T. William Bentley

Structural effects on the solvolytic reactivity of carboxylic and sulfonic acid chlorides. Comparisons with gas-phase data for cation formation.

Kinetic data for solvolyses of 28 acid chlorides in 97% w/w trifluoroethanol (TFE)-water spanning over 10 (9) in rate constant at 25 degrees C are obtained directly or by short extrapolation from published values. G3 calculations of the energy required for cation formation in the gas phase are validated from proton affinities and from other experimental data. G3 calculations of heterolytic bond dissociation enthalpies (HBDEs) for formation of cations from acid chlorides in the gas phase show the following trends when compared with the solvolysis rate constants: (i) electron-rich sulfonyl chlorides and most carboxylic acid chlorides, including thione derivatives, give a satisfactory linear correlation with a significant negative slope; (ii) most sulfonyl chlorides and some chloroformates and thio derivatives have higher HBDEs and fit another correlation with a small, negative slope. A significant deviation is observed for the acyl series (RCOCl), for which both solvolysis rates and HBDEs increase in the order R = Bu ( t ) < Pr ( i ) < Et < Me. The deviation may be explained either by a prior hydration mechanism or preferably by electrostatic effects on the formation of small cations. The above results of structural effects support independent evidence from solvent effects that cationic ionization reaction pathways (with nucleophilic solvent assistance or S N2 character) are involved in the solvolyses of acid chlorides.

Quantitative Charge-Tags for Sterol and Oxysterol Analysis

BACKGROUND Global sterol analysis is challenging owing to the extreme diversity of sterol natural products, the tendency of cholesterol to dominate in abundance over all other sterols, and the structural lack of a strong chromophore or readily ionized functional group. We developed a method to overcome these challenges by using different isotope-labeled versions of the Girard P reagent (GP) as quantitative charge-tags for the LC-MS analysis of sterols including oxysterols. METHODS Sterols/oxysterols in plasma were extracted in ethanol containing deuterated internal standards, separated by C18 solid-phase extraction, and derivatized with GP, with or without prior oxidation of 3β-hydroxy to 3-oxo groups. RESULTS By use of different isotope-labeled GPs, it was possible to analyze in a single LC-MS analysis both sterols/oxysterols that naturally possess a 3-oxo group and those with a 3β-hydroxy group. Intra- and interassay CVs were <15%, and recoveries for representative oxysterols and cholestenoic acids were 85%-108%. By adopting a multiplex approach to isotope labeling, we analyzed up to 4 different samples in a single run. Using plasma samples, we could demonstrate the diagnosis of inborn errors of metabolism and also the export of oxysterols from brain via the jugular vein. CONCLUSIONS This method allows the profiling of the widest range of sterols/oxysterols in a single analytical run and can be used to identify inborn errors of cholesterol synthesis and metabolism.

Stoichiometric solvation effects. Part 1. New equations relating product selectivities to alcohol–water solvent compositions for hydrolyses of p-nitrobenzoyl chloride

Rate constants at 25 °C are reported for solvolyses of p-nitrobenzoyl chloride (1) in water, D2O, and in acetonitrile–water, ethanol–water and methanol–water mixtures, and activation parameters are reported for solvolyses in water and in 5% ethanol– and methanol–water. Product selectivities are reported at 25 °C for a wide range of ethanol–water and methanol–water solvent compositions. A general theory is developed for third order solvolytic reactions in alcohol–water mixtures, for which there are four competing reactions with the following rate constants: kaa where alcohol is nucleophile and general base; kaw where alcohol is nucleophile and water is general base; kwa where water is nucleophile and alcohol is general base; and kww where water is nucleophile and general base. Values of kaa, and kww can be obtained from the observed first order solvolysis rate constants in the pure solvents. Two independent equations including product composition and solvent stoichiometry are devised to evaluate the two ‘hidden’ rate constants, kwa and kaw, and first order rate constants for solvolyses of 1 in methanol– and ethanol–water mixtures are then calculated from the four third order rate constants and the solvent stoichiometry. The results indicate that medium effects, other than those determined by solvent stoichiometry, make only a minor contribution to the solvent dependence of the first order solvolysis rate constants. Stoichiometric solvation effects also account for solvolyses in acetone– and acetonitrile–water mixtures, if it is assumed that water is nucleophile and either water or the cosolvent acts as general base.

Stoichiometric solvation effects. Part 2. A new product–rate correlation for solvolyses of p-nitrobenzenesulfonyl chloride in alcohol–water mixtures

For reactions involving nucleophilic attack in alcohol–water mixtures, a linear relationship between the reciprocal of product selectivities (S) and the molar ratios of alcohol and water solvents can be derived, if it is assumed that the reactions are second-order in protic solvent (e.g., with one molecule of solvent acting as a nucleophile and the other as a general base). The relationship {1/S=(slope)([alcohol]/[water])+ intercept} fits the products of solvolyses of p-nitrobenzenesulfonyl chloride in aqueous ethanol and methanol at 25 °C (determined by refrigerated RP–HPLC) within the range from water to 80% v/v alcohol–water. From the slopes and intercepts of these product plots and the one observed rate constant for hydrolysis in pure water, the observed first-order rate constants in alcohol–water mixtures up to 90%(v/v) can be calculated satisfactorily, further supporting the validity of the derived linear relationship; the kinetic model includes three third-order rate constants: kww, where water acts as both nucleophile and general base; kwa, water acts as a nucleophile and alcohol acts as a general base; kaw, alcohol acts as a nucleophile and water acts as a general base. Inclusion of a fourth rate constant, kaa, where the alcohol acts as a nucleophile and a second molecule of alcohol acts as a general base, is necessary to account for solvolyses in 90–99% alcohol–water; kaa can be calculated from the observed first-order rate constants in pure alcohols. Independent values of kaw and kwa can be obtained from kaa and the slopes and intercepts of linear relationships between S and the molar solvent ratio [water]/[alcohol] within the range 90–99% alcohol–water. The dominant effect of solvent stoichiometry and the absence of other substantial medium effects is confirmed by the approximately constant third-order rate constants, calculated from the observed first-order rate constants in acetonitrile–, acetone– and dioxane–water mixtures.

Evidence against appreciable internal ion pair return in the solvolyses of tertiary aliphatic halides. Measurement of α-methyl/hydrogen rate ratios in hexafluoropropan-2-ol–water

A good linear correlation between the logarithms of rate constants for solvolyses of 1-adamantyl(I) and 2-methyl-2-adamantyl (III) chlorides is interpreted as evidence that these solvolyses proceed by the same mechanism, rate-determining formation of contact ion pairs. This interpretation conflicts with two previous interpretations based on β-deuterium kinetic isotope effects for solvolyses of tertiary substrates, (i) suggesting the occurrence of rate-determining elimination from contact ion pairs; (ii) claiming a linear correlation between log (CH3/H) and log (CH3/CD3) rate ratios, where log (CH3/H) is the logarithm of rate ratios for solvolyses of tertiary substrates (R1R2-CH3CX) and the corresponding secondary substrate (R1R2HCX). Kinetic techniques for relatively fast solvolyses are used to study reactions in 97% w/w hexafluoropropan-2-ol–water, where nucleophilic solvent assistance is small, and so carbocation stabilities can be evaluated kinetically. Reaction of 2-chloro-2-methyladamantane is 107.4 times more rapid than that of 2-chloroadamantane, in agreement with studies using more nucleophilic solvents. The corresponding rate ratio for 2-bromo-2-methylpropane and 2-bromopropane is only 106.2, a higher ratio than is obtained in more nucleophilic solvents. It is proposed that nucleophilic solvent assistance is significant even for solvolysis of propan-2-yl substrates in hexafluoropropan-2-ol. Kinetic data measured directly at 25° for 2-exo- and 2-endo-norbornyl methanesulphonates give an exo/endo rate ratio of 1.59 x 103, in agreement with results obtained by temperature extrapolations. Some of the factors influencing (or helping to prevent) internal ion pair return are discussed.

A general anionic mechanism for thermodynamic control of regioselectivity in N-alkylation and acylation of heterocycles

Abstract Regioselective alkylation of 1,2,4-triazole (Ia, IIa) to 1-alkyl derivatives (Ib) may occur by nucleophilic displacement of the triazole anion, is thermodynamically-controlled (shown by a free energy diagram), and the position of equilibrium is relatively insensitive to the nature of the alkyl group.

Dual reaction channels for solvolyses of acyl chlorides in alcohol–water mixtures

Rate constants are reported for solvolyses at 0 °C of trimethylacetyl chloride (3) in 90–30% v/v acetonitrile–, acetone–, ethanol– and methanol–water mixtures, of adamantane-1-carbonyl chloride (4) in 90–60% acetone–, ethanol– and methanol–water mixtures, and of cyclopropanecarbonyl chloride (5) in 90–40% acetone–water. Quantitative product data (acid and ester) are also reported for solvolyses of trimethylacetyl chloride in 98–20% ethanol– and methanol–water mixtures. Product selectivities (S) show maxima in 90–95% alcohol–water mixtures, similar to those, reported previously for solvolyses of p-chlorobenzoyl chloride (1a), benzoyl chloride (1b), 2,4,6-trimethylbenzenesulfonyl chloride (2a) and 4-methoxy-2,6-dimethylbenzenesulfonyl chloride. (2b). Using rate–rate profiles, logarithms of rate constants are dissected into the competing reaction channels. Given the sharp maxima in S that occur at different alcohol compositions for different substrates, and the link to ‘breaks’ in rate–rate profiles, the results are consistent with competing mechanisms having different rate-limiting steps. The competing mechanisms involve two broad reaction channels: (1) nucleophilic attack by one molecule of solvent assisted by a second molecule of solvent acting as a general base catalyst—consequently, in aqueous alcohols there are four mechanistic combinations operating simultaneously within this one reaction channel; (2) nucleophilic attack by solvent occurs via a carbocationic reaction within the SN2-SN1 mechanistic spectrum, involving for example, a solvent-separated ion pair intermediate (SN1 ) or a concerted nucleophilic attack (SN2).

Rearrangement of (1,2,4-Triazol-4-yl)ethanols to (1,2,4-Triazol-1-yl)ethanols

Abstract The mechanism of rearrangement of β-hydroxyethyl-(1,2,4-triazoles) has been shown using crossover experiments to be intermolecular and free energy profiles show that reactions are thermodynamically-controlled.

Role of hydroxyl concentrations in solvatochromic measures of solvent polarity of alcohols and alcohol-water mixtures-evidence that preferential solvation effects may be overestimated.

For single solvents, primary alcohols and water, there is a good linear correlation (r = 0.994) between the solvent polarity index ET(30) and the molar concentration of OH groups (or 1000/Vm, where Vm is the solvent molar volume). The corresponding correlations for alcohol-water mixtures are plots vs. the sum of molar concentrations of alcohol and water, alternatively expressed as plots of ET(30)vs. volume fraction. Our quantitative treatment is an extension of recent theoretical and experimental results. In contrast, previous studies of alcohol-water mixtures have relied on plots of ET(30)vs. mole fraction, and have overestimated the effect of preferential solvation of solvatochromic dyes by the more hydrophobic alcohols.

A relationship between selectivity and solvent composition for nucleophilic attack on carbocations in alcohol–water mixtures

Rate constants and products of solvolyses of p-methoxybenzyl chloride 1, chlorodiphenylmethane 2(Y = Z = H), chloro(4-chlorophenyl)phenylmethane 2(Y = H, Z = Cl) and chlorobis(4-chlorophenyl)methane 2(Y = Z = Cl) are reported in ethanol– and methanol–water mixtures at 25 °C. Product selectivities (S), defined by: S=[ether product][water]/[alcohol product][alcohol solvent] are related to four rate constants for reactions involving one molecule of solvent as nucleophile and another molecule of solvent as general base catalyst (e.g. kwa involves water as nucleophile and alcohol as general base, and kww, kaw and kaa are defined similarly). A linear relationship between 1/S and molar ratios of solvent 1/S=(kwa/kaw)([alcohol solvent]/[water])+kww/kaw is derived theoretically and validated experimentally for solvolyses of the above substrates from water up to 70% alcohol–water—in this range of solvents, the contribution from kaa can be neglected. For solvolyses of p-methoxybenzyl chloride, S is independent of pH between pH 2 and 12, S decreases when acetone is added but increases if acetonitrile is added and for 90% ethanol–water S increases with added LiCl and LiClO4 and increases further if acetonitrile is also present.