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.

Trt Protecting Group References

• [1] R. Bernini, M. Maltese; Tetrahedron Letters 2010, 51, 4113 | Friedel–Crafts catalysts as assistants in the tritylation of less reactive hydroxyls
• [2] M. Smith, D. H. Rammler, I. H. Goldberg, H. G. Khorana; J. Am. Chem. Soc. 1962, 84, 3, 430, Studies on Polynucleotides. XIV.1 Specific Synthesis of the C3″-C5″ Interribonucleotide Linkage. Syntheses of Uridylyl-(3″→5″)-Uridine and Uridylyl-(3″→5″)-Adenosine
• [3] Journal of Pharmaceutical Sciences 2022, 111, 2201 | Trimethoxy Trityl Groups as a Potent Substituent for Anti-cancer Cytidine Analog Prodrugs
• [4] T. A. Khwaja, C. Heidelberger, Journal of Medicinal Chemistry 1970, 13, 64 | Fluorinated pyrimidines. XXXIII. Synthesis of methylated 5-fluoro-2′-deoxyuridine derivatives
• [5] J. Org. Chem. 2007, 72, 21, 8123 | Mild and Efficient Lewis Acid-Promoted Detritylation in the Synthesis of N-Hydroxy Amides:  A Concise Synthesis of (−)-Cobactin T
• J. Pearson, W. R. Roush, Handbook of Reagents for Organic Synthesis: Activating Agents and Protecting Groups (Wiley)
• P. Kocienski, Protecting Groups (Thieme Verlag)