Pyrroles

What are pyrroles?

Pyrroles are 5-membered heterocyclic aromatic compounds with one nitrogen atom and 4 carbons in a pentagonal ring. Apart from its interest as an aromatic system, the pyrrole is biologically important because its structure is part of the heme group, chlorophyll and other natural products related to vitamin B12 and bile pigments.

Among the reduced pyrroles, the most relevant natural compound is the amino acid proline:

fig-06

The unsubstituted compound, pyrrole is a liquid with a boiling point of 129 °C, which tends to darken when exposed to air or light. It is a dipole molecule, with a dipole moment directed from nitrogen to carbon. The magnitude of the dipole varies between 1.55 Debye and 3.0 Debye, depending on the solvent, and its ability to form hydrogen bonds.

Synthesis of the pyrrole ring

Commercially it can be prepared by fractional distillation of coal tar, or by passing furan, ammonia and water vapor over an alumina catalyst at 400 ºC.

In this process, if we replace the ammonia with an amine, we obtain the N-substituted pyrrole.

fig-07

In the laboratory, there are several synthesis methods:

Paal-Knorr synthesis of pyrroles

This is a general method for the preparation of furan, thiophene and pyrrole.

Part of 1,4-dicarbonyl compounds that are reacted with a wide variety of reagents, depending on the heterocycle we want to obtain.

For the specific case of pyrroles, the dicarbonyl compound is treated with ammonia (NH3) (or a derivative).

fig-08

Closely related to this synthesis are all those starting from a 1,4-difunctionalized compound. For example, using a dihalogenated derivative with amoniaco (NH3), pyrrole can be obtained.

fig-09

Hantzsch synthesis of pyrroles

It consists of a reaction between an α-haloketone and a β-dicarbonyl compound in the presence of amoniaco (NH3).

fig-10

The reaction mechanism starts with the reaction between ammonia (NH3) and the β-dicarbonyl compound gives rise to a vinylamine,

fig-11

and in a second step, this vinylamine reacts in turn with α-haloketone. The synthesis ends with a dehydration cyclization between the –OH and –NH2 groups.

fig-12

 

Knorr pyrrole synthesis

It is the most relevant synthesis method for pyrroles. It starts from a β-ketoester and an α-aminoketone. The β-ketoester can be exchanged for a β-diketone. However, single ketones usually give low yields in this synthesis.

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The α-aminoketone can generally be prepared in situ by nitrosation and reduction of a ketoester molecule.

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Subsequently, it is this aminoketone that reacts with a second molecule of ketoester.

fig-15

 

Many variations of this pyrrole synthesis reaction have been performed. The main limitation lies in the propensity of α-aminoketone to dimerize, when the ketone or ketoacid does not exhibit sufficient reactivity to condense rapidly.

Synthesis of pyrroles from acetylenedicarboxylic esters

This method consists of the reaction of the ester with the corresponding α-aminoketone.

fig-16

The mechanism probably consists of a Michael-type addition followed by cyclization.

fig-17

Synthesis of pyrroles by isonitrile cyclization

The reaction is carried out with tosylmethyl isocyanide, sodium hydride and the corresponding α,β-unsaturated carbonyl compound. The tosyl group is lost in the aromatization step following cyclization.

fig-18

Isonitriles are also called isocyanides and are characterized by their unusual structure. Together with carbon monoxide (CO) they are among the few stable compounds with divalent carbon. This stabilization is partly due to the contribution of polar forms at resonance.

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A base extracts the proton from the isonitrile and the anion reacts with an unsaturated electrophile.

fig-20

It is a 5-endo-dig process.

fig-21

Electrophilic substitution reactions in pyrroles

These heterocycles are π-excedents and therefore electron-rich. Consequently, the electrophilic aromatic substitution reaction (SEAr) can be carried out very easily.

Substitution occurs better at the C2 position than at the C3 position. This is due to better stabilization of the reaction intermediate in the attack on the position, as can be seen in the following scheme:

fig-22

The effect of substituents on the reactivity and position of substitution by electrophiles can be predicted, as in the case of benzene. An electron-donating substituent at the C2 position tends to direct at C3 or C5.

fig-23

When Y is an electron-withdrawing group, it directs the substitution reaction to C4 and to a lesser extent to C5 (meta director).

The effect of substituents on nitrogen is minor unless they are very bulky or strongly electron-withdrawing.

In both cases, substitution at the C3 position is favored.

For example, 1-tertbutylpyrrole undergoes Friedel-Crafts benzoylation at the C3 position.

The silylated pyrrole is particularly useful because it can be easily mono or di-brominated at the β-positions.

The bromopyrroles are very useful because they are used to prepare other β-substituted pyrroles via exchange and it is easy to remove the silyl group.

fig-24

The presence in the ring of a conjugative electron attracting group reduces the reactivity of pyrrole towards electrophiles and makes possible a more controlled substitution.

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Examples

Having seen this in general terms, let us now look at some examples of these reactions.

Nitration

Nitration cannot take place, with the usual sulfonitric mixture, because the products are resinified. Pyrrole is nitrated with acetyl nitrate (HNO3—Ac2O) to give 2-nitropyrrole.

fig-26

Halogenation

Pyrrole is easily tetra-halogenated in carbon tetrachloride (CCl4) and sulfuryl chloride (Cl2SO2) can yield the hexa-halogenated pyrrole.

fig-27

Acylation

With acetic anhydride (Ac2O) even without catalyst giving 2-acetal derivative.

fig-28

Reactions of pyrroles with aldehydes and ketones

The reaction of the pyrrole with the conjugated acids of ketones, or aldehydes, gives rise to an alcohol which rapidly dehydrates to give a carbonium ion which is stabilized by resonance. This can become, in some cases, the final product of the reaction.

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When the aldehyde used is 4-dimethylamino-benzaldehyde, the cation formed is bright red, and this is known as the Ehrlich test for pyrroles.

fig-29

The reaction with simpler aldehydes and ketones, as described above, also yields a cation. This cation can react with a second pyrrole molecule. By repeating this reaction successively, a polymer can finally be obtained, unless the C5 position of the pyrrole is substituted.

In some cases, it is possible to isolate cyclic tetramers from the reaction of pyrrole with aldehydes and ketones. For example, pyrrole reacts with benzaldehyde and acid in the presence of air to give tetraphenyl porphyrin in low yield.

fig-30

Reactions of pyrroles with acids

These heterocycles are acid-sensitive and can be protonated as if they were bases. Pyrrole forms an unstable cation of the type shown in the figure.

fig-31

These cations can evolve by opening the heterocycle or acting as an electrophile, and producing polymerization reactions.

Acid properties of pyrroles

The pKa the pyrrole is 17.5, thus comparable to methanol (MeOH), and its acidity increases as in the case of phenols, when electron attracting groups are present in the ring. Thus, nitro-pyrrole has a lower pKa with a value of 10.6.

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On the other hand, pyrrole can form alkaline salts with sodium amide in ammonia (NaNH2/NH3), and therefore reacts with Grignard reagents.

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Alkyl lithium reagents similarly produce the corresponding 1-lithium pyrroles.

Oxidation and reduction reactions in pyrroles

As an electron-rich heterocycle, pyrrole is not easily reduced because it can easily gain electrons. It resists Birch reduction with alkali metals in liquid ammonia. It is also resistant to catalytic hydrogenation leading to pyrrolidines, as this usually requires high temperatures and pressures (150—200 °C, 70 atm and nickel catalyst, Ni Raney).

Catalytically hydrogenates with difficulty to yield:

fig-34

On the other hand, oxidation reactions occur easily, as insoluble polymers are formed when treated with hydrogen peroxide (HOOH) or other oxidizing agents.

Addition and cycloaddition reactions in pyrroles

Normally, pyrroles do not undergo the Diels-Alder reaction, but there are some exceptions.

For example, N-carboethoxy pyrrole (YHANFZMYRFWIID-UHFFFAOYSA-N), reacts with dimethyl acetylene dicarboxylate (DMAD) to give adduct I in the figure.

fig-35

In N-amino pyrrole, it also undergoes cycloaddition with the same ester.

The reaction of 1-methyl pyrrole with a dialkyl ketone leads to the formation of a substituted alcohol at the C3 position, probably via an intermediate oxetane.

fig-36

Pyrroles can also undergo cycloaddition reactions with carbenes on the C2—C3 bond, but the adducts are unstable and continue to react.

For example, the addition of dichlorocarbene to 2,5-dimethyl pyrrole produces the compound 3-Cl-2,6-dimethyl pyridine in good yield. This is the so-called Reimer-Teimer reaction and is carried out with a strong base and chloroform (CHCl3).

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The pyrrole and alkyl pyrroles ring opens upon reaction with hydroxylamine in an acidic medium. The reaction probably occurs by nucleophilic attack of the hydroxylamine on the cation.

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The reaction is carried out at reflux with an alcoholic solution of hydroxylamine hydrochloride and gives succindialdoxime, as shown in the figure.

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Properties of substituted pyrroles

The pyrrole ring system is a good π-electron giver and this influences the properties of the substituents attached to the carbon atoms of the ring.

Pyrrolcarboxaldehydes

Pyrrolcarboxaldehydes are distinguished from most aromatic and aliphatic aldehydes by their low reactivity towards nucleophiles. Especially pyrrole-2-carboxaldehyde has greatly decreased reactivity due to different mesomeric structures.

fig-40

These compounds do not give the typical aldehyde reactions such as: the formation of cyanohydrins, nor do they give the Cannizzaro reaction, nor do they reduce to Fehling's solution.

Pyrroles with alkyl and alkyl-substituted groups

Alkyl groups on heterocycles behave in a similar way to alkylbenzenes. Among the reactions that can be carried out on these groups are oxidation.

fig-41

2-methyl pyrroles are easily halogenated in the side chain and can be acetoxylated with lead(IV) acetate.

The 3-methylpyrroles do not react under the same conditions. Among the alkylsubstituted groups, the high reactivity of the chloromethyl, hydroxymethyl and amino methyl groups should be noted, as they highlight the susceptibility to nucleophilic attack of the heterocycle. This is due to the ease with which halogen, water, or ammonia is lost, respectively.

fig-42

For example, with 2-methylhydroxy pyrrole, as illustrated in the following example.

fig-43

This cation can be attacked by other pyrrole molecules and can lead to the formation of polymers.

Pyrrole carboxylic acids

They decarboxylate easily, especially those containing electron-donating substituents. In addition, many of them decarboxylate upon reaching their melting point temperature.

The decarboxylation may be acid catalyzed and a possible mechanism may be as shown in the scheme.

fig-44

Displacement by electrophilic reagents of these compounds can also be carried out, for example with halogens.

fig-45

In addition, they also occur with diazocompounds.

fig-46

Hydroxy and amino pyrroles

The hydroxy derivatives of pyrroles are well known, but do not behave analogously to phenols. They exist predominantly in keto tautomeric forms.

fig-47

Tautomer II with the double bond at C3=C4 is preferred, unless an acyl group is present in which case tautomer I is favored. This is because it allows conjugation between the unshared electron pair and the acyl function.

fig-48

The amino pyrroles are exactly the same, predominantly in the tautomeric imino form.

fig-49

In both cases, hydroxy and amino are favored when there is an adjacent substituent that can form an intramolecular hydrogen bond, as for example in the following scheme.

fig-50

N-substituted derivatives

N-alkyl, N-aryl and N-acyl groups migrate to the C2 position by pyrolysis.

fig-51

Porphyrins and related pyrrolic natural products

The chemical structure of porphyrin is formed by a macrocycle in which four pyrrole units are linked by one-carbon bridges through the C2 and C5 positions of the pyrrole.

fig-52

Its structure is totally unsaturated. The four nitrogen atoms are ideally positioned to form chelates with metal cations. In fact, porphyrins easily form complexes with many metals. These compounds also occur in nature as metal complexes, the most important of which is hemin (heme). This heme group is the component of hemoglobin, which transports oxygen in the blood.

fig-53

Chlorophyll a is a closely related structure, with a saturated bond in the D-ring and also features magnesium Mg, instead of iron, Fe.

Other compounds with this structure are the bile pigments which are the oxidative degradation products of the heme group. Thus, one of them is bilirubin, which is the yellow pigment that causes the skin coloration characteristic of jaundice.

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