We present a de novo discovery of an efficient catalyst of the Morita-Baylis-Hillman (MBH) reaction by searching chemical space for molecules that lower the estimated barrier of the rate-determining step using a genetic algorithm (GA) starting from randomly selected tertiary amines. We identify 435 candidates, virtually all of which contain an azetidine N as the catalytically active site, which is discovered by the GA. Two molecules are selected for further study based on their predicted synthetic accessibility and have predicted ratedetermining barriers that are lower than that of a known catalyst. Azetidines have not been used as catalysts for the MBH reaction. One suggested azetidine is successfully synthesized and showed an eightfold increase in activity over a commonly used catalyst. We believe this is the first experimentally verified de novo discovery of an efficient catalyst using a generative model.
Multi-photochromic systemsi ncorporating individually addressables witching units are attractivef or development of advanced data storaged evices.H ere, we present the synthesis and properties of as election of such molecular systemsi ncorporating the dihydroazulene/vinylheptafulvene (DHA/VHF) photo-/thermoswitch. The influence of the linker (meta-phenylene vs. azulene-1,3-diyl vs. thiophene-2,5-diyl) separating two DHA units on the switching properties was investigated. An azulene-1,3-diyl spacer largely inhibited both the DHA-to-VHF photoisomerizations and the thermal VHF-to-DHA back-reactions;t he latter occurred ten times slower than for the related compound with a meta-phenyl-ene spacer.ADHA trimerc ontaining three DHA units aroundacentral benzene ring was found to undergo stepwise DHA-to-VHF photoisomerizations, whereas the thermal back-reactions occurred at similar rates for the three VHF entities.Ameta-phenylene-bridgedD HA dimerw as subjected to furthers tructural modifications at positionC-1 of each DHA,h avings trong implications for the switching events, and synthetic steps for further functionalizations at position C-7 of each DHA were investigated.F inally,t he molecular structure (from X-ray crystallographic analysis) between the meta-phenylene-bridgedDHA dimer and Cu I is presented.
The [2+2] cycloaddition ‐ retro‐electrocyclization (CA‐RE) reaction is a “click‐like” protocol for facile synthesis of donor‐acceptor chromophores from an alkyne and tetracyanoethylene. Herein we shed light on the mechanism of this reaction by detailed kinetics studies using 1H NMR spectroscopy. By considering several experiments simultaneously, a variety of mechanistic models was evaluated. Surprisingly, a model in which the final 1,1,4,4‐tetracyanobuta‐1,3‐diene product promoted the first step was the only one that described well the experimental data. This autocatalysis model also involved a non‐concerted, stepwise formation of the cyclobutene cycloaddition adduct. By proper choice of conditions, we were able to generate the transient cyclobutene in sufficient amount to verify it as an intermediate using 13C NMR spectroscopy. For its final retro‐electrocyclization step, simple first‐order kinetics was observed and only minor solvent dependence, which indicates a concerted reaction.
We present a de novo discovery of an efficient catalyst of the methanol-mediated Morita– Baylis–Hillman (MBH) reaction by searching chemical space for molecules that lower the es- timated barrier of the rate-determining step using a genetic algorithm (GA) starting from randomly selected tertiary amines. We performed five independent GA searches that resulted in 448 unique molecules, for which we were able to locate 435 true transition states at semiem- pirical level of theory. The predicted activation energies of all 435 molecules were all lower than that of 1,4-diazabicyclo[2.2.2]octane (DABCO), which is a popular catalyst of the MBH reaction. Virtually all the molecules contain an azetidine N as the catalytically active site, which is discovered by the GA since it is either not found in the initial population or discarded early only to be rediscovered as the search progresses. Many of the GA searches also intro- duce a substituent with a hydrogen bond donor that helps to stabilize the transition state and thus lower the barrier. Two molecules are selected for further study based on their synthetic accessibility as predicted by the retrosynthesis package Manifold. For these two molecules, we compute the entire free energy reaction profile at the DFT level and show that their rate- determining barriers are 1.7 and 2.4 kcal/mol lower than that of DABCO. Azetidines have not been used as catalysts for the MBH reaction so we experimentally verified our predictions. One of the molecules was successfully synthesized and is indeed more active than DABCO with an eight-fold increase in the rate-constant corresponding to a roughly 1 kcal/mol lower barrier, in good agreement with the predictions. We believe this is the first experimentally verified de novo discovery of an efficient catalyst using a generative model.
We present a de novo discovery of an efficient catalyst of the Morita-Baylis-Hillman (MBH) reaction by searching chemical space for molecules that lower the estimated barrier of the rate-determining step using a genetic algorithm (GA) starting from randomly selected tertiary amines. We identify 435 candidates, virtually all of which contain an azetidine N as the catalytically active site, which is discovered by the GA. Two molecules are selected for further study based on their predicted synthetic accessibility and have predicted ratedetermining barriers that are lower than that of a known catalyst. Azetidines have not been used as catalysts for the MBH reaction. One suggested azetidine is successfully synthesized and showed an eightfold increase in activity over a commonly used catalyst. We believe this is the first experimentally verified de novo discovery of an efficient catalyst using a generative model.
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