Fundamental Investigations in Organocatalytic Ring-Opening Polymerization: A Trek to New Catalysts

Organocatalysis is a powerful tool for polymer synthesis. It has been widely demonstrated that organocatalytic systems enable precise control over polymer microstructure, provide competitively fast reaction rates compared with metal-based catalysts, and effect a broad assortment of polymerization mechanisms. The added value of metal-free polymerizations is that they can be utilized in sensitive applications intolerant to the presence of residual metal-based catalysts. The initial focus of the present dissertation was placed on mechanistic studies in organocatalytic ring-opening polymerization (ROP) of cyclic esters alongside with subsequent development of new organocatalytic systems for ROP. ROPs of this kind can be mediated by a thiourea-based hydrogen-bond donating catalyst and a strong organic base. The two cocatalysts activate the monomer and initiator for the reaction to commence. The question is: how do the four species interact? The binding between thiourea and bases was investigated – an interaction that had not been previously considered. An array of binding constants between thiourea and various bases was obtained. Importantly, the binding constants proved to correlate with the δvalerolactone ROP rate depending upon the base used for the polymerization. The theory paved a way to the assessment of weaker bases in ROP. With the original theory working, a new goal was selected – to investigate the binding between thiourea and weak alkylamine bases. A range of binding constants was measured for various thiourea and alkylamine cocatalyst pairs. The correlation between the binding constants and the rate of L-lactide ROP was non-existent. However, enthalpy and entropy of cocatalyst binding were found to correlate with the L-lactide ROP rate. The more entropically favorable cocatalyst interactions yielded higher rates of L-lactide ROP. Additionally, the enthalpy and entropy of the thiourea-alkylamine binding exhibited enzyme-like compensation behavior similar enzyme-substrate analogues. Kinetic investigations demonstrated that thiourea-alkylamine mediated ROP of L-lactide exhibited a second-order rate dependence in thiourea. This observation prompted us to assess the effect of two thiourea motifs tethered in one molecule on the ROP rate. The new bis-thiourea catalyst provided exquisite control over ROP, yielded well-defined polymers (narrow polydispersities, predictable molecular weights), was able to polymerize a host of cyclic ester monomers, and brought a significant rate acceleration for polymerizations even at small catalyst loadings, compared with monothiourea catalyst. Seeking active and selective H-bonding catalysts, attention was attracted by the widely available triclocarban, formerly used as an antibacterial soap component. Triclocarban contains a urea functionality that renders the compound a potential H-bond donating catalyst. The examination of triclocarban as a ROP catalyst proved its efficiency for hydrogen-bonding ROP of a broad scope of monomers in different solvents. Having the ROP conditions optimized, extremely active triclocarban-based cocatalyst pairs were discovered. The polymers produced under triclocarban-mediated ROPs display precise macromolecular architecture. Mechanistically, it was proposed that the nature of the catalytic intermediate neutral hydrogen-bonded or charged imidate may change depending on the strength of base used in ROP. The quest for optimization and discovery of potent H-bond donating organic catalysts for ROP, rivaling the metal-based counterparts, continues. Further, attempts were undertaken in stereoselective organocatalytic ringopening polymerization (SROP) of lactide. The SROP of lactide is an attractive approach for the generation of polylactides with tunable materials properties. This reaction exemplifies mechanistic control at the molecular level, conferring different bulk properties to the resulting polymer. Conversely, analysis of the bulk material allows for the detailed understanding of the molecular level processes that gave rise to particular material properties. A series of small molecule H-bond mediated catalysts were developed for SROP of rac-lactide. Catalytic scaffolds leading to low, moderate, and high stereoselectivity were identified through structure-activity relationships. Future generation catalysts will be made building on these early observations.

x           Prize laureates Ziegler and Natta (we will refer the reader to widely available literature on this topic). Two major kinds of stereocontrol (scheme 1.1) over the monomer unit addition to a growing polymer chain are known. 4 First, chain-end control may be implemented. This type of control involves the growing chain end dictating which enantiomer is attached next to the polymer backbone. 4 Second, catalyst control, constituted by two types, (also known as enantiosite control in case of metal-based routes and dynamic kinetic resolution in the event of organic approaches) may take place. Enantiomorphic site control means that the catalyst determines the relative stereochemistry between two adjacent stereocenters in the growing polymer chain generated from a prochiral monomer (e.g. propylene, scheme 1). On the other hand (scheme 1), in the event of rac-lactide (rac-LA) we can encounter dynamic kinetic resolution (DKR) control implying that the catalyst "selects" the next chiral center of the monomer added to the growing polymer chain. 4,5 Tacticity is measured by statistical methods 4,5 and probabilities of isotactic (P m ) or syndiotactic enchainment (P r ) through chain-end control can be determined. Parameter α can also be determined statistically as a probability of tactic enchainment through enantiomorphic site control. In this chapter we consider various methods that can be implemented to conduct stereoselective polymerization of rac-LA using organocatalysis.

Organocatalytic Ring-Opening Polymerization
One underdeveloped tool for stereoselective polymerization is organocatalysis.
Organocatalysis facilitates formation of polymers that are utilized in a broad array of products, ranging from commodity packaging materials and microelectronic components, to specialized biomedical devices and drug delivery agents. 1, 2 Utilization of metal-based catalysts in polymerization poses the challenges of catalyst removal upon the polymeric material purification. 6 This circumstance becomes especially daring in designing polymers for sensitive areas, such as food packaging, microelectronics, and biomedical materials. 6 To counterbalance the purification difficulty, small molecule organic catalysts were introduced. 2,6 The initial research efforts in organocatalytic polymerization yielded the discovery of relatively effective organic polymerization catalysts that could not yet rival the performance of metal-based analogues. 6 Further research efforts introduced organic catalysts that can operate at small catalysts loadings, furnish high rates of polymerization, and exhibit precise control over macromolecular architectures. 10 A substantial slate of small molecule organocatalysts operate in the range of mole percent to sub-mole percent catalyst loadings with polymerization rates effecting polymer product formation from hours to seconds. A large number of catalytic systems provide exquisite control over polymerization via the polymerization execution in a "living" manner. "Living" polymerization is a chain-growth polymerization that is characterized by a) sequential addition of monomer units in a "one-by-one" mode to the growing polymer chain and b) linear dependence of polymer weight increase on time. The end result of "living" polymerization are polymers characterized by target molecular weights and narrow polydispersity indices (PDI). 2,6 PDI is a "polydispersity index" defined as the ratio of weight-average polymer molecular weight (M w ) to numberaverage molecular weight (M n ) of polymer (eq. 1).
Typical monomer substrates for organocatalytic ring-opening polymerization are cyclic species. 2,6 The set of substrates (figure 1.1) is a representative slate of the monomer pool and the reader can imagine the diversity of polymeric materials that can be generated.

Lactide in Organocatalytic Ring-Opening Polymerization
A very common monomer for both metal-catalyzed and organocatalytic ringopening polymerization is lactide (LA). 7,8 LA attracted substantial attention due to its wide availability as the monomer that can be derived from renewable resources (corn) and biodegradability of the resultant polymers. 7,8 LA is present in several forms naturally: L-LA, D-LA, meso-LA, and as a mixture of stereoisomers, rac-LA. This diversity in just a single monomer pool allows for production of polymeric materials with various arrangements of stereocenters in the polymer chain. 9 Different arrangements of stereocenters in the polymer chain can be both ragtag (no stereocontrol) and highly ordered (upon application of steresequence control protocols). 9 Here we provide (scheme 7) the rundown of outcomes for ROP of LA 4 . A pure enantiomer of LA, for instance, L-LA, upon ROP, affords a crystalline isotactic polymer with uniform (S)-stereocenters along the polymer backbone, unless the epimerization is involved in the polymerization process. As a result, a stereoregular poly-L-LA is generated. Upon stereocontrolled ROP of meso-LA, a syndiotactic polymer with alternating R-and Sstereocenters in the chain or a heterotactic polymer with alternating R-/R-and S-/S-pairs The other option is the alternating placement of (R-/R-) and (S-/S-) pairs of stereocenters in the polymer backbone, yielding a heterotactic polymer. 4   Particularly, phosphazene bases were established to be effective catalysts for ROP. 11 The phosphazene bases catalysts are commercially available and possess a wide range of homologues. The steric bulk of certain phosphazene bases is particularly interesting as it may restrict the reacting chiral species mobility, thereby exercising a form of stereocontrol. The absence of chiral motifs in the phosphazene base structure suggested the polymer chain-end control mechanism in the course of ROP. In the work by Hedrick and coworkers, the commercially available phosphazene base (figure 1.3) t-Bu-P 2 ( MeCN pK BH+ = 33.5) was selected as an organocatalyst for ROP of lactide monomers. 11 The polymerizations were set up by employing an alcoholic initiator and using toluene as a solvent. 11 The polymerization screening with variable conditions produced well-defined polylactides characterized by narrow PDI and controlled molecular The polymerization mechanism was suggested to operate via the alcoholic initiator activation due to the increase of the chemical shift of the alkoxy proton from 1.17 ppm in pure alcohol to 7.66 ppm in alcohol with added phosphazene base. The mechanism of stereocontrol was postulated to be of the polymer chain-end kind due to the absence of the chiral moieties in the catalyst structure. Each lactide enantiomer has an equal probability to undergo the first ring-opening event and the open propagating stereocenter of the i-th monomer will select the (i+1)-st inserted monomer stereocenter to continue the growth of the nascent polymer chain. The lowered temperature provides decreased mobility of the reactive species in solution and allows higher stereoselectivity in the course of ROP of rac-LA. 11 The research effort by Wade and coworkers built an outstanding case for stereoselective organocatalytic ROP of rac-LA. P 2 -t-Bu was shown to be a very fast organocatalyst for ROP of rac-LA exceeding stereocontrol abilities of a large slate of known organocatalysts and matching stereoselectivity parameters of exquisite metalbased catalytic systems. 11

Stereoselective Ring-Opening Polymerization Using N-Heterocyclic Carbenes
The application of zinc metal in a metal complexes with N-heterocyclic carbenes

Stereoselective Ring-Opening Polymerization Using Chiral Thioureas
Tremendous progress has been made to date in the field of utilization of thiourea H-bonding catalysts for ROP of cyclic ester monomers. 2,6 It was possible to achieve highly controlled ROP of a variety of achiral monomers using substituted thioureas and arrange these catalysts in terms of their efficiency to their metal-based counterparts. 2,6 Thioureas are capable, in particular, of fast and controlled ROP of lactide monomers.
However, the examples of achieving isoselective ROP of rac-LA using thiourea Hbonding catalysts are almost lacking in the polymer community. Previously, Waymouth and coworkers demonstrated a successful usage of bifunctional Takemoto catalyst for ROP of lactide. 10 The polymerizations produced well-defined polymeric products characterized by controlled molecular weights, narrow PDIs across the range of polymerization experiments and tolerable reaction times. 10 The echoing project undertaken by Chen and coworkers 16 achieved two major goals. First, the task of conversion of meso-lactide into rac-lactide was set. Second, the development of a stereoselective thiourea-based organocatalyst for ROP of rac-lactide was put in the offing 16 (scheme 1010).   As an added bonus, the execution of subsequent epimerization and enantioselective ROP is a feasible operation yielding excellent polymerization characteristics.

Phosphoric Acids
Binaphthol derivatives of phosphoric acid proved to be broadly applicable in a range of chiral transformations. The two key features of such compounds, the hydrogenbond donating unit and a chiral motif, rendered these substances as potential organocatalysts for stereocontrolled ROP of lactide. 17 The research project undertaken by Satoh and coworkers placed a number of binaphthol-derived phosphoric acids into the spotlight to exercise stereoselective ring- The mechanism of polymerization was proposed to take the dual route (sscheme 122). The two activating sites located in the catalyst structure are the acidic and basic moieties. By authors' proposal, the acidic moiety electrophilically activates the incoming LA monomer, whereas the basic moiety of the catalyst nucleophilically activates the growing polymer chain for the attack and subsequent ring-opening of the monomer. 17 was detected in the spectrum. 17 The mode of stereocontrol in the polymerization was postulated to be enantiomer-selective. To elucidate the stereoselectivity mode, the representative ROP in the optimized conditions was quenched at ~ 50% monomer conversion, and the unreacted monomer was extracted from the polymerization reaction mixture. The said unreacted monomer was subjected to the chiral HPLC analysis and the enantiomers traces demonstrated depletion in the content of one enantiomer. Thereby, the preference of the catalyst for a particular enantiomer of LA in ROP and root of the subsequent kinetic resolution of rac-LA were established. 17 The project successfully accomplished by Satoh and coworkers added one more brick into the nascent foundation of stereoselective organocatlytic polymerization of cyclic esters.

Stereoselective Ring-Opening Polymerization of rac-Lactide Using Cinchona Alkaloids
A project undertaken by Chen and Miyake explored the abilities of natural products, cinchona alkaloids, in the stereoselective ring-opening polymerization of rac- LA. An optimal alkaloid was established as an effective catalyst for partial kinetic resolution polymerization of rac-LA. 18 To begin with, a set of catalysts and initiators was chosen ( fig.7figure 7). The catalyst CD proved to be inactive for ROP of rac-LA after a variety of polymerization conditions was screened, including the application of external initiators, prolonged reaction times, and neat, monomer melt environment at an elevated temperature. 18 The relative weakness of the amino group in CD compared with ICD and the supposition that the hydroxy group of CD is not acidic enough compared with ICD to activate the monomer, CD was rendered incapable of ROP of LA and the spotlight was In conclusion, the successful step accomplished by Chen and Miyake, showcased effective application of an alkaloid from the cinchona family for enantioslective ROP of rac-LA, even though the achieved selectivity levels were unostentatious. The project nevertheless contributed a significant development into the field of stereoselective ROP of cyclic esters.

Densely Substituted Amino Acids
A team of researchers from Spain developed a series of unnatural densely substituted amino acids capable of excellently stereocontrolled ROP of rac-LA. 19 The inspiration for this project stemmed from previous successes achieved with chiral amino acids employed for asymmetric synthesis, chiefly in small-molecule transformations.
Initially, the authors deemed to try the almost proverbial catalyst, proline, for ROP of rac-LA since this catalyst, in particular, was a successful performer in a wide repertoire of asymmetric processes. 19 The standard conditions for polymerization screening were devised: solvent was determined by NMR in CDCl 3 , polymers weights were characterized by SEC, P m values were determined by 13 C NMR spectroscopy. 19 A bulkier derivative proline, Boc-L-Pro and DBU, were used at the 5 equivalents loading to the initiator for the ROP of rac-LA. The ~98% conversion, gave a polymer with M n = 8000 g/mol, PDI = 1.2, and the modest P m = 0.65. 19 In the same reaction scenario Boc-L-Pro was switched to DBU (known as a fast catalyst in itself for ROP of LA), and a slightly poorer controlled polymeric product was obtained with M n = 12200 g/mol, PDI = 2.1, and the worse P m = 0.50. 19 After attaining unsatisfying results with the two H-bonding catalysts, the authors started pursuing the path of the proline catalyst modification. The general idea was to increase the steric bulk of this catalytic species through installation of large functional groups on the proline ring. A series of multi-step synthetic processes (sscheme 414) furnished the densely substituted amino acid catalysts, exo-6 and endo-6. 19 Scheme 1.14. A general synthetic scheme depicting the route towards the catalysts employed in the study.
The standard conditions were applied for ROP of L-LA: both exo-6 and endo-6 produced polymers with controlled molecular weights and P m = 1.00 for both catalysts that signified no racemization occurrence during polymerization. The ROP of D-LA by exo-6 and endo-6 also furnished polymers with P m = 1.00. 19 99% ee 3 steps! Next, the challenging task was put on the line for exo-6 and endo-6. The challenging ROP of rac-LA was accomplished with exquisite performance indicators.
First, at the standard polymerization conditions exo-6/DBU at 50% conversion produced the polymer with M n = 3300 g/mol, PDI = 1.1, and P m = 0.96. Second, at the standard polymerization conditions endo-6/DBU at 51% conversion produced the polymer with M n = 3100 g/mol, PDI = 1.2, and P m = 0.90. Third, in the analogous conditions exo-6 and endo-6 together produced, at 98% conversion, a polymer with M n = 23000 g/mol, PDI = 0.60, yet a substantially poorer P m = 0.60. 19 The polymers obtained from rac-LA at ~50% conversion were characterized for targeted polymerization of either enantiomer in rac-LA with excellent levels of stereselectivity resulting in fine-tuned architectures of the produced polymers.

Conclusion
The state of the art of stereoselective ring-opening polymerization of cyclic esters has been highlighted and as of right now, it is present in a rather nascent stage.
However, the course of research in this underexplored and challenging field has seen substantial evolution. The attempts to achieve stereoselective ROP of rac-LA were constantly undertaken and various organocatalytic systems were utilized. Probably the first examples can be represented by N-heterocyclic carbenes as the agents of stereocontrolled ROP of rac-LA via chain-end mechanism, yielding moderate isotacticity of the polymeric product. 20 Everlasting explorations of hydrogen-bond donating thioureas bearing chiral motifs produced harbingers of using these compounds as potential catalysts for stereoselective ROP of rac-LA. For example, chiral thioureas proved to be efficient in dynamic kinetic resolution of other cyclic esters, azlactones. 21,22 The chain-end control systems got enhanced over time to afford remarkable isotacticities of polymers, as was demonstrated by the advent of phosphazenes as ROP catalysts. 11 Further research efforts in the area offered catalytic systems capable of enantiosite control over ROP of rac-LA with excellent performance indicators, as was demonstrated by chiral binaphthyl phosphoric acids. 17 The attention was later drawn to chiral cinchona alkaloids that were capable of partial kinetic resolution ROP of rac-LA. 18 Interestingly, the work with alkaloids burgeoned into the project interetwining alkaloid, binaphthyl, and thiourea motifs to produce powerful organocatalytic systems for ROP of rac-LA. 16 Circa the time this review was being written, the research pendulum swung towards the unnatural chiral amino acids established as potent catalysts for stereoselective ROP of rac-LA. 19 The scope of enantiosite control H-bonding catalytic systems for ROP of rac-LA appears to ever increase and it is possible to expect the emergence of new players on the stage in the foreseeable future. Additionally, there is also an emerging tendency in the expansion of chiral monomers scope, that will be a springboard to take the stereocontrolled ROP field to the next level towards new chiral polymeric materials. 23 This review chapter, as I trust, outlines the major milestones of research efforts in stereoselective ROP of rac-LA. My research aspiration is to implement innovation into the field and broaden the scope of metal-free catalytic processes of stereoselective ROP in particular and ROP in general. all other known non-covalent catalyst/reagent interactions during ROP. One stronglybinding catalyst pair behaves kinetically as a unimolecular catalyst species. The high selectivity and activity exhibited by these ROP organocatalysts is attributed to the strong binding between the two cocatalysts, and the predictive utility of these binding parameters is applied for the discovery of a new, highly active cocatalyst pair.

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][2][3] The asymmetrical thiourea, 1 in Scheme 1, is believed to selectively activate cyclic esters and carbonates for ROP The exact balance of interactions that must exist for a 'living' ROP to occur is impressive, 5 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.

Chemical Kinetics
Kinetic studies were undertaken to help elucidate the roles of 1 and DBU in the The resulting plot, Figure 1 for DBU which would occur upon a strong binding interaction between 1 and DBU.

Cocatalyst Binding
Inhibitory interactions by amine base cocatalysts upon 1 have been suggested by other researchers to decrease ROP rate. 5 In an illuminating study of several cocatalysts, it was found via 1 H-NMR binding studies that 1 and sparteine, an erstwhile favorite catalyst pair for the ROP of lactide, 9 exhibit a moderate binding constant of K eq (CDCl 3 ) = 6 ± 1. 5,18 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. 5,7 The potent H-bonding ability of DBU 19 and high activity of 1/DBU for ROP belie this concept. alcohol; eqs 1 and 2) to hold all reagents in close proximity during a rapid exchange of binding partners thereby accelerating the reaction. 21 However, the kinetic data suggest that the strong binding could serve to make a distinct catalytic species. 22 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.

Scheme 2.2. Proposed Cocatalyst Binding Mechanism for the ROP of VL.
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); 4 however some 1/amine base combinations result in almost zero transesterification of the resultant polymer after 4 h. 23 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 non-zero binding to 1) 4 to interrupt the 1•DBU pair (eq 4) versus that of VL (eq 5). These values (K eq = 0.003 vs K eq = 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]23 (4) 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 C 6 D 6 were measured either by the dilution or titration method 24  In the low binding constant regime, K eq correlates with polymerization rate, and cocatalyst binding constant appears to be a better predictor of catalytic activity than does pK a . The k obs 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) ( Table   1) as they are not active for the ROP of VL. Of these cocatalysts, only 1/DMAP exhibits ROP activity: k obs (LA)= 4.1 x 10 -3 min -1 . Both 1/pyridine and 1/proton sponge are inactive for the ROP of LA, but 1·pyridine displays weak binding (1·pyridine K eq = 9 ± 1) whereas 1·proton sponge exhibits none. The binding constant observed for 1·DMAP was the strongest of the three (1·DMAP K eq = 170 ± 30). A pK a explanation of ROP activity is unsuccessful for the case of DMAP vs proton sponge (in acetonitrile: DMAP-H + pK a = 18.2; 28 proton sponge-H + pK a = 18.7), 29,30 yet their ROP activities correlate well with the strength of their binding to 1. For the 1/pyridine system, its moderate binding constant yet lack of ROP activity could indicate that ROP is only feasible when cocatalyst binding becomes competitive with 1·lactone binding (1·VL K eq (C 6 D 6 ) = 44; 4 1·LA K eq (CDCl 3 ) = 2) 5 such that the cocatalysts are closely associated in solution.
The binding constant between 1 and DBU was the strongest measured, but this catalyst pair is not the most active of those examined for the ROP of VL.

BEMP/1 Catalyzed ROP
One of the most powerful applications of reaction mechanism elucidation is in the discovery of new catalyst species, and we sought to ply our increased understanding of 1/base catalyzed ROP to this end. While this work was ongoing, Dixon et al. reported the ROP of VL by a phosphazene-inspired bifunctional TU-iminophosphorane catalyst, 2 in eq 6. 31 (6) The bifunctional catalyst 2 exhibits 'living' ROP behavior, the usual relative monomer reactivity (k LA > k VL >> k CL ), and good selectivity for monomer. 31

Conclusion
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 pK a . The strongly binding 1/DBU system behaves kinetically as a unimolecular catalyst species, and it could be representative of a hydrogen-bonding analogue of socalled 'cooperative ion pairing' in asymmetric organocatalysis. 22 We agree with the conclusion of Bibal et al. that TU/amine base binding can be inhibitory to ROP 5,6 but submit that: 1) the phenomenon is much more general than first proposed; 2) the magnitude of the interaction may be a good predictor of cocatalyst activity; and 3) the point at which cocatalyst binding becomes counterproductive to catalysis is significantly higher than once believed. As organocatalysis strives to mimic the aweinspiring catalytic abilities of nature, it is important to fully understand the catalytic systems being employed. As it would happen, the roles of 1 and DBU in the ROP of VL are not very dissimilar from those of enzyme and cofactor. Further mechanistic studies are ongoing; such studies have already revealed one new catalyst system for ROP (1/BEMP) and they are expected to yield dividends in the form of more new catalyst systems.

General Considerations
All manipulations were performed in an MBRAUN stainless steel glovebox equipped with a gas purification system under a nitrogen atmosphere. All chemicals were purchased from Fisher Scientific and used as received unless stated otherwise.
Toluene and THF were dried on an Innovated Technologies solvent purification system with alumina columns and nitrogen working gas. Benzene-d 6

Determination of Binding Constant by the Dilution Method
A stock solution containing 1 (2.8 mg, 0.0075 mmol) and DBU (0.0011 mL, 0.0075 mmol) was prepared in deuterated benzene (1.5 mL). This solution was distributed to 6-10 NMR tubes, and each NMR tube was diluted with benzene-d 6 to give final concentrations ranging from 5 mM to 0.313 mM. 1 H-NMR spectra (referenced to residual benzene-H) were acquired for each tube at multiple temperatures and the chemical shift of the ortho-protons of 1 was noted. The K eq values were determined from the linearized (Lineweaver-Burke) forms of the binding equations (see ES), which are a powerful means of accurately measuring binding constants with fewer samples (versus curve fitting). 25 The binding constant for each 1/base pair was determined at elevated temperatures (303 -323 K). The enthalpy and entropy of binding were determined by plotting lnK eq versus 1/T to conduct a Van't Hoff analysis, and error was determined from linear regression at the 95% confidence interval.

Example Determination of k obs
In a glovebox under nitrogen atmosphere, one vial (baked at 140°C overnight) was loaded with a stir bar and δ-valerolactone (VL) (0.0927 mL, 1.00 mmol). A second dried vial was loaded with benzyl alcohol (0.0021 mL, 0.020 mmol), 1 (

Equations used for binding studies.
For dilution: Δδ/[base] = -2K eq Δδ + K eq δ C For titration: Δδ/[base] = -K eq Δδ + K eq δ C Where 35-37 : Δδ is the difference between the chemical shift of the observed ortho-protons in the TU-Base mixture and of pure TU; δ c is the chemical shift of the ortho-protons of TU in the complex, TU-Base; K eq is the binding constant between 1 and a Base.
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. 35 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. 37 Very accurate data can be obtained with fewer data points (versus curve fitting) because experimental errors from inaccurate concentration are attenuated in the linearized from. For this method, the accuracy of K eq versus number of data points has been tested in the literature and shown to be highly accurate with 5 data points. 36 These studies even omitted the plateau of the binding curve, 36 which was never the case in our studies. Further, computationally fitting the binding curve introduces indeterminable error from the fitting approximations. Error in the slope of the linear form (K eq ) is solely determined by the scatter in data (from residual error in concentration), and the error in Keq is exactly the error in the slope of the line, which can be determined from linear regression. 37  (lower) Van't Hoff plots of binding between 1 and various bases.

Introduction
Since

Cocatalyst Binding Thermodynamics
The binding constants, K eq in eq 1, between the alkylamine cocatalysts in

Kinetics
The

Effect of Alkylamine Base upon Calculated Cocatalyst Geometry
For the ROP of esters in nonpolar solvent, the a priori selection of a base cocatalyst which does not allow all its nitrogen atoms to bind to the 1 cocatalyst is predicted to provide the best ROP rate but lowest selectivity for monomer.

Comparison of Monomers and Base Cocatalysts
The multitude of competing and complementary interactions that occur during a "simple" transesterification event renders definitive conclusions regarding the effect of catalyst structure upon activity difficult. Taking the VL 8  In the case of VL, strong base cocatalysts are required for ROP, and strong binding constants to 1 are expected due to their increased basicity. In contrast, the alkylamine cocatalysts employed with 1 for the ROP of LA should be expected to exhibit weaker binding to 1 due to their reduced (vs amidine bases) basicity, as observed. Within a particular set of bases (strong or alkylamine), the effects of the base cocatalyst upon rate and selectivity do not follow trends in pKa. In this study, the three nitrogen base TACN was superior in reaction rate to the four nitrogen bases while a second three-nitrogen base, PMDETA, was slower still (see Table 1). Again, this suggests that pK a is not as important as cocatalyst binding in determining catalyst activity. However, when cocatalyst binding constants, K eq , are approximately equal in magnitude, as with the alkylamines, the enthalpy of cocatalyst binding is a better predictor of activity than binding constant proper. This is an extension of the previous observation. 8 For example, if the driving force for the association of a cocatalyst pair, like TACN to 1 or Me 6 TREN to 1 (ΔH° > 0), is the exclusion of solvent that occurs upon binding (ΔS° > 0), 16 then the reactivity exhibited by these cocatalysts would be expected to be markedly different than those cocatalyst pairs that are enthalpically bound (HMTETA, DABCO, PMDETA or TMEDA to 1). The former alkylamine/1 pairs are "preassembled" due to their mutual dislike of solvent and should be expected to be rapid ROP cocatalysts due to their enthalpically favorable binding to monomer/alcohol (ΔH° < 0), 23 as observed.

Conclusion
For the base/1 combinations examined herein and previously, 8

General Considerations
All manipulations were performed in a glovebox or via standard Schlenk technique under a nitrogen atmosphere in glassware baked overnight. All chemicals were purchased from Fisher Scientific and used as received unless stated otherwise.
THF and toluene were dried on an Innovative Technologies solvent purification system with activated alumina columns and nitrogen working gas. Benzyl alcohol, chloroformd, and benzene-d 6  package running on a 64 bit Windows 7 operating system was used for computations.

Binding Studies
Binding constants (K eq ) between 1 and alkylamine bases were determined in benzene-d 6 by the titration method and curve fitting as previously described. 12,13 The K eq values were determined by fitting the binding curve to the quadratic form of the binding equation with K eq and Δδ as variables. 26 The binding constant for each 1/base pair was determined at elevated temperatures (298−318 K). The enthalpy and entropy of binding were determined by Van't Hoff analysis, and error was determined from linear regression at the 95% confidence interval. where k obs is defined in eq. 5, and the error was determined by propagation of NMR integration error at ±10%. Only [1] and [base] were varied (from 5 to 25 mol % to Llactide) between individual kinetic runs.

Computations
Chemical computations were performed to gain a qualitative insight into cocatalysts interactions. Structures were built in the Spartan builder interface and geometry optimized using DFT at the B3LYP//6-31G** level of theory starting from the PM3 optimized structures. Geometry optimizations were performed in the gas phase.
Cartesian coordinates of the optimized structures and their energies are given below.

Equation Used for Binding Studies
Where 29-31 : δ obs is the observed chemical shift of the TU in the presence of base; δ H is the chemical shift of free TU in the absence of base; Δδ is the difference in the chemical shift of host and complex, (Δδ = δ Cδ H ); K is the binding constant, K eq .
The binding constants were determined by fitting the binding curve with the quadratic form of the binding equation shown above (K eq and Δδ variables). 29

Results and Discussion
Our approach was inspired by the use of bis(thiourea) catalysts in small molecule transformations as well as our own investigations into the nature of 1/base catalyzed ROP. 20 During the course of mechanistic studies into the 1/base catalyzed ROP of lactide initiated from benzyl alcohol, we observed that some 1/alkylamine combinations, like 1/Me 6 TREN in Scheme 1, exhibit second order kinetics in [1]. 21 This observation suggests that two 1 molecules are kinetically relevant in the ratedetermining step. The kinetic orders of the previously studied ROP reactions are base dependent, 21 which hints at the possibility of exploiting these differences for the  The reaction rate slows with a stoichiometric excess of HMTETA to 2 ( Table 1, entries 3 and 4), which suggests that 1:1 stoichiometry of base:2 is optimal for ROP.
The rate acceleration exhibited by 2 vs 1 is a general trend and is independent of the identity of the alkylamine cocatalyst being employed. Several commercially available alkylamines in combination with 1 have been shown previously to be effective cocatalysts for the ROP of lactide. 21,22 The effects of base cocatalyst identity upon ROP have been explained computationally 22    for the 1/base-catalyzed ROP of lactide. 16,22 Previously, the best means of effecting higher rates of ROP were to employ stronger bases which typically result in the rapid post polymerization broadening of Mw/Mn. 3,15 However, the higher rates of these 2/base-catalyzed ROPs are not   for small molecule transformations. Enhanced reaction rates have been observed when activation of two substrates is a possibility. 17 However, rate acceleration with bis(thiourea)s is not general, 7,18,19 although the introduction of chiral linkers facilitates increased enantioselectivity in some cases. 6,19 The bis(thiourea) 2 does not feature a chiral linker and was not expected to alter the stereoselectivity of the ROP vis-a-vis monothiourea 1. The polymers resulting from the 1/Me 6 TREN and 2/Me 6 TREN catalyzed ROP of rac-LA from benzyl alcohol (conditions from Table 2, entries 1 and 2) were analyzed by 13 C NMR (see Experimental Section). The 1 H decoupled 13 C NMR spectra suggested similar tacticities (P m (1) = 0.69; P m (2) = 0.66; where P m is the probability of propagating with the retention of stereochemistry). 16,24−26 This is consistent with previous suggestions that organocatalytic H-bonding catalysts display chain-end controlled stereochemistry. 16 The source of the rate acceleration exhibited by bis(thiourea) 2 is proposed to be the activation at a single monomer ester by both thiourea moieties. While the possibility of 2 simultaneously binding base and monomer or simultaneous binding of monomer and polymer cannot be ruled out, the observed second order dependence upon [1] for some 1/alkylamine catalyzed ROPs of L-LA strongly indicates that both thiourea moieties of 2 are involved in the activation of a single ester moiety in the transition state. 27 Presumably, the role of 2 is to enforce this favorable catalytic mode even in those 1/alkylamine systems which do not display second order dependence upon [1], Scheme

. This suggestion is consistent with computational studies of a bis(thiourea) catalyzed
Morita-Baylis-Hillman reaction wherein a bisTU-nitrate complex is believed to react with an uncomplexed aldehyde rather than bind both reagents prior to reaction. 28,29 With the exception of the short-strong variety, H-bonds are electrostatic in nature and do not require orbital overlap, 30 hence the mode of the 2-lactide activation could be due to direct, dual-thiourea activation of a single ester moiety or an activated-TU mechanism 31 (scheme 4.2). However, other unenvisioned processes are possible. Computational studies were conducted to differentiate between these mechanistic possibilities. Energies from geometry optimized structures (B3LYP/6-31G**) in CH 2 Cl 2 solvent and the gas phase suggest that the C 2 symmetric 2 structure leading to the activated-TU transition state is more stable than the C S structure required for a dual-thiourea activation mechanism by 5.7 or 9.4 kcal/mol, respectively, eq. 1 (see Experimental Section). Further, computations suggest that LA activation via the activated-TU structure (scheme 4.2, left) is lower in energy than the dual-thiourea activation structure (scheme 4.2, right), see Experimental Section. Future studies will be aimed at experimentally determining the source of this increased activity.

Conclusion
Achiral, bis(thiourea) H-bond donating molecules have been shown to be highly effective cocatalysts for the ROP of lactide. The rate accelerated 2/alkylamine systems retain ROP control, exhibiting the characteristics of a "living" polymerization, a high selectivity for monomer and marked activity at low catalyst loadings. The reaction rate enhancement is postulated to occur via an activated-TU mechanism, but ongoing mechanistic studies are expected to provide further insight into the source of the potency of the bis(thiourea) systems. The addition of a second thiourea moiety to these H-bond donating systems introduces the possibility of a multitude of structural variations, each of which could have dramatic ramifications on the course of the ROP.

General Considerations
All manipulations were performed in an MBRAUN stainless steel glovebox equipped with a gas purification system under a nitrogen atmosphere. All chemicals were purchased from Fisher Scientific and used as received unless stated otherwise.
Dichloromethane, toluene and THF (HPLC grade) were dried on an Innovative Technology solvent purification system with activated alumina columns. Thiourea catalysts were prepared as previously described. 7

Example ROP of L-Lactide
In a typical polymerization, L-LA (100 mg, 0.7 mmol) was added to a 20 mL

Determination of P m
The standard polymerization procedure was repeated but with rac-LA (100 mg, 0.7 mmol). The polymerization solution was stirred for enough time to achieve 90% conversion (to minimize postpolymerization reactivity). The reaction was quenched by the addition of benzoic acid and conversion determined by 1 H NMR. The polymer was then dialyzed in methanol for 24 h to remove any trace of monomer impurity. The pure monomer was dissolved in chloroform-d and analyzed by 1 H-decoupled 13 C NMR at 70 °C. The procedure for determining P m is thoroughly described elsewhere. 16,24−26 Briefly, the experimental intensities of the five tetrads resulting from the ROP of rac-lactide were simulated using MNova software. The theoretical intensities of these resonances are determined from Markovian statistics from the P m value. A calculated value of P m was determined using Excel by systematically varying P m subject to the minimization in the difference between the experimental and calculated tetrad intensities.

Computational Details
Computational experiments were performed in Spartan '14 (Windows 7).
Structures were geometry optimized at the DFT B3LYP/6-31G** level of theory in the gas phase. Energies in CH 2 Cl 2 solvent were calculated as Single Point energies from the DFT-optimized structures. Energies, computed structures, and coordinates of optimized structures are given in the Experimental Section.

Introduction
H-bond mediated ring-opening polymerization (ROP) has attracted interest due to the highly controlled nature of these transformations. 1−4 These mild, highly functional group tolerant catalysts, especially the bimolecular systems consisting of a  readily available H-bond accepting base cocatalysts and adds a synthetic step prior to conducting polymerization chemistry. Certainly, the ready availability of chemical reagents and catalysts facilitates the wide implementation of chemical transformations.
In this context, the antibacterial compound, triclocarban (TCC, figure 5.1), recently banned as a hand soap additive by the FDA, captured our attention. 16 It is an electrondeficient biaryl urea, similar to the slate of urea and multiurea H-bond donating catalysts that we recently showed to be highly active for ROP. 13 While TCC has attracted considerable scientific interest as an antibacterial compound, possible bioaccumulate, and possible environmental toxin, we believe that this readily available compound has not previously been employed as a catalyst. 17−19

Results and Discussion
The efficacy of TCC/amidine base combinations for the ROP of lactone monomers was evaluated, table 5.1. All reactions were conducted in C 6 D 6 and conversion monitored by 1   We have embarked on a research program aimed at mitigating the low activity of H-bond mediated transformations without sacrificing the precise control typical of these catalysts. In this vein, electron deficient aryl ureas have proved to be particularly efficacious; our lab previously disclosed the rapid rates exhibited by mono-, bis-, and tris-urea H-bond donors for the ROP of lactones. 13 In general, urea H-bond donors are more active for ROP than their corresponding thioureas. This trend extends to the urea anions which, besides being remarkably active and controlled catalysts for ROP, are much more active than the corresponding thiourea anions. 10,12 The uncharged H-bond   entry 2), which may constitute an advantage versus other highly active systems for ROP. 10,12,13 Urea H-bond donors remain active in polar, H-bond accepting solvent. A longstanding limitation of H-bond mediated catalysis is the often narrow window of nonpolar solvents in which these catalysts are operable. 20,21 We had previously observed that the urea H-bond donor 3-O remains active in THF and hypothesized that TCC would exhibit similar behavior, and a solvent screen was conducted for the  The enhanced efficacy of TCC and all urea H-bond donors in C 6 D 6 could be attributed to the stronger binding of ureas vs thioureas to monomer. 20 The limited solubility of TCC and n-O in nonpolar solvent in the absence of base cocatalyst limits the extent to which we can quantitatively probe this hypothesis by measuring binding constants to monomer. For example, TCC is insoluble in benzene in the absence of Hbond acceptor, and binding constants for this compound could not be measured.
However, the binding constants of 1-O and 1-S to CL were independently measured in C 6 D 6 and are consistent with the long-held hypothesis: for 1-O, K eq = 41 ± 1 (300 K) and for 1-S, Keq = 28 ± 1 (300 K). 24 However, a binding constant rationale cannot be used to explain the ROP activity observed in acetone. As expected, when the 1-O /monomer binding study is repeated in acetone-d 6 , there is no observed change in chemical shift of 1-O up to ∼ 1000 equiv of monomer, which suggests very weak (K eq ∼ 1) or no binding in acetone-d 6 . While we have previously observed 1-S to exhibit a marked effect on a ROP reaction in the near absence of binding to monomer, 29,30 these questions collectively reinforce a recently proposed mechanism. 12 (1) While this study was ongoing, "hyperactive" urea anions for ROP, generated by the action of alkoxides upon aryl and alkyl ureas, were disclosed; these systems are incredibly active yet controlled, exhibiting rates that rival traditional metal-based systems. 12 The proposed mechanism of action whereby an active urea anion catalyst is generated by the deprotonation of a urea by alkoxide is distinct from traditional H-bond mediated ROP by neutral catalysts, and we sought to investigate the feasibility of this mechanism for TCC/imine bases. As opposed to the quantitative deprotonation of TCC by potassium methoxide, one could envisage an equilibrium established between urea plus base and the corresponding salt, eq 1. 1 H NMR spectra in acetone-d 6   Higher reaction concentrations can be employed, but the reaction becomes difficult to monitor, fully converting within seconds at 2 M VL. The same ROP of VL fails to reach full conversion in THF or acetone-d 6 within 30 min. In C 6 D 6 , the ROP is highly controlled and exhibits the characteristics of a "living" polymerization (see

Mechanistic Considerations
We propose that the TCC/base cocatalyzed ROP of ester monomers proceeds through a mixed mechanism where the identity of the dominate catalyst largely depends on the pK a of the cocatalysts. The 1 H NMR spectrum of TCC plus Me 6 5.21). Accordingly, we propose that TCC/base cocatalyzed ROP is capable of effecting ROP through a classic dual H-bond mechanism mediated by neutral catalysts or an imidate mediated mechanism, the primary determination of which mode is dominate rests with the pK a of the base. In the case of TCC plus Me 6 TREN, we proposed a primarily neutral catalyst mechanism versus BEMP, which may proceed primarily through an imidate mechanism, scheme 5.1. Certainly, the rate of the TCC/BEMP ROP recalls that of the alkoxide-generated urea anions. 12 This mechanistic proposal is an extension of the recent work with "hyperactive" urea anion catalysts for ROP, taking into account weakly basic cocatalysts. 12 For the present system, it is unclear if the conjugate acid of the base serves as a H-bond donor or primarily serves to deprotonate the urea. The complicated and sensitive interplay of cocatalyst/reagent interactions requires more study to be thoroughly understood.

Conclusion
The antibacterial TCC has been shown to be a highly effective cocatalyst for ring-opening polymerization. The commercially available H-bond donor, when applied with an H-bond accepting base cocatalyst, is among the most active organic catalysts for the ROP of esters, yet it exhibits the characteristics of a "living" polymerization, producing well-defined polymers. The activity of this catalyst can be approximated by other mono-and dichloro biaryl urea H-bond donor(s), which adds synthetic flexibility for the generation of future H-bond donating ureas. We suspect that the ROP of lactone monomers is just one application that can offer new roles to old reagents, in this case, the antibacterial compound now banned in hand soap, TCC.

General Considerations
All chemicals were purchased from Fisher Scientific and used as received unless  1H-NMR spectra (referenced to residual benzene-H) were acquired for each tube at 300 K and the chemical shift of the ortho-protons of 1-O was noted. Binding constants were determined by the curve fitting method, [33][34][35] and these values match those determined from the Lineweaver-Burke method. 36,37 Binding curves are shown below.

Example synthesis of 1-(4-chlorophenyl)-3-phenylurea (mono-CC).
A                    6,7 One of the tasks still to be addressed is stereoselective ring-opening polymerization of racemic monomers. 8,9,10 The importance of stereoselective ROP lies in the ability thereof to afford a variety of polymer architectures depending on the arrangement of stereocenters in the polymer backbone. 11,12 For example, polymerization of rac-LA can afford an array of stereoregular polymers, such as syndiotactic, heterotactic, and isotactic kinds. 11,12 All of these polymeric species are differentiated on the basis of stereocenters sequenced in the polymer chain. Positioning of stereocenters at the microlevel leads to drastically different physical properties of the respective polymers at the macrolevel. 13 For instance, the melting points T m for various lactide stereopolymers vary widely: T m = 100 ºC for heterotactic PLA, T m = 140 ºC for syndiotactic PLA, T m = 160 ºC for purely isotactic L-or D-PLA, and T m = 220 ºC for isotactic stereoblock PLA. 13 The variable physical properties of PLAs differing in the sequence of stereocenters in the polymer backbone are very valuable from the standpoint of industrial applications of such polymers. 14 That makes the goal of harnessing control over the stereocenters sequencing in PLA a lucrative one to pursue.

Results and Discussion
Efforts aimed at the kinetic resolution of chiral cyclic esters are well-known. 16,17 Previous works devoted to chain-end controlled 15,18,19 and catalyst-controlled 20 The polymer analysis was carried out using decoupled 1 H NMR spectroscopic experiments using the established methods. 12,15 The region of the polymer in the NMR spectrum corresponding to different stereosequences was noted, the respective peaks were fitted 15 under the spectrum region using the MNova NMR software, and the probability for isotactic enchainment in the polymer, P m , was calculated according to Bernoullian statistics. 12 Small molecule mediated asymmetric synthesis is well-established and offers a wide assortment of catalysts. 24 First, commercially available TU catalysts were applied for ROP of rac-LA in our study. The catalyst screening commenced with the chiral alkaloid based TU 1 that, satisfyingly, produced a poly-rac-LA (PracLA) with P m = 0.81! Since the precedent of H-bonding chiral resolving agents for cyclic esters exists 16,17 , we decided to subject 1 to the respective experiment to elucidate its rac-LA resolution ability. The   Inspired by this result, we turned our attention to the distinguished Takemoto catalyst 2 that demonstrated high efficiency in a range of small-molecule transformations. 25 The performance of 2 in ROP of rac-LA proved modest with the PracLA showing P m = 0.61.
We continued with assessment of structure-property relationships in the H-bonding catalysts slate. Catalyst 7 gave P m = 0.59 ( A range of TU catalysts developed by Jacobsen proved to be efficient for a variety of small molecule asymmetric transformations. 24 Thus we selected one of Jacobsen's catalysts 26 -5 -to be applied for a macromolecular transformation. However, ROP or rac-LA mediated by this catalyst yielded PracLA with rather modest P m = 0.61.
Having the brief screening of commercial candidates completed, we transitioned to the synthetic efforts. We decided to widen the catalyst scope by engendering new candidates for stereoselective ROP of rac-LA.
Our group disclosed an achiral bis-TU catalyst that proved to be a great mediator for ROP of L-LA -both fast in terms of the ROP rate and selective to the monomer. 6 Therefore, we decided to explore the bis-TU functionality fusion with a chiral locus in one molecule (scheme 6.1) to attempt rate-accelerated and stereoselective ROP of rac-LA. The designed synthetic procedures (see ES) successfully furnished the (first in our lab) chiral bis-TU catalyst 6 (figure 6.1).
The chiral bis-TU 6 was applied for the ROP of rac-LA. In accord with our expectation, the polymerization proceeded in a faster manner (table 6.1) compared to other catalysts in the set. To our gladdening, when the obtained PracLA was subjected to 1 H decoupled NMR analysis, a good P m = 0.80 was calculated for the resulting polymer.    increase in the P m values when going from small to larger substituents in the chiral locus may be attributed to the crowded environment created at the growing chain end, that leads to the reduction of randomness in the addition of the LA enantiomers to the growing polymer chain. Hence, isotactic enchainment will be brought about.

Conclusion
The of the second vial were added to the first vial and the resulting mixture was vigorously shaken until homogenous whilst the vial with the mixture was closed. The obtained reaction mixture was transferred to an NMR tube, capped, and the reaction progress was monitored by NMR spectrometry. When the desired conversion of the monomer to polymer was achieved as determined by NMR spectrometry, the contents of the tube were promptly transferred into a clean vial and the reaction was quenched with at least 2 equivalents of benzoic acid to the amount of Me 6 TREN. The solvent was removed by rotary evaporations, the residue was dissolved in the minimal amount of dichloromethane to obtain a homogenous solution and the synthesized polymer was precipitated with addition of hexanes. The liquids were decanted and precipitate was subjected to high vacuum to remove volatiles. The dried polymer was later washed with methanol, subjected to high vacuum, and underwent decoupled 1 H NMR analysis to determine the probability of isotactic enchainment (P m ). In Microsoft Excel, the application of the "Solver" functionality allows to minimize the "Weighted error" by varying the P m value.  (table above), (500 MHz, chloroform-d).

Preparation of Catalyst 3
A 25 mL flame-dried Schlenk flask was charged with dry DCM (8 mL), then (1R, 2R)-trans-2-(1-piperidinyl)cyclohexylamine (674 mg, 3.70 mmol) was added. The mixture was stirred under a static blanket of nitrogen until homogeneous and 3,5bistrifluoromethylisothiocyanate (0.676 mL, 3.70 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature under nitrogen overnight, the solvent was removed by rotary evaporation, and the residue was purified with column mixture was stirred at ambient temperature under nitrogen overnight, the solvent was removed by rotary evaporation, and the residue was purified with column chromatography using EtOAc/Hexanes = 10/90 as an eluant, furnishing the target catalyst 4 as a white powder. Characterization matched the literature sources.

Boc-DAP-Leu
Intermediate product Boc-DAP-Leu was synthesized according to the adapted literature procedure. 29  Intermediate product DAP-Leu was synthesized according to the adapted literature procedure. 29

Preparation of catalyst 7
A 50 mL flame-dried Schlenk flask was charged with dry DCM (25 mL), then (1R, 2R)-trans-N-Boc-1,2-cyclohexanediamine (776 mg, 3.60 mmol) was added. The mixture was stirred under a static blanket of nitrogen until homogeneous and 3,5bistrifluoromethylisothiocyanate (0.7 mL, 3.80 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature under nitrogen overnight, the solvent was removed by rotary evaporation, and the residue was purified with column chromatography using EtOAc/Hexanes/TEA = 19/80/1 as an eluant, furnishing the target catalyst 7 (61%) as a white powder. Characterization matched the literature sources.