quinoline isoquinoline model

a) Basicity

Quinoline and isoquinoline behave like bases through the lone pair of nitrogen. In acid media they are protonated to form quinolinium and isoquinolinium salts.

quinoline basicity

quinolinium salt

isoquinolinium salt

Substituents modify basicity in a manner analogous to pyridine. Donor groups increase the basicity and attractor groups decrease it.

Quinoline and isoquinoline react with electrophiles through the benzene ring (carbocycle), due to its higher electronic richness, compared to the pyridine ring. The most favored positions are 5 and 8.

electrophile substitution 01

The reaction between halogenated derivatives of quinoline and isoquinoline with organolithics at low temperature produces the exchange of halogen for the metal, generating new organolithics on the ring.

lithiation 01

The nucleophiles add to carbon 2 of the quinoline, although under certain conditions it can also receive attacks on its carbon 4.

Isoquinoline is attacked by hard nucleophiles on carbon 1.
For this reaction to take place, the delocalization of the negative charge on the ring nitrogen is essential.
nucleophilic addition 01
Addition of an oxidant allows rearomatization of the priridine ring
nucleophilic addition 02

Halogenated quinolines in position 2,4 very easily undergo nucleophilic substitution reactions. For its part, isoquinoline can only give this reaction in position 1. All nucleophiles with the capacity to give S N 2 can participate in this reaction, bad nucleophiles such as water or alcohols require heat input.

nucleophilic substitution 01

In the Skraup synthesis, aniline reacts with a,b-unsaturated carbonyls in an acid medium to form 1,2-dihydroquinolines, which are transformed into quinolines by oxidation. The a,b-unsaturated carbonyl can be obtained by dehydration of 1,2,3-propanetrium.

Síntesis de Skraup de la Quinolina

In the Conrad-Limpach synthesis, quinolones are obtained by reacting aniline with 3-ketoesters. Under kinetic conditions the 4-quinolone is obtained and under thermodynamic conditions the 2-quinolone.

conrad limpach knorr 01

In the Combes synthesis, quinolines are obtained by reacting aniline with 1,3-dicarbonyls, in the presence of acid catalysis. In a first stage, the imine is formed, which tautomerizes to enamin,a, activating the aromatic ring by giving up the nitrogen pair. In the last stage, cyclization occurs by attack of benzene to the carbonyl of the chain

combes synthesis 01

The Friedländer synthesis prepares quinolines from an ortho-acetylated nitrobenzene and a ketone. The synthesis begins with an aldol condensation in a basic medium. Reduction of the nitro group to amino allows cyclization by imine formation.

friedlander synthesis 01

The reaction between 2-aminoethylbenzene and an alkanoyl halide in the presence of pyridine forms an amide. The amide is converted to the Vilsmeier electrophile by reaction with phosphorous oxytrichloride. The cyclization is produced by attack of the benzene to said electrophile. A final oxidation generates isoquinoline.

bischer napieralski synthesis 01

Pictet Spengler is a Mannich type reaction. In the first stage, the Mannich electrophile is formed by reaction of the amine with an aldehyde in a hydrochloric acid medium. In the final stage, the cyclization takes place by attack of the benzene on the Mannich electrophile. The isoquinoline is obtained after a double oxidation.

pictet spengler synthesis 01

The Pomeranz-Fritsch synthesis prepares isoquinolines by reacting benzaldehydes with protected a-aminoaldehydes in the form of acetals. In a first stage, the imine is formed by reaction between benzaldehyde and the amine. In a second step, the acetal is broken with aqueous sulfuric acid, leaving the aldehyde free, which cyclizes under benzene attack. pomerantz fritsch 01