Tunneling governs intramolecular proton transfer in thiotropolone at room temperature

Successfully tunneled: The rapid and temperature-independent intramolecular proton transfer in thiotropolone occurs entirely through quantum mechanical tunneling. For tropolone, tunneling across a smaller yet broader barrier leads to a slower rate of proton transfer for temperatures smaller than 240?K.     

Path Length Determines the Tunneling Decay of Substituted Carbenes

Quantum mechanical tunneling of atoms allows chemical reactions to proceed through barriers too high for thermally activated processes. This causes hydroxycarbenes to decay rapidly and at a temperature‐independent rate even at 11 K. In methylhydroxycarbene, tunneling causes decay through a mechanism that reveals a high but thin barrier rather than an alternative with a lower but broader barrier. No accurate estimates of the widths of such barriers and the lengths of tunneling paths were available. Herein, such a measure is provided by calculating the length of the tunneling paths by using instanton theory. Potential energies are provided by density functional theory verified by explicitly correlated coupled cluster CCSD(T) energies. Our results explain the decay efficiency in the known cases and suggest new substitutions to tune the effects of barrier widths and heights. Fluorination and replacement of the hydroxyl group by a thiol group change the qualitative character of the decay. Methylaminocarbene is predicted to be stable for thousands of years.     

Why Do Cycloaddition Reactions Involving C60 Prefer [6,6] over [5,6] Bonds?

The origin of the experimentally known preference for [6,6] over [5,6] bonds in cycloaddition reactions involving C₆₀ has been computationally explored. To this end, the Diels–Alder reaction between cyclopentadiene and C₆₀ has been analysed by means of the recently introduced activation strain model of reactivity in combination with the energy decomposition analysis method. Other issues, such as the aromaticity of the corresponding transition states, have also been considered. These results indicate that the major factor controlling the observed regioselectivity is the more stabilising interaction between the deformed reactants in the [6,6] reaction pathway along the entire reaction coordinate.     

Supramolecular Stabilization of Metastable Tautomers in Solution and the Solid State

This work presents a successful application of a recently reported supramolecular strategy for stabilization of metastable tautomers in cocrystals to monocomponent, non‐heterocyclic, tautomeric solids. Quantum‐chemical computations and solution studies show that the investigated Schiff base molecule, derived from 3‐methoxysalicylaldehyde and 2‐amino‐3‐hydroxypyridine ( ap ), is far more stable as the enol tautomer. In the solid state, however, in all three obtained polymorphic forms it exists solely as the keto tautomer, in each case stabilized by an unexpected hydrogen‐bonding pattern. Computations have shown that hydrogen bonding of the investigated Schiff base with suitable molecules shifts the tautomeric equilibrium to the less stable keto form. The extremes to which supramolecular stabilization can lead are demonstrated by the two polymorphs of molecular complexes of the Schiff base with ap . The molecules of both constituents of molecular complexes are present as metastable tautomers (keto anion and protonated pyridine, respectively), which stabilize each other through a very strong hydrogen bond. All the obtained solid forms proved stable in various solid‐state and solvent‐mediated methods used to establish their relative thermodynamic stabilities and possible interconversion conditions.     

Heavy‐Atom Tunneling in the Ring Opening of a Strained Cyclopropene at Very Low Temperatures

The highly strained 1H‐bicyclo[3.1.0]‐hexa‐3,5‐dien‐2‐one 1 is metastable, and rearranges to 4‐oxacyclohexa‐2,5‐dienylidene 2 in inert gas matrices (neon, argon, krypton, xenon, and nitrogen) at temperatures as low as 3 K. The kinetics for this rearrangement show pronounced matrix effects, but in a given matrix, the reaction rate is independent of temperature between 3 and 20 K. This temperature independence means that the activation energy is zero in this temperature range, indicating that the reaction proceeds through quantum mechanical tunneling from the lowest vibrational level of the reactant. At temperatures above 20 K, the rate increases, resulting in curved Arrhenius plots that are also indicative of thermally activated tunneling. These experimental findings are supported by calculations performed at the CASSCF and CASPT2 levels by using the small‐curvature tunneling (SCT) approximation.     

Conservation of Orbital Symmetry can be Circumvented in Mechanically Induced Reactions

In first‐principles molecular dynamics simulations of the mechanically induced ring‐opening of substituted benzocyclobutene we observe both con‐ and disrotatory ring‐opening reactions. We show that this finding does not contradict the fundamental principle that the orbitals develop continuously in time. However, it constitutes an exception from the principle of the conservation of orbital symmetry and thus is indeed an exception from the Woodward–Hoffmann rules. In contrast, the ring‐opening of unsubstituted cyclobutene proceeds in a conrotatory fashion. This shows that the breaking of the Woodward–Hoffmann rules is significantly facilitated by the substituents.     

Mechanism of the Catalytic Activity of Nucleophiles in the Stepwise Hydrolysis and Condensation Reactions of Tetramethoxysilane

Active ingredients : A model for the simplest hydrolysis reaction is applied to all stages of stepwise hydrolysis and condensation taking place during a sol–gel process. The picture shows the molecular structures of the transition states of the ammonia‐ (left) and OH^?‐promoted (right) condensation reactions of two Si(OH)₄ molecules, including an additional water molecule.

     

Disulfide Bond Cleavage: A Redox Reaction Without Electron Transfer

By using Car–Parrinello molecular dynamics (CPMD) simulations we have simulated a mechanically induced redox reaction. Previous single‐molecule atomic force microscopy (AFM) experiments demonstrated that the reduction of disulfide bonds in proteins with the weak reducing agent dithiothreitol depends on a mechanical destabilization of the breaking bond. With reactive molecular dynamics simulations the single steps of the reaction mechanism can be elucidated and the motion of the electrons can be monitored. The simulations show that the redox reaction consists of the heterolytic cleavage of the S? S bond followed by a sequence of proton transfers.     

The Primary Steps in Excited‐State Hydrogen Transfer: The Phototautomerization of o‐Nitrobenzyl Derivatives

The quantum yield for the release of leaving groups from o‐nitrobenzyl “caged” compounds varies greatly with the nature of these leaving groups, for reasons that have never been well understood. We found that the barriers for the primary hydrogen‐atom transfer step and the efficient nonradiative processes on the excited singlet and triplet surfaces determine the quantum yields. The excited‐state barriers decrease when the exothermicity of the photoreaction increases, in accord with Bell–Evans–Polanyi principle, a tool that has never been applied to a nonadiabatic photoreaction. We further introduce a simple ground‐state predictor, the radical‐stabilization energy, which correlates with the computed excited‐state barriers and reaction energies, and that might be used to design new and more efficient photochemical processes.     

Tuning Proton Conductivity by Interstitial Guest Change in Size‐Adjustable Nanopores of a CuI‐MOF: A Potential Platform for Versatile Proton Carriers

By exploiting the breathing behavior of nanopores, we have studied for the first time the dependency of the guest‐induced proton conductivity of an interpenetrated Cu^I metal–organic framework (Cu^I‐MOF, [ 1 ]) on various guest molecules. Proton conductivities of over 10^?3 S cm^?1 under humid conditions were induced by a series of guest molecules, namely N,N‐dimethylformamide, dimethyl sulfoxide, diethylamine, 1,4‐dinitrobenzene, nitrobenzene, pyridine, and 1H‐1,2,4‐triazole. A detailed investigation of the guest‐incorporated complexes revealed that low‐energy proton conduction occurs under humid conditions through the Grotthuss mechanism in [ 1 ?NB] and through the vehicle mechanism in the rest of the complexes. Single‐point energy computations revealed considerable stabilization upon guest encapsulation. To the best of our knowledge, [ 1 ] represents the first example in which considerably high protonic conductivity is triggered upon the facile incorporation of small molecules of such a variety. The investigation portrayed herein may be a stepping stone towards the rational design of proton‐conducting materials for practical applications.     

Theoretical Analysis of the Detailed Mechanism of Native Chemical Ligation Reactions

The method of native chemical ligation between an unprotected peptide α‐thioester and an N‐terminal cysteine–peptide to give a native peptide in aqueous solution is one of the most effective peptide ligation methods. In this work, a systematic theoretical study was carried out to fully understand the detailed mechanism of ligation. It was found that for the conventional native chemical ligation reaction between a peptide thioalkyl ester and a cysteine in combination with an added aryl thiol as catalyst, both the thiol‐thioester exchange step and the transthioesterification step proceed by an anionic concerted S_N2 displacement mechanism, whereas the intramolecular rearrangement proceeds by an addition–elimination mechanism, and the rate‐limiting step is the thiol‐thioester exchange step. The theoretical method was then extended to study the detailed mechanism of the auxiliary‐mediated peptide ligation between a peptide thiophenyl ester and an N‐2‐mercaptobenzyl peptide in which both the thiol‐thioester exchange step and intramolecular acyl‐transfer step proceed by a concerted S_N2‐type displacement mechanism. The energy barrier of the thiol‐thioester exchange step depends on the side‐chain steric hindrance of the C‐terminal amino acid, whereas that of the acyl‐transfer step depends on the side‐chain steric hindrance of the N‐terminal amino acid.     

Kinetics and Mechanisms for the Reactions of Phenyl Radical with Ketene and its Deuterated Isotopomer: An Experimental and Theoretical Study

Kinetics and mechanism for the reaction of phenyl radical (C₆H₅) with ketene (H₂C_β?C_α?O) were studied by the cavity ring‐down spectrometric (CRDS) technique and hybrid DFT and ab initio molecular orbital calculations. The C₆H₅ transition at 504.8 nm was used to detect the consumption of the phenyl radical in the reaction. The absolute overall rate constants measured, including those for the reaction with CD₂CO, can be expressed by the Arrhenius equation k=(5.9±1.8)×10¹¹ exp[?(1160±100)/T] cm³ mol^?1 s^?1 over a temperature range of 301–474 K. The absence of a kinetic isotope effect suggests that direct hydrogen abstraction forming benzene and ketenyl radical is kinetically less favorable, in good agreement with the results of quantum chemical calculations at the G2MS//B3LYP6‐31G(d) level of theory for all accessible product channels, including the above abstraction and additions to the C_α, C_β, and O sites. For application to combustion, the rate constants were extrapolated over the temperature range of 298–2500 K under atmospheric pressure by using the predicted transition‐state parameters and the adjusted entrance reaction barriers E_α=E_β=1.2 kcal mol^?1; they can be represented by the following expression in units of cm³ mol^?1 s^?1: k_α=6.2×10¹⁹ T^?2.3 exp[?7590/T] and k_β=3.2×10⁴ T^2.4 exp[?246/T].     

The Roles of Counterion and Water in a Stereoselective Cysteine‐Catalyzed Rauhut–Currier Reaction: A Challenge for Computational Chemistry

The stereoselective Rauhut–Currier (RC) reaction catalyzed by a cysteine derivative has been explored computationally with density functional theory (M06‐2X). Both methanethiol and a chiral cysteine derivative were studied as nucleophiles. The complete reaction pathway involves rate‐determining elimination of the thiol catalyst from the Michael addition product. The stereoselective Rauhut–Currier reaction, catalyzed by a cysteine derivative as a nucleophile, has also been studied in detail. This reaction was experimentally found to be extremely sensitive to the reaction conditions, such as the number of water equivalents and the effect of potassium counterion. The E1cB process for catalyst elimination has been explored computationally for the eight possible stereoisomers. The effect of explicit water solvation and the presence of counterion (either K⁺ or Na⁺) has been studied for the lowest energy enantiomer pair (1S, 2R, 3S)/(1R, 2S, 3R).     

A Theoretical Study of Ene Reactions in Solution: A Solution‐Phase Translational Entropy Model

Several density functional theory (DFT) methods, such as CAM‐B3LYP, M06, ωB97x, and ωB97xD, are used to characterize a range of ene reactions. The Gibbs free energy, activation enthalpy, and entropy are calculated with both the gas‐ and solution‐phase translational entropy; the results obtained from the solution‐phase translational entropies are quite close to the experimental measurements, whereas the gas‐phase translational entropies do not perform well. For ene reactions between the enophile propanedioic acid (2‐oxo‐1,3‐dimethyl ester) and π donors, the two‐solvent‐involved explicit+implicit model can be employed to obtain accurate activation entropies and free‐energy barriers, because the interaction between the carbonyl oxygen atom and the solvent in the transition state is strengthened with the formation of C?C and O?H bonds. In contrast, an implicit solvent model is adequate to calculate activation entropies and free‐energy barriers for the corresponding reactions of the enophile 4‐phenyl‐1,2,4‐triazoline‐3,5‐dione.     

Mechanism of the Tyrosine Ammonia Lyase Reaction—Tandem Nucleophilic and Electrophilic Enhancement by a Proton Transfer

Quantum mechanics/molecular mechanics calculations in tyrosine ammonia lyase (TAL) ruled out the hypothetical Friedel–Crafts (FC) route for ammonia elimination from L ‐tyrosine due to the high energy of FC intermediates. The calculated pathway from the zwitterionic L ‐tyrosine‐binding state (0.0 kcal mol^?1) to the product‐binding state ((E)‐coumarate+H₂N? MIO; ?24.0 kcal mol^?1; MIO=3,5‐dihydro‐5‐methylidene‐4H‐imidazol‐4‐one) involves an intermediate (IS, ?19.9 kcal mol^?1), which has a covalent bond between the N atom of the substrate and MIO, as well as two transition states (TS1 and TS2). TS1 (14.4 kcal mol^?1) corresponds to a proton transfer from the substrate to the N1 atom of MIO by Tyr300? OH. Thus, a tandem nucleophilic activation of the substrate and electrophilic activation of MIO happens. TS2 (5.2 kcal mol^?1) indicates a concerted C? N bond breaking of the N‐MIO intermediate and deprotonation of the pro‐S β position by Tyr60. Calculations elucidate the role of enzymic bases (Tyr60 and Tyr300) and other catalytically relevant residues (Asn203, Arg303, and Asn333, Asn435), which are fully conserved in the amino acid sequences and in 3D structures of all known MIO‐containing ammonia lyases and 2,3‐aminomutases.     

Origin of Orthogonality of Strain‐Promoted Click Reactions

Site‐specific labeling of biomolecules is rapidly advancing due to the discovery of novel mutually orthogonal reactions. Quantum chemistry studies have also increased our understanding of their relative rates, although these have until now been based on highly simplified reactants. Here we examine a set of strain‐promoted click‐type cycloaddition reactions of n‐propyl azide, 3‐benzyl tetrazine and 3‐benzyl‐6‐methyl tetrazine with cyclooctenes/ynes, in which we aim to address all relevant structural details of the reactants. Our calculations have included the obligatory handles used to attach the label and biomolecule as these can critically influence the stereochemistry and electron demand of the reaction. We systematically computed orbital gaps, activation and distortion energies using density functional theory and determined experimental rates for validation. Our results challenge the current paradigm of the inverse electron demand for this class of reactions. We found that the ubiquitous handles, when next to the triple bond of cyclooctynes, can switch the Diels–Alder type ligations to normal electron demand, a class we term as SPINEDAC reactions. Electron donating substituents on tetrazine can enhance normal demand but also increase distortion penalties. The presence and isomeric configuration of handles thus determine the reaction speed and regioselectivity. Our findings can be directly utilized in engineering genuine cycloaddition click chemistries for biological labeling.