Tautomerization Reaction Research Articles

Electric Field-Induced Sequential Prototropic Tautomerism in Enzyme-like Nanopocket Created by Single Molecular Break Junction.

Mastering the control of external stimuli-induced chemical transformations with detailed insights into the mechanistic pathway is the key for developing efficient synthetic strategies and designing functional molecular systems. Enzymes, the most potent biological catalysts, efficiently utilize their built-in electric field to catalyze and control complex chemical reactions within the active site. Herein, we have demonstrated the interfacial electric field-induced prototropic tautomerization reaction in acylhydrazone entities by creating an enzymatic-like nanopocket within the atomically sharp gold electrodes using a mechanically controlled break junction (MCBJ) technique. In addition to that, the molecular system used here contains two coupled acylhydrazone reaction centers, hence demonstrating a cooperative stepwise electric field-induced reaction realized at the single molecular level. Furthermore, the mechanistic studies revealed a proton relay-assisted tautomerization showing the importance of external factors such as solvent in such electric field-driven reactions. Finally, single-molecule charge transport and energetics calculations of different molecular species at various applied electric fields using a polarizable continuum solvent model confirm and support our experimental findings. Thus, this study demonstrates that mimicking an enzymatic pocket using a single molecular junction's interfacial electric field as a trigger for chemical reactions can open new avenues to the field of synthetic chemistry.

Catalytic pyrolysis mechanism of tetrabromobisphenol A by calcium oxide: A density functional theory study

In this paper, the mechanisms of catalytic pyrolysis of tetrabromobisphenol A (TBBPA) by calcium oxide (CaO) were studied through density functional theory methods. The results indicate that the phenolic hydroxyl group of TBBPA is the preferred site for CaO to extract protons, and the generated anion further transforms into 2,6-dibromophenol via demethylation and hydrogen transfer reactions. The reaction activity of CaO with hydrogen bromide is relatively high, with an energy barrier of 133.2 kJ/mol. CaO produces calcium ions, which combine with bromine ions to form calcium bromide to achieve the purpose of fixing bromine. In addition, the participation of calcium ions results in the OH bond being easier to crack, which further lowers the reaction energy barrier of keto-enol tautomerism reactions H2O produced during catalytic pyrolysis also has an obvious catalytic effect, and the energy barrier of the keto-enol tautomerism reaction decreased from 309.1 kJ/mol to 150.6 kJ/mol with the participation of H2O.

Kinetics of direct and water‐mediated tautomerization reactions of four‐membered cyclic lactims to amides or lactams

AbstractAs part of a series of studies of hydrogen‐atom transfer or tautomerization reactions of imidic acid‐amide species, ──═─ ═──, we report the rate constants for a set of 16 four‐membered cyclic compounds at low, 50–300 K, and high, 500–1500 K, temperatures. The compounds are labeled according to the two ring groups X and Y, which can be , NH, CH, N, O, or C(O) and which are at some remove from the reactive site. These rate constants are for both the direct reaction and for that mediated by an additional water molecule, which facilitates the hydrogen transfer reaction. In the latter case, we show that the rate of reaction from a pre‐reaction complex is rapid at temperatures down to 50 K and dominated by quantum mechanical effects as evaluated by small‐curvature and quantized‐reaction‐states tunneling. In addition, we present thermochemical data such as enthalpies of formation, entropies, isobaric heat capacities, and enthalpy functions for these largely unknown species, which span a range of compounds from ‐propiolactone to 1,3‐diazetidine‐2,4‐dione.

Electronic and Nuclear Quantum Effects on Proton Transfer Reactions of Guanine-Thymine (G-T) Mispairs Using Combined Quantum Mechanical/Molecular Mechanical and Machine Learning Potentials.

Rare tautomeric forms of nucleobases can lead to Watson-Crick-like (WC-like) mispairs in DNA, but the process of proton transfer is fast and difficult to detect experimentally. NMR studies show evidence for the existence of short-time WC-like guanine-thymine (G-T) mispairs; however, the mechanism of proton transfer and the degree to which nuclear quantum effects play a role are unclear. We use a B-DNA helix exhibiting a wGT mispair as a model system to study tautomerization reactions. We perform ab initio (PBE0/6-31G*) quantum mechanical/molecular mechanical (QM/MM) simulations to examine the free energy surface for tautomerization. We demonstrate that while the ab initio QM/MM simulations are accurate, considerable sampling is required to achieve high precision in the free energy barriers. To address this problem, we develop a QM/MM machine learning potential correction (QM/MM-ΔMLP) that is able to improve the computational efficiency, greatly extend the accessible time scales of the simulations, and enable practical application of path integral molecular dynamics to examine nuclear quantum effects. We find that the inclusion of nuclear quantum effects has only a modest effect on the mechanistic pathway but leads to a considerable lowering of the free energy barrier for the GT*⇌G*T equilibrium. Our results enable a rationalization of observed experimental data and the prediction of populations of rare tautomeric forms of nucleobases and rates of their interconversion in B-DNA.

Exploring the Correlation between Azido-Tetrazolo Tautomerizations and Isomer Structures: Electron Density of Bonding N Atoms and N-N Bond Polarity.

Azido-tetrazolo tautomerizations between azido N-heteroaromatic compounds and tetrazole-fused energetic materials can produce a new generation of high-energy density compounds. Density functional theory (DFT) computations are performed to explore the relationship between reaction barriers and electron densities of bonding N atoms, i.e., the terminal N1 and heterocyclic N2 atoms, for six reported tautomerizations. The results reveal four linear correlations between reverse reaction barriers (Gr) and the electron densities of N1 and N2 atoms in the product. N1 electron density (ρN1) and N-N bond polarity, as measured by the difference between the electron densities on the two N atoms (ΔρN = ρN1 - ρN2) in products, are inversely proportional to the reverse reaction barriers. They are also proportional to the energy barrier differences between the forward and reverse reactions (ΔG = Gf - Gr). Polar solvents, including DMSO, water, and acetone, can effectively increase the reverse reaction barriers (Gr) by improving the stability of products. This regularity is further confirmed by its application to four additional tautomerizations and can be used to screen out unfavorable azido-tetrazolo tautomerization reactions and increase the success rate of such synthesis.

Kinetics of direct and water‐mediated tautomerization reactions of five‐membered cyclic amides or lactams

AbstractAs part of a series of studies of hydrogen‐atom transfer or tautomerization reactions of imidic acid–amide species, , we report the rate constants for a set of 24 five‐membered cyclic compounds at low, 50–300 K, and high, 500–1500 K, temperatures. These rate constants are for both the high temperature direct reaction and for that mediated by an additional water molecule which facilitates the hydrogen transfer reaction at low temperatures. In the latter case we show that the rate of reaction from a pre‐reaction complex can be rapid at temperatures down to 50 K on a 1 ms timescale and is dominated by quantum mechanical effects as evaluated by small‐curvature and quantised‐reaction‐states tunnelling. In addition, we present thermochemical data such as enthalpies of formation, entropies, isobaric heat capacities and enthalpy functions for these largely unknown species which span a range of compounds from pyrolidinone to oxo‐tetrazoles.

Surface-Accelerated String Method for Locating Minimum Free Energy Paths.

We present a surface-accelerated string method (SASM) to efficiently optimize low-dimensional reaction pathways from the sampling performed with expensive quantum mechanical/molecular mechanical (QM/MM) Hamiltonians. The SASM accelerates the convergence of the path using the aggregate sampling obtained from the current and previous string iterations, whereas approaches like the string method in collective variables (SMCV) or the modified string method in collective variables (MSMCV) update the path only from the sampling obtained from the current iteration. Furthermore, the SASM decouples the number of images used to perform sampling from the number of synthetic images used to represent the path. The path is optimized on the current best estimate of the free energy surface obtained from all available sampling, and the proposed set of new simulations is not restricted to being located along the optimized path. Instead, the umbrella potential placement is chosen to extend the range of the free energy surface and improve the quality of the free energy estimates near the path. In this manner, the SASM is shown to improve the exploration for a minimum free energy pathway in regions where the free energy surface is relatively flat. Furthermore, it improves the quality of the free energy profile when the string is discretized with too few images. We compare the SASM, SMCV, and MSMCV using 3 QM/MM applications: a ribozyme methyltransferase reaction using 2 reaction coordinates, the 2'-O-transphosphorylation reaction of Hammerhead ribozyme using 3 reaction coordinates, and a tautomeric reaction in B-DNA using 5 reaction coordinates. We show that SASM converges the paths using roughly 3 times less sampling than the SMCV and MSMCV methods. All three algorithms have been implemented in the FE-ToolKit package made freely available.

Unraveling Halochromism of Azo‐Based Sulphonamide and Its Real‐World Applications: A Combined Experimental and Theoretical Approach

AbstractHalochromic azo dyes have versatile applications, including sensing and anti‐counterfeiting, due to their reversible color‐changing properties. In this work we investigated the structure‐dependent halochromism of azo compound (E)‐4‐((2‐hydroxynaphthalen‐1‐yl)diazenyl)benzenesulfonamide (HDBS) and explore its potential applications using experimental and theoretical approaches. Different spectroscopic techniques confirm the structural change in the dye as a consequence of tautomerism reaction upon changing pH (7 to 13). The stable form of hydrazone is isolated and characterized. Based on the spectroscopic characterization, it is concluded that the azo form exists at pH ≤ 9, whereas the hydrazone form at highly alkaline pH. To understand the origin of the absorption peaks, the stability, and tautomerism in water, DFT and TD‐DFT calculations are performed. A reasonable agreement between the theoretical and experimental observations enabled us to unravel the structure‐dependent halochromism. Further, we have shown that HDBS‐coated paper can be a real‐time visual sensor to monitor fish freshness and for anti‐counterfeiting ink. It changes colors with pH shifts, alerts consumers about the status of food. Additionally, erasable paper strip reduces paper waste and chemical pollution. The findings presented in this work provide a promising avenue for the development of halochromic azo compounds with potential applications in sensing and anti‐counterfeiting.

Kinetics of direct and water‐mediated tautomerization reactions of nucleobases at low temperatures ⩽200 K

AbstractDetailed chemical kinetic mechanisms for the synthesis of complex organic molecules in the interstellar medium are at an early stage of developement. That such synthesis must take place is well‐known from chemical analysis of sampled asteroids. As molecular complexity increases the number of possible structural isomers also increases with the consequence that the nascent species may adopt a different spatial arrangement, to the lowest energy one. As part of a program of investigations of the hydrogen atom transfer reaction or tautomerization of imidic acid–amide species H‐O=C‐N‐ O=C‐N‐H we have studied the kinetics for a number of nucleobases, namely cytosine, thymine and uracil where a cyclic form of tautomerism (lactim–lactam) is encountered. Together with a fourth, 5‐aza‐uracil (1,3,5‐triazine‐2,4(1H,3H)‐dione), we report on the rates of reaction at low temperatures 50–200 K for both the direct unimolecular process and the similar transformation mediated by an additional water molecule. We show that these tautomerization reactions can be categorized into three classes, and highlight the importance of quantum mechanical tunneling on the rate constants at these low temperatures. We further present some thermochemistry data, such as formation enthalpies, entropies, isobaric heat capacities and enthalpy functions.

Opportunities and challenges in Upscaling the production of N,N-dimethylaminoethanol from bio-based glycolaldehyde

In recent years, significant focus has been placed on the sustainable chemical production of ethanolamines using bio-based feedstocks. Thorough investigations have been conducted to explore and refine laboratory-scale methodologies. However, important parameters for successfully scaling up these processes to meet industrial productivity standards are often overlooked. In this article, the feasibility of scaling up the production of N,N-dimethylaminoethanol (DMAE) from bio-derived industrial glycolaldehyde (GA) was investigated. By determining a minimum kLa value of 0.27 s−1, a 97 % selectivity towards DMAE at complete GA conversion was ensured, irrespective of the reactor configuration. This improvement led to a substantial productivity increase, reaching up to 1526 kg DMAE/m3.h. Additionally, it was observed that impurities present in the industrial crude GA feedstock lowered the DMAE selectivity to 76 %. Notably, the presence of acidic impurities within the crude feedstock was identified as the main cause of the imbalance between the hydrogenation, dehydration, and tautomerization reaction, ultimately resulting in the formation of undesired diamines. This article elucidates potential engineering approaches to enhance the selectivity and productivity for the industrial production of bio-based ethanolamines.

Probing the water mediated proton transfer in histidine tautomerization

Histidine tautomerism plays a key role in the aggregation of amyloid peptides, which is important for understanding the origin of Alzheimer’s disease as well as its diagnosis and treatment. Herein, density functional theory calculations were performed using explicit water molecules and joint implicit/explicit water cluster models to explore the catalytic mechanism and the key role of water assistance effect in the histidine tautomerization reaction. To clarify the proton transfer mechanism involved in histidine tautomerization, three to five water molecules were used to catalyze the proton transfer process governing the transition between the histidine tautomers. Potential energy calculations showed that hiε·(H2O)n tautomerism proceeds via a single proton transfer pathway. Systematic analyses of the hydrogen bonds and charge distribution of the key components indicated that tautomerism can be promoted by reducing the number of assistant water molecules or involving the joint implicit/explicit water solvent effect. This study provides theoretical insights into the mechanism of water-assisted histidine isomerization as it relates to the Aβ aggregation hypothesis of Alzheimer’s disease.

Revelation of bimolecular tautomerization induced by the concerted and radical interactions in lignin pyrolysis

Bimolecular interactions play crucial roles in lignin pyrolysis. The tautomerization of key intermediates has a significant impact on the formation of stable products, whereas bimolecular tautomerization has been rarely clarified. In the present work, the bimolecular tautomerization mechanism induced by both concerted and radical interactions was proposed and carefully confirmed. A characteristic β-O-4 lignin dimer, 2-phenoxy-1-phenylethanol (α-OH-PPE), was used as the model compound to reveal two representative keto-phenol and enol-keto tautomerism mechanisms, based on theoretical calculations combined with pyrolysis experiments. The results indicate that the unimolecular tautomerism as the rate-determining step limits product generation, due to fairly high energy barriers. While the free hydroxy compounds and radicals derived from initial pyrolysis can further initiate bimolecular tautomerism reactions through the one-step concerted hydroxyl-assisted hydrogen transfer (hydroxyl-AHT) and two-step radical hydrogen abstraction interactions, respectively. By alleviating and even avoiding the large ring tension of tautomerism, the unstable tautomers (2,4-cyclohexadienone and 1-hydroxystyrene) can be rapidly tautomerized into stable phenol and acetophenone with the help of intermolecular interaction. Benefitting from the significant advantage of retro-ene fragmentation in breaking the β-O-4 bond to form tautomers, a large amount of stable phenolic and ketone products can be generated following bimolecular tautomerization in the pyrolysis of β-O-4 linked lignin.

Structurally diverse spirocyclic polycyclic polyprenylated acylphloroglucinols from Hypericum ascyron Linn. and their anti-tumor activity

Ten spirocyclic polycyclic polyprenylated acylphloroglucinols (PPAP), hunascynols A–J (1–10), and 12 known analogs were isolated from the aerial parts of Hypericum ascyron Linn. Compounds 1 and 2, which share a 1,2-seco-spirocyclic PPAP skeleton, could be derived from spirocyclic PPAP, with a common octahydrospiro[cyclohexan-1,5′-indene]-2,4,6-trione core, through a cascade of Retro-Claisen, keto-enol tautomerism, and esterification reactions. Aldolization of normal spirocyclic PPAP yielded 3, which has a caged framework with a 6/5/6/5/6 ring system. The structures of these compounds were determined using spectroscopy and X-ray diffraction. The inhibitory activities of all isolates were tested in three human cancer cell lines and a zebrafish model. Compounds 1 and 2 displayed moderate cytotoxicity against HCT116 cells (IC50 6.87 and 9.86 μM, respectively). The mechanisms of these compounds were evaluated using Western blot assays. Compounds 3 and 5 inhibited the growth of sub-intestinal vessels in zebrafish embryos. Further, the target genes were screened using real-time PCR.

Ultrafast Proton Transfer Pathways Mediated by Amphoteric Imidazole

Imidazole, being an amphoteric molecule, can act both as an acid and as a base. This property enables imidazole, as an essential building block, to effectively facilitate proton transport in high-temperature proton exchange membrane fuel cells and in proton channel transmembrane proteins, enabling those systems to exhibit high energy conversion yields and optimal biological function. We explore the amphoteric properties of imidazole by following the proton transfer exchange reaction dynamics with the bifunctional photoacid 7-hydroxyquinoline (7HQ). We show with ultrafast ultraviolet-mid-infrared pump-probe spectroscopy how for imidazole, in contrast to expectations based on textbook knowledge of acid-base reactivity, the preferential reaction pathway is that of an initial proton transfer from 7HQ to imidazole, and only at a later stage a transfer from imidazole to 7HQ, completing the 7HQ tautomerization reaction. An assessment of the molecular distribution functions and first-principles calculations of proton transfer reaction barriers reveal the underlying reasons for our observations.

Substituent effects in the tautomerization of imidic acids R−C(OH)=NH → R−C(O)NH2: Kinetic implications for the formation of peptide bonds in the interstellar medium

AbstractA number of amides, RC(O)NH2, have been detected spectroscopically in the space between the stars. Naturally the study of how these are formed is an important question on the path of chemical evolution from the elements C, H, N, O, P, … to life because the so‐called peptide‐bond −C(O)−NH− is a key linkage in poly‐amino acids or proteins. Both cyanides and water are abundant in the interstellar medium (ISM) and it has been suggested [J Phys Chem A. 2021;126:924‐939] that these react on water–ice grains, catalyzed by acid H3O+, to form firstly imidic acids R−C≡ N + H2O → RC(OH)NH and subsequently to amides. Here we explore the kinetics in the gas‐phase of the intramolecular tautomerization reaction of the imidic acids for R = H, HO, NC, H2N, HC(O), H3C, HOCH2, H2CCH,H3C(O), H2NCH2, C2H5, and CN, particularly at low temperatures where quantum mechanical small curvature and quantized reactant states tunneling are dominant. The most reactive imidic acid is H2NC(OH)NH which goes on to form urea, one of three known amides in the interstellar medium (ISM), which can self‐react to form cytosine and uracil two canonical nucleobases in RNA. The thermochemistry (, , , ) of the imidic acids and amides is also reported as well as the tautomerization of sulfur and phosphorus analogs HC(SH)NH and HC(OH)PH.

Improving a Methane C-H Activation Complex by Metal and Ligand Alterations from Computational Results.

We present results for a series of complexes derived from a titanium complex capable of activating C-H bonds under mild conditions (PNP)Ti═CHtBu(CH2tBu), where PNP = N[2-PiPr2-4-methylphenyl]2-. In addition to the initial activation of methane, a tautomerization reaction to a terminal methylidene is also explored due to methylidene's potential use as a synthetic starting point. Analogous complexes with other low-cost 3d transition metals were studied, such as scandium, titanium, vanadium, and chromium as both isoelectronic and isocharged complexes. Our results predict that V(IV) and V(V) complexes are promising for methane C-H bond activation. The V(V) complex has a low rate-determining barrier for methane activation, specifically 16.6 kcal/mol, which is approximately 12 kcal/mol less than that for the Ti complex, as well as having a moderate tautomerization barrier of 29.8 kcal/mol, while the V(IV) complex has a methane activation barrier of 19.0 kcal/mol and a tautomerization barrier of 31.1 kcal/mol. Scandium and chromium complexes are much poorer for C-H bond activation; scandium has very high barriers, while chromium strongly overstabilizes the alkylidene intermediate, potentially stopping the further reaction. In addition to the original PNP ligand, some of the most promising ligands from a previous work were tested, although (as shown previously) modification of the ligand does not typically have large effects on the activity of the system. Our best ligand modification improves the performance of the V(V) complex via the substitution of the nitrogen in PNP by phosphorus, which reduces the tautomerization barrier by 5 to 24.4 kcal/mol.

Tautomerisation Mechanisms in the Adenine-Thymine Nucleobase Pair during DNA Strand Separation.

The adenine-thymine tautomer (A*-T*) has previously been discounted as a spontaneous mutagenesis mechanism due to the energetic instability of the tautomeric configuration. We study the stability of A*-T* while the nucleobases undergo DNA strand separation. Our calculations indicate an increase in the stability of A*-T* as the DNA strands unzip and the hydrogen bonds between the bases stretch. Molecular Dynamics simulations reveal the time scales and dynamics of DNA strand separation and the statistical ensemble of opening angles present in a biological environment. Our results demonstrate that the unwinding of DNA, an inherently out-of-equilibrium process facilitated by helicase, will change the energy landscape of the adenine-thymine tautomerization reaction. We propose that DNA strand separation allows the stable tautomerization of adenine-thymine, providing a feasible pathway for genetic point mutations via proton transfer between the A-T bases.

Kinetics, mechanism, and tautomerism in ametryn acid hydrolysis: From molecular structure to environmental impacts

The excessive use of pesticides and the demand for environmentally friendly compounds have driven the focus to detailed studies of the environmental destination of these compounds. Degradation by hydrolysis of pesticides, when released into the soil, can result in the formation of metabolites with potentially adverse effects on the environment. Moving in this direction, we investigated the mechanism of acid hydrolysis of the herbicide ametryn (AMT) and predicted the toxicities of metabolites through experimental and theoretical approaches. The formation of ionized hydroxyatrazine (HA) occurs with the release of the SCH3- group and the addition of H3O+ to the triazine ring. The tautomerization reactions privileged the conversion of AMT into HA. Furthermore, the ionized HA is stabilized by an intramolecular reaction that provides the molecule in two tautomeric states. Experimentally, the hydrolysis of AMT was obtained under acidic conditions and at room temperature with HA as the main product. HA was isolated in a solid state through its crystallization as organic counterions. The mechanism of conversion of AMT to HA and the experimental investigation of the reaction kinetics allowed us to determine the dissociation of CH3SH as the rate-controlling step in the degradation process that culminates in a half-life between 7 and 24 months under typical acid soil conditions of the Brazilian Midwest – region with strong agricultural and livestock vocation. The keto and hydroxy metabolites showed substantial thermodynamic stability and a decrease in toxicity compared to AMT. We hope that this comprehensive study will support the understanding of the degradation of s-triazine-based pesticides.

Tautomerization reactions of thiobarbituric acid: A detailed kinetic study using combined canonical variational transition state theory and QTAIM approach

AbstractThe kinetics of tautomerization reactions of thiobarbituric acid were thoroughly investigated at the B3LYP/6‐311+G(3df,2p) level of theory and elevated temperatures from 260 to 1000 K. The kinetic parameters were determined by employing canonical variational transition state theory (CVT). The quantum tunneling effect was included by centrifugal‐dominant small‐curvature semiclassical adiabatic ground‐state approximation method. Intrinsic reaction coordinate (IRC) analysis was performed to certify a unique connection from an obtained transition state configuration to optimized structures of reactant and products. The reaction forces and reaction force constants were computed across the IRC of each reaction. Then, using extremums of reaction forces, each reaction was partitioned into three stages containing reactant, transition state, and product stages. The extent of reactions was followed along with three reaction stages. The dependence of kinetic parameters and curvature of Arrhenius plots on temperature were investigated and discussed in the framework of CVT. To further unveil the mechanism of the reactions, the quantum theory of atoms in molecules was employed. To do this aim, QTAIM descriptors on the bond critical point (BCP) of involved bonds including the density of electrons, Laplacian of the density of electrons, Lagrangian kinetic energy, potential energy, and energy density were computed and surveyed along with reaction extent through IRC.

Cu-Catalyzed Decarboxylative Annulation of N-Phenylglycines with Maleimides: Synthesis of 1H-Pyrrolo[3,4-c]quinoline-1,3(2H)-diones

A novel protocol for the construction of functionalized 1H-pyrrolo[3,4-c]quinoline-1,3(2H)-diones (PQLs, 3) from N-phenylglycines and maleimides was developed. The cascade reaction was enabled by heating a mixture of the two substrates in the presence of di-tert-butyl peroxide (DTBP) as an oxidant and anhydrous CuBr as a catalyst in chlorobenzene. Consequently, a diverse series of PQLs 3 were synthesized in moderate-to-good yields (43-73%). The synthesis of the PQLs was enabled via a one-pot cascade reaction that proceeded through subsequent oxidative decarboxylation, 1,2-addition, intramolecular cyclization, tautomerization, and aromatization reactions. This protocol can be used for the synthesis of functionalized PQLs via a one-pot oxidative decarboxylation annulation reaction rather than through a series of multistep reactions, making it suitable for both combinatorial and parallel syntheses of PQLs.