The main protecting groups for alcohols are ethers, silyl ethers and acetals. Here’s an overview of their structures, protection and deprotection conditions.
For more details on some of these protecting groups, check out these articles. For each group, we explain the context, mechanisms for protections and deprotections, 3D models and examples (ranging from easy to hard). O-PMB | O-Trityl | | O-TBS | O-MOM | O-THP | O-MEM | O-SEM
When are Alcohol Groups Protected During Organic reactions?
This might be an obvious question we explain here already: Why do we need protecting groups to begin with?
It’s all about getting what you want, while avoiding what you don’t want.
Protecting groups are temporary shields for reactive functional groups to prevent side reactions and maximize chemoselectivity of reactions.
When we modify more complex molecules, we might want a specific functional group to react selectively while preserving other hydroxyl groups presentin the molecule. The synthesis of carbohydrates (and other natural products, like oxygenated terpenoids) thus often requires protecting groups for alcohols.
The issue comes from one of the first reactivities we learn about in organic chemistry: the chemistry of water (H2O) and alcohols, like methanol (CH3OH). The “-OH” hydroxyl group is a nucleophile and can interfere with reactions of other functional groups.
It is somewhat possible to selectively functionalize some groups without protecting groups, for instance by leveraging relative reactivity due to steric hindrance. Primary hydroxyl groups react faster than secondary hydroxyls. However, for the assembly of complex molecules with dozens of reactive functional groups, protecting groups are basically impossible to avoid.
Let me know if you would like additional summaries of protecting group classes (e.g., for amines etc.). If you’re interested in practice problems in organic chemistry, check out the free problem sets.
The Alloc protecting group is used to protect amines. It is removed with catalytic Pd(PPh3)4 and thus orthogonal to many PGs.
This article explains Alloc protection and its unique deprotection mechanism.
👀 In the 3D structure, you see that the allyl group is not planar with the carbonyl!
What is the Alloc Protecting Group?
The Alloc protecting group is related to the Allyl protecting group and orthogonal to almost every other protecting group out there.
It might seem complicated, but it’s just a fancy version of a carbamate protecting group based on two structures: 1) A carbamate which if present in its free form (-OH), can decarboxylate to release the original amino group. Other carbamate protecting groups we’ve seen like Boc, Cbz or Fmoc work this way. They just have a different “trigger” group. 2) An O-allyl group that is activated towards nucleophilic attack of palladium(0) to form of allyl-palladium complexes. Instead of e.g., a tBu group present in Boc which gets “triggered” by acid, this one is triggered by Pd(0)!
Due to the mild deprotection conditions, the group has seen significant application in the synthesis of complex peptides and carbohydrates as a solid alternative to e.g., Boc.
Alloc Protection Mechanism
Alloc protection is trivial and follows the same logic like other carbamates: Nucleophilic attack of the amine to some sort of activated Alloc reagent, typically AllocCl (allyl chloroformate – so like CbzCl for Cbz) or Alloc2O (diallyl dicarbonate – like Boc2O!).
Exemplary conditions are i) AllocCl, pyridine in THF; ii) AllocCl, DMAP, NEt3 in CH3CN; iii) Alloc2O in dioxane, H2O or in CH2Cl2; iv) Alloc-OSu, NEt3, CH2Cl2
Alloc deprotection mechanism
As already alluded to, the magic of this group is in the activated allyl group (given it’s connected to the oxygen of the carbamate). The deprotection is a catalytic cycle, initiated by coordination of Pd(0) and oxidative addition to form an allyl-palladium(II) complex.
The carbamate ligand can dissociate from the complex and decarboxylate to give our desired deprotected amine (again, the same logic as we saw with Boc, Cbz and Fmoc).
But how do we regenerate our catalyst Pd(0) and get rid of the allyl group? There are two options: 1) Nucleophiles can attack the complex and transfer the allyl group, reducing Pd(II) to give Pd(0). Morpholine is one of the key allyl transfer reagent in the text books, but other amines (Me2NH•BH3), C-H acids (e.g., dimedone, barbituric acid)… can be used. 2) Hydride donors can reduce the allyl group via reductive elimination, giving butene. Silanes (such as PhSiH3 / phenylsilane) are common but other hydride donors such as formic acid, SnBu3H (tributylstannane) or sodium borohydride (NaBH4) exist.
If no additional allyl transfer reagent / scavenger would be added, the cycle would not be closed and we would see undesired allylation of our deprotected amine (because it’s a nucleophile).
If you are crazy but want some of that OG E. J. Corey chemistry swag [1], you can also use Ni(CO)4. This compound is extremely toxic and highly volatile… but why would you if you can use palladium?! Fun fact: The name of Corey’s co-worker in the paper [1] is “Suggs” – so yeah, working with nickel carbonyl suggs!
Pd(0) is unstable. To not prepare it fresh, it can be formed from Pd(II) precursorcatalysts like Pd(PPh3)2Cl2 and reductants such as silanes. Not all Pd(0) reactions start with Pd(0)!
Examples of Alloc PROTECTION in Organic Synthesis
This first example [2] shows the orthogonality of Alloc – here, with Fmoc and a methyl ester. In this case, the borane-dimethylamine complex is used as a nucleophilic allyl transfer reagent.
Our second example [3] is from the total synthesis of antillatoxin. This marine natural product was isolated from some exotic cyanobacteria and, in addition to being toxic to shrimp (lol), might have interesting bioactivity (antiproliferation of cells via inhibition of tubulin polymerization).
You’ll see that two allyl groups were deprotected in one step – one from an amino group, and one from an ester. This set up the final intramolecular cyclization step to form the lactam (cyclic amide) in the product.
That’s All(oc) for this article! (ok, bad pun…) Feel free to check out my other articles on protecting groups, my page or my videos!
Alloc Protection experimental procedure [4]
“A mixture of amine (0.0842 mmol), NaHCO3(44 mg, 0.53 mmol, 6 equiv), THF (3 mL), and H2O (3 mL) at room temperature was treated with allyl chloroformate (28 μL, 0.26 mmol, 3 equiv). The reaction mixture was stirred at room temperature for 12 h, extracted with EtOAc (200 mL, 100 mL), and the combined organic layers were washed with saturated aqueous NaCl (200 mL), dried over Na2SO4, and concentrated in vacuo. Column chromatography provided 38 (48.8 mg, 87% over 2 steps) as a white foam.”
Alloc deprotection experimental procedure [4]
“A stirred solution of 40 (8.61 g, 8.2 mmol, 1.0 equiv) in CH2Cl2 (82 mL) at 0 ̊C under Ar was treated with PhSiH3 (7.1 ml, 57 mmol, 7.0 equiv) followed by Pd(PPh3)4 (0.95 g, 0.82 mmol, 10 mol %). The reaction mixture was stirred at 0 °C for 1 h and concentrated under reduced pressure. Column chromatography provided the semi-pure amine (7.79 g) as a yellow solid.”
Alloc Protecting Group References
General: P. G. M. Wuts, T. W. Greene: Greene’s Protective in Organic Synthesis (Wiley)
[1] Cleavage of allyloxycarbonyl protecting group from oxygen and nitrogen under mild conditions by nickel carbonyl | E. J. Corey, J. William Suggs | J. Org. Chem. 1973, 38, 3223
[2] P. J. Kocienski: Protecting Groups (Thieme)
[3] Total Synthesis and Revision of Absolute Stereochemistry of Antillatoxin, an Ichthyotoxic Cyclic Lipopeptide from Marine Cyanobacterium Lyngbya majuscula | Fumiaki Yokokawa, Hideyasu Fujiwara, Takayuki Shioiri | Tetrahedron 2000, 56, 1759
[4] Next-Generation Total Synthesis of Vancomycin | Maxwell J. Moore, Shiwei Qu, Ceheng Tan, Yu Cai, Yuzo Mogi, D. Jamin Keith, Dale L. Boger | J. Am. Chem. Soc. 2020, 142, 16039
The SEM protecting group is used to protect alcohols and amines. SEM is removed with fluoride (F–) or acid (H+).
2-(Trimethylsilyl)ethoxymethyl (SEM) is an acetal-type protecting group for alcohols, but can be used for other nucleophiles like amines as well. Here we cover SEM protection and deprotection mechanisms, as well as examples.
No surprise, SEM is related to MEM and the simpler MOM protecting group. But note the TMS!
👀 Here is an interactive 3D structure of SEM.
What is the SEM Protecting Group?
The SEM protecting group is essentially a combination of the MEM group and a TMS group. The presence of silyl group means that fluoride can play a part in deprotection as well.
When attached to an alcohol, it forms a much less reactive acetal. However, just like other similar protecting groups, it can also be added to other nucleophiles like amines. SEM is stable under various conditions, including bases, reductants, organometallic reagents, oxidants and mild acids.
The SEM group was invented in 1980 by Lipshutz and Pegram [1], so just a few years after introduction of MEM by E. J. Corey.
SEM Protection Mechanism
The protection is MOM and MEM all over again. 1. Option: Treatment with SEM chloride and DIPEA (N, N-diisopropylethylamine) or another weak base. Deprotonation occurs after nucleophilic attack. 2. Option: Treatment with a strong base like NaH (KH, n-BuLi, …)and SEMchloride. Experimentally / in the lab, only base is added to the alcohol first – and only after some time (e.g., 1h to ensure the alkoxide is formed), SEMCl is added.
Again, note the activation and higher reactivity of such alkylating agents due to the adjacent oxygen.
SEM deprotection mechanism 1: Fluoride (F–)
The presence of silicon in SEM allows for deprotection with fluoride anions (high thermodynamic affinity for the very strong Si-F bond). These mechanisms proceed via formation of the pentavalent siliconate intermediate.
The siliconate is unstable and can trigger a beta-elimination decomposition. This releases three neutral molecules: TMSF, ethylene and formaldehyde. We can just draw everything in one single step and take a proton from the solution (under acidic conditions like HF, the oxygen might be protonated already prior to decomposition).
The benefit of fluoride is that it the conditions are often orthogonal / compatible with many functional and protecting groups. However, compared to ordinary silyl ethers (e.g., TMS), SEM deprotection tends to require higher temperatures, longer reaction times, or in some cases the use of additives (HMPA).
Exemplary fluoride deprotection conditions for SEM are i) TBAF, DMF; ii) HF, MeCN; iii) LiBF4, (MeCN-H2O).
SEM deprotection mechanism 2: Bronsted Acid (H+)
Though less preferred than fluoride-mediated deprotection, acidic hydrolysis also works for SEM. This is another parallel to MOM, MEM and THP. There are more mechanistic options , but the direct path is probably the most likely one.
i) Direct path: The oxygen of our protected alcohol is protonated and achieves the deprotection in the simplest manner.
ii) Indirect path: The other ether oxygen is protonated, and goes via the hemiacetal intermediate (formaldehyde is lost in the solution or upon work-up). This is what we’ve seen for MEM or MOM.
iii) Beta elimination: What we’ve seen during the fluoride deprotection, but now just in the acidic variant.
What about relative stability? According to Kocienski [2], SEM is more labile than MOM and MEM under acidic conditions. (Obviously, fluoride does not remove MOM). On the other hand, Greene [3] notes that SEM are very robust groups and often difficult to remove.
The truth is probably more the latter. Here is an example from the total synthesis of taxol by Kuwajima [4].
“We also investigated the Birch reduction of derivatives of 25a with various protecting groups on the C2-OH: reaction of the di-tert-butylsilylene derivative 25b induced C2−O bond cleavage predominantly (eq 3). Use of the C2-O-SEM substrate 25c gave a much more satisfactory result (eq 4), but we encountered much difficulty in removing the SEM group at a later stage; the SEM group was thus deemed to be unsuitable for the present purpose.”
Lesson: Higher yield is not always better! Sometimes, we have to accept lower yields in the early steps of a synthesis to finish it!
Examples of SEM PROTECTION in Organic Synthesis
Our first example shows the orthogonality of SEM and MOM [3]. Harsher conditions are needed to remove SEM, but our MOM groups survive at 100 °C without issue.
The second example is really interesting.
Question: Although this reaction uses similar conditions as our first example, we are far from our nice 98% yield of a single product. Can you guess the structures of the three products?
Solution: OK, first of all we do see a MOM group but the first example taught us that these do not fly off when exposed to fluoride sources (unless we cook them in e.g., HF).The first insight is that the triethylsilyl (TES) group might also be a victim of the fluoride deprotection. So we might expect a mixture of SEM- and TES-deprotected products.
Indeed, product 1 is SEM- and TES-deprotected one whereas product 2 is only TES-deprotected.
But what about product 3?
Beware of interrupted deprotections!
Instead of beta-elimination and release of ethylene (and formaldehyde), it looks like we have a proto-desilylation. The ethyl group remains on the ether, and we basically have a one-carbon extended MOM group now. Why could this SEM group just not be bothered to leave? Uhm, we do not know. That’s chemistry for you.
We have seen a few of these tricky questions with other protecting groups, where, e.g., the presence of an intramolecular nucleophile can lead to side products.
As we mention often, many alcohol protecting groups can also be used to protect carboxylic acids or amines. As we see in our third example [5], SEM can also used to protect the nucleophilic nitrogen in heterocycles like imidazole.
This acidic deprotection was particularly sluggish. At 25 °C, >200 equivalents of TFA were added over two batches and ultimately just gave 20% yield. As we see, SEM is indeed hard to remove!
We’re done! If you learned something, make sure to check out my other articles on protecting groups, my page or my videos!
SEM Protection experimental procedure [6]
“To a dry 100 mL round-bottom flask under argon was added anhydrous DMF (40 mL) and NaH (0.293 g, 60%, 7.31 mmol); then the solution was cooled to 0 °C. In a separate flask the alcohol (1.021 g, 4.87 mmol) was dissolved in DMF (10 mL), and then this solution was added dropwise by cannula to the NaH/DMF mixture. The reaction mixture was stirred at 0 °C for 2 h, and then 2-(trimethylsilyl)ethoxymethyl chloride (1.067 g, 6.33 mmol) was added. After 10 h saturated NH4Cl solution (10 mL) was added, and this mixture was extracted with ethyl acetate. The combined organic layers were washed with water (3 × 25 mL) and brine (1 × 25 mL), dried over Na2SO4, and then concentrated to give a crude solid which was purified using flash chromatography (hexanes–ethyl acetate, 1:1) to give 12 as a light brown solid (1.25 g, 78%).”
SEM deprotection experimental procedure [6]
“To a 100 mL round-bottom flask, the alcohol was added (0.396 g, 0.84 mmol) and dissolved in DMF (50 mL). To this was added tetramethylethylenediamine (0.293 g, 2.53 mmol) and TBAF (1.0 M in THF, 2.53 mL, 2.53 mmol), attached a reflux condenser and set the reaction for heating at 45 °C for 20 h. After confirming the completion of the reaction by LCMS (m/z 340), the reaction was allowed to cool to room temperature and to it was added saturated solution of NH4Cl. The contents were transferred to a separatory funnel containing 100 mL of water. Extraction was done using ethyl acetate, and the combined organic layer was washed with water, followed by brine, dried over sodium sulfate, and evaporated the solvents to give a crude solid which after flash chromatography purification using hexane–ethyl acetate (1:1) gave 8 as a buff solid (0.202 g, 71%).”
SEM Protecting Group References
[1] β-(Trimethylsilyl)ethoxymethyl chloride. A new reagent for the protection of the hydroxyl group | Bruce H. Lipshutz, Joseph J. Pegram | Tetrahedron Letters 1980, 21, 3343
[2] P. J. Kocienski: Protecting Groups (Thieme)
[3] P. G. M. Wuts, T. W. Greene: Greene’s Protective in Organic Synthesis (Wiley)
[5] Discovery of Bis-imidazolecarboxamide Derivatives as Novel, Potent, and Selective TNIK Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis | Vladimir Aladinskiy, Chris Kruse, Luoheng Qin, Eugene Babin, Yaya Fan, Georgiy Andreev, Heng Zhao, Yanyun Fu, Man Zhang, Yan Ivanenkov, Alex Aliper, Alex Zhavoronkov, Feng Ren | J. Med. Chem. 2024, 67, 19121
[6] Tale of Two Protecting Groups—Boc vs SEM—for Directed Lithiation and C–C Bond Formation on a Pyrrolopyridazinone Core | Reji N. Nair, Thomas D. Bannister | Org. Process Res. Dev. 2016, 20, 1370
The MEM protecting group protects alcohols as stable acetals. MEM is removed with protic acids (H+) and more importantly, Lewis acids.
2-Methoxyethoxymethyl (MEM) is an acetal-type protecting group for alcohols. This article explains MEM protection and deprotection mechanisms, as well as examples.
MEM is related to the simpler MOM protecting group. It’s rather oldschool, but the additional ether group brings an interesting twist!
👀 Quite a few oxygens – I hope this interactive 3D model helps!
What is the MEM Protecting Group?
The MEM group belongs to the class of acetal (‘double-ether’) protecting groups which are much less reactive than their free alcohol counterparts. Fun fact: The MEM group was introduced in 1976 by the legendary chemist E. J. Corey and co-workers [1], just like the TBS/TBDMS and allyl protecting groups.
MEM is stable under various conditions, including strong bases, reductants, organometallic reagents, oxidants and mild acids. What makes it unique is the selective cleavage with Lewis acids (see below).
MEM Protection Mechanism
The protection conditions are identical to MOM: 1) Treatment with MEM chloride and DIPEA (N, N-diisopropylethylamine) or another weak base. Deprotonation occurs after nucleophilic attack. 2) Treatment with a strong base like NaH and MEM chloride. Experimentally / in the lab, only base is added to the alcohol first – and only after some time (e.g., 1h to ensure the alkoxide is formed), MEMCl is added.
MEMCl is another case of an activated alkylating agent. The adjacent oxygen can facilitate departure of the chloride, creating a highly electrophilic oxonium ion. (No surprise it’s also bad for you – it alkylates your DNA!)
MEM deprotection mechanism 1: Bronsted Acid (H+)
Just like MOM or THP, we can get rid of MEM with acid, tough typically stronger / more forcing conditions are required. Thus, it is possible to selectively remove THP, MOM or PMB groups in the presence of MEM. The simplest mechanism starts with protonation of our protected oxygen in the acetal system. This cation can release of our free alcohol and form some type of byproduct (depending on solvent).
The alternative / indirect mechanismwould be protonation of the other oxygen atom, going through a hemiacetal intermediate. With water in the solvent or upon work-up, this unstable species releases formaldehyde and gives our free alcohol.
So what makes MEM unique versus MOM? Due to the presence of an additional ether oxygen, the acetal is much more labile when exposed to Lewis acids. Due to this additional lone pair, we have bidentate coordination to metals such as i) ZnBr2, ii)TiCl4, – or like we’ve seen for MOM, also more Lewis acidic species like iii)TMSI.
The productive mechanism is now kind of the opposite as before – it is the oxygen of our protected alcohol that cleaves the protecting group. This oxonium intermediate is ultimately hydrolysed (either water present in the reaction or upon work-up), releasing formaldehyde and giving our deprotected product.
Examples of MEM in Organic Synthesis
Our first example [2] is really chill. Simple introduction of MEM, just like we’ve talked about.
Too easy for you? Well, check this one out:
Upon treatment of the compound above, two products were observed in significant yield. What are they?
One of the products surely is the normal MEM-deprotected alcohol. After all, this is an article about MEM and we’ve just seen than ZnBr2 will act as a Lewis acid and remove the group. We cannot say with certainty, but this is probably the major product 1.
But what about product 2? If you have no ideas, go back to the mechanism above and look at what happens after initial break-down of MEM!
Always watch out for neighbouring group participation!
The answer is very cool: Our starting material has a sneaky hydroxyl group that can attack our oxonium intermediate. This occurs because the intramolecular reaction is very fast – even despite the tertiary alcohol being very hindered. This means that we do not go through the intermolecular bromide-hydrolysis pathway, but rather form a cyclic acetal!
That’s it! If you learned something, make sure to check out my other articles on protecting groups, my page or my videos!
MEM Protection experimental procedure [2]
“To a solution of alcohol (4g, 40 mmol) in CH2Cl2 (100 mL)under N2 was added MEM chloride (7.5g, 60mmol) and DIPEA (7.8g, 60mmol) at 25 °C and the reaction mixture was stirred at rt for 5 h. Water (30 mL) was added to the reaction mixture and CH2Cl2 was used to extract the mixture. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give 7.4g of crude product. Flash chromatography of the residue on silica gel gave 6.1g (80%) of MEM protected alcohol as a colorless liquid.”
MEM Protecting Group References
General: P. G. M. Wuts, T. W. Greene: Greene’s Protective in Organic Synthesis (Wiley)
[1] A new general method for protection of the hydroxyl function | E.J. Corey, Jean-Louis Gras, Peter Ulrich | Tetrahedron Letters 1976, 17, 809
[2] Total Synthesis of (±)-Deoxypenostatin A. Approaches to the Syntheses of Penostatins A and B | Barry B. Snider, Tao Liu | J. Org. Chem. 2000, 65, 8490
The MOM protecting group protects alcohols as acetals. MOM is introduced with MOMCl and removed with acid (H+).
Methoxymethyl is the simplest acetal protecting group for alcohols. This article covers mechanisms for MOM protection and deprotection, and examples.
MOM is quite common and similar to protecting groups such as THP, so it’s a “must-know” for students!
👀 Here’s an interactive 3D model of the MOM protecting group.
What is the MOM Protecting Group?
Protecting groups serve to minimize unwanted side reactions during organic synthesis. When protecting alcohols, methoxymethyl ethers actually form a type of acetal (‘double-ether’). These are much less reactive than the free alcohol.
Remember – just like with other protecting groups – that different nucleophiles can be protected with the same protecting group. This is why MOM is also used to protect phenols, carboxylic acids (still a nucleophilic oxygen) as well as amines (nucleophilic nitrogen). Introduction and removal (typically acid) follow the same logic, so most study materials focus on just the protection of alcohols.
MOM Protection Mechanism
Two protection conditions are most common for alcohols: 1) Treatment with MOM chloride and DIPEA (N, N-diisopropylethylamine) or another weak base. Here, deprotonation occurs after nucleophilic attack. 2) Treatment with the strong base NaH (or KH) and MOM chloride. Here, deprotonation occurs first and nucleophilic attack is second. Experimentally / in the lab, only base is added to the alcohol first – and only after some time (e.g., 1h to ensure the alkoxide is formed), MOMCl is added.
Note that the lone pairs on the oxygen on MOMCl actually activate the departure of the chloride. This creates a highly reactive, electrophilic oxonium ion which is captured by the alcohol. This makes MOMCl a very powerful alkylating agent and carcinogenic (it alkylates your DNA base pairs which is not what you want). So, special care in the lab is required.
A safer alternative protocol is the following: 3) Use of dimethoxy methane and an acid. This reaction is different as it is an acetal exchange reaction and uses an excess of reagent to drive the equilibrium.
mOm deprotection mechanism
The standard MOM deprotection is acidic hydrolysis. Protonation activates the acetal system towards release of our free alcohol. Less importantly, the remaining stabilized cation forms a byproduct after trapping by the solvent. This is pretty similar to the THP deprotection.
Note that you can also draw the alternative / indirect mechanism with protonation at the other oxygen, leading to a hemiacetal intermediate and ultimately our free alcohol upon elimination of formaldehyde.
Exemplary deprotection conditions are: i)HCl in aqueous EtOH; ii) TFA (trifluoroacetic acid) in dichloromethane; iii) PPTS (pyridinium p-toluenesulfonate) in tBuOH.
Alternatively, reactive electrophiles / Lewis acids like TMS+ can also be used to remove MOM groups. A key method is use of TMSBr (the mechanism follows a similar logic of nucleophilic attack).
Classes often teach you a single method (to preserve your sanity) of protection or deprotection, but having different options at our disposal helps in the lab when we deal with complex molecules that have other protecting groups!
Examples of MOM in Organic Synthesis
Now that we now the basics, let’s check out two use cases of MOM and connect it to other protecting groups we have learned about.
The first example [1] shows that lability does not equal lability. We’ve learned that the PMB protecting group can be cleaved under acidic conditions. However, HCl (generated in situ from AcCl and MeOH) here selectively removed the MOM group while retaining the PMB group. Chemistry is pretty experimental!
The second example [2] is a fancy regioselective introduction of the MOM group. This procedure achieves MOM protection at the more sterically hindered alcohol of a vicine diol which should be less reactive with reagents like MOM-Cl (secondary vs. primary alcohol). The trick here is to create the orthoester first as a detour. It can then be reduced with DIBAL-H which exhibits preference in coordination and hydride reduction, leaving the MOM group hanging at the more hindered alcohol!
Appreciate you reading the full article! Feel free to check out other protecting groups, my page or my videos!
MOM Protection experimental procedure [3]
“An oven-dried 3-neck 500 mL round-bottom flask equipped with a stir bar was charged with alcohol 16 (15.5 g, 78.18 mmol, 1.0 eq.), DIPEA (40.41 g, 312.72 mmol, 4.0 eq.) and DCM (160 mL) under Ar. The resulting suspension was cooled down to 0 °C and freshly distilled MOMCl (18.88 g, 234.50 mmol, 3.0 eq.) was added dropwise over a period of 10 min. NaI (5.80 g, 39.09 mmol, 0.5 eq) was added to the reaction solution, and the resulting mixture was allowed to warm to 25 °C, and stirred for 16 h. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (300 mL) and diluted with DCM (100 mL).The two layers were separated and aqueous layer was extracted with DCM (2 × 100 mL). Combined organic phases were washed with saturated sodium chloride solution (1 × 100 mL)，dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography to give 17 (17.5 g, 92% yield) as colorless liquid.”
MOM deprotection experimental procedure [3]
“31 (68 mg, 0.142 mmol, 1.0 eq.) was dissolved in DCM/TFA = 15/1 (3 mL) at 25 °C. The resulting suspension was stirred at 25 °C for 12 h, when TLC analysis of the crude mixture showed full conversion. The reaction mixture was diluted with DCM (2 mL) and treated with sat. aq. NaHCO3 (4 mL). The layers were separated and the aqueous phase was extracted with DCM (2 x 3 mL). Combined organic phases were washed with sat. aq. NaCl (1 × 5 mL)，dried over anhydrous MgSO4 and concentrated under reduced pressure to give the crude product. The crude residue was purified by preparative TLC to provide isorosthin L (35 mg, 71% yield) as a white solid.”
mom Protecting Group References
[1] P. G. M. Wuts, T. W. Greene: Greene’s Protective in Organic Synthesis (Wiley)
[2] A convenient procedure for the regioselective monoprotection of 1,n-diols | M. Takasu, Y. Naruse, H. Yamamoto | Tetrahedron Lett. 1988, 29, 194
The Troc protecting group protects amines in organic synthesis. Troc is introduced with TrocCl and deprotected with reduction (Zn).
Troc (also 2,2,2-trichloroethoxycarbonyl) is a rather exotic but versatile protecting group. Let’s learn about its unique mechanisms!
👀 Here’s an interactive 3D model – chlorines in green!
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 just one of the three groups decarboxylates. The others are not true Troc groups but were instead masking the free acid. If we do not have a free carbamate or carbonate after reductive elimination, we do not see a decarboxylation.
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 acetals. THP is introduced with DHP and acid, and removed through acidic solvolysis.
THP (tetrahydropyranyl) is a less common hydroxyl protecting group than silyl-based ones like TBS. It’s interesting as it has a unique nature and mechanism.
👀 Here’s an interactive 3D model of the THP protecting group.
You’ll realize that it’s essentially a beefier version of MOM!
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 or DHP. 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 is similar to MOM deprotection and actually also similar 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.
“To a 100-mL, single-necked, round-bottomed flask equipped with a magnetic stir-bar, argon inlet with septum, was charged with dihydropyran (1.5 equiv), followed by CH2Cl2 (15 mL) and PPTS (177.4 mg, 0.706 mmol, 0.1 equiv). The contents were cooled to 0 °C in an ice-bath. Then a suspension of iodobenzyl alcohol 9 (2.08 g, 7.06 mmol) in CH2Cl2 (10 mL) was added at 0 °C over 10 min. After addition, the contents were warmed to rt. Dihydropyran (0.97 mL, 10.59 mmol, 1.5 equiv) was added again to the mixture after 30 min, because the starting material was still observed by TLC analysis. After another 30 min of stirring, H2O (50 mL) was added and the mixture was extracted with CH2Cl2 (3 x 50 mL). The organic layers were combined and washed with brine (2 x 50 mL), dried with Na2SO4, filtered and the solvent was removed under reduced pressure by rotary evaporation. The crude material was further purified using column chromatography (SiO2, 70 g; hexanes/EtOAc, 3:1) to afford (2.67 g, >99%) THP ether 26 as a colorless wax.”
THP deprotection experimental procedure [3]
“To a solution of alkene 12 (38.6 mg, 0.047 mmol) in 2-propanol (0.95 mL), p-toluenesulfonic acid monohydrate (21.7 mg, 0.114 mmol) was added at 0 °C and stirred for 17 h at room temperature. The reaction mixture was diluted with water, extracted with dichloromethane, washed with brine, and dried over sodium sulfate. The residue was purified by thin layer chromatography (hexane/ethyl acetate = 5/1). Alcohol 13 (34.6 mg, quant.) was obtained as a colorless oil.”
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
[2] Total synthesis of (+)-papulacandin D | Scott E. Denmark, Tetsuya Kobayashi, Christopher S. Regens | Tetrahedron 2010, 66, 4745
[3] Total Synthesis of Eutyscoparol A and Violaceoid C | Takatsugu Murata, Takuto Iwayama, Teppei Kuboki, Shotaro Taguchi, Shou Tsugawa, Takumi Yoshida, Hisazumi Tsutsui, Ayana Shimauchi, Yukiho Kosaka, Isamu Shiina | Asian Journal of Organic Chemistry 2024, 13, e202400148
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. Here, we explain properties and mechanisms of acetals.
What Are Acetal Protecting Groups?
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.
The trityl protecting group protects alcohols and other nucleophiles. Tr is deprotected with acids like acetic acid or TFA.
The trityl group(Tr or Trt) is an acid-labile protecting group that might remind you of Boc! Here we explain the “standard” trityl and exciting,more advanced versions!
👀 Here’s an interactive 3D model of the trityl protecting group.
You can see it’s quite bulky!
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).
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. TBS 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 options 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
The most common TBS protection conditions are 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 (likely higher as basic stability > acidic)
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.
1.Acidic hydrolysis works through protonation of the protected oxygen atom, followed by associate hydrolysis with a pentavalent silicon intermediate.
2.Fluoride-mediated deprotection is based on nucleophilic attack onto silicon, giving a pentacoordinate siliconate intermediate that can release our deprotected product. This is like the imidazole catalysis we’ve seen during TBS protection.
The thermodynamic driving force is the formation of the exceptionally strong Si-F bond (>30 kcal/mol stronger than 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.
3.Basic hydrolysis can theoretically also occur with TBS ethers, even though have high stability towards bases. However, at very forcing basic conditions, TBS ethers can hydrolyse (e.g., excess LiOH, dioxane, EtOH, H2O, 90 °C). The mechanism is also based on nucleophilic addition to silicon, followed by Si-O bond breaking.
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. It can be removed through fluoride anions or more forcing acidic conditions.
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.
“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).”
