SEM Protecting Group: SEM Protection & Deprotection Mechanism

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 SEM 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), 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.

Exemplary acidic deprotection conditions are i) excess TFA (trifluoroacetic acid); ii) excess PPTS (Pyridinium p-toluenesulfonate).

Stability of the SEM Protecting group

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)
• [4] Enantioselective Total Synthesis of (−)-Taxol | Hiroyuki Kusama, Ryoma Hara, Shigeru Kawahara, Toshiyuki Nishimori, Hajime Kashima, Nobuhito Nakamura, Koichiro Morihira, Isao Kuwajima | J. Am. Chem. Soc. 2000, 122, 3811
• [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