Non-nucleophilic base

As the name suggests, a non-nucleophilic base is a sterically hindered organic base that is a poor nucleophile. Normal bases are also nucleophiles, but often chemists seek the proton-removing ability of a base without any other functions. Typical non-nucleophilic bases are bulky, such that protons can attach to the basic center but alkylation and complexation is inhibited.

Non-nucleophilic bases

A variety of amines and nitrogen heterocycles are useful bases of moderate strength (pK_a of conjugate acid around 10-13)

• N,N-Diisopropylethylamine (DIPEA, also called Hünig's Base^[1]), pK_a = 10.75
• 1,8-Diazabicycloundec-7-ene (DBU) - useful for E2 elimination reactions, pK_a = 13.5
• 1,5-Diazabicyclo(4.3.0)non-5-ene (DBN) - comparable to DBU
• 2,6-Di-tert-butylpyridine, a weak non-nucleophilic base^[2] pK_a = 3.58
• Phosphazene bases, such as t-Bu-P₄^[3]

Non-nucleophilic bases of high strength are usually anions. For these species, the pK_as of the conjugate acids are around 35-40.

• Lithium diisopropylamide (LDA), pK_a = 36
• Silicon-based amides, such as sodium and potassium bis(trimethylsilyl)amide (NaHMDS and KHMDS, respectively)
• Lithium tetramethylpiperidide (LiTMP or harpoon base)

Other strong non-nucleophilic bases are sodium hydride and potassium hydride. These compounds are dense, salt-like materials that are insoluble and operate by surface reactions.

Some reagents are of high basicity (pK_a of conjugate acid around 17) but of modest but not negligible nucleophilicity. Examples include sodium tert-butoxide and potassium tert-butoxide.

Example

The following diagram shows how the hindered base, lithium diisopropylamide, is used to deprotonate an ester to give the enolate in the Claisen ester condensation, instead of undergoing a nucleophilic substitution.

This reaction (deprotonation with LDA) is commonly used to generate enolates.

References