Non-Aromatic Heterocycles 153Four-membered rings
Oxetane and azetidine are considerably less reactive towards ring-opening (strain-relieving) nucleophilic processes than
their three-membered counterparts (oxetane reacts with hydroxide anion 10^3 times more slowly than does oxirane).
However, oxetane will react, for example, with organolithium reagents in the presence of boron trifl uoride, and azetidine
is opened, for example, on heating with concentrated hydrochloric acid.
The most important four-membered system is undoubtedly the -lactam ring, which is present in, and essential for the
biological activity of, the penicillin and cephalosporin antibiotics (see page 177). -Lactams are very susceptible to ring-
opening via nucleophilic attack at the carbonyl carbon – in stark contrast to fi ve-membered analogues (pyrrolidones) or
acyclic amides, which are resistant to nucleophilic attack at carbonyl carbon. In addition, -lactams are hydrolysed by a
specifi c enzyme, -lactamase, the production of which is a mechanism by which bacteria become resistant to such anti-
biotics. Substitution of the acetoxy group in a 4-acetoxyazetidinone by nucleophiles is an important synthetic method:
the reaction proceeds via addition to an intermediate imine, rather than by direct displacement.
-Lactones (propiolactones) are also readily attacked at the carbonyl carbon, for example they are particularly easily
hydrolysed compared with simple esters, or fi ve- or six-membered lactones. However, a second mode of nucleophilic
attack – SN2 displacement of carboxylate via attack at C-4 – occurs with many nucleophiles; the example of this given
below shows the use of a homochiral -lactone, available from serine.
Five- and six-membered rings
Pyrrolidine and piperidine are somewhat better nucleophiles than diethylamine, principally because the nitrogen
is less hindered – in the heterocycles the two alkyl ‘substituents’, that is, the ring carbons, are constrained back and
away from the nitrogen, and approach by an electrophile is thus rendered easier. The pKaH values of pyrrolidine
(11.27) and piperidine (11.29) are typical of amine bases (diethylamine, 10.98); morpholine (8.3) is a somewhat
weaker base.
Piperidines, like cyclohexanes, adopt a preferred chair conformation. Both an N-hydrogen and an N-alkyl substituent
take up an equatorial orientation, though in the former case the equatorial isomer is favoured by only a small margin.