Commonly used solvent DMSO dimethyl sulfoxide

DMSO is a colorless and transparent liquid at room temperature, and an association with a chain polymer structure will be formed between molecules when the purity is higher, resulting in a higher melting point (18.45℃) and boiling point (189℃). The following table also lists other important physical constants and thermodynamic data for DMSO. Similar to DMF, this compound can also be used as a polar aprotic solvent, miscible with water and most common organic solvents, but more polar than the former. DMSO can dissolve many organic and inorganic compounds well, coupled with low toxicity, and is widely used in academic and industrial applications. At present, people mainly start from dimethyl sulfide (Me2S), using O2 or NO2 as oxidant to produce DMSO industrially.

Important physical constants and thermodynamic data of DMSO

DMSO can also be used as a reactant in a variety of organic chemical reactions. As early as 1957, Professor WilliamM.Weaver and others from PurdueUniversity in the United States dissolved α-bromoketones with different structures in DMSO, and the C-Br bond in some substrates could be efficiently converted into carbonyl groups at room temperature, and DMSO was first found to have a certain oxidation activity. DMSO has been acting as a solvent for a long time. Since then, people have begun to explore other applications of this compound in the field of organic synthesis, and the well-known organic reactions such as Pfitzner-Moffatt oxidation and Swern oxidation all use DMSO as an oxidizing agent to oxidize alcohols to corresponding aldehydes/ketones.

α-bromoketone is oxidized to α-carbonyl aldehyde under the action of DMSO

Pfitzner-Moffatt oxidation and Swern oxidation

Structurally, DMSO contains two methyl groups, which can theoretically be used as C1 synthons to introduce various fragments such as methyl (CH3), methylene (-CH2-) and even formyl (CHO) and cyanide (CN) into the parent molecule. For example, in 2015, Professor Cao Hua of Guangdong Pharmaceutical University reported a Cu-catalyzed selective 3-position C-H bond formylation of imidazopyridine. Among them, DMSO can produce methyl radical through single electron transfer (SET) pathway, and after coupling with imidazolpyridine, methylation intermediate B is obtained, and B is further oxidized under the action of O2 to obtain the target product. In addition, the methylsulfonyl (SOMe) part of DMSO can also be used as a source of methylthioyl (-SMe) and methylsulfonyl (-SO2Me) for different types of chemical transformation.

Application of DMSO as synthetic block in organic synthesis

Cu catalyzes the selective 3-position C-H formylation of imidazopyridine

Previously we mentioned that pure DMF has good thermal stability. Dr. Yang Qiang used differential scanning calorimeter (DSC) to analyze the thermal decomposition of DMF at high temperature, and found that there was no obvious decomposition of DMF when it was heated to 400℃ in N2 atmosphere, but only when it was mixed with other reaction components such as acids, bases, halogen-containing compounds, and heated to a specific temperature could the reaction be out of control. DMSO is not, in contrast, using DSC to determine the thermal stability of pure DMSO, the exothermic decomposition will occur at about 278℃. Using an accelerated calorimeter (ARC), this compound also does so at its boiling point (189 ° C).

In 2016, Dr. B. Todbrandes of SIGroup Company combined the earlier studies of others, and used a variety of calorimetric systems and gas chromatography-high resolution mass spectrometry (GC-HRMS) to comprehensively optimize and analyze the thermodynamic data and products of DMSO thermal decomposition. The result is a summary of all the possible products from the decomposition of this compound. As the table below shows, its composition is complex. It is generally believed that DMSO will first decompose into HCHO and MeSH when heated, and then obtain mixed products such as Me2S, MeSSMe and H2O after subsequent conversion. In addition, DMSO can also form Me2S and Me2SO2 through self-disproportionation reaction.

Summary of possible products from thermal decomposition of DMSO

Possible reaction pathways for thermal decomposition of DMSO

Of course, if DMSO is used as a solvent mixed with a specific reaction component, the initial exothermic decomposition temperature (onsettemperature) will be lower, thus increasing the chance of safety problems. Although reaction accidents caused by DMSO have not been uncommon since the 1950s, they do not seem to have attracted enough attention. Some journals and books still list DMSO as a high safety factor solvent. In the early years, in order to save costs, some enterprises recycled DMSO in the reaction post-treatment system by means of rectification, which led to personal injury and death. For this purpose, Dr. Yang Qiang also wrote in the Chemical journal Org.ProcessRes.Dev. Published an article entitled PotentialExplosionHazardsAssociatedwiththeAutocatalyticThermalDecompositionofDimethylSulfoxideandItsMixtures, According to the types of reactants mixed with DMSO, the potential hidden dangers of the corresponding system after heating up are explained one by one, and the alarm is sounded for everyone.

acid

As early as the early 20th century, it was realized that Brønsted acid greatly promoted the thermal decomposition of DMSO. In 1959, the United States dupont (E.I.D uPontdeNemoursandCompany) HaroldR. Dr Nace found that primary and secondary (quasi) halogenated alkane (X = Cl, Br, OSO2Ph) heating to 100 ~ 160 ℃ in DMSO can be converted into the corresponding aldehydes, ketones, At the same time, low boiling point by-products such as Me2S, MeSH and MeSSMe are produced. In the reaction process, Brønsted acid HX will also be generated. If Na2CO3 is not added as an acid binding agent, a large amount of HCHO will appear in the system, indicating that HX has an important effect on the thermal decomposition of DMSO.

The (pseudo-) halogenated alkanes are heated into the corresponding aldehydes and ketones in DMSO

Dr. B. Todbrandes mentioned above added 1% (mass fraction) H2SO4 and MsOH to DMSO respectively, and analyzed its exothermic decomposition by DSC. Compared with DMSO, the initial temperature of thermal decomposition of both products decreased significantly (192 ℃, 226℃, respectively), and the heat released increased to a certain extent. Others have also reported the effects of various Brønsted acids mixed with this solvent on the above thermodynamic data, which Dr. Yang Qiang summarized and plotted in a table. The results are shown in the table below. For the concentrated HCl (37wt%) that is often used, the mixing system shows significant exothermic decomposition at 110 ° C.

Effects of different Brønsted acids mixed with DMSO on their exothermic decomposition

This problem is not limited to the addition of Brønsted acid as an additive in the reaction, it is more easily overlooked that the reactant and its intermediate molecules themselves contain COOH with Brønsted acidity. For example, in 2006, Dr. MarcusBollyn of AgFA-Gevaerten.v systematically evaluated the safety of the entire synthesis process of p-carboxyphenylhydrazide (15) as a raw material for the construction of the active ingredient 21 of photographic photographic materials, which involves a four-step chemical conversion. The intermediates 17-20 retain COOH, and DMSO has been used as a solvent.

Synthesis of active component 21 of photographic materials

He used ARC to analyze the exothermic decomposition of each step of the reaction, and found that the thermal decomposition starting temperature of DMSO in all reaction systems dropped significantly, reaching the lowest of 112℃, especially in the last step, expanding the synthesis scale will bring great hidden dangers. In contrast, the thermal stability of benzoic acid intermediates 17 was significantly improved by converting them into the corresponding sodium salt redesign cyclization process. Finally, they made appropriate improvements to the synthesis process, switched to batch synthesis to ensure safety, and opened the reaction system and extended the feeding time. In the last step, 2-methoxypropanol is added as a mixed solvent.

At this point, it is necessary to mention the Pfitzner-Moffatt oxidation reaction again. DMSO is used as both solvent and oxidizer, and Brønsted acid (such as

anhydrous H3PO4 and Cl2CHCOOH) with catalyst load is added to promote the reaction smoothly. It is conceivable that safety problems will arise when the scale

of response is expanded. For the oxidation of α-hydroxyamide 24 to 1, 2-diketone 25, Dr. ZheWang of AbbVie proposed to use DMAc as the solvent and control

the amount of DMSO at 8 equivalent, which can not only efficiently complete the target conversion, but also ensure the safety of large-scale synthesis.

Optimization of conditions for scaling up

reaction by Pfitzner-Moffatt oxidation

These two works are also introduced to remind everyone that although there are certain hidden dangers in mixing DMSO with acid, if the reaction design cannot be avoided, effective measures can be taken to reduce its risk as much as possible.