One catalyst to rule them all: a journey from bulk to atom-level control

8

Introduction
Catalysis is nowadays a milestone for a variety of industrial chemical processes that would be impossible to sustain by traditional chemical means. Indeed, catalysis has the role of enabling reactions that would otherwise be too slow, inefficient, or unselective.

The term ‘catalysis’ was coined in 1835 by Jöns Jakob Berzelius, who described substances that facilitate chemical reactions without being consumed during the reaction itself. The history of catalysis continued with a Nobel Prize awarded to Wilhelm Ostwald in 1909 for his contribution in establishing the thermodynamic and kinetic underpinnings of catalytic processes. Another catalysis-centred Nobel Prize was awarded in 1912 to Paul Sabatier for his studies on catalytic hydrogenation. The 20th century was the century in which industrial catalysis began to flourish, with landmark applications such as the Haber-Bosch process for ammonia synthesis and catalytic cracking in petroleum refining. In the second half of the century, organometallic chemistry rose to prominence alongside the development of homogeneous transition metal catalytic systems—fields recognized with Nobel Prizes awarded to Ziegler and Natta in 1963, and to Wilkinson and Fischer in 1973.The science of catalysis did not rest with the rise of the 21st century; indeed, it continues to have a huge impact on the world, which is reflected by the acknowledgement of numerous Nobel Prizes to Knowles, Noyori, and Sharpless (2001); Chauvin, Grubbs, and Shrock (2005); Ertl (2007); and Heck, Negishi, and Suzuki (2010) (1, 2). These important honours which represent the extreme interest in catalysis science from the scientific community were followed and supported by an exceptional rise in industrial applications, demonstrated by the vast number of patents filed, and by the estimation that nowadays 90% of industrial chemical processes include one or more catalytic steps (3).

 

Since the 20th century, catalysis has undergone significant transformations, paralleling advances in coordination chemistry, materials science, and nanotechnology. Each shift, from molecular homogeneous systems to supported metal catalysts and then to isolated atomic species, has addressed specific industrial and environmental challenges. The evolution of catalysis is not merely a technological development, but it reflects a broader shift in how chemists design molecules and processes with precision and sustainability in mind. Understanding this trajectory is essential to appreciate where the field is heading and the opportunities it holds for innovation (1, 2) .

 

Palladium homogeneous catalysis – Domino reactions

Homogeneous catalysis involves soluble metal complexes that provide well-defined coordination environments for substrates. The typical homogeneous catalyst, except for acid-base catalysis, consists of a metal central atom surrounded by one or more ligands; their interplay is central in determining the activity, productivity, and selectivity of the catalyst (1). Palladium (Pd) along with other transition metals, is one of the pillars of homogenous catalysis, particularly widely used for cross-coupling reactions such as Suzuki, Heck, and Sonogashira couplings (2, 4).

 

One of the most fascinating applications of Pd catalysis, is in the so-called domino or cascade reactions, where multiple transformations occur in a single operational step: intermolecular carbon-carbon bond-forming reactions are used to couple small fragments into bigger and much more complex structures, as depicted in Figure 1 (5).
A domino reaction is a process involving two or more bond-forming transformations that take place under the same reaction conditions without adding additional reagents and catalysts and in which the subsequent reactions result as a consequence of the functionality (Figure 1).

This effect can be exploited by repeating the same reaction type several times or by combining it with different transformations. For instance, Pd-catalyzed domino reactions are widely exploited in the synthesis of complex natural and pharmaceutical products, enabling concise routes to otherwise challenging molecular frameworks (1, 6). Domino procedures are subject to continuous study and development, with both the goals of increasing the effectiveness for existing procedures, and of developing new innovative methods as can be seen for the synthesis of 1,7,8,8a-tetrahydro-3H-oxazolo[3,4-a]pyrazin-6(5H)-ones which sequence is reported across Figure 2 and 3, and for domino reactions of indolecarboxylic acid allylamides (5, 6).

 

However, homogeneous systems present challenges. A comparison between homogeneous and heterogeneous catalytic systems in reported in Table 1.
Homogeneous catalysts utilization bring some difficulties, including catalyst and product recovery because they are present altogether in the same phase. The issue of metal leaching is also particularly problematic in pharmaceutical applications, where metal residues must be strictly controlled. These limitations have prompted efforts to develop supported and more easily recoverable catalytic systems, exploring heterogeneous catalysis (1).

 

Nanoreactors and supramolecular catalysis

Fundamental chemical principles change when systems are confined to spaces with extremely reduced dimensions, as for the nanoscale and for sub-microliter volumes. Confined spaces are object of great investigation for their possible applications as nanoreactors to carry out more sustainable organic reactions (8). Indeed, to bridge the gap between homogeneous catalysis efficiency and heterogeneous catalysis practicality, researchers have developed nanoreactors and supramolecular catalysts. These systems confine the catalytic species within a defined micro- or nanoscale environment, often enhancing selectivity and mimicking the behaviour of enzymes (9, 10).

 

Different types of nanoreactors have been explored, differentiating themselves based on different approaches: sometimes the synthetic generation is preferred, such as for nanopores or nanoholes, otherwise structures that are native to biological structures are exploited, such as protein pores, channels, or membrane-less organelles (8). Industrial challenges, such as scalability, fouling of nanoreactors, and high costs are the main factors that prevent diffusion in industry of this technology (11). However, while still largely academic these approaches are pushing the boundaries of what is possible in reaction design, as in the case of graphene-based supramolecular nanoreactors especially developed and tuned to allow the fast synthesis of imines in water (8).

 

The rise of Single-Atom Catalysis

Single-atom catalysis (SAC) represents a frontier in heterogeneous catalysis science, where isolated metal atoms are dispersed on supports like metal oxides, carbons, or metalorganic frameworks (12–14). These systems combine the high specificity of homogeneous catalysis with the stability and recyclability of heterogeneous catalysts, and at the same time are characterized by a high sustainability because of reduced metal load and high efficiency (14). Indeed, the appeal of SACs lies in their maximal atom economy, in the sense that every metal atom is potentially a catalytically active site, and their tuneable coordination environments. Unlike catalysts that range from bulky to nanoparticles, where many atoms are buried under the surface or inactive, single atoms are fully exposed and can be designed to mimic the active sites found in homogeneous complexes or enzymes (12–14).

 

Applications for SACs have been demonstrated in oxidation reactions, selective hydrogenations, and electrocatalytic processes. It was demonstrated, for example, the ability of copper SACs to effectively catalyse Ullman-type C-O coupling, enhancing catalyst recovery while at the same time avoiding the use of bulk metals and toxic ligands (14, 15). A decrease in metal loading and a use of milder conditions are often accompanied by an increase in performance as reported for photocatalytic hydrogen evolution (6-13-fold increase in photocatalytic activity over the metal clusters), and for silane oxidation in water (turnover frequency as high as 50200 h−1) (16–18). As also demonstrated by the release of patents on this topic, industrial interest is growing rapidly, as SACs promise lower costs due to reduced metal usage and high selectivity, key factors in fine chemical and pharmaceutical manufacturing; single atom catalysis also meets specific paradigms of biomedicine, in terms of on biosensing, anticancer therapy, antibacterial treatment, and oxidative-stress cytoprotection (14, 19, 20).

 

Frontier research in catalysis and future perspectives

Sustainability is a great driving force for research in catalysis. Earth-abundant metals like iron and nickel are being explored as alternatives to more precious metals (21, 22). Recyclable supports, solvent-free processes, and green solvents like water, deep eutectic solvents, or supercritical CO2 are becoming standard objectives (23, 24). Catalysis research is becoming increasingly interdisciplinary, incorporating machine learning, in situ spectroscopy, and materials design. Meanwhile, additive manufacturing technologies, such as fuse deposition modelling and stereolithography 3D printing, are being investigated to fabricate custom catalytic reactors with enhanced mass and heat transfer properties (25, 26). Energy-related catalysis is another major focus: electrocatalysis for water splitting, CO2 reduction, and nitrogen fixation aims to replace fossil-based routes with more sustainable alternatives, while photocatalysis is also advancing, with semiconductor-based systems achieving promising efficiencies and reducing energy consumption by exploiting light utilization (27, 28).

 

Conclusions

The evolution from homogeneous to single-atom catalysis reflects the broader trajectory of chemical science toward higher precision, efficiency, and sustainability, also telling us about the challenges that science and industry, had and have to overcome in the last centuries until today. Each step, whether the use of palladium catalysts, confined nanoreactors, or atomically dispersed metals, has opened new avenues for countless discoveries and applications.

 

While challenges remain, particularly in scalability, long-term stability, and sustainability, the conceptual and technological advancements in catalysis over the past few decades are paving the way for transformative innovations in materials, energy, and pharmaceutical fields.

 

 

 

Figure 1. Typical reaction scheme for a domino reaction.

 

Figure 2. Domino process for the preparation of 1,7,8,8a-tetrahydro-3H-oxazolo[3,4-a]pyrazine compounds (6).

 

Figure 3. Proposed mechanism for the cyclization catalyzed by Pd based catalyst. I the starting material is subdued by additive oxidation by the palladium complex. II is cyclizated to intermediate III by Pd mediated rearrangement. The presence of copper enables the other cyclization through the intermediate IV, leading to the bicyclic final product V (5, 6).

 

Table 1. Advantages and disadvantages of homogeneous and heterogeneous catalysis (1, 7).

 

References and notes

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