Nucleophilicity measurement

Once we determine that a reagent is acting as a nucleophile, we measure how fast it functions that way with the term nucleophilicity. Nucleophilicity measures how quickly a reagent will attack another compound. For example, we saw above that water can function as a nucleophile because it has lone pairs that can attack a compound. But the hydroxide ion will clearly be more nucleophilic—the hydroxide ion has a negative charge, so it will attack compounds/fli ter. 

FIGURE 13.3 Comparison between calculated nucleophilicity (to-, in eV) and experimental efficiency (nucleophilicity measure) for anions in the X- + CH3C1 reaction. (Reprinted from Jaramillo, P., Perez, P., Contreras, R., Tiznado, W., and Fuentealba, P., J. Phys. Chem. A, 110, 8181, 2006. With permission.)... 

Now- we can understand this difference between nucleophilicity and basicity. Nucleophilicity measures how fast things happen, which is called kinetics. Basicity measures stability and the position of equilibrium, which is called thermodynamics. Throughout your course, you will see many reactions where the product is determined by kinetic concepts, and you will also see many reactions where the product is determined by thermodynamic concepts. In fact, there will even be times, where these two factors are competing with each other and you will need to make a choice of which factor wins kinetics or thermodynamics. 

The cysteine has a lowered pKa value, which amplifies its nucleophilicity. Measurement of the pH profile of the rate of... 

Nucleophilicity measures the ability of a nucleophile to react at an electron-deficient center. It should not be confused with basicity, although often there are parallels between the two. Whereas nucleophilicity considers the reactivity (i.e., the rate of reaction) of an electron-rich species at an electron-deficient center (usually carbon), basicity is a measure of the position of equilibrium in reaction with a proton. 

Nucleophilicity roughly parallels basicity when comparing nucleophiles that have the same attacking atom (Table 11.2). For example, OH is both more basic and more nucleophilic than acetate ion, CHsCO , which in turn is more basic and more nucleophilic than H2O. Since nucleophilicity measures the affinity of a Lewis base for a carbon atom in the S 2 reaction, and basidty measures the eifBnity of a base for a proton, it s esisy to see why there might be a correlation between the two kinds of behavior. ... 

Nucleophilic strength depends on two factors, the nature of the substrate (s) and the strength of the nucleophile, measured by its nucleophilicity (n). Nucleophilic strength for a given species is given by the Swain-Scott equation [ log = (s) (n) ] where n = 0 for water at 25°C, s - 2.00 for methyl... 

There is some dependence on the basicity of the nucleophile, measured by the pK value of its corresponding acid particularly in series of structurally related nucleophiles. Examples are in the reactions of m- and p-substituted anilines with l-chloro-2,4-dinitrobenzene [1] and of substituted phenoxide ions with halogenonitrobenzenes [9]. Similarly, the reactivities of m- and p-substituted thiophenoxide ions with l-chloro-2,4-dinitrobenzene closely parallel their basicities [56]. 

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). 

The mechanisms by which nucleophilic substitution takes place have been the subject of much study Extensive research by Sir Christopher Ingold and Edward D Hughes and their associates at University College London during the 1930s emphasized kinetic and stereochemical measurements to probe the mechanisms of these reactions... 

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... 

Rate increases with increasing po larity of solvent as measured by its dielectric constant e (Section 8 12) Polar aprotic solvents give fastest rates of substitution solvation of Nu IS minimal and nucleophilicity IS greatest (Section 8 12)... 

Nucleophilicity (Section 8 7) A measure of the reactivity of a Lewis base in a nucleophilic substitution reaction... 

Compounds of types (286) and (287) are in tautomeric equilibria with 4- or 5-hydroxyazoles. However, the non-aromatic form is sometimes by far the most stable. Thus oxazolinone derivatives of type (287) have been obtained as optically active forms they undergo racemization at measurable rates with nucleophiles (77AHC(21)175). Reactions of these derivatives are considered under the aromatic tautomer. 

If it is assumed that ionization would result in complete randomization of the 0 label in the caihoxylate ion, is a measure of the rate of ionization with ion-pair return, and is a measure of the extent of racemization associated with ionization. The fact that the rate of isotope exchange exceeds that of racemization indicates that ion-pair collapse occurs with predominant retention of configuration. When a nucleophile is added to the system (0.14 Af NaN3), k y, is found to be imchanged, but no racemization of reactant is observed. Instead, the intermediate that would return with racemization is captured by azide ion and converted to substitution product with inversion of configuration. This must mean that the intimate ion pair returns to reactant more rapidly than it is captured by azide ion, whereas the solvent-separated ion pair is captured by azide ion faster than it returns to racemic reactant. 

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... 

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