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The Importance of Novel Synthetic Methodologies in Driving Green Chemistry:  
09:00am - 11:15am USA / Canada - Pacific - April 7, 2021
Chihui An, Organizer, Presider; Kevin Maloney, Organizer, Presider
Track: [ORGN] Division of Organic Chemistry
Division/Committee: [ORGN] Division of Organic Chemistry
Wednesday
Production of affordable medications in continuous flow
09:00am - 09:45am USA / Canada - Pacific - April 7, 2021
Peter Seeberger, Presenter
Track: [ORGN] Division of Organic Chemistry
Continuous chemical processes enable chemistry that is often impossible in batch.1 In this lecture I will discuss the work of my group between 2011 and about 2016 that resulted in new catalytic methods, continuous photochemistry and chemical assembly systems, where flow-reaction modules are linked together in an interchangeable fashion to access a wide chemical space will be introduced.2 I will focus on the production of much needed medications against malaria (artemisinin derivatives) 3 and HIV (Efavirenz). 4
For subsequent work on the green production of artemisinin and its derivatives please see he lecture of Prof. Kerry Gilmore in this symposium.

Wednesday
Photocatalysis using base metals
09:45am - 10:30am USA / Canada - Pacific - April 7, 2021
Tehshik Yoon, Presenter
Track: [ORGN] Division of Organic Chemistry
Heavy metal coordination complexes have proven to be ideal in photocatalytic applications across many subfields of chemistry, including in synthesis. Base metal complexes have very different photochemistry and are attractive not only because they have significantly greater terrestrial abundance but also because they offer new reaction strategies for photocatalytic synthesis.
Wednesday
Three case studies describing Amgen’s innovative approach to manufacturing an exceedingly complex API
10:30am - 11:15am USA / Canada - Pacific - April 7, 2021
Track: [ORGN] Division of Organic Chemistry
This presentation details some of Amgen’s innovative process development work on an exceedingly complex clinical drug candidate in the form of three vignettes. We first discuss the development and execution of a scalable photo [2+2] cycloaddition using continuous manufacturing to debottleneck the supply chain. Secondly, we detail a green, biocatalytic approach to the asymmetric synthesis of a stereodefined small-ring intermediate. Lastly, we share a combined computational modelling and high-throughput screening approach to leverage dramatic improvements in material throughput in a challenging macrocyclic ring closing metathesis step. Taken together, these innovative chemistries and technologies have driven sizeable reductions in process waste and the elimination of undesirable reagents and raw materials in the manufacturing process.
Nanocellulose: From Fundamentals to Function:  
09:00am - 12:00pm USA / Canada - Pacific - April 7, 2021
Falk Wolfgang Liebner, Presider; Glenn Larkin, Presider; Tiffany Abitbol, Organizer, Presider; Joice Jaqueline Kaschuk, Organizer, Presider; Michael Reid, Organizer, Presider; Jaana Vapaavuori, Organizer, Presider
Track: [CELL] Division of Cellulose and Renewable Materials
Division/Committee: [CELL] Division of Cellulose and Renewable Materials

Nanocellulose has become an important class of renewable nanomaterials with the potential to enhance existing materials and enable new categories of hybrid functional materials. Thorough characterization of particle morphology, size distribution, and surface chemistry is critical to fully optimize and exploit nanocellulose in different application arenas, for instance as viscosifying agents, emulsifiers, catalytic supports, strength additives, and in functional and smart materials with distinct and tunable properties (optical, electronic, magnetic, piezoelectric, and mechanical). This symposium aims to bridge the gap between fundamental research and nanocellulose utilization, connecting fundamental understanding and thorough characterization at the particle-level to the development of new nanocellulose-based functional materials. Characterization of cellulose nanofibrils and cellulose nanocrystals as well as their application in novel nanomaterials will be highlighted with a strong focus on the links between nanocellulose properties and applications.

Wednesday
Introductory Remarks
09:00am - 09:05am USA / Canada - Pacific - April 7, 2021
Track: [CELL] Division of Cellulose and Renewable Materials

Wednesday
Synthesis of microcapsules consisting of a hexadecane core and a cellulosic shell for thermal energy storage
09:05am - 09:30am USA / Canada - Pacific - April 7, 2021
Track: [CELL] Division of Cellulose and Renewable Materials
Organic phase change material (PCM) has an ability to store and release a large amount of energy in a wide range of temperature by the latent heat of fusion upon melting and crystallization. The encapsulation of PCM is necessary to stabilize PCM from an undesirable reaction and leaching. A PCM microcapsule whose shell is made of cellulosic biomass could be an option for better utilization of low-value bioresources. This study aims to prepare microcapsules containing hexadecane (PCM) encapsulated by a cellulosic shell from cellulose nanofibrils (CNF) through a sonochemical technique. High-intensity ultrasonication at the CNF-hexadecane interface created a oil-in-water emulsion, followed by the partial melting and possible crosslinking of CNF to form the cellulosic shell surrounding the hexadecane core. The formation of PCM microcapsules was investigated by visual inspection, FT-IR, and confocal laser scanning microscopy (CLSM) with a selective hydrophobic core fluorescent dyeing. The morphology and size distribution of the microcapsules were studied by SEM and CLSM, which ranged from 4 to 10 µm. Among various weight percents of CNF in water and hexadecane-water ratios, the maximum loading of PCM was determined to be 90% from 0.3% CNF in water and 2:1 water-oil ratio, respectively, by thermal gravimetric analysis. The microcapsules exhibited 132.5 J/g (upon heating) and 141.1 J/g (upon cooling) as stored and released energy, respectively, between -10 and 45 °C. After 200 repeated heating/cooling cycles, the energy loss was only around 1% compared with the initial thermal energy of the microcapsules. Incorporating the PCM microcapsules into TEMPO-oxidized cellulose nanofibril (TOCNF) film increased the thermal stability of microcapsules, which could be useful as a thermal energy storage (TES) material in building applications
Wednesday
Dense and organized cellulose nancrystals emulsion droplets as model to study enzyme action
09:30am - 09:55am USA / Canada - Pacific - April 7, 2021
Track: [CELL] Division of Cellulose and Renewable Materials

Lignocellulosic materials are of the most promising renewable feedstocks available for human exploitation. Its biological conversion with enzymes offers producing a range of sugar residues in an ecofriendly way (low energy and water consumption). Enzymatic hydrolysis at high solid loadings (≥15% w/w) would render the conversion process more economically feasible. However, this remains a challenge given the poor understanding we have of enzyme activity in a dense medium, limited diffusion of the enzyme and changed mode of action. We prepared a low volume and highly organized model platform to mimic enzymatic activity. It is known that highly concentrated suspensions of rod-like cellulose nanocrystals (CNCs) (200 nm long x 10 nm section) self-assemble to form stable cholesteric liquid crystalline (LC) phases with pitches of few tens of microns. We thus prepared droplets of such highly concentrated suspension resulting in 100 to 200 µm diameter droplets in LC form presenting concentric organization. Using deep-UV synchrotron radiation, the localization of proteins is probed either in organized and disordered areas using their autofluorescence. Two proteins are compared, an economically significant enzyme (glucanase GH7) and a control protein, bovine serum albumine (BSA). We will highlight the different technical challenges of such investigation and describe the influence of the proteins on CNC organization and vice versa.

Wednesday
Aqueous surface-modification of cellulose nanofibrils towards reinforced composites
09:55am - 10:20am USA / Canada - Pacific - April 7, 2021
Track: [CELL] Division of Cellulose and Renewable Materials
Cellulose nanofibrils (CNFs) have proven useful as reinforcement fillers in a range of composite materials owing to their high strength and stiffness. Unfortunately, the hydrophilicity of CNFs makes it incompatible with polymer matrix and results in agglomeration, making CNFs difficult to disperse in polymer composites. Surface modification strategies can enhance the hydrophobicity of CNF, resulting in good dispersion within the composites. Herein, a simple, customizable, polymer grafting strategy in water is used to produce polymer wrapped CNF. Detailed characterization assisted to optimize reaction conditions and confirm successful polymer grafting on the CNFs. Subsequent compounding with a polymer matrix produced composites which show enhancement in mechanical properties. Various CNF surface chemistries, tailored to the polymer matrix functionality, were investigated. Overall, these polymer-modified CNFs show promise as reinforcing agents in composite materials for a range of potential advanced material applications.
Wednesday
Intermission
10:20am - 10:40am USA / Canada - Pacific - April 7, 2021
Track: [CELL] Division of Cellulose and Renewable Materials

Wednesday
A variety of water-soluble polymers were evaluated to increase the mechanical response of cellulose nanofibrils (CNF) films. The two best performing candidates, polyvinyl alcohol (PVA) and poly(2-ethyl-2-oxazoline) PEOX, were chosen for further testing. Different concentrations of the polymers in addition to different molecular weights and hydrolysis degrees were studied. Due to the enhancement in the performance of TEMPO cellulose nanofibril (TOCNF) films, other CNFs were tested with the two best performing polymers. An increase of 113% in the modulus, 93% in the ultimate tensile strength (UTS), and 134% in the work of failure (WOF) were achieved by chlorite TOCNFs with 0.44mmol/g carboxylate groups; 48% in modulus, 93% in UTS, and 98% in WOF for hypochlorite TOCNF (1.5 mmol/g carboxylate content); and 68% in modulus, 35% in UTS, and a decrease in WOF due to embrittlement in mechanical CNF (mCNF) were observed. The toughening mechanism was attributed to the creation of hydrogen bonds between the CNFs and the hydrophilic polymers added. The presence of such mechanisms was indirectly confirmed by zeta potential and rheology.

Wednesday
Withdrawn
11:05am - 11:30am USA / Canada - Pacific - April 7, 2021
Track: [CELL] Division of Cellulose and Renewable Materials

Wednesday
The physicochemical effect of sugar alcohol plasticizers on oxidised nanocellulose gels and extruded filaments
11:30am - 11:55am USA / Canada - Pacific - April 7, 2021
Track: [CELL] Division of Cellulose and Renewable Materials
Oxidised cellulose nanofibrils (OCNFs) have previously shown promise for the production of extruded filaments with high tensile strength properties. However, they also exhibit poor wet strength due to swelling upon immersion in water. This has resulted in the use of chemical cross-linkers, or co-extrusion with multivalent cations, or cationic polymers, to inhibit this. Interestingly, alcohols have also been reported to promote attraction between fibrils in primarily aqueous gels, which suggests that they could also be used to limit filament swelling. Sugar alcohols (SAs), in particular, are less volatile than other alcohols, are often used as ‘natural’ plasticizers, and many have FDA approval for use in food products.
Here, we report on the effect of incorporating SAs (glycerol, sorbitol and maltitol) in the OCNF gel before filament extrusion. Whilst their presence weakens the initial gel structure (Figure 1a), they enable the continuous wet spinning of OCNF filaments that are stable in aqueous media (Figure 1b). Analysis – including rheology, confocal fluorescent spectroscopy, and QCM-D – of the OCNF/SA systems lead us to conclude that the relative hydrophilicity of the SA and its ability to protonate surface carboxyl groups upon drying are key parameters regarding the physicochemical effects observed.
<b>Figure 1. a) </b>Rheological properties of OCNF-SA gels. Storage (closed symbols) and loss (open symbols) moduli of the pure OCNF gel (black diamonds), and OCNF gels with glycerol (green triangles), sorbitol (red circles) and maltitol (blue squares). <b>b)</b> Confocal fluorescent spectroscopy images of i) pure OCNF filament and OCNF filaments with ii) glycerol, iii) sorbitol, and iv) maltitol after immersion in water for 30 min.

Figure 1. a) Rheological properties of OCNF-SA gels. Storage (closed symbols) and loss (open symbols) moduli of the pure OCNF gel (black diamonds), and OCNF gels with glycerol (green triangles), sorbitol (red circles) and maltitol (blue squares). b) Confocal fluorescent spectroscopy images of i) pure OCNF filament and OCNF filaments with ii) glycerol, iii) sorbitol, and iv) maltitol after immersion in water for 30 min.


Wednesday
Concluding Remarks
11:55am - 12:00pm USA / Canada - Pacific - April 7, 2021
Track: [CELL] Division of Cellulose and Renewable Materials

Structure and Dynamics of Amyloids and Precursors by NMR:  
09:00am - 11:50am USA / Canada - Pacific - April 7, 2021
Jean Baum, Organizer; Andrew Nieuwkoop, Organizer; Prof. Mei Hong, Presider
Track: [PHYS] Division of Physical Chemistry
Division/Committee: [PHYS] Division of Physical Chemistry
Wednesday
Introductory Remarks
09:00am - 09:05am USA / Canada - Pacific - April 7, 2021
Track: [PHYS] Division of Physical Chemistry

Wednesday
Atomic-resolution structural studies of polyglutamine protein aggregates from Huntington’s disease
09:05am - 09:30am USA / Canada - Pacific - April 7, 2021
Track: [PHYS] Division of Physical Chemistry
The 1990s saw the discovery that Huntington’s disease has its primary genetic origins in the expansion of CAG repeats in the huntingtin gene. Since then, resolving the structural features of polyglutamine protein deposits have been a holy grail in efforts to understand and treat the fatal neurodegenerative disease. Despite the seemingly “simple” primary structure of the polyglutamine domain, this proved to be a significant challenge. In an integrative structural biology approach, we have been tackling this challenge, dissecting the structural features of the pathogenic protein assemblies, bit by bit. A complex aggregation pathway yields polymorphic samples, in which variations in structure (and mobility) occur between samples, within samples, within individual protein fibrils and even within the misfolded proteins themselves. Notably, among many parameters, we recently discovered a remarkable impact of the protein concentration on the polymorphic behavior. We have employed an integration of solid-state NMR, electron microscopy and X-ray methods (among others) to gain complementary atomic-level and supramolecular data. I will discuss the current status of our work, including our newest models of the ordered, but “stochastically assembled”, fiber core and the surface-exposed flexible domains. Unlike most pathogenic amyloids, the core (featuring the expanded polyglutamine) adopts a highly specific antiparallel β-sheet structure, that is characterized by a striking doubled ssNMR peak pattern. Aside from our models of the mature deposits, I will discuss their connection to pivotal nucleation and multistep aggregation pathways, which are implicated in disease onset. Molecular chaperones and antibodies may be deployed to target key steps, with an aim of inhibiting pathogenic deposition or directing the misfolding process to less toxic polymorphic variants.
<b>Figure</b> - Mutant huntingtin exon 1 forms nano-fibrillar protein deposits (see by electron microscopy), via an amyloid-like aggregation pathway involving the nucleation of β-sheet-based amyloid structure. Integrative structural biology yields structural models of the mature fibrils.

Figure - Mutant huntingtin exon 1 forms nano-fibrillar protein deposits (see by electron microscopy), via an amyloid-like aggregation pathway involving the nucleation of β-sheet-based amyloid structure. Integrative structural biology yields structural models of the mature fibrils.


Wednesday
A mechanism of potential cross-β (amyloid) fibril toxicity will have to be mediated by the (abnormal) interaction of the fibril with cellular binding partners. We are studying the fibril surface in the context of huntingtin exon-1 (HTTex1) important in Huntington’s Disease (HD). The core of HTTex1 fibrils is formed by its polyQ domain, which is expanded in HD. The Pro-rich C-terminus of HTTex1 fibrils is highly dynamic as shown by solid-state NMR and EPR. Consequently, we proposed a bottle brush model of HTTex1 fibrils in which the C-terminus forms the surface of the fibrils in the form of dynamic bristles. We show that the differences between HTTex1 fibrils of different toxicity are located in the C-terminus rather then the polyQ domain. Small fibrils with highly dynamic C-termini are more seeding competent, more accessible to protein-protein interaction, and more toxic than long, entangled fibrils.
To describe the dynamics and conformational space of this C-terminus in detail, we measured site-specific R1 and R2 rates, and residual dipolar couplings via a combination of solution and solid-state NMR. We measured distance distributions throughout the C-terminus using DEER EPR. Finally, we ran MD simulations of that are in good agreement with the experimental data. With a detailed description of the HTTex1 fibril surface in hand, we are studying the interaction of HTTex1 C-terminus with the co-chaperone DNAJB1 using solid-state NMR and EPR.
Using MD simulations in combination with solid-state NMR and EPR data, we modeled of the dynamic proline-rich domain (PRD) of HTTex1 fibrils that is key for fibril interactions and toxicity.

Using MD simulations in combination with solid-state NMR and EPR data, we modeled of the dynamic proline-rich domain (PRD) of HTTex1 fibrils that is key for fibril interactions and toxicity.


Wednesday
Huntington’s disease is a fatal neurodegenerative condition arising from polyglutamine expansion within the Huntingtin protein leading to fibril accumulation in neurons. The initial multimerization events occur on the submillisecond timescale and involve sparsely populated species that can be probed at atomic resolution by NMR. Using a minimalistic construct comprising the N-terminal amphiphilic domain and seven glutamines, we uncover a branched oligomerization pathway, one leading to a tetramer comprising a dimer of coiled-coil helical dimers, and the other resulting in a nonproductive, partially helical, dimer. profilin-I, an abundant intracellular protein, that inhibits fibril formation acts by binding to the two polyproline repeats C-terminal to the polyQ region and block the productive pathway while leaving the unprodictive pathway unaffected. The results illuminate the contribution of the N-terminal amphiphilic domain in prenucleation events that precede fibril formation.
Wednesday
Intermission
10:20am - 10:35am USA / Canada - Pacific - April 7, 2021
Track: [PHYS] Division of Physical Chemistry

Wednesday
Shedding light on the disorder: A sensitive look into protein folding with hyperpolarized solid-state NMR
10:35am - 11:00am USA / Canada - Pacific - April 7, 2021
Henrike Heise, Presenter
Track: [PHYS] Division of Physical Chemistry
NMR-spectra obtained at cryogenic temperatures below 150 K usually suffer from severe inhomogeneous line broadening, as flexible parts of molecules may be trapped in different conformations with different chemical shifts. While broad lines result in limited resolution and thus are considered an unwanted side-effect of low temperatures, they encode valuable information about conformational distributions of flexible molecules. In this contribution we combine dedicated isotope labeling techniques with DNP-enhanced MAS-NMR-spectroscopy of proteins in frozen solution to shed light onto different conformational ensembles sampled by protein backbone as well as by amino acid side chains.
We exploit DNP-enhanced MAS NMR spectroscopy at low temperatures (~100K) to investigate conformational ensembles of intrinsically disordered proteins IDPs. Such proteins are not represented by a single well-defined structure but rather by a full conformational ensemble of structures which can interconvert rapidly. Traditional biophysical methods like solution NMR spectroscopy and FRET measurements usually determine ensemble averages and do not give direct insight into the conformational distributions. In frozen solution the full conformational ensemble is trapped and can be examined simultaneously, for example by (DNP-enhanced) solid-state NMR-spectroscopy. First, we studied the distribution of backbone conformations in the intrinsically disordered protein α-synuclein in frozen solution in different surroundings by evaluating the inhomogeneously broadened line-shapes of the Cα/Cβ cross peak. We could estimate the amount of disordered regions in fibrillar α-syn and delineate the membrane binding regions of α-syn in contact with membrane surfaces in in different protein to lipid ratios. We also found that secondary chemical shifts of neighboring amino acids tend to be correlated, a finding which suggests the formation of transient secondary structure elements.
We also investigated the distribution of rotameric states sampled by amino acid side chains in well-folded as well as in intrinsically disordered proteins and model peptides. This distribution drastically depends on the local and global structure of the protein and exceeds the conformational space documented in the pdb database. Our experimental results match well the results from a combined DFT/solution NMR-study.

Wednesday
It has been known since the early days of structural biology on the Alzheimer’s amyloid-β peptide (Aβ) that assembly can proceed along multiple distinct pathways. Different Aβ assemblies can be distinguished based on which residues are involved in β-strands and how the β-strands arrange into β-sheets. We will present solid-state NMR data on a 150 kDa (30 molecules) oligomer of the 42-residue variant Aβ(1-42). NMR data indicate the presence of 2 β-strands and that one β-strand is assembled into a parallel β-sheet while the other forms an antiparallel β-sheet. We are aware of no previously measured or proposed Aβ structure that rationalizes this β-strand configuration. Cryo-EM imaging of the 150 kDa oligomer revealed a previously unknown symmetry and a central pore, making it possible for us to propose a new domain-swapped molecular structural model that explains the NMR and the cryo-EM data. This model motivates specific theories on the mechanism of peptide assembly into oligomers and why a β-sheet assembly could form stable oligomers without forming amyloid fibrils. Our model provides a basis for us to propose explanations for the following experimental observations: oligomers 1) are limited in size; 2) do not seed the formation of fibrils; 3) do not bind thioflavin T; and 4) can increase permeability of cell membranes.
Left: Chart of model-predicted (colors) and NMR-detected (stars) inter-residue proximities. Middle: Cryo-EM image and 2D reconstructions (insets). Right: Proposed Model

Left: Chart of model-predicted (colors) and NMR-detected (stars) inter-residue proximities. Middle: Cryo-EM image and 2D reconstructions (insets). Right: Proposed Model


Wednesday
1H-detection and dynamic nuclear polarization-enhanced NMR of Ab1-42 fibrils
11:25am - 11:50am USA / Canada - Pacific - April 7, 2021
Prof Robert Griffin, Presenter
Track: [PHYS] Division of Physical Chemistry
Research on Alzheimer’s disease (AD) needs rapid and reliable high-throughput characterization, so to address the structural diversity of Ab plaques and rationalize the role of peptide length, mutations, and post-translational modifications in their formation. These problems are beyond the capability of currently available techniques. Magic-angle spinning (MAS) NMR spectroscopy is an ideal technique for studying amyloids at atomic resolution but suffers from low sensitivity, requiring relatively large amounts of samples and extensive signal acquisition periods. Recent advances in 1H-detection at fast MAS and dynamic nuclear polarization (DNP) have ushered in a new era for NMR-based structural biology, but their potential has not yet been demonstrated for the structural investigation of complex amyloid assemblies. Here we show that resolved and sensitive 2D and 3D correlations are obtained on 13C,15N-enriched and fully-protonated samples of M0Ab1-42 fibrils by 1H detected NMR at ωr/2π =110 kHz and high field (23.4 T/ 1000 MHz for 1H) at room temperature and 13C detected DNP MAS NMR at ωr/2π=40 kHz and high field (18.8 T/ 800 MHz for 1H) at low temperature. These spectra enable nearly complete resonance assignment of the core of M0Ab1-42 (K16-A42) using sub-mg sample quantities, as well as the detection of numerous unambiguous inter-nuclear proximities defining both the structure of the core and the arrangement of the different monomers. Overall, this work demonstrates the possibility of expeditious structural analysis of amyloid fibrils without requiring preparation of large sample amounts, and illuminates the path to the study of unlabeled AD peptides derived from tissue samples available in limited quantities.
Molecular Crystal Polymorphism: How, When and Why Molecules Pack in the Solid State:  
09:00am - 11:45am USA / Canada - Pacific - April 7, 2021
Maria Baias, Organizer; Gregory Beran, Organizer; Mark Tuckerman, Presider
Track: [PHYS] Division of Physical Chemistry
Division/Committee: [PHYS] Division of Physical Chemistry
Wednesday
Can we distinguish between CSP-generated structures that could be found and those that could never be found?
09:00am - 09:30am USA / Canada - Pacific - April 7, 2021
Track: [PHYS] Division of Physical Chemistry
The majority of crystal structure prediction (CSP) studies generate structures that are more thermodynamically stable than some observed polymorphs, raising the question of why we do not observe more polymorphs.Sometimes, this is because the right experiment has not yet been done, and a non-routine experiment can be designed from the computer-generated structure and its physical properties, which finds the new polymorph. This has been done by subliming onto a template crystal, or crystallising under pressure or in a strong magnetic field. However, some structures are artefacts of the static crystal modelling used in CSP. Performing Molecular Dynamics simulations can show that groups of CSP structures cannot be distinguished when the dynamic motion of molecules in the crystals is taken into account, thus reducing the number of unobserved thermodynamically competitive structures. Such simulations are sensitive to the realism of the entire potential energy surface, and so there is a challenge in determining a force-field that will realistically model cases where the transformation to more stable structures is so facile that the intermediate structures cannot be observed. There are cases of irreproducible polymorphs that challenge methods of determining which CSP generated structures can be observed. Current lattice energy based CSP methods are just a zeroth-order approximation to predicting how an organic molecule can crystallize, which could be made more useful if systematically enhanced with Molecular Dynamics screening approaches.
Wednesday
Crystal structure prediction (CSP) aims to reduce the risk and improve the efficiency of pharmaceutical drug manufacturing by correctly predicting the low energy crystal polymorphs of organic molecules from minimal information, such as the chemical diagram. Traditionally, CSP approximates the solid form energy landscape at ambient temperature using energy-minimized crystal structures at 0 K. While this approach is often successful in predicting the low energy structures, it neglects the crucial role of thermal effects on polymorph stabilities. Moreover, it often leads to overprediction of polymorphism since crystal structures trapped in shallow lattice energy minima at 0 K often coalesce into the same ensemble of crystal structures at ambient temperature. To address these issues, we have developed a robust multi-stage approach that uses a combination of molecular dynamics, free energy calculations, information entropy clustering, and PXRD matching to characterize the relevant set of ambient temperature crystal structures. Enhanced sampling simulations are used to assess the likelihood of polymorphic transitions between crystal structures and identify unique metastable forms. We demonstrate our approach on the crystal polymorphs of sulfamerazine.
Wednesday
Polymorphism properties and transformation pathways under nanoconfinement
10:00am - 10:30am USA / Canada - Pacific - April 7, 2021
Michael Ward, Presenter
Track: [PHYS] Division of Physical Chemistry
Polymorphism in solid-state materials can be a doubleedged sword. The dependence of physicochemical properties on crystal structure can result in new, and possibly advantageous, functions in metastable polymorphs. Conversely, the unanticipated appearance of a new crystal form of a commercial compound can be costly. Consequently, the discovery of new forms, the factors influencing their occurrence, and characterization of polymorphic phase transitions are paramount. the sizes of organic crystals grown under nanoscale confinement are not appreciably different than those expected at or near the size of critical nuclei. Consequently, nanoconfinement allows the manipulation and examination of crystallization, as well as transformation pathways, at a length scale for which the kinetics of crystallization and thermodynamics of nuclei intersect. This has been most apparent in the observation of size-dependent polymorphism, in which normally metastable phases become thermodynamically favored forms when confined in nanoscale pores. This presentation will describe recent discoveries that exemplify the influence nanoscale confinement on the polymorph stability rankings as well as on phase transformation pathways, focusing on benzamide, the first reported example of polymorphism of molecular crystals, a flufenamic acid, one of the most remarkable and well studied examples of polymorphism.
Wednesday
Intermission
10:30am - 10:45am USA / Canada - Pacific - April 7, 2021
Track: [PHYS] Division of Physical Chemistry

Wednesday
Topology, molecular simulation, and machine learning as routes to exploring structure and phase behavior in molecular and atomic crystals
10:45am - 11:15am USA / Canada - Pacific - April 7, 2021
Mark Tuckerman, Presenter
Track: [PHYS] Division of Physical Chemistry
Organic molecular crystals frequently exist in multiple forms known as polymorphs. Structural differences between crystal polymorphs can affect desired properties, such as bioavailability of active pharmaceutical formulations, lethality of pesticides, or electrical conductivity of organic semiconductors. Crystallization conditions can influence polymorph selection, making an experimentally driven hunt for polymorphs difficult. Such efforts are further complicated when polymorphs initially obtained under a particular experimental protocol “disappear” in favor of another polymorph in subsequent repetitions of the experiment. Consequently, theory and computation can potentially play a vital role in mapping the landscape of crystal polymorphism. Traditional crystal structure prediction methods face their own challenges, and therefore, new approaches are needed. In this talk, I will show, by leveraging concepts from mathematics, specifically geometry and topology, and statistical mechanics in combination with techniques of molecular simulation, traditional methods, and machine learning, that a new paradigm in crystal structure prediction may be emerging. Examples demonstrating prediction of structures of crystals, co-crystals, and phase transitions will be presented.
<i>Upper left</i> – Illustration of classification NN with input layer consisting of symmetry functions and Steinhardt order parameters.  <i>Upper right</i> – Learning curve for the molybdenum system.  <i>Lower left</i> – Free energy profile in the path CV averaged over 50 trajectories.  <i>Lower right</i> – Example transition trajectory.

Upper left – Illustration of classification NN with input layer consisting of symmetry functions and Steinhardt order parameters. Upper right – Learning curve for the molybdenum system. Lower left – Free energy profile in the path CV averaged over 50 trajectories. Lower right – Example transition trajectory.


Wednesday
Diabat method for polymorph free energies: Extension to molecular crystals
11:15am - 11:45am USA / Canada - Pacific - April 7, 2021
Track: [PHYS] Division of Physical Chemistry
Lattice-switch Monte Carlo and the related diabat methods have emerged as efficient and accurate ways to compute free energy differences between polymorphs. In this work, we introduce a one-to-one mapping from the reference positions and displacements in one molecular crystal to the positions and displacements in another. Two features of the mapping facilitate lattice-switch Monte Carlo and related diabat methods for computing polymorph free energy differences. First, the mapping is unitary, so that its Jacobian does not complicate the free energy calculations. Second, the mapping is easily implemented for molecular crystals of arbitrary complexity. We demonstrate the mapping by computing free energy differences between polymorphs of benzene and carbamazepine. Free energy calculations for thermodynamic cycles, each involving three independently computed polymorph free energy differences, all return to the starting free energy with an extremely high degree of precision. The calculations provide a force field independent validation of the method, and demonstrate the precision of the individual free energy differences.

Advances in Functionalized Polyolefin Synthesis:  
09:00am - 11:40am USA / Canada - Pacific - April 7, 2021
Brad Carrow, Organizer; Changle Chen, Organizer; Damien Guironnet, Organizer; Eva Harth, Organizer, Presider; Michael Abrams, Presider
Track: [PMSE] Division of Polymeric Materials Science and Engineering
Division/Committee: [PMSE] Division of Polymeric Materials Science and Engineering
Wednesday
Post-polymerization modification as a synthetic route to defined polyethylene polymers and block copolymers
09:00am - 09:30am USA / Canada - Pacific - April 7, 2021
Track: [PMSE] Division of Polymeric Materials Science and Engineering
We report on a new and innovative post-polymerization modification procedure for the synthesis of defined polyethylene polymers. Reactive precursor polymers based on poly[N-(acryloyloxy)phthalimide] can undergo thermally- and photochemically-induced metal-catalyzed decarboxylations yielding polyethylenes. The presented route towards various polyethylene structures via decarboxylation reactions establishes a new field in polymer chemistry, namely the straightforward and efficient synthesis of different polyethylene-block copolymers.
General reaction pathway for thermally- and photochemically-induced decarboxylations yielding polyethylenes.

General reaction pathway for thermally- and photochemically-induced decarboxylations yielding polyethylenes.


Wednesday
Complementary functional polyolefin architectures by uni- and bidirectional insertion polymerization
09:30am - 10:00am USA / Canada - Pacific - April 7, 2021
Track: [PMSE] Division of Polymeric Materials Science and Engineering
The development of practical routes to functional polyolefins (f-PO) directly from simple alkenes with tunable microstructure and sequence control is a long-standing challenge. This presentation will discuss complementary strategies we have pursued to access different f-PO architectures. A series of P(V)-P(III) ligands have been discovered that generate nickel(II) catalysts capable of producing linear, statistical f-PO copolymers with molecular weights and sequences that mimic linear low-density polyethylene. Mechanistic data have established how these catalysts differ from existing systems by accessing unusual “electron-rich metal cation” behavior that tempers Lewis acidity, needed for functional group compatibility, while maintaining electrophilic character for high intrinsic reactivity. Alternatively, functional groups can be positioned exclusively at chain ends to access telechelic f-PO using bidirectional catalysts that are rapidly assembled from abundant starting materials.
Wednesday
Thermodynamic interactions in polydiene/polyolefin blends
10:00am - 10:30am USA / Canada - Pacific - April 7, 2021
Track: [PMSE] Division of Polymeric Materials Science and Engineering
Polymer blends exhibit properties that are highly dependent on interactions between components, typically quantified by the Flory-Huggins interaction parameter, χ. Prediction of blend phase behavior requires characterization of the temperature dependence of χ. Polyolefins and polydienes are important materials with commercial relevance in elastomer applications. The majority of previous studies on the thermodynamics in polyolefin and polydiene systems have focused on polymer pairs within the same class (i.e. polyolefin/polyolefin and polydiene/polydiene blends), which generally exhibit a small and weakly temperature dependent χ. There is little quantitative information on thermodynamic interactions in systems that contain both polydienes and polyolefins. We have characterized interactions in polyolefin and polydiene blends, composed of 1,2-polybutadiene, 1,4-polyisoprene, poly(ethyl ethylene), and poly(ethylene-co-ethyl ethylene), utilizing small angle neutron scattering (SANS). SANS data were analyzed through Random Phase Approximation and Zimm analyses in order to extract χ as a function of temperature. We observed an unusually large χ parameter in these polydiene/polyolefin blends. We also studied the impact of partial saturation of the polydiene on the thermodynamics of polydiene/polyolefin blends. The applicability of the random copolymer theory to predict χ(T) behavior in these blends was evaluated.

Wednesday
Thermodynamics and structural properties for ROMP of allylic cyclopentene to produce precision, isotactic polyolefins
10:30am - 10:50am USA / Canada - Pacific - April 7, 2021
Track: [PMSE] Division of Polymeric Materials Science and Engineering
A detailed investigation of the thermodynamics of polymerization is necessary when trying to fully encapsulate the process of producing polyolefins. This investigation yields insight into how to produce isotactic polyolefins outside of a two-carbon branch periodicity, allowing for on insight on the structure-property relationships of tactic polyolefins. In order to probe the thermodynamics and structure-property relationship, ring-opening metathesis polymerization of bulky, allylic cyclopentenes were studied to provide the enthalpies and entropies of polymerization. These values can be advantageously compared to the regioregularity of the polyolefin microstructure to examine the effect of a bulky substituent. While low ring strain monomers have typically been thought to be driven via enthalpy, a complex relationship between the enthalpy and entropy of polymerization has been found. By better understanding the relationships between the thermodynamic parameters and regioregularity of the polymerization, a unique portion of the polymer genome can be better understood. Synthesis and the preliminary investigation of these properties will be discussed.

Wednesday
C-H functionalization of polyolefins
10:50am - 11:20am USA / Canada - Pacific - April 7, 2021
Frank Leibfarth, Presenter
Track: [PMSE] Division of Polymeric Materials Science and Engineering
Polyolefins are high-volume, low-cost engineering thermoplastics with high tensile strength, low density, attractive chemical resistance, and excellent processability. Currently, ployolefins constitute nearly 60% of world polymer production. For their ubiquity, however, these hydrocarbons do not interface with other materials, drastically limiting their ability to form composites, coatings, adhesives, or to be used in high-performance engineering applications. There is a considerable unmet need to develop chemistry that transforms these abundantly available commodity polymers into functional materials without resorting to de novo synthesis. To address this challenge, our approach to polyolefin C–H functionalization takes advantage of the high parent N–H bond dissociation energies of amidyl radicals to create custom reagents for the mild and selective addition of thiocarbonyl groups to commercial polyolefins. The versatile chemistry of these thiocarbonyl groups enable the rapid diversification of polymer function through simple chemical manipulations, thus generating a wealth of new materials from a universal synthetic platform. Initial work has developed both photochemical and thermal approaches to modify commercial polyolefins without polymer degradation. The presentation will focus on our current work, including comprehensive reagent design and optimization efforts, including probing radical identity and lifetime in situ, to make this process viable for functionalization within a reactive extruder. Furthermore, structure–property studies will demonstrate the emergent properties derived from polyolefin C–H functionalization.
Wednesday
Polymer stereoregularity, often referred to as tacticity, has been shown to dramatically influence material properties. Despite advancements in coordination-insertion polymerization methods used for the synthesis of stereoregular poly(α-olefin)s, polar isotactic polymers have remained a challenging synthetic target. Inspired by recent progress in the field of small-molecule asymmetric ion pairing catalysis, we have explored the use of chiral anions and chiral hydrogen bond donors to achieve polar thermoplastics through the stereoselective cationic polymerization of vinyl ethers. In this lecture, I will discuss a combination of kinetic investigations, temperature dependent stereoselectivity analyses, and computational studies that elucidate key design principles. Further, I will present a systematic evaluation of monomer substrates that establishes key structure-reactivity and structure-property relationships for stereoselective homo- and copolymerization, including the use of enantioenriched monomers.