Organonitriles

Organonitriles are organic substances that contain the cyano (-C = N) group. Nitriles have wide commercial applications that include solvents, synthetic intermediates, pharmaceuticals, and monomers, to name just a few. As a class of substances, there are two types of toxicity associated with exposure to nitriles acute lethality and osteolathyrism. Some nitriles are known to cause both. The mechanisms by which nitriles cause these toxic effects, the corresponding relationships between nitrile structure and toxic potency for each effect, and the use of this information as a basis to design substances that may need to contain the functionality of the cyano group but will cause minimal toxicity have been discussed in detail [7]. Only the biochemical mechanism and SARs related to acute lethality of nitriles are discussed here. More detailed discussions are available [7, 8, 61]. 

It is also interesting to note the influence of methyl substitution on toxicity. For example, methyl substitution of 26 (LD50 = 0.57 mmol kg-1) at the 3-position greatly reduces toxicity (28, LD50 = 2.80 mmol kg-1), whereas methyl substitution at the 2-position (a-carbon) greatly increases it (29, LD50 = 0.29 mmol kg-1). A similar pattern 

The observation that subtle changes in the structure of organonitriles can have profound effects on acute lethality seems puzzling at first, but becomes clear when consideration is given to the mechanism by which nitriles are acutely lethal. The mechanism for the acute lethality of nitriles is directly related to their propensity to release cyanide as a result of bioactivation (hydroxylation at the a-carbon) by cytochrome P450 [61]. 

Not surprisingly, nitriles that liberate cyanide more readily are more toxic. Logically, structural features that are expected to increase a-carbon radical formation and stability are likely to favor hydrogen atom abstraction from the a-carbon. The more quickly hydrogen atom abstraction occurs at the a-carbon, the more quickly cyanohydrin formation occurs and the more quickly cyanide is released and, hence, the more toxic the nitrile is expected to be. 

It is important to note that cytochrome P450-mediated hydroxylation can also occur at other carbon positions (i.e., positions other than that a to the cyano group) [8]. However, such hydroxylation does not result in cyanide release and represents a detoxication pathway. In fact, it is likely that most nitriles, even the toxic ones, are hydroxylated at multiple carbon positions [8]. The more toxic nitriles, however, are those in which metabolism at the a-carbon predominates. 

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Organonitrile complexes of transition metals. B. N. Storhoff andH. C. Lewis, Coord. Chem. Rev., 1977,23,1-29 (156). 

Our groups developed a catalytic C-CN bond cleavage of organonitriles catalyzed by the Fe complex (Scheme 49) [163, 164]. In this reaction, an organonitrile R-CN and EtsSiH are converted into EtsSiCN as a result of the C-CN bond cleavage and the Si-CN bond formation, and the R-H product. This is the first example of the catalytic C-CN bond cleavage of acetonitrile. 

A new route to 1,2,4-oxadiazoles and their complexes via Pt- and Pd-mediated 1,3-dipolar cycloaddition of nitrile oxides to organonitriles, has been reported. The sequence of the metal-mediated [2 + 3] cycloaddition offers an alternative route for the preparation of oxadiazoles. 

Tab. 4 Values of the Pl ligand parameter for organonitriles (N=CR) at metal centers Ms with a different electron-richness (Es) [24]...

M = Mo orW) with alkyl halides has opened the way for the electrosynthesis of organoamines, organohydrazines, cyanides, aminocarhynes organonitriles, and amino acids. These are discussed in Sect. 3.4 [35, 43, 44]. 

An intermolecular coupling reaction between three organonitrile molecules and a silicon-tethered diyne is reported to give good yields of pyrrolo[3,2-f]pyridine derivatives <2004JA7172>. The reaction is promoted by a low-valent zirconocene species (Equation 13). 

In addition, the chemist may infer the structural characteristics that reduce toxic potency, thereby providing a rational basis to design new, less toxic analogs. Typically, in larger data sets the relationship between structure and activity is more apparent, but small data sets can nonetheless be fairly useful. The application of SARs for the design of safer chemicals is demonstrated below using aliphatic carboxylic acids and organonitriles, two classes of important commercial chemical substances. 

Scheme 4.4 Mechanism by which organonitriles are acutely lethal. Nitriles that can form a more stable radical on the a-carbon tend to be more lethal because they form the cyanohydrin intermediate more readily, which decomposes to release cyanide, which is highly toxic.

Similarly, it is plausible to expect that the more lethal organonitriles, such as 2-methylbutyronitrile (29) and phenylacetonitrile (30) (discussed in Section 4.3.2) would be rendered much less toxic if the hydrogen atoms on the carbon atom adjacent to the cyano moiety were replaced with fluorine atoms, as illustrated by structures 50 and 51, respedively. 

All of the organonitrile adducts of nickel(II) contain nickel(II) coordinated to six nitrogen atoms of the RCN molecules, as exemplified by the structure of [Ni(MeCN)s]2+ cation where the MeCN donor is coordinated in a nearly linear array (Ni—N—C angles average 172°) with Ni—N distances in the range 203-212 pm.1109... 

Organonitriles are usually taken as weak c-donors and n-acceptors (contrasting in that aspect the isoelectronic CO and explaining the lability of the complexes), but recent LCAO-MO calculations6 indicate a potential a-donor character in MeCN. Relevant orbital energies for this ligand are shown in Figure 1. 

As a class of compounds, nitriles have broad commercial utility that includes their use as solvents, feedstocks, pharmaceuticals, catalysts, and pesticides. The versatile reactivity of organonitriles arises both from the reactivity of the C=N bond, and from the ability of the cyano substituent to activate adjacent bonds, especially C—H bonds. Nitriles can be used to prepare amines, amides, amidines, carboxylic acids and esters, aldehydes, ketones, large-ring cyclic ketones, imines, heterocycles, orthoesters, and other compounds. Some of the more common transformations involve hydrolysis or alcoholysis to produce amides, acids and esters, and hydrogenation to produce amines, which are intermediates for the production of polyurethanes and polyamides. An extensive review on hydrogenation of nitriles has been recendy published (10). 

Previous work has shown that the base hydrolysis of organonitriles is increased by a factor of ca. 108 on coordination to pentaamineruthenium(III) and by about 10s on coordination to Co111 and Rh111. A base-independent pathway is also observed with Rum, due to water attack on the coordinated nitrile.330 The relative nucleophilicities of hydroxide ion and water for attack on N-coordinated nitriles are ca. 109 (Table 22). 

The interactions of compounds containing the oxime group with coordinated organonitriles are very important in template syntheses [384,413-416], These reactions take place as a nucleophilic addition and lead to the formation of complexes with unusual iminoacyl ligands. The iminoacylation reaction was studied in detail for various oximes and organonitriles, coordinated to PtCl4 [384,413-416]. Thus, the template transformation (3.192) of the discussed type in case of the oximes 744 takes place in acetonitrile or chloroform and yields complexes of the type 745 [413a] ... 

The described transformation is interesting because the vicinal dioxime groups do not participate in substitution of organonitrile groups, when traditional chelate compounds would be formed, but join the organonitriles of one of their OH groups, yielding addition products [415],... 

Nitrilases (E.C. 3.5.5.1) promote the mild hydrolytic conversion of organonitriles directly to the corresponding carboxylic acids.19 However, less than 20 microbially derived nitrilases had been characterized at the start of this work, despite their potential synthetic value. The paucity of enzymes and the limited substrate scope of the handful of enzymes available have limited practical commercial development of nitrilase-catalyzed conversions, except in a few cases. Accordingly, we engaged in a discovery effort centered around exploiting the natural diversity available within our environmental DNA libraries and have discovered and characterized more than 200 new sequence unique nitrilases.20 All of the newly discovered nitrilases possess the conserved catalytic triad Glu-Lys-Cys that is characteristic for this enzyme class.19... 

Organonitrile-functionalized mesoporous silicas such as MCM-41 and MCM-48 have been used to immobilize dioxoMo(VI) complexes such as Mo02X2(THF)2 (with X = Br or Cl) (218). The catalytic potential of these hybrid material was evaluated for the epoxidation of cyclooctene with r-BuOOH as the oxygen source. Notwithstanding the high activities claimed, pronounced Mo leakage was observed. Indeed, it was shown that cyclooctene continued to be converted after the solid catalyst was removed from the reaction mixture (218). 

OHKAWA, H., OHKAWA, R., YAMAMOTO, I., CASIDA, J.E., Enzymatic mechanisms and toxicological significance of hydrogen cyanide liberation from various organothiocyanates and organonitriles in mice and houseflies., Pest. Biochem. Physiol., 1972,2,95-112. 

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