Reliable density functional theory (DFT) methods for thermally driven cyclization reactions remain insufficiently established, particularly for systems in which proton transfer, conformational preorganization, and weak environmental effects jointly shape the energy landscape. Here, we present a systematic benchmark of DFT exchange–correlation functional/basis-set combinations against CCSD(T) reference energies for the thermal Conia–Ene cyclization, using chain length and explicit water assistance as chemically relevant probes of functional performance. Representative reaction profiles were constructed for two model substrates (hex-5-ynal and hept-6-ynal), considering pathways with and without explicit water, in both gas phase and implicit solvent. The reaction proceeds stepwise through enolization followed by cyclization, with enolization defining the intrinsic kinetic bottleneck in the water-free pathway (ca. 70 kcal mol–1). Explicit water selectively lowers this barrier by up to 30 kcal mol–1 through proton-transfer mediation, whereas the cyclization barrier is primarily controlled by chain length through transition-state preorganization; implicit solvation has only a minor energetic effect. Across 38 approximate exchange–correlation functionals and 14 basis sets, range-separated hybrids provide the most accurate and balanced description of both activation barriers and reaction energies. In particular, ωB97XD and CAM-B3LYP-D3BJ achieve near-chemical accuracy, with mean absolute errors close to 1 kcal mol–1 when combined with triple-ζ basis sets containing polarization and diffuse functions. Comparable accuracy is also achieved by the double-hybrid functionals mPW2PLYP and DSD-PBEP86, albeit at a substantially higher computational cost. Overall, this study establishes a practical CCSD(T)-referenced benchmark and identifies robust DFT protocols for modeling thermal Conia–Ene cyclizations, with expected transferability to more complex substrates and confined environments.
We investigated the energetics and bonding of lithium hydride clusters (LiH)n (n = 1-6) using a composite ab initio scheme inspired by W2 theory to achieve sub-kcal/mol accuracy. This approach combines CCSD(T) results extrapolated to the complete basis set limit with a rigorous treatment of core-valence correlation, scalar relativistic effects, and the diagonal Born-Oppenheimer correction. Our results show that while Hartree-Fock theory captures the primary electrostatic binding, correlation effects are crucial for determining the energetic preference of compact isomers over cyclic rings. A parallel density functional theory study shows that while standard hybrid functionals like B3LYP-D4 and M06-2X exhibit larger deviations, the double-hybrid revDSD-PBEP86-D4 functional closely matches our benchmarks, delivering sub-kcal/mol accuracy. Structural and chemical bonding analyses, including intrinsic bond orbital, nucleus-independent chemical shift, and many-body expansion (MBE) methods, reveal high ionic character and multi-center bonding (3c-2e and 4c-2e) within the (LiH)n clusters. MBE analysis of the interaction energy of the monocyclic clusters with respect to the LiH molecules reveals that the two- and three-body terms are consistently negative (stabilizing), while all higher-order terms are negligible. We find that σ-aromaticity in these systems is predominantly local and bond-centered. As the rings expand, the interior becomes magnetically decoupled from the σ-skeleton, precluding the formation of a global ring current. These results establish definitive benchmarks for the stability of prototypical electron-deficient clusters.
Emmanouil C. Semidalas, Filippos Drakopoulos, E. A. Routsi et al.· Journal of Chemical Physics· 0 citations
Halogen bonding (XB) is often analyzed in terms of isolated dimers, yet under realistic solution conditions, it coexists with a dense, rapidly fluctuating network of weaker contacts whose net effect on bond strength is difficult to quantify. Here, we combine gas-phase quantum-chemical calculations with explicit-solvent ab initio molecular dynamics (AIMD) in chloroform to dissect how specific noncovalent interactions modulate the I···N halogen bond in ortho-, meta-, and para-C6F4I2···HMTA complexes. Gas-phase DFT, Quantum Theory of Atoms in Molecules (QTAIM), Natural Bond Orbital (NBO), and SAPT0 analyses show that the intrinsic I···N bond in the three isomers is relatively strong and nearly degenerate, with equilibrium distances around 2.83 Å and very similar electronic descriptors. In contrast, AIMD in CHCl3 reveals that the solution-phase geometry reflects a dynamic balance between frequent, short-lived C–H···N contacts to HMTA, which act anticooperatively and lengthen the halogen bond by ≈0.02–0.05 Å, and less populated but more cooperative donor-side C–H···I and C–H···F contacts to the C6F4I2 fragment, which shorten it by up to ≈0.05 Å. A contact-resolved and microstate-based analysis shows that each isomer samples a small number of recurrent solvation motifs with characteristic patterns of C–H···N/C–H···I/C–H···F coordination, and that the relative populations of these motifs control the average I···N distance in solution. Targeted cluster calculations containing only one additional interaction at a time demonstrate that extra C–I···N halogen bonds are intrinsically anticooperative toward the primary I···N bond, whereas C–H···F hydrogen bonding, π···π stacking, and especially C–H···I contacts provide genuine cooperative reinforcement, in line with the trends observed in AIMD. Together, these results establish a quantitative solution-phase hierarchy of cooperative and anticooperative motifs around σ-hole donors and rationalize why gas-phase dimers systematically overestimate halogen-bond robustness relative to chloroform solution, where anticooperative C–H···N hydrogen bonding is ubiquitous. More broadly, the combination of explicit-solvent AIMD with contact-resolved and microstate-based analysis provides a transferable framework for dissecting environmental cooperativity in halogen-bonded and other σ-hole-driven assemblies in liquid phases.
D. V. Krutin, A. Titova, M. Kaplanskiy et al.· Journal of Physical Chemistr...· 0 citations
Predicting site selectivity during the earliest stages of solvation in multifunctional organic molecules remains a complex challenge in chemical physics. In this work, we use high-resolution rotational spectroscopy and quantum-chemical calculations to decode the hydration landscape of N,N-diethylacetyloxyamine (DEAcA), a molecule featuring competing sp3 nitrogen and carbonyl oxygen acceptors. While the isolated monomer preferentially adopts a syn configuration driven by the electric dipole moment minimization and the synergistic alleviation of oxygen-oxygen electrostatic repulsion, microsolvation ((H2O)n, n = 1-3) reveals an exclusive preference for the highly basic nitrogen site. We demonstrate that the 14N nuclear quadrupole coupling (NQC) constants provide direct experimental evidence of the cooperative polarization that strengthens the nascent water chain. Crucially, at the tetrahydrated level (n = 4), we identify a sharp transition in the solvation regime: the global minimum shifts to a cyclic water tetramer anchored at the carbonyl oxygen. This structural pivot marks the boundary where localized stereoelectronic control yields to the collective stabilization of the solvent network. These findings provide a rigorous benchmark for modeling the transition from molecular recognition to bulk-like solvation in complex organic systems.
Filippo Baroncelli, L. Evangelisti, J. López et al.· Journal of the American Chem...· 0 citations
A systematic density functional theory study of hydrogen bonding, cooperative binding, and Grotthuss proton transfer in PVA/CA/H₃PO₄ proton exchange membranes is presented. Twenty-three calculations were performed at the B3LYP-D3BJ/6-31G* level using ORCA 6.1.1, encompassing geometry optimisation, potential energy surface scanning, transition state verification, nudged elastic band analysis, natural bond orbital analysis, electron localisation function mapping, and a 65-atom crosslinked wet membrane model. The esterification energy is − 12.4 kJ/mol; single H₃PO₄ binding is − 78.1 kJ/mol; and cooperative binding of two H₃PO₄ molecules reaches − 203.0 kJ/mol. The gas-phase proton transfer barrier of 37.8 kJ/mol is reduced to 19.5 kJ/mol in the fully crosslinked wet environment, with the product state 9.3 kJ/mol more stable than the reactant. NBO bond-order analysis and ELF mapping support a local hydrogen-bond-mediated proton-transfer event, representing an elementary proton-hopping step rather than direct proof of a complete long-range Grotthuss conduction mechanism. A 20-step desorption PES (+ 75.9 kJ/mol) combined with hydration analysis (ΔG = − 278.0 kJ/mol) provides a quantum-mechanical interpretation of partial acid retention. DFT-predicted IR frequencies reproduce all major peaks within 0–110 cm⁻¹.
Anodic intramolecular cyclization reactions have substantial synthetic utility for formation of cyclic carbon–carbon or carbon–heteroatom bonds. For cases of intramolecular trapping of a cation radical by a protic nucleophile, the cyclization step coincides with a substantial increase in substrate acidity and thus may exhibit particularly pronounced solvent effects. In this computational work, we employ both quantum chemical (QM) and quantum mechanics/molecular mechanics (QM/MM) methods to compute solvent effects on free energy profiles for cyclization and deprotonation reaction steps for cation radical intermediates of substrates representative for anodic intramolecular cyclizations. We find substantial solvent contribution to the thermodynamic driving force for cation radical cyclization; for example, methanol and tetrahydrofuran solvents provide ∼30–35 kJ/mol driving force to form cyclic oxonium cation radicals and ∼15–25 kJ/mol driving force to form cyclic ammonium cation radicals, compared to baseline reactions in dichloromethane solvent. Given that these solvent shifts are on par with the innate cyclization reaction thermodynamics, the choice of solvent plays a crucial role in promoting/driving the cation radical cyclization step. Methanol is particularly effective at facilitating rapid deprotonation of the cyclic cation radical intermediate, which may lead to the full electrochemical process (e.g., second electron transfer) proceeding heterogeneously at the anode.
Shahriar N. Khan, John H. Hymel, Jesse G. McDaniel· Journal of Organic Chemistry· 0 citations
Free energies of solvation (ΔGsol) in a prototypical liquid alkane, cyclohexane, have been computed for 101 organic molecules at 25 °C. Monte Carlo statistical mechanics (MC) was used with free-energy perturbation theory (FEP) and both OPLS united-atom (UA) and all-atom (AA) force fields. Updated OPLS-UA parameters are provided along with thermodynamic results for 23 liquid alkanes; the modifications make the UA and AA force fields fully compatible. The average errors for ΔGsol in comparison to experimental data are ca. 0.5 kcal/mol for both force fields. This supports general use of the UA model, since it reduces the required computation times by 5-10-fold. The largest errors are about 1 kcal/mol and occur for small molecules with relatively large dipole moments and for perfluorocarbons. The former case is attributable to the lack of solvent-polarization in the force fields, and the latter issue can be remedied by reducing the Lennard-Jones well depth for the interaction of saturated carbon and fluorine. Results for free energies of hydration are also provided for the 101 solutes in TIP4P water and the average error is again 0.5 kcal/mol. The combined results provide cyclohexane/water free energies of transfer with average errors of 0.7 kcal/mol. In conjunction with prior results for solvation in benzene and perfluorobenzene, the 0.5 kcal/mol level of accuracy seems general for the performance of current generation, nonpolarizable force fields. Implications for modeling hydrophobic effects and protein-ligand binding are also considered.
W. Jorgensen, J. Tirado-Rives· Journal of Chemical Theory a...· 0 citations