On-surface synthesis – Ullmann coupling reactions on N-heterocyclic carbene functionalized gold nanoparticles

Abstract

Organic on-surface syntheses promise to be a useful method for direct integration of organic molecules onto 2-dimensional (2D) flat surfaces. In the past years, there has been an increasing understanding of the mechanistic details of reactions on surfaces, however, mostly under ultra-high vacuum on very defined surfaces. Herein, we expand the scope to gold nanoparticles (AuNps) in solution via an Ullmann reaction of aryl halides connected via N-heterocyclic carbenes (NHCs) to AuNps. Through design and syntheses of various organic precursors, we address the influence of the contact angle, reactivity of the halogen and the proximity of the entire coupling partner on on-surface reactivities, thus, establishing general parameters governing organic on-surface syntheses on AuNps in solution, in comparison with the reactivity on defined surfaces under ultra-high vacuum. The retention of such halogenated Nps even at higher reaction temperatures holds great promise in the fields of materials engineering, nanotechnology and molecular self-assembly, while expanding the toolbox of organic chemistry synthesis in accessing various covalent architectures.

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Introduction

The idea of confining reactions to a flat substrate has led to the transition of a chemical environment from a typical three-dimensional reaction space in the solution phase to a seemingly two-dimensional platform.^1–21 This new environment has the potential to facilitate alternative reaction pathways to those available in solution, giving rise to new selectivities and intermediates which are otherwise difficult to obtain via in-solution organic synthesis.^{1–9,12,14,19} A prototype of this on-surface synthesis via molecule-by-molecule manipulation was reported by Ebeling and coworkers,²² who attained a high degree of selectivity between the homo- and hetero-coupling of aryl halides by adsorbing the reaction partners to a 2D Au(111) surface followed by dehalogenation with voltage pulses. The generated radicals were dragged and dropped, using a CO-functionalized tip of an atomic force microscope (AFM), to provide organic structures which are difficult to access via in-solution synthesis.²² Similarly, the group of Glorius²³ synthesized and deposited N-heterocyclic carbenes (NHCs) on crystalline gold surfaces under high vacuum and performed an Ullmann coupling of these moieties to obtain covalently linked ballbot-type repeating units of NHCs, bound to single Au ad-atoms. A combination of scanning tunnelling microscopy (STM), non-contact AFM, X-ray photoelectron spectroscopy (XPS) and density functional theory (DFT) calculations was used to determine the conformational properties, steric influence, binding mode, electronic properties, and the surface alignments of these new covalent architectures.²³ Nevertheless, these aforementioned techniques require organic precursors to be deposited under ultra-high vacuum (UHV) conditions onto highly defined single crystalline flat surfaces. Only then, visualization with AFM is possible. That way, only single molecules are produced and as such, the process is not suitable for syntheses of larger, isolatable amounts of materials. With the option to attain bulk materials in Ullmann reactions in a selective manner, we moved from defined planar surfaces under high vacuum to nanoparticles in solution, and devised a protocol for Ullmann coupling reactions using NHC-functionalized gold nanoparticles (AuNps) as a reaction platform. Our system offers advantages compared to the system of Glorius,²³ such as: (1) it avoids sublimation of molecules to the surface allowing the use of high molecular weight precursors as starting materials. This fact allows expanding the scope of on-surface reactivities to different varieties of organic materials. (2) It extends the availability of products from single molecules to larger amounts of materials, since reaction products are no longer limited by the amount of radicals being dragged and dropped using the tip of an AFM. (3) It expands the concept of on-surface synthesis to organo-halogen-functionalized nanoparticles, whose prospects range from molecular self assembly^24,25 to enhancement of X-ray computed tomography (CT) scans.²⁶ In general, the technique delivers Nps functionalized with a new covalent organic network cover, which is a new class of organic materials. In addition, we aimed to transfer parameters that control on-surface syntheses on highly controlled surfaces under high vacuum to Np in solution. Furthermore, we investigated parameters that control on-surface syntheses, by a systematic variation of the NHC-coupling precursor, for example, determining the effect of the contact angle of the hybrid material through positioning the halogen in ortho-, meta- and para-positions, probing the effect of the tether length on on-surface Ullmann coupling reactions and exploiting the different reactivities of aryl chlorides, bromides and iodides towards on-surface functionalizations. The devised organic–inorganic hybrid material studied in this work consists of a core, the shell, a binding group, an organic linker, and a reaction partner (Scheme 1). The core of the hybrid material comprises a majority of Au atoms in the oxidation state zero (0). The shell consists of the Au-surface atoms and are directly bound to the organic ligand, in the present case a σ (carbene) electron-donating group.²⁷ As the orbitals of the metal interact with the ligands, metal–metal interactions are reduced.^27,28 These metal–ligand interactions enhance stabilization and prevent Np agglomeration.^27,29–31 We chose carbenes as organic ligands due to their strong binding to the AuNps similar to the previous system reported by the group of Glorius.²³ More importantly, the tilted geometry of carbenes enables the groups at the wingtip positions to point towards the surface of the Np resulting in an increased proximity of the reacting partners to the surface of the AuNps.^1,3,9,21,32 Therefore, variation of the binding group allows the alteration of the geometry, and hence, the chemical reactivity of the hybrid material. That way, for example, the selectivity of either inter- or intramolecular Ullmann reactions should be controllable. The linker part of the organic ligand separates the AuNp from the aromatic moiety and can be used to effectively tune the distance between the AuNp and the aromatic group.^33–35 Finally, an aryl halide was chosen as the reaction partner for the Ullmann-coupling reaction of the hybrid material, which was functionalized at a suitable position. Putting all these described elements together, 1f-AuNp was designed as a model system for our on-Np-surface functionalization (Scheme 2). In this case, the organic–inorganic hybrid material performs the function of a catalyst (the AuNp), stabilizing agent (the NHC) and reactant (reaction partner at the wingtip positions) in the investigated Ullmann coupling reactions.

Scheme 1 Schematic representation of the organic–inorganic hybrid material and the different parameters studied in this work.

Scheme 2 Syntheses of NHC-functionalized AuNps, 1a to 1g-AuNp. For the functionalized Nps (1f-AuNp and 1g-AuNp), a condensed representation depicting two exemplary ligands is shown to illustrate the on-Np-surface reaction.

Results and discussion

Synthesis and characterization of NHC-functionalized AuNps

We envisaged that the retrosynthesis of the target compound 1f-AuNp could be achieved from a one-pot, three-component Mannich-type reaction of 1a, 1b and 1c as opposed to imidazole alkylations or the use of orthoesters for symmetrical immidazolium salts, as reported in the literature.^36–38 Therefore, we began with two equivalents of 1a in an AcOH/H₂O mixture (3 : 1) and introduced one equivalent of 1b to form the corresponding diamine.³⁷ We then added one equivalent of 1c to close the ring (Scheme 2). The addition of 3 M HCl and heating the reaction to 40 °C furnished the imidazolium compound 1d in 86% yield. The ¹H-NMR spectrum of 1d showed a diagnostic singlet at 10.26 ppm corresponding to the proton at the C2 position of the imidazolium ring, sandwiched by the two nitrogen atoms. The reaction of 1d with K₂CO₃ furnished the N-heterocyclic carbene in situ, which was trapped with chloro(dimethylsulphide) gold(I) to give 1e in 73% yield. The formation of 1e was confirmed by the loss of the singlet for the NHC proton appearing at 10.26 ppm in its ¹H-NMR spectrum, accompanied by an emergence of a signal at 183.22 ppm in the ¹³C-NMR spectrum, corresponding to the carbene carbon atom of the C–Au bond. These two observations are indicative of successful in situ carbene generation and coordination to the gold(I) precursor.^39–41 Complex 1e was reduced to the nanoparticles using a biphasic water/DCM medium as developed by Prezhdo, Brutchey, and co-workers for the synthesis of NHC-stabilized AgNps.^42,43 Unlike the monophasic media, biphasic solvent systems provide a different pathway with different reaction kinetics, in which the reduction of the gold(I) complex takes place slowly, providing uniformly sized AuNps.^39,44 After aqueous workup, the resulting crude AuNps were thoroughly washed with tetrahydrofuran to remove any unbound ligand furnishing 1f-AuNp.

The functionalized AuNps were characterized using matrix assisted laser desorption ionization mass spectrometry (MALDI-MS), transmission electron microscopy (TEM), dynamic light scattering (DLS), thermogravimetric analysis (TGA), energy dispersive X-ray spectroscopy (EDX) and X-ray diffraction (XRD). Matrix-assisted and/or laser desorption/ionization mass spectrometry (MALDI-MS or LDI-MS) has been proven to be a useful method for the characterization of NHC's on AuNps and, in some cases, shows the abstraction of gold adatoms, giving rise to Au(NHC)₂ species.^45–47 Similar results were obtained in the present study: the simulated and experimental MALDI-MS data showed an abstraction of an Au atom which gave rise to the mass peak at 1060.92 corresponding to the Au(NHC)₂ motif (Fig. 1a and S11†). This result confirmed that we have not only the AuNps but also the ligands directly attached to the AuNps.

Fig. 1 Characterization of 1f-AuNp. (a) MALDI-MS spectra of 1f-AuNp: bottom spectrum: simulated mass spectrum and top spectrum: experimental mass spectrum. Spectra show a mass peak at 1060.9282 (calc. 1060.9333), corresponding to (NHC)₂Au⁺ fragments, indicating that the ligands are attached to the AuNps. (b) TEM and size distribution (inset) of 1f-AuNp with an average diameter of 4.1 ± 0.9 nm. (c) DLS spectrum of 1f-AuNp with a hydrodynamic diameter of 22.0 nm and (d) thermogram of 1f-AuNp, with an NHC : Au core mass ratio of 72 : 28.

TEM analysis of the resulting Nps revealed the formation of spherical AuNps with an average diameter of 4.1 ± 0.9 nm (Fig. 1b). However, this technique only enables the visualization of the nanoparticles’ metallic core and excludes the organic shell of the Nps due to the much lower contrast of the organic shell, relative to the Au core.^40,41,48,49 We thereby employed dynamic light scattering (DLS) to measure the overall hydrodynamic diameter of the functionalized AuNps in dichloromethane (DCM). As shown in Fig. 1c and S5,† the hydrodynamic diameter of the dispersed AuNps in DCM was estimated at ∼22.0 nm. This increase in the hydrodynamic diameter is consistent with the fact that DLS measurements take into account the diameter of the gold core, NHC ligands attached to the AuNps, the electrostatic potential generated by the Nps and the entire solvent cage.

Thermogravimetric analysis (TGA) was used to determine the ratio of Au to NHC ligands in the resulting Nps (Fig. 1d). There was a gradual decomposition at 245 °C, corresponding to 4.76% weight loss of the functionalized Nps. At 248 to 382 °C, there was a massive decomposition corresponding to 71.8% of the entire mass of the Np.

At higher temperatures up to 700 °C, no further phase change was observed indicating a 28.2% composition of the Au core. Taking into account the weight percent of NHC from TGA analysis and the diameter of AuNps from TEM measurements, we were able to calculate the average number of NHCs on each Np following the method employed by Johnson and co-workers.³⁹ An average number of ≈2680 NHC molecules was present on the surface of the AuNp. Note that the NHC/1f-AuNp value might be inflated as it depends on the number of Au atoms in the Np, and the calculation of the number of Au atoms assumes a smooth spherical particle.³⁹ Nevertheless, this value indicates a high coverage of NHC per AuNp, as opposed to single molecules reported on a planar 2D Au surface.^22,23 In addition, the calculated value is in excellent agreement with literature reports for NHC-functionalized AuNps of similar core sizes.^{28,39–41,44,48,50}

We employed energy dispersive X-ray spectroscopy (EDX) to determine the chemical composition of the AuNps. Peaks at 0.20, 0.24, 1.45 and 2.20 keV correspond to C Kα, N Kα, Br Lα, and Au Mα, respectively (Fig. S7†). Additionally, the X-ray diffraction (XRD) profiles of the AuNps (Fig. S9†) showed reflexes at 38.5, 44.3, 64.5, and 77.7°, corresponding to the Au (111), (200), (220), and (311) lattice planes of Au, thus, indicating that the synthesized Nps are constructed from Au atoms.⁵¹

Ullmann coupling reaction on the surface of AuNps

As mentioned above, the design of the presented organic–inorganic hybrid system combines the coupling partners, catalyst and reducing agent, all in one entity, with the aryl halides close to the surface of the Np.^{27,32,52–54} Recent work by Camden and coworkers has shown that the geometry of these NHCs on nanoparticles is not far off from that on a 2D surface, and they rather exist in both flat and vertical configurations.⁵³ However, a linker molecule provides suitable distance between the aromatics and the AuNps. Several functional groups have been employed as linker molecules, but these functional groups have to be chemically inert towards the exact application of the hybrid material.^{33–35,55,56} Moreover, a linker should be of optimum length, which minimizes electronic and steric effects between the AuNps and the aromatic moiety, while also enabling desired flexibility and motion of the entire ligand – that allows on-surface reactivity – when attached to the AuNps. We thereby settled for an ethylene chain as a linker, since it is chemically inert under Ullmann conditions, provides a suitable distance between the AuNps and the aromatic moiety, and in turn, avoids the flipping away of the reacting partner, which arises from a high degree of flexibility of ligands with long chain lengths, when attached to the Nps.^56,57

With these criteria in mind, we selected 1f-AuNp, which has a linker of two carbon atoms, with the bromine situated at the meta-position (Fig. 2). Accordingly, the reaction of 1f-AuNp with 12 equivalents of K₂CO₃ furnished 1g-AuNp. We employed attenuated total reflectance infrared spectroscopy (ATR-IR) and surface enhanced Raman spectroscopy (SERS) to analyze the successful coupling reaction on the surface of AuNps, which were used in characterizing similar hybrid systems.^{32,39,41,48,53,54,58,59} IR spectra showed a strong reduction in the intensity of the band at 1070 cm⁻¹, which is assigned to the C–Br vibration frequency. This decrease indicates that some of the C–Br bonds have been replaced by another, a C–C bond (Fig. 3a). The rest of the spectrum was unperturbed, indicating that the functionalized AuNp was only modified at the bromine position. In addition, SERS spectra showed a complete disappearance of the band at 665 cm⁻¹ (C–Br bond), relative to the SERS spectrum before the reaction.

Fig. 2 N-Heterocyclic carbenes studied in this work. The compounds marked in black were successfully synthesized, while those marked in red did not undergo on-surface Ullmann coupling reactions.

Fig. 3 Ullmann coupling of 1f-AuNp. (a) IR spectra and (b) SERS spectra AuNps before the reaction (red) and after the Ullmann reaction (black).

EDX analysis of the reacted Np showed a 10.5% increase in the C composition of the sample, 11.7% decrease in Br composition, and a corresponding 0.3% decrease in Au composition (Fig. S7 and S8†). These observations are also in accordance with a coupling reaction at the C–Br bond since Ullmann reaction is driven by the leaching of Au to AuBr. The loss of Au in Ullmann reaction has been observed and reported in the literature. For example, the group of Kantam observed 9.5% leaching of Au with a significant decrease in yield after three cycles of Ullmann reactions.⁶⁰ Similarly, the group of Jin also saw leaching of Au in Ullmann reaction and a reduced yield after about five cycles.⁶¹ Moreover, the observation that bromine can still be traced in the composition of 1g-AuNp suggests that the reaction did not reach 100% conversion. It contained both the reacted and the unreacted ligands, attached to the same surface of the AuNp. However, the formation of aryl–Au bonds via oxidative addition is rather unlikely, as several reports have shown that in Au-promoted Ullmann reactions, the process does not stop at the stage of oxidative addition. In this case, the cycle of reductive elimination is completed and eventually the C–C coupling product is formed.^61–65

Furthermore, the on-Np-surface coupling reaction was confirmed using MALDI-MS. MALDI-MS spectra showed a mass peak at 903.09 corresponding to the mass of 1g-AuNp with an abstraction of an Au atom in the form of the Au(NHC)₂ motif, just as expected (Fig. S13†), thus indicating that the successful on-surface reaction of the aryl moiety of 1f-AuNp was achieved. This spectrum was also in perfect agreement with the calculated spectrum for the proposed structure on the surface of the AuNp (Fig. S13†). In addition, we observed a MALDI mass peak of two coupled units with two open ring dimers, which corresponds to the reduction of the C–Br band observed in the SERS and IR spectra (Fig. S14†). This result supports that the on-Np-surface reaction is not limited to two coupling units but can exist in a chain-like manner, leading to multiple coupled units on the surface of the AuNps. Nonetheless, MALDI analyses of 1g-AuNp also showed the mass of the starting material as 432.99 (Fig. S12†) corresponding to the mass observed in the ESI-MS of Id (page S4†). These data also corroborate the results of EDX spectroscopy, which allude that the reacted nanoparticles comprise both reacted and unreacted NHC-ligands bound to the same surface of the AuNp.

Next, we attempted an intermolecular hetero-Ullmann coupling of compound 1f-AuNp with p-bromobenzonitrile under the same reaction conditions for the intramolecular homo-Ullmann reaction. However, there was no evidence for a hetero-coupling reaction between 1f-AuNp and p-bromobenzonitrile, suggesting that the tilted geometry of the carbenes leads preferably to an intramolecular homo-Ullmann reaction over intermolecular hetero-Ullmann reaction.

We then probed how the proximity of the halogen towards the surface of AuNps influences on-Np-surface Ullmann reaction, by varying the Br substitution from meta to ortho and para positions, and repeated the Ullmann reactions with the above conditions applied for 1f-AuNp. However, we were unable to obtain the expected products (2g-AuNp and 3g-AuNp). SERS of 3g-AuNp and ATR-IR spectroscopy of 2g-AuNp showed a reasonable retention of the starting material, with SERS bands at 631, 770 and 1071 cm⁻¹ (Fig. S21†), corresponding to the C–Br bond, C–C aliphatic chain at the wingtip position, and benzene groups, respectively. This result can be rationalized as the two Br atoms from two adjacent aryl units need to be in proximity with the Au surface to enable an oxidative addition followed by a reductive elimination, which then furnishes the coupled product on the Np. In the case of 2f-AuNp and 3f-AuNp, the geometry does not fit and no insertion can occur.

Additionally, we tested the reactivities of different halogens towards on-Np-surface coupling reactions by varying the halogen from Br to Cl and I. Applying the same reaction conditions, we were unable to obtain the desired coupling products, 4g-AuNp and 5g-AuNp. The SERS spectrum of 5g-AuNp deviated from that of the starting material, 5f-AuNp (Fig. S22†). There was a significant intensification of C–C aliphatic chains due to the pronounced band at 733 cm⁻¹. In addition, there was a slight retention of aromatic rings due to the band at 998 cm⁻¹. These two concurrent observations indicate a degradation of 5f-AuNp at the reaction temperature. In addition, the ATR-IR spectrum of 5g-AuNp showed significant broadening of the signals and appearance of new bands relative to the starting material (Fig. S18†), bolstering the conclusion from the SERS data. This is plausible, as aryl iodides have been reported to be more reactive than their bromide and chloride counterparts, requiring lower temperatures of activation in the in-solution and on-surface coupling reactions.⁶⁶ To also validate this known phenomenon for on-Np-surface reactivity, we repeated the on-surface Ullmann reaction of 5f-AuNp while reducing the reaction temperature from 120 to 100 °C. Under these conditions, we were able to obtain 5g-AuNp, whose coupling product is essentially the same as that obtained from the previously studied precursor, 1f-AuNp (Fig. S20†).

Also, for 4f-AuNp, no coupling was observed. This is expected and in accordance with the lower reactivity of aryl chlorides. Interestingly, the TEM analysis of 4f-AuNp showed deviation from the other Nps, such as a lack of size uniformities, slight distortion in core shapes and increased diameters of these Nps with an average Au core size of 35 ± 24 nm (Fig. S3†). Therefore, this behavior could not be excluded to explain the unsuccessful formation of 4g-AuNp, since surface reaction and surface catalysis are dependent on shapes, sizes, porosity, diffusion rates and surface areas of Nps.⁶⁷

Next, we studied how the orientation of the entire reaction partner towards the AuNp influences reactivity on the Np-surfaces. We varied the length of the linker from C₂ to C₅ and repeated the same Ullmann reaction. Again, we were unable to obtain the coupling product 6g-AuNp from 6f-AuNp. This can be attributed to the fact that the coupling partners are too flexible and can flip away from the surface of the Np to minimize sterics, which in turn, minimizes the proximity between the aryl halide moiety and the surface of the AuNp. In addition, it has been established that NHC ligands can move easily on surfaces via a unique ballbot-type motion, in which the NHC first pulls out an Au adatom (as also observed in this study), and then rides on it across the surface.^23,32,54,68 This distinctive mode of mobility is fundamental to the formation of surface assembled monolayers (SAMs). This ballbot-type motion is more and more hindered as the ligand size increases and is, therefore, a function of the ligand size and ligand electronics.^23,68 Thus, a combination of the aforementioned effects can rationalize the lack of reactivity of 6f-AuNp towards Ullmann reaction.

We proceeded with further characterization of the successfully functionalized AuNp (that is 1g-AuNp) to determine the nature and/or existence of the nanoparticles after on-Np-surface Ullmann reaction. TEM showed an increase in core sizes with an average core size of 17 ± 9 nm (Fig. S4†). Additionally, the DLS spectrum of 1g-AuNp (Fig. S6†) revealed a hydrodynamic diameter of 33.8 nm with a zeta potential value of 0.180 mV, which is suggestive of a neutrally charged ligand and a tendency of precipitation when dispersed in CH₂Cl₂. EDX analyses of 1g-AuNp showed an Au Mα signal at 2.2 keV, indicating the retention of the AuNps after the reaction. In addition, the XRD profile of the reacted AuNps showed reflexes at 38.5, 44.3, 64.5, and 77.7°, which correlate with the face-centered cubic unit cell of AuNps. It is noteworthy to mention that the XRD reflexes became more pronounced relative to the AuNp prior to the on-surface reaction. This phenomenon is due to an increase in sizes, as the reflexes due to AuNps become relatively more pronounced in this size regime.⁵¹ This observation is in accordance with the result of the TEM and DLS measurements. The abstraction of an Au adatom by the reacted ligands – which was observed by MALDI MS experiments – also suggests the retention of these Nps after being subjected to Ullmann reaction conditions. All data point to the fact that the nanoparticles still remained as nanoparticles after having undergone a successful on-surface Ullmann reaction.

Conclusion

By varying the planar 2D surfaces of gold(111) to a rough surface of gold nanoparticles and fine-tuning the different segments of a hybrid material, we were able to utilize the bonding geometry of NHCs on AuNps to successfully achieve an Ullmann coupling of aryl halide moieties connected via NHC on a one-system hybrid material functioning as the catalyst and reacting partner. The synthesis of the nanoparticles was characterized by a combination of MALDI-MS, TEM, DLS, TGA, zeta potential value measurements, EDX, and XRD. While reactions and retention of the nanoparticles were confirmed by a combination of IR, SERS, EDX, MALDI-MS, XRD, TEM, and DLS, we studied how the nature and proximity of the halogen and that of the reacting partner to the surface of the Nps influenced the reactivity on surfaces. Our work supports that an appropriate organic ligand, suitable halogen position, moderate chain length, and moderate reactivity of halogen are influential towards the selectivities of Ullmann coupling on AuNps, thus, opening new prospects in organic on-surface synthesis to a promising class of organic–metal hybrid materials.

Data availability

General information, synthetic procedure, TEM, DLS, and EDX analysis results, XRD patterns, MALDI spectra, ATR-IR, SERS, and NMR spectra, and additional references are provided in the ESI.†

Author contributions

H. A. Wegner conceptualized the project and interpreted the data. N. Ukah modified the concept, implemented it, conducted all experiments, interpreted the data and analyzed all results. Both authors were involved in the manuscript preparation.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the LOEWE Program of Excellence of the Federal State of Hesse (LOEWE Focus Group PriOSS ‘Principles of On-Surface Synthesis’) and Justus Liebig University, Giessen, Germany. In addition, the authors wish to express their sincere gratitude to Anne Schulze, Limei Chen, Max Müller, Klaus Peppler and Christian Bauer for the TEM, SERS, MALDI, EDX and XRD measurements.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4nr03065f

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