Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Benzyl chloroformate: Difference between pages

{{Chembox

|Watchedfields = changed

|verifiedrevid = 464396150

|ImageFile =Benzyl-chloroformate-2D-skeletal.png

|ImageName = Skeletal formula of benzyl chloroformate

|ImageFile1 =Benzyl-chloroformate-3D-balls.png

|ImageName1 = Ball-and-stick model of the benzyl chloroformate molecule

|PIN = Benzyl carbonochloridate

|OtherNames = Benzyl chloroformate<br />Benzyloxycarbonyl chloride<br/>Z-Chloride

|Section1={{Chembox Identifiers

|ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

|ChemSpiderID = 9958

|InChI = 1/C8H7ClO2/c9-8(10)11-6-7-4-2-1-3-5-7/h1-5H,6H2

|InChIKey = HSDAJNMJOMSNEV-UHFFFAOYAW

|StdInChI_Ref = {{stdinchicite|correct|chemspider}}

|StdInChI = 1S/C8H7ClO2/c9-8(10)11-6-7-4-2-1-3-5-7/h1-5H,6H2

|StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

|StdInChIKey = HSDAJNMJOMSNEV-UHFFFAOYSA-N

|CASNo_Ref = {{cascite|correct|CAS}}

|CASNo = 501-53-1

|PubChem = 10387

|EC_number = 207-925-0

|RTECS = LQ5860000

|UNNumber = 1739

|UNII = 170BP0DD31

|SMILES = ClC(=O)OCc1ccccc1

|Section2={{Chembox Properties

|Appearance = colorless liquid, may appear yellow due to impurities

|Odour = pungent

|C=8 | H=7 | Cl=1 | O=2

|Density =1.195 g/cm³

|BoilingPtC = 103

|BoilingPt_notes = (20 [[Torr]])

|Solubility = degrades

|RefractIndex = 1.519 (589 nm)

|Section7={{Chembox Hazards

|GHSPictograms = {{GHS06}}{{GHS09}}

|GHSSignalWord = Danger

|HPhrases = {{H-phrases|314|410}}

|PPhrases = {{P-phrases|260|264|273|280|301+330+331|303+361+353|304+340|305+351+338|310|321|363|391|405|501}}

|ExternalSDS = [http://msds.chem.ox.ac.uk/BE/benzyl_chloroformate.html External MSDS]

|FlashPtC = 80

}}

}}

'''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.

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]].<ref name=":1">{{Cite book|url=https://org.chem.uoa.gr/istoriki_exelixi_toy_ergastirioy_organikis_chimeias_historical_development_of_organic_chemistry_laboratory/afieroma_ston_leonida_zerba_dedication_to_prof_leonidas_zervas/i_symboli_toy_l_zerba_stin_epistimi_tis_chimeias_contribution_of_l_zervas_in_the_science_of_chemistry/|title=The Chemistry of Polypeptides|publisher=Plenum Press|year=1973|isbn=978-1-4613-4571-8|editor-last=Katsoyannis|editor-first=P. G.|location=New York|doi=10.1007/978-1-4613-4571-8|s2cid=35144893|access-date=2021-04-01|archive-date=2022-10-13|archive-url=https://web.archive.org/web/20221013010830/https://org.chem.uoa.gr/istoriki_exelixi_toy_ergastirioy_organikis_chimeias_historical_development_of_organic_chemistry_laboratory/afieroma_ston_leonida_zerba_dedication_to_prof_leonidas_zervas/i_symboli_toy_l_zerba_stin_epistimi_tis_chimeias_contribution_of_l_zervas_in_the_science_of_chemistry/|url-status=dead}}</ref><ref name="Zervas">{{cite journal|last1=Bergmann|first1=Max|last2=Zervas|first2=Leonidas|author2-link=Leonidas Zervas|year=1932|title=Über ein allgemeines Verfahren der Peptid-Synthese|trans-title=On a general method of peptide synthesis|journal=[[Berichte der deutschen chemischen Gesellschaft]]|volume=65|issue=7|pages=1192–1201|doi=10.1002/cber.19320650722|author1-link=Max Bergmann}}</ref> This was the first successful method of controlled [[Peptide synthesis|peptide chemical synthesis]] and for twenty years it was the dominant procedure used worldwide until the 1950s.<ref name=":1" /> To this day, benzyl chloroformate is often used for [[Amine|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.<ref>{{cite journal|title=Carbonate derivatives of methyl α-<small>D</small>-mannopyranoside and of <small>D</small>-mannose |first1=L. |last1=Hough |first2=J. E. |last2=Priddle |journal=J. Chem. Soc. |date=1961 |volume=1961 |pages=3178–3181 |doi=10.1039/JR9610003178}}</ref>

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.<ref name=":4">{{Cite web|last1=Theodorakopoulos|first1=I.|last2=Tsatsas|first2=G.|date=1981|title=Dedication to Prof. L. Zervas (from the Minutes of the Academy of Athens)|url=https://org.chem.uoa.gr/istoriki_exelixi_toy_ergastirioy_organikis_chimeias_historical_development_of_organic_chemistry_laboratory/afieroma_ston_leonida_zerba_dedication_to_prof_leonidas_zervas/|url-status=live|access-date=31 Mar 2021|website=Laboratory of Organic Chemistry|publisher=University of Athens, Department of Chemistry|language=el|archive-url=https://web.archive.org/web/20211219023240/https://org.chem.uoa.gr/istoriki_exelixi_toy_ergastirioy_organikis_chimeias_historical_development_of_organic_chemistry_laboratory/afieroma_ston_leonida_zerba_dedication_to_prof_leonidas_zervas/ |archive-date=2021-12-19}}</ref>

== Amine protection ==

Benzyl chloroformate is commonly used in [[organic synthesis]] for the introduction of the benzyloxycarbonyl (formerly called carboxybenzyl) [[protecting group]] for [[amine]]s. The protecting group is abbreviated '''Cbz''' or '''Z''' (in honor of discoverer [[Leonidas Zervas|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 [[Oligopeptide|oligopeptides]] (1932) where the following general reaction is performed to protect the ''N''-terminus of a serially growing oligopeptide chain:<ref name=":1" /><ref name="Zervas" />

:[[File:Cbz to protect N-terminus.svg|600px]]

This reaction was hailed as a "revolution" and essentially started the distinct field of synthetic peptide chemistry.<ref name=":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&nbsp;°C<ref name="Zervas"/>

* Benzyl chloroformate and [[magnesium oxide]] in [[ethyl acetate]] at 70&nbsp;°C to reflux<ref>{{Cite journal|last=Dymicky|first=M.|date=1989-02-01|title=Preparation of Carbobenzoxy-<small>L</small>-Tyrosine Methyl and Ethyl Esters and of the Corresponding Carbobenzoxy Hydrazides|journal=Organic Preparations and Procedures International|volume=21|issue=1|pages=83–90|doi=10.1080/00304948909356350|issn=0030-4948}}</ref>

*:[[File:Cbz deprot-en.svg|none|573x573px]]

* Benzyl chloroformate, [[DIPEA]], [[acetonitrile]] and [[scandium trifluoromethanesulfonate]] (Sc(OTf)₃)<ref>{{Cite journal|title=A Formal Asymmetric Synthesis of Anatoxin-a Using an Enantioselective Deprotonation Strategy on an Eight-Membered Ring|doi=10.1002/(SICI)1521-3773(19990712)38:13/14<1985::AID-ANIE1985>3.0.CO;2-7 |first1=Varinder K. |last1=Aggarwal |first2=Paul S. |last2=Humphries |first3=Ashley |last3=Fenwick |date=1999 |journal=Angewandte Chemie International Edition |volume=38 |issue=13–14 |pages=1985–1986|pmid=34182674}}</ref>

*:[[File:Cbz proticetion-en.svg|none|442x442px]]

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 [[catalyst]]s is the usual method for deprotection.<ref name=":1"/><ref>{{cite book|url=https://books.google.com/books?id=doe9NwgJTAsC&pg=PA46 |title=Peptides from A to Z: A Concise Encyclopedia |first1=Hans-Dieter |last1=Jakubke |first2=Norbert |last2=Sewald |date=2008 |publisher=John Wiley & Sons |isbn=978-3-527-62117-0}}</ref> [[Palladium on charcoal]] is typical.<ref>{{Cite journal|last1=Felpin|first1=François-Xavier|last2=Fouquet|first2=Eric|date=2010-11-02|title=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|journal=Chemistry – A European Journal|language=en|volume=16|issue=41|pages=12440–12445|doi=10.1002/chem.201001377|pmid=20845414|issn=1521-3765}}</ref>

:[[File:Cbz_deprot.png|none|540x540px]]

Alternatively, [[Hydrogen bromide|HBr]] and strong Lewis acids have been used, provided that a trap is provided for the released benzyl carbocation.<ref>{{cite book|title=Protecting Groups in Organic Synthesis |author=Theodora W. Greene |author2=Peter G. M. Wuts|publisher=J. Wiley|edition=3|year=1999|isbn=978-0-471-16019-9}}</ref>

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]].<ref>{{cite journal |last1=Scattolin |first1=Thomas |last2=Gharbaoui |first2=Tawfik |last3=Chen |first3=Cheng-yi |title=A Nucleophilic Deprotection of Carbamate Mediated by 2-Mercaptoethanol |journal=[[Organic Letters]] |date=2022 |volume=24 |issue=20 |pages=3736–3740 |doi=10.1021/acs.orglett.2c01410 |pmid=35559611 |s2cid=248776636 }}</ref>

==References==

{{Reflist}}

== External links ==

*{{ICSC|0990|09}}

{{Organic reactions}}

[[Category:Chloroformates]]

[[Category:Benzyl esters]]

[[Category:Reagents for organic chemistry]]

[[Category:Foul-smelling chemicals]]