Electrophiles, ambident

There are molecules that have two-electron deficient centers capable to react with nucleophiles. Such molecules are called ambident electrophiles. The reactivity profile is susceptible to the same kind of analysis as the one we have had above for the reaction of ambident nucleophiles with electrophiles. In the reaction of an electrophile with a nucleophile, it is the LUMO of the electrophile that interacts with the HOMO of the nucleophile. As such, the higher the HOMO and/or the lower the LUMO to reduce energy gap between the two, the faster will be the reaction. Alternatively, the better the match of the HOMO and LUMO coefficients, the more effective will be the reaction. 

Most nucleophiles attack a,p-unsaturated ketones faster at the carbonyl carbon than at the p-carbon. The attack at the p-carbon is generally the result of a slower, but 

Likewise, the lithium enolate 89 reacts with cyclohexenone 90 at -78 °C to give the product of attack at the carbonyl carbon (direct attack) 91. However, warming the reaction mixture to room temperature allows this step to revert to the starting materials, which react again to form the thermodynamically more stable product of conjugate addition 92 [35]. The enolates formed from p-dicarbonyl compounds do not allow the isolation of the product of direct attack because the first step is even more easily reversible in these instances. 

Many additions to a,p-unsaturated carbonyl compounds, take advantage of coordination to the oxygen by a metal cation or a proton, or even just a hydrogen bond. This is true for hydrides and carbon nucleophiles. In such a situation, the LUMO coefficient is largest at the carbonyl carbon, but not at the p carbon. Thus, even soft nucleophiles can be expected to attack directly at the carbonyl carbon when Lewis or protic acid catalysis is involved. It is likely that the difference in the 

Hydroxide and alkoxide ions, both hard nucleophiles, react with ethyl acrylate 93, an a,p-unsaturated ester, by direct attack at the carbonyl carbon to bring about ester hydrolysis and ester exchange, respectively. However, the enolate 94, a soft nucleophile, reacts in conjugate manner to form 95 predominantly. In an alternate pathway, it is also likely that the enolate 94 reacts through the oxy anion (hard nucleophile) directiy at the carbonyl carbon (hard electrophile) to generate the species 96, which rearranges in an oxy anion accelerated [3.3] sigmatropic shift manner, as shown, to form 97 and, thus, the above product 95. However, it is not certain that such a direct attack by the enolate is not more rapid and reversible. 

The attack of a nucleophile on a conjugated system is susceptible to the same kind of analysis that we gave to the attack of an electrophile on a conjugated system. In most cases, all the molecular orbital factors, both those affecting the product stability and those in the starting materials, point in the same direction. We use the 

LUMO of the conjugated system (and the HOMO of the nucleophile, of course) as the important frontier orbitals, as in Fig. 4.11, which shows electrophilic reactivity at the site where the arrow points for a range of carbon electrophiles. In each case, there is a high coefficient of the LUMO at the site of attack each of them also has a high total electron deficiency at this site and, with the possible exception of pyridine, the tetrahedral intermediate obtained from such attack is lower in energy than attack at the alternative sites. 

A conjugate acceptor system with two 6+ sites can be attacked at either site. The thermodynamic product will be the most stable of the possible products. A Af/ calculation shows that the thermodynamic product is the 1,4 or conjugate addition product, primarily because of the greater bond strength of the C=0 bond than the C=C bond. Any equilibrium would produce the conjugate addition product. 

Because the effect of an electronegative group diminishes with distance, the carbonyl carbon in this system will have the greatest partial plus and therefore will be harder and attract a hard, negatively charged nucleophile best the 1,2 product or normal addition product will be the kinetic product for hard nucleophiles. Soft nucleophiles therefore prefer conjugate attack. Finally, if one site is very sterically hindered, attack at the more open site will dominate. 

NaBH4 or KBHR3 1,4 (mainly) Softer hydride source 

Use the rule on the reverse reaction to determine if the overall reaction is reversible (p/fnbH vs pA),bH of product anion). 

If irreversible, then use HSAB principle hard with hard, soft with soft, since the Nu stays where it first attaches. 

1 The Pyridinium Cation. The pyridinium cation 4.126 is even more readily attacked by nucleophiles at C-2 and C-4 than pyridine 4.124. Looking at the product side of the reaction coordinate, the linearly 

However, if we look at the LUMO (see p. 60), we find that it has the form 4.128, similar to t/ 4 of benzene, but polarised by the nitrogen atom. The polarisation reduces the coefficient at C-3, and the coefficient at C-4 is larger than that at C-2, as can be seen from the simple Hiickel calculation for pyridine itself 4.124,18 which gives LUMO coefficients of 0.454 and -0.383, respectively, and an energy of 0.56/3 (compare benzene with 1/3 for this orbital). Thus, soft nucleophiles should attack at C-4, where the frontier orbital term is largest. Again this is the case cyanide ion, bisulfite, enolate ions, and hydride delivered from the carbon atom of the Hantsch ester 4.130 react faster at C-4 than at C-2.368 

The Coulombic term will also lead to faster reaction at the ortho than at the para position. The frontier orbital term, however, should favour attack at the para position. Thus the ESR spectrum of the benzyl radical (see p. 171), which has the odd electron in an orbital which ought to be a model for the LUMO of a Z-substituted benzene, shows that there is a larger coefficient in the para position than in the ortho. 

There is some evidence which supports this analysis (Fig. 4.16).369 (a) With a charged activating group, as in the diazonium cations 4.133 and 4.134, attack at the ortho position is faster than attack at the para position 

The ease with which fluorine can be displaced from benzene rings is such that it does not always need activating groups like nitro to stabilise the intermediate anions—oligofluorobenzenes can undergo substitution reactions. An attempt,371 using frontier orbital theory, to explain the selectivity with which one of several fluorine atoms is displaced has been contested in favour of a more general electrostatic analysis.372 

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This section is organized according to the electrophilic center presented to the nucleophilic nitrogen of the active species. This organization allow s a consistent treatment of the reactivity. However, a small drawback arises when ambident electrophilic centers are considered, and these cases are treated as if the more reactive center were known, which is not always the case. 

D. Reactions with Ambident Electrophilic Reagents bearing an spC Electrophilic Center... 

The problem is more complicated when the ambident nucleophile. 2-aminothiazole, reacts with an ambident electrophilic center. Such an example is provided by the reaction between 2-amino-5-R-thiazole and ethoxycarbonyl isothiocyanate (144), which has been thoroughly studied by Nagano et al. (64, 78, 264) the various possibilities are summarized in Scheme 95. At 5°C, in ethyl acetate, the only observed products were 145a, 148. and 150. Product 148 must be heated to 180°C for 5 hr to give in low yield (25%) the thiazolo[3.2-a]-s-tnazine-2-thio-4-one (148a) (102). This establishes that attack 1-B is probably not possible at -5°C. When R = H the percentages of 145a. 148. and 150 are 29, 50, and 7%, respectively. These results show that ... 

Amberlyst resin 538 Amberlyst-15 (H+) 762 f. ambident electrophile 456, 478 ambident nucleophile 78 amides... 

This means there are 42 entries that have the words AMBIDENT and NUCLEOPHILE somewhere in them in the titles, keywords, or index entries. We can now, if we wish, display any or all of them. But a particular entry might have these two words in unrelated contexts, for example, it might be a paper about ambident electrophiles, but which also has NUCLEOPHILE as an index term. We would presumably get fewer papers, but with a higher percentage of relevant ones, if we could ask for AMBIDENT NUCLEOPHILE, and in fact, the system does allow... 

The 1,2,4-triazine ring is an ambident electrophile, and reacts with enamine-type nucleophiles. For example, addition of enamine 78 to a solution of triazine 77 in acetic anhydride furnished the pyrrolotriazine 31 (Equation 24) <2003TL2421>. 

The presence of two electrophilic reaction centers in the molecule of o -unsaturated carbonyls is responsible for their ability to participate in the synthesis of heterocycles. Such compounds can react as ambident electrophiles owing to delocalization of electron density in a C=C-C=0 system. The addition of nucleophiles to these molecules can proceed in one of two main directions—via attack of the carbonyl group (1,2-addition) or involving the / -carbon (1,4-addition). 

The properties of dimethyl carbonate, (MeO)2CO, as an ambident electrophile have been investigated by analysis of the products of its reaction with various nucleophiles having different hard-soft character. Results were in good agreement with the Hard-Soft Acid-Base theory, hard nucleophiles attacking the hard C=0 group and soft nucleophiles the soft Me group (Scheme ll).37... 

Apart from the above two major general reaction pathways, there are some further possibilities for instance, [bis(trifluoroacetoxy)iodo]benzene reacts as an ambident electrophile and is attacked by hard nucleophiles at its carbonyl carbon, whereas iodylarenes may react similarly from carbon rather than iodine. Alkynyl iodonium salts are actually tetraphilic electrophiles, whereas iodosylbenzene reacts also as a nucleophile from oxygen. Diaryl iodonium salts serve as arylating reagents, mostly homolytically other iodonium salts transfer groups such as perfluoroalkyl, vinyl, alkynyl or cyano to several nucleophiles in various ways. 

These compounds are characterized by their tautomerism, and they exhibit ambident electrophilic reactivity. 

Though exhibiting both electrophilic and nucleophilic reactivity, ketoenamines usually react as ambident nucleophiles at their nitrogen or (and) Cp atom. Ambident electrophiles are therefore suitable partners for cyclization yielding heterocycles. 

A nice example of the solvent-dependent dual reactivity of an electrophilic crypto-cationic species has been given by Hiinig et al. [663]. Ambident electrophilic a-enones react with nucleophiles such as the anion of the benzaldehyde O-(trimethylsilyl)-cyanohydrin (Nu ) in diethyl ether exclusively by 1,4-addition. In tetrahydrofuran (THF) or 1,2-dimethoxyethane (DME), the 1,2-adduct is formed predominantly on the addition of HMPT or [12]crown-4 it is formed exclusively cf. Eq. (5-133). 

Mcthoxycarbenium ion is an ambident electrophile reaction can occur at either C or O. Nucleophilic attack at the C atom results in mcthoxymetbylation. Displacement of formaldehyde results in mcthylation of the nucleophile. The latter reaction is prevalent with aromatics. Thus the reaction of the reagent with benzene gives toluene in high yield. 

The main feature of these compounds is their tautomerism and resultant ambident electrophilic reactivity. Their reactivity is therefore highly dependent upon the electron distribution within the ring. Electrophilic attack occurs P to either the ring nitrogen or sulfur, whereas nucleophilic attack tends to take place at the a-position, normally C-2. Nucleophiles can also deprotonate the heterocycle, acting as bases. 

Activated vinylcyclopropanes (19) are an interesting class of ambident electrophiles two modes of ring-opening, referred to as 1,5 and 1,7 attacks, have been observed (equation 17). ... 

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