Molecular structure effects in the asymmetric transfer hydrogenation of functionalized dihydroisoquinolines on (S,S)-[RuCl(η 6-p-cymene) TsDPEN]

Article abstract of DOI:10.1007/s10562-013-0996-4

The asymmetric transfer hydrogenation of five dihydroisoquinolines (DHIQs) was studied by NMR spectroscopy. The DHIQs differed by substitution with methoxy groups, which had a significant effect upon the reaction performance in terms of reaction rate and enantioselectivity. The differences are most probably related to the basicity of DHIQs.

Full text of DOI:10.1007/s10562-013-0996-4

Catal Lett (2013) 143:555–562
DOI 10.1007/s10562-013-0996-4
Molecular Structure Effects in the Asymmetric Transfer
Hydrogenation of Functionalized Dihydroisoquinolines
on (S,S)-[RuCl(g6-p-cymene)TsDPEN]
•
Jirı Vaclavık Jan Pechacek Beata Vilhanova
•
•
ˇ´
Petr Sot Jakub Januscak Vaclav Matousek Jan Prech
´
´
´ ˇ
´
´
ˇ
•
•
•
•
ˇˇ´
Simona Bartova Marek Kuzma Petr Kacer
´
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ˇ
•
•
´
´
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Received: 18 January 2013 / Accepted: 17 March 2013 / Published online: 2 April 2013
Ó Springer Science+Business Media New York 2013
Abstract The asymmetric transfer hydrogenation of five
dihydroisoquinolines (DHIQs) was studied by NMR spec-
troscopy. The DHIQs differed by substitution with meth-
oxy groups, which had a significant effect upon the reaction
performance in terms of reaction rate and enantioselectiv-
ity. The differences are most probably related to the basi-
city of DHIQs.
the linker and by the number and placement of methoxy
groups.
Substituted chiral THIQs usually invoke desirable
pharmacological effects only in the form of single enan-
tiomer [2]. The presence of the other optical isomer may
decrease the desired effect or even result in completely
different consequences. Given the number of synthetically
prepared active pharmaceutical ingredients (APIs) derived
from this cyclic structure (see below), the development and
optimization of sophisticated enantioselective methods of
their synthesis is sought-after.
Keywords ATH ꢀ Kinetics ꢀ Imines ꢀ NMR ꢀ Bader
1 Introduction
Asymmetric transfer hydrogenation (ATH) conducted
on ruthenium organometallic compounds maintains a solid
position among such methods and extensive research is
undertaken in this direction [3]. Among the most frequently
used catalysts lies Noyori’s half-sandwich complex (S,S)-
[RuCl(g6-p-cymene)(N-p-toluenesulfonyl-1,2-diphenyleth-
ylene-1,2-diamine)], which in the presence of a HCOOH/
triethylamine mixture (H2-donor) efficiently reduces dihy-
droisoquinolines (DHIQs) and thus affords enantiopure
(R)-THIQs [4, 5].
Isoquinoline-based molecules lie within the most important
naturally-occurring alkaloids and form a significant group
of biologically active species. These compounds have
various pharmacological effects, which are enabled by their
structural similarity with endogenous neurotransmitters.
For example, 1-Me-3,4-THIQ is known to have antipar-
kinsonian effects and its methoxylated derivatives have
also been studied in this regard [1]. The tetrahydroiso-
quinoline (THIQ) building block is also found in the
structures of non-depolarizing neuromuscular-blocking
agents such as atracurium, cisatracurium, doxacurium, and
mivacurium, which differ from each other by the length of
In this work, a kinetic NMR study of ATH of five dif-
ferent DHIQs was performed. Their structures differ by
various methoxy-substitutions of the DHIQ skeleton. The
fifth examined substrate is a precursor for the production of
aforementioned mivacurium [6].
ˇ
´
´
ˇ
´ˇ
´
ˇˇ´
J. Vaclavık ꢀ J. Pechacek ꢀ B. Vilhanova ꢀ P. Sot ꢀ J. Januscak ꢀ
ˇ
ˇ
V. Matousek ꢀ J. Prech ꢀ P. Kacer (&)
2 Experimental
Department of Organic Technology, Institute of Chemical
´
Technology, Technicka 5, 166 28 Prague 6, Czech Republic
e-mail: kacerp@vscht.cz
2.1 Instrumentation
´
´
S. Bartova ꢀ M. Kuzma
NMR spectra were acquired using spectrometers Varian
UNITYInova-400 (1H 399.89 and 13C 100.55 MHz) and
Bruker Avance III 400 MHz (1H 400.00 and 13C
Laboratory of Molecular Structure Characterization, Institute
of Microbiology, v.v.i., Academy of Sciences of the Czech
´ ˇ ´
Republic, Vıdenska 1083, 142 20 Prague 4, Czech Republic
123

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J. Vaclavık et al.
556
100.58 MHz). 1H and 13C NMR spectra of substrates were
measured in chloroform, whose residual signals (dH
7.265 ppm, dC 77.00 ppm) were used as internal standards
for the chemical shift scale. Reaction kinetics were measured
in CD3CN (dH 1.931 ppm). Standard software was used, as
supplied by the manufacturers (Varian Inc., Palo Alto,
U.S.A., or Bruker BioSpin GmbH, Rheinstetten, Germany).
Gas chromatography was conducted on Varian CP-3800
with a flame ionization detector (FID) equipped with a non-
polar 60 m column (Varian VF-1) with the inner diameter
of 0.25 mm and a polydimethylsiloxane stationary phase
(0.25 lm). Nitrogen was used as a carrier gas.
water (200 mL) after cooling down to room temperature.
The solution was acidified by addition of concentrated
hydrochloric acid (20 mL). The aqueous phase was sepa-
rated and washed with toluene (3 9 40 mL). Solid impuri-
ties were removed by filtration and the solution was alkalized
with concentrated solution of sodium hydroxide (280 g) in
water. The product precipitated in the form of a milky
emulsion, which was extracted with toluene (5 9 40 mL).
Combined organic extracts were washed with water (50 mL)
and brine (50 mL), dried over anhydrous magnesium sulfate
and concentrated on a rotary evaporator (10 torr, bath temp
65 °C). The obtained brown oil was distilled under reduced
pressure (120 °C, 8 torr) to afford the product in the form of
1
2.2 Chemicals
slightly yellowish oil. Yield of 1: 5.2 g, 49 %. H NMR
(400.00, MHz, CDCl3, 303.2 K): d 2.374 (3H, t, J = 1.5 Hz,
1-CH3), 2.689 (2H, m, H-4), 3.652 (2H, tq, J = 7.5, 1.5 Hz,
H-3), 7.163 (1H, m, H-5), 7.275 (1H, m, H-7), 7.323 (1H,
ddd, J = 7.4, 7.4, 1.4 Hz, H-6), 7.462 (1H, dd, J = 7.6,
1.4 Hz, H-8). 13C NMR (100.58 MHz, CDCl3, 303.2 K): d
23.17 (1-CH3), 25.96 (C-4), 46.85 (C-3), 125.19 (C-8),
126.78 (C-7), 127.32 (C-5), 129.49 (C-8a), 130.45 (C-6),
137.32 (C-4a), 164.14 (C-1).
Phenethylamine, 2-(3-methoxyphenyl)-ethylamine, 2-(4-
methoxyphenyl)-ethylamine, 2-(3,4-dimethoxyphenyl)-eth-
ylamine, phosphorusoxychloride, tetraphosphorusdecaoxide,
triethylamine, formic acid, (1R)-(-)-menthyl chlorofor-
mate, (R)-(-)-(2,2,2-trifluoro-1-(9-anthryl)ethanol) and(S,S)-
[RuCl(g6-p-cymene)(N-Ts-diphenylethylenediamine)] were
purchased from Sigma-Aldrich (Steinheim, Germany). N-[2-
(3,4-dimethoxyphenyl)ethyl]-3,4,5-trimethoxyphenylacetamide
was obtained from CMS Chemicals. Ethanol, methanol,
diethyl ether, xylene, toluene and chloroform were obtained
from Penta (Czech Republic), CDCl3 and CD3CN from
Chromservis (Czech Republic).
2.3.2 6-Methoxy-1-methyl-3,4-dihydroisoquinoline (2)
N-[2-(3-methoxyphenyl)ethyl]acetamide was prepared
from 2-(3-methoxyphenyl)ethylamine (5.0 g, 33 mmol)
using the same procedure like for the synthesis of
N-(2-phenylethyl)acetamide. Yield of N-[2-(3-methoxy-
phenyl)ethyl]acetamide: 6.1 g, 96 %.
2.3 Synthesis of Substrates
The compounds were synthesized by Bischler–Napieralski
cyclization [7] of related amides, which were prepared by
acylation of starting amines.
N-[2-(3-methoxyphenyl)ethyl]acetamide
(12.0 g,
62.1 mmol) was used for the preparation of 6-methoxy-1-
methyl-3,4-dihydroisoquinoline following the same pro-
cedure like for the synthesis of 1-methyl-3,4-dihydroiso-
quinoline. Yield of 2: 6.6 g, 61 %. 1H NMR (400.00, MHz,
CDCl3, 303.2 K): d 2.374 (3H, t, J = 1.5, 1-CH3), 2.701
(2H, m, H-4), 3.642 (2H, m, H-3), 3.836 (3H, s, 6-OCH3),
6.705 (1H, m, H-5), 6.792 (1H, m, H-7), 7.435 (1H, m,
H-8). 13C NMR (100.58 MHz, CDCl3, 303.2 K): d 22.93
(1-CH3), 26.60 (C-4), 46.41 (C-3), 55.32 (6-OCH3), 111.96
(C-7), 112.84 (C-5), 122.92 (C-8a), 127.42 (C-8), 139.63
(C-4a), 161.45 (C-6), 164.42 (C-1).
2.3.1 1-Methyl-3,4-dihydroisoquinoline (1)
Phenethylamine (5.0 g; 41 mmol) and triethylamine
(7.3 mL, 51 mmol) were dissolved in dichloromethane
(150 mL). The reaction mixture was stirred and acetyl
chloride (3.6 mL; 50 mmol) was added dropwise during
15 min at 25 °C. The mixture was further stirred at 45 °C
for 30 min. Water was added to the reaction mixture,
which was cooled to room temperature. The organic phase
was separated, washed with 5 % hydrochloric acid
(100 mL), 5 % solution of sodium carbonate (100 mL) and
water (100 mL), then dried over anhydrous magnesium
sulfate and concentrated on a rotary evaporator (10 torr;
60 °C). The product was obtained in the form of honey-like
oil. Yield of N-(2-phenylethyl)acetamide: 6.5 g, 97 %.
N-(2-phenylethyl)acetamide (12.0 g, 73.6 mmol) and
tetraphosphorus decaoxide (190 g, 0.67 mol) were dissolved
in dry xylene (250 mL) under argon atmosphere. The mix-
ture was stirred at 160 °C for 6 h and then hydrolyzed with
2.3.3 7-Methoxy-1-methyl-3,4-dihydroisoquinoline (3)
N-[2-(4-methoxyphenyl)ethyl]acetamide was prepared
from 2-(4-methoxyphenyl)ethylamine (5.0 g, 33 mmol)
using the same procedure like for the synthesis of N-(2-
phenylethyl)acetamide. Yield of N-[2-(4-methoxy-
phenyl)ethyl]acetamide: 5.3 g, 84 %.
N-[2-(4-methoxyphenyl)ethyl]acetamide(6.0 g,31 mmol)
and phosphorus oxychloride (14.5 mL, 155 mmol) were dis-
solved in dry xylene (150 mL) under argon atmosphere.
123

Molecular Structural Effects in Asymmetric Transfer Hydrogenation
557
The mixture was stirred at 160 °C for 3 h and then hydro-
lyzed with water (100 mL) after cooling down to room
temperature. The solution was acidified by addition of con-
centrated hydrochloric acid (15 mL). The aqueous phase
was separated and washed with toluene (3 9 30 mL). Solid
impurities were removed by filtration and the solution was
alkalized with concentrated solution of sodium hydroxide
(260 g) in water. The product precipitated in the form of a
milky emulsion, which was extracted with toluene
(5 9 40 mL) at 50 °C and then with diethyl ether
(2 9 50 mL) at 25 °C. Combined organic extracts were
washed with water (50 mL) and brine (50 mL), dried over
anhydrous magnesium sulfate and concentrated on a rotavap
(10 torr, bath temp 50 °C). The obtained brown oil was was
distilled under reduced pressure (120 °C, 1 torr) to afford the
product in the form of slightly yellowish oil. Yield of 3:
0.92 g, 17 %. 1H NMR (400.00, MHz, CDCl3, 303.2 K): d
2.315 (3H, t, J = 1.5 Hz, 1-CH3), 2.564 (2H, m, H-4), 3.579
(2H, tq, J = 7.5, 1.5 Hz, H-3), 3.760 (3H, s, 7-OCH3), 6.842
(1H, dd, J = 8.2, 2.6 Hz, H-6), 6.962 (1H, d, J = 2.6 Hz,
H-8), 7.031(1H, m, H-5). 13C NMR (100.58 MHz, CDCl3,
303.2 K): d 22.95 (1-CH3), 24.91 (C-4), 47.02 (C-3), 55.19
(7-OCH3), 111.20 (C-8), 115.40 (C-6), 127.93 (C-5), 129.19
(C-4a), 130.04 (C-8a), 158.28 (C-7), 163.90 (C-1).
Phosphorus oxychloride (47 mL, 500 mmol) was added
gradually over 30 min. The mixture was stirred at 100 °C
for 4 h. The volatiles were removed on a rotary evaporator
and a yellow solid was obtained, which was hydrolyzed
with water (100 mL). The solution was alkalized with
concentrated solution of sodium hydroxide (120 g) in
water. After reaching pH = 12, concentrated solution of
sodium sulfite (1.3 g, 10 mmol) was added to minimize the
oxidation of the product. The slurry was cooled down to
35 °C and extracted with chloroform (4 9 60 mL). Com-
bined organic extracts were washed with water
(2 9 30 mL), dried over anhydrous magnesium sulfate and
concentrated on a rotary evaporator (10 torr, bath temp
50 °C). Crude product (35 g) was obtained as a yellow
solid, which was recrystallized from methanol (150 mL).
1
Yield of 5: 22 g, 63 %. H NMR (400.00, MHz, CDCl3,
303.2 K): d 2.710 (2H, m, H-4), 3.745 (3H, s, 7-OCH3),
3.777 (2H, m, H-3), 3.853 (6H, s, 30,50-OCH3), 3.878 (3H,
s, 40-OCH3), 3.935 (3H, s, 6-OCH3), 6.776 (1H, s, H-5),
6.839 (1H, s, H-20), 6.864 (1H, s, H-8). 13C NMR
(100.58 MHz, CDCl3, 303.2 K): d 26.29 (C-4), 47.56 (C-
3), 56.15 (30,50-OCH3), 60.86 (40-OCH3), 106.00 (C-20),
126.52 (C-7), 127.39 (C-5), 127.84 (C-8), 128.45 (C-8a),
134.46 (C-10), 130.68 (C-6), 138.91 (C-4a), 139.02 (C-40),
152.89 (C-30, 50), 166.87 (C-1).
2.3.4 6,7-Dimethoxy-1-methyl-3,4-dihydroisoquinoline (4)
N-[2-(3,4-dimethoxyphenyl)ethyl]acetamide was prepared
2.4 Kinetic Experiments
from
2-(3,4-dimethoxyphenyl)ethylamine
(5.0 g,
Triethylamine and formic acid (i.e., the azeotropic mixture)
were pre-mixed (2:5) in CD3CN in an NMR tube and a 1H
NMR spectrum was measured in order to shim properly.
Catalyst dissolved in CD3CN was added in the tube and let
react with the azeotrope for 5 min, and the reaction was
started by adding the substrate solution thereto. The rubber
stopper was pierced to prevent pressure generation caused
by gases formed during the reaction. 1H NMR spectra were
acquired in regular 3–5 min intervals.
28 mmol) using the same procedure like for the synthesis
of N-(2-phenylethyl)acetamide. Yield of N-[2-(3,4-dime-
thoxyphenyl)ethyl]acetamide: 5.8 g, 94 %.
N-[2-(3,4-methoxyphenyl)ethyl]acetamide
(6.0 g,
27 mmol) was used for the preparation of 6,7-dimethoxy-
1-methyl-3,4-dihydroisoquinoline following the same pro-
cedure like for the synthesis of 7-methoxy-1-methyl-3,4-
dihydroisoquinoline. Yield of 4: 3.8 g, 68 %. 1H NMR
(400.00, MHz, CDCl3, 303.2 K):
d 2.331 (3H, t,
J = 1.5 Hz, 1-CH3), 2.603 (2H, m, H-4), 3.595 (2H, m,
H-3), 3.878 (3H, s, 7-OCH3), 3.885 (3H, s, 6-OCH3), 6.657
(1H, s, H-5), 6.956 (1H, s, H-8).). 13C NMR (100.58 MHz,
CDCl3, 303.2 K): d 23.34 (1-CH3), 25.63 (C-4), 46.90 (C-
3), 55.85 (6-OCH3), 56.09 (7-OCH3), 108.85 (C-8), 110.09
(C-5), 122.37 (C-8a), 130.99 (C-4a), 147.30 (C-7), 150.67
(C-6), 163.52 (C-1).
2.5 Determination of Enantioselectivity
2.5.1 Derivatization by (1R)-(-)-menthyl chloroformate
Saturated solution of sodium carbonate or sodium
hydroxide was used to quench the reaction and the samples
were extracted by diethyl ether from the alkalized solution.
The organic phase was dried by sodium sulfate, diethyl
ether was stripped in a stream of argon and reconstituted to
acetonitrile. To an amount of worked up sample containing
up to 2 mg of the THIQ product, (1R)-(-)-menthyl
chloroformate (10 lL) and triethylamine (20 lL) were
added and this mixture was analyzed by GC for
enantioselectivity.
2.3.5 6,7-Dimethoxy-1-(30,40,50-trimethoxybenzyl)-3,4-
dihydroisoquinoline (5)
N-[2-(3,4-dimethoxyphenyl)ethyl]-3,4,5-trimethox-
yphenylacetamide (39.1 g, 100 mmol) and was dissolved
in dry acetonitrile (250 mL) under argon atmosphere.
123

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J. Vaclavık et al.
558
2.5.2 Chiral Solvation by Pirkle’s Alcohol
carried out. Substrates 1–4 differ only by methoxy-substi-
tution in positions 6 and 7, and substrate 5 contains both
these methoxyl groups and a 1-(30,40,50-trimethoxy)benzyl
moiety.
Saturated solution of sodium carbonate or sodium hydroxide
was used to quench the reaction and the samples were
extracted by diethyl ether from the alkalized solution. The
organic phase was dried by sodium sulfate, diethyl ether was
stripped in a stream of argon and the sample was dissolved in
CDCl3. (R)-(-)-(2,2,2-trifluoro-1-(9-anthryl)ethanol) (Pir-
kle’s alcohol) was added so that the alcohol:amine ratio was
at least 3:1. As the amount of THIQ in the sample was
unknown, the ratio was controlled by spectra integration.
The reactions were conveniently performed in an NMR
tube and monitored by acquiring 1H spectra in regular
3–5 min intervals. An example is shown in Fig. 1, where
substrate 1 was hydrogenated in an NMR tube and two
signals were used for the determination of conversion:
1-methyl of the substrate (d = 2.57 ppm) and the same
methyl pertaining to the product (d = 1.67 ppm). The
acido-basic properties of the reaction mixture continuously
changed during the reaction, which is reflected by the
change of chemical shift in time.
2.5.3 Molecular Modelling
The geometry optimizations and frequency jobs were per-
formed using the standard Gaussian09 [8] package at the
DFT level of theory employing the B3LYP [9, 10] com-
bination of functionals. Tight convergence criteria were
used in all optimizations. Both DFT and MP2 [11] were
used to compute single-point energies, and the latter was
used for the natural bonding orbital (NBO) analysis giving
NPA charges. All calculations were conducted using the
cc-pVTZ [12] basis set. All structures were confirmed by
frequency analyses to be true minima. Grid-based Bader
charge analysis was done with Bader Charge Analysis
software (version 0.28) [13, 14]. Structures where solvation
was considered were recalculated using the integral equa-
tions formalism variant of polarization continuum model
(IEFPCM [15]) with UFF radii (i.e., the whole optimization
process was redone with IEFPCM applied). Solvation was
set up using an unmodified dielectric constant for aceto-
nitrile (e = 35.688).
Our group recently performed an extensive study [16]
on the influence of various reaction parameters on the
reaction performance. The parameters were optimized for a
reaction in a stirred batch reactor, i.e. higher concentration
due to subsequent workup of every sample for GC analysis.
The azeotrope:substrate ratio was also relatively higher
(corresponds to lower rates), which in combination with
concentration resulted in reasonable reaction rate. In this
work, the reaction conditions were selected to fit the
reaction in NMR spectrometer. The concentration of sub-
strate was decreased from 0.073 M to 0.044 M and the
azeotrope:substrate molar ratio was decreased from 8.8 to
4. Therefore, the rate decrease caused by lower substrate
concentration was compensated by changing the azeo-
trope:substrate ratio in favour of the reaction rate.
The kinetic curves from the ATH of substrates 1–5 are
shown in Fig. 2, and zero-order rate constants with enan-
tiomeric excess (ee) are given in Table 1.
With 7-methoxy derivatives (entries 3, 4 and 5), the
reaction rate was significantly higher than in cases where
no methoxy group was present in position 7 (entries 1 and
2). The ATH of substrate 2 bearing the 6-methoxy group
occurred with considerably lower reaction rate (entry 2).
However, the positive influence of the 7-methoxy group
seems to overcome the detrimental effect of the 6-methoxy
3 Results and Discussion
The ATH of five model substrates using the catalyst (S,S)-
[RuCl(p-cymene)TsDPEN] (TsDPEN = N-p-toluenesulfo-
nyl-1,2-diphenylethylene-1,2-diamine) (Scheme 1) was
Scheme 1 Structures of studied
substrates 1–5 and catalyst
(S,S)-[RuCl(p-
MeO
N
N
N
MeO
cymene)TsDPEN]
1
2
3
Ts
Cl Ru
H2N
N
(S)
MeO
MeO
MeO
Ph
(S)
N
N
Ph
[RuCl(p-cymene)TsDPEN]
MeO
OMe
OMe
4
5
OMe
123

Molecular Structural Effects in Asymmetric Transfer Hydrogenation
559
Similar trends were observed in terms of enantioselec-
tivity, which was higher in the ATH of all methoxylated
substrates compared to 1 (entry 1). The presence of one
methoxy group in the substrate molecule (entries 2 and 3)
led to an ee increase of 4–5 percentage points (pp), while
more methoxy groups afforded ees higher by 9–10 pp
(entries 4 and 5). We attribute this to substituent effects on
the aromatic ring of the substrate, which affect the CH/p
attraction between the catalyst and the substrate. This weak
interaction is considered to be the cause of enantioselec-
tivity in this ATH system [17].
Fig. 1 1H NMR spectra of ATH of substrate 1 showing the region of
1-methyl signals. The signal of the substrate decreased with time,
while the product was being formed
In order to find an explanation of observed behaviour,
substrates 1–5 were examined by methods of molecular
modelling and in particular, the charge distribution on the
C=N bond was calculated using Mulliken charges, NPA
charges, and grid-based Bader analysis [13]. Substrates
were examined in both non-protonated and protonated
forms, and the latter was also calculated with considering
the solvation effects using acetonitrile as a solvent. The
results are summarized in Table 2.
Unfortunately, the expected correlation was not found in
most of the calculations. One exception is the Bader charge
analysis on carbon atoms of non-protonated substrates
using DFT, where the reaction rate increases with
increasing electron density on the carbon atom of the C=N
double bond.
Fig. 2 Kinetic curves obtained by measuring ATH of 1–5 using
(S,S)-[RuCl(p-cymene)TsDPEN]
substituent when these two are present together (entries 4
and 5). The bulky 1-(30,40,50-trimethoxybenzyl) moiety of
substrate 5 further contributed to the reaction performance
(entry 5). All this evidence suggests that the presence of
methoxy groups in the molecule of substrate usually leads
to a substantial increase of the reaction rate.
A Bader charge should represent the total electronic
charge on an atom. For that reason, the charge on carbon
atoms in 1–5 is close to 5 e- (instead of 6 e-) and the
charge on nitrogen atoms is over 8 e- (instead of 7 e-).
The C=N bond is clearly polarized, which is depicted for
the case of substrates 2 and 3 in Fig. 3. The figure also
Table 1 Initial reaction rates of ATH of substrates 1–5
-1 a
)
Entry
Substrate
k (mmol min-1 mg
Relative rateb
ee (%)c
cat
1
2
3
4
5
1
2
3
4
5
0.0024
0.0014
0.0039
0.0033
0.0045
0.52
0.31
0.87
0.73
1.00
84d
89d
88d
93d
94e
Molar ratios S/C = 100; HCOOH/TEA = 2.5; (HCOOH-TEA)/S = 4; c(substrate) = 0.044 M, total volume = 800 lL
a
Least squares linear regression was used for the calculation of zero-order rate constants k up to conversion 20 % (linear region)
b
Relative reaction rate to the most reactive substrate
c
Enantiomeric excess
d
GC
e
NMR
123

´ ´
J. Vaclavık et al.
560
Table 2 Calculated Mulliken, NPA and Bader charges on the atoms of the C=N bond of substrates 1–5, which are sorted according to the
relative reaction rate
Substrates
2
1
4
3
5
Relative rate
0.31
89
0.52
84
0.73
93
0.87
88
1.00
94
ee (%)
pKa (–0.20)a
Non-protonated substrates
6.76
6.40
6.39
5.87
6.04
DFT
Mulliken
C
0.053
0.057
0.052
0.055
0.042
N
-0.191
-0.186
-0.191
-0.184
-0.188
Bader
C
5.2577
5.2869
5.3017
5.3862
5.3917
N
8.0114
8.1462
8.2147
8.1498
8.038
MP2
Mulliken
C
0.071
0.071
0.070
0.069
0.040
N
-0.257
-0.249
-0.254
-0.246
-0.236
NPA
C
0.357
0.345
0.352
0.34
0.354
N
-0.506
-0.491
-0.502
-0.486
-0.484
Bader
C
5.1053
8.2554
5.1402
8.4192
5.1334
8.4761
5.2471
8.4631
5.2516
8.289
N
Protonated substrates
DFT
Mulliken
C
0.146
0.161
0.143
0.156
0.088
N
-0.072
-0.058
-0.074
-0.057
-0.052
Bader
C
5.4212
8.1674
5.4692
8.0738
5.4391
8.1411
5.436
5.4215
8.3034
N
8.3979
MP2
Mulliken
C
0.194
0.203
0.194
0.202
0.120
N
-0.141
-0.125
-0.141
-0.122
-0.116
NPA
C
0.574
0.584
0.571
0.582
0.578
N
-0.563
-0.542
-0.563
-0.541
-0.563
Bader
C
5.4380
8.4406
5.4380
8.4406
5.4913
8.4757
5.4187
8.7208
5.4271
8.6109
N
Protonated substrates with solvation
DFT
Mulliken
C
N
0.175
0.190
0.172
0.186
0.127
-0.045
-0.032
-0.045
-0.030
-0.034
Bader
C
5.3863
8.1258
5.4006
8.0823
5.4566
8.2575
5.3631
8.1408
5.452
N
8.2455
123

Molecular Structural Effects in Asymmetric Transfer Hydrogenation
561
Table 2 continued
Substrates
2
1
4
3
5
MP2
Mulliken
C
N
0.220
0.229
0.220
0.228
0.160
-0.113
-0.099
-0.110
-0.094
-0.097
NPA
C
0.583
0.586
0.582
0.584
0.590
N
-0.538
-0.520
-0.536
-0.517
-0.536
Bader
C
5.3996
8.4475
5.3105
8.4455
5.4158
8.614
5.3663
8.4183
5.2976
8.5756
N
The values showing correlation with the catalytic activity are given in bold
a
Values calculated by advanced chemistry development (ACD) software, as provided by SciFinderÒ
Fig. 3 Partitions of total
electron density on C and N
atoms of the imine bond of
substrates 2 and 3. The bonds
are polarized with nitrogen
atoms being partially negative
and carbon atoms partially
positive
shows that the calculated electronic differences between
the two substrates are very subtle and cannot be determined
visually.
cannot fully reflect the real behaviour of the molecules.
Unfortunately, a more complex insight would be very
difficult to implement.
However, a promising correlation can be drawn from the
calculated pKa values (Table 2). The reaction rate increases
with decreasing basicity of the substrates. Substrate 5 does
not perfectly fit, probably because of the fact that it is
structurally rather far from substrates 1–4 considering that
the calculation algorithm for pKa is based on Hammett
equations.
4 Conclusion
The results demonstrate a strong effect of the methoxy
substituents on the reaction performance in terms of both
reaction rate and enantioselectivity. Changing the position
of single methoxy group resulted in drastic differences in
reactivity. The presence of methoxy groups remarkably
increased the reaction’s enantioselectivity, reaching ees of
up to 94 %. From the presented data we can draw a con-
clusion that less basic substrates are hydrogenated with
higher reaction rates. However, given the complexity of the
catalytic system, viable explanation of observed phenom-
ena by DFT calculations is still elusive.
It needs to be pointed out that this catalytic system is
rather complicated in several ways. The catalyst can be
present in several forms such as ruthenium chloride,
hydride, a so-called 16e- complex [18], formate [19], or a
solvate species [20]. The concentration of all these ruthe-
nium compounds changes during the reaction. The sub-
strate and triethylamine are in acido-basic equilibrium with
formic acid, which affects the reaction performance sig-
nificantly [21, 22], and the outcome of the reaction is a salt
(THIQ-H? HCOO-), whose formation continuously shifts
the acido-basic equilibrium in the course of reaction. For
all these reasons, such a one-sided approach like calculat-
ing charges on individual atoms or pKa of the substrate
Acknowledgments This work was financially supported by the
Grant Agency of the Czech Republic (Grant GACR 104/09/1497 and
P106/12/1276), and by grant for long-term conceptual development of
Institute of Microbiology RVO: 61388971. The access to computing
and storage facilities owned by parties and projects contributing to the
123

´ ´
J. Vaclavık et al.
562
National Grid Infrastructure MetaCentrum, provided under the pro-
gram ‘‘Projects of Large Infrastructure for Research, Development,
and Innovations’’ (LM2010005), is highly acknowledged. The access
to the CERIT-SC computing and storage facilities provided under the
program Center CERIT Scientific Cloud, part of the Operational
Program Research and Development for Innovations, reg. no. CZ.
1.05/3.2.00/08.0144, is appreciated.
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AD, Farkas O, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ
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