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Interrogating selectivity in catalysis using molecular vibrations


The delineation of molecular properties that underlie reactivity and selectivity is at the core of physical organic chemistry1,2,3,4,5, and this knowledge can be used to inform the design of improved synthetic methods or identify new chemical transformations6,7,8,9. For this reason, the mathematical representation of properties affecting reactivity and selectivity trends, that is, molecular parameters, is paramount. Correlations produced by equating these molecular parameters with experimental outcomes are often defined as free-energy relationships and can be used to evaluate the origin of selectivity and to generate new, experimentally testable hypotheses6,10,11,12. The premise behind successful correlations of this type is that a systematically perturbed molecular property affects a transition-state interaction between the catalyst, substrate and any reaction components involved in the determination of selectivity10,11. Classic physical organic molecular descriptors, such as Hammett4, Taft3 or Charton5 parameters, seek to independently probe isolated electronic or steric effects3,4,5,6,13,14. However, these parameters cannot address simultaneous, non-additive variations to more than one molecular property, which limits their utility. Here we report a parameter system based on the vibrational response of a molecule to infrared radiation that can be used to mathematically model and predict selectivity trends for reactions with interlinked steric and electronic effects at positions of interest. The disclosed parameter system is mechanistically derived and should find broad use in the study of chemical and biological systems.

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Figure 1: Approaches to interrogating reaction mechanisms.
Figure 2: Using infrared vibrations and Sterimol values to correlate enantioselectivity.
Figure 3: Using infrared vibrations to correlate enantioselectivity.
Figure 4: Using infrared vibrations to correlate site selectivity.
Figure 5: Developing a comprehensive model.


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This work was supported by the US National Science Foundation (CHE-0749506). We thank S. J. Miller and S. Yoganathan for discussions and for providing the peptide catalyst used in these studies. The support and resources of the Center for High Performance Computing at the University of Utah are gratefully acknowledged.

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A.M. and M.S.S. had the idea for the work; A.M. and E.N.B. performed the experiments; A.M. carried out computational and modelling analyses; A.M., E.N.B. and M.S.S. wrote the manuscript.

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Correspondence to Matthew S. Sigman.

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Milo, A., Bess, E. & Sigman, M. Interrogating selectivity in catalysis using molecular vibrations. Nature 507, 210–214 (2014).

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