Alkylation of Amines (Sucks!)

Why Alkylation Of Amines (aka “The Williamson Ether Synthesis, But For Amines” ) Usually Doesn’t Pan Out

• Making a more-substituted amine from a less-substituted amine through treatment with an alkyl halide often fails, because the product amine is more nucleophilic than the starting amine.
• In some cases this is desired, as in the formation of alkylammonium salts with an excess of alkyl halide (e.g. CH₃I)
• In other cases, the best approach to making a more substituted amine from a less substituted amine is generally reductive amination.

Table of Contents

1. “The Williamson Ether Synthesis, But For Amines” : Why Does This Reaction Suck?
2. The Runaway Train of Amine Alkylation, Step 1: S_N2
3. Step 2: Alkylation Is Followed By An Acid-Base Reaction…
4. …Liberating An Amine That Is A Better Nucleophile: Step 3: A Second SN2
5. Step 4: Another Acid-Base Reaction Makes An Even  Better Nucleophile
6. The Runaway Train Continues
7. The Reaction Tends To Stop  At Tertiary Amines. Usually. 
8. Summary: Alkylation Of Amines  Generally Sucks. Here Are  Some Workarounds
9. Notes, plus “Exhaustive Methylation”
10. (Advanced) References and Further Reading

1. Why Does This Reaction Suck?

Trends in the basicity of amines provide a classic example of why chemistry is so interesting; it’s deciphering the delicate trade-offs between various general factors in specific cases that gives chemists a buzz. The miraculous starts looking obvious.
– The Curious Wavefunction (Ash Jogalekar)

Today, let’s talk about how to make amines. It’s not as straightforward as you might think.

See if you can fill in the blank in the following skill-testing question:

 Let’s walk through the thought process. We need to form a C-N bond. The N of NH₃ has a lone pair and is a good nucleophile. So, much like the Williamson ether synthesis, maybe we can use an alkyl halide like ethyl bromide (CH₃CH₂Br) and boom! done.

It doesn’t quite turn out that way. In the words of the scientist who investigated this thoroughly:

“The interaction of ethyl bromide and ammonia… conduces largely to the formation of triethylamine”.

[ref:  Werner,  J. Chem. Soc. 1918, p. 899]

Formation of a primary amine through alkylation of ammonia turns out to be a pretty low-yielding reaction. (For reasons of economy, we generally want to use reactions that form one dominant product in high yield to avoid tedious separations: this doesn’t qualify.)

This is part of the fun* of learning organic chemistry. Just when you think you might have things figured out, along comes a curveball. 

Why does this reaction. for lack of a better word, suck?

2. The Runaway Train of Amine Alkylation, Step 1: S_N2

Let’s look at the first reaction that would happen the moment that a solution of ammonia is combined with ethyl bromide: nucleophilic substitution (via the S_N2 mechanism)

3. Step 2: Alkylation Is Followed By An Acid Base Reaction

So far so good. We’ve formed our C-N bond. Since the reaction is in excess ammonia, an acid-base reaction can then lead to the neutralization of at least some of the ammonium salt, yielding us our neutral primary amine.

So now we have the primary amine. We’re done, right?

Not so fast. See, relative to substitution reactions, acid-base reactions are fast, so this deprotonation event will occur before the first substitution reaction has consumed all of the remaining ethyl bromide.

That means that ethylamine will be present in the same flask with ethyl bromide.

So?

4. Step 3: The Acid-Base Reaction Liberates An Amine Nucleophile That Is Even Better Than The Starting Amine

Well, ethylamine is itself a good nucleophile. In fact, it’s an even better nucleophile than ammonia itself, because of the electron-donating alkyl group [Link: 5 factors that affect the basicity of amines]

How much better? If we use pK_aH as a proxy for nucleophilicity (reasonable,  since steric hindrance isn’t a factor here) we have a pK_aH of 10.7 for ethylamine versus 9.2 for NH₃. That’s about 10^1.5 = 30 times more nucleophilic.

The ethylamine created by the first S_N2 will start gobbling up the ethyl bromide…  instead of NH₃!

We’ve created a monster! 

via GIPHY

Even if we try to stack the deck with (say) a 15-fold excess of NH₃, the reaction of ethylamine will still be faster by a factor of (30/15) = 2. [That’s what Werner did, above; the yield of EtNH₂ was 34% under those conditions, versus 11% for just 1 equiv of NH₃.]

5. Step 4: Another Acid-Base Reaction Makes An Even Better Nucleophile

Now we have the diethylammonium product in the presence of excess base, which will lead to at least some formation of diethylamine.

You know what that means? Another nucleophile has been produced that will compete with NH₃ for the remaining ethyl bromide.

How does the nucleophilicity compare to ammonia and ethylamine?

The pK_aH of diethylamine is about 11.0, making it slightly more nucleophilic than ethylamine!

6. The Runaway Train Continues

Diethylamine, being a stronger nucleophile than both ammonia and ethylamine, will react faster with the remaining ethyl bromide than either of those two species.  This will form triethylammonium bromide, which can then be deprotonated (using any one of the amine bases in solution) to form neutral triethylamine.

Now we have three nucleophilic amine species all swimming around in solution at the same time, before all of our ethyl bromide has been consumed.

This soup containing multiple amine products is the kind of reaction that my friend Jeff would describe in his lab notebook as a “BFM”. (The “B” is for “big”, and the “M” is for “mess”….) 

7. The Reaction Tends To Stop At Tertiary Amines…

The “runaway train” usually stops at the tertiary amine stage. In this specific case, the pK_aH of triethylamine is 10.75, a little less than diethylamine. [Recall that pK_aH refers to basicity, not nucleophilicity: the basicity of NEt₃ is attenuated here due to the lowered solubility of the conjugate acid in water. [more here]. ]

The nucleophilicity of triethylamine is less than that of diethyl amine largely because the triethylamine nitrogen is tertiary, which will increase steric hindrance and slow down the reaction rate.

For this reason, formation of tertiary amines from secondary amines via alkylation is thus, for the most part, exempt from our broad “amine alkylation is crap” statement.

8. Summary: Alkylation of Amines Generally Sucks. Here Are Some Workarounds

Otherwise, workarounds must be used.  There are plenty. Azides are good nucleophiles for example, and they can be alkylated without incident and reduced to amines afterwards. The Gabriel Synthesis is another workaround. 

What about our skill-testing question from the top of the article?

Here’s a reaction that most organic chemists would consider to be the best general way to make amines: a reaction called reductive amination. 

Here’s a little sneak preview.

We’ll talk about how this reaction works in the next post , on reductive amination.

Notes

Note 1. Alkylation of ammonia mostly stopped at the tertiary amine stage.

Although tertiary amines tend to be less nucleophilic than secondary amines, they are still nucleophiles, and when treated with excess alkyl halide under forcing conditions they can be converted to quaternary ammonium salts.

The best example of this is with methyl iodide, in a reaction called exhaustive methylation. Recall that methyl halides are the fastest-reacting alkyl halides in S_N2 reactions due to their low steric hindrance.

Treatment of amines with a large excess of methyl iodide leads to their quaternary ammonium salts. As we’ll see in a future post, these quaternary ammonium salts can behave as excellent leaving groups in elimination reactions (and, rarely, substitution reactions) to give alkenes, particularly in the Hofmann elimination.

(Advanced) References and Further Reading

1. —The preparation of ethylamine and of diethylamine
   Emil Alphonse Werner
   J. Chem. Soc. Trans. 1918, 113, 899-902
   DOI: 10.1039/CT9181300899
   An early report on the synthesis of alkylamines by alkylation of ammonia with ethyl bromide, and the second paragraph begins with “This is a faulty procedure, since it conduces largely to the formation of the less useful triethylamine, with consequent loss in the yields of the primary and secondary bases”.
2. Cesium Effect:  High Chemoselectivity in Direct N-Alkylation of Amines
   Ralph Nicholas Salvatore, Advait S. Nagle, and Kyung Woon Jung
   The Journal of Organic Chemistry 2002, 67 (3), 674-683
   DOI: 1021/jo010643c
   The selective monoalkylation of amines is possible, provided you know how.
3. Efficient and selective N-alkylation of amines with alcohols catalysed by manganese pincer complexes
   Saravanakumar Elangovan, Jacob Neumann, Jean-Baptiste Sortais, Kathrin Junge, Christophe Darcel & Matthias Beller
   Nature Communications 2016, 7:12641
   DOI: 10.1038/ncomms12641
4. Selective Synthesis of Secondary and Tertiary Amines by Reductive N‐Alkylation of Nitriles and N‐Alkylation of Amines and Ammonium Formate Catalyzed by Ruthenium Complex
   Iryna D. Alshakova, Dr. Georgii I. Nikonov
   ChemCatChem 2019, 11 (21), 5370-5378
   DOI: 10.1002/cctc.201900561
   Both papers are on essentially the same reaction. The mechanism of these reactions shows that it is basically a ‘one-pot’ reductive amination. The alcohol is oxidized in situ and an excess of alcohol serves as a reductant.
5. Aqueous N-alkylation of amines using alkyl halides: direct generation of tertiary amines under microwave irradiation
   Yuhong Jua and Rajender S. Varma
   Green Chem., 2004, 6, 219-221
   DOI: 10.1039/B401620C
   This paper demonstrates that alkylation of secondary amines yields tertiary amines, obviously. But more importantly, quaternary ammonium salts are only formed with difficulty; this paper does not report any quaternary ammonium salt formation even after extended microwave heating of a secondary amine with excess alkyl halide.