Carbinolamine stabilization

While the usual eonsequence of hydration of enamines is eleavage to a secondary amine and an aldehyde or ketone, numerous cases of stable carbinolamines are known (102), particularly in examples derived from cyclic enamines. The selective terminal hydration (505) of a cross-conjugated dienamine-vinylogous amide is an interesting example which gives an indication of the increased stabilization of the vinylogous amide as compared to simple enamines, which is also seen in the decreased nucleophilicity of the conjugated amino olefin-carbonyl system. 

Combination of the hydroxyl ion with the mesomeric cation involves the removal of a double bond. For the quaternary pyridinium compounds this causes the total loss of the aromaticity. For quaternary quinolinium and isoquinolinium compounds, the aromatic character of one of the two rings is lost, and for the quaternary acridinium compounds that of one out of three. Hence., the order of stabilities of these compounds (determined by Hantzsch ) is explained. - Comparison of quaternary 3,4-dihydroisoquinolinium compounds and their isoquinolinium analogs with respect to the equilibrium (5) (4) shows that a much higher hydroxyl ion concentration is necessary for the isoquinolinium ions to form the carbinolamine. This is because the transition from the quaternary 3,4-dihydroisoquinolinium ions into the undissociated carbinolamine involves significantly smaller loss of mesomeric energy than that for the quaternary isoquinolinium hydroxides. ... 

The binding of pyridoxal 5 -phosphate (vitamin Be) to enzymes has been modelled using homo- and co-polypeptides containing L-lysine as a source of reactive amino groups. This has now been extended to reaction of pyridoxal with polyallylamine, with the polymer acting as a control that cannot provide amido -CO- or -NH- functions to stabilize the Schiff base products, as occurs in enzymes and polypeptides. Rate constants for the formation and hydrolysis of the imines have been measured and interpreted in terms of formation of the carbinolamine (in its neutral or zwitterionic form). 

The carbinolamine formed from R2NH lacks an H on N, and its dehydration involves instead loss of the acidic o H to give the resonance-stabilized eneamine. 

MI10902>, where the carbinolamine is presumably stabilized through nitrogen conjugation with an aromatic system. The subject of N- dealkylation has been authoritatively reviewed recently by Lindeke and Cho (B-82MI10905). 

Step 4 The oxygen-protonated carbinolamine loses water to give a nitrogen-stabilized carbocation. 

Propanal reacts with ammonia in acetonitrile to give a hexahydrotriazine (17 R = Et) chloroethanal (17 R = CH2CI) reacts similarly, but in lower yield.24 The reactions proceed via carbinolamines, but increasing chloro substitution (17 R = CHCI2/CCI3) stabilizes the intermediate and disfavours trimerization. hi the case of propanal, forward and reverse rate and equilibrium data are reported, with dehydration of the carbinolamine rate determining. The course of the reactions with some primary amines is also reported. 

We chose the four above-mentioned reaction schemes specifically to indicate that, despite the wide use of these synthetic approaches and the relatively well-known chemistry of Schiff bases, they actually remain widely unstudied. For over a century, the mechanisms by which these reactions were suggested had no experimental justification. It is easy to note the similarities in formation of the intermediate cyclic N,0 hemiacetals (carbinolamines) (26a-d). These compounds are usually found to be relatively stable and isolable34 (see also Section V,B,l,a), in contrast to the unstable acyclic carbinolamines. The dehydration step also requires further investigation because the initial dehydration product may be stable, it may exist in tautomeric equilibrium, or it may be converted spontaneously to the more stable isomer ring, depending on the relative stabilities of the various isomers. If a detailed mechanism for these reactions is known, control of experimental conditions can be used to direct reaction products and improve yields. 

Generally, alkaloids are more stable in toluene, ethyl acetate, and alcoholic solutions. In the case of alkaloids containing carbinolamine functions, reactions with alcohols (chloroform contains 1-2% of ethanol as stabilizer ) will occur (e.g., O-methyl pseudostrychnine formed from pseudostrychnine (Bisset et al. 1965). Such carbinolamines, among others, are often found as oxidation products formed from N-oxides or as intermediates in biosynthetic pathways. 

Another approach to aldehydes by partial reduction of acid derivatives involves introduction of groups that stabilize the partially reduced intermediate against elimination of water. The aziridine ring has this effect because of the I-strain that is introduced if elimination occurs. The partially reduced carbinolamine intermediates are stable to further reduction, and aldehydes are formed on subsequent... 

The differences in hydrolysis of pyrrolidine and morpholine enamines have been rationalized by consideration of the stabilities of exo-double bonds in five- and six-membered rings. Thus (233) is more stable than (232) and is less easily converted into the carbinolamine, and reversion of the carbinolamine to give (233) is considered to be easier than the analogous process to give (232). The greater incorporation of deuterium in the pyrrolidine case was explained on the basis of its greater propensity to equilibrate with the parent enamine. 

Like the hemiacetal, the carbinolamine is not a final product in acid. Further steps in the two reactions are all similar. An OH is protonated, and then lost as water (note that OH is not the leaving group) to give a resonance-stabilized cation (Fig. 16.48). 

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