Benzyl group

In IUPAC nomenclature, the prefix benzyl refers to a {{chem2|C6H5CH2}} substituent, for example benzyl chloride or benzyl benzoate. Benzyl is not to be confused with phenyl with the formula {{chem2|C6H5}}.

The term benzylic is used to describe the position of the first carbon bonded to a benzene or other aromatic ring. For example, {{chem2|(C6H5)(CH3)2C+}} is referred to as a "benzylic" carbocation. The benzyl free radical has the formula {{chem2|C6H5CH2•}}. The benzyl cation or phenylcarbenium ion is the carbocation with formula {{chem2|C6H5CH2+}}; the benzyl anion or phenylmethanide ion is the carbanion with the formula {{chem2|C6H5CH2-}}. 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.

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 {{chem2|C6H5C(O)\s}}. Likewise, benzyl should not be confused with the phenyl group {{chem2|C6H5\s}}, abbreviated Ph.

The enhanced reactivity of benzylic positions is attributed to the low bond dissociation energy for benzylic C−H bonds. Specifically, the bond {{chem2|C6H5CH2\sH}} 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:

:CH3C6H4CH3 + 3 O2 -> HO2CC6H4CO2H + 2 H2O

Millions of tonnes of terephthalic acid are produced annually by this method.{{Ullmann|first=Richard J. |last=Sheehan |title=Terephthalic Acid, Dimethyl Terephthalate, and Isophthalic Acid |doi=10.1002/14356007.a26_193}}

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: ({{chem2|ArCHR2 -> ArCBrR2}}).{{Cite book|title=Organic chemistry : structure and function|last=C.|first=Vollhardt, K. Peter|others=Schore, Neil Eric, 1948-|isbn=9781319079451|edition= 8e|location=New York|oclc=1007924903|date = 2018-01-29}} Any non-tertiary benzylic alkyl group will be oxidized to a carboxyl group by aqueous potassium permanganate ({{chem2|KMnO4}}) or concentrated nitric acid ({{chem2|HNO3}}): ({{chem2|ArCHR2 -> ArCOOH}}).{{Cite book|title=Principles of organic synthesis.|last=Chandler)|first=Norman, R. O. C. (Richard Oswald|date=1993|publisher=Blackie Academic & Professional|others=Coxon, J. M. (James Morriss), 1941-|isbn=978-0751401264|edition= 3rd.|location=London|oclc=27813843}} Finally, the complex of chromium trioxide and 3,5-dimethylpyrazole ({{chem2|CrO3\sdmpyz}}) will selectively oxidize a benzylic methylene group to a carbonyl: ({{chem2|ArCH2R -> ArC(O)R}}).{{Citation|last=Johnston|first=Jeffrey N.|title=Chromium(VI) Oxide–3,5-Dimethylpyrazole|date=2001|encyclopedia=Encyclopedia of Reagents for Organic Synthesis|publisher=American Cancer Society|language=en|doi=10.1002/047084289x.rc170|isbn=9780470842898}} 2-iodoxybenzoic acid in DMSO performs similarly.{{Cite journal|last1=Baran|first1=Phil S.|last2=Zhong|first2=Yong-Li|date=2001-04-01|title=Selective Oxidation at Carbon Adjacent to Aromatic Systems with IBX|journal=Journal of the American Chemical Society|volume=123|issue=13|pages=3183–3185|doi=10.1021/ja004218x|pmid=11457049|issn=0002-7863}}

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.

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){{Cite book|title=Greene's Protective Groups in Organic Synthesis|edition= 4th|publisher=Wiley Online Library|last1=Wuts|first1=Peter G. M.|last2=Greene|first2=Theodora W.|doi=10.1002/0470053488|year = 2006|isbn = 9780470053485|s2cid= 83393227}}{{Cite journal|last1=Fukuzawa|first1=Akio|last2=Sato|first2=Hideaki|last3=Masamune|first3=Tadashi|date=1987-01-01|title=Synthesis of (±)-prepinnaterpene, a bromoditerpene from the red alga Yamada|journal=Tetrahedron Letters|volume=28|issue=37|pages=4303–4306|doi=10.1016/S0040-4039(00)96491-8}}
• :File:BnProtectedalcohol.png
• Monobenzylation of diols can be achieved using Ag₂O in dimethylformamide (DMF) at ambient to elevated temperatures{{Cite journal|last1=Van Hijfte|first1=Luc|last2=Little|first2=R. Daniel|date=1985-10-01|title=Intramolecular 1,3-diyl trapping reactions. A formal total synthesis of (±)-coriolin|journal=The Journal of Organic Chemistry|volume=50|issue=20|pages=3940–3942|doi=10.1021/jo00220a058|issn=0022-3263}}
• Primary alcohols can be selectively benzylated in presence of phenol functional groups using Cu(acac)₂{{Cite journal|last1=Sirkecioglu|first1=Okan|last2=Karliga|first2=Bekir|last3=Talinli|first3=Naciye|date=2003-11-10|title=Benzylation of alcohols by using bis[acetylacetonato]copper as catalyst|journal=Tetrahedron Letters|volume=44|issue=46|pages=8483–8485|doi=10.1016/j.tetlet.2003.09.106}}

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

• Removed using hydrogenolysis{{Cite journal|last1=Smith|first1=Amos B.|last2=Zhu|first2=Wenyu|last3=Shirakami|first3=Shohei|last4=Sfouggatakis|first4=Chris|last5=Doughty|first5=Victoria A.|last6=Bennett|first6=Clay S.|last7=Sakamoto|first7=Yasuharu|date=2003-03-01|title=Total Synthesis of (+)-Spongistatin 1. An Effective Second-Generation Construction of an Advanced EF Wittig Salt, Fragment Union, and Final Elaboration|journal=Organic Letters|volume=5|issue=5|pages=761–764|doi=10.1021/ol034037a|issn=1523-7060|pmid=12605509}}
• :File:BnEtherExample.png
• 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)

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

File:PMB_Ether.png

• Strong base such as powdered potassium hydroxide or sodium hydride and p-methoxybenzyl halide (chloride or bromide){{Cite journal|last1=Marco|first1=José L.|last2=Hueso-Rodríguez|first2=Juan A.|date=1988-01-01|title=Synthesis of optically pure 1-(3-furyl)-1,2-dihydroxyethane derivatives|journal=Tetrahedron Letters|volume=29|issue=20|pages=2459–2462|doi=10.1016/S0040-4039(00)87907-1}}{{Cite journal|last1=Takaku|first1=Hiroshi|last2=Kamaike|first2=Kazuo|last3=Tsuchiya|first3=Hiromichi|date=1984-01-01|title=Oligonucleotide synthesis. Part 21. Synthesis of ribooligonucleotides using the 4-methoxybenzyl group as a new protecting group for the 2′-hydroxyl group|journal=The Journal of Organic Chemistry|volume=49|issue=1|pages=51–56|doi=10.1021/jo00175a010|issn=0022-3263}}
• 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{{Cite journal|last1=Trost|first1=Barry M.|last2=Waser|first2=Jerome|last3=Meyer|first3=Arndt|date=2007-11-01|title=Total Synthesis of (−)-Pseudolaric Acid B|journal=Journal of the American Chemical Society|volume=129|issue=47|pages=14556–14557|doi=10.1021/ja076165q|issn=0002-7863|pmc=2535803|pmid=17985906}}
• Trifluoromethanesulfonic acid (TfOH) in dichloromethane at 0 °C{{Cite journal|last1=Mukaiyama|first1=Teruaki|last2=Shiina|first2=Isamu|last3=Iwadare|first3=Hayato|last4=Saitoh|first4=Masahiro|last5=Nishimura|first5=Toshihiro|last6=Ohkawa|first6=Naoto|last7=Sakoh|first7=Hiroki|last8=Nishimura|first8=Koji|last9=Tani|first9=Yu-ichirou|date=1999-01-04|title=Asymmetric Total Synthesis of Taxol\R|journal=Chemistry – A European Journal|language=en|volume=5|issue=1|pages=121–161|doi=10.1002/(SICI)1521-3765(19990104)5:1<121::AID-CHEM121>3.0.CO;2-O |issn=1521-3765 |doi-access=free}}
• :File:PMBAlcohol.png

• 2,3-Dichloro-5,6-dicyano-p-benzoquinone (DDQ){{Cite journal|last1=Hanessian|first1=Stephen|last2=Marcotte|first2=Stéphane|last3=Machaalani|first3=Roger|last4=Huang|first4=Guobin|date=2003-11-01|title=Total Synthesis and Structural Confirmation of Malayamycin A: A Novel Bicyclic C-Nucleoside from Streptomyces malaysiensis|journal=Organic Letters|volume=5|issue=23|pages=4277–4280|doi=10.1021/ol030095k|issn=1523-7060|pmid=14601979}}
• :File:PMBDeprotection.png
• Conditions for deprotection of benzyl group are applicable for cleavage of the PMB protecting group

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{{Cite journal|last1=Kuehne|first1=Martin E.|last2=Xu|first2=Feng|date=1993-12-01|title=Total synthesis of strychnan and aspidospermatan alkaloids. 3. The total synthesis of (±)-strychnine|journal=The Journal of Organic Chemistry|volume=58|issue=26|pages=7490–7497|doi=10.1021/jo00078a030|issn=0022-3263}}
• :File:Bn_protection_with_bnbr.png
• Benzaldehyde, 6 M HCl and NaBH₃CN in methanol{{Cite journal|last1=Cain|first1=Christian M.|last2=Cousins|first2=Richard P. C.|last3=Coumbarides|first3=Greg|last4=Simpkins|first4=Nigel S.|date=1990-01-01|title=Asymmetric deprotonation of prochiral ketones using chiral lithium amide bases|journal=Tetrahedron|volume=46|issue=2|pages=523–544|doi=10.1016/S0040-4020(01)85435-1}}
• :File:Bn_protection_with_benzaldehyde.png

• Hydrogenation in the presence of the palladium catalyst{{Cite journal|last1=Zhou|first1=Hao|last2=Liao|first2=Xuebin|last3=Cook|first3=James M.|date=2004-01-01|title=Regiospecific, Enantiospecific Total Synthesis of the 12-Alkoxy-Substituted Indole Alkaloids, (+)-12-Methoxy-Na-methylvellosimine, (+)-12-Methoxyaffinisine, and (−)-Fuchsiaefoline|journal=Organic Letters|volume=6|issue=2|pages=249–252|doi=10.1021/ol0362212|issn=1523-7060|pmid=14723540}}

File:QIGLEZ.svg with H atoms omitted for clarity.{{cite journal|doi=10.1021/om300820b|title=Highly Variable Zr–CH2–Ph Bond Angles in Tetrabenzylzirconium: Analysis of Benzyl Ligand Coordination Modes|journal=Organometallics|volume=31|issue=23|pages=8208–8217|year=2012|last1=Rong|first1=Yi|last2=Al-Harbi|first2=Ahmed|last3=Parkin|first3=Gerard}}]]

• Benzylamine

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