Hydrogenation of Aldehydes Catalyzed by an Available Ruthenium Complex

Article abstract of DOI:10.1021/acs.orglett.6b00060

A readily available ruthenium(II) catalyst was developed for the catalytic hydrogenation of aldehydes with a TON (turnover number) up to 340000. It can be performed without base and solvent, showing highly industrial potential. High chemoselectivity can be achieved in the presence of alkenyl and ketone groups. Further application of this protocol in glucose reduction showed good efficiency. Theoretical studies revealed that the rate-determining step is the hydrogenation step, not the carboxylate-assisted H₂ activation step.

Full text of DOI:10.1021/acs.orglett.6b00060

Letter
pubs.acs.org/OrgLett
Hydrogenation of Aldehydes Catalyzed by an Available Ruthenium
Complex
Xuefeng Tan,† Guozhen Wang,† Ziyue Zhu,† Conghui Ren,† Jinping Zhou,† Hui Lv,† Xiaoyong Zhang,‡
Lung Wa Chung,*,‡ Lina Zhang,*,† and Xumu Zhang*,†
†College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, People’s Republic of China
‡Department of Chemistry, South University of Science and Technology of China, Shenzhen 518055, China
S
* Supporting Information
ABSTRACT: A readily available ruthenium(II) catalyst was developed for the
catalytic hydrogenation of aldehydes with a TON (turnover number) up to
340000. It can be performed without base and solvent, showing highly
industrial potential. High chemoselectivity can be achieved in the presence of
alkenyl and ketone groups. Further application of this protocol in glucose
reduction showed good efficiency. Theoretical studies revealed that the rate-
determining step is the hydrogenation step, not the carboxylate-assisted H2
activation step.
ldehyde is an abundant natural product, and its reduction to
group tolerance, and even solvent-free conditions is highly
Athe corresponding alcohol plays a significant role in modern desirable. Herein, we developed a well-defined catalyst for highly
efficient catalytic hydrogenation of aldehydes. The catalyst
features a 1,3-bis(diphenylphosphino)propane (DPPP) ligand
and two glycine anion ligands to form the ruthenium(II)
complexes Ru1 (Figure 1). Ru1 can be easily obtained by a
synthetic chemistry. Compared to stoichiometric used reducing
reagents1 (e.g., NaBH4), catalytic hydrogenation with transition
metalcomplexesaffordedasustainableandalternativewayforthis
essential transformation. Notably, the [(diphosphine)(diamine)-
RuCl2] catalysts developed by Noyori and co-workers gave
prominent performance for carbonyl compounds reduction.2
Although this methodology has been widely used for asymmetric
hydrogenationofketonesduetoitshighefficiencyunderthebasic
conditions,2,3 few examples were reported in the case of
aldehydes.3a,4 A facile self-aldol side reaction under the basic
conditions limits application of the catalytic hydrogenation of
aldehydes. Hence, hydrogenation of aldehydes under neutral or
acidic conditions is highly desirable.
Noyori and co-workers developed a base-free system using the
catalyst RuH(BH4) (BINAP) (diamine) for ketone reduction.5
Morris and co-workers reported the RuH(CCPh) (diamine)
(PPh3)2 complexes for the acetophenone reduction in the
absence of the adding base.6 However, these systems were
sensitive to various reaction parameters, such as specific
functional groups and moisture. Dupau and co-workers explored
the anionic ligand effect, replacing the halide ion in
[(diphosphine) (diamine)RuCl2] with a carboxylate ion, which
led to a great improvement of catalytic efficiency and a high
selective hydrogenation of aldehydes in the presence of alkenes.7
However, this [(diphosphine) (diamine)Ru(RCO2)2] catalyst
needs 1 mol % of special acid (e.g., benzoic acid) as additive to
obtain a higher TON (turnover number). Recently, investigation
of inexpensive metals, such as iron8 and cobalt,9 led to a new path
of this reduction. Other researches focused on the modification of
ligand, such as substitution of phosphine ligand to sulfur10 and
NHCs.11
Figure 1. Chemical and crystal structure of Ru1.
one-step synthesis using the inexpensive phosphine ligand and
amino acid. Ru1 has been crystallographically characterized, and
its molecular geometry is presented in Figure 1.12 When we
applied this kind of the catalysts to catalytic hydrogenation of
aldehydes under neutral and solvent-free conditions, unexpected
efficiency(TONupto340000)wasobtained. Thehydrogenation
is chemoselective not only to CC bond but also to the more
challenging ketone moiety. A very challenging substrate in
homogeneous catalytic reaction, glucose, has been chemo-
selectively hydrogenated to sorbitol with good efficiency.
To satisfy the practical industrial use, a catalyst with high
efficiency, highchemoselectivity, easyavailability, multifunctional
Received: January 17, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00060
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Table 1. Solvent Effect for Hydrogenation of Benzaldehyde
Using Ru1
Table 2. Substrate Scope of the Hydrogenation Catalyzed by
Ru1
a
a
b
entry
solvent
MeOH
S/C
yield (%)
1
200000
500000
200000
500000
200000
500000
200000
500000
200000
500000
200000
500000
100000
200000
500000
96
60
2
MeOH
i-PrOH
i-PrOH
THF
3
>99
62
4
5
>99
29
6
THF
7
1,4-dioxane
1,4-dioxane
hexane
hexane
toluene
toluene
DCM
97
8
8
b
entry
substrate
S/C
yield (%)
9
>99
37
c
10
11
12
13
14
15
1
S1
300000
400000
150000
200000
200000
250000
20000
91 (94)
81 (85)
94 (>99)
86 (91)
96 (>99)
82 (82)
94 (96)
67 (72)
92 (97)
71 (75)
98 (>99)
79 (81)
92 (93)
77 (81)
94 (97)
86 (88)
92 (96)
77 (80)
96 (97)
90 (94)
95:0
c
>99
19
2
S1
3
S2
<1
4
S2
>99
64
5
S3
6
S3
a
7
S4
Reaction conditions: benzaldehyde (10 mmol), H2 (50 bar), solvent
b
(2 mL), 100 °C, 24 h. Yield was determined by GC analysis; n-
8
S4
50000
tridecane was used as internal standard.
9
S5
50000
10
11
12
13
14
15
16
17
18
19
20
S5
100000
100000
150000
100000
150000
100000
150000
100000
150000
100000
150000
100000
S6
Initially, we investigated the hydrogen pressure effect by
altering the pressure from 10 to 70 atm in the hydrogenation of
benzaldehyde at 100 °C. Results showed that the higher pressure
was beneficial to this reaction. We then explored the solvent effect
using benzaldehyde as standard substrate at 100 °C and 50 atm of
H2 (Table 1). Many solvents were compatible for this reaction,
except dichloromethane. Even under solvent-free conditions,
there is no obvious activity difference compared to the best
performing solvent i-PrOH.
S6
S7
S7
S8
S8
S9
S9
S10
S10
S1 + S11
Then, we explored the substrate scope in the presence of Ru1
without any additives (Table 2). A variety of substrates can be
hydrogenated to the corresponding alcohols with extremely high
efficiency. In the case of benzaldehyde reduction, a TON of
340000 was obtained on gram scale (50 mmol, 5.3 g), which
demonstrated great potential for industrial production (Table 2,
entries 1 and 2). For the other aryl aldehydes, the π-electron-
donating methoxy group, whether para- or meta-substituted, gave
better results than the electron-withdrawing fluorine group
(Table 2, entries 3−8). The hindered 1-naphthaldehyde can also
be reduced smoothly with a TON of 750000 under the standard
conditions. The heterocyclic aryl compound, furfural, can also be
efficiently hydrogenated to form a furfuryl alcohol. For aliphatic
aldehydes, primary and secondary substitution at α-position both
performed well with almost the same reaction activities (Table 2,
entries 13−18). In addition, this catalyst has a high chemo-
selective ability to CC double bonds, e.g., citronellol (Table 2,
entries 19 and 20). No CC bond reduction product was
detected. Moreover, when a mixture of benzaldehyde and
acetophenone was used as substrate (Table 2, entry 21), we
observed100%conversionofbenzaldehydetothealcohol, andno
acetophenone reduction product appeared.
d
21
a
Reaction conditions: aldehyde (10 mmol), H2 (50 atm), 100 °C, 24
b
h. isolated yield; yield in parenthese was determined by GC.
c
d
Substrate (50 mmol). S1 + S11 (5 mmol:5 mmol), Ru1 (1 × 10−4
mmol).
a
Table 3. Hydrogenation of Glucose Catalyzed by Ru1
b
product (%)
entry
S/C
T(°C)
additive (M)
sorbitol glucose sorbitan
1
2
3
4
5
6
7
8
9
1000
2000
1000
2000
1000
2000
5000
2000
5000
100
100
120
120
140
100
100
100
100
95
59
95
58
92
83
73
83
64
3
27
2
0.6
1.4
0.6
1
35
<1
7
0.4
4
MeSO3H (0.1)
MeSO3H (0.1)
H3PO4 (0.5)
H3PO4 (0.5)
6
9
7
3
It is well-known that the most abundant biomass, cellulose, is
composed of glucose unit, essentially a hemiacetal, and there
exists an equilibrium between its hemiacetal and aldehyde forms
in water. We envision using the catalytic hydrogenation reaction
to reduce the aldehyde to alcohol, leading the equilibrium toward
the aldehyde, and then the aldehyde is reduced to alcohol
(sorbitol, Table 3). Because of the high density of the hydroxyl
17
3
a
Reaction conditions: glucose monohydrate (2 mmol), i-PrOH/H2O
b
(1 mL:1 mL), H2 (50 atm), 24 h. Yield was determined by HPLC
analysis; manitol was used as internal standard.
B
DOI: 10.1021/acs.orglett.6b00060
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Figure 2. Free-energy reaction profile of the Ru-catalyzed hydrogenation of aldehyde in solution for two reaction models.
group in glucose, a multifunctional group tolerant catalyst is
highly desirable in its reduction. First, we carried out this
hydrogenation under neutral conditions by changing the
temperature from 100 to 140 °C (Table 3, entries 1−5).
However, the temperature has no obvious influence on the yield
of sorbitol, and the TON can only reach up to 1180 (Table 3,
entry 2) with a low conversion of glucose and trace dehydration
product sorbitan. We envisioned that the lower percentage of the
aldehyde form in solution prevented the reaction. Therefore, we
tried some acid additives to promote the formation of aldehyde
form rapidly. Several acids were tested as additives under different
concentrations. Methanesulfonic acid under 0.1 M gave the best
result (TON 3650, Table 3, entry 7), and phosphoric acid also
showed positive effect on this reaction (Table 3, entry 9).
To elucidate the reaction mechanism of this Ru-catalyzed
hydrogenation of aldehydes, we carried out density functional
theory (DFT, using B3LYP-D3 method) calculations with the
real Ru1 catalyst (Figures 2 and SY in Supporting Information).13
Two different mechanistic pathways involving H2 activation
followed by hydrogen transfer of aldehyde were examined,
depending on the coordination mode of the amine moiety of the
ligand (models 1 and 2). As shown in Figure 2, the pathway with
the coordination of the amine part (model 1) is energetically
more favorable than that with dissociation of the amine part
(model 2) by 3.7 and 2.7 kcal/mol in gas phase and solution,
respectively. Both pathways start with the addition of one H2
moleculetotheRucatalyst, followedbyheterolyticcleavageofthe
H−H bond catalyzed by a carboxylate oxygen of the ligand and by
the metal to give Ru(II) hydride intermediates 5 and 6. The
computed free-energy barrier for the H2 activation via TS3−5 is
about 21.2 kcal/mol in solution, which is much lower in free
energy than that via TS4−6 for the model 2 by 7.5 kcal/mol in
solution. After rotation and the addition of the aldehyde, a stable
intermediate 8 is formed with the formation of one new hydrogen
bonding between the aldehyde and the carboxylic group (along
with a loss of hydrogen bond between the carboxylic group and
hydride ligand). Then, concerted proton transfer with hydride
transfer through 9-m-r TS8−10 takes place in an outer-sphere
manner and directly gives a Ru(II)−alcohol intermediate 10 with
the barrier of 26.0 kcal/mol above 1 in solution. Finally,
dissociation of the alcohol and rechelation of the carboxylate
group to the metal regenerate the catalyst Ru1.
The overall reaction is computed to be exergonic by 5.4 kcal/
mol. The initial H2 activation step was found to be the rate-
determining step with the free-energy barrier of 20.1 kcal/mol for
the model 1inthe gasphase, whichis3.7 kcal/mol lower thanthat
forthemodel2.ThebarrierviaTS3−5isslightlyincreasedto21.2
kcal/mol in solution, whereas the activation barrier for the
subsequent hydrogenation step is significantly increased to 26.0
kcal/mol in solution. Therefore, the hydrogenation step becomes
the rate-determining step in solution for the favorable path with
the model 1. The rate-determining outer-sphere H+/H− transfer
step in model 1 account for the high chemoselectivity of the
hydrogenation of aldehyde and ketone.
In conclusion, a highly efficient catalyst for the catalytic
hydrogenation of aldehydes to alcohols was developed
successfully. The brief reaction conditions, high efficiency
(TON up to 340000), high chemoselectivity, and functional
group tolerance indicated its potential of industrial practical
production. It is noteworthy that the challenging substrate,
glucose, can be hydrogenated with good efficiency. Theoretical
studies revealed that the rate-determining step is the hydro-
genation step, not the carboxylate-assisted H2 activation step,
which perfectly explained the highly chemoselective hydro-
genation of aldehydes.
ASSOCIATED CONTENT
* Supporting Information
■
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.6b00060.
Synthesis and characterization of catalyst, detailed
experimental procedures, and computational details
(PDF)
X-ray crystallgraphic data for Ru1 (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
* E-mail: oscarchung@sustc.edu.cn.
* E-mail: zhangln@whu.edu.cn.
* E-mail: xumu@whu.edu.cn.
Author Contributions
X.T. and G.W. contributed equally.
C
DOI: 10.1021/acs.orglett.6b00060
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
no. CCDC 1063360. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[Fax: + 44 (1223)336033 or E-mail: deposit@ccdc.cam.ac.uk].
(13) See computational details and results in the Supporting
Information.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support through a grant from Wuhan
University (203273463), the Natural Science Foundation of
Hubei Province (2014CFB181), “111” Project of the Ministry of
Education of China and the National Natural Science Foundation
of China (Grant Nos. 21372179, 21432007, and 20874079), and
The Major Program of National Natural Science Foundation of
China (21334005).
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DOI: 10.1021/acs.orglett.6b00060
Org. Lett. XXXX, XXX, XXX−XXX