Heterocyclic Chemistry: Properties of Heteroaromatic Compounds
In this section, we will see the properties of heteroaromatic compounds especially their ability as nucleophile and as base. Besides that, we will also see the 5-membered heteroaromatic can also act as an acid. All those properties can be derived from its structure and the bonding.
Just to reiterate again for this section, the quoted value of pKa in the discussion of basicity is the pKa of its conjugate acid.
To begin with, we will discuss the properties of 6-membered ring heteroaromatic such as pyridine. The lone pair electrons in pyridine are located in sp2 orbitals and also perpendicular to the π system. This bonding scheme makes pyridine as a good nucleophile and pyridine is quite common to use as catalyst in esterification of acyl chloride.
The reaction proceeds via:
Pyridine is not nucleophilic enough to deprotonate alcohols (pKa of pyridine's conjugate acid is 5.2) and the derivates of pyridine are commonly used in this reaction, such as 4-dimethylaminopyridine (DMAP).
Besides its nucleophilicity, pyridine could also act as a base due to the lone pair electrons do not involve in aromaticity. However, pyridine has lower pKa (5.2) than 6-membered ring piperidine.
This different of basicity is due to the position of the lone pair electrons on N atom. In saturated heterocycles such as piperidine the lone pair electrons are in sp3 orbitals which has less s-character while in pyridine those electrons are in sp2 orbitals. This means the electrons on N atom in pyridine is more closely bound to the nucleus than in piperidine; hence the electrons are less available for protonation. The basicity of pyridine can also be affected by the substituent on the ring as shown in the series below.
Compound 2 or DMAP shows higher pKa than pyridine 1 which means 2 is a better base than 1. This is due to the electron donating NMe2 group which increase the electron density into the ring and also N atom. This makes the N atom is more electron rich which makes a better base and also nucleophile. Besides that, NMe2 group can also stabilise the conjugate acid via resonance as both N atoms are sp2 hybridised.
In the other sides, when sticking an electron donating group such as in 4-nitropyridine, 3, causes the reverse effect such as in 2. This is due to the electrons are pulled away from the ring which makes it less available for protonation.
In pyrazine 4, one of the C atoms is replaced by N atom and this makes it less basic, even less basic than 3. This is due to the inductive effect of N atom which is more electronegative than C atom. This replacement disfavours the protonation and also the cation formation.
In 2,6-dimethylpyridine 5, it becomes slightly basic due to Me group is a weak electron donating group and it donates via inductive effect. However, 5 is worse nucleophile than pyridine despite better base of 5. This is caused by the 2 Me groups give steric hindrance to the N atom which makes it less available for nucleophilic attack. This steric hindrance does not apply for small electrohile such as proton.
Meanwhile, the 5-membered heteroaromatic has a contrast reactivity than the 6-membered ring pyridine. This is due to the lone pair electrons are in p-orbitals which is part of the π system. Hence, the electrons are not available for nucleophilic attack or protonation.
The 5-membered N-heteroaromatic pyrrole has pKa of its conjugate acid is -3.8 but this basicity can be increased by sticking electron donating groups such as Me group as shown below.
Because of the lone pair electrons involve in aromaticity, pyrrole does not protonate on N atom but the reaction takes place at 2-position.
A series of 5-membered heteroaromatic below has different by replacing one of the C atoms with heteroatom would give different characters of basicity as shown below.
From all those compounds above, the protonation site would be on N atoms. From the series above there is a decrease in basicity of thiazole and oxazole relative to imidazole and this is caused by the electronegative effect of O and S which lowering the pKa values. If we see the pKa of imidazole's conjugate acid, it is close the physiological pH which is close to 7. This has a consequence for example amino acid histidine which has imidazole functional group involves in proton transfer in enzyme active site. This high pKa of imidazole is due to the positive charge is stabilised by resonance structure.
Another property of the 5-membered ring heteroaromatic is it also can act as an acid. In this part, all the value of pKa is the pKa of the heteroaromatic NOT the of its conjugate acid.
The acidity of the 5-membered ring such as pyrrole is similar to amides and this acidity is due to the loss for N-H bond. This is due to the negative charge can be delocalised in π system which means spreading the charge. Besides that, adding more N into the ring would lower the pKa which means the proton becomes more acidic.
This is due to the electronegative N atom would stabilise the negative charge better. Worth to notice, the pKa of tetrazole is very low and similar to carboxylic acid (pKa ~ 3) which has consequence that it can be used in drugs, such as in indomethacin, to compensate the patients who have carboxylic acid intolerance.
This N-H bond could also act as H-bonding donor which has an implication increasing the melting point such as in imidazole (m.p. 90 °C). However, replacing this hydrogen with another functional group such as Me group would consequently remove the H-bonding which means lowering the melting point.
If we examine the structure of imidazole closely, we will see in imidazole it has an imine and enamine functional group within the ring. This structure has consequence that tautomerisation could occur.
In the substituted imidazole, it might look like the R group is moving but actually it is the H atom that moves which is the principle of tautomerisation.
The same properties of acidity is also observed in fused 5-membered ring heteroaromatic with benzene ring such as indole and it has pKa ~ 17. The negative charge of the conjugate base of indole could be delocalised ino 10 π electrons system. Furthermore, indole rings also present in natural products such as LSD, strychnine and tryptophan.
To begin with, we will discuss the properties of 6-membered ring heteroaromatic such as pyridine. The lone pair electrons in pyridine are located in sp2 orbitals and also perpendicular to the π system. This bonding scheme makes pyridine as a good nucleophile and pyridine is quite common to use as catalyst in esterification of acyl chloride.
Besides its nucleophilicity, pyridine could also act as a base due to the lone pair electrons do not involve in aromaticity. However, pyridine has lower pKa (5.2) than 6-membered ring piperidine.
In the other sides, when sticking an electron donating group such as in 4-nitropyridine, 3, causes the reverse effect such as in 2. This is due to the electrons are pulled away from the ring which makes it less available for protonation.
In pyrazine 4, one of the C atoms is replaced by N atom and this makes it less basic, even less basic than 3. This is due to the inductive effect of N atom which is more electronegative than C atom. This replacement disfavours the protonation and also the cation formation.
In 2,6-dimethylpyridine 5, it becomes slightly basic due to Me group is a weak electron donating group and it donates via inductive effect. However, 5 is worse nucleophile than pyridine despite better base of 5. This is caused by the 2 Me groups give steric hindrance to the N atom which makes it less available for nucleophilic attack. This steric hindrance does not apply for small electrohile such as proton.
Meanwhile, the 5-membered heteroaromatic has a contrast reactivity than the 6-membered ring pyridine. This is due to the lone pair electrons are in p-orbitals which is part of the π system. Hence, the electrons are not available for nucleophilic attack or protonation.
The 5-membered N-heteroaromatic pyrrole has pKa of its conjugate acid is -3.8 but this basicity can be increased by sticking electron donating groups such as Me group as shown below.
A series of 5-membered heteroaromatic below has different by replacing one of the C atoms with heteroatom would give different characters of basicity as shown below.
Another property of the 5-membered ring heteroaromatic is it also can act as an acid. In this part, all the value of pKa is the pKa of the heteroaromatic NOT the of its conjugate acid.
This N-H bond could also act as H-bonding donor which has an implication increasing the melting point such as in imidazole (m.p. 90 °C). However, replacing this hydrogen with another functional group such as Me group would consequently remove the H-bonding which means lowering the melting point.
If we examine the structure of imidazole closely, we will see in imidazole it has an imine and enamine functional group within the ring. This structure has consequence that tautomerisation could occur.
The same properties of acidity is also observed in fused 5-membered ring heteroaromatic with benzene ring such as indole and it has pKa ~ 17. The negative charge of the conjugate base of indole could be delocalised ino 10 π electrons system. Furthermore, indole rings also present in natural products such as LSD, strychnine and tryptophan.
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