Org Prep Daily

June 14, 2007

We don’t need no orbitals

Filed under: Uncategorized — milkshake @ 9:48 am


Some organic chemistry textbooks like to give the student a ‘solid understanding’ of the theory of chemical bond before explaining any actual chemistry. If you are into this kind of thing, you can sink very deep into quantum chemistry. But you can be a just as productive synthetic chemist without bothering with the MO stuff. There are stereo-electronic effects that are influencing the product distribution or equilibrium in some commonly used reactions and systems – and you have to memorize that this is in fact what happens. You may be curious to learn the deeper explanation – but if not you can still use the reaction.

This orbital thing is actually not hard to learn – unless you want to do it on professional level, writing a quantum-computation-based modeling programs. It is just another qualitative and visually-helpful device, not much different from the sticks and balls approach, a device that reflects some aspect of the reality but is based on simplification and memorization (“this is how electron pairs in pi orbitals look like, trust me”). I don’t have a problem with MO’s – just with the educators who try to make it into a bigger science than it really is and to intimidate the unfortunate undergrads.

The MO-based approach to teaching organic chemistry reflects the hopes of 60’s and 70’s that organic chemistry can be neatly categorized and explained by few simple principles. Woodward-Hoffmann rules were a great breakthrough not necessarily for the synthetic chemistry (the electrocyclic reaction governed by these rules are not as frequently used as for example Pd- arylations) but for the self-confidence of organic chemists. This coincided with great advances in spectroscopy and computation that allowed to make a meaningful discussion about unstable intermediates, transition states and so on. The hope at that time was that a new fundamental understanding of entire classes of reactions would emerge, that  new synthetic reactions and retrosynthetic disconnecion schemes could be discovered through computation. Chemistry textbooks based on the  functional group transformations were abandoned in favor of textbooks based on reaction mechanism classifcations, sometimes to a terrible effect.

So if you are in early stages of learning organic chemistry and if you are being put off by MO diagrams, you can relax. Orbitals are helpful but they are not as deep or useful as some textbooks would make you believe – definitely not usefull on the level of collected procedures in Organic Syntheses or a handbook of protective groups. Teacher, leave the kids alone.

June 10, 2007

On boring medchem talks

Filed under: industry life — milkshake @ 6:34 pm

Sitting through the endless tables of analogs with a steady dribble of nearly identical slides can be a pretty stupefying experience. Especially if the listeners do not care much about the details of the work or if they get lost. In the past I had to give some medchem talks for audience that included biologists, pharmacology and animal studies folks and computer guys and, worst of all, the management. (Some of the business types in the industry have only faint appreciation of what the lab work is about – for them, research just costs too much money and is never finished on time.)

A simple trick that I copied from Tarantino movies has worked for me quite well: With the mixed audience, you skip through the introduction in two sentences. You tell about your best and latest results – right on the first slide. While they stare at this thing that hit them out of the blue, you are explaining what it is and how it compares with the situation you had when you joined the project  – and how that relates to what was wanted. This will focus the listeners on what is important in the presentation and what direction is your talk headed.

On the second slide you go back and begin at the beginning. You take the audience through the ups and downs of the project (you put it together into a coherent story about how you made a plan and was hopeful but the hope was soon crushed by hitting an unprecedented snag so you had to come up with alternatives – but you had also few pleasant surprises along the way, etc.) At the end you recap the summary for the second time so everybody understands what was the stuff that you did and why – but while you summarize you also add the plans for the near future. It looks good when you provide some raw time estimate about by when you hope to find out if the project is still headed in the right direction. You explain what the fall-back option might be if it did not.

The advantage of this scheme is that it helps to keep the interest going. It makes it easier for the non-technical audience to catch “This is where I was, this is where I am – and now I’ll tell you how I got there and what happened meanwhile”. You can get through without dumbing down your presentation. The non-chemists maybe won’t get as much from some weird reaction mechanism – but if you present your technical material with a sufficient enthusiasm and if the leitmotiv we-are-improving-the-stuff-one-step-at-a-time is clear, then they will not suffer. (You may even look smarter if you go through your stuff allegretto without providing a primer on the basics; HOBt and DCC structures can appear sophisticated to a nonchemist…). You can also drop in some self-deprecating comments (as to avoid looking smug) or a tongue-in-cheek joke. If you don’t make them smile at least you shouldn’t make them yawn. At the end you should have a decent acknowledgement – not overtly brown-nosing but showing a fuzzy apprecition for the help you get from your colleagues (including colleagues in other departments) and the gratitude to your immediate advisor – for putting up with you.

The non-scientific people in the audience (for example the CEO and his stooges) need to get the impression that you are a competent, smart and motivated but unpretentious guy who is making a steady progress.  The subliminal meaning of your presentation should be “Things happen in the research that one cannot anticipate but this young man has the drive and common sense to make it work in the end”


Presenting is matter of practice combined with a few confidence-boosting tricks: You can adopt a chatty, conversation-like tone as if you are talking to a good friend (a visiting former classmate) while you are drawing for him on the sash of your hood. Act as if you are still amused about the twists and turns that a medchem project can take – a mild irony in fact is a good way to convey to a non-technical audience what research feels like from inside.

There is no reason to worry about making fool of yourself: even though there might be better chemists in the audience then you are, you happen to know much more about your project then what they can possibly think up during your talk. Don’t be afraid to say “I don’t know” (it should be followed by “But I think one possibility is that…”) The chances are that in the discussion at the end you will be asked about stuff that you thought through already, months ago.

Please, whatever you do – don’t read bullet points -ridden text from Powerpoint slides, slowly and verbatim.

June 6, 2007

Spiroindoline from Fischer indole synthesis

Filed under: mechanisms — milkshake @ 12:19 am

There is a rather helpful paper from Merck Process group from 1997:


I repeated the procedure with Alloc -protected piperidine carboxaldehyde. Without the final mesylation, I got the NH indoline in the incredible yield 37% after some tedious workup (acidic extraction of the product into water etc., then a big column) and the product then crystallized nicely. The final compound was completely inactive in our project. But the joy of spiroannelation – priceless. 

June 5, 2007

Bartoli Does Not Like You

Filed under: mechanisms — milkshake @ 2:38 pm


Following a close literature precedent in Bioorg. Med. Chem. Lett. 15, 2005, 4867-71, I was trying to make an intermediate piece from a substituted nitroaniline using Bartoli indole synthesis [J. Chem. Soc. Perkin 2, 1991, 657-663]. I got some indole alright. The yields are average of two runs at one gram scale, workup was done with sat NH4Cl. I think this qualifies in the “Look what happened to me doc – it’s all black” category. 

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