Catalyst Screening followed by TLC-MS for Reaction Progress Analysis using KitAlysis™

By: Sarah Trice, Thorsten vom Stein, Michael Schulz,

Introduction

Catalyst screening is an important prerequisite in organic synthesis. KitAlysis™ High-Throughput Screening Kits showcase the most widely used catalytic methods of synthetic chemists, translated into an off-the-shelf screening system to quickly and efficiently identify or optimize suitable catalytic reaction conditions.

To evaluate the screening an analysis tool is needed. Thin layer chromatography (TLC) allows for a fast and cost-effective determination of the reaction progress by parallel analysis of the samples on one plate. This setup perfectly fits to the parallel synthesis utilizing KitAlysis™.

This application note displays the use of the KitAlysis™ High-Throughput Buchwald-Hartwig Amination Reaction Screening Kit for the optimization of the coupling of aryl bromide and diphenylamine combined with an evaluation of the result with TLC-MS analysis.

                        1                                        2                                                                                      3

 

Figure 1. Schematic reaction showing the coupling of aryl bromide (1) and diphenylamine (2) to form biphenyl-4-yl-di-p-tolyl-amine (3), where the product has a molecular weight of 349.468 g/Mol.

Results and Discussion

The two reactants, aryl bromide and diphenylamine, were applied in addition to the samples. The samples were clearly visible under UV-light, therefore no derivatization was necessary. Figures 2a, 2b and 2c show the developed plate under white light, at 254 nm and at 366 nm.
 

Track Samples / Catalysts KITALYSIS-CN Concentration Application volume Rf of product and educts
1 BrettPhos Pd G3 KitAlysis™ sample filled up with 1 ml THF 2.0 µL 0.50
2 CPhos Pd G3 KitAlysis™ sample filled up with 1 ml THF 2.0 µL 0.50
3 DavePhos Pd G3 KitAlysis™ sample filled up with 1 ml THF 2.0 µL 0.50
4 P(tBu3) Pd G2 KitAlysis™ sample filled up with 1 ml THF 2.0 µL 0.50
5 J009 Pd G3 KitAlysis™ sample filled up with 1 ml THF 2.0 µL 0.50
6 MorDalPhos Pd G3 KitAlysis™ sample filled up with 1 ml THF 2.0 µL 0.50
7 BINAP Pd G3 KitAlysis™ sample filled up with 1 ml THF 2.0 µL 0.50
8 RuPhos Pd G2 KitAlysis™ sample filled up with 1 ml THF 2.0 µL 0.50
9 SPhos Pd G2 KitAlysis™ sample filled up with 1 ml THF 2.0 µL 0.50
10 tBuXPhos Pd G3 KitAlysis™ sample filled up with 1 ml THF 2.0 µL 0.50
11 XantPhos Pd G3 KitAlysis™ sample filled up with 1 ml THF 2.0 µL 0.50
12 XPhos Pd G3 KitAlysis™ sample filled up with 1 ml THF 2.0 µL 0.50
13 amine educt 1 mg/mL 1.0 µL 0.19
14 Ar-Br educt 1 mg/mL 1.0 µL 0.77

Good reaction progress was observed in tracks 1 – 5 and 8 – 12. Byproduct formation somewhat different in the lower Rf value region as well as amine educt amount (Rf 0.19). Significant concentrations of educts were observed in tracks 6 and 7 (MorDalPhos Pd G3, BINAP Pd G3).

    

            Figure 2a. Developed plate under white light               Figure 2b. Developed plate at 254 nm

 

Figure 2c. Developed plate at 366 nm

Confirmation of reaction product by mass spectrometry: Formation of ACN adduct via radical ionization

 

Figure 3. Mass spectrum (ESI+) of product [M+ACN]
 

 


Biphenyl-4-yl-di-p-tolyl-amine
(M=349.568 g/Mol)

 

Application data
Chromatography Plate HPTLC Silica gel 60 F254 MS-grade
Sample preparation Fill up the KiTAlysis™ samples with 1mL tetrahydrofuran (THF)
Educts: Dissolve 1 mg each in 1 mL THF
Sample application ATS 4 sample applicator (Camag), 6 mm bandwise
Application volume 1.0 µl track 13-14 / 2.0 µL track 1-12
Mobile phase n-Heptane / dichloromethane 6/1 (v/v) + 0.1% trifluoroacetic acid
Migration distance 5 cm
Migration time 10-11 min
Extraction Extraction equipment Plate Express (Advion)
Extraction solvent Acetonitrile / water 95/5 (v/v) + 0.1 % formic acid
Extraction flow 0.2 mL/min
Detection Documentation equipment TLC Visualizer (Camag)
Wavelength scan at white light, 254 nm, 366 nm
Staining -
MS equipment Single quadrupole mass spectrometer Expression CMS (Advion)
MS detection ESI(+) mode (m/z 50 - 1200)

 

Ordering information
KitAlysis™ 24-well Reaction Block and Inertion Box Combination Starter Kit Z742108
KitAlysis™ High-Throughput Buchwald-Hartwig Amination Reaction Screening Kit KITALYSIS-CN
KitAlysis™ High-Throughput Suzuki-Miyaura Cross-Coupling Reaction Screening Kit KITALYSIS-SM
KitAlysis™ High-Throughput Medium (5, 6, 7) Ring Closing Metathesis Reaction Screening Kit - Pack of 2 KITALYSIS-RCM
KitAlysis™ High-Throughput 24 Pd Precatalyst Reaction Screening Kit-Pack of 2 KITALYSIS-PD
HPTLC silica gel 60 F254 MS-grade 1.00934
Acetonitrile hypergrade for LC-MS LiChrosolv® 1.00029
Trifluoroacetic acid for spectroscopy Uvasol® 1.08262
Dichloromethane for liquid chromatography LiChrosolv® 1.06044
n-Heptane for liquid chromatography LiChrosolv® 1.01261
Tetrahydrofuran for liquid chromatography LiChrosolv® 1.08101