Nucleophilic Catalysts and Organocatalyzed Zwitterionic Ring-opening Polymerization of Heterocyclic Monomers

OLIVIER COULEMBIER

1.1 Introduction

Organocatalysis refers to a form of catalysis whereby the rate of reaction is increased by an organic molecule preferably used in substoichiometric amounts. The use of organic molecules to perform chemical reactions is not a new concept and organocatalytic reactions look back on a respected history. Both cyanohydrin synthesis from quinine alkaloids and proline-catalyzed Robinson annulation belong to the most popular dated examples of organocatalytic reactions. Although organic molecules have been used at the beginning of the chemistry, their narrow scope of reactions has not really stirred scientific interest in the past. Nowadays, thanks to clever and sometimes serendipitous discoveries, the picture is changing and organocatalysis is becoming an indispensable part of organic chemistry, offering a wide diversity of reactions, catalysts and processes.

While most of the organo-based reactions concern the enantioselective preparation of small molecules, organocatalysis also offers number of prospects in the polymer community and proposes advantages over metal-based and bioorganic methods. In this chapter, special attention is devoted to organocatalyzed ring-opening polymerization (ROP) of cyclic monomers and more especially the zwitterionic ROP (ZROP) from nucleophilic catalysts.

1.2 Definition of ZROP

ZROP is a chain polymerization in which a growing macromolecule bears two ionic chain carriers of opposite signs at its two ends and which usually grows from one of them. The zwitterion propagating species — either obtained from a neutral nucleophilic initiator or a neutral electrophile — is initially poorly active since the electrostatic work needed for parting the opposite charged ions is the largest when they are close together. Stabilization of a zwitterionic species may involve the positive end of one zwitterion propagating chain acting as the counter-ion of the carbanion end of another zwitterion propagating chain. Termination of the reaction may be caused by the presence of a protic nucleophile or by a charge cancellation step of the highly polar dimer leading to linear and cyclic structures, respectively. While neutral electrophiles have already been used in ZROP, zwitterionic polymerizations typically employ neutral nucleophiles that react with heterocyclic monomer to in situ produce the zwitterionic initiator (Scheme 1.1).

To date, several types of organic molecules have been employed as neutral nucleophiles to initiate ZROPs of cyclic monomers. Similarities with simple acylation reactions are unquestionable and allows pyridine-based molecules, imidazoles, amidines, tertiary amines, phosphines and N-heterocyclic carbenes (NHCs) to be used as initiating agents. Considering Scheme 1.1 (bottom of the scheme) as the general way of polymerization, the latent electrophile present on the cyclic monomer (Z) is most of time a carbonyl function. Strained lactones, thiolactones, N-caboxyanhydrides, carbosilanes and cyclic carbonates are then good candidates to undergo nucleophilic ZROP (see Chapter 11).

1.2.1 Pyridine-based Initiation

More than 50 years ago, ß-lactones such as ß-propiolactone and ß-pivalolactone started to be polymerized by pyridine-based nucleophilic initiators. For several reasons, the course of such ZROP was very complex, involving chain growth and step growth kinetics as well as elimination reactions regarding the type of initiator and monomer used. When moderate bases such as pyridine, 4-methylpyridine and 4-(N,N-dimethylamino)pyridine (DMAP) were used for the ZROP of pivalolactone, linear chains having one pyridinium ion and a carboxylate ion as end groups were observed by 1H NMR and MALDI-ToF analyses. The absence of cyclic structures suggested that the ZROP proceeded exclusively from the CO2- anion (Scheme 1.2, top). In the case of ß-propiolactone and ß-butyrolactone (BL), complete elimination of the pyridinium ions and formation of acrylate and crotonate end groups, respectively, were observed (Scheme 1.2, bottom).

The catalytic potential of donor-substituted pyridines is well established since the report on DMAP by Litvinenko et al. in 1967 and by Steglich et al. two years later. A catalytic improvement was reported in 1978 for 4-(pyrrolidinyl)pyridine (PPY), and in 2003 with 9-azajulolidine. Annelated pyridine derivative is a powerful organocatalyst not only suitable for acylation reactions, but also for other transformations such as the aza-Morita Baylis Hillman reaction.

The commercially available DMAP catalyst is often the common choice for acylation reactions proceeding by a nucleophilic mechanism involving an acyl pyridinium ion intermediate (Scheme 1.3). The amplified reactivity of aminopyridine derivatives — up to four orders of magnitude higher than pristine pyridine in representative acyl transfer — may come from the greater equilibrium concentration of the acyl pyridinium intermediate and its increased electrophilicity because of looser ion pairing.

In 2001, Hedrick et al. demonstrated that Lewis basic amines such as DMAP and PPY were highly effective for the ROP of lactide (LA) monomers. Although other works on metal-free processes were published earlier, his report is considered today as the nucleating agent in the field of the organocatalytic approach to the living ROP of lactones. The motivations of such research came from the realization of the potentially dangerousness of the organometallic catalysts used so far in the preparation of polyesters produced for biomedical and electronic applications. The catalytic behavior of both DMAP and PPY in the ROP of LA was studied in dichloromethane at 35 1C using ethanol (EtOH) as initiator in the presence of 0.1 to 4 equivalents of amine as compared to EtOH. Under anhydrous conditions, no polymerizations were observed in the absence of initiating alcohol. Narrowed PLAs were produced for a degree of polymerization (DP) ranging from 30 to 120 in 20 to 96 h. By contrast to most organometallic-promoted polymerizations, the dispersity was kept extremely low well after complete conversion with no noticeable molecular weight modifications. The living character of the polymerization was deduced from the linear evolution of the molecular weight as a function of the conversion, the predictable molar masses and the low dispersities. This living character is the manifestation of the rapid initiation and the weakly nucleophilic propagating species (secondary alcohol) that is active only to the cyclic diester monomer, precluding undesirable transesterification reactions.

Polymerization was originally proposed to occur via a "monomer-activated" mechanism through nucleophilic activation of the LA (Scheme 1.4, route A). 1H NMR analyses confirmed that the obtained PLA chains are end-capped in a position by an ester function generated from the initiating alcohol and in ? by a hydroxyl group. This suggests that for such mechanism the alkoxide/acyl pyridinium zwitterion generated by the nucleophilic attack of the DMAP on the LA is subjected to a proton transfer from the initiating/propagating alcohol and an acylation from the resultant alkoxide. However, subsequent computational studies realized by Bourissou et al. predicted that a base-catalyzed pathway would be of lower energy (Scheme 1.4, route B). Those simulations were realized in gas phase, implying that in solution, and especially in the presence of alcohol initiators, the nucleophilic monomer activation could be predominant. In 2012, both Hedrick's and Bourissou's uncertain mechanistic concepts were conciliated. Kinetic studies demonstrated that DMAP, generally used in excess as regard to the initiating alcohol, plays a double dealing and is involved in both nucleophilic activation of the LA and the basic activation of the initiating/ propagating alcohol. It was demonstrated that ~2 DMAP molecules complete the coordination sphere of the initiating/propagating alcohol and that any excess of DMAP is involved in the nucleophilic activation of the monomer (Scheme 1.5). Interestingly, in the same study, the equimolar ratio of DMAP and N,N'-dicyclohexylcarbodiimide (DCC) was demonstrated to better control the ROP of L-LA. As compared to the DMAP alone, a DMAP/ DCC mixture was proved to be the only catalytic system totally responding to a livingness criterion.

Ironically, if DMAP represents a very effective catalyst for the metal-free ROP of LA, it is also one of the less active. To circumvent that problem, Péruch et al. applied in 2010 the concept of "dual catalysis" to enhance the polymerization activity. That notion, where a Lewis acid supports a nucleophile to gain an increased catalytic effect, broadly falls in the categories of cooperative (synergistic) or cascade catalysis, depending on the proposed polymerization mechanism and is related to the chemistry of frustrated Lewis pairs. In their study, Péruch et al. developed an organo-catalytic system containing both basic and acidic sites activating cooperatively the alcohol chain end and the LA monomer. To this end, equivalent amounts of DMAP and its protonated form (DMAP.HX) were used as a dual catalytic system for L-LA polymerization initiated by different alcohols (Scheme 1.6). It was shown that the corresponding DMAP/DMAP.HX systems are significantly more active than DMAP alone, and yield well-controlled poly(L-lactide) up to 15 000 g mol-1 in DCM at 40 °C after 48 h. While enhancement of the reaction was demonstrated highly dependent on the nature of the counter-anion (CF3SO3- > CH3SO3- > Cl-), transesterification reactions were prevented by fine-tuning the experimental conditions. Note also that this synergetic concept was later applied by Kakushi et al. by protonating DMAP with diphenyl phosphate.

Next to lactide, a series of other monomers have also been polymerized with pristine DMAP (Figure 1.1). Alkyl-substituted LA were studied by Moeller and coworkers starting in 2004. In their study, authors did compare the catalytic efficiency of DMAP to the well-known tin(II) 2-ethylhexanoate (Sn(Oct)2) catalyst. Used in the same concentration (1.5 mol% vs. monomer, [ROH]0/[DMAP]0 = 2), DMAP was demonstrated more active than its metallic homologue. After 24 h in bulk at 110 °C, a 65% conversion was recorded for LA-Me showing good control in terms of molecular weight and dispersity values. By using an excess of DMAP ([ROH]0/[DMAP]0 = 0.5), polymerizations of LA-Me, LA-iPr, LA-Be and LA-Hex reached 35, 80, 95 and 97% conversion, respectively, in only one hour. Interestingly, this result indicates that DMAP is more efficient in polymerizing steric-hindered lactides (with good control in both Mn and ÐM) than Sn(Oct)2 catalyst.

In 2006, Bourissou et al. employed DMAP to catalyze the polymerization of the lactic O-carboxyanhydride (Lac-OCA, Figure 1.1). This a-lactone equivalent exhibited remarkable reactivity compared to LA in DMAP catalyzed ROP (Scheme 1.7). Depending on the targeted DP (10–600), complete monomer conversions were obtained in minutes to hours (in CH2Cl2, 0.75 M, [ROH]0/[DMAP]0 = 1) while four days were necessary for DMAP to catalyze a DP 10 in LA at 35 °C. Such differences in terms of activity between the two monomers is due to the liberation of carbon dioxide when Lac-OCA is ring-opened and not to the mechanism strictly speaking, which, based on computational investigations, is ascribed to a base-catalyzed route. The optimized intermediates and transition states substantiate the role of multiple hydrogen bonding, evidencing the possibility of the DMAP acting as a bifunctional catalyst. Remarkably, if a basic-catalyzed mechanism may lead to the deprotonation of the a-methine hydrogen of OCA during a ROP process, no detectable amount of epimerization of the stereogenic carbon atom of Lac-OCA was observed by homonuclear decoupled 1H NMR spectroscopy.

To face the low propensity of DMAP to polymerize other lactones than LA, e.g. e-caprolactone (CL) and ?-pentadecalactone (PDL), Dove et al. explored the cooperative effects between Lewis acids and the DMAP organobase (beyond others). While a cocatalysis with YCl3 and AlCl3 delivered intermediate and no activity, respectively, the combination of DMAP with MgI2 was revealed to be a very active catalytic duo for both PDL and CL polymerizations. In only two hours, PPDL and PCL samples of 70 000 g mol-1 (ÐM ˜ 1.8) and 29 000 g mol-1 (ÐM ˜ 1.3), were prepared in toluene at 110 °C and in THF at 70 °C, respectively.

1.2.2 Imidazole-based Initiation

Next to DMAP, the less toxic imidazole has also been proved to be an efficient catalytic system for transesterification reactions between aliphatic acid esters and alkyl alcohols. In 2003, imidazole was demonstrated as being as efficient as DMAP for a series of reactions between anhydrides and various alcohols under microwave treatment. At the beginning of the 21st century, Kricheldorf and coworkers highlighted the ability of imidazole to promote and lead polymerizations of a-amino acid N-carboxyanhydrides (NCA) and L-LA. A series of NCAs from sacrosine (Sar), D,L-leucine (Leu), D,L-phenylalanine (Phe) and L-alanine (Ala) was prepared and polymerized in dioxane at 60 °C for two days and various NCA-to-imidazole ratios. As attested by 1H-NMR spectroscopy and MALDI-ToF spectrometry, the authors concluded that polymerizations of Sar, Leu and Phe led majorly to the formation of cyclic oligopeptides obtained from the combination of chain-growth, step-growth and cyclization processes (Scheme 1.8, route B). Comparatively, in the case of poly(Ala), the solubility of the secondary polymer structure induced the rapid precipitation of the growing macromolecule preventing the cyclization step and leading to linear poly(Ala) (Scheme 1.8, route A).

The rare combination of both chain- and step-growth processes has also been observed during the L-LA polymerization initiated/catalyzed by imidazole-based molecules. Bulk polymerization of L-LA (~100 °C) results in complete polymerization within two days. After four hours of reaction, even-numbered PLA cycles were observed and obtained from end-to-end cyclizations. Authors demonstrated that all prepared cycles were amorphous, suggesting a base-catalyzed racemization from reversible deprotonation of the LA a-CH group by the imidazole molecule (Scheme 1.9). Longer reaction times favored the equilibration with odd-numbered PLA cycles and has been observed total after eight hours at 150 °C. If several protic heterocycles are also tested (Figure 1.2), the N-methyl imidazole is the only one active in bulk, leading to cyclic PLA (with several by-products). The formation of PLA macrocycles is explained by a zwitterionic mechanism as outlined in Scheme 1.10.

1.2.3 Amidine/Guanidine-based Initiation

Lewis bases such as DMAP and imidazole-based molecules present the ability to promote acylation processes due to their adequate nucleophilicities. Among potential other candidates, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) have also been demonstrated highly active in representative reactions despite the fact they have also been termed as "non-nucleophilic" bases. Mayr and coworkers clarified the situation by determining quantitatively their nucleophilicities and their Lewis basic characters. As compared to DMAP, both nucleophilicities and Lewis basicities gradually increase in the series DMAP