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Blowing things up with heterocycles, featuring Werner E. Bachmann

You may have seen the recent article by Jyllian Kemsley (C&EN) on how authorities dealt with what they called the “largest cache of homemade explosives ever found in the U.S.”  (See also here and here.) George Djura Jakubec’s home was so infested with explosives and the chemicals used to make them that a firewall was built around the home so it could be burned down.

If you’ve ever looked at the structures of explosives (out of mere curiosity of course), you can’t help but appreciate the abundance of heterocycles.  Browsing Agrawal and Hodgson’s 2007 book entitled Organic Chemistry of Explosives (Wiley) reveals hundreds of explosive heterocycles.  Just for fun, let’s look at a couple, which will also give me a chance to touch on the accomplishments of one of my favorite chemists, Werner E. Bachmann from the University of Michigan.

HMTD, a peroxide

While Agrawal and Hodgson state that “no peroxide has found practical use as an explosive, a consequence of the weak oxygen-oxygen bond leading to poor thermal and chemical stability and a high sensitivity to impact,”  this hasn’t stopped terrorists and folks who like to make bombs at home. I can thus imagine the concern of the hazmat team when they found six quart-sized jars of hexamethylenetriperoxidediamine (HMTD) in Jakubec’s stash.  HMTD, made simply from hexamine and hydrogen peroxide in the presence of citric acid, is unstable and extremely dangerous to manufacture.

N-Nitroamines (Nitramines) and Werner E. Bachmann

Hexamine is also the starting material for two classic secondary explosives, RDX and HMX, shown above.  Secondary explosives are those that are rather stable compounds, requiring a primary explosive to get the ball rolling.

RDX (cyclonite, hexogen, Royal Demolition eXplosive, or cyclotrimethylenetrinitramine) is the most important military high explosive in the U.S.  It’s second to nitroglycerin among common explosives in strength and is a component of C-4 and Semtex.  It played a huge role in World War II, as we’ll see in a minute.

The most common method of its manufacture is the Bachmann process, where hexamine is nitrated in the presence of ammonium nitrate.  I must digress for a moment.  I got to know of Werner Bachmann’s accomplishments when I was at the University of Michigan, where he was a professor from 1925 until his untimely death in 1951.  The Department of Chemistry honored him annually with the Bachmann Lecture, where a distinguished organic chemist was invited to give a talk and attend a banquet.  Having introduced a few of the speakers, I had the chance to comment on Bachmann’s achievements in the opening remarks.

It’s really worth reading a biographical memoir of Bachmann (pdf) by the famous heterocyclic chemist Robert C. Elderfield, also from the University of Michigan, published by the National Academy of Sciences.

An exerpt:

In the summer of 1940 the National Defense Research Committee was established and in the fall of that year a group of organic chemists, most of whom were ignorant of the chemistry of explosives, met in Roger Adams’s residence in Urbana, Illinois, to discuss how they could best contribute to the budding war effort. Among the neophytes was Werner Bachmann and among the topics discussed was how best to manufacture and use a high explosive known in this country as Cyclonite and in England as RDX. The potential military value of RDX as the most powerful of the nonatomic high explosives had already been appreciated. However, in this country there was no knowledge at the time as to how it could be used safely and no practical process for its manufacture. It subsequently developed that the British had largely solved the problem of the use of the explosive and had developed a fairly satisfactory batch process for its manufacture. To Bachmann was assigned the problem of devising a more efficient and economical manufacturing process.

In some respects Bachmann’s achievement in discovering an efficient new method for preparing RDX testifies most eloquently to the amazing versatility and experimental technique of this extraordinary chemist. He had no previous experience in the chemistry of explosives, and was best known for his elegant syntheses of complicated molecules such as the sex hormones. When Bachmann first learned that his assignment under the NDRC program was to be the development of a practical method for the large-scale manufacture of the highly sensitive RDX, he records that his “heart sank.”

In January of 1941, J. C. Sheehan, who had just completed his doctoral thesis with Bachmann, began work on a novel approach to the synthesis of RDX. In the conventional British process for making RDX, hexamethylenetetramine is treated with 98-100 percent nitric acid, as is shown in equation (1).

C6H12N4 + 3 HNO3 –> C3H6O6N6 + 3 HCHO + NH3       (1)

This direct nitration method suffers from at least two serious disadvantages: large excesses of nitric acid must be employed for optimum yield, and one half of the equivalent of formaldehyde is lost, principally through oxidation by the nitric acid. Thus, the maximum amount of RDX possible is one mole from one mole of hexamethylenetetramine, and the actual yield is considerably less. In 1940 Bachmann learned that Ross and Schiessler at McGill University had obtained RDX from formaldehyde, ammonium nitrate, and acetic anhydride in the absence of nitric acid, but no details of their experiments were available. Although equation (2) is undoubtedly an oversimplification of the reaction, it occurred to Bachmann and Sheehan to attempt utilization of the by-products of the nitrolysis to obtain a second mole of RDX. In this way, if two moles of ammonium nitrate and six moles of acetic anhydride were present during the nitrolysis of hexamethylenetetramine, then two moles of RDX might be obtainable from one mole of hexamethylenetetramine.

C6H12N4 + 4 HNO3 + 2 NH4NO3 + 6 (CH3CO)2O –> RDX + 12 CH3CO2H     (2)

Although exploratory experiments were discouraging and frequently led to spectacular “fume-offs,” from a few reactions a small amount of RDX was obtained. After each experiment, Bachmann, who personally spent long hours in the laboratory, would carefully and ingeniously design a variation in the experimental conditions until finally, after literally dozens of experiments, the reaction conditions which permitted control of the process were worked out and a consistent yield of RDX was obtained. A memorable occasion was the day on which Bachmann and Sheehan isolated more than 100 percent yield of RDX based upon one mole of hexamethylenetetramine to demonstrate conclusively that a “combination” process was prevailing. The enthusiastic encouragement given by Roger Adams and J. B. Conant was most heartening in the early phase of the work. It now became important to adapt the process for relatively large-scale use. A number of scaled-up reactions were carried out involving quantities as large as several kilograms. Owing to the hazardous nature of the reaction these experiments were conducted on Sunday mornings and at other times when the University buildings were sparsely occupied.

The RDX prepared by the new process was at first considerably more sensitive to impact than was RDX from the direct nitrolysis reaction. At one point an urgent telegram was received from the U.S. Bureau of Mines Laboratory in Bruceton, Pennsylvania, reporting that an RDX sample submitted to them for evaluation was highly sensitive and should be handled with extreme care. This sensitivity was later traced to the presence of impurities, in particular to a small amount of a high-melting substance termed HMX (HM—high melting), and to a lesser extent to an impurity termed BSX (BS—Bachmann and Sheehan).

In the early phase of this work the armed services showed little interest in RDX as a military explosive, but during the summer of 1941 Admiral Blandy, then Chief of the Bureau of Ordnance, after consultation with top scientists of the Office of Scientific Research and Development, recognized the potentialities of RDX for use in rockets, torpedoes, and aerial bombs. The greater explosive power as compared to TNT (RDX has 150 percent of the power of TNT on a weight basis; on a volume basis, which is important for certain applications, RDX is approximately twice as powerful by virtue of its greater density) offered tremendous potential advantages. In addition, its markedly greater brisance, or shattering power, made RDX the ideal explosive for use in shaped charges, the principle behind the bazooka.

Several companies undertook the development of the new combination process, but the efforts of Tennessee Eastman were the most successful. At Kingsport, Tennessee, the largest munitions plant in the world was constructed to produce RDX by the new process on ten continuous production lines. It has been reported (Scientists against Time by James Phinney Baxter, 3d) that RDX was produced in this way at the rate of 360 tons per day. The production of RDX by the direct nitration process would not only have been considerably more expensive but would have involved much larger quantities of critically short corrosion-resistant materials for handling the nitric acid. It has been estimated that the saving to the government in plant cost alone was over two hundred million dollars.

The contribution of RDX to Allied success in the Second World War can scarcely be overestimated. Although RDX was considered too sensitive to fire from conventional artillery, it found wide application in rocket heads, in the 12,000-pound “Tallboys,” in block-busters, and in the torpedoes which sank the “unsinkable” German battleship Tirpitz. Thus Bachmann, the very prototype of the unassuming scientist, was able to make an outstanding contribution to his country’s and to the free world’s victory by bringing to bear his extraordinary scientific prowess, his imagination, and his perfection in laboratory technique.

Simultaneously with and subsequent to his work on RDX he also carried on important investigations on the oxynitration of benzene as a route to picric acid and on various aspects of the penicillin problem. The strain created by these wartime researches and the effort devoted to them undoubtedly contributed to the serious undermining of his health.

In recognition of his services Bachmann was the recipient of the Naval Ordnance Award in 1945, and in 1948 he was granted the Presidential Certificate of Merit by the United States government and the King’s Medal by the British government.

The strain and effort of the war years finally took their toll and, with his health undermined, Werner Bachmann died of heart failure at the age of forty-nine on March 22, 1951.

Although Bachmann’s career was a relatively short one, he published over one hundred and fifty papers, featuring such accomplishments as the first total synthesis of a steroidal sex hormone (equilinen), the Gomberg-Bachmann reaction for the synthesis of biaryls from aryl diazonium ions, and some pivotal early work in the synthesis of penicillin.  John C. Sheehan, a Ph.D. student of Bachmann’s who worked on the RDX project, went on to accomplish the first synthesis of penicillin V as a faculty member at MIT.

One more thing.  If you enjoy watching explosions in slow motion, especially seeing shock waves, check it out (fast forward to 2:42 for the good stuff):

Tetrazole synthesis, Part II: Harnessing the tetrazole-azidoazomethine equilibrium

Welcome to the second part of our Tour de Tetrazoles. In Part I, we saw that tetrazoles, particularly 5-substituted versions, are often made from nitriles and an azide source. Toxic and explosive hydrazoic acid can be formed in this chemistry, but we saw that there are ways to minimize its production.

Now let’s take a look at another general approach to tetrazoles, namely the concerted electrocyclic ring-closure of azidoazomethines. This chemistry will allow us to access a variety of tetrazoles, including fused-bicyclic versions, often under azide-free (and hydrazoic acid-free) conditions.

The tetrazole-azidoazomethine equilibrium

Azidoazomethines, also known as imidoyl azides, can undergo a concerted electrocyclization reaction to tetrazoles:

The tetrazole-azidoazomethine equilibrium

The position of the equilibrium depends on the nature of the substituents: electron-withdrawing groups on the azomethine nitrogen favor the open form, whereas hydrogen and normal organic substituents favor the tetrazole (leading reference and theoretical studies).

Fascinating, but there’s more: This equilibrium is an excellent entry point for tetrazole synthesis. Anything you can do to make the azidoazomethine will, with the right substituents, lead to the tetrazole.

Accessing azidoazomethines, and thus tetrazoles

If you can make the azidoazomethine, you’ll get the tetrazole. So, how does one make azidoazomethines? There are two primary methods, namely (1) the use of an activated amide to acylate sodium azide and, (2) the diazotization of amidrazones, themselves available by acylation of hydrazine with an activated amide:

Routes to azidoazomethines

Notice that the amidrazone method doesn’t require sodium azide or its equivalents, prompting some to call this an “azide-free” method.  A word of caution, though: It’s conceivable that the azidoazomethine could eliminate azide, so hydrazoic acid may still be lurking.  Use caution.

Example: Azidoazomethines (and thus tetrazoles) by Duncia’s method

John Duncia at du Pont reported a nice way to access azidoazomethines (and thus tetrazoles) from amides and TMSN3 using diethyl azodicarboxylate and triphenylphosphine. Shown below is a more recent application of Duncia’s method by discovery chemists Li, Tino, and co-workers at Bristol-Myers Squibb, who synthesized BMS-317180, a GHS agonist.

BMS discovery route using Duncia's method for tetrazole synthesis

The Process R&D group at BMS later felt that the issues of high exothermicity, TMSN3 safety, and PPh3PO removal warranted another approach to the tetrazole for scale-up.

Example: Azidoazomethines (and thus tetrazoles) from amidrazone diazotization

The BMS process group ultimately decided to avoid azide chemistry altogether by using amidrazone diazotization chemistry. Hydrazinolysis of the oxazoline shown below gave an amidrazone that was then diazotized to give the azidoazomethine (not shown) and thus the tetrazole on a 40 kg scale.  Superb.

BMS's Process for Tetrazole Synthesis on Large Scale

By the way, you can also make 5-substituted tetrazoles from amidrazones, though it’s not as common as the nitrile/azide method discussed in Part I of this post. Here’s an example :

Amidrazone route to 5-substituted tetrazoles

Fused bicyclic tetrazoles: An ideal application of the azidoazomethine-tetrazole equilibrium

Azidoazomethines where the azomethine (imine) is part of a ring, e.g. 2-azidopyridines and 4-azidopyrimidines, undergo electrocyclization to provide fused bicyclic tetrazoles. Historically, this is where the azidoazomethine-tetrazole chemistry began, with work by Bülow (1909; azidopyrimidines), Benson (1954, azidopyrimidines), Boyer (1959, azidopyridines), and McKee (1962, azidopyrimidines). The following example is from McKee’s lab at UNC and Montgomery’s lab at SRI (see also here). Both the azide and diazotization methods were used successfully.

McKee and Montgomery fused tetrazole synthesis

Finally, remember that the position of the azidoazomethine-tetrazole equilibrium depends on the electron density around the tetrazole? McKee used that knowledge to develop a new purine synthesis: Converting the above amine (electron donor) to the imidate shown below (electron acceptor) caused the azidoazomethine-tetrazole equilibrium to shift to favor the latter, which upon heating gave a purine. There’s some great stuff in the old literature.

McKee Purine Synthesis by shifting the tetrazole-azidoazomethine equilibrium

McKee, by the way, was the professor that got me interested in heterocyclic chemistry… see an earlier post for that story.

I hope you’ve enjoyed this Tour de Tetrazoles. I know there are some tetrazole experts out there, so please share some of your knowledge in the Comments.

Deconstructing the Knorr pyrrole synthesis

It’s time for some “oldie-but-goodie” heterocyclic chemistry, namely the Knorr pyrrole synthesis.  What’s left to be said about this venerable route to pyrroles?  Well, I’d like to point out that it should probably be termed the Knorr pyrrole syntheses (plural).  As usual with chemistry, things are more complex than they first appear.

Here’s the upshot:  There are two fundamentally different pyrrole connectivities that are produced under the Knorr umbrella.  Let’s look at what they are and then delve a little deeper into the connectivity that is often overlooked.

What is the conventional Knorr synthesis?

If you were to consult a reference source or ask someone to describe “the Knorr pyrrole synthesis,” you’d probably find something like this:

The Knorr is usually considered to be the condensation of an α-aminocarbonyl compound with another carbonyl compound, typically an active methylene compound such as a β-ketoester, in the fashion shown above, generally proceeding by (i) condensation of the amine with the other carbonyl compound and (ii) an intramolecular aldol (Knoevenagel) condensation.  Using an organizational system that I employ in my heterocyclic chemistry course, it’s a [3+2]-a,c approach, i.e., it makes the bonds at the “a” and “c” faces of the pyrrole by combining a three-atom component and a two-atom component.

Getting specific, one of my favorite examples is Hamby and Hodges’ 1993 work at Parke-Davis, featuring a Weinreb amide approach to the α-aminocarbonyl compound and reductive deprotection to the amine in the presence of the β-ketoester:

Most [3+2]-a,c Knorr examples produce pyrroles with an electron-withdrawing group (EWG) at the 3-position, but there are examples without it.

The Fischer-Fink variant of the Knorr pyrrole synthesis

If you look a bit further into the Knorr synthesis, you find examples that I would classify as [3+2]-a,d variants.  Here, the α-aminocarbonyl compound contributes two pyrrole atoms rather than three; the other carbonyl compound (typically a 1,3-diketone) contributes three atoms rather than two.  These reactions proceed by (i) condensation of the amine with the other carbonyl compound to form bond a and (ii) an intramolecular aldol condensation to form bond d.  If the amine bears two electron-withdrawing groups (as it does in much of the early work), one is lost during the reaction.

This variant of the Knorr synthesis is perhaps best termed the Fischer-Fink variant after the discoverers of traces of these compounds in traditional Knorr syntheses that employ ethyl acetoacetate (H. Fischer and E. Z. Fink, Hoppe-Seyler’s Z. Physiol. Chem. 1944, 280, 290 and 1948, 283, 152 and this link).

It was Kleinspehn in 1955 who figured how to obtain a majority of the [3+2]-a,d connectivity: simply use diethyl malonate rather than ethyl acetoacetate.  Paine and Dolphin later improved Kleinspehn’s method by preforming the amine rather than carrying out an oxime reduction in situ.  The Paine/Dolphin method is notable in that it works regioselectively with unsymmetrical 1,3-diketones and has found wide application in porphyrin synthesis.

Let’s look at a couple of my favorite examples of the Fischer-Fink variant of the Knorr pyrrole synthesis.

Elliott and co-workers at BioCryst used an α-cyano aldehyde rather than a 1,3-diketone, producing a 2-carboxy-3-aminopyrrole, an intermediate in their synthesis of some PNP-inhibitory pyrrolopyrimidinones (9-deazaguanines):

Prashad and co-workers in the process group at Novartis later used the Elliott chemistry to prepare a related PNP-inhibitor.  Both the BioCryst and Novartis groups used cyanamide as the cycloguanidinylating agent to produce the pyrrolopyrimidinones, a method that can be traced back to the work of my early mentor Robert McKee at UNC-CH, the subject one of my earlier posts.

The Fiesselmann-type modification of the Fischer-Fink variant

Okay, that’s a mouthful, but I think it’s worth treating this [3+2]-a,d method separately.  In the Fischer-Fink chemistry, a 2-aminomalonate is used, one of the esters being lost in the cyclization reaction.  Starting in the 1980s, examples began to appear where a simple glycinate is used; the second ester is omitted.  Thus, the condensation of simple α-amino esters with 1,3-diketones or their equivalents produces 2-carboxypyrroles as shown in the following example by Mataka (Synthesis, 1983, 157-159):

As far as I can tell, there isn’t a standard way to refer to these reactions.  They remind me of the Fiesselmann thiophene synthesis, which involves the condensation of α-mercaptoacetates with 1,3-diketones and their equivalents, so I’ll call these Fiesselmann-type modifications of the Fischer-Fink variant of the Knorr pyrrole synthesis.

Here are a few more examples of the Fiesselmann-type pyrrole syntheses.  Note the complementary regiochemistry of the last two examples.

Bottom line

The greater Knorr synthesis umbrella produces two basic connectivities resulting from [3+2]-a,c or [3+2]-a,d constructions.

Knorr-o-philes please weigh in.

[Jan. 21, 2012:  Edited Fischer-Fink citation to include earlier work.]

Toward the ideal reaction – Part 2

Toward the Ideal Reaction – Part 2

In Part 1, the concept of an ideal reaction for biomolecule labeling was outlined:  One step, no protecting groups, fast, efficient, specific, no catalyst or reagents, no external stimulus, and easy cleanup.  Jäschke’s work on oligonucleotide labeling via the inverse-demand Diels-Alder cycloaddition of tetrazines with norbornenes was featured.

Let’s look at some other chemistry and invite an expert guest, Jack Hodges, to chime in.  He also has a few things to say about big pharma versus small companies.

What about click chemistry?  Well, about that copper…

When one thinks of simple addition reactions for biomolecule labeling, click chemistry comes to mind.  Sharpless’s copper-catalyzed dipolar cycloaddition of azides with alkynes to produce triazoles is the de facto standard click reaction, but, well, it uses copper.  Not ideal.  Plus, the copper may cause problems in the applications we’re focusing on.

Naturally, ingenious chemists have jumped on that problem.

Copper-free click reactions – dial in some strain, maybe change the dipole

How do you speed up dipolar cycloadditions to alkynes without using copper?

You can fool around with the electronics of the alkyne, but then you run the risk of making it susceptible to unwanted reactions.

Alternatively, it’s well-known that dipolar cycloadditions are faster with strained dipolarophiles.  Bertozzi harnessed this effect for click chemistry via cyclooctynes (so-called SPAAC reactions, for strain-promoted alkyne-azide cycloadditions).  Others have joined the fray.

Another approach is to swap out the azide for a speedier nitrone dipole (SPANC reactions), as reported by the groups of van Delft and McKay.

Here’s an example of what we’re talking about, using van Delft’s bicyclononynes (BCNs):

Insights from a guest expert:  Dr. Jack Hodges

To give us an inside look at the state of the art in this area, we have with us my colleague Jack Hodges, ex-WLPD/Pfizer, who now leads the chemistry effort at Berry & Associates, Inc. (B&A), a firm that specializes in nucleic acids chemistry.  Some of you may recall Jack’s prominence in the early days of combinatorial chemistry, where he published seminal articles on the use of polymer-supported scavengers.  He has recently negotiated a scientific and business relationship between B&A and SynAffix, B.V. to provide a line of SPAAC reagents for the oligonucleotide field that are derived from van Delft’s BCN.

Will Pearson:  Jack, what are some of the challenges of using click chemistry in the oligonucleotide field?  

Jack Hodges:  There are plenty of examples of people who have used Cu-catalyzed Click reactions on oligonucleotides but there are also other examples where the Cu(I) catalyst has been reported to cause partial degradation of the oligo.  The partial degradation paper we always note in our product literature is Kanan, M.W., et al., Nature, 2004, 431, 545-9.  There are probably other similar reports.  This problem doesn’t seem too surprising to me since both Cu(I) and Cu(II) can coordinate to heteroatoms, and nucleic acids are full of heteroatoms.  Whether or not you believe Cu(I) is a serious problem around oligos, my feeling is that if you don’t need it, why bother?  There are numerous recipes for making Cu(I) in-situ for traditional Click reactions and often it takes a fair amount of investigation to find the one that will work for your application.  The Cu-free approach does away with all that.  Just put the strained alkyne and the azide together and the triazole forms.  The old fashioned expression is “dump and stir”.  Somehow “dump and stir” doesn’t have as nice a connotation as “Cu-free Click” or the sound of the quirky acronym “SPAAC” (short for strain-promoted azide/alkyne cycloaddition), but in practice it is just that simple.

WP:  For copper-free click reactions of azides with alkynes, there are quite a few competing techniques.  Would you please tell us about your path to selecting van Delft’s BCNs, giving us a little perspective on the various technologies that are available?  What made BCNs your top choice for commercialization?  (B&A also sells compounds based on Schultz & Pigge’s MFCOs.)

JH:  There are two things that attracted us to BCN.  First the BCN synthesis looks attractive from a commercial standpoint.  It starts with 1,5-cyclooctadiene (which is about as cheap an 8-membered ring compound as one can buy) and requires relatively few synthetic steps, each of which look to be scalable.  Second, BCN has the lowest calculated LogP value among the other popular cyclooctynes in the literature.  This makes BCN desirable in terms of maintaining the viable biological properties for oligos and other biological macromolecules to which it is attached.  DIFO is pretty close to BCN in terms of LogP but it is much harder to synthesize.  To be fair, BCN-OH is still hugely more lipophilic than propargyl alcohol.  So if you absolutely need to avoid lipophilicity, maybe the traditional Cu-catalyzed Click is your best bet.

WP:  What should we know about IP and licensing in this field?

JH:  So far as I am aware, the only issued US Patent for Cu-free Click reagents and methods belongs to UC Berkeley (US 7,807,619).  There are other published patent applications that may well lead to additional patent coverage in this field.  It seems pretty clear that SPAAC reagents and methods fall outside the broad coverage of the Scripps patents that cover Sharpless’s Cu-Catalyzed Click methodology.

WP:  The classic ways to attach things to oligonucleotides involve amine acylation or thiol alkylation.  Besides click chemistry, what other bioorthogonal conjugation methods do you believe are useful for the modification of oligonucleotides?

JH:  Another Click reaction, oxime formation, is gaining steam with oligos.  B&A now sells some oxyamine and aldehyde reagents that can be incorporated during oligo synthesis or via post-synthetic modification.  Based upon their current popularity, we will be expanding our oxyamine product offerings.

WP:  While I’ve got you here, is there anything you’d like to say about your experience of working in a small chemistry company versus your time in big pharma?

JH:  On the whole both experiences have been very positive.  I had a great run in the pharma industry when it was still a vibrant place for doing top notch research.  For most of my 22-year career in pharma, drug companies embraced the financial risk of drug discovery.  That made it fun to be a chemist working in big pharma.  I don’t think the same fun is there today because drug companies got too big via mergers.  As they grew, the lower productivity of research staff that occurred while they were distracted immediately following a merger (when there is an inevitable re-evaluation, repositioning, and reorganization of research endeavors) somehow became part of the justification for the industry to reduce the overall amount of research investment.  To me, pharma companies today have all caught the same disease.  They all seem downright fearful of research investment.  To the scientists in the trenches, it can appear as if their management puts as high a priority on trying to minimize risk as it does trying to discover drugs.  Perhaps Bruce Roth’s recent article in C&E News says it better than I do here. (WP:  Links here and at Chemjobber here; see also Firestone’s perspective here and at In the Pipeline here.)

Today, I am very happy working in a privately-held specialty chemical company.  The ‘you eat if you can sell it’ attitude of small company life certainly keeps a scientist’s daily activities interesting, especially in a world where foreign competitors seem to always have a lower labor cost.  This environment drives Berry & Associates to work on the most difficult problems of our customers.  There we can provide products of tremendous value to cutting edge biological technologies.  To highly educated and experienced chemists, such work is as fun as it is profitable.

WP:  You’ve been working with heterocycles for most of your career.  Looking back so far, what accomplishment in that field do you feel is most significant?

JH:  Ten years later, I still get inquiries about my lithiooxazole paper that was published in JOC in 1991.  It didn’t feel like super-remarkable chemistry at the time but people still read that paper.  Editorially speaking, I guess that is a darn good reason to publish results that initially surprise you.  You can save others from the same surprises!

Hooked on heterocycles

I have a question: How did you get hooked on heterocycles?

I’ll go first:

A failed exam, cocaine, and a crusty chemist:  How I came to love heterocyclic chemistry.

I became an azaphile during my undergraduate days at UNC-Chapel Hill, a process that involved failing a final exam, becoming enraptured by the chemistry of lysergic acid, morphine, and cocaine, then being turned down for undergraduate research.  Well, initially at least.

At some point, anything with a nitrogen atom in it became fascinating, especially if the nitrogen was in a ring.  Everything else started to look… bare.

How did this happen?  I can trace it back to Professor Robert L. McKee, a “heterocyclic chemist’s heterocyclic chemist” at UNC.  He’s no longer with us, but he’s worth a tribute, as you’ll see.

You know those dreams where you’re not prepared for the final exam?

I had Professor McKee for two classes, one that proved traumatic, the other enlightening, both being important to my baptism into heterocyclic chemistry.

First, the trauma.

I walked into the final exam for McKee’s second semester organic chemistry class with a strong A average and a lot of confidence.  I loved the class and had studied hard for the final.  But my confidence quickly faltered as I found out that he had made two final exams, one for those with an A average and one for everyone else.  Huh?

I sat down and looked at it, and there were all these crazy rings with nitrogen atoms sprinkled all over them, none of which I’d never seen.  And the questions were unintelligible.

I walked to the front of the room to ask what was going on, and Professor McKee told me that the “A” students were supposed to have read Chapter 10 on Nucleic Acids on their own, for the exam, which would be entirely on that topic.  I had somehow missed this announcement, despite attending every single lecture.

I sat back down and tried, but I couldn’t answer a single question.  I got maybe ten points.

My “A” became a “B”, which McKee told me was generous.

I still get sweaty thinking about this.

Nonetheless, it exposed me to purines, pyrimidines, nucleosides, and nucleic acids, prime denizens of the world of heterocyclic chemistry.

Ironically, I would end up as VP of a company that specializes in nucleic acids chemistry some twenty-five years later.

I’d like to see that exam again.

Onward to enlightenment…


With my tail between my legs, I enrolled in UNC’s advanced organic chemistry course, taught by none other than my beloved Professor McKee.

Things went much better this time.

We used Noller’s Advanced Organic Chemistry, an old textbook even back then.  I loved it because it had plenty of history and was rather descriptive in its approach.  It was also heavily slanted towards heterocyclic chemistry.

What I remember most were McKee’s lectures on the chemistry of lysergic acid, morphine, and cocaine.  These were beautiful molecules and came with such rich chemistry.  I can’t say I remember much else from the class, but that was enough; I was hooked on heterocycles.

It felt empowering to know something about the drugs that were making the rounds back then.  Even more exciting was the realization that powerful physiologically-active substances can actually be synthesized.  From scratch!

Pearson/Mans synthesis of (+)-cocaine

I remember sitting on the bed in my dorm room at UNC with a ball-and-stick molecule of cocaine, thinking, “I wonder how I might make this?”  Not because I wanted to use it or sell it, mind you; just because it was beautiful.

Fast forward to 2004, when Douglas Mans, a talented graduate student in my research group at the University of Michigan, synthesized (+)-cocaine, the enantiomer of natural (-)-cocaine.  Full circle.

Do you really want to do undergraduate research with this guy?

Sometime during this period, my budding interest in heterocyclic chemistry led me to stop by McKee’s office.  It was attached to a one-man lab, and since he was getting near retirement, he no longer had graduate students.

I was struck by the dark, archaic lab crowded with hundreds of vials of crystals, each labeled with hand-drawn structures of unique heterocycles.  I could swear there was also a retort containing some bubbling liquid.  I wanted to get in there and make something!

A few things concerned me, though.

First, he smoked a pipe.  In the lab.  Not good.

Second, he tasted all of his compounds.  Even as a neophyte, I knew this couldn’t be a good thing, and I quickly made an association between this practice and the various growths I could see on his skin.  He was old-school though, and taste was part of compound characterization.

Despite my misgivings, I asked this kindly, crusty man if I could work for him.  His response was quick:  “If you want to do research and continue on to graduate school, you need to go work for someone other than me.”

He suggested Ernest Eliel, whose area was stereochemistry, a topic I also loved.  I joined Eliel’s lab, where I managed to get some heterocyclic chemistry in:  We published the first example of neighboring group participation involving a four-membered ring sulfur intermediate, a thietane.

And we used Barry Trost’s method for making the thietane intermediates, relevant in that I ended up getting my Ph.D. with Barry at Wisconsin, working on… things with lots of nitrogens!

So, how did you get hooked on heterocycles?