Benzyl chloroformate
Names | |
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Preferred IUPAC name
Benzyl carbonochloridate | |
Other names
Benzyl chloroformate
Benzyloxycarbonyl chloride Z-Chloride | |
Identifiers | |
3D model (
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ChemSpider | |
ECHA InfoCard
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100.007.205 |
EC Number |
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PubChem CID
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RTECS number
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UNII | |
UN number | 1739 |
CompTox Dashboard (EPA)
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Properties | |
C8H7ClO2 | |
Molar mass | 170.59 g·mol−1 |
Appearance | colorless liquid, may appear yellow due to impurities |
Odor | pungent |
Density | 1.195 g/cm3 |
Boiling point | 103 °C (217 °F; 376 K) (20 Torr) |
degrades | |
Refractive index (nD)
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1.519 (589 nm) |
Hazards | |
GHS labelling: | |
Danger | |
H314, H410 | |
P260, P264, P273, P280, P301+P330+P331, P303+P361+P353, P304+P340, P305+P351+P338, P310, P321, P363, P391, P405, P501 | |
Flash point | 80 °C (176 °F; 353 K) |
Safety data sheet (SDS) | External MSDS |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Benzyl chloroformate, also known as benzyl chlorocarbonate or Z-chloride, is the
The compound was first prepared by Leonidas Zervas in the early 1930s who used it for the introduction of the benzyloxycarbonyl protecting group, which became the basis of the Bergmann-Zervas carboxybenzyl method of peptide synthesis he developed with Max Bergmann.[1][2] This was the first successful method of controlled peptide chemical synthesis and for twenty years it was the dominant procedure used worldwide until the 1950s.[1] To this day, benzyl chloroformate is often used for amine group protection.
Preparation
The compound is prepared in the lab by treating benzyl alcohol with phosgene:
- PhCH2OH + COCl2 → PhCH2OC(O)Cl + HCl
Phosgene is used in excess to minimise the production of the carbonate (PhCH2O)2C=O.[3]
The use of phosgene gas in the lab preparation carries a very large health hazard, and has been implicated in the chronic pulmonary disease of pioneers in the usage of the compound such as Zervas.[4]
Amine protection
Benzyl chloroformate is commonly used in organic synthesis for the introduction of the benzyloxycarbonyl (formerly called carboxybenzyl) protecting group for amines. The protecting group is abbreviated Cbz or Z (in honor of discoverer Zervas), hence the alternative shorthand designation for benzyl chloroformate as Cbz-Cl or Z-Cl.
Benzyloxycarbonyl is a key
This reaction was hailed as a "revolution" and essentially started the distinct field of synthetic peptide chemistry.[1] It remained unsurpassed in utility for peptide synthesis until the early 1950s when mixed anhydride and active ester methodologies were developed.
Although the reaction is no longer commonly used for peptides, it is nonetheless very widespread for amine protection in other applications within organic synthesis and total synthesis. Common procedures to achieve protection starting from benzyl chloroformate 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[5]
- Benzyl chloroformate, scandium trifluoromethanesulfonate (Sc(OTf)3)[6]
Alternatively, the Cbz group can be generated by the reaction of an isocyanate with benzyl alcohol (as in the Curtius rearrangement).
Deprotection
Alternatively, HBr and strong Lewis acids have been used, provided that a trap is provided for the released benzyl carbocation.[9]
When the protected amine is treated by either of the above methods (i.e. by catalytic hydrogenation or acidic workup), it yields a terminal carbamic acid which then readily decarboxylates to give the free amine.
2-Mercaptoethanol can also be used, in the presence of potassium phosphate in dimethylacetamide.[10]
References
- ^ S2CID 35144893. Archived from the originalon 2022-10-13. Retrieved 2021-04-01.
- ^ .
- .
- ^ Theodorakopoulos, I.; Tsatsas, G. (1981). "Dedication to Prof. L. Zervas (from the Minutes of the Academy of Athens)". Laboratory of Organic Chemistry (in Greek). University of Athens, Department of Chemistry. Archived from the original on 2021-12-19. Retrieved 31 Mar 2021.
- ISSN 0030-4948.
- PMID 34182674.
- ISBN 978-3-527-62117-0.
- PMID 20845414.
- ISBN 978-0-471-16019-9.
- S2CID 248776636.