Reaction optimization and Real-time Analysis using ThalesNano’sPlatform and MettlerToledo’s FlowIR™ Spectrometer

Phoenix Flow Reactor™ Application Note

In this application note we report on the optimization of hydrogenation, oxidation and ring-closing reactions and their real time analysis. Homogeneous and heterogeneous reactions were performed in ThalesNano’s H-Cube Pro™, Gas Module, and Phoenix Flow Reactor™ systems, while these reactions were monitored by Mettler Toledo’s FlowIR™ device.

INTRODUCTION

Flow chemistry reactors are enabling tools for chemists to perform a wide variety of reactions. Due to the excellent mixing and large exposed surface to volume ratio, reactions are better controlled and the process is more advantageous compared to batch. Using flow technology can dramatically reduce optimization and reaction time.

ThalesNano’s H-Cube Series is a revolutionary bench top continuous flow system family with built-in hydrogen production capability and a disposable catalyst cartridge system (CatCart®) for safe and fast hydrogenation reactions. With no external storage of hydrogen necessary, the members of the H-Cube Series, the H-Cube®, H-Cube® Pro, H-Cube® Mini, and H-Cube® Midi, can be used safely in almost any laboratory environment. The H-Cube® Series can be used from mgs to half-kilo production per day.

ThalesNano’s Gas ModuleTM allows for additional gas types to be introduced to a flow reactor such as the H-Cube® Pro. With 13 gases to choose from, it very precisely controls the mass flow rate of a gas at high pressures for use in catalyst testing and modeling experiments.

The Phoenix Flow Reactor™ is a high-temperature module compatible with the H-Cube® Series, allowing reactions up to 450 °C and 100 bar. The reaction zone in the Phoenix Flow Reactor™ may vary depending upon the chemistry and desired scale, allowing production in mg-kg/day. Loop reactors are inserted for homogeneous reactions and fixed bed reactors are inserted for heterogeneous reactions.

Infrared spectroscopy offers a detection method for chemistries that are difficult to follow by conventional analytical methods such as gas or liquid chromatography.

FlowIR™ is a dedicated Fourier Transform Infrared Spectroscopy (FTIR) instrument for in situ, real-time monitoring of continuous flow chemistry, enabling researchers to save valuable time and materials when screening and optimizing their reactions.

Being able to monitor continuous flow chemistry while in operation allows users to:

  • rapidly screen reaction conditions, leading to faster process optimization.
  • utilize the iC IR™ software, Mettler Toledo’s Reaction Analysis Software, making mid-infrared spectroscopy practical for organic chemists while retaining the power and flexibility required by full-time spectroscopists.

Dramatic improvements in visualizing data and reporting results remove barriers that free chemists to focus on their chemistry. The iC IR™ software helps chemists to reach:

  • Easy Data Collection and Instrument Control.
  • Intuitive Data Analysis and Real Time Visualization.
  • Quick Reporting and Data Exchange.

Figure 1: Interface of the iC IR™ Reaction Analysis Software during data analysis.

EXPERIMENTAl SETUP

Hydrogenation reactions were carried out in the H-CubeH-Cube® Pro reactor. The H-CubeH-Cube® Pro reactor has a built-in Simplex optimization algorithm that helps chemists to determine optimal reaction conditions.

The CatCart® system was designed to make the use of pyrophoric catalysts safer and easier to handle.

Oxidation experiments were carried out in a coupled H-Cube® Pro Gas Module system, where an oxygen cylinder was connected to the Gas Module, which regulated the amount of oxygen entered into the reaction area of the H-CubeH-Cube® Pro, using the same CatCart® system. The last example, which is a homogenous Paal-Knorr synthesis, was performed in the Phoenix Flow Reactor™, connected to an H-CubeH-Cube® Pro, which provided the high-pressure capability required for the reaction. In this case, a 16 mL SS loop was used as the reaction zone.

Before proceeding with a reaction, the FlowIR™ system was properly configured and aligned. Back-ground and reference spectra were collected. Mettler Toledo offers Diamond (DiComp) or Silicon (SiComp) sensor tips: both detect in the range of 4000 to 650 cm-1, only differing in the diamond absorption region.

We used the DiComp sensor with a blind region of2250–1950 cm−1 in the experiments described in this application note. Available sensor head volumes are 50 μl and 10 μl. The reactions carried out inThalesNano’s flow reactors were monitored by the FlowIR™ instrument via either manual injection into the sensor head or by connecting it in-line with the flow reactor.

Since infrared spectroscopy can be sensitive to temperature changes, it is important to carry out the measurement at an accurately controlled, constant temperature. Due to this, a heater controller was connected to the FlowIR™, and the temperature was set during all measurements to 25 °C.

Figure 2:The H-Cube Pro™ flow reactor with pump

Figure 3: ThalesNano CatCarts® – 30×4 mm and 70×4 mm catalyst area (and a MidiCart)

Figure 4: Mode of injection into the head (left). FlowIR™ volume heads – 10 μL and50 μL (right).

Figure 5: FlowIR™ connected in-line to heater controller and flow reactor.

CARBONYL REDUCTION

4-chlorobenzaldehyde was selectively reduced to 4-chlorotoluene using a 10% Pd/C filled CatCart® in the H-Cube Pro™ flow reactor (Reaction parameters are shown in Table 1).

The reaction was monitored by the FlowIR™ instru-ment after manual injection of the samples. Using the iC IR™ program, the spectra of the samples were analyzed.
After solvent subtraction, characteristic wavelengths were chosen for the starting compound (1210 cm-1) and for the desired product (1488 cm-1). The reaction samples were also analyzed by GC-MS, to confirm the IR spectroscopy results.

Figure 6: IR spectrum of the reaction mixtures. The spectra of the starting material (ref.: 00:01:38) is extracted from the spectra.

By following the intensity of the selected wavelengths, the changes in the amount of starting material as well as the product were monitored (Figure 7).

The red line in Figure 7 follows the same trend as the selectivity values for 4-chlorotoluene obtained by GC-MS. Therefore, the peak at 1488 cm-1 represents exclusively the 4-chlorotoluene product. The green line decreases to a near-zero value after Sample 1, which is in agreement with the 100% conversion values given by GC-MS (Table 1)

Reaction parameters for the optimization were determined by the Simplex algorithm built into the H-Cube Pro™. Reaction conditions and GC-MS results for comparison can be seen in Table 1.

The optimal conditions were found to be 10 °C, 58 bar pressure and 0.3 mL/min flow rate at 100% H2production rate. Notably, at higher temperatures, dehalogenated product may form. In addition, the reaction requires a low flow rate: when the residence time chosen is shorter, the hydrogenation gives 4-chlorobenzylalcohol as the product.

Sample Temp (°C) p (Bar) Flow Rate (mL/min) Conversion (% GC-MS) Selectivity (% GC-MS)
1 0 (Starting Material)
2 70 38 1.5 100 5
3 70 62 1.5 100 8
4 100 50 1.5 100 30
5 80 50 2.1 100 9
6 97 70 1.9 100 24
7 112 51 2.2 100 20
8 128 64 1.6 100 4
9 92 54 2 100 43
10 59 72 1 100 72
11 57 36 0.7 100 68
12 39 58 1 100 91
13 13 58 0.3 100 91

Table 1: Reaction parameters and their results, determined by GC-MS.

Figure 7: Trends of product and starting material peaks.

REDUCTION OF D-GLUCOSE INTO D-SORBITOL

Reduction of D-glucose into D-sorbitol was carried out in the H-Cube Pro™ flow reactor and optimized using in-line infrared analysis.

First, mixtures of glucose and sorbitol were prepared (0-100%) in 0.1 M total concentration. These standard solutions were manually injected into the FlowIR™ instrument and the infrared samples were collected. After solvent subtraction the 2nd derivative of the spectra was formed and 1098 cm-1 wavelenth was chosen to monitor the glucose concentration.

Figure 8: A section of the infrared spectra.

A calibration line was drawn from the measured intensities (Figure 9). This shows that the peak intensity of 1098 cm-1 is in linear correlation with the glucose concentration.

Figure 9: Calibration line for glucose content of standard solutions.

The IR spectra were collected automatically during each experiment every 30 seconds by the iC IR™ program. Reaction parameters are displayed in Table2, with the corresponding spectra in Figure 10. Conversion rates of the reaction (Samples 1-5.) were determined by reading the intensity of the 1098 cm-1peak and the new reaction parameters were determined based on the results.

Sample Temp (°C) p (Bar) Flow Rate (mL/min) Conversion (% GC-MS) Selectivity (% GC-MS)
1 0 (Starting Material)
2 70 38 1.5 32 32
3 70 62 1.5 30 13
4 100 50 1.5 81 79
5 80 50 2.1 31 27
6 97 30 1.9 65 65
7 98 29 1.2 77 77
8 100 48 0.9 79 79
9 102 47 0.9 85 82

Table 2: Reaction parameters and conversion values of Sample 1-5 *conversion byFlowIR™

Figure 10: Detection of Glucose content of 4 standard solutions and reaction Samples (1-5)

Using the real-time analysis data allowed us to optimize the reaction very fast and reach 95% conversion. The optimal conditions for the reduction of glucose are 120 °C, 80 bar pressure and 0.7mL/min flow rate using 100% H2 production.

OXIDATION OF ANISALCOHOL

0.1 M Anisalcohol in AcOH was selectively oxidized to the corresponding aldehyde using oxygen gas and a CatCart® filled with 1% Au/TiO2 as catalyst in theH-Cube Pro™ Gas Module system while monitoring the reaction online.

Solvent subtraction and second derivative data treatment were used to improve the analysis. Figure 12 presents a section of the infrared spectrum where the desired product (839 cm<sup>-1</sup>) can be monitored.

Figure 12: IR spectrum of the reaction mixtures. Sample 1 is the starting material.

Reaction parameters for the optimization were determined by the Simplex algorithm built into the H-Cube Pro™. Table 3 represents the used reaction conditions and the corresponding GC-MS results

Figure 13 shows the intensities of the two selected wavelengths in Samples 1-9. All the results were double-checked by GC-MS, just as in the previous reactions, and showed excellent correlation with the IR data.

In Sample 3, significant amount of side product was formed. The trend line of product and starting material sum up to less than 80%. The decrease in product peak in Sample 5 indicates the temperature and flow rate sensitivity of the reaction. The optimal conditions – highest selectivity together with the highest conversion – are 102 °C, 47 bar pressure and 0.9 mL/min flow rate.

Figure 11: The H-Cube Pro™ flow reactor with Gas Module and HPLC pump.

Sample Temp (°C) p (Bar) H2 (%) Flow Rate (mL/min) c (M) Conversion (%)
1 50 20 100 1 0.1 10
2 80 20 100 1 0.1 30
3 100 80 100 1 0.1 55
4 110 28 100 0.8 0.1 85
5 120 80 100 0.7 0.1 95

Table 3: Reaction parameters given by the Simplex method and their results.

Figure 13: Trends of product and starting material peaks.

PAAL-KNORR SYNTHESIS OF PYROLLES

Ring closing reactions of 2,5-hexanedione and 1-phenyl-2,5-hexanedione with liquid ammoniawere carried out in a 16 mL loop reactor using the Phoenix Flow Reactor™ coupled with the H-Cube Pro™. After the reaction, product samples were manually injected into the FlowIR™.

The starting material solution, product solution, and a pyrrole solution as reference (0.2 M in MeOH each) were injected in the FlowIR™ spectrometer. Characteristic peaks were identified for each compound using the iC IR™ analysis program.

The starting material solution, product solution, and a pyrrole solution as reference (0.2 M in MeOH each) were injected in the FlowIR™ spectrometer. Characteristic peaks were identified for each compound using the iC IR™ analysis program.

Figure 14 shows how the functional groups were identified during the synthesis of 2,5-dimethylpyrrole. While Table 4 and Figure 15 contain data on the synthesis of 2-phenyl-5-methylpyrrole. Table 4 shows the reaction parameters applied during the reactions, and also indicates that on Figure 15 Sample 1 and 5 were starting materials.

Figure 15 shows the intensities of the two selected wavelengths in Samples 1-5 during the synthesis of 2-phenyl-5-methylpyrrole. The data gained from the infrared spectra shows good agreement with those obtained from GC-MS. The optimal conditions for the ring formation were found to be 100 °C, 60 bar and 1 mL/min flow rate.

Sample Temp (°C) Flow Rate (mL/min) Conversion (%)
1 0 (Starting Material)
2 25 1 41
3 25 0.5 30
4 100 1 95
5 - - 0 (Starting Material)

Table 4: Reaction parameters and conversion values of Sample 1-5.

*conversion by GC-MS

Phoenix Flow Reactor

Figure 13: Phoenix Flow Reactor™ with HPLC pump, CatCarts® and loop reactor.

Figure 14: Detection of different functional groups in the IR spectrum.

Figure 15: Trends of product and starting material peaks in the synthesis of 2-phenyl-5-methylpyrrole.

CONCLUSION

Three types of reactions – hydrogenation, oxidation, and a ring-closure – were performed with ThalesNano’s flow reactors and successfully monitored either in offline (manually injecting the samples) or online manner with Mettler Toledo’s FlowIR™ spectrometer. Since the nature of the performed reactions required the use of different flow equipment under different reaction conditions, the versatility of the met-hodology can be seen, as well as the speed of analysis.

LEGAL INFORMATION

CatCart and H-Cube are registered trademarks of ThalesNano Inc.

H-Cube Pro and Phoenix Flow Reactor are trademarks of ThalesNano Inc.

FlowIRand iC IR are trademarks of Mettler-Toledo Interna-tional Inc.