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About gaussling

Gaussling is a senior scientist in the chemical business. He occasionally breaks glassware, spreads confusion and has been known to generate new forms of hazardous waste. Gaussling also digs aerospace, geology, and community theatre.

18F-Glucose

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The story of PET, Positron Emission Tomography, has evolved over decades of advancement. To begin, tomography, detectors and computers had to be invented. Separately, positron emission as a medically viable radiation source had to be identified and validated. Positron decay occurs when a neutron deficient nucleus emits a positron and a neutrino to convert a proton to a neutron. This brings the p/n ratio to a more stable state.

A substance for delivering a dose of isotope must be found. In the case of 18Fluorine, it is prepared as an inorganic salt like K18F or elaborated as an organic molecule like 2-deoxy-2-[18F]fluoro-D-glucose.

How did it come about that the 18Fluorine in the position where it is? I’ve not found mention of this in the literature so far. Looking through Chem Abstracts I have noticed there are numerous synthetic pathways leading to fluorine at that position. Could it have been placed there because research found that it was most biochemically similar to glucose? Or was it the more mundane reason that fluorination at position 2 gave the best yields and purity or was the cheapest and easiest to make?

18F has replaced the oxygen (OH) group at position 2 of glucose, thus the prefix “2-deoxy-2-[18F]fluoro-“

There are recent radioligand compounds that are used as PET (Positron Emission Tomography) diagnostic agents which selectively bind to the prostate specific membrane antigen receptor where they can undergo positron emission revealing the site of prostate cancer cells. 18F-glucose was first synthesized in 1967 in Czechoslovakia at Charles University by Dr. Josef Pacák and was first tried as a radiotracer by Abass Alavi in 1976 at the University of Pennsylvania on volunteers. PET scanning came along later. Cancer cells consume glucose a bit faster than normal cells so the 18F-glucose will tend to accumulate to a slightly greater extent and reveal their position by positron annihilation. This yields two 511 keV x-rays 180o apart and is identified by a ring coincidence detector. A single detection event is discarded.

Today, 18F-glucose is being superseded by many 18F PET preparations that are designed to interact with specific receptors. This interaction is called “conjugation”. In the case of Prostate Cancer there is PSMA, Prostate Specific Membrane Antigen, targeted by Pylarify (piflufolastat F 18) which is designed to bind with fatty acid binding protein 3 (FABP3). I just received a 6 millicurie (222,000 Becquerel) intravenous dose of this positron emitter just today for a PET/CT scan.

Synthetic Strategies Affording 18F-glucose

First, I have to say that the name 18F-glucose is a bit of a misnomer in that it is not glucose nor did it ever even start out as glucose. It is a 2-deoxy-2-18fluoro analog of D-glucose. It originates from D-Mannose whose OH groups were specially protected from side reaction by capping 4 of them with acetyl (Ac) groups and carrying away the hydrogens. The OH at position 2 of the D-Mannose precursor is converted to a triflate (OTf).

In chemical synthesis there is usually more than one possible strategy for getting to a target molecule. In the case of 18F-glucose, whatever pathway we choose must be rapid and efficient owing to the very short half-life of the 18F. The preparation must be done in as few half-lives as possible.

When it comes to a great many sugar derivatives, synthesizing them from scratch is just crazy. They are structurally and stereochemically complex. They have numerous hydroxyl groups in chemically different locations on the molecule and selective modification of one and not another can be quite involved. The world is awash in sugars (e.g., sucrose, starch and cellulose) from natural sources and many varieties are commercially available for developmental use. Better to adapt available sugars for modification than starting from earth, air, fire and water.

Source: Gaussling.

Getting 18F attached to a sugar can go along on one of two basic strategies- electrophilic addition of fluorine or nucleophilic addition. The first is called “electrophilic” addition where electrophile means “electron loving”. In electrophilic addition, the 18F reagent must be electron deficient requiring that the intended carbon skeleton is relatively electron rich. Electron rich means that there are oxygen or nitrogen atoms present with their lone-pair electrons, or pi-bonds present with their off-axis pi-electrons. Equations (a) and (b) below show two examples of electrophilic addition of 18F to a sugar analog.

The fluorinating reagents are (a) 18F enriched F2 and (b) acetyl hypofluorite, [18F]AcOF. Both fluorinating reagents feature fluorine atoms that are electron deficient and therefore electrophilic. Atomic and molecular fluorine are by nature quite electrophilic, but negatively charged fluoride is nucleophilic.

Source: Cole EL, Stewart MN, Littich R, Hoareau R, Scott PJ. Radiosyntheses using fluorine-18: the art and science of late stage fluorination. Curr Top Med Chem. 2014;14(7):875-900. doi: 10.2174/1568026614666140202205035. PMID: 24484425; PMCID: PMC4140448.

Nucleophilic addition of 18Fluoride is shown in reaction (c) wherein the OTf group is installed specifically to be displaced from the back side by 18F anion. A “nucleophile” is an attacking species that is able to bond directly with a carbon nucleus by virtue of having a lone pair of electrons available for bond making. A nucleophile is frequently negatively charged but can also be neutral in some cases.

The general strategy for the nucleophilic substitution synthesis of 18F-glucose is this: Protect all of the hydroxyl groups of D-Mannopyranose as an acetate except for one which serves as a “leaving group“. This leaving group is called a trifluoromethanesulfonate, or just “triflate“. This triflate is then displaced by 18Fluoride anion by an SN2 substitution. In plain English, 18Fluoride anion forms a C-F bond as the triflate anion is breaking its C-O bond in a process called nucleophilic substitution.

Oh, one more thing. The 18fluoride anion(-) must be made more reactive by keeping the inhibiting potassium cation (K+) in a “cage” so it can lose some of its electrostatic attraction to the negatively charged 18fluoride. Strong electrostatic attraction of K+ to 18F– will impede fluoride’s aptitude for triflate displacement. See below for Kryptofix 222. K+ wrapped in neutral Kryptofix 222 is called a “weakly coordinating ion”.

Ok, so there are some funny things you ought to know about this substitution business on a 6-member ring. Hydrogen atoms are not drawn because it is a pain. First, carbon always wants to have 4 bonds to it and oxygen just two bonds. Second, a 6-carbon ring with all single bonds can be twisted into several shapes or conformations. One of them is favored by virtue of having the least “strain” in it. That would be the “chair” conformation. It looks vaguely like a lawn chair.

Source: Gaussling. Shapes that cyclic, 6-carbon rings can take. In reality, the rings flip back and forth across the different conformations, but they tend to spend the most time in the lowest ring strain shape which is the chair.

Selective chemical synthesis happens only because some reaction pathways are fast while others are slow. Some possible reaction pathways are so slow that effectively they do not happen.

Making 18F

The 18F isotope does not exist in nature due to its 1.83 hour half-life. It decays by positron and neutrino emission to stable 18O. 18F must be prepared by slamming a suitable precursor nucleus with a nuclear particle like a proton or a deuteron with a cyclotron or linear accelerator. Yes, commercial cyclotrons are available for purchase.

Some Sugar Facts

What helps when thinking about sugars is to detach them from the matter of sweetness. Sugars are far too diverse and important to get hung up on sweetness.

Look at the blue O-H groups on the α-D-Mannopyranose and compare it to the  α-D-Glucopyranose shown above. See how they are hanging on the ring? One is directed up and the other is pointing outward and down a bit. This simple inversion in orientation produces the chemical difference between the two sugars making them distinctly different chemical substances.

Source: Gaussling. How the 18-Fluorine gets attached to a sugar. D-Mannose is first derivatized by capping off 4 of the hydroxyl groups as acetates, OAc, and one as a triflate, OTf. 18-Fluoride backside attack will displace the triflate, –OTf. Of the –OTf and the –OAc, the –OTf is displaced much faster. The faster pathway dominates. The Ac groups are removed from their oxygens by base hydrolysis leaving OH groups on the ring behind. This results in the 18Fluorinated glucose.

In the reaction scheme above the 18F– is shown displacing the –OTf group from below, establishing a C-18F bond and causing the C-H to flip to the upper side like an inverting umbrella. The scheme is only partially correct. What isn’t shown is the positive counterion to the 18F– anion. The fluoride must be charge balanced by a positive ion which could be just a theoretical bare-naked ion or solvated potassium ion, K+.

In solution, ions or dipolar molecules interact with solvent molecules by Van der Waals forces or stronger dipolar influence. Going down the Group 1 elements on the periodic table from Lithium to Francium, all form 1+ cations, but also the radius of the ion increases. If you think of the ionic radius as being the distance from the nucleus to the distance that a solvent molecule can bump into, the Van der Waals radius, then as we drop down Group 1, a square picometer of “surface” of the ion carries less and less of the cationic charge at any given moment. This means that attractive or repulsive forces with that square picometer diminish as we go down the group, thus lowering the attractive forces. Very often potassium cation is acceptable, but it can be helped along.

While much of the time K+ is sufficiently non-interfering, but as happens occasionally the fluoride anion tends to bind to the potassium cation a bit too tightly. This can substantially slow the rate of transfer of 18F anion to the carbon of the sugar ring. To get around this, either the potassium must be replaced with another more charge diffuse cation like tetrabutylammonium+ or cesium+, the K+ can be “wrapped” in a protective organic “jacket or shield” that will prevent the K+ and the 18F– ions from getting too close to one another and bound too tightly. We would call the protected K+ a non-interfering or charge diffuse cation.

The cyclic amino polyether “ligand” that is used in this case in Kryptofix [2.2.2]. The single positive charge of the K+ is somewhat spread over the surface of the much larger Kryptofix [2.2.2]-potassium complex and diffuses the positive charge. This has the effect of “separating or loosening” an otherwise tight ion pair (K+F–) in solution. Once detached from potassium, the 18F– ion is able to react much faster to form the 18F-Glucose.

18F-Glucose must be synthesized in a radiopharmacy, also called a nuclear pharmacy, nearby the point of administration to the patient given its very short half-life. The 18F is produced in a commercially available cyclotron or linear accelerator either by proton bombardment of stable but scarce 18O enriched water or by deuteron bombardment of the stable isotope 20Neon.

18F-glucose is a sugar and undergoes metabolic trapping by phosphorylation with hexokinase inside the cell, giving it a phosphate group with a negative charge, inhibiting its transport to outside the cell. This allows the phosphorylated 18F-glucose to accumulate inside the cell, concentrating 18F to release more positron decays from the cell.

Frequently Wrong but Never in Doubt

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America’s boob of an ex-president #45 is now grandstanding in the bible business. You know, the guy who said out loud that grabbing women by the p#$$/ has been a successful “dating” strategy for him. He has recently been hawking trading cards, golden sneakers and now an unsuccessful social network. While his worth on paper went up by several billion overnight, it seems to be driven by his fanbase and not by business fundamentals. Stocks go up and stocks go down. Many public offerings start strong and peter out rapidly.

Through the magic of nepotism his daughter-in-law is co-chair of the RNC, guaranteeing the flow of GOP money towards his campaign and legal fund. Between this and the evangelical preachers bloviating every Sunday on hero #45, his support has become the eternal dumpster fire of American politics.

The business failures of #45 are numerous and are easily found on the Google. Despite the lies, civil suits, criminal indictments, encouragement of stochastic terrorism and support of a great many shady characters many of whom are now in prison because of their connection to him, he continues to bank support from millions of admirers. It’s a real phenomenon.

American is the land of opportunity where a huckster can lie his way to become president. Say amen!

Radiopharmaceuticals with 68-Gallium

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Prologue: What follows is a look at the use of 68Gallium as part of a positron emitting radioligand from an organometallic chemist’s point of view. I’m not from nuclear medicine nor am I a radiation oncologist.

It had to happen … the other shoe has dropped. My stage-4 prostate cancer has come charging back for round 2 after 9 years. Again, I’ve taken a personal interest in radiation oncology. Recently, my PSA shot up steeply through the 4.0 ng/dL threshold triggering an appointment with my radiation oncologist who has ordered a PET/CT scan. Back in 2015 I finished 18 months of hormone ablation (chemical castration) and got the PSA from 29 down to 0.01 with Lupron injections and earlier, a large cumulative dose of x-radiation in the lower abdomen. I have to say that while I experienced no discomfort at all in this round of treatment, I did lose body hair and muscle mass.

PET/CT scanning is an important tool in locating prostate cancer cells. Riding the platform in and out of the scanner is expensive but important. Unfortunately for me, the CT contrast agent is a potent emetic so the scanner becomes an expensive vomitorium ride.

The story of PET, Positron Emission Tomography, has evolved over decades of advancement. To begin, tomography, detectors and computers had to be invented. Separately, positron emission as a medically viable radiation source had to be identified and validated. A substrate for selective delivery of the isotope must be found. In the case of 18Fluorine, it is available as an organofluorine molecule like 18F-Glucose. It turns out that the 18F-Glucose concentrates in clinically useful places and K18F does not.

Positron Emitters

Atomic nuclei that are deficient in neutrons can have an instability leading to emission of a positron (anti-electron with a + charge), also called a β+ decay, which lessens the neutron deficiency by ejecting a positive charge from the nucleus. When a positron is ejected from the nucleus it finds itself immediately swarmed by the electron clouds of surrounding atoms and molecules and doesn’t travel very far. When a positron encounters a negatron (regular electron, β−), they annihilate one another and emit two gamma photons of 511 keV energy at 180 degrees apart. This is a mass to energy conversion. Loss of one positive charge from the nucleus gives rise to a transmutation of the atom causing a one-unit drop in atomic number, that is it goes from n+ to (n – 1)+, but retains most of its atomic weight. In this case, 6831Gallium undergoes positron decay to 6830Zinc.

Positron emitters include 11Carbon (T1⁄2 = 20.4 min), 13nitrogen (T1⁄2 = 10 min), 15oxygen (T1⁄2 = 2 min), 18fluorine (T1⁄2 = 110 min), 64copper, 68gallium, 78bromine, 82rubidium, 86yttrium, 89zirconium, 22sodium, 26aluminium, 40potassium, 83strontium, and 124iodine. This a list given by Wikipedia, but there are many more in more comprehensive tables.

The actual mechanism of β-type emission requires a venture into fundamental particles called quarks. Protons and neutrons are composite particles called hadrons, not fundamental particles. Protons and neutrons are each comprised of 3 quarks, but with a different combination of “up and down flavors” where flavor refers to the species of quark. There are 6 flavors of quarks: up, down, charm, strange, top, and bottom. Interconversion between protons and neutrons can occur if one of the 3 top or bottom quarks changes flavor. By all means, if this interests you, take a dive into it. I shall stop here.

Beta emission diagram at quark level.

Positron emitters tend to have a short radioactive half-life as well as a limited chemical half-life in the body before they are cleared out through the kidneys or other routes. Ideally, the goal is to deliver a high radiation dose selectively to a target tissue as fast as is safe then disappear. Prolonged irradiation to surrounding tissue is undesirable. The optimal radiopharmaceutical will be highly target selective and have a short half-life. A selective radiopharmaceutical is one that will accumulate in a desired cell type or organ. Accumulation can be aided through simple solubility, the ability to undergo transport through a cell wall, affinity to a specific receptor and the ability to function fast enough to resist the various clearance mechanisms.

A short half-life means that the radioactivity per gram of radioisotope, specific activity in Becquerels per gram, will be at its maximum after activation. Though the radioactivity may be intense, the radiation dose can be controlled by the amount of mass administered. With radioisotopes, there are two kinds of purity to consider: Chemical purity referring to the atoms and molecules present; Radiological purity referring to the presence or absence of other radioactive isotopes. To provide maximum safety and effectiveness, the specific radioisotope with the desired decay mode should be the only source present. If your desired source is an alpha emitter, you don’t need spurious quantities of a gamma emitter present because of inadequate purification.

Economical methods of preparing positron emitters had to be addressed. To fully exploit PET for any given situation, tissue selectivity of radioligands had to be determined and selective positron radiopharmaceuticals developed. Due to the short half-life of these radioisotopes, rapid and safe methodologies to produce them by efficient nuclear transformations, isotope isolation followed by chemical synthesis had to be developed. It is important that isotope generation, isolation and attachment to a ligand be done nearby the hospital for the proper activity to reach the patient.

Positron emitter production involves a nuclear reactor for neutron activation or a cyclotron accelerating protons or deuterons in the preparation. Because both of these sources are highly destructive to organic molecules, an inorganic radioisotope is produced separately and chemically modified to produce an inorganic species that can be chelated or otherwise attached to a radiopharmaceutical. This technique evolved from simple radiography in the 1930’s to a large array of techniques and applications today. The reader is invited to take a dive into this topic.

Since my cancer experience began, a few new radiotherapies and imaging agents have landed in oncology space for prostate cancer. Recently I posted on Pluvicto PSMA (Prostate Specific Membrane Antigen) which was before I knew about my current prostate situation. PSMA is a transmembrane protein present in prostatic cells. Pluvicto uses a chelated 177Lutetium beta emitter as the destructive warhead and a peptidomimetic fragment for binding to the PSMA receptor.

A Brief Interlude into Quality Factor

It should be noted that the various forms of particle (alpha, beta, or neutron) or electromagnetic radiation (x-ray or gamma) have differing abilities to penetrate and cause ionization of within matter. There is a factor for this which is used to refine dosage calculations. It is called the Quality factor, Q.

The destructive effects of radiation stem from its ability to ionize matter along its path. Ionization is a disruptive effect that may result in fragmentation of molecules or crystal lattices into reactive positive or negative ions. Single electron radical species may be formed as well. It is possible for some fraction of the disrupted molecules to recombine if the fragments haven’t already diffused away or gone on to further transformations.

The deleterious effects of radiation on living tissue stems from the amount of disruptive energy transferred to tissues along the path of each particle. Charged particles like electrons, protons and alpha particles tend to dump their energy into matter rapidly and along a short path making them less penetrating than neutrons or electromagnetic rays in general.

Quality factor, Q, is a dimensionless coefficient that is multiplied by an absorbed dose to give a more realistic estimation of radiation energy absorption. Interestingly, the Q for neutrons varies with energy and rises to a maximum around 0.5 to 1 MeV of energy and falls off at higher energies.

The larger the Q factor, the larger the corrected radiation effect. X-, gamma, and beta radiation have a Q factor lower than the others by a factor of 10 to 20. The x- and gamma rays will tend to pass through matter leaving a small amount of their energy to disruption. In radiation therapy this is compensated for by just increasing the fluence or the exposure time.

Source: U.S. Nuclear Regulatory Commission

For clarity, x-rays are generated from the electron cloud around an atom via electron transitions. For instance, if an electron is dislodged from an inner, low energy orbital, another electron can occupy that vacancy by the emission of an x-ray. Gamma rays originate from nuclear energy transitions. Often a nuclear decay might result in a new nucleus that is not at its ground state and would be categorized as metastable. This metastable state, which has its own half-life, can collapse to its ground state by the emission of a gamma ray matching the loss of energy by the nucleus.

Neutrons

Free neutrons are special. They undergo beta decay with a short half-life outside the nucleus having t1/2 = ~ 10-15 minutes, depending on the information source. Not having a charge, they tend to be more penetrating than other particles. However, effective shielding can be had with a hydrocarbon like paraffin or water by virtue of the high concentration of hydrogen nuclei present in these substances. Neutrons are not affected by charge repulsion from an atomic nucleus and therefore can collide and interact with the hydrogen nucleus (a proton). They can scatter from hydrogen nuclei, leaving behind some of their kinetic energy with each collision (see “Neutron Lethargy“). This scattering is the basis for using water to moderate the neutrons in a nuclear reactor. Neutrons are cooled by repeated collisions with hydrogens in water to the point where their kinetic energy of 0.025 eV, which from the Maxwell-Boltzmann distribution corresponds to a temperature of 17 oC, thus the term “thermal neutrons“.

Many elements absorb neutrons, increasing the atomic weight and very often altering the stability of the nucleus leading to a radioactive decay cascade. This is what is happening in neutron activation. In the case of water, the ability of free neutrons to collide with hydrogen nuclei allows them to dislodge hydrogen ions or free radicals from organic and biomolecules resulting in ionization and makes them quite hazardous to living things.

Radioligands

Drugs like Pluvicto are referred to as a radioligand. There is a radioisotope connected to an organic “ligand” for selective binding to a specific protein receptor. A radioligand is injected and diffuses its way a particular receptor where it binds. As it turns out, due to the gamma radiation also emitted by 177Lu, Pluvicto is a radioligand that can also be located in the body by the gamma radiation it emits. In general, a radioligand can be used for two endpoints: To find and signal the location of a particular cell type; and to find and vigorously irradiate a particular cell type.

There are recent radioligand compounds that are used as PET (Positron Emission Tomography) diagnostic agents which selectively bind to the PSMA receptor where they can undergo positron emission revealing the site of prostate cancer cells by tomography. 18F-glucose was first synthesized in 1967 in Czechoslovakia at Charles University by Dr. Josef Pacák and was first tested as a radiotracer by Abass Alavi in 1976 at the University of Pennsylvania on volunteers. Positron tomography came along later. Cancer cells consume glucose faster than normal cells so the 18F will tend to accumulate to a slightly greater extent and reveal their position by positron annihilation. The two 511 keV x-rays simultaneously detected at 180o apart are identified by a ring coincidence detector. A single detection event is discarded.

Dr. Abass Alavi, University of Pennsylvania. First use of 18F-Glucose on humans.
Dr. Josef Pacák (1927-2010), of Charles University in Czechoslovakia. First to prepare 18F-Glucose.

A radioligand that received FDA approval the same day as Pluvicto was Locametz or Gallium (68Ga) gozetotide. This gallium radioligand targets PSMA as does Pluvicto but is only a PET diagnostic agent.

Locametz or Gallium (68Ga) gozetotide. Source: Pharmeuropa.

Locametz has 4 carboxylic acid groups, a urea group and two amide groups aiding water solubility and numerous sites for hydrogen bonding of this radioligand to the receptor. The organic portion of the Locametz is called gozetotide, named “acyclic radiometal chelator N,N’-bis [2-hydroxy-5-(carboxyethyl)-benzyl] ethylenediamine-N,N’-diacetic acid (HBED-CC).” The 68Ga (3+) cation is shown within an octahedral complex with a single hexadentate ligand wrapping around it. The short 68 minute half-life of 68Ga requires that a nuclear pharmacy be nearby to prepare it. The short half-life of 68Ga or other positron emitters as well as the possibility of destructive radiolysis to the ligand prevents preparing a large batch and stocking it. Locametz must be synthesized and transported prior to use. This rules out remote or rural hospitals.

Nuclear Chemistry

So, where does one obtain 68Gallium? Well, there are several methods out there. 68Ge/68Ga generators are produced commercially. One company is GeGantTM who offers 1-4 GBq of 68Ga. (Note: 1 GBq is 1,000,000,000 disintegrations per second).

Diagram courtesy of Gaussling.

From the scheme above we see the workings of a 68Ga generator. The ligand attachment is performed exterior to the generator. Atomic nuclei that are neutron deficient like 68Germanium can transform a proton to a neutron. There are two ways this can happen. In Electron Capture (EC) an inner “s” electron can be absorbed by a proton converting it to a neutron and emitting a neutrino by the weak nuclear force. This lowers the atomic number by 1, in this case 6832Germanium becomes 6831Gallium. The other mechanism is for the nucleus to emit a positron (anti-electron) and eject 1 positive charge as a positron (and an antineutrino) from the nucleus, resulting in a new neutron. The atomic weight remains constant, but the atomic number drops by one. If available energy in the nucleus is less than about 1 MeV, an electron capture is more favorable than positron emission.

Once you know about the 68Ge electron capture reaction leading to the 68Ga isotope you have to ask, where does the 68Germanium come from? There are a few different ways to make and concentrate 68Ge and the method you use depends on the equipment available to you. One way is to accelerate protons to a high energy in a cyclotron and slam them into atoms heavier than germanium, such as rubidium or molybdenum. The collision with break the target nuclei into pieces by a process called “spallation“.

Diagram courtesy of Gaussling.

Cyclotrons

The first cyclotron was independently invented by Ernest Lawrence 1929-1930 at UC Berkeley. It was the first cyclic particle accelerator built. The idea of the cyclic accelerator was first conceived by German physicist Max Steenbeck in 1927. In 1928-1929 Hungarian physicist Leo Szilard filed patent applications for a linear accelerator, cyclotron, and the betatron for accelerating electrons. Unfortunately for both Steenbeck and Szilard, their ideas were never published or patented so word of the ideas were never made public.

Where does one go to get a cyclotron? One company is Best Cyclotron Systems. If you are not sure of how a cyclotron works, check out the image below from Wikipedia. Note: A cyclotron can only accelerate charged particles like protons, electrons, deuterons and alpha particles which are introduced into the middle of the machine. A key component is the “D” or Dee, so-called because of their D-shape. The cyclotron has two hollow, coplanar Dees which are each connected to a high voltage radiofrequency generator. The Dees are open chamber-shaped electrodes that alternately cycle through positive and negative high voltage attracting and repelling charged particles under the influence of a powerful magnet. Because charged particles change their trajectory under the influence of a magnetic field, the particles follow a curved path of increasing diameter, accelerating until they exit the Dees and careen into the target.

Source: Wikipedia.


Refinery Utilization Rates Low, Gas Prices Rising

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Gasoline prices are expected to rise sharply over the next few weeks owing to low refinery utilization rates in the US. Refinery utilization rates in the US have remained below 87 % for 8 straight weeks. The number that the industry prefers is around 93-95 %. Gasoline stockpiles are below the 5-year seasonal average by 2 % and continue to fall. In the last few months refinery stoppages have been due to weather and maintenance.

The flow of petroleum in the world is comparatively tranquil until it gets to a refinery. There it is heated to several hundred oC, pressurized, passed through distillation columns and split into various streams, passed through different catalysts and cracked into fragments, contacted with hot acids, brutalized with superheated steam, converted into reformates, blended and then sent to a tank farm before heading out to your local gas station. All of this is done with hot, highly flammable hydrocarbons in a continuous flow system. Operators and computers monitor flow rates, temperatures, pressures and fill levels in vessels. Unusable vapors are sent to a flare tower for removal from the facility lest they accumulate and create an explosion hazard. That these places do not explode frequently is a wonderment and attests to the coordinated skill of a great many people.

Texas City.

Gasoline and Diesel Prices are Creeping Upwards

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First, the word is out. According to the EIA, the US was the world’s leading oil producer for the 6th straight year in 2023 producing 12.6 million barrels per day.

It is common for people to blame rising US gasoline and diesel prices only on restrictions in crude oil production and alleged government regulatory overreach. Indeed, pressure on the gas and oil supply side or even just the threat of it can lea to unstable retail gasoline and diesel prices. What is less appreciated is the role of petroleum refineries on prices. To be sure, there is always price speculation on both the wholesale and retail sides of gas and diesel pricing to consider no matter the throughput. Like everywhere else, sellers in the petroleum value chain seek to charge as much as they possibly can 24/7/365. Everyone is itching to charge more but are hindered by competition and risk.

Refineries are only one of several bottlenecks in the gasoline and diesel supply chain that can influence retail prices. In principle, more gas and oil can always be produced at the wellhead by increased exploration or increased imports. Even so, there are constraints on transporting crude to refineries. Pipelines have flow rate limitations and storage tank farms and ocean tanker fleets all have finite capacity. Another bottleneck today is access to both the Suez and Panama canals. Suez Canal traffic is threatened by Houthi missile strikes on commercial shipping in the Red Sea and the Panama Canal seems to be drying up. The result is increased shipping costs and delays for international transport which the consumer will have to bear.

What do refineries do?

Refineries are very special places. Within the refinery there is 24/7 continuous flow of large volumes of highly flammable liquids and gases that are subjected to extreme temperatures and pressures for distillation, cracking, alkylates, hydrogenations and reformates. The whole refinery is designed, built and operated to produce the fastest and highest output of the most valuable group of products- fuels. This group would include gasoline, diesel, aviation fuel, and heating oil.

Petrochemicals account for approximately 17 % or refinery output. These petrochemical streams account for pharmaceutical raw materials, polymer products, coatings and films, synthetic fibers, personal hygiene products, synthetic rubber, lubricating grease and oils, paint, cleaning products and more. Regardless of what we may think of plastics and other synthetic materials, the 17 % produced by refineries feeds a very large fraction of the global economy. If plastic bags went away overnight, the whole world would begin to search immediately for alternatives like wood, metal or cotton/wool/flax/hemp.

Occasionally technological challenges confront refineries. An early challenge was the production of high octane anti-knock gasoline. This was investigated thoroughly as early as the 1920’s as the demand for more powerful automotive and aircraft engines was rising. Luckily for the USA, UK, and Germany, the anti-knock problem was solved just prior to WWII. This breakthrough led to aircraft engines with substantially increased power per pound of engine weight.

Leaded Gas

The petroleum that goes into gasoline is naturally rich in a broad range of straight chain hydrocarbon molecules. Straight chain hydrocarbons were used in the early days of happy motoring, but the engine power remained low. While these straight chain hydrocarbons have valuable heat content for combustion, the problem with these molecules is that in a piston engine, they cannot withstand the pressures in the compression stroke that would give greater power. To get maximum power from a gasoline engine, it is desirable to have the piston move up and down as far as possible for maximum power delivery to the crankshaft. However, a long stroke length means greater compression and higher pressure near the top of the compression stroke. Straight chain hydrocarbons could not withstand the higher pressures coming from the compression stroke and would detonate prior to reaching top of the cycle. This effect results in knocking or destructive pre-detonation with power loss.

Tetraethyllead was invented in 1921 by Thomas Midgley, Jr, working at General Motors. After some deadly and dissatisfying work by DuPont, General Motors and Standard Oil Company of New Jersey started the Ethyl Gasoline Corporation in 1924, later called Ethyl Corporation, and began to produce and market tetraethyllead. Within months of startup, the new company was faced with cases of lead poisoning, hallucinations, insanity and fatalities.

The first commercially successful fuel treatment to prevent this pre-detonation was tetraethyllead, (C2H5)4Pb, produced by Ethyl. This is the lead in “leaded” gasoline. The use of (C2H5)4Pb began before WWII and just in time to allow high compression aircraft engines to be built for the war. It allowed for higher powered aircraft engines and higher speeds for the allies which were applied successfully to aerial warfare. The downside of (C2H5)4Pb was the lead pollution it caused. Tetraethyllead is comprised of two chemical features- lead and 4 tetrahedrally arranged ethyl hydrocarbon groups. The purpose of the 4 ethyl groups (C2H5) on (C2H5)4Pb was their ability to give hydrocarbon solubility to a lead atom. It was the lead that was the active feature of (C2H5)4Pb that brought the octane boosting property. At relatively low temperature the ethyl groups would cleave from the lead leaving behind a lead radical, Pb., which would quench the combustion process just enough to allow the compression cycle to complete and the spark plug to ignite the mixture as desired.

Data from Wikipedia.

While tetraethyllead was especially toxic to children, it was also quite hazardous to (C2H5)4Pb production workers. Its replacement was only a matter of time.

Data from Wikipedia.

Fuel additives were found that would reduce engine fouling by scavenging the lead as PbCl2 or PbBr2 which would follow the exhaust out of the cylinder. While this was an engineering success, it released volatile lead products into the atmosphere.

Data from Wikipedia.

Eventually it was found that branched hydrocarbons could effectively inhibit engine knock or pre-detonation and could replace (C2H5)4Pb … which it did. While lead additives have been banned for some time from automotive use, general aviation has been allowed to continue with leaded aviation gas (avgas) in light piston engine aircraft like 100 octane low lead (100LL). Only recently has leaded avgas become a matter of public concern.

A refinery not only engineers the production of fuel components, it must also formulate blends for their customers, the gas stations, to sell. The formulations will vary with the season and the location. Some gasolines have ethanol, other oxygenates like MTBE, octane boosters, detergents and more. One parameter is the volatility of the fuel. When injected into the cylinder, it must evaporate at some optimum rate for best fuel efficiency. This will depend on the vapor pressures of the components.

Back to Refineries

The production volumes of the individual fuel products will not match the contents of the crude oil input. Gasoline is the most valuable product, but more gasoline leaves the refinery than arrives in the crude. Any given grade of gasoline has many, many components and the bulk of them have somewhere around 8 carbon atoms in the hydrocarbon chain. Wouldn’t it be nice if longer hydrocarbon chains could be broken into smaller chains to be added into the gasoline mix? And guess what, that is done by a process called “cracking”. A piece of equipment called a “cat cracker” uses a solid ceramic catalyst through which hot hydrocarbon gases pass and get cut into smaller fragments.

But what about straight chain hydrocarbon molecules? Wouldn’t it be nice to “reform” them into better and higher octane automotive fuels? There is a process that uses a “reformer” to rearrange hydrocarbon fuels to give better performance. The products from this process are called reformates.

Reforming is a process that produces branched, higher-octane hydrocarbons for inclusion in gasoline product. Happily, it turns out that gasoline with branched hydrocarbons are able to resist pre-detonation and have come to replace tetraethyllead in automotive fuels entirely. Today we still refer to this lead free gasoline product as “unleaded”.

Octane and Cetane Ratings

Octane rating is a measure of resistance to pre-detonation and is determined quantitatively by a single-cylinder variable compression ratio test engine. Several octane rating systems are in use. RON, the Research Octane Number, is based on the comparison of a test fuel with a blend of standard hydrocarbons. The MON system, Motor Octane Number, covers a broader range of conditions than the RON method. It uses preheated fuel, variable ignition timing and higher engine rpm than RON.

Some gasoline is rated in the (R + M)/2 method which is the just average of the RON and MON values.

In both the RON and MON systems, the straight chain hydrocarbon standards are n-heptane which is given an octane rating of 0 and the branched hydrocarbon 2,2,4-trimethylpentane, or isooctane, which is given an octane rating of 100.

Tetraethyllead and branched hydrocarbons are octane boosters. Methyl tert-Butyl Ether (MTBE), ethyl tert-butyl ether, and aromatics like toluene are also used to boost octane values. Internal combustion engines are built to use a gasoline with a minimum octane rating for efficient operation. A rating of 85 or 87 are often the octane ratings of common “unleaded” gasoline. Higher compression ratio engines require higher octane fuel- premium grade -to avoid knocking.

For comparison, diesel has a RON rating of 15-25 octane so it is entirely unsuitable for gasoline engines. Diesel has its own system called the Cetane rating. The Cetane Number is an indicator of the combustion speed of the diesel and the compression needed for ignition. Diesel engines use compression for ignition unlike gasoline engines which use a spark. Cetane is n-hexadecane which is a 16-carbon straight chain with no branching. Cetane is given a Cetane Number (CN) of 100. Similar to the Octane rating, the branched 16-carbon hydrocarbon heptamethylnonane, or isocetane, is given a CN of 15. Included in the Cetane number.

Refineries must keep close tabs on seasonal demand for their various cetane and octane-rated products as well as the composition of the crude oil inputs which can vary. Each gasoline product stream has performance specifications for each grade. While gasoline is a refined product free from water, most sulfur and solid contaminants, it is not chemically pure. It is a product that contains a large variety of individual hydrocarbon components varying by chain length, branching, linear vs cyclic, saturated vs unsaturated members that together afford the desired properties.

Specific Energy Content

Absent ethanol, the combustion energy values of the various hydrocarbon grades are so similar as to be negligeable. The energy content of pure ethanol is about 33 % lower than gasoline. Any energy differences would be due to subtle differences in blending to achieve the desired octane rating or proprietary additives like detergents. A vehicle designed to run on 85 octane will not receive a significant boost in power with 95 octane unless it is designed to operate on higher octane fuel.

Source: Wikipedia

From the Table above and looking at the polypropylene (PP) and polyethylene (PE) entries then comparing to gasoline, we see that the specific energies are the same. The two polymers and gasoline are saturated, hydrocarbons so it is no wonder they have the same specific energies. Polystyrene is a bit lower in specific energy because the hydrogen content is lower, reducing the amount of exothermic H2O formation as it burns. The point is that by throwing away millions of tons of PP or PE every year, we are throwing away a whopping amount of potential fuel for combustion and electrical energy generation.

Petroleum based liquid fuels burn readily because of their high vapor pressure and low flash points. Polyolefins like PP and PE by contrast have virtually no vapor pressure at room temperature and consequently are difficult to ignite. In order to burn, polyolefins need to be thermally cracked to small volatile fragments in order to provide enough combustible vapor for sustained combustion. Plastic fires tend to have an awful smell and dark smoke because the flame does a poor job of energizing further decomposition to vapor.

Going from E10 to E85, the specific energy density drops considerably from 43.54 to 33.1 MegaJoules per kilogram (MJ/kg). Replacing a significant quantity of gasoline with the already partially oxidized ethanol lowers the potential energy. In the tan colored section, we can see the elements silicon to sodium. These elements are either very oxophilic or electropositive and release considerable heat when oxidizing. Some metals amount to a very compact source of readily oxidizable electrons.

Refinery Troubles

According to the US Energy Information Agency (EIA) US refinery output in the first quarter of 2024 has dropped overall by 11 % and has fallen as low as 81 % utilization. Decreasing inventories are causing rising retail prices. Still, average gasoline and diesel prices are currently below the same time period in 2023.

According to EIA, the US Gulf Coast has seen the largest 4-week average drop in refinery utilization at 14 % since January, 2024. This is attributed in part to the early start of maintenance shutdowns of Motiva Port Arthur and Marathon Galveston Bay refineries which account for 7 % of US capacity.

Galveston Marathon Refinery. Source: Google Images.
Motiva, Port Arthur, TX. Source: Google images.

Weather has factored-in this year as refinery production was halted in several locations in the US. A severe winter storm shut down the TotalEnergies’ 238,000 barrel-per-day refinery in Port Arthur, Texas.

TotalEnergies, Port Arthur, TX.

Oil production in North Dakota fell to half. Oil production was estimated to have fallen between 600,000 and 650,000 barrels per day.

Exxon Mobil Corp returned a fluidic catalytic cracker and a coker to normal operation at its 564,440 barrel per day refinery in Baytown, Texas.

ExxonMobil Corp, Baytown, TX. Source: Google Maps.

A Flint Hills Resources 343,000 barrel per day refinery in Corpus Christi, Texas, was significantly impacted by unseasonably cold weather including freezing rain.

Flint Hills Resources, Corpus Christi, TX. Source: Google Maps.
Flint Hills Resources East Plant, Corpus Christi, TX. Source: Google Maps.

The largest refinery in the Midwest, BP’s 435,000 barrel per day refinery in Whiting, Indiana, was taken off-line by a power outage and forced a 10 % drop in refinery utilization in the Midwest the first week in January. Normally the Midwest region produces as much gasoline and diesel as it consumes. This rich local supply leads to somewhat lower prices in the region.

BP’s Whiting, IN, refinery along the southern shore of Lake Michigan, between Gary and South Chicago.

Pluvicto (TM) PSMA-targeted radiotherapy: Updated

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[Note: This is an updated post from the original posted one year ago.]

March 22, 2022. Swiss drugmaker Novartis has released Pluvicto, “the first FDA-approved targeted radioligand therapy (RLT) for eligible patients with mCRPC that combines a targeting compound (ligand) with a therapeutic radioisotope (a radioactive particle). Pluvicto is expected to be available to physicians and patients within weeks.“

Pluvicto features a chelated 177Lutetium ion (half-life 6.7 days) which is the source of the molecule’s radioactivity. Lutetium is the heaviest of the lanthanide elements and the name comes from the Latin Lutetia Parisiorum which was the predecessor to the city of Paris, France.

Novartis PluvictoTM (177Lutetium vipivotide tetraxetan)

Pluvicto has been approved in the US for the treatment of metastatic prostate cancer. Several things are notable about the Pluvicto molecule. The molecule contains a PSMA-specific peptidomimetic feature with an attached therapeutic radionuclide, where PSMA stands for Prostate Specific Membrane Antigen. Peptidomimetic refers to a small chain that resembles a stretch of protein forming amino acids. This peptidomimetic fragment, which interestingly contains a urea linker, is designed as the tumor targeting piece of the drug. Connected to it is a chelated radioactive 177Lutetium cation (below, upper right). The tumor targeting fragment binds to the cancer cell. While bound to the cell, the short-lived radioisotope undergoes two modes of decay. The 177Lu has two decay modes. One emits a medium energy beta particle (Eβmax = 0.497 MeV) which is limited to a maximum of 0.670 millimeters of travel. This is the kill shot that will damage the attached and nearby target cells. The short path length of the beta ray in vivo limits the extent of surrounding damage by any given decay. Once the 177Lu emits a beta particle it becomes 177Hafnium.

Source: Ashutosh, et al. 177Lu decays to ground state 177hafnium 78 % of the time. In the three other beta decays to three hafnium excited states, each collapses to ground state by 6 possible gamma emissions.

The other mode of 177Lu decay is gamma emission by 177mLu, a nuclear isomer or metastable form of 177Lu. Gamma radiation is much more penetrating than beta radiation. The gammas can be detected from the outside of the patient allowing monitoring of dose and location of the drug. Even though gamma rays are more penetrating than beta rays, they produce many fewer ion pairs per centimeter as they traverse the tissue making them less effective per photon in tissue destruction compared to alpha and beta particles. For instance, alpha particles from therapeutic radionuclides like 223Radium used to treat prostate cancer are much more destructive because they produce many ion pairs per centimeter.

A Small Side-Track into Radon Decay

Not all radioactive isotopes are alike. Some, like 177Lu, offer only a single decay event while others are part of a domino series of decays. The decay of naturally occurring 222Radon begins a series of decay events (Radon’s daughters), with some decays being quite rapid, multiplying the radiological effect per initiating atom. Inhaling an alpha emitter like 222Radon is a gamble. Until the 222Rn decays, it is just an inert noble gas. But when it alpha decays in your lungs, it is converted to the 218Polonium which alpha decays to 214Lead which beta decays to 214Bismuth which beta decays to 214 Polonium which alpha decays to 210Lead which beta decays to 210Bismuth which beta decays to 210Polonium which alpha decays to stable 206Lead where the chain stops. Each of the daughter products is a reactive, nonvolatile metal.

Each 222Radon atom gives rise to 8 successive radiation emissions, 4 of which are alpha emissions. These new radioactive elements are called “Radon’s daughters”. This makes radon especially insidious. Note the half-lives in the graphic. Source: EPA.

Neutron Activation of 176Lutetium

How does one obtain 177Lu? There are two pathways of nuclear chemistry that can be used, each with plus and minus attributes. The easiest pathway to execute would be the absorption of a thermal neutron by the lighter lutetium isotope 176Lu followed by a gamma emission from the new 177Lu. Gamma emissions result from metastable coproduct 177mLu that is in an excited state. It can de-excite by losing the excited state energy by the release of a gamma photon.

An excellent review of this topic is by: Ashutosh, Dash; Maroor, Raghavan; Ambikalmajan, Pillai; and Furn F. Knapp, Jr. Nucl Med Mol Imaging. 2015 Jun; 49(2): 85–107. doi: 10.1007/s13139-014-0315-z.

Where does one get thermal neutrons and what is “thermal” about them? Thermal neutrons are produced in a water-cooled nuclear reactor. It turns out that nature has bestowed a wonderful gift on 176Lu. It has a very large neutron capture cross section of 2090 barns for producing 177Lu. The metastable 177mLu isomer has a cross section of only 2.8 barns.

The unit “barn” is the unit of the effective target area of a nucleus and is equivalent to 10-28 m2, or 100 square femtometers. The capture cross section of a nucleus is dependent on the energy (or temperature) of a neutron and is proportional to the probability of a collision. Here is a brief reference on nuclear cross sections. The colorful etymology of the term “barn” is recalled here.

For comparison, the capture cross section of 239Plutonium is on the order of 750 barns with 0.025 electron volt neutrons. We can see that the capture cross section of the 176Lu is much larger than that of 239Pu. The word “thermal” comes from the kinetic energy corresponding to the most probable speed of a free neutron at a temperature of 290 K (17 °C or 62 °F).

The transmutation [176Lu + 0n —> 177Lu + 177mLu] is clean and direct with no other chemical elements to interfere. With its large capture cross section,176Lu is well suited to absorb a neutron. The down side is that the isotopic abundance of 176Lu is only 2.8 %. The other 97.2 % of Lu can also undergo neutron activation leading to chemical and radiological contamination of the desired 177Lu. Isotopic separation of 176Lu from the other Lu isotopes is difficult and not very scalable. By the way, the lutetium is neutron activated as the refractory oxide, Lu2O3. These lanthanide oxides are simple to prepare and can be dissolved in acid afterwards to produce Lu3+ cation for further chemistry.

Neutron Activation of 176Ytterbium

The other major channel to 177Lutetium is from neutron activation of 176Ytterbium, 176Yb. Generally speaking, the heavy lanthanides like Yb and Lu are less abundant than the light lanthanides on the left side of the series. All of the lanthanides have a 3+ oxidation state and similar ionic radii making them difficult to chemically separate, where “difficult” means that numerous steps are needed in purification often resulting in low yields. A few of the lanthanides have oxidation states other than +3. It turns out that Yb3+ can be selectively reduced by chemistry to Yb2+ in the presence of Lu3+ using sodium amalgam as the reductant. This happy fact allows for plausible chemical separation of Lu from Yb. Furthermore, Yb will amalgamate while Lu does not.

A Google search of Pluvicto or 177Lutetium will produce many good links of a technical and non-technical nature.

Pluvicto, PSMA-targeted radiotherapy
(lutetium 177Lu vipivotide tetraxetan)
for PSMA-positive prostate cancer
7.4 GBq (200 mCi) IV Q6W up to 6 doses

Temple Hollowing

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Something new to be neurotic about- temple hollowing. Among facial reconstruction professionals, this is not news. It hardly ranks as a disfigurement, just one of many effects of aging.

Just when I thought I’d heard of everything, along comes the aesthetic condition of temple hollowing. This condition results from the underlying tissues of the temple thinning to produce a hollowed-out effect. The result is an older, more peanut shaped or skeletal appearance to one’s head.

It is a normal consequence of aging or excessive exercise. By injecting a filler, temple hollowing can be filled in to produce a more youthful appearance.

I’ll place this in either the “Who knew?” or the “Who cares?” basket.

Now that I am aware of this aesthetic anomaly, I suppose I will see it everywhere.

Journal of Interesting Constraints Editor Retires

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Guapo, Arizona. Journal of Interesting Constraints: Dark Matter (JICDM) Editor-in-Chief Prof. Ralph Huey of Poltroon University Physics Department (PU) has announced that he will be retiring from the Editor-in-Chief position after 12 years of service. Prof. Huey has been appointed to the Regent Registrar endowed chair at PU beginning in August, 2024.

JICDM is dedicated to the rapid communication of negative results and theoretical dead ends discovered in the field of dark matter. Scientists wishing to announce evidence-constrained research of dark matter/dark energy physics are invited to submit their manuscripts and vitae. A Journal of Interesting Constraints for both Quantum Gravity and String Theory are being contemplated with an announcement expected after the 2024 Nobel Prise awards are announced.

A poster session beginning at 2:00 PM highlighting Dr. Huey’s work in the field of Quantum Word Processing followed by a colloquium with guest speaker Professor Irwin Corey from the University of Kornhole, Kentucky, speaking on “Quantum Yarn Theory: The Burlap Model of Space-Time” in honor of Dr. Huey’s retirement from JICDM. The lecture begins at 4:00 PM, August 2, 2024 in the Timothy Leary Memorial Auditorium, Potato Science Building, Poltroon University. Open bar begins at 3:30.

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**Thanks to Sabine Hossenfelder for the interesting constraints idea.

A Bottomless Pit of Awful

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Note: I’m having a difficult time not posting on the many ways I’m sickened by you-know-who. This is one more but is blessedly short.

To my great chagrin, there are tens of millions of US citizens who can look at the photo below and not sicken at the patronizing spectacle of a former real estate mogul turned reality TV showman’s hamming it up with a clownish embrace of the flag and laying on a fully puckered kiss for good measure. The guy is a one-man traveling burlesque show. This picture is part of his brand.

#45 Smoochin’ Old Glory.

This is a pose cynically staged to appeal to the many citizens who cannot recognize a charlatan when he is standing in front of them. It is an exaggerated and garish display of idolatry posing as patriotism. Patriotism is many things but not this.

American Isolationism and the World

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The reverberations of Trump’s South Carolina comments on NATO continue. Being a thuggish racketeer himself, he sees something like freeloading or racketeering in the motives of the NATO states. With his disparaging rants about NATO and proposing that the US stands back while Putin pushes west, he emboldens the Kremlin to maintain their aggression in the hope of the US standing down. There should be no mistaking Putin’s motives- he wants to recover the territory once controlled by the Soviet Union. Some suspect that Belarus will be annexed next.

Isolationism has been a Republican reflex since before the formation of NATO. It seems to be a part of the libertarian worldview of the isolated and rugged individualist. Either they do not care about the global balance of power or are ignorant of it. We are seeing a wave of Russian aggression disguised as self-defense or the defense of “ethnic Russians” living across borders. Hitler used this trick to grease the skids for his takeover of the Sudetenland in neighboring Czechoslovakia in 1938.

Putin’s invasion of Ukraine was partly justified with the lie that Ukraine is infested with Nazis who are threatening Mother Russia. In 2014 Putin had slyly marched into southern Ukraine annexing the Crimean Oblast. Shielded from critics by his extensive blackout of international media, Putin dispatched troops for the “Special Military Operation”.

On September 30, 2022, Putin gave a speech declaring annexation of Donetsk, Kherson, Luhansk and Zaporizhzhia. In an angry, ranting speech Putin said “They don’t want us to be free, they want us to be a colony; they don’t want equal partnership, they want to steal from us,”

In Ukraine, Russia has inadvertently revealed itself to the world as a paper tiger. However, they are still in possession of a large stockpile of tactical and strategic nuclear weapons with its own triad of delivery systems. Russia’s policy has always been to use nuclear weapons in the event of the possible downfall of the state. By that they mean the downfall of Putin by outside forces. Russia is not burdened by having a policy of “no first use” of nuclear weapons like the West.

So what about Putin’s comment that “They don’t want us to be free …”. This is the autocrat who has shut down all independent news reporting within Russia, disconnected internet access to much of the world, normalized defenestration and has criminalized even the smallest whiff of dissent. Like autocrats often do, he accuses others of what he does himself. His rationale is that harsh measures are necessary to resist outside threats. He also claims that the West wants to steal from Russia. When you are an isolated and naturally secretive country, accusations of thievery are a soft sell. Accusations like this are part of the feedback loop of paranoia, hardening resolve to resist by being more secretive and brutal.

Imagine the ridiculous folly of attempting to invade or colonize Russia or take resources from it for any reason. Really, who the hell wants to be in control of Russia other than some Russian? What would a foreign invader of Russia hope to accomplish by taking control of this giant, multiethnic country? Decades of bickering, insurgency and violence? The taiga? It is a stupid plan, yet Putin frightens the population with visions of American attack and along with its sexual perversion.

Putin’s lessons from history come from Soviet times when the KGB watched for spies behind every tree and surveillance of the citizenry was justified for “state security”, a catchall for close control of its citizens. Escape from the USSR was difficult and getting caught could mean long imprisonment in a gulag.

Putin’s protestations are little more than a trademark display of strongman fulminations meant to justify the slaughter of his own military in Ukraine. I’m surprised he doesn’t do it shirtless on horseback to display his lean and mean musculature.

The Russian people deserve much better than a long history and an extended future of oppression. The region has seen immense suffering over the decades from invasion by Hitler, deadly oppression from Stalin and privation and imprisonment by its own leadership. Today, the strong arm of the Kremlin regime reaches deep into their lives, preventing a popular uprising or just expressions of discontent. What Russia lacks is an army of martyrs willing to die for freedom because that is what it would take. Putin keeps them comfortable enough to stay out of politics.