Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Di-tert-butyl dicarbonate: Difference between pages

{{DISPLAYTITLE:Di-''tert''-butyl dicarbonate}}

| Watchedfields = changed

| verifiedrevid = 477001173

| Name = Di-''tert''-butyl dicarbonate

| ImageFile = Di-tert-butyl-dicarbonate-2D-skeletal.png

| ImageSize =

| ImageName =

| ImageFile1 = Di-tert-butyl-dicarbonate-based-on-similar-xtals-3D-balls.png

| PIN = Di-''tert''-butyl dicarbonate

| OtherNames = Di-''t''-butyl pyrocarbonate<br />Boc anhydride<br />Boc₂O

| Section1 = {{Chembox Identifiers

| ChEBI_Ref = {{ebicite|correct|EBI}}

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

| EC_number = 246-240-1

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = Z10Q236C3G

| Section2 = {{Chembox Properties

| C=10|H=18|O=5

| Appearance = Colorless solid or oil

| Density = 0.95&nbsp;g·cm^&minus;3

| Solubility = Insoluble

| Solvent = other solvents

| SolubleOther = Soluble in most organic solvents

| MeltingPtC = 22 to 24

| MeltingPt_notes =

| BoilingPtC = 56 to 57

| BoilingPt_notes = (0.5&nbsp;mmHg)

| Section7 = {{Chembox Hazards

| ExternalSDS =

| MainHazards = Very toxic on inhalation T+, LC₅₀ = 100 mg/m³ (4 hr, rat)}}

| Section8 = {{Chembox Related

| OtherCompounds = [[Ethyl chloroformate]]<br />[[Phosgene]]<br />[[Diethyl pyrocarbonate]]<br />[[Dimethyl dicarbonate]]

'''Di-''tert''-butyl dicarbonate''' is a [[reagent]] widely used in [[organic synthesis]].<ref>M. Wakselman, "Di-''t''-butyl Dicarbonate" in ''Encyclopedia of Reagents for Organic Synthesis'' (Ed: L. Paquette) 2004, J. Wiley & Sons, New York. {{doi|10.1002/047084289X}}.</ref> Since this compound can be regarded formally as the acid anhydride derived from a ''tert''-butoxycarbonyl (Boc) group, it is commonly referred to as '''Boc anhydride'''. This [[pyrocarbonate]] reacts with [[amine]]s to give [[tert-butoxycarbonyl|''N''-''tert''-butoxycarbonyl]] or so-called Boc derivatives. These carbamate derivatives do not behave as amines, which allows certain subsequent transformations to occur that would be incompatible with the amine [[functional group]]. The Boc group can later be removed from the amine using moderately strong acids (e.g., [[trifluoroacetic acid]]). Thus, Boc serves as a [[protective group]], for instance in [[solid phase peptide synthesis]]. Boc-protected amines are unreactive to most bases and [[nucleophile]]s, allowing for the use of the [[Fluorenylmethyloxycarbonyl chloride|fluorenylmethyloxycarbonyl]] group (Fmoc) as an orthogonal protecting group.

==Preparation==

Di-''tert''-butyl dicarbonate is inexpensive, so it is usually purchased. Classically, this compound is prepared from [[Tert-Butanol|''tert''-butanol]], [[carbon dioxide]], and [[phosgene]], using [[DABCO]] as a base:<ref name=pope>{{cite journal| vauthors = Pope BM, Yamamoto Y, Tarbell DS |title=DI-tert-BUTYL DICARBONATE|journal=Organic Syntheses|volume=57|year=1977|pages=45|issn=0078-6209|doi=10.15227/orgsyn.057.0045}}</ref>

[[File:Synthesis of Boc anhydride.png|400px]]

This route is currently employed commercially by manufacturers in China and India. European and Japanese companies use the reaction of [[sodium tert-butoxide|sodium ''tert''-butoxide]] with carbon dioxide, catalysed by [[p-toluenesulfonic acid|''p''-toluenesulfonic acid]] or [[methanesulfonic acid]]. This process involves a distillation of the crude material yielding a very pure grade.

Boc anhydride is also available as a 70% solution in [[toluene]] or [[tetrahydrofuran|THF]]. As boc anhydride may melt at ambient temperatures, its storage and handling is sometimes simplified by using a solution.

==Protection and deprotection of amines==

{{main article|tert-butyloxycarbonyl protecting group}}

The Boc group can be added to the amine under aqueous conditions using di-''tert''-butyl dicarbonate in the presence of a base such as [[sodium bicarbonate]]. Protection of the amine can also be accomplished in [[acetonitrile]] solution using [[4-dimethylaminopyridine]] (DMAP) as the base.<ref>{{ cite journal |author1=Yochai Basel |author2=Alfred Hassner | title = Di-''tert''-butyl Dicarbonate and 4-(Dimethylamino)pyridine Revisited. Their Reactions with Amines and Alcohols | journal = [[J. Org. Chem.]] | year = 2000 | volume = 65 |issue=20 | pages = 6368–6380 | doi = 10.1021/jo000257f |pmid=11052078 }}</ref>

Removal of the Boc in [[amino acid]]s can be accomplished with strong acids such as [[trifluoroacetic acid]] neat or in [[dichloromethane]] or with [[HCl]] in [[methanol]].<ref>{{cite journal|vauthors = Williams RM, Sinclair PJ, DeMong DE, Chen D, Zhai D|title=ASYMMETRIC SYNTHESIS OF N-tert-BUTOXYCARBONYL a-AMINO ACIDS. SYNTHESIS OF (5S,6R)-4-tert-BUTOXYCARBONYL-5,6-DIPHENYLMORPHOLIN-2-ONE|journal=Organic Syntheses|volume=80|year=2003|pages=18|issn=0078-6209|doi=10.15227/orgsyn.080.0018}}</ref><ref>{{cite journal |author1=E. A. Englund |author2=H. N. Gopi |author3=D. H. Appella | title = An Efficient Synthesis of a Probe for Protein Function: 2,3-Diaminopropionic Acid with Orthogonal Protecting Groups | journal = [[Org. Lett.]] | year = 2004 | volume = 6 | pages = 213–215 | doi = 10.1021/ol0361599 | pmid = 14723531 | issue = 2}}</ref><ref>{{cite journal |author1=D. M. Shendage |author2=R. Fröhlich |author3=G. Haufe | title = Highly Efficient Stereoconservative Amidation and Deamidation of α-Amino Acids | journal = [[Org. Lett.]] | year = 2004 | volume = 6 | pages = 3675–3678 | doi = 10.1021/ol048771l | pmid = 15469321 | issue = 21}}</ref> A complication may be the tendency of the [[t-butyl cation]] intermediate to alkylate other nucleophiles; scavengers such as [[anisole]] or [[thioanisole]] may be used.<ref>{{cite journal | doi = 10.1111/j.1399-3011.1978.tb02896.x | title = Removal of t-Butyl and t-Butoxycarbonyl Protecting Groups with Trifluoroacetic acid | year = 1978 | last1 = Lundt | first1 = Behrend F. | last2 = Johansen | first2 = Nils L. | last3 = Vølund | first3 = Aage | last4 = Markussen | first4 = Jan | journal = International Journal of Peptide and Protein Research | volume = 12 | issue = 5 | pages = 258–268 | pmid = 744685}}</ref><ref>{{cite book | doi = 10.1002/9783527631827.ch1 | chapter = 1. Protection Reactions | author = Andrew B. Hughes |editor1=Vommina V. Sureshbabu |editor2=Narasimhamurthy Narendra | volume = 4 | title = Amino Acids, Peptides and Proteins in Organic Chemistry: Protection Reactions, Medicinal Chemistry, Combinatorial Synthesis| year = 2011 | pages = 1–97 | isbn = 9783527321032 }}</ref>

Selective cleavage of the N-Boc group in the presence of other protecting groups is possible when using AlCl₃.

Reaction with [[trimethylsilyl iodide]] in acetonitrile followed by methanol is a mild and versatile method of deprotecting Boc-protected amines.<ref>{{ cite journal |author1=Michael E. Jung |author2=Mark A. Lyster | title = Conversion of alkyl carbamates into amines via treatment with trimethylsilyl iodide | journal = [[J. Chem. Soc., Chem. Commun.]] | year = 1978 | pages = 315–316 | doi = 10.1039/C39780000315 | issue = 7 }}</ref><ref>{{ cite journal |author1=Richard S. Lott |author2=Virander S. Chauhan |author3=Charles H. Stammer | title = Trimethylsilyl iodide as a peptide deblocking agent | journal = [[J. Chem. Soc., Chem. Commun.]] | year = 1979 | pages = 495–496 | doi = 10.1039/C39790000495 | issue = 11 }}</ref><ref>{{ cite journal | doi = 10.1016/0040-4020(82)87002-6 | title= Iodotrimethylsilane—a versatile synthetic reagent| year = 1982 | last1 = Olah | first1 = G | last2 = Narang | first2 = S. C. | journal = [[Tetrahedron (journal)|Tetrahedron]] | volume = 38 | issue = 15 | pages = 2225 }}</ref><ref>{{ cite journal |author1=Zhijian Liu |author2=Nobuyoshi Yasuda |author3=Michael Simeone |author4=Robert A. Reamer | title = ''N''-Boc Deprotection and Isolation Method for Water-Soluble Zwitterionic Compounds | journal = [[Journal of Organic Chemistry|J. Org. Chem.]] | year = 2014 | volume = 79 |issue=23 | pages = 11792–11796 | doi = 10.1021/jo502319z | pmid = 25376704 }}</ref>

The use of [[triethylsilane]] as a [[carbocation]] scavenger in the presence of trifluoroacetic acid in [[dichloromethane]] has been shown to lead to increased yields, decreased reaction times, simple work-up and improved selectivity for the deprotection of ''t''-butyl ester and ''t''-butoxycarbonyl sites in protected amino-acids and peptides in the presence of other acid-sensitive protecting groups such as the [[Carboxybenzyl|benzyloxycarbonyl]], [[Fmoc|9-fluorenylmethoxycarbonyl]], ''O''- and ''S''-benzyl and ''t''-butylthio groups.<ref name="MehtaJaouhari1992">{{cite journal|last1=Mehta|first1=Anita|last2=Jaouhari|first2=Rabih|last3=Benson|first3=Timothy J.|last4=Douglas|first4=Kenneth T.|title=Improved efficiency and selectivity in peptide synthesis: Use of triethylsilane as a carbocation scavenger in deprotection of t-butyl esters and t-butoxycarbonyl-protected sites|journal=Tetrahedron Letters|volume=33|issue=37|year=1992|pages=5441–5444|issn=0040-4039|doi=10.1016/S0040-4039(00)79116-7}}</ref>

==Other uses==

The synthesis of [[6-acetyl-1,2,3,4-tetrahydropyridine]], an important bread aroma compound, starting from [[2-piperidone]] was accomplished using ''t''-boc anhydride.<ref>{{cite journal |author1=T. J. Harrison |author2=G. R. Dake | title = An Expeditious, High-Yielding Construction of the Food Aroma Compounds 6-Acetyl-1,2,3,4-tetrahydropyridine and 2-Acetyl-1-pyrroline | journal = [[J. Org. Chem.]] | year = 2005 | volume = 70 | issue = 26 | pages = 10872–10874 | doi = 10.1021/jo051940a | pmid = 16356012}}</ref>

(See [[Maillard reaction]]). The first step in this reaction sequence is the formation of the [[carbamate]] from the reaction of the amide nitrogen with boc anhydride in [[acetonitrile]] using DMAP as a catalyst.

:[[Image:BOC application.png|450px|Schematic: synthesis of 6-acetyl-1,2,3,4-tetrahydropyridine]]

Di-''tert''-butyl dicarbonate also finds applications as a polymer [[blowing agent]] due to its decomposition into gaseous products upon heating.<ref>{{cite journal|last1=Wirth|first1=D.|title=Highly Expandable Foam for Lithographic 3D Printing|journal=ACS Appl. Mater. Interfaces|volume=12|issue=16|pages=19033–19043|date=8 April 2020|doi=10.1021/acsami.0c02683|pmid=32267677|s2cid=215603770 }}</ref><ref>{{cite book |last1=Wypych |first1=George |title=Handbook of Foaming and Blowing Agents - 1st Edition |date=20 February 2017 |publisher=ChemTec Publishing |isbn=978-1-895198-99-7 |pages=258 |edition=1st |url=https://www.elsevier.com/books/handbook-of-foaming-and-blowing-agents/wypych/978-1-895198-99-7 |accessdate=4 May 2020}}</ref>

== Hazards ==

Bottles of di-''tert''-butyl dicarbonate buildup of internal pressure in sealed containers caused by its slow decomposition to di-''tert''-butyl carbonate and ultimately ''tert-''butanol and CO₂ in the presence of moisture. For this reason, it is usually sold and stored in plastic bottles rather than glass ones.

The main hazard of the reagent is its inhalational toxicity. Its median lethal concentration of 100&nbsp;mg/m³ over 4 hours in rats<ref>{{Cite web|url=https://us.vwr.com/store/asset?assetURI=https://us.vwr.com/stibo/hi_res/eng_us/92/73/12019273.pdf|title=Material Safety Data Sheet|last=|first=|date=|website=|publisher=CHEM-IMPEX INTERNATIONAL INC|access-date=2016-09-10}}</ref> is comparable to that of [[phosgene]]<ref>{{Cite web|url=http://webwiser.nlm.nih.gov/getSubstanceData.do?substanceId=59&displaySubstanceName=Phosgene&STCCID=&UNNAID=&selectedDataMenuItemID=78|title=Phosgene|last=|first=|date=|website=Wireless Information System for Emergency Responders|publisher=US National Library of Medicine|access-date=2016-09-10}}</ref> (49&nbsp;mg/m³ over 50 min in rats).

==References==

<references/>

==External links==

* {{cite journal | doi = 10.1055/s-2001-12350 | title = Imidazole and Trifluoroethanol as Efficient and Mild Reagents for Destruction of Excess Di-tert-butyl Dicarbonate [(BOC)2O] | year = 2001 | last1 = Basel | first1 = Yochai | last2 = Hassner | first2 = Alfred | journal = Synthesis | volume = 2001 | issue = 4 | pages = 0550| s2cid = 97029361 }}

{{DEFAULTSORT:Di-Tert-Butyl Dicarbonate}}

[[Category:Reagents for organic chemistry]]

[[Category:Carbonate esters]]

[[Category:Dicarbonates]]

[[Category:Tert-Butyl esters]]