Rates Of Acid-catalyzed Hydrolysis Research Articles

Hydrolysis of imidazoline based corrosion inhibitor and effects on inhibition performance of X65 steel in CO2 saturated brine

The molecular characteristics of a TOFA/DETA based imidazoline inhibitor were evaluated by analysing the inhibitor protonation profile, the CMC and micelle size and the rate of acid-catalysed hydrolysis of the inhibitor to improve understanding of the corrosion inhibition performance of the main imidazoline component and its hydrolysis products. The ability of the TOFA/DETA imidazoline based corrosion inhibitor and its products of hydrolysis in retarding both uniform and localized corrosion were assessed and compared on wet-ground X65 carbon steel at 80 °C in CO2 saturated 3 wt % NaCl brines. The findings indicate that the imidazoline based inhibitor forms micellar solutions, with a characteristic micelle size of 18 ± 9 nm at the CMC (10 ± 1 ppm) in CO2 saturated 3 wt % NaCl brines, and that under such conditions (pH~4.1), the inhibitor is fully protonated which increases inhibitor solubility/dispersibility and enhances molecular adsorption of the positively charged imidazoline on the metal surface thereby improving inhibition performance. Hydrolysis of the imidazoline and amido-amine is acid-catalysed and the consumption of imidazoline follows a pseudo-first-order reaction mechanism with an activation energy of 72.0 ± 2.9 kJ mol-1. The study concludes that the pre-aged inhibitor has different effects on uniform and localized corrosion behavior of X65 carbon steel.

Synthesis and properties of the para-trimethylammonium analogues of green fluorescence protein (GFP) chromophore: The mimic of protonated GFP chromophore

At low pH, protons from the external, bulk solution can protonate the phenoxide group of the p-HBDI chromophore in wild-type green fluorescent protein (wtGFP) and its mutants, and likely continue to tentatively protonate the phenol hydroxyl group of the same chromophores. Because the protonated GFP chromophore is a transient, we prepare the stable p-trimethylammonium analogues (2a and 2b) of the GFP chromophore to mimic it and explore their properties. What we found is that the p-trimethylammonium analogues of the GFP chromophore have the highly electrophilic amidine carbon, blue-shifted electronic absorption, smaller molar absorptivity, smaller fluorescent quantum yield, and faster E-Z thermoisomerization rate. The amidine carbon of the p-trimethylammonium analogue (2b) of the GFP chromophore is the only site that is attacked by very weak nucleophile of water, resulting in ring-opening of the imidazolinone moiety. The half-life of its decay rate in D2O is around 33 days. Actually, acid-catalyzed hydrolysis of p-HBDI also results in ring-opening of the imidazolinone moiety. The ratio of the acid-catalyzed hydrolysis rate constants [kobs(p-HBDI)/kobs(1b)] between p-HBDI and 1b (p-dimethylammonium analogue of the GFP chromophore) is dramatically increased from 0.30 at pH = 2 to 0.63 at pH = 0. This is the evidence that more and more phenol hydroxyl groups of p-HBDI are tentatively protonated in a low-pH aqueous solution and that accelerates hydrolysis of p-HBDI in the way similar to the quaternary ammonium derivatives 2a and 2b in water. With this view point, 2a and 2b still can partially mimic the cationic p-HBDI with the protonated phenol hydroxyl group. Implication of the experiment is that the amidine carbon of the chromophore in wtGFP and its mutants at very low pH should be highly electrophilic. Whether ring-opening of the imidazolinone moiety of the GFP chromophore would occur or not depends on if water molecules can reach the amidine carbon of the chromophore inside wtGFP and its mutants.

Kinetic studies of acid-catalyzed hydrolysis of mixed cellulose ethers

The rate of acid-catalyzed hydrolysis of O-ethyl-O-methyl-cellulose (EMC) and O-methoxyethyl-O-methyl-cellulose (MEMC), respectively, has been studied. By a two-step depolymerization procedure and monitoring of all individual substitution patterns, rate constants were determined for glucosyl residues with each particular substitution pattern. Two MCs of DS 1.27 (MC1) and 1.95 (MC2) have been perethylated and permethoxyethylated and submitted to TFA hydrolysis in water/acetone in a heating block at 120 °C. EMC1 has also been hydrolyzed without acetone addition, under microwave irradiation, and after partial mechanical degradation by treatment with a sonotrode. For all hydrolyses, a slow (k-a) and, after about 10% conversion, a faster phase of hydrolysis (k-b) was found. Rate constants k-b were in the range of 2–4 × 10−4 s−1 for all peralkylated celluloses. In contrast to previously studied MC, hydrolysis in water/acetone was faster than in water, indicating the influence of solution state and the macromolecular character. No difference was observed for sonotrode pretreated EMC1, while microwave instead of heating block treatment accelerated hydrolysis by a factor of 30 under the chosen conditions. Selectivity with respect to the substitution patterns, expressed as the standard deviation of the individual rate constants ki (i = position of methyl), was higher in the slow initial phase (23–28%), while ranging between 9 and 18% in the main phase of hydrolysis with lower values for MEMC compared to EMC and, in case of EMC1, for aqueous TFA compared to acetone-containing mixtures. Randomness in hydrolytic cleavage is favored by water as solvent and apparently by microwave heating.

Cytosine deamination and the precipitous decline of spontaneous mutation during Earth's history

The hydrolytic deamination of cytosine and 5-methylcytosine residues in DNA appears to contribute significantly to the appearance of spontaneous mutations in microorganisms and in human disease. In the present work, we examined the mechanism of cytosine deamination and the response of the uncatalyzed reaction to changing temperature. The positively charged 1,3-dimethylcytosinium ion was hydrolyzed at a rate similar to the rate of acid-catalyzed hydrolysis of 1-methylcytosine, for which it furnishes a satisfactory kinetic model and a probable mechanism. In agreement with earlier reports, uncatalyzed deamination was found to proceed at very similar rates for cytosine, 1-methylcytosine, cytidine, and cytidine 5'-phosphate, and also for cytosine residues in single-stranded DNA generated from a phagemid, in which we sequenced an insert representing the gene of the HIV-1 protease. Arrhenius plots for the uncatalyzed deamination of cytosine were linear over the temperature range from 90 °C to 200 °C and indicated a heat of activation (ΔH(‡)) of 23.4 ± 0.5 kcal/mol at pH 7. Recent evidence indicates that the surface of the earth has been cool enough to support life for more than 4 billion years and that life has been present for almost as long. If the temperature at Earth's surface is assumed to have followed Newton's law of cooling, declining exponentially from 100 °C to 25 °C during that period, then half of the cytosine-deaminating events per unit biomass would have taken place during the first 0.2 billion years, and <99.4% would have occurred during the first 2 billion years.

Probing the influence of a 4,6-O-acetal on the reactivity of galactopyranosyl donors: verification of the disarming influence of the trans-gauche conformation of C5-C6 bonds.

The effect of a 4,6-O-alkylidene acetal on the rate of acid-catalyzed hydrolysis of methyl galactopyranosides and of spontaneous hydrolysis of 2,4-dinitrophenyl galactopyranosides has been studied through the synthesis and hydrolysis of analogs in which O6 is replaced by a methoxymethylene unit in which the methoxy group adopts either an equatorial or an axial position according to the configuration. Consistent with earlier studies under both acid-catalyzed and spontaneous hydrolysis conditions, the alkylidene acetal, or its 7-carba analog, retards hydrolysis with respect to comparable systems lacking the cyclic protecting group. The configuration at C6 in the 7-carba analogs does not influence the rate of acid-catalyzed hydrolysis but has a minor influence on the rate of spontaneous hydrolysis of the 2,4-dinitrophenyl galactosides, confirming earlier studies on the role played by the hydroxymethyl group conformation on glycoside reactivity. The benzylidene acetal is found to stabilize the α-anomer of galactopyranose derivatives relative to monocyclic analogs. Reasons for the α-selectivity of 4,6-O-benzylidene-protected galactopyranosyl donors bearing neighboring group-active protecting groups at O2 are discussed.

A computational study of acid catalyzed aerosol reactions of atmospherically relevant epoxides

Epoxides are important intermediates of atmospheric isoprene oxidation. Their subsequent reactions in the particle phase lead to the production of organic compounds detected in ambient aerosols. We apply density functional theory to determine the important kinetic factors that drive epoxide reactions in the particle phase. Specifically, the importance of acid catalysis and solvent polarity are investigated using a variety of epoxides and nucleophiles. The condensed phase is modeled using molecular clusters immersed in a dielectric continuum and a majority of the calculations are performed with the M062x density functional and the 6-311++G** basis set. Calculations of acid catalyzed epoxide hydrolysis transition states for simple primary, secondary and tertiary epoxides are consistent with an A-2 mechanism where the nucleophile (water) interacts with an epoxide carbon in the transition state. By applying transition state theory to this mechanism, the overall rate constants of epoxide reactions such as hydrolysis, organosulfate formation, organonitrate formation and oligomerization are determined. The calculations indicate that the acid catalyzed hydrolysis rate constant of 2-methyl-2,3-epoxybutane-1,4-diol (β-IEPOX--an isoprene epoxide produced under low NOx conditions) is approximately 30 times greater than 2-methyl-2,3-epoxypropanoic acid (MAE--methacrylic acid epoxide derived from isoprene and produced at high NOx concentrations). Furthermore, acid catalyzed organosulfate formation and epoxide oligomerization reactions are competitive and appear to be kinetically favorable over the hydrolysis of IEPOX.

Prednisolone-α-cyclodextrin-star poly(ethylene glycol) polypseudorotaxane with delayed pH-sensitivity as a targeted drug delivery system

The acylation of prednisolone 20-hydrazone with star poly(ethylene glycol) tetracarboxylic acid ( M = 20,000) has been used to prepare the corresponding pH-sensitive conjugate. With α-cyclodextrin, this conjugate forms a polypseudorotaxane, which was characterised by means of 1H NMR spectra, powder X-ray diffraction patterns and STM microscopy. The rate of acid-catalysed hydrolysis of the conjugate was studied under in vitro conditions in model media of hydrochloric acid solutions, phosphate and acetate buffers (pH 2–5.8). The acid-catalysed hydrolysis (at pH 2) of the polypseudorotaxane was ca 3.5 times slower than that of the original conjugate. After 1 h in this medium, 86% of the covalently attached prednisolone remained unchanged. The prepared polypseudorotaxane represents a promising peroral transport system of prednisolone with a pH-sensitive linker with delayed acid-catalysed hydrolysis thanks to protection at the molecular level using α-cyclodextrin.

Accelerated cellulose depolymerization catalyzed by paired metal chlorides in ionic liquid solvent

Efficient hydrolytic depolymerization of crystalline cellulose to sugars is a critical step and has been a major barrier for improved economics in the utilization of cellulosic biomass. A novel catalytic system involving CuCl 2 (primary metal chloride) paired with a second metal chloride, such as CrCl 2, PdCl 2, CrCl 3 or FeCl 3 in 1-ethyl-3-methylimidazolium chloride ([EMIM]Cl) ionic liquid solvent has been found to substantially accelerate the rate of cellulose depolymerization under mild conditions. These paired metal chlorides are particularly active for the hydrolytic cleavage of 1,4-glucosidic bonds when compared to the rates of acid-catalyzed hydrolysis at similar temperatures (80–120 °C). In contrast, single metal chlorides with the same total molar loading showed much lower activity under similar conditions. Experimental results illustrate the dramatic effect of the second metal chloride in the paired catalytic system. An array of characterization techniques, including electron paramagnetic resonance (EPR) spectroscopy, differential scanning calorimetry (DSC), X-ray absorption fine structure (XAFS) spectroscopy, and X-ray absorption near edge structure (XANES) spectroscopy, in combination with theoretical calculations at the DFT level, was used to reveal a preliminary understanding of possible mechanisms involved in the paired CuCl 2/PdCl 2 catalytic system. We discovered that Cu(II) was reduced during the course of the reaction to Cu(I) only in the presence of a second metal chloride and a carbohydrate source such as cellulose in the ionic liquid system. Our results suggest that Cu(II) generates protons by hydrolysis of water to catalyze the depolymerization step, and serves to regenerate Pd(II) reduced to Pd(0) by side reactions. Pd(II) likely facilitates the depolymerization step by coordinating the catalytic protons, and also promotes the formation of hydroxymethylfurfural (HMF). Our results also suggest that the C2-proton of the imidazolium ring is not activated by the paired metal-chloride catalysts.

ChemInform Abstract: Kinetics and Mechanism of the Acid-Catalyzed Hydrolysis of 1,1- Dimethoxyethene (Ketene Dimethyl Acetal) and Trimethoxyethene in Aqueous Solution.

Rates of acid-catalyzed hydrolysis of 1,1-dimethoxyethene and trimethoxyethene were measured in wholly aqueous solutions of perchloric acid, sodium hydroxide, and a series of carboxylic acid buffer solutions at 25 o C. The reactions show general acid catalysis and give substantial solvent isotope effects in the normal direction (k H /k D >1)

Deacidification for the conservation and preservation of paper-based works: A review

Embrittlement threatens the useful lifetime of books, maps, manuscripts, and works of art on paper during storage, circulation, and display in libraries, museums, and archives. Past studies have traced much of the embrittlement to the Bronsted-acidic conditions under which printing papers have been made, especially during the period between the mid 1800s to about 1990. This article reviews measures that conservators and collection managers have taken to reduce the acidity of books and other paper-based materials, thereby decreasing the rates of acid-catalyzed hydrolysis and other changes leading to embrittlement. Technical challenges include the selection of an alkaline additive, selecting and implementing a way to distribute this alkaline substance uniformly in the sheet and bound volumes, avoiding excessively high pH conditions, minimizing the rate of loss of physical properties such as resistance to folding, and avoiding any conditions that cause evident damage to the documents one is trying to preserve. Developers have achieved considerable progress, and modern librarians and researchers have many procedures from which to choose as a starting point for further developments.

Isolation, Purification and Characterization of Large-Ring Cyclodextrins (CD36∼ ∼CD39)

Large-ring cyclodextrins (LR-CDs) composed of more than 9 d-glucose units are not well studied. In this study, LR-CDs composed of 36, 37, 38 and 39 d-glucose units (CD36∼ ∼CD39) were isolated and purified from a LR-CD mixture, and their physicochemical properties including aqueous solubility, surface tension, specific rotation and acid-catalyzed hydrolysis rate were elucidated. The aqueous solubilities of CD36∼ ∼CD39 were greater than those of α-, β-, γ-CD, CD9, CD10, CD14 and CD26. CD36∼ ∼CD39 did not show any surface activity. The acid-catalyzed hydrolysis of CD36∼ ∼CD39 was a little faster than that of other LR-CDs (CD9∼ ∼CD35). There was no marked difference in specific rotation or the acid-catalyzed hydrolysis rate among CD36∼ ∼CD39. Furthermore, we compared these findings with the physicochemical properties of α-, β-, γ-CD and other LR-CDs (CD9∼ ∼CD35).

Effect of microenvironment pH of aluminum hydroxide adjuvant on the chemical stability of adsorbed antigen

The rate of acid-catalyzed hydrolysis of glucose-1-phosphate (G1P) when adsorbed to aluminum hydroxide adjuvant was significantly slower than the rate of hydrolysis of a solution of G1P at the same pH. It was concluded that the positively charged aluminum hydroxide adjuvant (iep 11.4) electrostatically attracted anions including hydroxyls to form a double layer surrounding the adjuvant particles. Thus, the pH of the microenvironment surrounding the aluminum hydroxide adjuvant was higher than the bulk pH. Adsorbed G1P hydrolyzed at a rate associated with the pH of the microenvironment of the surface of the adjuvant rather than with the pH of the bulk solution. Comparison of the rate constant for the hydrolysis of adsorbed G1P to the pH-stability profile of G1P in solution revealed that adsorbed G1P hydrolyzed at a rate associated with a pH that was approximately two pH units higher than the bulk pH. The results suggest that the chemical stability of antigens that degrade by pH-dependent mechanisms can be optimized by modifying the surface charge of the aluminum-containing adjuvant to produce the pH of maximum stability in the microenvironment of the adjuvant.

Kinetics and mechanism of hydrolysis of 3-diazobenzofuran-2-one and its hydrolysis product (3-hydroxybenzofuran-2-one)

Rates of acid-catalyzed hydrolysis of 3-diazobenzofuran-2-one, measured in concentrated aqueous perchloric acid and hydrochloric acid solutions, were found to correlate well with the Cox–Yates Xo excess acidity function, giving kH+ = 1.66 × 10–4 M–1 s–1, m‡ = 0.86 and kH+ /kD+ = 2.04. The normal direction (kH/kD &gt; 1) of this isotope effect indicates that hydrolysis occurs by rate-determining protonation of the substrate on its diazo-carbon atom. It was found previously that the next higher homolog of the present substrate, 4-diazoisochroman-3-one, also undergoes hydrolysis by this reaction mechanism but with a rate constant 15 times greater than that for the present substrate; this difference in reactivity can be understood in terms of the various resonance forms that contribute to the structures of these substrates. The product of the present hydrolysis reaction is 3-hydroxybenzofuran-2-one, which itself quickly undergoes subsequent acid-catalyzed hydrolysis to 2-hydroxymandelic acid. The acidity dependence of this subsequent hydrolysis is much shallower than that of the diazo compound precursor, and rates of reaction correlate as well with [H+] as with Xo. This is due in part to incursion of a nonproductive protonation on the hydroxy group of 3-hydroxy benzo furan-2-one that impedes hydrolysis and produces saturation of acid catalysis. Rates of hydrolysis of the hydroxy compound were also measured in dilute HClO4 and NaOH solutions as well as in CH3CO2H, H2PO4–, (CH2OH)3CNH3+, and NH4+ buffers, and the rate profile constructed from these data showed the presence of uncatalyzed and hydroxide ion-catalyzed reactions. This hydroxide-ion catalysis became saturated at [NaOH] [Formula: see text] 0.05 M, implying occurrence of yet another nonproductive substrate ionization. Key words: diazo compound hydrolysis, lactone hydrolysis, Cox–Yates excess acidity, acid catalysis, alcohol protonation.

Acid-catalyzed hydrolysis of the vinyl ether group of 4-methoxy-1,2-dihydronaphthalene. Effect of conformation on reactivity

Rates of acid-catalyzed hydrolysis of the vinyl ether group of 4-methoxy-1,2-dihydronaphthalene were measured in dilute aqueous perchloric acid solutions and also in a series of carboxylic acid buffers. These data give the hydronium-ion isotope effect kH/kD = 3.39 and provide a Bronsted relation with the exponent α = 0.70. The hydronium ion catalytic coefficient for this reaction is less, by a factor of 2.4, than that for the corresponding reaction of 3-methoxyindene. This rate difference is consistent with the coplanar arrangement of the vinyl and benzene groups in indene but non-coplanar disposition of these groups in dihydronaphthalene, and the consequent reduced ability of the benzene ring of dihydronaphthalene to stabilize the adjacent positive charge being put there in the rate-determining step of the vinyl ether hydrolysis rreaction.

Synthesis and Acid-Catalyzed Hydrolysis of Some 3-(4-Methoxyphenyl)propyl Glucuronates

3-(4-Methoxyphenyl)propyl D-glucuronate, 3-(4-methoxyphenyl)propyl methyl 4-O-methyl-α-Dglucopyranosiduronate, 3-(4-methoxyphenyl)propyl 1,2,3,4-tetra-O-acetyl-α-D-glucopyranuronate and 3-(4-methoxyphenyl)propyl 1,2-(S):3,5-di-O-benzylidene-α-D-glucofuranuronate were prepared as a model substances for the ester lignin-saccharide bonds. Rates of acid-catalyzed hydrolysis of the prepared compounds in 1 M HCl in acetonitrile-water 3 : 1 at 20 °C have been measured by LC-DAD analysis and it showed the low stability of the ester bonds towards acid hydrolysis.

Polymer-surfactant interactions demonstrated by a kinetic probe: degree of ionization

The effects of aggregates of poly(ethylene oxide) (PEO), poly(vinyl pyrrolidone) (PVP) and sodium dodecyl sulfate (SDS) in solution on the rates of acid-catalyzed hydrolysis of 2-(p-nonoxyphenyl)-1,3-dioxolane (p-NPD) were investigated. Comparisons of the rate vs. SDS concentration profiles in the absence and presence of polymer, show significant inhibition as a function of PEO and PVP concentrations. The observed first-order rate constant vs. SDS concentration profiles, in the presence of polymer, exhibit three distinct regions, as extensively documented for SDS. The transitions observed in the kinetic profiles coincide with the discontinuities in the specific conductivity vs. SDS concentration plots in the presence of polymers, and correspond to the critical aggregation concentration (CAC) and polymer saturation point (PSP). The degree of ionization of PVP-SDS complexes (0.38±0.01) was estimated by conductivity measurements by using the Evans equation.

A new 2'-hydroxyl protecting group for the automated synthesis of oligoribonucleotides.

We have developed a new type of 2'-hydroxyl protecting group for the automated machine synthesis of RNA oligomers: a 2-hydroxyisophthalate formaldehyde acetal (HIFA). The unique feature of this protecting group is that, as the bis ester, it is relatively stable to the acidic conditions that are used for repeated removal of dimethoxytrityl groups during chain elongation, but the final deprotection step in alkali, which cleaves the chain from the support and removes the base and phosphate protecting groups, converts it to the bis carboxylate and this can be removed relatively rapidly by treatment with mild acid. Conversion of the bis ester to the bis carboxylic acid increases the rate of acid-catalyzed hydrolysis of the acetal by 42-fold at pH 1, and, possibly, by 1320-fold at pH 3. The bis ester is 112 times more stable than the 1-(2-fluorophenyl)-4-methoxypiperidin-4-yl group (Fpmp) towards hydrolysis at pH 1, while the bis acid is only 2.35 times more stable than Fpmp at pH 3. In synthesis of the dimers UpU and UpG, with a coupling time of 5 min, the dimethoxytrityl cation assay indicated coupling yields of > 98%.

Use of the 1-(2-fluorophenyl)-4-methoxypiperidin-4-yl (Fpmp) and related protecting groups in oligoribonucleotide synthesis: stability of internucleotide linkages to aqueous acid.

The internucleotide linkage of uridylyl-(3'-->5')-uridine (r[UpU]) does not undergo detectable hydrolytic cleavage or migration in ca. 24 hr in 0.01 mol dm-3 hydrochloric acid (pH 2.0) at 25 degrees C. However, unlike r[UpU] and previously examined relatively high molecular weight oligoribonucleotides, oligouridylic acids are very sensitive to aqueous acid under the latter conditions (pH 2.0, 25 degrees C). Thus when the 1-(2-fluorophenyl)-4-methoxypiperidin-4-yl (Fpmp) group is used to protect the 2'-hydroxy functions in the synthesis of r[(Up)9U] and r[(Up)19U], the final unblocking process must be carried out above pH 3 if hydrolytic cleavage and migration are to be avoided. It is demonstrated that the rate of acid-catalyzed hydrolysis of the internucleotide linkages of oligoribonucleotides is sequence dependent. As Fpmp groups may be virtually completely removed from average partially-protected oligoribonucleotides within ca. 24 hr at pH 3 and 25 degrees C, it is concluded that Fpmp is a suitable 2'-protecting group even in the synthesis of particularly acid-sensitive sequences.

Some Pharmaceutical Properties of 2,3,6-partially Methylated-β- cyclodextrin and its Solubilizing and Stabilizing Abilities

AbstractThe pharmaceutical properties of 2,3,6-partially methylated-β-cyclodextrin(PMCD) were investigated. The aqueous solubility of PMCD was much higher than that of the parent βCyD, and it exhibited endothermic dissolution in contrast to that of the conventional heptakis-(2,6-di-O-methyl)-β-cyclodextrin(DMCD). The acid-catalyzed hydrolysis rate of PMCD was faster than those of the parent β-CyD and DMCD. The hemolytic activity (human erythrocytes) of PMCD was similar to that of DMCD. PMCD was a more effective solubilizer for poorly water-soluble drugs than the parent β-CyD; however PMCD is not as effective as DMCD. The stabilizing effect of PMCD on chemically unstable drugs was higher than that of the parent β-CyD.For 2,3,6 partially methylated-β-CyD(PMCD), in which the hydroxyl groups of cyclodextrin are substituted by a methyl group, the methylation ratios are as follows: 58–62% at the 2-position, 48∼52% at the 3-position, and 98∼100% at the 6-position1). This novel cyclodextrin derivative is synthesi...

Kinetics and mechanism of the acid-catalyzed hydrolysis of 1,1-dimethoxyethene (ketene dimethyl acetal) and trimethoxyethene in aqueous solution

Rates of acid-catalyzed hydrolysis of 1,1-dimethoxyethene and trimethoxyethene were measured in wholly aqueous solutions of perchloric acid, sodium hydroxide, and a series of carboxylic acid buffer solutions at 25 o C. The reactions show general acid catalysis and give substantial solvent isotope effects in the normal direction (k H /k D >1)