Many molecules in living organisms and pharmaceuticals share a structure in common called a β -amino alcohol, in which an amino group and a hydroxyl group sit on neighboring carbon atoms. These groups, important building blocks in biology and medicine are found in compounds such as sphingosine and ephedrine. In such molecules, the exact three-dimensional arrangement of atoms can greatly affect their biological activity, even if they have the exact chemical formula. Thus, chemists seeking to synthesize them require techniques that produce the specific version they need.
One common method is the well-studied Henry reaction, which joins an aldehyde and a nitroalkane to form a β -nitro alcohol that can be later reduced to a β -amino alcohol. However, most catalyst-based approaches to the Henry reaction produce what’s known as the syn form, where the two groups point to the same side of the molecule. The anti form, in which groups point to opposite sides of the molecule, has proven much harder to synthesize reliably.
To address this challenge, a research team led by Professor Takayoshi Arai from the Graduate School of Science at Chiba University, Japan, has designed a new catalyst that favors the anti form by leveraging several types of molecular interactions in a single system. Their study, which was published online in the journal Angewandte Chemie International Edition on September 24, 2026, was co-authored by Dr. Soushi Tsurusaki and Dr. Hidesato Iwama, both from the Graduate School of Science at Chiba University.
The researchers built their catalyst, called o -X-F 4 -PyBidine-Ni(OTf) 2 (X = Br or I), around a nickel complex containing a molecular structure called PyBidine. They introduced either bromine or iodine at a specific position on the catalyst to create a site capable of halogen bonding. In halogen bonding, a positive charge called the σ -hole forms on the surface of a halogen atom and establish electrostatic interactions with the functional groups. This non-covalent interaction helped position the aldehyde in a specific orientation. Hydrogen bonding, a more familiar attractive force that arises between a hydrogen atom and an electronegative atom, also helped hold the aldehyde in place and activate it. Meanwhile, nickel, alongside a base called triethylamine, activated the nitroalkane.
Together, these interactions positioned the two reacting molecules in a favorable stretched-out arrangement that led to the anti -product. Using alcohol as the solvent, the catalyst produced the anti form with up to 96:4 selectivity over the syn form for many reactant combinations. It also gave up to 99% enantiomeric excess, which means nearly all of the product was the same version of the two possible mirror images of the anti form. The method worked with many aromatic aldehydes, including those with a heterocyclic ring, and with several kinds of nitroalkanes. “ The coordinated functioning of diverse interactions on a single catalyst represents an advance in state-of-the-art catalytic chemistry ,” highlights Prof. Arai.
The bromine version of the catalyst was often more active than the iodine one, possibly because bromine is smaller and leaves more room for the molecules to approach. To understand the finer details of how the catalyst selectively controls the reaction, the team ran a series of computer simulations. These showed that the most favorable pathway involves a halogen bond between the bromine atom and the aldehyde’s aromatic ring, along with hydrogen bonding and interactions between nickel and the nitro group.
Overall, the findings of this work could provide a useful route for synthesizing anti- β -amino alcohols, since the nitro group in the reaction products can be readily converted into an amino group using well-established chemical methods. More broadly, the study demonstrates that halogen bonding can be used simultaneously with hydrogen bonding and metal coordination, as Prof. Arai explains, “ We demonstrated the higher-ordered cooperation of halogen bonds and hydrogen bonds on a metal catalyst in protic solvents, which is fascinating for the development of artificial metalloenzyme and halogen-bond-driven medicines .”
This type of cooperative catalyst design could provide new strategies for controlling chemical reactions and, in the longer term, contribute to the development of more complex catalytic systems.
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About Professor Takayoshi Arai from Chiba University, Japan
Professor Takayoshi Arai holds joint affiliations with the Graduate School of Science, the Soft Molecular Activation Research Center (SMARC), and Chiba Iodine Resource Innovation Center (CIRIC) at Chiba University. His research focuses on the development of new compounds and catalysts with specific functionalities and novel synthesis routes for known organic compounds for various applications, contributing to the advancements in catalysis and enantioselective synthesis. He has published over 150 peer-reviewed research articles on these topics.
Funding:
This research was supported by the IAAR Research Support Program, Chiba University, Japan, JSPS KAKENHI, grant number 26K01496 in Grant-in-Aid for Scientific Research (B).
Reference:
Title of original paper: Halogen-Bond-Assisted Anti -Selective Henry Reaction Promoted by a Chiral Nickel Catalyst
Authors: Soushi Tsurusaki 1 , Hidesato Iwama 1 , Risa Yoshida 1 , Sumire Kobayashi 1 , Ryuhei Chiba 1 , and Takayoshi Arai 1
Affiliations: 1 Soft Molecular Activation Research Center (SMARC), Chiba Iodine Resource Innovation Center (CIRIC), Synthetic Organic Chemistry, Department of Chemistry, Graduate School of Science, Chiba University, Japan
Journal: Angewandte Chemie International Edition
DOI: https://doi.org/10.1002/anie.7009966
Angewandte Chemie International Edition
Experimental study
Not applicable
Halogen-Bond-Assisted Anti-Selective Henry Reaction Promoted by a Chiral Nickel Catalyst
24-Sep-2026
The authors declare no conflicts of interest.