Enantioconvergent nucleophilic substitution via synergistic phase-transfer catalysis

Abstract

Catalytic enantioconvergent nucleophilic substitution reactions of alkyl halides are highly valuable transformations, but they are notoriously difficult to implement. Specifically, nucleophilic fluorination is a renowned challenge, especially when inexpensive alkali metal fluorides are used as fluorinating reagents due to their low solubility, high hygroscopicity and Brønsted basicity. Here we report a solution by developing the concept of synergistic hydrogen bonding phase-transfer catalysis. Key to our strategy is the combination of a chiral bis-urea hydrogen bond donor (HBD) and an onium salt—two phase-transfer catalysts essential for the solubilization of potassium fluoride—as a well-characterized ternary HBD–onium fluoride complex. Mechanistic investigations indicate that this chiral ternary complex is capable of enantiodiscrimination of racemic benzylic bromides and α-bromoketones, and upon fluoride delivery affords fluorinated products in high yields and enantioselectivities. This work provides a foundation for enantioconvergent fluorination chemistry enabled through the combination of a HBD catalyst with a co-catalyst specifically curated to meet the requirement of the electrophile.

Full text

Nature Catalysis | Volume 8 | February 2025 | 107–115 107
nature catalysis
https://doi.org/10.1038/s41929-024-01288-0
Article
Enantioconvergent nucleophilic
substitution via synergistic phase-transfer
catalysis
Claire Dooley 1, Francesco Ibba 1, Bence B. Botlik1, Chiara Palladino1,
Christopher A. Goult 1, Yuan Gao 2, Andrew Lister3, Robert S. Paton 4 ,
Guy C. Lloyd-Jones 2 & Véronique Gouverneur 1
Catalytic enantioconvergent nucleophilic substitution reactions of alkyl
halides are highly valuable transformations, but they are notoriously
dicult to implement. Specically, nucleophilic uorination is a renowned
challenge, especially when inexpensive alkali metal uorides are used as
uorinating reagents due to their low solubility, high hygroscopicity and
Brønsted basicity. Here we report a solution by developing the concept of
synergistic hydrogen bonding phase-transfer catalysis. Key to our strategy
is the combination of a chiral bis-urea hydrogen bond donor (HBD) and an
onium salt—two phase-transfer catalysts essential for the solubilization of
potassium uoride—as a well-characterized ternary HBD–onium uoride
complex. Mechanistic investigations indicate that this chiral ternary
complex is capable o f e na nt io di sc ri mination of racemic benzylic bromides
and α-bromoketones, and upon uoride delivery aords uorinated
products in high yields and enantioselectivities. This work provides a
foundation for enantioconvergent uorination chemistry enabled through
the combination of a HBD catalyst with a co-catalyst specically curated to
meet the requirement of the electrophile.
Nucleophilic substitutions represent a class of foundational reactions
in organic synthesis. Enantioconvergent catalytic variants whereby
racemic starting materials can be converted into enantiopure prod-
ucts are synthetically valuable, but difficult to implement. Studies by
Jacobsen
1
, List
2
and Sun
3
have enabled enantioconvergent substitu-
tions for carbon–carbon, carbon–nitrogen and carbon–oxygen bond
formation via the intermediacy of achiral carbocations (unimolecular
nucleophilic substitutions (SN1)) (Fig. 1a). Enantioconvergent bimolecu-
lar nucleophilic substitution (S
N
2) reactions are also known and feature
highly reactive electrophiles, such as carbonyls alpha substituted with
a leaving group—a class of substrates prone to racemization and there-
fore allowing for dynamic kinetic resolutions
4,5
. A recent report by
Sun6 demonstrates this principle with the enantioselective chlorina-
tion of α-keto sulfonium salts under liquid–liquid phase transfer with
NaCl (aq.) in the presence of a chiral thiourea hydrogen bond donor
(HBD) catalyst (Fig. 1a)6. Solutions that are based on more uncon-
ventional mechanistic scenarios have also been disclosed, includ-
ing a halogenophilic SN2X manifold, as well as elegant transition
metal-catalysed and photoredox cross-coupling reactions involving
radical intermediates (Fig. 1a)7–10.
The development of an enantioconvergent fluorination presents
its own challenges, especially when the nucleophile is an alkali metal
fluoride including poor solubility in organic solvents and competitive
elimination pathways
11,12
. The use of crown ethers or onium salts as
Received: 30 September 2024
Accepted: 23 December 2024
Published online: 13 February 2025
Check for updates
1Chemistry Research Laboratory, University of Oxford, Oxford, UK. 2School of Chemistry, University of Edinburgh, Edinburgh, UK. 3Oncology R&D,
AstraZeneca, Cambridge, UK. 4Department of Chemistry, Colorado State University, Fort Collins, CO, USA. e-mail: robert.paton@colostate.edu;
guy.lloyd-jones@ed.ac.uk; veronique.gouverneur@chem.ox.ac.uk
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Nature Catalysis | Volume 8 | February 2025 | 107–115 108
Article https://doi.org/10.1038/s41929-024-01288-0
as catalysts to solubilize alkali metal fluorides to form chiral F− species,
this has been largely employed for desilylative kinetic resolution pro-
tocols, which take advantage of the strength of Si–F bonds15,16. Similar
desilylation strategies were implemented to unmask nucleophilic func-
tionalities allowing for asymmetric C–C bond formation17. However, the
phase-transfer catalysts is a well-established way to increase the solubil-
ity of fluoride salts (KF and CsF) for halide substitution and is commonly
applied in the syntheses of fluorochemicals such as fluoroarenes via
nucleophilic aromatic substitution (S
N
Ar) chemistry
13,14
. It is notewor-
thy that although chiral polyether and ammonium salts have been used
Enantioconvergent approaches for nucleophilic substitutiona
R2
R1
R3
LG cat*
Nu
Racemate
Cat*
Enantioenriched
Enantioconvergent SN1 process
R1
R2R3LG
R1
R2
R3
Nu
Nu
Nu = [O], [N], [C]
R
Ref. 1
Example
Ref. 2
TMS
NH
Ar
OH
Ref. 3
Enantioconvergent SN2 process
R1
O
SPh2
R2
BF4
R1
O
SPh2
R2
R1
O
SPh2
R2
Cl
Cl
R1
O
R2
Cl
DKR
Enantioenriched
NaCl(aq.)
HBD cat*
Ref. 6
Solvent
–
*
*
–
*
Halogenophilic (SN2X) reaction
Radical nucleophilic substitution
R1
R2R3
X
Cat*
Nu R1
R2R3XNu R1
R2R3
Nu X
Chiral cation
Racemate Enantioenriched
R2HN
O
X
R1R2
R2HN
O
Nu
R1R2
[Cu] L*
(cat*)
hν
Racemate Enantioenriched
Ref. 7
Ref. 8
R2HN
O
R1
R2
via
+
–
R1
R2R3
Nu
Nu
+
[L*Cu(III)Nu]X
R1
R1
X
YHBD cat*
KF (solid)
R1
R1
F
Y
Up to 98%; 97:3 e.r.
Desymmetrization of meso-onium electrophiles with MF (HBPTC)
F
R1
R1
Y
Novel catalytic approach for asymmetric fluorination with alkali metal fluoride salts
Limited scope of onium ion electrophiles
Racemate Enantioenriched
Onium ion
precursor
(−KX (solid))
For example, refs. 18,19
b
Transient ion pair between
electrophile and fluoride
R1
R1
S
R2
R1
R1
NR2
R2
Meso-onium
electrophile
–
*
*
R3 = iPr, Et
R4 = CF3, 3,5-(CF3)C6H3
HBD catalyst:
Enantioconvergent fluorination under synergistic phase-transfer catalysis (this work)
R1R2
Br
R1R2
F
Synergistic
PTC for solubilization of KF
Fluorination of non-meso and non-onium electrophiles: benzylic halides and α-haloketones
Enantioenriched
FBr
R1
HR2
QR4
HBD cat*
QR4X
Onium
co-catalyst
c
R1R2
Br
Stabilized chiral
F–reagent
KF(solid) ++
QR4X
Synergistic phase-transfer catalysis
Insoluble
fluoride salt
Substrate racemization
*
*
*
Up to 99%; 97:3 e.r.
Ar R1
F
Ar
O
R1
F
Up to 97%; 98:2 e.r.
N
H
N
O
N
H
O
H
NR4
R4
R4
R4
R3
Fig. 1 | Enantioconvergent approaches for nucleophilic substitution.
a, Nucleophilic substitution via SN1, SN2, SN2X, transition metal-catalysed and
photoredox mechanisms. b, HBPTC for the desymmetrization of meso-
onium-type electrophiles with alkali metal fluoride salts (MF). c, S-HBPTC
(this work): enantioconvergent nucleophilic substitution of benzylic bromides
and α-haloketones with KF and two phase-transfer catalysts (a chiral HBD and an
achiral onium salt). hv, visible light; cat*, chiral catalyst; DKR, dynamic kinetic
resolution; TMS, trimethylsilyl; Nu, nucleophile; LG, leaving group.
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Nature Catalysis | Volume 8 | February 2025 | 107–115 109
Article https://doi.org/10.1038/s41929-024-01288-0
application of phase-transfer catalysis to asymmetric C–F bond forma-
tion remains underdeveloped. Our group disclosed hydrogen bond-
ing phase-transfer catalysis (HBPTC), which exploits the principles
of anion-binding catalysis as a solution for asymmetric nucleophilic
fluorination with alkali metal fluorides
18
. Chiral bis-urea catalysts were
developed, which bring these solid fluoride salts into solution, thereby
controlling the reactivity of the resulting hydrogen-bonded fluoride
ion and allowing for enantioselective fluorination of selected substrate
classes. HBPTC is currently limited to asymmetric desymmetrization
of onium-type electrophiles, including meso-episulfonium and aziri-
dinium salts (generated in situ from the corresponding alkyl halides
(Fig. 1b)
18,19
) or preformed achiral azetidinium salts
20
. Mechanistic
investigations have highlighted the importance of ion pairing between
these onium electrophiles and urea fluoride complexes for successful
fluorination under HBPTC with either CsF (lattice energy = 759 kJ mol
−1
;
US$72 mol−1) or the inexpensive but more energetically demanding salt,
KF (lattice energy = 829 kJ mol
−1
; US$8 mol
−1
)
21,22
. The extension of this
methodology to alkyl halides other than precursors of meso-onium
salts represents a notable challenge both in terms of reactivity and
enantioselectivity. In this Article, we disclose a solution to this problem
with the invention of synergistic HBPTC (S-HBPTC), a catalytic manifold
enabling the enantioconvergent substitution of racemic alkyl halides
with potassium fluoride.
In this scenario, two organocatalysts comprising a chiral HBD and
an achiral onium salt facilitate substrate racemization and contribute
to a catalytic cycle leading to a chiral HBD–onium fluoride ion pair for
enantioconvergent fluorination (Fig. 1c). This method grants access to
enantioenriched benzylic fluorides and α-fluoroketones—a valuable
synthetic advance considering the ubiquity of benzylic stereogenic
centres in pharmaceutical design and the well-known versatility of
ketones in synthesis23,24.
Results
Reaction development
We initially investigated the propensity of the secondary benzylic
bromide rac-1a to undergo reaction with CsF in toluene, under HBPTC
by the bis-urea (S)-3a. Although only trace conversion occurred at
room temperature, at 60 °C the reaction gave benzylic fluoride (R)-
2a (38%; 74:26 e.r.) and alkene 4a in an approximately equal ratio
(Fig. 2a, entry 1). The soluble fluoride source tetrabutylammonium
fluoride generated racemic 2a and the alkene 4a, also in a 1:1 ratio,
under otherwise similar reaction conditions (Supplementary Table 1).
In contrast, no reaction was observed with KF in place of CsF (Fig. 2a,
entry 2), thus NMR experiments were conducted to compare the
ability of the bis-urea catalyst (S)-3a to bring solid CsF and KF into
solution (toluene-d
8
).
1
H NMR spectroscopic analysis of bis-urea (S)-
3a after the addition of CsF revealed strong binding of the fluoride
ion, as indicated by the diagnostic deshielding (ΔδNH = 2–4 ppm) and
1H–19F scalar coupling (1hJNH–F = 60, 37 and 35 Hz) of the urea NH reso-
nances
21
. In contrast, no such changes were observed with KF, with
the resultant
1
H NMR representing unbound (S)-3a (Fig. 2b). These
data led us to reflect on the successful fluorination of β-chloroamines
with KF under HBPTC, and to hypothesize that in this instance the
reactive meso-aziridinium salt aids the solubilization of KF as an
onium-type phase-transfer agent in partnership with (S)-3a
19
. This
putative scenario encouraged us to revisit the attempted fluorina-
tion of benzylic bromide 1a with KF (Fig. 2a, entry 2) using a range of
onium salt co-catalysts (Supplementary Fig. 1). Although the onium
salt Ph4P+Br− (10 mol%) on its own failed to induce fluorination in
the presence of KF (2.5 equiv.) in toluene at 60 °C (Fig. 2a, entry 3),
when used in combination with bis-urea (S)-3a (10 mol%) the benzylic
fluoride 2a was generated in moderate yield (33%), chemoselectivity
(2a:4a = 6:1) and enantioselectivity (75:25 e.r.) (Fig. 2a, entry 4). This
dual catalytic platform (Ph
4
P
+
Br
−
and (S)-3a) not only enabled the use
of KF, but also greatly improved the selectivity for fluorination over
elimination, a key challenge in nucleophilic fluorination because of the
accompanying Brønsted basicity of fluoride
25,26
. These data prompted
an in-depth study on this discovered manifold, which we termed syn-
ergistic HBPTC (S-HBPTC). The reaction proceeded in the presence
of a range of ammonium and sulfonium halide co-catalysts; however,
tetraarylphosphonium salts ensured a higher level of enantiocontrol
(Supplementary Fig. 1). Employing an enantiopure onium co-catalyst
had no beneficial effect on the transformation, and no considerable
(mis)match effect was observed using either enantiomer of a chiral
ammonium salt (Maruoka phase-transfer catalysts), which gave 2a
with e.r. values of 71:29 and 73:27, respectively (Supplementary Fig. 1).
A marked increase in yield (61%; 24 h) and minimal improvement in
enantioselectivity were observed with Ph
4
P
+
I
−
instead of Ph
4
P
+
Br
−
as the
co-catalyst (Fig. 2a, entry 5), whereas an increased loading of Ph4P+I−
was not beneficial for yield or e.r. (Supplementary Table 2). Variation
of the urea catalyst was shown to exert the greatest effects on the
stereochemical outcome of the reaction. The bis-urea catalyst (S)-3f,
having 3,4-difluorophenyl substituents, led to a marked increase in
enantioselectivity (87:13 e.r.) (Fig. 2a, entry 7). A profound solvent
effect was observed with an inverse correlation between the dielec-
tric constant of the solvent and the enantiomeric ratio observed for
2a; solvents of lower polarity were optimal, with p-xylene selected as
the solvent of choice for this transformation (Fig. 2a). Further HBD
catalyst optimization investigated the impact of N-alkylation, which
ultimately led to the development of catalyst (S)-3h, which gave 2a
in 83% yield while maintaining enantioselectivity (87:13 e.r.) at 40 °C
(Fig. 2a, entry 8). The final conditions included the treatment of rac-1a
with KF (2.5 equiv.), catalysts (S)-3h (10 mol%) and Ph
4
P
+
I
−
(10 mol%) in
p-xylene (0.25 M) at 15 °C, which allowed for the formation of fluoride
2a in 76% yield and 92.5:7.5 e.r.; elimination at this lower temperature
was also further minimized (Fig. 2a, entry 9).
Evaluation of substrate scope
With optimized conditions established, a range of substrates were eval-
uated to probe the reaction scope and gain preliminary insights into
the mechanism for this enantioconvergent transformation (Fig. 3a).
Variation of the electronic substitution on the biphenyl scaffold had
minimal impacts on the enantioselectivity of the product (2a–2c).
Substrates based on a 1-napthalene structure (2h–2p, 2x and 2y) under-
went fluorination in the highest enantioselectivities (up to 97:3 e.r.).
Common functional groups, including amides (2f), ethers (2c and
2w), aryl halides (2b, 2r and 2w) and carboxylic (2ag) and sulfonate
esters (2v), were well tolerated under the reaction conditions. The mild
reaction conditions were highlighted by the tolerance of fluorophilic
functionalities, including boron pinacol ester (2t) and a trimethylsilyl
group (2u). Variation of the alkyl chain demonstrated that increasing
length from methyl to n-propyl had minimal impact on substitution
versus elimination, and the fluorinated products were isolated in up
to 86% yield and 96:4 e.r. (2h, 2l and 2p). Departing from phenyl-based
substrates, the reaction conditions were further extended to fluorinate
a range of O- and N-heteroaromatic motifs, including quinolines (2x
and 2y), indoles (2z), indazoles (2aa), benzofurans (2ab and 2ac) and
benzothiophenes (2ad). Finally, analogues of more complex bioactive
molecules were subjected to enantioconvergent fluorination, includ-
ing quazoline (2af; 65% yield; 78:22 e.r.)
27
, fenofibrate (2ag; 54% yield;
93:7 e.r.) and celestolide derivatives (2ah; 83% yield; 93.5:6.5 e.r.).
Although reactivity and enantioselectivity were maintained when
meta-substituents were present on the aryl ring (2g), the reactivity
diminished for substrates with large ortho- (2ai) or α substituents (2ak
and 2aj). The reaction conditions also did not allow for the fluorination
of a tertiary benzylic substrate (2al), which predominately underwent
elimination to form the corresponding alkene side product (see Sup
-
plementary Fig. 2).
The successful implementation of S-HBPTC towards the synthesis
of enantioenriched benzylic fluorides prompted investigation into
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Nature Catalysis | Volume 8 | February 2025 | 107–115 110
Article https://doi.org/10.1038/s41929-024-01288-0
the fluorination of other electrophiles. We opted for α-haloketones
because all current synthetic approaches towards enantioenriched
α-fluoroketones rely on electrophilic fluorinating reagents of poor
atom economy (for example, N-fluorobenzenesulfonimide)
28
. Gratify-
ingly, minor modifications to the system were required with urea (S)-3k
and Et4N+I− as the onium salt, allowing for the catalytic fluorination of
α-bromoketone 9a with KF in 65% yield and 95:5 e.r. (Fig. 3b and Sup-
plementary Table 6). Acetonitrile was selected as the solvent for this
transformation due to poor solubility of the substrates in solvents of
low polarity. Various α-bromoketones were subjected to the optimized
conditions, with good reactivity and enantioselectivity maintained
across electron-withdrawing and -donating functionalities (10c and
10f–10k). α-Fluoroketones furnishing elongated alkyl chains could also
be prepared in good yields and enantioselectivity at higher reaction
temperatures (10l and 10m). Of note, ketones featuring 1-naphthalene
scaffolds showed the highest enantioselectivities, corroborating
the fluorination of electrophiles featuring extended π systems
(10d and 10e).
Spectroscopic investigation
Preliminary mechanistic investigation aimed to gain understanding of
the synergistic role of the catalysts (Fig. 4a). Interactions of the HBD,
the onium salt and KF were investigated through a spectroscopic NMR
study of a combination of (S)-3h, KF and Ph3BnP+BF4− (Supplementary
Figs. 13–22). Ph
3
BnP
+
BF
4−
was selected for the non-coordinating nature
of the BF
4−
anion and for the presence of methylene protons, which
become diastereotopic in a chiral environment. The addition of KF to
a solution of (S)-3h or Ph3BnP+BF4− in toluene-d8 displayed no spectro-
scopic changes of proton resonances for (S)-3h or Ph3BnP+BF4−, sug-
gesting that no interaction with KF occurred when only one catalyst
was present. In contrast, on the addition of KF to a solution containing
both (S)-3h and Ph
3
BnP
+
BF
4−
, the
1
H NMR spectrum revealed substantial
deshielding of several proton resonances, consistent with the formation
of a new species. Three diagnostic doublets were detected at 12.7, 12.5
and 10.6 ppm (1hJNH···F = 51, 57 and 31 Hz), corresponding to the urea NH
protons (ΔδNH = ~+6 ppm Ha and Hc and + 3.5 ppm Hb)21. The 1hJNH···F scalar
coupling, verified by clean in-phase 1H–19F heteronuclear single quan-
tum coherence measurements (CLIP-HSQC), is indicative of hydrogen
bonding of the urea catalyst to fluoride, and its magnitude correlates
with the strength of the hydrogen bond interaction
29
. The generation
of a [Ph
3
BnP]
+
[UF]
−
complex (where UF represents urea fluoride) was
also confirmed by the
19
F NMR spectrum, which contained a signal at
−75 ppm (Supplementary Fig. 16) characteristic of the hydrogen-bonded
fluoride ion and a singlet at 22.3 ppm in the
31
P{
1
H} NMR spectrum (Sup-
plementary Fig. 17), which was assigned to the phosphonium cation of
the complex (ΔδP = ~−0.6 ppm from Ph3BnP+BF4−). Signals corresponding
to diastereotopic benzylic H(28) protons in the phosphonium ion indi-
cated a close association between Ph3BnP+ and the chiral [UF]− complex
(Fig. 4a). Collectively, the above data indicate that the urea and phos-
phonium salt can solubilize KF to generate a dynamically stable singular
ternary hydrogen-bonded complex. Nuclear Overhauser effect (NOE)
cross-peaks in the two-dimensional rotating frame Overhauser effect
Ph
Br
Ph
F
Urea catalyst (10 mol%)
Onium catalyst (10 mol%)
KF (2.5 equiv.)
rac-1a (R)-2a
Entry Onium Urea 2a (%) Ratio 2a:4a e.r.
Ph
+
2
Ph4P+Br–(S)-3a
4a
1
–(S)-3a
3
Ph4P+I–(S)-3a
4
(S)-3f
5
(S)-3h
6
(S)-3h
Conditions
(S)-3a
–
Ph4P+Br–
7
8
CsF
MF
KF
KF
KF
KF
KF
KF
KF
–
9KF
(S)-3a
Solvent
60°C, 24 h
60°C, 24 h
40°C, 48 h
40°C, 48 h
40°C, 48 h
15°C, 72 h
–
33 6:1 75:25
61 6:1 77:23
32 7:1 80:20
64 9:1 87:13
83 10:1 87:13
76 15:1 92.5:7.5
60°C, 24 h 0
0 –
– –
60°C, 24 h
60°C, 24 h 38 1:1 74:26
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
p-xylene
p-xylene
a
Ph4P+I–
Ph4P+I–
Ph4P+I–
Ph4P+I–
2a e.e. (%)
80
70
60
50
40
30
0
0 5 10 15 20
Dielectric constant ()
p-xylene
MTBE
1,2-DFB
DCE
THF
PhCF3
Solvent polarity effect:
Urea catalyst:
DCM
(S)-3a
1H NMR in toluene- d8(25 mM; 273 K)
1hJNH···F= 60, 37 and 35 Hz
12.5 12.0 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5
 1H (ppm)
6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5
NHaNHcNHb
No binding of KF
Binding of CsF
b
Toluene-d8
CsF
Toluene-d8
KF
(S)-3a R= iPr
R1= R2= R4 = CF3, R3 = H
(S)-3f R = iPr
R1= CF3, R2= R3 = F, R4 = H
(S)-3h R = 4-heptyl
R1= CF3, R2= R3=F, R4=
H
(S)-3k R = Et
R1= R2= R4=3,5-(CF3)2-C6H3,
R3= H
Solvent (0.25 M)
conditions N
R
H
N
O
N
H
O
H
N
R1
R1
R4
R2R3
N
H
N
O
N
H
O
H
N
F3C
CF3
CF3
F3C
Fig. 2 | Reaction optimization. a, Optimization of enantioselective fluorination
under S-HBPTC. Conditions: rac-1a (0.05 mmol) at 25 mM concentration.
19F NMR yields are reported. Enantiomeric ratios were determined using
high-performance liquid chromatography with a chiral stationary phase.
b, Spectroscopic study of the phase transfer of MF salts by bis-urea catalyst
(S)-3a. 1,2-DFB, 1,2-difluorobenzene; DCE, dichloroethane; MBTE, methyl tert-
butyl ester; THF, tetrahydrofuran.
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Article https://doi.org/10.1038/s41929-024-01288-0
(S)-3h (10 mol%)
Ph4P+I– (10 mol%)
KF (2.5 equiv.)
a Scope of benzylic fluorides
Ph
F F
Ph
2a
76%a
92.5:7.5 e.r.
F
F2b
89%
92:8 e.r.
F
ON
F
2e
70%
89:11 e.r.
2g
80%
90.5:9.5 e.r.
F
F
Ph
2d
53%
91.5:8.5 e.r.
2c
64%
92:8 e.r.
From
flurbiprofen
F F
2s
73%
94:6 e.r.
Br
F
2r
85%
92:8 e.r.
2q
57%a
89:11 e.r.
F
2h
95%
95.5:4.5 e.r.
F
2l
94%
92.5:7.5 e.r.
F
F
F
2p
59%
88:12 e.r.
F
2t
71%
91.5:8.5 e.r.
PinB
O
I
F
2w
52%
89:11 e.r.
TMS
F
2u
68%b
92:8 e.r.
N
F
2y
99%
97:3 e.r.
N
Boc
F
2z
65%
87:13 e.r.
N
N
F
2aa
70%
91.5:8.5 e.r.
N
F
2x
79%
93:7 e.r.
(70%, 94:6 e.r. Gram scale)c
F
2ab
74%
91:9 e.r.
O
O
F
2ac
85%
92:8 e.r.
N
N
O
O
F
2af
65%b,d
78:22 e.r.
From quazoline
tBu
F
2ah
83%
93.5:6.5 e.r.
From celestolide
O
OF
O
O
From fenofibrate
2ag
54%b
93:7 e.r.
F
O
R2NR = allyl
2f
63%
92:8 e.r.
F
N
O
O2ae
59%b
90:10 e.r.
F
F
Br
2o
86%
96:4 e.r.
S
F
FF
2i
87%
95:5 e.r.
2j
88%
96:4 e.r.
2n
74%
95:5 e.r.
2m
62%
92:8 e.r.
2ad
94%
90:10 e.r
F
2k
60%
96:4 e.r.
O
O
F
F
(S)-3k (10 mol%)
Et4N+I– (10 mol%)
KF (5 equiv.)
rac-9
Br F
O
Cl F
O
FF
O
O2NF
O
NC F
O
F
O
F
O
OF
O
FF
(S)-10
Ph
10a
65%
95:5 e.r.
O
F3CF
10b
68%
95:5 e.r.
10c
55%
96:4 e.r.
10d
96%e
98:2 e.r.
10e
97%e
96:4 e.r.
10f
91%
91.5:8.5 e.r.
10g
86%
93:7 e.r.
10h
86%
93:7 e.r.
10i
91%e
87:13 e.r.
10j
83%e
92:8 e.r.
10k
90%e
92:8 e.r.
10l
83%b
92:8 e.r.
10m
78%b
84:16 e.r.
b Scope of α-fluoroketones
TsO
F
2v
64%b
81:19 e.r.
Cl
p-xylene (0.25 M)
25
˚C, 24 – 72 h
MeCN (0.5 M)
5 °C, 72
–
96 h
(S)-3h
R3= 4-heptyl
N
R3
H
N
O
N
H
O
H
N
F3C
CF3
F
F
R1
F
(R)-2
R2
R1
Br
rac-1
R2
O
Br
R1
R2
O
R1
R2
F
OFOF
F
(S)-3k
R3= Et
R4 = 3,5-(CF3)2-C6H3
N
R3
H
N
O
N
H
O
H
N
R4
R4
R4
R4
Fig. 3 | Reaction scope. a, Scope of benzylic fluorides. b, Scope of α-fluoroketones. The yields of the isolated products are reported. aPerformed at 15 °C. bPerformed at
40 °C. c98% recovery of (S)-3h. dIn 1,4-difluorobenzene for 96 h. ePerfomed at 25 °C.
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N
R
N
O
N
O
N
F3C
CF3
Hc
F2
F1
Ha
Hb
F
P
H28
H30
H17
H35
H34
--- Hydrogen bonding
NOE (HOESY) correlation
NOE (ROESY) correlation
R = 4-heptyl
H14
2.60 Å
Ph
D/H Br
Br
(S)-3a (10 mol%)
Ph4P+
I– (10 mol%)
KF (2.5 equiv.)
Ph
D/HF
Ph
CH3/CD3
H
(S)-3a (10 mol%)
Ph4P+
I– (10 mol%)
KF (2.5 equiv.)
Ph
HF
CH3/CD3
kH/kD = ∼
= ∼ = ∼
= ∼1.1
kH/ kD 1.1
β-SKIE
α-SKIE
1a + 1a-d1
1a + 1a-d3
2a + 2a-d1
Ph
D/H
Ph
CH2/CD2
H
2a + 2a-d3
4a +4a-d1
4a +4a-d3
+
+
kH/ kD 1.2 (β-SKIE)
1.4
1.2
1.0
0.8
In ([RBr]0/[RBr]t)
0.6
0.4
0.2
0
1.4
1.2
1.0
0.8
In ([RBr]0/[RBr]t)
Yield or e.e. (%)
0.6
0.4
100
80
60
40
20
0
0.2
0
0 500,000
Time (s)
1,000,000
0
0 20 40
Time (h)
60 80
500,000
Time (s)
1,000,000
kH/ kD 3.0 (α-PKIE)
F
Ar
I
KF
KBr (solid)
[UPF]
complex
N N
O
ArAr
H H
Br
N N
O
ArAr
H H
Ion metathesis
Ar
Br
Ar
X
(X) = Br or I
Ar
F
X = I
N N
O
ArAr
H H
IPPh4
N N
O
ArAr
H H
Ph4+P I–
+
PPh4
PPh4
1
5
[UPBr]
complex
2
X = Br
Halide exchange
(S)-3h + Ph3BnP+BF4– + KF
[UPF] complex NHa··· F–1.72 Å (1.60 Å)
NHb··· F–1.88 Å (1.78 Å)
NHc··· F–1.70 Å (1.65 Å)
NMR (DFT)
a1H NMR in toluene- d8 (25 mM; 273 K)
1H
13.5
–72.0
–71.5
–71.0
13.0 12.5 12.0 11.5 11.0 10.5
19F CLIP-HSQC
Diastereotopic
CH2
Ph
Br
Ph
F
(S)-3h (10 mol%)
Ph4P+
I– (10 mol%)
KF (2.5 equiv.)
rac-1a (R)-2a
Ph
I
5a
(I)
(II)
(III)
(IV)
Predicted = ∼ 1.0
Predicted = ∼ 1.1
Ph
4a
+
1hJNH···F- = 51, 57and 31 Hz
o 1a(e.e.)
o 2a (e.e.)
o 1a
o 2a
o 4a
o 5a
o 1a
o 1a-d3
o 1a
o 1a-d1
1H 19F selective HOESY in toluene- d8 (25 mM; 273 K),tm = 0.3 s
β-SKIE = 1.1
α-SKIE = 1.1
Pro-(R)
3.08 3.20
< F–C–Br = 165.0°
C–Br = 2.72 Å
C–F = 2.02 Å
< F–C–Br = 162.3°
C–Br = 2.69 Å
C–F = 2.00 Å
3.31
3.55
2.47
3.60 1.89 1.80 1.76
Br
Br
1.94
1.82
F
1.86
F
Pro-(S)
[UF]·1a major TS
∆G‡∆G‡
= 81.7 kJ mol–1
[UF]·1a minor TS
= 88.9 kJ mol–1
NH(c) NH(a) NH(b)
H17
H34 and H35
H30
H28
b
c
d e
Toluene-d8 (0.25 M)
Toluene-d8 (0.25 M)
p-xylene (0.25 M)
14.0 13.5 13.0 12.5 12.0 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5
 1H (ppm)
 1H (ppm)
 19F (ppm)
14.0 13.5 13.0 12.5 12.0 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5
 1H (ppm)
Fig. 4 | Mechanistic investigations. a, Spectroscopic evidence for the formation
of [UPF] species. b, SKIE studies, predicted values and pseudo first-order kinetic
plots. [RBr]0, initial concentration of bromide substrate; [RBr]t, concentration
of bromide at time (t). c, Investigation into the enantiomeric excess of 1a and 2a
via ex situ time course monitoring. d, Diastereomeric transition state structures
(computed using: M06-2X-D3ZERO/def2-TZVPP (C, H) ma-def2-TZVPP).
e, Proposed catalytic cycle. CLIP-HSQC, clean in-phase heteronuclear single
quantum coherence; DFT, density functional theory; TS, transition state; tm,
mixing time delay.
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Article https://doi.org/10.1038/s41929-024-01288-0
spectroscopy (ROESY) NMR spectrum of the [Ph3BnP]+[UF]− complex
confirmed the identity of all three urea NH resonances, and cross-peaks
were also detected between the urea scaffold and an ortho-proton in
the benzyl group of the phosphonium cation (H(17)–H(30)) (Supple
-
mentary Fig. 22). The urea–phosphonium fluoride ([UPF]) complex was
further characterized by 1H–19F heteronuclear Overhauser spectroscopy
(HOESY). Strong NOE correlations were detected between the bound
fluoride ion and protons in both the urea and Ph
3
BnP
+
(Fig. 4a).
1
H–
19
F
NOE build-up curves were used to investigate the location of the fluoride
ion in the ternary [UPF] complex21. The HOESY analysis indicated that the
fluoride ion is in closest proximity to NH
a
and NH
c
, with near equidistant
binding (1.72 and 1.70 Å, respectively), and more remote (1.88 Å) from
NH
b
, which is adjacent to the 1,1′-binaphthyl backbone. This orientation
of the bound anion is in agreement with previous data obtained on
bis-urea–fluoride complexes of (S)-3a
21
. Notably, protons H(28), H(30)
and H(34/35) of the phosphonium cation in the [UPF] complex were also
found to be within 3 Å of the urea-bound fluoride, quantitatively show-
ing close spatial proximity between the cation and anion (Supplemen-
tary Table 13). Very different behaviour was found for [UPF] complexes
generated in the more polar solvent dichloromethane-d
2
(DCM-d
2
);
1
H NMR spectra of the resulting [UPF] complex displayed deshielding
of the urea NH signals (Δδ
NH
= ~3–5 ppm) accompanied by extensive
line broadening; no scalar coupling for NH was detected, although a
signal corresponding to a fluoride ion (−86 ppm) was detected by
19
F
NMR. This suggests that the dynamic stability of the [UPF] complex is
reduced through attenuation of the electrostatic interactions by the
DCM medium, which has a higher dielectric constant (Supplementary
Figs. 23–25)30. The inverse correlation between the dielectric constant
of the solvent and the enantiocontrol of (R)-2a (Fig. 2a; at 40 °C, tolu-
ene = 87:13 e.r. and DCM = 71:29 e.r.) may be related to this phenomenon,
with apolar solvents favouring the formation of a tighter ternary [UPF]
complex. Together, these data validate the synergistic role of the urea
HBD catalyst and onium salt in solubilizing KF with the formation of a
stable [UPF] ion pair.
Further experiments were performed to answer mechanistic ques-
tions on this catalytic manifold, including whether the fluorination
occurs via an S
N
1 or S
N
2-like mechanism and the mode of racemization/
ionization of the substrate depending on substitution type. We also
investigated the basis for the moderate rate acceleration observed
when onium iodide salts are employed as co-catalysts instead of onium
bromide salts and the nature of the non-covalent interactions between
[UPF] species and the electrophile. This study was carried out with
benzylic bromides due to their complex mechanistic regimen; for
α-haloketones, it is indeed reasonable to exclude an SN1 mechanism—
and therefore the possibility of ion pairing with a carbocationic inter-
mediate—for this class of substrates31.
Kinetic isotope effect study
The extent of ionization of the benzylic bromides in the nucleophilic
substitution was probed by determining
1
H/
2
H secondary kinetic isotope
effects (SKIEs) for reactions of 1a-d
1
(α-SKIE) and 1a-d
3
(β-SKIE). If the
benzylic bromide 1a undergoes substitution via a transient carboca-
tion and the commitment factor is large, significant normal kinetic
isotope effects (KIEs) would be expected (α-SKIE ≥ 1.1; β-SKIE ≥ 1.2) in
an apolar medium such as p-xylene or toluene32,33. Conversely, if C–F
bond formation accompanies bromide departure, smaller normal (α
and β) or inverse (α) SKIEs would be expected, depending on the degree
of synchronization
34
. The SKIEs were estimated via two intermolecular
competition experiments between the labelled substrates (1a-d
1
and
1a-d
3
) and 1a, analysed by quantitative
1
H and
19
F NMR spectroscopy.
The heterogenous reactions require continuous agitation to disperse
the solid KF in the medium and this periodic activation was provided
by conducting the reactions in sealed NMR tubes that were continu-
ously inverted by mechanical rotation when not in the spectrometer
35
.
Analysis of the temporal concentration data showed that the bromide
(1a and 1a-dn) was consumed with approximately pseudo first-order
kinetics to generate the fluoride (2a and 2a-d
n
) and alkene (4a and 4a-d
n
)
at a constant ratio. This indicates that both products are generated
by irreversible partitioning of the same reaction manifold, allowing
estimation of the KIEs arising from fluoride addition (α-SKIE = ~1.1 and
β-SKIE = ~1.1) and elimination (β-SKIE = ~1.2 and α-PKIE = ~3.0) (Fig. 4b).
The KIE data do not support a substantial charge-separated ionization of
the benzylic substrate and are more consistent with an S
N
2-like process
for the enantioconvergent fluorination under S-HBPTC in p-xylene,
which is further supported by predicted KIE values from computed
transition state structures (Supplementary Table 19). The values can
be compared with a β-SKIE of ~1.5 for fluoride addition and an α-PKIE
of ~5.8 for elimination in the uncatalysed homogeneous reaction of 1b
or 1b-d
3
with tetrabutylammonium fluoride in DCM, which has kinetics
that are more characteristic of an S
N
1/E1 process (Supplementary Fig. 41
and Supplementary Table 18).
Substrate racemization
An S
N
2-like mechanism for fluorination under S-HBPTC in p-xylene
requires efficient racemization of the benzylic substrate (1a) for high
yield and enantioselectivity to be obtained. Reaction monitoring eluci-
dated that 1a remains racemic over the course of the reaction (Fig. 4c),
suggesting that the rate of substrate racemization exceeds the rate of
fluorination, with a comparable trend observed for α-bromoketone 9a
(Supplementary Table 22 and Supplementary Fig. 58). No racemization
of enantioenriched benzylic bromide 1a (63:37 e.r.) was detected in
the absence of catalysts. However, racemization of 1a was observed
in the presence of (S)-3f (10 mol%) and to a lesser extent with Ph
4
P
+
I
−
(10 mol%). When enantioenriched 1a was subject to both the HBD and
onium catalyst, full racemization occurred (Supplementary Fig. 55).
Iodide effect
The rate of reaction approximately doubles when Ph
4
P
+
I
−
is employed in
the reaction instead of Ph
4
P
+
Br
−
. In situ
1
H NMR spectroscopic analysis
of the reaction mixture revealed that when Ph
4
P
+
I
−
is used benzylic
iodide 5a is detected, formed through the nucleophilic displacement
of 1a. Further investigations demonstrated that increasing the amount
of Ph
4
P
+
I
−
at identical (S)-3h loading (10 mol%) did not increase the
concentration of 5a, suggesting the participation of (S)-3h to form 5a
through initial solubilization of Ph4P+I− (Supplementary Figs. 44–46).
1
H NMR spectroscopic analysis of the periodic activation-mediated
33
fluorination of bromide 1a (or 1a-d1) in toluene-d8 showed that the
concentration of iodide 5a rapidly grows to reach a low and approxi-
mately constant concentration (~6.5% of [1a]
0
) over the majority of
the reaction evolution (Fig. 4c). However, the decay of [1a] in this case
remained pseudo first order, not pseudo zero order, with the observed
rate constant doubled compared with the reaction using Ph
4
P
+
Br
−
(Sup-
plementary Fig. 42). Thus, the generation of 5a, which may also undergo
nucleophilic attack by [UPF], is not essential for turnover or enantiose-
lectivity, but arises as a consequence of this ion metathesis step, result-
ing in the formation of a urea–phosphonium bromide complex [UPBr].
Computational investigations
A density functional theory analysis of [UPF] species ((S)-3f:Ph4P+:F−)
obtained following conformational analysis led to the identification
of several low-energy conformations with tridentate binding of (S)-3f
to fluoride, with the phosphonium cation displaying π–π stacking
and favourable CH–π interactions with the BINAM backbone. The
lowest-energy conformers of the [UPF] complex showed close spa-
tial proximity of the phosphonium to fluoride, with one very close
intermolecular CH···F contact (1.91 Å in the most stable conformer),
comparable with experimental HOESY NMR data (Supplementary
Table 23). Alternative conformations (3.5 and 3.7 kJ mol
−1
less stable in
Gibbs energy than the lowest-energy conformer) were also identified
with the phosphonium cation engaging in π–π stacking and CH–π
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Article https://doi.org/10.1038/s41929-024-01288-0
interactions between the urea motifs, positioning the cation behind
the tridentate-bound fluoride, leaving the surface of [UPF] open for
coordination of a substrate molecule (Supplementary Fig. 60).
Having determined some of the key structural features of the
[UPF] complexes, we investigated the catalyst–substrate interactions
responsible for enantiodiscrimination. Diastereomeric transition
state structures for the reaction of rac-1a with (S)-3f-derived [UF] pre-
dicted the activation free energies (ΔG
‡
) leading to the formation of
(R)-2a and (S)-2a to be 81.7 and 88.9 kJ mol−1, respectively (Fig. 4d). The
Curtin–Hammett predicted enantioselectivity (Boltzmann-weighted
ΔΔG
‡
= 5.8 kJ mol
−1
) gives an e.r. of 91:9 at 25 °C, in good agreement with
the absolute configuration and level of enantioenrichment obtained
experimentally (Fig. 2a). Both competing transition states show stabili-
zation of the benzylic substrate through dispersion-dominated interac-
tions of the substrate with the urea motif of the catalyst. However, a key
difference between the major and minor transition state structures is
the presence of a strong, direct CBnH–π interaction between the ben-
zylic proton of the substrate and the BINAM backbone of (S)-3f (Fig. 4d).
Computed non-covalent interaction isosurface plots qualitatively
reinforce this analysis (Supplementary Fig. 70).
Diastereomeric transition state structures were calculated for the
formation of 2h and 2y, which were shown experimentally to be more
selective. The predicted energy barrier, ΔG‡, of the lowest-energy tran-
sition state decreased from 81.7 kJ mol
−1
for 2a, to 75.8 and 75.5 kJ mol
−1
for 2h and 2y, respectively (Supplementary Figs. 66–69). Diastere
-
omeric transition state structures for the reactions of rac-1h and
rac-1y with (S)-3f predicted ΔG
‡
leading to the formation of (R)-2h
and (S)-2h to be 75.8 and 83.0 kJ mol−1, and ΔG‡ leading to the forma-
tion of (R)-2y and (S)-2y to be 75.5 and 83.6 kJ mol−1, respectively. The
Curtin–Hammett predicted enantioselectivities for rac-1h and rac-1y
(Boltzmann-weighted ΔΔG‡ = 6.6 and 7.2 kJ mol−1, respectively) gave
respective e.r. values of 93:7 and 95:5 at 25 °C, in good agreement with
the level of enantioenrichment determined experimentally (Fig. 3a).
As noted with 2a, a key difference between the major and minor transi-
tion state structures is the presence of strong, direct CH–π interaction
between the benzylic proton of the substrate and the BINAM backbone
of (S)-3f (Supplementary Figs. 66–69).
Proposed catalytic cycle
Together, the data suggest a catalytic cycle that involves initial halogen
exchange between rac-1a and Ph
4
P
+
I
−
facilitated by (S)-3h to form ben-
zylic iodide 5a and the [UPBr] complex (Fig. 4e, I–II). Ion metathesis
of [UPBr] with KF occurs to form the [UPF] species (III) and KBr. It is
notable that this phase-transfer step is observed spectroscopically from
[UPBr] and KF, but not from the [UPI] complex, with the rationale that
precipitation of KBr is a thermodynamic driving force in the catalytic
cycle (KBr lattice energy = 672 kJ mol
−1
; KI lattice energy = 632 kJ mol
−1
)
(Supplementary Figs. 47–50)22. Fluoride delivery from [UPF] to either
1a or 5a yields enantioenriched benzylic fluoride 2a irreversibly and
regenerates [UPBr] or [UPI], respectively (IV).
Conclusions
This study reports a catalytic strategy enabling enantioconvergent
nucleophilic substitution (S
N
2) of racemic alkyl halides (specifically,
benzylic bromides and α-bromoketones) with potassium fluoride,
an asymmetric fluorination process rendered possible through the
introduction of a second phase-transfer catalyst, an onium halide.
The data provide compelling evidence that the onium co-catalyst is
essential for phase transfer in fulfilling the ion pairing requirement to
solubilize potassium fluoride, together with the urea HBD catalyst, as
a well-identified [UPF] species. Extensive mechanistic investigations
undertaken with benzylic bromides indicated that both catalysts—but
more predominantly the HBD—participate in substrate racemization,
with the fluorination proceeding via an S
N
2-like mechanism. Favour-
able dispersion-dominated interactions between substrates and the
[UPF] complex allow for enantioconvergent substitution with fluoride.
We anticipate that S-HBPTC will offer new opportunities for fluorina-
tion chemistry as the co-catalyst does not necessarily need to be an
onium salt and can be selected to meet the specific requirements of
the electrophile.
Methods
General procedure for the uorination of benzylic bromides
To a 7 ml screw-cap vial equipped with a magnetic stirring bar we
sequentially added pre-ground potassium fluoride (2.5 equiv.), the
appropriate substrate (0.16–0.38 mmol; 1 equiv.), (S)-3h (10 mol%),
Ph
4
P
+
I
−
(10 mol%) and p-xylene (0.25 M). The vial was sealed and the
reaction was stirred at 1,200 r.p.m. at the appropriate temperature
for the specified time. The crude reaction mixture was directly puri-
fied by flash column chromatography to give the product. The solvent
was removed in perfluoroalkoxy (PFA) round-bottom flasks and the
products were stored in polypropylene vials at −20 °C.
General procedure for the fluorination of α-bromoketones
To a 7 ml screw-cap vial equipped with a magnetic stirring bar we
sequentially added pre-ground potassium fluoride (2.5 equiv.), the
appropriate substrate (0.4 mmol; 1 equiv.), (S)-3k (10 mol%), Et
4
N
+
I
−
(10 mol%) and MeCN (0.5 M). The vial was sealed and the reaction was
stirred at 1,200 r.p.m. at the appropriate temperature for 96 h. The
crude reaction mixture was directly purified by flash column chroma-
tography to give the product.
Data availability
Details on the materials and methods, optimization studies, mechanis-
tic studies, 1H, 13C and 19F NMR spectra and high-resolution spectrom-
etry, and infrared and chiral high-performance liquid chromatography
data are available in the Supplementary Information. All other data are
available from the authors upon reasonable request.
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Acknowledgements
This work was supported by AstraZeneca (CASE scholarship to
C.D.), the MUIR-PON programme PhD 37 cycle grant FSE REACT-EU
A.A. 2021/2022 (to C.P.), the European Research Council (grant
agreement 832994) (to V.G.), a University of Edinburgh Global
Research Scholarship (to Y.G.) and the National Science Foundation
(CHE-1955876), with computational resources from the Advanced
Cyberinfrastructure Coordination Ecosystem: Services & Support
(ACCESS) through allocation TG-CHE180056 (to R.S.P.). We thank G.
Pupo and Z. Chen for selected experiments. We thank T. D. W. Claridge,
J. R. D. Montgomery and C. Mycroft for valuable NMR discussions.
Author contributions
V.G. conceived of and supervised the project. C.D., F.I., B.B.B. and
C.P. designed and conducted the experimental work. C.D. and F.I.
performed all of the NMR studies. C.A.G. and R.S.P. performed and
interpreted all of the computational work. C.D. performed the kinetic
experiments. Y.G. and G.C.L.-J. interpreted the kinetic data. A.L.
assisted with discussions of experimental data. C.D., F.I., G.C.L.-J.,
R.S.P. and V.G. wrote the manuscript.
Competing interests
The authors declare no competing interests.
Additional information
Supplementary information The online version contains supplementary
material available at https://doi.org/10.1038/s41929-024-01288-0.
Correspondence and requests for materials should be addressed to
Robert S. Paton, Guy C. Lloyd-Jones or Véronique Gouverneur.
Peer review information Nature Catalysis thanks the anonymous
reviewers for their contribution to the peer review of this work.
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