Rate of quaternization

The steric and electronic effects of substituents on the electrophilic attack at the nitrogen atom have been discussed in the general chapter on reactivity (Section 4.02.1.3). All the conclusions are valid for pyrazoles and indazoles. The effect on equilibrium constants will be discussed in detail in the sections dealing with values (Sections 4.04.2.1.3(iv) and (v)) and the kinetic effects on the rates of quaternization in the corresponding section (4.04.2.1.3(vii)). 

The reactivity of isoxazole toward quaternization is compared with those of pyridine-2-carbonitrile, pyridine and five other azoles in Table 6 (73AJC1949). Isoxazole is least reactive among the six azoles and times less reactive than pyridine. There is also a good correlation between the rate of quaternization and basicity of the azole. 

Sheads studied the reactivity of over 100 alcohols with 2,1-benzisoxazoles with 70% aqueous perchloric acid in nitromethane 74DIS(B)147). The rates of quaternization by reaction with Mel in DMSO were also studied and the dynamics of the reaction investigated <74AJC122l). 

It would therefore be deduced that the availability of the electron pair, as influenced by the ring containing the nitrogen atom, the substituents present in that ring, and the steric environment, should affect the rate of quaternization. Furthermore, the solvent for the reactants and the nature of the group R in Eq. (1) would be expected to be important factors in determining the course of the reaction. In the following sections the importance of each of these factors is considered. 

Even in solution the relative rigidity of the polymer support can play a significant role in the reactivity of attached functional groups. Contrasting studies conducted with chloromethylated derivatives of poly(arylene ether sulfone) (Tg 175°C), phenoxy resin (Tg= 65°C) and polystyrene (Tg= 105°C) allow evaluation of chain rigidity effects. We have shown that the rates of quaternization of chloromethylated poly(arylene ether sulfones) and phenoxy resin deviate from the anticipated second order process at... 

In order to determine the efficiency of the polymers as reagents in nucleophilic catalysis, it was decided to study the rate of quaternization with benzyl chloride. Table I shows the second-order-rate constants for the benzylation reaction in ethanol. Comparison with DMAP indicates that poly(butadiene-co-pyrrolidinopyridine) is the most reactive of all the polymers examined and is even more reactive than the monomeric model. This enhanced reactivity is probably due to the enhanced hydrophobicity of the polymer chain in the vicinity of the reactive sites. 

The dielectric constant of the solvent in the microenvironment of the polymer chain has been shown to be different from that in the bulk solvent (19). This change in dielectric constant might enhance the nucleophilicity of the pyridine ring and therefore increase the rate of quaternization. The kinetic results are consistent with the observations of Overberger et al., (20), who showed that increased hydrophobic nature of the substrate led to faster reaction rates in nucleophilic catalysis. In the present case one would expect the butadiene copolymer to be more hydrophobic than the methylvinylether copolymer. An alternative synthesis of supernucleophilic polymers has been achieved using the following reaction sequence. 

Kinetic studies on the quaternization reaction of pentamethylpyridine (154A, Scheme 64) and its deuterated congener suggest that there may be an equilibium between this aromatic pyridine and its valence isomer, pentamethyl-Dewar-pyridine (154B). It is known that such valence isomers are stabilized by steric factors such as encountered in pentamethylpyridine.194195 On determining conductometrically the initial rate of quaternization with methyl iodide for polymethylpyridines in acetone, it was found that all but one followed clean bimolecular kinetics. Pen-... 

There is good evidence that the a-forms (X, R = R = Me) have a cis and the 3 a trans 5,9-dimethyl configuration with respect to the hydroaromatic ring B (with the piperidine ring as reference, (a- is the trans and the cis isomer). The rates of quaternization of a- are faster than those of the -isomers, reaction in the latter being hindered by the 9-methyl group (cf. (XI) and (XII) in addition,... 

Steric effects on the rates of quaternization of quinoline are magnified as the size of the alkylating agent is increased in the series methyl, ethyl, and isopropyl iodide. In order to reveal the changing steric effect, it is first necessary to eliminate the reduction in rate that naturally occurs as the electrophilic carbon atom of the alkylating agent undergoes sub-... 

In general, the effects of heteroatoms O, S, N, and Se on rates of quaternization of five-membered rings are so variable that only semi-quantitative predictions about their influence on the reactivities of new molecules can be made. 

The 1,5-, 1,8-, 2,5-, and 4,5-diazafluorenes and -fluorenones readily form monomethiodides with methylation occurring in the 1,5- and 1,8-compounds at the 1-position, in the 2,5-isomer at the 2-position, and in the 4,5-isomer at the 4-position. The rate of quaternization of the diazafluorenes is 10-30 times faster than that of the diazafluorenones <79CJC1506>. The diazafluorene quaternary salts on treatment with alkali in sodium acetate buffer yield pseudoazulenes (e.g. (11)) <79ZC374>. 

A kinetic study of the quaternization of (1), (2) and (3) and related heterocycles with dimethyl sulfate (74AJC1917, 65JCS6769) showed the order of activation by the heteroatom in benzazoles to be Se>NMe>S>0 (74AJC1917). Benzo fusion has very little effect on the rate of quaternization of thiadiazole, implying that development of benzenoid character in the product (9) is relatively unimportant as a driving force for the reaction (see Section 4.26.2.9). 

The quantitative effects of -substituents in decreasing the rates of these reactions are not additive and also depend considerably on solvent and alkylating agent. They are low in liquid sulfur dioxide as a solvent where solvation effects are small and the high dielectric constant increases the bond breaking in the transition state. For 3- and 4-substituted pyridines a Br nsted correlation exists between the rates of quaternization and the pKa values <1978AFIG(22)71 >. 

Although isothiazole (pif = 1.90) is less basic than thiazole, its rate of quaternization by dinitrophenyl acetate in water at 52°C is approximately 2.5 times higher (447). This deviation from the Bronsted relationship (A log k = /S.ApiC, with /S positive) is interpreted as a consequence of the a effect of the adjacent sulfur lone pair in isothiazole that is responsible for its higher nucleophilicity (448, 449). 

Ionization constants of 2-carboxypiperazine and the three dicarboxylic acids have been determined (1684), and the nucleophilic reactivity of piperazine compared to other amines in reactions with l-chloro-2,4-dinitrobenzene has been measured (1685). The rate of quaternization of l-ethoxycarbonyl-4-methylpiperazine with allyl bromide (/ = 2.25 1/mol min) and methyl iodide (10A = 1.22) have been measured in acetone-water solution (1686). The composition and structure of the 2-methylpiperazine-carbon disulfide complex has been investigated it was a mixture of l-dithiocarboxy-3-methylpiperazine (138) and the 2-methylpiperazine salt of l,4-bis(dithiocarboxy)-2-methylpiperazine (1687). 

Methylarsines and methylstibines are subject to a number of reactions such as oxidation, quaternization and complex formation, which could facilitate or inhibit their dispersal in the environment . It has been reported that environmentally important concentrations of halocarbons (Mel, MeBr and MeCl) are produced naturally and accumulate in the oceans and the atmosphere. Parris and Brinckman reported quantitative measurements of the rate of quaternization of trimethylstibine and trimethylarsine by alkyl halides in polar solvents. 

Reactions.—Nucleophilic Attack at Carbon. A number of studies of the kinetics of quaternization of phosphines have been reported, all of which lend support to an earlier suggestion that the transition state for such reactions is reactant-like. From the rates of quaternization of a series of heteroaryldiphenylphosphines (54) with a-bromoacetophenone, it was concluded that the r-excessive heterocyclic substituents are not significantly involved in pj,-d conjugative stabilization of the developing phosphonium centre in the transition state of the reaction. Similarly, there is little evidence of conjugative effects in the transition state for quat nization of... 

Methylation of benzoselenazoles with dimethyl sulfate has been reported to give the 3-methylbenzoselenazolium salts. The rate of methylation of a number of azoles, including benzoselenazoles, has been followed by nuclear magnetic resonance (NMR), and it is reported that rates were controlled by the inductive effect of the other heteroatom. There is a good Bronsted correlation between rates of quaternization and the pK of the azoles. 

Methobromides (54JA2431) and methoiodides [60AP74 63AP38 70-LA(737)24] of perhydropyrido[l,2-c][l,3]oxazines were prepared from the bases with the respective methyl halides. The rates of quaternization of 4-methylperhydropyrido[l,2-o][l,3]oxazmes (70T1217), three isomers of per-hydropyrido[l,2-c][l,3]benzoxazines (21-23) (70T1217), and all isomeric perhydropyrido[3,2,l-y][3,l]benzoxazines (25-28) [80JCS(P2)1778] with methyl iodide were measured in acetonitrile at 29-30°C. 

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