Goodbye transition metals – novel approach in organic synthesis

Controlling regioselectivity remains one of the major challenges in hydrocyanation. When an unsymmetrical alkyne undergoes this reaction, it typically yields a mixture of regioisomers. This complicates product separation, making it more difficult and costly. Now, scientists from the Institute of Physical Chemistry of the Polish Academy of Sciences have demonstrated a novel approach that addresses this problem. Their breakthrough enables full control over the reaction outcome — making hydrocyanation greener, more efficient, and more economical than ever before. Here is how it works.

Making complex organic molecules – such as those used in synthetic polymers, pharmaceuticals, or agrochemicals – often relies on catalysts that accelerate reactions and improve their efficiency. Among the valuable yet synthetically challenging targets are nitriles, which are increasingly popular due to their versatility: they can be readily converted into amines, carboxylic acids, aldehydes, and other useful compounds. However, synthesizing nitriles efficiently is not trivial. A common approach involves hydrocyanation – a reaction in which hydrogen cyanide (HCN) is added across carbon–carbon multiple bonds, especially the triple bonds present in alkynes.

Hydrocyanation, since its discovery over 70 years ago, has become a powerful strategy for the synthesis of nitriles. However, conventional implementations of this method face serious limitations – most notably, poor control over regioselectivity, especially when applied to unsymmetrical alkynes. Transition metal catalysts, such as nickel or palladium, are typically employed in these reactions, but they are often toxic, expensive, and raise concerns regarding environmental impact and sustainability. These drawbacks significantly limit the practical utility of traditional hydrocyanation, particularly in the synthesis of more complex molecules.

Now, researchers from the Institute of Physical Chemistry of the Polish Academy of Sciences – Aleksandra Zasada and Dawid Lichosyt – have demonstrated a more efficient and sustainable approach. In their recent study, they introduced a transition-metal-free dual-catalyst system based on triphenylphosphine (PPh₃) and triethylamine (TEA). This strategy avoids the need for metal complexes altogether. Instead of the classical direct hydrocyanation, the reaction proceeds through a reversible rearrangement of alkynes into allenes, followed by selective transfer of hydrogen cyanide (HCN) to the allene intermediate – all under mild, one-pot conditions. Presented method relies on the presence of electron-withdrawing groups, which enable the key alkyne–allene isomerization and support the overall reactivity. After extensive optimization, the two catalysts were shown to operate in a fully compatible manner. The resulting dual system enabled the synthesis of valuable vinyl nitriles in excellent yields – reaching up to 97%. It also proved compatible with structurally complex molecules, including derivatives of natural products, highlighting its potential for broader application in organic synthesis.

“The control of selectivity and typical reliance on expensive and toxic transition metal-based catalysts significantly hinder the utility of hydrocyanation Here, we report an exclusively regioselective hydrocyanation of unbiased alkynes, driven by base-catalyzed reversible alkyne-allene isomerization and phosphine-catalyzed HCN transfer to the allene.” – says Aleksandra Zasada

Perhaps most notable, the metal-free system is not only highly selective but also remarkably economical — estimated to be around 2,500 times cheaper than conventional transition metal-based methods. It avoids the formation of unwanted byproducts and eliminates the need for time-consuming purification steps, making the overall process significantly more efficient.

“The methodology enables an efficient synthesis of vinyl nitriles (40 examples) under mild conditions, achieving excellent yields, rare anti-stereoselectivity (up to 20:1) and broad functional group tolerance. Compared to conventional TM-based methods, it offers superior regioselectivity, yield efficiency, significant cost reduction and sustainability advantages.” – dr. Dawid Lichosyt remarks.

Another key advantage of the method is its ability to switch regioselectivity by simply replacing one of the catalysts. The researchers showed that exchanging the phosphine (PPh₃) for tetrabutylammonium cyanide (TBACN) allows for the selective formation of the complementary regioisomer — one that cannot be accessed using the original phosphine–amine system. This regiodivergent design provides a powerful tool for tailoring reaction outcomes, greatly expanding the method’s synthetic utility.

Dr. Dawid Lichosyt remarks: “Regioselectivity control is critical for the practical utility of hydrofunctionalization methodologies, but access to both regioisomers via a regiodivergent strategy is equally significant. Thus, we investigated the potential to switch the regioselectivity of the dual-catalytic system to exclusively produce the complementary isomer, which is inaccessible by the phosphine-amine catalytic system.”

Even better, this breakthrough is not limited to hydrocyanation alone. It demonstrates a general principle that could be extended to other hydrofunctionalization reactions — key transformations in organic chemistry where a hydrogen atom and a functional group are added across a multiple bond. The success of this metal-free, dual-catalyst strategy shows that selectivity can be achieved without relying on transition metals, using only well-matched combinations of simple organic catalysts. This opens up new possibilities for designing cleaner, more selective, and more accessible methods for building complex molecules — both in academic research and in industrial applications. Such control, achieved without relying on transition metals, represents an important step toward broader synthetic applicability.

This work was financially supported by the Polish National Science Centre, Poland (SONATA 2020/39/D/ST4/01152).

CONTACTS:

Dr. Dawid Lichosyt

Institute of Physical Chemistry of the Polish Academy of Sciences

Phone: +48 22 343 3218

email: dlichosyt@ichf.edu.pl

SCIENTIFIC PAPERS:

“Regioselective Hydrocyanation of Internal Alkynes Enabled by a Transition-Metal-Free Dual-Catalytic System”

Aleksandra Zasada, Dawid Lichosyt

Angewandte Chemie International Edition, 2025

DOI: https://doi.org/10.1002/anie.202500940