Transfer hydrogenation of levulinic acid from glycerol and ethanol using water-soluble iridium N-heterocyclic carbene complexes

Article abstract of DOI:10.1016/j.jorganchem.2020.121310

The upgrading of biomass derivatives to biofuels and chemicals through transfer hydrogenation (TH) is attractive relative to direct hydrogenation, especially when the hydrogen donors can be sourced renewably. Here we report the first process that uses glycerol, a renewable waste material from biodiesel processing, as a hydrogen donor in the catalytic TH of a biomass-derived platform chemical, levulinic acid, to selectively afford γ-hydroxyvaleric acid (GHV) and lactic acid (LA). GHV can be further converted to γ-valerolactone (GVL), a widely used platform chemical. Levulinic acid can be used directly, without esterification, which is typically needed for transfer hydrogenation. The process is efficiently facilitated by robust iridium N-heterocyclic carbene (NHC) complexes with sulfonate functional groups at low catalyst loading (1–10 ppm), affording quantitative conversion of levulinic acid in the presence of KOH to GHV, with >100,000 TON in 2 h at 150 °C, using 1 ppm catalyst. The most prolific catalyst, [(NHC-SO₃-)₂(CO)₂Ir]Na, can also facilitate transfer hydrogenation from other hydrogen donors, such as 2-propanol, potassium formate, and most notably, ethanol, which can also be derived from renewables. Ethanol is a highly efficient hydrogen donor for levulinic acid using this catalyst, affording >7,000 turnovers in 2 h using 10 ppm catalyst.

Full text of DOI:10.1016/j.jorganchem.2020.121310

Journal Pre-proof
Transfer hydrogenation of levulinic acid from glycerol and ethanol using water-soluble
iridium N-heterocyclic carbene complexes
Kai Wang, Jacob Heltzel, Evan Sandefur, Keira Culley, Gabriel Lemcoff, Adelina
Voutchkova-Kostasl
PII:
S0022-328X(20)30212-6
DOI:
https://doi.org/10.1016/j.jorganchem.2020.121310
JOM 121310
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 22 February 2020
Revised Date: 27 March 2020
Accepted Date: 17 April 2020
Please cite this article as: K. Wang, J. Heltzel, E. Sandefur, K. Culley, G. Lemcoff, A. Voutchkova-
Kostasl, Transfer hydrogenation of levulinic acid from glycerol and ethanol using water-soluble
iridium N-heterocyclic carbene complexes, Journal of Organometallic Chemistry (2020), doi: https://
doi.org/10.1016/j.jorganchem.2020.121310.
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Transfer Hydrogenation of Levulinic acid from
Glycerol and Ethanol Using Water-Soluble Iridium N-
heterocyclic Carbene Complexes
Kai Wanga, Jacob Heltzela, Evan Sandefura, Keira Culleya, Gabriel Lemcoffb and
Adelina Voutchkova-Kostala*
a Chemistry Department, the George Washington University, 800 22nd St NW, Suite 4000, Washington,
DC 20052 (USA), b Department of Chemistry, Faculty of Natural Sciences, Ben-Gurion University of the
Negev, P.O.Box 653, Beer-Sheva 84105, Israel
*Corresponding author contact: avoutchkova@gwu.edu
1

Abstract
The upgrading of biomass derivatives to biofuels and chemicals through transfer hydrogenation
(TH) is attractive relative to direct hydrogenation, especially when the hydrogen donors can be
sourced renewably. Here we report the first process that uses glycerol, a renewable waste
material from biodiesel processing, as a hydrogen donor in the catalytic TH of a biomass-
derived platform chemical, levulinic acid, to selectively afford
γ-hydroxyvaleric acid (GHV) and
lactic acid (LA). GHV can be further converted to -valerolactone (GVL), a widely used platform
γ
chemical. Levulinic acid can be used directly, without esterification, which is typically needed for
transfer hydrogenation. The process is efficiently facilitated by robust iridium N-heterocyclic
carbene (NHC) complexes with sulfonate functional groups at low catalyst loading (1-10 ppm),
affording quantitative conversion of levulinic acid in the presence of KOH to GHV, with >
-
100,000 TON in 2 hours at 150 °C, using 1 ppm catalyst. The most prolific catalyst, [(NHC-SO3
)2(CO)2Ir]Na, can also facilitate transfer hydrogenation from other hydrogen donors, such as 2-
propanol, potassium formate, and most notably, ethanol, which can also be derived from
renewables. Ethanol is a highly efficient hydrogen donor for levulinic acid using this catalyst,
affording >7,000 turnovers in 2 hours using 10 ppm catalyst.
Keywords
N-heterocyclic carbene; transfer hydrogenation; glycerol; ethanol; iridium; levulinic acid
Abbreviations
LA: levulinic acid; GVL: γ-valerolactone; GHV: γ-hydroxyvaleric acid; NHC: N-heterocyclic
2

1. Introduction
The upgrading of biomass derivatives to biofuels and chemicals typically requires the reduction
of high oxygen content.[1] While direct hydrogenation using H2 can be an effective catalytic
route, the use of milder conditions using transfer hydrogenation (TH) from H2-donors is proving
increasingly attractive for valorization of biomass. In addition to more modest infrastructure
requirements for processing, TH provides a way to potentially source H2 from other renewable
sources in a single process. Furthermore, in contrast to direct hydrogenation, TH can provide
selectivity for C=O over C=C bonds.[2] In recent years significant progress has been made
towards the development of TH strategies for biomass-derived substrates using both
homogeneous and heterogeneous catalysts.[3] The most commonly employed H2-donors are
isopropanol and formic acid, although the use of renewably sourced alcohols, such as ethanol
and glycerol, is also gaining interest.[2,4-8] While the most efficient methods to advance TH in
organic synthesis are promoted by organometallic catalysts, it is challenging to utilize transition
metal complexes in aqueous media, which are required for many biomass applications, due to
the lability of the ligands in water and low solubility of the complexes. An attractive methodology
that has been recently gaining momentum in order to circumvent this challenge is the use of
robust NHC ligands functionalized with ionizable groups that enhance stability and hydrophilicity
of the complex.[9]
One biomass-derived platform chemical that has proven to be a challenging substrate for
hydrogenation is levulinic acid (LA). LA can be obtained from starch and cellulose through
hydrolysis to hexoses, such as glucose and fructose, with subsequent dehydration to HMF and
rehydration to formic and LA.[10,11] Chemical conversion of LA to levulinate esters,
γ-
hydroxyvaleric acid (GHV), γ‐valerolactone (GVL), acrylic acid, 1,4 pentadiol, angelica lactone
‐
and δ‐aminolevulinic acid (DALA) are just some of the derivatizations explored to-date for
further valorizing this platform chemical.[12]
3

Hydrogenation of LA is expected to yield γ-hydroxyvaleric acid (GHV); however, under most
experimental conditions reported, the final product is γ‐valerolactone (GVL), which is formed via
an intermolecular esterification, either prior to or subsequent to hydrogenation (Scheme 1). This
is true both for direct hydrogenation,[8,13-26] as well as transfer hydrogenation, even in the
presence of base. Basic conditions are expected to suppress esterification, affording GHV as
the final product. It is feasible that the predominant focus in the literature on generation of GLV
rather than GHV is the result of the potential applications of GVL as a fuel additive and green
solvent.[27-34] However, new applications for GHV are making it into an attractive target in
itself: specifically, GHV can be used in the synthesis of poly(hydroxyalkanoate) (PHA) polymers,
which are not only biodegradable, but also have more favorable lifecycle environmental impact
than polyolefins.[35] Most commonly, GHV can be copolymerized with 3-hydroxybutyric acid to
produce biodegradable co-polymers with controllable material properties, but other PHAs based
on GHV can also readily be envisioned. In addition to its application as a monomer, GHV is also
a versatile synthetic building block for further functionalization.
Scheme 1. Conversion of levulinic acid (LA) to γ-hydroxyvaleric acid (GHV) and subsequently
to γ‐valerolactone (GVL) via hydrogenation and dehydration.
In order to contextualize the process reported herein, we offer comparison to reported
methods for TH of LA to yield GVL (methods that exclusively afford GHV have not been
reported). The most common are methods that utilize formic acid as H2-donor, using Au, Ru, Ag,
4

Pd, Rh and Ir catalysts.[36-42] Although formic acid can be derived from the same process as
LA, its corrosive character has limited some applications. The use of alcohols as H2-donors via
transfer hydrogenation has also been explored primarily with heterogeneous catalysts, such as
RANEY® Ni, [43] ZrO2, [44] ZrO(OH)2,[45] Zr-beta zeolites,[46,47] Zr-HBA, [48] porous
zirconium-phytic acid hybrid, [48] Zr coordination polymers,[49] and immobilized Zr(IV)-Schiff
base complexes. [50] Carbon-supported Pd [51] and Ru [62] have also been shown to
effectively catalyze the reaction with isopropanol and ethanol using microwave heating; in the
case of the Ru/C,[62] without a need for base. The only homogeneous example of TH of LA
using alcohols as H2-donor is from Williams et al., who showed that a Ru phosphine complex
can afford ~40 turnovers (TON) in 24 h (Figure 1). [62] The efficiencies of the most comparable
catalytic systems for this process, albeit with a different H2-source, are summarized in Figure 1,
with a full list available in the ESI-Figure S1. The key challenges that remains to be overcome
are low catalyst activity or stability (low TONs), the need to esterify LA as the alkyl levulinate
before hydrogenation,[8] and the expansion of H2 sources to alcohols derived from renewables.
Thus, the development of efficient and robust catalysts for LA transfer hydrogenation using
renewable alcohols as H2-donor and directly from LA is highly desirable.
5

O
O
Cat
O
+ H2-donor
+ donor byproduct + ROH
OR
Additives
O
LA
GVL
Ru(PPh3)3(CO)H2
Xanphos
Pd/C
Ru/C
Palkovits et al., 2019 62
Williams et al, 2007 52
Hasan et al., 2015 51
R = Me, H; 1.25 mol% cat, KOtBu
H2-donor: sec-phenethyl acohol
Yield: > 99%, 24 h, 110 oC toluene
R = H; 0.47 mol% Pd, KOH
H2-donor: IPA, EtOH
Yield: 86% mw, time and temp ND
TON = 212, TOF ND
R = H, alkyl, 0.28 mol% Ru
H2-donor: IPA
Yield: 99% 140 oC mw, 1 h
TON = 348; TOF = 348 h-1
TON: 40, TOF: 2 h-1
O
O
Cat
+ H2-donor
+ donor byproduct
OH
OH
Additives
O
OH
LA
GHV
H+/ - H2O
-
Ir(NHC-SO3 )2(CO)2
This work
R = H; 1 - 10ppm (0.001 - 0.01 mol%) Ir, KOH
H2-donor: glycerol, EtOH, IPA
O
O
Yield: >99% yield, 2 h, 150 oC
TON (gly) 101,000 : ; TOF: 50,500 h-1
GVL
Figure 1. Relevant comparative examples of transfer hydrogenation of LA to GVL and method
reported in this work (see ESI for more extensive list).
Two alcohols that can be sourced renewably are glycerol and ethanol. Due to recent
exploitation of fatty acids for biodiesel synthesis, glycerol production from biodiesel synthesis
has surpassed market demand. One of the attractive routes to glycerol valorization has been as
an effective H2-donor. [5, 53] Glycerol dehydrogenation ultimately affords lactic acid under basic
conditions, [54-56] which is in itself a value-added product. In addition, we have recently shown
that the conversion of glycerol to lactic acid is highly thermodynamically favorable under basic
6

conditions (∆G = -105.7 kcal/mol with G3B3, PCM water, see ESI Table S6) and can thus be
used to drive hydrogenation of challenging substrates. In the search for highly prolific catalysts
for the acceptorless dehydrogenation of glycerol, we have identified water-soluble Ir and Ru N-
heterocyclic carbene organometallic catalysts (NHCs) have significant advantages over less
hydrophilic catalysts, reaching turnover frequencies (TOF) of over 40,000 h-1.[54] We proposed
that the latter class of catalysts can facilitate efficient TH of biomass substrates in aqueous
media, such as 15 – 30% H2O:GVL used by Dumesic and Horvath. [34, 58-59] Here we report
the first TH of levulinic acid from glycerol in a highly efficient and selective process under mild
conditions, which forms two value-added products: GHV and lactic acid. GHV can be readily
transformed to GVL via acidification. The catalyst is also efficient with ethanol as H2-donor,
another alcohol that can be sourced renewably. c
2.
Materials and Methods
2.1 Synthetic procedures for ligands and catalysts
Ligand precursors (2,6-bis(1-imidazolyl)pyridine, 1,1'-methylenebis[imidazole] and 2-(Imidazol-
1-yl)pyridine were synthesized by previously reported methods. [54] Ruthenium compounds 1
and 5 were prepared by silver transmetalation from the corresponding imidazolium salts.[60]
Iridium compounds 2 – 4 were synthesized by direct metalation using [Ir(cod)OMe]2, as
previously described by us.[54] Catalyst synthesis and characterization are detailed in the ESI.
2.2 Experimental procedures for transfer hydrogenation
2.2.1. General procedure for transfer hydrogenation reactions using microwave heating:
A 10-mL microwave tube was charged with a magnetic stir bar, 0.4612 g glycerol (0.366 mL,
5.00 mmol), 0.286 mL aqueous KOH (14 M, 4.00 mmol), 0.0474 g levulinic acid (0.408 mmol),
0.0362 µmol catalyst (50 µL of 0.724 mM aqueous solution, < 0.01 mol% w.r.t. levulinic acid)
and 1.30 mL DI water. The resulting solution had a glycerol concentration of 2.5 M, KOH
7

concentration of 2.0 M, potassium levulinate concentration of 0.20 M and [Ir] catalyst
concentration of 0.0181 mM. The sealed vial was flushed with nitrogen, but air was not
stringently excluded using Schlenk technique. The reaction mixture was thoroughly stirred to
ensure adequate mixing and then placed in the cavity of an Anton Parr Monowave or CEM
Discover microwave reactors. The mixture was heated with 200 W power (maximum pressure
set to 250 psi) to 150 °C, or as indicated. The desired temperature was reached in less than 1
minute on average, and was held for 2 hours (unless otherwise indicated). After cooling to room
temperature product and reactant concentrations were quantitated by NMR based on this
external standard and by HPLC, as detailed in 2.2.3.
2.2.2. General procedure for transfer hydrogenation reactions using conventional heating:
For reactions performed using conventional heating, the same procedure was followed, but
using 20-mL reaction tubes that were placed in a Radleys Carousel 12 Reaction Station, and
heated to 150 °C (temperature of reaction block probe) for 24 hours. The reactions were flushed
with nitrogen, but air was not stringently excluded using Schlenk technique.
2.2.3. Product characterization
Reaction aliquots were analyzed by HPLC and NMR. HPLC was performed using a Shimadzu
Prominence-i (LC-2030C 3D) instrument equipped with a PDA detector and an RI detector
using a mobile phase of 0.005 M H2SO4 with a flow rate of 0.44 mL/min at 35 °C. Samples were
prepared by adding 1-mL of the sample to 0.22 mL of 5 M H2SO4 and filtering through a syringe
filter. The PDA detector scanned the range of 190-800 nm, affording traces at 190, 218, 254,
and 284 nm for analysis. For NMR analysis, a 0.100-mL aliquot of reaction solution was mixed
with equal volume of standard solution of 3-(trimethylsilyl)propionic-2,2,3,3-d4 acid sodium salt
(TSP) and 0.5 mL D2O. A comparison was made with reactions in which the TSP standard was
8

added at the beginning of reaction, rather than to each aliquot, and no major differences were
observed.
3. Results
3.1 Catalyst design and synthesis.
Catalyst design was guided by the following considerations. The selection of
organometallic (i.e. homogeneous), rather than heterogeneous catalysts, is intended to
capitalize on the ability to tune ligand architecture in order to optimize activity and selectivity for
this challenging reaction. Given that the optimized catalyst is intended to subsequently be
heterogenized as a robust, single-site heterogeneous catalysts, the ultimate utility of the
heterogeneous catalyst will minimize consumption of the precious metals. The choice of Ir and
Ru species is based on evidence that that complexes of these metals can have high activity for
transfer hydrogenation, especially from glycerol as H2-donor (there is only one homogeneous
example of TH of LA from alcohols [62], and Ir complexes have been previously shown to be
effective for TH of carbonyls from glycerol [53, 61]). N-heterocyclic carbenes (NHCs) were
selected as ligands based on their stability in aqueous media and their thermally-robust nature,
which are critical given that the TH reactions from glycerol typically require reaction
temperatures above 120 °C [61] and aqueous conditions. Furthermore, we expect that more
thermally robust catalysts will have a significant advantage in catalyst lifetime under microwave
conditions, where superheating can cause hotspots. Finally, the use of ionizable sulfonate
functionalization of the NHCs is guided by the need to increase the hydrophilicity of the
complexes so as to render them soluble in the aqueous glycerol media. We have previously
found the latter to be an important design criterion for catalysts used in TH of biomass-derived
substrates, significantly enhancing activity compared to catalyst precursors lacking the ionizable
9

groups.[54] Furthermore, this functionalization is compatible with the linker groups required to
subsequently immobilize the complexes onto supports.
We previously reported the high activity of compounds 1 – 5, bearing alkyl- and arylsulfonate-
functionalized NHCs (Chart 1), for glycerol dehydrogenation. [54] The synthesis and transfer
hydrogenation activity from glycerol of iridium compound 2 was previously reported by Peris et
al. [70-71] Ruthenium compounds 1 and 5 were prepared by silver transmetalation from the
corresponding imidazolium salts. [60] Compounds 2 – 4 were synthesized by direct metalation
using [Ir(cod)OMe]2, as previously described by us. [54]
Chart 1. Catalysts for TH of LA from glycerol.
3.2. Glycerol as H2-donor
10

TH of levulinic acid (LA) is expected to proceed according to Scheme 2, where the initial
dehydrogenation product of glycerol (dihydroxyacetone or glyceraldehyde) is rapidly converted
to lactate under basic conditions via dehydration and intramolecular Cannizzaro reaction.[2] The
hydrogen is transferred to levulinate to afford GHV. Despite attempts to identify the
intermediates to lactic acid involved in this process (dihydroxyacetone, glyceraldehyde and
pyruvaldehyde), none of these have been observed under re action conditions. We can thus
only assert that the intermediates formed is highly reactive under basic conditions.
The reporting of lactic acid formation, in addition to that of GHV, is important for the
following reasons. First, lactic acid is a value-added byproduct from the TH using glycerol, and
thus the value of lactic acid would likely be part of the economic rationale for using glycerol in
TH of biomass substrates. Furthermore, since lactic acid is formed in a multi-step process
(catalytic dehydrogenation to form DHA, followed by base-promoted reactions leading to
lactate), it is important to state whether TH reactions using glycerol form a full equivalent of
lactate as by-products. Second, some of the catalysts for TH of glycerol also facilitate the
acceptorless dehydrogenation (AD) of glycerol to DHA, which under basic conditions rapidly
forms lactic acid. The AD competes with TH, and for some catalysts, the latter process is faster.
As a result, some catalysts form lactic acid in excess of the desired hydrogenation product (in
this case, GHV). In addition to the relative rates of AD vs TH being dependent on the catalyst,
they also have distinct temperature-dependence and base concentration dependence, as we
previously detailed in the case of TH of CO2 from glycerol.[61] In the reaction described here,
we thus quantitate both GHV and lactic acid at different temperatures, and using different base
conditions (concentration and type of base).
Scheme 2. Transfer hydrogenation of levulinic acid (LA) from glycerol.
11

In order to identify optimal reaction conditions, catalytic activity of 4 was explored at different
temperatures, base concentrations and solvent ratios (Figures 2 and 3). Water was added as a
co-solvent to decrease the viscosity of glycerol and improve mass transfer of base. For speed of
optimization, the reactions were carried out using microwave heating for 2 hours.
12

15000
10000
5000
0
40000
30000
20000
10000
0
0
2
4
6
[KOH] (M)
Lactic acid
GHV
Figure 2. Effect of KOH concentration on the turnover numbers afforded by catalyst 4 for GHV
formation (primary y-axis) and lactic acid formation (secondary y-axis) in the TH of LA from
glycerol (Conditions: 0.01 mol% (10 ppm) cat 4, 0.20 M levulinic acid, 1.35 mL water, 0.366 mL
glycerol, KOH of concentration specified, 150 °C, 2 h using microwave heating, 200 W
maximum power, under air).
Reactions without base gave no conversion of LA and negligible lactic acid formation, which
was expected, given that both the glycerol dehydrogenation and the subsequent conversion to
lactic acid require base (Figure 2, ESI Table S1). In the absence of base, when the reaction is
under acidic conditions, we observe only ketals and negligible concentrations (< 5%) of the
levulinate esters. As KOH concentration is increased, the concentrations of GHV and lactic acid
increase correspondingly. The need for excess base relative to levulinic acid is not surprising,
given that one equivalent of base is consumed by LA to form the levulinate salt, and additional
base is needed to convert the primary dehydrogenation product of glycerol to the lactate salt.
13

KOH concentration of ~2 M affords full conversion of LA with quantitative selectivity for GHV
(12,260 TON). Under these conditions, the concentration of lactic acid is 2-3 times greater than
that of GHV (equivalent to 23,660 TON). The yield of lactic acid from glycerol in this reaction is
~17% (initial molar ratio of LA:glycerol is ~11.5). The quantity of lactic acid produced exceeds
that of GHV, even at lower base concentrations: for example, at 0.4 M KOH we observe 518
and 1,710 turnovers of GHV and lactic acid respectively. This is consistent with our previous
reports on TH of CO2 form glycerol, which suggest that TH from glycerol competes with
acceptorless dehydrogenation, and is related to base concentration.[8] Thus, as KOH
concentration is increased beyond 2 M, the TONs with respect to lactic acid generation also
increase.
We briefly explored the effect of substituting KOH with other hydroxide and carbonate bases
(Figure 3 and ESI Table S2). Sodium hydroxide afforded slightly lower yield and TON of GVL
compared to potassium hydroxide (95% yield, 11,620 TON). Both carbonate bases tested
afforded lower yields than the hydroxides, with potassium carbonate performing better than
sodium carbonate (31% vs 15% yields of GHV respectively). In the reactions with carbonate
base small amounts of formate were also observed, arising from TH of carbonate to formate, as
previously reported by us. [61]
14

Figure 3. Effect of base on the turnover numbers afforded by catalyst 4 for GHV and lactic acid
(also see ESI Table S2). Conditions: 0.01 mol% cat 4, 0.20 M levulinic acid, 2.0 M Base, 0.366
mL glycerol, water (2 mL total volume), 150 °C, 2 h using microwave heating, 200 W maximum
power, under air).
The reaction is quite sensitive to temperature: below 100 °C the TONs with respect to both
GHV and lactic acid are relatively low (1,260 and 2,310 TONs respectively in 2 hours). At 120
°C, the concentrations of GHV and LA produced are equal after 2 hours (8,090 and 8,090 TONs
respectively, corresponding to 66% yield of GHV). The reaction reaches quantitative yields of
GHV at 150 °C (ESI Table S3). At 180 °C the TONs of lactic acid further increase, but the GHV
yield decreases as small quantities of methyl-THF, formed by further hydrogenation, are
observed.
15

25,000
20,000
15,000
10,000
5,000
0
100
80
60
40
20
0
1
2
3
Catalyst
4
5
GHV
Lactic Acid
Yield% GHV
Figure 4. Turnover frequencies for TH of levulinic acid from glycerol using catalysts 1 - 5 (Chart
1). (Conditions: 0.01 mol% catalyst, 0.20 M LA, 2.0 M KOH, 0.366 mL glycerol, water (2 mL total
volume), 150 °C for 2 h using microwave heating, 200 W maximum power, under air).
Using the optimized conditions, we compared the activity of catalysts 1 - 5 at a loading of
<0.01mol % (Figure 4 and ESI Table S4). The two Ir(I) bis-NHC catalysts (3 and 4) showed
highest activity, with the carbonyl analog (4) surpassing the activity of the cyclooctadiene analog
(3) by a factor of ~ 2. Catalyst 4 affords quantitative conversion of 0.2 M potassium levulinate
with less than 0.01 mol% catalyst in 2 hours (TOFs of 6,130 and 11,830 h-1 for GHV and lactic
acid respectively). In comparison, the Ir(III) bis-NHC catalyst, 2, was approximately 5-fold less
active. The two Ru(II) NHC compounds (1 and 5) showed lower activity than the iridium
compounds.
To determine whether the catalyst loading could be further reduced, we increased the
concentration of LA 10-fold to 2 M, and [KOH] to 4 M, with a corresponding 10-fold reduction of
catalyst loading to < 0.001 mol%. Under these conditions we obtained 66% GHV yield in 1 hour
(66,700 TONs) and near-quantitative conversion after 2 hours (101,000 TONs) using microwave
16

heating, suggesting that catalyst loading can be successfully reduced. The rate of the reaction
using catalyst 4 was also compared using conventional heating. The time needed to reach
quantitative yield using conventional heating was significantly longer than that using microwave
heating (24 h vs. 2 h). This difference is likely due to (i) the lower accuracy in controlling
reaction temperature using conventional heating in a sealed tube vs microwave heating; and (ii)
the higher efficiency of microwave heating vs conventional heating of aqueous glycerol,
resulting in improved mass transfer of base. The trend is consistent with our previous reports on
the relative rates of glycerol dehydrogenation under aqueous conditions, [54] and with recent
reports of GVL transfer hydrogenation being accelerated by microwave heating. [51, 62]
The most active catalyst, 4, was the one previously identified by us as most prolific for
glycerol dehydrogenation; in fact, the relative activity of catalysts 1 - 5 for TH of LA follows the
same trend as that we previously observed for acceptorless dehydrogenation of glycerol.[54]
The two ruthenium NHC catalysts (1 and 5) were significantly less active than the iridium NHC
catalysts (2 – 4). Ru catalyst 1, which differs from 5 by a propylsulfonate imidazolium moiety
substituted on the pyridine, affords only a modest improvement of activity compared to 5.
Although further optimization of the ligand architecture around the ruthenium is likely to result in
improvements of catalytic activity, in light of the significantly higher activity observed with iridium
catalysts, we did not pursue further optimization of ruthenium complexes. Among the iridium
catalysts, the Ir(III) compound 2 is significantly less active than the two Ir(I) compounds (3 and
4).
Among the two Ir(I) analogs (dicarbonyl derivative 4 and cod analog 3), 4 is
significantly more active, surpassing the activity of the 3 by a factor of ~ 2. The seminal report
by Crabtree et al. on glycerol acceptorless dehydrogenation indicated that substituting the
cyclooctadiene (cod) ligand of non-sulfonated Ir(I) complexes with carbonyls afforded an
increase in glycerol dehydrogenation activity.[69] We thus prepared the corresponding
dicarbonyl complex 4 by passing CO gas through a solution of compound 3. Indeed, we find that
17

4 is significantly more active for both transfer hydrogenation activity of LA (Figure 4), as well as
for acceptprless dehydrogenation of glycerol; the latter was reported by us previously.[54] We
postulate that the difference in activity observed for 3 and 4 in the TH reaction could be due to
more favorable insertion into Ir-H of the levulinic acid carbonyl due to the effect of strong π-
acceptor (CO) ligands. However, as discussed in the subsequent paragraph, the presence of
the carbonyl ligands likely results in a significantly different mechanism for glycerol activation in
3 vs 4.
Given that Ir(III) complex 2 differs from 3 and 4 in both the oxidation state of iridium and the
chelating nature of the bis-NHC ligands, it is not possible to draw direct conclusions about the
effect of the higher oxidation state of the catalyst precursor. Attempts to synthesize the chelating
Ir(I) analog of 2 failed, likely due to instability of the Ir(I) D4h complex with the small bite angle of
the methylene-bridged bis-NHC ligand. However, one can expect that catalyst 2 facilitates the
reaction via a distinct mechanism compared to that of the most active dicarbonyl Ir(I) compound,
4. Ir(III) compounds likely undergo ligand substitution by glycerol, base-dependent
deprotonation to form Ir-alkoxide, ß-hydride elimination and insertion of the carbonyl. [63] As
proposed by Xiao et al., a similar mechanism can be used to account for acceptorless alcohol
dehydrogenation facilitated by Ir(III) compounds, where instead of carbonyl insertion, hydride
abstraction using H+ releases H2. [64] For Ir(I) compound 3, a similar mechanism is possible
because the cyclooctadiene (cod) is highly labile and can be readily substituted by glycerol.
However, carbonyls in 4 are not readily labile,[65] and we propose that the 16-electron Ir(I)
species instead undergoes O-H oxidative addition with glycerol to form an alkoxy hydride
complex; this step has precedents for Ir(I) complexes.[66-68] The resulting Ir(III) alkoxy hydride
complex (previously observed by NMR)[54] could more readily dissociate a carbonyl compared
to the Ir(I) species, given that expectedly lower bond dissociation energy due to decreased
backbonding of the more oxidized metal. The alkoxy glycerol complex subsequently can
undergo ß-hydride elimination, releasing dihydroxyacetone (DHA) via O-H reductive elimination,
18

and re-forming the Ir(I) species. Unfortunately, DHA is not observed under basic conditions, as it
quickly reacts to form lactate, likely via dehydration and intramolecular Cannizzaro reaction.[69]
This mechanism is consistent with the fact that no product is observed at 150 °C in the absence
of base, which is needed to thermodynamically drive the reaction by conversion of DHA to lactic
acid.
Given that the reaction forms two products, we attempted, albeit with limited success, to
efficiently separate them. Methods explored included selective freezing, extraction with organic
solvents and anion and cation exchange resins which may retain the lactate, hydroxide and
potassium ions. Unfortunately, none of these afforded clean separation of the products in our
hands, partly due to the challenge in separating two carboxylic acids with similar physical
properties. We can, however, show that upon acidification of the crude reaction GHV readily
converts to GVL, which can be more readily isolated (see ESI Figure S-3).
2.3. Activity with other H2-donors
19

14,000
12,000
10,000
8,000
6,000
4,000
2,000
0
100
80
60
40
20
0
Glycerol
Isopropanol
K-formate
Yield% GHV
Ethanol
H2-donor
TON GHV
Figure 5. Effect of H2-donor on the turnover numbers for GHV afforded by catalyst
4 for TH
of levulinic acid. Conditions: 0.01 mol% cat 4, 0.20 M levulinic acid, 2.0 M KOH, 2.5 M H2-
donor, water (2 mL total volume), 150 °C for 2 h, microwave heating in air.
In addition to glycerol, we find that the optimized system is also effective with other H2-
donors, such as 2-propanol, potassium formate and ethanol (Figure 5, ESI Table S5). For
consistency, these reactions were also performed in 1:1 H2-donor:water in closed vessels using
microwave heating in order to maintain temperature at 150 ºC. Under those conditions the
reaction with 2-propanol affords 82 % yield of GHV in 2 hours, compared to the quantitative
yield afforded with glycerol under the same conditions. The lower yield with 2-propanol could be
due to the fact that the thermodynamic driving force (Gibbs free energy of reaction, (∆G°aq) of
the reaction with glycerol, which forms lactate after dehydrogenation under basic conditions, is
significantly more favorable compared to that from the reaction with 2-propanol (-105 vs -9.7
20

kcal/mol for glycerol vs 2-propanol dehydrogenation, ESI Table S6). The lower activity with
potassium formate (4,650 TON, 38% yield) is due to the fact that under basic conditions the
catalyst has low activity for dehydrogenation of formate. Furthermore, under acidic conditions,
we previously found that it is in fact active for the reverse reaction – transfer hydrogenation of
CO2 from glycerol.[61] The activity for dehydrogenation of formic acid increases at lower pH, but
the reaction could not be performed at acidic pH under microwave conditions due to the
corrosive nature of the acid to the microwave components. Under conventional heating at reflux
(~100 ºC) the reaction with formic acid affords 75% yield of GHV in 24 h, demonstrating the
potential application of this system to formic acid as H2-donor.
The catalyst is also effective with ethanol, a primary alcohol, as H2-donor. Ethanol is an
attractive source of hydrogen due to its availability from renewables, but previous reports of LA
TH from ethanol over ZrO2-based catalysts at 150 ºC documented decreased GHV selectivity
due to formation of ethanol by-products (self-condensation products of acetaldehyde and
acetaldehyde-LA adducts).[8] There is only one prior report demonstrating the use of ethanol as
H2-donor for TH of LA using microwave pulse heating, but the reaction temperature could not be
reported. [51] With the 1:1 ethanol:water mixture catalyst 4 affords 68% of GHV in 2 hours
(7,580 TONs), and full conversion in 3 hours, with small amounts of ethyl acetate and
acetaldehyde as by-products from ethanol (ESI Figure S-4). Trace amounts of ethyl levulinate
and ketals were also identified by GC-MS. The reaction was also attempted in neat ethanol, and
affords comparable yield (70%) and selectivity.
4. Conclusions
Here we report an efficient catalytic approach for the upgrading of a biomass-derived platform
chemical, levulinic acid, to γ-hydroxyvaleric acid (GHV) via transfer hydrogenation (TH) from
renewably-sourced hydrogen donors - glycerol and ethanol. In this first report of the use of
21

glycerol as a hydrogen donor for the TH of levulinic acid, we show that a quantitative yield of
GHV can be achieved in the presence of base (KOH) in just 2 hours at 150 C with as little as 1
°
- 10 ppm homogeneous catalyst (TON 101,100; TOF: 50,550 h-1 with 1 ppm catalyst 4).
Moreover, levulinic acid can be used directly without esterification, a process which is often
required for transfer hydrogenation of this substrate. The reaction is catalyzed by robust
ruthenium and iridium N-heterocyclic carbene (NHC) complexes with sulfonate functional
groups at low catalyst loading (<10 ppm). The most active catalyst for TH from glycerol, [(NHC-
-
SO3 )2(CO)2Ir]Na (complex 4), was also previously identified as most efficient for acceptorless
dehydrogenation of glycerol to lactic acid. The Ir(III) complex was less active than the Ir(I)
complexes examined, while the Ru complexes tested were significantly less active than the
iridium species. Using ethanol instead of glycerol as H2-donor, the optimized catalyst affords
7,580 TONs of GHV in 2 hours. GHV can be readily converted to GVL upon acidification. Given
the robust nature of this catalyst, further efforts are being directed towards its immobilization as
a single-site catalyst for use in continuous flow reactors.
5. Acknowledgements
The authors thank the Kostal group for use of computational resources and assistance in
performing calculations. This work was supported by the National Science Foundation
CAREER award (number 1554963).
22

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27

•
Efficient homogeneous catalysts for upgrading of levulinic acid to γ-hydroxyvaleric acid
(GHV) via transfer hydrogenation from renewably-sourced hydrogen donors - glycerol
and ethanol.
•
•
Most efficient catalysts are iridium(I) N-heterocyclic carbene (NHC) complexes with
sulfonate functional groups.
Using glycerol as hydrogen donor, optimized catalyst affords quantitative conversion of
levulinic acid in the presence of base (KOH) with > 100,000 TON in 2 hours at 150
with microwave heating.
°C
•
Using ethanol instead of glycerol as hydrogen donor affords 7,580 turnovers of
γ-
hydroxyvaleric acid in 2 hours 150 C with microwave heating.
°

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: