Dimethyl Sulfoxide1

[67-68-5]  · C2H6OS  · Dimethyl Sulfoxide  · (MW 78.13)

(polar aprotic solvent: acidity scale;2 displacement reactions;3-11 dealkoxycarbonylations;12-21 oxidations22-31)

Alternate Name: DMSO.

Physical Data: mp 18.4 °C; bp 189 °C; d 0.917 g cm-3.

Solubility: miscible with water and numerous organic solvents in all proportions.

Form Supplied in: colorless, odorless liquid; widely available. Drying: anhyd material available by vacuum distillation from calcium hydride.

Handling, Storage, and Precautions: is readily absorbed through the skin and should always be handled with gloves in a fume hood; its reactions form foul-smelling byproducts and should be carried out with good ventilation, and the waste byproducts and liquids used for washing should be treated with Potassium Permanganate solution to oxidize volatile sulfur compounds; DMSO undergoes appreciable disproportionation to dimethyl sulfide (stench!) and dimethyl sulfone above 90 °C.

Solvent.

Acidity Scale.

Equilibrium acidities for numerous compounds in DMSO (pKa = 35.1) as the solvent have been determined. These acidities provide fundamental data for the evaluation of electronic and steric effects which occur on structural modification in organic molecules. The comparison of structural effects of acidities in DMSO with those found in the gas-phase are important in understanding solvation effects.2

Displacement Reactions.

Regiospecific displacement reactions are fundamental synthetic procedures for functional group interconversions. Although the rates of nucleophilic displacement reactions are dependent on solvent, substrate structure, nucleofuge, and nucleophile, the particular property of DMSO (and other polar aprotic solvents) is partially based on its ability to solvate cationic species. In effect, this leads to a less solvent-encumbered and more nucleophilic anion than in protic media.3 The order of anion nucleophilicity can be reversed in the change from a protic solvent (I- > F-) to DMSO (F- > I-). Numerous nucleophiles such as acetylides, azide, cyanide, halides, carboxylates, hydroxide, and alkoxides have been used in DMSO for displacement reactions. Hydroxide and alkoxide anions exhibit a dramatic enhancement in basicity in DMSO relative to protic media.

Representative displacements (SN2) are the conversion of the ditosylate to the dichloride (eq 1)4 and the formation of large-ring macrocycles by intramolecular cyclizations of o-bromocarboxylic acids (eq 2).5

Monosubstituted aryl fluorides can be prepared via SNAr displacements of chloride from activated aryl chlorides (eq 3).6

The N-benzylation of indole was readily accomplished by treatment with Benzyl Bromide in the presence of Potassium Hydroxide in DMSO at rt.7

Since the cyanide group is a synthon for a carboxyl group and related derivatives, cyanations in DMSO are valuable synthetic transformations for the conversions of appropriate alkyl halides or tosylates to nitriles.8 The conversion of a chiral propyl tosylate to a chiral nitrile has been reported (eq 4).9

Neutral nucleophiles such as amines in DMSO effect faster displacements than in comparable reactions performed in protic media.10 Treatment of an a-bromo ester with Ammonia in DMSO at rt yielded the a-amino ester (eq 5).

Sodium Borohydride in DMSO is an effective source of hydride anion for reductive displacements of halide or sulfonate groups.11 The selective removal of halide in the presence of an ester functionality was shown in the reduction of ethyl 2-bromohexanoate to ethyl hexanoate (86% yield, NaBH4, DMSO, 15 °C, 0.75 h).

Dealkoxycarbonylations.

Activated substrates such as malonate esters (see Ethyl Malonate), b-keto esters (see Ethyl Acetoacetate), and a-cyano esters (see Ethyl Cyanoacetate) find extensive utility in synthesis. The presence of these types of functionality lowers the pKa of the adjacent C-H bond, and deprotonation can be effected by relatively weak and inexpensive bases. The regioselective C-alkylation (or treatment with other electrophilic agents) of these enolates leads to the incorporation of a new C-C bond. The regiospecific substitution of the alkoxycarbonyl group by hydrogen (or other groups such as alkyl) is then desirable. Traditionally, this transformation has been performed via a basic or acidic hydrolysis of the substrate followed by thermolysis of the resultant diacid or acid. In commencing from malonate esters, a reesterification is then necessary to obtain the monoester. Substrates which bear other acidic or base-sensitive groups cannot be utilized in the hydrol ysis-decarboxylation procedure.

A useful methodology for the dealkoxycarbonylations of malonate esters, b-keto esters, a-cyano esters and a-alkyl- or arylsulfonyl esters to prepare esters, ketones, nitrile, and sulfonyl analogs, respectively, has recently been developed.12 This preparative procedure simply involves heating the substrate with water, or with water with added salts in a polar aprotic solvent such as DMSO (other aprotic solvents such as N,N-Dimethylformamide or Hexamethylphosphoric Triamide have found some use). Many salts have been utilized including sodium chloride, Lithium Chloride, Sodium Cyanide, and magnesium chloride.12 The mechanistic pathways for the dealkoxycarbonations are highly dependent on substrate structure.

Some monosubstituted malonate esters and b-keto esters undergo dealkoxycarbonylation in water-DMSO (eq 6). Selective dealkoxycarbonylations have been found for mixed malonate esters.12b

The synthetic utility of the DMSO/salt/water dealkoxycarbonylations can be illustrated by some recent applications. In a total synthesis of racemic b-vetivone, the chemoselective demethoxycarbonylation of a b-keto ester in the presence of another ester functionality was readily accomplished (eq 7).13 The silyl protective group was stable to the reaction conditions.

The demethoxycarbonylation of a b-keto ester led to racemic b-vetivone and epi-b-vetivone, from which pure racemic b-vetivone could be obtained by chromatography (eq 8).

In synthetic pathways to chiral a- and b-cuparenones, the demethoxycarbonylation of a b-keto ester in the presence of a benzyl ester was performed using Sodium Iodide in DMSO (eq 9).14

In a synthetic route leading to carbovir, the deethoxycarbonylation of a substituted a-nitro acetate analog was successful (eq 10).15

In a route to furanoid terpenes (eq 11)16 and in a synthetic step leading to the pheromone of the monarch butterfly (eq 12)17, substituted malonate esters have been readily demethoxycarbonylated.

The chemoselective removal of the malonate ester from a triester has been reported (eq 13).18

The demethoxycarbonylation of a phenyl sulfoxide substituted cyclopropyl malonate ester was reported to occur with 100% (E) diastereoselectivity (eq 14).19

In a pathway to erythrina alkaloids, a b-keto ester was deethoxycarbonylated with magnesium chloride in DMSO (eq 15).20

The deethoxycarbonylation of an a-cyano ester was also readily accomplished (eq 16).21

Oxidations.

The conversions of alkyl halides or tosylates to the corresponding aldehydes or ketones using DMSO as the oxidizing agent has found some synthetic application.22 Reactive halides or tosylates react with DMSO, initially forming the O-alkyl analogs which generally rearrange to the more stable oxosulfonium salts. If the O-alkyl intermediates undergo a facile elimination of dimethyl sulfide, carbonyl compounds are formed. This methodology was discovered by Kornblum and co-workers, who reported that a-bromo ketones were transformed into a-keto aldehydes by treatment with DMSO at rt.23 Other investigators reported similar transformations.24

Benzyl halides are readily converted on heating in DMSO into the corresponding aldehydes (eq 17).25

Benzylic tosylates can be converted to the corresponding aldehydes by treatment with DMSO in the presence of sodium bicarbonate at 100 °C for 5 min. Saturated primary halides can be converted to the tosylates and then oxidized by treatment with DMSO at 150 °C for a short period.23b

Although simple alkyl chlorides or bromides are inert to DMSO even at high temperatures, the conversion of 3-bromonortricyclene to nortricyclanone (69%) was accomplished by treatment with Silver(I) Tetrafluoroborate in DMSO for 1 h at rt followed by addition of Triethylamine.26 This silver-assisted DMSO oxidation procedure was studied more extensively and is a useful procedure for the synthesis of aldehydes and some ketones.27 The conversion of 1-bromobutane to butanal (83%) can be effected by a solution of AgBF4 in DMSO at room temperature.

Since the direct oxidation of aliphatic iodides can be accomplished using DMSO and sodium bicarbonate at 150 °C,28 the oxidation of alkyl chlorides or bromides with DMSO has been performed in the presence of Sodium Iodide.29 For example, treatment of 1-chloro- or 1-bromooctane with DMSO in the presence of sodium bicarbonate and NaI and heating the mixture at 105-115 °C for 1-2 h leads to octanal (73 and 60%, respectively).

Benzylamine hydrobromides and benzyl trialkyl quaternary salts can be oxidized to the corresponding aldehydes by DMSO.30 The oxidation of benzylamine hydrobromide with DMSO at 100-160 °C yielded benzaldehyde (95%).

The oxidation of aryl- or alkyl-substituted oxiranes by DMSO in the presence of molecular sieves and a catalytic amount of Trifluoroacetic Acid leads to a-hydroxy ketones (eq 18).31

Related Reagents.

See the articles immediately following and N,N-Dimethylpropyleneurea; Hexamethylphosphoric Triamide; 1-Methyl-2-pyrrolidinone; Potassium t-Butoxide-Dimethyl Sulfoxide; Potassium Hydroxide-Dimethyl Sulfoxide; Potassium Methoxide-Dimethyl Sulfoxide; RS029-.


1. (a) Fieser, L. F.; Fieser, M. FF 1967, 1, 296; 1969, 2, 157; 1972, 3, 119; 1974, 4, 192; 1975, 5, 263; 1977, 6, 225; 1979, 7, 133; 1980, 8, 198; 1981, 9, 189; 1982, 10, 166; 1984, 11, 214; 1986, 12, 212; 1988, 13, 124. (b) Dimethyl Sulfoxide: Basic Concepts of Dimethyl Sulfoxide; Jacob, S. W.; Rosenbaum, E. E.; Wood, D. C., Eds.; Dekker: New York, 1971; Vol. 1. (c) Martin, D.; Hauthal, H. G. Dimethyl Sulfoxide; Halsted: New York, 1975. (d) Gaylord Chemical Corporation, DMSO bulletin number 105; P. O. Box 1209, Slidell, LA 70459-1209, 1992; a review with numerous references.
2. (a) Bordwell, F. G. ACR 1988, 21, 456. (b) Taft, R. W.; Bordwell, F. G. ACR 1988, 21, 463. (c) Bordwell, F. G.; Cheng, J.-P.; Satish, A. V.; Twyman, C. L. JOC 1992, 57, 6542.
3. (a) Reichardt, C. Solvents and Solvent Effects in Organic Chemistry; VCH: Weinheim, 1988, pp 213-283. (b) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, 3rd ed.; Plenum: New York, 1990; Part B, Chapters 1 and 3. (c) March, J. Advanced Organic Chemistry, 4th ed.; Wiley: New York, 1992; Chapters 9, 10, and 13.
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8. Mathieu, J.; Weill-Raynal, J. Formation of C-C Bonds; Thieme: Stuttgart, 1973; Vol. 1, pp 378-388.
9. Casara, P.; Danzin, C.; Metcalf, B.; Jung, M. JCS(P1) 1985, 2201.
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21. Cuvigny, T.; Julia, M.; Rolando, C. JOM 1985, 285, 395.
22. Epstein, W. W.; Sweat, F. W. CRV 1967, 67, 247.
23. (a) Kornblum, N.; Powers, J. W.; Anderson, G. J.; Jones, W. J.; Larson, H. O.; Levand, O.; Weaver, W. M. JACS 1957, 79, 6562. (b) Kornblum, N.; Jones, W. J.; Anderson, G. J. JACS 1959, 81, 4113. (c) Nace, H. R.; Monagle, J. J. JOC 1959, 24, 1792.
24. (a) Major, R. T.; Hess, H.-J. JOC 1958, 23, 1563. (b) Hunsberger, I. M.; Tien, J. J. CI(L), 1959, 88.
25. Helms, A.; Heiler, D.; McLendon, G. JACS 1992, 114, 6227.
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27. Ganem, B.; Boeckman, R. K., Jr. TL 1974, 917.
28. Johnson, A. P.; Pelter, A. JCS 1964, 520.
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A. Paul Krapcho

University of Vermont, Burlington, VT, USA



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