The Mechanism of the Base-Catalyzed Addition of Thiols to Maleic Anhydride

Dmuchovsky, Basil; Vineyard, B. D.; Zienty, Ferdinand B.

doi:10.1021/ja01068a022

Cited by 41 publications

(33 citation statements)

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“…This explains why the DPRA findings reported indicate that, unlike PA, HPA and TMA, MA gives high (100%) peptide depletion with cysteine. There is also literature evidence, with kinetics, for a fast Michael addition reaction between MA and butanethiol in the presence of triethylenediamine in xylene at 25°C (Dmuchovsky et al ., ). Both carbons of the double bond have an electronegative substituent (CO.O.CO).…”

Section: Illustrative Examples Of the Chemistry Approachmentioning

confidence: 99%

Integrated testing and assessment approaches for skin sensitization: a commentary

Roberts

Patlewicz

2013

J of Applied Toxicology

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A Bayesian integrated testing strategy (ITS) approach, aiming to assess skin sensitization potency, has been presented, in which data from various types of in vitro assays are integrated and assessed in combination for their ability to predict in vivo skin sensitization data. Here we discuss this approach and compare it to our quantitative mechanistic modeling (QMM) approach based on physical organic chemistry. The main findings of the Bayesian study are consistent with our chemistry-based approach and our previously published assessment of the key determinants of sensitization potency, in particular the relatively high predictive value found for chemical reactivity data and the relatively low predictive value for bioavailability parameters. As it stands at present the Bayesian approach does not utilize the full range of predictive capability that is already available, and aims only to assign potency categories rather than numerical potency values per se. In contrast, for many chemicals the QMM approach can already provide numerical potency predictions. However, the Bayesian approach may have potential for those chemicals where a chemistry modeling approach cannot provide a complete answer (e.g. pro-electrophiles whose in cutaneo activation cannot currently be modeled confidently). Nonetheless, our main message is of the importance of leveraging chemistry insights and read-across approaches to the fullest extent possible.

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Section: Illustrative Examples Of the Chemistry Approachmentioning

confidence: 99%

Integrated testing and assessment approaches for skin sensitization: a commentary

Roberts

Patlewicz

2013

J of Applied Toxicology

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“…The low magnitude of the primary isotope effect in such cases is explained by 1) the non‐linearity of C‐H‐O in a bifurcate (triangular) transition state;48 2) the non‐synchronicity of CO (more advanced) with CH bond formation, and 3) the presence of a reversible association between RO(H/D) and the catalyst. Associative pre‐equilibria contribute inversely (<1) to the overall KIE 49. Overall, the measured primary KIE is in agreement with a concerted, asynchronous hydrogen‐bond network mechanism, but would not exclude a stepwise mechanism by itself.…”

Section: Resultsmentioning

confidence: 69%

Inner Workings of a Cinchona Alkaloid Catalyzed Oxa‐Michael Cyclization: Evidence for a Concerted Hydrogen‐Bond‐Network Mechanism

Hintermann

Ackerstaff

Boeck

2013

Chemistry A European J

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Cinchona alkaloids catalyze the oxa-Michael cyclization of 4-(2-hydroxyphenyl)-2-butenoates to benzo-2,3-dihydrofuran-2-yl acetates and related substrates in up to 99% yield and 91% ee (ee = enantiomeric excess). Catalyst and substrate variation studies reveal an important role of the alkaloid hydroxy group in the reaction mechanism, but not in the sense of a hydrogen-bonding activation of the carbonyl group of the substrate as assumed by the Hiemstra-Wynberg mechanism of bifunctional catalysis. Deuterium labeling at C-2 of the substrate shows that addition of RO-H to the alkenoate occurs with syn diastereoselectivity of ≥99:1, suggesting a mechanism-based specificity. A concerted hydrogen-bond network mechanism is proposed, in which the alkaloid hydroxy group acts as a general acid in the protonation of the α-carbanionic center of the product enolate. The importance of concerted hydrogen-bond network mechanisms in organocatalytic reactions is discussed. The relative stereochemistry of protonation is proposed as analytical tool for detecting concerted addition mechanisms, as opposed to ionic 1,4-additions.

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“…It is of interest to compare the present results with those from the earlier literature. Dmuchowsky et al25 reported third‐order kinetics − first‐order in each reactant and in the base catalyst − for the tertiary amine catalysed addition of thiols to maleic anhydride in xylene. Fourth‐order kinetics − second‐order in benzenethiol − were reported, however, by Klimenko et al26 for a similar system.…”

Section: Resultsmentioning

confidence: 99%

New Insight into the Mechanism of the Conjugate Addition of Benzenethiol to Cyclic and Acyclic Enones and of the Corresponding Uranyl−Salophen‐Catalysed Version

et al. 2003

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A thorough kinetic investigation of the triethylamine-catalysed addition of benzenethiol to 2-cyclopenten-1-one in chloroform shows that the highest energy transition state is a complex of thiol, enone, and base in a 1:1:1 ratio, but whether formation or disruption of the enolate−triethylammonium ion-pair intermediate is rate-limiting is uncertain. Intervention of a second thiol molecule in the assembly of the transition-state complex is ruled out, at least at thiol concentrations not exceeding 0.1−0.2 M. Thiol addition is accelerated significantly by uranyl−salophen complex 1 and its diphenyl derivative 2. The complicated kinetics are described to high precision by means of ad hoc integrated rate equations in which associations to the metal catalyst of the enone reactant and addition product are taken into account. The kinetics are [a]

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The Mechanism of the Base-Catalyzed Addition of Thiols to Maleic Anhydride

Cited by 41 publications

References 1 publication

Integrated testing and assessment approaches for skin sensitization: a commentary

Integrated testing and assessment approaches for skin sensitization: a commentary

Inner Workings of a Cinchona Alkaloid Catalyzed Oxa‐Michael Cyclization: Evidence for a Concerted Hydrogen‐Bond‐Network Mechanism

New Insight into the Mechanism of the Conjugate Addition of Benzenethiol to Cyclic and Acyclic Enones and of the Corresponding Uranyl−Salophen‐Catalysed Version

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