Thermodynamic imine formation

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... 

A dynamic combinatorial library of six components can be generated under thermodynamic control by imine formation and exchange combined with non-covalent bonding within the enzyme binding site and DCL was evaluated for their relative affinities toward the physiologically relevant human carbonic anhydrase hCA I and hCA II isozymes [66]. 

In the early 1960s, seminal work by Jencks and coworkers demonstrated that formation and hydrolysis of C=N bonds were proceeding via a carbinolamine intermediate, thus leading to a more general mechanism of addition reactions on carbonyl groups [17-19]. The dynamic nature of the reaction of imine formation can be exploited to drive the equilibrium either forward or backwards. Since the reaction involves the loss of a molecule of water, adding or removing water from the reaction mixture proved an efficient way to shift the equilibrium in either direction. The responsive behavior of imines to external stimuli makes the reversible reaction of imine formation perfectly suited for DCC experiments [20], Thermodynamically controlled reactions based on imine chemistry include (1) imine condensation/hydrolysis, (2) transiminations, and (3) imine-metathesis reactions... 

Figure 5-12 The thermodynamic cycle for DNA-directed imine formation and the measured equilibrium constants for each step (adapted from [107]).

As has been outlined for the Strecker synthesis, the Ugi reaction also proceeds via initial formation of a Schiff base from an aldehyde and an amine. The imine intermediate is attacked by the isocyanidc, a process which is supported by protonation of the imine by the carboxylic acid component. The resulting a-amino nitrilium intermediate is immediately trapped by the carboxylate to give an 6>-acyl imidiate. All steps up to this stage are reversible. Only the final oxygen to nitrogen acyl shift is irreversible and delivers the A-acyl-a-amino amide as the thermodynamically favored product which contains two amide groups. 

This contrary stereochemistry in the Bucherer - Bergs reaction of camphor has been attributed to steric hindrance of e.w-attack of the cyanide ion on the intermediate imine. Normally, equatorial approach of the cyanide ion is preferred, giving the axial (t>Mr/o)-amino nitrile by kinetic control. This isomer is trapped under Bucherer-Bergs conditions via urea and hydan-toin formation. In the Strecker reaction, thermodynamic control of the amino nitrile formation leads to an excess of the more stable compound with an equatorial (e.w)-amino and an axial (endo)-cyano (or carboxylic) function13-17. 

Alcohols will serve as hydrogen donors for the reduction of ketones and imi-nium salts, but not imines. Isopropanol is frequently used, and during the process is oxidized into acetone. The reaction is reversible and the products are in equilibrium with the starting materials. To enhance formation of the product, isopropanol is used in large excess and conveniently becomes the solvent. Initially, the reaction is controlled kinetically and the selectivity is high. As the concentration of the product and acetone increase, the rate of the reverse reaction also increases, and the ratio of enantiomers comes under thermodynamic control, with the result that the optical purity of the product falls. The rhodium and iridium CATHy catalysts are more active than the ruthenium arenes not only in the forward transfer hydrogenation but also in the reverse dehydrogenation. As a consequence, the optical purity of the product can fall faster with the... 

Figure 6. MNDO heat of formation hypersurface for singlet vinyl nitrene rearrangements to 2H-azirine, ketene imine and the thermodynamically most favorable isomer, acetonitrile.

Inverting the orientation of the C4-N3 imine unit of a 2,3,1-diheterabotine gives a boron heterocycle with a markedly different chemical reactivity. In effect, the weakly basic oxime- or hydrazone-type imine nitrogen in the 2,3,1-diheteraborine is replaced by a much more basic imidate- or amidine-type imine nitrogen in the 2,4,1-diheteraborine. Likely, the Lewis acid tendency of the boron is enhanced by the ready protonation of this basic N4, and the formation of a stable borate-based zwitterion becomes thermodynamically favored. 

In this section, reactions of zinc dienolates with carbonyl compounds, imines and conjugated enones will be considered all of these reactions have been proved to be reversible, and, hence, conditions favouring either kinetic or thermodynamic control will drive the reaction towards the formation of different regioisomers. Generally, equilibrating conditions lead to attack at the position of 190, as a thermodynamically more stable conjugated carbonyl or carboxylic compound is formed on the other hand, kinetic control leads to attack at the electron richer a-position. 

The synthesis of quadridentate imine chelates usually requires the combination of two equivalents of the carbonyl compound and a diamine, as in the formation of complexes of ligands (6),17 18 (7)19 and (8).20,21 In similar fashion, thermodynamic template reactions allow the very effective synthesis of quinquedentate and sexadentate metal complexes of ligands such as (9),22 (10),23 (ll),24 (12)25 and (13).26 Condensation of 1,1,1-tris(aminomethyl)ethane with pyridine-2-carbaldehyde alone yields... 

Thermodynamic template reactions allow the formation of hydrazones from hydrazines and carbonyl compounds, in the same manner as simple imines are formed. However, in many cases it is more convenient to form hydrazones in non-template reactions, as they are generally easier carbonyl derivatives to isolate than are simple imines. Hydrazone complexes often are capable of further manipulation and both aspects of synthesis and reactivity will be combined in this section. 

Reaction of 9-[chloro(dimethylamino)methylene]tetrahydropyrido[l, 2-a]pyrimidin-4-ones 608 and aldimines or ketimines 609 in chloroform and acetonitrile gave a diastereomeric mixture of tricyclic compounds 611 and 612 at room temperature (82BEP892120, 82TL2891). The formation of compound 610 and the formation of a 1 1 mixture of the tricyclic products 611 and 612 could be detected by H NMR spectroscopy (82TL2891). After refluxing the reaction mixtures, only the thermodynamic product 611 could be isolated in pure form. 9-[Chloro(dimethylamino)methylene] derivatives 608 (R = CN, COOEt) also reacted with cyclic imines to yield the corresponding tetra- and pentacyclic quaternary salts, similar to 611 and 612 (87H2615). 

D. Zhao, J. S. Moore, J. Org. Chem. 2002, 67, 3548-3554. Imine metathesis reactions in different solvents suggest that the formation of assemblies of stacked rings is the thermodynamic driving force for the exclusive cyclodimer formation D. Zhao, J. S. Moore, Macromolecules 2003, 36, 2712-20. 

MacLachlan and coworkers have formed large SPMs 91-93 using a simple, one-pot, template-free, [3 + 3] Schiff-base condensation procedure (Scheme 6.21). The yields of the macrocycles were 40-68%, and no evidence of acyclic oligomer or polymer formation was observed. This is presumably due to the reversibility of the imine condensation, which allows the most thermodynamically stable product to... 

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