photosyn
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Synthesis of N,N-Bis-(2-methoxyethyl)hydroxylamine, and ChatGPT
Another Polaroid-invented photographic developer I would like to test is N,N-Bis-(2-methoxyethyl)hydroxylamine. It's taught in various patents, one of
which is US3293034A - wherein the synthesis is achieved by oxidation of the secondary amine N,N-Bis-(2-methoxyethyl)amine with hydrogen peroxide. The
yield in that case is fairly low (20-ish % reported) and the secondary amine isn't that easy to obtain, and is fairly toxic.
So on a whim I got a friend to ask ChatGPT for a synthesis. It suggested reacting 2-Methoxyethanol with hydroxylamine, in the presence of sodium
hydroxide. All of these are easier to source. But I'm not sure if this is a complete fabrication by the ChatGPT algorithm or is a plausible mechanism.
There are a couple of 'tells' in the ChatGPT text that make me suspicious.
Firstly it suggests the reaction is carried out in an aprotic solvent (ethanol or acetonitrile) - but also suggests the hydroxylamine should be
prepared and used in aqueous solution. I find it hard to square one with the other - or is the small amount of water involved something to disregard?
Secondly it says that "The expected melting point for N,N-bis(2-methoxyethyl)hydroxylamine is approximately 70–75°C." As far as I'm aware, at room
temperature and pressure it should be a viscous liquid; the Polaroid patent suggests that it's separated from the other reaction products (of the
Polaroid method) by fractional distillation under vacuum.
EDIT: Thirdly, I see the CAS number given by the computer is wrong. it should be 5815-11-2.
So - is it worth giving this suggested procedure a try? Or are there any obvious reasons why it won't work?
For reference, here is the full procedure suggested by ChatGPT:
Synthesis and Work-up of N,N-Bis-(2-methoxyethyl)hydroxylamine
CAS Number: 16287-44-8
Chemical Formula: C6H15NO2
Synonyms: N,N-Bis(2-methoxyethyl)hydroxylamine, Bis(2-methoxyethyl)hydroxylamine
The synthesis of N,N-bis(2-methoxyethyl)hydroxylamine involves the reaction of hydroxylamine (NH₂OH) with 2-methoxyethanol (or ethylene glycol
monomethyl ether). The reaction typically occurs in the presence of a suitable base or activating agent that facilitates the alkylation of the
hydroxylamine with the 2-methoxyethyl group.
Here is a possible synthetic route, followed by a work-up procedure:
Synthesis of N,N-Bis(2-methoxyethyl)hydroxylamine
Materials:
• Hydroxylamine hydrochloride (NH₂OH·HCl) (or hydroxylamine solution)
• 2-Methoxyethanol (also known as ethylene glycol monomethyl ether, EGME)
• Sodium hydroxide (NaOH) (or sodium carbonate, Na₂CO₃)
• Solvent: Ethanol or acetonitrile (for the reaction)
• Acetone or ether (for washing)
• Ice bath (optional)
Procedure:
1. Preparation of Hydroxylamine Solution:
• If using hydroxylamine hydrochloride (NH₂OH·HCl), first prepare a solution by dissolving the hydroxylamine salt in a minimal amount of
water (about 10–15 mL). If using a hydroxylamine solution (for example, 30–35% concentration), this can be used directly in the reaction.
2. Activation of Hydroxylamine:
• Slowly add sodium hydroxide (NaOH) to the hydroxylamine solution to neutralize the hydrochloric acid and generate hydroxylamine free base.
Add enough NaOH to bring the pH to around 11-12.
• Stir the solution to ensure complete dissolution of the NaOH and activation of hydroxylamine.
3. Addition of 2-Methoxyethanol:
• 2-Methoxyethanol (ethylene glycol monomethyl ether) is then added dropwise to the activated hydroxylamine solution. Use 2.0-2.5 equivalents
of 2-methoxyethanol relative to hydroxylamine to ensure complete reaction.
• The reaction is typically conducted in an aprotic solvent such as ethanol or acetonitrile (both are effective solvents for this reaction).
4. Heating and Reaction:
• Heat the reaction mixture to reflux (around 70-80°C) for several 4-6 hours. The heating allows for efficient alkylation of the
hydroxylamine with the 2-methoxyethyl groups.
• Keep the reaction under reflux conditions to drive the reaction to completion and ensure the formation of
N,N-bis-(2-methoxyethyl)hydroxylamine.
5. Monitoring the Reaction:
• The reaction’s progress can be monitored by TLC (Thin Layer Chromatography) or NMR spectroscopy to confirm the formation of the desired
product. The disappearance of the starting hydroxylamine and the appearance of the bis-alkylated product will indicate completion.
Work-Up of N,N-Bis(2-methoxyethyl)hydroxylamine
After the reaction has gone to completion, the work-up procedure can begin to isolate and purify the product.
1. Cooling the Reaction Mixture:
• Once the reaction is complete, remove the heat and allow the reaction mixture to cool to room temperature.
2. Neutralization and Separation:
• Carefully neutralize any excess NaOH (or other base used) by adding dilute hydrochloric acid (HCl) dropwise until the pH of the mixture
reaches neutral (around pH 7). You can use a pH indicator paper to monitor this step.
• If necessary, extract the organic product into an appropriate solvent such as ethyl acetate or dichloromethane (DCM). Use a separatory
funnel for the extraction.
3. Washing and Drying:
• Wash the organic extract with water to remove any water-soluble impurities.
• Follow with a brine wash (saturated saline solution) to remove any remaining aqueous impurities.
• Dry the organic phase over an anhydrous drying agent like magnesium sulfate (MgSO₄) or sodium sulfate (Na₂SO₄) to remove any residual
water.
4. Solvent Removal:
• After drying, filter the drying agent and evaporate the solvent under reduced pressure using a rotary evaporator. This will give you a crude
product.
5. Purification:
• If the product is not sufficiently pure, purify it using column chromatography. A silica gel column can be used with an appropriate solvent
system, such as hexane/ethyl acetate or dichloromethane/methanol (gradient elution starting with non-polar solvents).
• Thin Layer Chromatography (TLC) should be used to check the purity during purification, and fractions containing the pure product can be
combined.
6. Final Product Isolation:
• After purification, collect the pure N,N-bis(2-methoxyethyl)hydroxylamine.
• Dry the final product under vacuum to remove any residual solvent.
Characterization:
1. Melting Point:
• The expected melting point for N,N-bis(2-methoxyethyl)hydroxylamine is approximately 70–75°C.
2. NMR Spectroscopy (Proton and Carbon):
• Proton NMR (1H NMR) will show distinct signals for the methoxy groups (-OCH3) and the CH2 groups in the 2-methoxyethyl side chains.
• The signal for the hydroxyl group (–OH) in the hydroxylamine moiety is expected to be exchangeable and could appear as a broad singlet
around 3-5 ppm.
• Carbon NMR (13C NMR) will show signals for the carbon atoms attached to oxygen in the methoxyethyl groups, as well as the naphthyl (–C-NH)
carbon.
3. Infrared (IR) Spectroscopy:
• The IR spectrum should show a broad O-H stretch around 3300 cm⁻¹ for the hydroxyl group. Also, there should be C–O stretches from the
ether groups (~1100–1150 cm⁻¹).
4. Mass Spectrometry (MS):
• The molecular ion peak should correspond to the molecular weight of the product (approximately 149.19 g/mol).
Safety Notes:
• Hydroxylamine hydrochloride and the product N,N-bis(2-methoxyethyl)hydroxylamine should be handled with caution, as hydroxylamine is toxic
and can be a potential explosive compound under certain conditions.
• Wear appropriate protective gloves, goggles, and lab coat when handling chemicals.
• Always work in a fume hood when handling volatile organic solvents like 2-methoxyethanol and acetonitrile.
• Dispose of all waste material according to local hazardous waste disposal regulations.
[Edited on 10-12-2024 by photosyn]
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DraconicAcid
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Mood: Semi-victorious.
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Funny. I asked ChatGTP how to make clam chowder, and it gave me the exact same procedure.
But seriously- has anyone heard of an alcohol acting as an alkylating agent towards and amine?
[Edited on 10-12-2024 by DraconicAcid]
Please remember: "Filtrate" is not a verb.
Write up your lab reports the way your instructor wants them, not the way your ex-instructor wants them.
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bnull
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It looks like the procedure for "bullshitium" that ChatGPT used to give me every once in a while.
My prompt,
| Quote: | | Hello. I want to synthesise N,N-bis-(2-methoxyethyl)hydroxylamine by reacting 2-methoxyethanol with hydroxylamine, in the presence of sodium
hydroxide. Could you help me please? |
resulted in a procedure very similar to yours, except it was to be
performed at 0-5 °C. After I played Thomas a few times ("are you sure this is going to work?"), the ever-apologizing ChatGPT said: | Quote: | | Given your valid concerns, I’d like to revisit and refine the procedure to ensure feasibility and accuracy. The method I initially described assumes
2-methoxyethanol can directly alkylate hydroxylamine, which is indeed unlikely in aqueous or neutral conditions due to its poor reactivity as an
alkylating agent. Upon reflection, this reaction requires more precise handling to ensure success. |
Then it
suggested me to | Quote: | | Convert 2-methoxyethanol to a more reactive derivative, such as 2-methoxyethyl tosylate or 2-methoxyethyl mesylate |
and use aprotic solvents. Why this works? It said | Quote: | | Tosylates/Mesylates are excellent leaving groups, making alkylation more favorable. The use of aprotic solvents avoids competitive hydrolysis or side
reactions. Hydroxylamine in its free or deprotonated form acts as a good nucleophile for alkylation. |
Boiling point was around 110-115 °C at reduced pressure. No melting point.
Given its tendency to hallucinations when the data is insufficient, I'd be surprised if the procedure ever resulted in something other than
frustration. As I said before, it is pretty good for translations and quite unhinged for something that demands creativity and not only textbook
quotations. It can tell some really good jokes occasionally.
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photosyn
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Ok. So, let’s scratch the clam chowder recipe.
How about this one?
https://www.lookchem.com/FreePDFArticle/15552-75-7.htm
“ N,N-Disubstituted hydroxylamines were prepared directly from secondary amines by a reliable method using an oxidizing task-specific ionic liquid,
choline peroxydisulfate.”
Very straightforward, and yields up near 100%. Too good to be true?
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bnull
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| Quote: | | Very straightforward, and yields up near 100%. Too good to be true? |
It looks good to me. I wonder if it will oxidise only the amino group and leave the ether alone. Edit: The oxidation of ether will be probably too
slow to lower the yield. But you still need the secondary amine.
In the patent where they perform the oxidation with hydrogen peroxide, was there any mention of what were the side products? I suspect that they come
from the cleavage of the ether, perhaps with an ether peroxide as intermediate. It would explain the low yield (in such case we can even treat
N,N-Bis-(2-methoxyethyl)hydroxylamine as a de facto side product).
[Edited on 11-12-2024 by bnull]
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photosyn
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There’s nothing in the patents about side products. They date from the 1960s so it may not have been that easy to investigate at that time. The
paper using ChPS says the problem with direct oxidation is the production of nitrones.
I have ordered some choline bitartrate and potassium chloride (to produce choline chloride) and I have some ammonium persulphate that may be used to
make the ChPS. I will order some of the amine, although it’s not cheap.
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