A Bit of Fentanyl Chemistry

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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 0.1 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 high yielding steps as possible. 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.

Passage Slowdown Through the Panama Canal and Some Rerouting at the Suez Canal

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The year 2023 has been a bad year to be a canal user. Between a drought aggravated by El Nino and a shooting war by Houthi terrorists, transit costs and risks have risen steeply.

The two major canals for transoceanic shipping in the world are seeing events affecting their operation which are beyond their control. The Panama Canal is suffering a slowdown in transits due to a drought reducing the water level of Gatun Lake which feeds the canal lock system. The Suez Canal is being affected by hostile Iranian-backed Houthis in Yemen threatening shipping in and out of Israel moving through the Red Sea. They claim to be after ships to and from Israel, but it doesn’t appear that their target identification is very good.

The Suez Canal does not use locks so it can pass more ships per day. While the Panama Canal suffers from drought limiting its throughput, the Suez Canal has no new physical impediments. It is affected by ship operators who elect to bypass the Houthi threat by going around the Cape of Good Hope. Since 17 November, 2023, 55 ships have rerouted around the Cape of Good Hope and 2,128 ships have passed through the Suez Canal according to Reuters.

The Panama Canal auctions-off transit slots on a daily basis. During normal conditions before the drought, there were 36 transits per day. At the start of December, 2023, that rate was at 22 transits per day and the cost of a transit has risen accordingly. As of 15 December, 2023, the transit rate was increased to 24 transits per day through both the Panamax and Neopanamax locks.

The US produces more gasoline than it consumes and most of the excess is exported from the Gulf Coast. For buyers along the Atlantic basin, the US produces the cheapest gasoline. The Gulf Coast also supplies refinery products to the Pacific rim via the Panama Canal.

Within the US, gasoline prices have been low owing to excess inventories. Because of the Panama Canal slowdown, some refineries may have to reduce production to prevent further inventory buildup, potentially resulting in increased prices generally and heating oil in particular.

Panama Canal “slots are prioritized according to highest bid in auction processes, full containers, market and customer rankings,” according to Reuters.

Howdy Arabia

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I heard a sarcastic moniker for Texas yesterday for the first time. It was “Howdy Arabia”. It was used by one of my favorite comedians, Trae Crowder, and refers to ultra-conservative xenophobic southern American culture. Crowder is from Tennessee and calls himself a progressive hillbilly or a liberal redneck. But Howdy Arabia has been around for a while as a Google search will show. The phrase “Y’all Qaeda” also bubbles up.

Why all of this intemperate 8th grade slander on an entire state? The abortion fiasco led by Texas Attorney General Ken Paxton happening in Texas presently is so foul and unnecessary that I can barely listen to it without becoming angry. Medical reality doesn’t seem to have a place in Paxton’s absolutist, linear brain. He is putting on a performance to display his Republican bona fides. His are the Bible belt constituents who elected him. In this sense, he is a duly elected official giving his voters what they want no matter the cost. It isn’t just Paxton- it is the entire GOP party apparatus at work.

Paxton is an aggressive, doctrinaire male exerting control over a woman’s body from a distance. He won’t be present as she suffers through this ordeal. He could have accepted the local court’s decision and allowed the woman to go forward with the procedure. Instead, he appealed to the Texas Supreme Court and ruled against the lower court’s decision. Further, he sent letters to local health care providers threatening severe legal consequences if they were to aid in the woman’s abortion. This is Republican Texas.

Idiots are elected by idiots.

Execution by Nitrogen Hypoxia

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It came out that the state of Alabama is preparing to execute a prisoner by nitrogen hypoxia. Oklahoma and Mississippi are the only other states that have authorized this method of execution. The prisoner, Kenneth Eugene Smith, had previously selected nitrogen hypoxia as a secondary means of execution. This decision was backed by the US Supreme Court. The first attempt to execute Smith by lethal injection failed because of the inability of workers to find a vein after 4 hours trying.

Smith’s attorneys have made the argument that this new form of execution claim that Smith is a “test subject for this novel and experimental method.” According to the Death Penalty Information Center, some have claimed that “those who support the use of nitrogen hypoxia can only theorize that the method will be painless and quick, but opponents have likened it to human experimentation.”

Criticism of the nitrogen hypoxia method have raised safety concerns for witnesses. It’s been argued that nitrogen escaping from the condemned man’s mask could threaten the health of those nearby, particularly the preacher standing close for spiritual comfort.

Critics say that the state of Alabama has not adequately prepared for the execution and the safety of witnesses and workers nearby.

“They could start to hyperventilate because their body would detect that they’re in a low oxygen environment,” said Dr. Joel Zivot, an anesthesiologist and associate professor at Emory University School of Medicine. “And that severe hyperventilation can lead to a stroke.” The doctor expressed concern that the method is full of unknowns and seemed quite skeptical of the method.

Seems to me that on basic principles alone, this method should work just fine. It would’ve been nice to read that the state had a written procedure that specified the type of mask and the nitrogen flow rate. As for the safety of others, minimally there should be an O2 concentration meter present, which is the case. The air exchange rate in the room can be measured and increased, assuming this is possible in an Alabama prison. Best of all, supplied air hoods or masks are widely available. This would only require an air compressor in fresh air.

The Squamous Chronicles: 10 Years Later

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It has been right at 10 1/2 years since I was treated for squamous cell throat cancer. This virally induced cancer is quite treatable with a high success rate. The treatment was simultaneous radiation and cisplatin. The x-radiation dose was 68 Gray in daily 2 Gray doses with 6 cisplatin infusions. The radiotherapy machine was an Intensity Modulated Radiation Therapy (IMRT). The source rotates around the stationary patient varying the beam size and intensity as it goes. The idea is to put the energy into the tumor and spare healthy tissue to the greatest extent possible. The neck is a very crowded place with many kinds of tissues you don’t want to zap too much.

Illustration showing variable intensity beam shaping from the IMRT on the right. Source: Semantic Scholar.

It took about 1 week for the radiation effects to show up. It began with a sore throat which quickly led to a stomach feeding tube. They snake a pointy-ended tube down your throat and poke it out of your belly. I had it in for about 6 weeks. I jammed my liquid food in with a 60 mL syringe.

Besides the considerable discomfort from the radiation, long term side effects were not terrible. My thyroid took a big hit as did my salivary glands and taste buds. Ten years of dry mouth has led to the loss of some teeth. And, there was difficulty in swallowing initially. This problem unexpectedly returned during my recent bout of pneumonia.

The cisplatin was given in 6 doses. The nursing staff in the infusion suite don considerable PPE while handling chemotherapeutic drugs due to the toxicity hazard. I had no noticeable symptoms from this treatment. But while in the infusion suite, I could hear numerous female patients who were groaning in misery and vomiting from their meds. It was heart wrenching.

Nine years ago I wrapped up radiation for my stage 4 prostate cancer. Though the dose was lower at 38 Gray, there were no real negative effects as with the throat radiation. This was followed by 2 years of chemical castration with Lupron. It is also called hormone ablation. Lupron interferes with the production of testosterone. It does not, however prevent the adrenal glands from producing it, but this is a minor source. The first effective treatment for prostate cancer was surgical castration done to halt testosterone production. This hormone accelerates the growth and spread of the cancer. These guys who take testosterone for body building have no idea about the other thing the hormone can do. Just my opinion.

Hormone ablation eventually becomes ineffective because over time the prostate cancer cells respond by increasing the number of androgen receptor proteins on the cell walls. After hormone ablation fails, more severe treatments are put into use.

My outlook is this- The throat cancer is unlikely to return, but the prostate cancer will eventually take me out. I’ve had plenty of time to ponder death since the cancer diagnoses. I’d much prefer to have a quick, fatal heart attack than a slow, wasting death from cancer. I jokingly mentioned this to my cardiologist. He replied that the heart attack might not kill me. Buzzkill.

Texas Abortion Case

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As of this date, the Texas Supreme Court has blocked a lower court decision by Travis County District Judge Maya Guerra Gamble that a Texas woman may obtain an abortion. Within hours the Texas Attorney General Ken Paxton sent letters to 3 area hospitals saying the temporary order would “not insulate hospitals, doctors, or anyone else, from civil and criminal liability for violating Texas’ abortion laws.”

The woman is currently in another state where her condition does allow for a legal abortion.

Apart from the usual hairball of arguments about abortion itself, I’m flabbergasted at the apparent absence of medical input relating to this law. Why isn’t there a medical board of OB/GYN specialists who have some authority in this? Were obstetrics medical school faculty consulted in the drafting of this law? Was the religious conservative pressure so great that OB/GYN best practices were just disregarded? Looks like an absolutist approach was taken and exceptions could be finely scrutinized with a bias towards “no.”

Is there a religious conservative in Texas who knows what an ectopic pregnancy is or any other dangerous medical condition? Pregnancy is a hazardous business and much can and does go wrong taking the life of one or both the infant and mother. Apparently in Texas, dying in childbirth is acceptable because it is God’s will and the rest of us have to respect the wishes of Republican believers.

Perhaps the Texas AG, Mr. Paxton, has the habit of denying/prosecuting abortions across the board and letting the matter go to the Supreme Court for a decision. This keeps him free of criticism from the anti-abortion mega-church preachers in Texas.

The whole thing stinks of ignorance and religious disregard for medical reality. The Texas state motto should be- “Frequently wrong, but never in doubt.”

Anti-Science or Pseudoscience Trend in India?

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The political party of Indian Prime Minister Narendra Modi is the Bharatiya Janata Party (BJP). This party won the 2014 general elections by a landslide, and again in 2019. Since then the BJP has reportedly aligned with the RSS, Rashtriya Swayamsevak Sangh, a paramilitary right-wing group. Modi has been accused of leading the country into what has been called a “Hindu religious autocracy.” The process of implementing a Hindu Nationalist agenda has been given the colorful name “saffronization.” No small part of it is the de-westernization of India.

Indian history and politics is very rich but unfamiliar to most westerners so I can’t go into detail other than to say that there is a strong Hindu Nationalism movement there. A level of rejection of Eurocentric values is to be expected given the history of British rule in the 20th century. India is a nuclear, space-faring nation today with much to be optimistic about.

Recently, Darwin’s theory of evolution has been removed from textbooks in 9th and 10th grade biology. The fear is that most students do not take biology later in their school years and therefore will have no understanding of this important aspect of biology. The decision to drop evolution from the 9th and 10th grade biology textbooks was a “content rationalization” made by a government organization called National Council of Educational Research and Training (NCERT). NCERT claims that they dropped discussion of evolution during the COVID-19 pandemic in order to streamline online classes. India currently has 256 million primary and secondary students.

This has resulted in an uproar by Indian academics, including artists, writers, historians and scientists. The notion held by most scientists and mathematicians around the world is that physical and biological science is secular, i.e. it should not contain cultural, historical or racial structural elements imposing subjectivity in modeling the physical world.

America’s Upcoming Self-Immolation

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The reader should know that I would much prefer to write about sciency topics like chemistry or mining geochemistry. But I have become aware of a political tsunami that could arrive at our shores in 2025. It is a planned sequence of actions aiming to convert our American civilization, its economy and politics so drastically as to be unrecognizable by the standards of today. It is breathtaking in its sweep and amounts to nothing less than a sociopolitical revolution. I refer to “Project 2025” organized by the Heritage Foundation. Short of a mainland invasion of North America, I am hard pressed to think of something that will so drastically alter the course of American civilization. Republicans are seeking to emplace a permanent conservative state. My view is this- screw ’em.

At present, the US is the global hegemon and has been one since WWII. Many nations resent this, especially China and Russia, and seek to become the major hegemonies themselves. They strongly desire to knock the US off the sandpile and take up residence for themselves. Trump’s America First policy would allow Russia and China to step up as US foreign influence is purposely relaxed. As the unity of the US/EU and NATO collapses, Russia’s influence in Eastern Europe will rise as they move forward to the reestablishment of a Soviet-scale state. China’s dominance along the South China Sea, Southeast Asia, Taiwan, Philippines, Indonesia, Malasia and Australia will grow, as they intend it to.

The expansion of Chinese and Russian influence will come as a result of the loss of global US influence. As technology and the quality of life expands across the world, US hegemony will necessarily diminish somewhat. What we can and should hold onto is our standing as an influential and thriving democracy.

To my many friends, colleagues and readers, all I can say is that now is not the time to shrink back into your shells and wait out the 2024 political season in the US. If your visual acuity takes you past your nose you will see that Project 2025 will strongly alter the function of the federal government. This is a step towards a dictatorial architecture that will directly affect our lives and our standing in the world.

Hyperbole? Visit the link and think it through for yourself.

Project 2025 is nothing less than a coherent plan to deconstruct the administrative function of the federal government, especially under the executive branch. The many designers of this project believe in the so-called “deep state” which, they say, is firmly nested in the ponderous federal bureaucracy. As a story it has the necessary elements of a conspiracy novel. There are protagonists, antagonists, narrators and enough historical detail to make their storyline convincing. In my view, the deep state exists in the form of dark money and the subsequent influence over politicians, mostly the recipients of big conservative money.

The US media will be of little help here and will relegate themselves to documenting the downfall for the infotainment of everyone around the world. Decades hence, dissertations and documentaries will be produced attempting to explain the collapse to authoritarianism to puzzled citizens.

But Project 2025 is more than just a rejiggering of the administrative apparatus of the federal government. Significantly, it aims to intensify the many powers of the federal bureaucracy directly into the hands of the president by aligning the federal workforce job security to be politically accountable to the president.

It represents a transition from a primary emphasis on expertise to that of political reliability for one’s career-sake. The plan will go into effect the first day of the next Republican president’s administration, be it Trump or otherwise. This is what the plan states in clear English.

In our federal government, laws are passed and placed into the Unites States Code, USC. This content is then translated into the Code of Federal Regulations, CFR, for promulgation. The CFR is a structure of regulations based on the USC for practical application and enforcement.

It is easy and quite lazy to claim that the US federal government is completely broken. It seems to be hypersensitive in some areas and intractably slow elsewhere. Nonetheless, much of it functions like it should behind the curtains. Do we really want a government that is incontestably and quickly responsive to the whims of a president? Or should there be checks and balances built into the system? Handing over more power to a morally bankrupt person like Trump is grossly irresponsible, stupid and may not be reversable. Other than a foreign invasion, this could not be more serious.

Chemical Nomenclature, Enantiomers and Polarized Light

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[Reissue under better title]

Due to a recent hospital stay with pneumonia, I found myself staggeringly bored. To stave off some of this I began to look into an antibiotic I was given that I had never heard of- Levofloxacin. The structure of this antibiotic was different from antibiotics I was previously familiar with. Natural I suppose, considering that I’ve been immersed in organo-transition metal chemistry for most of my industrial career. Metal-carbon bonds are quite useful in some sectors but not as drugs.

Levofloxacin is a good place to go deep diving into some of the murkier depths of chemical nomenclature. The complicated-looking chemical naming system exists to unambiguously represent the composition and shape of molecules. Certain features and properties of a molecule confer important attributes that need categorizing, thus requiring descriptive names rather than just a number. Every different chemical substance is, well, different and their chemical names must reveal a unique identity. Two or more substances with the same name leads to nothing but trouble.

Chemical substances can be grouped into categories to associate them with related aspects. We have noble gases, transition metals, hydrocarbons, pnictogens, polymers, acids, and bases etc. But the categories allow for variation when particular attributes are under discussion.

The names of chemical substances can be very off-putting to non-chemists and often does lead them to abandon their search for information. A few have even suggested that if you cannot pronounce the name it must be bad. Even worse than the polysyllabic and numbered character strings are the various synonyms. Consider simple toluene which is actually not so bad-

Directly from Chemical Abstract’s SciFinder.

In chemical nomenclature there is just a bit of flexibility in how numbers, syllables and name fragments can be assembled as the toluene example above shows, if you don’t read the rules too closely. The plethora of names come from historical trade names or long-time industrial use or may just predate systematic nomenclature now in use. There is also the German Beilstein and Gmelin organic and inorganic nomenclature as well, but these seem to be outdated.

As always, a proper chemical name describes the composition and 3-dimensional connectivity of the chemical structure of a molecule. These names are commonly listed in one of the two dominant styles of chemical nomenclature in the world- International Union of Pure and Applied Chemists (IUPAC) and Chemical Abstracts Service (CAS). IUPAC tends to be taught in undergraduate chemistry because it always has been and is maybe a trifle easier.

The CAS databases contain more than 200 million organic and inorganic chemical substances and about 70 million protein and nucleic acid sequences. There are two search platforms available in CAS- SciFinder and STN. STN is much more cryptic and harder to learn than SciFinder. Some say there are weaknesses in patent searching in SciFinder alone. For IP work I use SciFinder, Google Patents and the USPTO in combination. All three offer different kinds of searching capability.

Levofloxacin is a biocidal antibiotic effective against both gram-positive and gram-negative bacteria. It is an inhibitor of both DNA gyrase and topoisomerase IV enzymes which are involved in shaping the geometry of bacterial plasmids, or rings of bacterial DNA. Plasmids have to fit inside the bacterial cell wall and those that are not made compact enough are too long to allow successful formation of daughter cells in reproduction resulting in cell death. Other kinds of antibiotics are bacteriostatic and often work better in one or the other of Gram-Negative or Gram-Positive bacteria. Gram stains are effective with certain types of bacterial cell walls and not with others. The ability of a dye to stain a colony of bacteria a particular way is used to help identify bacteria.

Consider the name of Levofloxacin from IUPAC: (-)-(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid hemihydrate. The name is a string of characters with numbers indicating attachment points. The core of the structure is a 1,4-benzoxazine ring system which is festooned with a carboxylic acid and a few other groups. The core structure was identified and numbered previously by someone according to rules. The IUPAC name also specifies that it is a hemihydrate, meaning that there is one molecule of water associated with every two (hemi) molecules of Levofloxacin. For some reason the CAS name does not include the hemihydrate in the name, probably because it was not mentioned in the composition when registered with CAS. How it is in the IUPAC name is not known to me.

More pain. The IUPAC name above indicates “(-)-(S)-“. Molecules with “handedness” are said to be chiral and are not superimposable with their mirror images, similar to a right-hand being shape-incompatible with a left glove. These molecules can be prepared as individuals of single handedness or all of the way to a 50:50 mixture of left and right-handed. A 50:50 mixture of left and right-handed is called a “racemate” (RASS eh mate). Each handedness version is a type of isomer called an “enantiomer“. A substance consisting of a pure enantiomer is said to be “enantiomerically pure.”

Isolated enantiomers have the ability to rotate plane polarized light as measured by a polarimeter. Plane polarized light is a light beam where the electric field vectors of the electromagnetic radiation are all vibrating in a single plane. Obviously the magnetic vectors are polarized as well, but it is the electric field that is usually mentioned. The angle of the oscillating ray’s electric fields along the axis can be tilted one way or the other depending on the interaction with matter. Reflected light and skyglow are polarized as well. Molecules with handedness rotate the vibrational plane and by an angle dependent on the light frequency and the amount of chiral mass traveled through. Light that is rotated counterclockwise, or levorotary, has a (-) sign and signified with an “l” and light that is rotated clockwise is dextrorotary and has a (+) sign and signified with a “d.” If a molecule rotates plane polarized light, the substance is said to be “optically active.” The amount of rotation is dependent on the light frequency, frequently the sodium D line (actually a close doublet) which is often used as the standard source for this. Mercury lines, e.g., 354 nm, can be used if the D line results in a low measured rotation. Substances that do not rotate plane polarized light are often designated “dl” as an abbreviation for racemic.

D-Glucose, or dextrose, solutions rotate plane polarized light in the clockwise, dextrorotary direction, thus the “D” in the name.

Commercial L-lactic acid derived from fermentation is “L” for levorotary. This enantiomerically enriched lactic acid is used to make the lactide monomer for poly(lactic acid), PLA. Only the lactide dimer from L-lactic acid gives the desired PLA isomer. The racemic form of lactic acid is not useful for PLA due to undesirable physical properties in the polymer.

A ratio can be taken from an experimental sample that may range from 50:50 racemate to 100 % of a single enantiomer to give the optical purity of the chiral material, representing the proportion of pure enantiomer. Often the measure % ee, or percent enantiomeric excess is used to describe enantiomeric purity. A 95:5 mixture of enantiomers would have a 90 % excess enantiomeric of one enantiomer. Chemical synthesis of 99 % ee can be quite difficult.

A racemate does not have a net rotation of plane polarized light. The (-) sign represents the “levo” part of the levofloxacin, referring to counterclockwise rotation of plane polarized light. Prior to the appearance of reliable analytical methods for the determination of enantiomeric purity, polarimetry and optical rotation were the method of choice. Today, Gas Chromatography (GC) and High Performance Liquid Chromatography (HPLC) columns and chiral shift reagents for 1H-NMR that can provide baseline separation of enantiomers.

The (S) character in the name indicates the handedness of a molecule as determined by standard selection rules defined by an organization for assigning absolute configuration. “S” stands for the Latin word “sinister” meaning left-handed. There is no simple calculation to go between absolute configuration and sign. The (-) sign can indicate which particular enantiomer is under consideration with an easy measurement if it has been previously correlated. (-)-(R) and (+)-(S) enantiomers can and do occur. The “(S)” defines only the precise configuration of atoms about an asymmetrically situated atom in a molecule based on a few simple rules. The mirror image of (-)-(S)- would be (+)-(R)-, “R” for rectus meaning right-handed in Latin.

The first task in assigning a name to a molecule is to determine the “core” structure. This is the basis of the name. Your molecule will be a variety of “the core structure.” This is not so easy because IUPAC or CAS will have already done this and your choice may or may not match. Referring to the CAS name below, you can see that some structural fragments end in “-yl,” “-ic” or “-o”. These signal that the fragments are not the core structure, they are attachments. The core structure onto which everything else is attached is the “1,4-benzoxazine”. It is a standalone chemical name which may be modified. This is a very obscure fact that most won’t know, but the “-ine” suffix indicates that the core structure is an amine, full stop. Other nitrogen indicators like azo, aza, amino, ammonium, nitro, azido, etc, suggest a nitrogen group attachment to something else.

Does it help to have a college degree in chemistry to know this stuff? Sorry but yes. In the set of all worldly knowledge, this is pretty obscure.

The CAS name for levofloxacin is 7H-Pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid, 9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-, (3S)-. The core structure seems to be the 1,4-benzoxazine. CAS has a ring-system handbook that defines and numbers all of the known ring systems. The significance of CAS is that they assign and maintains the official CAS registry number, CASRN, which is depended upon world-wide for the exact composition and connectivity and geometry of substances. There is a very extensive rule book that rigidly defines a chemical name with rooms of CAS experts sitting in a building in Columbus, OH, to assign these names. For levofloxacin the CASRN is 100986-85-4. Today, CASRNs are usually directly searchable on Google. The final digit “4” is a check digit for error entry detection.

General comments about chemical features on Levofloxacin.

Yet more pain. The more formal official CAS name, however, does not indicate the direction of rotation of plane polarized light. I suppose this is considered experimental data not needed in the name. The CAS nomenclature only shows “(3S)-” in the name, indicating the absolute “S” configuration at position 3 of the molecule. The business of handedness or shape in 3-space of a molecule is called “stereochemistry” and arises in several ways. The rules for assigning the absolute configurations of R or S enantiomers may depend on the features of the molecule.

This business of molecular handedness is mostly an issue for biochemistry and pharmaceuticals. A great many- most?- biomolecules have handedness themselves and are therefore subject to interactions with other biomolecules or drugs that depend on the precise shapes for their interactions. This is very important for the interaction between molecules like an enzyme and substrate or ligand.

In the absence of other chiral molecules, two enantiomers will have the same chemical properties when individually pure. However, a racemate consists of a pair of enantiomers. The interactions between R and R or S and S enantiomers, will be different than the interactions between a racemic mixture of R and S or S and R enantiomers. If there is more than one chiral feature in a molecule- say two- then the molecule could be R, R or R, S, or S, S, or S, R. This gives two pairs of enantiomers, each called a “diastereomer.” For instance, one substance with R, S and another with R,R will be substances chemically and physically different called diastereomers. The presence of a diastereomer in an enantiomeric drug product would likely be deemed a contaminant and removed.

Source: David Darling

A druggable disease-state is one that can be positively influenced by a drug molecule. This commonly involves the drug molecule docking with an enzyme to activate it or deactivate it. These enzymes are very large diastereomers having many chiral atoms giving them complex shapes that can result if the formation of a pocket in the protein structure called the “active site.” This active site has very particular shape and charge features provided by the chiral amino acid chain of the protein. An active site will have a shape that is compatible with the close fitting of a drug or other molecule similar to a hand in a glove. Many of these active sites bind the shape and charge of one enantiomer of a drug molecule more effectively than the other for a better fit. The drug, or substrate, may just sit there and block the action of an enzyme, shutting it down or activate it continuously. Other active sites may bind a drug and change the shape of the enzyme causing the enzyme to speed up or slow down for a throttling or accelerating effect elsewhere on the enzyme. This is called the allosteric effect.

So, you may be asking- big deal, what does it matter? In the world of pharmaceuticals, many drug substances can exist as single enantiomers, racemates or diastereomers. Racemates may be easiest to manufacture, but very often one of the enantiomers is more biologically active than the other. In fact, one enantiomer may be disastrously harmful. The classic example is Thalidomide. The S form caused birth defects and the R form did not. Pure R enantiomer was safe from teratogenicity but a racemic mixture of R and S was not.

Conclusion. A superficial look at a chemical name opens up insights into the chemical nature of a substance. What makes each chemical substance unique is their distribution of charge in 3-dimensions. The distribution is affected by the types of the atoms present, geometric features of the 3-dimensional shape and the ability of the system to allow charge to accumulate in particular places of the molecule. These attributes mentioned also set up the type and vigor of reactivity the molecule will display.

If Q=7k, then y=mx + b

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US Senator, retired college football coach and conservative brainwave from Alabama Thomas Tuberville (R-AL) has dropped his blockade of US military promotions. He held up this ordinary staffing operation in order to protest the use of military funds for reimbursement of travel expenses to obtain abortions by military personnel.

This was a 4th down Hail Mary pass effort by a Bible Belt Republican Senator to move the needle on his conservative bona fides for conservative single-issue voters. Other similes may apply here, like the value of surprise plays.

It’s much like if y = mx +b, then Q must = 7k. Could be true depending on undisclosed information about the variables, but sometimes things are just as they appear- f**king stupid. This was a wrench-in-the-gears tactic designed to rattle his colleagues into submission. Nobody really wants to inhibit military readiness.

The idiot Tuberville was playing games with US military top-level staff and readiness but lost the game. This was a major league display of US political disfunction put on by a former college football coach who, as a group, are otherwise deified. More attention must be paid to resumes and credentials. Like other countries, in America, idiots elect idiots to office. After all, it was widely believed that a rich real estate developer with a long history of bankruptcies, fraud, law-suit harassment and sexual aggression was deemed inherently qualified to be US President based on his business experience. This particular idiocy has not fully played out yet.