Impact of Ligands and Metals on the Formation of Metallacyclic Intermediates and a Nontraditional Mechanism for Group VI Alkyne Metathesis Catalysts

Article abstract of DOI:10.1021/jacs.1c01843

The intermediacy of metallacyclobutadienes as part of a [2 + 2]/retro-[2 + 2] cycloaddition-based mechanism is a well-established paradigm in alkyne metathesis with alternative species viewed as off-cycle decomposition products that interfere with efficient product formation. Recent work has shown that the exclusive intermediate isolated from a siloxide podand-supported molybdenum-based catalyst was not the expected metallacyclobutadiene but instead a dynamic metallatetrahedrane. Despite their paucity in the chemical literature, theoretical work has shown these species to be thermodynamically more stable as well as having modest barriers for cycloaddition. Consequentially, we report the synthesis of a library of group VI alkylidynes as well as the roles metal identity, ligand flexibility, secondary coordination sphere, and substrate identity all have on isolable intermediates. Furthermore, we report the disparities in catalyst competency as a function of ligand sterics and metal choice. Dispersion-corrected DFT calculations are used to shed light on the mechanism and role of ligand and metal on the intermediacy of metallacyclobutadiene and metallatetrahedrane as well as their implications to alkyne metathesis.

Full text of DOI:10.1021/jacs.1c01843

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Article
Impact of Ligands and Metals on the Formation of Metallacyclic
Intermediates and a Nontraditional Mechanism for Group VI Alkyne
Metathesis Catalysts
Richard R. Thompson,§ Madeline E. Rotella,§ Xin Zhou, Frank R. Fronczek, Osvaldo Gutierrez,*
and Semin Lee*
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ABSTRACT: The intermediacy of metallacyclobutadienes as part
of a [2 + 2]/retro-[2 + 2] cycloaddition-based mechanism is a
well-established paradigm in alkyne metathesis with alternative
species viewed as off-cycle decomposition products that interfere
with efficient product formation. Recent work has shown that the
exclusive intermediate isolated from a siloxide podand-supported
molybdenum-based catalyst was not the expected metallacyclobu-
tadiene but instead a dynamic metallatetrahedrane. Despite their
paucity in the chemical literature, theoretical work has shown these
species to be thermodynamically more stable as well as having
modest barriers for cycloaddition. Consequentially, we report the synthesis of a library of group VI alkylidynes as well as the roles
metal identity, ligand flexibility, secondary coordination sphere, and substrate identity all have on isolable intermediates.
Furthermore, we report the disparities in catalyst competency as a function of ligand sterics and metal choice. Dispersion-corrected
DFT calculations are used to shed light on the mechanism and role of ligand and metal on the intermediacy of
metallacyclobutadiene and metallatetrahedrane as well as their implications to alkyne metathesis.
Scheme 1. Commonly Accepted Mechanism for Alkyne
Metathesis by Way of a MCBD Intermediate
INTRODUCTION
■
a
The catalytic formation of carbon−carbon bonds remains one
of the most crucial applications in organometallic chemistry.
Consequentially, cross-coupling, olefin metathesis, and poly-
merization reactions have all garnered extensive attention with
myriad studies on optimizing conditions, improving substrate
scope, and expanding the applications of these transformations
following their initial discoveries.1−4 On the other hand, alkyne
metathesis has been a relatively dormant field until recent
advances by Bunz,5 Furstner,6 Tamm,7 Moore,8 Zhang,9,10
̈
Buchmeiser,11−13 and Jia.14 These studies have demonstrated
that alkyne metathesis is an incredibly powerful tool for
generating pharmaceuticals,15 complex natural products,16−24
supramolecular structures,25−37 and polymers.5,38−44 The
currently accepted mechanism for alkyne metathesis consists
of a [2 + 2]/retro-[2 + 2] cycloaddition mechanism (Scheme
1) akin to those implicated in olefin metathesis. Significant
evidence for this pathway exists due to the isolation of a
number of metallacyclobutadiene (MCBD) intermedi-
ates.45−54 Typically, the directionality/reversibility of this
mechanism is taken for granted as the geometric flexibility of
most supporting ligands allows for facile reorganization within
the metallacyclic core. Despite the relative paucity of isolated
and characterized metallatetrahedrane (MTd) isomeric struc-
tures, speculation about their intermediacy has lingered since
1982.55 Further, computational studies indicate a greater
a
MTd formation is considered as an off-cycle intermediate.
Received: February 16, 2021
Published: June 10, 2021
https://doi.org/10.1021/jacs.1c01843
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© 2021 American Chemical Society
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thermodynamic stability for these species in comparison to the
more common MCBD.56,57 Theory also suggests that direct
interconversion between a metal alkylidyne and alkyne with a
MTd should be symmetry forbidden and thus implicate the
intermediacy of a MCBD en route to the MTd.58
novel tetrahedrane cores as was previously reported by
Cummins with a niobium cyclo-P3 complex to generate the
interpnictogen compound, AsP3.67
Recently, both our research group68 and Furstner’s69
̈
independently reported the same siloxide podand-based ligand
scaffold (SiP) for Mo(VI)-alkylidyne catalysts. Furstner and
The first alkyne metathesis-related metallatetrahedrane was
̈
reported by Schrock and Churchill in 1984 (Scheme 2a).53
co-workers identified a number of remarkable improvements in
substrate scope (including protic substrates) and moderate
tolerance to water using further optimized Mo(VI)-siloxide
podand catalysts, which they named “canopy catalysts”.70 On
the other hand, our group focused on the mechanistic studies
of the catalysts and reported the serendipitous discovery of the
exclusive formation of a Mo-based metallatetrahedrane
intermediate, MTd1 (Scheme 2d).68 The new Mo-metal-
latetrahedrane complex formed directly from 3-hexyne and the
Mo-alkylidyne catalyst supported by the SiP-ligand. In stark
contrast to previously reported species,52−54 the siloxide
podand-based Mo-metallatetrahedrane was identified as a
dynamic intermediate that interconverts with alkylidynes and
continues to behave as an alkyne metathesis catalyst. Given
that SiP-supported molybdenum alkylidynes represent an
incredible advancement in alkyne metathesis catalyst design,
coupled with the fact that MTd1 was the sole isolated
intermediate, we deemed a thorough understanding of
metallatetrahedrane formation a paramount question. We
recognized that the modular synthesis of the podand ligand
could serve as a platform for a systematic investigation on the
formation of metallacycles in both Mo(VI) and W(VI)
alkylidyne catalysts and, in turn, provide a blueprint for future
rational design. Here, we investigate the effect of ligands and
metal choice on the intermediate formation and their role in
catalysis, both experimentally and computationally.
Scheme 2. Precedence of Mo(VI)/W(VI)-Based
Metallatetrahedranes (MTd) Complexes
They first isolated a bent tungsten metallacyclobutadiene,
where the β-carbon protruded out-of-plane. This bent
metallacycle was viewed as a structural intermediate between
a planar metallacyclobutadiene and a metallatetrahedrane.
When trimethylphosphine (PMe3) was added, the bent
metallacyclobutadiene motif converted completely into a
tetrahedral structure. Soon after, another example was reported
by coordinating tetramethylethylenediamine (TMEDA) to a
W(VI)-MCBD complex, which converted into an octa-
coordinate metallatetrahedrane (Scheme 2b).52 In 1986,
Schrock and Churchill reported yet another metallatetrahe-
drane that formed directly from Mo(VI)- and W(VI)-
alkylidyne complexes when combined with 3-hexyne (Scheme
2c).51 These three cases, despite being isolated metal-
latetrahedranes, have been coordinatively saturated and
catalytically inert.51,52,54,59 Experimental research on the role
of Mo- and W-metallatetrahedranes and their implications to
alkyne metathesis remains underexplored and has been almost
dormant for more than 30 years.
Beyond mechanistic arguments, studying the stability of
early transition metal metallatetrahedranes is important for
better understanding fundamental organometallic bonding.
While cyclopentadienyl and cyclobutadienyl complexes are
well-known, classical organometallic ligands, their 3-member
ring analogues are much less well-studied and, even in
instances where they have been, it is often as cyclopropenylium
cations.60−62 As noted by Schrock, the binding of the C3
fragments to high-valent, early transition metal centers is
significantly stronger than with associated cyclopropenylium
adducts and thus can be considered chemically distinct.52−54
RESULTS AND DISCUSSION
Synthesis of Mo/W-SiP Catalysts. An important feature
of the SiP ligand, highlighted by both our group and Fu
■
̈
rstner’s,
was its rigidity.68,69 Specifically, both structural and theoretical
probing found the C3-symmetric scaffold to enforce the same
geometry on organometallic species and that gearing occurred
when modulation of one of the podand arms was attempted.
This trait is important given the considerable role ligand
distortion and geometry play on achieving putative MCBD
intermediates.6,7 Such distortions would be less necessary if an
alternative mechanism involving the experimentally isolated
MTd were implicated. With these concepts in mind, we set out
to synthesize a new, less sterically imposing, ethyl siloxide
podand (SiPEt) ligand to give a direct comparison to the
previously reported phenyl variant (SiPPh)68,69 with the idea
that structural rearrangements may be more facile. The use of
the alkyl substituted variant also allows for the deconvolution
of any effects the six aryl groups of SiPPh may have on MTd
formation. Furthermore, we produced the molybdenum and
tungsten catalysts with both ligands to investigate the role of
metal choice (Mo vs W) in both activity and more importantly,
on the identity and stability of intermediates.22 The synthesis
of both SiPR ligands, SiPPh (R = Ph) and SiPEt (R = Et), could
be achieved in good yield via lithiation of a tribromo-precursor
followed by treatment with R2SiCl2 and aqueous workup
(Scheme 3a). A sign of a marked difference between the two
ligands is the chemical shift of the O-H with those of SiPPh
coming in at 4.45 ppm while those associated with SiPEt are
upfield by nearly 1 ppm at 3.60 ppm. To further examine the
structural differences between the two ligands, we collected X-
Furthermore, the tetrahedrane-bonding motif is much more
63,64
common for the analogous cyclo-P3
ligand despite
phosphorus being considered an elemental “carbon-copy”.65
Cummins went as far as to show that treatment of a
molybdenum phosphide, (NtBuAr)3MoP, with either
diphosphorus (P2) or the phosphaalkyne, AdCP, resulted
in the related cyclo-P3 or cyclo-CP2 tetrahedranes, respec-
tively.66 An improved understanding on the synthesis and
stability of metallatetrahedranes could extend its synthetic
utility in transferring the cyclopropyl fragment to generate
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Scheme 3. (a) Synthesis of SiPR (R = Ph, Et) Ligands SiPPh
and SiPEt; (b) Synthesis of Catalysts Cat2−5 via
Protonolysis of Catalyst Precursors Pre1 and Pre2
ray diffraction data on single crystals of SiPEt (Supporting
Information Figure S44) to complement the data which was
already collected on SiPPh. While both compounds crystallized
in the space group P1
̅
, SiPPh contains a single molecule (as a
hydrate) in the asymmetric unit, SiPEt forms with two
independent molecules in the asymmetric unit and no solvent
cocrystallizing. In spite of these modest differences, all three
silanol OH groups in both independent molecules of SiPEt are
pointing to form intramolecular hydrogen-bonded pockets.
Salt-metathesis directly from ArCMoBr3(dme) (Ar = tolyl
and mesityl) was previously shown to be a viable route for
appending the SiP scaffold onto molybdenum.68 However, we
found that protonolysis of the silanol with a precursor tris-tert-
butoxide species (Scheme 3b) was a much more facile and
high yielding method.69,70 Specifically, we generated catalyst
precursor species with both molybdenum (Pre1)46 and
tungsten (Pre2), in high yields as colorless, crystalline solids.
Treatment of Pre1 or Pre2 with SiPPh or SiPEt allowed for the
synthesis of species Cat2−5 in good yields and all readily
crystallized when stored at −37 °C (Figure 1, Table 1). In all
cases, the SiP ligand was shown to coordinate to the metal
center in a mononuclear, tridentate fashion, regardless of the
increased Lewis acidity associated with tungsten relative to
molybdenum or the reduced sterics of the ethyl groups relative
to phenyl groups. The utility of 2,6-disubstitution on the
alkylidyne aryl group appears to be particularly useful in
preventing the same aggregation observed in related species
which lack it.69,70 Notably, the MC1 (carbyne) distances all
fall within the range of typical M-carbon triple bonds.71 The
most dramatic geometric difference among the four X-ray
structures is that the SiPEt-supported species have substantially
reduced dihedral angles between the metal carbyne and the
siloxide O−Si bonds, likely a result of increased flexibility.
Additionally, due to two independent molecules with markedly
different bond metrics crystallizing in the asymmetric unit of
Cat5, we can intuit the increased flexibility associated with the
SiPEt support. While it is tempting to draw a relationship
between W−C1 bond length as a function of W−O−Si angle
and/or C1−W−O-Si dihedral, in the context of the other W
alkylidynes, Cat3 and Pre2, no clear pattern seems to arise.
The identity of the R-group on SiP ligands has a modest effect
on the electrophilicity of the corresponding alkylidyne, as
gauged by 13C carbyne chemical shifts. For both the Mo and W
systems, there is a ∼6 ppm deshielding of the SiPPhderivatives,
relative to the SIPEt analogues.
Figure 1. Molecular structures of compounds Cat2−5 at 90 K
showing thermal ellipsoids at the 50% probability level with H atoms,
solvent, disordered groups, and peripheral phenyl groups omitted for
clarity. Mo: light blue, W: bright green, C: gray, O: red, Si: yellow.
Intermediates of Mo(VI) Catalysts. One of the most
intriguing findings associated with our previous report was the
isolation of a rare metallatetrahedrane (MTd1, Scheme 2d)
which was found to be dynamic in solution.68 Due to the SiP
ligand’s preference toward C3-symmetry, as well its presumed
rigidity, we were curious if it exclusively supported the
formation of metallatetrahedranes or if it would be possible
to isolate the more conventional metallacyclobutadiene
(MCBD) isomer.
As a control experiment, we examined the intermediate
species that are formed using the nontethered, tris-triphenylsil-
oxide molybdenum alkylidyne catalyst, Cat6. Our hypothesis
was that the nontethered three siloxide ligands could more
easily reorganize to the geometries associated with MCBD
intermediates.45,72,73 Furthermore, this experiment would test
whether the rigidity of the tripodal siloxide ligand itself is
responsible for the formation of MTd. CD2Cl2 solutions of
1
Cat6, exposed to 5 equiv to 3-hexyne gave broad H NMR
resonances (Supporting Information Figure S11) indicative of
rapid exchange between free and bound alkyne. However,
1
cooling the solution to −70 °C led to sharp H NMR peaks
and the presence of two sets of ethyl resonances ascribed to the
new MCBD organometallic species, MCBD1 (Scheme 4). In
1
particular, the 2:1 ratio of these new H NMR peaks and
distinct 13C NMR resonances at 147.2 and 249.8 ppm
(associated with the Cβ and Cα respectively) suggested the
formation of a Cs-symmetric MCBD intermediate (Figure
S12−S15). Overall, the formation of MCBD1 implied that
ligand rigidity and enforcement of C3-symmetry may play a crucial
role on formation of the metallatetrahedrane over the more
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Table 1. List of Bond Lengths (Å), Angles (deg), and Carbyne 13C (ppm) for Cat2−5
a
Cat2
Cat3
Cat4
Cat5
M−C1
M−OAvg
O−SiAvg
M−C1−C2
M−O−SiAvg
C1−M−O−SiAvg
13C
1.746(3)
1.870(1)
1.628(1)
177.0(3)
167.4(8)
115.1(3)
313.3
1.768(3)
1.873(5)
1.632(6)
174.9(3)
167.7(3)
121.6(8)
288.4
1.747(13)
1.879(5)
1.632(6)
174.95(10)
158.8(3)
74.4(7)
1.743(6)/1.760(5)
1.859(2)/1.859(2)
1.633(2)/1.657(3)
174.3(4)/175.6(4)
171.6(1)/165.5(2)
68.4(1)/57.7(2)
281.9
306.7
a
Two independent molecules in the asymmetric unit.
a
Scheme 4. Formation of Mo(OSiPh3)3(C3Et3), MCBD1
a
Confirmed by NMR at −70 °C.
conventional MCBD. While this manuscript was under review,
Furstner also reported spectroscopic evidence for MCBD1.
̈
Further, they were able to isolate crystalline material for this
elusive intermediate and scrutinize it via single crystal X-ray
diffraction studies to confirm its isomeric identity.74
The formation of MCBD1 from Cat6, as a result of increased
ligand flexibility suggests that geometry and secondary
coordination sphere may play a crucial role in the determining
the identity of metallacyclic intermediates. We therefore turned
our attention toward the impact of ancillary ligand sterics and
noncovalent interactions. Interestingly, when Cat4 was treated
with 6 equiv of 3-hexyne, incomplete transfer of the mesityl-
Figure 2. (a) 1H NMR of MTd1 highlighting the upfield shifted
methylene proton as a result of CH···π interaction. CH···phenylcentroid
distance highlighted in (b) X-ray crystal structure and (c) energy-
minimized structure and the corresponding (d) NCI plot of MTd1.
Green color represents van der Waals interaction.
1
carbyne was observed by both H and 13C NMR. Use of 20
equiv of alkyne substrate were required to fully drive such
elimination with Cat4; however, there were minimal signs of a
new organometallic bond. Our attempts to identify the fate of
the Mo-containing product were ultimately stymied due to the
high concentration of 3-hexyne required to drive the reaction
to completion which results in substrate polymerization.
Since no MTd species were observed using Cat4 and Cat6,
we hypothesized that both the C3-symmetry and phenyl
substituents of SiPPh and Cat1 were playing major roles in
stabilizing the MTd1 structure. Here we specifically focused on
the potential noncovalent CH···π-interactions between the
ethyl groups and the ligand phenyl groups. Spectroscopic
evidence for stabilizing CH···π-interactions can be observed
when comparing the highly shielded methylene protons of
MTd1 (1.62 ppm) against those reported by Schrock for an
MTd with related ethyl substituents but lacking phenyls in the
secondary coordination sphere (2.91 ppm).51 Furthermore,
cooling of the same solution of MTd1 to −60 °C resulted in a
splitting of the diastereotopic methylene protons with chemical
shifts centered at 0.88 ppm (Ha) and 1.98 ppm (Hb, Figure
2a). This is a result of differing magnetic environments
associated with Ha interacting with the adjacent π-surface of
the phenyl groups on SiPPh while Hb is not. This dramatic
disparity in magnetic environment was further corroborated by
Further evidence for CH···π-interactions can be found in the
solid-state structure of MTd1 with an average CH2···
phenylcentroid distance of 2.70 Å for ethyl groups (Figure 2b)
which is consistent with observed CH···π interaction
distances.75 Additionally, the energy minimized structure of
MTd1 also show CH2···phenylcentroid distances averaging at 2.64
Å (Figure 2c), which is consistent with the solid-state
structure. Finally, noncovalent interaction (NCI) plots show
clear signatures of van der Waals interaction between the ethyl
groups and the phenyl groups (Figure 2d). Taken together,
these results provide strong support for intramolecular CH···π-
interactions playing a subtle but crucial role in stabilizing the
unique MTd moiety, a design principal which will be further
investigated and exploited by our group in the coming years.
The use of alternative alkynyl-compounds was investigated
to gauge substrate scope for the MTd formation. Treatment of
Cat1 with 6 equiv of diparatolylacetylene failed to produce a
triaryl substituted analogue of the MTd, presumably due to the
increased sterics that lead to high energetic barrier to form this
1
species. Instead, H NMR revealed the original catalyst to be
the only organometallic species visible in solution. Use of the
longer chain alkyne, 5-decyne, produced a pentylidyne species
(Cat7, Figure 3a) which could be cleanly isolated and
characterized. Addition of 10 equiv of 5-decyne to Cat7
1
simulated H NMR chemical shifts on an energy minimized
structure with chemical shifts of 0.10 and 1.05 ppm for Ha and
Hb, respectively (Supporting Information Figure S57).
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Figure 3. (a) Formation of a pentylidyne (Cat7) and a metal-
latetrahedrane (MTd2) using 5-decyne. (b) Molecular structure of
compound MTd2 at 90 K showing thermal ellipsoids at the 50%
probability level with H atoms and peripheral phenyl groups omitted
for clarity. Mo: light blue, C: gray, O: red, Si: yellow. (c) Local
geometry about Mo1 in molecular structure of MTd2. Bond distances
are colored in blue and bond angles in red.
allowed for the observation of MTd2, as evidenced by a peak at
83.4 ppm in the 13C NMR spectrum which corresponds with
the C3R3 ring of a metallatetrane. Despite the large excess of
alkynyl substrate, MTd2 still exists in equilibrium with Cat7.
The isolation of Cat7 and its equilibrium with MTd2 suggests
that, previously unappreciated, alkyl length may contribute to
the delicate balance of isolable species supported by the SiP
ligand. The importance of chain length was further supported
Figure 4. (a) Synthesis of MCBD2−5 from Cat3 and Cat5. (b)
Molecular structures of compounds MCBD2−5 at 90 K showing
thermal ellipsoids at the 50% probability level with H atoms, solvent
and peripheral phenyl groups omitted for clarity. W: bright green, C:
gray, O: red, Si: yellow.
by Furstner while this manuscript was under review. They
̈
reported that an equilibrium mixture of the analogous methyl-
substituted MTd and MCBD was observed when the reaction
was performed using the shorter chain alkyne, 2-butyne.
However, crystallographic characterization of either species
was not reported.74 To our delight, storage of a concentrated
dichloromethane solution of the MTd2 reaction mixture for 6
months at −37 °C resulted in the serendipitous formation of
brown crystalline material which confirmed its identity via X-
ray diffraction studies. The solid-state structure of MTd2 is
shown in Figure 3b and 3c. The Mo1-centroid distance of
1.897 Å is comparable to those previously reported for MTd1
(1.884 Å). Furthermore, the CH2···phenylcentroid distance of
2.68 Å again suggests evidence of CH···π interactions as a
crucial element in stabilizing the tetrahedrane core. The
formation and crystallographic characterization of MTd2 as
only the second ever Mo-metallatetrahedrane suggests the
potential for the synthesis of a library of metallatetrahedranes
and the privileged role which SiPPh plays in supporting these
unique species.
Intermediates of W(VI) Catalysts and Reactivity
Studies. In order to investigate the effect of metal selection
on the intermediate formation, W(VI)-based catalysts Cat3
and Cat5 were treated with a slight excess of 3-hexyne (Figure
4a). Both reactions resulted in an immediate change of color
from yellow-orange to purple. Further, the 1H NMR spectra of
the immediate products indicated that the mesityl group was
retained in both cases. These “trapped” MCBD intermediates,
MCBD2 and MCBD3 were further confirmed by X-ray
diffraction studies (Figure 4b) which resemble similar species
recently reported by Fu
̈
rstner.76 Storage of C6D6 solution of
MCBD3 for 3 h at room temperature revealed the elimination
of 1-mesityl-1-butyne product as well as the formation of a new
organometallic product, MCBD5, with three distinct ethyl
environments, suggesting the product to be structurally (and
chemically) distinct from the C3-symmetric metallatetrahe-
drane previously reported. Interrogation of MCBD5 by 13C
NMR revealed resonances at 132, 222, and 229 ppm, indicative
of the β, α, and α′ ring resonances, respectively, of a
metallacyclobutadiene (Figure 4a). The enlistment of 2D
NMR techniques allowed for full assignment and correlation of
1
the germane H and 13C resonances. Specifically, NOESY
showed a cross peak between the methylene protons of α′ and
that of the proximal basal arene protons (Figure S35), itself
identifiable by its splitting and coupling from the other two
distal arene protons.
The same transformation of MCBD2 to MCBD4 could be
achieved by heating a C6D6 solution to 60 °C for 15 min.
1
However, H NMR spectra of MCBD4 in CD2Cl2 at room
temperature resulted in very broad peak widths and difficulty
locating all of the organometallic resonances. Lowering the
1
temperature to −70 °C allowed us to resolve the H and 13C
NMR spectra. MCBD4 also exhibited Cs-symmetry with 13C
resonances of 138, 230, and 235 ppm, indicative of the β, α,
and α′ ring resonances, respectively. It should be noted that
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Furstner reported the formation of MCBD4 over the course of
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̈
7 days at room temperature, as gauged by 1H and 13C NMR.76
From a mechanistic perspective, we deemed it crucial to not
just unequivocally establish the identities of MCBD4 and
MCBD5 as metallacyclobutadienes via NMR spectroscopy but
to analyze the geometry of their primary coordination sphere.
As such, single crystals of each were subjected to X-ray
diffraction studies (Figure 4b). Gratifyingly, both produced the
expected result with each conforming to a “long-short-long-
short” bonding motif along the W1−C1−C2−C3 ring (Table
2) indicative of localized π-environments.45,77 Despite this
Figure 5. (a) Synthesis of MCBD6 from Cat3. (b) Molecular
structure of compound MCBD6 at 90 K showing thermal ellipsoids at
the 50% probability level with H atoms, solvent and peripheral phenyl
groups omitted for clarity. W: bright green, C: gray, O: red, Si: yellow.
Table 2. List of Bond Lengths (Å) and Angles (deg) for
Metallacyclobutadienes MCBD4−6
MCBD4
MCBD5
MCBD6
another square-pyramidal (τ5 = 0.01) metallacyclobutadiene
and, as expected, the tolyl group points away from the basal
arene. Further analysis of the metallacycle shows the repeat of
the “long-short-long-short” bonding motif as well as the
exclusive preference of the two aryl groups being in proximity
to one another. This preference is presumed to minimize
excessive crowding near the basal arene as supported by
quantum mechanical calculations (vide infra, Table S6 in the
Supporting Information). On the basis of these observations,
we anticipate that control of MCBD formation in nonsym-
metrical alkynes via steric crowding could lead to the design of
highly selective alkyne metathesis catalysts.
W1−C1
C1−C2
C2−C3
C3−W1
1.9750(16)
1.420(2)
1.501(2)
1.8626(17)
76.26(10)
121.99(14)
78.26(10)
83.40(7)
0.04
1.967(2)
1.415(4)
1.487(4)
1.865(3)
77.04(16)
121.41(2)
77.04(16)
82.65(11)
0.10
1.963(5)
1.413(7)
1.504(6)
1.867(6)
77.3(3)
121.1(5)
78.5(3)
83.1(2)
0.01
W1−C1−C2
C1−C2−C3
C2−C3−W1
C3−W1−C1
a
τ5
a
τ5 = (β − α)/60° where β > α are the two largest angles at the
coordination center.
Alkyne Metathesis: Reaction Rates and Substrate
Scope. Previously, Furstner reported the improved tolerance
̈
bonding mode, there was negligible puckering of the ring
(MCBD4: 2.58°, MCBD5: 1.80°). This observation stands in
stark contrast to the fluxional, nonplanar species reported by
Schrock59 which was thought to be an intermediate between
the two isomeric extremes of MCBD and MTd. In addition,
both MCBD4 and MCBD5 assume a decidedly square-
pyramidal geometry at W with τ5 = 0.04 and 0.10, respectively.
This geometry appears to be retained in solution based on the
of SiPPh-supported Mo alkylidynes toward highly problematic
substrates including primary alcohols, phthalimides, secondary
and tertiary amines, among others.69 This improvement in
group functional tolerance did, however, come at a cost of
reduced reaction rates.68,69 In parallel to this, we undertook a
study to probe the effect both metal choice and ligand sterics
have on the dynamic scrambling of the mixed diarylalkyne, 1-
methoxy-4-(phenylethynyl)-benzene, at room temperature
using 1 mol % of catalysts Cat1−Cat5. The reaction progress
was monitored by 1H NMR until it reached equilibrium with a
statistical mixture of diarylalkynes (Figure 6). The experiments
1
spectroscopic differentiation of α and α′ in H and 13C NMR.
This latter point is seemingly unique among previously
reported metallacyclobutadienes including MCBD1 and likely
is a result of basal arene enforcing a break in symmetry.
Importantly, the isolation of MCBD4 using the identical SiPPh
support as was used for MTd1 shows that metal choice has a
dramatic effect on the identity of isolable metallacyclic
intermediates. The broad NMR resonances associated with
MCBD4 at room temperature, suggested the possibility that it
might be unstable to loss of 3-hexyne. Surprisingly, both
MCBD4 and MCBD5 retained their metallacyclic character
upon exposure to a vacuum. It should also be noted that MTd1
reverted back to Cat1 under similar conditions.
While 3-hexyne (or related, symmetric alkynes) historically
have served as model substrates for understanding the
geometry of MCBD intermediates,77 we next turned our
attention toward the use of asymmetric alkynes to gauge the
effect the basal arene has on the selectivity and geometry of
substrate approach. Treatment of Cat3 with p-tolylpropyne in
pentane (Figure 5a) was performed with the hypothesis that
the tolyl group of the substrate would face away from the basal
arene to avoid steric repulsion with the ligand scaffold. While
13C NMR supported the formation of another MCBD, violet
single crystals of the initial intermediate MCBD6 were
successfully obtained and subjected to X-ray diffraction studies
for probing the orientation of initial alkyne approach. X-ray
analysis (Figure 5b, Table 2) of MCBD6 revealed it to be
Figure 6. Dynamic scrambling of 1-methoxy-4-(phenylethynyl)-
benzene (0.1 mM in C6D6) catalyzed by 1 mol % of Cat3−5 at rt
1
monitored by H NMR.
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Figure 7. (a) Synthesis of Nitride1 via nitrile metathesis with Cat5. (b) Molecular structure of Cat5·PhCN at 90 K showing thermal ellipsoids at
the 50% probability level with H atoms omitted for clarity. W: bright green, C: gray, N: blue, O: red, Si: yellow. (c) Molecular structure of Nitride1
at 90 K showing thermal ellipsoids at the 50% probability level with H atoms and solvent omitted for clarity. W: bright green, C: gray, N: blue, O:
red, Si: yellow.
were performed in sealed NMR tubes (closed system) and the
substrate and products were nonvolatile. Therefore, the
methoxy (OCH3) peak integration ratio between the substrate
and product served as a useful handle for tracking the reaction.
It was already established that Cat2 was incapable of catalyzing
this reaction at room temperature.68 We also previously
reported that reducing the steric bulk on the alkylidyne by
replacing the mesityl group to a tolyl group remedied that
problem. The results of the scrambling experiment showed
dramatic difference in rates of reaction between the four
catalysts with the trend being Cat5 > Cat3 > Cat4 > Cat1
(Figure 6, see Figure S41 for Cat4 > Cat1). It was clear that
the catalysts Cat4 and Cat5 with the less bulky ligand were
faster at reaching equilibrium compared to Cat1 and Cat3,
respectively. The sigmoidal shape of the curve associated with
Cat4 was attributed to an initial inhibition of catalysis due to
the steric bulk of the mesityl group, the same culprit which
prevented Cat2 from engaging in catalysis at room temper-
ature. In light of the stability of the initial approach
intermediates such as MCBD2, MCBD3, and MCBD6, it
was surprising to see that Cat3 and Cat5 were more active
relative to their Mo(VI) counterparts. In contrast, intermedi-
ates derived from Mo(VI) either could not be observed or
were found to be much more dynamic. The relative stability of
W-MCBD species implies that retro-[2 + 2] reaction would
occur slowly in W(VI)-based catalysts.46 In addition, while this
rates were compared using the scrambling of diarylacetylene
substrates (Figure 6). Under similar conditions to those used
to observe and isolate MCBD2 and MCBD6, we were not able
to observe or isolate any triaryl MCBD intermediates derived
from Cat3 using 1-methoxy-4-(phenylethynyl)benzene as a
substrate. These results suggest that there is a significant
substrate-dependence on reaction rates in the W(VI)-based
catalysts (for a computational study of this substrate-
dependence on reaction rates, see Figure S58 and S59 in the
Supporting Information).
Historically, while tungsten-based catalysts have been
associated with higher reactivity, they have also been found
to be less compatible with functional groups due to the
heightened electropositivity and oxophilicity. As such, we
attempted a small substrate scope study on Cat5. Disappoint-
ingly, the only substrates which gave acceptable yields were
those with highly inert substituents such as ortho or para-
methyl, methoxy, and dimethylamino (Figure S43). Not
surprisingly, all carbonyl-containing substrates failed entirely
as did phenols. Cyano and thiophenyl species gave very poor
yields. Notably, increasing catalyst loading failed to improve
the outcomes.
The failure of Cat5 to provide acceptable yields with cyano-
substrates, while disappointing, did suggest the possibility of
nitrile metathesis as a means of catalyst deactivation. To better
investigate this possibility, Cat5 was treated with 1.06 equiv of
benzonitrile, leading to a purple-red solution which spec-
troscopically suggested the production of the benzonitrile
adduct, Cat5·PhCN (Figure 7a,b). An undisturbed pentane
solution of Cat5·PhCN at room temperature deposited dark
manuscript was under preparation, Furstner observed that a
̈
similar catalyst with W(VI) was slower in catalyzing a cross-
metathesis of an aryl-propyne substrate compared to an
isostructural catalyst with Mo(VI).76 In contrast, our reaction
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purple-red single crystals which unequivocally confirmed this
identity (Figure 7b). The metal center adopts the expected 5-
coordinate, square pyramidal geometry (τ5 = 0.33) which is
more distorted than the related Mo-acetonitrile analogue
transition state [W]-A-TS). In turn, this MCBD could undergo
a rapid isomerization (via a pseudorotation of the MCBD
moiety with a barrier of 9.1 kcal/mol) to form [W]-ent-B
followed by a retro-[2 + 2] to furnish the desired product (red
pathway). These barriers are reasonable with experimental
results for which the observed rate of reaction for alkyne
metathesis was approximately 1 h. Alternatively, as shown in
green, the symmetrical MCBD [W]-B could instead isomerize
to the most energetically favored (and experimentally observed
and characterized; see Figure 4) unsymmetrical MCBD [W]-
B′ (downhill by 9.1 kcal/mol with respect to [W]-B) via [W]-
B-TS-B′ (barrier of 10.7 kcal/mol) prior to undergoing alkyne
metathesis. We also explored the traditional mechanistic
pathway proposed for alkyne metathesis in which the MCBD
forms by [2 + 2] cycloaddition and the product is expelled by a
retro-[2 + 2] transition state directly from [W]-B′ to product
(Figure 8, green). However, the barrier for this process is
found to be prohibitively high in energy (38.7 kcal/mol via
[W]-D-TS) and therefore energetically inaccessible at the
experimental conditions. Consequently, we concluded that this
system does not follow the traditional [2 + 2]/retro-[2 + 2]
mechanism that has previously been proposed and instead the
C3-symmetric ligand changes the mechanism to [2 + 2]/
isomerization(pseudorotation)/retro-[2 + 2] as observed
reported by Fu
̈
rstner (τ5 = 0.17).60 The W1C1 distance of
1.777 Å is elongated relative to both independent molecules of
Cat5 (1.743 and 1.760 Å), while the W1−C1−C2 angle of
171.5° is comparable (174.3° and 175.6°). This relatively
linear angle is also distinct from the analogous Mo species
which had a noticeable kink of 161.4°.
Storage of a C6D6 solution of Cat5·PhCN for 6 h at room
temperature resulted in a new yellow solution as well as the
production of phenyl-mesityl acetylene, as gauged by 1H NMR.
While spectroscopic evidence of the new tungsten species was
obfuscated by poor solubility, fortuitous crystals grown from
slow-evaporation of the benzene solution gave proof of the
dinuclear metal nitride species, Nitride1 (Figure 7a,c). The
formation of metal-nitrides via metathesis of alkylidynes with
nitriles has previously been reported by Johnson78 and is the
microscopic reverse of the initial route by which siloxide-
support Mo alkyne metathesis catalysts could be synthesized.79
The solid-state structure of Nitride1 (Figure 7c) reveals it to
be dimeric with W1−N1 and W1−N1′ distances of 1.765 and
2.061 Å, respectively, indicative of distinct, localized W double
and single bonds. The geometry about each metal center is
best described as distorted trigonal bipyramidal (τ5 = 0.78)
with the shorter W−N1 bond occupying one of the equatorial
sites and the longer W−N1′ in the axial position. The trigonal
bipyramidal geometry of Nitride1 is unique among SiP-
supported metal compounds as all MCBD intermediates have
been decidedly square-pyramidal as was the acetonitrile adduct
independently by Fu
̈
rstner/Neese in parallel to this study74
(see Figure S63 in the Supporting Information for a
comparison of the energetics). Finally, we explored another
possible pathway in which the metallatetrahedrane [W]-C was
an on-cycle intermediate involved in product formation. As
shown in Figure 8 (blue), the MCBD [W]-B forms the nearly
isoenergetic metallatetrahedrane [W]-C directly via a ring-
closing transition state ([W]-B-TS) with a relative barrier of
16.6 kcal/mol (with respect to [W]-B). In this pathway, this
symmetrical metallatetrahedrane [W]-C can then undergo ring
opening followed by retro-[2 + 2] to form the alkyne
metathesis product. Overall, while the blue pathway is
energetically feasible, the pathway shown in red in Figure 8
is much lower in energy and therefore the most likely
mechanism the reaction follows. We also note that these
computational results are in accord with experiment where
only the thermodynamically more stable MCBD intermediate
(akin to [W]-B′) was observed and not the (much higher in
energy) transient MTd intermediate (akin to [W]-C).
of the Mo alkylidyne reported by Fu
̈
rstner.69 To our surprise,
the related pyridine adduct, (pyridine)(Ph3SiO)3MoN is
both monomeric and decidedly more square pyramidal with a
τ5 = 0.37.79 The differences in geometry between Nitride1 and
the different 5-coordinate Mo species reported by Furstner, as
̈
well as Cat5·PhCN, is likely due to the rigid geometric
constraints of the SiP ligand (in addition to the N atoms in
Nitride1 functioning as bridging ligands) overriding the strong
trans influence of multiply bonded ligands (i.e., nitride,
alkylidyne) which prefer occupying the apical position in
square pyramidal geometries.
Quantum Mechanical Calculations. To better under-
stand the ligand and metal effects on the formation of
intermediates, we turned to dispersion-corrected density
functional theory calculations [B3LYP-D3/def2TZVP-SDD-
(M)-CPCM(benzene)//B3LYP-D3/def2SVP-LANL2DZ(M)-
CPCM(benzene)] (where M is W or Mo depending on the
system being studied; see Supporting Information for
computational details and justification for the choice of
method).80−84 Initially, to reduce computational cost,85 the
conformationally flexible ethyl groups on the podand ligand
(SiPEt) were modeled as methyl groups (SiPMe) and the tolyl
substrate was modeled as a methyl. Overall, this method was
able to capture the structural parameters of the isolated species,
confirming the suitability of our computational method (see
Supporting Information Table S7). To explore the ligand
effect, we began our analysis by studying the mechanism for
alkyne metathesis and formation of MCBD and MTd species of
tungsten paired with the SiPMe and SiPPh ligands (Figure 8). In
the case of the SiPMe ligand (black values), the barrier for
concerted [2 + 2] cycloaddition to form the symmetrical
MCBD [W]-B intermediate is only 11.3 kcal/mol (via an early
Further, to probe the effect of the ligand on this process, the
reaction coordinate was then explored for the tungsten SiPPh
system (Figure 8; green values). Overall, similar energetics
were observed for the alkyne metathesis pathway but we
observed pronounced effects of the ligand scaffold on the
pathway for formation of the MTd intermediate. Specifically,
both the overall (17.5 kcal/mol vs 24.6 kcal/mol) and relative
(11.5 kcal/mol vs 16.6 kcal/mol) barriers for the MTd-
formation (via [W]-B-TS) are significantly lower and more
exergonic (4.2 kcal/mol vs 8.2 kcal/mol) with the more
sterically hindered ligand (green values). As such, qualitatively,
these results suggest faster and more favorable MTd-formation
via more sterically hindered SiPPh podand ligands.
Next we explored the reaction coordinates for the SiPMe and
SiPPh ligands for the molybdenum system (Figure 9). The
operative mechanism of alkyne metathesis in the case of either
ligand for the molybdenum catalyst is relatively the same as
that observed for tungsten but proceeds via a flatter surface.
Starting with the SiPMe ligand, [Mo]-A undergoes [2 + 2]-
cycloaddition via [Mo]-A-TS (barrier of 15.7 kcal/mol) to
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Figure 8. Energetics of MCBD and MTd formation via [2 + 2] cycloaddition for tungsten with SiPMe (outside parentheses) and SiPPh (inside
parentheses) ligands. Free energies (kcal/mol) are computed at the B3LYP-D3/def2TZVP-SDD(W)-CPCM(benzene)//B3LYP-D3/def2SVP-
LANL2DZ(W)-CPCM(benzene) level of theory. For enthalpy and electronic energies, refer to Figure S60 and S61. The red pathway shows the [2
+ 2] cycloaddition followed by pseudorotation and finally retro-[2 + 2] to yield product. Alternatively, the red pathway from the [2 + 2]
cycloaddition can lead to the blue pathway in which the metallatetrahedrane is involved in the product formation. The structures highlighted in
blue are accessible via the metallatetrahedrane pathway (blue lines). Notably, the green pathway in which the [2 + 2]/retro-[2 + 2] occurs with no
pseudorotation is energetically inaccessible.
form the very shallow symmetrical MCBD [Mo]-B (14.0 kcal/
mol) intermediate. The MCBD can then undergo a rapid
isomerization (via pseudorotation) with a barrier of 16.2 kcal/
mol to form [Mo]-ent-B, which then undergoes retro-[2 + 2]
via to form the desired product. On the other hand, the
symmetrical MCBD [Mo]-B can also isomerize to the
unsymmetrical and more thermodynamically favored MCBD
[Mo]-B′ via [Mo]-B-TS-B′ (barrier of 21.5 kcal/mol) prior to
product formation. However, this unsymmetric intermediate,
in contrast to the tungsten systems, is overall uphill in energy
by 10.2 kcal/mol compared to the catalyst [Mo]-A! These
results are in agreement with experimental evidence in which
the unsymmetrical (and significantly thermodynamically
unstable) MCBD [Mo]-B′ was not observed. On the other
hand, the metallatetrahedrane [Mo]-C (7.4 kcal/mol) which
forms by ring-closing of [Mo]-B via [Mo]-B-TS (barrier of
26.0 kcal/mol), is more thermodynamically favored than the
MCBD intermediates and is in qualitative accord with
experiment in which this intermediate is observed exper-
imentally (MTd1, Scheme 2). Notably, the computationally
predicted metallatetrahedrane [Mo]-C has similar structural
features to the X-ray structure (Table S8 in the Supporting
Information). It is worth noting that while the metal-
latetrahedrane [Mo]-C with both the truncated ligand and
substrate is uphill in energy from [Mo]-A, the system studied
experimentally (3-hexyne) yields a thermodynamically favor-
able metallatetrahedrane (see Figure S64 in the Supporting
Information). From the metallatetrahedrane intermediate
[Mo]-C, ring opening via [Mo]-ent-B-TS followed by retro-
[2 + 2] can lead to product formation. However, this pathway
(highlighted in blue, Figure 9) is higher in energy than the red
pathway ([2 + 2]/isomerization/retro-[2 + 2]) and therefore is
likely a secondary route toward product formation. Finally,
similar to the tungsten system, we also explored the traditional
[2 + 2]/retro-[2 + 2] mechanism in which the MCBD [Mo]-B
forms product prior to isomerization to [Mo]-ent-B, but, akin
to W-system, we found that the barrier for this pathway is
insurmountable and therefore is likely not operative for this
system.
We note that these computational results are consistent with
experimental observations for the SiPPh ligand, in which the
barrier to MCBD formation through the [2 + 2] transition
state is higher than that of the tungsten system (16.1 kcal/mol
vs 11.7 kcal/mol) given that slower reaction rates were
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Figure 9. Energetics of MCBD and MTd formation via [2 + 2] cycloaddition for molybdenum with SiPMe (outside parentheses) and SiPPh (inside
parentheses) ligands. Free energies (kcal/mol) are computed at the B3LYP-D3/def2TZVP-SDD(Mo)-CPCM(benzene)//B3LYP-D3/def2SVP-
LANL2DZ(Mo)-CPCM(benzene) level of theory. For enthalpy and electronic energies, refer to Figure S62 and S63. The red pathway shows the
[2 + 2] cycloaddition followed by pseudorotation and finally retro-[2 + 2] to yield product. Alternatively, the red pathway from the [2 + 2]
cycloaddition can lead to the blue pathway in which the metallatetrahedrane is involved in the product formation. The structures highlighted in
blue are accessible via the metallatetrahedrane pathway (blue lines). Notably, the green pathway in which the [2 + 2]/retro-[2 + 2] occurs with no
pseudorotation is energetically inaccessible.
observed for alkyne metathesis with the molybdenum system.
Akin to the tungsten system, the symmetrical MCBD [Mo]-B
with the SiPMe ligand (14.0 kcal/mol) is also energetically
favored to isomerize to the unsymmetrical MCBD [Mo]-B′
(10.2 kcal/mol), albeit this intermediate [Mo]-B′ is signifi-
cantly higher in energy (and uphill) than the analogous
structure for the tungsten system ([W]-B′). Overall, these
results are also consistent with experiment in which the MCBD
is not observed for molybdenum.
To investigate the steric effects of the ligand, we compared
the barriers to metallatetrahedrane formation for the SiPMe
system with the SiPPh. The destabilization of the SiPMe
molybdenum MTd can partially be attributed to greater steric
hindrance as the methyl fragments of the ligand and the
substrate are much closer in the case of the SiPMe ligand.
Furthermore, the noncovalent interactions in the SiPPh system
between the CH of the substrate and the π system of the
phenyl ring, which can be observed in the NCI plots (Figure
2d), are responsible for the stabilization of the MTd and the
transition state to its formation. However, the other stages of
the alkyne metathesis pathway are unaffected by the CH···π
interactions, which are not present in the NCI plots of the
MCBD (Supporting Information Figure S66). Energy
decomposition analysis (EDA) based on the absolutely
localized molecular orbitals86 (ALMO-EDA) method imple-
mented in Q-Chem 5.087 and described by Liu89 was utilized
to investigate the specific energetic contributions that control
MCBD or MTd formation. Specifically, the energy of the
MCBD and MTd intermediates for both metals was
decomposed into its energetic components including the
Pauli repulsion (ΔEPauli), the electrostatic (ΔEelstat), the
polarization (ΔEpol), and the charge transfer (ΔEct) energies
using the HF method with the 6-311G(d,p) basis set as
employed by Liu.88 It was found that ΔEelstat, or electrostatic
energy between the ligand and the alkyne substrate, appeared
to contribute to controlling the intermediate formation.
Overall, we observed that the ΔEelstat was lowest in the case
of the favored intermediate (MCBD for W and MTd for Mo;
see Figure S67 and S68). Furthermore, the distortion energy90
required to convert the geometry of the intermediate into the
transition state geometry was also calculated for the MCBD
and MTd formation transition states. It was found that the low
distortion energy required to form the MCBD in the case of
tungsten drives the formation of this intermediate and explains
this observed preference while the distortion energy does not
appear to play a role in the preference for the MTd in the
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Authors
molybdenum case (see Figure S69 and S70). Instead, for
molybdenum it appears to be the favorable CH···π interactions
in the MTd intermediate that drive its formation. Overall, the
formation of the metallocyclobutadiene or metallatetrahedrane
intermediates using these podand ligands appears instead to be
dependent on the nature of the metal with the favorable
electrostatic energy between the ligand and substrate leading to
its preference for the MCBD intermediate in the case of
tungsten and the MTd intermediate in the case of
molybdenum.
Richard R. Thompson − Department of Chemistry, Louisiana
State University, Baton Rouge, Louisiana 70803, United
States; orcid.org/0000-0002-2181-9846
Madeline E. Rotella − Department of Chemistry and
Biochemistry, University of Maryland, College Park,
Maryland 20742, United States; orcid.org/0000-0002-
7973-2452
Xin Zhou − Department of Chemistry, Louisiana State
University, Baton Rouge, Louisiana 70803, United States;
orcid.org/0000-0003-1531-8698
Frank R. Fronczek − Department of Chemistry, Louisiana
State University, Baton Rouge, Louisiana 70803, United
States; orcid.org/0000-0001-5544-2779
CONCLUSIONS
■
The metallatetrahedrane has been a scantly investigated
organometallic species despite its potential role in alkyne
metathesis as well as its similarity to analogous heteroatom-
based E3 species which are abundant in the chemical literature.
This work has shown, both experimentally and computation-
ally, that isolation of such species requires a confluence of
myriad and subtle factors including metal choice, supporting
ligand rigidity, and the presence of noncovalent interactions.
The greater electrophilicity of W (relative to Mo) stabilizes
MCBD over MTd, regardless of all other factors. The ability of
ancillary ligand(s) to more readily distort to accommodate
catalyst geometries also leads to a MCBD preference. Finally,
CH···π interactions appear to be indispensable in stabilizing
the MTd. We have also shown that while the greater
electrophilicity of tungsten results in faster scrambling of
alkyne substrate, this comes at the significant reduction of
functional group tolerance. Significantly, the WC bond was
found to be capable of undergoing metathesis with the CN
bond of benzonitrile, resulting in bridging nitride species,
suggesting that SiP-supported species show potential for
catalyzing nitrile-alkyne cross metathesis.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c01843
Author Contributions
§R.R.T. and M.E.R. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by NSF CHE 1956302. S.L. is
grateful for the start-up funds from the College of Science and
the Office of Research and Economic Development at
Louisiana State University. O.G. is grateful to the NIGMS of
the NIH (R35GM137797), University of Maryland College
Park for start-up funds, Nathan Drake Endowment, and
computational resources from UMD Deepthought2 and
MARCC/BlueCrab HPC clusters and XSEDE (CHE160082
and CHE160053.)
REFERENCES
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c01843.
■
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AUTHOR INFORMATION
Corresponding Authors
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