**3. Influence of the reaction conditions**

The spectroscopic methods were applied to understand the influence of the base in depth.

gether with pure formic acid or the mixture of formic acid and TEA with different molar ratio were used. Employing pure formic acid was accompanied by the formation of the ruthenium-hydride species, which solely decomposed under acidic conditions. Furthermore, TEA addition has positive effect regarding the formation of catalytic hydride (**Figure 3**, complex **b**), positive effect was observed to the ratio of TEA/formic acid 5:1, and above this value no significant improvement in the case of hydride concentration was observed.

TsDPEN and (3) a species, which is assumed to be the second diastereomer of the ruthenium-hydride. After NMR experiments, ESI+ FT-ICR MS to observe active rutheniumhydride species using TEA/formic acid in molar ratio 5:2 was applied. The MS spectrum contained three clusters, the first one, with *m/z* 595.1500 which belonged to the 16 e- complex (**Figure 3**, complex **c**), the second one, was determined as the cluster of active ruthenium-hydride associated with TEA. The last one, was assigned to the associate of a precatalyst (**Figure 3**, complex **a**) with TEA. From the results obtained, authors suggested that the binding of the base could be realized by three different ways: (1) the base is coordinated to the central Ru atom, (2) the base forms N⋅⋅⋅H-N bond with chiral ligand of the catalyst, or (3)

ligand (**Figure 4**). To exactly determine which is the right way, the application of the VDC analytical method combined with IR spectroscopy concluded that the protonated base is

TsDPEN ligand. The consequence of these findings can be that the base selection has a huge

**Figure 4.** A scheme of binding of both substrate (red) and base (blue) to the active site of ruthenium-hydride species.

impact on the reaction rate and enantioselectivity of the ATH of cyclic imines.

H-NMR spectrum, three intermediates were found in the mixture: (1) rutheni-




)(η6 *p* cymene)(*S,S)-*

For the NMR examinations, the mixture of [Ru(Cl)(η6

42 New Advances in Hydrogenation Processes - Fundamentals and Applications

um-hydride species, (2) ruthenium formate complex [Ru(HCOO-

Also, using <sup>1</sup>

the protonated base forms a N+

connected with the catalytic complex *via* N+

Similar to every chemical reaction, it is important to carry out asymmetric transfer hydrogenation under specific reaction conditions, particularly ratio between the reaction rate and the enantioselectivity optimized as much as possible. The first comprehensive parametric study [10] focused on the determination of the best possible reaction conditions for ATH of cyclic imines, especially 3,4-dihydroisoquinoline derivates. This study thus involved clarifying the best attainable value of temperature, reaction mixture concentration or substrate to catalyst molar ratio (S/C).

Primarily, the attention was paid to the concentration in the reaction mixture as one of the important parameters. Two experiments were performed with different S/C molar ratios, S/C = 100 and S/C = 200, and other crucial molar ratios set to: formic acid/TEA = 2.5, hydrogenation mixture/substrate = 8.8, and the temperature set to 30°C. The major difference was observed in reaction ratio. For S/C = 200 the reaction ratio was slightly lower and also the difference grew with an increasing concentration. Probably, this fact can be explained by a certain amount of the catalyst being blocked by the protonated base, resulting in a lower reaction rate than in the case of the experiment with S/C = 100. The final outcome of this first set of experiments is as follows: reaction rate increases with an increasing of the reaction mixture concentration. This can be probably explained that at higher concentrations, the reaction rate is no longer limited by the frequency of effective collisions between active ruthenium-hydride species and the protonated molecule of the substrate but by the total amount of ruthenium-hydride intermediate present in the reaction mixture. Furthermore, the differences of the reaction mixture, related to the mass of the catalyst with different S/C ratios, were examined afterward as the S/ C ratio is parameter that generally affects the course of catalytic reactions. As a result, it was confirmed that modifying S/C ratio leads to different reaction rates, regardless of the influence of the catalyst amount.

The second basic important parameter for every chemical reaction is the temperature. For this reaction, the measurement of its effect on both, the reaction rate and the enantioselectivity was conducted in the range of 10–50°C (**Figure 5**). Increasing the reaction rate with an increasing temperature was expected and could be considered common. However, the decrease of enantioselectivity was observed with an increasing temperature. This fact can be explained by Yamakawa's supported theory that two transition states exist. One would lead to the preferred configuration of the product; the other would lead to the other configuration. The so-called unfavorable transition state will prevail at a higher temperature and the nonpreferred product would become more abundant.

The amount of the hydrogenation mixture is also important for the process of ATH. The mixture of formic acid and TEA provides hydrogen for the hydrogenation itself. The most commonly used molar ratio for these two is 2:5. The variation of this amount was expected to have a major influence on the course of the reaction and thus several hydrogenation mixture/ substrate ratios were tested, where the concentrations were set to 7%, as well as S/C = 100, formic acid/TEA = 2.5, and the temperature to 30°C. Contrary to the original expectation, increasing the amount of the hydrogenation mixture leads to a decrease in the initial reaction rate (**Figure 5**). Therefore, two working hypothesis were considered to explain such behavior. The first, under a strong acidic condition, the catalyst's ligand became protonated, and subsequently deco-ordinated from the Ru atom, followed by the loss of catalytic activity and the second one, in a large excess of hydrogenation mixture, the protonated triethylamine is also in large excess over the protonated substrate and sterically hinders active site of the catalyst for substrate.

**Figure 5.** Graphical summary of the results obtained in parametric study of ATH.

The variation of the ratio between formic acid and triethylamine, the two components of the hydrogenation mixture, could provide an insight into several subtle aspects of the reaction mechanism. Also, several visual differences between reaction mixtures containing different molar ratios of TEA and formic acid were observed, yellow color for mixtures containing higher molar ratio between formic acid and triethylamine and orange color for the mixture with higher amount of base. This fact indicates that the catalytic complex undergo some significant changes in excess of acid followed by loss of activity of the catalyst. Although, using higher amount of the TEA also showed that the reaction perform much more slowly than usual. Explanation for this phenomenon could be really simple; the excess of TEA probably neutralizes all of the formic acid and by this disable the reaction itself. However, according to the results obtained during the study, azeotropic mixture of formic acid/TEA (molar ratio 5:2) seems to be an optimal as the source of hydrogen for the purpose of ATH (**Figure 5**).
