Triazaadamantyl N-heterocyclic carbenes (NHC-TA): water-soluble ligands and silver complexes

Abstract

We report high-yielding preparations of two water-soluble NHC preligands bearing triazaadamantyl (TA) neutral hydrophilic groups. The NHC-TA derivatives were utilized in the synthesis of [AgCl(NHC-TA)] complexes, whose characterization included ¹⁰⁹Ag resonance determination. The hydrolytic stability of the silver complexes was found to depend on the NHC-TA ligand.

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The remarkable progress brought about by N-heterocyclic carbene (NHC) ligands has established them among the most versatile ligands in organometallic chemistry, comparable to phosphines or cyclopentadienyls.¹ Their stability and strong metal–NHC bonds have enabled the design of robust complexes that are useful in catalysis for key reactions, such as C–H activation, cross-coupling, and olefin metathesis.²

The binding features of NHC ligands³ have also promoted research in organometallic chemistry using water as a solvent.⁴ Once thought unsuitable, water is now recognized as a green medium offering advantages like enhanced reactivity, selectivity, and milder conditions,^5,6 thanks to pioneering studies by Breslow,⁷ Joó,⁸ and Kuntz.⁹

A large number of hydrophilic ligands have been developed for the preparation of water-soluble metal complexes.^4,10 One of the most popular water-soluble phosphines is PTA (1,3,5-triaza-7-phosphaadamantane, Fig. 1a), which was first synthesized and used as a ligand in metal chemistry by Daigle et al.,¹¹ and much later applied in metal catalysis in water,¹² attracting attention and triggering research efforts on hydrophilic complexes with this cage-structured adamantane-like phosphine.^5,13

Fig. 1 (a) Water-soluble phosphine; (b) first isolated NHC; (c) NHCs targeted in this work.

Phosphines have regularly been used as references to compare the behavior of NHC ligands.¹ The first stable crystalline carbene isolated by Arduengo in 1991 was 1,3-bis(adamantyl)-imidazol-2-ylidene (IAd, Fig. 1b), another cage-structured adamantane-like derivative.¹⁴ Considering the extensive development of NHC chemistry following this discovery, and the parallel growth of PTA chemistry, since the early 1990s, it is striking that no NHC ligand—or its metal complex—containing triazaadamantyl substituents has yet been reported. Here, we introduce silver complexes containing N-heterocyclic carbene ligands N-substituted with 1,3,5-triaza-7-adamantyl groups (NHC-TA, Fig. 1c).

Our assumption at the outset of this work was that NHCs would be useful as ligands for use in aqueous media due to the robustness of the M–NHC bond against oxidation and hydrolysis, together with the well-known easy tunability of their properties through tailored and versatile functionalization, combined with the fact that the hydrophilicity of azaadamantanes, such as PTA and its derivatives, arises from the good hydrogen-acceptor ability of the tertiary nitrogen groups of the cage framework.¹⁵ Thus, after having identified a convenient synthetic procedure to access 1,3,5-triazaadamantan-7-amine TA-NH₂ (see SI), we set out the synthesis of NHC precursors N-substituted with triaazaadamantyl groups, starting with ITA·HCl (Scheme 1a), analogous to the precursor of Arduengo's carbene (Fig. 1b).

Scheme 1 a) (i) AcOH, 60 °C, 15 min, (ii) HCl, r.t., 5 min; (b) (i) H₂O, HCl, r.t., o.n., (ii) CH₂Cl₂/MeOH (20 : 1), NaHCO₃.

Various approaches have been described for the synthesis of sterically encumbered N,N-disubstituted imidazolium salts.¹⁶ We have tested one-pot routes involving the sequential addition of paraformaldehyde, amine TA-NH₂, and glyoxal in the presence of hydrochloric acid,¹⁷ and cyclization pathways of the preformed 1,4-diazadiene (i.e., di-(1,3,5-triazaadamantan-7-yl)ethane-1,2-diimine)¹⁸ using different C1 building blocks for the ring closing and different sources for the chloride counter anion, such as paraformaldehyde/HCl,¹⁹ or chloromethyl alkyl ethers,^19c,20 or the paraformaldehyde/Me₃SiCl couple as in the expedient syntheses developed by Hintermann.²¹ All attempts afforded complex mixtures of addition compounds or no reaction at all. Instead, we managed the synthesis of ITA·HCl by adapting the multicomponent and straightforward synthesis reported by Baslé and Mauduit (Scheme 1a).²² The one-pot procedure is described as being efficient for the chiral non-symmetrical N,N′-substitution pattern of NHCs tethering carboxylic or cycloalkyl functions, which are otherwise inaccessible; we have also previously used this synthesis to diversify the available NHC precursors of this type.²³ Gratifyingly, we also found this strategy to be successful for symmetrically substituted ITA·HCl in preparations up to multigram scale (6.1 g) in virtually quantitative yields.

Another structure substituted with the triazaadamantyl motif in which we are interested is based on an imidazo[1,5-a]pyridine skeleton (Scheme 1b). Imidazo[1,5-a]pyridinylidenes were introduced into organometallic chemistry in 2005 by the groups of Glorius and Lassaletta, as versatile and stable NHC ligands.²⁴ Thanks to their π-extended robust bicyclic framework, they rank among the strongest heteroatomic σ-donors,²⁵ and can also provide singular environments (e.g., L-shaped or axially chiral NHC ligands) in proximity to the metal center through easy substitution at the C5 position of the pyridinyl ring.²⁶

As for ITA·HCl, various methods and conditions were attempted to synthesize IpyTA·HCl (e.g., picolinaldehyde, TA-NH₂, formalin and HCl in EtOH;²⁷ pyridylimine py-2-CH=N-TA,²⁸ paraformaldehyde and SiMe₃Cl in toluene or ethyl acetate;²¹ or py-2-CH=N-TA and K₂CO₃ in chloromethyl methyl ether).²⁹ However, in our hands the only effective method for the synthesis of the pyridinium salt IpyTA·HCl is an adaptation of that described by Hutt et al. (Scheme 1b),³⁰ consisting of the nucleophilic attack of the amine on the formyl group, followed by cyclization with formalin, in the presence of HCl, again in a one-pot procedure assessed up to gram scale (7.6 g) in quantitative yield.

Cyclization to form both heterocycles is confirmed by their NMR spectra (see SI). Thus, the protons of the imidazolic moieties are observed downfield (8–10 ppm) as a triplet and a doublet (1 : 2) for ITA·HCl, and as two doublets (1 : 1) for IpyTA·HCl, due to ⁴J_H–H coupling (1.8–1.6 Hz) within the synthesized five-membered rings. In addition, the carbon in the carbenic position resonates at 133 or 125 ppm, respectively, similar to the chemical shifts observed for the corresponding non-azo adamantly-substituted analogues.^17b,30 Two ¹⁵N resonance frequencies for ITA·HCl (197 (Imz) and 47 (TA) ppm) and three for IpyTA·HCl (205 (Imz), 193 (py) and 48 (TA) ppm), are found by ¹H,¹⁵N-HMBC correlation.

The molecular structure of ITA·HCl was determined using X-ray diffraction methods carried out with single crystals obtained from aqueous solution. As shown in Fig. 2, the desired structure is confirmed. The presence of crystallization water molecules interacting with an adamantyl nitrogen atom and the chloride ion via hydrogen bonds is also observed. The cation exhibits C_2v symmetry, with an N1–C2–N1a angle (108.4(2)°)—within a range typical for other imidazolium rings (108–110°)—and C2–N bond lengths of 1.383(2) Å, consistent with their expected bond multiplicity.¹⁴ All triazaadamantyl group atoms adopt the expected tetrahedral arrangement.

Fig. 2 Molecular structure of ITA·HCl showing two of the crystallization water molecules. Thermal ellipsoids depicted at 50% probability. Selected bond lengths (Å) and angles (°): N1–C1 1.383(2), N1–C2 1.334(2), N1–C3 1.474(2), C1–C1a 1.346(3), C3–C4 1.539(2), C3–C8 1.531(2), N2–C7 1.474(2), N3–C6 1.478(2), N1–C2–N1a 108.4(2), C1a–C1–N1 107.2(1), C2–N1–C1 108.6(1), C1–N1–C3 125.0(1), C2–N1–C3 126.4(1), N1–C3–C4 110.0(1), C8–C3–C4 108.9(1), N2–C8–C3 109.3(1), C5–N3–C6 108.7(1), C7–N2–C9 108.1(1).

Both azolium salts are highly soluble in water, with solubilities of 150 and 144 g/100 mL (4.0 and 4.9 mol L⁻¹) at r.t. for ITA·HCl and IpyTA·HCl, respectively, which exceed those of PTA (24 g/100 mL or 1.5 mol L⁻¹),¹² or IAd·HCl (1.25 g/100 mL or 0.03 mol L⁻¹). The five-membered ring in IpyTA·HCl undergoes H/D-exchange in D₂O (completed in a couple of days, but immediate for the proton on the carbenic position), in a process that is fully reversible by simply replacing D₂O with H₂O. Interestingly, although both salts are sparingly soluble in CH₂Cl₂ or in MeOH, a cooperative effect has been noticed with these solvents, in which suspensions of any of these salts in CH₂Cl₂ rapidly turn to solutions by the addition of just a few drops of MeOH (20 : ≤1v/v). It is precisely this mixture of solvents that has enabled the synthesis of the silver NHC complexes.

Silver(I)–NHC complexes are appealing due to their structural plasticity, the key role they play as carbene transfer agents to other metals, and important applications in biomedicine and in catalysis.³¹ The direct deprotonation of imidazolium salts using silver bases, such as Ag(OAc), Ag₂O, or Ag₂CO₃, has been reported by the Bertrand, Lin, and Danopoulos groups, respectively, as straightforward synthetic protocols that circumvent the often difficult generation and handling of free carbenes.³² A wide range of solvents has been used in the silver oxide pathway,^31a,b including alcohols. Therefore, we utilized the Ag₂O route with the triazaadamantyl azolium salts in CH₂Cl₂/MeOH mixtures (Scheme 2).

Scheme 2 Synthesis of [AgCl(NHC-TA)] complexes.

The procedure allows the isolation of the two silver complexes in a moderate yield (≥65%, see SI). The synthesis of [AgCl(ITA)] requires the presence of molecular sieves (4 Å) to ensure the complete consumption of the initial ITA·HCl. The same occurs when using Ag(OAc) as the silver source. In this case, an excess of a strong base (K₂CO₃, 3 equiv.) is also needed to obtain comparable results. In contrast, no drying material is required when preparing [AgCl(IpyTA)] with Ag₂O.

The deprotonation of the preligands leading to the silver complexes results in the absence of proton resonances assignable to carbene positions (9–10 ppm) and ⁴J_H–H coupling in the remaining protons of the imidazolic rings in their NMR spectra. The coordination of the ligands to the silver centers is supported by the ¹³C-chemical shifts found for the carbene carbons (singlets at 175 and 168 ppm, for [AgCl(ITA)] and [AgCl(IpyTA)], respectively). These values are in good agreement with those reported for [AgCl(IAd)] (174 ppm)³³ and related [AgCl(imidazo-pyridinylidene)] complexes (168–172 ppm).²⁶ The ¹⁵N chemical shifts for [AgCl(IpyTA)] (217 (Imz), 209 (py) and 48 (TA) ppm), could also be determined by ¹H,¹⁵N-HMBC.

The existence of dynamic processes involving heteroleptic and homoleptic silver species in equilibrium (i.e., [AgCl(NHC)] ⇋ [Ag(NHC)₂]⁺AgCl₂⁻) has been evidenced for several complexes of this type.^31–34 The observation of the carbene carbon peaks as singlets indicates a fast exchange of ligands between metal centers on the NMR time scale, thereby precluding the ¹J_C–Ag couplings with ¹⁰⁷Ag (52% abundance) and ¹⁰⁹Ag (48%), both spin ½ nuclei. However, the ¹⁰⁹Ag resonance for [AgCl(ITA)] could be determined by ¹H,¹⁰⁹Ag-HMBC experiments, by slowing down that exchange. In studies with [AgCl(IMes)], John et al. have shown that this indirect detection relies on the coupling with the imidazolic protons (⁴J_H–Ag ≃ 2 Hz), only observable at temperatures low enough to slow down the dynamic process.³⁵ We have observed ⁴J_H–Ag coupling at −40 °C for [AgCl(ITA)] in CDCl₃ (averaging 2.2 Hz with both silver isotopes), and the correlated ¹⁰⁹Ag-chemical shift at 679 ppm (Fig. 3). We repeated the experiment with [AgCl(IAd)], whose heteroleptic structure in the solid state is known,³³ finding the ¹⁰⁹Ag resonance at 669.4 ppm in CDCl₃ and at −40 °C, a value that is close to that found for [AgCl(ITA)].

Fig. 3 (a) NMR resonance for the imidazolic protons of [AgCl(ITA)] in CDCl₃ at 25 °C (top), −40 °C (bottom). (b) ¹⁰⁹Ag-¹H(Imz) correlation detected for [AgCl(ITA)] at −40 °C in CDCl₃.

The two [AgCl(NHC-TA)] complexes dissolve readily in water, undergoing immediate hydrolysis of the Ag–C_carbene bond. In wet DMSO, however, [AgCl(ITA)] rapidly releases the imidazolium cation (t_1/2 = 24 h), whereas [AgCl(IpyTA)] remains unchanged for at least two weeks in an open NMR tube in DMSO-d₆. In water, the shift towards charged homoleptic species (i.e., [Ag(NHC)₂]⁺X⁻) is favored by the poor stability of AgCl₂⁻ in H₂O (Scheme 3).³⁶ The steric hindrance in the bis-NHC structures appears to be fatal for the Ag–C_carbene bond in water, which is inherently labile in an NHC transfer agent. However, the species with the IpyTA ligand are better protected against hydrolysis in DMSO, most likely due to the less hydrophilic environment and lower steric hindrance caused by this ligand, together with better solvation and shift of the equilibria to [AgCl(IpyTA)] in this solvent.

Scheme 3 Equilibria involving mono- and bis-NHC-TA silver(I) species proposed to participate in their hydrolysis.

In summary, the present study introduces water-soluble chimeric ligands that combine features of PTA and NHC structures. Efficient high-yielding procedures for the synthesis of two NHC-TA preligands up to multigram scales have been developed. The utility of these novel precursors has been assessed through the synthesis of [AgCl(NHC-TA)] complexes, which exhibit variations in their hydrolytic stability. Further work is underway to explore the scope of the chemistry of this type of ligand and complex, and their applications in water.

Author contributions

J. S.-G.: investigation, validation, data curation. R. A. and A. M.: resources, formal analysis, data curation. C. G.-A.: methodology, supervision, funding acquisition. J. C. F.: conceptualization, supervision, funding acquisition, writing – original draft. All authors contributed to the writing, review and editing process of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the supplementary information (SI). Supplementary information: experimental details and characterization data. See DOI: https://doi.org/10.1039/d5dt02870a.

CCDC 2505167 contains the supplementary crystallographic data for this paper.³⁷

Acknowledgements

This work was supported by the Spanish MICINN (PID2020-114637GB-I00), the CAM (EPU-INV/2020/013) and the UAH (GP2025-03).

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