Methyl iodide substituted pyridine

Berg et al. defined a different ortho steric constant. The model reaction is the quatemization of substituted pyridines with methyl iodide in acetonitrile solution. 

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. 

By changing the reactivity of the alkylating agent, it is possible to vary the magnitude of an ortho steric effect. Thus, the reactivity of 2-substituted pyridines toward Mel in acetone is linearly related on a logarithmic scale to the reactivity of the same substrates toward methyl fluorosulfonate in benzene. The fluorosulfonate is about 104 times more reactive than the iodide, and so the transition state for quaternization occurs earlier. The earlier transition state gives rise to a smaller steric effect the slope of the plot demonstrating the dependence of the steric effect on reactivity is 0.69.76... 

A mixture of 1- and 2-alkylated products was obtained from reaction of 5-methylpyrazolo[4,3-b]pyridine with methyl iodide in ethanolic sodium hydroxide.111 Methylation of reduced pyrazolo[4,3-c]pyrid-3-ones gave either 1- or 3a-substituted products (Scheme 3).149... 

The nucleophilic properties of pyridine nitrogen have been assessed in studies on pyridine-catalyzed Schotten-Baumann reactions133 and aromatic sulfonyl chloride hydrolyses,134 from which highly accurate Bronsted and Hammett treatments arise. There is some doubt as to the mechanism of this reaction.45 Equations (13) and (14) accurately express the reactivity of 3- and 4-substituted pyridines toward ethyl iodide (using rate for equilibrium constants),133 while rates of N-methylation of 2-substituted pyridines have been used to estimate both steric and electronic effects.136... 

Relative Energies and Entropies of Activation in the Reaction of Methyl Iodide with Substituted Pyridines in Nitrobenzene... 

Heating compound 299 with phosphorus pentasulfide in a mixture of dioxane and pyridine gave 7-(2,3,5-tri-0-benzoyI-/3-D-ribofuranosyl) thieno[3,4-d]pyrimidin-4(3//)-thione 374, in 49% yield. Thione 375, obtained by debenzoylating compound 374, was converted into the 4-methyl-thio-7-/3-D-ribofuranosylthieno[3,4-d]pyrimidine 376 by reaction with excess methyl iodide in 0.1 N aqueous sodium hydroxide. Substitution of the... 

Metalation of the parent heterocycle with phenyllithium produced (71a) or (71b) after quenching with cyclohexane or DMF (72JHC1157,75JHC379), respectively, indicating metalation at C-3. Treatment of (71c) with n-butyllithium followed by methyl iodide produced the C-4 substituted compound (71d). The anion was also quenched with various carbonyl compounds (80TL2195). Treatment with Raney nickel afforded 4-methylimidazo[l,5-fl]pyridine (71e). 

In the laboratory of P. Kocovsky, novel pyridine-type P,A/-ligands were prepared from various monoterpenes. The key step was the Krohnke pyridine synthesis, and the chirality was introduced by the a,(3-unsaturated ketone component, which was derived from enantiopure monoterpenes. One of these ligands was synthesized from (+)-pinocarvone which was condensed with the acylmethylpyridinium salt under standard conditions to give good yield of the trisubstituted pyridine product. The benzylic position of this compound was deprotonated with butyllithium, and upon addition of methyl iodide the stereoselective methylation was achieved. The subsequent nucleophilic aromatic substitution (Sw/ r) gave rise to the desired ligand. 

The effect of variation in structure for example changing, the leaving group in the series fluoride, chloride, bromide, iodide and azide ion, has been used extensively in mechanistic studies but results should be viewed only in a confirmatory sense because the essentially gross structural change could cause equally gross mechanistic changes. The selectivity of the reaction between 2-substituted pyridines and methyl iodide appears... 

Harris et al. reported (11) a large variation of the deuterium KIE in the Menschutkin reaction of methyl iodide with substituted pyridines (equation 3 X and Y = CH3, H, and Cl). Because this large variation seems to be good evidence for a change of TS in this series of reactions, the carbon KIE was measured. Reactions were carried out under the same conditions as reported... 

Figure 3. Carbon-13 and a-deuterium KIEs for reactions of methyl iodide with substituted pyridines plotted against relative rates.

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