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.

Carbynes ! ! !

An article on carbynes brought back memories of the Spring of 1961 when I convinced Woodward to let me work on an original idea about carbenes for my PhD thesis.  Back then you had to pass 8 cumulative exams (given monthly) before you could start such work.  It took me 9.

At the time, carbenes were a rather speculative idea, but it seemed to me that they could be generated by photolysis of a diazocarbonyl compound. I thought they might be involved in the Wolff rearrangement

One of the joys of organic chemistry back then (and hopefully now) is that if you have an idea, just build a molecule to test it.

So here’s the idea the great man bought.

l. Condense acrylic acid with cytopentadiene by a Diels Alder reaction.  Because of steric effects the acid will point below the ring system

2. Form the acyl chloride

3. React with diazoMethane to form the diazocarbonyl — there will be no change in the orientation of the carbonyl relative to the ring system

4. Photolyze — a a carbene is formed it would be in perfect position to form a cyclopropane on the other side of the ring system, pretty much proving its existence.

Malheureusement, having the worst lab technique in the world and being very frightened by what I’d heard about diazoMethane, I couldn’t get the idea to work.

However the idea was good, and a friend who kept on in chemistry becoming a department head told me that I was right.

Which brings us to the current article [ Nature vol. 554 pp. 36 – 38, 86 – 91 ’18 ] http://www.nature.com/magazine-assets/d41586-018-01308-7/d41586-018-01308-7.pdf.

A carbyne is basically R – C where the carbon has 3 electrons not forming covalent bonds (two are paired).  As you might imagine, carbynes are quite reactive.  However both articles talk about a carbyne equivalent which is R – C = N2, which IMHO is not a carbyne at all.  It is intrguing that it would be if the N2 were photolyzed off a la 1961, but that isn’t what happens in the paper.  It remains as the intermediate performs all sorts of interesting chemistry, forming an Aryl – C (R) = N2 moiety etc. etc.

One interesting aside is that carbynes were one of the first molecules found in interstellar space.

Can anyone out there enlighten me as to why R – C = N2 is a carbyne equivalent.  Neither paper provides an explanation.

 

 

The New Clayden pp. 694 – 756

There’s not much new to say about Chapter 28, on retroSynthetic analysis, since the first edition.  Given the general disrespect that monster syntheses seem to engender today,.  Here’s a repeat of  what I wrote about the chapter years ago.

Retrosynthetic analysis and Moliere

Chapter 30 of Clayden, Greeves et. al. concerns retrosynthetic analysis, but what in the world does this have to do with Moliere?  Well, he wrote a play called Le Bourgeois Gentilhomme back in 1670 and played the central character, Monsieur Jourdain, himself in its first performance (before king Louis XIV).  Jean Baptiste Lully, one of the best composers of the time (Bach hadn’t been born yet) wrote the score for it and also played a role.  M. Jourdain was a wealthy bourgeois gentilhomme who wanted to act like those thought better (e.g. the nobility) at the time.  So he hired various teachers to teach him fencing, dancing and philosophy. The assembled notables watching the play thought it was a riot (did not the French invent the term, nouveau riche).  He was taught the difference between poetry and prose, and was astounded to find that he’d been speaking prose all his life.

So it is with retrosynthetic analysis and yours truly. Back in ’60 – ’62 we studied the great syntheses that had been done to learn from the masters (notably Woodward).  Watching him correctly place 5 asymmetric centers in a 6 membered ring of reserpine was truly inspiring.  Even though Corey had just joined the department, the terms retrosynthetic analysis and synthon were nowhere to be found.  The term is almost a tautology, no-one would think of synthesizing something by making an even more complicated molecule and then breaking it down to the target.  So synthetic chemists have been speaking retrosynthetic analysis from day 1 without knowing it.

Probably the reason that things have become so formalized, is that we have many more reactions at our disposal presently.  Silyl enol ethers and lithium enolates were not in evidence back then (as I recall) — although we spent a lot of time with aldols, Diels Alder’s and Claisen’s back then.   One of the things I hope to acquire reading Clayden (and probably others) is the ability to read the syntheses of today and enjoy them, the way I do an unfamiliar string quartet.  Synthesis back then was an art form, and apparently it still is.  People question its utility (I wonder what Woodward would say), but just how do you use a string quartet? Grooving on the entries in TotallySynthetic.com etc. is still probably a year (and 700 pages of Clayden) away, if not longer.

So it is with retrosynthetic analysis and yours truly. Back in ’60 – ’62 we studied the great syntheses that had been done to learn from the masters (notably Woodward).  Watching him correctly place 5 asymmetric centers in a 6 membered ring of reserpine was truly inspiring.  Even though Corey had just joined the department, the terms retrosynthetic analysis and synthon were nowhere to be found.

Here are some notes a questions on the first chapter of heterocyclic chemistry.  The chapter explains why they react the way they do to electrophilic and nucleophilic aromatic substitution.  Pretty obvious is you remember about electronegativity, where the orbitals are, and old fashion resonance structures stabilizing positive and negative charges.  Clear as a bell, so there aren’t many notes and questions.

 

p. 725 — “Pyridine is a weak base with a pKa (for its conjugate acid) of 5.5”  Why not say the pkaH of pyridine is 5.5?

p. 728 — What is Cl-CO2-Et and how do you make it?

p. 731 — How do you make Br3- ??? Pyridine + HBr + Br2 ??

p. 739 – Epibatidine — [ Proc. Natl. Acad. Sci. vol.  100 pp. 11092 – 11097 ’03 ] The frogs don’t make the stuff — it’s from the insects and plants that they eat — then they ship it to their skin.   It’s an even more fantastic explanation than jumping genes or convergent evolution.

p. 744 — The sulfur ylid chemistry converting a ketone to oxirane is found on p. 665.

p. 744 — I always wondered what tetrazoles were doing in so many drugs.  Now I know — they are substituting for COOH, as their pKa is the same (about 5). 

p. 745 — How to make a single carbon atom (while taking your life in your hands) — fantastic.  Kudos to the chemists who did this — presumably they are still intact.   I well remember the terror I had of diazomethane when I worked with it back in the 60s.