New catalytic approach to accessing key intermediate carbocation

December 21, 2020

Human civilization in the 21st century is largely sustained by modern chemical technologies. The raw materials used in the manufacturing of a wide range of products, from clothing to plastics and pharmaceuticals, are mainly produced through efficient catalytic conversion of cheap feedstock chemicals into value-added organic commodities. In many cases, the chemical reactions involving organic compounds take place through short-lived reaction intermediates, such as carbocations.

Carbocations are chemical species containing a positively charged carbon atom. In general, these molecules are highly reactive toward many chemical transformations, and they frequently occur in many key reactions that have revolutionized synthetic and physical organic chemistry. Carbocation intermediacy is known to be responsible for a wide range of fundamental reactions, such as substitution, elimination, and rearrangement. The utilization of these reactions has significantly expanded the repertoire of available retrosynthetic approaches in chemical synthesis. Due to its extensive influence in the field of organic chemistry, the 1994 Nobel Prize in chemistry was awarded in recognition of the advancement in carbocation chemistry.

However, the intrinsic instability of carbocation often becomes a major bottleneck in synthetic chemistry. The carbocations are short-lived intermediates in most reactions, and while their lifetimes can vary depending on the type of reaction, it is usually within a scale of a few nanoseconds, which are billionths of a second, or shorter. Therefore, it is extremely challenging to control its reactivity or perform spectroscopic observation. For these reasons, the catalytic accessibility of the carbocation-mediated reaction has been largely restricted, and it is also difficult to suppress the unwanted formation of other side products.

To address this problem, a team of researchers led by Prof. CHANG Sukbok at the Center for Catalytic Hydrocarbon Functionalizations within the Institute for Basic Science (IBS, South Korea) have developed a novel catalyst capable of accessing transient carbocation intermediates in order to achieve regiocontrolled elimination reaction. Using this new catalyst, they have succeeded in producing two types of ring-shaped molecules called γ- and β-lactams, which are highly sought after in synthetic, organic, and pharmaceutical chemistry.

Traditional catalysts are mostly limited to generating the carbocation intermediates and do not influence the regioselectivity of the reaction. Therefore, it is often required to add costly elimination pathways to remove undesirable products. IBS researchers challenged this issue by developing a multifaceted catalytic system. In 2018, they independently developed a novel iridium catalyst that converts hydrocarbons into versatile γ-lactams, a technological feat that was published in Science. This catalyst was further repurposed to directly engage in both generation and selective conversion of carbocation intermediates. The key to success is that the customized catalyst temporarily generates Ir-nitrenoid species, whose electrophilicity is high enough to access carbocation species and insert bonds into carbon-carbon double bonds.

In this study, a quantum chemistry simulation used dioxazolone as a model substrate to analyze the reaction mechanism in detail and find the optimal structure of potential catalysts. According to such computer predictions, they identified that a ligand in the catalyst can play a critical role of an internal base to selectively abstract one specific proton between two competing sites within a carbocation. Through further optimization, they tailored a new high-quality catalyst with unprecedented selectivity (>95%) for the desired allylamide products over enamides.

This customized catalyst was readily applicable for the preparation of γ-lactams and a more challenging process of producing β-lactams. γ-lactams have been recognized as a key structural motif in both natural and synthetic molecules, which include a number of drugs used in cancer therapy. On the other hand, β-lactam is one of the most important classes of antibiotic agents and pharmaceutical products, as exemplified by penicillin G and its derivatives.

In addition to its ability to control the regioselectivity, the use of the new catalyst further extends into asymmetric reactions. The catalyst also succeeded in synthesizing chiral compounds with excellent enantioselectivity of up to 98%. Enantioselective synthesis is extremely important in the pharmaceutical industry, as the same molecule with different chirality may have entirely different biological activity. For example, (R)-enantiomer of thalidomide provides therapeutic effects, while its (S)-enantiomer causes birth defects. As the separation process is expensive, many drugs are sold as racemic mixtures. Therefore, it is expected that this technology will find widespread applications in pharmaceutical chemistry to synthesize a wide class of clinical drugs while minimizing their side effects.

Professor Chang said, "The research was initiated by Dr. HONG Seung Youn who came up with this creative idea. He also actively led the theoretical investigation and experiments of this study. These findings have not only made new academic advances that opened a new avenue for accessing temporary carbocation intermediates, but also will provoke further developments with many intriguing applications."
This research was published in Nature Catalysis (impact factor: 30.471) on 21 December 2020.

Institute for Basic Science

Related Chemistry Articles from Brightsurf:

Searching for the chemistry of life
In the search for the chemical origins of life, researchers have found a possible alternative path for the emergence of the characteristic DNA pattern: According to the experiments, the characteristic DNA base pairs can form by dry heating, without water or other solvents.

Sustainable chemistry at the quantum level
University of Pittsburgh Associate Professor John A. Keith is using new quantum chemistry computing procedures to categorize hypothetical electrocatalysts that are ''too slow'' or ''too expensive'', far more thoroughly and quickly than was considered possible a few years ago.

Can ionic liquids transform chemistry?
Table salt is a commonplace ingredient in the kitchen, but a different kind of salt is at the forefront of chemistry innovation.

Principles for a green chemistry future
A team led by researchers from the Yale School of Forestry & Environmental Studies recently authored a paper featured in Science that outlines how green chemistry is essential for a sustainable future.

Sugar changes the chemistry of your brain
The idea of food addiction is a very controversial topic among scientists.

Reflecting on the year in chemistry
A lot can happen in a year, especially when it comes to science.

Better chemistry through tiny antennae
A research team at The University of Tokyo has developed a new method for actively controlling the breaking of chemical bonds by shining infrared lasers on tiny antennae.

Chemistry in motion
For the first time, researchers have managed to view previously inaccessible details of certain chemical processes.

Researchers enrich silver chemistry
Researchers from Russia and Saudi Arabia have proposed an efficient method for obtaining fundamental data necessary for understanding chemical and physical processes involving substances in the gaseous state.

The chemistry behind kibble (video)
Have you ever thought about how strange it is that dogs eat these dry, weird-smelling bits of food for their entire lives and never get sick of them?

Read More: Chemistry News and Chemistry Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to