Nucleophilicity reactivity, measurement

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). 

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 parameter 5 is a measure of the susceptibility of the substrate to nucleophilic attack, and n a measure of the nucleophilic reactivity as defined by a reference reaction. The rate constants for attack at saturated carbon are used to define the values of n.14 Table 10-4 lists the values of n for certain nucleophiles. This particular compilation lists the... 

The reactions of /3-propiolactone with various nucleophiles in 39 percent water-61 percent dioxane at 50 °C provide an example. Figure 10-4 shows the LFER correlation. The reaction constant for this seven-membered series is s = 0.77. It is a measure of the nucleophilic reactivity relative to the reference reaction. 

In Eq. (10-17), parameters a and b measure the sensitivity of the reaction to these nucleophilic parameters. Since H measures proton basicity and En the electron-donation ability, this treatment models nucleophilicity as a combination of electron loss and electron pair donation. The Edwards equation is thus an oxibase scale of nucleophilic reactivity. Table 10-5 summarizes the nucleophilic parameters. 

In this connection, it is helpful to look first at the reactivity of the anions. There is no generally acceptable measure of nucleophilic reactivity since both the scale and order of relative reactivities depend on the electrophilic centre being attacked (Ritchie, 1972). However, in the present reaction, the similarity in the reactivity of the different anions is remarkable. Thus, the Swain and Scott n-values (cf. Hine, 1962) indicate that the iodide ion should be 100 times more reactive than the chloride ion in nucleophilic attack on methyl bromide in aqueous acetone. In the present reaction, the ratio of the rate coefficients for iodide ions and chloride ions is 1.4. This similarity led to the suggestion that these reactions are near the diffusion-controlled limit (Ridd, 1961). If, from the results in Table 5, we take this limit to correspond to a rate coefficient (eqn 19) of 2500 mol-2 s 1 dm6 then, from the value of ken for aqueous solutions at 0° (3.4 x 109 mol-1 s 1 dm3 Table 1), it follows that the equilibrium constant for the formation of the electrophile must be ca. 7.3 x 10 7 mol-1 dm3. This is very similar to the equilibrium constant reported for the formation of the nitrosonium ion (p. 19). The agreement is improved if allowance is made for the electrostatic enhancement of the diffusion-controlled reaction by a factor of ca. 3 (p. 8) the equilibrium constant for the electrophile then comes to be ca. 2.4 x 10-7. 

Here q SN) is the electron population (not the charge) on atom k, etc. (see below). Note that/ is just the average of/j. and /k. The condensed Fukui functions measure the sensitivity to a small change in the number of electrons of the electron density at atom k in the LUMO (/ "), in the HOMO (fk ), and in a kind of intermediate orbital (/j° ) they provide an indication of the reactivity of atom k as an electrophile (reactivity toward nucleophiles), as a nucleophile (reactivity toward electrophiles), and as a free radical (reactivity toward radicals). 

The principal focus of our examination of the experimental data in Tables IV through IX will be the dependence of the quantity log(ks/kH2o)r on the structures of both the sulfur nucleophile and the haloaliphatic substrate. Log(ks/kH2o)r (referred to here as the "substrate selectivity" for reaction r) is a measure of the selectivity of a particular substrate between each of the sulfur nucleophiles and H2O with respect to halogen displacement via substitution (if r SN) or dehydrohalogenation (if r E). The use of log(ks/kjj2o)r f°r this purpose serves two functions It "normalizes" sulfur nucleophile reactivity data to a common point of reference, and it gives an indication of the importance of each sulfur nucleophile in reactions with the substrate of interest, relative to the most abundant nucleophile in natural waters, H2O. 

The nucleophilic reactivities of silyl enol ethers (58, R1 = alkyl) and silyl ketene acetals (58, R1 = 0-alkyl) have been measured for the triphenylsilyl (R2 = H5) substrate, and its perfluoro analogue (R2 = F5), using benzhydrylium cations as reference electrophiles.224 The triphenyl compound is 10 times less reactive than its trimethyl equivalent, but the perfluorination causes the C=C nucleophilicity to drop by 3-4 orders of magnitude. The new compounds have been placed on scales of nucleophilicity taken from the literature. 

It seems likely that the magnitude of p represents the "extent of electron demand at phosphorus , in the T. S. or in other words is a measure of "electron transfer" in the T.S., a term (=z) which appears in the semi-empirical equations describing the nucleophilic reactivity of tricoordinated phosphorus. This concept is reinforced by (i) the observation (from the data of Bokonov. and Goetz ) that p-values based on the pKg values of protonated phosphines increase with increasing pKa, i.e. increase with a shift of the equilibrium (eqn. 4) to the left and... 

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). 

As explained earlier, Figures 1 and 2 will not be greatly changed if data in solution are used. Individual bases will move up or down, parallel to the lines shown. Therefore, under the normal conditions for nucleophilic substitution, ease of oxidation (E0 ) and Brpnsted basicity are not independent parameters for bases where the donor atom is a second-row element. Either parameter may be used as a measure of nucleophilic reactivity. 

The process represented by V — IV occurs, however, in the solvolysis of a preionized material, such as triethyloxonium fluorophosphate, which was employed by Kevill and Lin (21) to establish a scale of nucleophilicity parameters, N. Because the effect of variable anion stabilization by solvent was not subtracted, whether their N values measure true and only nucleophilic reactivities is uncertain. This doubt would be dispelled, however, by an experiment in which the reagent would be treated with small amounts of nucleophile in a better anion-stabilizing solvent, such as TFA, or even sulfuric acid. 

Nevertheless, the use of relative reactivities to characterize carbenic philicity is restrictive the apparent philicity is related to the alkenes selected for the relative reactivity measurements. What if the set of alkenes were expanded by the addition of an even more electron-deficient alkene Such a test was applied in 1987 [65], using a-chloroacrylonitrile, 26, which is more 7t-electron deficient than acrylonitrile, 27. We found that PhCF or PhCCl added 15 or 13 times, respectively, more rapidly to 26 than to 27. In preferring the more electron-deficient olefin, the carbenes exhibited nucleophilic character. However, because they also behave as electrophiles toward other alkenes (Table 4), they must in reality be ambiphiles. In fact, we now realize that all carbenes have the potential for nucleophilic reactions with olefins the crucial factor is whether the carbene s filled a orbital (HOMO)/alkene vacant Ji orbital (LUMO) interaction is stronger than the carbene s vacant p orbital (LUMO)/aIkene filled k orbital (HOMO) interaction in the transition state of the addition reaction. [63]... 

To assess the importance of nucleophilic substitution reactions of naturally occurring nucleophiles it is necessary to have some measure of their reactivity, relative to OH" and HjO. A number of properties of nucleophiles, all of which are some measure of the nucleophile s ability to donate electrons to an electrophile, have been used to correlate nucleophilic reactivity. These closely related properties include basicity, oxidation potential, polarizability, ionization potential, electronegativity, energy of the highest filled molecular orbital, covalent bond strength, and size (Jencks, 1987). 

The concepts are linked but are not the same. Nucleophilic reactivity is measured by the rate of reaction, whereas base strength is measured by the equilibrium constant, K. Here, we can use the acidity of the acid HX to get an idea of the ability of X" as a leaving group in nucleophilic substitution, since both Eqs. (3.8) and (3.9) have X" on the right-hand side ... 

Nucleophilicity A measure of the reactivity of a Lewis base in a nucleophilic substitution reaction. 

Edwards attempted to improve the correlation of nucleophilicity with substrate reactivity by considering separately two different components of nucleophilic reactivity. Two equations were presented, and the distinction between them is not always clear in the literature. In deriving equation 8.38, Edwards noted that basicity is only one measure of a nucleophile s tendency to donate electrons, the other being its oxidation potential. To the extent that the transition structure for an Sn2 reaction resembles a partially oxidized... 

Attempts to obtain general measures of nucleophilic reactivity include that of Ritchie [59]. He initially measured rate constants for combination of anionic nucleophiles with organic cations, such as triarylmethyl and tropylium cations, and was able to obtain the relation given in Equation 6.1 for nucleophilicity. Here, k and q are respectively the rate constants for reaction of the cation with the nucleophile and with water. 

The rates of several substitution reactions at palladium(n) have been measured in methanol. For rra 5-[PdL2(N02)2] + Y ->-fra//j-[PdL2(N02)Y] + NO2-, where L = PPr"s, AsEtg, or piperidine and Y = Cl, N3-, Br, I, SCN, or (NH2)2CS, a set of nucleophilic reactivity constants npd = log ( alMeOHj/Ari) has been calculated, where and refer to rate constants for the solvolytic path and for direct nucleophilic attack on the complex rra/ij-[Pd(PPr 3)2(N02)2l. All the complexes studied obey the linear free-energy relation log kz = jnpd + log kx, where j is a nucleophilic discrimination factor. The npd sequence resembles that already found for platinum(n) complexes. 

Sufficient results are lacking to quantitatively test equations (46), (49), and (50). Procurement of appropriate data, therefore, is desirable. The right hand side of equation (49) has been tested by plotting the variation of a against the variation of pit a of the conjugate acid of the nucleophile (taken as a measure of nucleophilic reactivity) to... 

Site-specific reactivity indices are arrived at by considering electronic information at specific locations in the molecule. The electrophilic and nucleophilic superdelocalizabilities at atom i are energy-weighted atomic electron densities. The electrophilic superdelocalizability roughly measures the availability of electrons at atom i nucleophilic superdelocalizability measures the availability of room on atom i for additional electron density. While these indices are atomic in nature, they may be classified as whole molecule descriptors if atom i is a fixed position in a series of congeners, or if the maximum superdelocalizability among all the atoms is chosen. 

The presence of B(OH>3 increases the rate of hydrolysis of ionized phenyl salicylate (PS ) by nearly 10 -fold compared to the rate of hydrolysis of phenyl benzoate under essentially similar conditions (Equation 2.34). However, the hydrolysis of PS crtn also occur with measurable rate in the absence of B(OH)3. Nearly 10 -fold rate enhancement due to the presence of boric acid is attributed to the boric-acid-induced intramolecular reaction involving transition state TS,6. An alternative and kinetically indistinguishable mechanism involving transition state TSiy has been ruled out on the basis of the absence of enhanced nucleophilic reactivity of tertiary and secondary amines toward phenyl salicylate in the presence of borate buffer. 

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