A chiral tricyclic terpene possessing a 6,6,6-tricyclic framework and a 3,3-dimethyl-7-oxooctylidenyl side chain undergoes a double ring-closing reaction to give two chiral pentacyclic terpenes in a ratio of 4:3 via an intramolecular Michael addition followed by aldol condensation under basic conditions. Three new stereogenic centers are introduced in the initial Michael annulation reaction. Stereoselective installation of an ethoxycarbonyl group at C17 of the two pentacyclic terpenes separately gives the corresponding highly functionalized pentacyclic terpenoids with seven stereogenic centers. The structures and stereochemistry of key intermediates and products are established through X-ray crystallographic analysis. A mechanism is proposed for explaining the stereochemistry in the Michael annulation reaction.
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Determining Michael acceptor reactivity from kinetic, mechanistic, and computational analysis for the base-catalyzed thiol-Michael reaction
A combined experimental and computational study of the reactivities of seven commonly used Michael acceptors paired with two thiols within the framework of photobase-catalyzed thiol-Michael reactions is reported. The rate coefficients of the propagation ( k P ), reverse propagation ( k -P ), chain-transfer ( k CT ), and overall reaction ( k overall ) were experimentally determined and compared with the well-accepted electrophilicity parameters of Mayr and Parr, and DFT-calculated energetics. Both Mayr's and Parr's electrophilicity parameters predict the reactivities of these structurally varying vinyl functional groups well, covering a range of overall reaction rate coefficients from 0.5 to 6.2 s −1 . To gain insight into the individual steps, the relative energies have been calculated using DFT for each of the stationary points along this step-growth reaction between ethanethiol and the seven alkenes. The free energies of the individual steps reveal the underlying factors that control the reaction barriers for propagation and chain transfer. Both the propagation and chain transfer steps are under kinetic control. These results serve as a useful guide for Michael acceptor selection to design and predict thiol-Michael-based materials with appropriate kinetic and material properties.
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- Award ID(s):
- 1808484
- NSF-PAR ID:
- 10300053
- Date Published:
- Journal Name:
- Polymer Chemistry
- Volume:
- 12
- Issue:
- 25
- ISSN:
- 1759-9954
- Page Range / eLocation ID:
- 3619 to 3628
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract Covalent adaptable networks (CANs) based on the thiol–Michael (TM) linkages can be thermal and pH responsive. Here, a new vinyl‐sulfone‐based thiol–Michael crosslinker is synthesized and incorporated into acrylate‐based CANs to achieve stable materials with dynamic properties. Because of the reversible TM linkages, excellent temperature‐responsive re‐healing and malleability properties are achieved. In addition, for the first time, a photoresponsive coumarin moiety is incorporated with TM‐based CANs to introduce light‐mediated reconfigureability and postpolymerization crosslinking. Overall, these materials can be on demand dynamic in response to heat and light but can retain mechanical stability at ambient condition.
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The domino Michael/Michael reaction between ( E )-7-aryl-7-oxohept-5-enals and trans -cinnamaldehydes was investigated by using modularly designed organocatalysts (MDOs). It was found that both the enamine and iminium catalytic modes of the MDOs are switchable and can be individually switched on and off by using appropriate combinations of the precatalyst modules and the reaction conditions. When both the enamine and iminium catalysis modes of the MDOs are switched on, the desired domino reaction products can be obtained in good yields and stereoselectivities under optimized conditions.more » « less
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A kinetic analysis of a “declick” reaction is described. Compound 1 , previously reported to couple an amine and a thiol ( i.e. “click”) under mild aqueous conditions to create 2 , undergoes release of the unaltered coupling partners upon triggering with dithiothreitol ( DTT ). In the study reported herein various aniline derivatives possessing para-electron donating and withdrawing groups were used as the amines. UV/vis spectroscopy of the declick reaction shows time-dependent spectra lacking isosbestic points, implying a multi-step mechanism. Global data fitting using numerical integration of rate equations and singular value decomposition afforded the spectra and time-dependence of each species, as well as rate constants for each step. The kinetic analysis reveals a multi-step process with an intermediate where both thiols of DTT have added prior to expulsion of the aniline leaving group, followed by rearrangement to the final product. Hammett plots show a negative rho value on two of the steps, indicating positive charge building ( i.e. reduction of a negative charge) in the step leading to the intermediate and its rate-determining breakdown. Overall, the kinetic study reported herein gives a complete mechanistic picture of the declick reaction.more » « less
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null (Ed.)Developing an engineerable chemical reaction that is triggerable for simultaneous chemical bond formation and cleavage by external cues offers tunability and orthogonality which is highly desired in many biological and materials applications. Here, we present a chemical switch that concurrently captures these features in response to chemically and biologically abundant and important cues, viz. , thiols and amines. This thiol/amine-triggerable chemical switch is based on a Triggerable Michael Acceptor (TMAc) which bears good leaving groups at its β-position. The acceptor undergoes a “trigger-to-release” process where thiol/amine addition triggers cascaded release of leaving groups and generates a less activated acceptor. The newly generated TMAc can be further reversed to liberate the original thiol/amine by a second nucleophile trigger through a “trigger-to-reverse” process. Within the small molecular volume of the switch, we have shown five locations that can be engineered to achieve tunable “trigger-to-release” kinetics and tailored reversibility. The potential of the engineerable bonding/debonding capability of the chemical switch is demonstrated by applications in cysteine-selective and reversible protein modification, universal self-immolative linkers, and orthogonally addressable hydrogels.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/d1py00363a
