Cocktail type catalysis

Metal complexes can lose ligands, change oxidation state, form clusters or nanoparticles, and release highly reactive fragments. Nanoparticles can leach atoms or small clusters into solution, redeposit metal back onto a support, 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 turnover.

The concept of cocktail-type catalysis emerged from this mechanistic tension. The concept was developed by Ananikov and co-workers in the project studying dynamic nature of metal-catalyzed reactions, especially palladium systems. 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.

From catalyst identity to catalyst population

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 supported particle or 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 Pd ₂(dba)₃, a canonical palladium precursor used across cross-coupling chemistry. The compound was widely considered a convenient molecular source of Pd(0), but detailed analysis showed that samples 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 “What is the single active species?" to “How does the entire catalytic population evolve, and which members of that population 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 competent 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, 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, redeposit as nanoparticles or participate in a parallel pathway.

Both directions can operate in one reaction. The same metal can move through several forms during turnover. 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 can all arise when the catalytic population changes over time.

Why this creates new opportunities

Evolution 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 problem. 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 classified experimentally: 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, this distinction is critical. A supported Pd nanoparticle can be a surface catalyst, a reservoir of soluble Pd, 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 interconverting network. The reaction outcome depends on which exchange processes 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. Such examples show that the concept is not only a historical formulation, but a working mechanistic vocabulary used by independent research groups.

The ideal catalyst of the future may not be the most rigid structure, but the most controlled dynamic system: one that forms the right active species at the right moment and suppresses 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 reproducibility, minimize waste and provide more reliable scale-up. 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: characterization before and after the reaction is necessary, but often insufficient. The most important species may exist only during catalysis. A recovered solid may not represent the operating state. A soluble complex detected before the reaction may disappear under turnover conditions.

Therefore, cocktail-type catalysis requires a time-resolved and multiscale research strategy. Kinetic analysis must be combined with poisoning experiments, catalyst recycling studies, high-resolution mass spectrometry, NMR, electron microscopy, X-ray methods, operando spectroscopy, 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, individual regions of catalyst surfaces and 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 population in motion. Some members of that population are active, some are dormant, some are reservoirs and some are sinks. The observed catalytic performance is the result of the network.

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