Chemistry Blog

Jan 27

Skillful writing of an awful research paper

Apparently, laboratory instructors and undergraduate mentors aren’t the only ones with the bane of reading insanely terrible research papers – the editor of the ACS journal Analytical Chemistry, Royce Murray, clearly has had his fill as well, according to his editorial in the current ASAPs.

His humor is very similar to that found in The Onion, and reminded me of How to Write a Scientific Paper on Improbable Research.

Brilliant. The only thing that has made me laugh out loud this hard lately was catching a part of the show ‘Ancient Aliens’ on the History Channel last night in which someone said that “one possible explanation of why the Mayans vanished was because they were aliens.”

In all seriousness, though, it is an understatement to say it’s quite obvious that scientific writing isn’t emphasized as well as it should be, it should be addressed at the undergraduate level as early as possible.

Jan 23

Yes, it’s been done: coffee flavour chemistry

When I was much younger, and my interest in chemistry was just beginning to influence my thoughts of post-secondary school and (a lifetime away) a career, there were hints of my destiny that came in the form of somewhat perverse interests.

One of these was my profound interest in the chemical constituents of coffee. A non-chemist simply sees a cup of coffee for what their nervous system and digestive see it: a black liquid that tastes bitter, inhibits your appetite, and gives you about a two hour energy boost. However, being the child of two coffee snobs who also happened to be career scientists, I had different notions.

What makes a good cup of coffee? People have their preferred brands, countries of origin, or even vintages, if you have that much money to throw away. There are even those who eat an obscenely expensive bean that has been digested and excreted by the Asian palm civet. But can you actually taste the difference? And more importantly, what makes up the difference in flavour?

Most coffees are simply described in terms of acidity, roast, and some vague notes about other flavours (vanilla, caramel, berries, chocolate). This, to me, was completely unsatisfactory. Little did I know that coffee flavour chemistry is a legitimate field of study, as is the study of flavours and scents in general.

In my slightly-more-recent searches on the topic, I stumbled across a book entitled Coffee Flavour Chemistry; a better match for my childhood fascination could not have been conceived. Though now somewhat out of date, the book represented a major achievement in the field in 2002 when it was written by Ivon Flament, and contains some very interesting information and a comprehensive review of the work done in identifying coffee’s chemical components. It identifies over one thousand compounds present in both green and roasted coffee beans, describing their aromas and their significance in the overall flavour of the coffee. Intuitively, the most important constituents of coffee flavour are the ones with the highest “signal-to-concentration” ratio, or how easily they can be detected at a certain concentration. Some of the most important constituents can be seen below, with their described flavours:

The majority of these compounds are of course formed via the well-known Strecker degradation and the Maillard reaction.  These, as well as other important aspects of the roasting of coffee beans, are discussed within the book.

Perhaps what I found most interesting are the techniques used to determine what are called “odour activity values”, which essentially amount to a quantification of how strong a compound’s odour is at a given concentration.

The methods used for finding these values are actually gas-chromatographic olfactometry, which is exactly what you think it is: they run a GC, and have someone sniffing the end of the column, who presses a button each time they smell a compound. I laughed at this when I read it, not because it’s unreliable (quite the contrary), but because imagining running a column with a panel of “sniffers” at the end instead of a mass spectrometer is quite an image indeed.

The original method (GC-olfactometry) was purely qualitative in terms of odours, but later methods known as CHARM (a proprietary technique involving dilution-to-threshold) and AEDA (aroma extract dilution analysis, a similar method) have overshadowed it in recent years. Yet another method, named with a classic, groan-inducing acronym is “GC-SNIF”, which stands for “gas chromatography-surface of nasal impact frequency”, in which panels of test subjects are used to determine how “smellable” a compound is at a single concentration, producing averaged and normalized curves for the detection of smells.

Apart from being a funny image, these methods of analysis (which are almost always used in conjunction with purely analytical methods) illustrate an interesting point about flavour chemistry. While GC or LC data, as well as mathematical methods such as canonical analysis or principal component analysis are useful for predicting simple properties, the use of human organoleptic testing is essential to actually understanding the results.

Another salient point that was mentioned was the perception of quality. In a 1986 paper, Liardon and Spadone discovered that while the degree of coffee roasting was correlated to a large number of compounds and their concentrations, the quality of the coffee did not appear to be correlated to any of them. One of the few quantitative differences that could be established based on quality was that between green C. arabica and C. robusta beans. Robusta tended to have higher concentrations of methanol, acetone, pyridine, methylpyrazine, and furfural, and also seemed to be unique in that they contained methyl formate, t-butyl alcohol, and furfuryl alcohol, not found in Arabica strains. Robusta beans are widely perceived to be inferior in flavour and aroma to arabica beans, which is why many coffee packages will declare themselves to contain “100% arabica beans” to avoid confusion and distinguish themselves.

So what does this tell us? After skimming through the book I came away with two lessons: the first is that while computers and statistical analyses become more and more powerful every day, it seems there is usually a place for subjective human-generated data.  Without olfactory analyses from panelists, much of the work on coffee and its constituents would have been completely useless. The second is that while this data is essential to understanding the importance of certain compounds in generating a specific flavour, it is almost worthless when trying to establish a causal link between specific compounds and the perceived quality of the coffee (edit: this is not strictly true for identifying fundamental flaws in the bean due to parasites, mould, or poor growing conditions, which can all be identified by screening for certain compounds). For the most part, as everyone has heard so many times in their life: there’s just no explaining some people’s tastes.

However, I think for most of us in grad school, the fact remains that the most important compound in coffee is one which contributes almost nothing to its odour profile:

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.

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