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. 2019 Feb 22;363(6429):838-845.
doi: 10.1126/science.aav5606.

Scalable and safe synthetic organic electroreduction inspired by Li-ion battery chemistry

Byron K Peters #  1 , Kevin X Rodriguez #  1 , Solomon H Reisberg  1 , Sebastian B Beil  1 , David P Hickey  2 , Yu Kawamata  1 , Michael Collins  3 , Jeremy Starr  3 , Longrui Chen  4 , Sagar Udyavara  5 , Kevin Klunder  2 , Timothy J Gorey  2 , Scott L Anderson  2 , Matthew Neurock  6 , Shelley D Minteer  7 , Phil S Baran  8
Affiliations

Scalable and safe synthetic organic electroreduction inspired by Li-ion battery chemistry

Byron K Peters et al. Science. .

Abstract

Reductive electrosynthesis has faced long-standing challenges in applications to complex organic substrates at scale. Here, we show how decades of research in lithium-ion battery materials, electrolytes, and additives can serve as an inspiration for achieving practically scalable reductive electrosynthetic conditions for the Birch reduction. Specifically, we demonstrate that using a sacrificial anode material (magnesium or aluminum), combined with a cheap, nontoxic, and water-soluble proton source (dimethylurea), and an overcharge protectant inspired by battery technology [tris(pyrrolidino)phosphoramide] can allow for multigram-scale synthesis of pharmaceutically relevant building blocks. We show how these conditions have a very high level of functional-group tolerance relative to classical electrochemical and chemical dissolving-metal reductions. Finally, we demonstrate that the same electrochemical conditions can be applied to other dissolving metal-type reductive transformations, including McMurry couplings, reductive ketone deoxygenations, and epoxide openings.

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Conflict of interest statement

Competing interests: P.S.B. serves on a scientific advisory panel for Asymchem.

Figures

Figure 1:
Figure 1:. Background and reaction development.
A) Dissolving metal reduction on scale is not sustainable, B) Voltage range challenges for reductive electrochemistry, C) Electrochemical Birch precedence, D) Applying Li-ion battery technology to synthetic electrochemistry, E) Optimization of a simple electrochemical alternative to Birch reduction; GSW = Galvanized Steel Wire.
Figure 2.
Figure 2.. Experimental and computational analysis of the electroreduction of phenethyl alcohol
(3). A) Kinetic profile for the relative concentration of arene (3) and diene (4) in a control experiment involving pre-electrolysis of LiBr solution and Li0/solvated electrons detection experiment with naphthaldehyde. B) Reaction coordinate diagram from DFT computations of reaction intermediates for the reduction of 3 using either solution-phase Li0 mediation as an electron source (red, top), or a heterogeneous zinc electrode at −2.25 V vs. NHE as an electron source (blue, bottom); TSET1 = transition state for electron transfer 1; TSPT1 = transition state for proton transfer 1; TSPT2 = transition state for proton transfer 2; TSads = transition state for adsorption; NB = no barrier; ads superscripts refer to adsorbed species. C) Left: Plot of concentration of 4 generated per time under the standard reaction conditions, indicating zero order kinetics with respect to both the formation of 4 and consumption of 3; final yield of 4, 70%. Right: Plot of concentration of 4 generated per time under, varying the flow of current. Right, inset: Jordi-Burés analysis of current rate dependence, showing current dependence that approximates 1st-order kinetics.
Figure 3.
Figure 3.. Electrochemical data used to determine the role of various reaction components.
A) Comparative SWVs of 1mM naphthalene (5) at 10 (blue) and 100 (red) Hz, B) ATR IR of DMU without (red) and with (blue) LiBr, C) Scheme of the proposed mechanism of electrochemical Birch reduction, D) Proposed intermediate preceding the protonation.
Figure 4:
Figure 4:. Scope of the electrochemical Birch reaction
, encompassing arenes and heterocycles, and comparison to other modern Birch alternatives. NR = no reaction.
Figure 5.
Figure 5.. Scope of other reductive electroorganic transformations
A) Scope of the electrochemical reduction in a variety of other reactions, B) Modular scaleup of Birch reduction in flow
See this image and copyright information in PMC

References

    1. Rabideau PW, Marcinow Z, The Birch reduction of aromatic compounds. Org. React. (Hoboken, NJ, U. S.) 42, 222 pp (1992).
    1. Rabten W, Margarita C, Eriksson L, Andersson PG, Ir-Catalyzed Asymmetric and Regioselective Hydrogenation of Cyclic Allylsilanes and Generation of Quaternary Stereocenters via the Hosomi-Sakurai Allylation. Chem. - Eur. J 24, 1681–1685 (2018). - PubMed
    1. Peters BK et al., Enantio- and Regioselective Ir-Catalyzed Hydrogenation of Di- and Trisubstituted Cycloalkenes. J. Am. Chem. Soc 138, 11930–11935 (2016). - PubMed
    1. Liu J et al., Regioselective Iridium-Catalyzed Asymmetric Monohydrogenation of 1,4-Dienes. J. Am. Chem. Soc 139, 14470–14475 (2017). - PubMed
    1. Paptchikhine A, Itto K, Andersson PG, Sequential Birch reaction and asymmetric Ircatalyzed hydrogenation as a route to chiral building blocks. Chem. Commun. (Cambridge, U. K.) 47, 3989–3991 (2011). - PubMed

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