Di-tert-butyl dicarbonate: Difference between revisions

| 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

| IUPACNamePIN = Di-''ttert''-butyl dicarbonate

| OtherNames = diDi-''tertt''-butyl pyrocarbonate<br />Boc anhydride<br />Boc₂O

| Section1 = {{Chembox Identifiers

| Section2 = {{Chembox Properties

| MolarMassDensity = 2180.2595&nbsp;g&middot;mol·cm^&minus;13

| SolubleOther = Soluble in most organic solvents

|Section3 Section7 = {{Chembox StructureHazards

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

'''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. {{DOIdoi|10.1002/047084289047084289X}}.</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 [[carbonate esterpyrocarbonate]] reacts with [[amine]]s to give [[tert-butoxycarbonyl|''N''-''tert''-butoxycarbonyl]] or so-called Boc derivatives. These Thesecarbamate derivatives do not behave as amines, which allows certain subsequent transformations to occur that would havebe otherwiseincompatible affectedwith 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 Itamines isare unreactive to most bases and [[nucleophile]]s, allowing for anthe orthogonaluse of the [[Fluorenylmethyloxycarbonyl chloride|fluorenylmethyloxycarbonyl]] group (FMOC-ClFmoc) protectionas an orthogonal protecting group.

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>{{OrgSynthcite journal| authorvauthors = B.Pope M. PopeBM, Yamamoto Y. Yamamoto, andTarbell D. S. TarbellDS | title = Dicarbonic acid, bis(1,1DI-dimethylethyl) estertert-BUTYL DICARBONATE| collvol journal=Organic 6 Syntheses| collvolpages volume= 418 57| year = 1988 1977| prep pages= cv6p041845|issn=0078-6209|doi=10.15227/orgsyn.057.0045}}</ref>

This route is currently employed commercially by manufacturers in China and India. European and Japanese companies use the reaction of [[sodium tert-butylatebutoxide|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.

{{main article|Terttert-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>{{OrgSynthcite journal| authorvauthors = R.Williams M. WilliamsRM, P.Sinclair J. SinclairPJ, D.DeMong E. DeMongDE, D. Chen, and D., Zhai D|title=ASYMMETRIC prepSYNTHESIS =OF v80p0018N-tert-BUTOXYCARBONYL |a-AMINO titleACIDS. =SYNTHESIS 4-MorpholinecarboxylicOF acid(5S, 66R)-oxo4-2,3tert-diphenylBUTOXYCARBONYL-5, 1,16-dimethylethyl ester, (2S,3R)DIPHENYLMORPHOLIN-2-ONE|journal=Organic Syntheses| volume = 80 | year=2003|pages = 18 | year issn= 20030078-6209|doi=10.15227/orgsyn.080.0018}}</ref><ref>{{cite journal | author 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 | author author1= D. M. Shendage, |author2=R. Fröhlich, |author3=G. Haufe | title = Highly Efficient Stereoconservative Amidation and Deamidation of &alpha;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 | editor 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>

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 | author author1= T. J. Harrison and |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 secondaryamide aminenitrogen with boc anhydride in [[acetonitrile]] withusing DMAP as a catalyst.