Role of dppf Monoxide in the Transmetalation Step of the Suzuki-Miyaura Coupling Reaction

Article abstract of DOI:10.1021/acs.organomet.1c00090

Diphosphine ligands are frequently used in palladium-catalyzed Suzuki-Miyaura (S-M) reactions. Despite their widespread application in both academic and industrial settings, their role in the B-to-Pd transmetalation has not been firmly established. We combined electrochemistry, NMR spectroscopy, and DFT calculations to elucidate the role of dppf (1,1′-bis(diphenylphosphino)ferrocene) in this key elementary step of the S-M reaction. We observed that excess dppf inhibits transmetalation involving PhB(OH)2 and dppf-ligated arylpalladium(II) complexes, while an optimal [base]/[PhB(OH)2] ratio maximizes the concentration of a [Pd-O-B] key intermediate. In situ oxidation of dppf to the diphosphine monoxide dppfO can take place in the presence of base, leading to dppfO-ligated arylpalladium(II) complexes, which readily undergo transmetalation at room temperature. These findings suggest guidelines for the rational optimization of diphosphine-promoted S-M reactions.

Full text of DOI:10.1021/acs.organomet.1c00090

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Article
Role of dppf Monoxide in the Transmetalation Step of the Suzuki−
Miyaura Coupling Reaction
Pierre-Adrien Payard,* Antoine Bohn, Damien Tocqueville, Khaoula Jaouadi, Emile Escoude, Sanaa Ajig,
Annie Dethoor, Geoffrey Gontard, Luca Alessandro Perego, Maxime Vitale, Ilaria Ciofini,*
Simon Wagschal,* and Laurence Grimaud*
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ABSTRACT: Diphosphine ligands are frequently used in palladium-
catalyzed Suzuki−Miyaura (S-M) reactions. Despite their widespread
application in both academic and industrial settings, their role in the
B-to-Pd transmetalation has not been firmly established. We
combined electrochemistry, NMR spectroscopy, and DFT calcu-
lations to elucidate the role of dppf (1,1′-bis(diphenylphosphino)-
ferrocene) in this key elementary step of the S-M reaction. We
observed that excess dppf inhibits transmetalation involving
PhB(OH)2 and dppf-ligated arylpalladium(II) complexes, while an
optimal [base]/[PhB(OH)2] ratio maximizes the concentration of a
[Pd−O−B] key intermediate. In situ oxidation of dppf to the diphosphine monoxide dppfO can take place in the presence of base,
leading to dppfO-ligated arylpalladium(II) complexes, which readily undergo transmetalation at room temperature. These findings
suggest guidelines for the rational optimization of diphosphine-promoted S-M reactions.
he metal-catalyzed cross-coupling of organoboron de-
rivatives with electrophiles, known as the Suzuki−
generally limits the rate of the overall cross-coupling process,
the TM step has been the subject of several thorough
mechanistic studies.
T
Miyaura (S-M) reaction, has become one of the most
important synthetic transformations in modern organic
chemistry.1,2 It is widely applied on an industrial scale to
manufacture active pharmaceutical ingredients and fine
chemicals.3 The mechanism of this reaction has been the
subject of several experimental and theoretical studies.4−7 As
displayed in Scheme 1, it is generally admitted to involve three
elementary steps: an oxidative addition (OA), a trans-
metalation (TM), and a reductive elimination (RE). As it
The TM can either proceed through the addition of the
boronate [Ar′B(OH)3]− to the OA product5b,6a−d,g−k or from
the association of the boronic acid with the Pd hydroxo
complex (Scheme 1).5g−i,l The rate of this step can be finely
tuned by the base/boronic acid ratio,5g,i,l and the Denmark
group gave the first experimental evidence of the key
intermediate, the heterobimetallic [Pd−O−B] key species,
which completed the description of the mechanistic scenario
(Scheme 1).5b,n,o,q
Diphosphines such as 1,1′-bis(diphenylphosphino)ferrocene
(dppf), 1,2-bis(diphenylphosphino)ethane (dppe), and 1,3-
bis(diphenylphosphino)propane (dppp) are commonly used
ligands in palladium-catalyzed Suzuki−Miyaura cross-cou-
plings.1k The mechanistic picture emerging from existing
studies, which have almost exclusively focused on monodentate
phosphine ligands, is difficult to extend to chelating
diphosphines in a straightforward manner.
Scheme 1. General Mechanism of the S-M Cross-Coupling
Reaction
Received: February 14, 2021
Published: April 12, 2021
https://doi.org/10.1021/acs.organomet.1c00090
© 2021 American Chemical Society
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In particular, a mechanistic model should explain how
bidentate ligands can accommodate the formation of the key
[Pd−O−B] and [Pd−O−B]′ species, both of which are
necessary for the TM to occur according to the mechanism
reported in Scheme 1. This issue has not been addressed
systematically in the literature. Denmark and co-workers
observed a slightly reduced transmetalation rate when dppf
was employed instead of PiPr3 and conjectured the need of
generating a coordinatively unsaturated intermediate,5o whose
nature could not be firmly established. A theoretical study
focusing on the S-M reaction promoted by complexes of the
model ligand H2PCH2CH2PH2 investigated only an associative
mechanism, for which very high energy barriers were
computed.6f
These two reports and the frequent use of diphosphine
ligands in S-M cross-couplings prompted us to investigate the
B-to-Pd transmetalation in the case of diphosphines. We
observed that the oxidation of dppf, a diphosphine widely used
in S-M reactions applied to the total synthesis of natural
products,1 could take place under conditions mimicking a
typical catalytic reaction, yielding the monoxide dppfO. Our
results highlight the potentially crucial role of this in situ
generated species in diphosphine-mediated S-M reactions
(Scheme 2).8
which corresponds to a difference in activation energy of
approximately 3 kcal mol−1. These observations indicate that
dppf strongly inhibits B-to-Pd transmetalation. The TM turns
out to be the second elementary step of the S-M reaction to be
inhibited by excess dppf, as it has been shown that extra
diphosphine also inhibits OA by hampering the formation of
the reactive 14-electron complex [Pd0(dppf)].11
To rationalize these kinetic results, we estimated the energy
barriers of the TM by DFT calculations (see the computational
details in the Supporting Information) (Figure 1C and Figure
S6). The slower TM rate with dppf in comparison to that with
PPh3 could possibly be due to a dissociative mechanism, in
contrast with the working hypothesis previously formulated by
Huang et al.6f Indeed, as first demonstrated by Goossen and
Thiel,6c the TM with PPh3-ligated Pd(II) requires partial
phosphine decoordination and takes place via a four-centered
transition state involving the concerted formation of a Pd−C
bond and cleavage of Pd−B bonds. Similar behavior is
predicted for dppf (Figure 1C and Figure S6).
With the complex [Pd−O−B] as the starting point (A), the
cleavage of one P−Pd bond can be assisted by one OH of the
boronate moiety to form complex B. This release is
endothermic (+12.8 kcal mol−1) and almost entropically
neutral (+9.8 cal mol−1 K−1), leading to an overall endergonic
process. For comparison, the same process involving PPh3 lies
2.6 kcal mol−1 lower in energy (+7.3 kcal mol−1), driven by the
strong positive entropic contribution (+59.3 cal mol−1 K−1).
Nonetheless, complex B cannot directly take part in TM since
the phenyl moiety on the boron center is too far from the Pd
center (dC−Pd = 3.42 Å). Therefore, prior to TM a ligand
exchange between the OH and Ph linked to the boron atom is
required, leading to the formation of complex C. The two pre-
TM complexes C-cis (+12.8 kcal mol−1) and C-trans (+15.7
kcal mol−1) can be formed depending on the relative position
of the two aromatic rings with respect to the Pd center. For
clarity, in the main text and figures we will refer only to the
most stable cis conformer, while all data corresponding to the
trans conformer are available in the Supporting Information. In
the case of dppf, both isomers are 4−5 kcal mol−1 higher in
free energy in comparison to the PPh3 analogues. Finally, both
cis and trans transition states were optimized, lying at 24.5 and
27.5 kcal mol−1, respectively. The energy barrier for phosphine
decoordination directly affects these transition states. In the
case of PPh3, the most favorable TS-cis was localized at +21.9
kcal mol−1, i.e. about 3 kcal mol−1 lower in comparison to dppf,
corresponding roughly to a factor of 102 on the kinetics of the
reaction.13 Both experimental and theoretical studies thus
point toward a slower transmetalation rate when diphosphine
ligands are used. However, when the formation of the coupling
product Ar-Ph was monitored in the absence of added dppf,
the reaction proceeded more quickly, and it was essentially
complete after 30 min (Figure 1B, black curve). In the latter
case, the kinetic curve of formation of Ar-Ph displayed an
induction period, which is either typical of an autocatalytic
reaction or hints at the in situ generation of an active species
from a less reactive precursor.10 The induction period varies
from nearly 1 h at low base concentration to a few seconds at
high base concentration (Figure S23). This is in agreement
with the instantaneous reaction reported by Denmark and co-
workers,5n as the TM was studied starting from complex 3 with
1 equiv of boronic acid (corresponding to [OH−]/[PhB-
(OH)2] = 1). Consistent with the concentration profiles
(Figure 2C), this induction period probably results from the
Scheme 2. Hypothesis on the Tole of dppfO in S-M
Reactions Proposed in This Paper
RESULTS AND DISCUSSION
■
The oxidative addition complex cis-[PdII(Ar)Br(dppf)] (2, Ar
= 4-F-C6H4) was prepared by ligand exchange between trans-
[PdII(Ar)Br(PPh3)2] (1) and dppf (Figure 1A) to study TM
involving PhB(OH)2 using tetrabutylammonium hydroxide
(TBAOH) as a base.
Inhibiting Effect of Extra Diphosphine on the TM. We
first investigated the effect of excess ligand on the B-to-Pd TM
starting from either the OA complex 1 or 2 and different
amounts of added PPh3 or dppf. The ratio [OH−]/[PhB-
(OH)2] ≈ 0.6 (6 equiv/10 equiv) previously reported to
maximize the TM rate in the case of PPh3-ligated complexes
was used.5g The formation of the coupling product Ar-Ph was
monitored by 19F{1H} NMR spectroscopy (Figure 1B).9
In the case of complex 1 in the presence of additional PPh3
(2 equiv), the coupling reaction was almost complete after 10
min (Figure S5a). Formation of Ar-Ph followed a first-order
law with an apparent rate constant of kapp = 3.3 × 10−3 s−1.5g
No intermediate could be detected in this case, in agreement
with TM being rate determining.5g In stark contrast, in the case
of complex 2, in the presence of 1 equiv of dppf (Figure 1B,
green curve), TM was very slow and only 20% conversion was
observed after 90 min. Under these conditions, the kinetics
could be fitted by a first-order rate law and the apparent rate
constant was estimated to be kapp = 3.2 × 10−5 s−1 (Figure
S5d). The ratio between the two rate constants is about 100,
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Figure 1. (A) Synthesis of complex 2 by ligand exchange from 1. (B) Reaction monitoring of the formation of 4-fluoro-1,1′-biphenyl from 2 (20
mM in DMF) with PhB(OH)2 (10 equiv) and 6 equiv of TBAOH (1.5 M in H2O) at 20 °C, in the presence of varying amounts of dppf. (C) The
most favored pathways for the TM and RE with dppf and PPh3 as ligands (see Figure S6 for the alternative trans pathway), studied by DFT
calculations. Computed relative Gibbs free energies are reported in kcal mol−1 at 298 K. Enthalpies (kcal mol−1) and entropies (cal K−1 mol−1) are
reported in parentheses.
formation of a reactive species generated from either complex
3 or 4. To shed light on this surprising behavior, we
investigated in more detail the nature of the potential
intermediates of the dppf-mediated S-M coupling.
using i-Pr3P as the ligand (Figures S12−S19).5o The 31P{1H}
NMR titration of a solution containing complex 2 and 10 equiv
of PhB(OH)2 with TBAOH demonstrated that the optimal
[OH−]/[PhB(OH)2] ratio is about 0.5−0.6 so as to maximize
the formation of the productive intermediate 4 (Figure 2B). It
is worth noting that this optimal ratio can also vary depending
on the quantity of boroxine present as an impurity in the
boronic acid (Figures S20 and S21).4b
Intermediates of the TM Step. When it is treated with
TBAOH at −20 °C, complex 2, characterized by its reduction
potential R2 at −1.75 V vs SCE in DMF, evolved to a new
complex with a reduction peak R3 at −2.2 V (Figure 2A and
Figure S8). This new peak was assigned to the corresponding
hydroxo complex [PdII(Ar)(OH)(dppf)] (3), and the
structure was confirmed by 31P{1H} and 19F{1H} NMR
(Figures S9−S11).5o While the hydroxo complex 3 was stable
at −20 °C, it rapidly decomposed at room temperature in the
absence of PhB(OH)2, thereby generating dppfO, as attested
by CV showing the characteristic reduction peak of the latter
compound (R5 at −2.46 V vs SCE, Figure 2D). At the same
time, the formation of fluorobenzene and 4-fluoro-1,1′-
biphenyl was also observed by 19F{1H} NMR (Figures S10
and S24). In analogy with the well-described reduction of
Pd(II) precatalysts in basic media,12 complex 3 probably
evolved through a reductive elimination to give dppfO-ligated
Pd(0) along with the protodemetalation product Ar-H and the
homocoupling product Ar-Ar, which were detected by 19F{1H}
NMR (Figure 2D).14
The TM process was monitored by 19F{1H} NMR using a
ratio [OH−]/[PhB(OH)2] = 0.5. Immediately after the
addition of TBAOH, both 3 and 4 could be observed (Figure
2C, red curve), while some of the starting complex 2 remained
(Figure 2C, blue curve). After an induction period of about 25
min, the cross-coupling product rapidly formed (Figure 2C,
black curve). Interestingly, the additional intermediate Pd(II)
complex 5 could be detected as a triplet at −124.4 ppm
(Figure 2C, orange curve). Complex 5 accumulated during the
reaction monitoring in parallel with a dramatic increase of the
TM reaction rate (orange curve, Figure 2C). This behavior
seems to point to complex 5 as being the active form of aryl-Pd
toward transmetalation.
Role of Diphosphine Monoxide dppfO. To assess the
potential catalytic role of dppfO or dppfO-ligated Pd species
and shed light on the structure of complex 5, the TM in the
presence of 0.15 equiv of dppfO was studied (Figure 3B,
purple curve). An induction period similar to that observed in
the absence of additives was found (Figure 3B, blue curve).
Importantly, the effect of extra dppfO is less pronounced than
that of dppf (Figure 3B, green curve). This suggests that the
When PhB(OH)2 was added to the in situ generated
[PdII(Ar)(OH)(dppf)] (3), the new reduction peak R4 was
detected at −2.09 V vs SCE (Figure 2A). The latter was
attributed to the formation of the mixed complex [Pd−O−B]
(4), in analogy with the data reported by the Denmark group
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Figure 2. (A) CV performed toward the reduction potentials of a DMF solution containing 0.1 M of TBABF4 at −20 °C at a scan rate of 0.2 V s−1
with 2 (2 mM) (blue), with 2 equiv of TBAOH (1.5 M in H2O) (red), and after addition of PhB(OH)2 (3.3 equiv corresponding to a ratio [base]/
[boronic acid] of 0.6) (green). (B) 31P{1H} NMR of a solution of complex 2 (20 mM) in DMF in the presence of PhB(OH)2 (10 equiv), upon
increasing the amount of TBAOH (1.5 M in H2O). A coaxial insert containing a solution of H3PO4 in DMSO-d6 was used for locking and as an
internal standard for integration. (C) Reaction monitoring of complex 2 (10 mM in DMF) with PhB(OH)2 (10 equiv) in the presence of TBAOH
(5 equiv) at 20 °C, monitored by 19F{1H} NMR. (D) Formation of dppfO from 2 and 3 (Ar = 4-F-C6H4). CV performed toward the reduction
potentials of a DMF solution containing 0.1 M of TBABF4 at rt, at a scan rate of 0.2 V s−1 with isolated complex 3 (2 mM (red) and after 4 min
(brown) and CV of 2 mM of isolated dppfO (black).
19F{1H} NMR (Figure S31) and no induction period was
addition of dppfO alone does not lead to an active species.
When 0.1 equiv of Pd0(dba)2 was introduced (with or without
apparent in this case (Figure 3B). This suggested that complex
0.1 equiv of dppfO; Figure 3B, black and brown curves), no
induction period could be detected and both reactions were
complete within less than 20 min. In both cases, the
protodemetalation product Ar-H and the homocoupling
product Ar-Ar were observed, suggesting the concomitant
decomposition of 3.
We hypothesized that the presence of Pd(0) promotes the
dppf/dppfO ligand exchange to form the less coordinated
dppfO-ligated aryl-Pd(II) complex. When in situ generated
[Pd0(dppfO)2] (prepared by mixing Pd0(dba)2 and dppfO,
vide infra) was added to a DMF solution of complex 2, the
31P{1H} spectrum was quite complex, most probably due to a
rapid exchange of ligands on the NMR time scale, but the
signal corresponding to complex 5 was clearly observed by
5 is the active complex for TM and that it is formed in the
presence of dppfO-ligated Pd0.
A CV analysis of a mixture Pd0(dba)2 with 2 equiv of dppfO
demonstrated that a stoichiometric amount of dppfO was able
to displace all of the dba from the coordination sphere of
Pd(0) (Figures S25−S27), thus suggesting a strong affinity of
dppfO for Pd(0). This contrasts with what was observed with
dppf, since the addition of 2 equiv of dppf on Pd0(dba)2
resulted in the formation of the mixed complex [Pd0(dba)-
(dppf)] (Figure S28).11a The resulting [Pd0(dppfO)2] was
characterized for the first time by 31P{1H} NMR (Figure S29)
and by CV (oxidation peak O1 at +0.5 V vs SCE). This peak
disappeared after addition of an excess of 4-F-C6H4Br,
confirming that this Pd(0) species is able to perform the
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Figure 3. (A) Oxidative addition with Pd0(dppfO)2. (B) 19F{1H} NMR monitoring of the formation of 4-fluoro-1,1′-biphenyl from 2 (20 mM in
DMF) with 10 equiv of PhB(OH)2 and 6 equiv of TBAOH at 20 °C. (C) 19F{1H} NMR monitoring of the formation of 4-fluoro-1,1′-biphenyl
from 2 (blue, 10 mM in DMF) and 5 (orange, 10 mM in DMF), both with 10 equiv of PhB(OH)2 and 6 equiv of TBAOH at 20 °C. (D) Pathway
for the TM process with dppfO as the ligand studied by DFT calculations. Computed relative Gibbs free energies are reported in kcal mol−1 at 298
K. Enthalpies (kcal mol−1) and entropies (cal K−1 mol−1) are reported in parentheses.
initial OA step (Figure S30).15 [PdII(Ar)Br(dppfO)2] could be
the RE step was also predicted to be faster with
monocoordinated dppfO-ligated Pd species in comparison to
the dppf analogue (Figure S35).
1
prepared and characterized by H, 13C, 19F{1H}, and 31P{1H}
NMR and by ESI-MS (Figure 3A and Figure S2−4). Spectral
data of this complex were identical with those of the previously
observed complex 5 (vide supra, Intermediates of the TM
Step), which kinetics data indicated as a crucial intermediate.
When isolated complex 5 was treated with PhB(OH)2 and
TBAOH, no induction period was observed and the TM was
completed within 10 min (Figure 3C and Figure S32).
DFT calculations further confirmed that TM is favored with
dppfO in comparison to TM with dppf (Figure 3D versus
Figure 1D). In agreement with the experimental results, the
ligand exchange reaction between [Pd0(dppfO)] and the dppf-
ligated [Pd−O−B] to form dppfO-ligated complex A′ is only
slightly endergonic (+4.1 kcal mol−1) and the formation of
complex B′ is favored (−9.7 kcal mol−1). Coordination of the
aromatic moiety to form complexes cis- or trans-C′ is even
more favorable, and as expected, the transition states for the
TM step are very low lying (+7.2 and +11.2 kcal mol−1 for the
cis and trans isomers, respectively), accounting for the high
activity of hemilabile-ligated Pd species for TM. Additionally,
CONCLUSIONS
■
This work addressed three key points regarding the use of
diphosphine ligands in the Suzuki-Miyaura reaction concerning
(i) their effect on TM rate, (ii) the need for decoordination
prior to TM, and (iii) the possible inhibitory effects of
diphosphine ligands. In the course of our study, we observed
that TM involving [PdIIArBr(dppf)] and PhB(OH)2 in the
presence of OH− proceeds with an induction period,
suggesting that this complex needs to be converted to a
more reactive species, which could be the actual intermediate
of the catalytic cycle in S-M reactions. We have proved that
dppf actually inhibits the TM, and DFT calculations pointed
out the need of partial decoordination of dppf for the TM to
occur. Moreover, we showed that the dppfO generated from
the in situ oxidation of dppf has a high affinity for Pd(0)
species. Pd0(dppfO)2 is able to perform oxidative addition to
ArBr to give a dppfO-ligated aryl-Pd(II), which in turn is very
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reactive in the TM with PhB(OH)2, as confirmed both
experimentally and theoretically.
France; orcid.org/0000-0001-5661-6128; Email: pierre-
adrien.payard@univ-lyon1.fr
Finally, this study accounts for the widespread use of
[PdII(dppf)Cl2] as a precatalyst for Suzuki−Miyaura cross-
couplings, which is a direct precursor of dppfO-ligated Pd(0).
The diphosphine ligand is required for the reduction of most
commercially available Pd(II) precatalysts,12 but diphosphine
monoxides could constitute efficient ligands to stabilize Pd(0)
species and promote both the oxidative addition and the
transmetalation steps.
Ilaria Ciofini − PSL University, Institute of Chemistry for
Health and Life Sciences, I-CLeHS, CNRS-Chimie ParisTech,
F-75005 Paris, France; orcid.org/0000-0002-5391-
4522; Email: ilaria.ciofini@chimie-paris.psl.eu
Simon Wagschal − Discovery Product Development and
Supply, Janssen Pharmaceutica, 8200 Schaffhausen,
Switzerland; orcid.org/0000-0003-1979-5838;
Email: swagscha@its.jnj.com
Laurence Grimaud − Laboratoire des Biomolécules, LBM,
́
Département de Chimie, Ecole Normale Supérieure, PSL
COMPUTATIONAL DETAILS
■
University, Sorbonne Université, CNRS, 75005 Paris,
France; orcid.org/0000-0003-3904-1822;
Email: laurence.grimaud@ens.psl.eu
All DFT calculations were performed using the Gaussian 09 program
(Rev. A02).16 The structures of all minima and transition states were
optimized using the M06 functional17 and the following basis sets:
6-31G for C, H, F, and B; 6-31+G(d) for O and P; LANL2DZ for Pd
and Fe with the associated effective core potential LANL2.18 Bulk
solvent effects were taken into account using the PCM method as
implemented in Gaussian.19 The default cavity parameters and static
and optical dielectric constants for DMF were used. The nature of all
stationary points was checked by analytical frequency calculations.
Computed harmonic frequencies were employed to calculate free
energies at 298 K and 1 atm pressure with the usual approximations.
Authors
Antoine Bohn − Laboratoire des Biomolécules, LBM,
́
Département de Chimie, Ecole Normale Supérieure, PSL
University, Sorbonne Université, CNRS, 75005 Paris, France
Damien Tocqueville − Laboratoire des Biomolécules, LBM,
́
Département de Chimie, Ecole Normale Supérieure, PSL
University, Sorbonne Université, CNRS, 75005 Paris, France
Khaoula Jaouadi − Laboratoire des Biomolécules, LBM,
EXPERIMENTAL SECTION
́
■
Département de Chimie, Ecole Normale Supérieure, PSL
Synthesis of [Pd0(dppfO)2(4-F-C6H4)(Br)] (5). The reaction was
carried out under argon. To a stirred mixture of [Pd0(dba)2] (50 mg,
0.087 mmol) in degassed CH2Cl2 (5 mL) were added 1-bromo-4-
fluorobenzene (95 μL, 0.7 mmol) and 2.1 equiv of dppfO20 (104 mg,
0.18 mmol). After vigorous stirring at ambient temperature (red-
brown solution), the flask was fitted with a reflux condenser and
heated in an oil bath at 50 °C overnight. The reaction mixture was
warmed to room temperature, an then the solution was evaporated to
a volume of approximately 1 mL and treated with degassed petroleum
ether (5 mL). The dark red precipitate was filtered underan inert
atmosphere, washed with petroleum ether, and dried in vacuo to
produce complex 5 (100 mg, 80%). 31P{1H} NMR (121 MHz,
DMF): δ 25.3 (br s), 16.1 (d, JP-F = 3.0 Hz) ppm. 19F{1H} NMR
(282 MHz, DMF): δ = −124.4 (t, JP−F = 3.0 Hz) ppm. MS (ESI+,
MeCN) m/z (%): 1341.1 (100) [(M − Br)+].
University, Sorbonne Université, CNRS, 75005 Paris, France
Emile Escoude − Laboratoire des Biomolécules, LBM,
́
Département de Chimie, Ecole Normale Supérieure, PSL
University, Sorbonne Université, CNRS, 75005 Paris, France
Sanaa Ajig − Laboratoire des Biomolécules, LBM,
́
Département de Chimie, Ecole Normale Supérieure, PSL
University, Sorbonne Université, CNRS, 75005 Paris, France
Annie Dethoor − Laboratoire des Biomolécules, LBM,
́
Département de Chimie, Ecole Normale Supérieure, PSL
University, Sorbonne Université, CNRS, 75005 Paris, France
Geoffrey Gontard − Institut Parisien de Chimie Moléculaire,
CNRS UMR 8232, Sorbonne Université, 75252 Paris, France
Luca Alessandro Perego − Discovery Product Development
and Supply, Janssen Pharmaceutica, 8200 Schaffhausen,
Switzerland; orcid.org/0000-0002-6502-3268
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.organomet.1c00090.
■
Maxime Vitale − Laboratoire des Biomolécules, LBM,
sı
́
Département de Chimie, Ecole Normale Supérieure, PSL
University, Sorbonne Université, CNRS, 75005 Paris,
France; orcid.org/0000-0002-6740-2472
Cartesian geometries and absolute energies (XYZ)
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.organomet.1c00090
Experimental 31P NMR chemical shifts and calculated
shielding constants and additional data on the effect of
computational parameters on structures and shielding
constants (PDF)
Notes
The authors declare no competing financial interest.
Accession Codes
ACKNOWLEDGMENTS
■
CCDC 1993547 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
P.-A.P. is grateful to the ENS Paris Saclay and Solvay for a
Ph.D. grant. We acknowledge Dr. D. Lesage for the mass
spectrometry analyses. K.J. thanks ANR-17-CE07-0018 Hyper-
Silight for Ph.D. grant. We thank Prof. A. Boutin, P. J. Yao, and
Dr. Q. Chen for useful discussions. We thank Janssen
Pharmaceutica and Bristol-Myers Squibb for funding the
project.
AUTHOR INFORMATION
Corresponding Authors
Pierre-Adrien Payard − Laboratoire des Biomolécules, LBM,
Département de Chimie, Ecole Normale Supérieure, PSL
■
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mol−1). In both cases, the RE is much faster than the TM, confirming
the latter to be the RDS.
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