Functional-Group Compatible Electrooxidation Synthesis of Key Antibiotic Intermediate Rifamycin O

Functional-Group Compatible Electrooxidation Synthesis of Key Antibiotic Intermediate Rifamycin O | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Functional-Group Compatible Electrooxidation Synthesis of Key Antibiotic Intermediate Rifamycin O Jianguo Wang, Lihao Liu, Shaoming Zhu, Kai Li, Yuhang Wang, Suiqin Li, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7115804/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Rifamycin O (RO), a key intermediate in the antibiotic drug rifaximin synthesis, faces several production challenges including low yield, purity issues, and environmental concerns. Here, we report an electrochemical synthesis strategy achieving RO production via electrooxidation of rifamycin B (RB) resulting in a 92% high yield. Trace water addition improves the functional-group compatibility during RB electrooxidation, substantially elevating the RO yield by 10%. Mechanistic studies reveal that trace water regulates methanol's hydrogen bond network, facilitates the dissociation of the hydroxyl group in the carboxylic acid, and enriches RB at the electrode/electrolyte interface, thereby achieving thermodynamic and kinetic synergistic optimization of RB electrooxidation. Systematic optimization of flow electrolyzer parameters further improves performance. The scale-up experiment with an electrode area of 400 cm² electrode demonstrates high yield and space time yield. The present work establishes the electrochemical synthesis of RO, providing a sustainable paradigm for pharmaceutical electrosynthesis. Physical sciences/Chemistry/Electrochemistry/Electrocatalysis Physical sciences/Chemistry/Chemical synthesis/Flow chemistry Physical sciences/Chemistry/Green chemistry/Sustainability antibiotic electrooxidation functional-group compatibility rifamycin trace water Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Antibiotics represent a class of therapeutic agents extensively utilized in clinical medicine, serving as a cornerstone for combating infectious diseases. 1 Rifamycins, a subclass of ansamycin antibiotics, exhibit potent broad-spectrum antimicrobial efficacy by targeting both Gram-positive and Gram-negative bacterial pathogens. 2,3 Semisynthetic derivatives of rifampin, such as rifapentine, rifamycin sodium, and rifaximin, have long been established in clinical practice for the treatment of tuberculosis, leprosy, and AIDS-related mycobacterial infections (Scheme 1a). 4,5 Rifamycin O (RO), a crucial intermediate in rifaximin synthesis, is synthesized via electrooxidation of rifamycin B (RB), which is produced by Streptomyces mediterranei. Traditional oxidation methodologies employing stoichiometric oxidants (Na 2 S 2 O 8 , NaNO 2 , MnO 2 ; Scheme 1b) suffer from several limitations. 6,7 The yield and purity of RO remain relatively low, and the production process generates substantial wastewater and waste solids, raising environmental concerns and posing challenges to industrial production. Consequently, developing eco-efficient RO production methods constitutes an imperative. Electrochemistry provides an efficient and sustainable strategy for organic synthesis by replacing traditional oxidizing agents with electrical energy. 8,9,10,11,12 The electrochemical strategy facilitates the transformation of complex organic molecules under mild conditions, while enabling precise regulation of reaction rates through current intensity modulation and enhanced selectivity via controlled reaction potentials. 13,14,15 Because of these benefits, electrochemistry is increasingly attracting the attention of researchers. 16,17,18 However, current research predominantly focuses on the electrooxidation of small molecules, 14,19,20,21 whereas complex molecular electrooxidation faces significant challenges, including limited functional-group compatibility, 22,23 poor regioselectivity control, 23 and sluggish mass transport kinetics. These limitations collectively hinder the scalability and practical implementation of complex molecular electrooxidation. Antibiotic molecules, as complex structures, contain multiple functional groups, complicating their late-stage electrochemical modifications because of competing reaction sites and functional-group incompatibility. Consequently, achieving the electrochemical synthesis of rifamycin O with high selectivity and space-time yield remains a significant challenge. Flow electrolyzer play a pivotal role in electrochemical scale-up production. Compared to conventional batch systems, flow electrolyzer offers distinct advantages: enhanced mass/heat transfer, higher operational repeatability, improved safety, and effective suppression of side reactions. 24,25,26,27 However, critical aspects such as cathode-anode interactions, diaphragm selection, and electrolysis mode optimization remain insufficiently understood. These knowledge gaps pose significant challenges for parameter optimization and industrial scaling, necessitating systematic investigation of flow electrolyzer systems. Here, we develop a straightforward and green electrooxidation method for rifamycin O production (Scheme 1c). The addition of trace water diminishes the electrooxidation potential of RB, increases the interfacial charge transfer rate, and improves the functional-group compatibility during RB electrooxidation to achieve high yield and space-time yield. In-situ infrared spectroscopy and electrochemical analysis reveal that trace water addition regulates the hydrogen bond network, reduces the carboxyl group's proton-transfer energy barrier, and promotes the dissociation of the hydroxyl group in the carboxylic acid. Simultaneously, water induces RB enrichment at the electrode/electrolyte interface, achieving thermodynamic and kinetic synergistic optimization of RB electrooxidation. Additionally, systematic parameter optimization of the flow electrolyzer further enhances the reaction efficiency. Finally, the scalability of RB electrooxidation was demonstrated through a scale-up experiment using a large-scale flow electrolyzer. Results Method Development. A novel method for the electrooxidation of rifamycin B was developed. The method employed methanol as the solvent and LiClO 4 as the supporting electrolyte, with the trace water addition (0.5 mL, 2 vol%) to enhance the electrooxidation effect. A RO yield of 90% and a rifamycin S (RS) yield of 2% were achieved under optimal conditions (entry 1). The absence of water resulted in a RO yield of 82% (entry 2), indicating that water is beneficial for electrooxidation of RB. The use of an undivided electrolyzer led to a decrease in yield (entry 3), resulting in a modest RO yield of 77%. Furthermore, no oxidation product was observed in the absence of current (entry 4), suggesting that electrons act as oxidants and that the occurrence of electrooxidation reactions necessitates electron transfer from RB to the electrode surface. The selection of supporting electrolytes significantly influences the electrocatalytic microenvironment, thereby affecting both the reaction rate and product selectivity (Supplementary Fig. 1a). However, the extensive use of various electrolytes in industrial processes can lead to substantial solid waste pollution. Consequently, the choice of electrolyte must take into account factors such as separability, recyclability, safety, and cost-effectiveness. Electrolyte screening was conducted in an undivided electrolyzer. Tetrabutylammonium hydrogen sulfate (TBHS) was chosen as the supporting electrolyte due to its previously mentioned characteristics (entry 5). However, the readily hydrolyzable nature of RO under acidic conditions resulted in a significantly low yield (27%), accompanied by a substantial amount of RS (50%). The utilization of sodium hydroxide (NaOH) and potassium fluoride (KF) as basic electrolytes (entry 6 and 7) yielded only trace amounts and 57% yield, respectively. This may be attributed to the dissociation of phenolic hydroxyl groups on RB caused by the presence of Lewis bases and Brønsted bases, leading to complex oxidation reactions. Additionally, substantial peroxide byproducts (25% and 13%) were observed alongside low RO yields (1% and 57%). LiClO 4 as the electrolyte provided the most favorable outcome, achieving 77% RO yield (entry 3). However, the use of perchlorate raises safety concerns for scale-up experiments, as it is mechanically sensitive in the presence of organic materials or metals and poses toxicological hazards. Consequently, potassium chloride (KCl) was identified as a suitable alternative (entry 8). Despite a decrease in yield to 74%, the proposed approach may help mitigate the risks associated with subsequent amplification experiments. Electrode materials can be defined as catalysts for electrochemical reactions, as their selection significantly influences interfacial charge transfer processes. Supplementary Fig. 1b shows the cyclic voltammetry (CV) curves for RB electrooxidation with various electrode materials. The results indicate that graphite felt (GF, black line) and graphite plate (GP, orange line) electrodes exhibit significantly higher anodic oxidation currents than other materials. In contrast, the current responses of nickel foam (NF), nickel plate (NP), and platinum (Pt) electrodes are comparatively low, highlighting the superior performance of carbon-based materials for RB electrooxidation. Subsequently, the GF exhibited the highest oxidation current, owing to its three-dimensional porous structure. This architecture not only provides abundant active sites but also facilitates efficient contact between the reaction substrate and the electrode surface (Supplementary Fig. 2). 28 In contrast, the graphite plate (GP) anode achieved a significantly lower yield of 70% (entry 9), which is lower than that obtained with GF as the anode (entry 3) (Supplementary Fig. 1c). In an undivided electrolyzer, the anode and cathode share the same reaction chamber, leading to inevitable interference of cathodic processes on the anode reaction. The impact of cathode materials on RB electrooxidation was evaluated to quantify cathode effect. The results indicated that the use of different cathode materials significantly affected the electrooxidation of RB (Supplementary Fig. 1d). The NP (entry 10) achieved the highest RO yield at 78%, while the NF (entry 11) only attained 68%. The observed disparity led to the decision to employ a divided electrolyzer to alleviate cathodic influence on the reaction (entry 3). Additionally, it was observed that the electrooxidation of RB was inhibited by increasing the temperature. RO yield of only 73% was obtained at a reaction temperature of 30 °C, while RS increased (entry 12). The electrochemical technique and high-performance liquid chromatography (HPLC) were employed to investigate the electrooxidation process of RB in a divided electrolyzer. Fig. 1a illustrates that the oxidation current is relatively weak for the pure methanol solution. Upon addition of RB, a significant increase in current density was observed (red line). A pronounced current occurred when the applied potential reached ~ 0.20 V vs. SCE, suggesting rapid electron transfer between RB and the electrode surface. Furthermore, the electrooxidation rate of RB showed a voltage-dependent enhancement. Fig. 1b presents the chronopotentiometry curve and charge-time correlation during RB electrooxidation. The anode potential was maintained at approximately 0.37 V vs. SCE in the process of RB electrooxidation. The potential persisted until substrate depletion occurred, followed by a distinct voltage surge. HPLC was performed to monitor the concentration changes of RB, and the product RO. Fig. 1c shows that the peak intensity of RB decreased and RO increased as the reaction time increased. Simultaneously, the color of the electrolyte transitioned from the initial orange (RB) to yellow (RO) (the inset image in Fig. 1c). The HPLC profile of the electrooxidation of RB after 4200 s is detailed in Supplementary Fig. 3. Quantitative analysis via external standard calibration revealed 99% RB conversion and 82% RO yield under anhydrous conditions (Fig. 1d). Notably, a reduction in the yield of RO was observed during the final reaction phase. The observed decrease is attributed to the diminishing concentration of RB, leading to reduced electrooxidation rates. To compensate for the diminished reaction rate, elevated overpotential was required, which induced over-oxidation of RO and consequently reduced product yield. Analysis of the Promoting Effect of Trace Water. A series of experiments were performed to investigate the underlying catalytic mechanism. LiClO 4 was employed as the electrolyte to eliminate potential confounding effects arising from the limited solubility of KCl in methanol and to clarify the role of water. LSV revealed that the current density of RB electrooxidation increased upon the addition of 0.5 mL water (pink curve, Fig. 2a). The chronopotentiometric (E-t) curves recorded at current densities of 5 and 10 mA/cm² (Fig. 2b) showed a marked reduction in the overpotential for RB electrooxidation when water was introduced (solid curves) compared to the control system (dashed curves). The complex molecular structure of RB presented challenges for functional-group compatibility. The introduction of trace water lowered the overpotential, inhibited side reactions involving other functional groups at high potentials and improved functional-group compatibility, thus enhancing the electrooxidation yield of RB. The enhancement of electrooxidation of RB by trace water was further verified through constant current electrolysis experiments conducted at 5 mA/cm². Following the trace water addition, the yield of RO increased from 82% to 90%, as illustrated in Fig. 2c (Scheme 2, entry 1). Similarly, when KCl was used as the electrolyte (Supplementary Fig. 4), a significant increase in the RO yield was observed following the introduction of trace amounts of water, from 82% to 92%. These findings suggest that water facilitates RB electrooxidation via an electrolyte-independent mechanism. Furthermore, the effect of different additional water volumes on the electrooxidation of RB was investigated. Fig. 2d illustrates the relationship between varying water content, expressed in equivalent form, and the electrooxidation of RB. As the water content increased from 10 to 30 eq, the RO yield exhibited a linear growth from 82% to 88%. However, once the water content reaches 58.5 eq or more, further increases do not lead to significant enhancements in yield. Based on the stoichiometric equation of the RB electrooxidation reaction (RB → RO + H 2 ), the absence of water in the equation indicate that it does not function as a reactant in the electrooxidation process. The observed finding suggests that water inclined to modify the solvent system and the electrochemical reaction microenvironment, thereby promoting the electrooxidation of rifamycin B. 29,30,31 As illustrated in Supplementary Fig. 5, the volume of water added is expressed in milliliters. The further increase in the yield of RO can be attributed to the reduced solubility of RO at high water volumes (1 mL or 2 mL), which results in its precipitation during the reaction. The observed phenomenon impedes the subsequent overoxidation of solid RO on the electrode surface, leading to a modest increase in yield. A similar phenomenon is observed in the KCl electrolyte system (Supplementary Fig. 6), where the electrooxidation of RB is gradually enhanced with increasing water content. The constant potential electrolysis experiments performed at 0.35 V vs. SCE further demonstrate that trace water addition significantly enhances the electrooxidation kinetics of RB (Fig. 2e). In the absence of water, the current density for the electrooxidation of RB is less than 5 mA/cm 2 . The introduction of water markedly increases the current density, reaching ~10 mA/cm 2 during the initial phase of the reaction. Subsequently, the current density sharply decreased as the reaction progresses, indicating the rapid transformation of the substrate. As shown in Supplementary Fig. 7, complete RB conversion (~99%) was achieved within 2200 s with water addition, whereas it takes nearly twice as long (4400 s) to achieve the close conversion rate (95%) in the absence of water. These results demonstrate that the addition of trace water significantly enhances the electrooxidation kinetics of RB. Electrochemical impedance spectroscopy (EIS) was performed to probe interfacial charge transfer and reaction kinetics. The Nyquist semicircle diameter for RB electrooxidation decreased significantly upon water addition, suggesting reduced charge transfer resistance and an accelerated charge transfer rate, thereby enhancing the RB electrooxidation rate (Fig. 2f). Tafel analysis was performed to assess the electrocatalytic kinetics of RB electrooxidation with and without water (Supplementary Fig. 8). The Tafel slope decreased from 60.5 mV/dec (without water) to 50.2 mV/dec upon water addition. The reduced Tafel slope confirms that water accelerates the electrooxidation kinetics of RB. To probe trace water enhanced mechanisms, changes in RB, 2a, and 3a within methanol solutions containing varying water contents were analyzed by FTIR spectroscopy (Fig. 3a-3b, and Supplementary Fig. 9). For RB, 2a, and 3a, spectral measurements were conducted in methanol/water mixtures of varying compositions, using the solvent (methanol/water mixture) as the spectral background. The resulting spectra reflect substrate interactions within methanol's hydrogen-bond network after background spectrum subtraction. FTIR spectral analysis demonstrated that RB, 2a and 3a exhibited comparable spectral characteristics (Fig. 3a), which were ascribed to their analogous benzene -ring skeleton structure, hydroxyl (-OH) group, and methanol hydrogen bond network. The O-H stretching vibration peak of the carboxyl group (-COOH) in 3a appeared at 3260 cm -1 . For 2a and RB, the O-H absorption bands were broadened and shifted towards higher wavenumbers (2a: 3310 cm -1 ; RB: 3350 cm -1 ). 3 The result phenomenon arises from the presence of O-H peaks with distinct vibrational intensities in 2a and RB. The higher wavenumber region corresponds to the phenol hydroxyl group vibration with weaker hydrogen bonding, while the lower region is associated with the carboxyl hydroxyl group vibration exhibiting stronger hydrogen bonding. 32 Additionally, characteristic peaks (e.g., C-H symmetric stretching at 2800 cm -1 , C=O stretching at 1710 cm -1 , and C-O-C asymmetric stretching at 1200 cm -1 ) demonstrated high consistency across all three samples, with only minor wavenumber shifts observed. 3,33,34,35,36 Unlike methanol, whose single hydroxyl group (–OH) acts as both hydrogen bond donor and acceptor, water has two donor sites and two acceptor sites. 37 This structure creates a stronger hydrogen bond network in water. As water content increases, a mixed network forms, intensifying hydrogen bonding involving methanol. 38,39,40 Water molecules integrate into the solvent shell of the substrate by disrupting the original methanol hydrogen bond network, forming interactions with the hydroxyl groups of the substrate. 30,41,42,43 Such modification results in a change to the substrate microenvironment. As demonstrated in Fig. 3b, with an increase in water content, a splitting of the O-H peaks of RB becomes evident, with the small acromion at 3268 cm -1 shifting to a low wave number, the 3350 cm -1 peak undergoing a shift to a high wavenumber, and ultimately, two split peaks emerge, while the remaining peaks remain relatively unchanged. These observations suggest that water significantly modulates the chemical behavior of O-H bonds in the substrate molecules through disrupting the methanol hydrogen bond network. For carboxylic acid O-H groups, the hydrogen bond strength increases, which is beneficial to reduce the proton transfer energy barrier of carboxylic groups and promote the dissociation of hydroxyl group in the carboxylic groups. Conversely, phenolic hydroxyl groups exhibit weakened hydrogen-bonding interactions, leading to suppressed O-H dissociation. In a manner analogous to that of RB, the infrared spectrum of compound 2a also exhibited the splitting phenomenon of the O-H stretching vibration peak (Supplementary Fig. 9a). Additionally, 3a (containing only carboxylic acid groups) showed a pronounced carboxylic acid O-H peak red shift (Supplementary Fig. 9b). The result indicates that it is a general approach to adjust the strength of the methanol hydrogen bond network by introducing a trace amount of water, thus modulating the strength of the substrate O-H bond. Electrochemical tests were employed to further verify the influence of trace water addition on O-H bond energy variations in carboxylic acid O-H groups and phenolic hydroxyl groups. Utilizing glass carbon electrodes to circumvent mass transfer interference engendered by the capillary effect of GF (Fig. 3c). With increasing water content, the hydrogen bond network is strengthened, the intermolecular interaction force is enhanced, the system viscosity increases, and the electrical conductivity decreases (Supplementary Fig. 10). These combined effects should result in a current drop phenomenon for the CV curve. The addition of water to the simple methanol solution slightly inhibits the current, in accordance with the law of conductivity decrease (Supplementary Fig. 11). Furthermore, the decline in RB and 2a peak currents in the presence of water suggests that the diffusion of reactants is inhibited (Fig. 3c), which is consistent with the enhancement of the hydrogen bond network. Notably, the introduction of water was observed to enhance current density and negatively shift the electrooxidation potential for RB, 2a, and 3a. These result proves that the introduction of water leads to a modification of the bond energy of the O-H bond in these substrates, thereby resulting in a change to the CV curve. Crucially, compound 3a contains exclusively -COOH groups, thereby eliminating interference from phenolic hydroxyl groups, yet a substantial current increase is still observed. The result finding suggests that the regulation of water on the -COOH bond energy is the primary factor contributing to the enhancement of RB electrooxidation performance. The introduction of trace water enhances the methanol hydrogen bond network and restructures the substrate solvation shell. Water molecules form hydrogen bonds interaction with carboxylic acid groups (-COOH), reducing the proton transfer energy barrier of the carboxylic groups and promoting O-H bond dissociation. These effects collectively optimize the thermodynamics of RB electrooxidation, enhance its reaction efficiency and improve the functional-group compatibility. In-situ infrared spectroscopy (IRAS) was employed to further elucidate water's role (Fig. 3d-3f). In the water-free RB solution, the 3100-3600 cm -1 vibrational band corresponds to methanol’s O-H stretching vibration, with a peak centered at 3304 cm -1 . The vibration peak at 2830 cm -1 corresponds to the C–H stretching vibration of methanol. As the applied potential increases from 0.00 V to 0.70 V vs. SCE, the intensity of the characteristic methanol peaks gradually increases, indicating enrichment of methanol at the interface. Notably, the O-H stretching peak exhibited no significant shift, implying that the hydrogen-bond network strength at the electrode surface remained stable under varying potentials. 31 In the presence of water, the in-situ IRAS spectra exhibit significant changes. At high potential (0.30 V ~ 0.70 V vs. SCE), the methanol O-H stretching vibration peak shifts to 3280 cm -1 , indicating that trace water strengthens the interfacial hydrogen-bond network. A new O-H peak emerges at 3350 cm -1 , corresponding to the phenolic hydroxyl group vibration of RB under low potential conditions (OCP ~ 0.25 V vs. SCE). The result reveals RB molecular enrichment on the electrode surface. These findings demonstrate that trace water not only optimizes RB electrooxidation thermodynamics but also promotes RB accumulation and increases interfacial RB concentration, thereby enhancing reaction kinetics. The effect of the potential on the shifting of the stretching vibration peak of O-H was the further investigated. As illustrated in Supplementary Fig. 12, the electrooxidation potential of RB is demonstrated under in-situ IRAS testing conditions. In the absence of water, the RB electrooxidation potential was observed at 0.35 V vs. SCE. Upon increasing the potential beyond this threshold, the infrared O-H stretching peak remained stable at approximately 3304 cm -1 without significant deviation (Fig. 3f). These results indicate that voltage elevation under water-free conditions induces negligible variation in interfacial RB concentration. The electrooxidation potential of RB was lowered by water addition (Supplementary Fig. 12), with a significant oxidation current appearing at 0.30 V vs. SCE. As the potential increased (ocp ~ 0.25 V vs. SCE), a notable shift in the infrared spectral profile was observed, with the O-H stretching vibration peak representing the phenolic hydroxyl group manifesting at 3350 cm -1 and assuming a dominant position. As the potential exceeded 0.30 V vs. SCE, RB electrooxidation initiated, causing RB consumption and interfacial concentration decrease. The electrooxidation process induced methanol's O-H stretching peak resurgence at 3280 cm -1 and broadened the absorption spectrum through methanol-phenolic hydroxyl band overlap. These observations suggest that trace water modulates the hydrogen-bond network, leading to preferential RB enrichment on the electrode surface. The elevated RB concentration at the interface enhances electrooxidation kinetics, thereby improving reaction efficiency. In summary, trace water addition regulates the methanol hydrogen bond network, modifies the solvent shell of the reactant, and facilitates hydrogen bond interaction between water and the hydroxyl group in -COOH. These effects reduce the proton transfer energy barrier of the carboxyl group, promotes O-H bond dissociation, and optimizes RB electrooxidation thermodynamics. Furthermore, trace water induces RB enrichment at the electrode/electrolyte interface, increases interfacial RB concentration, and enhances RB electrooxidation kinetics. Simultaneously optimizing the thermodynamics and kinetics of RB electrooxidation achieves high yield with improved functional-group compatibility (Fig. 3g). A possible mechanism for electrooxidation of Rifamycin B is shown in Supplementary Fig. 13. 44 Upon applying potential, rifamycin B undergoes single-electron transfer at the electrode surface to generate an aryl radical cation. This cation is captured by the substrate’s carboxyl group, accompanied by proton transfer. Trace water forms hydrogen bonds with RB's carboxyl groups, lowering the proton transfer barrier of carboxylic acid groups. These effects facilitate cationic intermediate capture by the carboxyl groups. The resulting aryl radical is further oxidized at the electrode, followed by phenolic hydroxyl deprotonation to afford the product. At the cathode, H₂O reduction yields OH⁻ and H₂; OH⁻ migrates across the anion exchange membrane into the anode chamber, neutralizing H⁺ from the anode and stabilizing the pH to inhibit RO hydrolysis. S ystematic optimization and scale-up application of flow electrolyzer. Inherent mass transport limitations in batch electrolyzers restrict the scalability of RB electrooxidation. Without stirring, the current density decreased significantly as the number of cyclic voltammetry (CV) cycles increased (Supplementary Fig. 14). In contrast, stirring maintained stable current density throughout CV cycling. These results demonstrate that enhanced mass transfer is critical for achieving the scalability of RB electrooxidation. A flow electrolyzer was conducted to enhance mass transfer and enable scalable electrooxidation (Fig. 4a, Supplementary Fig. 15). Fig. 4b presents the structural diagram of the continuous flow electrolyzer, employing both continuous flow and intermittent production methods for RB electrooxidation. Operation of the flow system (Fig. 4c) increased RB oxidation current density from 6.8 mA/cm 2 to 51.7 mA/cm 2 , representing a 7.6-fold increase. This improvement reduces reaction time, minimizes the hydrolysis of RO, accelerates substrate exchange on the electrode surface, and reduces the risk of peroxidation. Fig. 4d illustrates the yield and conversion rate of rifamycin B at varying current densities in flow electrolyzer. The flow electrolyzer system achieved 94% yield with ~100% conversion at 10 mA/cm 2 , surpassing the 90% yield and 99% conversion observed in the batch H-type electrolyzer at 5 mA/cm 2 (entry 1). These results demonstrate that process intensification improves both current density and RB electrooxidation efficiency. Increasing the current density resulted in a reduction of rifamycin O yield (88% at both 30 and 40 mA/cm²), which can be attributed to RO peroxidation under high potential conditions. Further current increases (50-100 mA/cm 2 ) exacerbated yield losses, adversely affecting RB electrooxidation. Screening experiments identified 10 mA/cm 2 as the optimal efficiency current density, though this low current density poses scaling up production challenges. Increasing the current density results in a higher formation of by-products, making it challenging to achieve an optimal balance between space time yield and selectivity. To resolve the apparent contradiction between space time yield and selectivity, product and byproduct evolution was analyzed at 40 mA/cm 2 (Fig. 4e). HPLC identified key byproducts at 24 minutes (Supplementary Fig. 3). RO yield increased rapidly with charge input during the initial reaction phase, while peroxide formation showed a more gradual growth. As theoretical time (600s, blue area) (theoretical time 825s) approached, the production rate of RO slowed down significantly (pink line), while the formation rate of peroxide products gradually increased (green line). Notably, between 900-1000 s (Q=40 C), only 2% RB conversion occurred (theoretical Q=6.6 C for 2% conversion), with most electrons diverted to peroxide generation. The HPLC chromatogram inset in Fig. 4e reveals significantly intensified peroxide peaks from 600 to 1000 s. The high current is indicative of a faster interfacial charge transfer rate, which requires a sufficiently elevated substrate concentration to meet the necessary interfacial electron exchange rate. During mid-to-late reaction stages, declining substrate concentration leads to insufficient interfacial reactant supply for continuous electron transfer. This causes charge accumulation at the electrode, raising the local potential and promoting RO peroxidation, thereby reducing product yield. The stage electrolysis method effectively resolves the trade-off between space time yield and selectivity. As demonstrated in Fig. 4f, this approach employs an initial high current density (40 mA/cm 2 ) to accelerate electrooxidation, followed by reducing the current to 10 mA/cm 2 to suppress peroxide formation. The final RO yield reached 93%, comparable to direct low-current electrolysis (Fig. 4g). Remarkably, the space time yield of 12.0 kg/(m 3 ·h) significantly exceeds that of batch H-type electrolysis (1.0 kg/(m 3 ·h)) and flow direct electrolysis (4.8 kg/(m 3 ·h)) (Fig. 4h). These results validate current-regulated electrochemical reaction kinetics as a viable strategy to minimize byproducts and optimize process outcomes. In electrochemical systems, diaphragm selection critically alters the electrolyte environment in cathodic/anodic regions, thereby modulating reaction effect. RB yield varies significantly with different diaphragms (Fig. 4i): BPM and AEM achieve 93% and 94% yields respectively, whereas PEM yields only 77%. HPLC analysis under PEM conditions revealed substantial RS formation due to RO hydrolysis under acidic conditions. As shown in Fig. 4j, post-electrolysis pH shifts markedly: PEM decreases from pH 1.3 to 0.6, while BPM and AEM increase to 1.6 and 1.8 respectively. These results demonstrate that anode-region pH variations are the key determinant of yield differences across AEM, PEM, and BPM systems. As shown in the RB anodization reaction (RB → RO + 2H + + 2e - ), H⁺ accumulation at the anode lowers pH, promoting RO hydrolysis and reducing yield. In the AEM system (Fig. 4i, red area), OH - migration from the cathode neutralizes anodic H + during electrolysis, stabilizing pH and delaying RO hydrolysis to maximize yield. Conversely, in PEM systems (Fig. 4k, blue area), K + migration impedes H⁺ transport from the anode, 45 causing continuous pH decrease and RO hydrolysis, thereby lowering yield. BPM achieves comparable yields to AEM due to similar H⁺ neutralization mechanisms. Given BPM operational challenges, AEM was selected for further investigation. Therefore, by optimizing the membrane material to regulate the pH in the anode region, and thereby influencing the anode reaction, this is a useful strategy. Furthermore, the impact of the cathode solution on the anode reaction was taken into consideration. RB yields showed 2% variation (Supplementary Fig. 16a) at varying NaOH concentrations (0.5-3 M) in the cathode. Higher NaOH concentrations increased the cathode region chemical potential, driving OH⁻ migration into the anode region and raising its pH (Supplementary Fig. 16b). At 3 M NaOH, the post-reaction anode pH reached its maximum (pH 1.8 vs. initial 1.3), effectively suppressing RO hydrolysis and improving yield. The multi-parameter optimization strategy provides critical insights for scaling up RB electrooxidation processes. To assess the scalability of the rifamycin B electrooxidation process (Fig. 5a), a large-scale flow electrolyzer with 40-fold increased electrode area (10 cm 2 → 400 cm 2 ; Fig. 5b-c, Supplementary Fig. 17) was operated under continuous flow. Stage electrolysis reduced total reaction time while suppressing RO hydrolysis and overoxidation (Fig. 5d). During the initial phase, a constant current of 16 A was applied, yielding a cell voltage around of 3.20 V. Upon reaching 645 s, the current was decreased to 4 A to mitigate over-oxidation, accompanied by a voltage drop to 2.10 V. A pronounced voltage surge served as the reaction termination criterion. HPLC analysis confirmed 99% RB conversion with 89% yield. High-purity rifamycin O (99.3% by HPLC) was obtained with 82% isolated yield via sequential rotary evaporation and cooling recrystallization. Furthermore, the large-scale flow electrolyzer achieves a space time yield of 36.7 kg/(m 3 ·h), which significantly surpasses the performance of the small-scale flow electrolyzer (12.0 kg/(m 3 ·h), 3.06-fold) (Fig. 5e). The result underscores the efficacy and scalability of the electrooxidation of rifamycin B and providing a paradigm for scale-up of organic electrosynthesis. Discussion In summary, we present a novel electrochemical reaction for the preparation of rifamycin O. Rifamycin O was obtained in a flow electrolyzer with a yield of 93% and a space time yield of 12.0 kg/(m 3 ·h) through the optimization of the reaction conditions and the electrolyzer system. Furthermore, a 50g rifamycin B scale-up experiment was conducted under 400 cm 2 electrode area, resulting in the attainment of high yield (82%) and space time yield (36.7 kg/(m 3 ·h)). Trace water addition regulates methanol's hydrogen-bond network, facilitates the dissociation of the hydroxyl group in the carboxylic acid, and concurrently enriches RB at the electrode/electrolyte interface. This synergistic thermodynamic and kinetic optimization improves functional-group compatibility, achieving high yield in RB electrooxidation. Furthermore, parameter optimization in the flow electrolysis system demonstrates that stage electrolysis technology enhances spacetime yield while leveraging anion-exchange membrane ion transport to regulate anode solution pH. The present approach establishes a sustainable paradigm for pharmaceutical electrosynthesis. Methods Solvents and Reagents Commercially available chemicals were utilized in the experiment without undergoing any further purification. Rifamycin B was provided by Zhejiang Changhai Pharmaceutical Co., Ltd，purity 90%. Methanol (HPLC, Sinopharm Chemical Reagent Co., Ltd), LiClO 4 (98%, Aladdin Biochemical Technology Co., Ltd), KF (99.5%, Aladdin Biochemical Technology Co., Ltd), NaOH (98%, Shanghai Titan Scientific Co., Ltd), Tetrabutylammonium Hydrogen Sulfate (98%, Macklin Biochemical Co., Ltd), KCl (99.8%, Macklin Biochemical Co., Ltd). Electrochemical measurements All cyclic voltammetry (CV), linear sweep voltammetry (LSV) measurements and electrochemical impedance spectroscopy (EIS) were performed using a employing an Ivium-n-Stat electrochemical workstation in a three-electrode system. The working electrode was composed of GF (4 cm 2 ), the counter electrode consisted of Pt plate (4 cm 2 ), and the reference electrode employed was Saturated calomel electrode (SCE). The anolyte was composed of RB (0.36 g, 0.48 mmol), 0.05 mol/L LiClO 4 , 0.5 mL H 2 O in 25 mL MeOH solution. The scan rate of CV and LSV was maintained at 50 mV·s −1 and 10 mV·s −1 , respectively. The frequency ranged of EIS from 100000 to 0.1 Hz with an amplitude of 5 mV, and the potential applied 0.30 V (vs SCE). High‐performance liquid chromatography (HPLC) analysis The concentration variations of RB and its oxidation products during the electrochemical reactions were monitored through high-performance liquid chromatography (HPLC, SHIMADZU Corp., LC-2050) on aliquots taken from the electrochemical cells with an ultraviolet visible detector set at 276 nm. Mobile Phase: [A] 9.48g/L ammonium formate solution (adjust the pH to 7.2 with ammonia water [B] Methanol-acetonitrile mixture solution (7:3). Gradient elution procedure: 0.0-12.0 min, 50% [B]; 12.1-45.0 min, 66% [B]; 45.1-50.0 min, 50% [B]. Detector: UV 276 nm; Temperature 40°C; Flow rate = 1.4 mL/min. 100 μL of the electrolyte solution was withdrawn from the cell during chronoamperometry testing and diluted to 1.0 mL with methanol and ultrapure water, and then 10 μL of the diluted solution was injected directly into a Thermo AcclaimTM MIX-Mode WAX-1 C18 column (5 μm 120 Å 4.6 mm × 250 mm). The yield results were calculated as the mean average following the completion of three replicate experiments. Undivided batch electrolyzer reaction The electrooxidation of RB were performed using a employing an Ivium-n-Stat workstation in a two-electrode system. The anolyte was composed of RB (0.36 g, 0.48 mmol), 0.05 mol/L LiClO 4 , 0.5 mL H 2 O in 25 mL MeOH solution, with constant current of 20 mA (current density is 5 mA/cm 2 ) was carried out. The working electrode was composed of GF (4 cm 2 ), the counter electrode consisted of Pt plate (4 cm 2 ). The reaction was terminated when the electric quantity reaches 1.8 F/mol. A magnetic stir bar (2 cm) was used, and the reaction mixture was stirred (400 rpm) during electrolysis. The yield of product was determined by HPLC and measured by external standard method. Divided batch electrolyzer reaction The electrooxidation of RB were performed using a employing an Ivium-n-Stat workstation in a two-electrode system. Using AEM8040 as the membrane. The anolyte was composed of RB (0.36 g, 0.48 mmol), 0.05 mol/L LiClO 4 , 0.5 mL H 2 O in 25 mL MeOH solution, with constant current of 20 mA (current density is 5 mA/cm 2 ) was carried out. The catholyte was composed of 3 M NaOH. The working electrode was composed of GF (4 cm 2 ), the counter electrode consisted of Pt plate (4 cm 2 ). The reaction was terminated when the electric quantity reaches 1.8 F/mol. A magnetic stir bar (2 cm) was used, and the reaction mixture was stirred (400 rpm) during electrolysis. The yield of product was determined by HPLC and measured by external standard method. Divided flow electrolyzer reaction The electrooxidation of RB were performed using a employing an Ivium-n-Stat workstation in a two-electrode system. Using AEM8040 as the membrane. The anolyte was composed of RB (1.44 g, 1.92 mmol), 0.05 mol/L LiClO 4 , 2 mL H 2 O in 100 mL MeOH solution, with constant current of 100 mA (current density is 10 mA/cm 2 ) was carried out. The catholyte was composed of 3 M NaOH. The working electrode was composed of GF (10 cm 2 ), the counter electrode consisted of Nickl form (10 cm 2 ). The reaction was terminated when the electric quantity reaches 1.8 F/mol. The cell voltage during constant current electrolysis was monitored. The magneton was stirred to ensure uniform mixing of the reaction solution, and a peristaltic pump was employed to pump electrolytes into the reaction system. At the end of the reaction, the reaction solution was concentrated under reduced pressure on a rotary evaporator until a small amount of solid was produced. The solution was then cooled and recrystallized in order to obtain the product, rifamycin O. The yield of product was determined by HPLC and measured by external standard method. The stage electrolysis study utilizes the same methodological approach as previously delineated, with the exception that, upon the application of the current, the initial electric quantity of 1.62 F/mol was conducted at 40 mA/cm 2 , and the final quantity of 0.18 F/mol was conducted at 10 mA/cm 2 . Scale-up a mplification experiment The electrooxidation of RB were performed using a employing an Ivium-n-Stat workstation in a two-electrode system. Using AEM8040 as the membrane. The anolyte was composed of RB (50 g), 0.05 mol/L KCl, 80 mL H 2 O in 4 L MeOH solution. The initial electric quantity of 1.62 F/mol was conducted at 16A (40 mA/cm 2 ), and the final quantity of 0.25 F/mol was conducted at 4A (10 mA/cm 2 ). The catholyte was composed of 3 M NaOH. The working electrode was composed of GF (400 cm 2 ), the counter electrode consisted of Nickl form (400 cm 2 ). The cell voltage during constant current electrolysis was monitored. The magneton was stirred to ensure uniform mixing of the reaction solution, and a peristaltic pump was employed to pump electrolytes into the reaction system. At the end of the reaction, the reaction solution was concentrated under reduced pressure on a rotary evaporator until a small amount of solid was produced. The solution was then cooled and recrystallized in order to obtain the product, rifamycin O. The yield of product was determined by HPLC and measured by external standard method. In situ electrochemical IRAS measurement In situ infrared reflection absorption spectroscopy (IRAS) measurements were performed on ThermoFisher Nicolet iS50 (dector: MCT/A; number of scans:32; moving mirror speed: 1.8988). A custom three‐chamber electrochemical cell was used and filled with 20 mL MeOH solution containing a predetermined amount of LiClO 4 , H 2 O and RB. The anode and reference electrodes were a platinum sheet and an SCE electrode, respectively. The 10 mg graphite was dissolved in 990 μL ethanol and 10 μL Nafion, and 1 mL was dropped on the surface of the gold film, and thoroughly dried under an infrared lamp. Before sample measurements, a background spectrum of reaction solution was recorded and ratioed against each spectrum of the aqueous sample. Between each measurement, the sample cell was thoroughly washed with MeOH and water, followed by drying. Calculation of conversion, selectivity, faradaic efficiency and space-time yield The conversion (%) and the selectivity (%) were calculated using equations (1) and (2): Declarations Data availability All data that support the findings of this study are present in the paper and the Supplementary Information. Further information can be acquired from the corresponding authors. Acknowledgments The authors acknowledge the financial support from National Natural Science Foundation of China (22322810), the National Key R & D Program of China (2022YFA1504200), and the Fundamental Research Funds for the Provincial Universities of Zhejiang (RF-C2023004). Author contributions L.H.L. performed the experiments and wrote the paper. S.M.Z and K.L. performed the partial experiments. Y.H.W., S.Q.L. and J.H.H contributed to the discussion of the results. P.H., C.Q. and R.X.L provided useful suggestions on experiment designs. X.Z. and J.G.W. designed the research, and wrote the paper. All the authors commented on and revised the manuscript. Competing interests The authors declare no competing interests. Additional information Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. 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Solid-state characterization of rifampicin samples and its biopharmaceutic relevance. Eur. J. Pharm. Sci. 22 , 127-144 (2004). Tolvaj L, Faix O. Artificial Ageing of Wood Monitored by DRIFT Spectroscopy and CIE L*a*b* Color Measurements. 1. Effect of UV Light. Holzforschung 49 , 397-404 (1995). Pethes I, Pusztai L, Temleitner L. Evolution of the hydrogen-bonded network in methanol-water mixtures upon cooling. J. Mol. Liq. 386 , 122494 (2023). Zhang N, Shen Z, Chen C, He G, Hao C. Effect of hydrogen bonding on self-diffusion in methanol/water liquid mixtures: A molecular dynamics simulation study. J. Mol. Liq. 203 , 90-97 (2015). Fileti EE, Chaudhuri P, Canuto S. Relative strength of hydrogen bond interaction in alcohol–water complexes. Chem. Phys. Lett. 400 , 494-499 (2004). Bakó I, Megyes T, Bálint S, Grósz T, Chihaia V. Water–methanol mixtures: topology of hydrogen bonded network. Phys. Chem. Chem. Phys. 10 , 5004-5011 (2008). Cook JL, Hunter CA, Low CMR, Perez-Velasco A, Vinter JG. Preferential Solvation and Hydrogen Bonding in Mixed Solvents. Angew. Chem. Int. Ed. 47 , 6275-6277 (2008). Ze H , et al. In Situ Probing the Structure Change and Interaction of Interfacial Water and Hydroxyl Intermediates on Ni(OH)2 Surface over Water Splitting. J. Am. Chem. Soc. 146 , 12538-12546 (2024). Cybulski SM, Scheiner S. Hydrogen bonding and proton transfers involving the carboxylate group. J. Am. Chem. Soc. 111 , 23-31 (1989). Deffieux D, Fabre I, Courseille C, Quideau S. Electrochemically-Induced Spirolactonization of α-(Methoxyphenoxy)alkanoic Acids into Quinone Ketals. J. Org. Chem. 67 , 4458-4465 (2002). Fan Y-L , et al. Critical Practices in Improving the Electrochemical Oxidation of 5-Hydroxymethylfurfural to 2,5-Furandicarboxylic Acid in 0.1 M KOH. ACS Sustainable Chem. Eng. 12 , 3256-3264 (2024). Table 1 Table 1 is available in the Supplementary Files section. Schemes Scheme 1 is available in the Supplementary Files section. Scheme 2 is not available with this version. Additional Declarations There is NO Competing Interest. Supplementary Files 3SupplementaryInformation.docx Supplementary Information Scheme1.jpeg Scheme 1. Schematic illustration of Rifamycin series. a Intermediates of rifamycin series. b Chemical reagent oxidation and c electrooxidation of rifamycin B. Table1.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7115804","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":491100686,"identity":"479ee087-4397-4375-bcc8-ab35c5dd6a50","order_by":0,"name":"Jianguo 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00:50:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7115804/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7115804/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87868567,"identity":"6d400f9c-b60f-4fbe-8387-b559ffc622d0","added_by":"auto","created_at":"2025-07-29 21:34:51","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":420260,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAnalysis of Rifamycin B electrooxidation. a\u003c/strong\u003e LSV analysis in the presence or absence of RB. \u003cstrong\u003eb\u003c/strong\u003e Anode potential and charge passed for the electrooxidation of RB. \u003cstrong\u003ec\u003c/strong\u003e HPLC chromatogram (inset: color change of electrolyte before and after electrolysis). \u003cstrong\u003ed\u003c/strong\u003e Relative concentration of RB and RO.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7115804/v1/d7e26583620f3aa36233fc51.png"},{"id":87868401,"identity":"35928703-604a-4663-ab8a-a2dc3cbb3cc9","added_by":"auto","created_at":"2025-07-29 21:26:51","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":327589,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePromoting Effect of Trace Water. a\u003c/strong\u003e LSV analysis in the presence or absence of water. \u003cstrong\u003eb\u003c/strong\u003e Voltage comparison at different current densities. \u003cstrong\u003ec\u003c/strong\u003e Yield comparison. \u003cstrong\u003ed\u003c/strong\u003e Effect of different water quantity on the electrooxidation of RB. \u003cstrong\u003ee\u003c/strong\u003e Constant potential electrolysis experiment at 0.35V vs. SCE in the presence or absence of water. \u003cstrong\u003ef\u003c/strong\u003e Nyquist curve at 0.30 V vs. SCE.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7115804/v1/e69d123751315548fecaf74b.png"},{"id":87868111,"identity":"2d25ab6e-ba82-4518-ad15-89abcf08ab09","added_by":"auto","created_at":"2025-07-29 21:18:51","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":708399,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProposed mechanisms.\u003c/strong\u003e \u003cstrong\u003ea\u003c/strong\u003e FTIR spectra of RB, 2a and 3a. \u003cstrong\u003eb\u003c/strong\u003e FTIR spectra of RB in methanol solutions with different water contents. \u003cstrong\u003ec\u003c/strong\u003e CV analysis in the presence or absence of water. IRAS spectra of electrooxidation of RB in the \u003cstrong\u003ed\u003c/strong\u003eabsence or \u003cstrong\u003ee\u003c/strong\u003e presence of water. \u003cstrong\u003ef\u003c/strong\u003e Experimental frequencies of the O–H stretching mode as a function of the applied potential. \u003cstrong\u003eg\u003c/strong\u003e Proposed mechanisms for electrooxidation of RB promoted by a trace amount of water.\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-7115804/v1/3a3ffe0edc29b447e1dd58ce.png"},{"id":87868131,"identity":"b6a99038-ea51-44c7-8bf2-07755f58b5c4","added_by":"auto","created_at":"2025-07-29 21:18:52","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":674703,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOptimization of Flow electrolyzer.\u003c/strong\u003e \u003cstrong\u003ea\u003c/strong\u003e Diagram of the flow electrolyzer system. \u003cstrong\u003eb\u003c/strong\u003e Structural diagram of the flow electrolyzer. \u003cstrong\u003ec\u003c/strong\u003e LSV analysis of batch and flow electrolyzer. \u003cstrong\u003ed\u003c/strong\u003e Comparison of conversion and yield at different current densities. \u003cstrong\u003ee\u003c/strong\u003e Yield and peroxidation product with electrolysis time at 40 mA/cm\u003csup\u003e2\u003c/sup\u003e. \u003cstrong\u003ef\u003c/strong\u003e Stage electrolysis method. \u003cstrong\u003eg\u003c/strong\u003e Yield and \u003cstrong\u003eh\u003c/strong\u003e Space time yield for stage electrolysis and direct electrolysis. \u003cstrong\u003ei\u003c/strong\u003e Yield of PEM, BPM and AEM. \u003cstrong\u003ej\u003c/strong\u003e Electrolyte pH of the anode side before and after electrolysis. \u003cstrong\u003ek\u003c/strong\u003e Illustration of the roles of the PEM and AEM.\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-7115804/v1/e8f675af35ff10f1649d76e9.png"},{"id":87868129,"identity":"67aa6dd6-1a6d-4b2a-80a1-0369a0feddd1","added_by":"auto","created_at":"2025-07-29 21:18:52","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":402657,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLarge-scale electrolyzer. a\u003c/strong\u003e Electrooxidation of RB on 50g scale. \u003cstrong\u003eb\u003c/strong\u003e Illustration of the flow electrolyzer. \u003cstrong\u003ec\u003c/strong\u003e Comparison photograph of the large-scale flow electrolyzer and the small-scale flow electrolyzer (inset: Electrode area comparison). \u003cstrong\u003ed\u003c/strong\u003e Cell voltage and charge passed for the electrooxidation of RB. \u003cstrong\u003ee\u003c/strong\u003e space time yield of different electrolyzer.\u003c/p\u003e","description":"","filename":"floatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-7115804/v1/9e3a06b34e1ea5766b6b98d2.png"},{"id":89143041,"identity":"3ea72888-075e-4c48-9707-e40cea3bb8aa","added_by":"auto","created_at":"2025-08-15 10:08:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3513521,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7115804/v1/37253e42-82f2-4cfd-8e9d-8042fce951a8.pdf"},{"id":87868116,"identity":"f3963dd4-05e0-4c18-bfcc-63d328dc30be","added_by":"auto","created_at":"2025-07-29 21:18:51","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":8900461,"visible":true,"origin":"","legend":"Supplementary Information","description":"","filename":"3SupplementaryInformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-7115804/v1/d880d63a0e8a5623e7901fe5.docx"},{"id":87868114,"identity":"e9b14c0e-c805-4a51-b09c-90da6aeadbdc","added_by":"auto","created_at":"2025-07-29 21:18:51","extension":"jpeg","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":347436,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 1. Schematic illustration of Rifamycin series. a\u003c/strong\u003e Intermediates of rifamycin series. \u003cstrong\u003eb\u003c/strong\u003e Chemical reagent oxidation and \u003cstrong\u003ec\u003c/strong\u003e electrooxidation of rifamycin B.\u003c/p\u003e","description":"","filename":"Scheme1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7115804/v1/09ab75aea13aa1f624bdae4d.jpeg"},{"id":87868115,"identity":"31a8b107-34b4-4587-8f23-2110d7d8815b","added_by":"auto","created_at":"2025-07-29 21:18:51","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":78760,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7115804/v1/3d56d1987b06ce0221f6e535.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Functional-Group Compatible Electrooxidation Synthesis of Key Antibiotic Intermediate Rifamycin O","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAntibiotics represent a class of therapeutic agents extensively utilized in clinical medicine, serving as a cornerstone for combating\u0026nbsp;infectious diseases.\u003csup\u003e1\u003c/sup\u003e Rifamycins, a subclass of ansamycin antibiotics, exhibit potent broad-spectrum antimicrobial efficacy by targeting both Gram-positive and Gram-negative bacterial pathogens.\u003csup\u003e2,3\u003c/sup\u003e Semisynthetic derivatives of rifampin, such as rifapentine, rifamycin sodium, and rifaximin, have long been established in clinical practice for the treatment of tuberculosis, leprosy, and AIDS-related mycobacterial infections (Scheme 1a).\u003csup\u003e4,5\u003c/sup\u003e Rifamycin O (RO), a crucial intermediate in rifaximin synthesis, is synthesized via electrooxidation of rifamycin B (RB), which is produced by Streptomyces mediterranei. Traditional oxidation methodologies employing stoichiometric oxidants (Na\u003csub\u003e2\u003c/sub\u003eS\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e8\u003c/sub\u003e, NaNO\u003csub\u003e2\u003c/sub\u003e, MnO\u003csub\u003e2\u003c/sub\u003e; Scheme 1b) suffer from several limitations.\u003csup\u003e6,7\u003c/sup\u003e The yield and purity of RO remain relatively low, and the production process generates substantial wastewater and waste solids, raising environmental concerns and posing challenges to industrial production. Consequently, developing eco-efficient RO production methods constitutes an imperative.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eElectrochemistry provides an efficient and sustainable strategy for organic synthesis by replacing traditional oxidizing agents with electrical energy.\u003csup\u003e8,9,10,11,12\u003c/sup\u003e The electrochemical strategy facilitates the transformation of complex organic molecules under mild conditions, while enabling precise regulation of reaction rates through current intensity modulation and enhanced selectivity via controlled reaction potentials.\u003csup\u003e13,14,15\u003c/sup\u003e Because of these benefits, electrochemistry is increasingly attracting the attention of researchers.\u003csup\u003e16,17,18\u003c/sup\u003e However, current research predominantly focuses on the electrooxidation of small molecules,\u003csup\u003e14,19,20,21\u003c/sup\u003e whereas complex molecular electrooxidation faces significant challenges, including limited functional-group compatibility,\u003csup\u003e22,23\u003c/sup\u003e poor regioselectivity control,\u003csup\u003e23\u003c/sup\u003e and sluggish mass transport kinetics.\u0026nbsp;These limitations collectively hinder the scalability and practical implementation of complex molecular electrooxidation. Antibiotic molecules, as complex structures, contain multiple functional groups, complicating their late-stage electrochemical modifications because of competing reaction sites and functional-group incompatibility. Consequently, achieving the electrochemical synthesis of rifamycin O with high selectivity and space-time yield remains a significant challenge.\u003c/p\u003e\n\u003cp\u003eFlow electrolyzer play a pivotal role in electrochemical scale-up production. Compared to conventional batch systems, flow electrolyzer offers distinct advantages: enhanced mass/heat transfer, higher operational repeatability, improved safety, and effective suppression of side reactions.\u003csup\u003e24,25,26,27\u003c/sup\u003e However, critical aspects such as cathode-anode interactions, diaphragm selection, and electrolysis mode optimization remain insufficiently understood. These knowledge gaps pose significant challenges for parameter optimization and industrial scaling, necessitating systematic investigation of flow electrolyzer systems.\u003c/p\u003e\n\u003cp\u003eHere, we develop a straightforward and green electrooxidation method for rifamycin O production (Scheme 1c). The addition of trace water diminishes the electrooxidation potential of RB, increases the interfacial charge transfer rate, and improves the functional-group compatibility during RB electrooxidation to achieve high yield and space-time yield. In-situ infrared spectroscopy and electrochemical analysis reveal that trace water addition regulates the hydrogen bond network, reduces the carboxyl group\u0026apos;s proton-transfer energy barrier, and promotes the dissociation of the hydroxyl group in the carboxylic acid. Simultaneously, water induces RB enrichment at the electrode/electrolyte interface, achieving thermodynamic and kinetic synergistic optimization of RB electrooxidation. Additionally, systematic parameter optimization of the flow electrolyzer further enhances the reaction efficiency. Finally, the scalability of RB electrooxidation was demonstrated through a scale-up experiment using a large-scale flow electrolyzer.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eMethod Development.\u0026nbsp;\u003c/strong\u003eA novel method for the electrooxidation of rifamycin B was developed. The method employed methanol as the solvent and LiClO\u003csub\u003e4\u003c/sub\u003e as the supporting electrolyte, with the trace water addition (0.5 mL, 2 vol%) to enhance the electrooxidation effect. A RO yield of 90% and a rifamycin S (RS) yield of 2% were achieved under optimal conditions (entry 1). The absence of water resulted in a RO yield of 82% (entry 2), indicating that water is beneficial for electrooxidation of RB. The use of an undivided electrolyzer led to a decrease in yield (entry 3), resulting in a modest RO yield of 77%. Furthermore, no oxidation product was observed in the absence of current (entry 4), suggesting that electrons act as oxidants and that the occurrence of electrooxidation reactions necessitates electron transfer from RB to the electrode surface.\u003c/p\u003e\n\u003cp\u003eThe selection of supporting electrolytes significantly influences the electrocatalytic microenvironment, thereby affecting both the reaction rate and product selectivity (Supplementary Fig. 1a). However, the extensive use of various electrolytes in industrial processes can lead to substantial solid waste pollution. Consequently, the choice of electrolyte must take into account factors such as separability, recyclability, safety, and cost-effectiveness. Electrolyte screening was conducted in an undivided electrolyzer. Tetrabutylammonium hydrogen sulfate (TBHS) was chosen as the supporting electrolyte due to its previously mentioned characteristics (entry 5). However, the readily hydrolyzable nature of RO under acidic conditions resulted in a significantly low yield (27%), accompanied by a substantial amount of RS (50%).\u003c/p\u003e\n\u003cp\u003eThe utilization of sodium hydroxide (NaOH) and potassium fluoride (KF) as basic electrolytes (entry 6 and 7) yielded only trace amounts and 57% yield, respectively. This may be attributed to the dissociation of phenolic hydroxyl groups on RB caused by the presence of Lewis bases and Brønsted bases, leading to complex oxidation reactions. Additionally, substantial peroxide byproducts (25% and 13%) were observed alongside low RO yields (1% and 57%). LiClO\u003csub\u003e4\u003c/sub\u003e as the electrolyte provided the most favorable outcome, achieving 77% RO yield (entry 3). However, the use of perchlorate raises safety concerns for scale-up experiments, as it is mechanically sensitive in the presence of organic materials or metals and poses toxicological hazards. Consequently, potassium chloride (KCl) was identified as a suitable alternative (entry 8). Despite a decrease in yield to 74%, the proposed approach may help mitigate the risks associated with subsequent amplification experiments.\u003c/p\u003e\n\u003cp\u003eElectrode materials can be defined as catalysts for electrochemical reactions, as their selection significantly influences interfacial charge transfer processes. Supplementary Fig. 1b shows the cyclic voltammetry (CV) curves for RB electrooxidation with various electrode materials. The results indicate that graphite felt (GF, black line) and graphite plate (GP, orange line) electrodes exhibit significantly higher anodic oxidation currents than other materials. In contrast, the current responses of nickel foam (NF), nickel plate (NP), and platinum (Pt) electrodes are comparatively low, highlighting the superior performance of carbon-based materials for RB electrooxidation. Subsequently, the GF exhibited the highest oxidation current, owing to its three-dimensional porous structure. This architecture not only provides abundant active sites but also facilitates efficient contact between the reaction substrate and the electrode surface (Supplementary Fig. 2).\u003csup\u003e28\u003c/sup\u003e In contrast, the graphite plate (GP) anode achieved a significantly lower yield of 70% (entry 9), which is lower than that obtained with GF as the anode (entry 3) (Supplementary Fig. 1c).\u003c/p\u003e\n\u003cp\u003eIn an undivided electrolyzer, the anode and cathode share the same reaction chamber, leading to inevitable interference of cathodic processes on the anode reaction. The impact of cathode materials on RB electrooxidation was evaluated to quantify cathode effect. The results indicated that the use of different cathode materials significantly affected the electrooxidation of RB (Supplementary Fig. 1d). The NP (entry 10) achieved the highest RO yield at 78%, while the NF (entry 11) only attained 68%. The observed disparity led to the decision to employ a divided electrolyzer to alleviate cathodic influence on the reaction (entry 3). Additionally, it was observed that the electrooxidation of RB was inhibited by increasing the temperature. RO yield of only 73% was obtained at a reaction temperature of 30 °C, while RS increased (entry 12).\u003c/p\u003e\n\u003cp\u003eThe electrochemical technique and high-performance liquid chromatography (HPLC) were employed to investigate the electrooxidation process of RB in a divided electrolyzer. Fig. 1a illustrates that the oxidation current is relatively weak for the pure methanol solution. Upon addition of RB, a significant increase in current density was observed (red line). A pronounced current occurred when the applied potential reached ~ 0.20 V vs. SCE, suggesting rapid electron transfer between RB and the electrode surface. Furthermore, the electrooxidation rate of RB showed a voltage-dependent enhancement. Fig. 1b presents the chronopotentiometry curve and charge-time correlation during RB electrooxidation. The anode potential was maintained at approximately 0.37 V vs. SCE in the process of RB electrooxidation. The potential persisted until substrate depletion occurred, followed by a distinct voltage surge.\u003c/p\u003e\n\u003cp\u003eHPLC was performed to monitor the concentration changes of RB, and the product RO. Fig. 1c shows that the peak intensity of RB decreased and RO increased as the reaction time increased. Simultaneously, the color of the electrolyte transitioned from the initial orange (RB) to yellow (RO) (the inset image in Fig. 1c). The HPLC profile of the electrooxidation of RB after 4200 s is detailed in Supplementary Fig. 3. Quantitative analysis via external standard calibration revealed 99% RB conversion and 82% RO yield under anhydrous conditions (Fig. 1d). Notably, a reduction in the yield of RO was observed during the final reaction phase. The observed decrease is attributed to the diminishing concentration of RB, leading to reduced electrooxidation rates. To compensate for the diminished reaction rate, elevated overpotential was required, which induced over-oxidation of RO and consequently reduced product yield.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAnalysis of the Promoting Effect of Trace Water.\u0026nbsp;\u003c/strong\u003eA series of experiments were performed to investigate the underlying catalytic mechanism. LiClO\u003csub\u003e4\u003c/sub\u003e was employed as the electrolyte to eliminate potential confounding effects arising from the limited solubility of KCl in methanol and to clarify the role of water. LSV revealed that the current density of RB electrooxidation increased upon the addition of 0.5 mL water (pink curve, Fig. 2a). The chronopotentiometric (E-t) curves recorded at current densities of 5 and 10 mA/cm² (Fig. 2b) showed a marked reduction in the overpotential for RB electrooxidation when water was introduced (solid curves) compared to the control system (dashed curves). The complex molecular structure of RB presented challenges for functional-group compatibility. The introduction of trace water lowered the overpotential, inhibited side reactions involving other functional groups at high potentials and improved functional-group compatibility, thus enhancing the electrooxidation yield of RB.\u003c/p\u003e\n\u003cp\u003eThe enhancement of electrooxidation of RB by trace water was further verified through constant current electrolysis experiments conducted at 5 mA/cm². Following the trace water addition, the yield of RO increased from 82% to 90%, as illustrated in Fig. 2c (Scheme 2, entry 1). Similarly, when KCl was used as the electrolyte (Supplementary Fig. 4), a significant increase in the RO yield was observed following the introduction of trace amounts of water, from 82% to 92%. These findings suggest that water facilitates RB electrooxidation via an electrolyte-independent mechanism.\u003c/p\u003e\n\u003cp\u003eFurthermore, the effect of different additional water volumes on the electrooxidation of RB was investigated. Fig. 2d illustrates the relationship between varying water content, expressed in equivalent form, and the electrooxidation of RB. As the water content increased from 10 to 30 eq, the RO yield exhibited a linear growth from 82% to 88%. However, once the water content reaches 58.5 eq or more, further increases do not lead to significant enhancements in yield. Based on the stoichiometric equation of the RB electrooxidation reaction (RB → RO + H\u003csub\u003e2\u003c/sub\u003e), the absence of water in the equation indicate that it does not function as a reactant in the electrooxidation process. The observed finding suggests that water inclined to modify the solvent system and the electrochemical reaction microenvironment, thereby promoting the electrooxidation of rifamycin B.\u003csup\u003e29,30,31\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eAs illustrated in Supplementary Fig. 5, the volume of water added is expressed in milliliters. The further increase in the yield of RO can be attributed to the reduced solubility of RO at high water volumes (1 mL or 2 mL), which results in its precipitation during the reaction. The observed phenomenon impedes the subsequent overoxidation of solid RO on the electrode surface, leading to a modest increase in yield. A similar phenomenon is observed in the KCl electrolyte system (Supplementary Fig. 6), where the electrooxidation of RB is gradually enhanced with increasing water content.\u003c/p\u003e\n\u003cp\u003eThe constant potential electrolysis experiments performed at 0.35 V vs. SCE further demonstrate that trace water addition significantly enhances the electrooxidation kinetics of RB (Fig. 2e). In the absence of water, the current density for the electrooxidation of RB is less than 5 mA/cm\u003csup\u003e2\u003c/sup\u003e. The introduction of water markedly increases the current density, reaching ~10 mA/cm\u003csup\u003e2\u003c/sup\u003e during the initial phase of the reaction. Subsequently, the current density sharply decreased as the reaction progresses, indicating the rapid transformation of the substrate. As shown in Supplementary Fig. 7, complete RB conversion (~99%) was achieved within 2200 s with water addition, whereas it takes nearly twice as long (4400 s) to achieve the close conversion rate (95%) in the absence of water. These results demonstrate that the addition of trace water significantly enhances the electrooxidation kinetics of RB.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eElectrochemical impedance spectroscopy (EIS) was performed to probe interfacial charge transfer and reaction kinetics. The Nyquist semicircle diameter for RB electrooxidation decreased significantly upon water addition, suggesting reduced charge transfer resistance and an accelerated charge transfer rate, thereby enhancing the RB electrooxidation rate\u0026nbsp;(Fig. 2f). Tafel analysis was performed to assess the electrocatalytic kinetics of RB electrooxidation with and without water (Supplementary Fig. 8). The Tafel slope decreased from 60.5 mV/dec (without water) to 50.2 mV/dec upon water addition. The reduced Tafel slope confirms that water accelerates the electrooxidation kinetics of RB.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;To probe trace water enhanced mechanisms, changes in RB, 2a, and 3a within methanol solutions containing varying water contents were analyzed by FTIR spectroscopy (Fig. 3a-3b, and Supplementary Fig. 9). For RB, 2a, and 3a, spectral measurements were conducted in methanol/water mixtures of varying compositions, using the solvent (methanol/water mixture) as the spectral background. The resulting spectra reflect substrate interactions within methanol's hydrogen-bond network after background spectrum subtraction.\u003c/p\u003e\n\u003cp\u003eFTIR spectral analysis demonstrated that RB, 2a and 3a exhibited comparable spectral characteristics (Fig. 3a), which were ascribed to their analogous benzene -ring skeleton structure, hydroxyl (-OH) group, and methanol hydrogen bond network. The O-H stretching vibration peak of the carboxyl group (-COOH) in 3a appeared at 3260 cm\u003csup\u003e-1\u003c/sup\u003e. For 2a and RB, the O-H absorption bands were broadened and shifted towards higher wavenumbers (2a: 3310 cm\u003csup\u003e-1\u003c/sup\u003e; RB: 3350 cm\u003csup\u003e-1\u003c/sup\u003e).\u003csup\u003e3\u003c/sup\u003e The result phenomenon arises from the presence of O-H peaks with distinct vibrational intensities in 2a and RB. The higher wavenumber region corresponds to the phenol hydroxyl group vibration with weaker hydrogen bonding, while the lower region is associated with the carboxyl hydroxyl group vibration exhibiting stronger hydrogen bonding.\u003csup\u003e32\u003c/sup\u003e Additionally, characteristic peaks (e.g., C-H symmetric stretching at 2800 cm\u003csup\u003e-1\u003c/sup\u003e, C=O stretching at 1710 cm\u003csup\u003e-1\u003c/sup\u003e, and C-O-C asymmetric stretching at 1200 cm\u003csup\u003e-1\u003c/sup\u003e) demonstrated high consistency across all three samples, with only minor wavenumber shifts observed.\u003csup\u003e3,33,34,35,36\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eUnlike methanol, whose single hydroxyl group (–OH) acts as both hydrogen bond donor and acceptor, water has two donor sites and two acceptor sites.\u003csup\u003e37\u003c/sup\u003e This structure creates a stronger hydrogen bond network in water. As water content increases, a mixed network forms, intensifying hydrogen bonding involving methanol.\u003csup\u003e38,39,40\u003c/sup\u003e Water molecules integrate into the solvent shell of the substrate by disrupting the original methanol hydrogen bond network, forming interactions with the hydroxyl groups of the substrate.\u003csup\u003e30,41,42,43\u003c/sup\u003e Such modification results in a change to the substrate microenvironment.\u0026nbsp;As demonstrated in Fig. 3b, with an increase in water content, a splitting of the O-H peaks of RB becomes evident, with the small acromion at 3268 cm\u003csup\u003e-1\u003c/sup\u003e shifting to a low wave number, the 3350 cm\u003csup\u003e-1\u003c/sup\u003e peak undergoing a shift to a high wavenumber, and ultimately, two split peaks emerge, while the remaining peaks remain relatively unchanged. These observations suggest that water significantly modulates the chemical behavior of O-H bonds in the substrate molecules through disrupting the methanol hydrogen bond network.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFor carboxylic acid O-H groups, the hydrogen bond strength increases, which is beneficial to reduce the proton transfer energy barrier of carboxylic groups and promote the dissociation of\u0026nbsp;hydroxyl group in the\u0026nbsp;carboxylic groups. Conversely, phenolic hydroxyl groups exhibit weakened hydrogen-bonding interactions, leading to suppressed O-H dissociation. In a manner analogous to that of RB, the infrared spectrum of compound 2a also exhibited the splitting phenomenon of the O-H stretching vibration peak (Supplementary\u0026nbsp;Fig. 9a). Additionally, 3a (containing only carboxylic acid groups) showed a pronounced carboxylic acid O-H peak red shift (Supplementary\u0026nbsp;Fig. 9b). The result indicates that it is a general approach to adjust the strength of the methanol hydrogen bond network by introducing a trace amount of water, thus modulating the strength of the substrate O-H bond.\u003c/p\u003e\n\u003cp\u003eElectrochemical tests were employed to further verify the influence of trace water addition on O-H bond energy variations in carboxylic acid O-H groups and phenolic hydroxyl groups. Utilizing glass carbon electrodes to circumvent mass transfer interference engendered by the capillary effect of GF (Fig. 3c). With increasing water content, the hydrogen bond network is strengthened, the intermolecular interaction force is enhanced, the system viscosity increases, and the electrical conductivity decreases (Supplementary\u0026nbsp;Fig. 10). These combined effects should result in a current drop phenomenon for the CV curve. The addition of water to the simple methanol solution slightly inhibits the current, in accordance with the law of conductivity decrease (Supplementary\u0026nbsp;Fig. 11). Furthermore, the decline in RB and 2a peak currents in the presence of water suggests that the diffusion of reactants is inhibited (Fig. 3c), which is consistent with the enhancement of the hydrogen bond network.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNotably, the introduction of water was observed to enhance current density and negatively shift the electrooxidation potential for RB, 2a, and 3a. These result proves that the introduction of water leads to a modification of the bond energy of the O-H bond in these substrates, thereby resulting in a change to the CV curve. Crucially, compound 3a contains exclusively -COOH groups, thereby eliminating interference from phenolic hydroxyl groups, yet a substantial current increase is still observed. The result finding suggests that the regulation of water on the -COOH bond energy is the primary factor contributing to the enhancement of RB electrooxidation performance. The introduction of trace water enhances the methanol hydrogen bond network and restructures the substrate solvation shell. Water molecules form hydrogen bonds interaction with carboxylic acid groups (-COOH), reducing the proton transfer energy barrier of the carboxylic groups and promoting O-H bond dissociation. These effects collectively optimize the thermodynamics of RB electrooxidation, enhance its reaction efficiency and\u0026nbsp;improve the functional-group compatibility.\u003c/p\u003e\n\u003cp\u003eIn-situ infrared spectroscopy (IRAS) was employed to further elucidate water's role (Fig. 3d-3f). In the water-free RB solution, the 3100-3600 cm\u003csup\u003e-1\u003c/sup\u003e vibrational band corresponds to methanol’s O-H stretching vibration, with a peak centered at 3304 cm\u003csup\u003e-1\u003c/sup\u003e. The vibration peak at 2830 cm\u003csup\u003e-1\u003c/sup\u003e corresponds to the C–H stretching vibration of methanol. As the applied potential increases from 0.00 V to 0.70 V vs. SCE, the intensity of the characteristic methanol peaks gradually increases, indicating enrichment of methanol at the interface. Notably, the O-H stretching peak exhibited no significant shift, implying that the hydrogen-bond network strength at the electrode surface remained stable under varying potentials.\u003csup\u003e31\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eIn the presence of water, the in-situ IRAS spectra exhibit significant changes. At high potential (0.30 V ~ 0.70 V vs. SCE), the methanol O-H stretching vibration peak shifts to 3280 cm\u003csup\u003e-1\u003c/sup\u003e, indicating that trace water strengthens the interfacial hydrogen-bond network. A new O-H peak emerges at 3350 cm\u003csup\u003e-1\u003c/sup\u003e, corresponding to the phenolic hydroxyl group vibration of RB under low potential conditions (OCP ~ 0.25 V vs. SCE). The result reveals RB molecular enrichment on the electrode surface. These findings demonstrate that trace water not only optimizes RB electrooxidation thermodynamics but also promotes RB accumulation and increases interfacial RB concentration, thereby enhancing reaction kinetics.\u003c/p\u003e\n\u003cp\u003eThe effect of the potential on the shifting of the stretching vibration peak of O-H was the further investigated. As illustrated in\u0026nbsp;Supplementary\u0026nbsp;Fig. 12, the electrooxidation potential of RB is demonstrated under in-situ IRAS testing conditions. In the absence of water, the RB electrooxidation potential was observed at 0.35 V vs. SCE. Upon increasing the potential beyond this threshold, the infrared O-H stretching peak remained stable at approximately 3304 cm\u003csup\u003e-1\u003c/sup\u003e without significant deviation (Fig. 3f). These results indicate that voltage elevation under water-free conditions induces negligible variation in interfacial RB concentration. The electrooxidation potential of RB was lowered by water addition (Supplementary\u0026nbsp;Fig. 12), with a significant oxidation current appearing at 0.30 V vs. SCE. As the potential increased (ocp ~ 0.25 V vs. SCE), a notable shift in the infrared spectral profile was observed, with the O-H stretching vibration peak representing the phenolic hydroxyl group manifesting at 3350 cm\u003csup\u003e-1\u003c/sup\u003e and assuming a dominant position. As the potential exceeded 0.30 V vs. SCE, RB electrooxidation initiated, causing RB consumption and interfacial concentration decrease. The electrooxidation process induced methanol's O-H stretching peak resurgence at 3280 cm\u003csup\u003e-1\u003c/sup\u003e and broadened the absorption spectrum through methanol-phenolic hydroxyl band overlap. These observations suggest that trace water modulates the hydrogen-bond network, leading to preferential RB enrichment on the electrode surface. The elevated RB concentration at the interface enhances electrooxidation kinetics, thereby improving reaction efficiency.\u003c/p\u003e\n\u003cp\u003eIn summary, trace water addition regulates the methanol hydrogen bond network, modifies the solvent shell of the reactant, and facilitates hydrogen bond interaction between water and the hydroxyl group in -COOH. These effects reduce the proton transfer energy barrier of the carboxyl group, promotes O-H bond dissociation, and optimizes RB electrooxidation thermodynamics. Furthermore, trace water induces RB enrichment at the electrode/electrolyte interface, increases interfacial RB concentration, and enhances RB electrooxidation kinetics. Simultaneously optimizing the thermodynamics and kinetics of RB electrooxidation achieves high yield with improved functional-group compatibility (Fig. 3g).\u003c/p\u003e\n\u003cp\u003eA possible mechanism for electrooxidation of Rifamycin B is shown in Supplementary\u0026nbsp;Fig. 13.\u003csup\u003e44\u003c/sup\u003e Upon applying potential, rifamycin B undergoes single-electron transfer at the electrode surface to generate an aryl radical cation. This cation is captured by the substrate’s carboxyl group, accompanied by proton transfer. Trace water forms hydrogen bonds with RB's carboxyl groups, lowering the proton transfer barrier of carboxylic acid groups. These effects facilitate cationic intermediate capture by the carboxyl groups. The resulting aryl radical is further oxidized at the electrode, followed by phenolic hydroxyl deprotonation to afford the product. At the cathode, H₂O reduction yields OH⁻ and H₂; OH⁻ migrates across the anion exchange membrane into the anode chamber, neutralizing H⁺ from the anode and stabilizing the pH to inhibit RO hydrolysis.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eS\u003c/strong\u003e\u003cstrong\u003eystematic optimization and scale-up application of flow electrolyzer.\u0026nbsp;\u003c/strong\u003eInherent mass transport limitations in batch electrolyzers restrict the scalability of RB electrooxidation. Without stirring, the current density decreased significantly as the number of cyclic voltammetry (CV) cycles increased (Supplementary\u0026nbsp;Fig. 14). In contrast, stirring maintained stable current density throughout CV cycling. These results demonstrate that enhanced mass transfer is critical for achieving the scalability of RB electrooxidation. A flow electrolyzer was conducted to enhance mass transfer and enable scalable electrooxidation (Fig. 4a,\u0026nbsp;Supplementary\u0026nbsp;Fig. 15). Fig. 4b presents the structural diagram of the continuous flow electrolyzer, employing both continuous flow and intermittent production methods for RB electrooxidation. Operation of the flow system (Fig. 4c) increased RB oxidation current density from 6.8 mA/cm\u003csup\u003e2\u003c/sup\u003e to 51.7 mA/cm\u003csup\u003e2\u003c/sup\u003e, representing a 7.6-fold increase. This improvement reduces reaction time, minimizes the hydrolysis of RO, accelerates substrate exchange on the electrode surface, and reduces the risk of peroxidation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFig. 4d illustrates the yield and conversion rate of rifamycin B at varying current densities in flow electrolyzer. The flow electrolyzer system achieved 94% yield with ~100% conversion at 10 mA/cm\u003csup\u003e2\u003c/sup\u003e, surpassing the 90% yield and 99% conversion observed in the batch H-type electrolyzer at 5 mA/cm\u003csup\u003e2\u003c/sup\u003e (entry 1). These results demonstrate that process intensification improves both current density and RB electrooxidation efficiency. Increasing the current density resulted in a reduction of rifamycin O yield (88% at both 30 and 40 mA/cm²), which can be attributed to RO peroxidation under high potential conditions. Further current increases (50-100 mA/cm\u003csup\u003e2\u003c/sup\u003e) exacerbated yield losses, adversely affecting RB electrooxidation. Screening experiments identified 10 mA/cm\u003csup\u003e2\u003c/sup\u003e as the optimal efficiency current density, though this low current density poses scaling up production challenges. Increasing the current density results in a higher formation of by-products, making it challenging to achieve an optimal balance between space time yield and selectivity.\u003c/p\u003e\n\u003cp\u003eTo resolve the apparent contradiction between space time yield and selectivity, product and byproduct evolution was analyzed at 40 mA/cm\u003csup\u003e2\u003c/sup\u003e (Fig. 4e). HPLC identified key byproducts at 24 minutes (Supplementary\u0026nbsp;Fig. 3). RO yield increased rapidly with charge input during the initial reaction phase, while peroxide formation showed a more gradual growth. As theoretical time (600s, blue area) (theoretical time 825s) approached, the production rate of RO slowed down significantly (pink line), while the formation rate of peroxide products gradually increased (green line). Notably, between 900-1000 s (Q=40 C), only 2% RB conversion occurred (theoretical Q=6.6 C for 2% conversion), with most electrons diverted to peroxide generation. The HPLC chromatogram inset in Fig. 4e reveals significantly intensified peroxide peaks from 600 to 1000 s. The high current is indicative of a faster interfacial charge transfer rate, which requires a sufficiently elevated substrate concentration to meet the necessary interfacial electron exchange rate. During mid-to-late reaction stages, declining substrate concentration leads to insufficient interfacial reactant supply for continuous electron transfer. This causes charge accumulation at the electrode, raising the local potential and promoting RO peroxidation, thereby reducing product yield.\u003c/p\u003e\n\u003cp\u003eThe stage electrolysis method effectively resolves the trade-off between space time yield and selectivity. As demonstrated in Fig. 4f, this approach employs an initial high current density (40 mA/cm\u003csup\u003e2\u003c/sup\u003e) to accelerate electrooxidation, followed by reducing the current to 10 mA/cm\u003csup\u003e2\u003c/sup\u003e to suppress peroxide formation. The final RO yield reached 93%, comparable to direct low-current electrolysis (Fig. 4g). Remarkably, the space time yield of 12.0 kg/(m\u003csup\u003e3\u003c/sup\u003e·h) significantly exceeds that of batch H-type electrolysis (1.0 kg/(m\u003csup\u003e3\u003c/sup\u003e·h)) and flow direct electrolysis (4.8 kg/(m\u003csup\u003e3\u003c/sup\u003e·h)) (Fig. 4h). These results validate current-regulated electrochemical reaction kinetics as a viable strategy to minimize byproducts and optimize process outcomes.\u003c/p\u003e\n\u003cp\u003eIn electrochemical systems, diaphragm selection critically alters the electrolyte environment in cathodic/anodic regions, thereby modulating reaction effect. RB yield varies significantly with different diaphragms (Fig. 4i): BPM and AEM achieve 93% and 94% yields respectively, whereas PEM yields only 77%. HPLC analysis under PEM conditions revealed substantial RS formation due to RO hydrolysis under acidic conditions. As shown in Fig. 4j, post-electrolysis pH shifts markedly: PEM decreases from pH 1.3 to 0.6, while BPM and AEM increase to 1.6 and 1.8 respectively. These results demonstrate that anode-region pH variations are the key determinant of yield differences across AEM, PEM, and BPM systems.\u003c/p\u003e\n\u003cp\u003eAs shown in the RB anodization reaction (RB → RO + 2H\u003csup\u003e+\u003c/sup\u003e + 2e\u003csup\u003e-\u003c/sup\u003e), H⁺ accumulation at the anode lowers pH, promoting RO hydrolysis and reducing yield. In the AEM system (Fig. 4i, red area), OH\u003csup\u003e-\u003c/sup\u003e migration from the cathode neutralizes anodic H\u003csup\u003e+\u003c/sup\u003e during electrolysis, stabilizing pH and delaying RO hydrolysis to maximize yield. Conversely, in PEM systems (Fig. 4k, blue area), K\u003csup\u003e+\u003c/sup\u003e migration impedes H⁺ transport from the anode,\u003csup\u003e45\u003c/sup\u003e causing continuous pH decrease and RO hydrolysis, thereby lowering yield. BPM achieves comparable yields to AEM due to similar H⁺ neutralization mechanisms. Given BPM operational challenges, AEM was selected for further investigation. Therefore, by optimizing the membrane material to regulate the pH in the anode region, and thereby influencing the anode reaction, this is a useful strategy.\u003c/p\u003e\n\u003cp\u003eFurthermore, the impact of the cathode solution on the anode reaction was taken into consideration. RB yields showed 2% variation (Supplementary\u0026nbsp;Fig. 16a) at varying NaOH concentrations (0.5-3 M) in the cathode. Higher NaOH concentrations increased the cathode region chemical potential, driving OH⁻ migration into the anode region and raising its pH (Supplementary\u0026nbsp;Fig. 16b). At 3 M NaOH, the post-reaction anode pH reached its maximum (pH 1.8 vs. initial 1.3), effectively suppressing RO hydrolysis and improving yield. The multi-parameter optimization strategy provides critical insights for scaling up RB electrooxidation processes.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;To assess the scalability of the rifamycin B electrooxidation process (Fig. 5a), a large-scale flow electrolyzer with 40-fold increased electrode area (10 cm\u003csup\u003e2\u003c/sup\u003e → 400 cm\u003csup\u003e2\u003c/sup\u003e; Fig. 5b-c, Supplementary Fig. 17) was operated under continuous flow. Stage electrolysis reduced total reaction time while suppressing RO hydrolysis and overoxidation (Fig. 5d). During the initial phase, a constant current of 16 A was applied, yielding a cell voltage around of 3.20 V. Upon reaching 645 s, the current was decreased to 4 A to mitigate over-oxidation, accompanied by a voltage drop to 2.10 V. A pronounced voltage surge served as the reaction termination criterion. HPLC analysis confirmed 99% RB conversion with 89% yield. High-purity rifamycin O (99.3% by HPLC) was obtained with 82% isolated yield via sequential rotary evaporation and cooling recrystallization. Furthermore, the large-scale flow electrolyzer achieves a space time yield of 36.7 kg/(m\u003csup\u003e3\u003c/sup\u003e·h), which significantly surpasses the performance of the small-scale flow electrolyzer (12.0 kg/(m\u003csup\u003e3\u003c/sup\u003e·h), 3.06-fold) (Fig. 5e). The result underscores the efficacy and scalability of the electrooxidation of rifamycin B and providing a paradigm for scale-up of organic electrosynthesis.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn summary, we present a novel electrochemical reaction for the preparation of rifamycin O. Rifamycin O was obtained in a flow electrolyzer with a yield of 93% and a space time yield of 12.0 kg/(m\u003csup\u003e3\u003c/sup\u003e\u0026middot;h) through the optimization of the reaction conditions and the electrolyzer system. Furthermore, a 50g rifamycin B\u0026nbsp;scale-up experiment was conducted under 400 cm\u003csup\u003e2\u003c/sup\u003e electrode area, resulting in the attainment of high yield (82%) and space time yield (36.7 kg/(m\u003csup\u003e3\u003c/sup\u003e\u0026middot;h)). Trace water addition regulates methanol\u0026apos;s hydrogen-bond network, facilitates the dissociation of the hydroxyl group in the carboxylic acid, and concurrently enriches RB at the electrode/electrolyte interface. This synergistic thermodynamic and kinetic optimization improves functional-group compatibility, achieving high yield in RB electrooxidation. Furthermore, parameter optimization in the flow electrolysis system demonstrates that stage electrolysis technology enhances spacetime yield while leveraging anion-exchange membrane ion transport to regulate anode solution pH. The present approach establishes a sustainable paradigm for pharmaceutical electrosynthesis.\u0026nbsp;\u003c/p\u003e\n"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eSolvents and Reagents\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCommercially available chemicals were utilized in the experiment without undergoing any further purification. Rifamycin B was provided by Zhejiang Changhai Pharmaceutical Co., Ltd，purity 90%. Methanol (HPLC, Sinopharm Chemical Reagent Co., Ltd), LiClO\u003csub\u003e4\u0026nbsp;\u003c/sub\u003e(98%, Aladdin Biochemical Technology Co., Ltd), KF (99.5%, Aladdin Biochemical Technology Co., Ltd), NaOH (98%, Shanghai Titan Scientific Co., Ltd), Tetrabutylammonium Hydrogen Sulfate (98%, Macklin Biochemical Co., Ltd), KCl (99.8%, Macklin Biochemical Co., Ltd).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eElectrochemical measurements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll cyclic voltammetry (CV),\u0026nbsp;linear sweep voltammetry (LSV) measurements and electrochemical impedance spectroscopy (EIS) were performed using a\u0026nbsp;employing an Ivium-n-Stat electrochemical workstation in a three-electrode system.\u0026nbsp;The working electrode was composed of GF (4 cm\u003csup\u003e2\u003c/sup\u003e), the counter electrode consisted of Pt plate (4 cm\u003csup\u003e2\u003c/sup\u003e), and the reference electrode employed was Saturated calomel electrode (SCE). The anolyte was composed of RB (0.36 g, 0.48 mmol), 0.05 mol/L LiClO\u003csub\u003e4\u003c/sub\u003e, 0.5 mL H\u003csub\u003e2\u003c/sub\u003eO in 25 mL MeOH solution. The scan rate of CV and LSV was maintained at 50 mV\u0026middot;s\u003csup\u003e\u0026minus;1\u003c/sup\u003e and 10 mV\u0026middot;s\u003csup\u003e\u0026minus;1\u003c/sup\u003e, respectively. The frequency ranged of EIS from 100000 to 0.1 Hz with an amplitude of 5 mV, and the potential applied 0.30 V (vs SCE).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eHigh‐performance liquid chromatography (HPLC) analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe concentration variations of RB and its oxidation products during the electrochemical reactions were monitored through high-performance liquid chromatography (HPLC, SHIMADZU Corp., LC-2050) on aliquots taken from the electrochemical cells with an ultraviolet visible detector set at 276 nm. Mobile Phase: [A] 9.48g/L ammonium formate solution (adjust the pH to 7.2 with ammonia water [B] Methanol-acetonitrile mixture solution (7:3). Gradient elution procedure: 0.0-12.0 min, 50% [B]; 12.1-45.0 min, 66% [B]; 45.1-50.0 min, 50% [B]. Detector: UV 276 nm; Temperature 40\u0026deg;C; Flow rate = 1.4 mL/min. 100 \u0026mu;L of the electrolyte solution was withdrawn from the cell during chronoamperometry testing and diluted to 1.0 mL with methanol and ultrapure water, and then 10 \u0026mu;L of the diluted solution was injected directly into a Thermo AcclaimTM MIX-Mode WAX-1 C18 column (5 \u0026mu;m 120 \u0026Aring; 4.6 mm \u0026times; 250 mm). The yield results were calculated as the mean average following the completion of three replicate experiments.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eUndivided batch electrolyzer reaction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe electrooxidation of RB were performed\u0026nbsp;using a\u0026nbsp;employing an Ivium-n-Stat workstation in a two-electrode system.\u0026nbsp;The anolyte was composed of RB (0.36 g, 0.48 mmol), 0.05 mol/L LiClO\u003csub\u003e4\u003c/sub\u003e, 0.5 mL H\u003csub\u003e2\u003c/sub\u003eO in 25 mL MeOH solution, with constant current of 20 mA (current density is 5 mA/cm\u003csup\u003e2\u003c/sup\u003e) was carried out. The working electrode was composed of GF (4 cm\u003csup\u003e2\u003c/sup\u003e), the counter electrode consisted of Pt plate (4 cm\u003csup\u003e2\u003c/sup\u003e). The reaction was terminated when the electric quantity reaches 1.8 F/mol. A magnetic stir bar (2 cm) was used, and the reaction mixture was stirred (400 rpm) during electrolysis. The yield of product was determined by HPLC and measured by external standard method.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eDivided batch electrolyzer reaction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe electrooxidation of RB were performed\u0026nbsp;using a\u0026nbsp;employing an Ivium-n-Stat workstation in a two-electrode system. Using AEM8040 as the membrane.\u0026nbsp;The anolyte was composed of RB (0.36 g, 0.48 mmol), 0.05 mol/L LiClO\u003csub\u003e4\u003c/sub\u003e, 0.5 mL H\u003csub\u003e2\u003c/sub\u003eO in 25 mL MeOH solution, with constant current of 20 mA (current density is 5 mA/cm\u003csup\u003e2\u003c/sup\u003e) was carried out. The catholyte was composed of 3 M NaOH. The working electrode was composed of GF (4 cm\u003csup\u003e2\u003c/sup\u003e), the counter electrode consisted of Pt plate (4 cm\u003csup\u003e2\u003c/sup\u003e). The reaction was terminated when the electric quantity reaches 1.8 F/mol. A magnetic stir bar (2 cm) was used, and the reaction mixture was stirred (400 rpm) during electrolysis. The yield of product was determined by HPLC and measured by external standard method.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eDivided flow electrolyzer reaction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe electrooxidation of RB were performed\u0026nbsp;using a\u0026nbsp;employing an Ivium-n-Stat workstation in a two-electrode system. Using AEM8040 as the membrane.\u0026nbsp;The anolyte was composed of RB (1.44 g, 1.92 mmol), 0.05 mol/L LiClO\u003csub\u003e4\u003c/sub\u003e, 2 mL H\u003csub\u003e2\u003c/sub\u003eO in 100 mL MeOH solution, with constant current of 100 mA (current density is 10 mA/cm\u003csup\u003e2\u003c/sup\u003e) was carried out. The catholyte was composed of 3 M NaOH. The working electrode was composed of GF (10 cm\u003csup\u003e2\u003c/sup\u003e), the counter electrode consisted of Nickl form (10 cm\u003csup\u003e2\u003c/sup\u003e). The reaction was terminated when the electric quantity reaches 1.8 F/mol. The cell voltage during constant current electrolysis was monitored. The magneton was stirred to ensure uniform mixing of the reaction solution, and a peristaltic pump was employed to pump electrolytes into the reaction system. At the end of the reaction, the reaction solution was concentrated under reduced pressure on a rotary evaporator until a small amount of solid was produced. The solution was then cooled and recrystallized in order to obtain the product, rifamycin O. The yield of product was determined by HPLC and measured by external standard method.\u003c/p\u003e\n\u003cp\u003eThe stage electrolysis study utilizes the same methodological approach as previously delineated, with the exception that, upon the application of the current, the initial electric quantity of 1.62 F/mol was conducted at 40 mA/cm\u003csup\u003e2\u003c/sup\u003e, and the final quantity of 0.18 F/mol was conducted at 10 mA/cm\u003csup\u003e2\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eScale-up a\u003c/strong\u003e\u003cstrong\u003emplification\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;experiment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe electrooxidation of RB were performed\u0026nbsp;using a\u0026nbsp;employing an Ivium-n-Stat workstation in a two-electrode system. Using AEM8040 as the membrane.\u0026nbsp;The anolyte was composed of RB (50 g), 0.05 mol/L KCl, 80 mL H\u003csub\u003e2\u003c/sub\u003eO in 4 L MeOH solution. The initial electric quantity of 1.62 F/mol was conducted at 16A (40 mA/cm\u003csup\u003e2\u003c/sup\u003e), and the final quantity of 0.25 F/mol was conducted at 4A (10 mA/cm\u003csup\u003e2\u003c/sup\u003e).\u003c/p\u003e\n\u003cp\u003eThe catholyte was composed of 3 M NaOH. The working electrode was composed of GF (400 cm\u003csup\u003e2\u003c/sup\u003e), the counter electrode consisted of Nickl form (400 cm\u003csup\u003e2\u003c/sup\u003e). The cell voltage during constant current electrolysis was monitored. The magneton was stirred to ensure uniform mixing of the reaction solution, and a peristaltic pump was employed to pump electrolytes into the reaction system. At the end of the reaction, the reaction solution was concentrated under reduced pressure on a rotary evaporator until a small amount of solid was produced. The solution was then cooled and recrystallized in order to obtain the product, rifamycin O. The yield of product was determined by HPLC and measured by external standard method.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eIn situ electrochemical IRAS measurement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn situ infrared reflection absorption spectroscopy (IRAS) measurements were performed on ThermoFisher Nicolet iS50 (dector: MCT/A; number of scans:32; moving mirror speed: 1.8988). A custom three‐chamber electrochemical cell was used and filled with 20 mL MeOH solution containing a predetermined amount of LiClO\u003csub\u003e4\u003c/sub\u003e, H\u003csub\u003e2\u003c/sub\u003eO and RB. The anode and reference electrodes were a platinum sheet and an SCE electrode, respectively. The 10 mg graphite was dissolved in 990 \u0026mu;L ethanol and 10 \u0026mu;L Nafion, and 1 mL was dropped on the surface of the gold film, and thoroughly dried under an infrared lamp. Before sample measurements, a background spectrum of reaction solution was recorded and ratioed against each spectrum of the aqueous sample. Between each measurement, the sample cell was thoroughly washed with MeOH and water, followed by drying.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eCalculation of conversion, selectivity, faradaic efficiency and space-time yield\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe conversion (%) and the selectivity (%) were calculated using equations (1) and (2):\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cimg 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2dtvv/3SawLsGDXm1T7foOcJ7Jxzzuk988wzaQQarr/++mQOCzLu3xOdj/g5yzY0/cKHDx/z5xgG2gXaL96uqe2aL9Ce0saS9wcffDCdA2/YyBN9ktpZ2sBHH300tcO1I2JmwaK3oIP0g1356KOPqn/bs2j3YeVVdhsqEL5XPSpQSrnxNc+T1y/81zfdQQpuqfGse72Tw3yQTz/9NDWWhP/LX/4y/W97La7wRzEnZSbcfPPNqUFkagX/4fzzz0/TJsgb0yxWrlyZGlDSeumll6ZXb5NKVHR9+PAxP45hoL2lLaJ9QvlTWz+bMK2qK5oKALSn9I3knWlhnJP+d955p3fjjTcmN+SNfa6BPZnZm1nT3owZJ4tSYeUGY+5F16fCH3/8sfo3GvhSEHM4WRTFjY4iiRIWYXQxbzw52kZIIyhyzJtFcUXRo/HsOgo5zvmeaiDfeuutZHaBUWi44IILkpnT5aFCCxLqYAQ3f0hoOvLFasaYxQ1vsnijxaAEbfX69evTCOSolVa1ZVqTINQmxcVYWlyVt1fyG9/k5dAPsLDm1ltvrR3EmOvBDbN4WJQK64UXXpjM0lMhC460Ip4nZIiv7+Grr75K5kEHHZTMQeGplNf1hPu3v/1th9XuZ5xxxkAKdQnyoUaSBuXKK69MinpbmMQNmg4hvvjii2S2KX1doIEk/wqzDRpNVqeyqGyYxnHz5s3pAaDN7zinBBhjFjYoqywaYQCCgQKgbUd5RWnl+qigLaN/YuQzDi58/PHHyYxv7H79618nMx8gwC9pa4IdWWiru+7IYhYPWrQ3joGbOt1qUSqs3Hwob8zL0cgd8J95RwLFikaBVyD6jB2FwxM09vETlVJiZYIaktJopaYFMAc0f8JlniuNBPOfpGBi0hDGz+mV4oxo7iqQblbfnXDCCekcSv4195WnavlFLsiAUdqo9PHqKJ9aoWkUbaPS5OXll1+uzpphVJjVqU2fBCU+0l2CeJClMcaMg5KyKjinvef6IEorD9pQ+oQq0Ebzpo72kT6GsHmwX7t27XZv7Hiwpr9idxUpF9rF4IorrkhmCfoc+si77767silD3PmOAxEGT+I2jmZh8Ktf/SqZdfpHpK0uCz1w7b///sncgalFCisdWQ3JKkjEwMGmz/2GZbsV7rjDrq8MJTeY+Isr0rWCUof8x7AJIyI/dSvsuK6VmBykLd9ZQNc48pWanPcbqW3X83TXpRnyuMlH3J0A4nX+A3HKjvhimDnagaFthanSmYcle+RHnkiDVrdGlKa4u4ExxowS2qNS+xPJ+5YSXKfdVn+jg/a/FD59gvoZ/LAau4T6MYVHHG1poU1V2x6RPWHS/hJvU/uq/JiFB3Uv123EoHUZqFdcr2PRKqxm7qHSUuGj8p9Dha+r3CjRuhm4afJwOG9qxE0z8QFkXDKkw6WBUjz5g1EJlfdMoF5R9wZBW660PWTVERWGugfVcUF+FbcxbTQpotipPnEP1W1BJHBbUnzN/GeUA0KEQVhN7atbLzOn0ImjsLQ97Q8K4TU9yZluDLLX3qCosVPYlFdb5yelsYti2wRhDNqJorTjbyZ1lTgJYy5AvigPxswWDBrEe9wsPGhXRvFAQtvU1j5ZYTVzDo0ZFbVNWekKygw3kBvJmSMlbdRo9HumI6WjhhGjcY7Id2mUxwV5m6miLyi32cqHHmzM/IN7adg3EmZ+QFsupTV/y9kF/OCX9qTNv1sBY0wtakhGjRThUT2kjAKlaZwPOnM1RUWv20bxJkOj3LORD9KNoj1XSr4xphs8mKC4DjI9QG9Cuz7UWGE1Zh7BFAeUHm5y4IanM0eBUKdesstB6UAZxY3clZQZ4uo6raJrmLoejy7Kj9zGPPFErrwqnSjBKDmlcOWWQxCG7OJBGCAFjaOUTvyrXHBDHDTAyCKCLLjeRUnXqIPiJWzOsY/X8jiU1rwD4JwwlFaFWSqfmBeOWI7UO9nHg04KN5K78oi8FFbekTHaK/eY6vCE0pkfed4IlxFfxTNop2mMmR9YYTVmnkCnTGeNMkDHTIdPp44SgmKQ2/EfO5SYCGHILdC5ozBERRAGUbC6hilQtLg+COSJOMifQDkhnVJuSIfSIKUuBz9RMRKktWQPknkuC9Kk8CRnyT2f7iB7/LShtMgtYSkv2Mc8RxRHrrDhH3lI+SRc5J/nVwombkDlGuuQ6lrMB/ERtuQR40JmeVlLwSR8wB1h5u6kgNfVQewJR3Ve4ZQeLIwx8xsrrMbMM6Q8xdE1dexRAZFdVDZQLLDLlSkpIREpK1ExKTFImAIlI3ffhuIpKS8oLFJcREmhA5Si6E40palOFoojKoiSu5QxQdi5glgH/qPSJUUwQnikOVL3IIAdhxRRQKHM5YMdR4R4Y77r4hC4J12x3kVUf3P5YJfLv04BB9KUlzl2uNdDizFm4bAoPxxgzHzmzTffTOYtt9ySTNBXbOIm37KLXyfjyzXQtGG4eP311zt9IWyQMIENydnwvOmTkCX4Mg+UNpXm4xDLli3r3XzzzZVNr/f+++9v+1qdIO6+8tM7+OCDK5tp2HSdNB133HGVzfaUZMGG6ZRBX8nabqN2fTSDj11ESGPXDdSJ66mnntr24RDi5dvuEcI76aSTqrNp+DhIX2GszqZRnlevXt0qc/KBnOPXa4g35rsUr0AmpIEN9Ou+BHfDDTek/OFG6OMqufxfe+215Db/dDXcddddybz88stTHtmUnE3qyX/80pMxZmFghdWYeQYKA51y7MT5Ljh2UUmQXa5slBQA3C7NvhTWpJhEBgkTpHgeeOCByeyKlMY8HilJq7KvmfHVuvhlN1DcuTL573//O5m5vSjJQp8v/s1vfpNMwSeX83RKaaxTiHOeeeaZ5J7y06eiIwqPryeJkh385z//SWauxCE3wo/ceOONKe3HHnts+hqSFEnRpti//fbbyTz33HOTmUMaS2UlWZaU/Lo6+OSTT6a07L777ikffLqZz27zDf+2hyxjzPzDCqsx8ww6/LwTRxHLR+9Q2HJ3+OVzwBGUEtzGES8pP11GQbuGKVA8oW4Erg6Ul1zBgk8++SSZRx99dDJBnwA86qijkimIGyU6V3pRxEr2UCeLL7/8Mpn/7//9v2QC+eaTy6XygTja3QRxffrpp0l+fB7z2muvra5Mo/D0eUR4+umnk5k/CDAiX1KgS/VII7nr1q1L+WDEMiJZ1+Xjo48+SmZd2X799dfJ3GuvvZIpHn744WIam0biKZO1a9cyp6H33XffJUWVz25bWTVmYWKF1Zh5hF7VRuVMo16xYy+5q0Ov9OOomEblBh0FFaUwBQpR/qq+DRRBFJRDDz20svkZTX048sgjkwl1ihNxl0ZRUY7qRlfbZLHTTjtV/6ZfU5eUrA8//DCZdcqXoCylJKJ48R16lLI4/QPy8PD3wAMPpP95nlH08weKO+64IynoF1xwQWXTS1MqxJVXXtl79NFHk1IbpwdISa/Lh0b124jfnkcxRgHP/Um5HaQOIodcuTfGLAyssBozj5ByFudxatQrjraJnXfeOSkEHMB8S5QDOna4//770wgeSlFUdKTwMZKGG/kv0TVMQPFECTrssMMqm24oj4zMoUBFpQQlidG5OLL2xRdfJJP4eLWNQgrEzSge5/no72effZbcE34cWZQs9thjj+1koVFCXmcrHj0goJDFdDKfFoUsT08O+WRkWkoi7lA4cwUfpRgID7kjb71mj3HwnzwrbxxMMbjvvvuSMqwRTdwSpqYf4I6pDSi1pdFU4pQMVe5A2pvm6SJDePbZZ5OJPFG+eVhAYVaYkY8//nhbunEvkAnTAvADlMuZZ57Z+93vfpfOjTELjOm1V8aY+QAruPvKWXU2DSur81t569bpbaX6CscOq81Z5Y17jr4StcNqbWA1OX452lZcdw0T6laId4Fw8Ut+46p12UUUDzKIuwqwohx75BhXzJMe8so18pLvrCBZRFmCZB/jKaWT8OWubvU8cI34lRZMzklDhLQTVoyH+HEf00J4XCfdCpP05WkgfNwpTA5klLuL8ebljFvs28pWsojyLJULeeIce+LEbSz3eJ2D9OdyMsYsHJbw07/ZjTFm7DBKxmhgX7Eozhc1xhhjSlhhNcbMGnpdnG/RZIwxxjThOazGmFmBOYbMp/zrX/9a2RhjjDHd8AirMWbsMLLKop6bbrqpuNWVMcYY04QVVmOMMcYYM9F4SoAxxhhjjJlorLAaY4wxxpiJxgqrMcYYY4yZaKywGmOMMcaYicYKqzHzGD5LuWTJknTEz4mOEj69ycp+xTPXq/z5bCnp0GdEFwLImE+TTnK+nn/++bTbg+pB/EzqQoF7SPkzxkwWVliNmcfwtagtW7ak/yeccEIyRwmK1PHHH9879NBD+fZrb+3atem7/Wa0HHLIIWmP2kmFPXRPPfXU3t13353qwYoVK3q/+MUvqqsLhxdffDHlbeXKlZWNMWZS8LZWxsxzGHE89thje5s2beodc8wxle1oYMTps88+S4cZP4zsrVu3rnfllVdWNqOF0dtXX301KWZd+fbbb3v77bdfGlm/9957K9uFy7777ttbvXr12MrAGDMcHmE1Zp7z8ccfJ3PUyiqK8EsvvdRbtWpVZWPmO0899VT1rzsPPfRQ+ujDb37zm8pm4cIUm61bt/YOOuigysYYMylYYTVmxFx77bVpPqK+m89rdc2N0zzTkl0OnefFF1+8bW4jIz/MI8x57bXX0mvMLnQNkzQxagu33HJLYzoFr41xx4Gyy2ie4iFORuqwJ07skA9yiOCGuZFxriTyFHVzPQlf7gkjnkf/JZQe3JE+lQvxkCeRx8250hnTks/1ZGQyzyfk7khzjuYOR9nnco4QT5xvTHrJl9LKtAMeQnS9rUxxc9VVV6X/TAngPOY1Qrry/FAWgnRgjxsgTZK18o4b0lxyo7SW7HKIl3SqbOvqOXUtukE5hyOPPDKZxpgJgikBxpjRsGbNmqkNGzZMbdy4kak2U+vXr59au3bt1DfffDO1bt26Hez4j92mTZuqEKbZsmXL1NKlS1N4uONYtWpVsuN/BDvCa2OQMEFp27p1a2XTDnnHz8qVK7flSfnGjjCBa9gRfyRPH/9xhzwF6cGOcCNyi4kb5Q878l4H7nDTV/p3kA32sWwUN9dwyzX8KS3Kv/KJe66TryhH1Q+VW8xrni/8I7uIZJqnrVS+0S//87DaIIzly5dXZ2WIk7iVHpWv8kI+432BPX6A/HGN81HcO8iB9JJP/uNW5xGlmTiBOkJ4pMcYM3lYYTVmDKjTpbMX6sRjhyi7vNOlg82VhJJbOmTsokJXR9cwRRdFJUfhSQkAFAbscoWhpIjlKLxciSvZSamJiqH8S4GsAze5oiLZxjIE7OrSjbzycKQISUGDkjvFl+eLuPL4lNdYblLAmiiF1YaU4Dooa9ISyxxKcZXui5yZ3jvEmcuW8xheVIoj2DXl1Rgzd3hKgDFj4M0330wmr9PFW2+9lUxWWgvZHXDAAckEXl32lZfeTTfdVNnU88477yRz//33T2Ydg4QpeH3c7+irs8HYc889q3+93m677ZbMfBcD2Y8adk7I+eGHH6p/9eTpUTj//e9/kxkp7cjAq2pkfNJJJ1U207ADADAdA+rcldI9CLySP+KII6qz0UCamb+qPJS48847084RXbY7K90XOTO9d5jygDtNQSFdyPuaa66pXPV6N9xwQ0rzRRddVNn8XD7HHXdcMo0xk4UVVmPGwMsvv5yUvaiEsDobu7g4SnZRWVKHnSsf6qB32mmnZMLrr7+eOt42ZWeQMIHOm06e7axmE81hZW4icwo1j3Y+8NNPPyVzl112SWYdXd0NCorlqLc20wPRgQcemMwcyosHm1z5BhTHXXfdtTqbhvti5cqVjfV1JvfOc889l0zqze67754e0Lg/SGN8cOB8VbaYUHkdtdJvjBkNVliNGQOlTpwOUYtJBJ167u79999PZt6ps8KbzjeOdqlzb2OQMEGd91FHHZXM2QDlh8UujEA+9thjaSutTZs2VVfnD11Gc8fF5s2bq3+jgQciqNuB4pNPPknm3nvvnUyhBU6nn356MgX3RZtSPZN7B2WU+2Fqerpb2r7r5ptv3q7ef/3118nca6+9kikefvjh3tKlSxuVaWPM3GGF1ZgRo5XbRx99dDIBJSx/tVpyVwdu6cjZH1Kg4M1kFLQUpvjwww+TOeqtsppghTb5ufHGG8c2XWAQ9Ir4sMMOS2YbyAqF58knn6xspsnDkUzzLaaoI3WgnEVKSjEjl5RnG3oY6cK777471Cb699xzT5LFiSeeWNn8XN+btowax73DfVKarhBHuJlOgVw8umrM5GKF1ZgRo9fscV6pRqJ+9atfJTOy8847pw6TA84///xk6pzO+bTTTksjR3Ezc4WJAoCbpu2buoYpuo7c5nz11VfbmSCFLR/9YwQ1Kk9SIJ5++ulk4u/xxx9P/6OCpvC++OKLZAqd6zr8+OOPyewy6olSKPkQBq+MUbouuOCCZAd1cYurr746Kd0qixjO5ZdfnuxgzZo1SbmM8elTp3lapejKLaOXGjFX/uDSSy/dLm7ATzwnLJQ/wqhT5IRe9zcp7CjfjNCjfOOegy2qkOWjjz663YNH6b7Imem9w+gtaZZCi8n0kjjSu8ceeyTz2WefTSZy5wENZZXRVcqiy3xcY8wsk5ZeGWNGBquU+514dTYNK4/z262vXCR3fWVmh5XhbN2DPX5ww3VW20c47yuVyY22+mmiS5igVf2DrpbWangd2kpKccYwWbEtuygryQk//FdaOLSiO4YnO21xxMF1IP7oNl/FHuE66ZA8OUij8iBKeclBroQVw6GsI+SrKa8xbOypU9gTLnnVCnn8xjSSR8XNtbyMY1iYef4iWknfJDcgjFxu+cp9KN0XOaO6d5QWwiulRTsbRP/yh5+8vIwxc48/zWqM2Q5GpVi00u/UF81IExvH9xWVgT5ZutBh430+GsCored1GmPmGk8JMLOGXs/p9d1M4VUeCpVe/5nR8MILLyQzzj80iw9e8zMtxMqqMWYSWNQKK3OVmG+1rPrcIiYKUNPihxzc6tN+dZ8JHBeMgBDvMArbbKcXOV922WW9devWbRu103w3yb5OkdXnE3EfYQ/FSy65JIXbNH/TdIf6fN999/XWrl07EQufZgPVq7x+LWa4F5kL+te//rWyMbMNZVBq9yLcr7TjakNpT+vc01+or2PHBe3kEInhEXddX0gbvljevphuqL5qnj/1UFsUUp9K9Y76hV3nQaw0MWARwlyuOHcMNA8unxPVBv7xx9yn2YR0Em9pjlYbs5le0sl8sziXDpgzxnw37JkHR5ryOXUqp6Z5dHKj+YxmODTHFXMxoTmfHHHu6GKF+ajIpG3uqhkPtOexTtbBPFv1YYA/zkvtuu5t2lfaS80LzvsOyl79H+0pfnLwg1/P8zVAfaLeqC8X1EPqidoRzTvP6x32+MV99F9i0SqsUk5zAXEjD6qwAmGNSwEk3GHSNCjEMeo8UBmRTenToTSG0b6UTxraLmnSIgo3osaY2QZFkHaqqcOlb2l7COA6bR7hYNKm1UF4uUIpP7lCgF18oCd87GLbqkGDmIc8LIhKrTHUIRTOHOypjxH106X6UxdOZNFOCajb5ubee+8tbvMzVzCsnu/BOC7yfSFHwR133JG2vTnllFMqm59hex22pamD1wV8nrFfuSubeng91W+8016exhgz27BFW900K17V89ozfka2BO0YHzpgOk7bl9AIL/9wwq9//etkah46vPLKK8mM24IRfl9BSH2LphDoC2xNU4F4xUu7Hbd6M4sX6iB16O9//3tl8zP6aEckfrI7B92LPaybpgcsWoVVXzm5/vrrk9kEcy6YZ6F5QoPMl2TekOa4YpYKI4Yf3XHw5R9gta6uEybXdM4cVpQ7zU+K80ExZU+4oPSocdU8EuasUfkULtdpQHUu/6AwOGjE6iD+vFHtCnles2bNDl9hqoN48k3bjTFm3NBGvfbaa2lHBZTTiJRVrndty9qgzUZxzD8aIoVY+/QC8UIet/bX1T63baDYXnPNNelzt4tlfrtp5rrrrkt9dNf6oP2586/MAYs7V61a1bvzzjsrmwLVSOuihFcqiKBpvpb2ItTrFM3fyYe0sYuvV4DhcF7Z6JUKfnAXX7Hk4fP6hvTE8EvxgYbXFV5d2jgnHfFVD3Hk6eU8twPNO8nBrmkIX6+YSmmHpikB2OdpbgO/xDeIH2OMGRW0ebRb9C2gNim2+V2R3xJ1bT1gH9tx/pfCydPWNiWA/qzUP5jFiepL2zSXCPUHfaIOTdWsm9q3qBVWQEA0MAgJYeaCQri5UoY7/ETkX5TmDQF2MbxS+Dn4KTVMarRiY0h4zDGKEH7un7TG9ELJDlSJqKBC+aurWFBKX4RGnfhoIFX5CY9z8iHZSfHnej4nJpI3wHXIXdfDGGO6onaPtg1zkA49onaqhOIo9QuKWygdOaX2knZXbSztL+eg9hmT9pk+hXPa5WHzZ+Y30gva+luBe+pL1CNyVK/jQFZk0e/DytZIn376aZonyevwvrK3bU4Pr136CtQOr134/B+vY7heh+YNHXjggckU/cYjffYS6sKfCf2GJL3a19YSmMQ3kzlHZ511VjL/8Y9/JBP4fCavAmayRyPfjIfdd9+9d+aZZ6aN6glP81ApG16l8ZqfMkJWbLmk6Q7Dwhzlft3vfAyCpkn48OFj/h/DwOdqaRvpT2iP59P2T88880xqb8n7gw8+mM4hTs/SNDraRj6/e84552zrb8ziQeuAqO9tMG3xj3/8Y5qn2mVazEcffVT92x5/OKAP8y9QYlCYUESlMGkSepw/ysE56HoJFSZfDIp+acSIA+T/qKOOSuYokGIqhRnFkgZzJnOO8EvDi7IobrvttqRQzgTCZWI2DR/flSedNHzI9+GHH05uMFevXp3coszSaOraJBIVXR8+fMzvYxh4oKatZHCibRHJuNh1112rf+3stNNO1b/pea60xeT93XffTeeknwVlGmAgb+x/DSymZZCHfsaYEgzMnXbaaSP5cqIV1oCE+eqrryZTIOi8IePo8mTBqGDJb+Tjjz+u/s0clDoaEJ6OAcXyiiuuSP9nwh/+8IekaLNAjAbsiCOOaH1SUkP41ltvJbMLa9euTcpxnWzbVs5C20pcfXCh62GMMV2gc2aRFQ/WPIyvX78+jUCOWmlVG5f3VfqITHxrp8VV+Qdm5LepHedtIwtrbr311tpBj5kMhpiFDfXnwgsvTLrVTJVVWLQKKyvg6xoRXvkDStPSpUt7r7/+ejofBJ6ugSfTOqSUNU0tEJs3b67+tUMFYVoAihkr5wd5bV+XXp6kly9f3nvkkUdSA8bRBg0h8vviiy8qm2ZoUJm+wFZWw4CMSGNbAzrOKQHGmMUJ7fjxxx+fOmZefQJvoVBeUVq7tPNdoY2jj6G91hQ20OCHpnGBtrrKBw7wS9qa4G0jbfhM36aZhYcGj/IHocif/vSnZOp+AN6i1m3/Jg466KDqX0a/Q16UMBGdCcCaMMxE8v7Nm+xY+COYgI6YtAAImGSOf4Ff3OSLnTjP42Cie1w4pPA1yVhuiEMoHNLFhGX5xw1+o1tQemLcOUym14R6EdNCGEysj+h6ns8mkGkeTx24yxcRIOdoRxrydAnyK9kYY8xsQbtM+0N7V0J9S9OCkxzaudg35GiBCmHTXisNpTYw7+9KfV0O1wg/70NyO/qD2D/mEPcgfYaZH1DfqAu5/iFUP/M6Rv2M+lNEC7nq6uWiVVhpBGgQuGkREAfnpQYFhQllCje4VwMhdI0jNli4UcPAtZJCBhRgdJNXANKkOGLjpDg58nSTl7pKoYaQg/+CcPGDPWYephqwugpaoqsfKip5jHIF2RMOB/9LDTjhE09dRTfGmHFBW9n2sEzbnbepOVyn7Y39EgcKXyl82kL1Dfgp9S+gvkjhldr3HPqG2D8I2RMmSgnxNrW7yo9ZeFD3os4TkS5ROkr1CrBverhZtAqrGRwaJyrooNDQ4i9XRgX2NGh1IwlqaOsaZPmva6wXC3o44KCxGAfq+JC3ymQ2iY2gMaNg3PfMfKRJEcVO92HdAEIEt3UKipnfjHKgSP1X0+CWW33TCI2NXv/wf5DR1QhKDk9ObU/1g0J4daMPixHkwU0/DuUdZRVZa3SFjqrpaXhcEKeVCzMqqMvjumcWO5Kt+hCz8FCfMFNo09vade8SYFr5n//5n7SQgMn9w670Y9L13XffnbasYqeBUcAnYVm9Srj5N4sXK+PYKk2wAIPFfCyKY9EHC/HY+ma2YbeKM844ozqbGazoblsAMCpY5OldJyYPbUE4jntmsUObsWHDhk476pj5CbthbN26dZuOMChRr3jssceSWUuluBpThCcnqglPPqMY9jfjRZPWRw1lz+u/uRhRjei10ShG6hn1IazZGFmT/DwyPHnotSajgcaY4eA+on8YRE/QG9Kub26tsBozRrgRUVQ0H4xOUXNysa+zy8Euzh3FXWnuWNuk9QjxoqwRFmESdkl5w47r+dEF4tBDDwdxaEpBvIYZkTKZN2ScEwZ+mQaiMEsKLNclLw6URblDRrKPB3LGjWQiGSMDhZWXjxYGcg1TDbdQOvMjz1texl0bf2QVZUwa8lewSpPcEA8yFEqj0o0MkBd2JSW7qVxBsictMR5Q/EJum+JuSw90kZ/qjdwQFulW3MaYycUKqzFjAiVBigGdIx0l53SiUsiiHZ0ydrnSiD0drMLioJPFLlcGsCPMNvBHJx07dSmmubIDSluuZLWBQkAcSid5IBzAnnBJr+xE3fYm+CfvhItfwkUpyhUOKZi4AdKd5035jTIkPsKWfGJcKK/EFSE9xCO5SE65O5V33QIV7FV2xK1w8rqQo3zhDn+KJ+ZTaZSd3ChsrhMOacAe2SsdKocYHjSVax5e9Kt8SV5Ncat8uqSni/ywJ80c8q/w8GeMmWyssBozZugo6RTz0Sbs6GSjUpZ3soC/OgUodtyEgx2ddxtSMHKFsBQ/qGPP3beRhyelIUJakEMERTHPM0gWKCQC5Yl4IthxRKKCBXVxCNxHRS9HSpaUL4EdeYo0yY80SdkSqjP4q4Ow8Ec+IlEWpK2UxpJ8lJ9oL7tcBti1lavijmVVJwfFE/OiOh7DLdX7rvLjOnYxPQovl48xZvKwwmrMmCkpNuooY6cvO9yLkl8oddxSENqUSnXmuVIF2JcU1pJS2QUUQhSOpjThJle6SnaEUUofChb2EaU3yieH6yUZQJOMBPnKFV75y8urSTlGkSIt+CWPlDlhc2BXhxSwJtmW0gglhbUUHrLOZQuE2VaupTpTV4+a4o5lKLsoly7yw8RfXp5d7xljzNzjXQKMGTNvvvlmMk888cRkgj6TeMEFFyQTZHfkkUcmE+T3iCOOSKaQ25122imZwCeE+4pE66d433777WQed9xxyRT6xJ4+uRfhk7l5GrrwzDPPpBWkfeUhfSo4h8/0cZ1PWoqSHfznP/9JZvzsJLDKlPAjN954Y5LFsccem3YCyFev8plMdhvIZSAko3PPPTeZOaSRHRP6imhlM80rr7ySzFxWyI/PJJd48sknU1p23333lI977rknfV6Z1bdNnxnGH+7ryps8k8ZSvC+99FJv1113rc6mIY15eHxvvq/YVmc/01auUMpznRzq4sYurjCXXZRLF/mpXH7zm98kU3S9Z4wxc48VVmPGzPvvv79DJ7t58+bUUUa7UmeMX8g71Keeeir5P+SQQyqbnzv9Nj766KNk7rnnnskUL7zwQjKjYg1SIE844YTKpjuk79NPP03blrCl2bXXXltdmYbvmcOvfvWrZMLTTz+dzAMPPDCZAuU9Vy6kOOZKEDJky61169al7aTyras++eSTZB5wwAHJzJGM6rbj+frrr5O51157JVM8/PDDxTSiUMWyiiDbtWvXMozZ++6775KixbfbYz0ogb86JRiUx7333juZQtvKnX766ckUuRxReFFsS+XeVq6lhw4eiLA79NBDK5ufKZUhdePwww+vzqYhPbm7LvL78ssvk/n//t//SyaQP+pGl3vGGDP3WGE1ZsyUOtmScllyV4KOnw5+9erVlc1051unDHQB//fdd18aTcuVY41sDrJPJSOYUhJRHNiHF6WCPVwjH374YTKlzOHvgQceSP9zZRGZ7bvvvtXZNHfccUdv6dKl241UL1u2rPrX61155ZW9Rx99NMlLI8ggBaZOidTDQxtxNBrlByUr9yflNlfAm0AOuRJYojQa3gYjkMgsPphINkcffXQyQQpvLPeu5ao6ozxTv2666ab0P69Hpbg1Ah7Lp+Sujjr5xTcSd911V4pj2HvGGDO7WGE1Zoyokz344IOTCRpxy195AwpI7GzPP//8ZKIMAeGddtppSSlCGRNSLg466KDkpknZ0Sv1xx9/PJmkR0oICkiOpiXUjUaWID0o4Mo/caBw5q+XkQOg0JBvRuv0mh07Xufjl/8onZ999ln6z8GraJRs0iwlW7LVa2rcPffcc0lBK6WfOPHDSCH/BWnPR/cie+yxRzKfffbZZPIRC5RvpgKgMCvMyMcff7wt3bgXyITX2vgByvrMM8/s/e53v0vndeAP5Z4wAVlTjgoHhZ/RXkbjJTPkSd5Q4uMIpKaY7L///smEr776qvo3nT/S1bVcf/zxx20m8Z533nnbfexB4UEpbtXnOPIudt555+RX/rvITyPhTA2QHKT4cq3tnjHGTABpJqsxZixokcjWsKhDCz3yBUH9jnfbwpDSohKu9RWQFGa8Dpz3ldjkBvf59RzSQFi4J2zijGmMEC5uB4G8sdBI6cbkPI+DFdtKh/LNohncY68FaITHdfKuMElXLkPCx53C5ECuubsYL+HERVK4xT5fOJWjciQ9pAuQveLUanTypLIlzrz84nWOprKIEH70h3xL+VS9qHMDhEPaIqSBvMX84bdLucY8YZIO3BBHDA9KcSMD/Ebq/HeVn8IkDNWrQe4ZY8zcsoSf/g1rjDFF+Jxov7Mvjr4aY4wxs4GnBBhjatECnXx1tTHGGDObeITVGFOEuX6a28qKe2OMMWau8AirMWYHGFllX8vly5enbYKMMcaYucQjrMYYY4wxZqLxCKsxxhhjjJlorLAaY4wxxpiJxgqrMcYYY4yZaKywGmOMMcaYicYKqzHGGGOMmWissBpjjDHGmInGCqsxxhhjjJlorLAaY4wxxpiJxgqrMcYYY4yZaKywGmOMMcaYicYKqzHGGGOMmWissBpjjDHGmInGCqsxxhhjjJlorLAGPvjgg961117bW7ZsWWWzOIj5fuONNyrbdr799tvk5/bbb69sxg9xXnzxxSneJUuW9M4+++xkV7JXnrg2CORnGH+TxPPPP5+OcYJ8P//88+qsO6Tr8MMPT+W077779p544onqyvyB+4T0D3K/mJ+h3nCfUf6jliH3LXWKOjabbVOEOk57RB2ZDU4++eR0mO2hLsx2HzUIg7bT999//6Jucxa8wkqD0eVQJdi6dWvv+++/T/9HCY1JKd54zFWDs9NOOyVzHPkeNcjokEMO6X333Xe99evX915++eXe008/XbR/8sknK1+LCzrKnXfeuXfKKaekhrpU1/IDBq2jl19+eW/t2rXpgacrNM6XXnpp78UXX0z3GgoL6Z105qNSPR+gDowD6v97771XnQ3GKMp6//3377377rvVmZkt5tN9GttpgUJKm0hbi5krsxdddFHvhRdeWLzt0dQCZ8WKFVP9RrE6m5pauXLlVMz2N998M7VmzZqpTZs2pfN169Ztd32UkA7CLoXfV7JS2uYK5VtymERIWymNdfaLEcqRI0Id5z6ok93SpUurs59lWaqL1N/ly5dXZ9MQNnbxHmuCcOeyng/Dhg0bdpCpmTnjvm8Je5hyy+v4sOR9jRkv8+k+LbXTpH/t2rXpfuA/9ZD6U2pbqVsbN26szhYPC3qElVHTu+++u7fPPvtUNjuy22679W688cbejz/+WNmMj6Z08OR0xhlnVGfGDA6vWa+66qreBRdcUNlMQx3nKHHMMcf0br311ups+rwO6u/q1aurs2kIF7v5MEo6DIweL9S8mR2hrPsKQnVm5gvz6T6ta6fh5ptvTm0wU9ruueeeZPf1118nM3Ldddf1fv/738/raWtDUSmui4a2p16eenSd/4w+ceRPMxqZxS3HqlWrkl0bct8GcesJi/h58hI8cXGOPXGSJ/5rpKLJr8CtRt1wWxqBawqHeHkKJG7cRSQb/OAXN1u2bKmu1iN544f0RD/Y5QdprbPHr2SUQ1kqv1yP6W/yV5c+8ssIObIibsKX3Eqyj3LFVN1S3dShsoj5xE0dyLzuusJWmE20xZODHPATyyuHPCsPOmIcpCuWCXmJ9xPXlT/iQW4cKi/+40ZlxEH9BMpG5ZaXB/65d5WmWK7cZ/Kng/Cxj+UdGSQfuk9wq7zUEdOAX8KJdhwQ7UkrNOVRIBddJ3zy10ZdPYa8DeC6ykMorZiRuvsTEzsO2ZXyK0p2nCvNhB3rQ5SBDoG8kEvJn1CdwA3p1/86FEd0ozhyf8hOsiRsZCuQl+qUiG1zTDtmrI8Q26v8KI3uiVh/OUp9YF73cE/6KTfSJnuVU115NtXhuvuUtNT1UfiJ4fFf4QHpkExjPpFTdAeD3jt5WdVB2okvl6kgzzEuyaFUNxcK9XfTAoWKQsWqQzcRFYEKQGXBDxVHYMcNo8pC5aaidKmEqtgRwiEMQUXFjeyUJnUI8eblmhp4zDa/gH/s8vRHf23hIBv+Y8c1IdlwU/JfN1GUXwncRz+EgT/OBWmJaRIle/5LRhHyRbhyq8YGe6jz15Q+ziUf3PA/hhMbOK7jFz/4VX3UufzE8gLOcRvlEcEef7EsIoonyoh0ldzjLq/LhF8XNuCHvLVBuHnY5C2WCSbnyEn5xY46hB3poO7yH7/Eq/iRI0iOlK/CxR92sTwIE7fEg1/FEcFPzLvkhn2U56D5IL344SAs0lGH0oY7gV0ePhCe8gRteUSWqlscpKuprAE3hEF4+FH94lzXiUfXVR78F8gil2Hb/am2Ky+P3A5yu7Y2DWQXIXzyIn/IKw8bu5huucnDypFcIrkd8RO2ZKvyAuRJnKQv2sU6RVngRnnDv5A7yVcywl8TxEH5KyzCJ43x3la65Yb044fwJaeu5dlWhyH3gzvlL7cvpQs74gbJFPum+1RlQbo42u4d3OTpySE9XCdupacE8ZJGIblZYV1AUMgUah1UFK5TsYTsBJWUihlRw9pUwQA3pUM3MBA+N48oVXKlicod6eKXSl6XfqWjSziQ2+Ev3kTADR7DykFmuR81DoQnSFtMo6izl4wipEONM+gmj/Hk/rqkT2nAXuTpUlyxzPCPneoNciaNefmo0axDccV8RFTv8yMvTyi544idUQ7yyTuQEoSRh4PfvJGVXGJ+8JeXA6i8YvnnsgfZxTwj6xiH7oNI7gdK4Q+Sj1xWJbnkSJlQXQHlPbZXpCHWsbY8EkZe3+I9ktOlHnPPx45d90upPKJdl/uT87w8utgRBuGLpnY1Qj5yeUjBAeSAn5KbPKycUny5HfLJ630eV6n+EEZeH7GL+cVPHjZ2belGlm19YOl+UN5imedpgtxu2PsUcnvSnd9/qmexziKHtvuUcAe5d1TnY15yuK6DfMZ7O0K8uKm7vhDxtlY1lOb8ab7IP//5z95999233erpW265JV375JNPktlGX/bbjn7Fq2ynYT4rq92Jj1WDRx55ZHVlR/J5sW1+mevTb2B7xx13XGUzzS677FL9m2aQNESQDasbI6xoJKw6XnrppZSmKM9TTz01XRtkBXobzGlmJ4Q999yzsumlnQUoA/JbxyDpY9VnzltvvZVMwoFYZsRL/KQDqHdXX311ql/aMooyYMVxXE2aozgOPPDAZNbRbzC31bt+w1rZ7ki/Ud7mjoP8N83BpsyHWZVNmRD2wQcfXNlMc9ZZZyWT+hTJ69ZMoV5SBqSDOXC6jwdl0HyU2hfVjzpOPPHEXr/jTvej4L7F7qGHHkrn1JW8rNryeNRRR6V7lGuqc8yhq6NLPSY8DsJj+zPm27Ux7P3ZFcIYpk1jt5Fzzjlnu/ufuk5ayd8rr7yS3B1xxBHJFHXzxgflgAMOSCY7dCAjaCqfSN6uw6uvvlr96/V23XXXVF9y+spm9a9MWx+ofubXv/51spspo7pPgXSz5VmEetZXTnfYWabtPh303unSTlPfaadpg8nnXXfdVV3Znr333juZXXWOhYAV1gGIFaP/ZLWtM49H14Ykcu6551b/foYGdb/99ut9+eWXaYumQWjy+9NPPyUzdgp1zCQNg5IrSDruvffeysXcMpvpYzI+Ssgdd9yRzlFGLrzwwvR/lAxSV1FO8oecUfLDDz9U/6YZVWffBp0MisBll12W8sd9PRPGmQ/CoszoIFG6OIAH3gceeCD9R3k6/fTT03/RlkcWeehhA0WFzldhDwv+UVRRAvbaa6/eo48+Wl2ZW4Zt0+KDXjy4L1TmTQ90M4Fyf/vtt3snnHBC77TTTktlOaoH+WuuuSa1NdqnlHDfeeedHRZXlmjqA//v//6vcjUaRn2flgZQhrlXx3HvAOGy9R9homCbaaywDslTTz1V/fsZKqqegAeByskhaDxoSF577bW0anCQhrCr348//rj6V2YmaaDBy6HBaZINT62lG32QTZW7Uso7SkATo0xfqbOJ8dNwxlFWlBGN1I2aK6+8svrXzjAPY11BgSjBCNC4oDxRqKjbjGCPIn/jzgejTIzsoZjyIMOo6+9+97s0mkUdevjhh7fLR9c8cp2Hry1btiR3KAdtNNXj8847LymEn376aUpz6c1DHcPcn12YSZvG3pc5+b0/KiWyBG0C9yrypC4df/zxqW2YKYwsskvI5s2b0ygp4dL2dGkXmvpAlfcodt8Zx31aGlUGlPdBGebe6QoPDsuWLa4PGTVhhXUI2H6Kp6q8EWXoXq9vZgKvbHi9pNdrg9Dmd4899khm/ooyZ9g0MApAh6ondsFoYVTKI4xewvXXX59MkXcIdY1f10aRsqFBotOKyicdTT4yFumavjZ4fQRsaRJh1CevNxplPemkk9LR9vSvsPXKaZwwcpaDPNteI0KUO1AnyCfKebym//lo4SjhjQl1tfSGY1BmKx96dXnnnXemOktnKTu2ujnssMMql9N0ySP1T+kkLLYCpH2re8DsUo95wPvtb3870KjVIPdnPI9umxi2TVu1alUq11whfe6555LJCDLEV8WDEvOQ55VyUFkgT/odypQPpswUwqUvIExGRxl57KKstvWB6mceeeSRZLbRVJ6jvE+B8izVb+IdVBke9t7p2k4jF9r/EpKZZL0YWFQKK0+kalTqnoZ50oRY4VQxpBgx2kXnzLwmnqZQzjCZL9TUQMcn4qanY56gGaUkjdwM3BTwxRdfbFMElU5dE21+6eDWrl2b5KDXFxya18ToBmnrkgbJUGkBKVp0ZoQv2TS9TuZGV6fAHEX84Jd96OK8TTV++QhMnb3SpXRSNowe0Pgxf414UL5IaxzBzP11SZ/ijg2R6ovqD0oNyi+yV70hHOLJO1GllZGALvP39DAQG36hMoavvvoqmXVICZf7CPWCBj2fpwk00nUNqyCfuPvss8+2C5/RCcqEBwKllf8oYepAsMMfslO5COokxAcXlUesE7ou9/rC2+OPP55M7nndB8hBsqA+R3sohT9IPri3+C/0P9rV8ec//znJkZFVwZQR6kq+t2OXPFJn/vSnP21rk6jD5Dl/iBJd6jH+GYEjP4Sr+JGX2pJchl3vT70mJe0oTJq/S77UbquOxLapS5umOZ+EgzvSjgJNmn75y19ua9NoB6RAUbaUMelUmPilnIGw6spVyi71BHfkV6N/5E1lwqtw5U2mlB/CJq54Xyn/KmvQtZgWylrlqIP8kY+6NENbH0g/Q5vJnFDkQ5rJT0yPaCvPmdynpXpAeeIWmUq+5Be5X3HFFelcMm27T4e5dyBvp/EvOcY08ZaCfeJLvP/++0l2yBrIK6PkpQGFBUP/qWpRsG7d9OrEePQb3erqNJzH6/gp2UG/cqcVhdj1K+h2qxBL5OFw5PELViz2K2Jyo1WC/QYx2XGtLk3Q5lfgh3TjjtWGuMUdKxzx0xaOVjvqiHmJacR906pJQfjEE9OEnYhx6Wiyz2VEekXMO2UY46nz15Q+wot+CKNkB/jBL3aERZh1IEdk3hXCVTwiT4eOEnneSwdpjvIC0sm1KOOcUjqwE6wiV32TXGI8uV/FlaeZMHM7zuvKg3g4J27C1Gr2WC7UX/khTXlYM81Hya4JwqPeRkp2oi2PrFimnil+/lOmTRBfUz1GZthzED7tJf/rZKjyAK7hFvv8/gTyoOuKl3P+E09JpkCeVDa4JdzYpoHsCC+2W4QpGeEeGUZyeZAH8kT6c7c5uFG4pEN+FT9xc44buYtpk72OUv7bZMKRX49lUqKtD4wyUZpV7qRH8L+pPIH/Cgf3Xe7TPM8xP+Q7ypR8KC6I/jhK8sNumHun1E6T3pgewkFW2NeRy5x4S+WwkFjCT19AxpgJgydsRiw0OtcGT+b9Br3Xb+QaR/pHDenktSKLBIwx8wdGNFmAq5E/wWjdmWeeuW2UeFQwgshIdF/Z2yHOxcIo2mnKh/nGzGmezbZ+rvEcVmMmlAcffLCzsgq8Guo/8ddugzIOeDVGOsexW4IxZnzwap1X+iXFkakdK1asqM7MKBlFO81COXbeWEzKKlhhNWZCQPljHhNKKscwW1lpFTkjJ7MBjS4Kq+ZRGWPmB5rTTVvDnE9G/jhQZJmry1zPUaO5m3G++WJkJu00fljE2bQv90LFUwKMmRBQWFlswkpdnqC7LLaqgw6IrWXG+dqNqQBsq2Rl1Zj5Ce3EI488sm3DfF5Vs3iSxUejvq95GGeBl1i3bt1A2+otRAZtp2ejXZ9krLAaY4wxxpiJxlMCjDHGGGPMRGOF1RhjjDHGTDRWWI0xxhhjzERjhdUYY4wxxkw0VliNMcYYY8xEY4XVGGOMMcZMNFZYjTHGGGPMRGOF1RhjjDHGTDRWWI0xxhhjzERjhdUYY4wxxkw0VljNgmTfffftLVmyJB3jgO/+X3zxxb1ly5alODDnGtLB97oXEirH+ZKvSawXo+b2229PeeN44403KltjjBkvVljNguTtt9/uLV++vLdy5crKZnSglKBAfffdd71PP/20t3HjxhSXGT2fffbZvJHtYqkXV155ZW/t2rXp/zHHHJNMY4wZN1ZYzYJkt912623durV3wgknVDaj46GHHuq99957vVtuuSXFc8opp/Tefffd6urcMTU11XvxxRers4UDo6zjhFFCRgtnyqTWi3Hw/fffj+Vh0Bhj6rDCahYkH3zwQTKPOuqoZI6Kzz//vPfAAw/0VqxY0dtnn30qWzOfeeGFF6p/w7PY6sXLL7/cO+yww6ozY4wZP1ZYzazwxBNPpJEy5vTRuWuuHyNb2NfZ5eCGOXSa20h4nOf8+9//TuYBBxyQzCa6hokdr3gZuWUkDbccTaA4az4j/p9//vlt8fD6mOvkk//YcQ1Z5WB39tlnb4sT96RbxDAFfuSeUUTiV1py/zkqh8MPPzylT+cc1157beVqmhg3YSqdMS3kM6afcJFFTu6OMJgWELn//vu3XRe5nCOkKc4rVbiAyYgo6BrHIAxSLyRLpQXZRTmQD8lT9rHc8I8b5Fdyw9Fkl0MdUVi4y2UH1J3cDXk9+uijKxfGGDMLTBkzZjZs2DC1Zs2aqW+++WaKKrd27dp03u/0pjZt2rSD3ZYtW5LdunXrqhCmwf+KFSvSgTvADW4JJ7Jq1arkro1BwgSljTx1hXDxQxzr169Pdso3duSddOCur/hMLV26NLkRyovSRxj4xV8EvytXrqzOpiGduMVe+VH+lJY6iFNh5rLJywZ3uCetxENZKi3IjDypDnDwn3A2btyY3ABx4A5/uAHlNc8Xecc+IpnmaSNdUX7Kg8jPh6FLvSjJAXlhx3/Sp7xLlpzjDzkhY9xwTW64jizIO3aSX7Qr1QvAjmuqF8SXy0H1BxkRlsLDjv/GGDNbWGE1swYdHB0dHV7s7LCjo5VCAeokI1JyojsouSWOXKErMUiYIAUqd98GfogrgsIhZUWUFLESuMmVEM5zOylxuSKFHQpKE4SFu1wxQbakO4LbPC9CMs6v4Z6wRJ073OT5KimZJYVVChdKXx2lsAalS70gHzG/oDRLaRSqG7l9pORGZRYfBLAryQ+/Mb3UPewE1zjP6wlh5fkwxphx4ykBZtZg5T7cdNNNaVEKaFucq6++etvcP9kddNBByQRe69533329vlLTOkeQ16b9zrZ38MEHVzZlBglT8Dq234kPNU9x7733rv5NgwyOOOKIbbKAXXbZpfo3Wvbcc8/q38/897//rf41E9MHvLJm0U1OnhfBa+e+crXDNdxTTqLOHfENy7PPPpvMQw45JJnjoq1e8EqevFL326BeMrWAqRF1q/Dr3Lz00ktpMRQLvgR2cb4pfq+66qpt95ymizA14t57761cTS8io5w1ZUIwReOkk06qzowxZnawwmpmjTfffDOZJ554YjLhrbfeSuYFF1yQTJDdkUcemUyQsnvcccclU0i5jYreO++8k0wUoiYGCVOw2KQt3HGgOayaSzifQOkpKbI5Xd0NAko5Cty4aasXqvu5G9X1nXbaKZmgennuuecms4Tc/OY3v0kmqN5eeumlyQTZxfmmr7zySjJRWqlLl112We+LL77obdq0KdUx8eSTT+6wiEwPg/k9Y4wx48YKq5k13n///R1G0DZv3pwWrES7V199dQd3H330UTLzkUKt8I5K8Ouvv95pFHSQMEGd9Ti2ymoCJeLOO+9MI11skzSV3ujPLxjVmyv0ADMuutQL6j7kdfKpp55K9T+OAKteNu1xKjfxoe7jjz9O5v77759MKD38ffnll8n85ptvUl2iTjGymsdHnkhb5Omnn05ml8WMxhgzSqywmlmDV5P5q0RGplBOIyV3JfRKnxG0qAjQAQ87CloXJvznP/9J5qi3ymqCETJGuv7617+2KuCzBa+E8zJrYtWqVen1NYpdJA8HmVP2uXLbpHBqBBF+/PHH6t/PoEQycpvHXYLX+sMwbL0g7chl9erVlc00emBrovRQ99prr+3woFZyVwe7F+RyYlcAgXzYugvGPcXCGGNyrLCaWUGKRZxXSueIMnH88cdXNj/D63g6SG2hdNZZZyXz8ccfTyZ+tTVRnHcHKAHM2cNNfMWZM0iYoNe6g44uSQngtWsEhS1XxuRGypNeFT/yyCPJRJlDJox85Yod4XFEvvrqq+1MkL/cfx3Eh1sOlBpG3lCgI6W4xSWXXJJM/Obh3H333ekanH/++cm8/vrrk4k74kZp4n9E85tVdsjrueeeS/9/+OGHZAJljBKnuIG6GOuFwvrHP/6RzJLi1kSXeqG8MbUDSMNpp52WlEm+HBVBaWfqRxMlN9T70oMeyip5V56lWDNHFeJ9EpVd6hgPlPglvUwhQLlW3RtUTsYYMyPS0itjxoxWYveVlMrm5xXc+UroldVKZ1aNxxXjuO93lulaXwlJ12N4QqvNCad0PdI1TOgrF0OtjiZcwufQVlLaQohDYWqlOQd+tLIde4WBP+wlI63gjuHJDney41B4yi8H+a0jxiH3yCCuQId4vU4++MFvDKe0Al6r13FDuDGvedjaUQH3/KeuKPy4KwJhxLhLZaywiCPPXxtd64VW4Sse8prviIBM8vTnlNyQH+wIM6L7Dhmq/AG/MS2l+HAvN8iMtCIb+SmVnzHGjIsl/PQbIGNMCyxQ6XfcxdHXhQijzYzkuYloZrHVC2OMmQs8JWCW4dUaioBeDc4UvvrD6zy9cjfjQV8KiquyjXG9MMaY2WHRKqzMeWNuHKMjdYeUQH0qse7QvMc2mPPFFjLr1q3bbg6dPqFIWPlnLwXp5brmNoqLLroozREk3Dq/ZmYwX++GG25I8w3j/pYLHc35lGm2Z7HWi0mGObW0s01toebfqv2mLc7bVYE97TvuaKPxl98PMTzc1A1GMLhAX+L7ySxEqPfUb81rp55T53X/cDDvPn4mmvsLu84DeEwJWKzUzftiPhf2cY4Wc7aYBxZhThfz13L7EsRBGPmcNeaEYU9auMZ/zXOMEEfTfEP8Mt+s5NcMj+bsMZ8yL7uFDHWNfHNQJ832LNZ6MalQBpqHzJG36RHabA780O7yn7YzL0euYa92l/6A87y9J17VA+b9En+cLwxcw2/T3GRj5iPUbe6hvC3kPqHOS4/Svcb9EXUr7PGL+/wezFn0i67qGjeEF4XKed5QAW5K9hEKhHhKizkoKBo8QVry8PBXalBzpGgTnzHGTDoog01KHIof7WFb24cb2mLc1bXpoDYyKpR6+Mj9kDba3YiU4tg34Ca27aQlDwt/bf2EMfMR6jV6TA72UbcB3X91OlcpnIjnsNbw4osvNm7cLXCD2ybuuOOOtBVM6bUhX+Jp+hwnw+p8uebWW29t3UuRV1v9xnPbdjXGGDPpnHPOOdu9JhS8LmTLO7baamv71F63ueNTvbSRcR9Ztct8xCHCa8p8m7Bf//rXydTHRYCt+XbeeefqbEfIBx/96HfSlY0xCwPuERbm/v3vf69sfoZ78uabb67OptF9UtJ5WLTKnuNN0wOssM4CpYavK1I+mavaBeKh0I0xZtKhk1qzZk3v97///XbzSKWs8hA+yt0X6j6hu2LFirSPrSB+FNFDDz20splGe+3qy2VdYP9a8uiPLZiFxnXXXZfqdpcPk8A999yTBu+0B3qEB9NVq1alrzrWYYU1gyf9LouoGPlkgn3b6nw1fHvvvXdlsz277rrrdhudR5i8fNttt/UefvjhyqYdGtitW7d6Yr8xZl6AQopiioJKe0nbxX8Uy1FvFUZbXCLvcH/66afq3/aUOmZGbEtfWQP6Ez4OcuONN1Y2xiwMuFfRNY477rjKpp6oV/HQWKfgct+XvooorLD24QlYq9hOPfXUynZHGPqWu91337228Yuo4av7bOPpp5+ePgVKAdFQ8+lDfRVn7dq1acSUV12M0mq3Agq+TSH95JNPqn9lULSVly6Ht80yxowLFFMUVDos2jdGYR577LHq6mSDss3IEW0ynTj9BCNInMfpXPpqG+2pd3Qx851///vfydxzzz2TWQf1Hb2KBzdGUeseBuHAAw9Mpj53nWOFtQ9zi6amF6D1NmzYUNnuyMqVK7e5++abb9KT9UyhsWNInQZ6v/32S0Pi2KEg8mqfuU8os8zzeuaZZ1K8oM9XDgtKsPLS5egyn1dERdeHDx+L6xgWlFYGARhhefDBBzu/ZpxrNHrKIMaZZ56Z+hA65jidiwEH2vNPP/00jUoxSNE0V8+YSUdvhtt0A+kQjz76aKrzepPSxEcffVT92x4rrBkoi22LqIDG9LvvvhtIkauDickUKOFpkjKjrCjSNHxPP/10UpaZA0W8PLXT4E0qqqA+fPhYfMcwMBrJwzqDAMwnvfDCC1vfIo2aQQYgmMolaJPpM8j7Z599lvoQBhl4c6fpXJirV69ObmnTGaQYZKqXMfMdFjeitPJQyv6sw2CFdczstNNOyXzrrbeS2QUV5gUXXJDMnKYVqUKLA+rwlABjzKTAGyNGHl977bWk/NGpdZn6NCgow7yyz8EuLsZS+/nqq68mU6gdzBdj5TCdCwW8bkCjaWcYYxYq2pGjbo5qG1ZYZwhD28wtrYNRUZ7cv/jii8qmGRroa665Js2JGuaV2ObNm9P0gja/45wSYIwxXeErUbwqRFnVWySmP6HA/ulPf6pcjYbf/va3yYwP4Ho9qbUDQBp4q8W8u6g0f/zxx8ksrXIWhM3CEqZzGbNQ0UNX3WAWA135tBfda4cddlgy6zjooIOqf9uzqBVWafkoeW3wqieHhowJ9U0KK/CKiAasC4w08KTf9KlHVqTWvb4iHp7sjTFm0smVVcF/7GjPcNMVdYj5nqqCt1a0nXzKWgtdmX7AyCvtdIQtexjppU3GHWEzmMDoKa/160DxvfrqqxvdMP8vTivI4XPddPhRWTZmkvjVr36VzK+++iqZJbh3pdByv3Gvcf/VvT3WA+H++++fzB2YWqTwpZO+4NJXFzjWNHz2dPny5dvclQ6+0NDE1upLV01fdIG6z/rJXl9y6SukO3xBAvQVCeIzxphJh3Ysb+8iXGtqmwXh6LOPOmjfaZtL7Sn2ckf4dV/S4gtWav8Jr/SFngifxsZ9Hp7saZs5+B+/jpVDPMTZJBtj5hrqcd39Sf1GV5GehYnbJv0E99zHdSxahXW2oUEtNWQRGtGSIgo0eCr4UgPLeZcGdTGjBweOtoeMLvAAofAs9/mDlAGO+InNrnAf192nOdyXxNfUCE8SudKXH6rntEFtnc9iQ21wnSKKvJBhl3aa67gzZpIZ5SCZ+uemgT0rrLMIDRYdwqifmgmPcLt2oosZZBU73plC50R4wyg+Zu7gXqHcBkXl3aWBpq7Nt4dIlC7ylz/Q6eEs1nM6FpT3tjdHZnBoz+dTvTGLF+oqI6MzhTanbSDJi65mEfYZvPvuu9N2J6VvZw8DOwowj5Zw8+/2TgLMWxnFLgPMcyOcmdL2IYdB+d///d9kelHa/IK5if3GsTrrziOPPJL8Nc1PBOYest8g9+aVV15Z2Y4HzQOtg7mXg664zxdFqH7Hes6cT7ZmYo9ozR01M4e28vDDDx97vTFmFLCrR/8BPrUHw8y5xo/mj7d+LKRSXI0ZOYzW8OQ102rGaBYjOW1PX11gasUoqz2j5qN4ujSzyyCv9UWXV1ZCb1NmA71qLr2K1igvbrqgkdS619olCBt5GmMWL7SLtHld3j4JvR3u+pbGCqsZC3p1mh95x0kHKaWWA6WUSiz06jY/8gquRQ1c02vKksLQNqk7wo1HeunwCReTeCLEhR35UPx1ykFbGsm3rkth0Fw27EoNAdflRzc+7nM0lzLG36SUNKWFo9TAkL5YlsiBPOevNtVIyR3x5MpjFzcgGeKGdOVxAWWTu+H/IEoZKP9tNCm2bXIdNE1C9ZTwBf+xq6uPJSSbQTudYeRpjDGDYIXVjBU6srqRLDp0rksJpJOkM89HUttGfdRZS0FQB0pYObjrMrKmzh4FjHRpQUVUiKSYEB5pwA3/sYuKA7SlkbDIN2GgXBGvlHfyXcqLwkQ+gDvCzOUX5aq8lOQscEMaYlrIF/HIjngjubxAymtU3PCPOylRCi+mpYsb4Jx8KP+KL6I6RrkRDgd+sOP/IOCvS92hPhO+5CByuZL+KNemMumC6gNlQXj8HzQ8yVSQtnheRywvY4wZB1ZYzdiQUhYVFkHnzbW8k9MIT6ROAQApaXkcpbAVZ5eRIBQKOuqo1NCZSzkCKUMxntII1SBpBOJGAYhx5Sju3A12UakG0k2YEc5R8NoopaVURpJXpCQLwsnTjXyiItjFDWGTrhg217ETXOM8z2eulHVBZRjjq6OkOOdIrrEuYjeogpmDf8IlLI5BlXLSnR9d6kmpjhljzCixwmrGRpOiiXJRulZShugw6xQMOsn8Gp00YeQKopS8NqWjTsHMUR6iUoACmqdnkDTKvqTIRggvVxCk6EUlSHnhGmFjIk+UGh4omqhLS15GdfJCPnm+kb3CjHKLtLlRukgHkCelKaahro6Rpjb55iCzrgoZyluT4lkn15inYZHsONrKN0cPmDENpLHtPgDyi19jjBkXbmHM2BhU0QSNEEU4LykY6pxRTCJ0sNjnigph1KUngjv81ylUgjzko0+5MjRoGqOCWUdJsQA9IMR0Ky86kC9pyeMtIQU4V3zyMqqTV51iqLxzPSrXkSY3uqaDciCeXGb4zZVMlQdhdGVQP8iHow6VccyXZN1U7m0gf/I77Air6s8waSC/+DXGmHHhba3M2HjvvffSJw9LcC3/pC3bW7z00kvbfSKRbbHYgih+tlF8/fXXydxrr72SKdhqp6+s7LD1EJ95rEtPhDhxx/fE6yCt5IGtiwT++spN77jjjqtsBk/jRx99lMymbbLqtub629/+lsKM6VZe+vd6OtiChO3P2rZlgrfeeiuZUfZ1ZdRXkraLl615clkI/PaV4FT+p556anGLtyY3X375ZTL7yljK07vvvpu2jMtlRvzII/L0008n84ADDkhmF1555ZWUvxNPPLGymRkq4yOPPDKZ8MILLyRzJtuj8QlR8swnTSln7ptBtrPCH8wkDcYYMy6ssJqxQed56KGHVmftPPTQQ8k899xzkwlS+A488MBklthll12qf9P7tb7zzjs7KKZ02oOkp0lZhbfffjuZMV3ECyVlqEsa4dVXX+2kVOfw7fHvvvuuk19kERXOOkjLymyvUpXRRRddlEyxbNmy6t90+DfddFP6H2XBnsGkE1CCUapI7z333JPsoIubOtiPFOU5EtPFXqEPPPBA+l96AKqDBwHk1VYnBN+IR6mvQ2Ucw3v//feH2hdW5N/kJ+xnnnkm1fk//elPlatmeKCbSRqGqbfGGNMVK6xmrGzevDmZdKZ0qmLNmjVJadOG4ygqfFBh7dq1xRGejz/+OClCKDO4hT322COZzz77bDKx//DDD3tHHHFEUlRQXqSYffLJJ8k86KCD0ujftddem85LnHDCCUnhUNoIJ9+cvTQSqpG/PffcM6UT94OkEYiXTcOb2GmnnZL5+OOPJ5MwNYKbK+TkhZFgfbgBk1G3008/PZ03QfmQHimBKqMNGzZsp/AxWotihLxwe9555/XOP//8dI204g9ZSGFUeBqFJY2iixuNLEt5jjKMI8eMrqKEUW8Ih7SvXr062WNXUnBzFH+uoDehUfe6sEtl/NlnnyUz5qUrubIq+I8dMoj3XglGsBmRRS7DQF1pq7fGGDMjmBdgzDjQohfNQe13/NWV6fl2zP/kOseKFeXNg3Gn+XF9RSPN24zz8jSfkTg0p1Px4k/zL/FDHNhzPYaRwzXNy+QopY2wsY8QF+ngYD6g6JpGzWMsySFH/pEJ7gmD89L8Q7lVfF3mKCo85EAc/Ce/pTmnUbbKD2UtWSjPpJPrSgvh5mXRxQ3gjrDlpiQzlQduyAdhaP4ofrrIAX95ObdB3omjlKa6Mi7Vh67gt8kP18hHHUqTjnxedhuEj79S3TDGmFGxhJ9+Y2OMmQfodXn+2UZGjO+77740LWAUMGLHJzcXc/PAaOPuu++eRpSHGfVkZFMjpwuZxZRXY8zc4SkBxswTeF3Oa+18sRWKFcrqoEpVE6+//vqin5PIAq2lQy62uuKKK9LDA9MhFjJMmaDusYjQGGPGiRVWY+YJce6q5hqixDInFW688cZkjgJGzLouMlqoDLrYKsJcWuaPXnPNNdtGxRcazHtlrjIj0N5ZwBgzbqywGjNPQAnauHFj2saJV9VLlixJC3xY7PLpp5+OTMFEGWahEQtp4kKzxYQWW8UdKwaFRU+UC+ihYqHANIDnnnsuPdiMcmTfGGPq8BxWY4wxxhgz0XiE1RhjjDHGTDRWWI0xxhhjzERjhdUYY4wxxkw0VliNMcYYY8xEY4XVGGOMMcZMNFZYjTHGGGPMRGOF1RhjjDHGTDRWWI0xxhhjzERjhdUYY4wxxkw0VliNMcYYY8xEY4XVGGOMMcZMNFZYjTHGGGPMRGOF1RhjjDHGTDRWWI2ZcJ5//vne2Wef3Tv55JMrm8nk9ttv7+277769JUuW9A4//PDeBx98UF3pxrffftt74oknkl/CMnMD5UZ9oxyXLVvWu/baa6srxvzM559/3rv//vvTPf/GG29Utgsf7g/uCe6NxZTvSWBBK6x0ejS6+SFQAPJr7igXDjSo871BQYnbeeede08++WRlM5nQgG/evLn32Wef9TZt2tT7/vvve7feemt1tTvk9b333qvORsuk1QeU80kDGR1//PG9a665pvfNN9/01qxZ07vlllsGfvgYFXVteH6YdkZR3/Iwfvjhh97WrVurs9FR6pvzY64e4Hfaaadk0sYtVsbZdjWFvaAV1iuvvDI1uitWrEjnGzZs6E1NTaX/8OKLL/a2bNmS/i9fvjzdePgxC4M77rij+jd/2W233XrHHHPMtjo8qaDUHHrooek/6UVxHbRRI6+nnHJKdTZ6Jqk+oBg+/PDD1dnk8PTTT6eO+JBDDknlcfPNN6c2k/O5IG/DeRgiPTo4X7p0abpm6uFe/PLLL6uz4bnuuuuqf73ePvvs0zvqqKOqs9FC3xwV4VjmHOvXr6+uzD7ke5dddqnOFh+jqkt1xDqWs+CnBNDocsCee+6ZzIgaYl5rUBHNwoCb6r777qvO5j+qw2Y4Jqk+MGq+atWq6sy0EdvwHB6OhhnJX0wwOn7xxRdXZ8NDGOMYTa2jqT++6KKLemeccUZ1ZmaLUdWlOlrrWP9pZcGzcuVKhlWn+k/jlc32cA03OVu2bNnmt/8UP7V27drqylQKa82aNek67pYvX56Ob775Jl3fuHFjOscv5oYNG5J9V/qFluIjXli3bl36z9EUFvH3nz5TnKSRMEgDdkJhYb9ixYqUfiDO3K/ixI9oy3uT3ID0x/gJK9IkO/4TNumJ8WBG2WMXD5W95MGBnyiXnJhPwuY//kiTZKb4YxykLbdTWOS7FBZ2Shtu8jImHg7JG3ecU2aRJtnH/CgcDsmthOqD0hrrASiueORuIjHvHH3FbYf4S2E05UvgJ6aVegB19aFNHlynfuKeOHEb09qlLpZQmDrkvum+jXnL8z9IW8E59oQT7z3iVHriIUhfXbnF+LEjP/wnTFBeOLjWdM/VIdkqzK7EMlLeSbuoa2vIR+5X7mI9aMs7dnVyA9U7xU+ZRJr8dyl33HAu/xy4A8kDu1I7HIllqANUbzCjLBVHpE7WTcS4miDseF9FOWEOe28J/Cl83Oq/yhma0qD6q0P+MGWHmzpUD1ReuKXuRGIacRfrKcT63NRe8V/XCIf/hN1UlwiP/MqedMT0dYm7ro5FrLD24RpuIghVFRyo3LhTAWGviosd1/lPoVI4+q+K1hR/iVgBKEjCVJxUmjqIk/Tgj3i5iVRRADtVZNySTsLjnDhVaYibOONNyDk05b1NblwnPtwC16Psm2THOelR+riGvfJLWAJ7+ROKi3AUttJVAr/KJ26JO8YvlMc8rmiHKTlyTWkgfA7krjwTdl7GpFvuCEt5JkwxkzpbgrjidYWHLHJiPHWQN8IjHCA95DO/9/Kw2vIFpElpJR7CxI3Sjl/OFQY0yYNyJm1yj8k511V2XetiCdIX802c8qu6xnXsuCdi2uUON4B8SAN2TW1F270HCjvSVm4xfvyTLtxjKg7JjLzhZlAII8oAiLcprLyMSAvyUbqb2hrsJHfcEw/2yiduoSnvbXIDznELui7a/Hctd1D6RJe6kIN/wokQn+LnP/AfO4UNTbJuAjd5nKQ1+iNM3Ch/MU3AdaV90HsLkBV2eTlEf21pIM8qqxg2KD24KaF6QNr5T1zETzkLwsBO6VEa8YcfDtwQP+kgLNwov8obcD3KjjAULsR8CtKCP6VP7SoMErfs6lhUCmvTkd+sCJbKHKEAqAQCP7HSCNxQaIICIw7CHAQVHv5FW4EClQE3efq58fL0qiLFm5Fz7AXx5zdIXd7b5Eb4ub/ovovsONcNJbCLN5HygSm4zs0SydOaQz514wnsYn0pxVWyww92kVJ5yi73G+MEuVMeZlJncygDwo71AIgDe+pSBLso/xLUsVz+6txieHlYbflShxLrDXHFcEvlAXXywC6vYwozNrCct9XFEqXyVBrzvBJfLEPdEzEO1YWmtoLwm+49yP1Al3KTv1gGgP2g91wJZEX4+UH4beAuTwMM29YoLfJbl/cucsv9RdkMIvemcgfOo6y61IWcUriqs7GdkB2m6CLrErgpHTFs3f+SCdA+xPtLaRrm3kJOdeWgdHRJA2ETVx4W53k7GyGNeVkht5juUbZXpDnKiXKL8s7dA2mJ8Ug+kS5xl+pYZFFta9UXOpLY4SjBquxzzjlnu1WJrF5mQQILJgRzXyOsQsZNvwJt87f77runa8Oufi7N3+qy2jmfs/vSSy+l+SExT6eeemq6lq8CZrW2IP6TTjpph7kled6hTW4HHHBAcscKT+WBLXRgENmVJr2/+uqr1b8yLBBgLiPzZFSGiruJkvyR5Vxz1llnJVMT4IetsyVYfAP7779/MsUf/vCHZA6T/3/+859pHmlMH4u14JNPPklmibZ8KS1xzhtz3Li3uywWKt3D1PWDDz64splG8iYfkWHqYhP5fUtevvvuuzT3lW2EjjzyyOrKjjS1FU33XhODlFs+73DYe66O2Ib3O9XKtp299967+jfNTNoazZ38+uuvkynyvHeRW1/xSG0rMoIom0HkPmgfMWxdqCP2F+LHH39M5iCyrkNlztFX8CrbabjHscdEjuSpLtxB7y36RdqC4447rrKZJq8TXdJAGV199dWpTHUvEO+7777buNiUepC3UcRBugH5jrK9on5zv7JDB+mjXjNXvAnSgixJC35VT3Nm2lZ6H9YG6hTcpsngouSPldNzTf/pqZi2e++9t3JRRivAu9AkN27at99+u3fCCSf0TjvttHRj58pyye8oZMdNp0aExpMbixtyvlKqhzOpsyV++umn6t80pY5pEPpP0MX0tXWWo85XF9iyJ1JSCmYLOtP99tsvPZy8/PLLle1gdLn36hi23MZ5z81EwRKlPLW1NQceeGD1r502uaF43HTTTWllNEoJey5HhpV7GzOpC1356KOPqn/TlPIxTLt+7rnnVv9+BkUJ+T377LNJlvRzXWm6t9T+lRZs53RJwwUXXJB2tdCOJQ899FDvwgsvTP9nyqjaKxTPf/3rX0mRRC5dtvpEAacOXXbZZUm5p96OAyusDbzwwgvVv5/JG5Q6Su66+h0njEaVOoy2tOU3QxNtcuNGYruaTz/9tLfrrrumfR/jCOA4ZYeCg3K+ZcuW9GTLTTZfUTnGp9aZ1NkS//d//1f9257Sk3IXnnrqqerfz5APGvsmuuSr1OFq5GoY6rZuoc7OJnQY7Iv62muvpW2mZqKkt917dQxbbjDOe26m2xAO09Zo5LALXeSG8onitnr16vTGK8Y/E7m3MWxdGJZhZF2Ch6A44ocsjj322KT4c7+3jQZGut5bH3/8cfWvTNc0IPM4yvrAAw9sGwlt4p133qn+/Qz+Yz0YZXtF+tla7NFHH+3ddtttjR8PoT6uWLEiyY77exQPknVYYa2BVzVUqrwTfO6556p/ZShonqBuuOGGVJCCypU/cc42euK7/vrrkym6NBq8ls1fxZRokxs3mG4ybl5ubl4X8Qp63LLjSVrh8urm7rvvTqM/8aafCbEjG6RTG5ZXXnklmSeeeGIyh62zJVRX7rnnnmQK5UtxQiyrJnjVhLxzJfKuu+7a9oqyRFu+tBfkVVddlUxBeTeFW4fqIXHGvOn/6aefnszZgpGOI444ItXZmdB074nSg+mw5QbjvueGZSZtDfWO0WLCaKKL3OLoFcoj953uuZnIvY0udWFUjLtdf+utt5I5jKLUdm/tscceycxfq+cMkgaNsjIVhAP5N8EoOGWTj3QySotsR91exXiYqoCCXfeKH5ieQvpKI98jZ2qBw0RnJj+T1TgpWGiydL8B2m5SuOw5mBS9bt301hebqsnHhMs51+NEa9Bk534lSpOMOXCLH2CCNdf6jVM6r6PfUadwFCdoMnPbJG3c4D9HYZIe8kTeYjqIi+vITPLAHenVeVPe2+SGSdjxHLc6b5Odwo9p5hp2hCvkjvi5Tvj8J/95vhR2jvKZu1F9kh3hKX7Fo3LCJC24zf2ByiPKUX7jxHfySzpU7sTDeXTTJnvlJ4+vDsLAre4b8kkeSF+kqb5FYvzkh/TJFMpDDKstX0A4MVzccQiFwTXSgd8meSBXxYc7Dv6X6hhxCtxhF92VIH+qVyrTOjnKLfHhXu4kC7nBLspE9SjWGdVRnUc/hF2SR7SvKzfFr7oicMO10j2HHeFy6HoJ3OreifW9Cyoj4iCciORIepAVR+5O13OZxfa3Lu9d5EbYypPkoetd/HcpdyAe/AL2uG+qCyUkL9wgV9Iru5gmwscuthNdZJ1D+PjhaKofCltyxCRs8se1mE7kFeGcNDXdW5JnbAuQJXZ5+E1piBA27uN9VgfxkcaYLuJXXMD/PI38J36he0H1AHCHXXSnOqZwkFH0k9clhUt8QP3gOnZcj27a4pYcYx2LLGiFVZUiP4SEGg9VUkBoCBN7Kh+CF7m//EZH8LGxiRVTNzTXc38iT5sqaW6Xk+c5VhCgknADxhsAO0F6sNeNrDBi+hW2jjwPTXLjWswH1+ONB3WyU9riUbIT5I1zNZyEq3Rx8D/mK0fudNTFD7rRkBn5wZ48YK8bM/eX2zWVMekkPyoT0q64I9gNW2dLEL/iVH4ieXrbwqUBUidLuLEOl2QimvIFyFjlTbgq80heHxSHjjzdxKF6qDB1r5TS2pT+HMqTMAmf/033LdeVDqUBWchvqc6U7EhftMe/7r1S2mMamsqtFJdouucIUzKIfiLYx7B1dKFLeZA+yZZ8KG1C9nKDGeteU96hSW6APLDX9bzeDir3uvRIoeE69aepLtShekc6cEvY8q+wS3aiTdaRmLZSWBHSJfeYyAw5NqVTtN1bgjBUTrQjuMUd4eOnLQ05hI3/ruBe4deV1ajaK/KncDiofwoHiBt70iN74sIOf4RLWjjHfpC4CS/WsZwl/PQdmzmAofd+oc/4Vd8o4TURc3H6Far1lZcxxswU2hzmCLLYY9JgRXtfWZnxXFljIkyVYR3AOOd7LkQ8h3WOYH7JF198MVHKqjHGzDaPP/54p4UnxiwUHnzwQSurQ2CFdQ5g8QiT22+88cbKZnLQ5PGvvvoqmcYYMw5YdMNI0xVXXNG68GQu0KIkBhaMmQkMULE7Bkoqx6i2slpseEqA2QY3VNwQnukKbG1hjDGLCaZr5btOuKs0w4LCykcJ2GD/1ltvncjpL/MBK6zGGGOMMWai8ZQAY4wxxhgz0VhhNcYYY4wxE40VVmOMMcYYM9FYYTXGGGOMMRONFVZjjDHGGDPRWGE1xhhjjDETjRVWY4wxxhgz0VhhNcYYY4wxE40VVmOMMcYYM9FYYTXGGGOMMRONFVZjjDHGGDPRWGE1xhhjjDETjRVWY4wxxhgz0VhhNcYYY4wxE40VVmOMMcYYM9FYYTXGGGOMMRONFVZjjDHGGDPRWGE1xhhjjDETjRVWk7j44ot7J598cnVmjDHGGDM5jEVh/eCDD3r3339/dWbmiueff7539tlntyqiKKv33XdfdTbN559/3rv99tt73377bWVjjDHGGDM3jFxhfeKJJ3ovvfRS76KLLqpseknpQSlatmxZb8mSJUmBQqmtA/coS4cffnhyz/86CKukkBE+9vhvizO6k9su5Onk4D8y0LW5ZOedd+6999571Vk99957b2/dunXV2TT77LNP76yzzuqdd955VlqNMcYYM6eMVGF94403eg8//HDvyiuvrGymkQL46aef9r755pv0//jjjy8qkNjtt99+vVdffbX317/+NbnPwxOM4qIc5zA6SPhnnHFGb2pqKh0nnHBCsuNahFHIXXfdNSls8WhD6XzqqadSOhXPk08+2fvyyy97u+++e+Vy7jjmmGN6++67b3U2OCit1113XWcF3hhjjDFmLPSVrJGxfPnyqY0bN1Zn02zYsGGKaPqKZ2Uzlf5jt3Llyspmmk2bNiX79evXVzb1bNmyZWrNmjXFcPBfyhp2xBHBb0xbF4h76dKlUytWrKj1S75J31xD/nL5lOgr6bXusOe6McYYY8xcMLIRVl6Db926tXfKKadUNtM8++yzydxtt92SCfzvK0HbjY7y2vm0005Lo5txOkEJ3N566629G2+8sbLZnl/84hfJJE2CkdW+ktnbY489Kpufpy8wgnjttdfuMPpax1VXXdX7/vvv08hqzFeEuaN77713dbYjjEZrmgT54T9TChgRZfQWO9KEHW5iXkDXNc2CqQiMFo8DRqpvu+226swYY4wxZnYZmcJ65513JiU057///W/1b3t4RQ8obnD99dcnJRBQ2qS8lZSwu+66q3fNNdfUKosozaTlnHPOSfNIUURRCF977bX0mjuyZs2aFO8tt9zSW7FixQ6KYQ5hSdHOlfOcuqkM4t13301xP/3000n5ZvoDnHnmmSmPF1xwQbI76aSTUvojKNn41TQLFNZTTz21Nf3IVUebW3HggQemuLq6N8YYY4wZJSNTWFncw1zQHCmIUkzFF198kcyddtopmShDy5cv7x100EG9zz77LI3WMiKKEhbnuqLA7rLLLr1DDjmksinz2GOPJWWU0VAUUUZucz+MgrLgiPg2bdqURitRcktza8XXX3+dzJJyPgjML5XCzYgy/zlWr16d8n7zzTcn2WF36KGHJoVRMkRWyBslV/74j/xyxTZnqppry0H+u6BR6Q8//DCZxhhjjDGzyUgUVilSKFY5er1/2WWXbXvljtL58ssvJ4UUJRIFEYUMxVKjlihrd999d/qvLbLw/8gjj7SOXIrvvvtu2wIqFlzlSnMEBVJpmvQtuVjYhnKKoir4v2rVqu0U264wCo1ir+kROXroeP/995NpjDHGGDObjHSXgBIopBs3bkyKFEoWr67/93//N40iaoTvp59+Smau8KJEghTdtWvXplf3bTC/E8WLaQMot0wFIO5jjz22cfQUxYxRWcVXQiPC77zzTjLnCpTxHEaehwEZadT1xRdfrGyNMcYYYyaDsSuswKgpr91RiJi3+cMPP6SRzCuuuCJdP+CAA5LJVlYlmGrAqCFbRqF4xnmYwMgg/zWyyJxQ0BQATBQx/P7jH/9IdnWg9JWmNgjCIpxhRjJHCfGjmJeQUm2MMcYYsxAYicKqkdA6hTPC/EtePz/66KPbXjXzOlu7BkQlTP9PP/30pNQyzzQ/gKkE/Jfii0KMQhchDhZx5fY5mzdv7l1yySXVWZl77rknmUxzqFMasWcV/zhg1T489NBDyRTkG2VaivqoUB5VXsYYY4wxs8rUiOgrnGlf0hLsVcr+rLhZunTpDnuhQr63KQf7mOKnCbKQuyEs7PFPOMC+qDFuxceerYpv7dq1yV0XtL9sX0FM/xUPJuerVq3aZleCa+SVMKI7/GFH+gTpwk5pk9+YH0zO4z64uCN9HE1paYOw8/iJq61sjDHGGGNGwcgUVilwOWw4jz0KFv+bFCeUNJQg3KMQoai1KVq4LSlOKFlSCBW/lDsgXMXFgaIYr3cB9yjFpDXG05ZPkHsdUgrjQTgxjbIDwidu2ef5g+iPY9D8CZR68qg8YaIEIzNjjDHGmHGzhJ++MjMSeOXO6/K2/UnN/ILFcSyI67o7gzHGGGPMKBmpwsoK/AsvvDAtrDILA5epMcYYY+aake4SwGKfP//5z62b15v5AYut2JPWW10ZY4wxZi4Z6QirYFTuk08+6fwlJTN5sBcte82eeOKJ232gwBhjjDFmthmLwmqMMcYYY8yomJUPBxhjjDHGGDMsVliNMcYYY8xEY4XVGGOMMcZMNFZYjTHGGGPMRGOF1RhjjDHGTDRWWI0xxhhjzERjhdUYY4wxxkw0VliNMcYYY8xEY4XVGGOMMcZMNFZYjTHGGGPMRGOF1RhjjDHGTDRWWI0xxhhjzERjhdUYY4wxxkw0VliNMcYYY8xEY4XVGGOMMcZMNFZYjTHGGGPMRGOF1RhjjDHGTDRWWI0xxhhjzERjhdUYY4wxxkw0VliNMQuaJUuWpOPkk0+ubIwxxsw3rLAGPvjgg961117bW7ZsWWVjuoIyMF8UgmHS+vzzz/fOPvvsRn/ffvtt74knnhg4fMLmmGSUr9tvv72yGR0lWXEv3n///dXZ8BD21NRUOj777LOUjya6tgGk7Y033qjOfga7UaR7PvL555+n+rHvvvsWZTNTutyD4yTWjXHkbxhimzOOe3M2IA/IdBzp516k3LpC+VKPzWSy4BVWja60HWqAtm7d2vv+++/Tf1OmrdNfiOy888699957rzqr54gjjui99NJL1Vk7F198cQr7lFNOSQ12Xi/zzpnzpuvjgA5lzz33HChfXaEzOeyww6qzaahfxHXRRRdVNsNz7733Vv96vZNOOimVTxtd2gDS9sILL+xwLxxzzDG9X/ziF6lcFyvIbxx0vQdLjKLN2mmnnZI5af0DchnHvTmfoc2ibTzrrLN6hxxySGW7PfT5tKHx4ePyyy/vrV27diAl18wiUwucFStWTPUb0OpsamrlypVTMdvffPPN1Jo1a6Y2bdqUztetW7fddbM9yBIZLkbId5e8U3+6uKOucUQ2btw4tXTp0hRGfk1QX3GD29mkKU3D0u8cprZs2VKdTaX7cBz1i3A3bNhQnTUzSBtAWkvlQBjkbbGBnJGd2tNR0/UezFm+fHn1b2aobowrf8MyjntzPkMdaSoj+n3qRKksdS3qDWYyWNAjrDw53X333b199tmnstmR3XbbrXfjjTf2fvzxx8rG1MFT66pVq6ozMxN47XTVVVf1LrjggspmGkZaH3300fT/1VdfTWYOfl977bXkdr7z/vvvbzcCcv755/cuvfTS6mw0MNp57LHH9s4555yRv8q97rrrer///e/TvRGhXO+7776Rx2cGh/If16ivmTwYTed+5G1HHddff31vxYoV1dn2oBOsXr16Ub8lmVQWtMJKhW2qtIIKWur8eUXL3BqOfI4hNwQVWq9mmVuVd1o5vGZgfhfuMQ8//PBkjz9uMs1D4r/cEUcMlzCIS/ESRv76Qmkj3bgh3NwN+Ylp6fLKjHB4JcfrJ4ULhEV8OgfC03wz4saUH9KH0iU74q/LA9c5muSrVzs6YjoUBwfuSmkVKm/cluRagjRpXhv+SGcX7rjjjt7KlStT3cuhLvJaCjkTdoQ5WWeccUbta67ZRHLliPKM5Z0fsZ5RHieccEJ1Nl1nUCzye3GmdYlpAf2H897y5ct7N910U2XbjaY2ANS+PP3008kUlCtTEP7nf/6nstmRXEYQzzmk8OocP0Ae29oB6k7012VuLfmN7ULMs+5J1fWu7Qbk6SUcwov3rvIGJbs6YppJW7xn+M+DAyhMofzIvtTGkD5ky3XieOqpp6or9XSRE+e6Tvi4bwL5KY+Y+CmBO9Wrkuxifohf5aBr2OtArhzRTmFGe/yRH65hn6chl2mEa9Gv7Kir5JOwY1+Vt4cleIj87W9/W53tCPHRfh566KGVzY7QNtP+xnuKdiavX2aWmR5oXTzwqqAp23rls379+vRKgNcD+ImvlLBjqgFugFcKvKLFXRPxNa78APHwupJ4CYM0cH3VqlXJjlfAgnRgTxrwxzlpEUobfuSGeGL6iUtTJXCDW+JpeoUiSF/MJ/7xR/iylx1hYq9Xsbz6jXlU+pQngf2g8lV8URYCO+ReSqtABlFm+CFOzgV+cn+kuyTLprTiDjdtr/AIA3exzkQ5zTZ5mvlPeuIrfdU35ABc45wjBze4F8gxl5vKjLiHqUsRwsnDJ87cPeERdlMbEKm7pnBiHiOES9y4IW2yI7zcH/bEITvlM+abvAjSTjhc50DWsexK4CbW5TwdXFcauK6081+orJQfUB3Q/Ux9xo3qCP4Jl/hEyQ44j3ZqNxWfZB6nacguQvjktamNUR3L3cT4SrTJSfKQXFVWTeC+1HcIwice3R+Ssc4BO/wp7QoHOSht2OEvpicvL8GUF2SLX7khDbgjHMld8iuBDORX9RM7+SUs/hOe5Ij86lBYymMOYSsfiqPOreIXqg+LcarPpGCFNUOVWDcwyE5wA5ZuXtw03UxcVyMFsTEBruc3g9IrfzQwsQFQvIJrNJYRbvTYwPE/poO8Egbu2iA9pca1ZE+YuV3JHed5HoaRr8op5o3/sSOHPA2EmctMDV+Ude5PnWVJltFdjjqFGHYJwqKsOEhj7FhySANhciAHDuyUxtKRy7gN/BAuYJbSXyoD2eUdQy4j3NTVQa7l7vPyAM5xW4L85vccMs3DUHqb2oAI4ebuQbKnLtWhcouyVP2I/vgf097WDpDevHzzvEfUGcdyI3zsdM9RNrF8SsqB0h7t8JOnhfTHsOrKss2ONBKW0P1H/kWp7PCXpylvY2gT6tzkdTnSJifMvL1pKhvAfyyb3D3XSVsEuygH4szdqIxjXSLPUaaAzPN2NOYRuqShjtyd6lG8B2TXJHuVtcowh3zoPpXbuvCQV55nM7d4W6saSq9q9Wrjn//8Z3rNpFciHLfccku69sknnySzRP8GT68J9Xqo9Pp4l112qf5Nw+tf+Prrr5P53XffpRXKvCrhdY7iFaSN1ycR4sMf4I9Vrv2bcVvad99993Rt2BW4o2ZY+TJvsN/Qptftgle1f/7zn6uzMrz66XcG28V36qmnpmvxlVDOs88+m+QY50iX6k3OW2+9lcwDDzwwmXUQFnNVKa9f/vKXvQcffLA2fOpVv+GlV07nzI+FL7/8cpt9v4Hu9Tuj9J/8DsMPP/yQ6u1ee+1VXMWv+qv6Gtljjz2qf9PTSFS3gXoJTa/pBoVXeLFMjzvuuB3uuXfffbf34osvVmfb09QGRPbee+9k5nWTnRXgo48+SmYJ6k6/E+397W9/q2ymoV7dc8891Vmv98gjj/ROPPHE6qy9HTjqqKPSfc815ACl9kZolXmsy4RPXdH0E8LjIDxeizJ3twtPPvnkNhkJ0q92cCaQRsLSa+QjjzyyutJMWxvDfc89Qp2J5O1ziTY5HXDAAcnkNbjqfVPZwDB9B3C/AvGQn4MPPjidC1bRA/IQ5557bmpzYvlQL+gflF7M0r1aSkPdXPwusANCjtrPEoqrNGWKsmC6QJc2GuhHJ6VPNNNYYR2A2CHR+dOY50dTw0MDwBw6bhpuhtKcuJxcqaERpKG77LLLUmNKOoahlHb2qQTNP4rHbDOMfGmIrr766tQRISc6sQceeKC1MwCUhlJ8cVuknP/+9787PByMGhpe0qb/ddAZSSG88sort9UL/pfmcdMBNeWtDjoyGnHqcEl5owNcsWJFmrvJdQ7m/ZGHqAw999xz2ylg44D4Yll2qQdtND0wDQsLzSg/KQN0yCirKJHUY45ly5Zt19G2tQOUuTpblN84V3FY8E+nT/nywKLFgXMNiup+++2XHs5efvnlyradpjbmp59+Sm700DEIbXKiHN9+++00f/u0005L5dj0YAzD9B3AosaIFFhRUt6oO9SZhx9+OJ1TL1Fiyc/jjz+e7DCl7M4HdG91WdNiJhcrrENSmnxPQ6Ubow4aQxRDViEyitfW8MTdCwifRoOOmJGhug74nXfeqf79DB1cTFspXtnRgdKYx2O2GVa+cZT1lVde6byrAcoB4ee0lU9J1nMBCiGdjEZFUFSjgjgqGCl75pln0qgWHW0uMzpARoJR5lEiGL1nkcdjjz1WuZguR/yPI33zEe5j6ixKAPUbJYeFZ6rHDz300Haj2V3bAa7zULJly5bkjvJqo6Q4qU6dd955SSH89NNPU3pKo191bN68ufr3M3EEb1hYqHPNNdekNxE333zzQHWqSxvz8ccfV/+600VO3Cfco7jZdddde8cff3xqo5sYtO8ogVJfgjRE/vKXv2x7YKJeouhdeOGFaTCAOjLf7l+UfUbQ4yCM3kKxg0iXe8PMPVZYh4BXmYxe5A3uXXfdte11TwmtggQaK5SM+NqvBCNRKCI0GIzuMMLF024dPLXjJsYFdHyEwUFHeMMNN2ynbNAw6dUlDSPpi8dsMqx8gY5Ao6yMRuTbRpXQCCZbnUTaOgQabGTdpkTn8LoWml5tDQqvtXndz9ZNNMaDpmkQGOn917/+lcoolxl1is6X9NCpMWKF0hRHcniQOP3006uzaTTyMZPXh3OFRq3ilAfQwyYKaBuUHXUW5UAKKHbcA/nWX13aAUYddX/jl+39KK+6eqE6qU5cEI7uORQYVl+XRuWa4P5iWkCMm7R9+OGH1dk0sT2C/LwE9YWPQTS9fSjR1saoLOOr8q60yQk5SBa4IQ2UZ77TRGSYviOidp86FuWq//n9qNFTRuY1LUJ2Z555Zu8Pf/hD+j9paNeRvJ4z6MLUqHhwf8H69euLgzLIhr7XTBD9DmXRsLVa4MBRNymbieRc71foyubnifaaAM6k7X5FTnb9hiNN3pbZRL/B2DZZnrQQRvRDeLhR3JgxXtLMef9GS+dcJ1654SBthCF3SlucpK+J9rgjbxykJV80UgL54A+3uTxiGJL1ijBpveQOcINb/IDcYTeIfAX+SSNpzalLg8ode+JBdsQpSv5IL/FwqMyQifId61AObvIFCiW61Nkc1Yl8YYbylYN78qDyLFEqT90XhCmZqM7ijnA5cEfcKl9kHWUvcBvDF6W4S+UBuMGt4hqGLm1AhHSTjhzy3DUtymNc/KL7PS/HLu0AcZMPxc257ts6FAam6kqsL/hHvoRBuFxTmpVutS0xH6oT+FddIJxYn2NYpB93uNG9RZylMiePuCEs7BQ/4REPyI5wcEfaFRb2yq9MkddvDsmIMOvKtU1OpIPrmCD56LwEYdb1HaoPpE0QN3bEI/CPXcwP/6ObCNeIN4K8S3W9axpKyC9hC5VZLA/qBXaUSx2SZek+zSFs3NbJnWvIQCidTfGb8bJoFFZVznjEmwvUGOnAT8kOaDTUsXFTxxurDm5c3MpPXvGxJz41pJj5jadGlGvcaKWbmBtL6cZd3uEBDYLiwS1+uoA70o5f+SGMeKjRGNYOhpFvBL+lRiuPT9C4IkOVjxp1kftTOnNZEydh4L9JplzHXxMKNx51fnJ75BUbWyjZAfWStNeFXSonKNkhM8LjyK8jl//v//v/tuuYIupQI4PUm5LdoOQyR2Ylu0hd/SSfdTItgftY56DOf1s7wP0dy4D/bfc4cVM/cE+eYpsClA/2HITPPcp/0ohfZKD4OGLaSZ/am1JaCEvpVXiYpEflGMPmwJ5wFC7pVf3DTnHIjrTGtrBLG4Md13BDWoiDsAiHcEu0yYl081/5IK0xXSWUfqVVZUNYCkdHyU7EclA4dfkgnFwm+CdPkUHTEMndIZdSPWqqWznkr1SWOQqTNORQd/Jr2CGzLmGb8VCuRWZO4AbxzTAaaOAnGToxyruusxgUwoqdnhr5COclhVXUKZKDQKOed2gg5aDUOUTobOgU5wvqxErliH1bfo0xo4V2cKbtP21Yk1Js5gbPYTULDuaEsUBgkmH+a79RTHPmRkFfEe29/vrr2xYUEH6ce8yiAuYnMoettLMBcxUvueSS6mw4mPPF/NXSdl2kp6+M7jDPM4cFXcyvni/ceuutaRV4Pl8ReVImmptrjJkdmANOWzPMojSgHWPh6DC7qJjxsgSttfpv5hAmibNakU7ON8rgoCCwQOKwww5LK3RZ9DPo4pC5QIsa6lZ6zwbIDiVzpsoVC/dWrFiROgv2vmXxCtsCsUiIBWYsPuqSTx44UL4n/T7Qgp08T6yi/sc//pFWrRtjZh+UTnZrWLdu3cAL8tiS7He/+93A/sz4scI6AbACNF+d62IZDJSuP/7xj2n1LIrOfNpyhZEAtr5ZCKNxKGuUhVY+L126NG14zujtIPkjHBTduVTkm6grs0lPtzGLCdoi9nvu2h8M6t7MLlZYjTHGGGPMROM5rMYYY4wxZqKxwmqMMcYYYyYaK6zGGGOMMWaiscJqjDHGGGMmGiusxhhjjDFmorHCaowxxhhjJhorrMYYY4wxZqKxwmqMMcYYYyYaK6zGGGOMMWaiscJqjDHGGGMmGiusxhhjjDFmorHCaowxxhhjJhorrMYsUr799tve2Wef3VuyZEnv2muvTXbPP/98b9999012t99+e62dMcYYM5ssmepT/TfGLCIOP/zw3oMPPtj7xz/+0bvlllt6GzZs6P3www+9iy66qHfyySf3Xnrppe3sUG6ffPLJnpsMY4wxs41HWI1ZpLz77ru9Qw45JP1funRp78svv0yKKZxwwgnJ/PDDD7fZHXroock0xhhjZhuPsBqzyGGk9fvvv+999tlnlU0vjbC+8847vU8//bS32267bbNjGgGKrjHGGDObeITVmEUMCuh7773XW7VqVWUzDdMB1qxZs01ZBexOOumk6swYY4yZPaywGrOI+eSTT5J59NFHJxM++OCDZB588MHJhDfeeCOZ0Z0xxhgzW1hhNWYR89ZbbyXzyCOPTCb8+9//TuYBBxyQTCi5M8YYY2YLK6xzCK9j2SaIuYFmMmB0kTmdbOW0GHj11Vd7y5cv3+7VPzJgEZYWZEVwd/HFF/c+//zzysYYY4wZP1ZY5wg6fBTVL774ovfYY49VtgsfXi2zPdKyZcvSvp4oh3rdPAmgpLHV06WXXpoUs4VOaV7qyy+/3DviiCOqs2kOOuigpMSyH+tvfvOb3j777FNdMcYYY8aPdwmYAxhZRVlFWbv33nsr28UBI8oo6TfeeGM6P++889Lq9LhCfRJglPH444/v3Xrrrdu2dTLGGGPM3OAR1jngoYce6m3dunWb0jbJMPqJcv3EE09UNjPjyiuvTEo6r5Y5DjvssDRyN1vcf//9aYS3bVSXkVaU1Wuuucavv40xxpg5ZtEqrChhvJLWa+mI7DlG/SlKRldvu+223tVXX73dvMEIcSr+cb8uRxElHtKVwyvxyy67rLdu3bqk5I0S4iPu999/P72CHwXIqq3cGC295JJLUr70OdI6NLJ6xx13JNMYY4wxO0J/zpSxugEeBotynUZrRjoPiDElYDGydevWqaVLlzIdYuqbb76pbKfZuHFjsl+zZk1lMzo2bNiQwib+JtauXZvcjZsVK1YU89lXUqeWL1++g2xGwaZNm1LeJOM2WQyCyo44miBflP/69esrmzKkD3fGGGOM2R76UvSIVatW1eoLUd/K+2au4XflypWt+saiHWFl0UjdqOFzzz3X6xfAWOaXPvvss2lVdtuilX4hpjSME55u2DT+3HPPrWym4Qnpqquu6t1zzz21o8Az4ZhjjknfoyePfDVplJvR/+///m8yiaMJ8kX5/vGPf2x85c8CI74CNe6RbmOMMWa+wToUdBpGSev0Bd7W1ulb6EIaYf3Tn/6UzDoW9RxWlBF4++23kwkoJgjvxRdfrGxGCyuwGTZvA0Vy3F8VYoieipYrd7wCx/6UU06pbEYHSrKmH1BR//rXvybFdVQQfv7Vpjq4gZg/y5ziOvbff/9kah9SY4wxxkxPA2Cnmb///e+VzY6gZ0A+MJbDANKTTz7ZOD1gUSus2gT9zTffTCaK1Pnnn9/717/+NZaRRUbyGK074YQTKpsyuEOJ05eGONc2UHV7tjJnE0UYN5oTgp86NIf0L3/5S2XzM9iXlGX8oOQRh+Z/sl+p4tW80ZKdYOT2+uuvT/8J75FHHknK8ajggYDV/Tx4KA1N21ORT26SOjQSvnnz5mQaY4wxpte77rrrdviEdwTdhYXLXd5W09cy2HTnnXdWNjuyqBVWhLxy5cptCgvD0atXr259nTwsX3/9dfWvmXfeeSeZ2guTgkSpY4pAac9WFDIWcj388MPpVTujluecc84Oe2lGXnnllaQ8n3XWWZXNNIxQYr/33ntXNj+DskzlW7t2be+WW25Jii2v4NmSCjmijEY7Kh92EfY3/e6775Iiufvuuye7Z555JpkzRYr+l19+2Xv88cfTyDlpve+++1K+Shx66KHJj0Z9SzAK+9///rc6M8YYYxY39Kn0nccdd1xlsyPoJiwwR4f58ccfK9t6GGzi7TJ9eYlFrbACo50InZFAlBK2XZprXn/99aSganSPQmfUlGkK+ZMMCiIKGaPCUrT1Kr9pJJenmNKT0U8//ZTMo446KpkR5pvq60cocSiGWkmvuD788MNtdiiDOaSNNKNYc/C/9EWlCGWDgls3uiyk6KNwa+usXXbZJdnttNNOyaxD39Qv0aT4N6F0dz2MMcaY+YA+4b3nnnsmM4c3rQxcSaf66KOPktnEgQcemMz//Oc/ycxZ9AorI4PACOWkfHEKxZDRVJ4yUNJQDqWA5TAkj9s4KqwFQnydqARPRjzFaA7voPDanekGUbnnE5+k8/LLL69spu3GvXAsgrIMcX9bPlIQlf/ZBPlIMe9yDEJJ4Z2PhzHGmPnHDz/8kMzSG2neWP7+979Pb31LMFCVTxeM1Cm3i15hFWwSnyuEKHaMbjJfE5M5kQia/6XOlyPf03VQKGiUSaYpoGgxofl3v/tddXV7NCT/29/+trKZ5uOPP06m5ujmaLHVMIuqlL58YRPpzEdsS5/9HAYpfm0L4VCkSVdMA3bjXrw2F+TK7nw9jDHGLCxYyMybzmOPPXabbqTpgdgxZXEYFr3CqmHtX/3qV8mMnHnmmWkU8uabb04jnCg+O++8cxoB3bBhQ+pwGaFlniT/MWeqsGrHgo0bNyZlFFD8StS9vv/b3/6WFNLSiCygdDNXt4Rendetiter86OPPjqZoPmhWiQGGuWN7saJFGnmwAjNaW2aYyMOOOCA6t+ODPvZWE8JMMYYs9govV3kA0SwadOmdB7f0HZl0Susr732WjLzeZQavURBFSitjEpeeOGF2/YUQ5mUUsZIaJNytMcee1T/6tGOBYyOarHVU089ley6gJLEoqa6V/Eoq6XFVgI58GqfV+klpMjG0Vsp/VHpK7kbJ1L0NQcGNKe1SRll9X+Tcg/Ug1133bU66844pwQYY4wxc4XWh4xjj/K66YyLWmFFKdWr93yVOIob9nzCM1+xpkVFKigpZfip2xwXUEBRBpnbWQefKkXZlALFK26tmuNVPgqn0GgoK+KB63vttVf6X1rwBMwpIcymOZ3kgVfpJUh7ruAhR/JVWjyFO6ZQ1K36GxWa8xLn07AoDJgUjiIfZSc0jaAOpbtOnmZ8MOrc9vlcY4wxs4/eSn/11VfJbENzXpt2C9B0Ru1/nrNoFVYU1F/+8pfpPyNofK0hR9stoUCWlB1GEaNy2QWmFTS9Ys7nfV5wwQVJQSQenmiiQoyCqG2bmF/LdUYTGUEtrfJH+SL8P/zhD5VNmSuuuCLJpJTn0rxUlL58JT1PSCixpItpFeNe9FRa4MV0DdKw33777SA70GgzMq5DqxVL8jTjh3pojDFmstCgHrsatUFfy1aYcOqpp26bRpjDG2/68Vp9Ycq0wvfkEdWWLVsqm2n6ClH65v8gbNiwIYXV74grm+HgW/8cOaSnr6RVZ9vDtX4Fq86akdu2b/vOV8gXcirJMELZ18lzsUK9pw7riPQbm9prg4L/9evXV2fGGGMmiVHpM0AYhEWYdVhh7QiC3LRpU3U2DXYbN26szrrRVVFqAsW5lB6FjZJVYtB4CQcFJFfU5zvkh3x1edhokudiRfWPI68buobcZlJvuK8IY6E+MBljzEKAvnTVqlXV2fAwEMLRhBXWAozqRMVOimB8iqBDLSmNXSDsmXTGehJBkVIYUsLqwh32SYj8UYkGVcwnFcqWm6tLueE2L/dJhHrQdqML6kGTAk7dIaw2ZRM31Kcc1c2Z1hfKaCYKrzHGmPFDnyGldRidBj/4pU9p82+FtQAKpUbg+J93nuqUOVBoBkUFPJOROxQCwojpiApsDpWhq1Jjph8AkOmkv5JG8ab8u46c68GlNLqsesnR1nDUKaykw/XMGGMWF/Qt9B2DDPBooK1pGkBkCT/9jsfMMiyA6ivCad9Wvsw0yMItM16YEM4evCwuYyuzSYW6ww4SOf0Go3GRGxPg2bi530hsW4jGIkR9+rb0CeAc3LIALzYf1Gkm4bfFb4wxxgyKv3Q1R9ChoxjsvffexR0KzNyAsso+u/fcc89EK6vAByzWVZsxf/PNN0l55GhTFlFSUVZRWrUTBHUQRbOLsgqHHXZY9e9n1q5dmw4rq8YYY0aNR1iNmcegfDLKOszXuNibls/lrVy5Mn1kgS1FSnvplpBfNR/sSXzaaaf1Pv30U78tMMYYM3I8wmrMPIY9cPN9cbvCl7h4hc+r/VtvvbWzshrRBzf4wAYj0lZWjTHGjAMrrMbMU5i+wIcPmj4H3ARfIGMaACOs11xzTe1mzk188skn6QtrKKr5hxkIj69VxYMPSZQ+SGGMMcY0YYXVmHkKyiLwdbNBQWnkC2nMZWXeKqO0xx9/fGelVd965jN7KLuaSxthxBZ7RnE1v3b16tVp7mz+KWRjjDGmCSusxsxTvvzyy2QO+iq/tEvA3//+96RYsjtCF2Vy5513TuYNN9zQW7NmTW0aNm/enHbDEPrErb4rbYwxxnTBCqsx8xxGRdlSCuWzbYS0pKwCr/QZaV26dGnasqrrCChTCi6//PLqbEeYY3v00Uen/6SNua4ouN5JwBhjzCBYYTVmnsLcU0ZFf/nLX6ZRzNNPP73TaGuurAoprYTZlaaFViiozLE99dRT0/xVRm///Oc/T/x2YcYYYyYPb2tljBkLLMb629/+lrbcQnlFsd60aVPvmGOOqVwYY4wx3fAIqzFmLLCvq7bcYuR3xYoVvccffzydG2OMMYNghdUYM3KYA8v8Vb7kJlBemUPLfFtjjDFmEKywGmNGDp96Zf4qX8PiK1jA4ivsGGk1xhhjBsFzWI0xxhhjzETjEVZjjDHGGDPRWGE1xhhjjDETjRVWY4wxxhgz0VhhNcYYY4wxE40VVmOMMcYYM9FYYTXGGGOMMRONFVZjjDHGGDPRWGE1xhhjjDETjRVWY4wxxhgz0VhhNcYYY4wxE40VVmOMMcYYM9FYYTXGGGOMMRONFVZjjDHGGDPRWGE1xhhjjDETjRVWY4wxxhgz0VhhXUS88cYbvSVLliRzVHz77be9J554onfyySf3br/99sp2fqK8HH744TvkhfxxTArPP/98Siflue+++6Z0TwKff/557/77709pmi/1gfR+8MEHKe3XXnttb9myZdWV4eEeI9zZgHpLmkctb+rYxRdfPFH1ftyMo40clklsczi4V7rcJ9T/SZBjV8Yh766ymmua+r5JYkErrAiexic/BJUzvzZfOtm5hI49NkQ777xz76WXXqrO5jfk5b333qvO2pkLRZFO49JLL+29+OKLva1btyblEMViUvjFL36R0jUuRiVzGmnagLPOOqt3yCGH9H766afe999/n46ZcswxxyQ5zLRcZrt+xfi4F15++eXqbGEyF/dviUlJRx3UY+rDKaecks65v9vuk4suuqj3wgsvDJW3Ut+d9816uNAxKcp9nt8uspoEBu375oSpBc4333wztWLFiimyumHDhsr2Z7Zs2ZKuLV++fKpfsSpb08SaNWumNm3aVJ1NgwzXrVtXnc1vuuaF+jQXeV65cmU6JhXqxjjrA/fqKECGeT0mzaR9VBDe2rVrq7PBGVVeu1Cqz5Ne12bCXN2/JWaznAcFGeVy4rzrfUL92bhxY3XWHbUjHKW+G+izkR19En39XEN68vtlEFnNNaRzUu6JEgt+SsBuu+2WDthzzz2TGWFkBRil2meffdJ/Uw9Pj/fdd191tnjhVc8kjWouFpA5IxYzhXrMCCsjoePkggsuSPfLMK9GR5XXLiy2+jxJ+Z3Nch4U3qZdddVVqR4Py3XXXdf7/e9/n+63QeDe7Cui1VmZXXbZpbd06dLevffeu62fnyvI36pVq6ozMxYqxXVBwxMPWc1HUwTXSqMIjL7Kb/+m2G6khLB4quM67njK49BTHk+UnOMXs+4JsQ6e1IgPv8TFUw9p4FBY69evT+fE0TaKQ3i4V3hCaVc6GY2ugzzhLh4Ki/+kMcqsJNNh5IJMkbXySrj9hiHFR/zY5fGV7AA/ij8vU8G1+JRJmlXWgCyVFh24j+ccIl6L4eYQLvmSW/4jT1GKoyRjiGkmDL1l0LlA/tgRNv/JF/EK1Rn8YpbSH9ONf8Ljv9zyX4eQm2gHpbJWeikr+Yl+8aPwFH+s4yXq8iIZC53rULhKZ7ymA/sIsoky7UJdXnNIRyxDMYhM6uoz4I8j5hfZ4ScS73vCamuP2updWzuBP12vi48wVO9xozzV5Rf7UhsJnMewkAUyEVzHriSreL/l1JVz3uYAMkBG2EV5K07SL7tSvDFdHIQV81AiT4NAXkor/5EJB+kuwTVkOyjkSfkpQdzDhJtTkjfE8uFaU1yqH9E9DCIrXcc94TXVnRiXwgfVgWhHOZOXGHYpfq6RBojh6H5QXqIdZUTYum9iHnXfIjfFXbpXu+b75xwtYCR4CTiHa6pcAoHFhguB406FiT3XES52XOc/hUch6X9sJOriL0H88odJWEAjgx2FrvBUiZoqN9fkLqaDSqKKiz3nTeCmlBfsSJsqKGFiFzuaYeSCO/zglv/Rn8oCO8oilmHJjvhjfJJHfuPmYeM+DwuiOyBfuMMefxHKq3SjCvwiezWInJNv7PJyJR15WiJKM34lO86VX9Iodyonyo64SaPC5r/KC3QPEJ6QnFU+SncuG9XbSG6H/1jWkonSC8pDhHAkW8XfVKeU55KbPHzlj7rDf0EcHNgp3fgr3YMKU3LsSimvOYSp/OTyHkQmkIcB1AX8UvaxTGIdIM/ISOGrnuRhCcJpqndt7USX+xg3pFNuCB832AvOYxrr2kjCjWFh6t4ifbJDBtiRXvzEPDahOAVhKjzJRHa4U30E0owd7ggHd8gNNzFe7FWOoDwo/BL4IewoI6E0E57KibCIt0TTtTZU/rHsRCyDYcF/Lm8gb5xznYN0lGQRwX0MA7rKivA5uI478kYZcV6Csuc6Yedu8BvbItVL3HHUyRS7mEfSjB3yEbkd8Sg8TNIO1D/suPfkVrKIacOP0taW7+bWcIFA5UBITUdeyRB2XpgSpChVOsCNCg0QPHG0NVw5KtxYWfhfZ9d2M5X8ch7TWmoUIqUwADt1kCJP0zByoSIj90gpv5RFXoa5HTdaLD/Fn8utZFcKv+ROacvlSD0p3YCilE91Rrl8SmkpgZs8TNKbp49z4o9QTthHJQDUCKnBwV9+D6ijjrJRvJHcjvLJwyK+WGalcMhnzA9pz+tnRGHERlPE8NUQxzoLpTIu1UmBO67lsmyjlNc68rgHlQmU0l+qQ9hxCMooxgV5W1mC+PJ6B23tRJf7mOsxTbqX8CtK+VU5RllRJ/O2TZ12DK+LrErUlXPJL+5yu5I7zmOYpDOXtZT40n0AkkXMo1CaY5tWlw8g7tx9V9QW5W0D5ZuXH25wmx9dyOVI2LnM8nqeUyqLLrKiDOra0ZL8hcKJ9wv/Y7pJcx4//4kvv0dxF2Vauh9KdkpHmzvZKY5B872otrXqC4sassNR4sknn+ydc845261CZAUdq/2Y1yOY+xphrhpu+oWwzd/uu++erk3iCrx+J9A76aSTtq1sPPvss5M5DMwnyvnhhx+SOaxcSNdvf/vb6mxmsGr1u+++S3ON2HLlyCOPrK6MDuZd9RusNG9LkHdk3DTHinmObCkSYX51vwNMdXFY8jhJG3z55ZfJFHvvvXf1b5qnn346mfvvv38yxR/+8IdkalcIyoe8RVhtOgz//Oc/d7ifCJ8ya+KMM85I8wBZRUzZMhe9aW7qq6++mkzNXy/BTgwXXnhhmhuXz23faaedkpnLEPbaa6/q389o7vxHH32UzNlgUJk0Uaq3cT5i17ayRF7vurQTbfexwohrFihr2nr8DgJh9RWA3sEHH1zZTMPOEkCdjZRkNQk7qJBO2phYRrfccku69sknnyQz56233krmgQcemMwSbXVDqJzr4mqCuttXwFI5qJ+CO++8c4e5tZ999lly21eItvXv1KW8XenCUUcdleLjPlI9nkn/2CQr6gj5i+Vz6qmnpmvMt66D/PeVzt4dd9xR2Uy33bGeP/zww0kGMX7+0/dzn1DH54pB8+19WBuoU3C7LM4q+eNmmjS4IW+66aakYHFT01GPkvfff7/6N80gcuFm5oYaJXRw++23X1I2xrVlD7KMjSvy7dJRlhSzUiM3E5qUtBJs9RTJlVHKJ1c6Zhtk+69//SspopTtKLamQ7lEQSrtpYoM6RQfeOCBbR3Z448/njqOE088MZ3PNeOQSSR/yJxJW1miFFZsJ2bjPo7owVuM+r6cDaISF4+ZKGElhlFK27jiiiuSqYEA2lYe8LuUA+0v7fGg8ICneo7Ch+JaUsZnQpQVgwml8uGhuQ7yT/nxMEJbRPo2b968Qztf6ltKA0xzwSD5tsLaAHvI5XRV6EruRq0MjgoqPJ3B6tWr09PNONM5iFzUGOWdxbDQaV9zzTW91157rXfzzTcP3Zm2EUdZ1Yh0URTrGlUUoVExaIP7f//3f9W/7YmNHQ3kqHjnnXeqfz+DDNtGAZA5+9I++uijvdtuuy1t1j0TrrzyyqSU/vGPf9xuVEfceOONafSb0WVGBUgj9WqSFJlRy6SJmbSVJZraia738ccff1z9+5lSWXahNJoOu+66a/Vv8nnqqaeqfz9DezCXI2xdyUdZGV2VEtsGo//4HQbiRXHasmVL79133x3rXq+MNpba57b7SHJ46KGHeq+88krv9NNPT+cRBhbq2n69MZorBsm3FdYaGC7nqSUfln7uueeqf2XoJFAwbrjhhu0KgQ5tNl8JdiWOvNBJo2jdc889lc3oGFYuPNnyyrHuZovkbvJzRpuOOOKIgUcZh0GjrCg0f/7znyvbeqhvPM3nnQd5yEdAusiiDho00CvNOjR1IK8LP/74YzI1kkj5MMLVNU3RXf4gcsIJJ6SGNR8N5HUX9aeO6J6Nza+++uptrztLEA+0ddR0VMiBkZW8HTjvvPN6l1xySXrQYzQAxbCuXklmpekC42JQmcyEYdvKEl3aibb7+IADDkhhoNTGMEjfoA+/Sg/5i2Hpf0k5mESYIkL7kivsd911V5JXCV6Jg6YGzATJfY899kjmMEgx435kdLVpwIGtuPSKmXa4aZSyDkbxVc7UtbvvvrvYRo8CtbfXX399MkWXhz7koHuQ1/95f0HZAwpthDKh/e7SH6oNg/h/pgya7wWvsFLhVOlKT9xqZOl4aBQFjR2d5y9/+cttc8F4ZX7uueem64SJH54O8ob61ltvTRWbV1aManCguGi+DYWxbNmy1qe1L774IpmxgigPMS+6Lvd1lPwy8qJGjPyTJ3XoJfQ0RiOGDLh5lX/NDQTJXCa0yaXEX/7yl9TgICvkxsHr1xxuWsKmkcGNRpMYsSONpIPREM5JL+d63Yvc1MErL3HUELfIhSPmh45Mec5vMDo6bkZexXR55UZ9I7zLLrtsWz0kfeQ9jiSQPvKZp6UO6qfySbgo0mvXrt3W2Cu/vN6O4dGIMSqR+0eRiP5RaLlPKB+lW6NtyFXhS1mjYaI8KB/yBtQ//Go+Fp2N7jnCPe6445I70Miu6h3+KAPckn4Oyk4NYQl1xKWGV/eQyvOxxx5L+Tv++OO366iQy/nnn5/Sx6H0RjdCihZKFhB2l/u/lNcSknGss4PKBPL6jD/qGfcM/4X+y2xrK0vU1Ttoayfa7mNGuVHQSRPzW7EjDOpVfFAr3b+lNhJlh7Cou8THwX9G2HVvY9dFViVK5azw4n2u8s/Dz91B7od8o5ww2ki9QyaYxF33VkAPiSUlX3Ut1ne5K91XTA0jfrUbxM09kLebTeCXNomyaBtd1fQH+Prrr5PZREmO5OdPf/rTNhnS51Fn6hR8UN0kDOWti6xob6V0cu9QPtxLtK/6ulgTPDwjl1LfTdlTV+nrlQZM4ooDEqV2RA8YtPv4IV1vvvlmsqOdlx+1m4PqKgPnu1+oCxatXMsP0W/Ad7im1WvAijZWfWLfv9m2W+Wb+8NthBVu+OEa8cSVmFoFx/Xcn8jTRrpyO87zPGJXInenfJK//k2Y7DDz1bAl+o1Gco9b0h/D5SjZiSa51EFaSZvSp/CVB+grP9vKinBZBYlJWiVjrUjEDeHgBj/Yca0u3SU70OpLxZdDXrvIU5AGwlI8/Rt5u9WfeRlyRBnkEBZ5U5jIL7pvKich2XONsEorN6nPsUxVxviN6Sc/Coe8ch33+WpupRd3+apclRlp0jXKWPFzEE+pPCJKX0Tx6uA6R24HxKn6lh+qb4L0ELbocv9DKa85eRkqnmFkktdn+dVRqi9KP6bkQbyxrcwphZPT1E7wX9dK97GgrFR3S/nP81tX1hDrOGEqXhH9cTTJKkfpj+Vc8jsTO+Be1D1IXDF/dVCPYt0FzmP4hFOyi+TxqbzysNsgD21+SLPikjzaiGmXe+qg6jQH/2P9KsF18qq6OIisqAfUK/xjTz7yOtsE4da5x57wFCd5Ub2AUr0RyIFz1U/ckj/sCbdLHjnHPreDQfLdXpJmbFCAbTeA2RHdXLrRJxU6h6iwzTY0CGoUzPbQ8NJoD4Ma2BzsqZN5vaQhjp2D8P1vJh3aL9raOgWiC1LiSmHQRo6aqLAC/1GwzPzHc1jnCF4ZMCzeZf6ImX/oNZJegZnJgle5/U5soFeSgvmrcdGZ4NXqQQcdtN1cVV5X9zvQHebg+v438wHar/Xr16e5rsPCFA8W/uVTD7g3eJU9SnitzOtlpn9oyg1rM4D5rG3TcMxkY4V1DmDeB3ulsdLYDI7mwZTmVs0lzPGhQWQOzqpVq9LcvrkChUhzqTjMjvz9739Pc6U0D6sryJP5YHS4cU4Yc3GZ36V5jYTL6nJWskd8/5v5BFukMT8yX7DVBfywMC2fj8i9w/6u+YPcTGEO6tT0m+O0EFLIPtqZ+ccShlmr/8ZMPEzK5ulZrFy5cmIaIZSW0047LS0mYLXmqBvjrpCOY489tjqbZtOmTXOWnkmHzpNdD7qOhqOwMuLE7hVbq4Vj1EMWYUVllT0Wuyy4M2Y+wNsI9mHu2o4M6t6YNqywGmOMMcaYicZTAowxxhhjzERjhdUYY4wxxkw0VliNMcYYY8xEY4XVGGOMMcZMNFZYjTHGGGPMRGOF1RhjjDHGTDRWWI0xxhhjzERjhdUYY4wxxkw0VliNMcYYY8xEY4XVGGOMMcZMNFZYjTHGGGPMRGOF1RhjjDHGTDRWWI0xxhhjzERjhdUYY4wxxkw0VliNMcYYY8xEY4XVGGOMMcZMNFZYjTHGGGPMRGOF1RhjjDHGTDRWWBcoTzzxRG/JkiXp4L8xxhhjzHxlzhTW22+/vbfvvvsmherwww/vffDBB9WVxc3zzz+fjpnw+eef915//fXe1NRUb9OmTb1zzjmnutLrXXvttem6McYYY8x8YU4UVpSmzZs39z777LOkUH3//fe9W2+9tbo6Wczm6OTFF1/c23nnnXunnHJKZTM89957bzKPOeaY3sqVK9N/uPzyy3tr1671A4Ixxhhj5g1LphiGm2UYVV23bl3vyiuvrGwmE0YiUSJffPHFymZ8MOIMo5YJ6ZfyKr799tvekUce2Xv55Zd7++yzT2VrjDHGGDOZeA5rDSh1q1atqs7GC4rxVVdd1bvgggsqm9HAg8F9992Xpl5Edtttt97q1auTMmuMMcYYM+mMVGF944030nxUFKVly5YlhQjFT5x88snpGqCg8V8jizmEhX/88PoapYtD4WGn8IiLaQYR5oEqLRxnn332dmkBwsBebmJ6Cfu9997rvfTSS+ka56Itn0wjwD154z9uiKeOO+64I722R5EUhHf//feneAiH/GjOr/JKOmRHfHn+NId169atO0xtID7y5qkBxhhjjJl4mBIwCjZu3Di1dOnSqb6ClM4xOV+xYsXUN998k+wE0a5bt646K4P/5cuXJ/+4Xb9+ffrfV76mtmzZkq4pLq7FMHETz3HH+dq1a9M5EAbpwy+QftysWbMmnUNfqUtHpC2fHApr1apVKXzizcMRuI9pFeRB+cJvnlfSqbQrfzrPwe2GDRuqs59ROMYYY4wxk8zIFFYUyKgQgpSrXJHCrk1hBRQ1ws1BEcwVMBRGFEdAGSUOTMH1qDQSRq6s4R97gftc0eyaz67KYJOyqWu5rOrs8rQKrpXQA4ExxhhjzCQzkikBvJrmtfPBBx9c2Uxz1llnJfOf//xnMochn38JTz75ZNqqiVfhOnh9z24DzAc95JBD0utwTL2e53qEMPbee+/qbJrvvvuucVeAQfOZh1/irbfeSuaBBx6YzFHAFIIoG2RRAtnmcjHGGGOMmTRGOof1hx9+qP5NE+dkjppNmzYlRSw/tOpd8zufffbZ3nXXXbfd1k4zZTbzOQzsNBBlYowxxhgznxmpwvrll19W/7Zn1113rf6NjhdeeKH69zPacB9l9dhjj+3ddNNNacSUvUhLsBdsTtMIq5jNfBpjjDHGLHZGorCiEC5dujRtoRRXquv/6aefnkzIV7IPA9tNEVe+wv25555Lpl6zN63MZ8SVaQEot4K0ffjhh9XZjgySz64cddRRyVSaZxPSvXz58urMGGOMMWYyGdkIK5vTM4f0+uuvT4oQB/9XrFixneL49NNPJ7M0uhnBP1/CKm29dM0116S4fvnLX6YtpZizyev/c889N13fZZddkqnRUkzCIky2imKeK9ME4LTTTkvbRBEGc11/97vfJXtgxPSdd95J/jR62yWfSu8DDzyQrjeh0d98mgF89dVXyYzXFHaUn+JQerrC/NWTTjqpOpveyostuAYJwxhjjDFm7EyNELZzYuU5wbLintX0cUsrVrFzLR7arimnzR3nrHDnGnEStyBOxYXJFlGkhTTF3QViegkr7ioA2voKN/FaUz61sj8ebbCbAOmMsAtADIPruR3HMPGBdlKIcmWHBPIVy8wYY4wxZq6Zk0+zmu1hxLevKPb6iuKsLeBipJldDWbjs7PGGGOMMTPBCuuEgALJYq6bb765shkfvPLn9T9zeLWrgjHGGGPMpDLSXQLM8Fx00UVpbmyXXQpmyl133dV78MEHrawaY4wxZl7gEdYJg8VdO++8c+1WXDOFkdwTTzzRyqoxxhhj5g1WWI0xxhhjzETjKQHGGGOMMWaiscJqjDHGGGMmGiusxhhjjDFmorHCaowxxhhjJhorrMYY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availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data that support the findings of this study are present in the paper and the Supplementary Information. Further information can be acquired from the corresponding authors.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors acknowledge the financial support from National Natural Science Foundation of China (22322810), the National Key R \u0026amp; D Program of China (2022YFA1504200), and the Fundamental Research Funds for the Provincial Universities of Zhejiang (RF-C2023004).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eL.H.L. performed the experiments and wrote the paper. S.M.Z and K.L. performed the partial experiments. Y.H.W., S.Q.L. and J.H.H contributed to the discussion of the results. P.H., C.Q. and R.X.L provided useful suggestions on experiment designs. X.Z. and J.G.W. designed the research, and wrote the paper. All the authors commented on and revised the manuscript.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAdditional information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePublisher\u0026rsquo;s note\u003c/strong\u003e Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eSupplementary Information\u0026nbsp;\u003c/strong\u003eaccompanies this paper at http://www.nature.com/ naturecommunications\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eReprints and permission information\u0026nbsp;\u003c/strong\u003eis available online at http://nature.com/reprints\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eQi F\u003cem\u003e, et al.\u003c/em\u003e Deciphering the late steps of rifamycin biosynthesis. \u003cem\u003eNat. 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Eng.\u003c/em\u003e \u003cstrong\u003e12\u003c/strong\u003e, 3256-3264 (2024).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table 1","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e\n"},{"header":"Schemes","content":"\u003cp\u003eScheme 1 is available in the Supplementary Files section.\u003c/p\u003e\n\u003cp\u003eScheme 2 is not available with this version.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"antibiotic, electrooxidation, functional-group compatibility, rifamycin, trace water","lastPublishedDoi":"10.21203/rs.3.rs-7115804/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7115804/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eRifamycin O (RO), a key intermediate in the antibiotic drug rifaximin synthesis, faces several production challenges including low yield, purity issues, and environmental concerns. Here, we report an electrochemical synthesis strategy achieving RO production via electrooxidation of rifamycin B (RB) resulting in a 92% high yield. Trace water addition improves the functional-group compatibility during RB electrooxidation, substantially elevating the RO yield by 10%. Mechanistic studies reveal that trace water regulates methanol's hydrogen bond network, facilitates the dissociation of the hydroxyl group in the carboxylic acid, and enriches RB at the electrode/electrolyte interface, thereby achieving thermodynamic and kinetic synergistic optimization of RB electrooxidation. Systematic optimization of flow electrolyzer parameters further improves performance. The scale-up experiment with an electrode area of 400 cm\u0026sup2; electrode demonstrates high yield and space time yield. The present work establishes the electrochemical synthesis of RO, providing a sustainable paradigm for pharmaceutical electrosynthesis.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e","manuscriptTitle":"Functional-Group Compatible Electrooxidation Synthesis of Key Antibiotic Intermediate Rifamycin O","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-29 21:18:46","doi":"10.21203/rs.3.rs-7115804/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b238829b-c5e3-4cda-ad8e-e075a61c7c28","owner":[],"postedDate":"July 29th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":52149528,"name":"Physical sciences/Chemistry/Electrochemistry/Electrocatalysis"},{"id":52149529,"name":"Physical sciences/Chemistry/Chemical synthesis/Flow chemistry"},{"id":52149530,"name":"Physical sciences/Chemistry/Green chemistry/Sustainability"}],"tags":[],"updatedAt":"2025-08-15T10:00:23+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-29 21:18:46","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7115804","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7115804","identity":"rs-7115804","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}