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.

 

 

Making an enzyme do a carbene reaction

The P450 cytochrome enzymes are the chemical workhorses of biosynthesis and xenobiotic detoxification.  As a neurologist I always had to worry about the way adding a new anticonvulsant to a an existing set would alter the body levels of all of them.  The new anticonvulsant would cause the P450 cytochrome enzyme metabolizing it to increase, and the new P450 might also chew up some of the others.  Phenobarbital was a particular problem this way.

Over 14,500 P450 genes have been found in various organisms. FYI the 450 in P450 comes from the absorption at 4500 Angstroms of the Fe++ in the heme group when complexed to carbon monoxide.  This is called the Soret band.  The P450 cytochromes are a superfamily comprising 36 known gene families, each consisting of 2 -20 discrete cytochromes.

The P450 cytochromes take 2 electrons from a reduced cofactor (NADPH) which itself gets the electrons from another molecule.  The cytochrome then binds an oxygen molecule splitting it so an oxygen atom is bound to the Fe++  (the other oxygen goes to water).  The oxygen is then used by the various enzymes to insert into C-H bonds with an incredible specificity (this produced by the conformation of the protein around the heme-iron-oxygen).

In Science vol. 339 pp. 283 – 284, 307 – 310 ’13 a group at Caltech which has been using direct evolution (randomly mutate a protein and select for the reaction you want) used a P450 cytochrome to accept diazo esters as reagents.  This formed a carbene linked to the Fe.  They found that it would add to olefins.  Further engineering (random selection actually) produced variants of the P450 to produce diastereoselective and enantioselective cyclopropanation of styrene.

It would be nice to see the crystal structures of the engineered enzymes carrying out the reactions, to see how they constrain the styrene to react so specifically.

So here we have chemists acting like the blind watchmaker of Dawkins.  It would be nice if theory was good enough to predict and design the P450 variants produced here a prioi, but it isn’t.  The editorialist calls it biomimicry in reverse.

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.