Benzyl group
In organic chemistry, benzyl is the substituent or molecular fragment possessing the structure R−CH2−C6H5. Benzyl features a benzene ring (C6H6) attached to a methylene group (−CH2−).[1]
Nomenclature
[edit]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, (C6H5)(CH3)2C+ is referred to as a "benzylic" carbocation. The benzyl free radical has the formula C6H5CH2•. The benzyl cation or phenylcarbenium ion is the carbocation with formula C6H5CH+2; the benzyl anion or phenylmethanide ion is the carbanion with the formula C6H5CH−2. 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
[edit]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 C6H5C(O)−. Likewise, benzyl should not be confused with the phenyl group C6H5−, abbreviated Ph.
Reactivity of benzylic centers
[edit]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[2][3] | 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 | similar to benzylic C-H |
| (C6H4)2CH−H | fluorenyl C–H bond | 80 | more activated vs diphenylmethyle (pKa = 22.6) | |
| (C6H5)2CH−H | diphenylmethyl C–H bond | 82 | "doubly benzylic" (pKa = 32.2) | |
| (C6H5)3C−H | 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:
Millions of tonnes of terephthalic acid are produced annually by this method.[4]
Functionalization at the benzylic position
[edit]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).[5] 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).[6] 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).[7] 2-iodoxybenzoic acid in DMSO performs similarly.[8]
As a protecting group
[edit]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.[9]
Alcohol protection
[edit]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)[9][10]
- Monobenzylation of diols can be achieved using Ag2O in dimethylformamide (DMF) at ambient to elevated temperatures[11]
- Primary alcohols can be selectively benzylated in presence of phenol functional groups using Cu(acac)2[12]
Deprotection methods
[edit]Benzyl ethers can be removed under reductive conditions, oxidative conditions, and the use of Lewis acids.[9]
- Removed using hydrogenolysis[13]
- 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
[edit]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)[14][15]
- 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[16]
- Trifluoromethanesulfonic acid (TfOH) in dichloromethane at 0 °C[17]
Deprotection methods
[edit]- 2,3-Dichloro-5,6-dicyano-p-benzoquinone (DDQ)[18]
- Conditions for deprotection of benzyl group are applicable for cleavage of the PMB protecting group
Amine protection
[edit]The benzyl group is occasionally used as a protecting group for amines in organic synthesis. Other methods exist.[9]
- Aqueous potassium carbonate and benzyl halide (BnCl, BnBr) in methanol[19]
- Benzaldehyde, 6 M HCl and NaBH3CN in methanol[20]
Deprotection methods
[edit]- Hydrogenation in the presence of the palladium catalyst[21]
See also
[edit]References
[edit]- ^ 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.
- ^ Xue, Xiao-Song; Ji, Pengju; Zhou, Biying; Cheng, Jin-Pei (2017). "The Essential Role of Bond Energetics in C–H Activation/Functionalization". Chemical Reviews. 117 (13): 8622–8648. doi:10.1021/acs.chemrev.6b00664. PMID 28281752.
- ^ Zhang, Xian-Man; Bordwell, Frederick G. (1992). "Homolytic bond dissociation energies of the benzylic carbon-hydrogen bonds in radical anions and radical cations derived from fluorenes, triphenylmethanes, and related compounds". Journal of the American Chemical Society. 114 (25): 9787–9792. doi:10.1021/ja00051a010.
- ^ Sheehan, Richard J. "Terephthalic Acid, Dimethyl Terephthalate, and Isophthalic Acid". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a26_193. ISBN 978-3527306732.
- ^ C., Vollhardt, K. Peter (2018-01-29). Organic chemistry : structure and function. Schore, Neil Eric, 1948- (8e ed.). New York. ISBN 9781319079451. OCLC 1007924903.
{{cite book}}: CS1 maint: location missing publisher (link) CS1 maint: multiple names: authors list (link) - ^ Chandler), Norman, R. O. C. (Richard Oswald (1993). Principles of organic synthesis. Coxon, J. M. (James Morriss), 1941- (3rd. ed.). London: Blackie Academic & Professional. ISBN 978-0751401264. OCLC 27813843.
{{cite book}}: CS1 maint: multiple names: authors list (link) - ^ Johnston, Jeffrey N. (2001), "Chromium(VI) Oxide–3,5-Dimethylpyrazole", Encyclopedia of Reagents for Organic Synthesis, American Cancer Society, doi:10.1002/047084289x.rc170, ISBN 9780470842898
- ^ 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. doi:10.1021/ja004218x. ISSN 0002-7863. PMID 11457049.
- ^ a b c d Wuts, Peter G. M.; Greene, Theodora W. (2006). Greene's Protective Groups in Organic Synthesis (4th ed.). Wiley Online Library. doi:10.1002/0470053488. ISBN 9780470053485. S2CID 83393227.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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. PMID 12605509.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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)5:1<121::AID-CHEM121>3.0.CO;2-O. ISSN 1521-3765.
- ^ 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. PMID 14601979.
- ^ 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.
- ^ 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.
- ^ 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. PMID 14723540.
- ^ Rong, Yi; Al-Harbi, Ahmed; Parkin, Gerard (2012). "Highly Variable Zr–CH2–Ph Bond Angles in Tetrabenzylzirconium: Analysis of Benzyl Ligand Coordination Modes". Organometallics. 31 (23): 8208–8217. doi:10.1021/om300820b.
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