Rates Of Solvolysis Research Articles

A Bis-Boron Amino Acid for Positron Emission Tomography and Boron Neutron Capture Therapy.

Trifluoroborate boronophenylalanine (BBPA) is a boron amino acid analog of 4‑boronophenylalanine (BPA) but with a trifluoroborate group (-BF3-) instead of a carboxyl group (-COOH). Clinical studies have shown that 18F-labeled BBPA ([18F]BBPA) can produce high-contrast tumor images in positron emission tomography (PET). Beyond PET imaging, BBPA is a theranostic agent for boron neutron capture therapy (BNCT). Because BBPA possesses an identical chemical structure to BNCT and PET, it can potentially predict the boron concentration for BNCT using [18F]BBPA-PET. The synthesis of BBPA was achieved by selectively fluorinating the α-aminoborate compound, taking advantage of the varying rates of solvolysis of the B-F bond. The study showcased the high-contrast [18F]BBPA-PET imaging in various tumor models, highlighting its broad applicability for both [18F]BBPA-PET and BBPA-BNCT. [18F]BBPA-PET tumor uptake remains consistent across various doses, including those used in BNCT. This enables accurate estimation of the boron concentration in tumors using [18F]BBPA-PET. With its dual boron structure, BBPA increases boron concentration in tumor cells and tumor tissues compared to BPA. Thus, less boron carrier is needed. This study introduces a new theranostic boron carrier that enhances boron accumulation in tumors, predicts boron concentration, and enhances the accuracy and effectiveness of BNCT.

A Bis‐Boron Amino Acid for Positron Emission Tomography and Boron Neutron Capture Therapy

Trifluoroborate boronophenylalanine (BBPA) is a boron amino acid analog of 4‑boronophenylalanine (BPA) but with a trifluoroborate group (‐BF3‐) instead of a carboxyl group (‐COOH). Clinical studies have shown that 18F‐labeled BBPA ([18F]BBPA) can produce high‐contrast tumor images in positron emission tomography (PET). Beyond PET imaging, BBPA is a theranostic agent for boron neutron capture therapy (BNCT). Because BBPA possesses an identical chemical structure to BNCT and PET, it can potentially predict the boron concentration for BNCT using [18F]BBPA‐PET. The synthesis of BBPA was achieved by selectively fluorinating the α‐aminoborate compound, taking advantage of the varying rates of solvolysis of the B‐F bond. The study showcased the high‐contrast [18F]BBPA‐PET imaging in various tumor models, highlighting its broad applicability for both [18F]BBPA‐PET and BBPA‐BNCT. [18F]BBPA‐PET tumor uptake remains consistent across various doses, including those used in BNCT. This enables accurate estimation of the boron concentration in tumors using [18F]BBPA‐PET. With its dual boron structure, BBPA increases boron concentration in tumor cells and tumor tissues compared to BPA. Thus, less boron carrier is needed. This study introduces a new theranostic boron carrier that enhances boron accumulation in tumors, predicts boron concentration, and enhances the accuracy and effectiveness of BNCT.

Effects of Ionic Liquids on the Nucleofugality of Bromide.

The nucleofugality of bromide was measured in solvent mixtures containing ionic liquids. The solvolysis rate constants of the bromides of well-defined electrofuges were determined in mixtures containing different proportions of 1-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide in ethanol. Temperature-dependent kinetic studies allowed an explanation of the observed solvent effects in different mixtures in terms of interactions in solution. Using the solvolysis data, the nucleofugality of bromide in these systems was determined. Likewise, nucleofugality data for bromide were determined in mixtures containing high proportions of seven further ionic liquids. These data allowed quantification of the effects of both varying the amount of ionic liquid and the nature of ionic liquid components on the nucleofugality of bromide. Importantly, ionic liquid mixtures were shown to affect the nucleofugality in a manner similar to chloride, providing a method for predicting the effects of ionic liquids on other electrofuges. Further, the ionic liquids were shown to move the transition state earlier along the reaction coordinate, meaning that there is less charge development in the transition state.

Stereoselective Solvolysis in the Synthesis of Dorzolamide Intermediates.

The key intermediate in the synthesis of dorzolamide, (4S,6S)-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-ol-7,7-dioxide, can be obtained in the diastereoisomerically pure form in two straightforward steps starting from diastereoisomeric mixtures of cis/trans-(6S)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-yl acetate, regardless of their ratio. The reaction of crucial importance in this scheme is a remarkably stereoselective solvolysis of the acetate ester in an acetone/phosphate buffer mixture as the solvent system. Investigation of this so far unrecognized stereoselective reaction reveals that it proceeds via an SN1-like pathway as indicated by the correlation of the solvolysis rate constants with the YOTs values of different solvent mixtures and by trapping of the reaction intermediate with sodium azide. The structure of (4S,6S)-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-ol-7,7-dioxide was confirmed by single-crystal X-ray analysis.

Imidazolium-methylene-trifluoroborate: A novel radioprosthetic group validated with preclinical 18 F-Positron Emission Tomography imaging of Prostate Specific Membrane Antigen in mice.

Organotrifluoroborates have gained acceptance as radioprosthetic groups for radiofluorination. Of these, the zwitterionic prosthetic group "AMBF3 " with a quaternary dimethylammonium ion dominates the trifluoroborate space. Herein, we report on imidazolium-methylene trifluoroborate (ImMBF3 ) as an alternative radioprosthetic group and report on its properties in the context of a PSMA-targeting EUK ligand that was previously been conjugated to AMBF3 . The ImMBF3 is readily synthesized from imidazole and conjugated via CuAAC "click" chemistry to give a structure similar to PSMA-617. 18 F-labeling proceeded in one step per our previous reports and imaged in LNCaP-xenograft bearing mice. The [18 F]-PSMA-617-ImMBF3 tracer proved to be less polar (LogP7.4 = -2.95 ± 0.03) while showing a significantly lower solvolytic rate (t1/2 = 8100 min) and slightly higher molar activity (Am) at 174 ± 38 GBq/μmol. Tumor uptake was measured at 13.7 ± 4.8%ID/g and a tumor:muscle ratio of 74.2 ± 35.0, tumor:blood ratio of 21.4 ± 7.0, tumor:kidney ratio of 0.29 ± 0.14, and tumor:bone ratio of 23.5 ± 9.5. In comparison with previously reported PSMA-targeting EUK-AMBF3 conjugates, we have altered the LogP7.4 value, tuned the solvolytic half-life of the prosthetic, and increased radiochemical conversion while achieving similar tumor uptake, contrast ratios, and molar activities compared with AMBF3 bioconjugates.

Mechanisms of the Aqueous Solvolysis of the Ring-opening of the Lactone Ring of Goniodomin A

The phycotoxin Goniodomin A is a Dinoflagellate of the Alexandrium genus and is a macrocyclic lactone. It is found widely in sea water and is known to open slowly the lactone in water. The cleavage of the lactone is sensitive to the pH of the water. As one changes the pH from ~6 to 8 its solvolytic rate dramatically increases. Treatment of kinetic data previously published indicates that there are two competing first-order reactions, an SN­1 and an intramolecular SN2, which is a pseudo first-order reaction.

Mechanism of solvolysis of substituted benzyl chlorides in aqueous ethanol

The mechanism of solvolyses of activated ortho-, meta- and para-substituted benzyl chlorides in aqueous ethanol has been studied by using the Hammett-Brown and Yukawa-Tsuno treatments as well as by correlating logarithms of solvolysis rate constants with relative stabilities of corresponding benzyl carbocations in water calculated at the IEFPCM-M06–2X/6-311+G(3df,3pd) level of theory. Benzyl chlorides containing strong conjugative electron-donors in the para-position solvolyze by the SN1 mechanism, whereas other activated benzyl chlorides solvolyze by the SN2 mechanism via loose transition states.

Effects of Ionic Liquids on the Nucleofugality of Chloride.

The nucleofugality of chloride has been measured in solvent mixtures containing ionic liquids for the first time, allowing reactivity in these solvents to be put in context with molecular solvents. Using well-described electrofuges, solvolysis rate constants were determined in mixtures containing different proportions of ethanol and the ionic liquid 1-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide; the different solvent effects observed as the mixture changed could be explained using interactions of the ionic liquid with species along the reaction coordinate, determined using temperature dependent kinetic studies. The solvolysis data allowed determination of the nucleofugality of chloride in these mixtures, which varied with the proportion of salt in the reaction mixture, demonstrating quantitatively the importance of the amount of ionic liquid in the reaction mixture in determining reaction outcome. Nucleofugality data for chloride were determined in seven further ionic liquids, with the reactivity shown to vary over more than an order of magnitude. This outcome illustrates that the components of the ionic liquid are critical in determining reaction outcome. Overall, this work quantitatively extends the understanding of solvent effects in ionic liquids and demonstrates the potential for such information to be used to rationally select an ionic liquid to control reaction outcome.

Direct catalytic conversion of bagasse fibers to furan building blocks in organic and ionic solvents

The applications of lignocellulosic wastes to produce a wide variety of products, including biochemicals, biomaterials, and biofuels, can be an effective solution for utilizing these valuable waste materials. In this study, the production of furan building blocks from bagasse fibers was investigated by treating unbleached fibers with NMMO, [Bmim]Cl, and TMAH at different temperatures using AlCl3 and CrCl2 as the catalysts. The resulted liquors were extracted with CH2Cl2 to obtain furan rich fraction. Analysis of extracted fractions with GC/MS indicates the production of various furanic compounds due to catalytic solvolysis with different solvents at elevated temperatures. 2(3H)-Furanone and 2-methyl-THF were the main products of catalytic treatment of bagasse fibers with NMMO. Treatment by [Bmim]Cl resulted in 2,5-dihydro furanone as the dominant product at elevated temperatures. Furan carboxylic acid methyl ester and 2,5-furan dicarboxylic acid dimethyl ester were the main TMAH reaction products with unbleached fibers. The results indicate that the type of solvent affects the solvolysis rate and dehydration of cellulose to furanic compounds. Moreover, increasing the temperature led to an increase in the formation of the furanic compounds.Graphical abstract

Properties of the tert-butyl halide solvolysis transition states.

We have obtained properties (or descriptors) of the transition states in the solvolysis of tert-butyl chloride, bromide and iodide. We show that all three transition states, in both protic and in aprotic solvents, are highly dipolar and are strong hydrogen bond acids and strong hydrogen bond bases, except for the tert-butyl iodide transition state in aprotic solvents, which has a rather low hydrogen bond acidity. Thus, the transition states are stabilized by solvents that are hydrogen bond bases (nucleophiles) and are hydrogen bond acids (electrophiles). We show also that the partition of the transition states between water and solvents is aided by both nucleophilic and electrophilic solvents and conclude that the rate of solvolysis of the three halides is increased by both nucleophilic and electrophilic solvents.

The Influence of a Terminal Chlorine Substituent on the Kinetics and the Mechanism of the Solvolyses of n-Alkyl Chloroformates in Hydroxylic Solvents.

A previous study of the effect of a 2-chloro substituent on the rates and the mechanisms of the solvolysis of ethyl chloroformate is extended to the effect of a 3-chloro substituent on the previously studied solvolysis of propyl chloroformate and to the effect of a 4-chloro substituent on the here reported rates of solvolysis of butyl chloroformate. In each comparison, the influence of the chloro substituent is shown to be nicely consistent with the proposal, largely based on the application of the extended Grunwald–Winstein equation, of an addition-elimination mechanism for solvolysis in the solvents of only modest solvent ionizing power, which changes over to an ionization mechanism for solvents of relatively high ionizing power and low nucleophilicity, such as aqueous fluoroalcohols with an appreciable fluoroalcohol content.

Correlation analysis of solvent effects on solvolysis rates: What can the empirical parameters of solvents actually say?

AbstractThe logarithm of heterolysis rates of 4‐methoxyneophyl tosylate, Et3CBr,tert‐BuCl, andtert‐BuBr in a set of 12 to 28 hydrogen‐bond (HB) and non‐HB donor solvents are correlated to four sets of solvent parameters: (a)ET(30), (b)π*,α,β, (c)SP,SdP,SA,SB, and (d)DI,ES,α1,β1. Disjointed results are found for Et3CBr because of an insufficient diversity of solvents. For the other solvolyses, the determination coefficientsr2are good to excellent, the gas‐phase values are fairly predicted, and the contributions of various intermolecular forces to the global solvent effect agree satisfactorily within the four solvent sets. However, the most complete description of the solvent effect is given by the four‐parameter sets because their parameters refer to a single intermolecular force, whereasET(30) andπ*correspond to a fixed blend of solute/solvent interactions. For the application of theDI,ES,α1, andβ1set to correlatetert‐BuCl solvolysis,r2= .976, lgk(gas) = −18.6 (experimental −19.3), and the contributions of HB donation (α1), electrostatic forces (ES), and dispersion‐induction (DI) to the solvent effect amounts to 59%, 21%, and 14%, respectively. The dependence of rates on the solvent HB basicity is nearly zero. The inclusion of the solvent cohesive energy density parameterinto the correlation equations does not improve these correlations.

Activation Parameter and Solvent effect on solvolysis of Ethyl benzoate in Aquo-organic Solvent System

The rate of solvolysis of ethyl benzoate was estimated volumetrically over the temperature range of 20°c to 40°c.in water-methanol mixture at different composition. The depletion and enhancement in value of isocomposition activation energy and iso-dielectric activation shows solvation in transition state and de-solvation in initial state respectively. The effect of solvent on reaction rate was tested in term of activation parameter. Simultaneous decrease in values of δH* and δS* with increase in value of δG* with solvent composition show that the reaction is Enthalpy domination and Entropy controlled. There is weak interaction between solvent and solute because the values of iso-kinetic temperature is less than 300 K/Mole2

The controversy about nonclassical ions: Finished too early?

AbstractThe debate on nonclassical ions centered almost exclusively on the behavior of 2‐norbornyl esters. The hallmark of a nonclassical charge distribution in solvolysis reactions was always seen in the seemingly exceptional fast reaction of the 2‐exo‐derivatives, with slow rates of the endo‐esters. While the nonclassical bridged structure of the free norbornyl ion has been unequivocally established, possible steric contributions to the rate differences in solution remained a matter of debate. Many formerly used solvents were less suited to exhibit uniform reaction mechanisms; the most appropriate solvent hexafluorisopropanol was introduced rather late. Solvolysis rates of many cyclic esters including medium rings can be predicted by force field calculated strain energy differences ΔSIsp3/sp2 between sp3 and sp2 states. Large deviations from the correlation are observed for 2‐tosyloxy norbornane‐ and for 17‐tosyloxy steroids; they indicate that both nonclassical charge delocalization and steric hindrance play a major role for the reactivity differences. These reach an unprecedented rate constant ratio of >30.000 between, eg, the 17‐steroid epimers, much larger than the ratio of 1.550 in 2‐norbornyl reactions. The presence of alkyl groups or hydrogen antiperiplanar to the leaving group can lead to extreme reactivities by 1,2‐shifts or Wagner‐Meerwein rearrangement if asymmetric bridged transition states can occur which approach the stability of tertiary cations. The long controversy about nonclassical ions illustrates how progress in science can deviate significantly from the ideal pathways lined out by Karl Popper.

Correlation of the rates of solvolysis of α-bromoisobutyrophenone using both simple and extended forms of the Grunwald-Winstein equation and the application of correlation analysis to related studies.

A Grunwald-Winstein treatment of the specific rates of solvolysis of α-bromoisobutyrophenone in 100% methanol and in several aqueous ethanol, methanol, acetone, 2,2,2-trifluoroethanol (TFE), and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) mixtures gives a good logarithmic correlation against a linear combination of NT (solvent nucleophilicity) and YBr (solvent ionizing power) values. The l and m sensitivity values are compared to those previously reported for α-bromoacetophenone and to those obtained from parallel treatments of literature specific rate values for the solvolyses of several tertiary mesylates containing a C(=O)R group attached at the α-carbon. Kinetic data obtained earlier by Pasto and Sevenair for the solvolyses of the same substrate in 75% aqueous ethanol (by weight) in the presence of silver perchlorate and perchloric acid are analyzed using multiple regression analysis.

Correlation analysis of the rates of solvolysis of 4-bromopiperidine: a reaction following a Grob fragmentation pathway.

A Grunwald-Winstein treatment of the specific rates of solvolysis of 4-bromopiperidine gives for aqueous ethanol, methanol, acetone, and dioxane a very good logarithmic correlation against the YBr solvent ionizing power values with a slope (m value) of 0.46±0.02, consistent with the operation of a synchronous Grob fragmentation mechanism. When the organic component of the solvent is 2,2,2-trifluoroethanol (TFE), the data points show a negative deviation, consistent with an appreciable deactivating interaction of the acidic TFE component of the solvent with the lone-pair of electrons present on the nitrogen.

Impact of Electronic Effects on the Nucleofugality of Leaving Groups

A short review of the development of nucleofugality and electrofugality scales based on solvolysis rates of benzhydryl derivatives is presented. Accordingly, the rate of the heterolytic step in the SN1 displacement reaction and the leaving group ability (nucleofugality) in a given solvent are related with the special linear free-energy relationship (LFER) equation: log k = s f (N f + E f). The impact of electronic effects in the leaving group (nucleofuge) on the overall SN1 reactivity of the substrate is given. The importance of inductivity, resonance, polarity and field effects in the leaving group moiety in the transition state is analyzed. Also, the effect of the negative hyperconjugation and the influence of other electronic effects in the leaving group on the height of the reaction intrinsic barrier are considered.1 Introduction2 Development of the Nucleofugality Scale3 Inductive and Resonance Effects4 Negative Hyperconjugation5 Intrinsic Barrier6 Conclusions

Electronic Properties of Triazoles. Experimental and Computational Determination of Carbocation and Radical-Stabilizing Properties.

Three fluorobenzenes substituted with meta-triazole groups have been prepared, and 19F chemical shifts indicate that these triazole groups are all inductively electron-withdrawing in character, with the 1,5-triazole being the most electron-withdrawing. σ+ values for these three triazoles have also been determined from solvolysis rates of substituted cumyl trifluoroacetates. When substituted in the para-position, the 1,4 and the 2,4-triazoles are cation-stabilizing, whereas the 1,5-triazole is carbocation-destabilizing. γ+ values indicate that the 1,4 triazole group is cation-stabilizing relative to the phenyl group, albeit the 1,5 triazole is significantly destabilizing relative to phenyl. These studies all suggest that the 1,5-triazole group exerts a strong electron-withdrawing effect on carbocations that is not offset by a resonance effect. The three triazole groups all enhance the methylenecyclopropane rearrangement rate and are therefore radical stabilizers. The smallest stabilizing effect is seen for the 1,5-triazole, and this is attributed to the triazole group being twisted out of conjugation in the developing benzylic radical. Finally, the anionic triazole group is the most effective radical-stabilizing group. Computational studies indicate that these triazole groups all stabilize benzylic radicals by a spin delocalization mechanism.

Spectroscopic investigation of bio-mimetic solvolysis of 6-(N,N-dimethylamino)-2,3-naphthalic anhydride in confined nanocavities.

Enzymes are biological catalysts that can vastly accelerate the reaction rate of a substrate by accommodating it within the active site. The local environment provided by the active site of a natural catalyst causes a significant rate-enhancement of the reaction as compared to that without catalyst. The solvolysis reaction of a 6-(N,N-dimethylamino)-2,3-naphthalic anhydride probe is investigated using UV-Vis and fluorescence spectroscopy in pure alcohols and in bio-mimetic nano-sized environments like surfactants, macrocyclic hosts and protein nanocavities. The solvolysis rate in alcohols is found to be regulated directly by the alkyl chain length and follows Arrhenius dependence. The hydrolysis rate of the probe in water under physiological conditions (pH 7.4, at 25 °C) is very slow. However, under identical conditions, the rate can be accelerated significantly by protein and supramolecular nanocavities. Therefore, such fundamental kinetic analysis of the understanding of this bio-mimetic solvolysis will allow us to design a novel probe-drug conjugate with efficient controlled-release and function.

Revisiting the Reactions of t‐BuX (X = Br, I) with Monoalcohols: A Mechanistic Analysis through Numerical Integration and Nonlinear Regression Methods

ABSTRACTThe reactions of two tertiary butyl halides, i.e., t‐BuBr and t‐BuI, with monoalcohols (methanol, i‐propanol, and t‐butanol) have been studied at several temperatures during extended periods of time to acquire kinetic data for both the solvolytic step and the subsequent reactions. Reaction progress was followed by conductimetry, and calibration curves were obtained for all systems under study to derive concentration versus time curves for the significant intermediate species, the formed acid, HX. The GMS comprehensive mechanism, previously proposed by Gonçalves, Martins, and Simões for these reactions, was successfully tested using numerical integration associated with nonlinear regression, confirming the predicted distinct behaviors for methanol (and for that matter also for primary alcohols), secondary, and tertiary alcohols. Results show that accurate rate constants could be obtained in all cases and that the step that follows solvolysis can affect significantly the solvolytic rate constant and therefore any consequent reliable mechanistic analysis.