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Версия для печати | Главная > Центр > Научные советы > Научный совет по катализу > ... > 2022 год > № 103

№ 103



  • Владимир Александрович ЛИХОЛОБОВ – к 75-летнему юбилею
  • XXIV Международная конференция по химическим реакторам
  • За рубежом
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Владимир Александрович Лихолобов - К 75-летнему юбилею


XXIV Международная конференция по химическим реакторам ХимРеактор-24


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Nickel catalyst enables versatile amine synthesis
Method creates hundreds of different amines from handy nitriles



Amines are ubiquitous in the pharmaceutical and chemical industries, and a nickel-based catalyst has now opened up a promising route to make these molecules from widely-available nitrile compounds (Science 2022, DOI: 10.1126/science.abn7565).

Primary amines, in which a nitrogen atom is bonded to just one carbon, are often made by reducing nitrile groups using hydrogen. It’s an efficient and cost-effective approach, widely used in the production of nylon, surfactants, and plastics. In contrast, the various methods used to make secondary or tertiary amines, where nitrogen carries two or three carbon groups, tend to be more complicated and involve more waste.

So chemists have been searching for ways to use nitriles to make secondary and tertiary amines using a process called hydrogenative coupling. This involves reacting a nitrile with hydrogen to produce a primary imine intermediate, and then coupling the imine to a primary or secondary amine. This coupling displaces the imine’s nitrogen in the form of ammonia, and forges a new C–N bond to produce a secondary or tertiary amine.

The problem is that route generally produces a mess of different products. One reason is that the imine intermediate can itself react with hydrogen to make an unwanted amine, which then muscles in on the coupling reactions.

A team led by Rajenahally Jagadeesh and Matthias Beller at the Leibniz Institute for Catalysis has now developed a catalyst that can steer the hydrogenative coupling reaction along the right course, ensuring high selectivity for the desired product. The key is to make sure that the reaction between the imine intermediate and hydrogen is much slower than the intended coupling reaction, which minimizes unwanted side reactions.

After testing a range of different catalysts and conditions, the researchers settled on a champion catalyst that contain nickel bound to a triphosphine ligand. The reaction worked well at 100–120 °C and 4000 kPa of hydrogen, and the team used this process to make more than 230 different amines. “We can make complex agrochemicals and pharma-ceuticals, and it also has a very wide applicability for the fine- and bulk-chemical industries,” says Jagadeesh.

The catalogue of compounds made with the reaction featured many chiral molecules, including the drug tecalcet, used to treat conditions related to the parathyroid glands. The method can also couple nitriles with ammonia, an approach the researchers used to make primary amines labeled with a nitrogen-15 isotope that could be used in metabolic studies. The team prepared a handful of products at the 10 g scale, and Jagadeesh says the reaction should be amenable to further scale-up.

“This research is excellent. I was overwhelmed to see how many amines could be prepared,” says Yasunari Monguchi at Daiichi University of Pharmacy. One particular advantage, Monguchi says, is that it uses a very simple catalyst system that relies on a commercially available ligand.

The reaction worked well with precursors containing a range of different functional groups, although it stumbled when faced with aldehydes, alkynes, and a few other groups. This versatility means the procedure could be used to modify nitrile-containing compounds at the end of a long synthesis—a strategy known as late-stage functionalization—to make many analogs of drug candidates for high-throughput screening, for example.

The team is now investigating the mechanism of the reaction and hopes to reduce the temperature and pressure of the reaction using a cobalt-based catalyst that is showing early promise.


Single catalyst molecules tracked in solution
Fluorescence microscopy traces Grubbs catalysts’ winding paths during polymerization


Fluorescent tags reveal the motion of active ruthenium catalysts stuck to the ends of polymer chains


The catalysts that buzz around inside a reaction are rather like a swarm of midges—you know they’re there, but each one is so small and fast that they seem impossibly difficult to track in flight. Until now.

For the first time, researchers have measured the motion of individual catalyst molecules during a reaction (J. Am. Chem. Soc. 2022, DOI: 10.1021/jacs.2c03566). Such insights could assist in the design of better catalysts, says Suzanne Blum of the University of California, Irvine, who led the work.

The research relied on superresolution fluorescence microscopy, which is already used to scrutinize the movements of single enzymes. But the technique has yet to tackle the challenges presented by imaging single molecules of chemical catalysts, Blum says. The team set their sights on a reaction that uses a ruthenium catalyst to add monomers to a growing polymer. Crucially, each catalyst molecule remains tethered to the end of a polymer chain, slowing the catalyst’s movement enough for reliable imaging.

During the experiment, the researchers interrupted the reaction once some polymer had formed and washed away any unreacted molecules. Then they added an extremely dilute solution of monomers tagged with fluorophores that briefly glow green when hit by blue light. These tagged monomers were incorporated into the polymer chains, right next to the ruthenium catalyst at the tip.

Giving the reaction a flash of blue light once every second provided regular updates on the positions of each polymer-bound fluorophore, and its adjacent catalyst. Meanwhile, unattached fluorophores still floating in solution moved around too quickly to register on the camera, so they did not muddle the images.

The microscope could pinpoint polymer-bound fluorophores to within 32 nm, enabling the team to calculate that about one-quarter of ruthenium catalysts were effectively stationary. A similar proportion moved around vigorously, traveling an average of 145 nm each second, while the remainder roamed more modestly.

This variation in movement may be due to the catalysts being more or less entangled in the spaghettilike mass of polymer chains, which could also affect the catalysts’ access to monomers or solvent molecules. “The most important finding from the experiment is that during polymeriza-tion the catalysts exist in many different environments,” Blum says.

If that environment is too cramped or restricts the supply of monomers, the polymer strand will grow more slowly. That could in turn affect how long different polymer strands grow, a key factor in determining the polymer’s bulk properties.

“A polymer is a complex sample; it’s always a distribution of molecular weights and lengths, and now we start to understand where this is orignating from,” says Johan Hofkens of KU Leuven, who works on single-molecule and superresolution microscopy. “I think it’s an interesting step forward to get this insight.”

Blum hopes that the method could help chemists to design catalysts that have more uniform motions during polymerization—for example, by tweaking their ligands so that they repel nearby polymer strands and ensure the catalysts can access a similar amount of monomers. This could produce more consistent chain lengths that improve the polymer’s material properties.

Her team is now applying the technique to other kinds of reactions. Not all reactions will be compatible with a fluorophore tag, Hofkens cautions. “But as long as you’re sure that you don’t disturb the process that you’re looking at, it’s a perfect technique, and it will find wider applications,” he says.


A greener path toward vanillin from paper pulp
A new electrocatalytic process makes vanilla’s main flavor compound from kraft lignin

Vanillin is one of the world’s most popular aroma chemicals and fra-grances. However, 85% of it is synthesized from petrochemical precursors, and the food chemical industry is eager to find more sustainable sources. Researchers have now developed an electrochemical method to obtain vanillin from lignin, a tough biopolymer that is a by-product of the paper industry (ACS Sustainable Chem. Eng. 2020, DOI: 10.1021/acssuschemeng.0c00162).

A new electrochemical process could maximize the production of vanillin from lignin, a renewable by-product of the paper pulping process.

Lignin, left over after cellulose fibers are removed from wood to make paper, contains a mix of aromatic compounds that chemists have found ways to transform into a range of useful products. In the new study, Siegfried R. Waldvogel of Johannes Gutenberg University Mainz and colleagues created vanillin via a simple reaction. They first dissolved lignin and caustic soda in water and heated the solution. Next, they applied an electric current to the high pH solution using inexpensive nickel electrodes, breaking down the lignin and oxidizing it to produce vanillin in yields of up to 4.7%. “This may not seem impressive, but it is a remarkable selectivity,” Waldvogel says. No toxic or noxious side products are produced. Scandinavian company Borregaard already produces vanillin commercially from lignin via a copper-catalyzed oxidation. However, the process requires high temperature and pressure, and costly purification steps to remove the catalyst, Waldvogel says. Also, it uses a more specialized lignin raw material, whereas the new approach uses lignin from the kraft process, which yields 90% of the world’s paper pulp. About 150 million t of kraft lignin is generated per year, Waldvogel says, making it the most widely available carbon-based material after crude oil.

“This process is greener than currently available alternatives,” says Pablo Ortiz, a process chemist specializing in sustainable development at VITO, the Flemish Institute for Technological Research. Moreover, he values the use of kraft lignin as starting material. “Potentially, this method has the possibility to give higher yields of vanillin than Borregaard’s,” which is 0.3% by weight overall.

Waldvogel’s team has a new grant from the European Commission to build a pilot plant for continuous vanillin production at larger scale. The researchers would eventually like to use crude kraft lignin directly from the pulping process—a basic raw material known as black liquor—to reduce the need for caustic soda and water.

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