Converting alkyl and aryl halides to nitriles uses cheap inorganic cyanides — NaCN and KCN — that dissolve poorly in most organic solvents. DMSO dissolves these salts and presents the cyanide as a bare, highly nucleophilic anion, which makes it the standard medium for aliphatic and activated aromatic cyanation.
R–X + NaCNDMSO, 80–120 °C→R–C≡N + NaX
Reaction 1: Nucleophilic cyanation — alkyl/aryl halide to nitrile
Where Cyanation in DMSO Is Used
Aliphatic nitriles made this way are versatile fine-chemical intermediates: hydrolysis gives carboxylic acids and reduction gives amines, so the route feeds substituted acetonitriles, benzylic nitriles, and heterocyclic nitrile building blocks en route to active ingredients. Pralidoxime chloride, an organophosphate antidote, introduces a nitrile-derived carbon onto a methylpyridine precursor in DMSO.
Activated aryl chlorides bearing electron-withdrawing groups ortho or para to the leaving group undergo direct aromatic cyanation in the same solvent. Unactivated aryl halides do not react with NaCN in DMSO and are routed to copper- or palladium-mediated routes instead.
Substrate Classes in Production
Primary alkyl bromides and tosylates react cleanly with NaCN in DMSO at 80–120 °C and need no catalyst, while activated aryl chlorides undergo aromatic substitution readily. Benzylic halides occupy an intermediate position, activated toward displacement by resonance under the same conditions.
The mechanism is a straightforward SN2 displacement for aliphatic substrates: the bare cyanide anion attacks the electrophilic carbon, displacing halide in a single concerted step. For activated aromatics, the pathway is addition–elimination: cyanide adds to the ipso carbon to form a Meisenheimer complex stabilized by the electron-withdrawing group, then chloride departs to restore aromaticity. In both pathways, DMSO’s role is to keep cyanide unsolvated and highly reactive.
| Substrate | Product / industry | DMSO cyanation role |
|---|---|---|
| Primary alkyl bromide / tosylate | Fine-chemical nitriles | Aliphatic nitrile formation |
| Activated aryl chloride | Aromatic nitrile intermediates | Benzonitrile formation |
| Methylpyridine (pralidoxime route) | Pharma antidote | Nitrile introduction |
Table 1: Representative cyanation applications in DMSO
Why DMSO Rather Than Protic or Amide Solvents
In protic solvents such as ethanol, cyanide is strongly hydrogen-bonded and only weakly nucleophilic, and moist systems hydrolyze CN⁻ to HCN, consuming reagent and releasing toxic gas. DMSO solvates the Na⁺ or K⁺ cation through its sulfoxide oxygen while leaving CN⁻ unsolvated, so the free cyanide concentration stays high and hydrolysis is minimized.
Its 189 °C boiling point lets the reaction reach 80–150 °C in atmospheric equipment, and dry DMSO needs no phase-transfer catalyst because the salt is already in solution. A small excess of cyanide (1.2–2.0 equivalents) ensures complete conversion, and dry solvent is preferred because residual water promotes HCN release on long heated runs. Against DMF, DMSO avoids high-temperature decomposition; against NMP, it carries no REACH reproductive-toxin classification, which simplifies plant operation.
References
- Friedman, L.; Shechter, H. J. Am. Chem. Soc., 1960, 82(5), 1001–1002.
- Rosenmund, K. W.; Struck, E. Ber. Dtsch. Chem. Ges., 1919, 52, 1749–1756.