Co-ordinated imines

In the same way that we were primarily concerned with reactions of nitriles in the previous section, we will be concerned with the attack of nucleophiles on imines in this section. Imines, R2C=NR, are the nitrogen analogues of carbonyl groups, and we saw in Chapter 2 that imines may be stabilised by co-ordination to a metal ion capable of back-donation to the ligand -levels. We shall investigate the synthetic utility associated with the formation of co-ordinated imines in a later chapter. However, it is also possible to promote the hydrolysis of the imine by co-ordination to a positively charged metal ion. 

Paradoxically, this imine is structurally very closely related to the amidate ester which is produced by the ethanolysis of 2-cyanopyridine in the presence of copper(n) (Fig. 4-14) There is indeed a very fine balance between destabilisation and stabilisation of the co-ordinated imine. 

Figure 4-31. The reduction of co-ordinated imines by dihydrogen or sodium borohydride.

Co-ordinated imines have also been shown to react with a wide range of other nucleophiles, resulting in a formal addition of HNu across the C=N bond (Fig. 4-28). 

The metal ion does, however, introduce a new subtlety into these reductions. The reduction of the two imine groups in the nickel(n) complex 4.10 is readily achieved with Na[BH4], The free tetraamine ligand would be expected to exhibit a facile pyramidal inversion at each nitrogen atom, whereas in the nickel(n) complex this inversion is not possible without significant weakening (or breaking) of the Ni-N bonds. In macrocyclic complexes it is very often found that the complex obtained by the reduction of a co-ordinated imine does not possess the same stereochemistry as that obtained by the direct reaction of the free amine with metal ion. 

Figure 5-49. The formation of a co-ordinated imine by the intramolecular reaction of an amido ligand with pyruvate at a kinetically inert cobalt(m) centre.

Figure 6-15. The reduction of a co-ordinated imine macrocycle may lead to a number of different diastereomers of the complex of the saturated macrocyclic ligand...

In addition to their thermodynamic stability, complexes of macrocyclic ligands are also kinetically stable with respect to the loss of metal ion. It is often very difficult (if not impossible) to remove a metal from a macrocyclic complex. Conversely, the principle of microscopic reversibility means that it is equally difficult to form the macrocyclic complexes from a metal ion and the free macrocycle. We saw earlier that it was possible to reduce co-ordinated imine macrocycles to amine macrocyclic complexes in order to remove the nickel from the cyclam complex that is formed, prolonged reaction with hot potassium cyanide solution is needed (Fig. 6-24). 

Let us start by considering the reaction of the copper(n) complex 6.49 with formaldehyde. Initially we might expect the diimine 6.50 to be formed, but this ignores the nature of the intermediates. As we saw earlier, the reaction of an amine with an aldehyde initially produces an aminol. Consider the addition of the second molecule of formaldehyde to 6.49. The product will be 6.51, which contains an imine and an aminol (Fig. 6-43). The imine is co-ordinated to a metal ion, and the polarisation effect is likely to increase the electrophilic character of the carbon. The hydroxy group of the aminol is nucleophilic and it is correctly oriented for an intramolecular attack upon the co-ordinated imine. The result is the formation of the copper(n) macrocyclic complex 6.52. 

Thecomplexes[CuLCl],H20and [CuL(NO3)],0.5H2O [L = iV-(2-hydroxy-ethyl)propane-1,3-diamine] have been prepared.N-Hydroxyethylethylene-diamine (hen) forms the complexes [Cu(hen)2X2] (X = Cl, Bf, NO3, or CIO ) and [Cu(hen)X2] (X = Cl or NO3). The co-ordinated ligand condenses readily with acetone to form complexes of 7,9,9-trimethyl-3,6,10,13-tetra-azapentadeca-6-en-l,15-diol. 8° The new stereospecific ligand iViV -bis-(2-carboxyphenyl)-ethylenedi-imine reacts with Cu " at pH 2.5-4.5 to form (199).8 ... 

It is often found that imines are stabilised towards hydrolysis by co-ordination of the nitrogen to a 7t-bonding transition metal. Of course, in the absence of significant 7C-bonding interactions, ligand polarisation is expected to have the opposite effect and activate the imine towards nucleophilic attack. 

The equilibrium between carbonyl compound, amine and imine is metal-ion dependent and the position of the equilibrium may be perturbed by the co-ordination of any of the components to a metal ion (Fig. 4-21). 

The balance between stabilisation and activation of the imine towards hydrolysis depends on the relative polarisation of the ligand and the back-donation from the metal, as discussed in Chapter 2. It is very difficult to successfully predict the overall stabilisation or destabilisation of a given imine towards hydrolysis in the presence of a given metal ion. Some imines are stabilised by co-ordination to copper(n), whereas others are destabilised (Fig. 4-23). 

Figure 4-21. Co-ordination of amine or imine to a metal ion may control the position of equilibria involving imines.

The presence of electrons in d orbitals, which may be involved in back donation, is not a prerequisite for the stabilisation of an imine by co-ordination some imines are stabilised by co-ordination to lead(n). The many factors involved (charge on metal, charge on ligand, back-donation, configuration of ligand, stabilisation of products, etc.) are interdependent and finely balanced. The formation of a chelated imine complex is an important factor, but once again examples are known in which chelated ligands are either activated or deactivated towards hydrolysis. 

In general, the greater the thermodynamic stability of the imine complex, the smaller the tendency towards hydrolysis. The hydrolysis of the imine formed from aniline and benz-aldehyde is enhanced 100,000 times in the presence of copper(n). The importance of the electron configuration of the metal ion is seen in the reactions of this same ligand the imine is stabilised with respect to hydrolysis on co-ordination to a d6 iron(n) centre. This may be partially ascribed to the effective back-donation from the low-spin d6 centre (Fig. 4-24). In this case, the free imine is reasonably stable to hydrolysis in the absence of metal ions. 

Many examples are known in which the co-ordination of an imine to a metal centre activates it towards nucleophilic attack by water to yield the aminol (aminoalcohol) or related derivative. In the absence of the metal ion, most aminols either dehydrate to yield imines or collapse to the parent amines and carbonyl compound. 

The next steps involve attack of the deprotonated ligand upon a second equivalent of the electrophilic aldehyde. This generates an alkoxide, which undergoes an intramolecular nucleophilic attack upon the imine to give a co-ordinated oxazolidinene, 5.9 (Fig. 5-19). 

At the beginning of this chapter we considered the ways in which co-ordination to a metal ion might control the reactions of a carbonyl compound. We considered the possible fates of the tetrahedral intermediate formed by the attack of a nucleophile upon the carbonyl carbon atom. In the case of a nucleophile such as ammonia or a primary amine another pathway leading to an imine is open. 

The position of the equilibrium between imine and carbonyl may be perturbed by interaction with a metal ion. We saw in Chapter 2 how back-donation of electrons from suitable orbitals of a metal ion may stabilise an imine by occupancy of the jc level. It is possible to form very simple imines which cannot usually be obtained as the free ligands by conducting the condensation of amine and carbonyl compounds in the presence of a metal ion. Reactions which result in the formation of imines are considered in this chapter even in cases where there is no evidence for prior co-ordination of the amine nucleophile to a metal centre. Although low yields of the free ligand may be obtained from the metal-free reaction, the ease of isolation of the metal complex, combined with the higher yields, make the metal-directed procedure the method of choice in many cases. An example is presented in Fig. 5-47. In the absence of a metal ion, only low yields of the diimine are obtained from the reaction of diacetyl with methylamine. When the reaction is conducted in the presence of iron(n) salts, the iron(n) complex of the diimine (5.23) is obtained in good yield. 

The design of polydentate ligands containing imines has exercised many minds over many years, and imine formation is probably one of the commonest reactions in the synthetic co-ordination chemist s arsenal. Once again, the chelate effect plays an important role in stabilising the co-ordinated products and the majority of imine ligands contain other donor atoms that are also co-ordinated to the metal centre. The above brief discussion of imine formation will have shown that the formation of the imine from amine and carbonyl may be an intra- or intermolecular process. In many cases, the detailed mechanism of the imine formation reaction is not fully understood. In particular, it is not always clear whether the nucleophile is metal-co-ordinated amine or amide. Some intramolecular imine formation reactions at cobalt(m) are known to proceed through amido intermediates. A particularly useful intermediate (5.24) in metal-directed amino acid chemistry is... 

In recent years, it has been shown that co-ordinated phosphines may also undergo reactions with carbonyl compounds. This is well exemplified in the reactions of [(MeHPCH2CH2PHMe)2Pd]2+ (Fig. 5-51). The reaction with formaldehyde yields a complex of an open-chain hydroxymethyl substituted ligand, the same species that is obtained from reaction of the free ligand. This is the phosphorus analogue of the aminol intermediate in imine formation. It is extremely unusual to obtain RP=CR2 systems in the absence of sterically demanding substituents. 

One of the paradoxes of metal-imine chemistry is the observation that in many cases the imine is stabilised with respect to nucleophilic attack by water upon co-ordination, but is still prone to attack by amines. We saw in Chapter 4 how the hydrolysis of imines may be either promoted or inhibited by co-ordination to a metal, and we also saw a number of examples involving nucleophilic attack on an imine by a variety of other nucleophiles. A special case of such a nucleophilic attack involves another amine. The consequence is a transimination reaction, as indicated in Fig. 5-53. Presumably, intermediates of type 5.26 are involved. The procedure is of some synthetic use for the preparation of imine complexes (Fig. 5-54). 

Another interesting example of metal-directed chemistry involving the stabilisation and reactivity of imines is seen in the reaction of pyridoxal with amino acids. This reaction is at the basis of the biological transamination of amino acids to a-ketoacids, although the involvement of metal ions in the biological systems is not established. The reaction of pyridoxal (5.27) with an amino acid generates an imine (5.28), which is stabilised by co-ordination to a metal ion (Fig. 5-55). 

Figure 5-54. Transimination may provide a method for the preparation of imines which are not readily accessible by other methods. This reaction illustrates a way of making NO donor ligands without the need for nucleophilic attack of amine on a co-ordinated 1,3-diketonate.

The complex is additionally stabilised by co-ordination of the phenoxide, and possibly the carboxylate, to the metal ion, illustrating the utility of chelating ligands in the study of metal-directed reactivity. We saw in the previous section the ways in which a metal ion may perturb keto-enol equilibria in carbonyl derivatives, and similar effects are observed with imines. The metal ion allows facile interconversion of the isomeric imines. The first step of the reaction is thus the tautomerisation of 5.28 to 5.29 (Fig. 5-56). Finally, the metal ion may direct the hydrolysis of the new imine (5.29) which has been formed, to yield pyridoxamine (5.30) and the a-ketoacid (Fig. 5-57). 

Probably one of the commonest reactions encountered in the template synthesis of macrocycles is the formation of imine C=N bonds from amines and carbonyl compounds. We have seen in the preceding chapters that co-ordination to a metal ion may be used to control the reactivity of the amine, the carbonyl or the imine. If we now consider that the metal ion may also play a conformational role in arranging the reactants in the correct orientation for cyclisation, it is clear that a limitless range of ligands can be prepared by metal-directed reactions of dicarbonyls with diamines. The Tt-acceptor imine functionality is also attractive to the co-ordination chemist as it gives rise to strong-field ligands which may have novel properties. All of the above renders imine formation a particularly useful tool in the arsenal of preparative co-ordination chemists. Some typical examples of the templated formation of imine macrocycles are presented in Fig. 6-12. 

Figure 6-14. The reduction of co-ordinated macrocyclic imines provides a method for the preparation of macrocyclic amines. The reaction above illustrates one of the standard methods for the preparation of cyclam. The metal ion may be removed from the nickel(n) complex by prolonged reaction with cyanide.

The co-ordination chemistry of macrocyclic ligands containing imine or hydrazone groups has been widely studied and, as expected, the presence of the imine functionality in the ring confers unusual redox properties to the complexes. 

The synthetic method may be seen to be complementary to direct nucleophilic displacement. Whereas amines often react relatively sluggishly in metal-mediated nucleophilic displacements, they usually undergo facile reaction with carbonyls to form imines. The reduction of the imines (free or co-ordinated) may then be achieved by reduction with Na[BH4] or (less conveniently) by direct hydrogenation. This provides a very convenient method for the preparation of cyclic amines (Fig. 6-14). 

Figure 6-40. The complex 6.41 undergoes an intramolecular nucleophilic attack at a second imine to generate a new macrocycle with the correct cavity size for cobalt(n). The lower structure shows the complex cation as it is found in the solid state. The cobalt ion is actually seven-co-ordinate, with axial water and methanol ligands (omitted for clarity).

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