Theory gaps in Chemistry

Representative open questions

Showing 30 of 76 — one per source paper, highest-quality first.

• Engineering of Asymmetric Dual-Atom Sites for Effective Oxygen Electrocatalysis (2026) · doi

  The adsorption strength of ADASCs toward key intermediates (e.g., *OOH, *O, *OH) tends to deviate due to insufficient precision in d-band center modulation.

• Mannich bases in medicinal chemistry and drug design (2015) · doi

  The discovery of the two simpler Mannich bases 323 and 324 represents a significant step forward in the development of clinically useful PNP inhibitors. However, the slow-onset nature of inhibition is lost when substituting the 5′-hydroxyl with alkylthio or arylthio groups.

• Ultrasound-assisted adsorption of congo red dye using green synthesized silver nanoparticles coated with chitosan (2026) · doi

  The paper reports monolayer chemical adsorption of Congo Red on Chi-AgNPs based on Langmuir isotherm fitting, but does not provide mechanistic evidence or spectroscopic analysis (FTIR, XPS) of the specific functional groups involved in dye-adsorbent interactions or the role of reactive oxygen species (ROS) generation during ultrasound-assisted adsorption.

• Real-time P$$_2$$O$$_5$$ quantification in industrial phosphoric acid using laser-induced breakdown spectroscopy: a paradigm shift in process analytical chemistry (2026) · doi

  The linear PLS model demonstrates no systematic nonlinearities in the 23-53% P2O5 concentration range, but the applicability of this linear relationship to extended concentration ranges outside this calibration window (either below 23% or above 53% P2O5) and whether nonlinear methods such as kernel PLS or support vector regression would improve predictions at extreme concentrations have not been evaluated.

• High-Entropy Catalysts for Biomass-Derived Chemicals Valorization: Mechanisms, Applications, and Opportunities (2026) · doi

  The selective oxidation mechanism of HMF using HEC catalysts remains unresolved: current designs achieve ~100% FDCA selectivity through consecutive aldehyde and hydroxyl oxidation, but designing HEC catalysts to selectively oxidize only the hydroxyl group or a single aldehyde group to produce HMCA, DFF, or FFCA intermediates instead of complete oxidation to carboxyl groups requires mechanistic clarification and rational catalyst design strategies.

• Photochemistry and photophysics of transition metal complexes: Quantum chemistry (2015) · doi

  The luminescent properties of [Ru(L)2(dppz)]2+ complexes in DNA environments are difficult to rationalize theoretically due to complex potential energy curves with multiple shallow minima and conical intersections between ILdppz, MLCTdppz, and MLCTanc states; detailed investigation of the electronic properties of lowest triplet states coupled with nuclear relaxation and environment effects in the biological context is essential but remains incomplete.

• Cyclooligophosphanes and their coordination chemistry (2021) · doi

  The isomerization behavior of hexa-tert-butyl-octaphosphane during coordination has been noted as unexpected (reference 26), but the mechanistic pathways governing isomerization in other substituted cyclophosphanes with varying steric and electronic profiles remain uncharacterized, preventing predictive design of stable coordination complexes.

• Olympian colour chemistry (2012) · doi

  The strategy of incorporating electron donor functions to convert bright single-peak photochromic dyes into neutral multi-peak absorbers has been demonstrated for Vivimed products, but the paper does not specify the quantitative structure-activity relationships governing how donor group position, electronic properties, or distance from the chromophoric centre controls the relative intensities and positions of absorption maxima in the visible spectrum.

• Biosensors: Enzyme Immobilization Chemistry (2018) · doi

  The selection criteria for choosing optimal immobilization strategies based on enzyme type and transducer type are mentioned as critical but are not explicitly detailed; systematic guidance on matching specific enzyme classes (oxidoreductases, transferases, hydrolases) with particular immobilization chemistries (covalent bonding, entrapment, polyelectrolyte multilayers, affinity) is absent.

• Methyl 2-deoxy-3,5-di-O-p-toluoyl-α-d-ribofuranoside: isolation, crystal structure and conformation (2026) · doi

  The anomeric effect and its complications in 2-deoxy-ribofuranose systems (ref. 25) are cited but not experimentally quantified for this specific compound; computational or spectroscopic determination of the anomeric effect magnitude in the methyl 2-deoxy-3,5-di-O-p-toluoyl derivative would clarify its structural stability.

• Transmetallation Reaction of Alkali and Alkaline-earth Metal Ions in Supramolecular Complex of [{Au6Cd3(tdme)2(D-pen)6}Cd4Na4](NO3)12 (2026) · doi

  The resistance of the CdII metal center to substitution was attributed to the absence of d-orbitals in alkali/alkaline-earth metals and their coordination preferences, but quantitative computational modeling (DFT or molecular dynamics) of the binding energy differences between CdII retention versus replacement scenarios was not performed to validate this mechanistic explanation.

• Synthesis of Tetravalent Boron Complexes with Pyrazolone-Based Ligand and their Drug-Likeness (2026) · doi

  While the Lewis acidity of the catecholate dianion in boron complexes was proposed to enhance coordination with azo-pyrazolone ligands, no structure-activity relationship (SAR) analysis was conducted correlating specific variations in boron-ligand geometry or electronic properties to predicted drug-likeness parameters or bioavailability.

• Basic Organometallic Chemistry (2016) · doi

  While the four-centre two-electron bonding model is presented for methyllithium's electron-deficient structure, the paper lacks comparative analysis with other organolithium compounds (n-butyllithium, phenyllithium) to determine whether this bonding description is generalizable across the organolithium compound class.

• Initial organotin chemistry (2014) · doi

  The polymeric structure of dialkyltin oxides [(R)2SnO]n with penta-coordinated tin atoms has been established in solid state, but the exact structural arrangement and coordination geometry in solution remains uncharacterized, particularly for derivatives with alkyl chains longer than butyl.

• Bis (N-Heterocyclic Carbene) Palladium Complex Immobilized Onto Fe3o4@Sio2 as a Catalyst for Sonogashira (Amine/Copper Free) and Hiyama Coupling of Arbr/Cl in Green Media (2026) · doi

  The paper demonstrates that K2CO3 and Cs2CO3 selectively enable Sonogashira coupling while NaOAc, NaOH, and KOH fail, but does not mechanistically explain why these specific bases are compatible with the Pd-NHC/Fe3O4@SiO2 catalyst system. Investigation of base-ligand interactions and their effect on palladium oxidation states during the catalytic cycle would elucidate the base selectivity.

• Coordination chemistry of poly(thioether)borate ligands (2010) · doi

  The structural and electronic differences between the bis-μ-oxo [(PhTttBu)Ni]2(μ-O)2 and μ-(η2:η2)-S2 disulfido [(PhTttBu)Ni]2(μ-(η2:η2)-S2) complexes are noted (formal metal oxidation state, dichalcogenide bond presence), but comparative computational studies elucidating how these differences arise from O2 versus S8 reactivity patterns and their respective mechanisms have not been performed.

• Coordination chemistry of tris(azolyl)phosphines (2018) · doi

  Tris(1,2,4-triazolyl)phosphine P(1,2,4Tz)3 in its reduced form is not effective in phosphate bridge formation, as demonstrated by uridine oligomerization reactions that yielded only monomers instead of oligoribonucleosides; the cause is attributed to ligand lability but has not been mechanistically characterized, requiring detailed kinetic and thermodynamic studies to understand phosphorus-nitrogen bond stability under oligomerization conditions.

• Organometallic Chemistry of Heterocycles (2010) · doi

  The study of C—P bond cleavage in derivatized furan and thiophene containing phosphine moieties within cluster-formation has been characterized, but systematic comparison of reactivity patterns between furyne and thiophyne clusters lacking this cleavage remains incomplete, limiting understanding of how ring aromaticity influences C—P bond stability in heterocyclic organometallics.

• Chemistry and Pharmacy (2012) · doi

  The paper identifies that the variability of medicament action remains unresolved since the water memory debate, yet provides no framework for investigating how modern analytical chemistry and organic synthesis techniques can account for variable physiological responses to chemically identical active ingredients. Detailed comparative studies of bioavailability and pharmacokinetic variability in structurally identical compounds across different pharmaceutical formulations are needed.

• Rocco Ungaro, 40 years of Calixarene chemistry (2016) · doi

  Multivalent guanidino-calixarene[4]arene derivatives with hexyl chains and arginine/lysine units show superior DNA transfection efficiency compared to commercial agents (Jet-PEI, LTX), but the mechanistic relationship between facial presentation of guanidinium/ammonium ion concentration and cellular internalization efficiency has not been quantitatively characterized.

• Multicomponent reactions in crop protection chemistry (2020) · doi

  While Mannich bases incorporating 1,2,4-triazole, 1,3,4-oxadiazole, and piperazine moieties demonstrate ketol-acid reductoisomerase inhibition, the structure-activity relationships (SAR) for these heterocyclic combinations have not been comprehensively mapped across different substitution patterns and ring fusion systems.

• Basic Coordination Chemistry for Biologists (2019) · doi

  The paper states that CFT cannot explain why hydroxide ion is a weaker field ligand than water despite having the same donor atom, and that negatively charged halide ions unexpectedly appear as weak field ligands. A quantitative model incorporating both electrostatic interactions and covalent character through LFT is needed to predict ligand field strength ordering for charged versus neutral oxygen and halide donors.

• The coordination chemistry of aluminium in neurodegenerative disease (2012) · doi

  While aluminium has been shown to induce amyloid-like fibrillar formation in human prion protein fragments and ataxin-3 variants, the coordination chemistry mechanisms responsible for these inductions remain uncharacterized. Determining the specific binding sites and stoichiometric ratios of Al3+ to these neurodegenerative disease-associated proteins is necessary to establish whether the Aβ42 model generalizes across the polyglutamine family.

• Shilov alkane platinum chemistry: 45 years (2015) · doi

  The mechanism of anaerobic methane oxidation by MCR enzyme remains unresolved between competing hypotheses: DFT calculations exclude electrophilic Ni(III) metallation of methane, but alternative radical-based H abstraction mechanisms are also thermodynamically infeasible given methane's C-H bond strength (~106 kcal/mol). The proposed concerted cleavage mechanism involving thiyl radical coM-S· and Ni(I) center requires experimental validation.

• Developments in Heterocyclic Microwave Chemistry (2016) · doi

  The metal-free microwave thermolysis of 2-azetidinone-tethered bis(allene)s shows that microwave irradiation suppresses keto-enol isomerization while maintaining regioselectivity, but the physical basis for this selective suppression of isomerization under microwave versus conventional heating has not been elucidated at the mechanistic level.

• Water extract rice husk as an efficient catalyst to synthesis of p-thymol tailored 1,2,4-triazole sulfanyls as potential antidiabetic candidates (2026) · doi

  The in vitro antidiabetic activity demonstrates that aliphatic sulfanyl groups (7a, 7c, 7d, 7e, 7h, 7i, 7j, 7k, 7L) show minimal inhibitory effects while methyl sulfanyl (7b), phenyl (7f), and 4-chlorophenyl (7g) substituents enhance activity, but the paper lacks quantitative structure-activity relationship (QSAR) modeling or computational prediction of how additional aromatic or heteroaromatic sulfanyl substitutions would influence α-amylase and α-glucosidase inhibition.

• Analytical Chemistry Today and Tomorrow (2012) · doi

  The reconciliation of contradictory relationships between metrological quality standards and problem-solving fitness-for-purpose approaches has not been fully operationalized. Specific quality compromise frameworks that simultaneously satisfy both high metrological standards and client information requirements across different analytical contexts require explicit definition and case-by-case validation.

• Dynamic Chemistry of Anion Recognition (2011) · doi

  The biased DCL behavior where hydrogen-bonding capsules persistently crystallize irrespective of oxoanion identity (SO42−, SO32−, CO32−) demonstrates exceptional selectivity, but the mechanistic basis for why certain building block combinations preferentially form encapsulation capsules rather than competing structures in large libraries remains theoretically underexplained and requires quantitative analysis of equilibrium constants in the DCL.

• Supramolecular polymer chemistry meets computational chemistry: theoretical simulations on advanced self-assembling chiral materials (2018) · doi

  The design challenge of creating modified pyrene derivatives that simultaneously maintain blue-emitting features while achieving supramolecular order remains unresolved; computational frameworks need to be developed that can predict excimer formation propensity during self-assembly to guide rational design of pyrene systems that suppress red-shifted excimeric emission.

• How Scientific is Chemistry? (2022) · doi

  The paper invokes Feyerabend's 'anything goes' philosophy and Sturgeon's law (90% of everything is crap) to justify the 'high risk–high gain' research approach in chemistry, but provides no systematic analysis of success rates or objective criteria for determining which risky chemistry projects (e.g., novel catalyst families, new reaction mechanisms) actually yield breakthroughs versus failed expenditures.