Synthesizing Zinc Reagents
The formation of new carbon-carbon bonds is essential in the synthesis of pharmaceutical active ingredients.
A widespread and commonly used approach is the use of organometallic reagents (e.g., RLi, RMgX, RZnX), which vary widely in reactivity and can be selected based on the specific reaction pathway desired.
Organozinc compounds (RZnX) are a class of Grignard reagents with slightly lower reactivity, and therefore tolerate the presence of functional groups that are incompatible with organomagnesium and organolithium compounds.
Organozinc compounds are very sensitive to oxygen and moisture, which leads to difficulties in handling and storage and limits the use of organozinc compounds in synthetic chemistry.
Lars Gössl’s team has established continuous synthesis routes for a large number of organozinc reagents on laboratory and pilot scale in order to overcome this limitation and to make organozinc reagents widely available to process chemists in different industries. Flow rates, solvents, metal activation mechanisms and initial concentrations of starting materials were varied.
Iron Powder Exchange CircleResearch results
It was found that the organic halides used could be fully converted by passing them through the reactor only once, and the yield of organic zinc carbonyls could reach 78-100%.
In addition, continuous conversion of a highly concentrated 2.0 M starting material was successfully achieved for the first time. The process reliability was fully ensured and good to very high yields of 84-100% were demonstrated.
Subsequently, the synthesis of selected zinc carbonyl compounds was also transferred to pilot scale with a liquid throughput of 18 liters/hour.
Full conversion of the organic halides was achieved for all syntheses at residence times of 1.5-14.0 minutes, with yields as high as 98% for the zinc carbonyl chlorides.
Laboratory scale studies
For the continuous synthesis of RZnX reagents, the researchers used a reactor designed and patented by Fraunhofer IMM. The reactor was fabricated using an additive manufacturing process and contains two different temperature zones to help optimize the synthesis.
The continuous synthesis of various organozinc compounds has been extensively studied on a laboratory scale. It was shown that mechanical activation can only get the reaction started and achieve significant conversions in the case of reactive organohalides. However, if less reactive starting compounds are used, more efficient chemical activation must be used. In most of the syntheses studied, the organohalides were fully converted with only one pass through the reactor. For a few compounds the starting material was not fully converted, but the conversion was still
satisfactory at over 90%.
With the reactor developed at the Fraunhofer Institute for International Metals Research, organozinc compounds can be produced for more than 4 hours without accepting losses in conversion and yield. Figure 2 shows an example of temperature variation for the synthesis of a 0.5 M solution of benzyl zinc bromide in THF.
