N,N-Diisopropylethylamine

Structure

DIPEA consists of a central nitrogen atom that is bonded to an ethyl group and two isopropyl groups. A lone pair of electrons resides on the nitrogen atom, which can react with electrophiles. However, the three alkyl groups on the nitrogen atom create steric hindrance, so only small electrophiles such as protons can react with the nitrogen lone pair.

Occurrence and preparation

DIPEA is commercially available. It is traditionally prepared by the alkylation of diisopropylamine with 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 from potassium hydroxide or calcium hydride.

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, DIPEA is a good base but a poor nucleophile, 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.

:[[File:Use_of_DIPEA_in_amide_coupling_between_acid_chloride_and_amine.png|frameless|600px]]

Alkylations

DIPEA has been investigated for its use as a selective reagent in the alkylation of secondary amines to tertiary amines by alkyl halides. This is often hampered by an unwanted Menshutkin reaction forming a quaternary ammonium salt, but is absent when DIPEA is present.

:[[Image:Use of Hunig's base for alkylating secondary amines.png|500px|The use of Hünig's base for alkylating secondary amines]]

Transition metal catalyzed cross-coupling reactions

DIPEA can be used as a base in a number of transition metal catalyzed cross-coupling reactions, such as the Heck coupling and the Sonogashira coupling (as illustrated below).

:[[File:Generic_Sonogashira_coupling_with_DIPEA_as_base.png|frameless|450x450px]]

Swern oxidation

Although triethylamine is traditionally employed as the hindered base in Swern oxidations, the structurally similar DIPEA can be used instead, as exemplified below.

:[[File:Swern_oxidation_with_DIPEA.png|frameless|450x450px]]

Examples of DIPEA used as a substrate

DIPEA forms a complex heterocyclic compound called scorpionine (bis([1,2]dithiolo)-[1,4]thiazine) upon reaction with disulfur dichloride that is catalyzed by DABCO in a one-pot synthesis.

:[[File:Sscorpionine_synthesis.png|450px|Hünig's base in the synthesis of [[scorpionine]]]]

Comparison with triethylamine

DIPEA and triethylamine are structurally very similar, with both compounds considered hindered organic bases. Due to their structural similarity, DIPEA and triethylamine can be used interchangeably in most applications. The nitrogen atom in DIPEA is more hindered than the nitrogen atom in triethylamine. However, triethylamine is a slightly stronger base than DIPEA; the pKa values of the respective conjugate acids in dimethyl sulfoxide are 9.0 and 8.5, respectively.

References

References

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