Anions and Nucleophilic Reactions

Chapter 3 considered elementary reactions and the information about their transition states that can be obtained by a variety of techniques. The next three chapters deal with complex reactions, in which intermediates are produced. These may be short lived, but they have an independent existence, show spectroscopic properties and can sometimes be trapped out of the reaction mixture. 

This chapter considers reactions in which anionic intermediates are involved. Anions are species that carry a negative charge. Also important 

Bases species (often anions) that can remove a proton from another molecule. 

Nucleophiles species with a lone pair of electrons that can be donated to an electron-deficient centre, normally a carbon atom, to form a covalent bond. 

After reading this chapter you should be able to  

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Based on the above-mentioned stereochemistry of the allylation reactions, nucleophiles have been classified into Nu (overall retention group) and Nu (overall inversion group) by the following experiments with the cyclic exo- and ent/n-acetales 12 and 13[25], No Pd-catalyzed reaction takes place with the exo-allylic acetate 12, because attack of Pd(0) from the rear side to form Tr-allyl-palladium is sterically difficult. On the other hand, smooth 7r-allylpalladium complex formation should take place with the endo-sWyWc acetate 13. The Nu -type nucleophiles must attack the 7r-allylic ligand from the endo side 14, namely tram to the exo-oriented Pd, but this is difficult. On the other hand, the attack of the Nu -type nucleophiles is directed to the Pd. and subsequent reductive elimination affords the exo products 15. Thus the allylation reaction of 13 takes place with the Nu nucleophiles (PhZnCl, formate, indenide anion) and no reaction with Nu nucleophiles (malonate. secondary amines, LiP(S)Ph2, cyclopentadienide anion). 

Both electrophilic and nucleophilic reactions can generate halogenopur-ines with differences in regioselectivity dependent on substituents and on the nature of the substrate (anion, neutral molecule, or cation). In the neutral molecule nucleophilic displacements occur in the order 2 > 4 > 6 in the anion the imidazole ring may be sufficiently 7r-excessive for attack to occur at C-2, and the nucleophilic substitution order becomes 4 > 6 > 2. Strong electron donors are usually necessary to promote 2-halogenation by electrophilic halogen sources. 

Polyamide macromonomers can be made by reaction of the terminal acyllactam function with an unsaturated nucleophile such as the anion derived fromp. vinylbenzyl amine 8I). The nucleophilicity of the latter is higher than that of the lactam anion, and the reaction is straightforward. 

A plausible mechanism for the formation of 4 is rationalized on the basis that photolysis of 3 results in [2-1-2] cyclization to thietane 4 and is subsequently followed by rearrangement to thiolactone 5 (Scheme 6). Ring opening of the initially formed thietane 4 leads to a zwitterion, which is facilitated by lone pair electrons of nitrogen and oxygen atoms, and nucleophilic reaction of the thiolate anion to carbonyl carbon gives 5. For the tricyclic thietane 4a, nucleophilic addition of the thiolate anion is difficult, and results in the formation of stable thietane 4a. 

Figure C shows an extreme case of the dependence of a substitution reaction rate on the nature of the incoming group. This happens to be the hydrolysis of the trisacetylacetonate complex of silicon (IV), cationic species, which Kirchner studied first—the rate of racemization or rate of dissociation. We studied the base-catalyzed rate of dissociation and showed that a large number of anions and nucleophilic groups, in general, would catalyze in the dissociation process. We found that the reaction rates were actually for a second-order process, so these units are liters per mole per second. But the reaction rate did vary over an enormous range—in this case, about a factor of 109—and this is typical of the sort of variation in rates of reaction (that you can get) for processes that seem to be Sn2 bimolecular displacement processes.

The second stage of the Swem oxidation, illustrated below, involves a nucleophilic displacement of the oxallyl group from the sulfur. In this step, the nucleophile is a chloride anion, and the reaction is facilitated by the decomposition of the leaving group into carbon dioxide gas, carbon monoxide gas, and a chloride anion. 

These reactions are reversible and proceed at moderate temperatures (0-120°C) when compounds with cumulated S-S bonds (polysulfanes, elemental sulfur) are considered. The activation energy and therefore the rate of reaction at a certain temperature very much depend on the particular compound. Interconversion reactions are promoted by UV radiation as well as by cationic, anionic, and nucleophilic catalysts. The reaction mechanisms will, of course, be different in these various cases. The various reaction types possible under noncatalyzed conditions and with exclusion of light have been critically reviewed by Steudel in 1982. " Originally it had been thought that homolytic bond scission is the first and rate-determining step in all cases. Dissociation energies... 

Equation 8.28 shows only the anionic nucleophile explicitly, since the counterion does not appear to take part in the reaction. Nevertheless, the counterion affects the solubility of a nucleophilic salt, which therefore can influence the polarity of the solvent needed for the reaction. An alternative to the use of a more polar solvent to dissolve a salt for nucleophilic substitution is to use crown ether additives. Crown ethers are cyclic polyethers that can coordinate with cations and therefore increase their solubility in organic solvents. The nomenclature provides the total number of atoms and the number of oxygen atoms in the ring. Compoimd 51 is 12-crown-4, and 52 is 18-crown-6 (Figure 8.32). Coordination of a crown ether with a cation helps to dissolve the salt in a less polar solvent and leaves the anion relatively unsolvated. The activation energy for substitution therefore does not include a large term for desolvation of the nucleophilic anion, and the reactions are fast. For example, adding dicyclohexano-18-crown-6 (53) to a solution of 1-bromobutane in dioxane was found to increase its reactivity with potassium phenoxide by a factor of 1.5 x 10. Moreover, Liotta and Harris were able to use KF solubilized with 18-crown-6 (52) to carry out Sn2 reactions on 1-bromooctane in benzene. ... 

You have learned quite a few tools that are useful for organic synthesis, including nucleophilic substitution reactions, elimination reactions, and the hydrogenation reactions covered in Sections 7.12—7.14. Now we wiU consider the logic of organic synthesis and the important process of retrosynthetic analysis. Then we will apply nucleophilic substitution (in the specific case of alkylation of alkynide anions) and hydrogenation reactions to the synthesis of some simple target molecules. 

In reactions 1 and 2, the species attacking the haloalkane is an anionic oxygen nucleophile. Reaction 3 shows that a halide ion may function not only as a leaving group, but also as a nucleophile. 

Reactions.—, i-Dithianyl Anions. The Corey-Seebach 1,3-dithianyl anion rates as one of the most popular sulphur anions and nucleophilic acylating agents, as demonstrated by its recent use in the syntheses of potential precursors of the macrocyclic antitumour agent maytansine, of cyclopentenones and other unsaturated ketones,of octoses, of lla-hydrox)rprogesterone, of deuteriated aldehydes, of alnusone, of the sex-attractant of the Douglas fir tussock moth, of l,4-diketones, of 3-s-butylglutaraldehyde, of linaloyl... 

Other reactions of synthetic utility can be observed when suitable nucleophiles are added to the reaction system. Typical examples of these nucleophiles are azide, cyanate, thiocyanate, and cyanide anions and thioanisole. Reactions using these nucleophiles provide a reaction path to functionalized vinyl derivatives. The transformations are successfully achieved by using triaryl-substituted alkenyl halides. The reactions with such nucleophiles provide an efficient path to heterocyclic compounds, among others. Some examples, such as the pyrroHnes, isoxazoHnes, isoquinolones, and thio derivatives, are prepared by this method and are shown in Equation 11.11. 

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

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