Nucleophilic substitution with ambident nucleophiles

A major distinction for nucleophilic reactions with ambident anions is whether they proceed with kinetic or thermodynamic control.80 N-Substituted saccharins (10) should be thermodynamically more stable because of amide character than the isomeric pseudosaccharin (3) of imidate structure. In fact 3 may be rearranged thermally to 10 in an irreversible reaction.96 The threshold for thermodynamic control appears to be lowered for electrophiles with multiple bonds, e.g., formaldehyde, reactive derivatives of carboxylic acids, but also quaternary salts of N-heterocyclic compounds.80 It will be seen that in those cases substitution indeed occurs at the nitrogen, not necessarily through thermodynamic control. 

In its reactions, the indolyl anion behaves as an ambident nucleophile the ratio of N- to P-substitution with electrophiles depends on the associated metal, the polarity of the solvent, and the nature of the electrophile. Generally, the more ionic sodio and potassio derivatives tend to react at nitrogen, whereas mag-nesio derivatives have a greater tendency to react at C-3 (see also 20.1.1.4), however, reaction of indolyl Grignards in HMPA leads to more attack at nitrogen. Complimentarily, more reactive electrophiles show a greater tendency to react at nitrogen than less electrophilic species. 

This study reports on the reactions of ambident nucleophiles with electron-deficient nitroaromatic and heteroaromatic substrates anionic complex formation or nucleophilic substitution result. Ambident behavior is observed in the case of phenoxide ion (O versus C attack) and aniline (N versus C attack). O or N attack is generally kinetically preferred, but C attack gives rise to stable thermodynamic control. Normal electrophiles such as 1,3,5-trinitrobenzene or picryl chloride are contrasted with superelectrophiles such as 4,6-dinitrobenzofuroxan or 4,6-dinitro-2-(2,4,6-trinitrophenyl)benzotriazole 1-oxide (PiDNBT), which give rise to exceptionally stable a complexes. Further interesting information was derived from the presence in PiDNBT of two electrophilic centers (C-7 and C-l ) susceptible to attack by the ambident nucleophilic reagent. The superelectrophiles are found to exhibit lesser selectivity toward different nucleophilic centers of ambident nucleophiles compared with normal electrophiles. 

A mechanism of this type permits substitution of certain aromatic and ahphatic nitro compounds by a variety of nucleophiles. These reactions were discovered as the result of efforts to explain the mechanistic basis for high-yield carbon alkylation of the 2-nitropropane anion by p-nitrobenzyl chloride. p-Nitrobenzyl bromide and iodide and benzyl halides that do not contain a nitro substituent give mainly the unstable oxygen alkylation product with this ambident anion ... 

At room temperature under photostimulation a-nitrosulfones react with a variety of nucleophiles via radical anion chain reactions interestingly, in none of the cases where the PhSOj group is involved in SrnI type of substitution does the O end of the ambident anion " play a role. This strong regioselectivity is reminiscent of the one reported for other ambident anions involved in these radical chain substitutions. ... 

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). 

Other interesting examples of intermolecular N-C-N transfragment replacement are the ones being found when 1,3-dimethyluracil (113, R = R" = H) and several of its C-5/C-6 mono-substituted or C-5,6 di-substituted derivatives react with different 1,3-ambident nucleophiles (77JHC537 84H(2)89). Reaction of (113, R = R" = H) with guanidine gives isocytosine 115 (R = R = H) in reasonable-to-good yields. 

Hydroxamic acids undergo facile nucleophilic Ai-arylation with activated aryl halides such as 31 (equation 22). While hydroxamates are known to be ambident nucleophiles in alkylation reactions, arylation of hydroxylamines results exclusively in Ai-substituted hydroxamates of type 32 (equation 22)". ... 

Kf., while not quantified experimentally, was recently introduced by Kirby and coworkers on the basis of product formation from O-attack at electrophilic P and C centers, as well as MO calculations incorporating the novel species, ammonia oxide, NH3+-0 . In common with other ambident nucleophiles, factors such as electronic, steric, kinetic and thermodynamic effects will determine actual extant pathways in a given system. Af-substituted hydroxylamines (see Scheme 1) can in principle partake of the equilibria shown in Scheme 2. Again, actual outcomes will be influenced by the aforementioned criteria. 

A major recent growth point in substitution reactions has been the synthesis of pteridine glycosides, especially ribosides for study as probes in DNA chemistry taking advantage of the fluorescent properties of pteridines (see Section 10.18.12.4). Typically these reactions are developments of standard methods of glycosylation used with purines and pyrimidines as nucleophiles. In these and in other cases, the ambident nucleophiles within the pterin... 

Alkyl halides are often used as substrates instead of alcohols. In such cases the salt of the inorganic acid is usually used and the mechanism is nucleophilic substitution at the carbon atom. An important example is the treatment of alkyl halides with silver nitrate to form alkyl nitrates. This is used as a test for alkyl halides. In some cases there is competition from the central atom. Thus nitrite ion is an ambident nucleophile that can give nitrites or nitro compounds (see 0-60).731 Dialkyl or aryl alkyl ethers can be cleaved with anhydrous sulfonic acids.732... 

In a mechanistically similar process, the neutral palladium(II) dipyridylamine complex (24), obtained by deprotonation of complex (23), underwent reaction with benzoyl chloride to give the substituted complex (25) together with some free ligand (Scheme 8).33 This particular reaction sequence could not be generalized because of the relative instability of other metal complexes related to compound (24). However, a more extensive series of electrophilic substitutions could be carried out on the neutral complex (26), which displayed ambident nucleophilic behaviour by reaction with benzyl chloride and benzoyl chloride at nitrogen and reaction with benzenediazonium fluoroborate at carbon (Scheme 9). 

Another aspect of regioselectivity with many nitrogen nucleophiles is the ambident nature of the nucleophile, which can lead to products of the same ring size through either N-cyclization or O-cyclization (see Scheme 12 for an example). As shown by entries 1 and 2 in Table 25, preferential N-cyclization to 3-lactams has been effected by use of sulfonyl or acyloxy substitution on nitrogen. However, these sub-... 

These results clearly show that the potential energy surface can contain a series of minima. The fact that selectivity in re-attack by the F ions can be observed indicates that the differences between the energy barriers for the secondary reactions control the distribution of the final products. The multistep character of these processes is further illustrated by the reactions observed when enolate anions are used as reactant ions. The ambident enolate anions may react with methyl pentafluorophenyl ether at the carbon or the oxygen site. If they react with the carbon site at the fluorine-bearing carbon atoms, then the molecule in the F ion/molecule complex formed contains relatively acidic hydrogen atoms so that proton transfer to the displaced F ion may occur. An example is given in (47) where the enolate anion, generated by HF loss, is not observed. An intramolecular nucleophilic aromatic substitution occurs instead and leads to a second F ion/ molecule complex. The F" ion in this complex then re-attacks the substituted benzofuran molecule formed, either by proton transfer or SN2 substitution. 

Thiophosphite ion, even upon irradiation, only attacks the halogen atom of Me2C(Cl)N02 in an S 2 attack on the halogen188. With azide anion as nucleophile, only low yields of substitution products have been obtained287,288. Much more effective nitrogen--centred nucleophiles in photostimulated reactions with a-halo nitroalkanes are the anions of nitroimidazoles186 and imidazoles187. With the ambident 4(5)-nitroimidazole anion, the 4-isomer is exclusively formed, with no indication of the 5-isomer (equation 72). 

Pyridine N-oxide. A special case of aromatic electrophilic substitution is provided by the ambident reactivity of pyridine /V-oxidc 4.55. Klopman used Equation 3.4 to calculate the relative reactivity (AE values) for electrophilic attack at the 2-, 3- and 4-positions as it is influenced by the energy of the LUMO of the electrophile. He obtained a graph (Fig. 4.8) which shows that each position in turn can be the most nucleophilic. At high values of / , - Es (hard electrophiles), attack should take place at C-3 at lower values of / , - Es, it should take place at C-4 and, with the softest electrophiles, it should take place at C-2. Attack at each of these sites is known the hardest electrophile SO3 does attack the 3-position, the next hardest (NC>2+) the 4-position, and the softest (HgOAc+) the 2-position. 

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