DMSO PRODUCT INFORMATION BULLETIN

DMSO
Bulletin # 123B

dimethyl sulfoxide
October 2007

Dimethyl Sulfoxide (DMSO)

a Dipolar, Aprotic Reaction Solvent
Introduction When dimethyl sulfoxide (DMSO) was first synthesized by the Russian chemist Alexander Saytzeff in 1867, it is unlikely he envisioned the multitude of uses for this compound in the 21st century. After its initial discovery, DMSO remained relatively obscure for almost a century. Around 1958, DMSO was rediscovered as a super solvent, because it would sometimes dissolve materials which would not dissolve in any other common solvent. Now DMSO is recognized as the most powerful of any readily available organic solvent because it will dissolve the greatest variety of substrates to the highest loading level. Due to DMSOs many advantages and high solvent power, it has become an early solvent choice in the design of many new chemical and pharmaceutical processes. Gaylord Chemicals solutions DMSO dissolves a tremendous array of organic molecules, carbohydrates, polymers, peptides, even many inorganic salts and gases. Loading levels of 50-60 wt. % are often seen with DMSO compared with 10-20 wt. % with typical solvents. This loading enhancement translates to dramatically improved process economics. Moreover, the unique solvent power of DMSO often allows the contraction of multi-step synthetic schemes. Cost effective one-pot reactions are not uncommon features of DMSO chemistry. The ability to dissolve charged or ionic materials extends to ionic intermediates and transition states, with attendant gains in reaction rates and yields. Gaylord Bulletin 102 includes substantial information pertaining to the solvency of inorganic, organic - including pharmaceutical - chemicals in DMSO. Contents Physical Characteristics of DMSO (page 2) Reaction Examples (pages 3-4) Examples of Compound Solubilities (pages 4-5) Health Overview (page 5-6) Environmental Overview (pages 6-7)
P.O. Box 1209 Slidell, LA 70459-1209 USA 1.800.426.6620 Office 1.985.649.0068 Fax info@gaylordchemical.com
Gaylord Chemical Company, L.L.C. (GCC) is the worlds leading provider of Dimethyl Sulfoxide (DMSO) solutions. Beginning in the early 1960s ,GCC has been dedicated to the development of new uses for DMSO. In order to meet customer-specific needs, GCC has pioneered the development of multiple grades of DMSO, including DMSO USP. -based approach has contributed to the development and growth of industries including pharmaceuticals, hydrocarbons, electronics, polymers, coatings, agricultural chemicals, and industrial cleaners. Gaylord Chemicals headquarters are located in Slidell, Louisiana with manufacturing, research, and development facilities in nearby Bogalusa, Louisiana. GCC remains the only producer of DMSO in the Western Hemisphere.

Gaylord Chemical Company, L.L.C.

Your Global Leader For DMSO Solutions!

Impressive Range of Uses Found for DMSO Since the early 1960s, many important pharmaceutical uses for DMSO have been found, as well as applications in an impressive range of industries including agricultural, polymer, coating and inks, electronic, compounding, catalyst sulfiding, and precision cleaning. Despite many exciting applications, DMSO is still underutilized relative to less powerful and more toxic solvents such as acetonitrile, N, N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), and dimethylacetamide. Thus, it appears likely that the unrealized potential uses of DMSO are enormous. Most chemists have a handful of favorite solvents. When these solvents fail to perform, they investigate less common solvents and may find DMSO. Considering the guidelines for solvent selection, however, rational solvent choice should lead to DMSO as the preferred solvent far more frequently. Guidelines for Selecting Your Reaction Solvent Physical properties Solvent power Toxicity Recyclability and environmental compatibility Some Characteristics of DMSO Highly polar High boiling Aprotic Hygroscopic Water white Water miscible Low order of toxicity Essentially odorless Organic liquid

Neat DMSO is relatively stable at its normal boiling point (189C). The rate of thermal decomposition is less than 2% on 24 hour reflux at 189C. The mechanism of thermal decomposition in the liquid phase is acid catalyzed, so that, protic acids significantly accelerate the rate of thermal decomposition. Under neutral or basic conditions DMSO is stable below 150C. At high temperatures (>150C) the use of DMSO under acidic conditions requires an acid scavenger such as sodium carbonate, sodium bicarbonate or zinc oxide. A major advantage of DMSO relative to DMF and NMP is its relative inertness to common bases, such as hydroxide, alkoxides, ammonia and amines. The use of NMP and DMF under highly basic conditions typically results in reduced yields due to side reactions, such as transamidation reactions, with the solvent. DMSO is an excellent solvent choice for reactions under highly basic conditions. Polar solvents have high dielectric constants: they are good insulators between charged particles in solution. DMF, N,N-dimethylacetamide (DMAC), NMP, and especially DMSO, separate anions from cations very effectively. The relative lack of solvation of anions in DMSO leads to dramatic rate enhancements is substitution reactions, including SN2 and nucleophilic aromatic substitution. For example, 107 fold rate enhancements in nucleophilic aromatic substitution have been reported in DMSO solution.

1.81A"

S+
96.4
o

1.48A"

CH3 O CH3
(II) Acetone

CH3

O
CH3

(I) DMSO

Physical Properties Liquid Range C Dipole Moment D Dielectric Constant Solubility Parameter Specific Gravity at 25C 4.3

DMSO 18.5 to 189 48.9 12.9 1.096

DMF -63 to 153 3.82 36.7 67 12.1 0.945 3.72 37.8

DMAC -20 to 166 4.09 32.2 95 11.2 1.027

NMP -24 to 202

Flash Point C (open cup) 95

77 (T.O.C.) 11.1 0.945

The larger the dielectric constant of a solvent the greater is the solvating ability for typical solutes. Since DMSO has the largest dielectric constant of the common dipolar aprotic solvents, it is not CH3 surprising that DMSO has been termed the super solvent. Another more subtle phenomenon which H affects solvating ability is stereochemistry. The structure of the DMSO molecule is not flat, like that of acetone, but is, rather, trigonal pyramidal in shape. There is a highly directional lone pair of electrons N at the apex of the pyramid, which further helps complex and otherwise solvate typical solute O molecules. N O OCH3 H3C Imazamethabenz-methyl [81504-85-8] CH3

Assert

DMSO will dissolve most aromatic and unsaturated hydrocarbons, organic nitrogen compounds, organic sulfur compounds, and many inorganic salts. It is miscible with most common organic solvents, such as alcohols, esters, ketones, lower ethers, chlorinated solvents, and aromatics. Saturated aliphatic hydrocarbons, however, are virtually insoluble in DMSO. As a reaction solvent DMSO has shown advantages in numerous reactions including addition, alkylation, displacement, cyclization, etherification, elimination, isomerization, condensation,

H3C

CH3

+ P CH-2

H3C
1) aq. workup 2) pentane extract

CH3

50 C, 16 hr. DMSO

3) wash, strip solvent 4) sublime

(V)
CH3

(IV)

73.4% m.p. 68-70oC

CH2

polymerization and solvolysis. Rate enhancements have been seen in several reaction types. Moreover, in free radical polymerizations, higher average molecular weights have been achieved when DMSO was used as a reaction solvent. Thus, ultra high molecular weight polyacrylonitrile, which is required in the manufacture of carbon fiber, is made in DMSO solution. The imidazolinones were developed for pre- and post-emergent broad spectrum weed control in soybeans. Products from this class of herbicide include Pursuit , Arsenal, and imazamethabenzmethyl.

DMSO is used as a reaction solvent to form the highlighted bond in the structure above. Use of DMSO results in higher loading levels and more cost-effective processes, due to the resulting decrease in reactor size or reactor occupancy. In addition, there are a number of reactions where the use of DMSO results in significantly superior yields relative to other solvents. For example, the Wittig reaction of carbonyl compounds, yielding alkenes, gives superior yield in DMSO with dimsyl

ion as the base. The dimsyl ion is the conjugate base of DMSO. It is best prepared by the reaction of DMSO with sodium hydride. (See Bulletin 110.) The Wittig reaction of certain hindered ketones, such as camphor (IV), fails in NMP solution, with hydroxide as the base. Camphor reacts to yield camphene (V), in excellent yield in DMSO with dimsyl ion as the base [See, for example, R. Greenwald et. al., J. Org. Chem., 28, 1129 (1963)].

Claisen condensation of an ester with an aralkyl ketone yields 1,3-diketones in higher yield in DMSO, with dimsyl ion as the base, than with other solvent/base combinations. For example, dibenzoylmethane was prepared in 94.5% yield via the reaction of methyl benzoate with acetophenone in DMSO/THF with dimsyl ion as the base [see R. Drewer et. al., U. S. Patent 5,344,992 (1994)].

Solubility of Imazethepyr in a Selection of Solvents Solvent DMSO Methylene Chloride Methanol Acetone Isopropanol Toluene Water Heptane Imazethepyr, g/liter 422.0 185.0 105.0 48.2 17.0 5.0 1.4 0.9

O OH N N N O

Imazethapyr Pursuit [81335-77-5] (V)

Because DMSO is miscible with water, facile clean up of chemical or pharmaceutical reactions using water or aqueous detergent is another benefit. Unique DMSO chemistry allows selective oxidations of reactive halides and alcohols and even allows protection/deprotection sequences via the

methylthiomethyl ether derivative [see T. W. Greene and G. M. Wuts, Protective Groups In Organic Synthesis, Ed., Wiley-Interscience, New York, p 21 (1991)]. Moreover, the isolation of products from concentrated DMSO may be accomplished by the addition of relatively small amounts of water. DMSO can be stripped on a thin film evaporator or otherwise recycled. Trace DMSO impurities in the product may be removed by aqueous, alcohol or ethyl acetate wash. Freeze drying may be an option for thermally sensitive substrates. Compound Solubilities Gaylord Chemical has taken the initiative to determine the solubilities of active pharmaceutical compounds (APCs) in DMSO. The database includes over a hundred common prescription and OTC pharmaceuticals. This information is available, in Bulletin 102 and on Gaylord Chemicals website (www.gaylordchem.com). It is hoped that two major classes of pharmaceutical professionals will benefit from the availability of this information: (1) formulation chemists developing topical solutions, creams, gels and patches for transdermal application; (2) discovery or synthesis chemists developing chemical analogs of known drugs. A sample of Gaylord Chemicals APC solubility database is shown below: Active Pharmaceutical Dextromethorphine HBr Diclofenac sodium Testosterone Triamcinoline Panthenol Capsaicin Cycobenzaprine HCl Metronidazole Prochlorperazine dimaleate Albuterol sulfate CAS # [6700-34-1] [15307-79-6] [23-1026-5] [124-94-7] [16485-10-2] [2444-46-4] [6202-23-9] [443-48-1] [84-02-6] [51022-70-9] Therapeutic Category antitussive anti-inflammatory androgen glucocorticoid cholinergic, vitamin topical analgesic muscle relaxant antiprotozoal antipsychotic bronchodilator Solubility in DMSO (wt. %) @ 25 C 39.3 33.3 21.6 13.6 12.2 >9.5 8.5 7.3 6.3 0.49

An example of solubility for an active agricultural compound is imazathepyr (V). The following table demonstrates the superior solubility of this active in DMSO.

Toxicity We know of no individual who has ever been harmed by routine, or accidental contact with DMSO. DMSO is the only dipolar aprotic solvent rated 3 (safest) for pharmaceutical applications by the

International Conference for Harmonization (ICH). In fact, DMSO is virtually non-toxic by every avenue of administration (oral, inhalation and dermal), has low aquatic toxicity and is biodegradable. OralResults of an oral test on rats show that DMSO is less toxic than other dipolar aprotic solvents. In fact, an LD-50 (Rat, oral) of 17.4 g/Kg shows that DMSO is less toxic by oral administration than ethyl alcohol (LD-50 (Rat, oral) = 7.06 g/Kg).
Solvent DMSO Oral LD-50 (Rat, g/Kg) Permeability Constant (g/ m2/hr) Cell Mortality % Dermal LD-50 (Rats g/ Kg) Chronic TLV 17.4 176 minimal 40.0 No Toxic Effect Observed DMF 2.8 98 100 4.7 10 ppm DMAC 4.3 107 100 2.2 10 ppm NMP 4.2 171 100 8.0 100 ppm

DermalDMSO penetrates human skin relatively rapidly. However, the rate of skin penetration is virtually the same as that of NMP and similar to that of other dipolar aprotic solvents. In fact, most solvents penetrate human skin at a measurable rate. The key issue is that DMSO penetrates human skin reversibly, that is, without permanent damage. Moreover, DMSO is, essentially nontoxic by skin penetration, as evidenced by the high LD-50 value of 40,000 mg/Kg (rat, dermal). InhalationDMSO has no threshold limit value (TLV) assigned for inhalation exposure. Results of extended inhalation toxicity test with rats exposed to saturated DMSO vapors showed no statistical difference in any organ of the DMSO exposed and control groups. OdorEarly production quantities of DMSO were discredited due to claims of objectionable odor. The cause of the odor was traced to impurities in the product, in particular, bismethylthiomethane or BMTM (CH3SCH2SCH3). Since 1997, Gaylord Chemical has eliminated BMTM impurities in its DMSO manufacturing process. Consequently, DMSO from Gaylord Chemical is now essentially odorless. Recyclability and Environmental Compatibility DMSO can be recovered efficiently from aqueous solutions, which leads to significant savings in material costs and/or reduced costs of disposal. DMSO does not form azeotropes with water and does not foam during vacuum distillation. This makes separation by distillation relatively facile. There has been a handful of reports in the literature of explosions during attempted DMSO recycle. Although neat DMSO is relatively thermally stable, in the presence of stoichiometric concentrations of halide ions, there is potential for explosive decomposition. Specifically, four simultaneous conditions are required for an explosion during attempted DMSO recycle, as follows: stoichiometric concentrations of bromide, chloride, or iodide ions acidic pH

Corporate Office 106 Galeria Blvd. Slidell, LA 70458 985-649-5464 info@gaylordchem.com Research and Technology Center 209 Industrial Blvd. Bogalusa, LA 70427 985-732-6308 technology@gaylordchem.com

Manufacturing Facility 420 Willis Ave. Bogalusa, LA 70427 985-732-6304 plant@gaylordchem.com

The information in this booklet is based on information available to us and on our observations and experiences. However, no warranty is expressed or implied regarding the accuracy of this data, the results to be obtained from the use thereof, or that any use will not infringe any patent. Each user must establish appropriate procedures for off-loading, handling, and use of the product(s). Since conditions for use are beyond our control, we will make no guarantee of results, and assume no liability for damages incurred by off-loading, handling, or use of the product(s). Nothing herein constitutes permission, or recommendation to practice any invention covered by any patent without license from the owner of the patent.

For samples or further information related to DMSO USP, please contact: Customer Service Gaylord Chemical Company (800) 426-6620 info@gaylordchem.com

For more information about Gaylord Chemical Company, L.L.C. please visit our website at: www.gaylordchemical.com In case of emergency phone: 1-985-732-8662 For sales information phone: 1-800-426-6620
P.O. Box 1209 Slidell, LA 70459-1209 USA 1.800.426.6620 FAX 1.985.649.0068 info@gaylordchem.com

Gaylord Chemical Company, L.L.C.

Your Global Leader For DMSO Solutions!