This thesis is divided into six parts, all centered around the development of dynamic (i.e., reversibly interacting) systems of molecules and their applications in dynamic combinatorial chemistry (DCC) and organic synthesis.

Part one offers a general introduction, as well as a more detailed description of DCC, being the central concept of this thesis. Part two explores the potential of the nitroaldol reaction as a tool for constructing dynamic systems, employing benzaldehyde derivatives and nitroalkanes. This reaction is then applied in part three where a dynamic nitroaldol system is resolved by lipase-catalyzed transacylation, selecting two out of 16 components.

In part four, reaction and crystallization driven DCC protocols are developed and demonstrated. The discovery of unexpected crystalline properties of certain pyridine β-nitroalcohols is used to resolve a dynamic system and further expanded into asynthetic procedure. Furthermore, a previously unexplored tandem nitroaldol-iminolactone rearrangement reaction between 2-cyanobenzaldehyde and primarynitroalkanes is used for the resolution of dynamic systems. It is also coupled with diastereoselective crystallization to demonstrate the possibility to combine several selection processes. The mechanism of this reaction is investigated and a synthetic protocol is developed for asymmetric synthesis of 3-substituted isoindolinones.

Part five continues the exploration of tandem reactions by combining dynamic hemithioacetal or cyanohydrin formation with intramolecular cyclization to synthesize a wide range of 3-functionalized phthalides.

Finally, part six deals with the construction of a laboratory experiment to facilitate the introduction of DCC in undergraduate chemistry education. The experiment is based on previous work in our group and features an acetylcholinesterase-catalyzed resolution of a dynamic transthioacylation system.

Crystallization-induced secondary selection from a tandem driven dynamic combinatorial library is presented. In a one-pot experiment, an initial nitroaldol equilibrium was kinetically driven by a tandem reaction resulting in a subsequent dynamic library of diastereoisomers. This library was then further driven by a phase change, resulting in amplification and isolation of a highly diastereomerically enriched and synthetically interesting isoindolinone.

This laboratory experiment introduces rocket science from a chemistry perspective. The focus is set on chemical propulsion, including its environmental impact and future development. By combining lecture-based teaching with practical, theoretical, and computational exercises, the students get to evaluate different propellant alternatives. To complete the task, they need to use several important curricular concepts, such as the breaking and formation of bonds, redox reactions, and thermodynamics. They also apply basic computational electronic structure calculations to investigate the energetic content of hitherto nonexisting alternatives. Finally, actual chemical rocket propulsion is demonstrated through the assembly and testing of a model rocket motor, employing a commercially available kit. The full experiment was developed for upper-level high school classes and is completed in a 3-h lab period. The experiment, or parts of it, has also been successfully used both in undergraduate programs and continuing education for teachers. 

The mechanism of a base-catalyzed one-pot reaction of 2-cyanobenzaldehyde and primary nitroalkanes, to produce 3-substituted isoindolinones, has been investigated. A route starting with a nitroaldol (Henry) reaction, followed by a subsequent cyclization and rearrangement, was supported by intermediate analogue synthesis and DFT calculations. Direct diastereoselective crystallization from the reaction mixture was also achieved and studied for a number of substrates. Furthermore, the 3-substituted isoindolinones are an interesting group of compounds, both present important natural products, as well as being precursors to other valuable building blocks.

In this laboratory experiment, high school students are challenged to prepare a six-layered chemical "rainbow" in a test tube. Students start with six unknown, colorless liquids and six pigments ranging from violet to red. The experiment is problem based and forces the students to apply their knowledge of solubility and density and combine it with creative and critical thinking to come up with a successful strategy to make the rainbow. This is followed by experimental testing to find the unique solution. Finally, coloring and correct layering of the liquids produces the final and aesthetically pleasing result, a chemical rainbow.

The study of dynamic nitroaldol systems aided the discovery of a diastereoselective crystallization process through amplification of 2-nitro-1-(pyridine-4-yl)propan-1-ol. The phenomenon was further developed into an effective procedure for asymmetic synthesis of pyridine-nitroalcohols and several substrates were screened to this end. These results demonstrate how work with larger dynamic systems facilitates and increases the likelihood of serendipitous discoveries.

An unexplored type of tandem reaction is used to kinetically resolve a dynamic combinatorial library resulting in quantitative amplification of an interesting 3-substituted isoindolinone.

A neighboring equatorial ester group plays a highly important role in the Lattrell-Dax (nitrite-mediated) carbohydrate epimerization reaction, inducing the formation of inversion compounds in good yields. On the basis of this effect, efficient synthetic routes to beta-D-mannosides and beta-D-talosides, from the corresponding beta-D-galactosides and beta-D-glucosides, have been designed. The present routes are based on multiple regioselective acylation via the respective stannylene intermediates, followed by inversions to the corresponding manno- and talopyranoside structures by nitrite or acetate substitution. It was found that the ester group was able to induce the inversion of its two neighboring groups in high yields following either a double parallel or a double serial inversion process. By combination of direct inversion, and neighboring- as well as remote-group participation, several beta-D-mannoside and beta-D-taloside derivatives were very conveniently obtained in good yields.

A dynamic multicomponent reaction concept has been successfully applied to the syntheses of 3-thioisoindolinones and tricyclic gamma-lactams. The reactions were efficiently designed and operated in the absence of any catalyst under mild reaction conditions, resulting in the convenient variation of substituents on the N- and S-positions of the target products.

A new tandem process based on reversible nucleophilic addition and intramolecular lactonization of methyl 2-formylbenzoate leads to the efficient synthesis of 3-functionalized phthalides, which are important precursors for the synthesis of quinone skeletons via Hauser–Kraus annulation. The reactions are successfully carried out under mild conditions in single operations.

(Chemical Equation Presented) A disturbance in the library: The nitroaldol (Henry) reaction was developed as an efficient C-C bond-forming route to dynamic combinatorial libraries (DCLs). These DCLs generated under thermodynamic control were coupled in a one-pot process with kinetically controlled lipase-mediated transesterification (see scheme). The asymmetric resolution of the DCLs by the enzyme led to enantiomerically pure β-nitroacetates in high yield.

A concept of tandem driven dynamic self-inhibition is demonstrated through dynamic inhibitors of acetylcholinesterase (AChE) using reversible transthiolesterification.