2,2,2-Trifluoroethanol-assisted imine hydrogenation by a Ru-monohydride

Article abstract of DOI:10.1016/j.ica.2015.03.009

The trans heterodiphosphane Ru-based compound of the formula [Ru(OAc)₂(CO)₂(PⁿBu₃)(PPh₃)] proved to be a suitable precatalyst for imine hydrogenation in 2,2,2-trifluoroethanol (TFE) without the addition of an external base. High-pressure (HP) NMR investigations combined with a DFT-study, carried out on a related model precatalyst, were indicating the formation of a cationic Ru-monohydride-2,2,2-trifluoroethanol (TFE) species that catalyzes the imine hydrogenation by a TFE-assisted outer-sphere reaction mechanism.

Full text of DOI:10.1016/j.ica.2015.03.009

Accepted Manuscript
2,2,2-Trifluoroethanol-assisted imine hydrogenation by a Ru-monohydride
Ivan Scodeller, Antonella Salvini, Gabriele Manca, Andrea Ienco, Lapo Luconi,
Werner Oberhauser
PII:
S0020-1693(15)00143-7
http://dx.doi.org/10.1016/j.ica.2015.03.009
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Reference:
Inorganica Chimica Acta
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11 March 2015
Please cite this article as: I. Scodeller, A. Salvini, G. Manca, A. Ienco, L. Luconi, W. Oberhauser, 2,2,2-
Trifluoroethanol-assisted imine hydrogenation by a Ru-monohydride, Inorganica Chimica Acta (2015), doi: http://
dx.doi.org/10.1016/j.ica.2015.03.009
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2,2,2-Trifluoroethanol-assisted imine hydrogenation by a Ru-
monohydride
Ivan Scodeller a, Antonella Salvini a, Gabriele Manca b, Andrea Ienco b, Lapo Luconi
b, Werner Oberhauser b,*
a Dipartimento di Chimica “Ugo Schiff”, Università di Firenze, via della Lastruccia 3-13, 50019
Sesto Fiorentino, Italy
b
Istituto di Chimica dei Composti Organometallici (CNR-ICCOM), Area di Ricerca CNR di
Firenze, via Madonna del Piano 10, 50019 Sesto Fiorentino, Italy
Corresponding author. Tel.: +39-055-5225284; Fax: +39-055-5225203
E-mail address: werner.oberhauser@iccom.cnr.it (W. Oberhauser)
ABSTRACT
The trans heterodiphosphane Ru-based compound of the formula [Ru(OAc)2(CO)2(PnBu3)(PPh3)]
proved to be a suitable precatalyst for imine hydrogenation in 2,2,2-trifluoroethanol (TFE) without
the addition of an external base. High-pressure (HP) NMR investigations combined with a DFT-
study, carried out on a related model precatalyst, were indicating the formation of a cationic Ru-
monohydride-2,2,2-trifluoroethanol (TFE) species that catalyzes the imine hydrogenation by a TFE-
assisted outer-sphere reaction mechanism.
Keywords: Imine hydrogenation; Ruthenium; 2,2,2-Trifluoroethanol; High pressure NMR
spectroscopy
1

1. Introduction
Amines are an important class of organic compounds which are applied in the synthesis of a
variety of biologically active molecules including natural and synthetic products [1]. The
hydrogenation of enamines and imines to amines is mostly catalyzed by well-defined Rh-, Ir- and
Ru-based catalysts [1]. Among them, Shvo’s dinuclear ruthenium [2] and Noyori’s RuCl(p-
cymene)(N-p-toluenesulfonyl-1,2-diphenylethylenediamine) catalyst [3] have been intensively
studied from a mechanistic point of view. In this context, inner- versus ligand-assisted outer-sphere
mechanisms were discussed to be operative under real catalytic imine hydrogenation conditions [4].
The inner-sphere-based catalytic imine hydrogenation reaction occurs on the Ru(II)-coordinated
imine, which implies the formation of a vacant coordination site on the metal centre for substrate
coordination.
In contrast, the ligand-assisted outer-sphere reaction mechanism (Scheme 1) involves a metal-
monohydride species (A) containing an ancillary ligand with a polar functional group such as OH or
NH.
Scheme 1. Ligand-assisted Ru-based imine hydrogenation (LXH = ligand with a polar functional
group.
The interaction between the substrate and the hydride species A forms species B (Scheme 1) [4].
H+ and H- are transferred to the substrate, either concerted [5] or stepwise (i.e. ionic mechanism)
2

[6], leading to a zwitterionic Ru-species (C) under the concomitant release of the amine product.
The catalytic cycle is then closed by a ligand-assisted heterolytic dihydrogen splitting (D) [7],
generating the initial Ru(II)-monohydride species. This latter species is mostly generated by the
action of an external strong base such as KOtBu3 [8]. Hence the presence of an internal base (i.e.
alkoxy or acetate group) in the precatalyst circumvents the undesired addition of a costly base,
which negatively impacts the environment. In this context, we used the Ru bis-acetate complex
[Ru(OAc)2(CO)2(PnBu3)(PPh3)] (1) [9] as precatalyst for the hydrogenation of selected imines to the
corresponding amine in different reaction media, obtaining with 2,2,2-trifluoroethanol (TFE) the
highest substrate conversion at moderate catalytic reaction conditions (i.e. T= 50 °C and p(H2) = 25
bar).
2. Experimental
2.1. Materials
1 [9], [Ru(OAc)2(CO)2(PnBu3)2] (2) [10a] and [Ru(OAc)2(CO)2(PPh3)2] (3) [10b] were
synthesized according to reported synthesis procedures. N-benzylideneaniline, N-benzylidene-p-
toluidine, benzaldehyde and p-fluoroaniline were purchased from Aldrich and used without further
purification. Toluene and THF were purified by distillation over Na/benzophenone, MeOH by
distillation over Mg and TFE by distillation over anhydrous potassium carbonate.
2.2. Instrumentation
31
Operando 1H and P{1H} high pressure (HP) NMR spectroscopic experiments were carried out
on a Bruker Avance DRX-300 spectrometer operating at 300.13 and 121.98 MHz, respectively,
using a 10 mm BB probe and a 10 mm sapphire tube (Saphikon, Milford, NH) equipped with a
home-made titanium high pressure charging head [11]. Chemical shifts (δ) are reported in ppm
relative to TMS (1H NMR) or 85% H3PO4 (31P{1H} NMR). GC analyses were carried out on a
Shimadzu GC 2010 equipped with a Phenomenex Zebron-5HT capillary column (15 m × 0.32 mm
3

× 0.1 µm) and a flame ionization detector. GC-MS analyses were performed on a Shimadzu
QP5000 apparatus, equipped with a 30 m (0.32 mm i.d., 0.50 µm film thickness) CP-WAX 52 CB
WCOT-fused silica column. Elemental analysis was carried out with a NA 1500 Carlo Erba
elemental analyzer.
2.3. Synthesis of N-benzylidene-p-fluoroaniline
p-Fluoroaniline (1.0 mL, 10.4 mmol) was added to MeOH solution (10.0 mL) of benzaldehyde
(0.8 mL, 7.8 mmol) and acetic acid (20 µL, 0.35 mmol). The solution was refluxed for 4 h, followed
by its cooling to room temperature. The crystalline product was filtered off, washed with water and
then dissolved in ethyl ether (15.0 mL). The organic solution was washed with diluted HCl, then
dried over anhydrous Na2SO4 and the solvent removed by vacuum distillation giving a slightly
yellow crystalline product (1.103 g, 71%). Anal. Calcd for C13H10FN (199.22): C, 78.37; N, 7.03;
H, 5.06. Found: C, 78.95; N, 6.89; H, 5.29. 1H NMR (300.13 MHz, CDCl3) δ 7.10 (m, 4H; ArH),
7.48 (m, 3H, ArH), 7.88 (dd, 3J(HH) = 7.5 Hz, 4J(HH) = 3.6 Hz, 2H, ArH), 8.45 (s, 1H, CH=N).
2.4. Operando (HP) NMR study
Three solutions (2.0 mL) of 1 (14.8 mg, 0.020 mmol) were prepared under a nitrogen
atmosphere, using as solvent neat C6D6 or two different solvent mixtures (i.e. 1:1 (v:v) C6D6/MeOH
or C6D6/TFE). Each solution was then transferred into a 10 mm sapphire tube, which was sealed
and introduced into the NMR probe at room temperature. Two additional solutions were prepared in
neat C6D6 or in a 1:1 (v:v) C6D6/TFE solvent mixture with N-benzylideneaniline (0.5 mmol),
1
dissolved together with 1. After the acquisition of 31P{1H} and H NMR spectra at room
temperature, the sapphire tube was successively removed from the NMR probe, charged with
dihydrogen (p(H2) = 50 bar) and reinserted into the NMR probe, followed by the acquisition of
NMR spectra at room temperature. Then the NMR probe was heated to 50 °C (i.e. catalytic reaction
temperature), followed by the acquisition of NMR spectra in time intervals of 0.5 h up to 1.5 h. The
4

NMR probe was then allowed to cool to room temperature, the excess dihydrogen gas released and
the catalytic solution objected to GC-MS analysis.
2.5. Conversion of [RuH2(CO)2(PnBu3)(PPh3)] into [RuH(OAc)(CO)2(PnBu3)(PPh3)] in the
presence of TFE or MeOH. An NMR experiment
A solution of [RuH2(CO)2(PnBu3)(PPh3)] (1(H)2) (3.6 mM) in C6D6 (0.75 mL) was synthesized
according to a reported procedure [12], giving the desired product with 84 % yield along with 2
(8%) and [RuH2(CO)2(PPh3)2] (3(H)2) (8%). The latter solution was equally divided in two
portions, followed by the addition of TFE (0.4 mL) to one portion and MeOH (0.4 ml) to the other
1
one. Afterwards 31P{1H} and H NMR spectra were acquired with both solutions. Acetic acid
31
1
(HOAc) (2.0 µL) was then added to each solution at room temperature and P{1H} and H NMR
were acquired with both solutions at room temperature in time intervals of 1 h.
2.6. Catalytic imine hydrogenation reactions
In a glass vial placed in a stainless-steel autoclave (150.0 mL), were successively added under a
nitrogen atmosphere, the precatalyst (0.005 mmol), substrate (0.5 mmol), solvent (8.0 mL) and p-
xylene (64.0 µL) as internal standard. Afterwards the autoclave was sealed, charged with
dihydrogen, heated in an oil bath and rocked for the desired reaction time, then cooled to room
temperature depressurized and the reaction mixture analyzed by GC and GC-MS.
2.7. Computational details
All calculations were performed at B97D-DFT level of theory [13a] within the Gaussian 09
package.S1 Solvent effects were modeled by using the Conductor Continuum Polarizable Model
(CPM) [13b,c] The Stuttgart-Dresden pseudo-potential has been used for ruthenium [13d], while 6-
31+G(d,p) for all other atoms with the important addition of the polarization functions d and p for
all atoms.
5

3. Results and discussion
The heterodiphosphane Ru-compound 1 has been screened in the imine hydrogenation reaction,
using different reaction media (i.e. toluene, THF, MeOH or TFE) and imine substrates. The
catalytic performance of 1 was compared to that of the related homodiphosphane counterparts 2
[10a] and 3 [10b], applying identical experimental conditions. The results of the catalytic reactions
are shown in Table 1.
Table 1
Imine hydrogenation catalyzed by 1-3 in different reaction media.
Entry
1
2
3
4
5
6
7
8
Precatalyst Solvent
T(°C)/p(H2) (bar)/t(h)
90/50/3
90/50/3
90/50/3
90/50/3
50/50/3
50/50/3
50/50/3
50/50/3
50/50/3
50/50/3
50/25/3
50/25/3
50/25/3
50/25/3
50/25/6
50/25/3
Substratea Conv.(%)
Toluene
THF
A
A
A
A
A
A
B
C
B
C
A
A
A
B
B
C
C
8
1
1
1
1
1
1
1
1
1
1
1
2
3
1
1
1
1
11
92
100
18
99
27
50
99
62
93
33
35
54
90
46
64
MeOH
TFE
MeOH
TFE
MeOH
MeOH
TFE
9
10
11
12
13
14
15
16
17
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
50/25/6
Catalytic conditions: precatalyst (0.005 mmol), substrate (0.5 mmol), solvent (8.0 mL),
t (3 h).
a
Substrate: A (N-benzylideneaniline), B (N-benzylidene-p-fluoroaniline), C (N-
benzylidene-p-toluidine).
Regardless of the precatalyst and type of imine used, the corresponding secondary amine was the
only organic product obtained.
6

A perusal of the catalytic results compiled in Table 1 shows that: (i) Under identical catalytic
conditions alcohols (i.e., MeOH or TFE) are much more suitable reaction media than toluene or
THF (Table 1, entries 3 and 4 vs 1 and 2); (ii) Regardless of the substrate employed, TFE reveals to
be the solvent of choice. In fact, much milder reaction conditions can be applied in TFE (i.e. 50 °C,
25 bar of dihydrogen); (iii) An increase of the Lewis-basicity of the imine nitrogen atom decreases
the catalytic activity (entry 11 vs 14 and 16); (iv) 1 proves to be significantly more active than the
homo-diphosphane counterparts 2 and 3. This latter experimental fact might be rationalized by a
faster conversion of 1 into catalytically active hydride species (i.e. mono- and dihydride) compared
to 2 and 3, as previously observed [12,14].
In order to shed light on the nature of the Ru-hydride species formed under catalytic imine
hydrogenation conditions, operando (HP) NMR experiments were carried out with 1 in different
reaction media such as 1:1 (v:v) solvent mixtures of C6D6/TFE, C6D6/MeOH or neat C6D6.
1
Selected 31P{1H} and H NMR spectra, acquired under identical experimental conditions (i.e. 50
°C, 50 bar of dihydrogen pressure, without substrate) are shown in Fig. 1.
Fig. 1. Operando (HP) NMR spectra of 1 acquired at 50 °C in different reaction media in the
1
presence of dihydrogen (50 bar): A) (31P{1H} NMR spectra; B) Hydride region of the H NMR
spectra: (a) 1:1 (v:v) C6D6/TFE solvent mixture; (b) 1:1 (v:v) C6D6/MeOH solvent mixture and (c)
neat C6D6.
1
The 31P{1H} and H NMR spectra (i.e. only hydride region is shown) presented in Fig. 1 clearly
demonstrate that: (i) 1 is only partially converted into hydride species, regardless of the reaction
7

solvent employed. (ii) In the presence of alcohols (i.e. TFE or MeOH) 1 is converted into the
[RuH(OAc)(CO)2(PnBu3)(PPh3)]
species
monohydride
(1(H))
and
the
dihydride
[RuH2(CO)2(PnBu3)(PPh3)] (1(H)2) (Fig.1, traces a and b). Both latter hydrides are in equilibrium
with 1. 1(H) is further in equilibrium with 1(H)2 and 1 molequivalents of HOAc [12,14]. (iii) The
molar ratio between 1(H) and 1(H)2 depends strongly on the type of alcohol present (i.e. in the
presence of TFE a 1(H)/1(H)2 molar ratio of almost 2 was determined by integration of the hydride
NMR signals (Figure 1, trace a), whereas in the presence of MeOH the latter ratio was inverted. (iv)
In neat C6D6, 1 transforms into 1(H)2, 2 and the dihydride of 3 (3(H)2) (Fig. 1, trace c) [14]. 2 and
3(H)2 are obtained as a result of a phosphane ligand scrambling reaction, as observed previously
[14].
Analogous operando (HP) NMR spectra, acquired in neat C6D6 or using an 1:1 (v:v) C6D6/TFE
solvent mixture under identical catalytic conditions as reported above but in the presence of
substrate (i.e. N-benzilideneaniline), showed 1 as the only phosphorus containing species in case an
1:1 (v:v) C6D6/TFE solvent mixture was used, corroborating the fact that 1(H) enters the catalytic
cycle, and depresses the formation of 1(H)2. In contrast, in neat C6D6, the same NMR pattern as
shown in Fig. 1 (trace c) was observed (Supporting information), which is indicating that neither
hydride species formed in C6D6 (i.e. 3(H)2 and 1(H)2) were catalytically active. In fact, a very
scarce catalytic activity was found in toluene (Table 1, entry 1).
In order to elucidate the influence of a protic solvent on the equilibrium between the hydride
species 1(H) and 1(H)2, we studied in separate NMR experiments the protonation of synthesized
1(H)2 with HOAc in the presence of MeOH or TFE. To this purpose, identical C6D6 solutions of
1(H)2 were treated with TFE/HOAc or MeOH/HOAc (i.e. 1:1 (v:v) C6D6/alcohol, 0.4 mL of alcohol
and 1.0 moleq of HOAc with respect to 1(H)2). The conversion of 1(H)2 into 1(H) was followed by
31
1H and P {1H} NMR spectroscopy and selected 1H NMR spectra (i.e. hydride region) of the latter
spectroscopic study are shown in Fig. 2.
8

1
Fig. 2. Selected H NMR spectra (hydride region) concerning the protonation reaction of 1(H)2: (a)
1(H)2 in C6D6; (b) 1(H)2 in 1:1 (v:v) C6D6/TFE; (c) after addition of HOAc to the latter solution and
spectra acquisition after 2 h; (d) 1(H)2 in 1:1 (v:v) C6D6/MeOH; (e) after addition of HOAc to the
latter solution and spectra acquisition after 2 h.
A small amount of 3(H)2 is formed during the synthesis of 1(H)2 as shown in Fig. 2, trace a. The
addition of equal amounts of TFE and MeOH to the C6D6 solution of 1(H)2 (Fig. 2, trace b and d,
respectively) leads to a shift and broadening of the hydride signal compared to the spectrum
acquired in neat C6D6 (Fig. 2, trace a). This spectroscopic behaviour is due to the formation of
hydrogen bonds between the hydride atoms of 1(H)2 and the hydroxyl group of the alcohol [15].
1(H)2 is stable in the presence of alcohols, characterized by a different pKa value (i.e. 12.4 (TFE)
and 15.5 (MeOH)) [16] and upon addition of HOAc to the latter solvent mixtures of 1(H)2,
conversion to 1(H) takes place, which is complete after 2 h in case TFE is present in the solvent
mixture (Fig. 2, trace c), whereas for the same time interval trace amounts of 1(H) were formed in
an 1:1 (v:v) C6D6/MeOH solvent mixture (Fig. 2, trace e). This experimental result led us to
conclude, that TFE, in contrast to MeOH, significantly accelerates the protonation of 1(H)2 shifting
the equilibrium towards 1(H). As a consequence, even in the presence of dihydrogen, 1(H) is the
dominant hydride species formed in the presence of TFE, as shown by the corresponding (HP)
NMR experiment (Fig. 1, trace a). Hence the catalytic activity observed is strongly related to the
9

amount of 1(H) present in equilibrium with 1 in different reaction media. As a result, under
identical experimental conditions, imine hydrogenation reactions conducted in TFE showed much
higher substrate conversion compared to MeOH (Table 1).
Since (HP) NMR experiments conducted in C6D6/TFE in the presence of 1 and substrate
confirmed the absence of 1(H) and 1(H)2, we deem 1(H) as the hydride species that enters the
catalytic cycle. Moreover, 1(H)2, in contrast to 1(H), is not endowed with an easily removable
ligand, which is a prerequisite for the catalytic activity.
DFT-calculations performed with the model compound [Ru(OAc)2(CO)2(PMe3)(PPh3)] (1’) (i.e.
PMe3 was chosen for simplicity reasons. PMe3 has a slightly smaller cone angle than PnBu3 (118° vs
132 °) [17], while the electronic properties are comparable. The relative free energy profile for the
conversion of 1’ into the model Ru-monohydride-acetate species 6’ in TFE is depicted in Fig. 3.
Fig. 3. Relative free energy profile for the conversion of 1’ into 6’ in TFE.
The crucial reaction steps for the latter conversion are: (i) The dissociation of acetate from 1’
giving the penta-coordinated intermediate 2’, which is stabilized by an κ2-O,O-acetate coordination
(3’); (ii) The coordination of dihydrogen to 2’ forming the non-classical dihydrogen complex 4’
[18] and (iii) the heterolytic dihydrogen splitting assisted by the free acetate anion (i.e. no transition
state (TS) was observed for the latter reaction, which we followed by a relaxed energy scan
10

(Supporting information)). An alternative intramolecular acetate-triggered dihydrogen activation
turned out to be ca. 6.0 kcal mol-1 less favourable compared to the intermolecular version. The
dissociation of acetic acid from Ru-monohydride HOAc adduct 5’ gives the Ru-monohydride
actetate species 6’.
Analogous DFT calculations regarding MeOH instead of TFE as reaction medium, gave an
almost identical free energy profile (Supporting information). In contrast, DFT calculations
performed with 1’ in C6H6 showed that PPh3 dissociation from metal centre is much more favoured
over the acetate dissociation to provide a free coordination site at ruthenium (i.e. +22.8 kcal mol-1
and +61.9 kcal mol-1 for PPh3 and acetate dissociation, respectively) (Supporting information). This
latter result is in agreement with the behaviour reported for 1 in C6H6 solution [14]. According to
DFT calculations 6’ enters the catalytic cycle by an acetate dissociation along with the formation of
a pentacoordinated Ru-species 7’ (Fig. 4). We also investigated the possible protonation of
coordinated acetate in 6’ by TFE [19]. As a result, two protonated isomeric Ru-species of the
formula [RuH(HOAc)(CO)2(PMe3)(PPh3)]+ were obtained. DFT-calculations revealed the carboxyl
oxygen atom to be more prone to protonation compared to the Ru-coordinated oxygen atom (i.e.
+34.0 kcal vs 39.1 kcal mol-1). In any case, acetate protonation is associated to significantly higher
free activation enthalpy compared to acetate dissociation from 6’. 7’ might have two possibilities to
enter the catalytic cycle in TFE as reaction medium, either by TFE (Fig. 4) or imine coordination
(i.e. CH3CH=NCH3 has been chosen as model imine) (Fig. 4).
The coordination of TFE to 7’ gives 8’, which is the key species for the TFE-assisted outer
sphere imine hydrogenation mechanism as shown in Fig. 4.
11

Fig. 4. Proposed catalytic cycle for the 8’-catalyzed imine hydrogenation reaction in TFE. ∆G and
∆E (italics) values are reported in kcal mol-1.
8’ transfers barrierless H+ (Ha) from coordinated TFE solvent molecule to the anchored imine
nitrogen atom giving intermediate 9’ (Fig. 4). In contrast, the protonation of the imine substrate by
acetic acid (Supporting information), instead of coordinated TFE, giving an iminium compound,
which accepts H- [20], is endergonic by +9.1 kcal mol-1. The positive charge of the iminium carbon
atom fosters the H- transfer from Ru to the iminium carbon atom leading to the amine adduct 10’.
This latter reaction is associated to a ∆E of +9.5 kcal mol-1 (i.e. since no TS was observed for the
latter reaction step, a relaxed energy scan of the C(imine)-Ru-hydride intermolecular distance in 9’
was carried out (Supporting information). Notable, the H+/H- transfer in TFE is significantly more
favoured compared to MeOH (i.e. -0.1 kcal mol-1 (TFE) vs +10.3 kcal mol-1 (MeOH)) (Supporting
information).
The amine formed coordinates to Ru giving species 11’. The regeneration of the key catalytic
species 8’ comprises: (i) The dissociation of the coordinated amine from 11’ (i.e. this reaction step
is expected to strongly depend on the Lewis-basicity of the amine; accordingly we found a drop of
the substrate conversion on increasing Lewis-basicity of the imine nitrogen atom (Table 1)). (ii) The
coordination of dihydrogen to 12’ is followed by an alkoxy group-assisted, heterolytic dihydrogen
12

splitting reaction [14,18]. A 8’-related Ru-species was proposed as catalyst for the ligand-assisted
outer-sphere hydrogenation of CO2 to formic acid [21].
The coordination of the model imine to the penta-coordinated intermediate 7’ giving 15’ is the
initial step of a classical inner-sphere imine hydrogenation mechanism (Fig. 5). Although the imine
coordination to 7’ is favoured over the TFE coordination (i.e. ∆G = -22.2 kcal mol-1 (imine
coordination) vs -2.8 kcal mol-1 (TFE coordination), the inner-sphere reaction mechanism shows a
high activation barrier for the hydride migration (i.e. +21.5 kcal mol-1 (inner-sphere) vs +9.5 kcal
mol-1 (outer sphere)) to give the penta-coordinated Ru-amido complex 16’ [7]. A relaxed energy
scan of the latter reaction revealed no TS, instead a continuously increasing energy upon
diminishing the Ru-H...C(imine) distance was observed (Supporting information).
Fig. 5. Proposed catalytic cycle for the 7’-catalyzed imine hydrogenation reaction in TFE. ∆G and
∆E (italics) are reported in kcal mol-1.
13

Moreover, the regeneration of catalyst 7’ foresees an intramolecular protonation reaction
mediated either by coordinated dihydrogen (i.e. Fig. 5, intermediates 17’ through 19’) or by
coordinated TFE (i.e. intermediates 20’ through 12’). In the latter case 12’ is formed which enters
the outer-sphere reaction mechanism (Fig. 4).
Importantly, not only the hydride migration in the inner-sphere mechanism is associated to a
high activation energy but also the regeneration of the catalyst 7’ needs much higher activation
energies compared to the outer-sphere reaction mechanism, making it hence less probable to be
operative.
4. Conclusions
[Ru(OAc)2(CO)2(PnBu3)(PPh3)] (1) was employed as precatalyst for the selective hydrogenation
of imines to the corresponding secondary amine carried out in different reaction media in the
absence of an additional base. (HP) NMR experiments carried out with 1 in the presence of an
alcohol reaction medium (i.e. MeOH, 2,2,2-trifluoroethanol (TFE)) and in the absence of substrate
clearly showed the formation of the corresponding mono- 1(H) and dihydride 1(H)2, which are in
equilibrium with 1 (i.e. main species even under catalytic conditions). The type of alcohol
determined the molar ratio between 1(H)/1(H)2, showing for TFE the highest ratio, which is
associated to a much higher catalytic activity found in TFE compared to MeOH. DFT calculations
carried out with a model compound of 1 in TFE and MeOH, indicated an alcohol-assited outer-
sphere reaction mechanism as the most probable catalytic imine hydrogantion mechanism. In this
respect, TFE showed, in contrast to MeOH, an almost barrierless H+/H- transfer to the imine
substrate.
14

Acknowledgements
G.M. And A.I. acknowledge ISCRA-CINECA HP grant “HP10BNL89W” and CREA (Centro
Ricerche Energia e Ambiente) of Colle Val d’Elsa (Siena, Italy) for computational resources.
Appendix A: Supplementary material
Operando (HP) NMR spectra of 1 acquired in the presence of substrate and supporting DFT
calculations. Supplementary data associated with this article can be found, in the online version , at
http://dx.doi.org/...
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17

Caption to the figures
Fig. 1. Operando (HP) NMR spectra of 1 acquired at 50 °C in different reaction media in the
1
presence of dihydrogen (50 bar): A) (31P{1H} NMR spectra; B) Hydride region of the H NMR
spectra: (a) 1:1 (v:v) C6D6/TFE solvent mixture; (b) 1:1 (v:v) C6D6/MeOH solvent mixture and (c)
neat C6D6.
1
Fig. 2. Selected H NMR spectra (hydride region) concerning the protonation reaction of 1(H)2: (a)
1(H)2 in C6D6; (b) 1(H)2 in 1:1 (v:v) C6D6/TFE; (c) after addition of HOAc to the latter solution and
spectra acquisition after 2 h; (d) 1(H)2 in 1:1 (v:v) C6D6/MeOH; (e) after addition of HOAc to the
latter solution and spectra acquisition after 2 h.
Fig. 3. Relative free energy profile for the conversion of 1’ into 6’ in TFE.
Fig. 4. Proposed catalytic cycle for the 8’-catalyzed imine hydrogenation reaction in TFE. ∆G and
∆E (italics) values are reported in kcal mol-1.
Fig. 5. Proposed catalytic cycle for the 7’-catalyzed imine hydrogenation reaction in TFE. ∆G and
∆E (italics) are reported in kcal mol-1.
18

Highlights
- Base-free imine hydrogenation with [Ru(OAc)2(CO)2(PnBu3)(PPh3)] (1) in different reaction
media.
- 2,2,2-trifluoroethanol (TFE) emerged as the solvent of choice for the 1-catalyzed imine
hydrogenation under mild conditions.
- TFE stabilizes very efficiently the monohydride of 1, which enters the catalytic cycle.
-A TFE-assisted outer-sphere reaction mechanism is favored over a classical inner-sphere
reaction mechanism.

Graphical Abstract - pictogram

Graphical abstract - synopsis
[Ru(OAc)2(CO)2(PnBu3)(PPh3)] was used as precatalyst to hydrogenate selected imines to the
corresponding amine in different reaction media and under base-free conditions. The solvent of
choice revealed to be 2,2,2-trifluoroethanol (TFE) which directly participated in an TFE-assisted
outer-sphere reaction mechanism by forming a Ru-monohydrate-TFE intermediate.