Nucleophilicity and Nucleofugality

In several of the reactions that you learned in introductory organic chemistry, and many of those that are discussed in Chapters 10 and 11, nucleophilic attack on an electron deficient center such as a carbocation or a polarized cr or -ir bond occurs. The ability of nucleophiles to participate in these reactions depends upon their molecular structure. A structural dependence suggests that there should be scales of relative nucleophilicity that depend upon the sterics, polarizability, and inductive/resonance properties of the nucleophile. Hence, changing the nucleophile becomes one of the tools that we have to study reactions. As with solvent and electronic substituent effects, LFERs provide insight into how the change in nucleophile structure affects the reaction. Similarly, the ability of a leaving group to depart 

The Use of the Schleyer Method to Determine the Extent of Nucleophilic Assistance in the Solvolysis of Arylvinyl Tosylates 

The solvolysis of vinyl tosylate i proceeds via an sp hybridized carbocation. The Grunwald-Winstein m value for this reaction was found to be small (0.62) for such an ionization reaction, indicating much less stabilization from the solvent than occurs in the ionization of f-butylchlor-ide. This small m value could be due to increased nucleophilic assistance, or stabilization of the carbocation by some other factor, making the role of the solvent less important. 

Stabilization of a vinyl cation via conjugation with phenyl 

To discover if any nucleophilic assistance occurs with /, the Schleyer method was used. Instead of plotting an entire series of solvents with different Y and N values, followed by the application of Eq. 8.42, the investigators simply chose two solvent systems with the same Y values, but differentnucleophilicities. Ethanol/water (98 2) and acetic acid both have Y values of-1.68, but Nqts values of 0.0 and -2.35, respectively (see Table 8.4). Following the kinetics of solvolysis of i revealed a difference in rate constants in the two solvents of only 25%. Given the large difference in N values, the small difference in rate constants indicates that nucleophilic assistance does not occur in the solvolysis of I. Therefore, the stabilization imparted by the benzene ring is the reason for the low m values. 

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The proportion of C-alkylation increases in the order OTs < Br < I, a sequence which is often associated with the balance of hardness between nucleophile and nucleofuge (Smith and Hanson, 1971). The work of Kurts et al. (1974) indicates that the overall reaction rate of the crown ether-assisted alkylation increases in the order Na+ < K+ < Rb+ < Cs+, which, according to these authors, reflects the increasing distance between cation and anion in the ion pairs. The high reactivity of the tetraphenylarsenate also fits in with this picture. The decrease of the kc/k0 ratio is only small in good cation-solvating solvents such as dimethyl sulfoxide (DMSO). Alkylation of the sodium derivative of [103] with ethyl iodide in DMSO gave kc/kQ = 15.7 addition of... 

Hammett s p = 1.07 in MeCN. The Ad -E route is the dominant reaction pathway, as revealed by the effects of the changes in the substituent, solvent, nucleophile and nucleofuge no competitive 5n1 reaction was observed. ... 

For thermoneutral identity reactions, there is no thermochemical driving force. In the case of non-identity nucleophilic substitution reactions - when the nucleophile and nucleofuge are different - reaction exothermicity may be taken quantitatively into account. This can be quite elegantly considered by applying the simple Marcus equation [104-109]. For cationic reactions, where interactions with the neutral nucleophile and nucleofuge are quite weak,... 

Hayami, J., Hihara, N., Kaji, A. Sn2 reactions in dipolar aprotic solvents. IX. An estimation of nucleophilicities and nucleofugicities of anionic nucleophiles studied in the reversible Finkelstein reactions of benzyl derivatives in acetonitrile - dissociative character of the reaction as studied by the nucleofugicity approach. Chem. Lett. 1979, 413-414. 

The more stable the negative charge of the nucleophilic atom, the less nucleophilic it is. For example, due to differing resonance stabilization, an alkoxide is more nucleophilic than a phenoxide, which in turn is more nucleophilic than a carboxylate. This trend reflects the relative basicities, as well. Below we will describe LFERs for nucleophilicity and nucleofu-gality that correlate the pfCgS of the conjugate acids of the nucleophiles and nucleofuges to sensitivity parameters Pnuc and Piq). 

One fact about the use of quaternary ions as phase transfer catalysts should be noted. In general, the large, lipophilic quaternary ions are soft in the HSAB sense [25]. As a consequence, the quat tends to pair with the softest anion available in solution. If both iodide ions and hydroxide ions were present, for example, the quat would pair with iodide. If reaction with hydroxide was desired, the catalyst would be poisoned by the presence of iodide. The source of an ion such as iodide could be from the catalyst originally added or it could be the leaving group in the substitution reaction. The choice of reaction conditions should therefore include a consideration of cation, anion, nucleophile and nucleofuge. 

In this reaction I" is the nucleophile, and Br" is called the leaving group (or nucleofuge). Beyond this, the classification symbolism may include a designation of the molecularity of the reaction. Molecularity is the number of reactant molecules included in the transition state. The above reaction is an 8 2 reaction, because both reactants are present in the transition state. On the other hand, this substitution... 

Two new reactivity indices related to electrophilicity and nucleophilicity, electro-fugality and nucleofugality, have recently been introduced by Ayers et al. [59-61]. Electrofugality AEe is defined as... 

Whereas the terms nucleophile and electrofile refer to bond-formation reactions, the terms "nucleofuge" and "electrofuge" refer to bond-cleavage processes (see footnote 3 of ref 2b). 

Sulfoximines are versatile reagents for diastereoselective and asymmetric synthesis. They continue to find many synthetic applications as both nucleophilic and electrophilic reagents. While the nucleophilic character of sulfoximine reagents has been well exploited,1 the use of the sulfoximine group as a nucleofuge is more recent and adds to the synthetic use of these compounds. The palladium(0)-catalyzed chemistry of allylic sulfoximines and the use of chiral sulfoximines as ligands in catalytic asymmetric synthesis are areas of recent development that have potentially useful applications. Further work is required to understand the factors that determine the diastereoselection and the stereochemical outcomes of these reactions. These studies will result in enhanced product diastereo- and enantioselectivities and make these reagents even more attractive to the wider synthetic chemistry community. 

Both nucleophilic and electrophilic attack on trigonal carbon can take place by two pathways (Fig. 5.4)—direct attack on one of the cr bonds attached to the double bond (path a), or by attack on the n bond (path b), with the formation of an ionic intermediate, followed by the loss, respectively, of a nucleofugal group X or an electrofugal group M. There are also formally unimolecular pathways, SN1 and SeI, with ionisation followed by capture by the nucleophile or electrophile, but the former is rare and the latter unknown. 

The species X- is called the nucleofuge. In each case, the attacking species, namely the nucleophile and the Bronsted-Lowry base, are fundamentally very similar. With respect to the electronic characteristics of the attacking species and the species that is being attacked, suggest what are the similarities that are shared by, and the differences that distinguish, these two reactions. 

Mayr and co-workers extended their investigations of nucleophilicity and basicity scales to the development of a scale of nucleofugality as well. They found that kinetic data could be correlated with a relationship in the form of equation 8.52. ... 

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