Catalytic Oxidative Deamination by Water with H2Liberation

Article abstract of DOI:10.1021/jacs.0c10826

Selective oxidative deamination has long been considered to be an important but challenging transformation, although it is a common critical process in the metabolism of bioactive amino compounds. Most of the synthetic methods developed so far rely on the use of stoichiometric amounts of strong and toxic oxidants. Here we present a green and efficient method for oxidative deamination, using water as the oxidant, catalyzed by a ruthenium pincer complex. This unprecedented reaction protocol liberates hydrogen gas and avoids the use of sacrificial oxidants. A wide variety of primary amines are selectively transformed to carboxylates or ketones in good to high yields. It is noteworthy that mechanistic experiments and DFT calculations indicate that in addition to serving as the oxidant, water also plays an important role in assisting the hydrogen liberation steps involved in amine dehydrogenation.

Full text of DOI:10.1021/jacs.0c10826

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Catalytic Oxidative Deamination by Water with H2 Liberation
Shan Tang, Michael Rauch,§ Michael Montag,§ Yael Diskin-Posner, Yehoshoa Ben-David,
and David Milstein*
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ABSTRACT: Selective oxidative deamination has long been
considered to be an important but challenging transformation,
although it is a common critical process in the metabolism of
bioactive amino compounds. Most of the synthetic methods
developed so far rely on the use of stoichiometric amounts of
strong and toxic oxidants. Here we present a green and efficient
method for oxidative deamination, using water as the oxidant,
catalyzed by a ruthenium pincer complex. This unprecedented
reaction protocol liberates hydrogen gas and avoids the use of
sacrificial oxidants. A wide variety of primary amines are selectively transformed to carboxylates or ketones in good to high yields. It
is noteworthy that mechanistic experiments and DFT calculations indicate that in addition to serving as the oxidant, water also plays
an important role in assisting the hydrogen liberation steps involved in amine dehydrogenation.
Scheme 1. Oxidative Deamination of Primary Amines
INTRODUCTION
■
Amine functional groups are fundamental structural motifs in
an abundance of biomolecules and pharmaceuticals.1 Over the
past few decades, great attention has been devoted to the
synthesis of amines by the amination of alcohols or
ketones.2−12 However, the reverse reactions, consisting of the
deamination of primary amines, have long been considered to
be important but synthetically challenging transforma-
tions.13−15 In contrast, the enzymatic oxidative deamination
of primary amines is a very common metabolic process in
living cells.16−19 Generally, this process is catalyzed by amine
dehydrogenases or copper amine oxidases, affording either
aldehydes or ketones.20−25 In the case of linear primary
amines, the generated aldehydes are further oxidized to
carboxylates in subsequent metabolic steps catalyzed by
aldehyde dehydrogenases (Scheme 1a). Because of the
importance of accessing new categories of carbonyl com-
pounds from bioactive amino compounds, oxidative deami-
nation has also received considerable attention by synthetic
organic chemists. A notable example is the use of oxidative
deamination in the synthesis of prostaglandin E1 by Corey and
coworkers.26 However, similar to other biocatalytic methods, a
narrow substrate scope hinders the application of enzymatic
oxidative deamination in organic synthesis.27,28 At the same
time, traditional synthetic methods for oxidative deamination
usually require the use of strong, toxic chemical oxidants, such
as permanganate or dichromate, to afford ketones or
aldehydes.29−32 Corey and co-workers described another
reaction strategy, utilizing mesitylglyoxals as sacrificial reagents
to promote the transformation of primary amines to ketones or
aldehydes via the formation of Schiff bases.33 More recently, a
biomimetic oxidative deamination of benzylic amines was
Received: October 13, 2020
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a b c d
, , ,
Table 1. Catalytic Oxidative Deamination of Linear Aliphatic Amines to Carboxylates by Water with H2 Liberation
a
General reaction conditions: amine (0.50 mmol), [Ru]-2 (0.0050 mmol), NaOH (1.0 mmol), water (2.0 mL), and dioxane (2.0 mL) were heated
in a closed system at 150 °C (silicon oil bath temperature, solvent reflux) for 48 h. Carboxylic acids were isolated after treatment of the carboxylates
with dilute hydrochloric acid. Yields of carboxylates 2f, 2m, and 2o were determined by 1H NMR using pyridine as an internal standard. 1H NMR
signals of the following groups were used for quantification: methoxyl C−H of 2f; aryl C−H of 2m ortho to the carboxylate; aryl C−H of 2o ortho
b
c
d
to the nitrogen and para to the carboxylate. [Ru]-2 (0.010 mmol) was used. Amine (0.25 mmol) was used. NaOH (1.5 mmol) was used.
reported, which employs an ortho-naphthoquinone as the
catalyst under aerobic conditions.34 Compared to the
enzymatic processes, traditional synthetic methods for the
oxidative deamination of linear primary amines usually suffer
from poor selectivity, affording a mixture of aldehydes, imines,
and carboxylic acids (Scheme 1b).35,36 Until now, all reported
methods required the use of sacrificial oxidants, which can be
problematic in being intolerant toward other oxidizable
functionalities and generating waste.37−47
Catalytic processes in organic synthesis using water as a
formal oxidant, with concomitant H2 liberation, are very rare
and are among the most atom-economical and environ-
mentally friendly approaches for the selective oxidation of
organic compounds.48−56 By utilizing ruthenium pincer
complexes as dehydrogenation catalysts, our group has
developed several catalytic oxidation reactions by water with
the concomitant generation of hydrogen gas.48−51 In 2016, we
reported that a bipyridine-based PNN-Ru complex ([Ru]-1)
catalyzed the oxidation of amino alcohols to amino
carboxylates in alkaline water in the absence of any sacrificial
oxidant.49 Notably, the amine moiety of the amino alcohols
was left untouched, even though no protecting group was used.
In another study, we observed the deamination of primary
aliphatic amines to alcohols by using an acridine-based PNP-
Ru complex ([Ru]-2) as a catalyst.57 To the best of our
knowledge, the highly desirable selective oxidative deamination
in the absence of added oxidant is unknown. Herein, we report
a green and efficient method for catalytic oxidative
deamination, employing complex [Ru]-2 or [Ru]-3 as a
catalyst and using water as an oxidant with H2 liberation
B
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(Scheme 1c). This reaction system is applicable to the
oxidative deamination of both aliphatic amines and amides
with remarkable selectivity. A wide range of linear primary
amines have been directly oxidized by water to carboxylates,
providing the first selective method for achieving this
transformation.13,14 Notably, this reaction strategy avoids the
use of any sacrificial oxidant. A mechanistic study of the
catalytic system suggests that in addition to serving as the
oxidant, water also plays an important role in facilitating
hydrogen liberation along the reaction pathway.
When 5-amino-1-pentanol was employed as the substrate, both
the amino and hydroxyl groups were oxidized, furnishing
glutaric acid in 52% yield after treatment with hydrochloric
acid (Table 1, entry 18). Compared to primary amines, lower
conversions were observed with secondary amines in the
catalytic oxidative deamination, which may be due to increased
steric hindrance during the amine dehydrogenation step. For
example, low yields were observed in the oxidative
deamination of N-methylbenzylamine and N-methyl-
butylamine, even with an increased catalyst loading (Table 1,
entries 19 and 20). Formate was detected in the crude reaction
mixture of N-methylbenzylamine by 13C NMR analysis, which
likely originated from the N-methyl group. In the case of cyclic
amines, oxidative deamination led to the formation of
dicarboxylic acids in slightly increased yields (Table 1, entries
21 and 22). Polyamides were found to be the major side
products in the reaction of bifunctional amines or cyclic
amines (Table 1, entries 17, 18, 21, and 22). Tertiary amines
such as N,N-dimethylbenzylamine and tri-n-butylamine were
also examined, but no reaction was observed.
It is well known that amides can undergo hydrolysis under
strongly alkaline conditions to generate amines.58 Since our
oxidative deamination reactions were also performed under
alkaline conditions, the possibility for the direct oxidative
deamination of amides was explored. Under reaction
conditions similar to those used with amines, the oxidative
deamination of N-octylacetamide and N-benzylacetamide was
indeed observed, affording octanoic and benzoic acid,
respectively, in moderate yields (Scheme 2a). 13C NMR
RESULTS AND DISCUSSION
■
Catalytic Oxidative Deamination of Amines and
Amides. The oxidative deamination of linear primary amines
was first studied using complex [Ru]-2 as the catalyst. An
alkaline water/dioxane (1:1 volumetric ratio) solution of these
amines, containing 1.0 mol % complex [Ru]-2, was heated in a
sealed tube at 150 °C (oil bath temperature) for 48 h, affording
the corresponding carboxylates in good to high yields (Table
1). For the representative n-butylamine (0.50 mmol), 24 mL of
hydrogen gas was collected after cooling the reaction mixture
to room temperature, amounting to a 98% yield (determined
by GC; see Supporting Information, Figure S1, for details).
Upon treating this reaction mixture with diluted hydrochloric
acid, butyric acid was isolated in 95% yield (Table 1, entry 1)
1
and NH4Cl was detected by H NMR (details in Supporting
Information, Figure S2). Linear primary amines with longer
chains also demonstrated high reactivity to give the
corresponding carboxylic acids (Table 1, entries 2 and 3).
Subjecting the bulky cis-myrtanylamine to the same reaction
conditions afforded the acid in a moderate yield of 71% (Table
1, entry 4). The oxidative deamination of 5-norbornene-2-
methylamine was accompanied by the hydrogenation of the
carbon−carbon double bond, furnishing 5-norbornane-2-
carboxylic acid in 65% yield (Table 1, entry 5). A slightly
higher catalyst loading of 2.0 mol % was used for the oxidative
deamination of 2-methoxyethylamine, affording 2-methoxy-
acetate quantitatively (Table 1, entry 6). Our catalytic system
also demonstrated high selectivity and efficiency in the
oxidative deamination of phenethylamine and tryptamine
(Table 1, entries 7 and 8). It should be noted that when
bulky primary amines were used as substrates for oxidative
deamination (Table 1, entries 4, 5, and 8), the corresponding
alcohols were the major byproducts. Activated primary amines
also showed high reactivity in our catalytic oxidative
deamination system. Notably, benzylamine was transformed
to benzoic acid in 98% isolated yield (Table 1, entry 9). The
yield of benzoic acid was not affected when a drop of mercury
or 1.0 equiv of triethylamine was added to the reaction of
benzylamine, excluding the involvement of metal nanoparticles
in the catalytic oxidative deamination process. Benzylamines
bearing electron-donating, electron-withdrawing, and halogen
substituents at the para position all showed high reactivity in
this transformation (Table 1, entries 10−13). Even an NH2
substituent at the para position was well tolerated (Table 1,
entry 13). 2-Aminomethylfuran and 3-aminomethylpyridine
were also efficiently converted to the corresponding carbox-
ylates (Table 1, entries 14 and 15). Isophthalic acid was
obtained in quantitative yield in the oxidative deamination of
1,3-phenylenedimethanamine (Table 1, entry 16). A higher
catalyst loading of 4.0 mol % was required to achieve good
reaction efficiency in the transformation of an aliphatic diamine
to its corresponding dicarboxylic acid (Table 1, entry 17).
Scheme 2. Catalytic Oxidative Deamination of Amides to
Carboxylic Acids with H2 Liberation
analysis of the reaction mixture obtained for N-benzylaceta-
mide indicated that the acetyl group was transformed to acetic
acid. A control experiment, conducted with the reaction of N-
benzylacetamide in the absence of the ruthenium catalyst,
resulted in only 26% conversion, with a 23% yield of
benzylamine. This observation suggests that the oxidative
deamination of benzylamine assists in driving the base-
promoted hydrolysis of N-benzylacetamide. Aside from N-
alkyl acetamides, lactams also underwent oxidative deami-
nation under similar reaction conditions. Using a higher
catalyst loading (2.0 mol %), dicarboxylic acids were isolated in
moderate to good yields (Scheme 2b). In all of the above
transformations, hydrogen gas was detected by GC, and
NH4Cl was identified by 1H NMR after treatment with
hydrochloric acid.
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Whereas the oxidative deamination of linear aliphatic amines
consistently produced carboxylates, branched primary amines
afforded ketones. As shown in Table 2, good selectivity and
ligands, thereby suppressing the catalytic activity of the
acridine-based ruthenium pincer complex.
Mechanistic Investigation. According to previous studies
by our group,59,60 as well as by Hofmann et al.,61 complex
[Ru]-2 undergoes reduction by alcohols or amines, under basic
conditions, to generate catalytically active dearomatized
complex [Ru]-3. As expected, the activity of complex [Ru]-3
was quite similar to that of complex [Ru]-2 in the oxidative
deamination of amines to afford carboxylates in the presence of
sodium hydroxide. To understand the role of base in this
transformation, control experiments were carried out with
benzylamine in the absence of base. Under these conditions,
using complex [Ru]-2 or [Ru]-3 as a catalyst resulted in
nonselective reactions, affording a mixture of benzyl alcohol,
benzoic acid, and N-benzylidenebenzylamine. In both cases,
benzyl alcohol was the major product, while dearomatized
complex [Ru]-3 gave a slightly higher yield of this alcohol
(Scheme 3a). Notably, complex [Ru]-3 also demonstrated
excellent catalytic activity in the direct oxidation of benzyl
alcohol to benzoate in the presence of sodium hydroxide
(Scheme 3b). However, when the reaction was conducted in
the absence of base, very low conversion was observed
(Scheme 3b). It appears that the acid product suppresses the
dehydrogenation of benzyl alcohol. Besides benzyl alcohol, the
imine byproduct, N-benzylidenebenzylamine, also underwent
efficient oxidative deamination catalyzed by complex [Ru]-3 in
alkaline water/dioxane (Scheme 3c). Since aldehydes are
believed to be generated from the imine intermediates in
aqueous solutions, the oxidation of benzaldehyde by water was
also investigated (Scheme 3d). In the absence of the
ruthenium catalyst, we observed the disproportionation of
benzaldehyde to benzyl alcohol and benzoate, but with very
low conversion. When complex [Ru]-3 was used as the
catalyst, full conversion of benzaldehyde to benzoate was
observed, along with the evolution of hydrogen gas.
Table 2. Catalytic Oxidative Deamination of Branched
Aliphatic Amines to Ketones by Water with H2
a b
,
Liberation
To gain further insights into the reactivity of complex [Ru]-
3, its interactions with a representative substrate, benzylamine,
as well as its respective oxidation products, were probed by
stoichiometric experiments (Scheme 3e). Mixing [Ru]-3 with
1.0 equiv of benzylamine in dioxane-d8 at room temperature
resulted in the immediate quantitative formation of the
corresponding benzylamine complex, [Ru]-4. This complex
exhibited a singlet at 76.39 ppm in the 31P{1H} NMR
spectrum, which is shifted only slightly downfield from [Ru]-3
a
General reaction conditions: amine (0.50 mmol), [Ru]-2 (0.0050
mmol), water (0.50 mL), and dioxane (2.0 mL) were heated in a
closed system at 150 °C (silicon oil bath temperature, solvent reflux)
for 48 h. Yields were determined by GC using mesitylene as an
b
internal standard. Amine (0.25 mmol) was used.
1
(75.63 ppm). By contrast, the hydride H NMR signal of
complex [Ru]-4, a triplet at −15.02 ppm (2JPH = 25.0 Hz),
exhibits a significant downfield shift compared to that of [Ru]-
3 (−20.84 ppm) (details in the Supporting Information).
Rapid amine coordination occurred even in the presence of 90
equiv of water in dioxane-d8, demonstrating the preference of
[Ru]-3 for the coordination of the amine substrate over that of
water. The three benzylamine oxidation products obtained
catalytically in the absence of base (i.e., benzyl alcohol, benzoic
acid, and N-benzylidenebenzylamine) were also examined
stoichiometrically for their interactions with [Ru]-3. Benzyl
alcohol and N-benzylidenebenzylamine showed no observable
coordination to the metal center in dioxane-d8, when mixed
with the complex in equimolar amounts. Benzoic acid, on the
other hand, reacted immediately with [Ru]-3 at room
temperature to give three distinct products. Upon heating
the reaction mixture to 80 °C, all products converged into one,
which was identified as benzoate complex [Ru]-5. X-ray-
quality crystals of this complex were obtained from a saturated
efficiency were achieved by heating a neutral water/dioxane
(1:4 volumetric ratio) solution of branched primary amines in
the presence of 1.0 mol % complex [Ru]-2. An excellent yield
of 94% was obtained for the oxidative deamination of 2-
aminooctane (Table 2, entry 1), while the reaction of 3-
aminopentane afforded 3-pentanone with a slightly decreased
yield of 74% (Table 2, entry 2). Oxidative deamination of
cycloalkylamines having different ring sizes afforded the
corresponding cyclic ketones in good to high yields (Table
2, entries 3−6). Aside from aliphatic primary amines, α-
methylbenzylamine and its analogues also demonstrated good
to high reactivity toward the formation of their respective
ketones (Table 2, entries 7−9). It is noteworthy that no imines
were observed, and alcohols were observed as the only organic
byproducts of the above-mentioned oxidative deamination
reactions. Unfortunately, natural amino acids did not undergo
this transformation, possibly because they act as bidentate
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Scheme 3. Mechanistic Experiments
pentane solution at −30 °C (Scheme 3e; details in the
Supporting Information, Figure S3). Significantly, treatment of
benzylamine complex [Ru]-4 with 1.0 equiv of benzoic acid in
dioxane-d8 quantitatively generated complex [Ru]-5, together
with free benzylamine, after heating to 80 °C (Scheme 3e).
This result indicates that amine coordination to complex [Ru]-
3 is reversible. By contrast, no reaction was observed when an
equimolar mixture of complex [Ru]-5 and benzylamine was
subjected to the same reaction conditions (Scheme 3e). The
formation of carboxylate complex [Ru]-5 is likely to be an off-
cycle process in the catalytic dehydrogenation of benzylamine.
In addition, we examined direct coordination of benzoate to
[Ru]-3 by mixing this complex with 1.0 equiv of
tetrabutylammonium benzoate in dioxane-d8/D2O (9:1), but
examine whether amine complex [Ru]-4 is an active
intermediate in the amine dehydrogenation process, we heated
a dioxane solution of this complex in a closed system at 150 °C
for 16 h. Interestingly, benzylamine was selectively converted
to benzonitrile (Scheme 3e).
The effect of water on the catalytic dehydrogenation of
benzylamine was then explored by using 1.0 mol % [Ru]-3 in
the absence and presence of water. When the reaction was
performed in dry dioxane, only a 20% conversion of
benzylamine was observed after 24 h at 150 °C, giving N-
benzylidenebenzylamine and benzonitrile in 16 and 2% yields,
respectively. By contrast, adding 1.0 equiv of water to the
reaction mixture led to a much higher conversion of
benzylamine, affording 83% N-benzylidenebenzylamine and
8% benzonitrile. As shown in Scheme 3f, the rate of amine
dehydrogenation in the presence of 1.0 equiv of water was
much faster than without water. These findings clearly
demonstrate that without a large excess of water, the
predominant reactions are amine dehydrogenation and its
subsequent coupling, generating the corresponding imine and
nitrile. Furthermore, water significantly enhances the rate of
amine dehydrogenation, leading to high conversion.
1
no significant coordination was observed by H and 31P NMR
spectroscopy. Furthermore, it was found that addition of
strong bases like NaOH is essential for obtaining high yields of
carboxylic acids in the catalytic oxidative deamination reactions
(see Supporting Information, Table S1, for the effect of
different bases on the conversion of benzylamine). It therefore
appears that the role of base in our system is to neutralize the
carboxylic acids as they are generated, thereby averting product
inhibition as well as driving the reaction forward. In order to
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Figure 1. Free-energy pathways for benzylamine dehydrogenation to imine catalyzed by complex [Ru]-3. Green dashed line: Amine
dehydrogenation with water participation. Red dashed line: Amine dehydrogenation without water participation. Free energies (kcal/mol) were
calculated at 423.15K relative to mer-[Ru]-3, water, and benzylamine and are calculated in a 1:1 water/dioxane continuum (all solutes are 1 M
except for H2 and H2O, which are at 1 atm and 27.75 M, respectively). Mass balance is ensured throughout. The CO and acridine-based ligands are
omitted for clarity.
DFT calculations were carried out to elucidate the role of
water in amine dehydrogenation catalyzed by complex [Ru]-3.
In a previous mechanistic study, we reported the formation of
lactams from cyclic amines and water utilizing the same
catalyst, in which dehydrogenation to imine was proposed to
occur via a Ru−OH intermediate generated from [Ru]-3 and
water rather than by the direct reaction of [Ru]-3 with the
amine.59 Utilizing benzylamine as a model substrate, we sought
to answer the same question to determine the source of the
initial hydrogen elimination in the current system (Figure 1).
As suggested in our former study,59 the fac isomer of [Ru]-3
(fac-[Ru]-3) is the active form of the dearomatized catalyst
and is accessible from the more stable mer isomer (mer-[Ru]-
3, treated as the reference energy point) under the catalytic
conditions (water/dioxane at 150 °C). The computation
indicates that amine coordination to the cis vacant site of fac-
[Ru]-3 (INT7) is more favorable than water coordination
(INT1), which is in agreement with the experimentally
observed trend above (Scheme 3e). However, the subsequent
amine dehydrogenation via TS2 has a higher energy barrier
than a multistep process involving water, namely, dehydrogen-
ation via TS1, followed by amine coordination and then
dehydration via TS3 to afford the ruthenium amido complex
(INT5). These findings are in accordance with the higher
acidity of water compared to that of amines. Thus, we propose
that the source of H2 in the reaction is the deprotonation of
water rather than amine, which underscores another
fundamental role of water in our catalytic process, namely,
assistance with H2 liberation. This is in line with our
aforementioned experimental results depicted in Scheme 3f
showing that the rate of benzylamine conversion increases
dramatically in the presence of water. Our calculations also
suggest that the activation energy for β-hydride elimination
from the ruthenium amido complex (TS4) is lower than that
of the hydrogen liberation steps, indicating that H2 elimination
is likely to be the rate-determining step in the amine
dehydrogenation process. In the subsequent reaction steps,
the generated imine undergoes facile hydrolysis to produce
benzaldehyde and ammonia. Further reaction of benzaldehyde
with water and base, catalyzed by the ruthenium catalyst,
affords the benzoate.56,62
CONCLUSIONS
■
We have developed a new reaction, namely, the oxidative
deamination of primary amines using water as the oxidant with
concomitant hydrogen evolution. The reaction is catalyzed by
an acridine-based ruthenium pincer complex. In contrast to the
existing oxidative deamination methods, this reaction does not
require added oxidants and does not generate waste. A wide
variety of linear primary amines were selectively and efficiently
transformed to carboxylates, and branched primary amines
were transformed to ketones. Notably, this catalytic reaction is
also applicable to the oxidative deamination of amides to
produce carboxylates. Our mechanistic studies indicate that
water, in addition to serving as the oxidant, also facilitates the
hydrogen liberation steps.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c10826.
■
sı
Experimental details of the synthesis procedures, NMR
spectra, X-ray data, and computational details (PDF)
Crystallographic data for [Ru]-5 (CIF)
AUTHOR INFORMATION
Corresponding Author
■
David Milstein − Department of Organic Chemistry,
Weizmann Institute of Science, Rehovot 76100, Israel;
orcid.org/0000-0002-2320-0262;
Email: david.milstein@weizmann.ac.il
F
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Jagadeesh, R. V. Simple ruthenium-catalyzed reductive amination
enables the synthesis of a broad range of primary amines. Nat.
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Authors
Shan Tang − Department of Organic Chemistry, Weizmann
Institute of Science, Rehovot 76100, Israel; orcid.org/
0000-0001-5662-8401
Michael Rauch − Department of Organic Chemistry,
Weizmann Institute of Science, Rehovot 76100, Israel
Michael Montag − Department of Organic Chemistry,
Weizmann Institute of Science, Rehovot 76100, Israel;
orcid.org/0000-0001-6700-1727
Yael Diskin-Posner − Chemical Research Support, Weizmann
Institute of Science, Rehovot 76100, Israel; orcid.org/
0000-0002-9008-8477
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Yehoshoa Ben-David − Department of Organic Chemistry,
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(16) Bender, D. A. Amino Acid Metabolism, 3rd ed.; Wiley: Hoboken,
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Weizmann Institute of Science, Rehovot 76100, Israel
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c10826
Author Contributions
§Michael Rauch and Michael Montag contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This research was supported by the European Research
Council (ERC AdG 692775). D.M. holds the Israel Matz
Professorial Chair of Organic Chemistry. S.T. is thankful to the
Israel Planning and Budgeting Committee (PBC) for a
postdoctoral fellowship. M.R. acknowledges the Zuckerman
STEM Leadership Program for a research fellowship.
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