Di-''tert''-butyl dicarbonate is a
reagent
In chemistry, a reagent ( ) or analytical reagent is a substance or compound added to a system to cause a chemical reaction, or test if one occurs. The terms ''reactant'' and ''reagent'' are often used interchangeably, but reactant specifies a ...
widely used in
organic synthesis
Organic synthesis is a special branch of chemical synthesis and is concerned with the intentional construction of organic compounds. Organic molecules are often more complex than inorganic compounds, and their synthesis has developed into one o ...
. 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
In organic chemistry, a dicarbonate, also known as a pyrocarbonate, is a compound containing the divalent ˆ’O−(C=O)−O−(C=O)−O−or −− functional group, which consists of two carbonate groups sharing an oxygen atom. These compounds ...
reacts with
amine
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituen ...
s to give
''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
In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the rest ...
. The Boc group can later be removed from the amine using moderately strong acids (e.g.,
trifluoroacetic acid
Trifluoroacetic acid (TFA) is an organofluorine compound with the chemical formula CF3CO2H. It is a structural analogue of acetic acid with all three of the acetyl group's hydrogen atoms replaced by fluorine atoms and is a colorless liquid with a ...
). Thus, Boc serves as a
protective group
A protecting group or protective group is introduced into a molecule by chemical modification of a functional group to obtain chemoselectivity in a subsequent chemical reaction. It plays an important role in multistep organic synthesis.
In many ...
, for instance in
solid phase peptide synthesis
In organic chemistry, peptide synthesis is the production of peptides, compounds where multiple amino acids are linked via amide bonds, also known as peptide bonds. Peptides are chemically synthesized by the condensation reaction of the carboxy ...
. Boc-protected amines are unreactive to most bases and
nucleophile
In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...
s, allowing for the use of the
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,
carbon dioxide
Carbon dioxide (chemical formula ) is a chemical compound made up of molecules that each have one carbon atom covalently double bonded to two oxygen atoms. It is found in the gas state at room temperature. In the air, carbon dioxide is transpar ...
, and
phosgene
Phosgene is the organic chemical compound with the formula COCl2. It is a toxic, colorless gas; in low concentrations, its musty odor resembles that of freshly cut hay or grass. Phosgene is a valued and important industrial building block, espe ...
, using
DABCO
DABCO (1,4-diazabicyclo .2.2ctane), also known as triethylenediamine or TEDA, is a bicyclic organic compound with the formula N2(C2H4)3. This colorless solid is a highly nucleophilic tertiary amine base, which is used as a catalyst and reagent i ...
as a base:
![Synthesis of Boc anhydride](https://upload.wikimedia.org/wikipedia/commons/4/4b/Synthesis_of_Boc_anhydride.png)
This route is currently employed commercially by manufacturers in China and India. European and Japanese companies use the reaction of
sodium ''tert''-butoxide with carbon dioxide, catalysed by
''p''-toluenesulfonic acid or
methanesulfonic acid
Methanesulfonic acid (MsOH) or methanesulphonic acid (in British English) is an organosulfuric, colorless liquid with the chemical formula and structure . It is the simplest of the alkylsulfonic acids (). Salts and esters of methanesulfonic aci ...
. 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
Toluene (), also known as toluol (), is a substituted aromatic hydrocarbon. It is a colorless, water-insoluble liquid with the smell associated with paint thinners. It is a mono-substituted benzene derivative, consisting of a methyl group (CH3) at ...
or
THF
Tetrahydrofuran (THF), or oxolane, is an organic compound with the formula (CH2)4O. The compound is classified as heterocyclic compound, specifically a cyclic ether. It is a colorless, water- miscible organic liquid with low viscosity. It is ...
. As boc anhydride may melt at ambient temperatures, its storage and handling is sometimes simplified by using a solution.
Protection and deprotection of amines
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
Sodium bicarbonate (IUPAC name: sodium hydrogencarbonate), commonly known as baking soda or bicarbonate of soda, is a chemical compound with the formula NaHCO3. It is a salt composed of a sodium cation ( Na+) and a bicarbonate anion ( HCO3−) ...
. Protection of the amine can also be accomplished in
acetonitrile
Acetonitrile, often abbreviated MeCN (methyl cyanide), is the chemical compound with the formula and structure . This colourless liquid is the simplest organic nitrile (hydrogen cyanide is a simpler nitrile, but the cyanide anion is not clas ...
solution using
4-dimethylaminopyridine (DMAP) as the base.
Removal of the Boc in
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
s can be accomplished with strong acids such as
trifluoroacetic acid
Trifluoroacetic acid (TFA) is an organofluorine compound with the chemical formula CF3CO2H. It is a structural analogue of acetic acid with all three of the acetyl group's hydrogen atoms replaced by fluorine atoms and is a colorless liquid with a ...
neat or in
dichloromethane
Dichloromethane (DCM or methylene chloride, methylene bichloride) is an organochlorine compound with the formula . This colorless, volatile liquid with a chloroform-like, sweet odour is widely used as a solvent. Although it is not miscible with ...
or with
HCl HCL may refer to:
Science and medicine
* Hairy cell leukemia, an uncommon and slowly progressing B cell leukemia
* Harvard Cyclotron Laboratory, from 1961 to 2002, a proton accelerator used for research and development
* Hollow-cathode lamp, a spe ...
in
methanol
Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical and the simplest aliphatic alcohol, with the formula C H3 O H (a methyl group linked to a hydroxyl group, often abbreviated as MeOH). It is a ...
. A complication may be the tendency of the
t-butyl cation intermediate to alkylate other nucleophiles; scavengers such as
anisole
Anisole, or methoxybenzene, is an organic compound with the formula CH3OC6H5. It is a colorless liquid with a smell reminiscent of anise seed, and in fact many of its derivatives are found in natural and artificial fragrances. The compound is ...
or
thioanisole
Thioanisole is an organic compound with the formula CH3SC6H5. It is a colorless liquid that is soluble in organic solvents. It is the simplest alkyl–aryl thioether. The name indicates that this compound is the sulfur analogue—the thioether rat ...
may be used.
Selective cleavage of the N-Boc group in the presence of other protecting groups is possible when using AlCl
3.
Reaction with
trimethylsilyl iodide in acetonitrile followed by methanol is a mild and versatile method of deprotecting Boc-protected amines.
The use of
triethylsilane
Triethylsilane is the organosilicon compound with the formula (C2H5)3SiH. It is a trialkylsilane. The Si-H bond is reactive. This colorless liquid is used in organic synthesis as a reducing agent and as a precursor to silyl ethers. As one of th ...
as a
carbocation
A carbocation is an ion with a positively charged carbon atom. Among the simplest examples are the methenium , methanium and vinyl cations. Occasionally, carbocations that bear more than one positively charged carbon atom are also encountere ...
scavenger in the presence of trifluoroacetic acid in
dichloromethane
Dichloromethane (DCM or methylene chloride, methylene bichloride) is an organochlorine compound with the formula . This colorless, volatile liquid with a chloroform-like, sweet odour is widely used as a solvent. Although it is not miscible with ...
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
benzyloxycarbonyl,
9-fluorenylmethoxycarbonyl, ''O''- and ''S''-benzyl and ''t''-butylthio groups.
Other uses
The synthesis of
6-acetyl-1,2,3,4-tetrahydropyridine
6-Acetyl-2,3,4,5-tetrahydropyridine is an aroma compound and Flavoring, flavor that gives baking, baked goods such as white bread, popcorn, and tortillas their typical smell, together with its structural homolog (chemistry), homolog 2-acetyl-1-pyrr ...
, an important bread aroma compound, starting from
2-piperidone was accomplished using ''t''-boc anhydride.
(See
Maillard reaction
The Maillard reaction ( ; ) is a chemical reaction between amino acids and reducing sugars that gives browned food its distinctive flavor. Seared steaks, fried dumplings, cookies and other kinds of biscuits, breads, toasted marshmallows, and man ...
). The first step in this reaction sequence is the formation of the
carbamate
In organic chemistry, a carbamate is a category of organic compounds with the general formula and structure , which are formally derived from carbamic acid (). The term includes organic compounds (e.g., the ester ethyl carbamate), formally o ...
from the reaction of the amide nitrogen with boc anhydride in
acetonitrile
Acetonitrile, often abbreviated MeCN (methyl cyanide), is the chemical compound with the formula and structure . This colourless liquid is the simplest organic nitrile (hydrogen cyanide is a simpler nitrile, but the cyanide anion is not clas ...
using DMAP as a catalyst.
:
Di-''tert''-butyl dicarbonate also finds applications as a polymer
blowing agent
A blowing agent is a substance which is capable of producing a cellular structure via a foaming process in a variety of materials that undergo hardening or phase transition, such as polymers, plastics, and metals. They are typically applied when ...
due to its decomposition into gaseous products upon heating.
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 CO
2 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 mg/m
3 over 4 hours in rats is comparable to that of
phosgene
Phosgene is the organic chemical compound with the formula COCl2. It is a toxic, colorless gas; in low concentrations, its musty odor resembles that of freshly cut hay or grass. Phosgene is a valued and important industrial building block, espe ...
(49 mg/m
3 over 50 min in rats).
References
External links
*
{{DEFAULTSORT:Di-Tert-Butyl Dicarbonate
Reagents for organic chemistry
Carbonate esters
Dicarbonates
Tert-butyl compounds