Formaldehyde

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

[30525-89-4] (3CH2O)

[110-88-3]

(ene reaction;1,2 Prins reaction;1,3 enolate trapping;4 alkylation; Mannich reaction; acetalization; condensation; reduction)

Alternate Names: paraformaldehyde; s-trioxane.

Physical Data: monomeric formaldehyde: mp -92 °C; bp -19.5 °C; d 1.067 g cm-3. Paraformaldehyde: mp 163-165 °C (dec). s-Trioxane: mp 64 °C, bp 114.5 °C, d 1.17 g cm-3 (65 °C); sublimes readily.

Solubility: formaldehyde gas: v sol water, up to 55%; sol alcohol, ether. Paraformaldehyde: slowly sol cold water; readily sol hot water with evolution of formaldehyde; insol alcohol, ether. s-Trioxane: readily sol water (21.1 g/100 mL at 25 °C), alcohols, ether, acetone, chlorocarbons, aromatics; sl sol pentane.

Form Supplied in: 37% aqueous solution (with 10 to 15% methanol to prevent polymerization) known as formalin; colorless and pungent liquid. Paraformaldehyde: polymer as a white crystalline powder. s-Trioxane: crystalline solid.

Preparative Methods: dry formaldehyde may be generated by heating solid paraformaldehyde or by decomposing with barium peroxide; ethereal solutions of monomeric formaldehyde can be obtained by pyrolysis of paraformaldehyde at 150 °C in a special apparatus; can be generated in situ from trioxane by Methylaluminum Bis(2,6-diphenylphenoxide) (MAPH).15

Handling, Storage, and Precautions: reported to be storable for an extended period at -78 °C under argon (unchecked OS procedure);5 irritating to mucous membranes; carcinogen; should be used only in a well-ventilated fume hood.

Ene Reaction.

Thermal ene reactions of paraformaldehyde with reactive 1,1-di- and trisubstituted alkenes occur at 180-220 °C.6,7 b-Pinene, for example, is transformed into nopol upon reaction with formaldehyde at 180 °C (eq 1).6 Extension of this reaction has been reported using acetic acid-acetic anhydride as solvent.8

Lewis acids such as Tin(IV) Chloride9 and Boron Trifluoride Etherate10 can facilitate addition of formaldehyde to alkenes to afford ene adducts. Thus reaction with 2,6-dimethyl-2,5-heptadiene in the presence of SnCl4 as catalyst provides lavanduol (eq 2).11 The BF3.Et2O-promoted reaction with the ethylidene steroid shown in eq 3 takes place exclusively from the less hindered a-face to produce the ene adduct with the natural steroid configuration at C-20.12

Organoaluminum reagents can also be utilized as promoters for ene reactions to give homoallylic alcohol ene adducts in high yield and selectivity, although g-chloro alcohols are formed in some cases as byproducts.13 Diethylaluminum Chloride-induced ene reactions of formaldehyde with 1,4-dienes occur selectivity at the less deactivated terminal bond, and subsequent quasi-intramolecular Diels-Alder reaction with formaldehyde as dienophile leads to the formation of a dihydropyran (eq 4).14 The formaldehyde-dimethylaluminum chloride complex acts on terminal alkynes to afford a-allenic alcohols and (Z)-3-chloroallylic alcohols as byproducts in a 2:3 ratio (eq 5).13b The aluminum reagent MAPH complexed with formaldehyde, generated from trioxane, also reacts with various alkenes to furnish ene adducts with excellent regioselectivities (see Methylaluminum Bis(2,6-diphenylphenoxide)).15

Prins Reaction.

The condensation of aldehydes and ketones with alkenes in the presence of Brønsted acids is usually called the Prins reaction. The main products of this alkene-aldehyde condensation, depending on experimental conditions, may be a 1,3-dioxane, a 1,3-diol, a homoallylic alcohol, or an a-chloro ether (see Formaldehyde-Hydrogen Chloride).3

Various catalysts have been used in the Prins reaction, although in the synthesis of 1,3-dioxane, sulfuric acid seems to be the most efficient. Thus stirring a mixture of formalin, sulfuric acid, and styrene under gentle reflux gives 4-phenyl-m-dioxane (eq 6).16

Prins reactions involving formaldehyde have been used to prepare prostaglandin intermediates. An example is the acid-catalyzed addition of formaldehyde to the unsaturated lactone in acetic acid at 60-80 °C to give a prostaglandin intermediate (eq 7).17

Reaction of a 1,4-diaryl-1-butene with paraformaldehyde catalyzed by a 1:1 mixture of Methylaluminum Dichloride and Dimethylaluminum Chloride resulted in cylization to form a 1-aryltetralin (eq 8). The mixed catalyst was found to be more effective than Me2AlCl alone.18

Enolate Trapping Reactions and Formation of a-Methylene Products.

Lactones when treated with Lithium Diisopropylamide in THF at -78 °C form enolate anions that react with gaseous formaldehyde to give the a-hydroxymethyl derivative. The product can be easily transformed to an a-methylene lactone by conversion to mesylate followed by treatment with refluxing pyridine (eq 9).19 This method was used for bis-a-methylenation in the total synthesis of deoxyvernolepin, which contains a dilactone structure (eq 10).20

a-Thiobutyrolactones,21 carboxylic acids,22 sulfonyl-hydrazones,23 enol phosphinites,24 and a,b-enones25 on treatment with lithium reagents and subsequent reaction with formaldehyde undergo the same reaction, providing aldol adducts.

a-Methylenation products can also result from reaction of the carbanion of a-alkyl b-keto esters or lactones with paraformaldehyde in THF, initially at -78 °C and followed by reflux (eq 11).26

D1-5a-Androsten-3-one in DMSO containing paraformaldehyde and BF3.Et2O when heated resulted in formation of the 4-methylene ketone (eq 12).27

Reductive Methylation.

The classical method of dimethylation of primary amines or monomethylation of primary and secondary amines involves reaction with formaldehyde and Formic Acid (eq 13).28

The use of either Sodium Borohydride29 or Sodium Cyanoborohydride30 in place of formic acid leads to the same reaction. However, NaCNBH3 is usually the preferred reducing agent since the methylated amines can be formed without reduction of carbonyl compounds in the substrate.31

Potassium hydridotetracarbonylferrate prepared from Potassium Hydroxide and Pentacarbonyliron is likewise effective for the dimethylation of primary amines in ethanol under carbon monoxide at 20 °C (eq 14).32 The use of a 1:1 molar ratio of amine and formaldehyde gives the monomethylated product.

Carbonyl compounds having a-methyl or a-methylene groups also undergo methylation with formaldehyde in the presence of potassium or Sodium Tetracarbonylhydridoferrate (eqs 15 and 16).33

Ethyl p-nitrophenylacetate undergoes reductive methylation upon reaction with aqueous formaldehyde by catalytic hydrogenation with Palladium on Carbon (eq 17).34

Hydroxymethylation.

Reaction of carbonyl compounds with formaldehyde in the presence of base results in the formation of hydroxymethylated products. For example, allyl b-keto esters react with formaldehyde and Potassium Carbonate to give the a-hydroxymethyl ketone in quantitative yield (eq 18).35 Sugar aldehydes undergo the same reaction with K2CO3.36

With a 2:1 ratio of formaldehyde and Diethyl Malonate and potassium bicarbonate as catalyst, the product is diethyl bis(hydroxymethyl)malonate (eq 19).37

Nitriles possessing at least one a-aryl group can be hydroxymethylated using paraformaldehyde and Triton B (Benzyltrimethylammonium Hydroxide) in pyridine (eq 20).38

Chromium tricarbonyl complexes of methoxyalkylbenzenes in the presence of Potassium t-Butoxide and formaldehyde undergo regiospecific alkylation only at the meta-position with respect to the methoxy group (eq 21).39

Reaction with Organometallic and Other Reagents.

Hydroxymethylation of Grignard reagents with formaldehyde can be represented by the synthesis of cyclohexymethanol using cyclohexylmagnesium chloride.40 Methylmagnesium Bromide, in the presence of a nickel-aluminum catalyst, acts on 1-trimethylsilyl-1-octyne to provide a mixture of addition products which react with formaldehyde to give di- and trisubstituted vinylsilanes (eq 22).41

Boric Acid is a useful catalyst for the cyclocondensation of phenol with formaldehyde to give benzodioxaborin.42 Phenylboronic acid, in combination with propionic acid, is found to be a more efficient catalyst.43 Thus a high yield of dioxaborin is obtained in the reaction with a slight excess of phenylboronic acid, and the free hydroxymethylated phenol is liberated by an exchange reaction or by oxidation with Hydrogen Peroxide (eq 23).

Silyl enol ethers of aldehydes and ketones react with trioxane in the presence of Titanium(IV) Chloride to give cross-aldol adducts in good yield (eq 24).44

Ytterbium(III) Trifluoromethanesulfonate, a Lewis acid stable in aqueous media, is found to be effective in catalytic hydroxymethylation of silyl enol ethers with formalin (eq 25).45

Synthesis of Heterocyclic Compounds.

Condensation of Ethyl Acetoacetate, formaldehyde, and Ammonia in 2:1:1 molar ratio furnishes a 1,4-dihydropyridine which is the first step in the synthesis of 2,6-lutidine (eq 26).46

Symmetric trimers such as sym-trithiane47 and hexahydro-1,3,5-tripropionyl-sym-triazine48 are obtained from formaldehyde reactions. The former is synthesized by passing Hydrogen Sulfide into a mixture of formalin and concentrated HCl, while the latter is prepared by addition of trioxane in propionitrile to a mixture of propionitrile and concentrated H2SO4 (eqs 27 and 28).

A general synthesis of piperidines involves the reaction of the acid salt of primary amines with allylsilanes and 2 equiv formaldehyde in H2O. The iminium ion generated from the amine and formaldehyde reacts with the allylsilane to give a homoallyl amine, which then can form the second iminium ion and H2O is captured to deliver the piperidinol (eq 29).49

Cyclization of the alkynylamine N-benzyl-4-hexyn-1-amine with formaldehyde, Sodium Iodide, and 10-Camphorsulfonic Acid gives the iodomethylenepiperidine (eq 30).50 In the absence of the iodide nucleophile, no cyclization is observed.

Reactions of (E)- or (Z)-vinylsilanes with an excess of paraformaldehyde and camphorsulfonic acid give the cyclized product with >98% retention of the double bond configuration of the starting reactants (eq 31).51

A series of imine condensations and chain cleavage occur when D-fructose is heated with ammonium hydroxide, basic copper(II) carbonate, and formaldehyde, which ultimately gives 4-hydroxymethylimidazole (eq 32).52

Condensation.

For the preparation of aurin tricarboxylic acid, solid Sodium Nitrite was added to concentrated sulfuric acid to produce nitrogen oxides, then salicyclic acid and formalin were added dropwise with vigorous cooling (eq 33).53

3,4-Diethylpyrrole can be converted to octaethylporphyrin by condensation with aqueous formaldehyde in benzene in the presence of p-Toluenesulfonic Acid; the water is removed and the methylenepyrrole tetramer is oxidized with oxygen (eq 34).54

The synthesis of p-t-butylcalix[4]arene is a three-step process which involves initial reactions of p-t-butylphenol, formalin, and a base, followed by pyrolysis at a later stage (eq 35).55 The procedure is limited to p-alkylphenols in which the p-alkyl group is highly branched at the position adjacent to the phenyl ring. A single-step procedure is also described for p-t-butylcalix[6]arene56 and p-t-butylcalix[8]arene,57 which requires a larger amount of base for the preparation of the hexamer.

Acetalization.

1,3-Diols react with formaldehyde in an excess of alcohol under acid catalysis, such as p-TsOH or ion exchange resin, to form cyclic acetals (eq 36).58

Cortisone, a steroid containing an a,a-dihydroxyacetone side chain, is converted into the bismethylenedioxy derivative by stirring with chloroform, formalin, and concentrated HCl (eq 37).59

Cannizzaro and Related Reductions.

In the presence of calcium oxide and water, cyclohexanone reacts with 5 moles of paraformaldehyde to give the pentaol shown in eq 38.60

p-Tolylmethanol is formed in a Cannizzaro reaction involving p-tolualdehyde and formalin in aqueous KOH (eq 39).61

An interesting preparation of p-dimethylaminobenzaldehyde from p-nitrosodimethylaniline is accomplished by reaction with dimethylaniline and 2 moles of formaldehyde in HCl solution. In the first step, one mole of formaldehyde is reduced and the other is oxidized to the formate level, furnishing the benzylidene derivative which is then hydrolyzed by exchange with formaldehyde (eq 40).62

Other Reactions with Nitrogen Compounds.

A reaction involving a mixture of formalin, ammonium chloride, and aqueous Sodium Cyanide provides N-(methylene)aminoacetonitrile (eq 41).63

Diethylaminoacetonitrile is prepared by adding formalin to a solution of sodium bisulfate, thereby forming the addition compound which is stirred in diethylamine after cooling, and the aqueous solution of sodium cyanide is added (eq 42).64

For the preparation of glycolonitrile, formalin is added to a stirred solution of Potassium Cyanide in water at 0-10 °C (eq 43).65

For Mannich-type reactions involving formaldehyde, see Formaldehyde-Dimethylamine.

Related Reagents.

Acetaldehyde; Formaldehyde-Dimethylamine; Formaldehyde-Hydrogen Bromide; Formaldehyde-Hydrogen Chloride; Methylaluminum Bis(2,6-diphenylphenoxide); Sodium Cyanoborohydride.


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Arnel B. Concepcion & Hisashi Yamamoto

Nagoya University, Japan



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