Thionyl Chloride1

SOCl2

[7719-09-7]  · Cl2OS  · Thionyl Chloride  · (MW 118.97)

(chlorination of alcohols,2 carboxylic acids,3 and sulfonic acids;4 dehydration of amides;5 formation of imidoyl chlorides,6 sulfur-containing heterocycles,7 and the Vilsmeier reagent)

Physical Data: 8 bp 76 °C; d 1.631 g cm-3.

Solubility: sol ethers, hydrocarbons, halogenated hydrocarbons; reacts with water, protic solvents, DMF, DMSO.

Form Supplied in: colorless to yellow liquid.

Purification: impurities cause formation of yellow or red colors. Iron contamination can cause a black color. Fractional distillation, either directly9 or from triphenyl phosphite10 or quinoline and linseed oil,11 has been recommended.

Handling, Storage, and Precautions: very corrosive and reactive; the vapor and liquid are irritating to the eyes, mucous membranes, and skin. Protective gloves should be worn when handling to avoid skin contact. Thionyl chloride should be stored in glass containers at ambient temperature and protected from moisture. It reacts with water to liberate the toxic gases HCl and SO2. Since most reactions using SOCl2 evolve these gases, they should be performed only in well-ventilated hoods. Above 140 °C, SOCl2 decomposes to Cl2, SO2, and S2Cl2. Iron and/or zinc contamination may cause catastrophic decomposition.12

Chlorides from Alcohols.

Thionyl chloride reacts with primary, secondary, and tertiary alcohols to form chlorosulfite esters (eq 1) which can be isolated.13 The fate of these esters depends on the reaction conditions, especially the stoichiometry, solvent, and base. If 2 equiv of alcohol and pyridine are used relative to thionyl chloride, dialkyl sulfites may be isolated (eq 2).14

When thionyl chloride is in excess, or when alkyl chlorosulfites are treated with thionyl chloride,15 alkyl chlorides are produced and the byproducts are HCl and SO2. The mechanism of this reaction may be SN1, SN2, SNi, or SN2 (with allylic or propargylic alcohols). In the absence of base the SNi mechanism operates; retention of configuration is observed in the alkyl chloride (eq 3).16 Considerable ionic character may be involved in this process and small amounts of elimination or rearrangement are common as side reactions.17

Thus, simple heating of the alcohol with thionyl chloride alone is often the preferred method for retaining the configuration of the alcohol in the chloride. Alternatively, use of amine bases, most commonly Pyridine,18 results in a shift in the mechanism to SN2 (eq 4) and consequently overall inversion. Excess pyridine may cause dehydrochlorination or alkylation of the base. If inversion of the substrate is desired or the stereochemical outcome need not be controlled, the use of pyridine or other amine base is recommended since the resulting high chloride concentrations minimize rearrangements and eliminations.19,17a Alternatively, catalysis of the chlorination by Hexamethylphosphoric Triamide results in inversion.20 With allylic substrates, rearranged products generally predominate, especially in nonpolar solvents.21 Use of Tri-n-butylamine as the base can result in unrearranged allylic products.22

Representative procedures are available for the chlorination of tetrahydrofurfuryl alcohol,23 benzoin,24 and ethyl mandelate.25 The use of thionyl chloride for this transformation usually gives less rearrangement and elimination than conc HCl, PCl3, or PCl5. For compounds which are acid-sensitive, Triphenylphosphine-Carbon Tetrachloride may be used.

Carboxylic Acid Chlorides from Acids.

Thionyl chloride has been the most widely used reagent for the preparation of acid chlorides. Carboxylic anhydrides also react with SOCl2, giving 2 equiv of the acid chloride.26 The procedure normally involves heating the carboxylic acid with a slight to large excess of SOCl2 in an inert solvent or with SOCl2 itself as the solvent. Operation at the boiling point of the solvent speeds removal of the byproducts, HCl and SO2. The ease of removal of the byproducts is the chief advantage of SOCl2 over PCl5 and PCl3. This simple procedure gives good yields of the acid chlorides of butyric,27 cinnamic,28 and adipic acid.29 The reactions are first order in each reactant and electron-withdrawing groups on the acid decrease the rate.30 Several agents have been developed for the catalysis of this reaction. Pyridine was historically the most common; its presumed mode of action is to ensure the presence of soluble chloride (as Pyridinium Chloride) which reacts with the intermediate as shown in eq 5. Catalytic pyridine ensures that the chlorination of certain diacids such as succinic acid proceeds completely to the diacid chloride rather than stopping at the anhydride.31 The preparation of aromatic acid chlorides also commonly uses pyridine as a catalyst (eq 6).32 Trichloroacetic acid, which is unreactive toward thionyl chloride alone, is chlorinated by the use of pyridine catalyst.33

N,N-Dimethylformamide is a particularly effective catalyst for the formation of acid chlorides with SOCl2 and is now commonly the catalyst of choice.34 The chloromethyleneiminium chloride intermediate is the active chlorinating species (see Dimethylchloromethyleneammonium Chloride).

Esters of amino acids may be produced directly from the amino acid, alcohol, and thionyl chloride. One procedure involves the sequential addition of thionyl chloride and then the acid to chilled methanol.35 Alternatively, benzyl esters have been prepared by the slow addition of SOCl2 to a suspension of the amino acid in benzyl alcohol at 5 °C.36

For the formation of acid chlorides, the competing reactions of concern are a-oxidation and acid-catalyzed degradation. The use of solid Sodium Carbonate in the reaction mixture can minimize the latter for some compounds.37 As shown in eq 7, even simple carboxylic acids with enolizable hydrogens a to the carboxylic functionality are subject to oxidation under standard chlorinating conditions.38 Since the unoxidized acid chloride is the precursor to the sulfenyl chloride, careful attention to stoichiometry and reaction time can effectively minimize this problem.

Sulfonyl and Sulfinyl Chlorides from Sulfonic and Sulfinic Acids.

Alkyl or arylsulfonyl chlorides are prepared by heating the acid with thionyl chloride; DMF catalyzes this reaction. (+)-Camphorsulfonyl chloride is produced in 99% yield without a catalyst.39 Use of the salts of sulfinic acids minimizes their oxidation; p-toluenesulfinyl chloride is produced in about 70% yield from sodium p-toluenesulfinate dihydrate with excess thionyl chloride.40 Phosphorus(V) Chloride is more commonly used for this transformation.

Nitriles and Isocyanides via Amide Dehydration.

Thionyl chloride dehydrates primary amides to form nitriles (eq 8); for example, 2-ethylhexanonitrile is produced in about 90% yield by heating with SOCl2 in benzene.41 Substituted benzonitriles are readily produced from benzamides.42 These reactions may also be catalyzed by DMF.43 N-Alkylformamides may be dehydrated to isocyanides.44

Reactions with Secondary Amides.

Treatment of N-alkyl or N-aryl secondary amides with thionyl chloride in an inert solvent such as methylene chloride results in the formation of imidoyl chlorides (eq 9).45 Upon heating, the imidoyl chlorides from N-alkylamides undergo scission to generate nitriles and alkyl chlorides via the von Braun degradation (eq 10).46

Reactions with Aldehydes and Ketones.

Aromatic or a,b-unsaturated aldehydes or their bisulfite addition compounds are converted to gem-dichlorides by treatment with SOCl2, either neat or in an inert solvent such as nitromethane (eq 11).47 This process is readily catalyzed by HMPA.48 Thionyl chloride may be preferred over the more commonly used PCl5 if removal of byproducts is problematic with the latter reagent.

Carbonyl compounds or nitriles49 with a-hydrogens may be oxidized at this position by thionyl chloride. This reaction appears more often as a troublesome side reaction than a useful synthetic procedure. Nitriles with one a-hydrogen produce a-cyanosulfinyl chlorides (eq 12) while those with two a-hydrogens give moderate yields of a-chloro-a-cyanosulfinyl chlorides.50

Oxidation of Activated C-H Bonds.

As shown in eq 13, extensive oxidation adjacent to carbonyl groups is possible with SOCl2 under relatively mild conditions.51 The process often stops after formation of the a-chlorosulfenyl chloride. Remarkably, these may be easily hydrolyzed back to the carbonyl compounds from which they were derived.52 Alternatively, they may be treated with a secondary amine such as morpholine followed by hydrolysis to yield the a-dicarbonyl compound. Similar oxidation of acid derivatives during acid chloride formation is possible (see above).

Methyl groups attached to benzenoid rings may be oxidized by SOCl2 without added catalysts. The range of reactivity is large and not well understood; the products may be monochlorinated or further oxidation to the trichloromethyl aromatic system is possible.53 2-Methylpyrroles are similarly oxidized.54 In systems with vicinal methyl and carboxylic acid groups, both oxidation of the methyl group and cyclization to a g-thiolactone can occur.55 In conjunction with radical initiators, SOCl2 can chlorinate alkanes.56 Aryl methyl ethers can be oxidized on the aromatic ring to give arylsulfenyl chlorides which may undergo further reactions.57 This latter process, which presumably occurs via electrophilic aromatic substitution, is another potential serious side reaction for active substrates.

Rearrangement Reactions.

Thionyl chloride can act as the dehydrating agent in the Beckman58 and Lossen rearrangements59 and promotes the Pummerer rearrangement.60

Synthesis of Heterocyclic Compounds.

Thionyl chloride and pyridine at elevated temperatures convert diarylalkenes, styrenes, and cinnamic acids to benzo[b]thiophenes61 and adipic acid to 2,5-bis(chlorocarbonyl)thiophene.62 Additional heterocycles which have been prepared include thiazolo[3,2-a]indol-3(2H)-ones,63 oxazolo[5,4-d]pyrimidines,64 and 1,2,3-thiadiazoles.65 Treatment of 1,2-diamino aromatic compounds with thionyl chloride gives good yields of fused 1,2,5-thiadiazoles.66

Other Applications.

Thionyl chloride has been used to convert epoxides to vicinal dichlorides67 and for the preparation of dialkyl sulfides from Grignard reagents.68 Phenols react with SOCl2 to produce aryl chlorosulfites and diaryl sulfites69 or nuclear substitution products. As shown in eq 14, Aluminum Chloride catalysis yields symmetric sulfoxides, while in the absence of Lewis acids, aromatic thiosulfonates are the principal products.70 Primary amines, especially aromatic ones, react with SOCl2 to produce N-sulfinylamines, which are potent enophiles and useful precursors to some heterocyclic compounds.71

Related Reagents.

Dimethylchloromethyleneammonium Chloride; Hexamethylphosphoric Triamide-Thionyl Chloride; Hydrogen Chloride; Oxalyl Chloride; Phosgene; Phosphorus(III) Chloride; Phosphorus(V) Chloride; Phosphorus Oxychloride; Phosphorus(V) Oxide; Triphenylphosphine-Carbon Tetrachloride; Triphenylphosphine Dichloride.


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David D. Wirth

Eli Lilly & Co., Lafayette, IN, USA



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