WO2009153374A1

WO2009153374A1 - Method for the preparation of hydroxytyrosol and 3-(3,4-dihidroxiphenyl)propanol from methylenedioxybenzenes

Info

Publication number: WO2009153374A1
Application number: PCT/ES2009/000341
Authority: WO
Inventors: Enrique ALVAREZ DE MANZANEDA ROLDÁN; Rachid Chahboun; Alí HAIDOOUR BENAMIN
Original assignee: Universidad De Granada
Priority date: 2008-06-20
Filing date: 2009-06-19
Publication date: 2009-12-23
Also published as: ES2332635A1; ES2332635B2

Abstract

The invention relates to a method for obtaining a compound having formula (II), in which a methylenedioxybenzene compound having general formula (I) is treated with an alkaline or alkaline earth salt of a glycol in an aprotic polar solvent, wherein substituent R represents a group selected from among: a linear or branched C₁-C₄alkyl, alkenyl or alkynyl group,optionally substituted at at least one C with at least one group selected from among -OH, -CO-, -NH₂, -COOH and -COOR', and wherein R' is a linear or branched C₁-C₄alkyl group. The compounds having formula (I) are advantageously obtained from safrole or piperonal.

Description

PROCEDURE FOR THE PREPARATION OF HYDROXYTIROSOL AND 3-

(3, 4-DIHYDROXIFENIDPROPANOL FROM

METHODENDIOXIBENCENS

FIELD OF THE INVENTION The present invention falls within the field of organic synthesis, in particular, of compounds with phenolic structure characterized by having a wide range of biological activities. Specifically, it refers to a new method of synthesis of compounds derived from catechol, such as hydroxytyrosol and 3- (3,4-dihydroxyphenyl) propanol, and other related, from natural precursor compounds.

BACKGROUND OF THE INVENTION For some years, organic compounds with antioxidant activity have been the subject of great interest, both in the pharmaceutical industry and in the food industry.

Numerous studies relate various inflammatory and cardiovascular diseases, and other processes, such as cancer and even aging, with free radicals and certain species with active oxygen [KB Beckman, et al., 1998, Physiol. Rev., 78, 447; B. Halliwel, et al., In Free radicáis in biology and medicine, ed. Oxford, Clarendon Press, 1989, pages 416-494]; for this reason, new therapeutic approaches based on the use of antioxidants as drugs are being investigated [G. Block, 1992, Nutrition Rev., 50, 207; AC Rice-Evans, et al., 1996, Free Radical Biol. Chem., 20,933]. On the other hand, the oxidation of food is one of the main causes of its deterioration, especially in those that have a high fat content. Antioxidants have been added to food for years to prevent this process, and these are widely used today for preservation.

Therefore, in recent years there has been a great interest in developing new antioxidants with great reducing capacity and minimal toxicity, for use in the prevention of certain diseases or in a better preservation of food.

Among the natural antioxidants, those that possess phenolic structure and, in particular, those derived from catechol, deserve to be highlighted. An important example is caffeic acid (1) and its derivatives, of which antiviral, anti-inflammatory and anti-arteriosclerosis properties have been described [M. Nardini, et al., 1995, Free Radical Biol. Med., 19, 541]. The phenolic derivatives present in olive oil deserve special mention, to which the beneficial effects of this food for health are largely attributed. Among them, 2- (3, 4-dihydroxyphenyl) ethanol (hydroxytyrosol) (2) stands out, which inhibits the oxidation of human low density lipoprotein (LDL), a critical stage in arteriosclerosis [F. Visioli, et al., 1995, Atherosclerosis, 117, 25]; this phenol also inhibits platelet aggregation [A. Petroni, et al., 1995, Thrombosis Res., 78, 151] and possesses anti-inflammatory properties [R. de la Puerta, et al., 1999, Biochem. Pharm , 57, 445] and antitumor [RW Owen, et al., 2000, Eur. J. Cancer, 36, 1235].

Another related antioxidant compound is 3- (3,4-dihydroxyphene.il) propanol (3), isolated from the aerial parts of Onopordon corymbosum [L. Cardona, et al. 2007, Food Chem., 103, 55].

There are numerous methods for obtaining this type of antioxidant compounds. In this sense, hydroxytyrosol (2) has been obtained by extraction methods of olive leaves [R. Capasso, et al., 1996, Appl. Biochem Biotechnol , 60, 365] or some by-products of the olive oil industry [R. Capasso, et al., 1994, Agrochimica, 38, 165: F. Visioli, et al., 1995, Experíentia, 51, 32]. Likewise, it has been obtained by various synthetic procedures: (i) through a laborious synthetic process from 3,4-dimethoxybenzaldehyde (veratraldehyde) (4) [R. Verhe, et al., 1992, BuIl. Liason Groupe Polyphenols, 15, 237] or (ii) by reduction of the expensive 3, 4-dihydroxyphenylacetic acid (5) with lithium aluminum hydride [R. Capasso, et al., 1999, J. Agrie. Food Chem., 47, 1745]. As for the homologue 3- (3, 4-dihydroxyphenyl) propanol (3), much less abundant in its natural sources, it has been synthesized by reduction with lithium aluminum hydride of commercially priced 3- (3,4-dihydroxyphenyl) propanoic acid (6) [A. Torres de Pinedo, et al., 2007, Food Chem., 103, 55].

However, despite the great interest of this type of compounds, to date there are no methods of obtaining interest at industrial and commercial level, since, as has just been exposed, most of the procedures known in the state of the technique involve extraction processes from their natural, very laborious and expensive sources that provide low yields, and the few synthetic processes described in the prior art are long or use very expensive starting products, so they are not of interest for its industrial scale.

Therefore, there is still a need in the state of the art to provide alternative synthesis methods, which at least partially overcome the disadvantages of the aforementioned procedures.

In this sense, the inventors of the present invention have discovered that it is possible to obtain this type of diphenols derived from catechol from precursors that have a methylenedioxybenzene fragment in their structure. These precursors, which are described below, are easily obtainable from very abundant natural substances in their natural and very cheap sources. The process for obtaining the present invention is simple, short and economical.

DESCRIPTION OF THE INVENTION

The present invention therefore relates to a new procedure for the preparation of diphenols derived from catechol from very abundant natural substances from their own sources, which are previously transformed into the corresponding methylenedioxybenzene precursors. The rupture of the methylenedioxy group results in the corresponding diphenol derived from catechol.

The process, hereinafter the process of the invention, comprises the transformation of a methylenedioxybenzene compound of the general formula (I) into the corresponding compound of the general formula (II) according to the following scheme:

(I) (H)

and where R represents in principle a substituent of a variable chemical nature that is not chemically transformed at this reaction stage, and which can be easily recognized by one skilled in the art. Preferably said R is a substituent whose chemical nature is conditioned by the chemical nature of the substituent R present in safrole (7) and piperonal (13), as evidenced herein, since these are advantageous compounds for obtaining the compounds of general formula (I).

In a particular embodiment R represents a group selected from: an alkyl group, an alkenyl group and an alkynyl group of 1 to 4 C atoms, linear or branched, optionally substituted in at least one of the C, with at least one group selected from: -OH, -CO-, -NH ₂ , -COOH and -COOR ', and where R' is a C _x - alkyl group C ₄ linear or branched.

In a preferred embodiment, the substituent R represents a group selected from: -CH ₂ CH ₂ CH ₃ , -CH = CHCH ₃ , CH ₂ OH, -CH ₂ CH ₂ OH, -CH ₂ CH ₂ CH ₂ OH, - CH (OH) CH ₂ CH ₃ , -CH ₂ CH (OH) CH ₃ , -CH = CHCH ₂ OH, -COOH, -CH ₂ COOH, -CH ₂ CH ₂ COOH and -CH = CHCOOH, and more preferably, is selected from: -CH ₂ OH, -CH ₂ CH ₂ OH, - CH ₂ CH ₂ CH ₂ OH, -CH = CHCH ₂ OH, -CH ₂ CH ₂ COOH and -CH = CHCOOH.

The starting compound of the general formula (I) is transformed into the compound of the general formula (II) by treatment with an alkaline or alkaline earth salt of a glycol. In a particular embodiment the glycol has the general formula III,

Hl

where each R ₁ independently represents a substituent that can be chosen from the group consisting of hydrogen, an alkyl group of 1 to 4 carbon atoms, linear or branched and an aryl group. In another particular embodiment the glycol is ethylene glycol.

The reaction takes place within a heated aprotic polar solvent, typically between

150 ⁰ C and 200 ° C. Preferably the solvent is a mixture of hexamethylphosphoramide (HMPA) and at least one polyether. Suitable examples of polyether type solvents are, among others, diethylene glycol dimethyl ether and triethylene glycol dimethyl ether. Upon completion of the reaction, the reaction mixture is subjected to distillation, to remove the solvent. Water is added to the residue and it is brought to acidic pH by the addition of a protonic acid, such as acetic acid, p-toluenesulfonic acid, sulfuric acid, phosphoric acid or hydrochloric acid, among others, and extracted with an organic solvent, such as diethyl ether, tert-butyl methyl ether, ethyl acetate or butanone, among others. The combined organic phases are washed with water and dried, providing the compound of general formula (II) after evaporation in vacuo.

In a particular embodiment an alkaline salt is used, which is selected from the disodium, dipotassium, and dilithic salt of ethylene glycol. In another particular embodiment the alkaline earth salt of ethylene glycol is magnesium. The salt can be prepared by adding the selected metal, its hydride, or any of its alkoxides, such as tert-butoxide, on a solution of the glycol in the polyether-hexamethylphosphoramide (HMPA) mixture, and heating at reflux of this during a period typically between 1-6 hours. The starting compound of formula (I) is added to this solution, and heating and stirring are maintained for a period, which typically ranges from 10-15 hours.

The starting compounds of formula (I) can be obtained commercially or easily synthesized by conventional reactions known to a person skilled in the art. Advantageously they are obtained from natural compounds, such as from safrole (7) and piperonal (13) abundant in its sources and economic. The structure of these compounds partly determines, together with the type of reaction or chemical reactions to which they are subjected, the nature of the substituent R in the starting compound of the general formula (I).

The chemical transformations to which safrole or piperonal are subjected to give the starting compounds of general formula (I), are conventional reactions known to a person skilled in the art and well documented in the literature. In this sense, the person skilled in the art can easily determine whether part of safrole or piperonal, to obtain, according to what case, the compounds of formula (I) in a simple manner.

In a particular embodiment of the process of the invention 2- (3, 4-dihydroxyphenyl) ethanol (hydroxytyrosol) (2) is obtained from the corresponding starting compound 10. This starting compound is obtained from safrole (7). The safrole is subjected to oxidative degradation of the double bond according to any conventional method known to an expert, such as: (i) by ozonolysis, followed by oxidative treatment to obtain acid 9, or reducer to give aldehyde 8; (ii) treatment with osmium or ruthenium tetroxide and sodium metaperiodate; or (iii) using a conventional oxidant, derived from chromium (VI) or manganese (VII), such as chromium trioxide or dichromate or permanganate salts to give the aldehyde of formula 8, or the acid of formula 9. Next compound 8 or 9 is reduced by any conventional method, such as (i) catalytic hydrogenation or treatment with hydride donor reagents, such as boron derivatives or aluminum, such as sodium borohydride or lithium aluminum hydride and its derivatives to give the starting compound 10. Optionally, the alcohol 10 can be obtained directly by means of safrole reductive ozonolysis (7).

8 R: CHO 12

9 R: COOH

10 R: CH ₂ OH

11 R: CH ₂ CH ₂ OH

In another particular embodiment of the process of the invention, 3- (3, 4-dihydroxyphenyl) propanol (3) is obtained from the starting compound 11, which is obtained from the natural safrole compound (7) by: (i) hydroboration and (ii) double bond oxidation, reactions that are carried out in a conventional manner and known to a person skilled in the art.

According to another particular embodiment of the process of the invention, 3,4-dihydroxybenzyl alcohol (15) is obtained by breaking the methylenedioxy group of 3,4-methylenedioxybenzyl alcohol (14). This alcohol is obtained in a conventional manner by reducing the aldehyde group of piperonal (13), by any conventional method, as already mentioned for aldehyde 10.

13 RrCHO

In another particular embodiment of the process of the invention, caffeic acid (1) is obtained by breaking the methylenedioxy group of the corresponding starting compound 12. This is in turn obtained from piperonal (13), by conventional reaction with malonic acid, or its derivatives, or with acetic anhydride and sodium acetate with heating.

13 R: CHO 12 R: CH = CHCOOH

(I)

In another particular embodiment from piperonal (13), compound 12 is obtained, which is hydrogenated by a conventional method. Next, the breakdown of the methylenedioxy group gives compound 6.

Therefore the process of the present invention allows in a simple and economical way to obtain compounds of interest for their antioxidant and / or anti-inflammatory properties, etc., which are useful in numerous fields of application such as food, pharmacy and Cosmetic

In another aspect the invention relates to the use of safrole (7) or piperonal (13) in obtaining the methylenedioxybenzene compound of the general formula (I) where R has the meaning defined above. Therefore, the invention also relates to a process for obtaining compounds of general formula (II) from safrole or piperonal. Due to the abundance of both, the process of the invention is interesting for its industrial scale.

In a particular embodiment, safrole is used in the preparation of a compound of formula (I) where R is selected from: -CH ₂ OH, -CHO, -COOH, -CH ₂ CH ₂ OH, - CH ₂ CHO, - CH ₂ COOH, -CH ₂ CH ₂ CH ₂ OH, -CH ₂ CH ₂ CHO and -CH ₂ CH ₂ COOH

In another particular embodiment the piperonal is used in the preparation of an intermediate compound of formula (I) where R is selected from: -CH ₂ OH, -CHO, -COOH, - CH ₂ CH ₂ OH, -CH ₂ CHO, -CH ₂ COOH, -CH ₂ CH ₂ CH ₂ OH, -CH ₂ CH ₂ CHO, CH ₂ CH ₂ COOH and CH = CHCOOH.

The following are illustrative examples of the invention, which are set forth for a better understanding of the invention, and which in no case should be considered a limitation on the scope thereof.

EXAMPLES

Example 1. Preparation of 4- (2-Hydroxyethyl) benzene-2-diol (hydroxytyrosol) (2) and 2- (3,4-dihydroxyphenyl) acetic acid (5).

1.1 Ozonolysis of safrole (7): Through a solution of safrole (7) (400 mg, 2.46 mmol) in CH ₂ Cl ₂ (15 ml), cooled to -78 ° C, an ozone stream was passed for 2 hours. After this time, argon was bubbled for a couple of minutes. A solution of ozonides in methylene chloride was obtained.

1.2. Preparation of 2- (benzo [d] [1/3] dioxol-5- yl) acetic acid (9):

The solution obtained in 1.1 was evaporated in vacuo and 3.5 ml of 97% formic acid and 1.7 ml of 30% hydrogen peroxide were added to the residue, the mixture being kept 12 hours at -78 ° C. After this time, the mixture was heated at reflux for 2 hours. It was allowed to cool to room temperature, diluted with water (15 ml) and extracted with ethyl ether (3 x 20 ml). The combined organic extracts, once dried with anhydrous sodium sulfate, evaporated in vacuo to provide 401 mg (91%) of acid 9. The spectroscopic properties of this substance are identical to those described in the literature (N. Cabedo et al., 2001, J ^" . Med. Chem., 44, 1794).

1.3. Preparation of 2- (Benzo [d] [1,3] dioxol-5- il) acetaldehyde (8):

About the solution obtained in 1.1, and cooled to -78 ⁰ C, Ph ₃ P (450 mg) was added and allowed to raise the temperature while stirring for 14 hours. After this time the solvent was evaporated in vacuo, obtaining 347 mg (87%) of aldehyde 8.

1.4. Preparation of 2- (Benzo [d] [1, 3] dioxol-5-yl) ethanol (10)

The resulting ozonolysis solution of 400 mg (2.46 mmol) of safrole (7) obtained in 1.1 was evaporated in vacuo and ethanol (15 ml) and sodium borohydride (378 mg, 10 mmol) were added on the residue. The mixture was stirred at room temperature for 12 hours. The io

20 ml of water were added to the solvent and the residue was added, then extracted with ethyl ether (3 x 15 ml). After gathering the organic extracts and drying them over anhydrous sodium sulfate, the solvent was evaporated, obtaining 376 mg (92%) of alcohol 10. This compound has properties consistent with those described in the literature (B. Elger et al., 2005, J ^" . Med. Chem., 48, 4618).

1.5. Preparation of 4- (2-Hydroxyethyl) benzene-l _/ 2-diol (hydroxytyrosol) (2):

It was split from 1.2 ml (21.8 mmol) of ethylene glycol, 840 mg (36.75 mmol) of finely chopped metal sodium and 6 ml of diethylene glycol dimethyl ether; The reaction mixture was heated to reflux, until dissolution of the metal, and 9 ml of hexamethylphosphoramide (HMPA) and 407 mg were added.

(2.45 mmol) of methylenedioxy derivative 10. The reaction was maintained at 170 ° C for 12 hours, and the reaction mixture was distilled in vacuo and the residue was diluted with water (30 ml) and brought to acidic pH with 2N hydrochloric acid . It was extracted with tert-butyl methyl ether (3 x 20 mL) and the combined organic phases were washed with water (3 x 30 mL), dried over anhydrous sodium sulfate and evaporated in vacuo, yielding 340 mg (89%) of hydroxytyrosol (2). This compound had identical properties to those described in the literature (R. Capasso et al., 1999, J. Agrie. Food Chem., 47, 1745).

1.6. Preparation of 2- (3,4-dihydroxyphenyl) acetic acid (5): The preparation was carried out in the same way as 1.5, starting from 562 mg (3.12 mmol) of methylenedioxy derivative 9, 1.6 ml (27.8 mmol) of ethylene glycol , 1.07 g (44.6 mmol) of sodium hydride and 7 ml of diethylene glycol dimethyl ether and 11 ml of hexamethylphosphoramide (HMPA). After refluxing for 3 hours, the metilendioxiderivado 9 was added, and the reaction at 175 ⁰ C was maintained for 15 hours to give 490 mg (95%) of 5. The obtained compound showed identical properties to those described in the literature (JC Vallejos et al., 1997, BuIl. Soc. CMm. Fr., 134, 101).

Example 2. Preparation of 3- (3,4-dihydroxyphenyl) propanol (3);

2.1 Preparation of 3- (Benzo [d] [I ₁ 3] dioxol-5-yl) propan-l-ol (11)

550 mg of safrole (7) (3.39 mmol) was dissolved in 15 ml of THF under an argon atmosphere and cooled to 0 ⁰ C. 7.3 ml of B ₂ H ₆ (4.11 mmol) was added, and left stirring at room temperature for 1 hour. It was then cooled again to ⁰ ° C, 12 ml of ethanol and then 6 ml of 30% hydrogen peroxide and 10 ml of a 3M solution of sodium hydroxide were added. It was kept under stirring at room temperature for 6 hours. Tetrahydrofuran was evaporated, diluted in 30 ml of ether and the aqueous phase washed with water (3 x 15 ml), and brine (3 x 15 ml). After drying with anhydrous sodium sulfate and evaporating the solvent in vacuo, 568 mg (93%) of alcohol 11 were obtained. The spectroscopic properties of this compound were identical to those described in the literature (A. Fauvel et al., 2005, Eur J. Org. Chem.,

3900).

2.2. Preparation of 3- (3,4-dihydroxyphenyl) propanol (3)

The production was carried out in the same way as in 1.5, starting at 550 mg (3.05 mmol) of methylenedioxy derivative 11, 1.5 ml (26.7 mmol) of ethylene glycol, 5.04 g (45.0 mmol) of potassium tert-butoxide and 8 ml of diethylene glycol dimethyl ether and 12 ml of hexamethylphosphoramide (HMPA). After heating to refluxing for 6 hours, methylenedioxy derivative 11 was added and heated at 165 ⁰ C for 15 hours, obtaining 470 mg (91%) of alcohol 3. This compound showed identical properties to those described in the literature (L. Cardona et al. , 1990, Phytochemistry, 29, 629).

Example 3. Preparation of 4- (Hydroxymethyl) benzene-1,2-diol

(fifteen);

3.1 Obtaining (Benzo [d] [1,3] dioxol-5-yl) methanol (14): 378 mg (10 mmol) of sodium borohydride was added over a solution of piperonal (13) (350 mg, 2.33 mmol) in ethanol (12 ml) and the mixture was kept under stirring at room temperature for 8 hours. The solvent was evaporated and 15 ml of water was added to the residue, then extracted with ethyl ether (3 x 15 ml). After gathering the organic extracts and drying over anhydrous sodium sulfate, the solvent was evaporated, obtaining 319 mg (90%) of alcohol 14. The spectroscopic properties of this compound coincide with those described in the literature (S. Relay et al., 2002 , Synth. Coma., 32,3533).

3.2. Obtaining 4- (Hydroxymethyl) benzene-1,2-diol (15):

Obtaining was carried out in the same way as 1.5, starting from 440 mg (2.89 mmol) of methylenedioxy derivative 14, using 1.4 ml (25.7 mmol) of ethylene glycol, 1.0 g

(43.3 mmol) of metallic sodium and 21 ml of diethylene glycol dimethyl ether. The temperature was maintained at 165 ⁰ C for 12 hours, and 390 mg (96%) of alcohol 15. This compound obtained has identical properties to those of a solution prepared by reduction of 3 shows, 4-dihydroxybenzaldehyde with sodium borohydride.

Example 4. Preparation of acid (E) -3- (3,4- Ib

dihydroxyphenyl) acrylic (1)

Obtaining was carried out in the same way as 1.5, starting with 470 mg (2.44 mmol) of methylenedioxy derivative 12, using 1.2 ml (21.7 mmol) of ethylene glycol, 840 mg (36.6 mmol) of metallic sodium and 18 ml of diethylene glycol dimethyl ether at reflux. It was heated at 180 ° C for 15 hours, and 410 mg (87%) of acid 1 was obtained. The compound obtained has the same properties as a commercial sample of caffeic acid (Sigma-Aldrich Chemical Co.)

Claims

1. Process for obtaining a compound of general formula (II) comprising treating a methylenedioxybenzene compound of general formula (I)

where the substituent R represents a group selected from:

an alkyl group, an alkenyl group and an alkynyl group of 1 to 4 C atoms, linear or branched, optionally substituted in at least one of the C, with at least one group selected from: -OH, -CO-, - NH ₂ , -COOH and -COOR ', and where R' is a linear or branched C _x- C ₄ alkyl group

with an alkaline or alkaline earth salt of a glycol in a heated aprotic polar solvent.

2. The method according to claim 1, wherein the substituent R represents a group selected from: -CH ₂ CH ₂ CH ₃ , -CH = CHCH ₃ , -CH ₂ OH, -CH ₂ CH ₂ OH, -CH ₂ CH ₂ CH ₂ OH, - CH (OH) CH ₂ CH ₃ , -CH ₂ CH (OH) CH ₃ , -CH = CHCH ₂ OH, -COOH, -CH ₂ COOH, - CH ₂ CH ₂ COOH and -CH = CHCOOH .

3. The method according to claim 2, wherein the substituent R represents a group selected from: -CH ₂ OH, -CH ₂ CH ₂ OH, -CH ₂ CH ₂ CH ₂ OH, -CH = CHCH ₂ OH, -CH ₂ CH ₂ COOH and - CH = CHCOOH.

4. Method according to claim 1 wherein the glycol has the following general formula

II! where each Ri independently represents a substituent that can be chosen from the group consisting of hydrogen, an alkyl group of 1 to 4 carbon atoms, linear or branched and an aryl group.

5. Method according to claim 4, wherein the glycol is ethylene glycol.

6. A method according to one of claims 1 or 5, wherein an ethylene glycol salt is used which is selected from the disodium, dipotassium, dilithic and magnesium salt.

7. The method of claim 1, wherein the aprotic polar solvent is a mixture of hexamethylphosphoramide and at least one polyether.

8. A process according to claim 1, wherein the polyether solvent is selected from diethylene glycol dimethyl ether and triethylene glycol dimethyl ether.

9. Method according to any of claims 1 to 8, which comprises the use of safrole or piperonal in the obtaining the methylenedioxybenzene compound of the general formula (I) wherein R has the meaning defined in any one of claims 1 to 3.

10. Use of safrole in the preparation of the compound of formula (I) where R is selected from:

-CH ₂ OH, -CHO, -COOH, -CH ₂ CH ₂ OH, -CH ₂ CHO, -CH ₂ COOH,

-CH ₂ CH ₂ CH ₂ OH, -CH ₂ CH ₂ CHO and -CH ₂ CH ₂ COOH

11. Use of piperonal in the preparation of the intermediate compound of formula (I) where R is selected from:

-CH ₂ OH, -CHO, -COOH, -CH ₂ CH ₂ OH, -CH ₂ CHO, -CH ₂ COOH,

-CH ₂ CH ₂ CH ₂ OH, -CH ₂ CH ₂ CHO, -CH ₂ CH ₂ COOH and CH = CHCOOH.