A noble metal-free triphenylamine-based coordination capsule with NADH mimics as a renewable vessel for enhanced biomimetic hydrogenation

Abstract

Inspired by natural photosynthesis, artificial photocatalysis approaches that rely on nicotinamide adenine dinucleotide (NADH) and its analogues have attracted extensive attention, but face significant challenges including the over-reliance on precious-metal electron mediators for NADH regeneration and diffusion-limited charge transfer dynamics. Herein, we report the first instance of intramolecular electron transfer coupled with a pseudo-intramolecular hydride transfer mechanism through covalent grafting of the triphenylamine group and an NADH mimic into one coordination capsule, enabling enhanced cofactor regeneration and biomimetic hydrogenation in the absence of noble metals. The presence of the photosensitive triphenylamine moiety triggered a directional intramolecular electron transfer pathway induced by visible light, thereby promoting highly effective and selective NADH mimic regeneration without any assistance from a noble metal complex. Furthermore, spatial constraints within the coordination capsule ensured the regeneration selectivity of the active NADH mimic by suppressing aggregation and diffusion. Subsequently, the active NADH mimic-decorated capsule facilitates the biomimetic reduction of benzoxazinones via a pseudo-intramolecular hydride transfer, with the enhancement of hydrogenation efficiency exceeding 240% over the benchmark system based on intermolecular electron transfer. This renewable vessel-mediated photosynthesis platform exhibited enzymatic kinetics following the Michaelis–Menten mechanism, expanding new horizons for the development of a novel noble metal-free artificial catalytic system.

---

Introduction

Guided by the principles of a series of natural reductases, biomimetic hydrogenation systems that proceed with the coenzyme nicotinamide adenine dinucleotide (NADH) or its mimics as hydrogen sources have progressively evolved over the past few decades.^1,2 Despite these advancements having underscored the enormous potential of synthetic chemistry in fine chemicals production, their practical application in these processes is hindered by the reliance on expensive cofactors that require efficient and selective regeneration for reusability.^3,4 Of particular interest is the photochemical approach using photosensitizers for cofactor regeneration, which has emerged as one of the most promising strategies arising from its availability and environmental sustainability.^5–8 Nevertheless, directly conducting the 2e⁻ selective regeneration of bioactive 1,4-NADH with the intrinsic 1e⁻ donating behaviour of photocatalysis faces tremendous difficulty in achieving desirable efficiency and selectivity.^9,10 To overcome this issue, conventional electron mediators, such as those precious metal complexes based on Rh, are widely recognized and used as 2e⁻ mediators to give hydride ions that are transferable to the cofactor in artificial photosynthetic systems.^11,12 Unfortunately, the addition of the noble-metal mediators compromises biocatalyst stability while also introducing issues related to the economic feasibility and cumbersome product separation and purification procedures.^13,14 In addition, the sluggish electron transfer among discrete catalytic components introduced a fundamental bottleneck, restricting the overall efficiency of existing solar-to-chemical systems.¹⁵ Therefore, developing an efficient regeneration approach is highly desirable to synergistically improve the catalytic efficiency, atom economy, cost-effectiveness, and sustainability of artificial biomimetic hydrogenation systems.

Coordination capsules are a kind of discrete supramolecular assembly featuring well-defined molecular architectures that enforce fixed spatial distances between organic ligands, offering a confined microenvironment emulating the pocket of natural enzymes.^16–21 These intriguing topologies, owing to their structural tunability, often exhibit emergent properties distinct from their subcomponents and unlock versatile functionalities for diverse applications, particularly exhibiting specific reactivity serving as biomimetic vessels to catalyze unique chemical transformations.^22–27 In recent years, our group has elaborately integrated active centers of NADH into ligands to assemble series of coordination capsules, enabling the in situ regeneration of active NADH mimics driven by an excited-state photosensitizer outside the pocket through an intermolecular electron transfer.^28–30 The well-defined geometries within the coordination capsule accounts for the high efficiency and selectivity, which prevent the inactivation of NADH mimics during photocatalytic regeneration but facilitate the pseudo-intramolecular hydride transfer towards preorganized substrates by host–guest interactions, exhibiting excellent biomimetic hydrogenation performance. Despite notable progress, existing solar-to-chemical artificial conversion systems face a key challenge with respect to matching the rapid pseudo-intramolecular hydride transfer of photoreactions with the suboptimal intermolecular electron transfer of the cofactor regeneration module.³¹ Lately, many efforts have been dedicated toward the elaboration of Rh complexes with photoresponsive groups or NADH mimics into one skeleton, with the aim of affording an intramolecular electron transfer pathway for the intensification of regeneration efficiency.^32–34 Nonetheless, engineering a newly available strategy that integrates efficient noble metal-free cofactor regeneration with chemical biomanufacturing by an optimized electron transfer pathway for implementing practical artificial conversion is yet to be explored. We envisioned that the direct covalent assembly of photoresponsive groups with NADH mimics into the backbone of a coordination capsule would establish a finely tuned intramolecular electron transfer pathway to enhance regeneration efficiency of NADH mimics for boosted biomimetic hydrogenation while eliminating the need for Rh complexes.

In this work, by covalently integrating triphenylamine (TPA) into a coordination capsule containing NADH mimics, a renewable molecular vessel was successfully obtained for the intensification of biomimetic hydrogenation based on photoinduced intramolecular electron transfer in tandem with pseudo-intramolecular hydride transfer (Scheme 1). Importantly, the direct covalent integration of TPA with NADH mimics into a coordination capsule ensured efficient and selective regeneration of NADH mimics through directional intramolecular electron transfer under visible-light irradiation. The confined cavity and rigid structure of such a coordination capsule spatially separated the NADH mimics to avoid their inactivation during photocatalytic regeneration and afforded accessible catalytic sites for biomimetic hydrogenation of substrates within its inner pocket. This biomimetic synthetic platform exhibited high efficiency and broad substrate compatibility in the solar-driven hydrogenation of benzoxazinones without noble-metal assistance, providing an attractive avenue for expansion of existing sustainable and environmentally friendly artificial photosynthesis.

Scheme 1 Schematic of the coordination capsule with covalently connected triphenylamine and NADH mimics, showing in situ regeneration of active sites and enhanced biomimetic hydrogenation through an integrated intramolecular electron transfer and pseudo-intramolecular hydride transfer pathway.

Experimental methods

Materials and instrumentation

All the chemicals and solvents were of reagent-grade quality obtained from commercial sources and used without further purification. The elemental analyses of C, H and N were performed on a Vario EL III elemental analyzer. ¹H NMR and ¹³C NMR spectra were recorded on a Bruker Avance 400 MHz spectrometer with TMS as the internal standard at δ 0.0 ppm. ESI-MS was carried out on an Agilent 6224 HPLC-TOF spectrometer using methanol as the mobile phase. UV-Vis spectra were recorded on a HP 8453 spectrometer. The solution fluorescence spectra were acquired using an Edinburgh FS 920 instrument. Electrochemical experiments were conducted on a CHI 660E workstation via the traditional three-electrode system, using a freshly polished glassy carbon electrode with a diameter of 5 mm as the working electrode, a platinum wire with 0.5 mm diameter as the counter electrode and an Ag/AgCl (3 M KCl) reference electrode. Isothermal Titration Calorimetry (ITC) experiments were performed using an isothermal titration microcalorimeter at atmospheric pressure and 298 K, giving association constant (K_a) values and the thermodynamic parameters. The guest solution in CH₃CN/H₂O (4 : 1 v : v, pH = 4.50) was sequentially injected from a 0.25 mL syringe into the host solution in the sample cell (1.30 mL in volume) while stirring at 250 rpm. All the thermodynamic parameters were obtained via the “independent” model.

Synthesis of dimethyl 1-benzyl-4-(4-(diphenylamino)-phenyl)-1,4-dihydropyridine-3,5-dicarboxylate

Methyl propiolate (1.68 g, 20 mmol), 4-(diphenylamino) benzaldehyde (2.73 g, 10 mmol), and benzylamine (1.07 g, 10 mmol) in acetic acid (2.0 mL) were heated at 80 °C for 30 min. After cooling, the mixture was poured into water (20 mL) and stirred for 1 h. The solid product was filtered and washed with Et₂O (30 mL × 3) to give dimethyl 1-benzyl-4-(4-(diphenylamino)-phenyl)-1,4-dihydropyridine-3,5-dicarboxylate, which was recrystallized by ethanol. Yield: 2.77 g, 52.3%. ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 7.50 (s, 2H), 7.41–7.37 (m, 2H), 7.35–7.33 (m, 2H), 7.30–7.26 (m, 5H), 7.05–6.99 (m, 4H), 6.96–6.93 (m, 4H), 6.82–6.80 (m, 2H), 4.80 (s, 2H), 4.69 (s, 1H), 3.58 (s, 6H). ¹³C NMR (101 MHz, DMSO-d₆, ppm): δ 191.04, 166.64, 147.60, 135.07, 131.46, 130.51, 129.97, 126.88, 124.75, 124.43, 123.61, 123.26, 120.29, 118.64, 117.33, 111.12, 51.97, 36.69.

Synthesis of 1-benzyl-4-(4-(diphenylamino)-phenyl)-1,4-dihydro-pyridine-3,5-dicarbohydrazide

A mixture solution of 80% hydrazine hydrate (50 mL) and dimethyl 1-benzyl-4-(4-(diphenylamino)-phenyl)-1,4-dihydro-pyridine-3,5-dicarboxylate (5.30 g, 10 mmol) was stirred at 85 °C for 24 h. The white precipitate was formed, which was collected by filtration, washed with methanol and dried in vacuum. Yield: 2.63 g, 49.7%. ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 8.72 (s, 2H), 7.39–7.25 (m, 9H), 7.22 (s, 2H), 7.08–7.06 (d, 2H), 7.03–6.99 (m, 2H), 6.94–6.92 (m, 4H), 6.80–6.78 (d, 2H), 4.97 (s,1H), 4.60 (s, 2H), 4.17 (s, 4H). ¹³C NMR (101 MHz, DMSO-d₆, ppm): δ 166.62, 147.25, 145.07, 141.18, 137.81, 133.83, 129.41, 128.64, 128.46, 127.65, 127.54, 123.49, 123.29, 122.67, 108.39, 56.85, 34.48.

Synthesis of H₂ZPD

1-Benzyl-4-(4-(diphenylamino)-phenyl)-1,4-dihydropyridine-3,5-dicarbohydrazide (5.30 g, 10 mmol) was added to an ethanol solution (50 mL) containing 2-pyridylaldehyde (2.35 g, 22 mmol). After 5 drops of acetic acid were added, the mixture was heated at 85 °C under magnetic stirring for 12 h. The resultant yellow solid was collected by filtration, washed with methanol and dried in a vacuum. Yield: 5.35 g, 75.5%. ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 11.41 (s, 2H), 8.59–8.58 (d, 2H), 8.25 (s, 2H), 7.84 (d, 4H), 7.53 (s, 2H), 7.43–7.32 (m, 7H),7.26–7.23 (m, 4H), 7.18–7.16 (d, 2H), 7.00–6.97 (m, 2H), 6.94–6.92 (d, 4H), 6.86–6.84 (d, 2H), 5.30 (s, 1H), 4.77 (s, 2H). ¹³C NMR (101 MHz, DMSO-d₆, ppm): δ 164.42, 153.99, 149.90, 147.71, 145.82, 145.72, 141.59, 138.16, 137.18, 136.13, 129.92, 129.08, 129.08, 128.28, 127.74, 124.46, 124.10, 123.71, 123.22, 120.03, 109.40, 57.66, 35.69. Elemental analysis calcd for C₄₄H₃₆N₈O₂: H, 5.12%; C, 74.56%; N, 15.81%; found: H, 5.09%; C, 74.49%; N, 15.77%. ESI-MS: calcd for C₄₄H₃₆N₈O₂ 708.30, found 709.31 [M + H]⁺.

Synthesis of the Zn-ZPD coordination capsule

The ligand H₂ZPD, which incorporates both the TPA unit and the dihydropyridine amido (DHPA) moiety – an NADH-mimicking active site – was obtained by condensing 1-benzyl-4-(4-(diphenylamino)phenyl)-1,4-dihydropyridine-3,5-dicarbohydrazide and 2-pyridylaldehyde. The coordination capsule Zn-ZPD was then prepared by the self-assembly of H₂ZPD (70.8 mg, 0.10 mmol) and Zn(ClO₄)₂·6H₂O (37.2 mg, 0.10 mmol) in a mixture of CH₃OH and DMF (2 : 1 by volume). X-ray-quality yellow block crystals of Zn-ZPD were obtained after the mixed solution was left standing for several weeks at room temperature. Yield: 37.4%. ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 11.56 (s, 1H), 8.57 (d, 2H), 8.28 (s, 2H), 7.88 (d, 4H), 7.59 (s, 2H), 7.43–7.34 (m, 7H), 7.27–7.23 (m, 4H), 7.17–7.15 (d, 2H), 7.01–6.98 (m, 2H), 6.93–6.91 (d, 4H), 6.84–6.83 (d, 2H), 5.39 (s, 1H), 4.80 (s, 2H). Elemental analysis calcd for Zn₄C₁₇₆H₁₃₆Cl₄N₃₂O₂₄·CH₃OH: H, 3.83%; C, 58.08%; N, 12.25%; found: H, 3.71%; C, 58.22%; N, 12.36%. ESI-MS: m/z: 1030.6188 [H₃Zn₄(ZPD)₄]³⁺, 1063.9370 [H₄Zn₄(ZPD)₄·ClO₄]³⁺, 1097.2567 [H₅Zn₄(ZPD)₄·2ClO₄]³⁺, 1545.4228 [H₂Zn₄(ZPD)₄]²⁺, 1595.4027 [H₃Zn₄(ZPD)₄·ClO₄]²⁺, and 1645.3811 [H₄Zn₄(ZPD)₄·2ClO₄]²⁺.

Crystallography

Diffraction data of the Zn-ZPD were collected on a Bruker SMART APEX CCD diffractometer using graphite-monochromated Mo-Kα radiation (λ = 0.71073 Å) and processed using the SMART and SAINT programs.^35,36 The structure was solved by intrinsic phasing and refined by least squares minimization using SHELXL within OLEX2.³⁷ Non-H atoms were refined with anisotropic displacement parameters. Hydrogen atoms in the backbones were fixed geometrically at calculated distances and allowed to ride on the parent non-hydrogen atoms, while some of the disordered solvent molecules were not treated during the structural refinements. The SQUEEZE procedure was applied.³⁸

Typical procedure for biomimetic hydrogenation

Photocatalytic hydrogenation reactions were carried out in a 10 mL flask, varying the amount of catalyst, and the substrate dissolved in CH₃CN/H₂O (4 : 1 v : v) was added to obtain a total volume of 5.0 mL. The solution mixture was adjusted to a specific pH value by adding H₂SO₄ or NaOH, and was measured using a pH meter. The flask was sealed with a septum, and the solution degassed by bubbling argon for 15 min under atmospheric pressure at room temperature. After that, the samples were irradiated by an LED lamp, with the reaction temperature maintained at 298 K using a water filter to absorb heat. ¹H NMR spectra were recorded to monitor the conversion (using 1,3,5-trimethoxybenzene as an internal standard). The crude product was purified by column chromatography.

Results and discussion

Preparation and characterization of the coordination capsule

Single-crystal structure analysis revealed that Zn-ZPD exhibited an M₄L₄ square configuration through the connection of four ligands and four zinc ions in an alternating fashion (Fig. 1a and Fig. S1). Each zinc ion was coordinated within an octahedral geometry by a pair of widely delocalized NNO chelators from two ligands positioned in a mer configuration,³⁹ preventing NADH mimics from being inactivated during regeneration. Four ligands containing DHPA were positioned on the parallel edges of the square capsule, with four phenyl rings outside of the cavity and four active H atoms inside the interior of the pocket. This arrangement guaranteed biomimetic hydrogenation from DHPA to the encapsulated substrate within the pocket. The TPA group was covalently linked to DHPA and extended to the outside of the cavity. This design facilitated the rapid intramolecular electron transfer for in situ regeneration of NADH mimics and provided a large opening window (about 9.0 Å for one edge). This dimension is consistent with the value determined by diffusion-ordered spectroscopy (DOSY) (radius r_H = 7.15 Å) (Fig. S3),⁴⁰ suggesting that the pocket of the Zn-ZPD was sufficiently large to encapsulate planar aromatic substrates. Moreover, the plentiful amide groups were situated around the charged pocket, offering abundant hydrogen bonding sites that facilitated substrate encapsulation.⁴¹

Fig. 1 (a) Self-assembly and crystal structure of the coordination capsule Zn-ZPD. Zn, cyan; N, blue; O, red; and C, grey. (b) ESI-MS of Zn-ZPD. (c) ESI-MS of Zn-ZPD upon addition of 10 equiv. of substrate 1 in CH₃CN. The insets show the theoretical and experimental isotopic patterns at m/z = 1030.6188 and 1179.3288, respectively.

The structural stability of Zn-ZPD in CH₃CN was characterized by electrospray ionization mass spectrometry (ESI-MS), which revealed in the spectra the serial isotopic patterns related to [H₃Zn₄(ZPD)₄]³⁺, [H₄Zn₄(ZPD)₄·ClO₄]³⁺ and [H₅Zn₄(ZPD)₄·2ClO₄]³⁺ species at m/z = 1030.6188, 1063.9370 and 1097.2567, respectively (Fig. 1b and Fig. S4). Upon addition of benzoxazinones (substrate 1), a new peak emerged at m/z = 1179.3288, which was assigned to [H₃Zn₄(ZPD)₄⊃(1)₂]³⁺ (Fig. 1c and Fig. S5), suggesting the formation of a 1 : 2 stoichiometric host–guest complex with good solution-phase stability. Additionally, formation of this complex was subsequently confirmed by observing the chemical shift changes in the ¹H NMR spectra of Zn-ZPD after mixing with substrate 1 (Fig. S6).⁴² Isothermal titration calorimetry (ITC) experiments showed that the data fit well to a 1 : 2 binding model with an association constant of 4.3 × 10⁴ M⁻¹ as simulated using an “independent” model (Fig. 2a and Fig. S7).⁴³

Fig. 2 (a) ITC experiment on Zn-ZPD upon the addition of substrate 1 showing the formation of a host–guest complex in CH₃CN/H₂O (4 : 1). (b) UV-Vis absorption spectra of Zn-ZPD upon the addition of substrate 1 and Hill-plot linear fitting. (c) Family of luminescence spectra of Zn-ZPD upon the addition of substrate 1 and Hill-plot linear fitting. (d) CV curves of H₂ZPD and Zn-ZPD ranging from 0 to −2 V and (e) ranging from 0 to 2 V in CH₃CN/H₂O containing 0.1 M TBAPF₆. Scan rate: 100 mV s⁻¹. (f) Schematic energy diagram showing the intramolecular electron transfer path.

UV-Vis absorption spectra of Zn-ZPD revealed strong absorbance peaks at 400 and 450 nm, which were assigned to the overlap of absorption bands of the TPA moiety and DHPA moiety. Upon adding substrate 1 to the solution of Zn-ZPD, two isosbestic points arose at 410 and 450 nm, suggesting the formation of a host–guest complex (Fig. 2b and Fig. S8).⁴⁴ Moreover, the titration of substrate 1 resulted in a prominent enhancement of Zn-ZPD luminescence (Fig. 2c and Fig. S9), indicating the occurrence of an interaction between Zn-ZPD and substrate 1.⁴⁵ Meanwhile, a 1 : 2 stoichiometric ratio in the host–guest complex was further confirmed by Hill-plot linear fitting, consistent with the results of the ITC and ESI-MS analyses. Subsequently, luminescence lifetime tests revealed that the luminescence of Zn-ZPD at 450 nm decayed in a clearly exponential fashion. There was no significant change in the luminescence lifetime of Zn-ZPD in the presence of substrate 1 (Fig. S10), suggesting that the electron transfer between Zn-ZPD and substrate 1 occurred via a pseudo-intramolecular pathway.⁴⁶

The activity evaluation for Zn-ZPD first focused on the hydrogenation reaction of benzoxazinones. A stoichiometric reaction was carried out by mixing the substrate 1 (2.0 mM) and Zn-ZPD (1.0 mM) in the presence of ascorbic acid (H₂A) for 12 h under dark conditions. The system gave 84% yield of product 1a, demonstrating that the NADH mimics within the capsule maintained the efficacy. Under identical conditions, replacing Zn-ZPD with the ligand H₂ZPD (4.0 mM) resulted in a dramatic decrease in yield, which was reduced to 31%, suggesting that the confined cavities of Zn-ZPD played a crucial role in the improvement of reaction efficiency through the formation of a host–guest complex.

The cyclic voltammetry analysis of Zn-ZPD revealed a distinct reduction wave at −1.2 V vs. Ag/AgCl, which was attributed to the characteristic NAD⁺/NAD˙ wave (Fig. 2d). The TPA moiety exhibited a ground state potential for TPA˙⁺/TPA at 1.35 V (Fig. 2e). The excited-state reduction potential for TPA˙⁺* was estimated to be −1.45 V, as calculated from the free energy change (E^0–0) (Fig. S11).⁴⁷ The more negative potential of the TPA excited state compared to that of the DHPA moiety ensured the feasibility of directional intramolecular electron transfer from the photo-excited TPA towards the DHPA moiety (Fig. 2f), laying the groundwork for cofactor regeneration during biomimetic photocatalysis.

Photocatalytic biomimetic hydrogenation

To evaluate the impact of the covalent linkage between TPA and DHPA on cofactor photoregeneration, a biomimetic photocatalysis reaction was performed in a flame-dried Schlenk quartz flask containing substrate 1 (4.0 mM) and H₂A (0.1 M) at room temperature under an argon atmosphere. Under irradiation from a 420 nm LED, the system with a catalytic amount of Zn-ZPD (0.04 mM) afforded the product 1a in 72% yield within 12 h (Table 1, entry 1). Nevertheless, employing H₂ZPD ligands (0.16 mM) as photocatalysts resulted in a substantially reduced yield of 30% under identical conditions (Table 1, entry 2). This remarkable 240% improvement for Zn-ZPD underscored the critical role of the pocket within the capsule in promoting hydrogenation efficiency through a rapid pseudo-intramolecular hydride transfer. To elucidate the contribution of the photoresponsive TPA core during catalysis, an isostructural square coordination capsule Zn-ZPD with a skeleton core containing only DHPA and no TPA, was selected as an ideal reference (Fig. S12).²⁹ Under the same conditions, replacing Zn-ZPD with Zn-ZPB and free TPA afforded a yield of 32% (Table 1, entry 3), confirming that the covalent integration of TPA and DHPA within a coordination capsule is conducive to boosting the regeneration efficiency of DHPA through a photoinduced intramolecular electron transfer process. Notably, extending the reaction time did not lead to a significant increase in the yield in the H₂ZPD-catalyzed system, indicating the presumed inactivation of the NADH mimics in the free ligand (Table 1, entry 4). In contrast, the progressive increase in yield observed for Zn-ZPD demonstrates that the topological structure of the coordination capsule contributes to the retained stability and activity of the NADH mimics during photocatalytic regeneration (Fig. 3b). Control experiments conducted in the absence of H₂A, Zn-ZPD, or light, resulted in only trace amounts of product (Table 1, entries 5–7), indicating that the hydrogenation of benzoxazinones requires the synergistic integration of all three factors.

Fig. 3 (a) Production varies as the concentration of 1 in the system containing Zn-ZPD (0.04 mM). Inset: dependence of the initial rate on the concentration of 1. (b) Yield varies as the concentration of Zn-ZPD in the system containing substrate 1 (4.0 mM). Inset: dependence of the initial rate on the concentration of Zn-ZPD. (c) Proposed mechanisms for the coordination capsule-mediated biomimetic hydrogenation, integrating the pseudo-intramolecular hydride transfer within the confined microenvironment and photoinduced intramolecular electron transfer for in situ regeneration of the NADH model.

Table 1 Photocatalytic performance of Zn-ZPD for biomimetic hydrogenation of benzoxazinones^a

Entry	Variation from the standard conditions	Yield (%)
a Standard conditions: Zn-ZPD (0.04 mM), substrate 1 (4.0 mM), H2A (0.10 M), CH3CN/H2O (4 : 1, pH = 4.50), followed by irradiation with a 420 nm LED at room temperature under an argon atmosphere for 12 h. The yields were determined by ^1H NMR analysis of the crude products, with 1,3,5-trimethoxybenzene as an internal standard. b The reaction time was extended to 18 h.
1	None	72
2	H2ZPD instead of Zn-ZPD	30
3	Zn-ZPB/TPA (0.04/0.16 mM) instead of Zn-ZPD	32
4^b	H2ZPD instead of Zn-ZPD	30
5	No H2A	Trace
6	No Zn-ZPD	Trace
7	Under dark conditions	Trace
8	A bulky substrate instead of substrate 1	Trace
9	Adding ATP (4 mM)	21

---

To figure out the role of the cavity in catalysis, a bulky substrate, 3-(4′-(tert-butyl)-[1,1′-biphenyl]-4-yl)-6-(4-(tert-butyl)phenyl)-2H-1,4-benzoxazin-2-one, whose size is larger than the pocket of Zn-ZPD, was introduced as a reactant. The result of biomimetic photocatalysis showed that only a trace amount of the target hydrogenation product was detected (Table 1, entry 8), indicating that the reaction is strictly dependent on encapsulation within the cavity. Furthermore, the addition of a competitive inhibitor, adenosine triphosphate (ATP), which is inactive toward hydrogenation but exhibits a higher association constant than substrate 1, according to the spectral and ITC titration data (Fig. S13–S15), resulted in a decreased yield (Table 1, entry 9), further supporting the suggestion that the hydrogenation proceeds within the pocket.⁴⁸ Additionally, the ESI-MS spectrum of Zn-ZPD after photocatalysis was consistent with that of the pristine catalyst, verifying that the basic structure of the catalyst remained unchanged (Fig. S17).

The kinetics of the biomimetic hydrogenation reaction were explored. When the concentration of Zn-ZPD was fixed, the initial rate of the reaction remained almost unchanged, even as the concentration of substrate 1 was changed significantly (Fig. 3a). Furthermore, with the concentration of substrate 1 maintained at a fixed level, the initial reaction rate of the hydrogenation exhibited a linear relationship with the concentration of Zn-ZPD (Fig. 3b). These dynamic tracking experiments revealed that the catalytic behaviour in the enzymatic process conformed to a Michaelis–Menten mechanism, and the initial reaction rate is governed by the concentration of the host–guest species rather than the substrate concentration.⁴⁹ Under optimal conditions, the applicability of this coordination capsule-catalyzed system was explored to leverage clean energy for biomimetic hydrogenation. A range of substrates with different substituents were converted to afford satisfactory output (Table 2), underlining the superior performance of such noble metal-free systems by integrating the intramolecular electron transfer and the pseudo-intramolecular hydride transfer for enhancing regeneration of NADH mimics and subsequent biomimetic hydrogenation.

Table 2 Activity evaluation of Zn-ZPD for the hydrogenation^a

a Standard conditions: Zn-ZPD (0.04 mM), substrate (4.0 mM), H₂A (0.10 M), CH₃CN/H₂O (4 : 1, pH = 4.50), followed by irradiation with a 420 nm LED at room temperature under an argon atmosphere for 12 h. The yields were determined by ¹H NMR analysis of the crude products, with 1,3,5-trimethoxybenzene as an internal standard.

---

Proposed mechanism

From a mechanistic viewpoint, the initial step involves substrate encapsulation within the cavity of Zn-ZPD through host–guest interactions (Fig. 3c), which is critical for the subsequent biomimetic transfer hydrogenation. This confinement enforces DHPA into close proximity to the substrate, thereby promoting the thermodynamically favorable hydride transfer from DHPA to the bound substrate through a pseudo-intramolecular pathway. Subsequently, the hydrogenated product is released and squeezed out accompanied by the generation of NAD⁺ mimics. Simultaneously, the photoresponsive TPA moiety undergoes excitation upon irradiation and triggers the rapid intramolecular electron transfer for in situ regeneration of the covalently linked NADH mimics, guaranteeing catalytic activity in the next cycle. In this system, H₂A functions as an essential electron donor, supplying necessary reducing equivalents critical for sustaining the photocatalytic cycle and assuring the high catalytic efficiency of the biomimetic hydrogenation system.

Conclusions

In summary, we achieved the integration of intramolecular electron transfer and pseudo-intramolecular hydride transfer by rationally installing a photoresponsive TPA group into a coordination capsule containing NADH mimics for enhanced cofactor regeneration and biomimetic hydrogenation of benzoxazinones without the need for noble metals. The covalent connection between photosensitive TPA and NADH mimics serves as a dedicated channel for smooth intramolecular electron transfer, permitting efficient regeneration of cofactor mimics. The spatial separation of the ligands within the coordination capsules prevents inactivation of DHPA, thereby guaranteeing selectivity during photocatalytic regeneration even without the assistance of a noble metal. The renewable vessels provide a confined cavity for rapid intramolecular hydride transfer hydrogenation of the encapsulated substrate, outperforming relevant biomanufacturing techniques and providing a novel paradigm for solar-to-chemical conversion exploiting noble-metal-free artificial catalysts.

Author contributions

Huali Wang and Bangzhou Xing contributed equally to this study. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Conflicts of interest

The authors declare no conflict of interest.

Data availability

The data supporting the findings of this study are available within the article and its supplementary information (SI) or from the corresponding author upon request. A reporting summary for this article is available. Source data are provided with this paper.

Supplementary information: experimental details, crystal structure and additional spectroscopic data. See DOI: https://doi.org/10.1039/d6qi00196c.

CCDC 2416930 contains the supplementary crystallographic data for this paper.⁵⁰

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant No. 22571031 and 22171034), the National Key Research and Development Program of China (Grant No. 2024YFA1510301), and the Fundamental Research Funds for the Central Universities (Grant No. DUT22LAB606).

References

1. J. M. Sperl and V. Sieber, Multienzyme Cascade Reactions− Status and Recent Advances, ACS Catal., 2018, 8, 2385–2396.
2. M.-W. Chen, B. Wu, Z. Liu and Y.-G. Zhou, Biomimetic Asymmetric Reduction Based on the Regenerable Coenzyme NAD(P)H Models, Acc. Chem. Res., 2023, 56, 2096–2109.
3. H. Wu, C. Tian, X. Song, C. Liu, D. Yang and Z. Jiang, Methods for the regeneration of nicotinamide coenzymes, Green Chem., 2013, 15, 1773–1789.
4. I. Zachos, C. Nowak and V. Sieber, Biomimetic cofactors and methods for their recycling, Curr. Opin. Chem. Biol., 2019, 49, 59–66.
5. G. Zhao, C. Yang, W. Meng and X. Huang, Recent advances in porous materials for photocatalytic NADH regeneration, J. Mater. Chem. A, 2024, 12, 3209–3229.
6. J. Kim, S. H. Lee, F. Tieves, D. S. Choi, F. Hollmann, C. E. Paul and C. B. Park, Biocatalytic C=C Bond Reduction through Carbon Nanodot-Sensitized Regeneration of NADH Analogues, Angew. Chem., Int. Ed., 2018, 57, 13825–13828.
7. Z.-W. Wang, X. Tan, Z.-H. Wu, J.-H. Chen, Y.-Z. Zhu and H.-F. Wang, High yield regeneration of 1,4-NAD(P)H via selective adsorption-/desorption-mediated visible-light photocatalysis on a noble-metal-free catalyst, J. Mater. Chem. A, 2025, 13, 8726–8733.
8. Y. Chai, Z. Pang, H. Jiang, C. C. Tsoi, L. Wan, Y. Du, H. Jia, Y. Zhu, D. Liu, F. Xie, G. Zhou and X. Zhang, Electron-mediator-free efficient photocatalytic regeneration of coenzyme NAD(P)H via direct electron transfer using ultrathin Bi₂MoO₆ nanosheets, Green Chem., 2025, 27, 623–632.
9. S. Immanuel, R. Sivasubramanian, R. Gul and M. A. Dar, Recent Progress and Perspectives on Electrochemical Regeneration of Reduced Nicotinamide Adenine Dinucleotide (NADH), Chem. – Asian J., 2020, 15, 4256–4270.
10. Y. Zhang, Y. Zhao, R. Li and J. Liu, Bioinspired NADH Regeneration Based on Conjugated Photocatalytic Systems, Sol. RRL, 2021, 5, 2000339.
11. W. Dong, C. Wang, Y. Zou, W. Wang and J. Liu, NAD(P)H-Inspired CO₂ Reduction Based on Organohydrides, ACS Appl. Mater. Interfaces, 2024, 16, 67073–67086.
12. Y. Chen, P. Li, J. Zhou, C. T. Buru, L. Đorđević, P. Li, X. Zhang, M. M. Cetin, J. F. Stoddart, S. I. Stupp, M. R. Wasielewski and O. K. Farha, Integration of Enzymes and Photosensitizers in a Hierarchical Mesoporous Metal–Organic Framework for Light-Driven CO₂ Reduction, J. Am. Chem. Soc., 2020, 142, 1768–1773.
13. X. Wang, T. Saba, H. H. P. Yiu, R. F. Howe, J. A. Anderson and J. Shi, Cofactor NAD(P)H Regeneration Inspired by Heterogeneous Pathways, Chem, 2017, 2, 621–654.
14. W. Wang and J. Liu, Hydride Transfer for NADH Regeneration: From Nature, Beyond Nature, Adv. Energy Sustainability Res., 2023, 4, 2200172.
15. S.-Y. Xu, P. Wang, S. Guo, S. Yao, C. Wang, T.-B. Lu and Z.-M. Zhang, Modulating Electron-Transfer via Covalent Assembly Polyoxometalate with Photosensitizer for Efficient H2 Evolution and Tandem Hydrogenation, Angew. Chem., Int. Ed., 2025, e23472.
16. Y. Yang, Y. Du, A. W. Heard and J. R. Nitschke, Allosteric regulation in metal–organic cages, Nat. Synth., 2025, 4, 537–551.
17. R. Ham, C. J. Nielsen, S. Pullen and J. N. H. Reek, Supramolecular Coordination Cages for Artificial Photosynthesis and Synthetic Photocatalysis, Chem. Rev., 2023, 123, 5225–5261.
18. M. Morimoto, S. M. Bierschenk, K. T. Xia, R. G. Bergman, K. N. Raymond and F. D. Toste, Advances in supramolecular host-mediated reactivity, Nat. Catal., 2020, 3, 969–984.
19. T. R. Cook and P. J. Stang, Recent developments in the preparation and chemistry of metallacycles and metallacages via coordination, Chem. Rev., 2015, 115, 7001–7045.
20. K. Iizuka, H. Takezawa and M. Fujita, Host-in-Host Complexation: Activating Classical Hosts through Complete Encapsulation within an M₉L₆ Coordination Cage, Angew. Chem., Int. Ed., 2025, 64, e202422143.
21. X.-W. Zhu, D. Luo, X.-P. Zhou and D. Li, Imidazole-based metal-organic cages: Synthesis, structures, and functions, Coord. Chem. Rev., 2022, 455, 214354.
22. Y. Xu, G. Li, S. Liang, G. De Leener, M. Luhmer, R. Lavendomme, E.-Q. Gao and D. Zhang, Engineering Cavity and Aperture Binding Sites Within a Metal–Organic Cage for Up- and Down-Regulation of Catalysis, Angew. Chem., Int. Ed., 2025, 64, e202507981.
23. Y.-L. Lu, Y.-P. Wang, K. Wu, M. Pan and C.-Y. Su, Activating Metal–Organic Cages by Incorporating Functional M(ImPhen)₃ Metalloligands: From Structural Design to Applications, Acc. Chem. Res., 2024, 57, 3277–3291.
24. M. Drexler, I. Kanavos, D. Krauss, G. Moreno-Alcántar, L. M. Smith, M. E. George, T. H. Witney, R. Lobinski, L. Ronga and A. Casini, Design of porous self-assembled homoleptic and heteroleptic Pd²⁺ cages incorporating silicon-based fluoride acceptors: the way towards nuclear imaging applications, Inorg. Chem. Front., 2025, 12, 6309–6325.
25. H. Liu, C. Guo, L. Li, Z. Zhang, Y. Hou, C. Mu, G.-L. Hou, Z. Zhang, H. Wang, X. Li and M. Zhang, Multicomponent, Multicavity Metallacages That Contain Different Binding Sites for Allosteric Recognition, J. Am. Chem. Soc., 2024, 146, 15787–15795.
26. C.-X. Chen, H. Rabaâ, H. Wang, P. C. Lan, Y.-Y. Xiong, Z.-W. Wei, A. M. Al-Enizi, A. Nafady and S. Ma, In Situ Formation of Frustrated Lewis Pairs in a Zirconium Metal Organic Cage for Sustainable CO₂ Chemical Fixation, CCS Chem., 2023, 5, 1989–1998.
27. S. Du, J. Lyu, Z. Yu, K. Su, W. Wang, X. Zhang and D. Yuan, Improving the Cellular Internalization of Zr(IV) Nanocages by Tuning Hydrophilicity and Lipophilicity, Angew. Chem., Int. Ed., 2025, 64, e202419602.
28. J. Wei, L. Zhao, C. He, S. Zheng, J. N. Reek and C. Duan, Metal–Organic Capsules with NADH Mimics as Switchable Selectivity Regulators for Photocatalytic Transfer Hydrogenation, J. Am. Chem. Soc., 2019, 141, 12707–12716.
29. L. Zhao, J. Wei, J. Lu, C. He and C. Duan, Renewable Molecular Flasks with NADH Models: Combination of Light-Driven Proton Reduction and Biomimetic Hydrogenation of Benzoxazinones, Angew. Chem., Int. Ed., 2017, 56, 8692–8696.
30. J. Wei, L. Zhao, Y. Zhang, P. Zhou, G. Liu and C. Duan, Light-switched selective catalysis with NADH mimic functionalized metal–organic capsules, Chem. Commun., 2023, 59, 71–74.
31. J. Wei, L. Zhao, Y. Zhang, G. Han, C. He, C. Wang and C. Duan, Enzyme Grafting with a Cofactor-Decorated Metal-Organic Capsule for Solar-to-Chemical Conversion, J. Am. Chem. Soc., 2023, 145, 6719–6729.
32. C. Liu, N. Li, Z. Zhang, Y. Gao, T. Cao, C. Yi, G. Li, Y. Li, W. Wei and G. He, Green-Box-Based Supramolecular Artificial Cofactor for Visible-Light-Driven Asymmetric Photo-enzyme Catalysis, J. Am. Chem. Soc., 2025, 147, 44021–44031.
33. A. McSkimming, M. M. Bhadbhade and S. B. Colbran, Bio-Inspired Catalytic Imine Reduction by Rhodium Complexes with Tethered Hantzsch Pyridinium Groups: Evidence for Direct Hydride Transfer from Dihydropyridine to Metal-Activated Substrate, Angew. Chem., Int. Ed., 2013, 52, 3411–3416.
34. H. Zhao, F. Huang, G. Liu, Y. Liu, Y. Wang, X. Liu, C. Xing, J. Gao, X. Yue and Y. Jiang, Rh-Functionalized Donor–π–Acceptor Covalent Organic Framework for Efficient Photocatalytic Nicotinamide Cofactor Regeneration, ACS Sustainable Chem. Eng., 2024, 12, 12775–12785.
35. SMART Data collection software (version 5.629), Bruker AXS Inc., Madison, WI, 2003.
36. SAINT, Data reduction software (version 6.45), Bruker AXS Inc., Madison, WI, 2003.
37. G. M. Sheldrick, Crystal Structure Refinement with SHELXL, Acta Crystallogr., Sect. C:Struct. Chem., 2015, 71, 3–8.
38. A. L. Spek, Single-crystal structure validation with the program PLATON, J. Appl. Crystallogr., 2003, 36, 7–13.
39. H. Wang, Y. Zhang, G. Ji, J. Wei, L. Zhao, C. He and C. Duan, Reserving Electrons in Cofactor Decorated Coordination Capsules for Biomimetic Electrosynthesis of α-Hydroxy/amino Esters, J. Am. Chem. Soc., 2024, 146, 29272–29277.
40. J. Su, F. Yin, X.-F. Duan, J.-Y. Zhou, L.-P. Zhou, C.-B. Tian and Q.-F. Sun, Ionic radius-dependent self-assembly of lanthanide organic polyhedra: structural diversities and luminescent properties, Inorg. Chem. Front., 2025, 12, 3073–3082.
41. H. Zhou, X.-Y. Pang, X. Xie, D. L. Phillips, H.-Y. Gong, J. L. Sessler and W. Jiang, Amide-Based Naphthotubes as Biomimetic Receptors for Acetal Protection and Other Substrates in Water via Noncovalent Interactions, J. Am. Chem. Soc., 2024, 146, 34842–34851.
42. H. Xu, T. K. Ronson, A. W. Heard, P. C. P. Teeuwen, L. Schneider, P. Pracht, J. D. Thoburn, D. J. Wales and J. R. Nitschke, A pseudo-cubic metal–organic cage with conformationally switchable faces for dynamically adaptive guest encapsulation, Nat. Chem., 2025, 17, 289–296.
43. D. Sun, Y. Wu, X. Han and S. Liu, The host–guest inclusion driven by host-stabilized charge transfer for construction of sequentially red-shifted mechanochromic system, Nat. Commun., 2023, 14, 4190.
44. J. Y.-W. Yeung, F. K.-W. Kong, F. K.-W. Hau, M. H.-Y. Chan, M. Ng, M.-Y. Leung and V. W.-W. Yam, Solvent-Dependent Supramolecular Host–Guest Assemblies of Platinum(II) Tweezers and a Guest System: From Discrete Molecules to High-Ordered Oligomers, Angew. Chem., Int. Ed., 2022, 61, e202207313.
45. L. Sévery, J. Szczerbiński, M. Taskin, I. Tuncay, F. Brandalise Nunes, C. Cignarella, G. Tocci, O. Blacque, J. Osterwalder, R. Zenobi, M. Iannuzzi and S. D. Tilley, Immobilization of molecular catalysts on electrode surfaces using host–guest interactions, Nat. Chem., 2021, 13, 523–529.
46. L. Zhao, J. Cai, Y. Li, J. Wei and C. Duan, A host–guest approach to combining enzymatic and artificial catalysis for catalyzing biomimetic monooxygenation, Nat. Commun., 2020, 11, 2903.
47. Y. Zhu, G. Liu, R. Zhao, H. Gao, X. Li, L. Sun and F. Li, Photoelectrochemical water oxidation improved by pyridine N-oxide as a mimic of tyrosine-Z in photosystem II, Chem. Sci., 2022, 13, 4955–4961.
48. D. Wang, L. Zhou, X. Zhang, Z. Zhou, Z. Huang and N. Gao, Supramolecular Switching of Liquid-Liquid Phase Separation for Orchestrating Enzyme Kinetics, Angew. Chem., Int. Ed., 2025, 64, e202422601.
49. D. M. Kaphan, M. D. Levin, R. G. Bergman, K. N. Raymond and F. D. Toste, A supramolecular microenvironment strategy for transition metal catalysis, Science, 2015, 350, 1235–1238.
50. CCDC 2416930: Experimental Crystal Structure Determination, 2026,  DOI:10.5517/ccdc.csd.cc2m40h9.

---

Footnote

† These authors contributed equally to this study.

---