Tertiary enamines protonation

Recently Stamhuis et al. (33) have determined the base strengths of morpholine, piperidine, and pyrrolidine enamines of isobutyraldehyde in aqueous solutions by kinetic, potentiometric, and spectroscopic methods at 25° and found that these enamines are 200-1000 times weaker bases than the secondary amines from which they are formed and 30-200 times less basic than the corresponding saturated tertiary enamines. The baseweakening effect has been attributed to the electron-withdrawing inductive effect of the double bond and the overlap of the electron pair on the nitrogen atom with the tt electrons of the double bond. It was pointed out that the kinetic protonation in the hydrolysis of these enamines occurs at the nitrogen atom, whereas the protonation under thermodynamic control takes place at the -carbon atom, which is, however, dependent upon the pH of the solution (84,85). The measurement of base strengths of enamines in chloroform solution show that they are 10-30 times weaker bases than the secondary amines from which they are derived (4,86). 

These results have led to the conclusion (11) that the formation of enammonium salts is kinetically controlled, while the protonation on the 3-carbon atom is subject to thermodynamic control, t Only tertiary enamines will be considered,... 

In the formation of salts, addition of a proton occurs at the free electron pair of one of the mesomerie forms of the enamine. The salts are usually derived from the immonium structure. With tertiary enamines, there is a substantial difference between the free bases which possess a fixed vinylamine structure and their immonium salts. 

Cyclic secondary amines lead to N-cyclized tertiary enamines which are of great synthetic use. The rates of hydrolysis and the pKa values for the dissociation of N-protonated enamines decrease in the case of N-cyclic 1-TV-isobutenes in the sequence from pyrrolidino (22b) to piperidino (22c) to the morpholino (22d) derivative73, i.e. the pyrrolidino enamines hydrolyse fastest. However, enamines of 3,3-dimethylazetidine74 analogous to 22e and acyclic tertiary enamines react even faster8. 

Data of the XH-NMR spectra of representative simple cyclic enamines are collected in Table 13. When C(2) bears no substituents, the chemical shift of the vinylic proton H(2) show approximately the trends observed for < C(2). In fact, for tertiary enamines derived from cyclopentanone and cyclohexanone, a good linear correlation is obtained between <5H(2) and <5C(2) (Figure 1) ... 

Table 4 collects rate constants for j3-carbon protonation of some tertiary enamines studied by Stamhuis and coworkers and by Sollenberger and Martin. These enamines comprise two sets, in each of which the amino group is varied, but the other substituents on the vinyl group remain the same. For the propiophenone-based enamines the data in Tables 2 and 4, though limited, indicate that the C-basicity order is the same whether measured by pA or the rate of protonation, namely morpholine < piperidine dimethylamine < pyrrolidine. We expect the same order to hold for other enamine sets provided they are based on a given carbonyl precursor. The C-basicity order is roughly the same as the iV-basicity order of the corresponding saturated amines, except that the dimethylamine and pyrrolidine enamines are more reactive toward C-protonation than predicted from the basicities of the parent amines. 

It remains to discuss the structure-reactivity results obtained by Capon and Wu this will be done in the context of equation 15 rate-controlling C-protonation by H30. One noteworthy result (see Table 10) is that, for the cyclohexenyl series 28, the change from a secondary to a tertiary enamine has very little effect on ky. By contrast, for series 27, the A -methylenamines are hydrolyzed at rates ranging from 20-800 times slower than the secondary analogues, while for series 29 the A-methylenamines are slower than their secondary counterparts by a factor of 15,000 to more than 400,000. For 27, L = CH3 and 29, L = CH3 it is apparently difficult to achieve the desired coplanarity of the amino and alkenyl moieties in the transition state (cf equation 4) which permits the conjugative donor properties of the amino group to be fully exploited. In agreement with this interpretation is the fact that for series 28, where the rates of hydrolysis of secondary and tertiary members are very similar, the p values for hydrolysis are also very similar = —3.45 and —3.26, respectively. For series 27 and more so... 

Enamines. The condensation of a secondary amine and a ketone to make an enamine is a well known reaction which has seen wide use in organic synthesis [176-178]. Imines of a primary amine and a ketone exist in a tautomeric equilibrium between the imine and secondary enamine forms, although in the absence of additional stabilization factors cf. Scheme 5.33), the imine is usually the only detectable tautomer. Nevertheless, the enamine tautomer is very reactive toward electrophiles and Michael additions occur readily [179]. The mechanism of the Michael additions of tertiary and secondary enamines are shown in Scheme 5.34. For tertiary enamines, the Michael addition is accompanied by proton transfer from the a -position to either the a-carbon or a heteroatom in the acceptor, affording the regioisomeric enamine as the initial adduct [180]. The proton transfer and the carbon-carbon bond forming operations may not be strictly concerted, but they are nearly so, since conducting the addition in deuterated methanol led to no deuterium incorporation [180]. 

Scheme 5.34. (a) Suprafacial Michael addition-proton transfer of a tertiary enamine [180], (b) aza-ene-like transition structure for secondary enamine Michael additions [179]. 

The preceding section described the preparation of enamines by mercuric acetate oxidation of tertiary amines. The initial product in these oxidations is the ternary iminium salt, which is converted to the enamine or mixture of enamines by reaetion with base. Thus iminium salts synthesized by methods other than the oxidation of tertiary amines or the protonation of enamines are potential enamine sources. 

The most general method for synthesis of cyclic enamines is the oxidation of tertiary amines with mercuric acetate, which has been investigated primarily by Leonard 111-116) and applied in numerous examples of structural investigation and in syntheses of alkaloids 102,117-121). The requirement of a tram-coplanar arrangement of an a proton and mercury complexed on nitrogen, in the optimum transition state, confers valuable selectivity to the reaction. It may thus be used as a kinetic probe for stereochemistry as well as for the formation of specific enamine isomers. 

Alkylation at Cp retards protonation at that site as it does for enols44 and enolates (see also Table 6). The effect is a modest one when steric hindrance to conjugation in the transition state is not too great the secondary enamines of series 29 are hydrolyzed but 4 to 7 times slower than those in series 28. Huge differences, factors of ca 106, exist between some of the tertiary members of 28 and 29, however. As discussed above, these differences are dominated by the inability of 29 (L == CH3) to take full advantage of conjugative stabilization in the transition state. 

Tertiary amines form complexes with mercury(II) ion, which then give iminium ions by loss of a proton. Addition of perchloric acid permits isolation of the iminium ion as the perchlorate salt and generally the more-substituted ion is favored (equation 14). Intramolecular trapping by a hydroxyalkyl group is also possible to form aminals (equation 15). The lactam products result from over-oxidation, which is promoted by heat. Basification on the other hand usually lows the isolation of enamines although hydroxyenamines have been obtained by reaction of enamines with mercury(II) acetate (equation 16), while dihydroaromatic systems undergo aromatization (equation 17). °... 

The reaction between all classes of amines (except tertiary) and either ketones or aldehydes is usually straightforward and generally leads to imines in the case of primary amines and to enamines with secondary amines, which bear only one labile proton on nitrogen (equation 4). 

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