Electrochemical Nozaki-Hiyama-Kishi Coupling: Scope, Applications, and Mechanism

Article abstract of DOI:10.1021/jacs.1c03007

One of the most oft-employed methods for C-C bond formation involving the coupling of vinyl-halides with aldehydes catalyzed by Ni and Cr (Nozaki-Hiyama-Kishi, NHK) has been rendered more practical using an electroreductive manifold. Although early studies pointed to the feasibility of such a process, those precedents were never applied by others due to cumbersome setups and limited scope. Here we show that a carefully optimized electroreductive procedure can enable a more sustainable approach to NHK, even in an asymmetric fashion on highly complex medicinally relevant systems. The e-NHK can even enable non-canonical substrate classes, such as redox-active esters, to participate with low loadings of Cr when conventional chemical techniques fail. A combination of detailed kinetics, cyclic voltammetry, and in situ UV-vis spectroelectrochemistry of these processes illuminates the subtle features of this mechanistically intricate process.

Full text of DOI:10.1021/jacs.1c03007

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Article
Electrochemical Nozaki−Hiyama−Kishi Coupling: Scope,
Applications, and Mechanism
Yang Gao, David E. Hill, Wei Hao, Brendon J. McNicholas, Julien C. Vantourout, Ryan G. Hadt,
Sarah E. Reisman,* Donna G. Blackmond,* and Phil S. Baran*
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ABSTRACT: One of the most oft-employed methods for C−C bond formation involving the coupling of vinyl-halides with
aldehydes catalyzed by Ni and Cr (Nozaki−Hiyama−Kishi, NHK) has been rendered more practical using an electroreductive
manifold. Although early studies pointed to the feasibility of such a process, those precedents were never applied by others due to
cumbersome setups and limited scope. Here we show that a carefully optimized electroreductive procedure can enable a more
sustainable approach to NHK, even in an asymmetric fashion on highly complex medicinally relevant systems. The e-NHK can even
enable non-canonical substrate classes, such as redox-active esters, to participate with low loadings of Cr when conventional chemical
techniques fail. A combination of detailed kinetics, cyclic voltammetry, and in situ UV−vis spectroelectrochemistry of these
processes illuminates the subtle features of this mechanistically intricate process.
achieved in a divided-cell setup,9 whereas Tanaka10 and
INTRODUCTION
■
Durandetti11 demonstrated galvanostatic means for achieving
The venerable Nozaki−Hiyama−Kishi (NHK) reaction, first
discovered in 19771 and formalized in 1986,2 is one of the
NHK reactions with Ni catalysts. The issues with these early
studies were the poor substrate scope, difficult setups (divided
most useful and reliable C−C bond-forming reactions in
organic synthesis (Figure 1).3 It generally involves the cross-
cell or reference electrodes), and the use of expensive
electrodes such as Pt. We thus undertook a clean-slate
approach to evaluate if the shortcomings of the prior art
could be addressed to overcome these limitations, which have
so far prevented any application of these electrochemical
methods. In this work, an electroreductively driven approach
to the NHK reaction is reported that exhibits a broad substrate
scope for real-world substrates and is operationally simple and
demonstrably scalable. Exemplified herein is the ability to
employ not only alkenyl halides in complex settings (both
racemic and with asymmetric induction) but also redox-active
coupling of an alkenyl halide with an aldehyde through the use
of stoichiometric Cr and catalytic Ni to afford an allylic alcohol
product.4 Versions of this reaction that are catalytic in Cr have
emerged using a stoichiometric metal reducing agent,5 and
asymmetry can be induced using chiral sulfonamide-based
ligands.6 Applications of the NHK reaction are manifold and
have emerged in natural product total synthesis,7 medicinal
chemistry, and even process chemistry settings. In fact, the
commercial route to the FDA-approved, natural-product-
inspired medicine Halaven utilizes this reaction more than
once.8 Given the enabling nature of this reaction and its
documented utility in industry, a more sustainable variant was
pursued to avoid the use of the often superstoichiometric
quantities of reducing agents employed to render the reaction
catalytic in Cr. In theory, the most inexpensive path to
achieving this is through electroreductive means, and three
reports point to this proof of concept as highlighted in Figure
1B.9−11 Grigg showed that a Pd variant of the NHK could be
Received: March 21, 2021
Published: June 15, 2021
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Table 1. Development and Optimization of the e-NHK
Coupling
Figure 1. Introduction to Nozaki−Hiyama−Kishi coupling.
esters.12,13 The latter transformation previously required 4
equiv of Cr salts and could not be rendered catalytic through
conventional chemical strategies.14 Finally, insights are
provided into both the canonical NHK and electrochemical
variant through a combination of detailed kinetics, cyclic
voltammetry, and in situ UV−vis spectroelectrochemical
studies.
a
b
c
1
0.2 mmol. Isolated yield. Yields determined by crude H NMR
d
using 1,3,5-trimethoxybenzene as the internal standard. Cr(II)/
Ni(II) are generated from a stainless steel anode (304L, Fe/Cr/Ni =
72/18/10).
ELECTROCHEMICAL NOZAKI−HIYAMA−KISHI
along with the need for careful control of potential (reference
electrode). Although the yield was low, the Tanaka
conditions10 (entry 4) benefitted from a more practical
procedure with a simple undivided cell setup and were
therefore chosen as a framework from which to optimize. The
development of a synthetically useful e-NHK reaction required
exploration of five main parameters: (1) oxophilic additives,
(2) ligands for Ni, (3) Ni source, (4) Cr source, and (5)
electrochemical parameters (electrode, electrolyte, current). A
summation of this study (for a more extensive summary, see
the Supporting Information) is outlined in Table 1 (entries 5−
18). The use of Cp2ZrCl2 (0.5 equiv) was found to be superior
to other common oxophilic additives such as silyl chlorides
(entries 5 and 6). A ligand screen demonstrated that
phenanthrolines performed better than bipyridines and that
n-Bu substitution at 2 and 2′ (L1) further improved the
reactivity (entries 7−10). The Ni and Cr sources also played a
vital role in reaction efficiency with NiCl2·glyme and CrCl2
proving optimal (entries 11−13). Electrochemically, an
inexpensive Al-based sacrificial anode and Ni-foam cathode
provided higher yield and both the electrolyte (TBAB) and
current settings (constant potential, undivided cell, no
reference electrode) were optimum (entries 14−18).
■
COUPLING: DEVELOPMENT AND SCOPE
Optimization studies began using alkyl aldehyde 1 and alkenyl
bromide 2. In its final manifestation, a 62% isolated yield of
allylic alcohol 3 could be obtained using only 20 mol % Cr
(Table 1, top). Operationally, the setup uses a simple
commercial potentiostat, and basic precautions to limit oxygen
and water content are employed (reactions conducted with an
Ar balloon). As the NHK reaction historically consists of
numerous reagents and additives, several iterative rounds of
optimization were conducted to arrive at the final protocol. At
the outset, known literature conditions (Table 1, entries 1−4)
were applied to these substrates, leading to low isolated yields
with no remaining starting materials. Although the conditions
11b
́
of Durandetti and Perichon
delivered the highest yield
(entry 3, 12% under the same conditions that led to similar
yields of exact products reported in that paper), they were not
a basis of our further optimization due to the experimentally
onerous requirement for a pre-electrolysis of a stainless-steel
anode (along with carefully weighing to determine the amount
of metal removed) followed by exchange with an iron anode.
Similarly, entries 1 and 2 were problematic due to the
requirement of slow syringe pump addition of the aryl halide
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a
Table 2. Scope of the e-NHK Coupling
a
Yields of isolated products are indicated in each case; yields in parentheses are from reactions under Tanaka’s condition determined by crude 1H
NMR using 1,3,5-trimethoxybenzene as the internal standard. TBAB = tetra-n-butylammonium bromide. Standard reaction conditions: aldehyde
(1.0 equiv), alkenyl bromide (2.0 equiv), NiCl2·glyme (2 mol %), L1 (3 mol %), CrCl2 (20 mol %), Cp2ZrCl2 (0.5 equiv), TBAB (0.1 M), DMF
(0.08 M), Al(+)/Ni foam(−), Ecell = 2 V, 4 F/mol.
With a concrete set of conditions in hand, the scope of e-
NHK was evaluated as depicted in Table 2 with direct
comparison in nearly all cases to past precedent (Tanaka,
Table 1, entry 4). Aside from operational complexities of past
e-NHK methods, the demonstrated use of alkyl aldehydes was
severely limited as well as the range of usable alkenyl halides.
In this work, a variety of both coupling partners could be
employedencompassing a broad range of functional groups
such as esters (8, 11, and 21), heterocycles (11, 16, and 17),
ethers (10, 12, 20, and 23), alkynes (10), alkyl chlorides (9
and 19), sulphones (22), and imides (25). The range of
suitable aldehydes was also expanded to include α,β-
unsaturated (31) and aryl systems containing cyclopropanes
(37), saturated heterocycles (33), and alkyl chlorides (32).
ASYMMETRIC VARIANT
■
Kishi’s breakthrough discovery on the use of ligands to induce
asymmetry was also translated to this electrochemical variant,
as depicted in Scheme 1.6 In this case, a stainless steel anode
proved ideal in terms of conversion and enantiocontrol, which
was modest (4.5:1) but on par with that observed in the purely
chemical version (cf. 44). The main difference in the
experimental setup involves a precoordination event of the
ligand to the Cr salt and proton sponge (1 h) followed by
addition to a solution of the remaining components and
subsequent electrolysis. In contrast to prior reports, the
electrochemical variant described herein does not require 2−
3 equiv of a metal reducing agent (Mn) and a full equivalent of
Zr.6d
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Scheme 1. Enantioselective Version of the e-NHK Coupling
a
b
Used for both Cr-complex formation and electrochemical reaction. Yields determined by crude 1H NMR using CH2Br2 as the internal standard;
c
d
e
er determined by Mosher ester analysis. Not determined. DIPEA was used for Cr-complex formation instead of a proton sponge. CH3CN was
used for Cr-complex formation; DMF/CH3CN (4:1 v/v). er reported by Kishi et al. using a stoichiometric CrCl2−L* complex.
f
With viable conditions for both the classical and asymmetric
NHK variants, five real-world examples of the latter manifold
were pursued using internal Eisai intermediates, some of which
are relevant to Halaven itself (Scheme 2).8a−c The chemo-
selectivity of these transformations is notable and bodes well
for adoption on a larger scale. Thus, aldehyde 46 could be
employed to deliver allylic alcohol 47a or 47b as the major
product as controlled by the ligand choice (Scheme 2A).
Similarly, aldehyde 48 could be engaged by alkenyl bromide 49
bearing homoallylic chloride to furnish either diastereomer as
the major product (Scheme 2B). The complex sugar-derived
aldehyde 5 could be easily alkenylated to controllably provide
diastereomer 52a or 52b based on the stereochemistry of the
ligand employed (Scheme 2C). The preparation of 52a was
accomplished on gram-scale demonstrating the robustness and
scalability of the e-NHK protocol. Even when both
components were complex, oxygen-rich architectures, a
serviceable yield of product was obtained with complete
control of diastereoselectivity (Scheme 2D). Notably, this
example demonstrates the use of enol triflates in the e-NHK
reaction. Finally, a macrocyclizing e-NHK reaction was
successful on aldehyde 56, delivering Halaven intermediate
57 in good yield (Scheme 2E).
chloride was found to be optimal rather than a Zr-based
oxophilic additive (entries 3−5). The use of CrCl3 rather than
CrCl2, a lower current (2.5 mA vs 5 mA, entry 7), and a Ni-
foam cathode (entry 8) proved essential. The scope of this
coupling was found to be identical to the chemical variant and
in nearly all cases provided a similar conversion to that
reported previously using only 20 mol % Cr vs 4 equiv and
only 1 equiv of RAE vs 2. In a few cases, however (Scheme
3C), chemical conditions proved superior (81, 83, and 84).
KINETICS INVESTIGATION OF BULK
ELECTROLYSIS
■
From a mechanistic standpoint, the classical NHK reaction has
been evaluated only sporadically and thus an in-depth study
was pursued in this work. Figure 2B outlines the main
mechanistic observations supported by kinetics, cyclic
voltammetry, and UV−vis spectroelectrochemistry. The
proposed classical NHK mechanism adapted to the electro-
chemical protocol is shown in Figure 2A (left). The proposed
mechanism involves a complex set of interconnected cycles:
low-valent Ni activates the vinyl halide in one cycle, while Cr
turns over the Ni catalyst and is in turn reduced by an external
chemical reductant. Cr participates in a second cycle involving
transmelation of the vinyl-Ni(II) species, followed by aldehyde
addition and trapping of the resulting Cr alkoxide species to
provide the product. These cycles may be envisioned as a set of
connected cogs, meaning that the overall rate will be controlled
by the slowest cog (cycle). To our knowledge, no detailed
kinetics studies have been performed. We undertook kinetic
studies15 of both the classical NHK and the optimized e-NHK
to develop further comparative insight into the mechanism. As
shown in Figure 2C, both protocols show a slight induction
period, but the e-NHK reaction proceeds nearly twice as
rapidly as the classical reaction using a chemical reductant. In
addition, the e-NHK reaction shows overlay in the “same
excess” protocol of reaction progress kinetic analysis (RPKA,
ELECTROCHEMICAL DECARBOXYLATIVE
NOZAKI−HIYAMA−KISHI COUPLING
■
Attention then turned to a recent disclosure using redox-active
esters (RAEs) in the NHK reaction (Scheme 3). In that
work,14 all 4 equiv of Cr were needed to achieve good
conversion (Scheme 3A, entry 1). Despite multiple attempts,
the use of exogenous metal reducing agents with lower Cr
levels proved unsuccessful (entry 2). In stark contrast to
conventional NHK reactions (vide supra), this problem was
singularly addressed using electroreductive conditions, which
in optimized form delivered a good yield of adduct 85 from
aldehyde 59 and RAE 58. In this transformation, a silyl
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a
Scheme 2. Applications of the e-NHK Coupling
a
Yields of isolated products are indicated in each case. See the Supporting Information for the reaction conditions. (A−E) Application of the e-
enantioselective NHK to five real-world examples including some that are relevant to the synthesis of Halaven.
see the Supporting Information), indicating no erosion of
electrode efficiency over the course of the reaction. Further
studies probed the effect of concentrations of reactants, Ni, Cr,
or Zr, as well as the effect of changing current (for e-NHK)
and Mn reductant (for classical NHK) (see the Supporting
Information). For both protocols, little change in rate was
observed with changes in any of these variables, with the
exception of the concentration of Cr and, in the case of e-
NHK, current. These findings suggest that the Cr(III)
reduction step controls the overall rate of the complex set of
reactions. This reveals an advantage of the e-NHK over the
classical reaction: the rate of the Cr reduction step may be
increased by increasing the current, while increasing the
concentration of the chemical reductant failed to substantially
alter the reaction rate. As discussed above, the e-NHK protocol
allows coupling of redox-active esters that fail in the classical
NHK protocol. This striking difference is demonstrated by
comparing the reaction progress profiles of the two protocols
for the reaction of RAE 58 with aldehyde 59, as shown in
Figure 2C. According to the proposed mechanism shown in
Figure 2A (right), it is hypothesized that the success of the e-
NHK decarboxylative variant can be attributed to this rapid
and selective Cr-reduction in contrast to chemical reducing
agents that lead to mostly decomposition of the RAE rather
than productive coupling. As shown in Figure 2F, reactions
initiated with CrCl3, which is relatively insoluble in DMF/
THF, exhibit an induction period that decreases with
increasing current. After the initial induction period, the
reaction rate becomes impervious to the magnitude of the
current, and the reaction exhibits zero-order kinetics in [58]
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Scheme 3. E-Decarboxylative NHK Coupling
a
b
0.2 mmol; yields determined by crude 1H NMR using 1,3,5-trimethoxybenzene as the internal standard. Isolated after desilylation (TBAF, THF)
c
of the crude mixture. Isolated as the corresponding triethylsilyl ether.
and positive order kinetics in both [Cr] and [59]. This
supports the proposal that the reactions at the electrode are
rapid and the rate-determining step becomes the reaction
between the Cr-alkyl species and the aldehyde (see the
Supporting Information for details).
techniques in characterizing species relevant to NHK
chemistry;16 thus, we were inspired to apply this approach to
examine the e-NHK. To confirm whether or not the e-NHK
had voltammetry consistent with an electrocatalytic mecha-
nism, we performed a series of analytical CV measurements.
CV of the e-NHK reaction mixture using CrCl2 precatalyst did
not display significant catalytic current for a potential sweep
from 0 to −3.5 V vs Fc+/0 (Figure S2). We suspected that the
rapid chemical reduction of Ni(II) (NiCl2·glyme and L4) by
CrCl2 obfuscated the voltammetry. When CrCl3·3THF was
used as the Cr source, however, a large cathodic current was
observed at −2.0 V vs Fc+/0 (Figure 2D, left, plum).
ELECTROANALYTICAL INVESTIGATIONS
■
To further elucidate the e-NHK electron transfer processes and
support the critical steps of the proposed mechanism, cyclic
voltammetry (CV) and UV−vis spectroelectrochemistry were
employed. Previous work by Berkessel and co-workers
demonstrated the utility of both of these electro-analytical
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Figure 2. Proposed mechanism and mechanistic studies. Part B: “xx” indicates that either Ni(0) or Ni(I) species is potentially operative in our
proposed mechanism. Part C, middle: Comparison of the dependence of reaction rates for classical NHK (purple bars, right) and e-NHK (orange
bars, left) on concentrations of 1, S11, NiCl2·glyme, CrCl2, Cp2ZrCl2, and Mn (for classical NHK) and current (for e-NHK). The designations (+)
and (−) indicate a reaction carried out with an increase or decrease, respectively, in the concentration of the noted variable. The percent deviation
of rate from standard conditions is given above each bar. See the Supporting Information for details and complete kinetic profiles. Part C, bottom
left: Comparison of reaction profiles for classical NHK (purple squares) with e-NHK (orange circles) for the reaction to form product 7 (see Table
1) using 0.08 M aldehyde 1 and 0.16 M vinyl bromide S11 in DMF. [NiCl2·glyme] = 0.0016 M; [L1] = 0.0024 M; [CrCl2] = 0.016 M; [Cp2ZrCl2]
= 0.04 M. For classical NHK: Mn powder = 0.16 M; [LiCl] = 0.16 M. For e-NHK: [TBAB] = 0.1 M; electrodes: (+)Al/(−)Ni foam; constant
current at 10 mA. Part C, bottom right: Comparison of reaction profiles for classical decarboxylative NHK (purple squares) with electrochemical
decarboxylative NHK (orange circles) for the reaction to form product 85 (see Scheme 3) using 0.08 M aldehyde 59 and 0.08 M redox active ester
58 in DMF/THF (see Scheme 3). [CrCl3] = 0.016 M; [TESCl] = 0.16 M. For classical NHK: Mn powder = 0.16 M. For e-NHK: [TBAClO4] =
0.1 M; electrodes: (+)Al/(−)Ni foam; constant current at 2.5 mA. Part D, left: Cyclic voltammetry of the e-NHK reaction under conditions for
spectroelectrochemical studies, prior to bulk electrolysis. Black: Cr(III)-based e-NHK mixture that does not contain the Ni(II). Teal: Cr(II)-based
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Figure 2. continued
e-NHK. Plum: Cr(III)-based e-NHK. All experiments contain [Cr] = 0.016 M, [NiCl2·glyme] = 0.0016 M, [L4] = 0.0024 M, [Cp2ZrCl2] = 0.04
M, [1] = 0.08 M, [S11] = 0.16 M, [TBAPF6] = 0.1 M, DMF, a Ni working electrode, and an Al counter electrode. CV data acquired with a 0.025
V/s scan rate. Part D, right: CrCl3·3THF: [CrCl3·3THF] = 2 mM. CrCl3·3THF + Ni(II) catalyst: [CrCl3·3THF] = 2 mM, [NiCl2·glyme] = 0.2
mM, [L4] = 0.3 mM. Ni(II) catalyst: [NiCl2·glyme] = 0.2 mM, [L4] = 0.3 mM. All CV experiments were run in DMF with [TBAPF6] = 0.1 M and
acquired with a scan rate of 100 mV/s, GC working electrode, and Al counter electrode. All potentials referenced to Fc+/0. Part E, left. [S11] = 160
mM, [1] = 80 mM, [CrCl2] = 16 mM, [Cp2ZrCl2] = 40 mM, [NiCl2·glyme] = 1.6 mM, [L4] = 2.4 mM (teal), [S11] = 160 mM, [1] = 80 mM,
[CrCl3·3THF] = 16 mM, [Cp2ZrCl2] = 40 mM, [NiCl2·glyme] = 1.6 mM, [L4] = 2.4 mM (plum), [S11] = 160 mM, [1] = 80 mM, [CrCl3·3THF]
= 16 mM, [Cp2ZrCl2] = 40 mM, [NiCl2·glyme] = 0 mM, [L4] = 0 mM (tangerine), and [CrCl3·3THF] = 16 mM (clover). Part E, right: UV−vis
of the Cr(II)-based e-NHK mixture prior to bulk electrolysis (solid teal), the Cr(II)-based e-NHK mixture after an applied potential of −1.5 V vs
Fc+/0 for 15 min and then an applied potential of −2.0 V vs Fc+/0 for 30 min (dashed teal), the Cr(III)-based e-NHK mixture prior to bulk
electrolysis (solid plum), and the Cr(III)-based e-NHK mixture after an applied potential of −1.5 V vs Fc+/0 for 15 min and then an applied
potential of −2.0 V vs Fc+/0 for 30 min (dashed plum). Absorbance data were baseline-corrected by taking the absorbance at 900 nm to be zero.
The asterisk indicates portions of the UV−vis absorbance data that have signal saturation inherent to the detector/light source used for these
experiments. Part F, middle left: Comparison of induction period with different current. [58] = 0.08 M, [59] = 0.08 M, [CrCl3] = 0.016 M,
[TESCl] = 0.16 M, [TBAClO4] = 0.1 M, with 2.5, 5, and 7.5 mA, respectively. Part F, middle right: reaction rate after removing the induction
period. Part F, bottom left: Comparison of the dependence of reaction rates on the concentration of 58, 59, and CrCl3.
To further identify potential species associated with this
catalytic wave, we acquired analytical CVs of the individual e-
NHK reaction components and then sequentially combined
components of the e-NHK reaction toward the complete
reaction mixture. The formal potential of CrCl3·3THF in DMF
was determined to be −1.06 V vs Fc+/0 with a peak-to-peak
separation, ΔEp, of 1.1 V at a scan rate of 100 mV/s, which
suggests slow electron transfer due to a large inner-sphere
reorganization energy (Figure 2D, right, plum). Upon addition
of Ni(II) to a solution of CrCl3·3THF, the main redox process
shifts to a half-wave potential of −1.2 V vs Fc+/0 and exhibits
greater reversibility (ΔEp = 0.130 V at 100 mV/s) (Figure 2D,
right, teal). While we cannot yet assign the nature of this
redox-active species, the influence of Ni(II) on the redox
behavior suggests the presence of a potential interaction
between the two metal species during electrocatalysis, which is
in accord with prior electrochemical studies.16 Introduction of
Cp2ZrCl2 and alkyl aldehyde 1 to the mixture of Cr(III) and
Ni(II) did not significantly change the CV of the Cr(III)/
Ni(II) mixture (Figure S4, clover vs teal line). In contrast,
addition of alkenyl bromide S11 to a solution of Cr(III),
Ni(II), and Cp2ZrCl2 yielded a significant cathodic current at
−2.0 V vs Fc+/0, which has an onset potential at a cathodic
wave that is only present when Ni(II) is in solution (Figure S7,
blue). Thus, we hypothesize that this catalytic current
originates from the electrocatalytic, low-valent Ni homocou-
pling of the alkenyl bromide, a reaction precedented by
from the resulting Cr(II) to the Ni(II) catalyst, which would
regenerate Cr(III) and form a proposed low-valent Ni species
that oxidatively adds to 1 for cross-coupling, as suggested by
the reaction pathways in Figure 2A. These results and those
discussed below point to a potential Cr(III) resting redox state.
After characterizing the catalytic current for the e-NHK
system, we next attempted to observe the proposed Cr(III)
catalyst resting state during bulk electrolysis by utilizing a
combination of ex situ UV−vis spectroscopy and in situ UV−
vis spectroelectrochemistry. The ligand field transitions of
pseudo-octahedral Cr(III) and high-spin, pseudo-octahedral
Cr(II) in ∼Oh symmetry provide excellent handles for
determining active components in the e-NHK mixture. For
example, the UV−vis spectrum of CrCl3·3THF dissolved in
DMF exhibits two bands with λmax = 677 and 487 nm. These
4
4
bands can be attributed to A2g
→
4T2g, T1g transitions,
respectively (Figure S23). Of note, a Fano antiresonance is
observed on the lower-energy ligand field transition (∼695
nm); this feature reflects the spin−orbit interaction between a
spectroscopically spin-forbidden ligand field excited state
2
2
(likely specific orbital components of either the Eg or T1g
states) with a vibrationally broadened spin-allowed ligand field
excited state.21,22 Antiresonances have been observed for
various other six-coordinate Cr(III) complexes.19,23 For Cr(II),
we observe a band at λmax = 843 nm, which can be assigned as
the 5Eg → 5T2g transition (Figure S21). We initially monitored
the reduction of Cr(III) to Cr(II) in the absence of other
components, confirming that one-electron reduction decreased
absorbance due to Cr(III) and increased absorbance due to
Cr(II) (Figure S28). We then probed the complete CrCl3·
3THF-based e-NHK reaction mixture during active electro-
catalysis. Both ligand field transitions for Cr(III) persisted at
open circuit potential (OCP) (Figure 2E, left, plum) and while
holding the potential at both −1.5 V vs Fc+/0 or −2.0 V vs
Fc+/0 (Figure 2E, right, plum), suggesting persistence of
Cr(III) during electrolysis. Interestingly, both absorptions for
Cr(III) slightly blue-shift and increase in intensity relative to
an independently prepared CrCl3·3THF sample (Figure 2E,
left, clover) as well as a non-electrolyzed CrCl3·3THF-based e-
NHK mixture that excluded Ni(II) catalyst (Figure 2E, left,
tangerine). One possibility for this shift is a change in the
inner-sphere coordination environment during redox cycling of
Cr(III/II) or an interaction between Ni and Cr(III). However,
a definitive conclusion cannot be drawn from these experi-
ments, and a future study will be directed at structural and
́
́
Nedelec and co-workers employing similar electrolysis
conditions.17 Next, we investigated the concentration depend-
encies of the catalytic wave and observed a linear correlation
between the peak catalytic current and both [CrCl3·3THF]
and [Ni(II)] (Figures S9 and S10).20 These electroanalytical
results differ from the observed kinetics of the reaction under
bulk electrolysis. We note that the analytical CV studies
require 8-fold more dilute concentrations, which can alter the
kinetics of the e-NHK and shift the Ni catalyst resting state
from a kinetically saturated species to another elementary step
that has a rate dependence on [Ni]. In electrocatalysis, a linear
relationship between [catalyst] and catalytic current is
expected for an electrocatalytic mechanism based upon ErCi′
(i.e., reversible electron transfer followed by an irreversible,
catalytic chemical step).18 The concentration dependence data
for Cr(III) and Ni(II) are indeed consistent with an e-NHK
mechanism that proceeds first by reversible cathodic electron
transfer to Cr(III) followed by irreversible electron transfer
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spectroscopic characterization of potential metal−metal
interactions.
All experimental procedures, analysis, and compound
characterization data (PDF)
We then performed UV−vis spectroelectrochemistry of the
e-NHK mixture using CrCl2 as the Cr source, despite the
absence of catalytic current in the analytical CV of this system.
Interestingly, upon addition of the Ni(II) catalyst to the CrCl2
e-NHK mixture at OCP, the Cr(II)-based 5E → 5T2 transition
immediately disappeared with concomitant appearance of
Cr(III) ligand field transitions (Figure 2E, left, teal). The
spectra suggest that CrCl2 rapidly reduces Ni(II) to a
catalytically active low-valent Ni complex. This is in agreement
with the lack of any detectable buildup of Cr(II) species during
active electrocatalysis for either the Cr(II)-based e-NHK or the
Cr(III)-based e-NHK reaction mixture. Temporal monitoring
of the bulk electrolysis for both the Cr(II)- and Cr(III)-based
e-NHK mixtures also revealed decreases in absorbance for
Cr(III) ligand field transitions (Figure 2E, right). The change
in [Cr(III)] at the beginning of bulk electrolysis could be
associated with either the induction period of the reaction or
the partial positive order in [Cr] observed during the bulk
electrolysis kinetic studies. Additionally, these in situ UV−vis
spectra of e-NHK bulk electrolysis support minimal buildup of
a putative low-valent Ni species during active electrocatalysis.
Taken together, the results from these electroanalytical
studies illustrate the following: (1) the thermodynamic and
kinetic redox properties of the Cr(III) are significantly different
in the presence of Ni(II), (2) the e-NHK electron transfer
processes likely proceed first by electrochemically reversible
cathodic electron transfer to Cr(III) followed by electrochemi-
cally irreversible electron transfer from Cr(II) to the Ni(II)
catalyst, (3) a Cr(III) species persists throughout the duration
of the e-NHK, which could correspond to a putative resting
state preceding rate-determining electron transfer observed
under bulk electrolysis conditions, and (4) there does not
appear to be an appreciable buildup of Cr(II) or low-valent Ni
species by UV−vis spectroscopy during active electrocatalysis.
AUTHOR INFORMATION
Corresponding Authors
■
Sarah E. Reisman − The Warren and Katharine Schlinger
Laboratory for Chemistry and Chemical Engineering,
Division of Chemistry and Chemical Engineering, California
Institute of Technology, Pasadena, California 91125, United
States; orcid.org/0000-0001-8244-9300;
Email: reisman@caltech.edu
Donna G. Blackmond − Department of Chemistry, Scripps
Research, La Jolla, California 92037, United States;
orcid.org/0000-0001-9829-8375; Email: blackmon@
scripps.edu
Phil S. Baran − Department of Chemistry, Scripps Research,
La Jolla, California 92037, United States; orcid.org/
0000-0001-9193-9053; Email: pbaran@scripps.edu
Authors
Yang Gao − Department of Chemistry, Scripps Research, La
Jolla, California 92037, United States
David E. Hill − The Warren and Katharine Schlinger
Laboratory for Chemistry and Chemical Engineering,
Division of Chemistry and Chemical Engineering, California
Institute of Technology, Pasadena, California 91125, United
States
Wei Hao − Department of Chemistry, Scripps Research, La
Jolla, California 92037, United States
Brendon J. McNicholas − Division of Chemistry and
Chemical Engineering, Arthur Amos Noyes Laboratory of
Chemical Physics, California Institute of Technology,
Pasadena, California 91125, United States
Julien C. Vantourout − Department of Chemistry, Scripps
Research, La Jolla, California 92037, United States;
orcid.org/0000-0002-0602-069X
Ryan G. Hadt − Division of Chemistry and Chemical
Engineering, Arthur Amos Noyes Laboratory of Chemical
Physics, California Institute of Technology, Pasadena,
California 91125, United States; orcid.org/0000-0001-
6026-1358
CONCLUSION
■
In summary, the NHK reaction, one of the most oft-employed
methods for C−C bond formation, particularly in natural
product total synthesis, has been rendered more sustainable24
using electroreductive conditions. Inspired by early proof-of-
concept work in this area, a careful choice of ligand, Cr, and Ni
sources and optimization of electrochemical parameters allow
the practitioner to avoid the use of superstoichiometric
metallic reducing agents and dramatically expand the scope
of those original reports. Application to Kishi’s asymmetric
variant as well as multiple realistic substrate classes is also
demonstrated. Most importantly, the RAE variant of the NHK
reaction, which cannot be rendered catalytic in Cr using
exogenous chemical reducing agents, can be uniquely enabled
electrochemically. Finally, a combination of detailed kinetics,
CV, and in situ UV−vis spectroelectrochemical studies teaches
new lessons about this useful transformation and may aid in
the invention and improvement of other electroreductive
processes with wide utility for synthesis.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c03007
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for this work was provided by NIH (GM-
118176), NSF (CCI Phase 1 grant 1740656 and Phase II grant
2002158), and Fujian Juhong Trade & Business Co. Ltd
(Y.G.). We thank Eisai for their generous donation of
compounds S24, S25, S26, S27, 53, 56, and L*. The authors
are grateful to Dr. Dee-Hua Huang and Dr. Laura Pasternack
(Scripps Research) for assistance with the nuclear magnetic
resonance (NMR) spectroscopy and to Dr. Jason Chen,
Brittany Sanchez, and Emily Sturgell (Scripps Automated
Synthesis Facility) for assistance with the HPLC, HRMS, and
LCMS analysis. Glovebox for anaerobic procedures provided
through NIH grant 1S10OD025208. R.G.H. acknowledges
financial support from Caltech and the Dow Next Generation
Educator Fund. Additional support was provided by the
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c03007.
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On Ni Catalysts for Catalytic, Asymmetric Ni/Cr-Mediated Coupling
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Beckman Institute Laser Resource Center supported by the
Arnold and Mabel Beckman Foundation.
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