Basicity of quinuclidine

This apparent characteristic enhancement in the basicity has been used quite frequently for the determination of the position of a double bond with respect to the nitrogen atom in unsaturated amines. The cases such as neostrychnine (134) and dehydroquinuclidine (139) in which the protonation at the 8-carbon atom cannot occur due to the lack of overlap between the electron pair on the nitrogen atom and the tt electrons of the double bond, since this would involve the formation of a double bond at the bridgehead— a violation of Bredt s rule—show a decrease in basicity. For instance the basicities of quinuclidine (140) and dehydroquinuclidine (139) have been shown by Grob et al. (82), to differ by 1.13 pK units in aqueous solution at 25. This decrease in basicity has been attributed to the electron-withdrawing inductive effect of the double bond. 

The basicity of quinuclidine, which depends on the electron density at the nitrogen atom, is close to that of aliphatic amines and N-alkylpiperidines. In condensed benzo- and dibenzoquinuclidine systems the basicity decreases due to the inductive effect of the benzene rings.26,29... 

The influence of the rigid structure on the basicity of quinuclidine derivatives30 is demonstrated by comparison of the pKa values of benzo- and dibenzoquinuclidines with the structurally allied diethyl-aniline and diphenylamine (see Table II). 

Much more important in determining pJCjH is how electron-rich the nitrogen is, and this is the cause of the glaring discrepancy between the basicity of quinuclidine and that of DABCO, or between the basicities of piperidine (p H 11-2) and morpholine (p-K"aH 9.8) or piperazine (pfCan 8.4). The extra heteroatom, through an inductive effect, withdraws electron density from the nitrogen atom, making it less nucleophilic and less basic. In this... 

Aliphatic amines cannot display any stabilization of the lone pair, hence the lone pair is free to exhibit its basic properties. Such would explain the relative basicities of quinuclidine and N,N,4-Trimethylaniline, but what of benzoquinuclidine Why is its relative basicity 10 times smaller than that of quinuclidine There can be no resonance stabilization of the lone pair of electrons on nitrogen (Bredt s rule). 

The basicity of quinuclidine, which depends on the electron density at the nitrogen atom, is relatively high (pKa 10.58) [16] and close to the basicity of the aliphatic amines (dimethylamine, pKa 10.77 diethylamine, pKa 10.93 tri-ethylamine, pKa 10.87) and the AT-alkylpiperidines (iV-methylpiperidine, pKa 10.08) [19]. In condensed benzo- and dibenzoquinuclidine systems (benzoquinuclidine, pKa 7.79 dibenzo-quinuclidine, pKa 4.46) the basicity [19] is lower because of the inductive effect of the phenyl groups [16, 20]. 

The influence of structural rigidity on the basicity of quinuclidine derivatives is shown [21] by comparison of the pKa of the benzo- (and dibenzo-) quinuclidines with those of the structurally similar diethylaniline (pKa 6.56) [19] and diphenylamine (pKa 0.79) [19]. 

One of the possible ways to stabilize the amine-halonium complexes is to increase the basicity of the amine, bearing in mind that an appropriate one must also not have easily removable P-hydrogens which will lead to oxidation of the amine and formation of an imine. Quinuclidine (pKa of quinuclidinium ion is 11.3 (55)) is 105-106-fold more basic than the pyridines and both the bromonium (10 (36)) and iodonium (11 (57)) BF4 salts have been made and characterized by X-ray crystallography. Interestingly, although the reaction must generally occur as outlined in Figure 7, neither of these ions shows any observable reaction... 

A comparison of calculated and measured proton affinities (basicities) of nitrogen bases relative to the proton affinity of ammonia as a standard is provided in Table 6-17. The calculations correspond to the usual theoretical models, and the experimental data derive from equilibrium measurements in the gas phase. The data span a large range the proton affinity of the strongest base examined, quinuclidine, is some 27 kcal/mol greater than that of the weakest base, ammonia. 

These structural peculiarities make some properties of quinuclidin-2-ones closer to those of aminoketones than of amides. The nitrogen of quinuclidin-2-one is easily protonated (common amides and lactams are O-protonated) and can be methylated. They are very basic (pK 5.33-5.6)44 compared with other amides (e.g., A-acetyl-piperidine, pK 0.4). 

The answer to this question only became apparent when it was observed that the reactions of substituted quinuclidines with 2,4-dinitrophenyl phosphate, p-nitrophenyl phosphate and phosphorylated pyridine show a decrease in rate with increasing basicity of the attacking quinuclidine (77). These second-order reactions clearly cannot have a negative amount of bond formation with the nucleophile in the transition state, so that this result forced us to think harder about what could cause zero or negative slopes in Br0nsted-type plots against the pK of the nucleophile. 

These results are consistent with the observation that increasing basicity leads to a more favorable solvation energy for transfer of pyridines from the gas phase to water. The available data are consistent with a value of d for desolvation of approximately —0.2 (10, 13-16). The observed P value of — 0.1 for the reactions of quinuclidines with 2,4-dinitrophenyl phosphate and phosphorylated pyridine would then reflect the difference between the value of Pd = —0.2 and a value of Pnuc = 0.1 for the bond-forming step (equation 2). 

The more negative values of Pnuc for quinuclidines, compared with those for pyridines and amines, are not a consequence of the greater basicity of the quinuclidines because different slopes are observed for the different compounds over the same range of basicity and no significant curvature of the Brpnsted plots occurs. Possibly, the smaller P values for the quinuclidines reflect a relatively early transition state because of steric hindrance for the reactions of tertiary amines. 

Saturated heterocycles containing five or more atoms have physical and chemical properties typical of acyclic compounds that contain the same heteroatom. For example, pyrrolidine, piperidine, and morpholine are typical secondary amines, and A-methylpyrrolidine and quinuclidine are typical tertiary amines. The conjugate acids of these amines have pK values expected for ammonium ions. We have seen that the basicity of amines allows them to be easily separated from other organic compounds (Chapter 1, Problems 70 and 71). 

In pyridine solutions, the statistically corrected relative catalytic coefficients of tertiary amines for 1-methylindene isomerization decreased in the order24 4. quinuclidine, 80 DABCO, 10 triethylamine, 1. The smaller catalytic effectiveness of DABCO than quinuclidine is attributable to its weaker basicity is —30eu for each of these bicyclic bases. On the other hand, triethylamine is about as basic as quinuclidine, but must lose considerable rotational freedom in the rate-limiting proton transfer. This is reflected in the more negative entropy of activation (—39eu) for the triethyl-amine-catalyzed reaction. In pyridine solution, there is a close correlation between pa s of the catalyzing base and A// for 1-methylindene isomerization. Asymmetric catalysis was demonstrated in the quinine-catalyzed isomerization of optically active 1-methylindene in pyridine at 25°C the dextrorotatory indene isomerized nearly twice as fast as its enantiometer247. 

Quinuclidine and DABCO are 40-60 times more reactive than triethylamine. This is again due to the way the ring structures keep the nitrogen s substituents away from interfering with the lone pair as it attacks the electrophile. You should contrast the effect that the cyclic structure has on the basicity of the amines none Triethylamine and quinuclidine are equally basic and, as you can see in the margin, so (more or less) are diethylamine, dibutyl-amine, and piperidine. A proton is so small that it cares very little whether the alkyl groups are tied back or not. 

A wide-ranging investigation of quinuclidine derivatives was started in 1953 by M. V. Rubtsov who in collaboration with M. I. Dorokhova devised a simple method for preparation of quinuclidine-2-carboxylic acid [62]. The synthesis is basically condensation of y-picoline with mezoxalic esters followed by reduction of the unsaturated diester (IX) to a piperidine compound (X) and cyclization of the bromoderivative thereof (XI) to 2,2-diethoxycarbonylquinuclidine (XII). Hydrolysis and partial decarboxylation of compound XII yield quinuclidine-2-carboxylic acid (XIII), a key substance in the synthesis of the various 2-sub-... 

Rotation about bonds which increases the dihedral angle between p-orbitals on adjacent atoms does decrease resonance interaction. For example, the increased basicity of the quinuclidin-2-one [25] may be attributed to decreased amide resonance. Similarly, the energy barrier to rotation about... 

Agganval and coworkers showed a direct correlation between the pA a of a series of quinuclidine catalysts and the reaction rate of the MBH. In the study, the reaction between 2-pyridinecarboxylaldehyde and methyl acrylate in the presence of 5 mol% of catalyst was performed with no solvent. They determined the reaction rate increased as the p a of the catalyst increased. For instance, in the presence of quinuclidine 10 (pATa = 11.3) a relative rate constant (krei) of 11.3 was reported however, when the less basic quinuclidone 22 (pA a = 6.3) was used the relative rate dropped significantly to 0.006 as shown in the table below. 

In addition to hydrogen halides, water is the most studied HBD in the gas phase. The structures of the complexes with water, dinitrogen, carbon monoxide, ozone, benzene, ethane, formaldehyde, formamide, 1,4-dioxane, ethylene oxide, tetrahydropyran, difluo-romethane, pyrazine, pyrimidine, pyridazine, benzonitrile, quinuclidine, ammonia, methy-lamine, trimethylamine and so on can be found in the Mogadoc database [29]. In the water-morpholine complex [30], water is hydrogen bonded to the nitrogen and not to the oxygen, as predicted by the higher HB basicity of amines than that of ethers. 

Steric effects are also important in determining nudeophilicity. The reaction between a base and a proton is sterically completely undemanding. However, an Sn2 reaction is sterically much more challenging—at the transition state (9.1), five groups must be accommodated around the central carbon atom. Thus, as well as softness and hardness, we need to consider size. Bulky species, such as PhjC" and tert-BuO , are good bases but very poor nucleophiles. Triethylamine and quinuclidine, 9.2, have similar basicity, but quinuclidine is the better nucleophile, because the alkyl groups are tied back and out of the way. 

---