Relative nucleophilicity

As we have seen, the nucleophile attacks the substrate in the rate-detennining 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 in methanol, a list of their- nucleophilicities relative to methanol as the standard nucleophile has been compiled. It is presented in Table 8.4. 

A qualitative difference in the type of solvation (not simply in the strength of solvation) in a series of nucleophiles may contribute to curvature. Jencks has examined this possibility. " " An example is the reaction of phenoxide, alkoxide, and hydroxide ions with p-nitrophenyl thiolacetate, the Br insted-type plot showing Pnuc = 0.68 for phenoxide ions (the weaker nucleophiles) and Pnu = 0.17 for alkoxide ions. It is suggested that the need for desolvation of the alkoxide ions prior to nucleophilic attack results in their decreased nucleophilicity relative to the phenoxide ions, which do not require this desolvation step. 

According to the theory of nucleophilicity (Edwards and Pearson, 1962 Bunnett, 1963 Pearson et al., 1968), the relative order of nucleophilicity relative to the major groups in biological molecules can be summarized as follows ... 

Current understanding of the leveling in reactivity of oximate a-nucleophiles, relative to aryloxide nucleophiles, with change in solvent medium, rests on ideas first proposed by Jencks, then developed by Bernasconi and subsequently applied to detoxification of... 

Nucleophile Relative rate Relative rate in protic media... 

Why are the differences in nucleophilicity relatively the same over many different substitution reactions Nucleophilicity describes the ability of the nucleophile to make an electron pair available to the electrophile (i.e., the alkylating agent). With this as the basic idea, the experimentally observable nucleophilicity trends can be interpreted as follows. 

Reduced reactivity toward sulfur-containing soft nucleophiles relative to cisplatin, including glutathione ... 

The following examples illustrate how the local steric electronic environment can reverse the expected selectivity for the deprotection of TIPS ether verses a TBS ether. The allylic TBS ether is also less nucleophilic relative to the TIPS ether because of electron withdrawing character of the olefin. ... 

TABLE 2. Examples of Important Environmental Nucleophiles, Their Nucleophilicities Relative to Water (n Values), and Estimated Concentrations of Nucleophiles ([nucl]50%) Necessary to Compete with Water in an SN2 Reaction with Primary Alkyl Bromides"... 

Quantitative Scales of Solvent Nucleophilicity. Solvolytic studies in solvents of low nucleophilicity led to renewed interest in quantitative measures of solvent nucleophilicity. Peterson and Waller (44) derived a scale of solvent nucleophilicity (Npw) from the rates of displacement by solvent of tetramethylenehalonium ions (VI) in liquid sulfur dioxide. The reaction is approximately half-order in carboxylic acid, possibly because dimer-monomer preequilibrium occurs (44). More recently, hydrolysis of the iodonium salt (VIII) in competition with anionic or solvent nucleophiles was studied. A scale of nucleophilicity relative to water was obtained by quan-... 

Common ion rate depression for solvolysis of RX with the same R but with different leaving groups X was followed only for a single system. From the a values obtained in the solvolysis of ( )- and (Z)-l,2-dianisyl-2-phen-ylvinyl-X, 16, in AcOH-AcO- (equation 9), relative reactivities toward the derived ion 17 were measured (74) (nucleophile, relative reactivity) OMs-, 0.16 OAc, 1.0 Cl , 15.2 Br 45.5 and AcOH, 0.0024. From other data, I will probably be at the top of a similar order (75) and 2,4,6-trinitrobenzene-sulfonate at the bottom (76). 

Strong solvation lowers the energy of an anionic nucleophile relative to the TS, in which the charge is more diffuse, and results in an increased E. Viewed from another perspective, the solvation shell must be disrupted to attain the TS and this desolvahon contributes to the activation energy. 

Nucleophilicities relative to a standard solvent can be quantified by the Swain-Scott equation (12)66, in which k and k0 are the second-order rate constants for reactions of the nucleophile and solvent respectively, and s is a measure of the sensitivity of the substrate to nucleophilicity n. By this definition, the nucleophilicity of the solvent is zero. For all reactions examined, there will be competition between attack by solvent (present in large excess) and reaction with added anionic nucleophiles. Hence, only n values well above zero can be obtained with satisfactory reliability. In the original work66, the solvent was water and all but one of the substrates were neutral s was defined as 1.0 for methyl bromide and was calculated to be 0.66 for ethyl tosylate the lowest reliable n value reported was 1.9 for picrate anion, but a value of < 1 for p-tosylate anion was reported66 in a footnote. 

Whether attack on the Re face forms the i or 5 enantiomer depends on the priority of the attacking nucleophile relative to the priorities of the groups attached to the carbonyl carbon. For example, we just saw that attack by hydride ion on the Re face of butanone forms (5)-2-butanol, but attack by a methyl Grignard reagent on the Re face of propanal forms (i )-2-butanol. 

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