Aziridine: ring strain promotes ring opening

Aziridine and azetidine are stable, if volatile, members of the saturated nitrogen heterocycle family, and aziridine has some interesting chemistry of its own. Like pyrrolidine and piperidine, aziridine can be acylated by treatment with an acyl chloride, but the product is not stable. The ring opens with attack of chloride, a relatively poor nucleophile, and an open chain secondary amide results.

You can view this ring opening as very similar to the ring opening of an epoxide—in particular, a protonated epoxide, in which the oxygen bears a positive charge. The positive charge is very important for aziridine opening because, when the reaction is done in the presence of a base, removal of the proton leads immediately to the neutral acyl aziridine, which is stable.

The ring opening of aziridine is a useful way of making larger heterocycles: anything that puts a positive charge on nitrogen encourages the opening by making N a better leaving group, whether it’s protonation or, as shown below, alkylation. Alkylation of aziridine in base gives the N-substituted aziridine as you might expect, but a second alkylation leads to a positively charged aziridinium salt that opens immediately to a useful bromoamine.

We have just mentioned the protonation of aziridine, and you might imagine from what we said earlier about the comparative nucleophilicity and basicity of nitrogen heterocycles and their acyclic counterparts that aziridine will be even more nucleophilic than pyrrolidine, and about as basic. Well, it isn’t. The idea that ‘tying back’ the alkyl groups increases nucleophilicity is only valid for unstrained five or six-membered rings: with small rings another effect takes over. Aziridine is, in fact, much less basic than pyrrolidine and piperidine: the pKa for its protonation is only 8.0. This is much closer to the pKa of a compound containing an sp² hybridized nitrogen atom—the imine in the margin, for example. This is because the nitrogen’s lone pair is in an orbital with much more s character than is typical for an amine, due to the three membered ring. This is an effect we have discussed before. 412–415 if you need to refresh your memory. There we compared three-membered rings with alkynes, explaining that both could be deprotonated relatively easily. The anion carries a negative charge in a low-energy orbital with much s character: the same type of orbital carries aziridine’s lone pair. The s character of the aziridine nitrogen’s lone pair has other effects too. The lone pair inter acts very poorly with an adjacent carbonyl group, so N-acyl aziridines such . The nitrogen atom is pyramidal and not planar, and the stretching frequency of the C=O bond (1706 cm⁻¹) is much closer to that of a ketone (1710 cm) than that of an amide (1650 cm⁻¹). The s character of the lone pair means that the nitrogen atom inverts very slowly, rather like a phosphine. Usually, it is not possible for nitrogen to be a stereogenic centre because inversion is too rapid—the transition state for nitrogen inversions (in which the lone pair is in a p orbital) is low in energy. But with an aziridine, getting the lone pair into a p orbital requires much more activation energy, so nitrogen can be stereogenic. The two stereoisomers of the N-substituted aziridine in the margin can be separated and isolated.

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"سوذبيز" تطرح أكبر قطعة من المريخ على الأرض في مزاد علني

أوبن أيه آي تعتزم إطلاق متصفح إنترنت يعمل بالذكاء الاصطناعي

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مواضيع ذات صلة

Reactions of saturated heterocycles

More heteroatoms in fused rings mean more choice in synthesis

Quinolones also come from anilines by cyclization to an ortho position

Quinolines and isoquinolines

Pyrimidines can be made from 1,3-dicarbonyl compounds and amidines

Pyrazoles and pyridazines from hydrazine and dicarbonyl compounds

Thermodynamics is on our side

There are thousands more heterocycles out there

Fusing rings to pyridines: quinolines and isoquinolines

Putting more nitrogen atoms in a six-membered ring

Benzo-fused heterocycles-Indoles are benzo-fused pyrroles

Five-membered rings with two or more nitrogen atoms Imidazole