Halex Fluorination in DMSO

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The Halex process exchanges chloride for fluoride on electron-poor aryl chlorides using potassium fluoride, producing the aryl fluorides behind fluoroquinolone antibiotics and fluorinated fine chemicals. DMSO is the industrial standard because no other common solvent dissolves KF and activates the fluoride anion as effectively.

Ar–Cl + KFDMSO, 150–200 °C→Ar–F + KCl

Reaction 1: Halex fluorination — activated aryl chloride to aryl fluoride

Where Halex Fluorination in DMSO Is Used

The largest application is the fluoroquinolone family — ciprofloxacin, levofloxacin, and moxifloxacin — where a fluorine atom on the quinolone ring is introduced by exchange on the corresponding chloro-quinolone intermediate in hot DMSO. The ring nitrogen and carbonyl activate the chloride, and bare fluoride displaces it at 150–200 °C.

The same route makes fluorinated intermediates from chloronitrobenzenes and chloropyridines, which feed agrochemicals and specialty fluorinated chemicals. DMSO is sometimes blended with sulfolane to raise the boiling point while retaining DMSO’s fluoride-activating properties. Water above about 0.2% blunts the bare-nucleophile effect and promotes hydrolysis to phenol, so KF is pre-dried and DMSO is dried over molecular sieves before charging the substrate.

More Industrial Fluorination

Halex is applied wherever an activated aryl or heteroaryl chloride must become the corresponding fluoride. The reaction is chemoselective for the activated chloride site, so other ring substituents survive, and the process supports both batch and continuous large-batch operation with onium-salt dispersion aids. Water above about 0.2% blunts the bare-nucleophile effect and promotes hydrolysis to phenol, so KF is pre-dried and DMSO is dried over molecular sieves before charging the substrate.

Table 1: Representative Halex fluorination applications in DMSO

Why DMSO Rather Than DMF or Sulfolane Alone

Potassium fluoride is poorly soluble in most solvents, and protic media hydrogen-bond F⁻ into unreactivity. DMSO solvates K⁺ strongly while leaving fluoride bare and highly nucleophilic; the resulting rate acceleration can be orders of magnitude faster than the same reaction in DMF, which is why DMSO is the workhorse.

Compared with the Balz–Schiemann route, Halex avoids diazonium decomposition, nitrogen gas, and boron trifluoride waste, and it beats direct F₂ or N–F fluorination on selectivity and reagent cost wherever an electron-withdrawing activating group is present. A DMSO/sulfolane blend then supplies the high heat-transfer and boiling point needed for continuous or large-batch operation. After reaction the mixture is quenched with water to dissolve salts and DMSO, and the solvent is recovered by distillation and recycled.