Reductive amination — mild hydride
Borch reductive amination
How the Borch reductive amination works, in 3 steps. Each step shows the structures and the curved arrows that move the electrons.
In short. A 3-step mechanism. Typical reagents: Amine, ketone/aldehyde, NaBH₃CN. Conditions: MeOH, pH 6–7 (AcOH), 25 °C. Bonds formed: C–N; C–H; bonds broken: C=O; B–H. Stereochemistry: New stereocentre usually racemic (unless chiral amine/ketone). Rate and selectivity: Iminium formation is rate-limiting; iminium reduced much faster than ketone at this pH.
At a glance
Step 1: Amine + ketone ⇌ iminium (pH 6–7)
An amine and a ketone condense to form an iminium ion at a pH carefully controlled (mildly acidic) to favor iminium formation over unreacted starting material.
Step 2: Cyanoborohydride reduces the iminium
Sodium cyanoborohydride (NaBH₃CN), a much milder and more selective hydride source than NaBH₄, delivers hydride to the iminium carbon — its reduced reactivity means it reduces the iminium far faster than it reduces the starting ketone itself.
Step 3: Chemoselectivity: iminium ≫ ketone
This selectivity for iminium over ketone is exactly what allows a one-pot mixture of amine, ketone, and hydride source to give a clean secondary or tertiary amine, without needing to pre-form and isolate the imine separately.
Abbreviations and terms
- MeOH
- Methanol. Polar protic solvent (also a nucleophile in solvolysis).
- AcOH
- Acetic acid. Weak acid and polar protic solvent.
- NaBH4
- Sodium borohydride. Mild hydride donor; reduces aldehydes and ketones but not esters.
- NaBH3CN
- Sodium cyanoborohydride. Mild reductant stable at pH 3–6; reduces iminium ions selectively (reductive amination).
- H2
- Hydrogen gas. Reductant for catalytic hydrogenation.
How it compares with related reactions
| Borch reductive amination | Eschweiler-Clark reaction | Leuckart-Wallach reaction | |
|---|---|---|---|
| Reagents | Amine, ketone/aldehyde, NaBH₃CN | Amine, excess CH₂O (formalin), excess HCO₂H | Ketone, HCO₂NH₄ (or HCONH₂ / R₂NH + HCO₂H) |
| Conditions | MeOH, pH 6–7 (AcOH), 25 °C | Aqueous, 80–100 °C | Neat, 160–185 °C |
| Stereochemistry | New stereocentre usually racemic (unless chiral amine/ketone) | Chiral centres α to N are not racemised | Racemic product at a new stereocentre |
| Rate / selectivity | Iminium formation is rate-limiting; iminium reduced much faster than ketone at this pH | Hydride transfer to the iminium is rate-limiting; CO₂ loss makes it irreversible | High temperature needed; iminium formation reversible, hydride transfer irreversible |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the Borch reductive amination?
Amine, ketone/aldehyde, NaBH₃CN. Conditions: MeOH, pH 6–7 (AcOH), 25 °C.
Which bonds are formed and which are broken?
Formed: C–N; C–H. Broken: C=O; B–H.
What is the stereochemical outcome?
New stereocentre usually racemic (unless chiral amine/ketone)
What controls the rate or the selectivity?
Iminium formation is rate-limiting; iminium reduced much faster than ketone at this pH
Study guides that help with this reaction
- SN1, SN2, E1 or E2? How to decide which mechanism wins
- Nucleophiles, electrophiles and leaving groups: what makes a reaction go