridyl)-A-4-thiazoline-2-thione reacts at sulfur with methyl iodide (111). Methyl substitution on the ring doubles the rate constant. This high reactivity at sulfur means that, even when an amino (112, 113) or imino group (114) occupies the 5-position of the ring, alkylation takes place on sulfiu. For the same reason, 2-acetonyi derivatives are sometimes observed as by-products in the heterocyclization reaction of dithiocarba-mates with a-haloketones (115, 116). 

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... 

Because of its high reactivity toward nucleophilic substitution methyl iodide is the alkyl halide most often used to prepare quaternary ammonium salts... 

Other measures of nucleophilicity have been proposed. Brauman et al. studied Sn2 reactions in the gas phase and applied Marcus theory to obtain the intrinsic barriers of identity reactions. These quantities were interpreted as intrinsic nucleo-philicities. Streitwieser has shown that the reactivity of anionic nucleophiles toward methyl iodide in dimethylformamide (DMF) is correlated with the overall heat of reaction in the gas phase he concludes that bond strength and electron affinity are the important factors controlling nucleophilicity. The dominant role of the solvent in controlling nucleophilicity was shown by Parker, who found solvent effects on nucleophilic reactivity of many orders of magnitude. For example, most anions are more nucleophilic in DMF than in methanol by factors as large as 10, because they are less effectively shielded by solvation in the aprotic solvent. Liotta et al. have measured rates of substitution by anionic nucleophiles in acetonitrile solution containing a crown ether, which forms an inclusion complex with the cation (K ) of the nucleophile. These rates correlate with gas phase rates of the same nucleophiles, which, in this crown ether-acetonitrile system, are considered to be naked anions. The solvation of anionic nucleophiles is treated in Section 8.3. 

The nitration of l,2,5-selenadiazolo[3,4-/] quinoline 77 with benzoyl nitrate affords the 8-nitro derivative 78, whereas methylation with methyl iodide or methyl sulfate afforded the corresponding 6-pyridinium methiodide 79 or methosulfate 80, respectively (Scheme 29). The pyridinium salt 80 was submitted to oxidation with potassium hexacyanoferrate and provided 7-oxo-6,7-dihydro derivative 81 or, by reaction of pyridinium salt 79 with phenylmagnesium bromide, the 7-phenyl-6,7-dihydro derivative 82. Nucleophilic substitution of the methiodide 79 with potassium cyanide resulted in the formation of 9-cyano-6,9-dihydroderivative 83, which can be oxidized by iodine to 9-cyano-l,2,5-selenadiazolo [3,4-/]quinoline methiodide 84. All the reactions proceeded in moderate yields (81IJC648). 

For substituted anilines (Thompson and Williams, 1977) and for 1-naphthylamine and a series of derivatives thereof (Castro et al., 1986a), k2 and the ratio Ar 2/Ar3 have been determined for nucleophilic catalysis with Cl-, Br-, SCN-, and SC(NH2)2. The values of k2 correspond fairly well to those found for the diazotization of aniline, but those of Ar 2/Ar3 increase markedly in the above sequence (Table 3-1). As k3 is expected to be independent of the presence of Cl- or Br- and to show little dependence on that of SCN- or thiourea, the increase in k 2/k3 for this series must be due mainly to 2. Indeed, the value of log(Ar 2/Ar3) shows a linear correlation with Pearson s nucleophilicity parameter n (Pearson et al., 1968). This parameter is based on nucleophilic substitution of iodine (as I-) in methyl iodide by various nucleophiles. The three investigations on nucleophilic catalysis of diazotization demonstrate that Pearson s criteria for bimolecular nucleophilic substitution at sp3 carbon atoms are also applicable to substitution at nitrogen atoms. 

The steric rather than the inductive origin of the secondary deuterium KIE is also suggested because kH/kD = 0.994 per deuterium found in the per-deuteropyridine-methyl iodide reaction is smaller (less inverse) than the kH/kn = 0.988 per deuterium found for the 4-deuteropyridine reaction. A secondary inductive KIE should be more inverse when a deuterium is substituted for a hydrogen nearer the reaction centre, i.e. at the meta- or ortho-rather than at the para-position of the pyridine ring. Thus, if the KIE were inductive in origin, the KIE in the perdeuteropyridine reaction should be more inverse than that observed for the 4-deuteropyridine reaction. If the observed KIE were the result of a steric KIE, on the other hand, a less inverse KIE per deuterium could be found in the perdeuteropyridine reaction, i.e. a less inverse KIE per deuterium would be expected if there were little or no increase in steric hindrance around the C—H(D) bonds as the substrate was converted into the SN2 transition state. Since the KIE per D for the perdeuteropyridine reaction is less than 1%, the transition state must not be sterically crowded and the KIE must be steric in origin. Finally, the secondary deuterium KIEs observed in the reactions between 2-methyl-d3-pyridine and methyl-, ethyl- and isopropyl iodides (entries 3, 7 and 9, Table 17) are not consistent with an inductive KIE. If an inductive KIE were important in these reactions, one would expect the same KIE for all three reactions because the deuteriums would increase the nucleophilicity of the pyridine by the same amount in each reaction. The different KIEs for these three reactions are consistent with a steric KIE because the most inverse KIE is observed in the isopropyl iodide reaction, which would be expected to have the most crowded transition state, and the least inverse KIE is found in the methyl iodide reaction, where the transition state is the least crowded. 

Table 23 The secondary a-deuterium and incoming nucleophile nitrogen KIEs found for the Sn2 reactions between p-substituted N,/V-dimethylanilines and methyl iodide in ethanol at 25°C.a...

Table 24 The calculated and experimental incoming nucleophile nitrogen, a-carbon and secondary a-deuterium KIEs for the SN2 Menshutkin reactions between p-substituted iV.jV-dimethylanilines and methyl iodide at 298 K.°...

The anion of methyl phenylacetate, formed by an electrogenerated base, was homocoupled with iodine or anodically mediated by iodide to afford dimethyl 2,3-diphenylsuccinate in high yield and high d, /-selectivity. This reaction probably does not involve free radicals but an iodination-nucleophilic substitution sequence [194,195]. 

Dibenzopyrrocolines have been prepared by intramolecular addition of benzyne intermediates and by nucleophilic substitutions, as shown in Scheme 6 with the synthesis of ( )-cryptowoline (2) and the related dehydro base 39 by Bennington and Morin (7). ( )-6 -Bromotetrahydroisoquinoline 37, prepared by standard procedures, when heated with copper powder in dimethylformamide afforded dibenzopyrrocoline 38 in low yield, and 39 was formed when 37 was allowed to react with potassium amide in liquid ammonia. Compound 39 was converted to ( )-cryptowoline iodide (2) by hydrogenolysis of O-benzyl ether 39 and quartemization with methyl iodide. 

Depending on the relative nucleophilicities, [Nu]50% ranges from micromolar to molar concentrations (Table 13.5). Although these values represent only order-of-magnitude estimates, they allow some important conclusions. First, in uncontaminated freshwa-ters (where bicarbonate typically occurs at about 10"3 M, chloride and sulfate occur at about 10 4 M, and hydroxide is micromolar or less, Stumm and Morgan, 1996), the concentrations of nucleophiles are usually too small to compete successfully with water in SN2 reactions involving aliphatic halides. Hence the major reaction will be the displacement of the halide by water molecules. In salty or contaminated waters, however, nucleophilic substitution reactions other than hydrolysis may occur Zafiriou (1975), for example, has demonstrated that in seawater ([CL] 0.5 M) an important sink for methyl iodide is transformation to methyl chloride ... 

Metalloporphyrin mono- and di-anions are readily formed, most conveniently by electrochemical methods, and as would be expected they behave as strong nucleophiles. They react rapidly with proton sources or with electrophiles such as methyl iodide, and the products are usually substituted on methine carbons 5 and 15 to give derivatives such as (63), which are called porphodimethenes. 

The immonium salt (98) on reaction with numerous nucleophiles yields 9-substituted indolizidines. From the reaction with benzylmagnesium chloride, (100 R = Ph) is obtained (100 R = C02Et) results from a Reformatsky reaction. Reaction of the bridgehead substituted indolizidines (100) with methyl iodide and base results in /3-elimination with ring opening, a nine-membered heterocycle (101) being formed. This type of reaction has been varied widely. 

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