Pyrrole: synthesis and reactivity

General Features

Pyrrole is a five-membered aromatic heterocycle with the formula C4H5N (or C4H4NH). Is an electron-rich species, considering that shows 6 π electrons  on 5 p orbitals (that's like saying 6 π electrons on 5 atoms). Each carbon partecipate with a single π electron, therefore 4 in total, while nitrogen atom provides two electrons ( a lone pair ). Considering that nitrogen provides two electrons for the aromaticity of the molecule, it doesn't behave like a base, accepting protons. Obviously isn't a basic species, as maybe we could think if we wouldn't observed carefully the structure. This feature is fundamental to understand the reactivity of this compound.

N.B → pyrrole is an AROMATIC (Huckel's rule), NOT BASIC, ELECTRON RICH structure

The presence of nitrogen atom (much more electronegative than carbon) has as consequence that the greatest part of the electron density is localized on it. Indeed that's what comes from an NMR:

mappa densità elettronica pirrolo

What's really important is that part of the electron density is spread on carbon atoms. This means that every atom of the five-membered ring is somehow nucleophilic. This will explain most of reactivity (nucleophilic aromatic substitution)

Acid - base properties 

Acid - base properties of pyrrole are closely related to the reactivity, and that's why we should pay a specific attention on it.

→ pyrrole "as base"

Pyrrole isn't definetely a basic molecule; accepting a proton involves employing an electron doublet that is part of the aromaticity of the molecule. Losing aromaticity means passing through a transition state extremely high in energy. The only way to have pyrrole reacting as base is to use extreme conditions. Under pH 0, precisely -4, is possible to obligate him to accept a proton. Where is the proton (H+) more likely to go?  The answer is linked to another question:

Which is the more stable "tautomer"?

comportamento-acido-base-pirrolo1

In the blue box is shown the more stable tautomeric form, or rather the one with the greatest degree of delocalization of the positive charge.

If you understand why the -2 position is the more likely to accept a proton, then you'll surely understand part of the reactivity towards electrophiles.

→ pyrrole as acid

Compared with many other organic compounds, pyrrole is a quite acid molecule. This means that can be deprotonated under weak condition. We must consider that we're not operating in acqueous environment (this mean, and therefore such a lower pKa (16.5) doesn't mean that pyrrole is a weak acid. Pyrrole is a good acid because its anion is stabilized by resonance. The negative charge can be succesfully delocalized on the ring:

pyrrole-acidity

N.B: the anion does not lose aromaticity because inside the ring we're still having 6 π electrons spreaded on the ring (p orbitals of nitrogen and carbons)

The most commonly used base to remove a proton from pyrrole's nitrogen atom is the hydride, that's a must have in every chemical lab.

Reactivity 

Let's have a look to different groups of reaction that can generally involve pyrrole.

- Electrophile aromatic substitution 

We said from the beginning that pyrrole is an electron rich species. In a way the heterocycle can therefore behave as a nucleophile. This obviously means that is extremely reactive towards electrophilic species, often too much reactive, considering that's extremely difficult to have just one position substituted.

Reattività pirrolo

In the scheme, there are three common pyrrole's reaction. First of all, considering that pyrrole is electron - rich can react even with very weak electrophiles, reactions that benzene would not absolutely give. That's what happen, for example, in the reaction with molecular bromine (Br2). In order to attach the substituent -Br on a benzene ring would have been necessary, ie to activate bromine with a Lewis acid (the problem with pyrrole is instead that the real product is a tetra-substituted pyrrole). The other two reactions are respectively a Friedel - Kraft acylation and alkylation.

As it is correctly shown in the Friedel - Kraft alkylation reaction, is likely to have pyrrole reacting with more than one electrophile molecule. In addition, the alkyl group is an activating group itself. Is a bit different the acylation reaction, considering that the acyl group is a deactivating group  ("takes off" electron density from the ring). Anyway we're going to see that even in this specific case is possible to insert another electrophile group on the ring without paricular difficulties.

Another question that may come to your mind is: on which position do the electrophiles center? If we have a look to the map of electron density we notiche that this (the electron density) is not that different from carbon to carbon.

As we said previously (above), pyrrole as base is a very good example to understand its reactivity as nucleophile. The only difference is the electrophilic species. When pyrrole act as a base the electrophile is H+ (E+): if we pay attention that paragraph suggested us that substitution reactions go through carbocationic intermediates, and therefore electrophiles will attach on the position that correspond to the most stabilized carbocations (this may help you → carbocations stability). In the pyrrole molecule -2 and -5 positions ( they are the same, the molecule is symmetric) allows the best delocalization (mesomeric effect) of the positive charge.

yy

In the example is clear how the positions for the entrance of the nucleophile are preferentially -2 and -5. If this position are already occupied, the electrophile easily goes to -3 and -4 positions.

The situation is different if the pyrrole already carries a deactivating group, such as an acyl group::
meta orientante

These resonance structures show how the electron density is drained particularly on -3 and -5 positions. These electron density gaps surely do not favor the entrance of the electrophile, that furthermore will attach  to the position not interested by the delocalization of the positive electric charge, in this case -4:

gruppo nitro

- pyrrole reactivity in acid environment

Is not possible to practice the nucleophilic aromatic substitution on the pyrrole ring:

1) is itself an electron rich molecule (tends rather to behave as a nucleophile)

2) if we try to exalt the reactivity putting it in acid environment, the only result we get is to make it polymerize:

As said before, pyrrole is for sure not basic. If we put pyrrole under extremely acid condition (approximately -4) we can obtain the protonated species (really high energy intermediate) for the time necessary to react as an electrophile with another molecule of pyrrole.

The result is a polymer named  "polypyrrole" or "pyrrole black", that is an organic conducting polymer, or more precisely a semiconductor (conduct electrical current only in one direction).

- pyrrole reactivity in basic environment

Pyrrole is definetely more acidic than corresponding secondary amines. Indeed we saw how can delocalize, spread the negative charge on the ring withouth losing aromaticity. Is therefore easy enough to generate the nitrogen anion. This can react as strong nucleophile on various substrates. For example on an alkyl halide:

anione all'azoto

If we can not deprotonate nitrogen because it's already substituted, treating it with a strong base will generate a negative charge on one of the 4 carbon atoms of the ring. Carbons more easily deprotonated are those adjacent (as you can probably imagine) to nitrogen atom (because of its electronegativity). Nitrogen makes partially positive (δ+) mentioned carbons, that are therefore available to gain electrons from CH bond to riequilibrate their electron density:

Hardness - softness

Hard - soft reactivity

In spite of the proton linked to the nitrogen atom is surely the more acidic, the nature of the base we use to deprotonate pyrrole (hard-soft) reflects on hard - soft behaviour of the anion. If we used an organolithium base the anion generated on pyrrole would react right at the nitrogen, while if we used a weaker base like a Grignard compound to deprotonate pyrrole this would react at the carbon (like a carbanion):

Hardness - softness

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