Chapter Four · failure evidence
What Cross-Coupling & C-H Functionalization got wrong, from 63 dissertations
Cross-coupling and C-H functionalization methods frequently underperform or fail due to competing side pathways, severe steric congestion, substrate decomposition, and suboptimal reaction components. Researchers often address these limitations by re-engineering catalytic and ligand systems, adjusting bases and reaction conditions, or redesigning the overarching synthetic sequence. These records come from PhD theses at 19 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.
Unfavorable synthetic routes and coupling partner strategies lead to reduced efficiency or reaction abandonment
Investigations across various cross-coupling processes revealed that poorly chosen coupling partners or unoptimized multi-step sequences often resulted in low yields, poor stereoselectivity, or inseparable mixtures. In response, authors frequently abandoned these routes in favor of alternative approaches such as tandem protocols, direct arylation, or switching to pre-formed coupling reagents.
Lost to a baseline
Direct coupling of tyrosine without activating tert-butyl group achieved only 10% yield compared to 90% yield with ortho-tert-butyl activation
Considered and rejected
Considered and rejected: Rejected NHTK (Nozaki-Hiyama-Takai-Kishi) reaction for C6-C7 coupling due to low/moderate yields on complex substrates.
Neue Entwicklungen in der Organobor-Chemie: mono-Zweifel-Olefinierung, Spartein-freie Chemie der Lithiierung/Borylierung und die Totalsynthese von Chondrochloren A · Leibniz Universität Hannover Repository
Tried and failed
transition metal-catalyzed cross-coupling of aryl bromides applied to triflated tyrosine derivatives. Reason: reaction failed to yield the desired biaryl coupling precursor
Tried and failed
double Suzuki cross-coupling on fused aromatic precursors applied to asymmetric fused-ring heteroaromatic core synthesis. Reason: failed to yield desired coupled product or gave only trace amounts
Synthesis of novel indacenodithiophene derivatives and their application in organic solar cells · Imperial
Lost to a baseline
NHTK coupling with tBuLi or CrCl2/NiCl2 gave poor selectivity (dr = 1 : 1.1) compared to lithiation-borylation chemistry (dr > 19 : 1).
Studies towards the total syntheses of Antroalbocin A, Berkeleyone A, Pentacaronic Acid, and Penisarin B · Leibniz Universität Hannover Repository
Lost to a baseline
Arylboronic acids showed 8-fold faster competitive cross-coupling rates than aryl neopentylglycolboronates under identical Ni(COD)2/PCy3/K3PO4/THF conditions (89% boronate remained unreacted at 100% mesylate conversion).
Nickel Catalyzed Borylation and Cross-Coupling of Representative C-O Based Electrophiles · Penn
Lost to a baseline
Two-step sequential cross-coupling of nonaflate 102b yielded 74% vs. 84% for the direct one-pot Rh/Pd tandem protocol.
Entwicklung Zirconocen-basierter Methoden zur C,C-Bindungsknüpfung und deren Anwendung in der Totalsynthese von (+)-Guignardon A Development of zirconocene-based methods for C,C-bond formation and their application in the total synthesis of (+)-guignardon A · open_UMR Marburg DSpace 10.0
Considered and rejected
Considered and rejected: Rejected synthetic route 1 for biatriosporin D (cross-coupling before acylation) due to poor regioselectivity and low yields (10-12%) in subsequent acylation steps.
Synthesis of antibacterial and biobased compounds · Iowa State
Considered and rejected
Considered and rejected: Rejected 8,8'-dimethoxy protecting groups in biaryl coupling because they could not be selectively deprotected without cleaving 2,2'-hydroxyl or ester protecting groups.
Considered and rejected
Considered and rejected: Rejected SRN1 radical-chain pathway for aryl iodide coupling based on failure of 1,4-dihalobenzene probes to yield dehalogenated or bis-coupled products.
Functionalization Of 2-Azaallyl Anions, Radicals And Benzylic Chloromethyl-Coupling Polymerization · Penn
Considered and rejected
Considered and rejected: Alternative C-C coupling routes utilizing 4,7-dibromobenzo[c][1,2,5]thiadiazole or benzo[c][1,2,5]thiadiazole-4,7-diyldiboronic acid with mono-arylated naphthalene partners were rejected due to lower precursor preparation yields and lack of synthetic divergence.
Multi-layer 3D chirality: Design, synthesis and applications · Texas Tech
Considered and rejected
Considered and rejected: Reductive Ni-catalyzed cross-coupling for cyanotryptophans was abandoned in favor of the Negishi coupling route due to poor reliability.
Further Exploring the Structure Activity Relationship (SAR) of MMV008138 and MMV1803522 · Virginia Tech
Considered and rejected
Considered and rejected: Direct coupling of 2,3-diamino-1,4-phenylene diboronic acid or N,N-diacetyl derivatives with 1,8-dibromonaphthalene was rejected due to repeated failures, pivoting to benzothiadiazole-4,7-diyldiboronic acid.
Multi-layer 3D chirality: Design, synthesis and applications · Texas Tech
Considered and rejected
Considered and rejected: Late-stage synthesis of benzothiophene amide [147] was abandoned in favor of performing aminolysis prior to Sonogashira cross-coupling due to poor yields and side reactions on the alkyne bond.
Synthesis of novel scaffolds as selective ligands for the alpha-beta interface of the GABA-A receptor Synthese neuer Strukturen als selektive Liganden für das alpha-beta Interface des GABA-A Rezeptor · DSpace-CRIS at TU Wien
Considered and rejected
Considered and rejected: Stille cross-coupling for P(E-NDI-T) rejected after monomer bromination failed, switching to direct arylation polymerization (DAP)
Design and Synthesis of Molecularly Encapsulated Conjugated Materials for Organic Electronics. · Cambridge
Considered and rejected
Considered and rejected: Rejected reversal Suzuki coupling using Bpin-substituted dialdehydes because overall yields did not improve enough over tetrayne boronic ester route.
Preparation, Properties, and Future Directions of Novel Zig-zag Edged Nanographenes · unevada
Considered and rejected
Considered and rejected: Rejected one-pot Suzuki-Miyaura borylation followed by Suzuki coupling for the FFAR1 tracer (16% yield) in favor of Suzuki coupling using commercial boronic acid (84% yield).
Synthese allosterischer Modulatoren für G-Protein-gekoppelte-Rezeptoren · open_UMR Marburg DSpace 10.0
Lost to a baseline
Prior synthesis of tag 1 by Miljanić and co-workers via Cu-catalyzed coupling of 1,2-dibromo-1,2-diphenylethene with C6F5H followed by Pd-catalyzed PhSnBu3 coupling gave only 42% overall yield, compared to 70% yield from triphenylvinyl carbanion and hexafluorobenzene
Fluorinated Tetraarylethenes: Universal Tags for the Synthesis of Solid State Luminogens · EPFL
Considered and rejected
Considered and rejected: Buchwald-Hartwig coupling for pyrimidine bioisostere 80 was rejected in favor of acid-catalyzed SNAr
Targeting the Ras superfamily via their regulatory GEF complexes · Oxford
Considered and rejected
Considered and rejected: Rejected Cadogen, Täuber, and Ullmann/Buchwald-Hartwig coupling routes to 2,7-diazacarbazole due to low yields and messy cyclizations.
Guanidinium Compounds: Synthesis, Oxoanion Binding, and Cellular Delivery · MIT
Considered and rejected
Considered and rejected: Rejected transition-metal-mediated cross-coupling polymerizations (Stille, Suzuki-Miyaura, Kumada) due to the requirement of electron-rich co-monomers, toxicity of organostannanes, and tedious palladium catalyst purification.
Competing side reactions like homocoupling and off-target insertions suppress cross-coupling selectivity
Undesired side pathways including homocoupling, over-coupling, decarboxylation, and intramolecular cyclization frequently outcompeted the targeted intermolecular bond formation. Catalytic species also inserted into non-target bonds or lacked site selectivity, generating isomer mixtures and lowering yields of the desired coupled products.
Tried and failed
cross-coupling with heterobihalogenated aromatic substrates applied to stereoselective palladium-catalyzed carboetherification. Reason: competing reactive sites led to low yields and poor chemoselectivity
Stereoselective palladium-catalyzed carboetherification of cyclopropenes via a tethering strategy · EPFL
Tried and failed
Pd-catalyzed Stille cross-coupling applied to heteroaryl ester cross-coupling with dibromoaryls. Reason: dominant homocoupling of the heteroaryl stannane precursor led to low product yields
Dancing with Light: Discrete Pi-Conjugated Chromophores for Solar Fuel Cell and Electrochromic Applications · Georgia Tech
Tried and failed
olefin cross-metathesis with Hoveyda-Grubbs second-generation catalyst applied to coupling complex sterically hindered terminal olefins. Reason: yielded exclusive homodimerization of one coupling partner instead of productive cross-coupling
Lost to a baseline
Decarboxylative cross-coupling of dipeptide 96 with peptide-EBX 93b gave low yield of 97b due to competing decarboxylation of 96.
Considered and rejected
Considered and rejected: Rejected synthesis route using bis-acetylene BINOL 27(S) due to over-coupling and inseparable chromatographic mixtures; adopted diiodo-BINOL 26(S) with ethynyl-functionalized partners instead.
Synthesis of Chiral Donor-Acceptor Dyes to Study Charge Transfer Dynamics in a Chiral Environment · Publikationssystem UB Tuebingen
Lost to a baseline
Cobalt-mediated reductive homocoupling of 2.15 and 2.16 gave only 26% yield of heterodimer 2.17 (statistical mixture), whereas diazene photolysis gave 66% selective coupling.
Tried and failed
Suzuki-Miyaura cross-coupling applied to substrates containing N-O bonds. Reason: Palladium catalyst inserted into the weak N-O bond rather than the aryl-halide bond
Chain Scissionable Resists Based on Poly(acetal) Motif for Extreme Ultraviolet Lithography · Cornell
Considered and rejected
Considered and rejected: Rejected direct arylation for indenofluorene (IDF) core due to lack of C-H selectivity causing beta/gamma coupling defects; used Suzuki-Miyaura instead.
Tried and failed
three-component copper-catalyzed multicomponent carboamination applied to electron-deficient alkenes with alpha-halo carbonyls. Outcome: did not generalise. Reason: side reactions dominated, yielding primarily Ullmann coupling or polymerization products
Development of transition metal-catalyzed olefin difunctionalizations · UT Austin
Tried and failed
Copper-catalyzed radical alkene carboamination applied to electron-deficient alkenes with aliphatic amines. Reason: Basic alkyl amines predominantly underwent competitive aza-Michael addition and Ullmann coupling side reactions
Development of transition metal-catalyzed olefin difunctionalizations · UT Austin
Tried and failed
intermolecular copper-catalysed cross-coupling applied to ortho-halo substituted amides. Reason: intramolecular cyclisation competed and completely outpaced the desired intermolecular amination
Exploring copper-catalysed Ullmann cross coupling reactions · Imperial
Considered and rejected
Considered and rejected: Rejected asymmetric ethyl N-diphenylmethylene glycine as a cross-coupling substrate because it predominantly underwent Cu-catalysed homocoupling instead
Catalytic and mechanistic studies towards understanding copper-catalysed C-C cross-coupling · Imperial
Steric congestion hinders transmetallation, reductive elimination, and multi-substitutions
Bulky secondary or tertiary centers, ortho-disubstituted aromatic rings, and congested carborane scaffolds severely impaired coupling progress. These steric barriers impeded elemental catalytic steps such as transmetallation and reductive elimination, often halting reactions at mono-substituted intermediates.
Lost to a baseline
For model coupling at room temperature, [Pd(cinnamyl)Cl]2/L6 gave lower yield (47%) than OA6 (90%) for ortho-substituted bromoarenes with primary amines.
Development of Deactivation-Resistant Catalysts for Pd-Catalyzed C–N Cross-Coupling Reactions · MIT
Tried and failed
cross-coupling via isolated oxidative addition complexes applied to late-stage amination of sterically hindered amines. Outcome: no signal. Reason: steric hindrance of the secondary amine prevented transmetallation or reductive elimination
Tried and failed
copper-mediated cross-coupling for disubstitution applied to ortho-carborane core functionalisation. Reason: Steric hindrance prevented second substitution, yielding only mono-substituted product
Carborane-containing materials and dopants for organic electronics · Imperial
Tried and failed
metallaphotoredox cross-electrophile coupling applied to hindered alpha-haloalkylboronates with alkyl bromides. Reason: sterically hindered secondary and tertiary radical precursors failed to couple efficiently under standard photoredox conditions
Developing Electroreductive Methodologies via a Radical-Polar Crossover Pathway · Cornell
Tried and failed
thermal condensation of diacids with boronic acids applied to ortho-disubstituted arylboronic acids. Reason: severe steric hindrance prevented coupling under thermal or microwave heating
Tried and failed
reductant-mediated thermal nickel-catalyzed cross-coupling applied to hindered secondary alcohol etherification. Outcome: did not generalise. Reason: steric hindrance of bulky secondary alcohols prevented productive coupling under thermal conditions
Mechanisms and Methods in Redox and Redox-Mediated Reactions Involving Open-Shell Intermediates · Harvard
Considered and rejected
Considered and rejected: Rejected cross-coupling methods (e.g. Suzuki coupling) for the synthesis of substituted BINOL libraries due to steric hindrance.
New cation-mediated enantioselective transformations and catalytic enantioselective photocyclization · Oxford
Considered and rejected
Considered and rejected: Rejected Ullmann-type coupling for synthesizing 1,2-di(thiophen-2-yl)-o-carborane after confirming steric limitations prevented di-substitution, switching to a Kumada-type Ni(II)-catalysed cross-coupling
Carborane-containing materials and dopants for organic electronics · Imperial
Electronically deactivated or sensitive substrates suffer decomposition and poor reactivity
Reactions struggled when applied to unactivated aliphatic systems, electron-deficient boronic esters, or fragile substrates prone to protodeboronation and detriflation. Heteroaromatic esters and isoxazoles decomposed under basic coupling conditions, while weak or unactivated nucleophiles failed to engage key intermediates.
Tried and failed
transition metal catalyzed transfer hydrogenative coupling applied to unactivated aliphatic alcohols. Outcome: did not generalise. Reason: conditions optimized for activated benzylic systems gave poor reactivity on less activated aliphatic substrates
Tried and failed
photoredox-catalyzed cross-coupling with aryl boronic acids applied to redox-active esters. Reason: failed to yield the desired cross-coupled arylation products
Investigation of oxetane reactive intermediates for the synthesis of 3,3-disubstituted oxetanes · Imperial
Tried and failed
Suzuki-Miyaura cross-coupling of halothiophenes with alcohol substituents applied to (2-bromothiophen-3-yl)methanol. Reason: Direct coupling gave less than 2% conversion across catalysts and bases, requiring an aldehyde intermediate
Thiocarbonyl Platform for Degradable Radical Polymers · Georgia Tech
Tried and failed
reductive cross-coupling with unprotected boronic acids applied to heteroarylboronic acid cross-coupling. Outcome: unstable. Reason: unprotected substrate underwent protodeboronation under reductive reaction conditions, degrading coupling efficiency
Tried and failed
Suzuki-Miyaura cross-coupling applied to heteroaromatic halides with electron-deficient or phenolic boronic esters. Reason: Phenol boronic esters caused decomposition via phenoxy anions, while bis-trifluoromethylated boronic esters were too electron-poor to react.
EXPLORATION AND DEVELOPMENT OF XYLOPYRINDE FLUORESCENT TOOLS FOR SPATIOTEMPORAL IMAGING · Penn
Tried and failed
slow reagent addition with mild base applied to base-sensitive heteroaryl cross-coupling substrates. Outcome: did not generalise. Reason: electrophilic methyl esters and 3-H isoxazoles still underwent base-induced decomposition
Development of Deactivation-Resistant Catalysts for Pd-Catalyzed C–N Cross-Coupling Reactions · MIT
Tried and failed
photoredox decarboxylative coupling with diverse nucleophiles applied to cyclopropenyl ester functionalization. Outcome: did not generalise. Reason: weak, heteroatomic, or electronically unactivated nucleophiles failed to couple with generated carbocation intermediates
Tried and failed
Buchwald-Hartwig amination with aniline applied to brominated aryl triflate substrates. Reason: Starting material was recovered or underwent detriflation instead of cross-coupling under palladium catalysis
Ineffective or mismatched catalysts and ligands lead to sluggish rates and catalytic poisoning
Standard precatalysts and phosphine ligands gave minimal conversion when coordinating functional groups in complex drugs poisoned or stalled the catalytic cycle. In other cases, certain ligands induced premature monoarylation or directly inhibited the generation of active organometallic intermediates.
Lost to a baseline
Buchwald biaryl phosphine ligands (t-BuXPhos, BippyPhos, etc.) provided only ~5% yield in sulfinamide coupling compared to 35% with P(t-Bu)2Me*HBF4.
Lost to a baseline
4CzIPN showed lower yield in NHC/photoredox dual-catalyzed cross-coupling of alkyl trifluoroborates and acid fluorides compared to Ir catalyst.
Tried and failed
catalytic cross-coupling using standard precatalyst systems applied to complex pharmaceutical core diversification. Reason: catalytic cycle stalled or poisoned by dense heteroatom coordination and functional groups in complex drugs
Tried and failed
BrettPhos-mediated Buchwald-Hartwig amination polymerization applied to polyarylamine synthesis from diamines and dibromides. Reason: selective monoarylation prevented secondary amine coupling needed for high degree of polymerization
MICROPOROUS SPIROCYCLIC POLYMERS FOR MEMBRANE SEPARATIONS OF CRUDE OIL MIXTURES · Georgia Tech
Tried and failed
adding phosphine ligands or radical initiators applied to copper-mediated Ullmann-type cross-coupling. Outcome: worse than baseline. Reason: additives inhibited the formation of the active organocopper intermediate
Towards the synthesis of multinuclear, branched and cyclic metallocene-containing complexes · Imperial
Tried and failed
lower-generation Buchwald-Hartwig precatalysts applied to cross-coupling polymerization of microporous polymers. Outcome: too slow. Reason: catalysts exhibited lower efficiency and excessive reaction times compared to fourth-generation variants
Polymer Membranes for the Separation of Complex Natural Hydrocarbon Feeds · Georgia Tech
Tried and failed
visible-light photoredox and copper dual catalysis applied to intermolecular oxidative alkene amination. Outcome: no signal. Reason: Standard photoredox catalysts and copper triflate failed to promote radical generation or coupling
Lost to a baseline
In the cross-coupling of 6-chloroquinoxaline with tert-butanol at 60 °C, 2-C3 gave only 15% GC yield compared to >95% for 4-C1
Suboptimal bases, oxidants, and solvent phases degrade coupling conversion
The use of single bases or poorly matched bases led to drastically reduced yields or substrate-dependent reaction failure compared to optimized dual-base or alternative base systems. In addition, alternative chemical oxidants gave lower yields than molecular oxygen, and biphasic reaction mixtures prevented necessary contact between coupling partners.
Lost to a baseline
In the optimization of the C-O coupling of 4-methoxyphenol with 2-chloro-3-methylpyridine to form 3-4c, using NaOtBu instead of BTPP/NaTFA afforded only 37% yield compared to 92% with the dual-base system.
Ligand-enabled advances in Ni-catalyzed cross-coupling · DalSpace
Lost to a baseline
Alternative chemical oxidants (TBHP, ammonium persulfate, iodosobenzene, H2O2) produced lower yields than molecular oxygen for vanadium-catalyzed phenol coupling.
Selective Oxidative Methods For Dehydrogenative Coupling And Hydrogen Peroxide Generation · Penn
Tried and failed
biphasic aqueous organic coupling reaction applied to bis-bromomethylated aromatic precursors. Reason: bi- or tri-phasic reaction mixtures prevented reagent interaction and product formation
Multi-tiered Conjugated Oligomers as Models to Mimic Pi-Pi Interactions in Semiconducting Conjugated Materials · Georgia Tech
Lost to a baseline
SPhos with K3PO4/[(MeCN)2PdCl2] achieves 90% yield in Suzuki-Miyaura coupling vs 16% under the thesis's NaOMe/toluene conditions.
Synthesis, Characterization and Application of Phosphazenyl Phosphines Synthese, Charakterisierung und Anwendung von Phosphazenylphosphinen · open_UMR Marburg DSpace 10.0
Considered and rejected
Considered and rejected: Rejected NH4OH as general base over NEt3 for Suzuki couplings due to strong substrate dependency and complete failure on certain substrates (2e, 2h, 3a, 3d)
Transition-metal compounds of (poly)-azoles Transition-metal compounds of (poly)azoles Übergangsmetallverbindungen mit (Poly)Azolen · DSpace-CRIS at TU Wien
Left open by the authors
Problems the authors named and did not get to.
Left open
Develop reaction conditions for Pd-catalyzed coupling of ortho,ortho-disubstituted aryl halides for atroposelective biaryl synthesis. Blocker: Requires synthetic organic chemistry wet laboratory to conduct reaction optimization and testing
Left open
Develop enantioselective rhodium-catalyzed reductive coupling reactions using cheap, benign terminal reductants. Blocker: Requires a synthetic chemistry wet lab, reagents, catalysts, and analytical equipment
Carbon-carbon bond formation via transition metal-catalyzed transfer hydrogenative carbonyl addition · UT Austin
Left open
Develop reductive cross-couplings for sterically hindered, less reactive aryl bromides and chlorides. Blocker: Requires a wet chemistry laboratory, synthetic reagents, and chemical analysis equipment.
Development of catalytic carbon-carbon bond forming reactions by leveraging the iodide effect · UT Austin
Left open
Develop atroposelective reductive biaryl cross-couplings between sterically hindered substrates using ruthenium catalysis. Blocker: Requires a synthetic chemistry wet lab, reagents, catalysts, and physical analytical equipment (e.g., HPLC, NMR).
Development of catalytic carbon-carbon bond forming reactions by leveraging the iodide effect · UT Austin
Left open
Develop reductive cross-couplings of sp2-sp3 partners using non-metallic reductants. Blocker: Requires wet lab synthetic organic chemistry experiments and specialized reagents
Left open
Optimize base-metal catalyzed Suzuki-Miyaura and Chan-Evans-Lam cross-coupling reaction conditions to eliminate homo-coupling byproducts. Blocker: Requires a wet chemistry laboratory, synthetic reagents, and analytical equipment to run and optimize chemical reaction conditions.
Applications of Catalysis in Hydroboration and Hydrosilylation of Unsaturated Organic Molecules · Texas Tech
Left open
Explore new catalytic cross-coupling pathways using dinickel-mediated oxidative addition while accounting for NHC 2-arylation. Blocker: Requires a wet-lab synthetic chemistry setup to synthesize nickel complexes and test catalytic reaction pathways.
Synthesis and analysis of low-valent NHC supported nickel complexes · Georgia Tech
Left open
Develop catalytic enantioselective couplings of methanol and ethanol for transferring alkyl and aryl groups without stoichiometric byproducts. Blocker: Requires a wet chemistry laboratory, synthetic reagents, and analytical equipment.
Commodity chemicals in enantioselective iridium-catalyzed carbonyl allylation · UT Austin
Left open
Optimize the synthesis process or develop alternative synthetic routes, such as dehydrogenative coupling, to reduce the cost of the cleavable comonomer. Blocker: Requires a wet chemistry laboratory, synthetic reagents, and physical experimentation.
Entropy Drives the Predictive Discovery of an Optimal Cleavable Comonomer for ROMP · MIT
Left open
Evaluate CuTc-mediated Ullmann-like coupling reactions using the bio-based solvent cyrene. Blocker: Requires a wet chemistry laboratory, specialized organometallic reagents, and physical reaction testing
Towards the synthesis of multinuclear, branched and cyclic metallocene-containing complexes · Imperial
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