Tag Archives: R. B. Woodward

We interrupt this program . . .

I’ll interrupt the series of posts on the brilliant article [ Science vol. 377 eabn5582 pp. 1 –> 20 ’22 ] to talk about working with the very frightening diazo methane 61 years ago.

I was able to convince Woodward to let me work on an idea of mine to show that carbenes were generated by photolysis of a diazo compound (this was suspected but not known at the time).

Here’s the idea

l. Condense acrylic acid with cyclopentadiene by a Diels Alder reaction.  Because of steric effects the acid points below the ring

2. Form the acyl chloride

3. React with diazoMethane to form the diazocarbonyl (no change in the orientation of the carbonyl relative to the ring.

4. Photolyze — if  a carbene is formed, it’s in perfect position to form a cyclopropane on the other side of the ring which if formed would pretty much prove the point.

Diazomethane was known to be quite explosive, and I spent a lot of time tiptoing around the lab when working with it.  Combine this with the worst lab technique in the world and I couldn’t get things to work. Subsequently the idea was shown to be correct, and an enormous amount of work has been done on carbenes.

So why interrupt the flow of posts about the brilliant  [ Science vol. 377 eabn5582 pp. 1 –> 20 ’22 ] ?

Because Science vol. 377 pp. 649 – 654 ’22 reports a simple (and nonexplosive) way to form carbenes from aldehydes.  Here’s what they say

“Common aldehydes are readily converted (via stable a-acyloxy halide intermediates) to electronically diverse (donor or neutral) carbenes to facilitate >10 reaction classes. This strategy enables safe reactivity of nonstabilized carbenes from alkyl, aryl, and formyl aldehydes via zinc carbenoids. Earth-abundant metal salts [iron(II) chloride (FeCl2), cobalt(II) chloride (CoCl2), copper(I) chloride (CuCl)] are effective catalysts for these chemoselective carbene additions to s and p bonds.”

How I wished I had this back then.

A beautiful molecule

OK class.  Pop quiz.  Draw the structure of C304 H264 (not a misprint).  To help you out there are 6 sharp NMR peaks (roughly the same size) between 7.8 and 8.5, a doublet at 8.6  and a large peak at 1.45.  This obviously tells you the molecule is quite symmetric.

Give up?   You can read about it’s elegant synthesis and structure in  Science vol. 363 pp. 151 – 155 ’19.  I doubt that Woodward ever thought of a molecule like this, but do not doubt that he would have loved the elegance of its synthesis, using techniques and reagents not available to him years ago.

Give up?  Does the fact the the molecule contains 40 benzene moieties help?  How about the 16 tButyl groups?

Does the fact that the dimensions of the molecule are 17.4 x 16.4 x 16.4 Angstroms help?  How about the fact that the molecule contains a central space which can comfortably fit a buckyball inside?

I’ll fill in some details tomorrow for those without access to the paper.  I’d love to see the NMR of a cyclophane derivative (which the authors haven’t made yet).

Bravo to all concerned in the paper.

Carbenes and a defense of Pre-Meds and Docs

Carbenes ! ! ! A whole 25 page chapter in the new Clayden about them ! It wasn’t like this back in the Spring of ’61.  Carbenes were new and exciting. It’s quite different presently in the department, but back then before you could start work on a PhD you had to pass 8 cumulative exams (cumes).  They were given monthly, so once you had 8 under your belt you could start. Until then, you hung around, took courses, went to seminars and made some money as a teaching assistant.  The rumor was that if you passed the first 8 you’d be nominated to be a Junior Fellow (I think Dan Kemp got in this way).  At any rate, I passed 8 of the first 9, and in May ’61 I was ready to begin work. 

The carbene chapter in Clayden is full of all sorts of ways to make carbenes, but back then we weren’t sure if they were involved in ordinary reactions.  I thought they might be involved in the Wolff rearrangement (see p. 1021 of the new edition) and figured out a way to prove it if they were.  Remember this is May ’61.   

Start with cyclopentadiene, do a Diels Alder with acrylic acid (or the acyl chloride, I forget which).   The addition puts the acyl group endo. React the acyl chloride with diazomethane to form the diazoketone.  Photolyze.  Back then we knew that carbenes reacted with olefins to form cyclopropanes.  If so photolysis of this diazoketone should produce a carbene right next to the double bond.  Formation of such a tangled up compound would prove it.

So I took my idea to Woodward, the great man bought it, and let me work on it as my PhD project (rather than one of his ideas).  I never got it to work due to my lousy lab technique, and my fear of blowing my head off with the explosive diazomethane (Tom Lowry had similar fears, but got diazomethane to work on his PhD project with Corey). 

Time for a social note.  When I stop to think of it, the system that got me to Woodward back then was truly remarkable.  I graduated from a 4 year high school of 212 kids which had never sent anyone to the Ivy League.  There were 48 graduates my year of whom half were boys.  None  of the 24 girls went to college and only 6 of the boys.  Yet 4 years later there I was, in a chemistry department which contained 6 nobel future Nobel laureates.

A fellow graduate student back then (now a department chair) grew up on a chicken farm 35 miles away.  A college classmate, the son of an immigrant shoemaker from Italy, later became the editor of PNAS.  Hopefully this country is continuing to do the same for immigrants and the children and grandchildren of immigrants such as ourselves. 

Over the years I’ve read a lot of snarky comments in various chemistry blogs about pre-meds from people attempting to teach them orgo.  Certainly many of them are justified.  Consider what happened when I tried to clean out one rotten apple from such a class —  https://luysii.wordpress.com/2010/08/24/son-of-a-responsibility-you-didnt-know-you-had/.

However, it’s now time for a little pushback.  

As of 5/61 I’d been studying organic chemistry among other things for just over two and a half years.  Yet that’s all it took to get me to the frontier of the field.   Compare that to med school. Starting 9/62 by 5/65 how close was I to knowing enough medicine to take care of a sick person?  Damned far.  Did I find med school harder than grad school?   I certainly did.  No one in our class found it easy, even the future Nobel laureate (although he seemed to spend a lot of his time playing bridge).  Presumably I was just as smart as I was 5/61.

By the summer of ’66 I’d be an intern, with a resident over me and an attending physician over him, to make sure I didn’t screw up.  By the summer of ’67 I’d be a first year resident, with an intern under me, a resident over me andy an attending over him, to make as sure as we could that we didn’t screw up.  By the summer of  ’68 I was in the service, again with an attending.  After finishing that and a residency, by the fall of ’72 I was on my own ready to take care of people with no one checking my work — some 8 years later.

So ease up on the pre-meds (but not academically).  They’ve got a lot longer and harder intellectual road ahead of them than you do.