Chapter Four · failure evidence
What Lewis Acid Catalysis got wrong, from 44 dissertations
Lewis acid catalysts frequently encounter operational failures including substrate degradation, catalyst poisoning by coordinating bases, and insufficient activation of unreactive substrates. In addition, practitioners face challenges with stereochemical control, excessive acidity driving side reactions, and suboptimal catalyst loadings during framework synthesis. These records come from PhD theses at 15 institutions, 2021 to 2026. Each links to its thesis. They were extracted by language models reading the full text, so treat each as a lead to read, not a verdict.
Ineffective substrate activation leads to negligible conversion or complete reaction failure
Screened Lewis acids frequently fail to achieve the required electrophilic activation of unreactive functional groups or electronically deactivated substrates. As a result, these reactions stall completely or deliver trace conversion unless paired with specific secondary promoters.
Tried and failed
Lewis acid catalyzed annulation applied to 1,4-dioxane synthesis from diols and oxetanols. Reason: Lewis acids failed to promote reaction or form desired cyclization product
Oxetan-3-ols as 1,2-bis-Electrophiles in a brønsted acid catalyzed synthesis of 1,4-Dioxanes · Imperial
Tried and failed
Lewis acid mediated fluoride abstraction applied to fluorophosphorane intermediates. Reason: strong Lewis acids failed to abstract fluoride from the organophosphorus fluoride adduct
(De)fluorination of Organic Substrates Mediated by Nontrigonal Phosphorus Triamide · MIT
Tried and failed
Lewis acid catalysis without Bronsted sites applied to cyclic sugar acetalization with aldehydes. Outcome: no signal. Reason: Lewis acids alone are insufficient to catalyze cyclic sugar acetalization, yielding zero product
Design and Synthesis of Bio-based Amphiphiles from Lignocellulosic Biomass · EPFL
Tried and failed
heterobimetallic activation with non-silver Lewis acids applied to catalytic ring-opening polymerisation. Outcome: no signal. Reason: harder Lewis acids failed to activate or completely inhibited polymerisation without specific cation-pi interactions
The development of switchable initiators for rac-Lactide ring-opening polymerisation · Imperial
Tried and failed
Lewis acid catalyzed cationic ring-opening polymerization applied to cyclic acetal monomers. Outcome: no signal. Reason: Screened Lewis acid metal halides exhibited complete lack of polymerization activity.
Developing Dynamic Plastics for Improved Sustainability and Energy Storage Technologies · Cornell
Tried and failed
Lewis base and dual Lewis acid-base catalysis applied to donor-acceptor aminocyclopropane ring opening. Outcome: no signal. Reason: Catalysts failed to activate the donor-acceptor cyclopropane toward reaction with electron-deficient alkenes
Ring-Opening Reactions of Aminocyclopropanes and Aminocyclobutanes · EPFL
Tried and failed
Lewis acid activation of alkyl bromide initiators applied to cationic ring-opening polymerization. Outcome: no signal. Reason: Zinc chloride failed to activate the bromide initiator, resulting in zero monomer conversion.
ADVANCED SYNTHETIC ROUTES TO CHEMICALLY RECYCLABLE POLYACETALS · Cornell
Tried and failed
Lewis or Brønsted acid catalysis applied to ring-closing carbonyl-olefin metathesis. Reason: Catalysts failed to promote the cycloaddition/cycloreversion sequence, resulting in 0% conversion
Tried and failed
metal triflate Lewis acid catalysis applied to donor-acceptor cyclopropane annulation. Outcome: worse than baseline. Reason: catalysts provided negligible conversion yielding less than 5% desired product at low temperature
Synthesis of Thiochromans via [3+3] Annulation of Aminocyclopropanes with Thiophenols · EPFL
Tried and failed
Lewis acid mediated alkylation of N,O-acetals applied to electron-deficient trifluoromethyl substituted substrates. Reason: strong electron-withdrawing deactivation prevented oxocarbenium/iminium formation
THE DEVELOPMENT OF LATE-STAGE FUNCTIONALIZATION STRATEGIES ENABLED BY OXIDATIVE ELECTROCHEMISTRY · Cornell
Tried and failed
boron or Lewis acid catalysis alone applied to carbohydrate redox isomerization and deoxygenation. Outcome: no signal. Reason: catalysts alone without photoredox activation gave trace (<2%) conversion
Considered and rejected
Considered and rejected: Rejected 1st generation route using Lewis/Brønsted acid intramolecular Friedel-Crafts cyclization of epoxyketone 14 due to arene deactivation from two chlorine atoms.
Tried and failed
Lewis acid or silver activation of benziodoxolones applied to synthesis of alkynyl hypervalent iodine reagents. Reason: acetoxy- and chlorobenziodoxolones failed to activate under Lewis acidic or silver-promoted conditions to yield target reagents
Substrates undergo degradation and non-selective bond cleavage under Lewis acidic conditions
Exposure to Lewis acid catalysts frequently causes sensitive starting materials to decompose, gel, or produce complex degradation mixtures. Catalysts often promote destructive pathways such as backbone cleavage, deacetylation, and undesired ether rupture over the target transformations.
Tried and failed
Lewis-acid-catalyzed carbohydrate condensation cascade applied to ketoses and alternative beta-dicarbonyl substrates. Outcome: did not generalise. Reason: yielded degradation, gelation, or unreacted starting material with minimal desired product formation
Tried and failed
Lewis acid promoted Diels-Alder cycloaddition applied to acid-sensitive diene oxazolidines. Outcome: unstable. Reason: Uncatalyzed reaction showed no conversion, whereas Lewis acid catalysts induced substrate degradation
Chemodivergent Asymmetric Synthesis via Catalytically Formed Chiral Auxiliary · EPFL
Tried and failed
olefin ring-closing metathesis with first-generation catalyst applied to macrocyclization of functionalized dienes. Reason: unreactive substrate failed to undergo macrocyclization even with additives, leading to decomposition under Lewis acid conditions
Cis Selective RCM Study to the 14-Membered Cyclic Subunit of Bielschowskysin. · Cambridge
Tried and failed
cationic polyene cyclisation for kinetic resolution applied to geometric isomer mixtures. Reason: lewis acid activation produced complex degradation mixtures rather than selective cyclisation
Tried and failed
Electrophilic aromatic dearylation using Lewis acids applied to unsaturated organosilicon polymers. Reason: The acid catalyst non-selectively cleaved both aryl substituents and backbone unsaturated bonds
Syntheses and studies of organosilicon compounds · Iowa State
Considered and rejected
Considered and rejected: Rejected triflate-based Lewis acids (TMSOTf, TfOH) for orthoester thioglycosidation because they caused anomeric mixtures and C-2 deacetylation.
Investigation of Synthesis and Application of Thioglycosides · Research Repository UCD
Considered and rejected
Considered and rejected: Rejected acidic promoters (e.g., Lewis/Brønsted acids) typically used with allylic alcohols due to incompatibility with nucleophilic boronate ate complexes.
Iridium-Catalyzed Enantioselective Allylation of Alkenyl Boronates · DSpace at UTSWMED
Tried and failed
Pd/Fe cocatalytic olefin aminoboration applied to Lewis-acid-sensitive strained bicyclic olefins. Outcome: did not generalise. Reason: Substrates containing Lewis-acid-sensitive functional groups were incompatible with the reaction conditions
Tried and failed
Intramolecular Friedel-Crafts acylation applied to functionalised phenyl ether intermediates. Reason: Lewis or Brønsted acids induced phenoxy-alkyl bond cleavage instead of cyclisation
Development of structurally novel FMS (CSF-1R) inhibitors for cancer · Imperial
Coordinating Lewis bases and basic solvents poison and deactivate catalytic centers
Lewis acidic catalysts readily coordinate with basic amines, nitrogen heterocycles, chelating diols, trace moisture, or Lewis-basic solvents. This competitive binding and quenching of active acidic sites inhibits turnover and leaves starting materials unreacted.
Considered and rejected
Considered and rejected: Rejected methanol/ethanol recrystallization without drying agents for imine substrates due to trace moisture poisoning the Lewis acid/superbase catalyst.
Organic Superbases in Catalytic Antimony-Carbon Bond Formation and Frustrated Lewis Pair Hydrogenation of Imines. · Texas Tech
Tried and failed
Lewis acid catalysis in Lewis basic solvents applied to nucleophilic alkylation of acetal intermediates. Reason: Strong Lewis basicity of the solvents hindered Lewis acid activation and suppressed reaction progress
THE DEVELOPMENT OF LATE-STAGE FUNCTIONALIZATION STRATEGIES ENABLED BY OXIDATIVE ELECTROCHEMISTRY · Cornell
Tried and failed
Lewis acid catalysis with lithium salts applied to heterocycle annulation from diols. Outcome: no signal. Reason: diol substrate chelated and deactivated the metal catalyst, preventing reaction
Oxetan-3-ols as 1,2-bis-Electrophiles in a brønsted acid catalyzed synthesis of 1,4-Dioxanes · Imperial
Tried and failed
dual hydrogen-bond donor catalysis with Lewis acids applied to multicomponent enantioselective allylation with amines. Reason: strongly basic amine nucleophiles form ammonium salts that inhibit the hydrogen-bond donor catalyst
Tried and failed
Lewis acid catalyzed epoxide ring opening applied to heterocycle-containing nucleophiles. Reason: Unhindered electron-rich nitrogen heterocycles coordinate competitively to the metal catalyst, causing catalyst poisoning and inhibition
Addressing the Extremes of Reactivity in Small-Molecule-Catalyzed Stereoselective Glycosylation · Harvard
Tried and failed
in-situ catalyst generation with excess ligand applied to epoxide ring-opening polymerization. Reason: Excess uncoordinated amine ligand poisoned the Lewis acidic catalytic centers, preventing monomer conversion
Tried and failed
Lewis or Brønsted acid catalyzed direct amination applied to tertiary alcohol substitution with amines. Reason: catalyst deactivation and poisoning by the basic amine nucleophile returned unreacted starting material
Investigation of oxetane reactive intermediates for the synthesis of 3,3-disubstituted oxetanes · Imperial
Tried and failed
Superacid catalysis in basic aprotic solvents applied to biaryl C-C bond cleavage. Reason: Exhaustive acid protonation by Lewis-basic solvents completely quenched the superacid catalyst.
Excessive Lewis acidity induces side reactions and uncontrolled reactivity
Overly strong Lewis acidity can compromise selectivity by activating monomers directly instead of initiators or by triggering competing elimination pathways. Furthermore, excessively acidic catalysts frequently underperform relative to less acidic counterparts or fail to form necessary complexes.
Tried and failed
extreme Lewis acid activation applied to deoxygenative fluorination of aliphatic alcohols. Reason: overly strong or weak Lewis acidity fails to promote the catalytic cycle effectively
Lost to a baseline
Lewis acid additives (e.g., Mg(ClO4)2, Sc(OTf)3, Ti(Oi-Pr)4) provided lower syn-to-anti epimerization levels than triethylamine alone.
Tried and failed
strong Lewis acid catalysts for controlled polymerization applied to cationic ring-opening polymerization of cyclic acetals. Outcome: unstable. Reason: Strong Lewis acids directly activate the monomer rather than the initiator, causing uncontrolled non-living polymerization.
Developing Dynamic Plastics for Improved Sustainability and Energy Storage Technologies · Cornell
Tried and failed
Lewis acid catalyzed benzannulation applied to indolyl dihydrofurans. Reason: competing rearomatization/elimination pathway selectively yielded furan instead of the annulated product
Lost to a baseline
P2-Et/[9-(4-CF3-C6H4)BBN] reached only 30% conversion at 80 bar H2 for N-benzylideneaniline, outperformed by the less Lewis acidic P2-Et/[9-(4-MeO-C6H4)BBN] (99%).
Organic Superbases in Catalytic Antimony-Carbon Bond Formation and Frustrated Lewis Pair Hydrogenation of Imines. · Texas Tech
Considered and rejected
Considered and rejected: Rejected diamagnetic isocyanide TMP adducts for matrix dilution due to excessive Lewis acidity preventing complexation, replacing with TMStrenTiCC4-dmap.
Developing Telecom Band-Compatible Molecular Color Centers for Quantum Networking · MIT
Chiral Lewis acid systems fail to provide adequate stereocontrol and enantioselectivity
Asymmetric transformations promoted by chiral Lewis acids often suffer from low enantioselectivity due to steric clashes, high temperatures, or competitive coordination. In some instances, increasing the Lewis acidity accelerates reaction rates but simultaneously erodes stereochemical fidelity.
Tried and failed
enantioselective 1,2-rearrangement via chiral lithium Lewis acid applied to sterically hindered, unsaturated, or basic boronates. Outcome: did not generalise. Reason: electronic mismatches, steric hindrance, and competitive Lewis base coordination degraded enantioselectivity
Considered and rejected
Considered and rejected: Abandoned Lewis acid-catalyzed asymmetric ATRA after extensive screening due to poor stereocontrol and Lewis acid inhibition of radical addition.
Synthesis and functionalization of α-Chiral Bicyclo[1.1.1]pentanes · Oxford
Considered and rejected
Considered and rejected: Abandonment of the chiral Lewis-acid / oxazolidinone approach (156 with Sc(OTf)3 / Ir(dFppy)3) for enantioselective dihydrophenalene synthesis due to failure to establish stereocontrol.
Photoannulierungen zu Dihydrophenalenonen und 1-Tetralonen · open_UMR Marburg DSpace 10.0
Considered and rejected
Considered and rejected: Abandoned chiral Brønsted/Lewis acid catalysis for desymmetrization due to high temperature requirements (>80 °C) causing low enantioselectivity (<=10% ee)
Chemical Investigations in Complex Alkaloid Synthesis · DSpace at UTSWMED
Considered and rejected
Considered and rejected: Rejected BIPHEP (L5) ligand in place of BINAP (L1); although it accelerated reaction rates via higher Lewis acidity, it led to lower enantioselectivity (86% vs 90% ee)
Suboptimal catalyst loading prevents crystalline framework formation and reduces yield
In framework synthesis and condensation reactions, ultra-low or improperly balanced catalyst loadings fail to promote necessary crystallisation. Deviations from the optimal catalyst concentration systematically diminish product yields.
Tried and failed
Lewis acid catalyzed one-pot stepwise framework synthesis applied to covalent organic framework crystallization. Reason: Ultra-low Lewis acid catalyst loading failed to yield crystalline product
DESIGNING NEXT-GENERATION FUNCTIONAL COVALENT ORGANIC FRAMEWORKS FOR WATER TREATMENT · Cornell
Tried and failed
increasing or decreasing Lewis acid catalyst loading applied to heterocycle condensation reaction. Outcome: worse than baseline. Reason: deviations from optimal catalyst concentration reduced product yield
Synthesis of Nitrogen-Containing and Nitrogen-Substituted Aromatic Compounds for Diverse Applications · Georgia Tech
Tried and failed
room-temperature Lewis acid-catalyzed one-pot stepwise synthesis applied to covalent organic framework crystallization. Reason: Reaction conditions and low catalyst loading failed to yield crystalline product
DESIGNING NEXT-GENERATION FUNCTIONAL COVALENT ORGANIC FRAMEWORKS FOR WATER TREATMENT · Cornell
Left open by the authors
Problems the authors named and did not get to.
Left open
Deprotect the acetal group of carboxylic acid 4.93 using Lewis acids without causing acid-catalysed decomposition. Blocker: Requires a wet chemistry laboratory, physical reagents, and analytical equipment to perform chemical reactions
Left open
Develop and screen polar-solvent-compatible Lewis acidic chiral catalysts for enantioselective Matteson homologations. Blocker: Requires wet-lab chemical synthesis and experimental reaction screening
Catalytic control over selectivity in the synthesis of glycosides and quaternary centers · Harvard
Left open
Study aldol addition of aldehyde substrates in polar, non-coordinating solvents like dichloroethane over Lewis acidic zeolites experimentally. Blocker: Requires a wet chemistry laboratory, synthetic zeolites, solvent reagents, and catalytic reactor testing equipment.
Promotion of Heterogeneous Acid and Base Catalysts for Biomass Upgrading · MIT
Left open
Develop a frustrated Lewis pair catalyzed [3+2] annulation of donor-acceptor aminocyclopropanes with electron-deficient alkenes. Blocker: Requires a wet lab, organic synthesis equipment, and chemical reagents.
Ring-Opening Reactions of Aminocyclopropanes and Aminocyclobutanes · EPFL
Left open
Investigate the kinetic behavior of epoxide polymerizations using non-1:1 stoichiometric ratios of amine and aluminum substituents in Lewis pairs. Blocker: Requires a wet chemistry laboratory and analytical instrumentation to conduct polymerization kinetics experiments.
Left open
Quantify N-Al Lewis pair interaction strengths in MOB catalysts and measure their effects on epoxide polymerization rate, molecular weight, and polymer composition. Blocker: Requires wet lab chemical synthesis and polymerization experiments with organoaluminum catalysts.
Left open
Develop reaction conditions or catalysts like oxophilic Lewis acids to achieve clean Edman-type single-step cyclization of carbamate terminal amines. Blocker: Requires wet lab chemical synthesis and reaction optimization.
Proving 2-aminobiphenyl nitric oxide probes in cells and designing sequence-defined oligomers for sequencing · UT Austin
Left open
Investigate the substrate scope and reaction mechanism of the Lewis acid-catalyzed Cope rearrangement. Blocker: Requires a wet organic chemistry laboratory and synthetic chemical reagents
Application of new methodologies using principles of green chemistry in organic synthesis · Texas Tech
Left open
Investigate allosteric control in tethered frustrated Lewis pairs under varied small molecules and external stimuli such as temperature and pressure. Blocker: Requires a synthetic chemistry wet lab to prepare complexes and measure reactivity under varying physical conditions
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