Nucleophilic substitution electrophilic centers

In the reactions with phosphonio-a-methoxycarbonyl-alkanides, the products of type 261 derived from 1,3-cycloaddition can rearrange to the tautomeric lif-pyrazolo-triazole (87MI2). The reaction of 3-diazopyra-zoles and 3-diazoindazole with acyl-substituted phosphonium ylides led to pyrazolo-triazine and indazolo-triazine derivatives 266 instead of the expected triazole compounds (8IJHC675). In this case, the ylides, which can exist as phosphonium enolates, possess nucleophilic and electrophilic centers in a /8-relationship, giving [7 + 2] or [11 -I- 2]cycloaddition reactions. With dimethylsulfonio-a-aroyl-methanides, very complex, temperature-dependent mixtures were obtained, in some cases with sulfur retention (87MI3). 

The solvation effect of water is based on its ability to surround the nucleophilic and electrophilic centers (by hydrogen bonding to the electrophilic H or the nucleophilic 0 HO—H—X and H2O—X" "), making collision more difficult in a bimolecular process. For ionization to complete with bimolecular processes, the counterion should be a weak nucleophile and/or a weak base in most cases. If the counterion is too basic, it can induce elimination that can be faster than ionization. If the counterion is too nucleophilic, bimolecular substitution processes will be faster. 

C.i.a. Sequential Hydroarylation (Hydroalkenylation)/Cyclization. Since the cis stereochemistry of addition pushes the substituents of the acetylenic moiety to the same side of the olefinic double bond, a cyclization reaction can follow the addition step when these substituents bear suitable nucleophilic and electrophilic centers, and the whole process resembles a valuable straightforward methodology for the preparation of cyclic compounds (Scheme 20). Cyclization can occur under hydroarylation(hydroalkenylation) conditions—either before or after the substitution of the carbon-hydrogen bond for the carbon-palladium bond—or by subjecting the isolated hydroarylation(hydroalkenylation) product to suitable reaction conditions. This strategy has been employed successfully to develop new routes to various heterocycles. 

One significant difference between nitrocarboaromatics and aromatic azines is the tendency of the activating center of the latter to react with electrophiles or compounds capable of hydrogen bonding, thereby accelerating nucleophilic substitution. 

Bowman has surveyed the reactions of cx-substituted aliphatic nitro compounds with nucleophiles, which undergo either S l substitution or polar reaction (Scheme 5.16).118 The reactions between a wide variety of nucleophiles and BrCH2N02 are shown in Scheme 5.17.119a b All the thiolates, PhS02 and I attack Br to liberate the anion of nitromethane. The hard nucleophiles, MeO , OH, and BH4 attack the hard H+ electrophilic center. Phosphorous nucleophiles attackthe oxygen electrophilic center, and only Me2S attacks the carbon electrophilic center. 

All reactions of benzotriazole derivatives of the type Bt-CR RbS discussed above are based on electrophilic or nucleophilic substitutions at the ot-carbon, but radical reactions are also possible. Thus, the first report on unsubstituted carbon-centered (benzotriazol-l-yl)methyl radical 841 involves derivatives of (benzotriazol-l-yl)methyl mercaptan. 3 -(Benzotriazol-l-yl)methyl-0-ethyl xanthate 840 is readily prepared in a reaction of l-(chloromethyl)-benzotriazole with commercially available potassium 0-ethyl xanthate. Upon treatment with radical initiators (lauroyl peroxide), the C-S bond is cleaved to generate radical 841 that can be trapped by alkenes to generate new radicals 842. By taking the xanthate moiety from the starting material, radicals 842 are converted to final products 843 with regeneration of radicals 841 allowing repetition of the process (Scheme 134). Maleinimides are also satisfactorily used as radical traps in these reactions <2001H(54)301>. 

Reactivity toward nucleophiles and comparison with other electrophilic centers 152 Paths for nucleophilic substitution of sulfonyl derivatives 156 Direct substitution at sulfonyl sulfur stereochemistry 157 Direct substitution at sulfonyl sulfur stepwise or concerted 158 The elimination-addition path for substitution of alkanesulfonyl derivatives 166 Homolytic decomposition of a-disulfones 172 10 Concluding remarks 173 Acknowledgement 174 References 174... 

To the extent that the N+ correlation is successful it means that the pattern of nucleophilic reactivity is not influenced by the nature of the electrophilic center at which substitution takes place. On the other hand, according to the concepts of the theory of hard and soft acids and bases (HSAB) as applied to nucleophilic substitution reactions (Pearson and Songstad, 1967) one would expect that a significant change in the HSAB character of the electrophilic center as an acid should lead to changes in the pattern of nucleophilic reactivity observed. Specifically, in substitutions occurring at soft electrophilic centers, soft-base nucleophiles should be more reactive relative to other nucleophiles than they are in substitutions at harder electrophilic centers, and in substitutions at hard electrophilic centers hard-base nucleophiles should appear relatively more reactive compared to other nucleophiles than they do in substitutions at softer electrophilic centers. 

There would seem to be two positions one can take with respect to the interpretation of the behavior revealed by Figs 1 and 2. The first, which would undoubtedly be favored by proponents of HSAB, is that the large deviations of the points for soft-base nucleophiles in Fig. 2 show that HSAB considerations do play an important role in determining the relative order of reactivity of a series of nucleophiles in nucleophilic substitutions at different electrophilic centers when those centers differ significantly in their degree of hardness , and that the failure to observe sizeable deviations from the correlation line in Fig. 1... 

Unfortunately, in many cases the reaction is not so straightforward it becomes complicated because of the nature of the activated component. There is another nucleophile in the vicinity that can react with the electrophile namely, the oxygen atom of the carbonyl adjacent to the substituted amino group. This nucleophile competes with the amine nucleophile for the electrophilic center, and when successful, it generates a cyclic compound — the oxazolone. The intermolecular reaction (path A) produces the desired peptide, and the intramolecular reaction (path B) generates the oxazolone. The course of events that follows is dictated by the nature of the atom adjacent to the carbonyl that is implicated in the side reaction. 

This section surveys the most important reactions of chiral organo-sulfur compounds. Some of these were touched on in the previous sections. For the sake of convenience, a variety of reactions occurring at the chiral sulfur center are divided into three main types of reactions racemization, nucleophilic substitution reactions, and electrophilic reactions. 

Organosulfur chemistry is presently a particularly dynamic subject area. The stereochemical aspects of this field are surveyed by M. Mikojajczyk and J. Drabowicz. in the fifth chapter, entitled Qural Organosulfur Compounds. The synthesis, resolution, and application of a wide range of chiral sulfur compounds are described as are the determination of absolute configuration and of enantiomeric purity of these substances. A discussion of the dynamic stereochemistry of chiral sulfur compounds including racemization processes follows. Finally, nucleophilic substitution on and reaction of such compounds with electrophiles, their use in asymmetric synthesis, and asymmetric induction in the transfer of chirality from sulfur to other centers is discussed in a chapter that should be of interest to chemists in several disciplines, in particular synthetic and natural product chemistry. 

Besides direct nucleophilic attack onto the acceptor group, an activated diene may also undergo 1,4- or 1,6-addition in the latter case, capture of the ambident enolate with a soft electrophile can take place at two different positions. Hence, the nucleophilic addition can result in the formation of three regioisomeric alkenes, which may in addition be formed as E/Z isomers. Moreover, depending on the nature of nucleophile and electrophile, the addition products may contain one or two stereogenic centers, and, as a further complication, basic conditions may give rise to the isomerization of the initially formed 8,y-unsaturated carbonyl compounds (and other acceptor-substituted alkenes of this type) to the thermodynamically more stable conjugated isomer (Eq. 4.1). 

A reaction described as Sn2, abbreviation for substitution, nucleophilic (bimolecular), is a one-step process, and no intermediate is formed. This reaction involves the so-called backside attack of a nucleophile Y on an electrophilic center RX, such that the reaction center the carbon or other atom attacked by the nucleophile) undergoes inversion of stereochemical configuration. In the transition-state nucleophile and exiphile (leaving group) reside at the reaction center. Aside from stereochemical issues, other evidence can be used to identify Sn2 reactions. First, because both nucleophile and substrate are involved in the rate-determining step, the reaction is second order overall rate = k[RX][Y]. Moreover, one can use kinetic isotope effects to distinguish SnI and Sn2 cases (See Kinetic Isotope Effects). 

The first two chapters dealt with formation of new carbon-carbon bonds by processes in which one carbon acts as the nucleophile and the other as the electrophile. In this chapter, we turn our attention to noncarbon nucleophiles. Nucleophilic substitution at both sp3 and sp2 centers is used in a variety of synthetic operations, particularly in the inverconversion of functional groups. The mechanistic aspects of nucleophilic substitutions were considered in Part A, Chapters 5 and 8. 

Note that the reaction at the phosphorus atom is postulated to occur by an SN2 (no intermediate formed) rather than by an addition mechanism such as we encountered with carboxylic acid derivatives (Kirby and Warren, 1967). As we learned in Section 13.2, for attack at a saturated carbon atom, OH- is a better nucleophile than H20 by about a factor of 104 (Table 13.2). Toward phosphorus, which is a harder electrophilic center (see Box 13.1), however, the relative nucleophilicity increases dramatically. For triphenyl phosphate, for example, OH- is about 108 times stronger than H20 as a nucleophile (Barnard et al., 1961). Note that in the case of triphenyl phosphate, no substitution may occur at the carbon bound to the oxygen of the alcohol moiety, and therefore, neutral hydrolysis is much less important as compared to the other cases (see /NB values in Table 13.12). Consequently, the base-catalyzed reaction generally occurs at the phosphorus atom leading to the dissociation of the alcohol moiety that is the best leaving group (P-0 cleavage), as is illustrated by the reaction of parathion with OH ... 

Not all radical aromatic substitutions are as immune to polar effects as is attack by phenyl. Some radicals reveal marked electrophilic or nucleophilic character. Oxygen-centered radicals, for example, are electrophilic, as would be expected if there is substantial polar contribution to the transition state. Table 9.13 lists partial rate factors for substitution by benzoyl radicals note that the orientation and activation trends found in typical electrophilic substitutions have begun to appear, but are still modest compared with the dramatic effects shown in Table 9.12 for a true heterolytic substitution.179... 

Swain and Scott found satisfactory correlations with Equation (27) which provided 5 values for a number of reactants. However, as indicated in Scheme 33, for the limited number of substrates conveniently studied,158,186 variations in 5 did not show a clearly discernible pattern (and no obvious correlation with reactivity). Moreover, Pearson and Songstad demonstrated that the correlations break down if extended to extremes of soft and hard electrophilic centers such as platinum, in the substitution of trara,s-[Pt(pyridine)2Cl2], or hydrogen in proton transfer reactions.255 Despite this, Swain and Scott s equation has stood the test of time and it is noteworthy that a serious breakdown in the correlations occurs only when the reacting atoms of both nucleophile and electrophile are varied. In this chapter we will restrict ourselves to carbon as an electrophilic center, and particularly, although not exclusively, to carbocations. 

In 1989 the synthesis and isolation of the first compounds with stable Xe—C bond were reported by Naumann and Tyrra285 and Frohn and Jakobs1068 by the introduction of the organic group through nucleophilic substitution called xenodeborylation [Eq. (4.256)]. The boron as Lewis acid center polarizes the Xe—F bond and thereby allows it to overcome the low electrophilicity of the Xe center to form the fluoroar-ylxenonium fluoroborates 366. When the reaction is carried out in anhydrous HF, all C6F5 groups of the borane are transferred to xenon [Eq. (4.256)].1069... 

Allylic electrophiles can react with nucleophiles either with or without allylic rearrangement [213], The outcome of such reactions will depend on whether or not an allylic carbocation is formed as intermediate, and on the steric requirement and hardness of the two electrophilic centers and the nucleophile. Bimolecular substitutions at allylic electrophiles which occur with rearrangement are called Sn2 reactions. 

We have already established that the carbene carbon is an electrophilic center and, hence, it should be very easily attacked by nucleophiles. In most reactions we believe that the first reaction step probably involves attachment of a nucleophile to the carbene carbon. In some cases, for instance with several phosphines (49) and tertiary amines (50), such addition products are isolable analytically pure under certain conditions (1 in Fig. 3). For the second step there exists the possibility that the nucleophilic agent may substitute a carbon monoxide in the complex with preservation of the carbene ligand (2 in Fig. 3). One can also very formally think of the carbene complex as an ester type of system [X=C(R )OR with X = M(CO)j instead of X = 0], because the oxygen atom as well as the metal atom in the M (CO) 6 residue are each missing 2 electrons for attainment of an inert gas configuration. So, it is not surprising that the... 

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