Determination of the Absolute Configurations of Chiral Alkanes – An Analysis of the Available Tools

Abstract

Knowledge of absolute configurations (ACs) is crucial to understand the properties and functions of chiral molecules. Although the development of asymmetric reactions has enabled access to a large variety of enantioenriched compounds, stereochemical assignments of chiral molecules, especially chiral alkanes, remain challenging. In this Minireview, we first summarize common analytical techniques for AC determination with a focus on chiral alkanes as analytical targets. Next, we describe some of our efforts over the last 20 years on syntheses and AC determination of chiral alkanes including [123]tetramantane, hexadeuterated neopentane, and trans‐perhydroazulene. Lastly, microscopic techniques and the crystalline sponge method are discussed as particularly promising approaches to revolutionize the field of stereochemical analysis.

Crystalline Sponge Method: X‐ray Structure Analysis of Small Molecules by Post‐Orientation within Porous Crystals—Principle and Proof‐of‐Concept Studies

“…There are no efficient and reliable methods for analyzing the absolute configuration of chiral hydrocarbon compounds [124] . Chemical conversion of hydrocarbons into known chiral compounds or the introduction of heavy atoms into the framework to be analyzed by X‐ray Bijvoet method is not easy because of the lack of appropriate functional groups for the chemical transformations.…”

Crystalline Sponge Method: X‐ray Structure Analysis of Small Molecules by Post‐Orientation within Porous Crystals—Principle and Proof‐of‐Concept Studies

“…There are no efficient and reliable methods for analyzing the absolute configuration of chiral hydrocarbon compounds. [124] Chemical conversion of hydrocarbons into known chiral compounds or the introduction of heavy atoms into the framework to be analyzed by X-ray Bijvoet method is not easy because of the lack of appropriate functional groups for the chemical transformations.Anonfunctionalized chiral hydrocarbon, 5a-androstane,was examined by the CS method, and the absolute structure of the hydrocarbon was reliably analyzed with aF lack parameter value of 0.067 (15).…”

Photoelectron Circular Dichroism as a Probe of Chiral Hydrocarbons

“…Clearly the former requires the presence of an absorption band and the availability of a suitable circularly polarized light source, while ORD, showing a dispersive signal, dies off very slowly from absorption bands, and may give a detectable signal far from those [1,2]. In fact, it was recently pointed out that while optical CD may often be unusable in the case of absorption bands in the VUV, e.g., in saturated hydrocarbon molecules, ORD is still usable [3,4].…”

“…A last important remark is the role of the theory and the availability of accurate models for the simulation of the experimental results. It is fair to say that up to the development of dependable Quantum Chemistry approaches to the calculation of optical chirality the crucial assignment of the absolute configuration was very difficult, as few empirical rules, as well as the chemical similarity of two related molecules, had very limited predictive power, and led to wrong assignments in the past [3,4].…”