US2676189A - Preparation of o-hydroxy aldehydes by oxidation of substituted phenols - Google Patents

Description

Patented Apr. 29, 1954 UNITED STATES ATENT OFFICE PREPARATION OF o-HYDROXY ALDEHYDES BY OXIDATION OF SUBSTITUTED PHE- NOLS ware

No Drawing. Application October 20, 1949, Serial No. 122,578

a Claims.

This invention relates to the production of hydroxy aldehydes, and, more particularly, to a method for oxidizing o-hydroxy benzyl alcohols to produce the corresponding o-hydroxy aldehydes.

It has been known that saligenin (o-hydroxy benzyl alcohol) can be oxidized to produce salicylaldehyde and salicylic acid. For example, Piria, Liebigs Annalen der Chimie, vol. 56, pages 42-43 (1845), and Trillat, Bulletin de la Societe Chimique, Third Series, vol. 29, page 45 (1903) disclose the oxidation of saligenin in the presence of platinum black, and Trillat states that saligenin is oxidized to salicylaldehyde in the presence of a platinum spiral. However, saligenin and its derivatives are readily oxidized to the acid; it is extremely difficult to conduct the oxidation in such a way that only the aldehyde is produced, and methods heretofore known for conducting such oxidation have resulted in comparatively low yields of the desired aldehydes. For example, saligenin has been oxidized by oxygen in the presence of platinum black, but it has not been found to be possible to convert more than five per cent of the saligenin to salicylaldehyde by this method. This oxidation has also been carried out (in air, in an oxygen atmosphere, under pressure; and in the absence of oxygen, as a dehydrogenation) in the presence of other catalysts (e. g., osmium, platinum oxide, platinum on zirconium oxide and platinum on pumice), but in no case has it been found to be possible to convert more than fifteen per cent of the saligenin to salicylaldehyde. The present invention is based upon the discovery of a new way for oxidizing saligenin or a substituted saligenin to the corresponding hydroxy aldehyde; the preferred embodiments of the new method can be used to effect a substantially greater yield of the desired aldehyde than has been achieved by the known method.

The principal object of the invention is to provide an improved method for producing salicylaldehyde or a substituted salicylaldehyde from saligenin or a substituted saligenin. More specific objects and advantages are apparent from the description which illustrates and discloses but does not limit the invention.

In accordance with the invention an o-hydroxy aldehyde is produced from saligenin or a substituted saligenin. Saligenin and substituted saligenins are hereinafter for convenience called substituted phenols. The substituted phenols that are used have one ortho substituent of the formula -CH2OH, any other substituent being a halo, alkyl or alkoxy group. The substituted phenol is treated with a lower alkoxide of aluminum to form an aluminum derivative of the substituted phenol. The aluminum derivative is then oxidized by the action of a carbonyl-containing compound, and the pH of the resulting mixture is adjusted to convert the aluminum salt to the hydroxy aldehyde.

Although the invention is not limited to the theoretical explanation that follows, it is believed that the following reactions occur when the process of the invention is used to convert saligenin to salicylaldehyde:

, (a) An aluminum derivative is formed by reaction between the saligenin and the lower alkoxide of aluminum; both the hydroxyls of saligenin form aluminum derivatives but each alu- ,minum atom may react so that it is linked Al-O CHr-O-Al-O-HzC- 4HOR in which R represents an alkyl radical.

(b) The desired oxidation is effected by the action of a carbonyl-containingcompound on the aluminum derivative. This reaction is illustrated by Equation 4, below, which shows acetone as the carbonyl-containing compound.

(c) 'The desired o-hydroxy aldehyde is pro- 'duced from the aluminum salt of the hydroxy aldehyde (shown as a product of Equation 4) by the action of an aqueous acid or by the action of an aqueous base followed by an aqueous acid.

As is illustrated by Equation l, a dynamic equilibrium condition is approached when a substituted phenol and a carbonyl-containing compound are reacted. It is usually desirable that the reaction proceed substantially to the equilibrium condition; in this way approximately the maximum yield of product is achieved with a minimum of recycling. However, it is feasible to stop the reaction before equilibrium is reached and thereby shorten the reaction :time. When reaction has proceeded to the desired extent, an aqueous acid or an aqueous base is added to the mixture to destroy the aluminum derivative and therebytoprevent further reaction in either direction. Equilibrium is achieved, under gentle reflux at atmosphericpressure, Withinabout ten hours. Ordinarily there is no reason to maintain the reaction mixture under reflux after equilibrium is achieved,but the y-i'eldof product is not affected by so continuing. Usually it is desirable that the reaction mixture be refluxed for at least about four hours and preferred that it be refluxed for at least about six hours. Ordinarily, conducting the reaction of the invention at pressures other than'atmospheric cannot be justified economically, so the maxi'num practical temperature is the reflux temperature at atmospheric pressure. ,It is, accordingly, usually desirable to conduct the reaction at about this temperature.

In general, as is hereinbefore stated, the method .ofthe invention is used to convert saligenin or a substituted saligenin to salicylaldehyde or a substituted salicylaldehyde. Although the method can sometimes be used when the saligenin has other substituents, it is usually pre ferred that the startingmaterial be saligenin or a halo-, alkyl-, or-alkoxy-substituted saligenin.

m bon atoms) vention involves the use of a fiuoro saligenin, most desirably 3-fluoro saligenin:

ticularly 3-fiuoro1salicylaldehyde:

i -F 41H which result when this starting material is used have'particular utility in the production of oxygen-carrying chelates (see J. Am. Chem. Soc, vol. 68, p.'.2254 ettseqJi The halosubstituents can beffiuoro, chloro, bromo,oor iodo. The alkyl substituent,:or:the alkylpart of the alkoxy substituent, canbe *primarygsecondary, or tertiary; the number of carbon atoms is limited only by prac .tical considerationswvhich:usually make it desirable that the alkyl or alkoxy radicalshave not more'than about sixteen carbon'atoms.

As has been'indicated, anialuminum derivative of a substitutedphenol is-produced by treatingthe substituted phenol with an aluminum alkoxide. :Ingeneral, the rate at which such derivatives are formed from an aluminum alkoxide .is an inverse function of the molecular weight of the alkoxy group thereof. Accordingly, it is usually desirable that the aluminum allioxide used beone in which the alkoxy radical is a lower alkoxy radical (i. e.,*has"notxmore than five car- Asisiindicated by Equations 1, 2 and 3, above, the alkoxyradical oi the aluminum :alkoxide is'converte'd to the corresponding alcoholin-theicourse .of'theiformation of the aluminum'qderivative :of the substituted phenol. "Primary and secondary: alcohols undergo oxidation zreactions simi'lar to "that undergone by a substituted phenol iin'accordance with the invention. ;-According'ly,iif the aluminum alkoxide usedis one having aiprimary'or secondary alkoxy :radical, the :alcohol produced therefrom shouldpbecompletely separated from the reaction "mixture *before the carbony1containing com- DOIIIld'I'lS added ithereto. .iBecause tertiary alcoholsdo notundergosuch an oxidation there is j'noneed'to remove tertiaryalcohols so produced from tertiaryalkoxy radicals, and the use .of aluminum :a-lkoxides comprising tertiary alkoxy 'radicalsris aipreferred embodiment of the invention. Aluminum tertiary butoxideis'the most advantageous material :for :such use because it isthe most readily: available and least expensive of those that yield tertiary. alcohols. :Ordinarily .it is?desirableithatithei'molar' ratio'of the lower aluminum alkoxide. to substituted phenol be from :aboutfiifi'? gtosabout;3.iand preferable-that it be :from about :litor. about 22.

in ':general, :any carbonyl-containing organic compound '(i.re.,:any:ketone or aldehyde) can be used to.;convert:the'aluminum derivative of a substitutedtphenol to 'the aluminum salt of the corresponding :hydroxy aldehyde. This is true Lbecause ;the :carbonyl lrgroup, is .the' part of :the tmoleculeseifective carrying llOllt ftheldesired -oxidation andgslibstituents thatzarei usual1y;pres- .ent with-rcarbonyl ;groups-do;not interfere with A particularly desirable embodiment of the in- .the :oxidation. For :exampla isuch vastly :dif-

stal

in which R is hydrogen, or an alkyl, aralkyl, alkenyl, alkynyl, aryl or allraryl radical. When R is anything other than hydrogen, the radical represented by R can be substituted with a halo or an alkoxy radical. R is alkyl, aralkyl, alkenyl, alkynyl, aryl or alkaryl. R. can be substituted with a halo or an alkoxy radical. It is usually desirable that the total number of carbon atoms in each of the radicals R and R be not more than twenty, and that there be not more than four halo substituents in either of these radicals. The halo substituent may be fiuoro, chloro, bronio or iodo. Apparently, aldehydes are less stable, under the conditions used in the practice of the invention, than are ketones; for this reason aldehydes are more active oxidizing agents for use in the practice of the invention than are ketones. Because aldehydes are more active, the dynamic equilibrium illustrated by Equation 4, above proceeds farther (i. e., converts a larger percentage of the aluminum derivative of the substituted phenol to the aluminum salt of the hydroxy aldeyhde) when an aldehyde rather than a ketone is the oxidizing agent. For this reason aldehydes are preferred carbonyl-containing compounds for use in the practice of the invention. The reaction is usually conducted under gentle reflux at atmospheric pressure, and it is desirable to use a substantial excess (e. g., from about to about 100 mols of the carbonyl-containing compound, and preferably from about to about mols thereof, per mol of the substituted phenol charged) of the carbonyl-containing compound to drive the equilibrium represented by Equation 4, above, in the desired direction. Therefore, it is usually advantageous to use a relatively high boiling carbonyl-containing compound. Accordingly, aromatic aldehydes, being high boiling compounds, and being members of the active class of carbonyl-containing compounds (i. e., aldehydes) are particularly desirable carbon-containing compounds for use in the practice of the invention. It is usually desirable that the aromatic aldehyde have from one to two benzene nuclei, any substituents attached thereto being alkyl, alkoxy, or halo radicals. It is advantageous that no alkyl or alkoxy radical have more than six carbon atoms, and that the total number of carbon atoms in the aromatic aldehyde be not more than twenty. O-chlorobenzaldehyde is an example of this preferred class of carbonyl-containing compounds.

As is indicated by Equation 4, above, an aluminum salt of the desired hydroxy aldehyde is produced by means of the reaction between the carbonyl-containing compound and the substituted phenol. This aluminum salt is convenient 1y converted to the desired ortho-hydroxy aldehyde by (a) adding an aqueous acid to the reaction mixture or (1)) adding an aqueous base 6, thereto and acidifying the salt formed. The organic material is then conveniently separated from the reaction mixture by a steam distillation or by solvent extraction. Since the desired oxidation reaction proceeds only between an aluminum derivative of a substituted phenol and a carbonyl-containing compound, the reaction is stopped by adding an aqueous acid or an aqueous base to the reaction mixture.

The following examples illustrate the new process, but are not to be construed as limiting the scope of the invention.

Example 1 An o-hydroxy aldehyde was produced from a substituted phenol according to the following procedure:

Aluminum isopropoxide (10- grams), 3-fluoro saligenin (2.84 grams) and tertiary butyl alcohol (500 cc.) were refluxed for three hours, and tertiary butyl alcohol (about 300 cc.) was then distilled, together with substantially all the isopropyl alcohol, from the resulting products. Acetone (500 grams) was added to the residue, and the mixture so produced was refluxed gently for 20 hours, cooled, and filtered. The filtrate and sodium hydroxide (200 cc. of a 25 weight per cent aqueous solution) were then added to a distilling flask. The solids filtered from the reaction mixture were treated with sulfuric acid (50 cc. of a 10 weight per cent aqueous solution); when the aluminum complex had dissolved in the acid medium, the solution was made basic by the addition of sodium hydroxide (about 20 cc. of a 25 weight per cent aqeous solution) and the resulting basic solution was combined with the filtrate and sodium hydroxide in the distilling flask. The entire mixture was heated until all alcohol, acetone, and other volatile organic matter was distilled. The residue from the distillation was then acidified with aqueous sulfuric acid and the desired products separated from the other materials by a steam distillation. A. small amount of 3-fluoro salicylaldehyde separated from the distillate of this steam distillation. The distillate was treated with toluidine (3 grams) in acetic acid (25 cc. of a 20 weight per cent aqueous solution). The Schiffs base so produced was separated by filtration and air dried. The amount of Schiffs base recovered (-0.20 gram) indicated a 4.4 per cent conversion of the 3- fiuoro saligenin to 3-fluoro salicylaldehyde.

Example 2 A procedure similar to that described in Example 1 was used'to produce 3-fluoro salicylaldehyde except that o-chloro-benzylaldehyde was used as the carbonyl containing compound. Aluminum isopropoxide (10 grams), 3-fiuoro saligenin (2.84 grams) and tertiary butyl alcohol (500 cc.) were refluxed for about sixteen hours. and volatile material was then distilled to concentrate the solution to cc. Tertiary butyl alcohol (300 cc.) and o-chlorobenzylaldehyde (300 cc.) were added to the concentrate and the resulting mixture was refluxed gently for sixteen hours, cooled, and filtered. Sulfuric acid (200 cc. of a 10 weight per cent aqueous solution) was added to the cooled mixture, and the reac-- tion mixture was then made alkaline by gradual additions of sodium hydroxide (a 50 weight per cent solution). The alkaline aqueous phase was separated from the organic phase in a separatory funnel, and the organic layer was then extracted twice more with 10 weight per cent aqueous 'cated a 47 per. cent conversion of the 3-fiuor0 saligenin to the corresponding-aldehyde.

Example-3 Aluminum :tertiary butoxide' was produced according to the following procedure:

A mixture of aluminum turnings (64 grams), mercuric chloride (0.5 gram) and tertiary butyl alcohol (200 grams) was refluxed gently. After refluxing for. one hour additional tertiary butyl alcohol (a total of 150 grams) was added at such a rate that the exothermic reaction did not overheat the mixture. Refluxing was continued for an additional sixteen hours.

An excess of the aluminum tertiary butoxide produced as described inthe preceding paragraph was mixed'with-5-chloro-3 fluoro saligenin grams) and o-chloro-benzylaldehyde (40 grams) was added. This mixture was held at a temperature between C. and C. for ten hours; the solids in the-flask were dissolved by adding 10 weight per cent aqueoussulfuric acid; this solution was then made alkaline and steam distilled; and the residue was acidified and steam distilled to-produce two gramsof crude 5-chloro-3-fiuoro salicylaldehyde.

Weclaim:

1. A method of producing an o-hydroxy aldehyde from a substituted phenol having (a) one ortho substituent of the formula CH2OH and (b) not more. than four other substituents each of whichis of the. class consisting of halo, alkyl and alkoxy, which method comprises (1) treating the substituted phenol with a lower alkoxide of aluminum to forman aluminum derivative of the. substituted phenol; (2) subjecting the aluminum derivative to the action of a carbonylcontaining organic compound to produce an aluminum salt of. the o-hydroxy aldehyde; and (3) adjusting the pH of the resulting mixture to convert the aluminum salt of the hydroxy aldehyde to the free hydroxy aldehyde.

2. A method of producing a halo-o-hydroxy saligenin (2); .subjectingthe, aluminum derivae tive to theaction-of acarbonyl-containing. organic compound to, produce. an aluminum salt of the o-hydroxy; aldehyde, and (3) adjusting the pH of the resulting mixture to convert the aluminum salt of the hydroxy aldehyde to the free hydroxy aldehyde.

3. A method-of producing a fiuoro-o-hydroxy aldehyde that comprises (1) treating a monofiuorosaligenin with tertiary-butyl aluminate to form an aluminum -derivative-*- of the fluorosaligenin, (2) subjecting the aluminum derivative to the action of an aldehyde to produce an aluminum salt of the o-hydroxy aldehyde, and (3) adjusting the. pH:ofithe1-resulting mixture. to convertthe aluminumsalt of the-hydroxy aldehyde to the free -hydroxy:aldehyde.

4...A method of producing 3-fluorosalicylaldehyde that comprises ('1) treating 3-fluorosaligenin with tertiary butyl. aluminate to form an aluminum derivative of the fluorosaligenin, (2) subjecting the aluminum derivative to the action of an aromatic aldehydeto produce an aluminum salt of the o-hydroxy aldehyde, (3) adjusting the pH of the resulting. mixture-to convert the aluminum salt of theghydroxy aldehyde to the free hydroxy aldehyde, and separating the 3-fiuorosalicylaldehyde.

References Citedzin the *file of this patent UNITED STATES PA'IENTS' Number Name Date 2,384,335 Oppenauer Sept. 4, 1945 2,576,065 Brittonet al. Novas, 19 31 OTHER REFERENCES Baker'et al.-Journ. Am. Chem. Soc, vol. 62, pages 3305 to 3314 (1940).

Davies'et al., J. Chem. Ind., vol. 62, p. 109 (1943). r

Adams, Organic Reactions, vol. II, page 181; 207, John Wiley & SonNew York (1944).

Yamashita et al., J. Chem. Soc. Japan, vol. (54, p. 506 (1943). Abstracted Chem. Abstracts, vol. 41, p. 3753 (1947).

Baker et al., Jour. Am. Chem. 800., vol. '70, pages 2594 to 2595 (1948).

Theilheimer, Synthetic Methods of Organic Chemistry, vol. 1, page 48, Interscience Publishers (1948).

Schinz'et al., Helv. Chim. Acta, vol. 31, p. 2235 (1948), vol. 6 (1951), John Wiley and Sons, New

York, p. 222-223.

Claims (1)

1. A METHOD OF PRODUCING AN O-HYDROXY ALDEHYDE FROM A SUBSTITUTED PHENOL HAVING (A) ONE ORTHO SUBSTITUENT OF THE FORMULA -CH2OH AND (B) NOT MORE THAN FOUR OTHER SUBSTITUENTS EACH OF WHICH IS OF THE CLASS CONSISTING OF HALO, ALKYL AND ALKOXY, WHICH METHOD COMPRISES (1) TREATING THE SUBSTITUTED PHENOL WITH A LOWER ALKOXIDE OF ALUMINUM TO FORM AN ALUMINUM DERIVATIVE OF THE SUBSTITUTED PHENOL; (2) SUBJECTING THE ALUMINUM DERIVATIVE TO THE ACTION OF A CARBONYLCONTAINING ORGANIC COMPOUND TO PRODUCE AN ALUMINUM SALT OF THE O-HYDROXY ALDEHYDE; AND (3) ADJUSTING THE PH OF THE RESULTING MIXTURE TO CONVERT THE ALUMINUM SALT OF THE HYDROXY ALDEHYDE TO THE FREE HYDROXY ALDEHYDE.