Formaldehyde-Hydrogen Chloride1


[50-00-0]  · CH2O  · Formaldehyde-Hydrogen Chloride  · (MW 30.03) (HCl)

[7647-01-0]  · ClH  · Formaldehyde-Hydrogen Chloride  · (MW 36.46)

(chloromethylation of activated aromatics1 and heteroaromatics,1b cyclophanes,2 aromatic polymers;1b,3 synthesis of chloromethyl ethers;4,1a lactones from phenylacetic acid5)

Preparative Methods: formaldehyde is usually in the form of formalin or paraformaldehyde. For aromatic chloromethylation, solvents such as glacial acetic acid, CS2, CCl4, or chloroform are often employed, although heterogeneous chloromethylations using excess aromatic as solvent are numerous.1b A Lewis acid catalyst (often Zinc Chloride but a range of other Friedel-Crafts type catalysts have been reported), or a protic acid catalyst (usually Sulfuric Acid, conc Hydrochloric Acid, syrupy Phosphoric Acid) is often necessary, especially if electron-withdrawing groups are present on the arene. Typically, a rapid stream of HCl is passed through the formaldehyde-substrate mixture in a suitable medium until no more gas is absorbed.

Handling, Storage, and Precautions: many chloromethylated compounds are lachrymatory. Chloromethyl ethers are carcinogenic. The reagents should be handled in a well-ventilated fume hood.

Chloromethylation Reaction.

Chloromethylation of arenes is a typical electrophilic aromatic substitution (ρ = -5).1a Alkylbenzenes like toluene and anisole give mixtures of ortho/para chloromethylated isomers and the proportion of meta always remains low (eq 1).

The reaction is facilitated by alkyl and alkoxy substituents and hindered by electron-withdrawing groups (halo, especially nitro). Increasing steric crowding of the substituent increases the para isomer at the expense of the ortho.1a,1b On the other hand, the proportion of ortho increases on going from fluorobenzene to iodobenzene.1a,1b Although substrate selectivities (KT/KB) are variable, depending on reaction conditions, isomer distributions do not change much.6

Bischloromethylated arenes are often observed as byproducts. Diarylmethane formation is a known side reaction in chloromethylation with CH2O/HCl, especially with reactive arenes.1 Use of AsCl3 or As2O3 as a chloromethylation catalyst apparently inhibits this side reaction.1a

Whereas there seems to be general agreement that CH2O/HCl is a chloromethyl alcohol equivalent, there is difference of opinion as to the exact nature of the chloromethylation electrophile.1a Thus HOCH2+ and CH2Cl+ have both been invoked.1a,6 O-Protonated chloromethanol (1), which is observable in solution under persistent ion conditions,7 has been suggested as a possible electrophile. Protonated formaldehyde (2) and chloromethylcarbenium ion (3) have also been proposed.1a,6 When acetic acid is used as solvent for chloromethylation, chloromethyl acetate or its protonated form may serve as the actual electrophile.

Bis(chloromethyl)ether (4) may be formed in situ in chloromethylation with CH2O/HCl and it is likely that this could also act as the chloromethylating agent (eq 2). It is believed that (4) can become the chloromethylation reagent in reactions involving deactivated aromatics in the presence of protic acids, where its formation and further reaction effectively competes with direct chloromethylation via CH2O/HCl.1a Environmental studies show that, under ambient conditions, (4) formation from CH2O/HCl in moist air is insignificant.8

Scope and Limitations.

Alkylbenzenes such as toluene, xylene isomers, tri-, tetra-, and pentamethylbenzenes, ethyl-, isopropyl-, isomeric butyl-, and pentylbenzenes are all chloromethylated with CH2O/HCl.1b,1c For example, mesitylene reacts with CH2O/HCl (gas) in conc HCl solvent to give a 55-61% isolated yield of a2-chlorodurene (eq 3).9

Biphenyl, diphenylmethane, indan, and tetralin also react.1b Whereas chloromethylations of halobenzenes are less efficient, haloalkylarenes are efficiently chloromethylated with CH2O/HCl.1b The presence of nitro group(s) makes chloromethylation difficult unless activating substituents are present. With nitrobenzene and nitrotoluenes, the meta isomer is predominant.1b The higher reactivity of chloromethyl methyl ether makes it the reagent of choice for chloromethylation of nitroalkyl- and dihaloalkylbenzenes. In such instances, the reactions are often conducted in 60% H2SO4 (eq 4).10

The CH2O/HCl reagent is suitable for chloromethylation of various polycyclic aromatic hydrocarbons,1b as well as heterocyclic aromatic compounds.1a,1b Thiophene gives 2-(chloromethyl)thiophene in 40-41% isolated yield,11 and 4-methylimidazole gives the 5-chloromethyl derivative (51-68%) (eq 5).12

Phenols react readily with CH2O/HCl but the initially formed product reacts further to give phenol-formaldehyde resin. Only if electron-withdrawing groups are present can the chloromethylation products be isolated.1b

Alkyl aryl ketones are chloromethylated at the side chain unless activating groups are present on the aromatic ring. It has been proposed that CH2OH+ attacks the enol tautomer.1a In the presence of activating groups, aromatic aldehydes and esters are chloromethylated. Otherwise, severe conditions are needed. p-Anisaldehyde chloromethylates in 90% yield with the CH2Cl group entering meta to the formyl group (eq 6). Aryl alkyl sulfides and diaryl sulfides are usually ring chloromethylated in good yields.1b

[2.2]Paracyclophane is chloromethylated with the CH2O/HCl reagent. The presence of an acyl group in one ring assures pseudogeminal substitution by the chloromethyl group (eq 7).2 This is a useful reaction for the synthesis of superphanes.

Chloromethylated phenethyl bromide is produced in >70% yield by chloromethylation with CH2O/HCl/ZnCl2 (75% para) and subsequently polymerized to chloromethylated styrene.13 The patent literature contains numerous examples of chloromethylation of polymers (for example polystyrene, divinylbenzene/styrene copolymer, and polyoxyphenylenes) using the CH2O/HCl reagent, although there is a larger tendency to use chloromethyl alkyl ethers instead.4c,14

Comparison with Other Chloromethylating Agents.

Because of the limitations that exist in chloromethylation of deactivated arenes, the more reactive Chloromethyl Methyl Ether and Bis(chloromethyl) Ether appear more suitable. However, these are carcinogenic and alternative routes have been sought.

Methoxyacetyl Chloride/Aluminum Chloride is suitable for chloromethylation of certain aromatics.15 The methoxymethyl cation has been suggested as the electrophile (eq 8).

The less volatile long-chain halomethyl alkyl ethers prepared from alkanols and CH2O/HCl in chlorinated solvents have been used successfully for the chloromethylation of arenes and polystyrene.4c The amount of (4) produced is quite low and depends on the ROH:CH2O ratio.

1-Chloro-4-(chloromethoxy)butane and 1,4-bis(chloromethoxy)butane in combination with Tin(IV) Chloride or Zinc Bromide can be used for arene chloromethylation. Literature examples are limited to alkylbenzenes.6,15 Yields are 43-60%, depending on the arene (eq 9).

Synthesis of Chloromethyl Ethers.

Chloromethyl methyl ether can be prepared from MeOH/CH2O/HCl in 86-89% isolated yield.4a The corresponding benzyl ether was obtained from PhCH2OH in 83% yield.4b Controlled addition of CH2O to anhydrous MeOH or methylal saturated with HCl gas gives ClCH2OMe with little (4).16

Other Useful Reactions.

3,4-Dimethoxyphenylacetic acid reacts with CH2O/HCl to give the corresponding lactone (eq 10).5 Variations of this procedure are applicable to multi-ring compounds.17 sym-Trithiane is formed by reaction of H2S with CH2O/conc HCl.18 Long-chain thiols are chloromethylated with CH2O/HCl to give RSCH2Cl.19

Related Reagents.

Benzyl Chloromethyl Ether; Bis(chloromethyl) Ether; t-Butyl Chloromethyl Ether; Chloromethyl Methyl Ether; Chloromethyl Trimethylsilyl Ether; Formaldehyde; Formaldehyde-Hydrogen Bromide; Hydrogen Chloride; Methoxyacetyl Chloride; Zinc Chloride.

1. (a) Belen'kii, L. I.; Vol'kenshtein, Yu. B.; Karamanova, I. B. RCR 1977, 46, 891. (b) Olah G. A.; Tolgyesi, W. S. Friedel-Crafts and Related Reactions; Interscience: New York, 1964; Vol. 2, Part 2, Chapter 21. (c) Fuson, R. C.; McKeever, C. H. OR 1942, 1, 63.
2. (a) Truesdale, E. A.; Cram, D. J. JACS 1973, 95, 5825. (b) Hopf, H. Nachr. Chem. Tech. Lab. 1980, 28, 311.
3. Grundmann, R. Ger. Offen. 3 529 558 (CA 1987, 106, 196 979a). (b) Jpn. Kokai 59 089 307 (CA 1984, 101, 152 574g).
4. (a) Marvel, C. S., Porter, P. K. OSC 1932, 1, 369. (b) Conner, D. S.; Klein, G. W.; Taylor, G. N.; Boekman, Jr., R. K.; Medwid, J. B. OSC 1963, 4, 101. (c) Warshawsky, A.; Deshe, A. J. Polym. Sci., Polym. Chem. Ed. 1985, 23, 1839.
5. Finkelstein, J.; Brossi, A. OSC 1963, 4, 471.
6. Olah, G. A.; Beal, D. A.; Olah, J. A. JOC 1976, 41, 1627 and related references cited therein.
7. Olah, G. A.; Yu, S. H. JACS 1975, 97, 2293.
8. Frankel, L. S.; McCallum, K. S.; Collier, L. Environ. Sci. Technol. 1974, 8, 356.
9. Fuson, R. C.; Rabjohn, N. OSC 1955, 3, 557.
10. Susuki, H. BCJ 1970, 43, 3299.
11. Wiberg, K. B.; McShane, H. F. OSC 1955, 3, 197.
12. Halbritter, K. Ger. Offen. 2 800 148 (CA 1980, 92, 58 774w).
13. Daren, S. Eur. Pat. Appl. 345 478 A1, 1989 (CA 1990, 113, 5892d).
14. Tada, A.; Morita, T.; Teraue, T.; Kusumoto, Y. Eur. Pat. Appl. 150 332 A2 (CA 1985, 103, 215 991e).
15. Olah, G. A.; Beal, D. A.; Yu, S. H.; Olah, J. A. S 1974, 560.
16. Ens. L. A. Ger. Offen. 2 433 622 (CA 1975, 83, 9188p).
17. Volkmann, R.; Danishefsky, S.; Eggler, I.; Solomon, D. M. JACS 1971, 93, 5576.
18. Bost, R. W.; Constable, E. W. OSC 1943, 2, 610.
19. Broniarz, J.; Szymanowski, J.; Pernak, J.; Pujanek, M. Przem. Chem. 1977, 56, 253 (CA 1977, 87, 101 875r).

Kenneth K. Laali

Kent State University, OH, USA

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