Nucleophilic addition relationships

An especially interesting case of oxygen addition to quinonoid systems involves acidic treatment with acetic anhydride, which produces both addition and esterification (eq. 3). This Thiele-Winter acetoxylation has been used extensively for synthesis, stmcture proof, isolation, and purification (54). The kinetics and mechanism of acetoxylation have been described (55). Although the acetyhum ion is an electrophile, extensive studies of electronic effects show a definite relationship to nucleophilic addition chemistry (56). 

A very important relationship between stereochemistry and reactivity arises in the case of reaction at an 5 carbon adjacent to a chiral center. Using nucleophilic addition to the carbonyl group as an example, it can be seen that two diastereomeric products are possible. The stereoselectivity and predictability of such reactions are important in controlling stereochemistry in synthesis. 

Sander and Jencks introduced a linear free energy relationship for nucleophilic addition to carbonyls. The equilibrium nucleophilicity of a species HNu is given by... 

There are at least two other studies of competitive reactions to form the products of solvolysis and elimination reactions that may provide insight into the relationships between carbocation structure and reactivity toward nucleophile addition and deprotonation. 

Effects of substituents on stability/reactivity. Relationship of nucleophilic addition, substitution and enolisation. 

Our work on nucleophile addition to quinone methides is a direct extension of studies on the formation and reaction of ring-substituted benzyl carboca-tions,89,90,128 146 and has shown strong overlap with the interests of Kresge and coworkers. The main goal of this work has been to characterize the effect of the strongly electron-donating 4-0 substituent on the reactivity of the simple benzyl carbocation, with an emphasis on understanding the effect of this substituent on the complex structure reactivity relationships observed for nucleophile addition to benzylic carbocations. 

Such a charge transfer from the ligated arene can lead to (a) nucleophilic addition or substitution, (b) electron transfer, and (c) proton elimination/transfer, thus revealing the dose relationship between all of these processes. The reactivity of the arene ligands towards nudeophiles in (arene)ML complexes depends on the electrophilidty of the metal fragments [MLn], this increasing in the order [Cr(CO)3] < [Mo(CO)3] [FeCp]+ < [Mn(CO)3]+ [2]. For example, in (arene)FeCp+, which is widely used for synthetic purposes, a chloro or nitro substituent on the arene is readily substituted by such nudeophiles as amides, eno-lates, thiolates, alkoxides, and carbanions [45]. 

The concept of pseudobase formation by heteroaromatic cations is intimately related to the covalent hydration of heteroaromatic molecules16-19 and to Meisenheimer complex formation,20-25 although this relationship has not generally been emphasized in the literature until recently26,27. All such reactions involve the formation of -complexes by nucleophilic addition to electron-deficient aromatic species, and yet, extensive reviews of covalent hydration16-19 and of Meisenheimer complex formation20-25 have neither explicitly recognized their mutual relationship nor considered pseudobase formation. 

Pseudobase formation by nucleophilic addition to heteroaromatic cations is closely related to the long-known Meisenheimer complex formation by nucleophilic addition to an electron-deficient neutral aromatic molecule.20-25 In both cases nucleophilic attack on an electron-deficient aromatic ring produces a c-complex—an anionic Meisenheimer complex or a neutral pseudobase molecule. Despite the intense interest over the past few years in Meisenheimer complexes as models for er-complex intermediates in nucleophilic aromatic substitution reactions, there has been little overt recognition of the relationship between Meisenheimer complexes and pseudobases derived from heteroaromatic cations. In this regard, it is interesting that the pseudobase 165, which can be regarded as the complex intermediate that would be expected for an SNAr reaction between the l-methyl-4-iodoquinolinium cation and hydroxide ion, has been spectroscopically characterized.89... 

As a Stereochemical Prohe in Nucleophilic Additions. Historically, the more synthetically available enantiomer, (4R)-2,2-dimethyl-l,3-dioxolane-4-carhoxaldehyde, has been the compound of choice to probe stereochemistry in nucleophilic additions. Nevertheless, several studies have employed the (45)-aldeh-yde as a substrate. In analogy to its enantiomer, the reagent exhibits a moderate si enantiofacial preference for the addition of nucleophiles at the carbonyl, affording anti products. This preference for addition is predicted by Felkin-Ahn transition-state analysis, and stands in contrast to that predicted by the Cram chelate model. Thus addition of the lithium (Z)-enolate shown (eq 1) to the reagent affords an 81 19 ratio of products with the 3,4-anti relationship predominating as a result of preferential si-face addition, while the 2,3-syn relationship in each of the diastere-omers is ascribed to a Zimmerman-Traxler-type chair transition state in the aldol reaction. ... 

The classification within this section is based on the structural (rather than the mechanistic) relationship between the starting materials and products. Mechanistically, all of the reactions considered in this section involve nucleophilic substitution as the first step, except for aromatic substitution via the aryne mechanism, which involves elimination followed by nucleophilic addition. 

Shono and his coworkers cleverly exploited [71] the preparative possibilities of dual nucleophile/base behavior according to the relationships set out in Scheme 25. Essentially, they argued that the production of a nucleophile (M in Scheme 25) could be maintained by deprotonation of its conjugate acid, provided that the initial product of nucleophilic reaction was sufficiently basic. The way this works is illustrated in the reaction [71] in Scheme 25. Reaction is initiated by direct reduction (of CCI4) but sustained through the deprotonation of CHCI3 by the product of nucleophilic addition to furfural. Several other examples are reported [71], and the reaction type may be extended to other systems for which MX is easily reducible to M and where the acidity of MH is higher than that of the protonated addition product, MYH (Scheme 23). 

Finally, several equilibrium and kinetic properties of aldehyde-bisulfite adducts were found to be linearly related Taft s a parameter (Betterton et al.t 1988). These compounds, which include a-hydroxymethane sulfonate and other a-hydroxyalkyl sulfonates, may be important reservoirs of S(IV) species inj clouds, fog, and rain. Fairly good relationships were found between equilibrium properties (e.g. acidity constants) and Sir values, but rates constants for) nucleophilic addition of S03 to the aldehydes showed only a crude fit, Similarly, poor results were found in applying a to hydrolysis reactions of] volatile alkyl chlorides (T. Vogel, University of Michigan, personal communh cation, 1989), and this has been shown to be a general characteristic of reactioni of alkyl halides with nucleophiles (Okamoto et al., 1967). 

Why do nucleophiles at times follow a polar pathway, for example, the SN2 reaction or nucleophilic addition to the carbonyl group, whereas at other times these same nucleophiles might react via a SET process What is the relationship between these two general pathways and what factors influence which reaction pathway will be followed in any particular case This chapter analyzes this problem using the configuration mixing (CM) model (3-5) by comparing both reaction processes. 

Regardless of the details of the mechanism of nucleophilic addition to carbonyl groups, a useful empirical relationship has been established and is known as Cram s rule of steric control of asymmetric induction. The major diastereomer will correspond to transfer of the incoming group from the less hindered side of the carbonyl group in the conformation in which the carbonyl group is staggered between the two smallest substituents on the adjacent chiral center. 

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