Dynamic multiligand catalysis: A polar to radical crossover strategy expands alkyne carboboration to unactivated secondary alkyl halides

Article abstract of DOI:10.1016/j.chempr.2021.06.002

We describe a dual strategy in Cu catalysis based on an unprecedented dynamic multiligand coordination pool that triggers cooperative polar/radical pathways in a single catalytic cycle. This strategy has been applied to address a restricting limitation inherent to Cu-catalyzed B₂pin₂-carboboration of alkynes—the very low reactivity of the intermediate vinyl-Cu(I) species, which renders conventional methods ineffective with alkyl electrophiles other than simple primary halides. The crossover strategy enabled by ligand exchange in an organometallic intermediate overcomes this reactivity issue, expanding the scope of carboboration to unactivated secondary alkyl halides, and opens new avenues to access stereodefined tetrasubstituted vinylboronates. The method is regio- and stereoselective, shows excellent functional group tolerance, and allows the incorporation of complex carbo- and heterocyclic fragments at either reaction partner.

Full text of DOI:10.1016/j.chempr.2021.06.002

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Article
Dynamic multiligand catalysis: A polar to
radical crossover strategy expands alkyne
carboboration to unactivated secondary alkyl
halides
Shin-Ho Kim-Lee, Pablo
Maule o´ n, Ram o´ n G o´ mez
Array a´ s, Juan C. Carretero
pablo.mauleon@uam.es (P.M.)
ramon.gomez@uam.es (R.G.A.)
Highlights
Dynamic ligand exchange allows
polar/radical mechanistic shift on
a single metal core
Unlocks secondary alkyl
electrophiles in Cu-catalyzed
alkyne carboboration
Carbo- and heterocycles and
complex units incorporated at
either reaction partner
Alkyne valorization into richly
substituted, stereodefined
tetrasubstituted alkenes
This report describes a dynamic multiligand approach that enables cooperative
closed/open-shell pathways. This strategy has been applied to solve restricting
limitations in Cu-catalyzed carboboration of alkynes, opening chemical space to
unactivated secondary alkyl halides in the formation of richly substituted,
stereodefined tetrasubstituted vinylboronates. The method is regio- and
stereoselective, shows excellent functional group tolerance, and allows for the
incorporation of complex carbo- and heterocyclic fragments at either reaction
partner.
Kim-Lee et al., Chem 7, 2212–2226
August 12, 2021 ª 2021 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2021.06.002

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Article
Dynamic multiligand catalysis: A polar to radical
crossover strategy expands alkyne carboboration
to unactivated secondary alkyl halides
Shin-Ho Kim-Lee, Pablo Maule o´ n,1,2,* Ram o´ n G o´ mez Array a´ s, * and Juan C. Carretero1
1
1,
SUMMARY
The bigger picture
We describe a dual strategy in Cu catalysis based on an unprece-
dented dynamic multiligand coordination pool that triggers coopera-
tive polar/radical pathways in a single catalytic cycle. This strategy has
been applied to address a restricting limitation inherent to Cu-cata-
lyzed B pin -carboboration of alkynes—the very low reactivity of
the intermediate vinyl-Cu(I) species, which renders conventional
methods ineffective with alkyl electrophiles other than simple primary
halides. The crossover strategy enabled by ligand exchange in an
organometallic intermediate overcomes this reactivity issue, expand-
ing the scope of carboboration to unactivated secondary alkyl halides,
and opens new avenues to access stereodefined tetrasubstituted
vinylboronates. The method is regio- and stereoselective, shows
excellent functional group tolerance, and allows the incorporation of
complex carbo- and heterocyclic fragments at either reaction partner.
The invention of novel
approaches in catalysis is inherent
to the development of modern
society. In catalytic
transformations, those promoted
by transition metals have by far
been the most studied ones.
Central to these processes is the
use of ancillary ligands, which are
chemical entities capable of
tuning the reactivity of the metal
they are bound to. However,
sometimes only one ligand on the
metal is not enough to promote
complex transformations in which
more than one step is required to
reach the final product, halting at
a so-called ‘‘unreactive
2
2
INTRODUCTION
Transition metal catalyzed reactions typically involve an ancillary ligand that induces
1
,2
the specific reactivity required for a particular transformation. In multiple bond for-
intermediate.’’
1
mation reactions, however, traditional monocatalytic conditions [ML ] (Figure 1A)
rely on a single ligand to assist in numerous bond activation/formation events, often
resulting in low global efficiency and poor mechanistic flexibility to engage with
In this article, we introduce a
strategy based on the use of two
different ligands on a single metal.
Instead of operating
3
–8
different coupling partners. A common strategy employed to overcome these lim-
1
1
2
2
9–14
itations is the use of co-catalytic systems [M L /M L ] (Figure 1B).
approach based on a more efficient principle consists of assembling a multiligand sys-
An alternative
simultaneously on the metal, and
thus providing reactivity that
comes from the combination of
both units, we introduce a new
possibility—these two entities will
come on and off the metal core,
triggering alternate reactivity
patterns as they are required.
1
5,16
17,18
tem on a single metal core. After the pioneering work by Feringa
and Reetz
on
1
2
binary mixed-ligand complexes [ML L ], which has been applied to enhance catalytic
1
9–24
performance in many aspects (Figure 1C),
Buchwald set the grounds for a dynamic
1
2
system based on a two-ligand/one-metal catalytic mixture ([ML ]/[ML ]) that performs
two sequential C–N cross-coupling reactions in which each event was mediated by a
2
5
specific ligand. Inspired by this precedent, we sought to take one step further and
used a single metal/dynamic multiligand system in a process in which the catalyst,
instead of promoting two similar transformations, was able to trigger different types
of reactivities (e.g., polar and radical) via ligand exchange from a single intermediate,
wherein the ligands control the metal reactivity (Figure 1D). The reactions based on this
principle should fulfill two requirements: (1) a relatively unreactive intermediate in
which such an exchange is facile, and (2) a metal capable of engaging in multiple
pathways.
2
6–28
The Cu-catalyzed carboboration of internal alkynes,
a transformation applied to
the stereo- and regioselective synthesis of complex tetrasubstituted alkenes,
2212 Chem 7, 2212–2226, August 12, 2021 ª 2021 Elsevier Inc.

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Article
provides an ideal platform to test our hypothesis. Its full potential has been signifi-
cantly hampered by the small progress made regarding the electrophilic coupling
partner—while the use of strong s-donating ligands has facilitated carboboration
with activated electrophiles, the reaction with unactivated alkyl electrophiles re-
mains limited to primary alkyl halides with a narrow scope, despite the fact that these
2
9–37
are widespread electrophiles.
ophilicity of the relatively long-lived vinyl-Cu species.
metalation via Cu(I/III) oxidative addition is known to proceed with a considerable
This poor reactivity is likely due to the low nucle-
2
9,38–40
On the other hand,
4
1,42
energy barrier, which renders the polar mechanism inefficient for this purpose.
In contrast, Cu(I/II) single-electron oxidation is a smooth process that has long been
used to catalyze radical transformations involving aliphatic halides, such as atom
4
3–47
transfer radical additions and cyclizations.
Recent developments have shown
that activation of alkyl electrophiles by Cu catalysis into radical intermediates can
4
8,49
be followed up with an inner-sphere C–C bond formation, as illustrated by Liu
5
0
and Nishikata; this approach provides unique and powerful cross-coupling alter-
natives to the traditional closed-shell mechanism.
In view of the poor reactivity of the putative vinyl-Cu intermediate, along with the
inherent facility of Cu to readily alter its operating mechanism by changing the na-
ture of the ancillary ligand, we envisioned tackling the current limitations in alkylbo-
ration by harnessing dual, complementary reactivity from a single Cu catalyst using a
multiligand system (Figure 1E). Specifically, we planned a reaction that would pro-
ceed via (1) highly regio-/stereoselective borylcupration, promoted by s-donating
phosphine ligands, in tandem with (2) the action of a bidentate nitrogen donor
ligand that would enable radical cross-coupling of the vinyl-Cu intermediate with
alkyl electrophiles. Because of the limited coordination sites available at the Cu(I)
oxidation state, a dynamic ligand exchange would be essential for this strategy to
be successful. This approach would involve a reactivity crossover from closed to
5
1
52
open shell, as exemplified by the work of Fu and MacMillan using Ni catalysts.
Additionally, Mankad has disclosed the possibility to combine borylcupration with
radical coupling reactions using a Cu/NHC catalyst to achieve alkyne acylboration
5
3
from alkyl halides under 6 atmospheres of CO. Herein, we disclose a Cu-catalyzed
dynamic phosphine/1,10-phenanthroline system that triggers a polar to radical
crossover to enable carboboration of alkynes with secondary alkyl halides.
RESULTS AND DISCUSSION
2 2
To test our strategy, we chose 1-phenyl-1-butyne 1, B pin , and cyclohexyl bromide
as benchmark substrates. After extensive exploration using phosphines to promote
borylcupration across the alkyne, we found that the use of 1,10-phenanthroline de-
rivatives as additional ligands furnished carboboration product 3 with complete
b-regioselectivity and syn-stereoselectivity (entries 1–8, Figure 2; see Table S2 for
full optimization studies). Regarding the phosphine ligand, PBu
Cu afforded 3 in a 60% yield (entry 1), whereas a less s-donating P(p-C
Cu:L 1:1) led to a slightly lower yield (55%, entry 2). Optimal ligand performance
was reached by using a combination of PBu and P(p-C -OMe) (1:1 ratio, entry
), which furnished 3 in an 81% isolated yield. When a simpler 1,10-phenanthroline
2) was used as the N-ligand, the reaction yield dropped to 51%, whereas neocu-
3
at a 1:1 ratio to
6
H
4
-OMe)
3
(
3
6
H
4
3
1Organic Chemistry Department, Institute for
Advanced Research in Chemical Sciences
3
(
IAdChem), Universidad Aut o´ noma de Madrid,
8049 Madrid, Spain
(L
N
2
proine failed to render carboboration (entries 4 and 5). Importantly, the stereochem-
ical pattern that was observed strongly suggests that phosphine-promoted boryl-
cupration across the alkyne — and not radical addition — is the first event to take
place. On the other hand, TEMPO inhibited the formation of 3 (entry 6); in turn,
the reaction yielded the corresponding hydroboration product (see Figure 8), which
2Lead contact
*Correspondence:
pablo.mauleon@uam.es (P.M.),
ramon.gomez@uam.es (R.G.A.)
https://doi.org/10.1016/j.chempr.2021.06.002
Chem 7, 2212–2226, August 12, 2021 2213

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A Traditional monocatalytic system: ML1 controls multiple steps
E This work: Dynamic multiligand catalysisenables polar to radical crossover catalysis
in the carboboration of alkynes
1
R ML1
R1
ML1
2
R1
R2
R X
Overcomes
current limitations:
Poor reactivity in intermediates,
transmetallation only known with Pd
Polar mechanism. Limited to
primary alkyl electrophiles
1
1
2 2
B Cooperative bimetallic system: M L /M L control reactivity
het
R1
R2
Bpin
1
1
1
R1
M1L1 - M1L1 / + M2L2
R1
M2L2 R2X
R1
R2
R M L
R1
R2
Transmetallation
I
t
Lp-Cu O Bu
I
het
X
N
L -Cu X
B2pin2
C Enhanced catalytic performance by heteroleptic multiligand complexes
1
1
2
R1
ML1L2
2
R1
R2
LP = Phosphine
LP
R ML L
R X
Lp-CuI
LN-Cu X Bpin
II
Bpin
R2
[
Cu]
het
+
R1
R1
R2
LN
I
II
LN = Phenanthroline
D Dynamic multi-ligand system (unexplored)
Polar mechanism
Reversible
ligand exchange
Radical mechanism
1
R ML1
R1
L1
L2
R1
M- L2
R2X
R1
R2
M
-
High stereocontrol
Easily tunable
1º, 2º alkyl substitution
Broad scope, excellent
functional group tolerance
Success dependent on reversible ligand exchange
Figure 1. Strategies toward catalytic control in alkyne difunctionalization reactions
indicates a radical mechanism is operative in the C–C bond forming event. Finally,
control runs in entries 7 and 8 demonstrated the key cooperative effect of both
ligand families—while phosphine ligands alone fail to promote the formation of
2 N
the carboboration product (entry 7), 4,7-Me phen (L 1) alone afforded 3 in a poor
yield (17%, entry 8). For entries 5–8, the reaction afforded variable amounts of the
corresponding hydroboration product, which arose from a slow protonation process
of the intermediate vinyl-Cu(I) species. Because the reactivity of the vinyl-Cu inter-
mediate I in Figure 1 could be influenced by the electronic properties of the alkenyl
ligand, we extended this study to the electron-deficient alkyne 2 (entries 9–14). The
conditions described in entry 3 proved to be much less suitable in this case (4, 17%,
entry 9). However, replacing cyclohexyl bromide with its iodide analog showed a
promising increase in the conversion from substrate 2 to product 4 to 36%, which
further improved up to 59% by using L
P(p-C -OMe) (entries 10–12). Notably, the addition of TBAB improved the yield
up to 85% (entry 13). When this second set of conditions was applied to CyBr (entry
4), the efficiency significantly dropped (from 85% to 8%). These results manifest the
N 3
2 as the hard donor and PPh instead of
6
H
4
3
1
utility of a flexible ligand system that can be tuned to address the specific needs that
diverse substrates and/or reagents may require.
With useful conditions for both model substrates in hand, we studied the incorporation
of attractive coupling partners (Figure 3), initially testing hydrocarbon and heterocyclic
scaffolds in the reaction between electron-rich alkynes and alkyl bromides. For most
cases studied, the reaction took place smoothly to afford the corresponding tetrasubsti-
tuted vinyl boronates in 65%–80% yield. The variations studied include all-carbon elec-
trophiles (5–7), oxygen-based oxetane 8 and oxane 9, N-protected piperidines 10 and
1
1, and pyrrolidines 12 and 13. The latter was introduced as a single diastereoisomer (cis
configuration), which, consistent with a radical pathway, resulted in a 1:1 mixture of ste-
reoisomers. Different substitution patterns at the alkyne were well tolerated, including
electrophilic groups such as amide 14 and primary chloride 15. TBS-protected alcohol
1
7 was also tolerated—even with oxane in the electrophilic moiety—as well as acylated
alcohol 18. On the aromatic end, hydrocarbon-based aromatic scaffolds such as fluo-
renyl in 22, biphenyl in 23, or naphthyl in 24 worked well. Other functionalities were
also compatible with the reaction conditions, although for some electron-rich arenes
(
3 3
methoxyphenyl 19 or thienyl 28) replacing PBu with PCy turned out to be more suit-
able. To examine the compatibility of this method with higher structural complexity, and
2214 Chem 7, 2212–2226, August 12, 2021

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Cy
Bpin
R2
CuCl/LP/LN
R2
P
OMe
+
B2pin2
+
Cy X
3
N
N
t
N
N
N
N
NaO Bu
R1
LN
1
LN
2
LN
3
PAr3
1
or 2
THF, RT, 18 h
R1
3 or 4
Entry
Alkyne
X
P-Ligand
N-Ligand
Additive
Product
Yield (%)b
1
2
3
4
5
6
7
8
Br
Br
Br
Br
Br
Br
Br
Br
PBu3
LN1
LN1
LN1
LN2
LN3
LN1
--
--
60
PAr3
--
55
Cy
Bpin
Et
Et
3, 84 (81)c
PBu3 + PAr3 (1:1)
PBu3 + PAr3 (1:1)
PBu3 + PAr3 (1:1)
PBu3 + PAr3 (1:1)
PBu3 + PAr3 (1:1)
--
--
--
51
0
--
1
TEMPO
0
3
--
--
0
LN1
17
9
Br
PBu3 + PAr3 (1:1)
PBu3 + PAr3 (1:1)
PBu3 + PAr3 (1:1)
PBu3 + PPh3 (1:1)
PBu3 + PPh3 (1:1)
PBu3 + PPh3 (1:1)
LN1
LN1
LN2
LN2
LN2
LN2
--
17
Cy
Bpin
nBu
10
11
12
13
14
I
--
36
nBu
I
--
48
MeO2C
I
--
59
4, 85 (83)c
2
I
TBAB
TBAB
MeO2C
4
Br
8
a
t
Reaction conditions: 1 or 2 (1 equiv), B2pin2 (1.5 equiv), Cy-X (1.5 equiv), CuCl (15 mol%), LP (16 mol%), LN (20 mol%), NaO Bu (1.6 equiv), additive (1.0 equiv),
THF (0.1 M), RT, 18 h. bDetermined by 1H NMR (1,3,5-trimethoxybenzene as internal standard). cIn parenthesis, isolated yield after chromatography.
Figure 2. Discovery of a catalytic system for the carboboration of alkynes with cyclohexyl bromide and iodide
to show its potential use in the design of drug-like molecules, natural products and drug
derivatives were incorporated into the reaction components: the aromatic ring (estrone
2
8), the alkyl terminus of the alkyne partner (ribofuranose 29), and the alkyl bromide
(
Indomethacin 30 and Gibberellic acid 31). In all cases, the reaction resulted in practical
yields and no alteration in the scaffolds was detected. Due to the structural complexity
of the electrophilic components, in the case of 30 and 31, the amount of halide was low-
ered to 1.2 equivalents without a significant impact in the reaction yield.
Next, we examined the behavior of electron-deficient alkynes and alkyl iodides (Fig-
ure 4). Reaction with cyclopentyl iodide to form 32 took place with good yield (70%).
Again, we introduced saturated O- and N-based 4-, 5-, and 6-membered heterocy-
cles with satisfactory yields in the 52%–84% range (34–41). cis-4-Iodo-2-phenyltetra-
hydropyran (dr>9:1) afforded 37 as a single diastereoisomer with full retention of
configuration, most likely guided by axial interactions. However, as in the case of
1
3, stereochemical scrambling occurred when a diastereomerically pure proline-
based iodide was used as the electrophile (40, 70%, d.r.=1:1). Decorations at the
aryl fragment included electron-withdrawing groups such as a ketone in 45, amide
3
in 46, sulfonamide in 47, nitrile in 48, –CF in 49 and 50, and bromide in 51, as
well as heterocycles pyridine 52 and benzoimidazole 53. As discussed earlier, we
tested our method on electrophiles decorated with natural product derivatives.
b-Cholesteryl iodide reacted with full diastereoselectivity (56, 71%) as a single dia-
stereoisomer—again guided by axial interactions—and densely functionalized
structures such as saccharide 57 and alkaloid theophylline 58 also showed satisfac-
tory results (76% and 48%, respectively).
Finally, we investigated alkynes with alternative substitution patterns (Figure 4,
below). Diphenylacetylene coupled more efficiently with CyI (59, 84%) than with
CyBr (59, 67%) using the corresponding optimized conditions. We next tackled
Chem 7, 2212–2226, August 12, 2021 2215

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LP
R1
R2
Bpin
R2
+
+
B2pin2
[Cu]
LN
Br
R1
O
Boc
Cbz
O
N
N
Bpin
Et
Bpin
Et
Bpin
Et
Bpin
Et
Bpin
Et
Ph
Bpin
Et
Bpin
Et
Bpin
Et
3
, 81%
5, 79%
6, 74%
7, 41%
8, 75%
9, 70%
10, 79%
11, 73%
Boc
N
CO2Me
O
O
Bpin
Boc
N
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
Et
Bpin
Et
O
N
nBu
Ph
Cl
Ph
16, 74%
OTBS
OAc
18, 55%
Boc
MeO
19, 65%b,c
13, 53% (dr 1:1)a
1
2, 75%
14, 44%
15, 75%
17, 82%
Bpin
Bpin
Bpin
Bpin
Bpin
nBu
Bpin
Bpin
nBu
Bpin
nBu
nBu
MeO
nBu
nBu
nBu
nBu
S
F
tBu
Ph
MeO
25, 68%b,c
26, 80%b,c
27, 41%b
2
0, 67%
21, 63%
22, 81%
23, 80%
24, 80%
O
O
N
Cl
O
H
O
O
Bpin
O
SiEt3
O
Et3Si
Bpin
N
Bpin
Et
O
Cl
Bpin
Et
O
O
H
H
H
O
Me
nBu
N
O
H
O
O
O
Cl
29, 61% (dr 1:1)d
30, 66%e
31, 70%e
2
8, 75%
Reaction conditions: Alkyne (1 equiv), alkyl bromide (1.5 equiv), B2pin2 (1.5 equiv), CuCl (15 mol%), PBu3 (8 mol%), P(p-C6H4-OMe)3 (8 mol%), 4,7-dimethyl-1,10-phenanthroline
LN1) (20 mol%), NaO Bu (1.6 equiv), THF (0.1 M), RT, 18 h. aAlkyl halide used as single diastereoisomer. bPCy3 was used instead of PBu3. cTBABF4 (1.0 equiv) was used as
t
(
additive. dStarting material used as a mixture of anomers (1:1). eThe amount of alkyl halide was decreased to 1.2 equivalents.
Figure 3. Carboboration of internal alkynes bearing electron-rich aryl substituents using secondary alkyl bromides
dialkyl alkynes, which are particularly challenging substrates because in the absence
of the electronic bias exerted by an aryl group, the carboboration process could
yield two regioisomers. However, these substrates reacted smoothly with complete
5
4
b-regioselectivity directed by a propargylic ether (60, 66%). Whereas diphenylace-
tylene reacted well under both sets of conditions, dialkyl alkynes behaved better un-
der those identified for electron-deficient alkynes. Again, this finding highlights the
versatility of a strategy that can accommodate the specific needs of reagents or sub-
strates. When the benzyl group was switched to a silicon-based TBS group, a
decrease in the yield was observed (61, 45%). In contrast, we detected a slight in-
crease when the same protected propargylic alcohol was coupled with a smaller iso-
propyl unit (62, 66%), which points to steric congestion around the reaction site as a
t
t
factor in this family of alkynes. In agreement with this observation, BuBr and BuI
failed to react with 1 or 2 using the corresponding catalyst mixture. In the presence
of two directing groups (Ph and propargylic oxygen), carboboration was mainly
directed by the Ph group (63, 42%, regioselectivity 85:15).
2216 Chem 7, 2212–2226, August 12, 2021

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LP
R1
R2
Bpin
R2
+
+
B2pin2
[Cu]
LN
I
R1
Ph
O
O
Cbz
O
O
N
Bpin
Bpin
Bpin
nBu
Bpin
nBu
Bpin
nBu
Bpin
Bpin
Bpin
nBu
nBu
nBu
nBu
nBu
CO2Me
CO2Me
32, 70%
CO2Me
34, 76%
CO Me
CO Me
2
2
CO Me
CO2Me
CO Me
2
2
37, 81% (dr>98:2)a
4
, 83%
33, 82%
35, 84%
36, 66%
38, 52%
Boc
N
CO2Me
Boc
N
Bpin
Boc
N
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
nBu
nBu
nBu
nBu
nBu
O
Ph
Cl
OTBS
O
N
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
Ph
O
40, 70% (dr 1:1)a
3
9, 66%
41, 80%
42, 84%
43, 72%
44, 72%
45, 63%
46, 81%
O
Bpin
Bu
Bpin
nBu
Bpin
Bpin
nBu
Bpin
nBu
Bpin
Bpin
nBu
Bpin
nBu
nBu
nBu
O
O
N
S
N
N
N
CF3
Ph
NC
F3C
Br
CO2Et
4
7, 62%
48, 58%
49, 74%
50, 76%
51, 56%
Bpin
52, 41%
53, 77%
54, 82%
O
O
O
Boc
nBu
Me
N
N
N
N
N
H
H
Bpin
O
O
H
nBu
N
N
Me
Bpin
nBu
Bpin
O
O
H
O
nBu
O
O
O
CO2Me
CO2Me
CO2Me
58, 48%b
5
5, 63%b
56, 71% (dr>98:2)a,b
57, 76%
Other alkyne substitution patterns
Bpin
Bpin
OBn
Bpin
Bpin
Bpin
BnO
60, 63%
TBSO
61, 45%
TBSO
62, 66%
5
9, 84%
63, 42%
rr 85:15)
(
Reaction conditions: Alkyne (1.0 equiv), alkyl iodide (1.5 equiv), B2pin2 (1.5 equiv), CuCl (15 mol%), PBu3 (8 mol%), PPh3 (8 mol%), 1,10-phenanthroline (LN2) (20 mol%),
NaO Bu (1.6 equiv), TBAB (1.0 equiv), THF (0.1 M), RT, 18 h. aAlkyl halide used as single diastereoisomer. bThe amount of alkyl halide was decreased to 1.2 equivalents.
t
Figure 4. Carboboration of internal alkynes bearing electron-poor aryl substituents using secondary alkyl iodides. Other substitution patterns
In accordance with the data presented so far, it is reasonable to assume that an open-
shell mechanism outcompetes direct substitution when reacting with secondary alkyl
electrophiles. However, we were intrigued to know whether this behavior would also
apply to primary alkyl electrophiles. We observed (Figure 5) that the reaction of
alkyne 1 with 1-bromobutane delivered the carboboration product 64 with a 90%
Chem 7, 2212–2226, August 12, 2021 2217

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LP
R3
Bpin
R2
R1
R2
+
R3
+
2 2
B pin
X
[Cu]
LN
R1
Scope for electron-rich alkynes with alkyl bromidesa
Scope for electron-deficient alkynes with alkyl iodidesb
O
O
Cl
O
Boc
Bpin
N
Bpin
Et
N
N
Bpin
Bpin
Et
Bpin
Et
Bpin
nBu
O
Bpin
Et
nBu
nBu
MeO2C
7
1, 72%
MeO2C
MeO2C
Control experiments
6
5, 72%
66, 77%
67, 63%
7
2, 71%
73, 67%
6
4, 90%
w/ Bu-Br instead
of Bu-I: 12%
S
Control experiments
O
AcO
EtO2C
PhO
w/o LN2: 0%
Bpin
Et
Bpin
Et
Bpin
nBu
Bpin
nBu
NC
N
Bpin
Et
4
w/ TEMPO
2
(4.0 equiv): 0%
Bpin
nBu
w/ Bu-I instead
of Bu-Br: 0%
MeO C
MeO C
2
MeO C
2
2
76, 57%c
6
8, 70%
69, 78%
70, 67%
74, 72%
75, 73%
a
Reaction conditions: Alkyne (1 equiv), alkyl bromide (1.5 equiv), B2pin2 (1.5 equiv), CuCl (15 mol%), PBu3 (8 mol%), P(p-C6H4-OMe)3 (8 mol%), 4,7-dimethyl-1,10-phenanthroline (LN1) (20
mol%), NaO Bu (1.6 equiv), THF (0.1 M), RT, 18 h. bReaction conditions: Alkyne (1.0 equiv), alkyl iodide (1.5 equiv), B2pin2 (1.5 equiv), CuCl (15 mol%), PBu3 (8 mol%), PPh3 (8 mol%), 1,10-
phenanthroline (LN2) (20 mol%), NaO Bu (1.6 equiv), TBAB (1.0 equiv), THF (0.1 M), RT, 18 h. cThe amount of alkyl halide was decreased to 1.2 equiv.
t
t
Figure 5. Brief survey of primary alkyl halides as electrophiles
yield. Control experiments with the same reaction provided us with the following in-
formation: (1) the participation of radical species was confirmed by the addition of
TEMPO, which completely suppressed the reaction and suggested that a fast reac-
tion occurs between the butyl radical and the metal center. (2) The carboboration
N
product was not observed when L 1 was removed from the reaction, leading exclu-
sively to the corresponding hydroborylated product. This result highlights the poten-
tial of our approach, since it expands the scope of primary alkyl halides that can be
reacted with the alkyne. (3) The reaction did not take place when 1-iodobutane was
tested as a coupling partner. However, following the exact same pattern described
3 3 N
for secondary alkyl halides, a switch to PBu and PPh , and L 2 as the hard nitrogen
donor efficiently catalyzed the reaction of 2 and 1-iodobutane to afford 71 with a 72%
yield (Figure 5, right). Following this trend, each set of conditions led to the products
compiled in Figure 5 with yields typically around 70%—as shown, acetate (70) and
chloride (66) were perfectly suitable for the reaction conditions, as well as other useful
moieties such as phthalimide (73), phenylether (75), a potentially sensitive epoxide
(
69), or even a terminal alkene (68). Furthermore, different heterocyclic units such
as dioxolane in 65, indoles in 67 and 72, and the bioactive scaffold phenothiazine
in 76 were also introduced in satisfactory yields.
We conducted a series of experiments aimed at clarifying key mechanistic aspects of
this process. Said experiments have two specific goals: (1) elucidating the nature of
the species responsible for the borylcupration event and (2) establishing the nature
of the coupling with the electrophile. Initially, we studied the stoichiometric forma-
8
tion and reactivity of vinyl-Cu(I)L species (Figure 6). These intermediates were
2 2
formed by treatment of a mixture of 1-phenyl-1-butyne 1 and B pin with a solution
t
containing CuCl, NaO Bu, and the corresponding ligand to form either I (right, L =
phosphine) or II (left, L = phenanthroline), and their reaction with different electro-
philes showed the following results:
(
1) As anticipated, the treatment of complex I after 5 min with MeOD led to 77
with 75% yield (H:D 43:57), which confirms the fast and efficient formation of
2218 Chem 7, 2212–2226, August 12, 2021

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H
Bpin
Et
D
Bpin
Et
Ph
Ph
D2Oc
CyBr
MeODb
CyBr
7, 21%a
I
d-77, 75%a
7
II
Bpin
N
B2pin2
+
Bu3P
[Cu]
low deuteration
CuCl + LN1
CuCl + PBu3
H/D 43:57
N [Cu]
Bpin
Et
t
t
NaO Bu
NaO Bu
Ph
Et
Cy
Bpin
Et
Ph
Et
Ph
Cy
Bpin
Et
1
slow
metalation
fast
metalation
Ph
Ph
3
, 5%a
+ PBu3
+ LN1
CyBr
3, 0%a
CyBr
Cy
Ph
Bpin
Et
Cy
Ph
Bpin
Et
via I
3
, 43%a
3, 45%a
a
t
Reaction conditions: 1 (1 equiv), CuCl (1.0 equiv), B2pin2 (1.5 equiv), NaO Bu (1.6 equiv), first ligand: 4,7-dimethyl-1,10-phenanthroline (LN1) (1.1 equiv) or
PBu3 (1.1 equiv), THF (0.05 M), RT, 5 min. Then, second ligand (1.1 equiv) if used, and CyBr (1.5 equiv), 30 min. Yields determined by 1H NMR using 1,3,5-
trimethoxybenzene as internal standard. bMeOD (1.5 equiv) instead of CyBr. cD2O (5.0 equiv) instead of CyBr.
Figure 6. Reaction mechanism: stoichiometric studies
the vinyl-Cu(I)intermediatewhen phosphine isusedasligand. However, nocarbo-
boration product was detected when 1.5 equivalents of CyBr were added to the
N
reactionmixture.Inturn, performingthe reactioninthe presenceofL 1 (1.1equiv)
and CyBr (1.5 equiv) resulted in the formation of 3 with a 45% yield, indicating the
crucial role of phenanthroline in triggering the cross-coupling reaction.
(
2) When we used L
, treatment with D
yield (21%), which indicates that phenanthroline is much less efficient than PBu
N
1 as sole ligand to form II, after 5 min of borylcupration of alkyne
1
2
O yielded the hydroborylated product 77 with a very low
3
in the borylcupration event. Next, the reaction mixture was treated with CyBr
to afford 3 with a 5% yield. Along with entry 6 in Figure 2, in which the carbobo-
ration product was obtained using phenanthroline as the sole ligand under cata-
lytic conditions, this result indicates that it is possible to obtain both reactivity pro-
files, polar and radical, from this ligand alone. However, the very low yield
obtained under these conditions strongly points toward phosphine complexes
3
as catalysts for the initial borylcupration step. Finally, the addition of PBu and
CyBr to the reaction mixture resulted in the formation of the carboboration prod-
uct 3 with a 43% yield. This result can be understood considering that the addition
3 N
of PBu greatly accelerates the borylcupration process, and then that L 1 pro-
motes carboboration in the presence of CyBr. In addition, it is almost identical
to the result obtained for I (45%) and is particularly revealing in two ways: (1) It
corroborates the need for a two-ligand system to obtain a satisfactory carbobo-
ration reaction, and (2) it supports the hypothesis of equilibration between the
two ligands prior to the formation of 3.
Borylcupration
The stoichiometric experiments shown in Figure 6 suggest that phosphines catalyze
the initial borylcupration of the alkyne. Considering that the initial catalyst mixture
results in the formation of the corresponding heteroleptic phosphine/phenanthro-
line complexes (such as 100 and 101, which provide comparable results if used
instead of the precatalyst mixture, Figure 7.1; see Table S4) and the four coordina-
tion sites available in a Cu(I) complex, we reasoned that either phosphine or phe-
nanthroline should dissociate to effect borylcupration of the alkyne, thus gener-
ating two different catalysts (Cu-phosphine or Cu-phenanthroline). To study this
possibility, we explored a potential ligand exchange by MS analysis of the
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1. Carboboration using isolated heteroleptic precatalyst
[
Cu(phen)(PR )Cl]
3
nBu
(15 mol%)
Cy
Ar
Bpin yield:
100, R=Ph
101, R=Bu
N
+
B pin
+
CyI
2
2
N
5
5% from 100
t
Cu
NaO Bu (1.6 equiv)
TBAB (1.0 equiv)
nBu
Cl
MeO C
2
73% from 101
2
R3P
4
2. Catalyst speciation detected by FAB-MS
CuCl
+
phen
+
PBu3
+
PPh3
FAB-MS (m/z)
THF
monocoordinated complexes
heteroleptic complexes
homoleptic complexes
[
[
[
Cu(phen)]+ (243.0)
Cu(PBu3)]+ (265.1)
Cu(PPh3)]+ (325.0)
[(PBu )Cu(phen)]+ (445.2)
[Cu(phen) ]+ (423.1)
3
2
[(PPh )Cu(phen)]+ (505.0)
[Cu(PBu ) ]+ (467.2)
3
3 2
+
[(PPh )Cu(PPh )] (527.1)
3
3
3
. Borylation rate comparisona
CuCl/
CuCl/PR3
CuCl/phen/
t
PBu /PAr
1
1
+
B pin
2
2
+
+
HO Bu
77
3
PBu /PPh3
3
3
3
t
t
NaO Bu
t
1
+
B pin
+
HO Bu
77
1
+
B pin + HO Bu
77
2
2
2
2
t
t
NaO Bu
std. cond.b
NaO Bu
N-Ligand
+
B pin
2
2
CyBr
Additive
7
7 [no LN1]
77 [PBu3 (16 mol%)]
77 [PAr3 (16 mol%)]
77 [TBAB (1.0 equiv)]
77 [TBAI (1.0 equiv)]
77 [LN1 (20 mol%)]
3
[std. cond.]
a
Reaction conditions: 1 (1 equiv), alkyl bromide (1.5 equiv), B2pin2 (1.5 equiv), CuCl (15 mol%), PR3 (PBu3 (8 mol%) and PPh3 or P(p-C6H4-OMe)3 (8 mol%),
t
unless otherwise noted), 4,7-dimethyl-1,10-phenanthroline (L 1) or 1,10-phenanthroline (20 mol%) if required, NaO Bu (1.6 equiv), THF (0.1 M), RT, 18 h.
bStandard carboboration conditions, see Figure 2, entry 3.
N
Figure 7. Reaction mechanism: dynamic ligand exchange and kinetic studies
precatalytic species (Figure 7.2; see section S2.8). These studies confirm that the
catalyst mixture in THF solution rapidly results in the formation of heteroleptic
3 3
species Cu(phen)(PBu )Cl or Cu(phen)(PPh )Cl, which then undergo speciation in
+
rapid equilibria to form the mixed phosphine-complex [Cu(PBu
3
)(PPh
3
)] , homolep-
+
+
tic complexes [Cu(phen
2
)] and [Cu(PBu
3
)
2
] , and mono-coordinated species
+
+
+
[
Cu(phen)] , [Cu(PBu
3
)] , or [Cu(PPh
3
)] . These dynamic processes find direct pre-
5
5
cedence in the work by Delavaux-Nicot, Armaroli, and Nierengarten and Bess-
5
6
mertnykh-Lemeune, Kadish, and Beletskaya, in which complexes containing phe-
nanthroline and phosphines undergo instantaneous equilibration in solution, even
in non-coordinating solvents such as CH
2 2
Cl , and originate from their kinetic insta-
bility in solution with steric hindrance as the driving force in the thermodynamic
5
7
3
equilibria. Importantly, this study confirms that the formation of Cu-PR com-
plexes, shown in Figure 6 to be more effective catalysts than Cu-phenanthroline
for the borylcupration process, is indeed possible in the reaction media.
2220 Chem 7, 2212–2226, August 12, 2021

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To add further support to the role of phosphines as the catalyst for the initial boryl-
cupration process and to address the differential reactivity of phenanthroline and
both phosphines, as well as the effect of TBAB in this process, we performed the
following kinetic studies (Figure 7.3; see section S2.9, Figures S1–S3):
(
1) The hydroboration of substrate 1 to form 77 showed a similar kinetic profile
using either only phosphines or both phosphines and phenanthroline, albeit
slightly faster using the mixed phosphine system in the absence of phenan-
throline (Figure 7.3, left). This can be easily understood considering that, as
the MS study clearly shows, the presence of phenanthroline leads to compet-
itive ligand-association processes that decrease the amount of CuPR
reaction media.
3
in the
(
2) We next evaluated the effect of two phosphines in the borylcupration step.
The kinetic profile (Figure 7.3, center) shows that PBu (blue) is much faster
at the beginning of the reaction but shows asymptotic behavior earlier than
P(p-C -OMe) . Conversely, P(p-C -OMe) shows a slower but steadier
3
6
H
4
3
6
H
4
3
growth (green) that results in lower conversion. The use of the mixed phos-
phine system in the carboborylation reaction (red) combines the stability pro-
6 4 3 3
vided by P(p-C H -OMe) with the reactivity of PBu , starting slightly more
slowly at the beginning of the reaction but eventually reaching the same con-
version. Since the borylcupration step is catalyzed by only one phosphine
5
8
bound to Cu, the synergistic effect of both phosphines can be safely attrib-
uted to a reservoir effect.
(
3) The beneficial effect of TBAB was observed in reactions between alkynes
À
and alkyl iodides, reactions in which up to one equivalent of I is gener-
ated and accumulated in the reaction mixture. The sluggish halide ex-
change between alkyl iodides and TBAB (see section S2.9.3) indicates
that there is no change in the nature of the electrophile and suggests
that the difference must again lie in the borylcupration event. To study
this effect, we investigated the rates of hydroboration using either TBAB
or TBAI as additives (Figure 7.3, right), and observed that the presence
of TBAI led to worse conversion from 1 to 77 than TBAB. This observation
À
indicates that an excess iodide I is detrimental for borylcupration and
suggests that the addition of TBAB counters this deleterious effect. The
differences in yield (85% versus 63%) are equivalent to those observed
for the overall transformation (see Figure 2), confirming that this anion ef-
fect only influences the borylcupration step. Additionally, these results
indicate that the tetrabutylammonium cation has no apparent role in the
reaction mechanism.
Radical coupling
To investigate the nature of the C–C bond forming event, we initially directed our
efforts at exploring the inhibition effect exerted by TEMPO, indicated in the optimi-
zation studies in Figure 2 and in the study of primary alkyl halides. To do so, we con-
ducted two experiments (catalytic and stoichiometric) using TEMPO as a radical trap
(
Figure 8, equation 1). In both cases, along with inhibition of the process, we were
able to detect the formation of TEMPO-cyclohexyl (3%–10% yield). We next em-
ployed alkyl radical clocks as electrophiles to gather further support on the radical
nature of the second half of the process. Consistent with the previous data, the re-
action of 1 with cyclopropylmethyl bromide smoothly led to the corresponding
ring-opened product 68 (81% yield, equation 2). Moreover, the participation of
1
-hexenyl radical in the reaction with 1 was supported by the obtention of a mixture
of cyclic and non-rearranged species 78 and 79 in a 6:4 ratio (equation 3). Together,
Chem 7, 2212–2226, August 12, 2021 2221

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1
. TEMPO trapping and inhibition experimentsa
Cy
O
LP
H
Bpin
Et
O
N
N
(
1) Ph
Et
+
+ CyBr
[Cu]
LN
+
Ph
1
B pin
2
2
77, 48%
3%
using 1.1 equiv of Cu/LP/LN:
90%
10%
2
. Radical clocksa
LP
Bpin
Et
(
2)
Ph
Et
+
[Cu]
Br
LN
1
Ph
B pin
2
2
68, 81%
LP
Bpin
Et
0% (78/79 6:4)
(
3)
+
[Cu]
LN
+
Bpin
Et
Ph
Et
Br
Ph
1
Ph
B pin
2
2
7
8
79
8
3
. Competition experimentsa
CyBr
(
1.5 equiv)
LP
Cy
Ph
Bpin
nBu
Bpin
Et
(
4)
Ph
Et
+
[Cu]
LN
+
nBuBr
Et
Ph
1
(1.5 equiv)
3
65
B pin
2
2
8
7% (3/65 4:6)
CyBr
(
1.5 equiv)
LP
Cy
Bpin
H
Bpin
Et
(
5)
Ph
Et
+
[Cu]
LN
+
iPrOH
Ph
Et
Ph
1
(1.5 equiv)
B pin
2
3, 73%
77, 13%
2
4
. Hydroboration as reaction intermediatea
LP
H
Bpin
Et
No reaction
(
6)
+
CyBr
[Cu]
LN
(77 recovered)
Ph
77
B pin
2
2
a
Reaction conditions: Alkyne (1 equiv), alkyl bromide (1.5 equiv), B2pin2 (1.5 equiv), CuCl (15 mol%), PBu3
t
(
8 mol%), P(p-C6H4-OMe)3 (8 mol%), 4,7-dimethyl-1,10-phenanthroline (LN1) (20 mol%), NaO Bu (1.6
equiv), THF (0.1 M), RT, 18 h. bStoichiometric conditions: Alkyne (1 equiv), alkyl bromide (1.5 equiv), B2pin2
t
(1.5 equiv), CuCl (1.1 equiv), PBu3 (0.6 equiv), P(p-C6H4-OMe)3 (0.6 equiv), LN1 (1.1 equiv), NaO Bu (1.6
equiv), TEMPO (1.5 equiv), THF (0.05 M), RT, 1 h.
Figure 8. Reaction mechanism: cross-coupling as a radical process
the results indicated in equations 1–3 provide strong support for the participation of
alkyl radicals in the C–C bond forming event of this process, as well as to the pro-
posed polar to radical crossover. Third, a competition experiment in the carbobora-
tion of 1 using primary nBuBr and CyBr in a 1:1 ratio resulted in a mixture of both car-
boboration products 3 and 65 in a similar ratio (Figure 8.3; equation 4, prim/sec 6:4),
corroborating the fast nature of the coupling process between vinyl-Cu and the
radical for primary and secondary carbon centers. Further support for this rapid pro-
cess was found in an experiment on model substrate 1 and CyBr in the presence of
i
1
.5 equivalents of PrOH (equation 5): Although these conditions are routinely used
in the literature to protonate the vinyl-Cu(I) intermediate and release the
2222 Chem 7, 2212–2226, August 12, 2021

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Boryl-Cu species V is more
reactive than IV, as shown by:
- stoichiometric experiments
if interaction
with phen not
fast enough
Formation/equilibration of heteroleptic and
homoleptic complexes
N
N
-Bond
metathesis
Cu Bpin
VII
or
H
Bpin
-
kinetic profiles
+
B2pin2
t
R3P Cu Bpin
t
R3P Cu O Bu
VI
+
PR3
+
CuCl
+ NaO Bu
- tBuOBpin
VIII
N
N
RDS
R3P Cu
Bpin
-
XNa
Ligand
association
IX
Polar mechanism
N
N
N
PR3
Cu
+ phen
V
Cu
X
+
R3P
X
N
Radical mechanism
IV
Ligand
N
N
dissociation
R3P Cu
Bpin
X
X
Cu
+ R
Bpin
N
+
PR3
N
N
R-X
N
N Cu
Bpin
XI
- PR3
PR3
Cu
N
XAT
XII
- phenanthroline facilitates
oxidation from Cu(I) to Cu(II)
- phosphine dissociation required
to create vacancy on Cu
X
-
inhibited by TEMPO
III
R
Bpin
XIII
-
triggers radical clocks
-
radical coupling faster than protonolysis
Figure 9. Mechanistic proposal
corresponding hydroboration product, we observed that the carboboration product
was still the major product (73%) and only 13% of the hydroboration product 77,
3
thus corroborating the very fast nature of the ligand exchange and radical coupling.
Furthermore, despite such a high product selectivity, carboboration and hydrobora-
tion exhibited rather similar reaction rates when performed separately, suggesting
that the alkyl coupling step is not the rate determining step. Finally, the participation
of 77 as an intermediate was ruled out by exposure to the carboboration conditions
(
Figure 8.4, equation 6), resulting in full recovery of the unreacted substrate. Further-
5
9
more, we ruled out the activation of the Cu catalyst by visible light after performing
the reaction of 1 in a topaz vial, which smoothly led to carboboration with a 82% yield
-
as opposed to 81% yield when the reaction was performed under visible light.
The information obtained from these experiments provides a general view of how the
multiligand system works. This global view, summarized in Figure 9, depicts a
disjunctive mechanism in which each ligand is responsible for one of the steps.
Initially, a mixture of either heteroleptic compound III or the corresponding ligands
and CuCl, dissolved in THF, undergoes ligand exchange processes on Cu(I) salts
that results in a mixture in which homoleptic and heteroleptic complexes are in dy-
namic equilibrium. This disproportionation results in borylative insertion across the
alkyne by the more effective phosphine-complex VIII, which is generated by reaction
t
between V and NaO Bu (VI), and then subsequent s-bond metathesis with B
2
pin
2
to
form vinyl-Cu(I) intermediate IX. This claim is further supported by the similar boryla-
tion rate of Cu/PR , regardless of the presence of L 1 (Figure 7.3), in contrast to the
poor performance of phosphine-free CuCl/L 1 system in the borylcupration of 1 (see
3
N
N
stoichiometric experiments in Figure 6). At this point, the low nucleophilic reactivity
of intermediate IX, which would undergo hydrolysis in the presence of a proton, is
switched into a highly reactive single-electron reductant X after addition of the N-
based ligand. We have studied this ligand exchange computationally and compared
6
0
61
our results with those reported by Jover on a related system described by Grushin
see section S2.10 for details and full discussion, Schemes S1–S3; Table S5). Our re-
sults show a system that is fully reversible, with relative energies of 0.0, 5.4, and
.5 kcal for compounds IX, X, and XI, respectively. The complexation with
(
3
Chem 7, 2212–2226, August 12, 2021 2223

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phenanthroline in the presence of an alkyl halide facilitates oxidation and stabilizes
6
2–64
65
Cu(II)
by halogen atom transfer (XAT), generating a free alkyl radical. This sin-
gle electron transfer process is a well-established inner-sphere mechanism and re-
quires an available coordinative vacant on Cu, which supports dissociation of labile
6
6,67
PR
3
ligand prior to XAT.
At this stage, a rapid collapse of the free radical with
the Cu(II) center and the subsequent C–C bond formation takes place to release
the tetrasubstituted vinylboronate. As evidenced in our study, steric hindrance de-
creases reactivity in radicals, which can be attributed to a lack of radical collapse be-
6
8
tween a bulky radical and a densely substituted Cu(II) center. Finally, a Cu(phen)X
complex is formed, which reenters the ligand exchange equilibria to reform the active
species upon coordination with a phosphine.
Conclusions
In this work, we have developed a polar/radical crossover strategy that is enabled by dy-
namic multiligand catalysis on a Cu center. This strategy has been applied to solve the
low nucleophilicity of vinyl-Cu(I) intermediates in carboborations of internal alkynes
with alkyl halides and provides a general method to assemble a wide variety of tetrasub-
stituted vinylboronates bearing carbo- and heterocyclic substituents. Based on the use
of inexpensive phosphines and phenanthrolines, the system is flexible and adjustable to
couple alkynes of different electronic nature with secondary alkyl bromides and iodides.
The reaction takes place with excellent regioselectivity, circumvents the loss of stereo-
chemical information associated to atom transfer radical addition (ATRA) processes,
and shows excellent functional group tolerance. Our study suggests that this method
operates on an unprecedented catalytic system capable of executing sequential alkyne
metalationpromotedbyphosphines, followedbycross-couplingviafastradicalcollapse
withthe Cu(II)center, whichis promotedby phenanthroline. Further studies on theappli-
cation of this approach to solve other relevant synthetic problems are underway.
EXPERIMENTAL PROCEDURES
Resource availability
Lead contact
Pablo Maule o´ n pablo.mauleon@uam.es
Materials availability
Stable reagents generated in this study will be made available upon reasonable
request, but we will require payment and/or a completed materials transfer agree-
ment if there is potential for commercial/industrial application.
Data and code availability
This study did not generate datasets or codes.
SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.chempr.
2
021.06.002.
ACKNOWLEDGMENTS
We thank the Ministerio de Ciencia e Innovaci o´ n (MICINN) and Fondo Europeo de
Desarrollo Regional (FEDER, UE) for financial support (Agencia Estatal de Investiga-
ci o´ n/project PGC2018-098660-B-I00). S.-H.K.-L. thanks the Ministerio de Educa-
ci o´ n, Cultura y Deporte for FPU fellowship. Professors Mariola Tortosa, Alexander
T. Radosevich, and Andreas Pfaltz are gratefully acknowledged for their comments.
We are most grateful to our colleague Professor Enrique G o´ mez-Bengoa (UPV/EHU)
2224 Chem 7, 2212–2226, August 12, 2021

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for his skilled and efficient computational studies on the equilibrium between spe-
cies IX–XI.
AUTHOR CONTRIBUTIONS
Investigation, methodology, and validation, S.-H.K.-L.; conceptualization and
writing – original draft, review, and editing, S.-H.K.-L., P.M., and R.G.A.; supervision,
P.M., R.G.A., and J.C.C.; funding acquisition, J.C.C.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: January 26, 2021
Revised: March 28, 2021
Accepted: June 2, 2021
Published: June 29, 2021
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