Abstract
Noyori–Ikariya type [(arene)RuCl(TsDPEN)] (TsDPEN, sulfonated diphenyl ethylenediamine) complexes are widely used C=O and C=N reduction catalysts that produce chiral alcohols and amines via a key ruthenium–hydride intermediate that determines the stereochemistry of the product. Whereas many details about the interactions of the pro-chiral substrate with the hydride complex and the nature of the hydrogen transfer from the latter to the former have been investigated over the past 25 years, the role of the stereochemical configuration at the stereogenic ruthenium center in the catalysis has not been elucidated so far. Using operando FlowNMR spectroscopy and nuclear Overhauser effect spectroscopy, we show the existence of two diastereomeric hydride complexes under reaction conditions, assign their absolute configurations in solution, and monitor their interconversion during transfer hydrogenation catalysis. Configurational analysis and multifunctional density functional theory (DFT) calculations show the λ-(R,R)SRu configured [(mesitylene)RuH(TsDPEN)] complex to be both thermodynamically and kinetically favored over its λ-(R,R)RRu isomer with the opposite configuration at the metal. Computational analysis of both diastereomeric catalytic manifolds show the major λ-(R,R)SRu configured [(mesitylene)RuH(TsDPEN)] complex to dominate asymmetric ketone reduction catalysis with the minor λ-(R,R)RRu [(mesitylene)RuH(TsDPEN)] stereoisomer being both less active and less enantioselective. These findings also hold true for a tethered catalyst derivative with a propyl linker between the arene and TsDPEN ligands and thus show enantioselective transfer hydrogenation catalysis with Noyori–Ikariya complexes to proceed via a lock-and-key mechanism.
Highlights
Asymmetric transfer hydrogenation catalysts are widely used in industry and synthetic laboratories as a safe, selective, and high yielding means of producing valuable chiral alcohols and amines from simple ketones and imines.[1−4] The class of arene−ruthenium complexes with chiral sulfonated diphenyl ethylenediamine (TsDPEN) ligands developed in the mid
We have previously reported how online FlowNMR spectroscopy may be used to study the speciation and kinetics of Noyori’s catalyst during ketone transfer hydrogenation from isopropanol[12] and from formic acid/triethylamine mixtures.[11]
To the best of our knowledge, this is the first example where both major and minor hydride species involved in this widely used chemistry have been observed and their kinetics quantified under reaction conditions
Summary
Asymmetric transfer hydrogenation catalysts are widely used in industry and synthetic laboratories as a safe, selective, and high yielding means of producing valuable chiral alcohols and amines from simple ketones and imines.[1−4] The class of arene−ruthenium complexes with chiral sulfonated diphenyl ethylenediamine (TsDPEN) ligands developed in the mid. The outer-sphere mechanism originally proposed by Noyori and co-workers requires simultaneous transfer of both hydrogen atoms via a concerted 6-membered transition state.[19] When it is assumed that both diastereomers of 3 adopt the λ-configuration (gauche; as predicted by DFT calculations and seen in the experimental crystal structure), the (R,R)SRu-3a diastereomer would be expected to have a lower transition state energy barrier than (R,R)RRu-3b, since both hydrogen atoms are correctly aligned for the cyclic transition state in the former (Scheme 6).[41] Surprisingly, this has never been investigated in any of the numerous computational studies of this catalyst, and the relative activities and selectivities of the two diastereomeric Ru−H complexes have remained unknown. When the second aliquot of acetophenone was added, only the major hydride (R,R)SRu-6a was observed to change in concentration with (R,R)RRu-6b remaining constant, demonstrating that the minor hydride complex (R,R)RRu-6b was not involved in the catalytic product formation
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