Sciencemadness Discussion Board

THF oxygen sensitivity extent? / Methylation of primary Amine

SunriseSunset - 26-12-2015 at 22:20

I'm wanting to perform the reaction that methylates a primary amine. One of the best yielding methods I've been able to find so far involves a very common 2-step method a lot of you might already know about. My only concern really is I'm terrified of forming explosive peroxides with the solvent of choice here, which is THF. I'm pretty sure ether could be substituted, but it still poses the same problem.

I'm wondering if anyone has had any experience with performing this rxn under an inert atmosphere, or a partially inert atmosphere, that might have any pointers for me because I am very concerned about the danger of explosions especially peroxide. It would not be pretty to blow up any amount of THF inside a flask let alone roughly ~200ml of it. Thanks

The general outline goes,

A summarized first step: involves reflux for 16 h a solution of primary amine as the free base in ethyl formate. Removal of the volatiles yields an amide (n-formyl)

The Second step: A solution of the (previously mentioned) amide in anhydrous THF is added dropwise to a well stirred and refluxing solution of LAH in anhydrous THF under an inert atmosphere. The reaction mixture was held at reflux for 4 days. After being brought to room temperature, the excess hydride was destroyed with 4.7ml H2O in a nequal vol of THF etc...

Anybody have a better way to methylate primary amines? or know if a safer solvent that could be used instead of THF or ether? It would have to still dissolve the LAH. I've looked into DCM but I suspect it would react different.

One of the other methods I've looked at is the Zinc Chloride + Peraformaldehyde + NaBH4 in DCM. But it doesn't seem to point out that it would work well with methylating a primary amine, unless I missed something. I may have...

[Edited on 27-12-2015 by SunriseSunset]

byko3y - 27-12-2015 at 15:03

http://www.orgsyn.org/demo.aspx?prep=CV5P0976 - the only danger I see, except a regular LAH hazard (by hydrolysis with water).

SunriseSunset - 27-12-2015 at 17:11

thanks byko3y, this is very informative. I appreciate this

AvBaeyer - 27-12-2015 at 19:22

SunrsieSunset,

LAH reduction of formamides is one of the very best ways to prepare a monomethyl amine.

You really do not have to worry about peroxides using the chemistry you described. ANy peroxides initially present in the THF will be destroyed by the LAH. Running the reduction under inert atmosphere will prevent any further peroxide formation. If you work up the LAH reaction as soon as you can (ie, do not let the THF solution set around exposed to air) you will be fine.

AvB

SunriseSunset - 27-12-2015 at 23:38

AvB, Thanks. I'm going to try to find a good way to dry the THF safely and efficiently, while somehow making sure it doesn't contain too much oxygen....

Here's a quote of mine from another thread which explains the setup.
Quote:

24/40 250ml 3 neck RBF (half full) with a miniature pressure equalized addition funnel and tiny condenser.

I imagine using two of the Bloxygen Finish Preserver canisters. Prior to the reaction, put one attached to the top of the reflux condenser, and have the 2nd attached to the top of the addition funnel, then pushing out the air out through the 3rd neck, and putting a stopper on it the moment I stop spraying. Would have to have someone give me a hand or two obviously to do this. Then put a balloon on the top of the reflux condenser. and stoppering off the lid of the addition funnel. The reflux is a 96 hour one using anhydrous THF and LAH

.I'd probably use electrical tape to attempt keeping all possible openings more air-tight including the balloon to prevent the argon escape over the course of that time span.

Do you think this would work out?


JJay suggested the following:
Quote:

I'd use a U-tube filled with sulfuric acid instead of a balloon, with gas inlet adapters on top of the addition funnel (with a hose leading to the argon source) and reflux condenser (with a hose leading to the U-tube). You'll want to make sure the apparatus is completely purged... that will require running several volumes of argon through it.


I get that this reaction is safe to do when you use all of the necessary equipment properly and don't screw anything up. Does anyone have any personal experience with LAH reduction in THF? I'd probably feel safer if I knew that some of you have tried it, so I'm not the first to find out how bad a mistake could be. It mostly bothers me that the reflux (has to be?) 4 days long. That seems like plenty of time for something to either collect moisture or loose some inert gas over the time span.

[Edited on 28-12-2015 by SunriseSunset]

solo - 27-12-2015 at 23:49

Reference Information


Reductive methylation of primary and secondary amines and
amino acids by aqueous formaldehyde and zinc
Renato A. da Silva,a Ida´lia H. S. Estevam
Tetrahedron Letters
2007,48, 7680–7682



Abstract
Amines can be methylated when treated with formaldehyde and zinc in aqueous medium. Selective mono- or dimethylation
can be achieved by proper choice of pH, stoichiometry and reaction time. This method can also be applied for amino acids.

Attachment: Reductive methylation of primary and secondary amines and amino acids by aqueous formaldehyde and zinc.pdf (98kB)
This file has been downloaded 367 times

SunriseSunset - 28-12-2015 at 00:37

solo, I don't think that reference really says anything about methylating primary amines. it's about methylating either secondary amines or amino acids.

Scheme 1.
scheme1.jpg - 10kB

From what I understand, R is an abbreviation for a hydrocarbon chain, not a single Hydrogen.

In the (entries of 19, 21, 23 and 25), they're all amino acids.

If I'm overlooking something, please let me know. But I feel like in my case, I should be looking for a scheme that looks more like this:
otherscheme.jpg - 8kB

Please correct me if I'm wrong though.

[Edited on 28-12-2015 by SunriseSunset]

solo - 28-12-2015 at 08:00

.....you might want to review,

Eschweiler–Clarke reaction

https://en.wikipedia.org/wiki/Eschweiler%E2%80%93Clarke_reac...


...here is another method,

The Chemistry of A/-Substituted Benzotriazoles. Part 4.' A Novel and Versatile Method for the Mono-A/-alkylation of Aromatic and Heteroaromatic Amines
Alan R. Katritzky,' Stanislaw Rachwal
J. CHEM. SOC. PERKIN TRANS. I
1987, page 805


Attachment: php8EZBwt (603kB)
This file has been downloaded 479 times

SunriseSunset - 29-12-2015 at 00:14

Ah... you were right, it does work with primary amines. Alright. Thanks again

AvBaeyer - 29-12-2015 at 19:56

SunriseSunset,

Over my career I ran many LAH reductions in all types of ethereal solvents. The biggest problem was getting the LAH into the reaction flask without having its dust get everywhere. Solvents were dried by distillation from CaH with final drying with a bit of excess LAH in the reaction. Typically a static inert atmosphere (N2 or Ar if we had it) was maintained. Reactions in ether reflux were never left overnight or unattended. Long term reactions in THF were run in a thermostated bath set just under the bp of THF. Work ups were usually done using the method described in Fieser and Fieser, Reagents for Organic Synthesis, Vol 1 in the LAH entry. Alternatively, the reactions can be quenched by careful addition of wet sodium sulfate.

After looking again at the procedure you outlined in your first post, I cannot understand why an LAH reduction of a formamide takes 4 days. These are generally fairly fast reactions-hours not days. What is the amine that you are trying to methylate? Is the formamide poorly soluble in THF?

AvB

SunriseSunset - 30-12-2015 at 01:11

Yeah, I'm probably going to choose a different way. I don't have a hot plate that would maintain a temperature overnight, without anyone to help out, let alone 3 nights. I've been looking thinking about this one reference that uses dichloromethane as a solvent. Zinc Chloride + paraformaldehyde and NaBH4 as a reducing agent. It seems to take way less time and might be possible at room temperature.
Quote:

A mixture of benzylamine (0.54g, 5 mmol), zinc chloride (2.7g, 20 mmol) and paraformaldehyde (0.6 g, 20 mmol) in dichloromethane (25 mL) was stirred at room temperature for 1 h at room temperature under dry atmosphere. Sodium borohydride (0.76 g, 20 mmol) was then added and the resulting mixture was stirred for 1h. The reaction mixture was then quenched by addition of aqueous ammonia (40 mL, 2N), stirred for 10 min. and the organic layer was separated. The aqueous part was extracted with dichloromethane (25 mLx1) and the combined organic extracts were concentrated in vacuo after drying over anhydrous Na2CO3. The crude product was purified by flash chromatography over neutral alumina using hexane: diethyl ether (3:1) as the eluent to yield 0.48g (70%) of pure N,N-dimethylbenzylamine as a colourless oil; bp 181-183°C/760mmHg (Lit.7f 185°C/760mmHg).



That's a lot of very useful information, AveBaeyer. The material is recrystallized Oleamine [90015-00-2]. It's about a week old now and was synthesized from Oleamide. I believe it is soluble in rt. THF, if not partially.

AvBaeyer - 30-12-2015 at 19:08

SunriseSunset,

1. How would you control the reaction in CH2Cl2 that you referenced above to give only the monomethylamine? Highly unlikely that you could do that.

2. If you got oleamine (C18H37N) from oleamide (C18H35NO), you must have done some sort of reduction, no? How was that accomplished? Are you sure you have everything straight?

3. An old method for amine monoalkylation is to form the imine with benzaldehyde. The imine is then reacted with methyl iodide and the resulting salt hydrolyzed followed by appropriate work up. No reduction required.


AvB

JJay - 31-12-2015 at 00:35

Quote: Originally posted by AvBaeyer  
SunriseSunset,

Over my career I ran many LAH reductions in all types of ethereal solvents. The biggest problem was getting the LAH into the reaction flask without having its dust get everywhere. Solvents were dried by distillation from CaH with final drying with a bit of excess LAH in the reaction. Typically a static inert atmosphere (N2 or Ar if we had it) was maintained. Reactions in ether reflux were never left overnight or unattended. Long term reactions in THF were run in a thermostated bath set just under the bp of THF. Work ups were usually done using the method described in Fieser and Fieser, Reagents for Organic Synthesis, Vol 1 in the LAH entry. Alternatively, the reactions can be quenched by careful addition of wet sodium sulfate.

After looking again at the procedure you outlined in your first post, I cannot understand why an LAH reduction of a formamide takes 4 days. These are generally fairly fast reactions-hours not days. What is the amine that you are trying to methylate? Is the formamide poorly soluble in THF?

AvB


I am curious - what sort of trap did you use to keep air and moisture out of the reductions?

SunriseSunset - 31-12-2015 at 00:36

1) Supposedly I'd would imagine, by not using an access of paraformaldehyde. But Somehow... I still suspect nonetheless there would end up being 5-10% di-methylenation as a side product.

2) Hofmann degradation / Rearrangement from the amide. It worked in just water. I have a recent topic that has the method I used.

3) I looked into that but I think the reason I chose not to try it is because of methyl iodide. I know how to make ethyl and methyl iodide, but it's pretty toxic.

AvBaeyer - 31-12-2015 at 20:28

JJay,

We used oil bubblers, Firestone valves or just good quality balloons attached to a hypodermic needle inserted through a septum. By "static" I mean that we just turned the gas flow off once the desired reaction temperature had been achieved. Never had any problems.

AvB

AvBaeyer - 31-12-2015 at 20:35

SunriseSunset,

If you did a Hofmann rearrangement on "oleamide" (C18H35NO) you do not have "oleamine" (C18H37N). You have an amine with one less carbon atom: C17H35N. Am I missing something here?

AvB

SunriseSunset - 1-1-2016 at 20:58

No, you're right. I'm sorry I was in a game when I sent that and didn't have much time to reply back. Been busy the past two nights, I'll reply to as much as possible ASAP

JJay - 2-1-2016 at 01:13

Quote: Originally posted by AvBaeyer  
JJay,

We used oil bubblers, Firestone valves or just good quality balloons attached to a hypodermic needle inserted through a septum. By "static" I mean that we just turned the gas flow off once the desired reaction temperature had been achieved. Never had any problems.

AvB


Oil bubblers.... That sounds like a good idea. Sulfuric acid is probably overkill, but I think it would work.... Mineral oil is easier to work with.