Immonium ion

An important extension of these reactions is the Mannich reaction, in which aminomethyl-ation is achieved by the combination of formaldehyde, a secondary amine and acetic acid (Scheme 24). The intermediate immonium ion generated from formaldehyde, dimethyl-amine and acetic acid is not sufficiently reactive to aminomethylate furan, but it will form substitution products with alkylfurans. The Mannich reaction appears to be still more limited in its application to thiophene chemistry, although 2-aminomethylthiophene has been prepared by reaction of thiophene with formaldehyde and ammonium chloride. The use of A,iV-dimethyf (methylene) ammonium chloride (Me2N=CH2 CF) has been recommended for the iV,iV-dimethylaminomethylation of thiophenes (83S73). 

The interaction of acid chlorides (167 X = Cl) with imines in the presence of bases such as triethylamine may involve prior formation of a ketene followed by cycloaddition to the imine, but in many cases it is considered to involve interaction of the imine with the acid chloride to give an immonium ion (168). This is then cyclized by deprotonation under the influence of the base. Clearly, the distinction between these routes is a rather fine one and the mechanism involved in a particular case may well depend on the reactants and the timing of mixing. Particularly important acid chlorides are azidoacetyl chloride and phthalimidoacetyl chloride, which provide access to /3-lactams with a nitrogen substituent in the 3-position as found in the penicillins and cephalosporins. 

Important for the hydrolysis is the observation (10) that protonation of enamines with hydrogen chloride does not immediately lead to immonium salts, but in most, if not all, cases first to the formation of the corresponding enammonium ions, which afterward rearrange more or less rapidly to the more stable immonium ions [Eq. (1)] ... 

Step from general acid-catalyzed formation of immonium ions to general base-catalyzed hydration of these ions to the amino alcohol [Eq. (6)]. 

Second-Order Rate Constants for the Hydrolysis of Immonium Ions, Derived from l-(2-Methylpropenyl)Pyrrolidine at 24.8°C ... 

Direct attack of acetate ions on the a-carbon atom of the immonium ions in the acetate bulfer solutions is unlikely, but the catalyzing action involves the removal of a proton from a water molecule in its attack on the immonium ion. 

The concentrations of the different intermediates are determined by the equilibrium constants. The observation of immonium ions [Eq. (5)] in strongly acidic solutions by ultraviolet and NMR spectroscopy also Indicates that these equilibria really exist (23,26). The equilibria in aqueous solutions are of synthetic interest and explain the convenient method for the preparation of 2-deuterated ketones and aldehydes by hydrolysis of enamines in heavy water (27). 

Finally, it should be noted that at alkaline and neutral pH a concerted mechanism, involving /S-carbon protonation of the enamine and a simultaneous addition of a water molecule, leading to the amino alcohol, can be rejeeted, since the immonium ion appeared to be a real and deteetable intermediate. 

Notwithstanding the expected and also observed high reactivity of the intermediate immonium ions, the stabilization of the exocyclic double bond in the pyrrolidino derivative evidently prevents rapid nucleophilic attack of water and the hydration of this ion to the amino alcohol becomes a slow general base-catalyzed process in weakly acidic solutions [Eq. (6)]. 

Immonium ion based synthetic methodology a novel method for the N-methylation of dipeptides and amino acid derivatives via retro aza-Diels-Alder reactions [93]... 

Quinolizidine synthesis via intramolecular immonium ion based Diels-Alder reactions total synthesis of ( )-lupinine, ( )-epilupinine, ( )-criptopleurine and ( )-julandine [97]... 

The experimentally determined threshold energy E0 obtained for the immonium ion and corrected for the kinetic shift is 0 = 44 kcal/mol (see Table 10) and thus in very good agreement with the predicted activation energy. This agreement provides strong support for the proposed mechanism.1003... 

Two major product ions were observed from the CID of protonated glycylglycine (Gly-Gly)H+ at low kinetic energies 10 eV (CM). These were the immonium ion NH2CH a, and the protonated glycine (Gly)H+ which is the y, ion. The a, ion is... 

It is obvious that the Mannich reaction pathway and the immonium ion mechanism may occur simultaneously, especially at conditions of room temperature or greater. Formaldehyde-facilitated crosslinking reactions between molecules that both contain nucleophiles probably occur primarily by the immonium ion pathway, since the Mannich reaction proceeds at a slower rate. In addition, the Mannich reaction will cause nondescript polymerization between molecules that possess both active hydrogens and amine groups. It is best to utilize the Mannich reaction only when one of the molecules contains no nucleophilic groups but at least one active hydrogen, and the other molecule contains a primary or secondary amine. 

As shown in Table 11 and Scheme 112, a C-H bond of terminal alkynes is activated by an Au(i) species producing gold acetylenide intermediates, which react with immonium ions generated in situ from aldehydes and secondary amines to provide propargylamines in high yields. This reaction proceeds in water with 1 mol.% of Au(i) or Au(m)... 

Figure 6.7. A general chemical structure of immonium ions.

TABLE 6.1. List of the Most Important Immonium Ions... 

Ions present on the fragment ion spectrum can either be sequence specific (they can provide information about the sequence) or non-seqence-specific (they cannot provide direct information on the sequence). For example, all ions belonging to six basic ion series (a, b, c, x, y, z) are sequence specific, whereas immonium ions are not (but they still are valuable diagnostic ions). 

Reactions of immonium ions derived from ionized alkylamines. . . 226... 

The reduction in the selectivity of forming C2HgN+ as the alkyl chain length is increased reflects the enhanced rate of hydrogen exchange processes which allow a deuterium atom to be transferred to a position in which it is incorporated in the immonium ion. 

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