An evaluation of the Noyori system in reverse : Thermodynamic and kinetic parameters of secondary alcohol transfer dehydrogenation catalyzed by [(η6-1-iPr-4-Me-C6H4)Ru(HN-CR′R″-CR′R″NTs)], R′ = H, Me; Ph, R″ = H, Me

Article abstract of DOI:10.1016/j.molcata.2008.05.009

The 16 electron ruthenium complexes [(η⁶-1-isopropyl-4-methyl-benzene)(X-N)Ru(II)], where X-N is 2-amido-1-ethoxide (2), 1-N-p-tosyl-1,2-diamido-ethane (3), 1-N-p-tosyl-1,2-diamido-benzene (7), 1-N-(p-tosyl)-1,2-diamido-1,1,2,2-tetramethyl-ethane (8) and 1-N-(p-tosyl)-1,2-diamido-meso-1,2-diphenyl-ethane (9) have been evaluated as catalysts for the transfer dehydrogenation of secondary alcohols to ketones in acetone and/or cyclohexanone solvent. Complexes 2 and 3 cannot be isolated and decompose under these conditions. In contrast complexes 7, 8 and 9 are supported by ligands designed to resist β-hydride elimination and can with the exclusion of oxygen be held in solution for weeks. Complex 7 is not active as a catalyst. Complexes 8 and 9 are highly air-sensitive and active as catalysts for transfer (de)hydrogenations under oxidizing and reducing conditions, respectively. There is no coordinative inhibition of the catalysts by the ketone solvent under oxidizing conditions, but both catalysts show a correlation between the reaction rates and the ΔG values of the reactions with reactions leading to α, β-unsaturated ketones proceeding faster. For all alcohol/ketone substrate pairs where the ketone is not α, β-unsaturated, the hydrogenation reactions under reducing conditions (iso-propanol solvent) are at least one order of magnitude faster than the corresponding dehydrogenation reaction under oxidizing conditions (acetone solvent).

Full text of DOI:10.1016/j.molcata.2008.05.009

Journal of Molecular Catalysis A: Chemical 290 (2008) 1–14
Contents lists available at ScienceDirect
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journal homepage: www.elsevier.com/locate/molcata
Editors’ choice paper
An evaluation of the Noyori system “in reverse”: Thermodynamic and kinetic
parameters of secondary alcohol transfer dehydrogenation catalyzed by
[(␩6-1-iPr-4-Me-C6H4)Ru(HN-CRꢀRꢀꢀ-CRꢀRꢀꢀNTs)], Rꢀ = H, Me; Ph, Rꢀꢀ = H, Me
Matthias Bierenstiel, Magdalena Dymarska, Ebbing de Jong, Marcel Schlaf∗
Department of Chemistry, University of Guelph. The Guelph-Waterloo Center for Graduate Studies in Chemistry (GWC)2, Guelph, Ontario N1G 2W1, Canada
a r t i c l e i n f o
a b s t r a c t
The 16 electron ruthenium complexes [(␩6-1-isopropyl-4-methyl-benzene)(X-N)Ru(II)], where X-
N is 2-amido-1-ethoxide (2), 1-N-p-tosyl-1,2-diamido-ethane (3), 1-N-p-tosyl-1,2-diamido-benzene
(7), 1-N-(p-tosyl)-1,2-diamido-1,1,2,2-tetramethyl-ethane (8) and 1-N-(p-tosyl)-1,2-diamido-meso-1,2-
diphenyl-ethane (9) have been evaluated as catalysts for the transfer dehydrogenation of secondary
alcohols to ketones in acetone and/or cyclohexanone solvent. Complexes 2 and 3 cannot be isolated and
decompose under these conditions. In contrast complexes 7, 8 and 9 are supported by ligands designed to
resist ␤-hydride elimination and can with the exclusion of oxygen be held in solution for weeks. Complex
7 is not active as a catalyst. Complexes 8 and 9 are highly air-sensitive and active as catalysts for trans-
fer (de)hydrogenations under oxidizing and reducing conditions, respectively. There is no coordinative
inhibition of the catalysts by the ketone solvent under oxidizing conditions, but both catalysts show a
correlation between the reaction rates and the ꢀG values of the reactions with reactions leading to ␣,
␤-unsaturated ketones proceeding faster. For all alcohol/ketone substrate pairs where the ketone is not
␣, ␤-unsaturated, the hydrogenation reactions under reducing conditions (iso-propanol solvent) are at
least one order of magnitude faster than the corresponding dehydrogenation reaction under oxidizing
conditions (acetone solvent).
Article history:
Received 28 November 2007
Received in revised form 3 May 2008
Accepted 17 May 2008
Available online 28 May 2008
Keywords:
Alcohol oxidation
Transfer hydrogenation
Ruthenium complexes
Catalysis
© 2008 Elsevier B.V. All rights reserved.
1. Introduction
or acidic reaction conditions required by the oxidizing reagents
employed.
1.1. Motivation
One of the most active and versatile among the homogeneous
catalytic sec-alcohol/ketone oxidation/reduction systems are the
The reduction of ketones to secondary alcohols and the reverse,
i.e., the oxidation of secondary alcohols to ketones are funda-
mental reactions in synthetic organic chemistry and an enormous
variety of both stochiometric and catalytic methods have been
developed [1,2]. In contrast there exist only few methods for the
selective oxidation of vic-diols to the corresponding ␣-hydroxy-
ketones [3,4]. In particular, viable methods for the oxidation of
secondary hydroxyl functions in unprotected sugar polyalcohols
[5] and furanose and pyranose sugars to give the corresponding
furanuloses and pyranuloses are very rare [6,7]. A selective oxida-
tion of vic-diols is challenging because the ␣-hydroxy-ketones are
easily over-oxidized to diketones and ultimately carboxylic acids
through oxidative C–C bond cleavage [4] and also tend to show
uncontrollable secondary reactivity under the often either basic
metal-ligand bifunctional ruthenium complexes of the type [(␩6-
arene)Ru(XCH(C6H5)CH(C6H5)NHn)Y] (arene = 1-iPr-4-Me-C6H4 or
similar, X = O, NTs, Y = Cl, H or not present for n = 1, n = 1 or 2)
developed by Noyori and co-workers [8–12]. While the applica-
tion focus of these catalysts in their optically active forms has
been on the highly successful enantioselective transfer hydro-
genation of ketones using iso-propanol as both the solvent and
reducing agent, Noyori and co-workers also demonstrated that the
␩6-arene diamine ruthenium(II) based catalysts [(␩6-1-iPr-4-Me-
C6H4)Ru(H)(1R,2R- NH(Ts)-CH(C6H5)CH(C6H5)NH2)] (1H) or the
corresponding hydrogen deficient 16 electron complex (1) can suc-
cessfully be employed under oxidizing conditions (i.e., in acetone
solvent) without the presence of a base. This allows the kinetic
resolution of racemic benzylic or allylic alcohols achieving high ee
values (92–99%) at 50% conversion of one alcohol enantiomer to the
corresponding ketone within 6–36 h at 28 ◦C [13]. However to our
knowledge only benzylic and allylic alcohols have been oxidized
under the kinetic resolution conditions [13], while the transfer
∗
Corresponding author.
E-mail address: mschlaf@uoguelph.ca (M. Schlaf).
1381-1169/$ – see front matter © 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.molcata.2008.05.009

2
M. Bierenstiel et al. / Journal of Molecular Catalysis A: Chemical 290 (2008) 1–14
yield (6.2 g, 23 mmol). C13H22N2O2S, MM = 270 g mol−1 1H NMR
.
dehydrogenation of aliphatic alcohols or vicinal diols has not been
reported in the literature.
(DMSO-d6; 2.49 ppm) ı 7.56 (d; J = 8.0 Hz; 2H), 7.11 (d; J = 8.0 Hz;
2H), 2.28 (s, br, 3H), 0.93 (s, 6H), 0.90 (s, 6H). 13C NMR (DMSO-d6;
39.5 ppm) ı 142.1, 138.0, 128.2, 126.1, 59.7, 55.7, 25.9, 23.6, 20.8.
IR (KBr, cm−1) ꢁ 3383, 3246, 2979, 2427, 1910, 1598, 1579, 1457,
1387, 1362, 1299, 1218, 1180, 1151, 1107, 1048, 1015, 915, 810, 777,
687, 651, 557. High resolution MS (ESI, 3.5 kV spray voltage, m/z of
M + 1): 271.1479. Monoisotopic molecular weight: 271.1480, aver-
age molecular weight: 271.394.
2. Experimental
2.1. General
NMR spectra (400 MHz/1H; 100 MHz/13C) were measured in
DMSO-d6 with DMSO (ı 2.49, 1H; ı 39.5, 13C) and deuterated
chloroform (ı 7.24, 1H; ı 77.0, 13C) as the internal reference unless
indicated otherwise. NMR solvents were stored inside a dry-box
2.2.2. N-(p-Tosyl)-meso-1,2-diphenyl-1,2-diaminoethane (6) [14]
The compound was previously prepared by a different route
in optically pure form (the NMR spectra match those published
in reference [17]). p-Toluyl-sulfonyl chloride (0.64 g, 3.3 mmol) in
75 mL benzene was added drop-wise to a solution of meso-1,2-
diphenyl-1,2-diaminoethane (2.12 g, 10 mmol) in 40 mL benzene
and was stirred vigorously for 3 h. A white precipitate appeared
and was filtered and treated with 1 M hydrochloric acid (∼50 mL).
The remaining solid was filtered and filtrate made strongly basic by
addition of NaOH pellets (∼4 g). A white crystalline solid appeared,
was filtered, washed with 10 mL cold water and recrystallized
from a benzene/hexanes mixture. Yield 48% (1.75 g, 4.8 mmol).
˚
under argon atmosphere over 4 A activated molecular sieves. For
variable temperature measurements the spectrometer tempera-
ture controller unit was calibrated using a bimetal thermometer
directly inserted into the probe. DFT calculations were carried
on a PC using the Gaussian 03 suite of programs. GC analyses
were performed on a 30 m × 0.25 mm PEG column. The GC FID
was calibrated for alcohol and ketone substrates with cis-decalin
as an internal standard. GC–MS experiments were performed on
a Varian 3800, Saturn 2000 a 30 m × 0.25 mm PEG column with
70 V electron impact ionization or acetonitrile chemical ionization
technique. IR spectra were recorded with a Bomen FT-IR using
a 1.0 and 2.0 mm CaF2 liquid cell or a 15 ␮m cell containing a
Teflon® washer (15 ␮m) between two BaF2 cell windows. The IR
cells were filled with the oxygen sensitive 16-electron complexes
inside a glove box and carefully sealed from air atmosphere.
Electron impact (EI) mass spectrometry was conducted on a JEOL
HX110 double focussing mass spectrometer ionizing at 70 eV
with source temperature at 200 ◦C. Electrospray ionization (ESI)
mass spectrometry was conducted on a MicroMass QTOF Global
Mass spectrometer in a positive ionization mode (3.5 kV spray
voltage) at atmospheric pressure in acetonitrile. All experimental
preparations were conducted in a dry-box under argon atmosphere
and/or with usual Schlenk technique on a vacuum line. Acetone,
iso-propanol and CH2Cl2 were dried by distillation under argon
from anhydrous CaCl2, anhydrous K2CO3 containing LiAlH4 and
K2CO3, respectively, degassed and stored under argon. Water was
distilled under argon immediately before use. Alcohol and ketone
substrates, cis-decalin and common solvents were purchased from
commercial sources. All chemicals were reagent grade and used
after degassing through repetitive freeze–thaw cycles. N-(p-tosyl)-
1,2-diaminoethane [14], N-(p-tosyl)-ortho-diaminobenzene [15],
1,2-dinitro-1,1,2,2-tetramethylethane [16], 1,2-diamino-1,1,2,2-
tetramethylethane [16], meso-1,2-diphenyl-1,2-diaminoethane
C
21H22N2O2S, MM = 366 g mol−1 1H NMR (CDCl3; 7.24 ppm) ı 7.38
.
(d, J = 7.8 Hz, 2H), 7.25–6.85 (m, 10H), 6.76 (d, J = 7.8 Hz, 2H), 5.60 (s,
br, 1H), 4.39 (d, J = 5.6 Hz, 1H), 4.04 (d, J = 5.6 Hz, 1H), 2.24 (s, 3H),
1.57 (s, br, 2H). 13C NMR (CDCl3; 77.0 ppm) ı 142.9, 140.9, 137.1,
136.7, 129.2, 128.3, 128.2, 127.8, 127.7, 127.0, 126.9, 60.8, 63.4, 25.4.
IR (KBr, cm−1) ꢁ 3057, 3020, 2962, 1599, 1493, 1447, 1382, 1261,
1080, 1071, 953, 811, 698, 666, 573, 545.
2.2.3. (ꢂ6-1-Isopropyl-4-methyl-benzene)N-p-tosyl-ortho-
diaminobenzene ruthenium(II)
(7)
[p-Cymene RuCl2]2 (306 mg, 0.50 mmol) and N-(p-tosyl)-ortho-
diaminobenzene (248 mg, 1.0 mmol) were transferred into a 30 cm
long Schlenk tube with a stir bar. The Schlenk flask was evacuated
and re-filled with Ar three times and 15 mL dry, under Ar distilled
dichloromethane was added with a syringe. The red/orange solu-
tion was stirred for 10 min at room temperature and finely ground
potassium hydroxide (0.5 g) was added. The reaction mixture was
red coloured and stirred for additional 45 min at room tempera-
ture. Then, 15 mL of oxygen free water was added with a syringe
and the white solid and excess KOH were dissolved. The greenish
aqueous solution was removed with a canula and the remain-
ing dichloromethane solution was dried with CaH2 (∼0.4 g) until
hydrogen gas evolution stopped. The solution was filtered from
the remaining solids under Ar with a Schlenk frit. The solvent of
the filtrate was evaporated under reduced pressure and a red solid
was obtained in 82% yield (406 mg, 0.82 mmol). C23H25N2O2SRu,
MM = 495.1 g mol−1. Properties: The red complex is stable in air as
a solid and in solution; soluble in dichloromethane, benzene, iso-
propanol and acetone. 1H NMR (CD2Cl2; 5.31 ppm) ı 9.49 (s, br,
1H), 7.74 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz,
2H), 6.97 (dd, J = 7.6, 1.2 Hz, 1H), 6.74 (m, 2H), 5.67 (d, J = 6.4 Hz,
2H), 5.63 (d, J = 6.4 Hz, 2H), 2.57 (sept., J = 7.2 Hz, 1H), 2.35 (s, 3H),
2.22 (s, 3H), 1.24 (d, J = 6.8 Hz, 6H). 13C NMR (CD2Cl2; 53.7 ppm)
ı 151.5, 141.2, 139.5, 138.3, 128.1, 125.4, 119.0, 117.4, 116.3, 113.4,
100.6, 90.2, 79.6, 76.3, 30.9, 22.6, 20.1, 19.1. IR (KBr, cm−1) ꢁ 3299,
2962, 2360, 1476, 1456, 1321, 1307, 1140, 1086, 1036, 929, 847, 825,
665, 566.
[14]
and
N-(p-tosyl)-meso-1,2-diphenyl-1,2-diaminoethane
[14,17] were prepared according to published literature pro-
cedures. meso-1,2-diphenyl-1,2-diaminoethane is commercially
available.
2.2. Preparation of ligands and complexes
2.2.1. N-(p-Tosyl)-1,2-diamino-1,1,2,2-tetramethylethane (5)
In a 250 mL round bottle flask and with ice cooling, 1,2-
diamino-1,1,2,2-tetramethylethane (9.5 g, 82 mmol) was dissolved
in benzene (25 mL) and a solution of p-toluyl-sulfonyl chloride
(5.2 g, 27 mmol) dissolved in 50 mL benzene was added drop-wise.
After completion of the addition, the temperature of the reaction
mixture was kept at 40 ◦C for 3 h, then increased to refluxing tem-
perature for 30 min. After cooling to ambient temperature, white
solids precipitated, which were filtered and dried in vacuo yield-
ing 8.2 g of crude product. The product was dissolved in 1 M HCl
(50 mL), filtered through celite and the remaining clear solution
was cooled to 0 ◦C and 6 M NaOH (50 mL) was added carefully. The
resulting white precipitate was filtered and dried in vacuo. 85%
High resolution MS (EI, 70 eV; m/z of parent ion, normalized)
490.0507 (13.25%), 491.0680 (4.23%), 492.0455 (6.00%), 493.0649
(31.23%), 494.0583 (39.14%), 495.0664 (50.87%). Monoisotopic
molecular weight: 495.0680, average molecular weight: 494.580.

M. Bierenstiel et al. / Journal of Molecular Catalysis A: Chemical 290 (2008) 1–14
3
2.2.4. (ꢂ6-1-Isopropyl-4-methyl-benzene)-N-(p-tosyl)-1,2-diam-
ino-1,1,2,2-tetramethyl-ethane ruthenium(II) (8)
characteristic chemical shifts of the other ruthenium complexes
7 and 8. 1H NMR (acetone-d6, 2.09 ppm) 6.5–8.0 (br), 5.2–5.8
(br), 2.0–2.4 (br), 0.9–1.5 (br). 13C NMR (acetone-d6, 206.68 ppm,
29.92 ppm) 150–135, 124.7–122.1, 22.6, 20.1, 19.1. IR (KBr, cm−1) ꢁ
3057, 2961, 1917, 1598, 1494, 1447, 1382, 1261, 1081, 1071, 951, 811,
698, 664, 573, 545. High resolution MS (ESI, 3.5 kV spray voltage,
m/z of M + 1, normalized) 595.1025 (5%), 598.0909 (28%), 599.0887
(40%), 600.0873 (50%), 601.0767 (100%), 602.0969 (15%), 603.0881
(40%), 604.1102 (5%). Monoisotopic molecular weight: 600.1384,
average molecular weight: 599.732.
[p-Cymene RuCl2]2 (612 mg, 1.0 mmol) and N-(p-tosyl)-1,2-
diamino-1,1,2,2-tetramethyl-ethane (540 mg, 2.0 mmol) were
transferred into a 30 cm long Schlenk tube with a stir bar. The
Schlenk flask was evacuate and re-filled with Ar three times
and 30 mL of dichloromethane was added with a syringe. The
red/orange solution was stirred for 10 min at room temperature
and finely ground potassium hydroxide (1.0 g) was added. The
reaction mixture immediately turned deep purple and was stirred
for additional 15 min at room temperature. Then, 15 mL of oxygen
free water was added via syringe and the white solid and excess
KOH dissolved. The greenish aqueous solution was removed
with a canula and the remaining dichloromethane solution was
dried with CaH2 (∼0.8 g) until hydrogen gas evolution stopped.
The purple solution was filtered under Ar with a Schlenk frit
and the remaining solids were washed with 10 mL degassed
dichloromethane. The solvent of the purple filtrate was evaporated
under reduced pressure and a purple solid was obtained in 91%
2.3. Kinetic experiments
The reactions were carried out in a 7 mL screw top vial equipped
with a stir bar inside a glovebox under Ar atmosphere. GC-
monitoring was conducted typically after 6 h, 24 h, 48 h, 72 h, 7 d
and 14 d by direct injection of the crude reaction mixture.
2.3.1. Typical procedure under oxidizing/reducing condition
Alcohol/ketone substrate (1.0 mmol), 16-electron ruthenium
catalyst (0.010 mmol) and cis-decalin (∼50 mg) were dissolved in
5.0 mL acetone/iso-propanol in a 7 mL vial and stirred at room tem-
perature. The reaction was monitored by quantitative GC using
cis-decalin as the internal standard.
yield (914 mg, 1.82 mmol). C23H34N2O2SRu, MM = 503.7 g mol−1
.
Properties: The purple solid is stable in air for a few hours, how-
ever, in solution the complex decomposes instantaneously upon
exposure to air; soluble in dichloromethane, benzene, iso-propanol
and acetone. 1H NMR (C6D6; 7.15 ppm) ı 8.13 (d, J = 7.3 Hz, 2H,
CH-tosyl), 6.94 (d, J = 7.3 Hz, 2H, CH-tosyl), 6.85 (s, br, 1H, N–H),
5.17 (d, J = 5.1 Hz, 2H), 5.05 (d, J = 5.1 Hz, 2H), 2.30 (sept., J = 6.8, 1H),
2.00 (s, 3H), 1.90 (s, 3H), 1.25 (s, 6H), 1.11 (d, J = 6.4 Hz, 6H), 0.73
(s, 6H). 13C NMR (C6D6; 128.1 ppm) ı 147.6, 139.4, 128.7, 127.2,
98.7, 87.5, 82.5, 78.7, 74.1, 67.0, 32.0, 26.8, 24.6, 23.8, 21.1, 19.9.
IR (KBr, cm−1) ꢁ 3281, 2960, 1598, 1492, 1470, 1387, 1352, 1254,
1127, 1087, 1052, 1025, 931, 807, 816, 791, 657, 561. High resolution
MS (EI, 70 eV; m/z of parent ion; normalized) 498.1378 (1.19%),
501.1364 (2.92%), 502.1380 (3.70%), 503.1543 (5.35%), 504.1441
(8.33%), 505.1348 (2.79%), 506.1399 (5.01%), 507.1598 (1.46%).
Monoisotopic molecular weight: 504.1384, average molecular
weight: 503.652.
2.3.2. Typical procedure for equal-concentration experiments
Alcohol substrate (0.50 mmol), ketone substrate (0.50 mmol)
and cis-decalin (∼50 mg) were dissolved in 2.4 mL acetone (2.4 mL)
and iso-propanol (2.5 mL). Then, 16-electron ruthenium complex
(0.010 mmol) was added and the reaction mixture was stirred at RT.
The reaction was monitored by quantitative GC using cis-decalin as
the internal standard.
3. Results and discussion
3.1. Selection of catalyst system and oxidation substrates
2.2.5. (ꢂ6-1-Isopropyl-4-methyl-benzene)-N-(p-tosyl)-1,2-
diamino-meso-1,2-diphenyl-ethane ruthenium(II)
(9)
The most active ruthenium catalysts for “forward” reac-
tions, i.e., reductions of ketones in iso-propanol solvents, were
obtained with ␤-amino-ethanol and N-tosyl-1,2-diaminoethane
as the ligands [9]. Presumably the resulting complexes allow the
most facile access of substrates to the catalytically active centre
because of the least amount of steric repulsion with the ethylene
backbone [9,11,18]. Cyclopentanol, cyclohexanol and 1,2;5,6-O-
diisopropylidine ␣-d-gluco-furanoside (diacetone-glucose) were
chosen as model systems for sugar substrates for an initial evalua-
tion of ␤-amino-ethanol and N-tosyl-1,2-diaminoethane p-cymene
ruthenium complexes as catalysts in hydrogen transfer reactions
under oxidizing conditions, i.e., in acetone or cyclohexanone sol-
vent.
[p-Cymene RuCl2]2 (612 mg, 1.0 mmol) and N-(p-tosyl)-1,2-
diamino-meso-1,2-diphenyl-ethane (728 mg, 2.0 mmol) were
transferred into a 30 cm long Schlenk tube with a stir bar. The
Schlenk flask was evacuated and re-filled with Ar three times and
30 mL of dichloromethane was added with a syringe. A bright
red-orange precipitate formed after 5 min at room temperature
and finely ground potassium hydroxide (1.0 g) was added. The
red-orange precipitate dissolved and the reaction mixture was
dark-red coloured. After additional stirring for 45 min at room tem-
perature, 15 mL of oxygen free water (freshly prepared by refluxing
under Ar atmosphere) was added via syringe and the white solid
and excess KOH were dissolved. The brownish aqueous solution
was removed via a canula and the remaining dichloromethane
solution was dried with CaH2 (∼0.8 g) until hydrogen gas evolution
stopped. The dark-red solution was filtered under Ar with a
Schlenk frit and the remaining solids were washed with 10 mL
degassed dichloromethane. The solvent of the dark-red filtrate was
evaporated under reduced pressure and a red solid was obtained in
3.2. Transfer dehydrogenation reactions with known systems
The results of the oxidation of cyclopentanol, cyclohexanol and
diacetone-glucose with the ␤-aminoethanol p-cymene-ruthenium
hydride complex (2H), which was synthesized according to litera-
ture procedure [18], are shown in Table 1. The oxidation reactions
were monitored by quantitative GC using N-methyl-pyrrolidinone
(NMP) as the internal standard. The experimental technique and
actual activity of the catalyst was verified in a control experiment
by the quantitative reduction of acetophenone to 1-phenyl-ethanol
in iso-propanol after 6 h at room temperature using an authentic
catalyst sample from the same synthesis batch [8].
94% yield (1.12 g, 1.87 mmol). C31H34N2O2SRu, MM = 599.7 g mol−1
.
Properties: The red solid is stable in air, however, a solution of
the complex instantaneously decomposed upon exposure to air;
soluble in dichloromethane, benzene, iso-propanol and acetone.
Several recrystallization and isolation attempts of 9 failed with
the material giving very complex 1H NMR spectra. In the 13C NMR
spectrum broad overlapping signals observed, which coincide with
In all oxidation reactions, the initial colour of the reaction
solution is purple but turned to dark brown containing black

4
M. Bierenstiel et al. / Journal of Molecular Catalysis A: Chemical 290 (2008) 1–14
Table 1
Oxidation of secondary alcohols with p-cymene-Ru-␤-aminoethanol hydride (2H) as the catalyst
Entry
1b
Substrate
Solvent
Temperature (◦C)
Time (h)
48
Conversiona (%)
<2
Acetone
25
2b
Acetone
56
24
15
3b
4b
5
Acetone
25
56
48
24
48
24
<10
Acetone
46
40
70
Cyclohexanone
Cyclohexanone
25
6
100
7
8
9
Acetone
56
100
150
24
24
24
0c
Cyclohexanone
12d
Cyclohexanone
71d,e
Reaction conditions: 1.0 mmol alcohol substrate, 0.1 mmol 2H and NMP (∼100 mg) in 10 mL ketone solvent under Ar.
a
Production of ketone substrate determined by quantitative GC with NMP as internal standard.
In situ generation of catalyst with additional 0.30 mmol KOH.
Produced iso-propanol measured.
Produced cyclohexanol measured.
b
c
d
e
Isolation of sugar product failed.
precipitate after 24–48 h indicating the formation of ruthenium(0)
as by-product of catalyst decomposition. Even at the very high
catalyst load of 10 mol%, the room temperature oxidation of cyclo-
hexanol and cyclopentanol in acetone solvent was very slow giving
less than 15% conversion after 24–48 h (Table 1, entries 1,3,5).
An increase in temperature to 56 ◦C (b.p. of acetone) increased
the conversion of cyclopentanol and cyclohexanol to 15% and
46%, respectively. A higher temperature was reached when the
ketone solvent was cyclohexanone, which is not only preferred
as a higher boiling solvent but also releases ring strain energy
upon formation of cyclohexanol [19]. With cyclohexanone as the
hydrogen-acceptor, cyclopentanol was oxidized to cyclopentanone
in 70% yield after 24 h at 100 ◦C (Table 1, entry 6). Diacetone-
glucose was not oxidized with acetone as the hydrogen-acceptor
at 56 ◦C but oxidation occurred with cyclohexanone at 100 and
150 ◦C with 12% and 71% of cyclohexanol produced, which as a first
approximation should be equivalent to the amount of diacetone-
glucose oxidized. However, isolation attempts of the product of

M. Bierenstiel et al. / Journal of Molecular Catalysis A: Chemical 290 (2008) 1–14
5
Scheme 1. Different resting states of catalysts 2 or 3 under reducing and oxidizing condition.
the diacetone-glucose reaction (Table 1, entry 9) failed and NMR
analysis of the recovered solids revealed an intractable mixture of
organic compounds generated through undefined side-reactions
at the higher reaction temperature.
turned black within minutes and undefined solids were obtained.
We therefore hypothesize that the 16-electron complexes 2 and
3 undergo a ␤-hydride elimination reaction forming the imine
and aldehyde based ligands as shown in Scheme 2, immediately
followed by reductive elimination of the ligand leading to the
complete disintegration of the complexes and formation of ruthe-
nium(0). GC–MS analysis of the dark brown reaction mixture
was however inconclusive as even with mild chemical ionization
methods (acetonitrile) the presence of the very reactive imine
and aldehyde intermediates could not be unambiguously deter-
mined.
Implicit in these observations is that during catalysis under
reducing conditions, i.e., in iso-propanol solvent, the hydrogena-
tion of the 16-electron complexes 2 and 3, which by necessity must
also be formed as reactive intermediates during the catalytic cycle,
must be a lot faster than the ultimately destructive ␤-hydride
elimination process.
Important insights into the relative stability of the Noyori
catalyst under reducing and oxidizing conditions in acetone or
cyclohexanone solvent emerge from these results. Under reduc-
ing conditions in iso-propanol solvent the reaction mixture is
yellow-orange coloured indicating that the resting state is the 18-
electron ruthenium hydride complex 2H as illustrated in Scheme 1.
However, under oxidizing conditions in acetone or cyclohexanone
solvent, the deep purple colour suggest that the 16-electron
complex 2 is the dominant resting state (the same observa-
tions apply to the N-tosyl-1,2-diaminoethane complexes 3 and
3H).
We next attempted to use the 16-electron complexes 2 and 3
directly as the catalyst in order to establish whether this would
have a positive effect on the reaction rate as the initial step is
the dehydrogenation of the alcohol substrate. The syntheses of the
16-electron ␤-aminoethanol and N-tosyl-1,2-diaminoethylene-p-
cymene ruthenium complexes 2 and 3 (Chart 1) were conducted
in analogy to the reported synthetic procedure [8]. However, the
syntheses and isolation of both 16-electron complexes 2 and 3
failed. The purple colour of either 16-electron complex was briefly
observed after addition of KOH to a CH2Cl2 solution of the chloro
complexes 2Cl and 3Cl (cf. Scheme 1), but the reaction mixture
3.3. Design and synthesis of oxidation resistant ligands
To avoid ␤-hydride elimination, the synthesis of oxidation
resistant ethylene diamine ligands containing no ␤-hydrides or
disfavouring a ␤-hydride elimination, was planned and exe-
cuted. The three target ligands N-tosyl-ortho-diaminobenzene
(4), N-tosyl-1,2-diamino-1,1,2,2-tetramethylethane (5)andN-tosyl-
meso-diphenyl-1,2-diaminoethane (6) prepared as the racemic
mixture, are shown in Chart 2.
While the diamino compounds 4 and 5 do not contain any
␤-hydrides, the meso-1,2-diphenyl ligand (6) contains two ␤-
Chart 1. Structures of the 16 electron complexes ␤-amino-ethanol (2) and N-tosyl-
1,2-diaminoethane (3) p-cymene-ruthenium(II).
Chart 2. Degradation resistant ligands for the Noyori type catalysts.

6
M. Bierenstiel et al. / Journal of Molecular Catalysis A: Chemical 290 (2008) 1–14
Scheme 2. Possible decomposition products of 16-electron complexes 2 and 3 through ␤-hydride elimination.
Fig. 1. Exo- and endo-conformation of syn-disubstituted 1,2-diaminoethane 16-electron ruthenium(II) complexes.
Scheme 3. Synthesis of N-tosyl-1,2-diamino-1,1,2,2-tetramethylethane (5).
hydrogen atoms. A ␤-hydride elimination from a 16-electron
ruthenium complex of 6 was however not anticipated, as the
complexes of the corresponding diastereomeric ligands (R,R- and
S,S-configuration), which have an anti-arrangement of the phenyl
substituents, have been shown to be stable under oxidizing con-
ditions [13]. In the corresponding 18-electron complexes the
syn-disubstituted 1,2-diaminoethane ligands should preferably
coordinate to the ruthenium centre in an exo- rather than an endo-
conformation as illustrated in Fig. 1. In the exo-position the phenyl
ligands point away from the reactive catalytic centre thus enabling
a more facile access of an ketone to the hydride ligand. By the
same argument an alcohol would approach the ruthenium centre
in a 16-electron complex in such a way that the exo-conformation
of the hydride complex would be formed. The catalytic activities
of the syn- and anti-disubstituted ligand are comparable [17], but
the enantioselectivity of the reduction of aromatic ketones was
generally decreased with optically pure syn-disubstituted ethylene
ligands in ␩6-arene ruthenium complexes compared to those in the
anti-configuration. For the targeted non-enantioselective dehydro-
genation reactions this is however not relevant and we postulated
that the higher steric accessibility of the ruthenium centre imparted
by the syn-exo arrangement of the phenyl ligands would result in a
more active catalyst.
The synthesis of N-tosyl-ortho-diaminobenzene (4) was carried
out by tosylation of o-amino-aniline following known literature
procedures [15]. The new ligand N-tosyl-1,2-diamino-1,1,2,2-
tetramethylethane (5) was prepared by a three step synthesis as
shown in Scheme 3. The first step was the oxidative fusion of 2-
nitro-propane to 1,2-dinitro-tetramethylethane in ethanol solvent
with elemental bromine under basic conditions in 97% yield [16].
Subsequent reduction of the nitro groups to primary amines was
effected by elemental tin in acidic medium. The resulting white
solids were purified by steam distillation. Tosylation of the diamine
compound with substoichiometric p-tosyl chloride in pyridine sol-
vent gave 5 in 85% yield.
Scheme 4. Synthesis of N-tosyl-meso-1,2-diphenyl-1,2-diaminoethane (6).

M. Bierenstiel et al. / Journal of Molecular Catalysis A: Chemical 290 (2008) 1–14
7
no brown or black precipitates formed over the course of several
days. Instead solutions of complex 9 and its hydride derivatives
maintain their red colour and NMR spectrum appearance for days,
which prompted us to explore the catalytic activity of this mate-
rial under both reducing and oxidizing conditions and compare it
to that of complexes 7 and 9 (see below). During our study Wills
and co-workers described the use of enantiomerically pure 1S,2R-6
generating the corresponding 18-electron hydride complex in situ
under reducing conditions, but gave no characterization data for
this complex [17].
Chart 3. Structures of new ␤-hydride elimination resistant 16-electron ruthe-
nium(II) complexes.
3.5. Hydrogen transfer reactions with degradation resistant
ligands
As outlined in Scheme 4 the precursor to the third ligand,
meso-1,2-diphenyl-1,2-diaminoethane (6) was synthesized from
the reaction of neat benzaldehyde and ammonium acetate
under refluxing conditions in 50% yield after recrystallization
from methanol [17,20]. The meso-1,2-diphenyl-1,2-diaminoethane
compound obtained was subsequently mono-tosylated with sub-
stoichiometric amounts of p-toluyl-sulfonyl chloride in pyridine to
give racemic N-tosyl-meso-1,2-diphenyl-1,2-diamino-ethane (6) in
48% yield.
The catalytic transfer hydrogenation activity of the ortho-
diaminobenzene ruthenium complex 7 was investigated under
both oxidizing and reducing conditions. A typical reaction was
the oxidation of 1-phenyl-ethanol (1.0 mmol, 0.20 M) in 5.0 mL
degassed acetone with 0.010 mmol (1 mol%) ruthenium complex
7 and cis-decalin as internal GC standard at ambient tempera-
ture and Ar atmosphere. No catalytic activity was observed with
1-phenyl-ethanol and cyclohexanol after 7 days. After 4 weeks,
the contents of acetophenone and cyclohexanone were only ∼1%.
For an investigation of the catalytic hydrogenation activity under
reducing conditions, the same concentrations as under oxidizing
conditions were employed with acetophenone (1.0 mmol, 0.20 M)
as the substrate, 0.010 mmol (1 mol%) ruthenium complex 7 and
cis-decalin in 5.0 mL degassed iso-propanol solvent at room tem-
perature and under Ar atmosphere. Again the phenylene complex
7 showed no catalytic activity in reduction of acetophenone to 1-
phenyl ethanol and only very marginal activity for the conversion of
cyclohexanone to cyclohexanol (11% after four weeks). We attribute
the low reactivity of 7 to the ability of the ortho-diaminobenzene
to act as a non-innocent ligand, formally coordinating to the ruthe-
nium centre as an ortho-quinone type system as illustrated in
Scheme 5. This fundamentally alters the electronic environment of
the ruthenium centre compared to the typical Noyori system and
is reflected in differences of the NMR shifts of the arene ligand. The
aromatic hydrogens of the cymene ligand have a chemical shift of
5.17 and 5.05 ppm in the tetramethyl-ruthenium compound 8 but in
the ortho-diaminobenzene compound 7 the proton resonances are
shifted downfield by approximately 0.5 to 5.67 ppm and 5.63 ppm,
which indicates a higher ring current and thus more electron den-
sity donate towards the ␲*-orbitals of the cymene moiety. This
electron density must originate from a more electron rich ruthe-
nium centre than in the tetramethyl ruthenium complex, which in
turn can be rationalized through the resonance structure 7ꢀ on the
right of Scheme 5, which postulates a ruthenium(0) centre.
3.4. Synthesis and properties of the new Noyori type complexes
The three N-tosyl-1,2-diamine ligands 4, 5 and 6 were then used
to prepare the corresponding 16 electron ␩6-p-cymene ruthenium
complexes 7, 8 and 9. Their structures are shown in Chart 3.
All three complexes were synthesized in analogy to published
literature procedures [8,18]. The [(p-cymene)RuCl2]2 precursor
[21], synthesized from ␣-pinene and ruthenium(III) chloride
hydrate in refluxing ethanol, was reacted with one equiva-
lent N-tosyl-diamino ligand at room temperature in degassed
dichloromethane under Ar atmosphere giving the chloro com-
plexes, which can be isolated as solids in 82% (7Cl), 94% (8Cl) and
92% (9Cl) yield, respectively. The chloro complexes were however
not characterized, but directly further reacted to the 16-electron
complexes in the same solution. Addition of solid KOH, produced a
bright red coloured reaction mixtures of the corresponding 16 elec-
tron complexes with 7Cl and 9Cl and a deep purple colour with 8Cl.
The compounds 7 and 8 are new compounds while 9/9H have previ-
ously been generated in situ using the optically pure (1S,2R)-ligand
enantiomer [17]. The tetramethyl complex (8) and meso-diphenyl
complex (9) are both extremely air-sensitive when dissolved in
organic solvents, but can with the rigorous exclusion of oxygen
be held in solution for weeks while maintaining their catalytic
activity. All three 16 electron complexes can be isolated as solids
in very good to excellent yields and their identity and elemen-
tal composition is confirmed by high-resolution ESI mass spectra
[22]. Complexes 7 and 8 give well defined 1H and 13C NMR spec-
tra C6D6 and CD2Cl2, respectively, but the red solution of complex
9 in CD2Cl2 gives complex spectra showing a mixture of differ-
ent species with four hydride peaks at −5.65, −5.87, −6.26 and
−6.39 ppm (see Supplementary Material for images of NMR spec-
tra of all three complexes). An integration of the hydride signals
against all other protons present indicates that ∼22% of complex 9 is
present in a hydride form, suggesting partial reaction to several dif-
ferent hydride complexes via a ␤-hydride elimination pathway (cf.
Scheme 3). Complex 9 thus did not match our prediction of being
resistant to ␤-hydride eliminations and behaves differently than
the corresponding optically pure (1S,2S)-N-p-tolulenesulfonyl-1,2-
diphenyl-1,2-diaminoethane based complexes with anti oriented
phenyl substituents that result in well defined spectra and allowed
a rare X-ray crystallographic structure determination of a 16-
electron complex [8]. However, in contrast to complexes 2 and 3,
Hydrogen transfer reaction under reducing and oxidizing con-
ditions were carried out with a series of representative secondary
alcohol/ketone pairs and the tetramethyl complex (8) as the
catalyst. Standard conditions for the oxidation reactions were
again alcohol (1.0 mmol, 0.20 M) in 5.0 mL degassed acetone with
Scheme 5. Ortho-diaminobenzene acting as a non-innocent ligand on complex 7.

8
M. Bierenstiel et al. / Journal of Molecular Catalysis A: Chemical 290 (2008) 1–14
Fig. 2. Transfer dehydrogenation of secondary alcohols to ketones by 8.
Fig. 3. Transfer hydrogenation of ketones to secondary alcohols by 8.
0.010 mmol (1 mol%) ruthenium complex 8 at ambient temperature
and Ar atmosphere and cis-decalin as the internal GC standard. The
results of these oxidation reactions are shown in Fig. 2. The reduc-
ing conditions employed the same concentrations as the oxidizing
conditions, but with ketone substrate in iso-propanol solvent. The
results of the reductions are shown in Fig. 3. Under reducing con-
ditions with iso-propanol as solvent and hydrogen source, the
reaction mixture was yellow. In contrast, under oxidizing condi-
tions the colour was deep purple.
The catalytic hydrogen transfer activity of 8 under reducing con-
dition is much lower compared to the TON and TOF for 1, 2, or
3 reported by Noyori and co-workers, which reported a quanti-
tative reduction of acetophenone to 1-phenyl-ethanol within 24 h
[9,18]. The lower activity is likely a result of the steric hindrance
by the four methyl groups present on the ethylene backbone in
8. As shown in Fig. 3, cyclohexanone and ␤-tetralone were quan-
titatively reduced to their corresponding alcohols within ∼5 d at
room temperature and a 1 mol% catalyst load in iso-propanol sol-
vent. After 14 d acetophenone reacted to 95%, cyclopentanone 52%
and ␣-tetralone 37% to their corresponding alcohols. Under oxidiz-
ing conditions (Fig. 2) the order of reactivity is reversed compared to
the reducing conditions and the catalytic activity is even lower and
no quantitative oxidation of any substrate was observed even after
14 d. The 1-phenyl-ethanol content after 14 d is 69% compared to
82% of cyclopentanol. In order to probe the temperature response
of catalyst 8, reactions with the cyclohexanone/cyclohexanol and
␣-tetralone/␣-tetralol substrate pairs were carried out under both
reducing and oxidizing conditions at 22 and 50 ◦C. The data in
Table 2 summarizes the results of these reactions. Under both oxi-
dizing and reducing conditions the overall conversions of alcohol or
ketone starting material of the hydrogen transfer reactions as well
as the conversion after 24 h were increased at the elevated tem-
perature. However, even at the higher temperature cyclohexanol
was only 5% converted after 7 d compared to 3% after 7 d at room
temperature.
Noyori and co-workers reported that the reduction of ketone
substrates in iso-propanol solvent is first order with regards to the
ketone. Similarly, the oxidation of allylic and benzylic alcohols in
acetone solvent was first order in alcohol [13]. Thus assuming a
Table 2
Comparison of the performance of the ruthenium catalyst 8 under oxidizing and reducing conditions with complementary substrate/solvent pairs at 22 and 50 ◦C
Entry
1
Alcohola
Temperature (◦C)
Conversionb (%)
1% (24 h)
Entry
5
Ketonec
Temperature (◦C)
22
Conversiond (%)
50% (24 h)
22
3% (7 d)
98% (7 d)
2% (24 h)
6
7
8
50
22
50
75% (24 h)
2
3
50
22
50
5% (7 d)
96% (48 h)
4% (24 h)
15% (24 h)
63% (7 d)
24% (7 d)
4% (24 h)
29% (24 h)
4
85% (7 d)
28% (7 d)
a
Reaction conditions: 1.0 mmol alcohol, 0.010 mmol 8 and cis-decalin (∼50 mg) in 5.0 mL acetone under Ar atmosphere.
Determined by quantitative GC of produced corresponding ketone.
Reaction conditions: 1.0 mmol ketone, 0.010 mmol 8 and cis-decalin (∼50 mg) in 5.0 mL iso-propanol under Ar atmosphere.
Determined by quantitative GC of produced corresponding alcohol.
b
c
d

M. Bierenstiel et al. / Journal of Molecular Catalysis A: Chemical 290 (2008) 1–14
9
Table 3
Rate constants for the catalytic alcohol/ketone transfer de/hydrogenation by 8 in acetone/iso-propanol solvent assuming a pseudo first order rate law
a,c
b,c
Entry
Alcohol/ketone
Temperature [◦C]
Rate constant oxidation [s−1
]
Rate constant reduction [s−1
]
1
22
9.4 × 10−8
6.4 × 10−7
2
22
2.3 × 10−8
6.3 × 10−6
3
4
50
22
9.9 × 10−8
1.9 × 10−7
1.9 × 10−5
1.4 × 10−6
5
6
22
5.5 × 10−7
2.3 × 10−7
50
22
3.6 × 10−6
4.5 × 10−8
5.7 × 10−7
1.7 × 10−6
7
a
Reaction conditions: 1.0 mmol alcohol, 0.010 mmol 8 and cis-decalin (∼50 mg) in 5.0 mL acetone under Ar atmosphere.
b
c
Reaction conditions: 1.0 mmol ketone, 0.010 mmol 8 and cis-decalin (∼50 mg) in 5.0 mL iso-propanol under Ar atmosphere.
Determined from quantitaive GC measurements and semi natural logarithmic plot of ln (concentration of product) vs. time [s].
pseudo first order rate law in alcohol under oxidizing condition and
pseudo first order rate law in ketone under reducing condition we
determined the corresponding rate constants from the concentra-
tion vs. time plots of the substrates as determined by quantitative
GC (Figs. 2 and 3). Comparing the rate constants of the respec-
tive alcohol and ketone substrate pairs (Table 3) shows that the
rates of the reductions are generally one to two orders of magni-
tude faster than the corresponding rates of oxidation. The exception
is the ␣-tetralol/␣-tetralone pair for which the oxidation reaction
is markedly faster than the reduction, a fact that must be related
to the formation of a benzylic conjugated carbonyl function upon
oxidation of the alcohol. The implications of this phenomenon are
discussed in greater detail in later sections (vide infra).
The tetramethyl complex 8 was also tested in the oxidation of
cis-and trans-1,2-cyclohexanediol as the substrate (1.0 mmol) in
5.0 mL acetone and cyclohexanone solvent at room temperature
under Ar atmosphere. However, after 7 d only trace amounts (<2%)
of iso-propanol or cyclohexanol as well ␣-hydroxy-cyclohexanone
substrate were detected. The reactivity of the diol substrate was
in the same range as the oxidation of the cyclohexanol model sys-
tem and thus further studies were focussed on the oxidation of the
cyclohexanol model system.
and 84% after 14 d at room temperature. In contrast, the reduction
of ␣-tetralone yielded no reaction after 24 h and only 14% after 14 d.
While the tetramethyl complex 8 is stable in solution for 3–4 weeks
the diphenyl complex 9 starts to decompose after 2 weeks and
a brown precipitate appears, presumably formed via the already
discussed ␤-hydride elimination pathways.
3.6. Investigations into the coordinative inhibition of 16 electron
complexes
We hypothesized that one possible reason for the slower oxi-
dation reaction could be a coordinative inhibition of the catalysts
(8 and 9) under oxidizing conditions through coordination of ace-
tone or cyclohexanone solvent towards the Ru metal centre or
amide/amine functionality of the catalyst (Chart 4). Coordination
1
2
of acetone can in principle occur through an ␩ or ␩ coordina-
tion of the C O function, both of which have been shown to occur
at various metal centres [23,24], or by enolization of the acetone
and cooperative coordination of the resulting C C double bond and
hydroxyl function.
Complex 9 was tested with the same cyclohexanol/cyclo-
hexanone and ␣-tetralol/␣-tetralone substrate pairs under oxidiz-
ing and reducing conditions using the same standard concentra-
tions of 1.0 mmol substrate in 5.0 mL solvent, 1.0 mol% catalyst load
and cis-decalin as the internal GC standard. Cyclohexanol was oxi-
dized to cyclohexanone after 24 h only in trace amounts (<1%) and a
2% content was detected after 14 d at room temperature. In contrast,
the same catalyst is much more active under reducing conditions
68% of cyclohexanone were reduced to cyclohexanol after 24 h, 88%
after 48 and 95% after 72 h at room temperature. Under oxidizing
conditions, ␣-tetralol was oxidized to ␣-tetralone in 20% after 24 h
Chart 4. Conceivable inhibition of the catalyst through acetone-d6 coordination.

10
M. Bierenstiel et al. / Journal of Molecular Catalysis A: Chemical 290 (2008) 1–14
This hypothesis was investigated by a series of NMR experi-
ments. A sample of complex 8 was prepared in acetone-d6 and
scrambling of the amide proton (7.3 ppm) was observed at ambient
temperature in less than 24 h. In benzene-d6 and CD2Cl2 solvent
no scrambling was observed. All three solutions remained purple
in a sealed NMR tube for over 2 months at ambient temperature
and no decomposition was observed. In CDCl3 the complex decom-
posed to black precipitate after one week at room temperature.
The scrambling of the amide proton can be explained through a
rapid D/H exchange of acetone-d6 with the amide through ketone-
Scheme 6. Generic hydrogen-transfer reaction for calculation of ꢀG◦.
range or lower than 1600 cm−1 could be observed. On the basis
of NMR and IR evidence we therefore conclude that the Ru cen-
tre of 8 is inert towards coordination by the acetone solvent
and that the observed lower catalytic activity of the tetramethyl
Ru complex in the oxidation reaction cannot be attributed to an
inhibition of the 16-electron species by the surrounding ketone
solvent.
enol tautomerism of acetone in solution or through a possible
2
␩
coordination of the acetone enol to the Ru and NH moiety as
shown in Chart 4. To further test this hypothesis, a low temper-
ature 2H NMR experiment with 8 was carried out in acetone-d6
solvent at 400 MHz aiming to observe any olefinic signals of the
complexed enol form of acetone. The sample was cooled to −80 ◦C
and continuously shimmed observing the 2H solvent signal. The
sample was then allowed to thermally equilibrate at −80 ◦C for
15 min and the 2H spectrum was recorded, however no olefinic
2H signals were observed in the 3–6 ppm range. This means that
the either there is no exchange of D/H with the amide function
through the postulated ꢂ2 coordination mechanism or it occurs so
rapidly that even at −80 ◦C that the exchange of formed enol–Ru
complex and surrounding acetone is still too fast to be observed
on the time scale of the NMR experiment. To test for coordina-
tion of the non-enolized form of a ketone solvent, a 13C NMR
experiment was carried out with the same sample as well as cyclo-
hexanone and complex 8. For the second sample 30 mg of the
16-electron complex 8 was dissolved in 0.6 mL CD2Cl2, ten equiv-
alents of cyclohexanone added and the 13C NMR spectra recorded
at room temperature. The 13C NMR resonance of a carbonyl car-
bon complexed to a metal centre typically occur in the normal
3.7. Thermodynamic investigations and models
In the absence of evidence for any coordinative inhibition of
the catalysts under oxidizing conditions, our investigations cen-
tered on a thermodynamical approach in order to explain the
slower oxidation vs. reduction rates. A full kinetic analysis aimed
at gaining further insights into the reaction parameters was not
attempted on the basis of the following considerations: As illus-
trated in Scheme 1, there exist two distinct resting states of the
catalysts system in solution, the hydrogen deficient 16-electron
complex 8 and the hydrogen loaded 18 electron complex 8H.
Effectively, there are therefore two different catalysts at different
concentrations present in solution at any given time, the rela-
tive concentrations of which are a function of the redox potential
and concentration of the participating alcohol/ketone pairs (both
substrate and solvent). Determining these concentrations consti-
tutes a major challenge to developing any kinetic model and to
our knowledge no complete kinetic model and rate law taking
this fact into account is available for the Noyori system. In conse-
quence, we focused on thermodynamic parameters only, beginning
with thermochemical calculations of the free reaction enthalpies of
the isodesmic hydrogen transfer reactions. As the literature avail-
ability of experimental ꢀG◦ values for the ketone/alcohol pairs
selected by us is very limited, the relative free energies of the
participating alcohol and ketone substrate with acetone and iso-
propanol were determined through Gaussian 03 calculations by
density functional theory [25]. The standard free energy of the
transfer (de)hydrogenation of each alcohol with the acetone/iso-
propanol pair, i.e., ꢀG◦, was calculated for the generic reaction
shown in Scheme 6 and the equilibrium constants were calculated
from ꢀG◦ = −RT ln K at 298 K.
1
downfield range of carbonyl resonances for ␩ coordination but
the resonances for ␩2 coordinated carbonyl groups are observed in
the upfield range of 45–110 ppm [23]. However, even with exten-
sive data aquisition (4000 scans) no carbonyl resonances shifted
from those of free cyclohexanone (211.5 ppm) could be observed in
either experiment. In conclusion, all experimental NMR evidence
suggested that the exchange of the NH-proton occurs very rapidly
at room temperature and even −80 ◦C is too fast to be observed
on the NMR time scale. In the 13C and low temperature 2H NMR
experiment, no additional signals other than the free ketone were
observed. NMR thus fails to provide any evidence for a coordina-
tive inhibition of the 16-electron complex of 8 and 9 under oxidizing
conditions.
In order to correlate the calculated ꢀG◦ results with the reaction
actually carried out, ꢀGreaction was calculated for the conditions
using Eq. (1) shown below. The initial concentration of alcohol sub-
strate was 0.2 M and acetone solvent is present at 13.6 M. Plots of
ꢀGreaction vs. the concentration of produced ketone are shown in
Fig. 4.
In a corresponding IR experiment that in principle allows the
investigation of carbonyl coordination to a metal centre on much
faster time scales, the ꢁC
stretching frequency of acetone can
O
1
be used as a sensitive probe for coordination of acetone in a ␩
2
1
or ␩ fashion, however ␩ coordination of a ketone to a metal
centre lowers the ꢁC
with ␩ coordination of ketone to a metal centre the ꢁC
usually less than 100 cm−1. In contrast,
O
2
is
O
ꢀGreaction = ꢀG◦ + RT ln Q,
observed in the range of 1017–1160 cm−1 due to the loss in bond
order in carbon–oxygen bond [23,24]. One to ten equivalents of
acetone were added to a dichloromethane solution containing
complex 8 in a CaF2 cell with 0.2 mm optical path length. No
[ketone][isopropanol]
[alcohol][acetone]
Q =
,
x2
shift of the ꢁC
frequency was observed when comparing the
O
[ketone]produced = [isopropanol]produced =: x =
,
[0.2 − x][13.6 − x]
IR spectrum of this sample to reference IR spectra of acetone or
complex 8 recorded in dichloromethane. In another IR experi-
ment complex 8 (10 mg) was dissolved in neat acetone (0.5 mL)
and the IR spectrum was recorded using a cell with a very small
(15 ␮m) optical path length. Even with this very short optical
[alcohol]initial = 0.2 M, [acetone]initial = 13.6 M, T = 298 K
(1)
The calculated ꢀGreaction values for the majority of the
alcohol and ketone substrate pairs pass through and cluster
around the zero-line, i.e., they are essentially thermoneutral.
However the values for the ␣-tetralol/␣-tetralone, 1-phenyl-
path length, the intensity of the ꢁC
stretching frequency was
O
too strong so that the maximum bottomed out between 1707
and 1715 cm−1. Again no shifted signal in the 1600–1700 cm−1

M. Bierenstiel et al. / Journal of Molecular Catalysis A: Chemical 290 (2008) 1–14
11
since the calculation of the ꢀGreaction values involves taking the
differences of the absolute ꢀG values for an isodesmic reac-
tion, it is reasonable to assume that the errors cancel out at
least partially minimizing their effect on the relative results (see
below for a direct comparison of theoretical with experimental
results).
From the experimental data (Tables 2 and 3) it is apparent that
the reactions possessing a very negative ꢀG◦ value in either oxi-
dation or reduction direction were faster than those with lower
ꢀG◦ values. This observation suggests a relationship similar to the
Hammond postulate, i.e., for the hydrogen transfer reaction under
investigation, ꢀG‡ is correlated to ꢀG◦. With our observation that
the resting state of the catalyst is dependent on the redox envi-
ronment of the reaction partners involving solvents and alcohol
and ketone substrates, the actual rate of reaction is then a super-
position of the oxidation and reduction parameters for each of
the two catalytically active species, i.e., one would expect sub-
stantially different rates for the forward and reverse reaction. As
mentioned previously we refrained from trying to develop a full
kinetic model for the Noyori system, as it would require a simul-
taneous knowledge of the actual relative concentrations of the
two active catalysts species and the pairs ketones and alcohols
present, which experimentally is difficult to realize [26]. In order
to at least qualitatively detect the relative concentration of 8 in its
16-electron or 18-electron hydrogen loaded form, a simple exper-
iment was carried out inside a glove-box under Ar atmosphere.
Three solutions of 8 (5.0 mg) were prepared using (A) 5.0 mL ace-
tone, (B) 5.0 mL iso-propanol and (C) a mixture of iso-propanol
(2.5 mL) and acetone (2.5 mL). The acetone solution (A) was deep
blue-purple coloured. The iso-propanol solution (B) was orange-
yellow coloured after approximately 15 min at room temperature
and the 1:1 acetone: iso-propanol mixture (C) was dark red-purple
coloured. After addition of iso-propanol (1.0 mL) to (A) the colour
changed slightly to a reddish-purple similar to the solution (C).
A similar colour resulted in addition of acetone (1.0 mL) to (B).
After addition of 15 mL of iso-propanol i.e. a 1:20 mixture acetone:
iso-propanol, the colour intensity reduces due to concentration
effect but there is no change back to a yellow colour. Addition of
15 mL acetone to (A) produced a deep purple solution with a taint
of red. We therefore concluded that the 16-electron complex is
the predominant species in any iso-propanol/acetone solvent mix-
ture.
Fig. 4. ꢀGreaction calculated from DFT calculations as a function of produced ketone
in acetone solvent from the corresponding alcohols. (ꢀ) ␣-tetralone/tetralol, (♦)
cyclopentanone/cyclopentanol, (ꢀ) acetophenone, 1-phenyl-ethanol.
ethanol/acetophenone and cyclopentanol/cyclopentanone pairs
indicated in Fig. 4 are distinctively more negative suggesting that
the equilibrium constitutes a quantitative oxidation of the alco-
hol to the corresponding ketone. These results are in principle
congruent with the experimental values shown in Fig. 2, how-
ever the equilibrium for theses reactions had not been reached
after 14 d. The results of the DFT calculations of ꢀGreaction for
the reaction involving the reduction of ketones (0.2 M) in 5.0 mL
iso-propanol (13.1 M) are displayed in Fig. 5 and also show a
good correlation to the experimental data (Fig. 3). The reduc-
tion of ␣-tetralone is thermodynamically unfavoured and only a
marginal ␣-tetralol content can be obtained at the equilibrium.
The reductions of cyclopentanone and acetophenone are not as
favoured as the other calculated ketone substrates, but the plots
suggest that a quantitative conversion can be obtained at equilib-
rium.
Since the DFT calculations were carried out on the 6–31/g(d)
level for the gas phase environment a finite error must be attributed
to the calculated values. In solution hydrogen bonding does occur
especially in iso-propanol solvent which further affects the min-
imum energies and will influence the ꢀGreaction values. However
The kinetic data analysis was limited to determining the initial
rates for the reaction, for which in a first approximation the reactant
concentrations are known. Within this ultimately thermodynamic
approach to the problem, there is however one single situation
where there is no need in knowing the actual kinetic law of the
reaction in order determine a correlation between ꢀG◦ and initial
rates. This situation arises, when both the oxidized and reduced
substrate as well as the oxidizing and reducing solvent are present
in equal concentrations [27]. At time t = 0 this is a condition easily
realized experimentally. As expressed by Eq. (2), ꢀGreaction equals
ꢀG◦ at tinitial = 0, when the concentration of ketone and alcohol
substrate as well the concentrations of acetone and iso-propanol
solvent are set to be equal. Through cancellation of the respective
concentration values Q is 1 and hence ln Q is zero. The combined
ketone and alcohol concentration was set to 0.2 M with 0.010 mmol
ruthenium catalyst in order to be able to compare results with the
experimental and calculated data for the oxidation or reduction
reactions. Another advantage of the equal concentration experi-
ment is the direct experimental determination of ꢀG◦ from the
substrate and reactant concentration (by quantitative GC analysis)
once the equilibrium has been established. The error margin for this
determination is low as neither the numerator nor the denominator
of the equilibrium constant equation, K is close to zero.
Fig. 5. ꢀGreaction calculated from DFT calculations as a function of produced alcohol
in iso-propanol solvent from the corresponding ketone. (ꢀ) ␣-tetralone/tetralol, (♦)
cyclopentanone/cyclopentanol, (ꢀ) acetophenone, 1-phenyl-ethanol.

12
M. Bierenstiel et al. / Journal of Molecular Catalysis A: Chemical 290 (2008) 1–14
(2)
For the special situation of equal initial concentrations of all
measurements of the alcohol/ketone substrate concentration. The
standard free energy, ꢀG◦ can then be determined experimen-
tally through calculation of the equilibrium constant K when the
hydrogen transfer reaction has reached its equilibrium stage, i.e.,
the concentrations of the reactants do no longer change with time
[28].
The initial rates also obtained from the equal concentration
experiments are listed in Table 4 and are based on the observed
production or consumption of alcohol substrate, i.e., under overall
reducing condition ketone substrate reacts to the corresponding
alcohol substrate. Thus the initial rate is >0. A “negative” initial
rate in alcohol substrate indicates that the overall reaction favours
the consumption of alcohol, i.e., oxidation of the alcohol substrate
redox substrate pairs, it can also be assumed that the rate law for the
forward reaction (Eq. (3)) and the rate law of the backward reac-
tion (Eq. (4)) are only a function of the concentrations of ketone
and alcohol and catalyst in its hydrogen loaded and unloaded form,
respectively.
rforward (t = 0) = kforward × [ketone]initial × [cat-H2]
rreverse (t = 0) = kreverse × [alcohol]initial × [cat]
(3)
(4)
In this situation, the free energy of the hydrogen transfer reac-
tion of a given alcohol/ketone substrate pair can therefore be
visualized experimentally. The overall direction of the hydrogen
transfer reaction can easily be determined by quantitative GC
Table 4
Initial rates and ꢃGe◦xpof equal concentration reactions with ruthenium catalysts 8 and 9
Entry Alcohol/ketone
Tetramethyl catalyst (8)
Entry
Diphenyl catalyst (9)
b
d
ꢀGexp 5% ꢀGexp
Initial rate [10−9 mol L−1 s−1
]
ꢀGexp 5% ꢀGexp
Initial rate [10−9 mol L−1 s−1
]
[kJ mol−1
]
[kJ mol−1
]
a
c
1
2
−0.03 0.50
−1.3 0.5
9
−0.35 0.51
−4.6 12
1.18 0.52
76 10
10
1.05 0.52
229 22
3
4.45 0.87
127 14
11
4.66 0.91
235 35
4
5
−10.32 4.58
−223 16
12
13
−3.33 0.83
−257 40
2.96 0.65
158 27
0.97 0.52
103d
30
6
−1.69 0.59
−24 10
14
−0.20 0.50
−2.6 6.0
7
8
−11.46 4.58
−11.46 4.58
−281 14
−332 20
15
16
−1.78 0.59e
−5.72 1.86
−150 10
−476 10
Reaction conditions: 0.50 mmol alcohol, 0.50 mmol ketone, 32 mmol acetone (2.3 mL), 32 mmol iso-propanol (2.4 mL), cis-decalin (∼50 mg) and 0.010 mmol 8 or 9 at room
temperature under Ar atmosphere.
a
For error calculation see Supplementary Material.
Error determined from first order exponential approximation.
Approximated by first two data points.
Catalyst decomposition after 7 d.
b
c
d

M. Bierenstiel et al. / Journal of Molecular Catalysis A: Chemical 290 (2008) 1–14
13
reducing conditions, i.e., in excess alcohol solvent, the rate deter-
mining step occurs between the ketone substrate and the hydrogen
loaded complex. Thus even though the overall reaction is a gen-
uine equilibrium, the presence of two distinct active catalysts
for the forward and reverse reactions gives rise to distinct reac-
tion pathways with different activation barriers explaining the
marked differences in reactivity in oxidation vs. reduction hydro-
gen transfer reactions. This difference in reactivity as well as an
apparent inverse correlation between the initial rates of oxida-
tion with the ꢀGreaction for hydrogen transfer reactions under
oxidizing conditions, also renders the Noyori type system unsuit-
able for the catalytic synthesis of ␣-hydroxy-ketones from vicinal
diols.
Supplementary data
Fig. 6. Graph of initial rate vs. ꢀG◦
ruthenium catalysts 8 and 9.
of equal concentration experiment with
Details and numeric results of thermochemical DFT calculations
and equal concentration experiments. NMR data and spectrum
images for all new ligands and complexes synthesized.
exp.
Acknowledgements
occurs. To evaluate the reliability of the initial rate constant, the
standard deviation of the first order exponential fit of alcohol con-
tents were used to calculate the error margins of the initial rates
with a very conservative confidence interval. The initial rates also
obtained from the equal concentration experiments were plotted
against the experimental ꢀG◦ value in order to visualize a poten-
tial relationship (Fig. 6). A linear regression was calculated for both
ruthenium catalysts giving a correlation factor, R2, of 0.92 and 0.89
respectively.
Funding for this research project was provided by University of
Guelph, the Canadian Natural Science and Engineering Research
Council (NSERC) and the Canadian Foundation for Innovation (CFI).
M.B. would like to thank the Ernst Schering Research Foundation,
Berlin, Germany for a doctoral stipend.
Appendix A. Supplementary data
As the much faster oxidation of the secondary alcohols lead-
ing to the thermodynamically favoured ␣, ␤-unsaturated ketone
shows, there clearly is a correlation between the thermodynamic
driving force of the transfer dehydrogenation reactions and their
relative rates. Asthegraphs in Fig. 6 suggest the correlation between
the initial rates and ꢀG◦ values is in fact linear, however no linear
relationship between the logarithms of the rate constants and ꢀG◦
values – as would be expected for a classic linear free enthalpy rela-
tionship – was found and at present we have no theoretical model
to explain these results.
Supplementary data associated with this article can be found,
in the online version, at doi:10.1016/j.molcata.2008.05.009.
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M. Bierenstiel et al. / Journal of Molecular Catalysis A: Chemical 290 (2008) 1–14
[25] Details of the calculation parameters as well as the numerical results are given
in the Supplementary Material.
[26] NMR spectroscopy would be a logical choice here. However in our experi-
ence overlapping signals even at fields >400 MHz make the required accurate
quantitation by integration effectively impossible.
[27] By using equal concentration for all reactants including solvents, the reac-
tion is set-up in neutral. Thus depending on its ꢀG◦ value the reaction itself
determines if it “wants” to proceed into an oxidizing or reducing direction.
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ketone/alcohol pairs are contained in the Supplementary Material.