Controlled nucleophilic acyl substitution

Weinreb amide addition

How the Weinreb amide addition works, in 3 steps. Each step shows the structures and the curved arrows that move the electrons.

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In short. A 3-step mechanism. Typical reagents: Weinreb amide, R–MgX or R–Li (1 equiv); then H₃O⁺. Conditions: THF, –78 to 0 °C. Bonds formed: C–C; Mg–O/Mg–OMe chelate; C=O (ketone, at workup); bonds broken: C=O π; C–N (at workup). Stereochemistry: No new stereocentre unless R or R′ chiral. Rate and selectivity: Addition fast; chelate stable below ~0 °C.

At a glance

ReagentsWeinreb amide, R–MgX or R–Li (1 equiv); then H₃O⁺

Solvent / conditionsTHF, –78 to 0 °C

Bonds formedC–C; Mg–O/Mg–OMe chelate; C=O (ketone, at workup)

Bonds brokenC=O π; C–N (at workup)

StereochemistryNo new stereocentre unless R or R′ chiral

Rate / selectivityAddition fast; chelate stable below ~0 °C

Step 1: Nucleophile adds to the carbonyl

An organolithium or Grignard reagent attacks the carbonyl carbon of an N-methoxy-N-methylamide (a Weinreb amide), forming a tetrahedral alkoxide intermediate exactly as in any nucleophilic acyl substitution.

Step 2: Mg chelated by O⁻ and OMe

Instead of collapsing immediately, that alkoxide's nitrogen and the adjacent methoxy oxygen chelate the metal cation, locking the tetrahedral intermediate in place and preventing it from expelling the amine — this stabilized intermediate is the whole trick behind why this reagent works.

Step 3: Workup collapses to the ketone

Only on aqueous workup does the chelate break down and the intermediate collapse to release the ketone — because the reaction stops cleanly at the tetrahedral stage, exactly one equivalent of nucleophile adds, avoiding the over-addition problem that plagues adding organometallics directly to esters or acid chlorides.

Abbreviations and terms

R: R group. Any carbon substituent (alkyl, aryl…) whose identity does not matter for the mechanism.
Me: Methyl. –CH₃.
Ph: Phenyl. –C₆H₅.
OMe: Methoxy. –OCH₃.
THF: Tetrahydrofuran. Cyclic ether solvent; its oxygen lone pairs solvate Li⁺/Mg²⁺ so organometallics stay dissolved and reactive.

How it compares with related reactions

	Weinreb amide addition	Acid-catalyzed amide hydrolysis	Amide synthesis from an acid chloride and amine
Reagents	Weinreb amide, R–MgX or R–Li (1 equiv); then H₃O⁺	Amide, H₃O⁺ (HCl or H₂SO₄), H₂O	Benzoyl chloride, methylamine, aqueous NaOH
Conditions	THF, –78 to 0 °C	6 M acid, reflux (hours)	CH₂Cl₂ / H₂O (biphasic), 0–25 °C
Stereochemistry	No new stereocentre unless R or R′ chiral	No stereocentre created; α-stereocentres retained	No stereocentre; planar amide
Rate / selectivity	Addition fast; chelate stable below ~0 °C	Water attack / C–N cleavage rate-limiting; far slower than ester hydrolysis	Very fast; base neutralises HCl so the amine is not lost as its salt

Test yourself

Try to answer each question before opening it.

Which reagents and conditions are typical for the Weinreb amide addition?

Weinreb amide, R–MgX or R–Li (1 equiv); then H₃O⁺. Conditions: THF, –78 to 0 °C.

Which bonds are formed and which are broken?

Formed: C–C; Mg–O/Mg–OMe chelate; C=O (ketone, at workup). Broken: C=O π; C–N (at workup).

What is the stereochemical outcome?

No new stereocentre unless R or R′ chiral

What controls the rate or the selectivity?

Addition fast; chelate stable below ~0 °C

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