Quinolines and isoquinolines

What are quinolines and isoquinolines?

They are the fusion products of a benzene ring and a pyridine nucleus.

fig-01

Both substances are obtained from coal tar. These weakly basic heterocycles resemble pyridine in their stability against chemical attack. But there are some fundamental differences in their reactivity.

Both quinoline and isoquinoline can be considered as 10-electron π-aromatic and delocalized systems. Furthermore, experimental observations, carried out in oxidation reactions, suggest that these molecules resemble naphthalene because the character of the double bond is stronger in the 1,2-, 3,4- 5,6- and 7,8- positions than in the remaining ones.

The higher electron density at these positions exerts considerable influence not only on their reactions but also on the reactivity of the substituents attached at various positions of the ring.

As in the case of pyridine, the electron pair of nitrogen is not involved in the aromatization and therefore these substances easily undergo quaternization and conversion to N-oxides.

Quinoline is a stable liquid with a boiling point of 237 °C that is frequently used in the laboratory as a basic high-boiling solvent.

Isoquinoline has a melting point of 26.5 ºC in its pure state and a boiling point of 243 ºC.

Both ring systems are found in nature. For example, in the alkaloid quinoline which is used against malaria. The quinoline skeleton has been used as the basis for the design of many synthetic compounds against malaria.

For example, the case of chloroquine.

Synthesis of quinoline and derivatives

Anilines react with β-ketoesters giving rise to schiff bases (substituted imine, R—CH=NR’) and also by heating amides are obtained, which are slower to form but more stable. Both can be cycled in acidic media or by heating to the corresponding 2- and 4-quinolones, respectively.

Skraup synthesis

Skraup synthesis is the most general method to synthesize quinoline.

Part of the aniline and with glycerol and in an acid medium (sulfuric acid, H2SO4) and an oxidizing agent, quinoline can be obtained with good yields.

fig-02

The reaction mechanism involves the initial dehydration of glycerol to give acrolein.

fig-03

In a second step the acrolein undergoes 1,4-cycloaddition by the action of aniline to give a β-anilinopropaldehyde.

fig-04

Finally, in the third step of the mechanism the resulting aldehyde cyclizes, dehydrates and finally, the dihydroquinoline obtained is oxidized to quinoline.

fig-05

Variants of Skraup synthesis

There are different variants of Skraup synthesis. All of them start from aniline and aldehyde or ketone (in situ preparation), followed by cyclization to hydroquinoline, which is transformed to quinoline by oxidation.

The different syntheses together with the reaction conditions are summarized below.

fig-06

Two quinoline syntheses have been described whose reactions have different mechanisms from those of Skraup, etc.

  • This is the Plizinger synthesis that produces quinoline-4-carboxylic acids. It starts from a ketone and isatinic acid obtained in situ from isatin.

fig-07

  • Friedländer synthesis starting from o-amino-benzaldehyde and ketones.

fig-09

In both syntheses quinolines are formed by reaction of the amino group with the aldol condensation product.

fig-10

Synthesis of isoquinoline and its derivatives

  • Closure of a disubstituted benzene ring. Formaldehyde forms isoquinoline only by reaction with ammonia.

fig-11

If hydroxylamine (NH2OH) is used instead of ammonia, isoquinoline oxide results.

  • From β-phenylethylamine

fig-12

Phenylethylamines, substituted on the chain or on the ring, when the amine nitrogen is acylated can be cycled to isoquinolines by acid (e.g. P2O5, POCl3).

If there are no substituents that can be removed, dehydroisoquinoline 3,4 would be obtained.

  • Bischler-Napieralski synthesis

Starting from acylated 2-phenylethylamines, are oxidized

fig-13

  • Pictet-Gams isoquinoline synthesis

In β-phenylethylamine, a hydroxy group is introduced into the side chain, which bypasses the previous hydrogenation step.

These substances undergo rapid dehydration under the reaction conditions and are cyclized to give isoquinoline.

  • Pomeranz-Fritsch isoquinoline synthesis

In this synthesis, the starting point is benzaldehyde and diethylacetal of the aminoacetaldehyde which heated at 100 ºC give rise to a Schiff base followed by cyclization with the appropriate catalyst.

fig-14

In the cyclization step (intramolecular electrophilic substitution), the C4—C4a bond is formed by electron-donating substituents on the ring that facilitate the reaction.

Quinoline and isoquinoline reactions

The resonant structures for quinoline and isoquinoline would be as follows.

For quinoline, these are:

fig-15

Y para la isoquinoline:

fig-16

The values of their dipole moments are μ=2.1 and 2.6 Debye, respectively, which supports the participation of charge separation formulas.

In both the one and the other heterocycle, the pyridine ring is electron deficient. Therefore, the electrophilic substitution is better on the benzene ring and the oxidation, which depends on the availability of electrons, is more on the benzene ring which it oxidizes.

fig-17

On the contrary, reduction reactions occur on the pyridine ring.

fig-18

On the other hand, oxidation reactions on isoquinoline give pyridine-3,4-dicarboxylic acid (dipicolinic acid) together with the corresponding anhydride upon oxidation with alkaline potassium permanganate (KMnO4).

fig-19

These oxidation and reduction reactions occur with the same ease in pyridine itself and also these condensed heterocycles have in common, with pyridine, to possess a weak basic character, with a pKa = 4.8 and 5.4, respectively.

In addition, they can form quaternary salts and N-oxides in a manner completely parallel to pyridine and its derivatives.

Electrophilic aromatic substitution

Since the pyridine ring is electron deficient and this is further aggravated when there is (in acidic media) a protonation or quaternization, the electrophilic reagents preferentially attack the benzene ring.

Nitration and sulfonation

The quinoline is nitrated at C5 and C8 and the isoquinoline at C5, both nitration and sulfonation.

fig-20

However, if the benzene ring is substituted, the substituent exerts its influence for nitration.

Thus the second nitration, governed by the first NO2 is oriented at C6 and C7 as shown in the scheme.

fig-21

for other substitutes the orientation is in C5 as shown in the figure.

fig-22

The formation of N-oxides can activate the pyridine ring in the SEAr against certain reagents.

For example, quinoline N-oxide can be substituted on the pyridine ring by NO2, when nitrated with H2SO4/HNO3 at 60-100 ºC.

fig-23

There are several reactions of both quinoline and isoquinoline that do not follow the pattern we have seen for nitration and sulfonation.

For example, the main product of the nitration of quinoline with HNO3/AcOH.

fig-24

Isoquinoline gives the product nitrated at C4 in low yield.

fig-25

Quinoline and isoquinoline can be brominated in high yield by heating their hydrochlorides with bromine in nitrobenzene giving 4-bromo-quinoline and 4-bromo-isoquinoline.

We can assume that the reactants can be added to the heterocycles at bonds 1—2 and substitution occurs in the intermediate species.

fig-26

This reaction is different from that for pyridine. Thus, quinoline and isoquinoline undergo addition much more easily than pyridine on the nitrogen ring.

The initial attack of the electrophile on the nitrogen is followed by the addition of a nucleophile on the adjacent atom.

fig-27

A different type of (abnormal) substitution is the formation of quinolin-6-sulfonic acid in the sulfonation of quinoline at 300 ºC. This is the thermodynamic product of the reaction because the derivatives at C5 and C8 are destabilized and transpose to the C6 position.

fig-28

Nucleophilic substitution

These condensed heterocycles feature a pyridine ring that is π deficient. They are therefore susceptible to easy attack by nucleophilic reagents. The quinoline is substituted at the C2 position and the isoquinoline at C1.

When these positions are occupied, the reagent will attack the C4 position in quinoline and the C3 position in isoquinoline.

fig-29

Quaternization enhances the ability of pyridines to react with nucleophiles.

In this way, quinolines and isoquinolines react very easily, through their quaternary salts.

As an example we have Reissert reaction:

fig-30

This reaction is actually a nucleophilic addition, as is the following example:

fig-31

A general method to obtain substituted alkyl and alkenyl heterocycles is to treat the chlorinated heterocycle derivative with a Wittig reagent.

The intermediate ylide, to which it gives rise, hydrolyzes in a basic medium to give an alkyl derivative or reacts with a carbonyl uncompound to give an alkenyl derivative.

fig-32

Side chain reactivity

Generally, alkyl groups located in ortho- or para- positions with respect to the ring nitrogen in aromatic nitrogen heterocycles show higher reactivity.

Alkyl groups placed in positions other than the above have properties similar to those of normal alkyl benzenes.

Thus the C2 and the C4 alkyl quinoline have acidic character as in the case of pyridine and can react with aldehydes and ketones, the most active being 2-alkyl.

fig-33

Isoquinolines

Both methyl at the C1 and C3 positions show similar behavior. As expected, but has higher reactivity for methyl at C1 than at C3.

fig-34

However, the alkyl group in 3-methyl-isoquinoline has higher reactivity than the methyl group of 2-methyl-naphthalene. Thus the electronegativity of the heteroatom is transmitted to some degree to that position.

The hydroxy- and amino- quinolines and isoquinolines have phenolic and amine character those that are on the benzene ring or in the meta-position of the pyridine ring with respect to nitrogen.

The others, whose structure is presented are found as tautomers.

fig-35

Structure IV has no benzenoid ring, only quinoid. However, there is no evidence of behavior different from structures I, II and III.

Quinolyl-2-carboxylic acids undergo simple dexcarboxylation. When decarboxylation takes place in the presence of reactive carbonyl compounds, condensation occurs.

fig-36

The N-oxides of quinoline and isoquinoline undergo various transpositions as in the case of pyridine. Thus, when these oxides are heated in acetic anhydride, deoxygenation occurs and the acetoxy group is incorporated into the molecule.

fig-37

No transposition is observed at the C3 position of isoquinoline. Reacting quinoline N-oxide with sulfuryl chloride (SO2Cl2) yields 2- and 4-chloro-quinoline in a 1:17 ratio.

fig-38

The ratio of C2 and C4 isomers varies according to the substituents present.

Cyanine dyes

They are dyes containing quinoline rings. The first examples of these dyes, which are used as sensitizers of photographic emulsions, were prepared by base-catalyzed reaction of a methyl quinolinium salt with N-ethyl quinolinium iodide.

fig-39

The reaction takes advantage of two features of quinoline chemistry. The activation of the C4 position towards nucleophilic attack and the higher acidity of the methyl group at C2 and C4 positions.

This type of reaction is not limited to quinolinic compounds and has been extended to other heterocycles.

fig-40

The pyrvinium cation is an example of a mixed cyanine dye. This molecule also has a medicinal application for infection control.