The Skraup Reaction - How to Make a Quinoline

Recently, Derek Lowe was discussing reactions he hadn't done at his blog In the Pipeline. Among these were, in his own words "the widely disliked Skraup cyclization for quinolines". This was somewhat surprising to me. I have very limited experience with the Skraup reaction but it has worked for me and one of my former colleagues said it had always been a great reaction in his hands. Personally I was surprised how well it worked considering the reaction conditions. This is what I did: 

Easily the most extreme reaction conditions I have employed. Hardly surprising this is a lively reaction. Adding acrolein (boiling point of 53 oC) to a 70% sulfuric acid cocktail at 110 oC is rather exciting. Things are vaporising, spraying, hissing and instantly turns into jet black tarry goo. After 45 minutes the reaction is allowed to cool and then you attempt to work the black polymeric goo up with 25% aq. NaOH, brine and ethyl acetate. I suspect that the modest yield is due to loss of material during this annoying work-up. Scaling the reaction up is likely to improve the yield. The Skarup reaction is indeed performed on ridiculous industrial scale so it can't be all that bad. My system was rather elaborate containing two phenolic ethers and still I managed to pull out 47% and it was reproducible. Unfortunately, I cannot give full structural details as this was done in industry and I seem to recall some papers I signed explaining my life would end if I ever mentioned any of that stuff.

I should mention that it is rather important that you don't use too much acrolein as this will turn the whole thing into a rubbery solid (as I discovered) that is impossible to work with.

Anyway, the conditions I employed here a slightly different from the standard method so it may be worth giving a go if you are into quinolines. The full experimental details can be found here: C. O'Murcho, Synthesis, 1989, 880-882. By the way that's Zdenko Hans Skraup himself on the photo above. 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!

Career plans

Not surprisingly, most of Curly Arrows readers are early career chemists, predominantly PhD students and Post Docs. So although subjects such as publications, H index, impact factors etc. have been beaten to death elsewhere I thought I'd do a brief post on the topic here because it is very important for your career prospects that you start thinking of these things early on. When in the past I have been presented with a pile of job applications the first things I (and others) look at are:
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a) Name of applicant and of recent supervisors (to see if I know any of them)

b) Publication list
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So since 95% of the time I don't know the people the applications fate is determined in the course of 1 minute based on your publication list.

It sounds unreasonable but this is how you quickly eliminate 75% of the applicants. If you make it through the first screen then people actually sit down and read your application in detail, request references etc.

So if you want to get the dream job work hard and publish lots of papers. It doesn't have to be Nature papers the main thing is that your look productive (journals with impact factor >2 are fine for a synthetic organic chemist).

Unfortunately, too many supervisors will give you dead end piece of shite projects that are destined for the bin. Check your prospective boss out. How much does he publish, in what journals, talk to former and current students in the group etc. Also worth considering is whether the group publish papers with alphabetical author lists or not. The alphabetical approach can really screw your career in a fair few countries. When you apply for grants in Denmark they generally look for first and last authorship to determine your project input but also at which journals you published in to estimate the quality/impact of the work.

Having a decent track record and publication list is going to get you through the first screening round. However, to make it to the interview good references and relevant skills will obviously be very important. So think about it and start planning your career early on. 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!

What is a liquid?

I recently had dinner with some chemists and after a bit of red wine the question "What is a liquid?" popped up. The reason the question popped up is the gas sulfur hexaflouride. I had never heard of this stuff before but allegedly you can float solid objects on top of it. Intuitively, I would say that if a ship can sail in it it's a liquid but things clearly aren't that simple. There's quite a few videos with this stuff on the web. In this particular video they float an object on some SF6 in a fish tank (I'm assuming the video is not a hoax). So what is the definition of a gas/liquid? Obviously it' a density thing. Did anyone out there pay attention when they had physical chemistry and would they care to explain it to a simple preparative chemist? Also what is the least dense liquid out there? Besides pentane (0.626 g/cm3) I can't come up with much that has a density below 0.7. D!

What is Click Chemistry?

2001 was a big year for K.B. Sharpless. He received the coveted Nobel Prize in Chemistry and introduced the concept Click Chemistry. I had the great pleasure of meeting him in 2001 and his lecture on Click Chemistry completely changed the way I think about chemistry.
I do not do Click Chemistry or even Click Reactions but I like the overall concept and I fulfil about half of the Click Chemistry commandments in my daily research.
Most chemists have no idea what Click Chemistry really is and think making a triazole makes you a Click Chemist. This is incorrect and many papers are published with Click Chemistry in the title even though it isn't Click Chemistry! Click Chemistry is not a specific reaction it is a concept. Here's a condensed version of rules you have to fulfil to become a Click Chemist.:

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The reaction must be:
(1) modular
(2) wide in scope
(3) give very high yields
(4) generate only inoffensive byproducts
(5) stereopecific
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The process must be:
(6) simple reaction conditions
(7) readily available starting materials and reagents
(8) use no solvent or a solvent that is benign or easily removed
(9) simple product isolation by non-chromatographic methods
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Sharpless published an excellent paper introducing the concept
Click Chemistry: Diverse Chemical Function from a Few Good Reactions, H.C. Kolb, M.G. Finn and K.B. Sharpless, Angew. Chem. Int. Ed., 2001, 40, pp. 2004-2021.
D!

Curly Arrow - Established 18th October 2006

Curly Arrow has now been in business for two years. Things have been a bit random the last year primarily due to shifting between jobs and continents. Let's hope things will become a bit more structured in the coming year. Thanks to all bloggers for comments, endless enthusiasm and emails.
The year 2006-2007 all the top 10 visitors were from the US or UK. This year things are a bit different with Australia and Canada making an entry at 5th and 7th place and the first company (GSK) has made it on the list at 8th place. D!

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From 9 November 2007 to 4th November 2008

Absolute unique visitors: 21,250 (previous year 13,369)

Total visits: 37,513 (103 Visits/Day) [previous year 34,820 (89.47 Visits/Day)]

Average time on site: 1:28 minute (previous year 1:06 minute)

The 10 most frequent visitors identifiable:

(1) Princeton University (last year: Scripps Research Institute)

(2) Scripps Research Institute (last year: University of Cambridge)

(3) Oxford University (last year: Oxford University)

(4) University of Cambridge (last year: University of California)

(5) Flinders University (last year: Princeton University)

(6) State University of New York at Buffalo (last year: Columbia University)

(7) Carleton University (last year: University of Rochester)

(8) GlaxoSmithKline (last year: Harvard University)

(9) University of California Santa Barbara (last year: Pennsylvania State University)

(10) University of California Irvine (last year: North Dakota State University)

The Periodic Table of Elements

One of my non-chemist friends recently introduced me to The Periodic Table of Videos. This is a very cool and informative website.
I've learned lots of stuff since I started watching these videos. Thumbs up to the University of Nottingham for this excellent initiative. D!

Cisplatin is my friend!

One of my best friends has just recovered 100% from cancer because Cisplatin rocks. Here's a bit of inorganic chemistry courtesy of Wikipedia:

Cisplatin was first described by M. Peyrone in 1845 and this year it celebrates its 30th FDA approval anniversary. 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!