Design of Experiments Grants Mechanistic Insights into the Synthesis of Spermine-Containing PBAE Copolymers.

Successful therapeutic delivery of siRNA with polymeric nanoparticles seems to be a promising but not vastly understood and complicated goal to achieve. Despite years of research, no polymer-based delivery system has been approved for clinical use. Polymers, as a delivery system, exhibit considerable complexity and variability, making their consistent production a challenging endeavor. However, a better understanding of the polymerization process of polymer excipients may improve the reproducibility and material quality for more efficient use in drug products. Here, we present a combination of Design of Experiment and Python-scripted data science to establish a prediction model, from which important parameters can be extracted that influence the synthesis results of polybeta-amino esters (PBAEs), a common type of polymer used preclinically for nucleic acid delivery. We synthesized a library of 27 polymers, each one at different temperatures with different reaction times and educt ratios using an orthogonal central composite (CCO-) design. This design allowed a detailed characterization of factor importance and interactions using a very limited number of experiments. We characterized the polymers by analyzing the resulting composition by 1H-NMR and the size distribution by GPC measurements. To further understand the complex mechanism of block polymerization in a one-pot synthesis, we developed a Python script that helps us to understand possible step-growth steps. We successfully developed and validated a predictive response surface and gathered a deeper understanding of the synthesis of polyspermine-based amphiphilic PBAEs.

Bicyclo[1.1.0]butyl Radical Cations: Synthesis and Application to [2π + 2σ] Cycloaddition Reactions.

As the chemistry that surrounds the field of strained hydrocarbons, such as bicyclo[1.1.0]butane, continues to expand, it becomes increasingly advantageous to develop alternative reactivity modes that harness their unique properties to access new regions of chemical space. Herein, we report the use of photoredox catalysis to promote the single-electron oxidation of bicyclo[1.1.0]butanes. The synthetic utility of the resulting radical cations is highlighted by their ability to undergo highly regio- and diastereoselective [2π + 2σ] cycloaddition reactions. The most notable feature of this transformation is the breadth of alkene classes that can be employed, including nonactivated alkenes, which have so far been elusive for previous strategies. A rigorous mechanistic investigation, in conjunction with DFT computation, was undertaken in order to better understand the physical nature of bicyclo[1.1.0]butyl radical cations and thus provides a platform from which further studies into the synthetic applications of these intermediates can be built upon.

Bridging the information gap in organic chemical reactions.

The varying quality of scientific reports is a well-recognized problem and often results from a lack of standardization and transparency in scientific publications. This situation ultimately leads to prominent complications such as reproducibility issues and the slow uptake of newly developed synthetic methods for pharmaceutical and agrochemical applications. In recent years, various impactful approaches have been advocated to bridge information gaps and to improve the quality of experimental protocols in synthetic organic publications. Here we provide a critical overview of these strategies and present the reader with a versatile set of tools to augment their standard procedures. We formulate eight principles to improve data management in scientific publications relating to data standardization, reproducibility and evaluation, and encourage scientists to go beyond current publication standards. We are aware that this is a substantial effort, but we are convinced that the resulting improved data situation will greatly benefit the progress of chemistry.

Double Strain-Release [2π+2σ]-Photocycloaddition.

In pursuit of potent pharmaceutical candidates and to further improve their chemical traits, small ring systems can serve as a potential starting point. Small ring units have the additional merit of loaded strain at their core, making them suitable reactants as they can capitalize on this intrinsic driving force. With the introduction of cyclobutenone as a strained precursor to ketene, the photocycloaddition with another strained unit, bicyclo[1.1.0]butane (BCB), enables the reactivity of both π-units in the transient ketene. This double strain-release driven [2π+2σ]-photocycloaddition promotes the synthesis of diverse heterobicyclo[2.1.1]hexane units, a pharmaceutically relevant bioisostere. The effective reactivity under catalyst-free conditions with a high functional group tolerance defines its synthetic utility. Experimental mechanistic studies and density functional theory (DFT) calculations suggest that the [2π+2σ]-photocycloaddition takes place via a triplet mechanism.

Redefining the Synthetic Logic of Medicinal Chemistry. Photoredox-Catalyzed Reactions as a General Tool for Aliphatic Core Functionalization.

C(sp3)-rich aliphatic motifs in drug molecules are strongly associated with clinical success. Historically, the availability of compound libraries based on C(sp3)-rich cores has been limited due to the challenging direct functionalization of aliphatic rings. Instead, most small molecule drug-like libraries are diversified around central aromatic rings. Herein, we present a general approach to the synthesis of diversified libraries featuring aliphatic core rings via photoredox catalysis under mild conditions.

ortho-Selective Dearomative [2π + 2σ] Photocycloadditions of Bicyclic Aza-Arenes.

Dearomative photocycloadditions are valuable chemical transformations, serving as an efficient platform to create three-dimensional molecular complexity. However, the photolability of the original addition product especially within the context of ortho cycloadditions often causes undesired consecutive rearrangements, rendering these ortho cycloadducts elusive. Herein, we report an ortho-selective intermolecular photocycloaddition of bicyclic aza-arenes including (iso)quinolines, quinazolines, and quinoxalines by utilizing a strain-release approach. With bicyclo[1.1.0]butanes as coupling partners, this dearomative [2π + 2σ] cycloaddition enables the straightforward construction of C(sp3)-rich bicyclo[2.1.1]hexanes directly connected to N-heteroarenes. Photophysical experiments and DFT calculations revealed the origin of the [2π + 2σ] selectivity and indicate that, in addition to the originally proposed energy transfer or direct excitation pathways, a chain reaction mechanism is operative depending on the reaction conditions.

cis-Selective Hydrogenation of Aryl Germanes: A Direct Approach to Access Saturated Carbo- and Heterocyclic Germanes.

A catalytic approach of synthesizing the cis-selective saturated carbo- and heterocyclic germanium compounds (3D framework) is reported via the hydrogenation of readily accessible aromatic germanes (2D framework). Among the numerous catalysts tested, Nishimura's catalyst (Rh2O3/PtO2·H2O) exhibited the best hydrogenation reactivity with an isolated yield of up to 96%. A broad range of substrates including the synthesis of unprecedented saturated heterocyclic germanes was explored. This selective hydrogenation strategy could tolerate several functional groups such as -CF3, -OR, -F, -Bpin, and -SiR3 groups. The synthesized products demonstrated the applications in coupling reactions including the newly developed strategy of aza-Giese-type addition reaction (C-N bond formation) from the saturated cyclic germane product. These versatile motifs can have a substantial value in organic synthesis and medicinal chemistry as they show orthogonal reactivity in coupling reactions while competing with other coupling partners such as boranes or silanes, acquiring a three-dimensional structure with high stability and robustness.

Machine Learning for Chemical Reactivity: The Importance of Failed Experiments.

Assessing the outcomes of chemical reactions in a quantitative fashion has been a cornerstone across all synthetic disciplines. Classically approached through empirical optimization, data-driven modelling bears an enormous potential to streamline this process. However, such predictive models require significant quantities of high-quality data, the availability of which is limited: Main reasons for this include experimental errors and, importantly, human biases regarding experiment selection and result reporting. In a series of case studies, we investigate the impact of these biases for drawing general conclusions from chemical reaction data, revealing the utmost importance of "negative" examples. Eventually, case studies into data expansion approaches showcase directions to circumvent these limitations-and demonstrate perspectives towards a long-term data quality enhancement in chemistry.

Scalable high-repetition-rate sub-half-cycle terahertz pulses from spatially indirect interband transitions.

Intense phase-locked terahertz (THz) pulses are the bedrock of THz lightwave electronics, where the carrier field creates a transient bias to control electrons on sub-cycle time scales. Key applications such as THz scanning tunnelling microscopy or electronic devices operating at optical clock rates call for ultimately short, almost unipolar waveforms, at megahertz (MHz) repetition rates. Here, we present a flexible and scalable scheme for the generation of strong phase-locked THz pulses based on shift currents in type-II-aligned epitaxial semiconductor heterostructures. The measured THz waveforms exhibit only 0.45 optical cycles at their centre frequency within the full width at half maximum of the intensity envelope, peak fields above 1.1 kV cm-1 and spectral components up to the mid-infrared, at a repetition rate of 4 MHz. The only positive half-cycle of this waveform exceeds all negative half-cycles by almost four times, which is unexpected from shift currents alone. Our detailed analysis reveals that local charging dynamics induces the pronounced positive THz-emission peak as electrons and holes approach charge neutrality after separation by the optical pump pulse, also enabling ultrabroadband operation. Our unipolar emitters mark a milestone for flexibly scalable, next-generation high-repetition-rate sources of intense and strongly asymmetric electric field transients.

Capture and Separation of SO2 Traces in Metal-Organic Frameworks via Pre-Synthetic Pore Environment Tailoring by Methyl Groups.

Herein, we report a pre-synthetic pore environment design strategy to achieve stable methyl-functionalized metal-organic frameworks (MOFs) for preferential SO2 binding and thus enhanced low (partial) pressure SO2 adsorption and SO2 /CO2 separation. The enhanced sorption performance is for the first time attributed to an optimal pore size by increasing methyl group densities at the benzenedicarboxylate linker in [Ni2 (BDC-X)2 DABCO] (BDC-X=mono-, di-, and tetramethyl-1,4-benzenedicarboxylate/terephthalate; DABCO=1,4-diazabicyclo[2,2,2]octane). Monte Carlo simulations and first-principles density functional theory (DFT) calculations demonstrate the key role of methyl groups within the pore surface on the preferential SO2 affinity over the parent MOF. The SO2 separation potential by methyl-functionalized MOFs has been validated by gas sorption isotherms, ideal adsorbed solution theory calculations, simulated and experimental breakthrough curves, and DFT calculations.

Photochemical intermolecular dearomative cycloaddition of bicyclic azaarenes with alkenes.

Dearomative cycloaddition reactions represent an ideal means of converting flat arenes into three-dimensional architectures of increasing interest in medicinal chemistry. Quinolines, isoquinolines, and quinazolines, despite containing latent diene and alkene subunits, are scarcely applied in cycloaddition reactions because of the inherent low reactivity of aromatic systems and selectivity challenges. Here, we disclose an energy transfer-mediated, highly regio- and diastereoselective intermolecular [4 + 2] dearomative cycloaddition reaction of these bicyclic azaarenes with a plethora of electronically diverse alkenes. This approach bypasses the general reactivity and selectivity issues, thereby providing various bridged polycycles that previously have been inaccessible or required elaborate synthetic efforts. Computational studies with density functional theory elucidate the mechanism and origins of the observed regio- and diastereoselectivities.

Wettability-defined droplet imbibition in ceramic mesopores.

Wettability-defined liquid infiltration into porous materials in nature and several industrial applications is of fundamental interest. Direct observation of wetting-controlled imbibition in mesopores is anticipated to deliver important insights into the interplay between nanoconfined liquid movement and nanoscale wettability. We present a systematic study of water imbibition into mesoporous silica thin films with wetting properties precisely adjusted through chemical functionalization. We observe the liquid infiltration, resulting in an imbibition ring around the water droplet, by top-view imaging using a camera with collimated coaxial illumination. With decreasing hydrophilicity, the maximum imbibition area around the droplet decreases, accompanied by a simultaneous change in the imbibition kinetics and imbibition mechanism. Initially, the imbibition kinetics follow a modified Lucas-Washburn law that considers a strong influence of evaporation. However, with increasing imbibition time after reaching constant imbibition ring dimensions, the imbibition area starts to increase again, causing a deviation from the applied model. This observation is ascribed to water-mediated surface activation at the imbibition front, leading to a slightly increased wettability, which is also confirmed by water adsorption measurements. Furthermore, recently described spontaneous condensation-evaporation imbalances that cause oscillations of the imbibition front could be verified and were studied with regard to changing wetting properties. By increasing the contact angle of the material and therefore the partial pressure needed for capillary condensation, the amplitude of the imbibition front oscillations decreases. These results provide insights into the wettability-defined complex movement of water in mesoporous structures, which has practical implications, e.g., for nano/microfluidic devices and water purification or harvesting.

Enhancing Long-Term Motivation of Cardiac Patients by Applying Exergaming in Rehabilitation Training.

Although regular physical activities reduce mortality and increase quality of life many cardiac patients discontinue training due to lack of motivation, lack of time or having health concerns because of a too high training intensity. Therefore, we developed an exergaming based system to enhance long-term motivation in the context of rehabilitation training. We combined different hardware components such as vital sensors, a virtual reality headset, a motion detecting camera, a bicycle ergometer and a motion platform to create an immersive and fun experience for the training user without having to worry about any negative health impact. Our evaluation shows that the system is well accepted by the users and is capable of tackling the aforementioned reasons for an inactive lifestyle. The system is designed to be easily extensible, safe to use and enables professionals to adjust and to telemonitor the training at any time.

Endocavity Ultrasound Probe Manipulators.

We developed two similar structure manipulators for medical endocavity ultrasound probes with 3 and 4 degrees of freedom (DoF). These robots allow scanning with ultrasound for 3-D imaging and enable robot-assisted image-guided procedures. Both robots use remote center of motion kinematics, characteristic of medical robots. The 4-DoF robot provides unrestricted manipulation of the endocavity probe. With the 3-DoF robot the insertion motion of the probe must be adjusted manually, but the device is simpler and may also be used to manipulate external-body probes. The robots enabled a novel surgical approach of using intraoperative image-based navigation during robot-assisted laparoscopic prostatectomy (RALP), performed with concurrent use of two robotic systems (Tandem, T-RALP). Thus far, a clinical trial for evaluation of safety and feasibility has been performed successfully on 46 patients. This paper describes the architecture and design of the robots, the two prototypes, control features related to safety, preclinical experiments, and the T-RALP procedure.

Tandem-robot assisted laparoscopic radical prostatectomy to improve the neurovascular bundle visualization: a feasibility study.

OBJECTIVES: To examine the feasibility of image-guided navigation using transrectal ultrasound (TRUS) to visualize the neurovascular bundle (NVB) during robot-assisted laparoscopic radical prostatectomy (RALP). The preservation of the NVB during radical prostatectomy improves the postoperative recovery of sexual potency. The accompanying blood vessels in the NVB can serve as a macroscopic landmark to localize the microscopic cavernous nerves in the NVB. METHODS: A novel, robotic transrectal ultrasound probe manipulator (TRUS Robot) and three-dimensional (3-D) reconstruction software were developed and used concurrently with the daVinci surgical robot (Intuitive Surgical, Inc., Sunnyvale, CA) in a tandem-robot assisted laparoscopic radical prostatectomy (T-RALP). RESULTS: After appropriate approval and informed consent were obtained, 3 subjects underwent T-RALP without associated complications. The TRUS Robot allowed a steady handling and remote manipulation of the TRUS probe during T-RALP. It also tracked the TRUS probe position accurately and allowed 3-D image reconstruction of the prostate and surrounding structures. Image navigation was performed by observing the tips of the daVinci surgical instruments in the live TRUS image. Blood vessels in the NVB were visualized using Doppler ultrasound. CONCLUSIONS: Intraoperative 3-D image-guided navigation in T-RALP is feasible. The use of TRUS during radical prostatectomy can potentially improve the visualization and preservation of the NVB. Further studies are needed to assess the clinical benefit of T-RALP.