Lewis acid activation of nitriles

Low-valent Ru(II) [150] and Rh(I) complexes catalyze aldol and Michael reactions of 2-nitrilo esters. The sequence is thought to be initiated by nitrile complexation to the transition metal. This Lewis acid-activation is followed by an oxidative addition to give a metal hydride and a nitrile complexed enolate as shown in Sch. 36. Examples including diastereoselective Ru(II) catalyzed reactions [151] and enantioselective Rh(I)-catalyzed reactions [152-154] with the large trans-chelating chiral ligand PhTRAP are shown in Tables 8 and 9. 

Under neutral conditions Ru(II) complexes catalyze the nucleophilic addition of water to nitriles to yield amides [155], The reaction proceeds via external nucleophilic attack of water to the transition metal-activated nitrile. Under similar conditions 5-ketonitriles are converted into ene-lactams, a reaction that has found elegant application in a short diastereoselective synthesis of (-)-pumiliotoxin C (Sch. 37) [156]. 

Similarly, reaction of nitriles with amines or with alcohols yields amides (Sch. 38) [157] or esters, respectively (Sch. 39) [158]. 

MeCN PhlCHjljOH C11H23CN MeOH PhCHjCN /-PrCHjOH 

Under neutral conditions iridium hydride complexes catalyze addition between nitriles to give cyanoenamines (Sch. 40) [159]. This reaction implies simultaneous activation of both the a-C-H bond of the nitrile as a pronucleophile and the CN triple bond of the nitrile as an electrophile. 

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Ru(II) catalyzed Michael reactions of nitriles involve a-C-H activation these reactions are detailed in Section 14.3.6 (Lewis Acid Activation of Nitriles). 

Lewis acid activation works particularly well for weakly basic substrates that bind well to metal ions (Figure 6.6). Nitriles are excellent substrates for Lewis acid activation since they are weakly basic (pK, of protonated acetonitrile is about -10) [42] yet they bind well to metal ions (binding constant for acetonitrile to 6 is 2.5 m 1). Imines are about fifteen orders of magnitude more basic than nitriles. Thus, in neutral aqueous solutions, significant amounts of imines are protonated. Since protonated substrates are generally more reactive than metal coordinated ones (Table 6.1), Lewis acid activation of imines with metal ions in aqueous solutions is difficult. 

Lewis acid activates the nitrile function in the intermediate (97), which yields the product upon hydrolysis.Treatment of 3-(aryliminomethyl)-chromones (98) with ylides results in the formation of phosphorane-adducts (99). ... 

The Houben-Hoesch reaction proceeds via a straightforward electrophilic aromatic substitution mechanism. Following protonation or Lewis acid activation of the alkyl nitrile, nucleophilic attack by the electron-rich pyrrole selectively at C(2) produces the resonance stabilized intermediate 1. Elimination of H" reestablishes the aromaticity of the pyrrole, resulting in imine 2, which is rapidly hydrolyzed to produce the ketone 3. ... 

In the case of using acid catalysts, computational and experimental information currently supports Lewis acid activation of the nitrile.Such activation does not necessarily contradict mechanisms in which A1 or Zn azides are suggested to form, as azides are typically used in excess and could be involved in the nitrile activation process and delivery of the azide separately. 

Substitutionally inert Co(m) or Ir(m) complexes have been used to measure directly the effect of Lewis acid activation on the hydrolysis of an amide [35-37], a nitrile [38] and a phosphate triester [39] (Figure 6.4). The p/C, of the cobalt-bound water molecule in 5 is 6.6 [40], Thus the upper limit for the rate-acceleration due to Lewis acid activation with this metal in the hydrolysis of esters, amides, nitriles and phosphates should be close to 109-fold. Although the observed rate accelerations for the hydrolysis reac-... 

The efficiency of Lewis acid activation depends not only on the reactivity of the bound substrate but also on the equilibrium constant for coordination of the substrate. The equilibrium constants for binding of an amide, a nitrile and phosphates to Co(m) complexes have been measured (Figure 6.5). Formyl morpholine binds to 6 with an equilibrium constant of 0.4 m-1 [35]. Binding of acetamide to 6 could not be detected. The steric effect of the methyl group is expected to significantly lower the binding of acetamide compared with that of formyl morpholine. 

Nature of the Activation Effect One of the principal questions that may be interpreted with the help of theoretical methods is the reasons for the activation of nitriles toward DCA upon their coordination to a metal center. Traditionally, the reactivity of dipoles and dipolarophiles in the DCA reactions is explained in terms of the frontier molecular orbital (FMO) theory and depends on the predominant type of the FMO interaction. The coupling of nitrones with nitriles is usually controlled by the interaction of the highest occupied molecular orbital (HOMO) of nitrone and the lowest unoccupied molecular orbital (LUMO) of nitrile centered on the C N bond (so-called normal electron demand reactions). For such processes, the coordination of N CR to a Lewis acid (e.g., to a metal) decreases the LUMOncr energy, providing a smaller HOMOjii -one - LUMOncr and, hence, facilitates the DCA reaction (Fig. 13.1a). 

Signiflcantly, the authors speculated that the conversion was activated by the interaction of the Lewis acid with the nitrile nitrogen atom, a process apparently requiring an orbital flexibility (capacity to hybridize) or other electronic character inconsistent with properties found in lanthanide species. 

In the same year, a successful Lewis acid catalysis was developed by Sedelmeier et alP The group synthesized 5-substimted tetrazoles in a direct conversion using dial-kylaluminium azides (57), which are inexpensive, soluble in organic solvents and nontoxic (Scheme 9.9). The proposed mechanism for the 1,3-dipolar cycloaddition (Scheme 9.9A) suggests Lewis acid properties of the aluminium center activating the nitriles in the azide addition. Different 5-substituted tetrazoles (63) were obtained in excellent yields after a simple workup procedure (Scheme 9.9B). However, the reaction tanperature varied between -40 °C and 120 °C, depending on the reactivity of the substrates. 

The role of Lewis acids in the formation of oxazoles from diazocarbonyl compounds and nitriles has primarily been studied independently by two groups. Doyle et al. first reported the use of aluminium(III) chloride as a catalyst for the decomposition of diazoketones.<78TL2247> In a more detailed study, a range of Lewis acids was screened for catalytic activity, using diazoacetophenone la and acetonitrile as the test reaction.<80JOC3657> Of the catalysts employed, boron trifluoride etherate was found to be the catalyst of choice, due to the low yield of the 1-halogenated side-product 17 (X = Cl or F) compared to 2-methyI-5-phenyloxazole 18. Unfortunately, it was found that in the case of boron trifluoride etherate, the nitrile had to be used in a ten-fold excess, however the use of antimony(V) fluoride allowed the use of the nitrile in only a three fold excess (Table 1). 

Ferrocen-l,l -diylbismetallacycles are conceptually attractive for the development of bimetal-catalyzed processes for one particular reason the distance between the reactive centers in a coordinated electrophile and a coordinated nucleophile is self-adjustable for specific tasks, because the activation energy for Cp ligand rotation is very low. In 2008, Peters and Jautze reported the application of the bis-palladacycle complex 56a to the enantioselective conjugate addition of a-cyanoacetates to enones (Fig. 31) [74—76] based on the idea that a soft bimetallic complex capable of simultaneously activating both Michael donor and acceptor would not only lead to superior catalytic activity, but also to an enhanced level of stereocontrol due to a highly organized transition state [77]. An a-cyanoacetate should be activated by enolization promoted by coordination of the nitrile moiety to one Pd(II)-center, while the enone should be activated as an electrophile by coordination of the olefinic double bond to the carbophilic Lewis acid [78],... 

Early attempts to convert aliphatic nitriles into primary cyclopropylamines, in the same way as N,N-dialkylcarboxamides 44 are transformed to N,N-dialkylcyclopropylamines 47 under the action of Grignard reagents and Ti(OiPr)4, were unfruitful [136], However, Szymoniak et al. have found that the addition of a Lewis acid such as boron trifluoride etherate is necessary to activate azatitanacyclopentene 153 resulting from insertion of... 

In addition, the mechanism of the zinc-catalyzed [3+2] dipolar cycloaddition of azides and nitriles to form tetrazoles was examined <2003JA9983>. The energy barrier of the reaction is lowered by 5-6kcalmol 1 which corresponds to an acceleration of 3 1 orders of magnitude. The source of the catalytic activity seems to be the coordination of the Lewis acidic zinc halide to the nitrile, which is supported by model calculations. Also AICI3 was examined as another Lewis acid which catalyzes the reaction to a greater extent than ZnBr2-... 

Further development of this idea led to the proposal (56) that reactive B=C groups, for instance carbonyl systems, would be able to activate alcohol acceptors AH by generating a related A—B—C—H intermediate (Scheme 8, path I). It seemed that chloral might act as a catalyst along these lines. However, it turned out that the rate of decay in the transition state is too low in all systems tested thus far. Therefore, the carbonyl compound is more or less a substitute for a Lewis acid catalyst, as indicated in Scheme 8, path II. The high reactivity and diastereoselectivity in chloral-catalyzed reactions is attributable to the nitriles used as solvents in these reactions [see Section III.3.b and Ref. (62)]. 

There is obviously a relation with the classic activation of molecules by Lewis acids, but here we have confined ourselves to the activation of "soft" substrates by "soft" acids. Examples of "hard" acid activated reactions include Diels-Alder additions, nitrile solvolysis, ester solvolysis, ester formation, Oppenauer reactions etc (see Lewis acid catalysed reactions, 2.11). 

Carbon monoxide, hydrogen cyanide, and nitriles also react with aromatic compounds in the presence of strong acids or Lewis acid catalysts to introduce formyl or acyl substituents. The active electrophiles are believed to be dications resulting from diprotonation of CO, HCN, or the nitrile.58 The general outlines of the mechanisms of... 

With the exception of the Ru1 complex, a variety of metal ions activate the hydration reaction to a very consistent extent (106-108-fold). The relative constancy of the rate acceleration and the anomaly of the Ru11 complex are consistent with the view that it is the Lewis acidity of the metal ion which is essential for activation. In the Ru11 complex, considerable metal h-ligand -bonding is expected, resulting in back donation of electron density from the metal centre into the C=N bond. This view is supported by measurements of the C=N stretching frequency of free nitriles and of their complexes with Ru11 and the other metal ions.317... 

Thus, many metal ions catalyze the hydrolysis of esters [7,8], amides [9], and nitriles [10] via electrophilic activation of the C=0 or C=N group. This type of catalysis is characteristic of coordination complexes and is very common in metalloenzyme-mediated processes. Zinc(II), for example, is a key structural component of more than 300 enzymes, in which its primary function is to act as a Lewis acid (see Chapter 4). The mechanism of action of zinc proteases, e.g., thermolysin, involves electrophilic activation of an amide carbonyl group by coordination to zinc(II) in the active site (Figure 4). 

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