Functional groups are the foundation of organic chemistry as they define the structure, reactivity, and properties of organic compounds. Here, we explain what functional groups are (by looking at – wait for it – fruit salad), and introduce the most common functional groups. Did you know that functional groups were at the root of dispute and friendship of two chemistrylegends? Let’s get into it!
What are Functional Groups in Organic Chemistry?
Functional groups in organic chemistry are specific groups of atoms that have characteristic properties (e.g., polarity). Functional groups determine the reactivity of molecules.
Instead of blindly memorizing a long list of functional groups, let us try to understand three key ideas first.
1. Many functional groups are related to each other. For instance, by putting a C=O double bond next to an amine, we get an amide. Others are variants of each other. For example, a sulfur atom instead of an oxygen turns an ether group (R-O-R) into a thioether (R-S-R). When learning these groups, try to find the similarities and differences between them. There are different sub-families of functional groups. For instance, everything with a C=O double bond can be called a carbonyl. Aldehydes, ketones, amides, esters… are all relatives of the carbonyl family! Similarly, primary amines, secondary amines and tertiary amines are all amines!
2. Properties of functional groups are largely independent of the molecule’s broader environment. The hydroxyl group in ethanol behaves the same way as in octanol (even though the latter is much bigger!).
3. Connected to the above, functional groups have an inherent polarity and thus, nucleophilicity or electrophilicity (link). For example, aldehydes are electrophilic on carbon but nucleophilic on oxygen. This baseline polarity of each functional group actually already explains most of the organic chemistry reactions that you will encounter. Interconversion of functional groups can change this natural polarity. For instance, enol forms of carbonyls are not electrophilic at the central carbon anymore, and are nucleophilic at the alpha-carbon!
What are Functional Groups – SIMPLY EXPLAINED?
Functional groups are just like different fruits in a fruit salad. Let’s see how the points above match to this analogy.
1. Some fruits are related, like lemons and oranges as they are both citrus fruits. We mentioned carbonyls and ethers above. Another example are primary amines and tertiary amines – very similar but not identical!
2. Whether you catch a strawberry in one fruit salad or another one (these are different molecules in our analogy), they basically taste the same.
3. Lemons are inherently acidic. Well, carboxylic acids are also always acidic. (Sometimes more, sometimes less – due to things like inductive and mesomeric effects.) Just like fruits have characteristic taste, functional groups have characteristic properties. This also nicely illustrates the keto-enol interconversion or even the advanced idea of “Umpolung“. Here, chemists invert the natural reactivity of the original functional group. The key example is conversion of aldehydes to dithianeswhich can be nucleophilic at the carbon (instead of electrophilic)! Using our fruit analogy, by cooking and caramelizing lemons (Umpolung), we can make them more sweet instead of bitter.
History of Functional Groups in Organic Chemistry
Here’s some random background (if you know my content, you will realize I like this type of stuff): As the backbone of organic chemistry, functional groups as a concept have their origin in the early 19th century. At that point, elemental analysis had allowed chemists to determine the molecular formula of most inorganic compounds. These lack carbon-hydrogen bonds and are thus not organic (shocker!). The widespread theory of vitalism suggested that only living organisms can produce organic substances.
Many students know that the German chemist Friedrich Wöhler overthrew this theory by synthesizing urea from inorganic ammonium cyanate in 1828. Less known is the controversy between Wöhler and Justus Liebig: Both of them were doing experiments on inorganic salts that they believed had the molecular formula “AgCNO“. However, Liebig’s salt was a powerful explosive while Wöhler’s was not.
“The obvious conclusion was that one of the analyses must be wrong, and one of the chemists must be a poor analyst! Liebig, pushed by his aggressive character, rapidly accused Wöhler of erroneous results. But Liebig analyzed a sample of the silver cyanate supplied by Wöhler and verified that they were correct. At this point, Liebig openly admitted that he had made a mistake in his initial accusation. And curiously this was the starting point of a friendship and even a scientific collaboration between the two scientists.”
S. Esteban in J. Chem. Educ. 2008, 85, 9, 1201
The legendary Swedish chemist Berzelius (Wöhler’s professor) explained this controversy by proposing the concept of isomers. The realization that constitution of molecules can be different despite having the same atoms paved the way for discovery of all the functional groups we know today.
Common functional groups
Here are the most common functional groups. The bold ones are particularly important as they are invoked to explain some of the basic reactions in organic chemistry, such as nucleophilic substitutions (alkyl halides) or electrophilic additions.
Instead of belabouring basic information you can find everywhere already, I want to draw your attention to two themes:
Functional group relationships: What makes functional groups (in a certain row or across rows) similar? For instance, the first row are C-H hydrocarbon functional groups. Which functional groups are based on combinations of simpler functional groups? For example, an enone is an alkene that is connected to a ketone. Which functional groups are oxidized/ reduced versions of each other, and which have the same oxidation state? For instance, carboxylic acids are more oxidized versions of aldehydes and ketones, and have the same oxidation state as nitriles.This means nitriles can be converted to acids without reductants or oxidants!
Functional group polarity: What do the red and blue colored atoms correspond to? How does the polarity and reactivity differ across related functional groups? For example, why is the central carbonyl carbon blue in aldehydes and ketones, but not blue anymore in carboxylic acids? Why is the hydrogen of the O-H bond of the carboxylic acid blue but not blue for the C-H in the aldehyde? Should the carbons of alkenes and arenes be marked red or rather blue? What does this depend on?
Advanced: Functional group geometry: Can you rationalize all bond angles (e.g., alkynes vs. alkenes) and geometries of functional groups? Which parts of them are flat/ in one plane, and which ones are not? For example, why are in esters both the C=O and C-O-R bonds in the same plane? Why do esters prefer the Z-conformer where both C=O and C-O-R bond are facing the same side?
In other posts, we will deep dive into individual functional groups and families to explain properties and most common reactions in more detail. Functional groups clearly also form the basis of protecting groups and their reactivity.
Some final advice: Instead of learning a bunch of facts about 30 functional groups by heart in a brain dead manner, try to work first identify the commonalities and differences from a high level. The names might seem random at first but many of them will make sense once you take a look at what atoms or combinations of functional groups are present!
Did you know that while Coca Cola was getting consumers casually coked up in the late 19th century, chemistry titans were fighting an epic battle around cocaine synthesis? With a Nobel Prize on the line, the stakes were high, cocaine’s structural complexity was high… and everybody else was high too.
Keep reading to learn more about this molecule, as we dive deep into its history and chemistry. Regardless of if you’re a science nerd or amateur, you will learn a ton today – from nice history trivia and tales of careless, chain-smoking chemists, to innovative synthetic strategies that will remain classics in chemistry forever.
This post is purely educational.
Global cocaine use
So, what do the data tell us about cocaine? As one of the most abused substances globally, it’s clearly a huge problem. The number of users has increased faster than population growth. 30% of use comes from the US – and although popularity had been declining for some years, it has unfortunately rebounded more recently. There are no signs a slowdown. The UN even estimates that global use could more than double, in case emerging markets like Africa or Asia would intensify their consumption to similar levels like the Europe or US.
The world’s supply of cocaine originates virtually entirely in South America. The annual manufacture is at record levels of 2000 tons, which is a dramatic uptick from 2014, when the total was less than half as big. On the positive side, interceptions by law enforcement increased faster than production, with some countries seeing 5 to 10-x higher seizures.
Use isn’t everything. The number of overdose deaths involving cocaine has skyrocketed, notably in the US. This is due to the insane increase of synthetic opioids. The light pink line, which excludes these, suggests the US cocaine market has contracted from its peak.
Some researchers have even quantitatively investigated the link of mentions in song lyrics and substance use. The logic here is pretty simple. As rappers increasingly mention baking soda or coco in their songs, they contribute to cocaine popularity and associated deaths. According to the researcher’s statistic model, there is a 2 year lag before this kicks in. At least the use in lyrics seemed to have plateaued in their data.
On a more alarming note, use of even more dangerous crack cocaine has risen in the US and Europe. Compared to powdered hydrochloride salt, this free amine base reaches the brain quicker, making it far more addictive. But what mechanisms of cocaine make it so dangerously enticing for users?
As we will discover shortly, cocaine saw historical use as a local anesthetic. Cocaine stabilizes voltage-gated sodium ion channels in an inactive state. Cells lose their ability to propagate electrical signals, including pain response. Although some FDA-approved cocaine formulations exist, the medical use of cocaine is largely obsolete.
Cocaine’s mechanism of action
What about cocaine’s psychoactive effects? It acts at the synaptic cleft in the central nervous system by blocking certain transporter proteins. These transporters usually mediate the re-uptake of neurotransmitters serotonin, dopamine and noradrenaline. Cocaine mainly prevents reuptake of these agents, causing intense and extended stimulation of the nervous system. On one hand, this overstimulation messes with the body’s reward system. As we’ve seen in our ibogaine video, many psychoactive compounds influence a myriad of targets. The same is true for cocaine. For instance, it also binds opioid receptors – if you want to learn more, check out the literature.
The dopaminergic activity of cocaine makes it addictive, and repeated exposure leads to desensitization. This means people need larger doses to induce stimuli and fend off withdrawal symptoms. This is already problematic, but cocaine and its metabolites are also toxic for many organs such as the liver, brain or kidney. In the cardiovascular system, cocaine leads to an increased heart rate and blood pressure, while decreasing the supply of oxygen to tissues. Remember the sodium channel inactivation? This can change intracardial signals within the heart leading to dysrhythmias. The list of health risks is pretty long, so I hope we all agree that this is not worth it.
Discovery of Cocaine
But since when do we even know about the molecule cocaine itself? Meet the German chemist, Albert Niemann. Like many chemists we will mention today, he is not famous but actually quite the legend. He was in great company, as he was the graduate student of Friedrich Wöhler. This is the guy who synthesized urea – in 1828 from inorganic starting materials. This was a major milestone in organic chemistry, as it dispelled the vitalistic misconception that only living organisms could produce the organic chemicals of life.
Wöhler requested Karl von Scherzer to bring him some coca leaves. This Austrian dude was pretty much living the dream of every gen Z or millennial, as a nice inheritance gave him the financial freedom to quit his printing job and start traveling around. Instead of flying to Bali, von Scherzer participated in the first large-scale scientific expedition of the Austro-Hungarian empire in 1857. Coming home with a stash of coca leaves, he imported some of them into Germany. Just in time for a nice PhD project for Niemann. Although cocaine-enriched extracts were obtained from coca leaves in 1855 already, Niemann was the first to truly isolate and characterize the primary alkaloid. He unsurprisingly gave it the name cocaine and published his research in 1860, earning him his well-deserved PhD.
Niemann was a productive, top notch researcher. In the same year, he described the synthesis of mustard gas from sulfur dichloride and ethylene. Unfortunately, this might have been a case similar to Marie Curie. Niemann correctly noted the toxic properties of this blister agent which as many of you know, saw military use during the first world war. Niemann died shortly after in 1861 due to a devastating lung infection. Maybe, the exposure to mustard gas caused this?
After Niemann’s untimely death, another colleague in Wöhler’s research group concluded his research, determining cocaine’s molecular formula. It might ring a bell for more advanced viewers: this was the guy who coined the Lossen rearrangement reaction. Only thirty years later, Richard Wilstätter determined its true structure. This gentleman is the main character of our story.
Early use of cocaine
Before we dive into the chemistry, we should note that the West rapidly embraced cocaine. Initially, it gained acclaim for its local anaesthetic properties, particularly for calming involuntary eye movements during surgery. This was a significant breakthrough! One funny article described it like this: Patients no longer merely endured nerve pain from having their eyes cut; they even chatted pleasantly during their procedures.
Cocaine also found an advocate in Sigmund Freud, the father of psychoanalysis. After using it himself as a stimulant for the smallest of problems, Freud naively recommended it as therapy for various uses, including morphine or alcohol addiction.
His personal positive experiences clearly blinded him, but pharmaceutical companies also paid him to promote their products. Over time, he could not ignore negative consequences such as addiction, leading Freud to eventually reconsider his stance.
Cocaine’s integration into society also took a significant leap with the creation of Coca-Cola in 1886. Originally formulated as a coca wine substitute, Coca-Cola contained coca leaf extract including cocaine, along with caffeine from kola nuts. Due to growing incidence of cocaine addiction, the allrounder power-drink eventually eliminated cocaine from its formula.
Cocaine synthesis: Wilstätter’s Starting Material
Let’s talk chemistry. Wilstätter didn’t just determine cocaine’s structure – he also completed the first total synthesis of cocaine. Prepare for a wild ride!
His synthesis started from cycloheptanone. But why?
Well, it conveniently brings the largest ring present in cocaine’s structure. Degradation studies by Wilstätter, which we will not show in detail, already indicated that cocaine contains a seven-membered ring. To build up the structure back up, Wilstätter had to painstakingly functionalize the ring, and create the important amine bridge.
Cocaine synthesis: Functionalizing the core
The first few steps included condensation with hydroxylamine and reduction of the resulting oxime to give the amino group. This new group was eliminated through the Hofmann protocol. It starts with exhaustive methylation to the quaternary ammonium salt, followed by elimination with silver oxide and water. Overall, these four steps gave cycloheptene.
You’re likely thinking – wait a second, why didn’t he just perform a Shapiro reaction to save some steps? Well, this reaction was only discovered in the 1960s, so Wilstätter’s armamentarium of chemical reactions was limited.
One double bond is nice, but as you will see, we actually need three of them. Bromination gave the dibromide, temporarily removing the alkene. Addition of dimethyl amine led to substitution and elimination, giving a double bond. Before you get excited, this is not yet the amine for the tropine bridge. Rather, another Hofmann elimination gave the diene. Because this was such great fun, another bromination and elimination with quinoline as a weak base gave cycloheptatriene.
Now, kinda going a step backwards, the triene was reacted with hydrogen bromide. Due to the intermediary formation of the allylic cation, this regio-isomer is preferred as opposed to the other addition product. The newly introduced bromide group was substituted with dimethyl amin. At last, this is the amine that we need in cocaine. The next step was basically why the triene approach even worked. Reduction with sodium metal in ethanol reduced just one of the double bonds, resulting in a single isomer with the surviving alkene situated on the other side of the cycloheptane. Wilstätter himself commented himself that selective reduction is strange. The last preparatory steps were a bromination of the remaining olefin to the trans-dibromide which also formed the ammonium salt. This was neutralized with sodium carbonate, regenerating the electron pair of the amine. This set up the critical step of the synthesis.
Intramolecular alkylation en route to cocaine
So, our molecule now has a potent nucleophile – the amine – as well as electrophilic carbon-bromide bonds. In the energetic ground state, the groups don’t get close so there’s no reaction. However, cooking things up in ethanol provides sufficient flexibility for the ring to distort and get the amine close enough for a transannular SN2 reaction with the anti-bromide. As we’ve explained in detail in a previous video, the reaction proceeds through back side attack and a pentacoordinate transition state. This synthesis is racemic – you can check for yourself that an inverted configuration at the amine leads to the same product as it simply kicks out the other bromide instead.
The product is obtained in roughly 30% yield and from what I could tell reading Wilstätter’s work, it looks like he actually coined the term “intramolecular alkylation”. For 21st century chemists, this reaction looks simple, but for 1901, this is really insane foresight. Having created the tropane skeleton present in cocaine, we still have to demethylate the ammonium group, and functionalize the two ring positions.
Synthesis of Tropidine and tropine
To this end, elimination of the remaining bromide gave the double bond, setting up upcoming functionalizations. Then, the ammonium ion was converted to the neutral amine. Earlier, we’ve had the protonated amine which is why base was sufficient for neutralization. However, now we are looking at a tetra-alkyl ammonium. So, chloride anion exchange and heating removed one of the methyl groups via intermolecular SN2 reaction.
How do we wrap up the synthesis? Well, instead of the alkene, we need an ester and a hydroxy group that we can benzylate. High school chemistry tells us that we can easily add water to double bonds, but in this case, a direct hydration was impossible. Instead, this conversion took two steps. First, exposure to hydrogen bromide gave the secondary bromide. Under acidic conditions, hydrolysis of the bromide gave the alcohol.
Wilstätter and Ladenburg: Two Titans Clash
This step took quite some experimentation to get right, and actually it was a source of dispute between Wilstätter and Albert Ladenburg, another German chemist. Ladenburg had claimed the direct synthesis of the alcohol under cold hydrobromination conditions more than a decade earlier. Wilstätter criticized it, claiming year-long experiments did not replicate his findings.
Very sneakily, Ladenburg updated his experimental procedures in later publications – saying they were included insignificant modifications. However, Wilstätter saw this as a copy of his own research. His procedure strictly required acidic conditions and heat. To him, Ladenburg was hoping to cover up unsuccessful, fabricated findings without drawing too much attention.
This was not the end – within the same year, Ladenburg retaliated, accusing Wilstätter of defaming him by using cheap tricks. He claimed to had repeated the synthesis, not specifying what small amounts of tropine mean, and again downplaying his modifications. I checked his OG report and while correct that he explicitly mentioned use of increased temperatures, he did not add acids or water. You would not call me crazy when I say that Wilstätter’s conditions in blue look pretty important to enable hydrolysis of the bromide.
I’m sparing you the details – but this story really shows how challenging old school chemistry was. Good luck proving that someone did or did not synthesize a structure when the characterization method was doing random characterizations of platinum salts. Basically, Ladenburg was like trust me bro, I know these platinum salts very well.
To him, this was bullet-proof evidence, and he concludes his position as arrogantly as he could. I didn’t check subsequent correspondence but a web-text on Ladenburg noted that he had quite some personal hostilities, so I’m not surprised.
My vote goes to Wilstätter. Ladenburg, again in peak 1900s style, used the low volatility of his putative tropine product as an argument to prove its identity. Turns our whatever Ladenburg had, it was not tropine, as Wilstätter showed that tropine is in fact volatile. Ladenburg hid his sneaky changes to such a degree that even a gentleman reviewing and writing about the procedure did not catch the changing method. Although you might not like Ladenburg knowing this, we have to give credit where credit is due.
He was in fact the first chemist to synthesize an alkaloid. This means he is one of the founding fathers of total synthesis. Starting from 2-methyl pyridine, he synthesized coniine – a simple but toxic alkaloid – in two steps. First, a condensation reaction delivered allyl pyridine and second, complete reduction with sodium gave the target. Given the condensation required 250 °C, you won’t be surprised that the yield was “pretty bad” as Ladenburg put it – 45g out of 1kg of educt. Just like today’s synthetic chemists struggling in total syntheses, he had to perform multiple reaction cycles by recovering unreacted starting material. Ladenburg also managed to separate the enantiomers through separation of diastereomeric tartrate salts.
Cocaine Synthesis: final Steps
Back to cocaine. The conversion of tropidine to tropine was actually the missing link. Wilstätter himself proudly concluded his report that this step completed the total synthesis of various alkaloids, including cocaine. The remaining steps were already known so the synthesis was not discovered linearly. Let’s see how we can wrap things up. Of course, the newly formed hydroxyl group could be benzylated but that wouldn’t help us with the missing ester group.
Thus, the hydroxyl group was first oxidized to the ketone which allowed alpha-functionalization. Nucleophilic addition of the enolate with CO2 creates the last important C-C bond. The addition is diastereoselective for the axial product, opposite to the rest of the tropine skeleton.
Instead of direct esterification, the ketone was reduced first. You might be surprised, wondering why the hydride now has added from the bottom face? Don’t forget the bunny ears! In the equatorial product, the hydrogen enjoys almost perfect alignment with one of the oxygen’s lone pairs, leading to a short and strong intramolecular hydrogen bond. However, the reported yield was low with no info on product ratios, so we can’t really say what was thermodynamically or kinetically favored.
The last steps were pretty simple. First, the methyl ester was completed through acidic Fischer esterification. Finally, addition of the activated reagent benzoic anhydride introduced the benzyl group, concluding the first total synthesis of cocaine. All in all, Wilstätter’s effort spanned roughly 23 steps, and the net yield must have been horrendous.
This wouldn’t be a century-old tale without the chemists trying their synthetic cocaine, noting a bitter taste and characteristic feeling on the tongue. Wilstätter elucidated and/or synthesized other important molecules, including proline and cyclooctatetraene. He received the Nobel Prize in 1915, primarily actually due to this research on the structure and function of chlorophyll.
Robinson’s Cocaine Synthesis (1917)
Wilstätter’s total synthesis was remarkable feat of skill and perseverance, with the majority of the effort focusing on the synthesis of tropinone. Unfortunately, there’s always another chemistry legend out there getting ready to ruin your career. We’re talking about Robert Robinson, well known for his own Nobel Prize and coining key chemistry concepts we still use today – such as curly arrows representing electron movement.
Robinson published research in 1917 that made Wilstätter’s signature efforts look pretty outdated. Robinson didn’t hold back, noting that the method was so complicated that he didn’t even bother to recall it in detail. His argument was that the long and low-yielding synthesis did not represent an economically workable alternative to natural sources.
Robinson’s breakthrough finding was a one-pot reaction of three components, giving tropinone in an impressive 42% yield. If haven’t seen this one before, feel free to pause the video right now, and think about a potential mechanism for this reaction.
The reaction starts off with condensation of the nucleophilic methylamine to one of the electrophilic aldehydes. After loss of water, the intermediary imine is still nucleophilic and can form a ring by a second addition – turning it into a positively charged electrophile. The enol tautomer of the acetone dicarboxylate steps in and adds to the iminium in an intermolecular Mannich reaction.
Due to the carboxylate groups, the acetone reagent functions as a di-anion equivalent. After the addition, we can have a decarboxylation of one of the groups, and reprotonation. As the nitrogen regained its electron pair after the first Mannich reaction, it can kick out the adjacent hydroxyl group, creating yet another electrophile that is ready to undergo a second, now intramolecular Mannich reaction. A second decarboxylation affords tropinone in a process that is, as we would all agree, much simpler than Wilstätter’s approach.
Noyori’s Cocaine Synthesis (1974)
Note that by the early 20th century, the use of cocaine was peaking. Newspapers were filled with ads promoting the drug, and people were using it either recreationally or ironically, to overcome morphine addiction. Thousands of deaths from cocaine abuse prompted the US to regulate the drug in 1914. This removed cocaine from over-the-counter remedies and consumer products.
How did the chemistry evolve? For the sake of science of course, many chemists tried to synthesize tropane alkaloids in a more efficient manner. One elegant approach was described by Noyori in 1974, who is well known for his discovery of asymmetric hydrogenations. This won him the Nobel Prize together with Knowles in 2003. 1974 was actually the year when Noyori and co-workers initiated the synthesis of BINAP diphosphane.
Just like Robinson, Noyori attempted to simplify the synthesis of tropinone – the intermediate that Wilstätter only accessed painfully over dozen steps. He disconnected the same bonds but instead of Mannich reactions, he employed a cycloaddition to link the ring. Don’t blink, because this one is also very short.
The reagent diiron nonacarbonyl is a reactive source of iron(0) which can reduce the tetrabromoacetone to an oxyallyl intermediate. A [4+2] cycloaddition with a pyrrole creates the tropane structure. If you’re confused by the charges, the addition does form a positive charge on the central allyl carbon but the negative charge on the oxygen regenerates the ketone. Two reductions gave tropine – first, the superfluous double bond and bromides were removed with hydrogenation, and second, the ester was reduced to the methyl group.
Why even have these extra bromo groups and ester in the first place? Well, initial attempts with dibromo acetone instead of tetrabromo acetone as a precursor did not form the oxyallyl intermediate. Similarly, the direct use of N-methyl pyrrole led to electrophilic substitution products on the pyrrole, as opposed to cycloaddition. It makes sense use of the ester deactivates the pyrrole, taming its reactivity for substitutions. Noyori nicely overcame these challenges, but just like all other syntheses, the value of this synthesis was primarily in the chemistry, rather than allowing easier access of cocaine.
Cocaine Biosynthesis
As a side note on biochemistry, the biosynthesis of cocaine only fully solved in late 2022. This research showed that the biosynthesis of tropane alkaloids from different plant orders – here in green and pink – uses unique enzyme classes but arose independently at least twice during the evolution of land plants. Similar to Robinson’s one-pot tropinone synthesis, we have an electrophilic iminium which reacts with an activated nucleophile. However, compared to Robinson’s electrophile, this iminium is not doubly activated. This means that there is no dual addition and decarboxylation. Instead, there is enzyme magic to oxidize and cyclize the tropane ring. If you are interested in biosynthetic pathways, you can check out the clever isotope-labelling experiments which elucidated some pieces of the puzzle already in the mid-20th century.
Cocaine synthesis via Engineered Tobacco?
Many organic chemists think biochemistry is boring but check this out. By understanding biosynthetic pathways, scientists have recently genetically engineered tobacco plants to produce two new enzymes in their leaves.
This is far too complex for large scale criminal synthesis of cocaine, but pretty cool. Agrobacteria can transfer and insert parts of its DNA into plant cells – giving tobacco the tools to synthesize cocaine. In a funny parallel to the chemical synthesis of cocaine, the last step is a benzoylation. Tobacco produces endogenous benzoic acid, but the plants were treated with additional benzoic acid to further double the cocaine yield – which is way higher than I would have predicted.
Congrats, you now probably know more about cocaine than everybody else you know. Thanks for following my content, and see you in the next one!
If you are interested in the synthesis of psychedelics, check out the discussion of ibogaine, psilocybin, MDMA or THC-P.
Cocaine synthesis references
– UNODC, Global report on Cocaine 2023 (United Nations publications, 2023) – Estimating the incidence of cocaine use and mortality with music lyrics about cocaine | npj Digital Medicine 2021, 4, 100 – Cocaine: An Updated Overview on Chemistry, Detection, Biokinetics, and Pharmacotoxicological Aspects including Abuse Pattern | Toxins 2022, 14, 278 – DARK Classics in Chemical Neuroscience: Cocaine | ACS Chem Neurosci 2018, 9, 2358 – Cocaine Use Disorder (CUD): Current Clinical Perspectives | Subst Abuse Rehabil. 2022; 13: 25 – Ueber die Einwirkung des braunen Chlorschwefels auf Elaylgas | Justus Liebigs Annalen 1860, 113, 288 – Synthese des Tropidins | Ber. Dtsch. Chem. Ges. 1901, 34, 129 – Ueber die Umwandlung von Tropidin in Tropin | Ber. Dtsch. Chem. Ges 1902, 35, 1870 – Umwandlung von Tropidin in Tropin | Ber. Dtsch. Chem. Ges 1902, 35, 2295 – Synthese der activen Coniine | Ber. Dtsch. Chem. Ges 1886, 19, 2578 – Richard Willstätter and the 1915 Nobel Prize in Chemistry | Angew. Chem. Int. Ed. 2015, 54, 11910 – A synthesis of tropinone | J. Chem. Soc., Trans., 1917,111, 762 – New, general synthesis of tropane alkaloids | JACS 1974, 96, 3336 – Elucidation of tropane alkaloid biosynthesis in Erythroxylum coca using a microbial pathway discovery platform | PNAS 2022, 119, e2215372119 – Discovery and Engineering of the Cocaine Biosynthetic Pathway | JACS 2022, 144, 22000 (not 21809)
Ever struggle with how to identify if a group is a nucleophile vs. electrophile? If you are in a rush and don’t care about learning chemistry (bruh), the first sections got you. I recommend you try to truly understand the concept as it’s arguably the most important skill in organic chemistry.
Nucleophile vs electrophile: Summary
1. Nucleophiles (nucleus-loving) are neutral or negatively charged species that donate high energy electrons to form new bonds with electrophiles (electron-loving), which are neutral or positively charged species that can easily accept electrons
2.Nucleophiles are Lewis bases (e.g. NH3); electrophiles are acids (e.g. H+, BF3)
3. The chemical bonding occurs between the highest occupied (HOMO) of the nucleophile and the lowest unoccupied molecular orbital (LUMO) of the electrophile
4.Single atoms, sigma-bonds and pi-bonds can be nucleophilic or electrophilic – and the same molecule can contain both (one part nucleophilic, one part electrophilic)
Nucleophiles and electrophiles are complementary, they react with each other. You will never see a reaction where two groups react with each other as nucleophiles!
Level 0: Chemical bonds are like … financial transactions?
Chemistry is like finance! Simply swap electrons (chemical currency) for money.
If you’re a student, you’re likely broke(you are in need of, and easily accept money => you are electrophilic). You go to your parents to borrow some money for a dinner (they can donate money => they are nucleophilic). By getting money and the food, you get happier (you are energetically stable). Your parents are also stoked they can spend some time with their favorite child (they are also energetically stabilized).
This explains how we draw curly arrows, representing electron movement: There are no electrons at the electrophile (it is broke). Instead, the electron donation arrow starts at the nucleophile and points to the acceptor, the electrophile.
Level 1: Nucleophile vs electrophile
You have two options on how to remember which is which: 1. Not recommended: You force-memorize some analogy like above with no brain cell activation, setting you up for nice failures in organic chemistry exams
2. Recommended: You just use your brain and simply remember that “phile” means liking or loving (if you struggle to remember, you know a highly criminal term…)
Nucleophile
Electrophile
P*d*phile
What it has
Has more than enough electrons
Has some sort of positive polarization
Problems, chocolate & puppies
What it wants
Wants to share its electrons (likes positive charges)
Wants to accept other electrons (likes electrons)
Kids
Charge
Neutral or negative
Neutral or positive
Prison sentence
Orbitals
High-energy occupied
Low-energy unoccupied
Orbits around kids and playground
Acid or base
Lewis base
Lewis acid
Puts them in his base(ment)
The electrons that a nucleophile donates form the new bond with the electrophile. A simple example is the protonation of water. Which is the nucleophile vs electrophile?
Reviewing the more complex mechanism for the hydration of formaldehyde, you will realize that: 1. Specific atoms or also bonds can have nucleophilic or electrophilic behavior For example, in the first step, the carbonyl pi-bond is the electrophile. In the second step, the proton H+ is the electrophile.
2. For reactions with multiple mechanistic steps, there can be many different nucleophiles and electrophiles For example, after the first addition to the carbonyl, the previously nucleophilic water molecule turns into a cationic intermediate which is now electrophilic (which is why it reacts with another nucleophilic water in a deprotonation)
Level 2: Types of nucleophiles
How do we identify electron donors and electron acceptors? There are threecategories for both. It’s easier for nucleophiles, so let’s start there.
To donate an electron pair, you need to have an electron pair somewhere(duh). In our analogy, you need to find the bank vaults that are filled with cash(electrons)!
1A) Lone electron pairs, e.g., water H2O or ammonia NH3 (neutral nucleophile) Reaction example: Protonation of neutral bases 1B) Negative charges (also electron pairs), e.g., hydroxide OH– or cyanide CN– anions Reaction example: Basic hydrolysis of an ester 2) Bonding pi-orbitals, most notably C=C double bonds, e.g., alkene or aromatic ring Reaction example: Bromination of alkenes, electrophilic aromatic substitution 3) Bondingsigma-orbitals with highly electropositive atoms, e.g., methyllithium Li-CH3 Reaction example: Carbonyl reduction with LiAlH4, organometallics
This should make sense. These are the only “ways” you will ever find electrons in a molecule. Either as an unbound electron, in a pi-bond, or in a sigma-bond. This corresponds to the idea of highest occupied molecular orbitals (see below).
Level 2: Types of electrophiles
What about electrophiles? Two categories are similar, and one is different.
To accept an electron pair, you need to have an empty orbital somewhere (duh). Here, we need to find the empty wallets that are eager to get filled with money!
Like nucleophiles, we have pi- and sigma-bonds as acceptors (as they have empty orbitals that can be filled with electrons). However, instead of electron pairs for nucleophiles, we need to look for empty orbitals on single atoms. Think of the empty orbitals like filled purses
1A) Positive charges representing an empty p orbitals, e.g., proton H+ Reaction example: Protonation of any base 1B) Neutral molecule with empty p orbital, e.g., Lewis acids like BF3 or AlCl3 Reaction example: Friedel-Crafts acylation 2) Pi-bond next to electronegative/ stabilized system, e.g., carbonyl Reaction example: Aldehyde hydration, conjugate addition 3) Sigma-bond to electronegative atom, e.g., methyl iodide CH3-I Reaction example: SN2 reaction, bromination of alkenes
For both of these categories, I always represented the nucleophile as “Nu-” and electrophile as “E+”. But any combination of these categories works – e.g., an nucleophilic pi-bond can attack an electrophilic pi-bond!
If you know a fair share of reactions, try to think about additional examples for each!
Level 3: Orbitals
Let’s get to the bottom of this (without me writing another text book on orbitals).
Remember that reactions take place if molecules…
1. Overcometheir electronic repulsion via charge attraction and/or orbital overlap (all reactions have activation energies) 2. Have orbitals of appropriate energyto interact (if orbital energies are too different, there is no energy gain from bonding) 3. Orient in a geometry that allows their orbitals to overlap in a bonding interaction (if a key can’t get into a lock, the door can’t be unlocked)
Point #2 is critical: energy levels of the nucleophile and electrophile orbitals. The strongest stabilization comes from interacting orbitals with similar energies.
All molecules have many low-energy, unfilled orbitals and high-energy, empty orbitals (illustrative grey orbitals). We can ignore all because the energy differences between them are too large. The most relevant interaction will be the one between the lowest-energy unoccupied (LUMO) and highest-energy occupied molecular orbital (HOMO).
The higher-energy a HOMO is, the easier it can donate electrons into LUMOs. The lower-energy a LUMO is, the easier it can accept electrons.
This picture explains the types of electrophiles… 1A + B) Empty orbitals can be LUMOs (neutral or positively charged atom) 2) Pi-bonds always have an empty antibonding pi-star MO which can be a LUMO 3) Similarly, sigma-bonds have an antibonding sigma-star MO which can be LUMO
… and types of nucleophiles: 1A +B) Lone pairs can be HOMOs (neutral or negatively neutral charged atom) 2) Pi-bonds always have a filled bonding pi MO which can be a HOMO 3) Similarly, sigma-bonds have a filled bonding sigma MO which can be a LUMO
Recap: Nucleophile vs electrophile
By now you should be able to identify a nucleophile vs electrophile, and know the different types that exist. As an exercise, review reactions you already know or that I discuss on my channel, or functional groups (e.g., protecting groups) to apply your learnings.
There are more nuances and explanations which are not digestible in a single post. So, future posts will explain things like: – What are the most common nucleophiles and electrophiles? – How does conjugation to electron-donating or -withdrawing groups influence nucleophilicity or electrophilicity?
The TBS protecting group protects alcohols in organic synthesis, and is deprotected with fluoride anions (e.g., TBAF) or strong acids.
This bulky silyl PG is resilient, allowing for selective/ orthogonal deprotection of similar groups like TMS.
For silyl ethers, bigger is better! As they have 3 different mechanisms for deprotection, they’re a nice general learning opportunity for students.
👀 Here’s an interactive 3D model of the TBS protecting group.
What is the TBS Protecting Group?
TBS or TBDMS is short for tert–butyldimethylsilyl, a protecting group for alcohols. TBS was introduced by the legendary E. J. Corey in 1972 [1] as an evolution to simpler silyl ethers which had already been known. Note this was right around the time of Fmoc discovery, and relatively late in the history of organic synthesis.
The research already covered protection and deprotection conditions still used today. It is one of the most cited JACS publications ever. A decade later, Corey also introduced triflate reagents for silyl ether synthesis [2].
TBS Protection Mechanism
TBS protection by Corey uses TBS-Cl (forms hygroscopic white crystals) in DMF with imidazole or DMAP. Corey encountered challenges using TBS-Cl for protection of tertiary or hindered secondary alcohols. Use of TBS-OTf triflate (with 2,6-lutidine as base in solvents like dichloromethane) proved more potent for such cases.
The classic mechanism contains generation of an imidazolium intermediate which acts as a silyl transfer reagent for the actual silylation. The steps might look counterintuitive. Silicon, in contrast to carbon, can have five bonds at once! Both silylations likely proceed through associative substitutions with pentavalent silicon intermediates. However, you’re likely also fine drawing a concerted step.
Silyl ether protecting group Stability
Many different variants of silyl ethers exist. Despite their overall similarity, they can behave quasi-orthogonal due to different lability. Below, you can see the relative stability towards acidic and basic aqueous hydrolysis.
Silyl ether protecting group
Stability to acid
Stability to base
TMS (trimethylsilyl)
1
1
TES (triethylsilyl)
~60
~10-100
TBS (tertbutyldimethylsilyl)
~20’000
~20’000
TIPS (triisopropylsilyl)
~700’000
~100’000
Stability data from [3]
As you can see, bigger silyl ethers are more stable than smaller ones. This stability directly shows – TBDMS ethers are stable to chromatography and survive various reaction conditions which smaller ethers do not. With different labilities, chemists can deprotect TMS or TES ethers inpresence of TBS protecting groups (more below).
TBS Deprotection Mechanisms
There are three types of deprotection mechanisms for TBS and silyl ethers in general.
Acidic deprotection works through protonation of the protected oxygen atom, followed by associate hydrolysis with a pentavalent silicon intermediate.
The deprotection with hydroxide or fluoride anions follow similar mechanisms – direct nucleophilic attack onto silicon, followed by cleavage of the Si-O bond.
For fluoride-mediated deprotection, TBAF (tetrabutylammonium fluoride) is the archetypical fluoride source. However, other sources like HF or amine-HF complexes are also commonly used. The underlying thermodynamic driving force is the formation of the exceptionally strong Si-F bond (>30 kcal/mol stronger than Si-O) bond.
Selective Deprotections of silyl ethers
So, we have mentioned that selective deprotection of silyl ethers might be possible. The first category of reactions follows the steric stability we laid out above. Let’s look at some examples [4].
Pyridinium p-toluene sulfonate (PPTS) in protic solvents like MeOH is the mildest system for deprotection of TBS ethers. In this example, you can see that the conditions are controlled enough so that the bulkier TIPS group does not fall off. The same would go for TBDPS (tert-butyldiphenylsilyl).
The next step in the synthesis is addition of K2CO3 to the diol. What is the product?
This next example is sneaky. Don’t be fooled by seeing “TMS” and thinking it will immediately be less stable than TBS! Upon close inspection, we realize that this is actually a alkyl silyl group, part of the so-called SEM protecting group. The TMS group here survives protic acids but cleaves with fluoride anions.
Another question: Propose a mechanism the deprotection of SEM with TBAF!
Welcome to chemistry, it’s sometimes random
The second category of selective reactions does not follow any obvious rules. It’s really experimental randomness. A commonly cited example is from the synthesis of zaragozic acid C [5].
During this effort, it was possible to differentiate between two very similar TBS protecting groups. The use of dichloroacetic acid in MeOH was mild enough to selectively (90% yield) cleave only one of the TBS groups.
That same synthesis actually also nicely demonstrated the concept of selective protection based on steric hindrance. After full consumption and protection of the primary alcohol with TBS-Cl, the chemists threw in TMS-Cl to protect the tertiary hydroxyl group as well.
There’s a recent example (2024) of TBS randomness [6]. In the last synthetic steps towards (+)-heilonine, the authors performed a Clemmensen reduction with Zn in HCl to reduce the ketone. It would have been nice if this one-two punch would have directly delivered the natural product. However, for no apparent reason, only one of the two TBS groups fell off. So, a separate deprotection step with TfOH was required.
TBS Protection experimental procedure [7]
“To a solution of the diol (57.48 g, 0.354 mol) in DMF (354 mL) were added imidazole (96.52 g, 1.418 mol) and TBSCl (160.27 g, 1.063 mol) at rt. After stirring at 50 °C for 17h. H2O was added and the mixture was extracted with Et2O. The organic layer was washed with brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2; n-hexane:EtOAc = 10:1) to give the diTBS ether (138.48 g, 100%).”
TBS deprotection experimental procedure [7]
“To a solution of the alcohol (45.2 g) in THF (350 mL) was added TBAF (1.0 M in THF, 184 mL, 0.184 mol) at rt. After stirring at rt for 18 h, the mixture was concentrated in vacuo. The residue was purified by flash column chromatography (SiO2; n-hexane:EtOAc = 4:6→EtOAc) to give diol (29.1 g, 97% yield, 2 steps).”
Do you struggle to comprehend the SN2 mechanism, or the difference between SN2 vs SN1? You are not alone! All of us need models and practice to understand what the molecules look like in their 3D structure. On my channel, you can find some more visual explanations and animations that might help.
SN2 Mechanism: it takes two to tango
Our first model reaction is the nucleophilic substitution of 2-bromobutane with the phenolate anion, also called a Williamson ether synthesis.
2-Bromobutane is chiral as one of the carbons has four different substituents. We are looking at the (R)-enantiomer here – this will be important for the stereospecificity of the reaction. Electrophiles provide the LUMO for reactions, in this case the antibonding sigma star orbital between carbon and our leaving group. Note that bromide and iodide are particularly potent leaving groups due to high acidity of conjugate acids but also weak bonds with carbon. This is due to weak overlap of atomic orbitals, resulting in a low-energy sigma star that is accessible to our nucleophile, phenolate.
This electron-rich anion is completely planar due to conjugation of one of the oxygen electron pairs with the aromatic ring. Its HOMO is localized on the oxygen as you would expect – but we can also nicely see resonance with delocalization across the pi-system.
SN2 Transition state
To ensure decent orbital overlap, the substitution proceeds via back-side attack. Because the nucleophile needs to get pretty close to the already tetrahedral carbon, steric factors are more important for the SN2 reaction compared to SN1.
The SN2 mechanism proceeds in one concerted step with both electrophile and nucleophile present in the transition state – that’s why we call it 2, for bimolecular. The carbon-bromine bond is partially broken, and the carbon-oxygen bond partially formed. Remember that is just a transient energy maximum and not a real intermediate, carbons are never actually five-coordinate!
After the transition state, the product moves to a more comfortable conformation but importantly, features the inverted stereochemistry due to back side attack. This changes the (S) enantiomer in the starting material to the (R) enantiomer product. As a good leaving group, the bromide anion enjoys its solitude and buzzes off.
Steric effects in SN2 substitutions
Due to the five-coordinate transition state, more sterically hindered substrates react much slower or not at all. While it’s not intuitive on paper, the model nicely visualizes that surrounding substituents can block the nucleophiles back side attack. There’s simply too much unwanted repulsion. Instead, depending on reaction conditions like solvent polarity, we would see more step-wise SN1.
Intramolecular SN2 reaction Mechanism
Let’s look at a slightly more advanced example. I’m TotalSynthesis, so I just had to take a cute natural product that was isolated from random tropical algae in Brazil. As fate wanted it, this also has a secondary alkyl bromide, so it fits perfectly.
We’re interested in this epoxide opening step as it showcases a common question on diastereoselectivity. The reaction is intramolecular but is pretty similar to a SN2-type reaction. Given our fixed starting configuration, the side chain and the nucleophilic alkoxide hover on the bottom side of the ring.
As you can see, the nucleophile has a perfect position for the backside attack, leading to the 1,2-anti product. The leaving group is now much worse than bromide, but relieving the strain energy present in the epoxide drives the reaction forward.
Is there another potential substitution? Indeed, the other epoxide carbon is also an electrophile. However, the methyl group at this position adds some steric hindrance. Given the quaternary center, this substitution could also proceed stepwise or “asynchronous”, with C-O bond breaking being more advanced prior to addition.
Taking the longer approach forms a 7-membered ring. Compared to the six-member ring on the right, it’s not as rapidly formed or as stable – but the pathway is still significant with 19% yield.
After six additional reactions, a surprising twist showed that the original proposal was incorrect. It turned out this unique natural product never existed to begin with! Instead, it was a mis-assigned, already known molecule, which is even a bit cooler given it includes two bromides and even a chloride. Well, it happens to the best of us.
I’m looking forward to explaining simple, beginner-level content in addition to my other educational videos. Let me know if this helped you!
The Fmoc protecting group protects amines in synthesis, and is deprotected with bases such as secondary amines like piperidine.
You might not expect it, but this group is similar to other carbamates (Boc, Cbz) despite being orthogonal.
But, have you heard of Sulfmoc or Bsmoc? We will also discuss these to explain important chemistry concepts.
👀 Can you find the acidic C-H bond in this 3D model of Fmoc?
What is the Fmoc Protecting Group?
Fmoc is a fluorenylmethoxycarbonyl group that forms carbamates with amines. However, as a common theme, alcohols and other nucleophiles can also be protected.
Fmoc was introduced by Carpino in 1972 [1]. You will realize that this is pretty late in the game!Few base-sensitive amine protective groups were known. Chemists obviously already used protecting groups, but they were not as straight-forward. For example, the tosylethyloxycarbonyl group (base-labile with KOH/NaOEt) gave the stable carbamate salt which required a second step for decarboxylation.
Fmoc Protection Mechanism
The classic Fmoc protection is with Fmoc-Cl under Schotten-Baumann conditions (e.g. NaHCO3/dioxane/H2O or NaHCO3/DMF), or with anhydrous conditions (e.g. pyridine/CH2Cl2).
If you have seen more than one protecting group, this will not surprise you: The mechanism is attack of the nucleophilic amine to the highly reactive 9-fluorenylmethyl chloroformate. As chloride is the leaving group, the reaction liberates HCl which is neutralized by the base.
Fmoc-Cl can be handled easily (it’s a solid) – however, as it’s an acid chloride, is sensitive to moisture and heat. Thus (as for all protective groups), other “Fmoc+”-equivalent reagents offer more optionality.
Fmoc-OSu is most commonly used nowadays due to the increased stability of this succinimide carbonate. It also has lower unproductive formation of oligopeptides that can occur during preparation of Fmoc amino acid derivatives.
Additional options exist such as Fmoc-OBt or Fmoc-N3. However, you would rather deal with some harmless solids than explosive azides…
Fmoc DeProtecTION Mechanism With Base
Fmoc is typically deprotected with secondary amines in DMF. The mechanism has some parallels to Boc. Instead of a stabilized (tertiary) carbocation as an intermediate, Fmoc proceeds through a fluorenyl anion. But why is it stabilized? The position might not seem acidic at first sight.
Upon closer inspection, we see the deprotonated system fulfils Hückel’s rule for n=3 (14 electrons) and is aromatic! That’s why the pKa of fluorenyl is around ~23 (DMSO). This is basically a cyclopentadiene anion (whose aromaticity you will know) sandwiched between two benzene rings.
The intermediary carbanion can eliminate the carbamate in a E1cb mechanism, releasing dibenzofulvene. This side product lead to byproducts (e.g., reaction with nucleophilic amino acid groups) or polymers. This is why secondary amines like piperidine or morpholine are particularly handy!
They hit two birds with one stone. They cleave Fmoc, and also form a stable adduct with the dibenzofulvene. The “secondary” part is quite important as ammonia does not add to the fulvene system [1].
Fmoc DeProtecTION Speed
There is another reason why piperidine is the most commonly used base to deprotect Fmoc. This table compares half-lives for Fmoc-ValOH in presence of various amine bases in DMF.
Amine base used for Fmoc deprotection
Half life t1/2
20% piperidine
6 seconds
5% piperidine
20 seconds
50% morpholine
1 minute
50% dicyclohexylamine
35 minutes
50% diisopropylethylamine
10 hours
Half-life data from [2]
Piperidine (and morpholine) deprotection is virtually instantaneous on the second-scale. In contrast, secondary or tertiary amines deprotect Fmoc more slowly (hours) and require higher amounts of base. If you wonder, going from DMF to other solvents like DCM reduces the reaction rate.
Fmoc protecting group Orthogonality
Fmoc is very stable towards acid and electrophiles, tolerating reactive reagents like HBr, trifluoroacetic acid, sulfuric acid and thionyl chloride. Thus, its orthogonal to Boc.
However, it is only quasi-orthogonal to Cbz as it undergoes hydrogenolysis as well! It is less reactive than benzyl groups, so selectivity can be achieved. The reduction can occur under traditional (Pd/C, H2) or different transfer catalytic conditions. The final step of the synthesis of Enkephalin was triple-deprotection of O-Bn, CO2-Bn and N-Fmoc.
Question for you: Enkephalin is a human neuropeptide which binds to the body’s opioid receptors. What is the amino acid sequence of the enkephalin form here?
Fmoc Variants
Let us again look at some more advanced concepts. There are Fmoc-related variants that are more base-labile. By attaching electron-withdrawing substituents like sulfonic acid or halides.
What are the effects? Specifically, Sulfmoc increased proton abstraction by a factor 30 in DCM (vs. Fmoc) using 10% morpholine in DCM, or factor ~10 for 10% piperidine [3]. In specific cases, such labile groups might be pretty useful. By the way, Sulfmoc was introduced by Merrifield who won the Nobel Prize for inventing solid-phase peptide synthesis.
Evidently, this comes from acidification of the fluorenyl position. The 2,7-dibromo Fmoc analog has a pKa value of 17.9 or almost 5 units lower than normal Fmoc!
However, there’s an even cooler analog, also published by Carpino called Bsmoc. It can be cleaved under specific conditions which leave normal Fmoc in tact, but typical conditions with piperidine work as well [4].
Another test for your skills: What is the mechanism of N-Bsmoc cleavage with secondary amines? Don’t scroll to the answer below before thinking about it!
Fmoc in Peptide Synthesis
Fmoc was rapidly adopted in modern peptide chemistry [5]. Compared to the established Boc, it was easy to automate: no corrosive TFA is required, and reaction monitoring is easy due to the fluorene by-product (see deprotection). Fmoc SPPS machines were less expensive and avoided use of unpleasant hydrogen fluoride (HF). The conditions themselves were more compatible with modified peptides (e.g., modification with carbohydrates, phosphorylation…).
As another advantage, the Fmoc protecting group enables orthogonal combination of temporary and permanent protecting groups. During Boc SPPS, iterative use of TFA during each cycle leads to deprotection of small amounts of side-chain protecting groups and cleavage of peptide from polymer support.
Bsmoc solution
Let’s conclude with Bsmoc.
The innovative thing is that it functions as a protecting group and scavenger in one! It’s introduction is analogous to normal Fmoc, using the chloroformate or H-hydroxysuccinimide ester. Instead of a deprotonation with piperidine, we have a Michael addition to the conjugated sulfone.
The free carbamate proceeds to decarboxylate as always, but the piperidine stays on the Bsmoc group (thus, it’s a direct scavenger). You might not expect it but it’s very logical: The initial adduct rearranges after some time to the isomer where the double bond is conjugated to the benzene ring.
The ‘quasi-orthogonal’ conditions for Bsmoc-Fmoc are tris(2-aminoethyl)amine as a base. This primary amine cleaves Bsmoc rapidly while keeping Fmoc in tact. On the flip side, use of more hindered bases like diisopropylamine do not react with Bsmoc but cleave the Fmoc group! This is a consequence of steric hindrance slowing down the nucleophilic Michael addition.
I hope you learned something new today!
Fmoc Protection experimental procedure [6]
D-Threonine (5.00 g, 42.0 mmol) and Fmoc-succinamide (14.9 g, 44.1 mmol) were dissolved in a 2:1 v/v mixture of THF:saturated aqueous NaHCO3 (100 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction was then diluted with water (50 mL) and the pH of the mixture was adjusted to pH 9 via addition of saturated aqueous NaHCO3. The mixture was extracted with diethyl ether (3 x 50 mL) and the aqueous layer was acidified to pH 1 via addition of 1 M HCl. The acidic aqueous mixture was extracted with ethyl acetate (3 x 100 mL) and the combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford crude Fmoc-D-Thr-OH (14.3 g) as a white foam which was deemed to be sufficiently pure and used without further purification.
Fmoc deprotection experimental procedure [7]
In a vial, SM (2043 mg, 2.5mmol) was added and dissolved in 60 mL of acetonitrile. Then, morpholine (647 uL, 7.5mmol) was added while stirring. The reaction was stirred at room temperature for 24 hours, formation of product and full conversion was confirmed by LC-MS. The reaction was quenched by addition of water and extracted with DCM. The organic 9 phases were combined and washed with aqueous LiCl 5%, dried with sodium sulphate and filtered. The solvent was evaporated and crude product the crude product was purified by silica gel flash chromatography (0-5% MeOH in DCM).
The Cbz protecting group protects amines as less reactive carbamates in organic synthesis and is deprotected with hydrogenolysis.
N-Cbz is orthogonal to numerous protecting groups as it’s stable to bases and acids. Its removal by reduction is unique but it has similarities to other protecting groups!
👀 You can play around with this 3D model of the Cbz group! Note the orientation of the phenyl ring: it’s not co-planar with the carbamate!
What is the Cbz Protecting Group?
Cbz is a benzyloxycarbonyl group (formerly carboxybenzyl) and protects amines as carbamates. More rarely, chemists might use Cbz to protect alcohols as their carbonates.
Leonidas Zervas (no not the one from the movie “300”) introduced the Cbz group, thus also abbreviated as Z [1]. With this discovery, Leonidas and his advisor Bergmann spearheaded the field of controlled peptide chemistry. In the 1930s, Cbz unlocked the synthesis of previously inaccessible oligopeptides. Zervas continued to be a driving force in peptide chemistry, including development of other protecting groups.
Cbz Protection Mechanism
Cbz protection is typically performed with Cbz-Cl either under Schotten-Baumann conditions (carbonate base) or with an organic base. The mechanism is attack of the nucleophilic amine to the highly reactive chloroformate. As chloride is the leaving group, the reaction liberates HCl and requires some base.
Like we’ve seen for Boc, Cbz2O or other activated agents (e.g., Cbz-OSu) can offer more optionality, depending on the system. If you are into exotic reagents, you might like reagents A or B in the next figure – basically, anything with an activated “Cbz+” synthon works.
As is common the case, we can protect amines selectively given their higher nucleophilicity. However, there have been some reports of challenging selective protection of secondary amines over secondary alcohols. As always, our rules of thumb depend on the specific system at hand.
Cbz DeProtecTION Mechanism With Hydrogenolysis
Hydrogenolysis deprotects Cbz protecting groups, usually in an easy and rapid manner. The mechanism is a reduction with H2, releasing toluene and the free carbamate. Consequently, decarboxylation to the deprotected amine is very much favoured (particularly at elevated temperatures).
Besides molecular H2, it is possible to use other “H2 donors” through transfer hydrogenation reactions (e.g., see procedures below).
Cbz protecting group Orthogonality
Cbz is orthogonal to Boc, Trt, Fmoc and other common protecting groups. As mentioned, it was an essential part of the early days of peptide synthesis.
But beware thinking it’s fully orthogonal! Although Cbz tolerates some acid, harsh conditions can cleave it as well (e.g., excess HCl, HBr)! This mechanism includes protonation of the carbamate and liberation through SN2 and decarboxylation.
Beyond hydrogenation, Cbz can be susceptible to other transition metal catalysis as well, for instance Ni(0) or Pd(0). This interesting case reportdemonstrated selective removal of double Cbz-protected histidine [2] . Compared to heteroaromatic nitrogen atoms, originally basic amines did not engage in any reaction.
This is a great question for you: Suggest a mechanism for the reaction (note the other reagent!) and propose an explanation for the selectivity!
Cbz use cases and tricks
As always, it would be boring to just look at the simplest case of nitrogen protection and deprotection. Let’s briefly discuss three additional topics [3].
First, Cbz protects other nucleophilic functional groups like alcohols, phenols, thiols… as well. In these cases, an organic base (not carbonate) in dichloromethane or some ether-based solvent is typically used. To increase reactivity, NaH as base allows for protection of deactivated, tertiary alcohols:
Notably, Cbz-Cl as a reagent can activate pyridines to regioselective nucleophilic attack. The use of electrophiles for these purposes is a key concept in heterocyclic chemistry. There is a nice collection on 1-acylpyridiniums by the Baran Lab.
Third and coolest, the Cbz group can serve as a masked N-methylamine. Treatment with LiAlH4 exhaustively reduces the carbamate to the alkane.
Cbz Protection experimental procedure [4]
“To the SM (1.70 g, 2.64 mmol) in THF/H2O (2:1, 15 mL) was added NaHCO3 (443 mg, 5.27 mmol) and Cbz-Cl (0.56 mL, 3.96 mmol) at 0 °C and the solution was stirred for 20 h at the same temperature. The reaction mixture was diluted with H2O and extracted with AcOEt. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (40% AcOEt/n-hexane) gave 20 (1.85 g, 2.38 mmol) in 90% yield as a white powder.”
Cbz deprotection experimental procedure
[4] Normal hydrogenolysis To a solution of SM (20.7 mg, 15.0 micromol) in 2 mL of MeOH were added 5% Pd-C (6.4 mg), and the mixture was stirred at 60 °C for 40 h under atmospheric pressure of H2. Then, the catalyst was filtered of on pad of celite. The filtrate was concentrated in vacuo to give a crude material containing 27, which was used without purification for the next step.
[5] Deprotection of 5 Cbz groups in the final step via transfer hydrogenation. To a solution of protected caprazamycin A (32) (6.5 mg, 3.21 micromol) in EtOH/HCO2H (1.9 ml, v/v = 20:1) was added Pd black (66.5 mg, 625 micromol) at 25 °C, and the resultant mixture was stirred for 1.5 h at 25 °C. After filtration through celite, the filtrate was concentrated under reduced pressure. The resultant residue was purified by C18 reversed phase. Caprazamycin A eluted at 11-18 min as an isolated peak. The eluent was collected and concentrated under reduced pressure to give a pure caprazamycin A (3.6 mg, 98%) as a colorless powder:
The Boc protecting group protects amines as less reactive carbamates in organic synthesis, and is deprotected with acid.
The N-Boc group is a key topic during chemistry courses. Why? It nicely exemplifies important protecting group concepts and has an interesting deprotection mechanism.
👀 Here’s a 3D model to help you visualize the Boc protecting group.
What is the Boc Protecting Group?
Boc stands for tert-butyloxycarbonyl and protects amines as carbamates. More rarely, it is also used to protect alcohols as their carbonates. Boc is resistant to basic hydrolysis, many nucleophiles as well as catalytic hydrogenation. The fact that it can be removed with mild acid makes it orthogonal to other key protecting groups (see below).
Boc Protection Mechanism
The main method of Boc protection is use of Boc anhydride. Base is not strictly needed for the reaction with Boc2O (tert-butanol formed as product). However, bases like triethylamine or NaOH (amino acids) are sometimes used, depending on the system.
The mechanism is straight-forward: attack of the nucleophilic amine to the electrophilic anhydride. The carbonate leaving group can release CO2, providing a strong driving force for the reaction. This step is the same as for other carbamate protecting groups such as Cbz.
As we have seen for PMB, many variants of activated agents can exist. The same is true for Boc: while Boc anhydride is the most common reagent, others like the cheaper Boc-Cl (t-butyl chloroformate) or Boc-ON (oxyimino-nitrile reagent). As a common theme for protecting groups: Remember that amines are more nucleophilicity than alcohols, so you can selectively protect them in many cases.
Boc DeProtecTION Mechanism WITH Acid
Acids like TFA, HCl… can deprotect Boc groups. Protonation into the oxocarbenium triggers fragmentation into a stabilized tertiary cation (inductive effect). It later deprotonates to form gaseous isobutene. The fragmented carbamate can decarboxylate, releasing CO2(here you have a parallel of Boc anhydride introduction and its removal) and giving the free amine.
Given the high steric hindrance of the carbamate, the Boc group is not base-labile like methyl esters, for instance.
A potential issue are intermolecular side reactions of the intermediary t-butyl cation. An example from peptide chemistry is alkylation of nucleophilic amino acids methionine or tryptophan. That’s why you might see conditions which employ scavengers like thiophenol, anisole, cresol… to remove the reactive intermediate.
Boc protecting group Orthogonality
Boc protection is a key tool for heterocycle and peptide synthesis. In solid phase peptide synthesis (SPPS), it is used as a protecting group for alpha-amino groups and amino acids lysine, tryptophan and histidine.
Due to its acidic deprotection, it is orthogonal to other important amino acid protecting groups:
Fmoc (9-fluorenylmethoxycarbonyl) – removed with base
Cbz / Z (benzyloxycarbonyl) – removed with H2 reduction
Alloc (allyloxycarbonyl) – removed with transition metal catalysis (Pd)
However, Boc is not stable to Lewis acids or oxidative conditions. We have seen that the O-PMB protecting group is removable with DDQ. In one case [1], treatment of the PMB ether did not result in any desired deprotection.
Can you explain why this side reaction and overoxidation might have occurred?
Boc side reactions
In organic chemistry, surprises wait around every corner. Don’t assume that protecting groups stay on forever, and only cleave on demand!
Before, we have mentioned that alcohols are less nucleophilic than amines, allowing selective protections. In this example [2], the authors observed a N-O Boc transfer when preparing a chiral oxazolidinone auxiliary. Upon deprotection of the TBDMS group, the highly nucleophilic alkoxide grabs the Boc group from the nitrogen!
Overman et al used a more conscious Boc-participation in their synthesis towards the diazatricyclic core of sarain marine alkaloids. [3] Base generates the alkoxide which again attacks Boc. This time however, the group is not transferred (the negative charge would not be stabilized on the nitrogen, unlike the previous example). Instead, we see an intramolecular cyclization.
Boc in Peptide Synthesis
As alluded to above – particularly in the early days – the Boc protecting group proved very useful for solid-phase peptide synthesis (SPPS). However, in the late 20th century, the Fmoc protecting group started to replace Boc methodology.
Fmoc deprotection is generally milder than the moderate/ strong acidolysis steps used for Boc. More specifically, Fmoc proved more compatible with synthesis of amino acids that are susceptible to acid-catalysed side reactions.
A good example is the synthesis of the peptide gramicidin A which contains four acid-sensitive tryptophan residues. Using Boc chemistry, yields were in the range of 5-24%. Switching to Fmoc dramatically improved the yields, in some cases to 87% [4].
Closing Remarks
The Boc group is pretty cool, and its deprotection mechanism is a must-know for every organic chemistry student. The orthogonality to base- or reduction-labile protecting groups make it a top pick for many total and peptide syntheses.
However, like all protecting groups, it has its downsides. The carbamate carbon remains somewhat nucleophilic which opens avenues for surprising reactions, particularly intramolecular. Also, the acidic conditions and reactive tert-butyl-cations used can pose challenges to some systems. As always, smart planning and workarounds might be needed.
BOC Protection experimental procedure [5]
One pot Cbz->Boc switch “To a solution of Cbz-carbamate SM (3.5 g, 6.81 mmol) in MeOH (25 mL) were added Pd/C (10 % w/w, 200 mg, 0.19 mmol) and Boc2O (2.17 g, 9.9 mmol) at room temperature. The reaction mixture was stirred under a hydrogen atmosphere (balloon) at room temperature for 6 h. The reaction mixture was filtered through a pad of celite, and then concentrated in vacuo. Flash column chromatography (silica gel, hexanes:EtOAc 10:1 → 7:1) afforded Boc-carbamate 42 (2.94 g, 90 %) as an oil.”
BOC deprotection experimental procedure [6]
“Boc-L-allo-End(Cbz)2-OtBu (597 mg, 1 mmol) was dissolved in a mixture of TFA (10 mL) and water (1.0 mL). The mixture was stirred at room temperature for 3 h, then concentrated to give a brown oil. The resulting crude oil was azeotroped with toluene (3 x 10 mL) and concentrated in vacuo to remove any residual TFA.”
The PMB protecting group protects alcohols as less reactive ethers in organic synthesis, and is deprotected oxidatively or with strong acids.
In this article, we cover its protection & deprotection mechanisms and properties, reviewing key organic chemistry concepts. Here you can find many other protecting group summaries.
👀 Here’s a 3D model of the PMB group to help you visualize it.
What is the PMB Protecting Group?
PMB is a para-methoxybenzyl group, introduced by Yonemitsu in 1982 [1] to protect alcohols and other nucleophilic functional groups. Although PMB ethers are less stable to acid than normal benzyl ethers, they can uniquely be cleaved oxidatively (see below). This allows selective deprotection protocols which becomes critical in complex organic synthesis.
PMB Protection Mechanism
The main method of PMB protection is the Williamson ether synthesis. This reaction uses a moderately strong base to generate an alkoxide which undergoes SN2 substitution with an activated agent like PMB-Cl. Typical conditions include sodium hydride NaH in THF/DMF or DMSO. However, stronger bases like nBuLi work as well.
Beyond PMB-Cl, the reagent you will see most, there are also other methods of PMB protection. Beyond halide variants like PMB-I or PMB-Br, PMB-trichloroacetimidate with catalytic acid can also protect hindered tertiary alcohols. This is due to its higher reactivity. The PMB-pyridyl thiocarbonate with silver(I) is another example.
Interestingly, tetrabutylammonium iodide can be used catalytically for sluggish reactions as well. Here’s a question for you: Do you know how that catalysis works?
PMB DeProtecTION Mechanism WITH DDQ
This protective group differs from others in that it undergoes easy single electron transfer (SET) with DDQ (2,3-dichloro-5,6-dicyano-l,4-benzoquinone). The electron-donating methoxy group stabilizes intermediary radical and oxonium ion. Normal benzyl protecting groups oxidize as well, but much slower than PMB. Obviously, this is due to the O-PMB methoxy group.
After some proton exchanges, water captures the carbocation. As with every redox reaction, the electrons removed from O-PMB (oxidation) end up in the reduced hydroquinone product. Compared to the quinone in DDQ, this system is aromatic.
The hemiacetal formed after water addition can fragment to give the deprotected hydroxy – as well as anisaldehyde. One drawback of is unintended side reaction of the aldehyde or intermediary PMB cations with nucleophilic functional groups, as well as polymerization. Thus, it is common to add nucleophilic scavengers (e.g., thiols) that capture these reactive species. This is a common thread for some deprotections (e.g., Boc).
By the way, other oxidants like cerium(IV) ammonium nitrate (CAN) or NBS might work when DDQ fails.
PMB protecting group Orthogonality
The DDQ reduction (typically 1.1-1.5 equivalents DDQ in dichloromethane-water mixtures) leaves several functional groups and other protecting groups (MOM, THP, TBS, Bz…) alone. This makes PMB an interesting orthogonal protecting group.
However, electron-rich groups like dienes or trienes can be unintended victims of DDQ. This makes complete sense: electron-rich groups are nucleophiles and thus like to react with oxidants. In some cases, conjugation of dienes with electron-withdrawing groups sufficiently deactivates them, avoiding DDQ interference.
Also, always be on the lookout for unique systems and reactivities! The synthesis of sterepolide, an antibiotic fungal metabolite, exemplifies this concept in oxidative deprotections [2]. When using an excess of DDQ (8 equivalents), the authors found the allylic O-PMB over-oxidized directly to the ketone. In this case, this was convenient as it gave the target natural product, saving one step. However, this can complicate cases where we need deprotection only (most of the time).
Advanced Question: Special PMB Deprotection
As a twist on the previous information, you can ponder on this research [3]. Using 0.5 equivalents of oxalyl chloride led to efficient PMB deprotection of various substrates.
What could be a mechanism for this unique deprotection reaction?
Closing Remarks
PMB is a quite unique protecting group given the ability to remove it oxidatively (in addition to normal acid-mediated cleavage, not explicitly discussed here). In addition, PMB can also protect carboxylic acids, thiols, amines, amides… – or even phosphates! Basically, many other nucleophilic groups. The protection and oxidative removal make it a standard question in organic chemistry courses.
PMB protection experimental procedure [4]
“To an ice-water cooled solution of SM (3.91 g, 15.2 mmol, 1 equiv) in THF-DMF (100 mL-30mL) was added NaH (2.43 g, 60.8 mmol, 4 equiv, 60% suspended in mineral oil) portionwise. After addition, the reaction was stirred at the same temperature until cease of gas releasing, then p-methoxybenzyl bromide (6.11 g, 30.4 mmol, 2 equiv) in THF (25 mL) was slowly added at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, then quenched by slowly adding 1M solution of NaOMe in MeOH (15 mL). The reaction mixture was diluted with EtOAc (300 mL) and washed with water and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (hexanes : EtOAc = 25:1-10:1) to give 5.28 g of product as a colorless oil in 92% yield.”
PMB deprotection experimental procedure [5]
“To a solution of SM (1.97 g, 3.95 mmol) in CH2Cl2:0.1 M pH 7 sodium phosphate buffer (18:1, 47 mL) at 0 °C was added 2,3-dichloro-5,6-dicyano-p-benzoquinone (1.17 g, 5.14 mmol) slowly as a solid. The reaction was warmed to rt and stirred for 1 h. The crude mixture was directly loaded onto a silica gel column with a top layer of MgSO4:sand (1:1, 0.5 inches). Elution with 5% to 30% EtOAc in hexanes yielded the product (1.45 g, 97%).”
In this post, we will look at MDMA’s history and its chemical syntheses. We will dispel myths about MDMA’s discovery and review the first kilo-gram scale MDMA synthesis published in a journal. We also dissect impressive recent clinical data that suggest ecstasy might help up to millions of people affected by PTSD. This might not be surprising if you’ve seen our discussion of psilocybin, ibogaine or LSD.
How to Make MDMA?
I’m not sorry to disappoint you. This is purely educational and not a DIY-tutorial for illegal clandestine synthesis. Also, don’t use this information to rationalize your drug use. Long-term and side effects of MDMA can be severe and regular use is discouraged even by clinical advocates.
MDMA history
The origin of MDMA has quite some tales associated with it. For example, crediting various German scientists with its discovery, even though no documentation or basis for this can be found. MDMA also was not intended for use in World War 1. However, there was quite some military experimentation on stimulants later on in the 1950s. The first point at least goes in the right direction, but the history is much more intriguing than this.
The story actually starts with hydrastine, an anti-hemorrhagic natural product isolated from some random plant. By the 20th century, this drug became more expensive because the plant was becoming rarer and cultivation attempts failed. Therefore, the German company Merck was interested in finding ways to chemically synthesize it. They had a chad chemist reach out and offer a new, cheap synthetic procedure for hydrastine. For some reason, this guy signed the contract with Merck’s competitor Bayer which is quite funny. So the Merck scientists now had to find some new anti-hemorrhagic agents or new syntheses.
You can appreciate that hydrastine is basically a more beefed up version of MDMA. Not too shockingly, the Merck scientists produced MDMA as a side product, and were not interested in it at all. While their 1912 patent refers to MDMA’s structure for the first time, they did not pursue or test it. Thus, the first MDMA publication and synthesis was published only 50 years later. Things gained traction from there on.
MDMA Synthesis from Safrole
Let’s check out three syntheses of MDMA starting with Merck’s synthesis from 1912. Second, we will review a late 20th century approach and third, look at the 2022 kilo-scale MDMA synthesis. There are other clandestine methods, actually mentioned in quite a few papers, but obviously we will not discuss this here.
So safrole is a natural product used in the first half of the 20th century as a food flavor. 50 Cent would likely agree, it has a nice candy shop aroma. Human consumption was banned after people realized it increases rates of liver cancer. Feels like half of pesticides and food ingredients have the same story… Safrole was the starting material for Merck, but it can also be made synthetically in a few steps. Starting from Catechol, a double SN2 reaction forms 1,3-benzodioxole. Then, mono-bromination with NBS gives the aryl-bromide. Treatment with magnesium converts into a a Grignard reagent and used in a nucleophilic substitution with allyl bromide.
From safrole it’s only two steps: first, a normal Markovnikov-selective hydrobromination, and another SN2 with methylamine to get MDMA. Optionally, you can also throw in a Finkelstein halogen exchange to get better yields in the substitution.
MDMA Synthesis from Piperonal
The second synthesis from piperonal starts with a Henri condensation reaction, creating a nitro-olefin. This can be reduced in acidic conditions to the ketone and a reductive amination with methylamine gives MDMA. So this synthesis uses a bit less bromines but more redox chemistry.
Large Scale Synthesis of MDMA
The final synthesis is pretty sweet. It was published in 2022 by the MAPS PBC. This is a biopharma company and subsidiary of MAPS, a non-profit working to raise awareness and understanding of psychedelic substances. They required large amounts of MDMA to supply their two Phase 3 clinical trials, which we will check out shortly. This is the first-ever document kilogram scale preparation of ecstasy. The product is appropriate for clinical and potential licensed therapeutic use due to the process’ validation and GMP compliance.
Safrole and piperonal are controlled substances and thus highly regulated and difficult to obtain. Instead, the chemists used an arylbromide (an intermediate towards safrole) that is commercially accessible. This synthesis is similar to others we saw but comes with a twist. It starts again with a Grignard reaction but this time, with 1,2-propylene oxide as an electrophile. This epoxide nicely introduces the rest of the aliphatic chain, leaving a secondary alcohol which can, similar to other syntheses, be oxidized to the ketone. This ketone could be used without any purification in the final reductive amination step. You can check out the paper for more info – they go into some more details on validation and impurities. The experimental procedures are quite funny to read, as they ultimately isolate 3.6kg of MDMA HCl salt with over 99.4% purity.
PTSD Disease Burden
So they put in a lot of effort in this process – but why is it worthwhile to look at PTSD? As crazy as it sounds, 6-7% of people in the US experience PTSD at some point in their lives, with about 1/3 of cases classified as severe. Often, there are other conditions decreasing chances of successful therapy, so these high-risk patients need more effective treatments. Just as a side note, this did remind me of other shockingly high estimates from the US National Institute of Mental Health – for example, they also state that 19% of adults experience what they termed “any anxiety disorder” per year. This is probably exaggerated, of course anxiety is human but proper clinical disorders are probably not affecting 20% of adults every year.
As a last reason, many patients do not respond to first-line treatment with SSRIs – most notably, those are sertraline and paroxetine. The latter was actually part of the massive $3bn fraud settlement due to unlawful promotion and failure to report safety data. You might know that SSRIs are used in various depressive and anxiety disorders, so it would be nice to have a more targeted therapy or intervention. That’s why MAPS has been supporting MDMA clinical trials as early as 1992. All their advocacy and support culminated in two large-scale Phase 3 trials which were recently completed – we will dissect one of them.
MDMA-Assisted Therapy for PTSD
Let’s talk about study design before going into results – after an initial wash-out of any other psychiatric medications, patients went through four blocks consisting of various therapy sessions. The important points are the red experimental sessions – corresponding to the three occasions where patients in the treatment arm received an 80-120mg dose of MDMA. The individual therapy sessions consisted of supported introspection, experience sharing and probably some other things, and were conducted by trained clinical teams.
This was a placebo-controlled Phase 3 study, so the total 90 patients were randomized to two trial arms. You can see that the patients in each trial had quite comparable characteristics, which obviously is important if you want to compare the effect of a medication – for example, the average duration of PTSD was around 13-15 years for both segments, although there was quite a large variation. From a trial endpoint perspective, there are two important measurements to look at. The CAPS-5 score is based on a semi-quantitative questionnaire that sheds some light on how bad the PTSD is – a score in the 40s, as present in the trial baseline, means very severe PTSD. The Beck Depression Inventory score tells you how depressed someone is – here a score above 30 is also severe.
MDMA-Assisted Therapy for PTSD
How did these severely affected patients they respond to MDMA-supported therapy? Both PTSD severity and depression scores decreased significantly from baseline until end of the last therapy block. You can see that normal therapy also improves outcomes, so these seemingly fluffy therapy sessions are useful – but the effect with MDMA on top is clearly higher. At the end of therapy, patients in the treatment arm were much better off (only mild to moderate PTSD, lower depressive symptoms). Please note that guided therapy was still needed, so just taking MDMA wouldn’t have the same effect and could make it even worse.
While there were quite a few non-responders and only few patients in remission for placebo with therapy, the MDMA group had almost 40% of people completely PTSD-free and only few not responding at all. The nice thing was also that MDMA had an equally positive effect in high-risk people with other disorders, including the especially difficult-to-treat dissociative subtype of PTSD.
Last, MDMA had a quite good safety profile. Side effects like muscle tightness or appetite loss were more frequent in the treatment arm but most are harmless. I would guess that you would rather lose appetite and have some tight muscles, than be afflicted with severe PTSD. More severe adverse events, like suicide attempts or self-harm were actually only observed in the placebo control, probably because their intervention was less effective. So at least in the short-term, there were no concerning safety signals.
It is still a mystery how this works physiologically, but the literature speculates MDMA might reopen a window of neuroplasticity that allows for processing and release of fear and other emotions. Doing so, MDMA might support and catalyze therapeutic processing by allowing patients to stay emotionally engaged while revisiting traumatic experiences without becoming overwhelmed.
MDMA FDA approval in 2024?
The FDA already granted MDMA-assisted therapy a break-through designation in 2017 – so with this promising data in hand, MAPS PBC is expecting to file for FDA approval in late 2023. It will be interesting to see how they decide on this. Let me surprise you with another score which I intentionally left out earlier for simplicity, the Sheehan Disability Scale. This is measures how well an individual functions in key life dimensions, and it seems like MDMA-assisted therapy could also help thousands or millions of people become more functional and independent in their daily lives. Supposedly, US veterans report service-related disabilities that cost the government $73 billion per year. A sizeable chunk of these costs are probably due to PTSD, which might also encourage the FDA to approve MDMA-assisted therapy, at least for high risk patients.
I think this was quite a nice journey, going from almost ancient chemistry to modern clinical outcomes. Thanks for reading and until next time!
