Functional Synthetic Model for the Lanthanide-Dependent Quinoid Alcohol Dehydrogenase Active Site

Article abstract of DOI:10.1021/jacs.7b12318

The oxidation of methanol by dehydrogenase enzymes is an essential part of the bacterial methane metabolism cycle. The recent discovery of a lanthanide (Ln) cation in the active site of the XoxF dehydrogenase represents the only example of a rare-earth element in a physiological role. Herein, we report the first synthetic, functional model of Ln-dependent dehydrogenase and its stoichiometric and catalytic dehydrogenation of a benzyl alcohol. Density functional theory calculations implicate a hydride transfer mechanism for these reactions.

Full text of DOI:10.1021/jacs.7b12318

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Communication
A Functional Synthetic Model for the Lanthanide-
Dependent Quinoid Alcohol Dehydrogenase Active Site
Alex McSkimming, Thibault Cheisson, Patrick J. Carroll, and Eric J. Schelter
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b12318 • Publication Date (Web): 29 Dec 2017
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A Functional Synthetic Model for the Lanthanide-Dependent Quinoid
Alcohol Dehydrogenase Active Site
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Alex McSkimming, Thibault Cheisson, Patrick J. Carroll and Eric J. Schelter*
P. Roy and Diana T. Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 S 34th St., Philadelph-
ia, Pennsylvania 19104, United States
Supporting Information Placeholder
The study of well-defined synthetic model com-
pounds is essential for understanding the workings of
ABSTRACT: The oxidation of methanol by dehydrogen-
ase enzymes is an essential part of the bacterial me-
enzyme active sites, which in turn may inspire novel
thane metabolism cycle. The recent discovery of a lan-
catalysts.5 At present, however, reports of synthetic
thanide (Ln) cation in the active site of the XoxF dehy-
metal complexes of PQQ or analogues are scarce6 and
drogenase represents the only example of a rare-earth
only a handful of such compounds have been structural-
element in a physiological role. Herein, we report the
ly characterized.7 Furthermore, their reactivity has typi-
first synthetic, functional model of Ln-dependent dehy-
cally not been reported, with a few exceptions.6a-e To
drogenase and its stoichiometric and catalytic dehydro-
date, there are no reports of a synthetic lanthanide
genation of a benzyl alcohol. DFT calculations implicate
complex of PQQ or its surrogates.
a hydride transfer mechanism for these reactions.
Methanol dehydrogenase (MDH) enzymes play an
important role in the global carbon cycle, namely
through the bacterial methane metabolism pathway, by
catalyzing the oxidation of methanol.1 The active site of
MDH enzymes contains a pyrroloquinoline quinone
(PQQ) cofactor bound to a Ca2+ ion, which accepts for-
Scheme 1. a) Reaction between cofactor PQQ and alcohol
mally two electrons and two protons from an alcohol
substrates to give the catechol H2PQQ and b) the active
substrate to afford the corresponding aldehyde and cat-
echol (H2PQQ, Scheme 1a).2 It was recently demon-
site of Ln-dependent MDH from XRD data with bound
EtOH ligand.
strated that early lanthanide ions: La–Nd accelerated
There are a number of challenges associated with
cell growth of certain methanotrophic bacteria.3 An X-
synthesizing analogues of MDH active sites. First, PQQ
alcohol metabolism, and in one case were essential for
derivatives may coordinate to a metal ion in non-natural
binding modes, such as through the two quinone oxy-
ray structure of the XoxF-type MDH enzyme from
Methylacidiphilum fumariolicum SoIV revealed a Ln3+
gen atoms7c, 7d or the distal pyrrole and carboxylic acid
groups.7a Multiple quinoline quinones (QQs) may also
bind a single metal center or otherwise exhibit compli-
cated speciation.8 To overcome these potential prob-
lems we designed the ligand LQQ (Scheme 2), which in-
corporated a directing and sterically bulky chelator. An
important goal of this design was the structural charac-
terization of metal complexes of LQQ and the product(s)
of their reaction with substrates. We report herein the
synthesis of LQQ, its corresponding lanthanum complex
[La(LQQ)(NO3)3] and its stoichiometric and catalytic de-
hydrogenation of a benzyl alcohol substrate.
cation bound by the PQQ cofactor (Scheme 1b),3d the
first example of a lanthanide (or rare-earth) element in
a physiological role. Lanthanides evidently confer a
competitive advantage over Ca2+, with XoxF-MDH dis-
playing a 10-fold higher methanol affinity constant than
4
Ca-MDHs.3d, Furthermore, Ca-MDHs exhibit highest
activities at pH ~9 whereas XoxF-MDH functions opti-
mally at neutral pH and does not require ammonium
4
ions for activation.3d, Also, in contrast to Ca-MDHs,
XoxF-MDH catalyzes the oxidation of formaldehyde to
formate.3d, 4
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Proligand LQQ was synthesized in 11 steps from com-
rare example of a metal complex of a quinoline qui-
none7 and is the first such lanthanide complex. The X-
ray crystal structure of [La(LQQ)(NO3)3] revealed La(1) to
bound to the pyridyl nitrogen atom N(1) and a single
quinone oxygen O(1) of the
1
2
3
4
mercially available starting materials (Scheme 2). Metal-
lation of LQQ proceeded smoothly using [La(NO3)3(THF)4]
to obtain [La(LQQ)(NO3)3] in 90% yield as a moisture-
sensitive orange solid (Scheme 2). [La(LQQ)(NO3)3] is a
5
6
7
8
9
TBSCl,
NH2
OH
crotonaldehyde
SeO2
imidazole
DMF
91%
dioxane, 100 °C
6M HClꢀPhMe, 100 °C
24%
N
H
N
40%
N
O
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OH
OH
TBS = SiMe2tBu
OTBS
1
2
N
N
O
O
1ꢀN(CH2CONCy2)2ꢀ
2ꢀNH2ꢀC6H4 (8)
IBX
HCl
O
NCy2
LQQ
DCM
94%
DCMꢀMeCN
THFꢀMeOH
H
H
H
N
N
N
O
80%
91%
NCy2
O
OTBS
O
O
O
3
5
4
[La(THF)4(NO3)3]
MeCN, 1h
90%
N(4)
N(5)
4MePhCHO +
2 DBU—HNO3
4MeBnOH +
2 DBU
N(4)
O(3)
N(3)
67%
N(2)
N(1)
La(1)
N(3)
La(1)
O(3)
O(4)
O(1)
or
2 [Cp2Co]
C(2)
O(2)
N(2)
N(5)
91%
O(4)
N(1)
C(3)
O(1)
O(2)
[La(LQQ2–)(NO3)]2
[La(LQQ)(NO3)3]
Scheme 2. The synthesis of LQQ, [La(LQQ)(NO3)3] and [La(LQQ2–)(NO3)]2 with 50% thermal ellipsoid plots. H-atoms have been
omitted, cyclohexyl groups have been truncated and NO3 ligands are displayed in wireframe for clarity.
–
We expected that the relative ease of reduction of the
QQ moiety upon coordination to La would be reflected in
the ability of [La(LQQ)(NO3)3] to oxidize an alcohol sub-
strate. A CD2Cl2 solution of free ligand LQQ with a 4-fold
excess of 4MeBnOH11 gave no detectable aldehyde product
QQ moiety (Scheme 2 and S1), analogous to the coordi-
nation environment of the XoxF enzyme active site
(Scheme 1).3d, 4 Cyclic voltammograms (CVs) performed
on LQQ revealed a largely reversible process at E = –
½
0.95
V
vs. Fc/Fc+ for the quinone-semiquinone
1
(QQ/QQ•–) couple (Figure 1, dotted line) followed by an
irreversible process at Ec = –1.76 V assigned as for-
mation of the catecholate dianion (Q2–).9 For
[La(LQQ)(NO3)3], the QQ/QQ•– couple was observed at
by H NMR spectroscopy, upon mixing, even after 3 days.
In contrast, [La(LQQ)(NO3)3] reacted with 2.5 equiv 4MeBnOH
in
CD2Cl2
to
produce
+0.61 V higher potential (E = –0.34 V; ia/ic ≈ 0.8 at 100
½
mV s–1, Figure 1, solid line.) Two poorly reversible, over-
lapping reduction events were revealed on further ca-
thodic sweeps at –0.68 V and –0.77 V, which showed
return waves at –0.66 V and –0.52 V. Overall, the CV of
–
[La(LQQ)(NO3)3] was complicated by loss of NO3 lig-
and(s) and dimerization equilibria (vide infra); the
waves were not definitively assigned (Figures S31-36).
Importantly, the anodic shift of the QQ/QQ•– couple for
[La(LQQ)(NO3)3] compared to LQQ reflected stabilization
of the QQ•– anion by the bound metal ion.9a, 10
0
ꢀ0.3
ꢀ0.6
ꢀ0.9
ꢀ1.2
ꢀ1.5
ꢀ1.8
ꢀ2.1
E (V vs. Fc/Fc+)
Figure 1. Cyclic voltammograms of [La(LQQ)(NO3)3] (solid
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4MeBnOH having been consumed, indicating clean con-
version. Extending the reaction another 24 h increased
the yield of aldehyde to 96%. In the absence of
[La(LQQ)(NO3)3], no 4MePhCHO was produced within 24 h
under these conditions. Replacing [La(LQQ)(NO3)3] with 5
mol% [La(THF)4(NO3)3] or LQQ gave 4MePhCHO in 5% or
14% yield, respectively, after 21 h. These results show
the requirements of both La and the LQQ ligand for cata-
lytic turnover. The dehydrogenation of ~60 mg of
4MeBnOH, catalyzed by [La(LQQ)(NO3)3], was carried out
under the above conditions to afford 4MePhCHO and Fc
in 75% and 83% isolated yields, respectively, in 24 h.
Itoh and Fukuzumi reported dehydrogenation of etha-
nol (~15 turnovers in 65 h) by a mixture of [Ca(ClO4)2],
PQQTME, DBU and O2.6b Until our report, his was the
only non-biological example of alcohol dehydrogenation
catalyzed by a metal complex of a PQQ derivative. No-
tably, our system does not employ O2, which may oxi-
dize the aldehyde to give carboxylic acid byproducts.
line) and LQQ (dashed line) in CH2Cl2 with 0.1 M
[nPr4N][BArF ] at a scan rate of 100 mV s–1.
1
2
3
4
5
6
7
8
4
4MePhCHO in 30% yield in 24 h (67% yield in 3 days, Ta-
ble S3). As observed by Itoh and Fukuzumi in a related
system,6b, 6c addition of 2.2 equiv DBU accelerated the
dehydrogenation of 4MeBnOH by [La(LQQ)(NO3)3] with
4MePhCHO produced in 63±3% yield (1H NMR spectros-
copy) in <10 mins with completion of the reaction at
this point. No detectable quantity of 4MePhCO2H was
produced and only broad, indistinct peaks for LQQ con-
taining product(s) were observed (Figure S29). Perform-
ing the reaction on a preparative scale gave pure, black-
green [La(LQQ2–)(NO3)]2 in 67% yield. This dimer was also
synthesized from [La(LQQ)(NO3)3] and 2 equiv [Cp2Co]
(91%; Scheme 2). The considerably less basic, and thus
more physiologically relevant, 2,6-lutidine could be sub-
stituted for DBU (pKa ~7 c.f. ~12 for DBU).12 The reac-
tion, while slower, was still much faster (complete in
<24 h) than that in the absence of a base, and gave
4MePhCHO in 37% yield (Table S3). A control reaction of
LQQ with 1.2 equiv MeBnOH and 2.2 equiv DBU produced
only trace amounts (<3% yield) of 4MePhCHO in 30 min
(13% after 4 h). [La(LQQ2–)(NO3)]2 is the first structurally
characterized metal complex of a reduced quinoline
quinone. Notably, Itoh and Fukuzumi assigned the
product of the reaction of PQQTME, Ca2+, an alcohol
and DBU as a monomeric, singly deprotonated catechol
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For further insights into the reactivity and properties
of [La(LQQ)(NO3)3] we turned to computations. The gas-
phase structures of
LQQ, [La(LQQ)(NO3)3], putative
[La(LQQ•–)(NO3)3] and [La(LQQ2–)(NO3)]2 were optimized
by DFT methods and gave good agreement with XRD
metrics (Table S5). All carbonyl IR stretches were well
reproduced (Figures S38-40). In addition, a +0.51 V rela-
tive stabilization of [La(LQQ•–)(NO3)3] c.f. LQQ was pre-
•–
2–
complex,6b in contrast to fully deprotonated [La(LQQ
dicted, compared to +0.61 V observed experimentally
(Figure S37). Encouraged by the agreement of DFT cal-
culations with experimental data, we examined possible
mechanisms for the dehydrogenation of 4MeBnOH by
[La(LQQ)(NO3)3]. The catalytic pathway of MDH has been
considered to occur through one of two plausible
mechanisms: hydride transfer (HT) or addition-
elimination (AE).13 Although the HT mechanism is gen-
erally accepted for biological MDH enzymes,14 recent
computational work on Ln-XoxF indicated a possible
)(NO3)]2.
We hypothesized that, with a suitable terminal oxi-
dant and base, the dehydrogenation of 4MeBnOH by
[La(LQQ)(NO3)3] could be performed catalytically. A mix-
ture of 1 equiv 4MeBnOH, 2 equiv [Fc][PF6], 2 equiv 2,6-
lutidine (as DBU was incompatible with [Fc]+ salts) and
[La(LQQ)(NO3)3] (5 mol%) in CD2Cl2-CD3CN (2:1 v/v) was
monitored by 1H NMR spectroscopy (Figure S30). In <20
min, characteristic peaks corresponding to 4MePhCHO
were observed. After 21 h, 4MePhCHO had been pro-
duced in 84% yield (~17 turnovers) with 85% of the
preference
for
the
AE
mechanism.15
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Figure 2. DFT-calculated reaction coordinates for the dehydrogenation of 4MeBnOH by [La(LQQ)(NO3)3]: a) a 2,6-lutidine-
assisted HT mechanism; b) comparison of the AE (red traces) and HT (blue traces) mechanisms in the absence of base (solid
traces) and the influence of DBU (dotted trace) or 2,6-lutidine (dashed traces).
In the current work, the HT mechanism was consid-
ered first (Figures 2a and S47-48). In the first calculated
transition state (TS), a benzylic hydride was transferred
to the C(2)-QQ carbon atom from 4MeBnOH with con-
ferred with two free energy barriers of ~24 kcal mol–1,
consistent with a slow reaction at r.t. (ii) under catalytic
conditions HT should also be favored, as 2,6-lutidine
should enhance the rate by facilitating the enolization
process (iii) nitrate ligands are important in both mech-
anisms by acting analogously to the ‘proton-shuttle’
pendant carboxylate in the MDH.13-15
–
certed alcohol deprotonation by a NO3 ligand (TSHT,
∆G‡ = 24.2 kcal mol–1). This step afforded 4MePhCHO,
HNO3 and the hemiacetalate complex (Int2). Re-
protonation of Int2 by HNO3 to the hemiacetal (IntHT)
was nearly barrier-less. Enolization of IntHT was assisted
We have synthesized a functional model for the lan-
thanide-dependent XoxF-MDH enzyme. This complex
dehydrogenated a benzyl alcohol stoichiometrically and
catalytically under neutral and mildly basic conditions.
DFT investigations suggested a HT mechanism for these
reactions and, by extension, for MDH enzymes. Efforts
to expand these studies are underway, for example,
through variation of the nitrate co-ligands and the iden-
tity of the rare-earth cation on the catalytic activity of
our model system.
–
by a NO3 ligand to give the catechol complex with an
activation barrier of 22.9 kcal mol–1 (TSNO3). Explicit ac-
tion of 2,6-lutidine reduced the barrier for enolization
by ~15 kcal mol–1 (TSLut, ∆G‡ = 7.6 kcal mol–1). Deproto-
2–
nation of the catechol afforded dimeric [La(LQQ
)(NO3)]2, which was downhill by ~35 kcal mol–1.
The AE mechanism was also examined (Figures 2b
–
and S45-46). As expected,6b, 6c, 14b, 15 NO3 -assisted addi-
tion of 4MeBnOH at the C(2)-QQ carbon atom to give the
hemiketal complex (IntAE) had a low barrier of 8.1 kcal
mol–1 (Figure 2b). The barrier for the subsequent retro-
ene step (TSene) to yield the catechol complex (Cat) and
4MePhCHO was ~40 kcal mol–1 and base did not facilitate
this step. The activation energy for the retro-ene step
was lowered (ateTSene, ∆G‡ = 24.5 kcal mol-1) from the
deprotonated hemiketalate complex (ateIntAE) as similar-
ly calculated by others.15-16 However, formation of ateIn-
tAE over IntAE was only favored in the presence of DBU,
but not weakly basic 2,6-lutidine (Figure 2b, dashed and
dotted lines). Thus, in the presence of DBU,
[La(LQQ)(NO3)3] may undergo an AE mechanism, as re-
ported for Ca2+ complexes.6b, 6c
ASSOCIATED CONTENT
The Supporting Information is available free of charge via
the Internet at http://pubs.acs.org. Synthetic procedures
and spectroscopic data, NMR spectra from reaction mix-
tures, additional electrochemistry and computational data.
AUTHOR INFORMATION
Corresponding Author: *schelter@sas.upenn.edu
ACKNOWLEDGMENT
We thank the U.S. NSF (CHE-1608925) and University of
Pennsylvania for support of this work. The Camille and Henry
Dreyfus Postdoctoral Program in Environmental Chemistry is
acknowledged for a fellowship to T.C. This work used the Ex-
treme Science and Engineering Discovery Environment, which
is supported by the U.S. NSF, OCI-1053575.
Overall, our DFT study suggested that for the dehy-
drogenation of 4MeBnOH by [La(LQQ)(NO3)3]: (i) in the
absence of a base, the HT mechanism should be pre-
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