Integrating Activity with Accessibility in Olefin Metathesis: An Unprecedentedly Reactive Ruthenium-Indenylidene Catalyst

Article abstract of DOI:10.1021/jacs.9b05362

Access to leading olefin metathesis catalysts, including the Grubbs, Hoveyda, and Grela catalysts, ultimately rests on the nonscaleable transfer of a benzylidene ligand from an unstable, impure aryldiazomethane. The indenylidene ligand can be reliably installed, but to date yields much less reactive catalysts. A fast-initiating, dimeric indenylidene complex (Ru-1) is reported, which reconciles high activity with scaleable synthesis. Each Ru center in Ru-1 is stabilized by a state-of-the-art cyclic alkyl amino carbene (CAAC, C1) and a bridging chloride donor: the lability of the latter elevates the reactivity of Ru-1 to a level previously attainable only with benzylidene derivatives. Evaluation of initiation rate constants reveals that Ru-1 initiates >250× faster than indenylidene catalyst M2 (RuCl₂(H₂IMes)(PCy₃)(Ind)), and 65× faster than UC (RuCl₂(C1)₂(Ind)). The slow initiation previously regarded as characteristic of indenylidene catalysts is hence due to low ligand lability, not inherently slow cycloaddition at the Ru=CRR′ site. In macrocyclization and "ethenolysis" of methyl oleate (i.e., transformation into α-olefins via cross-metathesis with C₂H₄), Ru-1 is comparable or superior to the corresponding, breakthrough CAAC-benzylidene catalyst. In ethenolysis, Ru-1 is 5× more robust to standard-grade (99.9%) C₂H₄ than the top-performing catalyst, probably reflecting steric protection at the quaternary CAAC carbon.

Full text of DOI:10.1021/jacs.9b05362

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Communication
Integrating Activity with Accessibility in Olefin Metathesis: An
Unprecedentedly Reactive Ruthenium-Indenylidene Catalyst
Daniel Luis do Nascimento, Anna Gawin, Rafa# Gawin, Piotr A. Gu#ka,
Janusz Zachara, Krzysztof Skowerski, and Deryn Elizabeth Fogg
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b05362 • Publication Date (Web): 27 Jun 2019
Downloaded from http://pubs.acs.org on June 28, 2019
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Integrating Activity with Accessibility in Olefin Metathesis: An
Unprecedentedly Reactive Ruthenium-Indenylidene Catalyst
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¶
¶
Daniel L. Nascimento,† Anna Gawin,‡ Rafał Gawin,‡ Piotr A. Guńka, Janusz Zachara,
Krzysztof Skowerski,‡ and Deryn E. Fogg†*
†Center for Catalysis Research and Innovation, and Department of Chemistry and Biomolecular Sciences,
University of Ottawa, Ottawa, ON, Canada K1N 6N5. ‡Apeiron Synthesis, Duńska 9, Wrocław, Poland. Faculty
¶
of Chemistry, Warsaw University of Technology, Noakowskiego 3, Warsaw, Poland.
Supporting Information Placeholder
ABSTRACT: Access to leading olefin metathesis catalysts, including the Grubbs, Hoveyda, and Grela
catalysts, ultimately rests on the non-scaleable transfer of a benzylidene ligand from an unstable, impure
aryldiazomethane. The indenylidene ligand can be reliably installed, but to date yields much less reactive
catalysts. A fast-initiating, dimeric indenylidene complex (Ru-1) is reported, which reconciles high activity
with scaleable synthesis. Each Ru center in Ru-1 is stabilized by a state-of-the-art cyclic alkyl amino carbene
(CAAC, C1) and a bridging chloride donor: the lability of the latter elevates the reactivity of Ru-1 to a level
previously attainable only with benzylidene derivatives. Evaluation of initiation rate constants reveals that
Ru-1 initiates >250x faster than indenylidene catalyst M2 (RuCl2(H2IMes)(PCy3)(Ind)), and 65x faster than
UC (RuCl2(C1)2(Ind)). The slow initiation previously regarded as characteristic of indenylidene catalysts is
hence due to low ligand lability, not inherently slow cycloaddition at the Ru=CRR’ site. In macrocyclization
and “ethenolysis” of methyl oleate (i.e. transformation into -olefins via cross-metathesis with C2H4), Ru-1
is comparable or superior to the corresponding, breakthrough CAAC-benzylidene catalyst. In ethenolysis,
Ru-1 is 5x more robust to standard-grade (99.9%) C2H4 than the top-performing catalyst, probably reflecting
steric protection at the quaternary CAAC carbon.
Keywords. olefin metathesis, cyclic alkyl amino carbene, indenylidene, high activity, initiation, catalyst synthesis
Reported herein is a ruthenium metathesis catalyst
that integrates breakthrough productivity with a
robust, reliably-installed indenylidene ligand. The
advent of large-scale olefin metathesis processes in
CAAC catalysts in macrocyclic ring-closing
metathesis (mRCM)8 and cross-metathesis (CM)
routes to -olefins from renewable oils.9-12 The
CAAC catalysts thus hold significant potential in
the pharmaceutical and renewable-feedstock
sectors.1,12-14
pharmaceutical
manufacturing,1,2
and
the
associated demand for catalyst supply on scale,
bring to the fore long-neglected challenges in
scaleable catalyst synthesis. Chief among these is
the means by which the critical Ru=CRR’ site is
introduced.
Chart 1. Literature Metathesis Catalysts Discussed.
Interest extends beyond the important N-
heterocyclic carbene3 (NHC) complexes to new
cyclic alkyl amino carbene (CAAC)4 catalysts:
Chart 1. While metathesis in process chemistry1,2 is
dominated by NHC catalysts (HII, nG),5-7 bench-
scale studies report exceptional productivity for
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added to abstract the “extra” CAAC ligand
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(Scheme 1a).8 Limitations, however, are the <40%
yield, compounded by the multistep, low-yielding
synthesis of 1.33,34 We queried whether omitting 1
might enable access to dimeric Ru-1, in which the
precatalyst is stabilized by a dative Cl interaction.
The high lability, and consequently high metathesis
activity, conferred by dative chloride bonds has
been recognized since Herrmann’s pioneering
work on bimetallic metathesis catalysts containing
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one
[Ru]=CHR
site.35
While
bimolecular
A long-standing challenge, however, is the tradeoff
between metathesis activity, vs. the efficiency of
catalyst synthesis. Most active are Ru-benzylidene
catalysts (red; Chart 1).8-10 Despite attempts to
develop alternative synthetic methodologies,15
optimal routes to benzylidene catalysts continue to
rest on the reaction of a Ru precursor with an
aryldiazomethane, typically PhCHN2.16,17 PhCHN2
is toxic and unstable (indeed, potentially
explosive),18 to an extent that prevents purification.
Its low purity, in turn, limits stoichiometric control
elimination of the alkylidene moiety as RCH=CHR
is a documented risk for dimers containing two
[Ru]=CHR sites,19a,36-38 this reaction is highly
sensitive to alkylidene bulk.37,39 We thus regarded
the disubstituted indenylidene ligand as
a
potentially key asset in blocking alkylidene
elimination.
Accordingly, we treated UC with CuCl (Scheme
1b) in the absence of additional donors. A C1
ligand was successfully abstracted at 40 °C,
enabling transformation of UC into dimeric Ru-1 in
ca. 80% isolated yield. The structure of Ru-1 is
supported by X-ray analysis. Consistent with the
critical role of indenylidene bulk in inhibiting
bimolecular decomposition, the corresponding
reaction of CuCl with the second-generation
Grubbs catalyst RuCl2(H2IMes)(PCy3)(=CHPh) led
to rapid elimination of stilbene. In the absence of
CuCl, this reaction requires days at 60 °C.40
over
benzylidene
transfer.17,19
Significant
limitations to process scaleability result.
Indenylidene catalysts (blue, Chart 1) enable
straightforward, convenient, reliable installation of
the Ru-carbon double bond, via the high-yield
reaction of Ru precursors with propargyl
alcohol.20,21 However, study of the NHC
derivatives, most extensively M2, reveals very
inefficient initiation.22-32 Slow loss of the stabilizing
donor (PCy3, for M2) impedes entry into the
catalytic cycle at room temperature (RT), even for
the readily-cyclized diene diethyl diallylmalonate
2.10,28-30 Elevated temperatures are required to elicit
high activity, promoting catalyst degradation. Here
we report the novel CAAC-indenylidene catalyst
Ru-1, a labile chloride-bridged dimer, which
overturns this long-accepted limitation. Ru-1
exhibits unprecedented activity in demanding
metathesis reactions (indeed, at a level comparable
to the Grela-class catalyst nG-C1), establishing that
high-performing metathesis catalysts can be
accessed via simple, safe, scaleable chemistry.
Scheme 1. Synthesis of Ru-1.
NO2
(a)
Ph
OiPr
O2N
Cl
Cl
C1
1
Ru
C1
Ru
C1
Cl
OiPr
CuCl, toluene
80 °C, 20 min
Cl
nG-C1
38% (isolated; ref 8)
UC
(b) CuCl, CH2Cl2
40 °C, 30 min
This work
Ph
Cl
N
Ru
Cl
2
Ph
Ru-1
Ru-1
78% (isolated)
It should be noted that nG-C1 is itself accessible
without recourse to diazo technology, via CM of
the commercial indenylidene catalyst UC with the
chelating -methylstyrene reagent 1, when CuCl is
The metathesis activity of Ru-1 was benchmarked
against key CAAC and NHC catalysts in RCM of
diethyl diallylmalonate 2. Comparison with the
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state-of-the-art catalyst nG-C18 gives insight into
that measured for nG under the same conditions
(17,200), despite the higher lability expected for the
styrenyl ether ligand in nG, vs. a strongly-bound
CAAC donor.44
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the relative reactivity of the indenylidene and
chelating p-nitrobenzylidene ligands. Comparison
with UC reports on the impact of replacing a
CAAC donor with a much more labile dative
chloride, while comparison of nG-C1 with its
H2IMes analogue nG probes the impact of the
carbene. Catalyst loadings were chosen in light of
prior studies of RCM of 2 via indenylidene catalyst
M2.10,24-32 We suspected that the reported TONs
(ca. 20–2,000) might under-report catalyst
productivity, given near-quantitative conversions.
Initial catalyst loadings were therefore reduced to
0.005 mol% (i.e. 50 ppm Ru relative to 2; cf. 5–0.05
mol% in the literature reports). The resulting data
are summarized in Figure 1a.
As a metathesis reaction manifold of significant
current
interest,
we
next
turned
to
macrocyclization. Substrates such as prolactone 3
(Figure 2) are challenging because the ester
functionality contributes the sole conformational
bias toward cyclization.45 Oligomers are hence
typically formed as the kinetic products, but can be
recycled into macrocycles if catalyst activity and
longevity permit.46,47 High dilutions (5 mM, in the
case of 3) are essential to exert an entropic bias
sufficient to shift the ring-chain equilibrium in
favour of the macrocyclic rings.46,48 (Carrying out
mRCM of 3 at 20 mM, for example, yields ca. 40%
oligomers).8 A catalyst loading of 0.01 mol% thus
corresponds to sub-micromolar concentrations of
Ru. Combined with the internal, predominantly
trans-substituted nature of the oligomeric olefins,
this offers a stringent test of catalyst performance.
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Notwithstanding these challenges, Ru-1 enabled
fast, selective mRCM at 0.01 mol% Ru, achieving
TONs of ca. 9,000 within 10 min at 40 °C (Figure 2).
nG-C1 and UC exhibited similar, slower,
performance, while the productivity of H2IMes
catalyst nG was ca. 30% lower, and M2 failed to
react. At RT, Ru-1 enabled quantitative mRCM
within 20 min at 0.05 mol%, where UC reacted
much more slowly (44% yield at 2 h; Figure S2).
Figure 1. Turnover numbers (TON) at 2 h in RCM of
2. For numerical values, see Table S1. Catalyst
loadings are based on 2 active Ru centers in Ru-1.
Unexpectedly, Ru-1 exhibited RCM activity
comparable to the leading catalyst nG-C1 at RT at
this loading, and slightly higher activity at 9 ppm
Ru and 40 °C. The basis for this difference is
discussed below. Ru-1 also outperformed nG and
M2, in keeping with the trend established for
H2IMes vs. CAAC catalysts,9,10 which may arise
from faster decomposition of the H2IMes
complexes.41
At 0.002 mol% and 40 °C (Figure 2b), a TON of
27,500 was measured for Ru-1 (the highest yet
reported for a Ru catalyst at dilutions compatible
with selective mRCM).49 In comparison, the record
TON for NHC catalysts in this reaction is 16,000,
achieved by Kadyrov at 80 °C and 8 mM 3,50 with
rigorously purified diene and solvent, and
aggressive removal of ethylene to limit catalyst
decomposition.51,52 Under standard conditions,
reported TONs are ≤500.50,52,53
A further inhibiting factor for M2 is the low lability
characteristic of phosphines trans to an NHC
ligand,42,43 which limits TONs to 2,000 at 50 ppm
Ru. The higher RT productivity of UC (TON
12,000) suggests that the C1 ligand in UC is more
labile than the PCy3 ligand in M2 (confirmed
below), though catalyst lifetime is almost certainly
also relevant. Of note, this TON is nearly 60% of
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1,18-dimethyl 9-octadecenoate 6 and 9-octadecene
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7, formed via self-metathesis (SM) of MO or its
ethenolysis products.
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Table 1. Ethenolysis of Methyl Oleate: Cross-
Metathesis (CM) and Self-Metathesis (SM).a
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Pressure
(psi)
% Conv.
(% Yield)
Figure 2. mRCM of 3 at 40 °C. (a) Rate profiles and (b)
maximum TONs at 0.01 or (*) 0.002 mol% Ru, shown
alongside the best reported TONs for UC10 and M2.50
For the RT plot and numerical data, see SI.
Entry Catalyst
TON
1
2
3
4
5
6
Ru-1
20
16 (3)
39 (20)
28 (25)
18 (8)
39 (23)
9 (5)
6,000
40,000
50,000
16,000
46,000
10,000
Ru-1
110
200
400
200
200
Improved stability to ethylene appears to be an
Ru-1
important
contributor
to
the
exceptional
Ru-1
productivity of the CAAC catalysts. This tolerance
opens the door to ethenolysis of unsaturated
lipids,1,2 a reaction of keen interest for the
production of -olefins from renewable plant or
algal oils.1,12-14 Outstanding performance has been
reported in ethenolysis of methyl oleate (MO) with
nG-C1
HII-C2
a5 ppm catalyst = 0.0005 mol% Ru. TON based on 4/5.
Quantified by 1H NMR analysis (Figure S3).
The impressive activity of Ru-1 documented above
attests to the lability of the dative chloride donor,
relative to the stabilizing ligands present in
indenylidene catalysts such as M2 and UC. It also
supports the case made by Cavallo, Nolan and co-
workers, on the basis of DFT analysis, that slow
initiation of M2 and related catalysts is due to slow
ligand loss, not the resistance of the indenylidene
moiety to cycloaddition.30b,55,56
CAAC
catalysts,9-11,54
particularly
HII-C2.9
However, HII-C2 may be highly sensitive to
impurities. Costly, very high grade (99.995%)
ethylene was required for maximum productivity,
and a 40–70% drop in TON was reported on using
99.95 or 99.99% C2H4.9,10 We utilized affordable,
technical-grade C2H4 (99.9%) to probe the
robustness of Ru-1 relative to this breakthrough
catalyst.
To examine this key point, we measured initiation
rate constants (k1) for Ru-1 and selected other
catalysts, via the irreversible reaction with tert-
butyl vinyl ether (tBVE; Table 2).30b,57 The bulk of
tBVE retards metathesis to experimentally
convenient rates.58
Table 1 shows the impact of ethylene pressures on
cross-metathesis (CM) yields at 40 °C in neat MO.
A pressure of 200 psi proved optimal (entries 1–4),
possibly indicating a trade-off between ethylene
solubility and the cumulative impact of poisons.
Importantly, however, Ru-1 appears significantly
more robust than HII-C2, as indicated by TON
values of 50,000 and 10,000 (respectively) at 200 psi.
Steric protection may be higher for C1, in which
the quaternary carbon flanking the carbene site
bears a methyl and a phenyl group, as compared
with two methyl groups in C2 (Chart 1).
As expected, initiation was fastest with
benzylidene complex nG-C1 (in which the
inductive effect of the p-NO2 substituent increases
the lability of the ether donor),7 and slowest with
UC and M2. Notable is the 260x faster initiation of
Ru-1 relative to M2, and 65x relative to UC.
Indeed, nG-C1 initiates only 3.5x faster than Ru-1,
despite the steric barrier to metathesis at the
disubstituted Ru=CRR’ site. Clearly, incorporating
nG-C1 delivered CM yields similar to Ru-1, though
higher conversions of MO. The balance was due to
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crystallographic data, and NMR spectra.
a labile dative ligand greatly diminishes the barrier
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to indenylidene initiation, even relative to a
AUTHOR INFORMATION
classically fast-initiating7 benzylidene ligand.
Corresponding Author
Also striking is the slightly slower overall rate of
metathesis for nG-C1 vs. Ru-1 (Figs. 2a, S2),
despite threefold faster initiation. As the two
catalysts generate the same active species, the
lower net activity of nG-C1 suggests recapture of
free 4-nitro-2-isopropoxystyrene 1’ by the active
species. The rate difference is maintained even at
40 °C and sub-micromolar concentrations of Ru
and 1’ (Figure 2b). While heat and high dilutions
amplify engagement of nG-C1 in metathesis, they
are insufficient to inhibit re-uptake of 1’.59
email dfogg@uottawa.ca.
ACKNOWLEDGMENT
This work was funded by NSERC of Canada. X-ray
diffraction studies were financed by Warsaw University
of Technology.
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ki (s-1)
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(2)
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Ru=CRR’
259
4
Ru=CRR’ 3.33 x 10-6
Ru=CRR’ 0.83 x 10-6
M2
1
a 30 equiv tBVE; measured in CDCl3, 23 °C.
A tradeoff has long existed between the ease with
which an alkylidene ligand can be installed at Ru
centers, and the activity of the resulting catalysts.
The need for scaleable, high-yield routes to
metathesis catalysts, which obviate the unreliability
and risk of diazoalkane methodologies, is
becoming urgent with the increasing demand for
catalyst supply on scale. The foregoing overturns
the long-standing view that the synthetic
accessibility of Ru-indenylidene catalysts is
incompatible with high metathesis activity.
Catalyst Ru-1 exhibits a level of activity previously
attainable only with benzylidene catalysts,
indicating that the “fundamental” unreactivity of
prior indenylidene catalysts merely reflects the low
lability of the stabilizing ligands. In reconciling
high metathesis activity with straightforward,
reliable, safe installation of the alkylidene ligand,
this advance is anticipated to create new
opportunities in olefin metathesis.
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ASSOCIATED CONTENT
The Supporting Information is available free of charge
on the ACS Publications website.
PDF
file:
experimental
data,
rate
plots,
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Complexes:
A
Versatile, Highly Efficient Tool for Olefin
Grubbs, R. H.; Wenzel, A. G., Eds. Wiley-VCH: Weinheim,
2015; Vol. 1, pp 389–416.
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(30) Pyridine- and PPh3-stabilized indenylidene catalysts
are reported to exhibit even lower room-temperature activity
than M2. See refs 27, 28. A DFT study concluded that their slow
initiation is due to reduced steric pressure in the precatalyst.
See: Urbina-Blanco, C. A.; Poater, A.; Lebl, T.; Manzini, S.;
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(18) Sammakia, T., Phenyldiazomethane. In Encyclopedia of
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(31) Yu, B.; Li, Y.; He, X.; Hamad, F. B.; Ding, F.; Van
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(19) (a) Amoroso, D.; Snelgrove, J. L.; Conrad, J. C.;
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Adv. Synth. Catal. 2002, 344, 757–763. Exacerbating the problem,
use of the diazoalkane reagent in excess triggers alkylidene
elimination as (e.g.) PhCH=CHPh. See: (b) Amoroso, D.; Fogg,
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2815–2818.
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Block in the Preparation of Nitro-Substituted Hoveyda−Grubbs
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(35) Weskamp, T.; Kohl, F. J.; Hieringer, W.; Gleich, D.;
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First Coordinatively Unsaturated Group
8 Allenylidene
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(21) Boeda, F.; Clavier, H.; Nolan, S., Ruthenium–
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(22) Dixneuf, H. P.; Bruneau, C., Ruthenium Indenylidene
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(50) Kadyrov, R., Low Catalyst Loading in Ring-Closing
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(51) Burdett, K. A.; Harris, L. D.; Margl, P.; Maughon, B.
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(53) Tracz, A.; Matczak, M.; Katarzyna; Urbaniak;
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increasing steric pressure on the dissociating PCy3 ligand. See:
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of Indenylidene Derivatives in Olefin Metathesis Catalysts.
Beilstein J. Org. Chem. 2018, 14, 2956–2963. The rigidity of the
conventional indenylidene ligand is presumed to limit such
steric pressure relative to the conformationally mobile
benzylidene ligand. Steric pressure exerted by the [Ru]=CHPh
group has been shown to be central to the 275x faster loss of
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(36) Amoroso, D.; Yap, G. P. A.; Fogg, D. E., Deactivation
of Ruthenium Metathesis Catalysts via Facile Formation of
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(37) Bailey, G. A.; Foscato, M.; Higman, C. S.; Day, C. S.;
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Decomposition of Fast-Initiating Olefin Metathesis Catalysts. J.
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(38) For kinetics evidence for bimolecular decomposition,
see: Thiel, V.; Wannowius, K.-J.; Wolff, C.; Thiele, C. M.; Plenio,
H., Ring-Closing Metathesis Reactions: Interpretation of
Conversion–Time Data. Chem. - Eur. J. 2013, 19, 16403–16414.
(39) The successful deployment of chloride-bridged
dimers in ring-opening metathesis polymerization (see: (a)
Hansen, S. M.; Volland, M. A. O.; Rominger, F.; Eisentrager, F.;
Hofmann, P., A New Class of Ruthenium Carbene Complexes:
Synthesis and Structures of Highly Efficient Catalysts for Olefin
Metathesis. Angew. Chem., Int. Ed. 1999, 38, 1273–1276) reflects
the resistance of bulky [Ru]=CHR groups to bimolecular
elimination.
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(40) Higman, C. S.; Nascimento, D.; Ireland, B. J.;
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Closing
Metathesis:
A
Strategy
for
Accelerating
Macrocyclization at Ambient Temperatures. J. Am. Chem. Soc.
2018, 140, 1604−1607.
(41) Butilkov, D.; Frenklah, A.; Rozenberg, I.; Kozuch, S.;
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Containing Ruthenium Benzylidenes. ACS Catal. 2017, 7, 7634–
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(42) Lummiss, J. A. M.; Higman, C. S.; Fyson, D. L.;
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NHC Donation in Catalysis. Chem. Sci. 2015, 6, 6739–6746.
(43) Dharmasena, U. L.; Foucault, H. M.; dos Santos, E. N.;
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Ligands for Hydrogenation and Isomerization of Unactivated
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PCy3
from
GII
vs.
its
methylidene
analogue
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Grubbs Catalysts. Organometallics 2016, 35, 691–698.
(57) Engle, K. M.; Lu, G.; Luo, S.-X.; Henling, L. M.;
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2015, 137, 5782−5792.
(46) Monfette, S.; Fogg, D. E., Equilibrium Ring-Closing
Metathesis. Chem. Rev. 2009, 109, 3783–3816.
(58) Reaction with ethyl vinyl ether was dramatically
faster. For nG-C1, for example, reaction with 100 EVE was
complete in <1 min at 23 °C.
(47) Such simple “olfactory lactones” were recently
isolated at higher concentrations, by distilling off the cyclic
product to shift the ring-chain equilbrium. See: Sytniczuk, A.;
Dąbrowski, M.; Banach, Ł.; Urban, M.; Czarnocka-Śniadała, S.;
Milewski, M.; Kajetanowicz, A.; Grela, K., At Long Last: Olefin
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Chem. Soc. 2018, 40, 8895–8901.
(48) Conrad, J. C.; Eelman, M. D.; Duarte Silva, J. A.;
Monfette, S.; Parnas, H. H.; Snelgrove, J. L.; Fogg, D. E.,
Oligomers as Intermediates in Ring-Closing Metathesis. J. Am.
Chem. Soc. 2007, 129, 1024–1025.
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isopropoxystyrene, see: (a) Bates, J. M.; Lummiss, J. A. M.;
Bailey, G. A.; Fogg, D. E. ACS Catal. 2014, 4, 2387−2394. (b)
Griffiths, J. R.; Keister, J. B.; Diver, S. T. J. Am. Chem. Soc. 2016,
138, 5380−5391. For the original proposal, see ref 5. Of note,
alternative electron-deficient styrenyl ethers were reported to
resist recapture in H2IMes complexes. See: (c) Vorfalt, T.;
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(49) A TON of 62,000 could be achieved with nG-C1 at
higher concentrations (20 mM 3) at 70 °C. .
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>> faster initiation
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