Quinuclidines, quaternization

Grob and his co-workers117 and others118 have measured pK, values of 4-substituted quinuclidines (20) in water117 and 5% and 50% aq. EtOH and 50% aq. methyl Cellosolve,118 as well as quaternization... 

Protonation of the quinuclidine N by hydrochloric acid had only minor effect on the ee but quaternization led to a complete loss of enantioselection in all three reactions. This is a strong indication that the quinuclidine N of CD is involved in the crucial interaction between reactant and modifier. A H-bond (N-H-0 type interaction) has been proposed for the CD - ethyl pyruvate complex3, which interaction is not possible after methylation of the basic N atom of CD. 

The introduction of CN into the aniline molecule would be expected to reduce the nucleophilicity of NH2 and from the para position this should be more or less according to the Gp of CN. There is plenty of information regarding the analogous effect of /7-NO2, but examples involving CN are hard to find. It is easy, however, to find an example for the reduction of amine nucleophilicity by the +/effect of CN. Grob and Schlageter have presented extensive results for the quaternization of 4-X-substituted quinuclidines (c/ structure 7) with methyl iodide in methanol at 10.0 °C. According to Charton, the pj constant for this reaction is -1.12, and the log k values for X = H and CN are - 2.35 and... 

Quaternization of 2 proceeded to completion with no deviation from second order kinetics. (Figure 2) No neighboring group effect was observed. The kinetic data for the reaction of 2 with triethylamine and quinuclidine are summarized in Table II. Note that the reaction of quinuclidine is two orders of magnitude faster than that of triethylamine even after the rate has been moderated by mixing dioxane with the DMSO. 

Most observations of rate retardation in polymer modifications have been attributed to steric hindrance. In order to estimate the steric influence of the relatively bulky triethyIbenzylammonium substituent on unreacted site during quaternization, quinuclidine was chosen as nucleophile. It is well known that nucleophilicity of quinuclidine in displacement reactions is greater than that of triethylamine, since bicyclic amines are less sterically hindered. Preliminary experiments on the quaternization of chloromethylated polysulfone with quinuclidine in DMSO showed that the reaction velocity was too rapid to investigate using our experimental techniques, i.e., 85% conversion was obtained with three minutes. Therefore, we were forced to add a less polar solvent to DMSO in order to reduce the reaction rate. It was found that a 50 50 (v/v) mixture of dioxane and DMSO dissolved both chloromethylated and quaternized polysulfone so the rate could be measured in a homogeneous system. The introduction of a nonpolar solvent reduced the initial rate of triethylamine substitution fourfold (Table III, run 17). 

The initial velocity of quinuclidine substitution is significantly faster than that of triethylamine at the same temperature (Table III, runs 21-23), even though the former was investigated in a mixed solvent. Similar results were found in the quaternization of the model compound. If a steric effect were considered to be the sole factor producing the decrease in k with respect to kQ, one would expect that (1) hQ/k2 for quinuclidine substitution should be smaller than hQ/k2 for TEA substitution and/or (2) the initial linearity in the second order plot would extend beyond 52% conversion where deviation occurs in the triethylamine system. Experimental results refute these expectations rate retardation is enhanced in quinuclidine reactions, furtherfore, the break point is almost the same for both cases. 

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