Azetidines basicity

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). 

The basicity of 7-azabicyclo[2.2.1]heptane (31) (pX 10.8 for its conjugate acid in water at 25°) is little indication of the effect of ring strain, since azetidine and pyrrolidine have similar values. 

The gas phase proton affinities of azetidine and (3-lactams were measured by FTICR MS. Azetidine presents a gas phase basicity practically equal to that of /V-methylethanamine (92JA4728). 

Unsubstituted azetidine is synthesized on the kilogram scale by the condensation of 1-bromo-3-chloropropane with benzhydrylamine to give 1-benzhydrylazetidine followed by hydrogenolysis and basic workup (Scheme 18) (88SC205). 

The complicating termination reactions, arising because of the increased basicity of sulphide residues on the polymer backbone, compared with that of cyclic sulphide monomers, do not occur in the analogous polymerisations of azetidines such as l,3,3 -trimethyl-azetidine,... 

This has been nicely demonstrated and exploited by Woodward s syntheses of bicyclic systems of the penem type. They are typically formed in moderate to good yields upon refluxing the requisite substituted starting -lactams in toluene or xylene for extended periods. The key step is the introduction of the ylidic moiety into the 1-position of a 4-functionalized azetidin-2-one which itself can be obtained as a relay substance by degradation of natural penicillins or from easily available 4-acetoxyazetidin-2-one. The ester ylide function is built up by reaction first with alkyl hemiacetals of glyoxylates to give a hemiaminal and then successive replacement of the OH-group of the latter by Cl with thionyl chloride and finally of the chlorine atom by triphenylphosphane under basic conditions. 

First we describe the copolymerization of oxetanes, as an example for microstructure and structure/reactivity studies. Then we discuss the copolymerization of thietanes, azetidines and oxazolines. Finally, we show the relationship between structure of heterocyclics (basicity, ring strain) and their nucleophilic reactivity. 

Azetidines are thermally stable and less reactive than aziridines. They behave in their reactions almost like secondary alkylamines. The value of azetidine is 11.29 and so it is more basic than aziridine (pAT = 7.98) and even dimethylamine ( Ka = 10.73). Azetidines unsubstituted on the N-atom react with alkyl halides to give 1-alkylazetidines which can react further to give quaternary azetidinium salts. With acyl halides, they produce acylazetidines and with nitrous acid, they give 1-nitrosoazetidines. 

The p/fa of aziridine (7.98) shows it to be an appreciably weaker base than azetidine (11.29), the four-membered analogue, which is normal for acyclic amines and for five- and six-membered saturated amines. The low basicity is mirrored in the oxygen series, as measured by the ability of oxiranes to form hydrogen bonds. The explanation is probably associated with the strain in the three-membered compounds, meaning that the lone pair is in an orbital with less p-character than a normal sp nitrogen or oxygen orbital, and is therefore held more tightly. The rate... 

Highly electrophilic P-lactams such as 36 and 38 have been shown to react with stabilised phosphoranes to yield azetidin-2-methylenes 37 and 39 [30] respectively (Scheme 13). However this reaction did not occur with less reactive P-lactams e.g. monocyclic P-lactams or cephem derivatives. The olefins 37 and 39 can be used as protected P-lactams they are much more stable to basic and nucleophilic conditions, and they readily regenerate P-lactams by ozonolysis [30]. The de-esterification of 37 and 39 by conventional methods gave the acids (R = H) which are very weak antibacterial agents or P-lactamase inhibitors. 

Because the transition state structure is tight, the steric effect may become an important factor influencing nucleophilicity. The reduced steric demands around the nitrogen atoms of aziridines and azetidines are responsible, at least in part, for the greatly enhanced nucleophilicity toward ester carbonyl as compared with other amines having similar basicities (28). 

Four pharmacophores have been identified in CCR5 antagonists 6, namely, a tertiary basic amine, two tail hydrophobes one of which tolerates some polarity, and a (hetero)aryl head (Figure 3.5). In a series of these inhibitors, lipid permeability was very low and strategies to remove the amide function in tail hydrophobe 1 were progressed. Replacement of the secondary amide with a piperidine 7 or azetidine 8 moiety led to the discovery of compounds with increased intrinsic lipoidal membrane permeability and overall an improved in vivo pharmacokinetic profile [7]. 

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