How to choose TEA&DIPEA

Triethylamine (TEA) and diisopropylethylamine (DIPEA) are important organic bases in organic synthesis and are often used as acid binding agents. The alkalinity of these two organic bases is similar, but their other properties are quite different. Many people don't know how to choose these two organic bases in the process of doing experiments. Today we will introduce the following two organic bases in detail.

Brief introduction and comparison of properties of TEA and DIPEA

1 basic properties

Triethylamine: abbreviation of TEA, molecular weight: 101.19, density: 0.73, boiling point: 89.5 °C, melting point:-114.8 C, conjugated acid pKa= 10.75.

N,N- diisopropylethylamine: abbreviated as DIPEA/DIEA, molecular weight: 129.25, density: 0.74, boiling point: 127 °C, melting point:-46 C, conjugated acid pKEst = 10.9 (data source: Laboratory Chemical Purification Manual, PK

2 steric hindrance and stability

DIPEA has a large branched chain, and its steric hindrance is larger than that of triethylamine. Isopropyl will hinder the protonation of nitrogen atoms and inhibit nucleophilic side reactions, and its stability is good. Triethylamine has a small steric hindrance and is easy to participate in nucleophilic substitution side reactions. For example, triethylamine is easily acylated or alkylated with acyl chloride or halogenated hydrocarbon.

3 solubility

TEA is miscible with many organic solvents and soluble in water. DIPEA has poor solubility in some polar solvents and good solubility in nonpolar solvents (such as DCM, toluene) because of the existence of isopropyl.

For its hydrochloride, triethylamine hydrochloride is generally less soluble in organic solvents, while DIPEA hydrochloride is soluble in many organic solvents. If the product is also precipitated in the reaction solvent, a mixture of triethylamine hydrochloride and the product will generally be obtained by using triethylamine; If DIPEA is used, a relatively clean product can be obtained by direct filtration. On the contrary, if the product is dissolved in the reaction solvent and triethylamine is selected as the acid binding agent, it can be separated from the product by filtration.

Application of triethylamine and DIPEA in organic synthesis

Triethylamine and DIPEA can be used as acid binding agents, and they are also widely used in other organic synthesis reactions.

triethylamine

1. Catalyze Knoevenagel reaction: Triethylamine can catalyze the condensation reaction of active methylene compounds with aldehydes and ketones, and help the substrate to undergo nucleophilic addition and dehydration;

2. Catalyze Horner-Wadsworth-Emmons reaction (HWE reaction): HWE reaction requires the use of strong base (NaH, LDA, LiHMDS or sodium alkoxide), which requires high substrate. If lithium chloride is used as additive, the reaction can be carried out under the condition of weak base (DBU, TEA, etc.);

3. Hydrolyzing ester groups: The combination of triethylamine and lithium bromide can hydrolyze ester groups under mild conditions.

DIPEA

1. Polypeptide synthesis: DIPEA can reduce racemic products more effectively than triethylamine in polypeptide synthesis;

2. Palladium-catalyzed coupling: A, the large steric hindrance of DIPEA can reduce the competitive nucleophilic attack with the substrate; B, it can also be used as a mild reducing agent to reduce the stable Pd(II) precatalyst to active Pd(0) species in situ and activate the catalytic cycle; C, avoiding the combination of other ligands in the catalyst with palladium; D, in the palladium-catalyzed reaction involving zinc cyanide, the mild alkalinity of DIPEA reduces the decomposition risk of substrate at high temperature;

3. Photocatalytic decarboxylation reaction: DIPEA can initiate decarboxylation reaction and generate α-oxygen free radicals in photoredox catalysis.

How to choose triethylamine and DIPEA

Preference is given to triethylamine

1. Simple neutralization reaction: such as esterification reaction and amidation reaction, only acid is needed, and there is no active substrate (such as acyl chloride and halogenated hydrocarbon);

2. The product is easily soluble in organic phase: triethylamine hydrochloride can be precipitated and separated;

3. Low temperature reaction: triethylamine has a low boiling point, and most of it can be removed by simple rotary steaming;

4. Cost priority: triethylamine is relatively low in price and suitable for large-scale reaction.

Preference is given to DIPEA.

1. High alkalinity requirement: sufficient alkalinity can form stable salt with protonic acid;

2. There are active substrates: there are active substrates such as acyl chloride and halogenated hydrocarbon in the substrate, and the use of DIPEA can avoid the generation of nucleophilic by-products;

3. Metal-catalyzed coupling reaction: the steric hindrance of DIPEA can reduce the competitive nucleophilic attack with the substrate; It can also avoid coordination with the metal center;

4. The product is insoluble in organic solvents: DIPEA hydrochloride has good solubility in organic solvents, and the product can be separated from DIPEA hydrochloride by filtration;

5. Non-polar solvent system: DIPEA has better solubility in DCM or toluene and is suitable for anhydrous conditions;

6. Polypeptide synthesis: large steric hindrance reduces amino acid racemization;

7. High temperature reaction: DIPEA has a high boiling point, which can avoid the fluctuation of alkali concentration caused by volatilization at high temperature.