Influence of Temperature Controlled Fractional Distillation

Previously discussed results in batch reactive distillation experiments with initial starting molar fractions of x(R/S)-2-PeOH,0 = 0.10 ol∙ ol^-1 (section 5.3.2, Figure 5.17, B) as well as x(R/S)-2-PeOH,0 = 0.60 ol∙ ol^-1 (section 5.4.1, Figure 5.19, B) showed the possibility of in situ separation of the chiral target compound (S)-2-PeOH at the top of the column by fractional distillation with purities up to x(S)-2-PeOH,top,max = 0.8 ol∙ ol^-1. The applied fractional distillation was based on an automated temperature controlled operation to adjust the reflux ratio according to the procedure described in section 3.4. In order to investigate the influence of this fractional distillation at the top of the reactive distillation column on the purity of (S)-2-PeOH, identical catalyst amounts as well as identical distribution of the catalyst were applied at initial starting molar fractions of x(R/S)-2-PeOH,0 = 0.65 ol∙ ol^-1 and x(R/S)-2-PeOH,0 = 0.67 ol∙ ol^-1 (Figure 5.22, A). While the same reflux ratio was applied (rr = 9 (18:2) at t < 1035 min, rr = 0 at t > 1035 min), time points for changing the top temperature for fractional distillation is varied during column operation. The fractional distillation strategy is divided into the following steps. Initially, reflux was adjusted to take place at T 46 °C in the top of the column. This allows separation of formed low boiling 1-PrOH from RD with a boiling point of Tb = 42 °C at the applied operating pressure of p = 80 mbar. During the experiment, the temperature constraint is increased stepwise up to T 60 °C to obtain the target compound in situ at the column top.

The sum of fractional distillate samples in mass stripped at the column top (msum,top, filled and open triangles) and the measured temperature at the column top (Ttop, filled and open diamonds) are compared for the two experiments with x(R/S)-2-PeOH,0 = 0.65 ol∙ ol^-1 (open data points) and x(R/S)-2-PeOH,0 = 0.67 ol∙ ol^-1 (filled data points) over their proceeded reaction time (Figure 5.22, B).

Changing the time intervals of applying the individual temperatures at the top of the column is the major difference in operation between the two experiments. Stepwise adjustment of the temperature setting for fractional distillation is visualized by full lines operating the column with x(R/S)-2-PeOH,0 = 0.67 ol∙ ol^-1 and dashed lines in the case of x(R/S)-2-PeOH,0 = 0.65 ol∙ ol^-1. Starting with the sum of stripped sample mass at the column top at x(R/S)-2-PeOH,0 = 0.67 ol∙ ol^-1 (filled diamonds), a constant temperature controlled reflux at T 46 °C was applied for the fractional distillation up to t = 680 min. After an initially observed continuous increase of the sum of stripped sample mass at the column top up to msum,top = 147.2 g, a plateau is detected in between t = 440 - 680 min (msum,top = 147.9 ± 0.5 g). In this time period, the distillate was mainly composed of low boiling 1-PrOH (x1-PrOH,top = 0.77 ± 0.03 ol∙ ol^-1) and (S)-2-PeOH (x(S)-2-PeOH,top = 0.16 ± 0.02 ol∙ ol^-1). Residual compounds in the distillate samples were the faster reacting (R)-2-PeOH (x(R)-2-PeOH,top = 0.04 ± 0.01 ol∙ ol^-1) and PrBu (xPrBu,top = 0.03 ± 0.01 ol∙ ol^-1). The corresponding time dependent course of the molar fractions in the top of the column are depicted in appendix

section E (Figure E.4, A). Immediately after increasing the temperature for controlled reflux to T 49 °C, stripping of accumulated reactants at the RD column top started again. This effect was even enhanced by further increased temperature for controlled reflux up to T 60 °C resulting in E, Figure E.4, A). A similar trend over the course of the experiment can be observed in the measured temperature at the column top (Ttop, filled triangles). Before and during the plateau of the sum of fractional distillate samples, temperature stays nearly constant at a level of T = 46 °C. After changing the temperature for controlled reflux, the column temperature increased stepwise to the set temperature values.

Figure 5.22: Automated temperature controlled fractional distillation in reactive distillation experiments A: Scheme of reactive distillation equipment for experiments with x(R/S)-2-PeOH,0 = 0.67 ol∙ ol^-1 and 0.65 ol∙ ol^-1. B: Influence of changed time intervals of adjusted temperature constraints for fractional distillation on the sum of fractional distillate samples in mass (msum,top) and the temperature at the top of the column (Ttop). Operation conditions: p = 80 mbar, mBottom,0 = 800 g, mNZ435 = 45.3 g

For the sum of stripped sample mass at the column top in the second experiment with

x(R/S)-2-PeOH,0 = 0.65 ol∙ ol^-1 (open diamonds), reduced time intervals between the changes in

temperature for controlled reflux in the range of T 46 °C up to T 54 °C resulted in almost constant amounts fractionated at the column top up to msum,top = 215.7 g at t = 980 min. The corresponding molar fraction of the target compound (S)-2-PeOH at t = 980 min was x(S)-2-PeOH,top = 0.50 ol∙ ol^-1, including x1-PrOH,top = 0.45 ol∙ ol^-1, x(R)-2-PeOH,top = 0.02 ol∙ ol^-1 and xPrBu,top = 0.03 ol∙ ol^-1 (appendix section E, Figure E.4, B). Afterwards, further increase in the temperature constraint to T 60 °C allowed a fast removal of reactants from RD with a final msum,top = 357.3 g. This can be noted in the composition of the final fractionated top sample at t = 1074 min, wherein the target compound molar fraction is x(S)-2-PeOH,top = 0.95 ol∙ ol^-1 (x1-PrOH,top = 0.01 ol∙ ol^-1, xPrBu,top = 0.04 ol∙ ol^-1). With respect to the monitored temperature at the top of the column, stepwise increase in the column temperature in consequence of adjusting the temperature for fractional distillation is clearly visible in Figure 5.22, B in the course of open triangles.

In fact, the results of both experiments in Figure 5.22, B demonstrated the effect of automated temperature controlled fractional distillation during RD operation. As long as the temperature constraint for temperature controlled fractional distillation is below the boiling point of the desired target compound (S)-2-PeOH (T 46 - 55 °C), mainly low boiling 1-PrOH was withdrawn at the top of the column at rr = 9 (18 : 2). Simultaneously, this supports the KR reaction by constant removal of 1-PrOH and less removal of higher boiling compounds (i.e. (S)-2-PeOH). Generally, in a first step high enantiomeric excess of the target compound (S)-2-PeOH should be obtained by either constant or stepwise increasing the temperature for controlled fractional distillation prior to the adjustment of the temperature constraint to the boiling temperature of the target compound in the presented reaction case of kinetic resolution. Moreover, an observed plateau within the data points of initial molar fractions of x(R/S)-2-PeOH,0 = 0.67 ol∙ ol^-1 (filled diamonds in Figure 5.22, B) indicated the point of changing the temperature constraint. At an observed constant temperature at the top of the column, which is similar to the adjusted temperature constraint, an increased temperature constraint should be adjusted to prevent the formation of a plateau. This is successfully demonstrated for initial molar fractions of x(R/S)-2-PeOH,0 = 0.65 ol∙ ol^-1 by constantly increasing msum,top. In a second step, adjusting the temperature constraint near to the boiling point of the target compound (S)-2-PeOH (T 60 °C) generated fast stripping of reactant mixtures containing (S)-2-PeOH. This fast stripping procedure was applied for both experiments only in the end of the reaction for t > 1035 min to enhance reactant removal and to withdraw nearly pure (S)-2-PeOH in situ at the column top by operating without any reflux back into the column at rr = 0 (Figure 5.22, B).

Additionally, the discussed influence of the automated temperature controlled fractional distillation on the reaction performance (ee(S)-2-PeOH,top, x(S)-2-PeOH,top) at the top of the column was investigated for the initial starting molar fractions of x(R/S)-2-PeOH,0 = 0.65 ol∙ ol^-1 (Figure 5.23, A) and

x(R/S)-2-PeOH,0 = 0.67 ol∙ ol^-1 (Figure 5.23, B). Chosen parameters were the enantiomeric excess of the

target compound (S)-2-PeOH (ee(S)-2-PeOH,top, open and filled diamonds) and the corresponding purity (x(S)-2-PeOH,top, open and filled triangles) in dependency of the isolated yield (Y(S)-2-PeOH,isolated,top). All three parameters were investigated in withdrawn sample fractions at the column top. For the calculation of the isolated yield, the moles of (S)-2-PeOH in the withdrawn top samples are referred to the moles of (R/S)-2-PeOH in the beginning of the experiment. During the experiments, withdrawn samples at the top of the column were directly analyzed in gas chromatography to allow a fast response on conditions in the temperature constraint at different levels of ee(S)-2-PeOH,top. Hence, the shown isolated yield represents the analyzed samples at the top of the column without further purification steps.

Figure 5.23: Influence of varied temperature constraints for automated temperature controlled fractional distillation on the reaction performance in biocatalytic reactive distillation with A: x(R/S)-2-PeOH,0 = 0.65 ol∙ ol^-1 and B: x(R/S)-2-PeOH,0 = 0.67 ol∙ ol^-1. Vertical lines: adjustment of temperature constraint to T 60 °C. Operation conditions: similar to Figure 5.22. SD refers to maximum error estimation according to section 3.4.

In the first part of the reaction, ee(S)-2-PeOH,top was the decisive parameter for changing the temperature constraint in view of chiral compound synthesis. The reason for being the decisive parameter is, that a high ee(S)-2-PeOH,top indicates full kinetic resolution reaction, respectively. During this time period, the temperature constraint for fractional distillation was adjusted to T 46 - 54 °C

Thereby, increased purities of (S)-2-PeOH (x(S)-2-PeOH,top) were focused by changed composition of the reactant mixture at the column top. This change is caused by fractional distillation, which results in reduced molar fractions of PrBu and 1-PrOH besides the desired target compound (S)-2-PeOH. The point of changing the decisive parameter is indicated by a vertical line for both experiments (x(R/S)-2-PeOH,0 = 0.65 ol∙ ol^-1, Figure 5.23, A and x(R/S)-2-PeOH,0 = 0.67 ol∙ ol^-1, Figure 5.23, B). In both cases, high values for ee(S)-2-PeOH,top were reached at this specific point, although full kinetic resolution was only achieved for the experiment with starting molar fractions of x(R/S)-2-PeOH,0 = 0.65 ol∙ ol^-1. However, this effect can be related to the varied initial starting molar fraction and it is addressed and discussed in section 5.4.3. With respect to the isolated yield of the target compound, the applied fractional distillation strategy was able to increase the target compound fractions with high ee(S)-2-PeOH,top ( 90 %) and high purity (x(S)-2-PeOH,top 0.93 ol∙ ol^-1). In the presented data, the isolated yield in the period of the process with reduced enantiomeric excess was Yisolated,top = 12.1 % for x(R/S)-2-PeOH,0 = 0.65 ol∙ ol^-1 and Yisolated,top = 8.2 % for x(R/S)-2-PeOH,0 = 0.67 ol∙ ol^-1.

Hence, application of automated temperature controlled fractional distillation allowed successful column operation with respect to a well-timed change in the temperature constraint to withdraw nearly pure (S)-2-PeOH in situ at the column top. Similarly, previously discussed RD experiments in Figure 5.19, B with differently distributed NZ435 were performed with this fractional distillation strategy.

Concise summary of section 5.4.2:

• Stepwise fractional distillation by given temperature constraints at the top of the column results in further increased purities up to x(S)-2-PeOH,top = 0.93 – 0.95 mol∙mol^-1 at starting molar fractions of x(R/S)-2-PeOH,0 = 0.65 – 0.67 ol∙ ol^-1

• Two-step approach for fractional distillation allows in situ isolation of (S)-2-PeOH:

1^st part: enantiomeric excess is decisive parameter until high ee(S)-2-PeOH > 90 % is reached 2^nd part: purity is decisive parameter as long as high ee(S)-2-PeOH > 90 % is present