Theory gaps in Chemistry

Representative open questions

Showing 30 of 96 — 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.

• The role of the bis-trimethylsilylamido ligand, [N{SiMe3}2]−, in main group chemistry. Part 1: Structural chemistry of the s-block elements (2015) · doi

  The competing addition versus peripheral deprotonation pathways observed in reactions between rare earth bis-trimethylsilylamido compounds and K(Si{SiMe3}3) were identified but the factors controlling selectivity between these two mechanistic routes have not been systematically explored or optimized.

• 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.

• Green-Synthesised Gold Nanoparticles: A Sustainable Technological Platform for Cancer Theranostics and Biomedical Innovation (2026) · doi

  The mechanisms of selective cytotoxicity of green-synthesised AuNPs against cancer cells (MCF-7, HepG-2) versus normal cells (MCF-10A, HUVEC) have not been fully elucidated. While oxidative stress, ATP disruption, and apoptosis are mentioned, the specific molecular pathways and surface chemistry interactions between plant-capped AuNPs and cancer cell membranes require mechanistic investigation.

• Chemistry of Fungal Products (2011) · doi

  The paper demonstrates that dihydroartemisinin shows four-fold higher antimalarial activity than artemisinin itself, but does not elucidate the biochemical or pharmacological mechanism explaining this activity enhancement or identify which specific structural modification of the C-12 carbonyl group is responsible for the improved potency.

• Systematics and surprises in lanthanide coordination chemistry (2017) · doi

  The contraction in Ln-N and Ln-O bond lengths was measured for Ph3PO-thiocyanate complexes spanning La-Lu, but the ionic radius model predictions differed slightly from observed values (0.097 Å predicted vs. 0.104-0.115 Å observed). Refined crystal radii models or computational validation (e.g., DFT bond energy calculations) should be performed to explain these discrepancies across the lanthanide series.

• Flying DNA Cation Radicals in the Gas Phase: Generation and Action Spectroscopy of Canonical and Noncanonical Nucleobase Forms (2021) · doi

  TD-DFT calculations of open-shell DNA cation radical systems suffer from artifacts due to high-spin transitions, requiring inclusion of >100 excited electronic states to cover the experimental wavelength range. Improved computational methods for treating these systems are needed.