Benzyl group

Reactivity of benzylic centers

The enhanced reactivity of benzylic positions is attributed to the low bond dissociation energy for benzylic C−H bonds. Specifically, the bond C₆H₅CH₂−H is about 10–15% weaker than other kinds of C−H bonds. The neighboring aromatic ring stabilizes benzyl radicals. The data tabulated below compare benzylic C−H bond to related C−H bond strengths.

The weakness of the C−H bond reflects the stability of the benzylic radical. For related reasons, benzylic substituents exhibit enhanced reactivity, as in oxidation, free radical halogenation, or hydrogenolysis. As a practical example, in the presence of suitable catalysts, p-xylene oxidizes exclusively at the benzylic positions to give terephthalic acid:

${\displaystyle {\text{CH}}_3^{}{\text{C}}_6^{}{\text{H}}_4^{}{\text{CH}}_3^{}+3{\text{O}}_2^{}⟶{\text{HO}}_2^{}{\text{CC}}_6^{}{\text{H}}_4^{}{\text{CO}}_2^{}\text{H}+2{\text{H}}_2^{}\text{O}}$

Millions of tonnes of terephthalic acid are produced annually by this method.

Functionalization at the benzylic position

In a few cases, these benzylic transformations occur under conditions suitable for lab synthesis. The Wohl-Ziegler reaction will brominate a benzylic C–H bond: (ArCHR₂ → ArCBrR₂). Any non-tertiary benzylic alkyl group will be oxidized to a carboxyl group by aqueous potassium permanganate (KMnO₄) or concentrated nitric acid (HNO₃): (ArCHR₂ → ArCOOH). Finally, the complex of chromium trioxide and 3,5-dimethylpyrazole (CrO₃−dmpyz) will selectively oxidize a benzylic methylene group to a carbonyl: (ArCH₂R → ArC(O)R). 2-iodoxybenzoic acid in DMSO performs similarly.

As a protecting group

Benzyl groups are occasionally employed as protecting groups in organic synthesis. Their installation and especially their removal require relatively harsh conditions, so benzyl is not typically preferred for protection.

Alcohol protection

Benzyl is commonly used in organic synthesis as a robust protecting group for alcohols and carboxylic acids.

• Treatment of alcohol with a strong base such as powdered potassium hydroxide or sodium hydride and benzyl halide (BnCl or BnBr)
• Monobenzylation of diols can be achieved using Ag₂O in dimethylformamide (DMF) at ambient to elevated temperatures
• Primary alcohols can be selectively benzylated in presence of phenol functional groups using Cu(acac)₂

Deprotection methods

Benzyl ethers can be removed under reductive conditions, oxidative conditions, and the use of Lewis acids.

• Removed using hydrogenolysis
• Single electron process with Na/NH₃ or Li/NH₃

• Benzyl protecting groups can be removed using a wide range of oxidizing agents including:
  • CrO₃/acetic acid at ambient temperature
  • Ozone
  • N-Bromosuccinimide (NBS)
  • N-Iodosuccinimide (NIS)

• Trimethylsilyl iodide (Me₃SiI) in dichloromethane at ambient temperature (selectivity can be achieved under specific conditions)

The p-methoxybenzyl protecting group

p-Methoxybenzyl (PMB) is used as a protecting group for alcohols in organic synthesis (4-Methoxybenzylthiol is used to protect thiols).

• Strong base such as powdered potassium hydroxide or sodium hydride and p-methoxybenzyl halide (chloride or bromide)
• 4-methoxybenzyl-2,2,2-trichloroacetimidate can be used to install the PMB group in presence of:
  • Scandium (III) triflate (Sc(OTf)₃) in toluene at 0 °C
  • Trifluoromethanesulfonic acid (TfOH) in dichloromethane at 0 °C

Deprotection methods

• 2,3-Dichloro-5,6-dicyano-p-benzoquinone (DDQ)
• Conditions for deprotection of benzyl group are applicable for cleavage of the PMB protecting group

Amine protection

The benzyl group is occasionally used as a protecting group for amines in organic synthesis. Other methods exist.

• Aqueous potassium carbonate and benzyl halide (BnCl, BnBr) in methanol
• Benzaldehyde, 6 M HCl and NaBH₃CN in methanol

Deprotection methods

• Hydrogenation in the presence of the palladium catalyst