Nitrone

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General structure of a nitrone. Nitrone-general-structure-2D.png
General structure of a nitrone.

In organic chemistry, a nitrone is a functional group consisting of an N-oxide of an imine. The general structure is R1R2C=N+(−O)(−R3), where R3 is not a hydrogen. Their primary application is intermediates in chemical synthesis. A nitrone is a 1,3-dipole used in cycloadditions, and a carbonyl mimic.

Contents

Structure

Nitrones, as a tetrasubstituted double bond, admit cistrans isomerism. [1] :474

Generation of nitrones

Typical nitrone sources are hydroxylamine oxidation or condensation with carbonyl compounds. Secondary hydroxylamines oxidize to nitrones in air over a timescale of several weeks, a process cupric salts accelerate. [1] :476 [2] :332–333 The most general reagent used for the oxidation of hydroxylamines is aqueous mercuric oxide: [1] :476 [3]

NitrMech1.png

However, a hydroxylamine with two α hydrogens may unsaturate on either side. Carbonyl condensation avoids this ambiguity... [4]

NitrMech2.png

...but is inhibited if both ketone substituents are bulky. [1] :477

In principle, N-alkylation could produce nitrones from oximes, but in practice electrophiles typically perform a mixture of N- and O-attack. [1] :479 [2] :334

Reactions

Some nitrones oligomerize: [1] :483 [2] :334,337-338 [5]

NitrMech3.png

Syntheses with nitrone precursors obviate the issue with increased temperature, to exaggerate entropic factors; or with a nitrone excess.

Carbonyl mimic

Like many other unsaturated functional groups, nitrones activate the α and β carbons towards reaction. The α carbon is an electrophile and the β carbon a nucleophile; that is, nitrones polarize like carbonyls and nitriles but unlike nitro compounds and vinyl sulfur derivatives. [1] :483 [2] :338–340

Nitrones hydrolyze extremely easily to the corresponding carbonyl and N-hydroxylamine. [1] :491 [2] :344

1,3-dipolar cycloadditions

As 1,3dipoles, nitrones perform [3+2] cycloadditions. [6] For example, a dipolarophilic alkene combines to form isoxazolidine:

Nitrone cycloadditions Nitrone cycloaddition.png
Nitrone cycloadditions

Other ring-closing reactions are known, [7] including formal [3+3] and [5+2] cycloadditions. [6]

Isomerization

Deoxygenating reagents, light, or heat all catalyze rearrangement to the amide. Acids catalyze rearrangement to the oxime ether. [1] :489–490 [2] :345–347

Reduction

Hydrides add to give hydroxylamines. Reducing Lewis acids (e.g. metals, SO2) deoxygenate to the imine instead. [1] :490 [2] :343

See also

References

  1. 1 2 3 4 5 6 7 8 9 10 Hamer, Jan; Macaluso, Anthony (1964-08-01). "Nitrones" . Chemical Reviews. 64 (4): 473–495. doi:10.1021/cr60230a006. ISSN   0009-2665.
  2. 1 2 3 4 5 6 7 Delpierre, G. R.; Lamchen, M. (1965). "Nitrones" . Quarterly Reviews, Chemical Society. 19 (4): 329. doi:10.1039/qr9651900329. ISSN   0009-2681.
  3. Thiesing, Jan; Mayer, Hans (1957). "Cyclische Nitrone, II. Über die Polymeren des 2.3.4.5-Tetrahydro-pyridin-N-oxyds und verwandte Verbindungen". Justus Liebigs Ann. Chem. 609: 46-57. doi:10.1002/jlac.19576090105.
  4. Exner, O. (1951). "A New Synthesis of N-methylketoximes". ChemPlusChem . 16: 258-267. doi:10.1135/cccc19510258.
  5. Thiesing, Jan; Mayer, Hans (1956). "Cyclische Nitrone I: Dimeres 2.3.4.5-Tetrahydro-pyridin-N-oxyd". Chem. Ber. 89 (9): 2159-2167. doi:10.1002/cber.19560890919.
  6. 1 2 Yang, Jiong (2012). "Recent Developments in Nitrone Chemistry". Synlett . 23: 2293-97. doi:10.1055/s-0032-1317096.
  7. Murahashi, Shun-Ichi; Imada, Yasushi (15 March 2019). "Synthesis and Transformations of Nitrones for Organic Synthesis". Chemical Reviews. 119 (7): 4684–4716. doi:10.1021/acs.chemrev.8b00476. PMID   30875202. S2CID   80623450.