Rapid transfer hydrogenation of acetophenone using ruthenium catalysts bearing commercially available and readily accessible nitrogen and phosphorous donor ligands

Article abstract of DOI:10.1016/j.apcata.2018.11.031

The screening, synthesis and testing of Ru complexes generated from commercially available ligands or ligands that can be synthesised in one step, is described. The catalysts were tested for activity in the transfer hydrogenation of acetophenone by isopropanol, a probe reaction for hydrogen transfer processes between oxygenated species, often found in applications such as biomass upgrading and fine and specialty chemical synthesis. Ligand screening was conducted by in situ catalyst generation and examined NPN and NNN pincer type ligands bearing N–H or C[dbnd]N functional groups. The most active transfer hydrogenation catalysts were found to be those bearing N–H functionality, either as amino groups or as benzimidazole groups. Well-defined catalyst precursors were subsequently synthesised, including the novel complex [Ru(1)PPh₃(Cl)₂] (where (1) = bis(3-aminopropyl)phenylphosphine), the first reported Ru complex for this NPN ligand. Established (PN)₂ and PP/NN ketone hydrogenation catalysts were also screened for transfer hydrogen capability, of which [Ru(^PhPN)₂Cl₂] (where ^PhPN = 2-(diphenylphosphino)ethylamine) was the most active. Subsequently, [Ru(1)PPh₃(Cl)₂], [Ru(^PhPN)₂Cl₂] and [Ru(4)(PPh₃)₂Cl][Cl] (where (4) = 2,6-bis(2-benzimidazolyl)pyridine) were investigated more closely to compare rate constants (determined by reaction profile regression analysis) as a more accurate measure of catalyst activity over commonly reported turn over frequencies (TOF). The effect of the reaction products on the catalyst activity was evaluated using feed spiking experiments. Catalyst deactivation was shown to be prevalent and subsequently incorporated into a simple kinetic model which enabled more accurate reaction profile fitting and provided rate constants for both the transfer hydrogenation step and deactivation reaction.

Full text of DOI:10.1016/j.apcata.2018.11.031

Accepted Manuscript
Title: Rapid Transfer Hydrogenation of Acetophenone Using
Ruthenium Catalysts Bearing Commercially Available and
Readily Accessible Nitrogen and Phosphorous Donor Ligands
Authors: Drew J. Braden, Renan Cariou, John W. Shabaker,
Russell A. Taylor
PII:
S0926-860X(18)30586-6
DOI:
Reference:
https://doi.org/10.1016/j.apcata.2018.11.031
APCATA 16900
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Applied Catalysis A: General
Received date:
Revised date:
Accepted date:
8 June 2018
25 November 2018
27 November 2018
Please cite this article as: Braden DJ, Cariou R, Shabaker JW, Taylor RA, Rapid Transfer
Hydrogenation of Acetophenone Using Ruthenium Catalysts Bearing Commercially
Available and Readily Accessible Nitrogen and Phosphorous Donor Ligands, Applied
Catalysis A, General (2018), https://doi.org/10.1016/j.apcata.2018.11.031
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Rapid Transfer Hydrogenation of Acetophenone Using Ruthenium Catalysts Bearing
Commercially Available and Readily Accessible Nitrogen and Phosphorous Donor Ligands
Drew J. Bradena, Renan Carioub, John W. Shabakera, Russell A. Taylor b,1,*
,
a BP Products North America, 150 W. Warrenville Rd., Naperville, IL 60563 USA
b BP Chemicals, Saltend, Hull, HU12 8DS
1 Current address: Department of Chemistry, Durham University, South Road, Durham, DU1 3LE
* Corresponding author. Tel: +44 191 3342152. Email: russell.taylor@durham.ac.uk
Declarations of interest: none
Graphical abstarct
Highlights
 Commercially available and readily accessible Ru complexes bearing P and N donor
ligands are active transfer hydrogenation (TH) catalysts.
1

 A well-defined Ru NPN complex, bearing N-H functionality, is shown to be active for TH
for the first time.
 Experimental and kinetic models show deactivation to be prevalent in the well-
defined complexes studied.
 The rate constants for both transfer hydrogenation and deactivation were determined
through reaction profile regression analysis.
Abstract The screening, synthesis and testing of Ru complexes generated from commercially
available ligands or ligands that can be synthesised in one step, is described. The catalysts were
tested for activity in the transfer hydrogenation of acetophenone by isopropanol, a probe reaction for
hydrogen transfer processes between oxygenated species, often found in applications such as
biomass upgrading and fine and specialty chemical synthesis. Ligand screening was conducted by in
situ catalyst generation and examined NPN and NNN pincer type ligands bearing N-H or C=N
functional groups. The most active transfer hydrogenation catalysts were found to be those bearing
N-H functionality, either as amino groups or as benzimidazole groups. Well-defined catalyst
precursors were subsequently synthesised, including the novel complex [Ru(1)PPh3(Cl)2] (where (1)
= bis(3-aminopropyl)phenylphosphine), the first reported Ru complex for this NPN ligand.
Established (PN)2 and PP/NN ketone hydrogenation catalysts were also screened for transfer
hydrogen capability, of which [Ru(PhPN)2Cl2] (where PhPN = 2-(diphenylphosphino)ethylamine) was
the most active. Subsequently, [Ru(1)PPh3(Cl)2], [Ru(PhPN)2Cl2] and [Ru(4)(PPh3)2Cl][Cl] (where
(4) = 2,6-bis(2-benzimidazolyl)pyridine) were investigated more closely to compare rate constants
(determined by reaction profile regression analysis) as a more accurate measure of catalyst activity
over commonly reported turn over frequencies (TOF). The effect of the reaction products on the
catalyst activity was evaluated using feed spiking experiments. Catalyst deactivation was shown to
be prevalent and subsequently incorporated into a simple kinetic model which enabled more accurate
reaction profile fitting and provided rate constants for both the transfer hydrogenation step and
deactivation reaction.
Key Words: transfer hydrogenation; ruthenium; homogeneous catalysis; pincer ligands; reaction
kinetics
2

1. Introduction
Selective hydrogenation of carbonyl groups (C=O) is a broad field with applications across many
industries, especially the fine, specialty, and renewable chemicals industries. Transfer hydrogenation
(TH) of ketones to alcohols by homogeneous Ru complexes in isopropanol is a synthetically
practical and important probe reaction for such reduction processes in both academic and industrial
laboratories.[1-4] Scheme 1 shows the reduction of acetophenone to 1-phenylethanol by
isopropanol.
Scheme 1: Reduction of acetophenone via the catalysed hydrogen transfer from isopropanol.
Using isopropanol (iPrOH) as the reducing equivalent avoids the time consuming and waste-
producing work-up procedures associated with sodium borohydride reductions, and the hazards and
costs of high pressure equipment needed for hydrogenation using molecular hydrogen.[5]
Consequently, transfer hydrogenation can be considered a practical, green and safe reduction
method.
A variety of mechanisms for Ru-based transfer hydrogenation have been proposed that include both
inner sphere and outer sphere (ligand assisted) mechanisms.[6, 7] By changing the ligand
architecture, remarkable improvements to the activity of Ru based transfer hydrogenation catalysts
have been made. Of particular note, some of the CNN ruthenium complexes reported by the Baratta
group give TOFs on the order of millions (hr-1).[8] However, construction of Baratta’s ligand
scaffold is a multistep synthesis[9] (as is commonly the case for highly active transfer hydrogenation
complexes) and that is not always practical from an industrial perspective. Therefore the
development of easily synthesised Ru complexes with very high TOF for transfer hydrogenation is
still an important goal. Moreover, the greatest focus of research in transfer hydrogenation catalysis to
date has been in the area of asymmetric transfer hydrogenation, while somewhat neglecting the
common non-chiral analogue.
Herein we report our initial efforts to develop Ru-based transfer hydrogenation catalysts of synthetic
utility to the industrial research community. The present work describes the screening, synthesis and
3

testing of Ru complexes for the transfer hydrogenation of acetophenone using isopropanol as both
reducing agent and solvent. The synthesis and characterisation of a novel NPN complex is described.
To differentiate the activity of the Ru complexes better than standard initial rate approximations
(TOF), a kinetic model was developed and used to calculate the reaction rate constants.
2. Experimental
2.1 General considerations
All experiments were conducted under N2 using Schlenk line and other inert atmosphere techniques.
All ligands, complexes, solid reagents and NMR solvents were stored in a N2 filled glovebox.
Acetophenone was stirred over CaH2 overnight, distilled under reduced pressure and stored under N2
in a foil wrapped ampoule in a refrigerator. Toluene, triethylamine and isopropanol were dried over
CaH2 overnight, distilled and subsequently stored under N2 in an ampoule containing 4Å molecular
sieves. NMR solvents were used as received. The following compounds were purchased from
commercial sources and used as received and without characterisation: bis(3-
aminopropyl)phenylphosphine (Alfa Aesar); 2,6-bis(2-benzimidazolyl)pyridine, [RuCl2(PPh3)3],
acetophenone, CaH2 (Sigma Aldrich); [Ru(iPrPN)2Cl2], [Ru(PhPN)2Cl2] and [Ru(tBuPN)2Cl2] (Strem);
2,3-dimethyl-2,3-butanediamine dihydrochloride (TCI Europe). The following compounds were
prepared according to literature procedures: N,N-bis(1H-benzimidazol-2-ylmethyl)-N-amine,[10]
2,6-bis-[1-(2-methylphenylimino)ethylpyridine,[11] and [RuClH(PPh3)3•toluene].[12]
NMR spectra were recorded using a Bruker 300 MHz spectrometer. The 1H NMR and 13C NMR
chemical shifts were referenced to the residual protio impurity and 13C signal of the deuterated
solvent respectively.
Elemental analyses were carried out on an Exeter Analytical CE440 elemental analyser.
Gas chromatography (GC) analysis was conducted on an Agilent 7890A instrument equipped with
an Agilent 19091J-413 column (HP-5 5% Phenyl Methyl Siloxane 300 m x 320 μm x 0.25 μm) using
the following method: injection volume: 1.0 μL, He carrier gas, Split Ratio: 25:1, Flow rate: 50
mL/min, FID detector temperature: 250 °C; Temperature program: starting temperature; 50 °C (hold
for 6 mins), ramp 5 °C/min to 100 °C, ramp 10 °C/min to 240 °C. Elution time: 1-phenylethanol
14.82 min, acetophenone 14.95 min.
4

X-ray data were recorded on an Oxford Diffraction Gemini A Ultra diffractometer at 150 K using
Mo K radiation ( = 0.71073 Å), and were corrected for absorption based on multiple and
symmetry-equivalent reflections. The structure was solved and refined with programs of the SHELX
family. Selected crystal data: C30H36Cl2N2P2Ru·2CH2Cl2, Mr = 828.4, triclinic, space group P1, a =
12.4741(3), b = 17.2350(4), c = 17.4983(4) Å,  = 86.500(2),  = 73.931(2),  = 81.568(2), V =
3575.04(14) Å3, Z = 4; 33330 reflections measured, 14936 unique (Rint = 0.0275), 817 refined
parameters, 15 restraints to assist refinement of disordered solvent molecules, R (F, F2 > 2) =
0.0367, Rw(F2, all data) = 0.0881, goodness of fit (F2) = 1.039, final difference map features between
3
+0.94 and 1.38 e Å .
2.2 Synthesis of complexes
2.2.1 Complex [Ru(4)(PPh3)2Cl][Cl] (9)
A Schlenk flask was loaded with [Ru(PPh3)3(Cl)2] (1.2156 g, 1.268 mmol) and 2,6-bis(2-
benzimidazolyl)pyridine (4) (0.4088 g, 1.313 mmol), to which was added 25 ml of anhydrous
toluene. The mixture was stirred in an oil bath at 110 °C, for two hours, during which time a red-
brown precipitate had formed. The suspension was then stirred for 16 hours at room temperature,
after which time the solid was isolated via canula filtration and washed with 100 ml of anhydrous
diethyl ether 3 times. The solid was dried under vacuum for 72 hours. Isolated mass 1.07 g, 84%
yield. NMR data - 1H NMR (d4-methanol, δ): 8.53 (m, 2H), 7.60 (t, J = 8.0 Hz, 1H), 7.40 (m, 8H),
7.13 (m, 18H, PPh3), 6.88 (t, J = 7.7 Hz, 12H, PPh3), NH signals not observed due to rapid H/D
13
exchange with CD3OD. C{1H} NMR (d4-methanol, δ): 152.7, 152.1, 144.1 and 135.7 (quaternary
C), 134.4 (t, o-C of PPh3), 133.3 (aromatic C-H), 132.4 (t, i-C of PPh3),130.4 (s, p-C of PPh3), 128.8
(t, m-C of PPh3), 126.8, 124.5, 122.9, 122.1 and 113.6 (aromatic C-H). 31P{1H} NMR (d4-methanol,
δ): 22.1 (s). Elemental analysis calculated (%) for C55H43Cl2N5P2Ru: C 65.54, H 4.30, N 6.95;
found: C 65.40, H 4.42, N 7.03. Product is soluble in methanol, poorly soluble in ethanol, but
insoluble in acetone, acetonitrile and dichloromethane. A d4-MeOH NMR sample exposed to air was
observed to form crystals after 3 hours. However, no decomposition signals were observed in the
NMR spectrum. A sample of the solid exposed to air for 2 hours and returned to the glove box was
analysed by NMR; new unassigned signals appeared in both the 1H and 31P NMR spectra.
2.2.2 Complex [Ru(1)PPh3(Cl)2] (10)
5

A Schlenk flask was loaded with [Ru(PPh3)3(Cl)2] (2.0270 g, 2.114 mmol) and bis(3-
aminopropyl)phenylphosphine (1) (0.4816 g, 2.147 mmol), to which was added 17 ml of anhydrous
toluene to generate a yellow suspension. The mixture was stirred in an oil bath at 110 °C, for two
hours. The yellow suspension was then stirred for 16 hours at room temperature, after which time the
solid was isolated via canula filtration and washed with 100 ml of anhydrous diethyl ether 3 times.
The solid was dried under vacuum for 72 hours. Isolated mass 1.20 g, 86% yield. NMR data - 1H
NMR (CDCl3, δ): 7.71 (m with appearance of t, 6H) 7.43 (m with appearnce of t, 2H), 7.14-6.94 (m,
10H), 6.88 (m with appearance of t, 2H) 4.25, (br, 2H, NH), 3.39 (br, 2H, NH and CH), 3.08 (br, 1H,
CH), 2.23-1.81 (m, 10H, 9CH and NH), 0.68 (br, 1H, CH). 13C{1H} NMR (CDCl3, δ): 138.7 (d, i-C
of PPh), 137.0 (d, i-C of PPh3), 134.0 (d, o-C of PPh3), 131.2 (d, o-C of PPh), 128.4 (s, p-C of PPh3),
128.2 (s, p-C of PPh), 127.7 (d, m-C of PPh), 127.5 (d, m-C of PPh3), 42.3, 40.5, 33.3 (d, 1JPC = 26.9
Hz), 27.9 (d, 1JPC = 27.8 Hz), 26.1, 25.4. 31P{1H} NMR (CDCl3, δ): 48.8 (d, 2JPP = 34 Hz), 32.65 (d,
2JPP = 34 Hz). Elemental analysis calculated (%) for C30H36Cl2N2P2Ru: C 53.93, H 5.51, N 4.25;
found: C 53.72, H 5.51, N 4.52 Product is soluble in dichloromethane and chloroform, but insoluble
in methanol, ethanol, isopropanol and acetonitrile. The product is air sensitive in solution, turning
green on exposure to air. A sample of the solid exposed to air for 2 hours and returned to the glove
box was analysed by NMR; no new unassigned signals were observed in either the 1H or 31P NMR
spectra. Single crystals of [Ru(1)PPh3(Cl)2] were grown by layering hexane onto a DCM solution of
the complex to enable slow diffusion of the solvents.
2.3 General procedure for transfer hydrogenation of acetophenone:
In a glovebox, a Schlenk flask was loaded with the ruthenium complex and ligand (as necessary) and
an additional Schlenk flask was loaded with KOtBu. Separate stock solutions of acetophenone and
KOtBu in isopropanol were prepared. The acetophenone solution was added to the flasks containing
the ruthenium complexes and allowed to stir for 10 minutes before being immersed in an oil bath set
to 65 oC (the temperature of the reaction solution was measured to be 56 oC, the boiling point of
acetone). This reaction temperature was chosen rather than the standard 82 oC (boiling point of
isopropanol) to reduce the loss of acetone which would affect the equilibrium position. After 10
minutes, the reaction was initiated by addition of the KOtBu solution. The reaction progress was
monitored by taking 0.3 ml samples via syringe, aerating the sample in the syringe 3 times to prevent
any further reaction, and analysing the mixture by gas chromatography. Control experiments were
undertaken to confirm that aeration of the samples did quench catalytic activity.
2.4 Kinetic modelling
6

A general kinetic model for the transfer hydrogenation of acetophenone with isopropanol was
developed using Athena Visual Work Bench (Version 14.2). The model used as inputs the initial
concentrations of ruthenium complex, acetophenone, isopropanol, 1-phenylethanol, and acetone.
Material balances for a batch reactor where solved using the built-in differential equation solver. The
built-in nonlinear parameter estimation and statistical analysis package was used initially to estimate
1
values for rate constants of the forward reaction of a reversible transfer hydrogenation step, 푘푓 , and
2
1
2
the rate constant for an irreversible catalyst deactivation step, 푘푓 ,. The values of 푘푓 and 푘푓 were
subsequently used in the differential equation solver of Matlab to predict the reaction profile for each
catalyst run. The concentrations of acetophenone and 1-phenylethanol were used as model responses
to be compared with experimental data.
3. Results and Discussion
From the outset, we aimed to develop catalysts that utilise commercially available ligands or ones
easily prepared in one step from cheap reagents. For ruthenium mediated hydrogenation and transfer
hydrogenation of unsaturated hydrocarbons with C=O and C=N groups, a metal bound N-H bond
within the ligand framework has proved to be a hugely successful strategy for developing effective
catalysts[13] (though it should be noted that highly effective ruthenium transfer hydrogenation
catalysts lacking a metal bound N-H bond have been reported such as those by Plietker[14] and
Stradiotto[15]). Therefore ligands bearing N-H bonds or readily reducible imine groups were targets
for this work. We identified compounds (1), (2) and (3), shown in Scheme 2, as potential ligands for
effective transfer hydrogenation. To the best of our knowledge, these ligands have not been utilised
in ruthenium mediated transfer hydrogenation chemistry. Furthermore no ruthenium complexes of
ligand (1) have been reported. Compounds (1) and (2) are commercially available, while compound
(3) can be easily prepared from o-phenylenediamine and iminodiacetic acid in one step.[10] Reports
on the coordination chemistry of (1) are very limited[16] and it has not been reported as a ligand in
catalysis. Compound (2) has been extensively utilised as a ligand in iron oligomerisation
catalysis.[11, 17]. Benzimidazole ligands can form highly effective ruthenium hydrogenation
catalysts,[18, 19] and transfer hydrogenation catalysts[20-25] therefore bis-((2-
benzimidazole)methyl)-amine (3) was chosen for transfer hydrogenation screening. Compound (3)
has been utilised as a ligand in butadiene oligomerisation catalysis.[10] Furthermore, there is a single
report of the related compound 2,6-bis(2-benzimidazole)-pyridine (4), which is commercially
7

available, to form a ruthenium phosphine complex which is a highly efficient transfer hydrogenation
catalyst.[23] Therefore compound (4) was included in this study for comparison purposes.
Scheme 2. Structures of NPN and NNN precursor ligands used in this study for the preparation of Ru-based hydrogen
transfer catalysts.
3.1 Transfer Hydrogenation Catalyst Screening
The potential for the compounds (1-4) to form transfer hydrogenation catalysts was explored by in-
situ catalyst formation with [RuCl2(PPh3)3] for the transfer hydrogenation of acetophenone to 1-
phenylethanol using isopropyl alcohol as the hydrogen donor. The reactions were benchmarked
against [RuCl2(PPh3)3], a known transfer hydrogenation catalyst.[26-28]. However, a more recent
report indicates that under TH conditions, [RuCl2(PPh3)3] is actually a precursor for ruthenium
nanoparticles that are the active TH species.[29] Upon activation of the TH catalysts via the addition
of KOtBu, samples were collected over time and analysed for 1-phenylethanol production.
Figure 1 shows the observed 1-phenylethanol yields from acetophenone TH at 329 K using Ru
catalysts formed from ligands (1-4) and [RuCl2(PPh3)3] for reference. Compounds (1), (3) and (4)
resulted in active catalysts with comparable 1-phenylethanol yields at later residence times, all of
which were greater than [RuCl2(PPh3)3], the Ru pre-catalyst. However, significant differences in
initial turn-over-frequency (TOF) (trend (4) > (3) > (1)) were measured. Compound (2) resulted in a
catalyst that is less active than the Ru pre-catalyst, [RuCl2(PPh3)3]. Additionally, as alkali bases are
known to effect transfer hydrogenation in the absence of additional metals,[30, 31] a ruthenium free
benchmark was also conducted in order to ascertain the contribution of KOtBu towards the observed
reactivity. KOtBu was observed to contribute a low level of activity (less than 1% 1-phenylethanol
yield after 2 hours) under the conditions employed (Figure S1). Therefore the contribution from the
base was considered insignificant for the remainder of the studies.
8

Figure 1. Reaction profiles for the transfer hydrogenation of acetophenone using Ru complexes formed in situ from
ligands (1-4), including [RuCl2(PPh3)3] for reference. General conditions: [Ru complex] = 5.0 x 10-4 M, [KOtBu] = 1.0
x 10-2 M, [acetophenone] = 0.10 M; [iPrOH] = 12.9 M; temperature 329 K; N2 atmosphere. Ligand (1), (●); ligand (2),
(▲); ligand (3), (■); ligand (4), (○); no ligand, (□).
For comparison, additional well defined Ru complexes (Scheme 3) were tested under the same
screening conditions. Complexes (5-7) are commercially available and are pre-catalysts for the
hydrogenation of ketones (and imines).[32] To the best of our knowledge, complexes (5-7) have not
been reported as transfer hydrogenation catalysts. Complex (8) has been shown to be a pre-catalyst
for the hydrogenation of acetophenone, during which studies it was noted to effect “slow” transfer
hydrogenation of ketones in 2-propanol, though no further details were reported in the paper.[33]
Scheme 3: Structures of Ru pre-catalysts known to effect ketone and imine hydrogenation.
Complex (8) was synthesised by a new procedure: reacting the hydrochloride salt of the diamine
NH2CMe2CMe2NH2 (tmen) with [Ru(H)(Cl)(PPh3)3] in tetrahydrofuran (THF) in the presence of 20
equivalents of triethylamine (Scheme 4) (see Supplementary Information for further details). A
9

similar procedure has been reported in the patent literature for the synthesis of PN hydrogenation
catalysts.[34]
Scheme 4: Novel procedure for the preparation of complex (8).
Figure 2 shows the measured yields of 1-phenylethanol from acetophenone via TH at 329 K using
Ru pre-catalysts (5-8) and [RuCl2(PPh3)3] for reference. Complex (5), where R = Ph, was
significantly more active for the TH of acetophenone than the other pre-catalysts evaluated.
Complexes (6) and (7), where R = i-Pr and R = t-Bu respectively, showed comparable activity with
(6) being moderately more active. Complex (8) resulted in a catalyst with an activity similar to
[RuCl2(PPh3)3].
Figure 2 Reaction profiles for the transfer hydrogenation of acetophenone using Ru complexes synthesized using
complexes (5-8), including [RuCl2(PPh3)3] for comparison.. General conditions: [Ru complex] = 5.0 x 10-4 M, [KOtBu]
= 1.0 x 10-2 M, [acetophenone] = 0.10 M; [iPrOH] = 12.9 M; temperature 329 K; N2 atmosphere. Complex (5), (▲);
complex (6), (■); complex (7), (□); complex (8), (●); [RuCl2(PPh3)3], (○).
10

The high transfer hydrogenation activity of catalysts derived from ligands (1), (3) and (4) in the
presence of [RuCl2(PPh3)3] and also from pre-catalyst (5) encouraged us to study these materials
further for the transfer hydrogenation of acetophenone. As such, attempts to synthesise well defined
complexes derived from ligands (1), (3) and (4) were made so comparison of their reactivity could be
made with complex (5).
3.2 Synthesis of complexes
Complex [Ru(4)(PPh3)2Cl][Cl], (9), and novel complex [Ru(1)(PPh3)Cl2], (10), were successfully
isolated by refluxing equimolar amounts of the ligand and [RuCl2(PPh3)3] in toluene, however, under
analogous conditions no discernible products could be isolated from the reaction of (2) and
[RuCl2(PPh3)3] (Scheme 5).
Scheme 5: Synthesis of complexes (9) and (10).
Complex [Ru(4)(PPh3)2Cl][Cl], (9), has been previously synthesised by refluxing (4) with
[RuCl2(PPh3)3] in methanol.[23, 35] However, no 31P or 13C NMR data have been reported.
Furthermore, we have found the reported 1H NMR data[36] for (9) to be erroneous due to ligand
displacement by the NMR solvent used, (CD3)2SO (see Supplementary Information, Figure S5).
Therefore complex (9) and novel complex (10) were both characterised by elemental analyses, 1H,
13C and 31P NMR spectroscopy. Complex (10) was also characterised in the solid state by X-ray
crystallography. The solid state structure of complex (9) has been previously reported.[35]
Figure 3 shows a view of one of the crystallographically independent molecules of complex (10)
while Table 1 gives a summary of the key crystallographic data. The asymmetric unit consists of two
chemically identical but crystallographically independent ruthenium-centred complexes and four
molecules of dichloromethane. The tridentate ligand has a fac arrangement in the distorted
11

octahedral Ru coordination. The two chloro ligands are mutually cis, and the triphenylphosphine
ligand lies trans to one N atom and cis to the other donor atoms (N and P) of the tridentate ligand.
Figure 3. A view of one of the crystallographically independent complex molecules of [Ru(1)(PPh3)Cl2], (10), showing
the atom numbering scheme; H atoms are omitted for clarity.
Table 1 Selected bond lengths [Å] and angles [°] for [Ru(1)(PPh3)Cl2], (10).
Bond length
2.118(2)
Bond Angle
91.59(3)
100.85(3)
87.07(11)
91.16(8)
93.90(7)
89.88(3)
83.96(7)
78.06(7)
Ru1-N1
Ru1-N2
Ru1-Cl1
Ru1-Cl2
Ru1-P1
Ru1-P2
Cl1-Ru1-Cl2
P1-Ru1-P2
N1-Ru1-N2
P1-Ru1-N2
P1-Ru1-N1
P2-Ru1-Cl1
Cl1-Ru1-N1
Cl1-Ru1-N2
2.185(3)
2.4917(7)
2.4549(7)
2.2399(8)
2.3181(8)
Complex (9) exhibits a singlet in the 31P{1H} NMR spectrum (Figure S8) as expected for a trans bis-
phosphine complex. The 31P{1H} NMR spectrum of complex (10) (Figure S3) exhibits two doublets
with 2JPP = 34 Hz indicative of a cis bis-phosphine complex. 1H and 13C{1H} NMR spectra for
complexes (9) and (10) (Figures S2, S4, S6 and S7) match the proposed structures and will therefore
not be discussed further.
12

3.3 Reaction Kinetics of Highly Active Transfer Hydrogenation Catalysts
The catalytic activity of new homogeneous catalysts is very often reported in the form of turnover
frequency (TOF), usually with the units molprod.mol-1cat.hr-1. This value is commonly determined
from a single experimental data point derived after a set, elapsed period of time in the catalytic test.
However this routine method of catalyst evaluation is not appropriate for equilibrium controlled
reactions and/or highly active catalysts (see supplementary information for a fuller discussion).
To make more accurate activity evaluations of complexes (5), (9) and (10) using our batch reactions,
additional studies were undertaken to conduct regression analysis of reaction profiles (with limited
data points) to give an estimate of the reaction rate constants. Conditions similar to those employed
for the screening runs described above were used, however, due to the high TOF observed during
screening, reactions were run using lower catalyst concentrations relative to the substrate and
aliquots of the reaction mixture were initially taken at very short time intervals. To rule out the
possibility of any of the complexes being active for transfer hydrogenation in the absence of base,
samples were also taken prior to the addition of KOtBu. It should be noted that the concentration of
base has been observed to affect the observed rate of reaction in Ru mediated TH reactions,
particularly where low ratios of base to Ru (B/Ru) are employed.[28, 37, 38] This is exemplified by
Baratta’s study which showed that increasing the B/Ru ratio resulted in increasing reaction rates up
to B/Ru =10.[39] Additionally, in order to investigate possible inhibition effects of the products,
separate reactions were run with acetone or 1-phenylethanol added to the initial reaction mixture.
Figure 4 shows experimental results for the yield of 1-phenylethanol from complexes (9) (Fig. 4A),
(5) (Fig. 4B), and (10) (Fig. 4C) using three different initial feed mixtures – 1) no acetone or 1-
phenylethanol added (), 2) acetone added (), or 3) 1-phenylethanol added (). It should be
noted that Figure 4 shows the yield of 1-phenylethanol derived from acetophenone transfer
hydrogenation only. From a visual inspection it can be seen that none of the reaction profiles
exhibited product inhibition from either acetone or 1-phenylethanol though previous studies have
reported product inhibition for other Ru-based TH systems.[40, 41] It is also noted that the maximum
yield of 1-phenylethanol (derived from acetophenone) does not change not significantly by addition
of either acetone or 1-phenylethanol for complexes (9) and (5), suggesting that the equilibrium
position is not significantly affected by product spiking, under the conditions employed. A similar
study into Rh catalysed TH of acetophenone showed limited impact on acetophenone conversion at
13

similarly low acetone spiking levels.[42] The effect of base concentration on reaction rate has not
been studied here however, prior to the addition of base no product was detected in any of the
experiments, showing base to be essential to form catalytically active species from complexes (5),
(9) and (10). Further we should highlight that no induction period was observed in any of the
experiments conducted. As such catalyst generation was considered instantaneous upon addition of
base and therefore the concentration of base was not considered in the kinetic modelling.
Figure 4 Reaction profiles for the yield of 1-phenylethanol resulting from the transfer hydrogenation of acetophenone at
329 K in a nitrogen atmosphere using complex (9) (Figure 4A); complex (5) (Figure 4B); and complex (10) (Figure 4C).
Initial concentrations: [Ru complex] = 4.6 x 10-4 M, [KOtBu] = 1.0 x 10-2 M, [acetophenone] = 1.1 M, [iPrOH] = 11.3M,
[acetone] = [1-phenylethanol] = 0 (). Product inhibition experiments: additional to initial concentrations [acetone] =
0.2 M (); [1-phenylethanol] = 0.2 M ().
Rate expressions describing the production rate of 1-phenylethanol via the transfer hydrogenation of
acetophenone (eq. 1) in the absence of reactant and product inhibition typically have the form shown
in eq. 2, where kf is the forward rate constant, kr is the reverse rate constant, and [X] is the
concentration of species X in solution.
Acetophenone + Isopropanol
1-Phenylethanol + Acetone
(1)
(2)
푅1−푃ℎ퐸푡푂퐻 = 푘푓[퐴푐푒푡표푝ℎ푒푛표푛푒][퐼푃퐴] − 푘푟[푃ℎ푒푛푦푙푒푡ℎ푎푛표푙][퐴푐푒푡표푛푒]
14

The equilibrium constant for the reaction is defined by eq. 3.
푘
[푃ℎ푒푛푦푙푒푡ℎ푎푛표푙] [퐴푐푒푡표푛푒]
푒푞 푒푞
푓
퐾푒푞
=
=
(3)
푘
[퐴푐푒푡표푝ℎ푒푛표푛푒] [퐼푃퐴]
푒푞 푒푞
푟
In order to determine intrinsic rate constants, the experimental data was fitted to eq. 2 in Athena
Visual Work Bench (Version 14.2) to derive values of kf (forward rate constant) and kr (reverse rate
constant). The values of kf and kr were subsequently used in the differential equation solver of
Matlab to predict the reaction profile for each catalyst run. However, the predicted reaction profiles
were not able to satisfactorily replicate the experimental data. It was also noted that the catalyst
formed from complex (10) does not achieve high yields of 1-phenylethanol over the reaction time
tested and appears to have a decreasing catalyst activity compared to the initial rate. An additional
experiment utilising complex (9) at very low loading (complex:substrate:solvent =
1:10,000:1,300,000) showed that equilibrium conversion was not obtained despite very high initial
reaction rates (Fig. S11). These observations indicated to us that catalyst deactivation is significant
and should be accounted for in the kinetic model. Accordingly, parallel processes were modelled; a
reversible transfer hydrogenation reaction with a concurrent irreversible deactivation reaction. To
reduce the number of parameters to be determined through the regression analysis eq. 4 was used
1
instead of eq. 2, and the value of equilibrium the constant, 퐾푒푞 , derived as 0.48 from this work
(under the given reaction conditions from eq. 3). Accordingly, expressions for the formation of 1-
phenylethanol (푅1−푃ℎ퐸푡푂퐻) and catalyst deactivation (푅푑푒푎푐푡.) are given in eq. 4 and eq. 5,
respectively. A deactivation step which is second order in catalyst concentration was found to
provide the best fit for the experimental data (Fig. S12).
[
][
]
퐴푐푒푡표푝ℎ푒푛표푛푒 퐼푃퐴 −1
1
푅1−푃ℎ퐸푡푂퐻 = 푘푓 [푅푢] 퐾
(4)
(5)
[
]
1−푃ℎ푒푛푦푙푒푡ℎ푎푛표푙 [퐴푐푒푡표푛푒]
1
푒푞
2
[
]
2
푅푑푒푎푐푡. = 푘푓 푅푢
The experimental data was fitted to eq. 4 and eq. 5 in Athena Visual Work Bench (Version 14.2) to
1
2
derive values of 푘푓 and 푘푓 which were subsequently used in the differential equation solver of
Matlab to predict reaction profiles. The experimental data and predicted reaction profiles for
1
2
complexes (5), (9) and (10) are shown in Fig. 5. Calculated values of 푘푓 and 푘푓 are given in Table
2. Given that product inhibition is not apparent from the reaction profiles shown in Figure 4 and the
15

1
2
large values of error for kinetic constants in Table 2, values of 푘푓 and 푘푓 were not determined for
the inhibition experiments.
Figure 5 Experimental data for the yield of 1-phenylethanol resulting from the transfer hydrogenation of acetophenone
at 329 K in a nitrogen atmosphere using complex (9) (); complex (5) (); and complex (10) (). Predicted reaction
profiles are given as solid lines. Initial concentrations: [Ru complex] = 4.6 x 10-4 M, [KOtBu] = 1.0 x 10-2 M,
[acetophenone] = 1.1 M, [iPrOH] = 11.3M, [acetone] = [1-phenylethanol] = 0 ().
Table 2 Transfer hydrogenation kinetic coefficients estimated from kinetic model and model-determined equilibrium
constants for experiments with no product addition (benchmark)
Complex (10)
1
푘푓
푘푓
0.93
37
+/-
+/-
0.28
19
2
2
1
40
푘푓 /푘푓
Complex (5)
1
5.1
36
+/-
+/-
1.5
22
푘푓
푘푓
2
2
1
푘푓 /푘푓
7.0
Complex (9)
1
푘푓
푘푓
4200
140,000
33
+/-
+/-
2300
2
90,000
2
1
푘푓 /푘푓
As can be seen in Figure 4, for equimolar amounts of catalyst precursor used, complex (9) resulted in
the most active catalyst followed by complex (5), with complex (10) the least active catalyst.
16

Examination of the calculated rate constants in Table 2 reveals that the observed trends in catalyst
1
activity from Figure 4 are captured by the simple kinetic model. The value of 푘푓 for the catalyst
generated from complex (9) is nearly one thousand times greater than the catalyst generated from
complex (5) and over four thousand times greater than the catalyst generated from complex (10).
2
Interestingly the deactivation rate constant, 푘푓 , is determined to be larger than the rate constant of
1
2
1
the forward TH reaction, 푘푓 . Furthermore 푘푓 /푘푓 indicates that the complex (5) is relatively more
resistant to deactivation than either complex (9) or (10).
3.5 Comparison to other ruthenium TH systems
As mentioned above, remarkable improvements to the activity of Ru based transfer hydrogenation
catalysts have been made. Table 3 compares the results of selected TH catalysts for the TH of
acetophenone together with results from this study for complexes (5), (9) and (10). To be able to
make comparisons with other complexes, data for complexes (5), (9) and (10) has been evaluated as
TOF values. Le Floch’s phosphole/pyridine complex (11)[43] and Barrata’s CNN based complex
(12)[8] form two of the most active ruthenium catalysts for the transfer hydrogenation of
acetophenone when activated with base (Table 3, entry 1 and 2). Both catalysts exhibit TOF greater
than 1 x 106 hr-1. Complex (13), bearing a pyridine/benzimidazole/triazole NNN ligand, also
reportedly achieves very high TOF for the TH of acetophenone (705,600 hr-1, Table 3 entry 3)
though this value is derived from a sample taken 10 seconds after initiation.[21] While these values
are very high, none of these ligands are commercially available and cannot be made in a single step
which represents a barrier to commercial application.
17

Scheme 6: Structures of well-defined ruthenium TH catalysts referred to in Table 3.
Complex (9), bearing the commercially available NNN ligand 2,6-bis(2-benzimidazole)-pyridine,
has been shown to be a highly effective transfer hydrogenation catalyst (Table 3, entry 4). However
the single literature report gives an unclear estimation for when the product sample was taken (30-40
s), leading to a TOF range of 85,500-114,000 hr-1. In our hands, under similar conditions (although
at a lower temperature), complex (9) gave a TOF of 76,500 hr-1. Thus the TOF values of complex (9)
are very similar to the best TOF value (75,000 hr-1) for PP,NN ruthenium complexes bearing
commercially available ligands reported by Baratta (where PP is 1,3-bis(diphenylphosphino)propane
and NN is 2-aminomethylpyridine or ethylenediamine).[44] The commercially available complex (5)
is shown here to be a competent TH catalyst which has hitherto not been reported (Table 3, entry 6).
Despite the wide application of ruthenium pincer complexes in catalysis,[45, 46] NPN ruthenium
complexes for TH are remarkably scarce. To the best of our knowledge only two well defined NPN
ruthenium complexes have been reported for TH catalysis, complexes (14)[47] and (15)[48] (Figure
6). Zhang has reported the use of NPN ligands (16 - 19) to form TH catalysts with [RuCl2(C6H6)]2 in
situ, however only very modest TON and TOF were reported (Table 3, entries 10-13).[49, 50] On
the other hand, complex (14) gave high TOF for the TH of acetophenone, 70,200 hr-1 after 1 min
(Table 3, entry 8), while complex (15) gave very sluggish performance (TOF = 380 hr-1, Table 3,
entry 9). Braunstein reported that addition of PPh3 to the catalytic tests run with complex (15)
resulted in even lower TOF,[48] indicating that the poor performance of (15) compared to (14) may
18

be due to differences in the NPN ligands and not due to the absence of PPh3 in the coordination
sphere of the metal.
Scheme 7: Structures of NPN ligands used to form in situ ruthenium TH catalysts, as referred to in Table 3.
As the novel NPN complex (10) reported in this work contains N-H groups,[13] we had hoped that
the performance for TH of acetophenone would be comparable if not better than complex (14) which
contains oxazoline groups. Under similar conditions (albeit lower temperature), complex (10) gave
TOF values of 3,500 hr-1 (after 1 min) whereas complex (14) has a reported TOF value of 70,200 hr-1
(after 30 s). The moderate activity of (10) is substantially better than the TOF values reported for
complex (15) (380 hr-1, table 3, entry 9) or the in-situ generated catalysts reported by Zhang (less
than 400 hr-1, Table 3 entries 10-13). To date complex (10) is the first well defined NPN ruthenium
complex, bearing N-H functionality, which is active for the TH of acetophenone. Therefore this
report opens a new avenue for ligand design and catalyst development for the hydrogenation and
transfer hydrogenation of ketones and other polar unsaturated functional groups (e.g. aldehydes,
imines, and esters). While ligand (16) also bears N-H groups and is very similar to the NPN ligand
(1) in complex (10), ligand (16) was screened in-situ, at room temperature, with low substrate
loading and only sampled after 24 hours,[49] therefore the potential for NHx-P-NHx ligands to effect
productive TH catalysis was missed.
Table 3 A comparison of selected ruthenium pre-catalysts for the TH of acetophenone.
Catalyst
(11)
Ru:B:S
T (°C)
Time
15 hr
Conv. (%)
TOF (hr-1)
1.2 x 106
Ref
[43]
[8]
1
2
3
4
1:10,000:20 x 106 90
90
98
98
(12)
1:400:20,000
1:20:2,000
1:20:1,000
82
82
82
5 min
10 s
1.1 x 106 *
705,600
(13)
[21]
[23]
(9)
30-40s
1 min
15 min 74
1 min 5.6
15 min 20.9
95
55
85,500-114,000
76,500
6,860
7,720
1,920
This
work
This
work
5
6
(9)
(5)
1:20:2,300
1:20:2,300
56
56
19

1 min
15 min 6.8
30 s
15 min 88
30 min 95
2.5
3,540
642
70,200
3,520
380
This
work
7
8
(10)
(14)
(15)
1:20:2,300
1:24:1,000
1:24:200
1:15:100
1:15:100
1:15:100
1:15:100
56
82
82
58.5
[47]
[48]
[49]
[50]
[50]
[50]
9
1 hr
98
196
(16) +
[RuCl2(C6H6)]2
(17) +
[RuCl2(C6H6)]2
(18) +
[RuCl2(C6H6)]2
(19) +
[RuCl2(C6H6)]2
10
11
12
13
23
80
24 hr
96.0
4
12 min 72
360
92
2
80
80
1 hr
48
92
94
* TOF calculated at 50% conversion
While different mechanisms of TH exist for the conversion of carbonyl compounds,[6, 7] it is
beyond the scope of the work here to speculate on the active mechanisms for complexes (5), (9) and
(10). As discussed above, our experiments and data suggest that catalyst deactivation is a prevelant
problem for all three catalysts, despite distinctly different ligand types. Catalyst deactivation is often
not considered when determining intrinsic reaction parameters. Ligand backbone deprotonation and
subsequent decomposition has been observed for some ruthenium amino phosphine complexes,[12,
51] while ligand displacement has been observed in other ruthenium TH systems,[52-54], though
many other deactivation mechanisms may also be at play.[55] The exact mechanism of deactivation
for complexes (5), (9) and (10) is not yet known. However, observation that a higher order (squared
dependence) on ruthenium concentration for the rate of deactivation indicates nanoparticle formation
may be operative.[29]
Work is now underway to explore further the TH, and hydrogenation, capacity of the NPN ligand
framework and to determine the mechanisms of catalysis and deactivation. . Further reports on
industrially relevant TH and hydrogenation catalysts will be reported in the future.
4. Conclusions
In conclusion, we have reported on the use of commercially available and readily accessible NNN
and NPN pincer ligands to form ruthenium catalysts for the TH of acetophenone. In situ screening of
ligands bis(3-aminopropyl)phenylphosphine (1), 2,6-bis-[1-(2-methylphenylimino)ethylpyridine (2),
bis-((2-benzimidazole)methyl)-amine (3) and 2,6-bis(2-benzimidazolyl)pyridine (4) with
[RuCl2(PPh3)2] afforded more active catalysts over [RuCl2(PPh3)2] alone when an N-H functional
group was present in the ligand. Commercially available ester and ketone hydrogenation catalysts
[Ru(PhPN)2Cl2] (5), [Ru(iPrPN)2Cl2] (6) and [Ru(tBuPN)2Cl2] (7) were also screened for the TH of
20

acetophenone along with [Ru(tmen)(PPh3)2(H)(Cl)] (8). Surprisingly, complex (5) displayed
substantial TH activity, which has not been reported for this complex previously. To be able to
compare the activity of complex (5) with the most promising ligands from in situ screening, well
defined complexes of ligands (1) and (4) were synthesised. Attempts to isolate a well-defined
complex of ligand (3) were unsuccessful. The novel complex [Ru(1)(PPh3)Cl2], (10), is the first
reported ruthenium complex of ligand (1), and while complex [Ru(4)(PPh3)2Cl][Cl], (9), has been
previously reported, no 13C or 31P NMR data had been published. Furthermore, this work has shown
the reported 1H NMR data to be erroneous. To be able to compare the TH activity of catalysts (5), (9)
and (10) more accurately than simple TOF values, TH reaction profiles were used to estimate rate
constants by regression analysis (with limited data points). In the absence of base, catalysts (5), (9)
and (10) showed no catalytic activity while reaction spiking experiments revealed no significant
product inhibition (by acetone or 1-phenylethanol). Attempts to predict the reaction profiles using a
simple reversible TH reaction model failed to give satisfactory results. After catalyst deactivation
was found to be prevalent experimentally for complexes (9) and (10) a two step kinetic model
involving reversible TH and irreversible, second order catalyst deactivation was able to fit the
observed reaction profiles. Kinetic parameters derived from this model show that while complex
complex (9) is substantially more active than for TH than complexes (5) or (10), it is complex (5)
that is least prone to deactivation.
Acknowledgements
Professor Bill Clegg and Dr. Ross Harrington (Department of Chemistry, Newcastle University, UK)
are gratefully acknowledged for conducting the crystal structure determination. The authors would
like to thank Dr. Glenn Sunley (BP Chemicals, Hull, UK) for valuable discussions and the entire
analytical team at the Hull Research and Technology Centre (BP Chemicals, Hull, UK). BP
Chemicals is thanked for supporting the publication of this work.
Appendix A. Supplementary data
Supplementary data associated with this article can be found online.
Nomenclature
[1 − 푃ℎ푒푛푦푙푒푡ℎ푎푛표푙] = concentration of 1-phenylethanol, mol L-1
[퐴푐푒푡표푛푒] = concentration of acetone, mol L-1
[퐴푐푒푡표푝ℎ푒푛표푛푒] = concentration of acetophenone, mol L-1
21

[퐴푐푒푡표푛푒] = concentration of isopropanol, mol L-1
1
퐾푒푞 = overall equilibrium constant for transfer hydrogenation
푘푓 = forward rate constant for transfer hydrogenation, L mol-1 min-1
푘푟 = reverse rate constant for transfer hydrogenation, L mol-1 min-1
-1
-1
1
푘푓 = forward rate constant for transfer hydrogenation, L mol min
-1
-1
2
푘푓 = rate constant for catalyst deactivation, L mol min
1−푃ℎ퐸푡푂퐻 = overall rate of 1-phenylethanol production, mol L-1 min-1
푑푒푎푐푡. = rate of catalyst deactivation, mol L-1 min-1
푅
푅
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