MOM Protecting Group: MOM Protection & Deprotection Mechanism

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
• [3] Total Synthesis of Isorosthin L and Isoadenolin I Junli Ao, Chao Sun, Bolin Chen, Na Yu, Prof. Guangxin Liang | Angew. Chem. Int. Ed. 2022, 61, e202114489