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Comment by kragen | Hacker News Reader

Benchtop NMR spectrometers already exist (for decades now), and some are already cryogen-free, permitting room-temperature measurements, eliminating the dewar and cryogens which account for a lot of the mass and volume of traditional NMR spectrometers. We now have room-temperature superconductors, which might work to eliminate the bulky, heavy permanent magnets in current benchtop devices, though the pressures required may turn out to be impractical. Beyond that I can handwave at improved electronics and SQUIDs, but I don't really know.

Do you think there are some fundamental obstacles to miniaturizing NMR, and if so, what?

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Benchtops are at 60-90 MHz field strengths. That is not really enough to look at more complex molecules, the bigger routine NMR spectrometers are at 400-600 MHz (and there are even larger ones, but those are not used for small molecules that much). And even then those benchtops cost something close to 100k USD, that's quite far from affordable.

The "room temperature" superconductors are not used at room temperature in these cases, they're still cooled down. And so far the only spectrometer I know of where they are used is the still extremely new 1.2 GHz Bruker. And that one is almost certainly somewhere between 10 and 20 million USD. The new superconductors are low temperature superconductors, not room temperature. And even then they still work better at lower temperatures. At best you can remove the liquid helium from the system and use liquid nitrogen only, which is an advantage but still really far from room temperature.

Thank you for explaining!

Yes, I don't know if the current room-temperature superconductor material (which really is room temperature, 15°C) will ever be useful for this; it was only discovered in 02020, so it is very unlikely that anyone is using it in a product today, even if they find a way to apply the necessary pressure (267 GPa, thus requiring ultrahard anvils). You're probably thinking of something like YBCO, which is "high-temperature" in the sense you're describing, requiring only LN₂, not "room-temperature".

Costs change over time. There was a time when solar panels cost 100k USD, too. A lot of the costs you're describing are NRE; others are costs that can be reduced.

The new spectrometers are using YBCO, and they are many years beyond schedule. That whole thing turned out to be a lot harder than many people seemed to expect.

The magnets are not the only cost in NMR spectrometers, I think you're seriously understimating the amount of electronics in them. You need to detect very weak signals at several hundreds of MHz, that's not trivial.

How weak are they? Detecting very weak signals (-110 dBm) at hundreds of MHz and even GHz is routinely done by Wi-Fi cards and cellphone radios, and GPS receivers detect signals that are orders of magnitude weaker than that (routinely -150 dBm), but only at tens of MHz. My eyes routinely detect submillilux signals when I look at the stars at night, with an integration time of well under a second; if I'm doing the calculations correctly, that's about -70 or -80 dBm in the 100–1000 THz band. PMTs (including microchannel plates) and SPADs routinely detect optical signals much weaker than that.

To a significant extent you can detect arbitrarily weak signals with coding gain and longer averaging times, although if your benchtop machine already takes ten minutes to give you a result, you probably can't afford to wait more than about 36 dB longer, give you another 18 dB of SNR).

So, I'm not worried about the electronics or the signal processing; there's no such thing as an "amount of electronics". Precision analog equipment is not easy to design, calibrate, and build, but you only need a very small "amount" of it, and it can be mass-produced.

Take resistors. When I was a kid back in the 01980s normal resistors were ±20% carbon composition, which would drift by more than 20% over time or if overvolted, with fiendish temperature coefficients. Now you can't buy a ±20% resistor; most resistors are ±1%, ±0.1% resistors are commonplace, and ±0.01% resistors are easily available for a dollar or two. Precision resistors are now made with an extremum of resistance around room temperature, so the temperature coefficient there is literally zero.

No, what I'm worried about is the physics. I'm not surprised YBCO spectrometers turned out to be a pain in the ass; YBCO is a huge pain in the ass in every possible way. What do you think the physical obstacles are?

The signals are weak, but more importantly, the signals are being detected in a volume wiht a huge magnetic field. You can't even put a digital circuit anywhere in the amplifier. When I worked on the NMR all the monitors in the room were shifted toward the magnet, it would wipe your credit cards, and to adjust the amplifier involved sitting under a multi-ton device twiddling knobs to minimize the impedence.

Think of NMR as bespoke. Like a large luxury liner built for a rich individual. It's not ever going to be a zodiac.

As I understand it, the magnetic field doesn't have to be voluminous; it just has to be strong and uniform. It can be arbitrarily small as long as it's large compared to an atom, which is why benchtop NMR machines can exist at all, though they won't ever be truly miniature unless either we can also miniaturize the cryostats and refrigerant supply, or we can find a usable room-temperature superconductor. Am I misunderstanding something? As I said, you know a lot more about this than I do.

NMR is an ensemble measurement technique. You can't measure the magnetic moment of a single molecule. Instead, you need a highly pure sample and lots of it. That has to be in solvent (I'm leaving out solid spinning NMR here, that's a different ballgame entirely), enough solvent to keep the sample in solution.

I think you're wasting your time trying to improve NMR. The value of the technique isn't worth it.

benchtop NMR doesn't solve this problem, it's not powerful enough.

If you had improvements to NMR they would actually go first to other things than doing chemical analysis of anarchist drug batches. IE there are other industries that will buy all your machines if they existed.

The real question is why would you EVER use NMR for just about anything? It's really high cost and the total value of the data is lower than just about any other technique. It really only makes sense in research situations.

What are the companies, or at least the industries, that would buy all the machines?

Ultimately what everyday people will end up using is whatever is cheap and works well enough. Right now NMR isn't cheap, and neither is FT-IR or XRD, but these things change over time. Benchtop NMR is already good enough for distinguishing between significant classes of contaminants that could be in your purported insulin.

I'm typing this on a 50-gigaflops computer, which is faster than the Cray Y-MP Los Alamos had back in the 01990s, and people routinely buy teraflops video cards now, any one of which is faster than ASCI Option Red, if you remember that. I just drank a mass-produced soft drink out of a can made of aluminum, the metal Napoleon III preferred to gold to exhibit his wealth. Last year Chinese companies brought three covid vaccines to market within six months of the disease's discovery and started mass vaccinations, though most observers had predicted a minimum of 18 months. SpaceX is routinely landing reusable rockets on their tails now, and the world's energy infrastructure is rapidly shifting from fossil fuels to solar.

Things change. Today's science fiction is tomorrow's old news.

You can't really escape the physics here, you need a very strong and very homogeneous magnetic field for NMR and very sensitive electronics to detect the signal. That's not something we can do for cheap right now.

And even beyond that I don't think the area has enough volumen and is competitive enough to produce significantly lower prices. The high-field NMR area is almost a monopoly right now, the benchtops and lower field instruments are somewhat competitive. But even those are in price areas far beyond someone doing synthesis at home.

As I asked you above, how sensitive do the electronics need to be? How weak is the signal?

Some things change, but to make NMR cost effective would be cheating mother nature. The entire technique is based on producing a strong and homogenous magnetic field that can hold a lot of sample, only to probe the sample with weak RF and listen to its faint echoes.

Industrial diamonds got "cheap" but large ones never did.

You could be right; certainly you know a great deal more about the subject than I do.

What are the companies, or at least the industries, that would buy all the machines if you could make them much cheaper and/or better?

any purveyor of fine chemicals (polymers, etc) and petroleum processing company (hydrocarbon analysis).

Thank you very much!

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