Thesis projects 2024-2025 research group professor Wim Dehaen

Three slots (Organic chemistry 1-3) may be filled with any project of topics I-V below
One project is dedicated to topic III (dyes), one to macrocycles (topic II)

I. Heterocyclic and medicinal chemistry- Novel products with interesting biological properties
In this line of research, novel compounds are synthesized starting from either natural products or via
functionalization of known biologically active compounds. The biological activity is then improved bymaking these natural products more ”drug-like”; for instance by fusing with heterocycles or appending
polar groups. A recent research topic is based on the biological activity of certain triazolopyrimidines (andother fused pyrimidine analogs, results of a scaffold hopping exercise) that are new chemotypes of CXCR2
antagonists. A second topic of research is based on the functionalization of betulin or other terpenoid
molecules studied for their cytotoxic (anticancer) and antiviral properties. We recently reported a method
to prepare analogs of the natural product papaverine. Resulting libraries of compounds are tested for their
biological activity by the Rega institute of KU Leuven. Lead compounds resulting from this screening aresubsequently developed further in order to optimize the activity.

- New multicomponent reactions : synthetic methodology and target-driven synthesis
Multicomponent reactions (MCR) are one-pot processes that combine three or more substrates either
simultaneously or through a sequential-addition procedure that does not involve any change of solvent.
We work on devising processes where there is orthogonal reactivity of the functions A,B,C,D. Existingclassical heterocyclic reactions such as the Gewald reaction or 1,3-dipolar cycloaddition are modified to aMCR version; the challenge is to find orthogonal conditions for the reactions involved. Chief among theMCR developed in our lab is the synthesis of 1,2,3-triazoles, starting from enolizable ketones, primaryamines and p-nitrophenyl azide. Compounds generated via these MCR are once again screened for their
biological activity.

Recent papers :M. Van Hoof, L. Bynens, B. Daelemans, M. C. Gonzalez Rodriguez, L.Van Meervelt, S. De Feyter, W.
Dehaen, “Octahydropyrimido[4,5-g]quinazoline-5,10-diones : their multicomponent synthesis, selfassembly on graphite and electrochemistry” Chem. Comm. 2022, 58, 7686-7689.
S. P. Veettil, S. P. Parambil, M. Van Hoof, W. Dehaen, “A multicomponent approach toward angularly
fused/linear bitriazoles: a cascade Cornforth rearrangement and triazolisation” J. Org.
Chem. 2021, 86, 4346-4354.
- Synthesis of nitrogen-containing polycyclic compounds with potential biological activities
Recently, our group reported a metal-free route towards the synthesis of 1,2,3-triazoles via anorganocascade process. This has been applied widely, and was named the triazolization reaction. Thismethod opens up new opportunities to get polycyclic 1,2,3-triazoles after cyclization reactions ofappropriately functionalized monocyclic triazoles. For instance, in ongoing work, we have combined ourtriazolization reaction with a Pomeranz-Fritsch type cyclization and acid-catalyzed ring opening to resultin a short synthesis of the alkaloid papaverine (see scheme above). In future work, the same chemistry will
be applied for the synthesis of various nitrogen-containing polycyclic compounds with potential biologicalactivities.
DNA is one of the more promising biological targets of anti-tumor drugs. Therefore, in a first project, newpolyaza structures, triazole- and triazolium-based mono- and dicationic species will be prepared as
possible DNA intercalators, via our triazolization reaction on cyclic ketones and and diketones, incombination with cyclization, aromatization, or alkylation reactions.

We have several projects on medicinal chemistry together with the Rega institute (KU Leuven). We can
not give much details due to intellectual property reasons. Below are a few structures that were recentlyreported. You may check out the references :II. Supramolecular chemistry- Heterocyclic analogs of pillararenes
Pillar[n]arenes, as the name suggests, are macrocyclic molecules with a pillar like structure when viewed
sideways. After crown ethers, cyclodextrins, and calixarenes they are the newest in line of macrocycles.
Pillar[n]arenes have received wide recognition in a short period of time due to their superiority overexisting traditional host molecules, they. Their interesting structural features and their rigid electron-richcavity make them good candidates as host molecules. The project aims at the introduction of heteroatoms
as the bridging atom X. Diverse synthetic strategies will be used and optimized, starting from substitutedhydro- and benzoquinones. Both the synthesis and the supramolecular properties and assemblies of thenovel hosts will be investigated. Extensive use will be made of different spectroscopic and physical organictechniques.
-Thiapillararenes
Here, the bridging atom X is a sulfur rather than a methylene. The synthesis of these expanded derivatives
by cyclisations of different open chain building blocks, and the resulting supramolecular properties (hostguest chemistry) will be studied in detail.

-New ligands for radiochemical applications
New ligands will be synthesized for two different radiochemical applications. The ligands will be used forthe management of nuclear waste or in cancer treatment (radiotherapy). The development of the newligands will be performed in collaboration with SCK CEN in Mol.
Ligand synthesis for selective separation of americium (management of nuclear waste)
For this application there will be looked at water-soluble ligands containing soft nitrogen donors. Previous
research has shown that soft nitrogen donors increase the selectivity for americium over the otherlanthanides and actinides. Interesting ligands consisting of such soft nitrogen donors are the bistriazolyl
phenanthrolines (BTrzPhen). Therefore, new derivatives of this class will be developed and synthesized.

P. Zsabka, T. Opsomer, K. Van Hecke, W. Dehaen, A. Wilden, G. Modolo, M. Verwerft, K. Binnemans,
T. Cardinaels, “Solvent extraction studies for the separation of trivalent actinides from lanthanides with atriazole-functionalized 1,10-phenanthroline extractant” Solv. Extract. Ion Exch. 2020, 38, 719-734.

Synthesis of bifunctional chelators for actinium (radiotherapy)
Targeted radionuclide therapy (TRT) for cancer treatment gained a lot of interest over the last decade. A
promising radionuclide for TRT is 225Ac. Various novel chelators have been proposed over the last years toform a stable complex with 225Ac. Nevertheless, most of these chelators have a shortcoming regarding
complex formation with commercially available radionuclides (for imaging purpose). In this project,
existing chelators (e.g. FENTA) and novel chelators will be synthesized and tested for radiolabeling with225
Ac and other radionuclides (153Sm, 161Tb, and 177Lu). In a final stage, bifunctional derivatives of thechelators will be synthesized and screened in vitro and in vivo.

III Dyes- Selective functionalization of BODIPY dyes
The use of fluorescent molecules in new materials is receiving increasing attention in the scientific
literature. They are currently used in several organic materials such as LED’s, lasing materials and photonicdevices. 4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene (commercialized as BODIPY®) is currently one of themost studied fluorescent molecules. In recent years our group found and reported several methods ofsubstituting the BODIPY core. We are currently trying to expand these methods towards applications in
the field of new molecular materials, sensors and long wavelength emitting dyes. In this project, we will
use an aldehyde, amine, azide or other substituted derivatives of BODIPY, that are readily available fromour previous studies, to connect 1,2,3-triazoles in a new three-component 1,2,3-triazole synthesis
developed recently in our laboratory. The triazoles can then be deprotected to very polar diacids thathave good water solubility at neutral pH. The more promising BODIPY-triazole conjugates (from theproperties viewpoint) will be converted to activated esters or similar compounds that make conjugation
to biomolecules, such as DNA or peptides, or sensors possible.

- Synthesis and properties of a new class of BOPAHY dyes
The BOPAHY fluorophore is a new addition to the family of boron chelated dyes that we recently reported.
Further work will be done to get more data on the properties, to increase the stability and quantum yieldof fluorescence and to incorporate them into new sensor molecules. This work is carried out in close
collaboration with the group of Prof Daniel Escudero.
-Synthesis of azulene derivatives
The azulene chromophore is an isomer of naphthalene with interesting photophysical properties like antiKasha emission. We will study the synthesis and properties of differently substituted azulene derivatives
including the benzo fused analogs.

F. de Jong, D. Verhaeghe, K.Veys, J. Huang, S. P. Parambil, W. Dehaen, D. Escudero, E. Fron, M. Van derAuweraer, “In-depth analysis of the photophysics of BOPAHY dyes in solution, glass and film” Dyes andPigments 2022, 206, 110662.
K. Veys, F. De Jong, A. Adriaens, G. Coenen, K. Coenen, Y. De Ligt, Q. Meysman, T. Paredis, J. Stalmans,W. Dehaen, M. Van der Auweraer, D. Escudero, “Revisiting
the fluorescence of benzothiadiazole
derivatives : Anti-Kasha emission or not”ChemPhotoChem 2022, e202200262.
M. L. Hupfer, S. Ghosh, Y. Wang, T. Opsomer, T. G. Mayerhofer, W. Dehaen, M. Presselt, “Dichroic dipole
antenna membranes from aligned linear BOPHY dyes” Adv. Mat. Interfaces 2022, 9, 2101490.

IV Materials- Synthesis of hyperbranched polyketones
This work is done in close collaboration with prof Mario Smet. Hyperbranched polymer are prepared bytrimerisation of enaminones. The resulting materials have remaining enaminone functions which then canbe end functionalized by for instance 1,3-dipolar cycloaddition with azides. The resulting polyketones will
be used for instance as reusable oxidants in Oppenheimer reactions.
-Synthesis of solid phase reagents for the triazolization reactions
In this work, we will generate “catch and release” resins functionalized with electron poor azides functions
to carry out the triazolization reaction. This will allow for an easy separation of the aniline side products
from the desired triazole

V. Reactions in hydrotropes- Green chemistry
Hydrotropes are substances that enhance the solvent power of water towards organic molecules,including (bio)polymers. For instance, the known lignin processing in hydrotropes has remarkableadvantages such as simple recycling of the solution and an increase of the environmental friendliness.
HYDROMOR is a fundamental science oriented collaborative project (laboratories Dehaen, Fardim)
aiming at unlocking the outstanding potential of hydrotropes as novel and sustainable medium for: 1)
carrying out well known organic reactions, like alkylations in hydrotrope medium and comparing themfor sustainability with the state-of-the art 2) Rational design of chemical modification of lignin in waterbased media.

This is a new project.