Free Energy Of Activation Research Articles

Polyrate 2023: A computer program for the calculation of chemical reaction rates for polyatomics. New version announcement

Polyrate 2023: A computer program for the calculation of chemical reaction rates for polyatomics. New version announcement

Experimental and theoretical evaluation of interactions in liquid mixtures consisting bio-based solvent and 2-alkoxyethanols through viscometric study

Viscometric properties provide a deep and meaningful insight of the various interactions taking place in binary liquid mixtures. Recently, bio-based solvents have been either employed directly as green solvents or as a key component for the production of new solvent systems that are potentially less toxic and more bio-compatible. In this paper, we report experimental values of dynamic viscosity (η) for binary systems of bio-based solvent (gamma-valerolactone) with 2-alkoxyethanols at different temperatures (298.15–313.15 K; interval, 5 K), covering the whole composition range under atmospheric pressure of 0.1 MPa. On the experimental basis, kinematic viscosity (ν), viscosity deviation (Δη) and excess Gibbs free energy of activation for viscous flow (ΔG∗E) have been calculated. The derived properties, Δη and ΔG∗E were fitted to Redlich-Kister polynomial equation to obtain binary adjustable parameters and standard deviations between experimental and estimated values. Further, the viscosity-composition data have been correlated with various approaches including no adjustable parameter (Bingham, Arrhenius, Kendall and Kendall-Monroe), one adjustable parameter, (Grunberg − Nissan, Hind et al. and Katti-Chaudhri), two adjustable parameter (McAllister three-body and Heric-Brewer) and three adjustable parameter (McAllister four-body and Jouyban-Acree) relations. Moreover, for all the predicted viscosity values, the standard deviation percentages (σ%) were calculated to compare the quality of correlations with experimental data. Furthermore, the Graph theory was employed to correlate experimental Δη values and to analyse the patterns of molecular aggregation in the studied mixtures. The DFT calculations were also performed in the support of graph theory. The observed Δη data suggests that the dissociation of self-associated structures of pure components is more dominating factor than hetero-association for all the studied binaries.

Viscosities of 1,2-DAP + alkyl acetates binary liquid mixtures at T = 298.15–318.15 K: Theoretical interpretation by Graph theoretical approach (GTA) and Bloomfield and Dewan (BFD) model

The liquid mixtures are used as a solvent in most of the natural systems and chemical processes. Therefore, the physicochemical properties of liquid mixtures at different compositions and at different temperatures have a significant role in the optimization of chemical processes. In the present report, the dynamic viscosity (η) of 1,2-DAP (1,2-Diaminopropane) (1) with AAc (alkyl acetates) (C1-C4) (2) were measured at different temperatures (T = 298.15 to 318.15 K) at pressure 0.1 MPa. Deviation in dynamic viscosity, Δη, and excess Gibbs free energy of activation, G∗E, for these binary mixtures were calculated from measured dynamic viscosity data and fitted to Redlich-Kister polynomial equation (R.K.). Δη data were examined in terms of the Bloomfield and Dewan (BFD) model and Graph theoretical approach (GTA) to study the intermolecular interactions in binary mixtures. Further, different correlation like Hind-McLaughlin-Ubbelohde, Bingham, Arrhenius, Kendall, Heric-Brewer, Kendall-Monroe, Tamura-Kurata, Lulian, Grunberg-Nissan, Krishnan-Laddha Frenkel, Katti-Chaudhari, Heric and McAllister were used to correlate η values.

Volumetric, transport and acoustic properties of binary mixtures containing alkanol at 298.15–318.15 K

The measurement of density (ρ), viscosity (η) and ultrasonic speed (u) have been conducted at T = 298.15 K–318.15 K and at 0.1 MPa to study the intermolecular interactions between p–chlorotoluene with alkanol (C1–C2). These data were utilized to derive the excess properties like excess molar volume (VmE), deviation in viscosity (Δη), excess free energy of activation (ΔG*E), deviation in ultrasonic speed (Δu), and excess isentropic compressibility (κsE) for binary mixtures. Utilizing the VmE values, partial molar volume and excess partial molar volume were calculated. The Δη and κsE were investigated using theoretical models such as the Singh model and ab initio approach, which yielded interactional parameters that not only indicate the extent of unlike interactions and depolymerization of self–associated alkanol but also predicts the Δη and κsE for these systems. The conclusions of the ab initio approach were further validated by the Singh model for viscosity. The u data were further interpreted by various correlations and theories. Regarding correlation, Nomoto’s correlation demonstrated high predictive power for ultrasonic speed data, respectively, compared to other correlations. The resulting excess properties were fitted to Redlich–Kister polynomial equations. The VmE values were observed to be negative for p–chlorotoluene + alkanol systems at all temperatures. The study of the binary mixtures is significant because it sheds light on the nature of intermolecular interactions which has practical implications in areas such as chemical synthesis, solvent selection, and understanding the effects of solvents on reaction rates and product yields.

Conjugated Polymers from Direct Arylation Polycondensation of 3,4-Difluorothiophene-Substituted Aryls: Synthesis and Properties.

3,4-Difluorothiophene-substituted aryls, i.e., 1,4-bis(3,4-difluorothiophen-2-yl)-benzene (Ph-2FTh), 1,4-bis(3,4-difluorothiophen-2-yl)-2,5-difluorobenzene (2FPh-2FTh), and 4,7-bis(3,4-difluorothiophen-2-yl)-2,1,3-benzothiadiazole (BTz-2FTh), are synthesized as C─H monomers for the synthesis of conjugated polymers (CPs) via direct arylation polycondensation (DArP) with diketopyrrolopyrrole (DPP) and isoindigo (IID) derivatives as C─Br monomers. The Gibbs free energies of activation for direct arylation (ΔG298K , kcal mol-1 ) for α─C─H bonds of thiophene moieties as calculated by density functional theory (DFT) are 14.3, 16.5, and 16.4kcal mol-1 for Ph-2FTh, 2FPh-2FTh and BTz-2FTh, respectively, meaning that inserting an electron-deficient unit in 3,3',4,4'-tetrafluoro-2,2'-bithiophene (4FBT, ΔG298K : 14.6kcal mol-1 ) may cause a reactivity decrease of the C─H monomers. Photophysical and semiconducting properties of the resulting six CPs (i.e., DPP-Ph, DPP-2FPh, DPP-BTz, 2FIID-Ph, 2FIID-2FPh, and 2FIID-BTz) are characterized in detail. DPP-based CPs show ambipolar transport properties while IID-based ones exhibited n-type behavior owing to the deeper frontier molecular orbital energy levels of IID-based CPs. With source/drain electrodes modified with polyethylenimine ethoxylated, n-channel organic thin-film transistors with maximum electron mobility of 0.40, 0.54, 0.29, 0.05, 0.16, and 0.01 cm2 V-1 s-1 for DPP-Ph, DPP-2FPh, DPP-BTz, 2FIID-Ph, 2FIID-2FPh, and 2FIID-BTz, respectively, are fabricated. DPP-2FPh exhibits the best device performance due to the good film morphology and the highest intermolecular packing order.

Synthesis, Characterization and evaluation of two organic compounds as corrosion inhibitors for carbon steel alloy (C1010) in acidic medium of 0.1M HCl.

In this study, 4-chlorobenzodithioatebenzyltrimethylammonium and 4-methoxylbenzodithioatebenzyltrimethylammonium were synthesized and characterized by 1H-NMR, FTIR, UV-Visible and Mass techniques. Then they evaluated as corrosion inhibitors for carbon steel alloy (C1010) against corrosive environment of hydrochloric acid at different concentrations at 25 ˚C. both inhibitors revealed an excellent inhibition efficiency (97.95) % and (97.13) % at optimal concentrations (9) ppm and (8) ppm respectively. The effect of temperature on the corrosion was studied in absence and presence of the inhibitor, the raising of temperature leads to reduce the efficiency of the inhibitor and CR was enhanced. On the other hand, kinetic parameters such as activation energy , enthalpy of activation , entropy of activation and Gibbs free energy of activation were calculated which are insisted a physical adsorbed behavior for the inhibitor, an endothermic corrosion reaction whether in presence or in absence of the inhibitor and enhanced non-spontaneous behavior in presence of the certain inhibitor. Each one of the inhibitor has the mixed inhibition behavior.

Molecular docking and dynamics of a dextranase derived from Penicillium cyclopium CICC-4022

This study aimed to investigate the recognition mechanism of dextranase (PC-Edex) produced by Penicillium cyclopium CICC-4022 on dextran. Whole genome information of P. cyclopium CICC-4022 was obtained through genome sequencing technology. The coding information of PC-Edex was determined based on the annotation of the protein-coding genes using protein databases. The three-dimensional structure of PC-Edex was obtained via homology modelling. The active site and binding free energy between PC-Edex and dextran were calculated by molecular docking and molecular dynamics techniques. The results showed that the total sequence length and GC content of P. cyclopium CICC-4022 were 29,710,801 bp and 47.02 %, respectively. The annotation of protein-encoding genes showed that P. cyclopium CICC-4022 is highly active and has many carbohydrate transport and metabolic functions, and most of its proteases are glycolytic anhydrases. Furthermore, the gene encoding PC-Edex was successfully annotated. Molecular dynamics simulations indicated that van der Waals interaction was the main driving force of interaction. Residues Ile114, Asp115, Tyr332, Lys344, and Gln403 significantly promoted the binding between dextran and PC-Edex. In summary, this study explored the active site catalyzed by PC-Edex based on the binding pattern of PC-Edex and dextran. Therefore, this study provides genomic information on dextranase and data supporting the rational modification and enhancement of PC-Edex.

Efficient Empirical Valence Bond Simulations with GROMACS.

We describe a protocol to perform empirical valence bond (EVB) simulations using GROMACS software. EVB is a fast and reliable method that allows one to determine the reaction free-energy profiles in complex systems, such as enzymes, by employing classical force fields to represent a chemical reaction. Therefore, running EVB simulations is basically as fast as any classical molecular dynamics simulation, and the method uses standard free-energy calculations to map the free-energy change along a given reaction path. To exemplify and validate our EVB implementation, we replicated two cases of our earlier enzyme simulations. One of these addresses the decomposition of the activation free energy into its enthalpic and entropic components, and the other is focused on calculating the overall catalytic effect of the enzyme compared to the same reaction in water. These two examples give virtually identical results to those obtained with programs that were specifically designed for EVB simulations and show that the GROMACS implementation is robust and can be used for very large systems.

Physically Based Constitutive Modeling of Dynamic Strain Aging in C45 Steel

Abstract Dynamic strain aging (DSA) is a sudden increase in the strength of a material under certain combinations of temperatures and strain rates. Despite the phenomenon being reported in several other studies, the literature still lacks a specific constitutive model that can physically interpret its effect. Therefore, this work proposes a modification based on physical parameters to the Voyiadjis and Abed (VA) model to account for the effect of DSA in C45 steel. The resulting modified model is then coupled with an energy-based damage model to further capture the effect of material softening. Previously, in VA model, it was assumed that the total activation energy for overcoming the obstacles without external work remains the same which works well in the absence of DSA. However, during DSA, the mobile dislocations are pinned by the diffusing solute atoms. This results in an increase in the total activation free energy needed by the dislocations to overcome the obstacle. Thus, an increase in strength is observed. It is shown in the current work that utilizing the concept of increased solute concentrations at local obstacles, in conjunction with the physical description that the VA model is based upon, successfully captures the phenomenon of DSA in C45 steel. In addition, the metal experiencing softening after reaching its ultimate strength is due to the significant growth of voids and cracks within the microstructure. To capture this behavior, an energy-based damage parameter is incorporated into the proposed model. The coupled plasticity-damage model shows a good comparison with the experimental results.

Spin state-dependent in-situ photo-Fenton-like transformation from oxygen molecule towards singlet oxygen for selective water decontamination

The development of 1O2-dominanted selective decontamination for water purification was hampered by extra H2O2 consumption and poor 1O2 generation. Herein, we proposed the reconstruction of Fe spin state using near-range N atom and long-range N vacancies to enable efficient generation of H2O2 and sequential activation of H2O2 into 1O2 after visible-light irradiation. Theoretical and experimental results revealed that medium-spin Fe(III) strengthened O2 adsorption, penetrated eg electrons to antibonding p-orbital of oxygen, and lowered the free energy of O2 activation, enabling the oxygen protonation for H2O2 generation. Thereafter, the electrons of H2O2 could be extracted by low-spin Fe(III) and rapidly converted into 1O2 in a nonradical path. The developed 1O2-dominated in-situ photo-Fenton-like system had an excellent pH universality and anti-interference to inorganic ions, dissolved organic matter, and even real water matrixes (e.g., tap water and secondary effluent). This work provided a novel insight for sustainable and efficient 1O2 generation, which motivated the development of new-generation selective water treatment technology.

Turn on the luminescence channel by the suppression of conical intersection process for the sulfur-containing hydrogen-bonded molecules

The sulfur-containing hydrogen bonds exhibit notable potential in gene and protein engineering. As an important research direction of sulfur-containing hydrogen bonding dynamics, the excited-state intramolecular proton transfer (ESIPT) reaction of the thiol proton has garnered significant interest. Recently, Chou et al. synthesized a series of sulfur-containing H-bonded molecules, inclusive of 3-thiolflavone (3 TF), its trifluoromethyl derivative (3FTF), and its diethylamino derivative (3NTF), thereby inaugurating a new chapter in the ESIPT reaction of the thiol proton. Nevertheless, many open issues cannot be answered solely by experimental means and call for a detailed theoretical investigation, especially the relationship between the molecular excited-state properties and different luminescence properties of the three molecules. Herein, we validate that the molecules undergo the ESIPT reaction of the thiol proton and identify the time scale through the time-dependent density functional theory (TDDFT) calculation. Moreover, employing the spin-flip TDDFT approach, the analysis of the non-radiative transition process reveals that difference in Gibbs free energy of activation (ΔG⧧) for the transition from Frank-Condon point to minimum energy conical intersection (MECI) point primarily accounts for the different luminescence properties of the three molecules. Besides, we also reveal the reason for the abnormal blue-shifted fluorescence of the 3NTF in the aggregated state by the ONIOM (TDDFT: UFF) strategy. These findings are favorable to understanding the luminescence mechanism of sulfur-containing H-bonded molecules and provide a reference for the synthesis and design of the luminescent materials based on the molecules with thiol proton transfer properties.

Photo-switchable In(III)-to-In(I) site on oxygen vacancy-laden BiOCl surface for selective degradation of monocyclic aromatic compounds

Enrichment of OVs on oxide semiconductors is an effective strategy to promote their photocatalytic performances but limited by the maximum concentration allowed by lattice thermodynamics. Herein, we report that an In(I) doping strategy, realized by an UV light-induced reduction of a sluggish In(III) precursor, can promote OVs-laden BiOCl by up to 6.5 times for the visible-light sodium pentachlorophenate (PCPNa) degradation. The photocatalysis mechanism study highlighted the In(I) site as an electron transfer site could reduce PCPNa directly, related to the In(I) induced more negative conduction band and faster transfer of electron. Moreover, several monocyclic aromatic organic compounds (AOC) exhibited degradation selectivity over In(I) doped OVs-laden BiOCl (BOVs-In) by an electron reduction path, PCPNa with the lowest negative charge density on the benzene ring has been degraded fastest. Differently, the doped In(I) in BOVs-In mainly triggered the multiring Rhodamine B degradation by promoting the O2− generation not the directly electron reduction path. The electron transfer ability, band structure, and the free energy of O2 activation over BOVs-In were confirmed by TPV spectra, EPR spectra and DFT calculation. This study illustrates an In(I) doping strategy to couple with OVs engineering for champion photoactivity of BiOCl for AOC degradation under visible light irradiation.

Experimental and Theoretical Exploration of the Kinetics and Thermodynamics of the Nucleophile-Induced Fragmentation of Ylidenenorbornadiene Carboxylates.

Ylidenenorbornadienes (YNDs), prepared by [4 + 2] cycloadditions between fulvenes and acetylene carboxylates, react with thiol nucleophiles to yield mixtures of four to eight diastereomers depending on the symmetry of the YND substrate. The mixtures of diastereomers fragment via a retro-[4 + 2] cycloaddition with a large variation in rate, with half-lives ranging from 16 to 11,000 min at 80 °C. The diastereomer-enriched samples of propane thiol adducts [YND-propanethiol (PTs)] were isolated and identified by nuclear Overhauser effect spectroscopy (NOESY) correlations. Simulated kinetics were used to extrapolate the rate constants of individual diastereomers from the observed rate data, and it correlated well with rate constants measured directly and from isolated diastereomer-enriched samples. The individual diastereomers of a model system fragment at differing rates with half-lives ranging from 5 to 44 min in CDCl3. Density functional theory calculations were performed to investigate the mechanism of fragmentation and support an asynchronous retro-[4 + 2] cycloaddition transition state. The computations generally correlated well with the observed free energies of activation for four diastereomers of the model system as a whole, within 2.6 kcal/mol. However, the observed order of the fragmentation rates across the set of diastereomers deviated from the computational results. YNDs display wide variability in the rate of fragmentation, dependent on the stereoelectronics of the ylidene substituents. A Hammett study showed that the electron-rich aromatic rings attached to the ylidene bridge increase the fragmentation rate, while electron-deficient systems slow fragmentation rates.

Valorization of solid waste incinerator fly ash by geopolymer production for removal of anionic bromocresol green dye from water: Kinetics, isotherms and thermodynamics studies

In this study, solid waste incinerator fly ash (SWI-FA) based geopolymer adsorbents were prepared by alkalination of hazardous SWI-FA and cured at different temperatures of 30 0C (GP30), 50 0C (GP50), 70 0C (GP70), and 90 0C (GP90). The geopolymers were applied as low-cost adsorbents for the removal of anionic bromocresol green (BCG) dye from water under varying conditions. The precursor and geopolymers were characterized by XRD, SEM-EDS, FT-IR, and point of zero charge (PZC). The geopolymers were morphologically different with varying chemical compositions. The kinetic data were best described by the pseudo second order model. The experimental equilibrium adsorption data were fitted to Langmuir, Freundlich, Temkin and Dubinin-Radushkevich-Kaganer adsorption isotherm models. The Langmuir monolayer maximum adsorption capacities increased consistently with curing temperature, from 41.70 mg/g to 515.5 mg/g for GP30 and GP90, respectively, a new benchmark for these materials for anionic dyes. The thermodynamic parameters, namely enthalpy (ΔH<0), Gibbs free energy (ΔG<0), entropy (ΔS >0) and activation energy (Ea) indicated that the processes are spontaneous, exothermic, physical (Ea<5kJ/mol and ΔH<40kJ/mol) and enthalpy-driven. The adsorption mechanisms included strong electrostatic interactions and hydrogen bonding. The production of these geopolymers provides dual advantage of waste valorization with applications in depollution of water.

Synthesis, Reaction Mechanism, DNA Cleavage and Antitumor Properties of Naphthoquinone‐Based Enediynes

AbstractUnder physiological conditions, natural enediynes antibiotics generate free radicals through a cycloaromatization reaction. The resulting highly reactive radicals can abstract hydrogen atoms on the phosphate backbone of DNA, leading to high cytotoxicity. On the other hand, anthraquinone‐fused compounds such as daunomycin and adriamycin can insert into DNA through planar aromatic ring structures, resulting in strong DNA damage. To this end, a series of naphthoquinone‐based enediynes were designed and synthesized by adjusting the type of terminal alkyne to modulate their water solubility and radical generation property. Theoretical calculations suggest that the naphthoquinone‐based enediyne generates radicals through a rearrangement (1,3‐proton transfer) followed by Myers‐Saito cyclization processes, with a much lower activation free energy barrier than Bergman cyclization (24.2 kcal/mol vs 39.8 kcal/mol). Differential scanning calorimetry and electron paramagnetic resonance results showed that naphthoquinone‐based enediynes undergo cycloaromatization at relatively low temperatures, resulting in the generation of highly reactive radical species. The enediynes with optimal water solubility displayed strong DNA cleavage ability at micromolar level and high cytotoxicity towards Hela cells, providing a half‐inhibitory concentration of 8.19 μM.

Insights into the physicochemical properties of newly synthesized benzyl triethylammonium chloride-based deep eutectic solvents

In order to utilize deep eutectic solvents (DESs) as a replacement for conventional organic solvents for different applications, a detailed understanding of their physicochemical properties is extremely important. In this study, several novel DESs based on benzyl-triethylammonium chloride (BTEA) as a hydrogen bond acceptor (HBA) and acids/or alcohols as hydrogen bond donors (HBDs) have been synthesized. DESs have been thoroughly characterized and investigated for their physicochemical properties viz. thermal stability, glass transition temperature, viscosity (η), surface tension (γ), refractive index (nD), density (ρ), speed of sound (u), and conductivity (κ) in a temperature range of 293.15–343.15 K. The effect of temperature, type of HBDs, and alkyl chain length of HBDs of the DESs on the physicochemical properties are critically examined and discussed. Viscosity data are fitted to Vogel-Fulcher-Tamman (VFT) and Arrhenius models. A linear model was used to fit surface tension (γ), density, refractive index, and speed of sound data whereas conductivity data were fitted to a nonlinear equation. Primary data on physicochemical properties have been used to estimate the viscous flow parameters (activation entropy, activation enthalpy, and free energy of activation) and other derived parameters such as lattice energy, standard entropy, molar volume, intermolecular free length, and isentropic compressibility. A relationship between molar conductivity and dynamic viscosity has been established to evaluate the ionicity of the synthesized DESs. Insights into the structure–property correlations are discussed in detail.

Transport and optical properties of the binary liquid mixture containing 1,3-diaminopropane and alkyl acetates (C1-C4) at T= (303.15-318.15) K: experimental investigations and theoretical modelling

ABSTRACT Physicochemical properties of pure liquids and their liquid mixtures at different compositions and at different temperatures have a significant role in the optimisation of chemical processes. Present report involves the analysis of the physicochemical properties of 1,3-diaminopropane and alkyl acetate. The viscosity () and refractive index () of 1,3-Diaminopropane, 1,3-DAP (1), with alkyl acetates, AAc, (C1-C4) (2) were measured at different temperatures (T = 303.15 to 318.15 K) under the atmospheric pressure 0.1 MPa. Deviation in viscosity, , deviation in refractive index, , and excess Gibbs free energy of activation, for these binary mixtures were calculated from measured viscosity and refractive index data and fitted to Redlich-Kister polynomial equation (R.K.). The data were analysed in terms of the Graph theoretical approach (GTA) to study the interactions in binary mixtures. The values were also correlated by using Bloomfield and Dewan (BFD) model and various correlations. data were correlated by various relevant correlations.

Controlling Swing Rates in Macrocyclic Molecular Mortise Hinges.

Hinge motion is observed in macrocyclic, mortise-type molecular hinges using variable temperature NMR spectroscopy. The data is consistent with dynamic hinging from a folded-to-extended-to-folded enantiomeric state. Crystallographic and solution structures of the folded states are reported. Chemical shift predictions derived from crystallographic data corroborate fully revolute hinge motion. The rate of hinging is affected by steric congestion at the hinge axis. A macrocycle containing glycine, 1, hinges faster than one comprising aminoisobutyric acid, 2. The free energies of activation, ΔG≠ , for 1 and 2 were determined to be 13.3±0.3 kcal/mol and 16.3±0.3 kcal/mol, respectively. This barrier is largely independent of solvent across those surveyed (CD3 OD, CD3 CN, DMSO-d6 , pyridine-d5 , D2 O). Experiment and computation predict energy barriers that are consistent with disruption of an intramolecular network of hydrogen bonds. DFT calculations reveal a pathway for hinge motion.

Understanding the Fate of the Banert Cascade of Propargylic Azides: Sigmatropic versus Prototropic Pathway.

The Banert cascade is an efficient synthetic strategy for obtaining 4,5-disubstituted 1,2,3-triazoles. The reaction can proceed via a sigmatropic or prototropic mechanism depending on the substrate and the conditions. In this work, the mechanisms of both pathways from propargylic azides with different electronic features were investigated using density functional theory, quantum theory of atoms in molecules, and natural bond orbital approaches. The calculated energy barriers were consistent with the experimental data. Three patterns of electron density distribution on the transition structures were observed, which reflected the behaviors of the reactants in the Banert cascade. The stronger conjugative effects were associated with lower/higher free activation energies of sigmatropic/prototropic reactions, respectively. A clear relationship between the accumulation of the charge at the C3 atom of propargylic azides with the energy barriers for prototropic reactions was found. Thus, the obtained results would allow the prediction of the reaction's course by evaluating reactants.

Comprehensive Mechanistic View of the Hydrolysis of Oxadiazole-Based Inhibitors by Histone Deacetylase 6 (HDAC6).

Histone deacetylase (HDAC) inhibitors used in the clinic typically contain a hydroxamate zinc-binding group (ZBG). However, more recent work has shown that the use of alternative ZBGs, and, in particular, the heterocyclic oxadiazoles, can confer higher isoenzyme selectivity and more favorable ADMET profiles. Herein, we report on the synthesis and biochemical, crystallographic, and computational characterization of a series of oxadiazole-based inhibitors selectively targeting the HDAC6 isoform. Surprisingly, but in line with a very recent finding reported in the literature, a crystal structure of the HDAC6/inhibitor complex revealed that hydrolysis of the oxadiazole ring transforms the parent oxadiazole into an acylhydrazide through a sequence of two hydrolytic steps. An identical cleavage pattern was also observed both in vitro using the purified HDAC6 enzyme as well as in cellular systems. By employing advanced quantum and molecular mechanics (QM/MM) and QM calculations, we elucidated the mechanistic details of the two hydrolytic steps to obtain a comprehensive mechanistic view of the double hydrolysis of the oxadiazole ring. This was achieved by fully characterizing the reaction coordinate, including identification of the structures of all intermediates and transition states, together with calculations of their respective activation (free) energies. In addition, we ruled out several (intuitively) competing pathways. The computed data (ΔG‡ ≈ 21 kcal·mol-1 for the rate-determining step of the overall dual hydrolysis) are in very good agreement with the experimentally determined rate constants, which a posteriori supports the proposed reaction mechanism. We also clearly (and quantitatively) explain the role of the -CF3 or -CHF2 substituent on the oxadiazole ring, which is a prerequisite for hydrolysis to occur. Overall, our data provide compelling evidence that the oxadiazole warheads can be efficiently transformed within the active sites of target metallohydrolases to afford reaction products possessing distinct selectivity and inhibition profiles.