Iridium-Catalyzed Selective Cross-Coupling of Ethylene Glycol and Methanol to Lactic Acid

Article abstract of DOI:10.1002/anie.202002403

An atom-economic approach that has an unprecedented high selectivity for the synthesis of lactic acid (LA) based on a catalytic dehydrogenative cross-coupling by using inexpensive bulk ethylene glycol and methanol is described. This method relies on the synthesis and utilization of a novel iridium catalyst bearing three N-heterocyclic carbenes derived from 1,3-dimethylbenzimidazolium salts, and exhibits outstanding activity in the production of LA [turnover frequency (TOF) up to 3660 h^?1] owing to an elegant metal–ligand cooperation.

Full text of DOI:10.1002/anie.202002403

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Accepted Article
Title: Iridium-Catalyzed Selective Cross-Coupling of Ethylene Glycol
and Methanol to Lactic Acid
Authors: Tao Tu, Jiajie Wu, Lingyun Shen, Zhe-Ning Chen, Qingshu
Zheng, and Xin Xu
This manuscript has been accepted after peer review and appears as an
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202002403
Angew. Chem. 10.1002/ange.202002403
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Angewandte Chemie International Edition
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COMMUNICATION
Iridium-Catalyzed Selective Cross-Coupling of Ethylene Glycol
and Methanol to Lactic Acid
[
a]
[a]
[b]
[a]
[b]
[a,c,d]
Jiajie Wu, Lingyun Shen, Zhe-Ning Chen, Qingshu Zheng, Xin Xu,* and Tao Tu*
[
a]
J. Wu, L. Shen, Dr. Q. Zheng, and Prof. Dr. T. Tu
Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry
Fudan University
2005 Songhu Road, Shanghai 200438 (China)
E-mail: taotu@fudan.edu.cn
[b]
Dr. Z.-N. Chen, Prof. Dr. X. Xu
Collaborative Innovation Center of Chemistry for Energy Materials MOE Laboratory for Computational Physical Science
Fudan University
2005 Songhu Road, Shanghai 200438 (China)
E-mail: xxchem@fudan.edu.cn
[
[
c]
d]
Prof. Dr. T. Tu
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
354 Fenglin Road, Shanghai 200032 (China)
Prof. Dr. T. Tu
College of Chemistry and Molecular Engineering, Zhengzhou University
100 Kexue Avenue, Zhengzhou 450001 (China)
Supporting information for this article is given via a link at the end of the document.
Abstract: We report an atom-economic approach that has an
unprecedentedly high selectivity for lactic acid (LA) synthesis based
on a catalytic dehydrogenative cross-coupling using cheap and bulk
ethylene glycol and methanol. Our method relies on the synthesis and
utilization of a novel iridium catalyst bearing three N-heterocyclic
carbenes derived from 1.3-dimethylbenzimidazolium salts, which
exhibits an outstanding activity in producing LA (turnover frequency
-
1
(
TOF) up to 3660 h ) due to an elegant metal-ligand cooperation.
Lactic acid (LA) and its derivatives are important platform
molecules,[1-2] and have attracted extensive attention due to their
broad applications with projected market demand expected to
5
[1]
reach 4×10 tons per annum by 2022. However, the global
production capacity of LA is inadequate, owing to limitations with
conventional chemocatalysis- and fermentation-based process.[2]
Recently, two catalytic dehydrogenation approaches have been
developed for LA production either from sorbitol (C6, Figure 1a)[3]
or from glycerol (C3, Figure 1b),[4] which are environmentally
friendly and economically appealing.[5,6] It was commonly
regarded dihydroxyacetone (DHA) and glyceraldehyde (GAL) as
the key intermediates in both transformations (Figure 1).[3,4]
However, the major side products, included ethylene glycol
Figure 1. Catalytic transformation approaches for LA synthesis.
However, the direct catalytical cross-coupling between EGO
and MeOH is challenging,[10,11] as the viable catalyst has to be
bifunctional, which should not only selectively dehydrogenate
MeOH and EGO to formaldehyde and glycolaldehyde
simultaneously, but also selectively accelerate the aldol-type
cross-coupling to generate GAL rather than homo-coupling of
aldehydes or overoxidation, esterification, or polymerization of
EGO itself. Therefore, a metal-ligand cooperativity is crucial for
the hypothesized transformation. Herein, we realized the first
selective protocol for LA synthesis via dehydrogenative cross-
coupling between EGO and MeOH (Figure 1c), where all possible
byproducts are significantly suppressed. This is achieved by the
utilization of a novel highly active iridium (Ir) catalyst that bears
three N-heterocyclic carbenes (NHCs) derived from BenIm (i.e.,
(
EGO), methanol (MeOH), glycolaldehyde, and formaldehyde
from the unwanted C-C cleavage of GAL, were the main negative
issues for achieving high selectivity for these transformations.[4a]
In consideration that hydrogen-borrowing reactions have
exhibited a great potential for the construction of C-C bonds,[5,7]
particularly, in the methylation of alcohols,[8] the cross-coupling
between EGO and MeOH (from C2+C1 to C3, Figure 1c) should
theoretically be possible. This new protocol shall not only provide
a straightforward and atom-economic synthetic route for LA
production, but also inhibit the side reactions in the
dehydrogenation of sorbitol and glycerol so as to further increase
the selectivity and yield of LA. In addition, EGO and MeOH both
are inexpensive, renewable and bulky alcohols. Their global
1.3-dimethylbenzimidazolium) salts. This tris-NHC-Ir complex
exhibits excellent catalytic activity and selectivity, with a turnover
-1
frequency (TOF) up to 3660 h . The ligand effects can facilitate
the electron removal from the Ir(I) center, along with the
dehydrogenation of MeOH and EGO simultaneously, such that
the Ir(I) center is readily oxidized to yield an active Ir(III) species
in the catalytic cycle.
production capacities in 2016 are 34 and 80 million tons,
respectively,[
8a,9]
constituting appealing coupling partners for the
hydrogen-borrowing cross-coupling reactions.
1
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NHC-Ir complexes have been reported and acted as
[
4a,c]
bifunctional catalysts in the dehydrogenation of polyols
and
other reactions.[ A mononuclear Ir dihydride complex that bears
three NHCs was once isolated (in low yields; ~5-10%) from the
C3 to C3 transformation mixture under Crabtree’s standard
reaction conditions.[4a] Unfortunately, this tris-NHC-Ir compound
decomposed before its catalytic potential could be assessed, and
subsequent attempts to isolate it again proved unsuccessful.[4a]
As a strong -donor and a weak -acceptor, NHC is widely used
to tune the activity and the selectivity in various reactions.[12a-c]
Here, we postulated that increasing the -ring size and/or the
number of NHCs within the coordination sphere of the Ir complex
may enhance the steric bulkiness and the electron density of the
Ir center, which may facilitate the formation and the catalytic
function of the active tris-NHC-Ir compound.
12]
Accordingly, a series of NHC-Ir complexes, bearing one to
three NHCs, were synthesized using 1,3-dimethylimidazolium
(
(
S1: Im) or 1,3-dimethylbenzimidazolium (S2: BenIm) iodide
Figure 2). The mono-NHC-Ir(I) complexes (1a-b) were prepared
t
Figure 2. Syntheses of a) mono-NHC-Ir(I) complexes 1a-d, b) bis-NHC-Ir(I)
complexes 2aa-bd, and c) tris-NHC-Ir complexes 3a-2H, 3b, 3b-2H (3a was not
accessible).
from S2 and [Ir(COD)Cl]
2
(COD = 1,5-cyclooctadiene) with KO Bu
(tBu = tert-butyl) in good yields (~90%, Figure 2a).[12a] After the
ligand exchange with CO, complexes 1c-d were obtained in 89-
93% yields. The bis-NHC-Ir(I) complexes (2aa, 2ba, and 2bb)
were synthesized in moderate yields using [Ir(COD)Cl] and the
corresponding salts (S1 or S2) with NaH as the base (Figure 2b).
Subsequent ligand exchange gave complexes 2ab, 2bc, and 2bd
2
We then examined the feasibility of the dehydrogenative
cross-coupling of EGO and MeOH to LA using tris-NHC-Ir(I)
complex 3b as the catalyst. The reaction was performed at 140 °C
in the presence of 500 ppm 3b, with 5 mmol EGO and 1.5 equiv.
Ba(OH) ·8H O, in large excess of MeOH (2 mL). LA was formed
2 2
within one hour in a quantitative yield (based on EGO) with an
excellent selectivity (Figure 3), showing a high catalytic activity of
in excellent yields (95-96%). With Ir(acac)(CO)
2
(acac =
acetylacetonato), tris-NHC-Ir(I) complex 3b was successfully
synthesized (Figure 2c), while the tris-NHC-Ir(III) complex 3a-2H
with two hydrides was isolated directly rather than the anticipated
tris-NHC-Ir(I) complex 3a. Importantly, complexes 3a-2H and 3b
3b. Encouraged by this excellent result, other reaction
were stable in their solid-state (shelf-life more than 3 months at
parameters including solvent, base, and reaction temperature
were further surveyed (Table S1). Note that the yield and
selectivity of LA decreased dramatically when using protic
solvents like water, ethanol, or other primary alcohols; a similar
decrease was observed in a solvent-free case (Table S1, entries
o
2
5 C), and relatively stable for a couple of days in solution (e.g.,
MeOH and dichloromethane). Gratifyingly, the dihydride complex
3
b-2H was readily prepared from 3b in a moderate yield (>48%)
o
[12a]
4
by treatment with excess NaBH at 25 C in i-PrOH.
Subsequently, detailed structures of 2bd and 3b were
determined by single-crystal X-ray crystallography (Figure S39,
Tables S3 and S4). The complex 2bd contains one Ir(I) center
with two NHCs and two CO ligands (Table S3), adopting a cis
square planar geometry that is similar to 2ab.[6a] Crystal structure
analysis of complex 3b (Figure S39, Table S4) clearly showed
that the Ir(I) center connects to three NHCs and one CO ligand,
again forming a square planar geometry. The average Ir−CNHC
distance of 3b is 2.059(6) Å, which is slightly shorter than those
of 2bd (2.06(8) Å), indicating stronger Ir−C NHC interactions in 3b.
Density functional theory (DFT) calculations were performed
to elucidate the electronic nature of the Ir carbonyl complexes
bearing different number of NHCs. The calculations showed that
1
-6). To highlight the crucial role of the MeOH, we found that all
reactions with alternative solvent systems produced polyethylene
glycol as the major byproduct. Moreover, decreasing the amount
of MeOH from 10 to 5 or 2 equiv. resulted in inferior yields (>99%
vs. 83% or 57%, Table S1, entries 7-8).
2
The base, Ba(OH) , also had a substantial impact on the
transformation. Alkali metal hydroxides including LiOH, NaOH,
and KOH all exhibited lower activities (Table S1, entries 9–11),
whereas no reaction occurred with calcium hydroxide, probably
due to its poor solubility (Table S1, entry 12). When the amount
of Ba(OH)
a quantitative yield. Further decreasing the amount of Ba(OH)
.0 equiv. resulted in a slightly decreased yield (95%), along with
co-generation of a minor amount of the byproduct glycolic acid
~3%, assessed via HPLC; Table S1, entries 13-14). Lower
2
was decreased to 1.2 equiv., LA was still obtained in
2
to
1
the ionization potentials (IPs, in eV) anti-correlate to the number
+
of NHCs. IPs follow the trend of [Ir(Im)(CO)
3
]
(12.4) >
(
+
[
Ir(Im)
2
(CO)
2
]+ (11.0) > [Ir(Im)
3
(CO)] (9.7), which can be ascribed
temperatures also led to inferior yields (Table S1, entries 15-16).
Under the optimized reaction conditions, other NHC-Ir
complexes were also examined: the catalytic efficiency increased
along the mono < bis < tris sequence and that 3b exhibited a
higher TOF (2000 h ) than its analogue 3a-2H (1500 h ). These
results were likely attributed to our hypothesis that increasing the
number and the -ring size of the NHCs could facilitate oxidation
to the strong σ-donating and weak -accepting characters of the
NHCs. Additionally, IPs can be further reduced by expanding the
+

-conjugation
of
NHC:
[Ir(BenIm)(CO)
[Ir(BenIm)
3
]
(11.7)
>
[
Ir(BenIm) (CO)
2
2
]+ (10.5)
>
3
(CO)]+ (9.6). As we
−1
−1
expected, all these results reveal that ligand effects can facilitate
the electron removal from the initial complexes, leading to an easy
oxidation of the Ir(I) to yield the desired Ir(III) species.
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COMMUNICATION
of the Ir(I) to the Ir(III) species and improve the catalytic
a mixture of CH
3
OH/CD
3
OD (1:1) with an excess amount of KOH
performance. Furthermore, several viable Ir and Ru catalysts (4-
at 60 °C for 1 hour (conditions similar to the cross-coupling
reaction), two hydride signals appeared at −8.53 and −11.70 ppm,
respectively (Figure 4b). The correlation of the two hydrides in
two-dimensional correlation spectroscopy (2D-COSY) revealed
1
0) that exhibited
a
good catalytic activity in several
dehydrogenative[5d] and cross-coupling
[13]
reactions were also
investigated (Figure 3). Among them, the pincer-type Ru-PNP
[
5a,13b]
complexes (9 and 10)
displayed good TOFs (around 900
that the hydrides adopt a cis configuration (Figure S30), similar to
−
1
[13b]
h ), further attesting the superior catalytic activity of 3b (TOF
that previously reported for pincer complexes.
Nearly identical
-1
hydride signals were detected in the 1H NMR spectrum of tris-
NHC-Ir(I) 3b with KOH in a hot mixture of CH OH/CD OD (Figure
around 2000 h ). When the catalyst loading of 3b was reduced to
2
3
50 ppm, a TOF value as high as 3540 h−1 was obtained (Figure
), and an even slightly higher TOF of 3660 h−1 was observed with
3
3
4b), implying that tris-NHC-Ir(I) 3b could be converted into cis-
dihydride species tris-NHC-Ir(III) 3b-2H, which was further
supported by a 2D-COSY study (Figure S31). When similar
measurements were applied to 3b-2H with excess NaBH in i-
4
PrOH (Figure 2c), 1H NMR spectrum not only indicated the
the solid 3b-2H. Pleasingly, the reaction still proceeded smoothly
with the catalyst loading as low as 25 ppm (Table S1, entry 18),
producing LA in a quantitative yield with a turnover number (TON)
4
up to 4 × 10 within 48 hours.
presence of the cis-3b-2H associated with peaks at δ −8.50 and
−11.70 ppm, but also the trans-dihydride trans-3b-2H formation
with a single peak at δ −7.93 ppm, guided by a similar peak
reported in a prior study.[14]
A
plausible mechanism for the dehydrogenative cross-
coupling of glycol and MeOH to LA was sketched in Figure 4c.
Initially, CO dissociated from tris-NHC-Ir(I) 3b to form species I
with a free coordination site.[15] Both EGO and MeOH were then
dehydrogenated to give the corresponding aldehydes via
hydrogen-borrowing pathway along with the formation of the
dihydride Ir(III) species VII (Please see Figure S40 for more
details and the related discussions). The aldehydes underwent a
cross-aldol condensation to generate GAL, which further
underwent dehydration to form pyruvaldehyde and converted to
LA via an intramolecular Cannizzaro reaction under the high base
conditions.[4f] DFT calculations were performed to estimate the
2
free energy changes during the H release and found that ligand
effects apparently contribute to the catalyst regeneration to
complete the catalytical cycle (Table S7).
Considering the excellent yield and selectivity observed in the
tris-NHC-Ir-catalyzed dehydrogenative cross-coupling of EGO
with MeOH, the applicability in other reported bio-polyols was also
investigated. To our delight, when glycerol or sorbitol was applied
instead of EGO, excellent outcomes were also attained under the
otherwise identical reaction conditions. Remarkably, 86%
conversion, 85% yield with >99% selectivity for LA could be
achieved when sorbitol was dehydrogenated (one molecular
sorbitol generates 2 equiv. LA), which is much better than the
previous report (ca. 40% yield, one sorbitol for one LA
production),[ and further confirmed the metal-ligand cooperativity
is of vital importance for this type of transformation.
Figure 3. Catalytic activities of selected Ir and Ru complexes 1-10 in the
dehydrogenative cross-coupling of EGO and MeOH to LA (With 5 mmol EGO,
O and 2 mL MeOH at 140 oC for 1 h.
5
00 ppm catalyst, 1.2 equiv. Ba(OH) ·8H
2 2
Asterisks denote the catalyst loading at 250 ppm).
We subsequently performed several control experiments. The
commercially available Ir/C and freshly prepared Ir nanoparticles
exhibited much lower activities under the same reaction
conditions (1-3%, Table S2, entries 1-2). Mercury poisoning
experiments excluded the possibility of any nanoparticle
3]
[14]
participation (Table S2, entry 3). In contrast, addition of excess
PPh
significantly inhibited the reaction process (from 2000 h-1 to
In summary, we disclose an unprecedented dehydrogenative
cross-coupling approach using the biomass feedstock EGO and
MeOH to yield the platform molecule LA within one hour. The
metal-ligand cooperativity is of vital importance, in which catalytic
activity of the Ir(I) complexes increases in a sequence of mono-
NHC-Ir < bis-NHC-Ir < tris-NHC-Ir. The tris-NHC-Ir complexes
derived from benzimidazolium salts exhibits the best activity, with
3
-1
1
3
34 h , Table S2, entry 4), revealing that PPh can replace NHCs.
All these outcomes clearly suggested that complex 3b behaved
as a homogenous molecular catalyst in the reaction.
High-resolution mass spectroscopy (HR-MS) analysis of a
dichloromethane extract of the reaction mixture (Figure 4a and
S36) revealed that, either 3b or 3b-2H was added, we observed
−
1
quantitative selectivity and TOF up to 3660 h . The readily
available raw substrates, a highly active catalyst, and clean
hydrogen gas side product highlight the great potential of this new
atom-economic and formerly quite challenging dehydrogenative
discrete signals for both 3b (m/z: 659.23) and 3b-2H (m/z: 661.23,
+
Figure 4a). Besides, we also found an Ir complex Ir(BenIm)
3
I
(
m/z: 631.23, Figure 4a) and a peak at m/z 693.22 (Figure 4a),
which was attributed as the dihydride NHC-Ir(III) complex V, as
coordinated with glycolaldehyde. H NMR spectroscopic studies
C-C cross-coupling reaction, thereby opening up
sustainable avenue for the synthesis of platform molecules.
a new
1
were then carried out. When tris-NHC-Ir(III) 3a-2H was heated in
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1
Figure 4. a) Theoretical (top) and experimental (bottom) high-resolution mass spectroscopy spectra. b) Partial H NMR spectra of tris-NHC-Ir complexes 3a-2H
(
3
top), 3b (middle) with 10 equiv. KOH after heating and 3b-2H (bottom) in CH
3
OH and CD
3
OD (1:1) mixture. c) A plausible mechanism (ORTEP diagram of complex
−
b is provided; hydrogen and BF
4
anions have been omitted for clarity).
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Keywords: Lactic acid • cross-coupling • ethylene glycol •
methanol • N-heterocyclic carbene iridium complex
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Entry for the Table of Contents
COMMUNICATION
Jiajie Wu, Lingyun Shen, Zhe-Ning
Chen, Qingshu Zheng, Xin Xu,* and Tao
Tu*
Page No. – Page No.
Iridium-Catalyzed Selective Cross-
Coupling of Ethylene Glycol and
Methanol to Lactic Acid
An unprecedented dehydrogenative C-C cross-coupling with cheap and bulky
ethylene glycol and methanol has been developed by using a novel iridium catalyst
bearing three N-heterocyclic carbenes, which presents as a highly selective and
-1
atom-economic approach for lactic acid synthesis (TOF up to 3660 h ).
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