Chemistry Blog

Jan 21

Kudos to the Fagnou Group

I am continuously impressed by the publications that have appeared since Prof. Keith Fagnou’s shocking passing a little over a year ago. The chemical community still mourns; it is clear from these post-mortem publications that Fagnou’s – and his clearly dedicated and talented graduate students and post-docs – brilliance lives on. (Note – this is the same article that appears on Chemical Crystallinity.)

The chemistry that Fagnou has truly spearheaded, direct C-H functionalization, is a method of forming C-C, C-N, C-B, etc bonds without having to prepare one of the coupling partners, as in traditional transition-metal catalyzed cross-coupling reactions. Palladium, rhodium and ruthenium are commonly used catalysts in direct C-H functionalization reactions. Fagnou has published a great deal on arylation reactions of a wide variety of substrates and even a bit on direct benzylation reactions. Some fairly recent reviews are linked in a previous post at my own blog.

A recent publication in Journal of Organic Chemistry (doi: 10.1021/jo102081a), “Predictable and Site-Selective Functionalization of Poly(hetero)arene Compounds by Palladium Catalysis,” published by David Lapointe and coworkers, explores the development of two approaches to selectively functionalizing multi-ring systems – 1) using site-selective reaction conditions, and 2) a pathway with a particular order of reactivity according to a concerted metalation-deprotonation (CMD) mechanism. It is well-known in the field that a great many (hetero)arenes can be functionalized with (painfully) rigorous fine-tuning of the catalyst, ligand, additives, and other reaction conditions. Some substrates have been more difficult to functionalize than others, and selectivity of particular positions on these rings is always an issue – this publication tackles both issues.

To explore site-selective functionalization, the group used compounds with more than one available C-H bond for direct functionalization, and using multiple protocols specific for specific C-H bonds (Larossa’s conditions for C2 arylation of indoles, Gaunt’s Cu-catalyzed C3 arylation of indoles which is actually selective for meta to amido groups, and their own protocols for arylation of perfluorobenzenes and aromatic N-oxides) were able to successfully and selectively functionalize targeted C-H bonds in moderate yields. Here is an example with some decent yields, with reaction times ranging from 16 – 24 hours:

The alternative approach relies upon the CMD pathway as the operative mechanism, which favors electron-deficient substrates.  Several years ago, Echavarren published support of this mechanism by finding a preference for the most acidic C-H bond and requirement for a carbonate base, and Fagnou established the use of a pivalate additive, which was speculated to play a crucial role via CMD.   A recent mechanistic paper with aromatic N-oxides as the substrates strongly supports this mechanism.   The metal first inserts into the aryl-X bond, as expected, and in the key transition state, the pivalate coordinated to the metal deprotonates the C-H bond while the palladium forms a bond to the same C.  Reductive elimination (not shown) releases the arylated product.

In the current paper DFT calculations were found to agree quite well compared to competition reaction results of a series of heterocycles to elucidate the order of reactivity of the substrates.  Those presented in the paper are as follows, in order of reactivity – this is extremely convenient for the synthetic chemist who would like to utilize this chemistry.  And it’s just plain neat – the kind of thing that will hopefully end up in a textbook someday. (Note: the last two substrates are either switched in the text or switched in the image – they don’t agree in the paper and I haven’t looked at the supporting information closely.)

Reaction conditions: 0.5 eq. of each of two heteroarenes in the competition experiment, 0.125 eq. 4-bromotrifluorobenzene, Pd(OAc)2 5 mol%, PCy3.HBF4 (10 mol%), PivOH (30 mol%), K2CO3 (1.5 eq.), DMA (0.3M), 100ºC.

And finally, for an example of the method in action – note that the difference between using this method and the previously described is that here, there aren’t necessarily general optimized conditions available for each of the substrate classes here.  Examples of a few of these are peppered throughout the arylation literature but they aren’t like indoles, pyridines, N-oxides, perfluorobenzenes, imidazoles, and pyrazoles and don’t have their own special set of conditions (that I’m aware of at the moment).  Yields of included substrates range from 65-80%. Instead of optimizing conditions for each, the site of reactivity can be predicted with good specificity – here the indolizine C-H bond over the more electron-rich thiophene’s:

Instead of an aryl bromide, benzyl chloride can be used as the coupling partner as well, with published yields from 55-84%.

  • Lapointe, D., Markiewicz, T., Whipp, C. J., Toderian, A., Fagnou, K. (2011). Predictable and Site-Selective Functionalization of Poly(hetero)arene Compounds by Palladium Catalysis Journal of Organic Chemistry : 10.1021/jo102081a

Jan 19

Chemistry Dictionary for Word Processors – Version 3.0

**Get V3.0 here.**

Version 3.0 is here! User-Submissions! OO.o Extension!

Since releasing Version 2.0 of the Chemistry Dictionary in December 2008, we have had a user-submission form on this blog. If there were words missing from Version 2.0 of the Chemistry Dictionary, users could submit the suggested word and the words would be held in limbo until I got around to updating to Version 3.0.

Well, 2 years later, I finally got around to it. I emptied out the limbo file and went through each submission. Some were gibberish. Some were words that were legitimately misspelled, and thus of course not in the dictionary. Some appeared to be foreign or alternative spellings, and were also dismissed. The surviving words were added into the dictionary file to populate Version 3.0.

Also, I finally found a coherent walk-through on how to turn the dictionary file into a Dictionary Extension for Writer Versions 3.0 and higher. This was a big concern when 2.0 was launched. Version 2.0 had a workaround method of using the dictionary file in OO.o, but I couldn’t find a simple and easy way to make and submit a Dictionary Extension, so that project got shelved.

As I was sifting through the Limbo List, I found a forum with user-friendly instructions to make a Dictionary Extension. So, you open source users, you may now download the Chemistry Dictionary Extension from the main repository of Dictionary Extensions here. Even though it hasn’t officially been released until now, it’s already been downloaded almost 300 times according to the OO.o website (as of 1/19/11).

There is an install.txt file in the zip file which spells out how to install the dictionary for new users. It also includes update instructions for users wanting to upgrade from Version 2.0.

Also, a special note to Mac users. If you use iWork, you’ll have to install a separate version of the dictionary. See Update #1 below for information on using the chemistry dictionary with iWork. Unfortunately, the iWork files are still Version 2.0 and have not been updated to Version 3.0.
Update (1/29/11): the iWork file and installation instructions have been incorporated into the standard download. All word processors should be able to install the dictionary file from one download.

Enjoy Version 3.0!!!

(this post has been reformatted to preserve links to the dictionary file from other sources. We’ve also created a convenient, shortened url for the dictionary:

Read the original December, 2008, post and download the dictionary file here

Jan 09

You Can Take the Chemist Out of the Lab but…

Synthetic chemists make a living by mixing together materials in the right ratios at the right temperature for the right amount of time.

This description makes the correlation between chemistry and cooking obvious, at least for those of us who have done synthetic chemistry. For those in the greater public, there have been a few recent efforts to draw attention to this connection.

One is the recent ACS webinar “Kitchen Chemistry: Combining Chemistry and Culinary Delights for the Holiday” on December 9th.

A more mainstream example is the show “Good Eats” with Alton Brown on the Food Network.

In programs like this we see fundamental concepts like density taught through simple suggestions like measuring sugar by weight rather than volume. The video below is an example of Alton Brown loosely referencing chemistry to explain why onions make you cry, as well as techniques for preventing it.

I would have enjoyed seeing a few chemical structures in his explanation. For those who agree, here is the stepwise reaction:

While on the subject of cooking, I’d also like to explore an anecdote I’ve heard from more than one professor: when no longer doing wet work, their interest in cooking increased.

It has been six months since I made the transition from predominantly synthetic chemistry to pure spectroscopy and I can honestly say that, in spite of my wife’s greatest hopes, my disinterest in cooking remains.

Regardless, I have noticed that my knowledge of chemistry and my finely tuned stirring, pouring, measuring and other mechanical skills are helpful when I do. My experience in lab has also led to tendencies that may border on the obsessive compulsive – and I am not the only one. For example, over the years I have noticed that:

  • I check the meniscus while measuring out a volume of milk.
  • I wash my hands obsessively.
  • After drinking a glass of orange juice, I feel the need to rinse the bottom of the glass with water and then drink the diluted solution in order to quantitatively transfer the juice to my stomach.
  • After five years of washing glassware on a daily basis I absolutely loathe doing dishes.
  • I have witnessed a friend (an organic chemist) finish a glass of water, pour and swirl a small amount of soda in the bottom, dump it down the sink and then fill the freshly washed glass with soda to drink.

I have no doubt that other chemists have lab-based quirks in (and out) of the kitchen. What are yours?

Dec 18

Referees’ Quotes

Some choice referee quotes from Environmental Microbiology. Article: Referees’ quotes – 2010

  • Done! Difficult task, I don’t wish to think about constipation and faecal flora during my holidays! But, once a referee, always and anywhere a referee; we are good boy scouts in the research wilderness. Even under the sun and near a wonderful beach.
  • This paper is desperate. Please reject it completely and then block the author’s email ID so they can’t use the online system in future.
  • The type of lava vs. diversity has no meaning if only one of each sample is analyzed; multiple samples are required for generality. This controls provenance (e.g. maybe some beetle took a pee on one or the other of the samples, seriously skewing relevance to lava composition).
  • Very much enjoyed reading this one, and do not have any significant comments. Wish I had thought of this one.
  • It is sad to see so much enthusiasm and effort go into analyzing a dataset that is just not big enough.
  • You call the sample fresh water, this is confusing as it is saline water.
  • The biggest problem with this manuscript, which has nearly sucked the will to live out of me, is the terrible writing style.
  • The abstract and results read much like a laundry list.
  • The information in the tree figs. is pretty inscrutable.
  • There was little I could think of to improve this nice paper.
  • Ken, I would suggest that EM is setting up a fund that pays for the red wine reviewers may need to digest manuscripts like this one. (Ed.: this excellent suggestion was duly proposed to the Publisher. However, given the logistical difficulties of problem-solving within narrow time frames, combined with the known deleterious effect of transport on good wine, a modification of the remedy was adopted, namely that Editors would act as proxies for reviewers with said digestive complaints.)
  • The statement that glycolipids and phospholipids ‘may play an important role in stabilising the outer membrane’ is odd because this they definitely do in all Eubacteria.
  • Merry X-mas! First, my recommendation was reject with new submission, because it is necessary to investigate further, but reading a well written manuscript before X-mas makes me feel like Santa Claus.
  • Alfachetoglutarate.
  • I have to admit that I would have liked to reject this paper because I found the tone in the Reply to the Reviewers so annoying. It may be irritating to deal with reviewer’s comments (believe me, I know!) but it is not wise to let your irritation seep through every line you write!
  • The authors still confuse relative abundance of a transcript in a community transcript pool (which is what they are measuring) with upregulation or downregulation of genes (which they are not measuring).
  • One might call this not only a skillfully executed paper but also well-rounded and thorough, with unique aspects of microbial systematics and biochemistry The experimental work with chemostats is excellent. I have little to offer other than praise and a few minor comments.
  • Season’s Greetings! I apologise for my slow response but a roast goose prevented me from answering emails for a few days.
  • I started to review this but could not get much past the abstract.
  • Hopeless – Seems like they have been asleep and are not up on recent work on metagenomics.
  • This paper is awfully written. There is no adequate objective and no reasonable conclusion. The literature is quoted at random and not in the context of argument. I have doubts about the methods and whether the effort of data gathering is sufficient to arrive at a useful conclusion.
  • Stating that the study is confirmative is not a good start for the Discussion. Rephrasing the first sentence of the Discussion would seem to be a good idea.
  • The main emphasis in the title is the use of a widely used method. This is not very exciting news. The authors are not to be blamed here. Based on titles seen in journals, many authors seem to be more fascinated these days by their methods than by their science. The authors should be encouraged to abstract the main scientific (i.e., novel) finding into the title.
  • A weak paper, poor experimental design, comparison of sequences using different primers, no statistical analysis possible, carelessly written, poorly thought through.
  • There is a great deal of freely available genomic data in the world and the authors would be much better off training themselves on that while waiting for genomic data to be generated for their system.
  • This is a long, but excellent report. I had considered asking for EMSAs, but these will not significantly improve the study. It hurts me a little to have so little criticism of a manuscript.
  • Always dear EMI takes care of its referees, providing them with entertainment for the holiday time in between Xmas and New Year. Plus the server shows, as usual, its inhuman nature and continues to send reminding messages. Well, between playing tennis on the Wii, eating and drinking, I found time and some strength of mind to do this work.
  • At the risk of appearing unkind, the authors’ main selling point for this paper seems to be that it is the biggest soil pyrosequencing project so far. I fear we are entering a phase of repeating all of the studies carried out over the past 15 years, but now using pyrosequencing.
  • I agreed to review this Ms whilst answering e-mails in the golden glow of a balmy evening on the terrace of our holiday hotel on Lake Como. Back in the harsh light of reality in Belfast I realize that it’s just on the limit of my comfort zone and that it would probably have been better not to have volunteered.
  • I suppose that I should be happy that I don’t have to spend a lot of time reviewing this dreadful paper; however I am depressed that people are performing such bad science.
  • The presentation is of a standard that I would reject from an undergraduate student. Take Table 1: none of the data has units or an explanation. Negative controls gave a positive signal, but there is no explanation of why and how this was dealt with; just that it was different.
  • This is as solid a write up as I have seen, many spend much more time and space to say considerably less. It is a perfect example of a compact report.
  • The ecological theory invoked appears more as an afterthought than the true driving ambition of the study.
  • This paper is afflicted by the same problem of many others re omics: one mutant is made in gene X, authors compare the corresponding transcriptomes and produce a list of genes that go up or down, plus various pages of discussion. Period. Nice, but a bit insufficient, I am afraid. Authors may be invited to go beyond a mere description and document experimentally at least some of their predictions.
  • I found the manuscript to be well performed in all aspects, from the experimental design to the writing of the manuscript. I wish all manuscripts I review were of this quality.
  • I usually try to nice but this paper has got to be one of the worst I have read in a long time.
  • Well, I did some of the work the authors should have done!
  • To my knowledge the most comprehensive IVET analysis ever done; huge workload, meticulously executed research, concisely presented.
  • I feel like a curmudgeon, but I still have problems with this paper.
  • Sorry for the overdue, it seems to me that ‘overdue’ is my constant, persistent and chronic EMI status. Good that the reviewers are not getting red cards! The editors could create, in addition to the referees quotes, a ranking for ‘on-time’ referees. I would get the bottom place. But fast is not equal to good (I am consoling myself!).
  • I have accepted to see this one, but I still have 2 EM manuscripts whose reviews I have to complete (they will be done by tomorrow). Please be a bit benevolent with the deadline!
  • landmark paper on P. putida physiology.
  • The lack of negative controls. . . . results in the authors being lost in the funhouse. Unfortunately, I do not think they even realize this.
  • Preliminary and intriguing results that should be published elsewhere.
  • It is always a joy to review manuscripts such as this. Well-conceived, well executed, well edited. Clean. Pristine. From start to finish.
  • Reject – More holes than my grandad’s string vest!
  • The writing and data presentation are so bad that I had to leave work and go home early and then spend time to wonder what life is about.

Read the rest of this entry »

Dec 16

How to Succeed in Organic Chemistry – Student Response Edition

I just finished teaching my first full semester of organic chemistry as a real Ph.D. yesterday.  The semester overall went well, and I plan on reminiscing and writing out my thoughts over the past semester here sometime soon.

We had the final yesterday.  My bonus question on the final was “If you could go back to August 25th (the first day of class) and give yourself three pieces of advice on How to Succeed in Organic Chemistry, what three pieces of advice would you give yourself?”

Now, I put a whole paragraph on my syllabus (which they got on the first day of class on 25 Aug) titled How to Succeed in Organic Chemistry.  Many of the pieces of advice students mentioned were pieces of advice I put on that very syllabus… but no one listens to the professor I guess…  We also discussed this topic here on the blog several months ago, but with advice from the professor’s side of the lectern.  Again, no one listens to professors, so perhaps advice from the student’s side of the lectern will be heeded?

My favorite response: “Change your major … just kidding”

Anyway, here they all are.  Compiled and organized (with school specific entries removed).  If you’re a student taking organic chemistry, here is advice from fellow students for fellow students on How to Succeed in Organic Chemistry.  If you won’t believe your professor when (s)he tells you these same things, perhaps you’ll believe your peers.

Read the rest of this entry »

Dec 11

Separating the lanthanides: physical versus chemical methods?

How do you separate dirt?

Photo credit: Reuters**

There has been much talk about rare earth metals recently. In short, the People’s Republic of China has become the dominant source of rare earth* elements in the world; the PRC government has used that fact to their strategic advantage. I don’t really wish to get into the political debate; suffice it to say that I think there’s more smoke than fire here and that predictions of war are probably overblown.

There are quite a number of articles on the subject, but only one talked about the chemistry. I was struck by a quote in an article on by Tim Worstall, a trader in scandium and other rare earths (now there’s a job I didn’t know about):

Another possibility is that we find a new and different way to separate rare earths, as we find new and different sources for the ores. The main difficulty is that chemistry is all about the electrons in the outer ring around an atom, and the lanthanides all have the same number of electrons in that outer ring. Thus we can’t use chemistry to separate them. It’s very like the uranium business: Separating the stuff that explodes from the stuff that doesn’t is the difficult and expensive part of building an atomic bomb precisely because we cannot use chemistry to do it — we have to use physics.

It’s quite apparent that Mr. Worstall is referring to the unusual electronic configuration of the lanthanides, where the 4f orbitals are ‘hidden’ behind the 4d and 5d orbitals. This electronic configuration is also responsible for the lanthanide contraction, in which the atomic radii of the lanthanides are smaller than predictable by periodic trends.

However, I’m not quite sure what Mr. Worstall means when he draws a distinction between chemical and physical separation of the elements. Both this article (from Oxford) and the Wikipedia article on the lanthanides suggest that countercurrent exchange methods are used on industrial scale; it appears that separation is performed by means of ionic radii and size. While this certainly doesn’t rely on the reaction chemistry of the lanthanides (because it appears they all act similar), I have a difficult time calling these techniques physics-based.

Readers, can you shed any more light on the issue? Do you agree with Mr. Worstall’s distinction between chemical and physical means of purifying elements?

*It should be noted that the rare earths are, as they say, neither rare or nor earths.
**Photo from this International Business Times article.

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