Paraformaldehyde

(CH2O)n

[30525-89-4]  · CH2O  · Paraformaldehyde  · (MW 30.03)

(convenient source of anhydrous monomeric formaldehyde for aldol condensation;1 electrophilic source of halomethyl2 and hydroxymethyl groups;3 convenient source of Mannich reaction intermediates;4 homologation of alkynes;5 synthesis of macrocyclic ligands6)

Physical Data: mp 160-165 °C.

Solubility: sol organic solvents.

Form Supplied in: solid; widely available.

Handling, Storage, and Precautions: generally stable; irritant.

Introduction.

The need to carry out one-carbon homologations during the course of organic syntheses is widespread. Since Formaldehyde itself is a hygroscopic gas which forms the hydrate easily, the ability to utilize functional equivalents of formaldehyde is quite useful. The proper choice for the synthetic equivalent of a tenuous species like formaldehyde is dictated by the context. Unlike the two other most common precursors, formalin and trioxane, paraformaldehyde is rather easy to handle. It is compatible with most organic systems and displays useful reaction patterns. The polymeric acetal system cleaves easily under acidic conditions and, to a lesser extent, under basic and neutral conditions, to afford one-carbon homologs. On those occasions when a solution of the monomeric formaldehyde is needed, the best approach is the thermal cracking of paraformaldehyde, with the evolved gaseous monomer bubbled into a solution and used immediately.

Reactions with Enolates and Enols.

As the functional equivalent of formaldehyde, paraformaldehyde can afford aldol products, especially under acidic conditions wherein the enol intermediate is generated and conditions lead to unsaturated carbonyl compounds. Methyl ketones undergo reaction (eq 1) with paraformaldehyde to afford the vinyl ketones under acidic conditions.7 Similar results are obtained with other active hydrogen reactants such as the treatment of methyloxazolines with paraformaldehyde and acid.8 Under neutral aqueous conditions, multiple aldol reactions with cyclohexanone have been reported (eq 2).9

Noteworthy observations in this particular reaction are the ultimate reduction of the ketone, presumably via a crossed Cannizzaro reaction, and the ability to utilize large excesses of paraformaldehyde without major difficulties. Of course, both phenomena are related to the absence of a-hydrogens and resultant inability of formaldehyde to enolize.

While paraformaldehyde can be effective in enolate chemistry,10 the more common practice, when condensation onto a preformed enolate is required, is to generate a solution of monomeric formaldehyde through pyrolysis.1,11 One can isolate the resultant hydroxy ketone (eq 3),12 or force dehydration through the use of Methanesulfonyl Chloride,12 or a variety of organometallic agents.13 The monomer generated in this way also reacts readily with the dianions of carboxylic acids.14

Halomethyl and Hydroxymethyl Electrophiles.

The chloromethylation of aromatic systems2 and heteroaromatic compounds15 can be accomplished using paraformaldehyde, Zinc Chloride, and Aluminum Chloride. Similar chemistry allows bromomethylation of aromatic systems.16 Halomethyl esters can be obtained from carboxylic acids as well.17 The hydroxymethylation of anthraquinones has been reviewed3 and paraformaldehyde can be used for the protection of alcohols as the methoxymethyl group.18-20

The Mannich Reaction and other Iminium Ion Reactions.

While the trapping of an iminium ion (generated by the acid-catalyzed reaction of an amine and paraformaldehyde) by enols4 has been well investigated (eq 4),21,22 a variety of other nucleophiles are available, such as allylstannanes.23 Of particular note are those reactions which bring about cyclization. In this context a vinylsilane (eq 5)24 is effective, as is an alkene (eq 6).25

Homologation of Alkynes.5

While the terminal alkyne group is a relatively weak nucleophile, strong Lewis acids can bring about homologation, albeit with some isomerization (eq 7).

Macrocyclic Ligands.6

By making use of template control, aza macrocycles can be formed which act as organometallic ligands and sequestering agents (eq 8).


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2. Fieser, L.; Seligman, A. M. JACS 1935, 57, 942.
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11. Stork, G.; Isobe, M. JACS 1975, 97, 6260.
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13. Tsuji, J.; Nisar, M.; Minami, I. TL 1986, 27, 2483.
14. Pfeffer, P. E.; Sibert, L. S. JOC 1970, 35, 262.
15. Kochetkov, N. K.; Khomutova, E. D.; Bazilevskii, M. V. ZOB 1958, 28, 2736 (CA 1959, 53, 9187).
16. van der Made, A. W.; van der Made, R. H. JOC 1993, 58, 1262.
17. Knochel, P.; Chou, T.-S.; Joubert, C.; Rajagopal, D. JOC 1993, 58, 588.
18. Edwards, J. A.; Calzada, M. C.; Bowers, A. JMC 1964, 7, 528.
19. Kapnang, H.; Charles, G.; Sondengam, B. L.; Hemo, J. H. TL 1977, 3469.
20. Barluenga, J.; Bayon, A. M.; Asensio, G. CC 1984, 1334.
21. Wilds, A. L.; Nowak, R. M.; McCaleb, K. E. OSC 1963, 4, 281.
22. Hagemeyer, H. J., Jr. JACS 1949, 71, 1119.
23. Grieco, P. A.; Bahsos, A. JOC 1987, 52, 1378.
24. Overman, L. E.; Bell, K. E. JACS 1981, 103, 1851.
25. Shiotani, S.; Kometani, T. TL 1976, 767.

Richard T. Taylor

Miami University, Oxford, OH, USA



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