The Troc protecting group protects amines and alcohols from acid, base and electrophiles. It is deprotected by reduction.
Troc (also 2,2,2-trichloroethoxycarbonyl) is a really exotic but versatile protecting group. Let’s learn why.
What is the Troc Protecting Group?
Troc (2,2,2-trichloroethoxycarbonyl) can convert amines or alcohols into stable carbamate or carbonate derivatives. This leads to a similar effect that we see in groups like Fmoc or Boc: the previously nucleophilic amine or alcohols loses its reactivity (driven by delocalization of electrons into the carbonyl system).
The nice thing is that Troc is orthogonal as the deprotection conditions for Fmoc (base), Boc (acid) or silyl groups like TBS (fluoride) do not remove it. Instead, it has a unique mechanism of reductive beta-elimination to release the free group.
Did you know: The Troc group was introduced by the legendary Robert Burns Woodward in the 1960s? (see below)
Troc Protection Mechanism
The Troc protecting group is introduced by reacting the free amine or alcohol with 2,2,2-trichloroethyl chloroformate (Troc-Cl) with addition of a base.
Most common protection conditions are Troc-Cl with pyridine in CH2Cl2 or THF. If the starting material is very polar, Troc-Cl with NaOH or NaHCO3in water.
Troc Deprotection Mechanism
The Troc protecting group can be removed with certain reductive methods which all function via beta-elimination. Most common is use of zinc or other single-electron reductants that reduce the terminal carbon. The beta-elimination gives a free carbamate – an intermediate seen in mechanisms of many other protecting groups – that rapidly decarboxylates to the deprotected amine (or alcohol).
Most common deprotection conditions are Zn powder in THF/H2O or so-called couples/alloys consisting of mixtures of Zn-Pb or Cd-Pb. More rarely used, reduction with electrolysis also removes the Troc group.
Always remember protecting group stability or lability are always general (e.g., here: removal by reduction). Nothing in chemistry (or life) is black and white 🙂 Here is a neutral method (not reductive) using trimethyltin hydroxide. [1]
A fascinating point is that under the right conditions, Me3SnOH actually deprotects Troc selectively in the presence of methyl esters (you would expect that the methyl ester is quite labile to hydrolysis with hydroxide).
Troc PRotecting grouP in total synthesis
The very first introduction of the Troc protecting group was already… very advanced! Woodward and co-workers used the starting material below in the synthesis of cephalosporin C, an antibiotic natural product. [2]
What is the product after treating this molecule with Zn in aqueous AcOH?
This is a cool example where one of the three Troc groups does not decarboxylate (the one on the right). This is because it was not attached to a free alcohol, but rather, only the trichloroethoxy was masking the free acid. Because this is not a free carbamate or carbonate, we do not see a decarboxylation.
Thanks for checking out this article – feel free to read about other protecting groups! Below you can find typical Troc protection and deprotection conditions.
Troc Protection conditions [3]
To a solution of the alcohol (0.80 g, 1.48 mmol) in methylene chloride (30 ml) at 0 °C was added pyridine (0.96 ml, 11.84 mmol, 8 equiv) followed by 2,2,2-trichloroethyl chloroformate (0.8 ml, 5.92 mmol, 4 equiv), and the reaction mixture was stirred at 0 °C for 1 h. Saturated aqueous sodium bicarbonate (50 ml) was added and the organic layer was separated. The aqueous layer was extracted with methylene chloride (3 x 50 ml), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (2% EtOAc/hexanes) afforded protected product (0.98 g, 93%) as a colorless oil.
Troc deprotection conditions [4]
To a solution of protected Troc-amine (40 mg, 57 µmol) in 4 mL of MeOH was added activated zinc (400 mg). The mixture was stirred at 25 °C for 5 min, and glacial HOAc (4 mL) was added. The mixture was heated at 60 °C for 30 min, cooled and concentrated under reduced pressure. The residue was treated with 5 mL of 5% aqueous NaOH, and the solution was extracted with EtOAc (5 × 5 mL). The combined extracts were washed with brine, dried over anhydrous K2CO3, and concentrated under reduced pressure. Flash chromatography on silica gel (100:1 CH2Cl2/MeOH) gave 25 mg (86%) of the free amine as a viscous oil.
TROC Protecting Group References
P. G. M. Wuts, T. W. Greene: Greene’s Protective in Organic Synthesis (Wiley)
[1] Highly Chemoselective Deprotection of the 2,2,2 Trichloroethoxycarbonyl (Troc) Protecting Group | Barry M. Trost, Christopher A. Kalnmals, Jacob S. Tracy, and Wen-Ju Bai | Org. Lett. 2018, 20, 8043−8046
[2] The Total Synthesis of Cephalosporin C. | Woodward, R. B.; Heusler, K.; Gosteli, J.; Naegeli, P.; Oppolzer, W.; Ramage, R.; Ranganathan, S.; Vorbruggen, H. | J. Am. Chem. Soc. 1966, 88, 852− 853
The THP protecting group protects alcohols as THP ethers that are stable to electrophiles, bases and other reagents. It is acid labile.
THP is a much less common hydroxyl protecting group than silyl-based ones like TBS. It’s very simple but still has a unique nature and mechanism.
What is the THP Protecting Group?
Tetrahydropyranyl ethers were one of the first protecting groups for alcohols. Nowadays, they are seen less commonly, though still used. The THP group is easily removed under acidic conditions (mechanism below) and stable to organometallic nucleophiles, electrophiles (as the protected oxygen is less nucleophilic), reduction or base. The protected THP ethers are actually a type of acetal (‘double-ether’).
THP Protection Mechanism
THP protection uses acid catalysis and 3,4-dihydro-2H-pyran. The mechanism proceeds by THP pre-activation with acid, leading to a stabilized cation. Here, the oxonium is drawn but you can imagine the other resonance form with the positive charge on the carbon which is ultimately where the ion is most electrophilic. Our free hydroxyl group then attacks the carbon in a nucleophilic addition, and loses a proton to give the protected THP ether. The last step regenerates our acid catalyst.
The most common protection conditions are catalytic TsOH or pyridinium p-toluenesulfonate (PPTS, a form of TsOH with lower acidity) together with 3,4-dihydro-2H-pyran in dichloromethane.
THP Deprotection Mechanism
THP deprotection proceeds really similarly to THP protection – acid catalysis activates the acetal system towards dissociation of our initially protonated alcohol. Again, it’s the same stabilized cation intermediate but based on the choice of solvent used, we have different potential byproducts. The solvent is obviously present in large excess, so it will preferentially attack the carbocation instead of our just liberated hydroxyl group. For example, methanol gives the methyl-substituted THP ether while use of water would give the free hydroxyl group (this can open to the linear aldehyde).
The most common deprotection conditions are AcOH:THF:H2O or PPTS in EtOH.
THP PRotecting grouP Diastereomers
One of the drawbacks of the THP protecting group versus the TBS protecting group, beyond its lower stability, is that it introduces a second chiral center. If our starting material has already at least one chiral carbon, we form diastereomers. This can complicate the separation and identification (e.g., NMR) of products – because as you know, diastereomers have different physicochemical properties.
Interestingly, some older research [1] tried to make use of this ‘drawback’. In this work, the chemists used a THP-derivative as a chiral auxiliary for nucleophilic additions to an aldehyde in the molecule.
In these derivatives, one side of the aldehyde is shielded from nucleophilic attack while the other is exposed. This leads to very high diastereoselectivity at the newly formed carbon (a tertiary alcohol). It’s not terrible useful but interesting that a protecting group can be used to exert diastereoselectivity. You could imagine this potentially being useful in some complicated total syntheses.
Thanks for reading, and check out the other protecting group articles!
THP Protecting Group References
P. G. M. Wuts, T. W. Greene: Greene’s Protective in Organic Synthesis (Wiley)
[1] The tetrahydropyranyl group as a chiral auxiliary for the nucleophilic addition to α-alkoxy ketones | André B. Charette , Abdel F. Benslimane , Christophe Mellon | Tetrahedron Letters 1995, 36, 8557
The acetal protecting group protects carbonyls from bases, nucleophiles and hydride reduction. Among many variants, most common are dimethyl acetals, 1,3-dioxolanes and 1,3-dioxanes.
There is no single acetal protecting group! Rather, this is a broader family of similar protecting groups. Let’s check out the properties and mechanisms of acetal protection and deprotection.
What is the Acetal Protecting Group?
Acetals always protect carbonyl compounds. But how? This is where the variety can come from. On one hand, acyclic acetals form by reaction with an alcohol (-OH) or thiol (-SH) and catalytic acid. On the other, cyclic acetals form when carbonyls react with a diol or dithiol and catalytic acid.
Do you already know if cyclic or acyclic acetals are more stable? Why? (see below)
You will know that carbonyls are nucleophilic at the carbon. Any acetal protecting group renders it stable to these nucleophiles: aqueous and non-aqueous bases, organometallic reagents and hydrides. As always, we want to avoid unwanted reactions of one group (here, the carbonyl) to instead perform chemistry at another functional group. As we will see below, formation of acetals involves a two-step mechanism, including nucleophilic attack and subsequent dehydration, which drives the equilibrium towards product formation.
Difference between Acetal and Ketal
You might not be aware, but back in the day, people used to separate acetals – made from aldehydes – and ketals – made from ketones. Nowadays, acetal is the umbrella term that describes both – while ketal remains restricted to ketones (link to IUPAC definition).
Types Of Acetal Protecting groups
As mentioned, there are several relatives in the acetal protecting group family. The good thing is that they work very similarly!
=> You should simply know that acetals can be oxygen-based or less commonly, sulfur-based. The simplest acyclic acetal is the dimethyl acetal. Cyclic acetals have five-membered rings (1,3-dixolane; 1,3-dithiolane) six-membered rings (1,3-dioxane, 1,3-dithiane).
Acetal protection mechanism
As an example, 1,3-dioxolanes are prepared by treating carbonyls with ethylene glycol and acid. => Acetal protection or acetalization requires catalytic acid to activate the carbonyl (but only catalytic because the proton is regenerated in the final step) => Acetalization is a condensation as the original oxygen is kicked out as water
Typical conditions: Ethylene glycol and cat. TsOH (acid) in C6H6 as solvent at reflux.
Because every reaction is an equilibrium (imagine the arrows also going from right to left), chemists use ways to remove water from the reaction to ensure it can’t react back. For acetalizations, this involves using a Dean-Stark trap. The Dean-Stark trap is a glassware that collects water formed in a reaction through an azeotropic distillation. You might have heard about it – if not, does not matter. This is a physical removal – alternatively, dehydrating agents like trimethyl orthoformate can chemically remove the water by reacting with it (“scavenger”).
The same mechanism applies if we use other diols (e.g., to form six-membered 1,3-dioxanes), alcohols (e.g., methanol to form dimethyl acetals) or thiols to form sulfur-based acetal protecting groups.
Acetal Deprotection Mechanism
Deprotecting acetals is very similar to introducing them! The most common is an acid-catalyzed hydrolysis. Again, make sure you understand why it only requires catalytic acid (i.e., less than 1 “equivalent” of moles).
Typical conditions: Cat. pyridinium tosylate PPTS or HCl (as the acid) in a mixture of water (for the deprotection) and an organic solvent (to dissolve the starting material).
The sulfur-based acetals are special as they can also be removed with heavy metal salts – so Lewis acids like mercury(II) or silver(I) – or oxidants. The oxygen-based acetals are stable to these conditions. We will go into 1,3-dithianes and 1,3-dithiolanes into more detail in another post.
Acetal protecting group stability
Are cyclic or acyclic acetals more stable?
Cyclic acetals are more stable than acyclic ones. Why? Acidic hydrolysis starts with protonation (catalytic acid), and goes via the oxonium intermediate.
For the cyclic acetal, the newly released hydroxyl group is still in the same molecule – so the reverse reaction would be an intramolecular reaction which is very fast (entropically favored).
For acyclic acetals, formation of the oxonium cleaves off an alcohol as a separate molecule. Because the deprotection is in aqueous solvent, we have a lot of water molecules around. It is now much more likely water will attack the oxonium (leading to deprotection of the carbonyl) instead of the alcohol attacking. This is because we only have 1 molecule of alcohol formed for 1 molecule of starting material; on the other hand, we have a large excess of water molecules.
Acetal Protecting Group References
P. G. M. Wuts, T. W. Greene: Greene’s Protective in Organic Synthesis (Wiley)
“Why do they call it organic chemistry? Nothing about this feels natural.” A student, somewhere out there
Organic chemistry is often perceived as one of the most challenging subjects for students. Unfortunately, this creates a lot of anxiety and misconceptions about its complexity and requirements, particularly for students in adjacent fields like medicine, pharmacy or biology.
But why the bad reputation?
Concepts: Yes, organic chemistry is complex! After all, it deals with the literal wizardry of transforming living matter. The complexity (and bad teaching) can make many students feel overwhelmed – amplified by cumulative learning: missing foundational concepts makes it difficult to understand advanced ones.
Representation: Organic chemistry requires abstract thinking and relies on molecular drawings that are often not intuitive or tangible. After all, we are drawing 3D things on 2D paper. Fischer projections anyone?! (I hated these) (how to change: look at 3D model, simulate it online, practice practice)
Process:Teachers rush through content without explaining it properly, leading students to fall behind completely and/or rely on memorization to stay afloat (how to change: try to maximize the support at your uni with open doors, ask more senior students – if no support environment, look online and try to understand the why, write as many things out as you can to build your mental muscle…)
But do not despair – organic chemistry can be more accessible than you might think. Here are some ways to help you address these issues.
These tips are not some crazy 200 IQ approaches, but they require putting in the work – thoughtfully. It’s like getting fit: it’s relatively obvious what you need to do (eat healthy, work out, sleep…), but the challenging part is doing it!
1. Organic Chemistry Concepts
Build the foundation: Whatever level of class you are taking, first go back to your older materials. For introductory organic chemistry lectures this means understanding basic models like the atomic model (electrons, protons, neutrons) and orbitals and hybridization (if relevant in your class). Why do molecules inherently repel each other, and why do reactions occur nevertheless? What is a chemical reaction? Then, revisit concepts like electronegativity, nucleophilicity and electrophilicity (link), … I might work on a full list of concepts in future.
Understand the functional groups(link): Learn the structures of the most common functional groups in organic chemistry. Sorry, but there is some memorization involved. It’s just like learning a new language: you need to memorize at least new words! For this, you have to understand what a skeletal formula is, and how it differs to normal molecular drawings (next section). Again, I will go into more details in future but here are two easy exercises: =>Get a list of the 15-20 most common functional groups and draw their structures in skeletal formulas. Can’t remember a particular one, like the nitro group and its partial charges? Well, simply draw it 5 times for 2-3 days. You will know all of them in no time. Then, look at them and think about their similarities: For example, a thiol group is like a hydroxyl group (or an alcohol), just that the oxygen is replaced by sulfur which is in the same “group” in the periodic system. An ester is similar to a tertiary amide, just that the -OR group bound to the central carbonyl carbon is replaced by a -NR2 group. Tertiary amides are similar to secondary and primary amides, just that the number of alkyl rests versus hydrogens bound to nitrogen differ. => Google “pharmaceuticals” and check out their structures on Google images. Pick a random pharmaceutical – what functional groups can you identify? Which groups are ones you do not know yet? Do they look similar to any which you know already?
Work your way up the complexity of reactions: 😔 The bad news : There are a literal TON of reactions in organic chemistry. 😊The good news: Thankfully, you don’t have to know all of them, and many of them share the same logic and concepts. Here you should again start easy and build up. => Before trying to understand SN1 reactions or more difficult name reactions, first review acid-base reactions and oxidations/reductions. Then, get into additions. Then, substitutions and eliminations (SN2 and E2 first because they are just one step – then, SN1 and E1). After these, you can start to look at name reactions and complex transformations. For example, if you have are discussing electrophilic aromatic substitutions in class, you need to know how much simpler additions and substitutions work!
Focus on conceptual understanding: It’s normal to memorize things at the start, but really strive to understand the “why” behind reactions and mechanisms. For example: Why does a molecule X react in a substitution – where is its nucleophilic group? Why is the reagent Y an oxidant – which atom has a high oxidation number and gets reduced? Why does the reaction occur regioselectively at this position of the aromatic ring – are there electron-donating or electron-withdrawing substituents somewhere?
Create mind maps: Look at all the reactions you have studies in your class, and try to connect them based on their similarities. Or, connect different concepts: resonance impacts many other factors like acidity of a molecule. How? Electronegativity impacts intermolecular forces like hydrogen bonds and dipole effects. How? Diastereoisomerism impacts melting and boiling points. Why
Create analogies: Whenever you find a concept confusing or can’t remember it, create an analogy. For example, nucleophiles and electrophiles can correspond to rich and broke people, respectively. Electrophiles would like to borrow the electrons of the nucleophiles, creating a strong attraction. The process of the rich lending money to the poor is the nucleophile giving its electrons to the electrophile.
2. Representation
Master skeletal formulas: Organic chemistry relies on skeletal formulas which omit the explicit indication of carbon and most hydrogen atoms. Remember, each “bend” or end of a line represents a carbon atom, and hydrogen atoms are implied to fill the carbon’s required bonds.
Change your perspective: Molecules can be represented in various ways: Lewis structures, skeletal structures, Newman projections, Fischer projections… Each emphasizes different aspects of a molecule (e.g., stereochemistry). Practice switching between them to strengthen your spatial awareness. => Practice converting between full structures and skeletal formulas until it’s your second nature. Make sure you understand where electron pairs are present! => Convert between Newman projections and skeletal formulas. Are your Fischer projections your enemy? Well, go and solve literally 20 different problems. You will get the hang of it.
Use molecular models to visualize stereochemistry: Stereochemistry is a tricky topic because because it involves 3D thinking. Physical or digital 3D models of molecules can help you see how atoms are arranged in space. => Use online resources like MolView to visualize molecules. Struggling with chirality, enantiomers, and diastereomers? Go to town on the visualization. Rotate, inspect and understand the structures! If you have an university ChemDraw license, use Chem3D!
Practice electron pushing: Organic reactions are governed by electron movement. Curved arrows indicate this electron flow. Whenever you’re learning a new reaction, focus on understanding the arrows, which show how bonds are made and broken. If you can follow the electrons, you’ll have a better grasp on the mechanics of reactions. The same applies to resonance. Pick any molecule of your choice and draw all the different resonance structures. Why resonance structure is the most stable? How does resonance impact the reactivity of the molecule?
Color code drawings for clarity: Use different colors if that helps you. For example, always use red to indicate movement of electrons. Does the reaction involve partial charges? Color code them!
“Play chess” – think several moves ahead: At the beginning, you should write out every single step in a reaction. Once you are at the intermediate level (when you get to practicing retrosynthesis), try visualizing several transformations at once. How would my final product look like if I oxidize the alcohol in the molecule to the aldehyde and perform a Wittig reaction?
3. How to learn organic chemistry
Stay consistent with daily practice: We’ve all been guilty of cramming at some point. However, organic chemistry is best learned through regular practice. Even if you only have 15 minutes, do something related to the course every day—whether it’s reviewing notes, drawing mechanisms, or solving practice problems. The more often you engage with the material, the more familiar it becomes. => Every day, read about one new molecule of your choice. Think drugs against neurodegeneration are cool? Research the structures of Alzheimer’s drugs. What are their functional groups? How are they synthesized? Maybe you are into doing sports? Look at the different types of steroids and performance-enhancing drugs that there are! (Do NOT take them, just read about them…)
Activate your little brain cells: Look, we all are guilty of passively consuming information and entertainment. But instead of just reading textbooks or watching videos, actively engage with the content. Draw out mechanisms as you learn them, explain concepts in your own words, or quiz yourself on reaction types and mechanisms. Basically, anything you are not writing down or creating yourself, you will probably not remember!
Test yourself with practice problems: Organic chemistry is problem-solving heavy, so doing lots of practice problems is essential. Don’t be discouraged by mistakes or getting stuck – this is part of the learning process. The rate-limiting step (see what I did there?) might be how many good problems you can find – you know, ones with proper explanations. The quality of your problems will depend on your luck and teacher. I’m working on a problem book for chemistry myself – but yeah, go to town on Google and YouTube.
Emphasize understanding over memorization: I mentioned this one already – but given we are talking about the learning process here, I wanted to reiterate.
Create your own study materials: Summarize concepts, reactions, and mechanisms in your own words. Create summary sheets, mind maps (see above), or flashcards tailored to your learning style. Experiment and see what works for you! For the things that you will need to memorize (e.g., functional groups, pKa values, named reactions…), you should have a clear approach.
Team up: Organic chemistry is almost always more manageable when tackled with peers. Explain concepts to each other, discuss exercises together, and discuss tricky mechanisms. Your classmates are ahead of you? Great, you can suck out their insights and ask questions. You are ahead of your classmates? Great, help them and in doing so, you will further elevate your capabilities. Are you in university and not against earning an extra buck? Tutor students that are 1-2 years below your level.
Use office hours and ask for help early: If something doesn’t make sense, ask for help right away. Afraid of looking like a moron? Well, the odds are at least half of your class is feeling like morons as well, so don’t feel bad! Visit your professor or teaching assistant during office hours to clarify any misunderstandings. Addressing confusion early prevents small gaps in knowledge from turning into major issues later.
Use multiple resources: Don’t rely solely on one textbook or lecture notes. Different resources may explain the same concept in slightly different ways, and sometimes a different perspective makes things click. Use videos, alternative textbooks, online platforms, and forums to diversify your learning. No access to textbooks? Go to town on LibGen (google it).
Prioritize your effort: As mentioned, building the foundation is key. But once you get into intermediate territory, there are SO many things you could theoretically read about. In the best case, your textbook and/or teacher might have clear objectives or checklists of topics to know. Assess on what you need to work on most, and then go hard.
Is Organic Chemistry Hard?
So, is organic chemistry hard? Honestly – yes, it’s hard.
Is it as hard or terrifying as people make it out to be? No, not really. The great thing is that at some point, every new concept or reaction will be based on something you know already. After enough effort, there will be almost no cases where you really have absolutely no clue of how to approach a problem.
Is it the hardest subject you will study? Maybe, maybe not. Depending on your area of focus, it might come least naturally to you, versus other subjects. If you dislike chemistry and math, physical chemistry will haunt you even more.
To end on a positive: I loved organic chemistry more than any other subject but even I had been struggling with it initially. Resonance? Confusing as hell. Fischer projections? I couldn’t draw a single one correctly. The abbreviation of -Me for a methyl group (-CH3)? I thought it stood for “a generic metal” (lol). I asked A LOT of stupid “questions” (or in many cases did not ask them, which slowed down my progress). What had been a guessing game and brain-dead memorization, became almost second nature.
Whatever your journey in organic chemistry, I hope you can figure out how to make it a bit more bearable and more successful – however you define it: just passing, improving your grade, or really going beyond the class and mastering it.
I’m working on materials to help students unlock and practice organic chemistry. So if you are just getting started, stay tuned!
The trityl protecting group protects alcohols and amines, and can be deprotected with acids like acetic acid or TFA.
The trityl group is another acid-labile protecting group that might remind you of Boc! Here we explain the “standard” trityl and exciting,more advanced versions!
What is the Trityl Protecting Group?
Trityl stands for triphenylmethyl, a group most commonly used to protect free alcohols as ethers. As seen with other PGs, amines and thiols can also be protected (as they are also nucleophilic).
Trityl ethers saw most application in carbohydrate chemistry as their hydrophobicity was useful for protection of polar building blocks. In addition, their bulky size allows for selective protection of primary hydroxyls due to sterics. Over time, silyl PGs like TBS have replaced much of the use of Tr outside of carbohydrate chemistry. Nevertheless, we can learn some things by studying it!
Trityl Protection Mechanism
Trityl protection usually uses trityl chloride in pyridine which conveniently functions as a base, capturing the HCl by-product. Added DMAP (4-dimethylaminopyridine) can function as a base but also as a catalyst. You likely remember from other protecting groups (e.g., TBS) or reactions like acylation that DMAP works as a transfer reagent via initial nucleophilic addition to the activated reagent and transfer to our group of interest (not shown above).
Watch out as there are some pages online that imply a direct SN2-like attack of the free alcohol to Tr-Cl. You should know this is impossible; quaternary carbons do not undergo SN2! Instead, the protection proceeds as a SN1 via the stable trityl cation intermediate [1]. The large size allows the selective tritylation of primary alcohols in the presence of secondary alcohols as these react much slower due to steric hindrance.
No surprise, there are other ways to introduce trityl like TrOTf (recall just like for TBS) or trityl-pyridinium tetrafluoroborate, an even more reactive transfer reagent.
Trityl DeProtecTION Mechanism
Trityl is deprotected with Bronsted acids or less commonly also Lewis acids. In both mechanisms, the highly stable trityl cation is a common theme. This should remind you of the Boc group: The trityl cation here is basically a t-butyl cation (acidic Boc deprotection intermediate) on steroids.
Case 1: The deprotection with a Bronsted acid starts with protonation of the ether oxygen. This increases the “pull” on the O-C bond which can fragment to give our deprotected hydroxyl group. The resulting trityl cation is still reactive, so adding nucleophilic scavengers like 2-methyl-2-butene can avoid undesired reactions. By using acetic acid or formic acid, it is possible to deprotect trityl ethers in the presence of TBS ethers. If no sensitive groups are present, stronger acids like TFA obviously work as well.
Case 2: Using Lewis acids like BF3 works in a similar way; coordination to the oxygen lone pair facilitates O-C bond breaking and deprotection. Other Lewis acids like ZnBr2 or MgBr2 can be used for some substrates as well, particularly if two coordination sites are present (e.g., carbohydrates). In these cases, neighbouring group effects with bidentate coordination can be observed.
p-Methoxy Trityl Protecting Group
Do you expect the p-methoxy trityl variant to be (more) acid- or base-sensitive?
As a twist on the standard trityl group, chemists have also explored variants such as p-methoxy trityl. A nice synthetic study on nucleotides led to the discovery of such groups – already in 1962 [2]! Their results were as you might expect: By adding a p-methoxy group, we increase stability of the intermediary trityl cation due to the mesomeric electron-donating effect! This makes deprotection easier.
It turned out introducing one methoxy group increased the rate of deprotection by a factor of ten. While standard 5′-trityl-uridine required 48h for complete hydrolysis in 80% acetic acid at room temperature, the mono-methoxy-trityl MMTr group took just 2h! They also developed di- and trimethoxy trityls (i.e., one p-methoxy on each phenyl ring) which cleave in 15min and 1min, respectively. By the way, this change makes initial protection easier too because we also go through the trityl cation.
This di-methoxy DMTr group is one of the most used members of the trityl family due to its reactivity and selectivity for primary alcohols (primarily seen in automated solid-phase synthesis of nucleotides).
I hope you learned something new today!
Trityl Protection experimental procedure [3]
A mixture of di-TBS gemcitabine (671 mg, 1.47 mmol) and tritylating reagent (2.94 mmol, 2 equiv.) in dry pyridine (7.3 mL) was stirred overnight at room temperature. Methanol was added to the solution for quenching. After removal of the solvent, the residue was purified by flash column chromatography on silica gel to obtain the title compounds.
Trityl deprotection experimental procedure
Bronsted acid [4]: Compound II (200mg, 0.4mmole) was treated with 3ml of cold formic acid (97+%) for 3 min and then evaporated with an oil pump at room temperature. The residual gum was evaporated twice from dioxane, followed by evaporations from EtOH and Et2O. Finally, the residue was extracted with 10ml of warm H20, the insoluble triphenyl-carbinol was filtered, and the filtrate was evaporated in vacuo. The residual gum was dissolved in EtOH(1ml), dry Et2O (20ml) was added, and the product was precipitated with petroleum ether (30-60°, 10ml) (the gummy precipitate was chilled and scratched to induce crystallization). Recrystallization from the same solvent system gave fine needles of VI.
Lewis acid [5] To a mixture of 4 (2.0 mmol, 994 mg, 1.0 equiv) in CHCl3/MeOH (16 mL/4 mL) was added BF3·OEt2 (4.0 mmol, 0.5 mL, 2.0 equiv) at room temperature. The mixture was stirred at rt for 45 min and was then poured into EtOAc/H2O (100 mL/100 mL). The organic layer was washed with brine (100 mL), dried (Na2SO4), and filtered. After removal of solvent, CH2Cl2 (10 mL) and hexane (30 mL) were added sequentially to the crude product. The resulting solid was filtered and was washed with Et2O/hexane (2/3, 20 mL). The product was dried to give 474 mg of 12 (93%) as a white solid.
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).”
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%).”
