Amines
Reductive Amination
Last updated: September 21st, 2022 |
Making Substituted Amines Through Reductive Amination
- Direct alkylation of amines with alkyl halides is a difficult reaction to control.
- One alternative that works extremely well is to form the imine of an amine with an appropriate aldehyde or ketone, and then to reduce the imine to an amine. This is called reductive amination and avoids the problem of multiple alkylations.
- One common reducing agent for this purposes is sodium cyanoborohydride (NaBH3CN) which can selectively reduce imines in the presence of aldehydes. Many other reducing agents (NaBH4, NaBH(OAc)3, etc.) can be used as well.
- It’s possible to start with a primary amine and do two successive reductive aminations, obtaining a tertiary amine.
- Reductive amination does not work for forming bonds from nitrogen to aromatic rings.
Table of Contents
- How Do We Make This Amine?
- Reductive Amination To The Rescue
- Applying Reductive Amination
- Ketones Also Work
- Sequential Reductive Aminations
- Intramolecular Reductive Aminations
- Working Backwards: Planning A Reductive Amination
- Notes
- Test Yourself!
- (Advanced) References and Further Reading
1. How Do We Make This Amine, If Direct Alkylation Doesn’t Work?
Say you have a primary amine such as benzylamine and would like to make N-methylbenzylamine. How do you do it?
Direct treatment of benzylamine with an alkylating agent (e.g. methyl iodide, CH3I ) will result in significant formation of the undesired tertiary amine (i.e. di-alkylation).
Yes, you could try and separate out the secondary amine that’s formed from the tertiary amine, but we’re not going to settle for 10-30% yields here. Separating mixtures is fine on paper, but (trust me on this) it can be a real a pain in practice. Is there another way to do it?
2. Reductive Amination To The Rescue
Enter reductive amination!
While alkylation can happen multiple times on an amine, imines only form once on a given amine. Once the imine is formed, the C=N bond can be reduced, giving us a new alkyl group attached to nitrogen.
This is a much more controlled manner of forming nitrogen-carbon bonds.
We covered imine formation previously (See article: Imines – Properties, Reactions, Mechanisms). To refresh yourself on the mechanism, hover here and an image will pop up (link).
After the imine is formed, it must be reduced to the amine. It’s possible to use the familiar reducing agent sodium borohydride (NaBH4) for this process. You may recall that NaBH4 is used for the reduction of aldehydes and ketones.
There are two other commonly used reductants for reductive amination: sodium cyanoborohydride (NaBH3CN) and sodium tri-acetoxyborohydride (NaBH(OAc)3 ). For our purposes, they can be considered to be the same. In practice, NaBH3CN is a little bit better than NaBH4.
[For a discussion as to why NaBH3CN tends to be a better choice than NaBH4, see Note 2. In the schemes below, we’ll use NaBH3CN, but NaBH4 and NaBH(OAc)3 can be considered to work just as well. ]
3. Applying Reductive Amination
Reductive amination is extremely versatile and can be used to install a large variety of different alkyl groups on an amine. The nice part is that the groups just go on once.
The table below shows examples of how methyl, ethyl, propyl, butyl, and benzyl groups can be installed on an amine, by employing an appropriate aldehyde . (Note that reductive amination doesn’t work for installing a phenyl group. Why not? Note 1.]
4. Ketones Also Work
What about ketones? They work too! Employing a ketone will result in a branched alkyl substituent on the amine. For example, using acetone in the following reductive amination gives an isopropyl group.
5. Sequential Reductive Aminations
Another useful feature of reductive amination reactions is that two (or three if one starts with ammonia) reductive aminations can be employed in sequence. For example, look at the synthesis of the tertiary amine below.
Importantly, the sequence of reactions isn’t crucial here. We could have done the first reductive amination with benzaldehyde first, and acetone second, and still obtained the same product.
6. Intramolecular Reductive Aminations
Finally, there’s the intramolecular case, which always seems to give students a headache. If a molecule contains both an amine and a carbonyl, then it can cyclize to give a cyclic amine.
When drawing out the product of ring formation, I strongly advise counting and numbering your carbons. I’ve seen so many students make mistakes when redrawing that it’s well worth the time to double check that you haven’t left anything out.
7. Working Backwards: Planning A Reductive Amination
It might take some time to appreciate, but reductive amination is an extremely powerful way of making amines.
It’s very helpful to be able to think backwards from an amine product to what the starting materials look like.
Look at the following tertiary amine. It is connected to three carbons, which we can label a, b, and c. Each of these N–C bonds could potentially be formed through reductive amination, since they have C-H bonds.
That means that there are three possible ways of making this amine through reductive amination, all of them acceptable!
In short, reductive amination is a very powerful and useful protocol for the formation of amines.
Notes
Note 1. What about installing a phenyl group (see above)? For formation of bonds between nitrogen and sp2-hybridized carbons (e.g. alkenes or phenyl groups) or between nitrogen and sp-hybridized carbons (e.g. alkynes), reductive amination won’t work.
Think about it. Note that the carbon attached to the nitrogen doesn’t have a C-H bond. Therefore we can’t work backwards to the reduction of a C=N bond with a hydride source.
One must resort to alternative techniques. Buchwald-Hartwig cross coupling is one of them.
Note 2. Why sodium cyanoborohydride?
NaBH4 can be a perfectly acceptable reducing agent for reductive amination.
There’s one slight problem with this reagent, however. What if the NaBH4 ends up reducing the aldehyde or ketone before it has a chance to react with the imine? That would lead to lower yields. [In practice, this can be reduced somewhat by giving the imine sufficient time to form, and then adding in NaBH4.]
An even better approach involves the use of the slightly weaker reducing agent sodium cyanoborohydride (NaBH3CN).
Why use a weaker reducing agent?
Recall that formation of an imine is best done under mildly acidic conditions (pH 4 or 5). [At mildly acidic pH, the carbonyl oxygen is protonated, speeding up the rate of addition to the carbonyl carbon; if the solution is too acidic, however, the amine nucleophile will be converted into its (non-nucleophilic) conjugate acid, an ammonium salt, and no reaction will occur.]
Once the imine forms at pH 4-5, some of it will be converted into its conjugate acid, an iminium salt.
The advantage of using NaBH3CN is that it isn’t a strong enough reducing agent to reduce aldehydes or ketones, but it is a strong enough nucleophile to reduce iminium ions. Therefore more of the starting aldehyde/ketone will be converted into the amine. [This is particularly important when working with very precious samples of aldehyde].
Test Yourself!
Click to Flip
Click to Flip
Click to Flip
Click to Flip
Click to Flip
Click to Flip
(Advanced) References and Further Reading
- Cyanohydridoborate anion as a selective reducing agent
Richard F. Borch, Mark D. Bernstein, and H. Dupont Durst
Journal of the American Chemical Society 1971, 93 (12), 2897-2904
DOI: 1021/ja00741a013
The first report on the use of NaBH3CN as a reducing agent for reductive amination. - An improved method for reductive alkylation of amines using titanium(IV) isopropoxide and sodium cyanoborohydride
Ronald J. Mattson, Kahnie M. Pham, David J. Leuck, and Kenneth A. Cowen
The Journal of Organic Chemistry 1990, 55 (8), 2552-2554
DOI:1021/jo00295a060
Ti(OiPr)4 can be used as a Lewis acid to activate the ketone/aldehyde towards addition by the amine and the resulting imine can then be reduced in situ by NaBH3CN, which is a reductive amination. - Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride. Studies on Direct and Indirect Reductive Amination Procedures
Ahmed F. Abdel-Magid, Kenneth G. Carson, Bruce D. Harris, Cynthia A. Maryanoff, and Rekha D. Shah
The Journal of Organic Chemistry 1996, 61 (11), 3849-3862
DOI: 1021/jo960057x
NaBH(OAc)3 can also be used as a reducing agent in reductive amination procedures as an alternative to NaBH3CN, if one is concerned about cyanide ion concentrations in the product or waste stream. - Development of a Scaleable Route for the Production of cis-N-Benzyl-3-methylamino-4-methylpiperidine
David H. Brown Ripin, Stefan Abele, Weiling Cai, Todd Blumenkopf, Jeffrey M. Casavant, Jonathan L. Doty, Mark Flanagan, Christian Koecher, Klaus W. Laue, Keith McCarthy, Cliff Meltz, Mike Munchhoff, Kees Pouwer, Bharat Shah, Jianmin Sun, John Teixeira, Ton Vries, David A. Whipple, and Glenn Wilcox
Organic Process Research & Development 2003, 7 (1), 115-120
DOI:1021/op025599x
OPRD is a great source of reliable procedures, since reactions being scaled up need to be robust, high-yielding, not require exotic solvents or superstoichiometric amounts of overly expensive reagents, and have simple purification procedures (avoiding chromatography where possible). - One-Pot Reductive Amination of Conjugated Aldehydes and Ketones with Silica Gel and Zinc Borohydride
Brindaban C. Ranu, Adinath Majee, and Arunkanti Sarkar
The Journal of Organic Chemistry 1998, 63 (2), 370-373
DOI: 1021/jo971117h
Zn(BH4)2 can also be used as a reducing agent in reductive amination. - Single Stereodifferentiation Associated with Carbon Atom Insertion during the Oxonium Ion-Initiated Pinacol Rearrangement of Dihydrofuranyl and Dihydropyranyl Carbinols
Leo A. Paquette, James C. Lanter, and Jeffrey N. Johnston
The Journal of Organic Chemistry 1997 62 (6), 1702-1712
DOI: 1021/jo962019j
Prof. Leo Paquette demonstrates that stereodifferentiation is possible in pinacol-type rearrangements. - α-PHENYLETHYLAMINE
John C. Robinson, Jr. and H. R. Snyder
Synth. 1943, 23, 68
DOI: 10.15227/orgsyn.023.0068
A reductive amination using NH3 as the amine. - The 25th Anniversary of the Buchwald–Hartwig Amination: Development, Applications, and Outlook
Paola A. Forero-Cortés and Alexander M. Haydl
Organic Process Research & Development 2019, 23 (8), 1478-1483
DOI: 10.1021/acs.oprd.9b00161
A short review on the Buchwald-Hartwig amination, covering its development, applications, and future prospects. OPRD (along with Organic Syntheses) is a great place to look for reliable and robust reactions, as that is what is most valued in process chemistry, when developing reactions on a large scale.
Great post! Typo: reductive maintain -> reductive amination
Thank you. Damn autocorrect.
We are interested in reductive amination of secondary fatty amines to dialkylmethylamines with formaldehyde under hydrogen partial pressure, rather than solid reducing agents.
Also of interest is direct conversion of primary fatty nitriles to dimethylalkylamines with DMA. This seems to be less well-described in the available literature.
At industrial scale, conversions and yields above 95% are important.
Enjoyed your post!
The condensed and thorough explanation on reductive aminations. Thanks!
Glad it was useful to you Josh, cheers!
I have a question.
How can be explained difffent reactivity of imine (iminium ion) between (protonated) carbonyl with NaBH3CN?
The electrophile is the carbon, correct? And the more partial positive charge there is on that carbon, the better an electrophile it is, correct? Now draw the resonance form for the imine where you move the pair of electrons in the C-N pi bond to the nitrogen. Next, draw the conjugate acid (iminium) and do the same. Which resonance form do you think will be more stable between the two? Therein lies your answer.
Bottom line, protonation of the nitrogen results in a greater contribution from the resonance form where there is a positive charge on the carbon, and it’s more electrophilic.
In the table under “Applying Reductive Amination”, the benzaldehyde shown in “aldehyde to use” has an extra CH2.
Thank you. Will fix.
Can LAH reduce imines to amines?
I learnt that usually, excess amine must be used while carrying out reductive amination. Is this to increase the yield of the imine?
If yes, then would using excess of aldehyde/ketone also work?
Hey Britney – you want to use excess to make sure that the amine has a chance to react with all of the aldehyde/ketone first, before adding your hydride source. Once the hydride source is added any aldehyde/ketone that remains will be reduced to an alcohol rendering it useless for the process.
Doesn’t the section “Sequential Reductive Aminations” contradicts with the statement that “While alkylation can happen multiple times on an amine, imines only form once on a given amine”?
Ah. Yes, I see the source of your question. Maybe I should have written, “in the same reaction vessel”.
During the course of an alkylation reaction, an amine can be alkylated, and then that product can be alkylated again. So when you go to try an isolate the product, you may find that multiple alkylations have occurred.
In reductive amination, imines will only form once in the same reaction vessel, and once they’re reduced, that’s the end of the reaction. Only one new C-N bond will have formed.
Now, once you’ve isolated and purified the product, if it’s a primary or secondary amine there’s nothing stopping you from doing a *second* reductive amination with a different aldehyde.
Does that make sense?
Great Post.
It would be awsome to have a few references as well. I am especially interested in the NaBH3CN part.
Thank you
I would look it up in the Encyclopedia of Reagents for Organic Synthesis. The original reference I see is Borch. R, F. et. al. JACS, 1971, 93, 2897. https://pubs.acs.org/doi/10.1021/ja00741a013
Hi, nice post. I wanted to comment on a common misconception you have here though. From above:
“Recall that formation of an imine is best done under mildly acidic conditions (pH 4 or 5). [At mildly acidic pH, the carbonyl oxygen is protonated, speeding up the rate of addition to the carbonyl carbon; if the solution is too acidic, however, the amine nucleophile will be converted into its (non-nucleophilic) conjugate acid, an ammonium salt, and no reaction will occur.]”
The pka of a protonated amine is 9-12, whereas the pka for a protonated carbonyl is -6 or thereabout. Hence in a mildly acidic solution the carbonyl won’t be appreciably protonated at all in comparison to the amine. The first step of this mechanism is amine addition to the carbonyl. The mild acidity serves to rapidly protonate the oxygen after addition of the amine and facilitate proton transfer for the removal of water. At least that’s how I understand it. It’s been awhile since phys org. Most texts get this wrong as well.
I love your cite, awesome resource for teachers and students!
Cheers,
EBB
Thanks for this, I’m adding it to my correction queue! Although I may be mistaken, I see pKa’s of protonated carbonyls at about -2 or so. Still, that’s about 15 orders of magnitude to traverse, so you’re correct on this point.
I think this makes more sense as well, the acid “serves to rapidly protonate the oxygen after addition..” instead of protonating the carbonyl ahead of time. But, why does the mechanism appear this way in so many texts? Surely, the authors know the drastic pKa differences of a carbonyl oxygen and an amine (which is a base!). I wonder if in certain solvents the carbonyl actually is preferentially protonated? I use dichloromethane as the solvent for this reaction and it works twice as fast with a little acetic acid present. In any case, reaction mechanisms tend to be just good guesses with lots of contradictions if examined too closely.
Thank you. I”m making a note to research this step and correct.
thank you for making organic chemistry accessible and understandable, your work is impressive.
Just a question: in presence of alpha-H in the carbonyl partner, does the reaction passes through the enamine intermediate or is it favorite the tautomerization to the iminium ion always? In the first case, is still NaBH3CN or similar the best reductive agent?
It could form the enamine, but in the presence of acid, there will be equilibrium between the enamine and the iminium. So long as the iminium is formed reduction can occur.