N-Acyl lactam

Anionic polymerization of lactams was shown to proceed according to what is called the activated monomer mechanism. With bischloroformates of hydroxy-terminated poly(tetramethyleneglycol) and poly(styrene glycol) as precursors for a polymeric initiator containing N-acyl lactam ends, block copolymers with n-pyrrol-idone and e-caprolactam were obtained by bulk polymerizations in vacuum at 30 and 80 °C, respectively361. ... 

F. P. Bonina, L. Montenegro, G. Trapani, M. Franco, G. Liso, In vitro Evaluation of N-Acyl Lactam Esters of Indomethacin as Dermal Prodrugs , Int. J. Pharm. 1995, 124, 45-51. 

Sehring and Konz reported in 1956 that the reaction of lactim ethers with acid chlorides results in O-acyl lactims.105 In 1965, however, Stolle and Griehl108 stated that the earlier work was erroneous N-acyl lactams were formed (Scheme 17), and this certainly seems more likely. 

This undesirable side reaction is avoided in the polymerization of N-substituted lactams i.e., N-alkyl, N-aryl, or N-acyl lactams. Polymerization of N-substituted lactams proceeds differently, thus in the presence of hydrogen chloride the following sequence of reactions takes place [217]. 

The high speed of anionic polymerization is due to the fact that both reacting species are chemically activated and hence highly reactive the lactam anion represents an activated monomer with increased nucleo-philicity and the terminal N-acylated lactam unit represents an activated end group (growth centre) with increased acylating ability. 

Recently, however, Sebenda3) has proposed that in polymerization of the highly reactive N-acyl lactams initiated with salts bearing stable complex anions like AsF chain growth proceeds with polymeric acylium cations by attack at the N-atom and not at the O-atom as usually proposed ... 

Spectroscopic (NMR, IR) studies show, that protonation (or coordination with Lewis acids) occurs predominantly at the oxygen atom as depicted in Eq. (11-3)5,6). In the absence of other strong bases the positively charged C-atom in the protonated monomer is attacked by the N-atom of another lactam and primary amino- and N-acyl lactam end-groups are formed (11-3) ... 

Several reaction mechanisms were offered to explain the mechanism of anionic ring-opening polymerizations of lactams. One mechanism is based on nucleophilic attacks by the lactam anions at the cyclic carbonyl groups of N-acylated lactams. This leads to formations of intermediate symmetrical mesomeric anions that rearrange with openings of the rings [133, 134] ... 

Synthesis of enol triflate from N-acylated lactam has been reported. Comins synthesized (5)-pipecolic acid 33 (Scheme 19) from enol triflate 30 of piperidone derivative 29 by Pd-catalyzed carbonylation followed by aymmetric hydrogenation nsing a mthe-nium catalyst with (i )-BINAP. Preparation of the first enantiopure lactam-derived enol triflate from (5)-pyroglutamic acid was achieved, and the synthesis of a proline analog was obtained in good yield (86% de). ... 

Propagation proceeds essentially by acylation reactions between a nucleophile (donor) and the cyclic carbonyl group of the lactam or the N-acylated lactam (acceptor). Depending on the type of initiation (e.g., hydrolytic, cationic, and anionic), different donors and acceptors may be involved. Some examples are summarized in Table 6, where the main reacting donor-acceptor pairs are related to the various polymerization mechanisms. 

Indeed, in the above reaction, N-acylated lactams with amine hydrochloride terminal groups are generated. According to the most probable mechanism, the reaction involves several steps attachment of N atom to the positively charged C, proton transfer from one to the other N, and ring opening with proton transfer from -OH to -NHJ. 

Actually, this acylation reaction may involve the endo- as well as the exocyclic carbonyl of the terminal acyl lactam consequently, two propagation pathways are possible. Moreover, since the bimolecular aminolysis of N-acyl lactam may be schematized via formation of a tetrahedral intermediate, four pathways [21]-[22]-[23]-[24] are possible and amidine stmc-tures (21, 23) may be obtained as well (Scheme 9). 

The amine anion is highly reactive, unlike the lactam anion, as it is not stabilized by resonance, and rapidly imdergoes proton exchange with a lactam molecule, yielding an imide dimer (N-acyl lactam) and regenerating a lactam anion [47] ... 

The N-acyl lactam embodies the strongest electrophilic group in the system and the most susceptible site to be attacked by the nucleophilic lartam anion. Thus, the neutral N-acyl laaam acts as the growth centre at the chain end. Propagation proceeds, according to the free ion mechanism, by repeated nucleophilic attack of the lactam anion on the endocyclic carbonyl of the imide group, via formation of the tetrahedral bicyclic intermediate [49] ... 

On this basis, the N-acyl lactam (imide dimer) formed in [47] is highly reaaive toward the lactam anion and represents the initiating species necessary for the onset of the polymerization. In fact, while the amide linkage in the lactam monomer is not sufficiently reaaive (i.e., not enough elearon deficient), the... 

As shown in Scheme 14, three types of acid hydrogens exist, yielding to three reactive sites for C-acylation. In this respect, two are the most relevant carbonyl sites the exo- and the endocyclic carbonyl in N-acylated lactams (29 and 30), respectively, not considering the branched structure (31). As a result, six (in total) or, more probably, four possibilities arise, originating six (four) different p-ketoimide stmctures. 

In the case of reaction with the lactam anion, the N-acyl lactam growth centre is regenerated [69] ... 

An important consequence of these side reactions is the presence of water, irrespective of the fact that anionic polymerization starts in anhydrous conditions. Water is able to hydrolyze N-acyl lactams, p-ketoamides, p-ketoimides, and the imide branching points via fast base-catalyzed reactions. During these hydrolytic reactions, carboxylates, amine... 

When N-acyl lactam stractures are introduced in the system from the very bcgitming of the reaction or formed in situ from appropriate precursors, the anionic polymerization is defined activated the rate of the initiation step is much higher and the reaction temperature can be considerably lowered. 

Indeed, as already described, reartion (49] is much faster than reaction [46] by virtue of the higher reactivity of imide as compared to the amide group. When introducing N-acyl lactam acdvators, reaction ]46] is no longer necessary and an immediate chain initiation is obtained ... 

In general, in CL polymerization, an equivalent concentration of activator (A) (N-acyl lactam or N-carbamoyl lactam) and initiator (I), in terms of its functional groups, is the best compromise among polymerization rate, overall conversion, degree of polymerization, high polymer yield, and polyamide properties (see Section 4.14.10.3). 

Direct activators. Compounds beating the N-acyl lactam structure, that is, N-acyl-substituted lactams with electronegative substituents capable of inaeasing with the acylation ability of the endocyclic acyl group. Direct activators are essentially the iV-acyl lactams (of general structure 47) and N-carbamoyl lactams (48). 

Precursors. Substances forming the N-acyl lactam functionality in situ by the reaction with lactam or lactam anion, thus generating the growth centers (e.g., anhydrides, acyl halides,... 

The N-acyl lactams (47), e.g., N-acetyl-CL (AcCL), N-propionyl-CL (EtCOCL), and N-bis-isophthaloyl-CL (IPBCL), are the first type of activators that have been used and their role on chemistry and kinetics has been examined in depth, essentially in the anionic polymerization of Cfr in combination with sodium 8-caprolactamate or CLMgBr as initia-... 

Actually, it must be remarked that the isocyanate precursors reaction using N-carbamoyl derivatives differs from that with (monofunctional, bifunrtional, and also the trimer, PIT) can be N-acyl lactams in the first step (eqns [88] and [89]) ... 

In fact, the resulting polyamide chain has a propagating end with an N-acyl lactam moiety and the other end with the structure of a disuhstituted urea. On the contrary, using N-acyl lactams, the end groups are amides. 

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