Quantitative Structure-reactivity Relationship Research Articles

Structure-Reactivity Relationships in Borane-Based FLP-Catalyzed Hydrogenations, Dehydrogenations, and Cycloisomerizations.

ConspectusThe activation of molecular hydrogen by main-group element catalysts is an extremely important approach to metal-free hydrogenations. These so-called frustrated Lewis pairs advanced within a short period of time to become an alternative to transition metal catalysis. However, deep understanding of the structure-reactivity relationship is far less developed compared to that of transition metal complexes, although it is paramount for advancing frustrated Lewis pair chemistry.In this Account, we provide detailed insight into how Lewis acidity and Lewis basicity correlate to reactivity. The reactivity of frustrated Lewis pairs will be systematically discussed in context with selected reactions. The influence of major electronic modifications of the Lewis pairs is correlated with the ability to activate molecular hydrogen, to channel reaction kinetics and reaction pathways, or to achieve C(sp3)-H activations.First, we will describe how we entered this emerging field of research after quickly realizing that information was lacking on how the reactivity changes with modification of the frustrated Lewis pair. This led us to the development of a qualitative and quantitative structure-reactivity relationship in metal-free imine hydrogenations. The imine hydrogenation was utilized as the model reaction to experimentally determine the activation parameters of the FLP-mediated hydrogen activation for the first time. This kinetic study revealed autoinduced catalytic profiles when Lewis acids weaker than tris(pentafluorophenyl)borane were applied, opening up to study the Lewis base dependency within one system. With this knowledge of the interplay between Lewis acid strength and Lewis basicity, we developed methods for the hydrogenation of densely functionalized nitroolefins, acrylates, and malonates. Here, the reduced Lewis acidity needed to be counterbalanced by a suitable Lewis base to ensure efficient hydrogen activation. The opposite measure was necessary for the hydrogenation of unactivated olefins. For these, comparably less electron-releasing phosphanes were required to generate strong Brønsted acids by hydrogen activation. These systems displayed highly reversible hydrogen activation even at temperatures as low as -60 °C. A systematic study of these systems enabled the development of acceptorless dehydrocouplings of amines with silanes and dehydrogenations of aza-heterocycles by C(sp3)-H activations. Furthermore, the C(sp3)-H and π-activation was utilized to achieve cycloisomerizations by carbon-carbon and carbon-nitrogen bond formations. Lastly, new frustrated Lewis pair systems featuring weak Lewis bases as active components in the hydrogen activation were developed for the reductive deoxygenation of phosphane oxides and carboxylic acid amides.

Hansch’s analysis application to chalcone synthesis by Claisen–Schmidt reaction based in DFT methodology

Chalcones are bioactive compounds obtained from either natural sources or synthetic procedures and widely used due to their several biological properties. The most common experimental methodology in obtaining these compounds is Claisen–Schmidt reaction, which is a particular type of aldolic condensation. In this work, we have synthesized 23 chalcones and by density functional theory (DFT) calculation, we have studied the difference in reactivity of the several benzaldehydes and their effects on the yield of this reaction. From molecular orbital descriptors were obtained two quantitative structure–reactivity relationship (QSRR) models based on Hansch’s analysis. The results of this study showed that, for the most benzaldehydes (15 of 23 compounds), their reactivity was correlated with LUMO energy and global Electrophilicity Index (ω) values, which are determined in the first step of Claisen–Schmidt condensation mechanism (nucleophilic addition). Likewise, for the smallest group of benzaldehydes, their reactivity was related to their HOMO and ΔL − H (LUMO − HOMO) energies, which were determined in the second step of the mechanism (trans-elimination). This is the first report of a QSRR model analyzing the yield of chalcone synthesis based on DFT methodology.

Chiral Brønsted Acid-Catalyzed Enantioselective α-Amidoalkylation Reactions: A Joint Experimental and Predictive Study.

Enamides with a free NH group have been evaluated as nucleophiles in chiral Brønsted acid‐catalyzed enantioselective α‐amidoalkylation reactions of bicyclic hydroxylactams for the generation of quaternary stereocenters. A quantitative structure–reactivity relationship (QSRR) method has been developed to find a useful tool to rationalize the enantioselectivity in this and related processes and to orient the catalyst choice. This correlative perturbation theory (PT)‐QSRR approach has been used to predict the effect of the structure of the substrate, nucleophile, and catalyst, as well as the experimental conditions, on the enantioselectivity. In this way, trends to improve the experimental results could be found without engaging in a long‐term empirical investigation.

Development of Predictive Models for the Degradation of Halogenated Disinfection Byproducts during the UV/H2O2 Advanced Oxidation Process.

Previous research has demonstrated that the reverse osmosis and advanced oxidation processes (AOPs) used to purify municipal wastewater to potable quality have difficulty removing low molecular weight halogenated disinfection byproducts (DBPs) and industrial chemicals. Because of the wide range of chemical characteristics of these DBPs, this study developed methods to predict their degradation within the UV/H2O2 AOP via UV direct photolysis and hydroxyl radical (•OH) reaction, so that DBPs most likely to pass through the AOP could be predicted. Among 26 trihalomethanes, haloacetonitriles, haloacetaldehydes, halonitromethanes and haloacetamides, direct photolysis rate constants (254 nm) varied by ∼3 orders of magnitude, with rate constants increasing with Br and I substitution. Quantum yields varied little (0.12-0.59 mol/Einstein), such that rate constants were driven by the orders of magnitude variation in molar extinction coefficients. Quantum chemical calculations indicated a strong correlation between molar extinction coefficients and decreasing energy gaps between the highest occupied and lowest unoccupied orbitals (i.e., ELUMO-EHOMO). Rate constants for 37 trihalomethanes, haloacetonitriles, haloacetaldehydes, halonitromethanes, haloacetamides, and haloacetic acids with •OH measured by gamma radiolysis spanned 4 orders of magnitude. Based on these rate constants, a quantitative structure-reactivity relationship model (Group Contribution Method) was developed which predicted •OH rate constants for 5 additional halogenated compounds within a factor of 2. A kinetics model combining the molar extinction coefficients, quantum yields and •OH rate constants predicted experimental DBP loss in a lab-scale UV/H2O2 AOP well. Highlighting the difficulty associated with degrading these DBPs, at the 500-1000 mJ/cm2 UV fluence applied in potable reuse trains, 50% removal would be achieved generally only for compounds with several -Br or -I substituents, mostly due to higher molar extinction coefficients.

Room-temperature and temperature-dependent QSRR modelling for predicting the nitrate radical reaction rate constants of organic chemicals using ensemble learning methods

Experimental determinations of the rate constants of the reaction of NO3 with a large number of organic chemicals are tedious, and time and resource intensive; and the development of computational methods has widely been advocated. In this study, we have developed room-temperature (298 K) and temperature-dependent quantitative structure–reactivity relationship (QSRR) models based on the ensemble learning approaches (decision tree forest (DTF) and decision treeboost (DTB)) for predicting the rate constant of the reaction of NO3 radicals with diverse organic chemicals, under OECD guidelines. Predictive powers of the developed models were established in terms of statistical coefficients. In the test phase, the QSRR models yielded a correlation (r2) of >0.94 between experimental and predicted rate constants. The applicability domains of the constructed models were determined. An attempt has been made to provide the mechanistic interpretation of the selected features for QSRR development. The proposed QSRR models outperformed the previous reports, and the temperature-dependent models offered a much wider applicability domain. This is the first report presenting a temperature-dependent QSRR model for predicting the nitrate radical reaction rate constant at different temperatures. The proposed models can be useful tools in predicting the reactivities of chemicals towards NO3 radicals in the atmosphere, hence, their persistence and exposure risk assessment.

Modeling the reactivities of hydroxyl radical and ozone towards atmospheric organic chemicals using quantitative structure-reactivity relationship approaches.

The persistence and the removal of organic chemicals from the atmosphere are largely determined by their reactions with the OH radical and O3. Experimental determinations of the kinetic rate constants of OH and O3 with a large number of chemicals are tedious and resource intensive and development of computational approaches has widely been advocated. Recently, ensemble machine learning (EML) methods have emerged as unbiased tools to establish relationship between independent and dependent variables having a nonlinear dependence. In this study, EML-based, temperature-dependent quantitative structure-reactivity relationship (QSRR) models have been developed for predicting the kinetic rate constants for OH (kOH) and O3 (kO3) reactions with diverse chemicals. Structural diversity of chemicals was evaluated using a Tanimoto similarity index. The generalization and prediction abilities of the constructed models were established through rigorous internal and external validation performed employing statistical checks. In test data, the EML QSRR models yielded correlation (R (2)) of ≥0.91 between the measured and the predicted reactivities. The applicability domains of the constructed models were determined using methods based on descriptors range, Euclidean distance, leverage, and standardization approaches. The prediction accuracies for the higher reactivity compounds were relatively better than those of the low reactivity compounds. Proposed EML QSRR models performed well and outperformed the previous reports. The proposed QSRR models can make predictions of rate constants at different temperatures. The proposed models can be useful tools in predicting the reactivities of chemicals towards OH radical and O3 in the atmosphere.

ChemInform Abstract: Regioselective Construction of 1,3‐Diazaheterocycle Fused [1,2‐a][1,8]Naphthyridine Derivatives via Cascade Reaction of Quinolines with Heterocyclic Ketene Aminals: A Joint Experimental—Computational Approach

Abstract25 examples

Photodegradation of iodinated trihalomethanes in aqueous solution by UV 254 irradiation

Photodegradation of 6 iodinated trihalomethanes (ITHMs) under UV irradiation at 254 nm was investigated in this study. ITHMs underwent a rapid photodegradation process through cleavage of carbon-halogen bond with first-order rate constants in the range of 0.1–0.6 min−1. The effects of matrix species including nitrate, humic acid (HA), bicarbonate, sulfate, and chloride were evaluated. The degradation rate increased slightly in the presence of nitrate possibly due to generation of HO at a low quantum yield via direct photolysis of nitrate, while HA lowered the photodegradation rate of ITHMs due to its competitive UV absorption. Moreover, bicarbonate, sulfate, and chloride had no significant effect on photodegradation kinetics, as there is no UV absorption for these 3 species. In the study using surface water, treated water, and secondary effluent from a wastewater treatment plant, high turbidity and natural organic matters present in the water inhibited the photodegradation of ITHMs. The degradation rates of 6 ITHMs in UV/H2O2 system were rather comparable and significantly higher than those achieved in the UV system without H2O2. To develop a quantitative structure–reactivity relationship (QSAR) model, the logarithm of measured first-order rate constants was correlated with a number of molecular descriptors. The best correlation was obtained with a combination of 3 molecular descriptors, namely the bond strength of carbon-halogen to be broken in the rate-determining step, steric and electronic effects of all substituents to the carbon center.

Quantitative structure–reactivity study on sulfonation of amines, alcohols and phenols

Quantitative structure–reactivity relationship (QSRR) can be considered as a variant of quantitative structure property relationship (QSPR) studies, where the chemical reactivity of reactants in a specified chemical reaction is related to chemical structure. As follows, the sulfonation reaction yield of 24 amines, alcohols and phenols with sulfonyl chloride was studied by QSRR. Quantum chemical calculations (b3lyp/6-31+g (d)) were carried out to obtain the optimized geometry. The suitable set of molecular descriptors was calculated to represent the molecular structures of compounds, such as constitutional, topological, geometrical, electrostatic and quantum-chemical descriptors. The genetic algorithm (GA) was applied to select the variables that resulted in the best-fitted models. After the variable selection, multiple linear regression (MLR) was utilized to construct linear QSRR models. The maximum relative error in prediction (5.26) showed that the predictive ability of the model was satisfactory and it can be used for designing similar reactants with efficient sulfonation reaction.

Regioselective construction of 1,3-diazaheterocycle fused [1,2-a][1,8]naphthyridine derivatives via cascade reaction of quinolines with heterocyclic ketene aminals: a joint experimental–computational approach

A one-step, transition-metal-free protocol, involving facile post-treatment, for the regioselective synthesis of 1,3-diazaheterocycle fused [1,2-a][1,8]naphthyridine derivatives (3) from 2-chloroquinoline-3-carbaldehydes (ClQuAlds) (1) and heterocyclic ketene aminals (HKAs) (2) was developed via a joint experimental-computational approach. The computational prediction of the reactivity of two series of synthons was applied in the process of optimizing the reaction conditions, which relied on density functional theory (DFT) calculations together with concepts of frontier molecular orbital (FMO) theory and quantitative structure-reactivity relationship (QSRR) presumptions. The combined results enabled the proposal of a pre-synthetic prediction of global reactivity. The fully consistent results of the synthetic experiments with the in silico evaluation confirmed the rationality, effectiveness, and practicability of the new strategy. Notably, the joint method is not limited to the laboratory, but has applications ranging from routine to industry. This approach is likely to yield numerous insights to accelerate HKA-related synthetic chemistry that can be extended to numerous heterocycles. It thus opens up a novel entry towards rapidly investigating the reactivity of novel synthons with unique properties, a further step towards exploiting cascade reactions by avoiding the futile waste of time and resources.

In silico prediction of free-radical chain transfer constants for some organic agents in styrene polymerization

In the present work, quantitative structure–reactivity relationship (QSRR) approaches were used to predict the chain transfer constant log C x of some organic compounds as chain transfer agents in free-radical polymerization of styrene. The energy of the lowest unoccupied molecular orbital, hydrogen-bonding-dependent hydrogen donor charged area, first-order Kier and Hall index, final heat of formation/number of atoms, count of H donor sites, and Min>(0.1) bond order of a C atom were selected as the most relevant variables from the pool of calculated descriptors by the stepwise multiple regression feature selection method. Then, an artificial neural network and multiple linear regressions were utilized to construct the nonlinear and linear QSRR models. The standard errors in the prediction of log C x by the linear regression model were 0.641, 0.964, and 0.843 and by the neural network model were 0.049, 0.076, and 0.090 for training, internal, and external test sets, respectively. The predictivity of the artificial neural network model was further examined by cross-validation methods, which produce a Q 2 value of 0.85. The results of this study revealed the applicability of QSRR approaches in prediction of the chain transfer constant by using an artificial neural network.

A quantitative structure-reactivity relationship in N-acetyl oxazolidines: an electrostatic interaction controls rotamer population

The conformational population of Z and E isomers of the amide bond in N-acetyl oxazolidines is dictated by the electronic nature of the vicinal aryl ring. Experimental and theoretical data support a rationale based on a strong and stereodirecting charge-charge interaction that should be added to the arsenal of non-covalent interactions and whose influence can be more important than once thought.

ChemInform Abstract: New Aspects in the Chemistry of Some Cyclic Esters of Alkylphosphonates.

Abstract Several new methods for the synthesis of 2-alkyl-2-oxo-1,3,2-dioxa-phosphorinane (1) and -phosphepane (2) were conducted based on Arbuzov rearrangement, alcoholysis of RP(o)Cl2 with glycol using dilution method or alkylation of cyclic phosphite under PTC condition. The solvent effect on the 31P NMR chemical shift and the characteristic behaviours of the 13C NMR spectra of 1 was investigated. It was found that compd 1 with R=CH3 existed in an equilibrium of e and a forms. The mass spectra of 1 and 2 showed that the ring opening was in competition with the cleavage of P-C bond. According to the fragmentation pathway, 1 can be classified in two categories involving ring opening and cleavage of C-C or P-C bond. For compd 2 the ring opening was a dominant process. Alkaline hydrolysis of 1 and 2 was studied in aqueous dioxane. The hydrolytic process is classified as an AE reaction. Quantitative structure-reactivity relationship was established by multiple regressionanalysis involving the rate constant ...

Quantitative structure–reactivity relationship studies on the catalyzed Michael addition reactions

AbstractQuantitative structure–reactivity relationship (QSRR) can be considered as a variant of quantitative structure–property relationship (QSPR) studies, where the chemical reactivity of reactants or catalysts in a specified chemical reaction is related to chemical structure. In this manner, the Michael addition of some different substrates using different catalysts (SDS, silica gel, and ZrOCl2) was subjected to structure–reactivity relationship, quantitatively. Multiple linear regression (MLR) and partial least square (PLS) were used to perform the QSRR analysis. The resulted models for different catalyzed reactions showed that the catalysts probably act in different mechanisms since the models obtained for the catalysts included different parameters from substrate and enones. Overall, it was found that the reactivity in Michael addition reactions is controlled by coulombic (dipole and charge) interactions as well as the orbital energetic parameters. In the presence of different catalysts, the relative importance of these parameters is changed and hence the catalytic activity is changed. Copyright © 2008 John Wiley & Sons, Ltd.

A quantitative structure–reactivity relationship in decarboxylative Claisen rearrangement reactions of allylic tosylmalonate esters

First-order rate constants have been determined for the decarboxylative Claisen rearrangement reactions at 293 K of substituted methyl (E)-3-phenyl-2-propenyl 2-tosylmalonate esters, which show a linear free-energy relationship indicative of the development of positive charge on the benzylic position in the sigmatropic rearrangement transition-state.

Competition kinetics using the UV/H 2O 2 process: a structure reactivity correlation for the rate constants of hydroxyl radicals toward nitroaromatic compounds

The rate constants for hydroxyl radical reaction toward a set of nitroaromatic substrates k S, have been measured at 25 °C using competition experiments in the UV/H 2O 2 process. For a given pair of substrates S 1 and S 2, the relative reactivity β (defined as k S1/ k S2) was calculated from the slope of the corresponding double logarithmic plot, i.e., of ln[S 1] vs. ln[S 2]. This method is more accurate and remained linear for larger conversions in comparison with the plots of ln[S 1] and ln[S 2] against time. The rate constants measured ranged from 0.33 to 8.6 × 10 9 M −1 s −1. A quantitative structure–reactivity relationship was found using the Hammett equation. Assuming σ values to be additive, a value of −0.60 was obtained for the reaction constant ρ. This value agrees with the high reactivity and the electrophilic nature of HO radical.

Quantitative reactivity model for the hydration of carbon dioxide by biomimetic zinc complexes.

A quantitative structure-reactivity relationship has been derived from the results of B3LYP/6-311+G calculations on the hydration of carbon dioxide by a series of zinc complexes designed to mimic carbonic anhydrase. The reaction mechanism found is general for all complexes investigated. The reaction exhibits a low (4-6 kcal/mol) activation energy and is exothermic by about 8 kcal/mol. The calculations suggest an equilibrium between Lipscomb and Lindskog intermediates. The effectiveness of the catalysis is a function of the nucleophilicity of the zinc-bound hydroxide and the nucleofugicity of the zinc-bound bicarbonate. Hydrogen bridging of the bicarbonate to NH moieties in the ligands also plays an important role.

Systematic modulation of Michael-type reactivity of thiols through the use of charged amino acids.

A quantitative structure-reactivity relationship for the Michael-type addition of thiols onto acrylates was determined. Several thiol-containing peptides were investigated by examining the correlation between the second-order rate constant of their addition onto PEG-diacrylate and the pK(a) of the thiols within a peptide. By introducing charged amino acids in close proximity to a cysteine, the pK(a) of the thiol was systematically modulated by electrostatic interactions. Positive charges from the amino acid arginine decreased the pK(a) of the thiol and accelerated the reaction with acrylates while negative charges from aspartic acids showed the opposite effect. A linear correlation between thiolate concentrations and kinetic constants was found, confirming the role of thiolates as the reactive species in this Michael-type reaction. The relevant factors influencing the reactivity were the sign and the number of the neighboring charges, while the position of these charges had little effect on reactivity. These results provide a basis for the rational design of peptides, where the kinetics and thus selectivity of protein/peptide conjugation with polymeric structures via Michael-type addition reactions can be controlled.

A QSRR treatment of solvent effects on the decarboxylation of 6-nitrobenzisoxazole-3-carboxylates employing molecular descriptors.

A quantitative structure-reactivity relationship (QSRR) study of the decarboxylation rates of 6-nitrobenzisoxazole-3-carboxylic acid (Kemp, D. S.; Paul, K. G. J. Am. Chem. Soc. 1975, 97, 7305). employing the CODESSA program correlates the effect of 24 solvents with theoretical descriptors to provide a straightforward interpretation of these solvent effects in terms of molecular parameters.

Transformation of benzonitriles in anaerobic sediment and in sediment extract

Transformations of para-substituted benzonitriles in sediment and in sediment extract were studied. In raw anaerobic sediment, most of the benzonitriles were transformed to benzoic acids without benzamide intermediates. Very slow disappearance of benzonitrile in autoclave-sterilized sediment was explained by the chemical hydrolysis, while relatively rapid decrease in γ-irradiation-sterilized sediment indicated another abiotic mechanism. Hence, extracted protein fraction from sediment active against benzonitrile was surveyed. The obtained active fraction transformed para-substituted benzonitriles to corresponding benzoic acids without any intermediates, which resembled reported nitrilase enzyme activity. Quantitative structure-reactivity relationship (QSRR) analyses of para-substituted benzonitrile transformation-rate constants in raw sediment and in sediment extract fraction indicated that both of them had some correlation with hydrophobicity. This contrasted with the chemical hydrolysis of these compounds, which was controlled by electronic substituent constant (Hammett σ P ). This was an encouraging sign that the obtained sediment extract fraction is possibly responsible at least for part of the reaction in raw sediment. Various reaction mechanisms are present for degradation of xenobiotics in anaerobic sediment. This study presented the possible abiotic mechanism attributable to protein fraction in sediment. Further studies are necessary to understand the total reaction mechanisms in aquatic sediment.