Catalysis imine formation

Another type of bifunctional catalysis has been noted with a,cn-diamines in which one of the amino groups is primary and the other tertiary. These substituted diamines are from several times to as much as 100 times more reactive toward imine formation than similar monofunctional amines. This is attributed to a catalytic intramolecular proton transfer. 

Polyquinolines (PQ) are obtained by the Friedlander reaction of a bis-o-aminoaromatic aldehyde (or ketone) with an aromatic hisketomethylene reactant [Concilio et al., 2001 Stille, 1981]. The quinoline ring is formed hy a combination of an aldol condensation and imine formation (Eq. 2-221). Polymerization is carried out at 135°C in m-cresol with poly (phosphoric acid) as the catalyst. The reaction also proceeds under base catalysis, but there... 

One of the most spectacular and useful template reactions is the Curtis reaction , in which a new chelate ring is formed as the result of an aldol condensation between a methylene ketone or inline and an imine salt. The initial example of this reaction was the formation of a macrocyclic nickel(II) complex from tris(l,2-diaminoethane)nickel(II) perchlorate and acetone (equation 53).182 The reaction has been developed by Curtis and numerous other workers and has been reviewed.183 In mechanistic terms there is some circumstantial evidence to suggest that the nucleophile is an uncoordinated aoetonyl carbanion which adds to a coordinated imine to yield a coordinated amino ketone (equation 54). If such a mechanism operates then the template effect is largely, if not wholly, thermodynamic in nature, as described for imine formation. Such a view is supported by the fact that the free macrocycle salts can be produced by acid catalysis alone. However, this fact does not... 

Notice that an acid catalyst is normally added for imine formation. Without an acid catalyst, the reaction is veiy slow, though in some cases it may still take place (oximes, for example, will form without acid catalysis, but form much faster with it). It s important to notice that acid is not needed for the addition step in the mechanism (indeed, protonation of the amine means that this step is very slow in strong acid), but is needed for the elimination of water later on in the reaction. Imine formation is in fact fastest at about pH 4-6 at lower pH, too much amine is protonated and the rate of the first step is slow above this pH the proton concentration is too low to allow protonation of the OH leaving group in the dehydration step, Imine formation is like a biological reaction it is fastest near neutrality. 

Let s return to the mechanism of imine formation, and compare it for a moment with that of acetal formation. The only difference to begin with is that there is no need for acid catalysis for the addition of the amine but there is need for acid catalysis in the addition of the alcohol, a much weaker nucleophile. 

An interesting comparison of the activity of primary and tertiary amino groups linked to MTS silicas in the reaction of benzaldehyde with ethyl cyanoacetate (Scheme 3.21, R = CN, R ElOCO, Ph, II) was reported. The results showed that catalysis induced by tertiary amine was relevant to classical base activation of the methylene group followed by nucleophilic attack to the carbonyl function, whereas primary amines could activate the carbonyl group by imine formation followed by Mannich-like nucleophilic attack by the activated ethyl cyanoacetate, as shown in Scheme 3.9. 

The catalytic efficiency was at least partially due to the depression of lysine pfC values caused by the presence of neighboring protonated lysines in the folded helix, and the resulting increased propensity for imine formation. Although the peptide was partially disordered there appeared to be a correlation between helical content and catalysis and specific acid catalysis was an important feature of the reaction mechanism. Follow up publications by Allemarm in ordered polypeptide scaffolds showed enhanced activity [25]. 

The same scaffold was used to design catalysts for pyridoxal phosphate-dependent deamination of aspartic acid to form oxaloacetate, one half of the transamination reaction [8], and oxaloacetate decarboxylation [14]. Catalysis was due to binding of pyridoxal phosphate in close proximity to His residues capable of rate limiting 1,3 proton transfer. A two-residue catalytic site containing one Arg and one Lys residue was found to be the most efficient decarboxylation agent, more efficient per residue than the Benner catalyst, most likely due to a combination of efficient imine formation, pK depression and transition state stabilization. 

Replacement of an hydroxyl group in resorcinol, most probably through tautomerism and imine formation, has been effected by heating it in an autoclave with 1-aminobutane and a small amount of phosphoric acid at 200°C under pressure (13 bar) for 8 hours. Only the monobutylamino substitution product was obtained but by phase transfer catalysis on the reaction product, with a benzyttrimethylammonium salt, (formed in situ from a surfactant and potassium iodide), sodium hydroxide solution and 1-bromobutane for 20 hours at 60-80°C, 3-dibutylaminphenol was produced in 64% yield (ref. 106). 

A double imine formation. Such a process may be carried out without catalysis, but mild acid is usually helpful. The mechanism for the first condensation is shown in detail, the second in abbreviated form. 

Formation of pyrazines and quinoxalines has been a focal point of many years of study. The most common method to make these rings relies on the condensation of 1,2-diamines with 1,2-dicarbonyls in ethanol or acetic acid in 35-85% yields. The mechanism proceeds through a double imine formation. Recently improved methods have been reported, employing transition-metal catalysis and microwaves. ... 

B. Imine formation with weakly nucleophilic amines. These amines require acid catalysis in both the nucleophilic addition and the dehydration. 

---