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Benzyl chloroformate

Lianyungang Klinechem Co.,Ltd | Updated: Nov 30, 2018

Benzyl chloroformate is the benzyl ester of chloroformic acid. Also known as benzyl chlorocarbonate it is an oily colorless liquid although impure samples appear yellow. It is also known for its pungent odor. In contact with water it degrades.

Preparation

It is prepared in the lab by treating benzyl alcohol with phosgene. Phosgene is used in excess to minimise the production of the carbonate.[1]

Amine protection

The carboxybenzyl group (Cbz) is commonly used in organic synthesis for the introduction of the carboxybenzyl (abbreviated Cbz or Z) protecting group for amines. It is a key protecting group for amines, suppressing its nucleophilic and basic properties.

  • Cbz.PNG

Alternatively, as in the Curtius rearrangement, carboxybenzyl can be generated by the reaction of an isocyanate with benzyl alcohol.

Common amine protection procedures include:

  • Benzyl chloroformate and a base, such as sodium carbonate in water at 0 °C[2]

  • Benzyl chloroformate and magnesium oxide in ethyl acetate at 70 °C to reflux[3]

    • Cbz ref2.png

  • Benzyl chloroformate, DIPEAacetonitrile and scandium trifluoromethanesulfonate (Sc(OTf)3)[4]

    • Cbz proticetion.png

The method was first used by Max Bergmann and Leonidas Zervas in 1932 for the synthesis of peptides.[2] The abbreviation Z is in honor of Zervas.

Deprotection

Hydrogenolysis in the presence of a variety of palladium-based catalysts is the usual method for deprotection. Palladium on charcoal is typical.[5]

  • Cbz deprot.png

Alternatively, strong Lewis acids have been used, provided that a trap is provided for the released benzyl carbocation.[6]The protected amine can be deprotected by catalytic hydrogenation or treatment with HBr, yielding a terminal carbamic acid that then readily decarboxylates to yield the free amine. Typically hydrogen gas and activated palladium on carbon are used.[7] is a carbamate which is often used as an amine protecting group in organic synthesis.[8] It is commonly used in peptide synthesis where the carboxybenzyl protecting group is introduced by reacting the amine functionality with benzyl chloroformate in the presence of a weak base:

References

  1. ^ Hough, L.; Priddle, J. E. (1961). "Carbonate derivatives of methyl α-D-mannopyranoside and of D-mannose". J. Chem. Soc1961: 3178–3181. doi:10.1039/JR9610003178.

  2. Jump up to:a b Bergmann, MaxZervas, Leonidas (1932). "Über ein allgemeines Verfahren der Peptid-Synthese" [On a general method of peptide synthesis]. Berichte der deutschen chemischen Gesellschaft65 (7): 1192–1201. doi:10.1002/cber.19320650722.

  3. ^ Dymicky, M. (1989-02-01). "Preparation of Carbobenzoxy-L-Tyrosine Methyl and Ethyl Esters and of the Corresponding Carbobenzoxy Hydrazides". Organic Preparations and Procedures International21 (1): 83–90. doi:10.1080/00304948909356350ISSN 0030-4948.

  4. ^ Aggarwal, Varinder K.; Humphries, Paul S.; Fenwick, Ashley (1999). "A Formal Asymmetric Synthesis of Anatoxin-a Using an Enantioselective Deprotonation Strategy on an Eight-Membered Ring"Angewandte Chemie International Edition38 (13–14): 1985–1986. doi:10.1002/(SICI)1521-3773(19990712)38:13/14<1985::AID-ANIE1985>3.0.CO;2-7.

  5. ^ Felpin, François-Xavier; Fouquet, Eric (2010-11-02). "A Useful, Reliable and Safer Protocol for Hydrogenation and the Hydrogenolysis of O-Benzyl Groups: The In Situ Preparation of an Active Pd0/C Catalyst with Well-Defined Properties"Chemistry – A European Journal16 (41): 12440–12445. doi:10.1002/chem.201001377ISSN 1521-3765.

  6. ^ Theodora W. Greene, Peter G. M. Wuts (1999). Protecting Groups in Organic Synthesis (3 ed.). J. Wiley. ISBN 0-471-16019-9.

  7. ^ Jakubke, Hans-Dieter; Sewald, Norbert (2008). Peptides from A to Z: A Concise Encyclopedia. John Wiley & Sons. ISBN 978-3-527-62117-0.

  8. ^ Clayden, Jonathan; Greeves, Nick; Warren, StuartWothers, Peter (2001). Organic Chemistry (1st ed.). Oxford University Press. pp. 248, 652–654, 1484. ISBN 978-0-19-850346-0.


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