Methyl iodide, reaction with nucleophiles

The synthetic access to a broad variety of nucleophilic [ C]methyl and [ " C]methylene synthons has significantly widened the scope of [ C]methyl iodide. Reaction with... 

Potassium or lithium derivatives of ethyl acetate, dimethyl acetamide, acetonitrile, acetophenone, pinacolone and (trimethylsilyl)acetylene are known to undergo conjugate addition to 3-(t-butyldimethylsiloxy)-l-cyclohexenyl f-butyl sulfone 328. The resulting a-sulfonyl carbanions 329 can be trapped stereospecifically by electrophiles such as water and methyl iodide . When the nucleophile was an sp -hybridized primary anion (Nu = CH2Y), the resulting product was mainly 330, while in the reaction with (trimethylsilyl)acetylide anion the main product was 331. 

Compound LII, on the other hand, can be made readily. It can have either the planar tricovalent boron structure or the "triptych tetra-covalent structure. In the latter structure the nitrogen is attached to boron and should be considerably less basic and nucleophilic than usual. It does in fact react unusually slowly with methyl iodide and with acids. The neutralization reaction with acids in water is not only slow but of zero order with respect to the acid. It is believed to have a rate-determining transformation from the triptych to the more basic form as the first step. 

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. 

In the case of monomer 23 it appears that an equilibrium exists between ionic and covalent propagating species in polymerisations initiated by methyl iodide, though with OT counterion only ionic intermediates are observed. Presumably therefore the effective nucleophilicity of this monomer is very similar to that of I. N-(2-iodopropyl)-N-methyl formamide was prepared from an equimolar reaction of methyl iodide with 23, and H NMR spectroscopy in CD3CN showed that the following equilibrium was rapidly established ... 

The reaction has some similarity to the hydroformylation reaction described in Section 31-4B. The hydrogen iodide is required to transform methanol to methyl iodide. The rhodium catalyst then reacts with the methyl iodide as a nucleophilic reagent ... 

The Sn2 reaction of methyl iodide (iodomethane) with hydroxide ion is a concerted reaction, taking place in a single step with bonds breaking and forming at the same time. The middle structure is a transition state, a point of maximum energy, rather than an intermediate. In this transition state, the bond to the nucleophile (hydroxide) is partially formed, and the bond to the leaving group (iodide) is partially broken. Remember that a transition state is not a discrete molecule that can be isolated it exists for only an instant. 

Since the reaction of nucleophiles with methyl iodide can be measured much more easily and accurately by spectroscopic analysis of the product iodide ion, a subsequent set of n values was devised using Equation (44). The n value of methanol with methyl iodide is set at zero and the reaction constant, s, at unity. Values of n derived from the methyl iodide reaction are tabulated in Appendix 3, Table 5. 

A third characteristic that can make a molecule or an ion electrophilic is a relatively weak bond to an atom that can depart as a stable ion or molecule. These electrophilic species can be considered electron seeking because their reactions with nucleophiles CTeate stronger bonds and therefore more stable molecules, hi such cases, there is often no partial or full positive charge on the electrophilic atom. Molecular halogens (X2) are good examples. Their bonds are weak relative to the ones they form upon reaction with a nucleophile this process is further aided by release of a stable halogen anion (X ). Another example of a molecule that is electrophilic for these reasons is methyl iodide (we examine its reactions with nucleophiles in Chapter 9). There is little to no charge polarity in methyl iodide. However, the carbon is electrophilic because its bond to iodine is weak, and reaction with a nucleophile produces the stable iodide (I ) anion. 

Quatemization of the compounds 195b with methyl iodide and subsequent reactions with nucleophiles, e.g. potassium cyanide, thiophenol, and diethyl malonate, gave corresponding products 196-198 in 62-85 % yields [64]. 

Many replacement reactions are often much faster in polar aprotic solvents than in hydroxylic solvents. Thus, the reaction of methyl bromide with iodide is about 500 times faster in acetone than in methyl alcohol. In addition, methyl iodide reacts with chloride about a million times faster in DMF than in methyl alcohol. This happens because the OH group of hydroxylic solvents solvates anions, forming the hydrogen bond (ROH-"X -HOR). The solvated anions are therefore much less reactive. On the other hand, aprotic solvents having no hydrogen are unable to form hydrogen bonds. Anions in polar aprotic solvents are therefore more free, more reactive, and thus better nucleophiles. Another example of a strong solvent effect on a 8 2 reaction is the bimolecular replacement of bromide by azide in 1-bromobutane ... 

The reactivity of these group 4 metal complexes has been studied to some extent. Starting from complex [(6)MCl2], the reaction with nucleophiles such as alkylhthium led to the classical reactivity at M-Cl (Scheme 32) [89]. The reactions with strong electrophiles such as isocyanates, carbon dioxide, or carbodiimide did not show the expected insertion into the M=C bond, but rather a [2+2] cycloaddition. The basicity and nucleophilicity of the C center was proved by reactions with aromatic amines, phenols, aliphatic alcohols, or methyl iodide leading to the 1,2 addition product. 

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). 

Empirical measures of nucleophilicity may be obtained by comparing relative rates of reaction of a standard reactant with various nucleophiles. One measure of nucleophilicity is the nucleophilic constant ( ), defined originally by Swain and Scott. Taking methanolysis of methyl iodide as the standard reaction, n was defined as... 

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). 

As inert as the C-25 lactone carbonyl has been during the course of this synthesis, it can serve the role of electrophile in a reaction with a nucleophile. For example, addition of benzyloxymethyl-lithium29 to a cold (-78 °C) solution of 41 in THF, followed by treatment of the intermediate hemiketal with methyl orthoformate under acidic conditions, provides intermediate 42 in 80% overall yield. Reduction of the carbon-bromine bond in 42 with concomitant -elimination of the C-9 ether oxygen is achieved with Zn-Cu couple and sodium iodide at 60 °C in DMF. Under these reaction conditions, it is conceivable that the bromine substituent in 42 is replaced by iodine, after which event reductive elimination occurs. Silylation of the newly formed tertiary hydroxyl group at C-12 with triethylsilyl perchlorate, followed by oxidative cleavage of the olefin with ozone, results in the formation of key intermediate 3 in 85 % yield from 42. 

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