Successful activation of π electron system using halogen bond-donor iodine catalyst -- A novel method of synthesizing useful indole derivatives for drug development and other applications



Prof. Takayoshi Arai (director of the Soft Molecular Activation Research Center and the Chiba Iodine Resource Innovation Center) and specially appointed Assistant Prof. Satoru Kuwano (Molecular Chirality Research Center) of the Chiba University Graduate School of Science, Faculty of Science, have succededed in "developing π electron compound activation functions using a halogen bond-donor iodine catalyst" (Figure 1). This study was the result of joint research with Prof. Masahiro Yamanaka of the Rikkyo University Department of Chemistry.

Research overview

Figure 1: Synthesis of indole derivatives based on activation of π electron system compounds using a halogen bond-donor iodine catalyst

Study background and objective

Hydrogen bonds, which are the basic interaction of molecular recognition, are pervasive in living organisms and elsewhere. Although hydrogen bonds are widely used in the activation of reaction substrates, they do not have sufficient functional group selectivity for controlling advanced catalytic chemistry. The advancement of modern fine chemistry requires the introduction of novel activation modes that can achieve specific forms of activation. The halogen bond has attracted attention as a new interaction for creating functional molecules due to hopes it will be able to selectively activate highly soft chemical species (functional groups). It has previously been demonstrated in fields such as crystal engineering, biochemistry, and solution chemistry that halogen bond-donor iodine compounds form bonds with π electron compounds. However, there are no examples of the application of halogen bonds between an iodine compound and a π electron (C-I···π halogen bond) in catalytic chemistry, and the possibilites of application to functional molecule creation remain unexplored. In this study, our objective was to develop activation functions for π electron system compounds using a halogen bond-donor iodine catalyst, and to synthesize useful compounds.


Figure 2. [4+2] cycloaddition reaction using a halogen bond-donor iodine catalyst

① We discovered that when a halogen bond-donor iodine catalyst was reacted with 2-alkenyl indole, then stirred at room temperature in chloroform, the desired progression of a dimerization reaction was obtained at a high yield (Fig. 2). Further, combining 2-vinylindole and 2-styrylindole promoted a crossover [4+2] cycloaddition reaction, which obtained the desired product at a high yield. Analysis of the reaction mechanism using experimental chemistry and computational chemistry revealed that the cycloaddition reaction was driven by the formation of halogen bonds between iodine compounds and indole π electrons.

Figure 3: Comparison of iodine catalyst and Brønsted acid catalyst

② When the Brønsted acid catalyst trifluoroacetic acid is applied to a crossover [4+2] cycloaddition reaction, non-cyclic compound B is generated preferentially over target compound A (Fig. 3). Our results show that a halogen bond-donor iodine catalyst could be used as complementary tool for existing acid catalysts.

Figure 4: Analysis of transition states mediated by CI···π halogen bonds

③ Transition state analysis using computational chemistry showed that the iodine catalyst joins with a π electron at the indole 3 position via a halogen bond, which contributes to the stabilization of the transition state (Fig. 4). In the transition state conveying the primary diastereomer, the existence of an N-H···π interaction between an indole NH proton and a π electron on the benzene ring was also suggested.


There are no other examples of applying C-I···π halogen bonds in organic synthetic chemistry. This is an unexplored field of research. This study was the world's first application of C-I···π halogen bonds in catalytic chemistry, and was the result of pioneering research done at Chiba University.

Social contributions, ramifications

Development of new reactions that utilize C-I···π halogen bonds will make the synthesis of a wide variety of π electron-containing compounds possible, which would be a significant academic advancement. The ability to freely control halogen bonds in solution could lead to the creation of new functional molecules with halogen bonds such as in drugs and sensors. This study was the result of work on fusing halogen systems and π electron systems by Chiba University's Soft Molecular Activation Research Center, which was established to integrate the university's strong catalytic chemistry program, and work by the Chiba Iodine Resource Innovation Center on achieving higher functionality for iodine.

The results were published in Angewandte Chemie International Edition, a top chemistry journal.
Kuwano, S.; Suzuki, T.; Yamanaka, M.; Tsutsumi, R.; Arai, T. Angew. Chem. Int.Ed., [10.1002/ange.201904689].

This study was funded by the following grant-in-aids for scientific research: basic research (B) JP19H02709, young researchers 19K15553, and research in new academic fields JP16H01004 and JP18H04237 (precision controlled reactions) and JP18H04660 (hybrid catalysts). Assistance was also provided by the Futaba Foundation.

Explanation of terms

Halogen bonds:
Halogen bonds have attracted attention as a novel interaction with clear directionality that have applications in catalytic chemistry and the creation of functional molecules. However, because halogen bonds are formed by the positive charge on the back side of the RX bond of the molecular framework, it has been difficult to achieve stereoselectivity and other forms of high-level structural recognition.
π electron compounds:
In alkenes, alkynes, and aromatic compounds, in addition to the σ bond that forms the molecular framework, π electrons are used to form unsaturated bonds (also called π bonds). The π bond is higher in energy than the σ bond and determines the attributes (physical properties) of the molecule. An accurate understanding of π electrons is essential to understanding the reactivity of substrates. Recently, the functions of molecules with a large number of conjugated π electrons has attracted attention.
Indoles possess the structure shown at right and are common in biologically active natural products. Creating new methods of synthesizing molecules with indole skeletons is important for the development of new drugs.
Cycloaddition reaction:
Chemical reactions in which a π electron system is reacted with another π electron system (addition) to form a ring is called a cycloaddition reaction. These reactions are classified according to the number of backbone atoms of the molecule involved in the reaction. The example to the right is the famous Diels-Alder reaction, in which the number of backbone atoms is 4 for butadiene and 2 for ethylene, and is thus described as a "[4+2] cycloaddition reaction."
Soft Molecular Activation Research Center
Established at Chiba University on April 1, 2018, the center’s goal is to establish new concepts of molecular recognition and activation through the fusion of catalytic chemistry, analytical chemistry, and materials science. The center was founded to be a global research base for creating highly functional soft molecules. (director: Takayoshi Arai)
Chiba Iodine Resource Innovation Center
The center was selected for a fiscal 2016 Ministry of Education, Culture, Sports, Science and Technology project to build regional bases for science and technology demonstration, with the goal of achieving high functionality for iodine produced in Chiba. Equipped with state-of-the-art analytical instruments such as a 600 MHz NMR and XPS, the facility at the Nishi Chiba Campus was completed in spring 2018 to serve as a base for promoting joint research between industry, academia, and government. (director: Takayoshi Arai)

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