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nderstand what we had done to our electrodes after sending them many samples of functionalized electrodes see si for the workflow and design of these experiments and sending many emails stating something along the lines of i think these are the last set of electrodes we want to look at they were able to reveal that in the cases of successful reactions the electrode surface was littered with silver nanoparticles using s t em imaging and edx analysis this was an exciting discovery but we had absolutely no clue what these particles could be doing in our reaction after digging around in the literature it seems such electrodes have been used extensively in analytical sensor design the deposition of ag nanoparticles on carbon electrodes has been used to develop selective sensors for various types of analytes from hydrogen peroxide to nitrobenzene these sensors operate by either lowering the overpotential necessary for analyte reduction or by increasing the current response for analyte reduction through nanoparticle substrate interactions what had not been reported were cases in electrode decorated with silver nanoparticles support catalytic cross coupling reactions go figure to start exploring the effect these functionalized electrodes had on the cross coupling reaction i first had to find a way to miniaturize the system from our preparative electrodes to an analytic disk electrode that we could use in voltammetry studies i needed to try to shoot for roughly the same coverage of silver nanoparticles on this smaller surface as we had in the preparative reaction doing a little math revealed a good experimental starting point after a bit of tinkering i was able to plate silver nanoparticles on the analytical disk electrode reliably just using a dilute solution of ag and a supporting licl additive to ensure we were forming the same type of silver on this electrode as we were in the preparative reaction thankfully anodic stripping experiments replication of other ag np silver nanoparticle based voltammograms and s t em as well as edx analysis performed by paulo helped confirm that we have functionalized our analytic electrode with silver nanoparticles time to run some cv s this was probably the most tedious part of my entire phd there were tons of components to study in this reaction catalyst redox active ester vinyl iodide combinations of all of them with and without silver etc which led to me spending weeks at the cv and barely touching synthetic chemistry to add to this already monotonous undertaking the analytical electrode of which i only had one needed to be freshly plated with the silver nanoparticles each time to ensure the most reliable voltammograms could be produced we did not want to risk losing any of our silver during analysis this meant that after every measurement the electrode had to be oxidatively cleaned until there were no traces of silver sonicated in etoh dried and then checked again by cv to ensure that all the silver made it off this long sop meant that i could only really run 3 4 proper measurements a day and if you go through the si i will let you imagine how long it took to get that data i wish i could say that this led to a watershed in understanding as to what the specific role of silver was but as chemistry would have it no dice the cvs of certain reaction components had very subtle differences with and without silver and nothing that jumped out at us a clear indication of anything spectacular it was at this point that we sought out our next collaboration we teamed up with professor héctor abruña and cara gannett at cornell university to further probe this reaction using some more advanced voltammetry techniques to make a very long story short cara was able to expertly dissect our reaction and its components and study them all using rotating disk electrode rde voltammetry in very simplified terms rde allows you to gain better insight into the kinetics of electrochemical steps of a reaction i found this website super useful in explaining the technique https pineresearch com shop kb theory hydrodynamic electrochemistry rotating electrode theory after a few months cara was able to figure out several roles of the silver nanoparticle layer in summary the silver basically helps clean up the catalytic cycle for the cross coupling reaction it prevents catalyst degradation deactivation which is especially prevalent when using vinyl iodides bearing unprotected acids and prevents background consumption of redox labile functionality such as the redox active ester you can check out the paper and the si for more after having made this truly serendipitous discovery and working for nearly 2 years to understand the finding the project was brought back from the brink and was making a turn towards what we set out to accomplish a robust platform for terpene synthesis after demonstrating that the silver additive now allowed the reaction to tolerate free acids as well as many other functional groups we shifted our attention to developing an in situ protocol so that we could skip a step in redox active ester preparation we quickly found some very simple conditions acid nhpi dic thf 1hr and we were off to the races together we made 13 molecules that highlight the tolerance of various functional groups and demonstrate the plug and play nature of this synthetic strategy i won t talk too much about the synthesis as they are discussed in detail in the paper and si but i would like to shout out asymchem for demonstrating that both the generation of silver nanoparticles and the electrochemical coupling could be performed on 100g scale in recirculating flow thank you zhen and lijie for your time and expertise overall the tactics of this project came a long way from using alkylithiums and long arduous set ups now with the silver nanoparticle functionalized electrodes and the power of electrochemistry we were able to run this chemistry in a true dump and stir fashion to make polyenes in a streamlined fashion just to highlight how much electrochemistry changed the project the previous route developed towards the progesterone polyene required a large amount of pyrophoric reagents for the cross couplings tedious procedures protecting groups and intermediate functional group interconversions using electrochemistry and after developing the necessary tactics we could make the same polyene in fewer steps with no protecting groups and in an operationally simple fashion we recognize that this reaction sounds deceptively super hard to run it has nickel electrochemistry and nanoparticles it sounds like a nightmare however i assure you that it is so easy that even phil and his dilapidated hands can do it if i haven t made it totally clear yet this project was a true team effort no single person could have pulled this off single handedly paulo and scott were instrumental in our electrode surface understanding and their expertise in microscopy was invaluable as they revealed the crucial formation of silver nanoparticles héctor and cara brought us to understand the mechanistic underpinnings of the reaction and demystified the role of the nanoparticle functionalized electrode zhen and lijie showcased the scalability of the platform in an awe inspiring manner phil granted us grace guidance and patience as we have been telling him that were almost done for nearly 2 years finally stephen initiated this project a year before i joined and has been a great mentor to me he taught me a lot about synthesis and i am very grateful for his patience and generosity in letting a first year come into the project and try to stick electrodes in it so anyway that s the story about how a lucky hit in an additive screen resulted in the story we are blessed to be able to tell today max on behalf of team polyene posted by baranlab at 10 58 am 1 comment email this blogthis share to x share to facebook share to pinterest friday september 10 2021 reinventing oligonucleotide synthesis wow where to begin our latest endeavors on the p v front are now published in science now before talking about the research i must begin by giving a shout out upfront the rather large team who is responsible for everything in the paper it was an incredible collaboration and everyone had a crucial role to play bristol myers squibb yazhong huang shenjie qiu bin zheng stephen mercer richard olson mike schmidt ivar mcdonald and martin eastgate tsri wei hao julien vantourout natalia padial javier lopez rohan narayan donna blackmond and phil baran after the team s initial work developing the psi reagents for the stereocontrolled synthesis of phosphorothioate linkages much work remained to build out the p v platform both to include other types of desired p linkages but also to develop a protocol for using the novel reagents on an automated oligo synthesizer the development of these additional reagents ps2 po and racps all proceeded in different ways the challenges overcome in the syntheses of the ps2 and racps reagents were a simpler story so i ll direct you to finding that info in the publication on the other hand there is the p o reagent to the best of our knowledge there had never been a published p v reagent capable of forming a phosphodiester bond between two nucleosides with phosphoramidite like kinetics i e crazy quick the initial hit for such a reagent came in july of 2018 followed by my famous last words shouldn t take long to find the perfect p o reagent although the hit was exciting it required kotbu as a base and wasn t compatable with dbu or organic bases that would be amendable to an automated oligo synthesizer to address this we evaluated new p o reagents on several criteria 1 could they be made synthesis 2 could they be reacted with a nucleoside to afford a monomer loading 3 could they be coupled via an organic base with a second nucleoside to afford a dinucleotide coupling we had two ways of making the reagents either synthesizing 1 3 mercaptopropanols and reacting them with pocl 3 or by generating analogous compounds with 1 3 diols and pscl 3 followed by an interesting atom transposition using tbai we found a lot of things that could work and plenty that couldn t but only one scaffold was able to accomplish all 3 of our goals p o 5 the diphenyl scaffold after this discovery we investigated the aryl electronics and stereochemistry of the diphenyl backbone attempts to modulate the coupling efficiency through the aryl electronics proved negligible the stereochemistry was a more interesting questions because the first synthesis of this reagent used a racemic mixture of the mercaptopropanol generating a racemic mixture of p o reagents which upon loading onto a chiral nucleoside revealed a mixture of the possible isomers that one could imagine we began synthesizing single isomer versions of these reagents and observed that the syn scaffold epimerized into an inactive form during the loading step further investigation of the anti backbone revealed that the r r substituted system gave the fastest coupling times we next looked into the synthesis of this reagent the stereochemistry could be programed in via a noyori reduction and using pfp as a leaving group provided suitable physical properties to afford a solid reagent despite this success the reagent still had two flaws it wasn t stable enough could only survive about a week on the benchtop and it was still a mixture of isomers with one reacting much faster than the other sitting around the lab one day we thought to ourselves why don t start with the original psi a reagent we knew reacted at lighting speed and swap the s for o it seemed rather straightforward in practice we were never able to do this successfully on the psi reagent itself so we tried it on the psi loaded monomers instead although we could succesfuly perform s o transpositions on these monomers there were always side reactions associated with the transformation ultimately leading us to abandon this approach third times a charm as they always say so revisiting the idea of performing the s o transposition on the reagent itself we knew we the reagent formed with pftp psi was too reactive after making the p o version of itself so after generating psi alternatives with different leaving groups we found that we could successfully perform this transposition to generate a stable reagent most notably the 4 bromothiphenol version there s plenty more to the story we evaluated the kinetics of the p v molecules demonstrating that they are on par with phosphoramidite chemistry we developed a novel universal linker capable of performing oligo synthesis under the unusual basic conditions found in the p v protocol and we even took a trip to cambridge ma to visit our collaborators at bms and see and learn first hand how they were making oligonucleotides also if you ve read this far it s fair to assume you re a fan of the p v approach to oligos so check out our perspective on p v chemistry that was also just published in acs central science if you re still reading and want to follow the next steps of the p v story keep an eye out on elsiebio com or drop one of us a line to check out how were using the p v technology among other things to develop the next generation of oligonucleotide therapeutics and replace dogma with data kyle and the p v team posted by baranlab at 5 37 am 1 comment email this blogthis share to x share to facebook share to pinterest thursday april 15 2021 ika guest post on classic alternating current mode electrasyn 2 0 software update to support alternating polarity in constant voltage reaction mode author information chuanjun jiao ika works inc 3550 general atomics court ms g02 321 san diego ca 92121 1122 united states email charles jiao ika net note this report is not related to the recently added new function rapid alternating polarity rap the change described here is relevant only when the default alternating polarity function is used together with a reference electrode currently only alternating polarity function is supported to be used with a reference electrode and rap function is not compatible with a reference electrode in addition further software update is not necessary to a unit in which the rap function is already installed since the latest software supporting the rap function already includes this change background recently the reid group at university of strathclyde reported a mechanistic study of electrochemical benzylic oxidation with the use of electrasyn 2 0 chemelectrochem 2020 7 2771 during their study the group observed unexpected product distribution change when alternating polarity was applied during a constant voltage experiment with electrasyn 2 0 the report describes their careful investigation of this phenomenon and casts a practical consideration on users of ika electrasyn 2 0 here is the key points of their report unexpected outcome was obtained under the condition of constant potential reaction mode reference electrode on alternating p...
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