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Intrinsically chiral gold nanoclusters as enantiodiscriminating sensors for methamphetamines.

Periodic Reporting for period 1 - GOLDENSENS (Intrinsically chiral gold nanoclusters as enantiodiscriminating sensors for methamphetamines.)

Reporting period: 2017-07-01 to 2019-06-30

Chirality is one of the most-studied phenomena in chemical sciences. Its ubiquitous presence in biological systems leads to strong demand for development of asymmetric drugs, sensors, and catalysts. It is also expected to play an important role in the development of metamaterials. Chirality on the nanoscale has become an intensively investigated field in modern material sciences. Intrinsically chiral thiolate-protected gold clusters showed to possess a peculiar type of chirality where the distribution of the thiolate ligands on the surface create an asymmetric environment. These systems have risen a lot of attention due to their potential applications as chiral smart materials.
The main objective of this project is creating a new class of enantiodiscriminating sensors based on intrinsically chiral Au38(SR)24 nanoclusters (Figure). To achieve such goal, we focused our attention towards two main topics:
- Investigation of the chiral properties of Au38(SR)24 nanoclusters. In particular, we studied in detail the “transfer of chirality” occurring from the chiral surface of the cluster to the achiral ligand attached to it. This phenomenon holds great potential for the development of novel sensors since it allows to bestow transient chirality to the molecules attached at the surface of the cluster.
- Design of new thiolate ligands bearing functional groups able to establish specific interactions with the target molecules (methamphetamine derivatives).
- We show that the transfer of chirality for the intrinsically chiral gold cluster Au38(SR)24 is site dependent, i.e. it differs depending on the ligand binding sites. This is closely related to the dynamic nature of the ligands on the cluster surface. Using a combination of NMR techniques and molecular dynamics simulations, we could reveal the largely different conformational dynamics of the bound ligands, explaining the diverse diastereotopicities observed for the CH2 protons of the ligands. Although chirality is a structural property, our study reveals the importance of dynamics for the transfer of chirality (Figure).
- We synthesized a small library of different thiols with similar structure as 2PET (2-phenyl ethane thiol). Different functionalities were inserted in the phenyl ring of the 2PET moiety. These functionalized thiols were employed in the synthesis of Au38(SR)24. Unfortunately, it was not possible to obtain stable Au38(SR)24 clusters protected with such thiolate. We obtained clusters of different sizes and/or large undefined nanoparticles. In order to solve this problem two strategies were adopted: 1) The desired thiol is inserted via thiol exchange reaction on preformed Au38(SR)24 (where SR are alkyl thiols). 2) Dynamic covalent chemistry for the thiol functionalization directly on the cluster monolayer. Among the two new approaches, the dynamic covalent chemistry showed some interesting preliminary results, that will require future investigation.
1) Design and synthesis of different thiols with similar structure as 2PET. Different functionalities such as sulphonate, carboxylate and protonated amine were inserted in the phenyl ring of the 2PET moiety.
-These functionalized thiols were employed in the synthesis of Au38(SR)24. No stable Au38(SR)24 clusters were obtained with such thiols.

2) Testing thiol exchange reaction for the insertion of functionalized thiols on the monolayer of preformed Au38(SR)24 (where SR are alkyl thiols).
-The different solubility between Au38 cluster and the exchanging thiol did not allow (or partially) the substitution of thiols on the cluster surface.

3) Dynamic covalent chemistry was employed for the functionalization of the thiols directly on the cluster monolayer. Orthogonal reactions are employed to precisely modify reactive group of the thiols into the desired functional groups.

4) Nuclear magnetic resonance spectroscopy (NMR) investigation of Au38(SBut)24, (where SBut is butanethiol).
-We were the first able to assign the 4 sets of 1H-NMR signals of Au38 to its 4 symmetry-unique ligand environments (Figure).

5) We employed mono- and multidimensional NMR spectroscopy to observe the chirality transfer from the cluster to the ligand (see above) and to clarify how this phenomenon varies on the ligand monolayer.
- The analysis of the diastereotopicity clearly revealed that the chirality transfer is distinctly different for the different binding sites of Au38.

6) We employed molecular dynamics simulations to understand the origin of the chirality transfer and quantify the results obtain with NMR.
- The examination of the MD simulations showed how the mobility of each type of ligand is affected differently by the chiral disposition of the staples in Au38: from the least affected ligand to the most affected one. The information obtained on Au38 thiolate-monolayer allowed us to understand the dynamic aspect of the chirality transfer phenomenon.

All results have been widely shared in both academic and non-academic environments by different media:
- Scientific papers in top-qualified journals: ACS nano, Nanoscale, Nanoscale Horiz.
- Posters and oral presentations in different national and international conferences: ACS national meeting 255th (USA), ICCC43 (Japan) and others (7 in 2 years)
- Invited speaker at the CECAM workshop, IIT Genoa (Italy),
- Press releases at local and national level.
The information obtained on Au38 thiolate-monolayer allowed us to understand the dynamic aspect of the chirality transfer phenomenon, influencing greatly the future applications of these systems. The possibility to foresee how every ligand is affected by the Au38 surface provides the necessary tool to optimize the ligand structure in such way to obtain the highest possible chirality transfer. This would allow understanding and controlling the asymmetric interactions that the Au38 monolayer would establish with the external environment (e.g. molecules, chiral surfaces etc.). These asymmetric interactions could be employed for the creation of type of chiral recognition based on Au38(SR)24 nanosystems, fostering potential applications in sensing and catalysis.
In addition, the promising outcome of the project represent the fundamental for future important knowledge transfer from academia to industry and create collaboration with companies for development of chiral nanosystems. Thus, the project makes an impact in boosting European academia as well as European economy.