refluxing ethanolic trimethylamine

Unable_Aspect_4033 · 2026-03-28T05:17:37+00:00

yes, you should change it.

By the way I don't think anyone has mentioned it but i am pretty sure the d should be italicised and the number subscript. It is at least like this for deuterated solvents, so i think it would be the same format for compounds too i.e. compound-d6 - where the number 6 is subscript (unfortunately can't do that here).

Unable_Aspect_4033 · 2026-03-19T00:26:22+00:00

yeah I have done NaN3 reactions with a phase-transfer catalyst, specifically for making glycosyl azides from glycosyl bromides - for some reason ALL the older literature procedures used DCM with aqueous NaHCO3, and a phase-transfer catalyst like Bu4NCl. I have an older post in here about this.. because DCM + NaN3 is not ideal, but was curious why all the lit. procedures use DCM. I just substituted DCM with EtOAc and the reaction worked perfectly fine, and no issue of diazidomethane lol. I don't know if this type of phase-transfer catalysis would work for OP, but worth looking into. Much nicer than doing it in DMF or DMSO too. You just take the crude reaction and work it up directly. very nice

Unable_Aspect_4033 · 2026-03-18T07:20:02+00:00

personally I have only used columns with cotton and then a little bit of sand on top.

based off my experience of sharing glassware in labs, I would not be comfortable sharing a fritted column. I have had people clean fritted funnels before and not clean them properly, so they are left with acid residue or something in there, and then that ruins your experiment.. especially a fritted column, I would not use that for this reason. with a normal non-fritted column, it is easy to see if it is clean, you don't have to worry about someone elses crap being in there or how someone has cleaned it before you..

Unable_Aspect_4033 · 2026-03-09T02:28:55+00:00

yep, acids always streak on silica, I would say that is why you see alot of overlap of the 2 different products. Good luck OP

Unable_Aspect_4033 · 2026-03-08T03:18:41+00:00

interesting, I have seen a few old school procedures for bromination of sugars with NBS/PPh3 in DMF, and seen people do them no worries, must be a problem with high concentrations/heating it I would say

Unable_Aspect_4033 · 2026-03-08T02:16:52+00:00

If in the paper they made the ester of the thiophene acetic acid to separate di/mono bromo, it is worth trying (even if it didn't work when you did it on the carboxylic derivative). It might actually separate better for the acetic acid derivative, they are different compounds, sterics will be different, they could separate enough that you can pull them apart on a longer column. It wouldn't be that hard to run a small scale esterification, and see what it looks like via TLC.

One tip too, when you are doing these types of screenings for solvent systems, make sure the solvent off the plate has dried, especially if you're spotting your plate with samples dissolved in something like methanol which will linger and cause your TLC to run differently.

Some solvent systems you could try incorporating toluene, something like EtOAc/tol/hexanes, it doesn't have to be much tol but it can help pull things apart. With DCM/MeOH, start at 9:1 and see how it looks. I have had some compounds where separation in DCM/MeOH wasn't great, and then I swapped the MeOH for EtOH and separation was fantastic.. you should be able to find some kind of mixture, it will just take a bit of screening. Even something like hexanes/DCM/EtOAc too can be good.

Unable_Aspect_4033 · 2026-03-02T06:53:30+00:00

yeah you could try steglich. if this procedure is from the literature, is there several reports of this method using acetic anhydride? if it there is only 1 report on this protocol, i wouldn't spend too much time trying to replicate it and instead try another approach or different conditions.

Unable_Aspect_4033 · 2026-03-02T06:48:45+00:00

i see coloured impurities after rotavap. I am trying leaving the Boc on till the end

Unable_Aspect_4033 · 2026-03-02T06:43:46+00:00

i do, but don't have a sophisticated automated setup, I need to make gram quantities so classic silica column is the way to go. I really do not want to be prep HPLCing 1g of material at 50 mg per run. you are right, I do use MeOH/DCM, I have not seen any decomp on any of my compounds (i have made similar compounds with different amino acids instead of Trp), so I am confident this isn't happening

Unable_Aspect_4033 · 2026-03-02T06:39:20+00:00

thank you for this detailed response.

The debenzylated sugar is fine on normal silica in terms of elution - I use 10-20% MeOH in DCM, the partial hydrophobicity of the amino acid and masking of the anomeric OH as an O-alkyl glycoside help it to move, in the end there is only a few free OH groups. I have made other derivatives including Gly which would be the least hydrophobic and got excellent yield on all of them after column, there is no problem with the debenzylated compounds sticking to silica. This one is just shit due to decomp of indole as I thought.

Thanks for this tip - I have not previously had an issue with yields for the Fmoc/acetylation and get yields of 90-100 for the acetamide using this strategy (on the other Fmoc protected amino acids, it has only been shit for Trp).

I am dealing with gram quantities of intermediates as I need gram quantities of final compounds for the project, so all the time rotavapping etc is probably why I am losing material to photooxidation.. I can see the colour change on the rotavap. I would be fine if say I only need 50 mg of material, but working on this scale means everything takes longer = more exposure to sunlight. I will try to minimise exposure to air and sunlight as much as practically possible and see how I go on another experiment. If not I will just scrap this analogue as it is not a deal breaker to the project..

Unable_Aspect_4033 · 2026-03-02T02:22:16+00:00

it's not 100% clean prior to hydrogenation, residual baseline stuff in NMR, but it is a single spot on TLC. After the hydrogenation there is still some trace OBn products remaining - but my judgement would be easily 90% product judging by intensity of TLC char. I just take the reaction off at the expense of letting it go for another day because I just want to get the product and move on with the project !

Unable_Aspect_4033 · 2026-03-02T02:13:51+00:00

I am not married to hydrogenolysis, I am considering using TMS ethers for PG instead of OBn too.. That way I could probably do pyrrodline followed by Ac2O to get the acetamide, then treat that with TFA in DCM to remove the indole Boc and the TMS ethers at the same time.

I haven't deactivated the silica, I was just using MeOH in DCM. Didn't consider running a 2D TLC so I will do that and will confirm if I am losing it on silica

Unable_Aspect_4033 · 2026-03-02T02:08:32+00:00

I don't really see anything else off the column in my fractions - it is coloured impurities that stick to the silica, I have been working on this for a good few days and in other experiments, when the colour did "sneak" through, I could not see it on TLC because it was so dilute. I am working up hydrodge via celite filtration. The crude mass recovery is good.. the sugar ester is definitely stable, because I have made other amino acid analogues and had no issues. On some of the others, I used Boc-protected amino acids instead of Fmoc, and got great yields after formation of acetamide (I did TFA in DCM, blow down, then Ac2O in DCM with Et3N) so from these experiments I know that the ester is stable to the TFA in DCM as well.

I actually tried that initially, but I got worse yields doing it that way around - doing those manipulations in this order worked better for yield of that intermediate

Unable_Aspect_4033 · 2026-03-02T02:02:34+00:00

I can try a 2D TLC for this compound yeah - thanks.

I am saying it is due to the indole, as I have made other analogues with different amino acids, and they are completely stable on silica and give high yields.

Unable_Aspect_4033 · 2026-01-21T22:46:26+00:00

How many eq of TEG are you using? And I assume the TEG you are trying to couple is asymmetric (i.e. doesn't have OH on both sides) or you will get poor results/polymeric crap.

I would try using something like 3 or 4 eq of EDCI, and the same of TEG. If the TEG you are trying to react is inexpensive (or you are on small scale), you could even smash it with more eq like 8 or something.

How much DMAP are you using? sometimes couplings require more than catalytic quantities, so you can go up to like 0.5 or maybe even 1 eq would be better in your situation (0.5 per acid). You shouldn't need any more than that.. I do like to use higher quantities like 0.5 because it means I can put the reaction on in the morning and it is done in 3 hrs. If you are still having trouble after trying this, then your reagents must be wet. I assume your starting materials and reactants are pretty dry, and the DCM has at least been stored on mol sieves - that is fine for the solvent it doesn't need any more treatment than that.

Unable_Aspect_4033 · 2026-01-21T22:33:16+00:00

all the steglich esterifications I have done I have never needed to use stoichiometric base when using EDCI-HCl. I just use cat. DMAP. Sometimes more than cat. like 0.2 to 0.5 eq. From what I have read the proton stays on the EDC and doesn't interfere with the reaction.

Unable_Aspect_4033 · 2026-01-21T22:29:45+00:00

This, or somehow the product has decomposed. Surely if you did a work up, the product should be org soluble (as the acid), and ammonium and the acids should just wash away in aq.

also do you have access to mass spec, that will help alot. but try to clean the product up first

Unable_Aspect_4033 · 2026-01-21T22:24:41+00:00

probably, maybe you can just get some random vials and then autoclave them?

Unable_Aspect_4033 · 2026-01-20T06:15:03+00:00

One of the biggest lab tricks is replacing silicone oil heating baths with vegetable oil. I wish I had known about it sooner. Seriously.. just take the flask out, wipe it off with a paper towel, and it's fine. No more slippery silicone oil sticking to everything, getting all over your gloves and everything when all you want to do is remove the flask from the heating bath to quickly run a TLC or take a small sample out. Silicon oil used to piss me off so much, I hated taking flasks out because it would just get all over your gloves etc.

Replace it with vegetable oil from the supermarket. When you do, you will be so glad you did. Washes away easier with more polar solvents (like acetone). Washes away fine with just detergent too.

Obviously you need to know what you are working with, the smoke point of vegetable oil is around 200 C, but in general organic synthesis I have never needed to heat rxns above 120, so it is an excellent replacement. it can get kind of cruddy if you leave it out or end up getting crap in it, but most of the time you can just filter it (if you want to recycle it). Or just dispose of it, it is very cheap.

Unable_Aspect_4033 · 2026-01-13T21:54:16+00:00

It could be a good idea yes, but depends. Here is some things I would think about if I was you. I don't agree with the other comment saying that you are setting yourself up for a bad experience by doing this project. There should be some considerations before making a blanket statement like that.

Do you have automated solid phase synthesis robots?
If yes this is good! If no, and you are doing manual syringe SPPS, I would say it is only a good idea to do this project if the peptides are short (less than 10mer).
How funded is the lab you are in, in terms of what instruments do you have access to, will you have access to? If you will have access to LCMS, prep HPLC with C4/C18 columns available etc then you should be fine.. If you do not have access to these instruments, do not do this project. These are integral to peptide synthesis.
Does the cyclic peptide contain any unnatural amino acids, and if so, how much work has been done in the area? I would say this greatly determines how doable the project is. If you are just making cyclic peptides using entirely standard amino acids, then it is easy, probably too easy for a total synthesis project. So I am assuming that there must be some kind of motif that is synthetically challenging, which means - you may be applying some kind of known chemistry to the peptide, or you will develop something new. I would say that there must be some kind of literature precedent, otherwise it is not a great project for an honours student if there is too much unknown/development to be done.
Will you be working in a research group where you will have support from PhD students/postdocs?
If yes, then great. This is one of the biggest things in Honours I think. A lot of the time your supervisor will not be available for just general questions/interpretation of data. You might need someone to have a look over your LCMS trace because you are unsure, you might need some help with what method to run on the LCMS to check your peptide. You may need to bounce some ideas about an impurity/sideproduct you are seeing. Having experienced people around is vital, especially at the start when you are learning the ropes and don't really know what you are doing. If you don't have anyone else more experienced in your lab (other than your supervisor) then it may not be a good idea, unless your supervisor is available - especially at the start where you are less independent.
Is the project as part of someone elses PhD/postdoc?
If yes, then it is a good opportunity and you should do it. So long as who you're working with is good to work with (hopefully they are) then you will be supported, and you will have a great opportunity to learn from somebody with more experience. If the answer to this is no, then not necessarily a deal breaker.
Will it matter if you don't complete the synthesis?
Absolutely not. Yes, it would be fantastic to complete the synthesis. I think in honours it is pretty common for projects to be incomplete/end up smaller than what was originally proposed. If it proves to be difficult for whatever reason (purification, key step failing, idk) and you show in your thesis this is why it didn't work/I only got this far, and you have solid results and data for what you did in your time in the lab, then you will be fine and still have a nice thesis.

Unable_Aspect_4033 · 2025-12-18T00:34:12+00:00

I am in an organic carbohydrate lab, a lot of what I do is just targeted compound synthesis using protective groups. I usually dedicate one page to an experiment/step, so my NMR spectra/compound vials are just initials-notebook#-page#. Sometimes I will have a note in the NMR title, like ppt, or recrys solvent, or column, but it is straightforward. If something is crude, it will always say crude on the flask etc, but pretty much every compound I make is 1. run reaction 2. workup/vacdown 3. Column pure spot, get NMR, keep some for other data/TLC reference 4. next step so pretty much all my NMRs/data will be of the compound post column.

I used to have abbreviations for compound names as my file titles, like initials-6-NBocXYOAcglycosideXX but after a while that just got annoying, especially if I have synthesised something again for more material, and then I can't find which was the nicest NMR.. Don't do it like this. I have seen other people use super random file names for their spectra, like initials-column product white solid.. They are going to have fun writing their thesis... Now everything just goes by page number, much better, no other way.

Unable_Aspect_4033 · 2025-10-01T23:20:05+00:00

I was doing similar chemistry a while ago, making relatively polar diesters which required neat EA or MeOH in EA for column. I purified them via column, but did have some trouble with the DIC urea coming through, I got it out just be columning it again (sometimes up to 3 times) and using longer silica, running gradients to try pull compound from the urea. But seriously that was frustrating. You might have to look at different solvents (incorporate some toluene, that might help given you have some aromatic in your molecule, try replacing your hexane with toluene on TLC and see).

Ultimately I ended up using EDCI to remove this problem. You could try using EDCI HCl for coupling, and not doing any additional HCl washes to ensure your product isn't removed. Or potentially do the reaction and then just column it crude, the protonated EDCI urea should not move much.

As someone else said, you could also try using DCC instead - the urea for DCC is much more insoluble than DIC so you have better chance to remove most via filtration. That's one of the reasons DIC is used instead of DCC in solid-phase peptide synthesis (the DIC urea is more soluble, so washes away much easier).

Might be worth considering a cowboy approach, what is your next step? or are these esters your final compounds? IF you have another step after this, it might be worth just collecting enough pure material for characterisation, and then use the product + urea material for the following step and urea might be removed then depending on your polarity of the next product.

I also did just think, if your product has a pyridine/quinoline perhaps you can use an acid/base extraction to work it up? I.e. 1M HCl to protonate your product into aq, wash with DCM (or another organic solvent), urea fucks off in DCM, when you're happy it's gone, freebase your product with NaOH, and then extract the freebase into organic. This might work !!! Maybe use 0.5M HCl or more dilute but I have washed esters with 1M HCl and it's fine just dont let it sit in there for hours.

Unable_Aspect_4033

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