Science
Related: About this forumMicrofluidic electrochemistry for single-electron transfer redox-neutral reactions.
The paper I'll discuss in this post is this one: Microfluidic electrochemistry for single-electron transfer redox-neutral reactions (Yiming Mo,*, Zhaohong Lu,*, Girish Rughoobur, Prashant Patil, Neil Gershenfeld, Akintunde I. Akinwande, Stephen L. Buchwald,, Klavs F. Jensen,, Science 19 Jun 2020: Vol. 368, Issue 6497, pp. 1352-1357.)
In the days of Covid-19, I've taken to reading books cover to cover, something I don't normally do; usually I skip around for the "good parts." The degree to which this is intellectually limiting I cannot say, but these days, with many of my favorite libraries closed, coupled with the fact that I need to read almost as much as I need to eat - and I eat too much - I read full books, cover to cover, since I can't get library books any more and worry about running out of things to read.
The book I'm reading right now is about an elaborate scam run by an arrogant young woman and her (possibly) Svengali type boy friend, the young woman being Elizabeth Holmes and her boyfriend, Ramesh "Sunny" Balwani, and the book being Bad Blood: Secrets and Lies in a Silicon Valley Startup by John Carreyrou, a Wall Street Journal Reporter. The hero and heroine of the book were low level, but well educated, young technical people who entered the company the book describes, Theranos, thrilled with its rhetoric and goals, which they believed involved cutting edge, but were swiftly disillusioned because, well, they were smart and there was no earth shattering technology.
All the writing is somewhat dry, the book fascinates me, because, when I was a kid, I worked for a number of start up biotechs, some better than others - none of them fraudulent, although in some the technology failed to pan out - and I always believed that the tech was going to be "earth shattering" but eventually I figured out that "earth shattering" is supremely difficult.
The Theranos "technology" - there was no actual technology that was in any way new - purported to be able to run hundreds of clinical tests using a single drop of blood. Anyone who understands anything about bioanalysis - the disipline that over arches "clinical chemistry" 0 should have known that running hundreds of tests on a pin-prick of blood was patently absurd, but the "hook" for the scam did involve a claim appealing to the very real concept of microfluidics. Modern microfluidic devices are a feature of technology, and they are utilized in bioanalysis, for example in nanospray mass spectrometers, and recently a company did introduce a technology - a real technology - that is capable of using nanoliter droplets to access complex chemistries in biologic fluids without the void volumes associated with any kind of fluidics. (I have not studied this device in any detail, and a concern is the loss of orthogonal separations represented by chromatography, but the device is very real, and has been beta tested at major pharmaceutical companies.)
If one reads Bad Blood and actually possess a modicum of knowledge, one can see that Theranos did go through the scientific motions, and did hire real scientists, but compartmentalized them away from one another, but eventually they all caught on to the fraud and after attempting to address their concerns through channels, resigned in disgust. (One, tragically, a talented scientist named Ian Gibbons, actually committed suicide.)
But no, Theranos did not have microfluidic magic behind their putative device. They had nothing but the involvement of high level political and military figures on both the right and the left, George Schultz, Henry Kissinger, James Mattis, Bill Frist on the right, David Boies, William Perry on the center left; Elizabeth Holmes, the Theranos CEO, the arrogant young woman mentioned above gave fund raisers for Hillary Clinton, was praised by Bill Clinton in a public forum, and received written praise from Barack Obama. (Rupert Murdoch was an investor to the tune of $125,000,000 and to his credit - who knew he could do anything ethical - he did not quash the Wall Street Journal articles authored by Carreyrou that made his investment in Theranos worthless.)
Anyone can be credulous, even major political figures. (It is telling that there were no scientists on the Theranos board; her board was comprised entirely of major political and military figures, none of whom knew anything about science other than the fact that they claimed vaguely to like it.)
Enough drivel...about the paper.
The paper is about microfluidic devices that can perform tasks that are simply not possible on a larger scale. Since they are flow devices, they are amenable to continuous processes. As I recently discussed with a correspondent in another series of posts in this space, continuous processes are generally more economic and cleaner than batch processes.
From the paper's introduction:
Most of the reported synthetic electrochemistry relies on reactions on a single electrode with by-products generated on the other electrode, and, as such, the nature of the desired electrochemical transformations is either oxidative or reductive (10). In contrast, redox-neutral electrochemistry (i.e., paired or coupled electrosynthesis), which involves two desirable half-electrode reactions performed simultaneously, is underdeveloped, despite its relative material and energy efficiency (1012), and examples of radical-based redox-neutral electrosynthesis are even rarer (1315). In conventional paired electrochemistry setups, the difficulties associated with matching the generation and interelectrode transport rates of the different highly reactive intermediates pose substantial obstacles to achieving the selective transformation over alternative undesired pathways. Microfluidics, however, has been shown to offer controllable and rapid species transport within a micrometer channel (16), with recent applications in electrosynthesis for improved reaction performance (17, 18). To further exploit the capability of microfluidic electrochemistry, we sought to develop a microfluidic redox-neutral electrochemical (?RN-eChem) platform to overcome the challenges of photochemistry-inspired SET redox-neutral reactions that involve reactive intermediates generated from both electrodes.
The authors chose to explore a radical based chemical reaction, Kolbe Electrolysis, which generally gives a mixture of symmetric and asymmetric couplings when two carboxylic acids are the starting material, making it somewhat useless for industrial chemistry, at least industrial chemistry designed to make pure compounds. (The related Kolbe Reaction, by contrast, is one of the first large scale chemical reactions to be utilized in chemistry. It is utilized to make salicyclic acid from phenol, salicyclic acid being the precursor to the wonder drug aspirin.)
A figure from the paper shows some examples:
The caption:
(A) Comparison of photochemistry and electrochemistry for SET redox-neutral reactions. PC, photocatalyst; PCRed, ground-state PC; PC*Red, excited-state PC; PCOx, oxidized-state PC. (B) Concept of ?RN-eChem for the cross-coupling reaction of persistent and transient radicals. (C) Mechanism of redox-neutral electrochemical cross-coupling reaction of carboxylic acids and electron-deficient aryl nitriles. RCOOH, carboxylic acid (where R is the alkyl group); R, alkyl radical; EWG, electron-withdrawing group. (D) UV-Vis spectroelectrochemical lifetime measurement of BPDN radical anion. a.u., arbitrary units; Decomp., decomposition; [C], concentration; ?, wavelength. (E) Effect of interelectrode distance on reaction yield. Two batch setups were tested (fig. S5), and the setup with higher yield is presented in this plot. Me, methyl.
SET = Single Electron Transfer
The procedure for making the microflow device is briefly discussed in the paper:
More detail is given in the supplementary data:
Fabricating a small diameter and high aspect ratio deep hole in glassy carbon is challenging using the traditional milling process. Here, we used the laser micromachining process to microfabricate these fluid paths. In this process, the laser was used to oxidize the glassy carbon into carbon dioxide in the presence of atmospheric oxygen. The resulted carbon dioxide gas escaped to the environment, giving the efficient removal of glassy carbon. Deep holes were obtained by gradually moving the focus of the laser beam and removing the material layer-by-layer until the desired depth was achieved. A laser micromachining system from Oxford Lasers was used for drilling the holes. The laser source in the system was a Q-switched frequency-doubled Nd:YAG diode-pumped solid-state pulsed laser with a wavelength of 532 nm and a pulse duration of 20 ns. The laser was focused using a 100 mm focal length lens giving a spot size of 10 micrometers. For drilling holes, the average laser power of 1.4 W was used.
Generally, supplementary data is open sourced even when the full paper isn't. Interested parties can open it to see nice photographs of the apparatus and all kinds of cool experimental details.
Some reaction substrates:
The caption:
See the supplementary materials for detailed reaction conditions for each substrate; reactions were performed on a 0.4-mmol scale, unless otherwise noted. Asterisks indicate isomers observed, and in all cases the major isomer is depicted. Yields refer to the combined yield of all isomers. Boc, tert-butyloxycarbonyl; t-Bu, tert-butyl; Et, ethyl; rr, regioisomeric ratio.
The general scope of the reaction:
The caption:
(A) ?-Amino CH arylation. (B) Deboronative arylation. (C) Thiol-catalyzed allylic CH arylation. HAT, hydrogen atom transfer; i-Pr, isopropyl. (D) Minisci-type radical addition to heteroarenes. Mediators (Med) used are ferrocene or 4-methoxytriphenylamine. Ts, tosyl; DMSO, dimethyl sulfoxide; NHP, phthalimide. (E) Ni-catalyzed CO cross-coupling. dtbbpy, 4,4?-di-tert-butyl-2,2?-dipyridyl. Asterisks indicate high-performance liquid chromatography yield obtained from batch setup (fig. S5B) under identical electrochemistry conditions. See the supplementary materials for detailed reaction conditions.
Whether this approach is industrially viable will depend on the value and volume of the products formed. I have been involved with projects where the required world supply of highly potent antineoplastic drugs was roughly 5 to 10 kg, enough to treat many thousands of patients, all the patients in the world who needed the drug.
A high value product's synthesis is shown using the technology:
The caption:
See the supplementary materials for detailed reaction conditions. DMF, N,N?-dimethylformamide; PP, polypropylene.
The economic and environmental benefits of this technology will depend on solid phase printing of the device - which certainly seems possible - device life time and reliability and a number of other factors, but it is likely to have at least niche application, perhaps even broad application.
As I say about many of my posts, it's esoteric but hopefully interesting.
For those involved in being a father or celebrating a father, may you have the happiest of Father's days. Mine was perfect because I could wake up not only with love for my sons, but wake up to the news the fine young people who engineered the wonderful comedic humiliation of the Grand Orange Ignorant Racist. Love and kisses to those K-POP people, whoever and whatever K-POP people are. Bless you all.
This coming generation will be a great generation.
CatLady78
(1,041 posts)I am bookmarking this post.
I first heard about Theranos here:
https://logicmag.io/intelligence/interview-with-an-anonymous-data-scientist/
And thats close, but the issue is that no person with a PhD in AI starts one of these companies, because if you get a PhD in AI, youve spent years building a bunch of really shitty models, or you see robots fall over again and again and again. You become so acutely aware of the limitations of what youre doing that the interest just gets beaten out of you. You would never go and say, Oh yeah, I know the secret to building human-level AI.
In a way its sort of like my Dad, who has a PhD in biology and is a researcher back East, and I told him a little bit about the Theranos story. I told him their shtick: Okay, you remove this small amount of blood, and run these tests He asked me what the credentials were of the person starting it, and I was like, She dropped out of Stanford undergrad. And he was like, Yeah, I was wondering, since the science is just not there. Only somebody who never actually killed hundreds of mice and looked at their bloodlike my Dad didwould ever be crazy enough to think that was a viable idea.
That person is making some of the same points you were making.