Carbinolamine intermediate, dehydration

Reaction with secondary amines (Sec tion 17 11) Isolated product IS an en amine Carbinolamine intermediate can not dehydrate to a stable imine... 

Reaction with primary amines (Section 17.10) Isolated product is an imine (Schiff s base). A carbinolamine intermediate is formed, which undergoes dehydration to an imine. 

Reaction of primary amines with aldehydes and ketones (Section 17.10) Imines are formed by nucleophilic addition of a primary amine to the carbonyl group of an aldehyde or a ketone. The key step is formation of a carbinolamine intermediate, which then dehydrates to the imine. 

Stop-flow conditions that carbinolamine intermediate 4 dehydrates to form syn and anti oximes. The syn isomer 5 cyclized within several minutes to 3, while conversion of the anti form required several hours. 

Secondary amines are compounds of the type R2NH. They add to aldehydes and ketones to form carbinolamines, but their carbinolamine intermediates can dehydrate to a stable product only in the direction that leads to a carbon-carbon double bond ... 

Fig. 4.9 Carbinolamine bond. An amine can react with an aldehyde (left) to form a carbinolamine intermediate (center) that normally dehydrates to form a Schiff base (right). However, the exocyclic amine of a nucleoside base can form only the carbinolamine bond and not a Schiff base.

A recent study has employed deuterium labeling to show that the mechanism for the oxidative N-demethylation of nicotine may involve two modes of breakdown for a proposed carbinolamine intermediate, dealkylation with formaldehyde formation and dehydration to an iminium ion.72 The formation of such an sp2-hybrid intermediate may help to explain why both a primary and substantial / -secondary deuterium isotope effect were observed for the N-deethylation of the antiarrhythmic agent, lidocaine.73 In contrast, only a primary isotope effect was observed on the rate of oxidative O-deethylation of deuterated analogs of the analgesic, phenacetin. 77 These results indicate differences in the mechanism of oxidative 0- and N-dealkylation. A final example of the use of secondary deuterium isotope effects in studying enzymes involved in drug metabolism revealed an SN-2-like transition state for the transfer of a methyl group catalyzed by catechol-O-methyl transferase.73... 

The hapten was designed to trap the requisite Lys residue in the active site and then form the essential enamine intermediate 65 by dehydration of the tetrahedral carbinolamine intermediate 66. The trapping of a nucleophile in antibodybinding sites for enhanced efficiency of antibody catalysis had previously been reported by Wirsching and co-workers [75] and has been dubbed reactive immunization . By utihzing this reactive immunization strategy, two antibodies. 

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. 

Kinetic studies79 80 ha ve clarified the mechanism of formation of phenyl-hydra zones of aromatic aldehydes. It was found that, during the formation of bcnzaldehyde phenylhydrazonc 79 attack of the nucleophile is the ratedetermining step under slightly acidic conditions, whereas dehydration of the carbinolamine intermediate is the rate-determining step under neutral and basic conditions. 

Conducting the hydrogenolytic opening of the isoxazole ring on the bisketal 173 resulted in higher yields than when carried out on the corresponding bis-ketone. In the latter case the carbinolamine intermediate 176 is subject to dehydration to synthetically useless dihydropyridine type by-products. 

The change in rate-determining step from carbinolamine dehydration to carbinol amine formation occurs as the pH decreases [5,8,9]. As shown in Fig. 1 for the hydrolysis of substituted benzylidene-l,l-dimethylethyl amines, the pH rate profiles vary dramatically at lower pH values. The high pH rates are due to attack of hydroxide ion on protonated imine, which is the reverse of the dehydration of carbinolamine. At lower pH values the term due to water addition to protonated imine becomes substantial for those imines with electron withdrawing substituents. At even lower pH values the rate drops because of the change in rate determining step to the decomposition of the carbinolamine intermediate, which is the reverse of carbinolamine formation. In those cases where the zwitterionic intermediate formed by amine addition to a carbonyl compound ( j in Scheme 1) is very unstable, the required proton-transfer steps (kh Scheme 1) may become rate-determining. This... 

Isolated product is an enamine. Carbinolamine intermediate cannot dehydrate to a stable imine. 

The condensation probably proceeds via an intermediate hydroxy-hydrazine (43) analogous to the carbinolamine intermediate encountered in the condensation of amines with c u-bonyl groups. Though hydroxyhydiazines have never been isolated, evidence for their existence can be found in the occsisional appearance of azoxy compounds as by-products. These are presumably formed when oxidation of the hydroxyhydrazine (by excess nitrosobenzene) occurs fast enough to compete witih dehydration . 

A DFT mechanistic study of the formation of Schiff bases from acetaldehyde in water has looked at two amines of biological importance glycine and phosphatidylethanolamine, with an amine-phospholipid monolayer model being incorporated in the latter. The rate-determining step was found to be dehydration of the carbinolamine intermediate in both cases. Relative free energies of the intermediates and transition states were lower (compared to butylamine as a reference amine), these effects being ascribed to the carboxylic group and phospholipid environment, respectively. 

Steroidal a,j8-unsaturated ketones such as /l -3-ketones undergo a facile reaction with pyrrolidine to give the corresponding, d - -dienamines (111) (40,53). The reaction is much slower with morpholine and piperidine, which is undoubtedly due to the generation of the double bond exocyclic to the six-membered hetero rings in the step involving the dehydration of the intermediate carbinolamine (112) to the corresponding iminium ion (113). 

If the formation and breakdown steps of a mechanism involving a tetrahedral intermediate respond differently to changes in pH or catalyst concentration, then one can find evidence from plots of rate versus pH or rate versus catalyst concentration for a change in rate determining step and thus for a multistep mechanism. An example would be the maximum seen in the pH rate profile for the formation of an imine from a weakly basic amine (such as hydroxylamine). On the alkaline side of the maximum, the rate determining step is the acid-catalyzed dehydration of the preformed carbinolamine on the acid side of the maximum, the rate determining step is the uncatalyzed addition of the amine to form the carbinolamine. The rate decreases on the acid side of the maximum because more and more of the amine is protonated and unable to react. 

Mechanism. The neutral amine nucleophile attacks the carbonyl carbon to form a dipolar tetrahedral intermediate. The intramolecular proton transfer from nitrogen and oxygen yields a neutral carbinolamine tetrahedral intermediate. The hydroxyl group is protonated, and the dehydration of the protonated carbinolamine produces an iminium ion and water. Loss of proton to water yields the imine and regenerates the acid catalyst. 

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