Nucleophilic substitution reactions ambident nucleophiles

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... 

Ambident anions are mesomeric, nucleophilic anions which have at least two reactive centers with a substantial fraction of the negative charge distributed over these cen-ters ) ). Such ambident anions are capable of forming two types of products in nucleophilic substitution reactions with electrophilic reactants . Examples of this kind of anion are the enolates of 1,3-dicarbonyl compounds, phenolate, cyanide, thiocyanide, and nitrite ions, the anions of nitro compounds, oximes, amides, the anions of heterocyclic aromatic compounds e.g. pyrrole, hydroxypyridines, hydroxypyrimidines) and others cf. Fig. 5-17. 

It should be mentioned briefly that solvation phenomena should also influence the outcome in the case of ambident nucleophiles, at least to the extent to which these reagents are sensitive to solvent effects. With an ambident anion, which is not manipulated by countercations (formation of ion pairs), the more electronegative center should attack preferentially. The more this area is blocked by hydrogen bridges formed in protic solvents, or shielded by countercations, the more likely it is that the less electronegative end will react. If dipolar aprotic solvents are used, which can only solvate the cations, a preferential attack of the nonshielded more electronegative center is to be expected. It must be realized, however, that in substitution reactions employing cyanide ions, dipolar aprotic solvents have not been reported to enhance the formation of isonitriles. " ... 

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. 

Another attempt to use the host-guest complexation of simple cyclophanes has been reported by Schneider They take the easily accessible host 7, an analogue of which had been demonstrated by Koga to bind aromatic guest molecules by inclusion into its molecular cavity, and study its rate effects on nucleophilic aliphatic substitutions of ambident anions (NOf, CN, SCN ) on 2-bromomethylnaphthalene 8 and benzylbromide. Similar bimolecular reactions are well known in cyclodextrin chemistry and other artificial host systems . In addition to the rather poor accelerations observed (see Table 3) the product ratio is changed in the case of nitrite favouring attack of the ambident nucleophile via its nitrogen atom. 

Hydroxyl Group. Reactions of the phenohc hydroxyl group iaclude the formation of salts, esters, and ethers. The sodium salt of the hydroxyl group is alkylated readily by an alkyl hahde (WiUiamson ether synthesis). Normally, only alkylation of the hydroxyl is observed. However, phenolate ions are ambident nucleophiles and under certain conditions, ring alkylation can also occur. Proper choice of reaction conditions can produce essentially exclusive substitution. Polar solvents favor formation of the ether nonpolar solvents favor ring substitution. 

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. ... 

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)". ... 

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). 

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). 

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. 

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