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com
Application Note 6: Use of Labtrix® S1 for the Investigation of the Transfer Hydrogenation
of Acetophenone using Kanata Chemical Technology Catalysts
In conjunction with Kanata Chemical Technologies, the transfer hydrogenation of acetophenone 1 [1], to
afford (S)-1-phenylethanol 2 and (R)-1-phenylethanol 3, was evaluated under continuous fow conditions
and the results obtained compared to those generated using industry standardised batch methodology.
Using the micro reactor development equipment from Chemtrix BV, reaction conditions were rapidly
screened for two hydrogenation catalysts, Ru(p-cymene)[(S,S)]TsDPEN]BF
4
4 and Ru(p-cymene)(Py)
[(S,S)]TsDPEN]BF
4
5 (Figure 1), and the resulting conversions and enantiomeric excesses (ee’s) used to
highlight any advantages associated with this mode of operation [2].
Figure 1. Illustration of two hydrogenation catalysts provided by Kanata Chemical Technologies,
Ru(p-cymene)[(S,S)]TsDPEN]BF
4
(K44-0117) 4 and Ru(p-cymene)(Py)[(S,S)]TsDPEN]BF
4
(K44-0119) 5.
Reaction Conditions: Reactions were performed using the Labtrix
®
S1 system (Chemtrix BV, Figure 2a)
containing a 10 μl glass micro reactor (3023, Chemtrix BV, Figure 2b), with reactant solutions delivered to
the micro reactor via three 250 μl gas-tight syringes (SGE, UK).
Dr Charlotte Wiles and Dr Bongkot Ngamsom Chemtrix BV and Kanata Chemical Technologies
Application Note 6
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Figure 2. Schematic illustrating (a). the Labtrix
®
S1 system and (b). the reactor manifold used to investigate
the continuous fow transfer hydrogenation of acetophenone 1.
Reactant solutions were prepared in accordance with the batch protocol provided by Kanata Chemical
Technologies, whereby the frst solution contained acetophenone 1 (8.32 mmol) in iPrOH (3.5 ml) and the
second contained the catalyst 4 or 5 (1.70 x 10
-2
mol) and potassium hydroxide 6 (0.20 mmol) in
i
PrOH
(3.5 ml). Using this approach, a series of reaction conditions were investigated including reaction time
(10 min to 2 h) and reactor temperature (0 to 75 °C), employing the batch conditions of 2 h at 25 °C as a
benchmark.
Both batch and micro reactions were evaluated using offine GC-FID analysis ftted with a CP Chirasil-
DExCB chiral GC column (0.25 μm (coating) x 0.32 mm (i.d.) x 25 m (long), Varian), a He fow rate of 1 ml
min
-1
, injector temperature of 250 °C and a detector temperature of 300 °C. The analytical method used
employed an injection volume of 1 μl (split ratio 50:1) and an initial oven temperature of 90 °C, ramping to
190 at a rate of 12 °C min
-1
. Under the aforementioned conditions, analyte retention times were identifed
using commercially available synthetic standards (acetophenone 1 = 4.31 min, (R)-1-phenylethanol 3 =
5.53 min and (S)-1-phenylethanol 2 = 5.62 min); a typical GC chromatogram is presented in Figure 3.
Figure 3. (a). Illustration of a typical GC chromatogram obtained for a batch transfer hydrogenation
reaction, (b). product peaks enlarged for clarity.
Results and Discussion: Using the catalyst Ru(p-cymene)[(S,S)]TsDPEN]BF
4
(K44-0117) 4, the effect
of reaction time (10 to 120 min) was frstly evaluated within the micro reactor at 25 °C; whereby (S)-
1-phenylethanol 2 was the major enantiomer formed. As Table 1a illustrates, a trend of increasing
acetophenone 1 conversion, from 6.3 to 28.6 %, was observed with increasing reaction time; however, as
the reaction time increased, erosion of enantioselectivity was observed (96.8 to 96.0 % ee). Comparing
the results obtained with those from a batch reaction, Table 1b, it can be seen that comparable conversion
and enantioselectivities are obtained (Figure 4). The main difference between the reaction methodologies
is the fact that the screening data generated under fow conditions was obtained using signifcantly lower
volumes of catalyst and reagents than batch generated data.
Taking only the catalyst 4 into account, 5.24 x 10
-5
mmol was employed in fow (n = 3) vs. 1.70 x 10
-2
mmol
in a single batch reaction. The fow reactor methodology is therefore advantageous when assessing costly
and/or scare catalytic material; a feature which is particularly advantageous at initial stages of catalyst
development where large numbers of substrates are screened.
Application Note 6
Dr Charlotte Wiles and Dr Bongkot Ngamsom Chemtrix BV and Kanata Chemical Technologies
Solvent
(b).
(a).
1
2
3
(a).
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Table 1. Summary of the results obtained for the transfer hydrogenation of acetophenone 1 using K44-
0117 4 (a). under continuous fow (n = 3 for each condition) and (b). in batch at 25 °C.
Figure 4. Comparison of the conversions and ee’s obtained in micro and batch reactions after 2 h at room
temperature using catalyst K44-0117 4.
With this information in hand, the effect of reactor temperature was subsequently investigated within the
fow system, affording the users information about the reaction not currently explored in batch.
At Table 1a illustrates, employing 10 min as the standard reaction time the effect of reactor temperature
on enantioselectivity was investigated, with increases in temperature leading to erosion of reaction
enantioselectivity accompanied by an increase in conversion. Reducing the reactor temperature to
0 °C confrmed the need for low reactor temperatures in order to maintain high ee’s (97.0 %); this was
however at the expense of conversion (1.7 %) requiring an increase in reaction time to afford effcient
hydrogenation.
Repeating the previously described investigation for the second catalyst, Ru(p-cymene)(Py)[(S,S)]TsDPEN]
BF
4
(K44-0119) 5, the same trend was observed for batch and fow methodologies; however, reduced ee’s
were obtained in general when compared to catalyst 4.
Application Note 6
Dr Charlotte Wiles and Dr Bongkot Ngamsom Chemtrix BV and Kanata Chemical Technologies
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Summary: From the results described herein, it can be seen that it is possible to perform asymmetric
transfer hydrogenations under continuous fow conditions, utilizing alcoholic solvent systems. When
compared to batch methods, the use of micro reaction technology is advantageous as it enables rapid
reaction screening whilst dramatically reducing catalyst consumption. For Ru(p-cymene)[(S,S)]TsDPEN]
BF
4
(K44-0117) 4 the whole study was performed using less catalytic material than that required to execute
a single batch reaction, equating to a 324-fold reduction in catalyst consumption.
References:
[1]. M. J. Palmer and M. Wills, ‘Asymmetric Transfer Hydrogenation of C=O and C=N Bonds’, Tetrahedron:
Asymm., 1999, 10, 2045-2061.
[2]. X. Y. Mark, P. Laurino and P. H. Seeberger, ‘Asymmetric Reactions in Continuous Flow’, Beilstein J. Org.
Chem. 2009, 5, 19.
Acknowledgements: Dino Amoroso, Christine Sui-Seng and Kamaluddin Abdur-Rashid of Kanata Chemical
Technologies (www.kctchem.com) are thanked for their donation of catalysts 4 and 5,
along with the analytical information provided and useful discussions throughout this investigation.
Application Note 6
Dr Charlotte Wiles and Dr Bongkot Ngamsom Chemtrix BV and Kanata Chemical Technologies