Tough guys can run electrosynthesis

Here are some facts I took from one of my old lectures:

– Electrochemical alumunium production annually consumes more than 10% of electrical power in North America

– All oxidants and reductants accessible to organic chemists (chlorine, potassium permanganate, metallic sodium, hydrogen, to name a few) are produced in industry using electrochemistry

Shouldn’t these facts serve as reasons to use electrochemistry in order to run organic reactions directly, without involving all the waste associated with chemical reducing and oxidizing agents (we’re talking about chromium, lead, etc)? Think about it: if you pay electricity bills on time, electrons coming out of your electrical outlet will cost about 0.5 cents/mole… Curiously, the aforementioned considerations are not good enough to ensure widespread adoption of electrochemistry (otherwise there will be a lot more papers on this subject). The reason for this neglect lies in a steep barrier to entry into this field.

In the area of electrosynthesis, my lab has benefited tremendously from Tung Siu’s expertise. Tung was my first PhD student. When he came to my lab in 1999, Tung already had an undergraduate electrical engineering degree under his belt, which made it easy for him to engage in electrosynthesis. Tung was not intimidated…

Shockingly, I just realized that our last electrochemistry paper came out almost 10 years ago (… This work was done together with Tung and Christine Picard (now a Professor of Biology at Indiana U.: Ensuring continuity of projects is a big challenge in academic research and we somehow dropped the ball on electrochemistry in 2005… Now let’s fast forward to 2013. During this Christmas break I reasoned that it would be a perfect time to take our old Amel power supply off the shelf and see if that bad boy can still perform. Thankfully, Dmitry Pichugin was willing to help. Several years ago, Dmitry worked in my lab under the guidance of Igor Dubovyk. During his stay with us, Dmitry published a nice Angewandte paper together with Igor ( Of significance to our electrosynthesis aspirations, Dmitry is well versed in matters related to instruments and engineering (at the moment, he is working in our Departmental NMR facility). At 3:21pm, Dec. 27, Dmitry and I gave our Amel instrument a 2013 tune-up. Shono’s alpha-alkoxylation reaction ( was our test case. Do you want to see the easiest CH activation possible? Here it is! In the graphics shown below you will see our power supply and the reaction setup (2 graphite electrodes immersed into a methanolic solution of ethylpiperidine carbamate mixed with tetrabutylammonium tosylate as the supporting electrolyte). If you want, you can run this alkoxylation chemistry using graphite pencil inserts, it’s that simple. When I saw hydrogen bubbles at the cathode, I knew we were in business. Dmitry and I did not intend to push this reaction to completion. We ran it for 1.5 hours and just wanted to see the product. My PhD student Jeff St. Denis helped with the GC/MS analysis (thanks Jeff!). The most important outcome of this experiment is that things are working, we now have an updated standard operating procedure (even I can use this setup now), and I certainly hope that we will re-introduce electrochemistry back into our bag of tricks.




GC/MS analysis of our crude reaction

Holiday blog posts

My blog posts will be fairly irregular until January 3-4 as I plan to get ready for the new semester, prepare my lecture notes, and write some papers and a grant proposal. After January 3, I plan to resume my humble writings with a new vigour and on a regular basis, although I will no longer be on sabbatical.

I would like to wish everyone a happy and safe holiday season!

On acyl radicals

On this gloomy Friday evening in Toronto (accentuated by the fact that we were supposed to go to the movies with my wife, but I purchased the tickets online to the wrong theater…), I am going to talk about some thought-provoking radical chemistry. Earlier today, I was talking with my PhD student Jeff about some radical-related matters relevant to our own research. This discussion brought to light a paper that I have always found fascinating. The work deals with facile generation of acyl radicals. Acyl radicals are not that uncommon, especially when generated from seleno- and thioesters. However, radical cleavage of an aldehyde’s C(sp2)-H bond is a less precedented reaction that raises a few eyebrows. Back in 2005, Tomioka and colleagues reported a marvelous example of this process. In their efforts to add nucleophilic thiol-derived radicals to double bonds (with the ultimate hope of making 6-membered rings), the authors serendipitously discovered that thiol radicals prefer to abstract the aldehyde’s hydrogen, leading to facile generation of acyl radicals directly from aldehydes. The resulting intermediate went on to form the cyclopentanone shown below. Several years ago, Stoltz and co-workers put this chemistry to good use in their synthesis of cyanthiwigin F (


Adding colour to your science

Tonight I am happy to host Adam Zajdlik, a second year PhD student in my lab, on my blog. Over the past year or so, Adam has been tirelessly pushing the frontiers of boron chemistry. I was hoping that he would share some of the “tricks of the trade” on this page. Because TLC and its significance came up on this blog recently, it is fitting that Adam has his favorite spot visualization method to share. Here is how Adam develops boron-containing molecules in his TLC experiments.

“Curcumin is a diarylheptanoid found in the popular spice turmeric. It is a highly conjugated diketone and its enol form is thermodynamically favored (see inset A below) as it allows electron delocalization across the entire molecule. An interesting feature of Curcumin is its ability to coordinate with boronic acids to form brightly colored boronate conjugates (inset B). During the coordination process, electron density is donated from the curcuminoid pi system to fill boron’s valence shell. This lowers the LUMO of the pi system and leads to a red-shift of its UV/vis absorbance. Boron-coordinated curcuminoids are bright red in color, while curcumin is yellow in the absence of boron.

This visible change in color has enabled some interesting applications. The reaction of curcumin with boric acid to form the corresponding boronate complex (Rosacyanine) is a remarkably favorable process and can be harnessed to detect trace amounts of boric acid. This is a highly sensitive analytical tool and allows quantification of boric acid in slightly alkaline solutions at levels as low as 3 ppm (!). Curcumin is also used as a TLC stain that is selective for boronic acids and their derivatives. Most boronic acid analogues appear as bright red spots on TLC when stained with curcumin including free boronic acids, boronates esters, MIDA boronates and BF3K salts. This is an extremely useful extension of TLC reaction monitoring in the development of novel boron-containing molecules.”


Stitching with acetonitrile

Acetonitrile is rapidly turning into one of my favourite reagents. Its nucleophilicity can be quite instrumental under special circumstances, which is why acetonitrile is not just an overpriced HPLC solvent whose cost goes through the roof whenever Chinese economy tanks. The Ritter reaction instantly comes to mind whenever the nucleophilic properties of acetonitrile are considered. Of course, there are other examples, particularly in the organometallic literature.

Below is a recent case published by Lavilla and coworkers. This chemistry reminds us that acetonitrile can be a useful stitching element when employed at the right place and at the right time. The multicomponent reaction developed by the Lavilla group involves a cyclic imine that, upon activation by a Lewis acid (scandium triflate), undergoes a Mannich-type process. The resulting oxonium endpoint cannot undergo Povarov ring closure (my colleague Doug Stephan might call this a “Povarov-frustrated oxonium ion”). It appears that the oxonium ion’s reluctance to undergo Povarov reaction with the aromatic indoline fragment is due to geometrical constraints. Well, mother Nature hates voids and acetonitrile gladly fills the gap. The nucleophilic addition leads to the formation of a nitrilium ion (a special “hello” to my lab members is due at this point – they know what I am talking about), which is rapidly trapped by the nitrogen center. This is an awesome new multicomponent reaction that is rooted in the exceptional properties of acetonitrile.


Draw better structures, Dr. Yudin

A first year undergraduate student once came to see me during an office hour and posed a question involving thiophene. Some aromatic substitution, I think. He drew a molecule on the board. Those of you who teach organic chemistry might know the feeling… I looked at the structure and almost got upset by how unappealing it looked. For instance, the C-S-C angle was ridiculously close to 90 degrees. Of course, it takes time to know how to draw things well in chemistry and we all have been there. So I tried to encourage my visitor by saying: “You might want to take into account some geometrical considerations when you draw 5-membered rings. Your structure is somewhat unrealistic – where is the 120 degree C-S-C angle?”. Unbeknownst to him, the student was correct and should have jabbed me by saying: “Why don’t you learn your inorganic chemistry and know your bond lengths!”.

Indeed, the other day I was looking through some protein/inhibitor complexes in the pdb (Protein Data Bank). At some point, I said to myself: “Hmmm. Furan and thiophene are distinctly different!”. I checked other structures and indeed – sulfur’s d-orbitals, long C-S bonds, and associated geometrical preferences make their presence felt. Here is an expanded view that shows the two furan and thiophene fragments I looked at:

ImagePerhaps I need to know the chemistry of main group elements a bit better when I draw them in my structures. I think that from now I might make it a point to draw an angle that is close to 90 degrees in my thiophene structures. Will I actually do it? Who knows, probably not. But I do think that our tools of rendering molecules are adequate, yet not perfect. A lot of important features are “lost in translation”, so to speak.

Obsessive TLC habits

A week or so ago I had a discussion with one of my former students about what constitutes the most important skill to acquire in preparative synthetic chemistry. This is a complex and multilayered question simply because we have so many methods in our disposal. The list grows as new ways of interrogating molecules become accessible. Sometimes I think that we have way more than we need, to the point that instrumental cornucopia stifles the development of solid synthetic skills. When I was in graduate school there was a visiting scientist in our lab who was having a difficult time coping with his daily lab duties after our GC/MS machines broke down. This is an unfortunate situation that speaks to the “instrument addiction”. What did synthetic chemists do 40 years ago? They had less instrumentation, but I bet they were better prepared to do experimental science because they had no choice but to be resourceful. I do have some extreme views in this regard, as my students would testify. On a number of occasions I mentioned that we should just get rid of our two LC/MS systems because they provide too many false positives as well as false negatives (the worst possible combination!).

Now let’s get back to what I would consider to be the most important skill to acquire. I suppose that once an experimentalist knows how to efficiently isolate his/her products and set up reactions, everything comes down to following the reaction progress and developing top-notch observation skills. To me, it is all about TLC (thin-layer chromatography), which is the most accessible and rapid analytical tool possible. I think that we need to develop behaviours that are close to obsessive-compulsive in regards to how often we run TLC of our reactions and how early we apply our first TLC spot in a given case.


How often should one take a TLC measurement and when is a good time to take the first one? This is case-dependent and I am going to provide an example that strikes at the heart of the problem and makes us think (especially those of us who routinely deal with fairly unstable molecules). The reaction above comes from a total synthesis published by E. J. Corey and Scott Snyder several years ago. Scott told me about this example at a conference. If you run your first TLC of step 3 at 4 minutes after its start, it is too late and you will not get much product because the molecule is too unstable under the reaction conditions. However, once the reaction has been properly worked up after 3 minutes, the target molecule is isolable. I am sure there are many more examples like this out there and they all serve an important lesson. If you are a student, imagine that you are trying to make a sensitive intermediate and you are screening conditions that result in the infamous “messy TLC” description in your lab book. When did you take your first TLC?

From snow flakes to cellular permeability

I was under the weather last night, so there was no chance to publish my Friday post. But I am back now, sitting in our living room and marveling at the copious amount of snow that has fell upon us over the past 24 hours. I think it is easily 25cm, although I have not heard the official forecast. Now… Hydrogen bonds hold together the snowflakes I am looking at. The impressive cooperativity of these weak forces is responsible for the snowflake formation. In a totally unrelated domain, the cellular permeability of peptides and amino acid-derived small molecules is also related to hydrogen bonds. Peptides are typically awful in their ability to traverse non-polar cellular membranes, save for a few exceptions. Cyclosporine A (shown in inset A below) is among the better ones. The network of hydrogen bonds that you see provides for a fairly lipophilic conformation of this molecule and helps it go through cellular membranes by passive diffusion. Well, at least this is what people think now (you never know when we will all flip our minds upon discovery of a predominantly active pathway that involves a protein transporter for cyclosporine A). The lessons offered by the internally satisfied hydrogen bonds here extend to other areas. The inset B below shows a marvelous case from a paper by Jacobson and colleagues: The two molecules clearly have identical polar surface areas, yet the one on the right is 4 times more cell-permeable by virtue of the hydrogen bond marked in red.


So what should those, who want to design cyclic peptides with improved cellular permeability, take from all of this? I think the main lesson is that we need to continue our hard-target search for hydrogen bond pairs and they do NOT need to be restricted to what you see in the case of cyclosporine. The classical NH-O hydrogen bonds are cool, but we need to go way beyond that. Here is a paper that talks about glycine’s ability to engage its alpha C-H bonds in polar contacts (inset C) that lead to stabilization of inter-helical motifs in proteins: Does this mean that we want to see more glycines in cyclic peptides in order to make them have better chances of being cell-permeable? I am not sure. But I do know that glycine has two alpha C-H bonds and this is the reason why the likelihood of forming the “right” connection is simply higher for glycine. It follows that perhaps d-amino acids should be considered more often if these unusual hydrogen bond motifs are to be captured. Lastly, I will present another case that is well familiar to protein chemists – that of serine (inset D). Here is a paper showing that serine is a residue par excellence in “reaching over” and forming hydrogen bonds using its OH group: Someone has to take all of this protein chemistry knowledge and translate it into cyclic peptides. We may then indeed start to see trends that will emerge from “unusual suspects” for hydrogen bond formation in macrocycles. I do want to end by saying that these less common hydrogen bonds are fairly weak, but they sure have their place under the sun!

cis-Amides and their periodicity

Molecular diversity is a term that is familiar to synthetic chemists. A diverse collection of molecules is characterized by a broad representation of functional groups, chemotypes, ring sizes, and so on. How do we judge how rich is the conformational diversity of a given collection? My lab’s efforts in the area of peptide macrocyclization have made me think quite a bit about this matter. It is particularly enticing to make big gains without too much synthetic effort.

Time and again, I look for papers that provide straightforward mechanisms of controlling accessible conformational space. In this regard, cyclic peptides offer an unprecedented opportunity, particulalrly once proline is considered. Proline is known for its relatively high barrier for cis/trans interconversion, which makes the X-Pro motif (X is an amino acid) an interesting structural feature to explore. A paper by Rabenstein and co-workers cited below provides a marvelous demonstration of capturing cis-amide bonds in disulfide macrocycles. The authors have found that the corresponding linear peptides contain Cys-Pro bond in its predominantly trans form. However, cyclic peptides display periodicity in cis/trans geometry of the Cys-Pro bond (marked red in the graphic below). It turns out that macrocycles containing an odd number of amino acid residues are predominantly cis at the Cys-Pro juncture, whereas those with an even number of amino acids are predominantly trans. This finding is significant as it offers a tool to sample various conformations by changing the number of residues in a macrocycle. I’m afraid the precise nature of this intriguing phenomenon is unknown.


Azides by diazotransfer

Diazotransfer from activated azides to primary amines is a fascinating process that provides a useful route to organic azides using a fairly accessible reagent – (triflyl)azide. The mechanism of the reaction remains somewhat of an enigma. There are several metals, including zinc and copper, that catalyze this process. Prof. Chi-Huey Wong has used diazotransfer chemistry in several of his elegant approaches to azasugars and put forth a mechanism that involved 5-membered intermediates. Below I am showing a representative case. You will note that protected threonine is used in this process.


The resulting azido version of threonine is a useful building block. In fact, the reason for this post is that I have been looking at ways to circumvent some of the troubles encountered in really hindered amide couplings. One way to deal with this challenge is to mask the alpha-amino group by way of an azide, which is not sterically demainding (compared to some N-protected versions). Notably, this amino acid derivative is configurationally stable (to an extent, of course). Nicolaou and co-workers have put this versatile building block to good use in their synthesis of thiostrepton (