Teaching Experiment To Elucidate a Cation−π Effect in an Alkyne Cycloaddition Reaction and Illustrate Hypothesis-Driven Design of Experiments

Abstract

An organic chemistry experiment is described that is based on recent research to elucidate a novel cation-π interaction between tetraalkammonium cations and propargyl hydrazines. This non-bonded interaction is a key component of the mechanism of ammonium-catalyzed intramolecular cycloaddition of nitrogen to the terminal carbon of a C-C triple bond of the propargyl substrate. In this teaching experiment, reactions and control experiments are employed to demonstrate the testing of two alternative mechanistic hypotheses. Specifically, cyclization reactions are performed with a soluble base (sodium phenoxide) with and without tetrabutylammonium bromide under homogeneous conditions. Students observe that the added ammonium salt accelerates the reaction. They are then encouraged to develop a testable hypothesis for the role of the ammonium salt in the cyclization mechanism: typical phase transfer or other. IR spectroscopy is then used to directly observe a dose dependent shift of the alkyne stretching mode due to a cation-π interaction. In this experiment, undergraduate “researchers” were able to practice the scientific method on a contemporary system and see how data are generated and interpreted to adjudicate between rival hypotheses in a way that emulates authentic and current research in a lab setting. This experimental design was tested on students enrolled in the introductory undergraduate Organic Chemistry Lab.

A Brief Introduction to Chemical Reaction Optimization

“…Although there are several options for DoE designs, the statistical knowledge necessary for chemists to select the correct experimental procedure (based on their needs for a given experimental outcome) and analyze the resulting data is low. Because of the relative ease of the technique, DoE can be easily taught to chemistry students and adopted for use in academic laboratories as intuition-based methods are superseded. ,, Furthermore, the ubiquity of DoE in process laboratories in industry highlights that these statistical methodologies must be taught to chemists; this will help to develop the skillsets of the students and familiarize them with common optimization protocols that they are likely to encounter in future. For further detailed reading on statistical modeling within DoE, refer also to Telford and Severin and co-workers …”

Active Learning in the Undergraduate Chemistry Laboratory: Synthesis of Biodiesel from an Amazon Region Oil (Babassu): Keep It Simple!

“…For example, one needs to carry out 9 experiments (3 2 ; two experimental variables, each with three levels) to determine the effects on the yield of reaction time, e.g., 30, 60, and 90 min, and temperature, e.g., 25, 50, and 75 °C. This approach is much more efficient in comparison with the traditional trial and error approach, where one variable is changed at a time. , The use of DOE is not widespread at the undergraduate level, although some interesting didactic experiments on this subject were published. ,− …”

Cation−Π Interactions in Biochemistry: A Primer

“…In 2000 in this Journal, the use of the online program RasMol was reported to give students exercises in 3D visualization of macromolecules in the Protein Data Bank (PDB) and to enable students to determine π-type interactions, including π–π, CH−π, and cation−π . Subsequently, an organic chemistry experiment was designed to help students elucidate cation−π effects in a cycloaddition reaction . This present article expands on Cox’s pioneering work by precisely defining and geometrically constraining cation−π interactions in proteins, describing experimental work required to support the hypothesis of an energetically significant cation−π interaction, and providing quantitative data and exercises highlighting the enormous impact that cation−π interactions have on biochemistry.…”