Equilibria imine formation

The most important reaction of this type is the formation of imine bonds and Schiff bases. For example, salicylaldehyde and a variety of primary amines undergo reaction to yield the related imines, which can be used as ligands in the formation of metal complexes. However, it is often more desirable to prepare such metal complexes directly by reaction of the amine and the aldehyde in the presence of the metal ion, rather than preform the imine.113 As shown in Scheme 31, imine formation is a reversible process and isolation of the metal complex results from its stability, which in turn controls the equilibrium. It is possible, and quite likely, that prior coordination of the salicylaldehyde to the metal ion results in activation of the carbonyl carbon to amine nucleophilic attack. But it would be impossible for a precoordinated amine to act as a nucleophile and consequently no kinetic template effect could be involved. Numerous macrocyclic chelate systems have been prepared by means of imine bond formation (see Section 61.1.2.1). In mechanistic terms, the whole multistep process could occur without any geometrical influence on the part of the metal ion, which could merely act to stabilize the macrocycle in complex formation. On the other hand,... 

One published synthesis of this amine 17 is by reductive animation.2 Note that it is not necessary, nor usually desirable, to isolate the rather unstable imine as reduction with NaB(CN)H3 or NaB(OAc)3H occurs under the conditions of imine formation.3 Since the imine is in equilibrium with the starting materials, slightly acidic conditions must be used so that the protonated imine is reduced more rapidly than the aldehyde or ketone. These two reducing agents are stable down to about pH 5. 

Because a CO double bond is considerably stronger than a CN double bond, the equilibrium in these reactions often favors the carbonyl compound rather than the imine. In such cases it is necessary to drive the equilibrium to the product. This is usually accomplished by removing the water as it is formed. Some additional examples of imine formation are provided in the following equations ... 

Ketones and aldehydes also condense with other ammonia derivatives, such as hydroxyl amine and substituted hydrazines, to give imine derivatives. The equilibrium constants for these reactions are usually more favorable than for reactions with simple amines. Hydroxylamine reacts with ketones and aldehydes to form oximes hydrazine and its derivatives react to form hydrazones and semicarbazide reacts to form semicarbazones. The mechanisms of these reactions are similar to the mechanism of imine formation. 

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... 

The mechanism of imine formation (Mechanism 21.5) can be divided into two distinct parts nucleophilic addition of the 1° amine, followed by elimination of HgO. Each step involves a reversible equilibrium, so that the reaction is driven to completion by removing HgO. 

The nitrogen atom is more nucleophilic than the oxygen atom so we should start with the amine attacking the carbonyl group. The first product will be an imine and addition of the alcohol to that gives the product. Imine formation is acid-catalysed but occurs quite rapidly at neutral pHs and the intramolecular second step is fast. The whole system is under equilibrium but the other product, water, is driven off as an azeotrope with benzene so the equilibrium is driven over to give the... 

The application of the same principle to the formation of o-alanine is possible but lacks applicability due to its slowness. In this case, in the presence of ammonia, pyruvate is in equilibrium with its imine. This is reduced at the cathode under formation of racemic alanine. The L-alanine of the racemic mixture is reoxidized by L-alanine dehydrogenase under anodic regeneration of the necessary cofactor NAD to give pyruvate and ammonia, while the o-alanine is not accepted by the enzyme and accumulates in the reaction mixture. The drawback of this reaction is the kinetic control by imine formation, which is very slow, so that a complete inversion of a lOmAf solution of L-alanine would require 140 h [105]. 

Pyridoxal phosphate forms a noncovalent complex (K = 2.5 X M) with the enzyme before imine formation (281), while no such evidence was observed for reaction with pyridoxal (84) or cyanate (282). The phosphate group must, therefore, be involved in rapid formation of the noncovalent complex, and it seems likely that the existence of this complex explains why the phosphate derivative is a more effective inhibitor than pyridoxal. Apparent equilibrium constants for maximal imine formation have been determined as 3.2 X 10" M for pyridoxal at pH 8.5 (84) and 4.4 X 10 M for PLP at pH 7.7 (281). 

Equilibrium Constants for Imines Formation with 2-Methylpropanal... 

In the first step of the mechanism for imine formation, the amine attacks the carbonyl carbon. Gain of a proton by the alkoxide ion and loss of a proton by the ammonium ion forms a neutral tetrahedral intermediate. The neutral tetrahedral intermediate, called a carbinolamine, is in equilibrium with two protonated forms. Protonation can take place on either the nitrogen or the oxygen atom. Elimination of water from the oxygen-protonated intermediate forms a protonated imine that loses a proton to yield the imine. 

The direct observation of this reaction is difficult because of the small equilibrium constant for imine formation. This type of reaction is therefore commonly studied by trapping the imine as it is formed with hydroxylamine, which reacts rapidly to form an oxime. Because the equilibrium constant for formation of the imine between methyl amine and acetone is so small, the equilibrium is established very rapidly. (The observed rate constant for a reaction proceeding to an equilibrium position is larger than the first-order rate constant for the forward reaction [7].) Thus the addition of methylamine and acetone to an aqueous solution results in the establishment of an equilibrium concentration of imine (and iminium ion) in several seconds. In several studies described below wherein reactions subsequent to imine formation occur, it is common to find a presumption of rapid imine equilibria prior to the slower o-proton abstraction or decarboxylation events that occur subsequently. 

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

The macrocyles formed depend on the overall proportions of 1 and 2, the diamine chain length and the type of cation used as the template. Of importance is the fact that the imine formation is a reversible reaction. Expressed in the DCC sense, one can say that all products, the macrocycies and the nonrepresented oligomers and polymers, are in constant equilibrium, and that all the species represented in Fig. 22 constitute a virtual combinatorial library (VCL). From this library, the high proportion of a specific macrocycle can be obtained by the use of the appropriate conditions (type of metal template, relative proportion of reactants). 

Scheme 8.2 Reversible formation of an imine surfactant in a system where surfactant aggregation shifts the equilibrium towards formation of the imine that aggregates most efficiently.

By using solubility differences to drive the equilibrium toward imine formation in the first reaction of the combined steps, approximately 310,000 pounds per year of the problematic reagent, titanium tetrachloride, have been ehminated. This process change eliminates 220,000 pounds of 50% sodium hydroxide, 330,000 pounds of 35% hydrochloric acid waste, and 970,000 pounds of solid titanium dioxide waste per year. 

Imine formation is reversible because there are two protonated tetrahedral intermediates that can eliminate a group. The equilibrium favors the nitrogen-protonated tetrahedral intermediate because nitrogen is more basic than oxygen. However, the equilibrium can be forced toward the oxygen-protonated tetrahedral intermediate and therefore toward the imine by removing water as it is formed. 

As with imine formation, water must be removed as it is formed in order to force the equilibrium toward the enamine. 

In an aqueous solution, the open-chain form of o-glucose is in equilibrium with the two cyclic hemiacetals. Because formation of the cyclic hemiacetals proceeds nearly to completion (unlike formation of acyclic hemiacetals), very little glucose is in the open-chain form (about 0.02%). Even so, the sugar still undergoes the reactions discussed in previous sections (oxidation, reduction, imine formation, etc.) because the reagents react with the small amount of open-chain aldehyde that is present. As the open-chain compound reacts, the equilibrium shifts to produce more open-chain aldehyde, which can then undergo reaction. Eventually, all the glucose molecules react by way of the open-chain form. 

The other C=N systems included in Scheme 8.2 are more stable to aqueous hydrolysis than are the imines. For many of these compounds, the equilibrium constants for formation are high, even in aqueous solution. The additional stability can be attributed to the participation of the atom adjacent to the nitrogen in delocalized bonding. This resonance interaction tends to increase electron density at the sp carbon and reduces its reactivity toward nucleophiles. 

Dihydro-2/7- 74 and -4//-l,2-oxazines and thiazines 75 are interrelated by prototropy, being enamines and imines, respectively. In the case of oxazines, the imine form 75 is favored, and there are several well established examples of this system, including the parent heterocycle 75 (X = O) [84MI2]. No tautomeric equilibrium between the 2H and 4H forms has been observed under normal conditions in solution or in the solid state. However, the formation of intermediate 2H isomers 77 was proposed both for the conversion of 3-phenyl-5,6-dihydro-4//-l,2-oxazine 76 (R = Ph, r = R = H) into 2-phenylpyrrole(89TL3471) under strong basic conditions and for thermal decomposition of cyclopentene-fused 1,2-oxazine 76... 

The shielding effect of the vicinal phenyl substituent accounts for the favored attack of the cyanide from the opposite direction, giving rise to the (S)-diastereomers. However, it should be noted that imines of aliphatic aldehydes which bear an odd number of carbons in the main side chain surprisingly give (/ )-diastereomcrs, concluded from ORD data48. This opposite stereochemical course in the formation of these compounds has not been explained48. It might simply be due to crystallization of the (R)-diastereomer which continuously shifts the equilibrium (vide supra). 

---