Hydrochloric Acid1

ClH

[7647-01-0]  · ClH  · Hydrochloric Acid  · (MW 36.46)

(strong Brønsted acid used for general acid catalysis; preparation of salts of amines; preparation of alkyl, allyl, aryl, benzyl, and vinyl chlorides; protodemetalation reagent; in combination with hydrogen peroxide is an in situ source of chlorine for the preparation of alkyl and aryl chlorides)

Physical Data: aqueous solution: freezing point of ca. 31% solution -46 °C; forms constant boiling azeotrope containing 20.22% HCl with water (bp 108.58 °C/760 mmHg; d 1.096 g cm-3). Anhydrous gas: d 1.639 g L-1; mp -114.22 °C; bp -85.05 °C/760 mmHg.

Solubility: very sol water, protic solvents, ethers.

Form Supplied in: as anhydrous gas in cylinders; as aqueous solutions of various concentrations; widely available in all forms.

Analysis of Reagent Purity: titration.

Handling, Storage, and Precautions: hydrogen chloride is a corrosive, colorless, nonflammable gas which forms a white cloud when exposed to air; as concentrated solutions, hydrochloric acid is a colorless to light-yellow corrosive liquid which fumes when exposed to air; the acid can cause severe skin burns, damage to the respiratory and digestive tract, and/or visual damage; repeated exposure may cause dermatitis and photosensitization; the gas and solutions of hydrochloric acid should be handled with adequate ventilation and proper skin and eye protection. Use in a fume hood.

Acid Catalysis.

Hydrogen Chloride is completely ionized in all but the most concentrated aqueous solutions. In addition, the nucleophilicity2 of the halide ions follows the general order I- > Br- > Cl- > F-. Consequently, in many of the reactions in which it is employed, it is used as an acid catalyst. Reactions employing hydrochloric acid as a catalyst include the hydrolysis of esters to acids, the hydrolysis of nitriles and imides to amides, acids, and amines,3 the hydrolysis of amides to acids and amines,4 the hydrolysis of imines and enamines to ketones and amines, the hydrolysis of nitroso compounds to ketones, the hydrolysis of ketals, aminals, and enol ethers to ketones, the hydrolysis of acetals to aldehydes, and the hydrolysis of ethers to alcohols.5 Anhydrous hydrogen chloride in an alcohol is frequently used in Fischer esterifications and in acetalization reactions. Hydrochloric acid has been used to effect numerous molecular rearrangements. Carbon-carbon bond-forming reactions catalyzed by hydrochloric acid include the aldol condensation and the Mannich reaction.6 The Bergius-Willstatter saccharification process utilizes hydrochloric acid to convert cellulose to fermentable sugar.

Amine Salt Formation.

Many amines form solid hydrochloride salts. The low toxicity of chloride ion and favorable physical properties of many of these salts has resulted in the use of such salts for a large number of pharmaceuticals.7 Hydrochloride salts are also used for characterization of amines.

Chloroalkylation.

Concentrated hydrochloric acid and anhydrous hydrogen chloride have been used with Paraformaldehyde for the chloromethylation of aromatic compounds (eq 1). Formation of bis(chloromethyl) ether, a carcinogenic compound, under the reaction conditions is problematic. This side reaction has limited the use of the chloromethylation process.8 In the presence of thiols, acetaldehyde will react with hydrogen chloride to yield alkyl chloroethyl thioethers (eq 2).9

Amidomethylation.

N-Acylhemiaminals can react with pyrroles in ethanol saturated with hydrogen chloride to produce the amidomethylated product (eq 3). Such amidomethylations are more commonly performed using Sulfuric Acid as catalyst.10

Addition to Single Bonds in Three-Membered Rings.

Hydrogen chloride will react with some cyclopropanes to yield ring-opened products (eq 4). These addition reactions typically yield products expected from Markovnikov addition. D3-Carene (1) and D4-carene (2) both produce a mixture of sylvestrene dihydrochloride (3) and dipentene dihydrochloride (4).11

Anhydrous hydrogen chloride can react with oxiranes and aziridines to yield addition products (eqs 5 and 6). Oxiranes and aziridines derived from cyclohexenes open preferentially through axial attack by chloride.12 Other Lewis acids, including Aluminum Chloride, Tin(IV) Chloride, and Iron(III) Chloride, also produce 2-chloroethanols when reacted with oxiranes. In the presence of sulfur nucleophiles, good yields of the sulfur addition product may be obtained.13

Addition to Single Bonds in Five-Membered Rings.

Treatment of g-butyrolactone with hydrochloric acid produces 4-chlorobutyric acid in good yield (eq 7).14 Ring opening of 1,4-dihydro-1,4-epoxybenzene derivatives with hydrochloric acid results in isolation of the corresponding phenols (eq 8). This aromatization may be very regiospecific.15,5a

Reaction with Ethers.

In addition to the reactions with cyclic ethers cited above, hydrogen chloride reacts with acyclic ethers to produce the corresponding alcohols and chlorides (eq 9). The rate of the reaction is dependent upon the structure of the ether.16 In the presence of Zinc Chloride, hydrogen chloride reacts with propargyl ethers to produce propargyl chlorides (eq 10).17

Addition to Carbon-Carbon Multiple Bonds.1b

Hydrochloric acid reacts with alkenes to produce either alcohols or alkyl chlorides. Anhydrous hydrogen chloride is typically the reagent used for the preparation of alkyl chlorides (eq 11). The product of the reaction is dependent upon the substrate and reaction conditions; Markovnikov addition is typically observed, but addition may be either syn or anti. The kinetic product formed from addition of HCl to alkenes may be unstable under the reaction conditions and may rearrange to yield thermodynamically more stable products. Addition of hydrogen chloride to a-pinene (5) leads initially to pinene hydrochloride (6), which isomerizes mainly to bornyl chloride (7) containing some fenchyl chloride (8).18 Analogous rearrangements are observed with camphenes.19 Addition to some alkenes and alkynes may require elevated temperatures, elevated pressures, or addition of a Lewis acid. The reaction with alkynes produces vinyl chlorides and dichloroalkanes (eq 12).20 The addition to conjugated double bonds frequently leads to products which are a mixture of 1,2- and 1,4-addition products. When the diene is conjugated to an electron-withdrawing group, anti-Markovnikov addition is common.21 Selectivity may be observed in the reaction of butadiene derivatives.22 Allenes frequently give mixtures of products due to acid-catalyzed migration of double bonds. The major product at low temperature is frequently the product formed from protonation at the central allene carbon.23

Addition of anhydrous hydrogen chloride to 1-nitro-1-alkenes can produce 1,2-dichloroaldoximes (eq 13).24

Reactions with Alcohols.

Concentrated hydrochloric acid and anhydrous hydrogen chloride react with alcohols to produce alkyl chlorides (eq 14).25 Allylic,26 benzylic,27 or tertiary alcohols28 typically are most useful as substrates for conversion to chlorides. Rearrangement may occur. On a laboratory scale, hydrochloric acid has been largely replaced by the use of phosphorus reagents such as Triphenylphosphine/CCl4, Triphenylphosphine Dichloride, or Ph3P/Diethyl Azodicarboxylate/Cl- to achieve the conversion of an alcohol to a chloride.29 These reagents frequently give less rearrangement and more stereospecificity than hydrochloric acid, Phosphorus(V) Chloride, Phosphorus Oxychloride, Thionyl Chloride, Phosphorus(III) Chloride, or Dimethylchloromethyleneammonium Chloride. Treatment of alkyl phosphites, phosphonates, and diphenyl phosphinites derived from alcohols with hydrogen chloride produces the alkyl chloride in which inversion at carbon has occurred. Yields are lower and conditions are more rigorous than the corresponding reaction with Hydrogen Bromide.30

The reactions of carbohydrates and their derivatives with hydrogen chloride at the anomeric hydroxyl are examples of the facile conversion of alcohols to chlorides.31 Protected and unprotected sugars react with methanol in the presence of dilute hydrochloric acid to produce the methyl ether at the anomeric center.32

Reactions with Diazo Compounds.

The reaction of diazo compounds derived from a-amino acids or a-amino ketones with hydrochloric acid results in isolation of the corresponding racemic a-chloro carbonyl compound (eq 15).33

Reactions with Nitriles and Their Derivatives.

Addition of anhydrous hydrogen chloride to nitriles produces imidoyl chlorides (eq 16).34 Treatment of N-alkylimidoyl chlorides with hydrogen chloride results in isolation of the corresponding iminium halides (eq 17).35 Aryl cyanates react with hydrogen chloride to produce haloformimidinium halides (eq 18).36 Molecules containing two nitrile groups frequently give cyclic amidinium products.37 Hydrogen chloride reacts with nitrile oxides to yield hydroxamoyl chlorides (eq 19). Hydroxamoyl chlorides are also produced in the reaction of phenylnitromethane with hydrogen chloride and in the reaction of acetophenones with isopropyl nitrite and hydrogen chloride.38

Reaction with Nitrogen-Sulfur Bonds.

Hydrogen chloride has been used to cleave the nitrogen-sulfur bond of 2,2,2-trifluoro-1,1-diphenylethylsulfenyl-protected amines in high yield (eq 20).39

Hydrolysis of 1,1-Dichloroethylenes.

Hydrochloric acid in glacial acetic acid or alcohols has been used to convert 1,1-dichloroethylenes to carboxylic acids (eq 21).40 This reaction appears to require additional conjugation or the presence of an allylic leaving group to proceed smoothly. The use of sulfuric acid appears to be more general since additional conjugation is not required.41 Potassium Hydroxide has also been used to effect this hydrolysis.42

Silicon and Sulfur Chemistry.

Protodesilylation with hydrochloric acid is most useful for substrates in which the silicon-carbon bond to be cleaved is aryl (eq 22), vinylic (eq 23), benzylic, or allylic (eq 24).43 Phenylsilanes react with hydrogen chloride to yield benzene and the chlorosilane. The reaction is less facile than the reaction with hydrogen bromide.44 Increasing the electronegativity of substituents on silicon decreases the ease with which the aryl-silicon bond is broken. Hindered aryl silanes may require fluoride ion.45 Allylic protodesilylation normally occurs with double bond migration (eq 24).46 Protodesilylation of a silicon-carbon bond in which the carbon is sp hybridized may require the addition of a fluoride source (eq 25).47

Triethylaminosilanes are converted to the corresponding chlorosilanes in the presence of hydrochloric acid/sulfuric acid (eq 26).48

Silyl ethers may be cleaved using hydrochloric acid (eq 27).49 Fluoride ion is an alternative which is frequently used when the substrate is acid sensitive.

Acylsilanes have been obtained from 1-silyl-1-enol ethers (eq 28), 1-silyl-1-aminoethylenes (eq 29), and mixed O-alkyl-O-silyl acetals of acylsilanes (eq 30) upon treatment with dilute hydrochloric acid.50 Analogous chemistry has been observed with germanium and tin compounds.51

Phenylsilane reacts with anhydrous hydrogen chloride in ether in the presence of Aluminum Chloride to yield chlorophenylsilane (eq 31).52

Diphenylsilanediol yields the cyclic siloxane in moderate yield when treated with concentrated hydrochloric acid in ether at reflux (eq 32).53 This reaction is also effected using amines.

Thioacyl chlorides have been prepared from thioketenes and anhydrous hydrogen chloride at low temperatures (eq 33).54

Transhalogenation Reactions.

3-Bromo-4,5-dihydroisoxazole derivatives can be converted to the corresponding chlorides by treatment with hydrochloric acid and Lithium Chloride (eq 34).55

Organometallic Chemistry.

Carbon-metal bonds are typically cleaved by hydrochloric acid to yield the metal chloride and the hydrocarbon (eq 35).56 Oxygen-tin bonds are also cleaved by treatment with hydrochloric acid.57

Alkyl phenyl selenoxides react with hydrogen chloride to yield the alkyl chlorides (eq 36). Conversion to the bromide with hydrogen bromide proceeds faster and in higher yield.58

Treatment of the zirconium metallacycle shown with hydrochloric acid led to formation of the indole in high yield (eq 37).59

Treatment of a tungsten complex with 2 equiv of hydrochloric acid in ether led to formation of a new chlorotungsten compound (eq 38).60

1,1-Dihydroxy-2,3-diphenylgermirene is converted to the dichloride with anhydrous hydrogen chloride in benzene (eq 39).61

In Situ Generation of Chlorine and Hypochlorite.

Hydrochloric acid and Hydrogen Peroxide are an effective combination for the in situ generation of Chlorine (eq 40). This combination of reagents can be used for the halogenation of alkenes and aromatics.62

Treatment of 1,2-diphenylacetylene with HCl and Iodosylbenzene on silica gel appears to proceed through formation of chlorine to yield a mixture of (E)- and (Z)-1,2-diphenyl-1,2-dichloroethylene. However, under similar conditions, 1,1,2-triphenylethylene produces 2-chloro-1,1,2-triphenylethanol.63 Chlorides are obtained in higher yields than bromides, which are obtained in higher yields than iodides when HBr or HI are substituted for HCl in the reaction. 1-Phenylpropyne reacts with oxone (Potassium Monoperoxysulfate) and hydrochloric acid in DMF to produce 2,2-dichloropropiophenone in high yield.64 Replacement of oxone with m-Chloroperbenzoic Acid results in lower yields.

Related Reagents.

Formaldehyde-Hydrogen Chloride; Hydrogen Chloride.


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John E. Mills

R. W. Johnson Pharmaceutical Research Institute, Spring House, PA, USA



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