[Enthalpy]

Dear all,

would you know a trick to guess whether one hydrazine is badly toxic?

Hydrazine, MMH, UDMH are being phased out from satellites (ton amounts) and launchers (hundreds of tons) for being bad carcinogens, toxic, volatile, flammable - yuk. But others have no bad reputation. Tetramethylhydrazine is only classified as flammable. Pimagedine (aminoguanidine) was tested as a drug.

The Osiris applet tries to guess the toxicity of compounds
www.organic-chemistry.org/prog/peo
but I don't understand its criteria, maybe subsequences of N-N-C substituted or not. Not perfect: the applet identifies only a "tumor medium risk fragment" in UDMH.

Methylated hydrazines were preferred for performance, but other hydrazines may be safer, more efficient than equivalent amines and hydrocarbons, and easy to mass-produce. The Osiris applet imagines that diazetidyl and gem-dicyclopropylhydrazine are not very toxic. Both give 7s more specific impulse than RG-1, and gem-dicyclopropylhydrazine isn't quite flammable.

A tentative synthesis of gem-dicyclopropylhydrazine is appended. Variants include CHBr₂Cl, CHCl₃. Recycling the halogens on site would reduce the risks and costs, producing at an ammonia plant would limit the transports.

Thank you!
Marc Schaefer, aka Enthalpy

[pgk]

1). Hydrazine is basic and therefore, irritant and caustic to eyes, skin, as well to respiratory and gastrointestinal tract. Substituted hydrazines are less basic and therefore less irritant.
2). Hydrazine has intercalating properties, meaning that it can penetrate between the DNA chains, as being a small molecule and destroys the "zip-fastener" structure of DNA by forming H-bonds with DNA-bases and consequently, hydrazine is a highly carcinogenic and mutagenic substance. Substituted hydrazines are weaker intercalating agents, depending on their substitution and molecular size and therefore, less carcinogenic and mutagenic.
PS: Indeed, “Osiris” is a very useful application.

[Enthalpy]

Thanks pgk!

"Less carcinogenic and mutagenic" sounds discouraging, when considering hundreds of tons...

I had hoped some would be harmless enough, after Osiris (only a soft) ranks them so and pimagedine was swallowed by volunteers who survived over the trial duration.

So it would be a mere matter or size, not of combination of N and C substituted or not, secondary or tertiary...? Osiris tries to make such subtle differences, but I didn't grasp its explanations.

Or rather, some hydrazines are nasty and the others still unknown?

[wildfyr]

Or rather, some hydrazines are nasty and the others still unknown?

I would hazard that this is the best analysis. Anything more than the most basic toxicoligcal info is only collected with exhaustive, time consuming, and highly expensive research. Think of how much work it takes to get a compound through the FDA. I currently am working "with" the EPA to get some of our chemicals approved through TSCA, and we are very nervous because doing tox testing is quite expensive. I think its really hard to give a blanket toxicity statement to any compounds aside from the most obvious (like, say, hydroperoxdies are probably all bad for you).

[pgk]

There is no need to be discouraged. Some of them are neither carcinogenic nor mutagenic, such as pimagedine (aminoguanidine) and [2-(dimethylamino)ethyl]hydrazine.
You can search for the MSDS (Material Safety Data Sheet) of various substituted hydrazines and see their toxicity data in sections in Section 2 and Section 11, as well as their environmental impact in Section 12 and see what it fits.
e.g. MSDS Pimagedine Hydrochloride (aminoguanidine HCl),
https://www.caymanchem.com/msdss/81530m.pdf
MSDS [2-(dimethylamino)ethyl]hydrazine
http://datasheets.scbt.com/sds/aghs/en/sc-340263.pdf

Hint 1: Toxicity/ carcinogenicity, mutagenicity subcategories.
Category 1: Mild/ Suspicious to be but not proven in animals and humans
Category 2: Medium/ Proven in animals but not in humans
Category 3: Severe/ Proven in animals and humans

Hint 2: Roughly, carcinogenicity/mutagenicity category 1 classification permits the commercialization for professional use only but not the use in consumer goods. However, there are exceptions depending on the content whether being < 10% or < 1%, in relation with the subcategory.

Hint 3: Some manufactures/suppliers (e.g. Aldrich) refer to SDS (Safety Data Sheet), regarding the Safety document.

PS: “Osiris” is a useful tool to pre-estimate the toxicity of a chemical substance but you cannot trust a software for the safety of hundreds of tons of that substance. Contrary, what is cited in MSDSs and SDSs, is double checked.

[pgk]

But attention, if the product is entirely new with unknown toxicological and environmental data, you have to “co-work” with the competent authorities, e.g. EPA, OSHA in USA, ECHA in EEC member countries, etc. and being in accordance with the REACH Legislation for the commercialization/stocking in Europe, quantities > 1 ton per year.

[Enthalpy]

**mod wildfyr ** I am sorry enthalpy, I accidentally edited your post instead of quoting it! You will have to repost your response.

[Enthalpy]

Never mind, I remember what it was about:

How is the cancer risk measured? Exposing to the compound a group of mice with abnormal tumour tendency? Or can it be done on culture tissues?

And if the test lasts for a few months (does it?), is it a decent indication of long-term effects in humans?

How expensive is such a test: 10³, 10⁴, 10⁵ €?

[wildfyr]

I think its in the ballpark of a hundred thousand euros.

[Corribus]

How is the cancer risk measured? Exposing to the compound a group of mice with abnormal tumour tendency? Or can it be done on culture tissues?

Ames test is among the first (in vitro) steps.

https://en.wikipedia.org/wiki/Ames_test

[Enthalpy]

Ouch.

Well, if a fuel is for sure ze very best magic thing, 10⁵€ is cheaper than the sale price for the first flight. But testing a dozen fuels would be the wrong way.

Nice that in vitro tests can provide a first filter step.

[Enthalpy]

Ahum. The intermediate dicyclopropylamine seems hard to obtain, since several teams proudly announced their complicated way. The only similar route I saw uses alkoxy-oxysilane-cyclopropane.

I had hoped the increased reactivity of gem-dihalo would ease this step.

Or maybe all these teams want to use only liquids at moderate temperature?

[Enthalpy]

In case the route over dicyclopropylamine makes any sense, I've observed the aspect of some molecules in the ArgusLab software.

Di(bromocyclopropyl)amine is badly overcrowded, and chloro too. Starting this step with monohalocyclopropane should be less bad.

Bromodicyclopropylamine is strained, but chlorodicyclopropylamine little so and should be easier to obtain.

At least plain cyclopropane is stable at +400°C, while the usual Olin-Raschig process (ammonia with hypochlorite over chloramine to hydrazine) needs +5°C and +130°C.

[Enthalpy]

1,2-Diazetidines too have a N-N bond but the Osiris applet estimates they're harmless. They would be about as efficient as other strained amines.

Alkenes can make cis-1,2-cyclobutanes by photoaddition. I haven't seen the equivalent reaction with imines, so the appended tentative syntheses need luck. At least, they look simple.

With C+N=10, the dicyclopropyl would still catch fire a bit easily if warm (estimated bp=+190°C) and should be liquid at RT for being unsymmetric and deformable. The dimethyl would be badly flammable (estimated bp=+93°C) and the unsubstituted 1,2-diazetidine too (estimated bp=+115°C). Horvitz, Pope and Colgain synthesized the dimethyl in 1968 by a laboratory route
https://archive.org/download/DTIC_AD0042818/DTIC_AD0042818.pdf
and measured bp=+70°C, mp=-90°C, ρ=810kg/m³. The unsubstituted may freeze more readily.

I can't predict the stability at heat.

Marc Schaefer, aka Enthalpy

[wildfyr]

Perhaps you can save a step and react the monobromo cyclopropane with methanimine.

I'm pretty uncomfortable with your notation, are the hydrogens implied in your plain "N"s?