Organocatalytic Pathway to the Creation of Polymeric Materials with Some Mechanistic Investigations

The overarching theme of my research work involves understanding the mechanistic aspects of dually activated hydrogen-bonding catalyst systems and applying that knowledge to synthesize polymers from some of the less explored monomers. This entailed a thorough approach to some of the already hypothesized mechanisms in the polymer community and building on that with additional perspective on catalytic interactions. The other aspect of my research encompassed the application of these H-bond mediated catalysts in controlled ring-opening polymerization (ROP) of sulfur-based lactones. This allowed the growth in monomer scope using these catalysts for the first time. H-bonding catalysis, particularly the ones involving ureas and thioureas, began about a decade or so ago. The tremendous rise in organocatalytic ring-opening polymerization has sparked a wide range of catalysts developments in the past few years. Due to their lower cost, reduced toxicity and greener approach, the field has been booming ever since its inception. The wide range of architectures in polymer production that were seemingly difficult previously were possible with great control and selectivity. Using a bifunctional catalytic species, either as one unit or two separate entities, monomer activation and chain propagation can be achieved for polymer production. The first chapter in this dissertation delineates on that growth of dual activation process in organocatalysis as a book chapter “Bifunctional and Supramolecular Organocatalysts for Polymerization” in Organic Catalysts for Polymerization. My contribution to this review work has primarily focused on Dual Catalysts, Rate Accelerated Dual Catalysis and Supramolecular Catalysts. In the second chapter, we looked at the binding interaction that inherently is a determining factor in the dual activation process. We obtained binding constants between the cocatalytic pair of thiourea and a set of bases which allowed us to comprehend the reason behind enhanced selectivity and reaction control. Finally, we applied this phenomenon to test its feasibility with a new, very active cocatalyst pair for a wellcontrolled ROP of some common cyclic esters. I was involved in the latter part of this study where I applied our binding interaction knowledge to test via ROP using a commercial base and thiourea. As our understanding of the activation process grew, we determined that a higher order moiety of (thio)urea may prove to be an even better choice for increased rate and selectivity in polyester synthesis. It is with this notion that we developed a tris-urea motif for the monomeric activation of lactones, described in the third chapter. Although a rate acceleration is distinctly demonstrated using such a catalytic species, the molecular weight control or living behavior in ROP was never sacrificed along the way. My part in this study was only limited to the synthesis of this tris-urea catalyst with some initial reaction condition screening. Carrying that knowledge of catalytic interaction with monomer from the initial studies, we delved into the investigation of equilibrium process of the ROP in the fourth chapter. We observed a catalyst dependence on the overall reaction process of lactonebased ROP where a change in reactant and product interaction with the thiourea can be observed. This results in a similar Gibbs free energy difference between monomer to catalyst and polymer to catalyst. As a result, a change in monomer concentration (recoverable) can be seen at the reaction equilibrium with a change in catalyst concentration. This work was mainly performed by me, except the final recovery of the monomer at equilibrium. After this point, the scope of monomers that can undergo this dual activation was broadened with some of the sulfur-based monomers. Since previous literature studies demonstrated poor control in ROP of such monomers with the assistance of metal-based catalysts, the use of H-bonding catalysts was deemed to be very appropriate. With that in mind, I performed the first-ever organocatalyzed ring-opening polymerization of a sulfurized lactone, ε-thionocaprolactone, shown in fifth chapter. Both reaction control and living nature allowed the possibility of copolymer production using this monomer under the same H-bonding catalysis. A range of new polymeric materials were created at the end of this study. From that initial sulfur-based monomer, the study was extended to some of the less explored thionated monomers in sixth chapter. The same H-bonding organocatalysis was implemented here as well for a broad range of larger lactones (macrolactones). Besides validating the mechanistic aspects of these polymerizations, thermodynamics and kinetics of reaction were also evaluated. As expected for macrolactones over 10 ring sizes, entropic contribution showed dominance over enthalpy which was the case for 9-membered lactones or below. Further material characterizations are currently undergoing to shed light on future applications of these polymers. My contribution to this study involved mainly the synthesis of 8-membered lactones (ζ-heptalactone, ζ-thionoheptalactone), thiono-ethylene brassylate and optimization of reaction conditions for the polymerization of those

the cocatalytic pair of thiourea and a set of bases which allowed us to comprehend the reason behind enhanced selectivity and reaction control. Finally, we applied this phenomenon to test its feasibility with a new, very active cocatalyst pair for a wellcontrolled ROP of some common cyclic esters. I was involved in the latter part of this study where I applied our binding interaction knowledge to test via ROP using a commercial base and thiourea.
As our understanding of the activation process grew, we determined that a higher order moiety of (thio)urea may prove to be an even better choice for increased rate and selectivity in polyester synthesis. It is with this notion that we developed a tris-urea motif for the monomeric activation of lactones, described in the third chapter. Although a rate acceleration is distinctly demonstrated using such a catalytic species, the molecular weight control or living behavior in ROP was never sacrificed along the way. My part in this study was only limited to the synthesis of this tris-urea catalyst with some initial reaction condition screening.
Carrying that knowledge of catalytic interaction with monomer from the initial studies, we delved into the investigation of equilibrium process of the ROP in the fourth chapter. We observed a catalyst dependence on the overall reaction process of lactonebased ROP where a change in reactant and product interaction with the thiourea can be observed. This results in a similar Gibbs free energy difference between monomer to catalyst and polymer to catalyst. As a result, a change in monomer concentration (recoverable) can be seen at the reaction equilibrium with a change in catalyst concentration. This work was mainly performed by me, except the final recovery of the monomer at equilibrium.
After this point, the scope of monomers that can undergo this dual activation was broadened with some of the sulfur-based monomers. Since previous literature studies demonstrated poor control in ROP of such monomers with the assistance of metal-based catalysts, the use of H-bonding catalysts was deemed to be very appropriate. With that in mind, I performed the first-ever organocatalyzed ring-opening polymerization of a sulfurized lactone, ε-thionocaprolactone, shown in fifth chapter. Both reaction control and living nature allowed the possibility of copolymer production using this monomer under the same H-bonding catalysis. A range of new polymeric materials were created at the end of this study.
From that initial sulfur-based monomer, the study was extended to some of the less explored thionated monomers in sixth chapter. The same H-bonding organocatalysis was implemented here as well for a broad range of larger lactones (macrolactones). Besides validating the mechanistic aspects of these polymerizations, thermodynamics and kinetics of reaction were also evaluated. As expected for macrolactones over 10 ring sizes, entropic contribution showed dominance over enthalpy which was the case for 9-membered lactones or below. Further material characterizations are currently undergoing to shed light on future applications of these polymers. My contribution to this study involved mainly the synthesis of 8-membered lactones (ζ-heptalactone, ζ-thionoheptalactone), thiono-ethylene brassylate and optimization of reaction conditions for the polymerization of those monomers.
In the seventh chapter, I have included some of the other thionated monomer synthesis besides lactones and their preliminary ROP results. Though none of those monomers of amides and lactide functionality showed good prospect for organocatalyzed ROP, further growth in tuning the structure of the monomers may demonstrate a better way to synthesize polymers from such systems. Additionally, other applications of these sulfurbased polymers (i.e. newer copolymerizations, crosslinking ability) were reported for possible development in these materials in the future. This chapter fully encompasses all of these unfinished works that can be quite useful for a researcher to pick up at a later time.
The eighth chapter is quite different from the rest of the other chapters in this dissertation in that no organic catalysts were employed for the molecular transformation of styrene to stilbene. In fact, metal catalyst developed by Prof. Robert Grubbs was utilized for this transformation via cross-metathesis reaction. This was a manuscript for educational purpose of undergraduate laboratory setting where the ulitization of a well-known Nobel winning catalyst was used by students to form carbon-carbon bond from an olefinic motif.
My input in this experiment was mainly to assist the co-authors of the manuscript to carry out the reaction properly in the undergraduate laboratory with students comprising mostly of chemistry major as well as formulate a report to aid in the writing portion of the journal publication. for assisting me to be a better researcher over the last few years. In addition, I would like to give special shout out to Dr. Elizabeth Kiesewetter for helping me become adept at my synthetic and laboratory skills from when I started off research in my first year. As an avid follower of cricket, I take inspiration from some of the well-known athletes. In that regard, I would like to thank one such inspirational role model, Mahendra Singh Dhoni, for demonstrating how stresses can be turned into success with a calm, cool attitude at one's goals.
ix                      The purview of the catalysts in this chapter is ring-opening polymerization (ROP), especially of cyclic esters and carbonates. Conceptually, the catalysts in this chapter are ideally suited to effect highly controlled polymerizations. Catalysts for the ROP of lactones and carbonates effect polymerization by 1) activating the chain-end, 2) activating the monomer, or 3) activating both. By separating the roles of monomer and chain-end activation into discrete functions, the dual catalysts can be separately tuned to effect enchainment and thus minimize side reactions. Conceptually, a dual catalyst consists of both a hydrogen bond donor (HBD) (e.g. urea or thiourea) for monomer activation and a hydrogen bond acceptor (HBA) (e.g. tertiary amines) for chain-end activation. Such dual catalysts may be a single molecule, but in common practice, bimolecular cocatalysts are employed to activate monomer and initiator alcohol/chain end separately, Scheme 1.1.

LIST OF TABLES
The fountainhead of dual catalysis is undoubtedly the 2005 manuscript and its follow-up from Hedrick and Waymouth. 3,4 The roots of organocatalysis reach back more than 100 years to synthesis of quinine alkaloids, 5 and, in fact, organocatalysts were among the earliest catalysts for the synthesis of polyesters. 6 The renaissance of organocatalysis circa 2000 saw the application of supramolecular catalysts for small molecule synthesis. 7 However, it was the veritable Johnny Appleseeds of organocatalytic polymerization that disclosed supramolecular catalysts for ROP along their continuing journey of discovery and subsequently nurtured field such that it now encompasses many branches of questioning by several research groups. 4 The first supramolecular catalyst for ROP (the Takemoto catalyst, 1, Figure 1.1) was adapted from the work of Takemoto, who used chiral H-bonding catalysts for asymmetric Michael reactions. 8 The thiourea/amine base catalyst 1 was introduced into the polymerization community for the organocatalytic ROP of lactide. 4 The inspired (and somewhat miraculous) step of separating the roles of HBD and HBA into discrete cocatalysts facilitated modulation of the individual cocatalysts leading to the ROP of other monomers and launched a field, Figure 1.1. 3,4 The class of organic molecules that effects catalysis via supramolecular interactions are among the most controlled catalysts available for ROP. Part of this is due to the modular, highly-tunable nature of dual catalysts, which effect extremely controlled ROP (PDI = Ð = Dm = Mw/Mn < 1.1) of a host of different cyclic monomers. 9,10 Most of the research in the field of dual catalysis for organic polymerizations has been dedicated to the ROP of cyclic esters and carbonates; however, other monomers will be mentioned. Dual catalysts effect living polymerizations, which is a type of chain growth polymerization that proceeds without chain-transfer or termination. 11 This is ultimately a kinetic distinction, and it is often said that a polymerization exhibits the characteristics of a 'living'  11 In practice, these conditions arise when a polymerization has a fast initiation rate relative to propagation rate and few to no side reactions. We shall refrain from pointing out when a catalyst (system) exhibits the characteristics of a 'living' polymerization, and rather point out when it is either especially well-controlled or exhibits low levels of control.
Several, thorough reviews have been conducted in the wider field, 12-21 but not with quite the level of focus that the current platform provides. Hence, we will attempt to emphasize the virtues and deficits of the various catalysts, especially as they contrast to other organic catalysts for polymerization.

DUAL CATALYSTS
The dual catalysts for polymerization are a logical mechanistic conclusion of early organocatalysts for ROP, and H-bond mediated (supramolecular) polymerization mechanisms have been implicated for catalysts in a host of architectures. 2,[22][23][24] For example, the pyridine bases 4-(dimethylamino)pyridine (DMAP) and 4pyrrolidinopyridine (PPY) have been proposed to effect the zwitterionic ROP of lactones. [25][26][27][28] However, subsequent mechanistic studies suggest that the nucleophilic and H-bonding pathways are both accessible with the hydrogen-bonded pathway being energetically favorable. [29][30][31][32] An alcohol-activated mechanism of enchainment has been proposed for the phosphazene bases (e.g. P1-tBu, P2-tBu, t-BuP4, BEMP in Figure  The dual catalysis conceptual approach of separately activating the monomer and propagating chain end arises from these early organocatalysts which often suffered from low activity or reaction control. 4 Thiourea-mediated Stereoselective ROP The stereoselective ROP of rac-lactide is an attractive method for the generation of polylactides (PLAs) with highly regular or novel stereosequences, and the modular scaffold and rich diversity of chiral thiourea H-bond donors has proved an enticing target for several groups. The ROP of rac-or meso-lactide to generate highly tactic PLA has been well documented. [69][70][71] Briefly, stereoselective enchainment of the chiral monomer onto the chiral chain end can occur via control rendered by 1) the propagating chain end, 2) a chiral catalyst or 3) a mixed mechanism. 69,72,73 For the ROP of rac-LA, a high probability of propagating with retention of stereochemistry (Pm = probability of meso enchainment) will result in a highly isotactic PLA. 3,69 Waymouth and Hedrick reported the (R,R)-1 mediated ROP of rac-lactide to proceed with modest selectivity (Pm = 0.76); however, 2/(-)-sparteine catalyzed ROP of rac-LA rendered similar selectivity (Pm = 0.77). 3 The polymers did not display a melting point, suggesting low stereoregularity. 3 Exceeding these Pm values has become a benchmark of sorts for the stereoselective ROP of rac-lactide by H-bonding catalysts. Despite its successes, (-)-sparteine itself fell out of favor as an organocatalyst when it became scarce circa 2010, but a replacement base, benzyl bispidine, was disclosed which renders similar reaction rates and selectivity in the ROP of rac-lactide with 2, Pm = 0.74. 47,74 Recent research into photoresponsive azobenzene-based thiourea, 3, for the ROP of rac-lactide suggests a conceptual approach to switchable organocatalysts for ROP. 75,76 Catalysts that are switchable by external stimuli (i.e. redox pathways, lights, coordination chemistry etc.) 76 75 The ROP was proposed to proceed from the trans-isomer, presumably via a chain-end control mechanism. 3, 75 We make the safe prediction that switchable organic catalysts for ROP will play an important role in the next decade. 76 An activated-(thio)urea mechanism is proposed for multi-H-bond donor mediated ROP in non-polar solvent, but urea H-bond donors remain highly-active in polar solvent.
Kinetic studies on the several systems in benzene-d6 reveal the (thio)urea ROPs to be first order in monomer, initiator, and cocatalysts, suggesting one mono-/bis-/tris-H-bond donor acting at one monomer in the transition state. 48,53,54,105 H-bonds are electrostatic in nature and have low directionality, 106 which allows for the possibility of multi-(thio)ureas directly activating monomer in a multi-activation mechanism. Computational models suggest that tristhiourea 14 is C3 symmetric (all H-bonded), 105 and an analogue of 15 with n-propyl (versus ethyl) linking arms is highly inactive for ROP, 107 suggesting that the (thio)urea moieties prefer to bind to themselves. These experiments, along with computational studies, suggest an activated-(thio)urea mechanism is operative in non-polar solvent. 105 Traditional H-bonding catalysts (e.g. 2/base) become very inactive in polar solvent, which limits their utility. 3 The urea HBDs, however, remain highly active in polar solvents (e.g. acetone and THF). 105,108 Recent, and still-evolving, studies suggest that a different mechanism involving urea anions is operative in polar solvent. [58][59][60] Urea and Thiourea Anions The deprotonation of urea or thiourea with strong bases (alkoxides or metal hydrides) has been shown to produce the corresponding urea anion or thiourea anion (also: imidate or thioimidate) which are incredibly active for the ROP of lactones. 59 59,60 Polymerizations with VL and CL were also completed within seconds. 59 An ROP with similar activity can be achieved by a urea (e.g. 16) plus strong organic base (e.g. MTBD, DBU, BEMP) cocatalyzed ROP. 108 The latter method may be operationally simpler, and urea plus organic base cocatalyzed ROP may be more controlled, especially post polymerization. 108 The rates of the two methods appear to be very similar and mark a departure from early H-bond mediated ROP: seconds instead of hours or days! Remarkably, the ROPs remain highly controlled.  102,109 This mechanism is reminiscent of a bifunctional TBD-mediated ROP of lactones, 23,59 where the imidate can serve as both H-bond donor and acceptor. This same mechanism is believed to be operative for bis-and tris-urea H-bond donors in polar solvent as well. 48,53,105,108 An antibacterial compound, triclocarban (TCC, Scheme 1.6), was shown to be a very effective H-bond donating catalyst for the ROP of lactones when used with organic base cocatalysts. 108 It was proposed that this compound effects ROP through the same mechanism as other urea/strong base mediated polymerizations, and TCC/BEMP displays the same approximate rate and control behavior as trisurea (15)/BEMP, although the trisurea is more active (k15/kTCC ~4, VL). 105,108 We anticipate that the movement towards readily available reagents will prompt wider adoption of organocatalysts and facilitate new applications; the success of TBD may be due, at least in part, to its commercial availability.
To demonstrate this point, TCC/base cocatalyzed ROP was applied to the solvent-free polymerization of several lactones, which was previously limited due to 1) the presumed inactivity of urea HBDs in polar (monomer) solvent, and 2) the large amounts of catalyst required for neat conditions. 58 Solvent-free ROP catalyzed by TCC/base allowed for the one-pot synthesis of di-and tri-block copolymers, and TCC/alkylamines were effective for the solvent-free ROP of LA, 58 a longstanding challenge. 110 The reactions remained highly controlled and 'living' in nature despite solidifying prior to full conversion. Benzoic acid, which is widely used to quench organic catalysts by protonating amine bases, 2 forms an active ROP cocatalyst when mixed 1:1 with DBU. 128 137 Computational studies suggest that strong interactions are seen between 1-pyrenemethanol and the phenolate anion of m-betaine (relative to the other isomers), which is consistent with the rapid ROP with m-betaine versus the p-and oisomers. 137 Amino-Oxazoline The structures of amino-oxazolines and thiazolines are analogous to that of TBD.
An initial screening of the thiazoline catalyzed ROP of LA determined that thiazolines with electron withdrawing groups resulted in reduced ROP activity and produced atactic PLA. 139  Mechanistic studies suggest that ROP is initiated from the CD and that the lactone/CD inclusion complex is vital to catalysis. When ROP is attempted using an acylated CD (no free hydroxyls), no conversion to polylactone is observed, which suggests that CDs are covalently attached to the polylactone chain end in a normal CD-catalyzed ROP. 140 Further, suppression of the ROP of VL was noted with a β-CD/adamantane inclusion complex catalyst system. The adamantane guest is strongly inserted in the β-CD cavity, which excludes VL, suggesting that lactone/CD inclusion complexes are essential for ROP. 140 The mechanistic picture that emerges suggests that, initially, a complex is formed between lactone and CD at a ratio of 1:1, and a hydroxyl group at the C2-position attacks the monomer to begin enchainment. Further development of these or similar extremely mild catalysts for ROP could provide new and exciting methods of ultracontrolled ROP.

CONCLUSION
The narrative of this chapter can be summarized by following the circular evolution of dual catalysts away from and back towards the popular organocatalyst, TBD. When the TBD catalyzed ROP of lactones was disclosed in 2006, 23 it was the perfect storm of a successful catalyst. It is easy to use, readily available, highly active and exhibits decent selectivity for monomer and control (Mw/Mn ~ 1.2). While TBD was originally proposed to operate via a nucleophilic mechanism of enchainment, an H-bond mediated, bifunctional, mechanism was also envisaged. 23 This mechanism has been much debated, and it is not entirely certain which mechanism is operative and when. 32

INTRODUCTION
The multitude of polymer architectures and constructs that can be generated via organocatalytic ring-opening polymerization (ROP) is largely driven by the precise level of reaction control engendered by the catalysts. 1 4,5,18 The exact balance of interactions that must exist for a "living" ROP to occur is impressive, 6 and deep mechanistic insights into the robust and diverse set of H-bonding ROP organocatalysts will be the driving force for the development of the improved catalysts which precede new materials. In the following, we present evidence that 1 and amine base cocatalysts are highly associated in solution and that this binding is productive rather than inhibitory toward the high activity and selectivity of these 1/amine base systems. This increased mechanistic understanding is applied to the discovery of a new cocatalyst pair for ROP.  The determination of binding constants from the slope of the linear (Lineweaver-Burke) forms of the binding equation (above) has several benefits over fitting the binding curve. 20 It should be noted that the linearized form of the binding equations are rigorously true and can be derived from the equilibrium expression using simple algebra. 21 Very accurate data can be obtained with fewer data points (versus curve fitting) because experimental errors from inaccurate concentration are attenuated in the linearized form. For this method, the accuracy of Keq versus number of data points has been tested in the literature and shown to be highly accurate with 5 data points. 22 These studies even omitted the plateau of the binding curve, 22   This magnitude of binding constant was not thought to be inhibitory to catalysis, but the same study ascribed the reduced activity of some more strongly binding cocatalysts to an undesirable H-bond equilibrium that reduces the effective concentration of catalyst through self-inhibition. 6 Table 2.3). Such strong interactions have previously been posited (vide infra) between Coulombically tethered cocatalysts, 15 and strong cocatalyst binding is not necessarily inhibitory to ROP. All binding processes are reversible and rapid on the NMR time scale, and the ROP is determined by the approach to the equilibrium monomer concentration, [VL]eq. The strong 1·DBU binding constant may simply act in concert with other known interactions (1·VL and DBU·benzyl alcohol; Eqs. 1 and 2) to hold all reagents in close proximity during a rapid exchange of binding partners, thereby accelerating the reaction. 26 However, the kinetic data suggest that the strong binding could serve to make a distinct catalytic species. 27 The binding and kinetic data collectively describe a reaction process where highly self-associated cocatalysts can be cooperatively interrupted by VL and alcohol to result in a reaction turnover (Scheme 2.2).
The selectivity of 1/DBU for monomer in the ROP of VL can be rationalized by the magnitude of the 1·DBU binding constant. This selectivity has previously been attributed to the preference of 1 to bind to s-cis esters (monomers) versus s-trans esters (polymer backbone); 5 however, some 1/amine base combinations result in almost zero transesterification of the resultant polymer after 4 h. 28 The very dependence of postpolymerization transesterification upon the identity of the base cocatalyst suggests that factors other than the 1·ester binding constants control ROP selectivity. Indeed, the identity of the base cocatalyst dominates the equilibria which describe the ability of ethyl acetate (a surrogate for polymer, which exhibits a small but nonzero binding to 1) 5 to interrupt the 1·DBU pair (Eq. 2.4) versus that of VL (Eq. 2.5). These values (Keq = 0.003 vs Keq = 0.13, respectively), which can be found through thermodynamic sums, could account for the high selectivity of the ROP reaction. Further, altering the base cocatalyst would be expected to drastically alter the cocatalyst selectivity for monomer, as empirically observed. [1][2][3][4]28 Our study was continued on a variety of base cocatalysts (with 1) for ROP, and a relationship between cocatalyst binding and ROP activity was discovered. Binding constants to 1 in C6D6 were measured by either the dilution or titration method 19 values were also measured for each of these bases (see Table 2.  Table 2.1. In general, a strong 1·base binding constant is associated with rapid ROP, and weakly binding cocatalysts exhibit very low or zero ROP activity.
In the low binding constant regime, Keq correlates with polymerization rate, and cocatalyst binding constant appears to be a better predictor of catalytic activity than does pKa. The kobs for the systems that exhibited weak binding (1 with DMAP, pyridine, or proton sponge) were measured for the 1/base catalyzed ROP of L-lactide (LA) ( Further studies show that 1/BEMP is active for the ROP of VL, ε-caprolactone (CL), and trimethylene carbonate (TMC) but is inactive for β-butyrolactone (BL) ( Table 2.2). The For the organocatalytic ROP cocatalysts examined, the magnitude of the cocatalyst binding constant has been shown to be proportional to the ROP rate. For the bases studied, cocatalyst binding constant is a far better predictor of catalytic activity than pKa. The strongly binding 1/DBU system behaves kinetically as a unimolecular catalyst species, and it could be representative of a hydrogen-bonding analogue of so-called "cooperative ion pairing" in asymmetric organocatalysis. 27 We agree with the conclusion of Bibal et al. that TU/amine base binding can be inhibitory to ROP 6,7 but submit that (1)

INTRODUCTION
The H-bonding catalysts for ring-opening polymerization (ROP) stand out among the highly controlled polymerization methods for their ability to tolerate functional groups while precisely controlling molecular weight and polydispersity. 1-7 H-bond donating cocatalysts are believed to effect a "living" ROP via dual activation of monomer by a Hbond donor, usually a thiourea (TU), and activation of alcohol chain end by base cocatalyst. 8,9 The exquisite and remarkable combination of rate and selectivity present in other fields (e.g., olefin polymerization catalysis) 10,11 has yet to be paralleled in organocatalytic ROP, especially H-bond mediated transformations. The development of organocatalysts for polymerization has largely proceeded along divergent pathways toward highly selective 1,9,[12][13][14][15] or highly active [16][17][18][19] catalysts. Indeed, the low activity of organocatalysts for ROP has been specifically identified as a shortcoming of the field, whereas highly active metal-containing catalysts for ROP are well-known. 20, 21 We recently disclosed a bisthiourea (bisTU) H-bond donating cocatalyst, 2-S in Figure 3.1, for the ROP of L-lactide (LA), which displayed enhanced catalytic activity (over monoTU), but no reduction in reaction control. 22 During the process of extending the utility of this system to other lactone monomers, we developed a trisurea (trisU, 3-O in Figure  but when applied with a H-bond accepting cocatalyst, it is the most active ROP organocatalyst known, and one whose enhanced rate does not come at the expense of reaction control, Scheme 3.1.

General Considerations
All manipulations were performed in an MBRAUN stainless steel glovebox equipped with a gas purification system or using Schlenk technique under a nitrogen atmosphere. All chemicals were purchased from Fischer Scientific and used as received unless stated otherwise. Tetrahydrofuran and dichloromethane were dried on an Innovative Technologies solvent purification system with alumina columns and nitrogen working gas.

RESULTS AND DISCUSSION
The effects of bisTU on the ROP of δ-valerolactone (VL) and ε-caprolactone (CL) were evaluated, and the rate acceleration in the presence of 2-S versus 1-S is general to both lactone monomers. For the ROP of either VL or CL (2 M, 100 mg) from benzyl alcohol in C6D6, the application of 2-S/MTBD (2.5 mol % each) produces a rate acceleration over the traditional monothiourea (1-S/MTBD 5 mol % each) that is not associated with loss of reaction control, Table 3 This is consistent with previous suggestions that H-bond-mediated ROP operates via dual activation of monomer by 1 and of alcohol chain end by base. 1 Because H-bonds require no orbital overlap and are electrostatic in nature, 26 we cannot rule out a dual-thiourea activated mechanism, Eq. 1. However, computational studies for the activation of lactones by 2-S suggest an activated-TU mechanism is preferred over a dual-thiourea activation mechanism, Eq. 1; this assertion is also supported by the 2-S/alkylamine cocatalyzed ROP of lactide. 22,27 The series of thiourea H-bond donating catalysts was extended to a trisTU H-bond donor, 3-S, but this catalyst exhibits significantly reduced activity versus 1-S or 2-S in the TU/base cocatalyzed ROP of lactones,   Table 3.4). previous reports that suggest that H-bond donors featuring multiple (thio)urea moieties activate one reagent prior to the TU-reagent complex undergoing further chemistry, 22,32 and it is also consistent with a report of a urea-thiourea H-bond donating catalyst, which was proposed to be operative via an activated-(thio)urea mechanism. 28 Indeed, 1  A multiurea activated mechanism (e.g., Eq. 1), which is reminiscent of a solvophobic pocket, cannot be ruled out. However, the marked inefficacy toward ROP of 3-S, which is geometrically able to adopt a conformation featuring strong intramolecular H-bonds (see Figure 3.15 and 3. 16), suggests that the activated-urea mechanism is the more robust proposal.
Among catalysts for the ROP of lactones, the 3-O/base cocatalysts stand out due to the extremely rapid rate that they exhibit at room temperature. For comparison, we conducted the ROP of CL (2 M) from benzyl alcohol (1 mol %) with the bifunctional catalyst TBD, Table 3.2. The guanidine base, TBD (Figure 3.1), has been regarded as one of the most active organocatalysts available for the ROP of lactones. 16 The TBD catalyzed ROP of CL from benzyl alcohol ( In small molecule transformations, urea H-bond donating catalysts have been observed to possess similar activity to their heavy chalcogen counterparts. 33 The development of urea and thiourea H-bond donating catalysts continued apace until the turn of the millennium when several reports emerged that extolled the operational (e.g., increased solubility) 34,35 and synthetic (e.g., higher yields and enantioselectivities) [35][36][37] benefits of thioureas over ureas. In our estimation, the ubiquity of the thiourea motif in Hbond mediated transformations may be more due to the coincidental timing of these reports than any general superiority of thioureas over urea H-bonding catalysts. Indeed, ureas are more polar than thioureas and should be expected to be better H-bond activators, 33  are all operative in CH2Cl2, CHCl3, and THF albeit with slightly reduced reaction rates or Mw/Mn (see Table 3.5).
Preliminary studies suggest that these catalysts exhibit the same reactivity trends in small molecule transesterification and, hence, may have general applicability beyond ROP.
The transesterification of ethyl acetate (1.6 M) with benzyl alcohol (1.6 M) was conducted in C6D6. Observed rate constants (kobs) at early reaction time were measured for each Hbond donor/MTBD cocatalyzed transesterification. These rate constants show the same trends in catalyst activity that were observed for the ROP reactions: 3-O is the most rapid catalyst and it is 1−2 orders of magnitude more rapid than 1-S, (see Table 3.3). This suggests a general role for the increased activation of esters by urea H-bond donors (vs thioureas), yet the slower rates for the transesterification of s-trans (vs s-cis) esters accounts for the low rate of transesterification postpolymerization, (see Table 3.6).

3-O in vacuum
The effective concentration of 1, [1]EFF, is defined to be that in excess of DBU: Insert eq. S4 into eq. S3: Thiourea as catalyst interpretation: * + + ⇋ • + * (9) • + * ⇋ * + Insert definition of Keq10 into (S11) to get: (S12) Rearrange and insert eq. 7 into eq. S12 and rearrange to get: Insert eq. S4 into eq. S13: [ • ] +                Our group recently disclosed the ROP of an S-substituted lactone, εthiocaprolactone (tCL). 9 The ROP of this monomer was postulated to proceed through a classic transesterification mechanism mediated by H-bond activation of thioester by thiourea and thiol end group by base. 9 The other S-substituted caprolactone, εthionocaprolactone (tnCL, Scheme 5.1), has been the subject of only two published reports. 10,11 Under cationic polymerization conditions, the ROP of tnCL proceeds with quantitative inversion of substitution at the thionoester to generate the same poly(thiocaprolactone) previously reported by Overberger and our group. 9,12-14 The anionic ROP of tnCL from alkyllithium reagents retains the S-carbonyl substitution, but reaction control suffers, and this method does not allow for Mn control, copolymerization, or end group selection. 10

Determination of Binding Constant (Keq) between TnCL and 1
The binding constant (Keq) between 1 and tnCL was determined in benzene-d6 by the titration method and curve fitting as previously described. 20 is generated from ε-caprolactone (CL) via a one-step reaction with P4S10 (see Experimental Section); the reaction is workable on at least a 2 g scale (75% yield). 16,17 The application of DBU (5 mol %; Table 5  PtnCL was previously only available through the application of alkyllithiums at elevated temperatures which resulted in the uncontrolled ROP of tnCL. 10 Endo's ROP of tnCL initiated from DBU at elevated temperatures was more controlled than the alkyllithium ROP but resulted in scrambling of the S/O substitution (Scheme 5.1). 10  which suggests that the thiono/thio switching observed by Endo 10 is simply due to heating the reaction solution.
The application of the phosphazene base, BEMP (

Role of Thiourea in ROP
The presence of the thiocarbonyl in tnCL was expected to perturb the ability of Hbond donors to activate the monomer for ROP, yet the addition of thiourea 1 to the ROP solution clearly affects the course of the reaction. An NMR titration study [21][22][23] was conducted in C6D6 to determine the binding constant between 1 and tnCL, Keq = 1.6 ± 0.2 (in Eq. 5.1). The comparable binding between CL and TU was measured to be Keq = 42 ± 5.7 and a similarly dramatic perturbation from this latter strong binding value was previously measured for tCL, Keq = 2.7 ± 0.5. 9 The remarkable ability of 1 to activate tnCL and tCL toward ROP despite the weak binding exhibited by 1 toward these monomers suggests an incongruity in the approximation of "magnitude of binding" as "extent of activation". The low ceiling temperature of tnCL accounts for the low monomer conversions which are observed when the ROP of tnCL is attempted at elevated temperatures. 10 Kinetically, tnCL is more reactive than VL. VL will not undergo ROP in the presence of MTBD or DBU alone (no 1), and the increased reactivity of tnCL (vs VL) is attributed to the increased electophilicity of thionoesters (vs esters). In contrast, the thioester, tCL, was observed to exhibit behavior that is both more and less reactive than VL. 9 Copolymerization with δ-Valerolactone The observation of similar ROP thermodynamics for tnCL and VL suggests that random copolymerizations of these two monomers are possible.  Figure   5.14). The monomer feed can be adjusted to higher or lower VL/tnCL ratios to give gradient copolymers. 13 C NMR analyses also confirm the retention of C=S substitution in the copolymers (see Figure 5.14). Whereas PtnCL is an oil at room temperature for all molecular weights examined in our lab (<20 kg/mol), copolymers of tnCL and VL with greater than 70% VL are solid at room temperature. The materials properties (Tm, Tc, and Tdeg) of P(tnCL-co-VL) with varying tnCL content were analyzed by differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA, under N2). Polymers with increasing tnCL content show predictably reduced Tm, Tc, and Tdeg (Table 5.    Minor peaks could not be identified, but they are not consistent with H+, Li+, Na+ or K+ adducts of cyclic or linear PtnCL with benzyl alcohol or BEMP end groups.                          :

INTRODUCTION
Ring-opening polymerization (ROP) has come a long way with the advent of organocatalysis in 2001. 1 The range of monomers that have undergone polymerization by this technique using commercially available and cheaply synthesized catalyst systems have enabled a vast array of polymers to be produced with excellent rate, selectivity and control. [2][3][4][5] As our worldly demand for polyester production increases over the years for biomedical, plastics and microelectronic applications, the need for suitable, fine-tuned materials are also necessitated to meet those requirements. [6][7][8][9][10] If the pathways to make such materials are following organic catalytic systems, then the industrial viability of these processes are also attractive from a commercial perspective. Thus, research has been focused on expanding the polymer community's understanding of a breadth of monomers with organocatalysis over the past few decades. 1,4,[11][12][13][14] As the suite of monomers have extended over the years, some of the thiono-derivatives of lactones for polyesters have not been studied with organic catalysts which will be the aim of this manuscript.
Huisgen et. al. has looked at a range of lactones with different ring sizes along with their physical properties after ROP in 1950s. [15][16][17] Enzymatic catalysis with lipases i.e.
Novozym-435 have been conducted since then on many of these larger lactones (macrolactones). [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] Although it is apparent that dipole moments is one of the principal factors that can alter the physical properties (i.e. melting point and enthalpy of melting) of the polymers from these macrolactones, other factors like monomeric electrophilicity and enzyme-activated monomer intermediate formation could also play significant role in the enzymatic ring-opening polymerizations (eROP) based on previous studies. 18 Additionally, in the hydrolysis of these monomers, eROP can be governed by reaction temperature, solvent and initiator choice, and concentrations of enzymes and water content. 18 Other metal-based catalysts like tin (II) octoate have also been employed in the ROP of certain macrolactones. 13,19,[36][37][38][39][40][41] The trans-conformation in those systems were principally responsible for dictating the reduced energy level at ground state as ring strain becomes almost negligible and the cyclic lactones begin to act as open chain esters. 18 Metal alkoxides have also been implemented in the ROP of some lactones where equilibrium is generally reached rapidly in which the initiation process supersedes propagation and almost full elimination of termination. 19 We decided to study some of these strained and non-strained lactones and their thiono-counterparts in this following manuscript, namely, ζ-heptalactone (HL), ζthionoheptalactone (tnHL), η-nonalactone (NL), η-thionononalactone (tnNL), ωpentadecalactone (PDL), ω-thionopentadecalactone (tnPDL), ethylene brassylate (EB) and thiono-ethylene brassylate (tnEB) as shown in Scheme 6.1. There has been very few literature publications on the 8-and 9-membered lactones where eROP was exercised in the understanding of kinetics and thermodynamics of these macrolides, though copolymers with these monomers have been reported. 18,19,38,[42][43][44][45][46][47] A growth in research has been observed over the past few years in the production of macrolactones like PDL and EB due to their ductile and tensile enhancement as hydrophobicity augmented with increased alkyl chains. 20,37,[48][49][50][51][52][53] Hydrolytic degradation was also observed to have enriched for these polymers as metal catalysts i.e. zinc, yttrium, aluminum, magnesium were employed in the ROP for these substrates. The procedure to synthesize ζ-heptalactone (ζ-HL) was adopted from previous literatures with some modifications. 73,74 Initially, appropriate amount of m-CPBA (4.6 g, 18 mmol) was subjected to a round bottom flask, followed by the addition of dichloromethane (50 mL) and cycloheptanone (2.10 mL, 27 mmol). The reaction mixture was stirred at moderate speed for 5 days after which the reaction was quenched with 10% (w/v) sodium thiosulfate. The mixture was then washed with sodium bicarbonate followed by extraction with dichloromethane thrice. After drying with sodium sulfate, rotary evaporation was performed to yield a colorless oil. This oil was then purified by silica gel column chromatography with 1:1 mixture of ethyl acetate and hexane. Yield: 2.17 g, 95%.
Product matched previous literature characterization. 73,74 Synthesis of ζ-Thionoheptalactone (tnHL) This procedure for the synthesis of ζ-thionoheptalactone (tnHL) was also adapted from a previous literature study with some modifications. 75 71,75,77 Synthesis of η-Nonalactone (NL) Previous literature procedure was followed for the synthesis of η-nonalactone (η-NL) with few modifications. 51 Following this purification step, distillation with Kugelrohr was performed for about one hour at 40°C and 100 mtorr to yield a colorless oil as the product in 33% yield (3.22 g).
Product was validated with previous literature characterization. 51,78 Synthesis of η-Thionononalactone (tnNL) The procedure for the synthesis of η-thionononalactone (tnNL) was adapted from a previous literature study as well with some alterations. 77 Just like tnCL synthesis, 70

RESULTS AND DISCUSSION
Organocatalyzed ROP of HL and tnHL Similar to the tnCL approach previously studied by our group, 70  previous studies performed in our group with δ-valerolactone and ε-caprolactone. 80 Few other catalysts like 2 in conjunction with MTBD or BEMP were also tried. Though known to be quite strong in binding with a cocatalyst pair from a previous study, 81 DBU also showed remarkable control in polymer weight and polydispersity with a slower rate of ROP (see Table 6.1). A living characteristic feature was observed with increased monomer evolution to polymer by weight and narrow polydispersity when TCC/MTBD were implemented in the ROP of HL in benzene-d6 (see Figure 6.8a). A first-order kinetic rate plot also further demonstrated the living behavior of this system (see Figure 6.9a).
After the successful ROP performed by organocatalysis for HL, the thionated counterpart, tnHL, was underway. As depicted in Table 6.2, TCC/BEMP-catalyzed ROP of tnHL at 2 M concentration in C6D6 produced polymer faster than TCC/MTBD at 5 mol% loading, imitated from 1 mol% benzyl alcohol. This is quite contrasting to the ROP behavior of CL versus tnCL in terms of the rate. With a mono-thiourea motif, it was shown previously that tnCL could produce polymer faster than CL under the same conditions. 70,80 Since ureas could facilitate ROP by an imidate-like mechanism, 80,82 it is quite possible that the rate could change drastically between oxygenated and thionated systems. The application of 2 with MTBD further validated this point as the reaction slowed down significantly, while BEMP-catalyzed one did not proceed at all to the desired polymer. The H-bonding mechanism is possibly weaker with these larger ring systems which might be the cause of slow growth of polymer. A stronger phosphazene base like BEMP may become inhibitory to the polymer growth completely. However, TBD-catalyzed ROP of tnHL was the fastest, demonstrating the dual activation of monomer and initiation of the alcohol at the same time (see Table 6.2). This corroborates quite well with the TCC/base mediated catalysis, if the imidate-like mechanism is believed to be at play. Similar to the HL data, a linear evolution of molecular weight versus conversion portrayed the livingness of this system along with narrow polydispersity (see Figure 6.8b). A first-order kinetics plot also proved this point further (see Figure 6.9b).

Organocatalyzed ROP of NL and tnNL
Just like HL, the 9-membered oxygenated lactone, NL, was screened for optimal conditions of ROP. As before, the fastest organocatalyst systems, TCC and 2 were tried with different bases, MTBD, BEMP and DBU. Although a screening of solvents were also performed from tetrahydrofuran, dichloromethane, chloroform-d to benzene, toluene and acetone. Due to solubility preference, acetone was displayed to be the best solvent where TCC/BEMP produced controlled PNL in little over a day (entry-2, Table 6.3). A good control of molecular weight was also observed in both these systems with relatively narrow polydispersity. 18,19,26,44,45,83 Even though 2/BEMP produced PNL in benzene, molecular weight and polydispersity was not better than TCC/BEMP catalyzed ROP in acetone (entry-3, Table 6.3). A living nature of the polymerization system was observed with linear evolution of Mn versus conversion to polymer (see Figure 6.10a). A first-order kinetic plot also demonstrated the controlled behavior in the ROP of NL (Figure 6.11a).
Since TCC and 2 have been shown previously to perform ROP with fast rate from our previous studies, 71,80 these were again implemented to thionated NL (tnNL). Due to solubility, acetone was again the preferred solvent for ROP of tnNL, especially when catalyzed by TCC. No polymer was produced when 2 was used, either in conjunction BEMP, one of the best performing bases demonstrated before. 81 However, TCC was able to form PtnNL with BEMP (5 mol% of cocatalyst pair) at a much faster rate than PNL with relatively good control in molecular weight and polydispersity index (see Table   6.4). 18,19,45,83 The MTBD-catalyzed ROP of the same monomer in comparable conditions only produced about 75% of PtnNL (Table 6.4). An increase in molecular weight (Mn) versus conversion to polymer was observed with steady hold on polydispersity (see Figure   6.10b). A first-order kinetic plot was also indicative of the living trend of tnNL polymerization ( Figure 6.11b).
As shown by HL and tnHL, these 9-membered lactone systems also exhibited polymerization by the imidate-like mechanism we had proposed previously. This is particularly exemplified with tnNL where ROP was only possible with TCC, but not 2. Hbonding mechanism might not be at play as 3 was unable to produce polymer at all for NL (Table 6.4) and no polymerization took place for tnNL in conjunction with 2. Further studies need to be performed, in terms of molecular modeling to understand whether or not the cis/trans-isomerism is behind the poor or complete disfavor of H-bonding mechanism of these 9-membered lactones. Although enzymatic catalysis was performed for the oxygenated lactone before, high conversion, molecular weight and narrow polydispersity were always a challenge. Even though copolymers produced of these monomer with other lactones showed good control, complete homopolymerization with organic H-bond donating catalysts were never performed for these monomers. More investigation with binding and computer modeling may help to comprehend the overall mechanism for the ROP of NL and tnNL in the future.

Organocatalyzed ROP of tnPDL
The sulfur-containing thionated PDL (tnPDL) has not been studied with organic catalytic systems even though the oxygenated PDL is well studied. 20,27,38,39,50,84 Our approach to the ROP of tnPDL was mainly inspired from Dove's report. 50 Since it is welldocumented that lactones of larger ring sizes chiefly polymerize at an elevated temperature due to entropic contribution as the driving force of the reaction, 85,86 we attempted the same scenario with our fast known catalysts, TCC and 2 at a much higher monomer concentration (5 M) than usual. Similar to tnNL, no polymers were produced when 2 or 4 were used (Table 6.5). TCC was able to generate polymer with almost full conversion while displaying poor handle on polymer dispersity and molecular weight control ( conversion (see Table 6.6). This is quite consistent with previous ROP results of EB in toluene where 44% polymeric conversion is reached while neat conditions produced almost full conversion. 48,54 This is also in correlation with what can be expected of macrolactones of this size where entropy is driving the reaction forward with minimal or negligible contribution from enthalpy toward the polymeric process. 89 In fact, when we tried to obtain a Van't Hoff plot of the polymerization process of this system, we did not see any enthalpic impact on the reaction and only entropic contribution which was within NMR error.

Thermodynamics of Macrolactones
We had performed ROP of larger lactones (or macrolactones), especially tnPDL and tnEB to validate entropic driving force for these polymerization reactions. In fact, all the macrolactones, both oxygenated or thionated, demonstrated almost zero to very negligible enthalpic contribution while entropy was quite substantial compared to smaller lactones, like HL and tnHL. For NL and tnNL, there is a possibility of cis/trans-isomerism formation for the s-ester moiety. That could contribute to whether or not polymerization will proceed via H-bonding or imidate-like mechanism. Thermodynamic data suggests that polymerization is mainly governed by entropy as expected. 85,89 Future studies on the polymerization processes of these monomers (NL and tnNL) may shed light on the conformational change of the ester functionality, if there is any.

Mechanistic Aspects of ROP
Although this work is still currently undergoing, we can surmise based on the evidences presented to us from various ROP reactions that the TCC-based polymerizations generally follow a imidate-like mechanism while 2 proceeds in a traditional H-bond donating pathway (Scheme 6.3). This holds true for both the oxygenated and thionated monomers studied in this project. With the larger macrolactones (tnPDL), the entropic driving force is not enough for H-bond systems to cause polymer formation (see entry-3, Table 6.5), but is sufficient for imidate-mediated mechanism to occur. With tnEB, the transesterification mechanism that usually accompanies larger lactones generally prevents full polymer formation and lower molecular weights with imidate-based systems (Table   6.6). Non-organic catalysts might be able to lead to higher molecular weights for such a dual ester motif containing substrate, but that was not attempted by this research since organocatalysis was the backbone of this project. Future studies on binding interactions may lead to understand the overall mechanism of these macrolactones better.
The breadth of studies that have been performed on the oxygenated lactones and still undergoing is significant compared to the thionated lactone derivatives. [9][10][11]90,91 The lack of studies performed for the thionated counterparts could be due to controlled polymerization catalysts. The growth of H-bond donating catalysts in the last few decades have enabled an array of opportunities for these less explored substrates. It was with this objective that we had performed ROP to produce homopolymers of 8-, 9-, 16-, 17-(di-ester) membered lactones with some of the fast known (thio)urea based catalysts. As predicted, homopolymers were generated in good control of molecular weight and polydispersity for the smaller lactones until s-trans moiety of the ester becomes a dominant factor with larger ring size. 18,19 Moreover, unlike some of the other catalytic systems that produced thionated polymers in the past, our organic catalysts were able to retain thiocarbonyl in the final polymer. 92 Thermodynamic studies performed for the ROP of these lactones also correlated well with literature. 89 With these understandings and future experimentations to comprehend the mechanistic aspects of these systems will allow new material production.               1 Since that report, the field of organic catalysis, or commonly known as organocatalysis, has seen significant growth in research for fast, efficient, selective catalyst developments. [2][3][4] With the progress in catalyst improvements, the scope of monomers kept on expanding over the years. 5 Though the initial and even current research focuses mainly on a set of lactones and lactides, more studies are underway for extending that capacity. [6][7][8][9][10][11] As the demand for better materials in medicine, plastics and microelectronics which is where these polylactones are generally in use continue to amplify, research in the polymeric materials to meet these needs will remain active. [12][13][14][15] In our research group we have gone from relatively slow to some of the fastest, highly active, vastly selective catalysts in ROP over the last few years. [16][17][18][19][20] This enabled a wide range of monomers to be studied for polymer production in a living, controlled manner. Although more studies are currently underway for understanding the mechanistic aspects of these systems, a Hydrogen-bond mediated or imidate-mediated mode of action is believed to be in play according to the polymer community. This mechanism of action can be tuned based on the substrate or monomer to have a more effective activation process.
This has enabled polymer production for some of the previously uncontrolled, nonselective monomers. This report is an extension of further studies performed on a new set of monomers using these H-bonding catalysts.
Sulfur-containing polymers has prominent appeal in material designs due to the possibility of cross-linking. 21 Our research group has worked on the controlled, living ROP of ε-thiocaprolactone and ε-thionocaprolactone in the past. 22,23 These sulfur-containing 7membered rings produced polymers with good control and narrow dispersity when subjected to organic catalysts. The study on some more sulfur-containing monomers was extended with larger ring systems which generated polymers catalyzed for the first time by organocatalysts. 24 In continuation of broadening that scope of monomers we report some of the attempts made by our group in opening rings of systems other than thionolactones, namely thionolactams and thionolactides. Moreover, the possibility of cross-linking for these thionated monomers was attempted for one of the first thionolactone studied in our group.

Synthesis of ε-Thionocaprolactam
The procedure to synthesize ε-thionocaprolactam (ε-tnCLa) was adopted from Curphey's method with some modifications. 25  After removal of the solvent, a silica-gel flash column was run with dichloromethane to remove some leftover crude mixture from the synthesis. Recrystallization was carried out using diethyl ether which gave the pure product in solid crystals form. Yield: 1.15 g, 74%.
Then the reaction mixture was cooled in an ice-water bath for almost an hour after quenching the reaction with aqueous potassium carbonate solution and distilled water.  13 C spectrum respectively (see Figure 7.3).

Ring-Opening Polymerization Attempts of tnCLa
Similar to other thionated monomers that have undergone ROP, 23 A recent publication demonstrated the use of organic acids for the ROP of εcaprolactam. 27 We attempted similar approaches for tnCLa with a range of organic acids already available in our lab (Scheme 7.2). Even with the use of 10 mol% loading of these acid catalysts with 1 mol% benzyl alcohol at 100°C in chloroform-d, no polymeric conversion was noticed for up to 2 days. It was then the attempt with high boiling point solvents to try opening up this cyclic amide. Thus, diphenyl ether, 1,4-dioxane and toluene were tried with organic bases and 2 with no avail (Table 7.1).
Based on that publication, 27 those organic acids were successfully able to produce polyamides at a much higher temperature. Taking a leaf out of their work, we attempted to open tnCLa at 180-200°C using those acid catalysts (Scheme 7.2). Though PTSA yielded a 17% conversion after 3 days without solvent and initiator, the molecular weights were nothing but oligomeric peaks of short polymer chains supposedly (entry 11, Table 7.1).
Some alkoxides were also implemented to attempt ROP of this monomer, but no polymerization were observed for almost 24 hours at elevated temperature ( to commercially known lactones (δ-valerolactone), 23 we wanted to look at the other forms of copolymers that could be produced using these thionated systems. Since the statistical random copolymers of PtnCL-co-PVL showed an increased flexible nature from the homopolymers of PtnCL, we wondered if other ester motifs would help in making rubbery texture for the copolymers. With that thought, we started to look for crystalline-based polymers that can be easily synthesized. Due to a plethora of studies on a known crystalline polymer like PLLA, 28 we decided to incorporate this as a block into the system with PtnCL.
Our target was to produce a triblock copolymer (ABA-type) with crystalline-amorphouscrystalline moieties, or in other words, PLLA-PtnCL-PLLA. In order to be able to have such a triblock system, the initiator had to be different from our previous studies of copolymerizations (benzyl alcohol). We decided to go with 1,4-benzenedimethanol as the initiator where we hoped to initially form the B-block for the middle part followed by double A-block incorporation afterwards (Scheme 7.1).
Just as the thought process was envisaged, we carried out the polymerizations as planned. The B-block (tnCL) underwent homopolymerization with 1,4-benzenedimethanol at first. The pure form of PtnCL was then re-introduced to ROP with L-LA, hoping that the PtnCL block would act as a macroinitiator. Organic catalysts were utilized for carrying out the ROPs for these systems. A slate of copolymers of varying ratios of ABA blocks were produced in similar manner (see Table 7.3). As hypothesized, a general trend of enhanced flexibility in the polymer texture was observed with decreased PLLA content in the copolymer content physically. Further studies are currently in progress with our collaborator to understand the physical and mechanical properties of these materials.

Cross-Linking Abilities of Thionated Systems
Due to previous literature studies on Sulfur-containing polymers to create networks within themselves via cross-linking, 21 we wanted to look at that possibility with our thionated monomers as well. This was performed by dissolving a sample of PtnCL in dichloromethane first, followed by addition of equal volume of commercial bleach solution (containing mostly sodium hypochlorite). After stirring the mixture for about 2 days, a formation of thickened solid-like material was obtained. Following filtration to remove the solvent, the material that was attained was quite hard in its physical state. In fact, no common organic solvents were able to dissolve the substance which made it quite difficult to obtain NMR, GPC or any other analytical tools to understand the material. Due to the inability for solvents to dissolve the material, it was quite plausible that cross-linking might       being reported more than a decade after the Nobel Prize. 2 Indeed, the reaction has revolutionized several branches of chemistry and found applications in polymer, medicinal and organic chemistry. [3][4][5] The olefin metathesis reaction is an intra-or inter-molecular rearrangement reaction where one or more carbon-carbon double bonds are broken and reformed. Intramolecular metathesis is generally called ring-closing metathesis, while intermolecular reactions are cross-metathesis or, sometimes, homo-cross-metathesis to emphasize the use of only one reagent. Polymers can also be constructed via metathesis using acyclic diene metathesis (ADMET) or ring-opening metathesis polymerization (ROMP) methods. The process must be catalyzed, and olefin metathesis catalysts contain a metal center 6,7usually Ru or Moalthough organocatalytic methods for carbonylolefin metathesis have been reported. 8 In an uncontrolled olefin metathesis reaction, a random mixture of products is generated. The development of advanced (asymmetric) catalysts and inherent (substrate driven) kinetic or thermodynamic control often provides fewer products. In the present experiment, the sole metathesis partner, styrene, conspires to substantially reduce the complexity of the reaction products, giving trans-stilbene as the only non-volatile product, Scheme 8.1.
The Wittig reaction, a classic means of preparing olefins, serves as a natural foil for the metathesis experiment. In the Wittig reaction, an aldehyde or ketone is reacted with a phosphonium salt in the presence of base to yield an olefin, Scheme 8.2. Besides being a widely known organic reaction that undergraduates normally learn during sophomore organic chemistry, the Wittig reaction is robust. A host of phosphonium salts is available with which to make a massive diversity of alkene products. These reactions can be performed on large or small scale, are often high yielding and can easily be performed by student chemists. 9 The Wittig Reaction also has a Nobel Prize in Chemistry. 10 This reaction also is a hallmark example of a non-'Green' reaction, 11 and it displays poor atom economy, 12 meaning a considerable fraction of reagent mass is waste product, the triphenylphosphine oxide, which must be separated from the desired products. In contrast, metathesis catalysts are often used catalytically and then constitute a very small fraction of the reagent mass. Metathesis catalysts are also operative in a variety of solvents and can be used heterogeneously, which facilitates catalyst removal and recycling. 13 In our Advanced Organic Laboratory course, students are asked in two consecutive laboratory experiments to synthesize stilbene, first using Wittig chemistry and second by the cross-metathesis of styrene. The Wittig synthesis of stilbene, 9 which reacts benzaldehyde with benzyltriphenylphosphonium chloride in the presence of base, is selective for the cis-product (~60% cis-stilbene). This selectivity contrasts markedly with that of metathesis reaction, which produces entirely trans-stilbene. This notable difference starts the students on a journey of 'unpacking' the differences, virtues and deficits of the two methods.
This experiment was accomplished in an advanced organic chemistry course with 16 students in a section. Conducting the experiment with larger numbers of students (e.g. a non-majors sophomore organic course) is feasible, but the cost of Grubbs 2 reagent should be considered. Lab sections met twice in a week for 3-hour sessions. The experiment is performed over two lab sessions. On the first day, students are asked to follow a procedure to make stilbene without a partner. The metathesis experiment can easily be finished in a 3-hour lab period. On day two, students were asked to form a hypothesis and work in small groups to build a series of data to reach a conclusion. In the lab report, students are asked to compare and contrast the synthesis of stilbene with metathesis versus the Wittig reaction, performed as the previous experiment. The published Wittig procedure requires a single 3-hour lab period to complete. 9 In this experiment, we employ a Ru-centered catalyst (Grubbs 2nd generation catalyst) -(1,3-Bis(2,4,6-trimethylphenyl)-2imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexyl-phosphine)ruthenium which will perform the selective metathesis of styrene to make a single detectable product, trans-stilbene. 6,14 In this transformation, the diastereoselectivity of the reaction is entirely substrate driven, producing the thermodynamic ratio of stilbene, ~100% trans-stilbene.

Experimental Procedure
Since commercial styrene contains an inhibitor from the manufacturer which may disrupt the metathesis reaction, we removed the inhibitor in bulk before the lab period began. This was achieved by stirring a mixture of 3 g of alumina for every 20 mL of styrene for 5 minutes. Then the slurry was gravimetrically filtered through a qualitative filter paper to obtain pure styrene. The students can perform the purification individually on a reduced scale. Then a 20 mL scintillation vial was charged with a magnetic stir bar, Grubbs 2 (14.80 mg, 0.017 mmol) and dichloromethane (10 mL). Next, styrene (0.2 mL, 1.74 mmol) was added to the vial. The scintillation vial was then fitted with a polymer cone or foil backed cap and placed on a stir plate to stir for about 1 hour. After 1 hour, the solvent was removed under reduced pressure.
A miniature silica column was prepared. First, a pipette (8 x 142 mm) was plugged with a piece of cotton or glass wool on one end. The pipet was then filled with dry silica from ½ to ¾ of its volume. The crude product was dissolved in about 0.5 mL of dichloromethane. The silica plug was then wetted with hexanes and subsequently flushed with this solution of product in hexanes. An additional 20 -25 mL of hexanes was used to flush the contents of the product through the silica. The solvent was then removed of volatiles in vacuo and 1 H-NMR, IR and a melting point was obtained. Students use chemical shift in the 1 H NMR spectrum to identify cis-versus trans-stilbene, but melting point can also be used to identify which diastereomer is made.

Hazards
All synthesized products and intermediates should be handled with caution. Avoid contact with skin and in the event of accidental exposure, wash the afflicted area with copious amounts of water. Styrene is flammable, may cause skin irritation, is a serious eye irritant, a suspected carcinogen and suspected of damaging fertility or the unborn child. Grubbs

RESULTS AND DISCUSSION
This laboratory experiment was designed with two goals in mind: to give students experience with popular and versatile metathesis chemistry and to contrast this chemistry with the complementary Wittig reaction, which students performed previously in the semester from a published procedure. 9 The reactions are perfect foils: the Wittig is cisselective while metathesis makes all trans-stilbene; the Wittig requires stoichiometric reagents while metathesis is catalytic; both reactions require purification to remove catalyst or phosphine oxide, but different methods of purification are required. This experiment also employs common and advanced organic chemistry concepts and techniques that students will find useful in industrial or academic setting: rotary evaporation, filtration, flash chromatography on small scale, spectroscopic identification, thermodynamic versus kinetic selectivity, properties of diastereomers and catalysis.
The purification of the reaction is facile. Students generally obtained about 80-90% yield after the column chromatography purification. Because the reaction is so selective, melting point can also be used to identify the isomer (m.p. cis-stilbene = -5 °C, m.p. trans-stilbene = 122-126 °C), 15,16 and students find values of ~120-124 °C. This and IR spectroscopy provide reasonable proof of compound identity and purity; however, we asked students to use 1 H NMR spectroscopy to identify the product. The chemical literature indicates that the olefinic resonances for trans-stilbene (~7.15 ppm) appear markedly downfield of those for cis-stilbene (~6.57 ppm) in the 1 H NMR spectrum. 17 Further, close examination of the 6.1-8.0 ppm region of their spectrum reveals no spectroscopic indication of cis-product, indicating perfect diastereoselectivity. The reaction is under thermodynamic control and produces a minor amount (0.2%) of the cis-isomer, but this small amount cannot be detected by 1 H NMR or melting point analysis. We were not equipped in our lab; however, HPLC could be performed to detect cis-stilbene; a very small amount is expected to be present.
On the second day of experimentation, students are asked to form a hypothesis and work in teams to come to a conclusion.  This laboratory experiment is not, at its core, about stilbene or metathesis, but rather it is about introducing the students to the unclear nature behind the concepts of Green chemistry 18 and atom economy 12 by comparing two robust and complementary synthetic approaches. Students were able to understand the concept of atom economy by stating that the metathesis reaction produced less reagent waste product than the Wittig. However, some students insist the Wittig is more utilitarian due to the facile nature of separation in that lab experiment. To us, there is no clear answer as to which process is 'Greener' or less wasteful (atom economic plus purification waste), but some students were able to present nuanced arguments for both sides. We feel that being able to see the big pictureeven if it does not contain any clear answer(s)is a primary goal of comparing these two reactions.

NOTES TO INSTRUCTORS
Removal of Inhibitor. Styrene from a chemical supplier contains an inhibitor. The inhibitor may not be disruptive to the metathesis reaction, but it was removed prior to the lab period by stirring a mixture of 3 g of alumina for every 20 mL of styrene for 5 min.
Then, the slurry was filtered gravimetrically through qualitative filter paper. Uninhibited styrene will undergo auto polymerization over several days; this inhibitor-free styrene should be disposed of after the lab period, and the glassware cleaned. can be dispensed in a stock solution of CH2Cl2, but this stock solution has a finite lifetime.
Students were asked to syringe styrene directly from the dispensing area (in a hood) and transport the capped syringe back to their workspace. This greatly minimized exposure to styrene, which has a potent odor.
Purification by Silica Gel Chromatography. Our students purified their stilbene with a microscale, Pasteur pipette silica gel column. A glass wool/cotton plug was loaded into the column (8 x 142 mm glass pipette) using a 9 inch Pasteur pipette push rod, see Figure 8.1A in the student handout section. Then silica was loaded into the 8 x 142 mm pipette using weigh paper folded in half diagonally. A volumetric pipette bulb was used to force hexanes through the column with slight, constant pressure. The silica bed can crack if abrupt pressure changes are applied. A traditional silica gel column can also be employed, but once practiced, we find that the pipette column becomes a favorite tool for easy separations. Instructors may wish to check the setup for the column prior to elution of the product, depending on the class size. Students achieved the best and most facile separations when the product was loaded onto the column in a minimal volume of CH2Cl2 (< 0.5 mL) and eluted with hexanes (~25 mL). Students should be reminded to load the product solution entirely onto the silica before eluting with hexanes. Our students typically get an isolated yield of ~70-90 %. Students who do not obtain a yield of at least 60% may be able to flush their column with more hexanes to obtain residual product on the silica gel.
Identification of cis-versus trans-stilbene. Students will observe that the metathesis reaction produces ~100% trans-stilbene. The cis/trans ratio is most conveniently determined from 1 H NMR, where the chemical shift of the ethylene resonance is isomer-dependent: cis-stilbene at 6.60 ppm and trans-stilbene at 7.15 ppm. 3  Answer: Wittig processes confer high selectivity for the cis-isomer, which can be difficult to access using metathesis. Wittig reagents and methods are robust, structurally diverse and are often easy to separate from the product, but they must be used stoichiometrically. Metathesis catalysts are highly functional group tolerant, readily available and general (i.e. one can apply a SINGLE metathesis catalyst to many syntheses, but a new Wittig reagent is needed for every product).
The Grubbs reagents (we use the common term 'catalyst' in this document are really pre-catalysts or initiators) 1 are usually applied catalytically which minimized waste. However, the metathesis products can re-enter the catalytic cycle, eroding yield and stereocontrol (if present), depending on what type of olefin describe the product and reagent. 1 Stilbene is a Type II olefin with respect to Grubbs 1 st generation catalyst, 1 and it will not readily undergo subsequent metathesis.
However, if the product is symmetric (as with stilbene), these processes are not evident even if they occur 2. What is the cis/trans ratio produced by metathesis and how does it compare to the 7. Lab Technique/citizenship (10 pts): The lab should be returned to the condition in which you found it. Violations that are not attributable will be assessed to the whole class. Improper handling or use of equipment/chemicals will also cause deduction in points.

STUDENT HANDOUT
In a previous laboratory experiment, 1 stilbene was synthesized via a Wittig reaction.
The Wittig reaction is robust and widely-used in industrial and academic research labs. It is also a hallmark counterexample of a 'Green' 2 process, and the reaction exhibits poor atom economy. 3 That is, the mass of product divided by mass of 'wasted' Wittig reagent byproduct is low and can be less than unity, depending on the reaction. 1 Catalytic methods offer an alternative. The primary advantage of a catalytic approach is the ability to generate many moles of product for each mole of catalyst (i.e. a good catalyst will have a high turnover number, TON = mols substrate/mols catalyst) and keep waste to a minimum. The multitude of synthetic possibilities and advantages rendered by tuning ligand structureto change regiochemistry, stereochemistry, rate, and substrate scopemakes catalysis an attractive field of research. Stoichiometric (e.g. Wittig) and catalytic (e.g. metathesis) reactions have concomitant benefits and drawbacks. An overarching goal of the two stilbene synthesis experiments is to directly compare and contrast the two approaches.
Catalysts for olefin metathesis, particularly ruthenium (Ru)-containing catalysts, have revolutionized synthetic chemistry. 4 These catalysts have impacted pharmaceutical, 5 natural products 6 and polymer chemistry. 7 The development of olefin metathesis catalysts was awarded the 2005 Nobel Prize in Chemistry. 8 In this experiment, you will be using a Ru olefin metathesis catalystcommonly called Grubbs Catalyst, Second Generation or 'Grubbs 2'to perform the homodimerization (or cross-metathesis) of styrene. The diastereoselectivity (cis/trans selectivity) of the metathesis transformation is different than the Wittig process. 4 of styrene and gravimetrically filtering the slurry through qualitative filter paper. The instructor may do this prior to the laboratory session for the whole class.