Substituting Gaseous Reagents for Solid Alternatives

The aim of this project is to incorporate small alkyl chains into more complex organic molecules using easy to handle reagents. The type of reagents preferred in organic synthesis is solid, non-toxic, non- corrosive, and stable for a prolonged period of time without special precautions. Unfortunately, the reagents currently in use for the introduction of short alkyl chains do not fulfill these criteria in many cases, since they are often gaseous, toxic, or corrosive or even a combination of the aforementioned undesirable properties. So, what to do, in case you want to use such reagents, but change their properties to make handling easier? The hypothesis is that new reagents can be developed, which are solid and easy to handle themselves, but deliver in-situ the actual alkylation reagent, overall without experiencing the aforementioned unfavorable properties. For that purpose, we will look into several reagent classes, which can decompose under certain reaction conditions into reactive intermediates, which in turn can act as alkylating agents. Additionally, it has to be secured that the conditions required for liberating the alkylation reagent in-situ, are compatible with the other substrates, catalysts, and overall reaction conditions. The method development will start with selected test substrates and transformations, before the general scope of a certain method will be explored. Realizing this project will expand the scope of transformations which can be carried out under normal laboratory conditions without the need for special equipment (e.g. high-pressure reactors often required when working with gaseous reagents). Additionally, transformations with gaseous reagents are often actively avoided in university settings, where the reaction scale is typically in the mg region, and dosing gases in such small amounts is extremely difficult. Hence, this project will potentially open a new chemical space to be exploited in the future by chemists at all different types of institutions. Finally, the utility of the developed methods shall be demonstrated by the late- stage modification of known drug molecules.

In chemistry in general, and in synthetic chemistry in particular, the aim is to make reactions more sustainable. To this end, 12 principles of green chemistry have been defined, which deal with issues such as energy efficiency, chemical safety, reduced toxicity, waste avoidance and workplace safety. The SUGARS project tackled precisely these aspects. Among other things, it was possible to replace carcinogenic reagents with unproblematic alternatives, reduce waste through solvent-free reactions (solvents often account for >80% of waste), make reactions simpler and safer (gas reactions at high pressure were replaced by reaction conditions without the use of gases at normal pressure), and become more energy-efficient through significantly shorter reaction times. The following examples briefly illustrate the progress made in SUGARS: 1) The introduction of a methyl group (CH3, the smallest possible hydrocarbon group), was usually achieved using highly volatile and highly problematic (carcinogenic and teratogenic) reagents. In SUGARS, these reagents have been replaced by stable salts that allow safe handling. Methylation reactions are of great importance as they can often significantly improve the biological effect profile of drugs, which is known as the "magic methyl effect". 2) The use of so-called mechanochemical syntheses has increased energy efficiency on the one hand and reduced the use of solvents on the other. The principle is a mechanical mixing of the reaction partners, whereby mechanical energy instead of thermal energy enables the reaction. An additional effect is that the reaction times can also be significantly reduced in the absence of a solvent, in our best examples from 12 hours to just 30 seconds! These things have been applied to some of the most prominent reactions in organic chemistry, which has a direct impact on the way reactions will be carried out in this field in the future.