Formaldehyde-Hydrogen Bromide1

(HBr)

[10035-10-6]  · BrH  · Formaldehyde-Hydrogen Bromide  · (MW 80.92) (CH2O)

[50-00-0]  · CH2O  · Formaldehyde-Hydrogen Bromide  · (MW 30.03) ((CH2O)n)

[30525-89-4] (3CH2O)

[110-88-3]

(conversion of alcohols to bromomethyl ethers; bromomethylation agent for aromatic compounds)

Physical Data: HBr (gas): mp -89.6 °C; bp -66.8 °C; d rel. to air 2.71; HBr (48 wt % in water): bp 124.9 °C; d 1.490 g cm-3; HBr (30 wt % in acetic acid): d 1.354 g cm-3. H2CO (37 wt % in water): d 1.081-1.085 g cm-3; bp 96-99 °C; paraformaldehyde (HO(CH2O)nH n = 8-100): mp 120-170 °C (depending on degree of polymerization); trioxane: mp 61-62.5 °C; bp 114.5-115.5 °C.

Solubility: HBr: sol water, alcohols, polar organic solvents, acetic acid, propionic acid; H2CO (as a monomer/polymer equilibrium mixture): sol water, alcohols, acetone, acids; paraformaldehyde: sol (depolymerizes) water, alcohols; insol acetone, ether; trioxane: sol water, alcohols, ethers, ketones, aromatic and chlorinated hydrocarbons.

Form Supplied in: HBr gas: 48 wt % in water (colorless), 30 wt % in acetic acid (colorless); H2CO: 37 wt % aqueous solution (formalin) (colorless to slightly turbid; generally contains 10-15 wt % methanol as stabilizer); paraformaldehyde (white solid; contains 1-10% water); 1,3,5-trioxane (white solid).

Handling, Storage, and Precautions: HBr solutions turn yellow on storage as the result of bromine formation caused by air oxidation and exposure to light. HBr is highly toxic and corrosive and causes severe burns to eyes, skin, and mucous membranes. H2CO has a pungent suffocating odor, has an irritant action on eyes and skin, is highly toxic, and a cancer suspect reagent. Combination of HBr and H2CO may yield highly toxic bis(bromomethyl) ether (see carcinogenic Bis(chloromethyl) Ether). Handle in a fume hood.

Bromomethyl Ethers.

Bromomethyl alkyl ethers, which are useful for bromomethylation of aromatic compounds,1-5 are prepared by the reaction of an alcohol with an equimolar amount of paraformaldehyde and hydrogen bromide (eq 1).1,2,4,6 Use of metal chloride Lewis acid catalysts in the bromomethylation of aromatics with bromomethyl ethers2,3 sometimes gives chloromethylated compounds as well. Bromomethyl methyl and bromomethyl octyl ethers are commercially available.

Higher alcohols are reported to react more smoothly than lower alcohols.4 The reaction is best performed at low temperatures2,9 to suppress formation of dialkoxymethanes (acetalization of formaldehyde). Bromomethyl alkyl ethers, in particular those of lower alcohols, are sensitive to hydrolysis and best yields are therefore obtained when the water formed is efficiently removed from the reaction medium by using water-immiscible solvents such as CH2Cl2 or CHCl3 and/or by addition of desiccating agents like CaCl2.1,2,6 The reaction is quantitative in the case of primary alcohols. Secondary, tertiary, and benzylic alcohols form the corresponding bromides as side products.1c,2 Formation of toxic bis(bromomethyl)ether (from formaldehyde and HBr) is noted when an excess of formaldehyde with respect to the alcohol is used and/or for secondary, tertiary, or benzylic alcohols.2 No information is available on the toxicity of bromomethyl alkyl ethers, but it is likely that they are as toxic (carcinogenic) as the corresponding chloromethyl ethers (see Formaldehyde-Hydrogen Chloride and Bis(chloromethyl) Ether).7

Bromomethylation of Aromatic Compounds.

The combination formaldehyde-HBr is, in many cases, a suitable replacement for the more reactive but highly toxic bis(bromomethyl) ether and bromomethyl alkyl ethers in the bromomethylation of aromatic compounds (eq 2).1,8-10

Bromomethylation is less well documented than chloromethylation (see Formaldehyde-Hydrogen Chloride), but recipes for chloromethylation often can be adapted by substituting HBr for HCl.1a,b,10,11 Among the catalysts employed are mild Lewis acids (Zinc Chloride, Tin(IV) Chloride) and protic acids (Sulfuric Acid, Acetic Acid), and often HBr by itself suffices.1,3,6 Typical solvents are water, ether, chloroform, or (glacial) acetic acid. For aqueous systems, addition of a phase-transfer catalyst was found to improve rate and yield of the reaction.9 Generally, product yields are high.

The source of formaldehyde in the reaction has been the aqueous solution,1 paraformaldehyde,1,8 or trioxane.9 HBr can be introduced as a gas,1,10 as an aqueous solution,9 or in acetic acid solution.8,12 It can also be generated in situ from sodium bromide and mineral acid.1,13 The reactivity of the bromomethylating species is least in aqueous solvent systems and highest in anhydrous media containing ZnCl2 or H2SO4. Benzene can only be bisbromomethylated by the anhydrous reagent.13 The latter has a reactivity similar to bis(bromomethyl) ether, suggesting a common electrophile (i.e. the bromomethyl carbenium ion, +CH2Br), whereas in water-containing media the less reactive hydroxymethyl cation (+CH2OH) is the electrophile.3,4,11 Diarylmethane formation, i.e. condensation of the bromomethylated compound with the original aromatic compound, is the primary side reaction,1 but this is less prevalent than in chloromethylation and is frequently absent.8-10 Polycondensation with H2CO may occur with phenols (Bakelite formation), but this side reaction is suppressed by the presence of electron-withdrawing groups or by esterification of the phenol group.1a,c

Bromomethylation is generally applicable to aromatic compounds such as benzene,1,9 naphthalene (1-position),10,13a or anthracene (9,10-positions).1 The reaction is faster with activated aromatics like alkylbenzenes (toluene,9,13a mesitylene,8,9,12a t-butylbenzene,14 1- or 2-methylnaphthalene9a,10), phenols (2- or 4-nitrophenol,15a 4-alkylphenol,16b 2-bromo-4-phenylphenol,16b 2-(3-bromo-5-phenylsalicyl)-4-t-butylphenol16b), alkoxy-15b or aryloxybenzenes12c (no ether cleavage observed). The reaction is retarded or even completely suppressed (in the case of aqueous media) by electron-withdrawing substituents like F,14 Cl, Br,13a or CH2Br.8,9 In case of highly activated aromatics, the reaction is often difficult to stop after the introduction of one CH2Br group and, for phenols in particular, bis-bromomethylation is observed.16 For methylbenzenes the degree of bromomethylation can be controlled by adjusting the reaction temperature and/or the amount of reagent (e.g. selective mono-, bis-, or trisbromomethylation of mesitylene) (eq 3).8,9

Related Reagents.

Bromomethyl Methyl Ether; Formaldehyde; Hydrogen Bromide.


1. (a) Fuson, R. C.; McKeever, C. H. OR 1942, 1, 63. (b) Olah, G. A.; Tolgyesi, W. S. In Friedel-Crafts and Related Reactions; Olah, G. A., Ed.; Interscience: New York, 1964; Vol. II. pp 659-784. (c) Roedig, A. MOC 1960, 54, 484.
2. Warshawsky, A.; Deshe, A.; Gutman, R. Br. Polym. J. 1984, 16, 234.
3. Stephen, H.; Short, W. F.; Gladding, G. JCS 1920, 117, 510.
4. Vavon, G.; Bolle, J.; Calin, J. BSF 1939, 6, 1025.
5. Blair, C. M.; Henze, H. R. JACS 1932, 54, 399.
6. Lucien, H. W.; Mason, C. T. JACS 1949, 71, 258.
7. Heitman, W.; Strehlke, G.; Mayer, D. In Ullmann's Encyclopedia of Industrial Chemistry, 5th ed.; VCH: Weinheim, 1987; Vol. A10, p 33.
8. van der Made, A. W.; van der Made, R. H. JOC 1993, 58, 1262.
9. Mitchell, R. H.; Iyer, V. S. SL 1989, 52.
10. (a) Darzens, G.; Lévy, A. CR 1936, 202, 73. (b) Darzens, G. CR 1939, 208, 818.
11. Taylor, R. In Electrophilic Aromatic Substitution; Wiley: Chichester, 1990; p 219.
12. (a) Jenkner, H. (Chem. Fabrik Kalk GmbH) Ger. Offen 2 027 162, 1970 (CA 1972, 76, 245 908n). (b) Jenkner, H.; Buettgens, W. (Chem. Fabrik Kalk GmbH) Ger. Offen 2 302 319, 1974 (CA 1974, 81, 120 181d). (c) Jenkner, H.; Buettgens, W. (Chem. Fabrik Kalk GmbH) Ger. Offen 3 214 416, 1983 (CA 1984, 100, 6075h).
13. (a) Kubiczek, G.; Neugebauer, L. M 1950, 81, 917. (b) Alves, A. A.; da Rocha, N. V. P. An. Assoc. Bras. Quim. 1967, 26, 15 (CA 1969, 70, 37 318f).
14. Kraus, F. BSF 1953, C51.
15. (a) Bronne, G.; da Rocha, N. V. P. An. Assoc. Bras. Quim. 1967, 26, 23 (CA 1969, 70, 37 348r). (b) Tourinho, A. M.; da Rocha, N. V. P. An. Assoc. Bras. Quim. 1967, 26, 19 (CA 1969, 70, 37 357t).
16. (a) Bright, W. M.; Cammarata, P. JACS 1952, 74, 3690. (b) Böhmer, V.; Marschollek, F.; Zetta, L. JOC 1987, 52, 3200. (c) Böhmer, V.; Jung, K.; Schön, M.; Wolff, A. JOC 1992, 57, 790.

Alexander van der Made

Koninklijke/Shell Laboratorium Amsterdam, The Netherlands



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