Acridine reactivity

A few studies on solvolyses by alcohols and by water are available. The hydrolyses studied include displacement of alkylamino groups from acridine antimalarials and of halogen from other systems. In all cases, these reactions appeared to be first-order in the heterocyclic substrate. By a detailed examination of the acid hydrolysis of 2-halogeno-5-nitropyridine, Reinheimer et al. have shown that the reaction rate varies as the fourth power of the activity of water, providing direct evidence that the only reactive nucleophile is neutral water, as expected. 

It is notable that pyridine is activated relative to benzene and quinoline is activated relative to naphthalene, but that the reactivities of anthracene, acridine, and phenazine decrease in that order. A small activation of pyridine and quinoline is reasonable on the basis of quantum-mechanical predictions of atom localization encrgies, " whereas the unexpected decrease in reactivity from anthracene to phenazine can be best interpreted on the basis of a model for the transition state of methylation suggested by Szwarc and Binks." The coulombic repulsion between the ir-electrons of the aromatic nucleus and the p-electron of the radical should be smaller if the radical approaches the aromatic system along the nodal plane rather than perpendicular to it. This approach to a nitrogen center would be very unfavorable, however, since the lone pair of electrons of the nitrogen lies in the nodal plane and since the methyl radical is... 

Quinoxalines undergo facile addition reactions with nucleophilic reagents. The reaction of quinoxaline with allylmagnesium bromide gives, after hydrolysis of the initial adduct, 86% of 2,3-diallyl-l,2,3,4-tetrahydroquinoxaline. Quinoxaline is more reactive to this nucleophile than related aza-heterocyclic compounds, and the observed order of reactivity is pyridine < quinoline isoquinoline < phenan-thridine acridine < quinoxaline. ... 

Halogenations of quinoline, isoquinoline, acridine, and phenanthridine will be discussed here. Reaction usually occurs in a homocyclic fused ring rather than in the 7r-deficient pyridine moiety, especially in acidic media. Relatively mild conditions suffice, but under more vigorous regimes radical involvement can result in heteroring halogenation. Substituents are able to modify reactivity and regiochemistry. 

Some derivatives of luminol and acridine are currently used for the HPLC-CL detection. They are prepared by changing a substituent or introducing a new functional group into the luminol or acridine skeleton to give better CL efficiency or reactivity with analyte(s). 

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. 

The nitration of acridine (9 R = H) in sulfuric acid is an unsatisfactory reaction in that the mixed isomers produced are difficult to separate. The main product is 2-nitroacridine (9 R = N02) the order of reactivity being 2>4>1>3 and product ratio 130 25 5 1 respectively (B-66MI20600). Acridine AT-oxide, however, undergoes nitration at 0°C to produce 9-nitroacridine AAoxide (10) (60JCS3367). 

The general principle of methyl group reactivity is also seen in the oxidation of 7,9,10-trimethylbenz[c]acridine to give the 7-formyl compound (68), the 9- and 10-methyl groups being unaffected (Scheme 62) (64JCS5622). 

A number of other heterocycllcs have been similarly studied and shown by H nmr, to produce quaternary ammonium salts with living polyTHF.2- Moreover, their rates of reaction are a direct function of their basicities, the following order of reactivities being observed ethyl pyridine > pyridine > isoquinoline > quinoline > acridine. Aliphatic tertiary amines also react in the same way the order of reactivities was found to be triethylame > tributylamlne > dlethylanillne. In all cases studied, the quaternary ammonium salt once formed did not exchange with any excess oxonium lone. 

The reactions of the 4-halopyridines parallel those of the corresponding 2-isomers, with the exception that 4-halopyridines polymerize much more readily (e.g. to 903) because the pyridine nitrogen atom is not sterically hindered and is more basic (cf. Section 3.2.1.3.4). As expected, the chlorine atom in the 1-position of 1,3-dichloroisoquinoline is more reactive than that in the 3-position, thus, mild treatment with sodium ethoxide gives (904). Halogens in the 9-position of acridine are more reactive, e.g. (906) — (90S), (907). 

If the photochemical reaction is followed only by measuring the concentration of the light-absorbing ketone, it will indeed appear that the additive (acridine) acts as a quencher in reality it acts as a radical scavenger through a thermochemical reaction which is quite unrelated to the nature of the reactive excited state. 

The compositional data for 3-ring azaaromatic hydrocarbons appear to be consistent with the network for hydrodenitro-genation of acridine (36) and, based upon considerations of structure-reactivity, our proposed extension of it to other C HgN isomers. 

The decreasing reactivity of the most familiar aromatic heterocyclic compounds with nucleophilic reagents may be illustrated by the following sequence quinoxaline > acridine > phenanthridine > isoquinoline > quinoline > pyridine. Acridine is alkylated in the 4-position, phenanthridine and quinoxaline in the a-position, isoquinoline in the 1-position, and quinoline and pyridine in the 2- or 4-positions. Weaker nucleophilic reagents seem to enter the 4-position of the pyridine and quinoline rings. If the addition occurs readily and in good yield, the intermediate dihydro derivative may sometimes be isolated otherwise, the product of the subsequent oxidation results. In synthetic work the dihydro derivative is usually directly oxidized. 

The reactivity of the triplet state in photoreduction reactions was used by Nakamaru et al. (1969) to investigate the triplet state basicity of acridine. It should be possible to extend this method to any compounds in which an excited state reaction is affected by protonation. 

Apart from investigations of the mechanism of the Clemmensen reaction ensuing from the formation of 3, work on the reactivity of nitrenes (Section IV,A,4), as well as studies of photochemical rearrangements of acridine Af-oxides (Section IV,B), have led to 4-azaazulenes. 

An aza analogue with nitrogen occupying a reactive position in the carbocycle will be less reactive than an aza analogue in which a less reactive site is occupied. Thus, quinoline is less reactive than isoquinoline, and acridine (11.13) is expected to be less reactive than benzo[g]quinoline (11.5). 

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