Benzyl chloroformate

Benzyl chloroformate, also known as benzyl chlorocarbonate or Z-chloride, is the benzyl ester of chloroformic acid. It can be also described as the chloride of the benzyloxycarbonyl (Cbz or Z) group. In its pure form it is a water-sensitive oily colorless liquid, although impure samples usually appear yellow. It possesses a characteristic pungent odor and degrades in contact with water.

Benzyl chloroformate
Skeletal formula of benzyl chloroformate
Ball-and-stick model of the benzyl chloroformate molecule
Names
Preferred IUPAC name
Benzyl carbonochloridate
Other names
Benzyl chloroformate
Benzyloxycarbonyl chloride
Z-Chloride
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.007.205
EC Number
  • 207-925-0
RTECS number
  • LQ5860000
UNII
UN number 1739
  • InChI=1S/C8H7ClO2/c9-8(10)11-6-7-4-2-1-3-5-7/h1-5H,6H2 checkY
    Key: HSDAJNMJOMSNEV-UHFFFAOYSA-N checkY
  • InChI=1/C8H7ClO2/c9-8(10)11-6-7-4-2-1-3-5-7/h1-5H,6H2
    Key: HSDAJNMJOMSNEV-UHFFFAOYAW
  • ClC(=O)OCc1ccccc1
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
1.519 (589 nm)
Hazards
GHS labelling:
GHS06: ToxicGHS09: Environmental hazard
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).
checkY verify (what is checkY☒N ?)
Infobox references

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 protecting group for amines, suppressing the nucleophilic and basic properties of the N lone pair. This "reactivity masking" property, along with the ability to prevent racemization of Z-protected amines, made the Z group the basis of the Begmann-Zervas synthesis of oligopeptides (1932) where the following general reaction is performed to protect the N-terminus of a serially growing oligopeptide chain:[1][2]

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:

Alternatively, the Cbz group can be generated by the reaction of an isocyanate with benzyl alcohol (as in the Curtius rearrangement).

Deprotection

Hydrogenolysis in the presence of a variety of palladium-based catalysts is the usual method for deprotection.[1][7] Palladium on charcoal is typical.[8]

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
  1. Katsoyannis, P. G., ed. (1973). The Chemistry of Polypeptides. New York: Plenum Press. doi:10.1007/978-1-4613-4571-8. ISBN 978-1-4613-4571-8. S2CID 35144893. Archived from the original on 2022-10-13. Retrieved 2021-04-01.
  2. Bergmann, Max; Zervas, Leonidas (1932). "Über ein allgemeines Verfahren der Peptid-Synthese" [On a general method of peptide synthesis]. Berichte der deutschen chemischen Gesellschaft. 65 (7): 1192–1201. doi:10.1002/cber.19320650722.
  3. Hough, L.; Priddle, J. E. (1961). "Carbonate derivatives of methyl α-D-mannopyranoside and of D-mannose". J. Chem. Soc. 1961: 3178–3181. doi:10.1039/JR9610003178.
  4. 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.
  5. Dymicky, M. (1989-02-01). "Preparation of Carbobenzoxy-L-Tyrosine Methyl and Ethyl Esters and of the Corresponding Carbobenzoxy Hydrazides". Organic Preparations and Procedures International. 21 (1): 83–90. doi:10.1080/00304948909356350. ISSN 0030-4948.
  6. 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 Edition. 38 (13–14): 1985–1986. doi:10.1002/(SICI)1521-3773(19990712)38:13/14<1985::AID-ANIE1985>3.0.CO;2-7. PMID 34182674.
  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. 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 Journal. 16 (41): 12440–12445. doi:10.1002/chem.201001377. ISSN 1521-3765. PMID 20845414.
  9. Theodora W. Greene; Peter G. M. Wuts (1999). Protecting Groups in Organic Synthesis (3 ed.). J. Wiley. ISBN 978-0-471-16019-9.
  10. Scattolin, Thomas; Gharbaoui, Tawfik; Chen, Cheng-yi (2022). "A Nucleophilic Deprotection of Carbamate Mediated by 2-Mercaptoethanol". Organic Letters. 24 (20): 3736–3740. doi:10.1021/acs.orglett.2c01410. PMID 35559611. S2CID 248776636.
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