SunriseSunset
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THF oxygen sensitivity extent? / Methylation of primary Amine
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]
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byko3y
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http://www.orgsyn.org/demo.aspx?prep=CV5P0976 - the only danger I see, except a regular LAH hazard (by hydrolysis with water).
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SunriseSunset
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thanks byko3y, this is very informative. I appreciate this
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AvBaeyer
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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
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SunriseSunset
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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]
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solo
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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 315 times
It's better to die on your feet, than live on your knees....Emiliano Zapata.
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SunriseSunset
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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.
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:
Please correct me if I'm wrong though.
[Edited on 28-12-2015 by SunriseSunset]
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solo
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.....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 428 times
It's better to die on your feet, than live on your knees....Emiliano Zapata.
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SunriseSunset
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Ah... you were right, it does work with primary amines. Alright. Thanks again
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AvBaeyer
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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
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SunriseSunset
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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).
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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.
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AvBaeyer
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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
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JJay
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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?
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SunriseSunset
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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.
Why do chemists call helium, curium and barium the medical elements?
because if you cant helium or curium, you barium! - Heimerdinger
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AvBaeyer
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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
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AvBaeyer
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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
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SunriseSunset
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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
Why do chemists call helium, curium and barium the medical elements?
because if you cant helium or curium, you barium! - Heimerdinger
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JJay
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| 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.
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