Download Design and synthesis optimization of bis(β

WARSAW UNIVERSITY OF TECHNOLOGY
FACULTY OF CHEMISTRY
Major: CHEMICAL TECHNOLOGY
Maciej Damian Korzyński Design and synthesis optimization of bis(β-ketiminate) ligand
alkyl zinc and alkoxy zinc derivatives and their activity in
polymerization of rac-lactide Projektowanie i optymalizacja syntezy pochodnych alkilocynkowych
i alkoksycynkowych liganda bis(β-ketiminowego) i ich aktywność
w polimeryzacji rac-laktydu
Bachelor of Science in Engineering Thesis
carried out in the Division of Catalysis and Organic Technology
thesis supervisor dr inż. Karolina Zelga
WARSAW 2012
To my parents – for giving me opportunities in life To my uncle – for showing me the beauty of science To Mrs. Joanna Heropolitańska – Janik – for sharing her passion for chemistry To dr Karolina Zelga – for her time and knowledge LIST OF ABBREVIATIONS ROP – ring-­‐opening polymerization PLA – polylactide PLGA – copolymer of lactide and glycolide PDI – polydispersity index BDI – β-­‐diimine NHC – N-­‐heterocyclic carbene OctH – 2-­‐ethylhexanoic acid THF – tetrahydrofurane Me – methyl group Et – ethyl group i-­‐Pr – isopropyl group n-­‐Bu – n-­‐butyl group Ph – phenyl group Bn – benzyl group XRD – X-­‐ray diffractometry NMR – nuclear magnetic resonance TABLE OF CONTENTS 1 INTRODUCTION 1 2 LITERATURE REVIEW 2 2.1 LACTIDE AS A HETEROCYCLIC MONOMER 2.2 APPLICATIONS OF POLYLACTIDE 2.3 SYNTHESIS OF POLYESTERS 2.4 CATALYST IN COORDINATION ROP OF POLYESTERS 2.4.1 EVOLUTION OF THE CATALYST 2.4.2 INITIATING GROUP 2.4.3 AUXILIARY LIGANDS 2.4.4 ACTIVE METAL CENTER 2.5 MECHANISTIC CONSIDERATIONS 2.5.1 GENERAL INFORMATIONS 2.5.2 MECHANISM OF COORDINATION ROP 2.5.3 CATALYTIC COORDINATION ROP 2.5.4 STEREOSELECTIVITY 2 3 3 4 4 6 6 8 13 13 14 17 18 3 RESULTS AND DISCUSSION 20 3.1 3.2 3.3 3.4 3.5 3.6 3.7 20 21 24 26 28 29 31 LIGAND SYNTHESIS ALKYL ZINC COMPLEXES ALKOXY ZINC COMPLEX CATALYTIC ACTIVITY EVALUATION OPTIMIZATION OF THE PROCEDURES INDUSTRIAL SYNTHESIS SCHEMATIC DIAGRAM CONCLUSIONS 4 EXPERIMENTAL SECTION 32 4.1 PROCEDURES 4.2 CHARACTERIZATION DATA 32 34 5 REFERENCES 35 1 Introduction Polymers are of the utmost importance in terms of the contemporary materials science. Their diverse properties make them applicable in almost every branch of industry and present in our lives. In particular medical and biological uses are extensively examined. That is why so much research effort is devoted to develop new polymers and improve synthetic methods for those already known. Catalytic reactions draw the biggest attention due to their advantages resulting from the lack of necessity to use stoichiometric amounts of certain reagents. This feature not only lowers the cost of production, but also reduces the impact on the environment (less chemical waste and energy consumption). Development of inexpensive, active and selective catalyst is one of the goals of current works concerning polymerization. The other problem that we face is the polymer itself. Since the 1940s synthetic petrochemical-­‐based polymers have had a tremendous industrial impact. However, the use of the nonrenewable resources and the degradability of those materials are still their major drawbacks. The aim of this work was synthesis of alkyl zinc complexes and their transformation into alkoxy zinc derivatives. Then the said compounds were evaluated as catalysts for polymerization of a heterocyclic monomer. 1
2 Literature review 2.1 Lactide as a heterocyclic monomer Heterocyclic monomers are a vast class of compounds, which share the same structural motif – a ring containing heteroatom(s). One, particularly interesting group of these monomers are cyclic esters – lactones. Figure 2.1 Examples of lactones
The most prominent examples of cyclic esters are rac-­‐lactide (1), glycolide (2) and ε-­‐
caprolactone (3) and their polymers respectively (4, 5 and 6). This work will focus mainly on polylactide because of its unique features. Lactide can be produced via fermentation of renewable resources such as corn and sugar beets.[1] PLA sold under the trade name Nature Works is an effect of collaboration between Cargill Inc. and The Dow Chemical Co. The method they developed is environmental friendly (solvent-­‐free) and economical. Usage of corn-­‐derived dextrose as a substrate makes Nature Works the first synthetic polymer produced from annually renewable resources.[2] The next virtue of PLA (and also of other polyesters) is its biodegradability resulting from the presence of aliphatic polyester backbone, which is sensitive to hydrolysis. The product of this reaction is lactic acid, which is not harmful to human body and eliminated from organism via Krebs cycle as carbon dioxide and water. This means that PLA is bioassimilable. Polylactide presents suitable rheological and physical characteristics for industrial processing and there are well-­‐known processes that may improve performance of the final product.[3] Lactide can 2
also be copolymerized with glycolide in order to obtain PLGA, which expands the possibility to tune the properties of the resulting polymer. These advantages make PLA and PLGA possible future substitutes for petrochemical-­‐based polymers and rationalize the amount of research concerning their synthesis, analysis and processing. There are two synthetic pathways leading to polyesters and those will be presented further in the text. 2.2 Applications of polylactide Polylactide is employed in various applications. Undoubtedly, the most useful and sought for are medical products. Due to PLA’s nontoxicity and biodegradation over time, it can be used in bioassimilable sutures e.g. Dexon.[4] It is also utilized in stents (artificial tubes inserted into natural conduits in human body in order to prevent flow constriction caused by disease) and dialysis media. Potential usage in tissue repairing and engineering is also considered. PLA is already used in biodegradable implants and for fixation of fractured bones and joints instead of titanium pins.[5] The hallmark of such solution is no need for removal surgery. The second important field is pharmacology. PLA is used in controlled drug release devices, which allow us to keep constant drug dosage instead of spikes in its concentration and thus maintaining the drug concentration in the therapeutic window.[6] They also allow us to postpone drug processing in organism, which gives the substance an opportunity to reach the desired location in vivo and decreases possibility of side effects. PLA’s are also used in loose-­‐fill and food packaging. They are also encountered in disposable tableware, bottles, drink cups, rigid containers and flexible films. The largest disadvantage is low heat tolerance which is why hot beverages cannot be served in PLA cups.[7] As fibers polylactide is employed in production of non-­‐woven textiles. PLAs are potentially applicable in other products such as diapers and feminine hygiene products. 2.3 Synthesis of polyesters There are essentially two synthetic routes leading to polyesters.[8] The first one is the classic polycondensation reaction. In this method bifunctional monomer reacts with itself 3
yielding a macromolecule. In case of polylactide lactic acid is used as a substrate. The most severe problem that one encounters during such reaction is the formation of water molecules as a byproduct. Polycondensation reaches certain equilibrium and the increasing amount of water in the reaction mixture results in equilibrium state shifting towards substrate and in consequence -­‐ lower polymer weight. This problem can be overcome by means of e.g. azeotropic distillation or reduction of pressure in the system. However, those solutions affect the price of the final product. Figure 2.2 Polycondensation of lactic acid
An alternative approach is ring-­‐opening polymerization. In this reaction cyclic compounds are polymerized and the small molecule abstraction problem is non-­‐existent. The difference between polycondensation and ROP is that the latter requires an initiating agent/catalyst. ROP is also superior In terms of sequence of monomers in copolymerization and chain end group control. One can distinguish several mechanisms of ROP such as anionic, cationic, radical and coordination, on which this work will focus. The latter mechanism is applicable in case of polyesters synthesis using metal complex as a catalysts and will be thoroughly discussed later in this work. 2.4 Catalyst in coordination ROP of polyesters 2.4.1 Evolution of the catalyst The main goal of any catalytic process is to find the perfect catalyst. In case of coordination ROP of lactide the metal complex must present certain characteristics: 4
•
It must be active in the desired process •
It must be stable in the reaction conditions •
There must be a balance between reactivity and selectivity •
It should favor propagation instead of side reactions •
It should yield the product with narrow mass distribution (PDI close to 1) Investigation of coordination ROP has begun with employment of simple alkoxides as catalysts. One of the classical examples is aluminum alkoxide such as Al(Oi-­‐Pr)3.[9] Although it was useful in determination of the polymerization mechanism, its activity was not satisfactory. In order to find more active species trivalent lanthanum alkoxides Ln(OR)3 (Ln=La, Y; R=i-­‐Pr, n-­‐Bu) were prepared and evaluated in ROP of lactide.[10] The studies showed an increased activity compared to the aluminum complex and no catalyst induction time (period between mixing of reagents and the beginning of polymerization) was observed. Also oxoalkoxide clusters of the general formula Ln5(μ5-­‐O)(Oi-­‐Pr)13 were investigated, but the resulting polymer had a broader mass distribution, which makes the polylactide less useful.[11] Alkoxides of different metals such as tin, germanium, calcium and iron have been prepared and evaluated in ROP of lactide.[12-­‐17] These findings were crucial in terms of understanding coordination ROP. However, all of the mentioned complexes suffer from two important issues.[8] Firstly, alkoxides tend to aggregate or even form clusters. The final product is affected by e.g. size of the cluster, which makes some of the results irreproducible. Aggregation also leads to prolonging catalyst induction time. Secondly, presence of more than one alkoxide group per metallic center allows for more than one growing chain to be present at the coordination center, which further complicates the reaction. All above reasons and promising results of ROP on metal alkoxides stimulated search for well-­‐defined single-­‐site (one growing chain per metallic center) catalysts. There are structural features that are common for all of them and allow to write a general formula for such species -­‐ LnMR.[18] M stands for the active metal center, which is the most important part of catalyst. It defines its overall activity, coordination potential, bonding and resulting polymer. R denotes initiating group, which as its name suggests commences the polymerization process. It is also present in the final polymer as the end group. Despite the fact that auxiliary ligand(s) (Ln) do not participate directly in the process of polymerization, their role should not be diminished. Firstly, by altering the electronic nature of the ligand, which is bound to the metal it is possible to tune the properties of the coordination center. Secondly, their presence minimalizes the aggregation phenomenon. For reaction to begin the catalyst must be present in monomeric form, therefore either there is either no reactivity at all (if the aggregate is very stable) or eventually due to the reaction conditions the complex monomerizes and the reaction 5
starts. The third role of the auxiliary ligand(s) is suppression of the side reactions, which are presented in the chapter dedicated to mechanism. 2.4.2 Initiating group Historically alkoxides were the first class of compounds employed in coordination ROP. However, there are many moieties used as initiating agents such as amido (-­‐NR2), silyloxy (-­‐OSiR3), acetate (-­‐O(O)CCH3), alkyl (-­‐R), silylamido (-­‐N(SiR3)2) groups etc. These have tremendous influence on the behavior of the catalyst partly because of a different steric hindrence and partly due to change of polarization of metal-­‐initiating group bond, which is an important factor contributing to the activity of catalyst. Coates et al. investigated activity change associated with different initiating groups (without altering the metal center or the auxiliary ligand).[19] The results showed that the most active complexes are those bearing an alkoxide substituent. The main factor governing the reaction’s outcome is the electronegativity difference between the metal center and the initiating group. 2.4.3 Auxiliary ligands Although many chelating ligands are employed in ROP catalysts featuring various heteroatoms as donors, there are three most common groups that can be distinguished. These groups will be briefly described now. This work will not focus on monodentate ligands, because of their lesser importance. However, their existence needs to be noted. As a natural continuation of research on metal alkoxides bulky biphenolates and methylenebiphenolates were investigated and these are described as O,O-­‐donors.[20,21] Utilization of bulky aromatic alcohols in theory should have prevented the agglomeration, unfortunately it turned out to be invalid as the agglomeration was still a major issue. Introduction of additional, neutral substituents into the ligand molecule resulted in the diminished catalytic activity. This observation led to the conclusion that the less hindered the active metal center the more active catalyst is in coordination ROP. 6
Figure 2.3 Examples of O,O-donors
In order to circumvent the agglomeration problem the attention of the scientists was turned to N,N-­‐donor ligands. The presence of an additional substituent on the nitrogen increases the steric hindrence. Monomer does not insert into the metal-­‐nitrogen bond in presence of more active groups such as alkoxides, so these ligands cannot act as initiating groups. Within N,N-­‐donors two important groups of ligands can be pointed out: tridentate bispyrazolylhydroboranes (and analogues) and β-­‐diminate ligands (BDI). The former class of compounds completely prevents agglomeration as it was shown for zinc, calcium and magnesium complexes.[22] However, these complexes yield product with relatively broad mass distribution. The latter group of ligands (BDI’s) is extremely important. They are easy to synthesize or already available commercially. BDI’s will be thoroughly discussed in the next subchapter. Figure 2.4 Examples of N,N-donors (bispyrazolylhydroboranes and BDI’s respectively)
The last prominent group of ligands is called N,O-­‐donors. Again, there are two widely known species representing this type of ligands namely analogues of SALEN and Schiff base derivatives. SALEN based catalysts are moderately active, but allowed for good polymerization control.[23] In case of Schiff base derivatives the agglomeration phenomenon was either not present or resulted in the formation of dimers.[24] 7
Figure 2.5 Examples of N,O-donors (SALEN and Schiff base respectively) 2.4.4 Active metal center In order to fully understand structure of the catalyst one needs to analyze metals employed in coordination ROP. One important requirement regarding the coordination center is that the metal cannot undergo redox reactions easily and has to be inert towards β-­‐elimination of hydrogen.[25] Mostly main group metals are utilized such as lithium (Group 1), aluminum (Group 13) and tin (Group 14).[26-­‐28] Sodium and potassium alkoxides due to low electronegativity of the metal undergo ROP via anionic mechanism. In group 13 gallium was also investigated, but its complexes showed poor catalytic activity. As it is for bismuth only Bi(Oct)3 proved to be active in coordination ROP.[29] Exemplary structures are listed below. Figure 2.6 Examples of catalysts containing lithium and aluminum 8
Figure 2.7 Examples of catalysts containing aluminum and tin The most interesting metals are those found in the second group of periodic table namely magnesium, calcium and zinc. Despite the fact that zinc is not a main group element, it has similar properties to magnesium.[25] It is a result of its saturated d electron shell. The most important feature of those metals is that they are biocompatible. The fact that they are nontoxic and naturally present in the human organism overcomes the problem with polymer purification. Studies show that the polymer workup does not completely remove the catalyst residues completely. If medical applications are considered the product cannot contain toxic ions. As an example one can give tin and aluminum complexes. It is commonly known that tin ions are extremely harmful and recent studies show that aluminum deposits in brain may cause Alzheimer disease. The second important advantage of group 2 metals is that they are cheap, which is reflected reflects in the lower price of the catalyst and the final polymer. Zinc distinguishes itself among these elements. Coates et al. compared the catalytic activity of Mg, Zn and Ca and order of activity was established as Ca > Mg > Zn.[19] Unfortunately, the activity is not consistent with control of the reaction. Zinc complexes yielded polymers having very narrow mass distribution, being still very active. Chisholm at al. investigated the usage of trispyrazolyl-­‐ and trisindazolylhydroborate zinc complexes in ROP of lactide.[22,30] All compounds were found to be monomeric in solid state. 9
Figure 2.8 Zinc complexes with bulky tridentate ligands Complex 7 is moderately active. It converted 90% of the monomer in 60 days in room temperature in contrast to analogous magnesium complex, which needs only 60 minutes. However, zinc complexes are quite tolerant to moisture and air (7 decomposes after few days whereas magnesium compound is instantly decomposed). Chiral zinc derivative 8 was found to polymerize meso-­‐lactide faster than D-­‐ or L-­‐lactide. Compound 9 is barely active in lactide polymerization due to electronic factors. Figure 2.9 Zinc complexes of BDI ligands 10
Contribution of Coates at al. to development of ROP is immeasurable. Their research was focused on BDI ligands and catalysts synthesized in their group are presented.[19,31] Compounds 9, 10, 12, 13 and 16 were used in the initiating group dependence study described in chapter 2.4.2. It is worth adding that in the case of complexes 9, 12 and 13 they probably do not participate in the insertion of monomer, but instead they react with impurities resulting in proper initiating species. That delay causes large PDIs in the resulting PLA. The zinc derivative 16 is a very efficient catalyst (monomer conversion up to 94% in 0°C), which yields heterotactic polylactide with good sterocontrol. It is important to point out that the PDI’s of products were very low (1,1 to 1,4) What is more one can affect the tacticity ratio by altering R group (15, 16). The smaller the alkyl group the lower heterotacticity is observed. Similar activity was found for compound 17. Zinc complex 18 is active and yields primarily hetrotactic PLA. However, the mass distribution is not satisfactory. Figure 2.10 Zinc complexes of BDIs with an ether moiety in the aromatic ring and zinc
bisphenoxide derivative
Gibson et al. tried to synthesize tridentate BDIs by introduction of an ether moiety into the aromatic ring.[32] It occurred that there was no coordination in the case of zinc complexes (contrary to magnesium species). Both complexes are effective catalysts – 19 converts more then 80% of the monomer in 10 minutes and 20 90% in 30 minutes. Their only disadvantage is slow initiation. Polydispersity of resulting polymers is relatively low for these complexes (1,10 and 1,15 respectively). One example of bisphenoxide complex is 21, which is active in ROP only at elevated temperatures (80°C).[21] 11
Figure 2.11 Examples of the N,O-donor zinc complexes N,O-­‐donor zinc complexes were also tested in ROP of lactide. Compound 21 (X = N(SiMe3)2) presented good activity – 90% conversion achieved in 3 hours at room temperature.[24] Unfortunately the resulting PLA was atactic. Modification of the ligand bulkiness (22) by Wu et al. led to a heterotactic polymer with narrow mass distribution at expense of reactivity (proceeds in 60°C).[25] Apart from the ligand groups mentioned in subchapter 2.4.2 few different classes of ligands were used. Bis(phosphinimino)methyl ligand derivatives (e.g 23) were examined as structural analogues of BDI’s. The results of polymerization were worse than in the case of similar β-­‐diminate ligand derivatives in terms of activity and reaction control.[33] Figure 2.12 Examples of the zinc ROP catalysts 12
Hilmayer at al. synthesized dizinc-­‐monoethyloxide compound 24, which presented good activity and yielded atactic PLA with narrow mass distribution.[34] Triamine zinc complex 25 proved to be a poor catalyst for ROP of lactide (reaction occurred at 180°C) Guanidinate amide derivative 27 was found to polymerize lactide in a quick and controlled fashion.[35] It was shown that propagating species in this reaction are very stable. Also cationic complexes such as 26 were investigated, but the activity was moderate.[36] Recently researchers’ attention was drawn to NHC ligand bearing zinc complexes (e.g. 28) but research is still ongoing.[37] 2.5 Mechanistic considerations 2.5.1 General informations Variety of different compounds can be polymerized via ROP route, but there are two important factors that determine the overall success of the reaction – thermodynamics and kinetics.[18] The main driving force of ring-­‐opening polymerization is a ring strain in the molecule of the substrate, which is an effect of the deviation from nondistorted bond angle, repulsion between eclipsed hydrogen atoms and nonbonding interactions between substituents. It can be easily observed for molecules of cycloalkanes. The ideal angle between orbitals in sp3-­‐hybridized carbon is ca. 109,5°. In cyclopropane the same angle equals 60°, which means that opening of this ring would relieve the strain of the said molecule. This theory can be extrapolated to other classes of compounds including heterocyclic monomers. The ring strain can be easily measured using enthalpies of ROP. Larger strain results in a more exothermic reaction. It is commonly known that five and six-­‐membered rings are the most stable. It is a major problem because most of these compounds are unable to polymerize. The enthalpy of ring-­‐opening polymerization of these compounds is close to zero, or even positive. However, in case of rac-­‐lactide (which has a six-­‐membered ring) the ROP enthalpy was estimated to be negative and relatively high in absolute terms (ca. -­‐23 kJ/mol).[38] This peculiarity can be explained using X-­‐ray crystallographic data. Increased ring strain is caused by the presence of two ester moieties with a planar conformation. It is important to remember that this effect is not 13
strong and at higher temperatures the back reaction is not negligible and results in the increased concentration of the monomer. In most cases entropy decreases during ring-­‐
opening polymerization due to loss of translational degrees of freedom. ROP will only be thermodynamically favored (ΔG<0) if the the enthalpic factor compensates entropic factor (ΔH<TΔS). 2.5.2 Mechanism of coordination ROP Dittrich and Schulz proposed the mechanism of coordination ring-­‐opening polymerization in 1971.[39] Kricheldorf and Teyssie independently reported the experimental proof for this mechanism in 1980s.[40,41] This mechanism is sometimes called the coordination-­‐insertion mechanism. In the first step the monomer approaches catalyst ([M] is used instead of LnM fragment for clarity) molecule and donates the nonbonding electron pair located on carbonyl oxygen. The active metal center as a Lewis acid is able to accept this electron pair and in consequence the carbonyl carbon-­‐oxygen bond undergoes further polarization and activation. Eventually in the second step the monomer inserts into alkoxide – metal bond by means of a nucleophilic attack of alkoxy group on the carbonyl carbon. The next stage involves cleavage of acyl oxygen – carbon bond and opening of the ring. The resulting molecule is also an alkoxide, which can react further with the monomer yielding a polymer chain after some time. Hydrolysis of the growing chain gives the final product and a metal hydroxide. It is easily noticeable that the product has a hydroxyl group on one end, while on the second end the initiating group is present as a part of the ester moiety. 14
Figure 2.13 Mechanism of the coordination ROP Even though the mechanism itself is fairly simple, there are many variables that affect the process, namely: •
Size of the monomer ring and its substituents •
Parameters of the reaction – type of catalyst, solvent, monomer concentration and temperature •
Occurrence of side reactions One of the examples of how a change of conditions can alter the mechanism is ROP of rac-­‐lactide with Sn(Oct)2 carried out in a protic solvent such as methanol.[42] Reaction carried out in such manner is faster. There was a debate whether this reaction follows a coordination-­‐insertion mechanism, but recent findings (isolation and characterization of few intermediates) strongly support this theory. Still, there are concerns regarding the true nature of the initiating complex. There are few factors that have to be considered. Firstly, it is accepted that Sn(Oct)2 reacts with alcohol yielding covalent tin(II) alkoxide. This process may involve retention of the octanoate ligands or liberation of octanoic acid (OctH). Secondly, impurities present in monomer (in case of lactide it can be alcohol, lactic acid and water) may react with the catalyst and give new initiating species. Apart from the participation in initiation of ROP protic agents can affect the growing polymer chain in e.g. transestrification reaction (alcohols). Below there are sample equations illustrating the mentioned factors. 15
Sn(Oct)2 + ROH à (ROH)Sn(Oct)2 Sn(Oct)2 + ROH à (RO)Sn(Oct) + OctH RO(lactide)nSn(Oct) + ROH à (RO)Sn(Oct) + RO(lactide)nH
Figure 2.14 Possible reactions of the catalyst in presence of alcohol Theoretical calculations led to the prediction of the mechanism when methanol is used as a solvent. In the first step coordination of 2 molecules of MeOH occurs with retention of the octanoate ligands. In the second step intramolecular proton migration takes place, followed by gradual insertion into the OH bond of coordinated methanol. Figure 2.15 Mechanism of the coordination ROP in presence of methanol The last issue that should be mentioned while discussing mechanisms is the problem of transestrification side reactions that occur during the coordination ROP process.[18] These reactions are the main reason of wide molecular weight distribution. One possibility is intramolecular backbiting, which leads to macrocycles and shorter chains. The second possibility involves an intermolecular chain redistribution. 16
Figure 2.16 Side reactions in the coordination ROP
As it was said before the extent of side reactions depends strongly on the catalyst. They may take place at the beginning of the reaction and result in poor PDI of the final product. On the other hand when the transestrification takes place at the end of reaction it has less influence on the final weight distribution (as in the Al(Oi-­‐Pr)3 catalyzed ROP). In some cases optimization of reaction conditions may lead to limitation of side reactions and the polymerization can be considered as living. 2.5.3 Catalytic coordination ROP The polymerization process can be terminated using various reagents. However, most of them (such as water and mineral acids) destroy the active metal complexes. That is why there is a discussion whether they should be called metallic initiators or catalysts. In case of the well-­‐defined single-­‐site metal complexes we can easily propose catalytic cycle for ROP of lactones.[18] Termination of the growing polymer chain is achieved by means of alcohol that is the protonated form of the initiating group anion. This method is only applicable in case of catalysts bearing alkoxide group at the beginning of the reaction. The success of this solution relies on fast alcohol/ alkoxide exchange at the metal center. Carrying ROP out in such manner lowers the necessary amount of metal complex even to 0,01 mol %.[43] 17
Figure 2.17 ROP catalytic cycle 2.5.4 Stereoselectivity Rac-­‐lactide is an equimolar mixture of two stereoisomers – D-­‐lactide and L-­‐lactide.[18] This is the reason why stereocontrol of lactide ROP is an important and complicated issue. It is obvious that the properties of the final product depend on the microstructure of the polymer chain. One example of these properties may be melting point and glass transition temperature. Figure 2.18 Stereoisomers of lactide and polylactide
18
In contemporary materials science it is crucial to synthesize PLAs stereoselectively in order to achieve certain characteristics. Stereoregular crystalline polylactides are especially interesting because they retain their mechanical properties. The least interesting is the atactic PLA. Tacticity of the product can be determined using NMR spectroscopy and a brief description of the method will be included in Chapter 3. 19
3 Results and discussion It is easily inferred from the previous chapter that a lot of factors contribute to successful ring-­‐opening polymerization and that the search for the ultimate catalyst is still ongoing. The main objective of this thesis and research that was carried out was to expand the knowledge about coordination ROP. In 2009 Harder et al. published the article concerning magnesium, calcium and zinc complexes of (N,N)-­‐coupled bis(β-­‐ketimine) 1, which is an interesting example of (N,N)-­‐
bischelating ligand.[44] The only zinc derivative of this ligand reported was the ethyl zinc complex of 1, which was evaluated in CO2/cyclohexane oxide polymerization and proved inactive. 1
Figure 3.1 Structural formula of the ligand 1 The said ligand is both electron rich and sterically hindered. These properties make it both a desired auxiliary ligand in coordination ring-­‐opening polymerization and a useful partner in controlled oxygenation of alkyl zinc compounds, which is one of the main research areas of prof. Lewiński’s group. Oxygenation of alkylzinc compounds leads to alkoxides – the best initiating group in ROP. All these factors combined together suggest that further exploration of bis(β-­‐ketiminate) zinc derivatives is desired. The aim of this work was synthesis of ligand 1 followed by preparation of alkyl zinc complexes and their transformation into alkoxy zinc derivatives. Then these compounds were evaluated as catalysts for polymerization of rac-­‐lactide. The results are reported and discussed, along with schematic diagram for industrial catalyst synthesis proposal. 3.1 Ligand synthesis Bis(β-­‐ketimine) 1 can be prepared in a 3 step synthesis adapted from works of Sun et al. and Harder et al.[44,45] 20
Scheme 3.1 Ligand synthesis The first synthetic step was the preparation of β-­‐ketimine from acetylacetone and 2,6-­‐
diisopropylaniline. In order to ensure that diimination does not take place slight excess of diketone was used and formic acid was utilized instead of hydrochloric acid. The reaction was quite smooth and after simple workup the mixture was used in second step without further purification. The mixture was controlled by means of gas chromatography and the yield of the first step was 76%. In the second reaction triethyloxonium tetrafluoroborate was employed as an isomerizing agent, which altered the location of double bond and yielded ketenamine. The reagent is moisture sensitive therefore this reaction must be conducted under inert gas and with dehydrated solvent and amine. This step was followed by addition of hydrazine monohydrate. After 80 h reaction was completed and yellow precipitate was formed. After purification the overall yield was 19,4%. This synthesis performed twice and at the first time no product was formed. At the second attempt excess of triethyloxonium tetrafluoroborate was added to the reaction mixture, which resulted in immediate precipitation of product after hydrazine addition. Product was characterized using NMR spectroscopy. 3.2 Alkyl zinc complexes The next stage of the conducted work was the synthesis of alkyl zinc derivative of 1, namely ethyl zinc complex 2. It was prepared in a one-­‐step synthesis. 2 Scheme 3.2 Synthesis of ethyl zinc derivative 21
It was prepared in the reaction of 1 with diethyl zinc. The ligand molecule contains 2 labile protons. Addition of Et2Zn causes deprotonation and abstraction of ethane along with formation of the desired complex 2. The reaction proceeds relatively slow. Monocrystals were obtained after 1 week from concentrated reaction mixture as yellow blocks, tending to melt outside freezer. The NMR spectrum of the reaction mixture was recorded and the crystallographic structure was determined using XRD. Figure 3.2 Molecular structure of ethyl zinc derivative 2 Compound 2 crystallizes in P21/c space group possessing an inversion center, a 2-­‐fold screw axis and a glide plane. The angle between the β-­‐ketiminate units equals 105,54°. Zinc centers adopt a trigonal planar geometry. Table with the lengths and angles of the selected bonds is given below. Table 3.1 Selected bond lengths and angles for complex 2
Atom #1 Atom #2 Bond length [A] Atom #1 Atom #2 Bond length [A] Zn1 N1 1,948(8) Zn2 N3 1,962(4) Zn1 N2 1,958(5) Zn2 N4 1,961(8) Zn1 Cethyl 1,950(8) Zn2 Cethyl 1,97(1) Bonds Angle [°] Bonds Angle [°] N1-­‐Zn1-­‐Cethyl 133,01 N3-­‐Zn2-­‐Cethyl 128,12 Cethyl-Zn1-N2
131,92 Cethyl-Zn2-N4 136,27 N1-­‐Zn1-­‐N2 95,06 N3-­‐Zn2-­‐N4 95,57 These results correspond quite well with structure obtained by Harder et al. confirming their results at the same time. 22
In order to overcome difficulties with the compound’s 2 handling and to facilitate formation of crystals adduct 3 was formed by adding stoichiometric amount of 4-­‐picoline to the solution of 2. After 1 hour the reaction was completed. 3
Scheme 3.3 Synthesis of the 4-picoline adduct
Interestingly, complex 3 crystallized overnight in freezer as bright yellow plates suitable for X-­‐ray diffractometry. The crystallographic structure and the NMR spectrum of the pure product were obtained. The crystallographic data showed a presence of an inversion center, 3 perpendicular 2-­‐fold screw axis’ and 3 perpendicular glide planes consistent with Pbca space group. Zinc centers adopt a distorted tetrahedral geometry, while the angle between β-­‐ketiminate units is nearly the same as in 2 (104,61°). The two picoline rings are nearly parallel to each other and essentially perpendicular to the corresponding β-­‐ketiminate unit. It is worth noticing that the distance between zinc and ethyl group carbon is slightly longer in 3 than in 2. Figure 3.3 Molecular structure of the 4-picoline adduct 3
23
Table 3.2 Selected bond lengths and angles for complex 3
Atom #1 Atom #2 Bond length [A] Atom #1 Atom #2 Bond length [A] Zn1 N1 2,168(7) Zn2 N2 2,168(7) Zn1 N3 2,046(7) Zn2 N5 2,028(7) Zn1 N4 2,034(6) Zn2 N6 2,032(6) Zn1 Cethyl 2,009(7) Zn2 Cethyl 1,980(7) Bonds
Angle [°]
Bonds
Angle [°]
Cethyl -­‐Zn1-­‐N1 105,17 Cethyl-­‐Zn2-­‐N2 107,87 Cethyl -­‐Zn1-­‐N3 124,04 Cethyl-­‐Zn2-­‐N6 126,56 Cethyl -­‐Zn1-­‐N4 130,94 Cethyl-­‐Zn2-­‐N5 127,20 N3-­‐Zn1-­‐N4 91,77 N5-­‐Zn2-­‐N6 91,63 Attempts to prepare analogous THF adduct were unsuccessful and only compound 2 was obtained from the reaction mixture. 3.3 Alkoxy zinc complex With alkyl zinc derivatives 2 and 3 at hand the target alkoxide could be prepared. Classical approach to alkoxide synthesis involves alcoholysis of the adequate alkyl metal complex. This method is limited by disfavored abstraction of second alkyl group from zinc. Non-­‐classical route to alkoxides involves oxygenation of alkyl metal complexes. It is a very interesting reaction, which involves coordination of oxygen molecule to the metal center followed by an electron transfer and subsequent insertion resulting in alkylperoxide complex formation. Depending on the stability of the peroxide the reaction either stops or decomposition to alkoxide occurs. Different reactivity of alkyl compounds requires varied oxygenation conditions. The gentlest conditions involve introducing dehydrated air by means of diffusion in a freezer. In case of difficult partners pure oxygen in room temperature is utilized. The first compound to undergo oxygenation was 2. Procedure was performed using dehydrated air, which was introduced to Schlenk flask with the solution of 2 in toluene. 24
4
Scheme 3.4 Synthesis of the ethoxide zinc derivative During the reaction gradual color change from brown to pale yellow of the reaction mixture was observed. Complex 4 was obtained in a good yield. It crystallized overnight from the concentrated reaction mixture as yellow plates. The NMR spectrum of the pure compound was recorded and the structure was determined using XRD. Figure 3.4 Molecular structure of ethoxide zinc complex 4
Crystallographic data revealed a very interesting dimeric structure with four μ2 oxygen bridges. It crystallized in Pbcn space group possessing an inversion center, 3 glide planes, two 2-­‐fold screw axis’ and one 2-­‐fold rotational axis. Zinc centers again adopt distorted tetrahedral geometry. The angle between β-­‐ketiminate units is significantly smaller (74,97°). 25
Table 3.3 Selected bond lengths and angles for complex 4
Atom #1 Atom #2 Bond length [A] Atom #1 Atom #2 Bond length [A] Zn1 N1 2,003(5) Zn3 N5 2,003(5) Zn1 N2 1,981(5) Zn3 N6 1,981(5) Zn1 O1 1,977(4) Zn3 O1 1,953(4) Zn1 O2 1,953(4) Zn3 O2 1,977(4) Zn2 N3 1,989(5) Zn4 N7 1,989(5) Zn2 N4 2,002(5) Zn4 N8 2,002(5) Zn2 O3 1,960(5) Zn4 O3 2,012(3) Zn2 O4 2,012(3) Zn4 O4 1,960(5) Atoms Angle [°] Atoms Angle [°] N1-­‐Zn1-­‐N2 97,23 N5-­‐Zn3-­‐N6 97,23 N1-­‐Zn1-­‐O1 112,46 N5-­‐Zn3-­‐O1 125,99 N2-­‐Zn1-­‐O2 116,78 N6-­‐Zn3-­‐O2 124,99 O1-­‐Zn1-­‐O2 92,74 O1-­‐Zn3-­‐O2 82,74 N3-­‐Zn2-­‐N4 96,19 N7-­‐Zn4-­‐N8 96,19 N3-­‐Zn2-­‐O3 117,59 N7-­‐Zn4-­‐O3 124,73 N4-­‐Zn2-­‐O4 111,43 N8-­‐Zn4-­‐O4 127,75 O3-­‐Zn2-­‐O4 91,90 O3-­‐Zn4-­‐O4 81,90 Oxygenation of compound 2 with pure dioxygen resulted in the decomposition of substrate. Attempts to monomerize compound 4 were made using Lewis base (4-­‐
picoline), but they were unsuccessful. Also oxygenation of 3 was investigated, but it was not reactive towards oxygen in gentle conditions, which is consistent with the information that four-­‐coordinate alkyl zinc complexes are not prone to reaction with O2. 3.4 Catalytic activity evaluation The final stage of this work was evaluation of the synthesized compounds in ring-­‐
opening polymerization of rac-­‐lactide. Only polymerization with compound 2 was not investigated due to difficulties with its handling and low crystallization efficiency. All polymerization reactions were carried out in CH2Cl2 in anhydrous conditions under inert 26
gas atmosphere. Reactions were quenched using 5% (w/w) HCl aqueous solution .The first compound examined was the target alkoxide complex 4. Unfortunately, despite the information regarding the superiority of alkoxide initiation group bearing catalysts the prepared compound was completely inactive in ROP of rac-­‐
lactide. Two attempts to confirm this result were made using two independently prepared batches of 4. In the first experiment reaction was carried out in room temperature and monitored using NMR spectroscopy after 2 hours and 24 hours (when it was quenched). Only lactide was present in the reaction mixture. The second reaction lasted 2 days – first 24 hours at the room temperature and then (after NMR spectrum showed no conversion of the substrate) at 60°C. After the reaction was finished another NMR spectrum was recorded. Again, it suggested that pure monomer was present in the sample. This reluctance can be accounted for stability of complex 4 and a difficult access to the zinc centers (which is necessary for the reaction to occur) due to the large steric hindrence. It can be observed on the space fill structure of the said compound. Figure 3.5 Space fill model of complex 4 The second investigated compound 3, proved to be active in ROP of rac-­‐lactide at room temperature. Scheme 3.5 Polylactide synthesis The NMR spectrum after 24 hours showed a complete conversion of the monomer. It was stated in the literature review that it is possible to determine tacticity ratio using NMR 27
spectrum. As it is commonly known during polymerization the spectrum becomes complicated due to small, but still present differences between methine protons. Methine region is located between 5,1 and 5,3 ppm. In homodecoupled spectrum that region consists of several wide peaks. These are associated with lactide tetrads differing in their stereosequence in the polymer chain. Fortunately, using Bernoullian statistics it is possible to determine the relationship between the peak integral and the probability of heterotactic and isotactic enchainment of polylactide. Given below is the methine region of both the original and the decoupled NMR spectrum of the polymer obtained using catalyst 3. Figure 3.6 Methine region of the NMR spectra of polylactide (before and after decoupling) According to calculations, the probability of heterotactic enchainment is equal 0,63. It is possible that further optimization of the reaction conditions (e.g. lowering the temperature) could lead to a better result. 3.5 Optimization of the procedures Several procedures were optimized during the research that was carried out in order to prepare this thesis. In case of the ligand synthesis reaction time and substrates ratio (especially for the triethyloxonium tetrafluoroborate) were determined. Optimal reaction time was also chosen for compound 2. Notably the reaction was carried out at ambient temperature as opposed to the source article. Conducted experiments proved that the picoline adduct 3 is formed when stoichiometric amount as well as an excess amount of 28
4-­‐picoline was used. The reaction time and oxygen concentration were crucial in order to successfully obtain compound 4. Attempts to oxygenate complex 2 at ambient temperature resulted in the decomposition of the said compound. Moreover, the utilization of the pure dioxygen was futile. When the reaction was carried out in freezer with dry air the product was obtained after 1 hour. The prolongation of the reaction time does not result in an increased yield. 3.6 Industrial synthesis schematic diagram Considering potential application of the complex 3 in ring-­‐opening polymerization of rac-­‐lactide schematic diagram of the industrial synthesis is proposed. The whole process is conducted under inert gas atmosphere using dry solvents and reagents. In the first step the ligand is dissolved in toluene and after cooling the solution to -­‐70°C diethylzinc is added over the period of 5 minutes. The mixture is stirred for 6 hours at ambient temperature. In the next step stoichiometric amount of 4-­‐picoline is introduced and the mixture is stirred for another hour. Afterwards the solution is concentrated and allowed to crystallize in -­‐10°C. The crystalline product is removed, whereas the solvent is distilled from the mother liquor and the dry residue is obtained. This residue after a proper analysis might be commercialized as a less effective, yet cheaper catalyst. The distilled solvent is recuperated and can be reused in the following batch preparation. 29
30
3.7 Conclusions The aim of this work was the preparation of the alkoxide complex beginning from ligand synthesis followed by formation of alkyl zinc derivatives. The ethyl zinc complex was prepared along with its 4-­‐picoline adduct. The former was successfully transformed into the target ethoxide zinc derivative. Synthetic steps were optimized. All compounds were characterized by the means of NMR spectroscopy and X-­‐ray diffractometry. Additional ring-­‐opening polymerization activity studies were made. Structure of the tricoordinate ethyl zinc complex was confirmed. The 4-­‐picoline adduct presented interesting advantages. Introduction of the fourth substituent to the zinc center resulted in change of the geometry to the distorted tetrahedral. Four-­‐
coordinate zinc centers are not susceptible to oxygen attack and therefore are relatively stable in its atmosphere. What is more, in case of the 4-­‐picoline derivative the facilitation of the crystallization process (crystals are obtained faster and do not melt quickly outside a freezer) was achieved. These properties make it an attractive partner in ROP of lactide and its activity was proven. The industrial schematic diagram for the synthesis of the 4-­‐
picoline adduct was proposed. The desired ethoxide zinc derivative was prepared by oxygenation under gentle conditions. It presented interesting dimeric structure, but its stability resulted in the lack of reactivity in polymerization. Research that was carried out expands the current knowledge about the rules governing ROP of lactide. In this the thesis a new catalyst, which belongs to the group of homobimetallic complexes, is introduced. These are less commonly used. However, their activity proves that they are worth investigating. What is more the results presented in this thesis give interesting new perspectives for oxygenation reactions. 31
4 Experimental section 4.1 Procedures General Considerations. All reactions with air-­‐ and/or water-­‐sensitive compounds were carried out under dry nitrogen atmosphere using standard Schlenk line techniques. All solvents and 4-­‐picoline were dehydrated and oxygen-­‐free by means of initial treatment with molecular sieves and then purified according to common procedures. All commercially available reagents were purchased from Aldrich except diethylzinc, which was obtained from ABCR. Rac-­‐lactide was purified by recrystallization. Triethylamine was distilled prior to use from KOH and stored over molecular sieves. Acetylacetone, triethyloxonium tetrafluoroborate and 2,6-­‐diisopropylaniline were used as received. Diethylzinc was used as 2M solution in hexane. NMR spectra were recorded on Varian Mercury 400 (400 MHz) spectrometer. Crystallographic data were collected with four-­‐
circle diffractometer (Enraf Nonius FR590). Synthesis of 4-­‐(2,6-­‐diisopropylphenyl)iminopentan-­‐2-­‐one: A solution of 2,6-­‐
diisopropylaniline (10,65 g, 60 mmol) and acetylacetone (6,60 g, 66 mmol) in anhydrous methanol (100 ml) was placed in autoclave and 0,8 ml of formic acid was added. The mixture was stirred for 48 h at 70°C and after cooling to room temperature was extracted with diethyl ether (2x20 ml). Combined organic phases were washed with brine (15 ml) and dried with MgSO4 All volatiles were removed in vacuo and the product was obtained as a brown oil with 76% yield (11,83 g). Product was analyzed by means of gas chromatography. Synthesis of ligand 1: Triethyloxonium tetrafluoroborate (10,45 g, 55 mmol) was dissolved in dichloromethane (44 ml) and the solution was added over a period of 20 minutes to 4-­‐(2,6-­‐diisopropylphenyl)iminopentan-­‐2-­‐one (11,78 g, 45,4 mmol) in dichloromethane (55 ml) under nitrogen atmosphere. The mixture was stirred for 24 h at ambient temperature. An equimolar portion of triethylamine (4,61 g, 45,4 mmol) was slowly added added to the red-­‐brown solution after which it turned to dark-­‐red. After 20 32
minutes hydrazine monohydrate (1,14 g, 22,75 mmol) in triethylamine (20 ml) was added. The mixture was stirred for 80 h. All volatiles were removed in vacuo and the resulting oil was broken with isopropanol. The crude product was filtered and recrystallized from isopropanol to yield 1 as a yellow solid (5,99 g, 11,6 mmol, 25,5%). 1H NMR (400 MHz, C6D6, 25°C): δ = 12,0 (s, 2H, NH), 7,26-­‐7,16 (m, 6H, CHaryl), 4,71 (s, 2H, CH3CNCH), 3,24 (m, 4H, CH(CH3)2), 2,0 (s, 6H, CH3CN), 1,63 (s, 6H, CH3CN), 1,22 (d, 12 H, CH(CH3)2), 1,14 (d, 12 H, CH(CH3)2) ppm. Synthesis of ethyl zinc complex 2: Ligand 1 (166 mg, 0,32 mmol) was dissolved in toluene (4 ml) and diethylzinc solution (0,32 ml) was added at -­‐70°C and then stirred at ambient temperature for 6 h under nitrogen atmosphere. The mixture was concentrated and crystals (yellow blocks) were obtained at -­‐10°C. 1H NMR (400 MHz, C6D6, 25°C): δ = 7,15 (m, 6H, CHaryl), 4,45 (s, 2H, CH3CNCH), 3,15 (sept, 4H, CH(CH3)2), 2,1 (s, 6H, CH3CN), 1,59 (s, 6H, CH3CN), 1,30 (t, 6H, CH2CH3), 1,20 (d, 12 H, CH(CH3)2), 1,14 (d, 12 H, CH(CH3)2), 0,39 (q, 4H, CH2CH3) ppm. Synthesis of 4-­‐picoline adduct 3: To a stirred solution of 2 (224 mg, 0,32 mmol) in toluene (4 ml) 4-­‐picoline (0,1 ml) was added. The mixture slightly changed color from brown to red-­‐brown. After 1 h the solution was concentrated in vacuo. The product crystallized at -­‐
10°C as yellow plates. 1H NMR (400 MHz, C6D6, 25°C): δ = 8,48 (d, 4H, NCHpy), 7,15-­‐7,10 (m, 6H, CHaryl), 6,54 (d, 4H, CH3CCHpy), 4,75 (s, 2H, CH3CNCH), 3,20 (dsept, 4H, CH(CH3)2), 2,04 (s, 6H, CH3py), 1,72 (s, 6H, CH3CN), 1,69 (s, 6H, CH3CN) 1,24 (dd, 12 H, CH(CH3)2), 1,22 (t, 6H, CH2CH3), 1,15 (dd, 12 H, CH(CH3)2), 0,31 (dq, 4H, CH2CH3) ppm. Synthesis of ethoxide complex 4: Schlenk flask with a solution of 2 (224 mg, 0,32 mmol) in toluene (4 ml) under nitrogen atmosphere was equipped with special open-­‐end adapter. Dry air was introduced to the vessel and the flask was immediately placed in freezer (-­‐10°C). After 1 h adapter was changed for stopcock. The mixture was concentrated in vacuo and stored at -­‐10°C. Product was obtained as yellow plates. 1H NMR (400 MHz, C6D6, 25°C): δ = 7,15 (m, 12H, CHaryl), 4,51 (s, 4H, CH3CNCH), 3,40 (sept, 8H, CH(CH3)2), 2,10 (s, 12H, CH3CN), 1,94 (t, 12H, CH2CH3), 1,69 (s, 12H, CH3CN), 1,34 (d, 12 H, CH(CH3)2), 1,25 (q, 8H, CH2CH3) 1,23 (d, 12 H, CH(CH3)2) ppm. 33
Polymerization procedure: In the reaction [rac-­‐lactide]/[Zn] = 50. To a stirred solution of 3 in dicholoromethane rac-­‐lactide was added in dichloromethane under nitrogen atmosphere. The reaction was carried out for 24 h and the mixture was quenched with 5% aqueous solution of HCl. The mixture was extracted with CH2Cl2 and combined organic phases were washed with water. Evaporation of the solvent afforded polylactide. 4.2 Characterization data Table 4.1 Crystallographic data
Formula MW [g/mol] Crystal system Space group a [A] b [A] c [A] α [°] β [°] γ [°] V [A3] Z R 34
2 C38H58N4Zn2 701,76 monoclinic P21/c 15,1680(3) 16,2910(4) 20,9420(3) 90,00 132,62 90,00 3807,87 4 10,57 3 C50H72N6Zn2 888,04 orthorhombic Pbca 15,7880(6) 18,7410(8) 32,7400(6) 90,00 90,00 90,00 9687,21 8 9,74 4 C76H116N8O4Zn4 1467,52 orthorhombic Pbcn 15,5410(5) 30,3130(5) 17,1580(10) 90,00 90,00 90,00 8083,04 8 9,61 5 References 1.
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