Cocktail-type catalysis

Catalysis is usually introduced through an elegant mechanistic picture: a catalyst enters a cycle, binds substrates, lowers the activation barrier, releases the product and returns to its initial state. This picture is powerful, but it is also incomplete. Many catalytic systems used in real chemical synthesis do not remain as single-type well-defined species during the reaction. They change.

Mononuclear metallic centers can lose ligands, change oxidation state, form clusters or nanoparticles, rearranging into highly reactive fragments. Nanoparticles can release atoms or small clusters into solution, capture low-nuclearity metal forms back, restructure their surfaces or serve as reservoirs for transient species. In such systems, the catalyst that is placed into the flask is not necessarily the catalyst that performs the target transformation.

The concept of cocktail-type catalysis emerged from this mechanistic tension. The concept was developed by Ananikov and co-workers in the project devoted to studying the dynamic nature of catalytic systems based on transition metals, especially palladium. A review in Chemistry described the foundation for the concept of cocktail-type catalysis, while a review in the Chinese Journal of Catalysis described the historical discovery and development of the concept as a dynamic framework connecting homogeneous and heterogeneous catalysis.

Figure 1. From a single-type active species to an evolving catalytic ensemble.
Source: DOI 10.1021/om201120n.

From catalyst identity to catalyst ensemble

The central question behind cocktail-type catalysis is deceptively simple: what is the real form of the catalyst under the reaction conditions? In classical homogeneous catalysis, a soluble metal complex is commonly treated as the precursor to soluble active species. In classical heterogeneous catalysis, a metal surface is commonly treated as the active phase. Palladium chemistry showed that this separation can be too rigid.

A turning point came from the study of Pd2(dba)3, a canonical palladium precursor used across cross-coupling chemistry. The compound was widely considered a convenient source of molecular Pd(0) centers, but detailed analysis showed that it may contain substantial amounts of palladium nanoparticles. This was more than a purity issue. It revealed that a supposedly homogeneous precursor could introduce nanoscale metal species, and therefore the observed reaction rate, selectivity and catalyst loading could depend on hidden speciation.

The mechanistic question changed from "Which single catalyst form is really active?" to "How does the entire catalytic ensemble evolve, and which members of that ensemble matter at each stage?"

This change in wording is essential. A cocktail-type system may contain active species, dormant species, reservoir species and deactivation products at the same time. Some species may be catalytically active only during a short interval. Others may never enter the catalytic cycle directly but control the concentration of the species that do. The apparent catalyst is therefore an ensemble property.

Bottom-up and top-down routes to catalytic cocktails

Cocktail-type catalysis connects homogeneous and heterogeneous mechanisms through two complementary pathways. In the bottom-up pathway, a molecular precursor evolves into higher nuclearity species. Ligand dissociation, metal reduction, aggregation and cluster growth can convert a soluble complex into nanoparticles or other nanoscale states.

In the top-down pathway, a nanoparticle or supported metal catalyst releases soluble species into the reaction medium. These species may be single atoms, clusters or molecular complexes. They can enter solution-phase catalytic cycles, return to the surface, aggregate into nanoparticles or participate in parallel processes.

Both directions can be realized in one reaction. The same metal atom can move through several forms during the reaction. This is why cocktail-type catalysis is not merely an intermediate case between homogeneous and heterogeneous catalysis. It is a dynamic framework in which the boundary between them can be crossed repeatedly.

Why this explains difficult observations

Induction periods, sigmoidal kinetics, batch-to-batch variability, catalyst activation, catalyst degradation, poisoning behavior and incomplete recycling phenomena can all arise when the catalytic ensemble changes over time.

Why this creates new opportunities

The unexpected catalyst dynamics is not always failure. A nanoparticle may be a reservoir for highly active single atoms. A molecular precursor may be designed to release the active state gradually. A ligand may tune the balance between molecular and nanoscale channels.

From mechanistic complication to design principle

The significance of cocktail-type catalysis is that it turns catalytic complexity into a design tool. In the old view, leaching, aggregation or ligand degradation were often treated only as unwanted decomposition. In the cocktail-type view, these processes must be considered from a broader perspective: some are harmful, some are neutral, and some generate the most active form of the catalyst.

For palladium-catalyzed C–C and C–heteroatom bond formation reactions, this distinction is critical. A supported Pd nanoparticle can be a surface catalyst, a reservoir of soluble Pd, or a trap for active atoms or a deactivation product. A soluble Pd complex can be the operating catalyst, a precursor to nanoparticles or one member of a larger tangled network. The reaction outcome depends on which transformation routes dominate under the actual conditions.

This perspective is now used beyond the original palladium systems. Recent studies apply the language of catalyst cocktails to other transition metals and transformations, including iridium-based hydrodeoxygenation and palladacyclic precatalyst systems with multiple active pathways as a few examples. Such examples show that the concept is not only a historical formulation, but a working mechanistic vocabulary used by independent research groups.

The way to the ideal catalyst of the future may not be the way towards the most rigid catalyst structure, but the way towards most controllable dynamics, which allow generating different types of active species and suppressing unproductive sinks.

In this sense, cocktail-type catalysis is closely connected to green chemistry and sustainable synthesis. A better understanding of catalyst evolution can reduce metal loading, improve catalyst lifetime, increase reactions reproducibility, minimize waste and provide more reliable scale-up opportunities. The Editorial Board of the Russian Journal of Organic Chemistry, in a 2025 preface to special issues dedicated to Academician Ananikov, placed dynamic catalysis and cocktail-type catalysts among the fundamental advances associated with his work and connected them with next-generation catalysts, sustainable organic synthesis and green chemistry.

Studying a catalyst that changes while it works

The methodological consequence is clear: catalyst structure characterization before and after the reaction is necessary, but often insufficient. The most important species may exist only during catalysis. An isolated solid or soluble complex detected in the reaction mixture under static conditions may not accurately reflect the actual operating state of the catalyst.

Therefore, cocktail-type catalysis requires a time-resolved and multiscale analysis strategy. Kinetic measurements must be combined with poisoning experiments, catalyst recycling studies, high-resolution mass spectrometry, NMR spectroscopy, electron microscopy, X-ray methods, operando experiments, isotope labeling, computational modeling and increasingly machine-learning-assisted analysis. The later development of totally defined catalysis and 4D catalysis pushed this logic further by following individual particles, specified regions of catalyst surfaces and particular metal centers over time.

The most important message is that catalytic complexity should not be erased from the mechanism. It should be measured and used. The catalyst is a chemical ensemble in motion. Some members of that ensemble are active, some are dormant, some are reservoirs and some are sinks. The observed catalytic performance is the result of operation of the entire network of metallic species.

Selected publications

  1. Toward the Ideal Catalyst: From Atomic Centers to a “Cocktail" of Catalysts. Ananikov V.P.; Beletskaya I.P. Organometallics 2012, 31, 1595–1604. DOI: 10.1021/om201120n
  2. Pd2(dba)3 as a Precursor of Soluble Metal Complexes and Nanoparticles: Determination of Palladium Active Species for Catalysis and Synthesis. Zalesskiy S.S.; Ananikov V.P. Organometallics 2012, 31, 2302–2309. DOI: 10.1021/om201217r
  3. Catalytic C–C and C–Heteroatom Bond Formation Reactions: In Situ Generated or Preformed Catalysts? Complicated Mechanistic Picture Behind Well-Known Experimental Procedures. Kashin A.S.; Ananikov V.P. J. Org. Chem. 2013, 78, 11117–11125. DOI: 10.1021/jo402038p
  4. Evidence for “cocktail"-type catalysis in Buchwald–Hartwig reaction. A mechanistic study. Prima D.O.; Madiyeva M.; Burykina J.V.; Minyaev M.E.; Boiko D.A.; Ananikov V.P. Catalysis Science & Technology 2021, 11, 7171–7188. DOI: 10.1039/D1CY01601F
  5. Fully Automated Unconstrained Analysis of High-Resolution Mass Spectrometry Data with Machine Learning. Boiko D.A.; Kozlov K.S.; Burykina J.V.; Ilyushenkova V.V.; Ananikov V.P. J. Am. Chem. Soc. 2022, 144, 14590–14606. DOI: 10.1021/jacs.2c03631
  6. Toward Totally Defined Nanocatalysis: Deep Learning Reveals the Extraordinary Activity of Single Pd/C Particles. Eremin D.B.; Galushko A.S.; Boiko D.A.; Pentsak E.O.; Chistyakov I.V.; Ananikov V.P. J. Am. Chem. Soc. 2022, 144, 6071–6079. DOI: 10.1021/jacs.2c01283
  7. Time-Resolved Formation and Operation Maps of Pd Catalysts Suggest a Key Role of Single Atom Centers in Cross-Coupling. Galushko A.S.; Boiko D.A.; Pentsak E.O.; Eremin D.B.; Ananikov V.P. J. Am. Chem. Soc. 2023, 145, 9092–9103. DOI: 10.1021/jacs.3c00645
  8. 4D Catalysis Concept Enabled by Multilevel Data Collection and Machine Learning Analysis. Galushko A.S.; Ananikov V.P. ACS Catalysis 2024, 14, 161–175. DOI: 10.1021/acscatal.3c03889

Reviews on Cocktail-type catalysis

  1. Understanding Active Species in Catalytic Transformations: From Molecular Catalysis to Nanoparticles, Leaching, “Cocktails" of Catalysts and Dynamic Systems. Eremin D.B.; Ananikov V.P. Coordination Chemistry Reviews 2017, 346, 2–19. DOI: 10.1016/j.ccr.2016.12.021
  2. Transition metal “cocktail"-type catalysis. Prima D.O.; Kulikovskaya N.S.; Galushko A.S.; Mironenko R.M.; Ananikov V.P. Current Opinion in Green and Sustainable Chemistry 2021, 31, 100502. DOI: 10.1016/j.cogsc.2021.100502
  3. Discovery and development of cocktail-type catalysis. Maximov A.L.; Egorov M.P. Chinese Journal of Catalysis 2025, 78, 7–24. DOI: 10.1016/S1872-2067(25)64824-8
  4. Cocktail-Type Catalysis: An Emerging Concept in Metal-Mediated Transformations. Prima D.O.; Vatsadze S.Z. Organometallics 2025. DOI: 10.1021/acs.organomet.5c00117
  5. Cocktail of Catalysts: A Dynamic Advance in Modern Catalysis. Egorov M.P.; Lee V.Y.; Alabugin I.V. Chemistry 2025, 7, 109. DOI: 10.3390/chemistry7040109
  6. Dynamic “cocktail"-type catalytic systems in C–N bond formation reactions. Kostyukovich A.Y.; Sahharova L.T. Russian Chemical Reviews 2025, 94, RCR5181. DOI: 10.59761/RCR5181


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