Imines stabilisation

An unstable adduct between triphenylphosphine and a photochemically-generated dimethylgermylene has been characterised spectrophotometrically.The first 2,3-dihydro-l,3,2-X -benzodiazaphospholes (73) have been formed in the reactions of triphenylphosphine with g-benzoquinone di-imines stabilised by coordination.A complex of phenylnitrene with a tungsten pentacarbonyl acceptor has been trapped using triphenylphosphine. A kinetic study of the reactions of diazoalkanes with triphenylphosphine, leading to the phosphazenes (74), indicates a biphilic mechanism, the dominant interaction in the transition state involving the diazoalkane as a net electron donor,... 

In summary, the chemical usefulness of thiamine pyrophosphate depends on its ease of carbanion formation at C-2 which is not only a good nucleophile but also a reasonably stable leaving group. In addition the cationic imine stabilises the formation of a carbanion on the adjacent carbon bonded to C-2. 

However, difluoromethylation occurs when nucleophiles intercept difluoro-carbene generated under basic conditions, providing a route to difluoromethyl-ethers of phenols [33] and thiophenols [34]. The reaction with phosphite anion leads to the corresponding difluoromethyl phosphonate (see Sect. 2.3.2) while nucleophilic carbanions such as alkynes [35] also undergo formal alkylation, as do malonates [36,37]. An -difluoromethylaziridine was reported in a reaction with a glycine imine [38]. The scope of the established chemistry is summarised in Fig. 1. Bromodifluoromethylation occurs with a similar range of nucleophiles [39,40], and also with carbonyl-stabilised carbanions such as malonates [41,42]. 

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. 

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. 

In many cases, free imines are hydrolytically unstable. In general, it is difficult to form imines from carbonyl compounds and amines in aqueous solution. This is not always the case, and it is sometimes possible to form conjugated imines which are stabilised by delocalisation in aqueous conditions (Fig. 4-22). 

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). 

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. 

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. 

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... 

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). 

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). 

The role of the metal ion may be purely conformational, acting to place the reactants in the correct spatial arrangement for cyclisation to occur, or it may play a more active role in stabilising the enol, enolate, imine or enamine intermediates. The prototypical example of such a reaction is shown in Fig. 6-18. The nickel(n) complex of a tetradentate macrocyclic ligand is the unexpected product of the reaction of [Ni(en)3]2+ with acetone. There are numerous possible mechanisms for the formation of the tetradentate macro-cyclic ligand and the exact mechanism is not known with any certainty. 

Container molecules in general show an increasing number of applications and so do the container molecules based on imine type ligands. Many different shapes of open or nearly closed ones could already be synthesised. Those cages are known to encapsulate different types of guest molecules. This encapsulation can be selective and permanent or reversible. The container molecules described are also used for stabilisation of different compounds such as the allotrope P4. They can be used as gas or optical sensors. One of the described cages can also be opened and closed selectively. 

An elegant application of the oxidation of 2-aminofurans has been described by Nicolaou and co-workers (02JA2190, 02JA2202) in model studies directed towards the total synthesis of CP molecules. In this study, the isolable iminobutenolide 80 is formed by cyclisation of the alkoxide 79 (Method B, Section II.B.l.b). Without a stabilising substituent on the ring the equilibrium favours the imine 80 rather than the amine 81 (Scheme 16). However, it is postulated that there is sufficient 2-ami -nofuran in equilibrium for this to be rapidly oxidised to the hydroperoxide 83. At this stage, the final product is determined by the reaction conditions. In strongly acidic conditions, tautomerism to the amine 85 and hydrolysis rationalises the formation of the isolated anhydride 88. Under weakly acidic conditions, formation of... 

There is a further disadvantage in using simple Diels-Alder reaction of azadienes to make heterocycles. The products, e.g. 2 and 4 are themselves either imines or enamines and are inherently unstable and it is also necessary to stabilise them to make isolation of the heterocycle possible. 

All positions on each of the diazines, with the sole exception of the 5-position of a pyrimidine, are a and/or y to an imine ring nitrogen and, in considering nncleophilic addition/snbstitution, it mnst be remembered that there is also an additional nitrogen that is withdrawing electron density. As a consequence, all the monohalo-diazines are more reactive than either 2- or 4-halo-pyridines. The 2- and 4-halo-pyrimidines are particularly reactive because the anionic intermediates (shown below for attack on a 2-halo-pyrimidine) derive direct mesomeric stabilisation from both nitrogen atoms. 

Which electrophile is lost from the amino acid residue is, of course, controlled by the enzyme. One way this may occur is by the enzyme binding the PLP imine so that the electrophile is in close proximity to a suitable or base to aid abstraction and also so that the a orbital of the bond to be broken is periplanar with the p r acceptor system, i.e. orthogonal to the plane of the pyridine ring (XXXI). Maximal orbital overlap, stereoelectronic control, will lower the activation energy for the reaction. Aldol-type reactions can also occur with PLP as in the laboratory the key to making carbon-carbon bonds is the formation of a stabilised carbanion. Proton abstraction from the initially formed imine gives a masked carbanion which can nucleophili-... 

A new edition of Johnson s excellent book Ylides and Imines of Phosphorus has been published almost thirty years after the original and is indispensable to anyone who studies or uses ylides, phosphorus-stabilised carbanions or imines. 

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