Chloroacetic Acids
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`GUNTER KOENIG, Hoechst Aktiengesellschaft, Augsburg, Germany
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`ELMAR LOIIMAR, Hoechst Aktiengesellschaft, Koln, Germany
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`NORBERT RUPPRICH, Bundesanstalt fiir Arbeitsschutz, Dortmund, Germany
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`MARTIN LISON, CABB GmbH, Sulzbach, Germany
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`ALEXANDER GNASS, CABB GmbH, Gersthofen, Germany
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`U LLMAN N'S 3””
`_
`é,
`3%
`%§:§i.,_«
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`1.
`2.
`2.1.
`2.2.
`2.3.
`2.3.1.
`2.3.2.
`2.4.
`2.5.
`2.6.
`2.6.1.
`2.6.2.
`2.6.3.
`2.6.4.
`3.
`3.1.
`3.2.
`3.3.
`3.4.
`3.5.
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`Introduction .
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`Chloroacetic Acid .
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`Physical Properties .
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`Chemical Properties .
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`Production .
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`Hydrolysis of Trichloroethylene .
`Chlorination of Acetic Acid .
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`Quality Specifications .
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`Uses .
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`Derivatives .
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`Sodium Chloroacetate .
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`Chloroacetyl Chloride .
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`Chloroacetic Acid Esters .
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`Chloroacetarnide .
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`Dichloroacetic Acid .
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`Physical Properties .
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`Chemical Properties .
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`Production .
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`Quality Specifications.
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`Uses .
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`3.6.
`3.6.1.
`3.6.2.
`4.
`4.1.
`4.2.
`4.3.
`4.4.
`4.5.
`4.6.
`4.6.1.
`4.6.2.
`4.6.3.
`5.
`6.
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`9.
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`Derivatives .
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`Dichloroacetyl Chloride .
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`Dichloroacetic Acid Esters .
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`Trichloroacetic Acid .
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`Physical Properties .
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`Chemical Properties .
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`Production .
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`Quality Specifications.
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`Trichloroacetyl Chloride .
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`Trichloroacetic Acid Esters .
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`Trichloroacetic Acid Salts .
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`Environmental Protection .
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`Chemical Analysis .
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`Containment Materials, Storage, and
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`Transportation .
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`Economic Aspects .
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`Toxicology and Occupational Health. .
`References .
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`1. Introduction
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`Chloroacetic acid and its sodium salt are the most
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`industrially and economically important of the
`three chlorination products of acetic acid. The
`sections on physical and chemical properties,
`production, quality specifications, uses, and de-
`rivatives are reported separately for each of these
`three acids, whereas those on environmental
`protection, chemical analysis, containment ma-
`terials, storage,
`transportation, and economic
`aspects are considered together.
`
`acid [79-11-8] (CICHZCOOH, M, 94.50, mono-
`chloroacetic acid, chloroethanoic acid) is the
`most industrially significant [1]. It does not occur
`in nature and was first discovered as a chlorina-
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`tion product of acetic acid by N. LEBLANC1I1 1841.
`It was synthesized in 1857 by R. HOFFMANN, who
`chlorinated acetic acid by using sunlight to initi-
`ate the reaction. Discovery of other reaction
`accelerators, such as phosphorus, iodine, sulfur,
`or acetic anhydride, followed rapidly. Develop-
`ment of commercial processes, based mainly on
`acetic acid chlorination and later on acid hydro-
`lysis of trichloroethylene, followed.
`
`2. Chloroacetic Acid
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`Chlorinated acetic acids have become important
`intermediates in organic synthesis because of the
`ease of substitution of the Cl atoms. Chloroacetic
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`Pure chloroacetic acid is a colorless, hygro-
`scopic, crystalline solid, which occurs
`in
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`2.1. Physical Properties
`
`Ullmann’s Fine Chemicals
`© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Boschstr. 12, 69469 Weinheim. Germany
`ISBN: 978»3—527—33477~3 / D01: 10.1002/l4356007.a06_537.pub3
`
`FINCHIMICA EXHIBIT 2025
`ADAMA MAIQ‘-ITESHIM v. FINCHIMICA
`CASE lPR2016—OO577
`
`

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`Vol. 2
`
`Form
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`b
`55–56 C
`18.63 kJ/mol
`(liquid)
`(solid)
`
`g
`50–51 C
`15.87 kJ/mol
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`d
`43.8 C
`–
`
`474
`
`Chloroacetic Acids
`
`Table 1. Common physical data of chloroacetic acid
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`Parameter
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`fp
`Latent heat of fusion, DHf
`Density
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`Refractive index
`Surface tension, s (100 C)
`Viscosity, h
`70 C
`100 C
`130 C
`Degree of dissociation in water (potentiometric) (25 C)
`Dielectric constant (100 C)
`Electrical conductivity, lowest value measured (70 C)
`Specific heat capacity, cp
`Solid, 15–45 C
`Liquid, 70 C
`Liquid, 130 C
`Heat of combustion, DHc
`Heat of evaporation, DHv
`Heat of formation, DHf (100 C):
`Heat of sublimation, DHsubl (25 C):
`Heat of solution in H2O, DHsolv (16 C)
`Solid
`Liquid
`Flash point (DIN 51 758)
`Ignition temperature (DIN 51 794)
`Lower explosion limit in air (101.3 kPa)
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`* Rises steeply if traces of water present.
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`a
`62–63 C
`19.38 kJ/mol
`d65
`4 1:3703
`d20
`201:58
`n20
`D 1:4297
`35.17 mN/m
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`2.16 mPa s
`1.32 mPa s
`1.30 mPa s
`1.52  103
`16.8
`3.1 mS/cm*
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`144.02 J mol1 K1
`180.45 J mol1 K1
`187.11 J mol1 K1
`715.9 kJ/mol
`50.09 kJ/mol
`490.1 kJ/mol
`88.1 kJ/mol
`14.0 kJ/mol
`1.12 kJ/mol
`126 C
`460 C
`8 vol%
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`monoclinically prismatic structures existing in
`the a-, b-, g-, and also possibly the d-form. The
`a-form is the most stable and the most impor-
`tant industrially.
`Published physical data vary widely [1]. Some
`of the most common values appear in Tables 1
`and 2.
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`Chloroacetic acid has excellent solubility
`in water and good solubility in methanol,
`acetone, diethyl ether, and ethanol, but is only
`sparingly soluble in hydrocarbons and chlori-
`nated hydrocarbons. Chloroacetic acid forms
`azeotropes with a number of organic com-
`pounds [2]. The freezing points of various
`binary mixtures of chloroacetic acids are
`shown in Figure 1.
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`Table 2. Vapor pressure and solubility in water of the a-form of
`chloroacetic acid
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`Vapor pressure
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`Solubility in water
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`2.2. Chemical Properties
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`Temperature,
`C
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`Pressure,
`kPa
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`Temperature,
`C
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`g/100 g
`solution
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`g/100 g
`H2O
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`189
`160
`150
`140
`130
`100
`90
`80
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`101.3
`40
`28
`19
`13
`4.3
`2.6
`1.1
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`0
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`71
`76
`80.8
`85.8
`90.8
`95
`99
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`245
`317
`421
`604
`987
`1900
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`The high reactivity of the carboxylic acid
`group and the ease of substitution of the a-Cl
`atom are directly related. As a result, chloro-
`acetic acid is a common synthetic organic
`intermediate, either as the acid itself or as an
`acid derivative (e.g., salt, ester, anhydride, acyl
`chloride, amide, hydrazide, etc.). Some impor-
`tant
`reactions that are used for
`industrial
`applications are as follows.
`
`

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`Vol. 2
`
`Chloroacetic Acids
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`475
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`[79-14-1] (hydroxyacetic acid) and diglycolic
`acid [110-99-6] (2,20-oxydiacetic acid).
`Heating the salts gives glycolide, 1,4-diox-
`ine-2,5-dione [502-97-6]. Reaction with sodi-
`um or potassium hydrogensulfide forms thio-
`glycolic acid [68-11-1] and thiodiglycolic acid
`[123-93-3].
`Reaction with ammonia gives either aminoa-
`cetic acid [56-40-6] (glycine) as the main product
`or, depending on reaction conditions, nitrilotria-
`cetic acid [139-13-9]. If methyl chloroacetate
`reacts with ammonia at low temperature, chlor-
`oacetamide [79-07-2] is obtained. By reaction
`with tertiary amines in alkaline solution various
`commercially important betaines are formed
`(e.g., N-lauryl betaine [683-10-3]).
`Aromatic compounds, such as naphthalene,
`undergo electrophilic substitution with chloroa-
`cetic acid over suitable catalysts to form aryla-
`cetic acids.
`Reaction with potassium cyanide in a neutral
`solution gives the commercially important cya-
`noacetic acid [372-09-8], which is used as an
`intermediate in the production of synthetic caf-
`feine [58-08-2]. Reaction with potassium iodide
`forms iodoacetic acid [64-69-7].
`acids,
`The
`corresponding phenoxyacetic
`some of which are of industrial importance, are
`made by phenol etherification in the presence of
`sodium hydroxide. Another industrially signifi-
`cant ether formation process gives carboxy-
`methyl derivatives with a relatively high degree
`of etherification by reacting polysaccharides,
`such as cellulose, starch, guar, etc., in a strongly
`alkaline sodium hydroxide medium.
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`2.3. Production
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`A multitude of methods have been proposed and
`patented for the production of chloroacetic acid
`[1, 3–15]. Historically both the hydrolysis of
`1,1,2-trichloroethylene [79-01-6] catalyzed with
`sulfuric acid (Eq. 1), and the catalyzed chlorina-
`tion of acetic acid with chlorine (Eq. 2) were used
`to produce chloroacetic acid on an industrial
`scale, however, only the latter (and older) process
`is now used.
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`Figure 1. Freezing points of binary mixtures
`a) Acetic acid (AA), chloroacetic acid (CAA), dichloroacetic
`acid (DCA), trichloroacetic acid (TCA); b) Crystalline phase
`CAA; c) Crystalline phase AA
`
`Reaction with inorganic bases, oxides, and
`carbonates or with organic bases gives salts;
`some salts form adducts with chloroacetic acid.
`Sodium chloroacetate [3926-62-3] is an impor-
`tant commercial product.
`Chloroacetic acid esters are obtained by reac-
`tion with alcohols or olefins; methyl chloroace-
`tate [96-34-4], ethyl chloroacetate [105-39-5],
`and tert-butyl chloroacetate [107-59-5] are also
`important industrially.
`Chloroacetyl chloride [79-04-9] is produced
`from the acid by reaction with POCl3, PCl3, PCl5,
`thionyl chloride (SOCl2), phosgene (COCl2), etc.
`(see Section 2.6.2).
`Chloroacetic acid reacts with chloroacetyl
`chloride to form bis(chloroacetic)anhydride
`[541-88-8], which can also be obtained by dehy-
`dration of chloroacetic acid with P2O5 or by
`reaction of chloroacetic acid with acetic anhy-
`dride. Chloroacetyl chloride forms mixed anhy-
`drides with other carboxylic acids, e.g., acetic
`chloroacetic anhydride [4015-58-1].
`Nucleophilic substitution of the chlorine atom
`is an important reaction when the product is used
`as an intermediate in organic syntheses. For
`example, heating neutral or basic aqueous solu-
`tions hydrolyzes the chlorine atom. This is an
`industrial method of producing glycolic acid
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`

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`476
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`Chloroacetic Acids
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`Vol. 2
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`2.3.1. Hydrolysis of Trichloroethylene
`[13–15]
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`reduces the purification process for technical
`grades [34–38].
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`Equal amounts of trichloroethylene and 75 %
`sulfuric acid are reacted at 130–140 C in a
`continuous process so that with complete tri-
`chloroethylene conversion, the resultant reac-
`tion mixture contains about 50 % chloroacetic
`acid and 1–2 % water. This blend is vacuum
`distilled to give pure chloroacetic acid. During
`this process the vapors are washed with water,
`which is returned to the sulfuric acid as a
`diluent. The resultant hydrogen chloride gas is
`washed with the fresh trichloroethylene and
`then purified by freezing and absorbing in
`water. Trichloroethylene (1500–1850 kg) and
`H2SO4 (600 kg, 95 %) gives 1000 kg of fin-
`ished product and 700–750 kg of HCl gas as
`byproduct.
`The
`trichloroethylene method produces
`highly pure chloroacetic acid free of di- or
`trichloroacetic acid. The purification procedure
`consists of separation from trichloroethylene,
`sulfuric acid, and water. Despite the purity of
`the chloroacetic acid formed, this method has
`fallen into disuse because of the high cost of
`trichloroethylene and the large amount of HCl
`produced.
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`2.3.2. Chlorination of Acetic Acid
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`Synthesis. This method converts acetic acid
`into chloroacetic acid with high selectivity [1].
`This is achieved by using suitable catalysts
`[13, 16–33]. When acetic anhydride is the catalyst,
`the reaction mechanism is as follows (Eq. 3) [22]:
`
`ð3Þ
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`Various inhibitors have also been proposed
`to suppress formation of dichloroacetic acid,
`which results from chlorination of chloroacetic
`acid in the crude mixture. This eliminates or
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`Purification. The high degree of purity
`required for many products can only be ob-
`tained by separating the di- and trichloroacetic
`acids. Fractional distillation is unsuitable be-
`cause the boiling points of the three chlorinated
`acetic acids are so close. Azeotropic distillation
`[39] and extractive distillation [40, 41] have
`been suggested for separating dichloroacetic
`acid; it is doubtful, however, that these meth-
`ods are used.
`An industrially important purification pro-
`cesses is crystallization without use of a solvent.
`It is based on the higher melting point of the
`a-modification of chloroacetic acid. The di- and
`trichloroacetic acids are removed in the mother
`liquor.
`Crystallization is carried out either in sta-
`tionary finger crystallizers [42] or in agitated
`stirrer crystallizers. With the latter, the mother
`liquor is separated from the crystal slurry after
`crystallization by using a centrifuge [43, 44].
`The product is washed with water or acetic acid
`and discharged. The chloroacetic acid is usually
`melted and converted into flakes. In stationary
`machines, crystallization is carried out by using
`cold fingers. When all the chloroacetic acid has
`crystallized, the mother liquor is drained; the
`pure crystalline product
`is then melted and
`flaked.
`Another purification method that has been
`described is a thin-layer crystallization process
`with the raw material [45]. Use of a water content
`of 5–25 % without organic solvent is also possi-
`ble [46].
`Solvents have also been used for crystalli-
`zation. Solvents, such as carbon tetrachloride
`[44, 47], dichloromethane [48], or hydrocar-
`bons with three chlorine atoms (e.g., trichloro-
`ethylene), give crystals that are easy to filter
`[49].
`Common to all of these crystallization meth-
`ods is obtaining a mother liquor consisting of
`acetic acid, chloroacetic acid, and di- and tri-
`chloroacetic acids. In the most favorable cases,
`this mixture is further chlorinated to form the
`industrially useful
`trichloroacetic acid (see
`Section 4.3).
`Meanwhile, a more important purification
`method is the catalytic hydrodechlorination of
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`

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`Vol. 2
`
`Chloroacetic Acids
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`477
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`the undesired byproducts dichloro- and trichlor-
`oacetic acid. Di- and trichloroacetic acids in the
`chlorinated crude acid can be dechlorinated by
`catalytic hydrogenation at elevated temperature
`to form chloroacetic acid or acetic acid. Palladi-
`um on a carrier, such as carbon or silica gel, is
`normally employed [50].
`When the reaction is carried out in the vapor
`phase, dichloroacetic acid is dechlorinated pri-
`marily to acetic acid [51]. However, when Pd is
`used on a finely dispersed, inert carrier in the
`liquid phase at 130–150 C, dichloroacetic acid is
`dechlorinated selectively to form chloroacetic
`acid [52]. Modifications of this procedure, such
`as spraying the crude acid with hydrogen gas
`under vacuum [53] or trickling the acid over the
`catalyst in the fixed bed [54, 55] have also been
`described.
`Selectivity is increased if HCl is mixed with
`the crude acid before it and the circulating hy-
`drogen contact the catalyst in the fixed bed [56].
`Acid chlorides and anhydrides are saponified
`before dechlorination [57]. A particularly active
`and selective catalyst is Pd on silica gel (particle
`size 40–200 mm) [58]. Especially good results
`are obtained by employing a cocatalytically ef-
`fective additive, such as sodium acetate [59]. The
`catalyst can be made more effective by enrich-
`ment of the noble metal on its surface [60, 61].
`Spent catalyst can be reactivated by treatment
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`with chlorine [62, 63]. Pd catalysts on optimized
`active charcoal carriers give lower amounts of
`over-reduction byproducts (aldehydes, etc.) [64].
`For the hydrogenation step a loop reactor can be
`used [65].
`A reduction of dichloroacetic acid from 2000
`to 210 ppm can be achieved by treatment of crude
`chloroacetic acid with nonnoble metal catalysts
`without hydrogen at temperatures between 100
`and 140 C [66].
`An industrial-scale chlorination process is
`shown in Figure 2. The mixture of acetic acid,
`acetic anhydride, and recycled acetyl chloride is
`chlorinated at 90–140 C in reactor (a) or in
`several cascade reactors. Only traces of chlorine
`are still present in the HCl gas formed. Chlor-
`oacetic acid, acetic acid, and acetic anhydride are
`condensed by using water-cooled condensers (b)
`and then returned to the reactor. Acetyl chloride
`entrained in the HCl gas is condensed (c) in a
`subsequent
`low-temperature process and re-
`cycled. The HCl gas is further purified and
`usually converted into concentrated aqueous hy-
`drochloric acid.
`The crude acetic acids can be vacuum dis-
`tilled (d) before the hydrogenation step but this
`purification step is not obligatory. Di- and
`trichloroacetic acids in the crude distilled ma-
`terial are dechlorinated (f) to chloroacetic acid
`at 120–150 C, using a palladium catalyst and a
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`Figure 2. Chloroacetic acid obtained by the chlorination–hydrogenation process
`a) Chlorinating reactor; b) Condenser for acetic acid, acetic anhydride, chloroacetic acid; c) Condenser for acetyl chloride;
`d) Evaporator; e) Condenser for chloroacetic acid; f) Hydrogenation reactor; g) Hydrogen compressor; h) Condenser;
`i) Distillation column; j) Condenser for acetic acid
`
`

`
`478
`
`Chloroacetic Acids
`
`Vol. 2
`
`large excess of hydrogen. Acetic acid is taken
`overhead from the vacuum fractionation
`column (i); the bottom product is pure chlor-
`oacetic acid. Optionally, the chloroacetic acid
`can be further purified by distillation to remove
`high-boiling
`impurities
`like
`condensation
`products of aldehydes formed in the hydro-
`genation step.
`A total of 660–780 kg of acetic acid and
`780–1020 kg of chlorine are required per
`1000 kg of pure acid, depending on the method
`used (in crystallization processes, the mother
`liquors are regarded as lost). The process also
`gives 400–420 kg of HCl.
`
`2.4. Quality Specifications
`
`Chloroacetic acid is usually marketed to the
`following specifications:
`
`. Chloroacetic acid: min. 99.0 wt %,
`. Dichloroacetic acid: max. 0.2 wt %,
`. Acetic acid: max. 0.2 wt %,
`. Water: max. 0.2 wt %,
`. Iron: max. 5 mg/kg,
`. Lead: max. 1 mg/kg.
`
`Specially purified grades of chloroacetic acid
`are marketed with max. 0.05 % or even max.
`0.03 % dichloroacetic acid. Technical grades
`contain up to 2 % dichloroacetic acid.
`
`2.5. Uses
`
`Most of the chloroacetic acid produced is used to
`manufacture several hundred thousand tons an-
`nually of carboxymethyl cellulose [9004-32-4],
`CMC (! Cellulose Ethers). Starch can be re-
`acted with chloroacetic acid to give carboxy-
`methyl starch, which is as widely used as CMC
`(! Starch). Other polysaccharides modified
`with chloroacetic acid are less important.
`Another major application is the production of
`herbicides based on arylhydroxyacetic acids (!
`Chlorophenoxyalkanoic Acids). These herbi-
`cides are some of the most widely used. Chlor-
`oacetic acid and methyl chloroacetate are also
`employed for making the insecticide dimethoate
`and the herbicides benazoline and methyl
`b-naphthyloxyacetate.
`
`A third important outlet for chloroacetic acid
`is the manufacture of thioglycolic acid (mercap-
`toacetic acid [68-11-1]), obtained from reaction
`of chloroacetic acid with sodium or potassium
`hydrogen sulfide or other sulfur compounds (!
`Mercaptoacetic Acid). It is used as its salt, ester,
`or another derivative. The largest amount is
`employed to produce stabilizers for poly(vinyl
`chloride). Moreover, thioglycolic acid and its
`esters are used in hair cosmetics (! Hair
`Preparations).
`Another important industrial application is the
`production of long-chain betaines like N-lauryl
`betaine [683-10-3] that are used as surfactants for
`cleaners or personal care products.
`A minor use of chloroacetic acid is in the
`production of glycolic acid by saponification
`with an alkali hydroxide. Glycolic acid is used
`as an auxiliary in textile printing, leather treating,
`furs finishing, as a component for cleaners and
`as a peeling agent for skin surface treatment
`(‘‘alpha-hydroxy acids’’ [67]); the butyl ester is
`employed as a paint additive (Polysolvan O),
`and glycolic acid esters acylated with o-phthalic
`acid
`half-esters
`are
`used
`as
`plasticizers
`(! Plasticizers).
`Apart from the major fields of application
`mentioned above, chloroacetic acid and its deri-
`vatives are used in a multitude of other organic
`synthetic reactions. For example, caffeine and
`barbiturates, which are important hypnotics, can
`be made from cyanoacetic acid or its esters.
`Chloroacetic acid condenses with aromatic hy-
`drocarbons to form arylacetic acids. Reaction
`with naphthalene gives 1-naphthylacetic acid as
`the main product and 2-naphthylacetic acid as the
`byproduct. Both substances promote plant
`growth. Chloroacetic acid also is important in
`the syntheses of coumarin and vitamin B6
`(! Vitamins).
`
`2.6. Derivatives
`
`2.6.1. Sodium Chloroacetate
`
`Physical, Chemical Properties. The sodium
`salt ClCH2COONa [3926-62-3], Mr 116.5, is of
`particular importance. It is colorless and slightly
`hygroscopic, and has good storage stability. It
`dissolves readily in water (44 wt % at 20 C),
`giving a neutral solution. It has limited solubility
`
`

`
`Vol. 2
`
`Chloroacetic Acids
`
`479
`
`in other polar solvents and is insoluble in nonpo-
`lar solvents. It hydrolyzes in water, depending on
`temperature and time, forming glycolic acid and
`sodium chloride.
`
`Production. This salt is manufactured by
`reacting sodium carbonate with chloroacetic
`acid in batches or in a continuous process
`[68, 69].
`In exceptional cases, localized superheating
`(about 150 C) may occur during the reaction. If
`it does, slow thermal decomposition can take
`place, producing sodium chloride and polygly-
`colide as the main products with pronounced
`evolution of gas.
`Another method of manufacturing sodium
`chloroacetate is spraying molten chloroacetic
`acid together with 50 % caustic soda solution
`into a spray drier [70].
`The production of salts of chloroacetic acids
`in fluidized beds has been described [71].
`
`Uses. The uses for sodium chloroacetate are
`virtually the same as those for its free acid. The
`amount of salt required is less and depends on
`whether the free chloroacetic acid is used as an
`80 % aqueous solution or as a melt.
`
`2.6.2. Chloroacetyl Chloride
`
`Physical Properties. Chloroacetyl chloride
`[79-04-9], ClCH2COCl, Mr 112.95, is a colorless,
`highly corrosive liquid that has a pungent odor
`and fumes when exposed to moist air; bp 105 C
`
`
`(101.3 kPa), d204 1:42; n20D 1:454.
`
`Production. Chloroacetyl chloride is usually
`manufactured from chloroacetic acid by reaction
`with phosphorus trichloride,
`thionyl chloride,
`sulfuryl chloride, or phosgene. It is also obtained
`by chlorination of acetyl chloride in the presence
`of stronger aliphatic acids, preferably chloroace-
`tic acids, or from sodium chloroacetate and the
`usual chlorinating agents.
`One patent describes the manufacture of
`chloroacetyl chloride by chlorination of a mix-
`ture of 5–50 wt % acetyl chloride in acetic anhy-
`dride at 70–100 C [72]. Another claims reaction
`of chloroacetic acid and trichloroethylene in the
`presence of iron(III) chloride and hydrochloric
`acid at 150 C and 2 MPa [72]. Chloroacetyl
`
`chloride also has been obtained in 97.1 % yield
`and with a purity of 99.8 % by reacting chlor-
`oacetic acid with phosgene in the presence of
`palladium chloride at 110 C [74]. Chlorination
`of ketene, which must be present in an excess of
`at least 50 %, at 100–200 C gives chloroacetyl
`chloride with less than 7 % dichloroacetyl chlo-
`ride [75]. Chloroacetyl chloride can also be made
`from 1,2-dichloroethylene and oxygen by using
`catalysts, such as bromine.
`
`Uses. Chloroacetyl chloride is used for
`many syntheses, e.g., to make adrenaline, chlor-
`oacetic acid esters, and the anhydride.
`
`2.6.3. Chloroacetic Acid Esters
`
`Physical Properties. The methyl
`ester
`[96-34-4], ClCH2COOCH3, Mr 108.53,
`is of
`particular importance. It is a colorless liquid with
`a pungent odor, bp 128.5–131.5 C (101.3 kPa),
`fp 32.7 C, d20 1.236, soluble in alcohol and
`ether, and only sparingly soluble in water.
`Also important is the ethyl ester [105-39-5],
`ClCH2COOCH2CH3, Mr 122.55, bp 142–144 C
`(101.3 kPa), fp 26.0 C, d20 1.159, nearly in-
`soluble in water, and readily soluble in alcohol
`and ether.
`Of minor industrial importance is the tert-
`butyl ester [107-59-5], ClCH2COOC(CH3)3, Mr
`150.60, bp 157.5 C (101.3 kPa), d20 1.4259.
`
`Production. The methyl and ethyl ester can
`be manufactured from chloroacetic acid and
`either methanol or ethanol. In another method,
`trichloroethylene is converted into ethyl 1,2-
`dichlorovinyl ether, which can be readily hydro-
`lyzed to form chloroacetic acid ethyl ester.
`The tert-butyl ester can be manufactured from
`chloroacetic acid and isobutylene under pressure
`(3–12 bar) and elevated temperature (80–110 C)
`[76].
`
`Uses. The reactivity of the ester, which is
`greater than that of the free acid, makes it
`suitable for many syntheses, e.g., sarcosine,
`chloroacetamide, thioglycolic acid ester [77]
`for pharmaceuticals (vitamin A), and crop pro-
`tection agents
`(dimethoate). Condensation
`with aldehydes and ketones gives glycide es-
`ters [78]. Other uses are the synthesis of
`
`

`
`480
`
`Chloroacetic Acids
`
`Vol. 2
`
`heterocyclic compounds, e.g., 2-phenylimino-
`4-oxooxazolidine from the ester and phenyl
`urea [79], and the well-known condensation of
`chloroacetic acid and its esters with thioureas
`to form pseudothiohydantoins.
`
`2.6.4. Chloroacetamide
`
`Physical Properties. Chloroacetamide [79-
`07-2], ClCH2CONH2, Mr 93.52, colorless crys-
`talline needles, bp 224 C (101.3 kPa), fp 121 C,
`is soluble in water and alcohol, and sparingly
`soluble in all nonpolar solvents.
`
`Production. Chloroacetamide is obtained
`on an industrial scale by reaction of methyl-
`chloroacetate with ammonia at low temperature
`[80]. Manufacture from chloroacetic acid and
`cyanamide at 150–200 C also has been de-
`scribed [81].
`
`Uses. Chloroacetamide is a versatile inter-
`mediate. In addition, it has biocidal properties
`and, therefore, is used as an industrial preserva-
`tive. Because of its good solubility in water,
`chloroacetamide is a particularly suitable biocide
`for protection of the aqueous phase, e.g., in
`drilling fluids [82], in water-containing paints
`[83], and as a wood preservative [84]. Its insec-
`ticidal action on aphids [85] and its use as a
`hardener for urea and melamine resins [86] have
`also been described.
`Various derivatives have the same biocidal
`effect as chloroacetamide. For instance, N-octa-
`decylchloroacetamide is used as an antimicrobial
`plasticizer [87].
`
`3. Dichloroacetic Acid
`
`3.1. Physical Properties
`
`Dichloroacetic acid [79-43-6], 2,2-dichloroetha-
`noic acid, Cl2CHCOOH, Mr 128.95, bp 192 C
`(101.3 kPa), 102 C (2.7 kPa),
`fp 13.5 C,
`
`
`d204 1:564; n20D 1:466, vapor pressure 0.19 kPa (at
`20 C), dissociation constant 5102 mol/L (at
`18 C), is a colorless, highly corrosive liquid that
`gives off acidic vapors, which irritate the mucous
`membranes. It is miscible with water in any
`proportion. Dichloroacetic acid is readily soluble
`
`in the usual organic solvents, such as alcohols,
`ketones,
`hydrocarbons,
`and
`chlorinated
`hydrocarbons.
`
`3.2. Chemical Properties
`
`The two chlorine atoms of dichloroacetic acid are
`susceptible to displacement. For instance, with
`aromatic compounds, diaryl acetic acids are
`formed, and with phenol, diphenoxy acetic acids
`are the products. However, dichloroacetic acid is
`less prone to hydrolysis than chloroacetic acid. In
`the manufacture of CMCs and starches, the di-
`chloroacetic acid impurity in the chloroacetic
`acid gives rise to cross-linking, which is either
`desirable or undesirable, depending on the use of
`the end product.
`
`3.3. Production
`
`The most cost-effective production method is
`the hydrolysis of dichloroacetyl chloride (see
`Section 3.6.1). Moreover, 98 % dichloroacetic
`acid can be obtained in 90 % yield by hydroly-
`sis of pentachloroethane with 88–99 % sulfuric
`acid [88] or by oxidation of 1,1-dichloroace-
`tone with nitric acid and air [89]. Extremely
`pure dichloroacetic acid can be produced by
`hydrolysis of the methyl ester [90], which is
`readily available by esterification of crude di-
`chloroacetic acid. Furthermore, dichloroacetic
`acid and ethyl dichloroacetate can be obtained
`by catalytic dechlorination of trichloroacetic
`acid or ethyl trichloroacetate with hydrogen
`over a palladium catalyst [91].
`Separation of pure dichloroacetic acid from
`the other chloroacetic acids cannot be carried out
`by physical methods, especially fractional distil-
`lation, because the differences in boiling points,
`particularly between di- and trichloroacetic acid,
`are too small. The ester mixtures, on the other
`hand, can be satisfactorily fractionated in effi-
`cient distillation columns. In addition, mixtures
`of the salts of the three chloroacetic acids can be
`washed with water, alcohol, or water–alcohol
`solutions. The dichloroacetate can be dissolved
`preferentially and acidified to give pure dichlor-
`oacetic acid.
`Dichloroacetic acid can be produced in the
`laboratory by reacting chloral hydrate and potas-
`
`

`
`Vol. 2
`
`Chloroacetic Acids
`
`481
`
`Table 3. Technical data of dichloroacetic acid marketed by CABB
`
`Content
`
`Technical grade
`
`Pharma grade
`
`Dichloroacetic acid
`Chloroacetic acid
`Trichloroacetic acid
`Water
`fp
`Chloral hydrate
`Platinum-cobalt scale
`(Hazen, APHA number)
`
`min. 98.0%
`max. 0.2%
`max. 0.9%
`max. 0.3%
`min. 12C
`
`min. 99.0%
`max. 0.2%
`max. 0.9%
`max. 0.05%
`min. 12C
`100 ppm
`max. 50
`
`sium or sodium cyanide (Eq. 4).
`Cl3CCHOþH2OþKCN!HCNþKClþCl2CHCOOH
`
`ð4Þ
`
`3.4. Quality Specifications
`
`Dichloroacetic acid is a colorless liquid that is
`marketed, for instance, by CABB. Table 3 gives
`the technical data.
`
`3.5. Uses
`
`Dichloroacetic acid is used as a test reagent for
`analytical measurements during fiber manufac-
`ture [poly(ethylene terephthalate)] and as a me-
`dicinal disinfectant (substitute for formalin).
`Dichloroacetic acid is also used as a deblock-
`ing agent in the solid-phase synthesis of oligo-
`nucleotides. For this application a dichloroacetic
`acid is required that is substantially free of chlo-
`ral (trichloroacetaldehyde) [92, 93].
`Dichloroacetic acid, particularly in the form
`of its esters, is an important intermediate in
`organic synthesis. It is a reactive starting material
`for the production of glyoxylic acid, dialkoxy and
`diaroxy acids, and sulfonamides.
`
`3.6. Derivatives
`
`3.6.1. Dichloroacetyl Chloride
`
`Physical Properties. Dichloroacetyl chlo-
`ride [79-36-7], Cl2CHCOCl, Mr 147.40, is a
`colorless liquid, which has an unpleasant odor
`and fumes when exposed to moist air; bp 106–
`108 C (101.3 kPa),
`
`
`d164 1:5315; n16D 1:4638,
`vapor pressure 3.06 kPa (at 20 C).
`
`Chemical Properties. Dichloroacetyl chlo-
`ride undergoes not only reactions typical of acid
`chlorides, but also displacement reactions of the
`chlorine atoms in the 2-position. The chemistry
`of dichloroacetyl chloride and its derivatives is
`analogous in certain respects to that of glyoxylic
`acid. Thus, dichloroacetyl chloride reacts with
`ammonia and amines to form amino acids, with
`alcohols to form ester acetals and acetals, with
`benzene to form diarylacetic acids, and with
`phenols to form diphenoxyacetic acids.
`
`Production. Dichloroacetyl chloride is pro-
`duced by the oxidation of trichloroethylene. Ox-
`idation with oxygen to form a mixture of dichlor-
`oacetyl chloride and chloral has been known
`since the early 1900s [94]. Patents published in
`the 1960s describe methods to manufacture di-
`chloroacetyl chloride of > 98 % purity, e.g., at
`65–200 C and 0.2–2 MPa in the presence of
`free-radical initiators [95], using catalytic quan-
`tities of azo compounds and amines [96], and
`initiating oxidation with UV light and only add-
`ing organic nitrogen bases in quantities of 0.005–
`0.05 % once oxidation has begun [97]. Corre-
`spondingly, chloroacetyl chloride and trichlor-
`oacetyl chloride can be produced from 1,2-di-
`and tetrachloroethylene, but these methods are of
`little industrial significance because the products
`can be obtained more easily by other processes.
`Furthermore, dichloroacetyl chloride is man-
`ufactured from pentachloroethane and fuming
`sulfuric acid or from chloroform and carbon
`dioxide in the presence of aluminum chloride at
`high pressure [98]. It has also been produced
`from ketene and chlorine in the presence of sulfur
`dioxide [99].
`
`Uses. Dichloroacetyl chloride is used to
`manufacture dichloroacetic acid (see Section
`3.3). In addition, it can be employed for the
`production of esters and anhydrides. It is use