Hydrolysis of imines

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). 

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. 

---

Alkylation and hydrolysis of imines alkylation of aldehydes 10-107 Alkylation and hydrolysis of dithianes 10-108 Alkylation and hydrolysis of oxazines and similar compounds 10-109 Reaction of diazo aldehydes with boranes... 

Hydrolysis of imines, oximes, hydrazones, or other C=N compounds... 

Scheme 22 summarizes the mechanism proposed. As in the case of oxygen exchange between MeRe03 and H20, the proposed intermediate was not detected. Examples of analogous intermediates that carry out the hydrolysis of imines and the aminolysis of ketones are well documented (64-66). 

Just as imines may be viewed as nitrogen analogues of carbonyl compounds, the C=N group may also be viewed as carbonyl-like for interpretation of some of its reactions. For instance, nitriles are readily hydrolysed in acid to give carboxylic acids (see Section 7.6.1). This process begins in a similar manner to hydrolysis of imines. 

One simple example was the hydrolysis of imines hack to carbonyl compoimds via nucleophilic attack of water. The Mannich reaction is only a special case of nucleophilic addition to iminium ions,... 

The synthesis pathway of quinolizidine alkaloids is based on lysine conversion by enzymatic activity to cadaverine in exactly the same way as in the case of piperidine alkaloids. Certainly, in the relatively rich literature which attempts to explain quinolizidine alkaloid synthesis °, there are different experimental variants of this conversion. According to new experimental data, the conversion is achieved by coenzyme PLP (pyridoxal phosphate) activity, when the lysine is CO2 reduced. From cadeverine, via the activity of the diamine oxidase, Schiff base formation and four minor reactions (Aldol-type reaction, hydrolysis of imine to aldehyde/amine, oxidative reaction and again Schiff base formation), the pathway is divided into two directions. The subway synthesizes (—)-lupinine by two reductive steps, and the main synthesis stream goes via the Schiff base formation and coupling to the compound substrate, from which again the synthetic pathway divides to form (+)-lupanine synthesis and (—)-sparteine synthesis. From (—)-sparteine, the route by conversion to (+)-cytisine synthesis is open (Figure 51). Cytisine is an alkaloid with the pyridone nucleus. 

Hydrolysis of enol esters 0-83 Reduction of acyl halides 0-84 Reduction of carboxylic acids, esters, or anhydrides 0-85 Reduction of amides 0-95 Alkylation and hydrolysis of imines, alkylation of aldehydes 0-97 Alkylation and hydrolysis of dithi-anes... 

The effect of metal ions on the hydrolysis of imines is of considerable biological interest. A number of papers have discussed the effect of metal ions on the formation and hydrolysis of such compounds.389-400 Until recently detailed kinetic studies on imine hydrolysis were lacking, but a number of detailed investigations have now been carried out. The low solubility of many aromatic imines (which are generally more readily characterized) in aqueous solution has led to the use of mixed alcohol-water solvent systems which can lead to problems of interpretation. 

Formation of C—N bonds is frequently achieved by condensation reactions between amines and aldehydes or ketones. A typical nucleophilic addition is followed by elimination of water to give an imine or Schiff base [Figure 2.12(a)], Of almost equal importance is the reversal of this process, i.e. the hydrolysis of imines to amines and alde-hydes/ketones [Figure 2.12(b)], The imine so produced, or more likely its protonated form the... 

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). 

Imines readily hydrolyze under basic or acidic conditions. Figure 52 shows the acid-catalyzed hydrolysis of imines. When developing methods to detect imines, it is often necessary to use neutral pH conditions to optimize the stability of the imine. An example of imine formation and hydrolysis is found in the degradation chemistry of the API sertraline hydrochloride (Fig. 53) (86). 

Hydrolysis of imines and enamines forms aldehydes and ketones. 

The hydrolysis of imines is the reverse of the addition of amines to carbonyls, and the two-step scheme of Eq. (25) applies. 

The effect of metal ions on the hydrolysis of imines is of considerable biological interest. A number of papers have discussed the effect of metal ions on the formation and hydrolysis of such... 

Benzonitrile. Added benzonitrile to complex dissolved in THF at —10°C over 1 hr, stirred at — 10°C for 0.5 hr let warm for 1 hr hydrolyzed normally, but added 20% HC1 to crude solid product in isolation to complete hydrolysis of imine recrystallization from ethanol mp 53°C (lit. mp 60°C) 59%, benzylphenyl ketone (36). 

---