Controlled Synthesis Of Poly(2-oxazoline)s And Their Organocatalytic Property In Asymmetric Aldol Reactions

Poly(2-oxazoline)s are a class of synthetic polyamides which can be regarded as analogues of polypeptides and also of polypeptoids.The ring-opening polymerization of 2-oxazolines usually exhibits controlled/living feature,which provides ready access to various well-defined POXs,whereby the end-group functionality can be controlled during initiation and termination,and side-chain functionalities can be introduced by the copolymerization with a(protected)functional monomer.Nowadays poly(2-oxazoline)s have been received considerable attention due to their potential in biomedical applications.Meanwhile,in the past decade,quite a few studies were dedicated to the synthesis of POX-based polymers with the desire to explore new functional materials and expand further their application in various fields.To date,the cationic ring-opening polymerization(CROP)of 2-oxazolines is commonly initiated by organic acid esters such as methyl p-toluenesulfonate and methyl triflate under microwave radiation.However,this method still remains the some drawbacks.First,the mechanism of microwave effect is not clear although its accelerating effects on the reaction rate have been observed in most cases.It is for this reason,the existing commercialized microwave synthesizers are designed to work in a single-mode,being only suitable for small-scale synthesis.If enlarging the experiment scale,the heterogeneity of the multi-mode microwave radiation will lead to complex side reactions.Second,under microwave heating conditions,the reaction vessel is required to withstand high pressure,which puts forward strict requirements on large-scale synthesis.Finally,the most commonly used initiators(MeOTs and MeOTf)were proven to be highly toxic.Therefore,it is still very interesting to explore effective,practical and safe initiators for 2-oxazoline polymerization.In the first part of this dissertation,the CROP of 2-oxazolines using rare-earth metal triflates[RE(OTf)3]as initiator was investigated for the first time.For the polymerization of 2-ethyl-2-oxazoline(EtOx),five rare-earth catalysts(RE = Sc,Y,La,Lu,Dy)have proven their value as initiator for the polymerization;among them Sc(OTf)3 exhibiting the best results.Within 2 hours,the monomer conversion could reach as high as 90%at 90?,indicating a higher catalytic efficiency than MeOTs under identical conditions.As evidenced by the linear first-order kinetics together with the unimodel molar mass distribution for the resultant polymers with PDI values below 1.15,a good control of polymerization was achieved with this system.From reaction kinetic studies,the activation energy(Ea)and the frequency factor(A)were determind to be 69.54 kJ mol-1 and 9.77 × 107 L mol-1 s-1,respectively.Based on in situ NMR spectroscopic analysis and GPC analysis of PEtOx samples obtained from the control experiments,a possible initiating/propagating mechanism was proposed for the living cationic ring-opening polymerization.The Sc(OTf)3-initiated polymerization undergoes by an active chain end mechanism and every in situ-formed metallic active species consists of three identical onium sites and therefrom initiates simultaneously three equivalent propagating chains.Except for EtOx,4-or 5-substitued 2-oxazoline monomers can be also initiated by Sc(OTf)3 to give corresponding polymers with narrow PDIs(<1.20).It was found that 4-or 5-substitued monomers were more difficult to polymerize due to the steric effect.Conjugative effect or hydrogen bond involving the nitrogen atom on the oxazoline ring will lower the polymeric activity.Poly(2-oxazoline)shows promise as an ideal scaffold to construct artificial enzymes due to its unique peptide-like structure.In the second part,we designed and synthesized poly(2-oxazoline)-bound organocatalysts through a bottom-up protocol.The method involves the preparation of poly(2-oxazoline)s(POXNHBoc)as a parent polymer followed by subsequent modifications including attachment of N-Boc-L-proline to the side-chains via an amide linkage as well as removal of the protecting groups.The parent polymers were obtained in a controlled manner by living CROP initiated by Sc(OTf)3.The 1H NMR studies demonstrated that L-proline was anchored to side chain of the parent polymers in a nearly quantitative yield(the grafting ratio>95%).The resultant L-prolinamido-functionalized polymers have been successfully applied to catalyze the asymmetric Aldol reaction between cyclohexane(CH)and p-nitrobenzaldehyde(PNBA).It was found that the addition of catalytic amount of water(10 ?l)and trifluoroacetic acid(TFA)would improve the enantioselectivity.Interestingly,the spacer between the catalytic moiety and the tertiary polyamide backbone has a significant influence on both the conversions and stereoselectivities.When the spacer is one methylene group(P2 and P3),the catalytic effect of POXNHPro was better than that of P1,in which chiral L-prolinamide moiety is connected to the main chain through a five-atom linker.By using 10 mol%of the polymer as catalyst,the direct aldol reaction afforded the anti stereoisomer in high yield and a good enantioselectivity(92%ee).The results demonstrate that the polymeric catalysts are significantly more active than their monomeric counterpart,suggesting the polymer scaffold probably creates a favorable microenvironment to promote the catalysis.In the third part,we designed and synthesized a novel class of amphiphilic homo-and copolymers of 2-oxazoline bearing L-prolinamide moieties at the alkyl side-chain termini(Plc-P5c).1H NMR spectroscopic analysis showed that the copolymer composition was close to the feed ratio.In all cases,L-proline residue was efficiently introduced into the POX scaffolds,the amide coupling efficiency of the repeating monomeric units(grafting ratio)being more than 95%.As evidenced by dynamic light scattering(DLS)and transmission electron microscope(TEM)measurements,these amphiphilic polymers were found to self-assemble into micelle-type aggregates with a size of 10-30 nm in water.Furthermore,the nanoparticles do not have a definite core-shell structure as often observed with block copolymer micelles,judged from the 1H NMR spectra obtained in CDC13 and D2O.That is,the majority of hydrophilic prolinamide units were tucked into the hydrophobic inner core for the polymeric nanoparticles.The catalytic efficiency of the assembled micelles was investigated using the aldolisation of 4-nitrobenzaldehyde with cyclohexanone as a model reaction.The results showed that the polymeric nanoreactors exhibit much higher catalytic properties in aqueous media compared to their monomeric counterpart and non-amphiphilic reference polymer(P2),affording the anti-aldol products with a moderate stereoselectivity,which suggests that the formation of micelles is able to improve the organic conversion and the stereochemistry.Among them,the micelle system formed by homopolymer P1c exhibited best catalytic performance in terms of stereoselectivity.The reaction afforded the anti-aldol products with an 83:17 anti/syn ratio and-60%ee in good yield,and a higher enantioselectivity(75%ee)was achieved in the presence of TFA(0.5 equiv)as additive.Moreover,it has been proved that the polymer microstructure have a certain effect on the catalytic properties of the resultant nanoreactors.Although these polymeric micelles present some limitations and more work remains to be done to improve their stereoselectivity as well as to expand the substrate scope in the micellar catalysis,the present study provides a novel route for the biomimetic design of organocatalytic systems to carry out organic reactions in water.