Quinoline protonation

As much as the quinoline ring is concerned useful information on the existence or absence of ir-K-interactions with corresponding aromatic moieties in the selectands could indeed be derived by help of CIS of aromatic protons. Substantial upheld CIS in the range of AS = -0.24 to —0.37 ppm have been detected in the S -complex of DNB-Leu with the 0-9-tert-butylcarbamoyl-6 -neopentoxy-cinchonidine selector for the quinoline protons and the proton in para-position of the DNB group, while the corresponding / -complex was devoid of this effect [92], Essentially the same observation was made for the DNB-Ala-Ala selectand, but not for DNB-Ala-Ala-Ala,... 

Fig. 5.6 Changes in chemical shifts (in units of Hz at 600 MHz) of the quinoline proton resonances of dibucaine as a result of interaction with M P-1 and MP-2 in PS liposomes. (Reprinted from Fig. 16 of ref. 24 with permission from the Rockefeller University Press.)...

J lie decarboxylation is frequently the most troublesome step in this sequence. Attempts at simple thermal decarboxylation frequently lead to recycliz-ation to the lactam. The original investigators carried out decarboxylation by acidic hydrolysis and noted that rings with ER substituents were most easily decarboxylated[2]. It appears that ring protonation is involved in the decarboxylation under hydrolytic conditions. Quinoline-copper decarboxylation has been used successfully after protecting the exocyclic nitrogen with a phthaloyl, acetyl or benzoyl group[3]. 

As early as 1889 Walker (320), using samples of thiazole, 2,4-dimethylthiazoie, pyridine, and 2,6-dimethylpyridine obtained from Hantzsch s laboratory, measured the electrical conductivity of their chlorhydrates and compared them with those of salts of other weak bases, especially quinoline and 2-methylquinoline. He observed the following order of decreasing proton affinity (basicity) quinaldine>2,6-dimethyl-pyridine>quinoline>pyridine>2,4-dimethylthiazole> thiazole, and concluded that the replacement of a nuclear H-atom by a methyl group enhanced the basicity of the aza-aromatic substrates. 

The piC values of polymethine dyes depend on terminal group basicity (64) thus the protonation abHity diminishes if the basic properties of the residues decrease, passing from benzimidazole, quinoline, benzothiazole, to indolenine. On the other hand, the piC of higher homologues increases with chain lengthening. The rate constant of protonation is sensitive to other features, for example, substituents and rings in the chain and steric hindrance for short-chain dyes. 

Quinoline, 6-amino-protonation, 2, 341 Quinoline, 7-amino-protonation, 2, 341 Quinoline, 8-amino-alkylation, 2, 179 methylation, 2, 342 Quinoline, 4-amino-7-chloro-as antimalarial, 2, 517 Quinoline, 2-amino-3-cyanotetrahydro-synthesis... 

Condensation of an aniline with a dione with loss of water provides enamine 16. Ketone protonation and cyclization forms 18 followed by loss of water provides quinoline 4. Some have suggested the formation of dication 19 as a requirement to cyclization. Cyclization of 19 to 20 and subsequent conversion to quinoline 4 requires loss of water and acid. Another rendering of the mechanism takes into account participation of an electron-donating group (EDG), which stabilizes intermediate 21. 

The Knorr quinoline synthesis has been nicely extended by Hodgkinson and Staskun to include P-ketoesters that do not have protons at the 2 position of the starting keto-ester. 2,2 -dichloroanilides of type 14 can cyclize to provide quinolines such as 15 and 16 in good respective yields. ... 

Carboxylic acids with labile a-methylene protons react with isatin in the presence of strong aqueous base. In the total synthesis of methoxatin, the coenzyme of methanol dehydrogenase and glucose dehydrogenase, Weinreb employs a Pfitzinger condensation of an isatin 37 and pyruvic acid as a key step to provide the 4-quinolinic acid 38 in 50% yield under the standard basic conditions. ... 

The ionization constant of a typical heterocyclic compound (e.g., quinoline) designates the equilibrium involving a proton, a neutral molecule and its cation. With quinazoline, however, two distinct species (hydrated and anhydrous) are involved each of which is in equilibrium with its cation, and can be represented as in the reaction scheme, (7), (8), (3), and (4). 

Charton has recently examined substituent effects in the ortho position in benzene derivatives and in the a-position in pyridines, quinolines, and isoquinolines. He concludes that, in benzene derivatives, the effects in the ortho position are proportional to the effects in the para position op). However, he finds that effects of a-sub-stituents on reactions involving the sp lone pair of the nitrogen atoms in pyridine, quinoline, and isoquinoline are approximately proportional to CT -values, or possibly to inductive effects (Taft s a ). He also notes that the effects of substituents on proton-deuterium exchange in the ortho position of substituted benzenes are comparable to the effects of the same substituents in the a-position of the heterocycles. 

Spectroscopic evidence indicates that protonation of 2-fluoro-and 2-chloro-quinoline is not appreciable in O.OlJf aqueous hydrochloric acid. Protonation becomes evident in more strongly acidic solution in the case of the chloro compound without any accompanying decomposition, but the fluoro compound hydrolyzes to carbostyril under the latter conditions. The hydrolysis is acid-catalyzed, but it is doubtful whether protonation on the heterocyclic nitrogen is responsible, owing to its low basicity (presumably below that for the chloro compound). An alternative explanation in this case would be hydrogen bond formation with fluorine, Ar—F. .. H-O+H2. 

The usual order found with halogenonitrobenzenes is F > Cl Br I, the order of Cl and Br being variable, just as in heteroaromatic reactivity. The position of fluorine is of interest the available data indicate that it is usually the same as for nitrobenzene derivatives. Thus, in acid hydrolysis the order F > Cl for 2-halogeno-quinolines can be deduced beyond doubt since the fluoro derivative appears to react in the non-protonated form and the chloro derivative to resist hydrolytic attack even in the protonated form under appropriate conditions (Section II,D, l,d). Furthermore, in the benzo-thiazole ring, fluorine is displaced by the CHgO reagent at a rate 10 times that for chlorine. ... 

The catalytic effect of protons has been noted on many occasions (cf. Section II,D,2,c) and autocatalysis frequently occurs when the nucleophile is not a strong base. Acid catalysis of reactions with water, alcohols, mercaptans, amines, or halide ions has been observed for halogeno derivatives of pyridine, pyrimidine (92), s-triazine (93), quinoline, and phthalazine as well as for many other ring systems and leaving groups. An interesting displacement is that of a 4-oxo group in the reaction of quinolines with thiophenols, which is made possible by the acid catalysis. 

FtG. 1. Energy values for the neutral and two alternative protonated forms of imidazo[4,5-/]-quinoline. 

Calculated Proton Affinities and pK Values for Imidazo [4,5-/ Quinolines... 

Absorption and emission spectra of six 2-substituted imidazo[4,5-/]quinolines (R = H, Me, CH2Ph, Ph, 2-Py, R = H CH2Ph, R = Ph) were studied in various solvents. These studies revealed a solvent-independent, substituent-dependent character of the title compounds. They also exhibited bathochromic shifts in acidic and basic solutions. The phenyl group in the 2-position is in complete conjugation with the imidazoquinoline moiety. The fluorescence spectra of the compounds exhibited a solvent dependency, and, on changing to polar solvents, bathochromic shifts occur. Anomalous bathochromic shifts in water, acidic solution, and a new emission band in methanol are attributed to the protonated imidazoquinoline in the excited state. Basic solutions quench fluorescence (87IJC187). 

Bond orders, charges on the atoms in 1 l//-pyrido[2,l-Z)]quinazolin-l 1-one and its protonated form were calculated by quantum chemical calculations by the semiempirical AMI method. According to the results, the equilibrium conformation of the ring in 1 l//-pyrido[2,l-Z)]quinazolin-l 1-one is planar, while l//-pyrimido[l,2-u]quinolin-1-one adopts a conformation close to a half-chair due to the unfavorable interactions between the oxygen atom of the carbonyl group and the ring C-10 atom in the pen-position (97MI22). 

Compounds such as 2, 4, and 5 are known as proton sponges. Another type of proton sponge is quino[7,8-A]quinoline (6). Protonation of this compound also gives a stable monoprotonated ion similar to 3, but the steric hindrance found in 2, 4, and 5 is absent. Therefore 6 is a much stronger base than quinoline (7) (p/fg values of the conjugate acids are 12.8 for 6 and 4.9 for 7), but proton transfers are not abnormally slow. 

Alkylation of protonated nitrogen heterocycles (e.g., pyridines, quinolines) can be accomplished by treatment with a carboxylic acid, silver nitrate, sulfuric acid, and ammonium peroxydisulfate. The R group can be primary, secondary, or tertiary. The attacking species is R% formed by " ... 

Photochemical alkylation of protonated quinoline occurred with Ph2Se(02Cc-... 

---