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BOOK OF ABSTRACTS
12TH DOCDAYS
UNIVERSITY OF GRAZ
SEPTEMBER 14TH – 15TH
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DOCDAYS SUPPORTED BY:
3
TABLE OF CONTENTS
ONLINE REGISTRATION ............................................................................. 4
SOCIAL EVENING ....................................................................................... 6
SCHEDULE .................................................................................................. 7
PLENARY LECTURE 1 – PROF. RUDOLF PIETSCHNIG. ............................ 8
INDUSTRY TALK – PHILIPP SELIG FROM PATHEON .............................. 10
STUDENT TALKS 1-24 .............................................................................. 12
LIST OF PARTICIPANTS ............................................................................ 37
Content
4
ONLINE REGISTRATION
IN THE MAIN SLIDE OF THE EVENT WILL BE DISPLAYED A QR CODE THAT EACH
PARTICIPANTS HAVE TO SCAN IN ORDER TO GET THE CREDITS.
THIS HAS TO BE DONE IN THE MORNING (8:45-9:00) AND BEFORE THE STARTING OF THE
AFTERNOON SESSION (13:30-13:45).
THE DAILY REGISTRATION AT THE EVENT IS SIMPLE:
SCAN THE QR CODE WITH YOUR PHONE
OPEN THE LINK WITH YOUR BROWSER
ENTER YOUR NAME AND SURNAME
CONFIRM
5
INSTRUCTIONS FOR THE MEETING:
The meeting will be hold via “Zoom Webinar”; for those of you who have never used the platform
before, you do need to download Zoom on your computer and create an account. More information
can be found at the link: https://www.youtube.com/watch?v=fMUxzrgZvZQ.
Please during the meeting keep your microphone and camera off, unless you are required otherwise.
It is required of you to share your screen and turn on your camera and microphone during your
presentation. Therefore, have your power point presentation ready and check the correct functioning
of your camera and microphone before the meeting. You will share your screen during the whole
duration of your presentation and question time.
Every speaker has a slot of 20 minutes, which is composed of maximum 15 minutes of talk and 5
minutes of questions. Please keep your talk within the time limit.
In the 5 minutes of questions, every participant has to give a feedback, by filling an online evaluation
sheet. The link for the evaluation sheet will be posted on the online chat, after every talk. Every
participant can express his/her feedback by a single vote (in the form of 1 to 5, 1 being the highest
score, 5 being the lowest) and a voluntary comment or suggestion. Please make sure to express your
vote in the given time, it will not be possible to vote after the chair has closed the vote and has moved
on with the schedule.
After every talk, questions can be asked by using the function “raise your hand” in the online chat. The
chair of the session will then proceed with giving you the possibility to talk (according to the time
schedule). Please speak clear, loud and be concise.
6
SOCIAL EVENING:
The Social Evening will take place on Tue. September 15th from 6 pm at s'Biergartl. You will get a
personal coupon for food and drinks (you will get more information during the meeting).
s'Biergartl
Schönaugasse 41, 8010 Graz
From: https://www.google.com/maps, 2020
Schedule
7
MON. September 14th
TUE. September 15th
0845-0900 Online Registration 0845-0900 Online Registration
0900-0915 Opening, Welcome
Prof. Christof Gattringer
Prof. Frank Uhlig
0900-1000 Chair: Weinberger
IT01 Selig from Patheon
ST12 Mata Gomez
ST13 Pöcheim
0915-1000 Chair: Prof. Uhlig
PL01 Prof. Pietschnig
1000-1015 Coffee Break
1000-1015 Coffee Break
1015-1115 Chair: Pöcheim
ST01 Pompei
ST02 Guttmann
ST03 Köckinger
1015-1115 Chair: Guttmann
ST14 Walenta
ST15 Sagmeister
ST16 Lazzarotto
1115-1130 Coffee Break
1115-1130 Coffee Break
1130-1230 Chair: Sagmeister
ST04 Wolfsgrubger
ST05 Schwarz
ST06 Steinegger
1130-1230 Chair: Schlatzer
ST17 Steiner
ST18 Steller
ST19 Eggbauer
1230-1345 Lunch Break
1230-1345 Lunch Break
1345-1445 Chair: Jurkaš
ST07 Breukelaar
ST08 Schlatzer
ST09 Zelzer
1345-1445 Chair: Breukelaar
ST20 Wiedemaier
ST21 Jud
ST22 Fuchs
1445-1500 Coffee Break
1445-1500 Coffee Break
1500-1540 Chair: Steller
ST10 Kodolitsch
ST11 Maierhofer
1500-1540 Chair: Breukelaar
ST23 Bondi ST24 Hoffellner
1540-1555 Concluding remarks
1800 Social Evening s'Biergartl
8
PLENARY LECTURE
PL01 Prof. Rudolf Pietschnig
Plenary Lecture
9
Phosphorus - more than a carbon copy
Roman Franz, Fabian Roesler, Denis Kargin and Rudolf Pietschnig*
Institute of Chemistry, University of Kassel
Heinrich-Plett-Straße 40, 34132 Kassel, Germany
[email protected], www.uni-kassel.de/go/hym
The diagonal relationship between phosphorus and carbon has been inspiration for synthetic and
structural chemistry for decades. [1] More recently, the unique and variable bonding situation in many
organophosphorus compounds has be employed to endow molecular materials with fascinating
electronic properties.[2] In our contribution a survey of recent achievements in this area will be
presented with particular focus on reactivity, stereo control and luminescence of organometallic
phosphorus compounds. In vicinity of electron rich metallocene units phosphorus frameworks are
prone to electronic interaction and exchange processes.[3]
Fe
FeFe
Figure 1. The pronounced s-character of lone-pairs at trivalent phosphorus atoms entails subtle interaction in P-
heterocyclic compounds such as phospholes (1) or phospha ferrocenophanes (2, 3) where low valent group 14 elements
(E = Si, Ge, Sn, Pb) are adjacent to P-stereogenic centers.
The authors acknowledge financial support by the DFG (PI 353/8-1, PI 353/9-1, PI 353/ 11-1 and CRC
1319 (ELCH)).
References: [1] K. B. Dillon, F. Mathey, J. F. Nixon, Phosphorus: The Carbon Copy, Wiley, Chichester, England, 1998.
[2] T. Baumgartner, R. Réau, Chem. Rev. 2006, 106, 4681-4727.
[3] A. Lik, D. Kargin, S. Isenberg, Z. Kelemen, R. Pietschnig, H. Helten, Chem. Commun. 2018, 54, 2471-2474
[4] R. Pietschnig, Chem. Soc. Rev. 2016, 45, 5216 - 5231.
10
INDUSTRY TALK
IT01 Philipp Selig
Patheon, by Thermo Fisher Scientific
Industry Talk
11
Process Chemistry at Patheon, by Thermo Fisher Scientific
Philipp Selig
Patheon, by Thermo Fisher Scientific; Patheon Austria GmbH & Co KG
St.-Peter-Straße 25, 4040 Linz, Austria
Process Chemistry is the art of developing a laboratory synthesis into a universally applicable, quality-
controlled and safe large-scale production process.
Following a short presentation of our pharmaceutical production site in Linz, we will introduce you to
some of the most important aspects of process chemistry (safety, operability, quality) and shed some
light on the questions: Why do we need process chemistry, and what makes a good production process?
12
STUDENT TALKS
MON. September 14th
ST01 Simona Pompei
ST02 Robin Guttmann
ST03 Manuel Köckinger
ST04 Andreas Wolfsgruber
ST05 Romana Schwarz
ST06 Andreas Steinegger
ST07 Willem Breukelaar
ST08 Thomas Schlatzer
ST09 Sieglinde Zelzer
ST10 Katharina Kodolitsch
ST11 Maximilian Maierhofer
TUE. September 15th
ST12 Alejandro Mata Gomez
ST13 Alexander Pöcheim
ST14 Martin Walenta
ST15 Peter Sagmeister
ST16 Mattia Lazzarotto
ST17 Alexander Steiner
ST18 Beate Steller
ST19 Bettina Eggbauer
ST20 Fabian Wiedermaier
ST21 Wolfgang Jud
ST22 Andreas Fuchs
ST23 Riccardo Bondi
ST24 Lisa Hoffellner
ST 01
13
Biocatalytic demethylation of guaiacol derivatives
Simona Pompei, Christopher Grimm, Wolfgang Kroutil*
Institute of Chemistry, University of Graz
Heinrichstrasse 28, 8010 Graz, Austria
[email protected], https://www.uni-graz.at
The ether functionality belongs to the most common and unifying structural features found in nature.[1]
The ubiquitous distribution of the C-O-C bond is widely shown among natural products, as well as in
man-made flavorings, fragrances and pharmaceuticals.[2] Therefore, the formation or breakage of C-O
ether bonds are valuable synthetic transformations. Since the C-O bond energy is 360 kJ/mol,
microbial cleavage of the ether bond is an extraordinary phenomenon and inevitably requires a
considerable investment of energy.[1] Consequently, to cleave the ether bond chemically, strong acids
such as hydrobromic acid (HBr) are generally necessary. Ethers are, in fact, rather stable to hydrolysis
even in the presence of mild acids or bases.
Figure 1. Enzymatic quasi-irreversible demethylation of guaiacol derivatives coupled with thiol-methyl acceptors.
We herein present a biocatalytic approach requiring a methyltransferase reversibly catalyzing both O-
methylation of phenols and demethylation of methyl pheny ethers via a cobalamin cofactor which is
bound to a carrier protein. The two proteins used here originate from the anaerobic bacteria
Desulfitobacterium halfiense. Interestingly, the methylation of thiols was found to be quasi-
irreversible. As this methyl acceptors seemed to act as a “methyl group sink”, the thiols are ideal as
acceptors for a demethylation method.
The role of downstream methyl acceptor was essential to drive the direction of the reaction towards
demethylation. We tuned the reaction parameters (pH, donor and acceptor concentrations, protein
loading) to obtain a rather general method to achieve the demethylation of guaiacol derivatives. As
proof of applicability, the biotransformation was scaled up, whereby hydroxytyrosol was produced in
high purity manner in a single step.
References: [1] G. F. White, N. J. Russell, E. C. Tidswell, Microbiol. Rev. 1996, 60, 216.
[2] E. J. Barreiro, A. E. Kummerle, C. A. Fraga, Chem. Rev. 2011, 111, 5215-5246.
ST 02
14
Highly Accurate Geometries and Hydrogen-Bonded Energies of Small Systems
Robin Guttmann, A. Daniel Boese*
Institute of Chemistry, University of Graz
Heinrichstrasse 28, 8010 Graz, Austria
[email protected], https://www.uni-graz.at
As hydrogen-bonded systems are highly important in Biology and Chemistry, as almost all reactions
and systems are investigated and present in the liquid phase. In order to describe this phase properly,
the interactions have to be well understood and characterized. In order to do so, we calculate these
systems by state-of-the-art quantum mechanical post-Hartree-Fock methods. However, such
calculations are often not feasible for large systems due to the high computational costs. Therefore,
small model systems are often used as reference data for benchmarking various computational
methods. [1] A very promising benchmark set for intermolecular interaction energies and geometries is
the HB49 reference set, consisting of 49 complexes of small interacting molecules.[2]
In this talk, we will significantly extend and improve upon the existing HB49 reference data. First, we
use the so-called "gold standard" of quantum chemistry CCSD(T) for interaction energies as well as
for geometries. Second, we extend the benchmark set to also include non-equilibrium geometries via
constrained optimizations of 10 different intermolecular distances, leading to potential energy curves and thus a better description of the whole potential energy surface. Complete basis set extrapolations
and inclusion relaxation energies throughout lead to a further improvement of the obtained reference
data.
We find that the performed CCSD(T) geometry optimizations lead to small modifications of the
molecular structures compared to the original HB49 data. The resulting HB49x10 reference set
contains extremely accurate geometries and interaction energies for equilibrium as well as non-
equilibrium structures, which will enable high-quality benchmarks and development of new
computational methods for hydrogen bonds in particular.
Figure 1. Steps for highly accurate CCSD(T) interaction energies and geometries obtained with complete basis set
extrapolations (CBS).
References: [1] P. Morgante, R. Peverati, J. Comput. Chem. 2019, 40, 839-848.
[2] A. D. Boese, Mol. Phys. 2018, 113, 1618-1629.
ST 03
15
Continuous-flow Synthesis of Aryl Aldehydes by Pd-catalyzed Formylation of
Phenol Derived Aryl Fluorosulfonates Using Syngas
Manuel Köckinger1,2, Christopher A. Hone1,2, Paul Hanselmann3, C. Oliver Kappe1,2* 1Institute of Chemistry, University of Graz, NAWI Graz
Heinrichstrasse 28, 8010 Graz, Austria
[email protected], https://www.goflow.at 2Research Center Pharmaceutical Engineering GmbH (RCPE)
Inffeldgasse 13, 8010 Graz, Austria 3Microreactor Technology, Lonza AG, CH-3930 Visp, Switzerland
The fluorosulfonate group (-OSO2F) is a new and underutilized highly reactive functional group,[1]
which can be used as versatile intermediate in modern organic synthesis, particularly in the preparation
of biologically active compounds. The properties of fluorosulfonates are very similar to triflates, which
are one of the most commonly employed leaving groups. Aryl Fluorosulfonates (ArOFs) can be made
by the treatment of ArOH with sulfuryl fluoride (SO2F2), an inexpensive commodity chemical that is
widely used as an insecticide. Phenols are a particularly attractive and inexpensive starting material as
they are readily available from biomass. Building on previous knowledge on formylation reactions,[2]
we developed the first Pd-catalyzed formylation of ArOFs with syngas to yield aryl aldehydes using
stoichiometric amounts of syngas in continuous flow (Scheme 1). The optimized conditions were
applicable to a large set of substrates giving good to excellent yield of the corresponding arylaldehyde.
Scheme 1. Formation of Fluorosulfonates and subsequent Pd catalyzed continuous flow carbonylation using syngas in
good to excellent yields.
References: [1] J. Dong, L. Krasnova, M. G. Finn, K. Barry Sharpless, Angew. Chemie - Int. Ed. 2014, 53, 9430–9448.
[2] C. A. Hone, P. Lopatka, R. Munday, A. O’Kearney-McMullan, C. O. Kappe, ChemSusChem 2019, 12, 326–337.
ST 04
16
Ligand Directed Protein Profiling of Carbohydrate-Processing Enzymes:
From Challenging Synthesis to First Biological Results
Andreas Wolfsgruber, Tanja M. Wrodnigg*
Institute of Chemistry and Technology of Biobased Systems, Graz University of Technology
Stremayrgasse 9, 8010 Graz, Austria
[email protected], https://www.tugraz.at
Carbohydrate-processing enzymes (CPEs) are a group of proteins, which are responsible for the
metabolism of carbohydrates and their conjugates in living organisms. Malfunction of these enzymes
results in diseases, such as, lysosomal storage diseases, immunological diseases, cancer, diabetes or
bacterial as well as viral infections. [1] However, the role and the contribution of the carbohydrate part
is still unknown or unrealised. Regarding this, activity based protein profiling (ABPP) has become a
solid technique for studying and elucidating protein functions in highly complex biological
environments. For instance, Stubbs, Withers and Overkleeft, [2] have developed paradigmatic examples
of such activity-based probes for carbohydrate processing enzymes.
Another approach for protein profiling is to use ligand-directed chemistry. [3] In contrast to ABPP
methods, this strategy allows for traceless and target-selective chemical labeling of proteins while
restoring the enzyme activity for further applications such as real-time monitoring in living cells. In
this case, the probe (Figure 1) is equipped with a recognition part (warhead) that allows for reversible
interaction of the probe with the active site of the enzyme of interest, and a detectable agent (tag) for
identification. The reactive group in between is responsible for the connection of the warhead and the
tag and at the same time behaves as electrophile that can be attacked by an amino acid residue near the
outside of the ligand-binding pocket. It covalently attaches the tag to the target protein. Concomitantly,
the warhead dissociates from the active site, which results in retention of protein activity. [3]
Figure 1. Example of a potential iminosugar based LDPP probe.
Results of our work towards the design, synthesis as well as first biological evaluation of iminosugar-
based probes for activity-based protein profiling of CPEs by ligand directed chemistry will be
presented.
References:
[1] A. E. Stütz, T. M. Wrodnigg, Adv. Carbohydr. Chem. Biochem. 2016, 73, 225-302.
[2] M. N. Gandy, A. W. Debowski, K. A. Stubbs, Chem Commun. 2011, 47, 5037-5039; O. Hekmat, S. He, R.
A. Warren, S. G. Withers, J. Proteome Res. 2008, 7, 3282-3292; J. Jiang, T. J. M. Beenakker, W. W.
Kallemeijn, G. A. van der Marel, H. van den Elst, J. D. C. Codeé, J. M. F. G. Aerts, H. S. Overkleeft, Chem.
Eur. J. 2015, 21, 10861-10869.
[3] S. Tsukiji, M. Miyagawa, Y. Takaoka, T. Tamura, I. Hamachi, Nat. Chem. Biol. 2009, 5, 341-343; Y. Takaoka, A.
Ojida, I. Hamachi, Angew. Chem. Int. Ed. 2013, 52, 4088-4106.
ST 05
17
Exploring Thiol based Resins for the 3D-Printing of Medical Devices
Romana Schwarz1,2, Thomas Griesser1, Gregor Trimmel2* 1Institute of Chemistry of Polymeric Materials, Montanuniversitaet Leoben,
Otto-Glöckel-Straße 2, 8700 Leoben, Austria. 2Institute of Chemistry and Technology of Materials, Graz University of Technology
Stremayrgasse 9, 8010 Graz, Austria.
[email protected], https://www.tugraz.at
The last years have seen an increasing interest in the development of photo-polymerizable monomers
providing low cytotoxicity for the 3D printing of medical devices. In this PhD thesis, novel concepts
based on the thiol-X photo click chemistry are investigated and evaluated for the realization of
biocompatible photopolymers according to ISO 10993-5 (“Biological evaluation of medical devices -
Part 5: Tests for in vitro cytotoxicity”).
For the production of medical devices, which are in direct contact with human tissue, especially in the
case of mucosa or blood, non-network bound components like photoinitiators or their cleavage
products, but also residual monomers, stabilizers, degradation products or monomer impurities are of
major concern.[1] Many of these components state health risks when released to the human body by
migration processes. This contribution deals with the investigation of photocurable thiol-yne resins
covering several important aspects for the production of medical devices by UV based manufacturing
processes.
It turned out that these thiol based resins offer curing rates similar to acrylates, while providing much
higher conversion and lower monomer cytotoxicity.[2] This reactions leads to highly uniform polymeric
networks exhibiting a sharp and defined thermal glass transition together with outstanding toughness
which makes these polymers interesting for challenging applications such as medical implants.
The herein described monomer systems pave the way towards the individual fabrication of tissue
compatible photopolymers with tunable thermo-mechanical properties.
References:
[1] J. L. Ferracane, Resin composite-state of the art. Dental materials: official publication of the Academy of Dental
Materials 2011, 27, 29-38.
[2] A. Oesterreicher, S. Ayalur‐ Karunakaran, A. Moser, F. H. Mostegel, M. Edler, P. Kaschnitz, G. Pinter, G. Trimmel,
S. Schlögl, T. Griesser, Exploring thiol‐ yne based monomers as low cytotoxic building blocks for radical
photopolymerization. Journal of Polymer Science Part A: Polymer Chemistry 2016, 54, 3484-3494.
ST 06
18
TADF emitters for self-referenced optical sensing
Andreas Steinegger, Silvia Zieger, Ingo Klimant, Sergey M. Borisov*
Institute of Analytical Chemistry and Food Chemistry, Graz University of Technology
Stremayrgasse 9, 8010 Graz, Austria
Optical sensors based on luminescent materials have become an integral part of analytical chemistry
as they offer distinct advantages over conventional sensing schemes. Sensors for pH, ions, oxygen,
carbon dioxide, and other analytes already have been well established, but the field is still intensively
investigated in search for more advanced probes, expanding the scope of analytes and applications.
Most luminescent materials in these sensors emit prompt fluorescence or phosphorescence.
Thermally activated delayed fluorescence (TADF) is a type of luminescence with intermediate
properties between prompt fluorescence and phosphorescence; similar to fluorescence, the emission
of photons occurs from the excited singlet state and analogously to phosphorescence, the triplet state
with correspondingly long lifetimes is involved. These characteristics of TADF render it very
interesting for sensing applications. Since TADF relies on reverse intersystem crossing, it displays
temperature-dependent behavior and consequentially can enable optical temperature sensing.
Additionally, the inherently long lifetimes of TADF can render the dyes also susceptible to oxygen
quenching, and therefore may make them promising for oxygen sensing. For measurement, the
luminescence decay time is determined, which is inherently self-referenced. By choice of the
immobilization matrix, temperature (Fig. 1, left) or dual sensors for temperature corrected oxygen
sensing can be prepared (Fig. 1, right).
Figure 1. Left: sensor design and temperature dependency of the TADF decay time for two TADF emitters.[1]
Right: calibration planes depicting the luminescence response of a TADF emitting material to temperature and oxygen.[2]
References: [1] S. Zieger, A. Steinegger, I. Klimant, S. M. Borisov, ACS Sens. – in Revision
[2] A. Steinegger. S. M. Borisov, submitted
ST 07
19
Biocatalytic Reduction of Oximes Using Flavin-Dependent Ene-Reductases
Willem B. Breukelaar, Stefan Velikogne, Silvia Glück-Harter, Wolfgang Kroutil*
Institute of Chemistry, University of Graz
Heinrichstrasse 28, 8010 Graz, Austria
Flavin-dependent ene-reductases (EREDs), such as those of the Old Yellow Enzyme (OYE) family,
are a well described and studied class of enzymes, mostly applied for the enantioselective reduction of
activated C=C double bonds (Figure 1, top) . While a wide substrate scope has been established,[1] the
enzymes are not known for the reduction of C=heteroatom bonds. Recent work in our group has shown
that several ene-reductases reduce the oxime functionality of -keto--oximo esters very efficiently,
yielding tetrasubstituted pyrazines from non-enzymatic cyclisation and oxidation of the product
formed in biotransformation (Figure 1, bottom). Currently, we are working on a better understanding
of the mechanism, as well as application of this reactivity for the chemoenzymatic synthesis of chiral
amines.
Figure 1. General reaction schemes of the well described “traditional” use of EREDs for the reduction of activated C=C
double bonds (top) and the outline of this work, ERED-mediated reduction of an activated oxime to an amine
intermediate, followed by non-enzymatic cyclisation and oxidation to tetrasubstituted pyrazines (bottom).
The oxime reduction has been tested using a small substrate library (8 oximes) and six EREDs. This
has shown that various oximes are transformed with high efficiency (up to 77% product formation
within 24 hours), and that the experiments can easily be scaled up to preparative amounts. Typical
experiments using 2 mmol oxime yield 150-250 mg pyrazine, corresponding to isolated yields of up
to 62%.[2]
Currently, we are exploiting this unusual reactivity by synthesising and testing a library of oximes
derived from asymmetric malonates. Preliminary experiments have shown substrates of this
description to be accepted by the enzyme and transformed into the corresponding primary amine. This
work will be expanded further by establishing a substrate library and quantitative determination of
product formation and enantiomeric excess.
References: [1] Toogood, H. S.; Gardiner, J. M.; Scrutton, N. S. ChemCatChem 2010, 2, 892–914
[2] S. Velikogne, W. B. Breukelaar, F. Hamm, R. A. Glabonjat, S. Glück, K. Francesconi, W. Kroutil,
manuscript in preparation.
ST 08
20
Palladium-Catalyzed S-Allylation as Bioorthogonal Strategy
Thomas Schlatzer1,*, Julia Kriegesmann2, Christian F. W. Becker2, Rolf Breinbauer1 1Institute of Organic Chemistry, Graz University of Technology
Stremayrgasse 9, 8010 Graz, Austria 2Institute of Biological Chemistry, University of Vienna,
Währinger Straße 38, 1090 Vienna, Austria
Organopalladium species have proven as extremely useful tools for the selective modification of
peptides and proteins under biocompatible conditions. Therefore, numerous protocols based on
organopalladium reagents have recently emerged to artificially modify biomolecules.[1] In vivo many
nascent or folded proteins also undergo post-translational modifications (PTMs). An especially
noteworthy PTM is protein S-prenylation since this process does not only provide the protein with
hydrophobic anchors that allow binding to membranes but also is crucial for the activity of oncogenic
forms of Ras proteins.[2]
Figure 1. Reagent design and reaction mechanism of the Pd-catalyzed S-allylation.
In order to address this challenge, we developed an efficient method based on in situ prepared
π-allylpalladium complexes that are ideally suited for S-allylations overcoming prevalent difficulties
such as catalyst poisoning and thiol oxidation. The generated palladium species are highly functional
group tolerant and exhibit excellent chemo- as well as regioselectivity. This was mechanistically
investigated and applied on a broad set of thiol substrates including natural products such as
cephalosporins.[3] We then expanded the scope of our methodology to biomolecules enabling the
cysteine-selective prenylation (farnesylation, geranylgeranylation) of unprotected peptides and
proteins in aqueous solvents via a native thioether linkage. Therefore, this method offers access to
authentic, post-translationally modified proteins in vitro. Moreover, the broad utility of this new
ligation method was demonstrated by the incorporation of bioconjugation handles, an affinity tag and
a fluorophore into cysteine-containing peptides or proteins.[4]
References: [1] M. Jbara, S. K. Maity, A. Brik, Angew. Chem. Int. Ed. 2017, 56, 10644-10655.
[2] M. H. Gelb, L. Brunsveld, C. A. Hrycyna, S. Michaelis, F. Tamanoi, W. C. van Voorhis, H. Waldmann,
Nat. Chem. Biol. 2006, 2, 518-528.
[3] T. Schlatzer, H. Schröder, M. Trobe, C. Lembacher-Fadum, S. Stangl, C. Schlögl, H. Weber, R.
Breinbauer, Adv. Synth. Catal. 2020, 362, 331-336.
[4] T. Schlatzer, J. Kriegesmann, H. Schröder, M. Trobe, C. Lembacher-Fadum, S. Santner, A. V. Kravchuk,
C. F. W. Becker, R. Breinbauer, J. Am. Chem. Soc. 2019, 141, 14931-14937.
ST 09
21
Application of a new LC-MS/MS method for determination of Vitamin D
metabolites
Sieglinde Zelzer1,2, Andreas Meinitzer2, Markus Herrmann2, Walter Goessler1 1University of Graz, Institute of Chemistry, Universitätsplatz 1, 8010 Graz, Austria;
2Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University
of Graz, Auenbruggerplatz 15, 8036 Graz
[email protected], https://www.uni-graz.at
In recent years, determination of vitamin D has increased in importance due to the clinical relevance
of vitamin D deficiency and intoxication [1]. Assessment of the vitamin D status including metabolites
remains critical especially for persons with a 24-hydroxylase deficiency. This enzyme plays an
important role in calcium homeostasis by catalyzing the conversion of 25-hydroxyvitamin D3
(25(OH)D3) into 24,25-dihydroxyvitamin D3 (24,25(OH)2D3). Reduced enzymatic activity has been
reported to cause hypercalcemia and nephrotoxic diseases with of too high vitamin D levels [2]. In the
case of a 24-hydroxylase deficiency, it is very important to refrain from any kind of vitamin D
supplementation. To identify a disordered vitamin D metabolism the simultaneous determination of
25(OH)D3 and some other hydroxylated metabolites in serum samples is necessary. We established a
new LC-MS/MS method based on 4-Phenyl-1,2,4-triazole-3,5-dione (PTAD) derivatization with high
sensitivity, selectivity and good accuracy for 25(OH)D3, 25-hydroxyvitamin D2 (25(OH)D2) and
24,25(OH)2D3. The method was verified by external controls provided by the Vitamin D External
Quality Assessment Scheme (DEQAS) which is traceable to the National Institute for Standards and
Technology [3]. The clinical utility of this method has been confirmed in a patient with 24-hydroxylase
deficiency with an extreme low 24,25(OH)2D3 concentration. In the sample, we found an additional
analyte peak next to the 24,25(OH)2D3 response which was identified as 25,26-dihydroxyvitamin D3.
A comparison study between our LC-MS/MS method and the IDS-iSYS 25OHDS assay, an
immunoassay used in clinical routine showed a mean bias of -16.6 %. [4]. A possible cross reactivity
of the 24,25(OH)2D3 could explain this discrepancy.
Figure 1. Typical chromatogram for determination of 24,25-dihydroxyvitamin D3 concentration and the new identified
vitamin D metabolite 25,26-dihydroxyvitamin D3
References: [1] M. Herrmann, CL. Farrell, I. Pusceddu, N. Fabregat-Cabello, E. Cavalier, Clin Chem Lab Med. 2017, 55, 3-26.
[2] K. P. Schlingmann, M. Kaufmann, S. Weber, A. Irwin, C. Goos, U. John, et al, New Engl. J. Med. 2011, 365, 410-21.
[3] N. Binkley, CT. Sempos, J. Bone Miner Res. 2014, 29, 1709-14.
[4] S. Zelzer, W. Goessler, M. Herrmann M, J. Lab. Precis. Med. 2018, 3, 99.
24,25(OH)2D3
25,26(OH)2D3
Compound Precursor ion / Product ion (m/z)
24,25(OH)2D3 574.2 / 298.0
25,26(OH)2D3 574.1 / 298.1
ST 10
22
Construction of coordination polymers with bifunctional linkers
Katharina Kodolitsch1, Ana Torvisco2 and Christian Slugovc1 1 Institute for Chemistry and Technology of Materials, Graz University of Technology,
Stremayrgasse 9, 8010 Graz, Austria 2 Institute of Inorganic Chemistry, Graz University of Technology, Stremayrgasse 9, 8010 Graz,
Austria
In terms of the fabrication of Metal Organic Frameworks (MOFs), the assembly with desired structural
types is totally dependent on the judicious choice of appropriate organic spacers. In this regard, organic
linkers with N and/or O donors often have been employed as effective building blocks.[1]
Herein we report a truly green way to prepare potentially bidentate ligands namely 3-(1H-imidazol-1-
yl)propanoic acid derivates. The two-step synthesis includes an aza-Michael reaction of the imidazole
derivatives with enoates and an ester cleavage using one equivalent of NaOH in water. The obtained
ligands have been used for the preparation of coordination polymers with various metal salts from
water solutions, whereby herein special focus will be placed on zinc.
Starting from aqueous zinc(II) solutions and adding two equivalents of the ligand dissolved in water
led to the instantaneous formation of white precipitates. Of particular interest is the 2-methylimidazole
based linker because it forms a microcrystalline, microporous precipitate consisting of 1D coordination
polymers which are organized in a 3D scaffold held together by hydrogen bonding with crystal water
(see Figure above). The material does not lose its porosity and crystallinity upon drying. Molecules
bearing carboxylic acid groups such as the protein BSA or fluorescein could be incorporated into the
crystals. In contrast, the imidazole and 3-phenylimidazole based linkers initially form amorphous
precipitates which show permanent porosity upon drying. Prolonged heating of the amorphous
precipitate at 80°C leads to the formation of a crystalline material consisting of 2D coordination
polymer sheets linked via hydrogen bonding to form a 3D scaffold. Drying of these crystals however
led to the loss of crystallinity. However, encapsulation of guests (proteins, dyes) into the initial
precipitate is still feasible.
The contribution will deal with a structural description of the materials and a presentation of their
properties such as surface area, thermal stability, solubility in water and several puffer systems and
will discuss the encapsulation of guests.
References:
[1] S. Chen, Q.Liu, Y.Zhao, R.Qiao, L. Sheng, Z. Liu, S. Yang, C. Song, Cryst. Growth Des, 2014, 14, 3727-3741.
ST 11
23
A Fluorescent Optical Ammonia Sensor–Suitable for Online Bioprocess
Monitoring
Maximilian Maierhofer, Veronika Rieger, Torsten Mayr*
Institute of Analytical Chemistry and Food Chemistry, Graz University of Technology
Stremayrgasse 9/II, 8010 Graz, Austria
[email protected], https://www.tugraz.at/institute/acfc/home/
Optical sensors have found numerous applications in the last decades, e.g. optical sensors for oxygen
and pH are established in bioprocess monitoring. In bio processing ammonia is another key parameter
due to its toxicity at certain concentration levels.[1] Since this compound is often a by-product in
bioprocessing, online monitoring is desired. However, sensors for monitoring ammonia or ammonium
in bioreactors are rare. We present an ammonia sensor (Fig. 1 (b)) suitable for bioprocess monitoring.
Our system is based on an acid-base concept including a fluorescent pH-sensitive dye.[2] The sensing
layer is covered by a hydrophobic porous membrane, which excludes hydrophilic interfering materials.
Our target analyte, ammonia (NH3), diffuses through the barrier to the protonated dye whereby it
deprotonates the dye and switches off the NIR-emission. Read-out is performed with a commercially
available compact phase fluorimeter combined with optical fibers. Dual-lifetime referencing (DLR)
acts as detection method and Egyptian blue as reference material. A sensor performance in the range
of total ammonia concentration (TAC) from 1 to 100 mmol L-1 is demanded. By exchanging the dye,
the dynamic range of the sensor is shifted towards other concentrations opening different application
fields like environmental monitoring and chemical reaction monitoring. Depending on temperature
and ammonia concentration the response time t90 and the recovery time vary from 20 s up to 4 min
(Fig 1 (a)). The sensor performance is not influenced sufficiently by varying temperature (Fig. 1 (c)).
The sensor materials are chosen to withstand β-sterilization. Further experiments on other sterilization
methods will be studied in future. This sensor is planned to monitor reactions in bioreactor systems.
0 5000 10000 15000 20000 25000
5
10
15
20
25
30
35
40
0.03
10
dp
hi / °
Time / s
100
10
1
3
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0.1
1
3
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0.1
0.03
0.1 1 10 100 1000
0.0
0.1
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0.4
0.5
0.6
0.7
0.8
0.9
1.0
25°C
35°C
45°C
No
rm. co
t(p
hi)
TAC / mmol L-1
(a) (b) (c) Figure 1. (a) Sensor response at 25°C at seven different ammonia concentrations in mg L-1 (b) Optical ammonia sensor
attached to an optical fiber with a stainless screw-cap, diameter 5 mm; (c) Calibration plots of ammonia sensor monitored
at three different temperatures for TAC in mmol L-1. Mean values and standard deviations obtained from four sensors.
References:
[1] B. Timmer, W. Olthuis, A. van den Berg, Sensors and Actuators B: Chemical 2005, 107, 666–677.
[2] M. Strobl, T. Rappitsch, S. M. Borisov, T. Mayr, I. Klimant, Analyst 2015, 140, 7150–7153.
ST 12
24
Acyl Azide Generation and Amide Bond Formation in Continuous-Flow for the
Synthesis of Peptides
Alejandro Mata, U. Weigl, O. Floegel, Christopher A. Hone and C. Oliver Kappe*
Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical
Engineering GmbH (RCPE) Inffeldgasse 13, Graz 8010, Austria.
Institute of Chemistry, University of Graz Heinrichstrasse 28, 8010 Graz, Austria
[email protected], https://www.goflow.at
Acyl azides are valuable synthetic intermediates for the preparation of amides, amines, isocyanates,
ureas, ketenimines and carbodiimides.1 One particularly important application is their use for the
synthesis of peptides and proteins.2 There are a number of synthetic strategies to form peptides from
their corresponding amino acids.3 However, many of the traditional amide bond formation protocols
do not reach the high requirements of enantioselectivity necessary for active pharmaceutical ingredient
(API) synthesis. The acyl azide method is perhaps the best method for racemization-free peptide
segment condensation, which cannot be so readily achieved by other amide coupling methods.2,4
Figure 1. Acyl azide method for the preparation of dipeptides: 1) hydrazide formation; 2) acyl azide generation; and 3)
peptide coupling
A disadvantage of the acyl azide method is its rather laborious synthetic sequence that involves the
handling of a highly dangerous byproduct as azides anions. Despite the advantages described above,
the acyl azide method for the synthesis of peptides has been abandoned and it is strictly off-limits in
industrial scale. To overcome these safety concerns, continuous flow chemistry is presented as a key
tool to implement “forbidden” chemistry into safe processes.5 We envisioned a continuous-flow
protocol that would address the safe handling and quenching of such highly unstable and potentially
explosive intermediates. Microreactor technology enables the safe generation of acyl azides and their
reaction in situ in a telescoped process. A biphasic environment made possible the separation of azide
anions from the desired dipeptides and their posterior and immediate quench. The protocol has been
used to prepare various dipeptides (5 examples) free of epimerization (<1%). In combination with boc-
cleavage protocol (also investigated in continuous flow), we extended the scope to the formation of a
tripeptide.
References: [1] a) M. Balci, Synthesis 2018, 50, 1373-1401; b) S. Bräse, C. Gil, K. Knepper and V. Zimmermann, Angew.
Chem. Int. Ed. 2005, 44, 5188-5240.
[2] a) J. Meienhofer, in The Peptides: Analysis, Synthesis, Biology, Academic Press, London, UK, 1979, vol.
1, Ch. 4, pp. 197-239; b) Y. S. Klausner and M. Bodanszky, Synthesis 1974, 549-559.
[3] A. El-Faham and F. Albericio, Chem. Rev. 2011, 111, 6557-6602.
[4] a) K. Hofmann, A. Jöhl, A. E. Furlenmeier and H. Kappeler, J. Am. Chem. Soc. 1957, 79, 1636-1641; b) I.
A. L. Ali, Arkivoc 2008, 78-89; c) S. M. El Rayes, I. A. I. Ali and W. Fathalla, Arkivoc, 2008, 86-95;
[5] a) B. Gutmann, D. Cantillo and C. O. Kappe, Angew. Chem. Int. Ed. 2015, 54, 6688-6728; b) M.
Movsisyan, E. I. P. Delbeke, J. K. E. T. Berton, C. Battilocchio, S. V. Ley and C. V. Stevens, Chem. Soc. Rev.
2016, 45, 4892-4928.
ST 13
25
A Game of Reactivity – Why a Silandiide is Stable but the corresponding
Monosilanide is not
Alexander Pöcheim, Judith Baumgartner*, Christoph Marschner*
Institute of Inorganic Chemistry, Graz University of Technology
Stremayrgasse 9/IV, 8010 Graz, Austria
[email protected], https://www.uni-graz.at
Some 20 years ago, a method for an easy and direct access toward potassium silanides was
developed.[1] Since these days tremendous progress has been made as the initially on non-
functionalized oligosilanes based method was extended to a large scope of functionalities. In fact,
potassium silanides in proximity to halogen-, amino- or methoxy substituents offer an astounding
chemistry, where the main product depends on the applied reaction conditions.[2, 3]
Figure 1. Reaction of a 2,5-oligosilanyl substituted silole with potassium tert-butoxide leads to a labile monosilanide,
which can rearrange to an allyl anion or react further toward a silandiide depending on the applied reaction conditions.
Here, we describe the quite unexpected reactivity of a 2,5-oligosilanylsubstituted silole with potassium
tert-butoxide. The formed monosilanide is labile toward rearrangement yielding an allyl anion. This
rearrangement requires an unusual C-H activation in ortho-position of the attached phenyl moiety.
However, if the desilylation step toward the second silanide is sufficiently fast, for instance in the
presence of 18-crown-6, the silandiide is accessible which is not prone to rearrangement.
References: [1] C. Marschner, Eur. J. Inorg. Chem. 1998, 221–226.
[2] I. Balatoni, J. Hlina, R. Zitz, A. Pöcheim, J. Baumgartner, C. Marschner, Molecules 2019, 24, 3823.
[3] I. Balatoni, J. Hlina, R. Zitz, A. Pöcheim, J. Baumgartner, C. Marschner, Inorg. Chem. 2019, 58, 14185–
14192.
ST 14
26
Metal(loid)enrichment of Pleurotus ostreatus
Martin Walenta, Simone Braeuer, Walter Goessler*
Institute of Chemistry – Analytical Chemistry, University of Graz
Universitätsplatz 1/I, 8010 Graz, Austria
[email protected], https://chemie.uni-graz.at/de/analytische-chemie/forschung/ache/
Mushrooms do not only decompose and recycle organic matter, they also play a necessary role in the
global nutrient cycle and are therefore important components of every ecosystem in the world. Fungi,
neither plants nor animals, interact very strongly with their environment for example in the form of
symbiosis or as parasites. Furthermore, mushrooms become more and more important as a source of
protein, carbohydrates, vitamins and necessary trace elements such as selenium, iron or cobalt.
Pleurotus ostreatus were found to be of economic importance, since they have rather undemanding
cultivation conditions, a strong growth, can accumulate trace elements and have some interesting
medical applications such as inhibitor of tumor growth and inflammation or as a mean of lowering
blood pressure and blood lipid concentration.[1,2]
The aim of this study is to improve or find appropriate growing conditions for these mushrooms while
enriching them with different trace elements or their compounds. We started with selenium because
the enrichment of Pleurotus mushrooms with this element is well studied.[3-6]
The substrate consisting of 18 kg straw, 1.3 kg millet overgrown with mycelium and 0.8 kg lime were
homogenized in a mixing machine. For enrichment, 125 ml of a sodium selenite solution with various
concentrations were added during the homogenization resulting in a selenium concentration in the
substrate of 0.34 mg/kg and 0.76 mg/kg respectively. Next, 3 kg of the substrate were placed into six
separate plastic bags and the inoculated packs were incubated for three weeks at 25°C in the dark. For
fructification, they were placed in a fruiting room with a controlled temperature of 16°C and an air
humidity of 85 %. The mushrooms were collected over three flushes during a period of three months.
Addition of selenium did not influence the harvest volume.
After freeze-drying and milling to 0.1 mm, samples were digested with nitric acid. Thereafter,
36 elements were determined with inductively coupled plasma mass spectrometry.
First results showed that the enrichment was a success. The control mushrooms had a selenium
concentration between 0.038±0.001 to 0.095±0.002 mg/kg, while the enriched mushrooms had a
selenium concentration of 0.92±0.03 to 2.2±0.1 mg/kg and 1.4±0.1 to 4.1±0.2 mg/kg respectively. The
Se concentration in the first flush was always the lowest, even in the control mushrooms. Besides
selenium other essential trace elements such as Zn and Cu were also significantly accumulated in the
mushrooms, making these elements promising candidates for further enrichment experiments.
References: [1] A. Gregori, M. Švagelj, J. Pohleven, Food Technol. Biotechnol. 2007, 45, 238-249.
[2]L. Ma, Y. Zhao, J. Yu, H. Ji, A. Liu, International journal of biological macromolecules 2018, 111, 421.
[3] G. Kaur, A. Kalia, H. S. Sodhi, J Food Biochem 2018, 42, e12467.
[4] P. Bhatia, F. Aureli, M. D'Amato, R. Prakash, S. S. Cameotra, T. P. Nagaraja, F. Cubadda, Food chemistry 2013, 140,
225.
[5] P. Niedzielski, M. Mleczek, M. Siwulski, P. Rzymski, M. Gąsecka, L. Kozak, Eur Food Res Technol 2015, 241, 419.
[6] A. P. d. Oliveira, J. Naozuka, Microchemical Journal 2019, 145, 1143.
ST 15
27
A Modular Flow Platform for Real Time Control of Multistep API Synthesis
Using Model-Based Strategies
Peter Sagmeister, Rene Lebl, Jason D. Williams, David Cantillo and C. Oliver Kappe
Institute of Chemistry, University of Graz
Heinrichstrasse 28, 8010 Graz, Austria
[email protected], http://goflow.at/
In recent years continuous flow processing has attracted the interest of pharmaceutical manufacturers
for reasons including shortened synthetic routes, improved quality and enhanced sustainability
profiles. One important benefit of a continuous flow regime is the ease of implementation of process
analytical technology (PAT) tools for real time monitoring of process parameters and critical quality
attributes (CQAs) for single and multistep syntheses.[1] The chemical and pharmaceutical industries
are encouraged by regulatory agencies, such as the US Food and Drug Administration (FDA),[2] to
integrate process analytics and control technology (PACT) to continuous manufacturing, from an early
stage in development.[3, 4]
Figure 1. Conceptual representation of the model reaction and the process platform.
We showcase PACT in a multistep synthesis of the active pharmaceutical ingredient (API) mesalazine.
This three step synthesis of the API includes hazardous chemistry, use of an extreme process window
(elevated temperature and pressure) and multiphase chemistry. In the first stage, the process was
carefully designed in a modular continuous flow microreactor system and a PAT strategy was
implemented. Fundamental process understanding was developed by performing kinetic studies,
design of experiment (DoE) optimization and dynamic experiments for each individual step. Based on
this data, a parametric model and an artificial intelligence (AI) model have been developed to
implement predictive control strategies. In the second stage a central supervisory control and data
acquisition (SCADA) platform was implemented to unify analytical data acquired from the PAT tools
and control the process itself. Automatic tuning of the critical process parameters during the chemical
reaction, enabled by the control system, will enhance the robustness of the process. An automated
control strategy will anticipate system failures or deviations from the quality attributes and react before
they occur.
References: [1] P. Sagmeister, J. D. Williams, C. A. Hone, C. O. Kappe React. Chem. Eng. 2019, 4, 1571-1578
[2] FDA. PAT Guidance for Industry – A Framework for Innovative Pharmaceutical Development Manufacturing and
Quality Assurance, FDA, Rockville, MD, 2004, p. 16.
[3] L. L. Simon, H. Pataki et al. Org. Process Res. Dev. 2015, 19, 3−62
[4] C. Herwig Anal. Bioanal. Chem. 2020, in press
ST 16
28
Synthesis of Natural Products and Key Pharmaceuticals via 2-Oxoglutarate
Dependent Dioxygenases
Mattia Lazzarotto1, Lucas Hammerer1, Peter Hartmann1, Michael Hetmann 2, Karl Gruber 2,
Wolfgang Kroutil 1 * and Michael Fuchs 1 * 1 Institute of Chemistry, Organic and Bioorganic Chemistry, University of Graz, 8010 Graz, Austria
2 Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria
The synthesis of lignan natural products is essential to the development of new pharmaceuticals and
recently we could show that 2-oxoglutarate dependent dioxygenases (2-ODDs) can facilitate key-steps
in the synthetic pathway towards this compound class [1]. 2-ODDs are non-heme FeII dioxygenases
that activate molecular oxygen via 2-oxogluratate in order to perform a wide range of oxidative
reactions. Despite being an interesting class of enzymes these enzymes are seldom used for biocatalytic
purposes. Nevertheless, the chemoenzymatic synthesis of deoxy-, epi-, and Podophyllotoxin has been
developed in our laboratories. Remarkably, a 2-ODD from Podophyllum hexandrum is implemented
for the stereoselective cyclisation of the natural product’s scaffold starting from its precursor yatein.
This enzyme has shown an impressive biocatalytic performance as the reaction has been upscaled to
two grams to prove the scalability of the biocatalytic key step. This chemoenzymatic synthesis of epi-
podophyllotoxin is a novel, simple route, which is high yielding and low in step count (32% overall
yield over 4 steps) [1].
Figure 1. Natural products obtained via 2-ODDs biotransformations.
Moreover, we are now focused on other 2-ODDs, namely the Hyoscyamine 6β-Hydroxylase (H6H) a
key enzyme in the biosynthesis of scopolamine and the AsqJ from Aspergillus nidulans which is
involved in the synthesis of quinolone antibiotics. By screening the conditions of the
biotransformation, addition of additives, deactivation and mechanistic investigations we want to gain
a deeper understanding of the mechanistic principles inherent to this class of enzymes that may provide
an easier implementation of 2-ODDs in chemoenzymatic routes for relevant synthetic purposes. In fact
we are trying to apply the AsqJ for a chemoenzymatic synthesis of Tipifarnib [2]. In conclusion, with
our work we want to prove that 2-ODD are underestimated with regard to their biocatalytic potential.
References: [1]: Lazzarotto M., Hammerer L., Hetmann M., Borg A., Schmermund L., Steiner L., Hartmann P., Belaj F., Kroutil W.,
Gruber K., Fuchs M. Chemoenzymatic Total Synthesis of Deoxy-, epi -, and Podophyllotoxin and a Biocatalytic Kinetic
Resolution of Dibenzylbutyrolactones. Angew. Chem. Int. Ed. (2019), 58, 8226- 8230.
[2]: Angibaud P.R., Venet M. G., Filliers W., Broeckx R., Ligny Y. A., Muller P., Poncelet V.S., End D. W. Synthesis
Routes Towards the Farnesyl Protein Transferase Inhibitor ZANESTRATM. Eur. J. Org. Chem. (2004), 479-486.
ST 17
29
Photochemical benzylic brominations in continuous flow:
in situ generation of Br2, intensification and scale up
Alexander Steiner, Jason D. Williams, C. Oliver Kappe*
Institute of Chemistry, University of Graz, Heinrichstrasse 28, 8010 Graz, Austria
Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center
Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria.
[email protected], www.goflow.at
Benzyl bromides are important building blocks in the pharmaceutical, agrochemical and materials
industries. Their synthesis is usually accomplished by radical bromination, initiated either thermally
or photochemically. The use of N-bromosuccinimide (NBS), a stable and easy to handle crystalline
reagent, reduces the productivity due to the limited solubility and lower reactivity of NBS and leads to
increased solvent wastage.[1,2,3] Elemental bromine has the advantage of higher reactivity, however, its
use is complicated by storage issues, high vapor pressure, toxicity and the need for chlorinated
solvents. Flow technology, combined with the concept of in situ generation of the hazardous reagent,
can overcome these drawbacks, enabling fast and efficient bromination reactions under highly process
intensified conditions.
Figure 1. Schematic representation of the experimental setup: Combination of the two aqueous streams forms bromine
inside the reactor, which is mixed with the organic substrate stream. Irradiation by LEDs at 405 nm initiates the radical
bromination to yield the desired benzylic bromide.
Herein, we report the development of a Br2 generator for the photochemical benzylic bromination of
toluene derivatives in a Corning Advanced-Flow Lab Photoreactor.[4] The Br2 is generated from
concentrated aqueous hydrobromic acid and sodium bromate streams, providing exceptional mass
efficiency. Efficient mixing in the reaction plate ensures fast extraction of the bromine into the organic
phase, which consists exclusively of the neat substrate. Reaction times as low as 15 to 18 seconds for
monobromination or 100 seconds for a dibromination could be achieved, resulting in excellent yields
of the corresponding products. A scale-out run of the monobromination of 2,6-dichlorotoluene was
performed, producing 1.17 kg of the benzyl bromide in only 230 minutes processing time, with an
overall yield of 95% and a remarkably low PMI of 3.08. Furthermore, experiences in scaling up this
process by a factor of ~20, in a small production-scale reactor, will be described.
References: [1] F. Sabuzi, G. Pomarico, B. Floris, F. Valentini, P. Galloni, V. Conte, Coord. Chem. Rev. 2019, 385, 100-136.
[2] I. Saikia, A. J. Borah, P. Phukan, Chem. Rev. 2016, 116, 6837-7042.
[3] D. Cantillo, C. O. Kappe, React. Chem. Eng. 2017, 2, 7-19.
[4] A. Steiner, J. D. Williams, O. de Frutos, J. A. Rincón, C. Mateos, C. O. Kappe, Green Chemistry 2020, 22, 448-454.
ST 18
30
A Molecular Construction Kit for Metalloid Tin Clusters:
From Organotin hydrides to polyhedral compounds
Beate G. Steller, and Roland C. Fischer*
Institute of Inorganic Chemistry, Graz University of Technology
Stremayrgasse 9/V, 8010 Graz, Austria
[email protected], https://www.ac.tugraz.at
The number and structural diversity of polyhedral metalloid tin clusters RxSnn (n>x) remains still fairly
small. This extraordinary class of compounds has aroused great interest not only because of the
intrinsic beauty of the molecules, but also due to their unique electronic properties and bonding
situations. Their cluster core geometries frequently adopt atomic arrangements observed in the solid
states of their constituents and therefore can serve as molecular models for reactions at the surface of
the bulk element. [1] Additionally, metalloid tin clusters have recently gained interest in the context of
small molecule activation.[2]
Among other strategies, these compounds were accessed via the thermolysis of oligo-tin fragments,[3]
reduction of tin halides or amides,[4] dehydrogenation of organotin(IV) trihydrides,[5]
disproportionation of tin(I) halides[6] or the derivatisation of ZINTL ions.[7]
In course of our studies, we developed a straightforward one step synthetic protocol based on tin/tin
bond formation from organotin di- and trihydrides R4-nSnHn and low oxidation state diamides of
group 14 via the elimination of readily removable H-NR2. (Figure 1) Thereby, this concept allows not
only a large variation of the tin hydride as well as the amide species, but also like in a construction kit
the individual combination of these to access metalloid tin clusters. Several examples of these obtained
clusters will be presented.
Figure 1. Schematic illustration of cluster formation starting from tin hydrides and group 14 element amides.
References: [1] a) A. Schnepf, in: Structure and Bonding, Clusters – Contemporary Insight in Structure and Bonding, (Ed. S. Dehnen),
Springer, Cham, Germany, 2017, 174, 135-200. b) M. Driess, H. Nöth (Eds.) Molecular Clusters of the Main Group
Elements, Wiley-VCH, Weinheim, Germany, 2004.
[2] P. Vasko, S. Wang, H. M. Tuononen, P. P. Power, Angew. Chem. - Int. Ed. 2015, 54, 3802-3805.
[3] a) L. R. Sita, I. Kinoshita, J. Am. Chem. Soc. 1991, 113, 1856-1857 and J. Am. Chem. Soc. 1992, 114, 7024-7029.
[4] a) M. Wagner, M. Lutter, B. Zobel, W. Hiller, M. H. Prosenc, K. Jurkschat, Chem. Commun. 2015, 51, 153. b) N.
Wiberg, H.-W. Lerner, H. Nöth, W. Ponikwar, Angew. Chem. Int. Ed. 1999, 38, 1103. c) P. Prabusankar, A. Kempter, C.
Gemel, M.-K. Schröter, R. A. Fischer, Angew. Chem. Int. Ed. 2008, 47, 7234-7237. d) E. Rivard, J. Steiner J. C. Fettinger,
J. R. Giuliani, M. P. Augustine, P. P. Power, Chem. Commun. 2007, 32, 4919-4912.
[5] J.-J. Maudrich, C. P. Sindlinger, F. S. W. Aicher, K. Eichele, H. Schubert, L. Wesemann, Chem. – A Eur. J. 2016, 23,
2192-2200.
[6] C. Schrenk, A. Schnepf, Rev. Inorg. Chem. 2014, 34, 93-118.
[7] S. C. Sevov, J. M. Goicoechea, Organometallics 2006, 25, 5678-5692.
ST 19
31
Exploring the potential of chanoclavine synthase in Ergot alkaloid pathway
Bettina Eggbauer, Bianca Hengel, Peter Macheroux, Jörg Schrittwieser,Wolfgang Kroutil
Institute of Chemistry, University of Graz
Heinrichstraße 28, 8010 Graz
Ergot alkaloids constitute a group of indole-derived mycotoxins that are produced in various
filamentous fungi. Due to the potential pharmacological activities for pharmaceutical applications, the
chemical nature of this biomolecules and the biosynthetic routs have been studied for a long time.[1][2]
The biosynthesis of these generally quite diverse compounds follows a route via the intermediate
chanoclavine-1, which is produced by a ring closure step through two enzymes, a FAD-dependent
oxidoreductase (EasE) and a heme-binding catalase (EasC) after prenylation via a prenyltransferase
(DmaW) (Figure 1). Studies on these key enzymes, relying on complementation in fungal strains,
revealed EasE to be responsible for 1,3-diene formation and EasC the essential enzyme for oxidative
ring closure.[3,4] Although, a lot of characterization has been done, the difficulties in EasE protein
expression hampered in vitro studies. In order to facilitate the studies of ergot alkaloids and to
implement an in vitro production platform, one aim of this PhD thesis is the reconstitution of the early
steps in the pathway. Investigating heterologous protein expression, optimization of each step and
additional organic synthesis should finally give reasonable conversion to desired intermediates for
isolation.
Figure 2: Conserved initial part of ergot alkaloid pathway, synthesizing chanoclavine-l
Moreover, with the aim of ergot alkaloids as pharmaceutical ingredient, another focus of the research
will be based on production of semi-synthetic ergot-alkaloid derivatives. Implementation of the in vitro
reconstituted chanoclavine synthase and further organic synthesis should lead to active ingredients like
1-propyl-agroclavine for pharmaceutical application.
References:
[1] J. J. Chen, M. Y. Han, T. Gong, J. L. Yang, P. Zhu, RSC Adv. 2017, 7, 27384–27396.
[2] C. A. Young, C. L. Schardl, D. G. Panaccione, S. Florea, J. E. Takach, N. D. Charlton, N. Moore, J. S. Webb, J.
Jaromczyk, Toxins (Basel). 2015, 7, 1273–1302.
[3] C. A. F. Nielsen, C. Folly, A. Hatsch, A. Molt, H. Schröder, S. E. O’Connor, M. Naesby, Microb. Cell Fact. 2014,
13, 1–11.
[4] Y. Yao, C. An, D. Evans, W. Liu, W. Wang, G. Wei, N. Ding, K. N. Houk, S. S. Gao, J. Am. Chem. Soc. 2019,
141, 17517–17521.
ST 20
32
Synthesis and Characterization of Manganese-
Based Hydrogenase Model Systems
Fabian Wiedemaier, Nadia C. Mösch-Zanetti*
Institute of Chemistry, University of Graz
Schubertstrasse 1, 8010 Graz, Austria
[email protected], https://www.uni-graz.at
The [Fe-Fe]-hydrogenase catalyzes the reversible interconversion between molecular hydrogen and
protons (Scheme 1). Its active site (Figure 1a) consists of two sulphur bridged iron atoms which show
the in biology rare case of carbonyl and cyanido ligation.[1,2]
Scheme 1. Reaction catalyzed by [Fe-Fe]-hydrogenase
Besides Fe-based functional models[3] recently also Mn complexes are investigated towards their
capability to catalyze the reduction of protons to molecular hydrogen whereby usually an electrode
acts as the electron source.[4] The electrocatalytically active, manganese-based model systems
investigated in our group (e.g. 1) are based on thiopyridazin ligands which allow the formation of
sulphur bridged Mn-dimers similar to the enzyme. A facial tris-carbonyl pattern on each Mn atom
mimics the carbonyl and cyanido ligation. The catalytical characteristics of those model systems
investigated by electrochemical methods will be presented.
Figure 1. a) Active site of the [Fe-Fe]-hydrogenase, [1] b) Manganese-based functional model mimicking the active site
of [Fe-Fe]-hydrogenase
References: [1] D. Schilter, J. M. Camara, M. T. Huynh, S. Hammes-Schiffer, T. B. Rauchfuss, Chem. Rev. 2016, 116, 8693.
[2] D. J. Evans, C. J. Pickett, Chem. Soc. Rev. 2003, 32, 268.
[3] Y.-C. Liu, K.-T. Chu, R.-L. Jhang, G.-H. Lee, M.-H. Chiang, Chem. Commun. 2013, 49, 4743.
[4] V. Kaim, S. Kaur-Ghumaan, Eur. J. Inorg. Chem. 2019, 5041.
ST 21
33
Electrifying Radical Trifluoromethylations and Oxytrifluoromethylations of
Unactivated Scaffolds
Wolfgang Jud1,2, C. Oliver Kappe1,2, and David Cantillo1,2 1 Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, Graz, Austria
2 Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center
Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
[email protected], https://www.goflow.at
Synthetic electrochemistry has seen a resurgence in recent years as a method to effect redox processes
in a controlled manner by simply applying electricity to the reaction medium.[1] Electrochemical
methods have the capacity to generate radicals and other high energy intermediates under mild,
typically ambient conditions, which can provide with new strategies to solve challenging synthetic
transformations. C-H trifluoromethylations of unactivated substrates such as arenes and olefins are
examples of reactions that can only be tackled via radical chemistry.[2] Trifluoromethylations, in
general, are among the most pursued transformations in organic and medicinal chemistry during the
past decade due to the enhanced biological properties provided by the fluorinated moiety. Generation
of CF3 radicals from suitable reagents can be accomplished using thermal or photochemical methods,
as well as via stoichiometric amounts of redox reagents (e.g. tBuOOH). Electrochemical methods are
a very attractive alternative, as such redox processes can be enabled by electricity, which avoids the
use of often toxic or expensive reagents and reduces the generation of waste.
Herein, we present electrochemical procedures for the generation of CF3 radicals under ambient
conditions, which have been successfully applied to trifluoromethylations and
oxytrifluoromethylations of unactivated scaffolds. While the trifluoromethylation can be considered
as a simple radical addition/single-electron transfer sequence, the oxytrifluoromethylation entails a
paired electrolysis process in which the intermediate generated by the anodic oxidation event reacts
with the product of the concurrent cathodic reduction. Details on the reaction mechanisms including
cyclic-voltammetry data and radical trapping experiments will also be presented.
Figure 1. Electrolysis enables the release of trifluoromethyl radicals from suitable sources devoid of toxic or expensive
reagents, which subsequently can be trapped by unactivated substrates such as arenes or olefins.
References: [1] M. Yan, Y. Kawamata, P. S. Baran, Chem. Rev. 2017, 117, 13230; (b) S. R. Waldvogel, A. Wiebe, T.
Gieshoff, S. Möhle, E. Rodrigo, M. Zirbes, Angew. Chem. Int. Ed. 2018, 57, 5594.
[2] a) D. Staveness, I. Bosque, C. R. J. Stephenson, Acc. Chem. Res. 2016, 49, 2295; b) T. Koike, M. Akita,
Acc. Chem. Res. 2016, 49, 1937.
ST 22
34
Advanced testing of odorants in plastic materials
Andreas Fuchs1, Stefanie Engleder1, Jürgen Huber1, Theresa Kaltenbrunner1, Erich Leitner2* 1 Borealis Polyolefine GmbH
St.-Peter-Straße 25, 4021 Linz, Austria
[email protected], www.borealisgroup.com 2 Institute of Analytical Chemistry and Food Chemistry, Graz University of Technology
Stremayrgasse 9/2, 8010 Graz, Austria
[email protected], www.analytchem.tugraz.at
What is the most appropriate analysis technique to test for odour-active compounds in plastic materials
and where to start? In recent years, many advances were made regarding the instrumental analysis of
emission and odour testing. Hyphenation of different (automated) sample preparation regimes with
gas chromatography (GC) and mass spectrometry (MS) systems for emission testing were developed.
It was found that a commonly used approach typically involves solid phase microextraction (SPME)
coupled with GCxGC/MS systems. Contrarily to that, there might be more sensitive ways to perform
emission tests including emission chambers or advanced adsorbents. GC-olfactometry (GC-O),
another well-known technique in this respect would even involve the human being in the test setup but
was not discussed here [1-7].
The aim of this study was to compare and to investigate the potential of various emission testing setups
in order to characterise odorants in plastic materials. Different system from “fast and simple”
approaches to more complex one like two dimensional comprehensive GCxGC were used. In the
discussion a critical evaluation of the pros and cons of the different methods will be given. Where are
potential limitations in sensitivity and selectivity? What might influence method precision and
accuracy? Where does discrimination need to be considered?
With this study, a comprehensive overview of currently known approaches to instrumental analysis of
odour-active substances is presented. The advantages but also the limitations of the various analysis
setups are shown and discussed. Case studies involve e.g. headspace, thermodesorption and headspace
sorptive extraction using Twister® or MonoTrapTM systems as well as comprehensive GCxGC/TOF-
MS analyses.
References: [1] J. B. Phillips, J. Xu, Journal of Chromatography A 1995, 703, 327-334.
[2] G. Schomburg, Journal of Chromatography A 1995, 703, 309-325.
[3] M. Adahchour, J. Beens, R. J. J. Vreuls, U. A. T. Brinkman, TrAC Trends in Analytical Chemistry 2006, 25, 438-
454.
[4] M. Adahchour, J. Beens, R. J. J. Vreuls, U. A. T. Brinkman, TrAC Trends in Analytical Chemistry 2006, 25, 540-
553.
[5] E. Reingruber, J. Reussner, C. Sauer, A. Standler, W. Buchberger, Journal of Chromatography A 2011, 1218,
3326-3331.
[6] Ó. Ezquerro, B. Pons, M. a. T. Tena, Journal of Chromatography A 2002, 963, 381-392.
[7] R. V. Emmons, R. Tajali, E. Gionfriddo, Separations 2019, 6, 39.
ST 23
35
Bioinspired Tungsten-Acetylene Model Complexes for Acetylene Hydratase
Riccardo Bondi, Nadia C. Mösch-Zanetti*
Institute of Chemistry, University of Graz
Schubertstraße 1III, 8010 Graz, Austria
[email protected], https://www.uni-graz.at
Amid all the tungsten-dependent enzymes, acetylene hydratase (AH) is the only one that catalyzes a
non-redox reaction, which is the net hydration of acetylene to acetaldehyde. The active site of this
enzyme is composed of a tungsten(IV) center coordinated by four sulfur atoms deriving from two
molybdopterin cofactors (MPT), a water molecule and a cysteine residue (Figure 1a).[1] In order to
gain deeper insight into the mechanism of AH and to develop a functional model of this enzyme, the
bioinspired ligand 3-chloropyridine-2-thiolate (3-ClSPy) was used (Figure 1b). This ligand was chosen
to investigate the effect of an electron withdrawing substituent on the reactivity of the complexes.
Figure 1. a) Active site of AH. b) Bioinspired ligand used for this project: 3-chloropyridine-2-thiolate (3-ClSPy).
The synthesis of a suitable tungsten(IV) model complex started from the literature known metal
precursor [W(CO)3Br2(NCMe)2] (Scheme 1).[2] The initial reaction with NaL (L = 3-ClSPy) led to the
formation of [W(CO)3(L)2], via a straightforward salt metathesis, and the following treatment with
acetylene resulted in the synthesis of [W(CO)(C2H2)(CHCH-L)(L)]. The latter complex derives from
an intramolecular nucleophilic attack of the nitrogen atom of the ligand on the coordinated C2H2.[3]
Nevertheless, this product of insertion can be converted into [W(CO)(C2H2)(L)2] by heating it to 45 °C.
With a slightly different procedure, it was also possible to gain access to [W(CO)(C2H2)(L)2], avoiding
the formation of the product of insertion. Finally, the desired mononuclear tungsten(IV) complex
[WO(C2H2)(L)2] was obtained by oxidation of [W(CO)(C2H2)(L)2]. Additionally, a comparison to less
electron withdrawing systems will be discussed.
Scheme 1. Synthetic ways to gain access to tungsten(IV) model complex.
References: [1] G. B. Seiffert, G. M. Ullmann, A. Messerschmidt, B. Schink, P. M. H. Kroneck, O. Einsle, Proc. Natl. Acad. Sci. U
S A 2007, 104, 3073–3077.
[2] L. M. Peschel, F. Belaj, N. C. Mösch-Zanetti, Angew. Chem. Int. Ed. 2015, 54, 13018–13021.
[3] C. Vidovič, L. M. Peschel, M. Buchsteiner, F. Belaj, N. C. Mösch-Zanetti, Chem. Eur. J. 2019, 25, 14267–14272.
ST 24
36
Paper as food packaging material – a natural barrier?
Lisa Hoffellner, Erich Leitner*
Institute of Analytical Chemistry and Food Chemistry, Graz University of Technology
Stremayrgasse 9, 8010 Graz, Austria
[email protected], https://www.tugraz.at
Foodstuff can be packaged in many different materials and forms depending on various requirements.
In the packaging sector of dry food, paper and board are currently the most commonly used materials.
Although the use of paper is highly desired, because it has many favorable properties, including its
economic and ecological friendly characteristics, its application is also challenging. Food packaging
materials should be sufficiently inert to preclude the transfer of substances from the packaging into the
food, and it should preserve the organoleptic properties of the food products [1]. Paper can be made
from different fiber purities and sources and is a very complex three dimensional network, with pores
of different sizes. Therefore, it is often regarded as a permeable layer with limited barrier properties
[2]. Complex transfer processes can occur through migration or permeation. Especially low molecular
weight and volatile substances are of concern, because they might transfer from and through the
packaging into the packaged goods and vice versa. To be suitable as a food packaging material, paper
should protect the packaged goods from unwanted transfer of chemicals.
The aim of our work is to gain a fundamental understanding of the interdependence of transport
mechanisms of the paper matrix and volatile food aroma compounds. This may help to better
understand the paper network and to predict the behavior of a selected paper for a specific use. We
developed a fast and simple method based on gas chromatography and flame ionization detection
(GC/FID) or mass spectrometric detection (GC/MS) to measure the adsorption and desorption
behavior of selected volatile organic compounds on various virgin fiber paper samples. Considering
that paper fibers are composed of polar macromolecules, we distinguished between two compound
classes, polar and non-polar aroma compounds. Polar volatiles exhibit a high affinity, i.e., they strongly
adsorb on the surface of the investigated paper samples. Against the widespread theory, that paper
cannot act as a barrier layer, the polar aroma compounds used in our study were not transported through
the test paper samples. This might indicate that a food packaging made from virgin fiber paper can
protect the food up to a certain degree from unwanted transfer of polar chemicals.
References: [1] Parliament THEE, Council THE, The OF, Union P. L 338/4. 2004;(1935):4-17
[2] Geueke, B. (2016). Paper and board. Retrieved February 6, 2020, from
https://www.foodpackagingforum.org/food-packaging-health/food-packaging-materials/paper-and-board
LIST OF PARTICIPANTS
37
NAME AFFILIATION
1 Flock Michaela TU
2 Kroutil Wolfgang KFU
3 Pietschnig Rudolf PL, UK
4 Uhlig Frank TU
5 Philipp Selig Patheon, by Thermo Fisher Scientific
PHD STUDENTS
NAME AFFILIATION
6 Astria Efwita TU
7 Bierbaumer Sarah KFU
8 Bondi Riccardo KFU
9 Brandner Lea Alexandra TU
10 Breukelaar Willem KFU
11 Brudl Christoph TU
12 Burger Tobias TU
13 Cigan Emmanuel KFU
14 Civita Donato KFU
15 Ćorović Miljan KFU
16 Dalfen Irene TU
17 Edinger David KFU
18 Eggbauer Bettina KFU
19 Fischer Susanne TU
20 Frieß Michael TU
21 Fuchs Andreas TU
22 Fuchs Stefanie TU
23 Glotz Gabriel KFU
24 Goni Freskida TU
25 Gößler Gerhard KFU
26 Grimm Christopher KFU
27 Grössl Doris TU
29 Guttmann Robin KFU
30 Hallwirth Franz TU
31 Hartmann Peter KFU
32 Hoffellner Lisa TU
33 Hogrefe Katharina TU
34 Jovanovic Milica KFU
35 Jud Wolfgang KFU
36 Jurkaš Valentina KFU
37 Klokic Sumea TU
38 Kodolitsch Katharina TU
39 Köckinger Manuel KFU
40 Ladenstein Lukas TU
41 Lazzarotto Mattia KFU
42 Lembacher-Fadum Christian TU
43 Maierhofer Maximilian TU
44 Mata Gomez Alejandro KFU
LIST OF PARTICIPANTS
38
45 Müller Philipp TU
46 Pfleger Georg KFU
47 Pöcheim Alexander TU
48 Pommer Reinhold TU
49 Pompei Simona KFU
50 Pontesegger Niklas TU
51 Prieschl Michael KFU
52 Prohinig Jennifer TU
53 Püschmann Sabrina TU
54 Rappitsch Tanja TU
55 Ratzenböck Karin TU
56 Redolfi Sebastian TU
57 Russegger Andreas TU
58 Sagmeister Peter KFU
59 Schallert Viktor TU
60 Schlatzer Thomas TU
61 Schuh Lukas TU
62 Schreiner Till TU
63 Schweda Bettina TU
64 Simic Stefan KFU
65 Sorgenfrei Frieda KFU
66 Steinegger Andreas TU
67 Steiner Alexander KFU
68 Steller Beate TU
69 Schwarz Romana TU
70 Swoboda Alexander KFU
71 Tjell Anders TU
72 Vakalopoulou Efthymia TU
73 Von Keutz Timo KFU
74 Walenta Martin KFU
75 Weinberger Gernot TU
76 Wernik Michaela KFU
77 Wied Peter TU
78 Wiedemaier Fabian KFU
79 Wieser Philipp Aldo TU
80 Windischbacher Andreas KFU
81 Wolfsgruber Andreas TU
82 Yang Wei TU
83 Zelzer Sieglinde MedUni
84 Zukic Erna KFU
