''N'',''N''-Diisopropylethylamine, or Hünig's base, is an
organic compound
In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. The ...
and an
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 Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituen ...
. It is named after the German chemist Siegfried Hünig. It is used in
organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clayden, J.; ...
as a
base. It is commonly abbreviated as DIPEA, DIEA, or ''i''-Pr
2NEt.
Structure
DIPEA consists of a central
nitrogen
Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at se ...
atom that is bonded to an
ethyl group
In organic chemistry, an ethyl group (abbr. Et) is an alkyl substituent with the formula , derived from ethane (). ''Ethyl'' is used in the International Union of Pure and Applied Chemistry's nomenclature of organic chemistry for a saturated ...
and two
isopropyl
In organic chemistry, propyl is a three-carbon alkyl substituent with chemical formula for the linear form. This substituent form is obtained by removing one hydrogen atom attached to the terminal carbon of propane. A propyl substituent is ofte ...
groups. A lone pair of electrons resides on the nitrogen atom, which can react with electrophiles. However, as the two isopropyl groups and the ethyl group occupy much of the space surrounding the N atom, only small
electrophile
In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carries ...
s such as
protons
A proton is a stable subatomic particle, symbol , H+, or 1H+ with a positive electric charge of +1 ''e'' elementary charge. Its mass is slightly less than that of a neutron and 1,836 times the mass of an electron (the proton–electron mass ...
can react with the nitrogen lone pair.
Occurrence and preparation
DIPEA is commercially available. It is traditionally prepared by the
alkylation
Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effecting ...
of
diisopropylamine with
diethyl sulfate
Diethyl sulfate (DES) is a highly toxic, combustible, and likely carcinogenic chemical compound with the formula (C2H5)2SO4. It occurs as a colorless, oily liquid with a faint peppermint odor and is corrosive to tissue and metals. Diethyl sulfate ...
.
Pure DIPEA exists as a colorless liquid, although commercial samples can be slightly yellow. If necessary, the compound can be purified by
distillation
Distillation, or classical distillation, is the process of separation process, separating the components or substances from a liquid mixture by using selective boiling and condensation, usually inside an apparatus known as a still. Dry distilla ...
from
potassium hydroxide
Potassium hydroxide is an inorganic compound with the formula K OH, and is commonly called caustic potash.
Along with sodium hydroxide (NaOH), KOH is a prototypical strong base. It has many industrial and niche applications, most of which exp ...
or
calcium hydride
Calcium hydride is the chemical compound with the formula , and is therefore an alkaline earth hydride. This grey powder (white if pure, which is rare) reacts vigorously with water liberating hydrogen gas. is thus used as a drying agent, i.e. a ...
.
Uses and reactions
DIPEA is a sterically hindered organic base that is commonly employed as a proton scavenger. Thus, like
2,2,6,6-tetramethylpiperidine and
triethylamine
Triethylamine is the chemical compound with the formula N(CH2CH3)3, commonly abbreviated Et3N. It is also abbreviated TEA, yet this abbreviation must be used carefully to avoid confusion with triethanolamine or tetraethylammonium, for which TEA ...
, DIPEA is a good base but a poor
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 ...
, DIPEA has low solubility in water, which makes it very easily recovered in commercial processes, a combination of properties that makes it a useful organic reagent.
Amide coupling
It is commonly used as the hindered base in amide coupling reactions between a carboxylic acid (typically activated, for example, as an acid chloride, as illustrated below) and a nucleophilic amine. As DIPEA is hindered and poorly nucleophilic, it does not compete with the nucleophilic amine in the coupling reaction.
:
Alkylations
DIPEA has been investigated for its use as a selective reagent in the
alkylation
Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effecting ...
of
secondary 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 substituent such ...
s to
tertiary 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 substituent such a ...
s by
alkyl halide
The haloalkanes (also known as halogenoalkanes or alkyl halides) are alkanes containing one or more halogen substituents. They are a subset of the general class of halocarbons, although the distinction is not often made. Haloalkanes are widely ...
s. This is often hampered by an unwanted
Menshutkin reaction
In organic chemistry, the Menshutkin reaction converts a tertiary amine into a quaternary ammonium salt by reaction with an alkyl halide. Similar reactions occur when tertiary phosphines are treated with alkyl halides.
The reaction is the meth ...
forming a
quaternary ammonium salt
In chemistry, quaternary ammonium cations, also known as quats, are positively charged polyatomic ions of the structure , R being an alkyl group or an aryl group. Unlike the ammonium ion () and the primary, secondary, or tertiary ammonium cations ...
, but is absent when DIPEA is present.
:
Transition metal catalyzed cross-coupling reactions
DIPEA can be used as a base in a number of
transition metal
In chemistry, a transition metal (or transition element) is a chemical element in the d-block of the periodic table (groups 3 to 12), though the elements of group 12 (and less often group 3) are sometimes excluded. They are the elements that can ...
catalyzed
Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
cross-coupling reactions, such as the
Heck coupling and the
Sonogashira coupling
The Sonogashira reaction is a cross-coupling reaction used in organic synthesis to form carbon–carbon bonds. It employs a palladium catalyst as well as copper co-catalyst to form a carbon–carbon bond between a terminal alkyne and an aryl or v ...
(as illustrated below).
:
Swern oxidation
Although triethylamine is traditionally employed as the hindered base in
Swern oxidation
The Swern oxidation, named after Daniel Swern, is a chemical reaction whereby a primary or secondary alcohol is oxidized to an aldehyde or ketone using oxalyl chloride, dimethyl sulfoxide (DMSO) and an organic base, such as triethylamine. It is one ...
s, the structurally similar DIPEA can be used instead, as exemplified below.
:
Examples of DIPEA used as a substrate
DIPEA forms a complex
heterocyclic
A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring(s). Heterocyclic chemistry is the branch of organic chemistry dealing with the synthesis, properties, and ...
compound called scorpionine (bis(
,2ithiolo)-
,4hiazine) upon reaction with
disulfur dichloride
Disulfur dichloride is the inorganic compound of sulfur and chlorine with the Chemical formula, formula S2Cl2.
Some alternative names for this compound are ''sulfur monochloride'' (the name implied by its empirical formula, SCl), ''disulphur dich ...
that is catalyzed by
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 ...
in a
one-pot synthesis
In chemistry a one-pot synthesis is a strategy to improve the efficiency of a chemical reaction whereby a reactant is subjected to successive chemical reactions in just one reactor. This is much desired by chemists because avoiding a lengthy separ ...
.
:
Comparison with triethylamine
DIPEA and
triethylamine
Triethylamine is the chemical compound with the formula N(CH2CH3)3, commonly abbreviated Et3N. It is also abbreviated TEA, yet this abbreviation must be used carefully to avoid confusion with triethanolamine or tetraethylammonium, for which TEA ...
are structurally very similar, with both compounds considered hindered organic bases. Due to their structural similarity, DIPEA and
triethylamine
Triethylamine is the chemical compound with the formula N(CH2CH3)3, commonly abbreviated Et3N. It is also abbreviated TEA, yet this abbreviation must be used carefully to avoid confusion with triethanolamine or tetraethylammonium, for which TEA ...
can be used interchangeably in most applications. The nitrogen atom in DIPEA is more shielded than the nitrogen atom in triethylamine. However, triethylamine is a slightly stronger base than DIPEA; the
pKas of the respective
conjugate acid
A conjugate acid, within the Brønsted–Lowry acid–base theory, is a chemical compound formed when an acid donates a proton () to a base—in other words, it is a base with a hydrogen ion added to it, as in the reverse reaction it loses a ...
s in
dimethyl sulfoxide
Dimethyl sulfoxide (DMSO) is an organosulfur compound with the formula ( CH3)2. This colorless liquid is the sulfoxide most widely used commercially. It is an important polar aprotic solvent that dissolves both polar and nonpolar compounds a ...
are 9.0 and 8.5, respectively.
References
{{reflist
Alkylamines
Non-nucleophilic bases
Diisopropylamino compounds
Tertiary amines