Pyrrolidines basicities

The N-basicity of the commonly used amines (pyrrolidine > piperidine > morpholine) drops by 2-3 orders of magnitude as a consequence of electron pair delocalization in the corresponding enamines. This effect is most pronounced in morpholino enamines (see table below). Furthermore there is a tendency of the five-membered ring to form an energetically favorable exocyclic double bond. This causes a much higher reactivity of pyrroUdino enamines as compared to the piperidino analogues towards electrophiles (G.A. Cook, 1969). 

Photoelectron spectroscopic studies show that the first ionization potential (lone pair electrons) for cyclic amines falls in the order aziridine (9.85 eV) > azetidine (9.04) > pyrrolidine (8.77) >piperidine (8.64), reflecting a decrease in lone pair 5-character in the series. This correlates well with the relative vapour phase basicities determined by ion cyclotron resonance, but not with basicity in aqueous solution, where azetidine (p/iTa 11.29) appears more basic than pyrrolidine (11.27) or piperidine (11.22). Clearly, solvation effects influence basicity (74JA288). 

In aqueous solution, azetidine (p/sTa 11.29) is slightly more basic than pyrrolidine and larger-ring cyclic amines and appreciably more basic than aziridine. It forms an addition compound (m.p. - 9 to -6 °C) with trimethylboron which is more stable than that formed by pyrrolidine (50JA2926, 64HC(l9-2)885). Azetidinium salts are well known (Section 5.09.2.2.7). 

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). 

It is noteworthy that the kinetics indirectly provided the evaluation of the basicities of these enamines [Eq. (4)]. The pK values for 4-(2-methyl-propenyl)morpholinc, l-(2-methylpropenyl)piperidine, and l-(2-methyl-propenyl)pyrrolidine are 5.47, 8.35, and 8.84, respectively (27). Since the protonation of the j8-carbon atom does not possess the character of a real equilibrium at pH 7 and up [for compound 1 even at pH 1 and up] the basicity must be fully ascribed to the equilibrium between enamine and the corresponding nitrogen-protonated conjugate acid. 

The basicity of the enamine has an overriding influence on the yield of product. Good yields are obtained from the pyrrolidine enamines, poor yields from the piperidine enamines, and the morpholine enamines fail to... 

At higher temperatures the mixture of 10 and methyl vinyl ketone yields the 1,4-carbocyclic compound as described previously. Methyl isopropenyl ketone (5), ethyl acetylacrylate (d), 2-cyclohexenone (21), and 1-acetyl-1-cyclohexene (22) also undergo this type of cyclization reaction with enamines at higher temperatures. This cycloalkylation reaction occurs with enamines made of strongly basic amines such as pyrrolidine, but the less reactive morpholine enamine combines with methyl vinyl ketone to give only a simple alkylated product (7). Chlorovinyl ketones yield pyrans when allowed to react with the enamines of either alicyclic ketones or aldehydes (23). 

The phthalimido group is susceptible to basic reagents and thus must occasionally be protected. This is accomplished by treatment with pyrrolidine to open the ring (>90%), which can be closed by treatment with HE, B(0H)3, the, H2O, 73-99% yield. ... 

This reaction is restricted to ethylene and to secondary amines of high basicity (nude-ophUicity) and low steric bulk (Me2NH, pyrrolidine, piperidine). No high molecular weight products are formed. However, the same catalysts [107,108] as well as PdQj [108] also exhibit some activity for the hydroamination of ethylene with PhNH2 (Eq. 4.9). 

To probe interactions between active silanol sites and the isothiazolin-based biocides a number of model probes were investigated 12. The adsorbates (1-methylpyrro lidin-2-one, pyridine, pyrrolidine, pyrrole, 2-methylthiophene, 2-octyl-4-isothiazolin-3-one, 4,5-dichloro-2-octyl-4-isothiazolin-3-one and 2-cyclopenen-l -one,) varied in basicity, polarity and 7i-character. The amounts of the adsorbates retained by... 

Solubility - The oxidized polymer (VIII) has a greater solubility than the original polymer (VII). It was found to be soluble in acetone, chloroform, benzene, DMF and DMSO. Unlike the polymer (VII), (VIII) was not soluble in formic acid or trifluoroacetic acid that was expected since the pyrrole moiety is less basic than pyrrolidine. In the oxidized polymer, the pair of unshared electrons on the nitrogen atom are contributing to the pyrrole ring aromaticity, therefore, unavailable for protonation as in the case of polymer (VII). A comparison of the solubilities is given in Table I. 

The basicity of dimethoxycarbene (197) in solution is similar to that of pyrrolidine (pATa = 12.3). The gas phase proton affinity of pyrrolidine, 227... 

A comparable reaction was seen decades ago in the metabolism of methadone [173 - 175]. This well-known synthetic opiate undergoes A-demeth-ylation as a major metabolic reaction in humans and laboratory animals. The resulting secondary amine (11.168, Fig. 11.21) has never been isolated, as it undergoes practically instantaneous cyclization. The reaction is believed to proceed via the carbinolamine with formation of metabolite 11.169 as the major urinary metabolite in humans. This structurally intriguing basic compound is, in its neutral form, a pyrrolidine with an exocyclic C=C bond,... 

---