Throughout synthetic chemistry, the construction of molecules can be traced back to the formation of new carbon-carbon bonds. This overarching reaction is essential in the production of fine chemicals, including pharmaceutically active ingredients (APIs), fragrances, and agrochemicals. Reactive intermediates are often used for this purpose, including the class of organometallic reagents. In addition to the widely used organomagnesium compounds, better known as Grignard reagents (RMgX), and organolithium compounds (RLi), the significantly less reactive organozinc halides (RZnX) also have potential in synthetic chemistry. They are among the oldest organometallic reagents, but after the discovery of Grignard reagents and organolithium compounds, they were displaced by these and their use in synthetic chemistry was neglected for a long time. Their low reactivity in coupling reactions, combined with their high sensitivity to oxygen and moisture, make organozinc compounds difficult to handle and store. Their use in C-C bond-forming reactions was therefore underestimated for a long time, yet they offer great potential for use in coupling reactions that require high chemoselectivity.

In order to overcome their limited use in synthetic applications and make organozinc reagents widely available for synthetic chemistry, a continuous synthesis of various organozinc halides was investigated in a laboratory reactor originally developed and designed for the formation of Grignard reagents. Flow rates, solvents, the metal activation mechanism, and the initial concentration of the starting materials were varied. For this purpose, a bed of zinc granules was used, which provided an approximately 250-fold molar excess of Zn relative to the organic halide. The research work demonstrates the successful continuous synthesis of various organozinc halides using the developed reaction system, which allows a supply of fresh zinc during ongoing synthesis and thus enables a theoretically unlimited synthesis time. The excellent heat exchange properties of the laboratory reactor allowed safe operation of the synthesis through efficient removal of the heat released by the formation reaction.

It was found that complete conversion of the organic halides used in a single pass (residence time 1.3-26 min) through the reactor could be achieved with zinc organyl yields of 78-100 percent, while the undesirable Wurtz coupling reaction was reduced to a minimum. The synthesis of selected organozinc halides was also transferred to pilot scale, where a maximum liquid throughput of 18 l/h was achieved. With residence times of 1.5–13.6 min, complete conversion of the organic halide was achieved in all syntheses, with high zinc organyl yields of 88–98 percent. This led to highly efficient syntheses, which in turn enabled high productivity of the reactive intermediates. In addition, the feasibility of continuous conversion of highly concentrated 2.0 M starting materials was demonstrated for the first time using the synthesis of various organozinc halides. Compared to commercially available concentrations (usually 0.5 M), this represents a fourfold increase in concentration, which was described for the first time. Sufficient process reliability was ensured and good to very good yields of 84-100 percent were achieved with moderate residence times of 2.6-8.7 minutes.

It was proven that no solubility excess is responsible for the limitation of commercially available RZnX solutions to 0.5 M. The rapid and reliable process optimization of a scalable and continuous formation of organozinc halides was thus successfully demonstrated. In addition to the production of organozinc halides, their conversion in a continuous follow-up reaction was also demonstrated. The continuous conversion was investigated using two model reactions, which included the non-catalyzed Saytzeff reaction and the palladiumcatalyzed Negishi cross-coupling reaction. In the case of the Saytzeff reaction, allylzinc bromide was chosen as the reactive intermediate, which was converted with various electrophilic substrates in the form of aldehydes and ketones to secondary or tertiary homoallyl alcohols. The conversion was investigated as a twostep and one-pot approach. Low residence times of 2.0 min led to complete conversion of the respective electrophilic substrate, while isolated yields of the corresponding homoallyl alcohols of 66-97 percent were achieved, resulting in an efficient and highly productive synthesis.

In the case of the Negishi cross-coupling, which was carried out as a two-step synthesis, a fixed-bed reactor filled with Pd catalyst was used, in which the reaction of benzylzinc bromide with various functionalized organic halides was carried out. With residence times of less than one minute (23-32 s), a highly efficient cross-coupling reaction was achieved, resulting in target product yields of 84-92 percent. Both the Saytzeff and Negishi reactions were extended to include the conversion of highly concentrated organozinc compounds (approx. 2.0 M), which far exceed commercially available concentrations. Despite the high concentration of the starting compounds, no significantly higher by-product formation was detected in either reaction, which is reflected in high isolated yields (Saytzeff: 83 percent and 92 percent, Negishi: 72 percent and 79 percent). The one-pot Saytzeff reaction was also transferred to pilot scale to demonstrate the easy scalability of the conversion reaction. Using two selected compounds, a successful scale-up was demonstrated, delivering a liquid throughput of 13 l/h (residence time = 2.0 min). The homoallyl alcohols produced could be isolated with yields of 87 percent and 98 percent.

The research work demonstrates the quantity-optimized and demand-driven production of various organozinc halides as well as their conversion into synthetically relevant compounds. The continuous processing of zinc organyl synthesis and the conversion of reactive intermediates in a subsequent reaction could be transferred to highly productive syntheses with the help of specially developed reactors. The efficient, convenient, and safe production of organozinc halides has been demonstrated several times, which should strengthen the use of organozinc reagents in process chemistry. Compared to Grignard reagents and organolithium compounds, organozinc halides have a much lower reactivity, but it is precisely this property that gives them advantages, representing a high potential for synthetic chemistry.