Category Archives: Chemistry

A Swerve into the Weeds of Asteroid Mining

Notice: As an organic chemist and not a geochemist I will be using descriptions and vocabulary that may not ordinarily be used in geology. While a geochemist might easily write a lovely article that could bring tears to the eyes of the most sour geochemist, I will stumble forward with just my trailer park chemistry background- organometallic, organic, inorganic, physical and quantum chemistry.

When you step back and view mining technology as a whole, it becomes apparent that two of the largest scale inputs in mineral refining are water and electrical energy. On Earth diesel is also required in large quantities.

A good question for those who propose mining asteroids is this: Have you solved the water and electric power requirements for unit operations? Let’s say it is solved for one mineral. How will the value be mined, transported and gently lowered to the Earth’s surface without breaking into flaming pieces on re-entry or forming a crater in a city? Is there an element or mineral that is so valuable as to justify the costs and risks to be met for a space mining mission? Is it rhodium? Gold? Diamonds? Or what?

Do the people behind the fanciful images and hype believe that they only have to dock with the asteroid and grab valuable minerals from the surface? There is a good chance that the target ore will need exploration, excavation, and possibly some kind of blasting. The target elements may well be dispersed within the host rock. This will require comminution in preparation for further processing. The ore will likely need ore dressing which is the job of removing undesired rock from the valuable ore. This lowers the quantity of ore to be processed.

The rocky bodies in the solar system have surfaces of regolith. Regolith is an unconsolidated jumble of loose rock and dust presumably overlying a solid body. Given that the regolith may well be consist of rocks and dust accreted from a distant source, merely assaying the regolith might not reveal the minerals that could be there in abundance just below the regolith. There is no way around it- core samples will be needed to properly assess the economic geology.

PGM Mining on Earth

A look at the large-scale Platinum Group Metal (PGM) production activity in South Africa is instructive. The Bushveld Igneous Complex (BIC) near Limpopo and North-West provinces contains some of the richest PGM deposits in the world. The BIC is found in the Kaapvaal craton. The BIC also extends into Zimbabwe.

The Bushveld complex is located on a ‘craton‘ which is a section of continental crust that has been stable for 400 million years or so. Over that time period some portion of crust has not been subjected to subduction or rifting as an effect of continental drift. A craton is relatively untouched by continental drift over some lengthy time interval and as a consequence the crustal rocks found in a craton may be quite old. Here, ‘old’ means rock that has not been metamorphosed recently, vented out of a volcano or eroded and stratified in a sedimentary formation within several hundred MA.

The Bushveld complex is found in the Kaapvaal craton of South Africa, extending into Zimbabwe. A consequence of this location on a very stable parcel of continental crust is that vertical transposition of rock formations, i.e., subduction activity, has not led to metamorphism or folding of strata. This stability has allowed a relatively undisturbed magma chamber to form and cool, producing layered cumulates.

The formation of cumulates is a partitioning process within the magma chamber that produces solid minerals that can float or sink within the magma. Cumulates with higher density than the magma will tend to sink, building a layer, and lower density minerals will float to the top of the chamber and form an upper layer. In this way, minerals can self-purify and stratify by fractional crystallization.

While fractional crystallization can result in enhanced purity of specific minerals, the melt from which the crystals precipitate is also changing in composition. Magma is a viscous fluid and its components can undergo anion/cation exchange to produce new minerals upon further cooling. Anions include silicate, aluminate, sulfide, hydroxide, chloride, oxide, and a whole basket of metal oxyanions like titanate, tungstate, molybdate, chromate, etc. Cations include most every metal, sometimes including the noble metals. Every metal has a set of positive oxidation states that may be subject to reduction or oxidation to afford a different oxidation state or charge.

While both anions and cations present in magma have a particular charge, their individual size is important as well. Size and charge matter most when crystals are assembling. When, for instance, a calcium-containing mineral is crystallizing, the crystal lattice is subject to collisions with the whole gamut of species in the magma. If the temperature and pressure are appropriate, calcium (+2) cations nestle into a vacancy in the lattice. This is controlled by the concentration, temperature and Gibbs energy of the placement of the cation. However, if a different cation of +2 charge and similar ionic radius happens by, that different +2 cation may find itself occupying calcium’s place in the lattice. An example would be where the Ca⁺² cation was replaced by Mg⁺² or Fe⁺².

Mineral crystal formation is a type of equilibrium wherein lattice anions and cations at the surface of the crystal are in equilibrium with anions and cations in the melt. The rate of crystallization or dissolution is driven by several things. Substitution of a Ca⁺² ion in a lattice with Mg⁺² or Fe⁺² ions retains the charge balance in the lattice. But if a too large or too small +2 cation attempts to sit in place of Ca⁺², a mismatch occurs which may be energetically favorable, but as a result may be much more prone to removal by equilibration. The interloping cation could be of such a size that its heat of formation is small and therefore subject to replacement by equilibration. Or not. The resulting mineral could be comprised of Ca⁺² cations and M⁺² cations in a non-stoichiometric ratio. Or a new mineral comprising a stoichiometric ratio of both cations.

The anions in a mineral substance can be quite varied and several may exist in a mineral at the same time as in the case of anions silicate and aluminate.

The Stillwater Igneous Complex in Montana, USA; the Sudbury Basin in Canada; and the Norilsk-Talnakh deposits north of the arctic circle on the Siberian Craton.

The Stillwater Igneous Complex in south central Montana, USA. Source: Google Maps.

Image from Google Maps. Elevator shafts for the Sibanye-Stillwater K3 Shaft, South Africa.

Image from Google Maps. The Sibanye-Stillwater K3 shaft, South Africa.

Russia is the leading producer of palladium with 40 % of the global market. Norilsk Is also known as a center of non-ferrous metallurgy as well as noble metals. Norilsk Nickel, also known as Nornickel, is a mining and smelting company. Platinum Group Metals (PGM) have been recovered as a side stream of nickel and copper mining by Norilsk Nickel.

Open pit mile near Norilsk, Russia. Norilsk was originally started as a gulag in the far north of Siberia and eventually became a mining community.

The aerospace proponents of asteroid mining should spend some time at an actual mine. Breaking rock and hauling it around is simple on Earth but consider doing this in a vacuum at near-zero gravity. Look at all of the methods of conveyance and processing in operation at a mine that works only in a gravitational field. Blasting, front-end loaders, haul trucks, conveyor belts, crushers, ball and rod mills, flotation and settling tanks, lixiviation in sulfuric acid and several shifts of staff to operate and maintain it. Don’t forget the analytical lab and chemist or the maintenance group.

Proponents will always say that with the right technology, asteroid mining could work. But in the airgap between could and will is the nagging question of why? Maybe asteroid mining is best left to our descendants in the 22^nd century.

A human trip to an asteroid, which is always in orbital motion and probably rotating, to mine and return with paydirt for the investors will always be high cost. Bodies outside of the Earth-Moon system will be nearby only for a short time, depending on the orbital period of the asteroid. While our Earth is measurably overheating, the biosphere is disintegrating and political turmoil is rampant on Earth, perhaps we should focus closer to home?

Humanity must stay focused on critical housekeeping activity here on planet A. Monetizing the outer worlds can wait.

I do believe that eventually somebody will design mining technology to solve the unique problems of mining smaller asteroid bodies with negligeable gravity. Energy dense power sources will be needed to move commercial scale machines and ore. The big problem will be the economics. What mineral is so valuable as to justify the trillion-dollar expense of finding an asteroid with suitable quantities of mineral, up front R&D costs, and beneficiation and isolation of the mineral?

Minerals dispersed in the regolith matrix will need comminution, extraction by lixiviation, floatation, isolation and packaging. Now, we can get it back to earth orbit but then what? Do we just deorbit in the usual way?

Bringing home the paydirt

Let’s say they return 1000 kg (contained) of rhodium valued at todays price of $5400/toz (toz = troy ounce). 1000 Kg contained of rhodium = 32150.7 troy ounces, so 32150.7 toz x $5400/toz = $173,613, 780. However, just the rumor of 1000 kg of new rhodium about to come on the market will drive rhodium prices down. So, $174 million sounds like a lot of money and in a sense it is. But in aerospace and heavy industry, millions are quickly consumed.

Rhodium was chosen for its general scarcity and high price. There is no reason to suppose that rhodium will be more abundant on a given asteroid than on earth so numerous asteroids may need exploration by geologists. Core samples might be needed for the economic geologists to sketch out the size and value of an ore body.

There will be a threshold price of rhodium that must me exceeded before rocket launching and asteroid digging begins. This is how mining works on earth. Until then, the celestial rhodium discovery will just keep orbiting the sun into the future.

The North American craton. Source: Wikipedia.

An aspect of PGMs is that the very few mines that produce them do so in a unique geological feature on a craton. The mechanism for PGM mineralization in districts like the Bushveld Igneous Complex in South Africa took place in a magma chamber where over time the magma began to cool. Magma gets its minerals from the mantle far below and from the walls of the magma chamber. In subduction zones the subducting crust is pushed downwards causing rising temperatures.

Subducting oceanic crust is loaded with water in several forms. Many minerals are ‘hydrated’ meaning that one or more water molecules are strongly attached to the mineral. These might be called coordinated water. The oxygens are strongly attracted to a cationic feature of the mineral. Interstitial water molecules may be occupying voids in the mineral lattice. Discrete water is only weakly attached and may diffuse elsewhere. Interstitial and discrete water may evaporate readily if exposed to air or heat. At the elevated pressures and temperatures of magma at depth, the three kinds of water are hot enough to flash to steam if the pressure was released. However, as the magma rises to the surface to cooler surroundings and lower pressures, eventually the water will flash to the gas phase moving magma in the direction of lower pressure. Just below the surface the dissolved gases including CO₂, steam and SO₂ will expand as a gas and push magma to the surface causing a volcanic eruption.

As the magma cools, the substances with the highest melting point begin to crystallize. If the crystals that have a higher density than the magma, they will settle lower in the magma chamber and form a distinct layer. While this layer is building, other minerals will follow in a similar process. The layers of precipitated minerals are called cumulates.

The process of minerals selectively crystallizing and precipitating to the upper or lower zones of the magma chamber. The overall process is called fractional crystallization and layers called cumulates can form. In the photo below are several layers of dark chromite cumulate.

From the Bushveld Igneous Complex. Exposure of cumulate layering of dark chromite. Mining involves following the cumulate layers.

Now that I have expressed my doubts about asteroid mining, I must ask ‘Am I being a Luddite’? Maybe a little bit, but even the doubts of a Luddite can be on the mark now and then. Asteroid mining will be an adventure for a few astronauts, profitable for aerospace contractors and an entertainment spectacle for the public; however, resources seem better used on Earth for remediation of the biosphere, diplomatic solutions for the conflict of the week, lower hydrocarbon consumption and better education, especially in the area of civics.

The whole purpose of mentioning PGM geology and mining in a post titled Asteroid Mining is that we on Earth are fortunate to have concentrated mineral deposits that exist only because of unique geological processes. These processes only work in Earth’s gravitational field. The upwelling of lower density hot hydrothermal fluids. The formation of evaporites rich in borax. Lithium brines.

Take my uranium, please

The formation of cumulates in lava chambers relies on differential density driven by gravity. The ability of rain and snow runoff to mobilize gold sulfides will produce lode gold and placer deposits. The ability of oxygenated meteoric water to oxidize insoluble U⁴⁺ to soluble U⁶⁺ in sandstone formations to form concentrated roll front deposits. The ability of oxygen to switch uranium oxidation states from U⁴⁺ to produce a soluble form (U⁶⁺) that can migrate and concentrate leading to the partitioning of U⁶⁺/U⁴⁺ species. Underground formations of uranium can be dissolved in a solution of sodium bicarbonate by injection and pregnant solutions of the uranium carbonate can be brought to the surface as a solution. This solution is run through a column of ion exchange resin beads which exchange chloride ions for the uranium complex. Once loaded, the beads are washed with a special solution to remove the uranium (6+) concentrate.

Oxidation and isolation of U⁶⁺ from U⁴⁺. Graphics by Arnold Ziffel.

Our ability to mine and isolate minerals is uniquely enabled by planet earth. The ability of nature to dissolve, mobilize and concentrate minerals into ore bodies from highly dispersed placement in source rock has been positive for humanity. A great many elements are found in a dispersed condition in the continental crust. For some, there are natural processes for concentration. For others, they form secondary minerals that end up mined with the primary ore. A few like gallium, indium and bismuth are valuable but are only available as a side stream from the primary ore. Copper is an excellent example of a primary metal whose ore includes many other metals like zinc and bismuth. Copper can be electro-refined to 99.99 % purity. The slimes left behind after the electrolysis and dusts caught in ventilation systems can be enriched in useful metals and are often collected for processing.

The purpose of citing the large-scale processes in use on the home planet is not to suggest that asteroid mining must start out at large-scale. It would likely start out as a small-scale surface or underground operation with a small crew or with robotics. Only a few select minerals would be economically suitable for recovery. Platinum Group Metals are mentioned above because of their high intrinsic value and ability to exist as the native metal. If luck is with the astro-miners, the motherlode might be easily visible so later the gangue material can be chipped off. The process of trimming ore to retain the value and discard the gangue was called ore dressing. Being quite dense, the volume of PGM metal ore may be low, but the density and mass is quite high.

If a given asteroid has never been part of a larger system with magma and sufficient gravity to force stratification by density, the cumulate model may not apply. A given asteroid having never been exposed to bulk water and consequently never been subject to hydrothermal flows and weathering may not have minerals that here on Earth are known to be formed with water or partitioned as a result of hydrothermal flows. Lake and ocean sedimentary units are almost surely absent as are processes requiring aqueous migration through porous rock as in the case of uranium roll fronts.

Asteroid mining will be a totally new activity and most all of the natural geological processes on earth will have been absent. Many geological processes on earth produce economic ore bodies. These will be largely absent on an airless, dry asteroid.

One thing to consider: Most of the rock accessible at the Earth’s surface is not economic ore. The surface of the Earth brimming with carbonates, silicates and aluminates bound to a variety of ‘ordinary’ metals like calcium, magnesium, iron, sodium, potassium and a handful of other common metals. While there are important and valuable uses for these common metals, they are predominantly found dispersed in surface rock comprised of many individual minerals, or that an ore body is too small for economic recovery.

The fraction of the desired mineral in the ore can be highly variable. Depending on the market, some parts of the ore body may be economical to mine while other parts may not. This is why cores are drilled to locate the 3-dimensional extent of the ore body, estimate the potential value and minimize the expense of digging and processing uneconomical ore.

It seems reasonable to suppose that, just as much of the surface of the earth is covered with rocks made from mineral constituents of low economic value like crushed roadbed rock or sand and cement for concrete use, why should we assume that a given asteroid would be any better endowed with value than Earth’s surface? Asteroid mining will necessarily be preceded by expensive exploration. Obviously, right? But it means that considerable money and time will be spent up front finding an asteroid that is sufficiently ‘pregnant’ with valuable metal ore. Finding investors to fund exploration and mining development today is based on economic geology surveys and signed off by certified experts.

A mine is a hole in the ground with a liar standing at the top. –Attributed to Mark Twain

On Earth many mineral deposits have been located historically by surface exposures that are part of a larger ore body. The economics of isolating any one mineral or metal in the presence of the others will depend heavily on the % concentration of the target mineral, the processing methods available and the market price of the final product. A market downturn can last months, years or represent new long-term realities in demand for the product.

Easter Chemical Parade

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Poltroon University will be hosting the 15^th Annual Easter Chemical Parade in Guapo, Arizona, on Sunday, 20 April, 2025. Former Arizona Governor Barbara Hoskins will serve as Parade Marshal.

Advanced dye formulations will be on display coloring the floats and decorating the Poltroon MacGuyver Convention Center. Local manufacturers like Tuscon Anilin und Soda Fabrik (TASF) will graciously provide sparkly rare earth pigments for the youngsters to dye their eggs in a large playground vat.

The fairgrounds will feature entertainment chemistry booths where parents can hold thin layer chromatography elution races of mystery dyes. The fastest elution of the three spots is eligible for a stuffed animal prize. Fire extinguishers are provided.

Another booth will hold fractional distillation races with prizes for the largest heart cut. Contestants must clean their own glassware.

The Klaus Fuchs Uranium Facility will sponsor a uranium Easter Egg hunt looking for a geo-cached easter Egg containing uraninite ore. Playschool Geiger counters will be issued to children over 4 years of age who will search the convention center parking lot for the colorful uraninite eggs.

RIP Martin Karplus and a Newman Anecdote

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Theoretical chemist Martin Karplus passed away 28 Dec., 2024, at age 94. Karplus shared the 2013 Nobel chemistry prize with Arieh Warshel and Michael Levitt for their work in “the development of multiscale models for complex chemical systems,” for computer programs they developed in the 1970s.

Those who have studied proton nuclear magnetic resonance will recall the Karplus equation or curve relating hydrogen-carbon-carbon-hydrogen dihedral bond angles to proton-proton coupling constants, ³J_H,H, across 3 sigma bonds. If your molecule of interest is conformationally constrained such as an aliphatic ring, and there are coupled protons with the right splitting patterns, integrations and coupling constants, you may have some good data to prove/disprove a proposed structure in Acta Retracta.

The Karplus curve relating dihedral angle to proton-proton (¹H-¹H) coupling constants. The curve shown is the theoretical curve- measured coupling constants varied from the curve just a bit. **Source**: Wikipedia.

Newman Anecdote

Seeing the Newman projections above reminds me of the time I met him. It was 1993 and I and a faculty colleague found ourselves trudging through the hallowed chemistry department halls of her alma mater, The Ohio State University. We’re shuffling along when who should we spot working in his lab but the eminent Professor Mel Newman. Newman, who passed away later in 1993, was very near the end of his life then and looked every year of his age. My grad school research was in the area of stereochemistry and organic asymmetric synthesis, so I was naturally enthralled. We stepped in the lab like we owned the place and introduced ourselves. Newman was busy shaking a 2-Liter glass separatory funnel full of some jet-black liquid. We made sure not to startle him and let him set the funnel down into a ring stand before speaking. We exchanged pleasantries and I sputtered out words expressing my admiration and unexpected delight in meeting him- you know, fanboy stuff. He took the time to draw out the reaction chemistry he was performing and the target molecule. As I recall, it was a polyaromatic compound made with carbocation chemistry. Soon, we said our goodbyes and left.

On the way out of Columbus, OH, we stopped at a White Castle’s and enjoyed some sliders. It was a banner day- I met Mel Newman and had my first White Castle slider. It can get better than that, but probably not in Ohio.

For a chemist, the highest award is being recognized as an adjective for something, like Karplus Equation. Karplus made adjective status and that is an accomplishment most of us will never reach.

Proteins, Receptors and Some Chemistry of Fentanyl

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[Note: This is a much-updated revision of a previous post from March 24, 2023. I’ve brought in just a tiny bit of protein structure and how it relates to opioid receptors- but only slightly. I’m thinking of you, dear reader. I’ve succumbed to my compulsion to include chemistry tutorials in my posts.]

First, a lot of chemists could say a lot of things on this topic. This is what I have to say. This essay is not written for medicinal chemists or molecular biologists. They already know this stuff. This is for everyone else. Learning usually requires an expansion of your vocabulary and this is no different.

When it comes to illicit drug synthesis I’ve always been a bit of a Puritan. As an organic chemist I’ve always felt that it is morally indefensible and a waste of talent for a chemist to make or help make dangerous and illegal drugs. Putting potent, illegal drugs on the market is like leaving a hand grenade in a playground.

For myself and for many others, what is fascinating about drug molecules is how structural features on a drug molecule confer pharmacological effects on biological systems. The molecular-level effects are referred to as a structure/activity relationship, or SAR. The chemical structure of a drug molecule makes all of the difference in how a drug functions. Among the key features are water solubility, acidity/basicity, hydrogen bonding, resistance to metabolic degradation, and the manner in which charge is distributed on the drug molecule. As a reminder, in order for two molecules to react they must bump into one another in a particular way. And not just that, but bump into a particular spot oriented properly and with sufficient energy.

Drug molecules do not swim directly to the site they are intended to go. They must take a random walk through flowing, jostling biofluid molecules and a certain minimum dose must survive the ordeal before they are metabolized, excreted or both. Some pharmaceuticals, called “pro-drugs“, are constructed in a way that relies on the action of metabolic processes to change them into the active drug. This is because they have some kind of chemical vulnerability and must be whisked into the body in disguise. Many drugs are bind to blood proteins and may remain unavailable for their action.

What the protein can do depends in large part on the sequence of amino acids that it is comprised of and how it relaxes into a largish, kinked and contorted chain with helices and pleated sheets. A protein polymer is made of a chain of amino acids that can interact with other molecules or with itself. Some lengths of a protein may lie flat and be somewhat rigid while other lengths may coil into a helical form. A protein molecule made of these features can then bunch up into a wad of protein that holds a particular shape. Along the surface of this shape are bumps, folds and crevices. In these places, there may be exposed amino acids that can attract acidic or positively charged parts of a molecule. Other spots may attract basic features like nitrogen with its lone pair of electrons. Still other places will attract molecular features with poor water solubility or just low polarity.

Drugs are used to activate or inactivate the function of a protein. Living things use proteins in several ways. In the case of drug action, proteins are large chemical structures that can make or break chemical bonds. proteins that do this can do it catalytically, that is, one enzyme molecule can perform its function repeatedly. That’s not all. There are features along the length of a folded enzyme chain that can attract, bind and even deform a molecule that is bound to it. In doing so, a chemical transformation can occur at physiological temperatures that might otherwise occur only under more chemically forcing conditions. This ability of enzymes is crucial to life itself.

Another function of proteins is the ability to change their shape to open or block the passage of smaller ions and molecules through it. The cell walls in our body consist of a double layer of fatty, detergent-like molecules that are water repelling on one side and water attracting, or ‘hydrophilic’, on the other. The water repelling, ‘hydrophobic’ side consists of a long chain of 2 or 3 hydrocarbon chains that comingle with one another.

In order for a drug to function it must bump into the target biomolecule like an enzyme (protein) and at a particular location on the enzyme. Some drugs may remain unchanged and just spend a lot of time bound to the active site of an enzyme, preventing the intended biomolecule from doing so. Others may permanently bind to a protein or other molecule, thereby blocking it from doing its job for the life of the enzyme. And others, like aspirin, may leave behind a fragment of itself permanently blocking the active site of an enzyme. Some drugs prevent a protein or enzyme from working and are called antagonists. Others may activate it and are called agonists. What you aim for depends on the system you are trying to manipulate.

A dip into proteins

An atom, ion or molecule that binds with a metal or a protein is called a “ligand“. A ligand, pronounced ‘LIGG und’ by organikkers and inorganikkers, or ‘LYE gand‘ by ~~waterchemists~~ biochemists, can connect with a protein through one or more attachment points. The greater the number and strength of the attachment point(s), the more time the ligand will spend being attached. A ligand may even become permanently attached. Ligands purposely or externally provided for a desired outcome are considered as “drugs”. Ligands that cause an undesired outcome may be referred to as toxic. Not all ligands are aimed at human proteins, however, such as the beta-lactam antibiotics which bind with certain bacterial enzymes. This is a fascinating topic all by itself, but it is left as an exercise for the dear reader.

Ligands or drugs can have specific structural features that are associated with its activity or potency. This assembly of molecular features on the ligand is called a “pharmacophore“. An enzyme will have small region on its surface that can accommodate the “docking” of a ligand with the right shape and polarity

**Source**: Wikipedia. This image is from x-ray data showing a ligand snugly fitting into a pocket on a protein. Crystal structure of W741L mutant androgen receptor ligand-binding domain and (R)-bicalutamide complex. An example of a protein–ligand complex.

In the image above, a close look will show a drug molecule sitting in a space that is complementary to its shape and polarity. If it turns out that this space is where the normal biological ligand docks in order for the enzyme to do something to or with it, then the enzyme behavior has been altered. The drug molecule being bound by the enzyme blocks the site that is normally occupied by the biological ligand. The biological ligand may enter the site to be chemically altered, or it may be the natural signaling agent that activates or deactivates the enzyme. The activation/deactivation may be permanent or not.

Another possibility for ligand-type activity is that of a cofactor. When the cofactor docks to an enzyme, the shape of the enzyme changes -a common effect- and another docking site is activated, enabling the enzyme to function. Some cofactors are vitamins or are made from vitamins.

The amino acid chain making up the enzyme is folded up in a particular way depending on the amino acid sequence. The overall shape of the enzyme consists of ridges, bulges, clefts and can also include a hole straight through the structure. Each of the 20 amino acids available is unique by way of its particular kind of chemical functional groups that are attached. If we imagine the exterior ‘surface’ of the protein, the amino acid chain twists and turns giving a lumpy surface topography. The different amino acids with their unique attached side-groups can jut out from the chain and be accessible to external molecules.

Different substances that share these features may comprise a family of substances having similar activity. In the case of opioids like fentanyl, this active site is referred to as an “opioid receptor“. There are a several variants of opioid receptors distributed throughout the human brain.

Opioid receptors are transmembrane proteins. They sit immobilized within the cell membrane with their external receptor protuberances gently swaying in the warm biofluid currents. They lie in wait for a shapely substate to happen by and nestle into its special cleft and be rewarded with a small release of Gibbs Energy.

The lipid bilayer of a cell membrane, comprising comingling long-chain hydrocarbon tails, is very hydrophobic (water repelling). Transmembrane proteins are compatible (likes dissolve likes) with that environment and can exist imbedded within the cell membrane. In this position, with access to both interior and exterior sides of the membrane, the protein is set up to be a receptor. A receptor is a protein that by virtue of its shape and polarity can recognize complementary shapes and polarities of a specific range of signaling molecules such as a hormone and transmit or release a chemical signal to the other side of the membrane.

Source: Wikipedia. The enzymes above are called transmembrane proteins. The opioid receptors are of this variety.

**Source**: Wikipedia. Complementary shapes. This illustrates ‘recognition’ of opioids by opioid receptors. Different but similar shapes can also be complementary but with varying degrees of affinity. Close resemblance in shape allows drugs to function.

End biochem section

According to the DEA, fentanyl is the most serious drug threat the US has ever faced. In the 12 months ending January, 2022, there were 107,375 deaths from drug overdoses and poisonings. Of those, 67 % involved synthetic opioids like fentanyl.

Fentanyl is not found in nature. It is made in a reaction vessel or a bucket by a person. It is totally synthetic in origin and is prepared from other manufactured substances. The molecule is relatively simple and there are many places on it where new functional groups can be attached to produce designer analogs. Due to its startlingly high potency, a large number of doses can be made in fairly small batch equipment.

The explosion of fentanyl use is mind boggling. Drug cartels have taken to producing it themselves for greater profit and a more secure supply chain. The common syntheses are fairly simple, high yielding and, in the case of fentanyl, there are no stereochemical issues other than the atropisomerism of the amide bond. As far as purification goes, this isomerism is difficult to control and it is hard to believe that it is considered a problem by the “cooks” who make it.

A quick search of Google failed to bubble up information on what chemical form of illegal fentanyl commonly shows up on the street, whether as a free-base form or a salt. Like most amines, the free-base could be salted out of a reaction mixture by addition of an acid to a solution of free-base fentanyl in an organic solvent to produce the insoluble salt crystals. This solid material is then recovered by filtration. This is a common method of recovering amines from a reaction mixture.

It is worth looking at a synthesis of fentanyl to see what kind of chemistry is performed (see below). There is nothing remarkable about this synthesis- it’s just an example. A key raw material is the 4-piperidone hydrochloride on the upper left of the scheme. It is a piperidine derivative which is a feature of many drug substances. This one has 2 functionalities– the nitrogen and the C=O at the opposite end of the ring. Connections will be made at each end as the synthesis proceeds. The hydrochloride feature results from how the manufacturer chose to sell the product. Ammonium salts are frequently more shelf stable than the free amine.

The first step in the process below combines 4-piperidone hydrochloride with phenethyl bromide in the presence of cesium carbonate in solvent acetonitrile. In this transformation the nitrogen displaces the bromide to form a C-N bond connecting the fragments. Cesium carbonate is a base that scavenges acid protons. According to Wikipedia, cesium carbonate has a higher solubility in organic solvents than do the sodium or potassium analogs. Cesium carbonate is commonly used when a base stronger than sodium carbonate is needed. In order for the reaction to go forward, the HCl must be neutralized to liberate the free base. It is hard to imagine that the folks doing an illegal preparation are using a cesium base due to higher cost. The displacement of the bromide by nitrogen releases hydrobromic acid as well which must be removed from the mixture. Bromide is chosen because it is a good leaving-group. para-Toluenesulfonate, or tosylate, has been used as well.

Next, aniline must be added to the piperidone ring where the C=O is located. We have to end up with a single C-N bond connection from the aniline nitrogen to the C=O double bond then remove the oxygen and replace it with a hydrogen atom. Aniline is quite toxic and volatile with an LD₅₀ of 195 mg/kg (dog, oral). It stinks too. This sequence is referred to as a “reductive amination“, meaning that the oxygen is replaced by single bonds to nitrogen and hydrogen. Adding hydrogen to a molecule is referred to as a reduction. The authors of the work commented that of three hydrogen donors tried, sodium triacetoxyborohydride gave the best yields. These borohydrides donate hydrogen as the negatively charged hydride, H:^–.

Acetonitrile is a polar aprotic solvent that allows enough solubility to the reagents and intermediates so as to help the reaction along. Reductive amination classically proceeds through a C=N (imine) intermediate which then undergoes a hydrogen reduction of the bond to give the amine product.

The two-nitrogen intermediate is then fitted with a 3-carbon fragment bearing a C=O to the aniline nitrogen connected to the benzene ring. With this transformation, the amine nitrogen becomes an amide nitrogen. The fragment added is called propanoyl chloride (pro-PAN-oh-ill KLOR-ide) and involves the displacement of the chloride with the nitrogen producing hydrochloric acid. The purpose of the diisopropylethylamine base is to serve as an acid scavenger. The solvent was dichloromethane which is not uncommon for this kind of reaction. It has a low boiling point for easy removal by distillation and a slight polarity for dissolving substances that are somewhat polar. It is also inert to the reaction conditions.

It takes a high level of education, training and resources to design and perfect a process like the one above. However, it can be executed by most people after a bit of training. You don’t have to be a chemist to follow the procedure. The trick will be to avoid poisoning yourself from aniline or fentanyl exposure in the process.

However illegal fentanyl is made, the raw materials going into it must combine to give one unique final product. There are not an infinite number of pathways to fentanyl. However, structural variations of the raw materials could be chosen using the same basic reaction conditions to produce a spectrum of designer analogs. If specific molecules are outlawed, analogs can readily pop up to skirt regulations.

The people who make illicit fentanyl are sourcing the raw materials from somewhere. Unlike heroin, there are no natural substances in the manufacture of fentanyl. Heroin is just plant-based morphine that has been acetylated. Acetic anhydride is the choice commercial reagent for this. The acetic anhydride supply chain can be traced. Fentanyl, however, requires a supply chain for numerous fine chemicals. In the US, many substances are flagged by suppliers in a way that could cause the authorities to investigate the buyer. Furthermore, US commercial suppliers often could do a Dun & Bradstreet credit check on you to gauge your suitability as a customer. Commercial chemical suppliers will not ship to a residential address or PO box. So it takes a bit of business structure to get chemicals sent from established chemical suppliers to your address.

The way to avoid this hassle is to import from somewhere like Asia. Given the high potency of fentanyl, the mass of raw materials in a shipment could be very low. Most organic chemicals are whitish or colorless and can be mislabeled. The lower the molecular weight of a substance, the lower the mass that will be needed for the process. There are no high MW reagents in the scheme above.

Herein lies the problem with fentanyl. It requires raw materials that have legitimate uses in the chemical/pharmaceutical industry and these substances can received by unscrupulous operators who can repackage and divert shipments to the bad guys in countries along the Pacific coast of the Americas. It is just simple smuggling.

The estimated lethal dose of fentanyl for humans is 2 milligrams. According to one source, “The recommended serum concentration for analgesia is 1–2 ng/ml and for anesthesia it is 10–20 ng/ml. Blood concentrations of approximately 7 ng/ml or greater have been associated with fatalities where poly-substance use was involved.” Overdosing with fentanyl is reportedly treatable with naloxone. But this is only effective if your unconscious body is found by a sympathetic bystander and help is called in promptly. This is a very slender reed from which to hang your life.

It is left to the reader to look further into the pharmacology and therapeutic window details fentanyl. Suffice it to say that dosing yourself with illicit opioids is a stupidly risky business. The illegal opioid risk is multiplied by other additives or the possible presence of designer analogs which may be 10 to 100 times more potent. End-use safety is not a priority of those who make and distribute these opioids.

Given the estimated 2 mg lethal dosage, fentanyl should be regarded as a highly toxic substance. As long as there is demand for potent opioid substances, someone will provide it. When the oxycodone supply tightened recently, heroin demand rose. It’s a deadly whack-a-mole situation. The only answer is reduced demand.

Helium and the “Howling Gasser”

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Global demand for helium is expected to double by 2035. Helium is a critical, non-renewable resource used across the world. It is found in natural gas deposits in limited number of gas wells. Helium is the second most abundant element in the universe behind hydrogen. But this is averaged across the universe. Any helium the earth’s early atmosphere may have had has long ago diffused into space. At present, helium from terrestrial sources is derived from radioactive decay of uranium, thorium and daughter products within the Earth over eons of time. Underground structures suitable for the accumulation of natural gas may also accumulate helium.

Helium is useful in science and industry for many reasons, but mostly for its extreme chemical inertness and ultra-low boiling point. A gas with a very low boiling point, and if you manage to condense it, finds use as a low temperature coolant. Helium serves as an inert atmosphere in many applications including nuclear power, semiconductor manufacturing, welding and for pressurizing rocket propellant tanks. In liquid form, it boils at the low absolute temperature of 4.2 Kelvin (-261.1°C) and is indispensable as a cryogen for many applications from medical Magnetic Resonance Imaging (MRI) and quantum computing to other superconductor applications. Those of us who make great use of nuclear magnetic resonance spectroscopy (NMR) are highly dependent on it as an analytical tool. NMR has made identification and quality control possible in many kinds of chemical manufacture.

According to one source a single MRI unit can contain up to 2000 Liters of liquid helium and consume 10,000 Liters over its 12.8-year lifespan. If you condensed the helium gas into liquid from the balloons at the Macy’s Thanksgiving Day Parade, there would be enough liquid helium to keep two MRIs running for their lifetimes. The US presently has approximately 12,000 MRI units across the country. The good news is that helium recycling equipment can be fitted on to an MRI machine to greatly extend the life of a helium charge. Usually, a liquid helium dewar is immersed in a liquid nitrogen filled dewar which is inside a vacuum insulated container. The liquid nitrogen bath helps with the helium boil-off somewhat, even though the bp of nitrogen is considerably higher than that of helium, yet much lower than room temperature.

Source: Wikipedia. The Hugoton and Panhandle gas fields rich in helium. There are many other helium-rich gas fields in the US, but none as large as the Hugoton and Panhandle gas fields.

**Source**: Google Maps. Aerial view of the Cliffside Helium Plant. If there are actual cliffs near Cliffside then the panhandle folks are calibrated differently from me as to what constitutes a cliff.

Source: Wikipedia. The Excell helium plant, ca 1945. Note the company housing.

Helium is isolated from natural gas. According to the American Chemical Society, the US, Algeria and Qatar have the major the helium reserves while the US, Russia and Algeria are the top suppliers of helium. The majority of US reserves are in the Texas & Oklahoma panhandles and Kansas. The Cliffside helium plant is located a 15 miles NNW of Amarillo, TX, over the Cliffside dome. It is in the red circle on the upper left in the photo.

The Amarillo Helium Plant got its start in 1929 when the federal government bought 50,000 acres NNW of Amarillo for a helium extraction plant. The motivation was to accumulate helium for lighter than air aircraft like balloons and blimps.

**Source**: Google Maps. Cliffside Helium Plant, Amarillo, and Pantex.

It is interesting to note that the Pantex nuclear weapons plant is about the same distance but to the NE of Amarillo, TX. It is circled in red in the upper right. It is the primary site in the US where nuclear weapons are assembled, disassembled or modified. Uranium, plutonium and tritium bearing components are stockpiled there. Weapons that use tritium in their booster gas have a shelf-life constraint due to tritium’s very short half-life, so the gas must be periodically upgraded.

The facility opened in 1942 for the manufacture of conventional bombs and was shut down shortly after the Japanese surrendered in 1945. The site was purchased in 1949 by what is now Texas Tech and used for research in cattle-feeding operations. In 1951 it was surrendered to the Atomic Energy Commission (now the National Nuclear Security Administration) under a recapture clause.

So, we might ask the question: Why was anyone looking for helium in natural gas at the time? The easy answer is that nobody was looking for it. In May of 1903 in Dexter, Kansas, a crowd had gathered at a natural gas well to celebrate this exciting economic find. A celebration had been planned and the towns folk were there to see it ignited. It was called “a howling gasser” and there was much anticipation of a spectacular fire. After much ballyhoo and speeches, a burning bale of hay was pushed up to it in anticipation of ignition of the gas jet, but the burning bale was extinguished. This was repeated several times, but no fire. The disappointed crowd wandered off. Later Erasmus Haworth, the State Geologist and geology faculty member at the University of Kansas, got word of this curious event and managed to get a steel cylinder of gas sent to the university.

At the University Haworth and chemistry professor David F. McFarland determined that the composition of the Dexter gas was 72 % nitrogen, 15 % methane and 12 % of an “inert residue.” Soon, McFarland and chemistry department colleague Hamilton P. Cady began “removing the nitrogen from the gas sample by applying a spark discharge with oxygen over an alkaline solution.” This tedious procedure was soon replaced by using a glass bulb of coconut charcoal immersed in liquid air. This method had been shown to adsorb all atmospheric gases except helium, hydrogen, and neon at the temperature of boiling liquid air” (-310° F). The unabsorbed gas was collected in a glass tube and examined by emission spectroscopy. The spectrum showed all of the optical lines of helium. This discovery by McFarland and Cady showed that sizeable quantities of helium did exist on the Earth. The total amount of helium in the Dexter gas was 1.84 %.

**Graphic**: Atomic emission lines of helium. **Source**: chem.libretexts.org

The nagging question I have is how did the nitrogen content in the Dexter sample come to be? The thinking is that N₂ gas found in natural gas derives from chemical alteration of organic ammonium compounds deep in the natural gas forming strata. To a chemist “ammonium” has a specific meaning. To a geologist it may just mean “amine”: hard to tell. N₂ molecules are in a deep thermodynamic well, meaning that once formed, the nitrogen is very stable and not readily altered without large energy inputs. So, the formation equilibrium of N₂ could favor its formation rather than returning to a precursor.

The removal of nitrogen, called nitrogen rejection, is a normal part of natural gas processing. The incentive for its removal is that it lowers the BTU content and thus the value of the gas. According to one source, the Midland gas field in the Permian formation of Texas is unusually high in nitrogen, from 1 % to 5 %. Given that the usual specification for nitrogen content is 3 %, excessive nitrogen must either be reduced by dilution or removed.

The problem of nitrogen becomes especially acute for gas that is condensed to LNG (Liquified Natural Gas). Natural gas that has too much nitrogen in it has a higher partial pressure of nitrogen and as a result it occupies space in a pipeline or LNG carrier that could be occupied by a gas that pays- natural gas. Non-combustible gas in the liquefaction train at the LNG terminal wastes its processing capacity. The specification mentioned above becomes more problematic when it is realized that the N₂ content of natural gas may vary considerably from one wellhead to the next, adding to the overhead cost of quality control of the output gas.

Back to the Howling Gasser, the fact that the natural gas screaming out of the wellhead wouldn’t ignite was an extreme example of the effect of nitrogen in the formation. What saved the day was the high enrichment in helium. But, you would have to know to look for it. That a curious geologist and two chemists were able to isolate the helium and perform emission spectroscopy on it without a clue as to what it was stands as an excellent example of what curious, knowledgeable folks can do when given the resources. The state of Kansas is to be congratulated as well for providing the research facilities at the University of Kansas in Lawrence, KS.

Update: Huo Yao (Fire-Drug)- Predecessor to Gunpowder.

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[Note: This is an updated version of an earlier post.]

Recently I spent some time tracing the very early history of gunpowder or Huo Yao (China, ca 850 AD). It turns out that the earliest clear description of a gunpowder-like composition was described in a document produced during the Tang Dynasty. A document titled “Classified Essentials of the Mysterious Tao of the True Origins of Things” contained a list of particularly dangerous elixirs. A comprehensive history of Chinese science can be found in “Science and Civilisation in China, Volume 5: Chemistry and Chemical Technology, Part 4, Spagyrical Discovery and Invention: Apparatus, Theories and Gifts” by Joseph Needham. Within this list of hazardous compositions, a warning was offered citing the dangers of mixing and heating together realgar, salt peter, sulfur, and honey. The document tells of alchemists mixing this combination and heating it, resulting in a deflagration leading to burnt beards, faces, and hands as well as the loss of the structure to fire. This mixture has been translated as “fire-drug”.

There are earlier references to admixtures that could produce a violent effect, but the compositions are not disclosed. The information in the 850 AD document clearly describes the components of classic gunpowder- a nitrate oxidizer, sulfur or sulfide for low ignition temperature, and a carbohydrate reducing agent- honey. What is notable about gunpowder is that is a self-contained redox system containing two sides of the fire triangle– fuel and oxidizer in intimate contact. All that is needed for an exothermic reaction is initiation with some kind of energy stimulus.

A couple of thoughts on the realgar present in the mix. First, alchemists were commonly in the apothecary trade and made their living preparing medicaments, not so much searching for the philosopher’s stone. It is not unreasonable to suppose that the composition was intended for some medicinal effect. Realgar is red tetraarsenic tetrasulfide (As₄S₄), possibly with some amount of yellow Orpiment (As₂S₃), and may have been a common apothecary ingredient of the time. Crystalline realgar is a ruby-like, eye-catching substance and it is not surprising that it captured the fancy of alchemists.

**Source**: Wikipedia. Crystalline realgar, As₄S₄.

**Source**: Wikipedia. Crystalline orpiment, As₂S₃.

Second, realgar and orpiment are found in hydrothermal deposits as are copper, gold, silver, and mercury sulfides (metal sulfides as a group were referred to then by the obsolete term sulphuret). Back when roasting ore was widely practiced (and legal), it was common for miners in American lode gold districts to heap sulphuretted ores onto a wood pile and set it alight directly or air oxidize it in a reverberatory furnace. This process would actually ignite the sulphureted ore and in the case of gold and mercury, release the native metal. The point is that sulphuretted arsenic would be expected to contribute to the combustion process as a reducer of nitrate or just as a spectator fuel.

My understanding of sulfur’s role in gunpowder is that of a low-melting, combustible substance which, when ignited, maintains intimate thermal contact with the solid nitrate and carbon elements, transferring heat to trigger and sustain the deflagration or explosive redox reaction.

In medieval times, before blasting with gunpowder was available, it was common in hard rock mining to fracture rock by creating a large fire adjacent to a rock face to get it hot, then water was splashed on it in an attempt to fracture the hot rock by thermal shock. [In my lonely voice squeaking out from under my rock along the riverbank, I would offer that this activity might have presented the opportunity to discover that some (sulphuretted) minerals were combustible. Alternatively, building a ring of sulfuretted rock around a campfire may have led to the same discovery.]

Imaging Valence-Level Electrons in an Organic Molecule!!

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Just WOW!! A team from Nagoya University in Japan performing synchrotron X-ray diffraction experiments at SPring-8 were able to selectively extract an image of valence level electron density in the amino acid glycine. Did you get that? And guess what they found? The valence electrons were occupying a space the shape of a molecular orbital also derived from computation!! Amazing.

The aerial view of the facility is shown below. Despite the ring being situated on bedrock, the alignment of the magnets in the storage ring is so precise that the moon’s tidal forces can have a measurable impact on the ring’s performance.

Source: Spring-8. Schematic of the overall beamline.

**Source**: Spring-8. There are 62 beamlines coming from the synchrotron storage ring.

The experimental work in question is that of Takeshi Hara, Masatoshi Hasebe, Takao Tsuneda, Toshio Naito, Yuiga Nakamura, Naoyuki Katayama, Tetsuya Taketsugu, and Hiroshi Sawa*, “Unveiling the Nature of Chemical Bonds in Real Space”, Journal of the American Chemical Society, accepted July 10, 2024. https://doi.org/10.1021/jacs.4c05673. As of this writing the full journal citation was not available.

Density Function Theory (DFT) calculations were performed with Gaussian 16, revision A.03.

Below is an illustration by a Riken artist comparing the theoretical valence level molecular orbital (MO) of glycine by DFT calculations and the experimental valence electron density distribution, or VED, collected by synchrotron x-ray diffraction at SPring-8.

*Credit: Reiko Matsushita / RIKEN.* Results from the XRD study of glycine.

If you’ve been through college chemistry, then no doubt you are familiar with atomic orbital theory beginning with Linear Combination of Atomic Orbitals, LCAO. Beyond LCAO is MO theory which goes on to help in the understanding of optical, electronic, magnetic and bonding properties of molecules. In the 1980’s and 90’s commercial software became available (and affordable)

Experimental details from the JACS paper-

Single Crystal XRD Experiments and Structure Analysis.
Single crystal XRD experiments were conducted at BL02B1 beamline in SPring-8, using the quarter-circle diffractometer (Rigaku Co., Japan), with diffraction reflections detected by a two-dimensional semiconductor detector, PILATUS3 X CdTe (DECTRIS Ltd., Switzerland). X-ray energies of 40 and 37 keV were used for Glycine and Cytidine, respectively. Temperature variation was achieved using a helium-gas-blowing device (Japan Thermal Engineering Co., Ltd., Japan). The intensities of Bragg reflections were collected by CrysAlisPro program. Diffraction reflection averaging and crystal structure analysis were performed using SORTAV program and JANA2006 program, respectively. VESTA program was employed for drawing the crystal structure and electron density. The structural analyses of Glycine and Cytidine were performed at 45 and 35 K, respectively. In the present XRD experiments, the
resolution limit of Glycine was d_min = 0.28 Å [(sin θ/λ)max = 1.786 Å⁻¹] and that of Cytidine was d_min = 0.30 Å [(sin θ/λ)max = 1.6565 Å⁻¹]. Accurate determination of structure factor F_cal(K) is crucial for the VED analysis using the CDFS method to obtain phase terms of crystal structure factors. To achieve this requirement, we refined the structure parameters using only high-angle data, a technique known as “high-angle refinement” (Section S1).

VED Analysis Using the CDFS Method. The CDFS method, a technique for directly observing a 3D VED in crystals, employs single crystal X-ray diffraction data obtained from synchrotron radiation. A detailed explanation can be found in previous papers. In this method, the experimental VED distribution is derived by subtracting the calculated core electron density from the experimental total electron density. In both cases, Glycine (C₂H₃NO₃) and Cytidine (C₅H₉N₂O₃), the core electron density corresponds to 1s² orbital density of C, N, and O atoms. Therefore, the phase relationship and distribution of the hybridized orbitals by 2s and 2p should be visible.
DFT Calculation. Theoretical valence orbital calculations were performed using DFT with LC-BLYP functional (μ = 0.47)36 and ccpVTZ basis set by Gaussian 16 Revision A.03 program. The structure parameters determined in the present XRD experiments were used for the calculations (Tables S2 and S5). The structures, orbitals, and electron densities are illustrated using ChemCraft program, while the contour plots are drawn using the VESTA program.

Source: The Sawa paper cited above. The experiment was a single crystal X-ray Diffraction (XRD) study using the very narrow x-ray beam available from the synchrotron ring. The underlined text above reveals that the 1s² orbital electron density was subtracted from the total experimental electron density. This would leave the partially filled 2s and 2p valence level MOs in isolation.

While structural determination by x-ray diffraction has been around for a very long time, what makes this work notable is the detection and imaging of electron density in valence level MOs and the close correlation to computational modeling.

For more information about the SPring-8 synchrotron storage ring, visit their website. The name stems from “Super Photon ring–8 GeV”.

EPA Suspends all US Registrations of Dacthal Herbicide

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The Environmental Protection Agency announced on August 6th, 2024 there would be an emergency suspension on all registrations of the preemergent herbicide chlorthal-dimethyl, or dimethyl tetrachloroterephthalate (DCPA or Dacthal). It has been 40 years since the US EPA has issued such an emergency suspension of registrations. This order has immediate effect.

US patent US2923634A was granted to Diamond Shamrock 1960-02-02 with a single claim-

1. THE METHOD OF CONTROLLING UNDESIRABLE PLANT GROWTH WHICH COMPRISES CONTACTING SAID PLANT GROWTH WITH AN ACTIVE AMOUNT OF DIMETHYL 2,3,5,6-TETRAHALOTEREPHTHALATE.

An early patent claiming the use of DCPA, but not the composition.

**Graphic** and physicochemical data. PubChem. DCPA structure tilted just a bit for clarity. Octanol/water partition coefficient: log K_OW = 4.40 @ 25 °C, water solubility = 0.5 mg/l @ 25 °C, Vapor pressure: 2.5 x 10^-6 mm Hg at 25 °C

The octanol/water partition coefficient, log K_OW, sometimes called Log P, is a measure of how a substance will partition itself between 2 phases, a hydrophilic phase and lipophilic phase. This logarithm is used to give some insight into the type of living tissues a substance will tend to accumulate in on exposure or dosing. A log K_OH of 4.40 represents a ratio (antilog) of 25,119 to 1 favoring the octanol. This indicates considerable lipophilicity.

The industrial manufacture of DCPA is neither complicated nor difficult. The terephthaloyl chloride (pronounced: terra THAL oh ill chloride, soft TH as in “thing”) raw material is used in the manufacture of Kevlar and is readily made in several ways. Whether or not the DCPA manufacturer makes their own or outsources it is not available information. In either case, the terephthaloyl chloride is chlorinated to exhaustion (fully chlorinated) and then the methyl ester is prepared by contacting the chloride with methanol to form the diester (pronounced: DYE ester).

Why does DCPA have 4 chlorine atoms on it? Hard to say exactly what the thinking was, but from the process chemistry perspective forcing 4 chlorine atoms on the ring rather than just 1, 2, or 3 solves the problem of ending up with a dog’s lunch of mono-, di-, tri- and tetrachlorinated compounds in the product mix. Individually, each may have differing potency, selectivity, biochemical mechanisms, and human or environmental toxicological properties. Subsequent environmental and tox studies would be complicated by the potential of 4 analogs each possibly requiring individual testing at some point. Another thing to consider is that single component solids are much more easily purified by crystallization than a solution of solid components. A solution of mixed components can be quickly precipitated by cooling or concentrating, but pulling out one pure solid among many solid close analogs can be difficult and low yielding. Single component products are almost always better for ease of processing.

**Graphics** by John Jacob Jungleheimer Schmidt. The “oyl” fragment of the name indicates the presence of the acid chloride group.

DCPA is a selective non-systemic, or contact, herbicide used for pre-emergence control of annual grasses and some annual broad-leaved weeds. Coverage rates of 6-14 kg/hectare are common.

From PubChem: “/IT IS/ PRESENTLY APPROVED FOR USE ON TURF, ORNAMENTALS, STRAWBERRIES, AND AGRONOMIC CROPS INCLUDING COTTON, SOYBEANS, AND FIELD BEANS. /IT IS/ EFFECTIVE AGAINST SMOOTH & HAIRY CRABGRASS, WITCHGRASS, GREEN & YELLOW FOXTAILS, FALL PANICUM & OTHER ANNUAL GRASSES. /IT IS/ ALSO USEFUL AGAINST CERTAIN BROAD-LEAVED WEEDS SUCH AS CARPET WEED…PURSLANE & COMMON CHICKWEED. /IT IS/ TOLERATED BY MANY CROP PLANTS.”

DCPA is a relatively simple small molecule that is made from cheap and abundant early feedstocks like para-Xylene, Chlorine and Methanol. It has good potency and desirable selectivity in its ability to kill crabgrass in the presence of turf grass. The chemical process steps are well understood, each with a long history of successful use. It can be sold in solid form or in liquid form and may be applied by a large variety of methods. It can be applied for pre-emergence or folial use.

According to EPA “DCPA is a chlorinated benzoic acid herbicide which inhibits cell division of root tips in target plants. It controls many annual grasses and broadleaf weeds in a variety of agricultural crops and ornamental varieties (e.g., broccoli, onions, tomatoes, cabbage, cauliflower, dogwood, azalea). Annual agricultural use from 1998 through 2008 averaged approximately 500,000 pounds over 100,000 acres with broccoli and onions accounting for 79 percent of that use (Ratnayake, 2011). Information also suggests that on average 50 percent of broccoli is treated and 15 percent of onions (SLUA).“

As useful of an herbicide as it may be, it has a dark side that spooked the US EPA into issuing an unusual emergency suspension on August 6, 2024. In particular is the potential toxicity to the unborn and the risk to “post-application workers involved in tasks such as transplanting, weeding and harvesting.” Female farmworkers are at high risk since DCPA has been shown to be toxic to the fetus producing lifelong health problems. The reader is invited to read the link for details in the toxicology. The successive degradation of DCPA is shown below. In addition to hydrolysis, it is also subject to photodegradation in sunlight.

**Graphics** by John Jacob Jingleheimer Schmidt.

Why wasn’t this discovered earlier? I’m not an EPA pesticide guy, but discovering the specific toxicity of herbicides registered many years previously requires some kind of trigger to get an investigation started. Today, other than an overt incidence of toxic effects making the news, that trigger can be the Registration Review Overview conducted by EPA every 15 years for each registered pesticide.

Having interacted with a certain division of the USEPA for the last 3 years, I can say that there are many intelligent and knowledgeable scientists, engineers and other professionals who try to get things done in a very constricted space bounded by layers upon layers of federal laws converted into regulations. They are about as loved as the Internal Revenue Service and, like IRS, are forced to work wildly understaffed and with an IT system that is decades out of date. A doff of the hat to EPA.

Reuters Receives Raw Materials for Fentanyl

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The news service Reuters recently published an article on the ease with which the raw materials for the production of the opioid Fentanyl. From their $3600 expenditure on raw materials they estimate they could have produced $3 million worth of Fentanyl.

For an estimated 74,702 Americans in 2023, Fentanyl provided them with a narcotic experience prior to death. The lethal dose is reported to be 2 milligrams for an adult. It is 20 to 40 times more potent than heroin.

Outside of medical use Fentanyl should be described as a highly (neuro)toxic substance rather than just an opioid. Yes, it is an illegal narcotic, but it is also a potent deadly poison. Hidden with other illegal drugs in pill form, it is just a highly toxic contaminant.

On January 5, 2024, I posted a piece titled “A Bit of Fentanyl Chemistry” which is reproduced below. It turns out that the Janssen synthetic chemistry I wrote about then is quite close to what the investigators at Reuters had in mind for their story. In the world of chemical commerce, a process using easily available raw materials is highly favored.

My take-home message from the Reuters story is that unless China seriously clamps down on those who export the raw materials, all that is left to do is to suppress demand. The import of Fentanyl raw materials is aided by deceptive packaging and small quantities needed. Worse, Fentanyl raw materials have other uses in pharmaceutical chemistry and are too useful to completely shut down. The death and incarceration that Fentanyl can bring in the US does not appear to be sufficiently convincing to the at-risk American population. Nothing new here.

=========================

A recent raid on a clandestine drug lab in the Hatzic Valley east of Vancouver, BC, netted 25 kg of “pure” fentanyl and 3 kg which had already been cut for street use. Precursor chemicals used to manufacture the fentanyl were also seized. Along with the drug, the raid also seized 2,000 liters of chemicals and 6,000 liters (about 30 drums) of hazardous chemical waste, according to an RCMP news release 2 November, 2023.

The police said that the seizure represented 2,500,000 street doses.

In August of 2023 the police in Hamilton, Ontario, announced the results of Project Odeon. This was a large-scale sweep of illicit drug production in the Hamilton and Toronto area. From January 1, to July 30, 2023 there were 606 incidents related to suspected opioid overdoses and 89 suspected drug related deaths in the Hamilton area. Twelve people were charged for a total of 48 criminal charges. The police disclosed the following items that they seized-

An operational fentanyl drug lab at 6800 Sixteen Road, Smithville.
A dismantled fentanyl drug lab at 4057 Bethesda Road, Stouffville.
Approximately 3.5 tons of chemical byproduct from fentanyl production.
800 gallons of chemicals commonly used in the production of fentanyl
Lab equipment commonly used in the production of fentanyl
64.1 kg of illicit drugs, including 25.6 kg of fentanyl, 18 kg methamphetamine, 6 kg of ketamine
A loaded, Glock firearm and ammunition and four extended magazines
Over $350,000 of seized proceeds, including cars, jewelry, furniture and cash

Fentanyl is a synthetic drug first prepared in 1959 in Belgium by Paul Janssen (1926-2003). Janssen was the founder of Janssen Pharmaceuticals, now a subsidiary of Johnson & Johnson. In addition to fentanyl, the Jenssen team developed haloperidol, the ultrapotent carfentanil, and other piperidine based congeners. Piperidine itself is a DEA List 1 substance in the US.

Carfentanil is just modified fentanyl. **Graphics**: Will O. de Wisp

The elephant in the room with fentanyl is its extraordinary potency as an opioid. In pharmacology, potency is a quantitative measure of the amount of dose needed to elicit a specific effect on an animal or human in terms of dose weight per kilogram of body mass. Potency is subject to variability across a population and rises to an asymptote which can be difficult to pin down. For these reasons potency is reported at 50 %. For highly potent drugs like fentanyl, the measure is expressed as milligrams or micrograms of dose per kilogram body weight (mg/kg or mcg/kg body weight). One milligram per kilogram is one part per million (ppm).

When matters of toxicity arise, it is important to remember the maxim that “the dose makes the poison”. This observation traces back to Paracelsus in the mid-sixteenth century.

“All things are poison, and nothing is without poison; the dosage alone makes it so a thing is not a poison.”
– Paracelsus, 1538. Source: Wikipedia

Fentanyl acts much like morphine in regard to its affinity for one particular opioid receptor. Morphine is commonly the “standard” with which other opioids are compared. For instance, fentanyl is said to be 50-100 times more potent than morphine. Only 2 mg of fentanyl is equivalent to 10 mg of morphine. Carfentanil is more potent still at 10,000 times the potency of morphine.

Morphine is an agonist which activates the μ-opioid receptor. Activation of this receptor with morphine produces analgesia, sedation, euphoria, decreased respiration and decreased bowel motility leading to the earthly delights of constipation. Fentanyl is thought to interact with this receptor as well.

Original fentanyl synthesis by Janssen. **Graphics**: Will O. de Wisp

So, how is fentanyl synthesized? See the synthetic scheme above. I’ll just comment on the Janssen synthesis and some issues. I have no idea of how it is made out in there by the Mexican cartels and in ramshackle American trailer parks. The synthesis above has some steps that may be undesirable for backwoods or jungle operations like hydrogenation. In the first step, aniline will be needed to make the phenyl imine. It’s pretty toxic and stinks to high heaven. Next, lithium aluminum hydride is needed to reduce the imine double bond to an amine. This innocent looking grey powder is very hazardous and should only be used by an experienced chemist. It is also available as a solution in tetrahydrofuran. The next step is the formation of the amide with propionic anhydride. While the reaction entails a simple reflux, you still have to isolate the product. Once you have recovered the amide, the benzyl protecting group on the piperidine nitrogen must be removed. It allowed amide formation exclusively on the upper aniline nitrogen and has served its purpose. Finally, the piperidine nitrogen must be festooned with a phenylethyl group and phenylethyl chloride was used to afford the fentanyl product.

An excellent review of the pharmacology and drug design of this family of opioids, see Future Med Chem. 2014 Mar; 6(4): 385–412.

In chemical synthesis generally, substances are prepared in a stepwise manner and with as few steps as possible to give high isolated yields. To begin, one must devise a synthesis beginning with commercially available raw materials as close to the target as possible. If the product has many fragments hanging off the core structure, it’s best to solve that problem early. Synthetic chemistry is almost always performed in a non-interfering solvent that will dissolve the reactants and allow the necessary reaction to occur. A low boiling point is preferable for ease of distillation. An important side benefit from a solvent is that it will absorb much of the heat of reaction which can be considerable. Left on its own, a reaction might take its solvent to the boiling point by self-heating, generating pressure and vapor. The benefit from evaporation or reflux boiling is that as a solvent transitions from liquid to vapor there is a strong cooling effect which helps to control the temperature. An overhead condenser will return cooled solvent to prevent solvent loss.

You can do any chemical synthesis in one step with the right starting materials. Unfortunately, this option is rarely available. The next best option is to take commercially available starting materials through a known synthetic scheme. People who run illicit drug labs are never interested in R&D. They want (and need) simple chemistry that can be done by non-chemists in buckets or coke bottles at remote locations. Chemical glassware can be purchased but sometimes the authorities will be notified of a suspicious order. This is especially true with 12 liter round bottom flasks.

The most difficult and risky trick to illicit drug synthesis is obtaining starting materials like piperidine compounds in the case of fentanyl and its congeners. In the case of heroin, acetic anhydride shipments have been investigated for a long time because it is used to convert morphine to heroin- an unusually simple one-step conversion. Solvent diethyl ether is similarly difficult to get outside of established companies or universities. Many other common drug starting materials are difficult to obtain legally in the US or EU by the criminal element. However, China is thought to be a major supplier of starting materials outside the US and EU. Countries with remote coastlines, loose borders, lackadaisical or corrupt law enforcement reduce the barriers for entry of drug precursors.

China in particular has a large number of chemical plants that make diverse precursors for legitimate drugs. Unfortunately, some of these precursors can also be used for illicit drugs or existing technology adapted for this use. Precursors can be sold to resellers who can do as they please with them. Agents may represent many manufacturers and can mask the manufacturer’s identity and take charge of the distribution abroad. Shady transactions become difficult for authorities to detect and trace. The identity of illicit precursor chemicals are easily altered in the paperwork to grease the skids through customs. Resellers can repackage chemicals to suitable scale, change the paperwork and jack up the price for export. It has been my experience that many if not most Chinese or Japanese chemical manufacturers conduct business through independent export agents. However, behind the curtains there often a byzantine web of connections between companies and agents, so you may never know who will manufacture your chemical. As an aside, this complicates getting technical information from the manufacturer since the agent will not disclose a contact at that manufacturer.

Highly potent drugs like fentanyl must be taken in very small dosages which means that kilo-scale batch quantities of drug result in many individual sales per kilo. Small quantities of highly potent drugs are more easily smuggled than bulky drugs like weed with its strong odor.

There is a down-side to the illicit manufacture of drugs like fentanyl. It is quite toxic at very low dosages and must be handled with the greatest of care lest the “cook” and other handlers get inadvertently and mortally poisoned. Good housekeeping helps, but I have yet to see a photo of a tidy drug lab.

Fentanyl can be sold as a single drug but perhaps is cut with a solid diluent that some random yayhoo decided was Ok to use. Other drugs of abuse like heroin may be surreptitiously spiked with fentanyl to kick up the potency. In either case, a given dosage may or may not be safe even for a single use. There is no way for a user to know. Also, the concentration or homogeneity of mixed solids may be subject to wide variation. For more than a few people, their first fentanyl dose will be their last.

Chemicals on My Yard: Prodiamine and Dicamba

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In the US, it’s common to enhance one’s home with greenery, notably a grass lawn. However, a lawn requires ongoing attention. I have a lawn care service fertilize and treat our lawn with herbicides throughout the growing season. Recently, I’ve scrutinized the herbicides they use. They used prodiamine and dicamba.

Hold on a minute. Wasn’t the 2020 registration of dicamba nullified recently in federal court? Yes, it was. Why has it been sprayed on my lawn? The ruling applies to the use of dicamba on soybean and cotton crops that have been genetically modified to be resistant to it. The high volatility of dicamba has been quite deleterious to crops in adjacent farmland and to plants that are pollinated by bees because of drift resulting in crop losses and sharp decrease in honey production. Dicamba is a broadleaf herbicide, though not effective against grasses.

A Brief Meteorological Interlude

Nature continually directs hostility towards our lawns and gardens, both from above and the sides. Living in a semi-arid climate with only 14 inches of annual moisture, the lack of precipitation is immediately detrimental. The desiccating rays from the sun, located only 8 light minutes away, evaporate vital moisture from plants and soil. Compounding the problem, dehydrating winds whisk away the moisture cooking off the soil. Since moist air is more buoyant than dry air, it rises and is carried away by convection into the prevailing winds.

At higher elevations, the combination of increased moisture and decreased temperature can lead to cloud formation. Moisture ascending from the ground combines with the air above. The lower temperatures at these heights cause the moisture to transition from a gaseous to a liquid state, resulting in clouds. This change, although it appears innocent, has thermal consequences. For humidity to condense into liquid, the surrounding air temperature, which reveals “sensible” heat, must be low enough to absorb the “insensible” or latent heat released during condensation without causing a significant rise in temperature. If not, an increase in temperature would hasten the shift from condensation back to evaporation. There is a delicate equilibrium in this phase transition.

As latent heat is released, the air’s density decreases, enhancing its buoyancy and causing it to rise further. The ascending misty air cools, allowing more moisture to condense, which adds to the cloud’s mass. But wait, there’s more—

A rising air parcel causes the surrounding air to be drawn inward from below towards the ascending convective column. Consequently, a significant volume of air may be uplifted, enhancing the moisture levels above the ground contributing to the formation of a convective cumulus cloud. Latent heat supplies part of the energy needed for the vertical ascent of air. This cycle persists until a net downward movement of rain occurs, pulling down cooler air from higher altitudes. The cessation of upward momentum in cloud formation leads to a rapid downward surge of air with the rain, which, upon reaching the ground, spreads out horizontally, occasionally at high speeds. This explains why cool gusts of wind often signal the approach of a rainstorm.

Prodiamine

On to Prodiamine and Dicamba. These two herbicides provide broad coverage by virtue of different biochemical mechanisms. Dicamba is a selective postemergent broadleaf systemic herbicide.

Prodiamine is a pre-emergent herbicide effective on crabgrass and annual blue grass, goosegrass, spurge, chickweed. A pre-emergent herbicide like prodiamine is injected into the soil where it binds to soil particles. A close analog called Trifluralin, prodiamine without the NH₂ group, has been shown to have sufficient volatility that sufficient vapor can penetrate root tissue where it expresses its activity.

**Source**: Jinyi Chen, Qin Yu, Eric Patterson,Chad Sayer, Stephen Powles,” Dinitroaniline Herbicide Resistance and Mechanisms in Weeds”, *Front. Plant Sci.,* *Sec. Crop and Product Physiology*, 24 March 2021 Volume 12 – 2021 | https://doi.org/10.3389/fpls.2021.634018.

Prodiamine was invented by Sandoz and went to market in 1987. In 1996 Sandoz merged with Ciba-Geigy to form Novartis. In 2000 Novartis spun out its agrochemicals and genetically modified crops business and with AstraZeneca formed Syngenta, which is now part of the Syngenta Group, purchased by Sinochem in 2017.

**Graphic**: By Sam Scratch. A series of Dinitroaniline root inhibitors.

Comments on Patenting of Chemicals

When a biologically active substance is discovered, usually is the case that particular features and the shape of the molecule are crucial to the activity. Not just attachments but also the spatial relationship between them. The subject molecule is likely to be active in interacting with a pocket on an enzyme. That pocket has a particular 3-D shape that the molecule has to fit. Not only that, but the enzyme pocket is likely to have protein amino acid groups that have an affinity for charged or water insoluble features on the incoming molecule.

Looking at the prodiamine structure and analogs above, we can see that all of the analogs share certain features: two Nitro groups, -NO₂; 1 Aniline nitrogen group with one or two hydrocarbons attached, -N(hydrocarbon)₂ groups; a single 6-member hexagon ring (a benzene ring) from which to hang all of the appendages. Opposite to the top aniline nitrogen is an attachment present which 4 of the 6 analogs have: a -CF₃ (trifluoromethyl) group attached. This doesn’t happen by accident- someone decided that it should be there because something useful happens with it there. A -CF₃ group acts to pull electrons in the ring to lean in that direction, affecting how the electron charge is distributed on the whole molecule. Another analog has a -S(=O)₂-NH₂ group. This thing, called a sulfonamide group, also pulls ring electrons towards it. Why -CF₃ versus -S(=O)₂-NH₂? Perhaps one is more potent or selective than the other or possibly because one was claimed in a patent and at the time the other was not. Either one could be a me-too herbicide. Analogs of a basic motif arise frequently in a competitive marketplace.

Often times, when a new and successful motif of pharmaceutical or agrochemical comes along, the race begins for competitors to develop close analogs, though being careful not to infringe on any patents. With chemical patents the composition of matter can be claimed, the method for making the substance as well as the method of use. Composition of matter, method of manufacture and use claims are often split into separate patents for IP safety in case one patent gets knocked down. What’s more, a composition of matter patent can be written so as to claim a vast number of analogs to broaden the IP real estate. This is called a Markush claim where a variable letter substitutes for a large or small set of chemical groups. A single structural framework can have many Markush groups giving rise to an astronomically large set of claimed combinations. Some companies, hide the composition of the best analogs in the Markush claims so as to minimize competitive intelligence losses to competitors.

Dicamba

A weed is a valueless plant growing wild that is in competition with a desired crop. The three major morphological categories are: grasses, sedges, and broadleaf weeds. A weed represents lost soil fertility.

Dicamba is a member of the benzoic acid subgroup of the aromatic carboxylic acid group of herbicides. This group of compounds are synthetic auxins, or plant hormones, that interfere with plant growth.

**Source**: Robin Mesnage, Michael Antoniou, “6 – Mammalian toxicity of herbicides used in intensive GM crop farming”, *Herbicides: Chemistry, Efficacy, Toxicology, and Environmental Impacts, Emerging Issues in Analytical Chemistry*, **2021**, Pages 143-180. https://doi.org/10.1016/B978-0-12-823674-1.00007-9.

Other popular herbicides

Other carboxylic acid herbicides besides dicamba are the 2,4-D analogs.

**Graphics**: Sam Scratch. The much-dreaded toxicant dioxin (TCDD) was a side product in the manufacture of the herbicide 2,4,5-T. When 2,4,5-T was blended with 2,4-D to make agent orange, the dioxin came along.

Of the numerous forms of the dioxins, the species that is often discussed is the 2,3,7,8-TCDD version. The positions and number of chlorine atoms varies. The mechanism above shows the dioxin analog coming from 2,4,5-T. The 3-ring structure of TCDD is the dioxin core structure.

**Graphics**: Sam Scratch. How dioxin was formed in the 2,4,5-T process. The chemical mechanism begins with the displacement of 1 chlorine atom of the 1,2,4,5-tetrachlorobenzene by a hydroxide anion turning the tetrachoro ring into 2,4,5-trichlorophenol. In the presence of NaOH, the phenol turns into a phenolate which attacks the chloroacetic acid to form 2,4,5-T. However, a competing reaction involving the trichlorophenolate attacking another molecule of itself over a few steps can lead to the cyclization of the trichlorophenolate to the 2,3,7,8-TCDD. The displacement of a ring chlorine is somewhat slower than the displacement of a chlorine from acetic acid, so dioxin formation would be a minor side product.

2,4-D is a synthetic auxin, similar to dicamba in mechanism, that causes uncontrolled and unsustainable cell growth. The herbicide is absorbed through the leaves and is moved to the meristem where uncontrolled cell growth follows.

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Chemicals on My Yard: Prodiamine and Dicamba