Isoquinoline basicity

Crude oils contain nitrogen compounds in the form of basic substances such as quinoline, isoquinoline, and pyridine, or neutral materials such as pyrrole, indole, and carbazole. 

Of the total tar bases in U.K. coke-oven and CVR tars, pyridine makes up about 2%, 2-methyl pyridine 1.5%, 3- and 4-methylpyridines about 2%, and ethylpyridine and dimethylpyridines 6%. Primary bases, anilines and methylanilines, account for about 2% of the bases in coke-oven and CVR tars and 3.5% of the bases in low temperature tars. The main basic components in coke-oven tars are quinoline (16—20% of the total), isoquinoline (4—5%), and methyl quinolines. These dicycHc bases are less prominent in CVR and low temperature tars, in which only a minority of the basic constituents have been identified. 

The chemistry of these polycyclic heterocycles is just what you miglu expect from a knowledge of the simpler heterocycles pyridine and pyrrole Quinoline and isoquinoline both have basic, pyridine-like nitrogen atoms, anc both undergo electrophilic substitutions, although less easily than benzene Reaction occurs on the benzene ring rather than on the pyridine ring, and r mixture of substitution products is obtained. 

N-Heteroaromatic compounds like pyridine, pyridazine, pyrazine, isoquinoline, and their derivatives42,250 react with diphenyl cyclopropenone in a formal (3+2) cycloaddition mode to the C=N bond of the heterocycle. As expected from the results discussed earlier (p. 67), the reaction is initiated by attack of nitrogen at the cyclopropenone C3 position and followed by stabilization of the intermediate betaine 390 through nucleophilic interaction of the Cl/C3 bond with the activated a-site of the heterocycle, giving rise to derivatives of 2-hydroxy pyrrocoline 391—394). In some cases, e.g. diphenyl cyclopropenone and pyridine42, further interaction with a second cyclopropenone molecule is possible under the basic conditions leading to esters of type 392. 

Isoquinoline (pK 5.4) has similar basicity to quinoline and pyridine, and also undergoes A -alkylation and A -acylation. Nitration occurs... 

Boiling an ethanolic solution of 4//-pyridazino[6,l-fl]isoquinoline (42) in the presence of KOH for 6 h gave the 4-unsubstituted derivative 53, which was A-acylated with benzoyl chloride (83JOC1084). Heating the A-benzoyl derivative 54 in boiling ethanol in the presence of KOH for 36 h afforded the 2-hydroxy derivative 55, which was also prepared from 56 by basic hydrolysis and subsequent acylation with benzoyl chloride. A decarboxylation-oxidation product 50 was also isolated from the reaction mixture. 

Hence, lithium salt 343a is trapped by aldehydes, and subsequent intramolecular attack of the intermediate alkoxide on the lactam moiety leads to pyridinophanes 405a and b. Ethanolysis of lactam 288 under acidic or basic conditions, even at —78°C, affords ester 406, whereas the reactions of lactams 288 and 290 with 4-methyl-l,2,4-triazoledione (MXAD) give mixtures of cycloadducts 407a and b or the respective isoquinolines. Tricyclic 290 when irradiated suffers loss of carbon monoxide to form butadiene 408. 

The synthesis of the basic skeleton of 1-benzylisoquinoline alkaloids has been reported by Uff et al. 15) starting from isoquinoline and benzyl chloride (Scheme 5). The preparation of Reissert compound iV-benzyl-l-cyano-l,2-di-hydroisoquinoline (4) was performed in a dichloromethane-water two-phase system with potassium cyanide and benzoyl chloride in about 64-69% yield. The deprotonation of 4 with sodium hydride in dimethylformamide solution, the subsequent alkylation with benzyl chloride, and the final alkaline hydrolysis could be performed as a one-pot reaction sequence to supply 1-benzylisoquinoline (25) in an overall yield of 75-84%. 

The parent naphthyridines have basic strengths lower than those of quinoline (4.94) and of isoquinoline (5.40) (c/. Table 6), which has been attributed to the relayed inductive effect of one doubly bound nitrogen atom to the other. The greater basic strengths of the 1,6-and 1,7-isomers as compared to the 1,5- and 1,8-compounds appear to indicate that... 

Quinoline and isoquinoline are basic in nature. Like pyridine, the nitrogen atom of quinoline and isoquinoline is protonated under the usual acidic conditions. The conjugate acids of quinoline and isoquinoline have similar pA a values (4.85 and 5.14, respectively) to that of the conjugate acid of pyridine. 

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. 

Isoquinoline [119-65-3] M 129.2, m 24 , b 120 /18mm, d 1.0986, n 1.6148. Dried with Linde type 5A molecular sieves or Na2SO4 and fractionally distd at reduced pressure. Alternatively, it was refluxed with, and distd from, BaO. Also purified by fractional crystn from the melt and distd from zinc dust. Converted to its phosphate (m 135°) or picrate (m 223°), which were purified by crystn and the free base recovered and distd. [Packer, Vaughn and Wong JACS 80 905 795(S]. The procedure for purifying via the picrate comprises the addition of quinoline to picric acid dissolved in the minimum volume of 95% EtOH to yield yellow crystals which are washed with EtOH and air dried before recrystn from acetonitrile. The crystals are dissolved in dimethyl sulphoxide (previously dried over 4A molecular sieves) and passed through a basic alumina column, on which picric acid is adsorbed. The free base in the effluent is extracted with n-pentane and distd under vacuum. Traces of solvent are removed by vapour phase chromatography. [Mooman and Anton JPC 80 2243 1976. ... 

C. Interpretation of Equilibrium Data For pyridine, quinoline, isoquinoline, and acridine, the differences in the 7r-electronic energies of the protonated form and the free base have been calculated at several levels of sophistication, from the HMO method to the Cl SCF method.191 The A W values obtained are linearly interrelated, which supports the view that the HMO data are meaningful. In this connection, considerable attention has been paid to the role of solvation energies in acido-basic equilibria.161... 

Oxo-4//-pyrimido[2,l-a]isoquinoline-3-carboxylic acids and their 6,7-dihydro derivatives were prepared by the hydrolysis of ethyl 4-oxo-4H-pyrimido[2,l-a]isoquinoline-3-carboxylates (97) and their 6,7-dihydro derivatives (98) under acidic (in a boiling mixture of acetic acid and cone, hydrochloric acid) and basic conditions (in 2% sodium hydroxide solution, and in a boiling mixture of 2% sodium hydroxide and ethanol) [78USP4127720 84JAP(K)84/172472 85EUP143001]. 

Treatment of 3,6-dihydroxy-3,4-dihydro-2//-pyrido[2,l-h][l,3] thiazinium salt (86) with orthophosphoric acid at 140°C for 34 h or with cone, sulfuric acid at ambient temperature for 5 h afforded 1 1 and 3 1 mixtures of pyrido[2,l-6][l,3]thiazine (87) and thiazolo[3,2-a]pyridine (88), respectively (70ACS2949). Under basic conditions, only extensive destruction of 86 was observed. When 3-hydroxy-2,3,4,6-tetrahydro[l,3]thiazino[2,3-a]isoquinolin-6-one was left to stand in cone, sulfuric acid at room temperature overnight, 4,6-dihydro[l,3]thiazino[2,3-a]isoquinolin-6-one was obtained in 61% yield (72ACS1620). 9-Oxido-3,4-dihydro-2H-pyrido[2,l-h] [l,3]thiazinium betaine did not undergo cycloaddition even under extreme conditions [81JCR(S)208],... 

Alkaloids are basic plant natural products that typically have a nitrogen atom as part of a heterocyclic ring system and indeed are classified on this basis. Thus major classes of alkaloids are based on indole, isoquinoline, pyrrolidine, piperidine, pyrrolizidine, quinoline, tropane, quinolizidine or other heterocyclic ring systems. Other alkaloids are basic monoterpenoid, sesquiterpenoid, diterpenoid, steroid, purine, pyrimidine or peptide entities. Some of these compounds are exceptionally toxic [1,6, 7-12]. 

The o values of rings annelated to pyridine in systems such as quinoline, isoquinoline, benzoquinolines, acridine, and phenanthridine and determined by the basicity of the ring nitrogen atom are predicted186 and found to be small.33,34 This is an important point stressed and elucidated previously,181 and demonstrating the validity of the basic assumptions of the Hammett equation. 

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