Publishable Quality

Some people I know are chasing papers, and so are gathering necessary data on all their compounds, including spectra of "publishable quality".

It got me to thinking why this standard exists. More importantly, that some of the things I make can never be that pure.

In some of my compounds I see rogue peaks in the 1H NMR, which I just cannot assign. Just two singlets. They are not part of the same molecule, and no, it's not DMF.

There's a tentative link to dissolved oxygen, taking into account that in various solvents (not dried) the ones that tend to have a higher ability to dissolve oxygen they appear more prominently. They shrink with degassing, but even with freshly distilled solvent,and several freeze-pump-thaw cycles they are there. They do not interfere with any reaction, and the integration is negligible, I just ignore them, but they are there.

Now, this is a compound that's been made before, and not a particularly important one, but there are peaks in the spectrum I cannot assign, so technically it wouldn't be publishable, if it were a more important molecule.

The peaks also disappear in the NMR of the product in the next step. Neither of these products are purified in any other way than extraction or evapouration, so it isn't huge issue here.

There are more important compounds that I make that cannot be purified in a conventional manner without a bucket-load of solvent and time. So it makes more sense to "telescope" the material and purify at a later stage when it is easier, or just to not bother isolating them.

I would struggle to get "publishable" quality spectra of these compounds - but I still use them in my synthesis because they're clean enough for that.

I guess that's my argument, if publishing is partly about reproducibility, then shouldn't "publishable quality" be whatever is good enough for its purpose. A random intermediate that doesn't affect much - should that have to be shown as 99.9% pure?

If the next step depends on purity - absolutely, but if it doesn't then whatever quality spectrum you look at and say "Yep, that'll do" should be publishable quality in my opinion. Even if it is reasonably important to your synthesis.

I guess it's true, though, that you may only be asked to publish spectra of the more important compounds, although we've all seen papers that show all of them.

A squeaky bum moment

I have been trying to perform what seems like a simple alkylation.

The reaction never proceeds cleanly, and although it's a simple column,  yields are never above 35%.

I've tried all kinds of conditions to achieve higher yields and a cleaner reaction.

I decided to go for the big guns, and crack out the NaH for a Williamson style etherification.

Here's the bit I didn't think through. My starting material contains an azide, and although I tried to check the stability of azides to hydride, I didn't think about the by-product - hydrogen!

I couldn't find much evidence around azides and hydride, other than one or two procedures, so I figured if others had used hydride in the presence of azides it would be fine.

So I went and dissolved my material in DMF, and added the NaH, and then I froze, eyes wide, as the effervescence took hold.

There were plenty of bubbles of hydrogen, and I was, at first, a little worried.

Once hydrogen evolution had ceased, I did a quick mass spec. No evidence of azide reduction whatsoever. All I saw was the alkoxide (or sodiated starting material!). Either way no evidence of an amine, sodiated or otherwise.

It was only one equivalent of hydrogen, in a solvent that I assume doesn't dissolve it that well, without any catalyst, I don't know what I was really worried about.

Still wasn't that clean though...

Column Chromatography Quirks

Chemtips is having a column chromatography themed week. As rightly stated, everyone has their own way of packing and running a column.

I thought I'd share mine with you.

Firstly, lightly plug to avoid sand and silica leaking through the tap, then add sand until the barrel  is at its widest so the material travels through the silica at a uniform surface area.

I then add the required amount of silica, and attach the tap to a vacuum and leave it for at least 5 minutes, and add sand to the top to protect the silica.

Then add a measured amount of starting eluent while the column is still under vacuum, and the vacuum draws the mobile phase through the column, packing it tightly. Shut off the tap as the solvent reaches the sand at the bottom and start applying pressure with a pump.

I then run the rest of the solvent through until it reaches the sand on the top. The amount of solvent collected taken away from the amount you started with gives you a column volume.

Then I load my compound, I like to wet load in DCM, usually because most thing I column are super soluble in DCM. I run the sample into the top of the column and then fill up with starting eluent.

I run one column volume through and then start collecting. If I've run the material several times before, doing it on a large scale and know what I'm looking for, I will sometimes run just enough solvent through into waste before starting to collect just as my product arrives. I do usually go for a wide margin of error, for instance, if I were to expect my product after 2 and half column volumes, I would start collecting after 2. I helps save time on larger (3-5 g) columns.

For non-polar compounds, I tend to go classic with ethyl acetate/hexanes (or petrol), but I've often found diethyl ether and hexanes to give surprisingly good separation, and often overlooked.

For polar compounds, My favourite is DCM/methanol, and if it is acidic/basic Then I use 10% acetic acid or ammonium hydroxide (respectively) in methanol as 1-10% in DCM. Do not go above 10% with the ammonia mixture, you will get an emulsion as water is only soluble to around 1% in DCM.

I have had luck with mixtures of acetone in ethyl acetate (20-50% acetone) if you want to avoid chlorinated solvents and want neutral conditions. It will shift almost anything without dissolving silica but offers less separation than DCM/methanol.

How does anyone else do theirs?

Microwaves in Organic Synthesis

I have been having a love affair with microwaves.

Not least they give me a quick meal - they give me a quick reaction.

In my lab, there is no a microwave synthesiser, but it was before then I realised the true power of microwaves.

I needed a specific coumarin, or at least, specifically I needed a coumarin with an aromatic amine to diazotise. Buying one in seemed boring.

I did a Pechmann condensation using an appropriately substituted phenol (3-aminophenol), neat, in a domestic microwave oven at 500 W using a potassium phosphate catalyst.

The reaction went to completion in 5 minutes. I got a mixture of 50/50 isomers, inseparable, but I was sold.

We then got an actual microwave designed for synthesis, able to cope with high pressures. I went and did some similar condensation reactions, neat, with solvent and molten.

It's true - do one reaction in them and you're hooked. Any reaction that requires elevated temperature you want to try in a microwave. Literally.

I have done complexations to transition metals in one hour, (thermally 8-24 hr), I have done Fischer esterifications in minutes, and aminolysis in an hour, reduced from an overnight reflux, and countless carbonyl condensations (including imines!).

I've even done some amide bond formation through active esters in them. Activate at rt with DCC, filter into a MW vessel, add amine and base, 30 minutes and it's gone to completion, and very cleanly. Higher yields than I would normally get, stirring at rt (I think this is a solubility thing).

Formation of acid chlorides in neat thionyl chloride take 10-15 mins too.

Abstractions of halides from transition metals using silver salts works well. The particular one I do is over in 2 hours or less (it usually takes 5 or so), with the added bonus that the microwave is sealed anyway, so it is in the dark.

I'm not sure why it is so good, nobody else seems sure why microwaves have such an effect.

Most of the time, I heat the solvent 10 - 20 degrees above their bp's. I guess the pressure helps increase the bp, so expand the volume of the solvent, maybe that helps.

The real reason I think I use it is because it's not in my fumehood. I can do a high temperature reaction without needing my hotplate, it's completely out of the way.

It has its drawbacks. Mostly scale. You can fit maybe 20 mL of solvent in the largest sealed vessels (pushing it). We have an attachment to fit an rbf, but the maximum is 100 mL. That may seem like a lot to some, but I have seen a few reactions that won't go very far without microwaves, and need to be done on scale to build stock. You don't get a pressurised system this way though, small batch production is necessary, but for most applications this isn't an issue.

Expense is another, parts and vessels, particularly specialised vessels. Gas addition kits are pretty cool, but expensive. You can pressurise the vessel with, say, hydrogen  and you microwave your mixture with you Pd catalyst or whatever, and cool the vessel at the same time with compressed air. This means that your directing most of the energy from the microwaves directly to the catalyst and not the solution (apparently). This heats the surface of the catalyst and makes it more active. Removal of benzyl groups takes a few minutes under these conditions.

That has been my love affair with microwaves so far, we've had a few troubles, but we're still friends.

Mental Health Aspects of Post-graduate Study

There has started a dialogue between Chemjobber and Not the Lab discussing Grad School to use its American moniker.

Here in Blighty post-graduate study appears to be quite different from my point of view, although I would admit that it depends who you supervisor is and what they are aiming for, as I'm sure is the case all over the world in obtaining PhDs.

The first couple of posts have been very interesting  including comments, and other bloggers notably Derek Lowe) have shared their thoughts/experiences as well. It really is worth checking these out, and the comments, they are very insightful, and often relatable.

So here goes, I thought I'd chip in my two cents.

I am in year 3 of 4 of my PhD, having to submit at the end of year 4.

Firstly, my circumstances differ from most doing PhDs in the UK. I have a guaranteed 4 years of funding, which is great, but I have around 4 times more hours teaching responsibility to "earn my keep."

Most in my University will do some to help out, but I am bound by contract to 180 hours a year. Which can reach 200 factoring in marking scripts.

Now, when you crunch the numbers, I am probably better off (being funded during writing-up), but it is the fact that those 180 hours come within one or two months usually, as I demonstrate synthetic-based practicals to Year 1 and 2 students, which come all at the same time.

This means I have a whole month of no lab time, which does make me panic sometimes. I feel like nothing is getting done, so I force myself to run reactions, and feel better about myself. After running 3 or 4 reactions a week, I have 3 or 4 products to purify, and no time to do it.

I commit myself to playing sports at the weekend - I give myself that because I am all too aware of pushing myself too far, I already know not to dig too a deep a hole, but sometimes I do out of desperation of not being able to be at my bench.

I try and catch up on reading/writing during my teaching month, but invariably marking gets in the way, but I have to tell myself that it's for the greater good.

Because of this, the summer is precious to me. I supervise master's students during term time in my research lab as well  which often requires re-teaching all aspects of synthetic chemistry. I don't have summer students (usually, that may change over this summer) so summer is my time, and I work very hard, but it means I don't take a summer holiday - I feel like I can't afford the time off.

You would think that having master's students joining my research for 6 months would be useful, but it adds to my frustrations as for the last 3 and a half years, I have supervised 5 students, none of whom have managed to contribute real progress to the aim of the project.

I set them off repeating well established reactions that I have done and know will work to get them used to the lab and to stock pile starting materials. Some just can't do it, some seem to get possessive over their master's thesis and do the reactions and test they need to make a rounded body of work to report a 6 month stint in the lab, rather than contributing.

I kind of get that. Your PhD project can seem like the most important thing in the world to you, it's precious, and it's all yours. And that's what I think is one of the major factors in stress levels and frustrations, and even depression in grad school. It's unhealthy to be so personally invested in a single thing, and it is hard to realise that.

I'm glad I have, I have started to see a PhD as an opportunity to learn as many new skills, try out as many reactions and use as many reagents as I can.

Some people I have seen come and go over the years I've been here work so hard at one thing, but can't ever perfect it, and work harder and harder at it to achieve that perfection,dedicate more time and out-of-hours working, and it's hard to rip yourself away because it seems so important to you.

The most important I think is your boss.

I know people that work for ambitious young academics, constantly on their heels to get results, to publish and promote their name.

I know people who work for established academics, constantly on their heels to get the latest paper out - it's all about turnover.

I know people who work for people who think that hard work means long hours.

Then there's me. My supervisor has been around a while, and already made a decent name for himself, and now casts his incredibly knowledgeable eye over several small projects over several departments, and can certainly help with getting funding.

I am ambivalent towards my relationship with my supervisor. I enjoy the freedom he gives, I am able to pursue whichever avenue of investigation I want to - he very much knows he won't really be affected if I were to fail - and I really enjoy the ownership of my project (not too much though! - see above). He never approached me to see how I am doing or what I am up to, and he is usually busy and has a lot of meetings.

The one comfort, is that he has so much experience it feels like he could solve any problem I could come across, but I always try very hard to solve it first, because it's MY project (very much a theme, here). But it's nice to have that safety net. As long as I show him an NMR or graph every so often to show him progress, he seems content.

The flipside I don't feel any pressure but my own. I am already apprehensive that I won't get pushed enough to obtain the right results in good time, and won't receive enough direction in concluding my studies and writing up. I must be pro-active and ask for guidance.

I feel like having a master's degree before starting a PhD, like Vinylogous Aldol, definitely helped. It gave me little taste of what I'd be getting myself into, working alongside PhD students doing real research in a real lab, but this is the norm in the UK. It is much more rare to go into a PhD after a BSc, with no real research experience, but it is done. 

When all is said I done, I do love doing my PhD, the benefits, both short- and long-term, seem to outweigh any negativity I have experienced thus far.

I am aware I am lucky, it is all down to circumstance, but even those who seem have it easy still can find it hard sometimes. It is important to surround yourself with good people, and people who can empathise and share you concerns and gripes. I think this has helped me and my friends the most over the past few years. Someone to have good moan with over a pint or two.

Secondary amine formation

Hope everyone has enjoyed their celebrations, but it's back to the grindstone now!

I've been spending a fair bit of time pondering secondary amine formation.

There are a number of methodologies to achieve this.

Conventionally alkylating gives a mixture of secondary and tertiary amines, and if it's the secondary amine you want, it will be the last of the column, making large scale prep a bit of a nightmare.

Reductive amination always crops up when discussing this topic, and it is a good way of stopping at the secondary amine, with a small amount of collateral damage usually. It can also be useful for the suppression of quaternisation in tertiary amine formation.

The problem I have with it I think, is working with a lot of amines, is purification. Column chromatography on amines is best avoided, especially on scales above a few mmol. I will only ever column derivatised or protected amines unless it's on a small scale for analytical purposes.

The other qualm I have with this is that the aldehyde partners I require most often are not commercially available, nor are trivial to synthesise, often several steps with protection/deptrotection and purification.

The best method hands-down is the aza-Michael reaction. A lovely procedure I follow includes an equimolar ratio of amine to acrylonitrile in protic solvent, overnight at rt, rotovap, quantitative. But, I am all too aware of it's limited scope.

I have seen recently this paper in JOC that uses CsOH to suppress over-alkylation. I tried it with my substrate and I saw up to 4:1 selectivity by LC/MS, but, after a column only achieved 2:1, not the 10:1 they claim in the paper. And again, for me, a column is best avoided.

The method I have settled for recently is to nosylate the amine and alkylate with pot carb, then column. Deprotection (without thiophenol!) gives essentially pure amine with a basic wash.

Nice and easy, and no free amine to column. The best thing is the nosyl group can be used orthogonal to the Boc group.

Happy Christmas and a Merry New Year.

The lab is shut off and my workspace and hood all wiped down ready for the Christmas shutdown period.

It just leaves me to wish you all a relaxing festive period. I hope Santa brings you everything you want!

See you in the new year.