Catalytic Reversible Hydrocyanation

No Need for Hydrogen Cyanide

  • Figure 1: Context of the work.Figure 1: Context of the work.
  • Figure 1: Context of the work.
  • Fig. 2: Scope of the new hydrocyanation reaction. [1] Ratio of linear to branched products. [2] 1.5 equiv. of reagent 1 instead of 5 equiv. [3] GC-yield. [4] 10 mol% Ni-cat, 10 mol% DPEPhos, 40 mol% AlCl3. [5] 15 equiv. of 1 used as reagent, 15 mol % Ni catalyst.
  • Fig. 3: Scope of the retro-hydrocyanation. [1] GC-yield.

The catalytic hydrocyanation of alkenes is an important reaction for research laboratories and the chemical industry. The traditional approach to hydrocyanation is limited by the use of highly toxic, corrosive and explosive hydrogen cyanide gas (bp 27°C). This limitation can now be overcome through the use of a recently reported transfer hydrocyanation strategy that does not rely on HCN gas.

Nitriles and alkenes are important synthetic intermediates in organic synthesis and their interconversion is crucial for the preparation of fine chemicals. The traditional approach to transform alkenes into nitriles uses the addition of HCN across an alkene by the so-called hydrocyanation reaction (Figure 1A) [1]. This process has found applications in the preparation of bulk chemicals – for example over 1 million tons of adiponitrile are produced each year through the hydrocyanation of butadiene (DuPont Process) [1]. Although the hydrocyanation is an industrially important reaction, it has found limited applications in laboratory scale research and fine chemical synthesis, mostly because of the extreme toxicity of HCN. Additionally, the HCN-mediated hydrocyanation reaction can be sluggish because HCN itself tends to deactivate the catalyst [1]. Finally, the reverse process, namely the transformation of a nitrile into an alkene (retro-hydrocyanation), is challenging to achieve because of the unfavorable thermodynamics of such a process. A distinct approach that would enable the reversible interconversion of alkenes and nitriles without the use of HCN would thus likely become a very attractive tool for chemical synthesis.

Transfer reactions
Functional group transfer reactions are important tools in organic synthesis. A notable example is the transfer hydrogenation reaction that provides a safer and operationally simpler alternative to the use of hydrogen gas in redox reactions (Figure 1B) [2]. In this process, a molecule of H2 is transferred between a sacrificial reagent and a substrate under gas-free conditions. This thermodynamically controlled process has led to unusual applications in organic synthesis (so-called borrowing hydrogen reactions) because the H2 molecule can be temporarily borrowed, thus altering the normal reactivity of a given molecule.

It is reasonable to expect that the transfer of other small gaseous molecules (e.g. HCN, HF, HI, F2) could provide a similarly powerful tool for alkene hydrofunctionalization.

Development of a practical ´transfer hydrocyanation reaction that avoids HCN
In a recent contribution published in the journal Science, Fang et al. have realized a reversible, gas-free transfer of HCN between alkenes and nitriles through a transfer hydrocyanation mechanism (Figure 1C) [3]. The method uses an inexpensive Ni-catalyst, generated in situ from Ni(COD)2 and DPEPhos, in combination with a simple Lewis acid. While most examples have been performed using the inexpensive but flammable Me2AlCl, non-flammable AlCl3 was also shown to exhibit good activity as the co-catalyst. The reaction was used in over 60 examples of transfer hydrocyanation reactions and can tolerate a wide range of structural and functional diversity.

A key feature of the developed process is the ability to perform, on demand, the forward reaction, hydrocyanation, and the reverse reaction, retro-hydrocyanation under very similar reaction conditions. The key to control the process is the use of simple driving forces. For the forward reaction, formation of a gaseous by-product (isobutene) drives the process. In the case of the retro-hydrocyanation, the release of norbornadiene’s ring strain drives the otherwise thermodynamically challenging reverse reaction.

A wide range of alkenes can be used in the transfer hydrocyanation reaction (Figure 2). Particularly noteworthy is the anti-Markovnikov selectivity obtained when using styrene derivatives, since this selectivity is complementary to the traditional hydrocyanation giving the branched isomer. The method also tolerates several functional groups, a feature highlighted in the late-stage hydrocyanation of complex alkene substrates derived from natural products. For larger scale applications, the inexpensive industrial solvent butyronitrile can be used as a reagent.

The reverse reaction can readily transform nitriles into synthetically useful alkene products (Figure 3). This procedure is particularly useful in laboratory scale research because it enables the use of the nitrile group as an activating group for the formation of challenging C-C bonds. As an illustration of this concept, the method was used in the construction of complex aromatic products and in the two step installation of a chiral quaternary vinyl group into an estrone derivative, a challenging task using normal synthetic approaches.

The transfer hydrocyanation reaction is a powerful tool for the interconversion of alkenes and nitriles that is safer than traditional methods and exhibit unusual selectivity. Due to the simplicity of the procedure, low cost of the reagents and broad scope, this new protocol is directly applicable to the preparation of nitriles and alkenes in research laboratories across academia and industry. The forward reaction, transfer hydrocyanation, might also find applications in the production of fine chemicals. The large scale production of nitriles could be envisaged if the economics of the process could be further improved, for example through the development of more active catalysts and efficient recycling of the alkene by-product.

Bill Morandi
Independent Max-Planck Group Leader
Max-Planck-Institut für Kohlenforschung
Mühlheim an der Ruhr

[1] Laura Bini, Christian Müller, Dieter Vogt: Mechanistic Studies on Hydrocyanation Reactions, ChemCatChem, 2, 590, (2010). DOI:10.1002/cctc.201000034

[2] Graham E. Dobereiner, Robert H. Crabtree: Dehydrogenation as a Substrate-Activating Strategy in Homogeneous Transition-Metal Catalysis, Chemical Reviews, 110, 681, (2010). DOI:10.1021/cr900202j.

[3] Xianjie Fang, Peng Yu, Bill Morandi: Catalytic reversible alkene-nitrile interconversion through controllable transfer hydrocyanation, Science, 351, 832, (2016). DOI:10.1126/science.aae0427.

[4] Julian C. Lo, Yuki Yabe, Phil S. Baran: A Practical and Catalytic Reductive Olefin Coupling, Journal of the American Chemical Society, 136, 1304 (2014). DOI:10.1021/ja4117632.


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