Ullmann's Encyclopedia of Industrial Chemistry || Hydroxycarboxylic Acids, Aliphatic

� 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Article No : a13_507

Hydroxycarboxylic Acids, Aliphatic

KARLHEINZMILTENBERGER,Hoechst Aktiengesellschaft, Gersthofen, Federal Republic

of Germany

1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . 481

2. General Characteristics . . . . . . . . . . . . . . . 481

2.1. Physical Properties . . . . . . . . . . . . . . . . . . 482

2.2. Chemical Properties . . . . . . . . . . . . . . . . . 482

3. Preparation . . . . . . . . . . . . . . . . . . . . . . . . 484

4. Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . 486

5. Specific Aliphatic Hydroxycarboxylic Acids

of Commercial Significance . . . . . . . . . . . . 486

5.1. Glycolic Acid (Hydroxyacetic Acid,

2-Hydroxyethanoic Acid) . . . . . . . . . . . . . 486

5.1.1. Preparation . . . . . . . . . . . . . . . . . . . . . . . . . 487

5.1.2. Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 487

5.1.3. Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . 487

5.2. Hydroxypropionic Acids and

b-Propiolactone . . . . . . . . . . . . . . . . . . . . . 488

5.3. Hydroxybutyric Acids . . . . . . . . . . . . . . . . 488

5.4. (R,S)-Malic Acid [(R,S)-Hydroxysuccinic

Acid, (R,S)-Hydroxybutanedioic Acid] . . . 489

6. Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . 490

References . . . . . . . . . . . . . . . . . . . . . . . . . 491

1. Introduction

Hydroxycarboxylic acids are widely distributedin nature, playing an important role as metabolicintermediates in both plants and animals. Exam-ples can be found in the tricarboxylic acid cycleleading to the degradation (b-oxidation) of fattyacids, as well as in the fermentation of sugars.Hydroxycarboxylic acids are also excreted in theurine, especially in metabolic disorders. Thus,diabetics are incapable of further metabolizingthe b-hydroxybutyric acid and acetoacetic acidderived from butyric acid, so these materials aresimply eliminated.

One of the first reports of a naturally occurringhydroxycarboxylic acid occurred in 1780 whenSCHEELE described the isolation of (R)-(�)-lacticacid from soured milk. The substance is formedduring the fermentation of lactose by lactobacilli.SCHEELE also discovered S-(�)-malic acid (in1785), S-(þ)-tartaric acid (in 1769), and citricacid (in 1784) isolating each as its calcium salt.Another member of the group, glycolic acid, is aconstituent of unripe fruit, especially grapes.Related natural substances include tartronic, hy-droxystearic, mandelic (see ! Hydroxycar-boxylic Acids, Aromatic), and numerous otherfruit- or sugar-derived acids.

Definition. In contrast to the purely aromat-ic hydroxycarboxylic acids (phenolic carboxylicacids), which contain phenolic hydroxyl groupson the aromatic nucleus and thus displayenhanced acidity, aliphatic hydroxycarboxylicacids are characterized by purely aliphatic alco-hol hydroxyl groups.

Aliphatic hydroxycarboxylic acids may haveone or several hydroxyl groups, together with oneor more carboxyl groups. In the simplest case, themonohydroxymonocarboxylic acids, the com-pounds can be conveniently subdivided into threecategories:

1. 2- or a-hydroxycarboxylic acids,2. 3- or b-hydroxycarboxylic acids, and3. hydroxycarboxylic acids with the hydroxyl

group located in the 4- (i.e., g-) position, oreven more remote from the carboxyl group.

Table 1 lists several commercially importanthydroxycarboxylic acids and related compounds,grouped in accordance with the above scheme.

2. General Characteristics

The overall characteristics of a hydroxycar-boxylic acid are a function of the number of

DOI: 10.1002/14356007.a13_507

hydroxyl and carboxylic acid groups present aswell as their relative placement.

2.1. Physical Properties

Most naturally occurring hydroxycarboxylicacids are chiral and thus exhibit optical activity.In pure form, they are usually crystallizable.Hydroxycarboxylic acids have exceptionallyhigh boiling points relative to correspondingunsubstituted acids with the same chain length.This is a consequence of association among thehydroxyl groups. For this reason, many of thesecompounds cannot be distilled without decom-position, even under vacuum.

Table 2 summarizes the physical properties ofthe commercially important hydroxycarboxylicacids and their derivatives listed in Table 1.

2.2. Chemical Properties

Hydroxycarboxylic acids readily form the ex-pected salts at the carboxyl group. The acidity ofa- and b-hydroxycarboxylic acids is enhancedrelative to the corresponding unsubstituted acidsbecause of the proximity of the polar hydroxylgroup. Compounds in this category may beesterified at either the carboxyl or the hydroxylfunction by reaction with other alcohols or acids,respectively. The actual course of such reactionsdepends once again on the placement of thehydroxyl group relative to the carboxylic acidgroup.

Both a- and b-hydroxycarboxylic acids read-ily form esters with other alcohol groups but thelatter also have a tendency to eliminate waterunder the reaction conditions. The g- and d-hydroxycarboxylic acids undergo intramolecular

Table 1. Commercially important hydroxycarboxylic acids and derivatives

482 Hydroxycarboxylic Acids, Aliphatic Vol. 18

esterification to form lactones, this reaction beingfaster than intermolecular esterification. Com-pounds in which the hydroxyl group is moreremote from the acid moiety are again subjectto normal esterification.

a-Hydroxycarboxylic Acids dimerize withelimination of water to produce six-memberedcyclic diesters called 1,4-dioxane-2,5-dionesaccording to IUPAC. These are commonlyreferred to as lactides, because the phenomenonwas first encountered with lactic acid.

The process may be accompanied by intermo-lecular esterification, which produces linearpolyesters.

Note that the latter type of esterification,known as estolide formation, is not restricted toa-hydroxycarboxylic acids. Another importantcharacteristic of both a- and b-hydroxycar-boxylic acids is that the proximity of the twofunctional groups weakens the intervening C�Cbond(s). Thus, treatment of such compoundswith sulfuric acid results in the elimination offormic acid, which decomposes in the presenceof concentrated sulfuric acid to carbon monoxideand water.

The rest of the chain is converted into alde-hydes (in the case of a-hydroxycarboxylic acids)or ketones (in the case of b-hydroxycarboxylicacids) with one fewer carbon atom.

Table 2. Physical properties of the hydroxycarboxylic acids listed in Table 1

Hydroxycarboxylic acid mp, �C bp, �C Density, Refractive pK25A1

,

d204 index, n20D (25 �C)

Glycolic acid 78 – 80 100 (decomp.) 1.49 (at 25 �C) 3.81

n-Butyl glycolate 178 – 186 or 82 – 97 (at 2.7 kPa) 1.015 – 1.023 1.423 – 1.4246

(R,S)-Mandelic acid 118 – 121 1.300 3.37

(R,S)-Lactic acid 23 – 33 119 – 123 (at 1.6 – 2 kPa) 1.206 (25 �C) 1.4392 3.86

(R,S)-a-Hydroxybutyric

acid

43 – 44 138 (at 1.9 kPa) or 260 (decomp.) 1.125

Hydracrylic acid syrup decomp. 1.0474 1.4489 4.51

b-Propiolactone �33.4 51 (at 1.4 kPa) or 162 (decomp.) 1.1460 1.4135

(R,S)-Tropic acid 118 160 (decomp.)

(R,S)-b-Hydroxybutyric

acid

48 – 50 or 94 – 96 (at 0.01 kPa) or 130 1.4424 4.39

syrup (at 1.5 – 1.9 kPa)

g-Hydroxybutyric acid �17 decomp. 4.71

g-Butyrolactone �43.5 206 1.13 1.4352

(R,S)-Ricinoleic acid 5 230 – 235 (at 1.2 kPa) 0.94 (at 15 �C) 1.46393

(at 45 �C)

(R,S)-Glyceric acid syrup

Tartronic acid 156 – 158

(decomp.)

2.31

(R,S)-Malic acid 131 1.601 3.4

(R,S)-Tartaric acid 205 3.03

meso-Tartaric acid 159 – 160 3.11

Citric acid 153 1.665 3.13

Vol. 18 Hydroxycarboxylic Acids, Aliphatic 483

This elimination reaction proceeds so smooth-ly that it is used for quantitative determination ofcertain hydroxycarboxylic acids. Thus, lacticacid is converted easily to acetaldehyde, andb-hydroxybutyric acid to acetone. Oxidativecleavage is also possible. For example, treatmentof a-hydroxycarboxylic acids with hydrogenperoxide in the presence of iron(II) ions leadsto easy elimination of carbon dioxide to produceagain aldehydes containing one fewer carbonatom in the chain.

b-Hydroxycarboxylic Acids readily undergointramolecular elimination of water to producea,b-unsaturated carboxylic acids; e.g.,

Thus, b-hydroxypropionic acid (hydracrylicacid) can be dehydrated to acrylic acid, and b-hydroxybutyric acid to crotonic acid.

The g- and d-hydroxycarboxylic acids under-go dehydration even at room temperature, yield-ing g- and d-lactones. The corresponding freeacid may be regenerated in aqueous alkalinemedium, but often it is stable only in the formof its salts. Lactones are internal esters of hydro-xycarboxylic acids.

Treatment of a lactone with ammonia pro-duces the corresponding lactam.

The related derivatives of a-hydroxycar-boxylic acids, the three-membered a-lactones,are unstable and are considered only as reactionintermediates. Four-membered lactones (b-lac-tones from b-hydroxycarboxylic acids) areknown, but special methods are required to pre-pare them [1], [2]. The exceptional reactivity ofthese compounds is a consequence of their highlystrained rings. For example, they react withammonia to form amides of the correspondinghydroxycarboxylic acids, which are subject tofurther conversion to amino acids.

Because of the properties described above, thehydroxyl group of a hydroxycarboxylic acid canbe converted into various derivatives. Thus,treatment of lactic acid with hydrogen bromideresults in a-bromopropionic acid. Hydrogen io-

dide can be used to reduce a hydroxycarboxylicacid to the corresponding unsubstituted acid,which is particularly easy with acids from thesugar family.

Saccharic acid lactones are converted easily topolyhydroxyaldehydes (aldoses).

Phosphorus Pentachloride leads to replace-ment of the hydroxyl group in a hydroxycar-boxylic acid by chlorine, with the carboxyl groupsimultaneously converted into an acid chloridemoiety. Treatment with thionyl chloride resultsin an unstable sulfurous ester of the acid chloride,which will react, with an alcohol to give ahydroxyester or with ammonia to yield a hydro-xyamide. If the hydroxyl group is protected byacetylation, thionyl chloride treatment leads onlyto the corresponding acid chloride.

3. Preparation

In addition to their isolation from natural sources,hydroxycarboxylic acids can also be obtained bya number of synthetic routes. One generalapproach involves hydrolysis of a halocarboxylicacid:

X��R��COOHþOH�!HO��R��COOHþX�

This route is in most cases quite straightfor-ward for the preparation of a-hydroxycarboxylicacids (e.g., glycolic acid), but b- and g-halocar-boxylic acids lead instead to the correspondinglactones.

Certain hydroxycarboxylic acids may also beprepared by acid- or base-catalyzed hydration ofan unsaturated carboxylic acid.

For example, either maleic or fumaric acid canserve as a source of racemic tartaric acid, andacrylic acid can be converted in this way to b-hydroxypropionic acid (hydracrylic acid).

a-Hydroxycarboxylic Acids may be pre-pared by the action of zinc and an alkyl iodideon an oxalate ester. Cyanohydrin synthesis isanother synthetic route to a-hydroxycarboxylicacids, one example being the synthesis of (R,S)-


lactic acid from acetaldehyde via lactonitrile:

Another interesting preparative method in-volves diazotization as a means of deaminatingan amino acid:

a-Olefins react with liquid dinitrogen tetrox-ide at 15 – 20 �C to produce nitrate esters of a-hydroxycarboxylic acids, compounds whoseelectrochemical reactivity is described in [3].

b-Hydroxycarboxylic Acids can be preparedfrom epoxides by treatment with hydrogencya-nide, followed by hydrolysis of the intermediatenitriles:

An alternative is the Kolbe nitrile synthesisinvolving addition of hypochlorous acid to anolefin. This results initially in a chlorohydrin,which can be converted with cyanide ion to ahydroxynitrile, which is then hydrolyzed:

b-Hydroxycarboxylic acids can also be pre-pared from a-halocarboxylic acid esters by Re-formatsky reaction with an aldehyde or ketone inthe presence of activated zinc [4]. Another ap-proach utilizes b-lactones, which are readilyaccessible through ketene treatment of aldehydesor ketones [5]. Thus, acetaldehyde reacts withketene in the presence of zinc salts to give b-

butyrolactone. Finally, esters of b-ketoacids aresubject to catalytic hydrogenation, a method thatis also applicable to the synthesis of g- and d-hydroxycarboxylic acids from the correspondingg- and d-ketoesters.

For example, catalytic hydrogenation of acet-oacetic esters give the esters of (R,S)-b-hydro-xybutyric acid.

Both g- and d-hydroxycarboxylic acids can beprepared by alkaline hydrolysis of the correspond-ing halo acids. In this case, the products arenormally isolated in the form of alkali-metal salts.

Dihydroxycarboxylic Acids may be made byreaction of unsaturated fatty acids (e.g., oleicacid) with hydrogen peroxide or peracid, inwhich epoxides are formed as intermediates.Polyhydroxy acids are also commonly preparedfrom unsaturated carboxylic acids, usually bypermanganate oxidation.

Many of the methods described above lendthemselves equally well to the synthesis of poly-basic hydroxycarboxylic acids. For instance, tar-tronic acid has been prepared both by hydrolysis ofmonobromomalonic acid or by sodium amalgamreduction of mesoxalic acid (ketomalonic acid):

Another approach starts with glycerol, whichupon oxidation with potassium permanganateyields tartronic acid, whereas treatment withnitric acid yields glyceric acid.

As in this case, careful selection of oxidizingagent often enables various hydroxycarboxylicacids to be obtained by starting with the sameprecursor, a point well illustrated by the oxida-tion of sugars (aldoses and ketoses). Mild


oxidizing agents such as aqueous bromine or dilutenitric acid attack only the aldehyde functions ofaldoses (! Carbohydrates: Occurrence, Struc-tures and Chemistry), producing glyconic acids(e.g., gluconic acid from glucose). Such glyconicacids (also called ‘‘onic acids’’) are stable only inalkaline solution, where they exist as alkali-metalsalts. The free acids rapidly cyclize to g- or d-lactones, with the g-lactones preferred.

More powerful oxidizing agents such as con-centrated nitric acid result in polyhydroxy diba-sic acids (saccharic acids), which immediatelycyclize to lactones. Thus, glucose leads to glu-caric acid; mannose to mannaric acid; and galac-tose to mucic acid (galactaric acid). Even morevigorous oxidation causes cleavage of the carbonchain, yielding lower hydroxydicarboxylic acids.

Numerous branched and unbranched hydro-xycarboxylic acids may be prepared by cleavageor oxidation (with alkaline permanganate, chro-mic acid, dilute nitric acid, or concentrated nitricacid) of a variety of starting materials [6–9].Enzymatic production by fermentation is becom-ing increasingly important.

4. Analysis

The literature describes an array of color reac-tions for qualitative determination of hydroxy-

carboxylic acids. These include the yellow colorobtained in the presence of iron(II) chloride,characteristic complexation phenomena withcopper salts, and the distinctive color producedwith ammonium vanadate. Nevertheless, none ofthese reactions can be regarded as truly specific.

The most satisfactory approach to quantita-tive analysis involves acidimetric titration ofcarboxyl groups. Because of the nearly universaltendency to lactone formation in equilibriumwith the free acid, free and total acids must bedetermined separately. Thus, lactones are treatedin the same way as other esters: Hydrolysis withexcess NaOH is followed by back titration withacid. Other recommended methods for quantita-tive analysis rely on acetylation of hydroxylgroups or esterification of carboxyl groups, withsubsequent determination of the resulting water.

Instrumental methods of analysis are playingan increasingly important role, including IR,NMR and MS spectroscopy and, especially, chro-matography (e.g., thin-layer chromatography andHPLC). Nevertheless, such methods prove reli-able only if they are carefully adapted to suit thespecific problem. A typical procedure involvesmethylation or silylation, followed by identifica-tion and quantification with GC – MS [7].

5. Specific AliphaticHydroxycarboxylic Acids ofCommercial Significance

5.1. Glycolic Acid (HydroxyaceticAcid, 2-Hydroxyethanoic Acid) [10]

The chemical structure, molecular mass, andCAS registry number of glycolic acid are givenin Table 1. Its physical properties are listed inTable 2 and in the following material:

mp:

a-Modification 78 – 80 �Cb-Modification, metastable 63 �C

Heat of combustion �697.23 kJ/mol

Heat of solution in water

(infinite dilution) �11.71 kJ/mol

Dissociation constant (at 25 �C) 1.54�10�4

pH (1 M solution) 2.4

Solid glycolic acid forms colorless, monoclinic,prismatic crystals. The acid is freely soluble in


water, methanol, ethanol, acetone, and ethyl ace-tate. Glycolic acid is only slightly steam volatile andcannot be destilled under vacuum; attempts result inself-esterification with loss of water, leading to di-and polyglycolides. However, newer results showthat glycolic acid can be vaporized without decom-position. In the vapor phase it can be dehydroge-nated catalytically to glyoxylic acid [11].

5.1.1. Preparation

Glycolic acid is usually produced by hydrolysisof molten monochloroacetic acid with 50 %aqueous sodium hydroxide at 90 – 130 �C. Theresulting glycolic acid solution has a concentra-tion of ca. 60 % and contains 12 – 14 % sodiumchloride. The salt may be removed by evapora-tive concentration, followed by extraction of theacid with acetone [12]. Attempts have also beenmade to conduct the hydrolysis with acid cata-lysts at 150 – 200 �C with water or steam underpressure [13]. In this case, the byproduct ishydrogen chloride, rather than sodium chloride,which can be removed by distillation. The prin-cipal disadvantage of the method is the need forrelatively large volumes of water.

Glycolic acid is produced commercially in theUnited States (Du Pont) by treating formalde-hyde or trioxymethylene with carbon monoxideand water in the presence of acid catalysts at>30 MPa [14]. Another process, previously uti-lized by Degussa, involves electrolytic reductionof oxalic acid [15]. The compound can also beprepared in 90 % yield by hydrolysis of thecorresponding nitrile, obtained by reaction offormaldehyde with hydrocyanic acid [16].

5.1.2. Uses

Glycolic acid is available commercially as eithera 57 % (Hoechst) or a 70 % (Du Pont) aqueoussolution. Total annual consumption worldwide isca. 2000 – 3000 t of solution.

Glycolic acid is used in textile dyeing, print-ing, and creaseproofing. The fact that it can forma chelate with calcium(II) ions makes it well-suited to hide deliming in the leather industry, aswell as to inclusion in alum and chrome mordantsand in fur-processing operations. The compoundhas little tendency to cause corrosion, and this

characteristic, coupled with its bactericidal prop-erties, makes it suitable for incorporation intoacidic cleansing agents. It is especially well-adapted to cleansing operations involving milkcontainers, milk-processing equipment, anddrinking fountains, as well as rust and scaleremoval in heat exchangers and pipelines. Gly-colic acid inhibits the growth of iron-oxidizingbacteria. The use of glycolic acid eliminates theneed for simultaneous addition of chelatingagents and bactericides. The effectiveness ofglycolic acid as a complexing agent also con-tributes to its use in copper polishes, as an etchingagent for lithographic plates, and in the prepara-tion of electropolishing and galvanizing baths.

Safety Considerations. According to section1.4 of the hazardous materials regulation, GefStoff V (Federal Republic of Germany), and tothe EEC guidelines, glycolic acid solutions are‘‘corrosive.’’

Analysis. Glycolic acid may be detected qual-itatively by the violet color formed with 2,7-dihy-droxynaphthalene [17]. The preferred method ofquantitative analysis (in the absence of other acidicor hydrolyzable substances) is acidimetric titration.Because of the tendency of lactide formation freeand total acid must be determined separately.

5.1.3. Derivatives

The glycolic acid esters methyl glycolate [96-35-5], bp 147 – 149 �C, and ethyl glycolate [623-50-7], bp 158 – 159 �C, both serve as startingmaterials for the laboratory preparation of pureglycolic acid [18] and were formerly employedas solvents for resins and for nitro- or acetylcellulose. Apart from these two materials, onlycarboxymethyl cellulose [9004-32-4], (! Cel-lulose Ethers, Section 4.1. and n-butyl glycolatehave commercial significance.

n-Butyl Glycolate (see Table 1)

Physical Properties. n-Butyl glycolate is acolorless liquid, which is miscible with most or-ganic solvents. Its physical properties are summa-rized in Table 2. The solubility in water is limitedto 8 wt % (20 �C), although the compound itselfmay contain up to 25 wt % water.


Production. n-Butyl glycolate is producedby treatment of sodium chloroacetate with n-butyl alcohol at 125 – 160 �C, followed by vac-uum distillation [19].

Applications. n-Butyl glycolate is used pri-marily as a varnish additive, valued because of itslow volatility. Trade names include Polysolvan-O (Hoechst) and GB-Ester (Wacker). It conferssmooth spreading properties and high gloss onnitrocellulose varnish. For acetyl cellulose, it iseffective as a blush inhibitor under conditions ofhigh humidity. Due to its good blending proper-ties, n-butyl glycolate is also used as an additivein alkyd resins and oil-based paints.

Safety Considerations. n-Butyl glycolate isnot regarded as hazardous.

5.2. Hydroxypropionic Acids and b-Propiolactone

Of the two isomeric hydroxypropionic acids,only a-hydroxypropionic acid (! Lactic Acid)is optically active.

b-Hydroxypropionic Acid (HydracrylicAcid, 3-Hydroxypropanoic Acid) [20] (seeTable 1).

Physical Properties. The most importantphysical properties of b-hydroxypropionic acidare listed in Table 2); its dissociation constant at25 �C is 3.11�10�5. b-Hydroxypropionic acidforms a highly acidic syrup, which loses waterupon heating.

Preparation. b-Hydroxypropionic acid canbe prepared by alkaline hydration of acrylic acidor by treatment of ethylene chlorohydrin withsodium cyanide, followed by hydrolysis of theresulting b-hydroxypropionitrile. It is also readi-ly obtained by hydrolysis of the commerciallyimportant and easily accessible compound b-propiolactone.

b-Propiolactone (Oxetan-2-One) [21] (seeTable 1).

Physical Properties [1]. The physical prop-erties of b-propiolactone are summarized inTable 2 and in the following material:

Standard heat of formation �330.0 kJ/mol

Standard heat of combustion �1422.0 kJ/mol

b-Propiolactone is a colorless, highly reactiveliquid, that is soluble in water, alcohol, acetone, andchloroform (solubility in water at 25 �C, 37 vol %).

Chemical Properties. b-Propiolactone reactswith alcohols, acid chlorides, ammonia, and waterto yield b-substituted propionic acid derivatives.The most important characteristic of the sub-stance is its ability to polymerize. This highlyexothermic process occurs simply by warming,although it is also catalyzed by both acid and base.

Preparation. b-Propiolactone is synthesizedby passing equimolar amounts of ketene andformaldehyde into either acetone or b-propiolac-tone itself. The reaction is carried out at lowtemperature (<20 �C) with a yield of ca. 90 %[5]. Both aluminum chloride and zinc chloridehave been employed as catalysts, and the use ofmethyl borate has also been suggested.

Applications. As late as 1974, b-propiolac-tone was used in the United States in the prepara-tion of acrylic acid and acrylate esters [22].Today, its principal significance is as a reactiveintermediate in organic syntheses; a small amountis treated with ammonia to provide b-alanine. b-Propiolactone was also used as a disinfectant. Itappeared to be an attractive replacement forformaldehyde due to its 25-fold greater disinfect-ing power, but it has since been abandoned be-cause of its carcinogenic properties.

Safety Considerations. In the EEC hazard-ous materials guideline and in the Gef Stoff V(Federal Republic of Germany) b-propiolactoneis classed as a strong carcinogen and is consideredextremely dangerous at concentrations �1 wt %.

5.3. Hydroxybutyric Acids

Of the three structural isomers a-, b-, and g-hydroxybutyric acid, only the a- and b-acids are


optically active. Racemic mixtures of each can beseparated into optical antipodes by way of thecorresponding strychnine or brucine salts. Allthree acids are soluble in water, ethanol, diethylether, and numerous organic solvents, and de-compose readily on dry distillation. b-Hydroxy-butyric acid easily loses water to give crotonicacid, and g-hydroxybutyric acid is transformedeven at low temperature to g-butyrolactone.

(R,S-)-a-Hydroxybutyric Acid [(R,S-)-2-Hydroxybutanoic Acid] [23], (see Table 1).The physical properties of (R,S)-a-hydroxybu-tyric acid are listed in Table 2.

Preparation. (R,S)-a-Hydroxybutyric acidresults as main product from treating butyralde-hyde with alkaline sodium hypochlorite solutionor from heating a-bromobutyric acid with form-amide at 150 �C.

(R,S-)-b-Hydroxybutyric Acid [(R,S-)-3-Hydroxybutanoic Acid] [24], (see Table 1).Physical Properties.Themp of racemic b-hydro-xybutyric acid is 48 – 50 �C; it is commonlydescribed in the literature as a syrupy liquid (seeTable 2). Pure (R)-(�)-b-hydroxybutyric acid[625-72-9] is a solid with mp 49 – 50 �C.

Preparation. (R,S)-b-Hydroxybutyric acidresults from hydrolysis of b-butyrolactone,which in turn can be produced by the additionof ketene to acetaldehyde in the presence ofboron trifluoride or zinc salts [5]. The compoundis also prepared by reduction of acetoacetic acidwith sodium amalgam in alkaline solution.

g-Hydroxybutyric Acid (4-Hydroxybuta-noic Acid) [25] (see Table 1).

Physical Properties. The most importantphysical properties of g-hydroxybutyric acidare listed in Table 2. The dissociation constantat 25 �C is 1.93�10�5. At ambient tempera-ture, the acid is a liquid and consists in part oflactone.

Preparation. g-Hydroxybutyric acid isobtained from g-butyrolactone by alkaline hy-drolysis and isolated as the alkali-metal salt. g-Butyrolactone is produced by dehydrocycliza-tion of 1,4-butanediol.

Applications. Hydroxybutyric acids wereutilized in the manufacture of plasticizers, buttheir current applications are quite limited. Therelated lactones are some times used as startingmaterials or intermediates in organic synthesis.

Optically active b-hydroxybutyric acid is animportant pharmacological agent [26]. Biode-gradable poly(�(R)-(�)-b-hydroxybutyric acids(named PHB) have been used in the context ofcontrolled long-term parenteral application ofdrugs through implantation. These materials of-fer a number of advantages relative to otherimplantation polymers [e.g., poly(methacrylicacid) derivatives, poly(glycolic acid), poly(lacticacid)] [27]. Poly(b-hydroxybutyric acid) has alsobeen considered as a potential textile material.

g-Hydroxybutyric Acid has been used as ananesthetic and pain killer. It has a stabilizingeffect on blood pressure and induces a state ofunconsciousness, characteristics that have en-couraged its application especially in geriatrics[28].

5.4. (R,S)-Malic Acid [(R,S)-Hydroxysuccinic Acid, (R,S)-Hydroxybutanedioic Acid] [29], [30]

(see Table 1.)

Physical Properties (see Table 2). Malicacid is a colorless, odorless, crystalline sub-stance. It is highly soluble in water (100 g ofwater dissolves 126.3 g of malic acid at 20 �C),methanol, ethanol, acetone, ether, and other polarsolvents. Because it is a dibasic acid, it has twodissociation constants: at 20 �C, KA1 ¼ 3.9�10�4 and KA2 ¼ 1.4�10�5.

Preparation. (R,S)-Malic acid is preparedcommercially in the United States and Canada byhydration of maleic anhydride (! Maleic andFumaric Acids) [31]. The sole manufacturer inthe United States is Alberta Gas, with an annualcapacity of ca. 5000 t. In this process maleic acidis heated at ca. 180 �C (under a pressure of ca.1 MPa), malic acid is yielded as the main prod-uct. Byproducts are maleic and fumaric acids.The latter can be separated by filtration andreturned to the process stream because of its lowwater solubility.


The filtrate is then concentrated; this causesseparation of the malic acid, which is purified bymultiple washings, evaporation, and recrystalli-zation until the contents of fumaric and maleicacids are reduced to 7.5 and <500 ppm, respec-tively. Additional purification is required to pre-pare pharmacological-grade material [32], [33].

Applications. (R,S)-Malic acid closely re-sembles both citric and tartaric acids in its physi-cal and chemical properties. However, the com-pound has a more neutral flavor, so it is oftenpreferred when the flavor of citric acid is consid-ered objectionable. Examples include theimpregnation of packing material for foodstuffssuch as cheese or the acidification required dur-ing preparation of baked goods. It is widely usedin the food industry as an acidulant and, to a lesserdegree, as an acidity regulator. Relative to citricor tartaric acid, the flavor imparted by malic acidis not only more neutral but also of longer dura-tion. Thus, citric acid imparts a strongly acidictaste to the tongue almost immediately, but theeffect is brief. With malic acid, the sensation isless intense, but it lasts longer and is moreconsistent. Soft-drink manufacturers have dis-covered that this property helps mask the after-taste associated with certain nonnutritive sweet-eners and leads to a more balanced flavor profile.Moreover, synergistic effects are observed be-tween these sweeteners and malic acid, whichpermit reductions of up to 20 % in the amount ofsweetener required and 10 % in malic acid. Con-sequently, significant economic benefits may berealized. The economic picture is also influencedfavorably by the fact that malic acid is availableas an anhydrous powder.

Malic acid is used primarily as an ingredient inhard candys and other sweets, jams, jellies, andvarious canned fruits and vegetables. Most coun-tries authorize its use as an additive in foodstuffs.

(R)-(þ) -Malic acid [636-61-3] and (S)-(�)-malic acid [97-67-6] are isolated from naturalsources by resolution of (R,S)-malic acid with theaid of an optically active base. (S)-(�)-Malic acidis also available through microbiological fer-mentation of fumaric acid [33]. The levorotatoryS-enantiomer is widely distributed in fruit and

displays the following characteristics that differfrom those of the racemate: mp, 100 �C; d204 ,1.595; a18

D , �2.3� (7 wt % in H2O). The com-pound is soluble to the extent of 36.4 g in 100 gof water at 20 �C.

6. Toxicology

As previously noted, most important aliphatichydroxycarboxylic acids occur as natural pro-ducts. Because they serve as intermediates inplant and animal metabolic pathways, they donot exhibit many exceptionally toxic properties.Thus, only a few compounds listed in Table 1 areincluded in the Register of Toxic Effects ofChemical Substances prepared by NIOSH [35].Certain hydroxycarboxylic acids (e.g., lactic,malic, tartaric, and citric) are even accepted asfood additives or preservatives in most countries.

The following toxicity data for citric acid aretaken from the NIOSH list [35, p. 945]:

LD50 (oral, rat) 11 700 mg/kg

LD50 (oral, mouse) 5 040 mg/kg

LD50 (oral, rabbit) 7 000 mg/kg

Glycolic Acid was also permitted as a foodpreservative but later came to be consideredsuspect [36]. Today, it is described as moderatelytoxic, with the following data [35, p. 386],

LD50 (oral, rat) 950 mg/kg

LD50 (oral, guinea pig) 920 mg/kg

A derivative of glycolic acid n-butyl glycolateis described as displaying narcotic properties. Itis also an irritant to both skin and mucous mem-branes. Nevertheless, it is markedly less toxicthan glycolic acid, having an LD50 (oral, rat) of4595 mg/kg.

The lowest reported lethal dose for b-hydro-xypropionic acid (hydracrylic acid) derives fromintravenous injection into rats: LD50 (i.v., rat) ¼50 mg/kg [35, p. 447].

A derivative of b-hydroxypropionic acid b-propiolactone is of considerable interest becauseof its viricidal and bactericidal properties, andwas used medically in sterilization and disinfec-tion. Nevertheless, it has since been found to be a


mutagen [37]. Animal studies have providedincontrovertible evidence that the compound dis-plays carcinogenic properties irrespective ofwhether it is delivered orally, topically on theskin, or by intravenous, intraperitoneal, or sub-cutaneous injection [38], [35, p. 1326]. b-Pro-piolactone is a powerful irritant to the skin andeyes. The following toxicity data have beenreported:

LC50 (inhalation, rat) 25 ppm, 6 h

LD50 (i.v., mouse) 345 mg/kg

Because of its cytotoxic properties, b-propio-lactone has been added to Category A 2 of theofficial list of carcinogenic materials [39].

By contrast, g-butyrolactone is completelyfree of these cytotoxic characteristics. Despitenumerous animal studies, no evidence has beenobtained to suggest carcinogenicity. Nonethe-less, the compound is moderately toxic, havingan LD50 (oral, rat) of 1800 mg/kg [35, p. 946].The narcotic effects observed when g-butyrolac-tone is administered orally or intraperitoneallyhave been ascribed to g-hydroxybutyric acid,from which it is derived.

From animal studies, the sodium salt of g-hydroxybutyric acid is known to possess narcoticproperties [40]. A dose of ca. 40 mg/kg leads tonearly natural sleep in humans, with essentiallyno side effects.

References

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Further Reading

W. Aehle (ed.): Enzymes in Industry, 3rd ed., Wiley-VCH,

Weinheim 2007.

G. T. Blair, J. J. DeFraties: Hydroxy Dicarboxylic Acids,

‘‘Kirk Othmer Encyclopedia of Chemical Technology’’,

5th edition, John Wiley & Sons, Hoboken, NJ, online DOI:

10.1002/0471238961.0825041802120109.a01.

R. Datta: Hydroxycarboxylic Acids, ‘‘Kirk Othmer Encyclo-

pedia of Chemical Technology’’, 5th edition, John Wiley

& Sons, Hoboken, NJ, online DOI: 10.1002/

0471238961.0825041804012020.a01.pub2.

W.-D. Fessner, T. Anthonsen (eds.): Modern Biocatalysis,

Wiley-VCH, Weinheim 2009.


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Ullmann's Encyclopedia of Industrial Chemistry || Hydroxycarboxylic Acids, Aliphatic