Synthetic Processes toward Nitriles without the Use of Cyanide: A Biocatalytic Concept Based on Dehydration of Aldoximes in Water

Abstract While belonging to the most fundamental functional groups, nitriles represent a class of compound that still raises challenges in terms of an efficient, cost‐effective, general and, at the same time, sustainable way for their synthesis. Complementing existing chemical routes, recently a cyanide‐free enzymatic process technology based on the use of an aldoxime dehydratase (Oxd) as a biocatalyst component has been developed and successfully applied for the synthesis of a range of nitrile products. In these biotransformations, the Oxd enzymes catalyze the dehydration of aldoximes as readily available substrates to the nitrile products. Herein, these developments with such enzymes are summarized, with a strong focus on synthetic applications. It is demonstrated that this biocatalytic technology has the potential to “cross the bridge” between the production of fine chemicals and pharmaceuticals, on one hand, and bulk and commodity chemicals, on the other.


Introduction
Rapid depletion of our global resources,w hich is also true for noble metals, prompts us to rethinkt he production methods for many of today's chemical compounds. Increasing product demandi na ll segmentso ft he chemical industry forces us to develop reliable and, at the same time, sustainable production processes, which can meet our needs now and in the future. Biocatalysis is considered to represent one of the key technologies for enabling such processes. [1][2][3][4][5][6] Often biocatalytic processes run under milder conditions, compared with many chemical processes,a nd excel at selectivity,a nd the access to biocatalysts is not affected by limited raw-material sources, as in case of ar ange of preciousm etals used in chemocatalysis. Whereas the economy of such metal-catalyzed processes often depends on varying price and availability of the corresponding metal, biocatalysts can be simply produced by fermentation. Additionally,p recious metals need to be efficiently recycled and have to be restricted in their exposure towards animals, humans,a nd environment due to their,a tl east in part, high toxicity. Biocatalysts,o nt he other hand, are completely biode-gradablea nd can be easily produced under optimizedc ultivation procedures. However,t he successive implementationo f biocatalytic processes into the chemical industry should always be regarded and used as an alternative to complement chemocatalytic processes. [7] Thus, biocatalysis, as such an additional alternative, shouldbeviewed as an opportunity for broadening the chemical repertoire and not as the all-promising solution to every synthetic problem.I na biding by these standpoints, new and fascinatingp ossibilities open up.
To day,m ainly four approaches are used in the chemical industryf or nitrile synthesis, depending on the structure and application of the produced nitrile. [8,9] One of the most important production processes for nitrilesb ya nnual tonnage is the double hydrocyanation of 1,3-butadiene to yield adiponitrile. Adiponitrile is ak ey intermediate in nylon production and is almoste xclusively hydrogenated to hexamethylenediamine. In addition, adiponitrile is synthesized by electro-hydrodimerization of acrylonitrile. Acrylonitrile, an unsaturated nitrile, is accessibleb ym eanso fa nother important industrial process technology for nitrile synthesis:a mmoxidation. This process utilizes unsaturated hydrocarbons, ammonia, and air to yield the corresponding nitrile. Because ammoxidation benefits from the easy modificationofC ÀHb onds next to aC =C-moiety, aromatic nitriles( starting from toluene derivatives) are also accessible. Lastly,a mides can be dehydrated towards their corresponding nitrilesu nder elevated temperatures and in the presence of heterogeneousc atalysts. This process is mostly used for the synthesis of fatty nitrilesd ue to the higha ccessibility of long-chain, aliphatic fatty acids as startingm aterials. The formed fatty nitriles are hydrogenated (mainly heterogeneously) towards fatty amines, which are used as surfactants or lubricant additives. If one evaluates these processes, in spite of their impressive utilization on al arge scale, severald rawbacks are also apparent. For example, highly toxic hydrogen cyanide has to be used forh ydrocyanation approaches. Moreover,f atty amide formation and dehydration to fatty nitrilesf rom fatty acids represents at edious and energy-intensivep rocess with excessive temperatures of around 300 8Ct op roceed efficiently. Comparable harsh conditions are also applied in the gas-phase ammoxidation process, which raises selectivity and side-product formation concerns.A sf or ammoxidation,a cetonitrile and hydrogenc yanide can be formed as side products, whereas the double hydrocyanation of butadiene also leads to regioisomerso fa diponitrile.I nt he case of amide dehydration, purification by distillation is of paramount importance to obtain the nitrile in high purity.
Avoiding the abovementioned drawbacks, ab iocatalytic concept based on the dehydration of aldoximes in water,t hus yieldingt he desired nitrilesw ithh igh selectivity,h as recently turnedo ut to be ap romising approach for am ild, sustainable nitrile synthesis. The required aldoximesa re easily accessible by condensation of the bulk chemical hydroxylamine with aldehydes (Scheme 1). The required aldehydes are themselves broadly accessible by homogeneous catalyzed hydroformylation of alkenes with syngaso rb yo xidation of alcohols by meanso f, for example, a( piperidin-1-yl)oxylr adical as ac atalyst ands odium hypochlorite as an oxidation agent. [10,11] The enzymesu tilized for this biotransformation are the aldoxime dehydratases (Oxds). Oxds, belonging to the enzyme class of lyases (EC 4.99.1.5-4.99.1.7), were first described in 1998 by Asano et al.,a nd their high potential for organic synthesis has just recently been intensively explored. [12][13][14][15][16][17][18][19] The independence of such enzymes from the need for cofactors anda lready high specific activity of the wild-type enzymes for many substrates (includinga ryl-aliphatic, aliphatic, aromatic,a nd chiral aldoximes) may allow this enzyme class to act as a" bridge builder" in the future between the fine and bulk chemical industries. In particular, for the latter industrial segment, many enzyme classes are still struggling today due to their (relatively) high cost andl imited productivity, which makes them,a lthough highly valuable, for example, in the pharmaceutical industry, [20][21][22] often not profitable for bulk chemistry applications.
The key advances in Oxd catalysis of recent years, with respect to synthetic applications,are summarized in the following.
In Scheme 2, the proposed reactionm echanismo fO xd enzymes for the dehydrationr eaction of aldoximes to nitriles is shown. [35] In case of an oxidation of the heme iron centeri on to Fe 3 + ,al oss of activity has been observed. Ah ypothesis for this loss of activity was proposed by Kobayashi et al., [35] who explained this effect by aredox-dependentchange in the coordination structure of the aldoxime-hemec omplex. Usually,t he aldoxime nitrogen is bound to the iron and, in the case of Fe 3 + in the active center, the aldoxime binds through the oxime oxygen, which causesaloss of activity.I ng eneral,t he first step of the mechanism is the coordination of the aldoxime nitrogen to the ferrous iron in the active site of the Oxd and furtherf ixation of the aldoxime substrate by hydrogen bonds between the OH group of the aldoxime and the serine and distal histidine residues. In the next step, the histidine residue is protonated by the argininer esidue, which leads to an increase of the electrophilicity of the aldoxime OH functionality. After the elimination of water and electron transfer from the ferrous iron to the aldoxime nitrogen, an Fe IV species is formed and the aldoxime a-proton is then coordinatedt ot he deprotonated histidine residue and the serine side chain. In the final step, the aldoxime intermediate is deprotonated and an electron transfer to the Fe IV speciesp roceeds, thus releasing the nitrile and recovering the ferrous iron in the ground state. Protons hifts of the histidine and arginine residues complete the catalytic cycle.
In general, the dehydration of PAOx has been chosen as a standardr eactionf or the determination of the catalytic activity of Oxds because this substrate was identified as an atural substrate derived from phenylalanine. However,t he Oxd enzymes not only accept PAOx as as ubstrate, but show ab road substrate spectrum. With their catalytic activity and high robustness in synthetic processes, Oxds enablea na ttractive access to nitriles without the use of toxic cyanideasar eagent.T he aldoximes ubstrates can be easily prepared from the corre-Scheme1.Alternative synthetic route towards nitriles by using aldehydes accessed by hydroformylationo fa lkenes or oxidation of alcohols as startingm aterials. Aldehydes are condensed with hydroxylamine to give aldoximes, whichc an subsequently serve as substrates for Oxd-catalyzed nitrile synthesis. Nitriles can later be used for several transformations, resulting in valuable chemical products. Figure 1. X-ray structure (left) and the active site (right) of OxdRE,c onsisting of heme b, includingF e II and serine, histidine, and arginine residues, which representthe catalytic triad. [37] sponding aldehydes and hydroxylamine as ac heap bulk chemical. In many cases, aldehydes are commerciallya vailable or easily accessible from cheap raw materials. For example, aldehydes can be prepared in an elegant fashion throught he hydroformylation of alkenes or oxidationo fa lcohols. [10,11] Ac omparisono ft he chemoenzymatic synthesis of nitrilesf rom aldehydes by using Oxds for the dehydration of aldoximes andh ydrocyanation, as as elected well-known example of "classical" nitrile synthesis, is shown in Scheme 3.
In the following sections, we describe the capability of Oxd enzymest oa ct as catalysts in synthetic processes for the cyanide-frees ynthesis of nitrilesa tm oderate reaction temperatures in water as as ynthetic alternative to form nitriles, thus complementing existing approaches, such as hydrocyanation, ammoxidation, and amide dehydration.

Enantioselective Synthesis of Chiral Nitriles
Oxds have been provena sv ersatile biocatalystsfor the synthesis of chiral nitriles. Initial studies in the early 2000s proved that aldoximes with ac hiral center in the a-position of the oxime moiety werea ccepted as substrates by many Oxds; however, the stereochemical course of these reactions had not been investigated. [25,30,31,33,34,36,38] In this initial work, (E/Z)-2phenylpropionaldoxime and (E/Z)-mandelaldoxime were found to be accepted by up to five differentO xds and showed K m values ranging from 1.70 to 11.9 mm,a sw ell as specific activi-ties of 0.57-18.1 Umg À1 . [19] The stereoselective synthesis of nitriles, starting from racemic aldoximes, was investigated in detail jointly by the groups of Asano and Grçger, [39] who discoveredint heir preliminary studies that OxdB was able to convert racemic 2-phenylpropionaldoximew ith high enantioselectivity towards( S)-2-phenylpropionitrile if solelyt he E-isomer of the aldoxime was used as ar acemic substrate. [18] Furthermore, it was found paramount to conduct the biotransformations at 8 8Ct os uppresst he thermal E to Z isomerization of the aldoxime, since the inversion barrier of the lone pair of nitrogen is rather low.B ased on these initial results, we then expanded the substrate scope for this type of chiral nitrile synthesis and the applied biocatalyst toolbox broadly,d emonstrating that Oxds did accept ab road range of racemic aldoximes for chiral nitrile synthesis. [12] In particular, substrates with their stereogenic centeri nt he a-position, as well as as trongs teric differentiationo ft he substituentsa tt he chiral center,s howed high enantioselectivity over the reaction course, yielding the corresponding nitriles with up to 99 %e nantiomeric excess( ee)i n these kinetic resolutions. Furthermore, it is noteworthy that Oxds can change their enantiopreference upon changing the substratef rom the E-to Z-racemate. Thisu nique stereochemical property has av aluables ynthetic consequence, since,w ith the same enzyme and based on the same racemic aldehyde, both enantiomersa re enantioselectivelya ccessible by using either the E-or Z-isomer of the racemic aldoxime as as ubstrate (Scheme 4). [12] For example, upon separating the E-and Z-isomers of 2-(3bromophenyl)propanal oxime and using them separately in a biotransformation with OxdFG, the (S)-nitrile is obtained in 87 % ee at 37 %c onversion, if startingf rom the E-isomer of the aldoxime. However,i ft he Z-isomer of the aldoxime is used, the (R)-nitrile is obtainedw ith 88 % ee at 51 %c onversion. [12] This stereochemical phenomenon is, in general, quite unusual in catalysis and, from as ynthetic perspective, advantageous because it avoidst he necessity to screen for further enzymes with the opposite enantiopreference, if ap roper separationo f the aldoxime isomers can be conducted.

Synthesis of Aromatic Nitriles and Utilization of Biorenewable Feedstocks as Raw Materials
Af urtherc lass of nitrilesi mportant for various industrial segments are aromatic nitriles. Among them, af ocus in recent years has been on those that are accessible from biorenewable feedstocks. An example is 2-furonitrile,w hich is an intermediate in the field of fine chemicals and pharmaceuticals, as well as ap otential sweetener. [40] 2-Furonitrile can be synthesized, for example, by the ammoxidation of furfural in ag as-phase process at temperatures of > 400 8C. [40] As an alternative approach startingf rom furfural, which is availablef rom pentoses as ab iorenewable raw-materials ource,t he synthesis of 2-furonitrile by utilizing Oxd enzymes was reported. [36,41,42] The chemoenzymatic synthetic concept and ap reparative result are shown in Scheme 5. At ask of this study was to gain access to ar ecombinantf orm of the Oxd from Rhodococcus sp. strain YH3-3 (OxdYH3-3). This Oxd was found to convert some aromatic aldoximes and also proved to be suitable to convert furfural oxime. [36] Thus, the gene of OxdYH3-3 wasc loned into expression vectors and expressed in Escherichia coli. [41] With this whole-cellc atalyst in hand, 2-furonitrile was successfully synthesized throught his biocatalytic dehydration of 2-furfuraldoxime (Scheme 5). Because Oxds were usually found to be (mostly) inactive for the conversion of aromatic aldoximes to nitriles, [19] this recombinant OxdYH3-3p rovides ac atalyst for practical access towardsa romatic nitriles through this enzymatic route. [41] Furthermore, mutants of OxdYH3-3 wereg enerated by directed evolution, which showed an up to sixfold increased activity for the synthesis of 2-furonitrile and 3-cyanopyridine compared with the activity of the wild-type enzyme. [42]

Synthesis of Aliphatic Nitriles with Utilization as Bulk and Commodity Chemicals
Aliphatic nitriles are af urther class of nitrilest hat are widely used in industry. [9,43] Directa pplicationso fs uch nitrilesa re particularly known for short-chain nitriles,s uch as acetonitrile, whereas al arge portion of the longer-chaina liphatic nitriles serve as intermediates for hydrogenation to the corresponding amines.F or example, the resulting fatty amines canb ef ound in many household products, as well as industrial products, with aw orldwide demand reported to be 800 000 tons in 2011. [44] Furthermore, here, fats and oils as renewable building blocksc an serve as araw-material source and, thus, as an alternative to petrochemicals.
Already in early work with Oxds, such enzymes weres hown by the group of Asano to catalyze the dehydration of aliphatic aldoximes to give aliphatic nitriles. [38] For example, it was demonstrated that Oxds formed acetonitrile upon starting from acetaldoxime as the smallest substrate for Oxds. When using whole cells with OxdB, an early quantitative conversion of 97 % Scheme4.Access to bothenantiomers of the samenitrile with the same enzyme, depending on the E-or Z-configurationoft he racemic aldoxime.
to acetonitrile was observed at as ubstrate concentration of 0.1 m ( % 18 gL À1 )o fa cetaldoxime. In the same work, linear aliphatic aldoximes with ac hain length between three and six were also found to be converted by different Oxds. At as ubstrate concentration of 0.3 m ( % 35 gL À1 )h exanalo xime, quantitative conversion was achieved with OxdB as ab iocatalyst within 3hreaction time at 30 8C. However,i na ddition to linear aliphatic aldoximes,b ranched ones, such as isobutyraldoxime and isovaleraldoxime,w ere also found to be converted by Oxds. Based on thesei nitial studies, ad etailed process development of aliphatic nitrile synthesis by using OxdB in whole cells as ac atalystw as conducted very recently by the group of Grçger, who utilized n-hexanaloxime, n-octanaloxime,a nd ndecanaloxime as model substrates. [14] Selected results are shown in Ta ble 1, demonstrating the high volumetric productivity of OxdB as ac atalystf or aliphatic nitrile synthesis. It is noteworthy that these biotransformations can be conducted at as ubstrate loading of up to 1.4 kg of aldoxime per liter of aqueous reactionm edium, leading to the desired aliphatic nitriles with conversions exceeding 90 %a nd even reaching quantitative conversion in some cases.
These substrate loadings are among the highest ever reported in biocatalysis, in particular, for conversions of nearly waterinsoluble substrates in aqueous medium. Because the productivity of OxdB for the synthesis of aliphatic nitrilesi sa lso very high, this biocatalytic reactionr epresents ap rocess with promising potential for being transferred to an industrial scale in the future.
Immobilization of Oxds for applicationsi na queous medium was also studied,r evealing high stability of OxdB whole cells entrappedi nc alcium alginate beads and coated with tetraethoxysilane. [45] Furthermore,O xds were found to be active in pure organic solventifasuperabsorber-based immobilization technique was used (Scheme 6). [15,46] Because manya ldoximes, especially long-chain aliphatic aldoximes, are barely soluble in aqueous reactionm edium, this possibility enables the use of this Oxd biocatalyst in organic medium, in which the aldoxime is better soluble. Thiss uperabsorber-immobilized Oxd catalyst turned out to be suitable for application in ac ontinuous process with ap acked-bed reactor, showings ufficients tabilitya nd, thus, high remaining activity for ar un time of at least 3h (Scheme 6). [15] Furthermore, this Oxd catalyst, which is entrapped in as uperabsorber,c an also be applied as af luid heterogeneous phase in as egmented flow mode. [46] Because, in industry,mostaliphatic nitriles, in particular, fatty nitriles, are utilizeda si ntermediates for the production of the corresponding amines, [43] the development of novel hydrogenation methods for their synthesis is also af ield of current interest. Industrial valuablep rimary aliphatic amines can be synthesized starting from thesealiphatic nitriles by hydrogenation. However,t he hydrogenation of nitrilesi navery selective manner is still ac hallenge, especially if utilizing heterogeneous catalysts. [47] The group of Kirchner, [48] and based on their work recently also our group, [47] investigated homogeneous manganese catalysts for such transformationsw ith high selectivities. For example, n-octanenitrile can be selectively hydrogenated to n-octan-1-amine with > 99 %c onversion and > 99 %s electivity by using such am anganese catalyst( Scheme 7). [47] In addition, researchers from BASF reported the application of Oxds for the synthesis of citronellyl nitrile, which is used as af ragrance compound. [49] In these reactions, runningu nder neat conditions directly in citronellal oxime, the Oxds were also used as whole-cellc atalysts,l eadingt oq uantitative conversion after 90 hat3 08C. This example underlines the high industrial potential of Oxds and it shows the opportunity to use Oxds in ap ure organic system under neat conditions, thus leadingtoh igh space-timey ields.
In addition to process development of individual reaction steps, process integration of various reaction steps towards cascades without the need for intermediate purification represents av ersatile concept for industrial production.A ddressing the combination of enzymatic and classic chemical and che- Table 1. Preparativeb iotransformationo fa liphatic aldoximes to nitriles by using OxdBi nwholecells. [14] Entry Scheme6.Flow-based biocatalytic synthesis of n-octanenitrile by means of OxdB whole cells immobilized in superabsorber and used in apacked-bed reactor. [15] The photo and graphicoft his schemei sr eproduced from reference [15]. mocatalytic reactions, [50] ac hemoenzymatic cascade with Oxds for aliphatic nonanenitrile synthesis, starting from 1-octene as ar eadily availabler aw material, wasd eveloped. [16] This chemoenzymatic cascade combines the hydroformylation of 1-octene to n-/iso-C 9 -aldehydes with subsequent condensation of these aldehydes with hydroxylamine under the formation of aldoximes, followed by the biocatalytic dehydration of the aldoximes to the nitriles (Scheme 8). [16] The initial hydroformylation step was conducted in ab iphasic system consisting of water and 1-octene by using ar hodiumc omplex with the commercial triphenylphosphine-3,3',3''-trisulfonic acid trisodium salt (TPPTS)l igand as ac atalyst. The catalysti sw ater soluble, thus enablingas imple separation of the organic product-substrate mixturef rom the catalyst. After this phases eparation, the organic phase mainly consists of n-nonanal and 2-methyloctanal as products, resulting from the hydroformylation of 1-octene and an isomer of 1-octene. This mixture was then treated with hydroxylamine in aqueous reaction medium, followed by heating overnight to remove residual traces of hydroxylamine, which causes deactivation of the Oxd. Subsequently,t he aldoxime mixture was converted by an Oxd using an aqueous reaction medium. Using this chemoenzymatic cascade reaction, an overall conversion of 67 %a nd ay ield of the desired n-/iso-C 9nitriles of 41 %w as obtained, thus demonstrating that after optimization the Oxd-basedb iotransformation was also compatible with the chemical reactions teps for the synthesiso f the aldoxime substrates.

Synthesis of Nitrile-Substituted Fatty Acids
Furthermore, Oxd enzymesh ave also been successfully applied in the synthesis of terminal aliphatic nitrilesb earing ac arboxyl-ic acid moiety as af urther functional group (Scheme 9). [51] Such bifunctional molecules are of interestf or polymer productionb ecause the nitrile group can be subsequently converted into an amino moietyb ym eans of hydrogenation, thus furnishing w-amino-substituted fatty acids as monomers for polyamides.
Access to the aldoxime substrates was realized by means of the hydroformylation of terminal aliphatic alkenes and subsequentt reatment with hydroxylamine. The resulting aldoximes were then convertedi nto the desired cyano-substituted fatty acids with quantitative conversion at as ubstrate concentration of 10 mm,w hereas the conversionsd ecreased with increasing substrate concentration, leadingt oaconversion of less than 50 %a ts ubstrate concentrations of 100 mm and above. This approachi sa lso suitable for the synthesis of nitrile-substituted aliphatic carboxylic acids (and thus, w-amino acid polymer precursors)s tarting from unsaturated fatty acids as biorenewable feedstocks. For example, cross-metathesis with oleic acid and ethylene furnishes dec-9-enoic acid, which then is transformed, by means of hydroformylation ands ubsequent oxime formation, into the C 11 -aldoxime as as ubstrate for enzymatic dehydration. This biotransformation then gives aC 11 -carboxylic acid bearing an itrile moiety as as ubstituent.

Synthesis of Aliphatic Dinitriles
Another potentiala pplicationa rea for the industrial use of Oxds in the field of commodity chemicals is the biocatalytic synthesis of aliphatic dinitriles. [13] Among them, adiponitrile is the one with the highest production volume, being in the range of about one milliont ons annually. [9] Adiponitrile is utilized mainly for the manufacture of 1,6-hexanediamine as a monomer for polymerization with adipic acid to give nylon-6,6, which is produced on the multimillion-ton scale per year.A s an alternative to current existing methods, such as the hydrocyanation of butadiene, as the main appliedp rocess in terms of productionv olume, recently the capability of Oxd enzymes for transforming the bis-aldoxime of adipaldehyde into adiponitrile wassuccessfully demonstrated (Scheme 10).
This cyanide-free approach towards adiponitrile is conducted in water as as olventa nd at al ow reactiont emperature (30 8C). The process has been already demonstrated on a1Lr eaction scale with 50 gL À1 substrate loading, leading to full conversion within 27 hi nt he presenceo farecombinantw hole-cell catalyst bearing OxdB as abiocatalyst.
Furthermore, other linear dinitriles (C 4 -C 10 )w ere shown to be converted by Oxds under similar reaction conditions. The bis-aldoxime substrates can be synthesized startingf rom the correspondingb is-aldehydes or their acetal-protected derivatives. These examples underline that Oxds also accept bis-aldoximes as substrates very well, as exemplified for linear aliphatic representatives of this compound class. [13] Recently,n ot only the oxidation of monoalcohols to aldehydes, but also the oxidation of diols to dialdehydes, was successfully performed by means of a( 2,2,6,6-tetramethylpiperidin-1-yl)oxyl-catalyzed oxidation in nitriles as asolvent. [11] Summary and Outlook Although their synthetic potentialh as only recently been studied more intensively,O xds have already provent ob eh ighly capable for the synthesis of chiral nitriles, aromatic nitriles, aliphatic nitriles, and aliphatic dinitriles.I nc ase of chiral nitriles, such enzymesa re able to yield both enantiomers of an itrile, despite using the same enzyme, due to the dependency of the enantiopreference on the E-a nd Z-configuration of the utilized racemic aldoxime substrate, thus enabling the opportunity to gain access to both enantiomerso fachiral nitrile building block with the same enzyme. Furthermore, the potential of Oxd enzymesf or the synthesis of bulk chemicals has been demonstrated by the liter-scale synthesis of the polyamide intermediate adiponitrile, with up to 50 gL À1 substrate loading. In addition, Oxds have been implemented in ac hemoenzymatic reaction cascade to obtain fatty nitriles, startingfrom alkenes in combinationw ith hydroformylation. Fatty nitriles, as af urther nitrile product class of industriali nterest, can be prepared by Oxds in av ery productivem anner at substrate loadingso f up to 1.4 kg L À1 of reaction medium. For the future,w ee xpect that the utilization of Oxds in the cyanide-free synthesis of nitriles under mild reactionc onditions will gain furtheri ncreasing interest for preparing nitrile products from various segments of the chemical industry,s uch as commodity chemicals, bulk and fine chemicals, andpharmaceuticals.