[ecnerwalc3321]

Hello,

I’m planning to convert an alcohol group to a thiol.  I’ve thought about the reaction and wanted to run it by you guys to see if it’s kosher and whether it’s feasible since we would have to order HBr and thiourea. I have what we call Tc1 (4-tricyanovinyl-[N-(2-hydroxyethyl)-N-ethyl]aniline).  The molecule is shown in the attachment. It is a red solid crystal. 


I was thinking initially to brominate it by adding excess aqueous HBr and heating it in a small scintillation vial.  Any additional liquid (water and HBr) is driven off by evaporation.    The molecule is stable at temperatures up to 200C so in the process of heating (although not necessarily to that temperature), the OH group should be substituted by Br. 

This next step(s) is where I’m not sure.  The product would then be dissolved in some solvent (water? recommendations? Solvents to avoid?) and thiourea would be added.  Heating might be required.  I’m not sure how to purify the product, that is, to remove the excess thiourea and whatever products are formed.  Hopefully it would precipitate out or something when cooled. 

Any insight or suggestions using alternative routs would be appreciated.  I’m pretty sure that the general chemistry should work based on what I’ve read, but in practice I know that things could be much more complicated.  I don’t have much of the TC1 so I’m trying to iron out all the possible kinks before trying any synthesis. 

[Dan]

You could probably make the hemithioaminal by treating the hemiaminal with H₂S - you will be the least popular person in the lab after that. You might get conjugate addition to the methlenemalononitrile as well, but that should be reversible.

If you want to go down the activation route, I think I'd personally start with converting to the chloride with SOCl₂ etc. I'd be worried about the nitriles in HBr.

[opsomath]

I am also worried about Michael addition to that super electron deficient double bond.

The thiourea reaction is a great one, but in my opinion any nucleophilic sulfur is likely to add to the double bond as well It may be possible to make the reaction work anyway, but you will be competing with that as a side reaction...



If I had to do this reaction, I would start by turning that alcohol into a leaving group some other way. Either use thionyl chloride or PBr3 to make the halogenated version like Dan said, or make the tosylate/mesylate and either use that directly or convert it to the iodide by a Finkelstein reaction:

https://www.thieme-connect.de/ejournals/pdf/10.1055/s-2003-37650.pdf

Once you get the OH group converted, if you want to try the thiourea route you can dissolve the starting material in ethanol and add it to a solution of thiourea in ethanol. Use TLC to monitor the reaction, only use one equivalent of thiourea. Then hydrolyze with base and extract the product into an organic solvent to recover. Here is an example of the thiourea prep:

http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv4p0401

You don't have to isolate the thiouronium salt, I usually preferred to just add base to the ethanol solution, then extract into ether with a lot of water washes to remove the alcohol. However, if you can isolate the salt that is probably the way to go since you have a limited amount of starting material.

Let me ask, why do you want the thiol out there? There may be ways to accomplish something that can do what you want without risking nucleophilic sulfur attacking that double bond.

[ecnerwalc3321]

Thank you two for your responses.  Like both of you mentioned, I wasn't sure what was going to happen to the nitriles and the double bonds that are present in the molecule.    I have access to thionyl chloride and making the chloride should be simple enough- just dissolve the TC1 in SOCl2 w/heat and evaporate the liquid. 

Opsomath, when you say to hydrolyze with base, do you mean to add some aqueous NaOH to the resulting solution and add say, chloroform?  Would the TC1 go into the chloroform phase if it is a salt?

TC1 is used as a rotor probe that we commonly use in our lab for molecular fluorescence.  We often dope it into various polymers to probe for aging effects and glass transition behavior.  Currently, I want to covalently label it onto styrene-butadiene rubber.  The thiol group on the TC1 would enable me to ultimately do a thiol-ene reaction (vinyl groups on SBR with thiol on TC1 probe). 

[opsomath]

That is an interesting process, the selective fluorescent tagging of the remaining unsaturated bonds in SB rubber...have you done this sort of thing before and know that it works?

Yes, that is exactly what I mean by hydrolyze with base. I finally found the procedure I was basing my old stuff in grad school off of; a link to the paper is below. The TC1-thiol shouldn't be a salt at any reasonably alkaline pH, so it should pop right into an organic phase. That's assuming that it doesn't instantly polymerize upon forming in a basic environment, which I am not guaranteeing. -_-

If this reaction turns out to be problematic, I'd look into making the thiol by attaching another segment containing a protected thiol. For instance, you could make a linker with a acetylthio group at one end and an acid chloride at the other end, and react that with your alcohol.

http://pubs.acs.org/doi/pdf/10.1021/la970823a

[ecnerwalc3321]

Thanks for the clarification.  I've done some reactions in the past and found that practice is way different than theory.  I'll try it some time this week and will post if I run into anything unusual. 

I work in a polymer physics lab.  We regularly use fluorophores to measure polymer thin film properties such as glass transition and aging effects.  It's an interesting concept- fluorophores, such as pyrene, coumarin, etc undergo a radiative decay (fluorescence) and a nonradiative decay route (vibration) when excited.  When these are doped into a polymer, say polystyrene, and cooled through the polymer's glass transition temperature, the density of the polymer changes and the nonradiative decay route becomes more restricted.  This results in a change in fluorescence intensity that we can use to determine Tg, etc.  I've found that fluorophores which possess conjugated rings, such as pyrene, anthracene, etc "react" with SBR in a way so that it appears that energy is not conserved.  to make a long story short, I've started using these rotor dyes but they need to be anchored onto something, such as a polymer chain. 

[Dan]

The thiol group on the TC1 would enable me to ultimately do a thiol-ene reaction (vinyl groups on SBR with thiol on TC1 probe).

So actually you do not need hemithioaminal reactivity, just thiol reactivity?

An extra methylene spacer between N and S will avoid the thioaminal functionality and probably substantially simplify the reactivity of the thiol and its alcohol/halide precursors, something like this:

[Babcock_Hall]

Thioacetate and thiophosphate (followed by hydrolysis) are other ways to add a thiol group.  I don't know whether or not they would be helpful in this instance.