[542-78-9]  · C3H4O2  · Malondialdehyde  · (MW 72.07)

(behaves as multifunctional compound;1 aldehyde reactions;2-4 forms both cyclic and acyclic acetals;5 may react as vinylog of formic acid;6-8 chelates with metal ions as b-dialdehyde;8 behaves as push-pull alkene9)

Alternate Names: MDA; malonaldehyde; 1,3-propanedial.

Physical Data: free aldehyde: hygroscopic needles; mp 72-74 °C; sodium salt: mp 245 °C (dec); UV lmax (0.1 N HCl) 245 nm (ε 12 800), (0.1 N NaOH) 267 nm (ε 29 400); 1H NMR (D2O) d 5.73 (t, 1H, J = 10.1 Hz), 9.08 (d, 2H, J = 10.1 Hz); 13C NMR (D2O) d 110.3, 193.6; pKa (H2O) = 4.5.1

Solubility: sodium salt: sol EtOH, MeOH, H2O; moderately sol CH2Cl2; insol ether.

Form Supplied in: can be generated in situ from commercially available malondialdehyde bis(dimethyl acetal) [102-52-3] or bis(diethyl acetal) [122-31-6]. However, it is unstable and is best handled as its sodium salt.

Handling, Storage, and Precautions: unstable and easily polymerizes. The generation of MDA in situ from the hydrolysis of its bis-acetals results in the formation of a number of side products, including b-alkoxyacrolein, 3,3-dialkoxypropionaldehyde, and fluorescent condensation polymers of MDA. Crystalline sodium MDA, which is much more stable than MDA, is the recommended synthetic reagent. Sodium MDA, if stored under nitrogen in a refrigerator, is stable for months.

Preparation of Sodium Malondialdehyde.

This reagent is most conveniently prepared by the acid hydrolysis of malondialdehyde bis(dimethyl acetal) with 1 N HCl and then conversion of the released MDA to its sodium salt by treatment with 5 N NaOH (pH 10).1 Sodium MDA crystallizes from ethanol-ether as white needles.

Derivatives of Malondialdehyde.

A number of 2-substituted derivatives of MDA are known, including alkyl, aryl, halo, nitro, amino, cyano, diazo, formyl, and methylene compounds.10-15

Structure of Malondialdehyde.

MDA exists almost entirely in its enolic form. There are three possible tautomeric forms of enolic MDA, all of which are interconvertible by the processes of tautomerization and carbon-carbon single bond rotation.3,16-18 In organic solvents such as CCl4 and CHCl3, the major form is the intramolecularly hydrogen-bonded cis form. In polar hydroxylic solvents such as water, MDA exists largely as the trans form (eq 1).3

Reactions of Malondialdehyde.

MDA behaves in some respects as a typical aldehyde. Thus it forms dianils3 and cyclic and acyclic acetals,5 and forms chelates with metal ions.8 MDA may also be looked upon as a vinylog of formic acid in that it undergoes reactions that are typical of carboxylic acids, such as salt formation and conversion to vinylogous esters with diazomethane.6-8 In some of its reactions, MDA behaves as a push-pull alkene and participates in both nucleophilic and electrophilic substitution reactions.9 For example, MDA undergoes nucleophilic attack at the terminal positions in its reaction with amines and electrophilic substitution at C-2 in its reaction with bromine (eqs 2 and 3).3,9,19,20

MDA reacts with dimethyl 3-oxoglutarate to form phenolic or bicyclic adducts, depending on the pH of the reaction.20 The synthesis of secologanin, a biosynthetic precursor of secoiridoid glycosides, was achieved using sodium MDA in a key step of the synthesis (eq 4).21

The thiobarbituric acid (TBA) test is used extensively as a spectrophotometric method for the detection of peroxidation of unsaturated fatty acids.22 The assay apparently is for the detection of MDA, and the red pigment (TBA-MDA adduct) formed is a mixture of equilibrating structures of the type (1).23

Nucleic acid bases are modified by MDA. For example, treatment of guanosine or deoxyguanosine with MDA results in the formation of a nucleoside with a tricyclic base as the primary product. Further reaction of this adduct with MDA produces a compound bearing a tetracyclic base moiety (eq 5).24-27 The modification of other nucleic acid bases has also been studied.28,29

Interestingly, MDA reacts with amines and amino acids in the presence of a monoaldehyde to produce highly fluorescent and stable dihydropyridines.1,30,31 A plausible mechanistic explanation of this transformation involves the condensation of MDA with the amine to form an enaminal (eq 6), and with the additional aldehyde to produce an alkylidene MDA derivative. Subsequent Michael reaction between these two species, followed by cyclization and elimination of water, results in the formation of the dihydropyridine (eq 7).

Methylenemalondialdehydes (alkylidenemalondialdehydes), intermediates in the synthesis of the aforementioned dihydropyridines, were first utilized under conditions of in situ generation by Woodward and co-workers in the synthesis of cephalosporin C.32 Various masked forms of MDA have also been used in synthesis (see, for example, Cho et al.33).

Related Reagents.

Formic Acid; Glyoxal; Succindialdehyde.

1. Turner, G. A. Ph.D. Thesis, University of Iowa, 1987.
2. Saslow, L. D.; Waravdekar, V. S. JOC 1957, 22, 843.
3. Nair, V.; Vietti, D. E.; Cooper, C. S. JACS 1981, 103, 3030.
4. Buttkus, H.; Bose, R. J. JOC 1971, 36, 3895.
5. Botteghi, C.; Soccolini, F. S 1985, 592.
6. Huttel, R. CB 1941, 74, 1825.
7. Bredereck, H.; Effenberger, F.; Schweizer, E. H. CB 1962, 95, 803.
8. Osman, M. M. HCA 1972, 55, 239.
9. Lloyd, D.; McNab, H. AG(E) 1976, 15, 459.
10. Reichardt, C.; Halbritter, K. LA 1975, 470.
11. Arnold, Z.; Sauliova, J. CCC 1973, 38, 2641.
12. Coppola, G. M.; Hardtmann, G. E.; Huegi, B. S. JHC 1974, 11, 51.
13. Reichardt, C.; Schagerer, K. LA, 1982, 530.
14. Reichardt, C.; Ferwanah, A. R.; Pressler, W.; Yun, K. Y. LA 1984, 649.
15. Reichardt, C.; Halbritter, K. AG(E) 1975, 14, 86.
16. Rowe, W. F., Jr.; Duerst, R. W.; Wilson, E. B. JACS 1976, 98, 4021.
17. Seliskar, C. J.; Hoffmann, R. E. J. Mol. Struct. 1982, 96, 146.
18. Frisch, M. J.; Scheiner, A. C.; Schaefer III, H. F.; Binkley, J. S. JCP 1985, 82, 4194.
19. Trofimenko, S. JOC 1963, 28, 3243.
20. Bertz, S. H. JOC 1985, 50, 3585.
21. Tietze, L. F.; Meier, H.; Nutt, H. LA 1990, 253 and earlier references.
22. Autoxidation in Food and Biological Systems; Simic, M. G.; Karel, M., Eds.; Plenum: New York, 1980.
23. Nair, V.; Turner, G. A. Lipids 1984, 19, 804.
24. Moschel, R. C.; Leonard, N. J. JOC 1976, 41, 294.
25. Seto, H.; Okuda, T.; Takesue, T.; Ikemura, T. BCJ 1983, 56, 1799.
26. Nair, V.; Turner, G. A. Abstracts of Papers, 186th National Meeting of the American Chemical Society, Washington; American Chemical Society: Washington, 1983; ORGN 74.
27. Marnett, L. J.; Basu, A. K.; O'Hara, S. M.; Weller, P. E.; Rahman, A. F. M. M.; Oliver, J. P. JACS 1986, 108, 1348.
28. Nair, V.; Turner, G. A.; Offerman, R. J. JACS 1984, 106, 3370.
29. Nair, V.; Offerman, R. J.; Turner, G. A. JOC 1984, 49, 4021.
30. Nair, V.; Offerman, R. J.; Turner, G. A. JACS 1986, 108, 8283.
31. Nair, V.; Offerman, R. J.; Turner, G. A.; Pryor, A. N.; Baenziger, N. C. T 1988, 44, 2793.
32. Woodward, R. B.; Heusler, K.; Gosteli, J.; Naegeli, P.; Oppolzer, W.; Ramage, R.; Ranganathan, S.; Vorbruggen, H. JACS 1966, 88, 852.
33. Cho, I-S.; Gong, L.; Muchowski, J. M. JOC 1991, 56, 7288.

Vasu Nair

The University of Iowa, Iowa City, IA, USA

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