Quinone Reduction by Organo-Osmium Half-Sandwich Transfer Hydrogenation Catalysts

Article abstract of DOI:10.1021/acs.organomet.1c00358

Organo-osmium(II) 16-electron complexes [Os^II(η⁶-arene)(R-PhDPEN)] (where η⁶-arene =para-cymene or biphenyl) can catalyze the reduction of prochiral ketones to optically pure alcohols in the presence of a hydride source. Such complexes can achieve the conversion of pyruvate to unnatural http://www.w3.org/1999/xlinkd-lactate in cancer cells. To improve the catalytic performance of these osmium complexes, we have introduced electron-donor and electron-acceptor substituents (R) into thepara(R₁) ormeta(R₂) positions of the chiral R-phenyl-sulfonyl-diphenylethylenediamine (R-PhDPEN) ligands and explored the reduction of quinones, potential biological substrates, which play a major role in cellular electron transfer chains. We show that the series of [Os^II(η⁶-arene)(R-PhDPEN)] derivatives exhibit high turnover frequencies, enantioselectivities (>92%), and conversions (>93%) for the asymmetric transfer hydrogenation (ATH) of acetophenone-derived substrates and reduce duroquinone and menadione to their di-alcohol derivatives. Modeling of the catalysis using density functional theory (DFT) calculations suggests a mechanism involving formic acid deprotonation assisted by the catalyst amine groups, phenyl-duroquinone stacking, hydride transfer to Os^II, possible CO₂coordination, and tilting of the η⁶-arene ring, followed by hydride transfer to the quinone. These findings not only reveal subtle differences between Ru(II) and Os(II) catalysts, but also introduce potential biological applications.

Full text of DOI:10.1021/acs.organomet.1c00358

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Article
Quinone Reduction by Organo-Osmium Half-Sandwich Transfer
Hydrogenation Catalysts
̈
Elizabeth M. Bolitho, Nathan G. Worby, James P. C. Coverdale, Juliusz A. Wolny, Volker Schunemann,
and Peter J. Sadler*
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ABSTRACT: Organo-osmium(II) 16-electron complexes [OsII(η6-
arene)(R-PhDPEN)] (where η6-arene = para-cymene or biphenyl) can
catalyze the reduction of prochiral ketones to optically pure alcohols in
the presence of a hydride source. Such complexes can achieve the
conversion of pyruvate to unnatural D-lactate in cancer cells. To improve
the catalytic performance of these osmium complexes, we have introduced
electron-donor and electron-acceptor substituents (R) into the para (R1)
or meta (R2) positions of the chiral R-phenyl-sulfonyl-diphenylethyl-
enediamine (R-PhDPEN) ligands and explored the reduction of
quinones, potential biological substrates, which play a major role in
cellular electron transfer chains. We show that the series of [OsII(η6-
arene)(R-PhDPEN)] derivatives exhibit high turnover frequencies,
enantioselectivities (>92%), and conversions (>93%) for the asymmetric
transfer hydrogenation (ATH) of acetophenone-derived substrates and
reduce duroquinone and menadione to their di-alcohol derivatives. Modeling of the catalysis using density functional theory (DFT)
calculations suggests a mechanism involving formic acid deprotonation assisted by the catalyst amine groups, phenyl-duroquinone
stacking, hydride transfer to OsII, possible CO2 coordination, and tilting of the η6-arene ring, followed by hydride transfer to the
quinone. These findings not only reveal subtle differences between Ru(II) and Os(II) catalysts, but also introduce potential
biological applications.
phenyl diphenylethylenediamine) are readily synthesized by
reacting Ph-DPEN, 2-propanol, and [RuCl2(η6-arene)]2 dimer
under atmospheric conditions and exhibit high enantioselec-
tivities (99%) and conversions (98%) for the reduction of
ketones and imines.9−19 In this case, the enantioselectivity is
controlled by the phenyl groups of the chiral-chelated DPEN
ligand, allowing selective reduction of ketones/imines through
a six-membered pericyclic transition state (TS).16,20
In 2015, we reported a series of remarkably stable, easy-to-
synthesize 16-electron osmium(II) complexes, analogous to
the second-generation Noyori catalysts, with the general
formula [OsII(η6-p-cym)(Ph-DPEN)] (Figure 1).21 These
complexes exhibit high catalytic activity for ATH of
acetophenone-derived substrates (99% ee and 99% conversion)
compared to analogous Ru(II) catalysts and do not require
chemical activation prior to catalysis.20
INTRODUCTION
■
Asymmetric transfer hydrogenation (ATH) involves metal-
mediated catalytic transfer of hydride to a prochiral substrate
(i.e., ketone or imine) in an enantioselective manner, to form a
chiral product. This is of much industrial interest owing to the
importance of optically active alcohols and amines in both
agrochemicals and pharmaceuticals. For example, acetophe-
none is an industrial substrate which undergoes ATH
enantioselectively to form (S) or (R)-1-phenylethanol, which
are used as chiral precursors for a variety of applications
including drugs, preservatives, fragrances, flavors, and
cosmetics.1 ATH catalysts are widely used in drug synthesis,
while enzymatically catalyzed enantioselective reductions are
crucial in many steps of cell metabolism.2
In 2001, Noyori et al. developed chiral ruthenium complexes
with the general formula [RuII(diphosphane)(diamine)Cl2]
which catalyze the ATH of aldehydes, ketones, and imines with
impressive enantiomeric excesses (ee) of 97−99%.3−8 The
enantioselectivity of such catalysts is controlled by the chirality
of the phosphine group (i.e., BINAP) and the sterics of the
incoming ketone/imine. Second-generation RuII half-sandwich
catalysts with the general formula, [RuII(η6-p-cym)(Ph-
DPEN)], (where p-cym = para-cymene and Ph-DPEN =
Received: June 15, 2021
© XXXX The Authors. Published by
American Chemical Society
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MS to demonstrate that lysosomes and biological thiols (e.g.,
glutathione and cysteine) can play crucial roles in catalyst
deactivation inside cells.23 We also showed that such
complexes are partially accumulated into cells by active
(energy-dependent) mechanisms and remain intact in the
cytosol where catalysis likely occurs.23
In addition to the catalytic reduction of pyruvate, it is
relevant to explore other potential biological substrates present
in the cytosol or cell organelles to focus on identifying new
intracellular targets and to improve catalytic performance. In
particular, quinones play major roles in electron transport in
mitochondria, reactions which may contribute to a catalytic
mechanism leading to cell death. Quinones can protect cells
through various pathways, including modification of redox
homeostasis, anti-inflammatory activities, or release of
detoxification enzymes.24 Notably, the two-electron reduction
of quinones is known to be a major detoxification mechanism
for most quinones;25 hence, investigation of quinones as
substrates for catalysis is of significant interest. The cofactor
vitamin K1 (phylloquinone) undergoes intracellular redox
chemistry via its reduction (by nicotinamide adenine
dinucleotide, NADH) or epoxidation, essential reactions in
blood coagulation, and cell proliferation.26 The derivative
vitamin K3 (menadione) has shown promising tumor-killing
properties.27 Menadione causes intracellular oxidation via the
production of ROS disturbing the intracellular redox balance
(oxidative stress-induced cytotoxicity).27,28
Figure 1. (a) Structure of Noyori’s second-generation 18-electron
half-sandwich ruthenium(II) pre-catalyst [RuII(η6-p-cym)((1R,2R)-
TsDPEN(H))Cl] (Ru-1). (b) General structure of coordinatively
unsaturated 16-electron osmium(II) catalysts [OsII(η6-arene)-
((1R,2R)(R-PhDPEN))] 116 (for R substituents see Table 1). *
Denotes chiral centers.
Complex 1, [OsII(η6-p-cym)TsDPEN] (where TsDPEN =
tosyl diphenylethylenediamine), can also catalyze reductions in
cancer cells, a possible basis for the design of anticancer agents
with novel mechanisms of action.20 Both the (1S,2S) and
(1R,2R) isomers of 1 exhibit moderate in vitro anticancer
activity against a panel of human cancer cell lines,20,22,23 the
potency of which can be drastically improved upon co-
administration with non-toxic concentrations of sodium
formate (an approved food additive) as the hydride source.
Moreover, 1 was the first reported Os(II) synthetic catalyst to
convert pyruvate (a metabolic substrate) enantioselectively to
unnatural D-lactate and was specific for cancer versus healthy
cells. This is significant, as cancer cells have elevated levels of
lactate, thus making their metabolism a viable therapeutic
target. Confocal microscopy studies of a fluorescently labeled
derivative of 1 revealed that this family of complexes can also
generate toxic reactive oxygen species (ROS) in vivo, which
may allow exploitation of the redox vulnerabilities of cancer
cells. Additionally, we have used synchrotron-XRF and ICP−
Here, we report the synthesis and characterization of a series
of novel 16-electron OsII half-sandwich complexes (1−16)
with the general formula [Os(η6-arene)(R-PhDPEN)] (arene
= p-cymene or biphenyl, R-PhDPEN = R-substituted phenyl
diphenylethylenediamine, Figure 1). Initially, the catalytic
activity of these complexes in the reduction of acetophenone
(a widely used screening candidate for ATH) was investigated
Table 1. Catalytic Conversion (%), Enantiomeric Excess (ee, %), and Turnover Frequency (TOF, h−1) for the Reduction of
Acetophenone to (S)- or (R)-1-phenylethanol by OsII Complexes 1−16 in Comparison with RuII Complex Ru-1 in the
a
1
Presence of 5:2 Formic Acid/Triethylamine Azeotrope for 24 h at 310 K as Determined by H NMR and Chiral GC
c
d
c
complex
catalyst chirality
R1
R2
R3
R4
conv. (%)
config.
ee
TOF (h−1
)
Ru-1
SS
CH3
CH3
H
H
H
n/a
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
n/a
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
98
99
99
99
99
98
99
99
97
98
98
99
98
99
98
99
98
S
99
99
99
95
96
98
96
97
95
92
97
95
99
98
95
95
99
23
1
b
1
RR
RR
RR
RR
RR
RR
RR
SS
R
R
R
R
R
R
R
S
63.6 0.6
61.7 0.6
69.3 0.7
84.8 0.8
105.5 0.9
b
2
CH3
H
3
4
5
CF3
H
CF3
H
tBu
F
b
6
H
40
81
85
1
2
5
b
7
Br
H
b
8
I
H
b
9
RR
RR
SS
CH3
H
CF3
H
tBu
H
CH3
H
CF3
H
R
R
S
78.2 0.4
71.5 0.7
70.4 0.6
82.8 0.8
125.1 0.8
92.6 0.9
92.8 0.8
95.7 0.8
b
10
H
H
H
H
11
12
13
14
15
16
SS
S
RR
RR
RR
SS
R
R
R
S
F
Br
I
H
H
H
H
H
H
a
b
c
d
ee were determined in triplicate and were within 0.5%. Previously reported data.21,23 Determined by H NMR. Determined by chiral GC.
1
B
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Table 2. Catalytic Conversion (%), ee (%), and TOF (h−1) for the Reduction of 2-Chloroacetophenone or 4-
Methoxyacetophenone Using RR-Configured catalysts 1, 5, 13, and 16 in the Presence of 5:2 Formic Acid/TEA Azeotrope for
1
24 h at 310 K as Determined by H NMR and Chiral GC
a
b
c
b
X
Y
catalyst
S/C
conv. (%)
config.
ee (%)
TOF (h−1
n.d.
)
CH2Cl
CH2Cl
CH2Cl
CH3
CH3
CH3
H
H
H
1
5
13
1
5
13
100
100
100
100
100
100
97
99
99
67
70
88
S
S
S
R
R
R
94
98
98
n.d.
98
99
111.0 0.6
138.8 0.8
n.d.
OCH3
OCH3
OCH3
34.4 0.5
53.2 0.9
a
b
c
1
S/C = substrate/catalyst mol ratio. Determined by H NMR. Determined by chiral GC.
and later applied in a biological context to two quinones
(duraquinone and menadione) to further probe the potential
scope for their catalytic activity inside cancer cells. Density
Functional Theory (DFT) calculations suggest that the
mechanism of catalytic reduction of quinones by such catalysts
with formate as the hydride donor may have some unusual
features.
complexes with biphenyl as the arene was significantly higher
for the enantioselective reduction of acetophenone compared
to the analogous OsII p-cymene complexes (2.3× faster for
fluorine complex 14 versus 6, Table 1).
t
Catalysts bearing Bu groups at the para (R1, Figure 1)
positions (5 and 13, p-cymene and biphenyl, respectively)
exhibited higher catalytic turnover frequencies (TOF = 105.5
0.9 and 125.1 0.8 h−1) for the enantioselective reduction
of acetophenone. Remarkably, these reactions were faster than
for the parent compounds [OsII(η6-p-cym)(TsDPEN)] (1,
63.6 0.6 h−1) and [OsII(η6-biph)(Ph-DPEN)] (9, 78.2 0.4
h−1) and >5× faster than that of Noyori’s ruthenium catalyst
(23 1 h−1), while maintaining high enantioselectivity (98%)
and conversions (99%). The bulky electron-donating tert-butyl
groups of 5 and 13 may hinder the rotation of the large
electron-withdrawing arene groups, stabilizing the pericyclic
transition state resulting in faster ATH.21,31−33
RESULTS AND DISCUSSION
■
Synthesis and Characterization. We introduced various
substituents (R) into chiral R-phenyl-sulfonyl-diphenylethyle-
nediamine (Ph-DPEN) ligands by coupling phenylsulfonyl
t
chlorides carrying electron donors CH3 or Bu or electron
acceptors CF3, F, Br, or I in para (R1) or meta (R2) positions
for (1S,2S) or (1R,2R)-diphenylethylenediamine (DPEN)
using a reported method.29 All ligands (L1−L4) were
1
recrystallized from hot ethyl acetate, characterized by H and
13C NMR, HR-MS with purity >95% assessed by CHN
analysis. The new ligands were then reacted with [Os(η6-p-
cymene)Cl2]2 or [Os(η6-biphenyl)Cl2]2 dimers (synthesized
using reported methods),21,30 via a previously reported
biphasic reaction,21 in the presence of a base to generate
enantiomerically pure half-sandwich complexes 1−16 (Table
Moving the substituent position from para (R1) to meta (R2)
on the PhDPEN ligand influenced the catalytic activity.
Comparison of p-cymene complexes 3 (p-CF3) and 4 (m-
CF3) revealed that 3 (69.3 0.7 h−1) catalyzed the reduction
of acetophenone at a significantly slower rate compared to 4
(84.8
0.8 h−1). The same trend was observed for the
1
1). All OsII complexes (1−16) were characterized by H and
biphenyl p-CF3 and m-CF3 analogues (11 and 12,
respectively). This may imply that strongly electron-with-
drawing groups at the meta position stabilize a partial negative
charge on the adjacent carbon, enhancing the acidity of the
osmium center. In contrast, the p-CH3 and m-CH3 p-cymene
analogues (1 and 2) give rise to no change in the catalytic
activity (p = 0.0179); however, a small increase in TOF was
observed for the biphenyl analogues 9 (78.2 0.4 h−1) and 10
13C NMR, UV−visible spectroscopy, and HR-MS and CHN
analyses, all with >95% purity.
Catalytic Reduction of Acetophenone Derivatives.
The effect on the catalytic activity of the phenylsulfonyl ring
electron-donor or electron-acceptor substituents was inves-
tigated. Initially, we assessed the ATH catalytic activity of 1−
16 toward acetophenone in the presence of formic acid as a
(71.5
0.7 h−1). This is perhaps due to enhanced steric
1
hydride source, as determined by both H NMR spectroscopy
repulsion from the meta-CH3 and the bulky biphenyl group,
and gas chromatography−flame-ionization detection (GC−
amplified in 10 versus 9.34
FID) (Table 1). The time dependence of the catalytic
1
To explore the substrate diversity of tert-butyl complexes 5
and 13 (the most promising for acetophenone reduction), we
also screened their catalytic potential against acetophenone
derivatives 2-chloroacetophenone and 4-methoxyacetophe-
none (Table 2). The TOFs and conversion of 2-chloroaceto-
phenone to 2-chloro-1-phenylethan-1-ol were determined by
comparing the relative 1H NMR integrals of the product
doublet (CH2Cl, 3.35 ppm) and diminishing reagent doublet
(o-ArH, 7.57 ppm), Supporting Information, Figure S2.
Similarly, the reduction of 4-methoxyacetophenone to
1-(4-methoxyphenyl)ethan-1-ol was monitored by the 1H
NMR product quartet (CHOH, 4.37 ppm) and the reduction
reactions was monitored by H NMR. The catalytic turnover
frequency (TOF) (h−1) was determined from 1H NMR spectra
by monitoring the decrease in intensity of the singlet of
acetophenone (2.10 ppm) and the formation of the quartet for
1-phenylethanol (4.75 ppm). Acetophenone is prochiral, and
the chirality of the 1-phenylethanol product was determined by
chiral gas chromatography (GC) against known retention
times for the (S) or (R) alcohol products. Complexes 1−16 all
achieved high catalytic conversion (>98%) and ee (>92%) for
this reduction, exhibiting maximum turnover frequencies of
>61 h−1, which is ca. 3× faster than that of Noyori’s ruthenium
catalyst (23 1 h−1).21 Interestingly, the catalytic activity of
C
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Table 3. Catalytic Conversion (%), and TOF for Reduction of (a) Duroquinone and (b) Menadione Using Catalysts 1, 5, 13,
1
and 16 in the Presence of 5:2 Formic Acid/TEA Azeotrope for 12 h at 310 K as Determined by H NMR
catalyst
S/C
conv. (%)
TOF (h−1
)
duroquinone (a)
menadione (b)
1
5
13
16
5
200
200
200
200
200
200
98
99
97
92
87
96
48.1 0.4
67.9 0.6
55.5 0.3
36.5 0.5
94
2
3
13
145
of the reagent singlet (CH3, 2.03 ppm, Supporting
Information, Figure S3).
characterized by nuclear magnetic resonance (NMR) (1H, 13C,
1H COSY, H−13C HSQC, H−13C HMQC) and ESI-MS.
The reduction of duroquinone in the presence of tert-butyl
complex 5 and formic acid was monitored over 24 h, and the
identity of the product was investigated (Supporting
Information, Figure S4). The color of the solution changed
from light to dark yellow instantly, and after 24 h, it was
brown. The sharp 1H NMR signals confirmed the formation of
durohydroquinone, the fully reduced aromatic dialcohol
(Supporting Information, Figures S4). Notably, the four
equivalent methyl groups (CH3) were downfield shifted from
1.95 to 2.06 ppm and the reduction of both ketone groups to
alcohols (7.33 ppm, OH) was observed. The DEPT 13C NMR
spectrum further confirmed the structures, displaying three
carbon environments: 146.1, 121.8, and 13.4 ppm (Supporting
Information, Figure S5). The disappearance of the strongly
deshielded carbonyl carbons of duroquinone (187.2 ppm) and
appearance of the aromatic alcohols (121.8 ppm) confirmed
the formation of durohydroquinone. 1H−13C HSQC and
HMBC NMR (Supporting Information, Figures S6 and S7)
and ESI-MS (m/z calcd for C15H17O2N2 [M + 2Na−H]+,
211.1; found: 211.3) also supported this assignment. As all
NMR spectra were highly resolved, it is likely that any
paramagnetic intermediates were short-lived during the
catalytic conversions.
1
1
tert-Butyl complexes 5 (arene = p-cym) and 13 (arene =
biph) were shown to catalyze the reduction of 2-
chloroacetophenone to the corresponding S-configured alcohol
with high conversion (99%), ee (98%), and TOF (111.0 0.6
and 138.8
0.8 h−1). In contrast, the reduction of 4-
methoxyacetophenone by 5 and 13 revealed lower percentage
conversions (70 and 88%, respectively) and TOF (34.4 0.5
and 53.2
0.9 h−1), but still maintained higher ee (98 and
99%) under the same conditions. A higher catalytic turnover
for both substrates was observed for biphenyl complex 13
compared to the p-cymene analogue 5 (the same trend
observed for acetophenone itself), likely owing to the increased
electron-withdrawing properties of biphenyl.
Catalytic Reduction of Quinones. This family of organo-
osmium catalysts exhibits enhanced anticancer activity in vitro
when a hydride source is added,20,23 and can convert cellular
pyruvate to unnatural D-lactate, leading to cell death.20
However, catalytic turnover for this reaction inside cells was
extremely low,20 which is partially attributable to in-cell
deactivation of the catalyst (e.g., by thiols and lysosomes) in
the cytosol,23 but perhaps other cellular molecules can also act
as substrates. Understanding the intracellular catalytic activity
of these complexes may be crucial for their progression toward
preclinical development. Therefore, we have investigated the
possibility that quinones are potential substrates for ATH.
Quinones are highly redox-active and are capable of cycling
with their semiquinone radical anions, allowing the generation
of toxic ROS,35 perturbing cellular redox homeostasis through
the oxidation of biomolecules (such as lipids, proteins, and
DNA).24 To further explore the versatility of organo-osmium
complexes toward biological substrates and possible in-cell
catalysis, we have screened our most active catalysts for their
ability to reduce quinones in the presence of formic acid.
The ability of this family of complexes to catalyze the
reduction of the quinones, duroquinone and menadione, was
investigated using the three most promising osmium catalysts
(5, 13, and 16), in addition to parent compound 1. The
catalytic reduction of duroquinone and menadione in the
presence of 5:2 formic acid/TEA azeotrope was monitored,
and the reduction products for each quinone substrate were
Next, the TOF and percentage conversion of duroquinone
1
to durohydroquinone were determined using H NMR by
comparing the relative integrals of the newly formed
durohydroquinone singlet (CH3, 1.74 ppm) and diminishing
duroquinone singlet (CH3, 1.44 ppm), Supporting Informa-
tion, Figure S8. The OH peak for the product (7.33 ppm) was
not integrated due to exchange broadening. All three of the
complexes analyzed (1, 5, 13) demonstrated high conversions
(>92%) and TOFs (>36 h−1, substrate/catalyst molar ratio =
200) for duroquinone. Unlike the ATH of aromatic ketones,
the p-cymene complex 5 (67.9
0.6 h−1) catalyzed the
reduction of duroquinone faster than that of the biphenyl
analogue 13 (55.5 0.3 h−1) and parent compound 1 (48.1
0.4 h−1). Duroquinone is a highly conjugated planar substrate
with steric hindrance around both keto groups (two adjacent
methyl groups). Substrate steric bulk may disfavor the
transition state for reduction, and thus, complexes with an
D
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Figure 2. DFT energy reaction coordinate describing the pathway for the catalytic reduction of duroquinone to durohydroquinone in the presence
of 1 and formic acid.
extended η6-arene (biphenyl) may further obstruct the
substrate approach.
of the carbonyls in menadione is less sterically hindered (no
adjacent CH3 group), thus is more susceptible to nucleophilic
attack. This exposed carbonyl could drive the initial reduction
via the semi-quinone intermediate (gaining aromaticity),
increasing the energetic favorability of forming the fully
reduced product (second reduction).
A similar NMR approach was used to confirm the product
formed when menadione reacts with osmium catalysts 5 or 13
in the presence of formic acid for 24 h (Supporting
Information, Figure S9). The light-yellow menadione solution
immediately darkened (2 min) and after 24 h appeared black,
which on extraction gave rise to bright purple needle-like
crystals. This correlates with the crystalline purple appearance
of menadiol reported in the literature,36 suggesting that
menadione undergoes reduction to its aromatic diol (ESI-
MS: m/z calcd for C15H17O2N2 [M + 2ACN + H]+, 257.1,
This appears to be the first example of the reduction of
quinones by synthetic half-sandwich osmium(II) complexes
and may have implications for transfer hydrogenation reaction
in cells. The reduction of menadione results in increased
oxidative stress in cells by redox cycling and the generation of
ROS, which can lead to cell deathparticularly for cancer cells
which survive and proliferative under extreme conditions. For
example, ascorbate can induce oxidative stress which kills
breast cancer cells via the in-cell reduction of menadione.37
The ability for 1 to reduce menadione is consistent with the
reported generation of ROS in cells and in zebrafish
embryos.22 Hence, translation of this work into a biological
context may allow identification of further biomolecules
involved in the anticancer mechanism(s) of action. Likewise,
duroquinone allows the regeneration of quinone reductases in
cells and can raise the NAD+/NADH ratio, which helps cells to
survive in low NAD+ conditions,38,39 thus promoting cell
survival. Interestingly, this complements the ability of 1 to
catalytically convert 1,4-NADH to NAD+.40 Optimization of
such catalysts under biologically relevant conditions may give
rise to the identification of new substrates, providing further
insights into the catalytic mechanism(s) of action in cancer
cells.
DFT Modeling of Quinone Catalysis. In order to
elucidate the mechanism for the catalytic reduction of
duroquinone in the presence of complex 1 and formic acid,
DFT calculations were performed (Figure 2). DFT is a
valuable tool in bioinorganic chemistry which can be used to
model the structure and properties of complexes by providing a
solution obtained upon minimization of the density func-
tional.41
At the start of the reaction, the calculations show the
catalyst, quinone substrate (duroquinone), formic acid
(HCOOH), and water (DFT-1, Figure 2, see also pdb file
1.pdb in Supporting Information) with duroquinone parallel to
1
found: 257.2). Distinctive changes in the H NMR spectrum
corresponded to menadiol formation with the expected
chemical environments (Supporting Information, Figure S9).
The two peaks for strongly deshielded non-equivalent alcohol
substituents at 9.39 (HOCCH) and 8.29 ppm (HOCCH3),
correlated to the adjacent C−H carbon (111.8 ppm) and CH3
carbon (17.0 ppm), respectively in the 1H−13C HMBC
spectrum (Supporting Information, Figure S10). The OH
proton at 8.29 ppm is shielded by the adjacent electron-
donating CH3 group. Furthermore, the CH3 group (2.31 ppm)
and neighboring downfield CH group (1H 6.66 ppm, 13C 111.8
ppm) correlated strongly in both COSY and HMBC spectra
(Supporting Information, Figure S11 and S12).
All 1H and 13C NMR assignments were confirmed in the 2D
1H−13C HSQC spectrum (Supporting Information, Figure
S12). Menadiol formation likely proceeds via the semiquinone
intermediate, favorably gaining aromaticity driven by the
additional stabilization from extended conjugation via
resonance with the fused phenyl ring. The percentage
conversions and TOFs for the reduction of menadione to
menadiol by tert-butyl complexes 5 and 13 were determined by
1
comparing the relative H NMR integrals of the menadiol
singlet (CH3, 2.44 ppm) and diminishing menadione singlet
(CH3, 2.10 ppm), Supporting Information, Figure S13. Both 5
and 13 exhibited high conversions (>87%) and TOFs (>94
2 h−1) for the reduction of menadione (Table 3). Interestingly,
the biphenyl complex (13) catalyzed the reaction more
efficiently than the p-cymene analogue (5), with TOFs of
145 3 and 94 2 h−1, respectively. Unlike duroquinone, one
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Figure 3. DFT structures for the catalytic reduction of duroquinone in the presence of SS-1 (Os) or SS-Ru-1 and formic acid. (a) Intermediate 3a
(Figure 2, 77 kJ/mol) showing an Os−H bond (1.608 Å) is formed, while linear CO2 remains in the second coordination sphere forming a T-
shaped contact with the hydride and a C−H bond length of 2.46 Å. The η6-coordination of the arene is retained. (b) Optimized structure of SS-Ru-
1 showing Ru−HCO2− coordination via a Ru−H bond of distance 1.72 Å. Note that the optimized structure of the Ru complex corresponds to a
different diasteroisomer (the absolute configuration of the N,N′ ligand is retained, yet the absolute configuration of the metal center is different).
Atom colors: H light gray; C dark gray; N violet; O red; S, yellow; Ru teal; Os dark cyan. Some C atoms of the duroquinone ring are labeled with
black dots to aid identification.
one of the phenyl groups of DPEN with an onset of (two C−C
contacts of 3.68 and 3.60 Å) stacking interactions. Interest-
ingly, the O-atoms of formic acid point away from the osmium
catalyst, and instead, it is orientated with its H-atom toward
the OsII center with an H−Os distance of 3.05 Å. As the
reaction proceeds, formate is deprotonated by transferring H+
to the NH group of the catalyst (DFT-2, Figure 2, file 2.pdb in
Supporting Information), with the water molecule now in close
proximity to formate. In the structure of DFT-2, duroquinone
is still roughly parallel to the phenyl group of DPEN, with
previously mentioned C−C contacts of 3.72 and 3.45 Å,
respectively. As the reaction proceeds further, two inter-
mediates are formed, DFT-3a and DFT-3b (Figure 2), with
the former being lower in energy. In intermediate DFT-3a (77
kJ/mol, see the file 3a.pdb in Supporting Information) an Os−
H bond (1.608 Å) is formed (Figure 3). The CO2 molecule
stays in the second coordination sphere, forming a T-shaped
contact with the hydride with a C−H distance of 2.46 Å
(Figure 3). The η6-coordination of the arene is retained
(Figure 3). Alternatively, in the intermediate DFT-3b (Figure
2) (82 kJ/mol, see file 3b.pdb in Supporting Information),
both bent CO2 (O−C−O angle of 124.6°) and hydride (H−)
are bound to the osmium center with bond distances of 2.206
and 1.580 Å, respectively. This causes a weakening of the arene
coordination, with a mean Os−C distance of 2.464 Å
compared to 2.397 Å for the second hydride complex, a
greater elongation of two of the Os−C bonds by ca. 0.2 Å. The
consequent ring-tilt in the coordinated η6-arene of the para-
cymene allows the duroquinone to approach on the opposite
side to the reactive Os−H bond (Figure 2). In this structure,
the duroquinone is no longer parallel to the phenyl groups of
DPEN. It is notable that we were unable to optimize any
structure with the HCO2− bound to osmium. However, for the
Ru analogue, Ru−HCO2− coordination was found with a Ru−
H distance of 1.72 Å (Figure 3). Finally, the quinone accepts
hydride from Os−H and a proton from solution, to reduce
both CO groups of the duroquinone substrate to form
durohydroquinone (DFT-4, Figure 2, see file 4b.pdb in
Supporting Information). The osmium catalyst 1 is regen-
erated in the process.
EXPERIMENTAL SECTION
■
Chemical Reagents. Osmium trichloride (OsCl3·3H2O) was the
kind gift of Heraeus. (1R,2R) and (1S,2S)-1,2-diphenylethylenedi-
amine were purchased from Alfa Aesar, respectively. All benzene-
sulfonyl chlorides, acetophenone, 2-chloroacetophenone, 4-methoxy-
acetophenone, duroquinone, 5:2 formic acid triethylamine azeotrope,
β-nicotinamide adenine dinucleotide (disodium salt), anhydrous
magnesium sulfate, and anhydrous dichloromethane were purchased
from Sigma-Aldrich (UK), along with all deuterated solvents: d6-
benzene, d-chloroform, and DMSO-d6. All commercial solvents were
purchased from Sigma-Aldrich (UK).
Electrospray Ionization Mass Spectrometry. Ligands and
complexes were dissolved in the minimum amount of DCM and
diluted in acetonitrile and analyzed on a high-resolution Bruker maXis
II Q-TOF mass spectrometer (electrospray in positive mode) with a
scan range of m/z 50−3000 (1 Hz spectra rate). The quinone
reduction products were dissolved in acetonitrile and analyzed on a
low-resolution single quad Agilent 6130B (electrospray in positive
mode) with a scan range of either m/z 400−1000 or m/z 50−500.
Elemental Analysis. Carbon, hydrogen, and nitrogen (CHN)
analyses was performed in duplicate by Warwick Analytical Services
on an Exeter Elemental Analyser CE440.
Chiral Gas Chromatography. GC experiments were conducted
using the GC−FID, CHROMPAC cyclodextrin-β-236M-19, 50 m ×
0.25 mm × 0.25 μm, P = 15 psi, H2 gas, T = 473 K.
Microwave Reactor. For the synthesis of osmium dimers, a CEM
Discovery SP Microwave Reactor was used in p-cymene and biphenyl
dimer synthesis (10 min, 413 K, 200 W, and 250 psi), and biphenyl
complex synthesis (10 min, 393 K, 150 W, and 250 psi).21,23
Nuclear Magnetic Resonance. Unless otherwise stated, all
samples were prepared in DMSO-d6 in 5 mm NMR tubes and
recorded at 298 K using Bruker AVANCE III HD 500 MHz or Bruker
AVANCE III HD 400 MHz (1H) instruments. For kinetic studies, the
Bruker AVANCE III HD 400 MHz was used to record spectra every
2−10 min at 310 K. Bruker TOPSPIN 3.0 and SpinWorks Java
(2019) were utilized to process all data.
DFT Calculations. The relevant structures were optimized using
the B3LYP exchange−correlation functional42 and CEP-31g basis
set43 and Grimme D3 dispersion correction.44 All calculations have
been performed with Gaussian 16.45 The Gaussians IEFPCM option
was used to model the formic acid as solvent. The modeling was
performed for the duroquinone reduction with the SS-1 complex as
the catalyst. The formation of the hydride complex introduces an
additional chirality center on the osmium leading to diasteroisomer-
ism. In our modeling, we considered only one diastereoisomer with
the above given absolute configuration of the ligand. The structure of
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the diasteroisomer is shown in the pdb files 3a.pdb and 3b.pdb in
Supporting Information.
2H, ArH), 7.24−7.14 (m, 7H, ArH), 6.86−6.75 (m, 5H, ArH), 4.63
3
3
(d, J(H,H) = 9.5 Hz, 1H, NHCHPh), 4.47 (d, 1H, J(H,H) = 10.0
Hz, NH2CHPh), 1.19 (s, 9H, Ar(CH3)3); 13C NMR (125 MHz,
DMSO-d6, 298 K): δ 154.6, 137.6, 135.3, 134.2, 128.6, 128.2, 127.6,
127.5, 126.1, 125.1, 61.5, 58.4, 45.3, 30.7; HRMS (ESI): m/z calcd for
C24H29N2O2S [M + H]+, 409.1871; found, 409.1875. Elemental
analysis Calcd (%) for C24H28N2O2S: C, 70.58 (70.56); H, 6.94
(6.91); N, 6.90 (6.86).
Synthesis and Characterization of Ligands. General Syn-
thesis of Benzenesulfonamide Ligands (L1−L4). To a solution of
(1R,2R)-1,2-diphenylethylenediamine or (1S,2S)-1,2-diphenylethyle-
nediamine (1 mol equiv) and triethylamine (1 mol equiv) in
anhydrous dichloromethane (50 mL) cooled in an ice bath, the
chosen sulfonyl chloride (1.2 mol equiv) in anhydrous dichloro-
methane (150 mL) was added dropwise over 1 h. The ice bath was
removed, and the reaction mixture was stirred for 5 h. The product
was extracted with distilled water (3 × 10 mL), dried over magnesium
sulfate, and concentrated in vacuo with diethyl ether to yield a solid.
N-(2-Amino-1,2-diphenylethyl)-3-methylbenzenesulfonamide
(RR-L1). Synthesized as per the general procedure using (1R,2R)-1,2-
diphenylethylenediamine (0.7 g, 3.20 mmol, 1 mol equiv), triethyl-
amine (46 mL, 3.2 mmol, 1 mol equiv), and 3-methylbenzenesulfonyl
chloride (0.464 mL, 3.2 mmol, 1 mol equiv). The product was
recrystallized in hot ethyl acetate to yield a pale yellow amorphous
Synthesis and Characterization of Complexes. Complexes 1,
6, 7, 8, and 9 were synthesized as previously reported.20,23
General Synthesis of Osmium p-Cymene Complexes. Osmium p-
cymene-chlorido dimer ([Os(η6-p-cym)Cl2]2, 1 mol equiv) was
dissolved in DCM and benzenesulfonamide ligand (2.15 mol equiv)
were stirred in DCM (15 mL). KOH (∼50 mg) was added followed
by water (to dissolve the base). A color change from yellow was
observed upon vigorous stirring. The organic layer was concentrated
in vacuo to typically yield a red-orange solid which was recrystallized
from DCM/hexane.
1
solid (0.99 g, 2.95 mmol, 92.3%). H NMR (500 MHz, DMSO-d6,
[Os(p-cym)(m−CH3−BsDPEN)] (2). Synthesized as per the general
procedure using [Os(η6-p-cymene)Cl2]2 (51.5 mg, 0.065 mmol, 1 mol
equiv) and RR-L1, N-((1R,2R)-2-amino-1,2-diphenylethyl)-3-meth-
ylbenzenesulfonamide (47.6 mg, 0.13 mmol, 2 mol equiv). A rapid
color change from a yellow to dark orange solution was observed in
the bottom (organic) layer upon addition of KOH (56.1 mg, 1 mmol,
15 mol equiv). The solid was recrystallized from DCM/hexane to
yield a dark brown amorphous solid (43.1 mg, 0.061 mmol, 93.8%).
1H NMR (500 MHz, DMSO-d6, 298 K, TMS): δ 8.16 (s, 1H, NH),
7.49 (d, 2H, 3J(H,H) = 7.0 Hz, SO2ArH), 7.30−7.07 (m, 11H, ArH),
298 K, TMS): δ 7.35−7.30 (m, 1H, SO2ArH), 7.24−7.17 (m, 3H,
SO23ArH), 7.16−7.08 (m, 5H, ArH), 7.04−6.87 (m, 5H, ArH), 4.39
3
(d, J(H,H) = 7.6 Hz, 1H, NHCHPh), 4.00 (d, J(H,H) = 7.6 Hz,
1H, NH2CHPh), 2.19 (3H, CH3ArSO2); 13C NMR (125 MHz,
DMSO-d6, 298 K): δ 142.5, 141.1, 139.5, 137.9, 132.2, 128.3, 127.5,
127.3, 126.6, 123.2, 64.9, 60.6, 20.6; HRMS (ESI): m/z calcd for
C21H23N2O2S [M + H]+, 367.1480; found: 367.1476. Elemental
analysis Calcd (%) for C21H22N2O2S: C, 68.87 (68.83); H, 6.09
(6.05); N, 7.69 (7.64).
3
N-(2-Amino-1,2-diphenylethyl)-4-(trifluoromethyl)-
benzenesulfonamide (RR-L2). Synthesized as per the general
procedure using (1R,2R) or (1S,2S)-1,2-diphenylethylenediamine
(0.36 g, 1.69 mmol, 1 mol equiv), triethylamine (0.23 mL, 1.65 mmol,
1 mol equiv), and 4-(trifluoromethyl)benzene sulfonyl chloride (0.51
g, 2.07 mmol, 1.2 mol equiv). A white amorphous solid (0.306 g,
6.97−6.79 (m, 1H, ArH), 5.87 (d, 1H, J(H,H) = 5.5 Hz, Os-ArH),
5.75 (d, 1H, 3J(H,H) = 5.5 Hz, Os-ArH), 5.55 (d, 1H, 3J(H,H) = 5.0
3
Hz, Os-ArH), 5.43 (d, 1H, J(H,H) = 5.0 Hz, Os-ArH), 4.65 (s, 1H,
NCHPh), 3.88 (d, 1H, 3J(H,H) = 3.5 Hz, NHCHPh), 2.45−2.34 (m,
1H, Os-ArHCH(CH3)2), 2.18 (s, 3H, Os-ArHCH(CH3)2), 2.12 (s,
3H, Os-ArHCH(CH3)2), 1.24 (d, 3H, 3J(H,H) = 6.5 Hz, Os-
1
3
ArHCH3), 1.13 (d, 3H, J(H,H) = 6.5 Hz, SO2ArHCH3); 13C NMR
0.7267 mmol, 44.1%) was formed. H NMR (500 MHz, DMSO-d6,
298 K, TMS): δ 7.59−7.50 (m, 4H, ArH), 7.15−7.04 (m, 5H, ArH),
(125 MHz, DMSO-d6, 298 K): δ 146.9, 144.7, 137.5, 131.1, 127.7,
127.4, 126.9, 126.4, 126.0, 123.5, 90.3, 82.0, 79.4, 76.3, 73.4, 71.0,
70.5, 67.0, 32.0, 23.3, 22.9, 20.8, 20.1; UV/Vis λmax, 278, 405, 472 nm;
HRMS (ESI): m/z calcd for C31H35N2O2OsS [M + H]+, 691.2034;
found, 691.2028. Elemental analysis Calcd (%) for C31H34N2O2OsS:
C, 56.64 (54.60); H, 5.36 (5.30); N, 4.02 (3.98).
6.97−6.75 (m, 5H, ArH), 4.37 (d, 3J(H,H) = 6.5 Hz, 1H, NHCHPh),
3
3.98 (d, J(H,H) = 6.5 Hz, 1H, NH2CHPh); 13C NMR (125 MHz,
DMSO-d6, 298 K, TMS): δ 145.4, 142.9, 139.8, 131.9, 131.6, 128.1,
127.9, 127.8, 127.7, 127.5, 127.1, 126.9, 126.1, 65.6, 61.0; HRMS
(ESI): m/z calcd for C21H20F3N2O2S [M + H]+, 421.1198; found,
421.1190. Elemental analysis Calcd (%) for C21H19F3N2O2S: C, 60.00
(59.99); H 4.56 (4.56); N, 6.61 (6.66).
[Os(p-cym)(p−CF3−BsDPEN)] (3). Synthesized as per the general
procedure using [Os(η6-p-cymene)Cl2]2 (58.7 mg, 0.074 mmol, 1 mol
equiv) and N-((1R,2R)-2-amino-1,2-diphenylethyl)-3-methylbenze-
nesulfonamide (RR-L2) (59.0 mg, 0.14 mmol, 2 mol equiv). A
rapid color change from a yellow to deep red solution was observed
upon addition of KOH (56.1 mg, 1 mmol, 15 mol equiv) addition.
The solid was recrystallized from DCM/hexane to yield a dark brown,
N-(2-Amino-1,2-diphenylethyl)-3-(trifluoromethyl)-
benzenesulfonamide (RR-L3). Synthesized as per the general
procedure using (1R,2R) or (1S,2S)-1,2-diphenylethylenediamine
(0.73 g, 3.42 mmol, 1 mol equiv), triethylamine (0.48 mL, 3.41 mmol,
1 mol equiv), and 3-(trifluoromethyl)benzenesulfonyl chloride (0.655
mL, 4.09 mmol, 1.2 mol equiv). The product was recrystallized with
hot ethyl acetate to yield a pale yellow crystalline solid (0.414 g, 0.984
1
amorphous solid (44 mg, 0.061 mmol, 93.7%). H NMR (500 MHz,
DMSO-d6, 298 K, TMS): δ 8.30 (s, 1H, NH), 7.61−7.42 (m, 5H,
1
3
mmol, 28.8%). H NMR (500 MHz, DMSO-d6, 298 K, TMS): δ
ArH), 7.24−7.10 (m, 9H, ArH), 6.04 (d, J(H,H) = 5.2 Hz, 1H,
8.95−8.87 (m, 1H, NH2), 7.83 (d, 3J(H,H) = 8.0 Hz, 1H,
F3CArH), 5.92 (d, 3J(H,H) = 4.8 Hz, 1H, F3CArH), 5.84 (d, 3J(H,H)
3
3
F3CCHCHCH), 7.79 (d, J(H,H) = 8.5 Hz, 1H, F3CCHCHCH),
= 4.8 Hz, 1H, F3CArH), 5.76 (d, J(H,H) = 5.2 Hz, 1H F3CArH),
7.66 (s, 1H, F3CCHC), 7.57 (t, 3J(H,H) = 7.5 Hz, 1H,
F3CCHCHCH), 7.33−7.25 (m, 5H, ArH), 6.94−6.85 (m, 5H
ArH), 4.81 (d, 3J(H,H) = 10.0 Hz, 1H, NHCHCH), 4.59 (d,
3J(H,H) = 10.5 Hz, 1H, NHCHCH); 13C NMR (125 MHz, DMSO-
3
4.26 (s, 1H, NCHPh), 3.90 (d, J(H,H) = 4.0 Hz, 1H, NHCHPh),
2.36−1.99 (m, 4H, ArCH3 and ArCH(CH3)2), 1.33 (d, 3H,
3
ArCH(CH3)2), 1.23 (d, J(H,H) = 7.6 Hz, 3H, ArCH(CH3)2); 13C
NMR (125 MHz, DMSO-d6, 298 K): δ 130.8, 128.7, 128.3, 127.8,
127.4, 127.0, 126.3, 82.6, 74.9, 73.0, 72.2, 68.2, 64.7, 57.5, 22.7, 20.8,
186; UV/Vis λmax, 323, 403, 479 nm; HRMS (ESI): m/z calcd for
C31H31F3N2O2SOs [M + H]+, 745.1674; found, 745.1746. Elemental
analysis Calcd (%) for C31H31F3N2O2OsS: C, 50.09 (50.12); H, 4.19
(4.21); N, 3.71 (3.77).
d6, 298 K, TMS): δ 173.0, 142.1, 135.1, 134.1, 130.1, 128.3, 128.2,
127.7, 127.6, 122.9, 61.7, 58.1, 32.3; HRMS (ESI): m/z calcd for
C21H20F3N2O2S, [M + H]+, 421.1198; found, 421.1196. Elemental
analysis Calcd (%) for C21H19F3N2O2S: C, 59.97 (59.99); H, 4.59
(4.63); N, 6.67 (6.63).
[Os(p-cym)(m−CF3−BsDPEN)] (4). Synthesized as per the general
procedure using [Os(η6-p-cymene)Cl2]2 (54.2 mg, 0.069 mmol, 1 mol
equiv) and N-((1R,2R)-2-amino-1,2-diphenylethyl)-4-
(trifluoromethyl)benzenesulfonamide (RR-L3) (56.3 mg, 0.14
mmol, 2 mol equiv). A rapid color change from a yellow to a red
solution was observed upon addition of KOH (56.1 mg, 1 mmol, 15
mol equiv). The solid was recrystallized from DCM/hexane to yield a
N-2-Amino-1,2-diphenylethyl-4-(tert-butyl)benzenesulfonamide
(RR-L4). Synthesized as per the general procedure using (1R,2R)-1,2-
diphenylethylenediamine (0.76 g, 3.58 mmol, 1 mol equiv),
triethylamine (0.50 mL, 3.58 mmol, 1 mol equiv), and 4-(tert-
butyl)benzenesulfonyl chloride (1.17 g, 5.01 mmol, 1.4 mol equiv).
The product was recrystallized from hot ethyl acetate to yield a white
1
solid amorphous solid (1.267 g, 3.10 mmol, 86.7%). H NMR (500
MHz, DMSO-d6, 298 K, TMS): δ 8.75 (s, 1H, NH2) 7.31−7.27 (m,
1
dark red amorphous solid (40 mg, 0.062 mmol, 84.4%). H NMR
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(500 MHz, DMSO-d6, 298 K, TMS): δ 8.35 (s, 1H, NH), 7.80−7.70
(m, 1H, ArH), 7.64−7.54 (m, 2H, ArH), 7.52−7.40 (m, 2H, ArH),
[Os(bip)(p−CF3−BsDPEN)] (11). Synthesized as per the general
procedure using [Os(η6-biphenyl)Cl2]2 (67 mg, 0.081 mmol, 1 mol
equiv) and (1S,2S)-2-amino-(1,2-diphenylethyl)-4-(trifluoromethyl)-
benzenesulfonamide (SS-L2) (63 mg, 0.15 mmol, 2 mol equiv). A
color change from yellow to a red solution was observed upon the
addition of KOH (56.1 mg, 1 mmol, 12 mol equiv). The solid was
recrystallized from DCM/hexane to yield a red amorphous solid (50
3
7.31−7.09 (m, 9H, ArH), 6.00 (d, J(H,H) = 5.0 Hz, 1H, Os-ArH),
5.88 (d, 3J(H,H) = 5.0 Hz, 1H, Os-ArH), 5.79 (d, 3J(H,H) = 5.5 Hz,
3
1H, Os-ArH), 5.70 (d, J(H,H) = 5 Hz, 1H, Os-ArH), 4.27 (s, 1H,
NCHPh), 3.88 (s, 1H, NHCHPh), 2.55 (s, 3H, Os-ArCH3), 2.33−
2.09 (m, 1H, Os-ArCH(CH3)2), 1.26 (m, 6H, Os-ArCH(CH3)2); 13
C
1
mg, 0.066 mmol, 81.3%). H NMR (500 MHz, DMSO-d6, 298 K,
NMR (125 MHz, DMSO-d6, 298 K): δ 146.0, 145.1, 128.8, 127.7,
126.9, 126.2, 126.0, 82.4, 79.9, 73.0, 71.0, 70.4, 67.0, 32.1, 24.0, 23.0;
UV/Vis λmax, 269, 410, 485 nm; HRMS (ESI): m/z calcd for
C31H32F3N2O2OsS [M + H]+, 745.1674; found, 745.1745. Elemental
analysis Calcd (%) for C31H31F3N2O2OsS: C, 50.08 (50.12); H, 4.19
(4.21); N, 3.72 (3.77).
TMS): δ 8.58 (s, 1H, NH), 7.77−7.76 (m, 2H, F3CCCHCH), 7.51−
7.45 (m, 4H, ArH), 7.38−7.35 (m, 4H, ArH), 7.32−7.31 (m, 2H,
3
F3CCCHCH), 7.12−6.91 (m, 7H, ArH), 6.60 (d, J(H,H) = 6.5 Hz,
3
1H, Os-ArH), 6.48 (d, J(H,H) = 5.0 Hz, 1H, Os-ArH), 6.42 (t,
3J(H,H) = 5.5 Hz, 1H, Os-ArH), 6.25 (t, 3J(H,H) = 6.5 Hz, 1H, Os-
ArH), 6.21 (t, 3J(H,H) = 6.5 Hz, 1H, Os-ArH), 4.08 (d, 3J(H,H) = 1
[Os(p-cym)(p-tBu-BsDPEN)] (5). Synthesized as per the general
procedure using [Os(η6-p-cymene)Cl2]2 (51.4 mg, 0.065 mmol, 1 mol
equiv) and N-(1R,2R)-2-amino-(1,2-diphenylethyl)-4-(tert-butyl)-
benzenesulfonamide (RR-L4) (53.04 mg, 0.130 mmol, 2 mol
equiv). A rapid color change from a yellow to a dark orange solution
was observed upon addition of KOH (56 mg, 1 mmol, 15 mol equiv).
The solid was recrystallized from DCM/hexane to yield a dark orange
3
Hz, 1H, NCHPh), 3.72 (d, J(H,H) = 4.5 Hz, 1H, NHCHPh); 13C
NMR (100 MHz, DMSO-d6, 298 K, TMS): δ 152.1, 145.7, 145.0,
143.8, 137.8, 134.3, 128.7, 128.3, 127.5, 126.7, 126.4, 126.3, 126.2,
126.0, 124.8, 81.6, 56.0, 47.8, 18.6; UV/Vis λmax, 259, 412, 485 nm.
HRMS (ESI): m/z calcd for C33H28F3N2O2OsS [M + H]+, 765.1361;
found, 765.1336. Elemental analysis Calcd (%) for
C33H27F3N2O2OsS: C, 52.00 (51.96); H, 3.59 (3.57); N, 3.69 (3.67).
[Os(bip)(m−CF3−BsDPEN)] (12). Synthesized as per the general
procedure using [Os(η6-biphenyl)Cl2]2 (67.4 mg, 0.081 mmol, 1 mol
equiv) and N-(1S,2S)-2-amino-(1,2-diphenylethyl)-3-methylbenzene-
sulfonamide (SS-L3) (64.06 mg, 0.15 mmol, 2 mol equiv). A color
change from yellow to a deep red solution was observed upon
addition of KOH (56.1 mg, 1 mmol, 12 mol equiv). The solid was
recrystallized from DCM/hexane to yield a dark red amorphous solid
(45.6 mg, 0.060 mmol, 74.8%). 1H NMR (500 MHz, DMSO-d6, 298
K, TMS): δ 8.63 (s, 1H, NH), 7.84−7.59 (m, 3H, ArH), 7.57−7.21
(m, 8H, ArH), 7.16−6.83 (m, 8H, ArH), 6.53 (s, 1H, Os-ArH),
6.45−6.28 (m, 2H, Os-ArH), 6.25−6.12 (m, 1H, Os-ArH), 5.74 (s,
1H, Os-ArH), 4.10 (s, 1H NCHPh), 4.71 (s, 1H NHCHPh); 13C
NMR (125 MHz, DMSO-d6, 298 K): δ 145.5, 144.6, 144.7, 137.7,
129.5, 128.9, 128.7, 128.3, 127.6, 127.4, 126.9, 126.7, 126.1, 82.9,
81.8, 75.0, 72.7, 72.2, 71.1, 68.6, 67.8, 54.9; UV/Vis λmax, 289, 365,
512 nm; HRMS (ESI): m/z calcd for C33H28F3N2O2SOs [M + H]+,
765.1438; found, 765.1437. Elemental analysis Calcd (%) for
C33H27F3N2O2SOs: C, 52.01 (51.96); H, 3.60 (3.57); N, 3.71 (3.67).
[Os(bip)(p-tBu-BsDPEN)] (13). Synthesized as per the general
procedure previously stated using [Os(η6-biphenyl)Cl2]2 (59.8 mg,
0.072 mmol, 1 mol equiv) and N-(1R,2R)-2-amino-(1,2-diphenyleth-
yl)-4-fluorobenzenesulfonamide (RR-L4) (61.23 mg, 0.15 mmol, 2
mol equiv). A color change from yellow to a deep red solution was
observed upon the addition of KOH (56 mg, 1 mmol, 12 mol equiv).
The solid was recrystallized from DCM/hexane to yield a red
1
amorphous solid (49 mg, 0.071 mmol, 98.2%). H NMR (500 MHz,
DMSO-d6, 298 K, TMS): δ 8.12 (s, 1H, NH), 7.49 (d, 3J(H,H) = 8.0
Hz, 2H, CHCSO2), 7.28−7.22 (m, 8H, ArH), 7.20−7.16 (m, 2H,
ArH), 7.12 (d, 3J(H,H) = 8.0 Hz, 2H, CHCHCSO2), 5.90 (d,
3J(H,H) = 5.5 Hz, 1H, Os-ArH), 5.77 (d, 3J(H,H) = 6.0 Hz, 1H, Os-
3
3
ArH), 5.59 (d, J(H,H) = 5.5 Hz, 1H, Os-ArH), 5.41 (d, J(H,H) =
3
5.5 Hz, 1H, Os-ArH), 4.32 (s, 1H, NCHAr), 3.88 (d, J(H,H) = 4.5
Hz, 1H, NHCHAr), 2.20 (s, 3H, Os-ArCH3), 2.08 (s, 1H, Os-
ArCH(CH3)2), 1.27 (s, 9H, O2SArC(CH3)3), 1.23 (d, 3J(H,H) = 7.0
Hz, 3H, Os-ArCH(CH3)2), 1.10 (d, 3J(H,H) = 7.0 Hz, 3H, Os-
ArCH(CH3)2); 13C NMR (125 MHz, DMSO-d6, 298 K): δ 153.1,
146.9, 144.9, 141.9, 127.6, 127.4, 126.9, 126.8, 126.6, 126.2, 126.0,
124.5, 90.2, 82.1, 79.4, 73.6, 31.9, 30.9, 23.2, 20.1; UV/Vis λmax, 262,
406, 474 nm; HRMS (ESI): m/z calcd for C34H41N2O2OsS [M +
H]+, 733.2426; Found, 733.2490. Elemental analysis Calcd (%) for
C34H40N2O2OsS: C, 55.85 (55.87); H, 5.51 (5.52); N, 3.87 (3.83).
General Synthesis of Osmium Biphenyl Complex. Osmium
biphenyl dimer ([Os(η6-biphenyl)Cl2]2 1 mol equiv) and benzene-
sulfonamide ligand (2.15 mol equiv) were stirred in DCM (3 mL) in a
microwave vial and then placed in a CEM Discovery-SP microwave
reactor for 10 min (393 K, 150 W, 250 psi). To remove any unreacted
osmium dimer, the brown solution was filtered and then combined
with freshly ground KOH (56.1 mg, 1 mmol, 12 mol equiv). Vigorous
stirring was continued for 30 min until a color change from yellow to
red-orange was observed. Distilled water (10 mL) was added while
stirring for a further 15 min. The aqueous layer was extracted with
DCM (3 × 5 mL) and concentrated in vacuo to yield a solid, which
was recrystallized with DCM/hexane.
[Os(bip)(m−CH3−BsDPEN)] (10). Synthesized as per the general
procedure using [Os(η6-biphenyl)Cl2]2 (50.4 mg, 0.061 mmol, 1 mol
equiv) and N-(1R,2R)-2-amino-(1,2-diphenylethyl)-3-methylbenze-
nesulfonamide (RR-L1) (44.9 mg, 0.12 mmol, 2 mol equiv). A
color change from yellow to dark red solution was observed upon
addition of KOH (56.1 mg, 1 mmol, 12 mol equiv) addition. The
solid was recrystallized from DCM/hexane to yield a dark orange
amorphous solid (35.9 mg, 0.051 mmol, 82.9%). 1H NMR (500 MHz,
DMSO-d6, 298 K, TMS): δ 8.52 (d, 3J(H,H) = 5.5 Hz, 1H,
NHCHPh), 7.67−7.64 (m, 2H, SO2ArH), 7.47−7.37 (m, 5H, Os-
ArH), 7.21−7.02 (m, 11H, ArH), 6.91 (s, 1H, ArH), 6.43−6.42 (m,
1H, Os-ArH), 6.23−6.20 (m, 1H, Os-ArH), 6.19−6.13 (m, 2H, Os-
ArH), 6.07−6.05 (m, 1H, Os-ArH), 4.24 (s, 1H, NCHPh), 3.76 (d,
3J(H,H) = 4.5 Hz, 1H, NHCHPh), 2.08 (s, 3H, SO2ArHCH3); 13C
NMR (125 MHz, DMSO-d6, 298 K): δ 146.5, 144.1, 137.9, 137.4,
131.2, 128.7, 128.4, 128.3, 127.7, 127.4, 127.0, 126.5, 126.4, 126.4,
126.0, 123.4, 82.6, 81.5, 75.9, 73.2, 71.4, 70.4, 68.2, 67.4, 20.8; UV/
Vis λmax, 269, 415, 490 nm; HRMS (ESI): m/z calcd for
C33H31N2O2OsS [M + H]+, 711.1721; found, 711.1714. Elemental
analysis Calcd (%) for C33H30N2O2OsS: C, 55.96 (55.91); H, 4.31
(4.27); N, 3.98 (3.95).
1
amorphous solid (48 mg, 0.06 mmol, 78.2%). H NMR (500 MHz,
3
DMSO-d6, 298 K, TMS): δ 8.48 (d, 1H, J(H,H) = 5.0 Hz, NH),
7.71−7.66 (m, 2H, SO2ArH), 7.50−7.43 (m, 3H, ArH), 7.38−7.33
(m, 2H, SO2ArH), 7.16−7.06 (m, 8H, ArH), 7.03−6.95 (m, 4H,
3
ArH), 6.47 (d, 1H, J(H,H) = 5.5 Hz, Os-ArH), 6.33−6.28 (m, 1H,
3
Os-ArH), 6.18−6.15 (m, 2H, Os-ArH), 6.14 (t, 1H, J(H,H) = 5.5
Hz, Os-ArH), 4.12 (s, 1H, NCHPh), 4.72 (d, 1H, 3J(H,H) = 4.0 Hz,
NHCHPh), 1.26 (s, 9H, SO2ArHC(CH3)3); 13C NMR (125 MHz,
DMSO-d6, 298 K): δ 152.9, 146.4, 144.0, 141.0, 137.9, 128.9, 128.7,
128.4, 127.5, 127.4, 126.9, 126.7, 126.4, 125.9, 124.5, 82.9, 81.6, 76.0,
74.0, 71.8, 70.0, 68.4, 67.6, 30.9; UV/Vis λmax, 278, 412, 487 nm;
HRMS (ESI): m/z calcd for C36H37N2O2OsS [M + H]+, 753.2191;
found, 753.2191. Elemental analysis Calcd (%) for C36H36N2O2OsS:
C, 57.61 (57.58); H, 4.86 (4.83)’ N, 3.77 (3.73).
[Os(bip)(p-F-BsDPEN)] (14). [Os(η6-biphenyl)Cl2]2 and N-
(1R,2R)-2-amino-(1,2-diphenylethyl)-4-fluorobenzenesulfonamide
were synthesized as previously described.21 Complex 14 was
synthesized as per the general procedure previously stated using
[Os(η6-biphenyl)Cl2]2 (70 mg, 0.084 mmol, 1 mol equiv) and N-
(1R,2R)-2-amino-(1,2-diphenylethyl)-4-fluorobenzenesulfonamide
(57 mg, 0.161 mmol, 2 mol equiv).21 A color change from yellow to
deep red was observed upon addition of KOH (57 mg, 1 mmol, 12
mol equiv). The solid was recrystallized from DCM/hexane to yield a
1
dark red amorphous solid (49.1 mg, 0.0491 mmol, 84.9%). H NMR
H
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Article
(500 MHz, DMSO-d6, 298 K, TMS): δ 8.52 (s, 1H, NH), 7.77−7.72
TRIN-β-236M-19, 50 m × 0.25 mm × 0.25 μm, carrier gas = H2, T =
383 K, pressure = 15 psi, FID temperature = 523 K, injection
temperature = 493 K. Data were analyzed on Windows Clarity
Chromatography Suite.
Reduction of Acetophenone. Reactions were performed as per the
general chiral GC procedure using complexes 1−16 (5 μmol, 1 mol
equiv), 5:2 formic acid/triethylamine (500 μL), and acetophenone
substrate (0.117 mL, 1 mmol, 200 mol equiv), using optically pure
(R) and (S) 1-phenylethanol samples as standards.
Reduction of 2-Chloroacetophenone. Reactions were performed
as per general chiral GC procedure previously stated using complexes
5 and 13 (0.76 μmol, 1 mol equiv), 5:2 formic acid/triethylamine
(500 μL), and 2-chloroacetophenone substrate (23.5 mg, 152 μmol,
200 mol equiv), using optically pure (R) and (S) 2-chloro-1-
phenylethanol alcohol samples as standards.46
Reduction of 4-Methoxyacetophenone. Reactions were per-
formed as per general chiral GC procedure previously stated using
complexes 5 and 13 (0.76 μmol, 1 mol equiv), 5:2 formic acid/
triethylamine (500 μL), and 4-methoxyacetophenone (20.4 mg, 152
μmol, 200 mol equiv), using optically pure (R) and (S) 1-(4-
methoxyphenyl)ethanol samples as standards.46
3
(m, 2H, FCCH), 7.70−7.34 (m, 7H, ArH), 7.24−7.19 (t, J(H,H) =
5.5 Hz, 2H, FCCHCH), 7.17−7.07 (m, 3H, ArH), 7.06−6.98 (m, 2H,
ArH), 6.98−6.92 (m, 2H, ArH), 6.91−6.77 (m, 3H, ArH), 6.55 (d,
3J(H,H) = 6.0 Hz, 1H, Os-ArH), 6.38 (d, 3J(H,H) = 5.5 Hz, 1H, Os-
ArH), 6.32 (t, 3J(H,H) = 5.5 Hz, 1H, Os-ArH), 6.18 (t, 3J(H,H) = 6.0
3
Hz, 1H, Os-ArH), 6.13 (d, J(H,H) = 5.5 Hz, 1H, Os-ArH), 4.11 (s,
1H, NCHPh), 4.73 (d, 3J(H,H) = 4.0 Hz, 1H, NHCHPh); 13C NMR
(125 MHz, DMSO-d6, 298 K): δ 146.0, 144.0, 140.1, 137.8, 128.0,
128.7, 128.5, 128.4, 128.3, 127.6, 127.4, 126.7, 126.6, 126.4, 126.0,
114.6, 74.5, 74.0; UV/Vis λmax, 260, 417, 486 nm; HRMS (ESI): m/z
calcd for C32H28FN2O2OsS [M + H]+, 715.1394; found, 715.1464.
Elemental analysis Calcd (%) for C32H27FN2O2OsS: C, 54.87
(54.92); H, 4.86 (4.82); N, 4.94 (4.93).
[Os(bip)(p-Br-BsDPEN)] (15). [Os(η6-biphenyl)Cl2]2 and (1R,2R)-
2-amino-(1,2-diphenylethyl)-4-bromobenzenesulfonamide were syn-
thesized as previously described.21,23 Complex 15 was synthesized as
per the general procedure previously stated using [Os(η6-biphenyl)-
Cl2]2 (68.0 mg, 0.082 mmol, 1 mol equiv) and N-(1R,2R)-2-amino-
(1,2-diphenylethyl)-4-bromobenzenesulfonamide (66 mg, 0.15 mmol,
2 mol equiv). A color change from yellow to deep red solution was
observed upon the addition of KOH (56.1 mg, 1 mmol, 12 mol
equiv). The solid was recrystallized from DCM/hexane to yield a dark
1H NMR Kinetic Studies for the Reduction of Acetophe-
none-Derived Substrates. General 1H NMR Kinetic Studies
Method. Under a nitrogen atmosphere, osmium complexes (1 mol
equiv) were dissolved in deuterated benzene (100 μL) and vigorously
stirred with 5:2 formic acid/triethylamine (500 μL) for 30 min. The
substrate (200 mol equiv) was combined with the reaction mixture
which was transferred to an NMR tube (5 mm diameter) with a
pieced lid. The reaction was monitored at 310 K in a Bruker
AVANCE III HD 400 MHz spectrometer and done in triplicate for
statistical coherence. In each triplicate, two reactions were monitored
for 2 h, whereby the final reaction was observed for 12 h to establish
reaction completion. The average turnover number (TON) used was
calculated, and hence, the TOF (h−1) was derived. Experiments were
conducted at physiological temperature (310 K) for biological
relevance. Statistics were compared using Welch’s t-test at the 95%
confidence limit.
1
red amorphous solid (40 mg, 0.0426 mmol, 64.9%). H NMR (500
MHz, DMSO-d6, 298 K, TMS): δ 8.53 (s, 1H, NH), 7.77−7.61 (m,
2H, F3CCCH), 7.52−7.29 (m, 5H, ArH), 7.24−6.76 (m, 12H, ArH),
6.59−6.47 (m, 1H, Os-ArH), 6.42−6.26 (m, 2H, Os-ArH), 6.22−6.00
(m, 2H, Os-ArH), 4.08 (s, 1H, NCHPh), 4.72 (d, 1H, 3J(H,H) = 5.0
Hz, NHCHPh); 13C NMR (125 MHz, DMSO-d6, 298 K): δ 147.6,
145.7, 144.6, 144.3, 138.4, 131.4, 129.8, 128.8, 127.6, 127.4, 126.9,
126.7, 126.3, 126.1, 124.0, 82.2, 74.9, 69.3, 61.0, 57.9, 52.7, 48.8, 24.8;
UV/Vis, λmax, 256, 318, 549.6 nm; HRMS (ESI): m/z calcd for
C32H28BrN2O2OsS [M + H]+, 775.0592; found, 775.0644. Elemental
analysis Calcd (%) for C32H27BrN2O2OsS: C, 49.70 (49.67); H, 4.56
(4.52); N, 4.67 (4.62).
[Os(bip)(p-I-BsDPEN)] (16). [Os(η6-biphenyl)Cl2]2 and (1S,2S)-2-
amino-1,2-diphenylethyl)-4-iodobenzenesulfonamide were synthe-
sized as previously described.21,23 Complex 16 was synthesized as
per the general procedure previously stated using [Os(η6-biphenyl)-
Cl2]2 (67.9 mg, 0.082 mmol, 1 mol equiv) and N-(1S,2S)-2-amino-
(1,2-diphenylethyl)-4-iodobenzenesulfonamide (98 mg, 0.16 mmol, 2
mol equiv). A color change from yellow to deep red solution was
observed upon the addition of KOH (56.1 mg, 1 mmol, 12 mol
equiv). The solid was recrystallized from DCM/hexane to yield a red
amorphous solid (57 mg, 0.069 mmol, 85.2%).1H NMR (500 MHz,
DMSO-d6, 298 K, TMS): δ 8.54 (s, 1H, NH), 7.72−7.66 (m, 2H,
IC(CH)2(CH)2), 7.50−7.42 (m, 3H, ArH), 7.40−7.33 (m, 4H, ArH),
7.19−7.08 (m, 4H, ArH), 7.04−6.97 (m, 2H, IC(CH)2(CH)2), 6.96−
6.89 (m, 4H, ArH), 6.53 (d, 3J(H,H) = 7.0 Hz, 1H, Os-ArH), 6.34 (t,
3J(H,H) = 7.0 Hz, 2H, Os-ArH), 6.19 (t, 3J(H,H) = 7.0 Hz, 1H, Os-
ArH), 6.14 (t, 3J(H,H) = 7.0 Hz, 1H, Os-ArH), 4.08 (s, 1H,
1
Reduction of Acetophenone. Reactions were as per general H
NMR kinetic study procedure previously stated using complexes 1−
16 (5 μmol, 1 mol equiv), d6-benzene (100 μL), 5:2 formic acid/
triethylamine (500 μL), and acetophenone substrate (0.117 mL, 1
mmol, 200 mol equiv).
Reduction of 2-Chloroacetophenone. Reactions were performed
as per the general 1H NMR kinetic study procedure previously stated
using complex 1, 5, 13, and 16 (0.76 μmol, 1 mol equiv), d6-benzene
(100 μL), 5:2 formic acid/triethylamine (500 μL), and 2-
chloroacetophenone substrate (23.5 mg, 152 μmol, 200 mol equiv).
4-Methoxyacetophenone 1H NMR Kinetic Studies. Reactions
1
were performed as per the general H NMR kinetic study procedure
previously stated using 5 and 13 (0.76 μmol, 1 mol equiv), d6-
benzene (100 μL), 5:2 formic acid/triethylamine (500 μL), and 4-
methoxyacetophenone substrate (20.4 mg, 152 μmol, 200 mol equiv).
Catalytic Reduction of Quinones. General 1H NMR Kinetic
Studies. Under a nitrogen atmosphere, osmium complexes (1 mol
equiv) were vigorously stirred in 5:2 formic acid/triethylamine (300
μL) for 30 min. Simultaneously, the quinone substrate (200 mol
equiv) was dissolved and vigorously stirred in deuterated benzene
(200 μL) and 5:2 formic acid/triethylamine (200 μL) for 30 min. The
two reaction mixtures were combined and transferred into an NMR
tube (5 mm diameter) with a pieced lid. The reaction was monitored
by 1H NMR at 310 K; TOF calculated as stated previously in
acetophenone kinetic studies.
3
NCHPh), 4.72 (d, J(H,H) = 5.5 Hz, 1H, NHCHPh); 13C NMR
(125 MHz, DMSO-d6, 298 K): δ 146.1, 144.8, 144.2, 137.7, 136.7,
128.9, 128.7, 128.4, 128.3, 127.6, 127.4, 127.0, 126.7, 126.4, 126.3,
126.0, 82.7, 74.0, 72.1, 68.5; UV/Vis λmax, 329, 411, 489 nm; HRMS
(ESI): m/z calcd for C32H28IN2O2OsS [M + H]+, 824.0531; found,
824.0525. Elemental analysis Calcd (%) for C32H27IN2O2OsS: C,
46.89 (46.83); H, 4.36 (4.32); N, 4.39 (4.41).
Chiral GC. General Chiral GC Method. Under a nitrogen
atmosphere, the osmium complex (1 mol equiv) was dissolved in
5:2 formic acid/triethylamine (500 μL), followed by addition of
acetophenone-derived substrate (200 mol equiv) and stirred for 24 h
(310 K). One drop of reaction mixture was combined with saturated
sodium hydrogen carbonate (1 mL) and ethyl acetate (1 mL) and
filtered through a column of silica. Samples were then analyzed by
chiral GC to determine ee and conversions (%). Chiral GC
measurements were carried out by Jonathan Barrios-Rivera and Sam
Forshaw (University of Warwick) on a Hewlett-Packard 5890
instrument linked to PC running DataApex Clarity software.
Measurements were obtained using a CROMPAC CYCLODEX-
Reduction of Duroquinone. Reactions were performed as per the
1
general H NMR kinetic study procedure using complexes 1, 5, 13,
and 16 (0.76 μmol, 1 mol equiv), d6-benzene (200 μL), 5:2 formic
acid/triethylamine (500 μL), and duroquinone (25 mg, 0.152 mmol,
200 mol equiv).
Reduction of Menadione. Reactions were performed as per
1
general H NMR kinetic study procedure using complexes 5 and 13
(0.76 μmol, 1 mol equiv), d6-benzene (200 μL), 5:2 formic acid/
I
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triethylamine (500 μL), and menadione (26.2 mg, 0.152 mmol, 200
mol equiv).
TOFs were significantly higher for the less sterically hindered
menadione over duroquinone, with a TOF of 145 3 h−1 for
13. In order the further probe this, we used DFT to investigate
the catalytic reduction of duroquinone in the presence of such
complexes, The DFT calculations revealed interesting features
in the mechanism, involving formic acid deprotonation assisted
by the catalyst amine groups, phenyl-duroquinone stacking,
hydride transfer to OsII, possible CO2 coordination and tilting
of the η6-arene ring, followed by hydride transfer to the
quinone. Notably, we were unable to optimize any structure
with the HCO2− bound to the osmium, yet, for the ruthenium
analogue, the Ru−HCO2− coordination was found with a Ru−
H distance of 1.72 Å.
Overall, this study provides the first evidence for the
reduction of quinones by this family of osmium catalysts,
demonstrating their remarkable substrate versatility for transfer
hydrogenation reactions. Optimization of such catalysts under
biologically relevant conditions may give rise to novel catalytic
mechanisms for destroying cells and treating cancer.
Determination of Duroquinone Reduction Product. Reactions
were performed as per the general product determination procedure
using complex 5 (1.52 μmol, 1 mol equiv), 5:2 formic acid/
triethylamine (500 μL) and duroquinone (25.0 mg, 0.152 mmol, 100
mol equiv), and yellow crystals. This yielded a brown crystalline solid
1
(21.6 mg, 0.130 mmol, 85.5%). H NMR (500 MHz, DMSO-d6, 298
K, TMS): δ 7.33 (s, 2H, OH), 2.06 (s, 12H, CH3); 13C NMR (125
MHz, DMSO-d6, 298 K): δ 146.1, 121.8, 13.4. Further analyzed by
1H−1H COSY (resolution insufficient for publication), 1H−13C
1
HSQC and H−13C HMBC NMR spectroscopy. LRMS (ESI): m/z
calcd for C15H17O2N2 [M + 2Na−H]+, 211.1; found, 211.3.
Determination of Menadione Reduction Product. Reactions were
performed as per the general product determination procedure using
complex 13 (1.52 μmol, 1 mol equiv), 5:2 formic acid/triethylamine
(500 μL) and menadione (26.2 mg, 0.152 mmol, 100 mol equiv,
yellow powder). This yielded a purple crystalline solid (21.9 mg,
0.126 mmol, 82.7%). 1H NMR (500 MHz, DMSO-d6, 298 K, TMS):
δ 9.39 (s, 1H, HOCCH), 8.29 (s, 1H, HOCC(CH3)), 8.10 (d,
3
3J(H,H) = 8.4 Hz, 1H, PhH), 8.04 (d, J(H,H) = 8.4 Hz, 1H, PhH),
7.43 (t, 3J(H,H) = 7.2 Hz, 1H, PhH), 7.36 (t, 3J(H,H) = 7.2 Hz, 1H,
PhH), 6.66 (s, 1H, HOCCHC(CH3)), 2.31 (s, 3H, HOCC(CH3));
13C NMR (125 MHz, DMSO-d6, 298 K): δ 146.2, 142.2, 127.0, 125.4,
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.organomet.1c00358.
■
sı
1
124.3, 124.0, 122.3, 122.1, 119.1, 111.8, 17.0. Analyzed by H−1H
COSY, 1H−13C HSQC and 1H−13C HMBC NMR spectroscopy;
LRMS (ESI): m/z calcd for C15H17O2N2 [M + 2ACN + H]+, 257.1;
found, 257.2.
NMR for the catalytic reduction of acetophenone, 2-
chloroacetophenone, 4-methoxyactophenone, duroqui-
none, and menadione using 5 (PDF)
DFT file for intermediate 1 (PDB)
DFT file for intermediate 2 (PDB)
DFT file for intermediate 3a (PDB)
DFT file for intermediates 3b (PDB)
DFT file for the Ru analogue of intermediate 3a (PDB)
CONCLUSIONS
■
Organo-osmium(II) complexes [OsII(η6-arene)(R-PhDPEN)]
can catalyze reduction of prochiral ketones to optically pure
alcohols in the presence of a hydride source. We are
particularly interested in the use of synthetic catalysts for
transfer hydrogenation reactions in cells, for which these
Os(II) complexes have potential advantages over their better-
known Ru(II) analogues, being highly active and stable as
active 16-electron catalysts. To improve their catalytic
performance, we have introduced electron-donor and
electron-acceptor substituents (R) into the para (R1) or meta
(R2) positions of the chiral R-phenyl-sulfonyl-diphenylethyl-
enediamine (Ph-DPEN) ligands and for the first time explored
the reduction of quinones, potential biological substrates which
play major roles in cellular electron transfer chains. These
complexes exhibited remarkably high turnover frequencies
toward reduction of acetophenone-derived substrates in the
presence of formic acid, with high enantioselectivity (>92%)
and conversions (>93%). Interestingly, the catalytic activity of
such complexes was improved with the tert-butyl substituent in
the para-position, achieving TOFs more than 40% higher than
that of the parent methyl-substituted complexes, while
maintaining high enantioselectivity (>98%) and conversions
(>98%). Consequently, these tert-butyl-containing catalysts
were screened for the reduction of quinones.
AUTHOR INFORMATION
Corresponding Author
■
Peter J. Sadler − Department of Chemistry, University of
Warwick, Coventry CV4 7AL, U.K.; orcid.org/0000-
0001-9160-1941; Email: p.j.sadler@warwick.ac.uk
Authors
Elizabeth M. Bolitho − Department of Chemistry, University
of Warwick, Coventry CV4 7AL, U.K.
Nathan G. Worby − Department of Chemistry, University of
Warwick, Coventry CV4 7AL, U.K.
James P. C. Coverdale − Department of Chemistry, University
of Warwick, Coventry CV4 7AL, U.K.
Juliusz A. Wolny − Fachbereich Physik, Technische Universität
Kaiserslautern, D-67663 Kaiserslautern, Germany
Volker Schunemann − Fachbereich Physik, Technische
̈
Universität Kaiserslautern, D-67663 Kaiserslautern,
Germany
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.organomet.1c00358
Biological quinones can provide protection to cells by
modification of redox homeostasis in response to stress (e.g.,
chemotherapeutics). The two-electron reduction of quinones
is a major detoxification mechanism for quinones; thus,
research into quinones as substrates for in-cell catalysis is of
significant interest. Here, we investigated the reduction of
quinones by this family of organo-osmium(II) catalysts in the
presence of formic acid. The kinetic reduction of duroquinone
and menadione to their di-alcohol derivatives (durohydroqui-
none and menadiol, respectively) exhibited promising
conversions (>87%) and TOF (>36 h−1). Interestingly, the
Notes
The authors declare no competing financial interest.
§E.M.B. and N.G.W. shared first author.
ACKNOWLEDGMENTS
■
We thank Diamond Light Source and Warwick Collaborative
Postgraduate Research Scholarship (PhD award for E.M.B.),
the Engineering and Physical Sciences Research Council
J
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(EPSRC grant no EP/P030572/1). We thank J. Barrios-Rivera
and S. Forshaw (University of Warwick) for assistance with
chiral GC−FID measurements, L. Song for mass spectrometry,
I. Prokes for NMR spectroscopy, and Heraeus for the gift of
osmium trichloride. V.S. and J.A.W. acknowledge support by
the research initiative NANOKAT, as well as Allianz fur
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Hochleistungsrechnen Rheinland−Pfalz (AHRP) for providing
CPU-time within the project TUK-SPINPLUSVIB.
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