Exposure of PdAu₂₄(2-PET)₁₈ (2-PET: 2-phenylethylthiolate) to BINAS (1,1-binaphthyl-2,2-dithiol) leads to species of composition PdAu₂₄(2-PET)_18−2x(BINAS)x due to ligand exchange reactions. The BINAS adsorbs in a specific mode that bridges the apex and one core site of two adjacent S(R)–Au–S(R)–Au–S(R) units. Species with different compositions of the ligand shell can be separated by HPLC. Furthermore, site isomers can be separated. For the cluster with exactly one BINAS in its ligand shell only one isomer is expected due to the symmetry of the cluster, which is confirmed by High-Performance Liquid Chromatography (HPLC). Addition of a second BINAS to the ligand shell leads to several isomers. In total six distinguishable isomers are possible for PdAu₂₄(2-PET)₁₄(BINAS)₂ including two pairs of enantiomers concerning the adsorption pattern. At least four distinctive isomers are separated by HPLC. Calculations indicate that one of the six possibilities is energetically disfavoured. Interestingly, diastereomers, which have an enantiomeric relationship concerning the adsorption pattern of chiral BINAS, have significantly different stabilities. The relative intensity of the observed peaks in the HPLC does not reflect the statistical weight of the different isomers. This shows, as supported by the calculations, that the first adsorbed BINAS molecule influences the adsorption of the second incoming BINAS ligand. In addition, experiments with the corresponding Pt doped gold cluster reveal qualitatively the same behaviour, however with slightly different relative abundances of the corresponding isomers. This finding points towards the influence of electronic effects on the isomer distribution. Even for clusters containing more than two BINAS ligands a limited number of isomers were found, which is in contrast to the corresponding situation for monothiols, where the number of possible isomers is much larger.

Thiolate-protected gold clusters are promising candidates for imaging applications due to their interesting, size-dependent properties. Their high stability and the ability to functionalize the clusters with biocompatible ligands render the clusters interesting for various imaging techniques such as fluorescence microscopy or second-harmonic generation microscopy. The latter nonlinear optical effect has not yet been observed on this type of ultrasmall nanoparticle. We hereby present second- and third-harmonic generation and multiphoton fluorescence of two thiolate-protected gold clusters: Au₂₅(SCH ₂CH₂Ph)₁₈ and Au₃₈(SCH₂CH₂Ph)₂₄. At a fundamental wavelength of 800 nm, the Au₃₈(SCH₂CH₂Ph)₂₄ cluster is active. In contrast, Au₂₅(SCH₂CH₂Ph)_18 does not yield significant SHG signal. We ascribe this to the center of inversion in the Au₂₅ cluster. Measurements on chiral Au₂₅(capt)₁₈ (capt: captopril) gave an SHG response, supporting this interpretation. We also observed third-harmonic generation at a fundamental wavelength of 1200 nm. At 800 and 1100 nm, the clusters decompose after short illumination time but are stable at illumination at 1200 nm. This may be exploited in combined deep tissue imaging and photothermal heating for theranostics applications

Over recent years, research on thiolate-protected gold clusters Aum(SR)n has gained significant interest. Milestones were the successful determination of a series of crystal structures (Au102(SR)44, Au25(SR)18, Au38(SR)24, Au36(SR)24, and Au28(SR)20). For Au102(SR)44, Au38(SR)24, and Au28(SR)20, intrinsic chirality was found. Strong Cotton effects (circular dichroism, CD) of gold clusters protected by chiral ligands have been reported a long time ago, indicating the transfer of chiral information from the ligand into the cluster core. Our lab has done extensive studies on chiral thiolate-protected gold clusters, including those protected with chiral ligands. We demonstrated that vibrational circular dichroism can serve as a useful tool for the determination of conformation of the ligand on the surface of the cluster. The first reports on crystal structures of Au102(SR)44 and Au38(SR)24 revealed the intrinsic chirality of these clusters. Their chirality mainly arises from the arrangement of the ligands on the surface of the cluster cores. As achiral ligands are used to stabilize the clusters, racemic mixtures are obtained. However, the separation of the enantiomers by HPLC was demonstrated which enabled the measurement of their CD spectra. Thermally induced inversion allows determination of the activation parameters for their racemization. The inversion demonstrates that the gold–thiolate interface is anything but fixed; in contrast, it is rather flexible. This result is of fundamental interest and needs to be considered in future applications. A second line of our research is the selective introduction of chiral, bidentate ligands into the ligand layer of intrinsically chiral gold clusters. The ligand exchange reaction is highly diastereoselective. The bidentate ligand connects two of the protecting units on the cluster surface and thus effectively stabilizes the cluster against thermally induced inversion. A minor (but significant) influence of chiral ligands to the CD spectra of the clusters is observed. The studied system represents the first example of an intrinsically chiral gold cluster with a defined number of exchanged ligands, full control over their regio- and stereochemistry. The methodology allows for the selective preparation of mixed-ligand cluster compounds and a thorough investigation of the influence of single ligands on the cluster’s properties. Overall, the method enables even more detailed tailoring of properties. Still, central questions remain unanswered: (1) Is intrinsic chirality a ubiquitous feature of thiolate-protected gold clusters? (2) How does chirality transfer work? (3) What are the applications for chiral thiolate-protected gold clusters? In this Account, we summarize the main findings on chirality in thiolate-protected gold cluster of the past half decade. Emphasis is put on intrinsically chiral clusters and their structures, optical activity, and reactivity.

The Au₁₀₂(p-MBA)₄₄ cluster (p-MBA: para-mercaptobenzoic acid) is observed as a chiral compound comprised of achiral components in its single-crystal structure. So far the enantiomers observed in the crystal structure are not isolated, nor is the circular dichroism spectrum known. A chiral phase transfer method is presented which allows partial resolution of the enantiomers by the use of a chiral ammonium bromide, (−)-1R,2S-N-dodecyl-N-methylephedrinium bromide ((−)-DMEBr). At sufficiently low concentration of (−)-DMEBr, the phase transfer from water to chloroform is incomplete. Both the aqueous and organic phases show optical activity of near mirror image relationship. Differences in the spectra are ascribed to the formation of diastereomeric salts. At high concentrations of (−)-DMEBr, full phase transfer is observed. The organic phase, however, still displays optical activity. We assume that one of the diastereomers has very strong optical activity, which overrules the cancelation of the spectra with opposite sign. Comparison with computations further corroborates the experimental data and allows a provisional assignment of handedness of each fraction.

The ligand exchange reaction between Au₃₈(2-PET)₂₄ (2-PET: 2-phenylethanethiolate) clusters and enantiopure planar chiral [2.2]paracyclophane-4-thiol 1 (PCP-4-SH) was studied using High Performance Liquid Chromatography (HPLC) and mass spectrometry. It is shown that even at the initial stage of the reaction at least three out of the four symmetry-unique sites are exchanged leading to different regioisomers of composition Au₃₈(2-PET)₂₃(PCP-4-S)₁. Using HPLC it was possible to isolate one specific regioisomer. The latter is stable at room temperature and at slightly elevated temperatures. However, at 80° C the adsorbed thiolate (PCP-4-S) moves between different symmetry-unique sites. These observations have implications for the preparation of mixed ligand shell clusters with specific ligand patterns.

The structure and optical properties of a set of R-1,1´-binaphthyl-2,2´-dithiol (R-BINAS) monosubstituted A-Au₃₈(SCH₃)₂₄ clusters are studied by means of time dependent density functional theory (TD-DFT). While it was proposed earlier that BINAS selectively binds to monomer motifs (SR-Au-SR) covering the Au₂₃ core, our calculations suggest a binding mode that bridges two dimer (SR-Au-SR-Au-RS) motifs. The more stable isomers show a negligible distortion induced by BINAS adsorption on the Au₃₈(SCH₃)₂₄ cluster which is reflected by similar optical and Circular Dichroism (CD) spectra to those found for the parent cluster. The results furthermore show that BINAS adsorption does not enhance the CD signals of the Au₃₈(SCH₃)₂₄ cluster.

The recently reported crystal structure of the Au₂₈(TBBT)₂₀ cluster (TBBT: para-tert-butylbenzenethiolate) is analyzed with (Time-Dependent-) Density Functional Theory (TD-DFT). Bader charge analysis reveals a novel trimeric Au₃(SR)₄ binding motif. The cluster can be formulated as Au₁₄(Au2(SR)₃)₄(Au₃(SR)₄)₂. The electronic structure of the Au146+ core and the ligand-protected cluster were analyzed and their stability can be explained by formation of distorted eight-electron superatoms. Optical absorption and Circular Dichroism (CD) spectra were calculated and compared to the experiment. Assignment of handedness of the intrinsically chiral cluster is possible.

The ligand exchange reaction between monodisperse Au₂₅(2-PET)₁₈ (2-PET: 2-phenylethylthiolate) clusters and 1,1′-binaphthyl-2,2′-dithiol (BINAS) was long thought to induce decomposition of the cluster (Si et al., J. Phys. Chem. C, 2009). We repeated the experiment and analyzed the reaction products using MALDI-TOF mass spectrometry. The spectra clearly indicate successful ligand exchange, bidentate binding of the BINAS ligand and intact Au₂₅ clusters. The reaction products are identified as Au₂₅(2-PET)_18−2x(BINAS)_x (x = 1–4) for a 24 h reaction with a 50-fold molar excess of BINAS. Two likely binding motifs are discussed. Analysis of atomic distances in both the cluster and the free ligand indicates interstaple binding connecting the central sulfur atom of the protecting (SRAu)₂SR with the outer sulfur atom of a second unit. The results presented have implications on the binding position of BINAS in Au₃₈(SR)_24−2x(BINAS)_x clusters.

The two enantiomers of the Au40(2-PET)24 cluster were collected using HPLC and analyzed by MALDI-TOF mass spectrometry, UV-vis- and CD-spectroscopy. The flexibility of the cluster surface allows racemization of the intrinsically chiral cluster at elevated temperatures (80 – 130 °C) which was monitored following the optical activity. The determined activation energy (25 kcal/mol) lies in the range of previously reported values for Au38 nanoclusters whereas the activation entropy deviates significantly from the one in Au38. The latter may indicate that the racemization can take place via different mechanisms.

Intrinsically chiral thiolate-protected gold clusters were recently separated into their enantiomers and their circular dichroism (CD) spectra were measured. Introduction of the chiral R-1,1’-binaphthyl-2,2’-dithiol (BINAS) into the ligand layer of rac-Au₃₈(2-PET)₂₄ clusters (2-PET: 2-phenylethylthiolate, SCH₂CH₂Ph) was shown to be diastereoselective. In this contribution, we isolated and characterized the diastereomeric reaction products of the first exchange step, A-Au₃₈(2-PET)₂₂(R-BINAS)₁ and C-Au₃₈(2-PET)₂₂(R-BINAS)₁ (A/C, anti-clockwise/clockwise) and the second exchange product, A-Au₃₈(2-PET)₂₀(R-BINAS)₂. The absorption spectra show minor, but significant influence of the BINAS ligand. Overall, the spectra are less defined compared to Au₃₈(2-PET)₂₄, which is ascribed to symmetry breaking. The CD spectra are similar to those of the parent Au₃₈(2-PET)₂₄ enantiomers, readily allowing the assignment of handedness of the ligand layer. Nevertheless, some characteristic differences are found between the diastereomers. The anisotropy factors are slightly lower after ligand exchange. The second exchange step seems to confirm the trend. Inversion experiments were performed and compared to the racemization of Au₃₈(2-PET)₂₄. It was found that the introduction of the BINAS ligand effectively stabilizes the cluster against inversion, which involves a rearrangement of the thiolates on the cluster surface. It therefore seems that introduction of the di-thiol reduces the flexibility of the gold-sulfur interface.

Chiral thiolate-protected gold clusters of atomic precision have gained increasing interest in recent years due to their potential use in catalysis, sensing or bioapplications. While the protection of gold clusters with chiral ligands is a rather trivial task, it was found that the clusters can bear intrinsically chiral features, most obvious in the arrangement of the protecting ligands on the surface of the cluster. Recent efforts showed the separation of the enantiomers of such intrinsically chiral gold clusters. This technique can be used for the prediction of chirality in structurally unknown clusters. Activation barriers for the racemization of Au₃₈(SR)₂₄ were determined. As this involves a huge rearrangement of the ligands, the flexibility of the gold-thiolate interface is demonstrated. Furthermore, the ligand exchange reactions between intrinsically chiral clusters and bidentate chiral thiols were studied. A limited, regioselective exchange was found. Most importantly, the reaction is diastereoselective and allows tailoring of gold clusters that are protected with a defined layer of ligands.

The ligand exchange reaction between racemic Au₃₈(2-PET)₂₄ (2-PET: 2-phenylethylthiolate) clusters and enantiopure 1,1’-binapththyl-2,2’-dithiol (BINAS) was monitored in situ using a chiral HPLC approach. In the first exchange step, a clear preference of R-BINAS towards the left-handed enantiomer of Au₃₈(2-PET)₂₄ is observed (about four times faster than reaction with the right-handed enantiomer). The second exchange step is drastically slowed compared to the first step. BINAS substitution deactivates the cluster for further exchange, which is attributed to (stereo)electronic effects. The results constitute the first example of a ligand exchange reaction in a thiolate-protected gold cluster with directed enrichment of a defined species in the product mixture. This may open new possibilities for the design of nanomaterials with tailored properties.

We predict and analyze density-functional theory (DFT) -based structures for the recently isolated Au₄₀(SR)₂₄ cluster. Combining structural information extracted from ligand-exchange reactions, circular dichroism and transmission electron microscopy leads us to propose two families of low-energy structures that have a chiral Au-S framework on the surface. These families have a common geometrical motif where a non-chiral Au₂₆ bi-icosahedral cluster core is protected by 6 RS-Au-SR and 4 RS-Au-SR-Au-SR oligomeric units, analogously to the “Divide and Protectâ€� motif of known clusters Au₂₅(SR)18^-/0, Au₃₈(SR)₂₄ and Au₁₀₂(SR)₄₄. The strongly prolate shape of the proposed Au₂₆ core is supported by transmission electron microscopy. Density-of-state-analysis shows that the electronic structure of Au₄₀(SR)₂₄ can be interpreted in terms of a dimer of two 8-electron superatoms, where the 8 shell electrons are localized at the two icosahedral halves of the metal core. The calculated optical and chiroptical characteristics of the optimal chiral structure are in a fair agreement with the reported data for Au₄₀(SR)₂₄.

Thiolate-protected gold nanoparticles and clusters combine size-dependent physical properties with the ability to introduce (bio)chemical functionality within their ligand shell. The engineering of the latter with molecular precision is an important prerequisite for future applications. A key question in this respect concerns the flexibility of the gold – sulfur interface. Here we report the first study on racemization of an intrinsically chiral gold nanocluster, Au₃₈(SCH₂CH₂Ph)₂₄, which goes along with a drastic rearrangement of its surface involving place exchange of several thiolates. This racemization takes place at modest temperatures (40 – 80 °C) without significant decomposition. The experimentally determined activation energy for the inversion reaction is ca 28 kcal/mol, which is surprisingly low considering the large rearrangement. The activation parameters furthermore indicate that the process occurs without complete Au-S bond breaking.

Chirality unveiled: Thiolate-protected Au₄₀(SR)₂₄ clusters were enantioenriched using an HPLC approach. CD spectra show strong mirror-image responses, indicating the intrinsic chirality of a cluster of unknown structure protected with achiral ligands.

Ligand exchange reactions on size-selected Au₃₈(2-PET)₂₄ and Au₄₀(2-PET)₂₄ clusters (2-PET: 2-phenylethylthiol) with mono- and bidentate chiral thiols was performed. The reactions were monitored with MALDI mass spectrometry and the arising chiroptical properties were compared to the number of incorporated chiral ligands. Only a small fraction of chiral ligands is needed to induce significant optical activity to the clusters. The use of monodentate camphor-10-thiol (CamSH) leads to comparably fast exchange on both clusters. The arising optical activity is weak. In contrast, the use of bidentate 1,1’-binaphthyl-2,2’-dithiol (BINAS) is slow, but the optical activity measured is strong. Moreover, a non-linear behaviour between optical activity and number of chiral ligands is found in the BINAS case for both Au₃₈ and Au₄₀, which may indicate different exchange rates of enantiopure BINAS with the enantiomers of inherently chiral clusters. This is ascribed to effects arising from the bidentate nature of BINAS. This is the first study where chiroptical effects are directly correlated with the composition of the ligand shell.

Bestowing chirality to metals is central in fields such as heterogeneous catalysis and modern optics. Although the bulk phase of metals is symmetric, their surfaces can become chiral through adsorption of molecules. Interestingly, even achiral molecules can lead to locally chiral, though globally racemic, surfaces. A similar situation can be obtained for metal particles or clusters. Here we report the first separation of the enantiomers of a gold cluster protected by achiral thiolates, Au₃₈(SCH₂CH₂Ph)₂₄, achieved by chiral high-performance liquid chromatography. The chirality of the nanocluster arises from the chiral arrangement of the thiolates on its surface, forming 'staple motifs'. The enantiomers show mirror-image circular dichroism responses and large anisotropy factors of up to 4×10^−3. Comparison with reported circular dichroism spectra of other Au₃₈ clusters reveals that the influence of the ligand on the chiroptical properties is minor.

Chiral gold clusters stabilised by enantiopure thiolates were prepared, size-selected and characterised by Circular Dichroism and mass spectrometry. The product distribution is found to be ligand dependent. Au₂₅ clusters protected with camphorthiol show clear resemblance of their chiroptical properties with their glutathionate analogue.

Size Exclusion Chromatography (SEC) on a semi-preparative scale (10 mg and more) was used to size-select ultrasmall gold nanoclusters (< 2 nm) from polydisperse mixtures. In particular, the ubiquitous byproducts of the etching process towards Au₃₈(SR)₂₄ (SR: thiolate) clusters were separated and gained in high monodispersity (based on mass spectrometry). The isolated fractions were characterized by UV/Vis spectroscopy, MALDI mass spectrometry and electron microscopy. Most notably, the separation of Au₃₈(SR)₂₄ and Au₄₀(SR)₂₄ clusters is demonstrated.

The thiolate-for-thiolate ligand exchange reaction between the stable Au₃₈(2-PET)₂₄ and Au₄₀(2-PET)₂₄ (2-PET: 2-phenylethanethiol) clusters and enantiopure BINAS (BINAS: 1,1′-binaphthyl-2,2′-dithiol) was investigated by circular dichroism (CD) spectroscopy in the UV/vis and MALDI mass spectrometry (MS). The ligand exchange reaction is incomplete, although a strong optical activity is induced to the resulting clusters. The clusters are found to be relatively stable, in contrast to similar reactions on [Au₂₅(2-PET)₁₈]^− clusters. Maximum anisotropy factors of 6.6 × 10^−4 are found after 150 h of reaction time. During the reaction, a varying ratio between Au₃₈ and Au₄₀ clusters is found, which significantly differs from the starting material. As compared to Au₃₈, Au₄₀ is more favorable to incorporate BINAS into its ligand shell. After 150 h of reaction time, an average of 1.5 and 4.5 BINAS ligands is found for Au₃₈ and Au₄₀ clusters, respectively. This corresponds to exchange of 3 and 9 monodentate 2-PET ligands. To show that the limited exchange with BINAS is due to the bidentate nature of the ligand, exchange with thiophenol was performed. The monodentate thiophenol exchange was found to be faster, and more ligands were exchanged when compared to BINAS.