Unravelling mechanistic features of organocatalysis with in situ modifications at the secondary sphere


Secondary-sphere interactions serve a fundamental role in controlling the reactivity and selectivity of organometallic and enzymatic catalysts. However, there is a dearth of studies that explicitly incorporate secondary-sphere modifiers into organocatalytic systems. In this work, we introduce an approach for the in situ systematic modification of organocatalysts in their secondary sphere through dynamic covalent binding under the reaction conditions. As a proof-of-concept, we applied boronic acids as secondary-sphere modifiers of N-heterocyclic carbenes that contained a hydroxy handle. The bound system formed in the reaction mixture catalysed the enantioselective benzoin condensations of a challenging substrate class that contains electron-withdrawing groups. Linear regression coupled with data visualization served to pinpoint the divergent origins of enantioselectivity for different substrates and decision tree algorithms served to formulate selection criteria for the appropriate secondary-sphere modifiers. The combination of this highly modular catalytic approach with machine-learning techniques provided mechanistic insights and guided the streamlined optimization process of a gram-scale reaction at low organocatalyst loading.

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Fig. 1: The influence of secondary-sphere modulation of NHCs on the benzoin reaction.
Fig. 2: Multivariate model of the enantioselectivity for 6 hour reactions across a set of electron-withdrawing aldehydes.
Fig. 3: Disentangling the effect of racemization.
Fig. 4: Binding studies of BA to NHC in THF.
Fig. 5: Cross-over experiments between the benzoin product and an additional aldehyde.

Data availability

All data generated or analysed during this study are available in this published article and its Supplementary Information files, or from the corresponding author upon request. Experimental procedures, results, characterization data, spreadsheets of parameters used in the models and MATLAB scripts used for model identification are accessible online as Supplementary Information.


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This research was supported by the Israel Science Foundation (Grant no. 1193/17). We thank M. Sigman, D. Toste, A. Neel and D. Pappo for fruitful discussions. D.V. acknowledges the PBC for a postdoctoral fellowship. S.C.G. acknowledges the Kreitman Graduate School for a postdoctoral fellowship. Z.A. acknowledges the Kreitman Graduate School for the chemo-tech scholarship. Mass spectra measurements were performed with the help of M. Shema-Mizrachi and M. M. Karpasas.

Author information




All the authors designed and performed the experiments and analysed the data. The Supplementary Information was compiled by S.C.G. and D.V., the product distribution by HPLC was performed by Z.A. and mathematical modelling was performed by A.M.

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Correspondence to Anat Milo.

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Supplementary information

Supplementary information

Supplementary experimental details and compound characterization data.

Supplementary data

Excel spreadsheet listing parameters used in combination with MATLAB scripts for model development.

MATLAB scripts

A compressed directory of all the scripts used for model development.

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Dhayalan, V., Gadekar, S.C., Alassad, Z. et al. Unravelling mechanistic features of organocatalysis with in situ modifications at the secondary sphere. Nat. Chem. 11, 543–551 (2019). https://doi.org/10.1038/s41557-019-0258-1

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