**1. Still Up-to-Date—Halogens in Active Agents**

For the discovery of new active agents, synthetic chemists frequently look into natural compounds and deduce lead structures and functionalities for the assembly of active agent libraries. Although most natural compounds are not halogenated, halogenation is spread over virtually all classes of secondary metabolites. Most of the halogenated natural compounds are of marine origin, while some are found in plants and insects as well [1]. Halogens appear in some form in 40% of all drugs being tested in clinical trials [2–4]. In addition to the fact that halogenations are an important structural motifs in natural substances and thus also in the resulting active substances, halogenations play a major role in the synthesis of many active substances. In the following, we want to figure out what is so special about the simple halogen moieties within molecules and reactions that make them so desirable, although the synthesis is very energy-demanding and carried out with toxic molecular halogens such as chlorine gas. In the second half of this review article we would like to show how nature realizes halogenations enzymatically and where we stand technologically to employ them as tools. In recent years, these enzymes have become even more prominent and the various scientific advances in this field have already been presented several times in an overview. These reviews also provide an up-to-date overview of the different enzymes, their substrate scope and biotechnological developments as well as the diversity of halo-compounds from all kingdoms of life [5–14]. The aim of this review is—among other things—to include a further point of view. In addition to the accurate arguments on the toxicity of elemental halogens and the cost-effectiveness of halide salts, a closer look at the actual costs of chlorine gas production was included, as well as a clear presentation that chemical halogenating reagents are all

based on the provision of these halogen gases. In addition, the most recent achievements for industrial applications e.g., by up-scaling processes, but also the distribution of these enzymes, as well as the break with assumed dogmas, such as conserved structural motifs, were taken into account.
