Electrophilic centres

Removal of the side chain gives a symmetrical pyrazine (48), best made from a single precursor according to disconnection (a). The side chain can be added by treatment of (48) with the alkyl lithium at the electrophilic centre next to nitrogen (LiH is displacedj. Ana lysis... 

Carbonyl compounds react with thiols, RSH, to form hemi-thioacetals and thioacetals, rather more readily than with ROH this reflects the greater nucleophilicity of sulphur compared with similarly situated oxygen. Thioacetals offer, with acetals, differential protection for the C=0 group as they are relatively stable to dilute acid they may, however, be decomposed readily by H20/HgCl2/CdC03. It is possible, using a thioacetal, to reverse the polarity of the carbonyl carbon atom in an aldehyde thereby converting this initially electrophilic centre into a nucleophilic one in the anion (31) ... 

Different procedures have been developed to generate thiodisaccharides, based on two strategies (a) generation of a glycosylthiol 44 and reaction with an electrophilic centre on the second sugar 45, (b) replacement of an -OH of the sugar with an -SH and reaction with a glycosyl donor 46 (Fig. 22). 

Similar weak interactions are observed in the ketoester [28] and the ketoacid [29] (Chadwick and Dunitz, 1979). The potential nucleophile is different in the two cases, and the potential nucleophilic and electrophilic centres are not very close together (interatomic distances a 2.773 and 2.912 A, respectively) compared with the shorter N---C=0 distances which can be observed but there is significant pyramidalization at the carbonyl carbon atom, and the carboxyl groups adopt what appear to be unfavourable conformations, which bring the potential nucleophile into the correct position for attack at C=0. 

HOMO-LUMO) interactions the LUMO being the antibonding cr x orbital [45], the HOMO a non-bonded electron pair, formally available at both 90° and about 180° to the C-X bond [46], Much similar work supports this interpretation. Contacts between halogens (X) and electrophilic centres E (all metal ions) [47] fall almost exclusively in the range 9O<0E<12O°, while, for better electron donors Nu, 0Nu generally lies between 150° and 180°. 

Fig. 14 Dependence of relative reactivity on (minimum) interatomic distance between the electrophilic centre and the carboxyl oxygen, for (a) sulphonamides [76] and (b) malonate half-esters [77]. Reprinted with permission from Jager et al. (1984). Copyright 1984 American Chemical Society.

Capon (1964 Capon and McManus, 1976) introduced a simple classification for reactions involving neighbouring group participation, in which G-n indicates participation by a nucleophilic group G in an n-membered cyclic transition state. For present purposes an extension of this symbolism is necessary in order that the abbreviations indicate the electrophilic centre also. 

As we have seen (Section 4, p. 191) the range of effective molarities associated with ring-closure reactions is very much greater than that characteristic of intramolecular general acid-base catalysis the main classification is therefore in terms of mechanism. By far the largest section (I, Tables A-D) gives EM s for intramolecular nucleophilic reactions. These can be concerted displacements (mostly at tetrahedral carbon), stepwise displacements (mostly addition-elimination reactions at trigonal carbon), or additions, and they have been classified in terms of the nucleophilic and electrophilic centres. 

Intramolecular general base catalysed reactions (Section II, Tables E-G) present less difficulty. A classification similar to that of Table I is used, but since the electrophilic centre of interest is always a proton substantial differences between different general bases are not expected. This section (unlike Section I, which contains exclusively unimolecular reactions) contains mostly bimolecular reactions (e.g. the hydrolysis of aspirin [4]). Where these are hydrolysis reactions, calculation of the EM still involves comparison of a first order with a second order rate constant, because the order with respect to solvent is not measurable. The intermolecular processes involved are in fact termolecular reactions (e.g. [5]), and in those cases where solvent is not involved directly in the reaction, as in the general base catalysed aminolysis of esters, the calculation of the EM requires the comparison of second and third order rate constants. 

In the preceding chapters we have seen how new bonds may be formed between nucleophilic reagents and various substrates that have electrophilic centres, the latter typically arising as a result of uneven electron distribution in the molecule. The nucleophile was considered to be the reactive species. In this chapter we shall consider reactions in which electrophilic reagents become bonded to substrates that are electron rich, especially those that contain multiple bonds, i.e. alkenes, alkynes, and aromatics. The jt electrons in these systems provide regions of high electron density, and electrophilic reactions feature as... 

Now let us go a step further, and conjugate the carbonyl group with a double bond. If we polarize the carbonyl as before, then conjugation allows another resonance form to be written, in which the P-carbon now carries a positive charge. Thus, as well as the carbonyl carbon being electrophilic, the P-carbon is also an electrophilic centre. 

When structurally alerting compounds (e.g. those possessing alkylating electrophilic centres) have given negative results in the standard battery. 

For instance, if the metal is lost by Sn2 attack on coordinated carbon, this constitutes R loss, and alkyl migration to an electrophilic centre such as coordinated CO may resemble R loss. R- loss may take place by simple homolysis, or by alkyl group transfer. Moreover, as Yamamoto has pointed out an electroneutral metal-carbon bond lengthening may be a prelude to more complex processes such as 0-elimination, or may lead to internal hydrogen abstraction rather than to actual free ligand release. 

The hydroboration of alkynylchlorosilanes gave chlorodimethylsilyl-diethylborylalkenes such as 57. The alkene possess two electrophilic centres on the silyl and boryl groups and they react with 2-lithiated thiazoles 58 to give the zwitterionic compound 59 which can drawn as resonance structures 59a or 59b <99JOM98>. 

In most simple aldehydes and ketnoes, including benzophenone, the longest wavelength absorption is a low intensity n - iz transition. The promotion of a n-electron, localized on O-atom to a n-orbital, leaves behind a positive hole on this atom. The charge density on C-atom is increased creating a bipolar state. The dipole moment of >C = O bond is reduced. Three primary processes are commonly encountered for this electrophilic centre ... 

The cycloaddition reactions to give oxetanes readily occurs whenTj state is ( , 7T ) in character and an electrophilic centre is created on carbonyl oxygen atom on photoexcitation (Section 8.1). Paterno-Buchi reaction. 

The most common deviation is the exceptionally high reactivity of nucleophiles, such as hydroperoxide, hypochlorite and hydroxamate ions, with atoms bearing lone-pair electrons next to the nucleophilic centre. This phenomenon, known as the alpha-effect287, is found for aminolysis reactions of esters also285, and is commonly observed for attack at electrophilic centres where reactivity depends fairly strongly on the basicity of the nucleophile. Negative deviations may be evidence of steric hindrance, or in a few cases, in particular that of hydroxide ion, may reflect special solvation effects on the pKa or the nucleophilicity (or both) of the nucleophile. 

From the qualitative point of view, the structure of the ethylene/ketene complex is similar to the geometry of the TS of the same system in cycloaddition reaction58. In 22, R (= 3.46 A) is the distance between the centre of mass of the ethylene and the carbon of the carbonyl group of ketene this carbon is the most electrophilic centre of the ketene. In the case of the complex between acetylene and ketene, the same distance between the centre of mass of acetylene and the carbon of ketene was evaluated (by the same method) at 3.60 A. 

Michael-type addition of a suitable nucleophile, e.g. thiols, on to the a,f)-unsaturated lactone. Such alkylation reactions are believed to explain biological activity, and, indeed, activity is typically lost if either the double bond or the carbonyl group is chemically reduced. In some structures, additional electrophilic centres offer further scope for alkylation reactions. In parthenolide (Figure 5.31), an electrophilic epoxide group is also present, allowing transannular cyclization and generation of a... 

Although the loss of some anionic or other good leaving group is the usual consequence of such reactions at carbon centres, this is not the case when the electrophilic centre is an element such as silicon, sulfur, phosphorus or a transition metal with available d orbitals in the valence shell. In these cases, a simple addition reaction may occur to give a product of increased co-ordination number. This may involve simple reactions such as the addition of an anion to a neutral molecule or more complex processes (Fig. 4-3). 

A co-ordinated hydroxide ligand will still possess some of the nucleophilic properties of free hydroxide ion, and this observation proves to be the basis of a powerful catalytic method, and one which is at the basis of very many basic biological processes. In general, hydrolysis reactions proceed more rapidly if a water nucleophile is replaced by a charged hydroxide nucleophile. This is readily rationalised on the basis of the increased attraction of the charged ion for an electrophilic centre. However, in many cases the chemical properties of the substrate are not compatible with the properties of the strongly basic hydroxide ion. This is exactly the situation that biological systems find themselves in repeatedly. For example, the uncatalysed hydration of carbon dioxide is very slow at pH 7 (Fig. 5-61). 

In this connection, it is helpful to look first at the reactivity of the anions. There is no generally acceptable measure of nucleophilic reactivity since both the scale and order of relative reactivities depend on the electrophilic centre being attacked (Ritchie, 1972). However, in the present reaction, the similarity in the reactivity of the different anions is remarkable. Thus, the Swain and Scott n-values (cf. Hine, 1962) indicate that the iodide ion should be 100 times more reactive than the chloride ion in nucleophilic attack on methyl bromide in aqueous acetone. In the present reaction, the ratio of the rate coefficients for iodide ions and chloride ions is 1.4. This similarity led to the suggestion that these reactions are near the diffusion-controlled limit (Ridd, 1961). If, from the results in Table 5, we take this limit to correspond to a rate coefficient (eqn 19) of 2500 mol-2 s 1 dm6 then, from the value of ken for aqueous solutions at 0° (3.4 x 109 mol-1 s 1 dm3 Table 1), it follows that the equilibrium constant for the formation of the electrophile must be ca. 7.3 x 10 7 mol-1 dm3. This is very similar to the equilibrium constant reported for the formation of the nitrosonium ion (p. 19). The agreement is improved if allowance is made for the electrostatic enhancement of the diffusion-controlled reaction by a factor of ca. 3 (p. 8) the equilibrium constant for the electrophile then comes to be ca. 2.4 x 10-7. 

Figure 7.5 Examples of the reactions to enhance or form the electrophilic centres of suicide inhibitors and their subsequent reaction with a nucleophile at the active site of the enzyme. The general structures used for the enzyme-inhibitor complexes are to illustrate the reactions the enzyme ester groups may or may not be present in the final complex...

---