Enantioselective Organocatalysis through Hydrogen Bond-Assisted Halogen (X) Bonding – Bond-X-Bond

We analyzed these failures by the long distance of the reactive site from the catalyst due to the length and directionality of the halogen bond.
To solve this problem, the Bond-X-Bond project proposes to prepare catalysts where the halogen bond cooperates with one or more hydrogen bond(s), allowing to create secondary interactions and increasing the rigidity of the structure to facilitate the positioning. stereochemical information near the substrate.

To start the project, we first tried to develop an efficient and flexible synthesis of our catalysts, which consist of iodoazolium ions carrying at least one hydrogen bond donor. To simplify this task, which is already a challenge in itself, we have favored achiral targets, in order to select the best hydrogen bond donor(s) by evaluating the cooperation of the hydrogen bond by physical methods. chemicals and monitoring the speed of different reactions. The key step in the synthesis is a nucleophilic substitution reaction of a benzylic bromide carrying the hydrogen bond donor by an iodoazole. A counterion exchange then allows a non-coordinating counterion to be installed to avoid its competition when interacting with Lewis bases. The first analyzes by ITC, NMR and the first tests in catalysis have so far not made it possible to characterize an XB / HB collaboration. A few weeks ago, a concurrent study on this subject in the iodopyridinium series was published by the Berryman group (Angew. Chem. Int. Ed. 2021, 60, 3685), with shorter spacers between the two donor functions of XB and HB. We are therefore in the process of preparing a publication on our first results to mark the ground, while working on a new series of compounds with shorter spacers.

To keep important elements of novelty in our project, we are of course continuing to develop our research hypotheses. In collaboration with several colleagues from our institute, we are working on other families of hydrogen bond donors, which were not mentioned in the initial ANR project: chloroazaphosphatrans and bis(iodoazole)boronium ions. We are going to study the possibility of inserting a hydrogen bond donor in these structures, which could then meet the initial specifications of the project.

1 publication in preparation, another one in the coming months

Developing new transformations and controlling their selectivities constitute the core of synthetic organic chemistry. Many kinds of selectivity issues can arise (chemo-, regio- and stereo-selectivities), often simultaneously, requiring a careful design of the reaction conditions to solve them. The most powerful tool to enable selective synthesis is catalysis, that is to say the use of tailored chemical entities that are able to accelerate the reaction without being consumed. Catalysts can be either heterogenous or homogeneous, and are also classified based on their structural features into three main families: metal catalysts (where a metal atom is responsible for the activity), biocatalysts (enzymes and their analogues), organocatalysts (purely organic molecules of low to moderate molecular weights). All three families have their inherent advantages and drawbacks.

Even though the origins of organocatalysis can be traced back to the 19th century, it is only since the beginning of the 21st century that it has emerged as an efficient and more widely applied synthetic tool. When compared to other catalysts, organocatalysts have the general advantages to be stable, easy to use, and non-toxic, making them interesting solutions in the context of green chemistry. Organocatalysis has developed around the concept of mode of activation that characterizes the nature of the interaction with the reaction partners. If many activation solutions exist with Lewis bases, Brønsted bases and Brønsted acids, Lewis acid organocatalysis still lags behind, and developing new activation possibilities is highly desirable.

Halogen atoms linked to an electron-withdrawing group develop a s-hole responsible for their Lewis acid character. As a result, they can take part in a non-covalent stabilizing association (?G° up to -50 kJ.mol-1) with Lewis bases, referred to as halogen bonding. This Lewis acid property is directly linked to the polarizability of the halogen atom so that it is mostly observed for the heaviest ones, especially iodine. Moreover, diversified neutral (perfluoroalkyl chains, perfluoroarenes…) or cationic (pyridinium or azolium rings) can take the role of the electron-withdrawing group. Halogen-bonding organocatalysis has started to emerge over the past five years but its enantioselective version is still largely underdeveloped. In the Bond-X-Bond project, we aim to synthesize and understand the behavior of new organocatalysts where hydrogen-bonding (HB) will assist halogen bonding (XB) activation to achieve enantioselectivity.