Benzyl group

(Benzyl group): Benzyl radical, benzyl amine, benzyl bromide, benzyl chloroformate and benzyl methyl ether. R = heteroatom, alkyl, aryl, allyl etc. or other substituents.

In organic chemistry, benzyl is the substituent or molecular fragment possessing the structure C₆H₅CH₂–. Benzyl features a benzene ring attached to a CH₂ group.^[1]

Nomenclature

In IUPAC nomenclature the prefix benzyl refers to a C₆H₅CH₂ substituent, for example benzyl chloride or benzyl benzoate. Benzyl is not to be confused with phenyl with the formula C₆H₅. The term benzylic is used to describe the position of the first carbon bonded to a benzene or other aromatic ring. For example, the molecule, is referred to as a "benzylic" carbocation. The benzyl free radical has the formula C
6H
5CH•
2. The benzylium carbocation has the formula C
6H
5CH+
2; the carbanion has the formula C
6H
5CH−
2. None of these species can be formed in significant amounts under normal conditions, but they are useful referents for discussion of reaction mechanisms.

Abbreviations

The abbreviation "Bn" is frequently used to denote benzyl groups in nomenclature and structural depictions of chemical compounds. For example, benzyl alcohol can be represented as BnOH. This abbreviation is not to be confused with "Bz", which is the abbreviation for the benzoyl group C₆H₅C(O)−, or the phenyl group C₆H₅, abbreviated "Ph".

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.

Bond	Bond	Bond-dissociation energy		Comment
		(kcal/mol)	(kJ/mol)
C6H5CH2−H	benzylic C−H bond	90	377	akin to allylic C−H bonds such bonds show enhanced reactivity
H3C−H	Methyl C−H bond	105	439	One of the strongest aliphatic C−H bonds
C2H5−H	Ethyl C−H bond	101	423	slightly weaker than H3C−H
C6H5−H	phenyl C−H bond	113	473	comparable to vinyl radical, rare
CH2=CHCH2−H	allylic C–H bond	89	372	such bonds show enhanced reactivity

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:

CH₃C₆H₄CH₃ + 3 O₂ → HO₂CC₆H₄CO₂H + 2 H₂O.

Millions of tonnes of terephthalic acid are produced annually by this method.^[2]

As a protecting group

Alcohol protection

Benzyl group protecting an alcohol

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

Most common protection methods

• Treatment of alcohol with a strong base such as powdered potassium hydroxide or sodium hydride and benzyl halide (BnCl or BnBr)^[3][4]

  

• Monobenzylation of diols can be achieved using Ag₂O in dimethylformamide (DMF) at ambient to elevated temperatures^[5]
• Primary alcohols can be selectively benzylated in presence of phenol functional groups using Cu(acac)₂^[6]

Most common deprotection methods

Benzyl ethers can be removed under reductive conditions, oxidative conditions, and the use of Lewis Acids.^[3]

Reductive conditions

• Removed using hydrogenolysis^[7]

  

• Single electron process with Na/NH₃ or Li/NH₃

Oxidative conditions

• 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)

Lewis acid-based

• 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.

The p-methoxybenzyl group

Most common protection methods

• Strong base such as powdered potassium hydroxide or sodium hydride and p-methoxybenzyl halide (chloride or bromide)^[8][9]
• 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^[10]
  • Trifluoromethanesulfonic acid (TfOH) in dichloromethane at 0 °C^[11]

    

Most common deprotection methods

• 2,3-Dichloro-5,6-dicyano-p-benzoquinone (DDQ)^[12]

  

• Conditions for deprotection of benzyl group are applicable for cleavage of the PMB protecting group

Amine protection

Benzyl group protecting an amine

The benzyl group is largely used as a protecting group for amines in organic synthesis.

Most common amine protection methods

• Aqueous potassium carbonate and benzyl halide (BnCl, BnBr) in methanol^[13]

  

• Benzaldehyde, 6 M HCl and NaBH₃CN in methanol^[14]

  

Most common amine deprotection methods

• Hydrogenation in the presence of the palladium catalyst^[15]

See also

• Benzylamine

References

1. Carey, F. A.; Sundberg, R. J. (2008). Advanced Organic Chemistry, Part A: Structure and Mechanisms (5th ed.). New York, NY: Springer. pp. 806–808, 312–313. ISBN 9780387448978.
2. Sheehan, Richard J. (2005), "Terephthalic Acid, Dimethyl Terephthalate, and Isophthalic Acid", Ullmann's Encyclopedia of Industrial Chemistry, Weinheim: Wiley-VCH, doi:10.1002/14356007.a26_193
3. Wuts, Peter G. M.; Greene, Theodora W. Greene's Protective Groups in Organic Synthesis (4th ed.). Wiley Online Library. doi:10.1002/0470053488.
4. Fukuzawa, Akio; Sato, Hideaki; Masamune, Tadashi (1987-01-01). "Synthesis of (±)-prepinnaterpene, a bromoditerpene from the red alga Yamada". Tetrahedron Letters. 28 (37): 4303–4306. doi:10.1016/S0040-4039(00)96491-8.
5. Van Hijfte, Luc; Little, R. Daniel (1985-10-01). "Intramolecular 1,3-diyl trapping reactions. A formal total synthesis of (±)-coriolin". The Journal of Organic Chemistry. 50 (20): 3940–3942. doi:10.1021/jo00220a058. ISSN 0022-3263.
6. Sirkecioglu, Okan; Karliga, Bekir; Talinli, Naciye (2003-11-10). "Benzylation of alcohols by using bis[acetylacetonato]copper as catalyst". Tetrahedron Letters. 44 (46): 8483–8485. doi:10.1016/j.tetlet.2003.09.106.
7. Smith, Amos B.; Zhu, Wenyu; Shirakami, Shohei; Sfouggatakis, Chris; Doughty, Victoria A.; Bennett, Clay S.; Sakamoto, Yasuharu (2003-03-01). "Total Synthesis of (+)-Spongistatin 1. An Effective Second-Generation Construction of an Advanced EF Wittig Salt, Fragment Union, and Final Elaboration". Organic Letters. 5 (5): 761–764. doi:10.1021/ol034037a. ISSN 1523-7060.
8. Marco, José L.; Hueso-Rodríguez, Juan A. (1988-01-01). "Synthesis of optically pure 1-(3-furyl)-1,2-dihydroxyethane derivatives". Tetrahedron Letters. 29 (20): 2459–2462. doi:10.1016/S0040-4039(00)87907-1.
9. Takaku, Hiroshi; Kamaike, Kazuo; Tsuchiya, Hiromichi (1984-01-01). "Oligonucleotide synthesis. Part 21. Synthesis of ribooligonucleotides using the 4-methoxybenzyl group as a new protecting group for the 2′-hydroxyl group". The Journal of Organic Chemistry. 49 (1): 51–56. doi:10.1021/jo00175a010. ISSN 0022-3263.
10. Trost, Barry M.; Waser, Jerome; Meyer, Arndt (2007-11-01). "Total Synthesis of (−)-Pseudolaric Acid B". Journal of the American Chemical Society. 129 (47): 14556–14557. doi:10.1021/ja076165q. ISSN 0002-7863. PMC 2535803. PMID 17985906.
11. Mukaiyama, Teruaki; Shiina, Isamu; Iwadare, Hayato; Saitoh, Masahiro; Nishimura, Toshihiro; Ohkawa, Naoto; Sakoh, Hiroki; Nishimura, Koji; Tani, Yu-ichirou (1999-01-04). "Asymmetric Total Synthesis of Taxol\R". Chemistry – A European Journal. 5 (1): 121–161. doi:10.1002/(SICI)1521-3765(19990104)5:13.0.CO;2-O. ISSN 1521-3765.
12. Hanessian, Stephen; Marcotte, Stéphane; Machaalani, Roger; Huang, Guobin (2003-11-01). "Total Synthesis and Structural Confirmation of Malayamycin A: A Novel Bicyclic C-Nucleoside from Streptomyces malaysiensis". Organic Letters. 5 (23): 4277–4280. doi:10.1021/ol030095k. ISSN 1523-7060.
13. Kuehne, Martin E.; Xu, Feng (1993-12-01). "Total synthesis of strychnan and aspidospermatan alkaloids. 3. The total synthesis of (±)-strychnine". The Journal of Organic Chemistry. 58 (26): 7490–7497. doi:10.1021/jo00078a030. ISSN 0022-3263.
14. Cain, Christian M.; Cousins, Richard P. C.; Coumbarides, Greg; Simpkins, Nigel S. (1990-01-01). "Asymmetric deprotonation of prochiral ketones using chiral lithium amide bases". Tetrahedron. 46 (2): 523–544. doi:10.1016/S0040-4020(01)85435-1.
15. Zhou, Hao; Liao, Xuebin; Cook, James M. (2004-01-01). "Regiospecific, Enantiospecific Total Synthesis of the 12-Alkoxy-Substituted Indole Alkaloids, (+)-12-Methoxy-Na-methylvellosimine, (+)-12-Methoxyaffinisine, and (−)-Fuchsiaefoline". Organic Letters. 6 (2): 249–252. doi:10.1021/ol0362212. ISSN 1523-7060.

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