Synthetically Versatile Nitrogen Acyclic Carbene Stabilized Gold Nanoparticles

Abstract N‐heterocyclic carbenes (NHCs) have received significant attention as gold nanoparticle stabilizers due to their strong binding affinity towards gold. However, their tunability is limited by the difficulty in obtaining nonsymmetric NHCs. In this regard, N‐acyclic carbenes (NACs) are attractive alternatives due to their high synthetic versatility, allowing easy tuning of their steric and electronic properties towards specific applications. This work reports the first series of stable and monodisperse NAC‐functionalized gold nanoparticles. These particles with sizes ranging 3.8 to 11.6 nm were characterized using NMR, UV/Vis and TEM. The nanoparticles display good stability at elevated temperatures and for extended periods both dried or dispersed in a medium, as well as in the presence of exogenous thiols. Importantly, these NAC‐stabilized gold nanoparticles offer a promising and versatile alternative to NHC‐stabilized gold nanoparticles.

Abstract: N-heterocyclicc arbenes (NHCs) have received significant attention as gold nanoparticle stabilizers due to their strong binding affinity towardsg old. However, their tunability is limited by the difficulty in obtaining nonsymmetricN HCs. In this regard, N-acyclic carbenes (NACs) are attractive alternatives due to their high synthetic versatility,a llowing easy tuning of their steric and electronic properties towards specific applications.T his work reports the first series of stable and monodisperse NAC-functionalized gold nanoparticles. These particles with sizes ranging 3.8 to 11.6 nm were characterized using NMR, UV/Vis andT EM. The nanoparticles display good stability at elevated temperatures and for extended periods both dried or dispersed in am edium, as well as in the presence of exogenous thiols. Importantly,t heseN AC-stabilized gold nanoparticles offer ap romisinga nd versatile alternative to NHC-stabilized gold nanoparticles.
Gold nanoparticles are amongst the most well-studied metalbased nanostructures, which find applicationsi ns ensing, [1] catalysis, [2] drug delivery, [3] bioimaging, [4] and photonics. [5] Althoughc onsiderable efforts werem adet ou nderstand, and tailor,the shape and properties of gold nanoparticles, their surface chemistry remained almostu nchanged for decades. [6] Only recent interest in N-heterocyclic carbenes as an alternative to thiol based surfactants has opened novel possibilities in this area of nanochemistry. [7] Although NHC-stabilized AuNPs (NHCAuNPs)h ave shown great promise for the development of novel nanomaterials, NHCAuNPs face severald rawbacks, which need to be addressed before they can be more widely adopted and applied. [7d, 8] While NHCAuNPs have shown excellent stability in av ariety of environmental conditions, ranging from high temperature to dispersibilityi nh igh ionic strength solutions, most of the known NHCAuNP examples readily degrade in the presenceo ft hiols. To obtain highly stable NHCAuNPs with improved thiol stability therefore necessitates careful design of the NHC ligand.H owever,s ynthetic access to functionalized or nonsymmetric NHCs can be difficult,t hereby limiting the versatility of NHCAuNPs.D eveloping novel nanomaterials whiche njoy the stability afforded by carbene ligands whilst possessing flexibility with regardst ol igand design and functionalization would therefore significantly broaden the possible applications of carbene stabilized AuNPs.
Nitrogen acyclic carbene (NAC) gold complexes are well knowna nd have especially been explored for catalytic applications. [9] As NAC gold complexes are commonly synthesized through simple addition of an amine to an electrophilici socyanide gold(I)c omplex, the widev ariety of amines to choose from lends versatility to the design and synthesis of NAC gold complexes,allowing researchers to tailor the ligands to specific functions. Further,t his synthetic approach also means that nonsymmetric NACs are easily prepared. Surprisingly,h owever, NAC-stabilized AuNPs have not been reportedt hus far.W e report here for the first time the use of NACs as surfactant ligands to stabilize plasmonic AuNPs which display good stability towards exogenous thiols. The methodology developed here should allow rapid access to nonsymmetric structures, thus openingn ew possibilities in gold nanomaterial development.
The NAC gold(I) chloride compounds (3a-3e)w ere synthesized from isocyanide gold(I) chloride precursors, following established reaction procedures (Scheme 1). [10] It is worth noting that one of the characteristics of NAC gold(I) chloride complexes is the presence of conformational isomers or rotamers. [11] This is especially evident in the 1 H-NMRs pectrum of compound 3a and 3b ( Figure S5 and S7, Supporting Information). Generally,two rotamers are observed in the 1 H-NMR (synanti and anti-syn), depending if the t butyl group is anti or syn to the gold. Both NAC residues R 1 and R 2 cannot be in an antipositiontot he gold, due to steric reasons. As ar esult, two sets of NMR signals can be detected. For the residue R 1 , t butyl and cyclohexyl groups were chosen to allow comparison of gold nanoparticles bearing ligands with different stericr equirements. For the R 2 groups, lipophilic amines bearing dodecylo r octyl hydrocarbon chains were used for the ligand synthesis to study the impact of stabilizers bearing differenth ydrocarbon chain lengths on the gold nanoparticle stability. Diethylamine was also utilized to prepare the compound 3c to demonstrate the flexibility regarding the choice of primary and secondary amine reagents for NAC ligand synthesis. NAC gold(I) compoundsw ere reduced using tBuNH 2 ·BH 3 , whereby upon addition of as olution of tBuNH 2 ·BH 3 to as tirred solutiono fc ompound 3a-e in THF,adeep red color is observed within minutes,i ndicating the formation of NACAuNPs. The red color was maintained as the reaction was stirred for severalh ours and no indication of precipitation was found. In order to obtain pure NACAuNPs, the reaction mixture was quenched with af ew drops of water,t hen the mixture was concentrated under reduced pressure and finally cleaned throughs everalw ashing and centrifugation steps using ethyl acetate as solvent. Interestingly,t he reduction of 3c yielded nanoparticles which are non-dispersible in ethyl acetate. Thus, 4c was purifiedv ia centrifugation from THF to removet he soluble side products, and stable nanoparticles were obtained after freeze dryingf rom water.
The successfulf ormation of AuNPs was indicatedb yt he presence of ap lasmon resonance band (PRB) in the UV/Vis spectrum at 517 nm (4a), 522 nm (4b), 523 nm (4c)5 20 nm (4d)a nd 525 nm (4e)( see Figure 1f or compound 4a and Figure S25, S27, S29 and S31 for 4b, 4c, 4d and 4e,r espectively). To show the binding of the NAC ligands onto the AuNP surface, 1 Ha nd 13 CNMR spectroscopy was carriedo ut. Hereby 13 CNMR is an especially useful methodf or providing insight into transformationso ft he chemical species present,w ith a low field shift of the carbene carbon signal indicating ac hange in its chemical environment, thus suggestingt he successful formationo fN ACAuNPs. [8h] The 13 Cc arbene NAC signal for complex 3b (Figure 2), 3c and 3e was detected as aw eak signal at 191.0, 189.5 and 190.7 ppm, respectively.A fter reduction al ow field shiftt o2 06.3 (4b)( Figure2)a nd 206.0 ppm (4e)r espectively was detected, whereas 4c displayed al ess pronounced low field shift at 200.3 ppm, indicating NACAuNP formation. Similars hifts between the molecular and the nanoparticles peciesh ave been reported for NHC-based particles, although the effect is less pronouncedt han in our case. [7d, 8h] Despite the absence of ad etectable carbene 13 Cs ignal for compounds 3a and 3d,ac hemical shift of the carbene NAC was detecteda t2 05.9 ppm for nanoparticle 4d,w hich is in good agreement with the other signals observed. Nonetheless, the other shifts observedb y 1 Ha nd 13 CNMR still support the presence of the NAC ligand in 3a and 3d,e ven though the carbene signal could not be directly observed. The nanoparticles 4a, 4b, 4d and 4e were dispersible in tolueneb ut not in water.I nterestingly,a lthough 4c was readily dispersed in water,i tw as not dispersible in most organic solvents. This is Scheme1.Generalprocedure for the synthesis of NAC-stabilizedg old nanoparticles. TEM images (Figure 3) from films obtained via drop casting of solutions of NPs 4a, 4b, 4d and 4e,i nt oluene, and 4c in water,a nd drying showedw elld efined spherical NPs for all samples. Imageso fs amples 4a, 4b, 4c and 4e showed narrowly dispersed AuNPs with as ize range of 3.9 AE 0.7 nm (4a), 3.8 AE 0.7 nm (4b), 4.5 AE 0.8 nm (4c)a nd 3.8 AE 0.7 nm (4e)r espectively,w hereas the reduction of complex 3d resulted in AuNPs which are significantly larger (11.6 AE 3.2 nm). Further, sample 4d also showedasignificantly broaders ize distribution of AE 28 %w hen compared to 4a, 4b, 4c and 4e,r espectively. It is worth noting, when comparing the TEM images 4a, 4b, 4d and 4e that cyclohexyl bearing NPs (4d and 4e)a re generally less regular in shape. This is especially obvious with sample 4d,w here triangles and rods are present.B ased on this observation, it appears that the substituents R 1 ,R 2 and R 3 play ac rucial role in determining the shape of the resulting NACAuNPs. When the R 1 substituent is cyclohexyl, instead of the more sterically demanding t butyl group, lessr egularly shaped NPs are obtained.
To investigate thermala nd chemicals tability of 4a, 4b, 4d and 4e,N ACAuNPs were either dispersed in tolueneo ri na 10 mm solution of 1-dodecanethiol in toluene.A s4c is water dispersible, stabilityt ests were performed in water or in a 10 mm solution of glutathione (GSH) in water at pH 7.4 in-stead. For thermals tability testing, the resultings olutions were heateda t2 5, 50 and8 0 8Cu pt o4 8h or untild egraded,  Chem. Eur.J.2020, 26,15859 -15862 www.chemeurj.org 2020 The Authors.C hemistry-AEuropeanJournal published by Wiley-VCH GmbH whereas samples containing 1-dodecathiol were studied at 25 and 50 8Cu pt o4 8h.T he stabilityo fa ll samples was monitored through any changes of the RPB by UV/Vis spectroscopy, whereby ar ed shift, peak broadening or reduction of peak intensity is indicative of aggregation (see Figure 1f or compound 4a and Figures S25-S32 for the remaining compounds). All particles showed good stabilityf or several hours at 25 8Ca nd a change in the RPB is detectablea fter 24 ha nd more pronounced after 48 h. However, 4c,w hich was dispersed in water,s howed ar ed shift of the RPB after 1hindicating nanoparticlea ggregation. This result was furtherc onfirmed through dynamic light scattering measurements, where the hydrodynamic radius was detected at around6 50 AE 200 nm indicating rapid aggregation of the nanoparticles. When the temperature is increased to 50 8C, af aster decomposition is observed and at 80 8Cm ost particles showed significant changes to the UV/Vis spectra after 24 h. However, at lower temperatures, the stability differencesi nn anoparticles bearing differentl igands were more apparent-nanoparticles with N-cyclohexyl substituents showed higherp ropensity to aggregate compared to those with N-t butyl substituents.F urther,p articles bearing N'-dodecyl substituents displayahigher stability than their N'-octyl counterparts. It should be noted that the observed stability of NACAuNPs is comparable or in certain cases exceeds reported thermals tabilities of NHC-stabilizedA uNPs. [7d, 8d,e,g,h] In NHCAuNPs,s ignificantly highert hermals tability is achieved either through bidentateN HC ligands [8e] or through the addition of acharged carboxylic acid group which helps to stabilize NHCAuNP in water solutions. [8d,g] However,A uNPs stabilized by small unchargedN HC ligands display similar [8d] or lower thermal stability. [8h] Next, the nanoparticle stability against exogenous thiols was investigated at 25 8Ca nd 50 8C-we omitted the studies at 80 8Ca st he particlesa lready showed significantly decreased stabilitya t5 0 8C. After exposure for 6h only particle 4a showedn os igns of aggregation or ripening, and this observation is in good agreement with the stability observedw ithout exogenous thiols present. However,a ll particles showed degradation after 24 ha nd 48 h. The stability of carbene stabilized AuNPs against thiols has proven to be ag eneral challenge and thus far only two reports have demonstrated significant improvements in stabilitya gainst exogenous thiols.O ne example was reportedb yC rudden et al. where increased stability towards thiols was achievedb yu tilizingc helating NHC ligands as surfactant. [8e] The second report is from our group, where water soluble histidine-2-ylidene stabilized gold nanoparticles displayed high stabilityt owards glutathione. [8g] Nevertheless, we have shown that NAC gold complexes can be used to prepare monodisperse NACAuNPs,i nasimilar fashion to NHC-stabilized AuNPs.
In conclusion, we have demonstrated that the use of NACs to stabilizeA uNPs is not only feasible, but also easily adapted from procedures used in NHCAuNP synthesis. Importantly,t he use of NACs as ligands offersa na ttractive alternative to NHCs due to their ease of synthesis and modification, offering great flexibility in ligand design,i nt he continuing quest towards ever more stable AuNPs. Futurew ork will, therefore, focus on modifying NACg old complexes to afford multi-dentate NACAuNP compounds.