Benzyl group explained

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

Nomenclature

In IUPAC nomenclature, the prefix benzyl refers to a substituent, for example benzyl chloride or benzyl benzoate. Benzyl is not to be confused with phenyl with the formula . The term benzylic is used to describe the position of the first carbon bonded to a benzene or other aromatic ring. For example, is referred to as a "benzylic" carbocation. The benzyl free radical has the formula . The benzyl cation or phenylcarbenium ion is the carbocation with formula ; the benzyl anion or phenylmethanide ion is the carbanion with the formula . None of these species can be formed in significant amounts in the solution phase under normal conditions, but they are useful referents for discussion of reaction mechanisms and may exist as reactive intermediates.

Abbreviations

Benzyl is most commonly abbreviated Bn. For example, benzyl alcohol can be represented as BnOH. Less common abbreviations are Bzl and Bz, the latter of which is ambiguous as it is also the standard abbreviation for the benzoyl group . Likewise, benzyl should not be confused with the phenyl group, 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 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^[2] ^[3]		Comment
		(kcal/mol)	(kJ/mol)
	benzylic C−H bond	90	377	akin to allylic C−H bonds such bonds show enhanced reactivity
	methyl C−H bond	105	439	one of the strongest aliphatic C−H bonds
	ethyl C−H bond	101	423	slightly weaker than
	phenyl C−H bond	113	473	comparable to vinyl radical, rare
	allylic C–H bond	89	372	similar to benzylic C-H
	fluorenyl C–H bond	80		more activated vs diphenylmethyle (pKa = 22.6)
	diphenylmethyl C–H bond	82		"doubly benzylic" (pKa = 32.2)
	trityl C–H bond	81	339	"triply benzylic"

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 H2OMillions 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: .^[4] Any non-tertiary benzylic alkyl group will be oxidized to a carboxyl group by aqueous potassium permanganate or concentrated nitric acid : .^[5] Finally, the complex of chromium trioxide and 3,5-dimethylpyrazole will selectively oxidize a benzylic methylene group to a carbonyl: . 2-iodoxybenzoic acid in DMSO performs similarly.^[6]

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)^{[7] [8]}

• Monobenzylation of diols can be achieved using Ag₂O in dimethylformamide (DMF) at ambient to elevated temperatures^[9]
• Primary alcohols can be selectively benzylated in presence of phenol functional groups using Cu(acac)₂^[10]

Deprotection methods

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

• Removed using hydrogenolysis^[11]

• 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)^{[12] [13]}
• 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^[14]
  • Trifluoromethanesulfonic acid (TfOH) in dichloromethane at 0 °C^[15]

Deprotection methods

• 2,3-Dichloro-5,6-dicyano-p-benzoquinone (DDQ)^[16]

• 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^[17]

• Benzaldehyde, 6 M HCl and NaBH₃CN in methanol^[18]

Deprotection methods

• Hydrogenation in the presence of the palladium catalyst^[19]

See also

• Benzylamine

Notes and References

1. Book: Carey . F. A. . Sundberg . R. J. . Advanced Organic Chemistry, Part A: Structure and Mechanisms . limited . 5th . Springer . New York, NY . 2008 . 806–808, 312–313 . 9780387448978.
2. 10.1021/acs.chemrev.6b00664. The Essential Role of Bond Energetics in C–H Activation/Functionalization. 2017. Xue. Xiao-Song. Ji. Pengju. Zhou. Biying. Cheng. Jin-Pei. Chemical Reviews. 117. 13. 8622–8648. 28281752.
3. 10.1021/ja00051a010. Homolytic bond dissociation energies of the benzylic carbon-hydrogen bonds in radical anions and radical cations derived from fluorenes, triphenylmethanes, and related compounds. 1992. Zhang. Xian-Man. Bordwell. Frederick G.. Journal of the American Chemical Society. 114. 25. 9787–9792.
4. Book: C., Vollhardt, K. Peter. Organic chemistry : structure and function. Schore, Neil Eric, 1948-. 9781319079451. 8e. New York. 1007924903. 2018-01-29.
5. Book: Chandler), Norman, R. O. C. (Richard Oswald. Principles of organic synthesis.. 1993. Blackie Academic & Professional. Coxon, J. M. (James Morriss), 1941-. 978-0751401264. 3rd.. London. 27813843.
6. Baran. Phil S.. Zhong. Yong-Li. 2001-04-01. Selective Oxidation at Carbon Adjacent to Aromatic Systems with IBX. Journal of the American Chemical Society. 123. 13. 3183–3185. 10.1021/ja004218x. 11457049. 0002-7863.
7. Book: Greene's Protective Groups in Organic Synthesis. 4th. Wiley Online Library. Wuts. Peter G. M.. Greene. Theodora W.. 10.1002/0470053488. 2006. 9780470053485. 83393227.
8. 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. 10.1016/S0040-4039(00)96491-8.
9. 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. 10.1021/jo00220a058. 0022-3263.
10. 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. 10.1016/j.tetlet.2003.09.106.
11. 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. 10.1021/ol034037a. 1523-7060. 12605509.
12. 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. 10.1016/S0040-4039(00)87907-1.
13. 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. 10.1021/jo00175a010. 0022-3263.
14. 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. 10.1021/ja076165q. 0002-7863. 2535803. 17985906.
15. 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. en. 5. 1. 121–161. 10.1002/(SICI)1521-3765(19990104)5:1<121::AID-CHEM121>3.0.CO;2-O . 1521-3765 . free.
16. 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. 10.1021/ol030095k. 1523-7060. 14601979.
17. 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. 10.1021/jo00078a030. 0022-3263.
18. 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. 10.1016/S0040-4020(01)85435-1.
19. 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. 10.1021/ol0362212. 1523-7060. 14723540.