Selective Catalytic Hydrogenations of Nitriles, Ketones, and Aldehydes by Well-Defined Manganese Pincer Complexes

Article abstract of DOI:10.1021/jacs.6b03709

Hydrogenations constitute fundamental processes in organic chemistry and allow for atom-efficient and clean functional group transformations. In fact, the selective reduction of nitriles, ketones, and aldehydes with molecular hydrogen permits access to a green synthesis of valuable amines and alcohols. Despite more than a century of developments in homogeneous and heterogeneous catalysis, efforts toward the creation of new useful and broadly applicable catalyst systems are ongoing. Recently, Earth-abundant metals have attracted significant interest in this area. In the present study, we describe for the first time specific molecular-defined manganese complexes that allow for the hydrogenation of various polar functional groups. Under optimal conditions, we achieve good functional group tolerance, and industrially important substrates, e.g., for the flavor and fragrance industry, are selectively reduced.

Full text of DOI:10.1021/jacs.6b03709

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Article
Selective Catalytic Hydrogenations of Nitriles, Ketones and
Aldehydes by Well-Defined Manganese Pincer Complexes
Saravanakumar Elangovan, Christoph Topf, Steffen Fischer, Haijun Jiao, Anke
Spannenberg, Wolfgang Baumann, Ralf Ludwig, Kathrin Junge, and Matthias Beller
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b03709 • Publication Date (Web): 24 May 2016
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Selective Catalytic Hydrogenations of Nitriles, Ketones and Alde-
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SaravanakumarElangovan,† Christoph Topf,† Steffen Fischer,‡HaijunJiao,† Anke Spannenberg,†
Wolfgang Baumann,† Ralf Ludwig,‡ Kathrin Junge†and Matthias Beller*,†
† Leibniz-Institut für Katalyse e.V. Albert Einstein Str. 29a, 18059 Rostock Germany
‡Institut fürChemie, Universität Rostock, Dr.-Lorenz-Weg 1, 18059 Rostock, Germany
ABSTRACT:Hydrogenations constitute fundamental processes in organic chemistry and allow for atom-efficient and
clean functional group transformations. In fact, the selective reduction of nitriles, ketones and aldehydes with molecular
hydrogen permits access to a green synthesis of valuable amines and alcohols. Despite of more than a century of devel-
opments in homogeneous and heterogeneous catalysis, continuing efforts in the creation of new useful and broadly appli-
cable catalyst systems exist. Recently, especially earth-abundant metals attracted significant interest in this area. In the
present study, we describe for the first time specific molecular-defined manganese complexes, which allow for the hydro-
genation of various polar functional groups. Under optimal conditions we achieve good functional group tolerance and
industrially important substrates, e.g. for the flavor and fragrance industry, are selectively reduced.
nickel,14 copper15 and zinc16 have been scarcely reported
for hydrogenation reactions and should offer potential for
INTRODUCTION
new applications.
Catalytic hydrogenations are of outmost importance in
organic synthesis and play a key role in the production of
numerous bulk products and intermediates in the chemi-
cal industry. From an ecologic point of view, reductions
using molecular hydrogen as reducing agent represent
one of the most efficient and atom economical transfor-
mations.1 In general, heterogeneous catalysts are well
established in the hydrogenation of non-demanding polar
functional groups, which often takes place at high tem-
peratures and/or pressures.2 Complementary, the devel-
opment of well-defined homogeneous complexes which
allow for selective reduction under milder conditions con-
stitutes a cutting-edge endeavor in modern catalyst de-
sign.3 In this context, the introduction of bifunctional
metal ligand catalysis by Noyori for the catalytic hydroge-
Figure 1.Selected examples of non-precious metal catalytic
nation of carbonyl compounds4 represents a break-
systems for (de)hydrogenation reactions.
through. Since then, significant progress has been made
in this field using mainly noble metal complexes,5 namely
Despite all these efforts, one of the most common metals,
manganese, is basically unknown for catalytic hydrogena-
tions.17In fact, manganese is the 3rdmost abundant transi-
tion metals in Earth’s crust after iron and titaniumand is
absolutely necessary for development, metabolism, and
the antioxidant system of humans. Nowadays millions of
tons of manganese ore are used mainly for iron and steel
manufacture. Without doubt, this element represents a
highly attractive candidate for the design of new cata-
lysts.18 While manganese complexes are frequently em-
ployed in oxidations, they are generally not employed for
catalytic reductions and only special hydrosilylation,
electrocatalytic reactions and very recently dehydrogena-
tions are known.19Here, we describe for the first time the
application of manganese pincer complexes in catalytic
hydrogenations of nitriles, ketones and aldehydes.
ruthenium, iridium, and rhodium. However, in terms of
sustainability such precious metals ought to be replaced
by inexpensive and widely abundant first row base met-
als.6
Seminal progress in this area includes the hydrogenation
of ketones enabled by iron catalysts by the groups of Ca-
sey,7 Morris8 and Milstein9 (Figure 1). In this respect, our
group10 as well as others11 demonstrated the applicability
of Fe pincer complexes for a variety of hydrogenation and
dehydrogenation reactions.12 Meanwhile, pincer-based Co
complexes have been successfully applied in the hydro-
genation of carbonyl compounds, imines, alkenes and
nitriles.13 Comparing the present success with defined
iron and cobalt catalysts, other base metal complexes of
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represent ideal drop-in catalysts for practical hydrogena-
RESULTS AND DISCUSSION
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tions.
(a)
Catalyst preparation.Based on our expertise using spe-
cific Fe and Ru pincer complexes for the dehydrogenation
of methanol10a,20 and the related hydrogenations of carbon
dioxide and carboxylic acid derivatives, we became inter-
ested in the preparation of defined manganese PNP pin-
cer complexes.
Br
H
Br
H
H
H
N
H
N
PiPr2
N
PiPr2
PiPr2
N
PCy2
CO
9
Mn
Mn
Mn
Mn
P
P
P
Cy2
P
CO
CO
Cl
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iPr2
iPr2
iPr2
Cl
CO
CO
CO
1
2
3
4
Figure 2. Manganese complexes used for this study.
(b)
Until now, such manganese type complexes are sparsely
discussed in the literature and have not been used in
catalysis.21At the start of this project, four manganese
pincer complexes bearing two different PNP ligands were
prepared (Figure 2). An initial attempt, i.e. reaction of
MnCl2 with the isopropyl-tagged PNP ligand afforded 4.
The molecular structure of this complex was confirmed
by X-ray diffraction analysis (see SI V). In order to prepare
the potentially active carbonyl-ligated manganese hydride
complex, 4 was reacted with CO, but unfortunately no
reaction occurred.Hence an alternative strategy was envi-
sioned: Upon reaction of commercially available
[MnBr(CO)5] with the corresponding PNP ligands in tolu-
ene at 100 °C air-stable dicarbonyl manganese complexes 1
and 2 were conveniently prepared in a straightforward
manner without the necessity of additional CO treatment
(Scheme 1).
Figure 3.Molecular structure of complex 1 (a) and 2 (b). Only
one of the two molecules of the asymmetric unit is depicted.
Displacement ellipsoids are drawn at the 30% probability
level. Hydrogen atoms except of that attached to nitrogen are
omitted for clarity.
Scheme 1.Synthesis of manganese pincer complexes
Br
Catalysis.After having some potential manganese cata-
lysts in hand, we started to investigate their behavior in
the hydrogenation of nitriles, ketones and aldehydes.
Based on the recent interest in the selective reduction of
carboxylic acid derivatives,23 our initial attempts focused
on the hydrogenation of benzonitrileas benchmark sub-
strate (Table 1). Catalytic experiments were performed
with complexes 1-6 (3 mol% cat., 120 °C, 50 bar H2, 24 h).
In the presence of 1 some activity was observed, but no
desired product (5% benzyl alcohol; see Table SI 7) was
formed. In contrast combining 1 with 10 mol% of base (t-
BuONa), which should form a more active amido manga-
nese complex vide supra resulted in 98% of benzylamine!
To the best of our knowledge this representsthe first cata-
lytic hydrogenation using a molecularly-defined manga-
nese complex.
H
N
H
PR2
100 °C
N
P
PR2
CO
Mn(CO)5Br
+
Mn
PR2
toluene, 20 h
R2
CO
R = iPr
R = Cy
1
2
R = iPr ( ) 93%
R = Cy ( ) 80%
The resulting bright yellow complexes were fully charac-
terized by NMR and IR spectroscopy, high resolution
mass spectrometry, X-ray22 and elemental analysis (see
SI). The IR (ATR) spectra of 1 and 2 contain strong CO
stretching vibrations at 1903 cm-1, 1815 cm-1 and 1913 cm-1,
1826 cm-1, respectively, which clearly indicate the coordi-
nation of two CO ligands to the metal center. X-ray analy-
sis reveals that one of the CO ligands is located trans to
the nitrogen atom and the other CO is located trans to
the bromide ligand (Figure 3).
Advantageously, complexes 1-2 are highly stable and do
not decompose easily in the presence of air. In fact, ex-
posing complex 1 as a solid for 25 days to air did not result
in any decomposition (see Figure SI 7,8)! However, in the
presence of strong base, deprotonation of the coordinated
amine will promote the liberation of the halide anion. The
resulting amido manganese complex should activate mo-
lecular hydrogen via heterolytic splitting to form an active
Mn-hydride species. Thus, we thought these complexes
Interestingly, complex 3 (see SI IV), which can be gener-
ated from 1 upon addition of base and H2 and also pre-
pared by treatment with sodium triethylborohydride
produced benzylamine in 81% yield. The lower product
yield in the benchmark reaction using the hydride com-
plex 3 is explained by it´s lower stability. Starting from
complex 1 slow formation of the active complex 3 should
take place and potential decomposition reactions of this
active species are minimized.
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(Scheme 2 and 3). In general, electron-donating and elec-
Table 1.Manganese-catalyzed hydrogenation of benzo-
nitrilea
tron-withdrawing substituents, e.g. chloride, fluoride,
bromide and the more labile amino group as well as het-
erocycles are well tolerated. Notably, the reduction of 4-
(trifluoromethyl)benzonitrile was easily up scaled to 5g
and 8i.HCl was isolated in 95% yield.
1
2
3
4
5
6
7
8
9
Entry
Complex
Conv (%)b
Yield (%)b
Scheme3. Catalytichydrogenation of aliphatic and di-
nitriles
1
2
3c
4
5
1
>99
>99
>99
0
98
87
81
0
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3
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4
[MnBr(CO)5] 5
CpMn(CO)3 6
0
0
6
0
0
aReaction conditions: Substrate (0.5 mmol), 1-6 (0.015
mmol), t-BuONa (0.05 mmol), i-PrOH (1 mL), 24 h, 120 °C, 50
bar H2. b Conversion and yield were determined by GC analy-
sis using hexadecane as an internal standard. Under similar
conditions in the presence of base complex 3 gave 81% yield
c
of benzylamine. Without base only 42% yield was observed.
Reaction conditions: Substrate (0.5 mmol), 1 (0.015 mmol),
t-BuONa (0.05 mmol), toluene (1 mL), 24-60 h, 100-120 °C, 50
bar H2. Isolated as aHCl salt. Conversion (>99%) was deter-
mined by GC analysis using hexadecane as an internal stand-
ard. a GC yield. b 25% corresponding saturated amine.
In addition to 1, the related complex 2 also allowed for
hydrogenation in high yield (87%). However, Mn(II) spe-
cies 4 and the commercially available complexes 5 and 6
in the presence and absence of the pincer ligand gave no
products. Evaluation of critical reaction parameters in the
presence of complex 1 revealed optimal results in toluene
as solvent and t-BuONa as base (see Table SI 7). Notably,
significant activity is observed even in the presence of 2
mol% catalyst and 30 bar of hydrogen (see Table SI 7).
Next, we explored the activity of the manganese catalyst
towards a collection of more demanding aliphatic nitriles.
As an example, benzyl nitrile was successfully hydrogen-
ated to the corresponding amine 10a in 96% isolated
yield. Noteworthy, the conjugated nitrile afforded a mix-
ture of the corresponding unsaturated (53%) and saturat-
ed (25%) amines. Interestingly, the isolated double bond
containing 5-hexene nitrile was selectively hydrogenated
to amine 10j without affecting the double bond. Finally,
the 1,4-disubstituted benzonitrile 10k was reduced to the
diamine and isolated in 80% under the standard reaction
conditions.
Scheme 2.Catalytic hydrogenation of various (het-
ero)aromatic nitriles
Scheme4. Mn-catalyzedhydrogenation of ketones
Reaction conditions: Substrate (0.5 mmol), 1 (0.015 mmol),
t-BuONa (0.05 mmol), toluene (1 mL), 24 h, 120 °C, 50 bar H2.
Conversion (>99%) and yield were determined by GC analy-
sis using hexadecane as an internal standard. a Isolated yield.
Reaction conditions: Substrate (1 mmol), 1 (0.01 mmol), t-
BuONa (0.03 mmol), toluene (1 mL), 24-48 h, 100 °C, 30 bar
H2. Conversion was determined by GC (Isolated yield in
parentheses). a GC yield. b 48 h.
Apart from nitriles, selective hydrogenation of aldehydes
(Scheme 5)and ketones (Scheme 4)to the corresponding
primary and secondary alcohols took place in the pres-
ence of 1 mol% of complex 1 and 3 mol% t-BuONa. Under
The applicability of catalyst system 1 is demonstrated in
the selective hydrogenation of various nitriles including-
substituted aromatic, benzylic, aliphatic and di-nitriles
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these conditions the manganese-based catalyst tolerates (supporting information Figure SI 29). The presence and
1
2
3
4
5
6
7
8
other reducible groups such as lactams (12e), esters (12f)
and isolated C=C bonds (12i, 12j). Notably, the cyclopro-
pyl-substituted ketone furnished a quantitative yield of
12b indicating that the reaction does not proceed via
stable radical intermediates. Additionally, the heterocy-
clic substrate 1-benzylpiperidin-4-one and 4-chromanone
were converted into alcohols 12g and 12h, respectively.
position of the hydride ligand is confirmed by using D2
for the in-situ generation of the deuterated analogue (3b)
of 3. Deuteration affects the resonance interaction be-
tween the stretching vibrations of the Mn-H and the op-
posite C-O bond. Thereby, the signal of the asymmetric
C-O vibration is shifted to lower frequencies (1815
ꢀ1810
cm−1). This effect is also confirmed by DFT calculations
(supporting information Figure SI 30).
Scheme5. Selectivehydrogenation of aldehydes
9
Br
H
H
H
1
(1 mol%)
t-BuONa (3 mol%)
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N
PiPr2
N
PiPr2
N
PiPr2
H2 (5 bar)
O
t-BuONa (3 equiv)
OH
Mn
Mn
Mn
P
iPr2
P
iPr2
CO
P
iPr2
CO
CO
toluene d8
R
H
R
H
10 bar H2, 60 o
toluene, 24 h
C
CO
3a
CO
CO
13
14
1
3
Ph
OH
OH
OH
C5H11
OH
CH2(CH2)4CH3
OMe
14c 90% (81%)b
14d 99% (96%)a
14a 99% (93%)
14b 92% (87%)
OH
OH
OH
78% (69%)
HO
14f
O
a
a
a
14e
14g
97% (89%)
90% (64%)
Reaction conditions: Substrate (1 mmol), 1 (0.01 mmol), t-
BuONa (0.03 mmol), toluene (1 mL), 24 h, 60 °C, 10 bar H2.
Conversion was determined by GC (isolated yield in paren-
theses). a 100 °C, 30 bar H2. b 3% Saturated alcohol observed.
(a) (b)
α, β-Unsaturated aldehydes reacted selectively under
mild conditions (10 bar H2, 60 °C; Scheme 5). Here, in all
cases only the carbonyl group was reduced to give the
corresponding unsaturated alcohol. Accordingly, 2-
octynal gave oct-2-yn-1-ol in excellent isolated yield
(96%). In addition, several natural products, e.g. citron-
ellal (3,7-dimethyloct-6-enal), perillaldehyde and 5-
hydroxymethylfurfural (HMF) gave the corresponding
primary alcohols in moderate to excellent yield. These
substrates are also applied on larger scale as monomers
for polymers (HMF) or intermediates in the flavor and
fragrance industry.Unfortunately, the isolation of the
bisbenzylic alcohol 14f was difficult because some de-
composition occurred during separation and isolation.
Figure 4.(a) IR spectra and frequencies [cm-1] of complex 1
(black) and in-situ generated complex 3 (red) recorded in
toluene at 25 °C. Inlay: 40x magnification of the N-H signals.
(b) H NMR (toluene d8) spectrum of complex 3 (hydride
region).
1
To illustrate the catalytic activity of complex 3 further
DFT calculations were performed on the hydrogenation of
acetonitrile and all computational details are given in the
Supporting Information. In agreement with a previous
study using an iron-based catalyst,10c we propose an outer-
sphere mechanism by a simultaneous transfer of the hy-
dride from the Mn center (Mn-H) and the proton from
the nitrogen (N-H) to the nitrile to give the correspond-
ing imine (Scheme 6). Then, the catalyst should be regen-
erated by addition of molecular hydrogen. The formed
imine can undergo a second reaction cycle and is finally
reduced to the corresponding amine.
Mechanistic investigations.To gain insight into the
nature of the catalytic active manganese species, NMR
investigations were carried out using complex 1 in the
presence of t-BuONa in toluene-d8 under 5 bar H2 at RT.
After 1 h, a red-orange solution formed which clearly
Scheme 6. Proposed outer-sphere mechanism for
nitrile hydrogenation [E = P(isopropyl)2]
1
exhibited a hydride triplet signal at -5.67 ppm in the H
NMR spectrum. Additionally, IR (toluene) measurements
showed full conversion of 1 into 3 and an unchanged co-
ordination of the pincer ligand and the two CO ligands
(Figure 4a). As compared to the bromide ligand, the hy-
dride ligand is much better σ donor which explains higher
electron density at the manganese center. In conse-
H
R
N
R
NH
H
N
E
H
E
N
E
E
3271 cm−1) and
1889 cm−1,
Mn
Mn
quence, the N-H frequency rises (3198
the C-O frequencies fall (symmetric: 1921
asymmetric: 1832
1815 cm−1), due to the increased π-
ꢀ
CO
CO
+H2
ꢀ
CO
(3)
CO
ꢀ
(3a)
electron donation from the manganese to the π-
antibonding orbitals on the carbonyl ligand. These shifts
are in good agreement with DFT-frequency calculations
To show the reversibility between the hydride 3 and ami-
do3a complexes, we computed the energetic parameters
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the presence of Hg indicate the homogeneous nature of
including the barrier and reaction energy of the concerted
1
2
3
4
5
6
7
8
H2 elimination. For the Mn complex 3, the computed
Gibbs free energy barrier for H2 elimination is 20.2
kcal/mol. In general, the reaction is slightly exergonic by
0.2 kcal/mol. Hence, a well-balanced equilibrium can be
established under H2 atmosphere. For the regeneration of
catalyst 3 via addition of H2, the barrier is 20.4 kcal/mol.
Interestingly, we found that the dissociation of the equa-
torial CO ligand is endergonic by 41.0 kcal/mol, indicating
the stability of this CO coordination. This agrees well
with the experimental results: Spectroscopic studies of
the reaction mixture vide supra proved the CO ligands to
be still intact. Comparing the hydrogenation of acetoni-
trile (CH3-CN) and benzonitrile (Ph-CN) using Mn com-
plex 3 gave similar results, but the computed Gibbs free
energy barrier is slightly higher (20.9 vs 17.8 kcal/mol,
respectively). In contrast to nitrile hydrogenation via a
concerted transfer of the N-H proton and Mn-H hydride
(Figure 5), we found a stepwise mechanism for the hydro-
genation of benzaldehyde; i.e.; a transition state for Mn-H
transfer to the carbon atom of the C=O group for the
breaking of the Mn-H bond and the formation of the C-H
bond, followed by an intermediate; and the second step is
the N-H proton transfer for the breaking of the N-H bond
and the formation of the O-H bond. Relative to the start-
ing materials (3 + PhCHO), the free energy barrier of Mn-
H hydride transfer is 15.64 kcal/mol; and the intermediate
is endergonic by 13.26 kcal/mol; and the N-H proton
transfer has free energy barrier of 11.94 kcal/mol. The
overall reaction is exergonic by 3.5 kcal/mol. These results
show that the potential energy surface for proton transfer
is very flat. It is interestingly noted that Jones et al.11i also
reported a similar stepwise reaction mechanism for the
hydrogenation of styrene by using the iron pincer com-
plex, and this is also in contrast with the concerted mech-
anism for the hydrogenation of aldehyde by using the
same catalyst.24.
the catalyst.
Summary
In conclusion, we have shown for the first time that spe-
cific manganese pincer complexes constitute versatile
reduction catalysts.26 Contrary to traditional belief mo-
lecular-defined manganese-amide centers permit the
practical activation of molecular hydrogen. The developed
pre-catalyst 1 is air-stable, easy to synthesize and simple
to activate by base and H2. This catalytic system allows for
the efficient and selective reduction of various polar func-
tional groups including aromatic and aliphatic nitriles as
well as ketones and aldehydes.
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EXPERIMENTAL SECTION
General Procedure for the hydrogenation of Nitriles:
Under an argon atmosphere a vial was charged with 1 (0.015
mmol), t-BuONa (0.05 mmol) and 1 mL of dry toluene in this
order. The orange red solution was stirred briefly before the
nitrile (0.5 mmol) was added. The capped vials were placed
in the alloy plate which was then transferred into the auto-
clave. Once sealed, the autoclave was purged 3 times with
hydrogen, then pressurized to 50 bar, heated up and kept at
120 °C for 24 or 36 h under thorough stirring. After the reac-
tion time the autoclave was cooled to RT, depressurized, and
the reaction mixture was analyzed by GC. The amine product
was isolated as its HCl salt.
ASSOCIATED CONTENT
Supporting Information.Additional experimental results,
complex synthesis,optimization of reaction conditions, spec-
troscopic data of the complexes, DFT calculations and NMR
data of isolated products. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
matthias.beller@catalysis.de
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank Dr. C. Fischer, Bianca Wendt, S. Buchholz, S.
Schareina and A. Koch (all at the LIKAT) for their excellent
technical and analytical support.
Figure 5. Catalytic intermediates: (a) transition state of the
transfer of the protic hydrogen to the nitrile-nitrogen and
hydride coordination to the corresponding carbon; (b) amido
complex (3a).
REFERENCES
(1) (a) Rylander, P. N Catalytic Hydrogenation in Organic Synthe-
sis, Acadamic Press, New York, 1979.(b) Andersson, P.
G.;.Munslo, I. J. Modern Reduction Methods, Wiley, New York
2008.
Finally, to evaluate the homogeneity of our catalytic sys-
tem, poisoning experiments were performed in the pres-
ence of varying amounts of PMe3, PPh3 and Hg.25In all the
cases no significant effects in the hydrogenation of ben-
zonitrilewere observed (see SI X). The constant activity in
the presence of PMe3 or Hg can be explained by an outer
sphere hydrogenation mechanism of a molecular-defined
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(26) To rule out that impurities in the manganese could be cata-
lyzing the reaction we bought Mn(CO)5Br from different ven-
dors (Alfa and Strem) and used these sources for the preparation
of complex 1. Performing the catalytic hydrogenation of benzo-
nitrile in the presence of complex 1 from different vendors no
significant difference in the yield of benzylamine was observed
(Alfa = 91% and Strem 95%). We thank a referee for pointing out
this experiment to us.
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