Acridine nucleophilic attack

Nucleophilic reagents attack pyridine at the a-position to form an adduct that rearomatizes by dissociation (Scheme 1). Only very strong nucleophiles, e.g. NH2-, RLi, LAH, Na-NH3, react, and for the second step to afford a substitution product (5), conditions that favour hydride loss are required. Adducts formed with hydride ions (from LAH) or carbanions (from lithium alkyls) are relatively more stable than the others at low temperature, and dihydropyridines (6) can be obtained by careful neutralization. Fusion of a benzene ring to pyridine increases reactivity towards nucleophiles, and attack is now found at both a- and y-positions in quinoline (7) and at C-l in isoquinoline (8). This may be attributed to a smaller loss of aromaticity in forming the initial adduct than in pyridine, and thus a correspondingly decreased tendency to rearomatize is also observed. Acridine reacts even more easily, but nucleophilic attack is now limited to the y -position (9), as attachment of nucleophiles at ring junctions is very rare. 

Quinoline 1-oxide undergoes nucleophilic attack by ozone to yield a hydroxamic acid (128), and 40% of the starting iV-oxide is recovered (Scheme 74). When an excess of ozone is employed the aldehydes (129) and (130) are obtained. Formation of these products has been attributed to electrophilic attack by ozone rather than further oxidation of (128), because in a separate experiment (128) yielded carbostyril on treatment with ozone. Isoquinoline 2-oxide yields 2-hydroxyisoquinolin-l-one, and acridine 10-oxide gives 10-hydroxyacridone and acridone in a similar manner to the above. Likewise, phenanthridine 5-oxide affords mainly 5-hydroxyphenanthridone. Quinoline 1-oxide undergoes oxidation by lead tetraacetate as shown (Scheme 75). 

Nucleophilic attack at ring carbon occurs in benzenes only when electron-withdrawing substituents are present. Even with pyridine, only the strongest nucleophiles react. This is because the formation of the initial adduct (2) involves de-aromatization of the pyridine ring and, once formed, many such adducts tend to re-aromatize by dissociation (1 2). Benzo fusion decreases the loss in aromaticity for the formation of the adduct and thus quinoline (3) and especially acridine (4) react more readily with nucleophiles. 

Acridine is less stable toward oxidizing agents and yields acridone (with Na2Cr207, HOAc). Some diazine derivatives are apparently oxidized directly to diazinones quinoxaline gives 153 (with K2S20s, H20) and quinazol-4-one yields 154 (with KMn04, CrOj). These reactions probably involve nucleophilic attack of water followed by oxidation of the adduct (see Section 3.2.1.6.3). 

Coupling reactions of the electrogenerated cation radicals can also occur. If the parent molecule is a good nucleophile, this can be considered as a nucleophilic attack by parent on its own cation radical. The nature of the electrochemical responses in CV and coulometry depend upon whether the coupled product can undergo further oxidation. For example, in the oxidation of aromatic aza-hydrocarbons such as acridine (AcH), studied by Marcoux and Adams (1974), the CV was characterized by an irreversible one-electron wave and coulometry showed an napp-value of one. An analysis of rotating disk voltammograms demonstrated that the reaction sequence (79)-(81) was more probable them that involving... 

A similar mechanism applies to the acridine phenyl esters and acridine N-oxide phenyl esters [21]. Quantum yields are not quite so high, and in the former case, dipolar aprotic solvents are required, presumably to enhance nucleophilic attack at the now less activated 9-position. Quinolinium (10) and phenanthridinium (11) esters are also chemiluminescent but with a lower efficiency [21] ... 

Nucleophilic Reactions of Aromatic Heterocyclic Bases Heterocyclic aromatic compounds containing a formal imine group (pyridine, quinoline, isoquinoline, and acridine) also react readily with nucleophilic reagents. A dihydro-derivative results, which is readily dehydrogenated to a new heteroaromatic system. Since the nucleophile always attacks the a-carbon atom, the reaction formally constitutes an addition to the C=N double bond. An actual localization of the C=N double bond in aromatic heterocyclic compounds is incompatible with molecular orbital theory. The attack of the nucleophilic reagent occurs at a site of low 77-electron density, which is not... 

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