Quinuclidine basicity

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. 

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... 

However, in more complicated amines, this straight correlation is violated. The bicyclic tertiary amine l-azabicyclo[4.4.4]tetradecane (22) and the acyclic tertiary amine n-Bu3N have nearly the same first IP (7.84 and 7.90 eV, respectively), but the proton affinity of the bicyclic amine is 20 kcal mol 1 lower than that of the acyclic52. On the other hand, for other bridge-head tertiary amines like l-azabicyclo[2.2.2]octane (quinuclidine, 20) and l-azabicyclo[3.3.3]undecane (manxine, 21) the expected relation between proton affinities and IP values is observed. The extraordinary properties of l-azabicyclo[4.4.4]tetradecane (22) are caused by its unusual conformation the nitrogen lone-pair is directed inward into the bicycle where protonation is not possible. In the protonated form, the strained out-conformation is adopted. This makes it the least basic known tertiary amine with purely saturated alkyl substituents. Its pKa, measured in ethanol/water, is only +0.693. Strain effects on amine basicities have been reviewed by Alder88. 

Heilbronner and coworkers94 have studied several 2-, 3- and 4-substituted quinuclidines (23-25) by PES and ICR spectroscopy. A linear correlation of the gas-phase basicities and the ionization energies—relative to the unsubstituted parent molecule—was established. Comparison of the solution pKa values with gas-phase basicities revealed that 2-substituted quinuclidines (23) exhibit sizeable solvent-induced proximity effects, i.e. that the corresponding quinuclidinium ions are more acidic in solution than expected on the basis of proton affinities. 

This has become something of a standard reaction, since several authors have successfully used different chiral catalysts to effect the conversion in very high chemical and enantiomeric yield. Bergson and Langstrom (41) were the first to show that acrolein and a-isopropylacrolein added to 2-carbomethoxy-l-indanone (A in eq. [6]) in benzene in the presence of the strongly basic tertiary amine (/ )-( + )-2-(hydroxymethyl)quinuclidine to yield optically active ketoesters. Unfortunately, the quinuclidine catalyst was not enantiomerically pure, and neither the chemical nor the optical yields of the aldehydo ester analogous to B (eq. [6]) were reported. 

The focus of this review is to discuss the role of Cinchona alkaloids as Brpnsted bases in organocatalytic asymmetric reactions. Cinchona alkaloids are Lewis basic when the quinuclidine nitrogen initiates a nucleophilic attack to the substrate in asymmetric reactions such as the Baylis-Hillman (Fig. 3), P-lactone synthesis, asymmetric a-halogenation, alkylations, carbocyanation of ketones, and Diels-Alder reactions 30-39] (Fig. 4). 

Preliminary mechanistic studies show no polymerization of the unsaturated aldehydes under Cinchona alkaloid catalysis, thereby indicating that the chiral tertiary amine catalyst does not act as a nucleophilic promoter, similar to Baylis-Hilhnan type reactions (Scheme 1). Rather, the quinuclidine nitrogen acts in a Brpnsted basic deprotonation-activation of various cychc and acyclic 1,3-dicarbonyl donors. The conjugate addition of the 1,3-dicarbonyl donors to a,(3-unsaturated aldehydes generated substrates with aU-carbon quaternary centers in excellent yields and stereoselectivities (Scheme 2) Utility of these aU-carbon quaternary adducts was demonstrated in the seven-step synthesis of (H-)-tanikolide 14, an antifungal metabolite. 

Baylis-Hillman reactions, the protonated amine was the governing factor in determining catalyst efficiency, thus making quinuclidine itself a better catalyst than 3-heteroatom substituted analogs, which are of reduced basicity/nucleophilic-ity and consequently give lower reaction rates. 

Scheme 6.147 visualizes two proposals for the mechanism of the 131-catalyzed Henry addition of nitromethane to benzaldehyde. In (A), benzaldehyde is achvated by the thiourea moiety through double hydrogen bonding to the carbonyl funchon, while the nitromethane is deprotonated and activated by the basic quinuclidine nitrogen [298] proposal (B), however, based on detailed DFT computations... 

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. 

So, a catalyhc synthesis of solefinacin (2) was developed at Dr. Reddy s Laboratories [28]. Mechanishc analysis reveals that the use of stoichiometric NaH is not required, as ethoxide anions are liberated. This anion is basic enough to deprotonate the (R)-quinuclidin-3-ol (31) and is capable of driving the reachon to completion, as shown in Scheme 14.8. The entire process is thus catalytic with respect to NaH ... 

Cinchona alkaloids, naturally ubiquitous /3-hydroxy tertiary-amines, are characterized by a basic quinuclidine nitrogen surrounded by a highly asymmetric environment (12). Wynberg discovered that such alkaloids effect highly enantioselective hetero-[2 -I- 2] addition of ketene and chloral to produce /3-lactones, as shown in Scheme 4 (13). The reaction occurs catalytically in quantitative yield in toluene at — 50°C. Quinidine and quinine afford the antipodal products by leading, after hydrolysis, to (S)- and (/ )-malic acid, respectively. The presence of a /3-hydroxyl group in the catalyst amines is not crucial. The reaction appears to occur... 

At the moment we have no good explanation for the observed acceleration except that it has a connection to the basic character of the quinuclidine part and the adsorption behavior of the cinchona molecule. In addition, we think that the rate and product determining steps occur on the platinum surface and that well defined interactions between the platinum surface (ensembles), one cinchona molecule and the a-ketoester are crucial. There are, of course, other possible explanations for the observed enantioselection. Wells and Thomas [80] have proposed that an array of... 

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). 

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). 

Early work from the McIntosh group [1 lh,85] and extensive research from the Dehmlow group [24e-i,48b] concerning chiral catalyst design is noted. Recently, Lygo and co-workers have reported short enantio- and diastereoselective syntheses of the four stereoisomers of 2-(phenylhydroxymethyl)quinuclidine. The authors report that these compounds, which contain the basic core structure of the cinchona alkaloids, will be examined as possible chiral control elements in a variety of asymmetric transformations [86]. 

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 pJCaH of the amines none Triethylamine and quinuclidine are equally basic and, as you can see in the margin, so (more or less) are diethylamine, dibutylamine, and piperidine. A proton is so small that it cares very little whether the alkyl groups are tied back or not. 

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