Pyrazole: synthesis and reactivity

Pyrazole is an aromatic heterocyclic compound characterized by a five membered ring with formula C3H3N2H. The two nitrogen atoms are adjacent and as we saw for imidazole one of them is a "pyrrole-like" nitrogen while the other is a "pyridine-like" nitrogen. In order to quickly refresh your memory, a "pyrrole-like" nitrogen is a non-basic nitrogen, with a lone pair involved in aromaticity, but rather acidic (can be deprotonated quite easily, i.e with NaH) whereas the "pyridine-like" nitrogen has a lone pair on a sp2 orbital and is therefore basic and nucleophilic.

Pyrazole structure is not as perfectly symmetric as imidazole one. Consequently, there are slight differences in reactivity and acid-base properties.pyrazole-structures

Actually, pyrazole exists in two tautomeric forms:

tautomeria pirazolo

As you can see from the map of electron density, this structure is not perfectly symmetric and therefore one of this two is prevailing over the other to some extent.

Acid - base properties 

pirazolo come base

pKa = 2,5

Just like imidazole pyrazole is an amphoteric substance. In addition, we have to say  that pyrazole is slightly more acidic, but, above all, much less basic. Why? How can we explain the lower alkalinity of pyrazole compared to imidazole?

For sure, this means that the resulting cation in pyrazole is not as stabilized as in imidazole. The "pyrrole-like" nitrogen behaves like a strong electro-withdrawing group. Electrowithdrawing groups are good in stabilizing negative charges, not the contrary (electron withdrawing group drain electron density). We can also consider the situation from the opposite perspective: in imidazole the cation is stabilized for inductive effect and  also less influenced by the electron withdrawing behaviour of nitrogen.

come mai il pirazolo è meno basico dell'imidazolo

Reactivity

Even this time the electron density map is a very useful tool:mappa densità elettronica pirazolo

The additional nitrogen atom (N) compared to pyrrole reduces the overall electron density on the remaining carbons!

We've to consider that in spite of pyrazole (and it's true for imidazole as well) is not as reactive as pyrrole in electrophilic aromatic substitution is still an electron-rich species, because has 6  π  electrons on 5 atoms and it is therefore much more reactive than benzene towards electrophiles.

Exactly as we expected it to be, the  carbon (-4 position) showing the higher electron density is the further from the two nitrogen atoms. Carbons adjacent to the nitrogen atoms are instead electron-deficient and they are indeed very little interested in doing electrophilic substitution.

-  electrophilic aromatic substitution 

pirazolo sost elettr

As we had correctly deduced considering the electron density map the electrophilic aromatic substitution happen at the "electron-rich" carbon, that is the farthest (-4 position) from nitrogen atoms.

- reactivity in basic environment (N - metallation, C - metallation)

The more acidic proton is of course that bound to the pyrrole-like nitrogen. If we treat pyrazole with a strong base we can easily generate a nitrogen atom that can afterwards react with an electrophile.

N.B: pyrrole-like nitrogen is the only one who can be deprotonated (pyridine-like nitrogen doesn't carry an hydrogen)

pirazolo anione azoto

If pyrrole-like nitrogen shows a substituent (in the example an alkyl group), the more acidic proton is the one on -5 carbon. Treating with a strong base we can therefore generate the carbanion that  just like the anion on nitrogen in the previous example can act as a  nucleophile in a second reaction:
pirazolo metallazione

Synthesis

-Pyrazole synthesis

How would you synthesize an heterocycle containing five atoms with 2 of them adjacent nitrogen atoms? A good approach, notwithstanding is no more the most commonly used, simply consists in using hydrazin and a 1-3 dicarbonyl compound, both reagents commercially available.

sintesi del pirazolo

reaction mechanism

If you want to get a nitrogen substituted pyrazole that is quite easy because you just have to use a substituted hydrazine, as, for example, an aryl-hydrazine:

sintesi di un pirazolo sostituito

- Pyrazolone synthesis

This molecule, a particular lactame with two adjacent nitrogen atom, very similar to pyrazole but with an additional carbonyl is the base for various pharmaceutical preparations and that's why we are showing the synthesis. Both reagents and the reaction mechanism are quite similar to what we've just seen for pyrazole; the only difference is that we're using a β - ketoester instead of a 1-3 dicarbonyl compound:

sintesi pirazolone

Facebooktwittergoogle_pluspinterestlinkedin