The Antistatic Portal

For a change I had to leave the office, put on a lab coat and go to the lab to weigh out some compound. I had a nice fluffy freeze dried substance that had to be transferred from one vial to another. I was faced with usual static electricity problem. The easy solution is to take your plastic gloves off and hope that your compound doesn't fly around the hood when you try to transfer it. However, as often as not this will not do the trick. For the same reason the antistatic gun has been developed (see picture).

If you "shoot" your vials a couple of times this will help, sometimes, maybe. I find it a bit of a lottery whether this works even without gloves on. Which brings me to the point of this post, the Mettler Toledo™ U-shaped Ionizer Antistatic System or as I call it "The Antistatic Portal". It reminds me of the movie Stargate as it's standing there next to your balance humming with electricity (see picture below). Basically the idea is that you just move the stuff that is being weighed through the portal and voila the problem is solved without travelling to distant planets and fighting Egyptian Gods.

Pretty neat and the damn thing actually works with plastic gloves and all so I can recommend this addtion to your lab (if you can afford it). D!

The Disconnection Approach - Automated!

In my time as a synthetic organic chemist the most important advance in the field was definitely the introduction of searchable databases such as SciFinder and Reaxys. Life before these involved spending days on end in the library flipping though dusty tomes of chemical abstracts and Beilstein. And at the end you weren't even sure if you missed something of critical importance. The introduction of open access LC-MS and high field NMR has also had a big impact for me by speeding things up considerably. However, besides these milestones I think that I have pretty much been doing chemistry the same way >25 years. Anyway, what I am getting at is "what will the next BIG thing be?" It's been a considerable time since we had a major technical breakthrough for the synthetic organic chemist. My colleagues and I have been discussing this for more than a decade and now I think I am spotting the next big thing - Chematica! Chematica was developed by Polish scientist Grzybowski and has been around for quite a while. Basically it is a computer programme that disconnects your molecule and suggests ways for you to synthesise it. What's changed since I first heard mention of Chematica ~5 years ago is that apparently now it works the way you would like it to. Recently Grzybowski and co-workers published an impressive paper where they synthesise 8 very different and rather challenging molecules. The abstract from the paper nicely summarises the achievement:

"Multistep synthetic routes to eight structurally diverse and medicinally relevant targets were planned autonomously by the Chematica computer program, which combines expert chemical knowledge with network-search and artificial intelligence algorithms. All of the proposed syntheses were successfully executed in the laboratory and offer substantial yield improvements and cost savings over previous approaches or provide the first documented route to a given target. These results provide the long-awaited validation of a computer program in practically relevant synthetic design."

You really should read this paper. These are not simple syntheses and would have taken quite some time to come up with if at all. Now it is still early days and Chematica is only for those with deep pockets. I am personally waiting for a quote right now and am very curious to see exactly how deep my pockets need to be. BUT it has started and I believe that now it's just a question of time (I'm guessing  less than 10 years) before you simply hit the disconnect button in ChemDraw, look through the suggestions that appear on your screen and pick the one that you like best.

And there is more. Another game changer is already here and everyone with a PC can do this: Machine Learning. My next post will be on this topic that we are already using to great effect at my work place. D!

Transfer of nasty stuff with a syringe and needle

Synthetic organic chemists often have to transfer something pyrophoric, toxic, volatile, smelly etc. from a commercially acquired sealed bottle such as a Sigma-Aldrich Sure/Seal bottle using a needle and syringe. Even with great care it has a tendency to drip from the needle tip, which is the last thing you are interested in. Now a Danish team has published a simple DIY solution that should be adapted broadly since it solves the problem and increases lab safety.

Basically they have developed a 3D printed mount for the sealed bottle that makes is easy and safe to remove what you need (using both hands) and the needle tip is contained inside a small airlock during transport to the reaction vessel. I have taken the liberty of inserting a figure from the paper above that describes the set-up nicely. If you use this set-up and remember to always employ Luer locked syringes I believe that most accidents can be eliminated and that we can avoid another Sheri Sangji incident in the future. D! 

Diazomethane and the Arndt-Eistert Homologation

For the past year we have been starting peptidomimetic chemistry up as a new research area in our group. Many chemists believe that peptide chemistry is easy and that peptide chemists aren't "real chemists". However, let me tell you from personal experience that there is absolutely nothing trivial about peptide chemistry. Even short sequences with normal alpha amino acids can be a nightmare to make, troubleshooting is complicated, purification can be a major pain and yields that a small molecule chemist would consider a total fail is generally acceptable in this area of research. Some years ago I was working with a Post Doc that came from Dieter Seebach's lab at ETH. He introduced me to beta amino acids and ever since I have been fascinated by the use of these building blocks in peptidomimetic research. Inspired by the work of Samuel Gellman we are focusing on the use of beta-3 amino acids in combination with alpha amino acids. Consequently, we synthesise beta-3 amino acids to incorporate these in our peptides.

There is a number of ways to make beta-3 amino acids but from personal experience one method stands out as the best route to these molecules: the Arndt-Eistert homologation. In this classic approach an alpha amino acid is converted to a diazoketone followed by the Wolff rearrangement to provide beta-3 amino acids. The Arndt-Eistert homologation basically homologates a carboxylic acid with one methylene group as shown in the scheme below.

The last step, the Wolff rearrangement, is carried out by sonicating the diazoketone in the presence of a silver catalyst (in the dark). Because nitrogen is evolved during the course of the reaction we normally have an empty balloon fitted on the flask to avoid pressure build up. I rather like the feature that the balloon slowly gets inflated during the course of the reaction as shown in the picture below.

Silver catalysed Wolff rearragement in a sonicator. Left t = 0 hr; Right t = 2 hr.

However, as you may have noticed there is a down side to the Arndt-Eistert homologation: diazomethane! The reagent has a fearsome reputation and I have heard of a couple of guys who have managed to blow themselves up and gone deaf in the process. Allegedly, one chemist at our department even managed to set fire to himself! This was a long time a go when less attention was being paid to laboratory safety and the accidents were due to sloppiness and improper handling of diazomethane. If you are careful and use the correct glassware (with clear seal joints) there is (almost) nothing to worry about. We have purchased the setup shown on the picture below. This is a very nice diazomethane still consisting of only three pieces that will produce up to 40 mmol of diazomethane in approximately one hour. We only use hot water as the heating source and keep everything behind a blast shield just in case. Diazomethan is generated from Diazald  as shown in the scheme below and used immediately. The procedure it quite simple. In the separatory funnel you place a solution of Diazald in ether this is added dropwise to a heated mixture of aqueous potassium hydroxide, ether and a high boiling alcohol [commonly 2-(2-ethoxy-ethoxy)ethanol]. Diazald reacts with the base to produce diazomethane that is distilled with ether to the receiving flask.

Notice that diazomethane is always handled in solution. The neat stuff is known to explode unpredictably so don't even think about doing that. Because of the way that diazomethane is produced it is hard to add an exact number of equivalents to a reaction. For the synthesis of diazoketones we simply go for an excess of diazomethane (approximately 2-3 equivalents based on a 70% yield of diazomethane). We commonly distill the diazomethan directly into the reaction flask to minimise handling. For the synthesis of beta-3 amino acids the alpha amino acid is first transformed into a mixed anhydride which is exposed directly to an excess of diazomethane.

Diazoinsane clear seal distillation kit purchased from Sigma-Aldrich.

Unlike diazomethane, Diazald is reasonably stable and easy to handle yellow solid. Unfortunately, Diazald has obtained a rather bad reputation despite being relatively safe to deal with as long as you don't eat it, set fire to it, beat it with a hammer or something similarly stupid. Consequently, it can be rather hard to get hold of. When I worked in Australia it was particularly problematic as it can only be shipped by road and isn't produced in the country! Here in Denmark we get it from Germany but it does take a while because they don't send it with the regular shipments so you have to plan a bit ahead.

If you think that playing around with beta-3 amino acids could be fun I can recommend the company Anand Chem based in Slovakia. They produce almost all beta-3 amino acids with the proteinogenic side chains of excellent quality at a highly competitive price. Depending on what they have in stock you may have to wait a couple of weeks for the stuff but it is worth the wait considering the quality and the price. D!

The Sand Bath - An Alternative to the Oil Bath

Yes, I am still alive! I have been out of the lab for a loooong time so the inspiration hasn't been there. However, I am now finding myself in the lab again and it appears that I will get to stay there for a while. And today inspiration struck.

Let's talk about oil baths. Good way to heat stuff up in a controlled way, BUT, what a bloody mess they are. The oil becomes disgusting after a while, the glassware gets nasty, ocassionally oil baths break and make the mess from hell....
So whenever possible I use an aluminium heating block. However, we have a limited number of these in a limited number of shapes and sizes. When a heating block isn't available my next choice is a sand bath. These are traditionally used when you have to heat something to a ridiculous temperature that oil can't handle. However, I use them for any reflux (see picture). The problem with these things is that heat transfer isn't particularly effective so it's only really good for reflux and not for heating something at a well defined temperature below the boiling point. Also it can be quite tricky for the sand bath to heat up in a well ventilated fume hood so it is generally a good idea to wrap a bit of aluminium foil around the bath to get the heating going. D!

If it works don't mess with it!

I'm currently in Brussels vistiting a collaborator. The research groups lab is absolutely fascinating and contains several old school mechanical contraptions that do a great job.
For your glassware drying pleasures:
For melting point determination (not sure how useful this device is but its looks cool):
It's not always necessary to upgrade to an expensive model with digitals controls to achieve the goal. Check out this solid phase synthesis shaker and the fantastic sound it makes - music to my ears. D!

Catalytic Hydrogenation Part II - Tips and Tricks

Well since I appear to be suffering from insomnia I may as well blog a bit. It's about time anyway.
All synthetic organic chemists will eventually be facing a catalytic hydrogenation. Catalytic hydrogenations are great because they are easy to perform, generally work well and it allows you to do a fair bit of rather useful chemistry. But remember not to set them on fire.
I have helped many chemists trouble shoot their hydrogenations so a post on the subject seems appropriate. I am by all means not an expert on this stuff but here are some things you may find useful.
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Which and how much catalyst should I use, what solvent is good?
For your basic reduction, e.g. debenzylation or reducing an olefin Pd on activated charcoal should be your first stop. Polar solvents such as methanol and ethanol are good. Even water is fine if your compound dissolves. But in reality anything that doesn't kill off your catalyst will work. I can recall using MeOH, EtOH, EtOAc, acetone, THF, DMF, AcOH. Sometimes I've even used mixtures for solubility reasons. I generally aim for a 10% (w/w) catalyst loading to start with.
Remember to have a large solvent surface area in your flask and stir it vigorously to allow the H2-atmosphere to get in there.
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What do I do when the standard condition don't work?
This is the tricky bit. There can be many reasons why it isn't going.

• Your catalyst could be old and inactive. Try a fresh pot.
• If your are trying to remove a protection group such as benzyl or Cbz from an alcohol or an amine try using acetic acid as the solvent. Protonating the heteroatom facilitates the reaction.
• Try using Pearlmann's catalyst Pd(OH)2 on activated charcoal which in my experience is a more active catalyst.
• Try heating the reaction.
• Try combinations of the above. E.g. heat the sucker using Pearlmann's catalyst in acetic acid.
• Your product or an impurity in your product may be poisoning the catalyst. This could mean that it just isn't going to work unless you remove the impurities that are giving you trouble or alternatively use a hydrogenator that allows high pressure and temperature. The classic piece of kit for this is the Parr shaker (see picture above) which looks like a steam train and makes the entire floor vibrate. Alternatively a more modern alternative such as a Parr series 5500 model could be used.
  

However, sometimes regardless of what you do the stuff just cannot be reduced. I personally tried this once and believe me I tried a lot of conditions. I could just about break any bond in my molecule except the one I wanted to get rid off. In the end I had to start over introducing a different protection group. The problem in this case was probably the positioning of a sulfur atom right next to the benzyl group I was trying to remove. In the final paper weeks of debenzylation attempts were summed up in one sentence, depressing. Some of the stuff I tried can be seen in the scheme. Four slightly different starting materials were tested. The most exciting result was decomposition.
In the next post we'll have a look at how to work the reaction up and have a quick glance at different catalyst systems and touch upon the mechanism. D

Whatman Phase Separators

I hope everyone had a merry Christmas and I wish you all a happy and prosperous New Year. Time for the first post of 2009.
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A former colleague of mine introduced me to the ingenious invention: Phase Separators. This is a big help in the lab and really saves me a lot of time, particularly with qualitative work. A Phase Separator is essentially a piece of filter paper that has been treated with silicone. If you fold it up and stick it in a funnel and pour a mix of organic solvent and water on it it will only let the organic solvent pour through. It only works well with solvents more dense than water, typically dichloromethane or chloroform. They are best employed for qualitative work where all that's required is a quick NMR to determine a ratio between isomers, whether a reaction is finished etc. For this type of work I basically transfer my reaction to a separation funnel with dichloromethane and wash it with appropriate aqueous phases. After the final wash the whole thing is poured directly into a Phase Separator, the organic phase is collected in a round bottom flask and concentrated in vacuo. I never observe any residual water in my NMR spectra so drying the organic solvent is unnecessary. D!

NMR Tube Cleaner Part 2

Some time ago I had a post about the amazing NMR tube cleaner. I love this piece of equipment and use it regularly. However, as some readers pointed out some people are remarkably good at breaking these things (repeatedly!). Where I work now we have a workshop and the guys there create the most amazing gear for us including an almost unbreakable NMR tube cleaner. It's made from hard plastic and metal and isn't affected by organic solvents. So if you are fortunate enough to also have access to a workshop you may consider ordering one of these beauties. D!

Anhydrous Solvents Part 2: The THF Still - Do's and Don'ts

The THF still is one of the most common reasons for serious fires at chemistry departments around the world. As solvent purification systems (SPS) become more and more common this problem will gradually disappear. However for now SPS is still pretty expensive so the THF stills will linger around for some time to come. There are many reasonable ways to construct a THF still. All you need for a basic THF still is:

• A round bottom flask
  
• A still head
  
• A reflux condenser
  
• An inert gas inlet and gas bubbler
  
• A heating mantle
  
• Sodium, benzophenone and some THF

The main reason why THF stills blow up is incompetent users. It only takes one sloppy chemists to screw things up in a big way. However, even with competent, careful chemists THF stills occasionally blow up. So what can you do to avoid the THF still disaster?

First and foremost train all users and/or limit the number of people allowed to turn it on and off. Have an on/off sheet where people record their name, time etc.

• Get a flow-stop switch - This clever little gizmo shuts the power off if the water stops running. This will stop most accidents before they happen. Your electrician will know what to do.
  
• Get a "hat" for your heating mantle (see picture) to avoid water dripping in and setting the whole thing on fire.
  
• Use Teflon joints or Teflon sleeves to protect joints from fusing (see picture)
  
• Don't use excessive amounts of sodium. Ideally use a sodium press to make thin sodium thread. This will give you a large surface area and ensure that you don't end up with a big fat ball of sodium when you eventually have to quench the still.
  
• Never turn the inert gas off.
  
• Have enough THF in the system. Always ensure that the round bottom flask (RBF) is filled sufficiently with THF to allow the still head to fill up and leave the RBF at least on third full.
  
• ONLY fill the THF still with dry THF. Don't just grab any old THF bottle from the solvent cabinet. Have THF bottles specifically for the still only.
  
• Don't put a stirring bar in the RBF. This will only result in a big fat ball of sodium down the track. Sodium wire is generally enough for controlled boiling. If you must add something throw some boiling chips in.
  
• BE PATIENT! Don't turn the heating mantle to the max because you are in a hurry. It take 30-60 minutes to get a THF still up and running in a controlled fashion.
  
• Place your heating mantle on a lab jack. When the shit hits the fan you can lower the heating mantle and stop heat transfer immediately.
  

I think that is enough for today. There are many things to consider and I have by no means covered everything but this should be a good start. D!

Melting point then and now - Kofler Hotbench vs. OptiMelt

I think that most chemists will agree that doing melting point determinations sucks big time. Especially when you have been putting it off for 6 months and have to do 22 in one day (yes I learnt my lesson and it took two days). Until recently I only knew of a few ways to determine melting points. My preferred method was to get a rough melting point using a Kofler Hotbench followed by an accurate determination using a full-on old school Reichert melting point microscope. The microscope beats getting your compound into a melting point tube and watching it melt through a crappy magnifying glass. Firstly, you place your crystals between two wafer thin glass plates (very simple). Secondly, you get to see your beautiful crystals through the microscope. On one occasion I managed to have a small rainbow in my crystals which sure beats staring at a melting point tube. Nevertheless, melting point determinations suck so I have toyed with the idea of having a camera record the melting in my absence and then come back a couple of hours later and fast forwarding the movie to the melting point and recoding the numbers. Now that would be easy.

As always someone else got the idea first and where I work now melting point determinations are fully automated using an OptiMelt system. It records a little movie and prints out the numbers while you are at home watching Buffy. Amazing stuff!
So what happened to the redundant Kofler Hotbench? I found it on display in the Departments historical collection of hopelessly ancient relics. Strange to think that where I worked only two months ago this was state of the art equipment. D!

Vacuum Control - updated!

It took 88 cardboard boxes and 1.5 km of packing tape to get my belongings packed up and on its way in a container destined for Denmark. Hopefully, I'll see it all at the other end in 2 months time. So with that stage of the move over and done I believe it's time for a post.

Rotary evaporators are great and we use them all the time but solvents have a bad tendency to bump and splash resulting in a mess. One way to partly control the mess is the use of a splash guard but it is still a pain. Chemists in industry generally don't have these bumping issues because they can afford a vacuum controller. These are great little gadgets where you punch the vacuum you would like to achieve in and hit go. On the more fancy systems even this is unnecessary as a clever little vapour pressure sensing device regulates the pressure ensuring the perfect distillation. However, these things are expensive and high maintenance so universities don't normally have them. Recently, a good friend that works at one of Australia's top institutions introduced me to a simple piece of glassware that essentially replaces the fancy vacuum controller at a very low cost (see picture left). The principle is very simple. The tap has two setting one allows passage through a wide glass tube and the other through a capillary tube. When you start the rotary evaporator you have the wide tube open and when the distillation starts you switch to the capillary tube. The capillary tube basically ensures that the current vacuum is maintained and stops it from going further down. Too easy! In addition the solvent recovery is dramatically improve saving the planet and importantly also your pump. All specifications for the gadget can be found in this paper:
Prevent the Loss of Volatile Solvents in Rotary Evaporators with a Simple Device, Daan van Leusen, Journal of Chemical Education, 1994, 71 (1), pp. 54-55. D!
One of the regular readers just emailed me a picture with a similar set-up to mine that does the same trick (See comments and picture right). The main difference is that this alternative set-up doesn't allow you to turn the vacuum off by turning the tap. Were I work we have a house vacuum system that requires a lot of tap turning so the set-up above is nice as this simplifies turning the vacuum off. However, if you are using a diaphragm pump this alternative is perfect and presumably also significantly cheaper to produce. D!

Low Vacuum Manifold

I couldn't believe my eyes when I saw this. The glass blower who made the manifold has missed the point. Five excellent high vacuum taps combined with a rubbish Teflon tap to produce a nice a shiny low vacuum manifold. Speaking of missing the point check this set up out using the same manifold. Spot 5 mistakes. D!

Grease

Some time ago I received an email from a reader regarding some problems keeping a constant vacuum during a distillation:

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"...What type of grease (if any) do you use for the ground glass joints during high (oil pump) vacuum distillation? I use the 'regular' Dow Corning High Vacuum Grease that comes in a funky aqua colored tube. Sometimes when I am carrying this out, all of the sudden partway through the distillation, the pressure will suddenly go from about 0.06-0.1 Torr (where it normally is) to maybe 0.6-1.0 Torr. It doesn't always happen but the effect on keeping track of the boiling point is irritating with the pressure all over the place..."

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This is a common problem and it's not necessarily a problem associated with the grease. Let's talk grease first. I have never used the grease mentioned above but I'm sure that there are many excellent greases available and this particular grease may also be good. However, I do know that if you stick to the correct Apiezon grease for your application you won't have any grease related problems. There is a whole range of Apiezon grease and for a high vacuum distillation I would recommend either Apiezon T or H. All the information you need to select the correct Apiezon grease is available here. Don't overdo it when you apply your grease otherwise you'll contaminate your material during distillation.

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Interestingly, I recently had a similar problem to that described above when setting up a high vacuum manifold. However, in this case the problem was not the grease but the use of inappropriate vacuum tubing. The vacuum I was operating at was much lower than that described above but the same vacuum surge phenomenon was observed. The solution to this problem is to buy Tygon tubing. It's expensive but it's worth all the money and you usually don't need more than a few meters anyway. Aldrich sell 10 foot pieces of Tygon. It's transparent, nonreactive, flexible, not brittle and doesn't leak. It's simply the best. There's a good post at Wikipedia on grease. Notice the smart way of applying grease using a syringe. Also if you are setting up a high vacuum manifold you should consider reading this post at Org Prep Daily. D!

NMR tube cleaner

I have a lot of NMR tubes and as a result I don't clean them very often and when I eventually decide to do something about it I'm faced with something like 30 dirty tubes. Now firstly if you work this way you have to soak the NMR tubes as soon as you are done with them. If you just let them evaporate to dryness you are in trouble. I normally just empty the tube and fill it to the lip with acetone and cap it. This way it wont dry out for months.

When I was cleaning my tubes the other day I had three synthetic organic chemists from three different countries walk up to me and ask what I was doing. This was somewhat surprising so I've decided to share with you what I thought was common knowledge: The NMR Tube Cleaner. These things are commercially available (expensive) or you can have your glass blower make one at a reasonable price. You can see my set up on the picture above. This is how it works:

(1) take the cap of your NMR tube and attach it to its base

(2) stick the tube in the cleaner (see picture) so that the cap seals the opening at the top

(3) squirt solvent(s) into the solvent opening (see picture).

The system is under vacuum and the solvent gets sucked through a thin tube that goes to the bottom of the NMR tube. It is very effective and I usually do a combination of solvents to get rid of everything. Its smart to have a three way tap between the cleaner and the pump so that you can let air into the cleaner without having to turn the vacuum off all the time. There's an NMR tube entry at Wikipedia that also describes the NMR tube cleaner. D!

Still breathing

I happened to look at Curly Arrow the other day...it's now been over a month since my last post! Not good, not good at all. Taitauwai even enquired about my well being. Well I'm still alive (sort of). My brain is slightly fried. I'm trying very hard to get some papers written whilst also attempting to set a new lab up, get my new projects going and phase new group members in and make their projects take off....yes I'm fairly busy. All my blogging time has effectively become paper writing time. Anyway, I have lots of things I would like to share at Curly Arrow and I'll try real hard to get some stuff posted. Whilst getting new gear for the lab I stumbled over an old box containing a virtually unused Vibro-Mischer - Das ideale rührwerk für Labor und Betrieb. Check out this nice poster I found in the box. That is one sexy model they picked to promote their products. If you click on the image you will get an enlarged version. D!

DIY Scoops!

Have you ever noticed how the dry ice scoop or any other communal scoop for that matter just disappears after a while? Where do the scoops go? Is there a secret valley in Africa where the scoops got to die? Anyway, there is a simple and environmentally benign way to produce personal scoops in abundance. All you need is a Stanley knife and an empty appropriately sized plastic container. The type of container used for storing inorganic salts such as sodium sulfate and the like is usually ideal. Basically you just cut the container to produce your own scoop perfectly designed for your requirements. It's free, it's homemade and it's yours! Go make one you know you want to. D!