{ "id": "ep40vqnsxs", "slug": "domino-reaction", "title": "Domino reaction", "updated": "2026-10-15", "topic_path": [ { "id": "physical", "label": "Physical world and mathematics", "api_url": "https://www.edgepedia.org/api/v1/topics/physical" }, { "id": "physical.chemistry", "label": "Chemistry", "api_url": "https://www.edgepedia.org/api/v1/topics/physical.chemistry" }, { "id": "physical.chemistry.methods", "label": "Chemical principles and methods", "api_url": "https://www.edgepedia.org/api/v1/topics/physical.chemistry.methods" }, { "id": "physical.chemistry.methods.chemical-synthesis", "label": "Chemical synthesis", "api_url": "https://www.edgepedia.org/api/v1/topics/physical.chemistry.methods.chemical-synthesis" }, { "id": "physical.chemistry.methods.chemical-synthesis.synthesis-overview", "label": "Chemical synthesis (overview and strategy)", "api_url": "https://www.edgepedia.org/api/v1/topics/physical.chemistry.methods.chemical-synthesis.synthesis-overview" } ], "geo": [ { "id": "geo.nongeo.t1946.physical.chemistry.methods.chemical-synthesis", "label": "Non-geographic · 1946 to 2000: Chemical synthesis", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t1946.physical.chemistry.methods.chemical-synthesis", "path": [ { "id": "geo.nongeo", "label": "Non-geographic", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo" }, { "id": "geo.nongeo.t1946", "label": "Non-geographic · 1946 to 2000", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t1946" }, { "id": "geo.nongeo.t1946.physical", "label": "Physical world and mathematics", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t1946.physical" }, { "id": "geo.nongeo.t1946.physical.chemistry", "label": "Chemistry", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t1946.physical.chemistry" }, { "id": "geo.nongeo.t1946.physical.chemistry.methods", "label": "Chemical principles and methods", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t1946.physical.chemistry.methods" }, { "id": "geo.nongeo.t1946.physical.chemistry.methods.chemical-synthesis", "label": "Chemical synthesis", "api_url": "https://www.edgepedia.org/api/v1/geo/geo.nongeo.t1946.physical.chemistry.methods.chemical-synthesis" } ] } ], "excerpt": "A domino reaction is an organic synthesis strategy in which two or more bond-forming reactions run sequentially in a single vessel without isolating intermediates, defined by Lutz F. Tietze.", "snippet": "A domino reaction is an organic synthesis strategy in which two or more bond-forming reactions run sequentially in a single vessel without isolating intermediates, defined by Lutz F. Tietze.", "node": "physical.chemistry.methods.chemical-synthesis.synthesis-overview", "markdown": "# Domino reaction\n\nA domino reaction is a synthetic organic chemistry strategy in which two or more bond-forming reactions run sequentially in a single vessel under identical conditions, with each later step occurring at a functionality generated by an earlier one, so that simple starting materials become complex products without isolating intermediates. Lutz F. Tietze defined the concept and gave it its name.[1](https://doi.org/10.1002/anie.199301313) • [2](https://stats.iupac.org/publications/pac/2004/pdf/7611x1967.pdf)\n\nThe terminology around it is loose. \"Tandem\" and \"cascade\" are applied to domino, multicomponent, and telescoped reactions alike and serve as general descriptors.[3](https://www.sciencedirect.com/science/article/abs/pii/S0040402007006126) Most, but not all, [multicomponent reactions](https://www.edgepedia.org/multicomponent-reaction) can be treated as a subgroup of domino reactions.[2](https://stats.iupac.org/publications/pac/2004/pdf/7611x1967.pdf) The sharp contrast is with telescoping, in which reagents or conditions are changed between steps; a true domino process has all components present from the start.[4](https://pubs.acs.org/acscii/article/12/8/1068/5207422/Domino-Strategies-in-Heterocycle-Synthesis)\n\n| Key fact | Detail |\n|---|---|\n| Definition | Two or more bond-forming reactions under identical conditions, later steps at functionalities formed earlier[2](https://stats.iupac.org/publications/pac/2004/pdf/7611x1967.pdf) |\n| Term introduced | [5](https://onlinelibrary.wiley.com/doi/10.1002/jhet.5570270105) • [1](https://doi.org/10.1002/anie.199301313) |\n| Substrate prerequisite | More than two functionalities of comparable reactivity that react in a fixed chronological order[6](https://content.e-bookshelf.de/media/reading/L-602994-7f6d083d9b.pdf) |\n| Classification | Eight mechanistic categories; 64 categories for two steps, 512 for three[6](https://content.e-bookshelf.de/media/reading/L-602994-7f6d083d9b.pdf) |\n| Practical benefit | One workup and purification; reduced solvent, waste, time, and energy[7](https://pmc.ncbi.nlm.nih.gov/articles/PMC10862128/) |\n| Landmark result | Pd-catalyzed Wacker/Heck domino to a vitamin E chroman precursor: 84% yield, 97% ee[8](https://hal.science/hal-02106065/document) |\n| Industrial barrier | Narrow substrate scope, high catalyst loading, low turnover numbers, insufficient robustness[4](https://pubs.acs.org/acscii/article/12/8/1068/5207422/Domino-Strategies-in-Heterocycle-Synthesis) |\n\n## How it works\n\nAll reagents, catalyst, and solvent are mixed in one flask, and the reaction steps proceed autonomously: one step triggers the next, and only a single workup and purification is needed at the end.[7](https://pmc.ncbi.nlm.nih.gov/articles/PMC10862128/) The sequence is time-resolved. Tietze argues that the term \"tandem\" does not capture this time-resolved character, because the steps occur in a fixed chronological order dictated by steric or electronic differentiation among the functionalities.[6](https://content.e-bookshelf.de/media/reading/L-602994-7f6d083d9b.pdf) The prerequisite is substrates carrying more than two functionalities of comparable reactivity.[6](https://content.e-bookshelf.de/media/reading/L-602994-7f6d083d9b.pdf)\n\nDomino processes are classified by the mechanism of the bond-forming steps into cationic, anionic, radical, pericyclic, photochemical, transition-metal-catalyzed, oxidative/reductive, and enzymatic categories. Counting only two steps gives 64 categories; adding a third gives 512. Homo domino processes combine steps of one category, such as the cationic/cationic sequence in a progesterone synthesis; mixed processes combine categories, as in the daphnilactone A synthesis with two anionic then two pericyclic steps.[6](https://content.e-bookshelf.de/media/reading/L-602994-7f6d083d9b.pdf)\n\n## How it is done\n\nNo step-by-step laboratory protocol has been published, but the design logic is documented. The chemist identifies a substrate with more than two functionalities of comparable reactivity and arranges them so they react in a fixed chronological order, controlled by steric or electronic differentiation; all components are then combined at the outset and the sequence runs without further intervention.[6](https://content.e-bookshelf.de/media/reading/L-602994-7f6d083d9b.pdf) • [4](https://pubs.acs.org/acscii/article/12/8/1068/5207422/Domino-Strategies-in-Heterocycle-Synthesis)\n\nThe contrast with telescoped one-pot practice is operational. In a telescoped process, each transformation is run to completion and additional reagents or catalysts are introduced to trigger the next event; in a domino process nothing is added after the start.[4](https://pubs.acs.org/acscii/article/12/8/1068/5207422/Domino-Strategies-in-Heterocycle-Synthesis) When in-pot adjustments are needed, they must be engineered chemically: in one reported one-pot synthesis, EtOH and TMSCl were added to generate HCl that converted Cs2CO3, written \\( \\mathrm{Cs_{2}CO_{3}} \\), into insoluble CsCl, deactivating the base in situ so the next step could proceed without workup.[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC5529999/)\n\n## Origin\n\nThe earliest widely cited precursor is Robert Robinson's 1917 synthesis of tropinone from succinaldehyde, methylamine, and acetonedicarboxylic acid, a double Mannich domino process giving tropinone in excellent yield without isolating intermediates; it was later improved by Schöpf.[10](https://doi.org/10.1039/ct9171100762) • [6](https://content.e-bookshelf.de/media/reading/L-602994-7f6d083d9b.pdf) Tietze's 1993 review with Uwe Beifuss, \"Sequential Transformations in Organic Chemistry: A Synthetic Strategy with a Future\" in Angewandte Chemie International Edition in English, cites Robinson's paper and set out the strategy.[1](https://doi.org/10.1002/anie.199301313) • [11](https://onlinelibrary.wiley.com/doi/10.1002/ange.19931050204)\n\nLater reviews variously credit the 1993 Angewandte paper or Tietze's 1996 Chemical Reviews paper, \"Domino reactions in organic synthesis\", as foundational.[12](https://benthamdirect.com/content/journals/mroc/10.2174/0118756298371578250503015424) Tietze consolidated the field in the 2006 Wiley-VCH monograph \"Domino Reactions in Organic Synthesis\" and a 2014 follow-up monograph.[6](https://content.e-bookshelf.de/media/reading/L-602994-7f6d083d9b.pdf) • [7](https://pmc.ncbi.nlm.nih.gov/articles/PMC10862128/)\n\n## Variants\n\nThe domino Knoevenagel–hetero-Diels–Alder (DKHDA) reaction combines mechanistically different reaction types and has been applied to the synthesis of heterocyclic natural products and analogs.[2](https://stats.iupac.org/publications/pac/2004/pdf/7611x1967.pdf) The Mannich reaction is itself a three-component domino process, described as one of the first domino reactions developed by humankind.[6](https://content.e-bookshelf.de/media/reading/L-602994-7f6d083d9b.pdf)\n\nCatalytic platforms have expanded the families. A [Cinchona](https://www.edgepedia.org/cinchona) alkaloid-promoted [Michael addition](https://www.edgepedia.org/michael-addition)/aldol route gives a (−)-[Huperzine A](https://www.edgepedia.org/huperzine-a) intermediate in 45% yield and 64% ee.[8](https://hal.science/hal-02106065/document) • [4](https://pubs.acs.org/acscii/article/12/8/1068/5207422/Domino-Strategies-in-Heterocycle-Synthesis) Metal-catalyzed variants include Tietze's Pd-catalyzed Wacker/Heck and three-component Wacker/carbonylation dominoes, asymmetric Heck-initiated dominoes reaching up to 94% ee, and copper-catalyzed Michael-initiated dominoes at 94–98% ee.[8](https://hal.science/hal-02106065/document) Organocatalytic dominoes flourished after 2000: Brandau, Maerten, and Jørgensen reported organocatalytic domino Mannich/aldol reactions to tetrahydrothiophenes; Rueping and Azap reported an asymmetric synthesis of isochinuclidines through the cooperative interplay of two Brønsted acids; Rios, Córdova, and colleagues a domino Michael/aldol to 2H-1-benzothiopyrans; Enders, Grondal, and Hüttl reviewed the field in 2007 and Grondal, Jeanty, and Enders positioned organocatalytic cascades as a total-synthesis tool in 2010.[13](https://doi.org/10.1021/ja065507+) • [14](https://doi.org/10.1002/ange.200603199) • [15](https://doi.org/10.1016/j.tetlet.2006.09.135) • [16](https://doi.org/10.1002/anie.200603129) • [17](https://doi.org/10.1038/nchem.539) Radical dominoes combine radical, cationic, anionic, redox, and transition-metal steps to give cyclizations, additions, fragmentations, ring-expansions, and rearrangements.[18](https://pubs.acs.org/doi/abs/10.1021/cs400995r) Rhodium-catalyzed dominoes include intermolecular linear cross-trimerization of two alkynes with an alkene using rhodium(I)/biaryl bisphosphine, giving chiral dienamides in 68–96% ee.[19](https://www.sciencedirect.com/science/article/abs/pii/S0022328X24000457)\n\n## Applications\n\nDomino chemistry is a mainstay of total synthesis and bioactive-molecule preparation. Using catalyst-controlled DKHDA chemistry, 12 of the 16 possible stereoisomers of emetine, which has four stereogenic centers, were synthesized; the DKHDA step gave three diastereomers in ratio 29:43:44 with 66% overall yield based on the aldehyde precursor, and transfer hydrogenation introduced the fourth stereocenter with diastereoselectivity greater than 98:1.[2](https://stats.iupac.org/publications/pac/2004/pdf/7611x1967.pdf) Hirsutine, accessible through such routes, inhibits influenza A virus (H3N2) with an \\( \\mathrm{EC}_{50} \\) of 0.40–0.57 µg/ml, about 11–20 times higher than the clinically used [Ribavirin](https://www.edgepedia.org/ribavirin).[2](https://stats.iupac.org/publications/pac/2004/pdf/7611x1967.pdf)\n\nThe vitamin E chroman precursor from the Wacker/Heck domino was obtained in 84% yield and 97% ee; the Wacker/carbonylation domino reached yields and ee up to 99% and fed a synthesis of 4-dehydroxydiversonol with an 80% yield, 96% ee key step.[8](https://hal.science/hal-02106065/document) Zhu and co-workers completed the first total synthesis of (+)-peganumine A with an organocatalytic asymmetric Pictet–Spengler cascade using Jacobsen's thiourea catalyst: 92% ee, 69% yield, gram scale, 7 steps, 33% overall yield.[20](https://pubs.rsc.org/en/content/articlehtml/2021/cs/d0cs00768d)\n\nThe efficiency framing comes from atom economy, step economy, and redox economy. By avoiding workup and isolation of intermediates, one-pot and domino syntheses reduce solvent, waste, time, labor, and cost.[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC5529999/) Rhodium-catalyzed dominoes specifically use less energy, solvents, reagents, and adsorbents than multistep alternatives.[19](https://www.sciencedirect.com/science/article/abs/pii/S0022328X24000457)\n\n## Limitations and alternatives\n\nThe nearest alternatives are telescoped one-pot sequences and conventional multistep synthesis. Telescoping trades the domino requirement that all components coexist for the freedom to change conditions or add reagents between steps; a one-pot reaction is an additive sequence of reagents, solvent modifications, and in situ quenching events, not a simple combination of separately optimized conditions.[4](https://pubs.acs.org/acscii/article/12/8/1068/5207422/Domino-Strategies-in-Heterocycle-Synthesis) • [9](https://pmc.ncbi.nlm.nih.gov/articles/PMC5529999/)\n\nSubstrate requirements are strict: the substrate must carry more than two functionalities of comparable reactivity ordered by steric or electronic differentiation, and steric effects can be decisive. In a 2024 electrochemical four-component isoxazole domino, electron-rich benzaldehydes and electron-deficient olefins often gave yields below 40%, and α-methyl styrene gave no product.[6](https://content.e-bookshelf.de/media/reading/L-602994-7f6d083d9b.pdf) • [21](https://pubs.rsc.org/en/content/articlehtml/2024/sc/d3sc05946d) Barriers to industrial adoption include narrow substrate scope, high catalyst loading, low turnover numbers, and insufficient robustness.[4](https://pubs.acs.org/acscii/article/12/8/1068/5207422/Domino-Strategies-in-Heterocycle-Synthesis)\n\nRecent directions include an electro-oxidative [1 + 2 + 1 + 1] annulation in an undivided cell, which uses water as an unusual oxygen source and proceeds by a radical pathway supported by TEMPO/BHT suppression and an isolated BHT adduct;[21](https://pubs.rsc.org/en/content/articlehtml/2024/sc/d3sc05946d) Organo-autocatalyzed six-step transamination metathesis relying on an in situ-formed pyrrolidinium salt, with yields up to 95% at room temperature without external catalysts;[4](https://pubs.acs.org/acscii/article/12/8/1068/5207422/Domino-Strategies-in-Heterocycle-Synthesis) and metallaphotoredox dominoes, the merger of transition-metal and photoredox catalysis, collected in a 2025 review with 2024 examples including asymmetric cross-electrophile couplings to chiral boronates and axially chiral tetrasubstituted allenes.[12](https://benthamdirect.com/content/journals/mroc/10.2174/0118756298371578250503015424)\n\n## References\n\n1. [Lutz F. Tietze, Uwe Beifuss (1993). Sequential Transformations in Organic Chemistry: A Synthetic Strategy with a Future. Angewandte Chemie International Edition in English.](https://doi.org/10.1002/anie.199301313)\n2. [Domino reactions in the synthesis of heterocyclic natural products and analogs (Tietze & Rackelmann, Pure Appl. Chem. 2004, DOI 10.1351/pac200476111967)](https://stats.iupac.org/publications/pac/2004/pdf/7611x1967.pdf)\n3. [Tetrahedron report number 802: The domino way to heterocycles](https://www.sciencedirect.com/science/article/abs/pii/S0040402007006126)\n4. [Domino Strategies in Heterocycle Synthesis: Advancing from Organocatalysis to Photo-/Organo-Autocatalysis (ACS Central Science Outlook)](https://pubs.acs.org/acscii/article/12/8/1068/5207422/Domino-Strategies-in-Heterocycle-Synthesis)\n5. [Domino-reactions: The tandem-knoevenagel-hetero-diels-alder reaction and its application in natural product synthesis (Tietze, J. Heterocyclic Chem., Jan 1990)](https://onlinelibrary.wiley.com/doi/10.1002/jhet.5570270105)\n6. [Domino Reactions in Organic Synthesis (Tietze, Brasche, Gericke, Wiley-VCH, 2006), Introduction text](https://content.e-bookshelf.de/media/reading/L-602994-7f6d083d9b.pdf)\n7. [Catalytic multi-step domino and one-pot reactions (Beilstein Journal of Organic Chemistry editorial, 2024)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10862128/)\n8. [Total syntheses based on enantioselective metal-catalyzed domino reactions (review)](https://hal.science/hal-02106065/document)\n9. [Pot economy and one-pot synthesis (Hayashi, Chem. Sci.)](https://pmc.ncbi.nlm.nih.gov/articles/PMC5529999/)\n10. [Robert Robinson (1917). LXIII., A synthesis of tropinone. Journal of the Chemical Society Transactions.](https://doi.org/10.1039/ct9171100762)\n11. [Sequentielle Transformationen in der Organischen Chemie eine Synthesestrategie mit Zukunft (Tietze, Angew. Chem., Feb 1993)](https://onlinelibrary.wiley.com/doi/10.1002/ange.19931050204)\n12. [Domino Reactions through Metallaphotoredox Catalysis (Bentham, 2025)](https://benthamdirect.com/content/journals/mroc/10.2174/0118756298371578250503015424)\n13. [Sven Brandau, Eddy Maerten, Karl Anker Jørgensen (2006). Asymmetric Synthesis of Highly Functionalized Tetrahydrothiophenes by Organocatalytic Domino Reactions. Journal of the American Chemical Society.](https://doi.org/10.1021/ja065507+)\n14. [Magnus Rueping, Cengiz Azap (2006). Kooperative Koexistenz: effizientes Zusammenspiel zweier Brønsted‐Säuren in der asymmetrischen Synthese von Isochinuclidinen. Angewandte Chemie.](https://doi.org/10.1002/ange.200603199)\n15. [Ramon Rios and colleagues (2006). Highly enantioselective synthesis of 2H-1-benzothiopyrans by a catalytic domino reaction. Tetrahedron Letters.](https://doi.org/10.1016/j.tetlet.2006.09.135)\n16. [Dieter Enders, Christoph Grondal, Matthias R. M. Hüttl (2007). Asymmetric Organocatalytic Domino Reactions. Angewandte Chemie International Edition.](https://doi.org/10.1002/anie.200603129)\n17. [Christoph Grondal, Matthieu Jeanty, Dieter Enders (2010). Organocatalytic cascade reactions as a new tool in total synthesis. Nature Chemistry.](https://doi.org/10.1038/nchem.539)\n18. [Catalytic Radical Domino Reactions in Organic Synthesis (ACS Catalysis Perspective, Sebren, Devery, Stephenson)](https://pubs.acs.org/doi/abs/10.1021/cs400995r)\n19. [Advances and prospects in rhodium catalyzed domino reactions (J. Organomet. Chem., 2024)](https://www.sciencedirect.com/science/article/abs/pii/S0022328X24000457)\n20. [Advances in polycyclization cascades in natural product synthesis (Chem. Soc. Rev., 2021)](https://pubs.rsc.org/en/content/articlehtml/2021/cs/d0cs00768d)\n21. [Electrochemical assembly of isoxazoles via a four-component domino reaction (Chemical Science, 2024)](https://pubs.rsc.org/en/content/articlehtml/2024/sc/d3sc05946d)\n\n---\n*Topic: Encyclopedia › Physical world and mathematics › Chemistry › Chemical principles and methods › Chemical synthesis › Chemical synthesis (overview and strategy)*\n\n*Initially written Sep 29, 2026 · Edited: Oct 15, 2026*\n\n*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*\n\nLicense: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license\n", "same_as": [], "url": "https://www.edgepedia.org/domino-reaction", "markdown_url": "https://www.edgepedia.org/domino-reaction.md", "license": { "name": "Edgepedia Community License 1.0", "url": "https://www.edgepedia.org/edgepedia/license", "summary": "Free with credit, commercial use included. AI training is open to everyone. For other uses, organizations over USD 100M in revenue or 100M monthly users license separately.", "spdx": "LicenseRef-Edgepedia-Community-1.0" }, "credit": "\"Domino reaction\", Edgepedia (EdgeChat), https://www.edgepedia.org/domino-reaction. Edgepedia Community License 1.0.", "credit_md": "\"[Domino reaction](https://www.edgepedia.org/domino-reaction)\", Edgepedia (EdgeChat), [https://www.edgepedia.org/domino-reaction](https://www.edgepedia.org/domino-reaction). [Edgepedia Community License 1.0](https://www.edgepedia.org/edgepedia/license).", "credit_html": "\"Domino reaction\", Edgepedia (EdgeChat), https://www.edgepedia.org/domino-reaction. Edgepedia Community License 1.0.", "speakable": "A domino reaction is an organic synthesis strategy in which two or more bond-forming reactions run sequentially in a single vessel without isolating intermediates, defined by Lutz F. Tietze." }