Theory gaps in Chemistry

Representative open questions

Showing 30 of 43 — one per source paper, highest-quality first.

• QM/MM hybrid simulation of enzyme-Mn synergistic catalysis for quinazolinones: computational determination of activation energy and transition state (2026) · doi

  While the SMD solvation model demonstrated 0.3-0.5 kcal/mol superior accuracy over PCM and COSMO models, the mechanistic basis for this improvement in predicting free energy of enzyme-Mn synergistic catalysis remains unelucidated; investigation into how SMD's refined solvent polarity and cavity effects specifically enhance transition state stabilization in this system is required.

• 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.

• 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 Sonogashira coupling reaction shows a critical temperature threshold between 60 °C (no product) and 70 °C (significant product formation), yet the paper does not investigate the thermodynamic or kinetic factors governing this sharp transition. Detailed mechanistic studies—including activation energy determination and intermediate characterization—are needed to understand the catalytic cycle of the Bis(N-heterocyclic carbene) palladium complex.

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

  While [PhTttBu]Ni(CO) activates S8 to form the μ-(η2:η2)-S2 disulfido dinickel(II) complex, the reaction requires approximately one week at room temperature compared to hours for oxygenation at -78°C; the factors governing the substantially different reactivity rates between O2 and S8 activation with nickel(I) poly(thioether)borate complexes have not been systematically investigated.

• 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.

• 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.

• Developments in Heterocyclic Microwave Chemistry (2016) · doi

  The microwave-assisted synthesis of tricyclic isoquinolinones via Ru(II)/Cu(II)-catalyzed alkyne-amide annulation shows that electron-withdrawing groups on the alkyne moiety have no marked effect on yields, contrasting with the pronounced electronic effects observed on the amide aromatic ring. The underlying mechanistic basis for this differential electronic sensitivity in the two reaction components requires clarification.

• 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.

• The Burgeoning of Mechanically Interlocked Molecules in Chemistry (2019) · doi

  The Outstanding Questions section identifies the need to determine how mechanical energy from MIM degrees of freedom can be transformed into other forms of energy and whether energy storage is a viable application, but no concrete examples or energy conversion pathways have been demonstrated in the literature cited.

• Discovery of unprecedented prenylated indole piperazines and pyrazines through cryptic biosynthetic gene cluster heterologous expression (2026) · doi

  While chemical synthesis of compound 14 was performed to verify FlzE substrate promiscuity, the regioselectivity of prenylation on the indole ring (C2 vs. C3 positions) and the mechanism by which FlzE directs selectivity toward specific regioisomers for different indole substrates have not been elucidated.

• 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.

• 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.

• A universal atomically dispersed cobalt catalyst for alkylation of ketones alcohols and lignin-derived compounds (2026) · doi

  The alkylation reactions employ varying solvent systems (tert-BuOH for ketones, toluene for secondary alcohols) and different base additives (K3PO4 or KOMe) depending on substrate type. The mechanistic basis for solvent and base selection, and optimization of these parameters across structurally diverse lignin-derived substrates, remains unexamined.

• Redox chemistry of aquatitanium(II), Ti2+(aq) (2011) · doi

  The Mo(V) transients generated from different reductants (Ti(II), Ti(III), V(II), Ge(II), Eu(II)) exhibit non-matching molar absorbances at 430 nm (Table 10, ranging from 0.33 to 1.54 × 10⁻³ M⁻¹ cm⁻¹) despite similar kinetic behavior. The structural identity and speciation differences of these Mo(V) intermediates require direct characterization to explain the absorbance discrepancies.

• Recent developments in the chemistry of azaferrocenes (2010) · doi

  The low catalytic activity of Pd(II) bisazaferrocene complexes 146, 147, 153, and 154 toward ethylene polymerization was attributed to unfavorable enthalpic and entropic factors, but quantitative thermodynamic measurements and computational modeling of these specific complexes have not been reported to elucidate the precise mechanistic origins of their poor performance.

• Thermodynamics in Chemistry (2012) · doi

  The paper demonstrates that thermodynamic equilibrium constant expressions cannot directly predict yields without catalyst development research and surface thermodynamics optimization, yet provides no framework for quantitatively linking surface thermodynamic properties of catalysts to measurable improvements in ammonia synthesis yield.

• Coordination and catalytic chemistry of phosphinoferrocene carboxamides (2017) · doi

  The amide substituents on (R,Rp)-120-derived ligands 121 and 122 significantly affect reaction rate (22-45% conversion) but show only minor influence on enantioselectivity (~40% ee across all variants); the mechanistic basis for this disconnect between steric/electronic effects on catalytic efficiency versus stereoselectivity requires detailed kinetic and structural studies.

• Fine and hyperfine interactions with multi-level spin relaxation of the purified Giese-salt in veterinary medicine: Prussian blue compound ammonium-ferric-hexacyano-ferrate (2026) · doi

  The ferromagnetic interaction mechanism in Prussian blue compounds remains controversial regarding whether it is dominated by nearest-neighbor high-spin coupling or other mechanisms; direct measurements of the FeII−C≡N−FeIII bond length variations in purified Giese-salt samples and correlation with magnetic anisotropy energy density K and ferromagnetic cluster transition temperature are required to resolve this ambiguity.

• Cloud chemistry (2011) · doi

  The role of metal ion catalysts (Mn^2+ and Fe^3+) in O2-mediated S(IV) oxidation is mentioned as 'thought to be needed' but lacks quantitative rate coefficients and detailed reaction mechanisms; the relative contribution of catalyzed O2 oxidation versus O3 and H2O2 pathways under typical cloud conditions (pH 3-5, specified metal ion concentrations) remains unquantified.

• Formal organocatalytic fluoronitromethane addition to tetrahydroisoquinolines through a CDC process (2026) · doi

  The organocatalytic fluoronitromethane addition to tetrahydroisoquinolines shows complete failure with ortho-substituted aromatic groups (o-F compound 4h yielded no product), but the mechanistic basis for this steric inhibition remains unexamined. Further investigation into how ortho-substituent size and electronic properties affect the iminium intermediate formation and CDC addition step is needed to establish substitution pattern boundaries.

• Investigation of the effect of solvent polarity and viscosity on the Stokes shift of chromeno[2,3-b]indoles (2026) · doi

  While the paper demonstrates ultra-high Stokes shifts in chromeno[2,3-b]indoles through intramolecular charge transfer mechanisms, quantitative structure-property relationship (QSPR) models correlating specific molecular substituents with Stokes shift values across the full polarity-viscosity solvent parameter space have not been developed for this compound class.

• Indium-based Metal Organic Frameworks (In-MOFs) for Electrochemical Reduction of Carbon Dioxide to Formate (2026) · doi

  The synergetic effects of indium nodes and BDC ligands on catalyst morphology and electrochemical performance require deeper mechanistic understanding beyond the current EIS and Tafel analysis.

• Chemistry: progress since 1860—reflections on chemistry and chemistry education triggered by reading Muspratt’s Chemistry (2022) · doi

  Modern chemical theory frameworks (atomic structure, bonding, thermodynamics, kinetics, Periodic Table, 3D structural formulae) were almost entirely undeveloped in 1860, highlighting the problems of building a coherent picture of the chemical world without access to such frameworks.