Nucleophiles and reactivity

As the phosphonium diylides, lithium phosphonium yldiides, first described by Schlosser and Corey (Ph3P=CR-Li R=H, C3H7) [60-62], have a high nucleophilicity and reactivity. Recently, the a-silylated lithium phosphonium yldiide 20 has been prepared from the stable phosphanyl-(silyl)carbene 19 and alkyl-lithium (Scheme 13). The first crystal X-ray diffraction study of such a reagent was proposed for 20 and its reaction with methyl iodide or phosphorus elec-... 

Numerous carbene complexes have since been prepared by this method [1,52,60,499-503], even utilizing highly reactive diazoalkanes such as diazomethane [504], Because of their high nucleophilicity and reactivity, non-acceptor-substituted diazoalkanes can displace even strongly bound ligands, such as phosphines. Examples of such reactions are shown in Figure 3.20. 

Because of the high nucleophilicity and reactivity of diazoalkanes, catalytic decomposition occurs readily, not only with a wide range of transition metal complexes but also with Brpnsted or Lewis acids. Well-established catalysts for diazodecomposition include zinc halides [638,639], palladium(II) acetate [640-642], rhodium(II) carboxylates [626,643] and copper(I) triflate [636]. Copper(II)... 

If the halide contains an electron withdrawing group, the negative charge in the ylide is delocalized, decreasing its nucleophilicity and reactivity. Aldehydes may still react, but ketones most likely will not. 

The rate-determining step in the catalytic cycle is the oxidative addition of CH3I to 4.1. Oxidative additions of alkyl halides are often known to follow Sa2 mechanisms. This appears to be also the case here. The net negative charge on 4.1 enhances its nucleophilicity and reactivity towards CH3I. 

The presence of two negative charges in close proximity makes this new reagent 174 extremely reactive. Its carbanionic sites, at C-1 and C-3, however, differ sharply in their nucleophilicity and reactivity. The different surroundings of the carbanionic centers in this system makes the carbanion at C-3 better stabilized than at C-1. Therefore, electrophilic attack should be directed primarily at C-1. In fact, the addition of one equivalent of an electrophile to a solution of 174 leads to a highly selective attack at the terminal carbon atom. The product of this reaction, 175, still retains a carbanionic center and with the addition of another electrophile the formation of a second bond occurs selectively at C-2. In this manner, the dianion 174 is an excellent three-carbon building block for the synthesis of ketones of type 176 or four-carbon building block for the synthesis of esters of the type 177. 

Some of the earliest correlations between nucleophilicity and reactivity focused solely on the pKn of the conjugate acid of the nucleophile. If one keeps the electronic and steric properties of a series of nucleophiles similar, and uses the same solvent for the analyses, reactivity does nicely correlate with the basicity of the nucleophile Kt, see Chapter 5). An LFER as defined in Eq. 8.48 can be used to correlate the data. This structure-function relationship is called a Brensted relationship. 

Phenols arc highly reactive 0-nucleophiles and allylated easily with allylic carbonates under neutral conditions. EWGs on phenols favor the reac-tion[213]. Allylic acetates are used for the allylation of phenol in the presence of KF-alumina as a base[214]. 

FIGURE 8 10 Hydrogen bonding of the solvent to the nucleophile stabilizes the nucleophile and makes It less reactive... 

Primary benzyhc halides are ideal substrates for Sn2 reactions because they are very reactive toward good nucleophiles and cannot undergo competing elimination... 

You have already had considerable experience with carbanionic compounds and their applications in synthetic organic chemistry The first was acetyhde ion m Chapter 9 followed m Chapter 14 by organometallic compounds—Grignard reagents for example—that act as sources of negatively polarized carbon In Chapter 18 you learned that enolate ions—reactive intermediates generated from aldehydes and ketones—are nucleophilic and that this property can be used to advantage as a method for carbon-carbon bond formation... 

In most of their reactions phenols behave as nucleophiles and the reagents that act on them are electrophiles Either the hydroxyl oxygen or the aromatic ring may be the site of nucleophilic reactivity m a phenol Reactions that take place on the ring lead to elec trophilic aromatic substitution Table 24 4 summarizes the behavior of phenols m reac tions of this type... 

As conjugated systems with alternating TT-charges, the polymethine dyes are comparatively highly reactive compounds (3). Substitution rather than addition occurs to the equalized TT-bond. If the nucleophilic and electrophilic reactions are charge-controHed, reactants can attack regiospeciftcaHy. 

This addition is general, extending to nitrogen, oxygen, carbon, and sulfur nucleophiles. This reactivity of the quinone methide (23) is appHed in the synthesis of a variety of stabili2ers for plastics. The presence of two tert-huty groups ortho to the hydroxyl group, is the stmctural feature responsible for the antioxidant activity that these molecules exhibit (see Antioxidants). 

Fig. 2. Cephalosporin P-lactam reactivity where Nu is a nucleophile and X is a leaving group (a) path followed for nucleophiles (b) when Nu is the serine OH of an enzyme (ie, Nu = Enz Ser OH) deacylation may precede expulsion of the leaving group and both pathways (a) and (b) may be observed.

Dichloro- (59JA2464), 2,4,6- and 2,4,7-trichloro- (56JCS4621) and 2,4,6,7-tetrachloro-pteridine (41LA(548)83) have not yet been studied regarding their physical properties due to their high instability and reactivity towards nucleophiles. 

Theoretical reactivity indices of heteroaromatic systems distinguish reactivity toward electrophilic, nucleophilic and homolytic reactions. 

A number of benzazetidines have been produced by nucleophilic and cyclo-additions to the highly reactive benzazetes. In some cases these are isolated, but in others they rearrange by reactions which are initiated by ring opening of the benzazetidine to an azaxylylene (Section 5.09.5.2.2). 

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. 

---