Question

In the chemical synthesis of DNA and RNA, hydroxyl groups are normally converted to triphenylmethyl (trityl) ethers to protect the hydroxyl group from reaction with other reagents. Triphenylmethyl ethers are stable to aqueous base but are rapidly cleaved in aqueous acid. $$ \mathrm{RCH}_{2} \mathrm{OCPh}_{3}+\mathrm{H}_{2} \mathrm{O} \stackrel{\mathrm{H}^{+}}{\longrightarrow} \mathrm{RCH}_{2} \mathrm{OH}+\mathrm{Ph}_{3} \mathrm{COH} $$ (a) Why are triphenylmethyl ethers so readily hydrolyzed by aqueous acid? (b) How might the structure of the triphenylmethyl group be modified to increase or decrease its acid sensitivity?

Short answer

Question: Explain the reasons for the ready hydrolysis of triphenylmethyl ethers by aqueous acid and how modifications to the structure of the triphenylmethyl group can affect its acid sensitivity. Answer: Triphenylmethyl ethers are readily hydrolyzed by aqueous acids due to the steric hindrance and electron repulsion provided by the three phenyl groups attached to the central carbon atom. This destabilizes the positive charge on the central carbon during the hydrolysis process, making it more susceptible to attack by the nucleophile (water). Modifications to the structure of the triphenylmethyl group can alter its acid sensitivity by changing either the steric hindrance or the electron distribution. Introducing electron-donating groups on the phenyl rings will increase acid sensitivity, while introducing electron-withdrawing groups or decreasing the size of substituents will decrease acid sensitivity.

Step-by-step solution

(a) Reasons for ready hydrolysis of triphenylmethyl ethers by aqueous acid

Triphenylmethyl ethers are readily hydrolyzed by aqueous acids due to the steric hindrance and electron repulsion provided by the three phenyl groups attached to the central carbon atom. This destabilizes the positive charge on the central carbon during the hydrolysis process, making it more susceptible to attack by the nucleophile (water). The overall process can be explained in the following steps. Step 1: Protonation $$ \mathrm{RCH}_{2} \mathrm{OCPh}_{3} + \mathrm{H}^{+} \longrightarrow \mathrm{RCH}_{2} \mathrm{OCPh}_{3}^{+} \mathrm{H} $$ The trityl ether reacts with a proton (from an aqueous acid) which results in the protonation of the oxygen atom and a positive charge formation. Step 2: Nucleophilic attack $$ \mathrm{RCH}_{2} \mathrm{OCPh}_{3}^{+} \mathrm{H} + \mathrm{H}_{2} \mathrm{O} \longrightarrow \mathrm{RCH}_{2} \mathrm{OH} + \mathrm{Ph}_{3} \mathrm{COH} $$ Due to the destabilization caused by steric hindrance and electron repulsion, the positively charged carbon atom is readily attacked by a nucleophile (water in this case) which leads to the cleavage of the bond between the oxygen and carbon atoms. The trityl group loses a proton and forms triphenylmethanol, and the RCH2 group forms an alcohol, which was the goal of protection in the first place.

(b) Modifying the structure of the triphenylmethyl group

To modify the structure of the triphenylmethyl group and alter its acid sensitivity, we can make changes to either the steric hindrance or the electron distribution. 1. Increase acid sensitivity: The acid sensitivity can be increased by introducing electron-donating groups (-OH, -OCH3, or -NH2) on the phenyl rings. This will increase the electron density on the central carbon, making it more susceptible to the protonation and nucleophilic attack. 2. Decrease acid sensitivity: On the other hand, decreasing acid sensitivity can be achieved by introducing electron-withdrawing groups (-NO2, -CN, or -CF3) on the phenyl rings. This will decrease the electron density on the central carbon and make it less susceptible to protonation and nucleophilic attack. Additionally, decreasing the size of the substituents will reduce steric hindrance and make the trityl ether less reactive.

Key concepts

Hydrolysis

Hydrolysis is an essential chemical reaction that involves breaking bonds in a molecule with the addition of water. In the context of triphenylmethyl ethers used in DNA and RNA synthesis, hydrolysis is crucial in removing protective groups after synthetic steps are complete.
In the hydrolysis of triphenylmethyl ethers, the reaction is facilitated by an aqueous acid. The process begins with protonation, where an acid donates a proton to the oxygen in the ether bond. This protonation step destabilizes the bond, setting the stage for a nucleophilic attack, where water, acting as a nucleophile, attacks the positively charged carbon.
Through a series of detailed steps, hydrolysis effectively cleaves the protective ether group, freeing the hydroxyl group for further reactions or analysis.

Nucleophilic Attack

A nucleophilic attack occurs when a nucleophile, an electron-rich species, seeks out a positively charged or electron-deficient atom or group in a reaction. This is a central step in the hydrolysis process of triphenylmethyl ethers.
During the reaction, after the ether's oxygen atom is protonated and gains a positive charge, water acts as the nucleophile. Water is attracted to the electron-deficient carbon atom adjacent to the oxygen. As it approaches, water donates a pair of electrons to form a new bond while the existing bond breaks concurrently, leading to the cleavage of the ether linkage.
This nucleophilic attack is efficient due to the preceding protonation step, which increases the susceptibility of the carbon atom to nucleophilic assault.

Steric Hindrance

Steric hindrance refers to the restriction experienced by molecules when their geometry prevents reactions with other molecules. In the case of triphenylmethyl ethers, steric hindrance plays a significant role in the molecule's reactivity.
The triphenylmethyl group is bulky, with three phenyl rings attached, creating a physical barrier that affects the molecule's approachability by reagents. This bulkiness can destabilize certain reaction intermediates; specifically, the congested environment around the central carbon in triphenylmethyl ethers contributes to shifts in how reactions such as hydrolysis proceed.
This steric bulk around the central carbon atom helps to destabilize positive charges during reactions, making the carbon more prone to nucleophilic attacks when proper conditions, like protonation, are met.

Electron Donating Groups

Electron donating groups (EDGs) are substituents that push electron density towards other atoms, typically enhancing reactivity in certain chemical contexts. In modifying triphenylmethyl ethers, introducing EDGs can increase acid sensitivity.
Examples of electron donating groups include -OH, -OCH₃, and -NH₂. When these groups are added to the phenyl rings around the central carbon, they increase the electron density there, making the carbon less stable and more reactive to acidic conditions.
This increased reactivity can subsequently make the ether group more prone to protonation and nucleophilic attack during hydrolysis, facilitating the efficient removal of protecting groups used in synthesis.

Electron Withdrawing Groups

Electron withdrawing groups (EWGs) draw electron density away from an atom or group, often reducing an atom's reactivity to electrophilic or nucleophilic attacks. For triphenylmethyl ethers, introducing such groups can decrease acid sensitivity.
By incorporating EWGs like -NO₂, -CN, or -CF₃ onto the phenyl rings, the electron density around the central carbon is reduced. This reduction makes the carbon atom more stable and less susceptible to protonation and subsequent nucleophilic attack.
This strategy can be useful in stabilizing the triphenylmethyl ether under acidic conditions, allowing chemists to tune reactivity and stability based on specific synthetic requirements.