Selectivity of Grignard Reagent Formation: From Semibatch to Continuous Lab and Pilot Scale

Deitmann, Eva; Dahms, Kai; Maskos, Michael; Ziegenbalg, Dirk; Menges-Flanagan, Gabriele

doi:10.1021/acs.oprd.3c00305

Cited by 2 publications

(2 citation statements)

References 41 publications

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“…For the continuous synthesis of RZnX reagents, a reactor that was originally designed and patented by Fraunhofer IMM for the formation of Grignard reagents was used (Figure ). − The reactor was produced using additive manufacturing processes, which on the one hand offer a cost-effective manufacturing method and on the other hand enable reactor geometries and heat exchanger structures that are not accessible using conventional manufacturing techniques. The reactor was made from two identical halves, which were then welded together.…”

Section: Results and Discussionmentioning

confidence: 99%

“…The conversion of the organic halide and the detection of any byproducts, especially Wurtz coupling products, are determined by gas chromatography (FID) after quenching the raw product. The undesired Wurtz coupling reaction, also known as homocoupling, is the reaction between the already-formed zinc organyl and the organic halide, resulting in the formation of a corresponding organic dimer and a zinc salt. ,,− The formation of Wurtz coupling products leads to a loss of yield of the organozinc compound and to a reduction in the quality of the product solution obtained. For this reason, Wurtz coupling should be suppressed as much as possible.…”

Section: Results and Discussionmentioning

confidence: 99%

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Continuous Scalable Synthesis and Concentration Variation of Organozinc Compounds

Gössl,

Dahms,

Menges-Flanagan

et al. 2024

Org. Process Res. Dev.

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In the production of pharmaceutically active ingredients, the formation of new carbon−carbon bonds is essential. A widespread and frequently employed method is the use of organometallic reagents (e.g., RLi, RMgX, RZnX), which differ greatly in their reactivity and are selected according to the specific reaction pathway desired. Organozinc compounds (RZnX) represent a class of compounds whose reactivity is lower than that of the widely used Grignard reagents and far below that of organolithium compounds, allowing them to tolerate the presence of functional groups incompatible with organomagnesium and organolithium compounds. Organozinc compounds are highly sensitive to oxygen and moisture, which results in difficult handling and problematic storage and limits the use of organozinc compounds in synthetic chemistry. In order to overcome this limitation and make organozinc reagents widely accessible for process chemists of varying industries, a continuous synthetic route to a large number of organozinc reagents was established on a laboratory and pilot scale. Flow rates, solvents, the metal activation mechanism, and the initial concentration of the starting materials were varied. For this purpose, a bed of Zn granules was used, which provides an approximately 250-fold excess of Zn throughout the reaction. The formed zinc organyls were analyzed by manual titration and GC analysis after quenching to determine conversion and yield as well as possible side product formation. For the formation of monozinc organyls, a lab-scale reactor originally designed for the formation of Grignard reagents was used, including a Zn replenishing unit. The main objective of this work was to establish the scalable continuous formation of organozinc reagents, which enables fast and safe process optimization. It was found that complete conversion of the organic halides used could be achieved in a single passage through the reactor with zinc organyl yields of 78−100%. Furthermore, the continuous conversion of highly concentrated 2.0 M starting materials was successfully carried out for the first time. Sufficient process reliability was ensured, and good to very good yields of 84−100% were demonstrated. The synthesis of some selected zinc organyls was then also transferred to a pilot scale, where a maximum liquid throughput of 18 L/h was achieved. With residence times of 1.5−14.0 min, complete conversion of the organic halide was achieved in all syntheses with high zinc organyl yields of up to 98%.

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Section: Results and Discussionmentioning

confidence: 99%

Section: Results and Discussionmentioning

confidence: 99%

Continuous Scalable Synthesis and Concentration Variation of Organozinc Compounds

Gössl,

Dahms,

Menges-Flanagan

et al. 2024

Org. Process Res. Dev.

Self Cite

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Organozinc Reagents: Highly Efficient Scalable Continuous Conversion in Various Concentrations and Reaction Types

Gössl,

Dahms,

Menges-Flanagan

et al. 2024

Org. Process Res. Dev.

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Organometallic reagents play a crucial role in today’s synthetic chemistry. They are used in the production of active pharmaceutical ingredients (APIs), fragrances, and agrochemicals, among other things, as they are instrumental and invaluable to form new carbon–carbon bonds. In addition to the widely used organolithium and organomagnesium compounds, better known as Grignard reagents, organozinc compounds are predestined coupling partners in C–C bond formation. Even though organozinc compounds are among the oldest organometallic compounds, they have long been superseded by the more reactive Grignard reagents (RMgX) and lithium organyls (RLi). The low reactivity of organozinc compounds in combination with a high sensitivity to oxygen and moisture lead to difficult handling and problematic storage. Their usefulness for C–C bond formation was therefore underestimated for a long time but has experienced a renaissance in recent decades. In a previous publication, the scalable continuous synthesis of organozinc compounds in different concentrations and solvents was demonstrated. The organozinc compounds were produced in both laboratory and pilot scale with good to very good yields and the formation of highly concentrated organozinc compounds was also confirmed. To build on this work, the continuous conversion of organozinc compounds is described below. Two different reaction types were investigated: the noncatalyzed Saytzeff reaction and the palladium-catalyzed Negishi cross-coupling reaction. The former was carried out in both a two-step and a one-pot approach. The reactive allylzinc bromide was chosen as the organometallic reagent, which was reacted with various aldehydes and ketones to yield secondary or tertiary homoallyl alcohols. In the Saytzeff reaction, residence times of 2.0 min were sufficient to achieve complete conversion of the carbonyl compound and isolated yields of 66–98%. The conversion of the carbonyl compound was monitored using an online process IR spectrometer with flow cell. In the case of the Negishi coupling, a fixed-bed reactor filled with Pd catalyst was used. The syntheses investigated were focused on the reaction of benzylzinc bromide with various functionalized organic halides. The Negishi coupling provided complete to near complete conversion of the electrophilic substrate with isolated yields of 72–92% at residence times of 23–32 s. Both the Saytzeff and Negishi reactions were extended to include the conversion of highly concentrated 2.0 M organozinc compounds. The former delivered yields of 83% and 92%, the latter 72% and 79%. The Saytzeff conversion was additionally transferred to pilot scale to demonstrate the ease of scalability. The synthesis of two selected compounds was successfully transferred to pilot scale, where a liquid throughput of 13 L/h was achieved. The main objective of this work was to establish various catalyzed and noncatalyzed conversions of organozinc reagents, particularly at high organozinc reagent concentrations to enable fast and safe process intensification, op...

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Selectivity of Grignard Reagent Formation: From Semibatch to Continuous Lab and Pilot Scale

Cited by 2 publications

References 41 publications

Continuous Scalable Synthesis and Concentration Variation of Organozinc Compounds

Continuous Scalable Synthesis and Concentration Variation of Organozinc Compounds

Organozinc Reagents: Highly Efficient Scalable Continuous Conversion in Various Concentrations and Reaction Types

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