Linear α,ω-dinitriles are of very high importance as precursors for the polymer industry, especially for nylons and polyurethanes. The most prominent example is adiponitrile (1,6-hexanedinitrile) which is produced on an annual scale of over 1 million metric tons.[38,39]
The main use of adiponitrile is the hydrogenation towards hexamethylenediamine[106] that is a key building block for the production of polyamides like Nylon 6.6.[38,39,107] The first approaches towards the synthesis of adiponitrile are based on chlorine chemistry, which are nowadays obsolete because of the tremendous amount of waste that was produced via this route and lacking sustainability.[39,108] The large waste amounts also severly hindered the economical profit. Today, there are two dominant production processes for adiponitrile.
The first one was developed by Baizer from the company Monsanto in the early 1960s and is based on the electro-hydromerization of two molecules of acrylonitrile (Figure 9).[109]
While this process is still applied today, it has certain selectivity problems.
The second process, which is today the dominant one, was developed by DuPont and is based on the use of butadiene. Two molecules of hydrogen cyanide react in a terminal addition reaction to butadiene to directly yield adiponitrile (Figure 9).[110] While this process is nowadays successfully applied on large scale, it still has the major drawback of the high toxicity of hydrogen cyanide. Additionally, the regioselectivity of the addition reaction is somewhat problematic.
One of the biggest challenges in the field of future’s chemicals product tree is the task to enable access to existing bulk chemicals by changing the raw material basis, replacing hazardous methodologies and reagents by more environmentally benign processes. For aliphatic, linear α,ω-dinitriles, several attempts have been investigated over the last years and decades in order to find new production processes (especially for adiponitrile). Some of the newly investigated approaches for green-chemistry based nitrile synthesis (especially adiponitrile) utilize heterogeneous catalysis like non-noble metal oxides-based nanocatalysts or homogeneous catalysis, utilizing an iron nitrate/TEMPO system.[111,112]
While these approaches are quite elegant avoiding the use of cyanides and starting from readily available alcohols (like 1,6-hexanediol), some limitations exist. The heterogeneous approach suffers from high reaction temperatures (≥130 °C) and runs at elevated pressure of five bar of pure molecular oxygen (O2), thus raising safety issues. The homogeneous approach runs at mild reaction conditions but high catalyst loading (5 mol%) and tedious separation of the used iron nitrate and TEMPO are drawbacks. On the other hand, nature provides unique opportunities for organic synthesis. Thus, it is worth to identify natural approaches towards the preparation of specific functional groups and adapt them to chemical synthesis.
Since Oxds showed great potential in the synthesis of several aliphatic mononitriles (see chapter 2) and chiral nitriles (see chapter 3), the broad investigation of Oxds’ potential for the synthesis of the industrially important aliphatic, linear α,ω-dinitriles was deemed to be investigated.[52,70,74,76,77,86,87,89,103,113] In the following, the results of this biocatalytic production process that avoids the usage of cyanide are presented.
Figure 9: Today’s production processes towards adiponitrile and the newly envisioned, biocatalytic production route via Oxd catalysis.
Biocatalytic synthesis of linear dinitriles
4.2 S UBSTRATE SYNTHESIS BASED ON DIALDEHYDES OR THEIR ACETALS
The new approach for the biocatalytic α,ω-dinitrile synthesis is based on the preparation of the dialdoximes as key intermediate, which is afterwards dehydrated twice by the aldoxime dehydratase to yield the dinitrile. As a consequence, the author had to synthesize the dialdoximes out of the corresponding α,ω-dialdehydes (Scheme 27). It was decided to investigate substrates with a carbon chain length of 3-10 carbon atoms since dinitriles of this chain length have a high relevance in the chemical industry. Due to their high reactivity, most α,ω-dialdehydes are only available in their protected form as acetals. One other α,ω-dialdehyde, glutaraldehyde (C5 dialdehyde), can be commercially purchased as aqueous solution. For the other α,ω-dialdehydes with a chain length of 6-10 carbon atoms, a synthetic approach had to be found which allowed access to bigger quantaties of them.
The availability of the dialdehydes is so low because the double, n-terminal hydroformylation of dienes like butadiene towards adipaldehyde has severe selectivity issues that are still object of research.[114–117] The best reported result reaches up to 73%
selectivity for the double n-terminal hydroformylation of butadiene towards adipaldehyde.
However, the formed adipaldehyde has to react in situ with two molecules of a dialcohol to form the stable bis-acetal. This additional protection step makes the process economically unattractive.[114]
Scheme 27: Synthetic approach towards linear, aliphatic α,ω-dinitriles starting from dialdehydes or the acetals.
For the preparation of the C3 and C4-dialdoxime from their bis-dimethyl acetals they were in situ cleaved by addition of the hydrochloride salt of hydroxylamine to release the dialdehydes. After neutralization with sodium carbonate, the dialdoxime instantly starts to precipitate from the reaction solution. Glutaraldehyde (C5) was directly used for the dialdoxime synthesis from a commercial source. Adipaldehyde, the most intriguing substrate, had to be synthesized in larger quantaties. For this, trans-1,2-cyclohexanediol was oxidized with sodium periodate (NaIO4, Scheme 28). The largest reaction scale was 110 mmol of trans-1,2-cyclohexanediol, which had to be conducted in 2 liter round bottom flasks (Figure 10). Regarding the C7-C10 dialdehydes, a very recently reported protocol by Bobbitt et al. was utilized.[118] The reagent for this oxidation is called Bobbitt’s salt and it represents a tetrafluoroborate salt of a 2,2,6,6-Tetramethylpiperidinyloxyl (TEMPO) derivate (Scheme 28). Other approaches for the selective alcohol oxidation like the Dess-Marin periodinane and other ones have also been reported, but are way more complicated and restricted.[119] Both approaches yield the dialdehydes in very high yields and in multi gram scale, paving the way towards larger scale reactions.
Afterwards, the α,ω-dialdehydes were converted in analogy to the C3-C4 substrates by directly converting the α,ω-dialdehydes with hydroxylamine hydrochloride and sodium carbonate in aqueous solution, yielding the α,ω-dialdoximes with good yields (Scheme 29).
Scheme 28: Synthesis of the α,ω-dialdehydes with a chain length of 6-10 carbon atoms by oxidation of trans-1,2-cyclohexanediol or α,ω-dialcohols.
Scheme 29: Synthesis of the α,ω-dialdoximes by conversion with hydroxylamine
Biocatalytic synthesis of linear dinitriles
Interestingly, while the dialdoximes may appear as rather simple molecules, almost nothing is known about them in the literature or they have not been reported at all in many cases![120,121] While monoaldoximes are often oils or solids that melt are rather low temperatures, α,ω-dialdoximes are very high melting solids that rather decompose at highly elevated temperatures than melting at all. These properties go hand in hand with the high stability of the α,ω-dialdoximes. While the α,ω-dialdehydes are highly reactive and prone to decomposition via oxidation, aldol reaction etc., the α,ω-dialdoximes showed no sign of deterioration when stored at room temperature for several months. This property might be helpful in technical applications since they eliminate the need for severe safety precautions to protect the substances from decomposition.The synthesized α,ω-dialdoximes can be simply purified via filtration and drying in vacuo, yielding them with purities of up to ≥99%.
Figure 10: 2 liter scale reaction for the preparation of adipaldehyde starting from trans-1,2-cyclohexanediol.
Regarding the α,ω-dinitriles of interest, commercial reference compounds were purchased for establishing analytical methods to quantify the later conducted activity assays of the Oxds.