Structure, Spectroscopy, and Reactivity of a Mononuclear Copper Hydroxide Complex in Three Molecular Oxidation States

Article abstract of DOI:10.1021/jacs.0c03867

Structural, spectroscopic, and reactivity studies are presented for an electron transfer series of copper hydroxide complexes supported by a tridentate redox-active ligand. Single crystal X-ray crystallography shows that the mononuclear [CuOH]1+ core is stabilized via intramolecular H-bonds between the H-donors of the ligand and the hydroxide anion when the ligand is in its trianionic form. This complex undergoes two reversible oxidation processes that produce two metastable "high-valent"CuOH species, which can be generated by addition of stoichiometric amounts of 1e- oxidants. These CuOH species are characterized by an array of spectroscopic techniques including UV-vis absorption, electron paramagnetic resonance (EPR), and X-ray absorption spectroscopies (XAS), which together indicate that all redox couples are ligand-localized. The reactivity of the complexes in their higher oxidation states toward substrates with modest O-H bond dissociation energies (e.g., 4-substitued-2,6-di-tert-butylphenols) indicates that these complexes act as 2H+/2e- oxidants, differing from the 1H+/1e- reactivity of well-studied [CuOH]2+ systems.

Full text of DOI:10.1021/jacs.0c03867

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Article
Structure, spectroscopy and reactivity of a mononuclear
copper hydroxide complex in three molecular oxidation states
Tong Wu, Samantha N. MacMillan, Khashayar Rajabimoghadam,
Maxime A. Siegler, Kyle M. Lancaster, and Isaac Garcia-Bosch
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c03867 • Publication Date (Web): 12 Jun 2020
Downloaded from pubs.acs.org on June 13, 2020
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-@>A2@A>4E(?=42@><?2<=D(1;3(>412@8B8@D(<5(1(:<;<;A2941>(2<==4>(7DF
3><C834(2<:=94C(8;(@7>44(:<942A91>(<C831@8<;(?@1@4?(
Tong Wu,† Samantha N. MacMillan,§ Khashayar Rajabimoghadam,† Maxime A. Siegler,# Kyle M. Lancaster§,*
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and Isaac Garcia-Bosch†,*
†Department of Chemistry, Southern Methodist University, Dallas, Texas 75275, United States
§Department of Chemistry and Chemical Biology, Cornell University, Baker Laboratory, Ithaca, New York 14853, United States
# Johns Hopkins University, Baltimore, Maryland 21218, United States
Copper, redox-active ligands, intramolecular H-bonding interactions, Cu-dependent monooxygenases, H-atom abstraction
ABSTRACT: Structural, spectroscopic, and reactivity studies are presented for an electron transfer series of copper hydroxide complexes
supported by a tridentate redox-active ligand. Single crystal X-ray crystallography shows that the mononuclear [CuOH]1+ core is stabilized via
intramolecular H-bonds between the H-donors of the ligand and the hydroxide anion when the ligand is in its trianionic form. This complex
undergoes two reversible oxidation processes that produce two metastable “high-valent” CuOH species, which can be generated by addition
of stoichiometric amounts of 1e! oxidants. These CuOH species are characterized by an array of spectroscopic techniques including UV-vis
absorption, electron paramagnetic resonance (EPR) and X-ray absorption spectroscopies (XAS), which together indicate that all redox cou-
ples are ligand-localized. The reactivity of the complexes in their higher oxidation states towards substrates with modest O–H bond dissocia-
tion energies (e.g. 4-substitued-2,6-di-tert-butylphenols) indicates that these complexes act as 2H+/2e! oxidants, differing from the 1H+/1e!
reactivity of well-studied [CuOH]2+ systems.
Introduction
[LCuOH]2– complex) is capable of performing two sequential H-
atom abstractions from phenols. This reactivity differs from the
well-established 1H+/1e! oxidations promoted by mononuclear
[CuOH]2+ cores. 13-15
High-valent copper complexes have been invoked as active in-
termediates in the hydroxylation of C–H bonds performed by Cu-
dependent metalloenzymes.1,2 For example, lytic polysaccharide
monooxygenases (LPMOs) catalyze the oxidative degradation of
cellulose using a mononuclear Cu center bound by two histidines,
one acting as a bidentate ligand (Figure 1A).3,4 It has been pro-
posed that the active species responsible for the oxidation of the
cellulose substrate is a [CuO]1+ intermediate, which could be in
equilibrium with a [CuOH]2+ analogue.5 In most of the members of
this family of enzymes, a tyrosine residue is found in the vicinity of
the active center. Recent reports have found that some LPMOs
react with H2O2 (an alternative oxidant6,7) to generate a metastable
Cu-tyrosyl species,8 which could be the active 2e! oxidant (Figure
A. &#' 7C4=<BC91?8<; <6 3599@9<>5 31?19CD54 2C (,)+
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galactose-oxidase, in which the dehydrogenation of alcohols to
aldehydes is observed.10
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Inspired by our recent work on Cu complexes bearing bidentate
redox-active ligands11,12, we describe the synthesis and characteriza-
tion of a mononuclear copper hydroxide complex bound by a tri-
dentate redox-active ligand scaffold that stabilizes the CuOH core
via intramolecular H-bonding interactions (see Figure 2). This
[LCuOH]2– complex can be chemically oxidized using ferrocenium
(Fc+) to generate two “high-valent” CuOH species, [LCuOH]1–
and [LCuOH], that are characterized by multiple spectroscopies.
The [LCuOH] species (generated by adding 2 equiv of Fc+ to the
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Figure 1. First step of cellulose degradation catalyzed by Cu-
dependent LPMOs (A) and putative 2e! oxidants capable of perform-
ing C–H hydroxylation (B).
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O.S.2
tBuCuOH(H+)2
.
Thus tBuCuOHO.S.4 can be considered CuI and tBuLH3, see S.I.) and tBuCuOH(H+)O.S.3, which can oxidize
a
2H+/2e! oxidant. However, our experimental evidence suggests
1
2
the phenolic substrates. Hence, the stoichiometry of the reaction
dictates that 1 equiv of tBuCuOHO.S.4 can lead to three H–atom
O.S.2
that the reduced complex tBuCuOH(H+)2
is unstable and un-
transfer events (details given below).
3
4
dergoes a disproportionation reaction to generate the cuprous
O.S.1
complex tBuCuOH(H+)3
(that ultimately decomposes to release
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Figure 5. Summary of the reactivity of CuOH cores with 4-substituted-2,6-di-tert-butylphenols (A) and organic products derived from the H atom
abstraction (B).38
Reactivity with 4-substituted 2,6-di-tert-butylphenols - stoichi-
ometry. The reaction between tBuCuOHO.S.4 and 50 equiv of 2,6-
DTBP was carried out at 298 K and monitored by UV-vis absorp-
tion spectroscopy (see Figure 6A). The reaction proceeded in a
two-step fashion. In the first step, UV-vis absorption features of
tBuCuOHO.S.4 decayed rapidly with concomitant formation of a UV-
vis absorption band centered near 625 nm. This resembles the
spectrum of tBuCuOHO.S.3, which was assigned as the Cu product
spectra in Figure 6A). Addition of 2
equiv of pyr-H+ to
tBuCuOHO.S.2 triggered the formation of 0.5 equiv of tBuCuOHO.S.3
suggesting that tBuCuOHO.S.2 undergoes disproportionation upon
protonation (see Figure S78 - S80). Both reaction steps exhibited
the growth of very absorptive features near 425 nm, which corre-
spond to the formation of 3,3$,5,5$-tetra-tert-butyldiphenoquinone
(DPQ, "max 425 nm, % = 7.2·104 M–1cm–1 in DMF), the C–C cou-
pling product derived from the 2H+/2e! oxidation of 2,6-DTBP.37
This product is formed via H–atom abstraction of 2,6-DTBP to
produce a fleeting phenoxyl radical (2,6-DTBP!), which undergoes
dimerization to the diphenol H2DPQ (Figure 5B).39 The 2H+/2e!
oxidation of the diphenol product leads to the final diphenoqui-
none DPQ. Under the employed reaction conditions, a UV-vis
absorption band appeared corresponding to DPQ, but its high
molar absorptivity led to spectral saturation (see Figure 6A).
derived from the 1H+/1e! reduction/protonation of tBuCuOHO.S.4
tBuCuOH(H+)O.S.3 (green spectrum in Figure 6). tBuCuOH(H+)O.S.3
,
could be independently generated by adding 1 equiv of pyridinium
triflate (pyr-H+) to a solution of tBuCuOHO.S.3 tBuCuOHO.S.3 + H+
(
tBuCuOH(H+)O.S.3, see also Figure 12).38 In the second step of
the reaction, tBuCuOH(H+)O.S.3 reacted with the phenol to produce
the diprotonated tBuCuOH(H+)2
complex, which is unstable
O.S.2
and decays in the presence of phenol to CuI products (see orange
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does not contribute as significantly to the overall BDE ((pKa
ants were added to tBuCuOH(H+)2O.S.3 and the reactions were mon-
(
tBuCuOHO.S.2 tBuCuOHO.S.3) = 5 – 9; 9 – 12 kcal/mol). On the
/
1
2
3
4
itored by UV-vis absorption spectroscopy, which revealed that
reductants with E0 more negative than –0.4 V (CoCp2, Me10Fc and
Me8Fc) could reduce tBuCuOH(H+)2O.S.3, but Me2Fc could not (E1/2
= -0.07 V vs Fc0/+ in DMF).
other hand, protonation of tBuCuOHO.S.3 to generate
tBuCuOH(H+)O.S.3 led to small changes in the basicity of the com-
plex ((E1/2
a substantial increase of the reduction potential of the protonated
( /
tBuCuOHO.S.3 tBuCuOH(H+)O.S.3) = 2; 3 kcal/mol) but
5
6
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O.S.3
counterparts ((E1/2
(
tBuCuOH(H+)2
/
tBuCuOH(H+)O.S.3) ~ 0.4
V; 9 kcal/mol), which enables tBuCuOH(H+)O.S.3 to oxidize phenol-
ic substrates like tBuCuOHO.S.4. Overall, the versatility of the
tBuCuOH platform, which is able to reversibly reach three physical
oxidation states and three different protonation states, is funda-
6
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mental to achieving the unprecedented 2H+/2e! oxidation reactivi-
ty described in this article.
Comparison of tBuCuOHO.S.4 with other “high-valent” copper
complexes. Previous reports have extensively studied the reactivity
of mononuclear [CuOH]2+ complexes towards C–H and O–H
bonds and it has been found that these species act as strong
1H+/1e! oxidants (BDE of 90 kcal/mol), abstracting hydrogen
atoms from the substrates via an HAT mechanism (Figure
13A).13,58 Recent studies have also described that analogous “high-
valent” [CuX]2+ complexes also behave as a 1H+/1e! oxidants.37,59
Zhang and coworkers have recently reported that a [CuF]2+ species
carried out the fluorination of C-H bonds via H atom abstraction
(performed by one equiv of [CuF]2+) followed by radical rebound
(performed by a second equiv of [CuF]2+), suggesting that this
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“high-valent” complex acted as 1e! oxidant.59 This differs from the
2e! reactivity of tBuCuOHO.S.4, capable of performing two consecu-
tive H atom abstractions.
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We hypothesize that the superior oxidative power of an
LCuIIIOH complex58 (depicted in Figure 13A) compared to
tBuCuOHO.S.4 (90 kcal/mol in THF vs. 83 kcal/mol in DMF) results
from the stronger basicity character of the reduced complex
LCuIIOH (pKa in THF similar to the strong base DBU) and from
the slightly higher redox potential of LCuIIIOH (see Figure 13A).
The inclusion of the H-bonding donors on the ligand scaffold,
which we believe allow for stabilizing the CuOH cores in different
molecular oxidation states, could also be preventing a richer oxida-
tive reactivity towards external substrates. Karlin and coworkers
have recently reported that fine-tuning of these H-bonding interac-
tions can stabilize mononuclear Cu/O2 entities, but also enhance
their oxidative reactivity.35,60
?
&!
0+://1.%
0+:///1.%
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Conclusions
9*:+:1.(.!
1"2"%
%
Recent studies have proposed that the oxidation of C–H bonds
in LPMO occurs via formation of a Cu-oxyl complex that can per-
form the 2e! oxidation of strong C–H bonds via H–atom abstrac-
tion followed by OH rebound (Figure 13).5,7 In this report, we
describe that the [CuOH]1+ cores bearing a redox-active ligand
react with phenolic O–H bonds via two consecutive 1H+/1e!
events. This differs from the reactivity of galactose oxidase model
systems in which Cu complexes bound by redox-active ligands
(L!CuII) typically perform the oxidation of alcohols (RCH2OH) to
aldehydes (RCHO) via alkoxide coordination to the Cu center
(L!CuIIOCH2R) followed by an intramolecular 1H+/2e! oxidation
(L!CuIIOCH2R -> LHCuI + RCHO).25,61 Interestingly, the H!
abstraction reactivity of the CuOH complexes reported is not trig-
gered by the oxidation of the CuOH core, which maintains its phys-
ical oxidation state, but rather by oxidizing and/or protonating the
ligand scaffold, a strategy that might also be utilized by some Cu-
"8 '(2
9*:+:1.(.! 1"2"&
9 3
9
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"8 '(2
/12 . ,( C=;D$EGD
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9
9 13
#$' $ &"%("!
Figure 13. 2e! oxidations performed by the putative Cu-oxyl interme-
diate of LPMOs compared with the 1e! reactivity of [CuOH]2+ com-
plexes (A). 13,58 2e! reactivity found for the [CuOH]1+ cores reported in
this article (B).
Bordwell analysis – Comparison of the BDEs. The enhanced ox-
idative power of tBuCuOHO.S.4 compared to tBuCuOHO.S.3 can be
rationalized in terms of the higher reduction potential of
tBuCuOHO.S.4 tBuCuOHO.S.3) = 0.77 V; 18
( /
kcal/mol), whereas the change in the pKa for the reduced products
tBuCuOHO.S.4 ((E1/2
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dependent monooxygenase enzymes.5,62 Ongoing studies are fo-
cused on modifying our copper complexes by tuning the electron-
ics of the redox-active backbone, altering the stereoelectronics of
the H–bond donors and utilizing various anions, which we believe
will boost the oxidative power of these reactive M-O(H) cores and
(5) Ciano, L.; Davies, G. J.; Tolman, W. B.; Walton, P. H. Bracing cop-
per for the catalytic oxidation of C–H bonds. Nat. Catal. 2018, 1, 571-577.
(6) Meier, K. K.; Jones, S. M.; Kaper, T.; Hansson, H.; Koetsier, M. J.;
Karkehabadi, S.; Solomon, E. I.; Sandgren, M.; Kelemen, B. Oxygen Activa-
tion by Cu LPMOs in Recalcitrant Carbohydrate Polysaccharide Conver-
sion to Monomer Sugars. Chem. Rev. 2018, 118, 2593-2635.
(7) Bissaro, B.; Streit, B.; Isaksen, I.; Eijsink, V. G. H.; Beckham, G. T.;
DuBois, J. L.; Røhr, Å. K. Molecular mechanism of the chitinolytic peroxy-
genase reaction. Proc. Nat. Acad. Sci. 2020, 117, 1504-1513.
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will allow for monooxygenase-like 2e! functionalization of C–H
substrates (H! abstraction followed by !OH rebound).
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The Supporting Information is available free of charge on the ACS
Publications website.
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Synthetic, experimental and other details, Figures S1−S78 and Tables
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:/.%+,(&*#+,):.&+*(
<>>4?=<;38;6(:A@7<>(
kml236@cornell.edu
igarciabosch@smu.edu
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berger, S.; Siegler, M. A.; Swart, M.; Garcia-Bosch, I. Catalytic Aerobic
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and Steric Parameters of a Redox-Active Tris(amido) Ligand. Inorg. Chem.
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+, &!((
Samantha N. MacMillan: 0000-0001-6516-1823
Kyle M. Lancaster: 0000-0001-7296-128X
Isaac Garcia-Bosch: 0000-0002-6871-3029
*<@4?((
The authors declare no competing financial interest.
: '*+0("!$)"*.((
We thank the Robert A. Welch Foundation (grant N-1900-20190330
to I.G.B.) and the National Institutes of Health (NIH award number
R15GM128078 to I.G.B.) for financial support. K.M.L. thanks NSF
(CHE-1454455) for support. We thank Prof. Pia Vogel (Dept. of Biol-
ogy at Southern Methodist University) for help with the EPR meas-
urements. XAS data were obtained at SSRL, which is supported by the
U.S. Department of Energy, Office of Science, Office of Basic Energy
Sciences under Contract No. DE-AC02-76SF00515. The SSRL Struc-
tural Molecular Biology Program is supported by the Department of
Energy’s Office of Biological and Environmental Research, and by
NIH/HIGMS (including P41GM103393).
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the phenols are similar in DMF and DMSO, since the pKa values of weak
DMF
acids are comparable in both solvents (pKa
= 1.56 + 0.96 pKaDMSO) and
the redox potentials of our complexes in DMSO are identical to the ones
found in DMF.
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ing the oxidation of the phenols via disproportionation of
tBuCuOH(H+)2O.S.2) and are currently being studied in detail.
(57) Note: While the pKa’s were measured at -40 ºC, the reactivity and
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O.S.2
ring. Similarly, we propose that tBuCuOH(H+)2
is an aqua complex with
one of the amines of the tridentate ligand protonated but other protonation
isomers are possible.
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