Chlorination of quinoline

Chlorination. Electrophilic chlorination of quinoline (66) in neutral medium showed a positional selectivity order of 3 > 6 > 8. The 5- and 8-positions should be sterically hindered to some extent. Hammett cr+ values predict an order for electrophilic substitution of 5 > 8 = 6 > 3. Treatment with chlorine at 160-190°C converted quinoline into a mixture of 3-chloro-, 3,4-dichloro-, 3,4,6- and 3,4,8-trichloro-, 3,4,6,8-tetrachloro-, and 3,4,6,7,8-pentachloro-quinolines. At lower temperatures ( 100°C) the major product was 3-chloroquinoline, albeit in low yield. The 4-substituted species may have arisen from an addition-elimination or radical process (70JHC171). 

Exhaustive chlorination of quinoline over antimony pentachloride leads to fragmentation into perchlorobenzene and hexachloroethane (1882JCS412). Direct uncatalyzed chlorination of quinoline at 160-190 °C gives at least five chloroquinolines (Scheme 29) among the ten products of reaction detected by gas chromatography (70JHC171). Substitution at position... 

Chlorination of quinoline in the presence of aluminum chloride results in substitution in the benzene ring no evidence was found of attack at positions 2, 3 or 4. A route to the important wide-spectrum insecticide chloropyriphos from 2-methylpyridine involves two chlorination steps (Scheme 32) (B-74MI20500). 

Chlorination of quinoline in the presence of silver sulfate in sulfuric acid gives 5-chloro, 8-chloro- and 5,8-dichloro-quinoline (63CI(L)1840, 66MI20601). Similarly, addition of iodine to quinoline and silver sulfate in sulfuric acid at 150-200 °C gives 5-iodo-, 8-iodo- and 5,8-diiodo-quinoline (Scheme 8). It is thought that I+ is the electrophile (64CI(L)1753, 66MI20602). 

Electrophilic chlorination of quinoline under neutral conditions occurs in the orientation order 3 > 6 > 8. Hammett ct+ values predict an order for electrophilic substitution of 5 > 8 = 6 > 3. The reactivity order can be affected by substitution of an electron-withdrawing group in the benzene ring, which directs the chlorination to the pyridine ring. Thus, NCS in acetic acid or sulfuryl chloride in o-dichlorobenzene converts 8-nitroquinoline into 3-chloro-8-nitroquinoline in high yield (91M935). 

Chlorination of quinoline at 160-190°C without solvent gave polysubstitution with proportions of products implying the reactivity order 3, 4 >... 

Halogenation. Direct halogenation of quinoline proceeds at the 2-position. Fluorination and bromination are known, but they proceed using forcing conditions (eqs 24 and 25). lodination proceeds under milder conditions, but requires an additional titanium-based reagent (eq 26). Chlorination of quinoline without prior activation has not been reported. 

In the Meisenheimer reaction of quinoline 1-oxides chlorine atoms usually enter the 2-and 4-positions, but not exclusively. 2,4-Dibromoquinoline 1-oxide was 6-chlorinated (57MI1), and the 5- and 6-nitroquinoline 1-oxides were 3-chlorinated to some extent (44JOC302). This reaction with phosphoryl chloride-phosphorus pentachloride has also been used in the preparation of chlorinated phenanthrolines (88YZ1148). 

Reduction of the heterocyclic ring and incorporation of a nitro function affords a compound with antischistosomal activity, oxamniquine (60). Its synthesis begins with chlorination of 2,6-dimethyl-quinoline, which proceeds regiospecifically on the methyl group adjacent to the ring nitrogen (56). 

Bromination of pyridine is much easier than chlorination. Vapour phase bromination over pumice or charcoal has been studied extensively (B-67MI20500) and, as with chlorination, orientation varies with change in temperature. At 300 °C, pyridine yields chiefly 3-bromo-and 3,5-dibromo-pyridine (electrophilic attack), whilst at 500 °C 2-bromo- and 2,6-dibromo-pyridine predominate (free radical attack). At intermediate temperatures, mixtures of these products are found. Similarly, bromination of quinoline over pumice at 300 °C affords the 3-bromo product, but at higher temperatures (450 °C) the 2-bromo isomer is obtained (77HC(32-1)319). Mixtures of 3-bromo- and 3,5-dibromo-pyridine may be produced by heating a pyridine-bromine complex at 200 °C, by addition of bromine to pyridine hydrochloride under reflux, and by heating pyridine hydrochloride perbromide at 160-170 °C (B-67MI20500). 

The aluminum chloride complex of quinoline is also brominated in a similar manner, except that less 8-bromoquinoline is formed, presumably reflecting steric hindrance by the aluminum chloride complexed at nitrogen. The 5,6- and 5,8-dibromoquinolines and 5,6,8-tribromo derivative can also be obtained by this procedure. Reaction of the complex with chlorine gives the 5,8-dichloro and 5,6,7,8-tetrachloro derivatives (67JHC410, 64JOC329). 

To substantiate this mechanism, haloquinolines (75) were used. The strategy was to hinder sterically the addition of superoxide. In the case of 6-chloroquinoline, the products were the same as those formed from quinoline, except that they were chlorinated, which was expected because position 6 is not involved in either mechanism. Halogen substitution on the pyridine moiety in part directed oxygen addition to the benzene moiety, which was consistent with superoxide addition onto the more accessible positions on the benzene ring of the halogenated radical cation. This result supports the fact that a cycloaddition mechanism can take place in the photocatalytic degradation of quinoline. This mechanism has been proposed in the case of other aromatics, such as 4-chlorophenol (76) and 4-chloro-catechol (77). 

Further studies of electrophilic substitution using the 2,3-dihydrothiazolo analogue (320) show that regioselective bromination can be effected in the 7-position (347) at low temperature. Chlorination with sulfuryl chloride, however, occurs exclusively in the 5-position. The 5-chloro derivative (348) can be further nitrated in the 7-position. By analogy, bromination of quinoline analogues (349) occurs in the azine ring, in the 5-position. The [3,2-a]pyrimidine analogue (350 R=H) similarly yields the 7-bromide. The activation by... 

The nuclear-substituted halogens of aromatic /V-hetereocycles may also be susceptible to hydrogenolysis. In particular, those at the 2 and 6 positions of pyridines and at the 2 and 4 positions of quinolines are readily hydrogenolyzed, as shown in eqs. 13.129— 13.131. In the example shown in eq. 13.131, it was noticed that the rate of hydrogenolysis of the 4-chlorine was considerably greater than that of the 7-chlorine in the presence of an excess of alkali, and the selective dechlorination of the 4-chlorine was successful in an alcoholic solution containing 1.25 equiv of potassium hydroxide at room temperature and atmospheric pressure.240... 

A mixture of the chlorinated products of quinolin-8-ol containing 57 to 74% of 5,7-dichloroquinolin-8-ol (chloroxine), 23 to 40% of 5-chloroquinolin-8-ol, and not more than 4% of 7-chloroquinolin-8-ol. 

Several conjugated diolefins have been made by heating bromo olefins with solid potassium hydroxide or excess quinoline. In the latter case, the bromo olefins were made available by allylic bromination of olefins with N-bromosuccinimide. /S-phenylbutadiene is obtained in 46% yield by the action of pyridine on the corresponding secondary chloride. Chlorination of n-butyl chloride gives an isomeric mixture of dichlorides from which low yields (18-30%) of butadiene are obtained by passing the vapors over soda lime at about 700°. ... 

By chlorinating kynurenic acid with phosphorus pentachloride and oxychloride and by successive addition of quinoline to the reaction product, the authors obtained a colored substance, soluble in ethanol and giving a brilliant red-violet color with maximum absorption at 556-557 mp, of remarkable stability. 

Dichlorophenol has been prepared by the chlorination of phenol with chlorine gas in the presence of nitrobenzene and fuming sulfuric acid, by the decomposition of the diazotate of 2,6 dichloro-4-aminophenol, eind by the decarboxylation of 3,5-dichloro-4-hydroxybenzoic acid in quinoline or dimethyl-aniline. ... 

Expanded studies in this direction revealed that chlorination of the quinoline and phenyl rings in 2-aryl-4-quinolinyl-2 -piperidinyl methanols may diminish phototoxicity [49]. Further molecular modifications in 2-substituted quinine derivatives showed that replacement of the 2-phenyl group by trifluoromethyl groups could further reduce phototoxicity with retention of antimalarial activity [50]. This observation was systematically exploited at the Walter Reed Army Research Institute culminating in the discovery of mefloquine (23a) [51]. The other effective anhmalarials,... 

Direct lithiation, i.e. C-deprotonation of quinolines requires an adjacent substituent, such as chlorine, fluorine or alkoxy. Historically, what is probably the first ever strong base C-lithiation of a six-membered heterocycle was the 3-lithiation of 2-ethoxyquinoline. Both 4- and 2-dimethylaminocarbonyloxyquinolines lithiate at C-3 4-pivaloylaminoquinoline lithiates at the peri position, C-5. Quinolines with an ortfto-directing... 

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