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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline

« More Layoffs, And What They Might Mean | Main | Nobel Season »

October 4, 2007

No Problem At All

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Posted by Derek

I was listening to a seminar speaker today, who as an aside mentioned forming an ester as “about the easiest reaction that you can do”. He had a point. If you have a free carboxylic acid, combining it with an alcohol and some acid will generally give you some amount of the ester, and most of the time it’s a high-yielding reaction. But there are problems if the acid is next to a chiral center, or if there are other functional groups that don’t like being cooked with acid catalyst. So while this one is easy, I’m not ready to give it the title. (The speaker had had trouble with it himself).

But if it’s not the winner, what is? Displacement of a leaving group with a powerful nucleophile (fluoride, azide, cyanide) is usually pretty foolproof, but we’ve all dealt with structures that are too hindered to do it well (or decide to eliminate and form an alkene instead when forced). Reduction of an aldehyde to an alcohol is also hard to mess us – good old sodium borohydride – but chiral centers next to aldehydes are untrustworthy in the extreme. You may get your alcohol, only to find that the dying aldehyde left you a scrambled stereocenter in its will.

How about forming an oxime from the aldehyde instead? I haven’t had to do that nearly as much as the other reactions mentioned, but every time it seemed like (as an old labmate of mine put it) “a reaction that my grandmother could do”. And if you want to cheat a bit, and start from a really reactive system, then it’s hard to beat formation of an amide from an acid chloride, which is why you see so many amides. But my pick for a reaction that can’t fail is another one from the leg-up category: the formation of a urea from an isocyanate. It has to be an awfully hindered or non-nucleophilic amine for that not to work, or a really weird isocyanate. Anyone have an easier reaction than that?

The problem with talking about these things, though, is that when they fail you, you feel like a complete dodo. I once had a primary alcohol that I just could not put a TBDMS protecting group on, and I still remember the looks of pity in the eyes of my co-workers when I would complain about it. When something like that turns on you, you find yourself wondering if maybe you should have gone to truck-driving school instead, like Mom always wanted.

Comments (21) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. such.ire on October 4, 2007 8:57 PM writes...

I'm always a big fan of the Parikh-Doering oxidation. Not as temperature-finicky as the Swern, easy to weigh out the reagents, and generally pretty good yield. My lab hands were crappy when I was doing synthesis, but this was one reaction that almost always worked for me.

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2. Jose on October 4, 2007 9:03 PM writes...

I shared a lab with a postdoc who had some very sage advice. Whenever you wanted to chuck it all in and become a plumber or a truck driver, when chemistry was laughing at you (say, a debenzylation with Pd/C went to gradeuex), just recrystallize some old, grotty yellow-orange NBS. You'll feel like a god, irregardless of any other reactions you have stirring!

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3. psi*psi on October 4, 2007 9:17 PM writes...

Hmmm. I'd vote for the Sonogashira with a qualifier or two: aryl iodide, silyl acetylene. Although I guess you could, I don't know, not degas the solvent?

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4. Handles on October 4, 2007 10:24 PM writes...

A labmate had trouble removing a boc group from an amine once. The t-butyl came off fine, but the carbamate just wouldnt budge...

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5. bink on October 4, 2007 11:44 PM writes...

A former labmate of mine was working on synthesizing a nice, large natural product with a central ester bond. The last reaction - formation of the ester - gave her A LOT of problems. She had to deal with an acid with an alpha-stereocenter, and a secondary alcohol with a nice, juicy quaternary carbon at the beta position... but it's just forming an ester right? Big deal!

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6. ZAL on October 5, 2007 1:47 AM writes...

It happened to me sooo often! The last failed debenzylation with H2-Pd/C is just one week old!

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7. processchemist on October 5, 2007 3:03 AM writes...

Many people in drug discovery think that with Pd catalyzed cross couplings you can put together almost any multiaryl system, independently from the functions on the building blocks, also if there's quite a lot of articles saying that things don't go smoothly every time ....

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8. kiwi on October 5, 2007 7:20 AM writes...

"The problem with talking about these things, though, is that when they fail you, you feel like a complete dodo."

lol exactly what i was thinking. having once spent 3 weeks trying to make an ester (mitsunobu reaction being only thing that worked, everything else you can think of crashed and burned), i felt like a right twit.

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9. John Spevacek on October 5, 2007 7:41 AM writes...

I think I can top all of you. I can't saponify stearic acid right now. Well, actually I can, but I can't get the stearate to gel properly. People have been doing this reaction for millenia, and I can't get it right.

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10. MiddleO'Nowhere on October 5, 2007 8:32 AM writes...

I had an aromatic nitration I was trying to do using nitric and sulfuric acids with acetic acid as a solvent from an old procedure (1923). It never once worked. It's the kind of reaction we have undergrads do in lab on multigram scales, and I couldn't do it.

Thankfully I found a different route.

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11. bink on October 5, 2007 9:02 AM writes...

I remember trying to Boc-protect an amine once. I was following a procedure from another (competent) research student in the bench across from mine. The result of this Boc-protection?

Reported yield: 95%
My yield: 25%

Now I can do the same protection in 95% yield, but as a first year student, that was embarrassing.

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12. CMC guy on October 5, 2007 9:48 AM writes...

My bane was attempting to acetylate anilines- certain anilines and acids combos(even as acid chlorides)just gave piss poor results and trends/patterns didnt follow any rules.

I also assume not talking about making salts because sometimes in testing formulations it can be difficult to get acid-base reactions to go (although mostly just need energy such as heating which not 1st choice).

When I see a transformation in Larock that has many procedures I usually approach with caution as can mean very substrate dependant (but not always) which is why people had to work out new ways

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13. Carbochem on October 5, 2007 10:25 AM writes...

I think click chemistry reactions are by far the easiest reactions I have ever done.

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14. Mark M on October 5, 2007 10:50 AM writes...

Forming an alkynyl bromide from a terminal alkyne using catalytic silver ion was about the easiest things I ever did. Most Finkelsteins were also trivial.

Sure is nice to do one of these easy reactions once in awhile---cant pound your head against the wall all day, EVERY day.

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15. milkshake on October 5, 2007 2:47 PM writes...

Since combichem is intended to explore large diversity space, one ends up putting lots of bizzare building blocks into a combichem library and you can be certain there will be at least one building block/combination that will fail even the most trivial reactions.

Apart from the humility, combichem experience teaches to appreciate the electronic effects when considering the reactivity of building blocks.

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16. Polymer Bound on October 5, 2007 5:58 PM writes...

"I think click chemistry reactions are by far the easiest reactions I have ever done."

By definition, isn't it? Click chemistry need not be a copper mediated 3+2 cycloaddition.

http://en.wikipedia.org/wiki/Click_chemistry

milkshake: amen.

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17. TMS on October 5, 2007 7:14 PM writes...

Here is a statement from Georg Buchi (Perhaps paraphrased) "When there are dozens of ways to do a transformation it just means that none of them are any damn good."

A colleague of mine once gave me what I now consider sage advice. He said if you want reactions that really work look to the beginning steps of a 20 to 30 step total synthesis. They have to work well or the synthesis would never have gotten finished.

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18. Dennis on October 5, 2007 10:05 PM writes...

I'm just a stupid undergrad, but I spent months trying to oxidize a friggin alcohol to a ketone with no luck. I don't know how many different oxidants I tried. I mean, I'm not some sort of synthetic wizard(yet), but come on!

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19. Anonymous BMS Researcher on October 6, 2007 3:45 PM writes...


Any other readers remember Scottie's line about tribbles: "no tribble at all"?

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20. eugene on October 8, 2007 10:45 AM writes...

"I'm just a stupid undergrad, but I spent months trying to oxidize a friggin alcohol to a ketone with no luck."

It's a tertiary alcohol; there is your problem. (Sorry, sorry... couldn't help it).

I once had to make a building block based on a dipyridine methane architecture (that forms pretty well and is stable). Change one of the pyridines (or both) for a pyrimidine though, and no dice. Nothing worked and the boss was getting impatient and incredulous. I finally figured out that it does form, but decomposes in about an hour. Even got an NMR of it before it turned into black tar. No wonder there were no reports of it in the literature.

Still, this was when I was new and I remember the boss coming in to set up the same reaction after I told him for the 10th time that it's never going to work. Needless to say, we never mentioned this building block ever again afterwards.

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21. kayesdee on October 9, 2007 1:21 PM writes...

I would like to up the original question with an (actually two) additional limit:

1. What is the easiest organic reaction that can be done in water as solvent (not reagent)? Any reaction conditions are OK ;)

2. And now replace "easiest" with "cheapest and easiest" 8)

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