Exploiting Carbonyl Groups to Control Intermolecular Rhodium-Catalyzed Alkene and Alkyne Hydroacylation

Article abstract of DOI:10.1021/jacs.7b05713

Readily available β-carbonyl-substituted aldehydes are shown to be exceptional substrates for Rh-catalyzed intermolecular alkene and alkyne hydroacylation reactions. By using cationic rhodium catalysts incorporating bisphosphine ligands, efficient and selective reactions are achieved for β-amido, β-ester, and β-keto aldehyde substrates, providing a range of synthetically useful 1,3-dicarbonyl products in excellent yields. A correspondingly broad selection of alkenes and alkynes can be employed. For alkyne substrates, the use of a catalyst incorporating the Ampaphos ligand triggers a regioselectivity switch, allowing both linear and branched isomers to be prepared with high selectivity in an efficient manner. Structural data, confirming aldehyde chelation, and a proposed mechanism are provided.

Full text of DOI:10.1021/jacs.7b05713

Article
pubs.acs.org/JACS
Exploiting Carbonyl Groups to Control Intermolecular Rhodium-
Catalyzed Alkene and Alkyne Hydroacylation
Thomas J. Coxon, Maitane Fernandez, James Barwick-Silk, Alasdair I. McKay, Louisa E. Britton,
́
Andrew S. Weller, and Michael C. Willis*
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
S
* Supporting Information
ABSTRACT: Readily available β-carbonyl-substituted alde-
hydes are shown to be exceptional substrates for Rh-catalyzed
intermolecular alkene and alkyne hydroacylation reactions. By
using cationic rhodium catalysts incorporating bisphosphine
ligands, efficient and selective reactions are achieved for β-
amido, β-ester, and β-keto aldehyde substrates, providing a
range of synthetically useful 1,3-dicarbonyl products in
excellent yields. A correspondingly broad selection of alkenes
and alkynes can be employed. For alkyne substrates, the use of
a catalyst incorporating the Ampaphos ligand triggers a regioselectivity switch, allowing both linear and branched isomers to be
prepared with high selectivity in an efficient manner. Structural data, confirming aldehyde chelation, and a proposed mechanism
are provided.
cle,8b,9a,11b,14a or transforming the group by a second,
INTRODUCTION
■
frequently in situ,16 transformation.14d However, these
The development of reactions based on metal-catalyzed
manipulations could be avoided if the chelating unit was a
functionalization of C−H bonds is revolutionizing organic
common, synthetically valuable functional group, desired in a
synthesis and is delivering a series of nontraditional bond
broad range of structures. When considering possible
constructions as reliable synthetic tools.1 Metal-catalyzed
candidates to satisfy these criteria, the carbonyl group is the
alkene and alkyne hydroacylation reactions, in which a C−C
standout choice; carbonyl groups are arguably the most
multiple bond is formally inserted into the formyl C−H bond
versatile functional groups in organic synthesis, and in addition
of aldehydes, are examples of such nontraditional reactions and
to participating in a host of synthetically useful transformations
are becoming established as synthetically useful processes.2
they also feature in numerous designed molecules and natural
Although a small number of nonchelation-controlled methods
products (Scheme 1c). In this Article we show for the first time
have been developed,3,4 as have reactions based on the use of
how simple carbonyl groups such as amides, esters, and ketones
carboxylic acid derivatives under reducing conditions,5 the
can perform as effective chelating groups and deliver alkene and
majority of metal catalyzed hydroacylation reactions employ
alkyne hydroacylation reactions of exceptional scope and utility.
some form of substrate chelation as this has proven to be an
effective strategy to attenuate undesirable reductive−decarbon-
RESULTS AND DISCUSSION
■
ylation pathways (Scheme 1a). In addition, chelation-controlled
Although carbonyl groups are well established as directing
groups in a number of C−H functionalization protocols,17 they
have not been employed in hydroacylation chemistry. Guided
by the topology of previously successful chelating aldehydes
(Scheme 1b), we envisioned that 1,3-dicarbonyl arrangements
would provide effective motifs for rhodium-catalyzed hydro-
acylation. To examine this hypothesis we initially evaluated a
range of known hydroacylation catalysts in the coupling
reaction between β-amido aldehyde 1a18 and 1-octyne (Scheme
2). It was apparent that excellent conversions and yields could
be achieved using several catalysts. The main variation observed
was in the regioselectivity of the transformation, with both the
linear (2a(l)) and branched isomers (2a(b)) being formed in
processes often benefit from mild reaction conditions and an
increased substrate scope. Lochow and Miller first introduced
this concept when they employed an aldehyde containing a
pendant alkene as a coordinating group, to promote an
intermolecular alkene hydroacylation reaction.6 More recently,
aldehydes featuring P-,7 O-,8 N-,9 and S-based chelating groups
have all been reported (Scheme 1b).10 Chelating alkene
substrates have also been employed effectively.11 Collectively,
these chelation-based methods have allowed significant
advances, including the development of regio-8e,12 and
enantioselective reactions,8a,13 as well as applications in target
synthesis.14
The caveat to the success of these chelation-based reactions
is that the chelating group is present in the products;15
strategies to address this include incorporating the coordinating
atom or group into a target structure, often a heterocy-
Received: June 2, 2017
© XXXX American Chemical Society
A
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for the branched isomer.20 The most efficient and selective
system for the formation of the linear isomer was achieved
using a dcpe-derived catalyst at 5 mol % loading, delivering β-
keto amide 2a in 90% isolated yield with >20:1 regioselectivity.
Using this catalyst system we next examined the scope of the
transformation with respect to different alkynes and β-amido
aldehydes (Table 1). Isolated yields were consistently high
when aldehyde 1a was combined with a range of terminal
alkynes. The use of phenyl acetylene derivatives with both
electron-donating and electron-withdrawing groups (2b−d)
was well tolerated. A broad range of alkyl substitution patterns,
including branching and carbocycles, could be incorporated
(2e−k). Furthermore, a wide variety of alkynes containing
different functional groups, including nitrile, chloro, alcohol,
acetal, and ether substituents, were successfully employed (2l−
r). The reaction between aldehyde 1a with 3-butyn-2-ol
delivered saturated ketone 2r as the product, resulting from a
rhodium-catalyzed isomerization of the initially formed enone.
Having demonstrated the robustness of the methodology
toward variation of the alkyne partner, we next examined a
series of β-amido aldehydes. Variation of the substituent at the
α-carbon was achieved without incident, allowing the
incorporation of various aryl, alkyl, and alkenyl substituents
(2s−z). In addition, α,α-disubstitution was also possible and
had minimal effect on reaction efficiency (2aa−ab). We then
explored the use of amides with different substitutions at the
nitrogen atom, and a variety of cyclic and noncyclic secondary
amines performed extremely well in reactions with 1-octyne
(entries 2ac−ae), as did a Weinreb amide (2af). We were
pleased to observe that the presence of a free N−H bond did
not compromise reactivity (2ag). This observation led to the
use of a phenyl alanine-derived aldehyde, which delivered
coupled product 2ah in excellent yield and enantiopurity.
Finally, a cyclic β-amido aldehyde was also subjected to the
hydroacylation conditions and provided the 2-piperidone-based
product 2ai in excellent yield. All of the transformations
described above were performed using a 5 mol % catalyst
loading; however, it was possible to reduce this to only 0.5 mol
% when larger-scale reactions were conducted (see 2a).
Scheme 1. (a) Chelation-Controlled Intermolecular
Hydroacylation, (b) Common Chelating Motifs, and (c) β-
Carbonyl Aldehydes in Hydroacylation, with Representative
β-Dicarbonyl Target Molecules
Scheme 2. Initial Ligand Evaluation for the Hydroacylation
a
1-Octyne Using Amido Aldehyde 1a
With a robust method to deliver linear β-amido enones
established, we next explored the possibility of selectively
accessing the corresponding branched isomers. Further
optimization from our initial result employing an Ampaphos-
derived catalyst (Scheme 2) allowed a selective process to be
developed. The optimal conditions involved performing the
reactions at lower temperature (−20 °C versus 55 °C) and
increased concentration (2.0 M versus 1.0 M), and these were
then applied to a series of alkynes and aldehydes (Table 2).
The scope of the branched selective hydroacylation of alkynes
proved less general than in the case of the linear selective
reaction; however, a wide range of alkynes and aldehydes could
still be successfully employed. Methyl-substituted amido
aldehyde 1d provided high selectivity with aliphatic alkynes,
including a chloro-substituted example (3a−d). However, the
use of sp2-C-substituted alkynes resulted in a significant drop in
selectivity, although the branched isomer was still the major
component (3e,f). The α-substituent of the amido aldehyde
substrates could be modified without significantly influencing
the outcome of the reactions, with a range of substituents of
varied steric profile being tolerated (3g−l). Finally, the use of
alternative amido groups provided the desired branched
products with excellent selectivities (3m,n).
a
Reaction conditions: 1a (1.0 equiv), 1-octyne (1.2 equiv), [Rh-
(nbd)2]BF4 (5 mol %), ligand (5 mol %), acetone, 55 °C, 16 h.
b
c
Isolated yields. 10 mol % Rh and ligand. Conversions. Used as the
preformed complexes [Rh(dtpm)(C6H5F)][BArF4] and [Rh-
(Ampaphos)(C6H5F)][BArF ], respectively. ArF = C6H3-3,5-(CF3)2.
4
some cases. Small bite angle ligands such as dcpm and dppm,19
which deliver the greatest linear selectivity for β-S-chelating
aldehydes, only provided moderate selectivity when using
amido aldehyde 1a. Interestingly, the sterically congested small
bite angle ligands Ampaphos and dtpm exhibited a preference
B
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a
Table 1. Linear Selective Alkyne Hydroacylation Using β-Amido Aldehydes
a
Reaction conditions: 1 (1.0 equiv), alkyne (1.2 equiv), [Rh(nbd)2]BF4 (5 mol %), dcpe (5 mol %), acetone, 55 °C, 1 h. Isolated yields of single
b
isomers. 3-Butyn-2-ol used as substrate.
Initial attempts to employ internal alkynes as substrates
yielded mixed results; reaction of 1-phenyl-1-propane under the
optimal conditions for the linear selective reaction promoted
complete conversion of the aldehyde, although a 2:1 mixture of
regioisomers was obtained. Re-evaluation of diphosphine
ligands showed that several were able to promote complete
conversion. However, DPEphos was unique in also providing
control of the regioselectivity of the reaction, delivering an
isolated yield of the linear isomer of enone 4a of 73% (Table
3). These conditions were applied to a variety of internal
alkynes, including nonsymmetric alkynes possessing ester,
ketone, and branched alkyl groups adjacent to the triple bond
(4a−f). Interestingly, when ethyl non-2-ynoate was employed,
the selectivity could be completely switched by substituting
DPEphos for the ligand dcpe, enabling the formation of both
isomers selectively. When applied to alternative substrates, the
dcpe-derived catalyst was generally poorly effective. Finally,
good to excellent yields were achieved with symmetrical alkynes
(4g−i), including the hydroacylation of diphenylacetylene,
which has proved a challenging substrate to combine with other
classes of aldehydes.21
Having established mild and effective conditions for alkyne
hydroacylation using β-amido aldehydes, we next focused on
expanding the methodology to the hydroacylation of alkenes. In
general, alkene hydroacylation has proved far more challenging
than alkyne hydroacylation, often necessitating higher catalyst
loadings, very specific ligand requirements, or the use of
activated substrates. Considering these precedents, several
catalyst systems were re-explored for the hydroacylation of 1-
octene with β-amido aldehyde 1m (Scheme 3). The reactivity
varied considerably compared to the alkyne reactions, with only
the ligands dppm and dcpm providing any conversion to the
hydroacylation adduct; however, overall this was significantly
reduced. Most importantly, for the first time since we started
C
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Table 2. Branched Selective Alkyne Hydroacylation Using β-
Amido Aldehydes
Scheme 3. Evaluation of Alkene Hydroacylation Using
a
a
Mono- and Disubstituted Aldehydes
a
1
Conversions measured by H NMR spectroscopy.
product 7. The presence of these two compounds indicated a
probable, relatively rapid, C−H activation that is followed by a
trifurcation of possible pathways: productive alkene hydro-
acylation, unproductive aldehyde hydroacylation and reductive
decarbonylation. Further investigation showed that the use of
α,α-disubstituted aldehydes completely suppressed these latter
two side reactions. For example, reaction of α,α-dialkylated
aldehyde 1k with 1-octene using a dppm-derived catalyst
provided alkene hydroacylation adduct 5b in 73% yield. A final
optimization proved that complete conversion to the desired
product was possible if an excess of alkene was used in
combination with 5 mol % of a preformed dcpm catalyst.
These optimized conditions were applicable to a wide variety
of alkenes, and in all cases excellent yields of the hydroacylation
adducts were obtained (Table 4). Several useful functional
groups could be introduced, including ketones, esters, amines,
hydroxyl, and halide (5f−l). Interestingly, a styryl derivative
could be successfully used in these reactions, providing ketone
5m. Styrenes have been a particularly challenging class of
alkene to use with earlier generations of chelating aldehy-
des.4k,11a,b,22 A number of disubstituted alkene substrates were
also explored; however, both 1,1- and 1,2-disubstituted
examples were unreactive under these conditions. A variety of
aldehydes were explored, including examples with different
substituents in the nitrogen atom or in the α-position (5n−s).
Aldehydes containing a free N−H or a cyclic core also
performed well in the reaction with alkenes. Similar to our
earlier observations with alkynes, when performing reactions at
a larger scale the catalyst loading could be decreased to 1 mol %
without any effect on the reactivity (5e).
a
Reaction conditions: aldehyde (1.0 equiv), alkyne (1.2 equiv),
[Rh(Ampaphos)(C6H5F)][BArF ] (5 mol %), acetone [2.0 M], −20
4
°C, 18 h. ArF = C6H3-3,5-(CF3)2. Isolated yields of branched products.
Selectivities determined by 1H NMR spectroscopy of unpurified
b
reaction mixtures. Isolated as an inseparable mixture of l+b isomers.
Table 3. Hydroacylation of Internal Alkynes Using β-Amido
Aldehyde 1a
a
Having established that amides could be exploited to control
alkyne and alkene hydroacylation processes, we set about
exploring the use of alternative carbonyl-derived directing
groups. We began with the synthesis of the ethyl ester
counterpart of our standard β-amido aldehyde 1a. However, it
soon became apparent that this ester was inactive in the
targeted reactions. We attributed this lack of reactivity to the β-
ester substrate existing predominantly as the enol tautomer (as
a
1
rr = regioisomer ratio. Reaction conditions: 1a (1.0 equiv), alkyne
seen by H NMR spectroscopy). In comparison, all of the β-
(1.2 equiv), [Rh(nbd)2]BF4 (5 mol %), DPEphos (5 mol %), acetone
[1.0 M], 55 °C, 1 h. Isolated yields of single isomers. Selectivities
determined by 1H NMR spectroscopy of unpurified reaction mixtures.
amido aldehydes we had prepared existed in their respective
keto forms. To remove this issue we prepared an α,α-
disubstituted variant, which by design could only exist in the
keto form. When the dialkylated ester was subjected to our
optimal conditions for the hydroacylation of amido aldehyes
with terminal alkynes, the corresponding linear product was
obtained with good control of regioselectivity and in an
our investigations with this class of aldehydes, the presence of
two side products was observed in the reaction mixture:
decarbonylation product 6 and Tischenko-style dimerization
D
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Table 4. Hydroacylation of Alkenes Using β-Amido
Aldehydes
Table 5. Hydroacylation of β-Formyl Esters and β-Keto
a
a
Aldehydes
a
Reaction conditions: aldehyde (1.0 equiv), alkyne (1.2 equiv),
[Rh(nbd)2]BF4 (5 mol %), dcpe (5 mol %), acetone [1.0 M], 55 °C, 1
b
h. Isolated yields of single isomers. 3-Butyn-2-ol used as substrate.
Scheme 4. Application to the Synthesis of Heterocycles
a
Reaction conditions: 1 (1.0 equiv), alkene (3.0 equiv), [Rh(dcpm)-
(C6H5F)][BArF ] (5 mol %), acetone [2.0 M], 55 °C, 18 h. ArF =
C6H3-3,5-(CF3)2. Isolated yields. Single regiosomers. 7.5 mol %
4
b
catalyst.
excellent 90% yield (Table 5, 8a). Variation of the cyclopentyl
group on the α-carbon atom to a methyl−benzyl or methyl−
butyl arrangement did not affect the reactivity significantly, with
the corresponding linear adducts obtained in high yields
(entries 8b,c).
Ketones were the final class of carbonyl compounds to be
explored. Similar to the ester series, monosubstituted β-keto
aldehydes also exhibited a significant enol component, and we
again decided to use dialkylation to block this. To our delight,
when the corresponding α,α-disubstituted β-keto aldehyde was
subjected to the reaction with 1-octyne, employing our optimal
conditions, the hydroacylation product was obtained in an
impressive isolated yield of 95% (8d). This result was
successfully extended to several alternative alkynes of varying
steric demand and featuring a range of functional groups (8e−
j). In addition, variation of the substituents in either the α- or
α′-position of the ketones proved possible (8k−n).
To illustrate the synthetic potential of the developed
chemistry we briefly explored its use in heterocycle synthesis
and combined the use of amido aldehyde substrates with
various heterocycle-forming methods previously developed in
our laboratories (Scheme 4).14a−d Amido aldehydes were
combined, using the standard reaction conditions, with three
alkynes containing functional groups designed to promote
heterocycle formation. Following hydroacylation, the adducts
were subjected to the published cyclization conditions, to
deliver pyrrole 9a, quinoline 9b, and furan 9c. In addition, the
alkene hydroacylation adduct 5k was converted into tetrahy-
dropyridine 9d by treatment with TFA. Finally, enone 2a was
combined with t-Bu-hydrazine to provide dihydropyrazole 9e.
The results presented in this report demonstrate that β-
carbonyl-substituted aldehydes are exceptional substrates for a
E
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broad range of Rh-catalyzed hydroacylation reactions. Given
the success of these substrates, it was of interest to explore
whether the β-carbonyl-substituted aldehydes coordinate to
rhodium in an analogous manner to β-S-aldehydes, despite
possessing attenuated donating ability. In order to observe
potentially reactive intermediates, the moderately active
Xantphos catalyst system (Scheme 2) was selected for the
initial studies, in the anticipation that this ligand, which shows
less flexibility than DPEphos, would enable intermediate
species to be observed. We have previously demonstrated
such changes in activity in the hydroacylation of β-S-
aldehydes.10a Addition of 1 equiv of the β-amido aldehyde
(1j) to an acetone solution of the Rh(I) precatalyst
Hz]; while in the 13C{1H} NMR spectrum the acyl group is
observed at δ 224.0 [J(RhC) = 36.7 Hz; J(PC) = 5.9 Hz].
Complex 10b is stable toward reductive decarbonylation,
remaining unchanged (31P NMR spectroscopy) when heated to
55 °C in acetone for 24 h. This is no doubt due to the
stabilizing influence that the κ3-Xantphos ligand has by
protecting the cis vacant site necessary for initial carbonyl
deinsertion.10a,24 In addition, the product of carbonyl
deinsertion would possess a tertiary Rh−CR3 bond in a
strained 4-membered metallacyclic Rh−O−C−C ring, which is
likely to be unfavored. This could well explain the lack of
decarbonylation products observed in alkene hydroacylation
using α,α-disubstituted aldehydes (Table 4).
Complexes such as 10b are generally accepted as
intermediates in Rh(I)-catalyzed hydroacylation, and analogous
Rh(III) β-S-acylhydride complexes have been shown to afford
the products of hydroacylation on addition of the alkene or
alkyne.12a,25 To demonstrate this here, addition of 9 equiv of β-
amido aldehyde (1j) and 10 equiv of 1-octyne to 10b (0.075
M) was monitored by 1H NMR spectroscopy at 55 °C
(Scheme 5). After 24 h partial consumption of aldehyde was
observed, to form the linear enone product, 2aa (43% NMR
yield), consistent with the initial results of in situ screening,
albeit using a different aldehyde (Scheme 2). In addition to 2aa,
a significant amount (39%) of a 1:0.23 mixture of 1,2,4-tri-n-
hexylbenzene:1,3,5-tri-n-hexylbenzene (11) products formed by
[Rh(κ3-P,O,P-Xantphos)(η2-PhCCPh)][BArF ] (10a, ArF = 3,5-
4
(CF3)2C6H3)23 resulted in an immediate color change from red
to pale yellow and complete conversion to a new complex as
indicated by 31P{1H} NMR spectroscopy (Figure 1). Upon
a
Scheme 5. Reaction Conditions with Catalyst 10b, Reaction
b
1
Profile as Measured by H NMR Spectroscopy, and a
Proposed Mechanism for Hydroacylation with Xantphos
c
Catalyst
Figure 1. Synthesis of complex 10b and solid-state structure.
Displacement ellipsoids are shown at the 50% probability level.
Selected bond distances (Å) and angles (deg): Rh1−H1, 1.45(2);
Rh1−O1, 2.2895(10); Rh1−O3, 2.1584(10); Rh1−C40, 1.9408(16);
Rh1−P1, 2.2803(4); Rh1−P2, 2.2702(4); P1−Rh1−P2, 160.651(14).
[BArF ]− anions are not shown.
4
isolation by recrystallization from 1,2-difluorobenzene/pentane
the complex was identified as the Rh(III) β-amido−acylhydride
complex [Rh(mer-κ3-P,O,P-Xantphos)(H)(COC{C4H8}CO-
{OC4H8N})][BArF ] (10b) by NMR spectroscopy and
4
single-crystal X-ray diffraction. These data show that C−H
activation of the aldehyde has occurred to give a Rh(III)−
acylhydride with a supporting β-amide Rh···O interaction. The
solid-state structure of 10b is shown in Figure 1. The Xantphos
ligand adopts a mer-κ3-P,O,P-Xantphos geometry with the acyl
group sitting trans to the Xantphos ligand’s oxygen atom
[Rh1−C40, 1.9408(16); Rh1−O1, 2.2895(10) Å], while the β-
amido group sits trans to the hydride [Rh1−O3, 2.1584(10)].
a
Reaction conditions: aldehyde (1.0 equiv), alkyne (1.0 equiv), NMR
yields, ratio of 1,2,4-tri-n-hexylbenzene:1,3,5-tri-n-hexylbenzene
(1:0.23) as determined by H NMR. Time concentration plot for
catalysis; aldehyde, 1ab (red triangle), product, 2ab (blue square),
benzenes, 10c (green circle). Proposed Mechanism: L = e.g., alkyne,
1
b
1
The hydride ligand was located and freely refined. In the H
NMR spectrum the hydride is observed at δ −14.7 as a doublet
of triplets [J(RhH) = 27.2; J(PH) = 9.3 Hz]; the 31P{1H} NMR
spectrum displays a single environment at δ 29 [J(RhP) = 128
c
Xantphos shown in abbreviated form.
F
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alkyne cyclotrimerization was observed. A temporal profile for
this reaction is shown in Scheme 5, demonstrating that
hydroacylation and cyclotrimerization are competitive pro-
cesses, thus resulting in incomplete consumption of aldehyde in
hydroacylation. The catalytic cyclotrimerization of alkynes has
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4
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CONCLUSIONS
■
We have developed the Rh(I)-catalyzed carbonyl-directed
hydroacylation of alkynes and alkenes. Amide-, ester-, and
ketone-substituted aldehydes can all be employed as substrates.
The methodology utilizes mild reaction conditions and
tolerates the introduction of a wide variety of functional
groups, delivering hydroacylation adducts in excellent yields
with high levels of linear selectivity. Modification of the catalyst
design allows access to branched products from alkyne
hydroacylation. We provide structural data to support β-
carbonyl chelation. The β-carbonyl-substituted aldehydes we
introduce in this report combine extraordinary reactivity with
rich synthetic utility and, as such, remove the principal
limitation of chelation-controlled hydroacylation methods.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b05713.
CIF file for Rh1P2O4B1N1C82F24H61 (CIF)
Experimental procedures and supporting characterization
data and spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: michael.willis@chem.ox.ac.uk.
ORCID
Andrew S. Weller: 0000-0003-1646-8081
Michael C. Willis: 0000-0002-0636-6471
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was supported by the EPSRC (EP/K024205/1, EP/
M024210/1), the EPSRC Centre for Doctoral Training in
Synthesis for Biology and Medicine (EP/L015838/1, to J.B.-
S.), ERC Marie Curie Actions (DEGENHA 656493, to M.F.),
and the Clarendon fund of the University of Oxford (T.J.C.).
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DOI: 10.1021/jacs.7b05713
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DOI: 10.1021/jacs.7b05713
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX