Manganese-Catalyzed Hydrogenation of Esters to Alcohols

Article abstract of DOI:10.1002/chem.201604991

Homogeneous catalytic hydrogenation of esters to alcohols is an industrially important, environmentally benign reaction. While precious metal-based catalysts for this reaction are now well known, only very few catalysts based on first-row metal complexes were reported. Here we present the hydrogenation of esters catalyzed by a complex of earth-abundant manganese. The reaction proceeds under mild conditions and insight into the mechanism is provided based on an NMR study and the synthesis of novel Mn complexes postulated as intermediates.

Full text of DOI:10.1002/chem.201604991

A Journal of
Accepted Article
Title: Manganese-Catalyzed Hydrogenation of Esters to Alcohols
Authors: Noel Angel Espinosa-Jalapa, Alexander Nerush, Linda
Shimon, Gregory Leitus, Liat Avram, Yehoshoa Ben-David,
and David Milstein
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10.1002/chem.201604991
Chemistry - A European Journal
COMMUNICATION
Manganese-Catalyzed Hydrogenation of Esters to Alcohols
Noel Angel Espinosa-Jalapa, Alexander Nerush, Linda J. W. Shimon, Gregory Leitus, Liat Avram,
Yehoshoa Ben-David and David Milstein.*
co-workers.[8e]
Abstract: Homogeneous catalytic hydrogenation of esters to
alcohols is an industrially important, environmentally benign
reaction. While precious metal-based catalysts for this reaction are
now well known, only very few catalysts based on first-row metal
complexes were reported. Here we present the hydrogenation of
esters catalyzed by a complex of earth-abundant manganese. The
reaction proceeds under mild conditions and insight into the
mechanism is provided based on an NMR study and the synthesis
of novel Mn complexes postulated as intermediates.
Although manganese is third only to Fe and Ti in earth
abundance, catalytic reactions based on manganese complexes are
9]
less exploited.[6a,
Particularly, hydrogenation and dehydro-
genation reactions catalyzed by well defined manganese complexes
are very rare. We recently reported the first example of a catalytic
Michael addition reaction of nitriles to carbonyl compounds[9a] and
the first dehydrogenative coupling of alcohols and amines to form
imines and H2 catalyzed by a PNP pincer manganese complex
[Mn(PNP*)(CO)2] (the asterisk denotes the dearomatized
ligand).[9b] Recently Kirchner reported the coupling of alcohols and
amines to form imines catalyzed by a series of manganese pincer
complexes, which are stabilized by a PNP ligand based on the
2,6-diaminopyridine scaffold[9c] and Beller reported the
hydrogenation of nitriles, ketones and aldehydes with an aliphatic
Ester hydrogenation represents one of the most important
industrial processes for the production alcohols, with applications
in cosmetics, pharmaceuticals and in the production of biodiesel.[1]
Traditional reduction of esters generally involves the use of
stoichiometric amounts of hydride reagents, generating large
amounts of hazardous waste.[2] Industrial hydrogenation of esters
involves high pressure and temperature.[3] In recent years, several
homogeneous catalysts based on precious-metals, such as
ruthenium[4] and osmium[5] were developed for ester
hydrogenation, mostly under mild conditions.
PNHP-type
hydride
manganese
pincer
complex
[Mn(PNHP)(H)(Br)(CO)2][9d,e]
Herein, we report the hydrogenation of esters catalyzed by a
manganese complex (Scheme 1).
The development of earth-abundant first-row transition
metal-based catalysts for chemical transformations is of much
current interest.[6] In this context, very few examples of ester
hydrogenation based on earth-abundant metals were reported.
Pincer-type complexes, which operate by metal-ligand cooperation
(MLC)[7] are particularly attractive for this purpose, since bond
activation in such systems proceeds without formal change in the
metal oxidation state, obviating the tendency of first row metal to
undergo one electron processes, as opposed to two-electron
processes common for second- and third-row metals. In 2014 we
reported hydrogenation of trifluoroacetic esters, by a PNP iron
pincer complex trans-[Fe(PNP)(H)2(CO)] (PNP = 2,6-bis(di-tert-
butylphosphinomethyl)pyridine).[8a] As demonstrated, the reaction
proceeds by an outer-sphere mechanism through nucleophilic
attack of a hydride ligand on the ester carbonyl group.[7d, 8a] Shortly
after, Beller[8b] and Guan[8c] independently reported broad-scope
hydrogenation of non-activated esters catalyzed by an iron
aliphatic pincer complex [Fe(PNHP)(H)(CO)(BH4)] with no added
base. We have reported recently hydrogenation of esters by a
PNNH cobalt pincer complex [Co(PNNH)(Cl)2] (PNNH = N-((6-
((di-tert-butylphosphanyl)methyl)pyridine-2-yl)methyl)propan-2-
amine) in the presence of NaHBEt3.[8d] In this case, a mechanism
involving C=C hydrogenation of an ester enolate intermediate was
shown to take place. Co-catalyzed hydrogenation of carboxylic
acids and esters was recently reported by Elsevier, de Bruin and
Scheme 1. Ester hydrogenation reported in this study.
Complex 1 is readily obtained upon stirring of a solution of
the PNNH ligand and [Mn(CO)5Br] in THF for 60 hours at room
temperature. Subsequent concentration of the reaction mixture and
precipitation from THF by addition of diethyl ether yields complex
1 as an orange powder. The IR spectrum of 1 exhibits two strong
absorption bands at 1828 (νasym) and 1909 cm-1 (νsym) in 1:1 ratio in
agreement with two carbonyls in cis position. The 31P{1H} NMR
spectrum shows a singlet at 118.7 ppm. Single crystals suitable for
X-ray analysis were obtained by slow diffusion of pentane into a
concentrated solution of complex 1 in CH2Cl2.[10] The PNNH
pincer ligand binds to the metal center in a meridional fashion with
the two carbonyl ligands located cis to each other (C – Mn – C =
86.25°), and the bromide in an axial position, completing a
distorted octahedral coordination sphere (see Supporting
Information (SI)).
Recently our group reported the synthesis and reactivity of a
series of analogous [Ru(PNNH)(CO)(H)(Cl)] pincer complexes,
which showed exceptional reactivity in hydrogenation and
dehydrogenation processes.[4a] Exploring the catalytic activity of
the PNNH complex 1, attempted hydrogenation of hexyl hexanoate
under 20 bar of H2 and catalyst loading of 1 mol% in toluene was
not successful (Table 1, Entry 1). However, addition of a base (2
mol%), under the same conditions did result in hexanol formation.
Using of tBuOK or potassium bis(trimethylsilyl)amide, hexanol
was obtained in 31% and 54% yields, respectively (Entries 2, 3).
When KH was used as a base, full conversion to hexanol was
observed under the same conditions (Entry 4). We have observed
that, when preparing the reaction mixture at room temperature,
[*]
Dr. N. A. Espinosa-Jalapa, A. Nerush, Y,
Ben-David, Prof. D. Milstein
Department of Organic Chemistry
The Weizmann Institute of Science
76100 Rehovot (Israel)
E-mail: david.milstein@weizmann.ac.il
L. J. W. Shimon, G. Leitus, L. Avram
Department of Chemical Research Support
The Weizmann Institute of Science
76100 Rehovot (Israel)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201xxxxxx.
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addition of tBuOK or KHMDS resulted in a dark green color, in
line with ligand deprotonation, as previously observed with the
analogous PNNH ruthenium complexes upon deprotonation.[4a] In
contrast, no color change was observed at room temperature upon
addition of KH, due to its insolubility under these conditions. The
Table 2. Catalytic hydrogenation of esters using the manganese precatalyst 1.
Table 1. Base optimization for manganese-catalyzed hydrogenation of hexyl
t
Conv
(%)[a]
Yield
[%][b]
Entry
Ester
Alcohol
hexanoate.
[h]
1
23
50
99
99
99
98
2[b]
Entry
Base
Time (h)
Conv (%)[a]
Yield (%)[a]
1
2
3
4
-
22
22
23
23
-
-
3[b]
4[b]
5[b]
6
43
43
21
22
43
50
28
28
36
28
99
99
99
99
99
99
95
99
99
99
99
98
tBuOK
KHMDS
KH
39
55
99
31
54
99
Reaction conditions: substrate (1.0 mmol), toluene (1.0 mL), internal
standard (xylene, 1 mmol), 100°C. [a] Products confirmed by GC-MS.
Conversions and Yields were determined by 1H NMR with an internal
standard (xylene).
99
lack of immediate reaction with the precatalyst at ambient
temperature, can be a practical advantage, avoiding handling the
more sensitive active catalyst. Moreover, using KH does not
generate a conjugate base in solution, avoiding potential side
reactions.
99 / 90
99
7
Next, the scope of the reaction was examined with various
esters using the precatalyst [Mn(PNNH)(CO)2(Br)] (1) (1 mol%)
and KH (2 mol%) (Table 2). Thus, hydrogenation of 1 mmol of
hexyl hexanoate under 20 bar H2 at 100°C in toluene, resulted in
99% yield of hexanol (Entry 1). Under the same conditions ethyl
butyrate was hydrogenated to give 98% yield of butanol and 91%
yield of ethanol after 50 hours (Entry 2). Since no other
compounds than butanol and ethanol were detected by
8[b]
9[b]
10[b]
11
12
98
94
1
99
GC-MS and H-NMR, the lower yield of ethanol is attribute to
losses due to its volatility.. When the reaction was performed at
shorter reaction time (22 hours, Table S3, Entry 2bis, see SI), small
amounts of ethyl acetate and butyl butanoate were also formed,
attributed to a transesterification reaction with the formed ethanol
and butanol. Cyclohexylmethyl acetate gave 99% yield of
cyclohexylmethanol (Entry 3), and no transesterification products
were observed. Hydrogenation of the secondary aliphatic ester
heptan-2-yl acetate resulted in 98% yield of heptane-2-ol (Entry 4).
Ethyl 3-phenylpropanoate was smoothly hydrogenated, rendering
99% yield of 3-phenylpropan-1-ol after 21 hours (Entry 5).
Similarly, ethyl 3-phenylpropanoate gave 99% yield of
phenylmethanol and 90% yield of butanol after 22 hours (Entry 6).
In order to get full hydrogenation of benzyl benzoate longer
reaction time was needed (43 hours, 99% yield benzyl alcohol,
Entry 7). Methyl esters were also hydrogenated. Methyl benzoate
gave 96% yield of benzyl alcohol after 50 hours (Entry 8).
Similarly, methyl hexanoate gave 94% yield of hexanol after 28
hours (Entry 9) and 1% of hexyl hexanoate, attributed to a
transesterification reaction with the formed hexanol (Table S3,
Entry 9, see SI). Methyl phenylpropanoate gave 99% of phenethyl
alcohol after 28 hours (Entry 10)
98[c]
78 / 99
13[d]
60
60
99
75
97 / 96
60
14[b, e]
Reaction conditions: substrate (1.0 mmol), toluene (1.0 mL), internal standard
(xylene, 1 mmol), 100°C. [a] Conversions and Yields were determined by 1H
NMR with an internal standard (xylene). Products confirmed by GC-MS. [b]
Yields of methanol and ethanol are not reported (see SI). [c] The diol is insoluble
in the reaction mixture. Isolated yield. [d] No hydrogenation of the vinyl group
was observed. [e] 1 (3%)/KH (6%). No hydrogenation of the nitrile group was
detected.
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. ε-Caprolactone was smoothly and quantitatively hydrogenated to
1,6-hexanediol (98% yield, Entry 11). The activated benzyl
trifluoroacetate gave 99% yield of benzyl alcohol and 78% of
2,2,2-trifluoroethanol (Entry 12), and no secondary products where
observed. Gratifyingly, allyl trifluoroacetate gave 97% yield of
2,2,2-trifluoroethanol and 96% of allyl alcohol (Entry 13), showing
high chemoselectivity to ester hydrogenation over C=C
hydrogenation. Hydrogenation of ethyl 4-isocyano-benzoate
required an increase of precatalyst loading to 3%, probably due to
competing nitrile coordination, and resulted in 61% yield of (4-
isocyanophenyl)methanol, with no hydrogenation of the nitrile
group detected (Entry 14).
lengths of the pyridine ring are almost equal, confirming that no
de-aromatization of the pyridine ring occurred, in line with no
deprotonation of the benzylic position. The Mn-N amido bond
(1.889 Å) is significantly shorter from Mn-amine bond (2.171 Å)
in 1, confirming the amine – amide conversion upon deprotonation.
Figure 1. ORTEP diagram of [Mn(PNN)(CO)2] (2) with thermal ellipsoids at
30% probability. The P(tBu)2 and NtBu groups are drawn as wire frames, and
the hydrogen atoms are partially omitted for clarity. Selected bond lengths (Å):
Mn1 – C20 = 1.775(2), Mn1 – C21 = 1.822(2), Mn1 – N1 = 2.018(2), Mn1 – N2
= 1.889(2), Mn1 – P1 = 2.2622(6), C1 – C2 = 1.501(3), C6 – C7 = 1.492(3),
C1 – P1 = 1.850(2), C7 – N2= 1.464(3). Selected bond angles (°): P1 – Mn1 –
N1 = 80.64(5), P1 – Mn1 – N2 = 141.76(6), N1 – Mn1 – C20 = 173.08(8), N1 –
Mn1 – C21 = 92.65(7), N2 – Mn1 – C20 = 104.86(8), N2 – Mn1 – C21 =
117.02(8), C20 – Mn1 – C21 = 87.22(9).[10]
Scheme 2. Synthesis of the amido [Mn(PNN)(CO)2] pincer complex 2.
Mechanistically, the fact that benzyl benzoate and methyl
benzoate undergo hydrogenation indicate that ester enolate
intermediates are not involved in the catalysis, unlike the case of
cobalt-catalyzed hydrogenation of esters.[8d] Aiming at gaining
insight regarding the nature of the active catalyst, deprotonation of
1 was performed. In principle, both deprotonation of the benzylic
position, leading to dearomatization of the pyridine ring, as well as
deprotonation of the N-H bond, are possible.[4a] Upon addition of
1.2 equivalents of tBuOK to a suspension of 1 in pentane the
solution became dark blue, yielding the novel amido
[Mn(PNN)(CO)2] complex 2 (Scheme 2). After filtration, the
pentane solution was stored at -18 °C, forming dark crystals of
pure complex 2. The IR spectrum of 2 (NaCl plates) shows two
strong bands at 1797 (νasym) and 1874 cm-1 (νsym) in 1:1 ratio,
indicating a 90° C-Mn-C angle. The 31P{1H} NMR spectrum
shows a singlet at 135.0 ppm, downfield shifted by ~ 16 ppm in
Exploring the catalytic activity of the novel amido complex 2
(1 mol%), hydrogenation of hexyl hexanoate under 20 bar H2 at
100 oC in toluene in the absence of base gave 96% yield of hexanol
after 22 hours, showing comparable catalytic activity as with the
catalyst prepared in situ from the PNNH complex 1 and catalytic
base (Table 1, Entry 1), indicating that 2 is the catalytically active
complex.
To gain more mechanistic insight, NMR investigations were
carried out using complex 2. Under H2 atmosphere (1 bar) at room
temperature, in an NMR Young tube, complex 2 in C6D6 reversibly
adds H2 to yield, after 10 min, a mixture of the hydride complex 3
and complex 2 in a ratio of 2 : 3, 1.0 : 0.6, as determined by
31P{1H} NMR (see SI). The hydride resonance appears at -1.71
ppm (d, 2JPH = 52.7 Hz) in 1H NMR and it shows a singlet at 143.4
ppm in the 31P{1H} NMR spectrum, 7.6 ppm downfield shifted in
comparison with complex 2. Complex 3 slowly isomerizes to yield
the hydride complex 4. Complex 4 exhibit a hydride resonance at -
1
comparison with 1. The H NMR spectrum of 2 exhibits only two
distinct resonances in the aromatic regime. Two resonances are
1
observed in H NMR for the protons at the two benzylic positions;
2
1.34 ppm (d, JPH = 55.2 Hz) in 1H NMR spectrum and a singlet at
a singlet at 4.53 ppm and a doublet at 3.08 ppm in 1:1 ratio (Figure
S5, see SI). This unexpected behavior is attributed to a dynamic
exchange process as confirmed by a VT-NMR experiment. As
described previously, a solution of complex 2 in [D8]Tol exhibits
143.8 ppm in 31P{1H} NMR spectrum. After 16 hours no changes
in the proportion of 2, 3 and 4 complexes were observed (2 : 3 : 4;
1.0 : 1.1 :1.2, determined by 31P{1H} NMR). Complex 3 was
independently prepared by treatment of complex 1 with NaHBEt3
under H2 atmosphere (1 bar) in [D8]Tol at -10°C and characterized
by low temperature NMR (0°C). In line with the proposed
geometry of 3, two resonances are observed in the carbonyl region
in the 13C{1H} NMR spectrum at 219.3 ppm (2JPC = 12.6 Hz) and
230.4 ppm (2JPC = 20.7 Hz). When this cold solution containing
complex 3 reaches room temperature it slowly forms a mixture of 2,
3 and 4 complexes (after 12 hours, proportion 2 : 3 : 4; 1.0 : 0.8 :
0.9, was determined by 31P{1H} NMR spectroscopy). The 13C{1H}
NMR of complex 4 is similar to that of 3; the carbonyl ligands
exhibit two resonances, at 218.4 ppm (2JPC = 12.5 Hz) and 229.8
ppm (2JPC = 19.7 Hz), slightly different chemical shifts compared
to 3 (see SI).
1
two resonances in H NMR for the protons at the two benzylic
positions at 298K. At 248K the peaks coalesced and at 222K there
is slow exchange, rendering two broad doublet at 4.42 and 2.79
ppm (Figure S7, see SI) due to the diasterotopicity of the protons at
the benzylic positions. No resonance due to the N–H proton was
observed, indicating deprotonation of the amine group. Two
resonances are observed for the carbonyl ligands in the 13C{1H}
NMR spectrum at 212.9 ppm and 207.8 ppm. X-ray diffraction of
single crystal of 2 (Figure 1) show meridional coordination of the
deprotonated PNNH pincer ligand.[10] Both carbonyl ligands are
located mutually cis (C20–Mn–C21 = 87.22°), completing a
distorted square pyramidal coordination sphere. The C – C bond
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This research was supported by the Israel Science Foundation, the
MINERVA Foundation and the Kimmel Center for molecular
design. D. M. holds the Israel Matz Professorial Chair of Organic
Chemistry. N. A. E.-J. thanks Mr. Armando Jinich for a
postdoctoral fellowship.
Keywords: homogeneous catalysis · pincer complexes ·
Scheme 3. Reversible activation of H2 by 2 at room temperature (1 bar H2)
through metal-ligand cooperation.
manganese · ester · alcohol
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hydride resonance at -1.71 ppm, the NOE difference spectrum
gives NOE enhancement for the resonance at 3.09 ppm (s), which
corresponds to the NH group and also for the resonance at 1.42
3
t
ppm (d, JHP = 12 Hz), due to the BuP group which points in the
same direction as the Mn-H (Figure 2, see SI). Upon selective
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t
t
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Figure 2. 1H NMR chemical shifts of the NOE correlations observed under
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In summary, the first example of ester hydrogenation
catalyzed by a complex based on earth-abundant manganese is
reported. This environmentally benign reaction proceeds under
o
mild conditions (100 C, 20 bar) and is of broad scope. In the
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activation takes place by metal-ligand cooperation (MLC), in
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in H2 activation via Mn-NR2 HMn-NHR2 equilibrium, leading to
coordinatively saturated syn and anti isomers. Further experimental
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This article is protected by copyright. All rights reserved.

10.1002/chem.201604991
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
Ester hydrogenation catalyzed by a complex
based on earth-abundant manganese is
reported. This environmentally benign reaction
proceeds under mild conditions and is of
broad scope. The catalytically active species
can be formed in situ by adding base to the
reaction mixture. It shows selectivity for ester
groups, C=C and CN groups not being
affected. The likely actual catalytically active
complex was also prepared and shown to
efficiently catalyze the reaction in absence of
added base.
N. A. Espinosa-Jalapa, A. Nerush, L.
J. W. Shimon, G. Leitus, L. Avram, Y.
Ben-David and D. Milstein.*
Page No. – Page No.
Manganese-Catalyzed Hydrogenation
of Esters to Alcohols
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