Liquid-phase hydrogenation of nitriles to amines facilitated by a co(ii)/zn(0) pair: a ligand-free catalytic protocol

Article abstract of DOI:10.1021/acs.joc.9b01544

The given report introduces a simple and user-friendly in situ method for the production of catalytically active cobalt particles. The approach circumvents the use of air-and moisture-sensitive reductants as well as the application of anhydrous Co-precursor salts. Accordingly, the described catalytic system is readily assembled under open-flask conditions by simply combining the components in the reaction vessel. Therefore, the arduous charging procedure of the reaction autoclave in a glovebox under an inert gas atmosphere is no longer necessary. In fact, the catalytically active material is obtained upon treatment of readily available Co(OAc)₂·4 H₂O with benign commercial Zn powder. The catalytic performance of the resultant material was tested in the heterogeneous hydrogenation of nitriles to the corresponding primary amines. Both activity and selectivity of the cobalt catalyst are significantly enhanced if a triflate-based Lewis acid and ammonia is added to the reaction mixture.

Full text of DOI:10.1021/acs.joc.9b01544

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Article
Liquid-phase Hydrogenation of Nitriles to Amines Facilitated
by a Co(II)/Zn(0)-Pair: A Ligand-free Catalytic Protocol
Daniel Timelthaler, and Christoph Topf
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01544 • Publication Date (Web): 27 Aug 2019
Downloaded from pubs.acs.org on August 28, 2019
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Liquid-phase Hydrogenation of Nitriles to Amines Facilitated by a Co(II)/Zn(0)-Pair: A Ligand-
free Catalytic Protocol
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Daniel Timelthaler, Christoph Topf*
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Institute of Catalysis (INCA), Johannes Kepler University (JKU), 4040 Linz, Austria
Abstract
The given report introduces a simple and user-friendly in situ method for the production of
catalytically active cobalt particles. The approach circumvents the use of air- and moisture-sensitive
reductants as well as the application of anhydrous Co-precursor salts. Accordingly, the described
catalytic system is readily assembled under open-flask conditions by simply combining the
components in the reaction vessel. Therefore, the arduous charging procedure of the reaction-
autoclave in a glovebox under an inert gas atmosphere is no longer necessary. In fact, the catalytically
active material is obtained upon treatment of readily available Co(OAc)2∙4 H2O with benign
commercial Zn powder. The catalytic performance of the resultant material was tested in the
heterogeneous hydrogenation of nitriles to the corresponding primary amines. Both activity and
selectivity of the cobalt catalyst are significantly enhanced if a triflate-based Lewis acid and ammonia
is added to the reaction mixture.
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Introduction
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The use of non-noble cobalt as catalytically competent center in various redox-transformations is
intrinsically related to outstanding progress in organic syntheses. This fact and the decent abundance
of Co renders it a promising candidate for superseding precious metals in certain catalytic processes.
Moreover, the pertinent metal is amenable to both heterogeneous1 as well as homogeneous2 catalysis
and this point adds a considerable degree of flexibility to the conceived production routes of valuable
industrial chemicals and the devised (retro)synthetic plans towards sophisticated target molecules.
In the field of heterogeneous catalysis significant contributions were achieved using pyrolytically
synthesized cobalt-borne nanoparticles that are integrated in an N-graphitic3 or a carbonaceous4
matrix. Such materials were successfully applied in, inter alia, the hydrogenation of nitriles, ketones
and alkynes. However, the preparation of the catalytically active composites represents an elaborate
multistep-process that requires rigorous compliance of the respective production steps and high
pyrolysis temperatures. Furthermore, the recently described manufacture of a kindred MOF-derived
material implies the use of the high-boiling and toxic dipolar-aprotic solvent dimethylformamide
(DMF).5 Accordingly, the development of more benign and energy-efficient strategies of related
augmented solid catalysts is still rewarding and highly sought-after.
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Highly reactive bulk metal catalysts such as Rieke Cobalt6 and RANEY® Co7 found widespread
applications in chemical synthesis but their fabrication and use requires careful handling and special
lab-technical precautions. Therefore, the invention of safer and less pyrophoric activated metals is an
ongoing endeavor in modern contemporary catalysis research. With respect thereof, the tamed
congeneric Urushibara-type8 alloys are indeed easier to manipulate though their production process
entails a lengthy leaching step and water-wasting washing procedures.
Recently, Wolf et al. reported on the synthesis and application of recyclable genuine Co nanoparticles
that effected the hydrogenation of various alkyne, alkene and polar imine motifs in selected substrates
at room temperature and low H2 pressure. The solid cobalt catalyst described therein is prepared
through the action of lithium naphthalenide on anhydrous CoCl2 in THF over a period of one day.9 In a
similar vein, Jacobi von Wangelin and coworkers introduced a very active solid cobalt catalyst that is
accessible from a CoBr2-LiEt3BH mixture. The resultant material readily facilitates the hydrogenation
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of alkenes, carbonyls, and imine moieties under mild reaction conditions.10 Soon later, Guan and Dai
devised an in situ system that produces a related heterogeneous catalyst upon reaction of anhydrous
CoBr2 with NaHBEt3 and which was successfully applied in the pressure hydrogenation of nitriles to
afford primary amines.11 Interestingly, if the Co(II)-center in their precursor salt is first complexed
with a PNP ligand and then treated with the hydride reagent, a soluble cobalt species is formed which
mediates dehydrogenative coupling towards imines.
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Regarding homogeneous catalysis, the vast majority of active systems relies on a cobalt central atom
held by multidentate phosphorus-based ligands incorporating pincer or tripodal architectures. Besides
the title transformation,12 the well-balanced reactivity-stability relationship of these soluble Co
complexes gives rise to a number of other highly relevant catalytic transformations including the
hydrogenation of aldehydes,13,14 ketones,13 esters,15 and a variety of atom efficient bond-forming
reactions.16 Strikingly, even the notoriously recalcitrant carboxylic acids are readily hydrogenated with
gaseous H2 under the action of a molecularly well-defined Co-triphos assembly.17
In a seminal work, Chirik and coworkers demonstrated that Co(II)-bisphosphine complexes are
effectively reduced to the corresponding phosphine-ligated Co(I) compounds in the presence of ten
molar equivalents of zinc. The thus activated cobalt species facilitate the enantioselective
homogeneous hydrogenation of enamides and their catalytic performance even competes with related
noble metal-based congeners.18
Within renovated context, we adopted this zinc-based in situ reduction approach and took advantage of
the catalytic activity of finely dispersed cobalt particles in the catalytic hydrogenation of nitriles (vide
supra). The pertinent catalytic transformation to yield (di)amines commands a privileged position in a
hierarchy of chemical processes arranged according to atom efficiency and sustainability. Most
importantly, the related products represent pivotal precursors to indispensable commodities as well as
specialty chemicals such as polymers, synthetic dyes, agrochemicals and pharmaceuticals.19
Herein we communicate an exceptionally simple and practical method for the in situ preparation of a
particulate cobalt catalyst capable of converting (di)nitriles to (di)amines under hydrogen pressure.
The catalytically active material is formed upon addition of readily available Co(OAc)2∙4 H2O and
innocuous Zn powder to the reaction mixture during the course of the hydrogenation
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process. Noteworthy, both the reaction vessels and the autoclave are charged under an ordinary
laboratory atmosphere. Hence, the tedious and time-consuming glovebox-related channel in-
and channel out-procedure, which is otherwise mandatory when working with anhydrous
CoX2 (X=Cl, Br) and air-sensitive borane reagents, is omitted. Furthermore, ammonia was routinely
added as an either aqueous or methanolic solution to the substrate/catalyst-assembly in order to
effectively suppress the formation of higher alkylated amines.20
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Results and Discussion
We commenced our study by treating a well-agitated solution of benzonitrile 1a in methanol with
5 mol% of Co(OAc)2∙4 H2O and 25 mol% of zinc metal in a 40 bar hydrogen atmosphere at 100 °C for
15 hours (Scheme 1). Delightfully, complete conversion of the nitrile was observed upon GC/MS-
analysis of the reaction mixture. However, in accordance with previous reports on catalytic nitrile
hydrogenation, the selectivity of benzylamine (2a) formation was well below 100% (see Table S1,
entry 3 in the supporting information) owing to a consecutive condensation reaction that produces the
imine coupling product Ph-CH=N-CH2-Ph. The latter is eventually hydrogenated to afford the
corresponding secondary amine. As formation of the pertinent imine necessarily involves the
expulsion of one equivalent NH3 from the reaction assembly, we anticipated that addition of ammonia
(one equivalent with respect to the substrate) to the reaction mixture would curb imine formation and
therefore the selectivity towards the primary amine product is expected to rise significantly (vide
supra). We examined two commercial diluted ammonia-solutions as additive, namely NH3 in
methanol (2 M) and a concentrated aqueous solution (18 M). The catalytic transformation employing
the methanolic solution gave rise to a mixture of the amine 2a and small amounts (1%) of the imine
byproduct Ph-CH=N-CH2-Ph. On the other hand, use of an aqueous solution led to the formation of
minute quantities (1-2%) of oxygenated side products such as benzylalcohol and benzylamide as well
as dibenzylamine (Figure 1). The alcohol and the amide are likely to result from reaction of water with
produced 2a and substrate 1a. This difference in selectivity rendered the methanolic system favorable
for the catalytic hydrogenation of benzonitrile 1a. However, other nitrile substrates were converted
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with higher selectivity on employing aqueous ammonia. Therefore, judicious choice of the ammonia
source is crucial for an optimized performance of the catalytic system.
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Scheme 1: Reaction products of the catalytic hydrogenation of benzonitrile 1a facilitated by a Co(II)/Zn(0)-couple in the
presence of 1 eq. NH3. Depending on the ammonia source, the main product 2a is accompanied by one and three
contaminants, respectively. aFormed byproducts if aqueous ammonia was used as additive.
Having identified this potent reaction-setup, we investigated the nature of the catalytically active
species thereof. Examination of the reaction solutions after autoclave decompression revealed the
formation of ferromagnetic metal particles, which were strongly attracted to the magnetic stirring bar.
These observations clearly indicate that the Co(II) ions originating from the precursor salt was reduced
to metallic Co(0).9 In order to establish the heterogeneous modus operandi of the pertinent catalyst we
performed Maitlis’ hot filtration test.21 As expected, no hydrogenation activity was observed upon
filtration of the hot reaction solution through a PTFE-membrane (0.2 µm pore size) after 2 hours
(under optimized conditions the reaction reaches completion within 6 h, vide infra) and reenacting the
catalytic transformation with the filtrate. Noteworthy, addition of fresh zinc to the spent reaction
solution did not result in the production of any further catalytically active material. If the
depressurized autoclave is transferred into an argon-filled glovebox, opened and then charged with
another aliquot of starting material, the Co/Zn-assembly is still active and can be reused directly after
the first run. We performed this recycling experiment with benzonitrile under optimized reaction
conditions (Figure 1) whereas no loss of catalyst activity was observed.
Sole
consideration
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reduction
reaction
Co(II) + Zn(0) → Co(0) + Zn(II) suggests that one equivalent of zinc metal per cobalt should suffice
for the complete cementation of metallic Co from its corresponding salt. However, if the catalytic
transformation is carried out with one equivalent of Zn vs. the precursor salt, incomplete nitrile
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conversion is observed (Table S3, entry 3) and residual Co(II) ions were found to be present in the
reaction solution as indicated by the associated characteristic pink color of the liquid portion of the
reaction mixture. Lest the catalytic performance of the system is compromised by insufficient catalyst
formation, zinc was thus used in a threefold molar excess with respect to the Co(II)-source. With this,
benzonitrile was almost completely converted to benzylamine upon reaction over night (100 °C,
40 bar H2). Yet, further raising the loading of the reductant (5 equiv.) did not have any impact on the
conversion of benzonitrile (Table S3, entries 1 and 2).
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Next, we investigated other non-noble metals and metalloids for their potential to bring about the
mandatory Co(II)-reduction and to mediate the title transformation, i.e. manganese, magnesium,
boron, and silicon. Inspection of Table S3 reveals that these four potential reducing agents are heavily
outperformed by Zn; only Mn enabled certain conversion of the substrate albeit the pertinent catalytic
performance seriously lags behind that of the respective Zn-based system. Reactions conducted with
Mg, B and Si as reducing agents were unsuccessful and did not result in any substrate conversion
(Table S3, entries 5-8).
Other commercial cobalt salts such as CoCl2∙6 H2O, Co(BF4)2∙6 H2O, and dry [Co(NH3)6]Cl3 were
then tested for their suitability to function as precursors to the pertinent catalytically active Co-
particles. Among these, the two Co(II)-salts worked as well as hydrated Co(OAc)2 under the same
reaction conditions (5 mol% Co(II)-salt, 100 °C, 40 bar, 15 h, 1 eq. NH3) thereby forming
benzylamine almost quantitatively. The investigated Co(III)-complex was especially intriguing since
this compound would not only represent a source of cobalt but would also provide the crucial
ammonia by virtue of its six built-in NH3 ligands. Interestingly, the performance of the respective
[Co(NH3)6]Cl3-borne catalytic protocol, could only compete with the examined Co(II)-hydrates when
both the reaction vessels and the autoclave were charged under an inert gas atmosphere (Ar). On the
other hand, full collapse of the catalytic activity was observed when the reaction set-up was assembled
on the bench outside the glovebox (Table S2, entries 7 and 8). Since convenient handling and
robustness are paramount to the catalytic protocol described herein, we consequently restrained from
using [Co(NH3)6]Cl3 as a precursor material.
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Deterred by the rather high cobalt(II)-salt loading of 5 mol% we decided to add a Lewis acid
cocatalyst (zinc triflate22) in order to decrease the overall metal content of the reaction solution while
still maintaining reasonable catalytic activity. Indeed, addition of 2 mol% of Zn(OTf)2 gave rise to
almost quantitative formation of benzylamine with a Co(OAc)2-loading of 2 mol% after reaction
overnight whereas only a mediocre yield (75%) was obtained when the analogous transformation was
conducted in the absence of any Lewis acid (Figure 1). The use of the latter is also well compatible
with the presence of water in the reaction solution and quite remarkably, the catalytic activity of the
system was drastically increased when 2 eq. of aqueous NH3-solution were applied; in this case,
benzonitrile hydrogenation was complete after 6 hours (Figure 1). Other popular Lewis acids such as
ZnCl2 and Al(OTf)3 also proved to be proper cocatalysts for the title transformation (vide infra).
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with 1 eq. NH3 (MeOH), 2 mol% Zn(OTf)2
with 2 eq. NH3 (H2O), 2 mol% Zn(OTf)2
with 2 mol% Zn(OTf)2
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Figure 1: Concentration/time diagrams for the pertinent catalytic hydrogenation of benzonitrile. The accelerating effect of
the Lewis acid and ammonia concentration is demonstrated. Note that the catalytic system is almost inactive with a catalyst
loading of 2 mol% Co without any additive. Furthermore, the presence of ammonia is vital for the component mixture to
develop catalytic activity. The sole presence of Zn(OTf)2 does not effect the given hydrogenation reaction. The specified
yields were determined by GC-MS-analysis using n-hexadecane as internal standard.
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Next, we investigated the influence of the reaction medium on the performance of the catalytic system
(Table S1 in the SI). Noteworthy, MeOH proved to be superior among the tested solvents although the
differences in product formation are not very distinct in the case of EtOH, i-PrOH, MTBE, and
n-heptane provided that aqueous NH3-solution is used as additive. In this series, benzonitrile was
almost completely converted to the desired benzylamine with only minute formation of byproducts.
Interestingly, eco-friendly water and the frequently used organic solvents THF and toluene gave rise to
only poor results in terms of substrate conversion. However, use of alcohols as solvents proved to be
the most promising option. As industrial processes should strive for replacing petroleum-based
solvents with mores sustainable analogues that are readily obtained by means of biomass degradation,
use of alcohols as solvents is also favorable following the principles of green chemistry. Furthermore,
methanol provides excellent solubility for the vast majority of organic substrates that are equipped
with polar functional groups.
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Eventually, we established the scope of the described Co-catalyzed heterogeneous nitrile-
hydrogenation. A broad variety of substrates was treated under similar conditions, striving for low
catalyst loadings and selective production of the primary amine. The latter were isolated as their
respective hydrochloride salts (3a-u) through precipitation from the reaction mixture upon addition of
dry hydrochloric acid. An overview of various synthesized organic ammonium salts together with their
isolated yields is given in Scheme 2. Inspection of the latter reveals that the introduced in situ-
prepared heterogeneous Co-catalyst is of general applicability for the hydrogenation of a variety of
nitriles by virtue of its decent functional group tolerance. The halogenated benzonitrile derivatives
1f-k were neatly converted to the respective amines without the occurrence of any intrusive
hydrodehalogenation side-reactions. Direct comparison of the hydrogenation outcome of mono-
chlorinated substrates 1f, 1g and 1h disclosed an interesting effect; whereas the ortho-substituted
chlorobenzonitrile showed very selective hydrogenation in a pure methanolic regime, the meta- and
para- substituted products 3g and 3h were only obtained in acceptable yield on raising the amount of
Lewis acid and using aqueous ammonia solution. This subtle dependence of product yield on the
polarity of the reaction medium was also observed on going from the parent benzonitrile to the
naphthalene kindred (compounds 3a, 3c, and 3d). The reaction product 2m proved to be rather
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recalcitrant since it could not be isolated neither on precipitation with hydrochloric acid nor through
column chromatography owing to decomposition of the amide. The hydrogenation of α,β-unsaturated
cinnamonitrile 1n solely produced 3-phenylpropylamine 2n, indicating that both 1,2- and 1,4-
hydrogenation took place. The reduction of acetonitrile 1q to form ethylamine 2q was hampered by
the high volatility of the latter and the low observed yields are unequivocally attributed to partial
evaporation of the product during work-up. Naturally, less volatile aliphatic nitriles such as 1p were
therefore smoothly hydrogenated and the isolated yields are comparable with those obtained upon
hydrogenation of their aromatic counterparts. Interestingly, highly relevant adiponitrile 1r was
selectively converted to hexamethylenediamine 2r if methanol was substituted with H2O as the
reaction medium. Owing to the low miscibility of the nitrile in water, a 2-phase system formed
promptly which was gradually transformed into a homogeneous system during the course of the
hydrogenation reaction as the corresponding diamine is well soluble in water. This difference in the
water-solubility of reactant and product may provide additional thermodynamic bias for the diamine
formation. It is worth mentioning here that cobalt cementation with zinc dust is industrially performed
for the electrowinning of Zn from aqueous ZnSO4-solutions.23 Hence, the given in situ protocol might
be a sound alternative for the large-scale synthesis of the important hexamethylenediamine.
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Noteworthy, 3-cyanopyridine did not show any reactivity in the given hydrogenation, presumably
because of catalyst deactivation through binding of the reasonably nucleophilic sp2-nitrogen onto the
cobalt surface. To cope with this problem, we decided to use an NH4Cl/NH3-mixture which causes the
protonation of the pyridine-nitrogen atom such that it is essentially rendered non-nucleophilic. Indeed,
this NH4Cl/NH3-buffer approach permitted access to the amine-tethered pyridine 2l, that was isolated
as its hydrochloride with good yields on precipitation with etheric HCl solution. Regrettably, on
applying this method to related heterocycles, viz. 4-cyanopyridine, 2-furonitrile, and
2-thiophencarbonitrile the reaction was sluggish and no useful reaction product could be isolated.
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a
Scheme 2. Products of nitrile hydrogenation with isolated yields and applied additive. Reaction conditions: nitrile 1a-u (0.5
mmol), Co(OAc)2∙4 H2O (0.01 mmol), zinc powder (0.03 mmol), Lewis acid as indicated, 100 mol% of indicated ammonia
b
solution, in 1.5 mL of solvent as indicated, 120 °C, 40 bar H2, reaction time: 15 h. 5 mol% of Co(OAc)2∙4 H2O were used.
cFormation only confirmed by GC analysis, decomposition during work-up. dCinnamonitrile was used as substrate.
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Oligomerization of initially formed reduction products was further identified as the principal
disruptive factor that arises whenever both electro- and nucleophilic motifs are present in the substrate
en route to amine formation. If, for example, 4-cyanobenzaldehyde 1u is directly subjected to the
given Co-based hydrogenation procedure, an orange insoluble precipitate is formed that escapes
analysis via routine methods (Scheme 3, left part). In order to circumvent this obtrusive side-reaction,
we installed a protecting group, i.e. 1,3-dioxolane, to first obtain compound 1v which was
subsequently hydrogenated to the benzylamine derivative 2v. Indeed, nucleophilic attack of the amine
group onto the reactive aldehyde motif was effectively bypassed on using this protection approach and
the target ammonium salt 3u was isolated in 80% yield (Scheme 3, right part). Note, that the dioxolane
moiety was cleaved in situ during product precipitation and hence a separate deprotection step was not
necessary.
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Scheme 3: Upon hydrogenation of unprotected 4-cyanobenzaldehyde 1u intensely colored and insoluble high molecular
weight products are formed (left image). Protection of the aldehyde motif with ethylene glycol, subsequent hydrogenation
and an eventual simultaneous precipitation-deprotection step affords the ammonium salt 3u. The turbidity in the right
reaction vessel originates from the presence of the Co- and Zn-particles.
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We reported on a ligand-free heterogeneous hydrogenation catalyst by in situ cementation of cobalt
particles from various cheap and readily abundant Co(II)-precursor salts with zinc powder. The
catalytically active species thus produced facilitate the hydrogenation of nitriles to yield primary
amines. Special equipment (glovebox, Schlenk vacuum manifold, pyrolysis oven) is not necessary,
neither for the preparation of the catalyst nor for assembling the reaction setup. Both selectivity and
activity of the catalytic system are influenced by the presence of ammonia and Lewis acid. Strikingly,
the pertinent Co(II)/Zn(0)-pair enables a water-based synthesis of the industrially relevant
hexamethylenediamine.
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Experimental Section
General Information. All chemicals were purchased from Merck (including Sigma Aldrich), Acros
Organics, Alfa Aesar, VWR, Roth, TCI, Lancaster Synthesis or Chem Lab and were used as received
without further purification. Hydrogenation reactions were carried out in a 300 mL autoclave from
Parr Instruments GmbH and the employed hydrogen was purchased from Linde Gas GmbH with a
purity of 5.0. Inert charging procedures were carried out in a LABmaster pro glovebox from Braun,
filled with argon (6.0 purity from Linde Gas GmbH). Dry solvents were received from a MB-SPS-7
solvent system from M. Braun GmbH. GC-MS analysis was carried out on a Shimadzu GC-MS QP-
2020 with helium (5.0 purity from Linde Gas GmbH.) as carrier gas. High-resolution mass
spectrometry was performed on a Thermo Fisher Scientific LTQ Orbitrap XL or on an Agilent
Technologies QTOF 6520 with ESI+ ion source for probes with m/z < 50. NMR measurements were
performed on a Bruker Avance 300 MHz spectrometer. Spectra for different cores were recorded as
follows: 300 MHz for 1H-NMR, 75.5 MHz for 13C and 282.4 MHz for 19F. Chemical shifts are listed in
parts per million (ppm) on the delta scale (δ). Axis calibration was performed using the residual non-
deuterated solvent for 1H-NMR as a reference.
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The hydrogen cylinder (200 bar, 50 liters) is placed in a safety storage cabinet that is equipped with an
integrated extraction unit. The pressure vessel is attached to a mechanical control panel that allows for
fine-adjustment of the desired H2-pressure used for the catalytic transformation. The charging of the
autoclaves is performed under an efficient fume hood that incorporates a hydrogen sensor. The latter is
electronically connected to a magnetic valve that immediately stops the H2-supply in case of any gas
leakage that might occur during the filling procedure. Furthermore, an optical as well as an acoustical
alarm signal is triggered as soon as free H2 is detected inside the hood.
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Protocol for screening of in situ reactions. A 4 mL glass vial was initially charged with a magnetic
stirring bar, cobalt(II) salt (0.02 – 0.05 mmol), Lewis acid (0.02 – 0.05 mmol), and commercial
100 mesh zinc powder from Alfa Aesar (0.06 – 0.15 mmol). After that, 1.5 mL of solvent were added
and to the resulting mixture the substrate (0.5 mmol) as well as ammonia (0.5 – 1.0 mmol) in methanol
or water were added. If a solid substrate was tested, it was placed in the vial prior to solvent addition.
The reaction vessel was then sealed with a septum cap that was subsequently penetrated with a needle.
The glass vials were then placed in a drilled Al-plate with a capacity to accommodate seven vessels.
Hereafter, the Al-inlet was transferred into the autoclave which was then tightly sealed. The autoclave
was flushed with hydrogen three times before being pressurized. After that, the autoclave was put on a
stirring plate and heated up to the required reaction temperature. On completion of the catalytic
transformation, the autoclave was allowed to reach room temperature. After that, the H2-pressure was
released, and 1 mL of solvent was added to each of the reaction vials. If the reaction was performed in
water, 2 mL of methanol were added to ensure homogeneity of the reaction mixture. Thereafter, the
solutions were degassed by stirring on air for 30 minutes and an aliquot of 20 µL was then taken from
each vial, mixed with 1 mL of methanol and eventually analyzed by GC-MS.
Synthesis of N-(4-cyanophenyl)acetamide (1m). In a 50 mL Schlenk flask, 575 mg of
4-aminobenzonitrile (4.87 mmol) were dried in vacuo and dissolved in 20 mL of dry dichloromethane.
The solution was then cooled to 0 °C and 567 µL of acetic anhydride (6.00 mmol, 1.26 eq.) were
subsequently added in small portions over a period of 15 minutes. The well-agitated reaction mixture
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was allowed to reach room temperature and hereafter stirring was continued for a further 19 h under an
atmosphere of N2. On completion of the reaction, the mixture was washed with saturated aqueous
NaHCO3 solution which gave rise to a white precipitate that was collected on a glass frit (POR 4) and
washed with 10 mL of DCM. The mother liquor was reduced on the rotary evaporator to give an
additional portion of the title compound together with a yellow oil that was eventually removed on
washing with n-heptane.
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N-(4-cyanophenyl)acetamide (1m). White amorphous powder: 682 mg (4.27 mmol, 88% yield).
Analytical data: 1H NMR (300 MHz, THF-d8, 20 °C): δ = 9.43 (s, NH), 7.78 (d, J = 8.82 Hz, 2H), 7.62
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(d, J = 8.78 Hz, 2H), 2.10 (s, 3H) ppm; C{1H} NMR (75.5 MHz, THF-d8, 20 °C): δ = 168.1, 143.6,
132.7, 118.7, 118.3, 106.1, 23.2 ppm; HRMS (ESI-Orbitrap) m/z: [M+H]+ Calcd for C9H9N2O:
161.0709; Found: 161.0710.
Protection of 4-formylbenzonitrile (1u). In a 50 mL round-bottom flask, 700 mg of
4-formylbenzonitrile 1u (5.34 mmol) and 96 mg of p-toluenesulfonic acid monohydrate (0.50 mmol,
0.095 eq.) were dissolved in 14 mL of toluene. After that 580 µL of ethylene glycol (10.4 mmol,
1.95 eq.) were added and the flask was connected to a Dean-Stark apparatus. The reaction mixture was
heated up to 105 °C in an oil bath and agitated for 15 h whereas the reaction progress was monitored
by GC-MS. On completion of the reaction, the mixture was allowed to reach room temperature and
then 10 mL of a saturated aqueous NaHCO3 solution were added. The aqueous phase was then
extracted three times with toluene in portions of 10 mL. The combined organic phases were dried with
sodium sulfate and the solvent was eventually removed in vacuo, affording 6ac as a yellow oil.
4-(1,3-dioxolan-2-yl)benzonitrile (1v).Yellow oil: 838 mg (5.34 mmol, 98% yield). Analytical data: 1H
NMR (300 MHz, CDCl3, 20 °C): δ = 7.67 (d, J = 7.98 Hz, 2H), 7.59 (d, J = 8.10 Hz, 2H), 5.85 (s, 1H),
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4.14 – 4.02 (m, 4H) ppm; C{1H} NMR (75.5 MHz, CDCl3, 20 °C): δ = 143.1, 132.2, 127.2, 118.6,
112.9, 102.4, 65.4 ppm; HRMS (ESI-Orbitrap) m/z: [M+H]+ Calcd for C10H9NO2: 176.0706; Found
176.0707.
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General procedure for the isolation of the hydrogenation products. The methanolic product
solution was transferred from the reaction vial to a 25 mL round-bottom flask. The volatiles were
removed under reduced pressure and the remains were taken up in 5 mL of dichloromethane (DCM).
Hereafter, the flask was rinsed with dichloromethane several times and the resulting organic phase was
washed with saturated NaHCO3 solution. The aqueous phase was extracted three times (up to five
times for more hydrophilic substrates) with DCM and the combined organic layers were dried with
sodium sulfate. Then, 3 mL of 2M hydrochloric acid in diethyl ether were added, resulting in
precipitation of a white solid for most compounds. The solid was collected on a glass frit (POR 4) and
the mother liquor was concentrated and cooled to -40 °C to afford further precipitation. Finally, the
combined white solids were dried on air and weighed.
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Benzylammonium chloride (3a). Synthesized according to the standard procedure. 51.6 mg
(0.500 mmol) of 1a were used. White crystalline powder: 67.0 mg (0.468 mmol, 94% yield).
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Analytical data: H NMR (300 MHz, D2O, 20 °C): δ = 7.53-7.45 (m, 5H), 4.20 (s, 2H) ppm; C{1H}
NMR (75.5 MHz, D2O, 20 °C): δ = 132.6, 129.2, 128.8, 43.1 ppm; HRMS (ESI-Orbitrap) m/z:
[M-Cl]+ Calcd for C7H10N: 108.0813; Found: 108.0805.
4-Methylbenzylammonium chloride (3b). Synthesized according to the standard procedure. 58.1 mg
(0.496 mmol) of 1b were used. White crystalline powder: 55.9 mg (0.356 mmol, 72% yield).
Analytical data: 1H NMR (300 MHz, D2O, 20 °C): δ = 7.78 (d, J = 8.82 Hz, 2H), 7.62 (d, J = 8.78 Hz,
2H), 4.09 (s, 2H), 2.10 (s, 3H) ppm; 13C{1H} NMR (75.5 MHz, D2O, 20 °C): δ = 139.6, 129.7, 129.5,
128.8, 42.8, 20.2 ppm; HRMS (ESI-Orbitrap) m/z: [M-Cl]+ Calcd for C8H12N: 122.0970; Found:
122.0963.
1-Naphthylmethylammonium chloride (3c). Synthesized according to the standard procedure.
78.0 mg (0.509 mmol) of 1c were used. White crystalline powder: 81.0 mg (0.420 mmol, 82% yield).
Analytical data: 1H NMR (300 MHz, D2O, 20 °C): δ = 7.94-7.83 (m, 3H), 7.63-7.43 (m, 4H), 4.50 (s,
2H) ppm; 13C{1H} NMR (75.5 MHz, D2O, 20 °C): δ = 133.4, 130.3, 129.9, 128.9, 128.1, 127.7, 127.2,
126.5, 125.5, 122.3, 40.1 ppm; HRMS (ESI-Orbitrap) m/z: [M-Cl]+ Calcd for C11H12N: 158.0970;
Found: 158.0965.
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2-Naphthylmethylammonium chloride (3d). Synthesized according to the standard procedure.
77.7 mg (0.507 mmol) of 1d were used. White crystalline powder: 77.9 mg (0.403 mmol, 80% yield).
Analytical data: 1H NMR (300 MHz, D2O, 20 °C): δ = 7.98-7.88 (m, 4H), 7.62-7.56 (m, 2H), 7.51 (dd,
J1 = 1.41 Hz, J2 = 8.49 Hz, 1H), 4.30 (s, 2H) ppm; 13C{1H} NMR (75.5 MHz, D2O, 20 °C): δ = 132.9,
132.8, 130.1, 128.9, 128.2, 127.9, 127.7, 127.0, 126.9, 125.9, 43.2 ppm; HRMS (ESI-Orbitrap) m/z:
[M-Cl]+ Calcd for C11H12N: 158.0970; Found: 158.0965.
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4-Methoxybenzylammonium chloride (3e). Synthesized according to the standard procedure.
66.2 mg (0.497 mmol) of 1e were used. White crystalline powder: 73.6 mg (0.425 mmol, 86% yield).
Analytical data: 1H NMR (300 MHz, D2O, 20 °C): δ = 7.43 (d, J = 8.73 Hz, 2H), 7.05 (d, J = 8.73 Hz,
2H), 4.14 (s, 2H), 3.85 (s, 3H) ppm; 13C{1H} NMR (75.5 MHz, D2O, 20 °C): δ = 159.4, 130.6, 125.1,
114.6, 55.4, 42.6 ppm; HRMS (ESI-Orbitrap) m/z: [M-Cl]+ Calcd for C8H12NO: 138.0919; Found:
138.0913.
2-Chlorobenzylammonium chloride (3f). Synthesized according to the standard procedure. 68.5 mg
(0.498 mmol) of 1f were used. White crystalline powder: 80.2 mg (0.453 mmol, 91% yield).
Analytical data: 1H NMR (300 MHz, D2O, 20 °C): δ = 7.61 – 7.38 (m, 4H), 4.35 (s, 2H) ppm; 13C{1H}
NMR (75.5 MHz, D2O, 20 °C): δ = 133.8, 131.2, 131.1, 130.1, 129.9, 127.8, 40.8 ppm; HRMS (ESI-
Orbitrap) m/z: [M-Cl]+ Calcd for C7H9ClN: 142.0424; Found: 142.0418.
3-Chlorobenzylammonium chloride (3g). Synthesized in accordance with the standard procedure.
68.5 mg (0.498 mmol) of 1g were used. White crystalline powder: 75.8 mg (0.428 mmol, 86% yield).
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Analytical data: H NMR (300 MHz, D2O, 20 °C): δ = 7.54-7.36 (m, 4H), 4.19 (s, 2H) ppm; C{1H}
NMR (75.5 MHz, D2O, 20 °C): δ = 133.4, 134.1, 130.7, 129.2, 128.7, 127.2, 42.5 ppm; HRMS (ESI-
Orbitrap) m/z: [M-Cl]+ Calcd for C7H9ClN: 142.0424; Found: 142.0418.
4-Chlorobenzylammonium chloride (3h). The title compound was synthesized in accordance with
the standard procedure. 69.1 mg (0.502 mmol) of 1h were used. White crystalline powder: 77.4 mg
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(0.437 mmol, 87% yield). Analytical data: H NMR (300 MHz, D2O, 20 °C): δ = 7.66-7.30 (m, 4H),
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4.19 (s, 2H) ppm; C{1H} NMR (75.5 MHz, D2O, 20 °C): δ = 134.5, 131.2, 130.4, 129.2, 42.4 ppm;
HRMS (ESI-Orbitrap) m/z: [M-Cl]+ Calcd for C7H9ClN: 142.0424; Found: 142.0418.
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4-Fluorobenzylammonium chloride (3i). Synthesized in accordance with the standard procedure.
59.8 mg (0.494 mmol) of 1i were used. White crystalline powder: 73.0 mg (0.453 mmol, 92% yield)
Analytical data: 1H NMR (300 MHz, D2O, 20 °C): δ = 7.50 (d, J = 5.61 Hz, 1H), 7.48 (d, J = 5.46 Hz,
1H), 7.21 (t, J1 = 8.75, 2H) 4.19 (s, 2H) ppm; 13C{1H} NMR (75.5 MHz, D2O, 20 °C): δ = 162.9 (d, J
= 246 Hz, 1C), 131.1 (d, J = 8.77 Hz, 1C), 128.6 (d, J = 3.18 Hz, 1C), 116.0 (d, J = 22.0 Hz, 1C) 42.4
ppm; 19F-NMR (282.4 MHz, D2O, 20 °C): δ = -113.2 (s, Ar-F) ppm; HRMS (ESI-Orbitrap) m/z:
[M-Cl]+ Calcd for C7H9FN: 126.0719; Found: 126.0713.
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2-Fluoro-6-methoxybenzylammonium chloride (3j). Synthesized according to the standard
procedure. 75.3 mg (0.498 mmol) of 1j were used. White crystalline powder: 81.3 mg (0.426 mmol,
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85% yield). Analytical data: H NMR (300 MHz, D2O, 20 °C): δ = 7.45 (q, J = 7.92 Hz, 2H), 6.95-
6.80 (m, 2H), 4.24 (s, 2H) 3.92 (s, 3H) ppm; 13C{1H} NMR (75.5 MHz, D2O, 20 °C): δ = 161.1 (d, J =
246 Hz, 1C), 158.8 (d, J = 6.86 Hz, 1C), 131.8 (d, J = 10.9 Hz, 1C), 107.8 (d, J = 22.1 Hz, 1C), 107.8,
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107.1 (d, J = 2.88 Hz, 1C) 56.1, 31.8 (d, J = 5.98 Hz, 1C) ppm; F-NMR (282.4 MHz, D2O, 20 °C):
δ = -117.4 (s, Ar-F) ppm; HRMS (ESI-Orbitrap) m/z: [M-Cl]+ Calcd for C8H11FNO: 156.0825; Found:
156.0820.
4-(Trifluoromethyl)benzylammonium chloride (3k). Synthesized according to the standard
procedure. 84.0 mg (0.491 mmol) of 1k were used. White crystalline powder: 87.6 mg (0.415 mmol)
84% yield). Analytical data: 1H NMR (300 MHz, D2O, 20 °C): δ = 7.80 (q, J = 8.04 Hz, 2H), 7.64 (d,
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J = 8.04 Hz, 2H), 4.29 (s, 2H) ppm; C{1H} NMR (75.5 MHz, D2O, 20 °C): δ = 136.6, 130.4 (q, J =
32.3 Hz, 1C), 129.3, 126.0 (q, J = 6.86 Hz, 1C), 124.0 (d, J = 272 Hz, 1C), 42.6 ppm; 19F-NMR (282.4
MHz, D2O, 20 °C): δ = -62.5 (s, CF3) ppm; HRMS (ESI-Orbitrap) m/z: [M-Cl]+ Calcd for C8H9F3N:
176.0687; Found: 176.0684.
3-Pyridinmethylammonium chloride (3l). Synthesized in accordance with the standard procedure.
51.4 mg (0.494 mmol) of 1l were used. White crystalline powder: 53.7 mg (0.372 mmol, 76% yield).
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Analytical data: H NMR (300 MHz, D2O, 20 °C): δ = 9.02-8.85 (m, 2H), 8.75 (d, J = 8.22 Hz, 1H),
8.18 (t, J = 6.99 Hz, 1H), 4.51 (s, 2H) ppm; 13C{1H} NMR (75.5 MHz, D2O, 20 °C): δ = 147.4, 142.0,
141.8, 133.0, 127.8, 39.6 ppm; HRMS (ESI-Orbitrap) m/z: [M-Cl]+ Calcd for C6H9N2: 109.0766;
Found: 109.0759.
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3-Phenylpropylammonium chloride (3n). Synthesized according to the standard procedure. 64.6 mg
(0.500 mmol) of 1n were used. White crystalline powder: 82.7 mg (0.483 mmol, 97% yield).
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2.70 (t, J = 7.67 Hz, 2H), 1.95 (p, J = 7.62, 2H) ppm; C{1H} NMR (75.5 MHz, D2O, 20 °C): δ =
140.9, 128.8, 128.4, 126.4, 39.0, 31.8, 28.4 ppm; HRMS (ESI-Orbitrap) m/z: [M-Cl]+ Calcd for
C9H14N: 136.1126; Found: 136.1122.
Cyclohexylmethylammonium chloride (3o). Synthesized according to the standard procedure.
54.6 mg (0.500 mmol) of 1o were applied. White crystalline powder: 60.0 mg (0.402 mmol, 80%
yield). Analytical data: 1H NMR (300 MHz, D2O, 20 °C): δ = 2.88 (d, J = 6.75 Hz, 2H), 1.83-1.61 (m,
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6H), 1.38-1.15 (m, 3H), 1.10-0.94 (m, 2H) ppm; C{1H} NMR (75.5 MHz, D2O, 20 °C): δ = 45.2,
35.4, 29.6, 25.6, 25.0 ppm; HRMS (ESI-Orbitrap) m/z: [M-Cl]+ Calcd for C7H16N: 114.1283; Found:
114.1277.
Pentylammonium chloride (3p). Synthesized according to the standard procedure. 41.6 mg
(0.500 mmol) of 1p were used. White crystalline powder: 59.2 mg (0.481 mmol, 90% yield).
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Analytical data: H NMR (300 MHz, D2O, 20 °C): δ = 3.01 (t, J = 7.53 Hz, 2H), 1.68 (p, J = 7.29,
2H), 1.42-1.30 (m, 4H), 0.91 (t, J = 6.95, 3H) ppm; 13C{1H} NMR (75.5 MHz, D2O, 20 °C): δ = 39.5,
27.7, 26.4, 21.4, 13.1 ppm; HRMS (ESI-Orbitrap) m/z: [M-Cl]+ Calcd for C5H14N: 88.1126; Found:
88.1119.
Ethylammonium chloride (3q). The title compound was synthesized according to the standard
procedure but the autoclave was cooled down to 0 °C before opening and work-up was performed
rapidly using cooled solvents owing to the low boiling point of ethylamine. 20.5 mg (0.500 mmol) of
1q were used. White crystalline powder: 19.3 mg (0.238 mmol, 48 % yield). Analytical data: 1H NMR
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(300 MHz, D2O, 20 °C): δ = 3.21 (q, J = 7.33 Hz, 2H), 1.29 (t, J = 7.33 Hz, 3H) ppm; 13C{1H} NMR
(75.5 MHz, D2O, 20 °C): δ = 46.7, 8.2 ppm; HRMS (ESI-Orbitrap) m/z: [M-Cl]+ Calcd for C2H8N:
46.0657; Found: 46.0659.
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1-Adamantylammonium chloride (3s). Synthesized in accordance with the standard procedure.
80.6 mg (0.500 mmol) of 1s were applied. White crystalline powder: 94.7 mg (0.471 mmol, 94%
yield). Analytical data: 1H NMR (300 MHz, D2O, 20 °C): δ = 2.71 (s, 2H), 2.08-1.98 (m, 3H), 1.72 (q,
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J = 14.37 Hz, 2H), 1.61-1.55 (m, 6H) ppm; C{1H} NMR (75.5 MHz, D2O, 20 °C): δ = 50.7, 38.8,
35.9, 31.3, 27.6 ppm; HRMS (ESI-Orbitrap) m/z: [M-Cl]+ Calcd for C11H20N: 166.1596; Found:
166.1594.
2-Phenylethylammonium chloride (3t). Synthesized according to the standard procedure. 58.6 mg
(0.500 mmol) of 1t were applied. White crystalline powder: 75.6 mg (0.481 mmol, 96% yield).
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Analytical data: H NMR (300 MHz, D2O, 20 °C): δ = 7.49-7.33 (m, 5H), 3.30 (t, J = 7.17 Hz, 2H),
3.02 (t, J = 7.28 Hz, 2H) ppm; 13C{1H} NMR (75.5 MHz, D2O, 20 °C): δ = 136.6, 129.1, 128.9, 127.3,
40.6, 32.7 ppm; HRMS (ESI-Orbitrap) m/z: [M-Cl]+ Calcd for C8H12N: 122.0970; Found: 122.0965.
4-Formylbenzylammonium chloride (3u). Synthesized according to the standard procedure. 87.5 mg
(0.500 mmol) of 1v were used. White crystalline powder: 69.5 mg (0.406 mmol, 81% yield).
Analytical data: 1H NMR (300 MHz, D2O, 20 °C): δ = 9.95 (s, 1H), 8.00 (d, J = 8.10 Hz, 2H), 7.66 (d,
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J = 8.04 Hz, 2H), 4.31 (s, 2H) ppm; C{1H} NMR (75.5 MHz, D2O, 20 °C): δ = 195.8, 139.6, 136.0,
130.6, 129.4, 42.7 ppm; HRMS (ESI-Orbitrap) m/z: [M-Cl]+ Calcd for C8H10NO: 136.0762; Found:
136.0757.
Procedure for the isolation of hexamethylenediammonium chloride (3r). As the standard
procedure led to poor isolated yields for compound 3r owing to its high hydrophilicity, a different
approach was pursued. On completion of the catalytic transformation, the two-phase reaction solution
(methanol-water) was transferred from the reaction vial to a 25 mL round-bottom flask. Methanol and
ammonia were removed at the pump and the remains were taken up in 5 mL of ethyl acetate. The flask
was rinsed with water and ethyl acetate several times and the combined washing phases were filtered
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through a pad of celite. The latter was thoroughly washed with ethyl acetate after filtration and to the
combined layers, 5 mL of hydrochloric acid in diethyl ether were added. The mixture was shaken
vigorously before complete removal of the volatiles in vacuo. The title compound was isolated as a
white solid.
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1,6-Diammoniumhexyl dichloride (3r). Synthesized in equivalence to standard procedure. 54.1 mg
(0.500 mmol) of 1r were used. White crystalline powder: 84.7 mg (0.450 mmol, 90% yield).
Analytical data: 1H NMR (300 MHz, D2O, 20 °C): δ = 3.03 (t, J = 7.55 Hz, 4H), 1.76 – 1.65 (m, 4H),
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1.48 – 1.40 (m, 4H) ppm; C{1H} NMR (75.5 MHz, D2O, 20 °C): δ = 39.4, 26.5, 25.1 ppm; HRMS
(ESI-Orbitrap) m/z: [M-2Cl-H]+ Calcd for C6H17N2: 117.1392; Found: 117.1385.
Associated Content
Supporting Information
Elucidation of the effect of different solvents on the catalyst performance; description of the influence
of various Co-precursors, reaction temperature and H2-pressure on the catalytic activity; study of the
aptitude of selected metals and metalloids to function as reducing agents; 1H-, 13C{1H}-, 19F NMR, and
HR-MS spectra of the isolated products.
Author Information
Corresponding Author
*E-mail: christoph.topf@jku.at
ORCID
Christoph Topf: 0000-0001-7595-3074
Notes
The authors declare no competing financial interest.
Acknowledgments
We gratefully thank Univ.-Prof. Dr. Marko Hapke from the INCA for fruitful discussions and the
generous support. Moreover, assoc. Univ.-Prof. DI Dr. Markus Himmelsbach from the department of
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Analytical Chemistry at the JKU is gratefully acknowledged for performing the HRMS measurements
of the isolated products.
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