DMSO substitution kinetics

Procedure 6.2 DMSO Substitution Kinetics of cis- and frans-Platin Temperature Dependence Study11... 

In this set of experiments you will synthesize both cis- and trans-platin complexes and study their substitution kinetics in DMSO. The primary focus of the chapter is on c/.v-platin biological reactivity you will investigate the binding of c/.v-platin to DNA adducts by NMR and molecular mechanics methods and assess drug cytotoxicity using a Chinese hamster ovary (CHO) cell line. 

In this experiment, we will study the kinetics of the first Cl- substitution in the cis- and /rara.v-platin complexes by DMSO solvent. Temperature dependence studies will enable the calculation of activation parameters (see Experiment 4.7). DMSO has been chosen for two reasons. First, the substitution kinetics are faster than in aqueous media and are more amenable for study in the teaching laboratory. Second, many drugs like cis- and irara.v-platin that have low aqueous solubility are dissolved in DMSO for cytotoxicity assays. Lippard s group first pointed out that, for the platinum(II) complexes, substitution is relatively rapid in DMSO and requires caution in interpreting cytotoxicity results. We too will use DMSO as a carrier solvent in Experiment 6.5. The results obtained in this kinetics experiment will alert you to the limitations of your cytotoxicity assay. 

Prepare a concentrated Stock A (3.0 mg/100 pi) of cw-platin from which Stocks B-I will be prepared Table 6.5 details the preparation of your Stocks for this experiment. To efficiently prepare your solutions in a timely fashion to minimize DMSO exchange (see Experiment 6.2), label 11 150 pi conical vials A-K. Add the appropriate volume of DMSO solvent indicated in column 6 to each vial. Prepare Stock A. Quickly make serial dilutions as indicated in Table 6.5, vortexing for rapid mixing (recall the rapid substitution kinetics of cwplatin in DMSO—Experiment 6.2 ). Note that the drug STOCK labels are identical to the well labels. After the addition of drug and medium the total volume in each well is 3.5 ml. 

A further paper by the same group deals with the kinetics of substitution of [Co(CN)5C1] by water and DMSO. The kinetic data can be interpreted in terms of the same scheme, and chromatographic analysis confirms the direct formation of a single, probably sulfur-bonded isomer of [Co(CN)5(DMSO)] from both [Co(CN)5Cl] and [Co(CN)5(OH2)]" . 

There is an interesting contrast in the substitution kinetics of plati-num(II) complexes and the complexes of cobalt(III) and chromium(III), in relation to the two solvents DMF and DMSO. As emphasised by solvolysis and isomerisation studies with both cobalt(III) and chro-mium(III), these two solvents differ in only minor ways. DMSO is a slightly stronger ligand, based on its resistance to substitution replacement by anions, but this difference is small as are the differences in their mutual interchange rates. - " ... 

In order to determine the exact reaction times necessary to reach specific degrees of substitution, kinetic experiments were carried out, on an 11 mg scale in an NMR tube under controlled temperature conditions. NMR spectra were recorded at 500 MHz on a Bruker DMX 500 using Bruker software. The samples were dissolved in deuterated DMSO in sample tubes 5 mm in diameter. Non-deuterated DMSO (5=2.50) was used as an internal standard. Figure 3 and 4... 

The usual kinetic law for S/v Ar reactions is the second-order kinetic law, as required for a bimolecular process. This is generally the case where anionic or neutral nucleophiles react in usual polar solvents (methanol, DMSO, formamide and so on). When nucleophilic aromatic substitutions between nitrohalogenobenzenes (mainly 2,4-dinitrohalogenobenzenes) and neutral nucleophiles (amines) are carried out in poorly polar solvents (benzene, hexane, carbon tetrachloride etc.) anomalous kinetic behaviour may be observed263. Under pseudo-monomolecular experimental conditions (in the presence of large excess of nucleophile with respect to the substrate) each run follows a first-order kinetic law, but the rate constants (kQbs in s 1 ruol 1 dm3) were not independent of the initial concentration value of the used amine. In apolar solvents the most usual kinetic feature is the increase of the kabs value on increasing the [amine]o values [amine]o indicates the initial concentration value of the amine. 

Nitrobenzoylamino)-2,2-dimethylpropanamide (143 R = Me) reacts in methanol-DMSO solution with sodium methoxide to yield 5,5-dimethyl-2-(4-nitrophenyl)imidazol-4(5//)-one (144 R = Me). The 4-methoxyphenyl derivative and the parent phenyl derivative react similarly, as do compounds in which variation of the 2-substitutent (R = Pr , Ph, 4-O2NC6H4) was made. The mechanism of the cyclization probably involves initial formation of the anion of the alkanamide (145), which adds to the carbonyl group of the benzamido moiety to yield the tetrahedral oxyanion (146) proton transfer and dehydration then yield the heterocycle (144). The kinetics of hydrolysis in water at 70 °C and pH 2-11 of A-glycidylmorpholine (147) have been reported. ... 

The reaction of ethyl 2,4,6-trinitrophenyl ether with aniline in dimethyl sulfoxide (DMSO) in the presence of Dabco occurs in two stages via the intermediate (6). Kinetic studies show that proton transfer is rate-limiting both in the formation of the intermediate and in the subsequent acid-catalysed decomposition to give 2,4,6-trinitrodiphenylamine. Phenoxide is a considerably better leaving group than ethoxide so that substitutions of phenyl 2,4,6-trinitrophenyl ethers and phenyl 2,4-dinitronaphthyl ether with aniline occur without the accumulation of intermediates. Both uncatalysed and base-catalysed pathways are involved. ... 

In solvent DMSO, the rate of reaction (17) (R = Me, X = Cl) was too fast to follow, but using the mixture DMSO-dioxan (1 9 v/v) at 24.7 °C, rate coefficients for the substitution of the gold(I) complex by several alkylmercuric salts were obtained. It was found that in this mixed solvent, reaction (17) followed first-order kinetics, first-order in the gold(I) complex and zero-order in the alkylmercuric salt. Furthermore, the first-order rate coefficient had the same value no matter what alkylmercuric salt was used (methylmercuric acetate, methylmercuric chloride, methylmercuric bromide, and ethylmercuric chloride were the salts used). At 24.7 °C, the first-order rate coefficient has the value 0.0083 sec-1, with a standard deviation of 0.0006 sec-1. 

A kinetic study in 50% aqueous DMSO has shown that the first step in the three-step mechanism (Scheme 24) proposed for the 5NV reaction between para-substituted (methylthio)benzylidene Meldrum s acids (61) and four aliphatic primary amines is rate determining.101 The evidence supporting this mechanism is that the reactions are second order kinetically and show no base catalysis. A value of /Wc = 0.32 for the reaction with primary amines is smaller than the /9nuc = 0.41 found for the reaction with the less reactive secondary amines, indicating that N-Ca bond formation is more... 

A kinetic study of the aminolysis of substituted (methylthio)benzylidene Meldrum s acids with aliphatic primary amines in aqueous DMSO has been reported.53 With all amines the reactions are strictly second order and proceed via a three-step mechanism. 

A study of the aminolysis of substituted (methylthio)benzylidene Meldrum s acids (81 z = MeO, Me, H, Br, CF3) with a series of aliphatic primary amines in aqueous DMSO revealed second-order overall kinetics, i.e. first order in (81) and first order in the amine. A three-step mechanism has been proposed, the first step being the rate-limiting addition of amines to form the tetrahedral intermediate which is followed by fast acid-base equilibration and then formation of (82) by a fast expulsion of the leaving group, catalysed by RNH3+ or H20.127... 

The reaction of o- and /7-halonitrobenzenes (Cl, Br, F) with the sodium salt of ethyl cyanoacetate in DMSO gave almost quantitatively the substitution products183. These reactions were found to be markedly diminished by adding small amounts of/>-, m- and o-DNBs, but were not influenced by addition of radical scavengers1843. Based on these results and kinetic studies it was suggested that they proceed via a non-chain radical nucleophilic substitution184. 

The kinetics of nucleophilic substitution at the silicon atom assisted by uncharged nucleophiles have been studied by Corriu et at. (248-251). Hydrolysis of triorganochlorosilanes induced with HMPA, DMSO, and DMF was used as the model. The reaction proceeded according to the third-order kinetic law, first order with respect to the nucleophile, the silane, and the silylation substrate. Very low values of activation enthalpy and high negative entropy of activation were observed (Table VI). These results were taken as evidence for the intermediacy of silicon hypervalent species (249,251) however, they are also perfectly consistent with... 

The first study of a nucleophilic aromatic substitution in which formation of a Meisenheimer-type complex and its subsequent decomposition were separately observable was reported by Orvik and Bunnett (1970). The study involved the reaction of 2,4-dinitro-l-naphthyl ethyl ether [7] with n-butyl- and t-butylamine in DMSO. The use of DMSO in this kinetic study enabled the rate behaviour to be unambiguously interpreted by avoiding complications due to aggregation phenomena, while stabilizing any a-complexes which are formed. The reaction sequence is given in equation (28). In this OEt... 

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