Introduction of Low-Barrier High-Throughput Experimentation in the Undergraduate Laboratory: Suzuki—Miyaura Reaction

Abstract

A contemporary undergraduate laboratory experiment incorporating parallel microscale experimentation was developed for the well-defined palladium catalyzed Suzuki–Miyaura cross coupling of 4-fluorophenylboronic acid with both 4-chloro- and 4-bromoanisole using 11 diverse phosphine ligands and one ligandless control. This laboratory introduces students to low-barrier high-throughput experimentation (HTE) technique that is widely utilized in both academic and industrial research settings. This experiment compliments current topics discussed in organic chemistry, inorganic chemistry, and organometallic chemistry lecture courses and serves to reinforce the students’ understanding of fundamental concepts of transition metal mediated cross-coupling reactions. Students are also exposed to common analytical tools (thin layer chromatography (TLC) and high-pressure liquid chromatography (HPLC)) used in research settings to analyze the corresponding experimental data.

(Ph3P)3CuCF3: Preparation and Application of an Air-Stable Trifluoromethylating Agent

“…The importance of organometallic reagents in the inorganic curriculum is supported by the Committee on Professional Training, a recent report providing modules for this field bridging students from the organic sequence to inorganic courses, and numerous recently reported laboratory exercises with elements of transition metal organometallics specifically utilized for organic transformations. − Despite this, currently there is only a single report of a copper-based organometallic reagent in this Journal , in the form of a lithium organocuprate (“Gilman”) reagent . However, no isolation or characterization was carried out as it was not relevant to their procedure.…”

“…This exercise is based on a previously reported, but far lengthier, protocol for trifluoromethylation of an aryl iodide. 9 The NMR-scale procedure allows students to determine the conversion progress (via appearance of product) using 19 F NMR spectroscopy. This introduces students to a common research approach of conducting small trials on an NMR scale before scaling up to synthetic quantities.…”

Buchwald–Hartwig Amination, High-Throughput Experimentation, and Process Chemistry: An Introduction via Undergraduate Laboratory Experimentation

“…Recently, high-throughput experimentation has also been introduced for undergraduate laboratories utilizing the Suzuki−Miyaura reaction. 20 Additionally, computationally guided syntheses are rapidly emerging to guide the design of synthetic routes to target molecules utilizing high-throughput experimentation. 21−24 Through guided-inquiry learning, students were introduced to air-free Schlenk techniques required of many transitionmetal-mediated reactions and high-throughput experiments often used in process chemistry.…”

“…In addition, even fewer of these examples introduce the concept of high-throughput experimentation to undergraduates, a particularly useful chemical application in catalysis and process chemistry, , also gaining ubiquity across all chemical research. Recently, high-throughput experimentation has also been introduced for undergraduate laboratories utilizing the Suzuki–Miyaura reaction . Additionally, computationally guided syntheses are rapidly emerging to guide the design of synthetic routes to target molecules utilizing high-throughput experimentation. − …”

Exploring the Effect of Phosphine Ligand Architecture on a Buchwald–Hartwig Reaction: Ligand Synthesis and Screening of Reaction Conditions

“…Palladium-catalyzed coupling reactions are fundamental methods in synthetic organic chemistry . Introductory-level textbooks have recently begun to include discussion of this area, and many instructional laboratory exercises are now available for showcasing the Suzuki–Miyaura coupling − and related reactions. − In contrast to these C–C σ-bond forming processes, the Pd-catalyzed coupling of amines with organic halides to form C–N σ-bonds, termed the Buchwald–Hartwig amination (BHA), is underrepresented in the instructional literature. Indeed, despite its broad utility, − only three instructional laboratory modules focusing on the BHA reaction have been reported.…”