Lamentations on Chemistry

Thanks to a friend in Grand Rapids, I was linked to a blog hosted by the NY Times called Tierneylab.com.  The writer of the post was sounding off about a pet peeve relating to the use of the term “Organic”.  It seems that there is some confusion as to the use of the adjective organic in relation to certain carbon-containing substances. Tempest in a teapot, you ask? Let the chemistry community decide.

The problem begins to show itself when astronomers and planetary scientists start describing carbon containing materials found in planetary exploration as organic.  Back on earth, the word organic is burdened with both common and scientific usage. So, when descriptions of organic materials found on other worlds begin to arise in discourse, the intent of the usage becomes unclear.

For instance, it could suggest to people that such discovered materials were put in place by some kind of life form. It could suggest to nondiscriminating audiences that the presence of carbon implies life, past, present, or future. Or it might well suggest to higher level audiences that biology-ready raw materials are in place.

The scientists working with the Phoenix Lander have an interesting analytical chore in front of them. Using a robotic platform on Mars, they want to distinguish the presence of organic vs inorganic carbon. What is meant by organic and inorganic is less than clear. But it seems that organic refers to something other than CO2 and carbonate.

In the relatively few journal articles I’ve seen relating to this, the authors are not always precise about the kinds of molecules they are referring to as organic. Irrespective of what is said in the articles, when this work gets to a public forum, the meaning behind the word organic becomes even less clear.   

The TierneyLab post does bring up an interesting question about what is necessary for a substance to be considered organic.  Do graphite, diamond, Buckyball, or soot forms of carbon qualify as organic? What about CO2, CS2, carbonates, CO, HCN, or calcium carbide? Does it make more sense to refer to organic and inorganic carbon, where inorganic carbon is defined as … well, what? 

Seriously, what would it be? CO2? Carbon dioxide is incorporated into glucose by plants and this seems quite organic.  Carbonate? This anion is used to balance our blood pH. Our own metabolic CO2 helps to provide carbonate. This product of metabolism should qualify as organic. CO? Well, Carbon monoxide undergoes Fischer-Tropsch reactions to produce aldehydes. This seems very organic as well. Perhaps the target is a substance with C-H bonds?

There is nothing inherently biological about the C-H bond. The Saturnian moon Titan is blanketed with a thick layer of CH4 (methane) and it seems unlikely that it is of biological origin. Indeed, hydrogen is the most abundant element in the universe and carbon the 4th. That hydrogen and carbon atoms could find each other to form trace methane in a proto solar system isn’t too much of a stretch.

Organic and Inorganic Carbon.  How about we just leave it all as organic? 

Here is what I think. It does matter if a scientist or writer is using language in an imprecise way. If writing or speech implies, for instance, that Mars is rich in life giving organic nutrients when in fact Martian organic matter is really carbonate and CO2, then I believe the language must be altered to reflect that condition. A writer should not leave an impression of past or incipient planetary fecundity when in fact the planet may be an inert ball of metal silicates dusted with a bit of carbonate when the 6 torr CO2 atmosphere kicks up a breeze.

For those of use who carry around an interest in nuclear science, there is a short but interesting article in the Daily Kos written by a chemist on the topic of the Hanford site in Washington.  Of particular interest is the link describing a radiological assay of a chemist who died at age 76 of cardiovascular disease.  At the time of death they found 540 kBq of activity in his body- 90 % in his skeleton. The gentleman had been involved in a glovebox explosion involving exposure to 241-Am at age 64.

What do you do with a radioactive corpse? One option is to donate your body to science. The WSU College of Pharmacy maintains a registry of data culled from uranium and plutonium workers. A recent description of donated bodies is found in this pdf. One donation is from a plutonium worker who was present in the 1965 fire at Rocky Flats. He retained an estimated 6.8 kBq of lung burden. They did not specify how this was determined.  Rocky Flats did have state of the art whole-body monitoring and a substantial health physics department.

Pu detection is a little tricky because one of the important markers for Pu contamination is 241-Am, an alpha and gamma emitter (Pu is a bad actor mostly because of internal alpha exposure).  Residual and highly active 241-Pu (104 Ci/g) beta decays to the highly active 241-Am.  Unfortunately, not all Pu isotopes decay into Americium. This Am isotope allows for gamma ray spectra to be gathered so an estimate of Pu exposure can be calculated. The ever popular 239-Pu isotope alpha decays to 235-U without much gamma emission. So, the calculation of Pu exposure and dose depends on knowing the purity of the Pu at issue.

C&EN has a web page devoted to a linked bibliography of safety-related letters to the editor. It is worth having a look at.  It is good to have a healthy interest in energetic reactions and incompatible substances.

In my quest to stimulate bench chemists to think like industrialists, I like to bring examples of chemistry from the literature to highlight a point I’m trying to make. The literature is full of transformations and research that serve as positive and negative examples of good scale-up thinking.

There are examples, however, that are less than choice in terms of green processing or good scale-up thinking. As I have said previously, green chemistry and good scale-up principles may not be equivalent concepts, but they can and often do run in parallel.

An interesting transformation is featured in the recent article entitled Efficient 1,2-Addition of Aryl and Alkenylboronic Acids to Aldehydes Catalyzed by the Palladium/Thioether-Imidazolinium Chloride System, by Kuriyama, Shimazawa, and Shirai, J. Org. Chem., 2008, 73, 1597-1600. [My apologies to the authors for their unanticipated role in this analysis.]

In this article a bond forming reaction between 1.5 eq of a boronic acid and 1.0 eq of an aldehyde is described affording a secondary alcohol. The transformation is catalyzed by 0.5 % Palladium allyl chloride dimer with 1 % of a custom imidazole carbene precursor in the presence of 2 eq CsF as base. The reaction mixture is heated to 80 C in dioxane and the chemistry is reported to be over in ca 20 minutes.

I am somewhat reluctant to be critical of chemistry that is done catalytically and is high yielding. But this transformation, solid science though it may be, would be difficult to justify taking to scale-up without an examination of alternative schemes.  Let me explain my thinking.

First, on the basis of atom efficiency alone, this process requires that a lot of different elements find their way into the pot. The tally is C, H, N, O, Cl, B, Pd, Cs, F, and S to just make a C-C bond to produce a benzyl alcohol. A scale-up chemist would have to ask, why not use a Grignard and the aldehyde? Granted, there may be incompatible functional groups on either Ar1 or Ar2 that would not tolerate a Grignard reagent. However, it is worth pointing out that the conventional way of making boronic acids is by addition of a boronic ester or fluoride to RMgX or RLi followed by hydrolysis. Compatibility is an issue there as well.

One might object that many of the diverse atoms used in the reaction are at a catalytic level and as such may not constitute a major cost or environmental insult. True enough for the user of the process. But the metal complex must be manufactured somewhere at a larger scale for distribution. Pd mining and beneficiation requires energy inputs and generates wastes. The same idea applies to the imidazolinium salt.

The reaction does seem to require 1.5 equivalents of boronic acid and 2 equivalents of cesium fluoride. Boronic acids are specialty synthetic intermediates whose manufacture generates its own waste stream. Furthermore, boronic acids can be on the expensive side. The use of a boronic acid as a latent nucleophile for a straightforward addition to an aldehyde seems somewhat extravagant.

Cesium fluoride residues (2 equivalents) will find their way into the aqueous waste stream and possibly to an incinerator where the solids may end up in roadway pavement or a landfill. While fluoride is an efficient base in this case, common sense suggests that carbonate may have a more benign fate in the environment owing to the fact that it decomposes to water and CO2. Unfortunately, the best yields are with cesium as cation.

Chemists seeking to apply this kind of coupling chemistry would be well advised to be extra careful in their IP diligence. The use of metal catalyzed coupling reactions may already be patented or applications may be pending for patents. The same comment applies to the use of imidazolinium carbenes. Industrial chemists would be well advised to look deeply into the carbene species for process and composition of matter claims. Ever since the Bayh-Dole Act, university patents have been popping up like dandelions.

I do not want to be too critical of this chemistry. It is an interesting transformation and certainly may be of use for some kind of product. But for scale-up, at first pass it seems too far from earth, air, fire, and water. I would say that for maximum profit, this process is more of a Plan B or Plan C scheme.

WordPress shows the blogger what search terms lead the searcher to your blog. One of the searches that lead a reader to this blog was “How to pass organic chemistry”.  Here is my answer-

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Being in the industrial minority in the chemistry blogosphere, I like to point out (on occasion) those bits of research that may catch the fancy of process chemists. Naturally, I wouldn’t presume to speak for all process chemists. But it is possible to draw a few generalizations.

One desirable modification of a process is commonly called “telescoping”.  To telescope a process is to collapse a multistep process into a smaller number of steps or unit operations. The overriding production goal is to reduce the unit cost of a product in terms of $/kg produced without sacrificing purity.  There are many ways to do this. Reducing the cost of feedstocks, reducing the number of direct labor hours, increasing the concentration of reaction mixtures (space yield), reducing overhead costs, etc. 

A reaction step is fairly easy to understand- one change or transformation is one reacton step. A unit operation is a little more arcane. A unit operation includes transformations, but also encompasses handling and isolation steps. Centrifugation, filtration, distillation, decantation, precipitation/xtallization, and packaging are examples of unit operations.

Another operation that is frequently underestimated in terms of its cost is “polishing”. This a phase where the crude product is subject to purification to specifications.  Polishing can be quite expensive. Indeed, taking a 96.5 % crude product to a 99 % spec can be more troublesome and require more skill than the initial synthesis.

There are a great many examples of telescoping and other process improvments in the literature. A reasonable example of telescoping is found in a recent JOC article- Lin, Lu J. Org. Chem., 2007, 72, 9757-9760.  The authors were able to demonstrate a one-pot preparation of triarylmethanes in two steps. The first step involved the addition of an arylboronic acid to an aromatic aldehyde through the agency of a Pd(bpy)2 catalyst. To the reaction mixture was added an “unfunctionalized” electron rich aromatic species. In this case, unfunctionalized means that no special leaving groups were on the ring.

The added aromatic underwent a Friedel-Crafts type alkylation with the intermediate diarylcarbinol to give the triarylmethane product in 57 % to 99 % overall yield.  The authors made a contribution to the store of knowledge in reaction chemistry. But they also had the presence of mind to improve the efficiency of the process as well.

There are some negatives. I don’t think anybody is automatically keen on running large scale reactions in nitromethane. Its explosability should give anyone pause when contemplating a scale-up. And, the third arene needs to be substantially electron rich. The addition of 1,4-dimethoxybenzene drops the yield to 57 %.

I recently spent some time listening to an acquaintance talk about his days as a student at MIT and as a grad student at Harvard in the early 1950’s.  He had Geoff Wilkinson for inorganic chemistry at MIT as an undergrad and later did his PhD with Wilkinson at Harvard.  Curiously, Wilkinson did radiochemistry in the Manhattan Project prior to joining academia. His radiochemistry experience compelled him to work fast and in test tubes, according to my friend.

My friend’s lab mate in Wilkinson’s group was Al Cotton. They started grad school together ca 1952 or so. This was shortly after the sandwich structure of ferrocene was proposed by Wilkinson’s fellow Harvard prof R. B. Woodward. Woodwards basis for this structure was on symmetry and a single IR stretch absorption. Spectroscopically, the original sigma bonding model didn’t fit the data.  Just prior to this, Wilkinson had begun work on a variety of organometallic Cp compounds. As the story goes, when Woodward expressed interest in making more Cp compounds, Wilkinson went to his office and “had words” with Woodward. Afterwards, Woodward moved on to other things.

My friend laughingly recalls the time he was chewed out by his P-Chem prof, the great George Kistiakowski and earlier, by Arthur Cope at MIT. He recalls being summoned to Cope’s office. Cope was wearing pink slacks which contrasted with his red hair. He was displeased about the impertinent back channel invitation my friend pitched to Linus Pauling to speak to the chemistry club. (I haven’t verified the color of Cope’s hair)

My friend recalls having E. J. Corey as a lab assistant while in an undergraduate lab at MIT. He joked that he saw Corey once at the beginning of the term and once at the end. My PhD advisor, Al Meyers, did his post doc with Corey some years later. Small world.

An interesting bit of chemistry was published by Berit Olofsson at Stockholm University in a recent JOC. The Olofsson lab has previously produced a method for the one-pot preparation of diaryliodonium triflates. This latest work provides diaryliodonium tetrafluoroborates (JOC, 2008, 73, 4602-4607). 

The preparation of I(III) compounds usually starts with an Ar-I compound undergoing oxidation followed by an electrophilic addition/substitution to another arene. Regioselectivity is obtained by choosing a donor with a leaving group such as a boronic acid, stannane, or silane.

What is clever about this process is the fact that a BF4 salt is directly produced. Two equivalents of boron trifluoride etherate are used in the reaction which evidently results in some kind of disproportionation producing the BF4 counter-anion. 

It is known that the reactivity of iodonium compounds is somewhat sensitive to the coordinating ability of the counter-anion, so BF4 is less undesirable than other choices (like chloride). Solubility is greatly influenced by the choice of counter-anion as well. This is particularly true in photo-initiator applications where the choice of carrier fluid may be limited.

So, I’m blundering through the literature on a snipe hunt when I run into this ICI patent- US 5,456,729. In the description, they teach a method of preparing an explosive composition using “lactic casein”. Having been in the dairy business long ago, and specifically having worked in a cottage cheese plant, I recognized this component as … cheese. Well, mostly. Example 5 discloses a composition comprising 25 % ammonium nitrate and 3 % lactic casein.

Unless you have lactose intolerance, cheese is not ordinarily an explosive. In the patent, the lactic casein is one of many examples of a foam stabilizer. Other stabilizers include animal and fish proteins as well as collagens. A collection of other chemical additives rounds off the list.

If they had specified gluten, they could have claimed the use of a pastrami and cheese on rye sandwich as stabilizer feedstock for their explosive composition.

The recent issue of Journal of Organic Chemistry, (JOC, 2008, 73(12)) has a few articles that are particularly interesting.

The article by Lipkus, et al., entitled Structural Diversity of Organic Chemistry. A Scaffold Analysis of the CAS Registry, JOC, 2008,73, 4443-4451, is a particularly ambitious bit of work that only CAS could do. This article describes a scaffold survey of more than 24 million organic compounds in the CAS Registry.

The data set was limited to carbon-based structures containing the heteroatoms H, B, Si, N, P, As, O, S, Se, Te, and the halogens.  Moreover, the work was further limited to framework structures containing rings or linked rings. Acyclic compounds were not included owing to the inapplicability of the framework definition in the search algorithm. Multicomponent substances and polymers are ignored as well.

Lipkus and coworkers found that half of the graph frameworks analyzed are described by only 143 framework shapes.  The remaining half are described by 836,565 graphs.

One of the key conclusions is quoted here-

“It is not surprising that some frameworks occur much more frequently than others. However, the extreme unevenness in the way frameworks are distributed among organic compounds is somewhat surprising. This is particularly true at the graph level, where it is found that only 143 framework shapes can describe half of the compounds. The fact that both graph and hetero frameworks have very topheavy distributions tells us that the exploration of organic chemistry space has tended to concentrate on relatively small numbers of structural motifs.”

Lipkus concludes that cost minimization is one of the drivers of this “… shaping the known universe of organic chemistry.” He comes to this conclusion due to the presence of a power law which describes this distribution. The power law he refers to is a linear log-log relationship that is indicative of what they refer to as the “rich-get-richer process”.

If I understand this correctly, a relatively small number of easily made or commercially available early precursors are comprised of ring graphs that, by virtue of modification, propagate into more complex analogs that retain the original graph. This has the effect of multiplying the frequency of a given graph.

The cost minimization aspect comes from the benefits of familiar chemistry and the commercial availability of a fairly limited set of ring graphs. Adding more rings will usually mean adding more molecular weight and adding problematic synthesis and separation issues.

The authors conclude that the lopsided distribution of organic compounds toward only 143 graphs comprises a bottleneck in drug discovery. They further suggest that more exploration in other areas of chemistry space may be worthwhile.